Development of Darunavir proliposome powder for oral delivery by using Box-Bhenken design.

The aim of this study is to develop Darunavir (DRV) proliposome powder for oral delivery. Darunavir-loaded oral proliposome powder (OPP) was prepared by a solvent evaporation technique with varying independent variables at three different levels. Based on different levels, proliposome powder formulation was optimized by using Box-Behnken design. The formulations were analyzed for its size distribution, entrapment efficiency, and surface morphology. Optimized proliposome batch A was evaluated for physical parameter, morphological parameters, entrapment efficiency, followed by in vitro, ex vivo, and in vivo studies. Oral proliposome powder showed good micromeritic properties with angle of repose was less than 30°, Carr's index and Hausner's ratio were also less than 21 and 1.25, respectively. The mean size of the vesicles was in the range of 180-290 nm. The assay and entrapment efficiency of pro-liposome powder formulations were 79.00 ± 0.2 and 93.46 ± 0.2%, respectively. In vitro release of DRV proliposome powder was 78.17 ± 0.1% after 24 h which shows good release from the vesicle of proliposome. Ex vivo permeation study shows 58.11% enhancement which shows good permeation. The optimize batch A of proliposome powder indicated 50% enhancement in the relative bioavailability as compared to the DRV suspension. The results showed that proliposome powder containing DRV can efficiently deliver in to the blood stream. This drug delivery system has been designed as a novel platform for potential oral delivery of drugs having poor water solubility and high first-pass metabolism.

Synthesis and Characterization of Long-Acting Darunavir Prodrugs.

Antiretroviral therapy (ART) has improved the quality of life in patients infected with HIV-1. However, complete viral suppression within anatomical compartments remains unattainable. This is complicated by adverse side effects and poor adherence to lifelong therapy leading to the emergence of viral drug resistance. Thus, there is an immediate need for cellular and tissue-targeted long-acting (LA) ART formulations. Herein, we describe two LA prodrug formulations of darunavir (DRV), a potent antiretroviral protease inhibitor. Two classes of DRV prodrugs, M1DRV and M2DRV, were synthesized as lipophilic and hydrophobic prodrugs and stabilized into aqueous suspensions designated NM1DRV and NM2DRV. The formulations demonstrated enhanced intracellular prodrug levels with sustained drug retention and antiretroviral activities for 15 and 30 days compared to native DRV formulation in human monocyte-derived macrophages. Pharmacokinetics tests of NM1DRV and NM2DRV administered to mice demonstrated sustained drug levels in blood and tissues for 30 days. These data, taken together, support the idea that LA DRV with sustained antiretroviral responses through prodrug nanoformulations is achievable.

Design, Synthesis, Biological Evaluation, and X-ray Studies of HIV-1 Protease Inhibitors with Modified P2' Ligands of Darunavir.

The structure-based design, synthesis, and biological evaluation of a series of nonpeptidic HIV-1 protease inhibitors with rationally designed P2' ligands are described. The inhibitors are designed to enhance backbone binding interactions, particularly at the S2' subsite. Synthesis of inhibitors was carried out efficiently. The stereochemistry of alcohol functionalities of the P2' ligands was set by asymmetric reduction of the corresponding ketone using (R,R)- or (S,S)-Noyori catalysts. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity. Inhibitors 3g and 3h showed enzyme Ki values of 27.9 and 49.7 pm and antiviral activity of 6.2 and 3.9 nm, respectively. These inhibitors also remained quite potent against darunavir-resistant HIV-1 variants. An X-ray structure of inhibitor 3g in complex with HIV-1 protease revealed key interactions in the S2' subsite.