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小规模标准化过饱和度和沉淀方法的实验室内和实验室间重现性研究。

Investigation of the Intra- and Interlaboratory Reproducibility of a Small Scale Standardized Supersaturation and Precipitation Method.

机构信息

Department of Pharmacy, University of Copenhagen , DK-2100 Copenhagen, Denmark.

Analytical Research and Development, H.Lundbeck A/S , Ottiliavej 9, DK-2500 Valby, Denmark.

出版信息

Mol Pharm. 2017 Dec 4;14(12):4161-4169. doi: 10.1021/acs.molpharmaceut.7b00419. Epub 2017 Nov 7.

Abstract

The high number of poorly water-soluble compounds in drug development has increased the need for enabling formulations to improve oral bioavailability. One frequently applied approach is to induce supersaturation at the absorptive site, e.g., the small intestine, increasing the amount of dissolved compound available for absorption. However, due to the stochastic nature of nucleation, supersaturating drug delivery systems may lead to inter- and intrapersonal variability. The ability to define a feasible range with respect to the supersaturation level is a crucial factor for a successful formulation. Therefore, an in vitro method is needed, from where the ability of a compound to supersaturate can be defined in a reproducible way. Hence, this study investigates the reproducibility of an in vitro small scale standardized supersaturation and precipitation method (SSPM). First an intralaboratory reproducibility study of felodipine was conducted, after which seven partners contributed with data for three model compounds; aprepitant, felodipine, and fenofibrate, to determine the interlaboratory reproducibility of the SSPM. The first part of the SSPM determines the apparent degrees of supersaturation (aDS) to investigate for each compound. Each partner independently determined the maximum possible aDS and induced 100, 87.5, 75, and 50% of their determined maximum possible aDS in the SSPM. The concentration-time profile of the supersaturation and following precipitation was obtained in order to determine the induction time (t) for detectable precipitation. The data showed that the absolute values of t and aDS were not directly comparable between partners, however, upon linearization of the data a reproducible rank ordering of the three model compounds was obtained based on the β-value, which was defined as the slope of the ln(t) versus ln(aDS) plot. Linear regression of this plot showed that aprepitant had the highest β-value, 15.1, while felodipine and fenofibrate had comparable β-values, 4.0 and 4.3, respectively. Of the five partners contributing with full data sets, 80% could obtain the same rank order for the three model compounds using the SSPM (aprepitant > felodipine ≈ fenofibrate). The α-value is dependent on the experimental setup and can be used as a parameter to evaluate the uniformity of the data set. This study indicated that the SSPM was able to obtain the same rank order of the β-value between partners and, thus, that the SSPM may be used to classify compounds depending on their supersaturation propensity.

摘要

在药物开发中,大量水溶性较差的化合物的出现增加了对赋形剂的需求,以提高口服生物利用度。一种常用的方法是在吸收部位诱导过饱和,例如在小肠中,增加可用于吸收的溶解化合物的量。然而,由于成核的随机性,过饱和药物递送系统可能导致个体间和个体内的可变性。能够确定过饱和度水平的可行范围是成功配方的关键因素。因此,需要一种体外方法,从中可以以可重复的方式定义化合物过饱和的能力。因此,本研究调查了体外小规模标准化过饱和和沉淀方法(SSPM)的重现性。首先进行了非洛地平的实验室内重现性研究,然后有 7 个合作伙伴提供了 3 种模型化合物(阿瑞匹坦、非洛地平和非诺贝特)的数据,以确定 SSPM 的实验室间重现性。SSPM 的第一部分确定了要为每种化合物研究的表观过饱和度(aDS)。每个合作伙伴独立地确定了最大可能的 aDS,并在 SSPM 中诱导了其确定的最大可能 aDS 的 100%、87.5%、75%和 50%。获得了过饱和度和随后沉淀的浓度-时间曲线,以确定可检测沉淀的诱导时间(t)。数据表明,t 和 aDS 的绝对值在合作伙伴之间不可直接比较,但是,通过对数据进行线性化处理,可以根据β值(定义为 ln(t) 与 ln(aDS) 图的斜率)获得三种模型化合物的可重现的排序。该图的线性回归表明,阿瑞匹坦具有最高的β值,为 15.1,而非洛地平和平菲诺贝特具有可比的β值,分别为 4.0 和 4.3。在提供完整数据集的五个合作伙伴中,有 80%的合作伙伴可以使用 SSPM 获得三种模型化合物的相同排序(阿瑞匹坦>非洛地平≈非诺贝特)。α值取决于实验设置,可作为评估数据集均匀性的参数。本研究表明,SSPM 能够在合作伙伴之间获得相同的β值排序,因此,SSPM 可用于根据化合物的过饱和倾向对其进行分类。

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