Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia; Department of Pharmacy, Uppsala University, Uppsala Biomedical Center, P.O. Box 580, SE-751 23 Uppsala, Sweden.
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
Adv Drug Deliv Rev. 2016 Jun 1;101:6-21. doi: 10.1016/j.addr.2016.02.005. Epub 2016 Feb 27.
The physicochemical properties of some contemporary drug candidates are moving towards higher molecular weight, and coincidentally also higher lipophilicity in the quest for biological selectivity and specificity. These physicochemical properties move the compounds towards beyond rule-of-5 (B-r-o-5) chemical space and often result in lower water solubility. For such B-r-o-5 compounds non-traditional delivery strategies (i.e. those other than conventional tablet and capsule formulations) typically are required to achieve adequate exposure after oral administration. In this review, we present the current status of computational tools for prediction of intestinal drug absorption, models for prediction of the most suitable formulation strategies for B-r-o-5 compounds and models to obtain an enhanced understanding of the interplay between drug, formulation and physiological environment. In silico models are able to identify the likely molecular basis for low solubility in physiologically relevant fluids such as gastric and intestinal fluids. With this baseline information, a formulation scientist can, at an early stage, evaluate different orally administered, enabling formulation strategies. Recent computational models have emerged that predict glass-forming ability and crystallisation tendency and therefore the potential utility of amorphous solid dispersion formulations. Further, computational models of loading capacity in lipids, and therefore the potential for formulation as a lipid-based formulation, are now available. Whilst such tools are useful for rapid identification of suitable formulation strategies, they do not reveal drug localisation and molecular interaction patterns between drug and excipients. For the latter, Molecular Dynamics simulations provide an insight into the interplay between drug, formulation and intestinal fluid. These different computational approaches are reviewed. Additionally, we analyse the molecular requirements of different targets, since these can provide an early signal that enabling formulation strategies will be required. Based on the analysis we conclude that computational biopharmaceutical profiling can be used to identify where non-conventional gateways, such as prediction of 'formulate-ability' during lead optimisation and early development stages, are important and may ultimately increase the number of orally tractable contemporary targets.
一些当代候选药物的物理化学性质正朝着更高的分子量发展，巧合的是，为了追求生物选择性和特异性，脂溶性也更高。这些物理化学性质使化合物超出了规则五（B-r-o-5）的化学空间，往往导致水溶性降低。对于这类 B-r-o-5 化合物，通常需要采用非传统的给药策略（即除了常规的片剂和胶囊制剂之外的策略），才能在口服后获得足够的暴露。在这篇综述中，我们介绍了用于预测肠道药物吸收的计算工具的现状、预测最适合 B-r-o-5 化合物的制剂策略的模型，以及获得对药物、制剂和生理环境相互作用的增强理解的模型。基于计算的模型能够识别出在生理相关液体（如胃和肠道液体）中低溶解度的可能分子基础。有了这个基线信息，制剂科学家可以在早期阶段评估不同的口服、可实现的制剂策略。最近出现了一些计算模型，可以预测成玻璃态的能力和结晶倾向，从而预测无定形固体分散体制剂的潜在用途。此外，用于评估在脂质中负载能力的计算模型，以及作为基于脂质的制剂的潜在用途的模型，现在也已经出现。虽然这些工具对于快速识别合适的制剂策略很有用，但它们并不能揭示药物在体内的定位和药物与赋形剂之间的分子相互作用模式。对于后者，分子动力学模拟提供了一个洞察药物、制剂和肠道液之间相互作用的机会。本文综述了这些不同的计算方法。此外，我们分析了不同靶点的分子要求，因为这些要求可以提供一个早期信号，表明需要采用制剂策略。基于分析，我们得出结论，计算型生物药剂学特征分析可用于确定非常规途径（如在先导优化和早期开发阶段预测制剂可行性）的重要性，最终可能会增加可口服治疗的当代靶点的数量。
