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

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 and safer procedure than a surgical implantation of an IT Baclofen pump.