Sinha Swagata, Ravi Punna Rao, Somvanshi Makarand, Rashmi S R
Department of Pharmacy, Birla Institute of Technology and Science Pilani, BITS-Pilani Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal District, Telangana, 500078, India.
Discov Nano. 2024 Dec 30;19(1):218. doi: 10.1186/s11671-024-04157-8.
Acalabrutinib (ACP) is a first-line treatment for chronic lymphocytic leukemia but suffers from poor and variable oral bioavailability due to its pH-dependent solubility, CYP3A4 metabolism, and P-gp efflux. Thus, the objective of this study was to improve the solubility and dissolution behaviour, in turn enhancing bioavailability, by formulating solid lipid nanoparticles (SLNs). ACP loaded SLNs (ACP-SLNs) were prepared via solvent-free hot emulsification followed by a double sonication process. A combination of glyceryl di-behenate and stearyl palmitate along with Tween 80 was used as the lipid phase to dissolve ACP. A 1% w/v Poloxomer188 solution served as the aqueous phase. The optimized ACP-SLNs were spherical in shape and had particle size of 234.7-257.5 nm, PDI of 0.261-0.320 and loading efficiency of 18.70 ± 1.78%. A typical biphasic release pattern was observed from ACP-SLNs in the in vitro dissolution studies under gastrointestinal and plasma pH conditions (> 90% drug release at pH 4.5 ± 0.2, 6.8 ± 0.2 (representing GIT), and 7.4 ± 0.2 (representing plasma) at 8, 16 and 24 h, respectively). The freeze-dried product was stable when stored at 5 °C for over 6 months. Compared with the bulk drug suspension, the ACP-SLNs suspension resulted in 2.29-fold increase in oral bioavailability and more importantly 2.46-fold increase in the distribution of drug to spleen. Additionally, inhibition of lymph production and flow by administering cycloheximide resulted in 46.01% decrease in the overall absorption of ACP-SLNs, indicating the significance of lymphatic uptake process in the oral absorption of ACP-SLNs.
阿卡替尼（ACP）是慢性淋巴细胞白血病的一线治疗药物，但由于其pH依赖性溶解性、CYP3A4代谢和P-糖蛋白外排作用，口服生物利用度较差且不稳定。因此，本研究的目的是通过制备固体脂质纳米粒（SLNs）来改善其溶解性和溶出行为，进而提高生物利用度。通过无溶剂热乳化结合二次超声处理工艺制备了载ACP的SLNs（ACP-SLNs）。使用二山嵛酸甘油酯和硬脂酰棕榈酸酯与吐温80的组合作为脂质相来溶解ACP。1% w/v泊洛沙姆188溶液用作水相。优化后的ACP-SLNs呈球形，粒径为234.7 - 257.5 nm，多分散指数（PDI）为0.261 - 0.320，载药效率为18.70±1.78%。在胃肠道和血浆pH条件下的体外溶出研究中，ACP-SLNs呈现典型的双相释放模式（在pH 4.5±0.2、6.8±0.2（代表胃肠道）和7.4±0.2（代表血浆）时，分别在8、16和24小时药物释放>90%）。冻干产品在5℃储存6个月以上时稳定。与原料药混悬液相比，ACP-SLNs混悬液使口服生物利用度提高了2.29倍，更重要的是药物在脾脏中的分布增加了2.46倍。此外，给予环己酰亚胺抑制淋巴生成和流动导致ACP-SLNs的总体吸收下降46.01%，表明淋巴吸收过程在ACP-SLNs口服吸收中的重要性。
