Centre for Research in Topical Drug Delivery and Toxicology, University of Hertfordshire, College Lane, Hatfield AL10 9AB, UK.
Centre for Research in Topical Drug Delivery and Toxicology, University of Hertfordshire, College Lane, Hatfield AL10 9AB, UK.
Eur J Pharm Biopharm. 2021 Dec;169:125-133. doi: 10.1016/j.ejpb.2021.10.004. Epub 2021 Oct 14.
Understanding drug miscibility in pharmaceutically relevant systems is essential for the development and optimisation of pharmaceutical dosage forms. This is particularly true for film forming systems which are designed to become supersaturated with drug, following application on the skin surface, whilst maintaining the physical stability of the drug for a suitable period to enhance drug delivery. For such formulations, chemical penetration enhancers as well as the drug are absorbed from the formulation into the skin, making understanding drug delivery from the films challenging. This study investigated the use of an optical differential scanning calorimetry (DSC) to understand drug miscibility in polymeric film forming systems and explain drug transport behaviour from film forming formulations, containing ibuprofen, a copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (Eudragit® E, EuE), a copolymer based on ethyl acrylate, methyl methacrylate and methacrylic acid ester with quaternary ammonium groups (Eudragit® RS, EuRS) and a copolymer based on methacrylic acid and methyl methacrylate (Eudragit® S, EuS), with and without the chemical penetration enhancer propylene glycol, across a model membrane. The optical DSC enabled the rapid screening of not only drug-polymer miscibility, but also drug-vehicle miscibility, while considering both the melting-point depression and melting enthalpy of the drug due to the presence of the polymer/polymer-based vehicle, obtained via thermal analysis by structural characterisation (TASC) and DSC analysis, respectively. The results obtained enable the polymers studied to be ranked in the order of EuE > EuRS > EuS, with EuE being more miscible with ibuprofen, and the incorporation of a penetration enhancer in the film forming system formulation was found to increase ibuprofen solubility in EuE- and EuRS- based films. The drug-polymer/vehicle miscibility information obtained via optical DSC provided understanding of drug transport from film forming systems with the higher miscibility of ibuprofen with EuE reducing drug transport through decreasing drug saturation in the film. The higher drug transport from films containing EuRS and EuS could also be linked to drug miscibility with the polymer and showed dependence on ibuprofen loading in the formulation. Overall optical DSC has been demonstrated to be a valuable tool for determining drug-vehicle miscibility for pharmaceutical product development.
理解药物在药学相关体系中的混溶性对于开发和优化药物剂型至关重要。对于成膜系统尤其如此，这些系统旨在在皮肤表面应用后使药物过饱和，同时保持药物的物理稳定性以延长药物输送时间。对于此类制剂，化学渗透增强剂以及药物都会从制剂中被吸收到皮肤中，这使得从薄膜中理解药物输送变得具有挑战性。本研究使用光学差示扫描量热法（DSC）来理解聚合物成膜系统中的药物混溶性，并解释含有布洛芬的成膜制剂的药物传输行为，布洛芬是一种基于二甲氨基乙基甲基丙烯酸酯、丁基甲基丙烯酸酯和甲基丙烯酸甲酯的共聚物（Eudragit® E，EuE）、一种基于丙烯酸乙酯、甲基丙烯酸甲酯和具有季铵基团的甲基丙烯酸酯的共聚物（Eudragit® RS，EuRS）和一种基于甲基丙烯酸和甲基丙烯酸甲酯的共聚物（Eudragit® S，EuS），含有和不含有化学渗透增强剂丙二醇，跨越模型膜。光学 DSC 不仅能够快速筛选药物-聚合物的混溶性，还能够快速筛选药物-载体的混溶性，同时考虑到药物由于聚合物/聚合物基载体的存在而导致的熔点降低和熔融焓，通过热分析结构特征（TASC）和 DSC 分析分别获得。所得结果能够对所研究的聚合物进行排序，EuE>EuRS>EuS，EuE 与布洛芬的混溶性更高，并且在成膜系统制剂中加入渗透增强剂会增加 EuE 和 EuRS 基薄膜中布洛芬的溶解度。通过光学 DSC 获得的药物-聚合物/载体混溶性信息有助于理解成膜系统中药物的输送，EuE 中布洛芬的更高混溶性通过降低薄膜中药物的饱和度来减少药物输送。EuRS 和 EuS 基薄膜中药物的更高输送也与药物与聚合物的混溶性有关，并与制剂中布洛芬的载药量有关。总体而言，光学 DSC 已被证明是一种用于确定药物载体混溶性的有价值的工具，可用于药物产品开发。
