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

摘要 膀胱过度活动(OB)是一种男性和女性都会受到困扰的疾病，是由人口老龄化引起的 据估计，美国的患病率高达39%，65岁以上女性的患病率为45%。OB随行 生活质量显著下降，跌倒、焦虑和抑郁的增加有据可查。毒枭 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-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，抗胆碱能药物超载的问题日益受到关注(尤其是 由于药物与药物的相互作用)导致额外的影响，如认知障碍和其他中枢神经系统的影响。 研究表明，M受体拮抗剂在OB治疗中的药效学效果很强。 与浓度-时间曲线下面积(AUC)相关，以及许多副作用与 最大血浆浓度(Cmax)。奥昔布宁是副作用最大的药物之一， 配制成粘贴剂，大大减少了由于恒定有效的药物而产生的胆碱能副作用 集中精神。不幸的是，这种贴片本身也有明显的副作用，主要是由于以下原因引起的严重皮肤刺激 有效给药所需的渗透促进剂。鉴于受OB困扰的人口非常多，而且 许多OB药物和配方未能充分治疗这种疾病，但仍有一个令人绝望的问题没有得到满足 医疗需要新的治疗方案。 与其他经皮给药方法相比，微针经皮给药具有多种优点 有记录在案。最近，可膨胀水凝胶微针(HMN)被证明是一种高效的 用于增加药物的皮肤渗透性的无痛方法，不含添加剂、锐剂或聚合物 进入循环的单体。我们选择了疗效最好的OB类药物--三氯托普铵 副作用最小，但仍受到生物利用度低和药代动力学变异性高的困扰 HMN。该产品将是一种无药物的HMN阵列，带有TC药物储存库，以实现严格受控的递送 为有效的AUC提供稳定的血药浓度。这个自我管理的补丁是 旨在提供为期一周的TC，并将是第一个具有出色疗效的OB治疗， 以及较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、具有易于翻译的PK的TC经皮给药方法， 有效性和初步临床前安全性数据，准备完成导致 一个Ind的开业。我们已经组建了一支由专家顾问和合作者组成的团队，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.