Abstract
The present study aimed to investigate the effect of Eudragit® E/HCl (E-SD) on the degradation of sirolimus in simulated gastric fluid (pH 1.2) and to develop a new oral formulation of sirolimus using E-SD solid dispersions to enhance oral bioavailability. Sirolimus-loaded solid dispersions were fabricated by a spray drying process. A kinetic solubility test demonstrated that the sirolimus/E-SD/TPGS (1/8/1) solid dispersion had a maximum solubility of 196.7 μg/mL within 0.5 h that gradually decreased to 173.4 μg/mL after 12 h. According to the dissolution study, the most suitable formulation was the sirolimus/E-SD/TPGS (1/8/1) solid dispersion in simulated gastric fluid (pH 1.2), owing to enhanced stability and degree of supersaturation of E-SD and TPGS. Furthermore, pharmacokinetic studies in rats indicated that compared to the physical mixture and sirolimus/HPMC/TPGS (1/8/1) solid dispersion, the sirolimus/E-SD/TPGS (1/8/1) solid dispersion significantly improved oral absorption of sirolimus. E-SD significantly inhibited the degradation of sirolimus in a dose-dependent manner. E-SD also significantly inhibited the precipitation of sirolimus compared to hydroxypropylmethyl cellulose (HPMC). Therefore, the results from the present study suggest that the sirolimus-loaded E-SD/TPGS solid dispersion has great potential in clinical applications.
Highlights
Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus that inhibits interleukin (IL)-2 and other cytokine receptor-dependent signal transduction mechanisms [1].Sirolimus is an immunosuppressive agent indicated for the prophylaxis of organ rejection in patients aged≥ 13 years receiving renal transplants [2]
Our group recently reported that of the 71 combination formulations we evaluated, the most efficient ternary solid dispersion for the enhanced bioavailability of sirolimus was hydroxypropylmethyl cellulose (HPMC)/d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) [9]
The bioavailability of the sirolimus/E-SD/tocopheryl polyethylene glycol succinate (TPGS) (1/8/1) solid dispersion was markedly higher than that of the physical mixture and sirolimus/HPMC/TPGS (1/8/1) solid dispersion, due to higher supersaturation and supersaturated concentration over an increased period of time, as well as enhanced stability in simulated gastric fluid [33]. These results suggest that the supersaturation and oral absorption of sirolimus were significantly increased by the amorphous E-SD/TPGS solid dispersion
Summary
Sirolimus ( known as rapamycin) is a macrocyclic lactone produced by Streptomyces hygroscopicus that inhibits interleukin (IL)-2 and other cytokine receptor-dependent signal transduction mechanisms [1]. The oral bioavailability of sirolimus can be improved by enhancing in vitro supersaturation via an amorphous solid dispersion. The. Eudragit® E solid dispersion is a well-established formulation system that enhances the bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs) [11,12,13]. Eudragit® E using hydrochloric acid for the enhancement of supersaturation and oral absorption of poorly water-soluble APIs [17,18]. They demonstrated that E-SD forms a micelle-like structure in different conditions, similar to a polymeric surfactant [19]. In vitro and in vivo characterization of the solid dispersions was conducted to focus on the effect of the E-SD solid dispersion on supersaturation and the oral absorption of sirolimus
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