Development of Tetrahydrocannabinol Prodrugs for Topical Treatment of Glaucoma

描述(由申请人提供)： 目前，FDA批准的9-四氢大麻酚(THC)的临床应用包括控制与化疗相关的恶心和呕吐，以及用于患有厌食和消瘦综合征的艾滋病患者的食欲刺激。然而，THC也具有治疗青光眼的巨大潜力，青光眼是第二大致盲原因，它可以降低眼压，并通过与眼组织上表达的大麻素受体相互作用，起到视网膜神经保护的作用。然而，到目前为止，缺乏有效局部注射THC的适当机制一直是一个限制因素。我们建议扩大THC研究的范式，以适当的药物设计和给药策略，通过局部给药来提高这种有价值的药物化合物的眼部生物利用度。该项目将验证这样一种假设，即选择新型亲水性氨基酸(AA)、二元酸(DCA)或其组合(AA-AA、AA-DCA)为基础的THC前药将改善经角膜渗透，并将表现出对酶和化学水解的最佳抵抗力。我们在目标1中的方法将是选择和合成THC前体药物及其盐类。具体来说，氨基酸和/或二元酸将以某种方式连接到THC，以产生代表各种计算的logP值、电荷和链长及其盐的THC前药(THC-AA、THC-AA-AA、THC-DCA和THC-AA-DCA)。合成的前体药物将通过高效液相色谱-质谱仪和核磁共振(1H和13C)等分析工具进行鉴定。在目标2下，将测定前药在眼组织匀浆、房水和玻璃体房水中的物理化学特性、水的溶解度、与pH有关的溶解度和稳定性，以及前药在眼组织匀浆和房水和玻璃体中的生物还原。体外渗透性将使用离体兔角膜进行评估。最后，Aim 3将确定选定的THC前药在新西兰白化兔体内的眼部生物利用度和药理活性。所选前体药物的降眼压性能将与母药THC的性能进行比较。将制备适用于局部给药的制剂。除了评估对眼压的影响外，最有效的前药/剂量的眼部生物利用度将在麻醉的兔模型中确定，使用双探头眼微透析技术采样房水和玻璃体。在这些研究中，还将测定最终时间点的血浆THC水平以及THC酸和11-羟基THC代谢物水平，以评估全身暴露。预计与THC相比，本申请中提出的创新THC前药将显著更具亲水性和稳定性，并且在局部应用后将显示出显著的降眼压活性。此外，这项研究将更好地了解局部给药后药物渗透到眼后组织所需的物理化学和制剂特性，从而有助于改进青光眼和其他许多眼病的治疗选择。 公共卫生相关性： 这一STTRI期应用旨在开发用于滴眼液局部给药的亲水性四氢大麻酚(THC)前药。这类前药在预防青光眼患者视力丧失或恶化方面将具有重要价值。

DESCRIPTION (provided by applicant): Currently, FDA approved clinical applications of 9-Tetrahydrocannabinol (THC) include control of nausea and vomiting associated with chemotherapy and for appetite stimulation for AIDS patients suffering from anorexia and wasting syndrome. However, THC also has significant potential in the treatment of glaucoma, the second largest cause of blindness, by decreasing intraocular pressure and by acting as a retinal neuroprotectant, through an interaction with the cannabinoid receptors expressed on the ocular tissues. To date, however, lack of an appropriate mechanism for effective topical delivery of THC has been a limiting factor. We propose to broaden the paradigm of THC research to appropriate drug design and delivery strategies to enhance ocular bioavailability, through topical administration, of this valuable medicinal compound. This project will test the hypothesis that selected novel hydrophilic amino acid (AA), dicarboxylic acid (DCA) or combination (AA-AA, AA-DCA) based THC prodrugs will improve transcorneal penetration and will demonstrate optimal resistance to enzymatic and chemical hydrolysis. Our approach in Aim 1 will be to select and synthesize THC prodrugs and their salts. Specifically, amino and/or dicarboxylic acids will be linked to THC in a manner to yield THC prodrugs (THC-AA, THC-AA-AA, THC-DCA, and THC-AA-DCA) representing a variety of computed logP values, charge and chain length and their salts. The identity of the prodrugs synthesized will be established using analytical tools such as HPLC-MS and NMR (1H and 13C). Under Aim 2, physicochemical characteristics, aqueous solubility, pH dependent solubility and stability in aqueous solutions, as well as bioreversion of the prodrugs in ocular tissue homogenates and aqueous and vitreous humor will be determined. In vitro permeability will be evaluated using isolated rabbit corneas. Finally, Aim 3 will determine ocular bioavailability and pharmacological activity of selected THC prodrugs in vivo in New Zealand albino rabbits. Intraocular pressure (IOP) lowering properties of the selected prodrugs will be compared to that of the parent drug, THC. Suitable formulations for topical delivery will be prepared. In addition to evaluating the effect on the IOP, ocular bioavailability of the most effective prodrug/dose will be determined in the anesthetized rabbit model using a dual probe ocular microdialysis technique to sample the aqueous and vitreous humor. Plasma THC levels, as well as THC acid and 11-hydroxy THC metabolite levels, at the final time point, will also be determined in these studies to estimate systemic exposure. It is expected that the innovative THC prodrugs proposed in this application will be markedly more hydrophilic and stable, compared to THC, and will show significant IOP lowering activity following topical application. Additionally, this study will provide a better understanding of the physicochemical and formulation characteristics necessary for drug penetration into the back-of-the eye tissues following topical administration and thus help improve treatment options for glaucoma as well as a host of other ocular diseases. PUBLIC HEALTH RELEVANCE: This STTR Phase I application is directed towards the development of hydrophilic tetrahydrocannabinol (THC) prodrugs for topical administration as eyedrops. Such prodrugs will be of great value in the prevention of loss or deterioration of vision in patients suffering from glaucoma.