Investigation of Combined Cyclodextrin and Hydrogel Formulation for Ocular Delivery of Dexamethasone Acetate by Means of Experimental Designs
Investigation of Combined Cyclodextrin and Hydrogel Formulation for Ocular Delivery of Dexamethasone Acetate by Means of Experimental Designs
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DOI：
10.3390/pharmaceutics10040249
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发表时间：
2018-12-01
期刊：
影响因子：
5.4
通讯作者：
Geze, Annabelle
中科院分区：
文献类型：
--
作者：
Mazet, Roseline;Choisnard, Luc;Geze, Annabelle
醋酸地塞米松（DXMa）已被证明可有效治疗角膜炎症，而不会增加眼内压。不幸的是，其水溶性差，与快速角膜前消除相关，导致局部眼部给药后药物生物利用度低和渗透性低。本研究的主要目的是使用环糊精改善DXMa的表观水溶解度。首先，使用羟丙基-β-CD（HP β CD）和羟丙基-γ-CD（HP γ CD）来提高水溶液中DXMa的浓度。β和γ HPCD衍生物允许在25 ℃下溶液中DXMa量分别增加500和1500倍。第二，为了改善复合物溶液滴入眼中后的持久性，将基于DXMa的CD溶液与市售眼用凝胶的制剂（CELLUVISC（R）、GEL-LARMES（R）和VISMED（R））进行了研究，并通过特殊的三次混料设计进行了优化，允许限定负载有0.7%（HP β CD）和2%（HP γ CD）DXMa的混合凝胶，其渗透压在可接受的生理范围内。最后，进行混合凝胶的体外药物释放测定，并与参考滴眼剂进行比较。与MAXIDEX（R）和DEXAFREE（R）类似，在含有HP β CD的混合凝胶的情况下，超过90%的药物在2小时内释放，而在含有HP γ CD的混合凝胶中，DXMa的释放是部分的，在2小时内达到约60%。这种差异将不得不通过离体和体内眼部递送实验进一步解决。
Dexamethasone acetate (DXMa) has proven its efficiency to treat corneal inflammation, without a great propensity to increase intraocular pressure. Unfortunately, its poor aqueous solubility, associated with a rapid precorneal elimination, results in a low drug bioavailability and a low penetration after topical ocular administration. The main objective of this study was to improve the apparent aqueous solubility of DXMa using cyclodextrins. First, hydroxypropy1-beta-CD (HP beta CD) and hydroxypropyl-gamma-CD (HP gamma CD) were used to enhance DXMa concentration in aqueous solution. The beta and gamma HPCD derivatives allowed the increase of the DXMa amount in solution at 25 degrees C by a factor of 500 and 1500, respectively. Second, with the aim of improving the persistence of the complex solution after instillation in the eye, the formulations of DXMa-based CD solutions with marketed ophthalmic gels (CELLUVISC (R), GEL-LARMES (R), and VISMED (R)) were investigated and optimized by means of special cubic mixture designs, allowing the defining of mixed gels loaded with 0.7% (HP beta CD) and 2% (HP gamma CD) DXMa with osmolality within acceptable physiological range. Finally, in vitro drug release assays from the mixed gels were performed and compared with reference eye drops. Similarly to MAXIDEX (R) and DEXAFREE (R), in the case of mixed gel containing HP beta CD, more than 90% of the drug was released within 2 h, while in mixed gel containing HP gamma CD, the release of DXMa was partial, reaching approximate to 60% in 2 h. This difference will have to be further addressed with ex vivo and in vivo ocular delivery experiments.