药物流行病学和药物安全性的进展

抽象的

治疗眼后部疾病的新型药物输送系统

惠特尼·沙茨

介绍：

眼睛是特殊的感觉器官，具有复杂而复杂的生命系统和生理学。眼睛对视觉至关重要，由各种防御屏障保护；从静态（膜性）屏障到动态（血管性）屏障。尽管这些屏障非常有效地保护眼睛免受外源性物质和外界压力的伤害，但它还是受到各种永久性视力损害疾病的影响，如白内障、结膜炎、青光眼、葡萄膜炎、糖尿病视网膜病变 (DR)、糖尿病性黄斑水肿 (DME)、老年性黄斑变性 (AMD)、巨细胞病毒 (CMV) 视网膜炎、视网膜色素变性 (RP)、视网膜静脉阻塞 (RVO)、影响眼睛前部和后部的眼内炎。到达手术部位所需的药物受其标志性屏障限制。防御系统在平稳输送方面会变成障碍，特别是如果眼睛后部出现问题。老年性黄斑变性是一种影响眼后部的眼部疾病，会逐渐损害清晰的局部视力，并可能极大地影响患者的生活质量。玻璃体内注射是蛋白质治疗药物给药的首选方式，每 4 个月给药一次可获得最大益处。减少连续给药可减轻治疗负担并增加耐受性，从而增加对长效给药 (LAD) 改进的需求。

将药物输送到眼睛，尤其是用于治疗后部感染，是一项复杂的任务，需要将药物输送到眼睛的边界之外，这些边界可用于限制药物和外来化合物的进入。将药物输送到眼药水、直接注射和基础制备的传统方法都存在限制其可用性的问题，尤其是对于分子量高且溶于水的药物。目前，大多数眼部疾病都是通过局部使用溶液来治疗的，对于水溶性药物，这些溶液被处理成眼药水，对于水不溶性药物，这些溶液被处理成药膏或水悬浮液。这些尺寸结构占目前已上市药物的约 90%。角膜代表局部应用药物进入眼睛的重要途径。环状封闭交叉点（小带闭塞）完全包围并有效封闭浅表上皮细胞，使角膜成为药物渗透的强大屏障。药物分子进入角膜组织似乎也影响了经角膜的渗透。局部应用药物的结膜浸润和吸收通常比角膜吸收高得多。此外，高泪液周转率和鼻泪管渗出加剧了快速和广泛的角膜前损伤，限制了结膜浸润的有效性。因此，滴眼药水后，不到 5% 甚至只有 1% 的药物进入角膜并进入眼内组织。有人建议，滴眼药水后，玻璃体中的最大浓度约为药水本身的十万分之一。

有时，将药物直接注射到玻璃体腔中，以在玻璃体和视网膜中实现高药物浓度。但是，为了在较长时间内保持药物浓度处于治疗水平，需要重复注射，因为药物在玻璃体中的半衰期通常相对较短。重复注射会导致患者不适，并可能导致并发症，例如玻璃体出血、感染以及眼球或视网膜损伤。此外，用于治疗后部疾病的大多数药物的治疗记录较低，可能需要在视网膜有毒或接近有毒水平的剂量下进行注射。使用结膜下或球后注射的眼周输送提供了一种更安全、更不显眼的玻璃体内注射替代方案；该区域已被确定为有控制的药物输送的潜在部位。虽然眼科药物的常规给药有时用于治疗玻璃体视网膜疾病，但由于血视阻断效率高，因此并不是一个有效的解决方案。获得眼部治疗水平的药物所需的大量基础剂量通常严重限制了这种方法的有效性；眼外组织的毒性是一个常见的障碍。此外，位于视网膜血管内皮细胞水平和视网膜色上皮中的血视阻断阻碍了某些药物从基础给药途径通过。

In view of these conveyance issues it isn't amazing that, regardless of representing over 55% of every single visual ailment, issues identified with the back portion represent under 5% of the ophthalmic medication showcase. A large portion of the at present accessible clinical treatments for the treatment of sicknesses bringing about loss of sight because of neovascularization in the eye i.e., laser photocoagulation treatment for diabetic retinopathy and photodynamic treatment for age-related macular degeneration utilize either careful mediation or fundamental conveyance of a remedial specialist as the conveyance strategy. The use of novel angiostatic operators, especially proteins or protein-like medications including hostile to vascular endothelial development factor (VEGF), lattice metalloproteinase (MMP) inhibitors, integrin agonists, shade epithelium-inferred factor (PEDF) and inhibitors of insulin-like development factor-1 and development hormone, will require progressively modern techniques for conveyance to guarantee action and adequacy of the medication over a drawn out timeframe and to limit sedate instigated inconveniences. Novel conveyance frameworks are likewise required for therapeutics with a significant level of fundamental poisonousness, for example, steroids. Various epic strategies are being worked on or in clinical use. Gadgets produced using both biostable (nondegradable) and from biodegradable polymers have been researched and examined. Gadgets produced using biodegradable polymers have the favorable position that they corrupt and accordingly vanish from the site of implantation after some time. The potential for additional turn of events, especially for protein operators, is huge; this improvement can exploit information acquired in conveyance of protein medications to different destinations.

Methodology and Theoretical Orientation: Since leeway from the eye is represented essentially by dispersion, restorative Fab was artificially conjugated to different multivalent frameworks by means of maleimide science to increment Fab half-life. Each Fab-conjugate applicant was evaluated dependent on a huge number of criterial including conjugation proficiency, proportion of Fab to transporter, hydrodynamic span, long terms soundness, thickness and action. Now and again, in vivo decency tests were performed to survey biocompatibility with visual tissues.

Findings: Assessment of every framework uncovered characteristics attractive for visual LAD. Frameworks made out of either PEG, HPMA or lipoprotein were viable in expanding Fab RH. Geometry didn't enormously impact RH however affected thickness. Biocompatibility study exhibited bearableness of PEG however not of lipoprotein bearer.

结论和意义：尽管体外 RH 测量对于预测玻璃体半衰期很有用，但平台生物相容性越来越令人困惑，并且一直是实现新技术的重大障碍。