US 20100311704A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0311704 A1 G00 berman (43) Pub. Date: Dec. 9, 2010

(54) PHARMACEUTICAL DELIVERY SYSTEMS Publication Classification FORTREATMENT OF SUBSTANCE ABUSE (51) Int. Cl. AND OTHER ADDICTIONS A 6LX 3/573 (2006.01) A63L/439 (2006.01) A63/4985 (2006.01) (76) Inventor: Lance L. Gooberman, A63L/454 (2006.01) Haddonfield, NJ (US) A6II 3/478 (2006.01) A6II 3L/27 (2006.01) Correspondence Address: A6IP 25/32 (2006.01) LERNER, DAVID, LITTENBERG, A6IP 25/34 (2006.01) KRUMHOLZ. & MENTLIK A6IP 25/36 (2006.01) 6OO SOUTHAVENUE WEST A6IP 25/30 (2006.01) (52) U.S. Cl...... 514/171; 514/282; 514/279:514/250; WESTFIELD, NJ 07090 (US) 514/326; 514/397: 514/491 (21) Appl. No.: 12/788,770 (57) ABSTRACT Disclosed are injectable pharmaceutical compositions that contain a therapeutically effective amount of an anti-addic (22) Filed: May 27, 2010 tive agent, an anti-inflammatory agent, and a pharmaceuti cally acceptable liquid carrier, methods of making the com Related U.S. Application Data positions, and uses thereof for treating addictions including Substance abuse (or addiction to an abused substance) and (60) Provisional application No. 61/217,337, filed on May addictive or compulsive behavior, by administering the com 29, 2009. position to a subject in need thereof. US 2010/031 1704 A1 Dec. 9, 2010

PHARMACEUTICAL DELVERY SYSTEMS tial therapeutic effect on alcohol abuse. Naltrexone, acamp FORTREATMENT OF SUBSTANCE ABUSE rosate, and disulfiram have been proven to be of a certain AND OTHER ADDICTIONS utility and approved for the treatment of alcoholism. Among these medications, the non-selective opioid antagonist naltr CROSS-REFERENCE TO RELATED exone is currently considered the pharmacological gold stan APPLICATIONS dard. 0001. This application claims the benefit of the filing date 0007. The National Institute on Drug Abuse estimates that of U.S. Provisional Patent Application No. 61/217,337 filed 72 million Americans, about one-third of the population, have May 29, 2009, the disclosure of which is hereby incorporated tried marijuana. Acute effects of marijuana use include herein by reference. memory and learning problems, distorted perception, diffi culty problem solving, loss of coordination, and increased BACKGROUND OF THE INVENTION heart rate. Long term abuse can cause the same respiratory problems observed in tobacco smokers, such as daily cough, 0002. Substance addiction is a chronic, relapsing disease phlegm production, increased risk of lung infections, and an characterized by a loss of control over drug use, compulsive increased chance of developing cancer of the head, neck and drug seeking and craving for a substance, use that persists lungs. Depression, anxiety, and job-related problems have despite negative consequences, and physical and/or psycho been associated with marijuana use. Longterm marijuanause logical dependence on the Substance. Substance addiction can result in addiction with compulsive use that interferes typically follows a course of tolerance, withdrawal, compul with daily activities. Cravings and withdrawal symptoms, sive drug taking behavior, drug seeking behavior, and relapse. Such as irritability, increased aggression, sleeplessness, and Addictive Substances include alcohol, caffeine, nicotine, can anxiety make it difficult for addicts to stop using marijuana. nabis (marijuana) and cannabis derivatives, opiates and other morphine-like opioid agonists such as heroin, phencyclidine 0008 Psychostimulants, such as cocaine and amphet and phencyclidine-like compounds, sedative ipnotics such as amines, cause euphoria, increased alertness, and increased benzodiazepines and barbiturates and psychoStimulants such physical capacity in humans. These Substances first increase as cocaine, amphetamines and amphetamine-related drugs dopamine transmission, but long term drug usage results in a Such as dextroamphetamine and methylamphetamine. Sub reduction of dopamine activity, leading to dysregulation of stance abuse and addiction are public health issues. They have the brain reward system and dysporia. The WHO estimates 33 significant social and economic impact on both the addict and million people around the world abuse amphetamines. Society by playing a major role in violent crime and the spread 0009 Chronic cocaine abuse can result in hyperstimula of infectious diseases. tion, tachycardia, hypertension, mydriasis, muscle twitching, 0003. According to the World Health Organization, an sleeplessness, extreme nervousness, hallucinations, paranoia, estimated 13 million people abuse opiates worldwide, includ aggressive behavior, and depression. Cocaine overdose may ing 9 million heroin addicts. More than 25% of opiate abusers lead to tremors, convulsions, delirium, and death resulting die from Suicide, homicide, or an infectious disease. Such as from heart arrhythmias and cardiovascular failure. HIV and hepatitis, within 10-20 years of becoming addicted. Desipramine, amantadine and bromocriptine have been Tolerance and physical dependence can develop within two to shown to decrease cocaine withdrawal symptoms. three days. 0010 Amphetamine withdrawal symptoms include EEG 0004. The goals for treatment of opiate addiction, as with changes, fatigue, and mental depression. Tolerance develops other types of substance addictions, are to discontinue the use over time and may be associated with tachycardia, auditory of the opiate while minimizing painful withdrawal symptoms and visual hallucinations, delusions, anxiety reactions, para and preventing relapse. Current treatments involve replacing noid psychosis, exhaustion, confusion, memory loss, and pro the addictive drug with a substitution of an opioid receptor longed depression with Suicidal tendencies. Current treat agonist or mixed agonist/antagonist. An alternative approach ments for amphetamine addiction include phenothiazines, consists of the use of an opioid receptor antagonist to block haloperidol, and chlorpromazine for hallucinations. the effect of the agonist. 0005 Alcohol is one of the most commonly abused sub BRIEF SUMMARY OF TEE INVENTION stances at a global level. Alcoholism leads to serious liver and cardiovascular disease and generates dependence resulting in 0011. The present invention provides an injectable phar severe mental disorders, Social problems and adverse conse maceutical delivery system for anti-addictive agents, quences including the division of families, tragic accidents examples of which include antagonists and aversive agents of and the reduction of work performance. According to the substances of abuse, which are useful in the treatment of WHO, alcohol consumption is responsible for 20-30% of Substance abuse and addictive or compulsive behaviors. oesophageal and liver cancer, liver cirrhosis, homicides, epi Thus, they can be administered non-surgically. In so doing, lepsy, and motor vehicle accidents world wide. Globally, they provide several advantages compared to Subcutaneous alcohol abuse leads to about 1.8 million deaths per year. implants, such as pellets, or oral dosage forms of anti-addic Compulsive behavior towards the consumption of alcohol is a tive agents which require patient compliance. For example, core symptom of the disorder. In recent years several the inventive delivery systems require less time for actual approaches have been investigated to help alcoholic patients administration and, over the course of time, fewer adminis to not only control alcohol drinking but also alcohol cravings trations. Since they are less invasive and do not require Sur and relapse. gical incision, there is no need for removal of Sutures and 0006. Several classes of medications such as naltrexone, there is no scarring. Further, there is less risk of infection. acamprosate, ondansetron, disulfiram, gamma hydroxybu Even further, the presence of the anti-inflammatory agent is tyrate (GHB), and topiramate have been tested for their poten believed to decrease any inflammatory response caused by US 2010/031 1704 A1 Dec. 9, 2010 the injection and the presence of a foreign Substance, and that ramide, propheptazine, promedol, properidine, propiram, attraction of phagocytic cells to the site of injection is propoxyphene Sufentanil, tramadol, tilidine, salts thereof, reduced. mixtures of any of the foregoing, mixed L-agonists/antago 0012. Accordingly, a first aspect of the present invention is nists, and the like. directed to an injectable pharmaceutical composition that 0016 Examples of addictive or compulsive behaviors that contains an anti-addictive agent, an anti-inflammatory agent, may be treated in accordance with embodiments of the and a pharmaceutically acceptable liquid carrier. Methods of present invention include pathological gambling, sex addic making the compositions are also provided. The anti-addic tion, addiction to pornography, compulsive overeating, com tive agent is present in a therapeutically effective amount, pulsive overexercising, compulsive overexercising, and com which broadly refers to that amount that can result in a reduc pulsive use of electronic gadgets and devices such as tion, decrease or even a cessation of addictive use or compul electronic video games and cellular telephones and commu sive behavior. nication devices such as BlackBerry(R) devices. 0013. A second aspect of the present invention is directed 0017 Anti-addictive agents that may be included in the to a method for treating Substance abuse (or addiction to an inventive pharmaceutical delivery systems include antago abused substance) by administering the composition to a nists. These agents act upon receptors, typically in the brain Subject in need thereof. In certain embodiments, the compo (and which may also be present in one or more other organs sition is used to treat a patient with an addition to opioids, Such as liver, lungs and kidney) and competitively bind the psychoactive stimulants, nicotine, and/or alcohol. receptor with higher affinity than the agonist, i.e., the Sub 0014. A third aspect of the present invention is directed to stance of abuse. Thus, they effectively block the receptorso as a method for treating an addictive or compulsive behavior by to prevent the body from responding to the substance of administering the inventive composition to a Subject in need abuse, or in the case of compulsive behavior, more generally thereof. In certain embodiments, the compulsive behavior is by blocking the positive reinforcing effect of the behavior. As an addiction to gambling, sex or pornography. explained herein, Some antagonists useful in the present invention may also produce a weak or partial agonist DETAILED DESCRIPTION response. Partial agonists bind and activate a given receptor, 00.15 Pharmaceutical delivery systems of the present but have only partial efficacy at the receptor relative to a full invention are useful in the treatment of addiction to sub agonist. They may also be considered ligands which display stances of abuse, and in the treatment of addictive or compul both agonistic and antagonistic effects—when both a full sive behaviors. The term addiction has been referred to as a agonist and partial agonist are present, the partial agonist recurring compulsion by an individual to engage in some actually acts as a competitive antagonist, competing with the specific activity, despite harmful consequences to the indi full agonist for receptor occupancy and producing a net vidual's health, mental state or social life. That is to say, it is decrease in the receptor activation observed with the full an uncontrolled, compulsive use or behavior. Embodiments agonist alone. of the present invention may thus be useful in treating addic 0018. In some embodiments, the active agent includes an tion to Substances of abuse including both recreational drugs opioid antagonist. An "opioid antagonist' is an opioid com and medications alike. Examples of recreational drugs pound or composition including any active metabolite of such include alcohol, e.g., ethyl alcohol, gamma hydroxybutyrate compound or composition that in a Sufficient amount attenu (GHB), caffeine, nicotine, cannabis (marijuana) and cannabis ates (e.g., blocks, inhibits, prevents or competes with) the derivatives, opiates and other morphine-like opioid agonists action of an opioid agonist. These agents exert their activity Such as heroin, phencyclidine and phencyclidine-like com by acting on one or more opioid receptors. At least three types pounds, sedative ipnotics Such as benzodiazepines, meth of opioid receptors, mu, kappa, and delta opioid receptors, aqualone, mecloqualone, etaqualone and barbiturates and have been reported. Opioid antagonists are generally classi psychoactive stimulants (also known as psychoStimulants) fied by their effects on the opioid receptors. Opioid antago Such as cocaine, amphetamines and amphetamine-related nists may antagonize central receptors, peripheral receptors drugs such as dextroamphetamine and methylamphetamine. or both. Naloxone and naltrexone are commonly used opioid Other examples include hallucinogens such as LSD, psilocy antagonist drugs that are competitive in that they bind to the bin, and extasy. Examples of addictive medications include, opioid receptors with higher affinity than agonists, but that do e.g., benzodiazepines, barbiturates, and pain medications not activate the receptors. This effectively blocks the receptor, including alfentanil, allylprodine, alphaprodine, anilleridine preventing the body from responding to opiates and endor benzylmorphine, bezitramide, buprenorphine, butorphanol, phins. clonitaZene, codeine, cyclazocine, desomorphine, dextro 0019 Many opioid antagonists are not pure antagonists moramide, dezocine, diampromide, dihydrocodeine, dihy but also produce Some weak opioid partial agonist effects, and dromorphine, dimenoxadol, dimepheptanol, dimethylthiam can produce analgesic effects when administered in high butene, dioxaphetyl butyrate, dipipanone, eptazocine, doses to opioid-naive individuals. Examples of Such com ethoheptazine, ethylmethylthiambutene, ethylmorphine, eto pounds include nalorphine, and levallorphan. However, the nitaZene fentanyl, heroin, hydrocodone, hydromorphone, analgesic effects from these drugs are limited and tend to be hydroxypethidine, isomethadone, ketobemidone, levallor accompanied by dysphoria, most likely due to action at the phan, levorphanol, levophenacylmorphan, lofenitanil, mep kappa opioid receptor. Since they induce opioid withdrawal eridine, meptazinol, metazocine, methadone, metopon, mor effects in people who are taking, or have previously used, phine, myrophine, nalbuphine, narceline, nicomorphine, opioid full agonists, these drugs are considered to be antago norlevorphanol, normethadone, nalorphine, normorphine, nists. Naloxone is one example of an opioid antagonist that norpipanone, opium, oxycodone, (e.g., OxyContin'M), oxy has no partial agonist effects. Instead, it is a weak inverse morphone, papavereturn, pentazocine, phenadoxone, phe agonist at mu opioid receptors, and is used for treating opioid nomorphan, phenazocine, phenoperidine, piminodine, pirit overdose. Buprenorphine, a semi-synthetic opiate (marketed US 2010/031 1704 A1 Dec. 9, 2010

in the U.S. by Teckitt Benckiser under the tradenames Temge 0024. The therapeutically effective amount of opioid sic, Buprenex, Suboxone and Subutex), is another example of antagonist contained in the composition may vary, depending an agent with partial agonist and antagonist actions. upon Such factors as the Solubility of the opioid antagonist in 0020 Examples of other opioid antagonists that may be the carrier, the Volume of the composition for injection, and used according to the invention include alvimopan, binaltor the desired time period over which release of the drug is phimine, buprenorphine, cyclazocine, cyclorphan, cypri sought. In general, amounts of opioid antagonist (e.g., naltr dime, dinicotinate, beta-funaltrexamine, levallorphan, meth exone) effective for treatment ranges from about 200 mg to ylnaltrexone, nalbuphine, nalide, nalmefene, nalmexone, about 1000 mg, and in some embodiments, about 200 mg to nalorphine, nalorphine dinicotinate, naloxonazine, naltren about 500 mg. or about 200 to 300 mg, or about 300 to about dol, naltrindole, oxilorphan, and pentazocine, or their phar 500 mg. Thus, the injectable composition may provide for macologically effective esters or salts, or free base forms prolonged release of opioidantagonist (e.g., naltrexone) as to thereof. sustain therapeutic blood levels which are typically in the 0021. The term “pharmaceutically acceptable salt” refers order of about 1 ng/ml blood, for about 2 weeks to about 1 to a formulation of a compound that does not cause significant month, 6 weeks, or even about 2 months. irritation to an organism to which it is administered and does 0025. In some embodiments, the anti-addictive agent not abrogate the biological activity and properties of the includes a cannabinoid receptor antagonist. These agents are compound. Pharmaceutical salts of basic compounds can be effective in the treatment of addiction to cannabinoids, nico obtained by reacting the compound with an acid Such as tine and hallucinogens. The cannabinoid receptors are a class hydrochloric acid, hydrobromic acid, Sulfuric acid, nitric of the G-protein coupled receptor superfamily. Their ligands acid, phosphoric acid, methanesulfonic acid, ethanesulfonic are known as cannabinoids. There are currently two known acid, p-toluenesulfonic acid, Salicylic acid and the like. For subtypes, CB1 which is expressed mainly in the brain, but example, naltrexone hydrochloride is a pharmaceutically also in the lungs, liver, and kidney, and CB2, which is mainly acceptable salt of naltrexone. Pharmaceutical salts of acidic expressed in the immune system and in hematopoietic cells. It compounds can be obtained by reacting the compound with a is also believed that there are novel cannabinoid receptors that base to form a salt Such as an ammonium salt, an alkali metal is, non-CB1 and non-CB2, which are expressed in endothelial salt, such as a Sodium or a potassium salt, an alkaline earth cells and in the CNS. Cannabinoid receptor antagonists may metal salt, such as a calcium or a magnesium salt, a salt of be selective for either the CB1 or CB2 receptor. The present organic bases such as dicyclohexylamine, N-methyl-D-glu invention contemplates the use of either or both CB1 and CB2 camine, tris(hydroxymethyl)methylamine, and salts thereof receptor antagonists. with amino acids such as arginine, lysine, and the like. 0026. Addictive substances (e.g., alcohol, opiates, Delta 0022. In some embodiments, the opioid antagonist is nal (9)-tetrahydrocannabinol (Delta(9)-THC) and psychostimu trexone. The term “naltrexone' may be used in a general way lants, including nicotine), against which the inventive com herein to refer to a free base of naltrexone, a pharmaceutically positions may provide treatment, elicit a variety of acceptable naltrexone salt (including hydrates and anhydrous chronically relapsing disorders by interacting with endog forms, e.g., naltrexone hydrochloride dihydrate and anhy enous neural pathways in the brain. In particular, they share drous naltrexone hydrochloride), a naltrexone metabolite, a the common property of activating mesolimbic dopamine maltrexone isomer, a naltrexone prodrug or mixtures thereof. brain reward systems, and virtually all abused drugs elevate Reference herein to “naltrexone' will be understood as dopamine levels in the nucleus accumbens. Cannabinoid-1 encompassing all such forms, unless the context clearly indi (CB1) receptors are expressed in this brain reward circuit and cates otherwise. modulate the dopamine-releasing effects of Delta(9)-THC 0023 Opioid antagonists, and particularly naltrexone, and nicotine. may be useful in the treatment of addiction to opioids and 0027 Rimonabant (SR141716), a CB1 receptor antago opiates (which although refer to natural and synthetic com nist, blocks both the dopamine-releasing and the discrimina pounds respectively, these terms are commonly used inter tive and rewarding effects of Delta(9)-THC in animals. changeably, and thus are used herein in a consistent manner). Although CB1 receptor blockade is generally ineffective in Opioids that may cause such addictive behavior include reducing the self-administration of cocaine in rodents and opioid agonists (natural, semi-synthetic and synthetic alike), primates, it reduces the reinstatement of extinguished partial opioid agonists and mixed opioid agonist/antagonists. cocaine-seeking behavior produced by cocaine-associated Examples of opioids that can be addictive include morphine, conditioned stimuli and cocaine priming injections. Simi codeine, methodone, fentanyl and heroin. Opioid antagonists larly, CB1 receptor blockade is effective in reducing nicotine may also be useful in the treatment of alcohol addiction, seeking behavior induced by re-exposure to nicotine-associ nicotine addiction and in the treatment of addictive or com ated Stimuli. In human clinical trials, rimonabant was shown pulsive behaviors including pathological gambling, sex to block the subjective effects of Delta(9)-THC in humans addiction, and addiction to pornography, compulsive overeat and prevents relapse to Smoking in ex-Smokers. Other ing, compulsive overexercising, compulsive overexercising, examples of cannabinoid receptor CB1 antagonists include and compulsive use of electronic gadgets and devices such as rosanabant, taranabant and CP-945598. electronic video games and cellular telephones and commu 0028. Therapeutically effective amounts of these agents nication devices such as BlackBerry(R) devices. While not that may be present in the injectable compositions generally intending to be bound by theory, it is believed that opioid range from about 100 to about 1000 mg. antagonists Such as naltrexone act by blocking the positive 0029. In some embodiments, the active agent includes a reinforcing effect of alcohol or the compulsive behavior, or in 5-hydroxytryptamine 3 (5-HT3) receptor antagonist. These the case of alcohol, by blocking the positive reinforcing effect agents are known to exert an anti-emetic effect and thus are which results from the release of endogenous opioids upon effective against nausea and Vomiting. These agents may be the consumption of alcohol. effective in treating addiction to psychoactive stimulants such US 2010/031 1704 A1 Dec. 9, 2010

as cocaine and amphetamines and methamphetamines. known as ALDH-2) and ALDH-II (also known as ALDH-1) Examples of 5-HT3 receptor antagonists that may be useful in are the major enzymes responsible for the oxidation of acetal the present invention include alosetron, aZasetron, dehyde. ALDH-I has a higher affinity for acetaldehyde than bemesetron, cilansetron, dolasetron, granisetron, indisetron, ALDH-II, and is thought to be the primary enzyme involved itasetron, ondansetron, palonosetron, propisetron, ramo in alcohol detoxification Keung, W. M., et al., Proc. Natl. setron, renZapride, tropisetron, and Zatosetron. Therapeuti Acad. Sci. USA 95:2198-2203 (1998). The discovery that cally effective amounts of these agents that may be present in 50% of the Asian population carries a mutation in ALDH-I the injectable compositions generally range from about 100 that inactivates the enzyme, together with the low occurrence to about 600 mg. of alcohol abuse in this population Supports the contention 0030. In some embodiments, the anti-addictive agent that it is this isozyme of ALDH that is primarily responsible includes a partial agonist of the nicotinic acetylcholine recep for alcohol detoxification. Recent studies also implicate tor, and specifically the C.B. Subtype of the receptor. An ALDH-I in the metabolism of monoamine neurotransmitters example is Varenicline, marketed in the U.S. by Pfizer under such as serotonin (5-HT) and dopamine (DA) Keung, W. M., the tradename CHANTIX. Varenicline has been reported to et al., Proc. Natl. Acad. Sci. USA95:2198-2203 (1998). both reduce cravings for and decrease the pleasurable effects 0034 Examples of ALDH inhibitors that may be useful in of cigarettes and other tobacco products, and through these the present invention include disulfiram, coprine, cyanamide, mechanisms it can assist patients in stopping Smoking. Thera 1-aminocyclopropanol (ACP), daidzin, cephalosporins, peutically effective amounts of these agents that may be antidiabetic sulfonyl ureas, metronidazole, and any of their present in the injectable compositions generally range from metabolites or analogs exhibiting ALDH-inhibiting activity about 100 to about 600 mg. including, e.g., S-methyl N,N-diethyldithiocarbamate, S-me 0031. In some embodiments, the anti-addictive agent thyl N,N-diethyldithiocarbamate sulfoxide, and S-methyl includes an aversive agent of a Substance of abuse. As used N,N-diethylthiocarbamate sulfoxide. herein, an aversive agent causes unpleasant symptoms in the 0035. In preferred embodiments, the injectable composi Subject or patient who is consuming the Substance of abuse. tion contains disulfiram. Disulfiram (IUPAC: diethylcarbam One Such type of agent Suitable for use in the present inven othioylsulfanyl diethylaminomethanedithioate, tion is an “alcohol aversive agent', which causes unpleasant CHNS), also known as CronetalTM, Abstenil TM, Sto symptoms in people who are also consuming alcohol (i.e., petylTM, ContrainTM, AntadixTM, AnietanolTM, ExhoranTM, ethanol). Thus, inventive pharmaceutical delivery systems AntabuseTM, EtabuseTM, AbstinylTM, ThiuranideTM, Espe that contain an alcohol aversive agent may be useful in the ralTM, TetradineTM, NoxalTM, TetraetiTM, is a potent irrevers treatment of alcoholism. ible inhibitor of ALDH-II and inhibits ALDH-I only slightly. 0032. The term “alcoholism’ includes alcohol abuse and Recent studies suggest that the inhibition of ALDH-I by dis alcohol dependence. The term “alcohol abuse' is defined in ulfiram occurs indirectly via its metabolites, e.g., S-methyl the Diagnostic and Statistical Manual of Mental Disorders N,N-diethylthiocarbamate sulfoxide (DETC-MeSO) You (DSM-IV). Alcohol abuse as a maladaptive pattern of alcohol rick, et al., Alcohol 4:463 (1987); Yourick, et al., Biochem. use that leads to clinically significant impairment or distress. Pharmacol. 38:413 (1989); Bart, et al., Alcohol 7:165 (1990); Symptoms include one or more of the following occurring Madan, et al., Drug Metab. Dispos. 23:1153-1162 (1995). within a 12-month period: (1) recurrent alcohol use that Ingestion of alcohol while taking disulfiram results in the results in a failure to fulfill major role obligations at work, accumulation of aldehydes, which causes tachycardia, flush School or home; (2) recurrent alcohol use in physically haZ ing, diaphoresis, dyspnea, nausea and Vomiting (also known ardous situations; (3) recurrent alcohol-related legal prob collectively as the disulfiram or disulfiram-ethanol reaction). lems; and (4) continued alcohol use despite having persistent More simply, this drug produces sensitivity to alcohol which or recurrent Social or interpersonal problems caused or exac results in a highly unpleasant reaction when the patient under erbated by the effects of the substance. Alcohol dependence treatment ingests even Small amounts of alcohol. In addition may be considered to exist when symptoms of abuse are to treatment of alcoholism, pharmaceutical delivery systems accompanied by three or more of the following: (1) tolerance of the present invention that include disulfiram may also be defined by either: (a) a need for markedly increased amounts useful in treatment of addiction to psychoactive stimulants, of alcohol to achieve intoxication or desired effect, or (b) particularly addiction to cocaine. markedly diminished effect with continued use of the same 0036. The amount of the aversive agent such as disulfiram amount of alcohol; (2) withdrawal manifested by either: (a) contained in the composition may vary depending upon Such characteristic withdrawal syndrome for alcohol or (b) alcohol factors as the potency of the agent, the Volume of the injection taken to relieve or avoid withdrawal symptoms; (3) alcohol and the desired time period over which release of the drug is taken in larger amounts over a longer period than as intended; sought. In general, amounts of the aversive agent (e.g., disul (4) a persistent desire or unsuccessful efforts to reduce or firam) effective for treatment (e.g., of alcoholism or addiction control drinking; (5) much time spent in activities necessary to psychostimulants such as cocaine) ranges from about 350 to obtain alcohol, use alcohol, or recover from its effects; (6) mg to about 1200 mg, and in some embodiments, about 500 important social, occupational, or recreational activities mg to about 800 mg. being given up or reduced because of drinking; and (7) con 0037 Combinations (e.g., mixtures) of two or more anti tinued use despite knowledge of having a persistent or recur additive agents, useful for the same purpose, may be present rent physical or psychological problem caused or exacerbated in the composition. by alcohol. 0038 Anti-inflammatory agents present in the inventive 0033 Alcohol aversive agents include inhibitors of alde compositions are effective to reduce blood flow to cellular hyde dehydrogenase. ALDH is an enzyme that is involved in elements, whether steroidal or non-steroidal, i.e., non-steroi the removal of acetaldehyde, a toxic metabolite of alcohol. dal anti-inflammatory delivery (NSAID, e.g., salicyclate, Although multiple forms of ALDH exist. ALDH-I (also ketorolac, naproxen, ibuprofen). Without intending to be US 2010/031 1704 A1 Dec. 9, 2010 bound by any particular theory of operation, Applicant Sugars, sodium chloride, or polyalcohols such as mannitol believes that the presence of the anti-inflammatory agent and Sorbitol, may also be present in the composition. Pro decreases the inflammatory response caused by the injection longed absorption of the injectable compositions can be and the presence of a foreign Substance, and that attraction of brought about by including in the composition an agent which phagocytic cells to the site of injection is reduced. Applicant delays absorption, for example, aluminum monostearate or also believes that the hydrophobicity of steroidal anti-inflam gelatin. matory agent keeps water away from the anti-addictive agent 0045 Sterile injectable solutions can be prepared by Such as naltrexone, thus, maximizing amount of injected drug incorporating the therapeutic compound in the required available for sustained absorption. amount in an appropriate solvent with one or a combination of 0039. By way of example, some steroids useful herein ingredients enumerated above, as required, followed by Ster include betamethasone dipropionate, betamethasone phos ilization (which can be conducted in accordance with stan phate, betamethasone Valerate, clobetasol propionate, corti dard pharmaceutical techniques, such as radiation, heat and Sone acetate, dexamethasone phosphate acetate, dexametha filter sterilization). Generally, dispersions are prepared by Sone micronized, fluocinonide, hydrocortisone acetate, incorporating the therapeutic compound into a sterile vehicle hydrocortisone sulfate, methyl prednisone acetate and triam which contains a basic dispersion medium and the required cinolone acetonide. other ingredients from those enumerated above. In the case of 0040. The amount of anti-inflammatory compound may sterile powders for the preparation of sterile injectable solu vary depending upon factors as the amount of drug to be tions, the preferred methods of preparation are vacuum dry released in a desired time, and the Volume of the composition ing and freeze-drying which yield a powder of the active administered. In general, the amounts range from about 10 ingredient (i.e., the therapeutic compound) optionally plus mg to about 120 mg, and in Some embodiments from about 20 any additional desired ingredient from a previously sterile mg to about 80 mg, and in yet other embodiments, from about filtered solution thereof. 30 mg to about 60 mg. 0046. The injectable compositions of the present inven 0041. The pharmaceutically acceptable carrier (or tion are typically administered Subcutaneously (e.g., in the vehicle) includes a biodegradable or bioerodible liquid. Both abdomen) or intramuscularly (e.g., gluteally, or in the arm or non-aqueous and aqueous liquids alike may be useful. The leg). The timing of the injection will vary on several factors, agents may be soluble in the carrier (in which case it may be including the overall health of the subject (a human or labo referred to as a solvent), thus forming an injection Solution, or ratory animal), the severity of the addiction being treated, and insoluble in which case the injectable composition is in the the like. In the case of opioid addiction, administration should form of a Suspension or dispersion (in which case the carrier be given after withdrawal symptoms have substantially sub may be referred to as a suspension or dispersion medium). sided (which are often ameliorated as a result of a detoxifi 0042 Examples of non-aqueous carriers include edible cation procedure). In the case of alcohol abuse, the patient oils typically vegetable oils. Examples of edible oils that may should not have alcohol in the system; otherwise, administra be useful in the present invention include cottonseed oil, corn tion of the inventive composition (e.g., containing disulfiram) oil, almond oil, groundnut corn oil, germ olive oil, germ olive will cause a severely unpleasant reaction. A breath test can be oil, castor oil, and sesame oil. Derivatives of the oils, such as administered beforehand. In general, duration of treatment hydrogenated forms of these oils, may also be useful. In some using the inventive compositions is within the discretion of embodiments, cottonseed oil, almond oil, sesame oil, or a the medical clinician. Typically, treatment continues so as to corn oil is present. Peanut and olive oils are less preferred. In achieve 1-2 years of abstinence and participation in a recov the case of aqueous Suspensions, the compositions may also ery program Such as a version of the 12-step program. contain, in addition to water, a dispersing or Suspending 0047. The invention will now be described in accordance agent, examples of which include synthetic and natural gums with the following non-limiting working examples. Such as tragacanth, acacia, alginate, dextran, cellulose deriva tives, (e.g., Sodium carboxymethylcellulose and methylcellu Example 1 lose), polyvinyl-pyrrolidone, and gelatin. Inventive Formulation 0043. The volume of carrier generally ranges from about 2 to about 10 ml, and in some embodiments, from about 2 to 0048 about 5 ml, and in yet other embodiments, from about 3 to about 4 ml. 0044) The composition is fluid to the extent that easy Ingredient Listing Qty. Unit syringability exists. It also should be stable under the condi Naltrexone 2.OOO 9. tions of manufacture and storage and be preserved against the Triamcinolone Acetonide O.200 9. contaminating action of microorganisms such as bacteria and (micronized), USP fungi. Thus, a preservative may be present. Exemplary pre Benzyl Alcohol, NF 2.0 mL servatives include materials that inhibit bacterial growth, Cottonseed Oil, NF S.O mL Such as hydroxybenzoates (e.g., ethyl and propyl hydroxy Cottonseed Oil, NF q.S. to 10.0 mL benzoates such as NipagenTM and NipasolTM), alcohol (e.g., lower alkanols such as ethanol), antimicrobial agents, ben 0049. The formulation described above was prepared to Zoic acid, Sodium benzoate, benzyl alcohols, Sorbic acid, prepare a 10 ml composition containing Naltrexone 200 parabens, isopropyl alcohol and others known to one of ordi mg/mL, Triamcinolone Acetonide 20 mg/mL. The composi nary skill in the art. Proper fluidity can be maintained, for tion was prepared by the following steps, namely: Sterilize example, by the use of a coating Such as lecithin, by the and depyrogenate all heat stable, reusable materials and maintenance of the required particle size in the case of dis equipment, then returned to ambient temperature; triturate persion, and by the use of Surfactants. Isotonic agents such as the naltrexone to forma fine, homogeneous powder, combine US 2010/031 1704 A1 Dec. 9, 2010

and mix the powder and the micronized triamcinolone Example 3 acetonide, thus forming a homogeneous powder blend; pre pare a liquid preparation by combining and mixing the benzyl Inventive Formulation #2 alcohol and the cottonseed oil (in an amount of 5.0 mL plus 0051 processing error adjustments, e.g., typically in the order of less than 5%), thus preparing a homogeneous liquid-like solu tion; incrementally adding the homogeneous powder blend to the homogeneous liquid-like solution, with continuous mix Ingredient Listing Qty. Unit ing, thus preparing a homogeneous liquid-like dispersion; Triamcinolone Acetonide (micronized), USP 1...SOO 9. add the additional cottonseed oil to the mixture to fill the Carboxymethylcellulose Sodium, USP O.23 9. Sodium Chloride, USP O.25 9. required batch size of 10.0 mL plus processing error adjust Benzyl Alcohol, NF O.3 mL ments, with continuous mixing, thus forming a homogeneous Polysorbate 80 1.2% Solution it 1.O mL liquid-like dispersion; transfer the final product into the rec Sterile Water for Injection, USP q.S. to 30.0 mL. ommended dispensing container, and a smaller quantity into iPolysorbate 80 1.2% Solution a separate dispensing container, which is to be used as the test Polysorbate 80, NF 0.6 mL sample for sterility and endotoxin testing; pursuant to manu Sterile Water for Injection, USP 50.0 mL facturer's specifications, dry-heat sterilize the mixture, then 0.052 The inventive formulation above was prepared return to ambient temperature and pressure, wherein the heat according to the following protocol, namely: following the ing is conducted at about 160° C., and the heating time is manufacturer's specification, sterilize and depyrogenate all conducted for 60 minutes. The temperature of the heated heat stable, reusable materials and equipment, then return to chamber must reach about 121° C. before exposure duration ambient temperature; incrementally add the Polysorbate 80 is timed. The test sample is validated for sterility and endot (0.6 mL) to the sterile water for injection (50.0 mL), with oxins in accordance to current U.S.P. 797 Regulatory Guide continuous mixing until homogeneously dispersed, thus lines. forming a homogeneous liquid-like solution; combine and mix micronized triamcinolone acetonide, carboxymethylcel Example 2 lulose Sodium, and sodium chloride to form a homogeneous powder blend; combine and mix the homogeneous liquid-like 0050. Three (3) mls of the formulation of example 1 were solution of the Polysorbate 80 with benzyl alcohol, thus pro injected into patients for purposes of treatment of opiate ducing a homogeneous liquid-like solution; add that Solution addiction. The table below shows levels of naltrexone in to the homogeneous powder blend with gentle mixing, thus saliva (in ng/ml) after various time periods post-injection. forming a homogeneous liquid-like dispersion; add sterile Patients 2 and 3 were administered two injections at different water to the mixture to fill to the required batch size (30.0 mL time periods. All other patients were administered one injec plus processing error adjustments), with continuous mixing, tion. thus forming a homogeneous liquid-like dispersion; transfer the final product into the recommended dispensing container, preferably with continuous mixing during the transfer pro cess in order to maintain homogeneity; following the manu Naltrexone Level facturer's specifications, autoclave sterilize the mixture (at a Patient Number Days After Injection ng ml heating temperature of 121°C. for 30 minutes, beginning as 1 3 3.7 1 12 7.8 of the time the heated chamber reaches 121°C.), then return 1 28 46.9 to ambient temperature and pressure (15 psi); and validate the 2 (first 2 8.8 test sample for Sterility and endotoxins, in accordance to injection current P.S.P. 797 Regulatory Guidelines. 2 7 1.5 2 28 O.6 0053 Although the invention herein has been described 2 (second 28 (after second 22.0 with reference to particular embodiments, it is to be under injection injection) stood that these embodiments are merely illustrative of the administered principles and applications of the present invention. It is after first sample) therefore to be understood that numerous modifications may 3 O 325.5 be made to the illustrative embodiments and that other 3 36 (based on sample 1.4 arrangements may be devised without departing from the taken before second spirit and scope of the present invention as defined by the injection) appended claims. 3 (second O (based on sample 140.9 injection taken after second administered injection) 1. An injectable composition comprising a therapeutically after first effective amount of an anti-addictive agent, an anti-inflam sample) matory agent, and a pharmaceutically acceptable liquid car 3 36 (after second O.6 injection) rier. 4 O 11.8 2. The composition of claim 1, wherein the anti-addictive 4 31 42.4 agent is an opioid receptor antagonist. 5 3 4.7 6 60 S.O 3. The composition of claim 2, wherein the opioid receptor 7 34 O antagonist is naltrexone. 4. The composition of claim 1, wherein the antagonist is a partial opioid agonist. US 2010/031 1704 A1 Dec. 9, 2010

5. The composition of claim 4, wherein the partial opioid 26. The method of claim 25, wherein the opioid is heroin, agonist is buprenorphine. morphine, codeine, methodone or fentanyl. 6. The composition of claim 1, wherein the anti-addictive 27. The method of claim 25, wherein the anti-addictive agent is Varenicline. agent is an opioid antagonist. 7. The composition of claim 1, wherein the anti-addictive 28. The method of claim 27, wherein the opioid antagonist agent is a cannabinoid receptor antagonist. is naltrexone. 8. The composition of claim 7, wherein the cannabinoid 29. The method of claim 24, wherein the substance of receptor antagonist is rimonabant. abuse is a cannabinoid, nicotine or a hallucinogen. 9. The composition of claim 1, wherein the anti-addictive 30. The method of claim 29, wherein the anti-addictive agent is a 5-hydroxytryptamine 3 (5-HT3) receptor antago agent is a cannabinoid receptor antagonist. nist. 31. The method of claim 30, wherein the cannabinoid 10. The composition of claim9, wherein the 5-HT3 antago receptor antagonist is rimonabant. nist is ondansetron. 32. The method of claim 24, wherein the human subject is 11. The composition of claim 1, wherein the anti-addictive a nicotine addict. agent comprises an aversive agent of a Substance of abuse. 33. The method of claim 32, wherein the anti-addictive 12. The composition of claim 11, wherein the aversive agent is Varenicline. agent is an inhibitor of alcohol dehydrogenase. 34. The method of claim 24, wherein the substance of 13. The composition of claim 12, wherein the inhibitor is abuse is a psychoactive stimulant. disulfiram. 35. The method of claim 34, wherein the psychoactive 14. The composition of claim 1, wherein the anti-inflam stimulant is cocaine. matory agent is a steroidal non-inflammatory agent. 36. The method of claim 34, wherein the anti-addictive 15. The composition of claim 14, wherein the steroidal agent is a 5-hydroxytryptamine 3 (5-HT3) receptor antago anti-inflammatory agent is triamcinolone acetonide. nist. 16. The composition of claim 1, wherein the liquid carrier 37. The method of claim 36, wherein the 5-hydrox comprises water. ytryptamine 3 (5-HT3) receptor antagonist is ondansetron. 17. The composition of claim 16, further comprising a 38. The method of claim 34, wherein the anti-addictive dispersing agent. agent is disulfiram. 39. The method of claim 24, wherein the substance of 18. The composition of claim 1, wherein the liquid carrier abuse is alcohol and the anti-addictive agent is an alcohol is a vegetable oil. aversive agent. 19. The composition of claim 18, wherein the vegetable oil 40. The method of claim 39, wherein the alcohol aversive is selected from the group consisting of cottonseed oil, agent is an inhibitor of alcohol dehydrogenase. almond oil, corn oil and sesame oil. 41. The method of claim 40, wherein the inhibitor of alco 20. The composition of claim 1, further comprising a pre holdehydrogenase is disulfiram. servative. 42. A method for treating an addictive or compulsive 21. The composition of claim 20, wherein the preservative behavior by administering, via injection, a composition com is benzyl alcohol, benzyl benzoate, or a mixture thereof. prising atherapeutically effective amount of an anti-addictive 22. The composition of claim 1, comprising naltrexone, a agent comprising an opioid antagonist, an anti-inflammatory Vegetable oil, and a steroidal anti-inflammatory agent. agent, and a pharmaceutically acceptable liquid carrier, to a 23. The composition of claim 22, wherein the vegetable oil human Subject in need thereof. is cottonseed oil, almond oil, sesame oil or corn oil, and the 43. The method of claim 42, wherein the addictive or steroidal anti-inflammatory agent is triamcinolone acetonide. compulsive behavior is pathological gambling, sex addiction, 24. A method for treating Substance abuse or addiction to addiction to pornography, compulsive overeating, compul an abused substance, comprising administering, via injection, sive overexercising, and compulsive use of electronic gadgets a composition comprising an anti-addictive agent, an anti and devices Such as electronic video games and cellular tele inflammatory agent, and a pharmaceutically acceptable liq phones and communication devices such as BlackBerry(R) uid carrier, to a human Subject in need thereof. devices. 25. The method of claim 24, wherein the human subject is an opioid addict, a nicotine addict or an alcoholic.