Development of Tetrahydrocannabinol Prodrugs for Topical Treatment of Glaucoma

用于局部治疗青光眼的四氢大麻酚前药的开发

• 批准号: 8058186
• 负责人: MAHMOUD A ELSOHLY
• 金额: $ 16.74万
• 依托单位: ELSOHLY LABORATORIES, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8058186
• 关键词: Acids; Acquired Immunodeficiency Syndrome; Affect; American; Amino Acids; Animal Model; Animals; Anorexia; Anti-glaucoma Agent; Aqueous Humor; Area; Back; Biological Availability; Blindness; CNR1 gene; CNR2 gene; Cannabinoids; Characteristics; Charge; Chemicals; Complex; Cornea; Desire for food; Deterioration; Development; Dicarboxylic Acids; Disease; Dose; Drug Delivery Systems; Drug Design; Drug Formulations; Eye; Eyedrops; FDA approved; Fright; Future; Glaucoma; Goals; Government; High Pressure Liquid Chromatography; Hydrolysis; In Vitro; Investigation; Length; Link; Medical; Microdialysis; Modeling; Nausea and Vomiting; Nerve Degeneration; Neuroglia; Neurons; Neuroprotective Agents; New Zealand; Optic Nerve; Oryctolagus cuniculus; Parents; Patients; Penetration; Permeability; Pharmaceutical Preparations; Phase; Physiologic Intraocular Pressure; Plasma; Prevention; Prodrugs; Property; Protocols documentation; Research; Resistance; Retina; Retinal; Retinal Ganglion Cells; Route; Salts; Sampling; Site; Small Business Technology Transfer Research; Solubility; Solutions; Surface; Techniques; Testing; Tetrahydrocannabinol; Therapeutic; Time; Tissues; Topical application; Vision; Visual Fields; Vitreous humor; Wasting Syndrome; analytical tool; aqueous; base; cannabinoid receptor; chemotherapy; clinical application; cost; cytotoxicity; hydrophilicity; improved; in vivo; innovation; interest; novel

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.

描述（由申请人提供）： 目前，FDA批准9-四氢大麻酚（THC）的临床应用包括控制化疗相关的恶心和呕吐以及刺激患有厌食和消耗综合症的艾滋病患者的食欲。然而，THC 在治疗青光眼（导致失明的第二大原因）方面也具有巨大潜力，它可以降低眼内压，并通过与眼组织上表达的大麻素受体相互作用，充当视网膜神经保护剂。然而，迄今为止，缺乏有效局部施用 THC 的适当机制一直是一个限制因素。我们建议将 THC 研究范式扩大到适当的药物设计和递送策略，以通过局部给药增强这种有价值的药物化合物的眼部生物利用度。该项目将测试以下假设：选定的新型亲水性氨基酸 (AA)、二羧酸 (DCA) 或基于 THC 前药的组合（AA-AA、AA-DCA）将改善经角膜渗透，并表现出对酶促和化学水解的最佳抵抗力。我们的目标 1 的方法是选择和合成 THC 前药及其盐。具体地，氨基和/或二羧酸将以产生代表各种计算的logP值的THC前药（THC-AA、THC-AA-AA、THC-DCA和THC-AA-DCA）的方式与THC连接，电荷和链长及其盐。合成的前药的身份将使用 HPLC-MS 和 NMR（1H 和 13C）等分析工具来确定。在目标 2 下，将确定物理化学特性、水溶性、pH 依赖性溶解度和水溶液稳定性，以及前药在眼组织匀浆、房水和玻璃体液中的生物回复性。将使用离体兔角膜评估体外渗透性。最后，目标 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。所选前药的眼内压 (IOP) 降低特性将与母体药物 THC 进行比较。将制备适合局部递送的制剂。除了评估对 IOP 的影响外，还将使用双探针眼部微透析技术对房水和玻璃体液进行采样，在麻醉兔模型中确定最有效的前药/剂量的眼部生物利用度。这些研究还将确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，以估计全身暴露量。预计与THC相比，本申请中提出的创新THC前药将显着更具亲水性和稳定性，并且在局部应用后将显示出显着的IOP降低活性。此外，这项研究将更好地了解局部给药后药物渗透到眼后部组织所需的物理化学和配方特性，从而有助于改善青光眼以及许多其他眼部疾病的治疗选择。 公共卫生相关性： 该 STTR 第一阶段申请旨在开发亲水性四氢大麻酚 (THC) 前药，作为滴眼剂进行局部给药。此类前药对于预防青光眼患者视力丧失或视力恶化具有重要价值。