EP1617831A1

EP1617831A1 - Combination of desoxypeganine and mecamylamine for the treatment of alcohol abuse

Info

Publication number: EP1617831A1
Application number: EP04727830A
Authority: EP
Inventors: Hilke Winterhoff; Joachim Moormann; Klaus Opitz
Original assignee: HF Arzneimittelforschung GmbH and Co KG
Current assignee: HF Arzneimittelforschung GmbH and Co KG
Priority date: 2003-04-25
Filing date: 2004-04-16
Publication date: 2006-01-25
Also published as: EA200501514A1; MY136408A; DE10318714B4; ZA200507213B; US20060199866A1; DE10318714A1; TW200427452A; JP2006524647A; MXPA05011249A; WO2004096200A1; KR20060006946A; CN1771029A; CA2523331A1; BRPI0410507A; AR044067A1; NO20054243L; CL2004000881A1; AU2004233564A1

Abstract

Disclosed is an active substance combination comprising desoxypeganine or a pharmaceutically acceptable derivative thereof and mecamylamine or a pharmaceutically acceptable derivative thereof. Said active substance combination is used for producing a medicament that is utilized for the treatment of alcohol abuse and/or alcohol addiction.

Description

COMBINATION OF DESOXYPEGANIN AND MECAMYLAMINE FOR TREATING ALCOHOL MISUSE

DESCRIPTION OF THE INVENTION

The present invention relates to pharmaceutical preparations which contain 3-deoxypeganine and / or ecamylamine. The invention further relates to the use of this combination of active substances for the therapy of harmful alcohol consumption and alcohol addiction,

PROBLEM

Of the numerous psychotropic substances with abuse potential, ethanol (commonly referred to as "alcohol") is the oldest, most widespread and by far the most important in terms of its health, social and economic effects. In Germany, there are around 1.6 million clinically dependent on alcohol and 2.7 million people with medically harmful alcohol consumption. About 5 million people are considered to be at risk of alcohol. About 40,000 people, including not only clinically alcohol-dependent people, but also people with high-risk alcohol consumption over long periods, die annually from the direct consequences of alcohol consumption. Significantly, the number of these deaths and alcohol withdrawal therapies has remained essentially constant in western industrialized countries, although total alcohol consumption has been declining for years, suggesting that this decrease in total alcohol consumption primarily due to reduced consumption or the waiver of broad strata of consumers who have been relatively health-conscious so far, while the Distribution of high-risk or harmful alcohol consumption hardly changed.

It is therefore the task of pharmacologically supporting the reduction of high-risk or harmful alcohol consumption - also and in particular of such consumption behavior that is not yet associated with clinical dependency.

STATE OF THE SCIENCE AND TECHNOLOGY

Five drugs are currently approved for drug therapy of alcohol abuse in European countries and / or in the United States of America. Of these, the bis (diethylthiocarbamoyl) disulfide (disulfiram, Antabus®) which has been in use for the longest time only has an aversive effect which does not influence the actual alcohol demand. While tiapride, an antagonist of dopamine that acts on the receptor subtypes D2 and D3, has gained little practical importance, the opiate receptor antagonist naltrexone (ReVia®, DuPont; Trexan®) and the acamprosate (N-acetylhomotaurin), which has a complex anti-excitatory effect, ; Ca pral®, Merck AG; Aotal®), which also influences noradrenergic and dopaminergic conduction pathways, is used to a much greater extent after acute withdrawal to prevent relapses in alcohol abuse. The anti-excitatory gamma-hydroxybutyrate (eg Alcover®, Gerot Pharmaceuticals) has recently become available in some European countries. However, naltrexone and gamma-hydroxybutyrate produce significant gastrointestinal and psychomotor side effects that impair compliance with the therapy. Naltrexone is also characterized by low oral bioavailability (approx. 5% of the amount taken is effective) moreover hepatotoxic, while gamma-hydroxybutyrate itself has addictive potential.

However, the long-term success of all of the pharmaceuticals listed here can be described as very limited overall, since they only cause marginal delays in relapse after withdrawal or a clinically minor reduction in the amount of alcohol consumed in the vast majority of patients. The fact that on average only about 30% of all patients are still abstinent one year after withdrawal treatment has not been influenced by these drugs in the long term.

The therapy of the early stages of a development of clinical alcohol dependence that often spanned decades (ICD-10 Code F10.2 of the World Health Organization, WHO) and in particular that which is not yet associated with clinical dependence, but with a high physical and psychiatric damage potential Harmful consumption of alcohol (ICD-10 Code F 10.1) would also require particularly low-side-effects medication, since the so-called "social drinkers" have little insight into the problem of drinking behavior due to the low level of suffering and therefore little willingness to endure such side effects.

Alcohol shares with all other addictive substances the ability to activate dopaminergic neurons in the mesolimbic system, which is a central component of the "reward system" in the brain that mediates pleasure and satisfaction. Dopaminergic therapy can either be done directly (by dopamine receptor agonists such as lisuride or bromocriptine), or indirectly by increasing the dopamine concentration locally available in the synaptic cleft (for example by inhibiting the breakdown of the neurotransmitters by monoamine oxidases). However, the pharmacology of alcohol is complicated, which is also reflected in the variety of therapeutic approaches described above. According to current estimates, the effects of alcohol, which are sedative, euphoric and impair cognitive and motor coordination, are due to the fact that ethanol interacts with the protein subunits of many neuronal receptors and thus modulates their function. Receptors that represent ion channels are particularly affected by this, even at concentrations that are still far too low to permanently disrupt neuronal membrane structures.

Modulators of cholinergic neurotransmission, which include cholinesterase inhibitors in particular, occupy a special position in alcoholism therapy that has received little attention. On the one hand, cholinergic drugs can improve cognition that is impaired by alcohol-related damage to the cholinergic conduction pathways, thereby increasing insight into the problem. On the other hand, cholinergic therapies can also bring about an immediate, non-cognitive reduction in the desire for alcohol. According to the current state of knowledge, this is mediated by the neuronal nicotinic acetylcholine receptors (nAChR), which are located not only on cholinergic but also on dopaminergic neurons in the mesolimbic system. These receptors are stimulated by increasing the acetylcholine concentration and then release more dopamine. In doing so, they simulate the dopamine release caused by alcohol, but without exerting its effects on other receptors and without causing extremely high dopamine concentrations, so that no significant addictive behavior is induced. In a broader sense, this therapeutic approach can be described as partial substitution therapy. Deoxypeganine (1,2,3, 9-tetrahydropyrrollo [2, 1-b] quinazoline) is a cholinesterase inhibitor that does not bind to nAChR in pharmacologically relevant concentrations and additionally inhibits monooxidase A (but not monoamine oxidase B). This substance is also extremely suitable for the therapy of alcohol abuse, as described in DE 199 06 974 and the documents WO 00/48600 and EP 1 154 776 derived therefrom.

One approach that is completely opposed to partial substitution therapy is the therapy of substance use by blocking the receptor systems activated by the respective agonistically active drug.However, if there is substance dependence, withdrawal symptoms can be triggered and there is therefore a high probability of relapse in substance use. This applies, for example, to the therapy of nicotine abuse by blocking nAChR with mecamylamine (N- (2,2,3-tetramethyl-bicyσlo [2.2.1.] Heptan-2-amine).

This racemic mixture of the optical isomers exo-S (+) and exo-R (-) -mecamylamine is an almost 100% orally bioavailable, centralized, non-subtype-specific and non-competitive antagonist of neuronal nAChR, which was established in the United States in 1956 Brand names Inversene® and Inversine® were introduced as antihypertensive agents in therapy. The two stereoisomers show differentiated, but essentially comparable behavior on the individual nAChR subtypes, whereby the exo-S (+) isomer has a certain selectivity for neuronal nAChR and could therefore have reduced peripheral side effects, particularly on the muscles. Since mecamylamine causes a substantial blockade of the parasympathetic nervous system at the effective doses of at least 25 mg / day in the treatment of essential hypertension and thus leads to an abundance of corresponding side effects, it has only been used since 1977 in exceptional cases. In year In 2000, mecamylamine was reintroduced to the United States for experimental therapy of certain neuropsychiatric disorders.

In US Pat. No. 6,083,962, combinations of specific antagonists with the substances with the potential to act as agonists at the corresponding receptors are claimed, in particular combinations of mecamylamine with nicotine for the therapy of nicotine abuse. This is based on the consideration that by administering nicotine in a pharmacologically suitable, non-addictive form (by means of a transdermal dosage form in particular, which causes an even and controlled release), part of the nAChR can be activated and thus the primary craving for nicotine can be satisfied , but prevent its continued consumption by blocking the remaining nAChR with mecamylamine administered at the same time. In fact, a pilot study showed a synergistic effect of such a fixed combination of active substances, which could be further increased by giving mecamylamine alone before quitting smoking (Drug Dev Res 1996; 38: 243-56; Exp Clin Psychopharmacol 1998; 6 (3): 331-43). According to the results of three phase III studies reported in 1998, however, a transdermally administered fixed combination of active substances had not proven to be superior to the nicotine patch. However, alcohol abuse is not addressed in any of the documents mentioned.

Blomq is et al teach in Eur J Pharmacol 1993; 249 (2): 207-13 and Eur J Pharmacol 1997; 334 (2-3): 149-56 that mecamylamine completely blocks the alcohol-induced increase in extracellular dopamine concentration in the nucleus accumbens of the rat, but without impairing the physiologically important basal level of dopamine release. It is therefore a blockade of the dopaminergic component of Alcohol activity, which the authors consider in conjunction with the above-described principles as an indirect effect mediated by nAChR. Furthermore, with reference to this work as a theoretical basis in Alcohol Clin Exp Res 2002; 26: 326-31 described an experiment on healthy volunteers who did not use alcohol or nicotine. In this study, mecamylamine, administered two hours before drinking alcoholic beverages, reduced the central stimulating psychotropic effects and presumably also the pharmacokinetics of alcohol. Neither of these three works mentions the combination and / or simultaneous administration of mecamylamine with other pharmacologically active substances, in particular not with cholinesterase inhibitors or nicotinic agonists.

In the published documents WO 00/35279 and WO 00/35280, the two isomers of mecamylamine are claimed for the therapy of a large number of conditions requiring medical treatment, including alcohol abuse. However, no biological data are given for this option, and combinations with other pharmacologically active substances for this therapeutic purpose are not even mentioned.

OBJECT OF THE INVENTION

According to the state of the art described above, in particular the fact that the pharmacology of alcohol abuse is far more complex than the addictive effect of nicotine, it was by no means possible for the person skilled in the art to assume that deoxypeganine, a substance which acts indirectly on nAChR by increasing the central acetylcholine concentration , a synergistic effect with mecamylamine (a direct inhibitor of nAChR) with regard to the reduction of alcohol consumption and Alcohol preference compared to non-alcoholic beverages. Surprisingly, however, that is exactly the case.

The invention thus relates to the combined use of deoxypeganine and mecamylamine to reduce alcohol consumption. The treatment can be carried out either by the simultaneous administration of the two active substances or by the sole administration of mecamylamine, immediately followed by a combination of the active substances according to the invention.

Example 1:

Reduction of alcohol consumption and alcohol preference in alcohol-preferential rats

The rat strain "AA", bred in Finland, has a genetically determined preference for alcohol, ie the animals prefer alcohol-free liquids to alcohol-free liquids to satisfy their fluid needs, even without pretreatment with alcohol. This strain has therefore been used in numerous studies on the pharmacology of alcohol and is characterized excellently.

Female AA rats (tested for alcohol preference and provided by the Public Health Institute in Helsinki) were kept individually with free access to standard food (Altro in 1324 granules), the

Ambient temperature 24 +/- 1 ° C and the light / dark change was 12/12 hours (dark period from 6 p.m. to 6 a.m.). Each cage contained two identical drinking vessels, one containing pure water and the other aqueous ethanol (10% v / v). The animals were given access to the vessels during the 12-hour dark phase and were free to choose between the two solutions during this time. To one To prevent getting used to a certain position in the cage, the positions of the bottles were changed daily. Before the experiments began, the animals were given a period of familiarization until a largely constant consumption of alcohol and water was guaranteed.

Deoxypeganine hydrochloride (hereinafter referred to as "DOP") was obtained from the Institute of Plant Pharmacology (Tashkent, Uzbekistan) and provided by LTS Lohmann Therapie-Systeme (Andernach, Germany) after checking its identity and purity. Mecamylamine was considered to be commercial preparation obtained from Sig a-Aldrich GmbH (Munich).

The treatment of the test animals was always carried out immediately before the start of the dark period. Mecamylamine was dissolved in 0.9% saline and administered in a volume of 5 ml / kg body weight by intraperitoneal injection. DOP was applied as an aqueous solution in a volume of 10 ml / kg using a pharyngeal tube. In the case of combination treatments, these administrations were carried out within a period of less than 10 minutes. At least two treatment-free days were always interposed before and after the treatment days.

The parameters alcohol consumption, water consumption and feed consumption (each in grams) as well as the alcohol preference were calculated using the formula:

(Consumption of alcoholic drinking solution x 100) Alcohol preference in%

(total fluid consumption)

The target parameters were monitored during the 12 hours of the dark period following the treatment, with intermediate results after the first 4 hours and final results after 12 hours. The statistical Evaluation of the test data was carried out with the t-test for dependent values. The results with regard to alcohol consumption and alcohol preference are summarized in Figures 1 and 2 and in Tables 1 and 2.

Table 1: Synergy between deoxpeganine p.o. (DOP) and mecamylamine i.p. (Mec) in reducing alcohol preference in female AA rats

*) Significant difference (p <0.05) compared to DOP 20 mg / kg in the respective experiment

When given 20 mg / kg po orally, DOP reduced alcohol consumption and alcohol preference, preferably within the first four hours after administration. Mecamylamine (1 mg / kg ip) alone had no effect, but potentiated the effect of DOP on both parameters. Lower doses of mecamylamine (0.5 or 0.75 mg / kg ip) were ineffective with regard to alcohol, while the potentiating effect could not be further increased by increasing the mecamylamine dosage to 1.5 mg / kg ip (tables 1 and 2). Table 2: Synergy between deoxpeganine po (DOP) and mecamylamine ip (Mec) in reducing the consumption of 10% aqueous ethanol solution by female AA rats.

**) Difference highly significant (p <0.01 or p <0.001) compared to DOP 20 mg / kg in the respective experiment

FABRICATION AND TREATMENT FORMS OF THE INVENTION

The administration according to the invention can take place either in the form of a single medicament with a fixed combination of both active ingredients, or else by administration in separate administration forms.

According to the invention, deoxypeganine HCl can be administered orally in the form of tablets or capsules, the daily dose being 50 to 750 mg and a daily dose of 100 to 400 mg being preferred, which can be divided into any number of individual doses. Furthermore, deoxypeganm-containing transdermal therapeutic systems and oral and parenteral administration forms with delayed release, as described in DE-199 06 974 and the documents WO 00/48600 and EP-1 154 776 derived therefrom be used, usable; the preferred daily dose is 50-250 mg and is preferably given in a single dose.

According to the invention, mecamylamine can be administered orally, for example in the form of the Inversin ™ preparation (Targacept, Inc., USA; tablets containing 2.5 mg of racemic mecamylamine hydrochloride), the daily dose being 2.5-20 mg and a daily dose of 2.5 - 7.5 mg is preferred. Likewise, transdermal systems or oral dosage forms with delayed release formulated according to the usual galenical methods can be used, the daily dose being 0.5-10 mg and preferably being administered in a single dose.

According to the invention, deoxypeganm and mecamylamine can also be administered in the form of medicaments which contain fixed combinations of the two active compounds, which, depending on the type of administration, are designed such that the daily dose of deoxypeganine is 50 to 750 mg and that of mecamylamine is 0.5 - Can be 20 mg.

It goes without saying for the person skilled in the art that this list is only exemplary and does not in any way preclude the use of known derivatives of the compounds mentioned above. For example, instead of the hydrochloride salt of deoxypeganine, its other physiologically compatible salts or addition compounds and, for certain dosage forms, the free base can also be used, in particular for transdermal formulations. In the same way, instead of deoxypeganm, the derivatives described in the literature are also to be understood insofar as these are cholinesterase inhibitors. These include that in Synthetic Coiamuns. 25 (4), 569-572 (1995) described 7-bromodeoxypeganine, which is described in Drug Des. Disc. 14, 1-14 (1996) 7-halo-6-hydroxy-5-methoxydesoxypeganine 7- Bromo-6-hydroxy-5-methoxydesoxypeganine, 7-chloro-6-hydroxy-5-methoxydesoxypeganine, 7-fluoro-6-hydroxy-5-methoxydesoxypeganine and 7-iodo-6-hydroxy-5-methoxydesoxypeganine as well as the in Ind. J. Chem. 24B, 789-790 (1985) described derivatives of deoxypeganine, wherein it should be noted that, especially in the older literature, deoxypeganm is often referred to as desoxyvasicin.

In the case of mecamylamine, not only is that e.g. commercially available under the name Inversine Race at, but also each of the two isomers described in WO 00/35279 and WO 00/35280, also in the form of the respective pharmaceutically acceptable salts and addition compounds, can be used for the preparation of dosage forms according to the invention. The term “salts” is to be understood as meaning, but not exclusively, the salts of the compounds according to the invention with hydrohalic acids and with simple organic acids, such as tartaric acid (tartrates), succinic acid (succinates), maleic acid (maleates), etc.

Furthermore, according to the invention, the treatment described above with combinations of deoxypeganm and mecamylamine can be preceded by a pretreatment which is carried out exclusively with racing ischemic mecamylamine or its individual isomers and is carried out with daily doses between 0.5 and 20 mg and between one day and five days can take.

The pharmaceutical forms which are used according to the present invention for the administration of a combination of 3-deoxypeganm or one of its pharmaceutically acceptable derivatives with mecamylamine or one of its pharmaceutically acceptable derivatives can contain one or more of the following additives:

- antioxidants, synergists, stabilizers;

- preservatives; - taste corrections;

- colorants;

- solvents, solubilizers;

- surfactants (emulsifiers, solubilizers, wetting agents, defoamers);

- viscosity and consistency influencers, gelling agents;

- absorption accelerator;

- adsorbents, humectants, lubricants;

- Decay and solution influencers, fillers (extenders), peptizers;

- Release delay.

This list is not exhaustive; the physiologically harmless substances in question are known to the person skilled in the art.

A combination of 3-deoxypeganm or one of its pharmaceutically acceptable derivatives with mecamylamine or one of its pharmaceutically acceptable derivatives can be administered orally or parenterally. For oral administration, drugs can be produced in known dosage forms, such as tablets, coated tablets or lozenges. In addition, liquid or semi-liquid dosage forms are also suitable, the active ingredient being present as a solution or suspension. Water, aqueous media or pharmacologically acceptable oils (vegetable or mineral oils) can be used as solvents or suspending agents.

The medicaments containing a combination of 3-deoxypegane or one of its pharmaceutically acceptable derivatives with mecamylamine or one of its pharmaceutically acceptable derivatives are preferably formulated as depot medicaments which are able to release these active substances to the organism in a controlled manner over a longer period of time , In addition, the administration of a combination of 3-deoxypeganm or one of its pharmaceutically acceptable derivatives with mecamylamine or one of its pharmaceutically acceptable derivatives according to the invention can also be carried out parenterally. For this purpose, transdermal or transmucosal dosage forms can be used particularly advantageously for the administration according to the invention of a combination of 3-deoxypeganm or one of its pharmaceutically acceptable derivatives with mecamylamine or one of its pharmaceutically acceptable derivatives, in particular adhesive transdermal therapeutic systems (active substance plasters). These make it possible to release the active ingredient over the skin to the patient to be treated in a controlled manner over a longer period of time.

Another advantage is that misuse is less easy with parenteral administration forms than with oral administration forms. Overdosing on the part of the patient can largely be ruled out by the predetermined active substance release area and the predetermined release rate. In addition, transdermal dosage forms are very advantageous due to other properties, e.g. B. Avoiding the first pass effect or better, more even control of blood levels.

Such transdermal systems, a combination of 3-deoxypeganine or one of its pharmaceutically acceptable derivatives with mecamylamine or one of its pharmaceutically acceptable derivatives, usually have an active substance-containing, pressure-sensitive polymer matrix which is covered on the side remote from the skin by an active substance-impermeable backing layer, and the adhesive, active ingredient-releasing surface is covered with a removable protective layer before application. The The manufacture of such systems and the raw materials and auxiliaries which can be used are fundamentally known to the skilled worker; for example, the structure of such transdermal therapeutic systems is described in German patents DE 33 15 272 and DE 38 43 239 or in US Patents 4,769,028, 5,089,267, 3,742,951, 3,797,494, 3,996,934 and 4,031,894 ,

So-called reservoir systems can be considered as alternative embodiments of transdermal therapeutic systems in plaster form for the administration of the active substance combination according to the invention, in which the active substances are present in a pouch consisting at least on the skin side of a membrane permeable to the active substances.

The combination of 3-deoxypeganm or one of its pharmaceutically acceptable derivatives with mecamylamine or one of its pharmaceutically acceptable derivatives according to the invention can be used in the therapy of harmful alcohol consumption and alcohol addiction in order to reduce the consumption of alcohol.

The combination according to the invention of 3-deoxypeganm or one of its pharmaceutically acceptable derivatives with mecamylamine or one of its pharmaceutically acceptable derivatives can be used for the production of medicaments for the therapy of alcohol abuse and / or alcohol addiction, in particular in order to reduce the consumption of the alcohol.

Claims

1. Active ingredient combination consisting of deoxypeganm or one of its pharmaceutically acceptable derivatives and mecamylamine or one of its pharmaceutically acceptable derivatives for the manufacture of a medicament for the treatment of alcohol abuse and / or alcohol addiction.

2. Active ingredient combination according to claim 1, characterized in that the pharmaceutically acceptable derivative of deoxypeganine is selected from the group consisting of deoxypeganine hydrochloride, 7-bro odesoxypeganine, 7-bromo-6-hydroxy-5-methoxydesoxypeganine, 7- Chloro-6-hydroxy-5-methoxydesoxypeganine, 7-fluoro-6-hydroxy-5-methoxydesoxypeganine and 7-iodo-6-hydroxy-5-ethoxydesoxypeganine exist.

3. Active ingredient combination according to claim 1 or 2, characterized in that the pharmaceutically acceptable derivative of mecamlyamine is selected from the group consisting of the salts of mecamylamine with hydrohalic acids or simple organic acids such as tartaric acid, succinic acid, maleic acid and the like.

4. Active ingredient combination according to one of the preceding claims, characterized in that the mecamylamine is present in the form of the racemic mixture of its two stereoisomers or in the form of one of its two stereoisomers.

5. Active ingredient combination according to one of the preceding claims, characterized in that the medicament in the form of a common dosage form for deoxypeganm or one of its pharmaceutically acceptable derivatives and Mecamylamine or one of its pharmaceutically acceptable derivatives.

6. Active ingredient combination according to one of claims 1 to 4, characterized in that the medicament is in the form of separate dosage forms for deoxypeganm or one of its pharmaceutically acceptable derivatives and mecamylamine or one of its pharmaceutically acceptable derivatives.

7. active ingredient combination according to one of the preceding claims, characterized in that the medicament is in the form of an oral or parenteral, preferably transdermally administered dosage form.

8. Active ingredient combination according to claim 7, characterized in that it is in the form of a pharmaceutical form which has a depot effect.

9. Active ingredient combination according to one of the preceding claims, characterized in that the daily dose of deoxypeganm or one of its pharmaceutically acceptable salts in an administration form to be administered orally is 50 to 750 mg, preferably 100 to 400 mg.

10. Active ingredient combination according to one of claims 1 to 8, characterized in that the daily dose daily dose of Deoxypeganm or one of its pharmaceutically acceptable salts in a dosage form to be administered transdermally is 50 to 250 mg.

11. Active ingredient combination according to one of the preceding claims, characterized in that the daily dose of mecamylamine in an administration form to be administered orally is 2.5 to 20 mg, preferably 2.5 to 7.5 mg.

12. Active ingredient combination according to one of claims 1 to 10, characterized in that the daily dose of mecamylamine in a dosage form with delayed release is 0.5 to 10 mg.

13. Use of an active ingredient combination according to one of the preceding claims for the treatment of alcohol abuse and / or alcohol addiction.

14. A method for the treatment of alcohol abuse and / or alcohol dependency, characterized by the administration of an active ingredient combination according to one of claims 1 to 12.

15. The method according to claim 14, characterized in that the administration of the active ingredient combination is preceded by a pretreatment with mecamylamine.