WO1985004099A1 - Sustained release oral dosage form for naproxyn - Google Patents

Sustained release oral dosage form for naproxyn Download PDF

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Publication number
WO1985004099A1
WO1985004099A1 PCT/US1984/000431 US8400431W WO8504099A1 WO 1985004099 A1 WO1985004099 A1 WO 1985004099A1 US 8400431 W US8400431 W US 8400431W WO 8504099 A1 WO8504099 A1 WO 8504099A1
Authority
WO
WIPO (PCT)
Prior art keywords
sustained release
methyl
alpha
methoxy
polyvinylpyrrolidone
Prior art date
Application number
PCT/US1984/000431
Other languages
French (fr)
Inventor
Charles H. Hsiao
Original Assignee
Key Pharmaceuticals, Inc.
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
Application filed by Key Pharmaceuticals, Inc. filed Critical Key Pharmaceuticals, Inc.
Priority to PCT/US1984/000431 priority Critical patent/WO1985004099A1/en
Priority to EP19840901535 priority patent/EP0178299A4/en
Publication of WO1985004099A1 publication Critical patent/WO1985004099A1/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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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

Definitions

  • the present invention relates to a sustained release preparation of (+)-6-methoxy-alpha-methyl-2- naphthaleneacetic acid (naproxen) . Specifically, it relates to an oral dosage form which provides a release period suitable for single daily dosing while exhibiting good bioavailability.
  • (+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid is a well known and widely used medication for pain relief, both generally and for specific maladies such as . arthritis.
  • (+)-6-methoxy-alpha-methyl-2- naphthaleneacetic acid is also suitable as an agent to relieve the periodic pains of menstruation.
  • (+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid over a prolonged period of time which comprises a therapeutically effective amount of (+)-6-methoxy- alpha-methyl-2-naphthaleneacetic acid to provide a sustained release thereof over said a prolonged period of time which is contained in compressed granules having from about 1 to about 30 parts by weight hydroxypropyl methylcellulose having a molecular weight of from about 20,000 to about 140,000 and about one to 30 parts by weight polyvinylpyrrolidone
  • the weight ratio of hydroxypropyl methylcellulose to polyvinylpyrrolidone is from about 3:1 to about 1:1, and more preferably is about 1:1.
  • a sustained release of (+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid contained in granules formed into said tablet, over a prolonged period, said tablet consisting essentially of a plurality of compressed granules consisting essentially of from about 1 to about 30 parts by weight hydroxypropyl methylcellulose and about 1 to 30 parts by weight polyvinylpyrrolidone and a lubricant for said granules, such as magnesium stearate.
  • the oral sustained release dosage unit form permits a sustained • release of (+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid over a period of about 24 hours,' eliminating the need for dosing at different periods of the day.
  • hydroxypropyl methylcellulose in an amount of about 20 to about 200 g, with 50 mg being preferred.
  • the hydroxypropyl methylcellulose has a molecular weight of about 20,000 to about 140,000, preferably between about 70,000 and about 110,000.
  • molecular weights of about 86,000 (Methocel K4M, Dow Chemical) and about 120,000 (Methocel K15M, Dow Chemical) .
  • polyvinylpyrrolidone present in an amount of about 20 to about 200 mg, preferably about 50 mg.
  • the polyvinylpyrrolidone has a molecular weight in the range of from about 8,000 to about 630,000, and more preferably from about 20,000 to about 216,000, with 40,000 being a particularly preferred embodiment (povidone) .
  • the tablet also includes a lubricant such as mag ⁇ nesium stearate to aid in the tableting process.
  • a lubricant such as mag ⁇ nesium stearate to aid in the tableting process.
  • the magnesium stearate may be replaced with other suitable tablet lubricants.
  • the tablet to the present invention may vary widely in the amount of
  • (+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid that is included.
  • 1,000 mg per tablet is indicated for the treatment of pain of arthritis, dysmenorrhea and other conditions, with 750 to 1,000 mg tablets being preferred.
  • the oral dosage form herein described provides a release period suitable for once a day dosing.
  • Blended together are 500 gm
  • the blend is granulated with about 160 ml deionized water, and the resulting granules are then dried at
  • About 180 ml deionized water is added to the polymeric blend and after intimate mixing the resulting granules are then dried at 50°C and ground through a 14 mesh screen.
  • the granulated mixture is lubricated with 5 gm magnesium stearate.
  • the resultant granules are then compressed into capsule-shaped tablets, each weighing 1,110 mg and containing 1,000 mg (+)-6-methoxy-alpha-methyl-2-napthaleneacetic acid.

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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)
  • Medicinal Preparation (AREA)

Abstract

Sustained release tablet and method for administration of (+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid over a prolonged period, a single administration of the sustained release tablet of the present invention providing a 24 hour administration of the drug. This oral sustained release dosage form is a tablet containing sufficient (+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid to provide a sustained release over a prolonged period contained in granules formed into said tablet, said tablet consisting essentially of a plurality of compressed granules consisting essentially of from about 1 to about 30 parts by weight hydroxypropyl methylcellulose and about 1 to about 30 parts by weight polyvinylpyrrolidone and a lubricant for the granules, such as magnesium stearate. The oral sustained release dosage unit form permits a sustained release of (+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid over a period of about 24 hours, eliminating the need for dosing at different periods of the day.

Description

SUSTAINΞD RELEASE ORAL DOSAGE FORM FOR KAPROXYN
Background of the Invention The present invention relates to a sustained release preparation of (+)-6-methoxy-alpha-methyl-2- naphthaleneacetic acid (naproxen) . Specifically, it relates to an oral dosage form which provides a release period suitable for single daily dosing while exhibiting good bioavailability.
(+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid is a well known and widely used medication for pain relief, both generally and for specific maladies such as . arthritis. (+)-6-methoxy-alpha-methyl-2- naphthaleneacetic acid is also suitable as an agent to relieve the periodic pains of menstruation.
Summary of the Invention
In accordance with a first aspect of the present invention there is provided a sustained release oral medication in dosage unit form for the delivery of
(+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid over a prolonged period of time which comprises a therapeutically effective amount of (+)-6-methoxy- alpha-methyl-2-naphthaleneacetic acid to provide a sustained release thereof over said a prolonged period of time which is contained in compressed granules having from about 1 to about 30 parts by weight hydroxypropyl methylcellulose having a molecular weight of from about 20,000 to about 140,000 and about one to 30 parts by weight polyvinylpyrrolidone
(povidone) having a molecular weight of from about
8,000 to about 630,000, more preferably 20,000 to
OMPI 216,000, and a lubricant for said compressed granules. In a preferred embodiment, the weight ratio of hydroxypropyl methylcellulose to polyvinylpyrrolidone is from about 3:1 to about 1:1, and more preferably is about 1:1.
In a second aspect of the invention there is pro¬ vided a method of providing a sustained release of (+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid, contained in granules formed into said tablet, over a prolonged period, said tablet consisting essentially of a plurality of compressed granules consisting essentially of from about 1 to about 30 parts by weight hydroxypropyl methylcellulose and about 1 to 30 parts by weight polyvinylpyrrolidone and a lubricant for said granules, such as magnesium stearate.
The oral sustained release dosage unit form permits a sustained • release of (+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid over a period of about 24 hours,' eliminating the need for dosing at different periods of the day.
Detailed Description of the Invention Included in the tablet is hydroxypropyl methylcellulose in an amount of about 20 to about 200 g, with 50 mg being preferred. The hydroxypropyl methylcellulose has a molecular weight of about 20,000 to about 140,000, preferably between about 70,000 and about 110,000. As preferred embodiments may be mentioned molecular weights of about 86,000 (Methocel K4M, Dow Chemical) and about 120,000 (Methocel K15M, Dow Chemical) . Also included is polyvinylpyrrolidone, present in an amount of about 20 to about 200 mg, preferably about 50 mg. The polyvinylpyrrolidone has a molecular weight in the range of from about 8,000 to about 630,000, and more preferably from about 20,000 to about 216,000, with 40,000 being a particularly preferred embodiment (povidone) .
The tablet also includes a lubricant such as mag¬ nesium stearate to aid in the tableting process. The magnesium stearate may be replaced with other suitable tablet lubricants.
The tablet to the present invention may vary widely in the amount of
(+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid that is included. The therapeutic range of 250 to
"1,000 mg per tablet is indicated for the treatment of pain of arthritis, dysmenorrhea and other conditions, with 750 to 1,000 mg tablets being preferred. The oral dosage form herein described provides a release period suitable for once a day dosing.
The following non-limiting examples serve to fur¬ ther illustrate the invention.:
_OMPI_ EXAMPLE I
Blended together are 500 gm
(+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid;
48 gm hydroxypropyl methylcellulose (mw = 86,000 (Methocel K4M, Dow); and 26 gm povidone (mw = 60,000).
The blend is granulated with about 160 ml deionized water, and the resulting granules are then dried at
50°C and ground through a 14 mesh screen. The granulated mixture is lubricated with 5 gm magnesium stearate. The resultant granules are then compressed into capsule-shaped tablets, each weighing 555 mg and containing 500 mg (+)-6-methoxy-alpha-methye-2- naphthaleneacetic acid.
According to U.S.P II dissolution test methods in simulated intestinal fluid, the following data were collected:
Time Percent
(in hours) Released
1 10
2 17
4 33
6 48
8 64
10 78
12 92
EXAMPLE II
Blended together are 500 gm (+)-6-methoxy-alpha- methyl-2-naphthaleneacetic acid; 25 gm hydroxypropyl methylcellulose (mw = 86,000 (Methocel K-4-M, Dow); and 25 gm povidone (mw = 40,000). About 180 ml deionized water is added to the polymeric blend and after intimate mixing the resulting granules are then dried at 50°C and ground through a 14 mesh screen. The granulated mixture is lubricated with 5 gm magnesium stearate. The resultant granules are then compressed into capsule-shaped tablets, each weighing 1,110 mg and containing 1,000 mg (+)-6-methoxy-alpha-methyl-2-napthaleneacetic acid.
According to U.S.P II dissolution test methods in simulated intestinal fluid, the following data were collected:
Time Percent
(in hours) Released
1 9
2 18
4 35
6 49
8 61
10 72
12 80
The sustained re ease of (+)-6-mei methyl—2-naphthaleneace :tic acid coupled with the relatively long half life of (+)-6-met oxy-alpha- methyl-2-naphthaleneacetic acid in the blood plasma demonstrate a 24 hour sustained release capacity in the in vitro conditions used in this example.

Claims

HAT IS CLAIMED IS:
1. A sustained release oral medication in dosage unit form for the delivery of (+)-6-methoxy-alpha- methyl-2-naphthaleneacetic acid over a prolonged period of time which comprises a therapeutically effective amount of (+)-6-methoxy-alpha-meth l- 2-naphthaleneacetic acid to provide a sustained re¬ lease thereof over said prolonged period of time which is contained in compressed granules having from about 1 to about 30 parts by weight hydroxypropyl methyl¬ cellulose having a molecular weight of from about 20,000 to about 140,000 and about 1 to about 30 parts by weight polyvinylpyrrolidone having a molecular weight of from about 8,000 to about 630,000, and a lubricant for said compressed granules.
2. A sustained release oral medication of *claim 1, wherein the weight ratio of hydroxypropyl methyl¬ cellulose to polyvinylpyrrolidone is from about 3:1 to about 1:1.
3. A sustained release oral medication of claim 1, wherein the weight ratio of polyvinylpyrrolidone to hydroxypropyl methylcelluose is about 1:1.
4. A sustained release oral medication of claim 1, wherein said hydroxypropylmethyl cellulose has a molecular weight of from about 70,000 to about 110,000.
5. A sustained release oral medication of claim 1,_ wherein said polyvinylpyrrolidone has a molecular weight of from about 20,000 to about 216,000.
6. A sustained release oral medication of claim
1, wherein the polyvinylpyrrolidone has a molecular weight of about 40,000.
7. A method of providing a patient in pain with a sustained dosage of (+)-6-methoxy-alpha-methyl-2- naphthaleneacetic acid over a prolonged period of time which comprises orally administering to said patient a
Figure imgf000008_0001
tablet consisting essentially of a therapeutically effective amount of (+)-6-methoxy-alpha-methyl-2- naphthaleneacetic acid to provide a sustained release thereof over said a prolonged period of time which is contained in compressed granules having from about 1 to about 30 parts by weight hydroxypropyl methylcellulose and about 1 to about 30 parts by weight polyvinylpyrrolidone and a lubricant for said compressed granules.
8. A method of claim 7, wherein the weight ratio of hydroxypropyl methylcellulose to polyvinylpyrrolidone is from about 3:1 to about 1;
9. A method of claim 7 . wherein the weight ratio of polyvinylpyrrolidone to hydroxypropyl methylcellulose is about 1:1.
10. The method of claim 7, wherein a substantially constant plasma level of (+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid is maintained over said prolonged period.
11. A method of claim 7, wherein said hydroxy¬ propyl methylcellulose has a molecular weight of from about 20,000 to about 140,000.
12. A method of claim 7, wherein said polyvinyl- pyrrolidone has a molecular weight of from about 8,000 to about 630,000.
13. A method of claim 7, wherein said polyvinyl¬ pyrrolidone has a molecular weight of about 40,000.
PCT/US1984/000431 1984-03-21 1984-03-21 Sustained release oral dosage form for naproxyn WO1985004099A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/US1984/000431 WO1985004099A1 (en) 1984-03-21 1984-03-21 Sustained release oral dosage form for naproxyn
EP19840901535 EP0178299A4 (en) 1984-03-21 1984-03-21 Sustained release oral dosage form for naproxyn.

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1984/000431 WO1985004099A1 (en) 1984-03-21 1984-03-21 Sustained release oral dosage form for naproxyn

Publications (1)

Publication Number Publication Date
WO1985004099A1 true WO1985004099A1 (en) 1985-09-26

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Family Applications (1)

Application Number Title Priority Date Filing Date
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Country Status (2)

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EP (1) EP0178299A4 (en)
WO (1) WO1985004099A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0519820A1 (en) * 1991-06-18 1992-12-23 Adir Et Compagnie Matrixtablet for the sustained release of indapamide after oral administration
WO1993010761A1 (en) * 1991-12-05 1993-06-10 Alfatec-Pharma Gmbh Medicament containing a 2-arylpropionic acid derivate as a nanosol and its preparation
EP0601508A2 (en) * 1992-12-11 1994-06-15 RECORDATI S.A. CHEMICAL and PHARMACEUTICAL COMPANY Liquid-suspension controlled-release pharmaceutical composition
US5527545A (en) * 1989-09-18 1996-06-18 Recordati S.A. Chemical And Pharmaceutical Company Liquid-suspension controlled-release pharmaceutical composition
EP1549598A1 (en) * 2002-06-07 2005-07-06 Cortical Pty Ltd Napththalene derivatives which inhibit the cytokine or biological activity of macrophage migration inhibitory factor (mif)
CN116270902A (en) * 2023-04-26 2023-06-23 南京同仁堂药业有限责任公司 Jingshu granule and preparation method thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4001390A (en) * 1974-04-04 1977-01-04 Shin-Etsu Chemical Co., Ltd. Method of coating pharmaceutical solid dosage forms
US4308251A (en) * 1980-01-11 1981-12-29 Boots Pharmaceuticals, Inc. Controlled release formulations of orally-active medicaments
US4389393A (en) * 1982-03-26 1983-06-21 Forest Laboratories, Inc. Sustained release therapeutic compositions based on high molecular weight hydroxypropylmethylcellulose

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4001390A (en) * 1974-04-04 1977-01-04 Shin-Etsu Chemical Co., Ltd. Method of coating pharmaceutical solid dosage forms
US4308251A (en) * 1980-01-11 1981-12-29 Boots Pharmaceuticals, Inc. Controlled release formulations of orally-active medicaments
US4389393A (en) * 1982-03-26 1983-06-21 Forest Laboratories, Inc. Sustained release therapeutic compositions based on high molecular weight hydroxypropylmethylcellulose
US4389393B1 (en) * 1982-03-26 1985-10-22

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0178299A4 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5527545A (en) * 1989-09-18 1996-06-18 Recordati S.A. Chemical And Pharmaceutical Company Liquid-suspension controlled-release pharmaceutical composition
US5670171A (en) * 1989-09-18 1997-09-23 Recordati S.A. Chemical And Pharmaceutical Company Liquid-suspension controlled-release pharmaceutical composition
EP0519820A1 (en) * 1991-06-18 1992-12-23 Adir Et Compagnie Matrixtablet for the sustained release of indapamide after oral administration
FR2677886A1 (en) * 1991-06-18 1992-12-24 Adir MATRIX COMPRESSOR FOR PROLONGED INDAPAMIDE RELEASE AFTER ORAL ADMINISTRATION.
WO1993010761A1 (en) * 1991-12-05 1993-06-10 Alfatec-Pharma Gmbh Medicament containing a 2-arylpropionic acid derivate as a nanosol and its preparation
EP0601508A2 (en) * 1992-12-11 1994-06-15 RECORDATI S.A. CHEMICAL and PHARMACEUTICAL COMPANY Liquid-suspension controlled-release pharmaceutical composition
EP0601508A3 (en) * 1992-12-11 1995-10-25 Recordati Chem Pharm Liquid-suspension controlled-release pharmaceutical composition.
EP1549598A1 (en) * 2002-06-07 2005-07-06 Cortical Pty Ltd Napththalene derivatives which inhibit the cytokine or biological activity of macrophage migration inhibitory factor (mif)
EP1549598A4 (en) * 2002-06-07 2008-01-23 Cortical Pty Ltd Napththalene derivatives which inhibit the cytokine or biological activity of macrophage migration inhibitory factor (mif)
CN116270902A (en) * 2023-04-26 2023-06-23 南京同仁堂药业有限责任公司 Jingshu granule and preparation method thereof

Also Published As

Publication number Publication date
EP0178299A1 (en) 1986-04-23
EP0178299A4 (en) 1987-04-28

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