US 2002001.9421A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0019421 A1 Biberman (43) Pub. Date: Feb. 14, 2002 (54) COMPOSITIONS AND THERAPY FOR Publication Classification SUBSTANCE ADDICTION (51) Int. CI.7. ... A61K 31/44; A61K 9/00 (76) Inventor: Roni Biberman, Tel-Aviv (IL) (52) U.S. Cl. .............................................. 514/343; 424/43 Correspondence Address: Eitan, Pearl, Latzer & Cohen-Zedek (57) ABSTRACT Stal Park Inhibitors of monoamine oxidase used in combination with 2011 Crystal Drive an addictive Substance, or a pharmacological derivative or Arlington, VA 2.2202-3700 (US) analogue thereof, are useful for the treatment of Substance 9 addiction disorders. In particular, the invention discloses (21) Appl. No.: 09/898,027 compositions, and methods of use thereof, comprising Sel egiline and nicotine for the treatment of cigarette SmokerS (22) Filed: Jul. 5, 2001 wishing to abstain. The compositions and methods of use thereof include oral, inhalant, parenteral and transdermal Related U.S. Application Data patch modes of therapy, whereby the subject benefits from the combined effects of a monoamine oxidase inhibitor in (63) Non-provisional of provisional application No. combination with an addictive Substance, or derivative 60/216,366, filed on Jul. 5, 2000. thereof. US 2002/0019421 A1 Feb. 14, 2002 COMPOSITIONS AND THERAPY FOR 0006 The acetylcholine receptors appear to be of two SUBSTANCE ADDICTION general Subtypes, One Subtype appears to have nicotine as an agonist or muscarine as an agonist. Both types of receptor FIELD OF THE INVENTION are found in the central nervous System as well as the autonomic nervous System. 0001. The present invention relates to medicinal compo Sitions and methods of treating Substance addiction, in 0007. Other compounds in addition to cholinergic and particular addiction to nicotine-containing tobacco products, anticholinergic drugs have been tested for the purpose of wherein administration to an addicted subject of inhibitors attenuating withdrawal Symptoms, including craving. These of monoamine oxidase combined with co-administration of include benzodiazepines, dopamine agonists, Serotonin ago an addictive Substance is used to alleviate withdrawal Symp nists, inhibitors of dopamine carboxylase, and inhibitors of toms and to change or eliminate patterns of addictive Serotonin reuptake or of dopamine reuptake. The neurotrans Substance consumption, in particular that due to cigarette mitter dopamine has been shown to be strongly linked to the Smoking, over both short and extended periods of time. internal mechanism of pleasure Sensation mechanism of animal, including human, brains. BACKGROUND OF THE INVENTION 0008 More recently developed strategies have focused 0002 The present disclosure is related to U.S. provisional on the genetic basis of drug addiction, in particular addiction patent application No. 60/216,366, filed on Jul. 5, 2000 and to nicotine. Thus it has been hypothesized that individuals in which is hereby is incorporated herein by reference. The whom nicotine is slowly metabolized are both more likely to Statistical risk of dying from lung cancer in the United States consume fewer cigarettes or not be Smokers at all. Thus has doubled in the past thirty years for male cigarette inhibition of the metabolism of nicotine, through either SmokerS and has quadrupled for female cigarette SmokerS. inhibition of the nicotine degrading enzymes or through Lung cancer has now displaced cardiovascular disease as the inhibition of the Synthesis of nicotine degrading enzymes. Single most important cause of exceSS mortality among 0009 Inhibitors of the intracellular enzyme monoamine Smokers. Yet, about 50 million Americans continue to oxidase (monoamine oxidase) have been traditionally used Smoke. in medical therapies for the treatment of disease of the 0003. The benefits for smoking cessation are many, and central nervous System, in particular depression and Parkin are summarized in a publication entitled “The Health Ben Son's disease. The use of monoamine oxidase inhibitors in efits of Smoking Cessation: A Report of the Surgeon Gen the treatment of addiction, in particular, tobacco product eral, 1990', available from the Office on Smoking and addiction, has been recurrently Suggested although, for lack Health, Center for Disease Control, Rockville, Md. Among of conclusive data, these therapeutic compounds are not the benefits summarized are that within twenty-four hours currently endorsed for this use by the medical establishment. the chance of a heart attack decreases, within about two 0010 Most significantly, despite the introduction of nico weeks to three months lung function increases up to thirty tine replacement therapies, most frequently administered in percent, and in one year the exceSS risk of coronary heart the form of transdermal patch or nicotine gum, addiction to disease becomes half that of a Smoker. tobacco products and the associated increased morbidity and 0004 Smoking cessation programs often address both the mortality continues to be a global epidemic. physiological factor and the psychological factor. The widely available "nicotine-releasing patches' have been SUMMARY OF THE INVENTION highly advertised, and are useful for maintaining a nicotine 0011. The invention provides a pharmaceutical composi habituated patient on nicotine while addressing further the psychological factors of addiction. Craving is the most tion comprising an amount of an inhibitor of monoamine consistently observed withdrawal symptom and is probably oxidase, an amount of an addictive Substance, or derivative best described as a combination of physiological and psy thereof, and a Suitable diluent or carrier. chological factors. To treat craving for nicotine, other modes 0012. The invention provides a pharmaceutical compo of nicotine replacement therapy have been introduced, Sition comprising an amount of an inhibitor of monoamine including administration of nicotine by oral chewing gum oxidase, an amount of an addictive Substance, or derivative and by inhalation with a carrier for absorption through the thereof, and a Suitable diluent or carrier, wherein Said respiratory mucosa, including the lungs. composition is adapted to administer both the inhibitor of 0005. In addition to nicotine replacement therapy, other monoamine oxidase and the addictive Substance, or deriva pharmacological therapies have been described based on tive thereof, via the same route of administration. compounds which are expected to influence the physiologi 0013 The invention provides a pharmaceutical compo cal mechanisms common to nicotinic agents. This is the Sition comprising an amount of an inhibitor of monoamine basis for the use of compounds which interact with acetyl oxidase, an amount of an addictive Substance or derivative choline receptors, or affect levels of the neurotransmitter thereof, and a Suitable diluent or carrier, wherein Said carrier acetylcholine, as a means for reducing the desire for nicotine is an oral tablet, capsule, a comestible article, an aerosol, or other addictive drugs. Atropine and Scopolamine are nebulized vapor, Smoke, or a transdermal patch, and wherein alkaloids that block the action of acetylcholine at muscarinic Said carrier is Suitable for parenteral administration, includ receptors to produce antispasmodic, antisecretory, and anti ing intradermal, Subcutaneous, intramuscular, intravenous, parkinsonism actions. PhySoStigmine is an inhibitor of the intrathecal, Sublingual, rectal, vaginal, intraocular, transder enzyme acetylcholinesterase, thereby raising the level of mal, respiratory mucosal, or pulmonary routes of adminis acetylcholine through inhibition of its metabolism. tration. US 2002/0019421 A1 Feb. 14, 2002 0.014. The invention provides a pharmaceutical compo PharmaProjects 2806; PharmaProjects 1122; Phar Sition comprising an amount of an inhibitor of monoamine maProjects 331; PharmaProjects 4433; RS-2232; UP-614 oxidase, an amount of an addictive Substance or derivative 04, or mixtures thereof. thereof, and a Suitable diluent or carrier, wherein Said 0018. The invention provides a pharmaceutical compo addictive Substance, or derivative thereof, is nicotine and Sition, wherein Said monoamine oxidase inhibitor is Sel Said carrier is an oral tablet, capsule, a comestible article, an egiline, Said carrier is an oral tablet, a capsule, a comestible aeroSol carrier a vapor, a Smoke, or a transdermal patch and article, an aeroSol, a vapor, a Smoke, or a transdermal patch, wherein Said carrier is Suitable for parenteral administration, and wherein Said carrier is Suitable for parenteral adminis including intradermal, Subcutaneous, intramuscular, intrave tration, including intradermal, Subcutaneous, intramuscular, nous, intrathecal, Sublingual, rectal, vaginal, intraocular, intravenous, intrathecal, Sublingual, rectal, vaginal, transdermal, respiratory mucosal, or pulmonary routes of intraocular, transdermal, respiratory mucosal, or pulmonary administration, routes of administration, and Said addictive Substance, or 0.015 The invention provides a pharmaceutical compo derivative thereof, is nicotine, cotinine, a nicotinic agonist, Sition comprising an amount of an inhibitor of monoamine a derivative of nicotine, a dopamine agonist, an opiate, oxidase, an amount of an addictive Substance or derivative morphine, heroin, methadone, buprenorphine, fentanyl, thereof, and a Suitable diluent or carrier, wherein Said i naloxone, codeine, an amphetamine,