Preformulation and formulation development of Fenrock, an Abuse-resistant Fentanyl Transdermal Patch

Project Summary Abstract Under this Fast Track proposalwe will develop Fenrockan abuse deterrent transdermal fentanyl patch based on our proprietary co crystal of naltrexoneNTXand its carefully selected conformermethyl furfuralMFFThis NTXMFFco crystalNTX Cohas the desired properties to stay in a crystalline solid form in the patch when applied to skin as intended but to dissociate to deliver NTX when abused by chewingswallowingsolvent extractionsmoking or heating and inhalingWe will first develop analytical methods needed to measure the three patch componentsfentanylNTX andMFFWe will perform preformulation studies to assess solid state interaction of NTX Co with fentanyl and various excipients as well as compatibility with various pressure sensitive adhesivesThe stability of NTX Co in the presence of fentanyl and the list of acceptable excipients and adhesives will determine potential compartmental designsWe will then begin formulation development by testing several potential fentanyl and NTX Co patch components compartments and characterizing them individually in in vitro in dissolution and flux across an artificial membrane under use and abuse simulationsThese results and adhesion testing will determine the Phase I milestoneselection of up to three patch prototype concepts with integrated fentanyl and NTX Co compartmentsPhase II of this proposal will begin with production of these three patch prototype designs and their in vitro testing under use and abuse paradigmsThese includeD tissue models of transdermal and buccal absorption and in vitro tests to mimic chewingswallowingsolvent extraction and volatilization by heating or smokingA final ex vitro test will assess transdermal absorption in excised human skinUp to two patch prototypes will be selected for a PK study in rats to compare fentanyl absorption rate to that of the Duragesicfentanyl patchBased on these dataone or two prototypes will be selected for a dermal irritation study in rats and a PK study in minipig that will guide the IND enabling studies in minipigthe required species for transdermal productsWe will use the rat conditioned place preference paradigm to determine the optimal relative doses of NTX Co and fentanyl such that enough NTX is released under scenarios of abuse to reduce the rewarding effects of fentanyl and provide a measure of safetyWith the PKdermal irritation and relative dose determination completedone formulation will be selected and a GLP tox lot manufacturedWe will then conduct a dose range finding study and the pivotalday GLP tox in minipigAt the completion of the proposed workFenrock will be ready for GMP scale up and clinical trialsProject Narrative Abuse and accidental misuse of transdermal fentanyl patches is a serious health issuewhen exposed to liquids or put in the mouthaday supply of this fast acting and highly potent opiate is delivered quicklyWe proposed to develop Fenrockan abuse deterrent transdermal fentanyl patch based on our proprietary co crystal of naltrexoneThe co crystal will remain in the patch undelivered when applied as intended but will release naltrexone to counteract the fentanyl if the patch is abused by chewingswallowingsolvent extractionsmoking or heating and inhaling