Nespi Marika, Ly Justin, Fan Yuchen, Chen Shu, Liu Liling, Gu Yimin, Castleberry Steven
Synthetic Molecule Pharmaceutical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Synthetic Molecule Pharmaceutical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
J Pharm Sci. 2025 Jan;114(1):566-576. doi: 10.1016/j.xphs.2024.10.043. Epub 2024 Oct 31.
In early drug development, amorphous spray-dried dispersions (SDDs) applied to enhance the bioavailability of poorly water-soluble compounds are typically administered to preclinical species via oral gavage in the form of suspensions. The liquid formulations are usually prepared on the same day of dosing to minimize the exposure of the amorphous material to the aqueous vehicle, thereby reducing the risk of crystallization. Dose-ability (e.g. syringe-ability) of the suspensions is also a critical factor for the administration, particularly when high doses, thus concentrations, are required for toxicology studies. As a result, it is standard practice during early formulation screening to assess the stability and the maximum feasible concentration of SDDs in various vehicles. In this study, we evaluated the impact of different vehicles on the performance of a model SDD in-vitro and in-vivo settings, to mitigate the risks associated with its administration in liquid form. A poorly water-soluble compound (GEN-A) was selected to screen various SDDs and generate the SDD model at 30 % drug load with HPMCAS-MF polymer carrier. The SDD was suspended in selected aqueous vehicles after a careful vehicle components screening, that included suspending agents (HPC-SL), solubilizers (PEG400, Propylene glycol), surfactants (Vitamin E TPGS, SLS, Tween 80, Poloxamer 188), and complexing agents (HP-β-CD, SBE-β-CD). The suspensions were characterized for stability, dose-ability and dissolution in biorelevant media, prior administration in pre-clinical species. The SDD dissolution profile revealed that the drug's supersaturation level was positively impacted by the presence of a surfactant (SLS) and a complexing agent (SBE-β-CD) with respect to a suspending agents (HPC-SL) in the vehicle. Similarly, the pharmacokinetics profiles of the drug following the administration of the SDD in a vehicle with a complexing agent (SBE-β-CD) achieved greater exposure compare to the SDD in a vehicle with a suspending agent (HPC-SL). These findings confirm a synergistic effect between the SDD and the vehicles, suggesting that this combination could be leveraged to maximize the advantages of the amorphous approach.
在药物研发早期，用于提高难溶性化合物生物利用度的无定形喷雾干燥分散体（SDD）通常以悬浮液的形式通过口服灌胃给予临床前动物。液体制剂通常在给药当天制备，以尽量减少无定形材料与水性载体的接触，从而降低结晶风险。悬浮液的可注射性（如可注射器性）也是给药的关键因素，特别是在毒理学研究需要高剂量（即高浓度）时。因此，在早期制剂筛选过程中，评估SDD在各种载体中的稳定性和最大可行浓度是标准做法。在本研究中，我们评估了不同载体对模型SDD在体外和体内环境中性能的影响，以降低其以液体形式给药相关的风险。选择一种难溶性化合物（GEN-A）来筛选各种SDD，并使用HPMCAS-MF聚合物载体以30%的载药量生成SDD模型。在仔细筛选载体成分（包括助悬剂（HPC-SL）、增溶剂（PEG400、丙二醇）、表面活性剂（维生素E TPGS、SLS、吐温80、泊洛沙姆188）和络合剂（HP-β-CD、SBE-β-CD））后，将SDD悬浮于选定的水性载体中。在给予临床前动物之前，对悬浮液的稳定性、可注射性和在生物相关介质中的溶出度进行了表征。SDD的溶出曲线表明，相对于载体中的助悬剂（HPC-SL），表面活性剂（SLS）和络合剂（SBE-β-CD）的存在对药物的过饱和水平有积极影响。同样，与含有助悬剂（HPC-SL）的载体中的SDD相比，在含有络合剂（SBE-β-CD）的载体中给予SDD后，药物的药代动力学曲线显示出更高的暴露量。这些发现证实了SDD与载体之间的协同作用，表明这种组合可用于最大化无定形方法的优势。
