Patent For Rabeprazole Sodium

9/16/2019 CN102138907A - Stable rabeprazole sodium freeze-dried preparation and preparation method thereof - Google Patents
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Stable rabeprazole sodium freeze-dried preparation and preparation method thereof
Abstract
CN102138907A
The invention relates to the eld of medicament preparations, and particularly relates to a stable
China
rabeprazole sodium freeze-dried preparation and a preparation method thereof. The freeze-dried
powder injection consists of active component rabeprazole sodium, a pharmaceutically acceptable
excipient and a pH regulator, wherein the pH regulator ensures that the pH of a solution is Download PDF Find Prior Art Similar
maintained in a range of between 10.5 and 12.5 when being dissolved once again before the
solution is not freeze-dried and after the solution is freeze-dried. The rabeprazole sodium freeze- Other languages: Chinese
dried preparation has the characteristic of high stability.
Inventor: 宋巧莉, 晁阳, 李纬, 钟雪彬
Worldwide applications
2010 CN
Application CN2010101036229A events
2010-02-02 Application led by 南京长澳制药有限公司, 南京

长澳医药科技有限公司
2010-02-02 Priority to CN2010101036229A
2011-08-03 Publication of CN102138907A
Info: Patent citations (2), Cited by (3), Legal events, Similar

documents, Priority and Related Applications
External links: Espacenet, Global Dossier, Discuss
Claims (6) Hide Dependent

translated from Chinese
A stable lyophilized formulation of rabeprazole sodium, mainly sodium rabeprazole, carbohydrates, PH adjusting agent.
https://patents.google.com/patent/CN102138907A/en?q=~patent%2fCN102138907A 1/13
2. The stable lyophilized formulation of rabeprazole sodium according to claim 1, characterized in that the carbohydrate is selected from mannitol, dextran 40, one or
more of glucose.
3. The stable lyophilized formulation rabeprazole according to claim 1, characterized in that the PH adjusting agent is potassium hydroxide, at least one of sodium
hydroxide.
The stable lyophilized formulation of rabeprazole sodium according to claim 1, characterized in that the amount of modi er to PH PH value of sodium rabeprazole in the
solution formulation lyophilized in preparation 10. 5 ~ 12. 5.
The stable lyophilized formulation of rabeprazole sodium according to claim 1, characterized in that also contain other pharmaceutically acceptable excipients
pharmaceutically acceptable.
Sodium rabeprazole preparation of a stable lyophilized powder according to claim 1, comprising: comprising: admixing sodium rabeprazole, pharmaceutically acceptable
excipients and other pharmaceutical adjuvants total added after 80% by volume dissolved with stirring in water for injection, added to adjust the pH adjusting agent pH
10. 5 ~ 12. 5, water for injection was added to the whole amount of the volume, add activated charcoal, ltered, sterile ltered, intermediate content determination,
quali ed the ltrate was potted in a vial of sterile, partially stoppered, freeze dried.
Description translated from Chinese
A stabilized sodium rabeprazole lyophilized formulation and preparation method
FIELD
[0001] The present invention relates to a stable lyophilized formulation of rabeprazole sodium and its preparation method. Background technique
[0002] Over the last decade antiulcer drug studies have tended to selectively inhibit gastric acid secretion drugs that are broadly divided into the following four categories:
(1) M- cholinergic receptor antagonists such as pirenzepine; (2) histamine H2- receptor antagonists, such as cimetidine and ranitidine; (3) promoting mucosal protective
agent, such as PGE2 prostaglandin analogs and the like; (4) a proton pump inhibitor (PPI) - H + / K + -APT inhibitors, such as omeprazole and rabeprazole sodium. M-
receptor antagonists due to side effects, and the antiulcer action is weak, gradually replaced by H2- receptor antagonists; the latter, although currently the ascendant, and
several improvements, but there are no indications and side effects and other defects. As cytoprotective agents because prostaglandin analogs and synthetic di culties,
and strength little effect, not ideal prospects. Development of the market in the 1980s PPI, because of its unique mechanism of action, the role of high speci city, the role
of intensive and long time, are widely used in a variety of disorders associated with acid increasingly popular.
[0003] Rabeprazole sodium is a substituted benzimidazole was the gastric cavity wall through the cytoplasmic proton pump bonding, inhibit gastric acid secretion.
Sodium rabeprazole (Sodium rabeprazole) following the omeprazole, lansoprazole latest substituted benzimidazole was secreted as a tip cell wall membrane proton
pump potent inhibitor of irritation caused by gastric acid and base inhibition of gastric acid secretion. Suitable for gastric ulcer, duodenal ulcer, gastric erosions clinical -
esophageal re ux disease, Helicobacter pylori, zolliner-ellison syndrome.
[0004] Rabeprazole sodium Chemical Name: 2-114- (3-methoxypropoxy) -3-methyl-pyridin-2-yl] methylsul nyl} -IH- benzo sodium imidazole, chemical structure: [0005]
[0006] Molecular Formula = C18H2tlN3NaO3S, molecular weight: 38,143.
[0007] Properties and Structure of rabeprazole sodium and omeprazole, lansoprazole similar substances are extremely acid-labile, light, heat, especially in the presence
of water, more violently Variety. Clinical application from home and abroad, benzimidazole-substituent species often develop an enteric solid formulations such as
enteric-coated tablets, enteric-coated capsules and the like, and the injection with the solid dosage forms such as injectable powder for injection listed as AstraZeneca
injection omeprazole.
[0008] Rabeprazole sodium is unstable under acidic conditions, easily destroyed in gastric acid, which is enteric-coated tablets or enteric capsules for oral absorption is
slow, with low bioavailability.
[0009] Further omeprazole for injection for clinical use has been reported discoloration, in order to make sodium rabeprazole achieve rapid onset and improve
bioavailability, improve stability and can be used in the clinical practice, the present invention It provides a new stable lyophilized formulation and preparation method of
containing sodium rabeprazole.
[0010] The structural properties of the drug is rabeprazole sodium, is unstable in an acidic environment and the presence of moisture, the key to provide a stable
lyophilized formulation of rabeprazole sodium of the present invention is to control rabeprazole formulation sodium rabeprazole formulation of the composition, and the
amount of residual moisture and lyophilized formulations of sodium rabeprazole and between the PH adjusting agents. SUMMARY
[0011] The present invention provides a stable lyophilized formulation of rabeprazole sodium and its preparation method.
[0012] provided rabeprazole freeze-dried powder of the present invention consists essentially of sodium rabeprazole active ingredient, a pharmaceutically acceptable
excipient and PH adjusting agent.
[0013] The excipient is a carbohydrate, selected from mannitol, dextran 40, lactose, glucose, one or several.
[0014] The pH adjusting agent to adjust primarily formulated as a solution of sodium rabeprazole freeze-dried powder prepared in the process of controlling the PH value
of 10. 5 ~ 12. 5, may be pharmaceutically acceptable to the general pH modi ers, such as potassium hydroxide, sodium hydroxide, and the like.
Sodium rabeprazole lyophilized powder [0015] The acceptable may also contain other pharmaceutical auxiliaries acceptable, such as sodium chloride, potassium
chloride, sodium citrate and the like.
[0016] The stabilized preparation of rabeprazole sodium in the lyophilized powder, comprising: admixing sodium rabeprazole, excipients and other pharmaceutical
acceptable excipients added to a total volume of 80% was stirred in water for injection after dissolution, the pH is adjusted in the pH adjusting agent 10. 5 ~ 12. 5, water
for injection was added to the whole amount of the volume, add activated charcoal, ltered, sterile ltered, and the content of the intermediate was measured after
passing the ltrate in a sterile canned a vial, partially stoppered, freeze dried.
[0017] A stabilized preparation according to the invention particularly sodium rabeprazole lyophilized formulation comprising:
[0018] (1) liquid preparation: the active ingredient is about rabeprazole sodium dissolved in 80% water for injection, added to pharmaceutically acceptable pharmaceutical
auxiliaries stirring to dissolve, mix;
[0019] (2) adjusting the pH: pH adjusting agent added in a range of chemical regulator 10. 5 ~ 12 5, make up water for injection.
A predetermined amount;
[0020] (3) depyrogenation: Add injection step O) the chemical solution was stirred 20 minutes with activated charcoal ltration;
[0021] (4) ltering: The ltrate of step (3) is carried out by pressure ltration sterilization lter sterilized;
[0022] (5) Filling: aseptically lling vials with 7ml control;
[0023] (6) lyophilised: freezing at low temperature vacuum drying.
[0024] Sodium rabeprazole taken lyophilized composition formulated as a solution, since sodium rabeprazole stable under alkaline conditions, it was investigated the
stability PH adjusting agent is added. The inventors investigated experimentally found that the stationary phase is preferably in the range ρΗΙΟ. 5~12. 5. The results in
Table 1 below:
[0025] Table 1 under different chemical conditions of pH stability
[0026]
[0027] Sodium rabeprazole prone to degradation under aqueous state, lyophilized moisture should be strictly controlled, the water content should not be too high,
otherwise the product will gradually occur explain during storage, one inventive stabilized sodium rabeprazole lyophilized formulation of a lyophilized product requires a
water content of not more than 5.0%, preferably 3.0% or less in control.
[0028] In use 2000ml water for injection 1000 rabeprazole lyophilized powder, for example, the preparation of the material by weight sodium rabeprazole used was freeze-
dried powder:
[0029] The sodium rabeprazole 20~40g
[0030] mannitol 20~400g
[0031] pH adjuster q.s.
[0032] water for injection to 2000ml
[0033] _
[0034] made 1000
[0035] The speci c steps are as follows:
[0036] The liquid preparation: the active ingredient is about rabeprazole sodium dissolved in 80% water for injection, a pharmaceutically acceptable carrier was added
with stirring to dissolve, mix;
[0037] adjusting the pH: pH adjusting agent added in a range of chemical regulator 5 10. 5 ~ 12, a predetermined amount of water for injection is made up;.
[0038] depyrogenation: In the chemical liquid injection was added and stirred 20 minutes with activated charcoal ltration;
[0039] ltering: ltering the above ltrate was ltered with a pressure lter sterilized by aseptic manipulation, pressure 0. IMpa
[0040] Filling: 100 for lling the clean booth cleanliness.
[0041] freeze-dried:
[0042] ① into the box before the LH, freeze dryer is turned on, the control HTF -5~0 ° C;
[0043] ② pre-freezing: When the temperature of the article reaches San _36 ° C, start time, pre-freezing for 4 hours;
[0044] ③ sublimation, secondary drying: vacuum, this vacuum box falls 10½ less, turn the heating;
[0045]
[0046] ④ article when the temperature reaches 30 ° C, after (San 5h) incubation large valve closing period, if no signi cant decline in the degree of vacuum, i.e.
lyophilization to indicate the end of the article has, may be out of the box.
Sodium rabeprazole lyophilized formulations provided herein [0047] present, the use of special excipients, i.e., carbohydrates and control the PH, is to give stability and
bioavailability have been greatly improved.
Detailed ways
[0048] By the following speci c examples further illustrate the invention, but the present invention is not limited to these examples, it should be understood that the
embodiments of the present invention is illustrative of the invention and not to limit the present invention. According to the spirit of the scope of the present invention is
carried out for a simple improvement of the present invention are within the requirements of the present invention.
[0049] Example 1 [0050] Prescription:
[0051] The sodium rabeprazole
[0052] Mannitol
[0053] sodium
[0054] Water for injection to
[0055] _
21. 24g
40g
Right amount
2000ml
[0056] made
1,000 bottles
[0057] The formulation amounts of mannitol, sodium rabeprazole placed in sterile containers, water for injection was added and stirred to dissolve and mix. PH adjusting
agent was added sodium hydroxide to adjust the drug solution in the range of 10 5 ~ 12. 5, a predetermined amount of make up water for injection. After completely
dissolved by adding 0.05% active carbon adsorption was stirred 20min, ltered sterilization decarburization, the content of the intermediate was measured after passing
the sterile ltrate in a vial canned, partially stoppered, freeze dried.
[0058] Example 2
[0059] Prescription:
[0060] 21. Mg sodium rabeprazole
[0061] 60g of mannitol
[0062] Potassium hydroxide
[0063] Water for injection to 2000ml
[0064] _
[0065] 1000 bottles made
[0066] The formulation amounts of mannitol, sodium rabeprazole placed in sterile containers, water for injection was added and stirred to dissolve and mix. PH adjusting
agent plus adjusted drug solution of potassium hydroxide in the range of 11.0 disabilities 0.5, made up to a predetermined amount of water for injection. After completely
dissolved by adding 0.05% active carbon adsorption was stirred 20min, ltered sterilization decarburization, the content of the intermediate was measured after passing
the sterile ltrate in a vial canned, partially stoppered, freeze dried.
[0067] Example 3
[0070] Dextran 40 40g
[0071] Sodium hydroxide q.s.
[0073] _
[0075] Dextran 40 were dissolved in hot water (above 80 ° C), the main agent was added and dissolved under stirring After cooling to room temperature, was added until
complete dissolution of sodium hydroxide pH adjusting agent pH was adjusted to 11.0 with disabilities 0.5, made up to nal volume with water for injection . 0.05%
activated carbon was added with stirring adsorption 20min, decarburization sterilization by ltration, the content of the intermediate was measured after passing the
sterile ltrate in a vial canned, partially stoppered, freeze dried.
[0076] Example 4
[0079] Lactose 60g [0080] Potassium hydroxide
[0082] _
[0084] The formulation lactose sterile container set amount of added water for injection was stirred to dissolve and mix. Adding pH adjusting agents adjusted drug
solution of potassium hydroxide in the range of 11.0 disabilities 0.5, made up to a predetermined amount of water for injection. After completely dissolved by adding
0.05% active carbon adsorption was stirred 20min, ltered sterilization decarburization, the content of the intermediate was measured after passing the sterile ltrate in a
vial canned, partially stoppered, freeze dried.
[0085] Example 5
[0088] 30g of mannitol
[0089] Lactose 30g
[0092] _
[0094] The formulation amounts of mannitol, lactose, sodium rabeprazole placed in sterile containers, water for injection was added and stirred to dissolve and mix. PH
adjusting agent was added sodium hydroxide to adjust the drug solution in the range of 0.5 11.0 disabilities, water for injection to make up to a predetermined amount.
After completely dissolved by adding 0.05% active carbon adsorption was stirred 20min, ltered sterilization decarburization
[0095] Example 6: Comparative Example
[0098] Sodium Chloride 20g
[0101] _
[0103] The formulation amount of sodium chloride, sodium rabeprazole placed in sterile containers, water for injection was added and stirred to dissolve and mix. PH
adjusting agent was added sodium hydroxide to adjust the drug solution in the range of 11.0 disabilities 0.5, made up to a predetermined amount of water for injection.
After completely dissolved by adding 0.05% active carbon adsorption was stirred 20min, ltered sterilization decarburization, the content of the intermediate was
measured after passing the sterile ltrate in a vial canned, partially stoppered, freeze dried.
[0104] Stability of the experimental data:
[0105] On day 0 were measured, and the content of related substances 5th and 10th day by HPLC.
[0106] The results show that good injection stability of the present invention. Storage can be kept stable in more than 2 years.
[0107] Table 2 Sample Prescription 60 ° C accelerated testing
[0108]
Patent Citations (2)
Publication number Priority date Publication date Assignee Title
WO2005065682A2 * 2003-11-05 2005-07-21 Lyka Labs Limited Rabeprazole containing formulation
CN101627996A * 2009-08-20 2010-01-20 山东罗欣药业股份有限公司 Rabeprazole sodium composition and preparation method thereof
Family To Family Citations
* Cited by examiner, † Cited by third party
Cited By (3)
Publication number Priority date Publication date Assignee Title
CN102512382A * 2011-12-23 2012-06-27 天津市汉康医药生物技术有限 Esomeprazole sodium pharmaceutical composition for injection
公司
CN103919737A * 2014-04-28 2014-07-16 南京长澳医药科技有限公司 Rabeprazole sodium freeze-dried powder injection and preparation method
thereof
CN105853377A * 2016-05-19 2016-08-17 武汉先路医药科技股份有限公 Sodium rabeprazole preparation for injection and preparing method thereof
司
Family To Family Citations
* Cited by examiner, † Cited by third party, ‡ Family to family citation
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CN2010101036229A 2010-02-02 2010-02-02 Stable rabeprazole sodium freeze-dried preparation and preparation method thereof
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Application Filing date Title
CN2010101036229A 2010-02-02 Stable rabeprazole sodium freeze-dried preparation and preparation method thereof
Legal Events
Date Code Title Description
2011-08-03 C06 Publication
2012-09-19 C10 Entry into substantive examination
2013-03-06 C53 Correction of patent for invention or patent application
2013-03-06 COR Change of bibliographic data Free format text: CORRECT: INVENTOR; FROM: ZHONG XUEBIN CHAO YANG LI WEI SONG
QIAOLI TO: ZHONG XUEBIN CHAO YANG LI WEI SONG QIAOLI LI ZHAN WU SUMIN ZHAO
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9/16/2019 CN102138907A - Stable rabeprazole sodium freeze-dried preparation and preparation method thereof - Google Patents

Patents (~patent/CN102138907A) 1 of 6480 Sign In

Back to results ~patent/CN102138907A;

Stable rabeprazole sodium freeze-dried preparation and preparation method thereof

Application CN2010101036229A events

2010-02-02 Application led by 南京长澳制药有限公司, 南京

2010-02-02 Priority to CN2010101036229A

2011-08-03 Publication of CN102138907A

Info: Patent citations (2), Cited by (3), Legal events, Similar

External links: Espacenet, Global Dossier, Discuss

Claims (6) Hide Dependent

Description translated from Chinese

A stabilized sodium rabeprazole lyophilized formulation and preparation method

[0006] Molecular Formula = C18H2tlN3NaO3S, molecular weight: 38,143.

[0022] (5) Filling: aseptically lling vials with 7ml control;

[0023] (6) lyophilised: freezing at low temperature vacuum drying.

[0025] Table 1 under different chemical conditions of pH stability

[0030] mannitol 20~400g

[0031] pH adjuster q.s.

[0032] water for injection to 2000ml

[0034] made 1000

[0035] The speci c steps are as follows:

[0040] Filling: 100 for lling the clean booth cleanliness.

[0049] Example 1 [0050] Prescription:

[0051] The sodium rabeprazole

[0054] Water for injection to

[0060] 21. Mg sodium rabeprazole

[0061] 60g of mannitol

[0063] Water for injection to 2000ml

[0065] 1000 bottles made

[0069] 21. Mg sodium rabeprazole

[0070] Dextran 40 40g

[0071] Sodium hydroxide q.s.

[0072] Water for injection to 2000ml

[0074] 1000 bottles made

[0078] 21. Mg sodium rabeprazole

[0079] Lactose 60g [0080] Potassium hydroxide

[0081] Water for injection to 2000ml

[0083] 1000 bottles made

[0087] 21. Mg sodium rabeprazole

[0088] 30g of mannitol

[0089] Lactose 30g

[0090] Sodium hydroxide q.s.

[0091] Water for injection to 2000ml

[0093] 1000 bottles made

[0095] Example 6: Comparative Example

[0097] 21. Mg sodium rabeprazole

[0098] Sodium Chloride 20g

[0099] Sodium hydroxide q.s.

[0100] Water for injection to 2000ml

[0102] 1000 bottles made

[0104] Stability of the experimental data:

[0107] Table 2 Sample Prescription 60 ° C accelerated testing

Patent Citations (2)

Publication number Priority date Publication date Assignee Title

WO2005065682A2 * 2003-11-05 2005-07-21 Lyka Labs Limited Rabeprazole containing formulation

Family To Family Citations

* Cited by examiner, † Cited by third party

Publication number Priority date Publication date Assignee Title

Family To Family Citations

* Cited by examiner, † Cited by third party, ‡ Family to family citation

Publication Publication Date Title

JP4886158B2 2012-02-29 Lyophilized pantoprazole preparation and pantoprazole injection