García-Otero Xurxo, Díaz-Tomé Victoria, Varela-Fernández Rubén, Martín-Pastor Manuel, González-Barcia Miguel, Blanco-Méndez José, Mondelo-García Cristina, Bermudez Maria A, Gonzalez Francisco, Aguiar Pablo, Fernández-Ferreiro Anxo, Otero-Espinar Francisco J
Pharmacology, Pharmacy and Pharmaceutical Technology Department, Faculty of Pharmacy, University of Santiago de Compostela (USC), 15705 Santiago de Compostela, Spain.
Molecular Imaging Group, University Clinical Hospital, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain.
Pharmaceutics. 2021 Jan 23;13(2):149. doi: 10.3390/pharmaceutics13020149.
Uveitis is a vision inflammatory disorder with a high prevalence in developing countries. Currently, marketed treatments remain limited and reformulation is usually performed to obtain a tacrolimus eye drop as a therapeutic alternative in corticosteroid-refractory eye disease. The aim of this work was to develop a mucoadhesive, non-toxic and stable topical ophthalmic formulation that can be safely prepared in hospital pharmacy departments. Four different ophthalmic formulations were prepared based on the tacrolimus/hydroxypropyl-β-cyclodextrin (HPβCD) inclusion complexes' formation. Phase solubility diagrams, Nuclear Magnetic Resonance (NMR) and molecular modeling studies showed the formation of 1:1 and 1:2 tacrolimus/HPβCD inclusion complexes, being possible to obtain a 0.02% () tacrolimus concentration by using 40% () HPβCD aqueous solutions. Formulations also showed good ophthalmic properties in terms of pH, osmolality and safety. Stability studies proved these formulations to be stable for at least 3 months in refrigeration. Ex vivo bioadhesion and in vivo ocular permanence showed good mucoadhesive properties with higher ocular permanence compared to the reference pharmacy compounding used in clinical settings ( of 86.2 min for the eyedrop elaborated with 40% () HPβCD and Liquifilm versus 46.3 min for the reference formulation). Thus, these novel eye drops present high potential as a safe alternative for uveitis treatment, as well as a versatile composition to include new drugs intended for topical ophthalmic administration.
葡萄膜炎是一种在发展中国家高发的眼部炎症性疾病。目前，市售的治疗方法仍然有限，通常会进行重新配方以获得他克莫司滴眼液，作为皮质类固醇难治性眼病的一种治疗选择。这项工作的目的是开发一种可在医院药房安全制备的、具有粘膜粘附性、无毒且稳定的局部眼用制剂。基于他克莫司/羟丙基-β-环糊精（HPβCD）包合物的形成，制备了四种不同的眼用制剂。相溶解度图、核磁共振（NMR）和分子建模研究表明形成了1:1和1:2的他克莫司/HPβCD包合物，通过使用40%（）的HPβCD水溶液可以获得0.02%（）的他克莫司浓度。制剂在pH值、渗透压和安全性方面也表现出良好的眼部特性。稳定性研究证明这些制剂在冷藏条件下至少3个月稳定。体外生物粘附和体内眼部滞留研究表明，与临床使用的参考药房配制剂相比，这些制剂具有良好的粘膜粘附特性和更高的眼部滞留时间（用40%（）HPβCD和泪然制备的滴眼液的眼部滞留时间为86.2分钟，而参考制剂为46.3分钟）。因此，这些新型滴眼液作为葡萄膜炎治疗的安全替代品具有很大潜力，并且是一种可包含用于局部眼用给药的新药的通用组合物。
