WO2018126303A1

WO2018126303A1 - Composition for treating alcohol addiction

Info

Publication number: WO2018126303A1
Application number: PCT/BE2018/000001
Authority: WO
Inventors: Philippe Kriwin; Roland Powis De Tenbossche
Original assignee: Individual
Current assignee: Individual
Priority date: 2017-01-05
Filing date: 2018-01-05
Publication date: 2018-07-12
Anticipated expiration: 2019-07-05

Abstract

Composition for treating human alcohol addiction or an alcoholic impulse control disorder or reducing the likelihood of relapse use of alcohol or practice of a behavior associated with an alcoholic impulse control disorder, said composition comprising enteric resistant active agent suitable for generating for at least 12 hours, advantageously for at least 24 hours, a C02 gas expulsion from the stomach through the esophagus.

Description

Composition for treating alcohol addiction

Said application claims the benefit of the priority of European patent applications EP17447001.3 and EP17447005.4 filed respectively on January 5, 2017 and August 25, 2017.

BACKGROUND OF THE INVENTION

As taught in US 2014/0072662, "Drug addiction is a chronic relapsing disorder, characterized by compulsion and craving to seek and take the drug, loss of control over drug intake, and emergence of negative emotional states when access to the drug is discontinued (Koob and Le Moal, 1997, 2008). Essentially, the path leading to addiction follows a course of social drug-taking, related with the hedonic effects of the drug (positive reinforcement) and known as drug recreational use. By increasing dosages, the recreational use may lead to perceiving the "need" or "craving" for the drug that in turn may move in a pattern of escalating compulsive use. This transition ultimately drives to a dependence state, where the continued drug use is rather aimed to prevent the withdrawal syndrome (negative reinforcement)."

The World Health Organization (WHO) defines substance addiction as using a substance repeatedly, despite knowing and experiencing harmful effects.

Substance addiction is a chronic, relapsing disease characterized by a loss of control over drug use, compulsive drug seeking and craving for a substance, use that persists despite negative consequences, and physical and/or psychological dependence on the substance. Substance addiction typically follows a course of tolerance, withdrawal, compulsive drug taking behavior, drug seeking behavior, and relapse. Substance abuse and addiction are public health issues with significant social and economic impact on both the addict and society by playing a major role in violent crime and the spread of infectious diseases. Addictive substances include alcohol, caffeine, nicotine, cannabis (marijuana) and cannabis derivatives, opiates and other morphine-like opioid agonists such as heroin, phencyclidine and phencyclidine-like compounds, sedative ipnotics such as benzodiazepines and barbiturates and psychostimulants such as cocaine, amphetamines and amphetamine-related drugs such as dextroamphetamine and methylamphetamine.

As stated in said document, "the World Health Organization (WHO) defines substance addiction as using a substance repeatedly, despite knowing and experiencing harmful effects. Substance addiction is a chronic, relapsing disease characterized by a loss of control over drug use, compulsive drug seeking and craving for a substance, use that persists despite negative consequences, and physical and/or psychological dependence on the substance. Substance addiction typically follows a course of tolerance, withdrawal, compulsive drug taking behavior, drug seeking behavior, and relapse. Substance abuse and addiction are public health issues with significant social and economic impact on both the addict and society by playing a major role in violent crime and the spread of infectious diseases. Addictive substances include alcohol, caffeine, nicotine, cannabis (marijuana) and cannabis derivatives, opiates and other mo hine-like opioid agonists such as heroin, phencyclidine and phencyclidine-like compounds, sedative ipnotics such as benzodiazepines and barbiturates and psychostimulants such as cocaine, amphetamines and amphetamine-related drugs such as dextroamphetamine and methylamphetamine.

Alcohol is one of the most commonly abused substances at a global level.

Particularly in Europe, about 58 million adults (16%) are classified as heavy drinkers, of which about 23 million (6%) are alcoholics. Europeans spend Euro 100 billion on alcoholic beverages annually, which is reflected by the high rate of alcohol consumption per capita of 10 litres of pure alcohol per year. Similarly, the alcohol consumption in North America in the last decade averaged 8.5 litres per year (Spanagel, 2009). Excessive alcohol drinking is a condition that in the United States affects more than 12% of the population at some point in their life (Hasin et al, 2007). Consuming and abusing these huge amounts of alcohol clearly drives to detrimental consequences with enormous socio-economic and health impacts on the world population. Elevated alcohol consumption is in fact associated with costly, adverse social consequences, such as disruption of families, crime, traumatic accidents, and lost productivity. Additionally, alcoholism leads to serious liver and cardiovascular disease and generates dependence resulting in severe mental disorders, social problems and adverse consequences including the division of families, tragic accidents and the reduction of work performance.

According to the WHO, alcohol consumption is responsible for 20-30% of oesophageal and liver cancer, liver cirrhosis, homicides, epilepsy, and motor vehicle accidents worldwide. Globally, alcohol abuse leads to about 1.8 million deaths per year. According to the European Status Report on Alcohol and Health 2010, the total tangible cost of alcohol to the European Union was estimated to be Euro 125 billion, equivalent to 1.3% of the gross domestic product. Actual spending on alcohol-related problems accounts for 66 billion of this, while potential production not realized due to absenteeism, unemployment and premature mortality accounts for a further 59 billion.

Compulsive behaviour towards the consumption of alcohol is a core symptom of the disorder. In recent years several approaches have been investigated to help alcoholic patients to not only control alcohol drinking but also alcohol cravings and relapse (Monti et al., 1993; Volpicelli et al. 1992; O'Brien et al. 1997).

Medications such as naltrexone, acamprosate, ondansetron, disulfuram, gamma hydroxybutyrate (GHB), and topiramate have been tested for their potential therapeutic effect on alcohol abuse belong to several classes (Volpicelli et al. 1992; O'Brien et al. 1997). Few of these phannacotherapeutics, such as naltrexone, acamprosate, and disulfuram, have been proven to be of a certain utility and approved for the treatment of alcoholism. Among these medications, the non- selective opioid antagonist naltrexone is currently considered the pharmacological gold standard. However, despite some promising results none of these

medications, including naltrexone, is of sufficient efficacy in alcoholism and prognosis remains poor.

Currently available pharmacotherapies for alcohol addiction are only moderately successful, continue to be viewed with considerable scepticism outside the scientific community and have not become widely adopted as treatments (Heilig et al, 2011). Indeed, the clinical diagnosis of alcoholism follows well established criteria as reported in the Diagnostic and Statistical Manual of Mental Disorders [currently in its fourth edition, (DSM IV), see table 1], contributing to eliminate some of the subjective judgment involved in making diagnoses. However, approximately three-quarters of those in the general population who meet diagnostic criteria for alcoholism never receive treatment (Hasin et al, 2007). Therefore, new therapeutic approaches for treatment of alcoholism are needed.

In the past, treatment for substance addictions focused on behavioural therapy, but dependence on many of these highly addictive substances is hard to break. In particular, addictions to alcohol, cocaine, and heroin are considered chronic, relapsing disorders. Also, concurrent abuse of multiple substances, such as nicotine, heroin, cocaine and alcohol, is common.

The associated medical, social and occupational difficulties that develop during the course of addiction do not disappear after detoxification and changes in brain due to addictive drugs endure long after the patient stops taking them, accounting for high risks of relapse (O'Brien and McLellan, 1996). Clinical evidence indicates that 40% to 60% of patients treated for drug dependence return to active substance use within a year following treatment discharge (McLellan et al, 2000).

The long-lasting, chronic nature of many addictions and high rates of recidivism present a considerable challenge for the treatment of drug and alcohol addiction, such that understanding of the neurobiological basis of relapse has emerged as a central issue in addiction research. Emotional and environmental factors

(conditioning stimuli) were listed among the main causes of relapse. For example, it is known that specific stress conditions such as loss of work and economic difficulties, or stimuli predictive of the presence of alcohol previously associated with its use, such as a bottle of the preferred wine and a bar-like environment, may strongly facilitate relapse in detoxified former alcoholics.

Clearly, there is a need in the art for new methods for treating and preventing addiction and the relapse use of addictive agents. The present invention meets these needs by providing methods and nutraceutical compositions useful in treating and preventing addiction, including addiction to addictive substances and practice of behaviours associated with impulse control disorders, as well as reducing relapse use of addictive substances and relapse practice of behaviours associated with impulse control disorders.

SUMMARY OF THE INVENTION

The present invention is directed to a composition and a method for treating alcohol substance addiction or an impulse control disorder or reducing the likelihood of relapse use of an alcohol substance or practice of a behavior associated with an alcohol impulse control disorder by administering to a subject in need thereof a composition including an effective amount of enteric resistant active agent suitable for generating for at least 12hours, in which the composition is effective to treat the substance addiction or impulse control disorder or reduce the likelihood of relapse use of the addictive substance or practice of the behavior associated with the impulse control disorder.

The invention relates thus to an oral composition at least suitable for treating human alcohol addiction or an alcoholic impulse control disorder or reducing the likelihood of relapse use of alcohol or practice of a behavior associated with an alcoholic impulse control disorder, said composition comprising enteric resistant active agent suitable for generating for at least 12hours, advantageously for at least 24hours, preferably for at least 3 days, or even more preferably for at least 7 days, a C02 gas expulsion from the stomach through the esophagus. This long time efficiency of the particles resistant in the acid gastric medium is appropriate for preventing recidivism risk.

The invention further relates to an oral composition for treating human alcohol addiction or an alcoholic impulse control disorder or reducing the likelihood of relapse use of alcohol or practice of a behavior associated with an alcoholic impulse control disorder, said composition comprising a growth medium appropriate for aldehyde producing bacteria, especially for aldehyde producing bacteria naturally present in the stomach, said growth media comprising advantageously a gelled phase. Advantageously, it comprises a carrier, especially a gas retaining/releasing means associated to/with a coating comprising a gelling agent and ethanol, especially comprising a sugar gelling agent and ethanol

While not being bound to any theory, it is expected that a better treatment of alcohol addiction is due to the better release of C02 gas dissolved into the gastric medium and/or a better oxidation of alcohol, and/or acetic acid comprised in the particles and/or a better growth of acetobacter aceti on the support resistant in the acid gastric medium and/or the up and down movement of the support within the gastric medium, whereby C02 is release, while oxygen is loaded before the downwards movement of the support in the gastric medium. While still not being bound to any theory, it is expected that some acetaldehyde is released in the stomach, whereby generating an Antabuse effect.

The composition of the invention is also advantageous for other health purposes, such as formation of acetic acid into the stomach, treating addiction against various addictive substances, such as cannabis, cocaine, etc., satiety,

The oral composition of the invention has one or more of the following details or characteristics:

• said enteric resistant active agent is suitable for generating for at least 12 hours, advantageously for at least 24hours, preferably for at least 3 days, or even more preferably for at least 7 days, a C02 gas bubbling within the stomach.

· Said enteric active agent is suitable for the growth of acetobacter bacteria's present in the stomach, especially acetobacter aceti present in the stomach,

• said enteric resistant active agent is suitable for lowering the C02 gas stomach content for at least 12 hours, advantageously at least 24 hours, preferably for at least 3 days. the said enteric resistant active agent is formed by active flake particles having a density higher than 1 (such as comprised between 1.1 and 2, especially between 1.2 and 1.8), a particle surface comprised between 1 and 50mm², especially between 1 and 20mm² (advantageously between 3mm² and 18mm², preferably between 5mm² and 15mm²), and gas retaining/releasing means selected from pits, cavities and open pores (pores with a diameter for example between lOOnm and 600nm).

said flake particles have a thickness of less than 2mm,

advantageously of less than 1mm, preferably from ΙΟμιη up to 500μη .

the said enteric resistant active agent is a gas retaining/releasing means adapted for collecting C02 gases dissolved within the enteric medium.

the gas retaining/releasing means is adapted for collecting C02 gases dissolved within the enteric medium, whereby lowering its apparent density below the enteric medium density,

the gas retaining/releasing means is adapted for collecting C02 gases dissolved within the enteric medium, and for generating a C02 bubbling within the enteric medium.

The oral composition comprises an effective dose of aldehyde producing bacteria (such as acetic acid producing bacteria, especially for patients with low aldehyde producing bacteria) and/or with a growth medium (such as alcohol or wine containing growth medium) appropriate for aldehyde producing bacteria, especially for aldehyde producing bacteria naturally present in the stomach, said growth media comprising advantageously a gelled phase. In this case, aldehyde producing bacteria are growing on the support and increases the aldehyde (for example vinegar) producing bacteria content within the stomach The gas retaining/releasing means is associated with a coating comprising a gelling agent and ethanol, especially comprising a sugar or gum gelling agent and ethanol. The gelling agent can be xanthan gum. The gelling agent can comprise a cellulose ether, vinyl alcohol, vinyl pyrrolidone, natural gum, acrylic polymer, polyoxyethylene - polyoxypropylene copolymer and mixtures thereof. The cellulose ether is advantageously selected from the group consisting of hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, methyl cellulose, hydroxypropyl ethylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxycellulose and mixtures thereof. The vinyl alcohol is preferably polyvinyl alcohol. The vinyl pyrrolidone is preferably polyvinylpyrrolidones. The natural gum is advantageously selected from the group consisting of karaya gum, locust bean gum, guar gum, gelan gum, xanthan gum, gum arabic, tragacanth carrageenan, pectin, agar, alginic acid, sodium alginate and mixtures thereof. The acrylic polymer is preferably selected from the group consisting of methacrylates, polyacrylates copolymers and mixtures thereof. The polyoxyethylene-polyoxypropylene copolymer is advantageously poloxamer.

The oral composition comprising from lOOmg up to 5g

(advantageously from 200mg up to lOOOmg, preferably from 500mg up to 800mg) of enteric resistant active agent suitable for generating for at least 12hours, advantageously for at least 24hours, preferably for at least 3 days, or even more preferably for at least 7 days, a C02 gas expulsion from the stomach through the esophagus.

The oral composition comprising an enteric degradable dosage form comprising loose particles of enteric resistant active agent or bound particles suitable to be converted into loose particles in the stomach (with or without disintegrant agent). The dosage form can be in the form of capsule or tablets, with an enteric degradable binding or capsule, or suspension. The oral composition further comprising an additional therapeutic agent, advantageously an antidepressant. In a particular

embodiment, the antidepressant is bupropion or sibutramine.

Antidepressants are drugs used to treat depression. The three neurotransmitters believed to be involved in depression are serotonin, dopamine, and norepinephrine. Certain types of antidepressants increase the levels of one or more of these neurotransmitters in the brain by blocking their reabsorption.

Several different classes of antidepressants have been identified, including selective serotonin reuptake inhibitors (SSRIs), tricyclic and tetracyclic serotonin and norepinephrine reuptake inhibitors (SNRIs), norepinephrine reuptake inhibitors (NRIs), norepinephrine and dopamine reuptake inhibitors (NDRIs), azaspirones, monoamine oxidase inhibitors (MAOIs), and atypical

antidepressants. SSRIs include, e.g., cericlamine, citalopram, clomipramine, cyanodothiepin, dapoxetine, duloxetine,

escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, imipramine, indalpine, indeloxazine, litoxetine, lofepramine, mianserine, milnacipran, mirtazapine, nefazadone, nortriptyline, paroxetine, sertraline, sibutramine, tomoxetine, trazodone, venlafaxine, and zimeldine. Amitriptyline, amoxapine, butriptyline, clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine, dothiepin, doxepin, imipramine, iprindole, lofepramine,

maprotiline, melitracen, metapramine, mianserin, mirtazpine, nortriptyline, propizepine, protriptyline, quinupramine, setiptiline, tianeptine, and trimipramine are all tricyclic and tetracyclic antidepressants. SNRIs include, e.g., amoxapine, atomoxetine, bicifadine, desipramine, desvenlafaxine, duloxetine, maprotiline, milnacipran, nefazodone, reboxetine, sibutramine, and venlafaxine. Nisoxetine, nortriptyline, reboxetine, talsupram, and tomoxetine are all examples of NRIs. NDRIs include, e.g., bupropion, hydroxybupropion, and tesofensine. Azaspirones include, e.g., buspirone, gepirone, ipsapirone, tandospirone, and tiaspirone. Buspirone is an anxiolytic (partial agonist at 5-HT1 autoreceptors) that may be provided with an antidepressant such as an SSRI. Specific MAOIs include, e.g., amiflamine, brofaromine, clorgyline, alpha-ethyltryptamine, iproclozide, iproniazid, isocarboxazid, mebanazine, moclobemide, nialamide, pargyline, phenelzine, pheniprazine, pirlindole, safrazine, selegiline, toloxatone, and tranlcypromine. Atypical antidepressants include, e.g., amesergide, amineptine, benactyzine, bupropion, clozapine, fezolamine, levoprotiline, lithium, medifoxamine, mianserin, minaprine, olanzapine, oxaflozane, oxitriptan, rolipram, teniloxazine, tofenacin, trazodone, tryptophan, and viloxazine. · the enteric resistant active agent is suitable for accelerating the oxidation of alcohol in the stomach, and/or the formation of acetic acid in the stomach.

• the enteric resistant active agent is of natural origin (such as pod or coat of seeds, such as of common bean or phaseolus vulgaris or white beans).

• The oral composition comprises glycine betaine (for example from lOOmg up to 800mg).

• The oral composition further comprising Acetobacter, especially acetobacter aceti.

· Any combinations of one or more details and characteristics

disclosed here above.

The invention relates also to a method of treating alcohol addiction or an alcohol impulse control disorder or reducing the likelihood of relapse use of alcohol or practice of a behavior associated with an alcoholic impulse control disorder, comprising admimstering to a subject in need thereof an oral composition according to the invention comprising an effective amount of enteric resistant active agent suitable for generating for at least 12hours, advantageously for at least 24hours, preferably for at least 3 days, or even more preferably for at least 7 days, a C02 gas expulsion from the stomach through the esophagus, wherein the composition is effective to treat the alcohol addiction or alcohol impulse control disorder or reduce the likelihood of relapse use of alcohol or practice of the behavior associated with the alcohol impulse control disorder.

The invention further relates to a method of treating alcohol addiction or an alcohol impulse control disorder or reducing the likelihood of relapse use of alcohol or practice of a behavior associated with an alcohol impulse control disorder, comprising administering to a subject in need thereof a composition according to the invention comprising an effective amount of enteric resistant active agent effective to treat the alcohol addiction or impulse control disorder or reduce the likelihood of relapse use of the alcohol or practice of the behavior associated with the impulse control disorder.

As used herein, unless the context makes clear otherwise, "treat," and similar word such as "treatment," "treating" etc., is an approach for obtaining beneficial or desired results, including and preferably clinical results. Treatment can involve optionally either the reducing or amelioration of a disease or condition, (e.g., addiction, relapse use, withdrawal), or the delaying of the progression of the disease or condition (e.g., addiction relapse use, withdrawal).

As used herein, unless the context makes clear otherwise, "prevent," and similar word such as "prevention," "preventing" etc., is an approach for preventing the onset or recurrence of a disease or condition, (e.g., addiction, relapse use, withdrawal) or preventing the occurrence or recurrence of the symptoms of a disease or condition, or optionally an approach for delaying the onset or recurrence of a disease or condition or delaying the occurrence or recurrence of the symptoms of a disease or condition. Preventing also includes inhibiting the onset or recurrence of a disease or condition, or one or more symptoms thereof, and reducing the likelihood of onset or recurrence of a disease or condition, or one or more symptoms thereof. Alcoholism is defined as a chronic relapsing disease. Therefore, studies on alcohol addiction are aimed not only at identifying remedies suitable to decrease alcohol consumption but also for alcohol seeking prevention. Activation of the brain stress system is thought to play a pivotal role in alcohol addiction, and stress is a major factor triggering relapse in abstinent alcoholics (Koob, 2008). Yohimbine, an a-2 adrenoceptor antagonist, increases cell firing and release of brain noradrenalin, and acts as a pharmacologic stressor (Abercrombie et al, 1988; Aghajanian and VanderMaelen, 1982; Holmberg et al, 1962; Le et al, 2005; Lee et al, 2004).

Yohimbine is known to increase anxiety-like symptoms related to alcohol abuse in humans (Charney et al, 1983; Umhau et al, 2011) and in rats, and importantly this drug has been shown to reinstate alcohol seeking following extinction in rats trained to self-administer alcohol (Le et al, 2005; Marinelli et al, 2007). This pharmacological stressor can therefore be used to investigate the effect of the composition of the invention on reinstatement of alcohol seeking behavior, as further described in the examples below.

The term addiction is used to describe a recurring compulsion by an individual to engage in some specific activity, despite harmful consequences to the individual's health, mental state or social life. The term "addiction" is often reserved for substance addictions, but as used herein with respect to the compositions and treatments of the present invention also refers to other compulsions, such as problem gambling, compulsive overeating and other impulse control disorders. Factors that have been suggested as causes of addiction include genetic, biological/pharmacological and social factors.

The medical community now makes a careful theoretical distinction between physical or physiological dependence (characterized by symptoms of withdrawal) and psychological dependence (sometimes referred to simply as addiction).

Addiction is now narrowly defined as "uncontrolled, compulsive use." If there is no harm being suffered by, or damage done to, the patient or another party, then clinically it may be considered compulsive, but to the definition of some it is not categorized as "addiction". In practice, the two kinds of addiction (physiological dependence and psychological dependence) are not always easy to distinguish. Addictions often have both physical and psychological components.

Physical dependence (or drug dependence) refers to a state resulting from habitual use of a drug, where negative physical withdrawal symptoms result from abrupt discontinuation. Examples of addictive agents for which a user may develop a physical dependence include nicotine, opioids, barbiturates, benzodiazepines, alcohol, i.e., ethyl alcohol, GHB, and methaqualone.

As used herein with respect to the disorders to be treated by the methods and compositions of the present invention, addictive agents includes any and all agents to which a subject can become addicted, either physically or psychologically, or both. As noted above, addictions to be treated by the methods and compositions of the present invention include addiction to chemical entities, such as drugs, e.g., ethyl alcohol, nicotine, or cocaine, as well as addiction to other behaviors, e.g., pathological gambling, pathological overeating, pathological use of electronic devices, e.g., smart phones, pathological use of electronic video games, pathological use of electronic communication devices, pathological use of cellular telephones, addiction to pornography, sex addiction, obsessive compulsive disorder, compulsive spending, binge eating disorder, food addiction, anorexia, bulimia, intermittent explosive disorder, kleptomania, pyromania, trichotillomania, compulsive overexercising, and compulsive overworking.

Addiction to addictive agents to be treated with the methods and compositions of the present invention include addictive recreational drugs, as well as addictive medications. Examples of addictive agents include, but are not limited to, alcohol, e.g., ethyl alcohol, gamma hydroxybutyrate (GHB), caffeine, nicotine, cannabis (marijuana) and cannabis derivatives, opiates and other morphine-like opioid agonists such as heroin, phencyclidine and phencyclidine-like compounds, sedative ipnotics such as benzodiazepines, methaqualone, mecloqualone, etaqualone and barbiturates and psychostimulants such as cocaine, amphetamines and amphetamine-related drugs such as dextroamphetamine and

methylamphetamine. Other examples include LSD, psilocybin, ecstasy and other hallucinogens. Examples of addictive medications include, e.g., benzodiazepines, barbiturates, and pain medications including alfentanil, allylprodine, alphaprodine, anileridine berizylmorphine, bezitramide, buprenoφhine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,

dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin,

hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofenitanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomoiphine, norlevorphanol, normethadone, naloφhine,

no ipanone, opium, oxycodone, OXYCONTIN®, oxynu^hone, papaveretum, pentazocine, phenadoxone, ρηεηοπιοφΐΜη, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene sufentanil, tramadol, tilidine, salts thereof, mixtures of any of the foregoing, mixed μ-agonists/antagonists, and the like.

While a subject may be addicted to a single addictive agent or behavior, frequently, a subject is addicted to two or more addictive agents or behayiors. Addiction to two or more addictive agents or addictive behaviors is referred to as polyaddiction, and may also be treated in accordance with the present invention. The subject treated in accordance with the present invention may be any animal, including a mammal, and, particularly, a human.

In particular embodiments, the subject is suffering from or at risk for addiction to any physically addictive agent or addictive or compulsive behavior, including, e.g., any of those described below. In particular embodiments, the subject is addicted to alcohol, cocaine, nicotine, marijuana, an opiate or other opioid agonist or methamphetamine or other psychostimulant, or phencyclidine and phencyclidine derivatives.

In particular embodiments, a subject is considered at risk of addiction or relapse to use of an addictive agent or practice of an addictive or compulsive behavior when the subject has previously been addicted to the same or a different addictive agent or addictive or compulsive behavior. In certain embodiment, the subject is considered at risk of addiction or relapse to use of an addictive agent or practice of an addictive or compulsive behavior when the subject is psychologically addicted to an addictive agent or addictive or compulsive behavior, even if the subject is no longer physically addicted.

In certain embodiments, the subject is addicted to or at risk of becoming addicted to a therapeutic agent provided to the patient to treat a disease or disorder, e.g., a pain medication. In a related embodiment, the subject may be at risk of abusing an addictive therapeutic agent, such as a pain medication. Abusing an addictive therapeutic agent, in certain embodiments, is understood to indicate using the agent for a reason different than or in addition to its prescribed use. In such a situation, a subject may be provided with both an addictive therapeutic agent alone or in combination with an additional therapeutic agent. For example, a subject suffering from pain, or at risk of pain, may be provided with an opioid agonist, to both provide analgesia and prevent or treat addiction to the opioid agonist.

Alcoholism, like many other addictions, is a chronic relapsing disorder

characterized by high recidivism rates. Two major factors triggering relapse behaviour are stress and environmental conditioning experiences (O'Brien et al. 1997; Monti et al. 1993; Shaham et al. 1995), which probably facilitate relapse to alcohol-seeking via distinct brain mechanisms. For example, activation of the mesolimbic dopamine system via an opioid-dependent mechanism (or via direct alterations in dopamine transmission in the basolateral nucleus of amygdala) seems to mediate the effect of drug-associated cues (Liu and Wiess 2002;

Ciccocioppo et al. 2001), and, extrahypothalamic CRF within the bed nucleus of the stria terminalis and median raphe nucleus is likely to mediate stress-induced reinstatement of drag-seeking behaviour (Erb et al 1998; Shaham et al. 1995; Le et al. 2000).

The present invention further includes unit dosage forms of pharmaceutical compositions comprising the active agent and possibly another therapeutic agent. Each unit dosage form comprises a therapeutically effective amount of a pharmaceutical composition of the present invention, when used in the

recommended amount. For example, a unit dosage form may include a therapeutically effective amount in a single tablet, or a unit dosage form may include a therapeutically effective amount in two or more tablets, such that the prescribed amount comprises a therapeutically effective amount. Tests on volunteers and formulations

Formulation 1

Phaseolus vulgaris beans have been broken so as to form large pod particles with a particle size of 5 - 10mm², and powder particles issued form the core of the Phaseolus vulgaris. The large pod particles and particles have been sterilized (heat treated).

The pod particles with a size larger than 5mm² have been recovered.

When placing the pod particles within a water glass with citric acid or acetic acid and with some oil, some particles are sinking while some others are floating. No movement of particles was observed.

When further adding to said water glass some sparkling water or Champaign, an upwards and downwards movement of pod particles was observed.

When using powder particles, the powder particles are sinking.

Pod particles could be administered as such, but for having an easier

administration, pod particles were placed in capsule degradable within the gastric medium, so that the pod particles are released within the gastric medium.

The capsules were filled with 300mg of thin pod particles of Phaseolus vulgaris with a surface size of 5 - 10mm². The two volunteers have taken once a week. It was observed that when the volunteers have taken one wine glass they had no addiction for taking a further wine glass. When taking however said second wine glass, they had some specific sensations, like belching, bloating, acid taste, nausea, etc., sensation convincing the volunteers not to further taken a glass wine. Said sensations were still acting two days after the administration of the bean pod particles, when the volunteers took a glass wine. It is expected that said effect is due to the growth of some acetobacter on the pods.

The dose to be administered can be selected in function of the addiction trouble to be treated and the severity thereof. It has to be noted the administration of a dose of acetobacter aceti had no effect or very limited effect during the time (less than 1 hour), while the drinking of a vinegar dose had no effect at all.

Formulation 2

Thin pod of Phaseolus vulgaris with a surface size of 5 - 10 mm² was mixed into a a growth medium comprising Acetobacteraceae, so as form pod provided with a layer comprising said bacteria. The so coated pods have been dried at 50°C or at a lower temperature, before being incorporated into gelatin capsules.

A problem existing with such formulation is that some bacteria species not naturally present in the body can be inoculated into the body.

Formulation 3

Thin pod of phaseolus vulgaris (heat treated for sterilizing the pods) have been first mixed with sugar powder and thereafter small amount of alcohol (whisky with a 40% ethanol content). Thereafter the mixture was compressed so as to shape tablets of about lOOOmg or lower. Water can be added if necessary for tableting purposes.

The tablets comprise about 200 to 300mg pods (dry weight); about 650 to 750mg sugar (powder), about 10 to 50mg disintegrant (such as crosspovidone or croscarmellose sodium), and about 5 to 20mg alcohol with an ethanol volume content of 40% (60% water ).

The tablets are able to be disintegrated within the stomach.

The tablets can be provided with a water soluble outer layer.

Formulation 4

Formulation 4 has been prepared in the manner as disclosed for formulation 3, except that the pod particles have been first mixed with some alcohol, before being mixed with sugar and a remaining amount of alcohol (especially wine). Formulation 5

Alcohol has been mixed with sugar, a disintegrant and a gelling agent, and then with the pods. The mixture is heated so as to induce the gelification.

Capsules (gelatin) have been filled with the hot gelled mixture, so as to form capsules with a pod content of about 200mg and an ethanol content of about 20mg. Formulations 3 to 5 are advantageous for the growth of the natural bacteria present in the stomach, able to form in acid medium some aldehyde.

Formulation 6

Pods are mixed into wine (12% volume alcohol content) in contact with air. After 1 month, the wine is converted at least partly into vinegar. The pods are then removed and air dried at a temperature below 60°C. The pods (in doses of 500mg to lg) are then placed into sachets. For the consumption, the pods are mixed in water before being gulped.

Claims

What We claim is:

1. Oral Composition at least suitable for treating human alcohol addiction or an alcoholic impulse control disorder or reducing the likelihood of relapse use of alcohol or practice of a behavior associated with an alcoholic impulse control disorder, said composition comprising enteric resistant active agent suitable for generating for at least 12hours, advantageously for at least 24hours, preferably for at least 3 days, or even more preferably for at least 7 days, a C02 gas expulsion from the stomach through the esophagus.

2. The oral composition of claim 1, whereby said enteric resistant active agent is suitable for generating for at least 12 hours, advantageously for at least 24hours, preferably for at least 3 days, or even more preferably for at least 7 days, a C02 gas bubbling within the stomach.

3. The oral composition of claim 1 or 2, whereby said enteric resistant active agent is suitable for lowering the C02 gas stomach content for at least 12 hours, advantageously at least 24 hours, preferably for at least 3 days.

4. The oral composition of any one of the preceding claims, whereby the said enteric resistant active agent is formed by active flake particles having a density higher than 1, a particle surface comprised between 1 and 50mm², advantageously between 1 and 20mm², and gas retaining/releasing means selected from pits, cavities and open pores.

5. The oral composition of the preceding claim, in which said flake particles have a thickness of less than 2mm, advantageously of less than 1mm, preferably from ΙΟμπι up to 500μιη.

6. The oral composition of any one of the preceding claims, in which the said enteric resistant active agent is a gas retaining/releasing means adapted for collecting C02 gases dissolved within the enteric medium.

7. The oral composition of the preceding claim, in which the gas

retaining/releasing means is adapted for collecting C02 gases dissolved within the enteric medium, whereby lowering its apparent density below the enteric medium density.

8. The oral composition of claim 6 or 7, in which the gas retaining/releasing means is adapted for collecting C02 gases dissolved within the enteric medium, and for generating a C02 bubbling within the enteric medium.

9. The oral composition of any one of the preceding claims, comprising from 1 OOmg up to 5g of enteric resistant active agent suitable for generating for at least 12hours, advantageously for at least 24hours, preferably for at least 3 days, or even more preferably for at least 7 days, a C02 gas expulsion from the stomach through the esophagus.

10. The oral composition of any one of the preceding claims, comprising aldehyde producing bacteria and/or with a growth medium appropriate for aldehyde producing bacteria, especially for aldehyde producing bacteria naturally present in the stomach, said growth media comprising advantageously a gelled phase.

11. The oral composition of the preceding claim, in which the gas

retaining/releasing means is associated with a coating comprising a gelling agent and ethanol, especially comprising a sugar gelling agent and ethanol.

12. The oral composition of any one of the preceding claims, comprising an

enteric degradable dosage form comprising loose particles of enteric resistant active agent or bound particles suitable to be converted into loose particles in the stomach.

13. The oral composition of any one of the preceding claims, comprising or being associated to a growth medium for aldehyde producing bacteria, especially Acetobacter aceti, most preferably Acetobacter aceti naturally present in the stomach.

14. The oral composition of the preceding claim, in which the growth medium comprises ethanol, and advantageously a gelification or gelling agent, preferably a sugar based gelling agent, especially comprising galactose unit, such as agar agar.

15. The oral composition of any one of the preceding claims, comprising or being associated to an effective dose of an acid working aldehyde producing bacteria, especially to Acetobacter aceti bacteria.

16. The oral composition of any one of the preceding claims further comprising an additional therapeutic agent, advantageously an antidepressant.

17. The oral composition of any one of the preceding claims, in which the enteric resistant active agent is suitable for accelerating the oxidation of alcohol in the stomach, and/or the formation of acetic acid in the stomach.

18. The oral composition of any one of the preceding claims, in which the enteric resistant active agent is of natural origin.

19. The oral composition of any one of the preceding claims, which comprises glycine betaine.

20. Oral Composition for treating human alcohol addiction or an alcoholic

impulse control disorder or reducing the likelihood of relapse use of alcohol or practice of a behavior associated with an alcoholic impulse control disorder, said composition comprising a growth medium appropriate for aldehyde producing bacteria, especially for aldehyde producing bacteria naturally present in the stomach, said growth media comprising advantageously a gelled phase.

21. The oral composition of the preceding claim, which comprises a carrier,

preferably a gas retaining/releasing means associated to/with a coating comprising a gelling agent and ethanol, especially comprising a sugar gelling agent and ethanol.

22. A method of treating alcohol addiction or an alcohol impulse control disorder or reducing the likelihood of relapse use of alcohol or practice of a behavior associated with an alcoholic impulse control disorder, comprising

administering to a subject in need thereof an oral composition according to any one of the preceding claims comprising an effective amount of enteric resistant active agent suitable for generating for at least 12hours,

advantageously for at least 24hours, preferably for at least 3 days, or even more preferably for at least 7 days, a C02 gas expulsion from the stomach through the esophagus, wherein the composition is effective to treat the alcohol addiction or alcohol impulse control disorder or reduce the likelihood of relapse use of alcohol or practice of the behavior associated with the alcohol impulse control disorder.

23. A method of treating alcohol addiction or an alcohol impulse control disorder or reducing the likelihood of relapse use of alcohol or practice of a behavior associated with an alcohol impulse control disorder, comprising administering to a subject in need thereof a composition according to any one of the claims 1 to 21 comprising an effective amount of enteric resistant active agent effective to treat the alcohol addiction or impulse control disorder or reduce the likelihood of relapse use of the alcohol or practice of the behavior associated with the impulse control disorder.