Noureddine Nahla, Zerrouk Naima, Nicolis Ioannis, Allain Patrick, Sfar Souad, Chaumeil Jean-Claude
Laboratoire de Pharmacie Galénique, Faculté de Pharmacie de Monastir, rue Ibn Sina, Monastir, 5000, Tunisia.
Drug Dev Ind Pharm. 2005 May;31(4-5):397-404. doi: 10.1080/03639040500214589.
After oral administration, drug absorption rate is recognized to be dependent on two major factors: dissolution and intestinal cells permeability. Caco-2 monolayer cells have been largely used as a permeation study model. In this study, a numerical approach funded on an exponential first-order time relationship was tested to compare immediate- and controlled-release tablets of theophylline using a dissolution-permeation system. The dissolution performance using USP II paddle apparatus was coupled to the permeability studies investigated in Caco-2 cell monolayers. The dissolved samples were taken at different times; their pH and osmolarity were adjusted to render them suitable to Caco-2 permeability studies (osmolarity = 300 mosm, pH = 7.4). The experimental data show that the dissolution fits the exponential first-order relationship rate. The permeability values were in a range of 4.45 10(- 6)-5.28 10(- 6) cm/s, and percentages of absorbed drug dose were dependent on the fraction initially present in the donor compartment, indicating that absorption of theophylline was dissolution rate limited. Plotting experimental absorbed fractions (F(a)) against experimental dissolved fractions (F(d)) show that permeation is the rate-limiting step in drug absorption process in the extended release form of theophylline. Our results demonstrate a general agreement between observed F(a)/F(d) relationships and theoretical F(a)/F(d) relationships obtained with our approach funded on dissolution and permeation behavior. We concluded that the couple dissolution-caco-2 system could be a useful tool to characterize intestinal permeation for a new formulation of a drug compared with the conventional one.
口服给药后，药物吸收速率被认为取决于两个主要因素：溶解和肠道细胞通透性。Caco-2单层细胞已被广泛用作渗透研究模型。在本研究中，测试了一种基于指数一级时间关系的数值方法，以使用溶解-渗透系统比较茶碱速释片和控释片。使用USP II桨法装置的溶解性能与在Caco-2细胞单层中研究的通透性相结合。在不同时间采集溶解样品；调整它们的pH值和渗透压，使其适合Caco-2通透性研究（渗透压 = 300 mosm，pH = 7.4）。实验数据表明，溶解符合指数一级关系速率。通透性值在4.45×10⁻⁶ - 5.28×10⁻⁶ cm/s范围内，吸收药物剂量的百分比取决于供体隔室中最初存在的部分，表明茶碱的吸收受溶解速率限制。将实验吸收分数（F(a)）与实验溶解分数（F(d)）作图表明，在茶碱缓释剂型中，渗透是药物吸收过程中的限速步骤。我们的结果表明，观察到的F(a)/F(d)关系与通过基于溶解和渗透行为的方法获得的理论F(a)/F(d)关系总体一致。我们得出结论，与传统剂型相比，溶解-Caco-2系统可能是表征新药物制剂肠道渗透的有用工具。
