Rodriguez-Aller Marta, Guinchard Sylvie, Guillarme Davy, Pupier Marion, Jeannerat Damien, Rivara-Minten Elisabeth, Veuthey Jean-Luc, Gurny Robert
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 30, Quai Ernest Ansermet, 1211 Geneva 4, Switzerland.
Department of Organic Chemistry, University of Geneva, 30, Quai Ernest Ansermet, 1211 Geneva 4, Switzerland.
Eur J Pharm Biopharm. 2015 Sep;95(Pt B):203-14. doi: 10.1016/j.ejpb.2015.04.032. Epub 2015 May 8.
Latanoprost is a practically insoluble prostaglandin F2α analog considered a first-line agent for glaucoma treatment. From a pharmaceutical point of view, latanoprost is challenging to be formulated as an eye drop due to its poor water solubility and the presence of an ester bond that needs to be cleaved in vivo but maintained unchanged during storage. Cyclodextrins (CDs) are known to form complexes with hydrophobic drugs, influencing their stability, availability, solubility, and tolerance in a non-predictable manner. A variety of CDs including native α, β, and γCDs as well as substituted hydroxypropylβCD, hydroxypropylγCD, dimethylβCD, sulphatedβCD, and propylaminoβCD were screened and the most appropriate CD for the formulation of latanoprost for an ocular topical application was selected. Among the tested CDs, propylaminoβCD had the best trade-off between latanoprost stability and availability, which was confirmed by its complex constant value of 3129M(-1). Phase-solubility and NMR investigations demonstrated that the propylaminoβCD effectively formed a complex involving the ester group of latanoprost providing protection to its ester bond, while ensuring proper latanoprost solubilization. Furthermore, in vivo experiments demonstrated that the latanoprost-propylaminoβCD formulation led to lower ocular irritation than the commercial latanoprost formulation used as a reference. The latanoprost-propylaminoβCD formulation was demonstrated to successfully address the main stability, solubility, and tolerance limitations of topical ocular latanoprost therapy for glaucoma.
拉坦前列素是一种几乎不溶的前列腺素F2α类似物，被认为是青光眼治疗的一线药物。从药学角度来看，由于拉坦前列素水溶性差且存在酯键，该酯键需要在体内裂解但在储存期间保持不变，因此将其制成滴眼液具有挑战性。已知环糊精（CDs）可与疏水药物形成复合物，以不可预测的方式影响其稳定性、可用性、溶解度和耐受性。对包括天然α、β和γ环糊精以及取代的羟丙基β环糊精、羟丙基γ环糊精、二甲基β环糊精、硫酸化β环糊精和丙基氨基β环糊精在内的多种环糊精进行了筛选，并选择了最适合用于眼部局部应用的拉坦前列素制剂的环糊精。在所测试的环糊精中，丙基氨基β环糊精在拉坦前列素稳定性和可用性之间具有最佳的权衡，其络合常数为3129M(-1)证实了这一点。相溶解度和核磁共振研究表明，丙基氨基β环糊精有效地形成了一种涉及拉坦前列素酯基的复合物，为其酯键提供保护，同时确保拉坦前列素的适当溶解。此外，体内实验表明，与用作参考的市售拉坦前列素制剂相比，拉坦前列素-丙基氨基β环糊精制剂导致的眼部刺激更小。拉坦前列素-丙基氨基β环糊精制剂被证明成功解决了青光眼局部眼部拉坦前列素治疗的主要稳定性、溶解度和耐受性限制问题。
