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

痉挛是肌肉张力增加和骨骼肌不受控制的、重复的、不自主的收缩。 肌肉.痉挛是中枢神经系统疾病患者的上运动神经元症状 病理学，如脑瘫（CP）、多发性硬化（MS）、创伤性脑损伤（TBI）和脊髓损伤 损伤（SCI）。三分之二的脑瘫儿童患有痉挛。患有严重痉挛性CP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 痉挛症状治疗不足的比例为46%-52.5%。 替扎尼定和巴氯芬是两种最常用的痉挛治疗药物。这两种药物都有一个非常 半衰期短，需要每天给药3-4次。这些药物在高浓度下会产生一些副作用。 血浆水平如肌无力、恶心、嗜睡和感觉异常，限制了它们的临床应用， 特别是在姑息性维持治疗的情况下。巴氯芬也可作为鞘内输注泵 （ITB）。ITB可减轻受累患者的痉挛状态，代表重度痉挛性痉挛的标准治疗 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， 有时需要住院ITB还引入了与泵和稳健性相关的风险， 鞘内导管的放置。合并症使患者易患ITB 并发症包括脓毒性感染和脑膜炎，占8.7%。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。 申报产品是一种小型非机械（被动）皮下植入物（储药器）， 在4个月或更长的时间内，替扎尼定的治疗水平一致。植入体由以下材料制成： 钛，通过套管针皮下植入上臂，在简单的 10-办公室里的小程序该技术基于一种独特的配方;替扎尼定和 某些产生酸的赋形剂，例如部分可溶的酸。酸的增溶作用保持pH值 在储库内低，并且在这样做时，促进替扎尼定的被动向外扩散。的溶解度 替扎尼定在被酸质子化后大大增强，因此浓度梯度驱动通量被 在由贮库内的恒定赋形剂溶解提供的酸性条件下更大。的 该技术已在另一种药物（利培酮）上得到临床验证，目前正处于II期临床研究阶段。 审判临床前概念验证已经完成，作为第1阶段赠款的一部分。的 目前的工作将完成成功准备和提交IND所需的所有活动， 可以开展I期临床研究。预期所提出的替扎尼定系统提供增强的 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程序 比手术植入巴氯芬泵更简单

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.