ION CHANNEL PHARMACOLOGY LLC — Department of Health and Human Services SBIR Phase I: 200

Description

Development and Evaluation of a polymer coated proprietary cream formulation ofresiniferatoxin nanoparticles for the Treatment of Pain Associated with DiabeticPeripheral Neuropathy Diabetes is a major problem in developed and developing countriesIt is estimated thatmillion adults will have diabetes globally by yearOne of the major complications of diabetes is diabetic peripheral neuropathyDPNresulting in pain from the extremities referred to as painful DPNPDPNTreatment options include centrally acting drugs such as antidepressantsanticonvulsants and opioids and topical agentsAddiction and over dose have become serious problems while treating painful conditions with opioidsFor the pastyearswe have been working on Transient Receptor Potential VanilloidTRPVreceptoran ion channel expressed in the peripheral terminals of sensory neurons that is activated by capsaicinan ingredient in hot chili pepperTRPVis considered as a target for next generation analgesicsPotent antagonists have been synthesized and shown to be effective in clinical trialsUnfortunatelyTRPVantagonists induced hyperthermia in clinical trials leading to their abandonment as a therapeutic armamentariumHoweverTRPVagonists have been useful to treat painful conditions by virtue of their ability to cause calcium influx leading to nerve terminal desensitization depletionRecentlyan eight percent capsaicin containing patchQutenzahas been approved for the treatment of PDPN in EuropeSince activation of TRPVdepolarizes the nerve terminal and generates action potentials leading to painlidocainea local anesthetic is applied to numb the area prior to application of capsaicin patchWe have been working on an ultrapotent TRPVagonistresiniferatoxinRTXobtained from the spurge Euphorbia resiniferawhich has a high affinity for the receptor and able to fully activate the receptor in femtomolar concentration rangesThereforelower concentrations can activate the channel slowly in a ramp like fashion avoiding rapid depolarization and preventing generation of action potentialsas a result RTX cream does not induce pain during applicationIn Aimwe will prepare a polymer coated proprietary cream formulation of RTX nanoparticlesfor which we have intellectual property rights and trade marked asNanoResinizinTMIn Aimwe will determine the lowest effective concentration range of RTX in the cream formulation by topical application in animal modelsrats and pigsof diabetes that alleviates pain associated with DPNWe will use radiant heat and a state of the art Diode laser fiber type selective stimulationDLssapproach for Aor C fibersThis method can be applied effectively in humans during the phase II of the translational phaseWe propose that NanoResinizinTM cream will be cost effective and can replace the use of capsaicinplus lidocaine to treat painful conditionsuse of which is both cumbersome and associated with significant side effectsSince the last submissionwe have prepared the RTX cream formulation and provide evidence using in vitro skin membrane preparations that RTX diffuses well across the skinFigOne of the major complications of diabetes is painful diabetic peripheral neuropathyPDPNSymptoms include electrical or stabbing sensationsparesthesiashyperesthesiaspins and needlesburning painand deep aching painWe have demonstrated that Transient Receptor Potential VanilloidTRPVion channel plays a significant role in different modalities of pain including PDPNRecentlytopical application of high concentrationof capsaicina TRPVagonsit has been approved for the treatment of PDPN in EuropeEight percent capsaicin patch has significant side effects such as erythemapruritis and severe burning pain during applicationWe have been studying an ultrapotent TRPVagonist resiniferatoxinRTXfor the pastyearsWe have shown that RTX fully and selectively activates TRPVreceptor at very low concentrations and induces depolarization block of nerve terminals and prevents transmission of painful informationIn this projectwe will develop a cream formulation of RTX nano particles that is effective by sustained activation of TRPVat very low doses without inducing any of the adverse effects of capsaicnespecially pain during application