Abstract
Objective The aim of the present study was to improve bioavailability of an important antiretroviral drug, Darunavir (DRV), which has low water solubility and poor intestinal absorption through solid dispersion (SD) approach incorporating polymer with P-glycoprotein inhibitory potential. Methods A statistical approach where design of experiment (DoE) was used to prepare SD of DRV with incorporation of P-glycoprotein inhibitors. Using DoE, different methods of preparation, like melt, solvent evaporation, and spray drying method, utilizing carriers like Kolliphor TPGS and Soluplus were evaluated. The optimized SD was characterized by DSC, FTIR, XRD, and SEM and further evaluated for enhancement in absorption using everted gut sac model, effect of food on absorption of DRV, and in vivo prospect. Results and Discussion DSC, FTIR, XRD, and SEM confirmed the amorphicity of drug in SD. Oral bioavailability studies revealed better absorption of DRV when given with food. Absorption studies and in vivo study findings demonstrated great potential of Kolliphor TPGS as P-glycoprotein inhibitor for increasing intestinal absorption and thus bioavailability of DRV. Conclusion It is concluded that SD of DRV with the incorporation of Kolliphor TPGS was potential and promising approach in increasing bioavailability of DRV as well as minimizing its extrusion via P-glycoprotein efflux transporters.
Highlights
Acquired Immunodeficiency Syndrome (AIDS) has been one of the most devastating pandemic diseases over the last few decades caused by its etiologic agent Human Immunodeficiency Virus (HIV)
The introduction of novel second-generation protease inhibitors (PIs) such as Darunavir Ethanolate (DRV) with activity against wild type HIV-1 virus and multidrug resistant strains requires at least four concomitant mutations in the viral genome for resistance development, providing clinicians with superior drugs to counter the development of resistance [4]
On the basis of the phase solubility study of DRV in different polymers, Soluplus and Kolliphor TPGS were selected as the two carriers for the formulation of solid dispersion (SD) based on the highest increase in the solubility of the drug in their respective aqueous solutions
Summary
Acquired Immunodeficiency Syndrome (AIDS) has been one of the most devastating pandemic diseases over the last few decades caused by its etiologic agent Human Immunodeficiency Virus (HIV). Latest reports reveal that globally 40 million people are infected with HIV including 2.1 million from India in 2013 [1]. No complete cure is possible for people with AIDS and life-long treatment with a combination of antiretroviral drugs; that is, Highly Active Antiretroviral Therapy (HAART) is the only therapeutic intervention with proven efficacy against HIV infection [2, 3]. HIV protease inhibitors (PIs) currently are the key components of first-line therapy in both treatment-resistant and treatment-experienced patients. The introduction of novel second-generation PIs such as Darunavir Ethanolate (DRV) with activity against wild type HIV-1 virus and multidrug resistant strains requires at least four concomitant mutations in the viral genome for resistance development, providing clinicians with superior drugs to counter the development of resistance [4]. DRV suffer from disadvantages such as low solubility in water (0.15 mg/ml) and poor intestinal uptake due to drug efflux through active efflux transporter Pglycoprotein (P-gp) and by drug metabolism via Cytochrome P450 (CYP) 3A [7, 8]
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