Method for preparing and using polyoxyethylated castor oil in pharmaceutical compositions

Abstract

A method is provided for preparing a pharmaceutical composition comprising: taking polyoxyethylated castor oil which if diluted 1:10 in water has a pH greater than 5 and aging the polyoxyethylated castor oil by exposing the polyoxyethylated castor oil to a gas comprising oxygen for a period of time, the exposure to the gas over the period of time causing an acidity of the polyoxyethylated castor oil to increase; and forming a pharmaceutical composition comprising the aged polyoxyethylated castor oil and a pharmaceutically active agent such as paclitaxel; wherein at least 80% of the potency of the pharmaceutically active agent is retained by the pharmaceutical composition after the pharmaceutical composition is stored for at least 7 days at 40° C.

What is claimed is:  
     
         1 . A method for preparing a pharmaceutical composition comprising: 
 taking polyoxyethylated castor oil which if diluted 1:10 in water has a pH greater than 6 and aging the polyoxyethylated castor oil by exposing the polyoxyethylated castor oil to a gas comprising oxygen for a period of time, the exposure to the gas over the period of time causing an acidity of the polyoxyethylated castor oil to increase; and    forming a pharmaceutical composition comprising the aged polyoxyethylated castor oil and paclitaxel;    wherein at least 80% of the paclitaxel potency is retained by the pharmaceutical composition after the pharmaceutical composition is stored for at least 7 days at 40° C.    
     
     
         2 . The method according to  claim 1 , further comprising adding an antioxidant to the aged polyoxyethylated castor oil.  
     
     
         3 . The method according to  claim 1 , further comprising adding a pharmaceutically acceptable alcohol to the aged polyoxyethylated castor oil.  
     
     
         4 . The method according to  claim 3 , wherein the pharmaceutically acceptable alcohol is ethanol.  
     
     
         5 . The method according to  claim 1 , further comprising adding a pharmaceutically acceptable glycol to the aged polyoxyethylated castor oil.  
     
     
         6 . The method according to  claim 5 , wherein the pharmaceutically acceptable glycol is propylene glycol or polyethylene glycol.  
     
     
         7 . The method according to  claim 1 , further comprising adding an antioxidant to the pharmaceutical composition.  
     
     
         8 . The method according to  claim 7 , wherein the antioxidant is vitamin E, vitamin C or their derivatives.  
     
     
         9 . The method according to  claim 7 , further comprising adding a pharmaceutically acceptable alcohol to the aged polyoxyethylated castor oil.  
     
     
         10 . The method according to  claim 1 , wherein aging the polyoxyethylated castor oil is performed for at least 30 minutes at a temperature range between 0° C. and 70° C.  
     
     
         11 . The method according to  claim 1 , wherein aging the polyoxyethylated castor oil is performed for at least 30 minutes at a temperature range between 30° C. and 70° C.  
     
     
         12 . The method according to  claim 1 , wherein aging the polyoxyethylated castor oil is performed for at least 30 minutes at a temperature range between 40° C. and 60° C.  
     
     
         13 . The method according to  claim 1 , wherein aging the polyoxyethylated castor oil is performed for at least 7 days at a temperature range between 40° C. and 60° C.  
     
     
         14 . The method according to  claim 1 , wherein aging the polyoxyethylated castor oil is performed for at least 30 minutes at a temperature range between 0° C. and 70° C. by sparging the polyoxyethylated castor oil with air.  
     
     
         15 . The method according to  claim 1 , wherein aging the polyoxyethylated castor oil is performed for at least 30 minutes at a temperature range between 40° C. and 60° C. by sparging the polyoxyethylated castor oil with air.  
     
     
         16 . The method according to  claim 1 , wherein aging the polyoxyethylated castor oil is performed for at least 30 minutes at a temperature range between 0° C. and 70° C. by pressurizing the polyoxyethylated castor oil to be at least 1.5 atmospheric pressure.  
     
     
         17 . The method according to  claim 1 , wherein aging the polyoxyethylated castor oil is performed for at least 30 minutes at a temperature range between 0° C. and 70° C. by pressurizing the polyoxyethylated castor oil to be at least 1.5 atmospheric pressure.  
     
     
         18 . The method according to  claim 1 , wherein at least 90% of the paclitaxel potency is retained by the pharmaceutical composition after the pharmaceutical composition is stored for at least 7 days at 40° C.  
     
     
         19 . The method according to  claim 1 , wherein at least 95% of the paclitaxel potency is retained by the pharmaceutical composition after the pharmaceutical composition is stored for at least 7 days at 40° C.  
     
     
         20 . The method according to  claim 1 , wherein the polyoxyethylated castor oil is selected from the group consisting of: Cremophor® EL and Cremophor® ELP.  
     
     
         21 . A method for preparing a pharmaceutical composition of paclitaxel comprising: 
 taking polyoxyethylated castor oil which if diluted 1:10 in water has a pH greater than 6 and aging the polyoxyethylated castor oil by exposing the polyoxyethylated castor oil to a gas comprising oxygen until the aged polyoxyethylated castor oil, if diluted 1:10 in water, has a pH equal to or less than 5.9; and    forming a pharmaceutical composition comprising the aged polyoxyethylated castor oil and paclitaxel.    
     
     
         22 . The method according to  claim 21 , wherein aging the polyoxyethylated castor oil is performed until the aged polyoxyethylated castor oil, if diluted 1:10 in water, has a pH less than or equal to 5.5.  
     
     
         23 . The method according to  claim 21 , wherein aging the polyoxyethylated castor oil is performed until the aged polyoxyethylated castor oil, if diluted 1:10 in water, has a pH less than or equal to 5.  
     
     
         24 . The method according to  claim 21 , wherein aging the polyoxyethylated castor oil is performed until the aged polyoxyethylated castor oil, if diluted 1:10 in water, has a pH equal to or less than 4.8.  
     
     
         25 . The method according to  claim 21 , wherein aging the polyoxyethylated castor oil is performed until the aged polyoxyethylated castor oil, if diluted 1:10 in water, has a pH between 3.7 and 5.9.  
     
     
         26 . The method according to  claim 21 , wherein aging the polyoxyethylated castor oil is performed until the aged polyoxyethylated castor oil, if diluted 1:10 in water, has a pH between 3.8 and 5.5.  
     
     
         27 . The method according to  claim 21 , wherein aging the polyoxyethylated castor oil is performed until the aged polyoxyethylated castor oil, if diluted 1:10 in water, has a pH between 3.9 and 5.  
     
     
         28 . The method according to  claim 21 , wherein aging the polyoxyethylated castor oil is performed until the aged polyoxyethylated castor oil, if diluted 1:10 in water, has a pH between 4 and 4.8.  
     
     
         29 . The method according to  claim 21 , further comprising adding an antioxidant to the aged polyoxyethylated castor oil.  
     
     
         30 . The method according to  claim 21 , further comprising adding a pharmaceutically acceptable alcohol to the aged polyoxyethylated castor oil.  
     
     
         31 . The method according to  claim 21 , wherein aging the polyoxyethylated castor oil is performed for at least 30 minutes at a temperature range between 0 and 70° C.  
     
     
         32 . The method according to  claim 21 , wherein at least 80% of the paclitaxel potency is retained by the pharmaceutical composition after the pharmaceutical composition is stored for at least 7 days at 40° C.  
     
     
         33 . The method according to  claim 21 , wherein at least 90% of the paclitaxel potency is retained by the pharmaceutical composition after the pharmaceutical composition is stored for at least 7 days at 40° C.  
     
     
         34 . The method according to  claim 21 , wherein at least 95% of the paclitaxel potency is retained by the pharmaceutical composition after the pharmaceutical composition is stored for at least 7 days at 40° C.  
     
     
         35 . The method according to  claim 21 , wherein aging causes the pH of the polyoxyethylated castor oil, if diluted 1:10 in water, to decrease without requiring an agent to be added that functions to increase the acidity of the polyoxyethylated castor oil.  
     
     
         36 . The method according to  claim 21 , wherein the polyoxyethylated castor oil is selected from the group consisting of: Cremophor® EL and Cremophor® ELP.  
     
     
         37 . A method for preparing a pharmaceutical composition comprising: 
 taking polyoxyethylated castor oil which if diluted 1:10 in water has a pH greater than 6 and aging the polyoxyethylated castor oil by exposing the polyoxyethylated castor oil to a gas comprising oxygen for a period of time, the exposure to the gas over the period of time causing an acidity of the polyoxyethylated castor oil to increase; and    forming a pharmaceutical composition comprising the aged polyoxyethylated castor oil, ethanol and paclitaxel;    wherein at least 80% of the paclitaxel potency is retained by the pharmaceutical composition after the pharmaceutical composition is stored for at least 7 days at 40° C.    
     
     
         38 . The method according to  claim 37 , wherein at least 80% of the paclitaxel potency is retained by the pharmaceutical composition after the pharmaceutical composition is stored for at least 7 days at 40° C.  
     
     
         39 . The method according to  claim 37 , wherein at least 90% of the paclitaxel potency is retained by the pharmaceutical composition after the pharmaceutical composition is stored for at least 7 days at 40° C.  
     
     
         40 . The method according to  claim 37 , wherein at least 95% of the paclitaxel potency is retained by the pharmaceutical composition after the pharmaceutical composition is stored for at least 7 days at 40° C.  
     
     
         41 . The method according to  claim 37 , wherein the pharmaceutical composition comprises 500-550 mg/mL of polyoxyethylated castor oil, and 40-60% of ethanol vol/vol.  
     
     
         42 . The method according to  claim 37 , wherein the pharmaceutical composition comprises 527 mg/mL of polyoxyethylated castor oil, and 49.7% of ethanol vol/vol.  
     
     
         43 . A method for preparing a pharmaceutical composition of paclitaxel comprising: 
 taking polyoxyethylated castor oil which if diluted 1:10 in water has a pH greater than 5 and aging the polyoxyethylated castor oil by exposing the polyoxyethylated castor oil to a gas comprising oxygen until the aged polyoxyethylated castor oil, if diluted 1:10 in water, has a pH equal to or less than 4.9; and    forming a pharmaceutical composition comprising the aged polyoxyethylated castor oil, ethanol and paclitaxel;    wherein at least 80% of the paclitaxel potency is retained by the pharmaceutical composition after the pharmaceutical composition is stored for at least 7 days at 40° C.    
     
     
         44 . The method according to  claim 43 , wherein aging the polyoxyethylated castor oil is performed until the aged polyoxyethylated castor oil, if diluted 1:10 in water, has a pH equal to or less than 4.7.  
     
     
         45 . The method according to  claim 43 , wherein aging the polyoxyethylated castor oil is performed until the aged polyoxyethylated castor oil, if diluted 1:10 in water, has a pH between 3.7 and 4.9.  
     
     
         46 . The method according to  claim 43 , wherein aging the polyoxyethylated castor oil is performed until the aged polyoxyethylated castor oil, if diluted 1:10 in water, has a pH between 3.9 and 4.3.  
     
     
         47 . The method according to  claim 43 , wherein at least 90% of the paclitaxel potency is retained by the pharmaceutical composition after the pharmaceutical composition is stored for at least 7 days at 40° C.  
     
     
         48 . The method according to  claim 43 , wherein at least 95% of the paclitaxel potency is retained by the pharmaceutical composition after the pharmaceutical composition is stored for at least 7 days at 40° C.  
     
     
         49 . The method according to  claim 43 , wherein the pharmaceutical composition comprises 500-550 mg/mL of polyoxyethylated castor oil, and 40-60% of ethanol vol/vol.  
     
     
         50 . The method according to  claim 43 , wherein the pharmaceutical composition comprises 527 mg/mL of polyoxyethylated castor oil, and 49.7% of ethanol vol/vol.  
     
     
         51 . A pharmaceutical composition comprising: 
 polyoxyethylated castor oil that has been modified by taking polyoxyethylated castor oil which if diluted 1:10 in water has a pH greater than 6 and aging the polyoxyethylated castor oil by exposing the polyoxyethylated castor oil to a gas comprising oxygen until the aged polyoxyethylated castor oil, if diluted 1:10 in water, has a pH equal to or less than 5.9; and    paclitaxel;    wherein the pharmaceutical composition does not comprise an agent added to the polyoxyethylated castor oil that functions to increase the acidity of the polyoxyethylated castor oil.    
     
     
         52 . The pharmaceutical composition according to  claim 51 , wherein at least 80% of the paclitaxel potency is retained by the pharmaceutical composition after the pharmaceutical composition is stored for at least 7 days at 40° C.  
     
     
         53 . The pharmaceutical composition according to  claim 51 , wherein at least 90% of the paclitaxel potency is retained by the pharmaceutical composition after the pharmaceutical composition is stored for at least 7 days at 40° C.  
     
     
         54 . The pharmaceutical composition according to  claim 51 , wherein at least 95% of the paclitaxel potency is retained by the pharmaceutical composition after the pharmaceutical composition is stored for at least 7 days at 40° C.  
     
     
         55 . The pharmaceutical composition according to  claim 51 , wherein the pharmaceutical composition further comprises ethanol.  
     
     
         56 . The pharmaceutical composition according to  claim 55 , wherein the pharmaceutical composition comprises 500-550 mg/mL of polyoxyethylated castor oil, and 40-60% of ethanol vol/vol.  
     
     
         57 . The pharmaceutical composition according to  claim 55 , wherein the pharmaceutical composition comprises 527 mg/mL of polyoxyethylated castor oil, and 49.7% of ethanol vol/vol.  
     
     
         58 . A pharmaceutical composition comprising: 
 polyoxyethylated castor oil that has been modified by taking polyoxyethylated castor oil which if diluted 1:10 in water has a pH greater than 5 and aging the polyoxyethylated castor oil by exposing the polyoxyethylated castor oil to a gas comprising oxygen until the aged polyoxyethylated castor oil, if diluted 1:10 in water, has a pH equal to or less than 4.9; and    paclitaxel;    wherein at least 80% of the paclitaxel potency is retained by the pharmaceutical composition after the pharmaceutical composition is stored for at least 7 days at 40° C.    
     
     
         59 . The pharmaceutical composition according to  claim 58 , wherein at least 90% of the paclitaxel potency is retained by the pharmaceutical composition after the pharmaceutical composition is stored for at least 7 days at 40° C.  
     
     
         60 . The pharmaceutical composition according to  claim 58 , wherein at least 95% of the paclitaxel potency is retained by the pharmaceutical composition after the pharmaceutical composition is stored for at least 7 days at 40° C.  
     
     
         61 . The pharmaceutical composition according to  claim 58 , wherein the pharmaceutical composition further comprises ethanol.  
     
     
         62 . The pharmaceutical composition according to  claim 61 , wherein the pharmaceutical composition comprises 500-550 mg/mL of polyoxyethylated castor oil, and 40-60% of ethanol vol/vol.  
     
     
         63 . The pharmaceutical composition according to  claim 61 , wherein the pharmaceutical composition comprises 527 mg/mL of polyoxyethylated castor oil, and 49.7% of ethanol vol/vol.  
     
     
         64 . The pharmaceutical according to  claim 61 , wherein the concentration of paclitaxel in the pharmaceutical composition is about 1-20 mg/g.  
     
     
         65 . A pharmaceutical comprising: 
 a sealed vial comprising: 
 polyoxyethylated castor oil that has been modified by taking polyoxyethylated castor oil which if diluted 1:10 in water has a pH greater than 6 and aging the polyoxyethylated castor oil by exposing the polyoxyethylated castor oil to a gas comprising oxygen until the aged polyoxyethylated castor oil, if diluted 1:10 in water, has a pH equal to or less than 5.9; and  
 paclitaxel;  
 wherein the pharmaceutical does not comprise an agent added to the polyoxyethylated castor oil that functions to increase the acidity of the polyoxyethylated castor oil.  
   
     
     
         66 . The pharmaceutical according to  claim 65 , wherein the vial further comprises ethanol.  
     
     
         67 . A pharmaceutical comprising: 
 a sealed vial comprising 
 polyoxyethylated castor oil that has been modified by taking polyoxyethylated castor oil which if diluted 1:10 in water has a pH greater than 6 and aging the polyoxyethylated castor oil by exposing the polyoxyethylated castor oil to a gas comprising oxygen until the aged polyoxyethylated castor oil, if diluted 1:10 in water, has a pH equal to or less than 5.9; and  
 paclitaxel;  
 wherein at least 80% of the paclitaxel potency is retained by the pharmaceutical after the pharmaceutical is stored for at least 7 days at 40° C.  
   
     
     
         68 . The pharmaceutical according to  claim 67 , wherein the vial further comprises ethanol.  
     
     
         69 . A pharmaceutical comprising: 
 a sealed vial comprising 
 polyoxyethylated castor oil that has been modified by taking polyoxyethylated castor oil which if diluted 1:10 in water has a pH greater than 5 and aging the polyoxyethylated castor oil by exposing the polyoxyethylated castor oil to a gas comprising oxygen until the aged polyoxyethylated castor oil, if diluted 1:10 in water, has a pH equal to or less than 4.9; and  
 paclitaxel;  
 wherein at least 80% of the paclitaxel potency is retained by the pharmaceutical after the pharmaceutical is stored for at least 7 days at 40° C.  
   
     
     
         70 . The pharmaceutical according to  claim 69 , wherein the vial further comprises ethanol.