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Keywords:

powder for reconstitution, in vitro and in vivo studies

Abstract:

Purpose. To develop suspendable powders for reconstitution of the next-generation HIV non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC278 with low water solubility, by using a spray-dry technology. Such powders would allow flexible dosing, e.g. on body weight basis, instead of a fixed drug amount when taking tablets. The selection of formulation excipients was based on their potential to create and maintain supersaturation solubility of the active compound in 0.01 M HCl. Materials and methods. Suitable water-soluble carriers for TMC278 were selected by a supersaturation screening and formulated into powders for reconstitution by spray-drying. The selected powders for reconstitution were then compared to a developed tablet formulation of TMC278.HCl, in vitro using dissolution and stability testing, and in vivo through administration to beagle dogs, fed immediately after dosing. Results. 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 substance and acceptable stability after one month storage at 25°C and 40°C. In dogs, TMC278 was more slowly absorbed from tablets than from the suspended powders for reconstitution. Compared to the tablet, the relative biovailability obtained with the powders ranged from 69 to 89% for TMC278/PVP-VA 64 1:9 (w/w) and from 85 to 157% for TMC278/PVP-VA 64/Cremophor EL 1:8.5:0.5 (w/w/w). Conclusions. Based on in vivo and in vitro performance, both powders are suitable for future clinical use. Their advantageous in vivo behaviour and opportunity for flexible dosing provides a platform for formulations for pediatric anti-HIV therapy.