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Details for Patent: 6,709,677

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Details for Patent: 6,709,677

Title: Sustained release heterodisperse hydrogel systems-amorphous drugs
Abstract:Sustained release oral solid dosage forms comprising agglomerated particles of a therapeutically active medicament in amorphous form, a gelling agent, an ionizable gel strength enhancing agent and an inert diluent, as well as processes for preparing and using the same are disclosed. The sustained release oral solid dosage forms are useful in the treatment of hypertension in human patients.
Inventor(s): Baichwal; Anand (Wappingers Falls, NY)
Assignee: Penwest Pharmaceuticals Co. (Patterson, NY)
Filing Date:Jun 12, 2001
Application Number:09/879,296
Claims:1. A method of preparing a bioavailable sustained release oral dosage form comprising combining (i) a medicament in amorphous form, (ii) a wetting agent and (iii) a sustained release excipient to obtain a mixture; said sustained release excipient comprising a gelling agent, an ionizable gel strength enhancing agent, ethylcellulose, and an inert diluent, the ratio of inert diluent to gelling agent being from about 1:8 to about 8:1, said ionizable gel strength enhancing agent increasing the gel strength of a gel formed when said solid dosage form is exposed to an aqueous solution, said gelling agent comprising xanthan gum and locust bean gum in a ratio of said xanthan gum to said locust bean gum of from about 1:3 to about 3:1; therafter drying and milling said mixture to obtain a sustained release product; and then forming said sustained release product into an oral dosage form.

2. The method of claim 1, wherein the medicament has an aqueous solubility of less than 10 g/liter.

3. The method of claim 1, wherein the wetting agent is polyethylene glycol.

4. The method of claim 1, wherein said medicament is selected from the group consisting of nifedipine, nimodipine, nivadipine, nitrendipine, nisolidipine, niludipine, nicardipine and felodipine.

5. The method of claim 4 wherein said medicament is nifedipine.

6. The method of claim 3, wherein the polyethylene glycol is mixed with water to form a polyethylene glycol-water slurry prior to its being combined with the medicament and the sustained release excipient.

7. The method of claim 1, wherein said gelling agent, ionizable gel strength enhancing agent, ethylcellulose and inert diluent are premanufactured as a sustained release excipient.

8. The method of claim 1, further comprising dissolving the medicament in the wetting agent and then adding the sustained release excipient to the medicament and wetting agent.

9. The method of claim 1, wherein said gelling agent further comprises an agent selected from the group consisting of alginates, carrageenan, pectin, guar gum, xanthan gum, locust bean gum, modified starch, a cellulosic material, and mixtures of any of the foregoing.

10. The method of claim 9, wherein said cellulosic material is selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose and hydroxypropyl cellulose and mixtures of any of the foregoing.

11. The method of claim 1 wherein said ionizable gel strength enhancing agent is selected from the group consisting of monovalent, divalent and multivalent organic or inorganic salts and mixture thereof.

12. The method of claim 1, wherein said ionizable gel strength enhancing agent is selected from the group consisting of an alkali metal sulfate, alkali metal chloride, alkali metal borate, alkali metal bromide, alkali metal citrate, alkali metal acetate, alkali metal lactate, alkaline earth metal sulfate, alkaline earth metal chloride, alkaline earth metal borate, alkaline earth metal bromide, alkaline earth metal citrate, alkaline earth metal acetate, alkaline earth metal lactate and mixtures thereof.

13. The method of claim 1, wherein said composition further comprises an amount of a pharmaceutically acceptable hydrophobic material effective to slow the hydration of the gelling agent when said solid dosage form is exposed to gastrointestinal fluid.

14. A method of treating a patient comprising administering a dosage form prepared according to claim 1 to a patient in need of antihypertensive treatment.

15. The method of claim 1, wherein the wetting agent comprises a pharmaceutically acceptable solid wetting agent.

16. The method of claim 15, wherein the wetting agent is a mixed surfactant/wetting agent system.

17. The method of claim 16, wherein the mixed surfactant/wetting agent system is selected from the group consisting of sodium lauryl sulfate/solid polyethylene glycol (PEG) 6000 and sodium lauryl sulfate/solid PEG 6000/stearic acid.

18. The method of claim 1, wherein the oral dosage form is coated with a hydrophobic polymer to a weight gain from about 1% to about 20%, by weight.

19. The method of claim 18, wherein the oral dosage form is coated with an enteric coating material in addition to the hydrophobic coating.

20. The method of claim 1, wherein the oral dosage form is coated with an enteric coating material.

21. The method of claim 20, wherein the enteric coating material is selected from the group consisting of cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate, methacrylic acid copolymer, shellac, hydroxypropylmethylcellulose succinate, cellulose acetate trimellitate, and mixtures of any of the foregoing.

22. The method of claim 1, wherein the oral dosage form is coated with a hydrophilic coating.

23. The method of claim 18, wherein the oral dosage form is coated with a hydrophilic coating in addition to the hydrophobic coating.

24. The method of claim 20, wherein the oral dosage form is coated with a hydrophillic coating in addition to the enteric coating.

25. The method of claim 19, wherein the oral dosage form is coated with a hydrophilic coating in addition to the hydrophobic coating and enteric coating.

26. A bioavailable sustained release oral solid dosage form comprising compressed agglomerated particles comprising a medicament in amorphous form having an aqueous solubility of less than about 10 g/l, a gelling agent comprising xanthan gum and locust bean gum in a ratio from about 1:3 to about 3:1, an ionizable gel strength enhancing agent, a hydrophobic material in an effective amount to slow the hydration of the gelling agent when said dosage form is exposed to gastrointestinal fluid, and an inert diluent, the ratio of inert diluent to gelling agent being from about 1:8 to about 8:1, wherein said medicament is suspended or dissolved in a pharmaceutically acceptable wetting agent prior to incorporation with the remaining ingredients of said dosage form, and wherein the amorphous form of said medicament affects the bioavailability of said oral dosage form.

27. The bioavailable sustained release oral solid dosage form of claim 26, wherein said hydrophobic material is ethylcellulose.

28. A method of treating a patient comprising administering a dosage form of claim 26 to said patient to achieve a therapeutic effective blood level of said medicament for about 12 to about 24 hours after administration.

29. The bioavailable sustained release oral dosage form of claim 26, wherein said medicament is selected from the group consisting of nifedipine, nimodipine, nivadipine, nitrendipine, nisolidipine, niludipine, nicardipine and felodipine.

30. The method of claim 26, wherein said medicament is nifedipine.

31. A method of preparing a bioavailable sustained release oral dosage form comprising: dry blending a medicament in amorphous form and a sustained release excipient to obtain a sustained release product; said sustained release excipient comprising a gelling agent comprising xanthan gum and locust bean gum in a ratio of said xanthan gum to said locust bean gum of from about 1:3 to about 3:1, an ionizable gel strength enhancing agent which increases the gel strength of a gel formed when said solid dosage form is exposed to an aqueous solution, ethylcellulose; and an inert diluent, the ratio of inert diluent to gelling agent being from about 1:8 to about 8:1; and forming said sustained release product into an oral dosage form.

32. The method of claim 31, further comprising admixing a wetting agent with the dry blended mixture of medicament, gelling agent, ionizable gel strength enhancing agent, ethylcellulose and inert diluent to form a wetting agent-based slurry, and then drying and milling the wetting agent-based slurry.

33. The method of claim 32, wherein said gelling agent, ionizable gel strength enhancing agent, ethylcellulose and inert diluent are recombined as a sustained release excipient.

34. The sustained release dosage form of claim 26, wherein said dosage form is coated with an enteric or hydrophobic polymer.

35. The sustained release dosage form of claim 26, wherein said dosage form is coated with a hydrophilic coating.

36. The sustained release dosage form of claim wherein said agglomerated particles is coated with a hydrophobic polymer to a weight gain from about 1 to about 20 percent, by weight.

37. The method of claim 31, wherein the sustained release oral solid dosage form is coated with a hydrophobic polymer to a weight gain from about 1% to about 20%, by weight.

38. The method of claim 31, wherein the oral dosage form is coated with a hydrophobic polymer to a weight gain from about 1% to about 20%, by weight.

39. The method of claim 38, wherein the oral dosage form is coated with an enteric coating material in addition to the hydrophobic coating.

40. The method of claim 31, wherein the oral dosage form is coated with an enteric coating material.

41. The method of claim 40, wherein the enteric coating material is selected from the group consisting of cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate, methacrylic acid copolymer, shellac, hydroxypropylmethylcellulose succinate, cellulose acetate trimellitate, and mixtures of any of the foregoing.

42. The method of claim 41, wherein the oral dosage form is coated with a hydrophilic coating.

43. The method of claim 38, wherein the oral dosage form is coated with a hydrophilic coating in addition to the hydrophobic coating.

44. The method of claim 40, wherein the oral dosage form is coated with a hydrophillic coating in addition to the enteric coating.

45. The method of claim 39, wherein the oral dosage form is coated with a hydrophilic coating in addition to the hydrophobic coating and enteric coating.
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