NANOPARTICULATE FORMULATIONS OF MODAFINIL

• US 20080317843A1
• Filed: 07/12/2007
• Published: 12/25/2008
• Est. Priority Date: 07/12/2006
• Status: Abandoned Application

• Current Assignee: Elan Pharma International Limited (Perrigo Company PLC)
• Original Assignee: Elan Corporation PLC (Perrigo Company PLC)
• Inventors: Liversidge, Gary, Jenkins, Scott A., Manser, David
• Application Number:
  US11/776,770
• Publication Number:
  US 20080317843A1
• Time in Patent Office: Days
• US Class Current: 424/456
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• 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 25/36 Opioid-abuse
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 present invention is directed to compositions comprising a nanoparticulate modafinil compositions, or a salt(s), or an enantiomer(s), or a prodrug(s), or a polymorph(s) or derivative thereof, having improved bioavailability. The nanoparticulate modafinil composition formulation particles of the composition have an effective average particle size of less than about 2000 nm and are useful in the treatment of dyssomnias, including but not limited to, narcolepsy, chronic fatigue, eating disorders, compulsive behaviors, ADHD, addictions, substance abuse, sleepiness, nervous system diseases, conditions, syndromes, and symptoms and related diseases, conditions, and symptoms.

Claims

1. A stable nanoparticulate composition comprising:

(A) particles comprising modfinil, or a salt, derivative, prodrug, or polymorph thereof, said particles having an effective average particle size of less than about 2000 nm in diameter; and

(B) at least one surface stabilizer.

2. The composition of claim 1, wherein said particles are in a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi amorphous phase, or a mixture thereof.

3. The composition of claim 1 further comprising one or more pharmaceutically acceptable excipients, carriers, or a combination thereof.

4. The composition of claim 1, wherein the surface stabilizer is selected from the group consisting of a non-ionic surface stabilizer, an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and an ionic surface stabilizer.

5. The composition of claim 1, wherein the composition comprises:

(a) about 40 to about 500 g/kg modfinil;

(b) about 10 to about 70 g/kg hypromellose;

(c) about 1 to about 10 g/kg docusate sodium;

(d) about 100 to about 500 g/kg sucrose;

(e) about 1 to about 40 g/kg sodium lauryl sulfate;

(f) about 50 to about 400 g/kg lactose monohydrate;

(g) about 50 to about 300 g/kg silicified microcrystalline cellulose;

(h) about 20 to about 300 g/kg crospovidone; and

(i) about 0.5 to about 5 g/kg magnesium stearate.

6. The composition of claim 5, further comprising a coating agent.

7. The composition of claim 1, wherein the composition comprises:

(a) about 100 to about 300 g/kg modfinil;

(b) about 30 to about 50 g/kg hypromellose;

(c) about 0.5 to about 10 g/kg docusate sodium;

(d) about 100 to about 300 g/kg sucrose;

(e) about 1 to about 30 g/kg sodium lauryl sulfate;

(f) about 100 to about 300 g/kg lactose monohydrate;

(g) about 50 to about 200 g/kg silicified microcrystalline cellulose;

(h) about 50 to about 200 g/kg crospovidone; and

(i) about 0.5 to about 5 g/kg magnesium stearate.

8. The composition of claim 7, further comprising a coating agent.

9. The composition of claim 1, wherein the composition comprises:

(a) about 200 to about 225 g/kg modfinil;

(b) about 42 to about 46 g/kg hypromellose;

(c) about 2 to about 6 g/kg docusate sodium;

(d) about 200 to about 225 g/kg sucrose;

(e) about 12 to about 18 g/kg sodium lauryl sulfate;

(f) about 200 to about 205 g/kg lactose monohydrate;

(g) about 130 to about 135 g/kg silicified microcrystalline cellulose;

(h) about 112 to about 118 g/kg crospovidone; and

(i) about 0.5 to about 3 g/kg magnesium stearate.

10. The composition of claim 9, further comprising a coating agent.

11. The composition of claim 1, wherein the composition comprises:

(a) about 119 to about 224 g/kg modfinil;

(b) about 42 to about 46 g/kg hypromellose;

(c) about 2 to about 6 g/kg docusate sodium;

(d) about 119 to about 224 g/kg sucrose;

(e) about 12 to about 18 g/kg sodium lauryl sulfate;

(f) about 119 to about 224 g/kg lactose monohydrate;

(g) about 129 to about 134 g/kg silicified microcrystalline cellulose;

(h) about 112 to about 118 g/kg crospovidone; and

(i) about 0.5 to about 3 g/kg magnesium stearate.

12. The composition of claim 11, further comprising a coating agent.

13. The composition of claim 1, additionally comprising one or more active compounds useful for the prevention and treatment of disease states, symptoms, syndromes, and conditions of the central nervous system (CNS).

14. The composition of claim 1 wherein said particles contain a reservoir which contains modfinil, or a salt, derivative, prodrug, or polymorph thereof, said reservoir being enclosed by a semi-permeable membrane which allows for water to be imbibed into said particles, thus generating pressure which forces said modfinil, or a salt, derivative, prodrug, or polymorph thereof, out of said particles.

15. The composition of claim 14 wherein said reservoir further comprises an osmotic agent.

16. A method of preparing the composition of claim 1 comprising contacting particles comprising said modfinil, or a salt, derivative, prodrug, or polymorph thereof, with at least one surface stabilizer for a period of time and under conditions sufficient to provide a nanoparticulate composition comprising modfinil, or a salt, derivative, prodrug, or polymorph thereof, having an effective average particle size of less than about 2000 nm in diameter.

17. A method of preventing and/or treating disease states, symptoms, syndromes, and conditions of the central nervous system (CNS) comprising administering a composition according to claim 1.

25. A dosage form comprising the composition of claim 14.

26. The dosage form of claim 25 comprising a blend of active ingredient-containing particles contained within a hard gelatin or soft gelatin capsule.

27. The dosage form of claim 25, wherein the active ingredient-containing particles are in the form of mini-tablets and the capsule contains a mixture of said mini-tablets.

28. The dosage form of claim 25 in the form of tablet.

29. The dosage form of claim 25 wherein the particles containing modafinil, or a salt, derivative, prodrug, or polymorph thereof, are provided in a rapidly dissolving dosage form.

30. The dosage form of claim 28 wherein the tablet is a fast-melt tablet.

33. The composition according to claim 1 wherein said modafinil is the r-isomer of modafinil.

34. The method according to claim 16 wherein said modafinil is the r-isomer of modafinil.

35. The dosage form according to claim 25 wherein said modafinil is the r-isomer of modafinil.

18. A pharmaceutical composition comprising a first component of active ingredient-containing particles and at least one subsequent component of active ingredient-containing particles, wherein at least one of said components comprises particles wherein modfinil, or a salt, derivative, prodrug, or polymorph thereof, is the active ingredient and at least one of said components further comprises a modified release coating, a modified release matrix material, or both, such that the composition, following oral delivery to a subject, delivers the active ingredient in a continuous, bimodal or multimodal manner.

19. The composition of claim 18 wherein said particles comprising modfinil, or a salt, derivative, prodrug, or polymorph thereof, comprise nanoparticles which comprise modfinil, or a salt, derivative, prodrug, or polymorph thereof.

20. The composition of claim 18 wherein said particles comprising modafinil, or a salt, derivative, prodrug, or polymorph thereof, are nanoparticles which comprise modafinil, or a salt, derivative, prodrug, or polymorph thereof.

21. The composition of claim 18 wherein each component comprises particles in which modafinil, or a salt, derivative, prodrug, or polymorph thereof, is the active ingredient.

22. The composition of claim 18, wherein the first component comprises an immediate release component and at least one subsequent component comprises a modified release component.

23. The composition of claim 18, wherein the active ingredient-containing particles are erodable.

24. The composition of claim 18 wherein said composition further comprises an enhancer.

31. A method for preventing and/or treating disease states, symptoms, syndromes, and conditions of the central nervous system (CNS) comprising the step of administering a therapeutically effective amount of the composition of claim 18.

32. The composition of claim 18 wherein the modified-release coating comprises a pH-dependent polymer coating for releasing a pulse of the active ingredient in said patient following a time delay of about 6 to about 12 hours after administration of said composition to said patient.

36. A pharmaceutical composition comprising particles of modafinil, enantiomers, polymorphs, hydrates, solvates, amorphous forms or mixtures thereof, wherein said particles consist of a first population of particles and a second population of particles, wherein the ratio of said first population of particles to said second population of particles is about 3:

7 by weight, wherein;

(a) said first population of particles comprises coarse particles having a diameter greater than about 240 microns; and

(b) said second population of particles comprises coarse particles having a diameter less than about 240 microns, wherein said second population of particles comprises nanoparticles having a diameter less than about 2000 nm.

37. The composition according to claim 36 wherein said particles of modafinil, enantiomers, polymorphs, hydrates, solvates, amorphous forms or mixtures thereof comprises about 10% nanoparticles by weight.

38. The composition according to claim 37 wherein said particles of modafinil, enantiomers, polymorphs, hydrates, solvates, amorphous forms or mixtures thereof comprises about 40%, 50%, 60%, 70%, or 80% nanoparticles by weight.

39. The composition according to claim 36 wherein the composition is in the form of a tablet or capsule.

40. The composition according to claim 36 further comprising one or more pharmaceutical acceptable excipients.

41. The composition according to claim 40 where in the one or more pharmaceutical acceptable excipients comprises one or more binders, diluents, disintegrants, surfactants, lubricants, glidants, and coloring agents.

42. An oral controlled release dosage form comprising the composition according to claim 36.

43. The composition according to claim 36 further comprising cyclodextrin provided that said cyclodextrin is not selected from the group consisting of hydroxylpropylbetacyclodextrin, betacyclodextrinsulfobutylether, and mixtures thereof.

44. A method of improving or maintaining bioavailability of modafinil comprising administering to a patient in need thereof the composition of claim 43.

45. A method of treating neurological based disorder selected from the group consisting of narcolepsy, obstructive sleep apnea/hypopnea syndrome, shift worker sleep disorder, improvement of wakefulness in patients with excessive daytime sleepiness associated with narcolepsy, and idiopathic hypersomnia comprising administering to a patient suffering from said disorder the composition of claim 43.

55. A method of treating neurological based disorder selected from the group consisting of narcolepsy, obstructive sleep apnea/hypopnea syndrome, shift worker sleep disorder, improvement of wakefulness in patients with excessive daytime sleepiness associated with narcolepsy, and idiopathic hypersomnia comprising administering to a patient suffering from said disorder the composition of claim 43.

46. A pharmaceutical composition comprising particles of modafinil, enantiomers, polymorphs, hydrates, solvates, amorphous forms or mixtures thereof, wherein said particles consist of a first population of particles and a second population of particles, wherein the ratio of said first population of particles to said second population of particles is about 3:

7 by weight, wherein;

(a) said first population of particles comprises coarse particles having a diameter greater than about 220 microns; and

(b) said second population of particles comprises coarse particles having a diameter less than about 220 microns, wherein said second population of particles comprises nanoparticles having a diameter less than about 2000 nm.

47. The composition according to claim 46 wherein said particles of modafinil, enantiomers, polymorphs, hydrates, solvates, amorphous forms or mixtures thereof comprises about 10% nanoparticles by weight.

48. The composition according to claim 47 wherein said particles of modafinil, enantiomers, polymorphs, hydrates, solvates, amorphous forms or mixtures thereof comprises about 40%, 50%, 60%, 70%, or 80% nanoparticles by weight.

49. The composition according to claim 46 wherein the composition is in the form of a tablet or capsule.

50. The composition according to claim 46 further comprising one or more pharmaceutical acceptable excipients.

51. The composition according to claim 50 where in the one or more pharmaceutical acceptable excipients comprises one or more binders, diluents, disintegrants, surfactants, lubricants, glidants, and coloring agents.

52. An oral controlled release dosage form comprising the composition according to claim 46.

53. The composition according to claim 46 further comprising cyclodextrin provided that said cyclodextrin is not selected from the group consisting of hydroxylpropylbetacyclodextrin, betacyclodextrinsulfobutylether, and mixtures thereof.

54. A method of improving or maintaining bioavailability of modafinil comprising administering to a patient in need thereof the composition of claim 53.