SBIR-STTR Award

Under this Fast-Track proposal, we will develop FenrockTM, an abuse-deterrent transdermal fentanyl patch based on our proprietary co-crystal of naltrexone (NTX) and its carefully selected conformer 5-methyl furfural (5-MFF). This NTX/5-MFF) co-crystal (NTX-Co) has 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 chewing, swallowing, solvent extraction, smoking or heating and inhaling. We will first develop analytical methods needed to measure the three patch components (fentanyl, NTX and 5-MFF). We 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 adhesives. The stability of NTX-Co in the presence of fentanyl and the list of acceptable excipients and adhesives will determine potential compartmental designs. We 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 simulations. These results and adhesion testing will determine the Phase I milestone: selection of up to three patch prototype concepts with integrated fentanyl and NTX-Co compartments. Phase II of this proposal will begin with production of these three patch prototype designs and their in vitro testing under use and abuse paradigms. These include 3D tissue models of transdermal and buccal absorption and in vitro tests to mimic chewing, swallowing, solvent extraction and volatilization by heating or smoking. A final ex vitro test will assess transdermal absorption in excised human skin. Up to two patch prototypes will be selected for a PK study in rats to compare fentanyl absorption rate to that of the Duragesic® fentanyl patch. Based on these data, one 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 minipig, the required species for transdermal products. We 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 safety. With the PK, dermal irritation and relative dose determination completed, one formulation will be selected and a GLP tox lot manufactured. We will then conduct a dose range finding study and the pivotal 28-day GLP tox in minipig. At the completion of the proposed work, Fenrock will be ready for GMP scale-up and clinical trials.

Public Health Relevance Statement:
8. Project Narrative Abuse and accidental misuse of transdermal fentanyl patches is a serious health issue: when exposed to liquids or put in the mouth, a 3-day supply of this fast-acting and highly potent opiate is delivered quickly. We proposed to develop FenrockTM, an abuse-deterrent transdermal fentanyl patch based on our proprietary co-crystal of naltrexone. The 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 chewing, swallowing, solvent extraction, smoking or heating and inhaling.

Project Terms:
absorption; addiction; Adhesions; Adhesives; analytical method; Artificial Membranes; base; Biological Assay; Breathing; Child; clinical lot; Clinical Trials; conformer; crystallinity; Crystallization; Dangerousness; Data; Deglutition; Dermal; design; Development; Dissociation; Dose; Drug Kinetics; Enhancers; Ensure; Evaluation; Excipients; experience; Fentanyl; Film; Formulation; Genetic Polymorphism; Health; Heating; Heroin; Human; In Vitro; in vitro testing; in vivo; Individual; irritation; Liquid substance; Mastication; Measures; method development; Methods; Miniature Swine; Modeling; Morphine; Naltrexone; Opiates; Oral cavity; Overdose; Pharmaceutical Preparations; Phase; Polymers; Preclinical Testing; preference; prescription opioid abuse; pressure; Process; process optimization; Production; Property; prototype; Rattus; Resistance; Rewards; Risk; Safety; scale up; simulation; Skin; Smoking; Solid; solid state; Solubility; solvent extraction; stability testing; System; Technology; Testing; Tissue Model; Toxic effect; Volatilization; Work

Under this Fast-Track proposal, we will develop Fenrock™, an abuse-deterrent transdermal fentanyl patch based on our proprietary co-crystal of naltrexone (NTX) and its carefully selected conformer 5-methyl furfural (5-MFF). This NTX/5-MFF) co-crystal (NTX-Co) has 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 chewing, swallowing, solvent extraction, smoking or heating and inhaling. We will first develop analytical methods needed to measure the three patch components (fentanyl, NTX and 5-MFF). We 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 adhesives. The stability of NTX-Co in the presence of fentanyl and the list of acceptable excipients and adhesives will determine potential compartmental designs. We 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 simulations. These results and adhesion testing will determine the Phase I milestone: selection of up to three patch prototype concepts with integrated fentanyl and NTX-Co compartments. Phase II of this proposal will begin with production of these three patch prototype designs and their in vitro testing under use and abuse paradigms. These include 3D tissue models of transdermal and buccal absorption and in vitro tests to mimic chewing, swallowing, solvent extraction and volatilization by heating or smoking. A final ex vitro test will assess transdermal absorption in excised human skin. Up to two patch prototypes will be selected for a PK study in rats to compare fentanyl absorption rate to that of the Duragesic® fentanyl patch. Based on these data, one 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 minipig, the required species for transdermal products. We 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 safety. With the PK, dermal irritation and relative dose determination completed, one formulation will be selected and a GLP tox lot manufactured. We will then conduct a dose range finding study and the pivotal 28-day GLP tox in minipig. At the completion of the proposed work, Fenrock will be ready for GMP scale-up and clinical trials.

Public Health Relevance Statement:
8. Project Narrative Abuse and accidental misuse of transdermal fentanyl patches is a serious health issue: when exposed to liquids or put in the mouth, a 3-day supply of this fast-acting and highly potent opiate is delivered quickly. We proposed to develop Fenrock™, an abuse-deterrent transdermal fentanyl patch based on our proprietary co-crystal of naltrexone. The 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 chewing, swallowing, solvent extraction, smoking or heating and inhaling.

NIH Spending Category:
Drug Abuse (NIDA only); Opioid Misuse and Addiction; Opioids; Substance Abuse

Project Terms:
3-Dimensional; absorption; addiction; Adhesions; Adhesives; analytical method; Artificial Membranes; base; Biological Assay; Child; clinical lot; Clinical Trials; conformer; crystallinity; Crystallization; Dangerousness; Data; Deglutition; Dermal; design; Development; Dissociation; Dose; Drug Kinetics; Enhancers; Ensure; Evaluation; Excipients; experience; Exposure to; Fentanyl; Film; Formulation; Genetic Polymorphism; Health; Heating; Heroin; Human; In Vitro; in vitro testing; in vivo; Individual; Ingestion; Inhalation; irritation; Liquid substance; Mastication; Measures; method development; Methods; Miniature Swine; Modeling; Morphine; Naltrexone; Opioid; opioid user; Oral cavity; overdose risk; Pharmaceutical Preparations; Phase; Polymers; Preclinical Testing; preference; prescription opioid abuse; pressure; Process; process optimization; Production; Property; prototype; Rattus; Resistance; Rewards; Risk; Safety; scale up; simulation; Skin; Smoking; Solid; solid state; Solubility; solvent extraction; stability testing; System; Technology; Testing; Tissue Model; Toxic effect; Volatilization; Work