Prevention of hiv-infection

Abstract

This invention relates to the use of a parenteral formulation comprising the NNRTI TMC278 for the long term prevention of HIV infection in a subject at risk of being infected by HIV, which comprises the intermittent administration of the said formulation at long time intervals.

1 - 9 . (canceled) 
     
     
         10 . A method for the avoidance of human immunodeficiency virus 1 (HIV-1) infection in an individual at risk of being infected by HIV-1 comprising
 administrating to such an individual, intermittently at a time interval of at least one week, a sustained release parenteral formulation comprising
 an effective amount of an HIV inhibitor 4-[[4-[[-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]-amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof, or a pharmaceutically acceptable acid-addition salt thereof, and 
 a pharmaceutically acceptable carrier, 
   wherein the effective amount is selected such that the blood plasma level is kept over the time interval at a level above about 4 ng/ml.   
     
     
         11 . The method according to  claim 10  wherein the administration time interval is once every two weeks. 
     
     
         12 . The method according to  claim 10  wherein the administration time interval is once every month or once every 4 weeks. 
     
     
         13 . The method according to  claim 10  wherein the administration time interval is once every two months. 
     
     
         14 . The method according to  claim 10  wherein the administration time interval is once every three months. 
     
     
         15 . The method according to  claim 10  wherein the blood plasma level is kept over the time interval at a level equal to or above about 15 ng/ml. 
     
     
         16 . The method according to  claim 10  wherein the blood plasma level is kept over the time interval at a level equal to or above 20 ng/ml. 
     
     
         17 . The method according to  claim 10  wherein the formulation is administered subcutaneously or intramuscularly. 
     
     
         18 . The method according to  claim 10  wherein the formulation is administered intramuscularly. 
     
     
         19 . The method according to  claim 10  wherein the HIV inhibitor 4-[[4-[[-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]-amino]benzonitrile is in base form, and wherein the base form of 4-[[4-[[-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]-amino]benzonitrile occurs in its E-isomeric form. 
     
     
         20 . A method of maintaining a blood plasma level of 4-1000 ng/ml of 4-[[4-[[-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]-amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof; or a pharmaceutically acceptable acid-addition salt thereof, in an individual at risk of being infected with HIV-1, comprising
 administering to such an individual, intermittently at a time interval of at least one week, a sustained release parenteral formulation, said formulation comprising
 a pharmaceutically acceptable carrier, and 
 a dose, calculated on a basis of 0.2 mg/day to 50 mg/day of the time interval, of 4-[[4-[[-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]-amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof; or 
 a pharmaceutically acceptable acid-addition salt thereof, 
   wherein the blood plasma level is maintained over the time interval.   
     
     
         21 . The method according to  claim 20  wherein the administration time interval is once every 3, 4, 5 or 6 weeks. 
     
     
         22 . The method according to  claim 20  wherein the administration time interval is once every 1, 2, or 3 months. 
     
     
         23 . The method according to  claim 20  wherein the administration time interval is once every month or once every 4 weeks. 
     
     
         24 . The method according to  claim 20  wherein the formulation is administered once every two months. 
     
     
         25 . The method according to  claim 20  wherein the administration time interval is once every three months. 
     
     
         26 . The method according to  claim 20  wherein the blood plasma level of 4-[[4-[[-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]-amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof; or a pharmaceutically acid-addition salt thereof is maintained over the time interval at a level equal to or above 15 ng/ml. 
     
     
         27 . The method according to  claim 20  wherein the blood plasma level of 4-[[4-[[-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]-amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof; or a pharmaceutically acceptable acid-addition salt thereof is maintained over the time interval at a level equal to or above 20 ng/ml. 
     
     
         28 . The method according to  claim 20  wherein the blood plasma level of 4-[[4-[[-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]-amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof; or a pharmaceutically acceptable acid-addition salt thereof is maintained over the time interval at a level equal to or above 40 ng/ml. 
     
     
         29 . The method according to  claim 20  wherein the blood plasma level of 4-[[4-[[-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]-amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof; or a pharmaceutically acceptable acid-addition salt thereof is maintained over the time interval at level below 40 ng/ml and above 4 ng/ml. 
     
     
         30 . The method according to  claim 20  wherein the carrier comprises sterile water and a solubilizer or a surfactant. 
     
     
         31 . The method according to  claim 30  wherein the solubilizer is a cyclodextrin or cyclodextrin derivative or a polyethylene glycol. 
     
     
         32 . The method according to  claim 20 , wherein 4-[[4-[[-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]-amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof; or a pharmaceutically acceptable acid-addition salt thereof is in base-form. 
     
     
         33 . The method according to  claim 20  wherein 4-[[4-[[-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]-amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof; or a pharmaceutically acceptable acid-addition salt thereof occurs in its E-isomeric form. 
     
     
         34 . The method according to  claim 32  wherein the base form of 4-[[4-[[-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]-amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof, occurs in its E-isomeric form. 
     
     
         35 . The method according to  claim 20  wherein the carrier comprises sterile water and a solubilizer or a surfactant. 
     
     
         36 . The method according to  claim 23  wherein the monthly dose of 4-[[4-[[-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]-amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof, ranges from 15 mg to 1,500 mg. 
     
     
         37 . The method according to  claim 23  wherein the monthly dose of 4-[[4-[[-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]-amino]benzonitrile, the E isomeric form thereof or the Z-isomeric form thereof, ranges from 30 mg to 300 mg. 
     
     
         38 . The method according to  claim 20  wherein the dose is calculated on a basis of 1 mg/day to 10 mg/day of the time interval.