Horizon Pharma Et. Al. v. Watson Laboratories, Inc. - Florida Et. Al.

Karen A.
Confoy FOX ROTHSCHILD, LLP

Formed in the Commonwealth of Pennsylvania
Princeton Pike Corporate Center 997 Lenox Drive, Building 3 Lawrenceville, New Jersey 08648 (609) 896-3600 Attorneys for Plaintiffs Horizon Pharma AG and Jagotec AG Robert F. Green Caryn C. Borg-Breen Jessica M. Tyrus Ann K. Kotze LEYDIG, VOIT & MAYER, LTD. Two Prudential Plaza, Suite 4900 180 North Stetson Chicago, Illinois 60601 (312) 616-5600 Attorneys for Plaintiff Horizon Pharma AG
Dennis A. Bennett GLOBAL PATENT GROUP, LLC 1005 North Warson Road Suite 201 St. Louis, Missouri 63132 (314) 812-8018 Attorneys for Plaintiff Horizon Pharma AG
John A. Bauer MINTZ, LEVIN, COHN, FERRIS, GLOVSKY AND POPEO, P.C. 666 Third Avenue New York, New York 10017 (212) 692-6795 Attorneys for Plaintiff Jagotec AG
UNITED STATES DISTRICT COURT FOR THE DISTRICT OF NEW JERSEY HORIZON PHARMA AG and JAGOTEC AG Plaintiffs, v. WATSON LABORATORIES, INC. FLORIDA, ACTAVIS PHARMA, INC., ANDRX CORPORATION., and ACTAVIS, INC. Defendants. Plaintiffs Horizon Pharma AG and Jagotec AG (collectively Plaintiffs) by their attorneys, for their complaint against Watson Laboratories, Inc. Florida, Actavis COMPLAINT FOR PATENT INFRINGEMENT CIVIL ACTION No. Document Filed Electronically
Pharma, Inc., Andrx Corporation, and Actavis, Inc. (collectively, Defendants) allege as follows: NATURE OF THE ACTION 1. This is an action for patent infringement arising under the patent laws of
the United States, Title 35, United States Code, arising from Watsons filing of an Abbreviated New Drug Application (ANDA) with the United States Food and Drug Administration (FDA) seeking approval to market a generic version of Horizons pharmaceutical product RAYOS prior to the expiration of United States Patent Nos. 6,488,960 (the 960 patent), 6,677,326 (the 326 patent), 8,309,124 (the 124 patent), 8,168,218 (the 218 patent), and 8,394,407 (the 407 patent) which cover RAYOS and its use. THE PARTIES 2. Plaintiff Horizon Pharma AG is a company organized and existing under
the laws of Switzerland, with a principal place of business at Kagenstrasse 17, CH-4153 Reinach, Switzerland. 3. Plaintiff Jagotec AG is a company organized and existing under the laws
of Switzerland, with a principal place of business at Eptingerstrasse 61, CH-4132 Muttenz, Switzerland. 4. On information and belief, Defendant Watson Laboratories, Inc. Florida On information and
(WLF) was formerly known as Andrx Pharmaceuticals, Inc.
belief, WLF is a corporation organized and existing under the laws of the State of Florida, with a principal place of business at 4955 Orange Drive, Davie, Florida 33314. On information and belief, WLF is in the business of, inter alia, developing,
manufacturing, and obtaining regulatory approval of generic copies of branded pharmaceutical products throughout the United States, including within this district. 5. On information and belief, Defendant Actavis Pharma, Inc. (Actavis
Pharma) was formerly known as Watson Pharma, Inc. On information and belief, Actavis Pharma is a corporation organized and existing under the laws of the State of Delaware, having a principal place of business at Morris Corporate Center III, 400 Interpace Parkway, Parsippany, New Jersey, 07054. On information and belief, Actavis Pharma is in the business of, inter alia, selling and distributing generic copies of branded pharmaceutical products in New Jersey and throughout the United States, including some that are manufactured by WLF and/or for which WLF is the named applicant of the approved ANDAs. 6. On information and belief, Defendant Actavis, Inc. (Actavis) was
formerly known as Watson Pharmaceuticals, Inc. (WPI) until on or around January 24, 2013. On information and belief, Actavis is a corporation organized and existing under the laws of the State of Nevada, having a principal place of business at Morris Corporate Center III, 400 Interpace Parkway, Parsippany, New Jersey, 07054. On information and belief, Actavis is in the business of, inter alia, developing, manufacturing, obtaining regulatory approval, marketing, selling, and distributing generic copies of branded pharmaceutical products throughout the United States, including within this district, through its own actions and through the actions of its agents and subsidiaries, including at least WLF, Actavis Pharma and Andrx Corporation. 7. On information and belief, Defendant Andrx Corporation (Andrx) is a
corporation organized and existing under the laws of the State of Delaware, having a
principal place of business at 4955 Orange Drive, Davie, Florida 33314. On information and belief, Andrx is in the business of, inter alia, marketing, selling, and distributing generic copies of branded pharmaceutical products throughout the United States, including within this district, through its own actions and through the actions of its agents and subsidiaries, including at least WLF. 8. On information and belief, WPI acquired Andrx Pharmaceuticals on or On information and belief, WPI renamed Andrx
around November 3, 2006. Pharmaceutials as WLF. 9.
On information and belief, WLF is a wholly-owned subsidiary of Andrx,
which is a wholly owned subsidiary of Actavis. 10. On information and belief, Actavis Pharma is another wholly-owned
subsidiary of Actavis. 11. On information and belief, Actavis organizes its operations by divisions
including at least Generics, Brands, and Distributionand, before the name change, WPI reported its financial results in its Securities and Exchange Commission (SEC) filings by reference to these divisions. On information and belief, WPI consolidated its financial results with subsidiaries in its SEC filings at least since 2007 and did not file separate reports to the SEC for each subsidiary. 12. On information and belief, Actavis Generics division is involved in the
development, manufacture, marketing, sale, and distribution of generic pharmaceuticals. On information and belief, each Defendant acts as an agent of the other and/or works in concert with each other as integrated parts of the Generics Division. On information and belief, the Generics Division develops and submits Abbreviated New Drug Applications
(ANDAs) to the FDA, relying on contributions from at least WLF, Actavis Pharma and Andrx. 13. On information and belief, the head of the Generics Division is an
employee of Actavis, the Generic Divisions products are developed and manufactured by at least WLF, and the Generic Divisions products are marketed, sold, and distributed throughout the United States, including in New Jersey, by at least Actavis Pharma. On information and belief, WLF, Actavis Pharma, and Andrx are parties to one or more contractual agreements regarding the distribution of generic pharmaceutical products. 14. On information and belief, each Defendant shares with the others at least
some common employees, officers, and directors. 15. On information and belief, WLF, Andrx, and Actavis Pharma are within
the control of Actavis for purposes of responding to discovery in this action. 16. On information and belief, Defendants collaborated in the research and
development of WLFs ANDA No. 204867 (Watsons ANDA) for prednisone delayedrelease tablets (the Watson Products), continue to collaborate in seeking approval of that application by the FDA, and intend to collaborate in the commercial manufacture, marketing, offer for sale and sale of the Watson Products throughout the United States, including in the State of New Jersey, in the event the FDA approves Watsons ANDA. 17. On information and belief, WLF has submitted to the jurisdiction of this
Court in at least six prior New Jersey actions (Astrazeneca AB, et al. v. Watson Labs., Inc. Florida, et al., Civil Action No. 13-3038; Astrazeneca AB, et al. v. Watson Labs., Inc. Florida, Civil Action No. 13-1669; Depomed, Inc. v. Actavis Elizabeth LLC, et al., Civil Action No. 12-1358; Warner Chilcott Co., et al. v. Watson Labs., Inc. Florida,
Civil Action No. 11-5989; Abbott Labs., et al. v. Watson Labs., Inc. Florida, et al., Civil Action No. 10-3241; Mallinckrodt Inc. v. Watson Labs., Inc. Florida, et al., Civil Action No. 10-6424). On information and belief, WLF has availed itself of the rights, benefits, and privileges of this Court by asserting counterclaims in at least one prior New Jersey action (Astrazeneca AB, et al. v. Watson Labs., Inc. Florida, et al., Civil Action No. 13-1669). 18. On information and belief, Actavis has submitted to the jurisdiction of this
Court in at least nine prior New Jersey actions (Astrazeneca AB, et al. v. Watson Labs., Inc. Florida, et al., Civil Action No. 13-3038; Auxilium Pharms., Inc., et al. v. Watson Labs., Inc. et al., Civil Action No. 12-3084;1 Depomed, Inc. v. Actavis Elizabeth LLC, et al., Civil Action No. 12-1358; Noven Pharms. v. Watson Labs., Inc., et al., Civil Action No. 11-5997;2 Shire LLC, et al. v. Amneal Pharms. LLC, et al., Civil Action No. 11-3781; King Pharms. Inc., et al. v. Actavis, Inc., et al., Civil Action No. 09-6585; Shire LLC v. Actavis South Atlantic, LLC, et al., Civil Action No. 09-479; King Pharms. Inc., et al. v. Actavis, Inc., et al., Civil Action No. 07-5041; Sanofi-Aventis U.S. LLC, et al. v. Actavis Totowa LLC, et al., Civil Action No. 07-3142). On information and belief, Actavis has availed itself of the rights, benefits, and privileges of this Court by asserting counterclaims in at least one prior New Jersey action (Auxilium Pharms., Inc., et al. v. Watson Labs., Inc. et al., Civil Action No. 12-3084). 19. On information and belief, Actavis Pharma has submitted to the
jurisdiction of this Court in at least six prior New Jersey actions (Astrazeneca AB, et al. v.
1
Watson Pharmaceuticals, Inc. submitted to the jurisdiction of this Court on July 6, 2012. Watson Pharmaceuticals, Inc. thereafter changed its name to Actavis Inc. 2 Watson Pharmaceuticals, Inc. submitted to the jurisdiction of this Court on November 4, 2011. Watson Pharmaceuticals, Inc. thereafter changed its name to Actavis Inc. 6
Watson Labs., Inc. Florida, et al., Civil Action No. 13-3038; Auxilium Pharms., Inc., et al. v. Watson Labs., Inc. et al., Civil Action No. 12-3084;3 Abbott Labs., et al. v. Watson Labs., Inc. Florida, et al., Civil Action No. 10-3241;4 Teva Neuroscience, Inc., et al. v. Watson Pharma, Inc., et al., Civil Action No. 10-5078;5 Duramed Pharms. v. Watson Pharma, Inc., Civil Action No. 07-5941;6 Hoffman La-Roche Inc., et al. v. Cobalt Pharms. Inc., et al., Civil Action No. 07-4539).7 On information and belief, Actavis Pharma has availed itself of the rights, benefits, and privileges of this Court by asserting counterclaims in at least one prior New Jersey action (Auxilium Pharms., Inc., et al. v. Watson Labs., Inc. et al., Civil Action No. 12-3084). On information and belief, Actavis Pharma is registered as a manufacturer and wholesale drug distributor in the State of New Jersey under the registration number 5003854. JURISDICTION AND VENUE 20. This Court has subject matter jurisdiction over this action pursuant to 28
U.S.C. 1331 and 1338(a). 21. This Court has personal jurisdiction over Defendants by virtue of, inter
alia, their presence in New Jersey, having conducted business in New Jersey, having availed themselves of the rights and benefits of New Jersey law such that they should reasonably anticipate being haled into court in this judicial district, previously consenting
3
Watson Pharma, Inc. submitted to the jurisdiction of this Court on July 6, 2012. Watson Pharma, Inc. thereafter changed its name to Actavis Pharma, Inc. 4 Watson Pharma, Inc. submitted to the jurisdiction of this Court on May 3, 2010. Watson Pharma, Inc. thereafter changed its name to Actavis Pharma, Inc. 5 Watson Pharma, Inc. submitted to the jurisdiction of this Court on December 23, 2010. Watson Pharma, Inc. thereafter changed its name to Actavis Pharma, Inc. 6 Watson Pharma, Inc. submitted to the jurisdiction of this Court on March 3, 2008. Watson Pharma, Inc. thereafter changed its name to Actavis Pharma, Inc. 7 Watson Pharma, Inc. submitted to the jurisdiction of this Court on September 1, 2011. Watson Pharma, Inc. thereafter changed its name to Actavis Pharma, Inc. 7
to personal jurisdiction in this Court, availing themselves of the jurisdiction of this Court, and having engaged in systematic and continuous contacts with the State of New Jersey through the marketing and sales of generic drugs throughout the United States, and in particular within this judicial district, through the receipt of revenue from the sales and marketing of generic drug products, including WLF products, within this judicial district, and through their intent to market and sell the Watson Products, if approved, to residents of this judicial district. 22. and 1400(b). PATENTS-IN-SUIT 23. On December 3, 2002, the U.S. Patent and Trademark Office (PTO) Venue is proper in this judicial district under 28 U.S.C. 1391(b) and (c)
duly and legally issued the 960 patent titled Corticosteroid Formulation. At the time of its issue, the 960 patent was assigned to Arakis, Ltd., Babraham Hall, Babraham, Cambridge, United Kingdom (now known as Sosei R&D Ltd., Chesterford Research Park, Little Chesterford, Saffron Walden, Essex, United Kingdom), which later assigned the 960 patent to Nitec Pharma AG (now known as Horizon Pharma AG), Kagen-Strasse 17, Reinach Switzerland CH-4153. Horizon Pharma AG is the sole current assignee of the 960 patent, which discloses and claims, inter alia, a pharmaceutical composition containing prednisone. A true and correct copy of the 960 patent is attached hereto as Exhibit A. 24. On January 13, 2004, the PTO duly and legally issued the 326 patent
titled Corticosteroid Formulation Comprising Less Than 2.5 mg Prednisolone for Once Daily Administration. At the time of its issue, the 326 patent was assigned to Arakis,
Ltd., Chesterford Research Park, Little Chesterford, Saffron Walden, Essex, United Kingdom (now known as Sosei R&D Ltd., Chesterford Research Park, Little Chesterford, Saffron Walden, Essex, United Kingdom), which later assigned the 960 patent to Nitec Pharma AG (now known as Horizon Pharma AG), Kagen-Strasse 17, Reinach Switzerland CH-4153. Horizon Pharma AG is the sole current assignee of the 326 patent, which discloses and claims, inter alia, a pharmaceutical composition containing prednisone. A true and correct copy of the 326 patent is attached hereto as Exhibit B. 25. On November 13, 2012, the PTO duly and legally issued the 124 patent
titled Delayed Release Tablet with Defined Core Geometry. Jagotec AG is the sole current assignee of the 124 patent, which discloses and claims, inter alia, a pharmaceutical composition containing prednisone. A true and correct copy of the 124 patent is attached hereto as Exhibit C. 26. On May 1, 2012, the PTO duly and legally issued the 218 patent titled
Delayed Release Tablet with Defined Core Geometry. Jagotec AG is the sole current assignee of the 218 patent, which discloses and claims, inter alia, a pharmaceutical composition containing prednisone. attached hereto as Exhibit D. 27. On March 12, 2013, the PTO duly and legally issued the 407 patent titled A true and correct copy of the 218 patent is
Delayed Release Tablet with Defined Core Geometry. Jagotec AG is the owner of the 407 patent, which discloses and claims, inter alia, a pharmaceutical composition containing prednisone. A true and correct copy of the 407 patent is attached hereto as Exhibit E.
RAYOS 28. Horizon Pharma, Inc. is the owner of the approved New Drug Application
No. 202020 (the RAYOS NDA) for prednisone delayed-release tablets in 1 mg, 2 mg, and 5 mg dosage strengths, which are sold by Horizon Pharma USA, Inc. under the trade name RAYOS. The RAYOS tablets are currently approved for use as an antiinflammatory or immunosuppressive agent for certain allergic, dermatologic,
gastrointestinal, hematologic, ophthalmologic, nervous system, renal respiratory, rheumatologic, specific infectious diseases or conditions and organ transplantation; for the treatment of certain endocrine conditions; and for palliation of certain neoplastic conditions. 29. Pursuant to 21 U.S.C. 355(b)(1), and attendant FDA regulations, the
960, 326, 124, 218 and 407 patents are listed in the FDA publication entitled Approved Drug Products and Therapeutic Equivalence Evaluations (the Orange Book) for the RAYOS NDA. 30. The 960 and 326 patents are listed in the Orange Book for the 1 mg and
2 mg strength RAYOS tablets. The 124 and 407 patents are listed in the Orange Book for the 1 mg, 2 mg, and 5 mg strength RAYOS tablets. The 218 patent is listed in the Orange Book for the 5 mg strength RAYOS tablets. 31. The 960, 326, 124, 218 and 407 patents cover the RAYOS product. WATSONS ANDA 32. On information and belief, WLF submitted ANDA No. 204867 (the
Watson ANDA) to the FDA, pursuant to 21 U.S.C. 355(j), seeking approval to market prednisone delayed-release tablets in 1 mg, 2 mg, and 5 mg dosage strengths. On
10
information and belief, the Watson ANDA is seeking approval to market the Watson Products as an anti-inflammatory or immunosuppressive agent for certain allergic, dermatologic, gastrointestinal, hematologic, ophthalmologic, nervous system, renal respiratory, rheumatologic, specific infectious diseases or conditions and organ transplantation; for the treatment of certain endocrine conditions; and for palliation of certain neoplastic conditions. 33. The Watson ANDA refers to and relies upon the RAYOS NDA and
contains data that, according to Watson, demonstrate the bioequivalence of the Watson Products and RAYOS. 34. Plaintiffs have received from WLF a letter, dated July 15, 2013 (the
Watson Notification), stating that WLF had included a certification in the Watson ANDA pursuant to 21 U.S.C. 355(j)(2)(A)(vii)(IV), that the 960, 326, 124, 218 and 407 patents are invalid or will not be infringed by the commercial manufacture, use or sale of the Watson Products (the Paragraph IV Certification). COUNT I FOR INFRINGEMENT OF U.S. PATENT 6,488,960 35. Plaintiffs reallege and incorporate by reference the allegations of
paragraphs 1-34 of this Complaint. 36. Defendants have infringed the 960 patent, pursuant to 35 U.S.C.
271(e)(2)(A), by submitting the Watson ANDA, by which Defendants seek approval from the FDA to engage in the commercial manufacture, use, offer to sell, sale, or importation of the Watson Products in 1 mg and 2 mg strengths prior to the expiration of the 960 patent.
11
37.
Defendants commercial manufacture, use, offer to sell, or sale of the
Watson Products within the United States, or importation of the Watson Products in 1 mg and 2 mg strengths into the United States during the term of the 960 patent would further infringe the 960 patent under 35 U.S.C. 271(a), (b) and/or (c). 38. This action is being filed within 45 days of receipt by Plaintiffs of the
Watson Notification dated July 15, 2013, which purportedly advised Plaintiffs of Watsons Paragraph IV Certification with respect to the 960 patent. 39. Upon information and belief, Defendants had actual and constructive
notice of the 960 patent prior to filing Watsons ANDA, and Defendants infringement of the 960 patent has been, and continues to be, willful. 40. Plaintiffs are entitled to the relief provided by 35 U.S.C. 271(e)(4),
including an order of this Court that the effective date of the approval of Watsons ANDA be a date that is not earlier than the expiration of the 960 patent, or any later expiration of exclusivity for the 960 patent to which they become entitled. 41. Plaintiffs will be substantially and irreparably harmed if Defendants are
not enjoined from infringing or actively inducing or contributing to infringement of the 960 patent. 42. 43. Plaintiffs have no adequate remedy at law. This case is an exceptional one, and Plaintiffs are entitled to an award of
attorneys fees under 35 U.S.C. 285. COUNT II FOR INFRINGEMENT OF U.S. PATENT 6,677,326 44. Plaintiffs reallege and incorporate by reference the allegations of
paragraphs 1-34 of this Complaint.
12
45.
Defendants have infringed the 326 patent, pursuant to 35 U.S.C.
271(e)(2)(A), by submitting the Watson ANDA, by which Defendants seek approval from the FDA to engage in the commercial manufacture, use, offer to sell, sale, or importation of the Watson Products in 1 mg and 2 mg strengths prior to the expiration of the 326 patent. 46. Defendants commercial manufacture, use, offer to sell, or sale of the
Watson Products within the United States, or importation of the Watson Products in 1 mg and 2 mg strengths into the United States during the term of the 326 patent would further infringe the 326 patent under 35 U.S.C. 271(a), (b) and/or (c). 47. This action is being filed within 45 days of receipt by Plaintiffs of the
not enjoined from infringing or actively inducing or contributing to infringement of the 326 patent. 51. Plaintiffs have no adequate remedy at law.
13
52.
This case is an exceptional one, and Plaintiffs are entitled to an award of
attorneys fees under 35 U.S.C. 285. COUNT III FOR INFRINGEMENT OF U.S. PATENT 8,309,124 53. Plaintiffs reallege and incorporate by reference the allegations of
271(e)(2)(A), by submitting the Watson ANDA, by which Defendants seek approval from the FDA to engage in the commercial manufacture, use, offer to sell, sale, or importation of the Watson Products in 1 mg, 2 mg and 5 mg strengths prior to the expiration of the 124 patent. 55. Defendants commercial manufacture, use, offer to sell, or sale of the
Watson Products within the United States, or importation of the Watson Products in 1 mg, 2 mg and 5 mg into the United States during the term of the 124 patent would further infringe the 124 patent under 35 U.S.C. 271(a), (b) and/or (c). 56. This action is being filed within 45 days of receipt by Plaintiffs of the
including an order of this Court that the effective date of the approval of Watsons
14
ANDA be a date that is not earlier than the expiration of the 124 patent, or any later expiration of exclusivity for the 124 patent to which they become entitled. 59. Plaintiffs will be substantially and irreparably harmed if Defendants are
attorneys fees under 35 U.S.C. 285. COUNT IV FOR INFRINGEMENT OF U.S. PATENT 8,168,218 62. Plaintiffs reallege and incorporate by reference the allegations of
271(e)(2)(A), by submitting the Watson ANDA, by which Defendants seek approval from the FDA to engage in the commercial manufacture, use, offer to sell, sale, or importation of the Watson Products in 5 mg dosage strength prior to the expiration of the 218 patent. 64. Defendants commercial manufacture, use, offer to sell, or sale of the
Watson Products within the United States, or importation of the Watson Products in 5 mg dosage strength into the United States during the term of the 218 patent would further infringe the 218 patent under 35 U.S.C. 271(a), (b) and/or (c). 65. This action is being filed within 45 days of receipt by Plaintiffs of the
Watson Notification dated July 15, 2013, which purportedly advised Plaintiffs of Watsons Paragraph IV Certification with respect to the 218 patent.
15
66.
Upon information and belief, Defendants had actual and constructive
attorneys fees under 35 U.S.C. 285. COUNT V FOR INFRINGEMENT OF U.S. PATENT 8,394,407 71. Plaintiffs reallege and incorporate by reference the allegations of
271(e)(2)(A), by submitting the Watson ANDA, by which Defendants seek approval from the FDA to engage in the commercial manufacture, use, offer to sell, sale, or importation of the Watson Products in 1 mg, 2 mg and 5 mg prior to the expiration of the 407 patent. 73. Watsons commercial manufacture, use, offer to sell, or sale of the Watson
Products within the United States, or importation of the Watson Products in 1 mg, 2 mg
16
and 5 mg into the United States during the term of the 407 patent would further infringe the 407 patent under 35 U.S.C. 271(a), (b) and/or (c). 74. This action is being filed within 45 days of receipt by Plaintiffs of the
notice of the 407 patent prior to filing Watsons ANDA, and Watsons infringement of the 407 patent has been, and continues to be, willful. 76. Plaintiffs are entitled to the relief provided by 35 U.S.C. 271(e)(4),
attorneys fees under 35 U.S.C. 285. PRAYER FOR RELIEF WHEREFORE, Horizon Pharma AG and Jagotec AG pray for a judgment in their favor against Defendants Watson Laboratories, Inc. Florida, Actavis Pharma, Inc., Andrx Corporation, and Actavis, Inc., and respectfully request the following relief:
17
A.
A judgment declaring that Defendants have infringed one or more claims
of U.S. Patent 6,488,960; B. A judgment declaring that Defendants have infringed one or more claims
of U.S. Patent 6,677,326; C. A judgment declaring that Defendants have infringed one or more claims
of U.S. Patent 8,309,124; D. A judgment declaring that Defendants have infringed one or more claims
of U.S. Patent 8,168,218; E. A judgment declaring that Defendants have infringed one or more claims
of U.S. Patent 8,394,407; F. A judgment pursuant to 35 U.S.C. 271(e)(4) preliminarily and
permanently enjoining Defendants, their officers, agents, servants, and employees, and those persons in active concert or participation with any of them, and their successors and assigns, from manufacturing, using, offering to sell, or selling the Watson Products in 1 mg and 2 mg dosage strengths within the United States, or importing the Watson Products into the United States, prior to the expiration date of the 960 patent; G. A judgment pursuant to 35 U.S.C. 271(e)(4) preliminarily and
permanently enjoining Defendants, their officers, agents, servants, and employees, and those persons in active concert or participation with any of them, and their successors and assigns, from manufacturing, using, offering to sell, or selling the Watson Products in 1 mg and 2 mg dosage strengths within the United States, or importing the Watson Products into the United States, prior to the expiration date of the 326 patent;
18
H.
A judgment pursuant to 35 U.S.C. 271(e)(4) preliminarily and
permanently enjoining Defendants, their officers, agents, servants, and employees, and those persons in active concert or participation with any of them, and their successors and assigns, from manufacturing, using, offering to sell, or selling the Watson Products in 1 mg, 2 mg and 5 mg dosage strengths within the United States, or importing the Watson Products into the United States, prior to the expiration date of the 124 patent; I. A judgment pursuant to 35 U.S.C. 271(e)(4) preliminarily and
permanently enjoining Defendants, their officers, agents, servants, and employees, and those persons in active concert or participation with any of them, and their successors and assigns, from manufacturing, using, offering to sell, or selling the Watson Products in 5 mg dosage strength within the United States, or importing the Watson Products into the United States, prior to the expiration date of the 218 patent; J. A judgment pursuant to 35 U.S.C. 271(e)(4) preliminarily and
permanently enjoining Defendants, their officers, agents, servants, and employees, and those persons in active concert or participation with any of them, and their successors and assigns, from manufacturing, using, offering to sell, or selling the Watson Products in 1 mg, 2 mg and 5 mg dosage strengths within the United States, or importing the Watson Products into the United States, prior to the expiration date of the 407 patent; K. If Defendants commercially manufacture, use, offer to sell, or sell the
Watson Products within the United States, or import the Watson Products in 1 mg and 2 mg dosage strengths into the United States, prior to the expiration of the 960 patent, including any extensions, a judgment awarding Plaintiffs monetary relief together with interest;
19
L.
If Defendants commercially manufacture, use, offer to sell, or sell the
Watson Products within the United States, or import the Watson Products in 1 mg and 2 mg dosage strengths into the United States, prior to the expiration of the 326 patent, including any extensions, a judgment awarding Plaintiffs monetary relief together with interest; M. If Defendants commercially manufacture, use, offer to sell, or sell the
Watson Products within the United States, or import the Watson Products in 1 mg, 2 mg and 5 mg dosage strengths into the United States, prior to the expiration of the 124 patent, including any extensions, a judgment awarding Plaintiffs monetary relief together with interest; N. If Defendants commercially manufacture, use, offer to sell, or sell the
Watson Products within the United States, or import the Watson Products in 5 mg dosage strength into the United States, prior to the expiration of the 218 patent, including any extensions, a judgment awarding Plaintiffs monetary relief together with interest; O. If Defendants commercially manufacture, use, offer to sell, or sell the
Watson Products within the United States, or import the Watson Products in 1 mg, 2 mg and 5 mg dosage strengths into the United States, prior to the expiration of the 407 patent, including any extensions, a judgment awarding Plaintiffs monetary relief together with interest; P. 285; Q. Costs and expenses in this action; and Attorneys fees in this action as an exceptional case pursuant to 35 U.S.C.
20
R.
Such other and further relief as the Court deems just and proper.
Date: August 26, 2013
/s/ Karen A. Confoy Karen A. Confoy FOX ROTHSCHILD, LLP 997 Lenox Drive, Building 3 Lawrenceville, New Jersey 08648 (609) 896-3600 Attorneys for Plaintiffs Horizon Pharma AG and Jagotec AG John A. Bauer MINTZ, LEVIN, COHN, FERRIS, GLOVSKY AND POPEO, P.C 666 Third Avenue New York, New York 10017 (212) 692-6795 Of Counsel for Plaintiff Jagotec AG
Robert F. Green Caryn C. Borg-Breen Jessica M. Tyrus Ann K. Kotze LEYDIG, VOIT & MAYER, LTD. Two Prudential Plaza, Suite 4900 180 North Stetson Chicago, Illinois 60601 (312) 616-5600 Attorneys for Plaintiff Horizon Pharma AG Dennis A. Bennett GLOBAL PATENT GROUP, LLC 1005 North Warson Road, Suite 201 St. Louis, Missouri 63132 (314) 812-8018 Of Counsel for Plaintiff Horizon Pharma AG
21
EXHIBIT A
|1|1111111111||||II||I|I1|||||||||||||||l|IHI11l1lIIIIIIIIIIHIIHIIIIIII US006488960B1
(12) United States Patent

Bardsley
(10) Patent No Us 6,488,960 B1 Dec. 3, 2002 (45) Date of Patent
(54) CORTICOSTEROID FORMULATION

(75) Inventor: Hazel Judith Bardsley, Cambridge
<GB>
(58)
Field of Search
514/179, 180; 424/465, 489
(56)
Relbrencw Cited
U.S. PATENT DOCUMENTS
5,792,476 A * 8/1998 Hallgren 424/465
(73) (*)
Assignee: Amkis Ltd. (GB) Notice: Subject lo any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. l54(b) by 0 days. 09/936,586 Mar. 14, 2000 PCT/GB00/00924 Sep. 13, 2001
FOREIGN PATENT DOCUMENTS

WO
95/08323 = < | 3/1995
A6 1 K/9/54
(21)
App1. No
OTHER PUBLICATIONS Rote Liste 1998, 31 037 Decortin H 1mg.* cited by examiner
(22) PCT Filed (86) PCT No 371 ()(1), (2), (4) Date: (sv)
Primary Examiner ames H. Reamer (74) Attorney Ageng or Firm-Saliwanchik, Lloyd &
Saliwanchik 7)
PC'l`Pub. No.: WO00/54780 PCT Pub. Date: Sep. 21, 2000
ABSTRACT
30)
Foreign Application Priority Data

(GB) 9905898
Mar. 15, 1999
(51) Int. C17 (52) U.s. Cl.
A61K 31/09 424/465; 424/485; 514/179 514/180
The present invention pertains to a unit dose formulation comprising 0.25 to 2 mg of a corticosteroid. This small dose can be used to treat rheumatoid arthritis, especially i f adapted to release at least 90% by weight of the corticosteroid, 2 to 8 hours after administration. 8 Claims, 1 Drawing Sheet
U.S. Patent
Dec. 3, 2002
Us 6,488,960 B1
Concentration (ng/ml)
50
40
30
20 10 0
0 6
I
L5
12
18
24
Time
Fig. 1
Us 6,488,960 B1
Arvidson et al (and in U.S. Pat. No. 5792496), a much lower dosage of the glucocorticoid was also effective. Given the state of the art and the known side-eifects of conicosteroids. FIELD OF THE INVENTION this increase in their therapeutic index is surprising According lo the present invention, a unit dosage com~ This invention relates to a controlled-release formulation. 5 prises 0.25 to 2 mg of a corticosteroid. Preferably, such a and in particular to a formulation of a corticosteroid, suitable dosage is in the form of a controlled-release formulation of for use in the treatment of rheumatoid arthritis. the type generally or specifically described in U.S. Pat. No. BACKGROUND OF THE INVENTION 5,792,476. Glucocor ticoids, and in particular prednisone and 10 Thus, in accordance with the present invention, a prednisolone, are widely used for the treatment of rheumacontrolled-close formulation of the drug is adapted lo release toid arthritis. The use of glucocorticoids may be ellicacious the drug at a predetermined period of time after but has disadvantages, particularly in terms of side~elfects administration, or at a predetermined time. Advantages of such as bone loss. the invention may include enhanced ellicaey, reduced sideIt appears to be generally recognised that it would be l effects, reduced Cmax and/or a reduced level of active material. desirable to use low doses of, say, prednisolone, in the treatment of rheumatoid arthritis. While it is clear that low DESCRIPTION OF THE INVENTION dose oral prednisolone can be eiiieacious, there is some controversy over what is actually meant by a low dose. The intention behind the invention is that the active 20 ingredient should be released at a predetermined time, e.g. Kirwan, New England J. Med. 333: 142-5 (1995), indibetween midnight and 6 a.m., e.g. 2 a.m. and 4 a.m., or a cates that a daily dosage of 7.5 mg prednisolone is elfective. predetermined time after administration. Thus, the user can This is supported by Boers et al, The Lancet 3502309-318 take the formulation before going to sleep, but have the full (1997). Boers et al also reports that a typical treatment of value of an effective dosage of the drug during the night, or rheumatoid arthritis following initial treatment with a non25 during sleep, at a dosage that has minimal sideeffects. steroidal anti-inliamrnatory dnug (NSAID) involves a high Accordingly, a predominant amount of the active ingredient, initial dose and, when the condition is under control, e.g. at least 90% by weight, is released at least 2 or 3 hours reduced doses, down to a "low maintenance" of 7.5 mg/day. after administration, and preferably no more than 6, 7 or 8 Gotzsche and Johansen, B. M. J. 316811-818 (1998), reviews a number of studies of low dose prednisolone in the 30 hours after administration. Formulations of the invention are intended for the treattreatment of rheumatoid arthritis. Most of these studies ment of disorders associated with the release of cytokines. ln report doses of at least 7.5 mg. There is one report, but from particular, the invention is suitable for the treatment of as long ago as 1967, of a 2.5 mg dose. inflammatory diseases, and most especially rheumatoid It is evident that, in clinical practice, rheumatologists taper the dose of glucocorticoid to as a low a level as they 35 arthritis, asthma, inflammatory bowel disease and atopic dermatitis. The dwg that is used in the formulation may be can, before symptoms return. There may be patients who are chosen accordingly. Examples are glucocortocoids and other stable on less than 5 mg prednisolone per day, but there is cor ticosteroids, e.g. budesonide, methylprednisolone, little or no clinical data to support that such a low dose is deflazacort, prednisone and prednisolone. lf desired, the actually providing any benefit. This is important, because in many of these patients, prednisolone may be contributing 40 active ingredient may be formulated as a pro-dnug, so that the active component is released in vivo. only side-effects. There is no evidence that any dose of The preferred route of administration of a formulation of prednisolone, lower than those generally used, is effective this invention is oral. However, it will be readily apparent to when given chronically for the treatment of rheumatoid those skilled in the art that other routes of administration arthritis. Arvidson et al, Annals of the Rheumatic Diseases 45 may be used, e.g. having regard to the nature of the condition being treated and the most effective means of achieving 56:27_31 (1997), reports that the timing of glucocorticoid delayed release. administration in rheumatoid arthritis may be important, in The dwg may be administered in any conventional forcontrolling the acute inflammatory aspects of the disease. In mulation that provides delayed release, via any suitable the reponed study, patients were woken at 2.00 a.m. and given 7.5 mg or 5 mg prednisolone. 50 route of administration. Conventional dosing parameters may be adopted, i.e. those which are known to or adapted to U.S. Pat. No. 5,792,476 claims a sustained-release forthe practice of those sldlled in the art. The daily dosage is mulation of a glucocorticoid such as prednisone or predusually at least 0.25 or 0.5 mg, eg. l to 2 mg, but will be nisolonhe. The formulation comprises 2.5-7 mg of the chosen according to the age, weight and health of the glucocorticoid and releases at least 90% of the drug during 40~80 minutes, starting about 1-3 hours after the entry of 55 Subject, and other factors that are routinely considered by the man skilled in the art. the drug into the small intestine. The intention is that the A formulation of the invention may be a unit dosage such formulation should be taken immediately before the patient as a tablet, capsule, ampoule, vial or suspension. A goes to sleep, that the drug should be released during sleep, controlled-release formulation may be in matrix, coating, and that the greatest symptoms of rheumatoid arthritis (which occur shortly before waking) should thus be treated 60 reservoir, osmotic, ion-exchange or density exchange form. It may comprise a soluble polymer coating which is dismost effectively. This is based on the same data as in solved or eroded, after administration. Alternatively, there Arvidson et al, supra, i.e. using doses of 5 or 7.5 mg may be an insoluble coating, e.g. of a polymer, through prednisolone given at 2 a.m. which the active ingredient permeates, as from a reservoir, SUMMARY OF THE INVENTION 65 diifuses, e.g. through u porous matrix, or undergoes osmotic This invention is based on the discovery that, in a study exchange. A further option for a controlled-release formudesigned to test the reproducibility of the results reported by lation involves density exchange, e.g. in the case where the
1 CORTICOSTEROII) FORMULATION
Us 6,488,960 B1
3
formulation alters on administration, e.g. from microparticles to a gel so that the active ingredient dilfuses or permeates out. Ion-based resins may also be used, the active component being released by ionic exchange, and wherein the rate of release can be controlled by using cationic or anionic forms of the drug. Another type of controlled-release formulation involves pulsed dosing. Further examples are given in U.S. Pat. No. 5,792,476. An example of a controlled dose of active ingredient is dosing with a tablet containing 1.25 mg prednisolone. In this example, a patient taking a controlled dose of 1.25 mg prednisolone takes the tablet a number of hours before it is due to be released. Time Zero on the plot (FIG. 1) denotes the earliest time at which active ingredient is released, probably midnight. The plasma levels achieved by release of the active agent at di5erent times (2, 4 and 6 a.m.) are shown.
4
(and probably remained blind), but no placebo tablets were used and it was possible for a patient to be un-blind. Patients invited to take part in the study had the following characteristics: Over 18 years old Had rheumatoid arthritis by the criteria of the American College of Rheumatology; see Arnett et al, Arthritis Rheum. 31:315-324 (1988) Had active disease as evidenced by 3 or more swollen and tender joints Were not taking glucocorticoid medication
15
10
Had not had intra-anicular glucocorticoid injections in the previous 3 weeks
Had no medical conditions which, in the opinion of the It can be seen that the range for Clnux obtained from the 125 mg prednisolone dose is from approximately 20 to 50 investigator, would contraindicate low dose prednisong/ml (total prednisolone which includes protein bound and lone therapy unbound active) depending on how quickly a patient absorbs 20 Informed consent was obtained and the patient prescripthe active ingredient. The time to Cmax or Tm is usually tion written by a doctor not associated with trial evaluation. between 1 and 3 hours, Where absorption is particularly fast, Medication was dispensed at 2 a.m. on each treatment day the Cnmx may be 100 ng/ml total prednisolone or higher (this after gently waking the patient. The patient was encouraged is not shown on the plot). The following Study provides the basis of the present 25 to settle back to sleep immediately. On the morning before medication and on each morning invention. on the day of medication, blood samples were taken at 8.30 Study Design a.m. and outcome assessments recorded then, and at noon, as The study was an assessor blind comparison of the eiects indicated above, of two doses of prednisolone (1 mg and 5 mg) given at 02.00. Patients stayed the night in hospital but were free to 30 Evaluation be up and about and to leave the hospital during the day. At Symptoms, signs and laboratory results were compared 2 a.m. on the appropriate days patients were woken gently, within and between patients, but the main assessment was administered the prednisolone, and settled back to sleep. visual inspection of the overall pattern of response. Means Blood samples and clinical assessments were made at 08.30 and further clinical assessments related to symptoms on the 35 and standard deviations were used to define variation rates day of drug administration at 12.00 and 08.30 the following and for calculating trial size for future studies. An overall day (except the final day when this last assessment was made assessment of practicality and the potential for more frebefore departure from the hospital). Patients were admitted quent (but smaller volume) blood taking was made by on Monday and had a "control" night that evening with no discussion arnongst the staff and patients involved. prednisolone but full assessment the following day. On each 40 Results of the following three nights prednisolone was administered. Three patients were able to take part in the study in the Patients went home on Friday afternoon but returned the following Monday to repeat the procedure. Allocation to 1 time available. One patient (3) was inadvertently given the mg or 5 mg prednisolone in the first or second week was by Hrst dose of treatment in the second week on the hrst night randomisation in sealed envelopes. The patient and assessor 45 in hospital. Patient 3 took prednisolone for the next two were not aware of which dose was given. nights and remained in hospital for a fourth night without Outcome prednisolone treatment. This patient's assessments have Clinical: Outcome was measured at 08.30 each day for: been included normally in the first week, but in the second swollen joint count (n=28); tender joint count (n=28); pain (0.100 mm, VAS). Outcome was measured at 12.00 each day 50 week they have been used diierently. Here, this patient's results have been included with those of the other patients in for. morning stihness (minutes); patient opinion of condition accordance with the dose of prednisolone received. This (0-100 mm, VAS); clinician opinion of condition (0-100 patient's final assessment (no prednisolone the night before) mm, VAS). Outcome was measured the following day for: whether the arthritis worse in the morning or afternoon on therefore appears as an extra day after the other patients in 55 the study. the previous day? (-1 morning, 0 equal, +1 afternoon). Serological: Seam samples were obtained at 08.30, kept The results for 5 mg prednisolone place the patients in this on ice for up to 1 hour, separated and stored at -70 C. to pilot study well within the range of findings published by measure: C-reactive protein (CRP); IL6 concentration; 6 Arvidson et al and reinforce the conclusions which can be soluble receptor (IL-6sR) concentration; byaluronate (HA) drawn from that paper. 60 concentration. The results from 1 mg prednisolone raise the possibility Procedure that even at this dose there may be an appreciable effect on Patients acted as their own control and took each dose of symptoms. Pain, EMS, pat1ent's opinion and clin1cian's prednisolone for three consecutive nights. They were ranopinion were statistically significantly reduced, even with domly. allocated by cards kept in sealed envelopes to either 1 mg prednisolone on three consecutive nights followed by 65 only three patients in the study. CRP and IL-6 were reduced significantly on 5 mg prednisolone and there was a tendency 5 mg on three consecutive nights, or the opposite sequence. The assessor was not aware of the treatment order allocation for reduction on 1 mg prednisolone.
Us 6,488,960 B1
5
TABLE 1
Mean and 95% confidence intervals for each variable More Dav Swollen Painful Dose Joinis Joints
OT
Pain
Less
EMS
L Opn
Cln Opn
CRP
HA
me
IL-6sR
Mean Results 20.3 18.7 21.0 20.0 20.3 20.3 15.3

19.0
2 3 10
11
187
18.3 12.3 18.0 17.3 14,0 12.0
37.7 26.0 20.3

16.7
-1.0
-0.7 -0.7
0.0 0.3 0.3 ~0.7
25.0 19.7 16.0
12 13 14
5 5 0
19.7 9.0
70.0 55.0 51.7 40.0 40.0 30.0 0 33.3
31.3 23,7 26.7 12.7 24.3 19.3 11.7 13.3
34.3 28.7 29.3 16.3 23.3 27.7 15.7 11.7 8.0
405 35.5 31.2 25.8 15.0 36.6 31.1 19.1 19.5
345.1
241 .9
320.3 372.5 396.3 322.5 339.5 193.9 363.5
44.1 28.1 31.1 22.8 19.3 30.3 18.5 13.8 107.1
31557.8 31959.9 31468.0 30898.9 22937.2 423%.2 3533 361727 32180.5
95% CI Resulls 0.7 1.3 3.5

3. 6
5.7 7,4 7.7

9.1
24.9 25.2 20.3

16.9
0.0 0.7 0.7

1.1
19.6 9.8 8.6

9.8
20.3 15.4 5.7

1
10 11 12 13 14
0 5 5 5
15.2 3.9 6.5 6.9
19.2 9.1 9.6 10.3
31.8 21.1 15.4
0.8 1.3 0.7
48.0 29.4 19.6
3 20.1 11.6
10.3 10.5 4.6 29.6 13.6 1.7
213.0 23.0 152.3 27.5 321.8 25.3 96.7 22.8 718.7 2 9 1 148.6 26.0 221.4 113.3
18.1 18.1 32.7 28,4 23.3 241 23.6 13,3
8838.9 10225 102209 11329.4 27617.3 23485.3 8919.1 70695
What is claimed is 1. A controlled-release formulation comprising from 0.25 mg to 2 mg of a corticosteroid selected from the group
30
effective amount of a controlled-release formulation com prising from 0.25 mg to 2 mg of a corticosteroid selected
consisting of prednisone, methylprednisolone, and

prednisolone, wherein said formulation is adapted to release at least 90% by weight of the corticosteroid 2 hours to 8 hours after administration. 2. The formulation according to claim 1, which comprises from 05 mg to 2 mg of the corticosteroid. 3. The formulation according to claim 1, which comprises from l mg to 1.25 mg of the corticosteroid. 4. The formulation according to claim 1, W herein the corticosteroid is prednisolone. 5. A method for the treatment of rheumatoid arthritis, Wherein said method comprises administering to a patient an
from the group consisting of prednisone,

methylprednisolone, and prednisolone, wherein said formulation is adapted to release at least 90% by weight of the corticosteroid 2 hours to 8 hours after administration. 6. The method according to claim 5, wherein the formulation comprises from 0.5 mg to 2 mg of the corticosteroid. 7. The method according to claim 5, Wherein the formulation comprises from 1 mg to 1.25 mg of the corticosteroid. 8. The method according to claim 5, wherein the corticosteroid is prednisolone.
=t < =l< >l * *
35
40
EXHIBIT B
||||||||||1||||||1111||||1|||||IIIIIIIIII|11|1II111|1|I|||H||||||||I||||| US006677326B2
(12) United States Patent

Bardsley et al
(10) Patent No.:

(45) Date of Patent:
U S 6,677,326 B 2
*Jan. 13, 2004
(54) CORTICOSTEROID FORMULATION COMPRISING LESS THAN 2.5 MG PREDNISOLONE FOR ONCE DAILY ADMINISTRATION
(75) Inventors: Hazel Judith Bardsley, Cambridge (GB); Robin Mark Bannister, Essex
(58) Field of Search (56) References Cited U.S. PATENT DOCUMENTS

5,792,476 A 8/1998 Hiillgren
514/179, 180
(GB); Julian Clive Gilbert, Essex (GB)

WO

W O 95/08323 A1 3/1 995
(73) (*)
As<ignee: Arakis, Ltd. (GB) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. This patent is subject to a terminal dis claimer.
OTHER PUBLI CATIONS Rote Liste, 1998, 31 037 Decortin H lmg. Buckley, L.M, et al., "Effects of Low Dose Corticosteroids on the Bone Mineral Density of Patients with Rheumatoid Arthritis" The Journal of R/teurnafolog 1995, pp. 1055_1059, vol. 22, No. 6 Cash, J.M. ct al. "Pituitary~Adrcna1 Axis Responsiveness to Ovine Corticotropin Releasing Hormone in Patients with Rheumatoid Arthritis Treated with Low Dose Prednisone" T/zeloumalofRheumatolog); 1992, pp. 1692_1696,Vo1. 19,
No. 11.
(21)
Appl. No.: 10/263,044 Oct. 1, 2002
(22> Filed (65)
Prior Publication Daw

US 2003/0149009 A1 Aug. 7, 2003
Primarv Examiner-James H. Reamer
(74) Attorney Agent, or Firm-Saliwanchik, Lloyd &

Saliwanchik 7)
Related U.S. Application Data

63) Continuation of application No. PCT/GB01/04181, filed on Sep. 19, 2001, and a continuation-in-part of application No. 09/9361586, filed on Sep. 13, 2001, now Pat. No. 6,488,960.
ABSTRACT
0)

(GB) (GB)
9905898 0023220
Mar. 15, 1999 Sep. 21, 2000
The subject invention concerns a unit dose formulation comprising less than 2.5 mg of prednisolone or an equivalent, equipotent amount of another cortioosteroid. One embodiment of a method of the invention concerns once daily administration of the unit dose formulation between midnight and 6 a.m. for the treatment of rheumatoid arthritis. 17 Claims, 1 Drawing Sheet
(51) Int. Ci7 (sz) U.s. Cl.
A61K 31/56 514/179; 514/1 80
U.S. Patent
Jan. 13, 2004
Us 6,677,326 B2
Concentration (nglml)
50
r'
40 304
;\
\l
\\
wr
`\
\ /
x
12 18 24
32 iV~
U
0+
0
6
Time
FIG. l
Us 6,677,326 B2
1
2
the dmg into the small intestine. The intention is that the formulation should be taken immediately before the patient goes to sleep, that the dwg should be released during sleep, and that the greatest secretion of cytokines (which occur shortly before waking) should thus be treated most effectively. This is based on the same data as in Arvidson et al., supra, i.e. using doses of 5 or 7.5 mg prednisolone given at 2 am.
10
C()R'1ÌC()S'lÈR()ID FORMULATION COMPRISING LESS THAN 2.5 MG PREDNISOLONE FOR ONCE DAILY ADMINISTRATION
CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of International Application PCT/GB01/04181, with an international filing date of Sep. 19, 2001, published in English under PCTArticlc 21(2), and is a continuation-in-part of U.S. application Scr. No. 09/936,S86, filed Sep. 13, 2001 now U.S. Pat. No. 6,488,
960.
BRIEF SUMMARY OF THE INVENTION This invention is based on the discovery that, in a study designed to test the reproducibility of the results reported by Arvidson et al. (and in U.S. Pat. No. 5,792,496), a much lower dosage of the glucocorticoid was also effective. Given the state of the art and the known side-effects of corticosteroids, this increase in their therapeutic index is surpnsmg According to the present invention, a unit dosage comprises less than 2.5 mg of prednisolone or an equivalent amount of a conicosteroid. Equivalence is in terms of potency. It will be understood that drugs vary in potency, and that doses can therefore vary, in order to obtain equivalent
effects.
FIELD OF THE INVENTION This invention relates to a controlled-release formulation, and in particular to a formulation of a corticosteroid, suitable for use in the treatment of rheumatoid arthritis. BACKGROUND OF THE INVENTION
15
20
Glucocorticoids, and in particular prednisone and prednisolone, are widely used for the treatment of rheumatoid arthritis. The use of glucocorticoids may be eficacious but has disadvantages, particularly in terms of side-effects 25 such as bone loss. It appears to be generally recognized that it would be desirable to use low doses of, say, prednisolone, in the treatment of rheumatoid arthritis. W hile it is clear that low dose oral prednisolone can be elficacious, there is some 30 controversy over what is actually meant by a low dose. Kirwan, New England J. Med. 3331142-5 (1995), indicates that a daily dosage of 7.5 mg prednisolone is effective. This is supported by Boers et al., The Lancet 3501309-318 35 (1997). Boers et al. also reports that a typical treatment of rheumatoid arthritis following initial treatment with a nonsteroidal anti-iniiammatory dmg (NSAID) involves a high initial dose and, when the Condition is under control, reduced doses, down to a "low maintenance" of 7.5 mg/day. 40 Gotzsche and Johansen, B. M. J. 3162811-818 (1998), reviews a number of studies of low dose prednisolone in the treatment of rheumatoid arthritis. Most of these studies report doses of at least 7.5 mg. There is one report, but from
Thus, in accordance with the present invention, a controlled-dose formulation of the drug is adapted to release the drug at a predetermined period of time after administration, or at a predetermined time. Advantages of the invention may include enhanced eliicacy, reduced sideelfects and/or reduced Cmax' Further or in addition, chronotherapeutic administration allows the use of a reduced level of active material. DESCRIPTION OF THE INVENTION
The intention behind the invention is that the active ingredient should be released at a predetermined time, e.g. between midnight and 6 a.m., e.g. 2 a.m. and 4 a.m., or a predetermined time after administration. Thus, the user can take the formulation before going to sleep, but have the full value of an eilective dosage of the dnig during the night, or during sleep, at a dosage that has minimal side~elfects. Accordingly, a predominant amount of the active ingredient, e.g. at least 90% by weight, is released at least 2 or 3 hours after administration, and preferably no more than 6, 7 or 8 as long ago as 1967, of a 2.5 mg dose. 45 hours after administration. It is evident that, in clinical practice, rheumatologists Formulations of the invention are intended for the treattaper the dose of glucoconicoid to as a low a level as they ment of disorders associated with the release of cytokines, can, before symptoms return. There may he patients who are e.g. TNF ot, IL-1, IL-2, IL-6 and IL-8. In particular, the stable on less than 5 mg prednisolone per day, but there is little or no clinical data to support that such a low dose is 50 invention is suitable for the treatment of inflammatory diseases, including polyarthropathies, and more especially actually providing any beneiit. This is important, because in rheumatoid arthritis, asthma, inflammatory bowel disease, many of these patients, prednisolone may he contributing chronic obstnuctive pulmonary disease, psoriasis, psoriatic only side-effects. There is no evidence that any dose of arthritis, polymyalgia rheumatica and atopic dermatitis. The prednisolone, lower than those generally used, is effective when given chronically for the treatment of rheumatoid 55 drug that is used in the formulation may be chosen accordingly. If desired, the active ingredient may be formulated as arthritis. a pro-drug, so that the active component is released in vivo. Arvidson et al., Annals of the Rheumatic Diseases Among active agents that can he used in the invention, 56:27-31 (1997), reports that the timing of glucocorticoid examples are glucocorticoids and other conieosteroids, e.g. administration in rheumatoid arthritis may be important, in controlling thc acute inflammatory aspects of the disease. In 60 budesonide, methylprednisolone, deflazacorl, fluticasone, prednisone and prednisolone. The appropriate dosage of the reported study, patients were woken at 2.00 a.m. and each such drug depends on its potency, given 7.5 mg or 5 mg prednisolone. U.S. Pat. No. 5,792,496 claims a sustained-release forEquivalent potency in clinical dosing is well known. mulation of a glucocorticoid such as prednisone or predInformation relating to equivalent steroid dosing (in a nonnisolone. The formulation comprises 2.5-7 mg of the glu- 65 chronotherapeutic manner) may be found in the British cocorticoid and releases at least 90% of the drug during Nadonal Formulary (BNF), 37 March 1999, the content of 40-80 minutes, starting about 1-3 hours after the entry of which is incorporated herein by reference.
Us 6,677,326 B2
3
The BNF guidelines are included in the table below. In addition, the proposed clinical dose equivalent to 1 Ing of prednisolone when administered in a chronotherapeutic manner is included in the table. More specifically, the following Table is of doses of steroids equivalent to mg of prednisolone and equivalence to 1 mg of prednisolone When administered in a chronotherapeutic manner according to this invention and 1 mg of prednisolone.
An example of a controlled dose of active ingredient is dosing With a tablet containing 1,25 mg prednisolone. In this example, a patient taldng a controlled dose of 1.25 mg prednisolone takes the tablet a number of hours before it is 5 due to be released. Time zero on the plot (FIG. 1) denotes the earliest time at which active ingredient is released, probably midnight. The plasma levels achieved by release of the active agent at dilferent times (2, 4 and 6 a.m.) are shown, It can be seen that the range for Cmax obtained from the 10 1.25 mg prednisolone dose is from approximately 20 to 50 ng/ml (total prednisolone which includes protein bound and Euuivalent dose in chronotheraneutic administration unbound active) depending on how quickly a patient absorbs the active ingredient. The time to Cm or Tm" is usually Equal to 5 mg between 1 and 3 hours. Where absorption is particularly fast, prednisolone Equal lo Steroid Normal dosing)* 1 mg prednisolone 15 the Cmax may be 100 ng/ml total prednisolone or higher (this is not shown on the plot). bctamelhasonc 750 #S 150 /lg corlisone acetate 25 m g The following Study provides the basis of the present 5 mg dcfiazacoxt 6 me 1.2 me invention. dexamethasone 750 N8 150 #8 Study Design hydrocorlisone 20 mg 4 me The study was an assessor blind comparison of the effects methyl prednisone 4 me 20 0.8 m g of two doses of prednisolone (1 mg and 5 mg) given at predmsone Sms 1 me triamcinolone 4m;z 0.8 me 02.00. Patients stayed the night in hospital but were free to be up and about and to leave the hospital during the day. At z a.m. on me appropriate days patients were woken gently, It is also known (BNF 37 March 1999) from clinical dosing equivalence that doses of triamcinolone, fluticasone 25 administered the prednisolone, and settled back to sleep. Blood samples and clinical assessments were made at 08.30 and budesonide are broadly similar in nasal administration and further clinical assessments related to symptoms on the (110 pg, 100 ,ug and 200 pg). Achronotherapeutic advantage day of drug administration at 12.00 and 08.30 the following may be expected upon dosing these drugs. day (except the final day when this last assessment was made Corticosteroids such as cortisone acetate and hydrocortisone are less preferred for use in the invention, owing to 30 before departure from the hospital). Patients were admitted on Monday and had a "control" night that evening with no their systemic side-effects on long-term use. Such compounds, having effect on glucose and mineral prednisolone but full assessment the following day. On each metabolism, will be known to those skilled in the art. of the following three nights prednisolone was administered. The preferred route of administration of a formulation of Patients went home on Friday afternoon but returned the this invention is oral. However, it will be readily apparent to 35 following Monday to repeat the procedure. Allocation to 1 those skilled in the art that other routes of administration mg or 5 mg prednisolone in the Hrst or second week was by may be used, e.g. having regard to the nature of the condition randomization in sealed envelopes. The patient and assessor being treated and the most effective means of achieving were not aware of which dose was given. delayed release. Outcome Clinical: Outcome was measured at 08.30 each day for: The drug may be administered in any conventional for- 40 swollen joint count (n=28); tender joint count (n=28); pain mulation that provides delayed release, via any suitable (0.l()0 mm, VAS). Outcome was measured at 12.00 each day route of administration. Conventional dosing parameters for: morning stiiness (minutes); patient opinion of condition may be adopted, i.c. those which are known to or adapted to (0_100 mm, VAS); clinician opinion of condition (0-100 the practice of those sldlled in the art. The daily dosage (relative to prednisolone) is usually at least 0.25 or 0,5 mg, 45 mm, VAS). Outcome was measured the following day for: whether the arthritis was worse in the morning or afternoon e.g. 1 to 2 mg, but will be chosen according to the age, on the previous day (-1 morning, 0 equal, +1 afternoon). weight and health of the subject, and other factors that are Serological: Semm samples were obtained at 08.30, kept routinely considered by the man sldlled in the art. on ice for up to 1 hour, separated and stored at -70 C. to A formulation of the invention may be a unit dosage such as a tablet, capsule, ampoule, vial or suspension. A 50 measure: C-reactive protein (CRP); IL-6 concentration; IL-6 soluble receptor (IL-6sR) concentration; hyaluronate (HA) controlled-release formulation may be in matrix, coating, concentration. reservoir, osmotic, ion-exchange or density exchange form. Procedure It may comprise a soluble polymer coating which is disPatients acted as their own control and took each dose of solved or eroded, after administration. Alternatively, there may be an insoluble coating, eg. of a polymer, through 55 prednisolone for three consecutive nights. They were randomly allocated by cards kept in sealed envelopes to either which the active ingredient permeates, as from a reservoir, 1 mg prednisolone on three consecutive nights followed by dilfuses, e.g. through a porous matrix, or undergoes osmotic 5 mg on three consecutive nights, or the opposite sequence. exchange. A further option for a controlled-release formuThe assessor was not aware of the treatment order allocation lation involves density exchange, e.g. in the case where the formulation alters on administration, e.g. from micropar- 60 (and probably remained blind), but no placebo tablets were used and it was pomible for a patient to be un-blind. ticles to a gel, so that the active ingredient diflitses or Patients invited to take part in the study had the following permeates out. Ion-based resins may also be used, the active characteristics: component being released by ionic exchange, and W herein Over 18 years old the rate of release can be controlled by using cationic or anionic forms of the dnig. Another type of controlled-release 65 Had rheumatoid arthritis by the criteria of the American formulation involves pulsed dosing. Further examples are College of Rheumatology; see Arnett et al., Arthritis given in U.S. Pat. No. 5,792,496. Rheum. 312315_324 (1988)
US 6,677,326 B2
5
Had active disease as evidenced by 3 or more swollen and tender joints Were not taking glucocorticoid medication Had not had intra-articular glucocorticoid injections in the previous 3 weeks 5 Had no medical conditions which, in the opinion of the investigator, would contraindicate low dose prednisolone therapy Informed consent was obtained and the patient prescription written by a doctor not associated with trial evaluation. 10 Medication was dispensed at 2 a.m. on each treatment day after gently waking the patient. The patient was encouraged to settle back to sleep immediately. On the morning before medication and on each morning on the day of medication, blood samples were taken at 8.30 is
a.m. and outcome assessments recorded then, and at noon, as
6
The results for 5 mg prednisolone place the patients in this pilot study Well Within the range of findings published by Arvidson et al. and reinforce the conclusions which can be drawn from that paper. The results from 1 mg prednisolone raise the possibility that even at this dose there may be an appreciable elfect on symptoms. Pain, EMS, patient's opinion and clinician's opinion were statistically signilicantly reduced, even with only three patients in the study. CRP and IL-6 were reduced significantly on 5 mg prednisolone and there was a tendency for reduction on l mg prednisolone. All patents, patent applications, provisional applications, and publications referred to or cited herein are incorporated bv reference in their entirety to the extent thev are not iriconsistcnt with the explicit ieachings of this spci:ification TABLE 1
Mean and 95% confidence intervals for each variable More or Less EMS
indicated above. Evaluation
Day
Swollen Painful Dose Joints Joints
Pain
L Opn
Cln Opn
CRP
HA
IL-6
IL-6sR
Mean Results 0
1
2
3 10 11
12 13 14
20.3 18.7 18.7 18.3 12.3 18.0 17.3 14.0 12.0
21.0 20.0 20.3 20.3 15.3 19.0 19.7 19.7 9.0
37.7 26.0 20.3 16.7 25.0 19.7 15.7 16.0 0.0
-0.7 -0.7
70.0 31.3 55.0 23.7 51.7 26.7 0.0 40.0 12.7 -0.3 40.0 24.3 -0.3 30.0 19.3 -0.3 20.0 11.7 -0.7 33.3 13.3 0.0 0.0 0.0 95% CI Resuhs 0.0 0.7 0.7
1.1
1.0
34.3 28.7 29.3 16.3 23.3 27.7 15.7

11,7
80
40.5 345.1 44.1 35.5 241.9 28 . 1 31.2 320.3 31 . 1 25.8 372.5 22.8 15.0 396.3 19.3 36.6 322.5 30.3 31.1 339.5 18.5 1 9 . 1 193.9 13.8 19.5 363.5 1 07.1
315578 31959.9 31468.0 30898.9 22937.2 423282 353316 36172.7 321805
0
1
2 3 10 11
12
13 14
0.7 1.3 3.5 3.6 15.2 3.9 6.5 6.9
5.7 7.4 7.7 9.1 19.2 9.1 9.6 10.3
24.9 25.2 20.3 16.9 31.8 21.1 15.4 7.8
0.8 1.3 0.7 0.7
19.6 9.8 8.6 9.8 48.0 29.4 19.6 6.5
20.3 15.4 5.7 12.9 30.2 20.1 11.6 6.2
14.1
17.1
213.0
15233
10.3
10.5
4.6 29.6 13.6 1.7 4.6
23.0 27.5 25.3 22.8

29 . 1
18.1 8838.9 1 8 . 1 10225.5
26.0 18.2
321.8 967 718.7 148.6 221.4 113.3
32.7 10220.9 28.4 11329.4 23.3 27617.3 24 . 1 234853 23.6 8919.1 13.3 7069,5
Symptoms, signs and laboratory results were compared What is claimed is Within and between patients, but the main assessment was 1. Aunit dose formulation comprising less than 2.5 mg of visual inspection of the overall pattern of response. Means prednisolone or an equivalent, equipotent amount of another and standard deviations were used to define variation rates 50 corticosteroid. and for calculating trial size for future studies. An overall 2. The formulation according to claim 1, which comprises assessment of practicality and the potential for more freat least 0.25 mg of prednisolone or said equivalent. quent (but smaller volume) blood taking was made by 3. The formulation according to claim 2, which comprises discussion amongst the stall and patients involved. 0.5 to 2 mg of prednisolone or said equivalent. T\.,...1._ I\ChLl1lb 55 4. The formulation according to claim 3, which comprises Three patients were able to take part in the study in the l to 1.25 mg of prednisolone or said equivalent. time available. One patient (3) was inadvertently given the 5. The formulation according to claim 1, adapted to first dose of treatment in the second week on the first night release at least 90% by weight of prednisolone or said in hospital. Patient 3 took prednisolone for the next two equivalent 2 to 8 hours after administration. nights and remained in hospital for a fourth night without 6. The formulation according to claim 1, Wherein said prednisolone treatment. This patient's assessments have 60 corticosteroid is a glucocorticoid. been included normally in the first week, but in the second 7. The formulation according to claim 1, wherein said Week they have been used differently. Here, this patient's corticosteroid is selected from the group consisting of results have been included With those of the other patients in prednisone, budesonide, methylprednisolone, Iluticasone, accordance with the dose of prednisolone received. This patient's final assessment (no prednisolone the night before) 65 betamethasone, and dellazacort. therefore appears as an extra day after the other patients in 8. The formulation according to claim 7, wherein said the study. corticosteroid is prednisone.
Us 6,677,326 B2
7
9. A method for the treatment of a patient sulfering from a condition selected from the group consisting of asthma, inflammatory bowel disease, psoriasis, psoriatic arthritis, polymyalgia rheumatica, chronic obstructive pulmonary
_|' .,., .__.1 _.|_ ..__ /;:1 -_L_.Z4J-..J -4L
8
13. The method according to claim 9, W herein the formulation is adapted to release at least 90% by weight of the prednisolone or said equivalent 2 to 8 hours after administration 14. The method according to claim 9, wherein said corticosteroid is a glucocorticoid. 15. The method according to claim 9, wherein said corticosteroid is selected from the group consisting of prednisone, budesonide, methylprednisolone, ilutacasone, betamethasone, and deflazacort. 16. The method according to claim 15, W herein said corticosteroid is prednisone. 17. The method according to claim 8, wherein said corticosteroid is administered between midnight and 6 a.m.
..
>
polyarthropathies, which comprises administering to the patient a unit dosage formulation comprising less than 2.5 mg of prednisolone or an equivalent, equipotcnt amount of another corticosteroid. 10. The method according to claim 9, W herein the formulation comprises at least 0.25 mg of prednisolone or said equivalent. 11. The method according to claim 10, Wherein the formulation comprises 0.5 to 2 mg of the prednisolone or said equivalent. 12. 'l`he method according to claim 11, wherein the formulation comprises 1 to 1.25 mg of the prednisolone or said equivalent.
10
:15
>| <
>| =
>l<
=i<
'| =
EXHIBIT C
nlm|||||m1|I|IImIIIIIIIIIImuIII|ImluII|I|1|u|||1|u|Ilulnlm
US008309124B2
(12> United States Patent

Vergnault et al
(54) DELAYED RELEASE TABLET WITH DEFINED CORE GEOMETRY
(75) Inventors: Guy Vergnault, Kcmbs (FR); Pascal Grenier, Kappelen (FR); Christophe Dragan, Geispitzen (FR) (73) Assignee: Jagotec AG,Mut'renz (CH) Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days.
EP EP EP JP
(10) Patent No.:

0 939 623 A1 1067910 A1 1275 381 A1
200 1 -0 10950
US 8,309,124 B2
Nov. 13, 2012
9/1999 1/2001 1/2003
1/2001 1/ 1 992 7/ 1 992 10/ 1 993 12/ 1996
*' ) Notice:
<21> App1.No.: 13/424,069

<22> Fil ed
Mar. 19, 2012
WO WO WO WO WO WO WO WO WO WO WO WO WO WO WO
WO WO WO WO WO
(65)
Prior Publication Data

US 201 2/0177734 A1 Jul. 12, 2012
WO-92/00064 A1 WO-92/ 1 1845 A1 WO-93/ 19741 A1 WO-96/40078 A1 WO-0 1/08421 A2 WO-0 1/528 19 A1 WO-0 1/68056 A1 WO-0 1/80 824 A2 WO-02/00204 A1 Wo.0200204 A1 W0_02/072033 WO~02/072034 A2 W0.02072034 A2 WO-03/026626 WO-03/075919 A1 WO-2004/0285 10 WO-2004/093 843 A1 WO-2004/093 850 A1 WO-2004/ 103349 A2 WO-200 5/027843 A2
2/2001 7/2001 9/2001

11/200 1 1/2002 1/2002
9/2002 9/2002 9/2002 4/2003 9/2003 4/2004 11/2004 11/2004 12/2004 3/2005
Related U.S. Application Data (63) Continuation of application No. 10/554,538, Hled as application No. PCT/1132004/001 693 on Apr. 23, 2004, now Pat. No. 8,168,21 8
OTHER PUBLICATIONS
Conte et al. "Press-coated Tablets for Time-programmed Release of Drugs," Biomaterials. 14.l3(1993): 1017-1023. Fukui et al. "Studies on Applicability of Press-Coated Tablets Using Hydroxypropylcellulose (HPC) in the Outer Shell for Time-Release Preparation." J. Controlled Release. 68.2(2000):215-223. GB Search Report dated Aug. 22, 2003 corresponding to GB 0309342.4. GB Search Report dated Oct. 23, 2003 corresponding to GB 0309342.4. International Search Report mailed Oct. 21, 2004 corresponding to PCT/152004/001693. Lin et al. "Compression Forces and Amount ofOuter Coating Layer Affecting the Time~Conf1ol1ed Disintegration of the CompressionCoated Tablets Prepared by Direct Compression With Micronized Ethylcellulose." .Z Pharmaceutical Sciences. 90.121 2005-2009. Zlaikina, A.P., "The Modern Therapeutic Tactics of Inilaxmnalory Bowel Disease, Consilium Medicum." Gastroenterology. 6.1: 2004. >z< cited by examiner
0)

(GB) 0309342.4
Apr. 24, 2003 (51)
Int. Cl (2006.01) A61K 9/20 424/464 (52) U.s.C1. (58) Field of Classification Search None See application file for complete Search histoly. (56) References Cited U.S. PATENT DOCUMENTS
5,279,832 A 1/1994 Greissinger et al 5,464,633 A 11/1995 Conte et al. 5,567,696 A 10/1996 McGuire et al. 5,792,476 A |< 8 / 1 9 9 8 Hallgren 6,183,780 B 1 2/2001 Van Ba1ken et al 4/2002 Ritschel et al. 6,365,185 B1 12/2002 Bardsley 6,488,960 B 1 6,599,284 B2 7/2003 Faour 6,620,439 B1 9/2003 Mehta 2004/0018327 A1 1/2004 Wvnn et al. 2005/0008702 Al 1/2005 Fzfour et al 2006/0057200 A1 3/2006 Schaeflier
Primary Examiner - Paul Dicldnson

424/465
(74) Attorney, Agent, or Hrm - Muriel Liberto, Esq.; Mintz Levin Cohn Ferris Glovsky and Popeo PC

EP EP EP
0 463 877 A1 0 673 645 A2 0 776 660 A2
1/1992 9/1995 6/1997
ABSTRACT (57) A tablet comprising a core containing an active agent, and a coating, the core being disposed within the coating such that the coating has a thickness about a longitudinal axis (X-Y) of about 4.85 to 4.95 nun. The position of the core within the coating dictating that the active agent is released rapidly after a lag time during which time no active agent is released.
14 Claims, 2 Drawing Sheets
U.S. Patent
Nov. 13, 2012
Sheet 1 of 2
US 8,309,124 B2
B
I I
I I
FIG . 1
U.S. Patent
Nov. 13, 2012
Sheet 2 of 2
US 8,309,124 B2
% Release - Prednisone 100.0
80.0
f
E
m
GJ
a> 60.0
cv
nc
'63
40.0
20.0
. 1
0.0
iz '-fa d
\-~ c\l N
~ fz
=fa Q
~ f > n <' <1' \n u'a o o r~ |~ oo oo c> m 2
~rz <= z \Q Q
\fa =z =Q <=: ~fa Q
=Q <2 \fe <2
Test medium: Temnerature:
Purified water 37C + 0.5C
lime [n]
Rotaion speed: 100 rpm
FIG. 2
Us 8,309,124 B2
1
2
peak plasma drug concentrations at a pre-detemiined time, irrespective of whether a patient is in a fed or fasted state. Time controlled release formulations are known in the art that are able to deliver drug substances with a defined release 5 :ale aller a lag time during which no drug substance is released. Such a dosage form is disclosed in WO 02/072033. This dosage form is characterized by a coating containing a natural or synthetic gum that gels in the presence of aqueous media, The coating acts as a bather to the ingress of aqueous 10 media into an active-agent-containing core and thereby creating a lag time during which no drug substance is released. The gellable coating acts as a medium through which drug is released in a delayed or modified manner. It is stated that the lag time can be modulated by varying the coating weight. 15 'I`here are several problems with such an approach: First, release of the drug occurs by means of diffusion through the gelled coating. In the case ofdrugs that have a narrow absorption Window, or in the case of drugs adapted to treat a rela20 tively small affected area ofthe GI tract or colon, once the lag time has expired it is desirable to release the drug as rapidly as possible to ensure that all or substantially all of the drug released at the desired site. A slow diffusion ofthe drug is not appropriate in such cases. Further, by attempting to control 25 lag time by controlling the coating weight, the formulator's latitude is limited in this regard, because increasing coating weight adds additional cost to the dosage form, and it also adds to the size of the dosage form, which may make it difficult to swallow for cenain patient populations such as 30 minors and for the elderly or infinn. Still further, merely adjusting coat weight does not ensure that a coating is of a desired thickness at a particular site. It remains that ifthe core is not correctly positioned within a die of a press coating machine, despite having selected a particular coat weight, 35 part of the coating may be unintentionally thinner than desired, resulting in unforeseen premature release ofthe drug. The applicant has now surprisingly found that by carefully selecting the geometry of a core within its coating, it is possible to manipulate the coating thickness at specific points on 40 the tablet to ensure an appropriate coating thickness to produce tablets having a specifically tuned lag time. Funhermore, because one is able to increase thickness where it is needed in the coating, one can reduce coating material to allow use of the minimum amount necessary to achieve the 45 desired release characteristics, thus saving on cost of materials and also reducing the overall tablet size. Still further, the applicant has found that by selecting appropriate core and coating materials, one is able not only to accurately control the lag time, one is also to ensure that all, 50 or substantially all, of the drug substance upon expiry of the lag time is released rapidly and at the absorption site, or the locally affected site. Accordingly, in a first aspect of the present invention there is provided a tablet comprising a core containing an drug 55 substance, and a coating aroturd said core, the core being disposed within said coating such that the coating thickness about an axis (X-Y) (see FIG. 1) is thicker than the coating about an axis (A-B) (see FIG. 1) orthogonal to (X-Y), and wherein the thickness of the coating about the axis (X-Y) is 60 selected such that the coating is adapted to mpture upon immersion in an aqueous medium after a period of between about 2 to 6 hours. According to the present invention, the coating thickness aboutthc axis (X-Y)is thicker than the coating about die axis 65 (A-B). The ratio ofthe thickness ofdie coating about the axis (X-Y) to the thickness ofthe coating about the axis (A-B) may be from 2.2 to 2.611 .0 to 1.6.
DELAYED RELEASE TABLET WITH DEFINED CORE GEOMETRY

RELATED APPLICATIONS This application is a continuation ofU.S. Ser. No. 10/554, 538, filed on Jan. 16, 2007, which is a 35 U.S.C. 371 of PCT/IB2004/001693, filed on Apr. 23, 2004, which claims priority to GB Application No. 0309342.4, hled on Apr. 24, 2003, all of which are incorporated herein by reference in their entireties. This invention is concerned with a tablet comprising a core containing a drug substance and a coating that is applied to said core by means of compression-coating techniques. The tablet can contain all manner of drug substances, but is particularly suitable for administering those that are advantageously released only after a predetermined lag time after administration. The tablets are particularly suitable for administering lucocorticosteroids selected from prednisone, prednisolone or methylprednisolone. Research into the chronopharmacological field has demonstrated the importance of biological rhythms in drug therapy. Very often, optimal clinical outcomes cannot be achieved if a drug is released constantly after ingestion. This is particularly die case if symptoms of a disease display circadian variations. ln such cases, drug release should vary in a manner that is sympathetic to these variations in order that dnlg plasma concentrations are at an optimal therapeutic level only when required to treat symptoms ofa disease state. ln particular, if symptoms of a disease become apparent at night, or in the early hours upon Waking, the time when a patient must take its medication in order to affect the best clinical outcome requires detailed consideration. For example, most asthma attacks occur in the early hours of the morning, e.g. 4 am to 6 am. This is a result of complex circadian rhythms such as the secretion ofhydrocortisone and adrenaline. Ischaemic heart diseases occur most often during the night or in the early waking hours around breakfast time. Stiffness and pain associated with rheumatoid arthritis and osteoarthritis occur in the early waking hours, which is believed to be as a result of the secretion of IL-6 in the early hours of the moming, e.g. around 2 am to 4 am. With conventional immediate release dosage lonns, synchronization of drug administration with a nocturnal circadian rhythm responsible for the symptoms experienced by a patient would require a patient having to be disturbed from sleep to take a medicament during the early hours of the morning in order to achieve the most efficacious clinical outcome. Of course, this would be highly inconvenient for a patient. Accordingly, there remains a need to provide dosage forms that can be taken at a convenient hour before bedtime that will release an effective dose of a dmg substance only after a pre-determined lag time in order to synchronise peak plasma concentrations of dmg widr a particular circadian rhythm. Funhermore, particularly in relation to dwg substances that have a narrow absorption Window, or in the case of drug substances that are adapted to treat a local condition in the colon such as Crohn's disease, ulcerative colitis, IBS and IBD there is also a need to provide a dosage fonn that rapidly releases the drug substances after reaching the end of the lag time Still further, having regard to the varied life styles of patients, 111 order to reduce die inter- and intra-subject varianee in bioavailability there is a need to provide a dosage form that releases a drug with a reliable lag time, and to provide
US 8,309,124 B2
3
In another aspect ofthe invention there is provided a tablet comprising a core containing an drug substance and a coating around said core, the core being disposed within said coating such that me coating diickness about an axis (X-Y).is thicker than the coating about an axis (A-B) orthogonal to (X-Y), and the thickness of the coating about the axis (X-Y) is at least about 2.2 mm, particularly about 2.2 to 2.6 mm, more particularly about 2.35 to 2.45 nun. The thickness of the coating around or about the axis (A-B) is not critical for controlling the lag time. Accordingly, the formulator has some latitude in selecting its thickness. It should not be so thick as to render the Hnal tablet to large, yet on the other hand the coating should not be so thin that the coating is render weak and liable to crack under the slightest mechanical stress. Preferably, the thickness of the coating about the axis (A-B) is about l .0 to about 1.6 mm. The coating thickness either side ofthe core on the axis (A-B) may or may not be equal. For example, on a Hrst side of the core (A-core) the coating may have a thickness ofabout l .2 to l .6 min, more preferably 1.35 to 1.45 mm, whereas on the other side of the core (B-core) the thickness may be about 1.0 to 1.4 mm, more preferably 1.15 to 1.25 mm. Accordingly, in a particular embodiment of the present invention there is provided a tablet comprising a core containing an drug substance, and a coating, the core being disposed within the coating such that the coating has a thickness about an axis (X-Y) of at least about 2.2 mm, more particularly about 2.2 to about 2.6 mm, still more particularly 2.35 to 2.45 mm, and the thickness ofthe coating about an axis (A-B) orthogonal to (X-Y) is between 1.0 and 1.6 mm. More particularly, along the axis (A-B) on a Hrst side of the core (A-core) the thickness may be about 1.2 to 1.6 mm, more preferably 1.35 to 1.45 mm, and on a second side of the core (B-core) the thickness may be about 1.0 to 1.4 rmn, more preferably 1.15 to 1.25 mm. Tablets ofthe present invention are formed by compression coating methods as will be described in more detail herein below. Compression coated tablets are generally formed by placing a portion of a powdered coating material in a die and tamping the powder into a compact form using a punch. A core is then deposited onto the compacted coating material before the remainder of the coating material is introduced into the die and compression forces are applied to form the coated tablet. To ensure that the core is placed on the tamped coating material to ensure its correct geometry relative to the coating in the tinal tablet form, it is preferable to employ means for positioning the core in relation to the coating material in a die. Typically such means may be provided by a pin punch. A pin punch is a pturch that has a convex surface that contacts the coating material to leave a small depression or hollow in the tamped coating material. Thus, when the core is placed into the die on the tamped material, it sits in the depression or hollow and its correct geometry is assured in the final tablet form. The thickness ofthe coating along and about the axis of the direction of movement of the ptuich (the "(A-B)" axis referred to above) is determined by the amount of coating material added to the die and the compaction force applied to form the tablet. On the other hand, the thickness ofthe coating along and about the "(X-Y)" axis is determined by the size of the core, its po sition within die die and the diameter ofthe die. It will be apparent to the sldlled person diat there is a plurality of axes (X-Y) orthogonal to dle axis of movement of the punch (the "A-B" axis), which extend radially from the centre of the tablet to its circumlerence, and when the relerence is
axes.
5
4
made to the thickness of the coating about an axis X-XC reference is being made the thickness about any or all ofthese During the compression ofthe coating around the core, the coating material above and below the core (the material along and about the (A-B) axis) is relatively highly compacted and dense. On the other hand, the coating material disposed along and about the (X-Y) axis is subjected to lower compaction forces and is relatively less dense. Accordingly, the material about the (X-Y) axis is relatively porous and permissive towards the ingress of aqueous media. The rate of ingress of the aqueous medium through the coating along the direction of the X-Y axis is, in part, responsible for controlling the release of the dmg substance from the core. Once the aqueous medium contacts the core, the core reacts by swelling or effervescing thereby to break open the core generally along the direction of ingress of the aqueous media (i.e. the X-Y axis) to fem to essentially two hemispheres of coating material that may remain conjoined, which has an appearance of an opened clam shell. The reaction of the core material to the presence of the aqueous medium is likewise in part responsible for controlling the release of dmg substance from the
core.
25
10
15
20
30
35
40
45
50
55
60
65
The hardness ofthe tablet is preferably at least 60 Newtons, e.g. 60 to 80 Newtons, and more particularly 60 to 75 Newtons. Hardness may be measured according to a process described in The European Pharrnacopoeia 4, 2.9.8 at page 201. The test employs apparatus consisting of 2 opposing jaws, one ofwhich moves towards the other. The fiat surfaces of the jaws are perpendicular to the direction of movement. The cnushing surfaces of the jaws are flat and larger than the zone of contact with the tablet. The apparatus is calibrated using a system with a precision of one Newton. The tablet is placed between the jaws. For each measurement, the tablet is oriented in the same way with respect to the direction of the applied force. Measurements are carried out on 10 tablets. Results are expressed in terms of the mean, minimum and maximum values (in Newtons) of the force needed to crush the tablets. Tablets having a hardness within this range are mechanically robust to withstand forces generated in the stomach, panicularly in the presence offbod. Furthermore, the tablets are sufliciently porous about the (X-Y) plane of the tablet to permit ingress ofphysiological media to the core at an appropriate rate to ensure that the dnug substance is released within an appropriate lag time, e.g. within 2 to 6 hours. As stated above, it is a preferred aspect of the present invention that the tablets are adapted to release a drug substance from the core after a pre-determined lag time, as well as being adapted to release all, or substantially all, ofthe drug sub stance within a very short period oftime after the expiry of the lag time. This ensures that all, or substantially all, of the drug is released at the intended absorption site along the GI tract, or onto the affected site ofthe G1 tract ifthe condition to be treated is a local topical condition. It is preferred that the tablets ofthe present invention release all. or substantiallv A . , all ofa drug substance within about % hour to about 1 hour after the selected lag time. This aspect of the present invention is important for delivering drugs having a rather narrow absorption Window in the upper Gl tract, such as the glucocorticosteroids referred to above. ln such cases, the drug should be released before the tablet can pass into the bowel, where absorption of such drugs is poor. It is made particularly important if the tablet is intended to perform in the same manner independent of the ellects ofibod. It is well known that the rate at which a tablet will pass through the GI tract will vary depending on whether
US 8,309,124 B2
5 6
ester wax and the like; or non-fatty hydrophobic substances a patient is in a fed or fasted state. In the fasted state, a tablet such as calcium phosphate salts, e.g. dibasic calcium phoswill typically clear the stomach within about % hour and l phate. hour alter ingestion, and tliereafter lake a lurther 4 to 5 hours Preferably the coating contains a calcium phosphate salt, to clear the utmer GI tract dirough the ileosecal iunction. ln a fed state, a tablet may take as long as 4 hours to be cleared 5 glyceryl behenate, and polyvinyl pyrollidone, or mixtures thereof, and one or more adjuvants, diluents, lubricants or from the stomach, and a further 4 to 5 hours to clear the upper fillers. GI tract. Accordingly, if a tablet is to release of all, or subPreferred components in the coating are as follows, with stantially all, of its dwg into the upper GI tract irrespective of generally suitable percentage amounts expressed as percentthe fed state of a patient, it is preferable that the release the 10 age weight of the coating. drug aHer the lag time occurs within a time limit referred to in Polyvinyl pyrollidone (Povidone) is preferably present in the paragraph above. amounts of about 1 to 25% by W eight or the coating, more It should be understood that whereas it is desirable that no particularly 4 to 12%, e.g. 6 to 8%. drug substance is released during the lag time, some release Glyceryl behenate is an ester of glycerol and behenic acid may occur. However, any release ofdmg substance during the 15 (a C22 fatty acid). Glyceryl behenate may be present as its lag time should not exceed 10% of the total amount of drug mono-, di-, or tri-ester form, or a mixture thereof. Preferably substance in the core it has an HLB value of less than 5, more preferably approxi The coating employed in a tablet according to the present mately 2. It may be present in amounts of about 5 to 85% by invention is preferably formed of insoluble or poorly water weight of the coating, more panicularly from 10 to 70% by soluble hydrophobic material. ln use, the coating optimally 20 weight, and in certain preferred embodiments from 30 to acts merely as a barrier to the ingress of aqueous physiologi50%. Calcium phosphate salt may be the dibasic calcium phoscal media thereby providing a drug release lag time. For the phate dihydrate and may be present in an amount of about 10 reasons set fbnh above, optimally the tablet should have the to 90% by weight ofthe coating, preferably 20 to 80%, e.g. 40 minimum thickness possible consistent Wim the desired lag time. Accordingly, employing water insoluble or poorly, 25 to 75%. The coating may contain other common tablet excipients soluble hydrophobic coating materials, one is able to produce such as lubricants, colourants, binders, diluents, glidants and a coating that is relative recalcitrant to the ingress ofmoisture taste-masking agents or flavourants. and so long lag times can be achieved with relatively thin Examples of excipients include colourants such a ferric coatings. 30 oxide, e.g. yellow ferric oxide; lubricants such as magnesium Funher, in order to achieve the rapid release of drug substearate; and glidants such as silicon dioxide, e.g. colloidal stance after the lag time has expired, it is desirable that the silicon dioxide. Yellow ferric oxide may be used in amounts coating contains no, or sub stantially no, ingredients that swell of about 0.01 to 0.5% by weight based on the coating; magand gel agents to such an extent that the coating acts as a nesium stearate may be present in amounts of l to 20% by diffusion barrier to the release of drug substance. ln this 35 weight of the coating, more preferably 2 to 10%, e.g. 0.5 to regard, it is preferable that the coating contains no, or subl.0%; and colloidal silica may be used in amounts of 0.1 to stantially no, materials such as natural or synthetic gums that 20% by weight of the coating, preferably 1 to 10%, more modulate release of the drug substance through an intact preferably 0.25 to l.0%. swollen coating. Drug substance is released from the core as The core comprises in addition to a dmg substance, a a result of the physical rupturing of the coating and not as a 40 disintegrating agent or mixtures ofdisintcgrating agents used result ofthe dmg substance diffusing through a swollen coatin immediate release fonnulations and well know to persons ing material. That the mechanism of drug release is substanskilled in the an. The disintegrating agents useful in the exercise of the present invention may be materials that ettertially dependent on the physical splitting of the coating, and vesce and or swell in the presence of aqueous media thereby not on a dillusion process through a swellable and gellable coating, means that a wide range of drug substances can be 45 to provide a force necessary to mechanically disrupt the coating material. delivered from tablets according to the invention in a reliable Preferably a core contains, in addition to the drug suband reproducible manner. stance, cross-linked polyvinyl pyrollidone and croscarmelThe tablet coating may contain one or more water insoluble lose sodium. or poorly soluble hydrophobic excipients. Such excipients The following is a list of preferred core materials. The may be selected from any of the known hydrophobic cellulo- 50 amounts are expressed in terms of percentage by weight sic derivatives and polymers including alkylcellulose, e.g. based on the weight of the core. ethylcellulose, hydroxypropyl cellulose, hydroxypropylmCross-linked polyvinyl pyrollidone is described above and ethyl cellulose, carboxymethyl cellulose, and derivatives is useful as a disintegrating agent, and may be employed in the thereof; polymethacrylic polymers, polyvinyl acetate and cellulose acetate polymers; latty acids or their esters or salts; 55 core in the amounts disclosed in relation to the core. Croscamellose sodium is an internally cross-linked sodium long chain fatty alcohols; polyoxyethylene alkyl ethers; polycarboxymethyl cellulose (also known as Ac-Di-Sol) useful as oxyethylene stearates; sugar esters; lauroyl macrogol-32 a disintegrating agent. glyceryl, stearoyl macrogol-32 glyceryl, and the like. Disintegrating agents may be used in amounts of 5 to 30% Hydroxypropylmethyl cellulose materials are preferably selected from those low MW and low viscosity materials such 60 by weight based on the core. However, higher amounts of certain disintegrants can swell to form matrices that may as E-Type methocel, and 29-10 types as defined in the USP. modulate the release of the dmg substance. Accordingly, Other agents or excipients that provide hydrophobic qualparticularly when rapid release is required after the lag time it ity to coatings may be selected from any waxy substance is preferred that the disintegrants is employed in amounts of known for use as tablet excipients. Preferably they have a HLB value of less than 5, and more preferably about 2. 65 up to 10% by weight, e.g. about 5 to 10% by weight. The core may additionally comprise common tablet excipiSuitable hydrophobic agents include waxy substances such as ents such as those describw above in relation to the coating carnauba wax, parallin, microcrystalline wax, beeswax, cetyl
Us 8,309,124 B2
7 8
hydramine, donepezil, flecamide, lluoxetine, labetalol, material. Suitable excipients include lubricants, diluents and Methadone, metoprolol, mianserin, nortripyline, Hllers, including but not limited to lactose (for example the ondansetron, oxprenolol, oxycodone, paroxetine, perhehexymono-hydrate), ferric oxide, magnesium stearates and colloilene, pethidine, promethazine, risperdone, thioridazine, ticlodal silica. Lactose monohydrate is a disaecharide consisting of one 5 pidine, timolol, trimipramine, venlafaxine, paracetamol, alprazolam, amiodarone, budesonide, buprenorphine, busglucose and one galactose moiety. It may act as a filler or pirone, Calcium Channel Blockers, earbamazepine, diluent in the tablets of the present invention. It may be cisapride, clarithromycin, clonazepam, cocaine, cortisol, present in a range of about l() to 90%, preferably from 20 to cyclosporine, dexamethasone, erythromycin, fentanyl, keto80%, and certain preferred embodiments from 65 to 70%. As stated above, it is an important aspect of the present 10 conazole, losartan, miconazole, midazolam, quinidine, sertraline, statins, tacrolimus, tamoxifen, 'l`CAs, triamzolam, invention that core is correctly located within the coating to zolpidem, or mixwes thereof. ensure that a tablet has the appropriate coating thickness. In Additional examples of drug classes and drugs that can be this way, lag times will be reliable and reproducible, and employed in tablets of the present invention include: intra-subj ect and inter-subject variance in bioavailability can be avoided. It is advantageous to have a robust in process 15 antihistamines (e.g., azatadine maleate, brompheniramine maleate, carbinoxamine maleate, chlorpheniramine maleate, control to ensure that tablets in a batch contain cores having dexchlorpheniramine maleate, diphenhydramine hydrochlothe appropriate geometry in relation to the coating. Controls ride, doxylamine succinate, methdilazine hydrochloride, can be laborious in that they require an operator to remove promethazine, trimeprazine tartrate, tripelennamine citrate, random samples from a batch and to cut them open to physically inspect the quality of the core (i.e. whether it is intact, 20 tripelennamine hydrochloride and triprolidine hydrochloride); and whether it is correctly located). Furthermore, if a signifiantibiotics (e.g., penicillin V potassium, cloxacillin sodium, cant number of tablets from the sample fail, a complete batch dicloxacillin sodium, nafcillin sodium, oxacillin sodium, caroftablets may be wasted. Applicant has found that ifone adds benicillin indanyl sodium, oxytetracycline hydrochloride, to the core a strong colourant such as iron oxide, such that the core visibly contrasts with the coating when as strong light is 25 tetracycline hydrochloride, clindamycin phosphate, clindamycin hydrochloride, clindamycin palmitate HCL, lincomyshone on the tablet, it is possible for any faults in the position ein HCL, novobiocin sodium, nifrofurantoin sodium, metronor integrity of the core to be picked up automatically by a idazole hydrochloride); antituberculosis agents (e.g., camera appropriately located adj acent a tabletting machine to isoniazid); inspect tablets as they are ej ected therefrom. ln this way, if a faulty tablet is identified it is possible to halt production and 30 cholinergic agents (e.g., ambenonium chloride, bethanecol correct any problems in the manufacturing process quickly, chloride, neostigmine bromide, pyridostigmine bromide); thereby potentially avoiding wastage ofbatch quantities of antimuscarinics (e.g., anisotropine methylbromide, clidtablets. inium bromide, dicyclomine hydrochloride, glyoopyrrolate, hexocyclium methylsulfate, homatropine methylbromide, Whereas colourants contained in the core are useful for this purpose, equivalent solutions are also possible. For example, 35 hyoscyamine sulfate, methantheline bromide, hyoscine hydrobromide, oxyphenonium bromide, propantheline broinstead of a colourant, one can include a material that is mide, tridihexethyl chloride); opaque to x-rays, such as barium sulphate. If an x-ray imager sympathomimetics (e.g., bitolterol mesylate, ephedrine, is then coupled to a tablet machine, the core will contrast with ephedrine hydrochloride, ephedrine sulphate, orciprenaline the coating material and the x-ray imager will pick up any faults in the positioning or integrity of the core in a similar 40 sulphate, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ritodrine hydrochloride, salbutamol sulfashion. phate, terbutaline sulphate); The amount ofdrug substance employed in tablets of the sympatholytic agents (e.g., phenoxybenzamine hydrochlopresent invention will depend on the panicular drug subride); miscellaneous autonomic drugs (e.g., nicotine); stance used, the condition of the patient and the nature and severity of the condition to be treated. A typical drug loading 45 iron preparations (e.g., ferrous gluconate, ferrous sulphate); haemostatics (e.g., aminocaproic acid); might be from l to 50% by weight of the core. cardiac drugs (e.g., acebutolol hydrochloride, disopyramide As stated above a Wide variety of drug substances may be phosphate, llecamide acetate, procainamide hydrochloride, employed in the present invention. Drugs for treating condipropranolol hydrochloride, quinidine gluconate, timolol tions the symptoms of which result from nocturnal circadian rhythms are particularly suitable. Accordingly, drugs for 50 maleate, tocainide hydrochloride, verapamil hydrochloride); antihypertensive agents (e.g., captopril, clonidine hydrochlotreating incontinence, sleep disorders, apnoea, asthma, epiride, hydralazine hydrochloride, mecamylamine hydrochlolepsy, bronchitis, parkinsonism, rheumatoid arthritis, allergic ride, mctoprolol tartrate); vasodilators (e.g., papaverine rl1in.itis and ischaemic heart diseases, cluster and migraine hydrochloride); headache, congestive head failure, and depression are particularly suitable for use in tablets according to the present 55 non-steroidal anti-inflammatory agents (e.g., choline salicylate, ibuprofen, ketoprofen, magnesium salicylate, meclofeinvention. Further, drug substances that are metabolized by namate sodium, naproxen sodium, tolmetin sodium); cytochrome P450 are also particularly suitable, they opiate agonists (e.g., codeine hydrochloride, codeine phosincludez phate, codeine sulphate, dextromoramide tartrate, hydrocAmitriptyline, caffeine, clomipramine, clozapine, fluvoxamine, haloperidol, imipramine, mexilitine, oestradiol, olan- 60 odone bitartrate, hydromorphone hydrochloride, pethidine hydrochloride, methadone hydrochloride, morphine sulzepine, paracetamol, propranolol, tacrine, theophylline, Warphate, morphine acetate, morphine lactate, morphine meconfarin, Bupropion, Cyclophosphamide, Celecoxib, ate, morphine nitrate, morphine monobasic phosphate, morDiclofenac, Flubiprofen, Ibuprofen, glimepirideindome, thaphine tartrate, morphine valerate, morphine hydrobromide, cin, naproxen, phenyloin, piroxicam, tenoxicam, citalopram, diazepam, lansoprazole, omeprazole, pantoprozole, pro- 65 morphine hydrochloride, propoxyphene hydrochloride); anticonvulsants (e.g., phenobarbital sodium, phenyloin panolol, topiramate, Aipranolol, chlorpromazine, clomisodium, troxidone, ethosuximide, valproate sodium); pramine, codeine, Desipramine, dextromethorphan, diphen-
US 8,309,124 B2
9
tranquilizers (e.g., acetophenazine maleate, chlorpromazine hydrochloride, liuphenazine hydrochloride, prochlorperazine edisylate, promethazine hydrochloride, thioridazine hydrochloride, triiiuoroperazine hydrochloride, lidiium citrate, molindone hydrochloride, thiothixinc hydrochloride); chemotherapeutic agents (e.g., doxorubicin, cisplatin, floxuridine, methotrexate, combinations thereof);
linirl lnwerino mmnteu (ao oemHlrn7il nlnfihrme HNTG10
10
acetate, 21 -succinate sodium salt, 21 -stearoylglycolate, 21-in-sulphobenzoate sodium salt, and its trimethylacetate. Methylprednisolone, as used above refers to the compound or and its salts and derivatives thereofincluding its 21 acetate,
2 1 -phosphate disodium salt, 2 1 -succinate sodium salt, and its
CoA reductase inhibitors, such as for example, atorvastatin, cerivastatin, Huvastatin, lovastatin, pravastatin, simvastatin); H.sub.2-antagonists (e.g., cimetidine, famotidine, nizatidinc, ranitidine HCI); anti-coagulant and anti-platelet agents (e.g., warfarin, cipyridamole, ticlopidine); bronchodilators (e.g., albuterol, isoproterenol, metaproterenol, terbutaline); stimulants (e.g., benzamphetamine hydrochloride, dextroarnphetamine sulphate, dextroamphetarnine phosphate, diethylpropion hydrochloride, fenfluramine hydrochloride, methamphetamine hydrochloride, methylphenidate hydrochloride, phendimetrazine tartrate, phenmetrazine hydrochloride, caffeine citrate); barbiturates (e.g., amylobarbital sodium, butabarmtai sodium, secobarbital sodium); sedatives (eg., hydroxyzine hydrochloride, methprylon); expectorants (e.g., potassium iodide); antiemetics (e.g., benzaquinamide hydrochloride, metoclopropamide hydrochloride, trimethobenzamide hydrochloride); gastro-intestinal drugs (e.g., ranitidine hydrochloride); heavy metal antagonists (e.g., penicillamine, penicillamine hydrochlodde); antithyroid agents (e.g., methimazole); genitourinary smooth muscle relaxants (e.g., flavoxate hydrochloride, oxybutynin hydrochloride); Vitamins (e.g., thiamine hydrochloride, ascorbic acid); unclassified agents (e.g., amantadine hydrochloride, colchicine, etidronate disodium, leucovorin calcium, methylene blue, potassium chloride, pralidoxime chloride. steroids, particularly glucocorticoids (e.g., prednisolone, methylprednisolone, prednisone, eortisone, hydrocortisone, methylprednisolone, betamethasone, dexamethasone, triamcinolone). Notwithstanding the general applicability of the tablets in relation to a wide range ofdrug substances, the present invention is particularly suited to delivery of the glucocorticosteroids aforementioned, and particularly prednisone, prednisolone and methylprednisolone. These steroids are useful in the treatment La, of rheumatoid arthritis and joint pain. As already stated, the symptoms of these conditions appear according to a circadian rhythm and with great predictability during the early hours of the morning. Accordingly, the glucocorticosteroids, and in particular prednisone are eminently suited for delivery [rom tablets according to this invention not only because of their narrow absorption window, but also because a tablet may be administered in the evening before bedtime anytime around 8 pm until midnight, e.g. around 10-12 at night, to deliver maximum plasma concentration of the drug substance before maximum secretion ofJL-6 (which occur around 2 am to 4 am), thereby effectively addressing the underlying causes of the morning symptoms. ln this way, these symptoms are more effectively treated. As used above, prednisone refers to the compound and its salts or derivatives diereof, including prednisone 21 acetate. As used above, prednisolone refers to the compound and its salts or derivatives including the 21 -acetate, its 21-tert-butyl
15
20
25
30
35
40
45
50
55
60
65
acetonatc Typically a core may contain about 0.1 to 50% by weight, more particularly l to 20%, still more particularly l to 10% by weight ofsteroid based on the total Weight of the core. In the case ofprednisone, it may be employed in amounts to provide a total weight per unit dosage form of l or 5 mg, to offer convenience and flexibility ofdosing, although dosage forms containing larger or smaller amounts of drug substance could be employed if desired. Particularly preferred tablets according to the invention comprising in the core a glucocorticosteroid selected from the group consisting of prednisone, prednisolone and methylprednislone, and cross-linked polyvinyl pyrollidone, crosslinked sodium carboxymethyl cellulose, and one or more adjuvants diluents, lubricants or filler materials as hereinabove described. Preferably the coating comprises a calcium phosphate salt, glyceryl behenate, cross-linked polyvinyl pyrollidone and one or more adjuvants, diluents, lubricants or nuer materials as hereinabove described. The composition ofone particularly preferred embodiment of the invention is: Core of 5 mg Prednisone Tablet: Prednisone 8.33% Lactose rnonohydrate 64.47% Povidone 6.67% Croscannellose sodium 18.33% Red terric oxide 0.5% Magnesium stearate Vegetable origin 1.0% Colloidal silicon dioxide 0.5% Coating Dibasic calcium phosphate dihydrate 50% Glyceryl behenate 40% Povidone 8.40% Yellow ferric oxide 0.1% Magnesium stearate Vegetable origin 1.0% Colloidal silicon dioxide 0.5% Another preferred embodiment is as follows: Core of 1 mg Prednisone Tablet: Prednisone 1.67% Lactose monohydrate 71 . 1 3% Povidone 6.67% Croscarmellose sodium 18.33% Red fenic oxide 0.5% Magnesium stearate Vegetable origin 1.0% Colloidal silicon dioxide 0.5% Coating Dibasic calcium phosphate dihydrate 50% Glyceryl behenate 40% Povidone 8.40% Yellow ierric oxide 0.1% Magnesium stearate Vegetable origin 1.0% Colloidal silicon dioxide 0.5% It is surprising tl1at the tablets containing the glucocorticosteroids display such rapid release given that the rate of release relies to some extent on the wetting of the core, and these steroids are rather hydrophobic in nature. The tablets described above are press-coated tablets comprising a core and a coating covering said core. However, variants of mis basic construction are within the ambit ofthe present invention. Thus, the press-coating may be further coated with an outer coating that may be functional and/or aesthetic in its design. For example, functional coatings may
US 8,309,124 B2
11
include the addition an immediate release coating containing a dwg substances that may be the same or different to the drug substance contained in the core. In this manner, the tablet can affect a pulsatile release that is of use in treating symptoms based on circadian rhythms, such as sleep disorders. In this regard one can employ sedative hypnotics in such dosage forms, for example those drug substances mentioned described in U.S. Pat. No. 6,485,746. Pulsatile release dosage forms may also find general applicability with a wide range of active substances for the treatment ofa wide range of indications to provide patients with a more convenient dosage schedule. For example, pulsatile release can provide an alternative to multiple administrations of immediate release fomis. Functional coatings also include enteric coatings covering the press-coating. Enteric coated forms may be of use in treating local conditions inthe bowel such as Crohn's disease, ulcerative colitis, IBS and IBD. In this embodiment, the enteric coating would prevent release of any drug before the tablet enters the bowel Aesthetic coatings include taste masking coatings and coloured coatings as a generally well known in the an. It is well known in the art that food can change the bioavailability of a drug, Food can alter the bioavailability of a drug by various means such as delaying gastric emptying, changes in gastrointestinal pH, changes in luminal metabolism, and physical and chemical reactions of food items with a dosage form or drug substance. This change in bioavailability as a consequence of food intake is often referred to as a "food effect", Food effects are quite common in modifiedrelease dosage forms, and also for drugs that have either poor solubility or poor permeability or both (BCS Class ll, Ill, and
12
from 10 pm to midnight, may be in a variety offed states, it is even more advantageous that Tmax should be independent of food intake. Medicaments that can have a pre-detemiined lag time, and which release drug substance after this lag time in a manner that provides a Tmax independent ofconsiderations of the fed or fasted state of a patient are of potentially great benefit, not only in relation to the glucocorticosteroids and the treatment of arthritis, but for other active substances that are advantageously delivered in synchronicity with a circadian rhythm, or even in relation to drug substances whose emcacy depends on their ability to be delivered accurately to a particular absorption site, or a locally diseased site along the GI tract and bowel. Such medicaments are provided by the present invention. Currently, there are no bioavailability or bioequivalence regulatory guidelines available for Tmax However, the Guidance For lndustry "Food Effect Bioavailability and Fed Bioequivalence Studies", US Department of Health (CDER) December 2002 suggests that any difference in Tmax should not be clinicallv relevant. Whether such a difference will be clinically relevant will depend on the drug delivered and the particular indication. Applicant has found that in respect of formulations ofthe present invention the effect of food on the median value of TM, is a difference of only about +/-20%, more particularly +/-10% Still further, applicant has found medicaments containing drug substances exhibiting no significant effect of food with respect to bioavailability of the dmg substance in terms of
and AUC.
10
15
20
25
30 Cm
IV).
The applicant has surprisingly found that a tablet that is adapted to release all, or substantially all, ofa dmg contained therein within a time (Tmg) ofbetwecn 2 and 6 hours (median time) after administration. Furthermore, the applicant has surprisingly developed a tablet adapted to release a drug substance after a lag time that can deliver a drug to a patient, which upon absorption the peak dmg concentration Cmax will be reached in a time Tmzut that is independent ol` a patient's food intake. Tmax is a term Well known in the art that refers to the time elapsed between drug administration and the maximum
plasma concentration Cm is reached. Cmax is also an art
35
40
45
recognized term that relates to the peak plasma concentration of a drug. Tmax is an important parameter particularly in relation to medicaments that are intended to be taken at a time convenicnt for a patient, but which release drug substances after a lag time in ordcr to synchronise drug release with a circadian rhythm, and in particular a nocturnal circadian rhythm. By way of example, the glucocorticosteroids, referred to above, e.g. prednisone, are useful in the treatment of i.a. arthritic conditions such as rheumatoid arthritis and osteoarthritis. Debilitating symptoms are often experienced by a patient upon waking. Current therapy requires a patient to take Decortin upon waking. However, this is not the most efficacious way of treating the symptoms, as they are believed to be associated with the secretion oflL-6, which occurs during the early morning hours, eg. from about 2 to 4 am.A mcdicament that can reach Cm that is coincident with or anticipates the release of IL-6 is potentially of greater benefit to a patient. Furthemiore, given the varied lifestyles oi' individuals, patients taking medicament between 8 pm and bedtime, e.g.
50
55
60
65
The "food effect" as it relates to the bioavailability ofdrug substances is a well documented phenomenon in relation to dwg delivery that describes the variance in uptake of a drug substance by patients depending upon whether the patients are in fed or fasted states. The presence or absence of a food effect may be quantified by making Area under the Curve (AUC) andor Cmax measurements according to methods Well known in the art. Typically AUC measurements and Cmax measurements are made by taking timed biological fluid samples and plotting the serum concentration of drug substance against time. The values obtained represent a number ofvalues taken from subjects across a patient population and are therefore expressed as mean values expressed over the entire patient population. By comparing the mean AUC and/ or Cmax values, one can determine whether a drug substance experiences a food effect. Food effect studies may be conveniently carried out on an adequate number of healthy volunteers, the number being sufficient to generate sufficient data for appropriate statistical assessment to be made. Preferably the number of subjects should not be less than 12. To study the effect of food on the bioavailability of a drug substance one may use any conventional study design known in the art, for example a randomised; balanced single-dose, two-treatment, two-period, two-sequence crossover design. Analysis may be carried outusing any ofdre programs known in the art such as SAS PROC GLM, software from the SAS institute, Cary N.C. ln quantitative terms, a drug substance may be said to exhibit no food effect ifa 90% conhdence interval (Cl) for the ratio of means (population geometric means based on log transfonned data) of fed and fasted treatments fall within the interval of0.8 to 1.25 for AUC and/or 0.7 to 1.43 for Cmax' Accordingly, the present invention provides in another of its aspects a tablet as defined herein above displaying a ratio AUC led/lasted alter single dosing of 0.8 to 1.25 or the ratio Cmax lewtasted after single dosing of 0.7 to 1.43.
Us 8,309,124 B2
13
A "fed" subject conveniently may be considered as a subject that has fasted for at least 10 hours before receiving a standard FDA recognised high fat meal. The medicament may then be administered with water shortly after completion ofthe meal, e.g. within 5 minutes thereof. Preferably no food should be taken for a period of eg. 4 hours after receiving medicarnent although small quantities of water may be permitted alter, e.g. 2 hours after receiving the medicament. A "fastw" subject conveniently may receive rnedicament with water after at least 10 hours fasting. Thereafter, no food may be taken for a period of, e.g. 4 hours although small quantities of water may be taken after, e.g. 2 hours after receiving medicament. A standard FDA high fat meal as referred to hereinabove may comprise any meal that would be expected to provide maximal perturbation due to the presence of food in the Gl tract. Said high fat meal typically may comprise 50% of its caloric value in fat. A representative example may be 2 eggs fried in butter, 2 strips of bacon, 2 slices toast with butter, 4 ounces tiied potato, and 8 ounces milk. By application of the teachings of the present invention tablets may be provided that display reduced variability in resumption/bioavailability levels achieved both for individual patients receiving a drug as well as between individu-
14
of the coating material as a result of centrifugal force. Subsequent compression to form the tablet may be adjusted to give tablets ofrequisite hardness. Prelerably, this compression force is 400 kg, although this may be adjusted by +/-30% 5 in order to give tablets of the required hardness. The amount of coating material fed into the die can be precisely defined having regard to the density of the coating material to ensure after compression that the tablet is formed with the required coating thickness about the (A-B) axis; and 10 the dimensions of the die is selected to provide the diickness about die X-Y axis. Should it be necessary to change the thickness of the coating, die of appropriate internal dimensions may be placed in the rotating platform, and the amount ol" coating material ted into the die may be adjusted accord15 ingly. Suitable rotary tablet machines having high process speeds are known in the art and need no further discussion here. Cores may likewise be fonned using a conventional rotary tablet machine. Cores are preferably compres sed under com20 pression forces suiticient to provide cores having a hardness of about 60 Newtons at least, e.g. 50 to 70 Newtons. Cores having hardness in this range give desired release characteristics. lf desired, the cores can be formed at the same time as the press coated tablets are produced. In such case, one might 25 employ a Manesty Dry Cota. Such a press consists of two als. The tablets of the present invention may be packaged in a side-by-side and inter-connected presses where the core is variety of ways. Generally an article for distribution includes made on one press before being mechanically transferred to a container for holding the tablets. Suitable containers are the other press for compression coating. Such equipment and well known to persons skilled in the art and include materials techniques for making tablets using such equipment are such as bottles, foil packs and the like. In addition, the con- 30 l<nownin the art and nomore needs tobe said ahmft this here. tainer will have a label and an insert that describes the con~ Cores are nreferablv formed according to wet Q granulation ./ U tents ofthe container and any appropriate warnings or instructechniques generally known in the art. ln a typical procedure, tions for use. It is an advantage of the present invention that core materials are sievw and blended. Granulating fluid, typithe insert and/or label may contain instructions that the tablet cally water is then added to the blend and the mixture is may be taken with or without food, or may be absent a 35 homogenized to form a granulate, which is then sprayed dried warning or instmction that the tablet should be taken only or dried on a fluid bed drier to obtain a granulate with requisite with food or only without food. residual moisture. Preferably the residual moisture content is The invention provides in another aspect, a method of from about 0.4 to 2.0% by weight. The granulate is then sized forming tablets as herein above described. The tablets may be by passing it through screens of desired aperture. At this formed on conventional press coating equipment. Typically 40 stage, any adjuvants are sized and added to the granulate to such equipment is composed ofa series ofdie are arranged on form the core composition suitable for compression. The a rotating platform. The die are removably mounted in the sldlled person will appreciate mat a coating composition can platform such that dilierently sized die may be employed as be formed in an analogous manner. The skilled person will appropriate. Each die is hollow to receive a lower punch. The also appreciate that granulates may be obtained having a punch is positioned within the die such that the upper surface 45 range of particle sizes. It is preferred that the coating granuof the punch and the inner surface of the die define a volume late has a fine fraction that is less than 30%. By "fine fraction" for receiving a precise amount coating material. Once loaded, is meant granulate having particle size of up to about 63 the platform is rotated until the die is positioned under an microns. upper punch. The upper punch is then urged down onto the Preferred features for the second and subsequent aspects ot coating material under a defined compression force and the 50 the invention may be as for the first aspect mutatis mutandis. coating material is pre-compressed or tamped between the FIG. 1: is a representation of a tablet in cross section upper and lower punch. A pre-formed core is then fed into die showing the coating and core and the axes (A-B) and (X-Y). to rest on the tamped coating. Conventional press coating FIG. 2: Shows an in-vitro dissolution profile of the dosage apparatus may be equipped with centering devices that enable form of Example 2. cores to be positioned both vertically and radially. This might 55 There now follows a series of examples that serve to illusbe achieved by a tamping process, whereby an initial amount trate the invention. of coating material is placed in a die and is tamped with a EXAMPLE 1 shaped punch, such as a pin punch, that leaves an indentation in the coating material in which to receive a core. Thereaher, Prepaiation of a Prednisone-Containing Tablet in a second filling operation, a precise amount of coating 60 material is fed into the die to cover the core, and an upper The active core was prepared for the press coated system as punch compresses the coating material with a defined comfollows. The composition of the core is detailed in Table l. paction force to form tablets according to the present invenLactose monohydrate (Lactose Pu1vis.H2O, Danone, tion The compression force applied during the tamping process 65 France and Lactose Fast Flo NF 316, Foremost Ing. Group is relatively light and is just suilicient to provide a bed of .USA) is a filling agent with interesting technical and funccoating material to receive the core and to prevent movement tional properties. Lactose Pulvis.H2O is used in a blend pre-
US 8,309,124 B2
15 16
200 and magnesium stearate were manually sieved using a pared by wet granulation and Lactose Fast Flo is used in a screen, with 1.0 nun apemlres. Half of the dry granuiate was blend prepared for direct compression. Microcrystalline cellulose (Avicel pH 101, FMC International, Ireland) is used put in a Niro-Fielder PMA 25~liter mixing granulator, lblas an insoluble diluent for direct compression. Polyvinyl pyrlowed by Aerosil 200 and then by the other half of the dry rolidone (Plasdone K29-32, ISP Technology, USA) is a 5 granulate. The ingredients were mixed for 2 min at impeller granulating agent, soluble in water, which has the ability of speed 250 rpm. Finally, magnesium stearate was added and binding the powder particles. Croscarmellose sodium (Acmixing was continued for 2 min at impeller speed 250 rpm. Di-Sol, FMC Corporation, USA) is used in the iorrnulation The coating blend was prepared according to the process as a super disintegrant. As the external phase, magnesium described below. Batch size for the balher blend was 13 kg. stearate (Merck, Switzerland) was added as a lubricant and io Weighed amounts of Emcompress, Compritol 888 AIO, silicon dioxide (Aerosil 200, Degussa AG, Germany) in Lactose pulvis.H20, Plasdone K29-32 and SicovitYelorder to improve flow properties of the granular powder. low 10 E 172 were manually sieved with a screen having 0.710 mm apertures. They were placed in a Niro-Fielder TABLE 1 PMA 65-liter mixing granulator. Then, the components were 15 homogeneously mixed for 6 min, at impeller speed 200 rpm, Content (mgjtabiet) Ingredients without chopper. Subsequently, the granulating solution (pu5.00 Prednisone rified water, 8. 1 2% ofthe weight of the dry blend) was added 39.10 Lactose (hictose Pulvis H20 NF 31 6) within 2 min at impeller speed 200 rpm and chopper speed 4.00 Polyvinyl pyrrolidonc (Plasdone K29~32) 1500 rpm using a nozzle 4.9 (spraying rate of 520 g/min). Sodium caxboxymethyl cellulose (Ac-Di-Sol ) 11.00 20 0.60 Mixing was continued for homogenisation and massing for l Magnesium stearate 0.30 Silicxm dioxide (Aerosil 200) min at impeller speed 400 rpm and chopper speed 3000 rpm. The mixed wet granulate was then dried in a Niro-Fielder 60.00 Total TSG 2 Huidised air bed dryer. The inlet temperature was maintained at 45 C. during drying. The drying lasted 33 min The coating of the prednisone press coated tablet is of a 25 to have residual moisture less than 2.5%. The yielded dry hydrophobic, W ater insoluble nature. This barrier is mainly granulate was calibrated in a Frewitt MGI 205 granulator composed of dibasic calcium phosphate (Emcompress, using a screen having 0.8 mm apertures for 4 min at speed 244 Mendell, USA) and glyceryl behenate (Compritol 88 SATO, osc/min (graduation 7). Appropriate amounts of Aerosil Gattefoss, France). Polyvinylpyrrolidonc (Plasdone K29200 and magnesium stearate were manually sieved using a 32) is a granulating agent, soluble in Water, which has the 30 screen with 1.0 mm apertures. ability ofbinding the powder particles. Yellow lerric oxide Half of the dry granulate was put in a Niro-Fielder PMA (SicovitYellow 10, BASF, Germany) was added as a dye. A 65-liter, followed by Aerosil 200 and then by the other half detailed composition of this barrier blend is given in table 2. of the dry granulate. The ingredients were mixed for 2 min at impeller speed 200 rpm, without chopper. Finally, magne35 TABLE 2 sium stearate was added and mixing was continued for 2 more minutes at impeller speed 200 rpm, without chopper. Comnosition of The coating 440 mg of coating blend was press coated on a core to provide press coated tablets (9 mm diameter). 305 mg of Content (%) Ingredients coating blend was press coated on a core to provide press 50.00 Dibasic calcium phosphate (Emcompress ) 40 coated tablets (8 rrnn diameter). These different press coat40.00 Glyccryl Behenatc (Compritol 888 ATO) ings were done utilising a Kilian RUD tahletting machine. 8.40 Polyvinylpyrrolidone (Plasclonc K29-32) First and second loadinghoppers are filled up with the coating 0.10 Yellow Fcrric Oxide (Sicovit yellow 10 E 172) 0.50 Silicon dioxide (Aerosil 200) granulate. Between the two loading hoppers, the machine is 1.00 Magnesium steaxate equipped with a transfer system adapted to feed the cores. For 45 each tablet, tl1e first loading hopper supplies with about half 100.00 Tomi of the quantity to be applied to the core. Then, the feeding svsfem provides :md positions a core centred the--~die. Suh'J""-. r'.' ~--~ """r'""'~ - ~~-~ - -~--~-- in --- ~ The required amounts ofprednisone, Ac -Di-Sol, Lactose sequently, the second loading hopper supplies with the other Pulvis H2O, Plasdone K29-32 were weighed and manuhalfofthe quantity to be applied to the core. The compression ally sieved with a screen having 0.710 mm apertures. The 50 step then occurs. components were homogeneously mixed in a Niro-Fielder PMA 25-liter mixing granulator for 6 min at impellcr speed TABLE 3 250 rpm without chopper. A prednisone assay was perfonned on this premix. Subsequently, the grarrulating solution (puriEquipment irrmlernented for the manufacturing process hed water, 25.47% of the weight of the dry blend) was added 55 Equipment Brand name/Type Marrufacturer/Supplier Within 4 min at irnpeller speed 250 rpm and chopper speed 1500 rpm, using a nozzle H1/4VV-95015 (spraying rate of Aromatic-Fielder AG, Mixing granulator Nlro~Fielder PMA Bubendorf, Switzerland 25/65 litres 250 g/min). Mixing was continued for homogenisation and Fluidised air bed Glatt WSG5 Maschinen und apparatebau AG, massing of the wet mass for 3 min at impeller speed 500 rpm Pratteln, Switzerland dryer 60 and chopper speed 3000 rpm. Fluidised air bed Niro-Fielder TSG 2 Aromatic-Fielder AG, The mixed wet granulate was then dried in a Glatt WSG5 Bubendorf, Switzerland dryer Frewitt MGI 205 Frewitt SA, Granges-Pacot, Granulator Huidised air bed drier. The inlet temperature was maintained Switzerland at 45 C. during drying. The drying lasted 20 min to get a Mettler Toledo AG, Greifensee, Infrared moisture Mettler PE 360 granulate with a residual moisture less than 2 .5%. The yielded Switzerland analyser Moisture Analyzer dry granulate was calibrated in a Frewitt MGI 205 granulator 65 Multilayer tablet Hata HT-AP55LS~ Elisabeth-Carbide, Antwerp, Belgirnn press U/3L using a screen with 0.8 mm apertures for 3 min at speed 244 osc/min (graduation 7). Appropriate amounts of Aerosil
US 8,309,124 B2
17
TABLE 3-continued
Eauinment imnlemented for the manufacturinfl nrocess
Ecnuiumelxt
18
formulation was fully bioequivalent with a Cmax of 97% and relative bioavailability of 101% (AUCO-fnf1iy) In the fed state, the median lag time was 4 hours. Cmax was 105% compared to Decortin, and relative bioavailability
5
Brand name/Type
Manufacturer/Supplier Kilian & Co GmbH, Cologne Germany
(AUCO-infirzity) was 113%.
DW coating tablet Kilian RUD press
Compared to the formulation in the semi-fasted state, the formulation in the fed state was 108% on C/nax and 112% on
A1ICO_i,,/ U,
EXAMPI~ 2
In Vitro Dissolution Prolile The in vitro dissolution profile ofa tablet containing a 5 mg loading of prednisone prepared according to the method of Example 1 was determined using USP dissolution apparatus No. 2 (paddles) and stationary baskets and applying a stirring rate of 100 rpm, The dissolution medium was purified water, with a volume of 500 ml. After 4 hours no dwg substance release is observed. However, within 4.5 hours there is approximately 80% release and by 5 hours 100% release of the drug substance (see FIG. 2), EXAMPLE 3 A study was carried out to determine the effect of food on the bioavailability of a 5 mg prednisone tablet described above. The study did not compare the tablet in the fed and fasted state. Rather, the study was adjusted to take into account the chrono-pharmacoldnetics of prednisone and the fact that it is to be administered in the evening, e.g. about 8 pm, which is required in order that the blood plasma levels will peak before secretion of IL-6 to improve the eilicacy of the treatment. Thus the study was designed to compare die tablet during real time administration and with likely food intake scenarios at this time. It was considered unreasonable that at 8 pm a subject would be approximately 8 hours fasted. Accordingly, the following food intdce scenarios were tested: a) To simulate a fasted state at 8 pm in the evening, a light meal was given 2% hours before administration that contained a limited number of calories (i.e. 22% of total daily calories and with a limited lat Content of 15.5 g) and being devoid of any slowly digestible nutrients. This is called the semi-fasted" state. The composition of this meal consisted ofbrown bread, margarine, cheese spread, an apple (sldn removed) and fmit cocktail in symp. b) Fed state is simulated by giving a higher fat meal % hour before dosing containing 35% of the daily intake of calories and 26 g of fat. An assumption made was that in the ca se ofthe semi-fa sted state, after 2% hours the stomach was already emptied, or substantially emptiw offood, The composition of the high fat meal was pasta with spaghetti sauce, soup and vegetables, Applejuice, lce cream and
ss
10
These results demonstrate that formulations of the present invention display excellent bioavailability With no significant effect of food. The invention claimed is 1. A method of administering a glucocorticosteroid active substance selected from prednisone, prednisolone, and methylprednisolone to a patient in need thereof comprising administering to the patient a dosage form comprising a core and a coating surrounding the core, wherein the core comprises the glucocorticosteroid active substance and funher comprises at least one disintegrating agent that, upon exposure to aqueous media, provides a force to rupture the coating, wherein the coating comprises at least one insoluble or poorly water so]luble hydrophobic material such that the glucocorticc>steroid active substance is released from the core as a result ofthe rupturing ofthe coating and not as a res;ult of the glucocorticosteroid active substance diifusing through the coating, provided that the coating doe;s not include an insoluble or poorly water soluble hy'drophobic material that is a polymer, and wherein the coating ruptures upon immersion in an aqueous mediuxn, regardless of pH of the aqueous medium, after a period of between about 2 to about 6 hours to release: the glucocorticosteroid active substance, and
15
20
25
30
35
provided that the closage foml does not comprise a further enteric coal ing. 2. The method accor'ding to claim 1, Wherein the dosage
40 form comprises 1 mg p;rednisone
45
3. The method aceording to claim 1, wherein the dosage form comprises 5 mg pi rednisone. 4. The method according to claim 1, wherein the coating does not include a disinttegratiug agent. 5. The method accor'ding to claim 1, wherein the dosage form releases at least 80% of the glucocorticosteroid active
substance after 4.5 hourrs .
6. The method according to claim 1, W herein the dosage

form releases about l0~0% of the glucocorticosteroid active 50 substance after 5 hours.
55
Whipped cream.
The methodology consisted ofan open, randomized, 3-period crossover single oral dose study with 7 days washout periods. The patient population consisted of 27 healthy male volunteers. The pharmacoldnetics of die formulation was compared for each of thc fed and semi-fasted states with a standard immediate release fonn (Deeortin) administered at 2 am. In the semi-lasted state the formulation exhibited a median lag time oI`3.5 hours. Relative to Decortin dosed at 2 am, the
60
65
7 . The method accortding to claim 1, wherein, in vivo, the release of the glucoconticostcroid active substance from the dosage form is independent of the effects of food. 8. A method of treatiing rheumatoid arthritis in a patient in need thereof comprisingg administering to the patient a dosage form comprising a core and a coating surrounding the core, wherein the core comprises the glucocorticosteroid active substanct2 and further comprises at least one disintegrating aggent that, upon exposure to aqueous media, provides a force to rupture the coating, wherein the coating comprises at least one insoluble or poorly water soluble hydrophobic material such that the glucocortict>steroid active substance is released from the core as a result ofthe rupturing ofthe coating ;ult of the glucocorticosteroid active substance diilixsing through the coating, provided that
Us 8,309,124 B2
19
the coating does not include an insoluble or poorly water soluble hydrophobic material that is a polymer,
20
11. The method according to claim 8, wherein the coating does not include a disintegrating agent. and 12. The method according to claim 8, wherein the dosage wherein the coating ruptures upon immersion in an form releases at least 80% of the glucocorticosteroid active aqueous medium, regardless of pH of die aqueous 5 substance after 4.5 hours. medium, aiier a period ofbelween about 2 to about 6 13. The method according to claim 8, wherein the dosage hours to release the glucocorticosteroid active subform releases about 100% of the glucocorticosteroid active stance, and substance aiier 5 hours. provided that the dosage form does not comprise a fur14. The method accordinil to claim 8. wherein. in vivo, the ther enteric coating. . . 10 release of the glucocortico eroid actie substance from the 9. The method according to claim 8, wherein the dosage dosage form is independent of the effects of food. form comprises 1 mg prednisone. 10. The method according to claim 8, Wherein the dosage
form comprises 5 mg prednisone. * > < i * * *
EXHIBIT D
\||||||||I|||l||Illll||||||||||l||||||I|I||l||||||I||||II||I|||||||||||||\
US008 168218132
(12> United States Patent

Vergnault et al
(75) Inventors: Guy Vergnault, Kembs Loechle (FR) Pascal Grenier, Kappelen (FR); Christophe Dragan, Geispitzen (FR) Assignee: Jagotec AG, Muttenz (CH) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.s.C. 154(b) by 1438 days. 10/554,538 Apr. 23, 2004 PCT/IB2004/001693 Jan. 16, 2007
(10) Patent No.:

5,464,633 5,567,696 5,792,476 6,183,780 6,365,185 6,488,960 6,599,284 6,620,439 2005/0008702
A
US 8,168,218 B2
May 1, 2012
(73) (*)
1 1/1995 Conte et al. 10/1996 McGuire et al. 8/1998 Hallgren 2/2001 Van Balken et al B1 !< 4/2002 Ritschel et al. .. B1 12/2002 Bardsley B2 7/2003 Faour B1 9/2003 Mehta A1 1/2005 Faour et al.
A A B1
424/473 604/892.1 424/473
(Continued) FOREIGN PATENT DOCUMENTS

EP 0 463 877 1/1992
(21) (22) (se)
Appl. No PCT Filed PCT No

371 ()(1),
(Continued) OTHER PUBLICATIONS

Zlatldna, A,P., "The Modern Therapeutic Tactics of lnflaimnatory Bowel Disease, Consilium Mcdicum," Gastroenterology 6(l):2004 (English machine translation appended).
(2), (4) Date: (87)
PCT Pub.No.: W02004/093843 PCT Pub. Date: Nov. 4, 2004
(Continued) Primary Examiner ~ Pau] Dickinson (74) Attorney, Agent, or Firm - Mintz Levin Cohn Ferris Giovsky and Popeo, P.C.; David E. Johnson, Esq.; Muriel Liberto, Esq. (57)
(65)

US 2007/01 10807 A1 May 17, 2007
(30)

(GB) 0309342.4
Apr. 24, 2003
ABSTRACT
(51) Int. C1 (2006.01) A61K 9/20 424/464 (52) U.S.Cl. None (58) Field oi Classification Search See application file for complete Search history. (56) References Cited U.S. PATENT DOCUMENTS
5,279,832 A 1/1994 Greissinger et al
A press-coated tablet comprising a core containing an dwg substance, and a coating, the core being disposed within the coating such that the coating has a first thickness about an axis A-B and a thickness about an onhogonal axis X-K such that the coating about the axis X-Y is thicker than the coating about the axis A-B, and is adapted to provide a lag time of between about 2 to 6 hours during which sub stantially no drug
substance is released.
9 Claims, 2 Drawing Sheets
B
I
I I
US 8,168,218 B2
Page 2
U.S. PATENT DOCUMENTS

2006/0057200 Al 3/2006 Schaeffer

EP EP EP EP EP JP 0 673 645
0 776 660 B1 0 939 623

1 275 381 1 067 910
9/1995 6/1997 2/2002

1/2003
WO WO WO WO WO WO
WO-02072034 WO 03/07591 9 WO 2004/ I 03349 WO 2004/093843 WO 2004/093850 WO 2005/027843
A2
A2 A1
A2
9/2002 9/2003 2/2004 11/2004 11/2004 3/2005
OTHER PUBLICATIONS
Conte et al. (1993). Biomalerials 14: 1017-1023. Fukui et al. (2000)..Z Controlled Release 68: 215-223. Lin et al. (2001). J Pharmaceutical Sciences 90: 2005-2009. GB Search Repon dated Aug. 22, 2003 corresponding to GB 0309342.4. GB Search Report dated Oct. 23, 2003 corresponding to GB 0309342.4. International Search Report mailed Oct. 21, 2004 corresponding to PCT/IB2004/001693.
5/2004
1/2001
wo
WO WO WO WO WO WO WO
2001-010950 WO 92/00064
WO 92/1 1 845
wo wo
WO 93/19741 WO 96/40078 A1 WO 01/08421 WO 01/52819 A1 WO 01/68056 WO 01/80824 WO~0200204 A1 WO 02/072033
1/1992 7/1992 10/1993 12/1996 2/2001 7/2001 9/2001

11/2001
1/2002 9/2002
* cited by examiner
U.S. Patent
May 1, 2012
Sheet 1 of 2
Us 8,168,218 B2
B
I I
I I
FI G. 1
U.S. Patent
May 1, 2012
Sheet 2 of 2
Us 8,168,218 B2
% Release - Prednisone 100.0
80.0
'
.
'ii
0:
(D cu G)
a> 60 . 0
40.0
20.0
0.0
=Q Ca =fe Q ~Q Q ~Q Q =Q \" \" (\| (\| C "') ") |' V'
Q uq q
Test medium Purified water Temperature: 37C + 0.5C Rotation speed; 100 rpm
Time lm
o co |~ 1\ oo oo cn o> 1*
m q q m q q uq
FIG. 2
US 8,168,218 B2
1
media. The coating acts as a barrier to the ingress of aqueous media into an active-agcnt~containing corc and thereby creating a lag time during which no drug substance is released. This invention is concerned with a tablet comprising a core The gellable coating acts as a medium through which drug is containing a drug substance and a coating that is applied to 5 released in a delayed or modified manner. It is stated that the said core by means of compression-coating techniques. The lag time can be modulated by varying the coating weight. tablet can contain al] manner of drug substances, but is parThere are several problems with such an approach: First, ticularly suitable for administering those that are advantarelease of the drug occurs by means of dilTusion through the geously released only alter a predetermined lag time after gelled coating. ln the case ofdrugs that have a narrow absorpadministration. The tablets are particularly suitable lor io tion window, or in the case of drugs adapted to treat a relaadministering lucocorticosteroids selected from prednisone, tively small affected area ofthe GI tract or colon, once the lag prednisolone or methylprednisolone. time has expired it is desirable to release the drug as rapidly as Research into the chronopharmacological Held has dempossible to ensure that all or substantially all of the drug onstrated the importance of biological rhythms in drug therapy. Very often, optimal clinical outcomes cannot be 15 released at the desired site. A slow diffusion ofthe drug is not appropriate in such cases. Further, by attempting to control achieved if a drug is released constantly alter ingestion. This lag time by controlling the coating weight, the formulator's is particularly the case if symptoms of a disease display latitude is limited in this regard, because increasing coating circadian variations. ln such cases, drug release should vary weight adds additional cost to the dosage fonn, and it also in a manner that is sympathetic to these variations in order that dwg plasma concentrations are at an optimal therapeutic 20 adds to the size of the dosage form, which may make it difficult to swallow for certain patient populations such as level only when required to treat symptoms ofa disease state. minors and for the elderly or inlirm. Still further, merely In particular, if symptoms of a disease become apparent at adjusting coat weight does not ensure diat a coating is of a night, or in the early hours upon walking, the time when a desired thickness at a particular site. It remains that if the core patient must take its medication in order to attect the best clinical outcome requires detailed consideration For 25 is not correctly positioned within a die of a press coating machine, despite having selected a particular coat weight, example, most asthma attacks occur in the early hours of the part of the coating may be unintentionally thinner than moming, e.g. 4 am to 6 am. This is a result of complex desired, resulting in unforeseen premature release ofthe drug. circadian rhythms such as the secretion ofhydrocortisone and The applicant has now surprisingly found that by carefully adrenaline. lschaemic heart diseases occur most often during the night or in the early waking hours around breakfast time. 30 selecting the geometry of a core Within its coating, it is possible to manipulate the coating thickness at specific points on Stiffness and pain associated with rheumatoid arthritis and osteoanhritis occur in the early W alking hours, which is the tablet to ensure an appropriate coating thickness to produce tablets having a specifically ttuied lag time. Furtherbelieved to be as a result of the secretion of IL-6 in the early more, because one is able to increase thickness where it is hours of the morning, eg. around 2 am to 4 am. With conventional immediate release dosage forms, syn- 35 needed in the coating, one can reduce coating material to allow use of the minimum amount necessary to achieve the chronization of drug administration with a nocturnal circadesired release characteristics, thus saving on cost ofmateridian rhythm responsible for the symptoms experienced by a als and also reducing the overall tablet size. patient would require a patient having to be disturbed from Still iilrther, the applicant has tbund that by selecting sleep to take a medicament during the early hours of the morning in order to achieve the most eflicacious clinical 40 appropriate core and coating materials, one is able not only to accurately control the lag time, one is also to ensure that all, outcome. Of course, this would be highly inconvenient for a or substantially all, of the drug substance upon expiry of the patient. lag time is released rapidly and at the absorption site, or the Accordingly, there remains a need to provide dosage forms that can be taken at a convenient hour before bedtime that will locally affected site. Accordingly, in a first aspect of the present invention there release an effective dose of a drug substance only after a 45 pre-determined lag time in order to synchronise peak plasma is provided a tablet comprising a core containing an drug substance, and a coating around said core, the core being concentrations of drug with a particular circadian rhythm. disposed within said coating such that the coating thickness Furthermore, particularly in relation to drug substances about an axis (X-Y) (see FIG. 1) is thicker than the coating that have a narrow absorption window, or in the case of dmg substances that are adapted to treat a local condition in the 50 about an axis (A-B) (see FIG. 1) orthogonal to (X-Y), and wherein the thickness of the coating about the axis (X-Y) is colon, such as Crohn's disease, ulcerative colitis, irritable bowel syndrome (IBS) and intlammatory bowel disease selected such that the coating is adapted to rupture upon immersion in an aqueous medium after a period ofbeween (IBD), there is also a need to provide a dosage form that about 2 to 6 hours. rapidly releases the drug substances after reaching the end of According to the present invention, the coating thickness 55 the lag time. Still further, having regard to the varied life styles of about the axis (X-Y) is thicker than the coating about the axis (A-B). The ratio ofthe thickness ofthe coating about the axis patients, in order to reduce die inter- and intra-subject vari(X-Y) to the thickness ofthe coating about the axis (A-B) may ance inbioavailability there is a need to provide a dosage form that releases a drug with a reliable lag time, and to provide be from 2.2 to 2.6:1.0 to 1.6. ln another aspect ofthe invention there is provided a tablet peak plasma drug concentrations at a pre-determined time, 60 comprising a core containing an drug substance and a coating irrespective ofwhether a patient is in a led or lasted state. around said core, the core being disposed within said coating Time controlled release formulations are known in the art such that the coating thickness about an axis (X-Y) is thicker that are able to deliver drug substances with a defined release than the coating about an axis (A-B) orthogonal to (X-Y), and rate after a lag time during which no dnlg substance is released. Such a dosage form is disclosed in WO 02/072033. 65 the thickness of the coating about the axis (X-Y) is at least about 2.2 mm, particularly about 2.2 to 2.6 mm, more parThis dosage form is characterized by a coating containing a ticularly about 2.35 to 2.45 mm. natural or synthetic gum that gels in the presence of aqueous
Us 8,168,218 B2
3
The thickness ofthe coating around or about thc axis (A-B) is not critical for controlling the lag time. Accordingly, the formulator has some latitude in selecting its thickness. It should not be so thick as to render the final tablet to large, yet on the other hand the coating should not be so thin that the coating is render weak and liable to crack under the slightest mechanical stress. Preferably, the thickness of the coating about the axis (A-B) is about 1.0 to about 1.6 mm. The coating thickness either side ofthe core on the axis (A-B) may or may not be equal. For example, on a lirst side of the core (A-core) the coating may have a thickness ofabout 1 .2 to 1 .6 mm, more preferably 1.35 to 1.45 mm, whereas on the other side of the core (B-core) the thickness may be about 1.0 to 1.4 mm, more preferably 1.15 to 1.25 mm. Accordingly, in a particular embodiment of the present invention there is provided a tablet comprising a core containing an drug substance, and a coating, the core being disposed within the coating such that the coating has a thickness about an axis (X-Y) of at least about 2.2 mm, more particularly about 2.2 to about 2.6 mm, still more particularly 2.35 to 2.45 mm, and the thickness ofthe coating about an axis (A-B) orthogonal to (X-Y) is between 1.0 and 1.6 mm. More particularly, along the axis (A-B) on a first side of the core (A-core) the thickness may be about 1.2 to 1.6 mm, more preferably 1.35 to 1.45 nun, and on a second side of the core (B-core) the thickness may be about 1.0 to 1.4 mm, more preferably 1.15 to 1.25 mm. Tablets of the present invention are fonned by compression coating methods as will be described in more detail herein below. Compression coated tablets are generally formed by placing a portion of a powdered coating material in a die and tamping the powder into a compact term using a punch. A core is then deposited onto the compacted coating material before the remainder ofthe coating material is introduced into the die and compression forces are applied to form the coated tablet. To ensure that the core is placed on the tamped coating material to ensure its correct geometry relative to the coating in the final tablet form, it is preferable to employ means for positioning the core in relation to the coating material in a die. Typically such means may be provided by a pin punch. A pin punch is a punch that has a convex surface that contacts the coating material to leave a small depression or hollow in the tamped coating material. Thus, when the core is placed into the die on the tamped material, it sits in the depression or hollow and its correct geometry is assured in the final tablet form. The thickness ofthe coating along and about the axis ofthe direction of movement of the punch (the "(A-B)" axis referred to above) is determined by the amount of coating material added to the die and the compaction force applied to form the tablet. On the other hand, the thickness of the coating along and about the "(X-Y)" axis is determined by the size of the core, its po sition within the die and the diameter ofthe die. lt will be apparent to the skilled person that there is a plurality of axes (X-Y) orthogonal to the axis of movement of the punch (the "A-B" axis), which extend radially from the centre of the tablet to its circumference, and when the reference is made to the thickness of the coating about an axis X-Y reference is being made the thickness about any or all of these
axes.
4
towards the ingress of aqueous media. The rate of ingress of the aqueous medium through the coating along the direction of the X-Y axis is, in part, responsible for controlling the release of the dwg substance from the. core. Once the aqueous medimn contacts the core, the core reacts by swelling or effervescing thereby to break open the core generally along the direction of ingress of the aqueous media (i.e. the X-Y axis) to form to essentially two hemispheres ofcoating material that may remain conjoined, which has an appearance of an opened clam shell. The reaction of the core material to the presence of die aqueous medium is likewise in part responsible for controlling the release of drug substance from the
core.
15
10
20
25
30
35
40
45
50
55
60
During the compression of the coating around the core, the coating material above and below the core (the material along and about the (A-B) axis) is relatively highly compacted and dense. On the other hand, the coating material disposed along and about the (X-Y) axis is subjected to lower compaction forces and is relatively less dense. Accordingly, the material about the (X-Y) axis is relatively porous and permissive
65
The hardness ofthe tablet is preferably at least 60 Newtons, e.g. 60 to 80 Newtons, and more panicularly 60 to 75 Newtons. Hardness may be measured according to a process described in 'lhe European Pharmacopoeia 4, 2.9.8 at page 201. The test employs apparatus consisting of 2 opposing jaws, one ofwhich moves towards die other. The Hat surfaces of die jaws are perpendicular to the direction of movement. The cmshing surfaces of die jaws are fiat and larger than the zone of contact with the tablet. The apparatus is calibrated using a system with a precision of one Newton. The tablet is placed between thejaws. For each measurement, the tablet is oriented in the same way with respect to the direction of the applied force. Measurements are carried out on 10 tablets. Results are expressed in terms of the mean, minimum and maximum values (in Newtons) of the force needed to crush the tablets. Tablets having a hardness within this range are mechanically robust to withstand forces generated in the stomach, particularly in the presence of food. Furthermore, the tablets are sufiiciently porous about the (X-Y) plane of the tablet to permit ingress ofphysiological media to the core at an appropriate rate to ensure that the drug substance is released within an appropriate lag time, e.g. within 2 to 6 hours. As stated above, it is a preferred aspect of the present invention that the tablets are adapted to release a drug substance from the core after a pre-determined lag time, as well as being adapted to release all, or substantially all, ofthe drug substancewithin a very short period oftime after the expiry of the lag time. This ensures that all, or substantially all, of the drug is released at me intended absorption site along me GI tract, or onto the affected site ofthe Gl tract ifthe condition to be treated is a local topical condition. lt is preferred that the tablets ofthe present invention release all, or substantially all ofa drug substance within about % hour to about 1 hour after the selected lag time. This aspect of the present invention is important for delivcring drugs having a rather narrow absorption window in the upper G1 tract, such as the glucocorticosteroids referred to above. ln such Cases, the drug should be released before the tablet can pass into the bowel, where absorption of such dnlgs is poor. lt is made particularly important if the tablet is intended to perform in the same manner independent of the effects of food. It is well known that the rate at which a tablet will pass through me GI tract will vary depending on whether a patient is in a fed or fasted state. In die fasted state, a tablet will typically clear the stomach within about 16 hom and l hour after ingestion, and thereafter take a mrther 4 to 5 hours to clear the upper GI tract through the ileosecal junction. In a fed state, a tablet may take as long as 4 hours to be cleared from the stomach, and a iiurther 4 to 5 hours to clear the upper GI tract. Accordingly, if a tablet is to release of all, or substantially all, of its drug into die upper GI tract irrespective of
US 8,168,218 B2
5
the fed state of a patient, it is preferable that die release the drug alter the lag time occurs Within a time limit referred to in the paragraph above. It should be understood that whereas it is desirable that 110 drug substance is released during the lag time, some release may occur. However, any release of drug substance during the lag time should not exceed 10% of the total amount of drug substance in the core. The coating employed in a tablet according to the present invention is prelerably formed of insoluble or poorly water soluble hydrophobic material. In use, the coating optimally acts merely as a barrier to the ingress of aqueous physiological media thereby providing a drug release lag time. For the reasons set forth above, optimally the tablet should have the minimum thickness possible consistent with the desired lag time. Accordingly, employing water insoluble or poorly soluble hydrophobic coating materials, one is able to produce a coating that is relative recalcitrant to the ingress ofmoisture and so long lag times can be achieved with relatively thin coatings, Further, in order to achieve the rapid release of drug substance after the lag time has expired, it is desirable that the coating contains no, or substantially no, ingredients that swell and gel agents to such an extent that the coating acts as a diffusion barrier to the release ol" drug substance. In this regard, it is preferable that the coating contains no, or substantially no, materials such as natural or synthetic gums that modulate release of the drug substance through an intact swollen coating. Drug substance is released from the core as a result of the physical rupturing of the coating and not as a result of the drug substance diffusing through a swollen coating material. That the mechanism ofdrug release is substantially dependent on the physical splitting of the coating, and not on a diffusion process through a swellable and gellable coating, means that a wide range of drug substances can be delivered from tablets according to the invention in a reliable and reproducible manner. The tablet coating may contain one or more waterinsoluble or poorly soluble hydrophobic excipients. Such excipients may be selected from any of the known hydrophobic cellulosic derivatives and polymers including alkylcellulose, e.g. ethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, and derivatives thereof; polymethacrylic polymers, polyvinyl acetate and cellulose acetate polymers; fatty acids or their esters or salts; long chain fatty alcohols; polyoxyethylene alkyl others; polyoxyethylene stearates; sugar esters; lauroyl macrogol-32 glyceryl, stearoyl macrogol-32 glyceryl, and the like. Hydroxypropylmethyl cellulose materials are preferably selected from those low MW and low viscosity materials such as E-Type methocel, and 29-10 types as defined in the USP. Other agents or excipicnts duat provide hydrophobic quality to coatings may be selected from any waxy substance known for use as tablet excipients. Preferably they have a HLB value of less than 5, and more preferably about 2. Suitable hydrophobic agents include waxy substances such as carnauba wax, paraffin, microcrystalline wax, beeswax, cetyl ester wax and the like; or non-fatty hydrophobic substances such as calcium phosphate salts, e.g. dibasic calcium phos~
phate.
6
Polyvinyl pyrollidone (Povidonc) is preferably present in amounts of about 1 to 25% by Weight or the coating, more particularly 4 to 12%, e.g. 6 to 8%. Glyceryl behenate is an ester of glycerol and behenic acid (a C22 fatty acid). Glyceryl behenate may be present as its mono-, di-, or tri-ester form, or a mixture thereof. Preferably it has an HLB value of less than 5, more preferably approximately 2. lt may be present in amounts of about 5 to 85% by weight of the coating, more particularly from 10 to 70% by weight, and in certain preferred embodiments from 30 to
50%.
10
15
20
25
30
35
40
45
50
55
60
Prelerably the coating contains a calcium phosphate salt, glyceryl behenate, and polyvinyl pyrollidone, or mixtures thereof, and one or more adjuvants, diluents, lubricants or fillers. Preferred components in the coating are as follows, with generally suitable percentage amounts expressed as percentage weight of the coating.
65
Calcium phosphate salt may be the dibasic calcium phosphate dihydrate and may be present in an amount ofabout 10 to 90% by Weight ofthe coating, preferably 20 to 80%, e.g. 40 to 75%. The coating may contain other common tablet excipients such as lubricants, colourants, binders, diluents, glidants and taste-masking agents or ilavourants. Examples of excipients include colourants such a ferric oxide, e.g. yellow ferric oxide; lubricants such as magnesium stearate; and glidants such as silicon dioxide, e.g. colloidal silicon dioxide. Yellow ferric o>dde may be used in amounts of about 0.01 to 0.5% by weight based on the coating; magnesium stearate may be present in amounts of l to 20% by weight of the coating, more preferably 2 to 10%, e.g. 0.5 to l.0%; and colloidal silica may be used in amounts of 0.1 to 20% by W eight of the coating, preferably l to 10%, more preferably 0.25 to l.0%. The core comprises in addition to a drug substance, a disintegrating agent or mixtures ofdisintegrating agents used in immediate release formulations and Well know to persons skilled in the art. The disintegrating agents useful in the exercise of the present invention may be materials that effervesce and or swell in the presence of aqueous media thereby to provide a force necessary to mechanically disrupt the coating material. Preferably a core contains, in addition to the drug substance, cross-linked polyvinyl pyrollidone and croscarmellose sodium. The following is a list of preferred core materials. The amounts are expressed in terms of percentage by weight based on the weight of the core. Cross-linked polyvinyl pyrollidone is described above and is useful as a disintegrating agent, and may be employed in the core in the amounts disclosed in relation to the core. Croscarmellose sodium is an internally cross-linked sodium carboxymethyl cellulose (also known as Ac-Di-Sol) useful as a disintegrating agent. Disintegrating agents may be used in amounts of 5 to 30% by weighbasea 01 the core. However, higher amounts of certain disintegrants can swell to form matrices that may modulate the release of the dmg substance. Accordingly, particularly when rapid release is required after the lag time it is preferred that the disintegrants is employed in amounts of up to 10% by weight, e.g. about 5 to 10% by weight. The core may additionally comprise common tablet excipients such as those described above in relation to the coating material. Suitable excipients include lubricants, diluents and fillers, including but not limited to lactose (for example the mono-hydrate), ferric oxide, magnesium stearates and colloidal silica. Lactose monohydrate is a disaccharide consisting of one glucose and one galactose moiety. It may act as a filler or diluent in the tablets of the present invention. lt may be present in a range of about 10 to 90%, preferably from 20 to 80%, and in certain preferred embodiments from 65 to 70%.
Us 8,168,218 B2
7 8
traline, statins, tacrolimus, tamoxifen, TCAS, triamzolam, As slated above, it is an important aspect of die present zolpidem, or mixtures thereof. invention that core is correctly located within the coating to ensure that a tablet has the appropriate coating thickness. In Additional examples of drug classes and drugs that can be this way, lag times will be reliable and reproducible, and employed in tablets of the present invention include: intra-subj ect and inter-subject variance in bioavailability can antihistamines (e.g., azatadine maleate, brornpheniramine be avoided. It is advantageous to have a robust in process maleate, carbinoxamine maleate, chlorpheniramine maleate, control to ensure that tablets in a batch contain cores having dexchlorpheniramine maleate, diphenhydramine hydrochlome appropnatc geometry ln relation ro me coating. LOHIYOIS ride, doxylamine succinate, methdilazine hydrochloride, can be laborious in that they require an operator to remove promethazine, trimeprazine tartrate, tripelennamine citrate, random samples from a batch and lo cut them open to physi- 10 tripelcnnaminc hydrochloride and triprolidine hydrochlocally inspect the quality of the core (i.e. whether it is intact, ride); and whether it is correctly located). Furthermore, if a signifiantibiotics (e.g., penicillin V potassium, cloxacillin cant number of tablets from the sample fail, a complete batch sodium, dicloxacillin soditun, nafcillin sodium, oxacillin oftablets may be wasted. Applicant has found that ifone adds sodium, carbenicillin indanyl sodium, oxytetracycline hydroto the core a strong colourant such as iron oxide, such that the 15 chloride, tetracycline hydrochloride, clindamycin phosphate, core visibly contrasts with the coating when as strong light is clindamycin hydrochloride, clindamycin palmitate HCL, linshone on the tablet, it is possible lor any faults in the position comycin HCL, novobiocin sodium, nitrofurantoin sodium, or integrity of the core to be picked up automatically by a metronidazole hydrochloride); antituberculosis agents (e.g., camera appropriately located adjacent a tabletting machine to inspect tablets as they are ej ected therefrom. In this Way, if a 20 isoniazid); cholinergic agents (e.g., ambcnonium chloride, bethanecol faulty tablet is identified it is possible to halt production and chloride, neostigmine bromide, pyridostigmine bromide); correct any problems in the manufacturing process quicldy, antimuscarinics (e.g., anisotropine methylbromide, clidthereby potentially avoiding wastage of batch quantities of tablets. inium bromide, dicyclomine hydrochloride, glycopyrrolate, Whereas colourants contained in the core are uselul ior this 25 hexocyclium methylsulfate, homatropine methylbromide, purpose, equivalent solutions are also possible. For example, hyoscyamine sulfate, rnethantheline bromide, hyoscine instead of a colourant, one can include a material that is hydrobromide, oxyphenonium bromide, propantheline broopaque to x-rays, such as baritun sulphate. If an x-ray imager mide, tridihexethyl chloride); is then coupled to a tablet machine, the core will contrast with sympathomimetics (e.g., bitolterol mesylate, ephedrine, the coating material and die x-ray imager will pick up any 30 ephedrine hydrochloride, ephedrine sulphate, orciprenaline faults in the positioning or integrity of the core in a similar sulphate, phenylpropanolamine hydrochloride, pseudoephefashion. drine hydrochloride, ritodrine hydrochloride, salbutamol sulThe amount of drug substance employed in tablets of the phate, terbutaline sulphate); present invention will depend on the particular drug subsympatholytic agents (e.g., phenoxybenzamine hydrostance used, the condition of the patient and the nature and 35 chloride); miscellaneous autonomic drugs (e.g., nicotine); severity of the condition to be treated. A typical drug loading iron preparations (e.g., ferrous gluconate, ferrous sulmight be from l to 50% by weight of the core. phate); As stated above a wide variety of drug substances may be haemostatics (e.g., aminocaproic acid); employed in the present invention. Drugs for treating condicardiac drugs (e.g., acebutolol hydrochloride, disopyrations the symptoms ofwhich result from nocturnal circadian 40 mide phosphate, flecainide acetate, procainamide hydrochlorhythms are particularly suitable. Accordingly, drugs for ride, propranolol hydrochloride, quinidine gluconate, timolol treating incontinence, sleep disorders, apnoea, asthma, epimaleate, tocainide hydrochloride, verapamil hydrochloride); lepsy, bronchitis, parkinsonism, rheumatoid arthritis, allergic antihypertensive agents (e.g., captopril, clonidine hydrorhinitis and ischaemic heart diseases, cluster and migraine headache, congestive heart failure, and depression are par- 45 chloride, hydralazine hydrochloride, mecamylamine hydrochloride, metoprolol tartrate ); vasodilators (e.g., papaverine ticularly suitable for use in tablets according to the present hydrochloride); invention. Further, drug substances that are metabolized by non-steroidal anti-inflammatory agents (e.g., choline salicytochrome P450 are also particularly suitable, they cylate, ibuprofen, ketoprofen, magnesium salicylate, include:-Amitriptyline, caffeine, clomipramine, clozapine, Huvoxamine, haloperidol, imipramine, mexilitine, oestradiol, 50 meclofenamate sodium, naproxen sodium, tolmetin sodium); opiate agonists (e.g., codeine hydrochloride, codeine phosolanzepine, paraeetamol, propranolol, tacrine, theophylline, phate, codeine sulphate, dextromorarnide tartiate, hydrocwarfarin, Bupropion, Cyclophosphamide, Celecoxib, odone bitartrate, hydromorphone hydrochloride, pethidine Diclofenac, Flubiprofen, Ibuprofen, glimepirideindome, thahydrochloride, methadone hydrochloride, morphine sulCin, naproxen, phenytoin, piroxicam, tenoxicam, citalopram, diazepam, lansoprazole, omeprazole, pantoprozole, pro- 55 phate, morphine acetate, morphine lactate, morphine meeonate, morphine nitrate, morphine monobasic phosphate, morpanolol, topiramate, Alpranolol, chlorpromazine, clomiphine tartrate, morphine valerate, morphine hydrobromide, pramine, codeine, Desipramine, dextromethorphan, diphenmorphine hydrochloride, propoxyphene hydrochloride); hydramine, donepezil, flecainide, Huoxetine, labetalol, anticonvulsants (e.g., phenobarbital sodium, phenytoin Methadone, metoprolol, mianserin, nortripyline, ondansetron, oxprenolol, oxycodone, paroxetine, perhehex- 60 sodium, troxidone, ethosuximide, valproate sodium); tranquilizers (e.g., acetophenazine maleate, chlorpromilene, pethidine, promethazine, risperdone, thioridazine, azine hydrochloride, fluphenazine hydrochloride, prochlorticlopidine, timolol, trimipramine, venlafaxine, paracetamol, perazine edisylate, promethazine hydrochloride, thioridazine alprazolam, amiodarone, budesonide, buprenorphine, bushydrochloride, triliuoroperazine hydrochloride, lithium citpirone, Calcium Channel Blockers, carbamazepine, cisapride, clarithromycin, clonazepam, cocaine, cortisol, 65 rate, molindone hydrochloride, thiothixine hydrochloride); chemotherapeutic agents (e.g., doxombicin, cisplatin, cyclosporine, dexamethasone, erythromycin, fentanyl, ketoiooxuridine, methotrexate, combinations thereof); conazole, losartan, miconazole, midazolam, quinidine, ser-
US 8,168,218 B2
9
lipid lowering agents (e.g., gemfibrozil, clohbrate, HMGCOA reductase inhibitors, such as for example, atorvastatin, cerivastatin, lluvastatin, lovastatin, pravastatin, simvastatin); H.sub.2-antagonists (e.g., cirnetidine, famotidine, nizati5 dine, ranitidine HCI); anti-coagulant and anti-platelet agents (e.g., warfarin, cipyridamole, ticlopidine); bronchodilators (e.g,, albuterol, isoproterenol, mctaproterenol, terbutaline); stimulants (e.g., benzamphetamine hydrochloride, dextro- 10 amphetamine sulphate, dextroamphetarnine phosphate, diethylpropion hydrochloride, feniiuramine hydrochloride, methamphetamine hydrochloride, methylphenidate hydrochloride, phendimetrazine tartrate, phenmetrazine hydro15 chloride, caffeine citrate); barbiturates (e.g., amylobarbital sodium, butabarbital sodium, secobarbital sodium); sedatives (e.g., hydroxyzine hydrochloride, methprylon); expectorants (e.g., potassium iodide); antiemetics (e.g., benzaquinamide hydrochloride, meto- 20 cloproparnide hydrochloride, trimethobenzamide hydrochloride); gastrointestinal drugs (e.g., ranitidine hydrochloride); heavy metal antagonists (e.g., penicillamine, penicillamine 25 hydrochloride); antithyroid agents (e.g., methimazole); genitourinary smooth muscle relaxants (e.g., tiavoxate hydrochloride, oxybutynin hydrochloride); vitamins (e,g., thiarnine hydrochloride, ascorbic acid); unclassihed agents (e.g., amantadine hydrochloride, 30 colchicine, etidronate disodium, leucovorin calcium, methylene blue, potassium chloride, pralidoxime chloride. steroids, particularly glucocorticoids (e.g., prednisolone, methylprednisolone, prednisone, cortisone, hydrocortisone, methylprednisolone, betamethasone, dexamethasone, triam- 35 cinolone). Notwithstanding the general applicability of the tablets in relation to a wide range ofdrug substances, the present invention is particularly suited to delivery of the glucocorticosteroids aforementioned and particularly prednisone, predniso- 40 lone and methylprednisolone. These steroids are useful in the treatment i.a, of rheumatoid arthritis and joint pain. As already stated, the symptoms of these conditions appear according to a circadian rhythm and with great predictability during the early hours of the morning. Accordingly, die glu- 45 cocorticosteroids, and in particular prednisone are eminently suited for delivery from tablets according to this invention not only because of their narrow absorption window, but also because a tablet may be administered in the evening before bedtime anytime around 8 pm until midnight, e.g. around 50 10-12 at night, to deliver maximum plasma concentration of the drug substance before maximum secretion ofIL-6 (which occur around 2 am to 4 am), thereby effectively addressing the underlying causes of the morning symptoms. In this way, these symptoms are more effectively treated. 55 As used above, prednisone refers to the compound and its salts or derivatives thereof, including prednisone 21 acetate. As used above, prednisolone refers to the compound and its salts or derivatives including the 21 -acetate, its 21-tert-butyl acetate, 21-succinate sodium salt, 21-stearoylglycolate, 60 21 -rn-sulphobenzoate sodium salt, and its trimethylacetate. Methylprednisolone, as used above refers to the compound or and its salts and derivatives thereofincluding its 21 acetate, 2 1 -phosphate disodium salt, 2 l -succinate sodium salt, and its
acetonate.
65
10
weight of steroid based on the total weight of the core. ln the case ofprednisone, it may be employed in amounts to provide a total weight per unit dosage form of l or 5 mg, to offer convenience and flexibility of dosing, although dosage forms containing larger or smaller amounts of drug substance could be employed if desired, Particularly preferred tablets according to the invention comprising in the core a glucocortico steroid selected from the group consisting of prwnisone, prednisolone and methylprednislone, and cross-inked polyvinyl pyrollidone, crosslinked sodium carboxymetbyl cellulose, and one or more adjuvants diluents, lubricants or Hller materials as hereinabove described. Preferably the coating comprises a calcium phosphate salt, glyceryl behenate, cross-linked polyvinyl pyrollidone and one or more adjuvants, diluents, lubricants or filler materials as hereinabove described. The composition ofone particularly preferred embodiment of the invention is: Core of 5 mg Prednisone Tablet: Prednisone 8.33% Lactose monohydrate 64.47% Povidone 6.67% Croscarmellose sodium 18.33% Red ferric oxide 0.5% Magnesium stearate Vegetable origin 1.0% Colloidal silicon dioxide 0.5% Coating Dibasic calcium phosphate dihydrate 50% Glyceryl behenate 40% Povidone 8.40% Yellow ferric oxide 0.1% Magnesium stearate Vegetable origin 1.0% Colloidal silicon dioxide 0.5% Another preferred embodiment is as follows: Core of 1 mg Prednisone Tablet: Prednisone 1.67% Lactose monohydrate 71.13% Povidone 6.67% Croscarmellose sodium 18.33% Red ferric oxide 0.5% Magnesium stearate Vegetable origin 1.0% Colloidal silicon dioxide 0.5% Coating Dibasic calcium phosphate dihydrate 50% Glyceryl behenate 40% Povidone 8.40% Yellow ferric oxide 0.1% Magnesium stearate Vegetable origin 1.0% Colloidal silicon dioxide 0.5% It is surprising that the tablets containing the glucocorticosteroids display such rapid release given that the rate of release relics to some extent on the wetting of die core, and these steroids are rather hydrophobic in nature. The tablets described above are press-coated tablets comprising a core and a coating covering said core. However, variants of this basic construction are within the ambit ofthe present invention. Thus, the press-coating may be further coated with an outer coating that may be functional and/or aesthetic in its design. For example, functional coatings may include the addition an immediate release coating containing a drug substances that may be the same or different to the drug substance contained in the core. In this manner, the tablet can affect a pulsatile release that is of use in treating symptoms based on circadian rhythms, such as sleep disorders. In this regard one can employ sedative hypnotics in such dosage forms, for example those dntg substances mentioned described in U.S. Pat. No. 6,485,746
Typically a core may contain about 0.1 to 50% by weight, more particularly l to 20%, still more particularly l to 10% by
Us 8,168,218 B2
11
Pulsatile release dosage forms may also find general applicability with a Wide range ofactive substances for the treatment ofa wide range ofindications to provide patients with a more convenient dosage schedule. For example, pulsatile release can provide an alternative to multiple administrations of immediate release forms. Functional coatings also include enteric coatings covering the press-coating. Enteric coated forms may be of use in treating local conditions in the bowel such as Crohn's disease, ulcerative colitis, IBS and IBD. In this embodiment, the enteric coating would prevent release of any drug before the tablet enters the bowel. Aesthetic coatings include taste masking coatings and coloured coatings as a generally Well known in the art. It is well known in the art that food can change the bioavailability of a drug. Food can alter the bioavailability of a drug by various means such as delaying gastric emptying, changes in gastrointestinal pH, changes in luminal metabolism, and physical and chemical reactions of food items with a dosage form or drug substance. This change in bioavailability as a consequence of food intake is often referred to as a "food effect". Food effects are quite common in modifiedrelease dosage forms, and also for drugs that have either poor solubility or poor penneability or both (BCS Class ll, Ill, and
12
or even in relation to dnig substances whose efficacy depends on their ability to be delivered accurately to a particular absorption site, or a locally diseased site along the GI tract and bowel. Such medicaments are provided by the present invention. Currently, there are no bioavailability or bioequivalence regulatory guidelines available for Tmax' However, the Guidance For lndustry "Food Effect Bioavailability and Fed Bioequivalence Studies", US Depanment of Health (CDER) December 2002 suggests that any diflerence in Tm" should not be clinically relevant. Whether such a difference will be clinically relevant will depend on the drug delivered and the particular indication. Applicant has found that in respect of formulations ofthe present invention the effect of food on the median value of Tm is a difference of only about +/-20%, more particularly +/-10% Still further, applicant has found medicaments containing dwg substances exhibiting no significant effect of food with respect to bioavailability of the dmg substance in terms of Cn," and AUC. The "food effect" as it relates to the bioavailability of drug substances is a well documented phenomenon in relation to drug delivery mat describes the variance in uptake of a dwg substance by patients depending upon whether the patients effect may be quantified by making Area under the Cuwe (AUC) and/or Cmax measurements according to methods well known in the art, Typically AUC measurements and Cmax measurements are made by taking timed biological fluid samples and plotting the serum concentration of drug substance against time. The values obtained represent a number ofvalues taken from subjects across a patient population and are therefore expressed as mean values expressed over the entire patient population. By comparing the mean AUC and/ or Cmax values, one can determine whether a drug substance experiences a food effect. Food effect studies may be conveniently carried out on an adequate number of healthy volunteers, the number being suflicient to generate sufficient data for appropriate statistical assessment to be made. Preferably the number of subjects should not be less than 12. To study the effect of food on the bioavailability of a drug substance one may use any conventional study design known i11 the art, for example a randomised, balanced single-dose, two-treatment, two-period, two-sequence crossover design. Analysis may be canied out using any ofthe programs known in the art such as SAS PROC GLM, software from the SAS institute, Cary N.C. ln quantitative terms, a drug substance may be said to exhibit no food effect ifa 90% confidence intewal (Cl) for the ratio of means (population geometric means based on log transformed data) offcd and fasted treatments fall within the intewal of0.8 to 1.25 for AUC andor 0.7 to 1.43 for Cmar Accordingly, the present invention provides in another of its aspects a tablet as defined herein above displaying a ratio AUC fed/fasted aher single dosing of 0.8 to 1.25 or the ratio Cm fed/fasted after single dosing of 0.7 to 1.43. A "fed" subject conveniently may be considered as a subject that has fasted for at least 10 hours before receiving a standard FDA recognised high fat meal. The medicament may then be administered with water shortly alter completion ofthe meal, e.g. within 5 minutes thereof. Preferably no food should be taken for a period oi e.g. 4 hours alter receiving medicament although small quantities of Water may be permitted after, e.g, 2 hours after receiving the medicament. A "fasted" subject conveniently may receive medicament with water after at least 10 hours fasting. Thereafter, no food
10
15
20
IV).
The applicant has surprisingly found that a tablet that is adapted to release all, or substantially all, of a drug contained therein within a time ( ag) ofbetween 2 and 6 hours (median time) after administration. Furthermore, the applicant has surprisingly developed a tablet adapted to release a dnug substance after a lag time that can deliver a drug to a patient, which upon absorption the peak drug concentration Cmax will be reached in a time Tniax that is independent of a patient's food intake. Tmax is a term well known in the art that refers to the time elapsed between drug administration and the maximum plasma concentration Cm is reached. Cm" is also an art recognized term that relates to the peak plasma concentration of a drug. 'rmax is an important parameter particularly in relation to medicaments that are intended to be taken at a time convenient for a patient, but which release drug substances after a lag time in order to synchronise drug release with a circadian rhythm, and in particular a nocturnal circadian rhythm. By way of example, the glucoconicosteroids, referred to above, e.g. prednisone, are useful in the treatment of i.a. arthritic conditions such as rheumatoid arthritis and osteoarthritis. Debilitating symptoms are often experienced by a patient upon waking. Current therapy requires a patient to take DeconinR upon waking. However, this is not the most efficacious way of treating the symptoms, as they are believed to be associated with the secretion oflL-6, which occurs during the early moming hours, e.g. from about 2 to 4 am. A rnedicament that can reach Cm" that is coincident with or anticipates the release of lL-6 is potentially of greater benent to a patient. Furthennore, given the varied lifestyles of individuals, patients taking rnedicament between 8 pm and bedtime, e.g. from 10 pm to midnight, may be in a variety offed states, it is even more advantageous that TW. should bc independent of food intake. Medicaments that can have a pre-determined lag time, and which release dwg substance after this lag time in a manner that provides a Tmax independent of considerations of the fed or fasted state ofa patient are ofpotentially great benefit, not only in relation to die glucocorticosteroids and the treatment of a1tMtis, but for other active substances that are advantageously delivered in Synchronicity with a circadian rhythm,
25 are in fed or fasted states. The presence or absence of` a lbod
30
35
40
45
50
55
60
65
Us 8,168,218 B2
13
may be taken for a period oi e.g. 4 hours although small quantities of water may be taken after, e.g. 2 hours alter receiving medicament. A standard FDA high fat meal as referred to hereinabove may comprise any meal that would be expected to provide maximal perturbation due to the presence of food in the Gl tract. Said high fat meal typically may comprise 50% of its caloric value in fat. A representative example may be 2 eggs fried in butter, 2 strips ofbacon, 2 slices toast with butter, 4 ounces ined potato, and 8 ounces milk. By application of the teachings of the present invention tablets may be provided that display reduced variability in resumption/bioavailability levels achieved both for individual patients receiving a dmg as Well as between individuals.
14
about the X-Y axis. Should it be necessary to change the thickness of the coating, die of appropriate internal dimensions may be placed in the rotating platform, and the amount of coating material fed into the die may be adjusted accordingly. Suitable rotary tablet machines having high process speeds are known in the art and need no further discussion here. Cores may likewise be formed using a conventional rotary tablet machine. Cores are preferably compressed under compression forces suiiicient to provide cores having a hardness of about 60 Newtons at least, e.g. 50 to 70 Newtons. Cores having hardness in dns range give desired release characteristics. lf desired, the cores can be formed at the same time as the press coated tablets are produced. In such case, one might employ a Manesty Dry Cota. Such a press consists of two side-by-side and inter-connected presses where the core is made on one press before being mechanically transferred to the other press for compression coating. Such equipment and techniques for making tablets using such equipment arc known in the art and no more needs to be said about this here. (fnres are ["""""'J nreferahlv ilirmed aecorflino '"""'"-C:tn wet srranulatinn D"""""'"""" techniques generally known in the art. In a typical procedure, core materials are sieved and blended. Granulating fluid, typically water is then added to the blend and the mixture is homogenized to form a granulate, which is then sprayed dried or dried on a fiuid bed drier to obtain a granulate with requisite residual moisture. Preferably the residual moisture content is from about 0.4 to 2.0% by weight. The granulate is then sized by passing it through screens of desired aperture. At this
10
15
The tablets of the present invention may be packaged in a variety ofways. Generally an article for distribution includes a container for holding the tablets. Suitable containers are well known to persons skilled in the art and include materials such as bottles, foil packs and the like. In addition, the con- 20 tainer will have a label and an insert that describes the contents ofthe container and any appropriate warnings or instructions for use. It is an advantage of die present invention that the insert and/or label may contain instmctions that the tablet may be taken with or without food, or may be absent a 25 warning or instruction that the tablet should be taken only with food or only without food. The invention provides in another aspect, a method of forming tablets as herein above described. The tablets may be formw on conventional press coating equipment. Typically 30 stage, a11y adjuvants are sized and added to the granulate to such equipment is composed ofa series ofdie are arranged on form the core composition suitable for compression. The a rotating platfbm. The die are removably mounted in the sldlled person will appreciate that a coating composition can platform such that differently sized die may be employed as be formed in an analogous manner. The skilled person will appropriate. Each die is hollow to receive a lower punch. The also appreciate that granulates may be obtained having a punch is positioned within the die such that the upper surface 35 range of particle sizes. It is preferred that the coating granuof the punch and the inner surface of the die define a volume late has a fine fraction that is less than 30%. By "fine fraction" for receiving a precise amount coating material. Once loaded, is meant granulate having particle size of up to about 63 the platform is rotated until the die is positioned under an microns. upper punch. The upper punch is then urged down onto the Preferred features for the second and subsequent aspects of coating material under a defined compression force and the 40 the invention may be as for the first aspect mutatis mutandis. coating material is pre-compressed or tamped between the FIG. 1: is a representation of a tablet in cross section upper and lower punch. A pre-formed core is then fed into die showing the coating and core and the axes (A-B) and (X-Y). to rest on the tamped coating. Conventional press coating FIG. 2: Shows an in-vitro dissolution profile of the dosage apparatus may be equipped with centering devices that enable form of Example 2. cores to be positioned both vertically and radially. This might 45 There now follows a series of examples that sewe to illusbe achieved by a tamping process, whereby an initial amount trate the invention. of coating material is placed in a die and is tamped with a shaped punch, such as a pin punch, that leaves an indentation EXAMPLE 1 in the coating material in which to receive a core. Thereafter, in a second filling operation, a precise amount of coating 50 Preparation of a Prednisone-Containing Tablet material is fed into the die to cover the core, and an upper punch compresses the coating material with a defined comThe active core was prepared for the press coated system as paction force to form tablets according to the present invenfollows. The composition of the core is detailed in Table 1. tion. Lactose monohydrate (Lactose Pulvis~H2O, Danone, 'Ihe compression force applied during the tamping process 55 France and Lactose Fast Flo NF 3 l 6, Foremost Ing. Group, is relatively light and is just sufhcient to provide a bed of USA) is a filling agent with interesting technical and funccoating material to receive the core and to prevent movement tional properties. Lactose PulvisII2O is used in a blend preof the coating material as a result of centrifugal force. Subpared by wet granulation and Lactose Fast Flo is used in a sequent compression to form the tablet may be adjusted to blend prepared for direct compression. Microcrystalline celgive tablets of requisite hardness. Preferably, this compres- 60 lulose (Avicel pH 101, FMC International, Ireland) is used sion force is 400 kg, although this may be adjusted by +/-30% as an insoluble diluent for direct compression. Polyvinyl pyrrolidone (Plasdone K29-32, ISP Technology, USA) is a in order to give tablets of the required hardness. The amount of coating material fed into the die can be trranulating V agent. v 1 soluble in water. , which has the abilitv .f of precisely defined having regard to the density of the coating binding the powder particles. Croscarmellose sodium (Acmatenal to ensure after compression that the tablet is formed 65 Di-Sol, FMC Corporation, USA) is used in the fonnulation as a super disintegrant. As the external phase, magnesium with the required coating thickness about the (A-B) axis; and die dimensions of the die is selected to provide the thickness stearate (Merck, Switzerland) was added as a lubricant and
US 8,168,218 B2
15
silicon dioxide (Aerosil 200> Degussa AG, Germany) in order to improve How properties of the granular powder. TABLE 1
5
16
0.710 mm apertures. They were placed in a Niro-Fielder PMA 65-liter mixing granulator. Then, the components were homogeneously mixed for 6 min, at impeller speed 200 rpm, without chopper. Subsequently, the granulating solution (purified water, 8. 1 2% ofthe weight of the dry blend) was added within 2 min at impeller speed 200 rpm and chopper speed 1500 rpm using a nozzle 4,9 (spraying rate of 520 g/min). Mixing was continued for homogenisation and massing for l min at impeller speed 400 rpm and chopper speed 3000 rpm. The mixed wet granulate was then dried in a Niro-Fielder TSG 2 fluidised air bed dryer. The inlet temperature was maintained at 45 C. during drying. The drying lasted 33 min to have residual moisture less than 2.5%. The yielded dry granulate was calibrated in a Prewitt MGI 205 granulator using a screen having 0.8 mm apenures for 4 min at speed 244 osc/min (graduation 7). Appropriate amounts of Aerosil 200 and magnesium stearate were manually sieved using a screen with 1.0 mm apertures. Half of the dry granulate was put in a Niro-Fielder PMA 65-liter, followed by Aerosil 200 and then by the other half of the dry granulate. The ingredients were mixed for 2 min at impeller speed 200 rpm, without chopper. Finally, magnesium stearate was addw and mixing was continued for 2 more minutes at impeller speed 200 rpm, without chopper. 440 mg of coating blend was press coated on a core to provide press coated tablets (9 mm diameter). 305 mg of coating blend was press coated on a core to provide press coated tablets (8 mm diameter). These different press coatings were done utilising a Kilian RUD tabletting machine. First and second loadinglioppers are Hlled up with the coating granulate. Between the two loading hoppers, the machine is equipped with a transfer system adapted to feed the cores. For each tablet, the first loading hopper supplies with about half of the quantity to be applied to the core. Then, the feeding system provides and positions a core centred in the die. Sub~ sequently, the second loading hopper supplies with the other halfofthe quantity to be applied to the core. The compression
step Lneu L)CCUI`S
Ingredients Prednisone Lactose (Lactose Pulvis H20 NF 316) Polyvinyl pyrrolidone (Plasdonc K29-32) Sodium cafooxymethyl cellulose (Ac~DiSol ) Magnesium steamte Silicon dioxide (Aerosil 200) Total
Content (mg/mb let) 5.00 39.10 4.00 11.00 0.60 0.30 60.00
10
The coating of the prednisone press coated tablet is of a hydrophobic, water insoluble nature. This barrier is mainly composed of dibasic calcium phosphate (Emcompress, Mendell, USA) and glyceryl behenate (Co1npritol 888ATO, Gattefoss, France). Polyvinylpyrrolidone (P1asdone K2932) is a granulating agent, soluble in water, which has the ability ol' binding the powder particles. Yellow ierric oxide (Sicovit Yellow 10, BASF, Germany) was added as a dye. A detailed composition of this barrier blend is given in table 2. TABLE 2
Combosition of the coatiniz Ingredients Dibasic calcium phosphate (Emcomprcss ) Glyceryl Behenate (Compritol 888 ATO) Polyvinylpyrrolidone (Plasdone K29-32) Yellow Ferris Oxide (Sicovit yellow 10 E 172) Silicon dioxide (Aerosil 200) Magnesium stearate Content (%) 50.00 40.00 840 Q10 0.50
1.00
15
20
25
30
lbtai
100.00
35
The required amounts ofprednisone, Ac-Di-Sol, Lactose Pulvis H2O, Plasdone K29-32 were weighed and manually sieved with a screen having 0.710 mm apenures. The components were homogeneously mixed in a Niro-Fielder PMA 25-liter mixing granulator for 6 min at impeller speed 250 rpm without chopper. A prednisone assay was perfomied on this premix. Subsequently, the granulating solution (purifled water, 25.47% ofthe weight of the dry blend) was added within 4 min at impeller speed 250 rpm and chopper speed 1500 rpm, using a nozzle Hl/4VV-95015 (spraying rate of 250 g/min). Mixing was continued for homogenisation and massing of the wet mass for 3 min at impeller speed 500 rpm and chopper speed 3000 rpm. The mixed wet granulate was then dried in a Glatt WSG5 fluidised air bed drier. The inlet temperature was maintained at 45 C. during drying. The drying lasted 20 min to get a granulate with a residual moisture less than 2 .5%. The yielded dry granulate was calibrated in a Frewitt MGI 205 granulator using a screen with 0.8 mm apertures for 3 min at speed 244 osc/min (graduation 7). Appropriate amounts of Aerosil 200 and magnesium stearate were manually sieved using a screen. with 1.0 mm apertures. Halfof the dry granulate was put in a Niro-Fielder PMA 25-liter mixing granulator, followed by Acrosil 200 and then by the other half of the dry granulate. The ingredients were mixed for 2 min at impeller speed 250 rpm. Finally, magnesium stearate was added and mixing was continued for 2 min at impeller speed 250 rpm. The coating blend was prepared according to the process described below. Batch size for the barrier blend was 13 kg. Weighed amounts of Emcompress, Compritol 888 ATO, Lactose pulvis-H2O, Plasdone K29-32 and Sicovit Yellow 10 E 172 were manually sieved with a screen having
TABLE 3
40
Ecluinmcnt imnlemenfed for the manllfachlrinsz nroccss
Equ ipment
Brzuld nzune/Type Niro~Fielder PMA 25/65 litres Glatt WSG5 Niro-Fielder TSG 2 Frewitt MGI 205 Mettler PE 360 Moistuurc Analyzer Hata HT-AP55LS-U/3L Kilian RUD
Manufactumr/Supplier Aromatic-Fielder AG, Bubendorfl Switzerland Maschinen und appamtebau AG, Pratteln, Switzerland Ammalic-Fielder AG, Bube11dor Switzerland Frewitt SA, Granges-Pacot, Switzerland Mettler Toledo AG Grcifensee, Switzerland Elisabeth-Carbide, Antwerp, Belgium Kilian & Co GmbH, Cologne, Genuany
Mixing
45 granulator Fluidised air bed dryer Fluidised air bed dryer Granulator 50 Infrared moisture analyser Multilayer tablet press Dry coating 55 tablet press
EXAMPLE 2
60
ln Vitro Dissolution Profile The in vitro dissolution profile ofa tablet containing a 5 mg loading of prednisone prepared according to the method of Example 1 was detennined using USP dissolution apparatus No, 2 (paddles) and stationary baskets and applying a stirring rate of 100 rpm. The dissolution medium was purified water, with a volume of 500 ml.
65
Us 8,168,218 B2
17
After 4 hours no drug substance release is observed. However, within 4.5 hours there is approximately 80% release and by 5 hours 100% release of the drug substance (see FIG. 2). EXAMPLE 3 A study was carried out to determine the effect of food on the bioavailability of a 5 mg prednisone tablet described above. The study did not compare the tablet in the fed and fasted state. Rather, the study was adjusted to take into account the Chrono-pharmacokinetics ofprednisone and the fact that it is to be administered in the evening, eg. about 8 pm, which is required in order that the blood plasma levels will peak before secretion of IL-6 to improve the ellicacy of the treatment. Thus the study was designed to compare the tablet during real time administration and with likely food intake scenarios at this time. It was considered unreasonable that at 8 pm a subject would be approximately 8 hours fasted. Accordingly, the following food intake scenarios were tested: a) To simulate a lasted state at 8 pm in the evening, a light meal was given 21/2 hours before administration that contained a limited number of calories (i.e. 22% of total daily calories and with a limited fat content of 15.5 g) and being devoid ofany slowly digestible nutrients. This is called the "semi-fasted" state. The composition of this meal consisted of brown bread, margarine, cheese spread, an apple (sldn removed) and fruit cocktail in syrup. b) Fed state is simulated by giving a higher fat meal % hour before dosing containing 35% of the daily intake of calories and 26 g offat. Anassumption made was that in the case ofthe semi-fasted state, after 2% hours the stomach was already emptied, or substantially emptied of food, The composition of the high fat meal was pasta with spaghetti sauce, soup and vegetables, Applejuice, Ice cream and whipped cream. The methodology consisted ofan open, randomized, 3-pe~ riod crossover single oral dose study with 7 days washout periods. The patient population consisted of 27 healthy male volunteers. The pharmacokinetics of the formulation was compared lor each of the led and semi-lasted states with a standard immediate release form (DecortinR) administered at 2 am. ln the semi-fasted state the formulation exhibited a median lag time of 3.5 hours. Relative to Decortink dosed at 2 am, the formulation was fully bioequivalent with a Cmax of 97% and relative bioavailability of 101% (AUC0_in/i,,i,y). ln the fed state, the median lag time was 4 hours. Cmax was 105% compared to DecortinR, and relative bioavailability (AUC0.i,v,,/i) was 113%. Compared to the formulation in the semi-fasted state, the formulation in the fed state was 108% on Cnzax and 112% on
AUCC-fy'inizy
c
18
Wherein coating material about the (X-Y) axis is relatively less dense than the coating material disposed about the (A-B) axis and the coating material about the (X-Y) axis is more permissive towards ingress of aqueous media than the coating material disposed about the axis (A-B), and wherein the axis (A-B) is the axis of the direction of movement of the punch used in the press-coating of the tablet: said tablet comprising the following ingredients Core of 5 mg prednisone tablet: Prednisone 8.33% as a percentage by weight in said core; Lactose monohydratc 64.47% as a percentage by weight in said core; Povidone 6.67% as a percentage by Weight in said core; Croscarmellose sodium 18.33% as a percentage by weight
in said Core;
10
15
20
25
30
Red ferric oxide 0.5% as a percentage by weight in said core Magnaium stearate Vegetable origin 1.0% as a percentage by Weight in said core; Colloidal silicon dioxide 0.5% as a percentage by weight in said core; Coating: Dibasic calcium phosphate dihydrate 50% as a percentage by weight in said coadng; Glyceryl behenate 40% as a percentage by weight in said coating; Povidone 8.40% as a percentage by weight in said coating; Yellow ferric oxide 0. l % as a percentage by weight in said coating; Magnesium stearate Vegetable origin 1.0% as a percentage by weight in said coating; Colloidal silicon dioxide 0.5% as a percentage by weight in said coating.
4 |.1_1-A...-..-...1:..,_ ..|..:... 1 1 wuciern, ._.I..._,.:..upuu 21LlUlllLlb' .\.I....I..I.~ L.cm.inc: Laurel aucurcung tu cialul
35
40
45
50
These results demonstrate that formulations of the present 55 invention display excellent bioavailability with no significant effect of food. The invention claimed is: 1. A press-coated tablet comprising a core containing 5 mg ofprednisone and a coating around thecore, said core being 60 disposed within said coating such that the coating thickness about an axis (X-Y) is thicker than the coating about an axis (A-B) orthogonal to (X-Y), Wherein the thickness ofthe coating about the axis (X-Y) is selected such that the coating ruptures upon immersion 65 in an aqueous medium after a period ofbetween about 2 to about 6 hours to release the drug,
tration to a patient, the lag time before drug release is 2 to 6 hours. 3. The tablet according to claim 1, said tablet having an in vitro dissolution profile using USP dissolution apparatus No. 2, at a stirring rate of 100 rpm and in a dissolution medimn of 500 mL purified water, wherein said dissolution profile comprises a median lag time of about 4 hours with at least 80% of a dwg substance being released after 4.5 hours and about 100% of the drug substance being released alter 5 hours. 4. The tablet according to claim 1 wherein intrasubject or inter-subject variability in Tmax differs by less than +/-20% whetherornot a patient is in a fed ora fasted (fed/fastw) state. 5. The tablet according to claim 1 wherein upon administration to a patient the ratio of Cmfzx fed/fasted upon single dosing is 0.7 to 1.43. 6. The tablet according claim 1 wherein upon administration to a patient the ratio of AUC fed/fasted upon single dosing is 0.8 to 1.25. 7. A pharmaceutical package containing a tablet according to claim 1 together with labelling or instmetions that the tablet can be taken with or without food. 8. A method of treating arthritic pain, allergies, asthma, Crohn's disease, ulcerative colitis, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) by providing to a patient in need of treatment a tablet according to claim 1. 9. A method of preparing a tablet according to claim 1 comprising the steps of: (a) forming a first granulate-containing coating material; (b) forming a core comprising a second granulate-containing core material; and (C) press coating the first granulate-containing coating material around the core.
>! <
>| <
> I<
> |=
>| <
EXHIBIT E
|1111\|||||||||1||||||||||||||1IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIq
US008394407B2
<12> United States Patent

Vergnault et al
(75) Inventors: GuyVergnault,Kembs (FR);Pascal Grenier, Kappelen (FR); Christophe Dragan, Geispitzen (FR) (73) Assignee: Jagotec AG, Muftenz (CH) Subject to any disclaimer, the term ofthis patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days.
Thls patent 1s subject to a termmal d1sclaimer.
(10) Patent No.: US 8,394,407 B2 (45) Date of Patent: *Man 12, 2013
5,567,696 A 10/1996 McGuire et al. 5,792,476 A 8/1998 Hallgrcn 6,183,780 B 1 2/2001 Van Balkcn et al 6.365.185 B1 4/2002 Ritschel et al. 6,488,960 B1 12/2002 Bardsley 6,599,284 B2 7/2003 Faour 6,620,439 B 1 9/2003 Mehta 6,733,784 B1 5/2004 Ayres 8,168,218 B2 *K 5/20 12 Vergnault et al 2004/0018327 A1 1/2004 Wynn et al. 2005/0008702 A1 1/2005 Faour et al. 2006/0057200 A1 3/2006 Schaeflier
424/464
( *' ) Notice:

EP
EP FD
EP EP EP JP
(21)
<22>
Appl. No.: 13/428,548

Fil ed
Mar. 23, 2012
A2 A1 1 275 381 A1 I 067 910 A1 2001_010950 A
0 463 877 0 673 645 0 776 660 0 939 623
A1
A2
1/ 1 992 9/ 1 995 6/ 1 997
2/2002
1/2003
5/2004 1/2001
(Continued) (65)

US 2012/0177739 A1 Jul. 12, 2012 OTHER PUBLICATIONS
Conte et al. (1993) Biomaterials 14: 1017-1023
Related U.S. Application Data (63) Continuation of application No. 10/554,538, filed as application No. PCT/1B2004/001693 on Apr. 23, 2004, now Pat. No. 8,168,218 30
(Continued)
Primary Examiner - Paul Dickinson

(74) Attorney, Agent, or Firm - Muriel Libeno, Esq.; Mintz Levin Cohn Ferris Glovsky and Popeo, P.C.

(GB) 0309342.4 (2006.01)
Apr. 24, 2003
(51> Int. cl A6IK 9/48
(57)
ABSTRACT
(52) U.S.Cl. 424/463 (58) Field of Classification Search None See application Hle for complete search history
5
References Cited U.S. PATENT DOCUMENTS

51279,832 A 5,464,633 A 1/1994 Greissinger et al 11/1995 Conte et al.
A tablet comprising a core containing an active agent, and a coating, the core being disposed within the coating such that the coating has a thickness about a longitudinal axis (X-Y) of about 4.85 to 4.95 mm. The position of the core within the coating dictating that the active agent is released rapidly after a lag time during which time no active agent is released. 19 Claims, 2 Drawing Sheets
E3
E 1
US 8,394,407 B2
Page 2

WO WO WO WO WO WO WO WO WO WO WO WO WO WO WO WO WO-92/00064 A1 WO-92/1 1845 A 1 WO-93/19741 A1 WO-96/40078 A1 WO-0 1/08421 A2 WO-01/52819 A1 WO-0 1/68056 WO-0 1/68056 A1 WO-01/80824 A2 WO-02/00204 A1 WO-02/072033 WO-02/072034 A2 WO-03/075919 A1 WO-03026626 A3 WO-2004028510 A1 WO-2004/093843 A1
1/1992
7/1992
10/1993 12/1996
WO WO WO
WO-2004/093850 A1 WO-2004/l03349 A2 WO-2005/027843 A2
11/2004 12/2004 3/2005
OTHER PUBLICATIONS
Fukui et al, (2000) J Controlled Release 68: 215-223. Lin et al. (2001) .L Pharmaceutical Sciences 90: 2005-2009. Zlatldna, A.P., "The Modem Therapeutic Tactics of Inflammatory Bowel Disease, Consilium Medicum", Gastroenterology 6 (1): 2004 (English machine translation appended), GB Search Report dated Aug. 22, 2003 corresponding to GB 0309342.4. GB Search Report dated Oct. 23, 2003 corresponding to GB 0309342.4. International Search Report mailed Oct. 21, 2001 corresponding to PCT/1B2004/001693.
2/2001 7/2001 9/2001 9/2001

11/2001 1/2002
9/2002 9/2002 9/2003

10/2003
4/2004 11/2004
* cited bv examiner
U.S. Patent
Mar. 12, 2013
Sheet 1 of 2
Us 8,394,407 B2
3
e a
vuArns.|\.ra\1rvv"1\|~r\lv-I
? s G. "s
U.S. Patent
Mar. 12, 2013
Sheet 2 of 2
Us 8,394,407 B2
% Reelease - Predniscma
,,........,.~..~....... M.. . . . . " ...... ..."~...-..\-~~ "V `"..`.._............. \~.--.--.-. ___,,,_....~-,_-;`::,;,\\~--;-:ww---w--~\-~.-\ _,.~\.~\~ ""-~`~."""-_~-" va W . ,,_,.,,,m\-,""`..._.__...---;~;..;= _...w...\ v` `_~,`~\. \w~\<~w\M~.- _...--"._ ___,_,,,,,_.-.-... .-..........._..."....."~ .
-'gQ0_(3
.,,`.-~`~,~-."-,..-- _ _,.,,_...w-.~.,.,w~-~....
s;>.<>
i.
m
a> ws
60.0
.Q
Q) az:
49.0
20.0
0 _ 0
fl~-~-~~-~<-~~~-~-~~~--~--~=---~---- Y
"W
`;"~"`.-- . -... ~'~;'
r,",,,~ù.1vg\.T.q.\q\\\--\\x1N
< 2 1 C i ~ ~ 5 ~\-1 ;'~B
Q "? Q
'\i
2 Q W
"9
<"
mg
'W
uzg
lf)
<9
gg
nr;
r--
<32
;"-
wg
<22
as
wg
07
:Q
ow m
<12
"Vast medium:
Tem perature;
Purifiad water
Tsrme im
Rataizcrs spead: wo m m
HQ. 2
US 8,394,407 B2
1
2
media into an active-agent-contailling core and thereby creating a lag time during which no drug substance is released. The gellable coating acts as a medium through which drug is released in a delayed or modified manner. lt is stated that the lag time can be modulated by varying the coating Weight. There are several problems with such an approach: First, release of the drug occurs by means of diffusion through the gelled coating. In the case ofdrugs that have a narrow absorption window, or in the case of drugs adapted to treat a rela tively small affected area ofthe Gl tract or colon, once the lag time has expiredit is desirable to release the drug as rapidly as possible to ensure that all or substantially all of the drug released at the desired site. A slow diifusion ofthe drug is not appropriate in such cases. Further, by attempting to control lag time by controlling the coating weight, the formulator's latitude is limited in this regard, because increasing coating weight adds additional cost to the dosage form, and it also adds to the size of the dosage form, which may make it difficult to swallow for certain patient populations such as minors and tbr the elderly or infimi. Still further, merely adjusting coat weight does not ensure that a coating is of a desired thickness at a particular site. It remains that ifthe core is not correctly positioned within a die of a press coating machine, despite having selected a particular coat weight, part of the coating may be unintentionally thinner than desired, resulting in unforeseen premature release ofthe drug. The applicant has now surprisingly found that by carefully selecting the geometry of a core Within its coating, it is possible to manipulate the coating thickness at specihc points on the tablet to ensure an appropriate coating thickness to produce tablets having a specifically tuned lag time. Furthermore, because one is able to increase thickness where it is needed in the coating, one can reduce coating material to allow use of the minimum amount necessary to achieve the desired release characteristics, thus saving on cost of materials and also reducing the overall tablet size. Still further, the applicant has found that by selecting appropriate core and coating materials, one is able not only to accurately control the lag time, one is also to ensure that all, or substantially all, of the drug substance upon expiry of the lag time is released rapidly and at the absorption site, or the locally aliected site. Accordingly, in a first aspect ofthe present invention there is provided a tablet comprising a core containing an drug substance, and a coating aromid said core, the core being disposed within said coating such that the coating thickness about an axis (X-Y) (see FIG. 1) is thicker than the coating about an axis (A-B) (see FIG. 1) orthogonal to (X-Y), and wherein the thickness of die coating about the axis (X-Y) is selected such that the coating is adapted to rupture upon immersion in a11 aqueous medituu after a period of between
about 2 to 6 hours.

This invention is concerned with a tablet comprising a core containing a drug substance and a coating that is applied to said core by means of compression-coating techniques. The tablet can contain all manner of drug substances, but is particularly suitable tbr administering those that are advantageously released only after a predetermined lag time after administration. The tablets are particularly suitable for administering lucocorticosteroids selected from prednisone, predni solone or methylpredni solone. Research into the chronopharmacological field has demonstrated the importance of biological rhythms in drug therapy. Very often, optimal clinical outcomes cannot be achieved if a drug is released constantly after ingestion. This is particularly the case if symptoms of a disease display circadian variations. ln such cases, drug release should vary in a manner that is sympathetic to these variations in order that drug plasma concentrations are at an optimal therapeutic level only when required to treat symptoms ofa disease state. ln particular, if symptoms of a disease become apparent at night, or in the early hours upon waking, the time when a patient must take its medication in order to affect the best clinical outcome requires detailed consideration. For example, most asthma attacks occur in the early hours of the moming, e.g. 4 am to 6 am. This is a result of complex circadian rhythms such as the secretion ofhydrocortisone and adrenaline. lschaemie heart diseases occur most often during the night or in the early waking hours around breakfast time. Stillness and pain associated with rheumatoid arthritis and osteoanhritis occur in the early waking hours, which is believed to be as a result of the secretion of lL-6 in the early hours of the morning, e.g. around 2 am to 4 am. With conventional immediate release dosage fonns, synchronization of drug administration with a nocturnal circadian rhythm responsible for the symptoms experienced by a patient would require a patient having to be disturbed from sleep to take a medicament during the early hours of the moming in order to achieve the most efficacious clinical outcome. Of course, this would be highly inconvenient for a patient. Accordingly, there remains a need to provide dosage forms that can be taken at a convenient hour belbre bedtime that will release an effective dose of a drug substance only after a pre-determined lag time in order to synchronise peak plasma concentrations of drug with a particular circadian rhythm. Furthermore, particularly in relation to drug substances that have a narrow absorption window, or in the case of drug substances that are adapted to treat a local condition in the colon such as Crohn's disease, ulcerative colitis, IBS and IBD there is also a need to provide a dosage fonn that rapidly releases die drug substances after reaching the end of the lag time Still further, having regard to the varied lite styles of patients, in order to reduce the inter- and intra-subject variance in bioavailability there is a need to provide a dosage form that releases a dwg with a reliable lag time, and to provide peak plasma dwg concentrations at a pre-determined time, irrespective of Whether a patient is in a fed or fasted state. Time controlled release formulations are known in the art that are able to deliver drug substances with a delined release rate after a lag time during which no drug substance is released. Such a dosage form is disclosed in WO 02/072033. This dosage form is characterized by a coating containing a natural or synthetic gum that gels in the presence of aqueous media. The coating acts as a barrier to the ingress of aqueous
5
10
15
20
25
30
35
40
45
50
55
60
65
According to the present invention, the coating thickness about the axis (X-Y) is thicker than the coating about the axis (A-B). The ratio of the thickness of the coating about the axis (X~Y) to the thickness ofthe coating about the axis (A-B) may be from 2.2 to 2.6:l.0 to 1.6. ln another aspect of the invention there is provided a tablet comprising a core containing an drug substance and a coating around said core, the core being disposed within said coating such that the coating thickness about an axis (X-Y) is thicker than the coating about an axis (A-B) orthogonal to (X-Y), and die thickness of the coating about the axis (X~Y) is at least about 2.2 nun, particularly about 2.2 to 2.6 mm, more particularly about 2.35 to 2.45 mm. The thickness of the coating around or about the axis (A-B) is not critical lor controlling the lag time. Accordingly, the
Us 8,394,407 B2
3
formulator has some latitude in selecting its thickness. It should not be so thick as to render the final tablet to large, yet on the other hand the coating should not be so thin that the coating is render weak and liable to crack under the slightest mechanical stress. Preferably, me thickness of the coating about thc axis (A-B) is about 1 .0 to about 1.6 mm. The coating thickness either side ofthe core on the axis (A-B) may or may .1 ~ r\ 1 ,~ . - 1 1-.1 /A \ not ne equal. FOI' example, on a nrst side OI me core tA-core) the coating may have a thickness ofabout 1 .2 to 1.6 mm, more preferably 1.35 to 1.45 mm, whereas on the other side of the 10 core (B-core) the thickness may be about 1 .0 to 1.4 mm, more preferably 1.15 to 1.25 mm. Accordingly, in a particular embodiment of the present invention there is provided a tablet comprising a core containing an dwg substance, and a coating, the core being dis- 15 posed within die coating such that the coating has a thickness about an axis O(-Y) of at least about 2.2 mm, more particularly about 2.2 to about 2.6 mm, still more particularly 2.35 to 2.45 mm, and the thickness ofthe coating about an axis (A-B) orthogonal to (X-Y) is between 1.0 and 1.6 mm. More par- 20 ticularly, along the axis (A-B) on a first side of the core (A-core) the thickness may be about 1.2 to 1.6 mm, more preferably 1.35 to 1.45 mm, and on a second side of the core (B-core) the thickness may be about 1.0 to 1.4 mm, more 25 preferably 1.15 to 1.25 mm. Tablets ofthe present invention are fonned by compression coating methods as will be described in more detail herein below. Compression coated tablets are generally fonned by placing a ponion of a powdered coating material in a die and tamping the powder into a compact form using a punch. A 30 core is then deposited onto the compacted coating material before the remainder ofthe coating material is introduced into the die and compression forces are applied to form the coated tablet. To ensure that the core is placed on the tamped coating material to ensure its correct geometry relative to the coating 35 in the Hnal tablet form, it is preferable to employ means for positioning the core in relation to the coating material ina die. Typically such means may be provided by a pin punch. A pin punch is a ptmch that has a convex surface that contacts the coating material to leave a small depression or hollow in the 40 tamped coating material. Thus, when the core is placed into the die on the tamped material, it sits in the depression or hollow and its correct geometry is assured in the final tablet form. The thickness ofthe coating along and about the axis ofthe 45 direction of movement of the punch (the "(A-B)" axis referred to above) is determined by the amount of coating material added to the die and the compaction force applied to form die tablet. On the other hand, the thickness ofthe coating along and about the "(X-Y)" axis is determined by the size of 50 the core, its position within the die and the diameter ofthe die. lt will be apparent to the skilled person that there is a plurality of axes (X-Y) orthogonal to die axis of movement of the punch (the "A-B" axis), which extend radially from the centre of the tablet to its circumference, and when the reference is 55 made to the diickness of the coating about an axis Xreference is being made the thickness about any or all ofthese
axes.
4 of the X-Y axis is, in part, responsible for controlling the

Lg substance from the core. Once the aqueous release of the dru medium contacts the core, the core reacts by swelling or effervescing thelreby to break open the core generally along the direction of ingress of the aqueous media (i.c. the X-Y axis) to fonn to e :ssentially two hemispheres of coating material that may renmain conjoined, which has an appearance of an opened clam shell. The reaction of the core material to the presence of the aqueous medium is likewise in part responsible for controlling the release of drug substance from the core.
During the compression ofthe coating around the core, the coating material above and below the core (the material along and about the (A~B) axis) is relatively highly compacted and dense. On the other hand, the coating material disposed along and about the (X-Y) axis is subjected to lower compaction forces and is relatively less dense. Accordingly, tl1c material about the (X-Y) axis is relatively porous and pennissive towards the ingress of aqueous media The rate of in ress of the aqueous medium through the coating along the direction
60
65
The hardness ofthe tablet is preferably at least 60 Newtons, e.g. 60 to 80 Newtons, and more particularly 60 to 75 Newtons. Hardness may be measured according to a process described in 'lhc European Pharmacopoeia 4, 2.9.8 at page 201. The test employs apparatus consisting of 2 opposing jaws, one ofwhich moves towards the other. The flat surfaces of the jaws are perpendicular to the direction of movement. The crushing surfaces of the jaws are flat and larger than the Zone of contact with the tablet. The apparatus is calibrated using a system with a precision of one Newton. The tablet is placed between thejaws. For each measurement, the tablet is oriented in the same way with respect to the direction of the applied force. Measurements are carried out on 10 tablets. Results are expressed in tenns of the mean, minimum and maximum values (in Newtons) of the force needed to crush the tablets. Tablets having a hardness within this range are mechanically robust to withstand forces generated in the stomach, particularly in the presence of food. Furthermore, the tablets are sufficiently porous about the (X-Y) plane of the tablet to permit ingress ofphysiological media to the core at an appropriate rate to ensure that the drug substance is released within an appropriate lag time, e.g. within 2 to 6 hours. As stated above, it is a preferred aspect of the present invention that the tablets are adapted to release a drug substance from the core after a pre-determined lag time, as well as being adapted to release all, or substantially all, ofthe dwg substance within a very short period oftime after the expiry of the lag time. This ensures that all, or substantially all, of the drug is released at the lntended absorption site along the Gl tract, or onto the affected site ofthe GI tract ifthe condition to be treated is a local topicalcondition. lt is preferred that the tablets ofthe present invention release all, or substantially all ofa drug substance within about % hour to about l hour after the selected lag time. This aspect of the present invention is important for delivering drugs having a rather narrow absorption window in the upper GI tract, such as the glucocorticosteroids referred to above. In such cases, the dwg should be released before the tablet can pass into the bowel, where absorption ofsuch drugs is poor. lt is made particularly important if the tablet is intended to perform in the same manner independent of the ellects of food, lt is well known that the rate at which a tablet will pass through the GI tract will vary depending on whether a patient is in a fed or fasted state. In the fasted state, a tablet will typically clear the stomach within about ' hour and 1 hour after ingestion, and thereafter take a further 4 to 5 hours to clear the upper GI tract dirough the ileosecal junction. In a fed state, a tablet may take as long as 4 hours to be cleared from the stomach, and a further 4 to 5 hours to clear the upper GI tract. Accordingly, if a tablet is to release of all, or substantially all, of its drug into the upper Gl tract irrespective of the fed state of a patient, it is preferable that the release me drug after the lag time occurs within a time limit referred to in the paragraph above.
Us 8,394,407 B2
5
It should be understood that whereas it is desirable that no drug substance is released during the lag time, some release may occur. However, any release ofdrug substance during the lag time should not exceed 10% of the total amount of drug
substance in the core.
5
6
Glyceryl behenate is an ester of glycerol and behenic acid (a C22 fatty acid). Glyceryl behenate may be present as its mono-, di-, or tri-ester form, or a mixture thereof. Preferably it has an HLB value of less than 5, more preferably approximately 2. It may be present in amounts of about 5 to 85% by weight of the coating, more particularly from 10 to 70% by weight, and in certain preferred embodiments from 30 to
50%.
10
The coating employed in a tablet according to the present invention is preferably formed of insoluble or poorly water soluble hydrophobic material. ln use, the coating optimally acts merely as a barrier to the ingress of aqueous physiological media thereby providing a drug release lag time. For the reasons set forth above, optimally the tablet should have the minimum thickness possible consistent Wim the desired lag time. Accordingly, employing water insoluble or poorly, soluble hydrophobic coating materials, one is able to produce a coating that is relative recalcitrant to the ingress ofmoistuure and so long lag times can be achieved with relatively thin coatings. Further, in order to achieve dw rapid release of drug substance alter the lag time has expired, it is desirable that the coating contains no, or substantially no, ingredients that swell and gel agents to such an extent that the coating acts as a diflilsion barrier to the release of drug substance. In this regard, it is preferable that the coating contains no, or substantially no, materials such as natural or synthetic gums that modulate release of the drug substance through an intact swollen coating. Drug substance is released from the core as a result of the physical mpturing of the coating and not as a result of thc drug substance difliising through a swollen coating material. That the mechanism of drug release is substantially dependent on the physical splitting of the coating, and not on a diilusion process through a swellable and gellable coating, means that a wide range of drug substances can be delivered from tablets according to the invention in a reliable and reproducible manner. The tablet coating may contain one or more water insoluble or poorly soluble hydrophobic exciplents. Such excipients may be selected from any of the known hydrophobic cellulosic derivatives and polymers including alkylcellulose, e.g. ethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, and derivatives thereof; polymethacrylic polymers, polyvinyl acetate and cellulose acetate polymers; fatty acids or their esters or salts; long chain fatty alcohols; polyoxyethylene alkyl ethers; polyoxyethylene stearates; sugar esters; lauroyl macrogol-32 glyceryl, stearoyl macrogol-32 glyceryl, and the like. Hydroxypropylmethyl cellulose materials are preferably selected from those low MW and low viscosiw materials such as E-Type methocel, and 29-10 types as defined in the USP. Other agents or excipients that provide hydrophobic quality to coatings may be selected from any waxy substance known for use as tablet excipients. Preferably they have a HLB value of less than 5, and more preferably about 2. Suitable hydrophobic agents include waxy substances such as carnauba wax, paraffin, rnicroerystalline wax, beeswax, cetyl ester wax and the like; or non-latty hydrophobic substances such as calcium phosphate salts, eg. dibasic calcium phosphate.
15
20
25
30
35
40
45
50
55
Preferably the coating contains a calcium phosphate salt, glyceryl behenate, and polyvinyl pyrollidone, or mixtures thereot and one or more adjuvants, diluents, lubricants or fillers. Preferred components in the coating are as follows, with generally suitable percentage amounts expressed as percentage weight of the coating. Polyvinyl pyrollidone (Povidone) is preferably present in amounts of about 1 to 25% by weight or the coating, more particularly 4 to 12%, e.g. 6 to 8%.
60
65
Calcium phosphate salt may be the dibasic calcium phosphate dihydrate and may be present in an amount ofabout 10 to 90% by Weight ofthe coating, preferably 20 to 80%, e.g. 40 to 75%. The coating may contain other common tablet excipients such as lubricants, colourants, binders, diluents, glidants and taste-masking agents or flavourants. Examples of excipients include colourants such a ferric oxide, e.g. yellow ferric oxide; lubricants such as magnesium stearate; and glidants such as silicon dioxide, e.g. colloidal silicon dioxide. Yellow ferric oxide may be used in amounts of about ().()l to 0.5% by weight based on the coating; magnesium stearate may be present in amounts of 1 to 20% by weight of the coating, more preferably 2 to 10%, e.g. 0.5 to l.0%; and colloidal silica may be used in amounts of 0.1 to 20% by weight of the coating, preferably l to 10%, more preferably 0.25 to l.0%. The core comprises in addition to a dmg substance, a disintegrating agent or mixmres of disintegrating agents used in immediate release fonnulations and well know to persons sldllcd in the art. The disintegrating agents useful in the exercise ofthe present invention may be materials that effervesce and or swell in the presence of aqueous media thereby to provide a force necessary to mechanically disnupt the coating material. Preferably a core contains, in addition to the drug substance, cross-linked polyvinyl pyrollidone and croscarmellose sodium. The following is a list of preferred core materials. The amounts are expressed in terms of percentage by weight based on the Weight of the core. Cross-linked polyvinyl pyrollidone is described above and is useful as a disintegrating agent, and may be employed in the core in the amotmts disclosed in relation to the core. Croscarmellose sodium is an intemally cross-linked sodium carboxymethyl cellulose (also known as Ac-Di-Sol) useful as a disintegrating agent. Disintegrating agents may be used in amounts of 5 to 30% bv weight based on the core. However, higher amounts of certain disintegrants can swell to form matrices that may modulate the release of the drug substance. Accordingly, particularly when rapid release is required after the lag time it is preferred that the disintegrants is employed in amounts of up to 10% by weight, e.g. about 5 to 10% by weight. The core may additionally comprise common tablet excipients such as those described above in relation to the coating material. Suitable excipients include lubricants, diluents and fillers, including but not limited to lactose (for example the mono-hydrate), ferric oxide, magnesium stearates and colloidal silica. Lactose monohydrate is a disaccharide consisting of one glucose and one galactose moiety. lt may act as a tiller or diluent in the tablets of the present invention. lt may be present in a range of about 10 to 90%, preferably from 20 to 80%, and certain preferred embodiments from 65 to 70%. As stated above, it is an important aspect of the present invention that core is correctly located within the coating to ensure that a tablet has the appropriate coating thickness. In this way, lag times will be reliable and reproducible, and
US 8,394,407 B2 7
8
antihistamines (e.g., azatadine maleate, brompheniramine intra-subj ect and inter-subject variance in bioavailability can maleate, carbinoxamine maleate, chlorpheniramine maleate, be avoided. It is advantageous to have a robust in process control to ensure that tablets in a batch contain cores having dexchlorpheniramine maleate, diphenhydramine hydrochlothe appropriate geometry in relation to the coating. Controls ride, doxylamine succinate, methdilazine hydrochloride, can be laborious in that they require an operator to remove 5 promethazine, trirneprazine tartrate, tripelemiamine citrate, random samples from a batch and to cut them open to physitripelennamine hydrochloride and triprolidine hydrochlocally inspect the quality of the core (i.e. whether it is intact, ride); and whether it is correctly located). Furthermore, if a signifiantibiotics (e.g., penicillin V potassium, cloxacillin cant ntunber of tablets from the sample fail, a complete batch sodium, dicloxacillin sodium, nafcillin sodium, oxacillin 10 oftablets may be wasted. Applicant has found that ifone adds sodium, carbenicillin indanyl sodium, oxytetracycline hydroto the core a strong colourant such as iron oxide, such that the chloride, tetracycline hydrochloride, elindamycin phosphate, core visibly contrasts with the coating when as strong light is clindamycin hydrochloride, clindamycin palmitate HCL, linshone on the tablet, it is possible for any faults in the position comycin HCL, novobiocin sodium, nitrofurantoin sodium, or integrity of the core to be picked up automatically by a metronidazole hydrochloride); antituberculosis agents (e.g., camera appropriately located adjacent a tabletting machine to 15 isoniazid); inspect tablets as they are ej ected therefrom. In this way, if a cholinergic agents (e.g., ambenonium chloride, bethanecol faulty tablet is identified it is possible to halt production and chloride, neostigmine bromide, pyridostigmine bromide); correct any problems in the manufacturing process quicldy, antimuscarinics (e.g., anisotropine methylbromide, clidthereby potentially avoiding wastage of batch quantities of 20 inium bromide, dicyclomine hydrochloride, glycopyrrolate, tablets. hexocyclium methylsulfate, homatropine methylbromide, Whereas colourants contained in the core are useful for this hyoscyamine sulfate, methantheline bromide, hyoscine purpose, equivalent solutions are also possible. For example, hydrobromide, oxyphenoniuin bromide, propantheline broinstead of a colourant, one can include a material that is mide, tridihexethyl chloride); opaque to x-rays, such as barium sulphate. lf an x-ray imager sympathomimetics (e.g., bitolterol mesylate, ephedrine, is then coupled to a tablet machine, the core will contrast with 25 ephedrine hydrochloride, ephedrine sulphate, orciprenaline the coating material and the x-ray imager will pick up any sulphate, phenylpropanolamine hydrochloride, pseudoephefaults in the positioning or integrity of the core in a similar drinc hydrochloride, ritodrine hydrochloride, salbutamol sulfashion. phate, terbutaline sulphate); The amount of dwg substance employed in tablets of the sympatholytic agents (e.g., phenoxybenzamine hydropresent invention will depend on the particular drug sub- 30 chloride); miscellaneous autonomic drugs (e.g., nicotine); stance used, the condition of the patient and the nature and iron preparations (e.g., ferrous gluconate, ferrous sulseverity ofthe condition to be treated. A typical drug loading phate); might be from l to 50% by weight of the core. haemostatics (e.g., aminocaproic acid); As stated above a wide variety of drug substances may be cardiac dmgs (e.g., acebutolol hydrochloride, disopymemployed in the present invention. Drugs for treating condi- 35 mide phosphate, flecamide acetate, procainamide hydrochlotions the symptoms of which result from noctumal circadian ride, propranolol hydrochloride, quinidine gluconate, timolol rhythms are particularly suitable. Accordingly, drugs for maleate, tocamide hydrochloride, verapamil hydrochloride); treating incontinence, sleep disorders, apnoea, asthma, epiantihypertensive agents (e.g., captopril, clonidine hydrolepsy, bronchitis, parldnsonism, rheumatoid arthritis, allergic rhinitis and ischaemic heart diseases, cluster and migraine 40 chloride, hydralazine hydrochloride, mccamylarnine hydrochloride, metoprolol tanrate); vasodilators (e.g., papaverine headache, congestive hean failure, and depression are parhydrochloride); ticularly suitable for use in tablets according to the present non-steroidal anti-inflarmnatory agents (e.g., choline saliinvention. Further, drug substances that are metabolized by cylate, ibuproien, ketoprofen, magnesium salicylate, cytochrome P450 are also panicularly suitable, they include: Amitriptyline, caffeine, clomipramine, clozapine, fluvox- 45 meclofenamate sodium, naproxen sodium, tolmetin sodium); opiate agonists (e.g., codeine hydrochloride, codeine phosamine, haloperidol, imipramine, mexilitine, oestradiol, olanphate, codeine sulphate; dextromoramide tartrate, hydroczepine, paracetamol, propranolol, tacrine, theophylline, Warodone bitanrate, hydromorphone hydrochloride, pethidine farin, Bupropion, Cyclophosphamide, Celecoxib, hydrochloride, methadone hydrochloride, morphine sulDiclofenac, Flubiprofen, Ibuprofen, glimepirideindome, thacin, naproxen, phenyloin, piroxicam, tenoxicam, citalopram, 50 phate, morphine acetate, morphine lactate, morphine meconate, morphine nitrate, morphine monobasic phosphate, mordiazepam, lansoprazole, omeprazole, pantoprozole, prophine tartrate, morphine valcrate, morphine hydrobromide, panolol, topiramate, Alpranolol, chlorpromazine, clomimorphine hydrochloride, propoxyphene hydrochloride); pramine, codeine, Desipramine, dextromethorphan, diphenanticonvulsants (e.g., phenobarbital sodium, phenyloin hydramine, donepezil, flecamide, fluoxetine, labetalol, Methadone, metoprolol, mianserin, nortripyline, 55 sodium; troxidone, ethosuximide, valproate sodium); tranquilizers (e.g., acetophenazine maleate, chlorpromondansetron, oxprenolol, oxycodone, paroxetine, perhehexyazine hydrochloride, fluphenazine hydrochloride, prochlorlene, pethidine, promethazine, risperdone, thioridazine, ticloperazine edisylate, promethazine hydrochloride, thioridazine pidine, timolol, trimipramine, venlafaxine, paracetamol, hydrochloride, trifluoroperazine hydrochloride, lithium citalprazolam, amiodarone, budesonide, buprenorphine, buspirone, Calcium Channel Blockers, carbamazepine, 60 rate, moliudone hydrochloride, thiothixine hydrochloride); chemotherapeutic agents (e.g., doxorubicin, cisplatin, cisapride, clarithromycin, clonazepam, cocaine, cortisol, floxuridine, methotrexate, combinations thereoD; cyclosporine, dexamethasone, erythromycin, fentanyl, ketolipid lowering agents (e.g., gemfibrozil, clonbratc, HMGconazole, losartan, miconazolc, midazolam, quinidine, serCoA reductase inhibitors, such as for example, atorvastatin, traline, statins, tacrolimus, tamoxifen, TCAS, triamzolam, 65 cerivastatin, liuvastatin, lovastatin, pravastatin, aimvastatin); zolpidem, or mixtures thereof. H.sub.2-antagonists (e.g., cimetidine, lamotidine, nizatiAdditional examples ofdrug classes and drugs that can be dine, ranitidine HCl); employed in tablets of the present invention include:
Us 8,394,407 B2
9 10
convenience and flexibility of dosing, although dosage fonns anti-coagulant and anti-platelet agents (e.g., warfarin, containing larger or smaller amounts ofdrug substance could cipyridamole, ticlopidine); be employed if desired. bronchodilators (e.g., albuterol, isoproterenol, metaproterParticularly preferred tablets according to the invention enol, terbutaline); stimulants (e.g., benzamphctaminc hydrochloride, dextro- 5 comprising in the core a glucocorticosteroid selected from the group consisting of prednisone, prednisolone and methylamphetamine sulphate, dextroamphetamine phosphate, prednislone, and cross-linked polyvinyl pyrollidone, crossdiethylpropion hydrochloride, fenfluramine hydrochloride, linked sodium carboxymethyl cellulose, and one or more methamphetamine hydrochloride, niethylphenidate hydroadjuvants diluents, lubricants or filler materials as hereinchloride, phendimetrazine tartrate, phenmetrazine hydro10 above described. Preferably the coating comprises a calcium chloride, caffeine citrate); phosphate salt, glyceryl behenate, cross-linked polyvinyl barbituratcs (e.g., amylobarbital sodium, butabarbital pyrollidone and one or more adjuvants, diluents, lubricants or sodium, secobarbital sodimn); tiller materials as hereinabove described. sedatives (e.g., hydroxyzine hydrochloride, rnediprylon); The composition ofone particularly preferred embodiment expectorants (e.g., potassium iodide); 15 of the invention is: antiemetics (e.g., benzaquinarnide hydrochloride, rnetoCore of 5 mg Prednisone Tablet: clopropamide hydrochloride, trirnethobenzamide hydrochloPrednisone 8.33% ride); Lactose monohvdratc 64.47% gastro-intestinal drugs (e.g., ranitidine hydrochloride); Povidone 6.67% heavy metal antagonists (e.g., penicillamine, penicillamine 20 Croscarmellose sodium 18.33% hydrochloride); Red ferric oxide 0.5% Magnesium stearate Vegetable origin 1.0% antithyroid agents (e.g., methimazole); Colloidal silicon dioxide 0.5% genitourinary smooth muscle relaxants (e.g., iiavoxate Coating hydrochloride, oxybutynin hydrochloride); vitamins (e.g., thiamine hydrochloride, ascorbic acid); 25 Dibasic calcium phosphate dihydrate 50% Glyceryl behenate 40% unclassihed agents (e.g., amantadine hydrochloride, Povidoue 8.40% colchicine, etidronate disodium, leucovorin calcium, methylYellow ferric oxide 0.1% ene blue, potassium chloride, pralidoxime chloride. Magnesium stearate Vegetable origin 1.0% steroids, panicularly glucocorticoids (e.g., prednisolone, Colloidal silicon dioxide 0.5% methylprednisolone, prednisone, cortisone, hydrocortisone, 30 Another preferred embodiment is as follows methylprednisolone, betamethasonc, dexamethasone, triamCore of 1 mg Prednisone Tablet: cinolone). Drnrlnicnnn 1 $704. Notwithstanding the general applicability of the tablets in Lactose monohydrate 71.13% relation to a wide range ofdrug substances, the present inven- 35 Povidone 6.67% tion is particularly suited to delivery of the glucocorticosterCroscarmellose sodium 18.33% oids aforementioned and particularly prednisone, prednisoRed ferric oxide 0.5% lone and methylprcdnisolone. These steroids are useful in the Magnesium stearate Vegetable origin 1.0% treatment i.a, of rheumatoid arthritis and joint pain. As Colloidal silicon dioxide 0.5% already stated, the symptoms of these conditions appear 40 Coating according to a circadian rhythm and with great predictability Dibasic calcium phosphate dihydrate 50% during the early hours of the morning. Accordingly, the gluGlyceryl behenate 40% coconicosteroids, and in panicular prednisone are eminently Povidone 8.40% suited for delivery irom tablets according to this invention not Yellow ferric oxide 0.1% Magnesium stearate Vegetable origin 1.0% only because of their narrow absorption window, but also 45 because a tablet may be administered in the evening before Colloidal silicon dioxide 0.5% bedtime anytime around 8 pm tuitil midnight, e.g. around It is surprising that the tablets containing the glucocorticosteroids display such rapid release given that the rate of 10-12 at night, to deliver maximum plasma concentration of the dmg substance before maximum secretion ofIL-6 (which release relies to some extent on the wetting of the core, and occur around 2 am to 4 am), thereby effectively addressing 50 these steroids are rather hydrophobic in nature. The tablets described above are press-coated tablets comthe underlying causes of the morning symptoms. In this way, prising a core and a coating covering said core. However, these symptoms are more effectively treated. variants of this basic construction are within the ambit ofthe As used above, prednisone refers to the compound and its present invention. Thus, the press-coating may be thrther salts or derivatives thereof, including prednisone 21 acetate. As used above, prednisolone refers to the compound and its 55 coated with an outer coating that may be ihnctional and/or aesthetic in its design. For example, functional coatings may salts or derivatives including die 21 -acetate, its 21-tert-butyl include the addition an immediate release coating containing acetate, 21-succinate sodium salt, 21-stearoylglycolate, a drug substances that may be the same or different to the drug 21-m-sulphobenzoate sodium salt, and its trimethylacetate. substance contained in the core. Methylprednisolone, as used above refers to the compound In this manner, the tablet can affect a pulsatile release that or and its salts and derivatives thereofincluding its 21 acetate, 60 is of use in treating symptoms based on circadian rhythms, 21-phosphate disodium salt, 21-succinate sodium salt, and its such as sleep disorders. In this regard one can employ seda acetonate tive hypnotics in such dosage forms, for example those drug Typically a core may contain about 0.1 to 50% by weight, substances mentioned described in U.S. Pat. No. 6,485,746 more particularly 1 to 20%, still more particularly l to 10% by weight of steroid based on dle total weight of the core. In me 65 Pulsatile release dosage forms may also find general applicability with a wide range ofactive substances for the treatment case ofprednisone, it may be employed in amounts to provide a total W eight per unit dosage lorm of 1 or 5 mg, to otler ofa wide range ofindications to provide patients with a more
US 8,394,407 B2
12
convenient dosage schedule. For example, pulsatile release can provide an alternative to multiple administrations of immediate release lorms. Functional coatings also include enteric coatings covering the press-coating. Enteric coated forms may be of use in treating local conditions in the bowel such as Crohn's disease, ulcerative colitis, IBS and IBD. In this embodiment, the enteric coating would prevent release of any drug before the tablet enters the bowel. Aesthetic coatings include taste, masking coatings and coloured coatings as a generally well known in the art. lt is well known in the art that food can change the bioavailability of a drug. Food can alter the bioavailability of a dwg by various means such as delaying gastric emptying, changes in gastrointestinal pH, changes in luminal metabolism, and physical and chemical reactions of food items with a dosage form or drug substance. This change in bioavailability as a consequence of food intake is often referred to as a "food effect". Food effects are quite common in modifiedrelease dosage forms, and also for drugs that have either poor solubility or poor permeability or both (BCS Class ll, lll, and absorption site, or a locally diseased site along the GI tract and bowel. Such medicaments are provided by the present invention Currently, there are no bioavailability or bioequivalence regulatory guidelines available for Tmax' However, the Guidance For Industry "Food Effect Bioavailability and Fed Bioequivalence Studies", US Department of Health (CDER) December 2002 suggests that any difference in Tmax should not be clinically relevant. Whether such a difference will be clinically relevant will depend on die drug delivered and the particular indication. Applicant has found that in respect of formulations ofthe present invention the effect of food on the median value of Tm is a difference of only about +/-20%,
10
15
more particularly +/-l0%

Still further, applicant has found medicaments containing drug substances exhibiting no significant effect of food with respect to bioavailability of the drug substance in terms of
Cmax and AUC.
20
IV).
The applicant has surprisingly found that a tablet that is adapted to release all, or substantially all, of a drug contained therein within a time (Tlag) ofbetween 2 and 6 hours (median time) after administration. Funhermore, the applicant has surprisingly developed a tablet adapted to release a drug substance after a lag time that can deliver a drug to a patient, which upon absorption the peak drug concentration Cmax will be reached in a time Tmax that is independent of a patient's food intake. 'l`,,,ax is a term well known in the art that refers to the time elapsed between drug administration and the maximum recognized term that relates to the peak plasma concentration of a drug. Tmax is an important parameter particularly in relation to medicaments that are intended to be taken at a time convenient for a patient, but which release dmg substances after a lag time in order to synchronise drug release widi a circadian rhythm, and in particular a nocturnal circadian rhythm. By way of example, the glucocorticosteroids, referred to above, e.g. prednisone, are useful in the treatment of i.a. arthritic conditions such as rheumatoid arduitis and osteoarthritis. Debilitating symptoms are often experienced by a patient upon waking. Current therapy requires a patient to take DecortinR upon waking. However, this is not the most efficacious Way of treating the symptoms, as they are believed to be associated with the secretion oflL-6, which occurs during the early mominghours, e.g. from about 2 to 4 am.A medicament that can reach C/:mx that is coincident Wim or anticipates the release of IL-6 is potentially of greater benefit to a patient. Funhennore, given the varied lifestyles of individuals, patients taking medicament between S pm and bedtime, e.g. from 10 pm to midnight, may be in a variety of fed states, it is even more advantageous that Tmax should be independent of food intake. Medicaments that can have a pre-determined lag time, and which release drug substance after this lag time in a manner that provides a Tmax independent of considerations of the fed or fasted state of a patient are ofpotentially great benefit, not only in relation to die glucocorticosteroids and the treatment of ardiritis, but for other active substances that are advantageously delivered in synchronieity Wim a circadian rhythm, or even in relation to drug substances whose eflicacy depends on their ability to be delivered accurately to a particular
25
30
plasma concentration CM is reached. Cnzax is also an art 35
40
45
50
55
60
65
The "food effect" as it relates to the bioavailability of drug substances is a well doctunented phenomenon in relation to drug delivery that describes the variance in uptake of a drug substance by patients depending upon whether the patients are in fed or fasted sfates. The presence or absence of a food effect may be quantified by making Area under the Cuwe (AUC) and/or Cmax measurements according to methods well known in the art. Typically AUC measurements and Cmax measurements are made by taking timed biological fiuid samples and plotting the serum concentration of drug substance against time. The values obtained represent a number ofvalues taken from subjects across a patient population and are therefore expressed as mean values expressed over the entire patient population. By comparing the mean AUC and/ or Cmax values, one can determine whether a drug substance experiences a food effect. Food effect studies may be conveniently carried out on an adequate number of healthy volunteers, the number being sufficient to generate sufficient data for appropriate statistical assessment to be made. Preferably the number of subjects should not be less than 12. To study the effect of food on the bioavailability of a drug substance one may use any conventional study design known in the art, for example a randomised; balanced single-dose, two-treatment, two-period, two-sequence crossover design. Analysis may be carried outusing any of the programs known in the art such as SAS PROC GLM, software from the SAS institute, Cary N.C. ln quantitative terms, a drug substance may be said to exhibit no food effect ifa 90% conndence interval (Cl) for the ratio of means (population geometric means based on log transformed data) offw and fasted treatments fall within the interval of 0.8 to 1.25 for AUC and/or 0.7 to 1.43 for C,.,.,, Accordingly, the present invention provides in another of its aspects a tablet as defined herein above displaying a ratio AUC fed/fasted after single dosing of 0.8 to 1 .25 or the ratio Cm" fed/fasted after single dosing of 0.7 to 1.43. A "fed" subject conveniently may be considered as a subject that has fasted for at least 10 hours before receiving a standard FDA recognised high fat meal. The medicament may then be administered with water shortly after completion ofthe meal, e.g. within 5 minutes thereof. Preferably no food should be taken for a period of, e.g. 4 hours after receiving medicarnent although small quantities of water may be permitted after, e.g. 2 hours after receiving the medicament. A "fasted" subject conveniently may receive medicament with water alter at least 10 hours fasting. Thereafter, no food
Us 8,394,407 B2
13
may be taken for a period of, e.g. 4 hours although small quantities of W ater may be taken after, e.g. Z hours after receiving medicament. A standard FDA high fat meal as referred to hereinabove may comprise any meal that would be expected to provide maximal perturbation due to the presence of food in the GI tract. Said high fat meal typically may comprise 50% of its caloric value in fat. A representative example may be 2 eggs fried in butler, 2 strips of bacon, 2 slices toast with butter, 4 ounces fried potato, and 8 ounces milk. By application of the teachings of the present invention tablets may be provided that display reduced variability in resumption/bioavailability levels achieved both for individual patients receiving a drug as well as between individuals.
14
thickness of the coating, die of appropriate internal dimensions may be placed in the rotating platfonn, and the amount of coating material fed into the die may be adjusted accordingly. Suitable rotary tablet machines having high process speeds are known in the art and need no further discussion here. Cores may likewise be formed using a conventional rotary tablet machine. Cores are preferably compressed under compression forces suiiicient to provide cores having a hardness of about 60 Newtons at least, e.g. 50 to 70 Newtons. Cores having hardness in this range give desired release characteristics. If desired, the cores can be formed at the same time as the press coated tablets are produced. In such case, one might employ a Manesty Dry Cota. Such a press consists of two side-by-side and inter-connected presses where the core is made on one press before being mechanically transferred to the other press for compression coating. Such equipment and techniques for making tablets using such equipment are known in the art and no more needs to be said about this here. Cores are preferably formed according to wet granulation techniques generally known in the art. ln a typical procedure, core materials are sieved and blended. Granulating fluid, typically water is then added to me blend and the mixture is homogenized to form a granulate, which is then sprayed dried or dried on a lluid bed drier to obtain a granulate with requisite residual moisture. Preferably the residual moisture content is from about 0.4 to 2.0% by weight. The granulate is then sized by passing it through screens of desired aperture. At this stage, any adjuvants are sized and added to the granulate to form the core composition suitable for compression. The sldlled person will appreciate that a coating composition can be formed in an analogous manner. The skilled person will also appreciate that granulates may be obtained having a range of panicle sizes. lt is preferred that the coating granulate has a fine fraction that is less than 30%. By "fine fraction" is meant granulate having particle size of up to about 63 microns. Preferred feamres forthe second and subsequent aspects of the invention may be as for the first aspect muratis mutandis. FIG. 1: is a representation of a tablet in cross section showing the coating and core and the axes (A-B) and (X-Y). FIG. 2: Shows an in-vitro dissolution profile of the dosage form of Example 2. There now follows a series of examples that serve to illustrate the invention.
10
15
The tablets of the present invention may be packaged in a variety of ways. Generally an article for distribution includes a container for holding the tablets. Suitable containers are Well known to persons skilled in the art and include materials such as bottles, foil packs and the like. In addition, the container will have a label and an insert that describes the contents ofthe container and any appropriate warnings or instructions for use. It is an advantage of the present invention that the insert and/or label may contain instructions that the tablet may be taken with or without food, or may be absent a warning or instruction that the tablet should be taken only with food or only without food. The invention provides in another aspect, a method of forming tablets as herein above described. The tablets may be formed on conventional press coating equipment. Typically such equipment is composed ofa series ofdie are arranged on a rotating plattonn. The die are removably mounted in the platform such that differently sized die may be employed as appropriate. Each die is hollow to receive a lower punch. The punch is positioned within the die such that the upper surface of the punch and the inner surface of the die define a volume for receiving a precise amount coating material. Once loaded, the platform is rotated until the is positioned under an upper punch. The upper punch is then urged down onto the coating material under a defined compression force and the coating material is pre~compressed or tamped between me upper and lower punch. A pre-tonned core is then led into die to rest on the tamped coating. Conventional press coating apparatus may be equipped with centering devices that enable cores to be positioned both vertically and radially. This might be achieved by a tamping process, whereby an initial amount of coating material is placed in a die and is tamped with a shaped punch, such as a pin punch, that leaves an indentation in the coating material in which to receive a core. Thereafter, in a second filling operation, a precise amount of coating material is fed into the die to cover the core, and an upper punch compresses die coating material widi a defined compaction force to form tablets according to the present invention. The compression force applied during the tamping process is relatively light and is just sufficient to provide a bed of coating material to receive the core and to prevent movement of the coating material as a result of centrifugal force. Subsequent compression to form the tablet may be adjusted to give tablets of requisite hardness. Preferably, this compression force is 400 kg, although this may be adjusted by +/-30% in order to give tablets of the required hardness. The amount of coating material fed into the die can be precisely defined having regard to the density of the coating material to ensure after compression that the tablet is formed with the required coating thickness about the (A-B) axis; and the dimensions of the die is selected to provide the thickness about the X-Y axis. Should it be necessary to change the
20
25
30
35
40
45
EXAMPLE l
50
Preparation of a Prednisone-Containing Tablet The active core was prepared for the press coated system as follows. The composition of the core is detailed in Table l. Lactose rnonohydrate (Lactose PulvisH2O, Danone, France and Lactose Fast Flo NF 316, Foremost lag. Group, USA) is a filling agent with interesting technical and fmrctional properties. Lactose Pulvis'H2O is used in a blend prepared, by wet granulation and Lactose Fast Flo is used in a blend prepared for direct compression. Microcrystalline cellulose (Avicel pH 101, FMC International, Ireland) is used as an insoluble diluent for direct compression. Polyvinyl pyrrolidone (Plasdone K29-32, ISP Technology, USA) is a granulating agent, soluble in water, which has the ability of binding the powder particles. Croscarmellose sodium (AcDi-Sol, FMC Corporation, USA) is used in the fonnulation as a super disintegrant. As the external phase, magnesium stearate (Merck, Switzerland) was added as a lubricant and
55
60
65
US 8,394,407 B2
15
silicon dioxide (Aerosi1 200, Degussa AG, Germany) in order to improve How properties of the granular powder. TABLE 1
5
16
The coating blend was prepared according to the process described below. Batch size for the barrier blend was 13 kg. Weighw amounts of Emcompress, Comprilol 888 ATO, Lactose pulvis'H20, Plasdone K29-32 and Sicovit Yellow 10 E 172 Wcrc manually sieved with a screen having 0.710 mm apenures. They were placed in a Niro-Fielder PMA 65-litre mixing granulator. Then, the components were homogeneously mixed for 6 min, at impeller speed 200 rpm, without chopper. Subsequently, the granulating solution (purified water, 8.12% of the weight ofthe dry blend) was added within 2 min at impeller speed 200 rpm and chopper speed 1500 rpm using a nozzle 4.9 (spraying rate of 520 g/min). Mixing was continued for homogenisation and massing for 1 min at impeller speed 400 rpm and chopper speed 3000 rpm. The mixed wet granulate was then dried in a Niro-Fielder TSG 2 Fluidised air bed dryer. The inlet temperature was maintained at 45 C. during drying. The drying lasted 33 min to have residual moisture less than 25%. The yielded dry granulate was calibrated in a Frewitt MGI 205 granulator using a screenhaving 0.8 mm apertures for 4 min at speed 244 osc/min (graduation 7). Appropriate amounts of Aerosil 200 and magnesium stearate were manually sieved using a screen with 1.0 mm apertures. Half of the dry granulate was pul in a Niro-Fielder PMA 65-liter, followed by Aerosil 200 and then by the other half of the dry granulate. The ingredients were mixed for 2 min at impeller speed 200 rpm, without chopper. Finally, magnesium stearate was added and mixing was continued for 2 more minutes at iinpeller speed 200 rpm, without chopper. 440 mg of coating blend was press coated on a core to provide press coated tablets (9 mm diameter). 305 mg of coating blend was press coated on a core to provide press coated tablets (8 mm diameter). These different press coatings were done utilising a Kilian RUD tabletting machine. First and second loading hoppers are filledup with the coating granulatc. Between the two loading hoppers, the machine is equipped with a transfer system adapted to feed the cores. For each tablet, the first loading hopper supplies with about half of the quantity to be applied to the core. Then, the feeding system provides and positions a core centred in the die. Subsequently, the second loading hopper supplies with the other halfofthe quantity to be applied to the core. The compression
step then occurs.
Ingredients Prednisone Lactose (Lactose Pulvis H20 NF316) Polyvinyl pyrrolirlone (Plasdonc K29~32) Sodium carhoxymcthyl cellulose (Ac-Di-Sol ) Magnesium stearate Silicon dioxide (Aerosil 200) Total
Content (mg/tablet) 5.00 39.10 4.00 11.00

0. 60 10
0.30 60.00
15
The coating of the prednisone press coated tablet is of a hydrophobic, water insoluble nature. This barrier is mainly composed of dibasic calcium phosphate (Emcompress, Mendell, USA) and glyceryl behenate (Compritol 888ATO, Gattefoss, France). Polyvinylpyrrolidone (Plasdone K2932) is a granulating agent, soluble in water, which has the ability of binding the powder particles. Yellow ferric oxide (Sicovit Yellow 10, BASF, Germany) was added as a dye. A detailed composition of this barrier blend is given in table 2. TABLE 2
Comnosition of the coating
20
25
30 Ingredienrs Dibasic calcium phosphate (Emcompress ) Glyceiyl Behenate (Compritol 888 ATO) Polyvinylpyrrolidone (Plasdone K29-32) Yellow Ferric Oxide (Sicovit yellow 10 172) Silicon dioxide (Aerosil 200) Magnesium stearate Total Content (%) 50.00 40.00 8.40 0.10 0.50 00 100.00
35
The required amounts ofprednisone, Ac-Di-Sol, Lactose Pulvis H2O, Plasdone K29-32 were weighed and manually sieved with a screen having 0.710 mm apertures. The components were homogeneously mixed in a Niro-Fielder PMA 25-litre mixing granulator for 6 min at impeller speed 250 rpm without chopper. A prednisone assay was performed on this premix. Subsequently, the granulating solution (puritied water, 25.47% ofthe Weight of the dry blend) was added Within 4 min at impeller speed 2.50 rpm and chopper speed 1500 rpm, using a nozzle H1/4VV-95015 (spraying rate of 250 g/min). Mixing was continued for homogenisation and rnassing of the wet mass for 3 min at impeller speed 500 rpm and chopper speed 3000 rpm. The mixed wet granulate was then dried in a Glatt WSG5 fluidised air bed drier. The inlet temperature was maintained at 45 C. during drying. The drying lasted 20 min to get a granulate with a residual moisture less than 2 .5%. The yielded dry granulate was calibrated in a Frewitt MGI 205 granulator using a screen with 0.8 mm apertures for 3 min at speed 244 osc/min (graduation 7). Appropriate amounts of Aerosil 200 and magnesium stearate were manually sieved using a screen, with 1.0 mm apertures. Half of the dry granulate was put in a Niro-Fielder PMA 25-litre mixing granulator, followed by Aerosil 200 and then by the odier half of the dry granulate, The ingredients were mixed for 2 min at impeller speed 250 rpm. Finally; magnesium stearate was added and mixing was continued lbr 2 min at impeller speed 250 rpm.
40
45
TABLE 3
50 Eciuioment implemented for the manufacturing process Equipment Mixing granulator
55
Brand name/Type Niro-Fielder PMA 25/65 litres Glntt WSG5 Niro-Fielder TSG 2 Frewitt MGI 205 Mettler PE 360 Moisture Analyzer Brand name/Type Hata HT-AP55LS-
M anufacturer /Supplier Aromatic-Fielder AG, Bubendorf, Switzerland Maschinen und apparatebau AG, Pratteln, Switzerland Aromatic-Fielder AG, Bubendor Switzerland Frewitt SA, Granges<Pacot, Switzerland Mettler Toledo AG, Greifensee, Switzerland Manufacturer/Supplier Elisabetl1~Carbide, Antwerp, Belgium Kilian & Co GmbH, Cologne, Germany
Fluidised nir bed dryer Fluidised air bed dryer Granulator
60
Infrared moisture analyser Equipment Multilayer tablet press Dry co ati ng 65 tablet press
U/3L
Kilian RUD
US 8,394,407 B2 17
EXAMPLE 2 In 'Vitro Dissolution Profile
18
These results demonstrate that formulations of the present invention display excellent bioavailability with no significant
eilect of iood.
The in vitro dissolution profile ofa tablet containing a 5 mg 5 What is claimed is: loading of prednisone prepared according to the method of 1 . A press-coated tablet comprising a defined core containExample 1 was detennined using USP dissolution apparatus ing a pharmaceutically active agent, and a compression coatNo. 2 (paddles) and stationary baskets and applying a stirring ing around said core, the core being disposed W ithin said rate of 100 rpm, The dissolution mwium was purified water, compression coating such that the coating thickness about an i0 with a volume of 500 ml. axis (X-Y) is thicker and less dense than the coating about an After 4 hours no drug substance release is observed. Howaxis (A-B) orthogonal to (X-Y), wherein said compression ever, within 4.5 hours there is approximately 80% release and coating is formed of an insoluble or poorly water soluble by 5 hours 100% release of the drug substance (see FIG. 2). hydrophobic material and said coating is sufficiently porous is aiJoutthe (X-Y) plane of the tablet to permit the ingress of EXAMPLE 3 aqueous media to the core at a rate to ensure release of the active agent after a period of time between 2 to 6 hours A study was carried out to detennine the effect of food on wherein said period of time is followed by rupture of the the bioavailability of a 5 mg prednisone tablet described coating along the X-Y axis, wherein the compression coating above. 20 lacks ingredients that swell and gel to such an extent that the The study did not compare the tablet in the fed and fasted coating acts as a diffusion barrier to the release of the active state. Radier, the study was adjusted to take into account the agent. chrono-pharmacoldnetics of prednisone and the fact that it is 2. The tablet of claim 1, wherein the coating thickness to be administered in the evening, e.g. about 8 pm, which is about the axis (X-Y) is about 2.2 mm to about 2.6 mm and the required in order that the blood plasma levels will peak before 25 thickness about the orthogonal axis (A-B) is about 1.0 to about 1.6 mm. secretion of IL-6 to improve the efticacy of the treatment, 3. The tablet of claim 1, wherein said water insoluble or Thus the study was designed to compare the tablet during real poorly soluble hydrophobic material is selected from the time administration and with likely food intake scenarios at group consisting of hydrophobic cellulosic derivatives and this time. It was considered unreasonable that at 8 pm a subject would be approximately S hours fasted. Accordingly, 30 polymers including alkylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, the following food intake scenarios were tested: and derivatives thereof; polymethacrylic polymers, polyvinyl a) To simulate a fasted state at 8 pm in the evening, a light acetate and cellulose acetate polymers, fatty acids, fatty acid meal was given 2% hours before administration that conesters, fatty acid salts, long chain fatty alcohols, polyoxyethtained a limited number of calories (i.e. 22% of total daily 35 ylene alkyl ethers, polyoxyethylene stearates, sugar esters, calories and widi a limited Bit content of 15.5 g) and being lauroyl macrogol-32 glyceryl, and stearoyl macrogol-32 devoid of any slowly digestible nutrients. This is called the glyceryl, and combinations thereof. "semi-fasted" state. 4. The tablet of claim 1, wherein the coating comprises The composition of this meal consisted of brown bread, calcium phosphate salt, glyceryl behenate, and polyvinyl margarine, cheese spread, an apple (skin removed) and fruit 40 pyrollidone, or mixtures thereof. cocktail in symp. 5. The tablet of claim 1, wherein the core comprises a b) Fed state is simulated by giving a higher fat meal 'A hour disintegrating agent. before dosing containing 35% of the daily intake of calories 6. The tablet of claim 1, further comprising cross-linked and 26 g of fat. polyvinyl pyrollidone and croscarmellose sodium. An assumption made was that in the case ofthe semi-fasted 45 7. The tablet of claim 1, wherein the active agent is a glucocorticosteroid selected from prednisone, prednisolone state, after 2% hours the stomach was already emptied, or or methylprednisolone. substantially emptied of food, . 8. The tablet of claim 7, wherein the active agent is predThe composition of the high fat meal was pasta with spanisone and the prednisone is present in an amount of l mg or ghetti sauce, soup and vegetables, Applejuice, Ice cream and 50 5 mg. whipped cream. 9. The tablet of claim 8, wherein the prednisone is present The methodology consisted ofan open, randomized, 3-pein an amount of 5 mg and the tablet comprises the following riod crossover single oral dose study with 7 days washout ingredients in each of the core and coating in a weight perperiods. The patient population consisted of 27 healthy male centage by weight ofeach of the core and coating: volunteers. Core: The phamiacoldnetics of the iormulation was compared 55 Prednisone 8.33% for each of the fed and semi-fasted states with a standard Lactose monohydrate 64.47% immediate release form (DecortinR) administered at 2 am. Povidone 6.67% In the semi-fasted state the fonnulation exhibited a median Croscarmellose sodium 18.33% lag time of3.5 hours. Relative to Decortinl dosed at 2 am, the Coating formulation was fully bioequivalent with a Cmax of 97% and 60 Dibasic calcium phosphate dihydrate 50% relative bioavailability of 101% (AUC0.,.a..y>. Glyceryl behenate 40% ln the fed state, the median lag time was 4 hours. Cmax was Povidone 8.40%. 105% compared to DecortinR, and relative bioavailability 10. The tablet of claim 1, wherein me active agent is a (AUC0_i,v,/iy) was 113%. Compared to the formulation in the semi~fasted state, the 65 sympadiomimetic agent, 11. The tablet of claim 10, wherein the active agent is lormulation in the led stale was 108% on Cmar and 1 12% on terbutaline sulphate. AUCO-iry'ir1 ity
US 8,394,407 B2
19
20
16. The tablet ofclaim 1, wherein at least 80% of the active agent is released after 4.5 hours. 17. The tablet of claim 1. wherein about 100% ofthe active agent is released after 5 hours. 18. A method ofadministering a glucocorticosteroid active substance selected from prednisone, prednisolone or methylprednisolone to a patient in need thereoi the method comprising administering the tablet of claim 7 to the subject. 19. A method of making the tablet of claim 1, the method comprising the steps of forming a first granulate containing coating material; providing a second granulate containing core material; forming the second granulate into a core; and press coating the first granulate around the core.
>F >l< =i< * >i=
12. The tablet of claim 10, wherein the active agent is present in amounts of 1 to 50% based on the weight of the core 13. The tablet ofclaini 1, wherein the tablet has an in vitro dissolution prolile using USP dissolution apparatus No. 2 at a stirring rate of 100 rpm and in a dissolution medium of 500 ml ofpurihed water such that there is a median lag time of about 4 hours and at least 80% of active agent is released after 4.5 hours and about 100% of the active agent is releasw after 5 hours. 14. The tablet of claim 13, wherein the active agent is selected from prednisone, prednisolone or methylprednisolone. 15. The tablet of claim 1, wherein the ratio of coating thickness about the X:Y to A:B axes is 1.3-2.6 to 1.
10
UNITED STATES PATENT AND TRADEMARK OFFICE
CERTIFICATE OF CORRECTION
PATENT NO APPLICATION NO
8,394,407 B2 13/428548 March 12, 2013
Page 1 ofl
DATED INVENToR(s)
Guy Vergnault et al
It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below
In the specification
At column 1, line number 11, the Word "lucocorticosteroids" Should be deleted and replaced
with the word "g1ucocorticoids'

At column 2, line number 59, the Word "an" should be deleted and replaced with the word
cc
aa
At column 4, line number 4, the Word "core" should be deleted and replaced with the Word
"coat At column 4, line number 60, the word "ileosecal" should be deleted and replaced with the word "ileocecal"
At column 11, line numbers 47-48, the Word "Deco-1'tin" should be hyphenated as "Decor
tin
Signed and Sealed this
Twenty-first Day of May, 2013

.f
. .
feresa Stanek Rea Acting Director ofthe United States Patent and Trademark Ojice

Horizon Pharma Et. Al. v. Watson Laboratories, Inc. - Florida Et. Al.

Caricato da

Informazioni sul documento

Copyright

Formati disponibili

Condividi questo documento

Condividi o incorpora il documento

Opzioni di condivisione

Hai trovato utile questo documento?

Questo contenuto è inappropriato?

Copyright:

Formati disponibili

Horizon Pharma Et. Al. v. Watson Laboratories, Inc. - Florida Et. Al.

Caricato da

Copyright:

Formati disponibili

Karen A.

Confoy FOX ROTHSCHILD, LLP

(WLF) was formerly known as Andrx Pharmaceuticals, Inc.

around November 3, 2006. Pharmaceutials as WLF. 9.

On information and belief, WLF is a wholly-owned subsidiary of Andrx,

Defendants commercial manufacture, use, offer to sell, or sale of the

paragraphs 1-34 of this Complaint.

Defendants have infringed the 326 patent, pursuant to 35 U.S.C.

This case is an exceptional one, and Plaintiffs are entitled to an award of

Upon information and belief, Defendants had actual and constructive

A judgment declaring that Defendants have infringed one or more claims

of U.S. Patent 8,394,407; F. A judgment pursuant to 35 U.S.C. 271(e)(4) preliminarily and

A judgment pursuant to 35 U.S.C. 271(e)(4) preliminarily and

If Defendants commercially manufacture, use, offer to sell, or sell the

Date: August 26, 2013

(12) United States Patent

(10) Patent No Us 6,488,960 B1 Dec. 3, 2002 (45) Date of Patent

(54) CORTICOSTEROID FORMULATION

514/179, 180; 424/465, 489

FOREIGN PATENT DOCUMENTS

PC'l`Pub. No.: WO00/54780 PCT Pub. Date: Sep. 21, 2000

Foreign Application Priority Data

Mar. 15, 1999

(51) Int. C17 (52) U.s. Cl.

A61K 31/09 424/465; 424/485; 514/179 514/180

Had not had intra-anicular glucocorticoid injections in the previous 3 weeks

Mean Results 20.3 18.7 21.0 20.0 20.3 20.3 15.3

37.7 26.0 20.3

25.0 19.7 16.0

70.0 55.0 51.7 40.0 40.0 30.0 0 33.3

31.3 23,7 26.7 12.7 24.3 19.3 11.7 13.3

34.3 28.7 29.3 16.3 23.3 27.7 15.7 11.7 8.0

405 35.5 31.2 25.8 15.0 36.6 31.1 19.1 19.5

320.3 372.5 396.3 322.5 339.5 193.9 363.5

44.1 28.1 31.1 22.8 19.3 30.3 18.5 13.8 107.1

31557.8 31959.9 31468.0 30898.9 22937.2 423%.2 3533 361727 32180.5

95% CI Resulls 0.7 1.3 3.5

5.7 7,4 7.7

24.9 25.2 20.3

0.0 0.7 0.7

19.6 9.8 8.6

20.3 15.4 5.7

15.2 3.9 6.5 6.9

19.2 9.1 9.6 10.3

31.8 21.1 15.4

0.8 1.3 0.7

48.0 29.4 19.6

10.3 10.5 4.6 29.6 13.6 1.7

18.1 18.1 32.7 28,4 23.3 241 23.6 13,3

8838.9 10225 102209 11329.4 27617.3 23485.3 8919.1 70695

consisting of prednisone, methylprednisolone, and

from the group consisting of prednisone,

(12) United States Patent

(10) Patent No.:

(58) Field of Search (56) References Cited U.S. PATENT DOCUMENTS

(GB); Julian Clive Gilbert, Essex (GB)

FOREIGN PATENT DOCUMENTS

Appl. No.: 10/263,044 Oct. 1, 2002

(22> Filed (65)

Prior Publication Daw

Primarv Examiner-James H. Reamer

(74) Attorney Agent, or Firm-Saliwanchik, Lloyd &

Related U.S. Application Data

Foreign Application Priority Data