药物溶解度对经巩膜给药的影响

Effect of drug solubility on transscleral drug delivery

经巩膜给药因其创伤性小，吸收面积大，靶向传递性好等特点已成为备受关注的治疗眼后段疾病的给药方式。但在治疗眼后段疾病时，其临床有效性不及玻璃体腔给药，其原因在于药物经巩膜进入眼内的生物利用度不仅受到巩膜、脉络膜、视网膜色素上皮等解剖屏障的影响，还受到眼压及眼内液体向外作用力和脉络膜血流的影响。同时所用药物的溶解度、溶出速度、相对分子质量、分子半径、脂溶性等药物本身理化性质对药物传递到视网膜的效率也有很大的影响。其中药物溶解度是影响经巩膜给药后药物在眼内生物利用度的首要因素，也是研究给药时调控的关键因素之一。因为溶解度高时药物从药源溶出的速度也快，大量的药物在巩膜表面溶出，很容易通过结膜和表层巩膜中的血液和淋巴循环进入全身而引起不良反应；当药物溶解度很小或在溶液中溶出速度太慢时，很快被结膜和表层巩膜中的血液和淋巴循环移除，在巩膜表面形成药物浓度梯度，难以穿透巩膜进入眼内。因此在经巩膜给药治疗眼后段疾病过程中，药物的溶解度成为影响药物眼内生物利用度的重要因素之一。通常，治疗眼后段疾病的药物多为亲脂难溶于水的药物，科学家通过使用助溶剂改变药物分子的晶型，使用分散剂做成脂质体或微球混悬液等来增加药物水溶性以达到局部应用的目的。因此提高难溶性药物的溶解度是开发经巩膜给药剂型的常用手段，以促进药物经巩膜渗透进入眼内。本文就药物的溶解度对经巩膜给药的影响以及增大难溶性药物溶解度的方法进行综述，以期为经巩膜给药的基础和临床研究提供更多的科学依据和指导。

Transscleral drug delivery has emerged as an attractive method for treating posterior segment eye disorders due to its less invasive,large scleral surface, and good capability for targeted drug delivery. However,in the clinical retina of posterior segment diseases,transscleral drug delivery is less efficient than intravitreal injection. This is due to the fact that drug is subjected to the multiple barriers before crossing into retina or vitreous, such as the sclera,choroid,retinal pigment epithelium, and even the counter-directional intraocular pressure and the associated fluid movement as well as choroidal circulation. At the same time, the properties of the drug itself, such as water solubility,dissolution rate,molecular weight and radius, and hydrophobicity also significantly affect the drug crossing into retina. Out of these factors, water solubility is the key factor for optimal transscleral drug delivery to achieve greater retina bioavailability. When a drug has high water solubility and applied to sclera surface, high local drug concentration will be absorbed into systemic circulation and cause side effects;when a drug has very limited water solubility,local drug concentration on the sclera cannot reach a high enough concentration gradient across the selera and choroid, therefore the limited available drug will be cleared by the blood and lymphatic circulation of the eonjunctiva and episclera] tissues. Therefore,water solubility has become a good venue for scientists to develop various formulations to improve the solubility and the delivery efficiency for transscleral drug delivery. The drugs which can be utilized to treat ehorioretinal diseases are often of hydrophobieity or low water solubility. These drugs can be formulated into various suspensions with the help of altered crystallinity, addition of excipient, or solubility promoting agents, as well as various particulates, such as liposomes or nanoparticles to optimize the drug solubility or dissolution rate. Therefore,increasing the solubility of poorly soluble drugs is a commonly used means of developing transscleral drug delivery formulations to promote drug penetration into the sclera. In this review, we synthesized the updated information regarding effect of drug solubility on transscleral drug delivery in hope that the article will benefit both basic and clinical researches for further exploration of transscleral drug delivery.