Chen Yuejie, Wang Shujing, Wang Shan, Liu Chengyu, Su Ching, Hageman Michael, Hussain Munir, Haskell Roy, Stefanski Kevin, Qian Feng
School of Pharmaceutical Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University , Beijing 100084, China.
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company , Lawrenceville, New Jersey 08648, United States.
Mol Pharm. 2016 Aug 1;13(8):2787-95. doi: 10.1021/acs.molpharmaceut.6b00391. Epub 2016 Jul 1.
Sodium lauryl sulfate (SLS), as an effective surfactant, is often used as a solubilizer and/or wetting agent in various dosage forms for the purpose of improving the solubility and dissolution of lipophilic, poorly water-soluble drugs. This study aims to understand the impact of SLS on the solution behavior and bioavailability of hypromellose acetate succinate (HPMC-AS)-based posaconazole (PSZ) ASDs, and to identify the underlying mechanisms governing the optimal oral bioavailability of ASDs when surfactants such as SLS are used in combination. Fluorescence spectroscopy and optical microscopy showed that "oil-out" or "liquid-liquid phase separation (LLPS)" occurred in the supersaturated PSZ solution once drug concentration surpassed ∼12 μg/mL, which caused the formation of drug-rich oily droplets with initial size of ∼300-400 nm. Although FT-IR study demonstrated the existence of specific interactions between PSZ and HPMC-AS in the solid state, predissolved HPMC-AS was unable to delay LLPS of the supersaturated PSZ solution and PSZ-rich amorphous precipitates with ∼16-18% HPMC-AS were formed within 10 min. The coprecipitated HPMC-AS was found to be able to significantly delay the crystallization of PSZ in the PSZ-rich amorphous phase from less than 10 min to more than 4 h, yet coexistent SLS was able to negate this crystallization inhibition effect of HPMC-AS in the PSZ-rich amorphous precipitates and cause fast PSZ crystallization within 30 min. 2D-NOESY and the CMC/CAC results demonstrated that SLS could assemble around HPMC-AS and competitively interact with HPMC-AS in the solution, thus prevent HPMC-AS from acting as an effective crystallization inhibitor. In a crossover dog PK study, this finding was found to be correlating well with the in vivo bioavailability of PSZ ASDs formulated with or without SLS. The SLS containing PSZ ASD formulation demonstrated an in vivo bioavailability ∼30% of that without SLS, despite the apparently better in vitro dissolution, which only compared the dissolved drug in solution, a small fraction of the total PSZ dose. We conclude that the bioavailability of ASDs is highly dependent on the molecular interactions between drug, surfactant, and polymer, not only in the solution phase but also in the drug-rich "oily" phase caused by supersaturation.
月桂醇硫酸酯钠（SLS）作为一种有效的表面活性剂，常被用作各种剂型的增溶剂和/或润湿剂，以提高亲脂性、水溶性差的药物的溶解度和溶出度。本研究旨在了解SLS对基于醋酸羟丙甲纤维素琥珀酸酯（HPMC-AS）的泊沙康唑（PSZ）无定形固体分散体（ASD）的溶液行为和生物利用度的影响，并确定当使用SLS等表面活性剂时，控制ASD最佳口服生物利用度的潜在机制。荧光光谱和光学显微镜显示，一旦药物浓度超过约12μg/mL，在过饱和的PSZ溶液中就会发生“油析”或“液-液相分离（LLPS）”，这导致形成初始尺寸约为300-400nm的富含药物的油滴。尽管傅里叶变换红外光谱（FT-IR）研究表明PSZ与HPMC-AS在固态下存在特定相互作用，但预溶解的HPMC-AS无法延迟过饱和PSZ溶液的LLPS，并且在10分钟内形成了含有约16-18%HPMC-AS的富含PSZ的无定形沉淀。发现共沉淀的HPMC-AS能够将富含PSZ的无定形相中PSZ的结晶从不到10分钟显著延迟至超过4小时，但共存的SLS能够消除HPMC-AS在富含PSZ的无定形沉淀中的这种结晶抑制作用，并导致在30分钟内快速的PSZ结晶。二维核Overhauser效应光谱（2D-NOESY）和临界胶束浓度/聚集浓度（CMC/CAC）结果表明，SLS可以在HPMC-AS周围聚集，并在溶液中与HPMC-AS竞争性相互作用，从而阻止HPMC-AS作为有效的结晶抑制剂。在一项交叉犬类药代动力学（PK）研究中，这一发现与含或不含SLS的PSZ ASD制剂的体内生物利用度密切相关。尽管含SLS的PSZ ASD制剂的体外溶出度明显更好，但仅比较了溶液中溶解的药物，即总PSZ剂量的一小部分，其体内生物利用度仅为不含SLS制剂的约30%。我们得出结论，ASD的生物利用度高度依赖于药物、表面活性剂和聚合物之间的分子相互作用，不仅在溶液相中，而且在由过饱和引起的富含药物的“油相”中。
