Møller Amalie, Schultz Hayley B, Meola Tahlia R, Müllertz Anette, Prestidge Clive A
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark; UniSA: Clinical & Health Sciences, University of South Australia, Adelaide, South Australia 5000, Australia.
UniSA: Clinical & Health Sciences, University of South Australia, Adelaide, South Australia 5000, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, University of South Australia, Mawson Lakes Campus, Mawson Lakes 5095, Australia.
Eur J Pharm Sci. 2021 Feb 1;157:105640. doi: 10.1016/j.ejps.2020.105640. Epub 2020 Nov 13.
Supersaturated silica-lipid hybrids have previously demonstrated improved in vitro solubilisation and in vivo oral bioavailability of poorly water-soluble drugs, however were only fabricated using a single lipid (LFCS type I formulations) and were not compared to their liquid precursors. This study investigated the influence of lipid formulation classification (type I vs. type II vs. type IIIA/SNEDDS) and physical state (liquid LBF vs. solidified with silica) on the in vitro solubilisation of the poorly soluble, weak base, anti-psychotic drug, blonanserin (BLON), from a supersaturated lipid-based formulation (LBF). Stable liquid supersaturated LBF were fabricated using BLON (loaded at 150% of its equilibrium solubility), and solidified through encapsulation within porous silica microparticles at a 1:1 ratio. Their physicochemical properties and in vitro solubilisation during lipolysis were compared. Supersaturated BLON was encapsulated in the non-crystalline form. All supersaturated LBF improved the solubilisation of pure BLON during lipolysis regardless of their lipid formulation type or their physical state (1.7- to 13.4-fold). SNEDDS achieved greater solubilisation than the type II formulations (1.4- to 1.7-fold). Furthermore, the liquid precursors achieved greater solubilisation than the silica solidified formulations (4.5- to 5.7-fold). Additionally, in an attempt to increase BLON solubilisation, a spray-dried SNEDDS and dual-loaded solidified super-SNEDDS solidified with silica pre-loaded with BLON was developed, however did not significantly improve solubilisation. Liquid SNEDDS were identified as the optimal oral supersaturated LBF strategy for BLON based on in vitro lipolysis studies. Solidification of LBF using silica is a viable strategy for improving stability, however for drugs such as BLON, solidification may impede in vitro release and solubilisation.
过饱和硅脂杂化物先前已证明可改善难溶性药物的体外溶解性能及体内口服生物利用度，然而其制备仅使用单一脂质（LFCS I型制剂），且未与其液体前体进行比较。本研究考察了脂质制剂分类（I型、II型、IIIA型/SNEDDS）及物理状态（液体LBF与用二氧化硅固化）对难溶性弱碱性抗精神病药物布南色林（BLON）在过饱和脂质体制剂（LBF）中的体外溶解性能的影响。采用BLON（以其平衡溶解度的150%负载）制备了稳定的液体过饱和LBF，并以1:1的比例通过包封于多孔二氧化硅微粒中进行固化。比较了它们的理化性质及脂解过程中的体外溶解性能。过饱和BLON以非晶态形式被包封。所有过饱和LBF均能改善脂解过程中纯BLON的溶解性能，无论其脂质制剂类型或物理状态如何（提高1.7至13.4倍）。SNEDDS的溶解性能优于II型制剂（提高1.4至1.7倍）。此外，液体前体的溶解性能优于二氧化硅固化制剂（提高4.5至5.7倍）。另外，为提高BLON的溶解性能，开发了喷雾干燥的SNEDDS及预先负载BLON并用二氧化硅固化的双负载固化超级SNEDDS，但并未显著提高溶解性能。基于体外脂解研究，液体SNEDDS被确定为BLON的最佳口服过饱和LBF策略。用二氧化硅固化LBF是提高稳定性的可行策略，然而对于BLON这类药物，固化可能会阻碍体外释放和溶解。
