The objectives of this study were to formulate microcrystals of entecavir-3-palmiate (EV-P), a palmitic acid ester of entecavir (EV), and evaluate the influence of particle size on its pharmacokinetic behavior following subcutaneous (SC) injection. Systemic toxicity and local tolerability of the hepatitis B anti-viral suspension were further evaluated in normal rats. EV-P microcrystals possessing median diameters of 2.1, 6.3, and 12.7 µm were fabricated using anti-solvent crystallization technique with polysorbate 20 and polyethylene glycol 4000 as steric stabilizer. Dissolution rate of EV-P microcrystals was controlled by adjusting the particle size, under sink condition. Pharmacokinetic profiles of 2.1 µm-sized and 6.3 µm-sized EV-P microcrystals were quite comparable (1.44 mg/kg as EV), over 46 days in rats. The absorption rate and extent of EV after SC injection of 12.7 µm-sized microcrystals were significantly retarded, due to its slower dissolution rate in aqueous media. No single-dose systemic toxicity was observed after SC injection of high dose of EV-P microcrystal suspension (30-300 mg/kg as EV). The microcrystals were tolerable in the injected site, showing mild inflammatory responses at a dose of 30 mg/kg. Therefore, the novel microcrystal system with median particle size of below 6.3 µm is expected to be a unique long-acting system of the anti-viral agent, improving patient's compliance with chronic disease.
Keywords: Anti-solvent crystallization; Entecavir-3-palmitate; Microcrystals; Particle size; Pharmacokinetics; Subcutaneous injection; Sustained delivery.
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