In-Situ Implant Formulation of Laurate and Myristate Prodrugs of Dolutegravir for Ultra-Long Delivery.
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abstract
The focus of present work was to synthesize prodrugs of dolutegravir (DTG) for ultra-long delivery purpose. The prodrug was synthesized by esterification of hydroxyl group with carboxyl group of fatty acid (lauric or myristic acid). The prodrugs were characterized by differential scanning calorimetry, X-ray powder diffraction, nuclear magnetic resonance, Fourier transformed infrared, near infrared-chemical imaging, pH-solubility, partition coefficient, and stability (solid and liquid). Stability studies were performed by exposing the powder drugs to 40C/75% RH for three months and buffer solutions at room temperature for 72 h. The prodrugs and drug were formulated into in-situ implant using biodegradable polymer. Thermal, spectral, and diffractometric data indicated formation of new chemical and solid forms. Formation of prodrugs resulted in lowering of melting point of DTG from 191.1C to 163.7 and 140.7C for DTG-Laurate and DTG-Myristate prodrugs, respectively. A decrease in solubility of 18.2-115.9 and 124.5-1594.9 folds was observed for DTG-Laurate and DTG-Myristate, respectively compared to DTG. Similarly, the prodrugs were highly lipophilic compared to DTG. Solid-state and pH-stability profiles of DTG and prodrugs were comparable. Implant formulation released 60.1% in 77 days compared to 95.6% in 35 days in the case of DTG-Myristate and DTG, respectively. In summary, combining prodrug and drug delivery approaches can be utilized for delivering drug for ultra-long period.
