Pharmaceutical compositions and treatment methods

• US 20040043973A1
• Filed: 12/13/2002
• Published: 03/04/2004
• Est. Priority Date: 03/16/2000
• Status: Active Grant

• Current Assignee: BioVie Inc.
• Original Assignee: Clarence N. Ahlem, Luis D. Carvalho, William Heggie
• Inventors: Carvalho, Luis D., Heggie, William, Ahlem, Clarence N.
• Granted Patent: US 7,396,827 B2
• Time in Patent Office: Days
• US Class Current: 514/179
• 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 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/568 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
• CPC Class Codes: A61K 31/5685 having an oxo group in position 17, e.g. androsterone
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0031 Rectum, anus
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: C07J 1/00 Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
• CPC Class Codes: C07J 1/0011 substituted in position 17 by a keto group
• CPC Class Codes: C07J 3/005 the carbon atom being part of a carboxylic function
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention provides compositions comprising formula 1 steroids, e.g., 16α-bromo-3β-hydroxy-5α-androstan-17-one hemihydrate and one or more excipients, typically wherein the composition comprises less than about 3% water. The compositions are useful to make improved pharmaceutical formulations. The invention also provides methods of intermittent dosing of steroid compounds such as analogs of 16α-bromo-3β-hydroxy-5α-androstan-17-one and compositions useful in such dosing regimens. The invention further provides compositions and methods to inhibit pathogen (viral) replication, ameliorate symptoms associated with immune dysregulation and to modulate immune responses in a subject using certain steroids and steroid analogs. The invention also provides methods to make and use these immunomodulatory compositions and formulations.

Claims

1. A method to treat or prevent a pathological condition selected from the group consisting of a pathogen infection, an autoimmune disease, an allergy or inflammation condition, a cancer or a precancer, a neurological disorder, a wound, a burn, a bone fracture, osteoporosis, acute myelitis, sarcoidosis or an immune suppression condition or unwanted immune response associated with a chemotherapy, a radiation therapy or aging in a subject in need thereof, comprising administering to the subject an effective amount of 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one hemihydrate.

2. The method of claim 1 wherein the pathological condition is a pathogen infection.

3. The method of claim 2 wherein the pathogen infection is a viral infection.

4. The method of claim 3 wherein the viral infection is a retrovirus infection.

5. The method of claim 4 wherein the retrovirus infection is an HIV-1, HIV-2, SIV or SHIV infection.

6. The method of claim 2 wherein the pathogen infection is a parasite infection.

7. The method of claim 6 wherein the parasite infection is a Plasmodium, Trypanosoma, Leishmania, Cryptosporidium or Pneumocystis infection.

8. The method of claim 2 wherein the pathogen infection is a bacterial infection.

9. The method of claim 8 wherein the bacterial infection is a Mycobacterium infection.

10. The method of claim 2 wherein the pathogen infection is a fungal or yeast infection.

11. The method of claim 10 wherein the fungal or yeast infection is a Candida, Aspergillus or Cryptococcus infection.

12. The method of claim 20, wherein the pathogen infection is an infection caused by a Togavirus, a Flavivirus, a Hepadnavirus, a Herpesvirus, a Papillomavirus, a Poxyirus, HHV-6, HHV-8, hepatitis B virus, hepatitis C virus, HSV-1, HSV-2, CMV, Escherichia, Haemophilus, Legionella pneumonia, Listeria, Mycoplasma, Mycobacterium, Neisseria, Pseudomonas, Rickettsia, Salmonella, Shigella, Streptococcus, Staphylococcus, Yersinia, Toxoplasma, Trichomonas, Chlamidya, Schistosoma, Strongyloides stercoralis, a gastrointestinal nematode, a helminth, a Microsporidium parasite or an Isosporum parasite.

13. The method of claim 1 wherein the pathological condition is a cancer or precancer.

14. The method of claim 13 wherein the cancer or precancer is a cancer or precancer arising in the throat, esophagus, stomach, intestine, colon, ovary, lung, breast or central nervous system.

15. The method of claim 13 wherein the cancer or a precancer is selected from the group consisting of melanoma, renal cell carcinoma, prostate cancer, benign prostatic hyperplasia, non-small cell lung cancer, bronchogenic carcinoma, renal cell cancer or carcinoma, a lymphoma, glioma, melanoma, pancreatic or gastric adenocarcinoma, human papillomavirus associated cervical intraepithelial neoplasia, cervical carcinoma, hepatoma and cutaneous T-cell lymphoma, ovarian cancer, cervical cancer, breast cancer, prostate cancer, liver cancer or carcinoma, a glioma, a leukemia, a colon cancer and recurrent condylomata acuminata.

16. The method of claim 1, wherein the immunosuppression condition or unwanted immune response is associated with an autoimmune disease.

17. The method of claim 16, wherein the autoimmune disease is systemic lupus erythematosus, osteoporosis, myasthenia gravis, Grave'"'"'s disease, diabetes, rheumatoid arthritis or osteoarthritis.

18. The method of claim 1 wherein the pathological condition is an allergy or inflammation condition.

19. The method of claim 18, wherein the allergy or inflammation condition is allergic bronchopulmonary aspergillosis, atopic asthma, allergic respiratory disease, allergic rhinitis, atopic dermatitis, lung fibrosis, subepithelial fibrosis in airway hyperresponsiveness, chronic sinusitis, perennial allergic rhinitis, Crohn'"'"'s disease, ulcerative colitis, inflammatory bowel disease, chronic diarrhea or fibrosing alveolitis.

20. The method of claim 1 wherein the pathological condition is a neurological condition.

21. The method of claim 1 wherein the neurological condition is AIDS associated dementia, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, schizophrenia or Multiple Sclerosis.

22. The method of claim 1 wherein the pathological condition is an immune suppression condition or unwanted immune response associated with a chemotherapy or a radiation therapy.

23. The method of claim 1 wherein the chemotherapy or radiation therapy is treatment of the subject with cyclosporin, cyclohexamide, mitomycin C, adriamycin, taxol, amphotericin B, cis-platin, a protease inhibitor, a nucleoside analog, a nucleotide analog, a corticosteroid or y-radiation.

24. The method of claim 1, 2, 13, 16, 18 or 20 wherein the subject is a human.

25. The method of claim 1 wherein the 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one hemihydrate is administered to the subject in a buccal or sublingual formulation.

26. The method of claim 1 wherein the 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one hemihydrate is administered to the subject as a parenteral suspension, liposome or colloid formulation.

27. The method of claim 25 or 26 wherein 0.05 to about 30 mg/kg/day of 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one hemihydrate is administered to the subject once or twice per day.

38. The product of claim 6 wherein the 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one hemihydrate comprises at least about 15% w/w of the 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one that is present.

28. 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one hemihydrate.

29. The 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one hemihydrate of claim 28 wherein less than about 3% w/w of 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one is present.

30. The 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one hemihydrate of claim 28 wherein less than about 2% w/w of 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one is present.

31. The 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one hemihydrate of claim 28 substantially free of other forms of 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one.

32. The 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one hemihydrate of claim 31 wherein less than about 3% w/w of 16α

-bromo-3β

-hydroxy-5 α

-androstan-17-one is present.

33. A product produced by the process of contacting 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one hemihydrate containing less than about 3% w/w of 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one and one or more excipients.

34. The product of claim 33 wherein the one or more excipients is one or more of a polyethylene glycol, propylene glycol, ethanol, benzyl alcohol and benzyl benzoate.

35. The product of claim 33 wherein the one or more excipients is one or more solid excipients.

36. The product of claim 33 wherein the one or more solid excipients is selected from the group consisting of binders, lubricants, inert diluents, preservatives and surface active or dispersing agents.

37. The product of claim 33 wherein the excipient is one or more of sucrose, mannitol, lactose and magnesium stearate.

39. The product of claim 33 wherein the 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one hemihydrate contains less than about 2% w/w of 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one.

40. The product of claim 39 wherein the one or more excipients is one or more of a polyethylene glycol, propylene glycol, ethanol, benzyl alcohol and benzyl benzoate.

41. The product of claim 33 wherein the one or more excipients is one or more solid excipients.

42. The product of claim 41 wherein the one or more solid excipients is selected from the group consisting of binders, lubricants, inert diluents, preservatives and surface active or dispersing agents.

43. The product of claim 33 wherein the excipient is one or more of sucrose, mannitol, lactose and magnesium stearate.

44. 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one hemihydrate having an average particle size of about 0.1-10 μ

m.

45. The 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one hemihydrate of claim 44 having an average particle size of about 0.5-5 μ

m.

46. The 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one hemihydrate of claim 44 having an average particle size of about 0.03-2 μ

m.

47. A product produced by the process of storing a formulation comprising 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one hemihydrate and one or more excipients at about 5-40°

C. for about 1-24 months in a closed container wherein the 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one hemihydrate is substantially free of other forms of 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one.

48. The product of claim 47 wherein the formulation is a solid formulation or a liquid suspension, liposome or colloid formulation and the 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one hemihydrate contains less than about 3% w/w of 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one.

49. The product of claim 47 wherein the formulation is a solid formulation for buccal or sublingual administration.

50. The product of claim 47 wherein the formulation is a liquid suspension, liposome or colloid formulation for parenteral, buccal or sublingual administration.

51. The product of claim 47 wherein the formulation is a solid, a suspension or a colloid and the 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one hemihydrate contains less than about 2% w/w of 16α

-bromo-3β

-hydroxy-5α

-androstan-17-one.

52. The product of claim 51 wherein the formulation is a solid formulation for buccal or sublingual administration.

53. The product of claim 51 wherein the formulation is a liquid suspension, liposome or colloid formulation for parenteral administration.