CN1402631A - Extended release formulation of etodolac - Google Patents
Extended release formulation of etodolac Download PDFInfo
- Publication number
- CN1402631A CN1402631A CN00814319A CN00814319A CN1402631A CN 1402631 A CN1402631 A CN 1402631A CN 00814319 A CN00814319 A CN 00814319A CN 00814319 A CN00814319 A CN 00814319A CN 1402631 A CN1402631 A CN 1402631A
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- etodolac
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
A sustained release formulation of etodolac for once daily administration is described.
Description
Invention field
The present invention relates to the slow releasing preparation of the etodolac that is administered once every day.
Background of invention
United States Patent (USP) 3,939,178 have disclosed etodolac (1,8-diethyl-1,3,4,9-Pentamethylene oxide. be (3,4-b)-indole-1-acetic acid or its pharmaceutically acceptable salt also).Reported already that it had pain relieving and antiinflammatory property.It also can treat gout (United States Patent (USP) 4,663,345) and treat rheumatoid arthritis (United States Patent (USP) 4,742,076) by rheumatoid factor in the reduction blood by uric acid level in the reduction human body blood.
Etodolac is approved the symptom and the table disease of may command osteoarthritis, rheumatoid arthritis, and may command pain.Conventional dosage is 800 milligrams to 1200 milligrams, divides to give for 2-4 time.This dosage regimen makes patient be difficult to obey and exist problem owing to very inconvenient to patient.This technical field personnel know that thereby slow-released system can reduce the submissiveness that administration frequency has increased patient.In addition, compare with the fluctuation that the conventional formulation of multi-agent administration is seen, the blood drug level of the treatment of the active component that the slow releasing pharmaceutical delivery system produces is stable.But, because the water solublity of etodolac is very low, is lower than 3 o'clock its dissolubility at pH and has nothing to do, so the slow releasing preparation of developing the etodolac that is administered once 24 hours effective or suitable every days has run into problem with pH.Dissolubility is to the maximum at 5 o'clock and increases gradually along with pH is increased to, increase linearly along with the pH maximum increases at 7 o'clock then.Observe pH5 and have 30 times to the difference in solubility between the pH7.
Michelucci etc. keep alkaline microenvironment pH in the tablet by adding rate of release modifier, thereby solve the problem of etodolac poor solubility in acid medium.United States Patent (USP) 4,966,768 have disclosed the etodolac extended release's type that is administered once every day.The dissolubility minimum that when adding sustained release rate modifier can guarantee by gastrointestinal tract pH is relied on.Use the mixture of hydrophilic polymer, hydroxypropyl emthylcellulose and hydrophobic polymer, ethyl cellulose that medicine is slowly discharged from dosage form.Using hydrophobic polymer can postpone solubilizing poorly and the stripping of hydrophobic drug etodolac in acid medium, is very necessary thereby use rate of release modifier.
United States Patent (USP) 4,704,285 have disclosed the hydroxypropylcelluloether ether component of using the fine grained particle diameter, and use identical chemical constituent but the thick hydroxypropylcelluloether ether component of particle diameter is compared, release active component for more time when the former can delay tablet aqueous sour environments contact down with 37 ℃.Said preparation is not suitable for as etodolac the medicine of solubilizing poorly in acid medium.
Summary of the invention
An object of the present invention is to provide the slow release formulation of the etodolac that is administered once suitable every day, comprise a kind of carrier substrate material, described carrier substrate material package is drawn together hydrophilic polymer, does not wherein have rate of release modifier.
The invention provides the slow release formulation of the suitable etodolac that was administered once in a day, it comprises etodolac and carrier substrate material, and wherein the carrier substrate material package is drawn together the hydrophilic polymer of one or more many viscosity grades, as hydroxypropyl cellulose.
Detailed Description Of The Invention
Be used for preferably micronization of etodolac of the present invention, increase its total surface area, and improve its dissolubility.Hydroxypropyl cellulose (HPC) is cellulosic poly-(hydroxypropyl) ether that part replaces, available from trade name Klucel
TM(Aqualon), Methocel
TM(Dow Chemical Co.) and Nisso HPC
TMAccording to the present invention, the carrier substrate material preferably includes the HPC of one or more viscosity grades.Be more preferably, hydroxypropyl cellulose is selected from the viscosity grade (under 20 ℃, 2% aqueous solution) of 6.0-10.0 centipoise (HPC-L) and 150-400 centipoise (HPC-M).The amount of HPC-L in preparation is about 5-40% weight, 5-20% weight preparation preferably, and the amount of HPC-M is about 5-25% weight, is more preferably the about 5-15% weight that accounts for preparation.HPC-L is quick swollen material, may command medicine disengaging at first from dosage form.HPC-M is control drug release speed in the time that prolongs.Two kinds of polymer obtain required external curve and pharmacokinetics curve once a day with suitable ratio.The scope of the mixed proportion of carrier substrate material is a 5-65% weight in the dosage form of the present invention, preferably about 10-35% weight.
According to the present invention, pharmaceutical composition can contain conventional drug excipient in addition, as diluent, binding agent, disintegrating agent, lubricant, coloring agent etc.According to the preferred embodiments of the invention, lactose is used as implant, and polyvinyl pyrrolidone (PVP) is as binding agent.
According to the present invention, pharmaceutical composition is preferably tablet.Tablet is the film coating preferably.
The following example for setting forth usefulness, is not to be used for limiting effective range of the present invention only.
Embodiment 1
| Component | Milligram/sheet |
| Etodolac | ??????600 |
| Lactose monohydrate | ??????166 |
| Hydroxypropyl cellulose (L) | ??????70 |
| Hydroxypropyl cellulose (M) | ??????150 |
| ??????PVP?K30 | ??????24 |
| Magnesium stearate | ??????10 |
| Pulvis Talci | ??????10 |
| ?????Aerosil?200 | ??????10 |
| Gross weight | ??????1040 |
| Time (hour) | Discharge the accumulative total percent of medicine |
| ????????1 | ?????7.5 |
| ????????2 | ?????15.1 |
| ????????4 | ?????32.2 |
| ????????6 | ?????48.5 |
| ????????8 | ?????63 |
| ????????10 | ?????75 |
| ????????12 | ?????85 |
| ????????14 | ?????97 |
Preparation method: with etodolac, HPC-L, HPC-M and lactose screening, dry blending 20 minutes.Make granulating mixture with PVP solution then.Dried particles in fluidized bed dryer, dry screening mixes with magnesium stearate, Pulvis Talci and Aerosil 200.Make last mixture film-making, use the Opadry coating.
Embodiment 2
| Component | Milligram/sheet |
| Etodolac | ????600 |
| Lactose monohydrate | ????166 |
| Hydroxypropyl cellulose (L) | ????50 |
| Hydroxypropyl cellulose (M) | ????120 |
| ????PVP?K30 | ????24 |
| Magnesium stearate | ????10 |
| Pulvis Talci | ????10 |
| ???Aerosil?200 | ????10 |
| Gross weight | ????990 |
| Time (hour) | Discharge the accumulative total percent of medicine |
| ???????????1 | ??????????11.7 |
| ???????????2 | ??????????22.8 |
| ???????????4 | ??????????43.3 |
| ???????????6 | ??????????61.0 |
| ???????????8 | ??????????75.7 |
| ???????????10 | ??????????92.5 |
| ???????????12 | ??????????100.7 |
Its preparation method and embodiment 1 are described same.
Embodiment 3
| Component | Milligram/sheet |
| Etodolac | ????600 |
| Lactose | ????186 |
| Hydroxypropyl cellulose (L) | ????70 |
| Hydroxypropyl cellulose (M) | ????110 |
| ?????PVP?K30 | ????24 |
| Magnesium stearate | ????10 |
| Pulvis Talci | ????10 |
| ????Aerosil?200 | ????10 |
| Gross weight | ????1020 |
| Time (hour) | Discharge the accumulative total percent of medicine |
| ????1 | ??????3.5 |
| ????2 | ??????10.8 |
| ????4 | ??????21.3 |
| ????6 | ??????44.3 |
| ????8 | ??????64.1 |
| ????10 | ??????87.7 |
| ????12 | ??????101.5 |
Preparation method is described identical with embodiment 1.
Embodiment 4
| Component | Milligram/sheet |
| Etodolac | ????600 |
| Lactose | ????165 |
| Hydroxypropyl cellulose (L) | ????150 |
| Hydroxypropyl cellulose (M) | ????75 |
| ?????PVP?K30 | ????24 |
| Magnesium stearate | ????10 |
| Pulvis Talci | ????10 |
| ????Aerosil?200 | ????10 |
| Gross weight | ????1044 |
| Time (hour) | Discharge the accumulative total percent of medicine |
| ????1 | ????9.1 |
| ????2 | ????22.6 |
| ????4 | ????46.9 |
| ????6 | ????69.8 |
| ????8 | ????87.2 |
| ????10 | ????99.4 |
| ????12 | ????102.3 |
| ????14 | ????102.8 |
Its preparation method is described with embodiment 1.
Embodiment 5
| Component | Milligram/sheet |
| Etodolac | ????600 |
| Lactose | ????155 |
| Hydroxypropyl cellulose (L) | ????135 |
| Hydroxypropyl cellulose (M) | ????85 |
| ?????PVP?K30 | ????24 |
| Magnesium stearate | ????10 |
| Pulvis Talci | ????10 |
| ????Aerosil?200 | ????10 |
| Gross weight | ????1029 |
| Time (hour) | Discharge the accumulative total percent of medicine |
| ????1 | ?????10.4 |
| ????2 | ?????22.2 |
| ????4 | ?????44.6 |
| ????6 | ?????62.3 |
| ????8 | ?????75.6 |
| ????10 | ?????85.2 |
| ????12 | ?????92.9 |
| ????14 | ?????99.4 |
Its preparation method is described identical with embodiment 1.
All embodiment that this paper discloses only use hydrophilic polymer even without rate of release modifier, also can obtain as United States Patent (USP) 4,966 the similar speed of 768 described drug releases.
Though the present invention was described with regard to its specific embodiment already, modification that it is specific and equivalent are obvious to present technique field personnel, should be included in the scope of the present invention.
Claims (11)
1. a slow release formulation compositions that is administered once suitable every day comprises etodolac and carrier substrate material, and wherein the carrier substrate material package is drawn together the hydroxypropyl cellulose of one or more viscosity grades.
2. compositions according to claim 1, wherein hydroxypropyl cellulose is selected from, and for 20 ℃ of following 2% aqueous solutions, viscosity grade is 6.0-10 centipoise (HPC-L) and 150-400 centipoise (HPC-M).
3. compositions according to claim 1 and 2, wherein HPC-L accounts for about 5-40% weight of preparation, and HPC-M accounts for about 5-25% weight of preparation.
4. compositions according to claim 3, wherein the amount of HPC-L accounts for about 5-20% weight of preparation, and HPC-M accounts for about 5-15% weight of preparation.
5. compositions according to claim 1, wherein the amount of carrier substrate material accounts for about 5-65% weight of preparation.
6. compositions according to claim 5, wherein the amount of carrier substrate material accounts for the 10-35% weight of preparation.
7. compositions according to claim 1, wherein pharmaceutical preparation is tablet.
8. compositions according to claim 7, wherein tablet is the film coating.
9. compositions according to claim 1, wherein pharmaceutical dosage form further comprises conventional drug excipient, comprises diluent, binding agent, lubricant.
10. compositions according to claim 9, wherein diluent is a lactose.
11. compositions according to claim 9, wherein binding agent is a polyvinyl pyrrolidone.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1210/DEL/99 | 1999-09-10 | ||
| IN1210DE1999 IN190974B (en) | 1999-09-10 | 1999-09-10 | |
| US09/648,949 | 2000-08-25 | ||
| US09/648,949 US6586005B1 (en) | 1999-09-10 | 2000-08-25 | Extended release formulation of etodolac |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1402631A true CN1402631A (en) | 2003-03-12 |
| CN1227001C CN1227001C (en) | 2005-11-16 |
Family
ID=26324703
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB008143196A Expired - Fee Related CN1227001C (en) | 1999-09-10 | 2000-08-30 | Extended release formulation of etodolac |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN1227001C (en) |
| AU (1) | AU6589200A (en) |
| WO (1) | WO2001019349A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101259113B (en) * | 2008-04-21 | 2013-02-13 | 沈阳药科大学 | Etodolac osmotic pump type controlled-release preparation and preparation thereof |
| CN106727390A (en) * | 2015-11-19 | 2017-05-31 | 哈尔滨圣吉药业股份有限公司 | A kind of etodolac sustained released tablets and preparation method thereof |
| CN106999438A (en) * | 2014-11-14 | 2017-08-01 | 药品配送国际有限公司 | Composition |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0206505D0 (en) * | 2002-03-19 | 2002-05-01 | Euro Celtique Sa | Pharmaceutical combination |
| AU2003214551A1 (en) * | 2002-04-11 | 2003-10-20 | Ranbaxy Laboratories Limited | Controlled release pharmaceutical compositions of carbidopa and levodopa |
| BRPI0611618A2 (en) * | 2005-06-22 | 2011-05-31 | Takeda Pharmaceutical | tablet |
| WO2007123021A1 (en) | 2006-04-12 | 2007-11-01 | Nippon Soda Co., Ltd. | Method for producing extended release tablet |
| TR200908308A1 (en) | 2010-01-18 | 2011-08-22 | Turgut İlaçlari A.Ş. | Sustained-release tablet formulation containing etodolac |
| CN102485215B (en) * | 2010-12-03 | 2013-05-15 | 沈阳药科大学 | Etodolac time-release pellet preparation and preparation method thereof |
| CN114699380A (en) * | 2021-12-27 | 2022-07-05 | 南京联智医药科技有限公司 | Etodolac tablet and preparation method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2178686A1 (en) * | 1995-06-13 | 1996-12-14 | Leslie G. Humber | Oral formulations of s(+)-etodolac |
| US6251430B1 (en) * | 1998-02-04 | 2001-06-26 | Guohua Zhang | Water insoluble polymer based sustained release formulation |
| US6106862A (en) * | 1998-08-13 | 2000-08-22 | Andrx Corporation | Once daily analgesic tablet |
-
2000
- 2000-08-30 WO PCT/IB2000/001208 patent/WO2001019349A2/en active Application Filing
- 2000-08-30 AU AU65892/00A patent/AU6589200A/en not_active Abandoned
- 2000-08-30 CN CNB008143196A patent/CN1227001C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101259113B (en) * | 2008-04-21 | 2013-02-13 | 沈阳药科大学 | Etodolac osmotic pump type controlled-release preparation and preparation thereof |
| CN106999438A (en) * | 2014-11-14 | 2017-08-01 | 药品配送国际有限公司 | Composition |
| US10675247B2 (en) | 2014-11-14 | 2020-06-09 | Drug Delivery International Ltd. | Press coated tablet prepared for delayed release of an active ingredient |
| CN106727390A (en) * | 2015-11-19 | 2017-05-31 | 哈尔滨圣吉药业股份有限公司 | A kind of etodolac sustained released tablets and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2001019349A3 (en) | 2001-08-09 |
| AU6589200A (en) | 2001-04-17 |
| CN1227001C (en) | 2005-11-16 |
| WO2001019349A2 (en) | 2001-03-22 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |