Abstract
The aim of this study was to investigate the physicochemical and in vitro/ex vivo characteristics of the pyrmidinedione IQP-0410 formulated into transdermal films. IQP-0410 is a potent therapeutic anti-HIV nonnucleoside reverse transcriptase inhibitor that would be subjected to extensive first pass metabolism, through conventional oral administration. Therefore, IQP-0410 was formulated into ethyl cellulose/HPMC-based transdermal films via solvent casting. In mano evaluations were performed to evaluate gross physical characteristics. In vitro release studies were performed in both Franz cells and USP-4 dissolution vessels. Ex vivo release and permeability assays were performed on human epidermal tissue models, and the permeated IQP-0410 was collected for in vitro HIV-1 efficacy assays in CEM-SS cells and PBMCs. Film formulation D3 resulted in pliable, strong transdermal films that were loaded with 2% (w/w) IQP-0410. Composed of 60% (w/w) ethyl cellulose and 20% (w/w) HPMC, the films contained < 1.2% (w/w) of water and were hygroscopic resulting in significant swelling under humid conditions. The water permeable nature of the film resulted in complete in vitro dissolution and drug release in 26 hours. When applied to ex vivo epidermal tissues, the films were non-toxic to the tissue and also were non-toxic to HIV target cells used in the in vitro efficacy assays. Over a 3 day application, the films delivered IQP-0410 through the skin tissue at a zero-order rate of 0.94 ± 0.06 µg/cm2/hr with 134 ± 14.7 µM collected in the basal media. The delivered IQP-0410 resulted in in vitro EC50 values against HIV-1 of 2.56 ± 0.40 nM (CEM-SS) and 0.58 ± 0.03 nM (PBMC). The film formulation demonstrated no significant deviation from target values when packaged in foil pouches under standard and accelerated environmental conditions. It was concluded that the transdermal film formulation was a potentially viable method of administering IQP-0410 that warrants further development.
Highlights
With over 25 million deaths attributed to AIDS since the first cases in 1981, 33 million individuals worldwide living with HIV, and over 2.5 million new infections yearly, HIV/AIDS continues to be a global emergency [1]
Combinations of nucleoside, nucleotide and nonnucleoside reverse transcriptase inhibitors and protease inhibitors have been effectively used in highly active anti-retroviral therapies (HAART) to significantly reduce HIV virus load in infected individuals for prolonged periods of time
The visual appearance of the films generally resulted in a translucent film with only the thickest films or those containing the most ethyl cellulose producing an opaque film
Summary
With over 25 million deaths attributed to AIDS since the first cases in 1981, 33 million individuals worldwide living with HIV, and over 2.5 million new infections yearly, HIV/AIDS continues to be a global emergency [1]. To combat this epidemic, combinations of nucleoside, nucleotide and nonnucleoside reverse transcriptase inhibitors and protease inhibitors have been effectively used in highly active anti-retroviral therapies (HAART) to significantly reduce HIV virus load in infected individuals for prolonged periods of time. The prevailing belief is that the addition of new anti-HIV agents to HAART regimens will provide additional clinical benefit with the development of new anti-HIV strategies and therapies
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