Process and formulation containing epothilones and analogs thereof

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.

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:  
       
         
           
           
               
               
           
         
       
       wherein, 
 Q is selected from the group consisting of:  
                     
 W is selected from —O— and —N(R 16 )—;  
 M is selected from the group consisting of oxygen, sulfur, —N(R 8 )—, and —C(R 9 R 10 )—;  
 each R 1 , R 2 , R 3 , R 4 , R 5 , and R 7  is, independently, selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and heterocyclo, and wherein when R 1  and R 2  are alkyl, they can be joined to form cycloalkyl;  
 R 6  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo, and substituted heterocyclo;  
 R 8  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, —C(═O)R 11 , —C(═O)OR 2 , and —S(O 2 )R 13 ;  
 R 9  and R 10  are each independently selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, —C(═O)R 14 , and —C(═O)OR 15 ; and  
 each R 11 , R 12 , R 3 , R 14 , R 15 , and R 16  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 pharmaceutical preparation comprising a surfactant, a solvent, a buffer, and a pH-adjusting ingredient, wherein the buffer and the pH-adjusting ingredient are selected so that when the pharmaceutical preparation is added to the infusion fluid to provide the formulation for administration, the pH differential is reduced.  
 
     
     
         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 (PtO 2 ), potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), potassium carbonate (K 2 CO 3 ), magnesium hydroxide (Mg(OH) 2 ), calcium hydroxide (Ca(OH) 2 ), and sodium bicarbonate (NaHCO 3 ).  
     
     
         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,  
       
         
           
           
               
               
           
         
       
       wherein, 
 Q is selected from the group consisting of:  
                     
 W is selected from —O— and —N(R 16 )—;  
 M is selected from the group consisting of oxygen, sulfur, —N(R 8 )—, and —C(R 9 R 0 )—;  
 each R 1 , R 2 , R 3 , R 4 , R 5 , and R 7  is, independently, selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and heterocyclo, and wherein when R 1  and R 2  are alkyl, they can be joined to form cycloalkyl;  
 R 6  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo, and substituted heterocyclo;  
 R 8  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, —C(═O)R 11 , —C(═O)OR 12 , and —S(O 2 )R 13 ;  
 R 9  and R 10  are each independently selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, —C(═O)R 14 , and —C(═O)OR 15 ; and  
 each R 11 , R 12 , R 13 , R 14 , R 15 , and R 16  is, independently, selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and heterocyclo;  
 wherein the compound of formula I has a pH of maximum stability that is different from the infusion fluid pH, to define a pH differential;  
 the process comprising dissolving the compound of formula I in a first, solution vehicle to provide an epothilone solution, wherein the solution vehicle includes at least one buffer and at least one pH-adjusting ingredient, the buffer and pH-adjusting ingredient being selected so that, when the epothilone solution is mixed with the infusion fluid to provide the formulation for administration, the difference between the pH of the formulation for administration and the pH of maximum stability for the compound is less than the pH differential.  
 
     
     
         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 (PtO 2 ), potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), potassium carbonate (K 2 CO 3 ), magnesium hydroxide (Mg(OH) 2 ), calcium hydroxide (Ca(OH) 2 ), and sodium bicarbonate (NaHCO 3 ).  
     
     
         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(R 16 )—;    M is selected from the group consisting of oxygen, sulfur, —N(R 8 )—, and —C(R 9 R 10 )—;    each R 1 , R 2 , R 3 , R 4 , R 5 , and R 7  is, independently, selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and heterocyclo, and wherein when R 1  and R 2  are alkyl, they can be joined to form cycloalkyl;    R 6  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo, and substituted heterocyclo;    R 8  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, —C(═O)R 11 , —C(═O)OR 12 , and —S(O 2 )R 13 ;    R 9  and R 10  are each independently selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, —C(═O)R 14 , and —C(═O)OR 15 ; and    each R 11 , R 12 , R 13 , R 14 , R 15 , and R 16  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.