Uchegbu Ijeoma F, Breznikar Jan, Zaffalon Alessandra, Odunze Uche, Schätzlein Andreas G
UCL School of Pharmacy, London's Global University, 29-39 Brunswick Square, London WC1N 1AX, UK.
Nanomerics Ltd. New Bridge Street House, 6th Floor, 2 London Wall Place, London EC2Y 5AU, UK.
Pharmaceutics. 2021 May 18;13(5):744. doi: 10.3390/pharmaceutics13050744.
Commercial topical ocular formulations for hydrophobic actives rely on the use of suspensions or oil in water emulsions and neither of these formulation modalities adequately promote drug penetration into ocular tissues. Using the ocular relevant hydrophobic drug, cyclosporine A (CsA), a non-irritant ocular penetration enhancer is showcased, which may be used for the formulation of hydrophobic actives. The activity of this penetration enhancer is demonstrated in a healthy rabbit model. The Molecular Envelope Technology (MET) polymer (N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan), a self-assembling, micelle-forming polymer, was used to formulate CsA into sterile filtered nanoparticulate eye drop formulations and the stability of the formulation tested. Healthy rabbits were dosed with a single dose of a MET-CsA (NM133) 0.05% formulation and ocular tissues analyzed. Optically clear NM133 formulations were prepared containing between 0.01-0.1% / CsA and 0.375-0.75% / MET polymer. NM133 0.01%, NM133 0.02% and NM133 0.05% were stable for 28 days when stored at refrigeration temperature (5-6 °C) and room temperature (16-23 °C), but there was evidence of evaporation of the formulation at 40 °C. There was no change in drug content when NM133 0.05% was stored for 387 days at 4 °C. On topical dosing to rabbits, corneal, conjunctival and scleral AUC levels were 25,780 ng.h g, 12,046 ng.h g and 5879 ng.h g, respectively, with NM133 0.05%. Meanwhile, a similar dose of Restasis 0.05% yielded lower values of 4726 ng.h/g, 4813 ng.h/g and 1729 ng.h/g for the drug corneal, conjunctival and scleral levels, respectively. NM133 thus delivered up to five times more CsA to the ocular surface tissues when compared to Restasis. The MET polymer was non-irritant up to a concentration of 4% /. The MET polymer is a non-irritant ocular penetration enhancer that may be used to deliver hydrophobic drugs in optically clear topical ocular formulations.
用于疏水性活性成分的商用局部眼用制剂依赖于使用混悬液或水包油乳液，而这两种制剂形式都不能充分促进药物渗透到眼组织中。以眼部相关的疏水性药物环孢素A（CsA）为例，展示了一种无刺激性的眼部渗透促进剂，其可用于疏水性活性成分的制剂。这种渗透促进剂的活性在健康兔模型中得到了证实。分子包封技术（MET）聚合物（N-棕榈酰-N-单甲基-N,N-二甲基-N,N,N-三甲基-6-O-乙二醇壳聚糖），一种自组装、形成胶束的聚合物，被用于将CsA制成无菌过滤的纳米颗粒滴眼剂制剂，并对制剂的稳定性进行了测试。给健康兔单次给药0.05%的MET-CsA（NM133）制剂，并对眼组织进行分析。制备了光学澄清的NM133制剂，其CsA含量为0.01 - 0.1%，MET聚合物含量为0.375 - 0.75%。NM133 0.01%、NM133 0.02%和NM133 0.05%在冷藏温度（5 - 6℃）和室温（16 - 23℃）下储存28天时稳定，但在40℃时有制剂蒸发的迹象。NM133 0.05%在4℃下储存387天时药物含量没有变化。给兔局部给药时，NM133 0.05%的角膜、结膜和巩膜的AUC水平分别为25780 ng·h/g、12046 ng·h/g和5879 ng·h/g。同时，相同剂量的0.05%的Restasis的药物角膜、结膜和巩膜水平分别为较低的4726 ng·h/g、4813 ng·h/g和1729 ng·h/g。因此，与Restasis相比，NM133向眼表组织递送的CsA高达其五倍。MET聚合物在浓度高达4%时无刺激性。MET聚合物是一种无刺激性的眼部渗透促进剂，可用于在光学澄清的局部眼用制剂中递送疏水性药物。
