WO2008024408A2

WO2008024408A2 - Pharmaceutical formulations of cannabinoids for application to the skin and method of use

Info

Publication number: WO2008024408A2
Application number: PCT/US2007/018585
Authority: WO
Inventors: Najib Babul
Original assignee: Theraquest Biosciences Inc
Current assignee: Relmada Therapeutics Inc
Priority date: 2006-08-22
Filing date: 2007-08-22
Publication date: 2008-02-28
Anticipated expiration: 2009-02-22
Also published as: WO2008024408A3

Abstract

The present invention is directed to pharmaceutical compositions of cannabinoid agonists for application to the skin and the use thereof for preventing or minimizing the risk of cannabinoid agonist abuse and/or cannabinoid agonist toxicity from either intentional or unintentional tampering. The present invention is also directed at a method of preventing or minimizing the risk of cannabinoid agonist abuse and/or cannabinoid agonist toxicity from either intentional or unintentional tampering.

Description

07 018585

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PHARMACEUTICAL FORMULATIONS OF CANNABINOIDS FOR APPLICATION TO THE SKIN AND METHOD OF USE

FIELD OF THE INVENTION

[0001] The present invention is in the field of abuse deterrent cannabinoid compositions for application to the skin and the use thereof.

BACKGROUND ART

[0002] Marijuana, often called "pot", "grass", "reefer", "weed", "herb", "mary jane" or "mj" is a greenish-gray mixture of the dried, shredded leaves, stems, seeds, and flowers of Cannabis sativa, the hemp plant. Most users smoke marijuana in hand-rolled cigarettes called "joints", among other names; some use pipes or water pipes called "bongs". Marijuana cigars called "blunts" have also become popular. To make "blunts", users slice open cigars and replace the tobacco with marijuana, often combined with another drug, such as "crack" cocaine. Marijuana also is used to brew tea and is sometimes mixed into foods.

[0003] The major active chemical in marijuana is delta-9- tetrahydrocannabinol (THC), which causes the mind-altering effects of marijuana intoxication. The amount of THC (which is also the psychoactive ingredient in hashish) determines the potency and, therefore, the effects of marijuana. Between 1980 and 1997, the THC content of marijuana available in the United States rose dramatically.

[0004] Marijuana is the most commonly used illicit drug in the United States.

More than 94 million Americans (40 percent) age 12 and older have tried marijuana at least once, according to the 2003 National Survey on Drug Use and Health (NSDUH). Marijuana use is widespread among adolescents and young adults. It is reported that in 2004, 16 percent of 8th-graders volunteered that they had tried marijuana, and 6 percent were current users (defined as 2007/018585

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having used the drug in the 30 days preceding the survey). Among 10th- graders, 35 percent had tried marijuana sometime in their lives, and 16 percent were current users. As would be expected, rates of use among 12th-graders were higher still. Forty-six percent had tried marijuana at some time, and 20 percent were current users.

[0005] The Drug Abuse Warning Network (DAWN), a system for monitoring the health impact of drugs, estimated that, in 2002, marijuana was a contributing factor in over 119,000 emergency department (ED) visits in the United States, with about 15 percent of the patients between the ages of 12 and 17, and almost two-thirds male.

[0006] In 2002, the National Institute of Justice's Arrestee Drug Abuse

Monitoring (ADAM) Program, which collects data on the number of adult arrestees testing positive for various drugs, found that, on average, 41 percent of adult male arrestees and 27 percent of adult female arrestees tested positive for marijuana. On average, 57 percent of juvenile male and 32 percent of juvenile female arrestees tested positive for marijuana.

[0007] Cannabis use is world-wide public health issue. According to the

United Nations Office for Drug Control and Crime Prevention (UNODCCP), Marijuana is the most widely used illicit drug in the world. It has been estimated that one in 11 cannabis users will become dependent (Anthony et al., Clin Psychopharmacol, 1994); rates of cannabis dependence in several countries (e.g., Australia, USA, South Africa) have increased substantially over the past decade (Bhana et al., S Afr Med J, 2002; SAMHSA₅ 2003), as well as the number of individuals seeking treatment (Stephens et al., Clin Psychol, 1993; Treatment Episode Data Set, 2002).

[0008] The principal psychoactive constituent of marijuana, THC, was not definitively identified until 1964 (Gaoni and Mechoulam, J Am Chem Soc, 1964). Unfortunately, marijuana is not a good source of THC due to the difficulties in isolation and purification. The development of a practical synthetic pathway (Razdan et al., Experientia, 1972) was a major boost to the subsequent pharmacological characterization of the effects of marijuana and synthetic cannabinoids. Advances in chemistry, behavioral pharmacology, molecular pharmacology and neurobiology have facilitated the identification and characterization of an endogenous cannabinoid system.

[0009] Initial evidence of a cannabinoid receptor came from work that demonstrated enantioselectivity for a number of the effects of THC (Edery et al., Arzneim-Forsch, 1972; Little et al., Pharmacol Biochem Behav, 1989; Martin et al., Life Sci, 1981). More direct evidence for the receptor emerged from the work of Devane et al. (MoI Pharmacol, 1988) showing that a synthetic cannabinoid resulted in site specific avid binding in the brain. This and other discoveries raised the tantalizing possibility that an endogenous cannabinoid ligand may exist.

[0010] The work of Mechoulam resulted in the isolation of anandamide, a derivative of arachidonic acid. This endogenous ligand competed for cannabinoid receptor. Similar to THC, it inhibited electrically stimulated contractions in the murine vas deferens and produced pharmacological effects such as antinociception, catalepsy, hypomotility, hypothermia.

[0011] The endogenous cannabinoids or endocannabinoids are all eicosanoids.

Examples include ΛT-arachidonoylethanolamine (anandamide) and 2- arachidonoyl glycerol. Endocannabinoids, together with cannabinoid CB₁ and CB₂ receptors constitute the endocannabinoid system. The discovery of this endocannabinoid system has spurred research directed at elucidating the physiologic and pathophysiologic roles of the system and, importantly, at identifying targets for pharmacologic intervention in pathologic states.

[0012] It is now known that mammalian tissues express at least two cannabinoid receptors, both of which are G-protein coupled. These are CBi receptors and CB₂ receptors.

[0013] Although CBi receptors are expressed by some non-neuronal cells, including the pituitary, immune cells, and reproductive tissue, they are found primarily in peripheral and central nerve terminals where they mediate inhibition of neurotransmitter release. CBi receptors are expressed predominantly in the CNS with especially high levels in cerebellum, hippocampus and basal ganglia. Indeed, of all neurotransmitters and hormone receptors, the CB₁ receptor is by far the most abundant. CBi receptors are also expressed to a much lesser extent in the peripheral nervous system as well as on the cells of the immune system, in the testis, heart and vascular tissues.

[0014] CB₂ receptors are found primarily on immune and hematopoietic cells outside (and also within) the central nervous system, where they appear to modulate cytokine release and immune cell migration.

[0015] Studies using CB₁ and CB₂ receptor knockout mice indicate that some of the effects of endocannabinoids are not mediated by either CBi or CB₂ receptors, suggesting the existence of additional yet to be identified sites of action. Some cannabinoid effects resist classification as either CBi and CB₂- mediated. Although some of these effects may not be mediated by specific receptors, there is growing evidence suggesting the involvement of additional receptors, which include TRPVi receptors and at least 2 G protein-coupled receptors (GPCRs) of unclear molecular identity that have only been defined pharmacologically (Wiley and Martin, Chemistry Physics of Lipids, 2002; Begg et al., Pharmacol Ther, 2005).

[0016] A number of pathologic states affect the huma cannabinoid system, including Alzheimer's disease, schizophrenia, depression, alcoholism, Parkinson's disease, stroke, premature labor, endotoxic shock, hepatic cirrhosis, atherosclerosis, cancer, bone implantation, glaucoma, emesis, pain and pruritus of various etiology (Pertwee, AAPS Journal, 2005; Mackie Annu Rev Pharmacol Tox, 2006).

[0017] There are also signs of upregulation or downregulation of the endocannabinoid system in a variety of animal in vivo models, including multiple sclerosis, amyotrophic lateral sclerosis, encephalitis, Alzheimer's disease, Parkinson's disease, Huntington's disease, pain, obesity, feeding, fasting, stress, memory, aging, hypertension, cirrhosis, septic shock, cardiogenic shock, cerebral ischemia, myocardial infarction, neurotoxicity, febrile seizures and various intestinal disorders (Pertwee, AAPS Journal, 2005). [0018] As a result of the large number of potential targets for pharmacologic intervention, efforts are underway to develop and test a variety of cannabinoid agonists and antagonists to prevent and treat various maladies. Presently, three non-specific cannabinoid receptor agonists are commercially available.

[0019] Nabilone (Cesamet™) and dronabinol (Marinol™) are oral synthetic

THC analogs which have been shown effective for the treatment of nausea and vomiting associated with cancer chemotherapy and AIDS-related cachexia. They also possess analgesic, anti-hyperalgesic and anti-inflammatory properties mediated by the cannabinoid receptor(s), possibly by an uncharacterized CB₂-HlCe cannabinoid receptor (Conti et al., Br J Pharmacol, 2002). Both drugs are scheduled under the Controlled Substances Act of 1970, as amended.

[0020] Unfortunately, nabilone and dronabinol produce a variety of effects including a number of psychotomimetic effects such as dizziness, drowsiness, euphoria, ataxia, anxiety, disorientation, depression, hallucinations, vertigo, and psychosis. While these psychic effects are undesirable for patients, they are often sought after by recreational drug users and individuals with an addiction disorder.

[0021] Addiction to drugs is characterized by long-lasting motivational disturbances including compulsive drug seeking, intense drug craving, use despite harm, the non-medical use and diversion of psychoactive substances, manipulation of the medical system and escalating drug use and risk taking behaviors. The neurobiological mechanisms underlying such behaviors are poorly understood. Cannabinoids play a modulatory role in drug seeking. An early signal came from the observation that the potent cannabinoid receptor agonist (6aR)-trans-3-(l , 1 -dimethylheptyl)-6a,7, 10, 1 Oa-tetrahydro- 1 -hydroxy- 6,6-dimethyl-6H-dibenzo [b,d] pyran-9-methanol was able to reinstate cocaine seeking behavior after several weeks of extinction of intravenous cocaine self- administration in the rat (De Vries, Nat Med, 2001). Further, this effect was completely abolished by the selective CB₁ receptor antagonist N-piperidinyl- 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl pyrazole-3-carboxamide, suggesting a role for cannabinoid agonists in cocaine relapse.

[0022] Similar effects have been shown in animals with a history of heroin, methamphetamine, alcohol and nicotine self-administration where cannabinoid receptor agonists have reinstated previously abolished drug seeking (De Vries et al, Psychopharmacology [Berl], 2003; Fattore et al, Eur J Neurosci, 2003; De Vries et al., Behav Brain Res, 2005; Anggadiredja et al., Neuropsychopharmacology, 2004).

[0023] Acute exposure of laboratory animals to cannabis extracts or cannabinoids produces a broad array of neurobiological effects including euphoria, sedation, analgesia, increased seizure threshold, memory impairment, hypothermia, appetite stimulation, motor inhibition, ataxia, incoordination, anxiety and antiemetic effects. Additionally, cannabinoids produce a number of peripheral effects, including hypotension, changes in adrenal function, immunosuppression, reductions in intraocular pressure and inflammation and gastrointestinal hypomotility (Chaperon et al., Critical Rev Neurobiol, 1999; Yamamoto et al., Jpn J Pharmacol, 2000; Maldonado et al, J Neurosci, 2002; Hewlett et al., Neuropharmacol, 2004; Pertwee, AAPS Journal, 2005; Gonzalez et al., Pharmacol Biochem Behav, 2005; Mackie Annu Rev Pharmacol Tox, 2006)

[0024] There is reasonable consensus that following prolonged exposure, to cannabinoids, pharmacologic tolerance laboratory animals. However, this development of tolerance has usually been observed when the cannabinoid is administered by the observer, rather in the setting of drug self-administration. In contrast to the laboratory setting, it is likely that such tolerance develops in the context of social cannabis use, with the possible exception of very heavy social use. It should be noted that another consequence of chronic cannabinoid exposure is the development of "behavioral sensitization", an attribute described previously in the literature for other drugs. This "behavioral sensitization" contributes to the increased drive and motivation for the drug substance that is being abused.

[0025] There exists considerable concern on the part of public health policy experts, addiction medicine specialists, pharmaceutical companies and government health regulators about the potential risk of drug abuse and drug diversion with the commercialization and widespread use of new cannabinoid agonists currently in development. Pharmaceutical companies have responded to the risk of abuse from cannabinoid agonists in different ways.

[0026] Some pharmaceutical companies with significant expertise in cannabinoid chemistry and discovery have elected to focus on therapeutic potential of cannabinoid antagonists to the exclusion of cannabinoid agonists.

[0027] Other pharmaceutical companies have decided to focus on CB₂ cannabinoid agonists since it is assumed that CB₂ receptors are found mainly outside of the brain, in immune cells and that CBi receptors are found throughout the body, but primarily in the brain.

[0028] However, the precise mechanism of action of CB₂ agonists is unknown and CB₂ agonists have also been found in the CNS. Additionally, there appear to be non-CBi and non-CB₂ mediated cannabinoid receptor agonism whose behavioral pharmacology has not been fully characterized (Hewlett et al., Pharmacol Rev, 2002).

[0029] An important drawback with the use of cannabinoid agonist is the risk of drug addiction, drug diversion and drug abuse. For instance, unsuspecting clinicians may prescribe a cannabinoid agonist to patients who have an underlying, undisclosed addiction disorder. Alternatively, unsuspecting clinicians may prescribe a cannabinoid agonist to patients with a malady amenable to treatment or prevention with a cannabinoid agonist who in turn divert a portion of their prescribed dose to other individuals for non-medical use.

[0030] There have also been documented cases of inappropriate prescribing or dispensing of psychoactive drugs by physicians and pharmacists, with its eventual diversion into the non-medical marketplace. Additionally, experience with other classes of psychoactive, abusable drugs suggest that non-medical supplies of pharmaceutical grade cannabinoid agonist will be available through prescription forgeries and break-ins into pharmacies.

[0031] Pharmaceutical dosage forms containing cannabinoid agonists will likely be used for non-medical purposes in a variety of settings: i) by patients with a malady amenable to treatment or prevention with a cannabinoid agonist who have developed an addiction disorder following initiation of the cannabinoid agonist; ii) by patients with an addiction disorder seeking cannabinoid agonists for their euphoriant properties and iii) by recreational drug users who may use cannabinoid agonists from time to time ("chippers") for pleasure seeking effects, analogous to the intermittent use of marijuana by many users.

[0032] Non-medical users of abusable drugs are either recreational drug users who may use such agents episodically, or individuals with an addiction disorder who may require frequent maintenance doses. Cannabinoid agonists may be ingested whole, crushed and ingested, crushed or vaporized and snorted, inhaled or injected intravenously after attempted extraction of the active pharmaceutical ingredient.

[0033] Addicts and recreational drug users commonly use abusable drugs by a variety of routes of administration. Common methods include 1) parenteral (e.g., intravenous injection of the melted, aspirated or extracted contents of transdermal patch, a tablet or capsule), 2) intranasal (e.g., snorting the melted, aspirated or extracted contents of transdermal patch, a tablet or capsule), 3) inhalation (e.g., combustion of an intact, tampered, use or unsused transdermal patch or the patcd or the melted, aspirated or extracted contents of transdermal patch, a tablet or capsule) and 4) episodic or repeated oral ingestion of the contents of intact or tampered tablets, capsules or patches (e.g., water or solvent immersed patches, crushed tablets).

[0034] One mode of abuse involves extraction of drug from transdermal delivery systems through tampering and extraction of drug for subsequent oral ingestion, snorting, inhalation or intravenous injection. Such tampering has been known to include extraction of the active substance from the transdermal resovoir by needle aspiration, oral ingestion of the active substance from the transdermal system, and solvent extraction of the active substance from the transdermal system.The abuse of transdermal patches of abusable drugs can involve a variety of methods including steeping the patch in hot water ("tea bag"); inhalation of patch contents; solvent extraction, followed by intravenous use; needle aspiration, followed by intravenous use; mechanical extraction, followed by intravenous use; solvent extraction, followed by oral, transmucosal, nasal and inhalation use; mechanical extraction, followed by oral, transmucosal, nasal and inhalation use; transdermal application of the contents of the tampered patch; combustion of the patch, followed by inhalation; and a combination of the above methods.

[0035] A number of strategies have been introduced to minimize the abuse of mood altering drugs. Primary among these schemes is a legal infrastructure that controls the manufacture, distribution and sale of such drugs. In the United States, the vast majority of drugs, including cannabinoid agonists that have clinically useful and approved uses are restricted to dispensing on a prescription-only basis. Most of these drugs are "scheduled" as "controlled drugs", such that distribution of the drug is subject to strict controls and overview. The idea behind scheduling drugs as "controlled" is to ensure that the drugs are dispensed only for the amelioration of legitimate therapeutic maladies, and not for any mood-altering effect "high" or euphoria that may be produced by the drug when used in supra-therapeutic doses or administered by non-approved routes or methods of administration.

[0036] While the scheduling of cannabinoid agonists will reduce diversion and abuse of drugs, it is unlikely to be entirely successful. For example, some persons who are legitimately prescribed the drugs sometimes divert the drugs to persons seeking their procurement for "recreational uses." These "recreational drug users" are frequently willing to pay significant sums of money for the drugs. In other cases, certain health professionals, unfortunately, have been found to be culprits in the non-approved distribution of controlled drugs. In yet other cases, the illicit source of controlled drugs is through unauthorized importation and smuggling from countries with less controlled distribution channels and through pharmacy break-ins.

[0037] It is believed that the most widely used diversion techniques at the

"street level" are "doctor shopping" and prescription forgeries. In the case of the former, individuals who may or may not have a legitimate ailment requiring a doctor's prescription for controlled substances visit numerous doctors, sometimes in several states, to acquire large amounts of controlled substances they abuse or sell to others.

[0038] Scheduling of cannabinoid agonist also has the unintentional consequence of causing physicians, fearful of being accused of permitting "overuse", to prescribe suboptimal doses of the drugs to patients in need of them, and to prescribe less effective drugs to patients that are not similarly scheduled. This fear of prescribing for legitimate medical conditions amenable to treatment with pharmaceutical cannabinoid agonist is likely to grow as new cannabinoid therapeutics become commercially available. We have coined this phenomenon as "cannabinophobia" or "cannabophobia".

[0039] There is a growing recognition in the medical community that a large number of patients suffer from the undertreatment of their medical condition when the treatment involves the use of psychoactive drugs, particularly those drugs which tend to diverted and abused. Pain is one example of such a medical condition amenable to treatment with abusable psychoactive agents such as cannabinoid agonists. Among the reasons frequently cited for undertreatment of pain, for example are: (1) the failure to prescribe enough drug at the right dosage interval to reach a steady-state threshold commensurate with the pain relief needed; and (2) the reluctance of many physicians to prescribe analgesics categorized as controlled substances based on concerns about addiction and fear of regulatory sanctions. For example, it has been reported that with respect to cancer pain, a large percentage of cancer patients suffer debilitating pain despite treatment with analgesics (Cleeland et al., New England Journal of Medicine 1994;330:592-596). [0040] Cannabinoids hold substantial promise for the prevention and treatment of a wide variety of medical conditions, including multiple sclerosis, amyotrophic lateral sclerosis, encephalitis, Alzheimer's disease, Parkinson's disease, Huntington's disease, pain, obesity, feeding, fasting, stress, schizophrenia, depression, alcoholism, stroke, premature labor, endotoxic shock, hepatic cirrhosis, atherosclerosis, pruritus of various etiology and cancer.

[0041] Therefore cannabinoid agonists are going to be widely used for a variety of pathologic states.

[0042] Cannabinoid agonists also have the potential to create a major epidemic of drug abuse involving an entirely new pharmacologic class of agents.

[0043] There is a need, therefore, for novel methods and pharmaceutical of deterring or preventing cannabinoid agonist abuse when administered by the transdermal route.

[0044] The abuse of pharmaceutical dosage forms of cannabinoid agonists will in many cases involve: (i) use of the cannabinoid agonist dosage form in tampered form as the sole abused drug (e.g., extraction of the cannabinoid with the use of mechanical [e.g., shearing, chewing, puncturing, needle aspiration], thermal [e.g., heating, melting], or chemical [e.g., organic and acqueous solvent extraction] energy, followed by administration orally, intranasally, inhalationally, parenterally or sublingually]; and (ii) use in coηjuction with opioid agonists.

[0045] Transdermal administration of cannabis has been described in US

Patent Nos. 6,113,940 and 6,328,992 to Brooke et al. Cannabis is defined as "pure cannabis or any compound or chemical component thereof, including tetrahydrocannabinol, cannabinol, cannabidiol and cannabichromene.

[0046] Administration of a liquid cannabinoid liniment to the skin has been described in US Patent No. 6,949,582 to Wallace, which provides for methods and compsitions for treating pain and inflammation. Cannabinoids are described as a "mixture extracted from the female plant Cannabis sativa L, including in combination: 9-Tetrahydrocannabinol (delta-9-THC), 9-THC Propyl Analogue, Cannabidiol, Cannabidiol Propyl Analogue, Cannabinol, Carmabichromene, Cannabichromene Propyl Analogue, Cannabigerol, cannabinoid terpenoids, and cannabinoid flavonoids.

[0047] Valiveti et al. (Pharm Res, 2004) describe the transdermal delivery of the synthetic cannabinoid WIN 55,212-2. A number other reports have described the "topical" administration of cannabinoids, mainly to the eye (Stander et al, Hautarzt, 2006; Oka et al., Eur J Pharmacol, 2006; Stander, Hautarzt, 2006; Oka et al, J Biol Chem, 2005; Jordt et al., Nature, 2004; El- Remessy et al., Am J Pathol, 2003; Yesilyurt et al., Pain, 2003; Dogrul et al., Pain, 2003; Chien et al., Arch Ophthalmol, 2003; Bereiter et al., Pin, 2002; Laine et al., Invest Ophthalmol Vis Sci, 2002; Jarvinen et al., Pharmacol Ther, 2002; Buchwald et al., Pharmazie, 2002; Laine et al, Pharm Res, 2001; Song et al., J Pharmacol Exp Ther, 2000; Pate et al, Life Sci, 1998; Pate et al, Curr Eye Res, 1995; Merritt et al., J Clin Pharmacol, 1981).

[0048] There are no described abuse or misuse deterrence methods for cannabinoid agonists, including coadministration with cannabinoid antagonists or opioid antagonists.

[0049] There are no commerially available transdermal dosage forms of cannabinoid agonists. Additionally, there are no commecially available abuse deterrent transdermal dosage forms of any abusable drug. There are no references to abuse deterrent transdermal dosage forms of cannabinoid agonists.

[0050] There is therefore ' a need for abuse deterent and tamper resistant transdermal dosage forms of cannabinoid agonists.

[0051] All of the above-mentioned patents are hereby incorporated by reference in their entirities.

[0052] Recently, a buccal spray containing THC and cannabidiol (Sativex™) was approved in Canada for the symptomatic relief of neuropathic pain in multiple sclerosis (April, 2005) and for the treatment of cancer pain unresponsive to opioids (August, 2007). The prescribing information warns physicians that the drug "should be used with caution in patients with a history of substance abuse, including alcohol abuse or dependence. Multiple substance abuse is common and marijuana, which contains the same active compounds, is a frequently abused substance. Therefore, SATIVEX® is not recommended in patients with addiction and drug abuse liability. " The prescribing information states about the following effects: "Following mild THC intoxication, symptoms include drowsiness, euphoria, heightened sensory awareness, altered time perception, reddened conjunctiva, dry mouth and tachycardia; following moderate THC intoxication, symptoms include memory impairment, depersonalization, mood alteration, urinary retention, and reduced bowel motility; and following severe THC intoxication, symptoms include decreased motor coordination, lethargy, slurred speech, and postural hypotension. Apprehensive patients may experience panic reactions and seizures may occur in patients with existing seizure disorders. "

[0053] There are no described abuse or misuse deterrence methods for cannabhioid agonists, including coadministration with opioid antagonists such as naltrexone, naloxone and nalmefene.

[0054] There is a need for novel methods of deterring or preventing cannabinoid agonist abuse.

[0055] There is a need for novel methods of preventing cannabinoid agonist toxicity from inadvertent or intentional tampering of formulations of cannabinoid agonists for application to eh skin (e.g., transdermal patches).

[0056] There is a need for novel methods of preventing cannabinoid agonist abuse from inadvertent or intentional tampering of formulations of cannabinoid agonists for application to eh skin (e.g., transdermal patches).

[0057] There is a need for novel methods of deterring or preventing cannabinoid agonist toxicity using multimodal abuse deterrence strategies.

[0058] There is a need for novel methods of deterring or preventing cannabinoid agonist abuse using multimodal abuse deterrent strategies.

[0059] There is therefore a need for abuse deterrent, tamper resistant and generally safer dosage forms of cannabinoid agonists for application to the skin which deter abuse by antagonizing co-abused substances that are not part of the dosage form, opioid agonists.

DETAILED DESCRIPTION OF THE INVENTION

[0060] It is an object of the invention to provide a transdermal dosage form of a cannabinoid agonist that is useful for decreasing the potential abuse of the cannabinoid agonist without affecting the therapeutic effects of the cannabinoid agonist or incurring the risk of precipitating signs and symptoms of cannabinoid withdrawal.

[0061] It is an object of the invention to provide a transdermal dosage form containing an effective dose of a cannabinoid agonist along with a dose of cannabinoid antagonist or an opioid antagonist which does not change the therapeutic efficacy of the cannabinoid agonist when the dosage form is transdermally administered intact, but which can prevent abuse if the dosage form is tampered with by interfering with the effect of the cannabinoid agonist.

[0062] It is an object of the invention to provide a method for preventing abuse of a transdermal cannabinoid agonist dosage form where the dosage form also includes a dose of cannabinoid antagonist or an opioid antagonist which is sequestered, e.g., is substantially not bioavailable when the dose is administered intact but is bioavailable when the dosage form is tampered with (e.g., in an attempt to misuse the dose of cannabinoid agonist).

[0063] It is an object of the invention to provide transdermal pharmaceutical dosage forms that are intended for or are suitable for use in the management of acute or chronic diseases or disorders where alteration of the cannabinoid agonist's therapeutic effects must be avoided, as in cases of tolerance, physical dependence or individual variability in hepatic metabolism or physiology.

[0064] It is an object of the invention to provide a method of treating diseases or disorders in human subjects with a transdermal dosage form of a cannabinoid agonist while reducing its misuse by oral, parenteral, intranasal, inhalational and/or sublingual route. [0065] It is another object of the present invention to provide transdermal pharmaceutical compositions of a cannabinoid agonist for decreasing the potential for abuse of the cannabinoid agonist contained therein.

[0066] It is a further object of the invention is directed to provide transdermal pharmaceutical compositions of a cannabinoid agonist which decrease the potential for abuse and co-abuse of opioid agonists that are not part of the dosage form.

[0067] It is a further object of the present invention to provide transdermal pharmaceutical compositions of a cannabinoid agonist for decreasing the potential for abuse and co-abuse of opioid agonists in the setting of polydrug abuse.

[0068] It is a further object of the present invention to provide transdermal pharmaceutical compositions of a cannabinoid agonist for indirectly deterring cannabinoid agonist abuse by drug addicts and/or recreational drug users by providing an aversive effect solely to the co-abused opioid agonist in the setting of polydrug abuse.

[0069] It is a further object of the present invention to provide transdermal pharmaceutical compositions of a cannabinoid agonist for preventing or minimizing the risk of cannabϊnoid agonist toxicity from either intentional or unintentional tampering.

[0070] It is another object of the present invention to provide transdermal pharmaceutical compositions of a cannabinoid agonist for deterring cannabinoid agonist abuse by drug addicts and/or recreational drug users.

[0071] It is another object of the invention to provide transdermal pharmaceutical compositions of a cannabinoid agonist which deters abuse by antagonizing co-abused substances that are not part of the dosage form.

[0072] It is an object of the invention to provide a method for preventing abuse of a transdermal cannabinoid agonist dosage form where the dosage form also includes a dose of cannabinoid antagonist or an opioid antagonist which is sequestered, e.g., is substantially not bioavailable when the dose is administered intact but is bioavailable when the dosage form is tampered with (e.g., in an attempt to misuse the dose of cannabinoid agonist).

[0073] It is an object of the invention to provide a method for preventing abuse of a transdermal cannabinoid agonist dosage form where the dosage form also includes a dose of cannabinoid antagonist or an opioid antagonist which is sequestered, e.g., is substantially not bioavailable when the dose is administered intact but substantially reduces or nullfies the effects of agonist when the dosage form is tampered with (e.g., in an attempt to extract the cannabinoid agonist from the dosage form for oral, inhalational, intravenous or intranasal misuse).

[0074] Some or all of the above objects and others are achieved by embodiments of the present invention, which is directed in part to a transdermal dosage form comprising a cannabinoid agonist and an aversive agent which is present in a substantially non-releasable form (i.e., "sequestered"). In this way, the cannabinoid agonists of the present invention can be formulated with a substantially non-releasable aversive agent to deter abuse and/or minimize cannabinoid agonist toxicity on tampering.

[0075] In preferred embodiments, the dosage form contains a transdermal therapeutically effective amount of the cannabinoid agonist, the dosage form providing a desired analgesic effect. Because the cannabinoid antagonist or an opioid antagonist is present in a substantially non-releasable^' form, it does not substantially block the therapeutic effects of the cannabinoid agonist when the dosage form is transdermally administered intact, and does not pose a risk of precipitation of withdrawal in cannabinoid tolerant or dependent patients.

[0076] One novel aspect of the invention concerns deterring or minimizing cannabinoid agonist misuse, abuse and tampering by targeting other co-abused drugs that are not part of the abuse deterrent dosage form but which are frequently found in the systemic circulation of drug abusers.

[0077] In certain embodiments, the dosage form of the present invention provides for the controlled release of the aversive agent at a rate sufficient to provide an abuse limiting release rate ratio of the aversive agent (e.g., a aversive agent or an opioid aversive agent or mixtures thereof) to the cannabinoid agonist when the dosage form is subject to abuse. The dosage from of the present invention provides improved safety, e.g., in case of accidental ingestion of a used system by children or household pets.

[0078] In certain embodiments, the dosage form contains a therapeutically effective amount of the cannabinoid agonist, the transdermal dosage form providing a desired therapeutic effect. Because the aversive agent is present in a substantially non-releasable form, it does not substantially block the therapeutic effects of the cannabinoid agonist or any co-administered opioid agonist when the dosage form is transdermally administered intact, and does not pose a risk of precipitation of withdrawal in cannabinoid or opioid tolerant and cannabinoid or opioid dependent patients.

[0079] In certain embodiments, the present invention is directed to a transdermal dosage form comprising (i) a cannabinoid agonist in releasable form and (ii) a sequestered aversive agent which is substantially not released when the dosage form is administered intact, wherein the agonist and aversive agent are interdispersed and are not isolated from each other in two distinct layers.

[0080] In certain embodiments, the dosage form provides a pharmaceutical composition for application to the skin comprising a therapeutically effective amount of cannabinoid agonist, or a pharmaceutically acceptable salt thereof or a mixture thereof; said therapeutically effective amount in a reservoir comprising: (i) a releasable cannabinoid agonist; (ii) a substantially non- releasable aversive agent; and (iii) a membrane layer.

[0081] In certain embodiments, the dosage form- provides a pharmaceutical composition for application to the skin comprising a therapeutically effective amount of cannabinoid agonist, or a pharmaceutically acceptable salt thereof ■ or a mixture thereof; said therapeutically effective amount comprising: (i) a releasable cannabinoid agonist in one reservoir; (ii) a substantially non- releasable aversive agent in another reservoir; and (iii) a barrier layer between said agonist and said aversive agent. [0082] In certain embodiments, the dosage form provides a pharmaceutical composition for application to the skin comprising a therapeutically effective amount of a releasable cannabinoid agonist and a substantially non-releasable aversive agent, or pharmaceutically acceptable salts thereof or mixtures thereof; said cannabinoid agonist and aversive agent incorporated into a matrix.

[0083] In certain embodiments, the dosage form provides a pharmaceutical composition for application to the skin comprising a therapeutically effective amount of a releasable cannabinoid agonist and a substantially non-releasable aversive agent, or pharmaceutically acceptable salts thereof or mixtures thereof; said cannabinoid agonist and aversive agent incorporated into an adhesive.

[0084] In certain embodiments, the dosage form provides a pharmaceutical composition for application to the skin comprising a therapeutically effective amount of cannabinoid agonist, or a pharmaceutically acceptable salt thereof or a mixture thereof; said therapeutically effective amount in a reservoir or a matrix or an adhesive, comprising: (i) a releasable cannabinoid agonist; (ii) a substantially non-releasable aversive agent; and (iii) a membrane layer, said membrane being substantially permeable to cannabinoid agonist and substantially impermeable to said aversive agent; wherein the dosage form releases the cannabinoid agonist from the dosage form to render said dosage form suitable for up to one day, or up to one week, or up to one month of administration to a human patient; wherein the dosage form substantially prevents release of the aversive agent; and said dosage form providing a therapeutic effect for up to one day, or up to one week, or up to one month.

[0085] In certain embodiments, the present invention is directed to a transdermal dosage form comprising (i) a cannabinoid agonist in releasable form and (ii) a sequestered aversive agent which is substantially not released when the dosage form is administered intact, wherein the agonist and aversive agent are separated by barrier layer, said barrier layer separating said aversive agent reservoir from said cannabinoid agonist reservoir, said barrier layer being substantially impermeable to said cannabinoid agonist and to said aversive agent, said dosage form substantially prevents release of the aversive agent.

[0086] In certain embodiments, the present invention is directed to a transdermal dosage form comprising (i) a cannabinoid agonist in releasable form and (ii) a sequestered aversive agent which is substantially not released when the intact dosage form is secured to a human patient for a period of up to about 4, 6, Yl, 16, 18 or 24 hours or up to about 2, 3, 4, 7, 10, 14, 21 or 30 days.

[0087] In certain embodiments, the present invention is directed to a transdermal dosage form comprising (i) a cannabinoid agonist in releasable form and (ii) a sequestered aversive agent which is substantially not released when the dosage form is administered intact, wherein the aversive agent is in the form of multiparticulates individually coated with a sequestering material which substantially prevents release of the aversive agent.

[0088] In certain embodiments, the present invention is directed to a transdermal dosage form comprising (i) a cannabinoid agonist in releasable form and (ii) a sequestered aversive agent which is substantially not released when the dosage form is administered intact, wherein the cannabinoid agonist and aversive agent are a separated by barrier layer, said barrier layer separating said aversive agent reservoir from said cannabinoid agonist reservoir, said barrier layer being substantially impermeable to said agonist and to said aversive agent, said dosage form substantially prevents release of the aversive agent.

[0089] In certain embodiments, the invention relates to a transdermal dosage form for administering a cannabinoid agonist through the skin, the dosage form having a reduced potential for abuse comprising (i) a cannabinoid agonist reservoir comprising a cannabinoid agonist; (ii) a aversive agent reservoir comprising a aversive agent; (iii) a barrier layer, said barrier layer separating said aversive agent reservoir from said agonist reservoir, said barrier layer being substantially impermeable to said agonist and to said 85

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aversive agent, wherein the dosage form (a) substantially prevents release of the aversive agent from the dosage form upon securing the dosage form to a human patient for a period of up to about one day, or up to about one week, or up to about one month; and (b) provides release of the aversive agent when the dosage form is subject to abuse, e,g., upon ingestion or substantial immersion of the dosage form in the solvent.

[0090] In certain embodiments, the transdermal dosage form of the invention comprises a cannabinoid agonist reservoir comprising a polymeric matrix comprising about 0.5 wt % to about 70 wt % of the cannabinoid agonist, and optionally a permeation enhancer. Preferably, the cannabinoid agonist reservoir comprises a single phase formulation free of undissolved components.

[0091] In certain embodiments, the transdermal dosage form of the invention comprises a cannabinoid agonist reservoir comprising an aqueous gel comprising up to about 20 wt % of the cannabinoid agonist, up to about 50 wt % permeation enhancer, and about 0.1 to about 25 wt % gelling agent.

[0092] In certain embodiments, the transdermal dosage form of the invention further comprises a cannabinoid agonist release rate controlling means disposed between the cannabinoid agonist reservoir and the skin. In certain aspects, the cannabinoid agonist release rate controlling means is less permeable to the cannabinoid agonist than to the permeation enhancer.

[0093] In certain embodiments, the transdermal cannabinoid agonist dosage form of the invention comprises a aversive agent reservoir comprising an aversive agent in a form that is not releasable through the barrier layer, the aversive agent being releasable from the dosage form upon being ingested or substantially immersed in a solvent. Preferably, the aversive agent reservoir comprises the aversive agent dispersed within a polymer, wherein the aversive agent is substantially insoluble in the aversive agent reservoir polymer. In certain embodiments, the aversive agent is dispersed in a matrix comprising a material that substantially prevents release of the aversive agent; or the aversive agent is complexed with an ionic resin. In additional embodiments, the aversive agent reservoir comprises the aversive agent in a multiparticulate form, wherein each particle is individually coated with a material that substantially prevents release of the aversive agent. In additional embodiments, the aversive agent reservoir comprises beads coated with the aversive agent, wherein the beads may be formed from glass or an inert or non-dissolvable polymer, and further wherein the coated beads are optionally coated with or dispersed in material that substantially prevents release of the aversive agent.

[0094] In certain embodiments, the transdermal dosage form of the invention comprises a barrier layer impermeable to the cannabinoid agonist and the aversive agent; wherein the barrier layer comprises a material that is insoluble in water, alcohol and organic solvents. The aversive agent reservoir is disposed on the skin distal surface of the barrier layer and the agonist reservoir is disposed on the skin proximal surface of the barrier layer.

[0095] In another embodiment, the transdermal dosage form of the invention an aversive agent release rate controlling means, wherein said aversive agent release rate controlling means substantially prevents release of the aversive agent from the dosage form upon securing the dosage form to a human patient for a period of up to about 12 hours, or up to about 24 hours, or up to about 72 hours, or up to about 168 hours, or up to about 240 hours, or up to about 504 hours, or up to about 745 hours; and provides release of the aversive agent when the dosage form is subject to abuse, e.g., upon ingestion or substantial immersion of the dosage form in the solvent. The aversive agent release rate controlling means is disposed on the skin distal surface of the aversive agent reservoir.

[0096] In certain embodiments of the invention, when the dosage form is tampered with or otherwise subject to common forms of abuse, e.g., upon ingestion or immersion in a solvent for a period of time, it substantially continuously provides a^" release rate ratio of the aversive agent to the cannabinoid agonist of about 0.001:1 to about 1000:1. about 0.005:1 to about 200:1; about 0.01:1 to about 100:1; about 0.05:1 to about 20:1; about 0.1:1 to about 10:1; about 0.5:1 to about 2:1, about 1:1 to about 1000:1; about 2:1 to about 100:1; about 5:1 to about 50:1, about 10:1 to about 100:1; about 2:1 to about 10:1; about 1:1 to about 20:1, about 2:1 to about 15:1; about 2:1 to about 40:1; and about 2:1 to about 4:1, wherein the period of time of immersion is up to about 1 minute to about 24 hours.

[0097] In certain embodiments, the invention relates to a transdermal dosage form for administering a cannabinoid agonist through the skin, the dosage form having a reduced potential for abuse, comprising (i) a cannabinoid agonist reservoir comprising an amount of cannabinoid agonist sufficient to treat or prevent a medical disorder, disease, malady or symptoms in a human patient for a period of up to about 4, 6, 8, 12, 16, 18, or 24 hours or up to about 2, 3, 4, 7, 10, 21, or 30 days; (ii) a aversive agent reservoir comprising a aversive agent, wherein the aversive agent in a form that is not releasable through the barrier layer, the aversive agent being releasable from dosage form upon being ingested or substantially immersed in a solvent; (iii) a barrier layer, said barrier layer separating said aversive agent reservoir from said cannabinoid agonist reservoir, said barrier layer being substantially impermeable to said cannabinoid agonist and to said aversive agent; and (iv) an aversive agent release rate controlling means disposed on the skin distal surface of the aversive agent reservoir, wherein said aversive agent release rate controlling means substantially prevents release of the aversive agent from the dosage form upon securing the dosage form to the skin of a human patient for the intended period of application, and further wherein the aversive agent release rate controlling means provides release of the aversive agent when the dosage form is subject to abuse, e.g., upon ingestion or substantial immersion of the dosage form in the solvent.

[0098] In certain embodiments, these characteristics are conferred by the inclusion of a aversive agent, which is itself formulated uniquely within the dosage form. The properties of this dosage form are developed to liberate the aversive agent in conditions of misuse or tampering yet a negligible amount of aversive agent would be released (an amount which does not affect therapeutic effect of the cannabinoid agonist experienced by the patient) under the prescribed conditions of use.

[0099] In yet other embodiments of the invention, the release for the aversive agent and cannabinoid agonist components of the dosage form is expressed in terms of a ratio of the release achieved of the aversive agent to the cannabinoid agonist upon ingestion or substantial immersion of the dosage form in a solvent. The ratio is therefore expressed as [aversive agent]/[cannabinoid agonist]. This can be readily evaluated using the in vitro and in vivo extraction methods described herein.

[00100] The invention is also directed to a method of treating or preventing diseases and disorders amenable to treatment with cannabinoid agonists with the dosage forms disclosed herein. The method can comprise providing a transdermal dosage form containing a cannabinoid agonist in a releasable form and an aversive agent in substantially non-releasable form; and transdermally administering the intact dosage form.

[00101] Another embodiment of the invention is directed to a method of preventing or treating pain with the disclosed dosage forms. In certain embodiments, the method of treating pain in patients with a dosage form having less abuse potential comprises providing a transdermal dosage form containing a releasable form of a cannabinoid agonist and a substantially non- releasable form of a aversive agent; and transdermally administering the dosage form.

[00102] Another embodiment of the invention is directed to a method of preventing or treating pain with the disclosed dosage forms. In certain embodiments, the method of treating pain in patients with a dosage form having less abuse potential comprises providing a transdermal dosage form containing a releasable form of a cannabinoid agonist and a substantially non- releasable form of a aversive agent; and transdermally administering the dosage form to provide a blood plasma level of agonist greater than the minimum analgesic concentration of the cannabinoid agonist. [00103] Another embodiment of the invention is directed to a method of preventing or treating diseases and disorders amenable to treatment with cannabinoid agonists with the disclosed dosage forms. In certain embodiments, the method of preventing or treating such diseases and disorders in patients with a dosage form having less abuse potential comprises providing a transdermal dosage form containing a releasable form of a cannabinoid agonist and a substantially non-releasable form of a aversive agent; and transdermally administering the dosage form to provide a blood plasma level of cannabinoid agonist greater than the minimum therapeutic concentration of the cannabinoid agonist.

[00104] In certain embodiments, the cannabinoid agonist is releasable when used according to the manufacturer's instructions. In other embodiments, the cannabinoid agonist is substantially releasable when used according to the manufacturer's instructions.

[00105] In certain embodiments, the aversive agent is non-releasable when used according to the manufacturer's instructions. In other embodiments, the cannabinoid agonist is substantially releasable when used according to the manufacturer's instructions.

[00106] When the dosage form of the invention comprising a substantially releasable or releasable cannabinoid agonist and a substantially non-releasable or nonreleasable aversive agent is intentionally or accidentally tampered, the rate and extent of cannabinoid agonist release increases. Since the dosage form also contains an aversive, the substantially non-releasable or nonreleasable aversive agent becomes substantially releasable or releasable aversive under conditions of intentionally or accidentally tampering, thereby reducing or nullifying the "high", "liking", pleasurable, euphoric, calming, anxiolytic, auditory and visual perceptual alterations, relaxing, analgesic, psychotomimetic or reinforcing effects of the cannabinoid agonist, the coadministered opioid agonist or the co-abused opioid agonist .

[00107] The invention is also directed to methods of preparing the dosage forms disclosed herein. In certain embodiments, the invention comprises a method of preparing a transdermal dosage form comprising pretreating a aversive agent to render it substantially non-releasable; and combining the pretreated aversive agent with a releasable form of cannabinoid agonist in a manner that maintains the integrity of the non-releasable form of the aversive agent.

[00108] In certain embodiments of the present invention, the cannabinoid agonist is in unsalified form and the aversive agent is in salified form.

[00109] In certain embodiments of the present invention, the octanol/water partition coefficient of the cannabinoid agonist is greater than the octanol/water partition coefficient of the aversive agent.

[00110] In certain embodiments of the present invention, the substantially non- releasable form of the aversive agent is vulnerable to mechanical, thermal and/or chemical tampering, e.g., tampering by means of mechanical, thermal or solvent extraction or aspiration of the transdermal dosage form. When thus tampered with, the integrity of the substantially non-releasable form of the aversive agent will be compromised, and the aversive agent will be made available to be released. In certain embodiments, when the dosage form is torn, dissolved in a solvent or heated, and administered orally, intranasally, inhalationally, parenterally or sublingually, the analgesic, euphoric, pleasurable, reinforcing, rewarding or toxic effects of the cannabinoid agonist or the opioid agonist is reduced or eliminated. In certain embodiments, the effect of the cannabinoid agonist or the opioid agonist is at least partially blocked by the aversive agent. In certain other embodiments, the effect of the cannabinoid agonist or the opioid agonist is substantially blocked by the aversive agent. In certain embodiments, the aversive agents precipitates signs or symptoms cannabinoid agonist or the opioid agonist withdrawal or abstinence in individuals who have developed tolerance to the cannabinoid agonist or the opioid agonist. In certain embodiments, the aversive agent precipitates aversive effects of cannabinoid agonist or the opioid agonist withdrawal which discourage future abuse of the dosage form. [00111] Accordingly, when the transdermal dosage form is not tampered with as to compromise the integrity of the coating, the aversive agent contained therein will not be substantially released during its usual period of application to the skin (dosing period), and thus would not be available for absorption.

[00112] In certain embodiments of the present invention, the ratio of the cannabinoid agonist and the aversive agent, present in a substantially non- releasable form, is about 1:10000 to about 10000:1 or about 1:1000 to about 1000:1 by weight, preferably about 1:100 to about 100:1 by weight, and more preferably about 10:1 to 1:10 by weight. The weight ratio of the cannabinoid agonist to aversive agent, as used in this application, refers to the weight of the active ingredients. Since the aversive agent is in a substantially non-releasable from, the amount of such aversive agent within the dosage form may be varied more widely, as the dosage form does not depend on differential biotransformation or pharmacodynamics for proper functioning. For safety reasons, the amount of the aversive agent present in a substantially non- releasable form is generally selected as not to be permanently harmful to humans even if fully released by tampering with the dosage form.

[00113] The benefits of the abuse-resistant dosage form are especially great in connection with transdermal dosage forms of potent cannabinoid agonists, which would provide valuable therapeutic benefits but would be prone to being abused. This is particularly true for transdermal dosage forms of cannabinoid agonists which would have a large dose of a desirable cannabinoid agonist intended to be released over a long period of time in each dosage unit and a substantial further amount of cannabinoid agonist intended to provide the flux for transdermal penetration (the latter can be 10 or even 100 or 1000 fold greater than the amount delivered across the skin). Drug abusers tamper such transdermal dosage forms so that the full contents of the dosage form become available for immediate absorption. Since such tampering of the dosage form of the invention results in the aversive agent also becoming available for absorption, the present invention provides a means for deterring such abuse. In addition, the present invention addresses 007/018585

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the risk of overdose from "dumping" effect of the full dose of the cannabinoid agonist if the product is accidentally crushed or swallowed by a child, domestic animal and the like.

[00114] In certain embodiments, a combination of two cannabinoid agonists is included in the dosage form with the aversive agent. In further embodiments, one or more cannabinoid agonist and a aversive agent is included and a further non-cannabinoid drug is also included for the treatment of the same medical condition as the cannabinoid agonist or for the treatment of a different medical condition. In certain embodiments, a combination of two aversive agents is included in the dosage form with the cannabinoid agonist(s).

[00115] In certain preferred embodiments of the invention, the dosage form optionally comprises, in addition to the cannabinoid agonist and the aversive agent(s) (selected from cannabinoid antagonists, opioid antagonists and combinations of the same), one of more additional agents that are referred to herein as an abuse intervention agent(s), in sequestered, partially sequestered, unsequestered, non-releasable, partially releasable or releasable form.

[00116] In preferred embodiments of the invention, the one or more aversive agents in sequestered (i.e., non-releasable or substantially releasable) form are chosen from the group comprising cannabinoid antagonists, opioid antagonists, and mixtures thereof.

[00117] Certain embodiments of the invention are directed to formulations wherein the agonist and aversive agent are interdispersed and are not isolated from each other in two distinct layers. However in certain embodiments, the agonist and aversive agent are interdispersed or partially interdispersed.

[00118] Certain embodiments of the invention are directed to formulations wherein the agonist and aversive agent are isolated from each other in two or more distinct reservoirs. Certain embodiments of the invention are directed to formulations wherein the agonist and aversive agent are isolated from each other in the same reservoirs.

[00119] In certain preferred embodiments of the invention, the dosage form comprises one or more cannabinoid agonists in releasable or substantially releasable form; and one or more aversive agents in a non-releasable or substantially releasable form when said dosage form is used as intended.

[00120] In certain preferred embodiments of the invention, the dosage form comprises one or more cannabinoid agonists in releasable or substantially releasable form, and one or more cannabinoid antagonists in non-releasable or substantially releasable form, when said dosage form is used as intended.

[00121] In certain preferred embodiments of the invention, the dosage form comprises one or more cannabinoid agonists in releasable or substantially releasable form, and one or more opioid antagonists in non-releasable or substantially releasable form, when said dosage form is used as intended.

[00122] In certain preferred embodiments of the invention, the dosage form comprises one or more cannabinoid agonists in releasable or substantially releasable form, and one or more cannabinoid antagonists and one or more opioid antagonists, each in a non-releasable or substantially releasable form, when said dosage form is used as intended.

[00123] The term "analgesic effectiveness" is defined for purposes of the present invention as a satisfactory prevention, reduction in or elimination of pain, along with a tolerable level of side effects, as determined by the human patient. The term "therapeutic effectiveness" is defined for purposes of the present invention as a satisfactory prevention or treatment of diseases and disorders amenable to treatment with a cannabinoid agonist, including their signs and symptoms, along with a tolerable level of side effects, as determined by the human patient. The phrase "risk of precipitation of withdrawal" means that the proper action of the formulation does not depend on a specific ratio of agonist to antagonist or differential metabolism of either.

[00124] The term "cannabinoid agonist" means a substance that binds to one or more cannabinoid receptor to exert an agonist or partial agonist effect.

[00125] An "agonist" is a ligand that binds to a receptor and alters the receptor state resulting in a biological response. Conventional agonists increase receptor activity, whereas inverse agonists reduce it (See Neubig et al, IUPHAR Committee on Receptor Nomenclature and Classification, Pharmacol Rev, 2003; Howlett et al., MoI Pharmacol, 1988).

[00126] . The term "cannabinoid antagonist" means an antagonist substance or an inverse agonist that binds to one or more cannabinoid receptor to exert an antagonist effect.

[00127] An "antagonist" is a drug or ligand that reduces the action of another drug or ligand, generally an agonist. Many antagonists act at the same receptor macromolecule as the agonist. (See Neubig et al, IUPHAR Committee on Receptor Nomenclature and Classification, Pharmacol Rev, 2003; Howlett et al., MoI Pharmacol, 1988).

[00128] The term "cannabinoid receptor" means a molecule that causes a specific physiologic, pathophysiologic or pharmacologic effect after binding to CB₁, CE$₂, non-CBi/CB₂ cannabinoid sites, TRPVi receptors, as well as other G protein-coupled receptors (GPCRs) that form part of the endocannabinoid system (Wiley and Martin, Chemistry Physics of Lipids, 2002; Begg et al., Pharmacol Ther, 2005; Howlett et al., Neuropharmacol, 2004; Pertwee, AAPS Journal, 2005; International Union of Pharmacology (IUPHAR) Receptor Database; Howlett et al., MoI Pharmacol, 1988).

[00129] The term "receptor" means a molecule within a cell, on a cell surface, on a membrane, in tissue, in fluid or otherwise found in humans that serves as a recognition or binding site to cause specific physiologic, pathophysiologic or pharmacologic effects. The term "receptor" also means a cellular macromolecule, or an assembly of macromolecules, that is concerned directly and specifically in chemical signaling between and within cells. Combination of a hormone, neurotransmitter, drug, ligand, or intracellular messenger with its receptor(s) initiates a change in cell function (Neubig et al, IUPHAR Committee on Receptor Nomenclature and Classification, Pharmacol Rev, 2003).

[00130] The term "a cannabinoid antagonist in a substantially non-releasable form", "a cannabinoid antagonist in a non-releasable form", "an opioid antagonist in a substantially non-releasable form¹¹, "an opioid antagonist in a non-releasable form", "an aversive agent in a substantially non-releasable form" or "an aversive agent in a non-releasable form", refers to said agent that is not released or substantially not released at one hour after the intact dosage form containing both cannabinoid agonist and the said agent is applied or secured to the skin (i.e., without having been tampered with).

[00131] The term "tampering" or "tamper" means any manipulation including by mechanical, thermal and/or chemical means which changes the physical properties of the dosage form, e.g., to liberate the cannabinoid agonist for immediate release if it is in sustained release form, or to make the cannabinoid agonist available for inappropriate use such as administration by an alternate route, e.g., parenterally inhalationally, intranasally. The tampering can be, e.g., by means of tearing, puncturing, aspirating, shearing, chewing, dissolution in a solvent, heating (e.g., greater than about 45° C), mechanical extraction, solvent extraction, solvent immersion, combustion, oral ingestion, or any combination thereof.

[00132] The term "at least partially blocking the [e.g., cannabinoid agonist or opioid agonist] effect" is defined for purposes of the present invention to mean that the aversive agent at least partially blocks the "high", "liking", pleasurable, euphoric, calming, anxiolytic, auditory and visual perceptual alterations, relaxing, analgesic, psychotomimetic or reinforcing effects, or induces signs or symptoms of physical withdrawal of the cannabinoid agonist, or the opioid agonist taken separately or together by the human subject or patient, thereby reducing the potential for abuse of the cannabinoid agonist in the dosage form and/or any co-abused opioid agonist, said opioid agonist not part of the dosage form of the invention.

[00133] The term "abuse", "misuse", "cannabinoid abuse", "cannabinoid agonist abuse", "cannabinoid agonist misuse", "opioid agonist abuse", "opioid agonist misuse" or "opioid abuse" with respect to the dosage form of the invention and opioid agonists, means single use, intermittent use, repeated use, recreational use and chronic use of the specified abusable drug or class of abusable drugs: (i) in quantities or by methods and routes of administration that do not conform to standard medical practice; (ii) outside the scope of specific instructions for use provided by a qualified medical professional; (iii) outside the supervision of a qualified medical professional; (iv) outside the approved instructions on proper use provided by the drug's legal manufacturer; (v) which is not in specifically approved dosage forms for medical use as pharmaceutical agents; (vi) where there is an intense desire for and efforts to procure same; (vii) compulsive use; (viii) through acquisition by manipulation of the medical system, including falsification of medical history, symptom intensity, disease severity, patient identity, doctor shopping, prescription forgeries; (ix) where there is impaired control over use; (x) despite harm; (xi) by procurement from non-medical sources; (xii) by others through sale or diversion by the individual into the non-medical supply chain; (xiii) for medically unapproved or unintended mood altering purposes.

[00134] The term "mood altering" is defined for purposes of the present invention to mean that the "high", "liking", pleasurable, euphoric, calming, anxiolytic, auditory and visual perceptual alterations, relaxing, psychotomimetic, rewarding, reinforcing and toxic effects of the abusable drug.

[00135] The term "abuse resistant", "abuse deterrent", "tamper resistant",

"deter abuse" ", "deter misuse", resist abuse" and "resist misuse" and "deter abuse" (as well of the words "resist" or "deter" when applied to abusable drugs of the invention) are used interchangeably in the context of the present invention and include pharmaceutical compositions and methods that resist, deter, discourage, diminish, delay and/or frustrate: (i) the intentional, unintentional or accidental physical, chemical or thermal manipulation or tampering of the dosage form (e.g., crushing, shearing, grinding, chewing, dissolving, tearing, puncturing, melting, needle aspiration, combustion, smoking, inhalation, insufflation, extraction by mechanical, thermal and chemical means, and/or filtration); (ii) the intentional, unintentional or accidental use or misuse of the dosage form outside the scope of specific instructions for use provided by a qualified medical professional, outside the supervision of a qualified medical professional and outside the approved instructions on proper use provided by the drug's legal manufacturer (e.g., intravenous use, intranasal use, inhalational use and oral ingestion to provide high peak concentrations); (iii) the intentional, unintentional or accidental conversion of a controlled release dosage form of the invention into a more immediate release form; (iv) the intentional and iatrogenic increase in physical and psychic effects sought by recreational drug users, addicts, and patients with pain who have an addiction disorder; (v) attempts at surreptitious administration of the dosage form to a third party (e.g., in a beverage); (vi) attempts to procure the dosage form by manipulation of the medical system and from non-medical sources; (vii) the sale or diversion of the dosage form into the non-medical supply chain and for medically unapproved or unintended mood altering purposes; (viii) the intentional, unintentional or accidental attempts at otherwise changing the physical, pharmaceutical, pharmacological and/or medical properties of the dosage form from what was intended by the manufacturer.

[00136] As used herein, the term "aversive agents", "aversion producing agents" and "aversive compounds" means to compounds contained within the dosage form that produce an aversive, undesirable, repugnant, distasteful, unpleasant, unacceptable physiologic or unacceptable psychic effects, or that pharmacologically block or reduce one or more of the following effects: mood alterations; euphoria, pleasure; a feeling of high; a feeling of drug liking; anxiolysis; sedation; calmness; a state of relaxation; psychotomimesis; hallucinations; alterations in perception, cognition and mental focus; hypersomnia; sexual gratification; sexual arousal; sexual desire and sexual anticipation; increased socialization; social anxiety; psychologically reinforcement; and psychologically rewards.

[00137] The term "sustained release" is defined for purposes of the present invention as the release of the cannabinoid agonist from the transdermal dosage form at such a rate that blood (e.g., plasma) concentrations (levels) are maintained within the therapeutic range (above the minimum effective concentration) but below toxic levels over a period of about 4 to about 745 . hours, preferably over a period of time indicative of about 12 to about 170 hours. As used herein, "sustained release" is interchangeable with "extended release", "controlled release", "modified release", "delayed release" and the like.

[00138] The term "subject" for purposes of treatment is used interchangeably with "patient", "male", "female", and includes any human who has a medical condition amenable to prevention or treatment with a cannabinoid agonist.

[00139] The terms "medical condition", "malady", "disease", "disorder" and

"pathological states" are used interchangeably and are intended to have their broadest interpretation to refer to any physiologic, pathologic or pathophysiologic state in a human that can be prevented, treated, managed or altered to produce a desired, usually beneficial effect.

[00140] "Drug", "drug substance", "substance", "therapeutic agent",

"pharmacological agent", "pharmaceutical agent", "active agent" and "agent" are used interchangeably and are intended to have their broadest interpretation as to any therapeutically active substance which is delivered to a living organism to produce a desired, usually beneficial effect. In general, this includes therapeutic agents in all of the major therapeutic areas.

[00141] "Pharmaceutically or therapeutically acceptable excipient or carrier" refers to a solid or liquid filler, diluent or encapsulating substance which does not interfere with the effectiveness or the biological activity of the cannabinoid agonist and which is not toxic to the hosts, which may be either humans or animals, to which it is administered.

[00142] The term "pharmaceutically acceptable salt" as used herein refers to a salt which is toxicologically safe for human and animal administration. Nonlimiting examples of salts include hydrochlorides, hydrobromides, hydroiodides, sulfates, bisulfates, nitrates, citrates, tartrates, bitartrates, phosphates, malates, maleates, napsylates, fumarates, succinates, acetates, terephlhalates, pamoates and pectinates. [00143] Mammalian tissues express at least two cannabinoid receptors, both of which are G-protein coupled. These are CBi receptors and CB₂ receptors. CBi receptors are expressed are primarily expressed in peripheral and central nerve terminals where they mediate inhibition of neurotransmitter release, hi the CNS, especially high levels of CBi receptors are found in the cerebellum, hippocampus and basal ganglia. CB₂ receptors are found primarily on immune and hematopoietic cells outside (and also within) the central nervous system, where they appear to modulate cytokine release and immune cell migration. Studies using CBi and CB₂ receptor knockout mice indicate that some of the effects of endocannabinoids are not mediated by either CBi or CB₂ receptors, suggesting the existence of additional yet to be identified sites of action. Some cannabinoid effects resist classification as either CBi and CB₂-mediated. There is growing evidence suggesting the involvement of additional receptors, which include TRPVi receptors and at least 2 G protein-coupled receptors (GPCRs) of unclear molecular identity that have only been defined pharmacologically.

[00144] The human cannabinoid system is involved in a number of pathological states, including Alzheimer's disease, schizophrenia, depression, alcoholism, Parkinson's disease, stroke, premature labor, endotoxic shock, hepatic cirrhosis, atherosclerosis, cancer, bone implantation, glaucoma, emesis and pain. Additionally, upregulation or downregulation of the endocannabinoid system is seen in a variety of animal in vivo models, including multiple sclerosis, amyotrophic lateral sclerosis, encephalitis, Alzheimer's disease, Parkinson's disease, Huntington's disease, pain, obesity, feeding, fasting, stress, memory, aging, hypertension, cirrhosis, septic shock, cardiogenic shock, cerebral ischemia, myocardial infarction, neurotoxicity, febrile seizures and various intestinal disorders.

[00145] Therefore cannabinoid receptors present a large number of potential targets for pharmacologic intervention and efforts are underway to develop and test a variety of cannabinoid agonists and antagonists to prevent and treat various maladies. Presently, three non-specific cannabinoid receptor agonists are commercially available. Nabilone (Cesamet™) and dronabinol (Marinol™) are oral synthetic THC analogs which have been shown effective for the treatment of nausea and vomiting associated with cancer chemotherapy and AIDS-related cachexia. A buccal spray containing THC and cannabidiol (Sativex™) was approved in Canada for the symptomatic relief of neuropathic pain in multiple sclerosis and for the treatment of cancer pain.

[00146] All cannabinoid agonists are scheduled under the Controlled

Substances Act of 1970. Cannabinoid agonists can produce a variety of adverse effects including a number of psychotomimetic effects such as dizziness, drowsiness, euphoria, ataxia, anxiety, disorientation, depression, hallucinations, vertigo, and psychosis. While these psychic effects are undesirable for patients, they are often sought after by recreational drug users and individuals with an addiction disorder. Cannabinoids play a modulatory role in drug seeking. They can reinstate cocaine seeking behavior after several weeks of extinction of intravenous cocaine self-administration. Similar effects have been shown in animals with a history of heroin, methamphetamine, alcohol and nicotine self-administration where cannabinoid receptor agonists have reinstated previously abolished drug seeking.

[00147] There is significant concern on the part of addiction medicine specialists and public health regulators about the potential risk of drug abuse and drug diversion with the commercialization and widespread use of new cannabinoid agonists currently in development. There is a need, therefore, for novel methods and pharmaceutical compositions to deter or preventing cannabinoid agonist abuse. There also a need for novel methods and pharmaceutical compositions to preventing cannabinoid agonist toxicity from inadvertent or intentional crushing of extended or sustained release formulations of cannabinoid agonists.

[00148] The sequestered aversive agent(s) included in the dosage forms of the present invention are designed to deter abuse of (i) the cannabinoid agonist

' contained in the dosage form, itself; or (ii) an opioid agonist that is taken by the patient, e.g., in an abuse situation; or (iii) both. In certain embodiments, the dosage form may include, in addition to the releasable cannabinoid agonist and the substantially non-releasable sequestered agent(s) mentioned above, other abuse deterrent substances in releasable or substantially non-releasable form, including various aversive agents know to practitioners of the art. [00149] In certain embodiments, the present invention comprises a releasable cannabinoid agonist and a partially or substantially releasable cannabinoid antagonist for application to the skin; said partially or substantially releasable cannabinoid antagonist not enhancing the efficacy of the cannabinoid agonist of the dosage form; and said partially or substantially releasable cannabinoid antagonist not diminishing the efficacy of the cannabinoid agonist of the dosage form by more than about 5%, or more than about 10%, or more than about 15%, or more than about 20%.

Cannabinoid Agonists with Sequestered or Releasable Cannabinoid Antagonists

[00150] Cannabinoid agonist abuse from the tampering of immediate release and particularly transdermal controlled release formulations can be minimized by combining the releasable cannabinoid agonist with a non-releasable or substantially non-releasable (i.e., sequestered) cannabinoid antagonist in the same dosage form, such that upon tampering, the cannabinoid antagonist becomes releasable, thereby: (i) reducing or eliminating the psychic effects of the drug desired drug addicts and recreational drug users; and (ii) reducing or eliminating the toxic effects of the drug in patients who have inadvertently tampered the dosage form and in drug addicts and recreational drug users.

Blunting Psychic Effects of Cannabinoid Agonists with Sequestered Opioid Antagonists

[00151] The endocannabinoid system is complex and interfaces with a number of other endogenous systems in physiologic and pathophysiologic states. One prominent system interaction for cannabinoid agonists is with the opioidergic system. [00152] Although cannabinoid agonists and opioid agonists are distinct pharmacologic classes of drugs, they possess a similar pharmacological profile, including antinociception, catalepsy, hypothermia, motor depression, hypotension, immunosuppression, sedation and reward effects (Manzanares et al., 1999; Massi et al., 2001; Varvel et al., 2004).

[00153] In vitro studies have shown that cannabinoid agonists and opioid agonists activate mu, delta and kappa opioid, and CBi, CB₂ and non-CBi/CB2 cannabinoid receptors, respectively, which are coupled to Gi/Go GTP-binding proteins that inhibit adenylyl cyclase, inhibit voltage-dependent calcium channels, stimulate potassium channels and activate the MAP kinase cascade (for review see Childers, 1991; Childers et al., 1992; Howlett, 1995).

[00154] Receptor mapping studies have shown a rather similar distribution of

CBi cannabinoid and μ-opioid receptors in the dorsal horn of the spinal cord (Welch and Stevens 1992; Hohmann et al., 1999; Salio et al., 2001) and in the CNS, including the caudate, putamen, dorsal hippocampus, and substantia nigra (Mansour et al., 1988; Herkenham et al., 1991; Mailleux and Vanderhaeghen, 1992; Rodriguez et al., 2001).

[00155] Chronic use of cannabinoid agonists and opioid agonists results in pharmacologic tolerance, physical dependence and addiction. Chronic cannabinoid agonist administration induces tolerance to the antinociceptive effect of opioids (Smith et al., 1994; Welch, 1997), while chronic exposure to opioid agonists results in tolerance to the antinociceptive effect of cannabinoid agonists (Bloom and Dewey, 1978; Hine, 1985; Smith et al., 1994; Thorat and Bhargava, 1994). Cross-physical dependence between opioid agonists and cannabinoid agonists has also been demonstrated (Bhargava, 1976, 1978; Hine et al., 1975; Vela et al., 1995; Yamaguchi et al., 2001; Del Arco et al., 2002). Administration of the opioid antagonist naloxone precipitates an abstinence syndrome in cannbinoid-tolerant rats (Hirschhorn and Rosecrans, 1974; Kaymakcalan et al., 1977). Similarly, the cannabinoid antagonist SR141716A precipitates abstinence in opioid agonist dependent rats (Navarro et al., 1998). Sustained suppression of CBi receptor activity with the cannabinoid antagonist SR141716A during opioid agonist administration reduces the signs and symptoms of opioid withdrawal (Rubino et al., 2000; Mas-Nieto et al., 2001).

[00156] Cannabinoid agonists and opioid agonists seem to interact in their antinociceptive effects as illustrated by the ability of their respective antagonists to reverse cannabinoid/opioid-induced analgesia (Welch, 1993; Reche et al., 1996a,b; Cichewicz et al., 1999). The concurrent administration of opioid agonsits and cannabinoid agonists results in an enhanced antinociceptive effect, compared with either solo administartion (Cichewicz et al., 1999; Smith et al., 1998; Welch and Eads, 1999; Cichewicz and McCarthy, 2003). Administration of subanalgesic and submaximal doses of cannabinoid agonists and opioid agonists result in synergy and this effect is abolished by cannabinoid receptor and opioid receptor antagonists (Reche et al., 1996a; Smith et al., 1998; Cichewicz, 2004).

[00157] The reward process is central to the development of addiction to psychoactive drugs. A commonly used experimental method of evaluating the reinforcing properties of drugs is the self-administration test. Available data suggest that there is an an interaction between opioids and cannabinoids with respect to reward processes. The cannabinoid antagonist SR141716A reduces self-administration of heroin (Chaperon et al., 1998; Braida et al., 2001; Mas- Nieto et al., 2001; Navarro et al., 2001; De Vries et al., 2003). The opioid antagonists naltrexone and naloxone reduce self-administration of THC (Tanda et al., 2000; Justinova et al., 2003, 2004) and the CBl agonist CP- 55,940 (Braida et al., 2001). Cannabinoid antagonists can also suppress "heroin-seeking" behavior after weeks of prior extinction (Fattore et al., 2003; Caille and Parsons, 2003; Solinas et al., 2003).

[00158] A majority of opioid-dependent individuals seeking treatment are polydrug abusers. The secondary illicit drug used most frequently in this population is marijuana. Prevalance estimates of marijuana use have ranged from 25% to 80% among cocaine andopiate abusers (Ball et al., 1988; Budney et al., 1996;Miller et al., 1990; Nirenberg et al., 1996; Saxon et al.,1993). Budney et al (Addiction, 1998) evaluated marijuana use among opioid abusers in patients enrolled in treatment for opioid dependence. Sixty-six per cent of participants were current marijuana users and almost all (94%) continued to use during treatment. In another study (Budney et al., Drug Abuse and Dependence, 1996) examining the relationship between marijuana use and sociodemographic, psychosocial, and drug-use variables in treatment-seeking opioid abusers, marijuana involvement was associated with less stable relationships, more frequent alcohol use, more financial difficulty, and engagement in more risky behavior including intravenous drug use and needle-sharing.

[00159] There is a need, therefore, for novel methods and compositions for deterring or preventing cannabinoid agonist abuse by targeting the role of opioid agonist in initiating and maintaining physical dependence, psychological dependence, tolerance and addiction to cannabinoid agonist.

[00160] Cannabinoid agonist abuse can be minimized by combining the releasable cannabinoid agonist with a non-releasable or substantially non- releasable (i.e., sequestered) opioid antagonist in the same dosage form, such that upon tampering, the opioid antagonist becomes releasable, thereby: (i) reducing or eliminating the psychic effects of the cannabinoid agonist desired drug addicts and recreational drug users; and (ii) reducing or eliminating the toxic effects of the cannabinoid agonist in patients who have inadvertently tampered the dosage form and in drug addicts and recreational drug users.

Blunting Psychic Effects of Co-abused Opioid Agonists Among Caπnabinoid Agonist Abusers with Sequestered or Releaseable Opioid Antagonists

[00161] One novel method of deterring or minimizing cannabinoid agonist misuse, abuse and tampering is to target other co-abused drugs that are not part of the abuse deterrent dosage form but which are frequently found in the systemic circulation of drug abusers.

[00162] Forensic analytical toxicology studies have repeatedly revealed that in a majority of subjects, there are multiple drugs of abuse in the systemic circulation and importantly, such polydrug abuse is believed to be an important contributor to the death of many subjects from drug abuse and intentional or unintentional drug overdose. This observation of the use of multiple drugs of abuse in the same subject, i.e., polydrug abuse has also been reported in the drug abuse and addiction medicine literature, where positive urine samples ("dirty urine") frequently contains more than one illicit drug. For example, a majority of opioid-dependent individuals seeking treatment are polydrug abusers. The secondary illicit drug used most frequently in this population is marijuana. Prevalence estimates of marijuana use have ranged from 25% to 80% among cocaine and opioid abusers (Ball et al., 1988; Budney et al., 1996; Miller et al., 1990; Nirenberg et al., 1996; Saxon et al.,1993). Budney et al (Addiction, 1998) evaluated marijuana use among opioid abusers in patients enrolled in treatment for opioid dependence. Sixty- six per cent of participants were current marijuana users and almost all (94%) continued to use during treatment. In another study (Budney et al., Drug Abuse and Dependence, 1996) examining the relationship between marijuana use and sociodemographic, psychosocial, and drug-use variables in treatment- seeking opioid abusers, marijuana involvement was associated with less stable relationships, more frequent alcohol use, more financial difficulty, and engagement in more risky behavior including intravenous drug use and needle-sharing.

[00163] The observation of polydrug abuse can be exploited to deter cannabinoid agonist abuse indirectly by antagonizing the pleasurable and mood altering effects of opioid agonists which are not part of the dosage form of the invention but may nevertheless co-abused by cannabinoid agonist abusers.

[00164] In certain embodiments, the present invention comprises a releasable cannabinoid agonist and a partially or substantially releasable opioid antagonist for application to the skin, said dosage form not directed at deterring or reducing the abuse potential of the cannabinoid agonist contained therein by pharmacologic antagonism of cannabinoid action by the opioid 18585

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antagonist; said dosage form instead directed at indirectly detering abuse, ' misuse, diversion and tampering of the cannabinoid agonist by antagonizing the effects of co-abused opioid agonists which are not part of the dosage form of the invention but which are present in systemic circulation as co-abused drugs in the setting of polydrug abuse.

[00165] In certain embodiments, the present invention comprises a releasable cannabinoid agonist and a partially or substantially releasable opioid antagonist for application to the skin; said dosage form directed at preventing the unapproved or surreptitious use of pharmaceutical grade or "street" grade opioid agonists for their mood altering effects by individuals who have been expressly informed by their clinicians not to take opioid analgesics due to a risk of misuse, abuse, addiction, drug-drug interaction or due a contraindication to the opioid agonists; said partially or substantially releasable opioid antagonist not enhancing the efficacy of the cannabinoid agonist of the dosage form; and said partially or substantially releasable opioid antagonist not diminishing the efficacy of the cannabinoid agonist of the dosage form by more than about 5%, or more than about 10%, or more than about 15%, or more than about 20%.

[00166] The object of the invention is to partially or substantially nullify the mood altering effects of opioid agonists in individuals who are prescribed cannabinoid agonists of the present invention and who are using said opioid agonists without the approval or medical supervision of their physician. The object of the invention is achieved by combining a releasable cannabinoid agonist and a partially or substantially releasable opioid antagonist in dosage forms for application to the skin.

[00167] The object of the invention is to reduce the potential for misuse and abuse of transdermal cannabinoid agonist dosage forms, both when said dosage form is used as directed in conjunction with the misuse or abuse of medically unauthorized or illicit opioid agonists, and when the dosage form is tampered with in an attempt to extract the cannabinoid agonist contained therein. This is achieved by exploiting the observation that cannabinoids are abused in the setting of polydrug abuse, frequently involving opioid agonists which are obtained via legitimate prescriptions, diversion from medical sources and illicit, non-medical sources. In the setting of polydrug abuse, the dosage form of the invention provides a substantial disincentive to use the cannabinoid agonist dosage form in conjunction with the misuse or abuse of medically unauthorized or illicit opioid agonists or to extract the cannabinoid agonist of the dosage form, since the intedispersed opioid antagonist contained in the same dosage form will nullify the effects of any co-abused opioid agonist, the latter not being part of the dosage form. Thus, abuse deterrence is obtained not by any direct action of the opioid antagonist on the cannabinoid agonist; instead, the inclusion of an opioid antagonist in the drug reservoir of the dosage form containing the cannabinoid agonist is a strategic intervention to exploit the patterns of drug abuse and co-abuse by nullifying or minimizing the effects of opioid agonist present in the systemic circulation of the polydrug abuser. Additionally, the transdermal dosage form of the invention also reduces the toxicity observed from polydrug abuse both in the setting of intentional abuse and accidental abuse.

Cannabinoid Agonists/ Antagonists

[00168] A number of assays are available to determine whether a drug is a cannabinoid agonist or cannabinoid antagonist, using in vivo and in vitro bioassay systems (Howlett et al., MoI Pharmacol, 1988).

[00169] Cannabinoid agonists are known or readily determined by individuals who practice the art. Preferably, the cannabinoid agonist useful for the present invention may be selected from the group consisting of inhibitors of cannabinoid agonist metabolism (e.g., without limitation, URB602, an inhibitor of monoacylglycerol lipase which catalyzes 2-arachidonoylglycerol hydrolysis) THC, nabilone, dronabinol, cannabidiol, 9-THC propyl analog, cannabidiol, cannabidiol propyl analog, cannabinol, cannabichromene, cannabichromene propyl analog, cannabigerol, cannabinoid terpenoids, cannabinoid flavonoids, endocannabinoids, anandamide, (R)- methanandamide,and 2-arachϊdonoylglycerol, THC-like ABC tricyclic cannabinoid analogues, exemplified by HU210 and desacetyllevonantradol; synthetic AC bicyclic and ACD tricyclic cannabinoid analogues, exemplified by CP55940, and CP55244 and aminoalkylindole compounds, exemplified by WIN55212-2, and their or their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixtures thereof. (Little et al., Pharmacol. Biochem. Behav, 1989;Howlett et al., Neuropharmacology, 1990; Johnson et al, In: Cannabinoids as Therapeutic Agents (Mechoulam, R., ed.), CRC Press, 1986; Howlett et al., MoI Pharmacol, 1988; D'Ambra et al., J Med Chem, 1992; Pacheco et al., J Pharmacol Exp Ther, 1991; Compton et al, J Pharmacol Exp Ther, 1992; Howlett et al, Pharmacol Rev, 2002; Fowler. Fundam Clin Pharmacol. 2006;20:549-62; Karanian and Bahr, Curr MoI Med 2006;6:677- 84; Singh and Budhiraja, Methods Find Exp Clin Pharmacol 2006;28: 177-83; Mackie and Stella, AAPS J 2006;8:E298-306; Pavlopoulos, Curr Pharm Des 2006;12(14):1751-69.). ] Cannabinoid antagonists are known or readily determined by individuals who practice the art. Preferably, the cannabinoid antagonist useful for the present invention may be selected from the group consisting of SR 141716A [Rimonabant or N-ρiperidino-5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methyl-3-pyrazole-carboxamide]), AM251, AM 281 ([N- moφholin-4-yl]-5-[2,4-yl]-5-[2,4-dichlorophenyl]-4-methyl-lH-pyrazole-3- carboxamide), AM630, -SR 144528 ([N-[(lS)-endo-l,3,3- trimethylbicyclo(2.2.1)heptan-2-yl]5-(4-chloro-3-methyl-phenyl)-l-(4- methylbenzyl)pyrazole-3-carboxamide]), 5-(4-chlorophenyl)-l -(2,4- dichlorophenyl)-3-hexyl-lh-l,2,4-triazole, 8-chloro-l-(2',4'-dichlorophenyl)- N-piperidin- 1 -yl-1 ,4,5 ,6-tetrahydrobenzo[6,7]cyclohepta[ 1 ,2-c]pyrazole-3- carboxamide 4a, pyrazole class cannabinoid antagonists (e.g., SR141716 and SR144528), aminoalkylindole class cannabinoid antagonists (e.g., AM630), imidazolinedione class cannabinoid antagonists and triazole class cannabinoid antagonists, pyridone derivative class cannabinoid antagonists, quinolone derivative class cannabinoid antagonists, tricyclic derivatives of 1- benzylpyrazole-3-carboxylic acid, HU-308, HU-210, cannabidiol, tricyclic pyrazoles, analogs of 8-chloro-l-(2',4'-dichlorophenyl)-N-piperidin-l-yl- l,4,5,6-tetrahydrobenzo[6,7]cyclohepta[l,2-c]pyrazole-3-carboxamide, 5-(4- chlorophenyl)-l-(2,4-dichlorophenyl)-3-hexyl-lh-l,2,4-triazole, and or their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixtures thereof.

[00171] In certain embodiments, the cannabinoid agonist useful for the present invention may be selected from the group consisting of THC, endocannabinoids, anandamide and 2-arachidonoylglycerol, THC-like ABC tricyclic cannabinoid analogues, exemplified by HU210 and desacetyllevonantradol; synthetic AC bicyclic and ACD tricyclic cannabinoid analogues, exemplified by CP55940, and CP55244 and aminoalkylindole compounds, exemplified by WIN55212-2.

[00172] In certain embodiments, the amount of the cannabinoid agonist in the claimed cannabinoid composition may be from about 10 ng to about 1000 mg, even up to about 200 mg. More preferably, the amount of the cannabinoid agonist is from about 10 ng to about 1200 mg, even more preferably from about 0.1 mg to about 1000 mg, and most preferably, from about 0.1 mg to about 700 mg.

[00173] In certain embodiments, the amount of the cannabinoid antagonist in the claimed cannabinoid composition maybe from about 10 ng to about 1000 mg.In some preferred embodiments, the cannabinoid agonist may be selected from compounds disclosed in U.S. Patent No. 7,217,732, 7,214,716, 7,169,942, 7,109,216, 7,091,216, 7,057,051, 6,995,184, 6,972,295, 6,943,266, 6,903,137, 6,864,291, 6,864,285, 6,525,087, 6,524,805, 6.509.367, 6,284,788, 5,948,777, 5,939,429, and 5,605,906, and in U.S. Patent Application No. 20070167514, 20070123505, 20070105914, 20070099947, 20070088058, 20070088025, 20070087390, 20070060638, 20070032517, 20070027144, 20060293299, 20060241165, 20060172019, 20060106071, 20060089356, 20060079557, 20060074086, 20050272763, 20050267161, 20050245554, 20050239828, 20050239133, 20050234061, 20050203112, 20050182103, 20050165118, 20050154202, 20050137173, 20050101542, 20050096379, 20050065189, 20050054679, 20050026986, 20050009902, 20040266861, 20040266841, 20040248956, 20040242593, 20040235854, 20040229928, 20040229850, 20040171613, 20040106614, 20040058820, 20040044051, 20040034090, 20040018151, 20030175822, 20030138508, 20030114495, 20020173528, 20020128302, 20020077322, and 20010034344, and their or their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereofor mixtures thereof. AU of the above patents and patent applications are hereby incorporatedbyreference intheir entirety. In some preferred embodiments, the cannabinoid antagonist may be selected from compounds disclosed in U.S. Patent No.7,247,628, 7,176,210, 7,153,997, 7,151,097, 7,132,414, 7,119,108,6,930,122, 6,642,258, 7,094,794, 6,916,838, 6,894,050, 6,875,782, 6,825,198, 6,734,176, 6,673,802, 6,630,507, 6,555,578, 6,509,367, 6,344,481, 6,344,474, 6,194,454, 6,100,259, 5,989,583, 5,939,429, 5,747,524, 5,596,106, and 4,205,952, and in U.S. Patent Application No.20070167514, 20070123505, 20070105914, 20070099947, 20070088058, 20070088056, 20070087390, 20070072907, 20070060638, 20070032517, 20070004772, 20060293299, 20060287341, 20060270655, 20060172019, 20060167049, 20060128673, 20060106071, 20060100208, 20060100205, 20060089356, 20060079556, 20050272763, 20050267161, 20050267155, 20050250769, 20050245554, 20050239828, 20050239133, 20050234061, 20050203112, 20050187253, 20050182103, 20050154202, 20050101542, 20050096379, 20050065189, 20050054679, 20050026986, 20040266841, 20040248956, 20040248944, 20040242593, 20040235854, 20040152736, 20040122074, 20040106800, 20040106614, 20040058820, 20040039024, 20040006105, 20030175822, 20030114495, 20030087933, 20020188007, 20020128302, and 20020026050, and their or their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixtures thereof. All of the above patents and patent applications are hereby incorporated by reference in their entirety.

[00175] For purposes of the present invention, the term "cannabinoid agonist" shall include combinations of more than one cannabinoid agonist, and also include the unsalified agonist, mixed agonist-antagonists, partial agonists, pharmaceutically acceptable salts thereof, stereoisomers thereof, ethers and esters thereof, and mixtures thereof.

[00176] For purposes of the present invention, the term "cannabinoid antagonist" shall include combinations of more than one cannabinoid agonist, and also include the unsalified agonist, mixed agonist-antagonists, partial agonists, pharmaceutically acceptable salts thereof, stereoisomers thereof, ethers and esters thereof, and mixtures thereof.

[00177] Some of the cannabinoid agonists and antagonists disclosed herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present invention is also meant to encompass all such possible forms as well as their racemic and resolved forms and mixtures thereof. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended to include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present invention as well.

[00178] As used herein, the term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms is space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers) . [00179] The term "chiral center" refers to a carbon atom to which four different groups are attached.

[00180] The term "enantiomer" or "enantiomeric" refers to a molecule that is nonsuperimposeable on its mirror image and hence optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction.

[00181] The term "racemic" refers to a mixture of equal parts of enantiomers and which is optically inactive.

[00182] The term "resolution" refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.

[00183] It is known that when coadministered with cannabinoid agonists, cannabinoid antagonists block the euphoric, pleasurable, reinforcing or toxic effects of the cannabinoid agonist. Furthermore, it is known that cannabinoid antagonist administration in the setting of dependence or pharmacologic tolerance to cannabinoid agonists results in aversive effects, which may include signs and symptoms of cannabinoid agonist withdrawal. It is believed that the method by which cannabinoid antagonists blocks the effects of cannabinoid agonists is by competitively binding at the cannabinoid receptors.

[00184] In certain embodiments of the present invention, the ratio of the cannabinoid agonist to the substantially non-releasable form of a cannabinoid antagonist in the dosage form is such that the effect of the cannabinoid agonist is at least partially blocked when the dosage form is tampered and administered orally, intranasally, inhalationally, parenterally or sublingually. Since the dosage form of the present invention, when administered properly as intended, would not substantially release the cannabinoid antagonist, the amount of such antagonist may be varied more widely than if the cannabinoid antagonist is available to be released upon application to the skin. For safety reasons, the amount of the antagonist present in a substantially non-releasable form should generally not be permanently harmful to humans even if fully released. The ratio of particular cannabinoid agonist to antagonist can be determined by one skilled in the art. [00185] In certain embodiments of the present invention, the ratio of the cannabinoid agonist to the cannabinoid antagonist, present in a substantially non-releasable form, is about 1:10000 to about 10000:1 or 1:1000 to about 1000:1 by weight, preferably about 1:100 to about 100:1 by weight, more preferably about 1:50 to about 50:1 by weight, and most preferably about 1:10 to 10:1 by weight. The weight ratio of the cannabinoid agonist to cannabinoid antagonist, as used in this application, refers to the weight of the active ingredients.

[00186] Notwithstanding the above definitions of "cannabinoid agonist",

"agonist", cannabinoid antagonist", "antagonist", "cannabinoid receptor" and "receptor", for the purposes of the present invention, 1) drugs that enhance the effect of cannabinoid agonists by inhibiting their metabolism or reuptake (for example, anandamide amidase inhibitors) are considered to be cannabinoid agonists; ^"~2) drugs that induce anandamide amidase inhibitor metabolism or induce CB₁, CB₂ and Mn-CB₁ /non-CB₂ cannabinoid agonist metabolism or enhance reuptake will be considered cannabinoid antagonists; 3) inverse cannabinoid agonists will be considered cannabinoid antagonists.

[00187] In certain embodiments, the effect of the cannabinoid agonist is at least partially blocked by the cannabinoid antagonist. In certain other embodiments, the effect of the cannabinoid agonist is substantially blocked by the cannabinoid antagonist. In certain embodiments, the cannabinoid antagonists precipitates signs or symptoms cannabinoid agonist withdrawal or abstinence in individuals who have developed tolerance to the cannabinoid agonist. In certain embodiments, the cannabinoid antagonist precipitates aversive effects of cannabinoid agonist withdrawal which discourage future abuse of the dosage form.

Opioid Agonists/ Antagonists

[00188] The term "opioid receptor" includes mu (μ), delta (δ), kappa (K) and/or nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptors, their subtypes and splice variants such as μi, μ₂, δj, δ₂, K₁, K₂ and K₃, etc, regardless of whether they also bind to or influence other receptor systems (e.g., norepinephrine reuptake inhibition, serotonin reuptake inhibition, NMDA receptor antagonism).

[00189] F°r the purposes of this invention, the term "opioid" is interchangeable with the term "opioid agonist", except when there is a specific reference to an opioid antagonist.

[00190] Opioid agonists include alfentanil, allylprodine, alphaprodine, anileridine, apomorphine, apocodeine, benzylmorphine, bezitramide, brifentanil, buprenorphine, butorphanol, carfentanil, clonitazene, codeine, cyclorphen, cyprenorphine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxyaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydroxymethylmorphinan, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallor- phan, levoφhanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, rnethylmorphine, metopon, mirfentanil, morphine, morphine-6-glucuronide, myrophine, nalbuphine, narceine, nicomoφhine, norlevorphanol, normethadone, nalorphine, nociceptin/orphanin FQ (N/OFQ), normorphine, norpipanone, ohmefentanyl, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenornoφhan, phenazocine, phenoperidine, pholcodine, piminodine, piritramide, propheptazine, promedol, profadol, properidine, propiram, propoxyphene, remifentanil, sufentanil, tapentadol, tramadol, trefentanil, tilidine, nalbuphine, or any opioid having agonist activity at an opioid receptor belonging to the phenanthrene, morphinan, benzomorphan, methadone, phenylpiperidine, propionanilide 4- anilidopiperidine, 4-aryl piperidines, and 4-Heteroarylpiperidines class, any opioid having agonist activity at an opioid receptor having the same pentacyclic nucleus as nalmefene, naltrexone, buprenorphine, levorphanol, meptazinol, pentazocine and dezocine, any drug having agonist activity at an opioid receptor which is a fentanyl analog, or their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixtures thereof. Opioid agonists also include drugs that bind to opioid receptors to exert agonist activity and are listed in the United States Controlled Substances Act of 1970, as amended, and regulations thereof, and drugs listed in the United States Psychotropic Substances Act of 1978, as amended, and regulations thereof.

[00191] The term "opioid antagonist" or "opioid receptor antagonist" means an antagonist substance that binds to one or more opioid receptor to exert an antagonist effect.

[00192] Opioid antagonists are known or readily determined by individuals who practice the art. Preferably, the opioid antagonists useful for the present invention may be selected from the group consisting of naltrexone, methylnaltrexone, nalbuphine, naloxone, nalmefene, cyclazocine, cyclorphan, oxilorphan nalorphine, nalorphine dinicotinate, nalmefene, nadide and levallorphan. In certain embodiments of the present invention, the ratio of the cannabinoid agonist and the opioid antagonist, present in a substantially non- releasable form, is about 1:10000 to about 10000:1 by weight or 1:1000 to about 1000:1 by weight, preferably 1:100 to about 100:1 by weight, more preferably about 1 :50 to about 50: 1 by weight, and more preferably about 1:10 to 10:1 by weight. The weight ratio of the cannabinoid agonist to opioid antagonist, as used in this application, refers to the weight of the active ingredients.

[00193] The present invention provides a transdermal dosage form of cannabinoid agonist useful for decreasing the potential for abuse of the cannabinoid agonist contained therein. The present invention includes a dosage form for application to the skin comprising a therapeutically effective amount of a cannabinoid agonist in combination with an opioid antagonist. The opioid antagonist is present in a substantially non-releasable form.

[00194] In some embodiments, the present invention includes a dosage form which comprises a releasable form of an opioid antagonist. [00195] The present invention also includes a dosage form which comprises a releasable form of an opioid antagonist, along with a cannabinoid agonist and coated opioid antagonist particles, the ratio of the agonist to the non-coated opioid antagonist being such, when secured or applied to the skin as intended, the dosage form is therapeutically effective.

[00196] In some embodiments, the present invention relates to cannabinoid agonist in releasable form and opioid antagonist in substantially non- releasable form (i.e., sequestered) when administered intact, said dosage forms having reduced potential for abuse in polydrug abusers. In some embodiments, the invention achieves its abuse deterrence by a novel method, namely by the effects of the sequestered opioid antagonist on co-abused opioid agonists in the setting of polydrug abuse under conditions where the dosage form of the invention is abuse or tampered (e.g., tearing, puncturing, scrapping, solvent immersion, solvent extraction, heating followed by ingestion orally, inhalationally, intranasally or parenterally), said opioid agonist not part of the dosage form and said dosage form having no significant direct effect on the cannabinoid agonist of the dosage form when the dosage form is used as directed or subject to abuse, and on any co-used opioid agonist when the dosage form of the invention is not abused or tampered.

[00197] In certain embodiments, the opioid antagonist present in a substantially non-releasable form does not substantially block the therapeutic effects of the cannabinoid agonist when the dosage form is administered as intended or intact (and does not pose a risk of precipitation of withdrawal in cannabinoid tolerant or dependent patients), but wherein the effect of the cannabinoid agonist is at least partially blocked by the opioid antagonist when said dosage form is tampered with, e.g., tearing, puncturing, scrapping, solvent immersion, solvent extraction, heating, followed by ingestion orally, inhalationally, intranasally or parenterally.

[00198] In certain embodiments, the opioid antagonist present in a substantially non-releasable form does not substantially block the therapeutic effects of the cannabinoid agonist when the dosage form is orally administered as intended or intact (and does not pose a risk of precipitation of withdrawal in cannabinoid tolerant or dependent patients), but can at least partially block the effect of the cannabinoid agonist and/or a co-abused opioid agonist(s) that is not part of the dosage form in the setting of polydrug abuse, when said dosage form is tampered with, e.g., tearing, puncturing, scrapping, solvent immersion, solvent extraction, heating, followed by ingestion orally, inhalationally, intranasally or parenterally.

[00199] In certain embodiments, the amount of the (sequestered) opioid antagonist in the claimed cannabinoid composition may be from about 10 ng to about 1000 mg.

[00200] In certain embodiments, the dosage form of the invention provides a release rate of the cannabinoid agonist that is greater following tampering than following securing the dosage form to the skin intact, said release rate measured by comparing the amount of cannabinoid agonist released from the dosage form for up to 24 hours as measured in- vitro via the dissolution of the dosage form in 900 mL of distilled water using a USP Apparatus 5 (paddle over disk method) at 50 rpm at 32 °C (the tampered dosage form) (USP 2005) versus the amount of cannabinoid agonist released from the intact dosage form into the body after securing the dosage form to the skin of a human or animal for an identical amount of time up to 24 hours; said amount released after tampering quantified by subtracting the amount of cannabinoid agonist in the dosage form after said dissolution test from the amount of cannabinoid agonist in the dosage form at the start of said dissolution test; and said amount released from the intact dosage form quantified by subtracting the amount of cannabinoid agonist in the dosage form after said application to skin from the amount of cannabinoid agonist in the dosage form at the start of said skin application. Using this method, in some embodiments, the ratio of release after tampering versus intact application to skin is greater than about 1.25:1, or greater than about 1.5:1 or greater than about 2:1, or greater than about 3:1 or greater than about 5:1, or greater than about 8:1 or greater than about 10:1, or greater than about 15:1 or greater than about 20:1, or greater than about 30:1 or greater than about 40:1, or greater than about 50:1 or greater than about 70:1, or greater than about 100:1 or greater than about 200:1, or greater than about 300:1 or greater than about 400:1, or greater than about 500:1 or greater than about 1000:1, or greater than about 2000:1 or greater than 5000:1. In certain embodiments, the dosage form of the invention provides a release rate of the cannabinoid agonist that is greater following tampering than following securing the dosage form to the skin intact, said release rate measured by comparing the amount of cannabinoid agonist released from the dosage form for up to 24 hours as measured in-vitro via the dissolution of the dosage form in 900 mL of 40% ethanol in distilled water using a USP Apparatus 5 (paddle over disk method) at 50 rpm at 32 ⁰C (the tampered dosage form) (USP 2005) versus the amount of cannabinoid agonist released from the intact dosage form into the body after securing the dosage form to the skin of a human or animal for an identical amount of time up to 24 hours; said amount released after tampering quantified by subtracting the amount of cannabinoid agonist in the dosage form after said dissolution test from the amount of cannabinoid agonist in the dosage form at the start of said dissolution test; and said amount released from the intact dosage form quantified by subtracting the amount of cannabinoid agonist in the dosage form after said application to skin from the amount of cannabinoid agonist in the dosage form at the start of said skin application. Using this method, in some embodiments, the ratio of release after tampering versus intact application to skin is greater than about 1.25:1, or greater than about 1.5:1 or greater than about 2:1, or greater than about 3:1 or greater than about 5:1, or greater than about 8:1 or greater than about 10:1, or greater than about 15:1 or greater than about 20:1, or greater than about 30:1 or greater than about 40:1, or greater than about 50:1 or greater than about 70:1, or greater than about 100:1 or greater than about 200:1, or greater than about 300:1 or greater than about 400:1, or greater than about 500:1 or greater than about 1000:1, or greater than about 2000:1 or greater than 5000:1. [00202] In certain embodiments, the dosage form of the invention provides a release rate of the aversive agent that is greater following tampering than following securing the dosage form to the skin intact, said release rate measured by comparing the amount of aversive agent released from the dosage form for up to 24 hours as measured in- vitro via the dissolution of the dosage form in 900 mL of distilled water using a USP Apparatus 5 (paddle over disk method) at 50 rpm at 32 ⁰C (the tampered dosage form) (USP 2005) versus the amount of aversive agent released from the intact dosage form into the body after securing the dosage form to the skin of a human or animal for an identical amount of time up to 24 hours; said amount released after tampering quantified by subtracting the amount of aversive agent in the dosage form after said dissolution test from the amount of aversive agent in the dosage form at the start of said dissolution test; and said amount released from the intact dosage form quantified by subtracting the amount of aversive agent in the dosage form after said application to skin from the amount of aversive agent in the dosage form at the start of said skin application. Using this method, in some embodiments, the ratio of release after tampering versus intact application to skin is greater than about 1.25:1, or greater than about 1.5:1 or greater than about 2:1, or greater than about 3:1 or greater than about 5:1, or greater than about 8:1 or greater than about 10:1, or greater than about 15:1 or greater than about 20:1, or greater than about 30:1 or greater than about 40:1, or greater than about 50:1 or greater than about 70:1, or greater than about 100:1 or greater than about 200:1, or greater than about 300:1 or greater than about 400:1, or greater than about 500:1 or greater than about 1000:1, or greater than about 2000:1 or greater than 5000:1.

[00203] In certain embodiments, the dosage form of the invention provides a release rate of the aversive agent that is greater following tampering than following securing the dosage form to the skin intact, said release rate measured by comparing the amount of aversive agent released from the dosage form for up to 24 hours as measured in- vitro via the dissolution of the dosage form in 900 mL of 40% ethanol in distilled water using a USP Apparatus 5 (paddle over disk method) at 50 rpm at 32 ⁰C (the tampered dosage form) (USP 2005) versus the amount of aversive agent released from the intact dosage form into the body after securing the dosage form to the skin of a human or animal for an identical amount of. time up to 24 hours; said amount released after tampering quantified by subtracting the amount of aversive agent in the dosage form after said dissolution test from the amount of aversive agent in the dosage form at the start of said dissolution test; and said amount released from the intact dosage form quantified by subtracting the amount of aversive agent in the dosage form after said application to skin from the amount of aversive agent in the dosage form at the start of said skin application. Using this method, in some embodiments, the ratio of release after tampering versus intact application to skin is greater than about 1.25:1, or greater than about 1.5:1 or greater than about 2:1, or greater than about 3:1 or greater than about 5:1, or greater than about 8:1 or greater than about 10:1, or greater than about 15:1 or greater than about 20:1, or greater than about 30:1 or greater than about 40:1, or greater than about 50:1 or greater than about 70:1, or greater than about 100:1 or greater than about 200:1, or greater than about 300:1 or greater than about 400:1, or greater than about 500:1 or greater than about 1000:1, or greater than about 2000:1 or greater than 5000:1. ] IQ certain embodiments, the dosage form of the invention provides a release rate of the cannabinoid agonist that is greater than the release rate of the aversive agent following securing the dosage form to the skin intact (untampered), said release rate measured by comparing the percent of cannabinoid agonist and the percent of aversive agent released from the intact dosage form into the body after securing the dosage form to the (depilated) skin of a human or animal for up to about 24 hours, or up to about 48 hours, or up to about 72 hours, or up to about 170 hours; said percent released from the intact dosage form quantified by subtracting the percent of cannabinoid agonist and aversive agent in the dosage form after said application to skin from the percent of cannabinoid agonist and aversive agent in the dosage form at the start of said skin application (100%). Using this method, in some embodiments, the ratio of percent release of cannabinoid agonist to aversive agent after intact application to said skin is greater than about 1.25:1, or greater than about 1.5:1 or greater than about 2:1, or greater than about 3:1 or greater than about 5:1, or greater than about 8:1 or greater than about 10:1, or greater than about 15:1 or greater than about 20:1 , or greater than about 30:1 or greater than about 40:1, or greater than about 50:1 or greater than about 70:1, or greater than about 100:1 or greater than about 200:1, or greater than about 300:1 or greater than about 400:1, or greater than about 500:1 or greater than about 1000:1, or greater than about 2000:1 or greater than 5000:1.

[00205] In certain embodiments, the dosage form of the invention provides a release rate of the cannabinoid agonist that is greater than the release rate of the aversive agent following securing the dosage form to the skin intact, said release rate measured by comparing the amount of cannabinoid agonist and the amount of aversive agent released from the intact dosage form into the body after securing the dosage form to the (depilated) skin of a human or animal for up to about 24 hours, or up to about 48 hours, or up to about 72 hours, or up to about 170 hours; said amount released from the intact dosage form quantified by measuring the area under the plasma concentration time curve (AUCo-O over the duration of skin application for the cannabinoid agonist and the aversive agent. Using this method, in some embodiments, the AUCo-_t ratio of cannabinoid agonist to aversive agent after intact application to said skin is greater than about 1.25:1, or greater than about 1.5:1 or greater than about 2:1, or greater than about 3:1 or greater than about 5:1, or greater than about 8:1 or greater than about 10:1, or greater than about 15:1 or greater than about 20:1, or greater than about 30:1 or greater than about 40:1, or greater than about 50:1 or greater than about 70:1, or greater than about 100:1 or greater than about 200:1, or greater than about 300:1 or greater than about 400:1, or greater than about 500:1 or greater than about 1000:1, or greater than about 2000:1 or greater than 5000:1.

[00206] In certain embodiments, the invention comprises a transdermal dosage form wherein the ratio of the amount of aversive agent (i.e., cannabinoid antagonist or opioid antagonist) to cannabinoid agonist released ^" from the intact dosage form into the body after securing the dosage form to the (depilated) skin of a human or animal for up to about 24 hours, or up to about 48 hours, or up to about 72 hours, or up to about 170 hours is greater than 1:10 or 1:30, preferably greater than 1:50 or 1:70, more preferably greater than 1:100 or 1 :300, even more preferably greater than 1:500 or greater than 1 :1000, and most preferably, greater than 1:2000, 1:5000 or 1 :10,000 (depending on the physicochemical, pharmaceutical and pharmacologic properties of the selected aversive agent and cannabinoid agonist, the concentration of the aversive agent in the transdermal dosage form and the selection of the aversive agent release controlling means), said amount released from the intact dosage form quantified by subtracting the amount of aversive agent and cannabinoid agonist in the dosage form after said application to skin from the amount of aversive agent and cannabinoid agonist in the dosage form at the start of said skin application. In certain embodiments, the invention comprises a transdermal dosage form wherein the ratio of the amount of aversive agent (i.e., cannabinoid antagonist or opioid antagonist) to cannabinoid agonist released from the intact dosage form into the body after securing the dosage form to the (depilated) skin of a human or animal for up to about 24 hours, or up to about 48 hours, or up to about 72 hours, or up to about 170 hours is greater than 1:10 or 1:30, preferably greater than 1:50 or 1:70, more preferably greater than 1 :100 or 1 :300, even more preferably greater than 1:500 or greater than 1 :1000, and most preferably, greater than 1:2000, 1:5000 or 1:10,000 (depending on the physicochemical, pharmaceutical and pharmacologic properties of the selected aversive agent and cannabinoid agonist, the concentration of the aversive agent in the transdermal dosage form and the selection of the aversive agent release controlling means), said amount released from the intact dosage form quantified by measuring the area under the plasma concentration time curve (AUCo-_t) over the duration of skin application for the aversive agent and cannabinoid agonist. [00208] In certain embodiments, the transdermal dosage form of the invention comprises an aversive agent (i.e., cannabinoid antagonist or opioid antagonist) and a cannabinoid agonist, wherein the amount of aversive agent released from the intact dosage form into the body after securing the dosage form to the (depilated) skin of a human or animal is less than about 0.001%, or less than about 0.005%, or less than about 0.05%, or less than about 0.1% or less than about 0.5%, or less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, of the amount of said aversive agent in the dosage form for each 24 hours period of application, said amount released from the intact dosage form quantified by subtracting the amount of aversive agent in the dosage form after said application to skin from the amount of aversive agent in the dosage form at the start of said skin application.

[00209] In certain embodiments, the transdermal dosage form of the invention comprises an aversive agent (i.e., cannabinoid antagonist or opioid antagonist) and a cannabinoid agonist, wherein the amount of aversive agent released from the intact dosage form into the body after securing the dosage form to the (depilated) skin of a human or animal is less than about 0.001%, or less than about 0.005%, or less than about 0.05%, or less than about 0.1% or less than about 0.5%, or less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, of the amount of said aversive agent in the dosage form for each 24 hours period of application, said amount released from the intact dosage form quantified by measuring the area under the plasma aversive agent concentration time curve (AUCo-t) over the duration of skin application.

[00210] In certain embodiments, the transdermal dosage form of the invention comprises an aversive agent (i.e., cannabinoid antagonist or opioid antagonist) and a cannabinoid agonist, wherein the amount of aversive agent released from the tampered dosage is at least about 0.5 fold more, or at least about 1 fold more, or at least about 2 fold more, or at least about 3 fold more, or at least about 4 fold more, or at least about 5 fold more, or at least about 7 fold more, or at least about 10 fold more, or at least about 20 fold more, or at least about 30 fold more, or at least about 40 fold more, or at least about 60 fold more, or at least about 80 fold more, or at least about 100 fold more, or at least about 150 fold more, or at least about 200 fold more, or at least about 300 fold more, or at least about 500 fold more, or at least about 700 fold more, or at least about 1000 fold more than the amount of aversive agent released from the intact dosage form into the body after securing the dosage form to the (depilated) skin of a human or animal for the same time period, said period of application from 1 minute to 120 minutes, said amount released from the intact dosage form quantified by subtracting the amount of aversive agent in the dosage form after said application to skin from the amount of aversive agent in the dosage form at the start of said skin application, and said amount released from the tampered dosage form quantified by subtracting the amount of aversive agent in the dosage form after placing the dosage form in the oral cavity of a human or animal from the amount of aversive agent in the dosage form at the start of said insertion in the oral cavity. ] The transdermal dosage form containing a cannabinoid agonist in combination with a substantially non-releasable form of an aversive agent includes, but are not limited to tablets or capsules. The dosage forms of the present invention may include any desired pharmaceutical excipients known to those skilled in the art. Specific examples of pharmaceutically acceptable carriers and excipients that may be used to formulate transdermal dosage forms of the present invention are described in the Handbook of Pharmaceutical Excipients, APhA Publications; 5 edition (January 5, 2006), compounds found on the FDA EAFUS database

(http://vm.cfsan.fda.gov/~dms/eafus.html); FDA Food Additives Status List (http://www.cfsan.fda.gov/~dms/opa-appa.html); FDAGRAS list and database; FDA Color Additive Status List

(http://www.cfsan.fda.gov/~dms/opa-appc.html); FDA Inactive Ingredients Database (http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm); Rowe, Sheskey and Owen, Handbook of Pharmaceutical Excipients, APhA Publications; 5th edition (2006); Remington: The Science and Practice of Pharmacy, 21st ed, Lippincott Williams & Wilkins (2005); United States Pharmacopeia-National Formulary (USP-NF), (USP 30 - NF 25, 2007), the International Programme on Chemical Safety (http://www.inchem.org/) and Health Canada's List of Acceptable Non-medicinal Ingredients (http://www.hc-sc.gc.ca/dhp-mps/prodnatur/legislation/docs/nnii- imn_listl_e.html), all hereby incorporated by reference in their entirety.

[00212] The benefits of the abuse-resistant dosage form are especially great in connection with dosage forms of potent cannabinoid agonists, which can provide valuable therapeutic benefits but are prone to being abused. This is particularly true for transdermal cannabinoid agonist products which have a large dose of a desirable cannabinoid agonist intended to be released over a period of time in each dosage unit. Drug abusers take such products and extract or otherwise damage the product so that the full contents of the dosage form become available for immediate absorption. Since such tampering of the dosage form of the invention results in the cannabinoid antagonist or opioid antagonist also becoming available for absorption, the present invention provides a means for deterring such abuse. In addition, the present invention addresses the risk of overdose to ordinary patients from "dumping" effect of the full dose of the cannabinoid agonist if the product is accidentally chewed or tampered.

[00213] The invention may provide for a safer product (e.g., lower risk of cannabinoid agonist toxicity), if the product is misused, as well as one with less risk of abuse.

[00214] In certain embodiments, a combination of two cannabinoid agonists is included in the formulation with the aversive agent, hi further embodiments, one or more cannabinoid agonist and an aversive agent is included and a further non-cannabinoid drug is also included for the treatment of the same medical condition as the cannabinoid agonist or for the treatment of a different medical condition. In certain embodiments, a combination of two or more aversive agents for interfering with the same or a different type of abuse [e.g., two cannabinoid antagonists; a cannabinoid antagonist and an opioid antagonist; or two opioid antagonist(s)] are included in the formulation with the cannabinoid agonist(s).

[00215] In yet other embodiments, the dosage form is co-administered with a non-cannabinoid agonist for the treatment of the same medical condition as the cannabinoid agonist or for the treatment of a different medical condition. All modes of co-administration are contemplated, including via oral, subcutaneous, direct intravenous, slow intravenous infusion, continuous intravenous infusion, intravenous or epidural patient controlled analgesia (PCA and PCEA), intramuscular, intrathecal, epidural, intracisternal, intramuscular, intraperitoneal, transdermal, topical, transmucosal, buccal, sublingual, transmucosal, inhalation, intranasal, epidural, intra-atricular, intranasal, rectal or ocular routes.

[00216] All pharmaceutical compositions and dosage forms for application to the skin are contemplated by the invention, including topical patch, transdermal patch, plaster, pastes, gel, liposomes, a liquid, semisolid, solution, suspension, lotion, cream, ointment, foam, sprayable aerosol, sprayable non- aerosol, provided they include (i) a releasable or substantially releasable cannabinoid agonist; and (ii) a non-releasable or substantially non-releasable aversive agent selected from cannabinoid antagonists, opioid antagonists or mixtures thereof.

[00217] In certain embodiments, the dosage form may include, in addition to the releasable cannabinoid agonist and the substantially non-releasable aversive agent, other abuse deterrent substances in releasable or substantially non-releasable form known to practitioners of the art.

[00218] In some embodiments, the cannabinoid agonist and aversive agent is a salt or complex of inorganic cation salts, organic salts such primary, secondary, tertiary and quaternary amines include substituted amines In some embodiments, examples of suitable pharmaceutically acceptable salts of xenobiotic include any of the inorganic cation salts such as sodium, potassium, lithium, magnesium, calcium, cesium, ammonia, ferrous, zinc, manganous, aluminum, ferric, and manganic; organic salts with primary, secondary, tertiary and quaternary amines, or mixtures thereof. Examples of such primary, secondary, tertiary and quaternary amines include substituted amines including but not limited to naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and mixtures thereof. More specifically, suitable amines include but are not limited to tromethamine, triethylamine, tripropylamine, dropopizine, 2-dirnethylaminoethanol, 2- diethylaminoethanol, lysine, arginine, ornithine, histidine, caffeine, procaine, Λf-ethylpiperidine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, frzs-(hydroxymethyl)aminornethane, N-methylglucamine, methylglycamine, theobromine, piperazine, piperidine, polyamine resins and the like, and mixtures thereof.

[00219] In some embodiments, examples of suitable pharmaceutically acceptable salts include aminoalcohols chosen from the group consisting of ethanolamine, 3-amino-l-propanol, (i?)-l-amino-2-propanol, (S)-I -amino- 2-propanol, 2-amino-l ,3-propandiol, iV-(2-hydroxyethyl)pyrrolidine, D-glucamine and L-prolinol, D-glucosamine, and iV-methylglucosamine.

[00220] In some embodiments, examples of suitable pharmaceutically acceptable salts include alkali and alkaline earth metals and salts of an organic nature, such as the salts of basic amino acids.

Additional Aversive Agent - Abuse Intervention Agents

[00221] In certain preferred embodiments of the invention, the dosage form optionally comprises, in addition to the foregoing cannabinoid agonist and the aversive agent(s) (selected from cannabinoid antagonists, opioid antagonists, and combinations of the same), one of more additional agents that are referred to herein as an abuse intervention agent(s), in sequestered, partially sequestered, unsequestered, non-releasable, partially releasable or releasable form. The abuse intervention agent(s) may comprise, for example, laxatives, cutaneous vasodilators, headache producing agents, emetics, emetogenic compound, nausea producing compounds, bittering agents, drugs that cause burning on irritation when in contact with tissue or mucous membranes (e.g., naso-mucosal irritants, oro-mucosal irritants, respiratory irritants), tissue irritants, gastrointestinal irritants, drugs that precipitate withdrawal effects, tissue dyes, lakes and colorants, beverage dyes, lakes and colorants, non-tissue staining beverage dyes, lakes and colorants (i.e, that do not stain or discolor the skin upon ingestion), fecal discolorants, urine discolorants, malodorous agents, opioid antagonists, benzodiazepine antagonists (e.g., flumazenil), and the like.

[00222] In certain particularly preferred embodiments of the invention, the abuse intervention agents are further selected from the group comprising (i) laxatives; (ii) cutaneous vasodilators; (iii) headache producing agents; (iv) emetics, emetogenic and nausea producing compounds; (iv) bittering agents (v) mucosal, naso-mucosal, oro-mucosal, respiratory, tissue and gastrointestinal irritants; (vi) tissue staining, non-tissue staining and beverage staining dyes, lakes and colorants; (vii) fecal and urine discolorants; and (viii) malodorous agents.

[00223] In certain particularly preferred embodiments of the invention, the abuse intervention agent comprises a non-toxic dye to deter surreptitious attempts at intoxication of another subject (e.g., in an alcoholic or nonalcoholic beverage).

[00224] In certain particularly preferred embodiments of the invention, the dosage form comprises an abuse intervention agent which comprises a nontoxic bittering agent to deter surreptitious attempts at intoxication of another subject (e.g., in an alcoholic or non-alcoholic beverage).

[00225] In certain particularly preferred embodiments of the invention, the dosage form comprises an abuse intervention agent which comprises a nontoxic bittering agent to deter oral or nasal ingestion of the dosage form.

[00226] In certain particularly preferred embodiments of the invention, the dosage form comprises an abuse intervention agent which comprises a nontoxic nasal irritant to deter oral or nasal ingestion of the dosage form. [00227] In some embodiments, the abuse intervention agent(s) may be in the dosage form in an amount that does not produce an aversive effect or aversion in any, many or substantially all patients when taken in accordance with the prescribing information or the manufacturer's instructions (for example, in small quantities), but which produce an aversive effect when taken in excess (e.g., higher dose or more frequently).

[00228] In some embodiments, the abuse intervention agent is one or more bittering agents selected from the group comprising T2R or TAS2R receptor agonists, phenylthiourea (phenylthiocarbamide), natural, artificial and synthetic flavor oils, flavoring aromatics, flavoring oils, oleoresins, spearmint oil, peppermint oil, eucalyptus oil, oil of nutmeg, allspice, mace, oil of bitter almonds, menthol, citrus oils including lemon, orange, lime, grapefruit, and fruit essences, sucrose derivatives, sucrose octaacetate, chlorosucrose derivatives, quinine, denatonium, denatonium saccharide and denatonium benzoate.

[002291 In some embodiments, the abuse intervention agent is one or more naso-mucosal, oro-mucosal, respiratory or tissue irritants selected from the group comprising transient receptor potential vanilloid 1 agonists, resiniferanoids, capsaicinoids, phorboid vanilloids, terpenoid 1,4-unsaturated dialdehydes, capsaicin, capsaicin analogs, resiniferatoxin, olvanil, pipeline, zingerone, anandamide, 12- and 15-(S)-hydroperoxy-eicosatetraenoic acids, 5 and 15-(S)-hydroxyeicosatetraenoic acids, phorbol 12-phenylacetate 13- acetate 20-homovanillate, 2 phorbol 12,13-didecanoate 20-homovanillate, leukotriene B(4), tinyatoxin, heptanoylisobutylamide, N-(3-acyloxy-2- benzylpropyl)-N'-dihydroxytetxahydrobenzazepine, tetrahydroisoquinoline thiourea analogs, heptanoyl guaiacylamide, isobutylamides, guaiacylamides, dihydrocapsaicin, homovanillyl octylester, nonanoyl vanillylamide, formic acid, acetic acid, propionic acidy, butyric acid, valeric acid, caproic acid, caprillic acid, capric acid, oxalic acid, malonic acid, succicnic acid, glu-taric acid, adipic acid, maleic acid, fumaric acid, citric acid, sodium lauryl sulfate, poloxamer, sorbitan monoesters, glyceryl monooleates, niacin, mustard, allyl isothiocyaanate and p-hydroxybenzyl isothiocyanate and acetylsalicylic acid.

[00230] In some embodiments, the abuse intervention agent is one or more emetogenic or nausea producing agents selected from the group comprising zinc and pharmaceutically acceptable salts thereof, dopamine agonists, apomorphine, ipecac, ipecacuanha, emetine, methylcephaeline, cephaeline, psychotrine, O-methylpsychotrine, ammonium chloride, potassium chloride, magnesium sulfate, ferrous gluconate, ferrous sulfate, aloin, algarot or antimonious oxychloride, antimony trichloride, folate, folic acid, niacin and nicotinamide.

[00231] In some embodiments, the abuse intervention agent is one or more cutaneous vasodilators selected from the group comprising niacin, nicotinuric acid, beta-hydroxybutyrate and nicotinic receptor agonists, including agonists at nicotinic receptor HM74A and nicotinic receptor GPRl 09A.

[00232] In some embodiments, the abuse intervention agent is one or more tissue dyes, lakes or colorants, or beverage dyes, lakes or colorants, or a beverage dye, lake and colorant that does not stain or discolor the skin upon ingestion, or a fecal discolorant or a urine discolorant selected from the group comprising Curcumin, Riboflavin, Tartrazine, Quinoline yellow, Sunset yellow FCF, Carmine, Carmoisine, Amaranth, Ponceau 4R, Erythrosine, Allura red AC, Patent blue V, Indigo carmine, Brilliant blue FCF, Chlorophylls, Copper complexes of chlorophylls and chlorophyllins, Green S, Caramel, Brilliant black BN, Vegetable carbon, Carotenoids, Alpha-, beta-, gamma-carotene, Capsanthin, Capsorubin, Lycopene, Beta-apo-8' carotenal, Ethyl ester of beta-apo-8' carotenoic acid, Xanthophylls, Lutein, Canthaxanthin, Beetroot red, Anthocyanins, Cyanidin, Delphidin, Malvidin, Pelargonidin, Peonidin, Petunidin, Calcium carbonate, Titanium dioxide, Iron oxides and hydroxides, Aluminum, Brilliant blue FCF, Indigotine, Alphazurine FG, Indanthrene blue, Fast green FCF, Alizarin cyanine green F, Quinizarine green SS, Pyranine concentrated, Orange II, Dibromofluorescein, Diiodofluorescein, Erythrosine yellowish Na, Erythrosine, Ponceau SX, Lithol rubin B, Lithol rubin B Ca, Toney red, Tetrabromofluorescein, Eosine, Tetrachlorotetrabromofluorescein, Phloxine B, Helindone pink CN, Brilliant lake red R, Acid fuchsine, Lake bordeaux B, Flaming red, Alba red, Allura red AC, Allura Red AC, Alizurol purple SS, Tartrazine, Sunset yellow, FCF, Fluorescein, Naphthol yellow S, Uranine, Quinoline yellow WS₅ Quinoline yellow SS, Brilliant blue FCF, Indigotine, Alphazurine FG, Alizurol purple SS. Sunset yellow FCF, Alumina, Aluminum powder, Annatto extract, Beta- carotene, Bismuth oxychloride, Bronze powder, Calcium carbonate, Canthaxanthin, Caramel, Chromium-cobalt-aluminum oxide, Chromium hydroxide green, Chromium oxide green, Cochineal extract, carmine, Copper powder, Dihydroxyacetone, Ferric ammonium citrate, Ferric ammonium ferrocyanide, Ferric ferrocyanide, Guanine, Iron oxides synthetic, Logwood extract, Mica, Potassium sodium copper chlorophyllin, Pyrogallol, Pyrophyllite, Talc, Titanium dioxide, Zinc oxide, FD&C blue #1, FD&C blue #2, D&C blue #4, D&C blue #9, FD&C green #3, D&C green #5, D&C green #6, D&C green #8, D&C orange #4, D&C orange #5, D&C orange #10, D&C orange #11, FD&C red #3, FD&C red #4, D&C red #6, D&C red #7, D&C red #17, D&C red #21, D&C red #22, D&C red #27, D&C red #28, D&C red #30, D&C red #31, D&C red #33, D&C red #34, D&C red #36, D&C red #39, FD&C red #40, FD&C red #40 lake, D&C violet #2, FD&C yellow #5, FD&C yellow #6, D&C yellow #7, Ext. D&C yellow #7, D&C yellow #8, D&C yellow #10, D&C yellow #11, FD&C lakes, D&C lakes, Ext. D&C lakes, FD&C blue #1 lake, FD&C blue #2 lake, D&C blue #4 lake, FD&C green #3 lake, D&C green #5 lake, D&C green #6 lake, D&C orange #4 lake, D&C orange #5 lake, D&C orange #10 lake, D&C orange #11 lake, FD&C red #4 lake, D&C red #6 lake, D&C red #7 lake, D&C red #17 lake, D&C red #21 lake, D&C red #22 lake, D&C red #27 lake, D&C red #28 lake, D&C red #30 lake, D&C red #31 lake, D&C red #33 lake, D&C red #34 lake, D&C red #36 lake, D&C violet #2 lake, FD&C yellow #5 lake, FD&C yellow #6 lake, D&C yellow #7 lake, Ext. D&C yellow #7 lake, D&C yellow #8 lake, D&C yellow #10 lake, Turmeric, Lactoflavin, Cochineal, carminic acid, Indigotine, Magnesium chlorophyll, Brilliant green BS, Black PN, Carbo medicinalis vegetabilis, Paprika oleoresin, Paprika oleoresin, Betanin, Beta-carotene, indigo carmine, iron oxides, sunset yellow FCF, titanium dioxide, ElOO, ElOl, E102, E104, EI lO, E120, E122, E123, E124, E127, E129, E131, E132, E133, E140, E141 , E142, E150, E151, E153, E160, E161, E162, E163, E170, E171, E172, E173 and phenazopyridine.

[00233] In some embodiments, the abuse intervention agent is one or more laxatives selected from the group comprising Bis(p-hydroxyphenyl)pyridyl-2- methane, bisacodyl, bisoxatin, anthraquinone, anthraquinone analogs and derivatives (e.g., buckthorn, casanthranol, cascara, hydroxy anthracene, glucofrangulin ), dantron, danthron, docusate (e.g., docusate sodium, docusate calcium, docusate potassium), gastrointestinal chloride channel activators (e.g., chloride channel subtype 2 activators), lubiprostone, magenesium salts (e.g., magnesium citrate, magnesium hydroxide, magnesium oxide), mannitol, oxyphenisatine, polyethylene glycol, poly(ethylene oxide) [PEO- 1500], sodium phosphate, phenolphthalein, senna, senna constituents and derivatives (e.g., sennoside A, sennoside B) and sodium picosulfate.

[00234] In some embodiments, the abuse intervention agent may be added to the formulation in an amount of less than about 80% by weight, preferably less than about 60% by weight, more preferably less than about 40% by weight of the dosage form, even more preferably less than about 20% by weight of the dosage form, and most preferably less than about 10 by weight of the dosage form (e.g., 0.000000000000001% to 1%, or 0.000000001% to 3%, or 0.0001% to 10%, or 0.001% to 5%, or 1% to 10%, or 0.001% to 2%, or 1% or 10%, or 2% to 7%) depending on the particular aversive agent used.

[00235] In some embodiments, the abuse intervention agent in the dosage form may be about 0.0000000000001 mg to about 2000 mg, or about 0.0000001 mg to about 1500 mg, or about 0.000001 mg to about 1000 mg, or about 0.0001 mg to about 1000 mg, or about 0.001 mg to about 1000 mg, or about 0.01 mg to about 1000 mg, or about 0.1 mg to about 1500 mg, or 1 mg to about 800 mg, or about 1 mg to about 500 mg, or about 1 mg to about 300 mg, or about 1 mg to about 150 mg, or about 5 mg to about 400 mg, or about 5 mg to about 200 mg, or about 0.00000000001 mg to about 200 mg, or about 0.00000000001 mg to about 100 mg, or about 0.00000000001 mg to about 50 mg, or about 0.0000001 mg to about 200 mg, or about 0.0000001 mg to about 100 mg, or about 0.00001 mg to about 400 mg, or about 0.0001 mg to about 300 mg.

[00236] In some embodiments, the amount of the abuse intervention agent in the dosage form of the present invention can be a fixed ratio in relation to the amount of cannabinoid agonist in the dosage form. By appropriately selecting the quantity of the other aversive agent in the dosage form, aversive effects can be avoided under conditions of proper medical use (e.g., manufacturers prescribing directions). However, under some conditions of abuse, for example excessive intake of the dosage form of the invention, the quantity of aversive agent consumed will exceed the "no effect" or "minimum effect" threshold, thereby producing one or more aversive effects, for example, e.g., nausea, emesis, diarrhea, laxation, cutaneous vasodilation, headache, bitter taste, naso-mucosal irritation, oro-mucosal irritation, reduction of the pleasurable, mood altering, rewarding, reinforcing, or other psychic and physiologic effects of the cannabinoid agonist or a co-abused drug.

[00237] In some embodiments, the "no effect" or "minimum effect" threshold amount of the abuse intervention agent can be exceeded when the dosage form of the invention is taken in excess of the manufacturer's recommendation by a factor of about 1.5, or about 2, or about 2.5, or about 3, or about 4, or about 5, or about 6, or about 7, or about 8, or about 10, or more than 10. In some embodiments, the production of an aversive effect can reduce or stop further abuse of the dosage form, thereby reducing the harm or toxicity of the drug in the subject who is tampering, misusing or abusing the dosage form, e.g., addicts, drug abusers and recreational drug users.

Treatments and Additional Active Drugs [00238] The cannabinoid agonist of the invention may be used for the prevention or treatment of any diseases and disorders, including without limitation, (i) pain; (ii) infectious, immunologic, cardiovascular, pulmonary, gastrointestinal, hepatic, biliary, nutritional, metabolic, endocrine, hematologic, oncologic, musculoskeletal, rheumatic, neurologic, psychiatric, genitourinary, gynecologic, obstetric, pediatric, otolaryngogologic, ophthalmic, dermatologic, dental, oral, and genetic disorders, diseases and maladies and signs and symptoms thereof; (iii) depression, schizophrenia, influenza, common colds, anxiety, panic attacks, agoraphobia, ADHD, insomnia, sleep disorders, nasal congestion, headaches, migraine, urinary incontinence, constipation, allergies, cough, pneumonia, COPD, asthma, fluid retention, acid reflux, peptic ulcers, hypertension, cardiac arrhythmias, hypercholesterolemia, CHF, fever, diarrhea, back pain, myofascial pain, osteoarthritis, neuropathic pain, cancer pain, acute pain, diabetes, muscle spasms, and rheumatoid arthritis, and signs and symptoms thereof; (iv) disorders, diseases and maladies, and signs and symptoms thereof referred to in Harrison's Principles of Internal Medicine, 16th Edition, 2004, Kasper DL, Braunwald W, Fauci A, Hauser S, Longo D, and Jameson JL (eds)].

[00239] In some preferred embodiments, the dosage form of the invention is used for the prevention or treatment of Alzheimer's disease, schizophrenia, depression, alcoholism, Parkinson's disease, stroke, premature labor, endotoxic shock, hepatic cirrhosis, atherosclerosis, cancer, glaucoma, emesis, pain, multiple sclerosis, amyotrophic lateral sclerosis, encephalitis, Huntington's disease, obesity, memory impairment, cognitive impairment, hypertension, cardiogenic shock, cerebral ischemia, myocardial infarction, neurotoxicity, febrile seizures and various intestinal disorders.

[00240] In some preferred embodiments, the dosage form of the invention may be give concurrently or contemporaneously with other therapeutic agents, said agents either part of the dosage form of the invention or given separately by the transdermal or non-transdermal route of administration and preferably selected from the group comprising decongestants, analgesics, analgesic psychotics, anxiol anti-ADHD drugs, psychostimulants, drugs to treat urinary incontinence, antihistamines, expectorants, antitussives, diuretics, anti-inflammatory agents, antipyretics, antirheumatics, antioxidants, laxatives, local anesthetics, proton pump inhibitors, motility modifying agents, vasodilators, inotropes, beta blockers, beta adrenergic agonists, drugs to treat asthma and COPD, antiinfectives, anti-migraine agents, antihypertensives, antianginal agents, gastric acid reducing agents, anti-ulcer agents, anticoagulants, lipid and cholesterol lowering drugs, anti-diabetic drugs, anti-epileptics, hormones, smooth muscle relaxants, skeletal muscle relaxants, bronchodilators, vitamins, trace minerals, amino acids, biological peptides and drugs to treat various infectious, immunologic disorders, cardiovascular, pulmonary, gastrointestinal, hepatic, biliary, nutritional, metabolic, endocrine, hematologic, oncologic, musculoskeletal, neurologic, psychiatric, genitourinary, gynecologic, obstetric, pediatric, otolaryngogologic, ophthalmic, dermatologic, dental, oral, and genetic disorders and diseases. The drug being used in combination therapy with the present invention can be administered by any route, including parenterally, orally, topically, transdermally, sublingually, and the like. The dosage form of the present invention may further include, in addition to a cannabinoid agonist and aversive agent (e.g., antagonist), one or more drugs that may or may not act synergistically therewith. Thus, in certain embodiments, a combination of two cannabinoid agonists may be included in the dosage form, in addition to the aversive agent (e.g., cannabinoid antagonist). For example, the dosage form may include two cannabinoid agonists having different pharmaceutical, physicochemical or pharmacologic properties, such as half-life, solubility, potency, and a combination of any of the foregoing. In yet further embodiments, one or more cannabinoid agonist is included and a further non-cannabinoid drug is also included, in addition to the aversive agent (e.g., cannabinoid antagonist). In a further embodiment, a non-cannabinoid drug is also included for the treatment of the same medical condition as the cannabinoid agonist or for a different medical condition. In some embodiments, the cannabinoid agonist is intended to prevent or treat acute or chronic pain. An included non-cannabinoid drug in such a dosage form may be used to provide additive, complementary, or synergistic therapeutic effects, including NSAIDs, NO-NSAIDs, COX-2 selective inhibitors, acetaminophen, nitroparacetamol, nitric oxide donors, tramadol, beta adrenergic agonists, alpha-2 agonists, selective prostanoid receptor antagonists, cannabinoid agonists, opioid receptor agonists, NO-opioid receptor agonists, local anesthetics, purinergic P2 receptor antagonists, NMDA receptor antagonists, gabapentin, pregabalin, gabapentinoids, ligands of alpha(2)delta subunits of voltage-gated calcium channels, neuronal nicotinic receptor agonists, calcium channel antagonists, sodium channel blockers, superoxide dismutase mimetics, p38 MAP kinase inhibitors, TRPVl agonists, dextromethorphan, dextrorphan, ketamine, glycine receptor antagonists, antidepressants, corticosteroids, and antiepileptics, and any other drugs that can be shown by a person proficient in the art to prevent or treat pain. ] The formulations of the invention may be used to treat painful conditions. As used herein, the term "pain" includes: (i) peripheral neuropathic pain, e.g., acute and chronic inflammatory demeyelinatingpolyradiculopathy, alcoholic polyneuropathy, chemotherapy-induced polyneuropathy, complex regional pain syndrome (CRPS) Type I and Type II, entrapment neuropathies (e.g., carpal tunnel syndrome), HIV sensory neuropathy, iatrogenic neuralgias (e.g., postthoracotomy pain, postmastectomy pain), idiopathic sensory neuropathy, painful diabetic neuropathy, phantom limb pain, postherpetic neuralgia, trigeminal neuralgia, radiculopathy (e.g., cervical thoracic, lumbosacral), sciatica, acute herpes zoster pain, temporomandibular joint disorder pain and postradiation plexopathy; and (ii) central neuropathic pain, e.g., compressive myelopathy from spinal stenosis, HIV myelopathy, multiple sclerosis pain, Parkinson's disease pain, postischemic myelopathy, post postradiation myelopathy, poststroke pain, posttraumatic spinal cord injury and syringomyelia; and (iii) cancer associated neuropathic pain, e.g., chemotherapy induced polyneuropathy, neuropathy secondary to tumor infiltration or nerve compression, phantom breast pain, postmastectomy pain, postradiation plexopathy and myelopathy; (iv) chronic pain, e.g., back pain, rheumatoid arthritis, osteoarthritis, inflammatory pain, non-inflammatory pain, myofascial pain, fibromyalgia, cancer pain, visceral pain, somatic pain, pelvic pain, musculoskeletal pain, post-traumatic pain, bone pain and idiopathic pain; (v) acute pain, e.g, acute postsurgical pain (including laparoscopic, laparatomy, gynecologic, urologic, cardiothoracic, arthroscopic, gastrointestinal, neurologic, orthopedic, oncologic, maxillofacial, ophthalmic, otolaryngologic, soft tissue, plastic, cosmetic, vascular and podiatric surgery, including abdominal surgery, abdominoplasty, adenoidectomy, amputation, angioplasty, appendectomy, arthrodesis, arthroplasty, arthroscopy, bilateral cingulotomy, biopsy, brain surgery, breast biopsy, cauterization, cesarean section, cholecystectomy, circumcision, commissurotomy, cordotomy, corneal transplantation, cricothoracotomy, discectomy, diverticulectomy, episiotomy, endarterectomy, endoscopic thoracic sympathectomy, foreskin restoration, fistulotomy, frenectomy, frontalis lift, fundectomy, gastrectomy, grafting, heart transplantation, hemicorporectomy, hemorrhoidectomy, hepatectomy, hernia repair, hypnosurgery, hysterectomy, kidney transplantation, laminectomy, laparoscopy, laparotomy, laryngectomy, lithotripsy, lobotomy, lumpectomy, lung transplantation, mammectomy, mammoplasty, mastectomy, mastoidectomy, mentoplasty, myotomy, mryingotomy, nephrectomy, nissen fundoplication, oophorectomy, orchidectomy, parathyroidectomy, penectomy, phalloplasty, pneumotomy, pneumonectomy, prostatectomy, psychosurgery, radiosurgery, ritidoplasty, rotationplasty, sigmoidostomy, sphincterotomy, splenectomy, stapedectomy, thoracotomy, thrombectomy, thymectomy, thyroidectomy, tonsillectomy, tracheotomy, tracheostomy, tubal ligation, ulnar collateral ligament reconstruction, ureterosigmoidostomy, vaginectomy, vasectomy, vulvectomy; renal colic; incisional pain; inflammatory incisional pain; nociceptive incisional pain; acute neuropathic incisional pain following surgery), renal colic, trauma, acute back pain, burn pain, burn dressing change pain, migraine pain, tension headache pain, acute musculoskeletal pain, acute exacerbation or flare of chronic back pain, acute exacerbation or flare of osteoarthritis, acute exacerbation or flare of chronic pain, breakthrough chronic non-cancer pain, breakthrough cancer pain, acute exacerbation or flare of fibromylagia, acute exacerbation or flare of rheumatoid arthritis, acute exacerbation or flare of myofacsial pain, acute exacerbation or flare of chronic idiopathic pain, acute exacerbation or flare of neuropathic pain, procedure related pain (e.g., arthroscopy, laparoscopy, endoscopy, intubation, bone marrow biopsy, soft tissue biopsy, catheterization), and other self-limiting pain states.

[00243] The present invention is further directed to a method of decreasing the potential for abuse of a cannabinoid agonist in a dosage form suitable for application to the skin. The method comprises providing the cannabinoid agonist in a transdermal dosage form as described herein.

[00244] The present invention is directed to a immediate and controlled release transdermal cannabinoid agonists which are formulated in order to reduce and minimize misuse, abuse and diversion. In certain embodiments, these characteristics are conferred by the inclusion of an aversive agent, which is itself formulated in a unique controlled release matrix. The properties of this formulation are developed to liberate the aversive agent in conditions of misuse or tampering yet a negligible amount of aversive agent would be released (an amount which does not affect therapeutic effect of the cannabinoid agonist experienced by the patient) under the prescribed conditions of use.

[00245] In certain embodiments of the invention, the release for the aversive agent (e.g., antagonist component) of the formulation is expressed in terms of a ratio of the release achieved after tampering, e.g., by solvent extraction, puncturing or tearing, followed by oral ingestion of a patch, relative to the amount released from the intact formulation upon application to the skin. [00246] Also disclosed are kits for use in treating or preventing diseases or disorders amenable to treatment with the dosage form of any of claims 1-91 comprising: (i) a dosage form of the invention; (ii) a container for the dosage form; and optionally, any of (iii) to (vii): (iii) a container for individual units of the dosage form (e.g., individual patches); (iv) educational instructions in any media about any medical condition, its etiology, pathophysiology, consequences and treatment, potential for abuse and diversion and methods for prevention of same and information on the proper use and disposal of the medication; (v) containers or bags for the safe disposal of any used or remaining unused dosage form, preferably child proof and flushable; (vi) tamper evident and child proof packaging for the kit and its contents (vii) disposable gloves, applicators and/or solvent to allow for the application and/or removal of the dosage form.

[00247] As used herein, the term "incidental exposure to water" refers to short- term exposure to high humidity or brief exposure to liquid water, such as during showering, sweat, and the like.

[00248] As used herein, the term "single phase polymeric composition" refers to a composition in which the cannabinoid agonist and all other components are solubilized in a polymer and are present at concentrations no greater than, and preferably less than, their saturation concentrations in the reservoir such that there are no undissolved components present in the composition over a substantial portion of the administration period; wherein all the components in combination with the polymer form a single phase.

[00249] As used herein, the term "component" refers to an element within the cannabinoid agonist reservoir, including, but not limited to, a cannabinoid agonist as defined above, additives, permeation enhancers, stabilizers, dyes, diluents, plasticizer, tackifyhig agent, pigments, carriers, inert fillers, antioxidants, excipients, gelling agents, anti-irritants, vasoconstrictors and the like. [00250] As used herein, a "cannabinoid agonist release controlling means" refers to a means to modulate the release rate of the cannabinoid agonist, such as rate control membranes generally known in the art.

[00251] As used herein, the term "antagonist release controlling means",

"cannabinoid antagonist release controlling means", "opioid antagonist release controlling means" and "aversive agent release controlling means" refers to a means to control the cannabinoid antagonist release rate, the opioid antagonist release rate, or both. The antagonist release controlling means, cannabinoid antagonist release controlling means, opioid antagonist release controlling means and aversive agent release controlling means modulate the ingress of solvent in to the aversive agent reservoir, thus modulating the release of the aversive agent during abuse while permitting the release of the aversive agent at a rate sufficient to inhibit abuse. The aversive agent release controlling means include physical means such as a layer, a membrane, a film, a coating, a sheet, a deposit, including but not limited to, a rate control layer, a rate control membrane, a porous or a microporous membrane, an impermeable film wherein the release is controlled through the edge of the patch. The aversive agent release controlling means also include chemical means and may be osmotically driven, concentration dependent, or may depend on the size and characteristics of the materials forming the aversive agent release controlling means. In certain embodiments, the aversive agent rate controlling means is incorporated within the aversive agent reservoir where the rate of release is governed by the osmotic bursting mechanism. The release rate of the aversive agent is controlled by factors such as the amount of aversive agent within the aversive agent reservoir, the aversive agent particle size, aversive agent salt osmotic pressure, and physical characteristics of the polymer matrix of the aversive agent reservoir.

[00252] The invention may provide for a safer product (e.g., lower risk of cannabinoid agonist toxicity), if the product is misused, as well as one with less risk of abuse. [00253] The phrase "transdermal dosage form", "transdermal pharmaceutical composition", "dosage form of the invention", "dosage form" and "transdermal system" of the present invention have the same meaning when referring to the transdermal invention containing the releasable cannabinoid agonist and a substantially non-releasable cannabinoid antagonist.

[00254] The term "transdermally administered", "secured", "applied"

"affixed", "used", "given", "attached" and "administered" with reference to the use of the transdermal dosage form of the invention all have the same meaning.

[00255] The term "dosage form of the invention" and "invention" is any dosage form for application to the skin comprising (i) a cannabinoid agonist; (ii) an aversive agent selcted from the group comprising cannabinoid antagonist(s), opioid antagonist(s) or mixtures therof; and optionally (iii) abuse intervention agents. Said dosage form for application to the skin may provide therapeutic effects anywhere in the body, locally and/or systemically (e.g., skin and skin structures, tissue and organs immediately below the area of skin application, tissue and organs in the vicinity of the area of skin application, tissue and organs distal to the area of skin application, in the central nervous system).

[00256] In some embodiments, transdermal dosage forms of the invention produce a local or peripheral effect on the skin and/or on adjacent tissue. In other embodiments, transdermal dosage forms of the invention produce a systemic effect. In yet other embodiments, transdermal dosage forms of the invention produce both a local or peripheral effect and a systemic effect.

[00257] The term "an antagonist in a non-releasable form", "an antagonist in a substantially non-releasable form", "a cannabinoid antagonist in a substantially non-releasable form", "a cannabinoid antagonist in a non- releasable form", "an opioid antagonist in a substantially non-releasable form", "an opioid antagonist in a non-releasable form", "an aversive agent in a substantially non-releasable form", and "an aversive agent in a non-releasable form", refers to one or more cannabinoid antagonist(s), one or more opioid antagonist(s), or mixtures thereof that is (are) not released or substantially not released after the intact dosage form containing both cannabinoid agonist and the aversive agent (cannabinoid antagonist, or opioid antagonist) is applied to the skin as intended by the manufacturer (i.e., without having been tampered with). For purposes of the invention, the amount released after transdermal administration of the intact dosage form may be measured using standardized in vitro or in vivo extraction test method. Such a dosage form is also referred to as comprising a "sequestered aversive agent", "sequestered cannabinoid antagonist" or "sequestered opioid antagonist". Aversive agents in non- releasable, substantially non-releasable or sequestered form do not change (i.e., increase or decrease) or substantially change the efficacy or safety of the cannabinoid agonist of the dosage form upon application to the skin as intended by the manufacturer (i.e., without having been tampered with).

[00258] The term "analgesic effectiveness" is defined for purposes of the present invention as a satisfactory prevention, reduction in or elimination of pain, along with a tolerable level of side effects, as determined by the human patient.

[00259] The term "therapeutic effectiveness" is defined for purposes of the present invention as a satisfactory prevention or treatment of diseases and disorders amenable to treatment with a cannabinoid agonist, including their signs and symptoms, along with a tolerable level of side effects, as determined by the human patient.

[00260] The phrase "risk of precipitation of withdrawal" means that the proper action of the dosage form does not depend on a specific ratio of agonist to antagonist or differential metabolism of either.

Tamper Evaluation

[00261] Tampering of transdermal dosage forms of abusable drugs can occur in a wide variety of ways and may involve unused and discarded dosage forms. Nonlimiting examples of methods to evaluate tampering include in vitro extraction methods and in vivo extraction methods.

[00262] In Vitro Tamper Evaluation Methods [00263] Nonlimiting examples of in vitro methods to evaluate tampering are provided below.

[00264] In general, the transdermal dosage form is placed in a standard extraction medium or solution, equilibrated to the target temperature and stirred. Examples of standard extraction media include but are not limited to aqueous medium such as distilled water, a salt solution, aqueous medium containing appropriate buffering agents to provide a pH of about 0.1 to 14 (e.g., aqueous medium containing phosphate buffer at pH 6.5, simulated gastric fluid, simulated intestinal fluid), an aqueous solvent similar to saliva; organic solvents such as alcohol (e.g. methanol, ethanol, isopropyl alcohol and the like), dimethylfuran, methylene chloride, chloroform, carbon tetrachloride, ether, acetone, benzene, toluene, hexane, pentane, dimethylformarnide, formaldehyde, ethyl acetate, methyl ethyl ketone; and common household materials such as, nail polish remover, rubbing alcohol, glycerin, mineral spirits, turpentine, vodka, cooking oil, vinegar, gasoline, kerosene, dry cleaning fluids and the like and mixtures thereof. The volume of the medium is adjusted to be below the solubility limit of the agonist and the antagonist. The temperature of the extraction can be varied within a range of ambient to near that of boiling, e.g., 20° C, 50° C and 75° C Aliquots of the extraction medium are removed at various time points, e.g., 0, 2, 5, 15, 60 and 120 minutes, and diluted with corresponding unused extraction medium. The samples are assayed for agonist and antagonist content by a sensitive and specific analytical method. If any one of the test methods satisfies the abuse limiting release rate ratio of the cannabinoid antagonist to the cannabinoid agonist in any of the above-mentioned.

[00265] In certain embodiments of the invention, tampering is evaluated by measuring the amount of the cannabinoid agonist and/or the aversive agent (i.e., one or more compounds selected from cannabinoid antagonist, opioid antagonists, or mixtures thereof) released via the dissolution of the dosage form in 900 mL of distilled water or 900 mL of 40% ethanol in distilled water using a USP Apparatus 5 (paddle over disk method) at 50 rpm at 32 °C (the tampered dosage form) (USP 2005).

[00266] In certain embodiments of the invention, tampering is evaluated by measuring the release rate of the cannabinoid agonist and/or the aversive agent (i.e., one or more compounds selected from cannabinoid antagonist, opioid antagonists, or mixtures thereof)the , in- vitro via the dissolution of the dosage form in 900 mL of distilled water or 900 mL of 40% ethanol in distilled water using a USP Apparatus 5 (paddle over disk method) at 50 rpm at 32 ⁰C (the tampered dosage form) (USP 2005), said amount released after tampering quantified by subtracting the amount of cannabinoid agonist and/or aversive agent (as applicable) in the dosage form after said dissolution test from the amount of cannabinoid agonist and/or aversive agent (as applicable) in the dosage form at the start of said dissolution test.

[00267] In certain embodiments of the invention, the dissolution conditions and test methods may be modified (e.g., apparatus, dissolution media, buffers, surfactants, enzymes, temperature, pH, rpm, sampling times and duration).

[00268] In Vivo Tamper Evaluation Methods

[00269] Nonlimiting examples of in vivo methods to evaluate tampering are provided below.

[00270] In certain embodiments of the invention, tampering is evaluated by measuring the amount of the cannabinoid agonist and/or the aversive agent (i.e., one or more compounds selected from cannabinoid antagonist, opioid antagonists, or mixtures thereof) released by placing the intact dosage form of the invention (in a form ready to be applied to the skin as intended) into the oral cavity of an animal, e.g., mice, rats, pigs, cats, dogs, primates (monkeys), humans, and the like for a predetermined period, e.g., from about 1 minute to about 2 hours. At the end of the test time period, the transdermal dosage forms are removed from the oral cavity and allowed to air dry. The transdermal dosage forms are analyzed for cannabinoid agonist and/or the aversive agent content (as applicable) and said amount released after tampering quantified by subtracting the amount of cannabinoid agonist and/or aversive agent (as applicable) in the dosage form after said test from the amount of cannabinoid agonist and/or aversive agent (as applicable) in the dosage form at the start of said test. In certain embodiment, the transdermal dosage forms are analyzed for cannabinoid agonist and/or the aversive agent content (as applicable) and said amount released after tampering quantified by measuring the area under the plasma concentration time curve (AUC_0-O of cannabinoid agonist and/or aversive agent (as applicable) over the duration of oral application. [00271] In certain embodiments of the invention, tampering is evaluated by measuring the amount of the cannabinoid agonist and/or the aversive agent (i.e., one or more compounds selected from cannabinoid antagonist, opioid antagonists, or mixtures thereof) released by placing the intact dosage form of the invention (in a form ready to be applied to the skin as intended) into the peritoneal cavity of an animal, e.g., mice, rats, pigs, cats, dogs, primates (monkeys), humans, and the like for a predetermined period, e.g., from about 1 minute to about 2 hours.

BRIEF DESCRIPTION OF THE FIGURES

[00272] Figure 1 depicts a cross-section through a schematic view of one embodiment of transdermal dosage form according to this invention. [00273] Figure 2 depicts a cross-section through a schematic view of another embodiment of transdermal dosage form according to this invention. [00274] Figure 3 depicts a cross-section through a schematic view of another embodiment of transdermal dosage form according to this invention. [00275] Figure 4 depicts a cross-section through a schematic view of another embodiment of transdermal dosage form according to this invention. [00276] Figure 5 depicts a cross-section through a schematic view of another embodiment of transdermal dosage form according to this invention.

METHODS OF CARRYING OUT THE INVENTION

[00277] Pharmaceutical composition and methods of the present invention contain a releasable or substantially releasable cannabinoid agonist and a substantially non-releasable or non-releasable aversive agent (selected from the group comprising one or more cannabinoid antagonists, opioid antagonists, and mixtures thereof), pharmaceutically acceptable salts or mixtures thereof and they are intended for application to the skin. All pharmaceutical compositions and dosage forms for application to the skin are contemplated by the invention, including topical patch, transdermal patch, plaster, pastes, gel, liposomes, a liquid, semisolid, solution, suspension, lotion, cream, ointment, foam, sprayable aerosol, and sprayable non-aerosol. Methods for the preparation of dosage forms for application to the skin, including those in the form of topical patch, transdermal patch, plaster, pastes, gel, liposomes, a liquid, semisolid, solution, suspension, lotion, cream, ointment, foam, sprayable aerosol, sprayable non-aerosol are disclosed in patents and in the art [e.g., Williams AC. Transdermal and Topical Drug Delivery, Pharmaceutical Press, London, 2003; Remington: The Science and Practice of Pharmacy ,21^st Edition, Lippincott Williams & Wilkins, Baltimore, 2005; Walters KA. Dermatological and Transdermal Formulations, Informa Healthcare, 1^st Edition, 2002; Transdermal Drug Delivery, Hadgraft J (ed), 2^nd Edition, 2002; Transdermal and Topical Drug Delivery Systems, Ghosh TK, Pfister W & Yum SI (eds), CRC, 1997; Transdermal Controlled Systemic Medications; Chien YW (ed), Marcel Dekker, 1987; Topical Drug Delivery Formulations, Osborne DW and Amann AH (eds), Informa Healthcare, 1989; Topical Drug Bioavailability, Bioequivalence, and Penetration, Shah VP and Maibach HI (eds), Springer, 1993; Jaroszeski MJ. Electrochemotherapy,

Electrogenetherapy, and Transdermal Drug Delivery: Electrically Mediated Delivery of Molecules to Cells. Humana Press, 1st edition 2000; Wille JJ. Skin Delivery Systems: Transdermals, Dermatologicals, and Cosmetic Actives. Blackwell Publishing, 1st edition, 2006; Gurny R and Teubner A (Eds). Dermal and Transdermal Drug Delivery: New Insights and Perspectives. CRC Press, 1993], hereby incorporated by reference in their entirety and U.S. Pat. Nos. 4,466,953; 4,470,962; 4,588,580; 4,626,539; 4,645,502; 4,746,509; 4,806,341; 4,814,173; 4,820,708; 4,826,677; 4,906,463; ,911,707; 4,911,916; 4,915,950; 4,917,676; 4,927,408; 4,938,759; 4,956,171; ,006,342; 5,026,556; 5,047,230; 5,069,909; 5,080,646; 5,135,480; 5,147,296; ,149,538; 5,169,382; 5,186,939; 5,203,768; 5,225,199; 5,232,438; 5,236,714; ,240,711; 5,250,527; 5,306,503; 5,310,559; 5,346,701; 5,374,645; 5,460,620; ,462,744; 5,464,387; 5,474,783; 5,503,844; 5,516,523; 5,556,635; 5,595,722; ,597,561; 5,599,554; 5,601,839; 5,629,014; 5,635,204; 5,656,286; 5,662,926; ,665,378; 5,679,373; 5,683,713; 5,686,112; 5,705,186; 5,730,999; 5,762,952; ,770,609; 5,807,957; 5,834,010; 5,843,979; 5,906,822; 5,908,846; 5,911,980; ,914,098; 5,948,433; 5,958,446; 5,985,317; 5,993,787; 5,993,849; 6,004,969; ,010,715; 6,024,976; 6,063,399; 6,110,488; 6,113,921; 6,139,866; 6,165,499; 6,171,294; 6,181,963; 6,197,789; 6,203,817; 6,207,183; 6,216,033; 6,219,576; 6,224,900; 6,238,284; 6,238,362; 6,251,920; 6,262,079; 6,264,977; 6,264,978; 6,267,982; 6,277,400; 6,280,766; 6,315,854; 6,316,023; 6,335,031; 6,335,328; 6,344,211; 6,365,178; 6,379,696; 6,395,494; 6,417,227; 6,417,365; 6,425,892; 6,436,433; 6,488,959; 6,520,329; 6,521,250; 6,537,571; 6,538,017; 6,548,510; 6,558,696; 6,571,983; 6,576,712; 6,599,511; 6,620,429; 6,623,763; 6,627,631; 6,627,749; 6,630,149; 6,630,505; 6,653,288; 6,689,379; 6,699,498; 6,710,061; 6,713,475; 6,733,775; 6,737,080; 6,740,657; 6,750,050; 6,750,291; 6,756,052; 6,780,504; 6,791,003; 6,797,105; 6,814,976; 6,838,078; 6,849,643; 6,868,286; 6,871,419; 6,881,208; 6,884,434; 6,890,939; 6,893,655; 6,899,894; 6,905,705; 6,916,486; 6,936,604; 6,936,661; 6,946,501; 6,951,642; 6,955,819; 6,955,842; 6,960,597; 6,987,110; 7,004,321; 7,011,843; 7,018,370; 7,029,692; 7,030,203; 7,048,942; 7,049,479; 7,054,682; 7,056,528; 7,070,808; 7,081,460; 7,083,781; 7,094,550; 7,114,422; 7,125,878; 7,150,881; 7,160,559; 7,175,853; WO 96/19975 and U.S. Patent Application Nos. 20010018582; 20010037104; 20020025334; 20020034535; 20020119187; 20020127254; 20030026829; 20030060479; 20030083609; 20030099695; 20030102246; 20030175328; 20030199644; 20030203991; 20040001882; 20040013716; 20040086551; 20040122105; 20040166147; 20040191322; 20040213832; 20040234583; 20040234584; 20040242770; 20050033065; 20050037059; 20050095279; 20050118244; 20050118245; 20050131337; 20050136101; 20050171464; 20050202073; 20050208117; 20050226922; 20060013865; 20060069344; 20060078600; 20060147439; 20060149183; 20060188558; 20060210617; 20060222691; 20060275352; 20070026054, hereby incorporated by reference in their entirety.

[00278] Non-limiting ways in which the aversive agent (e.g., cannabinoid antagonists and opioid antagonists) of the dosage form is made substantially non-releasable or non-releasable upon application intact to skin include one or more of the following, (i) enclosure of aversive agent in a separate reservoir; (ii) coating of aversive agent to make in non-releasable; (iii) salification of aversive agent; (iv) using a prodrug of aversive agent; (v) making the aversive agent hydrophilic; (vi) placing the aversive agent in an environment that reduces release through the membrane layer; (vii) covalently linking the aversive agent with a moiety that reduced release through the membrane layer or reduces penetration through the skin; (viii) making the aversive agent hydrophobic; and (ix) selecting a membrane layer that preferentially releases the cannabinoid agonist over the aversive agent.

[00279] Preferably, the aversive agent is present in a form that is substantially impermeable to the skin to which the transdermal dosage form of the invention is to be applied. The reservoir comprises the cannabinoid agonist and aversive agent dispersed within a polymer, preferably wherein the aversive agent is substantially insoluble in the reservoir polymer. The low solubility of the aversive agent in skin and polymer has several advantages, substantially minimizing undesirable interactions between the aversive agent and the cannabinoid agonist and improved stability/shelf life of the transdermal dosage form.

[00280] In certain embodiments, the aversive agent is dispersed in a matrix comprising a polymeric material which substantially prevents release of the aversive agent, preferably a thermoformable material; or the aversive agent is complexed with an ionic resin. In additional embodiments, the aversive agent reservoir comprises the aversive agent in a multiparticulate form, wherein each particle is individually coated with a polymeric material which substantially prevents release of the aversive agent, wherein the polymeric material is preferably a thermoformable material. In additional embodiments, the aversive agent comprises beads coated with the aversive agent, wherein the beads may be formed from glass or an inert or non-dissolvable polymer, and further wherein the coated beads are optionally coated with or dispersed in a polymeric material which substantially prevents release of the aversive agent, wherein the polymeric material is preferably a thermoformable material. Preferably, the aversive agent is present as a salt. As discussed above, the reservoir comprises the cannabinoid agonist and aversive agent dispersed within a polymer. Preferably, the aversive agent is dispersed in a matrix comprising a thermoformable material that substantially prevents release of the aversive agent. Alternatively, the aversive agent is present in a multiparticulate form, wherein each particle is individually coated with a polymeric material that substantially prevents release of the aversive agent. Preferably, the polymeric material which substantially prevents release of the aversive agent is hydrophobic, i.e., substantially prevents release of the aversive agent during normal use, minimizes the amount of aversive agent during incidental/casual exposure to solvents (moisture, e.g., sweat, during a shower), and when the dosage form is subject to abuse, e.g., upon ingestion or immersion in a solvent, releases the aversive agent in abuse nullifying amounts. Examples of a polymeric material which substantially prevents release of the aversive agent include, but are not limited to, polyethylene, polyoctene, polyvinyl acetate, polymethyl acrylate, polymethyl acrylate, polyethyl acrylate, polystyrene polymers and copolymers and mixtures thereof; polystyrene copolymers such as styrenic block copolymers (SIS, SBS, SEBS), ethylene copolymers such as polyethyleneoctene copolymers, ethylene-vinyl acetate copolymer (EVA), ethylenemethyl acrylate copolymers (EMA), ethylene-acrylic acid copolymer, ethylene-ethylacrylate copolymer, and the like, and combinations thereof. [00282] In additional embodiments, the aversive agent is complexed with an ionic resin. Examples of ionic resins include, but are not limited to sulfonated polystyrene resins, and the like.

[00283] In additional embodiments, the aversive agent reservoir comprises beads coated with the aversive agent, wherein the spheres or beads may be formed from glass, metals or an inert or non-dissolvable polymer, and further wherein the coated beads are optionally coated with or dispersed in a polymeric material which substantially prevents release of the aversive agent, as described above. The beads may be in any shape, size or form, but are preferably small sized, preferably less than 10 microns. Examples of an inert or non-dissolvable polymer include, but are not limited to polymethylmethacrylate, polycarbonate and polystyrene.

[00284] In some preferred embodiments, the invention provides for a transdermal dosage form comprises a transdermal dosage forms of about 0.5 to about 250 cm²; preferably about 1 to about 150 cm², more preferably 2 to about 100 cm², even more preferably about 4 to about 50 cm² or about 10 to about 20 cm².

[00285] Administration is maintained for 4 hours to 30 days; 1, 2, 3, and 7 day regimens being considered preferable. In preferred embodiments of the dosage form intended as 2, 3 or 7 day regimens, at least 1%, but not more than 50% of the total amount of the cannabinoid agonist in the dosage form is administered during approximately the first 24 hours of use; at least 2%,but not more than 60% of the total amount of the cannabinoid agonist is administered during approximately the first 48 hours of use; and at least 2%, but not more than 80%, of the total amount of the cannabinoid agonist is administered during the administration period. In preferred embodiments of the dosage form intended as 12 or 24 hour regimens, at least 1%, but not more than 50%, of the total amount of the cannabinoid agonist in the dosage form is administered during approximately the first 6 hours of use; at least 2%, but not more than 70%, of the total amount of the cannabinoid agonist is administered during approximately the first 8 hours of use; and at least 4%, but not more than 80%, of the total amount of the cannabinoid agonist is administered during the administration period.

[00286] On application to the skin, the cannabinoid agonist in the transdermal dosage form diffuses into the skin where it is absorbed into the bloodstream to produce its intended systemic effects. The onset of effect depends on various factors, such as, potency of the cannabinoid agonist, the solubility and diffusivity of the cannabinoid agonist in the skin, thickness of the skin, concentration of the cannabinoid agonist within the skin application site, concentration of the cannabinoid agonist in the reservoir and the nature and characteritics of the aversive agent in the resoirvoir and the interaction between the cannabinoid agonist and the aversive agent. The concentration of the cannabinoid agonist within the skin application sites are also significant in establishing an upper limit on the size of the transdermal dosage from.

[00287] When therapeutic effects are desired, the depleted transdermal dosage form would be removed and a fresh dosage form applied, generally to a new location. For example, the transdermal dosage form would be sequentially removed and replaced with a fresh dosage form at the end of the administration period to provide the required therapeutic effect. Since absorption of the cannabinoid agonist from the fresh transdermal dosage form into the new application area usually occurs at substantially the same rate as absorption by the body of the residual cannabinoid agonist within the previous application site of the transdermal dosage form, blood levels will remain substantially constant. Additionally, it is contemplated that doses may be increased over time and that concurrent use of other drugs for the treatment of the same malady or for a different malady may occur.

[00288] As discussed earlier, the transdermal dosage form of the invention provides release of the aversive agent at a rate sufficient to provide an abuse nullifying release when the dosage form is subject to abuse, misuse or tampering, e.g., upon ingestion or substantial immersion of the dosage form in the solvent. In this regard, the transdermal dosage form of the invention provides release of the aversive agent at a rate sufficient to block the effects of 007/018585

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the cannabinoid agonist, or as applicable, any co-abused opioid agonist, when the dosage form or its contents are ingested or otherwise administerd after tampering. As discussed earlier, and illustrated in the examples herein, the aversive agent release rate is controlled by varying the aversive agent concentration within the reservoir, the aversive agent salt particle size, the selection of the appropriate release controlling means, and the processing condition involved in the formation of the transdermal dosage form. As used herein, "a release rate ratio" refers to the ratio of a release rate of the aversive agent to the cannabinoid agonist over a given period of time measured using suitable standard techniques.

Transdermal Dosage Forms

[00289] Active-ingredient-containing transdermal drug delivery systems

("patches") are essentially divided into two major technical systems: reservoir systems and matrix systems. Both types of devices employ a backing layer that forms the protective outer surface of the finished transdermal system and which is exposed to the environment during use. A release liner or protective layer that forms the inner surface covers the polymeric adhesive which is employed for affixing the system to the skin or mucosa of a user. The release liner or protective layer is removed prior to application, exposing the adhesive, typically a pressure-sensitive adhesive.

[00290] In the "classic" reservoir-type device, the active agent is typically dissolved or dispersed in a carrier to yield a non-finite carrier form, such as, for example, a fluid or gel. In the reservoir-type device, the active agent is generally kept separate from the adhesive. The device has a pocket or "reservoir" which physically serves to hold the active agent and carrier, and which is formed in or by a backing layer. A peripheral adhesive layer is then used to affix the device to the user.

[00291] In a matrix-type device, the active agent is dissolved, dispersed or embedded in a semi-solid matrix made up of a single polymer or a blend of polymers (a carrier that typically is in a finite carrier form). The carrier form can be self-adhesive or non-adhesive. Non-adhesive matrix-type devices, that is, those which still rely on a separate adhesive means to affix the device to the user, employ a drug permeable adhesive layer (often referred to as an "in-line adhesive" since the drug must pass through this layer) applied over the drug matrix carrier layer. To better control the release rate of the releasable drug, the non-adhesive matrix-type devices often employ one or more additional drug permeable layers such as, for example, rate controlling membranes. The non-adhesive matrix-type devices often contain excipients, such as drug delivery enhancers, to help control the release rate. These devices are often referred to as multilayer or multilaminate.

[00292] In a "monolithic" or "monolayer" matrix-type device, the active agent is typically solubilized or homogenously blended (or in some embodiments, with the aversive agent sequestered through the use of a coating or other means to reduce its release) in an adhesive carrier composition, typically a pressure-sensitive adhesive or bioadhesive, which functions as both the drug carrier and the means of affixing the system to the skin or mucosa. Such devices, commonly referred to as drug-in-adhesive devices, are described in the prior art.

[00293] Suitable flexible, finite delivery systems include those in which the drug is solubilized or contained directly in an adhesive matrix, typically a preferably a pressure-sensitive adhesive, that also serves as the means for attachment to the skin or mucosa of a patient. In addition to this adhesive drug layer, a drug-in-adhesive or matrix transdermal system further comprises a drug impermeable backing layer or film on one side of the adhesive layer, and a release liner on the other side. The backing layer protects the adhesive layer of the transdermal patch from the environment and prevents loss of the drug and/or release of other adhesive layer components to the environment. The release liner is removed from the transdermal patch to expose the adhesive layer prior to topical application.

[00294] Simple monolithic transdermal systems incorporate their active agents, i.e., drugs, directly into a single pressure sensitive adhesive layer (or in some embodiments, with the aversive agent sequestered through the use of a coating or other means to reduce its release). These systems have the advantage of being thin, elegant, and relatively easy to manufacture, but must compromise between optimizing the adhesive matrix for drug delivery versus its ability to adhere to the skin. In some embodiments of the invention, application to the skin comprises a pharmaceutically acceptable carrier having uniformly dispersed within an amount of a releasable or substantially releasable cannabinoid agonist and a substantially non-releasable or non-releasable aversive agent, pharmaceutically acceptable salts or mixtures thereof. The composition may be applied directly onto the skin from a container for the same, such as a bottle or tube, and subsequently covered, if desired, with a protective overlay. It is preferable, however, to quantify the dose and the area of application by placing the composition in an impermeable container of the correct size to provide a unit dose which may be held on the skin by adhesive means or other appropriate fastening means. In operation this composition would administer the releasable or substantially releasable cannabinoid agonist and a substantially non-releasable or non-releasable aversive agent through the skin to produce the intended therapeutic effect. In addition to the releasable or substantially releasable cannabinoid agonist and a substantially non-releasable or non-releasable aversive agent, the dosage form may also contain a permeation enhancer for the cannabinoid agonist, thickeners and other additives, all as known to the art. ] In another embodiment, application of releasable or substantially releasable cannabinoid agonist and a substantially non-releasable or non- releasable aversive agent to the skin according to this invention involves a reservoir composition. The dosage form comprises a drug reservoir composition typically in the form of a gel or polymeric carrier having uniformly dispersed within releasable or substantially releasable cannabinoid agonist and a substantially non-releasable or non-releasable aversive agent or in some embodiments, having the aversive agent sequestered through the use of a coating or other means to reduce its release. The composition is preferably disposed between an impermeable backing, a cannabinoid agonist releasing US2007/018585

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means such as release rate controlling membrane and a cannabinoid agonist permeable adhesive, which are all known in the art. A cannabinoid agonist impermeable release liner is applied to the adhesive layer and is removed prior to application. Suitable materials for use in manufacturing the various layers are well known in the art. In one embodiment of the invention, the cannabinoid agonist is present in the reservoir composition in a form which is permeable through the rate controlling membrane and the aversive agent is present in the reservoir composition in a form which is impermeable through the rate controlling membrane. In practice, the dosage form of the invention would administer the cannabinoid agonist through the skin at the rate intended for therapeutic effect

[00296] In some embodiments, the present invention provides a dosage form for transdermal delivery of cannabinoid agonist to a subject through intact, damaged or injured skin over an extended period of time. In particular, the dosage form of the present invention provides for the controlled release of the cannabinoid agonist.

Single Reservoir Based Transdermal Dosage Forms

[00297J In certain embodiments, a transdermal application to the skin according to this invention comprises a pharmaceutically acceptable carrier having uniformly dispersed within an amount of a cannabinoid agonist in a skin permeable form and an abuse nullifying amount of an aversive agent in a skin impermeable form. The composition may be applied directly onto the skin from a container for the same, such as a bottle or tube, and subsequently covered, if desired, with a protective overlay. It is preferable, however, to quantify the dose and the area of application by placing the composition in an impermeable container of the correct size to provide a unit dose which may be held on the skin by adhesive means or other appropriate fastening means. In operation this composition would administer the cannabinoid agonist through the skin to produce the intended therapeutic effect, and the aversive agent would not significantly affect or diminish the therapeutic effect of the cannabinoid agonist, or as applicable, any co-abused opioid agonist. However, if attempts were made to tamper with and abuse the composition (e.g., by administration orally or intravenously, or by solvent extraction followed by oral or non-oral administration), the aversive agent would antagonize some or substantial portion of the cannabinoid agonist, or as applicable, any co-abused opioid agonist, thereby deterring abuse. In addition to the cannabinoid agonist and the aversive agent, the dosage form may also contain a permeation enhancer for the cannabinoid agonist (which should not significantly enhance the permeability of the aversive agent), thickeners and other additives, all as known to the art. The dosage form of the invention can be in the form of an ointment, patch, cream, gel, paste, solution or lotion, for example. ] In another embodiment, cannabinoid agonist and the aversive agent to the skin according to this invention involves a reservoir composition which has a reduced potential for abuse. The dosage form comprises a drug reservoir composition typically in the form of a gel or polymeric carrier having uniformly dispersed within a cannabinoid agonist and an abuse nullifying amount of an aversive agent. The composition is preferably disposed between an impermeable backing, a cannabinoid agonist releasing means such as release rate controlling membrane and a cannabinoid agonist permeable adhesive, which are all known in the art. A cannabinoid agonist and aversive agent impermeable release liner is applied to the adhesive layer and is removed prior to application. Suitable materials for use in manufacturing the various layers are well known in the art. In this embodiment of the invention, the cannabinoid agonist is present in the reservoir composition in a form which is permeable through the rate controlling membrane. The aversive agent is present in a form which is substantially not permeable through either the rate controlling membrane, the adhesive or the skin. In practice, the dosage form of the invention would administer the cannabinoid agonist through the skin at the rate intended for therapeutic effect, and the aversive agent would not significantly affect or diminish the therapeutic effect of the cannabinoid agonist, or as applicable, any co-abused opioid agonist. However, if attempts were made to tamper with and abuse the composition (e.g., by administration orally or intravenously, or by solvent extraction, or by combustion followed by oral or non-oral administration), the aversive agent would antagonize some or substantial portion of any cannabinoid agonist, or as applicable, any co- abused opioid agonist, thereby deterring abuse.

[00299] In some embodiments, the present invention provides a dosage form for topical or transdermal delivery of cannabinoid agonists to a subject through intact, damaged or injured skin over an extended period of time, the dosage form having reduced potential for abuse and toxicity. In particular, the dosage form of the present invention provides for the controlled release of the aversive agent at a rate sufficient to provide an abuse nullifying release when the dosage form is subject to misuse, abuse or tampering. In this regard, the dosage form of the invention provides release of the aversive agent at a rate sufficient to block the effects of any cannabinoid agonist, or as applicable, any co-abused opioid agonist in the setting of abuse, misuse and tampering.

[00300] In transdermal dosage forms of the invention, the release controlling means for the cannabinoid agonist and aversive agent may be a monolithic or a multilaminate layer comprising a material that substantially prevents release during incidental exposure to moisture. In particular, the release controlling means comprises a breathable or occlusive material comprising fabric, porous, microporous, spun-bonded, spun laced, track etched, or impermeable material comprising polyvinyl acetate, polyvinylidene chloride, polyethylene, polypropylene, polyurethane, polyester, ethylene vinyl acetate (EVA), polyethylene terephthalate, polybutylene terephthalate, rayon (synthetic textile fibers produced by forcing a cellulose solution through fine spinnerets and solidifying the resulting filaments), wood-pulp, spun laced polyester, coated paper products, aluminum sheet, and the like, and a combination thereof. In preferred embodiments, release controlling means comprises low density polyethylene (LDPE) materials, medium density polyethylene (MDPE) materials or high density polyethylene (HDPE) materials, and the like. In preferred embodiments, the release controlling means is a single LDPE layer. In additional preferred embodiments, the release controlling means comprises a microporous layer selected from the group consisting of Solupor microporous ultra high density polyethylene (UHDPE) materials/film (Solupor™ manufactured by DSM Desotech, Denmark), microporous polypropylene (Celgard™), RoTrac Polyester Capillary Pore Membranes (OYPHEN GmbH, Germany), spun laced polyester, polypropylene or polyethylene. The microporous layer can be further modified with surfactants such as Pluracare polyethylene oxide-polypropylene oxide block copolymers (BASF, Wyandotte, Mich.) or hydrophilic polymers such as polyvinylpyrrolidone to provide additional control over the release as discussed in greater detail below.

[00301] The release controlling means has a thickness of about 0.012 mm (0.5 mil) to about 0.125 mm (5 mil); preferably 0.025 mm (1 mil) to about 0.1 mm (4 mil); more preferably 0.0375 mm (1.5 mil) to about 0.0875 mm (3.5 mil); and even more preferably 0.05 mm (2 mil) to about 0.0625 mm (2.5 mil).

[00302] The transdermal dosage form according to this invention comprises cannabinoid agonist/aversive agent reservoir. The reservoir may be formed from standard materials as known in the art. For example, the reservoir is formed from a hydrophobic, a lipophilic and/or a non-polar polymeric material, such as, ethyleneoctene copolymers, ethylene-vinyl acetate copolymer (EVA), low density polyethylene (LDPE), high density polyethylene (HDPE), medium density polyethylene (MDPE), styrenic block copolymer thermoplastic elastomers, and the like. In preferred embodiments, the aversive agent reservoir is formed from EVA, ethyleneoctene copolymers, as described in greater detail below.

[00303] As discussed above, the reservoir comprises a substantially releasable cannabinoid agonist and an aversive agent in a substantially non-releasable form when the transdermal dosage form is used as recommended and/or during incidental exposure to water (e.g., sweat, showering, high humidity etc.), the aversive agent being releasable from the transdermal dosage form when dosage form is abused, i.e. upon being ingested or substantially immersed in a solvent. Preferably, the aversive agent is present in a form that is substantially impermeable to the skin to which the transdermal dosage form of the invention is to be applied. The reservoir comprises the cannabinoid agonist and aversive agent dispersed within a polymer, preferably wherein the aversive agent is substantially insoluble in the reservoir polymer. The low solubility of the aversive agent in skin and polymer has several advantages, substantially minimizing undesirable interactions between the aversive agent and the cannabinoid agonist and improved stability/shelf life of the transdermal dosage form.

[00304] In certain clinical situations, the co-administration of opioid agonists with cannabinoid agonists may be contraindicated, or the prescribing physician may specifically ask the patient or prohibit the concurrent use of an opioid agonist with a cannbinoid agonist (e.g., in patients at risk of drug abuse or drug diversion, or having a contraindication to such concurrent use). In certain embodiments, therefore, the invention contemplates use of cannbinoid agonist with an opioid agonist by the patient against the specific instructions of the prescribing physician. In such embodiments, one novel invention comprises an 1 an opioid antagonist as the aversive agent, said antagonist at least partially releasable when applied intact (i.e., as directed by the manufacturer or without tampering), said aversive agent release sufficient to at least partially block the effects of any co-abused or co-administered opioid agonists, and said aversive agent release insufficient to completely or substantially block the effects of the cannabinoid agonist of the dosage form.

[00305] In certain embodiments, the aversive agent is dispersed in a matrix comprising a polymeric material which substantially prevents release of the aversive agent, preferably a thermoformable material; or the aversive agent is complexed with an ionic resin. In additional embodiments, the aversive agent reservoir comprises the aversive agent in a multiparticulate form, wherein each particle is individually coated with a polymeric material which substantially prevents release of the aversive agent, wherein the polymeric material is preferably a thermoformable material. In additional embodiments, the aversive agent comprises beads coated with the aversive agent, wherein the beads may be formed from glass or an inert or non-dissolvable polymer, and further wherein the coated beads are optionally coated with or dispersed in a polymeric material which substantially prevents release of the aversive agent, wherein the polymeric material is preferably a thermoformable material. Preferably, the aversive agent is present as a salt.

[00306] As discussed above, the reservoir comprises the cannabinoid agonist and aversive agent dispersed within a polymer. Preferably, the aversive agent is dispersed in a matrix comprising a thermoformable material that substantially prevents release of the aversive agent. Alternatively, the aversive agent is present in a multiparticulate form, wherein each particle is individually coated with a polymeric material that substantially prevents release of the aversive agent. Preferably, the polymeric material which substantially prevents release of the aversive agent is hydrophobic, i.e., substantially prevents release of the aversive agent during normal use, minimizes the amount of aversive agent during incidental/casual exposure to solvents (moisture, e.g., sweat, during a shower), and when the dosage form is subject to abuse, e.g., upon ingestion or immersion in a solvent, releases the aversive agent in abuse nullifying amounts. Examples of a polymeric material which substantially prevents release of the aversive agent include, but are not limited to, polyethylene, polyoctene, polyvinyl acetate, polymethyl acrylate, polymethyl acrylate, polyethyl acrylate, polystyrene polymers and copolymers and mixtures thereof; polystyrene copolymers such as styrenic block copolymers (SIS, SBS, SEBS), ethylene copolymers such as polyethyleneoctene copolymers, ethylene-vinyl acetate copolymer (EVA), ethylenemethyl acrylate copolymers (EMA), ethylene-acrylic acid copolymer, ethylene-ethylacrylate copolymer, and the like, and combinations thereof.

[00307] In additional embodiments, the aversive agent is complexed with an ionic resin. Examples of ionic resins include, but are not limited to sulfonated polystyrene resins, and the like. [00308] In additional embodiments, the aversive agent reservoir comprises beads coated with the aversive agent, wherein the spheres or beads may be formed from glass, metals or an inert or non-dissolvable polymer, and further wherein the coated beads are optionally coated with or dispersed in a polymeric material which substantially prevents release of the aversive agent, as described above. The beads may be in any shape, size or form, but are preferably small sized, preferably less than 10 microns. Examples of an inert or non-dissolvable polymer include, but are not limited to polymethylmethacrylate, polycarbonate and polystyrene.

[00309] The aversive agent in the reservoir comprises an amount of the aversive agent sufficient to counter the euphoric, pleasurable, reinforcing, rewarding or toxic effects of any cannabinoid agonist or as applicable, co- absued opioid agonist, when the transdermal dosage form is misused, abused or otherwise tampered.

[00310] Preferably, the aversive agent is substantially insoluble in the polymer forming the reservoir.

[00311] In preferred embodiments, the reservoir is formed from a pharmaceutically acceptable pressure sensitive adhesive, preferably a polyacrylate or a styrenic block copolymer-based adhesive.

[00312] The adhesive reservoir or the adhesive coating is formed from standard pressure sensitive adhesives known in the art. Examples of pressure sensitive adhesives include, but are not limited to, polyacrylates, polysiloxanes, polyisobutylene (PIB), polyisoprene, polybutadiene, styrenic block polymers, and the like. Examples of styrenic block copolymer-based adhesives include, but are not limited to, styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene copolymer (SBS), styrene-ethylenebutene-styrene copolymers (SEBS), and di-block analogs thereof.

[00313] The acrylic polymers are comprised of a copolymer or terpolymer comprising at least two or more exemplary components selected from the group comprising acrylic acids, alkyl acrylates, methacrylates, copolymerizable secondary monomers or monomers with functional groups. Examples of monomers include, but are not limited to, acrylic acid, methacrylic acid, methoxyethyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, 2- ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl methacrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, tert-butylaminoethyl acrylate, tert- butylaminoethyl methacrylate, methoxyethyl acrylate, methoxyethyl methacrylate, and the like. Additional examples of appropriate acrylic adhesives suitable in the practice of the invention are described in Satas, "Acrylic Adhesives," Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed., pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989). The acrylic adhesives are commercially available (National Starch and Chemical Corporation, Bridgewater, N.J.; Solutia, Mass.). Further examples of polyacrylate-based adhesives are as follows, identified as product numbers, manufactured by National Starch (Product Bulletin, 2000): 87-4098, 87- 2287,87-4287, 87-5216, 87-2051, 87-2052, 87-2054, 87-2196, 87-9259,87- 9261, 87-2979, 87-2510, 87-2353, 87-2100, 87-2852, 87-2074, 87-2258, 87- 9085, 87-9301 and 87-5298. ] The acrylic polymers comprise cross-linked and non-cross-linked polymers. The polymers are cross-linked by known methods to provide the desired polymers. In preferred embodiments, the adhesive is a polyacrylate adhesive having a glass transition temperature (Tg) less than -10⁰C, more preferably having a Tg of about -20⁰C, to about -35°C. The molecular weight of the polyacrylate adhesive, expressed as weight average (MW), generally ranges from 25,000 to 10,000,000, preferably from 50,000 to about 3,000,000 and more preferably from 100,000 to 1,000,000 prior to any cross-linking reactions. Upon cross-linking the MW approaches infinity, as known to those involved in the art of polymer chemistry. [00315] In additional embodiments, the cannabinoid agonist reservoir may optionally contain additional components such as, additives, permeation enhancers, stabilizers, dyes, diluents, plasticizer, tackifying agent, pigments, carriers, inert fillers, antioxidants, excipients, gelling agents, anti-irritants, vasoconstrictors and other materials as are generally known to the transdermal art, provided that such materials are present below saturation concentration in the reservoir.

[00316] Examples of permeation enhancers include, but are not limited to, fatty acid esters of glycerin, such as capric, caprylic, dodecyl, oleic acids; fatty acid esters of isosorbide, sucrose, polyethylene glycol; caproyl lactylic acid; laureth-2; laureth-2 acetate; laureth-2 benzoate; laureth-3 carboxylic acid; laureth-4; laureth-5 carboxylic acid; oleth-2; glyceryl pyroglutamate oleate; glyceryl oleate; N-lauroyl sarcosine; N-myrϊstoyl sarcosine; N-octyl-2- pyrrolidone; lauraminopropionic acid; polypropylene glycol-4-laureth-2; polypropylene glycol-4-laureth-5dimethy- 1 lauramide; lauramide diethanolamine (DEA). Preferred enhancers include, but are not limited to, lauryl pyroglutamate (LP), glyceryl monolaurate (GML), glyceryl monocaprylate, glyceryl monocaprate, glyceryl monooleate (GMO), and sorbitan monolaurate. Additional examples of suitable permeation enhancers are described in the prior art.

[00317] In certain embodiments, the reservoir comprises diluent materials capable of reducing quick tack, increasing viscosity, and/or toughening the matrix structure, such as polymethyl methacrylate or polybutyl methacrylate (ELVACITE™, manufactured by ICI Acrylics, e.g., ELVACITE™ 1010, ELVACITE™ 1020, ELVACITE™ 20), high molecular weight acrylates, i.e., acrylates having an average molecular weight of at least 500,000, and the like.

[00318] In certain embodiments, particularly with styrenic block copolymer adhesive systems, a plasticizer or tackifying agent is incorporated in the adhesive composition to improve the adhesive characteristics. Examples of suitable tackifying agents include, but are not limited to, aliphatic hydrocarbons; aromatic hydrocarbons; hydrogenated esters; polyterpenes; hydrogenated wood resins; tackifying resins such as ESCOREZ™, aliphatic hydrocarbon resins made from cationic polymerization of petrochemical feedstocks or the thermal polymerization and subsequent hydrogenation of petrochemical feedstocks, rosin ester tackifiers, and the like; mineral oil and combinations thereof.

[00319] The tackifying agent employed should be compatible with the blend of polymers. For example, the styrenic block copolymers can be formulated with rubber compatible tackifying resins, end-block compatible resins such polymethyl styrene, or plasticizers such as mineral oil.

[00320] The transdermal dosage form further comprises a peelable protective layer. The protective layer is made of a polymeric material that may be optionally metallized. Examples of the polymeric materials include, polypropylene, polystyrene, polyimide, polyethylene, polyethylene terephthalate, polybutylene terephthalate, paper, and the like, and a combination thereof. Li preferred embodiments, the protective layer comprises a siliconized polyester sheet.

[00321] A preferred embodiment of the transdermal dosage form according to this invention comprises a patch, an impermeable barrier layer disposed distally, a reservoir containing a cannabinoid agonist and an aversive agent, a rate controlling means, and an amine resistant contact adhesive layer, covered by a peelable protective layer.

[00322] Although preferred embodiments of this invention utilize an amine resistant in-line adhesive, other means for maintaining the dosage form on the skin can be employed. Such means include a peripheral ring of adhesive outside the path of cannabinoid agonist from the dosage form to the skin, in which case the adhesive need not be amine resistant. The use of adhesive overlays or other fastening means such as buckles, belts, and elastic arm bands is also contemplated.

[00323] A wide variety of materials which can be used for fabricating the various layers of the transdermal dosage form according to this invention have been described above. This invention therefore contemplates the use of materials other than those specifically disclosed herein, including those which may hereafter become known to the art to be capable of performing the necessary functions.

Dual Reservoir Based Transdermal Dosage Forms

[00324] The present invention provides a dosage form for transdermal delivery of substantially releasable or releasable cannabinoid agonists and non- releasable or substantially non-releasable aversive agents to a subject, the dosage form having reduced potential for abuse, misuse, tampering, diversion and toxicity. When the dosage form is tampered, the aversive agent become substantially releasable or releasable, thereby reducing or nullifying the mood altering effects of the cannabinoid agonist and, as applicable, the co-abused opioid agonist and therefore deterring abuse, misuse, tampering, diversion and toxicity.

[00325] The aversive agent release controlling means dosage form substantially prevents release of the aversive agent from the dosage form upon securing the dosage form to a human patient for a period of up to about 4, 6, 12, or 18 hours, or 1, 2, 3, 7, 14, 21 or 30 days; and provides release of the aversive agent when the dosage form is subject to misuse, tampering or abuse, e.g., upon ingestion or substantial immersion of the dosage form in a solvent. The aversive agent release controlling means modulates the ingress of water/solvent into the aversive agent reservoir, thus modulating the release of the aversive agent during abuse, while permitting the release of an aversive agent at a rate sufficient to limit abuse. The aversive agent release controlling means include physical means such as a membrane, a film, a coating, a sheet, a deposit, including but not limited to, a rate control membrane, a porous or a microporous membrane, an impermeable film wherein the release is controlled through the edge of the patch. The aversive agent release controlling means also include chemical means and may be osmotically driven, concentration dependent, or may depend on the size and characteristics of the materials forming the aversive agent release controlling means. In certain embodiments, the aversive agent rate controlling means is incorporated within the aversive agent reservoir where the rate of release is governed by the osmotic bursting mechanism. The release rate of the aversive agent is controlled by factors such as the amount of aversive agent within the aversive agent reservoir, the aversive agent particle size, aversive agent salt osmotic pressure, and physical characteristics of the polymer matrix of the aversive agent reservoir. ] In preferred embodiments, the aversive agent release controlling means may be a monolithic or a multilaminate layer comprising a material that substantially prevents release of the aversive agent from the aversive agent reservoir during incidental exposure to moisture. In particular, the aversive agent release controlling means comprises a breathable or occlusive material comprising fabric, porous, microporous, spun-bonded, spun laced, track etched, or impermeable material comprising polyvinyl acetate, polyvinylidene chloride, polyethylene, polypropylene, polyurethane, polyester, ethylene vinyl acetate (EVA), polyethylene terephthalate, polybutylene terephthalate, rayon (synthetic textile fibers produced by forcing a cellulose solution through fine spinnerets and solidifying the resulting filaments), wood-pulp, spun laced polyester, coated paper products, aluminum sheet, and the like, and a combination thereof. In preferred embodiments, aversive agent release controlling means comprises low density polyethylene (LDPE) materials, medium density polyethylene (MDPE) materials or high density polyethylene (HDPE) materials, and the like. In preferred embodiments, the release controlling means is a single LDPE layer. In additional preferred embodiments, the aversive agent release controlling means comprises a microporous layer selected from the group consisting of Solupor microporous ultra high density polyethylene (UHDPE) materials/film (Solupor™ manufactured by DSM Desotech, Denmark), microporous polypropylene (Celgard™), RoTrac Polyester Capillary Pore Membranes (OYPHEN GmbH, Germany), spun laced polyester, polypropylene or polyethylene. The microporous layer can be further modified with surfactants such as Pluracare polyethylene oxide-polypropylene oxide block copolymers (BASF, Wyandotte, Mich.) or hydrophilic polymers such as polyvinylpyrrolidone to provide additional control over the aversive agent release as discussed in greater detail below.

[00327] The aversive agent release controlling means has a thickness of about

0.012 mm (0.5 mil) to about 0.125 mm (5 mil); preferably 0.025 mm (1 mil) to about 0.1 mm (4 mil); more preferably 0.0375 mm (1.5 mil) to about 0.0875 mm (3.5 mil); and even more preferably 0.05 mm (2 mil) to about 0.0625 mm (2.5 mil).

[00328] The transdermal dosage form according to this invention comprises a aversive agent reservoir, wherein the skin distal surface of the aversive agent reservoir is disposed on the aversive agent release controlling means. The aversive agent reservoir may be same size as the other layers of the patch or the aversive agent may be inset from the edge of the die cut patch. The aversive agent reservoir may be formed from standard materials as known in the art. For example, the aversive agent reservoir is formed from a hydrophobic, a lipophilic and/or a non-polar polymeric material, such as, ethyleneoctene copolymers, ethylene-vinyl acetate copolymer (EVA), low density polyethylene (LDPE), high density polyethylene (HDPE), medium density polyethylene (MDPE), styrenic block copolymer thermoplastic elastomers, and the like. In preferred embodiments, the aversive agent reservoir is formed from EVA, ethyleneoctene copolymers, as described in greater detail below.

[00329] As discussed above, the aversive agent reservoir comprises an aversive agent in a substantially non-releasable form when the transdermal dosage form is used as recommended and/or during incidental exposure to water (e.g., sweat, showering, high humidity etc.), the aversive agent being releasable from the transdermal dosage form when dosage form is abused, i.e. upon being ingested or substantially immersed in a solvent. Preferably, the aversive agent is present in a form that is substantially impermeable to the skin to which the transdermal dosage form of the invention is to be applied. The aversive agent reservoir comprises an aversive agent dispersed within a polymer, wherein the aversive agent is substantially insoluble in the aversive agent reservoir polymer. The low solubility of the aversive agent in skin and polymer has several advantages, substantially minimizing undesirable interactions between the aversive agent and the cannabinoid agonist, improved stability/shelf life of the transdermal dosage form, and substantially minimizing skin sensitization response from aversive agent exposure.

[00330] In certain embodiments, the aversive agent is dispersed in a matrix comprising a polymeric material which substantially prevents release of the aversive agent, preferably a thermoformable material; or the aversive agent is complexed with an ionic resin. In additional embodiments, the aversive agent reservoir comprises the aversive agent in a multiparticulate form, wherein each particle is individually coated with a polymeric material which substantially prevents release of the aversive agent, wherein the polymeric material is preferably a thermoformable material. In additional embodiments, the aversive agent reservoir comprises beads coated with the aversive agent, wherein the beads may be formed from glass or an inert or non-dissolvable polymer, and further wherein the coated beads are optionally coated with or dispersed in a polymeric material which substantially prevents release of the aversive agent, wherein the polymeric material is preferably a thermoformable material. Preferably, the a cannabinoid ntcannabinoid agonist is present as a salt.

[00331] As discussed above, the aversive agent reservoir comprises the aversive agent dispersed within a polymer. Preferably, the aversive agent is dispersed in a matrix comprising a thermoformable material that substantially prevents release of the aversive agent. Alternatively, the aversive agent is present in a multiparticulate form, wherein each particle is individually coated with a polymeric material that substantially prevents release of the aversive agent. Preferably, the polymeric material which substantially prevents release of the aversive agent is hydrophobic, i.e., substantially prevents release of the aversive agent during normal use, minimizes the amount of aversive agent during incidental/casual exposure to solvents (moisture, e.g., sweat, during a shower), and when the dosage form is subject to abuse, e.g., upon ingestion or immersion in a solvent, releases the aversive agent in abuse limiting amounts. Preferably, the polymeric material has a low melting point to allow processing of the aversive agent in solid phase and to prevent degradation of the aversive agent. Examples of a polymeric material which substantially prevents release of the aversive agent include, but are not limited to, polyethylene, polyoctene, polyvinyl acetate, polymethyl acrylate, polymethyl acrylate, polyethyl acrylate, polystyrene polymers and copolymers and mixtures thereof; polystyrene copolymers such as styrenic block copolymers (SIS, SBS, SEBS), ethylene copolymers such as polyethyleneoctene copolymers, ethylene-vinyl acetate copolymer (EVA), ethylenemethyl acrylate copolymers (EMA), ethylene-acrylic acid copolymer, ethylene-ethylacrylate copolymer, and the like, and combinations thereof.

[00332] In additional embodiments, the aversive agent is complexed with an ionic resin. Examples of ionic resins include, but are not limited to sulfonated polystyrene resins, and the like.

[00333] In additional embodiments, the aversive agent reservoir comprises beads coated with the aversive agent, wherein the spheres or beads may be formed from glass, metals or an inert or non-dissolvable polymer, and further wherein the coated beads are optionally coated with or dispersed in a polymeric material which substantially prevents release of the aversive agent, as described above. The beads may be in any shape, size or form, but are preferably small sized, preferably less than 10 microns. Examples of an inert or non-dissolvable polymer include, but are not limited to polymethylmethacrylate, polycarbonate and polystyrene.

[00334] The aversive agent reservoir comprises an amount of the aversive agent sufficient to counter the euphoric, pleasurable, reinforcing, rewarding or toxic effects of the cannabinoid agonist and as applicable, the co-abused opioid agonist, when the transdermal dosage form is misused, abused or otherwise tampered. Preferably, the aversive agent reservoir comprises about 2 to about 80 wt % of the aversive agent; more preferably about 5 to about 70 wt % of the aversive agent; even more preferably about 10 to about 60 wt % of the aversive agent.

[00335] Preferably, the aversive agent is substantially insoluble in the polymer forming the aversive agent reservoir. In particular, the material forming the aversive agent reservoir has a solubility for the aversive agent of about 0 wt % to about 30 wt % or about 0 wt % to about 20 wt %of the total polymer composition; more preferably about 0 wt % to about 15 wt % or about 0 wt % to about 10 wt %; and even more preferably about 0 wt % to about 5 wt % or about 0 wt % to about 3 wt %; and most preferably about 0 wt % to about 2 wt % or about 0 wt % to about 1 wt % of the total polymer composition. The aversive agent reservoir, has a thickness of about 0.0125 mm (0.5 mil) to about 0.1 mm (4 mil); preferably about 0.015 mm (0.6 mil) to about 0.0875 mm (3.5 mil); more preferably 0.025 mm (1 mil) to about 0.08 mm (3.3 mil); and even more preferably about 0.025 mm (1 mil) to about 0.075 (3 mil).

[00336] The transdermal dosage form according to this invention comprises an impermeable barrier layer wherein the aversive agent reservoir is disposed on the skin distal surface of the barrier layer, and a cannabinoid agonist reservoir is disposed on the skin proximal surface of the barrier layer. The barrier layer is impermeable to the aversive agent and the cannabinoid agonist; and comprises a material which is insoluble in water, alcohol and organic solvents. The barrier layer comprises a polymer such as polyolefin laminates (Dow Chemical, Midland, Mich.), acrylonitrile copolymer films (BAREX, BP Chemicals, KoIn, Germany), polyethylnapthalene (PEN), polyethylene terephthalate (PET), polyimide, polyurethane, polyethylene, metallized films and glass coated films where these films can include ethylene copolymers such as ethylene-vinyl acetate copolymer (EVA), and combinations thereof, hi preferred embodiments, the barrier layer comprises polyester such as PET laminated to a polymer such as polyurethane, polyethylene, and ethylene copolymers. In preferred embodiments, the barrier layer comprises polyester such as PET laminated to ethylene copolymers such as ethylene-vinyl acetate copolymer (EVA). The barrier layer as a multilaminate layer has a thickness of about 0.075 mm (0.3 mil) to about 0.125 mm (5 mil); preferably 0.025 mm (1 mil) to about 0.1 mm (4 mil); more preferably 0.0625 mm (1.5 mil) to about 0.0875 mm (3.5 mil); and even more preferably 0.025 mm (1 mil) to about 0.05 mm (2 mil). The polyethylene or EVA laminated layer of the preferred PET-PE laminates improves the adhesion of the aversive agent reservoir to the backing, and serves to prevent the facile removal of the aversive agent reservoir from the dosage form by the user in the setting of misuse, abuse or tampering.

[00337] The cannabinoid agonist reservoir is disposed on the skin proximal surface of the barrier layer, wherein at least the skin contacting surface of the cannabinoid agonist reservoir is adhesive. The cannabinoid agonist reservoir may be formed from standard materials as known in the art. For example, the cannabinoid agonist reservoir is formed from hydrophobic and/or lipophilic polymeric material, such as, hydrophobic polyurethane, ethylene- vinyl acetate copolymer (EVA) and the like. In preferred embodiments, the cannabinoid agonist reservoir is formed from a pharmaceutically acceptable pressure sensitive adhesive, preferably a polyacrylate or a styrenic block copolymer- based adhesive, as described in greater detail below. In preferred embodiments, the pressure sensitive adhesive has zero shear viscosity greater than 1-10⁹ poise at 25°C, as determined by the principle of time-temperature superpositioning of dynamic viscosity curves at various temperatures. This requirement serves to prevent adhesive cold flow, and the corresponding increased likelihood for cannabinoid agonist-aversive agent exchange at the edge of the dosage form.

[00338] The adhesive cannabinoid agonist reservoir or the adhesive coating is formed from standard pressure sensitive adhesives known in the art. Examples of pressure sensitive adhesives include, but are not limited to, polyacrylates, polysiloxanes, polyisobutylene (PIB), polyisoprene, polybutadiene, styrenic block polymers, and the like. Examples of styrenic block copolymer-based adhesives include, but are not limited to, styrene-isoprene-styrene block copolymer (SIS), styrene-butadϊene-styrene copolymer (SBS), styrene- ethylenebutene-styrene copolymers (SEBS), and di-block analogs thereof.

[00339J The acrylic polymers are comprised of a copolymer or terpolymer comprising at least two or more exemplary components selected from the group comprising acrylic acids, alkyl acrylates, methacrylates, copolymerizable secondary monomers or monomers with functional groups. Examples of monomers include, but are not limited to, acrylic acid, methacrylic acid, methoxyethyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, 2- ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl methacrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, tert-butylaminoethyl acrylate, tert- butylaminoethyl methacrylate, methoxyethyl acrylate, methoxyethyl methacrylate, and the like. Additional examples of appropriate acrylic adhesives suitable in the practice of the invention are described in Satas, "Acrylic Adhesives," Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed., pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989). The acrylic adhesives are commercially available (National Starch and Chemical Corporation, Bridgewater, NJ.; Solutia, Mass.). Further examples of polyacrylate-based adhesives are as follows, identified as product numbers, manufactured by National Starch (Product Bulletin, 2000): 87-4098, 87- 2287,87-4287, 87-5216, 87-2051, 87-2052, 87-2054, 87-2196, 87-9259,87- 9261, 87-2979, 87-2510, 87-2353, 87-2100, 87-2852, 87-2074, 87-2258, 87- 9085, 87-9301 and 87-5298.

[00340] The acrylic polymers comprise cross-linked and non-cross-linked polymers. The polymers are cross-linked by known methods to provide the desired polymers. In preferred embodiments, the adhesive is a polyacrylate adhesive having a glass transition temperature (Tg) less than -10⁰C, more preferably having a Tg of about -20°C, to about -35°C. The molecular weight of the polyacrylate adhesive, expressed as weight average (MW), generally ranges from 25,000 to 10,000,000, preferably from 50,000 to about 3,000,000 and more preferably from 100,000 to 1,000,000 prior to any cross-linking reactions. Upon cross-linking the MW approaches infinity, as known to those involved in the art of polymer chemistry.

[00341] The transdermal dosage form comprise cannabinoid agonist reservoirs comprising a component, including a cannabinoid agonist at concentration greater than, equal to, or less than the saturation concentration. As discussed above, in preferred embodiments the cannabinoid agonist reservoir comprises a single phase polymeric composition, free of undissolved components, containing an amount of the cannabinoid agonist sufficient to induce and maintain the required therapeutic effect of the cannabinoid agonist in a human for at least 4, 6, 8, 12, 16, 18 or 24 hours, or optionally, at least 2, 3, 7, 14, 21 or 30 days. The cannabinoid agonist should be soluble in the polymer forming reservoir in a form that is as discussed below. In preferred embodiments, the cannabinoid agonist is in the unsalified form.

[00342] The material forming the cannabinoid agonist has a solubility for the cannabinoid agonist of about 0.5 wt % to about 40 wt % of the total polymer composition, preferably of about 1 wt % to about 25 wt % of the total polymer composition; more preferably about 2 wt % to about 15 wt %; even, more preferably about 4 wt % to about 12 wt % of the total polymer composition. The reservoir with or without the adhesive coating has a thickness of about 0.0125 mm (0.5 mil) to about 0.1 mm (4 mil); preferably about 0.025 mm (1 mil) to about 0.0875 mm (3.5 mil); more preferably 0.0375 mm (1.5 mil) to about 0.075 (3 mil); and even more preferably about 0.04 mm (1.6 mil) to about 0.05 mm (2 mil). In some preferred embodiments, the cannabinoid agonist is preferably in unsalified form, wherein the material forming the reservoir has a solubility for the cannabinoid agonist of about 0.5 wt % to about 40 wt % of the total polymer composition, preferably of about 1 wt % to about 25 wt % of the total polymer composition; more preferably about 2 wt % to about 15 wt %; even more preferably about 4 wt % to about 12 wt % of the total polymer composition. The reservoir, with or without the adhesive coating, has a thickness of about 0.0125 mm (0.5 mil) to about 0.1 mm (4 mil); preferably about 0.025 mm (1 mil) to about 0.075 mm (3 mil); more preferably 0.0375 mm (1.5 mil) to about 0.0625 (2.5 mil); and even more preferably about 0.04 mm (1.6 mil) to about 0.05 mm (2 mil).

[00343] In additional embodiments, the cannabinoid agonist reservoir may optionally contain additional components such as, additives, permeation enhancers, stabilizers, dyes, diluents, plasticizer, tackifying agent, pigments, carriers, inert fillers, antioxidants, excipients, gelling agents, anti-irritants, vasoconstrictors and other materials as are generally known to the transdermal art, provided that such materials are present below saturation concentration in the reservoir.

[00344] Examples of permeation enhancers include, but are not limited to, fatty acid esters of glycerin, such as capric, caprylic, dodecyl, oleic acids; fatty acid esters of isosorbide, sucrose, polyethylene glycol; caproyl lactylic acid; laureth-2; laureth-2 acetate; laureth-2 benzoate; laureth-3 carboxylic acid; laureth-4; laureth-5 carboxylic acid; oleth-2; glyceryl pyroglutamate oleate; glyceryl oleate; N-lauroyl sarcosine; N-myristoyl sarcosine; N-octyl-2- pyrrolidone; lauraminopropionic acid; polypropylene glycol-4-laureth-2; polypropylene glycol-4-laureth-5dimethy- 1 lauramide; lauramide diethanolamine (DEA). Preferred enhancers include, but are not limited to, lauryl pyroglutamate (LP), glyceryl monolaurate (GML), glyceryl monocaprylate, glyceryl monocaprate, glyceryl monooleate (GMO), and sorbitan monolaurate. Additional examples of suitable permeation enhancers are described in the prior art.

[00345] In certain embodiments, the cannabinoid agonist reservoir comprises diluent materials capable of reducing quick tack, increasing viscosity, and/or toughening the matrix structure, such as polymethyl methacrylate or polybutyl methacrylate (ELVACITE™, manufactured by ICI Acrylics, e.g., ELVACITE™ 1010, ELVACITE™ 1020, ELVACITE™ 20), high molecular weight acrylates, i.e., acrylates having an average molecular weight of at least 500,000, and the like.

[00346] In certain embodiments, particularly with styrenic block copolymer adhesive systems, a plasticizer or tackifying agent is incorporated in the adhesive composition to improve the adhesive characteristics. Examples of suitable tackifying agents include, but are not limited to, aliphatic hydrocarbons; aromatic hydrocarbons; hydrogenated esters; polyterpenes; hydrogenated wood resins; tackifying resins such as ESCOREZ™, aliphatic hydrocarbon resins made from cationic polymerization of petrochemical feedstocks or the thermal polymerization and subsequent hydrogenation of petrochemical feedstocks, rosin ester tackifiers, and the like; mineral oil and combinations thereof.

[00347] The tackifying agent employed should be compatible with the blend of polymers. For example, the styrenic block copolymers can be formulated with rubber compatible tackifying resins, end-block compatible resins such polymethyl styrene, or plasticizers such as mineral oil. Generally the polymer is about 5-50% of the total adhesive composition, the tackifier is about 30- 85% of the total adhesive composition, and the mineral oil is about 2-40% of total adhesive composition.

[00348] The transdermal dosage form further comprises a cannabinoid agonist rate controlling means disposed on the skin contacting surface of the cannabinoid agonist reservoir, wherein at least the skin contacting surface of the cannabinoid agonist rate controlling means is adhesive. The cannabinoid agonist rate controlling means is made of a polymeric material such as ethyleήe-vinyl acetate (EVA), polyvinyl chloride (PVC), ethylene-ethyl acrylate copolymer, ethylene butylacrylate copolymer, polyisobutylene (PIB)₃ polyethylene (PE) such as low density polyethylene (LDPE), medium density polyethylene (MDPE), high density polyethylene (HDPE), and the like, and a combination thereof; the polymeric materials may be plasticized. In preferred embodiments, the cannabinoid agonist rate controlling means is adhered to the skin with an acrylic, silicone, or PIB adhesive material. The cannabinoid rate -I l l-

controlling means has a thickness of about 0.012 mm (0.5 mil) to about 0.125 mm (5 mil); preferably 0.025 mm (0.6 mil) to about 0.1 mm (4 mil); more preferably 0.0625 mm (0.8 mil) to about 0.0875 mm (3.5 mil).

[00349] The transdermal dosage form further comprises a peelable protective layer. The protective layer is made of a polymeric material that may be optionally metallized. Examples of the polymeric materials include, polypropylene, polystyrene, polyimide, polyethylene, polyethylene terephthalate, polybutylene terephthalate, paper, and the like, and a combination thereof. In preferred embodiments, the protective layer comprises a siliconized polyester sheet.

[00350] A preferred embodiment of the transdermal dosage form according to this invention comprises a patch, an aversive agent release controlling means, an aversive agent reservoir wherein the skin distal surface of the aversive agent reservoir is disposed on the aversive agent release controlling means, an impermeable barrier layer wherein the aversive agent reservoir is disposed on the skin distal surface of the barrier layer, a pouch formed from the impermeable barrier layer, a cannabinoid agonist reservoir, a cannabinoid agonist rate controlling means, and an amine resistant contact adhesive layer, covered by a peelable protective layer. The impermeable barrier layer is configured to provide a central volume which contains a cannabinoid agonist reservoir in the form of a gel having dissolved and suspended cannabinoid agonist therein.

[00351] Although preferred embodiments of this invention utilize an amine resistant in-line adhesive, other means for maintaining the dosage form on the skin can be employed. Such means include a peripheral ring of adhesive outside the path of cannabinoid agonist from the dosage form to the skin, in which case the adhesive need not be amine resistant. The use of adhesive overlays or other fastening means such as buckles, belts, and elastic arm bands is also contemplated.

[00352] A wide variety of materials which can be used for fabricating the various layers of the transdermal dosage form according to this invention have been described above. This invention therefore contemplates the use of materials other than those specifically disclosed herein, including those which may hereafter become known to the art to be capable of performing the necessary functions.

Matrix and Drug-in-Adhesive Based Transdermal and Topical Dosage Forms

[00353] In some preferred embodiments, the invention is a releasable cannabinoid agonist and substantially non-releasable aversive agent- containing silicone pressure sensitive adhesive formulation comprising a blend of releasable cannabinoid agonist and substantially non-releasable aversive agent suspended in a solvated silicone pressure sensitive adhesive. The selected solvent is one that can substantially or fully solvate or dissolve the adhesive while keeping the releasable cannabinoid agonist and substantially non-releasable aversive agent suspended in the solvated adhesive.

[00354] The formulation of the invention can be made by blending releasable cannabinoid agonist and substantially non-releasable aversive agent particles directly with one or more solvated silicone adhesives to form a suspension of releasable cannabinoid agonist and substantially non-releasable aversive agent particles in the solvated adhesive(s). Alternatively, the formulation can be made by first combining the releasable cannabinoid agonist and substantially non-releasable aversive agent particles with a silicone fluid to wet the particles and form a slurry, which slurry then can be blended with the solvated silicone adhesive(s) to also form a suspension of cannabinoid agonist and substantially non-releasable aversive agent particles in the solvated adhesive(s).

[00355] The above formulations are useful for making monolithic devices for transdermal administration of the invention.

[00356] In some preferred embodiments, the method of making a laminate comprises the steps of: (i) selecting a solvent that can substantially or fully solvate a silicone adhesive while keeping cannabinoid agonist and substantially non-releasable aversive agent particles, when blended with the solvated adhesive, suspended in the solvated adhesive; (ii) blending cannabinoid agonist and substantially non-releasable aversive agent particles with one or more silicone adhesives which are solvated with the above solvent, to form a blend formulation in which cannabinoid agonist and substantially non-releasable aversive agent particles are suspended in the solvated adhesives; (iii) casting the blend formulation onto a support material; and (iv) removing the solvent, to produce a laminate containing the support material and a cannabinoid agonist and substantially non-releasable aversive agent suspension-containing adhesive layer. In a preferred embodiment, the blend formulation formed in step (ii) is further treated prior to the casting step.

[00357] The blend formulation preferably is cast onto a backing layer or release liner. The solvent can be removed during drying by evaporation from the adhesive layer. The laminate can be further processed to produce a monolithic device containing a backing layer, cannabinoid agonist and substantially non- releasable aversive agent suspension-containing adhesive layer, and release liner.

[00358] In some preferred embodiments, the monolithic patch for application of cannabinoid agonist and substantially non-releasable aversive agent transdermally to the skin comprises: (i) a backing layer substantially impervious to the cannabinoid agonist and substantially non-releasable aversive agent to be administered transdermally; (ii) a cannabinoid agonist and substantially non-releasable aversive agent-containing adhesive layer in contact with at least a portion of the backing layer, the adhesive layer being cast from a formulation comprising a blend of cannabinoid agonist and substantially non-releasable aversive agent particles suspended in one or more solvated silicone adhesives; and (iii) a removable release liner in contact with the adhesive layer.

[00359] In some preferred embodiments, the monolithic patch for application of cannabinoid agonist and substantially non-releasable aversive agent transdermally to the skin comprises: (i) a backing layer substantially impervious to the cannabinoid agonist and substantially non-releasable aversive agent to be administered transdermally; and (ii) a cannabinoid agonist and substantially non-releasable aversive agent-containing adhesive layer in contact with the backing layer, the adhesive layer being cast from a formulation comprising a blend of cannabinoid agonist and substantially non- releasable aversive agent particles suspended in one or more solvated silicone adhesives.

[00360] In some preferred embodiments, the selected solvent is heptane.

[00361] In some preferred embodiments, the present invention provides a transdermal dosage with a therapeutic effect in a human patient for a period of up to about 4, or up to about 6, or up to about 8, or up to about 12 or about up to about 24 hours, or for a period of up to about 2, or up to about 3, or up to about 4 , or up to about 7 days. In some preferred embodiments, the present invention provides a transdermal dosage with a therapeutic effect in a human patient for a period of up to up to about 10, or up to about 14, or up to about 21, or up to about 28, or up to about 30 days.

[00362] In some preferred embodiments, the present invention provides formulations in which cannabinoid agonist and substantially non-releasable aversive agent particles are suspended in a solvent-based silicone adhesive. The cannabinoid agonist and substantially non-releasable aversive agent suspension is produced by blending cannabinoid agonist and substantially non-releasable aversive agent particles with a solvent-based silicone adhesive. The selected solvent is one that can substantially or fully solvate or dissolve the silicone adhesive. The selected solvent also must be suitable for preventing high concentrations, e.g., greater than about 1.0% w/w (dry weight), of cannabinoid agonist and substantially non-releasable aversive agent particles from dissolving in the solvated adhesive.

[00363] The total amount of cannabinoid agonist and substantially non- releasable aversive agent need not be suspended in the solvated adhesive, thus allowing for instances when a portion of the cannabinoid agonist and substantially non-releasable aversive agent is dissolved in the solvated adhesive. [00364] The solvent preferably is heptane, but also may be selected from other organic solvents, preferably closely related aliphatic solvents such hexane and octane, for example, as long as the selected solvent exhibits the above- described dissolution features.

[00365] The formulations made in accordance with the present invention are used to manufacture improved devices for delivering cannabinoid agonist and substantially non-releasable aversive agent transdermally, particularly monolithic transdermal patches. The devices may be manufactured by casting the formulation onto a support material such as a backing layer or release liner to form a cannabinoid agonist and substantially non-releasable aversive agent suspension-containing adhesive layer, which can be further processed to make a transdermal patch for delivering the cannabinoid agonist.

[00366] Thus, to manufacture a device having the advantages of the present invention, in some embodiments, one must first produce a formulation comprising a blend of cannabinoid agonist and substantially non-releasable aversive agent particles suspended in a solvated silicone adhesive, which formulation then is subsequently processed to make the device. Alternative methods for producing or achieving a cannabinoid agonist and substantially non-releasable aversive agent suspension-containing adhesive layer according to the invention may be apparent to persons skilled in the art, and these alternative methods thus also fall within the scope of the present invention.

[00367] In a preferred embodiment, one or more silicone pressure sensitive adhesives are dissolved in heptane, while cannabinoid agonist and substantially non-releasable aversive agent particles are mixed with a silicone fluid to form a slurry. The slurry of cannabinoid agonist and substantially non- releasable aversive agent in silicone fluid then is blended with a portion of the heptane-solvated silicone adhesive and passed through a high shear colloid mill or other mixing device to form a suspension. This suspension then is blended with the remaining heptane-solvated silicone adhesive to form the final (and more dilute) suspension. The composition then is cast onto a release liner and passed through an oven(s) to drive off the heptane. A backing film then is laminated onto the dried adhesive matrix.

[00368] In another preferred embodiment, the device or patch is produced by casting a blend of heptane-solvated adhesive(s) and suspended (solid) t cannabinoid agonist and substantially non-releasable aversive agent particles. A slurry is produced by mixing cannabinoid agonist and substantially non- releasable aversive agent directly with a portion of the heptane-solvated silicone adhesive(s). No silicone fluid is used. This slurry then is passed through a colloid mill or similar mixing device to form a suspension. This suspension then is blended with the remaining heptane-solvated silicone adhesive(s) to form the final (and more dilute) suspension that can be cast onto a release liner and passed through an oven to drive off the heptane. A backing film then is laminated onto the dried adhesive matrix.

100369] The silicone pressure sensitive adhesive preferably is solvated in about

20% to about 50% heptane, and more preferably in about 30% heptane. In addition to contributing to formation of a cannabinoid agonist and substantially non-releasable aversive agent suspension, other advantages of using heptane include decreased toxicity as compared to other solvents, which include, for example, toluene, xylene and other aromatics generally.

[00370] In some preferred embodiments, cannabinoid agonist and substantially non-releasable aversive agent particles are suspended uniformly in the solvated silicone adhesive as small particles, preferably crystalline particles.

[00371] In some preferred embodiments, it is believed that as the cannabinoid agonist leaves the system during the course of application, the suspended cannabinoid agonist in the system dissolves and replenishes the delivered drug.

[00372] Suitable silicone adhesives include pressure sensitive adhesives made from silicone polymer and resin. The polymer to resin ratio can be varied to achieve different levels of tack. Examples of useful silicone adhesives which are commercially available include the standard BioPSA series (7-4400, 7- 4500 and 7-4600 series) and the amine compatible (endcapped) BioPSA series (7-4100, 7-4200 and 7-4300 series) manufactured by Dow Corning. Preferred heptane-solvated silicone adhesives include BIO-PSA 7-4201, BIO-PSA 7- 4301, and BIO-PSA 7-4501.

[00373] In some preferred embodiments in which silicone medical fluid is used, the preferred amount of silicone pressure sensitive adhesive used is from about 75% to about 99% w/w (dry weight), and more preferably from about 80% to about 90% w/w (dry weight).

[00374] In some preferred embodiments in which one or more different silicone adhesives may be used, optionally in the presence of silicone medical fluid, the preferred combined amount of silicone pressure sensitive adhesive is from about 75% to about 99% w/w (dry weight), more preferably from about 85% to about 95% w/w (dry weight), and most preferably about 91% w/w (dry weight).

[00375] Preferred silicone fluids include high molecular weight polydimethylsiloxane, Dimethicone NF (Dow 360 Silicone Medical Fluid, 100 cSt and other viscosities). Preferred amounts of silicone fluid are from about 0% w/w to about 25% w/w (dry weight), more preferably from about 2% w/w to about 10% w/w (dry weight), even more preferably from about 5% w/w to about 8.5% w/w (dry weight), and most preferably about 6.5% w/w (dry weight). Preferred viscosities of the silicone fluid are from about 20 cSt to about 350 cSt, and most preferably about 100 cSt.

[00376] In some preferred embodiments, alternatives to silicone fluid, such as mineral oil, also may be used and are within the scope of the invention.

[00377] The width or thickness of the adhesive layer is that width which provides at least sufficient adhesion of the device to the skin of the host. The width or thickness also may vary depending upon such factors as the amount of drug to be delivered from the composition or adhesive layer and the desired wear period. In some preferred embodiments, the thickness of the adhesive layer will usually range from about 10 to 300 μm, more preferably 70 to about 140 μm. Expressed alternatively, in some preferred embodiments, the adhesive layer will be present at about 1 to about 30 mg/cm², more preferably about 7 to about 14 mg/cm². Variations also can be determined as a matter of routine experimentation by those of ordinary skill in the art. The width also need not be uniform and may vary around the perimeter of the device, e.g., to provide a specific geometric shape or to provide a tab for removal of a protective liner.

[00378] In some preferred embodiments, the cannabinoid agonist and substantially non-releasable aversive agent are administered preferably in unsalified and salified forms, respectively. The quantity of cannabinoid agonist in the adhesive layer is preferably that quantity sufficient to provide a pharmaceutically or physiologically effective dosage rate of the active agent to a human subject. The quantity of aversive agent in the adhesive layer is preferably that quantity sufficient to partially or completely block, blunt or nullify the mood altering and toxic effects of the cannabinoid agonist upon tampering. The quantity of cannabinoid agonist also is sufficient to maintain at least a partial suspension of the cannabinoid agonist in a solvated adhesive. This quantity can be readily determined by those of ordinary skill in the art without undue experimentation.

[00379] In some preferred embodiments, amounts are about 1% to about 10% w/w (dry weight), more preferably about 3% to about 7% w/w (dry weight), and most preferably about 4.0% w/w (dry weight) of cannabinoid agonist. In some preferred embodiments, amounts are about 5% to about 15% w/w (dry weight), more preferably about 8% to about 12% w/w (dry weight), and most preferably about 9.1% w/w (dry weight) of cannabinoid agonist.

[00380] In some preferred embodiments, a flux enhancer to promote the penetration of the cannabinoid agonist through the skin is included in the adhesive layer. Suitable flux enhancers include those described in U.S. Pat. No. 4,573,966, including, monovalent, saturated and unsaturated aliphatic and cycloaliphatic alcohols having 6 to 12 carbon atoms such as cyclohexanol, lauryl alcohol and the like; aliphatic and cycloaliphatic hydrocarbons such as mineral oil; cycloaliphatic and aromatic aldehydes and ketones such as cyclohexanone; N,N-di(lower alkyl)acetamides such as N,N-diethyl acetamide, N,N-dimethyl acetamide, N-(2-hydroxyethyl)acetamide, and the like; aliphatic and cycloaliphatic esters such as isopropyl myristate and lauricidin; N₅N-di(lower alkyl)sulfoxides such as decylmethyl sulfoxide; essential oils, nitrated aliphatic and cycloaliphatic hydrocarbons such as N- methyl-2-pyrrolidone and azone; salicylates, polyalkylene glycol silicates; aliphatic acids such as oleic acid and lauric acid, terpenes such as cineole, surfactants such as sodium lauryl sulfate, siloxanes such as hexamethyl siloxane; mixtures of the above materials; and the like.

[00381] The backing layer is preferably a thin film or sheet. In some instances, because of the area of skin to which the device is to be attached, the device, and therefore the backing layer, may be opaque or colored for cosmetic reasons. In one embodiment, it is a clear layer that is occlusive with respect to the active agent or drug, printed matter thereon. The backing layer normally provides support and a protective covering for the device.

[00382] The backing layer is preferably made of a material or combination of materials that is preferably impermeable, or at least substantially impermeable, to the adhesive layer and the cannabinoid agonist and substantially non- releasable aversive agent contained therein.

[00383] Suitable materials for the backing layer include those known in the art for use with pressure sensitive adhesives. For example, the backing layer can comprise a polyolefin, including polyethylene; a polyester; multi-layer EVA film and polyester; polyurethane; or combinations thereof. A preferred backing material is MEDIFLEX™ 1000, a polyolefin manufactured by Mylan Technologies, Inc. Other suitable materials include, for example, cellophane, cellulose acetate, ethyl cellulose, plasticized vinyl acetate-vinyl chloride copolymers, ethylene-vinyl acetate copolymer, polyethylene terephthalate, nylon, polyethylene, polypropylene, polyvinylidene chloride (e.g., SARAN™), ethylene-methacrylate copolymer (Surlyn), paper, cloth, aluminum foil and polymer-metal composites. [00384] The material that forms the backing layer may be flexible or non- flexible. Preferably, a flexible backing layer is employed to conform to the shape of the body member to which the device is attached.

[00385] In one embodiment, the medical device contains a protective release liner attached to the device at the surface to be adhered to the skin, namely the cannabinoid agonist and substantially non-releasable aversive agent- containing adhesive layer. The release liner is removed before the device is placed on the skin. The release liner is thus made of a material(s) that permits the liner to be easily stripped or peeled away from the adjacent pressure sensitive adhesive layer. The release liner may be made of the same materials suitable for use in the backing layer as discussed above. Such material is preferably made removable or releasable from the adhesive layer, for example, by conventional treatment with silicon polymers, fluoropolymers (e.g., Teflon™) or other suitable coatings on the surface thereof. The removal of the device from the release liner may also be provided by mechanical treatment of the release liner, e.g., by embossing the release liner.

[00386] Suitable release liners include those known in the art for use with pressure sensitive adhesive compositions. For example, the release liner can comprise a fiuorosilicone coated polyester. A preferred release liner is MEDIRELEASE™ 2500, manufactured by Mylan Technologies, Inc., or a fluoropolymer-treated polyester, such as Scotchpak™ 1022, manufactured by 3M Pharmaceuticals. The release liner, however, can comprise various layers, including paper or paper-containing layers or laminates; various thermoplastics, such as extruded polyolefins, such as polyethylene; various polyester films; foil liners; other such layers, including fabric layers, coated or laminated to various polymers, as well as extruded polyethylene, polyethylene terephthalate, various polyamides, and the like.

[00387] In one embodiment, the release liner includes a laminate of an outer foil layer and an inner layer of plastic, such as polyethylene or the like, which is rendered releasable not only by means of a siliconized coating, but which also includes an embossed or roughened surface. Embossment is described in U.S. Pat. No. 6,010,715, which is fully incorporated herein by reference.

[00388] In one embodiment of this invention, the patch further comprises a cannabinoid agonist and substantially non-releasable aversive agent-free adhesive layer or a substantially non-releasable aversive agent-free adhesive layer in between the backing layer and the cannabinoid agonist and substantially non-releasable aversive agent-free adhesive layer-containing adhesive layer. This additional adhesive layer extends beyond at least a portion of the cannabinoid agonist and substantially non-releasable aversive agent-free adhesive layer-containing adhesive layer to provide a further surface area that can adhere to the skin of the wearer, thereby enhancing the adhesive qualities of the device or patch. The size and shape of the backing layer will be essentially co-extensive with the size and shape of this additional adhesive layer. This cannabinoid agonist and substantially non-releasable aversive agent-free adhesive layer or a substantially non-releasable aversive agent-free adhesive layer can comprise any conventional adhesive, such as a polyisobutylene or an acrylic acid polymer, such as alkyl acrylate or methacrylate polymers, as found in any of a variety of commercially available transdermal patches or tapes.

[00389] The compositions of this invention possess sufficient adhesive properties that once the release liner is removed and the composition is applied to the skin the composition can remain in place for a period of time sufficient to distribute the desired amount of the drug contained therein with a low incidence of de-bonding.

[00390] One skilled in the transdermal art would readily recognize the possible sizes of devices or patches in accordance with the invention. The patch sizes preferably vary depending on the potency of the cannabinoid agonist and the aversive agent, and their respective physicochemical, pharmaceutical and pharmacologic properties, as well as the desired delivery rate of the cannabinoid agonist, preferably increasing in size as the desired delivery rate increases. [00391] The device, once formed, may be kept sealed in an air-tight pouch prior to use. The device of the present invention is used in the same manner as those devices which are conventional in the prior art. In particular, the release liner attached to the skin-side surface of the adhesive layer of the device for contact with the skin or mucosa of the host is removed and such surface of the adhesive layer is applied to the desired area of the skin.

[00392] Film-Forming Topical and Transdermal Dosage Forms

[00393] Film-forming topical and transdermal formulations and methods for the preparation of said dosage forms are known in the art, for example in US Patent Nos. 7,029,659; 7,083,781; 7,005,557; 6,962,691; 6,838,078; 6,797,262; 6,759,032; 6,730,288; 6,716,419; 6,582,680; 6,500,407; 6,458,339; 6,432,423; 6,306,411; 6,296,858; 6,254,877; 6,238,679; 6,238,654; 6,228,354; 6,126,920; 5,989,570; 5,948,882; 5,911,980; 5,906,822; 5,906,814; 5,869,600; 5,888,494; 5,807,957; 5,776,479; 5,711,943; 5,667,773; 5,589,195; 5,525,358; 5,508,024; 5,173,291 ; 5,017,369; 4,990,501; 4,978,527; 4,950,475; 4,584,192; 4,542,012; 4,393,076; 4,374,126; 4,199,564 and US Patent Application Nos. 20070025943; 20060193789; 20060165626; 20060064068; 20050191249; 20050186154; 20050186153; 20050186152; 20050025794; 20040161402; 20040071760; 20040022755; 20030224053; 20030194415; 20030194387; 20030118655; 20030086954; 20030082221; 20030077307; 20020142042; 20020132008; 20030026816; 20030026815; 20030007944; 20020022009, hereby incorporated by reference in their entirety.

[00394] The substantially non-releasable or non-releasable aversive may be prepared as described previously and herein and using methods know in the art.

[00395] Film forming dosage forms can provide topical and transdermal delivery of the cannabinoid agonist, pharmaceutically acceptable salts or mixtures thereof and have the advantage of being unobtrusive, more amenable to dose titration and easily applied to areas of the skin where patch application can be problematic (body contours, crevices, hairy skin, body extremities). For example, it is know that patients with painful diabetic neuropathy, painful HIV-neuropathy and other peripheral neuropathies that exhibit a "stocking and glove" distribution have difficulty applying topical patches, since the skin of the hands and feet does not easily lend itself to the application of a patch. Even when the application is to skin not involving the extremities, the area of application varies from patient to patient. This requires patients to cut the patch formulation to apply it to the affected area. A film-forming formulation is largely devoid of such disadvantages.

[00396] In some preferred embodiments, the film-forming formulation of the dosage form forms a film on the skin which exhibits excellent elasticity, flexibility and adhesion and is non-sticky.

[00397] In some preferred embodiments, the dosage form comprises a composition that includes a mixture of a polymer, cannabinoid agonist and substantially non-releasable aversive agent, pharmaceutically acceptable salts or mixtures thereof, a solvent, and optionally pharmaceutical excipients, adjuvants and auxiliary agents capable of being preserved within a container such that on release from the container, the composition forms a peelable, water removable or water-resistant, drug-releasing film on the surface of skin so as to deliver the cannabinoid agonist to the skin for local and/or systemic effects.

[00398] hi some preferred embodiments, the dosage form includes a film- forming material wherein the film is formed upon application of the formulation to the human skin. In some preferred embodiments, the composition can be manufactured as a commercial product in an appropriate device/apparatus for application of the composition to the skin of the subject. The amount of the composition that is delivered by the device to the skin can contain an effective amount of cannabinoid agonist and substantially non- releasable aversive agent in the composition. In some preferred embodiments, the composition may also include pharmaceutical excipients, adjuvants and auxiliary agents that possess multifunctional properties. The film is formed directly on the site of application after the composition is sprayed, rolled, spread or otherwise applied, and when dry the composition forms a film on the skin.

[00399] In some preferred embodiments, the film can be easily removed with water or can be peeled off. In some other preferred embodiments, the film can be may be substantially resistant to removal with water or can be peeled off; said film requiring the use of a detergent, friction, or solvent (e.g., aqueous, hydroalcoholic, or organic solvent) for easy removal.

[00400] In some preferred embodiments, the dosage form contains a polymer, for example, a polyvinyl alcohol (PVA), for example, a mixture of a first polyvinyl alcohol and a second polyvinyl alcohol of different viscosities. Other biocompatible polymers which are biologically inert polymers include cellulose, carboxymethyl cellulose, PVP/polyvinyl propylene, polyurethane, ethylene vinyl acetate, polyethylene, polypropylene, polystyrene or copolymers thereof. In some preferred embodiments, a preferred polymer is a polyvinyl alcohol, which confers sufficient viscosity to the composition so that it can form a film, which upon evaporation and concentration of the solvent can form a film that adheres to the skin.

[00401] In some preferred embodiments, the cannabinoid agonist and substantially non-releasable aversive agent, pharmaceutically acceptable salts or mixtures thereof can optionally be formulated in an alcohol-based solvent system, more particularly a lower alkyl alcohol (lower alkanol), for example, methanol, n-propanol, I-propanol, more preferably ethanol, or an alcohol solution or suspension, preferably an ethanol solution or suspension.

[00402] In some preferred embodiments, one or more hydrophobic substances can be included in the formulation, for example, fumed silica, to modify the release and skin flux characteristics of the formulation system.

[00403] In some preferred embodiments, the formulation may include additives such as solvents, plasticizers, solubilizers, emollients, and preservatives known in the art to be suitable for application to the skin.

[00404] In some preferred embodiments, the formulation may be applied to the skin using a variety of available devices, including a ball-tipped container (e.g., a rollette applicator), an atomizer, an aerosol container, a pressurized container or directly from a tube or bottle. In some preferred embodiments, the film-forming dosage form for application to the skin comprises cannabinoid agonist and substantially non- releasable aversive agent as suspension in a vehicle optionally containing a polymer or combination of polymers. The compositions of the invention preferably comprise cannabinoid agonist and substantially non-releasable aversive agent up to about 50% (e.g., 0.0001% to about 50%), more preferably up to about 10% (e.g., 0.0001% to about 10%) and most preferably up to about 5% (e.g., 0.0001% to about 5%) dissolved or suspended in one or more vehicles which comprise up to 99% of the composition (e.g., 0.0001% to about 99%). In some preferred embodiments, the composition may further contain one or more film former, solubilizer, permeation enhancer and plasticizer. In some preferred embodiments, the composition may contain one or more of these additives in amounts of up to about 20% film-former (e.g., 0.0001% to about 20%), up to about 20% solubilizer (e.g., 0.0001% to about 20%), up to about 20% permeation enhancer (e.g., 0.0001% to about 20%), and up to about 20% plasticizer (e.g., 0.0001% to about 20%). The composition may be sprayed or applied on the skin to form a stable, breathable film on the site, from which film the cannabinoid agonist acts locally on the skin surface or is transdermally available. Preferably, the composition further comprises up to about 15% (w/w) of one or more water-soluble additives (e.g., 0.0001% to about 15%). The cannabinoid agonist and substantially non-releasable aversive agent so deposited in the matrix of the film-former may remain solubilized or suspended. The exact formulation of the composition may vary depending on the selection of active agent or drug, the nature of the particular medicament used (for example, the solubility profile), the intended therapeutic effect, the anatomic location and the release profile desired. The compositions can be dispensed from any dispenser, preferably a dispenser which provides the composition as a spray, and may be used for systemic action or topical action. The cannabinoid agonist from the composition may be released over a period of time or immediately.

[00406] In some preferred embodiments, the compositions of the present invention are preferably applied in a metered dose over a predetermined surface area. Preferably, the composition is dispensed from a pump dispenser or from an aerosol dispenser. In the latter case, the composition additionally may comprise from about 10% to 90% of propellant in order to provide a suitable pressure within the aerosol dispenser. Generally, propellant is not required for compositions dispensed from a pump dispenser. However, if desired, such compositions may also comprise from about 10% to 90% of a propellant which is liquid at room temperature, for example, trichloromonofluoromethane.

[00407] In some preferred embodiments, the film-formers preferably include acrylic polymers or copolymers, including methacrylic polymers and copolymers. Preferred film-formers include a non-ionic copolymer of methyl methacrylate and butyl methacrylate (Plastoid™ B), a copolymer of dimethylamine ethyl methacrylate and a neutral methacrylic acid ester (Eudragit™ ElOO), ammonio methacrylate copolymer type B (Eudragit RS, USP/NF), ammonio methacrylate copolymer type A (Eudragit™ RL, USP/NF), methacrylic acid copolymer type A (Eudragit™ LlOO, USP/NF), methacrylic acid copolymer type B (Eudragit™ SlOO USP/NF), polyvinyl acetate, cellulose acetate, polyvinyl alcohol, povidone, povidone vinyl acetate, hydroxypropyl methyl cellulose, hydroxy ethyl cellulose, methyl cellulose and ethyl cellulose.

[00408] In some preferred embodiments, the breathability of the film is achieved by the absence of any occlusive backing membrane together with the generally hydrophilic properties of the film-forming polymer(s). In some preferred embodiments, these polymers can partially dissolve on exposure to moisture (from the skin or air), the dissolution resulting in the formation of a porous film. This porosity can be enhanced by including additional water- soluble additives, such as those detailed below. [00409] In some preferred embodiments, solubilizers include a copolymer of dimethylamine ethyl methacrylate and a neutral methacrylic acid ester (Eudragit™ ElOO, USP/NF); surfactants, for example, sodium lauryl sulfate; polyhydric alcohols, for example, propylene glycol or polyethylene glycol; vitamin E, vitamin E TPGS (tocopheryl polyethylene glycol 1000 succinate) and labrasol; or any two or more of the above in combination. Preferably, the solubilizer is a copolymer of dimethylamine ethyl methacrylate and a neutral methacrylic acid ester (Eudragit™ ElOO) in combination with, a non-ionic copolymer of methyl methacrylate and butyl methacrylate (Plastoid™ B). The solubilizers serve to dissolve the cannabinoid agonist in the chosen vehicle. Many of the solubilizers also enhance percutaneous penetration of cannabinoid agonist and/or act as humectants.

[00410] In some preferred embodiments, preferred plasticizers include triethyl citrate, dimethyl isosorbide, acetyltributyl citrate, castor oil, propylene glycol, and polyethylene glycol, or any two or more of the above in combination.

[00411] In some preferred embodiments, the permeation enhancer is preferably a lipophilic solvent, for example, dimethyl sulfoxide, dimethyl formamide or isopropyl myristate; a surfactant, for example, Tween or sodium lauryl sulfate; menthol; oleic acid, octyl dimethyl para-amino benzoic acid (Padimate O); mixed esters of capric and caprylic acid; or a polyhydric alcohol, for example, propylene glycol or diethylene glycol monoethyl ether EP (transcutol); or any two or more of the above in combination.

[00412] In some preferred embodiments, the vehicle can be water or a nonaqueous solvent. Preferred nonaqueous vehicles include acetone, isopropyl alcohol, methylene chloride, methyl-ethyl-ketone, absolute alcohol, ethyl acetate and trichloromonofluoromethane, methylene dimethyl ether or any two or more of the above in combination.

[00413] In some preferred embodiments, the aqueous or non-aqueous vehicle may additionally comprise (weight/weight of vehicle) up to 20% of one or more humectants. In some preferred embodiments, the humectants include polyhydric alcohols and polyvinyl pyrrolidone. Preferred polyhydric alcohols are propylene glycol, butylene glycol, polyethylene glycol, glycerol and sorbitol.

[00414] In some preferred embodiments, the water-soluble additive is propylene glycol, sodium lauryl sulfate, one or more polaxomers, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, cetomacrogol, polyethylene glycol or transcutol, or any two or more of the above in combination.

[00415] In some preferred embodiments, when the composition is dispensed as an aerosol, the vehicle may partly comprises a propellant in an amount to provide from about 10% to about 90% (w/w) of the composition. The propellant can be any pharmaceutically acceptable propellant which provides a suitable pressure within an aerosol dispenser, preferably a pressure of from about 20 p.s.i.g. to about 130 p.s.i.g. Preferred propellants include hydrocarbons, for example, propane, butane, isobutane, or dimethylether; hydrofluorocarbons and hydrochlorofluorocarbons, for example, dichlorodifluoromethane, trichloromonofluoromethane, dichlorofluoroethane, monochlorodifluoromethane, dichlorotetrafluoroethane, difluoroethane, tetrafluoroethane, heptafluoropropane; or compressed gases, for example, nitrogen or carbon dioxide.

[00416] In some preferred embodiments, the topical compositions are quick drying, non-occlusive formulations which cause marked enhancement of the skin permeation of the cannabinoid agonist both in vitro and in vivo when compared with existing transdermal patches. They offer the advantages of lower skin irritation, greater ease of use, increased dosage flexibility and a simpler method of manufacture when compared to existing transdermal patches.

[00417] In some preferred embodiments, the compositions are generally prepared by mixing the ingredients, without liquefied propellant, at a temperature of from 0 ⁰C to 100 ⁰C and at ambient pressure. If propellant is to be added, in some preferred embodiments, the resulting mixture is then charged with the liquefied propellant into an aerosol dispenser to achieve the final composition. Mixing is preferably carried out at a temperature of from 10 T/US2007/018585

-129-

°C to 25 °C. In some preferred embodiments, the mixed composition is placed in a pump dispenser, for example, a metered dose pump, which dispenses the composition typically without liquefied propellant since a pressurized atmosphere is not required. In some preferred embodiments, propellant which is liquid at room temperature may, however, be included in a pump dispenser composition as part of the aqueous vehicle. The composition so prepared is sprayed from the dispenser onto a topical site, at which site it forms a stable, plastic film or patch. In some preferred embodiments, the container is a conventional aerosol can having a conventional metered spray aerosol valve. In some preferred embodiments, the pump dispenser is preferably a conventional can or bottle having a conventional metered spray pump. In some preferred embodiments, the aerosol dispenser has an all position valve having a shroud that permits spraying when the dispenser is held at any angle. In this way, horizontal bottom surfaces, as well as horizontal top surfaces and vertical surfaces, can be sprayed. In some preferred embodiments, the valve actuator can be any actuator which produces a spray and not foam at the nozzle. In some preferred embodiments, the valve actuator can be any actuator which produces foam at the nozzle. In some preferred embodiments, the valve actuator is a mechanical breakup actuator, which employs mechanical forces rather than expansion and evaporation of the propellant to produce a spray. In some preferred embodiments, a typical mechanical breakup actuator has a conical or cylindrical swirl chamber with an inlet channel oriented perpendicular to the axis thereof. This structure imparts a swirling motion to the aerosol mixture upon discharge. The swirling motion occurs around the axis of the swirl chamber forming a thin conical film of discharged mixture, which breaks into droplets as it leaves the swirl chamber and travels in the direction of the axis thereof. The result is a fine, soft, dispersed spray which can be easily controlled to produce a stable thin film of even thickness completely contacting the application site. In dispensing a composition of the invention, the dispenser is typically held about 2.5 to 5 cm or 2 to 20 cm from the application site and produces a film of even thickness. In some preferred embodiments, the dispensers used in the present invention are compact units which can be conveniently used for quick and easy application of a medicament over a large surface area.

[00419] In some preferred embodiments, delivery of a controlled dosage of an embodiment of the invention which is a composition can be assisted with an adhesive patch which is a border for a non-patch portion, the non-patch portion having a specific area, for delivery to that specific area of skin. The patch can be of any shape, for example round or rectangular, and the proportion of the border to the non-patch interior is selected by one of skill in the art of design of adhesive patches, to remain in place for a limited period of time following application by any of the devices above. The patch is attached to the particular location of skin to be treated, and the composition is applied to the non-patch portion of exposed skin, for example, by spraying or spreading; the patch can be removed when the composition has dried to form a film, or can remain in place.

[00420] In general, a polymer which can form film upon application to the skin, poly(vinyl alcohol), thermoplastic polyurethane, cellulose, carboxyvinyl polymer, poly( vinyl pyrrolidone) etc. can be used.

[00421] In some preferred embodiments, the film-forming polymers have high elasticity to reduce interfere with activities of daily living, have a low glass transition temperature to reduce deterioration of the dosage form upon drying and have a low propensity for exfoliation from the skin.

[00422] In some preferred embodiments, the film-forming formulation is a polymer comprising: (i) polyurethane; (ii) an additional polymerization polymer which includes at a main or a side chain, a carboxylic acid derivative, i.e., a carboxylic acid alkyl ester and/or carboxylic acid alkyl amide and/or carboxylic acid alkyl aminoalkyl ester group; (iii) a active agent or drug; (iv) a solvent in which the film-forming agent is dissolved; and optionally, (v) other additives. [00423] In some preferred embodiments, the film-forming composition includes a water-soluble or water-dispersible vinyl polymer that includes amine group-containing side-chains and a copolymerized hydrophobic monomer.

[00424] In some preferred embodiments, the film-forming composition include: a water-soluble or water-dispersible vinyl polymer that includes amine group- containing side-chains and a copolymerized hydrophobic monomer; water; and a surfactant.

[00425] In some preferred embodiments, the surfactant is a nonionic surfactant, preferably having an HLB of at least about 14 and more preferably no greater than about 19. In certain embodiments, the compositions also include a surfactant having an HLB of less than about 14 or greater than about 19. In other embodiments, the compositions also include an anionic or amphoteric surfactant, such as one selected from the group consisting of sulfates, sulfonates, phosphates, phosphonates, ammonium sulfonate, amphoterics, and mixtures thereof.

[00426] In some preferred embodiments, the compositions include a hydroxycarboxylic acid buffer, which includes, for example, an alpha- hydroxycarboxylic acid such as lactic acid, malic acid, citric acid, or a mixture thereof.

[00427] In some preferred embodiments, the vinyl polymer has a glass transition temperature of at least about 30 ⁰C and more preferably at least about 50 ⁰C. In some preferred embodiments, the compositions further include a polymer having a higher Tg than that of the vinyl polymer having amine groups. Preferably, such a polymer is polyvinyl alcohol.

[00428] In some preferred embodiments, the dosage form is a film-forming composition that includes: a water-soluble or water-dispersible vinyl polymer including amine group-containing side-chains and a hydrophobic monomer; cannabinoid agonist and substantially non-releasable aversive agent; water; and a surfactant. [00429] In some preferred embodiments, the composition includes: a water- soluble or water-dispersible vinyl polymer prepared from monomers that include an amine group-containing monomer, about 1 wt-% to about 30 wt-% of a (C₆-C₂2)alkyl (meth)acrylic monomer, and about 15 wt-% to about 75 wt- % of a (C_!-C₄)alkyl (meth)acrylic monomer; water; and the cannabinoid agonist and substantially non-releasable aversive agent.

[00430] In some preferred embodiments, the preferred vinyl polymers are prepared from dimethylarnine oxide methacrylate, isobutyl methacrylate, methyl methacrylate. and a (Ci2-i8)alkyl methacrylate. In certain other preferred embodiments, preferred vinyl polymers are prepared from trimethylaminioethyl acrylate chloride, butyl acrylate, methyl methacrylate, and a (C₁2-is)alkyl methacrylate.

[00431] In some preferred embodiments, the film-forming composition includes: a water-soluble or water-dispersible vinyl polymer comprising amine group-containing side-chains and a copolymerized hydrophobic monomer; water; and cannabinoid agonist and substantially non-releasable aversive agent.

[00432] In some preferred embodiments, the film-forming dosage forms are aqueous-based and have the following characteristics: (i) relatively short dry times; (ii) transparent film for clear viewing of the underlying skin and tissue; (iii) good adhesion to the skin when dry; (iv) little or no tack when dry; (v) capable of releasing the cannabinoid agonist over a period of time; (vi) relatively easy removal, preferably without the need for organic solvent-based removers. In other embodiments, the film is transluscent or opaque and may optionally contain excipients, dye and/or colorants to impart a preferred color to the film.

[00433] In some preferred embodiments, the film-forming dosage forms are very stable and can survive prolonged exposure to elevated temperatures for up to one day, or up to one week, or up to one month. In some preferred embodiments, the film-forming dosage forms show no visible changes in color, turbidity, and the like. In some preferred embodiments, the film-forming dosage forms are stable upon exposure to low temperatures.

[00434] In some preferred embodiments, the dried film of the composition are flexible and durable (i.e., resistant to cracking, or flaking).

[00435] In some preferred embodiments, the film-forming dosage forms possess viscosities that ensure the formulations go on easily and form a relatively thin film that can dry rapidly. In some preferred embodiments, the Brookfield viscosity of a composition is no greater than about 1000 Centipoise (cps), more preferably no greater than about 500 cps, even more preferably no greater than about 250 cps, even more preferably no greater than about 100 cps, and most preferably no greater than about 50 cps. This low viscosity ensures that the composition can be painted on the skin with little effort in a uniform thin film that will dry rapidly.

[00436] In some preferred embodiments, dry times are preferably no greater than about 5 minutes, more preferably no greater than about 3 minutes, even more preferably no greater than about 2 minutes, and most preferably no greater than about 1.5 minutes on skin measured at 23 °C at 45-55% relative humidity.

[00437] In some preferred embodiments, the film-forming dosage form is applied to the skin and allowed to dry and remain in place for up to about 4 hours, or up to about 12 hours, or up to about 24 hours, or up to about 2 days, or up to about 3 days, or up to about 4 days, or up to about 7 days, or up to about 10 days, or up to about 14 days, or up to about one month.

[00438] Film-Forming Polymers

[00439] hi some preferred embodiments, one or more film-forming polymers are included in the compositions of the present invention to improve resistance to wash off, improve adhesion and/or reduce the tack of the compositions. In some preferred embodiments, film-forming polymers of the compositions are substantive and resist removal by prolonged exposure to fluids such as water, saline, sweat, yet can be easily and gently removed without the need for organic solvents. [00440] In some preferred embodiments, the compositions incorporate film- forming polymers that have both hydrophilic and hydrophobic moieties. In some preferred embodiments, the film-forming polymers are prepared from at least two monomers (i.e., a hydrophilic monomer and a hydrophobic monomer), and or from at least three monomers.

[00441] In some preferred embodiments, the film-forming polymer is a vinyl polymer that includes amine group-containing (i.e., amine-containing) side- chains and hydrophobic character. The term vinyl polymer refers to a polymer prepared from monoethylenically unsaturated monomers. The amine groups can be quaternary amine (i.e., quaternary ammonium) groups, amine oxide groups, and/or protonated tertiary amine groups.

[00442] In some preferred embodiments, the monoethylenically unsaturated amine group-containing monomers are monoethylenically unsaturated quaternary ammonium, amine oxide, and/or protonated tertiary amine group- containing monomers. In some preferred embodiments, the side-chain amine group-containing monomers are monoethylenically unsaturated quaternary amine, amine oxide, tertiary amine, or protonated tertiary amine group- containing (meth)acrylic monomers. In some preferred embodiments, the monoethylenically unsaturated amine group-containing monomers from which the film-forming polymers are formed are quaternary ammonium and amine oxide group-containing monomers. If desired, the tertiary amine group- containing monomers can be easily converted to protonated tertiary amine groups, amine oxide groups, or quaternary ammonium groups prior to or after polymerization by the appropriate chemical reaction as described herein. In the case of quaternary ammonium group-containing polymers, it is preferred that the polymer be prepared from the quaternary ammonium group- containing monomer. In the case of protonated tertiary amine group- and amine oxide group-containing polymers, it is preferred to first make the polymer from the corresponding tertiary amine and to subsequently covert the tertiary amine groups on the polymer to the protonated tertiary amine or amine oxide group. [00443] In some preferred embodiments, the amine group-containing monomers used to prepare the film-forming polymers are typically used in an amount of at least about 15 wt-%, preferably at least about 20 wt-%, more preferably at least about 25 wt-%, and most preferably at least about 30 wt-%, based on the total weight of polymerizable composition (preferably, based on the total weight of the polymer). The amine group-containing monomers used to prepare the film-forming polymers are typically used in an amount of no greater than about 70 wt-%, preferably no greater than 65%, more preferably no greater than about 60 wt-%, and most preferably no greater than about 55 wt-%, based on the total weight of polymerizable composition (preferably, based on the total weight of the polymer).

[00444] In some preferred embodiments, the monoethylenically unsaturated amine group-containing monomers are acrylic monomers. The acrylic monomers are understood to include (meth)acrylate (i.e., acrylate or methacrylate) and/or (meth)acrylamide (i.e., acrylamide or methacrylamide) monomers. In some preferred embodiments, the monomers include salts of trimethylaminoethyhnethacrylate, trimethylaminoethylacrylate, trimethylaminopropyl acrylamide, trimethylaminopropyl methacrylamide, and protonated salts of dimethylaminoethyhnethacrylate. Particularly preferred monomers are the chloride and methosulfate salts of trimethylarninoethylrnethacrylate.

[00445] Li some preferred embodiments, the monoethylenically unsaturated amine group-containing monomers are (meth)acrylate and/or (meth)acrylaτnide monomers. Preferred monomers include amine oxides of dimethylaminoethybnethacrylate, dimethylaminoethylacrylate, dimethylaminopropylacrylamide, and dimethylaminopropylmethacrylamide.

[00446] In some preferred embodiments, the amine group-containing monomers are present in a concentration sufficient to ensure water solubility or water dispersibility and substantivity of the composition. In some preferred embodiments, the amine-group containing monomer provide hydrophilic character to the polymer. However, other non-amine group-containing hydrophilic monomers may be used to prepare the film-forming polymer to assist in water solubility and/or stability. These include hydroxy-functional acrylates, polyethylene glycol-functional acrylates, vinyl-lactams such as N- vinylpyrrolidone and N-vinyl caprolactam, acrylamide, methacrylamide, hydrolyzed vinyl acetate (vinyl alcohol) and other monomers whose homopolymers result in water-soluble polymers.

[00447] In some preferred embodiments, in addition to an amine group- containing monomer, at least one hydrophobic monomer is used to prepare the film-forming polymers.

[00448] In some preferred embodiments, the vinyl polymer used in the compositions contains at least one copolymerized hydrophobic monoethylenically unsaturated alkyl (meth)acrylic monomer. As used herein, the "monoethylenically unsaturated" term in the alkyl (meth)acrylic monomer refers to the acrylic unsaturation. Preferably, "alkyl (meth)acrylic" monomers include (meth)acrylamides (e.g., octylacrylamide), (meth)acrylates, and combinations thereof. More preferably, the alkyl (meth)acrylic monomer is an alkyl (meth)acrylic acid ester (i.e., an alkyl acrylate or alkyl methacrylate), wherein the alkyl group has at least one carbon atom (on average). Preferably, the alkyl group has no greater than 50 carbon atoms, more preferably, no greater than 36 carbon atoms, and most preferably, no greater than 22 carbon atoms (on average). Alternatively stated, these alkyl (meth)acrylate monomers are (meth)acrylic acid esters of alkyl alcohols (preferably, non-tertiary alkyl alcohols), the alkyl groups of which preferably include 1 to 22 carbon atoms (on average). Of these, one preferred alkyl group includes 1 to 4 carbon atoms. Another preferred alkyl group includes 6 to 22 carbon atoms, more preferably 8 to 22 carbon atoms, and even more preferably 8 to 18 carbon atoms (on average). The alkyl group can optionally contain heteroatoms and can be linear, branched, or cyclic.

[00449] Examples of suitable alkyl (meth)acrylate monomers having shorter alkyl groups (C1-C4) useful in the present invention include, but are not limited to methyl acrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, and n-propyl methacrylate, n-butyl acrylate, and isobutyl acrylate, isobutyl methacrylate, t-butyl methacrylate, and the like. Particularly preferred of these are methyl methacrylate and isobutyl methacrylate.

[00450] Examples of suitable alkyl (meth)acrylate monomers having longer alkyl groups (C6-C22) useful in the present invention include, but are not limited to cyclohexyl methacrylate, decyl acrylate, 2-ethylhexyl acrylate, n- hexyl acrylate, isoamyl acrylate, isodecyl acrylate, isononyl acrylate, isooctyl acrylate, lauryl acrylate, lauryl methacrylate, stearyl acrylate, stearyl methacrylate, behenyl methacrylate, 2-methylbutyl acrylate, 4-methyl-2-pentyl acrylate, ethoxy ethoxyethyl acrylate, isobornyl acrylate, mixtures thereof, and the like. Particularly preferred of these are isobutyl methacrylate, n-butyl acrylate, 2-ethylhexyl acrylate, isooctyl acrylate, lauryl methacrylate, stearyl methacrylate, and mixtures thereof.

[004511 In some preferred embodiments, the monoethylenically unsaturated alkyl (meth)acrylic monomer(s) can be used in an amount of at least about 35 weight percent, and more preferably at least about 45 wt-%, and most preferably at least 50% wt-%, based on the total weight of the polymerizable composition (and preferably, based on the total weight of the polymer). In some preferred embodiments, the monoethylenically unsaturated alkyl (meth)acrylic monomer(s) can be used in an amount of no greater than about 85 wt-%, more preferably no greater than about 75 wt-%, and most preferably no greater than about 65 wt-%, based on the total weight of the polymerizable composition (and preferably, based on the total weight of the polymer).

[00452] hi some preferred embodiments, certain combinations of the amine group-containing monomers with long chain monomers are particularly useful. The long chain alkyl monomers help to lower the glass transition temperature (Tg) of the polymer system and to improve substantivity of the polymer and composition. In general, this lower Tg helps to promote both adhesion to skin.

[00453] In some preferred embodiments, the composition has no or relatively low tack. In some preferred embodiments, the film-forming polymers is formed from at least amine group-containing monomers, long chain (meth)acrylic monomers, and short chain (meth)acrylic monomers.

[00454J In some preferred embodiments, the long chain (meth)acrylic monomer (e.g., a (C6-C22)alkyl (meth)acrylic monomer) is preferably used to prepare the polymer in an amount of at least about 1 wt-%, more preferably at least about 3-wt-%, and most preferably at least about 5 wt-%, based on the total weight of the polymerizable composition (and preferably, based on the total weight of the polymer). The long chain (meth)acrylic monomer is preferably used to prepare the polymer in an amount of no greater than about 40 wt-%, more preferably no greater than about 30 wt-%, even more preferably no greater than about 20 wt-%, and most preferably no greater than about 15 wt-%, based on the total weight of the polymerizable composition (and preferably, based on the total weight of the polymer). Most preferred polymers include about 5 wt-% to about 15 wt-% long chain (meth)acrylic monomer.

[00455] In some preferred embodiments, the short chain (meth)acrylic monomer (e.g., a (Cl-C4)alkyl (meth)acrylic monomer) is preferably used to prepare the polymer in an amount of at least about 15 wt-%, more preferably at least about 25 wt-%, and most preferably at least about 30 wt-%, based on the total weight of the polymerizable composition (and preferably, based on the total weight of the polymer). The short chain acrylic monomer is preferably used to prepare the polymer in an amount of no greater than about 75 wt-%, more preferably no greater than about 65 wt-%, and most preferably no greater than about 60 wt-%, based on the total weight of the polymerizable composition (and preferably, based on the total weight of the polymer). Most preferred polymers include about 30 wt-% to about 60 wt-% short chain (meth)acrylic monomer,

[00456] In some preferred embodiments, the film-forming polymers are formed from two different short chain acrylic monomers. The first is a (Cl -C2)alkyl (meth)acryl/o monomer such as methyl methacrylate and the second is a (C3- C4)alkyl fimeth)acrylic monomer such as n-, t-, or iso-butyl acrylate. The very short chain monomer is present to increase the glass transition temperature to reduce the tack of the composition 'as well as provide some hydrophobicity. The (C3-C4)alkyl (meth)acrylic monomer is present to provide hydrophobicity as well as some flexibility to the film-forming polymer to ensure it does not easily flake off in use.

[00457] In some preferred embodiments, the molecular weight of the vinyl polymers is also preferably kept low in order to maintain a low viscosity composition. In some preferred embodiments, the molecular weight of the vinyl polymers is generally no greater than about 350,000 Daltons, no greater than about 250,000 Daltons, no greater than about 150,000 Daltons, and no greater than about 100,000 Daltons.

[00458] In some preferred embodiments, one or more substantive film-forming vinyl polymers are present in the compositions of the present invention in a total amount of at least about 2 wt-%, preferably at least about 3 wt-%, and more preferably at least about 5 wt-%, based on the total weight of composition. In some preferred embodiments, one or more substantive film- forming vinyl polymers are present in the composition in a total amount of no greater than about 10 wt-%, and more preferably no greater than about 8 wt- %, based on the total weight of composition.

[00459] In some preferred embodiments, the substantive film-forming vinyl polymer is present in an amount greater than the surfactant.

[00460] Surfactants

[00461] In some preferred embodiments, the formulation includes one or more surfactants to enhance solubility and stability of the polymer in the composition and to help the compositions to wet the skin and ensure a smooth uniform coating.

In some preferred embodiments, one or more surfactants are generally added to the compositions of the present invention in an amount of at least about 0.5 wt-%, based on the total weight of the composition. In some preferred embodiments, one or more surfactants are added to the compositions in an amount no greater than about 10 wt-%, more preferably no greater than about 7 wt-%, even more preferably no greater than about 5 wt-%, and most preferably no greater than about 3 wt-%, based on the total weight of the composition.

[00462] In some preferred embodiments, the surfactant is a nonionic surfactants, including polyalkoxylated, and polyethoxylated nonionic surfactants. In some preferred embodiments, surfactants of the nonionic type: (i) polyethylene oxide extended sorbitan monoalkylates (i.e., polysorbates); (ii) polyalkoxylated alkanols; (iii) polyalkoxylated alkylphenols; (iv) polaxamers; (v) polyalkoxylated esters; and (vi) alkyl polyglucosides.

[00463] In some preferred embodiments, the surfactant is a nonionic surfactants, including amphoteric surfactants. In some preferred embodiments, the amphoteric surfactants include: (i) ammonium carboxylate amphoterics; and (ii) ammonium sulfonate amphoterics.

[00464] In some preferred embodiments, the surfactant is anionic surfactants

(e.g., sulfonates, sulfates, phosphates) and amine oxides (e.g., alkyl and alkylamidoalkyldialkylamine oxides).

[00465] Vehicle

[00466] In some preferred embodiments, suitable liquid vehicles for the compositions include water, optionally in combination with acetone or an alcohol, particularly a (Cl-C4)alcohol (i.e., a lower alcohol) such as ethanol, 2-propanol, and n-propanol, and mixtures thereof. The preferred vehicle is injectable-grade water, i.e., USP grade "water for injection", however, other forms of purified water may be suitable such as distilled and deionized water.

[00467] In some preferred embodiments for applications to intact skin, it may be desirable to include a lower alcohol such as ethanol, isopropanol, or n- propanol.

[00468] In some preferred embodiments, the dosage form contains one or more buffers.

[00469] In some preferred embodiments, the dosage form contains one or more other optional ingredients, including but not limited to preservatives, antioxidants, solubilzing agents, emollients, humectants, fragrances, colorants, tackifiers, plasticizers, permeation enhancers (e.g., lauryl alcohol, oleyl alcohol, lauramide DEA, lauryl pyrrolidone-5-carboxylate, ascorhyl palmitate, glycerin, propylene glycol, and tetraglycol).

[00470] In some preferred embodiments, the dosage form provides low tack or nontacky dry films, which can be readily removed with water or detergent.

Detailed Description of the Preferred Embodiments

[00471] The following examples illustrate various aspects of the present invention. They are not to be construed to limit the claims in any manner whatsoever.

[00472] A wide variety of methods known in the art for the preparation of immediate release and controlled release dosage forms may be incorporated into the invention.

[00473] More than one substantially non-releasable aversive agent selected from the group comprising cannabinoid antagonists and opioid antagonists may be included in the dosage form either in the form of separate substantially non-releasable subunits, or combined into the same substantially non- releasable subunit. Said more than one substantially non-releasable aversive agent may comprise aversive agents from the same class of agents (e.g., more than one cannabinoid antagonist, or more than one opioid antagonist or more than one alcohol deterrent) or from a different class of agents (e.g., one cannabinoid antagonist, one opioid antagonist, one alcohol deterrent) or mixtures thereof.

[00474] Abuse intervention agents may optionally be incorporated into the same sub-unit as the substantially non-releasable aversive agent or into a different sub-unit or into the granulation or matrix material containing the cannabinoid agonist.

[00475] The percent loading of the cannabinoid agonist agent, the substantially non-releasable aversive agent and the abuse intervention agent may be varied depending on the physiochemical and pharmaceutical properties of said agent and ingredients (excipients), the pharmacologic effects of said agent and the desired degree of release or non-release from the dosage form.

100476] The ingredients used for the preparation of the releasable cannabinoid agonist and the substantially non-releasable aversive agent may be modified depending on the selection, dose and desired duration of effect of the cannabinoid agonist and the aversive agent. In some embodiments, a change in the dose or amount cannabinoid agonist and/or aversive agent does not require a change in amount of other ingredients. In other embodiments, a proportional change in the amount of other ingredients is required to maintain the desired properties. In yet other embodiments, a change in the dose or amount cannabinoid agonist and/or aversive agent necessitates a change in the nature and/or amount of ingredients to provide the required characteristics of the cannabinoid agonist (e.g., delivery rate, duration of effect, rate and extent of absorption, therapeutic concentrations and effect, etc.) and aversive agent (e.g., extent of non-release or sequestration, degree of abuse deterrence, etc).

[00477] Cannabinoid agonists of the invention have previously been described and defined in considerable detail. In the limited number of examples provided below, cannabinoid agonist refers to any compound selected from the group comprising THC (delta-9-tetrahydrocannabinol), nabilone, dronabinol, cannabidiol, cannabinol, cannabichromene, 9-THC propyl analog, cannabigerol, anandamide, 2-arachidonoylglycerol, HU210, desacetyllevonantradol, CP55940, CP55244, or WIN55212-2, or their pharmaceutically acceptable salts.

[00478] Aversive agents of the invention have previously been described and defined in considerable detail. In the limited number of examples provided below, aversive agent refers to cannabinoid antagonists or opioid antagonists. For the proposes of the examples provided below, aversive agents refer to any compound selected from the group comprising rimonabant, naltrexone, naloxone, nalmefene, N-methylnaltrexone, nalorphine, alvimopan, N- methylnalmefene, oxilorphan, AM251, AM281, AM630, SR144528, N- allyllevallorphan, nadide, and cyclorphan, or their pharmaceutically acceptable salts.

EXAMPLE l

[00479] Figures 1, depicts a preferred embodiment of the transdermal dosage form of the invention comprising a (1) patch, (2) an aversive agent release controlling means, (3) an aversive agent reservoir, wherein the skin distal surface of the aversive agent reservoir is disposed on the aversive agent release controlling means, (4) an impermeable barrier layer, wherein the aversive agent reservoir is disposed on the skin distal surface of the barrier layer, (5) a cannabinoid agonist layer disposed on the skin proximal surface of the barrier layer, wherein at least the (6) skin contacting surface of the cannabinoid agonist reservoir is adhesive, and (7) a peelable protective layer.

EXAMPLE 2

[00480] Figures 2, depicts a preferred embodiment of the transdermal dosage form of the invention comprising a (1) patch, (2) an aversive agent release controlling means, (3) an aversive agent reservoir, wherein the skin distal surface of the aversive agent reservoir is disposed on the aversive agent release controlling means, (4) an impermeable barrier layer, wherein the aversive agent reservoir is disposed on the skin distal surface of the barrier layer, (5) a cannabinoid agonist layer disposed on the skin proximal surface of the barrier layer, wherein at least the (6) skin contacting surface of the cannabinoid agonist reservoir is adhesive, (7) a peelable protective layer and (8) a cannabinoid agonist controlling means disposed on the skin contacting surface of the cannabinoid agonist reservoir, wherein at least the skin contacting surface of the cannabinoid agonist rate controlling means is adhesive.

EXAMPLE 3

[00481] Figures 3, depicts a preferred embodiment of the transdermal dosage form of the invention comprising a (1) patch, (2) an aversive agent release controlling means, (3) an aversive agent reservoir, wherein the skin distal surface of the aversive agent reservoir is disposed on the aversive agent release controlling means, (4) an impermeable barrier layer, wherein the aversive agent reservoir is disposed on the skin distal surface of the barrier layer, (5) the cannabinoid agonist is a single phase polymeric composition in which the cannabinoid agonist and all other components are present at concentrations no greater than, and probably less than, their saturation concentrations in the cannabinoid agonist reservoir, disposed on the skin proximal surface of the barrier layer, wherein the (6) skin contacting surface of the cannabinoid agonist reservoir may be formulated with (8) an adhesive coating, and (7) a peelable protective layer. This produces a composition in which no undissolved components are present.

EXAMPLE 4a ] Figures 4, depicts a preferred embodiment of the transdermal dosage form of the invention comprising a (1) patch, (2) an aversive agent release controlling means, (3) an aversive agent reservoir, wherein the skin distal surface of the aversive agent reservoir is disposed on the aversive agent release controlling means, (4) an impermeable barrier layer, wherein the aversive agent reservoir is disposed on the skin distal surface of the barrier layer, (5) the cannabinoid agonist is a single phase polymeric composition in which the cannabinoid agonist and all other components are present at concentrations no greater than, and probably less than, their saturation concentrations in the cannabinoid agonist reservoir, disposed on the skin proximal surface of the barrier layer, wherein the (6) skin contacting surface of the cannabinoid agonist reservoir may be formulated with (9) an adhesive coating, and (7) a peelable protective layer. This produces a composition in which no undissolved components are present. The dosage form of the invention further comprises (8) a cannabinoid agonist rate controlling means - disposed on the skin contacting surface of the cannabinoid agonist reservoir wherein at least the skin contacting surface of the cannabinoid agonist rate controlling means is adhesive.

EXAMPLE 4b [00483] Figures 5, depicts a preferred embodiment of the transdermal dosage form of the invention comprising a (1) patch, (2) an aversive agent release controlling means, (3) an aversive agent reservoir, wherein the skin distal surface of the aversive agent reservoir is disposed on the aversive agent release controlling means, (4) an impermeable barrier layer, wherein the aversive agent reservoir is disposed on the skin distal surface of the barrier layer, (a pouch formed from the impermeable barrier layer (5) a cannabinoid agonist reservoir, (6) a cannabinoid agonist controlling means, (7) an amine resistant contact adhesive layer, covered by a (8) a peelable protective layer. The impermeable barrier layer is configured to provide a central volume which contains an cannabinoid agonist reservoir in the form of a gel having dissolved and suspended cannabinoid agonist therein. Although preferred embodiments of this invention utilize an amine resistant in-line adhesive as shown in Figure 5, other means for maintaining the system on the skin can be employed. Such means include a peripheral ring of adhesive outside the path of cannabinoid agonist from the system to the skin, in which case the adhesive need not be amine resistant. The use of adhesive overlays or other fastening means such as buckles, belts, and elastic arm bands is also contemplated.

EXAMPLE 5

Methods of Manufacture

[00484] The transdermal dosage forms can be manufatured using methods well known in the art. The cannabinoid agonist reservoir and the aversive agent reservoir are manufactured according to known methods, as illustrated by non- limiting examples herein.

[00485] Aversive Agent Reservoir: The aversive agent reservoir can be formed by dry blending an aversive agent, preferably a salified aversive agent, with a polymeric material, preferable a thermoformable material, at high shear and temperature using equipment such as sigma blade mixers or extruders, either batch-wise or continuously. The extrudate is calendared to the desired thickness between release liners, followed by lamination at elevated temperature to a barrier film and/or a cannabinoid agonist rate controlling means.

[00486] In the case of a semi-continuous process, a polymeric material (e.g., ethylene-vinyl acetate copolymer (28 wt % VA)) is added to one feeder hopper of a continuous co-kneader or twin screw extruder (Coperion Buss Rneader, Stuttgart, Germany) at a rate of about 50 pounds per hour. A aversive agent, preferably a salified aversive agent is added to a second hopper at a rate of 58.7 pounds per hour. The extruder is operated to produce extrudate at a constant rate of approximately one pound per minute. After exiting from the extruder, the polymer-drug blend is calendared to a desired thickness (about 0.03 mm (1.2 mil)) between barrier layer (e.g., polyester/EVA) and release liner (siliconized polyester film). The trilaminate structure is wound on take-up rolls for further processing.

[00487] Parameters such as aversive agent loading, aversive agent reservoir thickness, membrane selection for the cannabinoid agonist rate controlling means, and surfactant modification of the cannabinoid agonist rate controlling means can be varied to achieve the targeted release rate of aversive agent to cannabinoid agonist for a variety of abuse circumstances. In preferred embodiments, surfactants are coated onto membrane materials forming the cannabinoid agonist rate controlling means using techniques such as dip- coating, gravure coating, and the like.

[00488] Cannabinoid Agonist Reservoir: The transdermal dosage forms are manufactured according to known methodology. A solution of the polymeric cannabinoid agonist reservoir material, as described above, is added to a double planetary mixer, followed by addition of desired amounts of the cannabinoid agonist, preferably in insalified form and optionally, a permeation enhancer. Preferably, the polymeric cannabinoid agonist reservoir material is an adhesive polymer, which is solubilized in an organic solvent, e.g., ethanol, ethyl acetate, hexane, and the like. The mixer is then closed and activated for a period of time to achieve acceptable uniformity of the ingredients. The mixer is attached by means of connectors to a suitable casting die located at one end of a casting/film drying line. The mixer is pressurized using nitrogen to feed solution to the casting die. Solution is cast as a wet film onto a moving siliconized polyester web. The web is drawn through the lines and a series of ovens are used to evaporate the casting solvent to acceptable residual limits. The dried cannabinoid agonist reservoir film is then laminated to a selected barrier and the laminate is wound onto the take-up rolls. In another process, the cannabinoid agonist reservoir can be formed using dry-blending and thermal film-forming using equipment known in the art. Preferably, the materials are dry blended and extruded using a slot die followed by calendaring to an appropriate thickness. Parameters such as cannabinoid agonist loading, cannabinoid agonist reservoir thickness, cannabinoid agonist selection, material selections and manufacturing process can be varied for preparing cannabinoid agonist reservoirs of the current invention. [00489] Transdermal Dosage Form: In subsequent operations, the transdermal agonist reservoir containing intermediate and the aversive agent reservoir containing intermediate are laminated and the individual transdermal dosage forms are die-cut, separated and unit-packaged using suitable pouchstock. The aversive agent reservoir containing intermediate may be laminated immediately after drying the cannabinoid agonist reservoir containing intermediate. Transdermal dosage forms are cartoned using conventional equipment.

EXAMPLE 6a

[00490] Monolithic transdermal cannabinoid agonist reservoirs according to

Figure 1 may be prepared containing 1.5 mg/cm² of cannabinoid agonist base. A polacrylate adhesive (National Starch 87-2287, 100 g) is solubilized in a solvent (ethyl acetate, 128 mL). Cannabinoid agonist base is added to the polacrylate adhesive solution in amounts sufficient to generate a mixture containing approximately 4 wt % of cannabinoid agonist in the adhesive solution and stirred to dissolve. The solution is cast on to a peelable protective liner such as a siliconized polyester film, and the solvent is evaporated to provide a 0.05 mm (2 mil) thick reservoir layer.

[00491] Similarly, monolithic transdermal cannabinoid agonist reservoirs are prepared using the polacrylate adhesive (National Starch 87-4287, 100 g), as described above.

EXAMPLE 6b

[00492] Monolithic transdermal cannabinoid agonist reservoirs according to

Figure 1 may be prepared containing 3 mg/cm² of cannabinoid agonist base. A polacrylate adhesive (National Starch 87-2287, 200 g) is solubilized in a solvent (ethyl acetate, 250 mL). Cannabinoid agonist base is added to the polacrylate adhesive solution in amounts sufficient to generate a mixture containing approximately 4 wt % of cannabinoid agonist in the adhesive solution and stirred to dissolve. The solution is cast on to a peelable protective liner such as a siliconized polyester film, and the solvent is evaporated to provide a 0.05 mm (2 mil) thick reservoir layer.

[00493] Similarly, monolithic transdermal cannabinoid agonist reservoirs are prepared using the polacrylate adhesive (National Starch 87-4287, 200 g), as described above.

EXAMPLE 6c

[00494] Monolithic transdermal cannabinoid agonist reservoirs according to

Figure 1 may be prepared containing 4.5 mg/cm² of cannabinoid agonist base. A polacrylate adhesive (National Starch 87-2287, 300 g) is solubilized in a solvent (ethyl acetate, 375 mL). Cannabinoid agonist base is added to the polacrylate adhesive solution in amounts sufficient to generate a mixture containing approximately 4 wt % of cannabinoid agonist in the adhesive solution and stirred to dissolve. The solution is cast on to a peelable protective liner such as a siliconized polyester film, and the solvent is evaporated to provide a 0.05 mm (2 mil) thick reservoir layer.

[00495] Similarly, monolithic transdermal cannabinoid agonist reservoirs are prepared using the polacrylate adhesive (National Starch 87-4287, 300 g), as described above. EXAMPLE 7

[00496] Monolithic transdermal cannabinoid agonist reservoirs are prepared as described in Example 6a, Example Ib and Example 6c, with the following exceptions. Materials are dry blended in the absence of ethyl acetate, and extruded using a slot die followed by calendaring to an appropriate thickness.

EXAMPLE 8

[00497] Monolithic transdermal cannabinoid agonist reservoirs according to

Figure 1 are prepared as follows. A polacrylate adhesive (National Starch 87- 2287, 500 g) and glyceryl monolaurate (GML, 10 g) is dissolved in a solvent (ethyl acetate, 640 mL). Cannabinoid agonist base is added to the polacrylate adhesive solution in amounts sufficient to generate a mixture containing approximately 4 wt % of cannabinoid agonist in the adhesive solution and stirred to dissolve. The solution is cast on to a peelable protective liner such as a siliconized polyester film and the solvent is evaporated to provide a 0.045 mm (1.8 mil) thick reservoir layer. The transdermal dosage form contains approximately 0.35 mg/cm² of cannabinoid agonist base.

[00498] Similarly, monolithic transdermal cannabinoid agonist reservoirs are prepared using the polacrylate adhesive (National Starch 87-4287, 100 g), as described above.

EXAMPLE 8a

[00499] Monolithic transdermal cannabinoid agonist reservoirs according to

Figure 1 are prepared as follows. A polacrylate adhesive (National Starch 87- 2287, 500 g) and glyceryl monolaurate (GML, 10 g) is dissolved in a solvent (ethyl acetate, 640 mL). Cannabinoid agonist base is added to the polacrylate adhesive solution in amounts sufficient to generate a mixture containing approximately 8 wt % of cannabinoid agonist in the adhesive solution and stirred to dissolve. The solution is cast on to a peelable protective liner such as a siliconized polyester film and the solvent is evaporated to provide a 0.045 mm (1.8 mil) thick reservoir layer. The transdermal dosage form contains approximately 0.35 mg/cm² of cannabinoid agonist base. [00500] Similarly, monolithic transdermal cannabinoid agonist reservoirs are prepared using the polacrylate adhesive (National Starch 87-4287, 100 g), as described above.

EXAMPLE 9

[00501] Monolithic transdermal cannabinoid agonist reservoirs as described in

Example 8a and Example 8b, with the following exceptions. Materials are dry blended, in the absence of ethyl acetate, and extruded using a slot die followed by calendaring to an appropriate thickness.

EXAMPLE 10

[00502] Monolithic transdermal cannabinoid agonist reservoirs are prepared comprising respectively, 0.25, 0.5, 0.75, 1.0, 2.0, 3.0, 6.0, 10.0 and 15.0 mg each of cannabinoid agonist base, per 2.54 cm², in a polacrylate adhesive (National Starch 87-4287, as described in Example 6a, Example 6b and Example 6c, above.

[00503] Similarly, monolithic transdermal cannabinoid agonist reservoirs are prepared using the polacrylate adhesive (National Starch 87-2287, 100 g), as described above.

EXAMPLE Il

[00504] Monolithic transdermal cannabinoid agonist reservoirs are prepared containing 0.25, 0.5, 0.75, 1.0, 2.0, 3.0, 6.0, 10.0 and 15.0 mg each of cannabinoid agonist base, and permeation enhancers (1 to 6 mg) comprising lauryl pyroglutamate, glycerol monolaurate, glycerol monocaprylate and glycerol monocaproate, respectively per 2.54 cm² as described in Example 10.

EXAMPLE 12

[00505] The transdermal cannabinoid agonist reservoir described above in

Examples 6 to 11 is laminated to the PET face of the PET/EVA barrier layer (for example as depicted in Figure 1) to provide a transdermal cannabinoid agonist reservoir containing intermediate.

EXAMPLE 13

[00506] The transdermal cannabinoid agonist reservoir described above in

Examples 6 to 11 is coated with an adhesive coating followed by lamination to the PET face of the PET/EVA barrier layer (for example as depicted in Figure 3) to provide a transdermal cannabinoid agonist reservoir containing intermediate.

EXAMPLE 14

[00507] The transdermal cannabinoid agonist reservoir described above in

Examples 6 to 11 is laminated to a cannabinoid agonist rate controlling membrane followed by lamination to the PET face of the PET/EVA barrier layer (for example as depicted in Figure 2) to provide a transdermal cannabinoid agonist reservoir containing intermediate.

EXAMPLE 15

[00508] The transdermal cannabinoid agonist reservoir described above in

Examples 6 to 11 is laminated to a cannabinoid agonist rate controlling membrane. The skin proximate surface of the cannabinoid agonist rate controlling membrane is coated with an adhesive coating followed by lamination to the PET face of the PET/EVA barrier layer (for example as depicted in Figure 4) to provide a transdermal cannabinoid agonist reservoir containing intermediate.

EXAMPLE 16

[00509] Aversive agent reservoir containing intermediates are prepared as follows. A thermoforrnable polymer (460 g), such as Engage™ ethylene- octene copolymer, (DuPont-Dow Elastomers, Midland, Mich.), is placed within the bowl of a high torque blender. The bowl is heated (150°C) and the polymer pellets are blended until the polymer pellets are sufficiently masticated to provide a molten mass (10 minutes). The aversive agent (540 g) is added to the mixing bowl, and the mixture is blended for about 30 minutes. The polymer melt is emptied from the blending bowl and extruded between two moving webs: an upper layer of 0.05 mm (2 mil) polyester/EVA film (EVA side toward the melt) and a lower layer of 0.075 mm (3 mil) siliconized polyester film. The three-layer film structure is passed through calendar rolls to size the aversive agent reservoir disposed on the barrier layer to about 0.025 85

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mm (1 mil) thickness. The moving web is taken up in roll form at the end of the extrusion line.

[00510] In a second pass through the line, the siliconized interleaving is removed and a microporous polyethylene film (SOLUPOR™™, DSM Solutech, Heerlan, the Netherlands) is heat laminated to the exposed aversive agent reservoir using a calendar. The microporous membrane provides the aversive agent release controlling means for the final transdermal dosage form. The resulting structure is taken up in roll form as an intermediate product comprising the aversive agent reservoir disposed on the aversive agent release controlling means or layer.

[00511] The aversive agent reservoir containing intermediate described above is laminated to the cannabinoid agonist-containing adhesive film exiting the drying ovens described in Examples 6 to 11 above, providing a six-layer film laminate: peelable liner, cannabinoid agonist reservoir; optionally containing a rate control membrane, barrier layer (polyester, EVA), aversive agent reservoir (polyethyleneoctene-aversive agent) and the aversive agent release controlling means (microporous polyethylene). The total film thickness is about 0.2 mm (8 mil).

[00512] The six-ply film is die-cut to individual transdermal dosage forms corresponding to cannabinoid agonist delivery areas of 0.5 to about 250 cm²; preferably about 1 to about 150 cm², more preferably 2 to about 100 cm², even more preferably about 4 to about 50 cm² or about 10 to about 20 cm².

EXAMPLE 17

[00513] Aversive agent reservoir containing intermediates are prepared as follows. A thermoformable polymer (460 g), such as Engage ethylene-octene copolymer, (DuPont-Dow Elastomers, Midland, Mich.), is placed within the bowl of a high torque blender. The bowl is heated (150⁰C) and the polymer pellets are blended until the polymer pellets are sufficiently masticated to provide a molten mass (10 minutes). The aversive agent (540 g) is added to the mixing bowl, and the mixture is blended for about 30 minutes. The polymer melt is emptied from the blending bowl and extruded between two moving webs: an upper layer of 0.075 mm (3 mil) fluoropolymer release liner film (fluorocarbon diacrylate coated polyester film), and a lower layer of 0.075 mm (3 mil) siliconized polyester film. The three-layer film structure is passed through calendar rolls to size the aversive agent reservoir disposed on the barrier layer to about 0.025 mm (1 mil) thickness. The moving web is taken up in roll form at the end of the extrusion line.

[00514J In a second pass through the line, one of the siliconized interleaving is removed and a microporous polyethylene film (SOLUPOR™, Solutech, Denmark) is heat laminated to the exposed aversive agent reservoir using a calendar. The microporous membrane provides the aversive agent release controlling means for the final transdermal dosage form. The resulting structure is taken up in roll form as an intermediate product comprising the aversive agent reservoir.

[00515] In the third pass through the line, the siliconized interleaving is removed and an adhesive layer, is laminated to the exposed aversive agent reservoir using a laminator, providing a four layer film laminate: adhesive layer, barrier layer, aversive agent reservoir (polyethyleneoctene-aversive agent) and aversive agent release controlling means (microporous polyethylene). The four ply film is die cut to individual units corresponding to form fill seal (FFS) system areas of 10, 20, 30, 40, 80, 100, and 225 cm².

[00516] Cannabinoid agonist reservoir containing intermediates are prepared as follows. Cannabinoid agonist base (1.4 Kg) is slurried in purified water (5 L, USP) in a vessel. Ethanol (25 Kg, USP) and water (65 L, USP) are mixed in a 40 gallon pressure vessel, the solution is stirred, and allowed to cool to room temperature. The cannabinoid agonist slurry is added to the ethanol solution, using water (4 L, USP) to rinse the vessel quantitatively. In a separate vessel, hydroxyethyl cellulose (2 Kg, QP 100,000 [HEC], NF) is slurried with water (4 L). The hydroxyethyl cellulose slurry is added with mixing to the cannabinoid agonist mixture in the 40 gallon mixer. The remaining hydroxyethyl cellulose is rinsed using water (2 L) and added to the large mixer 85

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vessel. The vessel is immediately stirred at 100 cycles/minute until the cannabinoid agonist reservoir mixtures gels.

[00517] The pressure vessel containing the cannabinoid agonist gel is attached to a multi-nozzle gel placement array mounted on a Bodolay Form-Fill- Sealing (FFS) machine. A laminate composed of the protective liner (peelable PET-silicone film), adhesive layer (silicone adhesive film, 1.57 mil), and cannabinoid agonist release rate controlling means (an EVA film (9% VA), 2 mil) is laid out onto the equipment used to build the form fill seal systems. The cannabinoid agonist reservoir is metered onto the protective liner/adhesive layer/cannabinoid agonist release rate controlling means such that the gel contacted the cannabinoid agonist release rate controlling means. The barrier layer (PET/EVA) is laid out such that it covered the gel. The EVA component of the barrier layer contacted the cannabinoid agonist release controlling membrane. The perimeter of the construction is heat laminated, forming the cannabinoid agonist portion of the system forming peripherally sealed systems with 245 mg of reservoir gel per 10 cm² system active drug release area. The film is die cut to individual units corresponding to cannabinoid agonist delivery areas of 10, 20, 30, 40, 80, 100, and 225 cm² to form the cannabinoid agonist reservoir containing intermediate.

[00518] The adhesive surface of the aversive agent reservoir containing intermediate is laminated onto the barrier layer of the cannabinoid agonist reservoir containing intermediate to form the transdermal dosage form having a form fill seal (FFS) cannabinoid agonist reservoir.

EXAMPLE 18

[00519] The aversive agent reservoir containing intermediate described in

Example 16 is laminated to the cannabinoid agonist reservoir described in Examples 14 and 15 above, providing a eight-layer film laminate: peelable liner, adhesive layer, cannabinoid agonist rate control membrane, cannabinoid agonist reservoir (cannabinoid agonist-adhesive layer), barrier layer (polyester, EVA), aversive agent reservoir (polyethyleneoctene-aversive agent) and aversive agent release controlling means (microporous 85

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polyethylene). The eight-ply film is die-cut to individual transdermal dosage forms corresponding to the cannabinoid agonist delivery areas.

EXAMPLE 19

[00520] A thermoformable polymer, polyolefϊn elastomer (460 g), such as

Engagee ethylene-octene copolymer, (DuPont-Dow Elastomers, Midland, Mich.), is melt blended (88-10O⁰C) with aversive agent (690 g) for about 1.5 to 2.5 hours. The mixture is extruded between differential release liners, calendared to a thickness of 0.025 mm (1 mil) to form an aversive agent reservoir. The aversive agent reservoir is laminated to the PE face of a PET- PE barrier film (Mediflex 1203, Mylan, St. Albans, Vt.), at 0-100⁰C, 71 psig, 4 ft/min. The remaining release liner is removed and the barrier layers are laminated at 60⁰C, 38 psig, 4 ft/min. The aversive agent release rate controlling means, e.g., SOLUPOR™ 10P05A, Pluronic-modified SOLUPOR™, Celgard microporous polypropylene (Grades 3401 and 3501), spun-bonded polypropylene, and polyethylene film are laminated to the aversive agent reservoir between 60 and 90 psig, 4 ft/min.

[00521] The PET face of the aversive agent reservoir containing intermediate described above is laminated to the cannabinoid agonist-containing adhesive film exiting the drying ovens described in Examples 6 to 11 above, at 24 ft/min, 25°C, 70 psig. The liner is replaced with a slit release liner to enable easy system removal from the liner, and die cut to the desired dimensions.

EXAMPLE 20

[00522] A thermoformable polymer, such as Elvax™ 210 ethylene-vinyl acetate copolymer (1.61 Kg, 28% vinyl acetate, E. I. DuPont de Nemours, Wilmington, Del.), is melt blended (77-88°C) with aversive agent (1.89 Kg) for about 1.5 to 2.5 hours. The mixture is extruded between differential release liners, and calendared (0.031 mm) to form an aversive agent reservoir. The aversive agent reservoir is laminated to the EVA face of a PET-EVA barrier film (Scotchpac 9733, 3M, Minneapolis, Minn.), at 80-85⁰C, 70-90 psig, 4-19 ft/min. The remaining release liner is removed and the aversive agent release rate controlling means, microporous polyethylene (e.g., SOLUPOR™ 10P05A, or Pluronic-modified SOLUPOR™,) is laminated to the aversive agent reservoir between 80-85°C, 50-54 psig, 4-24 fVmin.

[00523] The PET face of the aversive agent reservoir containing intermediate described above is laminated to the cannabinoid agonist-containing adhesive film exiting the drying ovens described in Examples 6 tol l above, at 24 ft/min, 25⁰C, 70 psig. The liner is replaced with a slit release liner to enable easy system removal from the liner, and die cut to individual transdermal dosage forms corresponding to cannabinoid agonist delivery areas.

EXAMPLE 21

[00524] The aversive agent reservoir containing intermediate described in the

Examples above are prepared with the following exceptions. Aversive agent release controlling means are prepared as follows. Pluronic Fl 08NF solutions (0.5, 1.0, and 2.0 wt %) are prepared in a solvent (3% water: 97% ethanol). The SOLUPOR™ material 10P05A is coated with the Pluronic solutions and dried at room temperature overnight, providing coating weights of 35 μg/cm², 50 μg/cm², and 90 μg/cm² for the 0.5, 1.0, and 2.0 wt % Pluronic solutions, respectively. These aversive agent release controlling means, i.e. surfactant- modified membranes are laminated to the aversive agent reservoir as described in the previous examples.

EXAMPLE 22

[00525] The aversive agent reservoir containing intermediate described in the

Examples above are prepared with the following exceptions. Aversive agent release controlling means (a salt-filled membrane which forms pores in situ upon exposure to water) are prepared as follows. Ethylene-vinyl acetate copolymer (EVA) with 28% vinyl acetate monomer (Elvax 210, E. I. DuPont de Nemours, Wilmington, Del.) is added to the hopper of a cryogrinder (10 Kg). The cryogrinder is then filled to the mark with liquid nitrogen and the top is sealed. The grinder is activated for about 10 minutes and the polymer pellets are comminuted to an average particle size of about 0.05 mm, and dried (using a stream of warm air) to obtain the ground polymer. 100526] Powdered sodium chloride, with approximately 2% magnesium sulfate, (National Formulary, about 10 Kg) is added to the hopper of a V- blender. The ground polymer (10 Kg) is then added to the hopper. The hopper is activated to rotate for approximately 15 minutes, to obtain a powder blend that is a consistent mixture of polymer and sodium chloride.

[00527] The powder blend is continuously fed to the addition-port of a single- screw extruder, the heating sections of which are pre-warmed to approximately 110⁰C At the end of the extruder, a flex-nip die is attached which has been set to an exit thickness of about 0.25 mm (10 mil). The extruder is operated to produce film that is fed to the rolls of a three-roll calendar. The roll-nip is set to produce a continuous film exiting the calendar that is about 0.03 mm (1.5 mil) thick. This film is wound on take-up rolls for further manufacturing use.

[00528] These aversive agent release controlling means, i.e. salt-containing film are laminated to the aversive agent reservoir as described in the previous examples. Final systems are die-cut and packaged. Upon immersion of such systems in water, the sodium chloride layer rapidly desorbs the water-soluble salt. The resulting film forms an in situ microporous membrane that provides a release rate ratio of the aversive agent sufficient to deter abuse.

EXAMPLE 23

[00529] The aversive agent reservoir containing intermediates as described in

Examples 16 to 22 are manufactured using an alternative continuous process. A gravimetric or volumetric feeder is used to feed thermoplastic polymer into a twin screw extruder, reciprocating single screw extruder ("co-kneader") or continuous compounder. The aversive agent is fed in a like manner into the melted polymer and mixed, and extruded into a calendar into the intermediate aversive agent reservoir laminate. Alternatively, the mixture is extruded into a strand or rod, cut into pellets (approximately 5-10 mm) and subsequently extruded in a second step.

EXAMPLE 24 Ϊ00530] The aversive agent intermediate containing reservoir described in

Examples 16 to 22 are prepared with the following exception. The intermediate aversive agent reservoir is extrusion coated directly to the EVA face of the barrier layer on a chill roll and the aversive agent rate controlling layer is laminated in the same process step.

[00531] The included examples are illustrative but not limiting of the methods and composition of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered and obvious to those skilled in the art are within the spirit and scope of the invention.

[00532] A wide variety of materials can be used for preparing the dosage form according to this invention. This invention therefore contemplates the use of materials other than those specifically disclosed herein, including those which may hereafter become known to the art to be capable of performing the necessary functions.

[00533] Other suitable substantially non-releasable forms of aversive agents

(i.e., sequestered agent) selected from the group comprising cannabinoid antagonists, and opioid antagonists, as defined in this invention may also^' be prepared by modification of the examples herein and by use of material other than those specifically disclosed herein, including those which may hereafter become known to the art to be capable of performing the necessary functions.

[00534] Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered and obvious to those skilled in the art are within the spirit and scope of the invention.

[00535] A wide variety of methods known in the art for the preparation of immediate release and controlled release dosage forms may be incorporated into the invention.

Claims

WHAT IS CLAIMED IS:

1. A transdermal dosage form for application to the skin comprising (a) a cannabinoid agonist; (b) an aversive agent which is sequestered in the intact dosage form but being releasable upon tampering of said dosage form, the aversive agent when released upon tampering of said dosage form at least partially blocking the effect of the cannabinoid agonist and/or at least partially blocking the effect of another abusable drug not included in the dosage form.

2. A transdermal cannabinoid agonist dosage form for application to the skin having a reduced potential for abuse, misuse, tampering, toxicity upon tampering and overdose, comprising: (a) a cannabinoid agonist reservoir comprising a cannabinoid agonist releasable to the skin; (b) an aversive agent reservoir comprising an aversive agent; (c) a barrier layer, said barrier layer separating said an aversive agent reservoir from said cannabinoid agonist reservoir, said barrier layer being substantially impermeable to said cannabinoid agonist and to said aversive agent, wherein the dosage form (i) substantially prevents release of the aversive agent from the dosage form upon application to the skin of a human patient for the intended dosing period of up to 1 day; or up to 3 days; or up to 7 days; or up to 10 days; or up to 30 days; and (ii) provides release of the aversive agent at a rate sufficient to at least partially block the effect of the cannabinoid agonist and/or at least partially block the effect of another abusable drug not included in the dosage form when the dosage form is subject to abuse, misuse, tampering or overdose.

3. A transdermal cannabinoid agonist dosage form for application to the skin having a reduced potential for abuse, misuse, tampering, toxicity upon tampering and overdose, comprising a mixture of: (a) a cannabinoid agonist releasable to the skin; and (b) an aversive agent substantially non-releasable to the skin, wherein the dosage form (i) substantially prevents release of the aversive agent from the dosage form upon application to the skin of a human patient for the intended dosing period of up to 1 day; or up to 3 days; or up to 7 days; or up to 10 days; or up to 14 days; or up to 30 days; and (ii) provides release of the aversive agent at a rate sufficient to at least partially block the effect of the cannabinoid agonist and/or at least partially block the effect of another abusable drug not included in the dosage form when the dosage form is subject to abuse, misuse, tampering or overdose.

4. A transdermal cannabinoid agonist dosage form for application to the skin having a reduced potential for abuse, misuse, tampering, toxicity upon tampering and overdose, comprising a mixture of: (a) a cannabinoid agonist releasable to the skin; and (b) an opioid antagonist partially or substantially releasable to the skin, wherein said dosage form (i) substantially releases the cannabinoid agonist and partially or substantially releases the opioid antagonist from the dosage form upon securing or administering the dosage form to a human patient for the intended dosing period of up to 1 day; or up to 3 days; or up to 7 days; or up to 10 days; or up to 14 days; or up to 30 days; (ii) when secured intact to skin, provides release of the opioid antagonist sufficient to at least partially block the effect of any concurrently used opioid agonist and (iii) provides further release of the opioid antagonist when the dosage form is subject to abuse, misuse, tampering or overdose.

5. The dosage form of claims 1 to 4, where the abuse, misuse, tampering or overdose involves attempts to liberate the cannabinoid agonist from the dosage form other than by application to the skin as intended by the manufacturer or the prescribing physician.

6. The dosage form of claims 5, where the abuse, misuse, tampering or overdose involves attempts to liberate the cannabinoid agonist from the dosage form by use of mechanical, thermal and/or chemical means or energy to changes the physical properties of the dosage form.

7. The dosage form of claims 6, where the abuse, misuse, tampering or overdose involves substantial solvent immersion, solvent extraction, tearing, puncturing, aspirating, shearing, dissolution, heating, swallowing or combustion of the dosage, followed by systemic administration of the cannabinoid agonist or the dosage form contents by the sublingual, buccal, transmucosal, oral, rectal, parenteral, intranasal, dermal and/or inhalational routes.

8. The dosage form of claims 1 to 4, wherein the release rate of the cannabinoid agonist is greater following tampering than following securing the dosage form to the skin intact, said release rate measured by comparing the amount of cannabinoid agonist released from the dosage form for up to 24 hours as measured in- vitro via the dissolution of the dosage form in 900 mL of distilled water or 900 mL of 40% ethanol in distilled water using a USP Apparatus 5 (paddle over disk method) at 50 rpm at 32 ⁰C (the tampered dosage form) (USP 2005), versus the amount of cannabinoid agonist released from the intact dosage form into the body after securing the dosage form to the (depilated or shaven) skin of a human or animal for an identical amount of time up to 24 hours; said amount released after tampering quantified by subtracting the amount of cannabinoid agonist in the dosage form after said dissolution test from the amount of cannabinoid agonist in the dosage form at the start of said dissolution test; and said amount released from the intact dosage form quantified by subtracting the amount of cannabinoid agonist in the dosage form after said application to skin from the amount of cannabinoid agonist in the dosage form at the start of said skin application, said ratio of release after tampering versus intact application to skin greater than 1.5:1.

9. The dosage form of claims 1 to 4, wherein the release rate of the aversive agent is greater following tampering than following securing the dosage form to the skin intact, said release rate measured by comparing the amount of aversive agent released from the dosage form for up to 24 hours as measured in-vitro via the dissolution of the dosage form in 900 mL of distilled water or 900 mL of 40% ethanol in distilled water using a USP Apparatus 5 (paddle over disk method) at 50 rpm at 32 ⁰C (the tampered dosage form) (USP 2005), versus the amount of aversive agent released from the intact dosage form into the body after securing the dosage form to the (depilated or shaven) skin of a human or animal for an identical amount of time up to 24 hours; said amount released after tampering quantified by subtracting the amount of aversive agent in the dosage form after said dissolution test from the amount of aversive agent in the dosage form at the start of said dissolution test; and said amount released from the intact dosage form quantified by subtracting the amount of aversive agent in the dosage form after said application to skin from the amount of aversive agent in the dosage form at the start of said skin application, said ratio of release after tampering versus intact application to skin greater than 1.5:1.

10. The dosage form of claim 8 and 9, wherein the ratio of release after tampering versus intact application to skin is greater than 3:1; or greater than 5:1, or greater than 10:1, or greater than 30:1 or greater than 50:1, or greater than 70:1 or greater than 100:1, or greater than 500:1.

11. The dosage form of claims 1 to 4, wherein the release rate of the cannabinoid agonist is greater than the release rate of the aversive agent following securing the dosage form to the skin intact (untampered), said release rate measured by comparing the percent of cannabinoid agonist and the percent of aversive agent released from the intact dosage form into the body after securing the dosage form to the (depilated or shaven) skin of a human or animal for up to about 24 hours, or up to about 48 hours, or up to about 72 hours, or up to about 170 hours; said percent released from the intact dosage form quantified by subtracting the percent of cannabinoid agonist and aversive agent in the dosage form after said application to skin from 100% at the start of 85

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said skin application, said percent ratio of release of cannabinoid agonist to aversive agent greater than 1.5:1.

12. The dosage form of claims 1 to 4, wherein the release rate of the cannabinoid agonist is greater than the release rate of the aversive agent following securing the dosage form to the skin intact (untampered), said release rate measured by comparing the amount of cannabinoid agonist and the amount of aversive agent released from the intact dosage form into the body after securing the dosage form to the (depilated or shaven) skin of a human or animal for up to about 24 hours, or up to about 48 hours, or up to about 72 hours, or up to about 170 hours; said amount released from the intact dosage form quantified by measuring the area under the plasma concentration time curve (AUCo-t) over the duration of skin application for the cannabinoid agonist and the aversive agent, said ration of release of cannabinoid agonist to aversive agent greater than 1.5:1.

13. The dosage form of claim 11 and 12, wherein the percent ratio of release of cannabinoid agonist to aversive agent after intact application to skin is greater than 3:1; or greater than 5:1, or greater than 10:1, or greater than 30:1 or greater than 50:1, or greater than 70:1 or greater than 100:1, or greater than 500:1.

14. The dosage form of claims 1 to 4, where the aversive agent is selected from one or more cannabinoid antagonists, one or more opioid antagonists, or mixtures thereof.

15. The dosage form of claim 14, where the aversive agent is one or more cannabinoid antagonists.

16. The dosage form of claim 14, where the aversive agent is one or more opioid antagonists.

17. The dosage form of claim 2 further comprising an aversive agent release rate controlling means.

18. The dosage form of claim 17 wherein the aversive agent release rate controlling means is disposed on the skin distal surface of the aversive agent reservoir.

19. The dosage form of claim 17 wherein the aversive agent release rate controlling means is selected from a group consisting of a layer, a membrane, a film, a coating, a sheet, and a deposit on the aversive agent reservoir.

20. The dosage form of claim 18 wherein the aversive agent release rate controlling means is selected from a group consisting of a rate control layer, a rate control membrane, a porous membrane and a microporous membrane.

21. The dosage form of claim 2 wherein said cannabinoid agonist reservoir comprises an amount of dissolved cannabinoid agonist sufficient to provide a cannabinoid agonist induced therapeutic effect in a human patient for the intended dosing period of up to 1 day; or up to 3 days; or up to 7 days; or up to 10 days; or up to 30 days.

22. The dosage form of claim 21, wherein said cannabinoid agonist reservoir comprises a single phase formulation free of undissolved components.

23. The dosage form of claim 21 wherein the cannabinoid agonist reservoir is formed from an adhesive polymer.

24. The dosage form of claim 23 wherein said cannabinoid agonist reservoir comprises a polymer having a solubility for a cannabinoid agonist of about 0.01 wt % to about 70 wt %.

25. The dosage form of claim 21 wherein the cannabinoid agonist reservoir further comprises a permeation enhancer.

26. The dosage form of claim 21, wherein the cannabinoid agonist reservoir comprises a polymeric matrix comprising about 0.5 wt % to about 70 wt % of the cannabinoid agonist, and optionally a permeation enhancer. 2007/018585

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27. The dosage form of claim 2 comprising an aqueous gel comprising up to about 20 wt % of the cannabinoid agonist, up to about 50 wt % permeation enhancer, and 0.1-25% gelling agent.

28. The dosage form of claim 22 further comprising a cannabinoid agonist release rate controlling means disposed between the cannabinoid agonist reservoir and the skin, wherein said release rate controlling means is less permeable to the cannabinoid agonist than to the permeation enhancer.

29. The dosage form of claim 2 wherein said aversive agent reservoir is disposed adjacent the skin distal surface of the barrier layer and the cannabinoid agonist reservoir is disposed adjacent the skin proximal surface of the barrier layer.

30. The dosage form of claim 29 wherein said aversive agent reservoir comprises the aversive agent dispersed within a polymer.

31. The dosage form of claim 2 wherein (a) the aversive agent reservoir comprises the aversive agent dispersed in a polymer or a copolymer selected from the group consisting of polyolefin, polyethylene, polyoctene, polyvinyl acetate, polymethyl acrylate, polymethyl acrylate, polyethyl acrylate, polystyrene, polyethyleneoctene copolymers, ethylene-vinyl acetate copolymer (EVA), ethylenemethyl acrylate copolymers (EMA), ethylene-acrylic acid copolymer, and ethylene-ethylacrylate copolymer; (c) the barrier layer comprises a comprises a polyester laminated to a polymer selected from the group consisting of polyurethane, polyethylene and ethylene copolymers; and (d) the cannabinoid antagonist release rate controlling means is a microporous layer selected from the group consisting of microporous ultra high density polyethylene (UHDPE), microporous polypropylene, polyester capillary pore membrane, spun laced polyester, polypropylene and polyethylene.

32. The dosage form of claim 4 where the opioid antagonist is in a form partially or substantially permeable to the skin to which it is intended to be applied.

33. The dosage form of claim 4 where the dosage form comprises a releasing means through which said cannabinoid agonist and opioid antagonist are released to the skin and a reservoir comprising a mixture of said cannabinoid agonist and said opioid antagonist, the reservoir separated on the side proximal to the skin by said releasing means.

34. The dosage form of claim 4 wherein the dosage form has a means for maintaining the drug reservoir in a cannabinoid agonist and opioid antagonist releasing relationship to the skin.

35. The dosage form of claim 4 optionally comprising a membrane layer, said membrane being substantially permeable to said cannabinoid agonist and partially or substantially permeable to said opioid antagonist.

36. The dosage form of claims 1 to 4, where the at least partially blocked effect is a high, liking, pleasurable, euphoric, calming, anxiolytic, relaxing, analgesic, psychotomimetic, reinforcing, rewarding, mood altering, favorable psychic, toxic, and/or auditory and visual perceptual altering effect.

37. The dosage form of claims 1 to 4, where the at least partially blocked effect is the intended therapeutic effect of the cannabinoid agonist.

38. The dosage form of claims 1 to 4, where the at least partially blocked effect is pain relief.

39. The dosage form of claims 1 to 4, where the at least partially blocked effect is that of the cannabinoid agonist.

40. The dosage form of claims 1 to 4, where the other abusable drug is an opioid agonist which is used or abused concurrently or contemporaneously with the dosage form.

41. The dosage form of claims 1 to 4, where the at least partially blocked effect is that of the opioid agonist which is used or abused concurrently or contemporaneously with the dosage form.

42. The dosage form of claims 1 to 4, where the at least partially blocked effect results in the precipitation of physical or psychological withdrawal or precipitation of an abstinence syndrome to the cannabinoid agonist.

43. The dosage form of claims 1 to 4, where the at least partially blocked effect results in the precipitation of physical or psychological withdrawal or precipitation of an abstinence syndrome to the opioid agonist which is used or abused concurrently or contemporaneously with the dosage form.

44. The dosage form of any of claims 1 to 4, wherein the aversive agent is in the form of multiparticulates coated with a sequestering material.

45. The dosage form of any of claims 1 to 4, which comprises multiparticulates in the form of inert beads coated with the aversive agent and overcoated with a sequestering material.

46. The dosage form of any of claims 1 to 4, wherein the aversive agent is in the form of multiparticulates individually coated with a sequestering material which substantially prevents release of the aversive agent and is subsequently overcoated with the cannabinoid agonist.

47. The dosage form of any of claims 1 to 4 comprises one or more cannabinoid agonists in releasable or substantially releasable form, and one or more opioid antagonist in a non-releasable or substantially non- releasable form, when said dosage form is used as intended.

48. The dosage form of any of claims 1 to 4 comprises one or more cannabinoid agonists in releasable or substantially releasable form, and one or more cannabinoid antagonist in a non-releasable or substantially non-releasable form, when said dosage form is used as intended.

49. The dosage form of any of claims 1 to 4, comprises one or more cannabinoid agonists in releasable or substantially releasable form, and one or more cannabinoid antagonist plus one or more opioid antagonists, each in a non-releasable or substantially non-releasable form, when said dosage form is used as intended.

50. The dosage form of any of claims 1 to 4, wherein the amount of the cannabinoid agonist in the claimed cannabinoid composition is from about 10 ng to about 1O g.

51. The dosage form of any of claims 1 to 4, wherein the amount of the aversive agent in the claimed composition is from about 10 ng to about 1O g.

52. The dosage form of any of claims 1 to 4, wherein the amount of the cannabinoid antagonist in the claimed composition is from about 10 ng to about 1O g.

53. The dosage form of any of claims 1 to 4, wherein the amount of the opioid antagoist in the claimed composition is from about 10 ng to about 1O g.

54. The dosage form of any of claims 1 to 4, further comprising a non- cannabinoid therapeutically active agent in releasable or substantially releasable form.

55. The dosage form of any of claims 1 to 4, further comprising one or more abuse intervention agent(s) in sequestered, partially sequestered, unsequestered, non-releasable, partially releasable or releasable form.

56. The dosage form of claim 55, wherein the abuse intervention agent is sequestered.

57. The dosage form of claims 55, wherein the abuse intervention agent(s) is selected from the group consisting of laxatives, cutaneous vasodilators, headache producing agents, emetics, emetogenic compound, nausea producing compounds, bittering agents, drugs that cause burning on irritation when in contact with tissue or mucous membranes (e.g., naso-mucosal irritants, oro-mucosal irritants, respiratory irritants), tissue irritants, gastrointestinal irritants, drugs that precipitate withdrawal effects, tissue dyes, lakes and colorants, T/US2007/018585

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beverage dyes, lakes and colorants, non-tissue staining beverage dyes, lakes and colorants (i.e, that do not stain or discolor the skin upon ingestion), fecal discolorants, urine discolorants, malodorous agents, opioid antagonists, benzodiazepine antagonists (e.g., flumazenil), and mixtures thereof.

58. The dosage form of any of claims 55 to 57, wherein the abuse intervention agent comprises a non-toxic dye to deter surreptitious attempts at intoxication of another subject.

59. The dosage form of any of claims 55 to 57, wherein the abuse intervention agent comprises a non-toxic bittering agent.

60. The dosage form of any of claims 55 to 57, wherein the abuse intervention agent comprises a non-toxic nasal irritant to deter oral or nasal ingestion of the dosage form.

61. The dosage form of claims 55 to 57, wherein the abuse intervention agent is one or more bittering agents selected from the group comprising T2R or TAS2R receptor agonists, phenylthiourea (phenylthiocarb amide), natural, artificial and synthetic flavor oils, flavoring aromatics, flavoring oils, oleoresins, spearmint oil, peppermint oil, eucalyptus oil, oil of nutmeg, allspice, mace, oil of bitter almonds, menthol, citrus oils including lemon, orange, lime, grapefruit, and fruit essences, sucrose derivatives, sucrose octaacetate, chlorosucrose derivatives, quinine, denatonium, denatonium saccharide and denatonium benzoate.

62. The dosage form of claims 55 to 57, wherein the abuse intervention agent is one or more naso-mucosal, oro-mucosal, respiratory or tissue irritants selected from the group comprising transient receptor potential vanilloid 1 agonists, resiniferanoids, capsaicinoids, phorboid vanilloids, terpenoid 1,4-unsaturated dialdehydes, capsaicin, capsaicin analogs, resiniferatoxin, olvanil, piperine, zingerone, anandamide, 12- and 15-(S)-hydroperoxy-eicosatetraenoic acids, 5 --and 15-(S)- hydroxyeicosatetraenoic acids, phorbol 12-phenylacetate 13-acetate 7 018585

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20-homovanillate, 2 phorbol 12,13-didecanoate 20-homovanillate, leukotriene B(4), tinyatoxin, heptanoylisobutylamide, N-(3-acyloxy-2- benzylρropyl)-N'-dihydroxytetrahydrobenzazepine, tetrahydroisoquinoline thiourea analogs, heptanoyl guaiacylamide, isobutylamides, guaiacylamides, dihydrocapsaicin, homovanillyl octylester, nonanoyl vanillylamide, formic acid, acetic acid, propionic acidy, butyric acid, valeric acid, caproic acid, caprillic acid, capric acid, oxalic acid, malonic acid, succicnic acid, glu-"taric acid, adipic acid, maleic acid, fumaric acid, citric acid, sodium lauryl sulfate, poloxamer, sorbitan monoesters, glyceryl monooleates, niacin, mustard, allyl isothiocyaanate and p-hydroxybenzyl isothiocyanate and acetylsalicylic acid.

63. The dosage form of any of claims 55 to 57, wherein the abuse intervention agent is one or more emetogenic or nausea producing agents selected from the group comprising zinc and pharmaceutically acceptable salts thereof, dopamine agonists, apomorphine, ipecac, ipecacuanha, emetine, methylcephaeline, cephaeline, psychotrine, O- rnethylpsychotrine, ammonium chloride, potassium chloride, magnesium sulfate, ferrous gluconate, ferrous sulfate, aloin, algarot or antimonious oxychloride, antimony trichloride, folate, folic acid, niacin and nicotinamide.

64. The dosage form of any of claims 55 to 57, wherein the abuse intervention agent is one or more cutaneous vasodilators selected from the group comprising niacin, nicotinuric acid, beta-hydroxybutyrate and nicotinic receptor agonists, including agonists at nicotinic receptor HM74A and nicotinic receptor GPRl 09 A.

65. The dosage form of any of claims 55 to 57, wherein the abuse intervention agent is one or more tissue dyes, lakes or colorants, or beverage dyes, lakes or colorants, or a beverage dye, lake and colorant that does not stain or discolor the skin upon ingestion, or a fecal discolorant or a urine discolorant. 18585

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66. The dosage form of any of claims 1 to 4, wherein the cannabinoid agonist is selected from the group consisting of THC (delta-9- tetrahydrocannabinol), nabilone, dronabinol, cannabidiol, cannabinol, cannabichromene, cannabigerol, cannabigerol, anandamide, (R)- methanandamide, 2-arachidonoylglycerol, HU210, desacetyllevonantradol, CP55940, CP55244, URB602, or W1N55212- 2.

67. The dosage form of any of claims 1 to 4, wherein the cannabinoid agonist is selected from the group consisting of 9-THC propyl analog, endocannabinoids, cannabinoid terpenoids, cannabinoid flavonoids, inhibitors of cannabinoid agonist metabolism, inhibitors of monoacylglycerol lipase, cannabidiol propyl analogues, cannabichromene propyl analogues, THC-like ABC tricyclic cannabinoid analogues, synthetic AC bicyclic cannabinoid analogues, synthetic ACD tricyclic cannabinoid analogues or aminoalkylindole compounds.

68. The dosage form of any of claims 1-4, 66 and 67, wherein the cannabinoid agonist is in the form of a pharmaceutically acceptable salt, prodrug, ester, analog, derivative, solvate, complex, polymorph, hydrate, racemate or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof.

69. The dosage form of any of claims 1-4, 66 and 67, wherein the cannabinoid agonist is CBi receptor selective.

70. The dosage form of any of claims 1-4, 66 and 67, wherein the cannabinoid agonist is CB₂ receptor selective.

71. The dosage form of any of claims 1-4, 66 and 67, wherein the cannabinoid agonist has mixed CBi receptor and CB2 receptor activity.

72. The dosage form of any of claims 1-4, 66 and 67, wherein the cannabinoid agonist is a non-CBj and non-CB₂ cannabinoid.

73. The dosage form of any of claims 1-4, 66 and 67, wherein the cannabinoid agonist is an anandamide amidase inhibitor.

74. The dosage form of any of claims 1-4, 66 and 67, wherein the cannabinoid agonist is an inhibitor of CB₁, CB₂ or HOn-CB₁AiOn-CB₂ cannabinoid agonist metabolism or reuptake.

75. The dosage form of any of claims 1 to 4, wherein the cannabinoid antagonist is selected from the group consisting of SR 141716A [Rimonabant or N-piperidino-5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methyl-3-pyrazole-carboxamide]), AM251, AM 281 ([N-morpholin-4-yl]-5-[2,4-yl]-5-[2,4-dichlorophenyl]-4-methyl-lH- pyrazole-3-carboxamide), AM630, SR 144528 ([N-[(lS)-endo-l,3,3- trimethylbicyclo(2.2.1)heptan-2-yl]5-(4-chloro-3-methyl-phenyl)-l-(4- methylbenzyl)pyrazole-3-carboxamide]), 5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-3-hexyl-lh-l,2,4-triazole, 8-chloro-l-(2',4'- dichlorophenyl)-N-piperidin- 1 -yl- 1 ,4,5 ,6- tetrahydrobenzo[6,7]cyclohepta[ 1 ,2-c]pyrazole-3-carboxamide 4a, SR141716, SR144528, 8-chloro-l-(2\4'-dichlorophenyl)-N-piperidm- l-yl-l^^jβ-tetrahydrobenzofβ^Jcycloheptatl^-clpyrazole-S- carboxamide, 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-3-hexyl-lh- 1,2,4-triazole or AM630, HU-308, HU-210.

76. The dosage form of any of claims 1 to 4, wherein the cannabinoid antagonist is selected from the group consisting of pyrazole class cannabinoid antagonists (e.g., SR141716 and SR144528), aminoalkylindole class cannabinoid antagonists (e.g., AM630), imidazolinedione class cannabinoid antagonists, triazole class cannabinoid antagonists, pyridone derivative class cannabinoid antagonists, quinolone derivative class cannabinoid antagonists, tricyclic derivatives of l-benzylpyrazole-3-carboxylic acid, tricyclic pyrazoles, analogs of 8-chloro-l-(2',4'-dichlorophenyl)-N-piperidin-l- yl- 1 ,4,5 ,6-tetrahydrobenzo[6,7]cyclohepta[l ,2-c]pyrazole-3- carboxamide.

77. The dosage form of any of claims 1-4, 75 and 76, wherein the cannabinoid antagonist is in the form of a pharmaceutically acceptable 2007/018585

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salt, prodrug, ester, analog, derivative, solvate, complex, polymorph, hydrate, racemate or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof.

78. The dosage form of claims 1-4, 75 and 76, wherein the cannabinoid antagonist is CBi receptor selective.

79. The dosage form of claims 1-4, 75 and 76, wherein the cannabinoid antagonist is CB₂ receptor selective.

80. The dosage form of claims 1-4, 75 and 76, wherein the cannabinoid antagonist has mixed CB₁ receptor and CB₂ receptor activity.

81. The dosage form of claims 1-4, 75 and 76, wherein the cannabinoid antagonist is a non-CBi and non-CB2 cannabinoid antagonist.

82. The dosage form of claim 1 to 4, wherein the cannabinoid antagonist is an inducer of anandamide amidase inhibitor metabolism.

83. The dosage form of claims 1-4, 75 and 76, wherein the cannabinoid antagonist is an inducer of CB₁, CB₂ and non-CB!/non-CB₂ cannabinoid agonist metabolism or reuptake.

84. The dosage form of any of claims 1-4, wherein the ratio of the cannabinoid agonist to the aversive agent is about 1:100 to about 100:1.

85. The dosage form of any of claims 1-4, wherein the ratio of the cannabinoid agonist to the aversive agent is about 10:1 to about 1:10.

86. The dosage form of any of claims 1-4, wherein the ratio of the cannabinoid agonist to the aversive agent is about 1:5 to about 5:1.

87. The dosage form of claim 1 to 4, wherein the opioid antagonist is: (i) μ-opioid receptor selective; (ii) δ-opioid receptor selective; (iii) K- opioid receptor selective; (iv) an antagonist which possess μ, δ and/or κ-opioid receptor activity and (v) optionally, also has non-opioid receptor pharmacologic activity.

88. The dosage form of claim 87, wherein the opioid antagonist is selected from the group consisting of alvimopan, naltrexone, methylnaltxexone, nalbuphine, naloxone, nalmefene, cyclazocine, cyclorphan, oxilorphan nalorphine, nalorphine dinicotinate, nalmefene, nadide and levallorphan.

89. The dosage form of any of claims 1-4, 87 and 88, wherein the opioid antagonist is in the form of a pharmaceutically acceptable salt, prodrug, ester, analog, derivative, solvate, complex, polymorph, hydrate, racemate or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof.

90. A method for treating or preventing medical conditions amenable to treatment with cannabinoid agonists comprising administering to a human patient in need thereof an effective amount of the dosage form of any of claims 1-89.

91. A method of claim 90, wherein the medical condition is Alzheimer's disease, schizophrenia, depression, alcoholism, Parkinson's disease, stroke, premature labor, endotoxic shock, hepatic cirrhosis, atherosclerosis, cancer, glaucoma, emesis, multiple sclerosis, amyotrophic lateral sclerosis, encephalitis, Huntington's disease, obesity, memory impairment, cognitive impairment, hypertension, cardiogenic shock, cerebral ischemia, myocardial infarction, neurotoxicity, febrile seizures and various intestinal disorders.

92. A method for treating or preventing pain, comprising administering to a human patient in need thereof an effective amount of the dosage form of any of claims 1-89.

93. The dosage form of claim 54, wherein the non-cannabinoid therapeutically active agent is an analgesic.

94. Kits for use in treating or preventing diseases or disorders amenable to treatment with the dosage form of any of claims 1-93 comprising: (i) a dosage form of the invention; (U) a container for the dosage form; and optionally, any of (iii) to (vii): (iii) a container for individual units of the dosage form (e.g., individual patches); (iv) educational instructions in any media about any medical condition, its etiology, pathophysiology, consequences and treatment, potential for abuse and diversion and methods for prevention of same and information on the proper use and disposal of the medication; (v) containers or bags for the safe disposal of any used or remaining unused dosage form, preferably child proof and flushable; (vi) tamper evident and child proof packaging for the kit and its contents (vii) disposable gloves, applicators and/or solvent to allow for the application and/or removal of the dosage form.