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Treatment for Cocaine Addiction (19) TZZ¥_Z_T (11) EP 3 170 499 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 24.05.2017 Bulletin 2017/21 A61K 31/27 (2006.01) A61K 31/16 (2006.01) A61P 25/00 (2006.01) (21) Application number: 16204193.3 (22) Date of filing: 31.08.2011 (84) Designated Contracting States: (72) Inventors: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB • LEDERMAN, Seth GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO New York, NY 10022 (US) PL PT RO RS SE SI SK SM TR • HARRIS, Herbert New York, NY 10022 (US) (30) Priority: 01.09.2010 US 379095 P (74) Representative: Bassil, Nicholas Charles et al (62) Document number(s) of the earlier application(s) in Kilburn & Strode LLP accordance with Art. 76 EPC: 20 Red Lion Street 11832859.0 / 2 611 440 London WC1R 4PJ (GB) (71) Applicant: Tonix Pharmaceuticals, Inc. Remarks: New York, NY 10022 (US) This application was filed on 14.12.2016 as a divisional application to the application mentioned under INID code 62. (54) TREATMENT FOR COCAINE ADDICTION (57) A novel pharmaceutical composition is provided therapeutic dose application or a single dose of a com- for the control of stimulant effects, in particular treatment bined therapeutically effective composition of disulfiram of cocaine addiction, or further to treatment of both co- and selegiline compounds or pharmaceutically accepta- caine and alcohol dependency, including simultaneous ble non-toxic salt thereof. EP 3 170 499 A1 Printed by Jouve, 75001 PARIS (FR) 1 EP 3 170 499 A1 2 Description and MDMA (3,4-methylenedioxymethamphetamine), better known as "Ecstasy." Clinically significant abuse or BACKGROUND dependence on these substances is classified by the Di- agnostic and Statistical Manual (DSM-IV) as follows: Am- [0001] All references cited in this specification, and 5 phetamine abuse (305.70)/ Amphetamine dependence their references, are incorporated by reference herein in (304.40); Cocaine abuse (305.60)/Cocaine dependence their entirety where appropriate for teachings of addition- (304.20); Phencyclidine abuse (305.90)/dependence al or alternative details, features, and/or technical back- (304.90); Nicotine dependence (305.1) (Amperican Psy- ground. chiatric Association, 2000). 10 [0005] Cocaine dependence has developed into a pub- CROSS-REFERENCE TO RELATED APPLICATIONS: lic health problem with negative medical, social, and eco- nomic effects. For example, in recent years cocaine-re- [0002] The present application which claims priority lated emergency room visits increased almost 50%. Co- from U.S. Provisional Patent Application No. 61/379,095, caine addiction or dependence affected approximately filed September 1, 2010, is a continuation in part from 15 2.4 million people in the United States in 2005. In the U.S. Patent Application Serial No. 12/145,792, filed June sense of this invention the term "addiction" may be de- 25, 2008, which is a divisional of U.S. Patent Application fined as a compulsive drug taking or abuse condition re- Serial No. 10/287,153, filed November 4, 2002 (aban- lated to "reward" system of the afflicted patient. The treat- doned), which claims the benefit of the filing date of U.S. ment of cocaine addiction or dependency has targeted Provisional Patent Application No. 60/338,901, filed No- 20 a lowering of dopaminergic tone to help decrease or at- vember 5, 2001, the entire contents of which are incor- tenuate the "reward effect. Behavioral interventions may porated by reference. help in treating cocaine addiction, but have not yet re- sulted in approved medications to treat these disorders BACKGROUND OF THE INVENTION despite many years of study. 25 [0006] Moreover, cocaine users tend to imbibe alcohol 1. Field of the Invention: concurrently to mellow the psychological anxiety and hy- peragitation frequently associated with chronic use of co- [0003] The present invention relates to compositions caine. It appears that almost 90% of cocaine abusers are and methods for preventing, ameliorating or treating ad- also dependent on alcohol. The consumption of both co- diction to cocaine, alcohol and similar nerve or psycho- 30 caine and alcohol has been suggested as reinforcing the stimulants. Such compositions and methods may be dependency and toxicity in the formation of the metabo- used to facilitate drug use cessation, and may comprise lite, cocaethylene. Alcohol abuse and dependence com- a combination of aldehyde dehydrogenase inhibitors and monly lead to other problems such as alcohol-related vi- monoamine oxidase inhibitors; more particularly, the olence, motor vehicle accidents, and medical conse- treatment may include a single dosage unit of such com- 35 quences of chronic alcohol ingestion including death. bined active ingredients. Such compositions will reduce [0007] The enzyme aldehyde dehydrogenase (ADLH) pleasurable experiences associated with use of alcohol, inhibitor disulfiram which is also dopamine-beta-hydro- cocaine, or stimulants. In addition, such compositions lase (DBH) inhibitor has been reported effective in stud- will produce unpleasant or aversive experiences when ies for reducing cocaine use (Carroll et al. Arch.Gen. Psy- used with alcohol, cocaine, or stimulants. Lastly, such 40 chiatry 2004;29:1123-1128), although perhaps not suit- compositions have mildly reinforcing properties that may able for all populations (Nich et al. Addict. Behavior 2004; enhance compliance with their use in subjects prone to 29:1123-1128). Selegiline , a monoamine oxidase substance abuse. (MAO)-B inhibitor, is known to block dopamine break- down, thus increasing synaptic dopamine levels and in- 2. Description of the Related Art: 45 hibit dopamine re-uptake (Ebadi et al. J. Neurosci. Res. 2002; 67:285-289). [0004] Cocaine, stimulants, and alcohol are recog- [0008] Although disulfiram and selegiline have been nized as the most commonly abused drugs. According available on the market for many years, their combined to the Diagnostic and Statistical Manual of Mental Disor- usehas never been studied systematically. Despite wide- ders (DSM-IV), problematic alcohol use is divided into 50 spread use, a single case report has appeared in the alcohol abuse and alcohol dependence. Cocaine abuse literature involving a significant adverse event (transient and dependence remains a substantial problem in the delirium) associated with administration of an MAO in- United States of America. Stimulants are drugs that tend hibitor tranylcypromine in a patient with a disulfiram im- to increase alertness and physical activity. The groups plant on therapeutic lithium (Blansjaar, B. A. 1995 Am J include pharmaceuticals such as amphetamines and the 55 Psychiatry 152:296.) It should be noted that tranylcy- street drugs commonly called "uppers" or "speed," and promine is an inhibitor of MAO-A and -B. Selegiline se- cocaine. Specific examples include cocaine, metham- lectively inhibits only the enzyme monoamine oxidase B phetamine, amphetamines, methylphenidate, nicotine, (MAO-B) at the low dose of 10 mg/day or less. Moreover, 2 3 EP 3 170 499 A1 4 the subject in the case report also had a therapeutic level Ingestion of alcohol while taking disulfiram results in the of Li+ (0.7 mM/L in serum), factors which may have con- accumulation of aldehydes, which causes tachycardia, tributed to the delirium. flushing, diaphoresis, dyspnea, nausea and vomiting (al- [0009] One of the pharmacotherapies that have been so known collectively as the disulfiram or disulfiram-eth- suggested for treating alcoholism, including facilitating 5 anol reaction). alcohol cessation, is the administration of agents that in- [0012] Although disulfiram has been available in the hibiting the enzyme aldehyde dehydrogenase (ALDH), UnitedStates formany decades, patientsfrequently have an enzyme involved in the removal of acetaldehyde, a difficulty complying with disulfiram treatment therapies. toxic metabolite of alcohol. Examples of ALDH inhibitors One reason for poor compliance is the lack of motivation include, e.g., disulfiram, coprine, cyanamide, 1-aminoc- 10 for the patient to continue to take disulfiram, that is, other yclopropanol (ACP), daidzin, cephalosporins, antidiabet- than self-motivation (i.e., there is no positive reinforce- ic sulfonyl ureas, metronidazole, and any of their metab- ment for taking disulfiram). Another reason is because olites or analogs exhibiting ALDH-inhibiting activity in- of the discomfort that arises if the patient ingests alcohol cluding, e.g., S-methyl N,N-diethyldithiocarbamate, S- during disulfiram therapy [McRae et al., supra; Swift, R. methyl N,N-diethyldithiocarbamate sulfoxide, and S-me- 15 M., supra; Kick, S., supra]. In fact, disulfiram has not prov- thyl N,N-diethylthiocarbamate sulfoxide. Patients who en to be useful in maintaining long-term sobriety [Kick, consume such inhibitors of ALDH experience mild to se- supra]. More recently, disulfiram has found use in the vere discomfort if they ingest alcohol. The efficacy of ther- treatment of cocaine addiction. It has been shown to re- apies using ALDH inhibitors depends on the patient’s duce cocaine abuse and relapse in several outpatient own motivation to self-administer the ALDH inhibitors, 20 clinical trials ((Carroll, Fenton et al. 2004); (Carroll, Nich e.g., oral forms of the inhibitors, or to receive additional et al. 1998); (George, Chawarski et al. 2000); (Petrakis, therapies, e.g., DEPO forms of disulfiram. In fact, patient Carroll et al. 2000)). Disulfiram is approved by the Food compliance is a significant problem with these types of and Drug Administration
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