PHARMACEUTICAL DOSAGE FORMS AND METHODS OF MANUFACTURING SAME

• US 20100166857A1
• Filed: 12/30/2009
• Published: 07/01/2010
• Est. Priority Date: 12/30/2008
• Status: Abandoned Application

• Current Assignee: Impax Laboratories Incorporated (Amneal Pharmaceuticals, LLC)
• Original Assignee: Impax Laboratories Incorporated (Amneal Pharmaceuticals, LLC)
• Inventors: Ting, Richard, Yan, Dong, Siew, Lee Foong, Chen, Tzu-Yuan, Pawar, Mahendra Sudhakar
• Application Number:
  US12/649,943
• Publication Number:
  US 20100166857A1
• Time in Patent Office: Days
• US Class Current: 424/465
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The invention provides solid dispersions of at least one insoluble active pharmaceutical ingredient, pharmaceutical dosage forms comprising the solid dispersions, and methods of manufacturing same. In an embodiment, a solid dispersion of the present invention includes a plurality of coated particles comprising inert particles with a coating, wherein the coating comprises an insoluble active pharmaceutical ingredient dispersed in a hydrophilic polymer, and wherein the inert particles comprise nonpareils; and a plurality of granules comprising an insoluble active pharmaceutical ingredient with at least one pharmaceutically acceptable excipient. In an embodiment, the insoluble active pharmaceutical ingredient in the coating and the insoluble active pharmaceutical ingredient of the granules are the same type. A solid dispersion of the present invention may optionally be encapsulated in capsules or compressed into a tablet. Also disclosed are methods of making solid dispersions and methods of reducing plasma triglyceride and increasing high-density lipoprotein employing the solid dispersion.

Claims

1. A solid dispersion comprising:

a plurality of coated particles comprising inert particles with a coating,

wherein the coating comprises fenofibrate dispersed in a hydrophilic polymer, and

wherein the inert particles comprise nonpareils; and

a plurality of granules comprising micronized fenofibrate with at least one pharmaceutically acceptable excipient.

2. The solid dispersion of claim 1 wherein the hydrophilic polymer of the coating is selected from the group consisting of polyethylene glycol, polyvinylpyrrolidone, polyvinylalcohol, vinylpyrrolidone-vinyl acetate copolymers, hypromellose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylcellulose, Poloxamer, polyacrylate, polymethacrylate, urea and sugar.

3. The solid dispersion of claim 2 wherein the hydrophilic polymer of the coating is hypromellose.

4. The solid dispersion of claim 3 wherein a ratio of the hypromellose to fenofibrate in the coating is from about 10:

1 to about 1;

10.

5. The solid dispersion of claim 1 wherein the granules are present at a percentage ranging from about 0% to about 60%, by weight, based on the weight of the fenofibrate.

6. The solid dispersion of claim 1 wherein the fenofibrate of the coating is further dispersed in a surfactant.

7. The solid dispersion of claim 6 wherein the surfactant is sodium lauryl sulfate.

8. The solid dispersion of claim 1 wherein the coated particles are further coated with a seal coating.

9. The solid dispersion of claim 1 wherein the plurality of granules are present in the solid dispersion at a percentage ranging from about 5% to about 65%.

10. A pharmaceutical dosage form comprising the solid dispersion of claim 1.

11. The pharmaceutical dosage form of claim 10 in a unit dose comprising from about 10 mg to about 200 mg fenofibrate.

12. The pharmaceutical dosage form of claim 10 in a unit dose comprising from about 10 mg to about 200 mg fenofibrate in the form of a single matrix tablet.

13. The pharmaceutical dosage form of claim 10 in a unit dose comprising from about 10 mg to about 200 mg fenofibrate in the form of an immediate release tablet.

14. The pharmaceutical dosage form of claim 13 wherein at least 85% of the total weight of fenofibrate in the solid dispersion is dissolved within 10 minutes when tested with a USP paddle method at 75 rpm, 900 mL of medium with 0.75% of sodium lauryl sulfate in water at about 37°

C.

15. The pharmaceutical dosage form of claim 13 which provides a mean C_max of fenofibric acid of about 4.0 μ

g/mL to about 8.0 μ

g/mL after administration of a single dose to a patient population in the fasted state based on a 120 mg dose of fenofibrate.

16. The pharmaceutical dosage form of claim 13 which provides a mean C_max of fenofibric acid of about 5.0 μ

g/mL to about 9.0 μ

g/mL after administration of a single dose to a patient population in the fed state based on a 120 mg dose of fenofibrate.

17. The pharmaceutical dosage form of claim 10 comprising a sufficient amount of granules in order to decrease relative bioavailability of fenofibrate as compared to a pharmaceutical dosage form that does not include granules.

18. A method of treating hypercholesterolemia in a patient comprising administering the pharmaceutical dosage form of claim 13.

19. A method of treating hypertriglyceridemia in a patient comprising administering the pharmaceutical dosage form of claim 13.

20. A method of preparing a solid dispersion comprising:

dissolving an insoluble active pharmaceutical ingredient and a hydrophilic polymer in a suitable solvent to form a solution;

preparing a plurality of coated particles by spray coating a plurality of inert particles with the solution using a fluid bed coating process;

preparing a plurality of granules by wet granulating a mixture of an insoluble active pharmaceutical ingredient with at least one pharmaceutical acceptable excipient; and

blending the plurality of coated particles and the plurality of granules.

21. The method of claim 20 wherein the insoluble active pharmaceutical ingredient in the solution and the insoluble pharmaceutical ingredient in the mixture are of a same type.

22. The method of claim 20 wherein the insoluble active pharmaceutical ingredient in the solution and the insoluble pharmaceutical ingredient in the mixture are in a micronized form.

23. The method of claim 20 wherein the insoluble active pharmaceutical ingredients are selected from the group consisting of analgesics, anti-inflammatory ingredients, anthelmintics, anti-arrhythmic ingredients, antibiotics, anticoagulants, antihypercholesterolemia ingredients, antidepressants, antidiabetic ingredients, antiepileptics, antihistamines, antihypertensive ingredients, antimuscarinic ingredients, antimycobacterial ingredients, zmtineoplastic ingredients, immunosuppressants, antithyroid ingredients, antiviral ingredients, anxiolytic sedatives, astringents, beta-adrenoceptor blocking ingredients, blood products and substitutes, cardiac inotropic ingredients, contrast media, corticosteroids, cough suppressants, diagnostic ingredients, diagnostic imaging ingredients, diuretics, dopaminergics, haemostatics, itninuriological ingredients, lipid regulating ingredients, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones, anti-allergic ingredients, stimulants and anorctics, sympathotnimetics, thyroid ingredients, vasodilators, and xanthines.

24. The method of claim 23 wherein the insoluble active pharmaceutical ingredients are antihypercholesterolemia ingredients.

25. The method of claim 20 wherein the insoluble active pharmaceutical ingredients are fibrates selected from the group consisting of bezafibrate, ciprofibrate, clofibrate, gemfibmzil, fenofibrate and pharmaceutically acceptable salts thereof.

26. The method of claim 25 wherein the insoluble active pharmaceutical ingredients are fenofibrate.

27. The method of claim 20 wherein the hydrophilic polymer in the solution is selected from the group consisting of polyethylene glycol, polyvinylpyrrolidone, polyvinylalcohol, vinylpyrrolidone-vinyl acetate copolymers, hypromellose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylcellulose, Poloxamer, polyacrylate, polymethacrylate, urea and sugar.

28. The method of claim 20 wherein the solution further includes a surfactant.

29. The method of claim 28 wherein the surfactant is selected from the group consisting of an anionic surfactant, a cationic surfactant, an amphoteric surfactant, a non-ionic surfactant and a mixture thereof.

30. The method of claim 28 wherein the surfactant is sodium lauryl sulfate.

31. The method of claim 20 wherein the coated particles are further coated with a seal coating.

32. The method of claim 20 wherein the plurality of granules are present in the solid dispersion at a percentage ranging from about 35% to about 65%.

33. A solid dispersion comprising:

a plurality of coated particles comprising inert particles with a coating,

wherein the coating comprises at least one insoluble active pharmaceutical ingredient dispersed in a hydrophilic polymer, and

wherein the inert particles comprise nonpareils; and

a plurality of granules comprising at least one insoluble active pharmaceutical ingredient with at least one pharmaceutically acceptable excipient.

34. The solid dispersion of claim 33 wherein the hydrophilic polymer of the coating is selected from the group consisting of polyethylene glycol, polyvinylpyrrolidone, polyvinylalcohol, vinylpyrrolidone-vinyl acetate copolymers, hypromellose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylcellulose, Poloxamer, polyacrylate, polymethacrylate, urea and sugar.

35. The solid dispersion of claim 34 wherein the hydrophilic polymer of the coating is hypromellose.

36. The solid dispersion of claim 35 wherein a ratio of the hypromellose to insoluble active pharmaceutical ingredient in the coating is from about 10:

1 to about 1;

10.

37. The solid dispersion of claim 33 wherein the granules are present at a percentage ranging from about 0% to about 60%, by weight, based on the weight of the active pharmaceutical ingredient.

38. The solid dispersion of claim 33 wherein the insoluble active pharmaceutical ingredient of the coating is further dispersed in a surfactant.

39. The solid dispersion of claim 38 wherein the surfactant is sodium lauryl sulfate.

40. The solid dispersion of claim 33 wherein the coated particles are further coated with a seal coating.

41. The solid dispersion of claim 33 wherein the plurality of granules are present in the solid dispersion at a percentage ranging from about 5% to about 65%.

42. The solid dispersion of claim 33 wherein the insoluble active pharmaceutical ingredient of the coating and the insoluble pharmaceutical ingredient of the granules are of a same type.

43. The solid dispersion of claim 33 wherein the insoluble active pharmaceutical ingredient of the coating and the insoluble pharmaceutical ingredient of the granules are in a micronized form.

44. The solid dispersion of claim 33 wherein the insoluble active pharmaceutical ingredients are selected from the group consisting of analgesics, anti-inflammatory ingredients, anthelmintics, anti-arrhythmic ingredients, antibiotics, anticoagulants, antihypercholesterolemia ingredients, antidepressants, antidiabetic ingredients, antiepileptics, antihistamines, antihypertensive ingredients, antimuscarinic ingredients, antimycobacterial ingredients, zmtineoplastic ingredients, immunosuppressants, antithyroid ingredients, antiviral ingredients, anxiolytic sedatives, astringents, beta-adrenoceptor blocking ingredients, blood products and substitutes, cardiac inotropic ingredients, contrast media, corticosteroids, cough suppressants, diagnostic ingredients, diagnostic imaging ingredients, diuretics, dopaminergics, haemostatics, itninuriological ingredients, lipid regulating ingredients, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones, anti-allergic ingredients, stimulants and anorctics, sympathotnimetics, thyroid ingredients, vasodilators, and xanthines.

45. The solid dispersion of claim 33 wherein the insoluble active pharmaceutical ingredients are antihypercholesterolemia ingredients.

46. The solid dispersion of claim 33 wherein the insoluble active pharmaceutical ingredients are fibrates selected from the group consisting of bezafibrate, ciprofibrate, clofibrate, gemfibmzil, fenofibrate and pharmaceutically acceptable salts thereof.

47. A pharmaceutical dosage form comprising the solid dispersion of claim 33.

48. The pharmaceutical dosage form of claim 47 in a unit dose comprising from about 10 mg to about 200 mg insoluble active pharmaceutical ingredient.

49. The pharmaceutical dosage form of claim 47 in a unit dose comprising from about 10 mg to about 200 mg insoluble active pharmaceutical ingredient in the form of a single matrix tablet.

50. The pharmaceutical dosage form of claim 47 in a unit dose comprising from about 10 mg to about 200 mg insoluble active pharmaceutical ingredient in the form of an immediate release tablet.

51. The pharmaceutical dosage form of claim 50 wherein at least 85% of the total weight of insoluble active pharmaceutical ingredient in the solid dispersion is dissolved within 10 minutes when tested with a USP paddle method at 75 rpm, 900 mL of medium with 0.75% of sodium lauryl sulfate in water at about 37°

C.

52. The pharmaceutical dosage form of claim 47 comprising a sufficient amount of granules in order to decrease relative bioavailability of the insoluble active pharmaceutical ingredient as compared to a pharmaceutical dosage form that does not include granules.