SUSTAINED DRUG RELEASE AND IMPROVED PRODUCT STABILITY USING NON-COVALENT PARTICLE COATING METHODS

• US 20130157992A1
• Filed: 12/20/2012
• Published: 06/20/2013
• Est. Priority Date: 12/20/2011
• Status: Active Grant

• Current Assignee: Keith Latham
• Original Assignee: IPE, Inc.
• Inventors: Latham, Keith R.
• Granted Patent: US 9,526,701 B2
• Time in Patent Office: Days
• US Class Current: 514/179
• 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 9/146 with organic macromolecular compounds
• 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 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2063 Proteins, e.g. gelatin

Abstract

The present invention relates to improved methods of making compositions and compositions made by these methods having improved stability and/or extended release of an active agent or drug upon administration. These compositions may generally comprise an active agent or drug non-covalently immobilized or bound to an excipient substrate. The active agent or drug may include a wide variety of drugs. Binding of the active agent or drug to the substrate may be achieved by evaporating a solvent containing the active agent dissolved therein or by triggering co-precipitation by addition of a precipitating solvent. Additional steps of vacuum removal of surrounding atmosphere and replacement with inert gas may provide additional stability. Present methods and compositions also facilitate manufacturing of drug products and may make these processes safer in some cases. The present invention further provides improved methods of treatment or administration, which may take advantage of improvements with present compositions.

Claims

1. A method comprising the following steps:

(a) dissolving an active agent or drug in a solvent to form a solution containing the active agent or drug; and

(b) evaporating the solvent from the solution until a substrate powder is formed, the substrate powder comprising the active agent or drug non-covalently bound to a substrate, wherein the substrate is a polymer or crystalline excipient.

2. The method of claim 1, wherein the active agent or drug is homogeneously distributed throughout the substrate powder formed in step (b).

3. The method of claim 1, wherein the evaporating step (b) comprises subjecting the solution to a reduced pressure or vacuum.

4. The method of claim 3, wherein the evaporating step (b) comprises subjecting the solution to an elevated temperature.

5. The method of claim 1, wherein the substrate comprises one or more of the following excipients:

cellulose, polydextran, silica, silicate, activated carbon, gelatin, collagen, polysaccharide, polypeptide, starch and polyethylene glycol.

6. The method of claim 1, wherein the solvent is an anhydrous solvent.

7. The method of claim 6, wherein the solvent comprises one or more of the following:

tetrahydrofuran, hexane, acetone, ethanol, methanol, methyl ethyl ketone, and ethyl acetate.

8. The method of claim 1, wherein the solvent has a boiling point of about 100°

C. or less.

9. The method of claim 1, wherein the solvent comprises water.

10. The method of claim 1, further comprising:

(c) adding the substrate to the solvent,

wherein step (c) is performed before or during the dissolving step (a).

11. The method of claim 10, wherein the substrate is dissolved in the solvent prior to step (b).

12. The method of claim 1, further comprising:

(c) adding the substrate to the solvent,

wherein step (c) is performed after the dissolving step (a).

13. The method of claim 12, wherein the substrate is dissolved in the solvent prior to step (b).

14. The method of claim 1, wherein the solvent comprises two or more solvents.

15. The method of claim 1, wherein step (a) further comprises dissolving a second active agent or drug in the solvent, the second active agent or drug becoming non-covalently bound to the substrate in step (b).

16. The method of claim 15, wherein the active agent or drug is triiodothyronine (T3) and the second active agent or drug is thyroxine (T4).

17. The method of claim 1, further comprising:

(d) adding a capping agent to the solvent,

wherein step (d) is performed prior to the evaporating step (b).

18. The method of claim 17, wherein step (d) is performed before or during the dissolving step (a).

19. The method of claim 17, wherein the capping agent is dissolved in the solvent prior to step (b) and becomes non-covalently bound to the substrate in step (b).

20. The method of claim 17, wherein the capping agent comprises one or more of the following:

magnesium stearate (Mg stearate), steric acid, or stearyl fumarate.

21. The method of claim 17, wherein the capping agent comprises a polypeptide.

22. The method of claim 21, wherein the capping agent comprises polyglutamic acid.

23. The method of claim 1, further comprising:

(e) dissolving a second active agent or drug in a second solvent to form a second solution; and

(f) evaporating the second solvent from the second solution to form a second substrate powder comprising each of the active agent or drug and the second active agent or drug non-covalently bound to the substrate.

24. The method of claim 23, further comprising:

(g) adding the substrate powder to the second solvent,

wherein step (g) is performed after the dissolving step (e) but prior to the evaporating step (f).

25. The method of claim 23, further comprising:

(g) adding the substrate powder to the second solvent,

wherein step (g) is performed before or during the dissolving step (e).

26. The method of claim 1, further comprising:

(h) dissolving a capping agent in a second solvent to form a second solution; and

(i) evaporating the second solvent from the second solution to form a second substrate powder comprising each of the active agent or drug and the capping agent non-covalently bound to the substrate.

27. The method of claim 26, further comprising:

(j) adding the substrate powder to the second solvent,

wherein step (j) is performed prior to the evaporating step (i).

28. The method of claim 1, wherein the active agent or drug is an iodinated L-thyronine congener.

29. The method of claim 28, wherein the active agent or drug is 3,5,3′

-triiodo-L-thyronine (T3).

30. The method of claim 29, wherein the substrate is cellulose.

31. The method of claim 29, wherein the solvent is an anhydrous organic solvent.

32. The method of claim 28, wherein the active agent or drug is L-thyroxine (T4).

33. The method of claim 32, wherein the solvent is an anhydrous organic solvent.

34. The method of claim 1, further comprising:

(k) dissolving a second active agent or drug in a second solvent to form a second solution; and

(l) evaporating the second solvent from the second solution to form a second substrate powder comprising the second active agent or drug non-covalently bound to a second substrate.

35. The method of claim 34, further comprising:

(m) combining the substrate powder and the second substrate powder and optionally adding one or more excipients to form a final formulation.

36. The method of claim 1, further comprising:

(n) replacing the atmosphere surrounding the substrate powder with an inert gas.

37. The method of claim 36, wherein the inert gas is one or more of:

Nitrogen (N₂), Carbon Dioxide (CO₂), Argon (Ar) or Xenon (Xe).

38. The method of claim 36, further comprising:

(o) repeating step (n).

39. The method of claim 1, further comprising:

(p) combining one or more excipients with the substrate powder to form a final formulation.

40. The method of claim 1, further comprising:

(q) combining one or more active agents or drugs with the substrate powder to form a final formulation.

41. The method of claim 40, wherein step (q) further comprises combining one or more excipients with the substrate powder to form the final formulation.

42. The method of claim 1, further comprising:

(r) forming the substrate powder into one or more dosage forms.

43. The method of claim 42, wherein step (r) comprises compressing the substrate powder into one or more tablets.

44. The method of claim 42, further comprising:

(s) placing the one or more dosage forms into a container; and

(t) filling the container with an inert gas.

45. The method of claim 39, further comprising:

(r) forming the final formulation into one or more dosage forms.

46. The method of claim 45, wherein step (r) comprises compressing the final formulation into one or more tablets.

47. The method of claim 40, further comprising:

(r) forming the final formulation into one or more dosage forms.

52. A composition comprising the substrate powder of claim 1.

53. A composition comprising the final formulation of claim 39.

54. A composition comprising the one or more dosage forms of claim 42.

48. A method comprising the following steps:

(a) dissolving an active agent or drug in a dispersing solvent to form a solution containing the active agent or drug;

(b) co-precipitating the active agent or drug and a substrate by adding a precipitating solvent to the solution to form a precipitate, the precipitate comprising the active agent or drug non-covalently bound to the substrate, wherein the substrate is a polymer or crystalline excipient.

49. The method of claim 48, further comprising:

(c) removing most of the dispersing solvent and the precipitating solvent; and

(d) drying the precipitate to form a substrate powder.

50. The method of claim 49, wherein the removing step (c) comprises:

(e) centrifuging the solvents and precipitate to form a pellet of the precipitate; and

(f) aspirating most of the dispersing solvent and the precipitating solvent.

51. The method of claim 49, wherein the drying step (d) comprises subjecting the precipitate to reduced or vacuum pressure.

55. A method comprising the following steps:

administering a pharmaceutical composition to an individual, the pharmaceutical composition comprising a substrate powder,

wherein the substrate powder comprises an active agent or drug non-covalently bound to a substrate, the substrate being a polymer or crystalline excipient.

56. The method of claim 55, wherein the substrate powder is formed by dissolving the active agent or drug in a solvent to form a solution and evaporating the solvent to cause the active agent or drug to bind to the substrate present in the solution.

57. The method of claim 55, wherein the individual has or is experiencing hypothyroidism, myxedema, or a myxedema coma.

58. The method of claim 55, wherein the active agent or drug is an iodinated thyronine congener.

59. The method of claim 58, wherein the active agent or drug is 3,5,3′

-triiodo-L-thyronine (T3).

60. The method of claim 59, wherein the administering step consists of administering the pharmaceutical composition only once per day, and wherein the administering step is repeated daily, the amount per single daily dosage of T3 in the pharmaceutical composition being in a range from about 10 μ

g to about 50 μ

g.

61. The method of claim 60, wherein the individual is maintained in a euthyroid state as a result of repeatedly administering the daily dosages of T3.

62. The method of claim 60, wherein the amount per single daily dosage of T3 is an amount effective to maintain the individual in a euthyroid state.

63. The method of claim 60, further comprising:

determining the levels of one or more gene products present in a sample or biopsy taken from the individual, the one or more gene products being downstream targets of T3; and

adjusting the single daily dosage of T3 based on the determined levels of the one or more gene products.

64. The method of claim 63, wherein the one or more gene products include one or both of transferrin and sex hormone binding globulin (SHBG).

65. The method of claim 60, further comprising:

adjusting the single daily dosage of T3 based on the clinical presentation of the individual.

66. The method of claim 58, wherein the active agent or drug is L-thyroxine (T4).

67. The method of claim 66, wherein the administering step consists of administering the pharmaceutical composition only once per day, and wherein the administering step is repeated daily, the amount per single daily dosage of T4 in the pharmaceutical composition being in a range from about 50 μ

g to about 200 μ

g.