COMPOSITIONS AND METHODS FOR DELIVERY OF POORLY SOLUBLE DRUGS

• US 20090061011A1
• Filed: 09/02/2008
• Published: 03/05/2009
• Est. Priority Date: 09/03/2007
• Status: Active Grant

• Current Assignee: Nanoshift, LLC
• Original Assignee: Nanotherapeutics, Inc. (National Resilience, Inc.)
• Inventors: TALTON, James D.
• Granted Patent: US 8,377,479 B2
• Time in Patent Office: Days
• US Class Current: 424/501
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61K 9/5021 Organic macromolecular compounds
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/36 Opioid-abuse

Abstract

Described herein are compositions comprising particles of poorly soluble drugs encapsulated by stabilizers. Further described are pharmaceutical compositions comprising such encapsulated compositions. Also described are methods of making such encapsulated particle compositions, and methods of making the corresponding pharmaceutical compositions. The encapsulated particle compositions described herein allow poorly soluble drugs to be administered with good bioavailability by routes that are non-invasive to patients, such as by oral administration.

Claims

1. A composition comprising particles of a poorly soluble drug encapsulated by a stabilizer.

2. The composition of claim 1, wherein the particles have an average diameter of less than 2 mm.

3. The composition of claim 2, wherein the particles have an average diameter of less than 500 μ

m.

4. The composition of claim 3, wherein the particles have an average diameter of less than 300 μ

m.

5. The composition of claim 1, wherein the poorly soluble drug is an opioid.

6. The composition of claim 5, wherein the opioid is chosen from buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, morphine, methylnaltrexone, nalbuphine, nalmefene, oxymorphone, oxycodone, pethidine, and tramadol.

7. The composition of claim 6, wherein the opioid is buprenorphine.

8. The composition of claim 7, wherein the buprenorphine is a buprenorphine salt.

9. The composition of claim 8, wherein the buprenorphine salt is buprenorphine.HCl.

10. The composition of claim 1, wherein the stabilizer is a polymer.

11. The composition of claim 10, wherein the stabilizer is a water-soluble polymer.

12. The composition of claim 10, wherein the stabilizer is a polymer of neutral charge.

13. The composition of claim 10, wherein the stabilizer is a water-soluble polymer of neutral charge.

14. The composition of claim 13, wherein the water-soluble polymer of neutral charge is chosen from polyethylene glycol (PEG), polyvinyl alcohol, polyvinylpyrrolidone, block copolymers of ethylene oxide and propylene oxide, and tetrafunctional block copolymers derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine.

15. The composition of claim 14, wherein the polymer is PEG.

16. The composition of claim 15, wherein the PEG has an average molecular weight ranging from about 100 Daltons to about 100,000 Daltons.

17. The composition of claim 16, wherein the PEG is PEG 3350.

18. The composition of claim 1, wherein the poorly soluble drug is present in an amount ranging from about 0.01% to about 90% by mass.

19. The composition of claim 18, wherein the poorly soluble drug is present in an amount ranging from about 0.01% to about 10% by mass.

20. The composition of claim 19, wherein the poorly soluble drug is present in an amount ranging from about 0.2% to about 5% by mass.

21. The composition of claim 20, wherein the poorly soluble drug content is about 0.5% by mass.

22. The composition of claim 1, further comprising at least one excipient.

23. The composition of claim 22, wherein the at least one excipient is a surfactant.

24. The composition of claim 23, wherein the surfactant is a nonionic surfactant.

25. The composition of claim 24, wherein the nonionic surfactant is a polysorbate surfactant.

26. The composition of claim 25, wherein the polysorbate surfactant is Tween 20.

27. A pharmaceutical composition comprising the composition of claim 1.

28. The pharmaceutical composition of claim 27, further comprising a second compound.

29. The pharmaceutical composition of claim 28, wherein the second compound is a second drug.

30. The pharmaceutical composition of claim 29, wherein the second drug is chosen from opioid receptor antagonists, anti-inflammatory drugs, and analgesics.

31. The pharmaceutical composition of claim 30, wherein the second drug is an opioid receptor antagonist.

32. The pharmaceutical composition of claim 31, wherein the second drug is naloxone.

33. The pharmaceutical composition of claim 32, wherein the naloxone is a naloxone salt.

34. The pharmaceutical composition of claim 33, wherein the naloxone salt is naloxone HCl.

35. The pharmaceutical composition of claim 27, wherein the pharmaceutical composition further comprises at least one excipient.

36. The pharmaceutical composition of claim 35, wherein the at least one excipient is chosen from polyethylene glycol (PEG), polyvinyl alcohol, polyvinylpyrrolidone, block copolymers of ethylene oxide and propylene oxide, and tetrafunctional block copolymers derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine.

37. A pharmaceutical composition according to claim 27, wherein the pharmaceutical composition is formulated for oral administration.

38. A method of making the composition of claim 1, the method comprising:

blending an opioid together with a stabilizer to form a mixture;

processing said mixture to form coarse particles having an average diameter ranging from about 0.1 mm to about 5 mm; and

processing said coarse particles to form fine particles having an average diameter ranging from about 0.1 mm to about 3 mm.

39. A method of making the composition of claim 1, the method comprising:

blending an opioid together with a stabilizer to form a mixture;

heating said mixture to a temperature sufficient for extrusion of the mixture;

extruding said mixture to form coarse particles having an average diameter ranging from about 0.1 mm to about 5 mm;

cooling said coarse particles; and

processing said coarse particles to form fine particles having an average diameter ranging from about 0.1 mm to about 3 mm.

40. A method of making a pharmaceutical composition, comprising the method of claim 38, and further comprising:

formulating the fine particles.

41. A method of making a pharmaceutical composition, comprising the method of claim 39, and further comprising:

formulating the fine particles.

42. A method of treating pain, comprising administering the pharmaceutical composition of claim 27 to a patient in need thereof.

43. The method of claim 42, wherein the poorly soluble drug is an opioid.

44. A method of treating opiate addiction, comprising administering the pharmaceutical composition of claim 27 to a patient in need thereof.

45. The method of claim 44, wherein the poorly soluble drug is chosen from methadone, naloxone, and naltrexone.

46. A composition comprising particles of buprenorphine encapsulated by PEG, wherein the buprenorphine content ranges from about 0.2% to about 4%.

47. The composition of claim 46, wherein the particles have an average diameter of less than 2 mm.

48. The composition of claim 47, wherein the buprenorphine is buprenorphine.HCl.

49. The composition of claim 46, wherein the PEG has an average molecular weight ranging from about 500 Daltons to about 10,000 Daltons.

50. The composition of claim 49, wherein the PEG is PEG 3350.

51. The composition of claim 46, further comprising a surfactant.

52. A pharmaceutical composition comprising the composition of claim 46 and naloxone.

53. The pharmaceutical composition of claim 52, wherein the composition is formulated for oral administration.