Pharmaceutical Dosage Chapter 9: Modified-Release Dosage Forms and Drug Delivery Systems Modified Release Dosage Forms With

h drug release features based on time, course, and/or location to accomplish therapeutic or convenient objectives (not offered by conventional or immediaterelease forms) Differentiated into: Extended-release Delayed release Extended Release Allows a reduction in dosing frequency from that necessitated by a conventional dosage forms, such as a solution or an immediate-release dosage form U.S. Food and Drug Administration (FDA) Tablets and capsules Taken once or twice daily Provides immediate release of drug: Provides promptly desired therapeutic effect Followed by gradual and continual release of additional amounts of drug maintaining effect over predetermined period of time Delayed Release Release the drug at a time other than promptly after administration Delay is time based or based on the influence of environmental conditions, like gastrointestinal pH Examples of Proprietary Modified-Release Oral Dosage Forms Delayed release Prilosec (Omeprazole) Enteric coated granules of Omeprazole placed in capsules Omeprazole is acid labile and is degraded by gastric acid. Use: treatment of duodenal ulcer Repeat Action Contain two single doses of medication: One: for immediate release Second: for delayed release Example: two layer tablets: One layer of drug for immediate release Second layer to release drug later as a second dose or in an extended-release manner Targeted Release Release towards isolating or concentrating a drug in body region, tissue, or site for absorption or for drug action Advantages of Extended-Release Dosage Forms over Conventional Forms Less fluctuation in drug blood vessels Frequency reduction in dosing Enhanced convenience and compliance Reduction in adverse side effects Reduction in overall health care costs Disadvantages of Extended-Release Dosage Form Loss of flexibility in adjusting the drug dose and/or dosage regimen Risk of sudden and total drug release or dose dumping due to failure of technology

Characteristics of Drugs Suited for Incorporation into an ExtendedRelease Exhibit neither very slow nor very fast rates of absorption and secretion Uniformly absorbed from the gastrointestinal tract Administered in small doses Good margin of safety For the treatment of chronic conditions Mechanisms by which Extended Drug Actions are Achieved Affecting the rate at which the drug is released by slowing the transit time of the dosage form through the gastrointestinal tract Challenges in Oral Drug Activity Gastric retention of a highly swellable, gastroretentive drug delivery system Three Ways the Rate of Drug Release from the Solid Dosage Forms be Modified Modifying drug dissolution: controlling access of biologic fluids by use of barrier coating Controlling drug diffusion reaction rates from dosage forms Chemical reaction or interaction between the drug substance or its pharmaceutical barrier and site-specific biologic fluid Controlled Release is Achieved by Constructing a Tablet of Two Basic Components A core of hydroxypropyl methylcellulose (HPMC) matrix that contains the active drugs One or two additional barrier layers that control the surface area diffusion of drug or drugs out of the core Different Technologies Employed in the Modification of Drug Release Rate Coated beads, granules and microspheres Using conventional pan coating or air suspension coating, a solution of the drug substance is placed on: Small inert nonpareil seeds (425 850 um) or beads made of sugar and starch Microcrystalline cellulose sphere (170 to 600 um) o More durable during production than sugar-based cores Ex: Theo-Dur Sprinkle, Spansules, Sequels Multitablet system Small spheroid compressing tablets 3 to 4mm in diameter Prepared to having varying drug release characteristics Placed in gelatin capsule shells to provide the desired pattern of drug release Each capsule may contain 8 to 10 minitablets Some uncoated for immediate release and others coated for extended drug release

Osmotic pump Oros System (Alza): pioneer oral osmotic pump drug delivery system Composed of: o Core tablet: Semipermeable membrane coating (0.4mm diameter hole produced by laser beam) Two layers: active layer (drug) and push layer (polymeric osmotic agent) Principle: osmotic pressure Examples: o Elementary osmotic pump o OROS PushPull o L-OROS Embedding drug in slowly eroding or hydrophilic matrix system Drug substance and excipient material (hydrophilic cellulose polymers): granules slowly erodes in body fluids releasing the drug adsorption Uncombined granules (without excipient) and drug excipient granules: immediate effect (uncombined granules) and extended action (drug excipient granules) Example: Oramorph SR Ion exchange resins Solution of a cationic drug passed through a column containing: On exchange resin: forming a complex by the replacement of hydrogen atoms Resin-drug complex: washed and tableted, encapsulated or suspended in an aqueous vehicle Release drug depend on: pH and electrolyte concentration on GIT Example: Hydroxcodone polistirex & chlorpeniramine politirex suspension (Tussionex Perinkinetic ER Suspension [Medeval]) and Phentermine resin capsules (Ionamin capsules) (Pharmanex) Incorporates: Polymer barrier coating bead technology Initial dose from uncoated portion and remainder from coated beads Complex formation Drug substance and chemical agents: complexes slowly soluble in body fluids (provides the extended release) depending on the environmental pH Salts of tannic acid (tannates): Rynatan (Wallace) Microencapsulated drug Microencapsulation: solids, liquids or gases enclosed in microscopic particles by formation of thins coatings of wall material around the substance Example: Bayer time release aspirin

Coacervation: most common method of microencapsulation (hydrophilic substance and colloidal drug dispersion) Advantage: administered drug dose: subdivided into small units spread over a large area of the GIT (enhance absorption by diminishing local drug concentrate) Embedding drug in inert plastic matrix system Drug substance and inert plastic material (polyethylene, polyvinyl acetate or polymetacrylate): granulated and compressed into tablets (released from the inert plastic matrix) Example: Gradumet (Abbott) Principle: diffusion Examples of Proprietary Modified-Release Oral Dosage Forms Extended-release Coated particles and beads Compazine Spansule Capsule o Coated pellets in capsule formulated to release initial dose promptly with additional drug for prolonged release o Use: antinausea, antivomiting Osmotic Glucotrol XL Tablets o Controlled-release GITS osmotic system o Ingredients: polyethylene oxide, hydroxypropyl cellulose, cellulose acetate o Use: antihyperglycemic Concerta o Tri-layer example using OROS Push-Pull Osmotic System o This medicine treats attention deficit hyperactivity disorder (ADHD) Hydrophilic or eroding matrix Oramorph SR Tablets o Sustained-release hydrophilic matrix system, based on polymer hydroxypropyl methylcellulose o Use: analgesic for severe pain Ion Exchange Resins Ionamin Capsules Inert Matrix Procanbid Tablets o Extended-release tablets with a core tablet of a nonerodible wax matrix coated with cellulose polymers o Use: antiarrhythmic Delayed Release Oral Dosage Form Enteric coated capsules and tablets (delayed release features) Remain intact in the stomach to yield their ingredients in the intestine Reasons Drug Remain Intact until it Reaches the Intestine To protect a drug destroyed by gastric fluids

To reduce gastric distress caused by drug particularly irritating to the stomach To facilitate GIT for drugs that is better absorbed from the intestine

Mathematical model for the relationship between the entire in vitro in vivo dissolution and release time course E.g. time course of plasma drug concentration of amount of drug absorbed

Repeat Action Tablets Prepared for initial dose of drug is released immediately second dose follows later 2 layers or coatings (separated by a slowly permeable barrier coating) Outer shell or coating: immediate release dose in tablets inner core (second dose) Controlled release is achieved by constructing a tablet of two components: A core of hydroxypropyl methylcellulose (HPMC) matrix that contains the active drugs One or two additional barrier layer that control the surface area diffusion of drug or drugs out of the core Drug Release Test (USP) For extended release and delayed release articles based on drug dissolution from the dosage unit against elapsed test time USP of Dosage Unit Demonstrated by either of two methods: weight variation or content uniformity Development of IVIVC Model Assessing IVIVC is important throughout product development and clinical evaluation Application for FDA approval: marketing and proposed approval for any proposed formulation or manufacturing To develop formulations with different release rates or single release rate If dissolution is independent of condition Obtain in vitro dissolution profiles and in vivo plasma concentration profiles Using appropriate mathematical approaches: estimate the in vivo absorption or dissolution time course for each formulation and subject Varian Biodis Dissolution Apparatus Varians BIO-DIS III Extended Release Testing Station for USP Apparatus 3 is ideal for extended release products or any dosage form requiring release profiling at multiple pH levels Bio relevant Flexible Compliant Easily configured VK 7000/7010 Dissolution Apparatus Reliable and robust 1L, 2L, and 4L apparatus Meets all current USP, JP, and EP requirements VK 7025 Dissolution Apparatus Standard Dosage Delivery Module (DDM) can be programmed to automatically deliver simultaneous or sequential dosages into vessels using either instantaneous or delayed starts AutoTemp In-vessel Temperature Sensing System Optional AutoSpindle Control IVIVC Model Development Level A

Level B Mathematical model of the relationship between summary parameters that characterize the in vitro in vivo time course E.g. models that relate the mean in vitro dissolution time to the mean in vivo dissolution time Mean in vitro dissolution time to the mean residence time in vivo, or the vitro dissolution rate constant Level C Mathematical model of the relationship between the amounts dissolved in vitro at particular time and a summary parameter that characterizes the in vivo time course Clinical Considerations in the Use of Oral Modifies-Release Dosage Forms Patients should be advised of: Dose and dosing frequency and instructed not to use them interchangeably or concomitantly with immediate release forms of the same drug Modified release product should not be changed to an immediate-release product without consideration of any existing blood level concentrations of the drug Modified release tablets and capsules should not be crushed or chewed (compromises drug release features) Nonerodible plastic matrix shells and osmotic tablet remain intact throughout GIT transit and the empty shells or ghosts from osmotic tablet may be seen in the stool Extended Drug Action Achieved (Other Routes than Oral Administration) Ocular drug product Parental system Vaginal inserts Subdermal implants Non-oral Modified Release Systems Ocular Drug Product Problem associated with ophthalmic solutions: rapid loss of administered drug due to the blinking of the eye & flushing effect of lacrimal fluids Extended periods of therapy achieved: formulations increase in contact time between the medication and the corneal surface by use of agents that increase viscosity of solutions by ophthalmic suspensions where drug particles slowly dissolve by slowly dissipating ophthalmic ointments or by the use of ophthalmic inserts Preparations designed to extend drug action which utilize viscosity increasing agents to increase corneal contact time: Pilocarpine HS Gel (Pilocarpine, Alcon) o Employs Carbopol 940 9synthetic HMW cross linked polymer of acrylic acid Timoptic XF (Timolol maleate, Merck)

Employs Gelrite (gellan gum) forming a gel upon contact with precorneal tear film

vagina, inserted into the upper 1/3 of the vaginal vault and worn continuously

Ophthalmic inserts: innovative achievement in the delivery of medication to the eye Occusert System (Alza) o Elliptical, flexible and with drug containing core surrounded on each side by a layer of hydrophobic ethylene or vinyl acetate copolymer membranes through which drug diffuses at a constant rate Lacrisert (Merck) o Rod-shaped, water soluble form of hydroxypropyl cellulose, soften and slowly dissolve, thickening the precorneal tear film & prolonging the tear film breakup Parenteral system Extended rates of drug action following injection may be achieved in a number of ways: Use of crystal or amorphous drug forms having prolonged dissolution characteristics o Slowly dissolving chemical complexes of the drug entity; solutions or suspensions of drug in slowly absorbed carriers or vehicles (as oleaginous) o Increased particle size of drug in suspension o Injection of slowly eroding microspheres of the drug o Slow IV infusion using controlled drug infusion pumps Vaginal Insert Cervidil vaginal insert (Forest Pharmaceutical) Rectangular polymeric pouch containing dinoprostone (Prostaglandin E2) in a cross-linked polyethylene oxide or urethane polymer releasing the drug at a predetermined controlled release rate for induction of labor Crinone gel (Wyeth-Ayerst) Bioadhesive vaginal gel containing micronized progesterone and the polymer polycarbophil in an oil in water emulsion system Used to assist in reproduction Estradiol vaginal ring (Estring Pharmacia & Upjohn) Unique method of administering estradiol Core of ring contains a reservoir of estradiol which releases immediately and at a continuous rate of 75ug per 24 hours over 90 days For treatment of urogenital symptoms associated with postmenopausal atrophy of

Subdermal implant Inserted under the skin by special injectors or by surgical incision termed implants Provides continuous long-term through the slow release of medication Examples: Goserelin acetate (Zoladex Implant, Zeneca) o Treatment of advanced prostatic cancer o Biodegradable product for subcutaneous injection with continuous medication release over a 4-12 week period Levonorgestrel (Norplant System, WyethAyerst) o Provides 5-year protection from pregnancy after subcutaneous insertion o Sterile flexible closed capsule made of silicone rubber tubing (silastic), a dimethylsiloxane or methylvinylsiloxane copolymer, containing synthetic progestin levonorgestrel o Insertion pattern facilitates removal of the expended capsules; following term of use, capsules are surgically removed and replaced with fresh capsules Table 9.2 Modified Release Tablets and Capsules Official in the USP Delayed release Aspirin delayed-release tablets Dirithromycin delayed-release tablets Doxycycline hyclate delayed-release capsules Erythromycin delayed-release capsules Oxtriphylline delayed-release tablets Extended release Aspirin extended-release tablets Diltiazem extended-release capsules Disopyramide phosphate extended-release capsules Ferrous fumarate and docusate sodium extended-release tablets Indomethacin extended-release capsules Isosorbide dinitrate extended-release tablets and capsules Lithium carbonate extended-release tablets Oxtriphylline extended-release tablets Phenylpropanolamine hydrochloride extendedrelease capsules Potassium chloride extended-release tablets Procainamide hydrochloride extended-release tablets

Propanolol hydrochloride extended-release capsules Quinidine gluconate extended-release tablets Theophylline extended-release capsules

Extended-release tablets with a core tablet of a nonerodible wax matrix coated with cellulose polymers. Use: antiarrhythmic

Table 9.3 Proprietary Modified-Release Oral Dosage Forms Delayed release E-Mycin (erythromycin) Delayed Release Tablets (Knoll) Tablets enteric coated with cellulose acetate phthalate, carnauba wax and cellulose polymers Use: antibiotic Asacol (mesalamine) Delayed Release Tablets (Procter and Gamble) Tablets coated with Eudragit S(methylacrylic acid copolymer B), a resin that bypasses the stomach dissolves in the ileum and beyond Use: treat ulcerative colitis Prilosec (omeprazole) Delayed release capsule (AstraMerck) Enteric coated granules of omeprazole placed in capsule Omeprazole is acid labile and is degraded by gastric acid Use: treatment of duodenal ulcer Extended-release coated particles and beads Toprol-XL (metoprolol succinate) Tablets (Astra) Drug pellets coated with cellulose polymers compressed into tablets Use: treatment of hypertension Indocin SR (indomethacin) Capsules (Merck) Coated pellets for sustained release Formulation includes polyvinyl acetate-crotonic acid copolymer and hydroxypropyl methylcellulose Use: analgesic, anti-inflammatory Compazine (prochlorperazine) Spansule Capsule (SmithKline Beecham) Coated pellets in capsule formulated to release initial dose promptly with additional drug for prolonged release Use: antinausea, antivomiting Extended-release inert matrix Desoxyn (methamphetamine HCL) Gradumet Tablets (Abbott) Drug impregnated in an inert, porous, plastic matrix Drug leaches out as it passes slowly through the GI tract Expended matrix is excreted in stool Use: attention deficit disorder Procanbid (procainamide HCl) Tablets (Parke-Davis)

Extended-release hydrophilic or eroding matrix Quinidex (quinidine sulfate) Tablets (Robins) Extended-release provided by hydrophilic matrix that swells and solely erodes. Use: antiarrythmic Oramorph SR (morphine sulfate) Tablets (Roxane) Sustained-release hydrophilic matrix system based on polymer hydroxypropyl methylcellulose Use: analgesic for severe pain Extended-release microencapsulated K-Dur Microburst Release System (potassium chloride) Tablets (Key) Immediately dispersing drug microencapsulated with ethylcellulose and hydroxypropyl cellulose Use: potassium depletion Extended-release osmotic Glucotrol XL (glipizide) Tablets (Pfizer) Controlled-release osmotic system Ingredients include polyethylene oxide, hydropropyl cellulose, cellulose acetate Use: antihyerglycemic Covera-HS (verapamil HCL) Tablets (Searle) A osmotic system Use: antihypertensive, antianginal