Taxane- and Taxoid-Protein Compositions

Abstract

Compositions comprising a taxane or taxoid, such as paclitaxel, and a protein, such as albumin or a metal-transferrin, such as gallium-transferrin, can be prepared by combining an aqueous protein solution with a second solution containing the taxane or taxoid, a non-ionic surfactant, and an alcohol; adjusting the pH of the combined solutions to between about 7.9 and about 8.3; and purifying the pH-adjusted solution to remove solutes having a molecular weight less than 10,000 Da. Such compositions can be prepared that are substantially free of non-ionic surfactants, such as Cremophor EL, and are useful in the treatment of cancers, such as breast cancer.

1 . A method for preparing a composition, comprising
 combining (A) a first aqueous solution comprising a protein; and (B) a second solution comprising (i) a taxane or taxoid; (ii) a non-ionic surfactant; and (iii) an alcohol, to provide a third aqueous solution;   adjusting the pH of the third aqueous solution to between about 7.9 and about 8.3; and   purifying the pH-adjusted third aqueous solution to remove solutes having a molecular weight less than 10,000 Da.   
     
     
         2 . The method of  claim 1 , wherein the protein is albumin, transferrin, metal-transferrin, prolactin, or an epidermal growth factor. 
     
     
         3 . The method of  claim 1 , wherein the protein is albumin. 
     
     
         4 . The method of  claim 1 , wherein the protein is metal-transferrin. 
     
     
         5 . The method of  claim 4 , wherein the metal-transferrin is gallium-transferrin, iron-transferrin, indium-transferrin, zinc-transferrin, manganese-transferrin, platinum-transferrin, or a mixture thereof. 
     
     
         6 . The method of  claim 1 , wherein the taxane or taxoid is paclitaxel, docetaxel, or mixtures thereof. 
     
     
         7 . The method of  claim 1 , wherein the non-ionic surfactant comprises ethoxylated castor oil. 
     
     
         8 . The method of  claim 1 , wherein the pH of the third solution is adjusted by adding a base. 
     
     
         9 . The method of  claim 8 , wherein the base is a hydroxide base. 
     
     
         10 . The method of  claim 9 , wherein the hydroxide base is sodium hydroxide, potassium hydroxide, lithium hydroxide, rubidium hydroxide, cesium hydroxide, calcium hydroxide, strontium hydroxide, barium hydroxide, or mixtures thereof. 
     
     
         11 . The method of  claim 1 , wherein pH-adjusted third solution is purified by dialysis against a buffer solution using a dialysis membrane having a molecular weight cutoff of 10,000 Da. 
     
     
         12 . The method of  claim 11 , wherein the buffer solution comprises Hank's Balanced Salt Solution. 
     
     
         13 . The method of  claim 11 , wherein the dialysis is repeated at least two times. 
     
     
         14 . The method of  claim 1 , wherein the purified pH-adjusted third solution is filter sterilized. 
     
     
         15 . (canceled) 
     
     
         16 . A composition comprising (i) a protein; (ii) a taxane or taxoid; and (iii) a pharmaceutically acceptable diluent, wherein the taxane or taxoid either (a) is bonded with the protein via a direct bond between the taxane or taxoid and the protein; or (b) forms a complex with the protein. 
     
     
         17 . The composition of  claim 16 , wherein the protein comprises albumin, transferrin, metal-transferrin, prolactin, or an epidermal growth factor. 
     
     
         18 . The composition of  claim 16 , wherein the protein comprises albumin. 
     
     
         19 . (canceled) 
     
     
         20 . The composition of  claim 16 , wherein the taxane or taxoid is paclitaxel or docetaxel. 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . The composition  claim 16 , wherein the taxane or taxoid is bonded with the albumin or metal-transferrin via a direct bond between the taxane or taxoid. 
     
     
         24 . The composition of  claim 16 , wherein the taxane or taxoid forms a complex with the albumin or metal-transferrin. 
     
     
         25 . A method for treating a cancer In a patient In need of such treatment comprising providing to the patient a therapeutically effective amount of a composition according to  claim 16 . 
     
     
         26 . The method of  claim 25 , wherein the cancer is a sarcoma, a lymphoma, a leukemia, a melanoma, a multiple myeloma, pancreatic cancer, esophageal cancer, bladder cancer, testicular cancer, thyroid cancer, brain cancer, gynecologic cancers, pediatric solid tumors, colorectal cancer, prostate cancer, liver cancer, renal cancer, gastric cancer, head and neck cancers, breast cancer, ovarian cancer, colon cancer, or lung cancer. 
     
     
         27 . The method of  claim 25 , wherein the cancer is breast cancer, ovarian cancer, colon cancer, or lung cancer.