Absorption Systems, Exton PA1 9341, USA.
Department Engineering Pharmacy Section, Miguel Hernandez University, 03550 San Juan de Alicante, Alicante, Spain.
Eur J Pharm Biopharm. 2021 Aug;165:1-12. doi: 10.1016/j.ejpb.2021.05.003. Epub 2021 May 7.
In vitro dissolution tests are widely used to monitor the quality and consistency of oral solid dosage forms, but to increase the physiological relevance of in vitro dissolution tests, newer systems combine dissolution and permeation measurements. Some of these use artificial membranes while others (e.g., in the in vitro dissolution absorption system 2; IDAS2), utilize cell monolayers to assess drug permeation. We determined the effect of the precipitation inhibitor Hypromellose Acetate Succinate (HPMCAS) on the supersaturation/permeation of Ketoconazole and Dipyridamole in IDAS2 and its effect on their absorption in rats. Thus the main objectives of this study were to determine: (1) whether dissolution and permeation data from IDAS2 could be used to predict rat plasma concentration using an absorption model and (2) whether the effect of the precipitation inhibitor HPMCAS on supersaturation and permeation in IDAS2 was correlated with its effect on systemic absorption in the rat. Predicted drug concentrations in rat plasma, generated using parameters estimated from IDAS2 dissolution/permeation data and a mathematical absorption model, showed good agreement with measured concentrations. While in IDAS2, the prolongation of Ketoconazole's supersaturation caused by HPMCAS led to higher permeation, which paralleled the higher systemic absorption in rats, Dipyridamole showed no supersaturation and, thus, no effect of HPMCAS in dissolution or permeation in IDAS2 and no effect on Dipyridamole absorption in rats. The ability of IDAS2 to detect supersaturation following a pH-shift supports the potential value of this system for studying approaches to enhance intestinal absorption through supersaturation and the accuracy of plasma concentration predictions in rats suggest the possibility of combining IDAS2 with absorption models to predict plasma concentration in different species.
体外溶出度试验广泛用于监测口服固体制剂的质量和一致性，但为了提高体外溶出度试验的生理相关性，较新的系统将溶出度和渗透测量相结合。其中一些使用人工膜，而另一些（例如，在体外溶出吸收系统 2 中；IDAS2）则利用单层细胞来评估药物渗透。我们确定了沉淀抑制剂羟丙甲纤维素琥珀酸酯（HPMCAS）对酮康唑和双嘧达莫在 IDAS2 中的超饱和度/渗透的影响及其对它们在大鼠中的吸收的影响。因此，本研究的主要目的是确定：（1）是否可以使用 IDAS2 的溶解和渗透数据通过吸收模型来预测大鼠血浆浓度，以及（2）沉淀抑制剂 HPMCAS 对 IDAS2 中超饱和度和渗透的影响与其在大鼠中的全身吸收的影响是否相关。使用从 IDAS2 溶解/渗透数据和数学吸收模型估计的参数生成的大鼠血浆中预测药物浓度与测量浓度吻合良好。虽然在 IDAS2 中，HPMCAS 延长酮康唑的超饱和度导致更高的渗透，这与大鼠中更高的全身吸收平行，但双嘧达莫没有超饱和度，因此在 IDAS2 中的溶解或渗透中没有 HPMCAS 的作用，也没有对大鼠中双嘧达莫的吸收作用。IDAS2 能够检测 pH 转换后的超饱和度，这支持了该系统用于研究通过超饱和度增强肠吸收的方法的潜在价值，并且大鼠血浆浓度预测的准确性表明了将 IDAS2 与吸收模型结合以预测不同物种的血浆浓度的可能性。
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