WO2001019349A2 - Extended release formulation of etodolac - Google Patents

Extended release formulation of etodolac Download PDF

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Publication number
WO2001019349A2
WO2001019349A2 PCT/IB2000/001208 IB0001208W WO0119349A2 WO 2001019349 A2 WO2001019349 A2 WO 2001019349A2 IB 0001208 W IB0001208 W IB 0001208W WO 0119349 A2 WO0119349 A2 WO 0119349A2
Authority
WO
WIPO (PCT)
Prior art keywords
composition
hpc
formulation
present
etodolac
Prior art date
Application number
PCT/IB2000/001208
Other languages
French (fr)
Other versions
WO2001019349A3 (en
Inventor
Rajeev S. Raghuvanshi
Ashok Rampal
Himadri Sen
Original Assignee
Ranbaxy Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from IN1210DE1999 external-priority patent/IN190974B/en
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Priority to AU65892/00A priority Critical patent/AU6589200A/en
Publication of WO2001019349A2 publication Critical patent/WO2001019349A2/en
Publication of WO2001019349A3 publication Critical patent/WO2001019349A3/en

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Classifications

    • 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

Definitions

  • the present invention relates to a sustained release formulation of etodolac for once daily administration.
  • Etodolac is approved for the management of signs and symptoms of osteoarthritis, rheumatoid arthritis and for the management of pain.
  • the conventional dosing regimen is 800 mg to 1200 mg given in 2-4 divided doses. This regimen can cause problems of compliance due to lack of patient convenience. It is well known to those skilled in the art that sustained release systems result in a decrease in frequency of administration thereby improving patient compliance. Furthermore, sustained released drug delivery systems produce constant therapeutic plasma levels of active ingredients as compared to fluctuations seen with multiple doses of a conventional formulation.
  • Patent No. 4,966,768 describes a sustained release dosage form of Etodolac for once-a-day administration.
  • the addition of a release rate modifiers ensures that pH dependent solubility is minimized throughout the gastrointestinal tract.
  • An admixture of a hydrophilic polymer, hydroxypropyl methyl- cellulose and a hydrophobic polymer, ethyl cellulose is used for sustaining the release of the drug from the dosage form.
  • the use of a hydrophobic polymer retards the dissolution of the poorly soluble and hydrophobic drug, etodolac, in acidic media thus necessitating the use of release rate modifiers.
  • U.S. Patent No. 4,704,285 discloses the use of fine particle sized hydroxypropyl cellulose ether composition for delaying the release of the active composition from a tablet longer upon contacting an aqueous acidic environment at 37 Q C compared to a chemically identical but coarser particle sized hydroxypropyl cellulose ether composition.
  • This formulation is not suitable for drugs like etodolac which are poorly soluble in the acidic media.
  • An object of the present invention is to provide a sustained release dosage form of etodolac suitable for once daily administration comprising a carrier base material which comprises only hydrophilic polymers wherein no release rate modifying agents are present.
  • a sustained release dosage form suitable for once-a-day administration of Etodolac comprising etodolac and a carrier base material, wherein the carrier base material comprises one or more multiple viscosity grades of a hydrophilic polymer such as hydroxypropyl cellulose.
  • the etodolac used in the present invention is preferably micronized to increase its total surface area and improve its solubility.
  • Hydroxypropyl- cellulose is a partially substituted poly (hydroxypropyl) ether of cellulose which is commercially available under the trade names KlucelTM (Aqualon), MethocelTM (Dow Chemical Co.), and Nisso HPCTM.
  • the carrier base material preferably comprises one or more viscosity grades of HPC.
  • hydroxypropyl cellulose is selected from the viscosity grades of 6.0 to 10.0 centipoise (HPC-L) and 150- 400 centipoise (HPC-M) for a 2% aqueous solution at 20 Q C.
  • HPC-L is present from about 5-40% w/w of the formulation or more preferably from 5-20% w/w of the formulation and HPC-M is present from about 5-25% w/w of the formulation or more preferably from 5-15% w/w of the formulation.
  • HPC - L is a rapidly swellable material and is responsible for controlling the initial release of the drug from the dosage form.
  • HPC-M controls the rate of drug release over an extended period of time.
  • the combined proportion of the carrier base material in the dosage form of the invention can range from 5-65% by weight or more preferably from about 10-35% by weight.
  • the pharmaceutical composition may additionally contain conventional pharmaceutical excipients such as diluents, binders, disintegrants, lubricants, coloring agent, etc.
  • lactose is used as the filler and polyvinyl pyrrolidone (PVP) as the binder.
  • the pharmaceutical composition is preferably in the form of tablets.
  • the tablet is preferably film coated.
  • Etodolac, HPC-L, HPC-M and lactose were sized and dry blended for 20 minutes. The mix was then granulated with solution of PVP. The granules were dried in a fluidized bed drier, dry sized and blended with magnesium stearate, talc and Aerosil 200. The final blend was tableted and coated with Opadry.
  • the method of manufacture was the same as described in Example 1.
  • the method of manufacture was the same as described in Example 1.

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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

EXTENDED RELEASE FORMULATION
OF ETODOLAC
FIELD OF THE INVENTION The present invention relates to a sustained release formulation of etodolac for once daily administration.
BACKGROUND OF THE INVENTION Etodolac (1 ,8-diethyl-1 ,3,4,9-tetrahydropyrano [3,4-b] indole-1 -acetic acid or a therapeutically acceptable salt thereof) is disclosed in U.S. Patent No. 3,939,178. It has been reported to have analgesic and anti-inflammatory properties. It has also been reported to be effective in the treatment of gout by lowering uric acid blood levels in humans (U.S. Patent No. 4,663,345) and in the treatment of rheumatoid arthritis by lowering rheumatoid factor blood levels (U.S. Patent No. 4,742,076).
Etodolac is approved for the management of signs and symptoms of osteoarthritis, rheumatoid arthritis and for the management of pain. The conventional dosing regimen is 800 mg to 1200 mg given in 2-4 divided doses. This regimen can cause problems of compliance due to lack of patient convenience. It is well known to those skilled in the art that sustained release systems result in a decrease in frequency of administration thereby improving patient compliance. Furthermore, sustained released drug delivery systems produce constant therapeutic plasma levels of active ingredients as compared to fluctuations seen with multiple doses of a conventional formulation. However, development of a sustained release formulation of etodolac effective for 24 hours or suitable for once-a-day administration poses problems due to a very low aqueous solubility of Etodolac which is pH indepen- dent below pH 3. The solubility then gradually increases with increasing pH up to 5 and then linearly increases with increasing pH up to 7. A thirty-fold difference between solubility at pH 5 to pH 7 has been observed.
The problem of poor solubility of Etodolac in the acidic media has been addressed by Michelucci et al. by the addition of a release rate modifying agent for maintaining an alkaline microenvironment pH within the tablet. U.S.
Patent No. 4,966,768 describes a sustained release dosage form of Etodolac for once-a-day administration. The addition of a release rate modifiers ensures that pH dependent solubility is minimized throughout the gastrointestinal tract. An admixture of a hydrophilic polymer, hydroxypropyl methyl- cellulose and a hydrophobic polymer, ethyl cellulose is used for sustaining the release of the drug from the dosage form. The use of a hydrophobic polymer retards the dissolution of the poorly soluble and hydrophobic drug, etodolac, in acidic media thus necessitating the use of release rate modifiers.
U.S. Patent No. 4,704,285 discloses the use of fine particle sized hydroxypropyl cellulose ether composition for delaying the release of the active composition from a tablet longer upon contacting an aqueous acidic environment at 37QC compared to a chemically identical but coarser particle sized hydroxypropyl cellulose ether composition. This formulation is not suitable for drugs like etodolac which are poorly soluble in the acidic media.
SUMMARY OF THE INVENTION An object of the present invention is to provide a sustained release dosage form of etodolac suitable for once daily administration comprising a carrier base material which comprises only hydrophilic polymers wherein no release rate modifying agents are present.
In accordance with the present invention, there is provided a sustained release dosage form suitable for once-a-day administration of Etodolac comprising etodolac and a carrier base material, wherein the carrier base material comprises one or more multiple viscosity grades of a hydrophilic polymer such as hydroxypropyl cellulose.
DETAILED DESCRIPTION OF THE INVENTION The etodolac used in the present invention is preferably micronized to increase its total surface area and improve its solubility. Hydroxypropyl- cellulose (HPC) is a partially substituted poly (hydroxypropyl) ether of cellulose which is commercially available under the trade names Klucel™ (Aqualon), Methocel™ (Dow Chemical Co.), and Nisso HPC™. In accordance with the present invention, the carrier base material preferably comprises one or more viscosity grades of HPC. More preferably, hydroxypropyl cellulose is selected from the viscosity grades of 6.0 to 10.0 centipoise (HPC-L) and 150- 400 centipoise (HPC-M) for a 2% aqueous solution at 20QC. HPC-L is present from about 5-40% w/w of the formulation or more preferably from 5-20% w/w of the formulation and HPC-M is present from about 5-25% w/w of the formulation or more preferably from 5-15% w/w of the formulation. HPC - L is a rapidly swellable material and is responsible for controlling the initial release of the drug from the dosage form. HPC-M controls the rate of drug release over an extended period of time. It is the appropriate ratio of the two polymers that provides the desired in vitro profiles and the once daily pharmaco- kinetic profiles. The combined proportion of the carrier base material in the dosage form of the invention can range from 5-65% by weight or more preferably from about 10-35% by weight.
According to the present invention, the pharmaceutical composition may additionally contain conventional pharmaceutical excipients such as diluents, binders, disintegrants, lubricants, coloring agent, etc. According to a preferred embodiment of the present invention, lactose is used as the filler and polyvinyl pyrrolidone (PVP) as the binder.
According to invention, the pharmaceutical composition is preferably in the form of tablets. The tablet is preferably film coated.
The following examples are illustrative only and are not intended to limit the effective scope of the present invention. EXAMPLE 1
Figure imgf000006_0001
Method of manufacture: Etodolac, HPC-L, HPC-M and lactose were sized and dry blended for 20 minutes. The mix was then granulated with solution of PVP. The granules were dried in a fluidized bed drier, dry sized and blended with magnesium stearate, talc and Aerosil 200. The final blend was tableted and coated with Opadry.
EXAMPLE 2
Figure imgf000007_0001
The method of manufacture was the same as described in Example 1 ,
EXAMPLE 3
Figure imgf000007_0002
Figure imgf000008_0001
The method of manufacture was the same as described in Example 1.
EXAMPLE 4
Figure imgf000008_0002
The method of manufacture was the same as described in Example 1. EXAMPLE 5
Figure imgf000009_0001
The method of manufacture was the same as described in Example 1.
All the examples described herein illustrate that even in the absence of a release rate modifying agent, use of hydrophilic polymers resulted in a similar rate of drug release as described in the example of U.S. Patent No. 4,966,768.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims

CLAIMS:
1. A sustained release dosage form composition suitable for once-a-day administration comprising etodolac and a carrier base material, wherein the carrier base material comprises one or more viscosity grades of hydroxypropyl cellulose.
2. The composition of claim 1 , wherein hydroxypropyl cellulose is selected from the viscosity grades of 6.0 -10 centipoise (HPC-L), and 150-400 centipoise (HPC-M), for a 2% aqueous solution at 20QC.
3. The composition of claim 1 or 2 wherein HPC-L is present from about 5-40% w/w of the formulation and HPC-M is present from about 5-25% w/w of the formulation.
4. The composition of claim 3, wherein HPC-L is present from about 5- 20% w/w of the formulation and HPC-M is present from about 5-15% w/w of the formulation.
5. The composition of claim 1 , wherein the carrier base material is present from about 5-65% by weight of the formulation.
6. The composition of claim 5, wherein the carrier base material is present from 10-35% by weight of the formulation.
7. The composition of claim 1 wherein the pharmaceutical dosage form is a tablet.
8. The composition of claim 7, wherein the tablet is film coated.
9. The composition of claim 1 , wherein the pharmaceutical dosage form further comprises conventional pharmaceutical excipients including diluents, binders, lubricants.
10. The composition of claim 9 wherein the diluent is lactose.
11. The composition of claim 9 wherein the binder is polyvinylpyrrolidone.
PCT/IB2000/001208 1999-09-10 2000-08-30 Extended release formulation of etodolac WO2001019349A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU65892/00A AU6589200A (en) 1999-09-10 2000-08-30 Extended release formulation of etodolac

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN1210DE1999 IN190974B (en) 1999-09-10 1999-09-10
IN1210/DEL/99 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
WO2001019349A2 true WO2001019349A2 (en) 2001-03-22
WO2001019349A3 WO2001019349A3 (en) 2001-08-09

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003080183A1 (en) * 2002-03-19 2003-10-02 Euro-Celtique S.A. Pharmaceutical combination of the cox-2 inhibitor etodolac and opioids
WO2003084514A1 (en) * 2002-04-11 2003-10-16 Ranbaxy Laboratories Limited Controlled release pharmaceutical compositions of carbidopa and levodopa
WO2007004425A1 (en) * 2005-06-22 2007-01-11 Takeda Pharmaceutical Company Limited Tablet containing poorly soluble active ingredient
EP2005946A1 (en) * 2006-04-12 2008-12-24 Nippon Soda Co., Ltd. Method for producing extended release tablet
WO2011087464A1 (en) 2010-01-18 2011-07-21 Turgut İlaclari A.S. Sustained release tablet formulation containing etodolac
CN102485215A (en) * 2010-12-03 2012-06-06 沈阳药科大学 Etodolac timed-release pellet and preparation method thereof
US10675247B2 (en) 2014-11-14 2020-06-09 Drug Delivery International Ltd. Press coated tablet prepared for delayed release of an active ingredient
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

Families Citing this family (2)

* Cited by examiner, † Cited by third party
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

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0748628A2 (en) * 1995-06-13 1996-12-18 American Home Products Corporation Oral formulations of S(+)-Etodolac
WO1999039698A1 (en) * 1998-02-04 1999-08-12 Duramed Pharmaceuticals, Inc. Sustained release formulation
WO2000009091A1 (en) * 1998-08-13 2000-02-24 Andrx Pharmaceuticals, Inc. Once daily analgesic tablet

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0748628A2 (en) * 1995-06-13 1996-12-18 American Home Products Corporation Oral formulations of S(+)-Etodolac
WO1999039698A1 (en) * 1998-02-04 1999-08-12 Duramed Pharmaceuticals, Inc. Sustained release formulation
WO2000009091A1 (en) * 1998-08-13 2000-02-24 Andrx Pharmaceuticals, Inc. Once daily analgesic tablet

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003080183A1 (en) * 2002-03-19 2003-10-02 Euro-Celtique S.A. Pharmaceutical combination of the cox-2 inhibitor etodolac and opioids
WO2003084514A1 (en) * 2002-04-11 2003-10-16 Ranbaxy Laboratories Limited Controlled release pharmaceutical compositions of carbidopa and levodopa
WO2007004425A1 (en) * 2005-06-22 2007-01-11 Takeda Pharmaceutical Company Limited Tablet containing poorly soluble active ingredient
EP2005946A1 (en) * 2006-04-12 2008-12-24 Nippon Soda Co., Ltd. Method for producing extended release tablet
EP2005946A4 (en) * 2006-04-12 2011-03-02 Nippon Soda Co Method for producing extended release tablet
US8617596B2 (en) 2006-04-12 2013-12-31 Nippon Soda Co., Ltd. Sustained-release tablet production process
WO2011087464A1 (en) 2010-01-18 2011-07-21 Turgut İlaclari A.S. Sustained release tablet formulation containing etodolac
CN102485215A (en) * 2010-12-03 2012-06-06 沈阳药科大学 Etodolac timed-release pellet and preparation method thereof
US10675247B2 (en) 2014-11-14 2020-06-09 Drug Delivery International Ltd. Press coated tablet prepared for delayed release of an active ingredient
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

Also Published As

Publication number Publication date
AU6589200A (en) 2001-04-17
CN1402631A (en) 2003-03-12
WO2001019349A3 (en) 2001-08-09
CN1227001C (en) 2005-11-16

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