Copolymer Composition and Nanoparticle Configuration Enhance in vitro Drug Release Behavior of Poorly Water-soluble Progesterone for Oral Formulations

Yue Zhang,1 Rui Zhang,1 Upulitha Eranka Illangakoon,1,2 Anthony Henry Harker,3 Christopher Thrasivoulou,4 Maryam Parhizkar,1,2 Mohan Edirisinghe,1 CJ Luo1 1Department of Mechanical Engineering, University College London, London WC1E 7JE, UK; 2UCL School of Pharmacy, University College London, London WC1N 1AX, UK; 3Department of Physics & Astronomy, University College London, London WC1E 6BT, UK; 4Cell & Developmental Biology, Division of Biosciences, University College London, London WC1E 6BT, UKCorrespondence: CJ Luo Tel +44 20 7679 3942Email chaojie.luo@ucl.ac.ukHypothesis: Developing oral formulations to enable effective release of poorly water-soluble drugs like progesterone is a major challenge in pharmaceutics. Coaxial electrospray can generate drug-loaded nanoparticles of strategic compositions and configurations to enhance physiological dissolution and bioavailability of poorly water-soluble drug progesterone.Experiments: Six formulations comprising nanoparticles encapsulating progesterone in different poly(lactide-co-glycolide) (PLGA) matrix configurations and compositions were fabricated and characterized in terms of morphology, molecular crystallinity, drug encapsulation efficiency and release behavior.Findings: A protocol of fabrication conditions to achieve 100% drug encapsulation efficiency in nanoparticles was developed. Scanning electron microscopy shows smooth and spherical morphology of 472.1± 54.8 to 588.0± 92.1 nm in diameter. Multiphoton Airyscan super-resolution confocal microscopy revealed core-shell nanoparticle configuration. Fourier transform infrared spectroscopy confirmed presence of PLGA and progesterone in all formulations. Diffractometry indicated amorphous state of the encapsulated drug. UV-vis spectroscopy showed drug release increased with hydrophilic copolymer glycolide ratio while core-shell formulations with progesterone co-dissolved in PLGA core exhibited enhanced release over five hours at 79.9± 1.4% and 70.7± 3.5% for LA:GA 50:50 and 75:25 in comparison with pure progesterone without polymer matrix in the core at 67.0± 1.7% and 57.5± 2.8%, respectively. Computational modeling showed good agreement with the experimental drug release behavior in vitro.Keywords: core-shell nanoparticles, oral formulations, bioavailability, drug delivery, poorly water-soluble drugs, progesterone, poly, lactide-co-glycolide, PLGA, copolymer, coaxial electrospray