Relevance of Liquid-Liquid Phase Separation of Supersaturated Solution in Oral Absorption of Albendazole from Amorphous Solid Dispersions

Amorphous solid dispersion (ASD) is one of the most promising formulation technologies for improving the oral absorption of poorly soluble drugs, where the maintenance of supersaturation plays a key role in enhancing the absorption process. However, quantitative prediction of oral absorption from ASDs is still difficult. Supersaturated solutions can cause liquid-liquid phase separation through the spinodal decomposition mechanism, which must be adequately comprehended to understand the oral absorption of drugs quantitatively. In this study, albendazole (ALZ) was formulated into ASDs using three types of polymers, poly(methacrylic acid-co-methyl methacrylate) (Eudragit) L100, Vinylpyrrolidone-vinyl acetate copolymer (PVPVA), and hydroxypropyl methylcellulose acetate succinate (HPMCAS). The oral absorption of ALZ in rats administered as ASD suspensions was not explained by dissolution study but was predicted using liquid-liquid phase separation concentration, which suggested that the absorption of ALZ was solubility-limited. The oral administration study in dogs performed using solid capsules demonstrated the low efficacy of ASDs because the absorption was likely to be limited by dissolution rate, which indicated the importance of designing the final dosage form of the ASDs.

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or continue reading here: Suzuki, K.; Kawakami, K.; Fukiage, M.; Oikawa, M.; Nishida, Y.; Matsuda, M.; Fujita, T. Relevance of Liquid-Liquid Phase Separation of Supersaturated Solution in Oral Absorption of Albendazole from Amorphous Solid Dispersions. Pharmaceutics2021, 13, 220. https://doi.org/10.3390/pharmaceutics13020220

Materials

ALZ was purchased from Sigma-Aldrich (St. Louis, MO, USA) and was ground using a mortar and pestle before use. Poly(methacrylic acid-co-methyl methacrylate) (Eudragit L100), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA64, PVPVA) were obtained from Evonik Industries AG (Essen, Germany), Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan), and BASF SE (Ludwigshafen am Rhein, Germany), respectively. Mannitol was supplied by Nacalai Tesque, Inc. (Kyoto, Japan). All chemicals were used as supplied.

Conclusions

ALZ was formulated into ASDs using three types of polymers: Eudragit, PVPVA, and HPMCAS, and their LLPS, dissolution, and oral absorption behaviors were investigated. The oral absorption in rats, where the ASDs were administered as suspensions, was not explained by the dissolution test but predicted by the LLPS concentration, which suggested the solubility-limited absorption of ALZ. The efficacy of the ASDs administered to dogs as solid capsules were likely to be limited by dissolution rate. Comprehension of particle size after LLPS appeared to be important for understanding the oral absorption in this case. This observation revealed the challenges in understanding supersaturation, LLPS, and crystallization behaviors occurring in the gastrointestinal tract for interpreting/predicting oral absorption. A formulation strategy that provides sufficiently fast disintegration and dissolution for achieving supersaturation was indicated to be important for ASDs.