Methods of use related to xerostomia

• US 20060040903A1
• Filed: 10/25/2005
• Published: 02/23/2006
• Est. Priority Date: 12/09/1997
• Status: Abandoned Application

• Current Assignee: David S. Alberts, Edward H. Kaplan, Martin Stogniew
• Original Assignee: David S. Alberts, Edward H. Kaplan, Martin Stogniew
• Inventors: Stogniew, Martin, Alberts, David S., Kaplan, Edward H.
• Application Number:
  US11/258,335
• Publication Number:
  US 20060040903A1
• Time in Patent Office: Days
• US Class Current: 514/114
• 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 31/13 Amines A61K31/04 takes precedence
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/145 having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2) isothiourea A61K31/155
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/66 Phosphorus compounds
• CPC Class Codes: A61K 31/661 Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 17/16 Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 27/16 : Otologicals
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 39/02 : Antidotes
• 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 relates to new uses of thermally stable, crystalline S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate, (amifostine) and other aminothiol compounds to treat and reverse toxicities caused by radiation treatment. In particular, the invention provides a method for treating or preventing xerostomia associated with the administration of radiation treatment of head and neck cancer.

Claims

1. A method for treating xerostomia associated with radiation therapy for head and neck cancer in a human, which comprises administering to said human a therapeutically effective amount of a dosage form comprising a thermally stable, sterile, crystalline compound of the formula:

R₁NH(CH₂)_nNH(CH₂)_mSR₂

or a pharmaceutically acceptable addition salt or hydrate thereof, wherein

R₁ is hydrogen, C₅-C₇ aryl, C₂-C₇ acyl, or C₁-C₇ alkyl;

R₂ is hydrogen, PO₃H₂ or R₃ wherein R₃ is R₁NH(CH₂)_nNH(CH₂)_mS—

;

n is an integer from 1 to 10; and

m is an integer from 1 to 10.

2. The method of claim 1, wherein R₂ is PO₃H₂.

3. The method of claim 2, wherein R₁ is hydrogen.

4. The method of claim 3, wherein n is 3 and m is 2.

5. The method of claim 4, wherein the compound is a thermally stable, sterile, crystalline amifostine hydrate.

6. The method of claim 5, wherein the compound is thermally stable, sterile, crystalline amifostine trihydrate.

7. The method of claim 6, wherein the crystalline amifostine trihydrate exhibits substantially the crystal structure having a space group of P2₁2₁2, and cell dimensions of about a=8.46 Å

, b=21.55 Å and

c=6.76 Å

.

8. The method of claim 6, wherein the crystalline amifostine trihydrate forms less than about 2% 2-[(3-aminopropyl)amino]ethane thiol when sealed in a nitrogen filled vial and heated to 40°

C. for one week.

9. The method of claim 6, wherein the crystalline amifostine trihydrate forms less than about 2% 2-[(3-aminopropyl)amino]ethane thiol when sealed in a nitrogen filled vial and heated to 40°

C. for four weeks.

10. The method of claim 6, wherein the crystalline amifostine trihydrate is thermally stable at about 4°

C. for at least two years.

11. The method of claim 6, wherein the crystalline amifostine trihydrate is thermally stable at about ambient temperature for at least two years.

12. The method of claim 1, wherein the dosage form further comprises an excipient.

13. The method of claim 12, wherein the excipient is mannitol.

14. The method of claim 1, wherein the dosage form is lyophilized.

15. The method of claim 6, wherein the dosage form comprises 500 mg of amifostine on an anhydrous basis.

16. The method of claim 1, wherein the amount of the crystalline compound administrated is from about 10 to 1000 mg/m².

17. The method of claim 1, wherein the amount of the crystalline compound administrated is from about 200 to 750 mg/m².

18. The method of claim 1, wherein the amount of the crystalline compound administrated is about 750 mg/m².

19. The method of claim 1, wherein the dosage form is administrated before the radiation therapy.

20. The method of claim 1, wherein the dosage form is administrated after the radiation therapy.

21. The method of claim 1, wherein the dosage form is administrated during the radiation therapy.

22. A method for treating xerostomia associated with radiation therapy for head and neck cancer in a human, which comprises administering to said human a therapeutically effective amount of a dosage form comprising a thermally stable, sterile, crystalline amifostine.

23. The method of claim 22, wherein the crystalline amifostine is an amifostine hydrate.

24. The method of claim 23, wherein the crystalline amifostine is an amifostine trihydrate.

25. The method of claim 24, wherein the crystalline amifostine trihydrate exhibits substantially the crystal structure having a space group of P2₁2₁2₁ and cell dimensions of about a=8.46 Å

, b=21.55 Å and

c=6.76 Å

.

26. The method of claim 25, wherein the crystalline amifostine trihydrate forms less than about 2% 2-[(3-aminopropyl)amino]ethane thiol when sealed in a nitrogen filled vial and heated to 40°

C. for one week.

27. The method of claim 25, wherein the crystalline amifostine trihydrate forms less than about 2% 2-[(3-aminopropyl)amino]ethane thiol when sealed in a nitrogen filled vial and heated to 40°

C. for four weeks.

28. The method of claim 25, wherein the crystalline amifostine trihydrate is thermally stable at about 4°

C. for at least two years.

29. The method of claim 25, wherein the crystalline amifostine trihydrate is thermally stable at about ambient temperature for at least two years.

30. The method of claim 22 where the dosage form is lyophilized.

31. The method of claim 22, wherein the dosage form further comprises an excipient.

32. The method of claim 31, wherein the excipient is mannitol.

33. The method of claim 22, wherein the dosage form comprises 500 mg of amifostine on an anhydrous basis.

34. The method of claim 22, wherein the amount of the crystalline compound administrated is from about 10 to 1000 mg/m².

35. The method of claim 22, wherein the amount of the crystalline compound administrated is from about 200 to 750 mg/m².

36. The method of claim 22, wherein the amount of the crystalline compound administrated is about 750 mg/m².

37. The method of claim 22, wherein the dosage form is administrated before the radiation therapy.

38. The method of claim 22, wherein the dosage form is administrated after the radiation therapy.

39. The method of claim 22, wherein the dosage form is administrated during the radiation therapy.