Abo Elela Mustafa M, ElKasabgy Nermeen A, Basalious Emad B
Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
AAPS PharmSciTech. 2017 Nov;18(8):2999-3010. doi: 10.1208/s12249-017-0789-y. Epub 2017 May 10.
Quetiapine fumarate (QF), an anti-schizophrenic drug, suffers from rapid elimination and poor bioavailability due to extensive first-pass effect. Intramuscularly (IM) injected lipospheres were designed to enhance the drug's bioavailability and extend its release. A central composite design was applied to optimize the liposphere preparation by a melt dispersion technique using Compritol® 888 ATO or glyceryl tristearate as lipid component and polyvinyl alcohol as surfactant. Lipospheres were evaluated for their particle size, entrapment efficiency, and in vitro release. The optimized QF lipospheres were prepared using a Compritol® 888 ATO fraction of 18.88% in the drug/lipid mixture under a stirring rate of 3979 rpm. The optimized lipospheres were loaded into a thermoresponsive in situ forming gel (TRIFG) and a liquid crystalline in situ forming gel (LCIFG) to prevent in vivo degradation by lipases. The loaded gels were re-evaluated for their in vitro release and injectability. Bioavailability of QF from liposphere suspension and bio-shielding in situ gels loaded with QF lipospheres were assessed in rabbits compared to drug suspension. Results revealed that the AUC obtained from the liposphere-loaded TRIFG was ∼3-fold higher than that obtained from the aqueous drug suspension indicating the bio-shielding effect of Poloxamer® 407 gel to inhibit the biodegradation of the lipospheres prolonging the residence of the drug in the muscle for higher absorption. Our results propose that bio-shielding in situ Poloxamer® 407 gels loaded with lipospheres is promising for the development of IM depot injection of drugs having extensive first-pass metabolism and rapid elimination.
富马酸喹硫平（QF）是一种抗精神分裂症药物，由于广泛的首过效应，其消除迅速且生物利用度差。设计肌内注射脂质球以提高药物的生物利用度并延长其释放。采用中心复合设计，通过熔融分散技术优化脂质球的制备，使用Compritol® 888 ATO或三硬脂酸甘油酯作为脂质成分，聚乙烯醇作为表面活性剂。对脂质球的粒径、包封率和体外释放进行了评估。在3979转/分钟的搅拌速率下，使用药物/脂质混合物中18.88%的Compritol® 888 ATO制备优化后的QF脂质球。将优化后的脂质球装入热响应原位形成凝胶（TRIFG）和液晶原位形成凝胶（LCIFG）中，以防止其在体内被脂肪酶降解。对负载后的凝胶重新评估其体外释放和可注射性。与药物混悬液相比，在兔体内评估了QF脂质球混悬液的生物利用度以及负载QF脂质球的生物屏蔽原位凝胶的生物利用度。结果显示，从负载脂质球的TRIFG获得的AUC比从水性药物混悬液获得的AUC高约3倍，这表明泊洛沙姆® 407凝胶的生物屏蔽作用可抑制脂质球的生物降解，延长药物在肌肉中的停留时间以实现更高的吸收。我们的结果表明，负载脂质球的泊洛沙姆® 407原位生物屏蔽凝胶对于开发具有广泛首过代谢和快速消除的药物的肌内长效注射剂具有前景。
