Microneedle Delivery of Trospium Chloride Optimized for Improved Tolerance and Patient Outcomes in Overactive Bladder Disease

摘要 膀胱过度活动症（OB）是一种困扰男性和女性的疾病，是由人口老龄化驱动的 据估计，在美国的患病率高达39%，在所有65岁以上的妇女中为45%。OB伴随着 生活质量显著下降，记录的福尔斯、焦虑和抑郁增加。毒蕈碱 拮抗剂（抗胆碱能药）是治疗的主要药物，但这些药物与 许多副作用和药物相互作用导致超过50%的患者停止治疗 在6-12个月内。此外，随着年龄的增长，越来越关注抗胆碱能药物超负荷（特别是 由于药物-药物相互作用），导致额外的影响，如认知障碍和其他CNS影响。 研究表明，毒蕈碱拮抗剂在OB治疗中的药效学功效是强烈的， 与浓度-时间曲线下面积（AUC）相关，许多副作用与 最大血浆浓度（Cmax）。奥昔布宁是副作用最大的药物之一， 作为一种粘性贴片，由于药物持续有效，大大减少了胆碱能副作用 浓度.不幸的是，该贴片有其显著的副作用，主要是严重的皮肤刺激， 有效递送所需的渗透增强剂。考虑到患有OB的人口非常多， 尽管许多OB药物和制剂未能充分治疗该疾病， 医疗需要新的治疗选择。 微针透皮递送相对于其他透皮方法的多个优点已经得到证实。 记录在案。最近，可溶胀的水凝胶微针（HMN）已被证明是高效的微针植入剂。 用于增加药物的皮肤渗透的无痛方法 单体进入循环。我们选择了曲司氯铵（TC），这是效果最好的OB药物 并且副作用最少，但却受到通过药物递送的低生物利用度和高药代动力学变异性的困扰。 HMN。该产品将是一种无药物的HMN阵列，具有TC药物储存器，以实现严格控制的输送 TC，提供具有一致血浆浓度的有效AUC。这种自我管理的贴片是 设计用于在一周内提供TC，并将成为第一种具有优异疗效的OB治疗， 以及高的患者依从性和满意度。 这项工作的最终结果将是一种新的，经皮给药的TC与容易翻译的PK方法， 有效性和初始临床前安全性数据，准备完成临床前开发活动， 我们已经组建了一个专家顾问和合作者团队，以确保成功 完成这项研究计划。

Abstract Overactive bladder (OB) is a disease that afflicts both men and women and is driven by the aging population with a prevalence estimated as high as 39% in the US and 45% for all women over 65. OB is accompanied with a significant loss of quality of life with documented increases in falls, anxiety, and depression. The muscarinic antagonists (anticholinergics) are the primary drugs for treatment, but these agents are associated with numerous side effects and drug-drug interactions leading to discontinuation of therapy in over 50% of patients in 6-12 months. Furthermore, with age there is a growing concern for anticholinergic drug overload (especially due to drug-drug interactions) leading to additional effects such as cognition impairment and other CNS affects. Studies have shown that the pharmacodynamics efficacy of muscarinic antagonists in OB therapy is strongly associated with area under the concentration-time curve (AUC) and that the many side effects are related to maximum plasma concentrations (Cmax). Oxybutynin, one of the agents with the most side effects, was formulated as an adhesive patch, which greatly reduced cholinergic side effects due to a constant effective drug concentration. Unfortunately, the patch had its own significant side effects, mainly serious skin irritations due to the permeation enhancers needed for effective delivery. Given the very large population afflicted with OB, and the many OB drugs and formulations which fail to adequately treat the disease, there remains a desperate unmet medical need for new therapy options. Multiple advantages of microneedle transdermal delivery over other transdermal methods have been documented. More recently, swellable hydrogel microneedles (HMN) have been shown to be a highly efficient and painless method for increasing the skin permeation of drugs without additives, sharps, or polymeric monomers entering the circulation. We have selected Trospium Chloride (TC), the OB drug with the best efficacy and least side effects, yet plagued by poor bioavailability and high pharmacokinetic variability for delivery via HMN. The product will be a drug-free HMN array with a TC drug reservoir to enable a tightly controlled delivery of TC, providing efficacious AUCs with consistent plasma concentrations. This self-administered patch is designed to deliver TC over the course of a week, and will be the first OB treatment with both excellent efficacy, as well as high patient compliance and satisfaction. The end result of this work will be a novel, transdermal delivery approach for TC with readily translatable PK, efficacy and initial preclinical safety data, ready to complete preclinical development activities leading to the opening of an IND. We have assembled a team of expert advisors and collaborators to ensure successful completion of this research plan.