Stable pharmaceutical composition of clopidogrel free base for oral and parenteral delivery

Abstract

The present disclosure provides ready-to-use, oil/water emulsion compositions with mean droplet size (intensity-average, nm) of 100-500 nm, where the oil phase comprises clopidogrel free base dispersed in pharmaceutical acceptable oil(s). The emulsion uses clopidogrel free base or premix of clopidogrel free base in oil(s) as the starting materials and may also contain one or more excipients such as surfactant and or co-surfactant, osmotic agent, pH adjustment agent, antioxidant, preservative, sweetener, and/or suspending agent, etc.

What is claimed is: 
     
         1 . A method to make a stable pharmaceutical oil/water emulsion composition with nanosized oil droplets for parenteral or oral administration, said method comprising the steps of:
 a) preparing an oil phase comprising clopidogrel by dispersing clopidogrel free base in an oil carrier;   b) preparing an aqueous phase comprising water and a pH adjustment agent;   c) incorporating a surfactant or optionally a co-surfactant in the oil phase or in the aqueous phase;   d) dispersing the oil phase in the aqueous phase to form a coarse emulsion and adjusting pH to about 9;   e) forming a final emulsion by sonicating or high pressure homogenizing the emulsion of step d), and adjusting pH to between 5.5 and 10;   f) filtrating the final emulsion; and   g) controlling product bioburden or sterility by aseptic process or terminal sterilization.   
     
     
         2 . The method of  claim 1 , wherein clopidogrel free base is obtained by converting clopidogrel salt to free base and separating counter ion from the free base. 
     
     
         3 . The method of  claim 1 , wherein clopidogrel free base is provided as a free base-oil carrier premix. 
     
     
         4 . The method of  claim 1 , wherein the oil carrier is soy bean oil, fish oil, medium chain triglycerides, olive oil, or mixture of them thereof, and the surfactant is egg lecithin. 
     
     
         5 . The method of  claim 1 , wherein the pH in step e) is adjusted to between 7 and 10. 
     
     
         6 . A method to treat a patient in need of a single highdose of clopidogrel, said method comprising:
 a) providing in a liquid form of a pharmaceutical oil/water emulsion composition prepared by dispersing clopidogrel free base in an oil carrier; preparing an aqueous phase comprising water and an pH adjustment agent; dispersing the oil phase into the aqueous phase by sonicating or homogenizing to form nanosized oil droplets; and   b) administering orally or parenterally a single dose of the composition, wherein the single dose contains up to 300 mg of clopidogrel free base.   
     
     
         7 . The method of  claim 6 , wherein the single dose of the composition contains no more no more than 1.2% of impurity A, no more than 1.5% of impurity C. 
     
     
         8 . The method of  claim 6 , wherein in step a) pH of the composition is adjusted to between 7 and 10.