Sustained Delivery of Tizanidine for Maintenance Treatment of Moderate to Severe Spasticity

替扎尼定持续给药用于中度至重度痉挛的维持治疗

• 批准号: 10383278
• 负责人: FRANCIS JOSEPH MARTIN
• 金额: $ 128.07万
• 依托单位: DELPOR, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383278
• 关键词: Abdomen; Acids; Adult; Affect; Automobile Driving; Award; Baclofen; Biological Assay; Bradycardia; Catheters; Cerebral Palsy; Child; Childhood; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Complication; Contracture; Data; Device Designs; Devices; Diffusion; Dimensions; Distress; Dose; Drowsiness; Drug Prescriptions; Excipients; Exposure to; Extravasation; Formulation; General Anesthesia; Grant; Half-Life; Health Care Costs; Hour; Hypotension; Implant; Implantation procedure; In Vitro; Incidence; Infection; Infusion Pumps; Lead; Legal patent; Length of Stay; Life; Local Anesthetics; Local anesthesia; Maintenance; Maintenance Therapy; Medical; Meningitis; Methods; Modeling; Motor Neurons; Multiple Sclerosis; Muscle; Muscle Spasticity; Muscle Tonus; Muscle Weakness; Nausea; Neuraxis; Operative Surgical Procedures; Oral; Outcome; Pain; Pathology; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Plasma; Population; Preparation; Procedures; Protocols documentation; Pump; Quality of life; Reporting; Research; Risk; Risperidone; Safety; Sampling; Sedation procedure; Self Care; Skeletal Muscle; Solubility; Spasm; Spasmolytics; Spastic Cerebral Palsy; Spinal cord injury; Sterilization; Stroke; Surgical Management; Symptoms; System; Technology; Testing; Therapeutic; Time; Titanium; Traumatic Brain Injury; Trocars; Upper arm; Validation; Xerostomia; analytical method; assay development; base; comorbidity; design; implantation; improved; manufacturing process; meetings; method development; multiple sclerosis patient; palliative; pediatric patients; pre-clinical; programs; protonation; safety study; septic; side effect; spasticity; standard of care; subcutaneous; success; symptom treatment; tizanidine; tool; treatment duration

Spasticity is an increase in muscle tone and uncontrolled, repetitive, involuntary contractions of skeletal muscles. Spasticity presents as upper motor neuron symptoms in patients with central nervous system pathology such as cerebral palsy (CP), multiple sclerosis (MS), traumatic brain injury (TBI) and spinal cord injury (SCI). Two thirds of all children with CP suffer from spasticity. Children with severe spastic CP are highly limited in daily life activities causing a reduced quality of life. The proportion of MS patients with inadequate symptom treatment for spasticity ranges from 46%- 52.5%. Tizanidine and Baclofen are two of the most prescribed drugs for spasticity treatment. Both drugs have a very short half-life and need to be administered 3-4 times per day. These drugs result in several side effects at high plasma levels such as muscle weakness, nausea, somnolence and paraesthesia, limiting their clinical utility, particularly in the palliative maintenance setting. Baclofen is also available as an intrathecal infusion pump (ITB). ITB reduces the spasticity of affected patients and represents the standard of care for severe spastic CP. However, intrathecal therapy requires a 1-3 hour surgery done under local or general anesthesia and requiring a hospital stay at times. ITB also introduces risks related to the pump and the robustness and placement of the intrathecal catheter. The combination of comorbidities predispose patients to ITB complications including septic infections, and meningitis in 8.7% of patients. In the pediatric population, the rate of complications is much higher (31%) requiring surgical management over a 3-year treatment period. The proposed product is a small non-mechanical (passive) subcutaneous implant (reservoir) which will deliver consistent therapeutic levels of tizanidine during a period of 4 months or longer. The implant body is made of titanium and it is implanted subcutaneously in the upper arm via a trocar, with local anesthetic during a simple 10-minute in-office procedure. The technology is based on a unique formulation; a mixture of tizanidine and certain acid generating excipients, such as partially soluble acids. The solubilization of the acid keeps pH within the reservoir low, and in doing so, promotes the passive outward diffusion of tizanidine. The solubility of tizanidine is greatly enhanced upon protonation by acids, and thus the concentration gradient driving flux is greater under the acidic conditions provided by constant excipient dissolution within the reservoir. The technology has been validated clinically with another drug (risperidone), which is currently in a Phase II clinical trial. The preclinical proof of concept has already been completed as part of the phase 1 grant award. The current effort will complete all activities required for the successful preparation and submission of an IND, so a Phase I clinical study can be launched. The proposed tizanidine system is expected to provide enhanced clinical outcomes with fewer side effects compared to oral medications, and a much simpler & safer procedure than a surgical implantation of an IT Baclofen pump.

痉挛是指肌张力增加以及骨骼不受控制的、重复的、不自主的收缩 肌肉。中枢神经系统患者痉挛表现为上运动神经元症状 脑瘫 (CP)、多发性硬化症 (MS)、创伤性脑损伤 (TBI) 和脊髓等病理学 损伤（SCI）。三分之二的脑瘫儿童患有痉挛。患有严重痉挛性脑瘫的儿童 日常生活活动高度受限，导致生活质量下降。 MS 患者的比例 痉挛症状治疗不充分的比例为 46% - 52.5%。 替扎尼定和巴氯芬是治疗痉挛最常用的两种药物。这两种药物都具有非常 半衰期短，每日需给药3-4次。这些药物在高浓度下会产生多种副作用 血浆水平，如肌肉无力、恶心、嗜睡和感觉异常，限制了其临床用途， 特别是在姑息性维护环境中。巴氯芬也可用作鞘内输液泵 （ITB）。 ITB 可减轻受影响患者的痉挛状态，代表严重痉挛的护理标准 CP。然而，鞘内治疗需要在局部或全身麻醉下进行 1-3 小时的手术，并且 有时需要住院。 ITB 还引入了与泵及其稳健性和 鞘内导管的放置。合并症的组合使患者易患 ITB 8.7% 的患者出现并发症，包括化脓性感染和脑膜炎。在儿科人群中， 并发症的发生率要高得多（31%），需要在 3 年的治疗期内进行手术治疗。 拟议的产品是一种小型非机械（被动）皮下植入物（储库），它将提供 替扎尼定在 4 个月或更长时间内保持一致的治疗水平。植入体主体由 钛，通过套管针植入上臂皮下，在简单的过程中使用局部麻醉剂 10 分钟的办公室程序。该技术基于独特的配方；替扎尼定的混合物和 某些产酸赋形剂，例如部分可溶的酸。酸的溶解保持pH值 在储库内低，这样做促进了替扎尼定的被动向外扩散。溶解度 酸质子化后替扎尼定大大增强，因此浓度梯度驱动通量为 在储库内恒定的赋形剂溶解所提供的酸性条件下更大。这 该技术已通过另一种药物（利培酮）的临床验证，目前处于 II 期临床 审判。作为第一阶段拨款的一部分，临床前概念验证已经完成。这 当前的工作将完成成功准备和提交 IND 所需的所有活动，因此 可以启动I期临床研究。拟议的替扎尼定系统预计将提供增强的 与口服药物相比，临床结果副作用更少，而且程序更简单、更安全 与 IT 巴氯芬泵的手术植入相比。