PROCESS AND FORMULATION CONTAINING EPOTHILONES AND ANALOGS THEREOF

• US 20100016385A1
• Filed: 09/11/2009
• Published: 01/21/2010
• Est. Priority Date: 11/04/2003
• Status: Active Grant

• Current Assignee: R-pharm us operating llc
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Gogate, Uday S., Haby, Thomas A., Naringrekar, Vijay H.
• Granted Patent: US 8,871,227 B2
• Time in Patent Office: Days
• US Class Current: 514/365
• CPC Class Codes: A61K 31/425 Thiazoles

Abstract

A process for formulating certain epothilones and analogs thereof for parenteral administration is provided wherein the pH of the formulation for administration can be controlled to enhance the stability and thus, potency of the epothilone, or analog thereof.

Claims

1. A pharmaceutical formulation for parenteral administration of an epothilone analog to a patient, the epothilone analog having the formula:

2. The pharmaceutical preparation of claim 1 wherein the pH-adjusting ingredient is a base, and the pharmaceutical preparation consists essentially of the epothilone analog compound, buffer, the base, the alcohol, and a nonionic surfactant.

3. The pharmaceutical preparation of claim 1 wherein the infusion fluid is saline, the pharmaceutical preparation has a pH in the range of about 6 to about 9, and the pH of the formulation for administration is in the range of about 6 to about 10.

4. The pharmaceutical preparation of claim 1 wherein the infusion fluid of the formulation for administration is dextrose, the pharmaceutical preparation has a pH in the range of about 6 to about 9, and the formulation for administration has a pH in the range of about 6 to about 10.

5. The pharmaceutical preparation of claim 1 wherein the buffer is present in the pharmaceutical preparation in a concentration between about 10 to about 20 mg/mL.

6. The pharmaceutical preparation of claim 1 wherein the compound of formula I is present in the formulation for administration in a concentration between about 0.1 mg/mL and about 0.9 mg/mL.

7. The pharmaceutical preparation of claim 15 wherein the base is sodium hydroxide and is present at a concentration of from about 0.01 mg/mL to about 1 mg/mL.

14. A kit for preparing a formulation for parenteral administration as defined in claim 1, the formulation for parenteral administration comprising:

i) an infusion fluid having an infusion fluid pH which infusion fluid is selected from the group consisting of saline and dextrose; and

ii) an epothilone analog compound of the formula;

15. The kit of claim 14, wherein the epothilone analog compound in the first vial is lyopilized, and the pharmaceutical preparation in the second vial is a reconstitution vehicle.

8. A process for parenterally administering to a patient an epothilone analog compound, with an infusion fluid having an infusion fluid pH, the compound having the formula,

9. The process of claim 8, wherein the solution vehicle is prepared to achieve a pH in the range of about 6 to about 9.

10. The process of claim 9, wherein the pH-adjusting ingredient is sodium hydroxide.

11. The process of claim 10, wherein the sodium hydroxide is present in the solution vehicle at a concentration of from about 0.01 mg/mL to about 1 mg/mL.

12. The process of claim 8, wherein the buffer is sodium lactate that is added to the solution vehicle at a concentration of from about 10 mg/mL to about 20 mg/mL.

13. The process of claim 8, wherein the buffer is sodium lactate solution, wherein about 60% of said buffer is added to the solution vehicle at a concentration of about 25 mg/mL.