Sustained 3-Month Delivery of Tizanidine for Maintenance Treatment of Moderate to Severe Spasticity

Spasticity is an increase in muscle tone and uncontrolledrepetitiveinvoluntary contractions of skeletal musclesSpasticity presents as upper motor neuron symptoms in patients with central nervous system pathology such as cerebral palsyCPmultiple sclerosisMStraumatic brain injuryTBIand spinal cord injurySCITwo thirds of all children with CP suffer from spasticityChildren with severe spastic CP are highly limited in daily life activities causing a reduced quality of lifeThe proportion of MS patients with inadequate symptom treatment for spasticity ranges fromTizanidine and Baclofen are two of the most prescribed drugs for spasticity treatmentBoth drugs have a very short half life and need to be administeredtimes per dayThese drugs result in several side effects at high plasma levels such as muscle weaknessnauseasomnolence and paraesthesialimiting their clinical utilityparticularly in the palliative maintenance settingBaclofen is also available as an intrathecal infusion pumpITBITB reduces the spasticity of affected patients and represents the standard of care for severe spastic CPHoweverintrathecal therapy requires ahour surgery done under local or general anesthesia and requiring a hospital stay at timesITB also introduces risks related to the pump and the robustness and placement of the intrathecal catheterThe combination of comorbidities predispose patients to ITB complications including septic infectionsand meningitis inof patientsIn the pediatric populationthe rate of complications is much higherrequiring surgical management over ayear treatment periodThe proposed product is a small non mechanicalpassivesubcutaneous implantreservoirwhich will deliver consistent therapeutic levels of tizanidine during a period ofmonthsThe implant body is made of titanium and it is implanted subcutaneously in the upper arm via a trocarwith local anesthetic during a simpleminute in office procedureThe technology is based on a unique formulationa mixture of tizanidine and certain acid generating excipientssuch as partially soluble acidsThe solubilization of the acid keeps pH within the reservoir lowand in doing sopromotes the passive outward diffusion of tizanidineThe solubility of tizanidine is greatly enhanced upon protonation by acidsand thus the concentration gradient driving flux is greater under the acidic conditions provided by constant excipient dissolution within the reservoirThe technology has been validated preclinically with another drugrisperidonewhich is currently in a Phase I clinical trialThe current effort will test multiple formulations based on this technology in vitro and in vivoThe goal of this study is to show favorable PK and local tolerance and thus complete the preclinical proof ofconcept for the proposed tizanidine systemSuch system is expected to provide enhanced clinical outcomes with fewer side effects compared to oral medicationsand a much simpler andampsafer procedure than a surgical implantation of an IT Baclofen pump PROJECT NARRATIVE Spasticity is a commondistressing and disabling complication in a high proportion of patients with cerebral palsymultiple sclerosistraumatic brain injuryspinal cord injuryand strokeCompared to existing spasticity treatment optionsthe proposed product will substantially improve safetymaintain efficacy during maintenance treatmentand increase overall treatment successThe final outcome will be an improvement in patient livesand a reduction in overall healthcare costs