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.

痉挛是指肌肉张力增加和骨骼不受控制的、反复的、不自主的收缩。 肌肉。痉挛表现为中枢神经系统患者的上运动神经元症状 病理，如脑瘫(CP)、多发性硬化症(MS)、创伤性脑损伤(TBI)和脊髓 损伤(SCI)。所有患有脑瘫的儿童中有三分之二患有痉挛。患有严重痉挛脑瘫的儿童 日常生活活动高度受限，导致生活质量下降。多发性硬化症患者的比例 痉挛症状治疗不足的比例在46%-52.5%之间。 替扎尼定和巴氯芬是治疗痉挛的两种最常用的处方药。这两种药物都有非常强的 半衰期短，每天需要给药3-4次。这些药物有几种副作用。 血浆水平，如肌肉无力，恶心，嗜睡和感觉异常，限制了它们的临床应用， 尤其是在姑息维持的情况下。巴氯芬也可用作鞘内输液泵。 (ITB)。ITB减少受影响患者的痉挛，代表了严重痉挛患者的护理标准 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 有时需要住院治疗。ITB还引入了与泵和坚固性相关的风险 鞘内导管的放置。合并合并症使患者易患ITB 8.7%的患者出现包括败血症感染和脑膜炎在内的并发症。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。 建议的产品是一种小型非机械(被动)皮下植入物(蓄水池)，将提供 在4个月或更长的时间内维持替扎尼定的治疗水平。植入体由以下材料制成 钛，通过套管针植入上臂皮下，在简单的手术中使用局部麻醉剂 10分钟的办公室内程序。这项技术基于一种独特的配方；替扎尼定和 某些产酸辅料，如部分溶解的酸。酸的增溶作用使其保持pH 在储集层内低，并在这样做时，促进了替扎尼定的被动向外扩散。水溶液的溶解度 替扎尼丁被酸质子化后大大增强，因此浓度梯度驱动通量是 在储层内赋形剂持续溶解所提供的酸性条件下，会产生更大的影响。这个 这项技术已经在另一种药物(利培酮)的临床上得到了验证，该药物目前处于二期临床 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。这个 目前的努力将完成成功编制和提交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更好的 与口服药物相比，副作用更少的临床结果，以及更简单和更安全的操作 而不是手术植入IT巴氯芬泵。