Abstract：
Efficient topical drug delivery remains a significant challenge in glaucoma management. Although nanoparticle formulations offer considerable promise, their complex preparation processes, co-delivery issues, and batch consistency have hindered their potential. A scalable fabrication strategy is developed here for preparing solid drug nanoparticles (SDNs) with enhanced drug delivery efficiency. Utilizing hydrophobic antiglaucoma drugs brimonidine (BM) and betaxolol (BX), uniform fixed combination BM/BX SDNs are fabricated through a continuous process, improving batch-to-batch consistency for combined glaucoma treatment. With trehalose being used as a lyoprotectant, BM/BX SDNs can be stored as dry powder and easily reconstituted in phosphate buffered saline. Importantly, reconstituted BM/BX SDNs form clear, homogenous solutions, and exhibit negligible cytotoxicity and irritation, making them well-suited for topical administration as eyedrops. Ex vivo and in vivo studies demonstrated that topically applied BM/BX SDNs permeate through the cornea significantly (about two fold to three fold) compared to their hydrophilic counterparts, i.e., brimonidine tartrate, and betaxolol hydrogen chloride. Notably, BM/BX SDNs displayed consistent intraocular pressure lowering effects in vivo in both normotensive rats and glaucoma mice. Collectively, this study demonstrates the potential of the scalable fabrication strategy and the resultant BM/BX SDNs for improving glaucoma management through eyedrops.
摘要：
有效的局部药物递送仍然是青光眼管理中的重大挑战。虽然纳米颗粒配方提供了相当大的前景，他们复杂的准备过程，共同交付问题，和批量一致性阻碍了它们的潜力。这里开发了一种可扩展的制造策略，用于制备具有增强的药物递送效率的固体药物纳米颗粒（SDN）。使用疏水性抗青光眼药物溴莫尼定（BM）和倍他洛尔（BX），通过连续工艺制造均匀固定组合BM/BXSDN，改善青光眼联合治疗的批次间一致性。海藻糖被用作冻干保护剂，BM/BXSDN可以作为干粉储存并容易地在磷酸盐缓冲盐水中重构。重要的是,重组的BM/BXSDN形式清晰，均匀溶液，并表现出微不足道的细胞毒性和刺激性，使它们非常适合作为眼药水的局部给药。离体和体内研究表明，与亲水对应物相比，局部施用的BM/BXSDN可显着（约2倍至3倍）渗透通过角膜。即，酒石酸溴莫尼定，和盐酸倍他洛尔.值得注意的是,BM/BXSDN在正常血压大鼠和青光眼小鼠体内均表现出一致的眼内压降低作用。总的来说，这项研究证明了可扩展制造策略和所得BM/BXSDN通过滴眼液改善青光眼管理的潜力。
