Formulations For Therapeutic Administration Of Thyroid Stimulating Hormone (TSH)

• US 20100048455A1
• Filed: 09/18/2007
• Published: 02/25/2010
• Est. Priority Date: 09/19/2006
• Status: Abandoned Application

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Magner, James, Skell, Jeffrey, Clark, Eliana
• Application Number:
  US12/441,836
• Publication Number:
  US 20100048455A1
• Time in Patent Office: Days
• US Class Current: 514/1.100
• CPC Class Codes: A61K 38/24 Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/06 of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4

Abstract

This disclosure generally relates to novel formulations containing the active ingredient thyroid stimulating hormone (TSH) having modified pharmacokinetic profiles as compared to prior art formulations.

Claims

1. A method for treating a thyroid condition in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising an effective amount of TSH and an effective amount of a pharmaceutically-acceptable polymer.

2. The method of claim 1, wherein the pharmaceutical composition provides a serum T₃ level in the patient of no more than 2.5 ng/ml over a 48-hour period after administration.

3. The method of claim 1, wherein the thyroid condition is selected from the group consisting of goiter and thyroid cancer.

4. The method of claim 1, wherein the pharmaceutical composition is delivered via intramuscular injection.

5. The method of claim 1, wherein an effective T_max of TSH in a serum of the patient is at least about 20% longer as compared to an effective T_max of TSH in the serum of the patient when a corresponding aqueous solution of TSH is administered.

6. The method of claim 1, wherein an effective C_max of TSH in a serum of the patient is at least about 20% lower as compared to an effective C_max of TSH in the serum of the patient when a corresponding aqueous solution of TSH is administered.

7. The method of claim 1, wherein the composition provides a serum T₃ level in the patient of no more than 2.5 ng/ml over a 48-hour period after administration.

34. The pharmaceutical composition of claim 3, wherein the composition comprises about 0.05% to about 5% sodium carboxymethylcellulose.

35. The pharmaceutical composition of claim 3, wherein the sodium carboxymethylcellulose has a molecular weight of about 70,000 to about 950,000.

8. A method for maintaining blood plasma concentration of TSH above 2.0 mIU/L in a patient suffering from a thyroid condition, comprising administering to the patient an effective amount of a pharmaceutical composition comprising an effective amount of TSH and an effective amount of a pharmaceutically-acceptable polymer, wherein the blood serum or plasma concentration of TSH is maintained above about 2.0 mIU/L for longer than about six hours after administration.

9. The method of claim 8, wherein the blood plasma concentration of TSH remains elevated for longer than about ten hours after administration, about fifteen hours after administration, about one day after administration, about two days after administration or about four days after administration.

14. The method of claim 8, wherein the thyroid condition is selected from the group consisting of goiter and thyroid cancer.

10. (canceled)

11. (canceled)

12. (canceled)

13. (canceled)

15. A method for providing a modified-release formulation of TSH comprising admixing an effective amount of TSH and an effective amount of a pharmaceutically-acceptable polymer, thereby providing a modified-release formulation.

16. The method of claim 15, wherein the TSH is TSH isolated from a mammal.

17. The method of claim 15, wherein the TSH is recombinant mammalian TSH.

18. The method of claim 16, wherein the mammal is a human.

19. The method of claim 15, wherein the pharmaceutically-acceptable polymer is a metabolically-clearable polymer.

20. The method of claim 15, wherein the pharmaceutically-acceptable polymer is injectable into a body.

21. The method of claim 15, wherein the pharmaceutically-acceptable polymer has a viscosity of about 40 to about 125 cps.

22. The method of claim 15, wherein the pharmaceutically-acceptable polymer is sodium carboxymethylcellulose.

23. The method of claim 22, wherein the sodium carboxymethylcellulose has an average molecular weight of between about 70,000 and about 950,000.

24. The method of claim 22, wherein the pharmaceutically-acceptable polymer is about 3% sodium carboxymethylcellulose.

25. The method of claim 15, wherein the concentration of TSH is between about 40 μ

g/ml and about 80 μ

g/ml.

26. A pharmaceutical composition comprising TSH and a pharmaceutically-acceptable polymer that allows modified release of the TSH into a bloodstream of a patient, wherein, when administered to the patient, the pharmaceutical composition provides an effective T_max of TSH in a serum of the patient that is at least about 20% longer than an effective T_max of TSH in the serum of the patient when a corresponding aqueous solution of TSH is administered, an effective C_max of TSH in a serum of the patient that is at least about 20% lower than an effective C_max of TSH in the serum of the patient when a corresponding aqueous solution of TSH is administered, or a combination thereof.

28. The pharmaceutical composition of claim 26, wherein the TSH is TSH isolated from a mammal.

29. The pharmaceutical composition of claim 28, wherein the mammal is a human.

30. The pharmaceutical composition of claim 26, wherein the TSH is recombinant mammalian TSH.

31. The pharmaceutical composition of claim 30, wherein the mammal is a human.

32. The pharmaceutical composition of claim 26, wherein the pharmaceutically-acceptable polymer is selected from the group consisting of a polysaccharide, a cellulose derivative, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, ethyl hydroxyethyl cellulose, hypromellose, calcium carboxymethyl cellulose, poly(ethylene glycol), a poly(ethylene glycol) polymer, poly(ethylene oxide), poly(propylene oxide), a polyoxyalkylene block copolymer, polyvinyl pyrrolidone, polyvinyl alcohol, polyproline, agarose, chitosan, carrageenan, polymeric chitosan, hyaluronic acid, chondroitin, chondroitin-4-sulfate, heparan sulfate, heparin, glycosaminoglycan, agar, pectin, gelatin, alginic acid, dextran, alpha-amylose, amylopectin, chitosan and a salt or ester of any of the foregoing.

33. The pharmaceutical composition of claim 26 wherein the pharmaceutically-acceptable polymer is sodium carboxymethylcellulose.

36. The pharmaceutical composition of claim 26, wherein the composition has a viscosity of at least about 40 cps.

37. The pharmaceutical composition of claim 26, wherein the composition has a viscosity of about 40 to about 125 cps.

27. (canceled)

38. A pharmaceutical composition comprising an effective amount of TSH and an effective amount of a pharmaceutically-acceptable polymer, wherein the composition has viscosity of at least about 40 cps, provides a serum T₃ level of no more than 2.5 ng/ml over a 48-hour period after administration to a patient in need thereof, provides an effective T_max of at least six hours after administration to a patient in need thereof, provides an effective C_max in serum of greater than about 2.0 mIU/L after administration to a patient in need thereof, or a combination thereof.

39. The pharmaceutical composition of claim 38, wherein the composition has a viscosity of at least about 50 cps, at least about 70 cps, or at least about 90 cps.

45. The pharmaceutical composition of claim 38, wherein the patient in need thereof is a patient suffering from a thyroid condition selected from the group consisting of goiter and thyroid cancer.

46. The pharmaceutical composition of claim 38, wherein the TSH is TSH isolated from a mammal.

47. The pharmaceutical composition of claim 46, wherein the mammal is a human.

48. The pharmaceutical composition of claim 38, wherein the TSH is recombinant mammalian TSH.

49. The pharmaceutical composition of claim 48, wherein the mammal is a human.

50. The pharmaceutical composition of claim 38, wherein the pharmaceutically-acceptable polymer is sodium carboxymethylcellulose having an average molecular weight between about 70,000 and about 950,000.

40. (canceled)

41. (canceled)

42. (canceled)

43. (canceled)

44. (canceled)

51. (canceled)

52. (canceled)