Ansamycin formulations and methods for producing and using same

• US 20060014730A1
• Filed: 04/04/2003
• Published: 01/19/2006
• Est. Priority Date: 04/10/2002
• Status: Abandoned Application

• Current Assignee: Conforma Therapeutics Corporation (Biogen, Inc.), Sharp Kabushiki Kaisha (Hon Hai Precision Industry Co., Ltd.)
• Original Assignee: Conforma Therapeutics Corporation (Biogen, Inc.)
• Inventors: Boehm, Marcus F., Ulm, Edgar H., Chen, Andrew X.
• Application Number:
  US10/510,807
• Publication Number:
  US 20060014730A1
• Time in Patent Office: Days
• US Class Current: 514/183
• CPC Class Codes: A61K 31/33 Heterocyclic compounds
• CPC Class Codes: A61K 31/395 having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• 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 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Ansamycin formulations and methods of producing and using the same are described and claimed. The formulations are emulsions that can be used directly in a patient, or be lyophilized and/or frozen, to be later used, e.g., upon re- or further hydration or processing.

Claims

1. A method of preparing an ansamycin emulsion comprising:

(a) providing an ansamycin or pharmaceutically acceptable salt thereof dissolved in an ethanol solution;

(b) mixing said ansamycin or pharmaceutically acceptable salt thereof with a medium chain triglyceride to form a first mixture;

(c) substantially removing said ethanol from said first mixture if it is present;

(d) combining the product of step (c) with an emulsifying agent and a stabilizer to form a second mixture;

(e) emulsifying said second mixture;

(f) optionally lyophilizing the product of step (e); and

(g) optionally hydrating the product of step (f).

2. The method of claim 1 wherein said ansamycin or pharmaceutically acceptable salt thereof is selected from a member selected from the group of geldanamycin, pharmaceutically acceptable salts of geldanamycin, geldanamycin derivatives and pharmaceutically acceptable salts of geldanamycin derivatives.

3. The method of claim 1 wherein said ansamycin or pharmaceutically acceptable salt thereof is selected from the group consisting of

4. The method of claim 1 wherein said medium chain triglyceride comprises one or more of caprylic acid and capric acid, wherein said emulsifying agent comprises a phosphotidylcholine, and wherein said stabilizer comprises sucrose.

5. The method of claim 1 wherein said emulsified second mixture has an average oil droplet size of about 400 nm or less.

6. The method of claim 1 wherein said second mixture is filter-sterilized.

7. The method of claim 1 wherein said drug in said emulsified second mixture is present at a concentration of about 3 mg/ml or less.

8. The method of claim 1 wherein said emulsifying step comprises using one or more members selected from the group consisting of mechanical mixing, ultrasonic irradiation, passage through a microfluidizer, and passage across one or more membranes.

9. The method of claim 1 further comprising the step (f) of lyophilizing the product of step (e).

10. The method of claim 9 wherein the product of step (f) is subsequently hydrated by use of a step (g).

11. The method of claim 10 further comprising packaging the product of step (g) or (f) in a container.

12. The method of claim 11 wherein said container is light-resistant.

13. The method of claim 1 wherein one or more of said steps is performed under reduced lighting.

14. The method of claim 1 wherein one or more of said steps is performed under an inert gas.

20. The method of claim 14 wherein said drug in said emulsified second mixture is present at a concentration of about 2 mg/ml or less.

23. An emulsion prepared using any one of the methods of claims 1-22.

34. The method of claim 1 wherein said emulsified second mixture has an average oil droplet size of about 200 nm or less.

37. The method of claim 1, 15, 30, or 31 wherein said ansamycin is

38. The method of claim 1, 15, 30, or 31 wherein said ansamycin is

41. The method of claim 38 wherein said emulsion comprises mannitol, one or more buffers and, optionally, dextrose.

42. The method of claim 41 wherein said emulsion comprises about 1-1.5% (w/v) ansamycin, about 5% (w/v) mannitol, and about 10-20 mM sodium acetate (pH˜

5).

43. The method of claim 38 wherein said emulsion comprises between about 1 and 10 mg/ml inclusive of said ansamycin.

15. A method of preparing an ansamycin emulsion, comprising:

(a) dissolving an ansamycin or pharmaceutically acceptable salt thereof in a preformed solution comprising an emulsifying agent dissolved in a medium chain triglyceride solution;

said dissolving optionally employing the application of heat;

(b) combining the product of step (a) with a stabilizer;

(c) emulsifying the product of step (b);

(d) optionally lyophilizing the product of step (c); and

(e) optionally hydrating the product of step (d).

16. The method of claim 15 wherein said ansamycin or pharmaceutically acceptable salt thereof is selected from a member selected from the group of geldanamycin, pharmaceutically acceptable salts of geldanamycin, geldanamycin derivatives and pharmaceutically acceptable salts of geldanamycin derivatives.

17. The method of claim 15 wherein said ansamycin or pharmaceutically acceptable salt thereof is selected from the group consisting of

18. The method of claim 15 wherein said medium chain triglyceride comprises one or more of caprylic acid and capric acid, wherein said emulsifying agent comprises soy phospholecithin, and wherein said stabilizer comprises sucrose.

19. The method of claim 15 wherein said emulsified second mixture has a mean oil droplet size of about 400 nm or less.

21. The method of claim 15 wherein said emulsifying step (c) comprises using one or more members selected from the group consisting of mechanical mixing, ultrasonic irradiation, passage through a microfluidizer, and passage across one or more membranes.

22. The method of claim 15 wherein one or more of said steps is carried out under inert atmospheric conditions.

35. The method of claim 15 wherein said emulsified second mixture has an average oil droplet size of about 200 nm or less.

24. An emulsion comprising an oil phase and an aqueous phase, wherein said oil phase comprises an ansamycin or pharmaceutically acceptable salt thereof, a medium chain triglyceride, and a lecithin, wherein said aqueous phase comprises one or more stabilizers, and wherein said emulsion is optionally one or more of lyophilized and frozen.

25. The emulsion of claim 24 wherein said ansamycin or pharmaceutically acceptable salt thereof is selected from a member selected from the group of geldanamycin, pharmaceutically acceptable salts of geldanamycin, geldanamycin derivatives and pharmaceutically acceptable salts of geldanamycin derivatives.

26. The emulsion of claim 24 wherein said ansamycin is or pharmaceutically acceptable salt thereof is selected from the group consisting of

27. The emulsion of claim 24 wherein said ansamycin or pharmaceutically acceptable salt thereof is soluble in said oil phase in a concentration range of between about 5-30 mg/ml inclusive.

28. The emulsion of claim 24 wherein said ansamycin or pharmaceutically acceptable salt thereof is present at a concentration of up to about 3 mg/ml in said emulsion.

29. The emulsion of claim 24 characterized by a mean droplet size of about 400 nm or less.

30. A method of treating or preventing a disorder in a mammal, comprising:

administering to a mammalian subject a pharmaceutically effective amount of the emulsion produced according to claim 24.

31. A method of treating or preventing a disorder in a mammal, comprising:

administering to a mammalian subject a pharmaceutically effective amount of an emulsion according to any one of claims 24-29.

32. The method of claim 30 wherein said disorder is selected from the group of disorders consisting of ischemia, proliferative disorders, infections, neurological disorders, tumors, leukemias, neoplasms, cancers, carcinomas, and malignant diseases.

33. The method of claim 31 wherein said proliferative disorder is selected from the group consisting of tumors, inflammatory diseases, fungal infection, yeast infection, and viral infection.

36. The emulsion of claim 24 characterized by an average oil droplet size of about 200 nm or less.

39. The emulsion of claim 24 wherein said ansamycin is

40. The emulsion of claim 24 wherein said ansamycin is

44. The emulsion of claim 40 wherein prior to said optional lyophillization, said emulsion comprises mannitol, one or more buffers and, optionally, dextrose.

45. The emulsion of claim 44 comprising about 1-1.5% (w/v) ansamycin, about 5% (w/v) mannitol, and about 10-20 mM sodium acetate (pH˜

5).

46. The emulsion of claim 40 comprising between about 1 and 10 mg/ml inclusive of said ansamycin.