Rao Shasha, Richter Katharina, Nguyen Tri-Hung, Boyd Ben J, Porter Christopher J H, Tan Angel, Prestidge Clive A
School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia , City East Campus, Adelaide, South Australia 5000, Australia.
Ian Wark Research Institute, University of South Australia , Mawson Lakes Campus, Mawson Lakes, South Australia 5095, Australia.
Mol Pharm. 2015 Dec 7;12(12):4424-33. doi: 10.1021/acs.molpharmaceut.5b00622. Epub 2015 Nov 12.
A Pluronic-functionalized silica-lipid hybrid (Plu-SLH) microparticle system for the oral delivery of poorly water-soluble, weak base drugs is reported for the first time. A highly effective Plu-SLH microparticle system was composed of Labrasol as the lipid phase, Pluronic F127 as the polymeric precipitation inhibitor (PPI), and silica nanoparticles as the solid carrier. For the model drug cinnarizine (CIN), the Plu-SLH delivery system was shown to offer significant biopharmaceutical advantages in comparison with unformulated drug and drug in the silica-lipid hybrid (SLH) system. In vitro two-phase dissolution studies illustrated significantly reduced pH provoked CIN precipitation and an 8- to 14-fold improvement in the extent of dissolution in intestinal conditions. In addition, under simulated intestinal digesting conditions, the Plu-SLH provided approximately three times more drug solubilization than the SLH. Oral administration in rats resulted in superior bioavailability for Plu-SLH microparticles, i.e., 1.6- and 2.1-fold greater than the SLH and the unformulated CIN, respectively. A physical mixture of Pluronic and SLH (Plu&SLH), having the same composition as Plu-SLH, was also evaluated, but showed no significant increase in CIN absorption when compared to unmodified CIN or SLH. This work represents the first study where different methods of incorporating PPI to formulate solid-state lipid-based formulations were compared for the impact on the biopharmaceutical performance. The data suggest that the novel physicochemical properties and structure of the fabricated Plu-SLH microparticle delivery system play an important role in facilitating the synergistic advantage of Labrasol and Pluronic F127 in preventing drug precipitation, and the Plu-SLH provides efficient oral delivery of poorly water-soluble weak bases.
首次报道了一种用于口服递送难溶性弱碱性药物的普朗尼克功能化硅脂杂化（Plu-SLH）微粒系统。一种高效的Plu-SLH微粒系统由Labrasol作为脂质相、普朗尼克F127作为聚合物沉淀抑制剂（PPI）以及二氧化硅纳米颗粒作为固体载体组成。对于模型药物桂利嗪（CIN），与未制剂化的药物和硅脂杂化（SLH）系统中的药物相比，Plu-SLH递送系统显示出显著的生物药剂学优势。体外双相溶出研究表明，pH值引发的CIN沉淀显著减少，在肠道条件下溶出程度提高了8至14倍。此外，在模拟肠道消化条件下，Plu-SLH提供的药物增溶量比SLH多约三倍。大鼠口服给药后，Plu-SLH微粒的生物利用度更高，即分别比SLH和未制剂化的CIN高1.6倍和2.1倍。还评估了具有与Plu-SLH相同组成的普朗尼克和SLH的物理混合物（Plu&SLH），但与未修饰的CIN或SLH相比，其CIN吸收没有显著增加。这项工作是首次比较不同掺入PPI方法来制备固态脂质基制剂对生物药剂学性能影响的研究。数据表明，制备的Plu-SLH微粒递送系统的新型物理化学性质和结构在促进Labrasol和普朗尼克F127在防止药物沉淀方面的协同优势中发挥重要作用，并且Plu-SLH为难溶性弱碱提供了高效的口服递送。
