Temozolomide powder formulation

Abstract

The present invention relates to a solid pharmaceutical composition of temozolomide that has good and consistent flowability as a powder and taste masking and is readily dispersible in an aqueous solution suitable for oral administration, e.g., as a dry sprinkle. This permits patients and healthcare workers to accurately measure doses and safely dispense the drug.

1 . A solid pharmaceutical composition that is readily dispersible in an aqueous solution suitable for oral administration, the composition comprising:
 (a) granules of temozolomide and one or more emulsifiers, the granules coated with a pH dependent coating composition comprising a pH dependent coating material; and   (b) a dispersant,   
       wherein at least 80% of the solid pharmaceutical composition dissolves within 30 minutes when tested according to USP I dissolution test (basket) in 900 mL of 0.1 N HCl at 37° C.±0.5° C. and a speed of 100 rpm. 
     
     
         2 . The composition of  claim 1 , wherein the emulsifiers are selected from sodium lauryl sulfate, poloxamer, saturated polyglycolized glyceride, labrasol, polysorbates, sorbitan esters, cremophor PEG-60 hydrogenated castor oil, PEG-40 hydrogenated castor oil, sodium lauryl glutamate, disodium cocoamphodiacetate, tyloxapol, lauroyl macrogol-6 glycerides, oleoyl macrogol-6 glycerides, linoleoyl macrogol-6 glycerides, propylene glycol monocaprylate, propylene glycol monocaprylate, propylene glycol monolaurate, polyglyceryl-3 dioleate, polyglyceryl-3 dioleate oleate, triglycerides medium-chain, propylene glycol dicaprylocaprate, diethylene glycol monoethyl ether, behenoyl polyoxyl-8 glycerides or PEGylated glyceryl behenate, glyceryl behenate, glyceryl dipalmitostearate, glyceryl behenate E471, diethylene glycol monoethyl ether, octylphenol ethoxylate, sodium deoxycholate, and a mixture of (i) refined soybean oil, (ii) glyceryl distearate and (iii) polyglyceryl-3 dioleate. 
     
     
         3 . The composition of  claim 1 , wherein the emulsifier is stearoyl macrogol-32 glycerides. 
     
     
         4 . The composition of  claim 1 , wherein the weight ratio of temozolomide and emulsifier is from about 1:1 to about 3:1. 
     
     
         5 . (canceled) 
     
     
         6 . The composition of  claim 1 , wherein the granules further comprise an adsorbent. 
     
     
         7 . The composition of  claim 6 , wherein the adsorbent is colloidal silicon dioxide. 
     
     
         8 . The composition of  claim 1 , wherein the composition is in the form of a powder. 
     
     
         9 - 13 . (canceled) 
     
     
         14 . The composition of  claim 8 , wherein the powder has a d 50  of no more than 420 microns. 
     
     
         15 - 22 . (canceled) 
     
     
         23 . The composition of  claim 1 , wherein the pH dependent coating composition is porous to water. 
     
     
         24 . The composition of  claim 1 , wherein the pH dependent coating material comprises an amino methacrylate copolymer. 
     
     
         25 - 28 . (canceled) 
     
     
         29 . The composition of  claim 1 , wherein the total organics content released from the composition according to the Spill Test is less than 200 ppm. 
     
     
         30 . The composition of  claim 1 , wherein the total organics content released from the composition according to the Spill Test is less than 150 ppm. 
     
     
         31 . The composition of  claim 1 , wherein the total organics content released from the composition according to the Spill Test is less than 100 ppm. 
     
     
         32 - 34 . (canceled) 
     
     
         35 . A temozolomide powder that is readily dispersible in an aqueous medium, the powder comprising:
 (a) granules comprising (i) from about 50 to about 75% by weight of temozolimide, (ii) from about 25 to about 50% by weight of emulsifier, and (iii) optionally, from about 0.1 to about 2.5% of an adsorbent, where the weight percentages are based on the total weight of the uncoated granules;   (b) a coating composition on the granules comprising (i) from about 40 to about 80% by weight of a pH-dependent coating material, (ii) from about 20 to about 60% by weight of glidant, and (iii) from about 0.1 to about 8% by weight of plasticizer, where the weight percentages are based on the total weight of the coating composition;   (d) from about 50 to about 75% by weight of dispersant;   (e) optionally, one or more of sweeteners, glidants, lubricants and flavours, based upon 100% total weight of temozolimide powder.   
     
     
         36 . A method of administering temozolomide to a patient in need thereof comprising orally administering to the patient a solution of the temozolomide powder of  claim 1 . 
     
     
         37 . The method of  claim 36 , wherein the patient suffers from glioblastoma or refractory anaplastic astrocytoma. 
     
     
         38 . A method of administering temozolomide to a patient in need thereof comprising orally administering to the patient the temozolomide powder of  claim 1  with a separate drink of water. 
     
     
         39 . A method of administering temozolomide to a patient in need thereof comprising orally administering to the patient a solution of the temozolomide powder of  claim 35 . 
     
     
         40 . The method of  claim 39 , wherein the patient suffers from glioblastoma or refractory anaplastic astrocytoma. 
     
     
         41 . A method of administering temozolomide to a patient in need thereof comprising orally administering to the patient the temozolomide powder of  claim 35  with a separate drink of water.