SUSTAINED RELEASE ORAL DOSAGE FORM FOR NAPROXYN

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 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.

Inventors: HSIAO CHARLES H, HSIAO, CHARLES, H.
Applicants: KEY PHARMA, KEY PHARMACEUTICALS, INC.
Application year: 1984
Main classification: A61K9
IPC codes: A61K9, A61K31