Macrolides

• US 7,297,703 B2
• Filed: 12/23/2004
• Issued: 11/20/2007
• Est. Priority Date: 12/07/1998
• Status: Expired due to Term

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Petit, Samuel, Navarro, Francois, Stone, Guy
• Primary Examiner(s): Kifle; Bruck
• Application Number:
  US11/020,860
• Publication Number:
  US 20050107418A1
• Time in Patent Office: 1,062 Days
• Field of Search: 540/456, 514/291
• US Class Current: 514/291
• CPC Class Codes: A61K 31/395 having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07D 498/18 Bridged systems

Abstract

A mixture comprising a poly-ene macrolide and an antioxidant. Preferably, the poly-ene macrolide is rapamycin and the antioxidant is 2, 6-di-tert.-butyl-4-methylphenol. The presence of the antioxidant improves the stability of the poly-ene macrolide to oxidation.

Claims

1. A solid mixture comprising a poly-ene macrolide and an antioxidant wherein the poly-ene macrolide is selected from the group consisting of rapamycin, a 16-O-substituted rapamycin, and a 40-O-substituted rapamycin and wherein the antioxidant is present in a catalytic amount.

2. A mixture according to claim 1, wherein the antioxidant is present in an amount of up to 1% based on the poly-ene macrolide weight.

3. A mixture according to claim 1 or 2, wherein the antioxidant is present in an amount of 0.01 to 0.5% based on the macrolide weight.

4. A mixture according to claim 3, wherein the antioxidant is selected from the group consisting of vitamin B, vitamin C, 2,6-di-tert-butyl-4-methylphenol (BHT), and combinations thereof.

5. A mixture according to claim 3, wherein the antioxidant is present in an amount of 0.2% based on the macrolide weight.

6. A pharmaceutical composition comprising as active ingredient, a mixture according to claim 1 or 2, admixed with one or more pharmaceutically acceptable carriers or diluents.

7. A pharmaceutical composition according to claim 6 for oral administration.

8. A process for stabilizing a poly-ene macrolide selected from the group consisting of rapamycin, a 16-O-substituted rapamycin, and a 40-O-substituted rapamycin, said process comprising:

(a) dissolving pure rapamycin, pure 16-O or pure 40-O-substituted rapamycin in an inert solvent;

(b) adding an antioxidant to the resulting solution in an amount up to 1% based on the rapamycin or 16-O or 40-O-substituted rapamycin, weight, and

(c) isolating the resulting mixture of the rapamycin or 16-O or 40-O-substituted rapamycin and the antioxidant.

9. The process of claim 8 wherein the antioxidant is selected from the group consisting of vitamin E, vitamin C, 2,6-di-tert.-butyl-4-methylphenol (BHT) and combinations thereof.

10. The process of claim 8 wherein the antioxidant is present in an amount of up to 1% based on the macrolide weight.

11. The process of claim 8 wherein the antioxidant is present in an amount of from 0.01 to 0.5% based on the macrolide weight.

12. The process of claim 8 wherein the antioxidant is present in an amount of 0.2% based on the macrolide weight.