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LEXINGTON, KY, United States

Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase II | Award Amount: 695.99K | Year: 2014

DESCRIPTION (provided by applicant): According to the National Survey of Drug Use and Health (NSDUH) of 2008, 7.2 million Americans are in need of treatment for Substance-Related Disorders (SRDs), and a large proportion of those need treatment for opiate pain reliever, heroin, and alcohol addiction. Naltrexone (NTX), an opioid antagonist, is currently used in oral tablet form to help maintain opioid addicts in a drug-free state. NTX is also FDA-approved for the treatment of alcohol dependence. Substantial clinical evidence exists for the benefits of NTX treatment in smoking cessation, especially in women. Very intriguing clinical trial data has also been observed in amphetamine-dependent individuals, which is especially important as methamphetamine dependence has no FDA-approved treatment options. Treatment with NTX in the 90's produced variable success rates in addicts; however, current clinical NTX therapy is being optimized based on human pharmacogenetic data. A 30-day depot injection of the drug has be


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 160.50K | Year: 2011

DESCRIPTION (provided by applicant): With over 8.5% of the U.S. population and 75 million people worldwide meeting the diagnostic criteria for alcohol use disorders (AUDs), alcohol abuse is among the top three preventable public health problems in the U.S.and the world. AUDs, commonly referred to as alcoholism, have a complex etiology where chronic alcohol associated neurodegeneration, withdrawal-related anxiety and persistent alcohol craving are predictive of high relapse and poor clinical outcomes. The treatment of AUDs would benefit from a pharmacological approach that could address these overlooked endpoints to improve clinical outcomes. However, of the three drugs currently FDA-approved for the treatment of excessive alcohol consumption, none address neurodegeneration, withdrawal or anxiety. Cannabidiol (CBD) is a drug that could improve these three syndromes. Transdermal drug delivery of cannabinoids is a viable alternative to oral dosing. Most of the cannabinoids are highly metabolized in the liver.The oral bioavailability of CBD is only about 6%, and very low plasma drug levels were detected in CBD oral dose clinical trials. It is highly possible that clinical trials of oral dose cannabinoids in patients have given inconsistent results because of apoor choice of drug dosage form. We hypothesize that a CBD transdermal dosage form can be developed, and that this dosage form could provide therapeutic levels of drug in a future clinical study with alcoholic patients. The long-term hypothesis of the overall project is that CBD will decrease withdrawal related anxiety and control alcohol craving, thereby decreasing high relapse susceptibility in alcoholics by modulating the endocannabinoid system. In the first step towards this goal, a proof of concept evaluation of CBD prodrugs delivered via transdermal microneedles will be conducted. CBD itself does not permeate the skin at a therapeutic rate, unless it is applied as a gel to a large skin surface area, as the area of transdermal application is directly proportional to the delivery rate. 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. AllTranz has preliminary data showing that CBD prodrugs alone do not improve skin permeation, unless the prodrugs are specifically designed for use with microneedles. Additionally, CBD delivery with microneedles alone is not significantly enhanced, as compared to optimized CBD prodrugs for microneedle delivery. Specifically we aim to synthesize prodrugs of CBD that will be very skin permeable in combination with a microneedle device. We then aim to assess their in vitro human skin permeation for optimum flux. In future studies we willdevelop the prototype product and apply for an IND and begin Phase I clinical trials in healthy controls and alcoholics. The future CBD transdermal system could also be tested in Phase II clinical trials for opiate addiction, analgesic effect, inflammation relief (arthritis), and nausea and vomiting treatment, as there is substantial preclinical/clinical data with CBD to justify therapeutic utility for these indications. PUBLIC HEALTH RELEVANCE: With over 8.5% of the U.S. population and 75 million people worldwide meeting the diagnostic criteria for alcohol use disorders (AUDs), alcohol abuse is among the top three preventable public health problems in the U.S. and the world. Currently approved pharmacological treatments in the treatment of alcoholism and other types of drug addiction are limited in that they do not address multiple aspects of addiction: craving, neurodegeneration, withdrawal and anxiety. The proposed preclinical research will accelerate testing of cannabidiol (CBD) in an appropriate delivery system to assess its potential benefits as a lead candidate in the search for novel alcoholism and other drug addiction pharmacotherapies. The future CBD transdermal system could also be tested in Phase II clinical trials for analgesic effect,inflammation relief, and nausea and vomiting treatment, as there is also substantial preclinical/clinical data with CBD to justify therapeutic utility for these indications.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 115.03K | Year: 2009

DESCRIPTION (provided by applicant): 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.

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