Modafinil modified release pharmaceutical compositions

• US 20050095294A1
• Filed: 09/17/2004
• Published: 05/05/2005
• Est. Priority Date: 09/18/2003
• Status: Active Grant

• Current Assignee: Cephalon Incorporated (Teva Pharmaceutical Industries Limited)
• Original Assignee: Cephalon Incorporated (Teva Pharmaceutical Industries Limited)
• Inventors: Patel, Piyush, Parikh, Alpa
• Granted Patent: US 8,153,159 B2
• Time in Patent Office: Days
• US Class Current: 424/470
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/2072 characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms A61K9/0004, A61K9/0056, A61K9/0065 take precedence
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/2886 having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer of the type active core-drug layer-inactive layer A61K9/209
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/26 Psychostimulants, e.g. nicotine, cocaine
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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

Pharmaceutical compositions comprising modafinil. The pharmaceutical compositions can have a release profile which is different than that of traditional pharmaceutical compositions of modafinil.

Claims

1. A pharmaceutical composition in unit dose form, wherein upon administration to a patient, the composition releases two or more amounts of a modafinil compound.

2. The pharmaceutical composition of claim 1 wherein, upon administration to a patient, the unit dosage form releases a first effective amount of a modafinil compound, followed by a time interval during which substantially no modafinil compound is released from the dosage form, and after which time interval a second amount of modafinil compound is released from the dosage form.

3. The pharmaceutical composition of claim 1 which comprises:

a) a core particle comprising an effective amount of a modafinil compound;

b) a first membrane comprising an enteric polymer;

c) a second membrane comprising a water-insoluble polymer and an enteric polymer wherein the water-insoluble polymer and the enteric polymer of the second membrane are present in the second membrane at a weight ratio of about 10;

1 to 1;

1;

wherein the core particle is coated with the first and second membranes, in either order, to form an active drug particle, and the total weight of the first and second membranes is about 15 to 80 weight percent of the total weight of the active drug particle.

4. The pharmaceutical composition of claim 3 further comprising an intermediate membrane comprising an organic acid wherein the intermediate membrane coats the core particle and is between the first and second membranes.

5. The pharmaceutical composition of claim 3 wherein the core particle is a non-pareil sugar seed coated with the modafinil compound and a polymeric binder.

6. The pharmaceutical composition of claim 3 wherein the core particle is prepared by precipitation, granulation and milling, or extrusion/spheronization.

7. The pharmaceutical composition of claim 3 wherein the enteric polymers are each independently selected from the group consisting of esters of cellulose, polyvinyl acetate phthalate, pH sensitive methacrylic-methylmethacrylate copolymers and shellac.

8. The pharmaceutical composition of claim 3 wherein the water insoluble polymer is selected from the group consisting of ethylcellulose;

polyvinyl acetate;

neutral copolymers based on ethyl acrylate and methylmethacrylate; and

copolymers of acrylic and methacrylic acid esters having quaternary ammonium groups.

9. The pharmaceutical composition of claim 3 wherein at least one of the membranes further comprises a plasticizer.

10. The pharmaceutical composition of claim 9 wherein the plasticizer is selected from the group consisting of triacetin, tri-butyl citrate, tri-ethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, castor oil, dibutyl sebacate, acetylated monoglycerides and mixtures thereof.

11. The pharmaceutical composition of claim 3 wherein the second membrane has sufficient thickness to prevent substantial release of the modafinil compound for a period of three to six hours after oral administration to a patient.

12. The pharmaceutical composition of claim 4 wherein the organic acid is selected from the group consisting of fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, and maleic acid.

13. The pharmaceutical composition of claim 3 wherein the pharmaceutical composition is a capsule.

14. The pharmaceutical composition of claim 13 wherein the capsule is a hard gelatin capsule.

15. The pharmaceutical composition of claim 13 wherein the capsule comprises a single form of the active drug particle such that the composition provides for a time-controlled pulsatile release of the modafinil compound upon oral administration to a patient.

16. The pharmaceutical composition of claim 15 wherein the modafinil compound is released three to six hours after oral administration to a patient.

17. The pharmaceutical composition of claim 13 wherein the capsule comprises two or more active drug particles with different release times.

18. The pharmaceutical composition of claim 13 wherein the capsule comprises multicoated particles of two or more drugs.

21. The pharmaceutical composition of claim 1 wherein the pharmaceutical composition comprises an immediate release formulation of a modafinil compound and a delayed extended release formulation of a modafinil compound.

22. The pharmaceutical composition of claim 21 wherein the amount of modafinil compound in the immediate release formulation is 60 to 90 percent by weight of the immediate release formulation.

23. The pharmaceutical composition of claim 22 wherein the immediate release formulation comprises about 79.9% racemic modafinil, about 9.9% lactose monohydrate, about 5% polyvinylpyrrolidone 90, about 5% crosslinked carboxymethylcellulose sodium, and about 0.5% magnesium stearate by weight.

24. The pharmaceutical composition of claim 21 wherein the delayed extended release formulation is a polymerically banded and enterically coated dosage form.

25. The pharmaceutical composition of claim 21 wherein the delayed extended release formulation is polymerically banded with at least 2 circumferential bands.

26. The pharmaceutical composition of claim 21 wherein the amount of modafinil compound in the immediate release formulation is 60 to 90% by weight of the immediate release formulation, and the delayed extended release formulation is a polymerically banded and enterically coated dosage form.

27. The pharmaceutical composition of claim 1 wherein the blood profile of a patient to whom the composition was administered corresponds substantially to the profile set forth in FIG. 2.

28. The pharmaceutical composition of claim 1 wherein the pharmaceutical composition comprises a formulation of immediate release modafinil compound and two different delayed sustained release formulations.

45. The pharmaceutical composition of claim 1, further comprising an effective amount of an antidepressant.

48. The pharmaceutical composition of claims 1, 3, 15, 21, 29, 35, 46, or 47 wherein the modafinil compound is racemic modafinil.

49. The pharmaceutical composition of claims 1, 3, 15, 21, 29, 35, 46, or 47 wherein the modafinil compound is the levorotatory form of modafinil.

50. The pharmaceutical composition of claims 1, 3, or 21, wherein the total amount of modafinil compound contained within the dosage form comprises 10 to 800 mg of racemic modafinil.

19. A method of making a drug delivery system which comprises:

a) preparing a core particle comprising a modafinil compound and a polymeric binder;

b) coating the core particle formed in step a) with a plasticized enteric polymer membrane; and

c) coating the plasticized enteric-coated core particle formed in step b) with a membrane comprising a mixture of a water insoluble polymer and an enteric polymer wherein the water insoluble polymer and the enteric polymer are present at a weight ratio of from about 10;

1 to 1;

1;

wherein the total weight of the membranes is 15 to 80 weight percent based on the total weight of the coated particles.

51. The method of claims 19 or 20 wherein the modafinil compound is racemic modafinil.

52. The method of claims 19 or 20 wherein the modafinil compound is the levorotatory form of modafinil.

20. A method of making a drug delivery system which comprises:

a) preparing a core particle comprising a modafinil compound-containing film forming composition;

b) coating the core particle formed in step a) with a plasticized enteric polymer membrane;

c) coating the plasticized enteric-coated core particle formed in step b) with an intermediate membrane containing an organic acid; and

d) coating the organic acid-coated particle formed in step c) with a membrane comprising a mixture of a water insoluble polymer and an enteric polymer wherein the water insoluble polymer and the enteric polymer are present at a weight ratio of from about 10;

1 to 1;

1;

wherein the total weight of the membranes is about 15 to 80 weight percent of the total weight of the coated particles.

29. A pharmaceutical composition in unit dose form, wherein upon administration to a patient, the unit dose form releases two or more effective amounts of a modafinil compound, wherein the first effective amount of the modafinil compound is an immediate release formulation and the second effective amount of the modafinil compound is a sustained release formulation.

30. The pharmaceutical composition of claim 29, wherein the sustained release formulation releases the effective amount of the modafinil compound over a 4 to 12 hour period after administration to the subject.

31. The pharmaceutical composition of claim 29, wherein the sustained release formulation further comprises at least one suitable polymer.

32. The pharmaceutical composition of claim 31, wherein the suitable polymer is hypromellose at 7 to 16.5 weight percent of the total weight of the sustained release formulation.

33. The pharmaceutical composition of claim 29, wherein the immediate release formulation is a granulation or a tablet.

34. The pharmaceutical composition of claim 29, wherein the unit dosage form is a capsule.

35. A pharmaceutical composition in unit dose form comprising a modafinil compound wherein the modafinil compound is released over a period of 3 to 12 hours after administration to a patient.

36. The composition of claim 35, wherein the modafinil compound is released over a period of 4 to 12 hours.

37. The composition of claim 35, wherein the modafinil compound is released over a period of 6 to 12 hours.

38. A method of treating a patient having a condition responsive to modafinil treatment by administering a pulsatile release dosage form of a modafinil compound to the patient.

40. The method of claims 38 or 39, wherein the condition is narcolepsy, sleepiness, excessive sleepiness, excessive daytime sleepiness associated with narcolepsy, Parkinson'"'"'s disease, urinary incontinence, multiple sclerosis fatigue, ADHD, Alzheimer'"'"'s disorder, sleep apnea, obstructive sleep apnea, depression, or ischemia.

41. The method of claims 38 or 39, wherein the condition responsive to modafinil is ADHD.

53. The method of claim 40 wherein the modafinil compound is racemic modafinil.

54. The method of claim 40 wherein the modafinil compound is the levorotatory form of modafinil.

39. A method of treating a patient having a condition responsive to modafinil treatment by administering a delayed extended release dosage form of a modafinil compound to the patient.

42. A method of treating a patient having a condition responsive to modafinil treatment by administering a sustained release dosage form of modafinil to the patient.

43. The method of claim 42, wherein the modafinil compound is released from 3 to 12 hours after administration.

44. The method of claim 42, wherein the condition is narcolepsy, sleepiness, excessive sleepiness, excessive daytime sleepiness associated with narcolepsy, Parkinson'"'"'s disease, urinary incontinence, multiple sclerosis fatigue, ADHD, Alzheimer'"'"'s disorder, sleep apnea, obstructive sleep apnea, depression, or ischemia.

55. The method of claim 44 wherein the modafinil compound is racemic modafinil.

56. The method of claim 44 wherein the modafinil compound is the levorotatory form of modafinil.

46. A pharmaceutical composition in unit dose form comprising an effective amount of a sustained release formulation of a modafinil compound.

47. A pharmaceutical composition in unit dose form comprising an effective amount of a delayed extended release formulation of a modafinil compound.