Molecular-properties based formulation guidance tree for amorphous and supersaturable mesoporous silica preparations of poorly soluble compounds.

IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Journal of pharmaceutical sciences Pub Date : 2024-10-29 DOI:10.1016/j.xphs.2024.10.040
Dipy M Vasa, Shih-Wen Wang, Matthew F Dunn, Erica Long, Suman A Luthra
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Abstract

A huge majority of new chemical entities (NCEs) advancing through the drug discovery pipeline often have poor aqueous solubility. This requires formulation scientists to search for solubility enhancement strategies, within the constraints of time and material. To address these challenges, a strategic platform formulation is often required for a rapid compound screening to enable early exploratory PK and toxicology studies. Through this work, we present an option of a material-sparing, high yielding and solubility-enabling amorphous API and HPMCAS-L co-loaded mesoporous silica-based formulation. The usability of this platform formation strategy was assessed for a physico-chemically diverse set of eleven compounds. The formulation approach was successful in stabilizing the model compounds mesoporous silica. Additionally, through the presence of HPMCAS-L, the precipitation risk in supersaturable aqueous environment was significantly reduced. Finally, this manuscript provides fundamental, computational and experimental molecular-properties based formulation guidance tree to a priori gauge the (1) possibility of generating solid-state stable amorphous formulations and (2) sustaining in vitro supersaturation in extreme non-sink dissolution conditions. This unique and conceptual formulation guidance tree is believed to be extremely beneficial to drug discovery formulators to triage NCEs and streamline solubility-enabling formulation efforts.

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基于分子特性的无定形和超稳定介孔二氧化硅难溶性化合物制剂配方指导树。
在药物研发过程中,绝大多数新化学实体 (NCE) 的水溶性往往很差。这就要求制剂科学家在时间和材料的限制下寻找提高溶解度的策略。为了应对这些挑战,通常需要一种战略性平台制剂来快速筛选化合物,以便进行早期的探索性 PK 和毒理学研究。通过这项工作,我们提出了一种无定形原料药和 HPMCAS-L 共负载介孔二氧化硅制剂的方案,该方案节省材料、产量高、溶解性好。我们针对物理化学性质各异的 11 种化合物评估了这一平台形成策略的可用性。制剂方法成功地稳定了模型化合物介孔二氧化硅。此外,由于 HPMCAS-L 的存在,在超饱和水性环境中沉淀的风险大大降低。最后,本手稿提供了基于计算和实验分子特性的基本制剂指导树,以先验地衡量(1)生成固态稳定无定形制剂的可能性和(2)在极端非沉降溶解条件下维持体外过饱和的可能性。相信这种独特的概念性制剂指导树能极大地帮助药物研发配方师分流非离子型药物,并简化溶解度促进制剂工作。
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来源期刊
CiteScore
7.30
自引率
13.20%
发文量
367
审稿时长
33 days
期刊介绍: The Journal of Pharmaceutical Sciences will publish original research papers, original research notes, invited topical reviews (including Minireviews), and editorial commentary and news. The area of focus shall be concepts in basic pharmaceutical science and such topics as chemical processing of pharmaceuticals, including crystallization, lyophilization, chemical stability of drugs, pharmacokinetics, biopharmaceutics, pharmacodynamics, pro-drug developments, metabolic disposition of bioactive agents, dosage form design, protein-peptide chemistry and biotechnology specifically as these relate to pharmaceutical technology, and targeted drug delivery.
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