Process and formulation containing epothilones and analogs thereof

• US 20050171167A1
• Filed: 11/03/2004
• Published: 08/04/2005
• Est. Priority Date: 11/04/2003
• Status: Abandoned Application

• Current Assignee: R-pharm us operating llc
• Original Assignee: R-pharm us operating llc
• Inventors: Naringrekar, Vijay H., Gogate, Uday S., Haby, Thomas A.
• Application Number:
  US10/979,958
• Publication Number:
  US 20050171167A1
• 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 preparation for administering to a patient a formulation for administration, the formulation for administration including an infusion fluid having an infusion fluid pH and a compound of formula I:

2. The pharmaceutical preparation of claim 1 wherein the compound of formula I is a compound of formula II:

3. The pharmaceutical preparation of claim 1 wherein the pH-adjusting ingredient is a base, the solvent is an alcohol, and the pharmaceutical preparation consists essentially of the buffer, the base, the alcohol, and a nonionic surfactant.

4. The pharmaceutical preparation of claim 3 wherein the alcohol is Dehydrated Alcohol.

5. The pharmaceutical preparation of claim 3 wherein the nonionic surfactant is a polyethoxylated castor oil.

6. The pharmaceutical preparation of claim 5 wherein the polyethoxylated castor oil is Cremophor EL®

surfactant.

7. The pharmaceutical preparation of claim 3 wherein the buffer is sodium lactate.

8. The pharmaceutical preparation of claim 3 wherein the base is sodium hydroxide.

9. The pharmaceutical preparation of claim 3 wherein the alcohol is Dehydrated Alcohol, the nonionic surfactant is Cremophor EL®

surfactant, the buffer is sodium lactate, and the base is sodium hydroxide.

10. The pharmaceutical preparation of claim 1 wherein the infusion fluid is selected from saline and dextrose.

11. 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.

12. 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.

13. 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.

14. 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.

15. The pharmaceutical preparation of claim 1 wherein the pH-adjusting ingredient is a base selected from one or more of platinum oxide (PtO₂), potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), potassium carbonate (K₂CO₃), magnesium hydroxide (Mg(OH)₂), calcium hydroxide (Ca(OH)₂), and sodium bicarbonate (NaHCO₃).

16. 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.

17. The pharmaceutical preparation of claim 1 wherein the buffer is selected from the group consisting of sodium phosphate, sodium citrate, sodium lactate, L-lysine, L-histidine, L-alanine, and tris-hydroxymethyl aminomethane.

18. The pharmaceutical preparation of claim 1 wherein the compound of formula I is lyophilized, and the pharmaceutical preparation comprises a reconstitution vehicle.

19. A process for administering to a patient a compound of formula I, with an infusion fluid having an infusion fluid pH, the compound of formula I having the formula,

20. The process of claim 19, wherein the pH-adjusting ingredient is a base, and the solution vehicle comprises the base, the buffer, Dehydrated Alcohol, and a nonionic surfactant.

21. The process of claim 19, wherein the pH-adjusting agent is a base, and the solution vehicle is prepared by mixing the buffer with an anhydrous alcohol, followed by the addition of the base and the surfactant.

22. The process of claim 19, wherein the pH-adjusting agent is a base, and the solution vehicle is prepared by mixing the base with an anhydrous alcohol, followed by the addition of at least one surfactant and then the buffer.

23. The process of claim 19, wherein the compound of formula I is a compound of formula II:

24. The process of claim 19, wherein the solution vehicle is prepared to achieve 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.

25. The process of claim 19, wherein the pH-adjusting ingredient is selected from one or more of platinum oxide (PtO₂), potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), potassium carbonate (K₂CO₃), magnesium hydroxide (Mg(OH)₂), calcium hydroxide (Ca(OH)₂), and sodium bicarbonate (NaHCO₃).

26. The process of claim 19, wherein the pH-adjusting ingredient is sodium hydroxide.

27. The process of claim 26, 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.

28. The process of claim 19, wherein the buffer is selected from the group comprising sodium phosphate, sodium citrate, sodium lactate, L-lysine, L-histidine, L-alanine, and tris-hydroxymethyl aminomethane.

29. The process of claim 19, wherein the buffer is sodium lactate or sodium lactate solution.

30. The process of claim 29, wherein the sodium lactate is added to the solution vehicle at a concentration of from about 10 mg/mL to about 20 mg/mL.

31. The process of claim 29, wherein the sodium lactate solution, about 60% is added to the solution vehicle at a concentration of about 25 mg/mL.

32. The process of claim 19, wherein the infusion fluid is 0.9% Sodium Chloride Injection or 5% Dextrose Injection.

33. The process of claim 19, further comprising lyophilizing the compound before dissolving the compound in the first solution vehicle.

34. The process of claim 33, wherein the lyophilization process is carried out in a chamber having a chamber pressure and a shelf fluid temperature, wherein the chamber pressure is maintained in the range of about 225 to about 275 microns, and the shelf fluid temperature is maintained in the range of about −

32°

C. to about −

28°

C.

35. The process of claim 34, wherein the lyophilization process is carried out in a chamber having a chamber pressure and a shelf fluid temperature, wherein the chamber pressure is maintained at about 250 microns, and the shelf fluid temperature is maintained at about −

30°

C.

36. A kit for preparing a formulation for administration, the formulation for administration comprising:

i) an infusion fluid having an infusion fluid pH; and

ii) a compound of formula I;

wherein,

Q is selected from the group consisting of;

W is selected from —

O— and

—

N(R¹⁶)—

;

M is selected from the group consisting of oxygen, sulfur, —

N(R⁸)—

, and —

C(R⁹R¹⁰)—

;

each R¹, R², R³, R⁴, R⁵, and R⁷ is, independently, selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and heterocyclo, and wherein when R¹ and R² are alkyl, they can be joined to form cycloalkyl;

R⁶ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo, and substituted heterocyclo;

R⁸ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, —

C(═

O)R¹¹, —

C(═

O)OR¹², and —

S(O₂)R¹³;

R⁹ and R¹⁰ are each independently selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, —

C(═

O)R¹⁴, and —

C(═

O)OR¹⁵; and

each R¹¹, R¹², R¹³, R¹⁴, R¹⁵, and R¹⁶ is, independently, selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and heterocyclo;

or a pharmaceutically-acceptable salt or solvate thereof, wherein,

the compound of formula I has a pH of maximum stability different from the infusion fluid pH to define a pH differential;

the kit comprising;

in a first vial, the compound of formula I; and

in a second vial, a pharmaceutical preparation comprising a surfactant, a solvent, a buffer, and a pH-adjusting ingredient, wherein the buffer and pH-adjusting ingredient are selected so that when the buffer and pH-adjusting ingredient are added to the infusion fluid to provide the formulation for administration, the pH differential is reduced.

37. The kit of claim 36, wherein the compound of formula I in the first vial is lyophilized, and the pharmaceutical preparation in the second vial is a reconstitution vehicle.

38. The kit of claim 36, wherein the compound of formula I is a compound of formula II:

39. The kit of claim 36 further comprising:

a third vial comprising the infusion fluid.