对于固体口服剂型,药物在肠液中的溶解度是影响产品性能和生物利用度的重要参数。溶解度和渗透性是生物药剂学和可开发性分类系统(DCS)中用于评估药物口服给药潜力的两个参数。肠溶解度随肠内容物而变化,并且认为禁食和进食状态之间的差异影响溶解度和生物利用度。在这项研究中,一种由九种培养基组成的新型饲喂状态模拟培养基系统已被用来测量七种药物的溶解度(布洛芬,甲芬那酸,呋塞米,双嘧达莫,灰黄霉素,扑热息痛和阿昔洛韦)先前在禁食状态DCS中进行了研究。结果表明,喂食九种培养基系统为每种药物提供了一定范围的溶解度值,并且溶解度行为与在喂食或禁食状态下进行的实验研究的公开设计一致。三种药物(灰黄霉素,扑热息痛和阿昔洛韦)表现出非常窄的溶解度分布,与禁食状态下发布的行为相匹配的结果,表明此属性不受模拟介质成分浓度的影响。每种药物的9个溶解度值可用于计算剂量/溶解度体积比,以使药物在DCS网格上的位置可视化。由于九种培养基组合物的推导,范围和分类可以被认为是生物等效的,并且可以与来自原始饲喂肠液分析的数据组合以提供基于群体的溶解度分布。这提供了关于药物溶解度行为的进一步信息,并且可以通过设计配方方法应用于质量。本研究中的进食结果与类似的已发表的禁食结果的比较突出表明,在食物效应研究中检测到的一些差异与体内行为相匹配。这表明喂食和禁食系统的组合可以是有用的体外生物制药性能工具。然而,应该注意的是,本研究中的饲喂培养基配方是基于液体膳食(EnsurePlus),这可能不代表通过摄入固体膳食实现的替代饲喂状态.然而,这种新颖的方法提供了关于可能的体内生物制药性能的更多体外细节,提高应用基于风险的方法的能力,以及研究基于溶解度的食物影响的潜力。因此,该系统值得进一步研究,但需要研究以扩大所测量药物的数量并将体外测量与体内结果联系起来。
For solid oral dosage forms drug solubility in intestinal fluid is an important parameter influencing product performance and bioavailability. Solubility along with permeability are the two parameters applied in the Biopharmaceutics and Developability Classification Systems (DCS) to assess a drug\'s potential for oral administration. Intestinal solubility varies with the intestinal contents and the differences between the fasted and fed states are recognised to influence solubility and bioavailability. In this study a novel fed state simulated media system comprising of nine media has been utilised to measure the solubility of seven drugs (ibuprofen, mefenamic acid, furosemide, dipyridamole, griseofulvin, paracetamol and acyclovir) previously studied in the fasted state DCS. The results demonstrate that the fed nine media system provides a range of solubility values for each drug and solubility behaviour is consistent with published design of experiment studies conducted in either the fed or fasted state. Three drugs (griseofulvin, paracetamol and acyclovir) exhibit very narrow solubility distributions, a result that matches published behaviour in the fasted state, indicating that this property is not influenced by the concentration of simulated media components. The nine solubility values for each drug can be utilised to calculate a dose/solubility volume ratio to visualise the drug\'s position on the DCS grid. Due to the derivation of the nine media compositions the range and catergorisation could be considered as bioequivalent and can be combined with the data from the original fed intestinal fluid analysis to provide a population based solubility distribution. This provides further information on the drugs solubility behaviour and could be applied to quality by design formulation approaches. Comparison of the fed results in this study with similar published fasted results highlight that some differences detected match in vivo behaviour in food effect studies. This indicates that a combination of the fed and fasted systems may be a useful in vitro biopharmaceutical performance tool. However, it should be noted that the fed media recipes in this study are based on a liquid meal (Ensure Plus) and this may not be representative of alternative fed states achieved through ingestion of a solid meal. Nevertheless, this novel approach provides greater in vitro detail with respect to possible in vivo biopharmaceutical performance, an improved ability to apply risk-based approaches and the potential to investigate solubility based food effects. The system is therefore worthy of further investigation but studies will be required to expand the number of drugs measured and link the in vitro measurements to in vivo results.