College of Pharmacy, Freie Universitaet Berlin, Berlin, Germany.
Eur J Pharm Biopharm. 2011 Aug;78(3):447-54. doi: 10.1016/j.ejpb.2011.03.018. Epub 2011 Apr 2.
Weakly basic drugs and their salts exhibit a decrease in aqueous solubility at higher pH, which can result in pH-dependent or even incomplete release of these drugs from extended release formulations. The objective of this study was to evaluate strategies to set-off the very strong pH-dependent solubility (solubility: 80 mg/ml at pH 2 and 0.02 mg/ml at pH 7.5, factor 4000) of a mesylate salt of weakly basic model drug (pK(a) 6.5), in order to obtain pH-independent extended drug release. Three approaches for pH-independent release were investigated: (1) organic acid addition in the core, (2) enteric polymer addition to the extended release coating and (3) an enteric polymer subcoating below the extended release coating. The layering of aspartic acid onto drug cores as well as the coating of drug cores with an ethylcellulose/Eudragit L (enteric polymer) blend were not effective to avoid the formation of the free base at pH 7.5 and thus failed to significantly improve the completeness of the release compared to standard ethylcellulose/hydroxypropyl cellulose (EC/HPC)-coated drug pellets. Interestingly, the incorporation of an enteric polymer layer underneath the EC/HPC coating decreased the free base formation at pH 7.5 and thus resulted in a more complete release of up to 90% of the drug loading over 18 h. The release enhancing effect was attributed to an extended acidification through the enteric polymer layer. Flexible release patterns with approximately pH-independent characteristics were successfully achieved.
弱碱性药物及其盐类在较高 pH 值时表现出水溶性降低，这可能导致这些药物从缓释制剂中出现 pH 依赖性甚至不完全释放。本研究的目的是评估一种策略，以抵消弱碱性模型药物甲磺酸盐（pKa 6.5）非常强的 pH 依赖性溶解度（在 pH 2 时溶解度为 80mg/ml，在 pH 7.5 时溶解度为 0.02mg/ml，相差 4000 倍），从而获得 pH 无关的缓释效果。研究了三种实现 pH 无关释放的方法：（1）在核心中添加有机酸，（2）在缓释涂层中添加肠溶聚合物，（3）在缓释涂层下添加肠溶聚合物亚涂层。将天冬氨酸分层到药物核心上以及用乙基纤维素/ Eudragit L（肠溶聚合物）共混物涂覆药物核心都不能有效地避免在 pH 7.5 时形成游离碱，因此与标准乙基纤维素/羟丙基纤维素（EC/HPC）包衣药物丸相比，不能显著提高释放的完全性。有趣的是，在 EC/HPC 涂层下添加肠溶聚合物层可以减少游离碱在 pH 7.5 时的形成，从而导致高达 90%的药物载量在 18 小时内完全释放。这种释放增强效果归因于通过肠溶聚合物层的延长酸化。成功实现了具有近似 pH 无关特性的灵活释放模式。
