Injectable composition

Abstract

A pharmaceutical formulation of paclitaxel and polyethoxylated castor oil is disclosed to be relatively acidified to a pH of less than 8.1 and preferably within a pH range of 5 to 7, inclusively. Ethanol is optionally included in the formulation which is adapted for use in a body for the treatment of cancer. A formulation method is disclosed and includes the step of mixing an acid with a carrier material, such as polyethoxylated castor oil, to form a carrier solution after which paclitaxel is added in an amount such that the resulting pH is less than 8.1 and preferably in a pH range of 5 to 7. Ethanol may optionally be slurried with the paclitaxel before mixing with the carrier solution. A variety of acidifying agents, a preferred one being anhydrous citric acid, are described.

I claim:  
     
         1 . A method for formulating a pharmaceutical paclitaxel composition such that the paclitaxel does not readily degrade, comprising the steps of: 
 mixing an acid with a carrier material to form a first carrier composition; and    mixing paclitaxel with said first carrier composition to form a pharmaceutical paclitaxel composition, such that said pharmaceutical paclitaxel composition retains at least 96.6% of the original paclitaxel potency when said pharmaceutical paclitaxel composition is stored at 40° C. for seven days.    
     
     
         2 . The method of  claim 1 , wherein said first carrier composition comprises polyethoxylated castor oil.  
     
     
         3 . The method of  claim 2 , wherein said first carrier composition further comprises ethanol.  
     
     
         4 . The method of  claim 1 , wherein said acid is an organic acid.  
     
     
         5 . The method of  claim 1 , wherein said acid is a mineral acid.  
     
     
         6 . The method of  claim 4 , wherein said acid is acetic acid.  
     
     
         7 . The method of  claim 4 , wherein said acid is citric acid.  
     
     
         8 . The method of  claim 7 , wherein said citric acid is anhydrous.  
     
     
         9 . The method of  claim 7 , wherein said citric acid is monohydrous.  
     
     
         10 . The method of  claim 7 , wherein said citric acid is hydrous.  
     
     
         11 . The method of  claim 2 , wherein said acid is an organic acid.  
     
     
         12 . The method of  claim 2 , wherein said acid is a mineral acid.  
     
     
         13 . The method of  claim 11 , wherein said acid is acetic acid.  
     
     
         14 . The method of  claim 11 , wherein said acid is citric acid.  
     
     
         15 . The method of  claim 14 , wherein said citric acid is anhydrous.  
     
     
         16 . The method of  claim 14 , wherein said citric acid is monohydrous.  
     
     
         17 . The method of  claim 14 , wherein said citric acid is hydrous.  
     
     
         18 . The method of  claim 3 , wherein said acid is an organic acid.  
     
     
         19 . The method of  claim 3 , wherein said acid is a mineral acid.  
     
     
         20 . The method of  claim 18 , wherein said acid is acetic acid.  
     
     
         21 . The method of  claim 18 , wherein said acid is citric acid.  
     
     
         22 . The method of  claim 21 , wherein said citric acid is anhydrous.  
     
     
         23 . The method of  claim 21 , wherein said citric acid is monohydrous.  
     
     
         24 . The method of  claim 21 , wherein said citric acid is hydrous.  
     
     
         25 . A method for formulating a pharmaceutical paclitaxel composition such that the paclitaxel does not readily degrade, comprising the steps of: 
 mixing an acid with a carrier material to form a first carrier composition; and    mixing paclitaxel with said first carrier composition to form a pharmaceutical paclitaxel composition, such that said pharmaceutical paclitaxel composition comprises no more than 2.3% total impurities when stored at 40° C. for seven days.    
     
     
         26 . The method of  claim 25 , wherein said first carrier composition comprises polyethoxylated castor oil.  
     
     
         27 . The method of  claim 26 , wherein said first carrier composition further comprises ethanol.  
     
     
         28 . The method of  claim 25 , wherein said acid is an organic acid.  
     
     
         29 . The method of  claim 25 , wherein said acid is a mineral acid.  
     
     
         30 . The method of  claim 28 , wherein said acid is acetic acid.  
     
     
         31 . The method of  claim 28 , wherein said acid is citric acid.  
     
     
         32 . The method of  claim 31 , wherein said citric acid is anhydrous.  
     
     
         33 . The method of  claim 31 , wherein said citric acid is monohydrous.  
     
     
         34 . The method of  claim 31 , wherein said citric acid is hydrous.  
     
     
         35 . The method of  claim 26 , wherein said acid is an organic acid.  
     
     
         36 . The method of  claim 26 , wherein said acid is a mineral acid.  
     
     
         37 . The method of  claim 35  wherein said acid is acetic acid.  
     
     
         38 . The method of  claim 35 , wherein said acid is citric acid.  
     
     
         39 . The method of  claim 38 , wherein said citric acid is anhydrous.  
     
     
         40 . The method of  claim 38 , wherein said citric acid is monohydrous.  
     
     
         41 . The method of  claim 38 , wherein said citric acid is hydrous.  
     
     
         42 . The method of  claim 27 , wherein said acid is an organic acid.  
     
     
         43 . The method of  claim 27 , wherein said acid is a mineral acid.  
     
     
         44 . The method of  claim 42 , wherein said acid is acetic acid.  
     
     
         45 . The method of  claim 42 , wherein said acid is citric acid.  
     
     
         46 . The method of  claim 45 , wherein said citric acid is anhydrous.  
     
     
         47 . The method of  claim 45 , wherein said citric acid is monohydrous.  
     
     
         48 . The method of  claim 45 , wherein said citric acid is hydrous.  
     
     
         49 . A method of making an article of manufacture comprising a sealed container and a pharmaceutical paclitaxel formulation contained therein, said method comprising the steps of: 
 (a) obtaining a sealable container;    (b) obtaining a pharmaceutical formulation comprising paclitaxel, a pharmaceutically-acceptable carrier, and an acid; said formulation being such that at least 96.6% of the paclitaxel potency is retained when the formulation is stored at 40° C. for seven days;    (c) placing said pharmaceutical formulation in said sealable container;    (d) sealing said sealable container; and    (e) storing said pharmaceutical formulation in said sealed container for at least seven days.    
     
     
         50 . The method of  claim 49 , wherein said first carrier composition comprises polyethoxylated castor oil.  
     
     
         51 . The method of  claim 50 , wherein said first carrier composition further comprises ethanol.  
     
     
         52 . The method of  claim 49 , wherein said acid is an organic acid.  
     
     
         53 . The method of  claim 49 , wherein said acid is a mineral acid.  
     
     
         54 . The method of  claim 52 , wherein said acid is acetic acid.  
     
     
         55 . The method of  claim 52 , wherein said acid is citric acid.  
     
     
         56 . The method of  claim 55 , wherein said citric acid is anhydrous.  
     
     
         57 . The method of  claim 55 , wherein said citric acid is monohydrous.  
     
     
         58 . The method of  claim 55 , wherein said citric acid is hydrous.  
     
     
         59 . The method of  claim 50 , wherein said acid is an organic acid.  
     
     
         60 . The method of  claim 50 , wherein said acid is a mineral acid.  
     
     
         61 . The method of  claim 59 , wherein said acid is acetic acid.  
     
     
         62 . The method of  claim 59 , wherein said acid is citric acid.  
     
     
         63 . The method of  claim 62 , wherein said citric acid is anhydrous.  
     
     
         64 . The method of  claim 62 , wherein said citric acid is monohydrous.  
     
     
         65 . The method of  claim 62 , wherein said citric acid is hydrous.  
     
     
         66 . The method of  claim 51 , wherein said acid is an organic acid.  
     
     
         67 . The method of  claim 51 , wherein said acid is a mineral acid.  
     
     
         68 . The method of  claim 66 , wherein said acid is acetic acid.  
     
     
         69 . The method of  claim 66 , wherein said acid is citric acid.  
     
     
         70 . The method of  claim 69 , wherein said citric acid is anhydrous.  
     
     
         71 . The method of  claim 69 , wherein said citric acid is monohydrous.  
     
     
         72 . The method of  claim 69 , wherein said citric acid is hydrous.  
     
     
         73 . A method of making an article of manufacture comprising a sealed container and a pharmaceutical paclitaxel formulation contained therein, said method comprising the steps of: 
 (a) obtaining a sealable container;    (b) obtaining a pharmaceutical formulation comprising paclitaxel, a pharmaceutically-acceptable carrier, and an acid; said formulation being such that the formulation comprises no more than 2.3% total impurities when said formulation is stored at 40° C. for seven days;    (c) placing said pharmaceutical formulation in said sealable container;    (d) sealing said sealable container; and    (e) storing said pharmaceutical formulation in said sealed container for at least seven days.    
     
     
         74 . The method of  claim 73 , wherein said first carrier composition comprises polyethoxylated castor oil.  
     
     
         75 . The method of  claim 74 , wherein said first carrier composition further comprises ethanol.  
     
     
         76 . The method of  claim 73 , wherein said acid is an organic acid.  
     
     
         77 . The method of  claim 73 , wherein said acid is a mineral acid.  
     
     
         78 . The method of  claim 76 , wherein said acid is acetic acid.  
     
     
         79 . The method of  claim 76 , wherein said acid is citric acid.  
     
     
         80 . The method of  claim 79 , wherein said citric acid is anhydrous.  
     
     
         81 . The method of  claim 79 , wherein said citric acid is monohydrous.  
     
     
         82 . The method of  claim 79 , wherein said citric acid is hydrous.  
     
     
         83 . The method of  claim 74 , wherein said acid is an organic acid.  
     
     
         84 . The method of  claim 74 , wherein said acid is a mineral acid.  
     
     
         85 . The method of  claim 83 , wherein said acid is acetic acid.  
     
     
         86 . The method of  claim 83 , wherein said acid is citric acid.  
     
     
         87 . The method of  claim 86 , wherein said citric acid is anhydrous.  
     
     
         88 . The method of  claim 86 , wherein said citric acid is monohydrous.  
     
     
         89 . The method of  claim 86 , wherein said citric acid is hydrous.  
     
     
         90 . The method of  claim 75 , wherein said acid is an organic acid.  
     
     
         91 . The method of  claim 75 , wherein said acid is a mineral acid.  
     
     
         92 . The method of  claim 90 , wherein said acid is acetic acid.  
     
     
         93 . The method of  claim 90 , wherein said acid is citric acid.  
     
     
         94 . The method of  claim 93 , wherein said citric acid is anhydrous.  
     
     
         95 . The method of  claim 93 , wherein said citric acid is monohydrous.  
     
     
         96 . The method of  claim 93 , wherein said citric acid is hydrous.  
     
     
         97 . A method for formulating a pharmaceutical paclitaxel composition such that the paclitaxel does not readily degrade, comprising 
 obtaining a composition consisting essentially of paclitaxel, polyethoxylated castor oil, ethanol, and an acid, said acid being in sufficient amount such that the paclitaxel stability of said composition is improved as compared to the paclitaxel stability of an identical composition without said acid; and    sealing said acid-containing paclitaxel composition in a container, wherein said pharmaceutical acid-containing paclitaxel composition retains at least 97.5% of the original paclitaxel potency when stored at 40° C. for 7 days.    
     
     
         98 . The method of  claim 97 , wherein said acid is an organic acid.  
     
     
         99 . The method of  claim 97 , wherein said acid is a mineral acid.  
     
     
         100 . The method of  claim 98 , wherein said acid is acetic acid.  
     
     
         101 . The method of  claim 98 , wherein said acid is citric acid.  
     
     
         102 . The method of  claim 101 , wherein said citric acid is anhydrous.  
     
     
         103 . The method of  claim 101 , wherein said citric acid is monohydrous.  
     
     
         104 . The method of  claim 101 , wherein said citric acid is hydrous.