期刊
BIOPHARMACEUTICS & DRUG DISPOSITION
卷 -, 期 -, 页码 -出版社
WILEY
DOI: 10.1002/bdd.2373
关键词
oral bioavailability; self-micellizing solid dispersion; stability; tacrolimus
The aim of this study was to develop a self-micellizing solid dispersion (SMSD) of tacrolimus (TAC) to improve its biopharmaceutical properties. SMSD/TAC and amorphous solid dispersion (ASD/TAC) formulations were prepared using different drug carriers. The SMSD approach showed enhanced physicochemical stability and oral absorption of TAC, with a significant improvement in dissolution behavior and 20-fold higher bioavailability compared to crystalline TAC.
The present study was undertaken to develop a self-micellizing solid dispersion (SMSD) of tacrolimus (TAC) to improve the biopharmaceutical properties of TAC. An SMSD formulation of TAC (SMSD/TAC) and amorphous solid dispersion formulation of TAC (ASD/TAC) were prepared with Soluplus(& REG;), an amphiphilic copolymer, and hydroxypropyl cellulose, respectively. Physicochemical properties were characterized in terms of morphology, crystallinity, storage stability, interaction of TAC with Soluplus(& REG;), and micelle-forming potency; pharmacokinetic behavior was also evaluated in rats. Tacrolimus in both formulations was in an amorphous state. After storage at 40 & DEG;C/75% relativity humidity for 4 weeks, there were no significant changes in the crystallinity of TAC between nonaged and aged SMSD/TAC, whereas slight recrystallization was observed in aged ASD/TAC. The results of circular dichroism (CD) and infrared spectroscopic analyses were indicative of the potent drug-polymer interaction in SMSD/TAC, possibly leading to the prevention of recrystallization. Compared with other TAC samples, SMSD/TAC exhibited significant improvement in the dissolution behavior of TAC through the immediate formation of fine micelles. After the oral administration of TAC samples (10 mg TAC/kg) to rats, there was marked enhancement in systemic exposure to TAC with both formulations; in particular, SMSD/TAC achieved an increase in bioavailability ca. 20-fold higher than crystalline TAC. The SMSD approach might provide an effective dosage form for TAC with enhanced physicochemical stability and oral absorption.
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