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Details for Patent: 5,286,493

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Details for Patent: 5,286,493

Title: Stabilized controlled release formulations having acrylic polymer coating
Abstract:A stabilized solid controlled release dosage form having a coating derived from an aqueous dispersion of an acrylic polymer is obtained by overcoating a substrate including a therapeutically active with an aqueous dispersion of the plasticized acrylic polymer and then curing the coated substrate at a temperature above the glass transition temperature of the plasticized acrylic polymer, until the coated dosage form attains a stabilized dissolution profile substantially unaffected by exposure to storage conditions of elevated temperature and/or elevated relative humidity.
Inventor(s): Oshlack; Benjamin (New York, NY), Chasin; Mark (Manalapan, NJ), Pedi, Jr.; Frank (Yorktown Heights, NY)
Assignee: Euroceltique, S.A. (LU)
Filing Date:Jan 27, 1992
Application Number:07/826,084
Claims:1. A method for obtaining a stabilized controlled release formulation comprising a substrate coated with an aqueous dispersion of a plasticized acrylic polymer for release of a dose of therapeutically active agent in the gastrointestinal tract, comprising

preparing a solid substrate comprising a therapeutically active agent,

overcoating said substrate with a sufficient amount of a plasticized aqueous dispersion consisting essentially of ammonio methacrylate copolymers which are copolymerizates of acrylic and methacrylic esters having a low content of quaternary ammonium groups acrylic and methacrylic acid esters having a permeability which is unaffected by the pH conditions prevailing in the gastrointestinal tract, in an amount sufficient to obtain a predetermined controlled release of said dose of said therapeutically active agent in the gastrointestinal tract, and

curing said coated substrate by subjecting said coated substrate to a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized acrylic polymer for at least about 24 hours and continuing the curing until an endpoint is reached at which said substrate provides a stable dissolution profile, said endpoint being determined by comparing the dissolution profile of the formulation immediately after curing to the dissolution profile of the formulation after exposure to accelerated conditions of one month at a temperature of 37.degree. C. and at a relative humidity of 80%.

2. The method of claim 1, further comprising determining the endpoint for the formulation by exposing the formulation which is uncured or substantially uncured to stressed storage conditions and obtaining dissolution profiles for the formulation until the dissolution profiles of the formulation are substantially stabilized.

3. The method of claim 2, further comprising modifying the formulation to obtain a desired dissolution profile of said therapeutically active agent based on said end point.

4. The method of claim 1, further comprising preparing said substrate for oral administration by coating said therapeutically active agent onto the surface of pharmaceutically acceptable beads, and preparing an oral dosage form by placing a sufficient quantity of cured coated beads into a capsule.

5. The method of claim 1, further comprising preparing said substrate for oral administration by incorporating said therapeutically active agent into a tablet.

6. The method of claim 1, wherein said acrylic polymer is prepared by mixing a first copolymer of acrylic and methacrylic and esters having a molar ratio of ammonium groups to (meth)acrylic esters of about 1:20 with a second copolymer of acrylic and methacrylic esters having a molar ratio of ammonium groups to (meth)acrylic esters of about 1:40, with a suitable plasticizing agent.

7. The method of claim 1, wherein said coated substrate is cured for a time period from about 24 to about 48 hours.

8. The method of claim 1 wherein said coated substrate is cured for about 48 hours.

9. The method of claim 1, wherein said therapeutically active agent is selected from the group consisting of antihistamines, analgesics, non-steroidal anti-inflammatory agents, gastro-intestinals, anti-emetics, anti-epileptics, vasodilators, anti-tussive agents, expectorants, anti-asthmatics, hormones, diuretics, anti-hypotensives, bronchodilators, antibiotics, antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, and stimulants.

10. The method of claim 1, wherein said therapeutically active agent is selected from the group consisting of hydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, salts of any of the foregoing, and mixtures of any of the foregoing.

11. The method of claim 1, wherein said therapeutically active agent is theophylline.

12. The stabilized product prepared according to the method of claim 1.

13. The stabilized product prepared according to the method of claim 4.

14. The stabilized product prepared according to the method of claim 5.

15. A stabilized controlled release solid dosage form for release of a dose of a therapeutically active agent comprising a substrate comprising a therapeutically active agent, said substrate overcoated with an aqueous dispersion consisting essentially of a plasticized copolymer of acrylic and methacrylic acid esters having a permeability which is unaffected by the pH conditions prevailing in the digestive tract, in an amount sufficient to provide a controlled release of said dose of therapeutically active agent in the gastrointestinal tract, said coated substrate being cured at a temperature greater than the glass transition temperature of the aqueous dispersion of the plasticized acrylic polymer for at least about 24 hours, until an endpoint is reached at which the coated substrate provides a stable dissolution profile, said endpoint being determined by comparing the dissolution profile of the formulation immediately after curing to the dissolution profile of the formulation after exposure to accelerated conditions of one month at a temperature of 37.degree. C. and at a relative humidity of 80%.

16. The stabilized controlled release solid dosage form of claim 15, wherein said therapeutically active agent is overcoated with said aqueous dispersion of plasticized ammonio acrylic polymer to a weight gain level from about 5 to about 15 percent.

17. The stabilized controlled release solid dosage form of claim 15, wherein said acrylic polymer coating is derived from a mixture of a first copolymer of acrylic and methacrylic acid esters having a molar ratio of ammonium groups to (meth)acrylic esters of about 1:20 and a second copolymer of acrylic and methacrylic esters having a molar ratio of ammonium groups to (meth)acrylic esters of about 1:40, the ratio of said first copolymer to said second copolymer being from about 10:90 to about 90:10.

18. The stabilized controlled release solid dosage form of claim 15, wherein said substrate comprises an inert pharmaceutically acceptable bead onto which said therapeutically active agent is coated.

19. The stabilized controlled release solid dosage form of claim 18, wherein a plurality of said coated, cured beads are placed in a capsule in an amount sufficient to provide an effective controlled release dose when contacted by an gastric and intestinal fluid.

20. The stabilized controlled release solid dosage form of claim 15 which has been cured for a time period from about 24 to about 48 hours.

21. The stabilized controlled release solid dosage form of claim 15 which has been cured for about 48 hours.

22. The stabilized controlled release solid dosage form of claim 15, wherein said substrate is compressed with or without additional inert ingredients into a tablet.

23. The stabilized controlled release solid dosage form of claim 15, wherein said therapeutically active agent is selected from the group consisting of antihistamines, analgesics, non-steroidal anti-inflammatory agents, gastro-intestinals, anti-emetics, anti-epileptics, vasodilators, anti-tussive agents, expectorants, anti-asthmatics, hormones, diuretics, anti-hypotensives, bronchodilators, antibiotics, antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, and stimulants.

24. The stabilized controlled release solid dosage form of claim 15, wherein said therapeutically active agent is selected from the group consisting of hydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, salts of any of the foregoing, and mixtures of any of the foregoing.

25. The stabilized controlled release solid dosage form of claim 15, wherein said therapeutically active agent is theophylline.

26. A stabilized controlled release solid dosage form comprising

a substrate comprising inert pharmaceutically acceptable beads onto which a therapeutically active agent is coated,

said substrate overcoated with an aqueous dispersion consisting essentially of a plasticized ammonio methacrylate copolymer derived from a mixture of a first copolymer of acrylic and methacrylic esters having a molar ratio of ammonium groups to (meth)acrylic esters of about 1:20 and a second copolymer of acrylic and methacrylic esters having a molar ratio of ammonium groups to (meth)acrylic esters of about 1:40, said first and second copolymers having a permeability which is unaffected by the pH conditions prevailing in the gastrointestinal tract, the ratio of said first copolymer to said second copolymer being from about 10:90 to about 90:10, said substrate being coated to a weight gain level from about 5 to about 15 percent and the amount of said ammonio methacrylate copolymer being sufficient to provide a predetermined controlled release of said therapeutically active agent in the gastrointestinal tract, the coated substrate cured at a temperature greater than the glass transition temperature of the aqueous dispersion of the plasticized acrylic polymer for at least about 24 hours, until an endpoint is reached at which said coated substrate provides a stable in-vitro release of said therapeutically active agent when exposed to accelerated storage conditions of one month at 37.degree. C. and 80% relative humidity.

27. The stabilized controlled release solid dosage form of claim 26 which has been cured for a time period from about 24 to about 48 hours.

28. The stabilized controlled release solid dosage form of claim 26 which has been cured for about 48 hours.

29. The stabilized controlled release solid dosage form of claim 26, wherein said substrate is compressed with or without additional inert ingredients into a tablet.

30. The stabilized controlled release solid dosage form of claim 26, wherein said therapeutically active agent is selected from the group consisting of hydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, and salts of any of the foregoing.

31. The stabilized controlled release solid dosage form of claim 26, wherein a plurality of said coated, cured beads are placed in a capsule in an amount sufficient to provide an effective controlled release dose when contacted by an aqueous solution.

32. The stabilized controlled release solid dosage form of claim 26, wherein said therapeutically active agent is selected from the group consisting of antihistamines, analgesics, gastro-intestinals, anti-emetics, anti-epileptics, vasodilators, anti-tussive agents, expectorants, anti-asthmatics, hormones, diuretics, anti-hypotensives, bronchodilators, antibiotics, antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, and stimulants.

33. The stabilized controlled release solid dosage form of claim 26, wherein said therapeutically active agent is theophylline.

34. A stabilized solid controlled release dosage form comprising a substrate comprising a therapeutically active agent, said substrate overcoated with a controlled release coating derived from an aqueous dispersion consisting essentially of a plasticized ammonio methacrylate copolymer, said ammonio methacrylate copolymer which is a copolymerizate of acrylic and methacrylic esters having a low content of quaternary ammonium groups being included in said coating in an amount sufficient to provide a controlled release of said therapeutically active agent in the gastrointestinal tract, said ammonio methacrylate copolymer having a permeability which is unaffected by the pH conditions prevailing in the gastrointestinal tract, said coated substrate being cured at a temperature above the glass transition temperature of the plasticized ammonio methacrylate copolymer for at least about 24 hours for a time period necessary to obtain a final product which provides a stable in-vitro release of said therapeutically active agent when exposed to accelerated storage conditions of one month at 37.degree. C. and 80% relative humidity.

35. A stabilized controlled release solid dosage form for release of a dose of a therapeutically active agent, comprising a substrate comprising a therapeutically active agent, said substrate overcoated with a controlled release coating of an aqueous dispersion of a plasticized ammonio methacrylate copolymers which are copolymerizates of acrylic and methacrylic esters having a low content of quaternary ammonium groups in an amount sufficient to provide release of said dose of therapeutically active agent in the gastrointestinal tract, said ammonio methacrylate copolymer having a permeability which is unaffected by the pH conditions prevailing in the gastrointestinal tract, said acrylic polymer being cured at a temperature greater than the glass transition temperature of the aqueous dispersion of the plasticized acrylic polymer for at least about 24 hours until an endpoint is reached such that a final product is obtained which provides a reproducible, stabilized dissolution profile, said endpoint being determined by comparing the dissolution profile of the formulation immediately after curing to the dissolution profile of the formulation after exposure to accelerated conditions of one month at a temperature of 37.degree. C. and at a relative humidity of 80%.
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