Currently buprenorphine (BUP) is used in the treatment of opioid abuse and for pain management. It can also be used improperly and abused as an opioid. In the United States, buprenorphine is marketed in sublingual and injectable forms. While the drug provides effective treatment, these forms of drug delivery are not desirable because of their peak plasma level related side effects and short duration of action. Transdermal delivery of drugs decreases peak-related side effects, and is ideal for chronic therapies as one patch can deliver a constant rate of drug for up to one week. Initial positive preliminary data has encouraged AllTranz to seek funding to develop new buprenorphine prodrugs and optimize their use through a transdermal patch or gel drug delivery system. Prodrugs are chemically modified parent drugs that are more skin permeable than the parent, and once they cross the stratum corneum quickly separate back into the parent drug and prodrug moiety. We will also create formulations for abuse deterrence for this opioid delivery system. Transdermal delivery systems, patches and gels, offer a number of improvements over other delivery systems. Patches and gels do not require swallowing, eliminating oral side effects and bitter opioid taste concerns; nor do they require skin puncture by needles, eliminating pain and patient visits to a physician. Permeation through the skin allows the drug to directly enter the systemic circulation and avoid the first pass effect, decreasing gastric side effects and liver damage effects in hepatocompromised drug abusers and critically ill patients. The transdermal BUP system that is available in Europe could benefit from a higher skin permeation rate, improvement in adhesion, an abuse deterrent mechanism, a smaller patch size, less residual drug remaining in the patch after use, and the ultimate dosing flexibility of a transdermal gel. Less drug needed in the formulation means less drug for potential abuse when the patch is removed, as currently the European marketed patches still contain fifty percent of their drug load at the end of treatment. To make abuse more difficult still, we will create an abuse deterrent formulation with opioid antagonist non-permeating prodrug and/or coated particles. The altered antagonist will remain in the patch or gel and not enter the body at a therapeutic rate, but will block the euphoria effect of BUP if abuse is attempted via the injectable or buccal routes. Specifically we aim to synthesize prodrugs of BUP and create an abuse deterrent component with naltrexone. We then aim to assess their in vitro human skin permeation for optimum flux. The optimal drugs will be combined and reassessed to see that the formulation provides increased permeation of BUP from prodrug during transdermal transport while the delivery of altered naltrexone is prevented. In further studies we will develop the prototype product and apply for an IND and begin Phase I clinical trials. We will create a marketable transdermal drug that will significantly ai in the treatment of heroin abuse and chronic pain.
Public Health Relevance: AllTranz is seeking funding to create a transdermal prodrug gel and improved patch of buprenorphine for treatment of opioid dependence and chronic pain. These transdermal systems would be abuse deterrent and more effective than currently marketed products of the controlled substance buprenorphine. The gel would be a non-invasive non-oral dosage form with ultimate dosing flexibility without the need for patch cutting. The patches will be designed to have less residual drug content after use making them more appealing from a regulatory perspective, they could have better adhesion properties if less of a more permeable drug could be used, and when higher delivery rates are desirable in terminal pain the patient would benefit from the increased drug loading possible with the faster prodrug permeation allowing a smaller patch size to be used.
Public Health Relevance Statement: Narrative: AllTranz is seeking funding to create a transdermal prodrug gel and improved patch of buprenorphine for treatment of opioid dependence and chronic pain. These transdermal systems would be abuse deterrent and more effective than currently marketed products of the controlled substance buprenorphine. The gel would be a non-invasive non-oral dosage form with ultimate dosing flexibility without the need for patch cutting. The patches will be designed to have less residual drug content after use making them more appealing from a regulatory perspective, they could have better adhesion properties if less of a more permeable drug could be used, and when higher delivery rates are desirable in terminal pain the patient would benefit from the increased drug loading possible with the faster prodrug permeation allowing a smaller patch size to be used.
NIH Spending Category: Brain Disorders; Drug Abuse (NIDA only); Neurosciences; Pain Conditions - Chronic; Substance Abuse
Project Terms: 6,14-Ethenomorphinan-7-methanol, 17-(cyclopropylmethyl)-alpha-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-alpha-methyl-, (5alpha,7alpha(S))-; Addiction, Opiate; Adhesions; Adverse effects; Back; Blood Circulation; Blood Plasma; Bloodstream; Bristol-Myers Squibb Brand of Naltrexone Hydrochloride; Buprenorphine; Chewing; Chronic; Chronically Ill; Circulation; Clinical Trials, Phase I; Critical Illness; Critically Ill; Data; Deglutition; Dependence, Opiate; Diffusion; Dorsum; Dosage Forms; Dose; Dose-Rate; Drug Delivery; Drug Delivery Systems; Drug Formulations; Drug Precursors; Drug Targeting; Drug Targetings; Drug abuser; Drugs; Du Pont Brand of Naltrexone Hydrochloride; Early-Stage Clinical Trials; Essex Brand of Buprenorphine Hydrochloride; Euphoria; Europe; European; Formulation; Formulations, Drug; Funding; Gel; Gr??nenthal Brand of Buprenorphine; Gr??nenthal Brand of Buprenorphine Hydrochloride; Gustation; Heroin Abuse; Horny Layer; Human; Human, General; In Vitro; Injectable; Injection of therapeutic agent; Injections; Lamepro Brand of Naltrexone Hydrochloride; Liver; Man (Taxonomy); Man, Modern; Marketing; Mastication; Medication; Misuses drugs; Morphinan-6-one, 17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxy-, (5alpha)-; Nalorex; Naltrexone; Narcotic Antagonists; Nausea and Vomiting; Needles; Nemexin; Opiate Addiction; Opiate Antagonist; Opioid; Opioid Antagonists; Oral; Orphan Brand of Naltrexone Hydrochloride; Pain; Pain Control; Pain Therapy; Pain management; Painful; Parents; Patients; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Physicians; Plasma; Pro-Drugs; Problem drug user; Prodrugs; Property; Property, LOINC Axis 2; Puncture procedure; Punctures; ReVia; Reckitt Benckiser Brand of Buprenorphine Hydrochloride; Reckitt Brand of Buprenorphine Hydrochloride; Research; Residual; Residual state; Reticuloendothelial System, Serum, Plasma; Route; Schering-Plough Brand of Buprenorphine Hydrochloride; Schering-Plough Brand of Naltrexone Hydrochloride; Serum, Plasma; Skin; Stomach; Stratum corneum; Subutex; Swallowing; System; System, LOINC Axis 4; Taste; Taste Perception; Temg??sic; Therapeutic; Transcutaneous Administration; Transdermal Administration; Transdermal Route of Drug Administration; Transdermal substance administration; Transtec; Treatment Side Effects; United Drug Brand of Naltrexone Hydrochloride; United States; Visit; body system, hepatic; buprenorphine abuse; chronic pain; chronic painful condition; design; designing; drug/agent; effective therapy; flexibility; gastric; improved; opiate abuse; opioid abuse; opioid addiction; opioid dependence; organ system, hepatic; particle; phase 1 study; phase 1 trial; phase I trial; prevent; preventing; protocol, phase I; prototype; public health relevance; side effect; therapy adverse effect; transdermal drug delivery; treatment adverse effect
