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Statistical investigation of the full concentration range of fasted and fed simulated intestinal fluid on the equilibrium solubility of oral drugs

机译:禁食和进食的模拟肠液全浓度范围对口服药物平衡溶解度的统计研究

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摘要

Upon oral administration the solubility of a drug in intestinal fluid is a key property influencing bioavailability. It is also recognised that simple aqueous solubility does not reflect intestinal solubility and to optimise in vitro investigations simulated intestinal media systems have been developed. Simulated intestinal media which can mimic either the fasted or fed state consists of multiple components each of which either singly or in combination may influence drug solubility, a property that can be investigated by a statistical design of experiment technique. In this study a design of experiment covering the full range from the lower limit of fasted to the upper limit of fed parameters and using a small number of experiments has been performed. The measured equilibrium solubility values are comparable with literature values for simulated fasted and fed intestinal fluids as well as human fasted and fed intestinal fluids. The equilibrium solubility data range is statistically equivalent to a combination of published fasted and fed design of experiment data in six (indomethacin, phenytoin, zafirlukast, carvedilol, fenofibrate and probucol) drugs with three (aprepitant, tadalafil and felodipine) drugs not equivalent. In addition the measured equilibrium solubility data sets were not normally distributed. Further studies will be required to determine the reasons for these results however it implies that a single solubility measurement without knowledge of the solubility distribution will be of limited value. The statistically significant media factors which promote equilibrium solubility (pH, sodium oleate and bile salt) were in agreement with published results but the number of determined significant factors and factor interactions was fewer in this study, lecithin for example did not influence solubility. This may be due to the reduction in statistical sensitivity from the lower number of experimental data points or the fact that using the full range will examine media parameters ratios that are not biorelevant. Overall the approach will provide an estimate of the solubility range and the most important media factors but will not be equivalent to larger scale focussed studies. Further investigations will be required to determine why some drugs do not produce equivalent DoE solubility distributions, for example combined fasted and fed DoE, but this simply may be due to the complexity and individuality of the interactions between a drug and the media components.
机译:口服给药时,药物在肠液中的溶解度是影响生物利用度的关键特性。还认识到简单的水溶性不反映肠道的溶解度,并且为了优化体外研究,已经开发了模拟的肠道介质系统。可以模拟禁食或进食状态的模拟肠介质由多个成分组成,每个成分单独或组合均可影响药物的溶解度,这一特性可以通过实验技术的统计设计进行研究。在这项研究中,已经进行了一项实验设计,该实验涵盖了从禁食下限到进食参数上限的整个范围,并使用了少量实验。测得的平衡溶解度值与模拟的禁食和进食的肠液以及人类禁食和进食的肠液的文献值相当。平衡溶解度数据范围在统计学上等同于六种药物(吲哚美辛,苯妥英,扎非司特,卡维地洛,非诺贝特和普罗布考)的已公开禁食和进食设计与三种不等同的(阿瑞吡坦,他达拉非和非洛地平)药物的组合。另外,测得的平衡溶解度数据集不是正态分布的。需要进一步的研究来确定导致这些结果的原因,但是这意味着在不了解溶解度分布的情况下进行单个溶解度测量将具有有限的价值。具有统计学意义的促进平衡溶解度的介质因子(pH,油酸钠和胆汁盐)与已发表的结果一致,但是在这项研究中确定的显着因子和因子相互作用的数量较少,例如卵磷脂不影响溶解度。这可能是由于较少的实验数据点降低了统计灵敏度,或者是因为使用整个范围将检查与生物无关的介质参数比率。总体而言,该方法将提供对溶解度范围和最重要的介质因素的估计,但将不等同于更大规模的研究。将需要进行进一步的调查以确定为什么某些药物不能产生等效的DoE溶解度分布,例如禁食和进食的DoE的组合,但这仅是由于药物与介质成分之间相互作用的复杂性和个性性所致。

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