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Keywords:

Administration, Oral, Animals, Anti-HIV Agents, Biological Availability, Chemistry, Pharmaceutical, Dogs, Drug Carriers, Drug Stability, Excipients, HIV Reverse Transcriptase, Male, Nitriles, Powders, Pyrimidines, Reverse Transcriptase Inhibitors, Solubility, Tablets, Technology, Pharmaceutical, Science & Technology, Life Sciences & Biomedicine, Pharmacology & Pharmacy, TMC278, Powder for reconstitution, Supersaturation screening, Dissolution, Oral bioavailability, HIV-1 REVERSE-TRANSCRIPTASE, NONNUCLEOSIDE INHIBITORS, DISCOVERY, TRANSMISSION, MICROBICIDES, Rilpivirine, powder for reconstitution, in vitro and in vivo studies, 1115 Pharmacology and Pharmaceutical Sciences, 3214 Pharmacology and pharmaceutical sciences

Abstract:

Powders for reconstitution of the next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC278 with low water solubility were developed by using a spray-dry technology. Their flexible dosing ability makes them suitable for patients looking for a different approach for antiretroviral (ARV) therapy. The selection of formulation excipients was based on their potential to create and maintain supersaturation solubility of TMC278 in 0.01 M HCl. Suitable water-soluble carriers for TMC278 were selected by a supersaturation screening to formulate powders for reconstitution by spray-drying. The selected powders for reconstitution were compared to clinical tablets of TMC278.HCl, in vitro using dissolution and stability testing, and in vivo through administration to beagle dogs, fed immediately after dosing. The spray-dried powders for reconstitution made up of TMC278/PVP-VA 64 1:9 (w/w) and TMC278/PVP-VA 64/Cremophor EL 1:8.5:0.5 (w/w/w) showed ease of suspendability, nearly complete dissolution of the drug and acceptable stability after one month storage at 25 and 40 degrees C. In dogs, TMC278 was more slowly absorbed from tablets than from the suspended powders for reconstitution. Compared to the tablet, the relative bioavailability obtained with the powders ranged between 69% and 89% for TMC278/PVP-VA 64 1:9 (w/w) and between 85% and 157% for TMC278/PVP-VA 64/Cremophor EL 1:8.5:0.5 (w/w/w). The absence of differences in vivo and in vitro between the powders made an eventual choice very difficult, yet their advantageous in vivo behaviour and flexible dosing possibility may provide a starting point for paediatric formulations.