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 method for the long-term treatment of HIV infection, comprising administering to a patient in need thereof by intramuscular or subcutaneous injection a pharmaceutical composition comprising a therapeutically effective amount of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (TMC278), a salt, a stereoisomer or a steriosomeric 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 TMC278 active ingredient is suspended, and   wherein the pharmaceutical composition is administered intermittently once every two weeks, once every three weeks, once every month, once every two months, once every three months, once every four months, or in the range of three months to six months.   
     
     
         2 . The method of  claim 2 , wherein the therapeutically effective amount is calculated on a basis of about 5 mg/day to about 50 mg/day of TMC278. 
     
     
         3 . The method of  claim 3 , wherein the therapeutically effective amount is calculated on a basis of about 10 mg/day to about 25 mg/day. 
     
     
         4 . The method of  claim 2 , wherein TMC278 is present in base form or in an acid addition salt form. 
     
     
         5 . The method of  claim 2 , wherein the surface modifier is poloxamer, α-tocopheryl polyethylene glycol succinate, polyoxyethylene sorbitan fatty acid ester or salts of negatively charged phospholipids. 
     
     
         6 . The method of  claim 5 , wherein the surface modifier is poloxamer 338, α-tocopheryl polyethylene glycol 1000 succinate, polysorbate 80 or egg phosphatidyl glycerol sodium. 
     
     
         7 . The method of  claim 6 , wherein the surface modifier is poloxamer 338. 
     
     
         8 . The method of  claim 6 , wherein the average effective particle size of the micro-or nanoparticles is
 a. below about 50 μm, about 20 μm, about 10 μm, about 1000 nm, about 500 nm, about 400 nm, about 300 nm, about 200 nm, about 100 nm or about 50 nm;   b. from about 50 nm to about 50 μm, from about 50 nm to about 20 μm, from about 50 nm to about 10 μm, from about 50 nm to about 1000 nm, from about 50 nm to about 500 nm, from about 50 nm to about 400 nm, from about 50 nm to about 300 nm, from about 50 nm to about 250 nm, from about 100 nm to about 250 nm, from about 150 nm to about 220 nm, from about 100 nm to about 200 nm, or from about 150 nm to about 200 nm;   c. about 50 nm to about 1000 nm;   d. about 50 nm to about 400 nm;   e. about 150 nm to about 220 nm;   f. about 130 nm; or   g. about 200 nm.   
     
     
         9 . The method of  claim 2 , wherein the therapeutically effective amount of TMC278 corresponds with a monthly dose of
 a. from about 150 mg to about 1500 mg;   b. from about 30 mg to about 300 mg; or   c. about 300 mg.   
     
     
         10 . The method of  claim 2 , wherein the pharmaceutical composition comprises by weight based on the total volume of the composition:
 a. from 3% to 50%, from 10% to 40% or from 10 to 30%, of TMC278   b. from 0.5% to 10% or from 0.5% to 2% of the surface modifier;   c. from 0% to 10%, from 0% to 5%, from 0% to 2%, or from 0% to 1% of one of more buffering agents;   d. from 0% to 10%, or from 0% to 6% of an isotonizing agent;   e. from 0% to 2% preservatives; and   f. water for injection q.s. ad 100%.   
     
     
         11 . The method of  claim 4 , wherein TMC278 is present as the E-isomer of the base form. 
     
     
         12 . The method of  claim 4 , wherein TMC278 is present as the E-isomer of the acid addition salt form. 
     
     
         13 . The method of  claim 10 , wherein the buffering agent is tartaric acid, maleic acid, glycine, sodium lactate, lactic acid, ascorbic acid, sodium citrates, citric acid, sodium acetate, acetic acid, sodium bicarbonate, carbonic acid, sodium succinate, succinic acid, sodium benzoate, benzoic acid, sodium phosphates, tris(hydroxymethyl)aminomethane, sodium bicarbonate, sodium carbonate, ammonium hydroxide, benzene sulfonic acid, benzoate sodium, benzoate acid, diethanolamine, glucono delta lactone, hydrochloric acid, hydrogen bromide, lysine, methanesulfonic acid, monoethanolamine, sodium hydroxide, tromethamine, gluconic, glyceric, gluratic, glutamic, ethylene diamine tetraacetic (EDTA), triethanolamine, or a mixture of at least two buffering agents. 
     
     
         14 . The method of  claim 10 , wherein the isotonizing agent is glucose, dextrose, sucrose, fructose, trehalose, lactose, a polyhydric sugar alcohol, a trihydric or higher sugar alcohol, glycerin, erythritol, arabitol, xylitol, sorbitol, mannitol, sodium chloride or sodium sulfate. 
     
     
         15 . The method of  claim 2 , wherein the therapeutically effective amount of TMC278 is calculated on a basis of about 10 mg/day to about 25 mg/day, TMC278 is present as the E-isomer of the base form, and wherein the surface modifier is poloxamer 338. 
     
     
         16 . The method of  claim 15 , wherein TMC278 is present in nanoparticle form. 
     
     
         17 . The method of  claim 16 , wherein the average effective nanoparticle size is from about 150 nm to about 220 nm 
     
     
         18 . The method of  claim 2 , wherein the pharmaceutical composition comprises TMC278, a salt, a stereoisomer or a steriosomeric mixture thereof, in nanoparticle form. 
     
     
         19 . The method of  claim 6 , wherein the relative amount by weight (w/w) of TMC278 to the surface modifier is in the range of 1:1 to about 20:1. 
     
     
         20 . The method of  claim 19 , wherein the relative amount by weight (w/w) of TMC278 to the surface modifier is about 1:1, about 1:2, about 4:1, about 10:1 or about 20:1.