作者
Myoung Jin Ho,Min Ho Jeong,Hoe Taek Jeong,Min Seob Kim,Hyun Jin Park,Dong Yoon Kim,Hyo Chun Lee,Woo Heon Song,Chang‐Hyun Kim,Choong Hyun Lee,Young Wook Choi,Yong Seok Choi,Young Taek Han,Myung Joo Kang
摘要
Herein, entecavir-3-palmitate (EV-P), an ester prodrug of entecavir (EV), was employed as a model drug, and the effect of drug particle size on in vivo pharmacokinetic profiles and local inflammatory responses, and those associations were evaluated following intramuscular (IM) injection. EV-P crystals with different median diameters (0.8, 2.3, 6.3, 15.3 and 22.6 μm) were prepared using the anti-solvent crystallization method, with analogous surface charges (-10.7 ~ -4.7 mV), and crystallinity (melting point, 160-170 °C). EV-P particles showed size-dependent in vitro dissolution profiles under sink conditions, exhibiting a high correlation between the median diameter and Hixon-Crowell's release rate constant (r2 = 0.94). Following IM injection in rats (1.44 mg/kg as EV), the pharmacokinetic profile of EV exhibited marked size-dependency; 0.8 μm-sized EV-P particles about 1.6-, 3.6-, and 5.6-folds higher systemic exposure, compared to 6.3, 15.3, and 22.6 μm-sized particles, respectively. This pharmacokinetic pattern, depending on particle size, was also highly associated with histopathological responses in the injected tissue. The smaller EV-P particles (0.8 or 2.3 μm) imparted the larger inflammatory lesion after 3 days, lower infiltration of inflammatory cells, and thinner fibroblastic bands around depots after 4 weeks. Conversely, severe fibrous isolation with increasing particle size augmented the drug remaining at injection site over 4 weeks, impeding the dissolution and systemic exposure. These findings regarding the effects of formulation variable on the in vivo behaviors of long-acting injectable suspension, provide constructive knowledge toward the improved design in poorly water-soluble compounds.