PARENTERAL FORMULATION FOR EPOTHILONE ANALOGS

摘要

A process for formulating certain epothilone analogs for parenteral administration is disclosed wherein the analog is dissolved in a mixture of at least 50% by volume tertiary-butanol in water, the mixture is lyophilized, the resulting lyophilized product is packaged in one vial with a sufficient amount of solvent comprising anhydrous ethanol and a suitable nonionic surfactant in a second vial. All steps are carried out with protection from light. In use, the contents of the second or diluent vial are added to the lyophilized product and mixed to constitute the epothilone analog and the resulting solution is diluted with a suitable diluent to produce a solution for intravenous injection containing the epothilone analog in a concentration of from about 0.1 mg/mL to about 0.9 mg/mL. A preferred surfactant is polyethoxylated castor oil and a preferred diluent is Lactated Ringer's Injection.

主权项

1. A process for formulating, for parenteral administration, an epothilone analog represented by formula I:wherein:
Q is selected from the group consisting of: M is selected from the group consisting of oxygen, sulfur, NR8, and CR9R10; each R1, R2, R3, R4, R5, R7, R11, R12, R13, R14 and R15 is, independently, selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl and heterocyclo, and wherein 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, R11C═O, R12OC═O and R13SO2; and each R9 and R10 is, independently, selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, R14C═O, and R15OC═O;and any salts, solvates, or hydrates thereof, comprising the following steps carried out under protection from light:
a) dissolving said epothilone analog in a mixture of at least about 50% by volume tertiary-butanol in water to form a solution; b) performing primary drying of said solution at a temperature of from about −10° C. to about −40° C. under high vacuum of from about 50 millitorr to about 300 millitorr for from about 24 hours to about 96 hours to form a lyophilized product; c) performing secondary drying of the resultant lyophilized product at a temperature of from about 10° C. to about 30° C. under high vacuum of from about 50 millitorr to about 300 millitorr for from 24 hours to about 96 hours; and d) packaging said lyophilized product in a first vial in combination with a second vial containing a sufficient quantity of an equal mixture by volume of a suitable nonionic surfactant and anhydrous ethanol to effect solution thereof.