Aqueous suspensions of tmc278

Abstract

This invention concerns pharmaceutical compositions for administration via intramuscular or subcutaneous injection, comprising micro- or nanoparticles of the NNRTI compound TMC278, suspended in an aqueous pharmaceutically acceptable carrier, and the use of such pharmaceutical compositions in the treatment and prophylaxis of HIV infection.

1 . A pharmaceutical composition for administration by intramuscular or subcutaneous injection, comprising a therapeutically effective amount of TMC278, a salt, a stereoisomer or a stereoisomeric mixture thereof, in the form of a suspension of micro- or nanoparticles comprising:
 (a) TMC278, a salt, a stereoisomer or a stereoisomeric mixture thereof, in micro- or nanoparticle form, having a surface modifier adsorbed to the surface thereof; and   (b) a pharmaceutically acceptable aqueous carrier; wherein the TMC278 active ingredient is suspended.   
   
   
       2 . A composition according to  claim 1  wherein the TMC278 is present as the E-isomer of the base form. 
   
   
       3 . A composition according to  claim 1 , wherein the surface modifier is selected from the group of poloxamers, α-tocopheryl polyethylene glycol succinates, polyoxyethylene sorbitan fatty acid esters, and salts of negatively charged phospholipids. 
   
   
       4 . A composition according to  claim 1 , wherein the surface modifier is selected from Pluronic™ F108, Vitamin E TGPS, Tween™ 80, and Lipoid™ EPG 
   
   
       5 . A composition of  claim 1 , wherein the average effective particle size of the TMC278 micro- or nanoparticles is below about 50 μm, in particular below about 200 nm. 
   
   
       6 . A composition of  claim 1 , wherein the average effective particle size of the TMC278 micro- or nanoparticles is about 130 nm. 
   
   
       7 . A composition according to  claim 1 , comprising by weight based on the total volume of the composition:
 (a) from 3% to 50% (w/v), or from 10% to 40% (w/v), or from 10% to 30% (w/v), of TMC278;   (b) from 0.5% to 10%, or from 0.5% to 2% (w/v) of a wetting agent;   (c) from 0% to 10%, or from 0% to 5%, or from 0% to 2%, or from 0% to 1% of one or more buffering agents;   (d) from 0% to 10%, or from 0% to 6% (w/v) of a isotonizing agent   (e) from 0% to 2% (w/v) preservatives; and   (f) water for injection q.s. ad 100%.   
   
   
       8 . The use of a pharmaceutical composition as defined in  claim 1 , for the manufacture of a medicament for the treatment of HIV infection, or for the prevention of HIV infection in a subject at risk of being infected by HIV. 
   
   
       9 . The use of  claim 8  wherein the medicament is for the long-term treatment of HIV infection, or for the long-term prevention of HIV infection in a subject at risk of being infected by HIV. 
   
   
       10 . The use according to  claim 8  wherein the medicament is for administration by intramuscular or subcutaneous injection; wherein the composition is administered intermittently at a time interval of one week to two years. 
   
   
       11 . The use according to  claim 8  wherein the pharmaceutical composition is administered at an interval of at least one month to one year. 
   
   
       12 . The use according to  claim 8 , wherein the pharmaceutical composition is administered at a time interval that is in the range of one week to one month, or in the range of one month to three months, or in the range of three months to six months, or in the range of six months to twelve months, or in the range of 12 months to 24 months. 
   
   
       13 . The use according to  claim 8 , wherein the pharmaceutical composition is administered once every two weeks, or once every month, or once every three months. 
   
   
       14 . A process for preparing a pharmaceutical composition as defined in  claim 1 , comprising.
 (a) obtaining TMC278 in micronized form;   (b) adding the micronized TMC278 to a liquid medium to form a premix/predispersion; and   (c) subjecting the premix to mechanical means in the presence of a grinding medium to reduce the average effective particle size.