WO2004078178A1

WO2004078178A1 - Buprenorphine compounds for treatment of alcohol dependence and excessive alcohol use

Info

Publication number: WO2004078178A1
Application number: PCT/SE2004/000293
Authority: WO
Inventors: Markus Heilig
Original assignee: Individual
Current assignee: Individual
Priority date: 2003-03-03
Filing date: 2004-03-03
Publication date: 2004-09-16
Anticipated expiration: 2005-09-03
Also published as: WO2004078178B1

Abstract

The invention relates to use of a buprenorphine compound or a pharmaceutical ac-ceptable salt or ester thereof for the preparation of a pharmaceutical composition for preventing or treating alcohol dependence and excessive alcohol use. It also concerns the use of a buprenorphine compound together with an opiate receptor antagonist and a method for treating or preventing of alcohol dependence and excessive alcohol use.

Description

Buprenorphine compounds for treatment of alcohol dependence and excessive alcohol use.

Technical field

The present invention relates to the use of buprenorphine compounds or a pharmaceutical acceptable salt or ester thereof for the preparation of a pharmaceutical for preventing or treating alcohol dependence and excessive alcohol use. It also concerns the use of buprenorphine compounds together with an opiate receptor antagonist and a method for preventing or treating alcohol dependence and excessive alcohol use.

Background

Buprenorphine or 6,14-Ethenomorphinan-7-methanol, 17-(cyclopropylmethyl)- alpha-( 1 , 1 -dimethylethyl)-4,5-epoxy- 18,19-dihydro-3-hydroxy-6-methoxy-alpha- methyl-, (5-alpha,7-alpha-(S)) is generally considered as a partial mu-opioid receptor agonist, and a full kappa-opioid receptor antagonist. It has documented efficacy use for treatment of pain and substitution treatment of heroin dependence.

The present inventors have shown that buprenorphine compounds at higher doses, or in combination with an opioid receptor antagonist, can be used for prevention of treatment of alcohol dependence/alcohol abuse. This is a novel use of the compound. Further, this use of the compound is based on a mechanism of action which in itself is novel.

Inconsistent effects on alcohol self-administration have previously been reported following administration of buprenorphine alone. This treatment resulted in either increased or decreased consumption depending on the post-treatment time interval and dose. Furthermore, effects were largely non-specific since they affected also water intake (June et al Psychopharmacology (Berl). 1998 Nov; 140(1): 29-37). In contrast to these findings, the present invention is also for the combined use of buprenorhine and an opioid receptor antagonist such as e.g. naltrexone. This combination is here demonstrated to utilise a different mechanism, i.e. nociceptine / ORL1 receptor activation. It produces consistent suppression of alcohol self- administration, eliminates the side effect and safety profile problems of buprenorphine when used alone, and can thus be used for treatment.

Summary of the invention.

The present invention relates to the use of buprenorphine compounds according to claim 1 or a pharmaceutical acceptable salt or ester thereof for the preparation of a pharmaceutical composition for preventing and treating alcohol dependence and excessive alcohol use.

It also concerns the use of buprenorphine together with an opiate receptor antagonist and a method for preventing and treating of alcohol dependence and excessive alcohol use.

Detailed description.

The present invention relates to the use of buprenorphine compounds of the formula:

and its non-toxic pharmaceutically-acceptable salts, wherein: R is hydrogen or methyl,

Rl is hydrogen, alkyl, alkenyl or alkynyl of up to 8 carbon atoms or cycloalkyl methyl of 4-6 carbon atoms, R2 is hydrogen, alkyl or alkenyl of up to 3 carbon atoms, phenyl or tolyl and R3 is cycloallcyl of 5-7 carbon atoms, alkyl or alkenyl of up to 8 carbon atoms or alkyl or alkenyl of up to 8 carbon atoms substituted on one of the carbon atoms numbered 1-4 (the carbon atom numbered 1 being adjacent to the carbon atom bearing the alcoholic hydroxy group) by cycloalkyl of 5-7 carbon atoms, phenyl, tolyl, alkoxy of 1-3 carbon atoms, phenoxy or tetrahydrofuryl or a pharmaceutical acceptable salt or ester thereof for the preparation of a pharmaceuti- cal composition for treatment of alcohol dependence and excessive alcohol use.

The inventors have shown that the effects of buprenorphine are in fact two-fold, leading to a biphasic effect on ethanol intake. At low doses, buprenorphine increases self-administration of alcohol in a pharmacologically validated animal model. This is demonstrated to occur through actions at opioid receptors, since the effect is completely blocked by systemic pre-treatment with the non-selective opioid receptor antagonist naltrexone. At higher doses, buprenoφhine markedly and dose depen- dently suppresses self-administration of alcohol (Example 1). This effect is not opioid mediated, since it is unaffected by pre-treatment with naltrexone (Example 5). Instead, it is demonstrated to be produced through actions at nociceptin/ORLl receptors, since mtracerebroventricular administration of a selective antagonist for this receptor type blocks the suppressing effect of buprenorphine on alcohol self- administration (Example 6).

The salts useful in the compositions of this invention include any pharmaceutically acceptable salt formed at the amine group of buprenorphine. Many such salts are known in the art, including those described in the following references, all incorporated by reference herein: S. Berge et al., "Pharmaceutical Salts", 66 J. Pharm. Sci. 1 (1977); P. Gould, "Salt selection for basic drugs", 33 Int. J. of Pharmaceutics 201 (1986); and World Patent Publication 87/05297, Johnston et al, published September 11, 1987.

The salt may be an acid addition salt or a salt with a base. Suitable acid addition salts include the hydrochloride, sulphate, methane sulphonate, stearate, tartrate, citrate and lactate salts or mixtures thereof. Preferred salts include the hydrohalic acid salts, such as hydrochloric acid.

Preferred salts of this invention also include mixtures of one or more buprenorphine compounds with a pharmaceutically acceptable acid. In such compositions, the buprenorphine and the pharmaceutically acceptable acid are mixed in the composition as discrete components. The pharmaceutically-acceptable acid is preferably present in an amount such that the number of equivalents of buprenorphine in the composition is about equal to the number of equivalents of acid in the composition (i.e., the number of moles of acid multiplied by the number of acid groups available on the acid).

Many such pharmaceutically acceptable acids useful herein are known in the art. Preferred pharmaceutically-acceptable acids include, for example, the hydrohalic acids (such as hydrochloric acid) sulphuric acid, phosphoric acid, and the carboxylic acids (such as acetic acid, propionic acid, citric acid, tartaric acid, malic acid, maleic acid, lactic acid, malonic acid, fumaric acid, salicylic acid, succinic acid, ascorbic acid, benzoic acid, and mixtures thereof. Particularly preferred pharmaceutically acceptable acids useful herein include citric acid and lactic acid.

The invention also concerns the use of a buprenorphine compound together with an opiate receptor antagonist. Preferably naltrexone is used as opiate receptor antagonist. The term "pharmaceutical composition", as used herein, means a combination of an effective amount of the buprenorphine compounds of the present invention or mixtures thereof, and at least one pharmaceutically acceptable excipient.

The phrase "an effective amount", as used herein, means a therapeutically effective amount of a compound or composition large enough to modify the symptoms and/or condition to be treated, but small enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgement. The effective amount of active ingredient for use in the pharmaceutical compositions and the methods of the invention herein will vary depending upon the severity of the alcohol abuse, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient being employed, the particular pharmaceutically-acceptable ex- cipients utilised, and like factors within the knowledge and expertise of the attending physician.

The daily doses depend on the individual to be treated and the severity of the condition. The skilled medical doctor can establish suitable doses. The daily dose for the buprenorphine compound is at least 8 mg, preferably least 10 mg and most preferred least 16 mg. The upper limit is set mainly by economic considerations to up to 60 mg preferably 50 mg and especially 48 mg per day. Suitably doses are 8-60 mg, preferably 10-50, especially 16-48 mg per day.

The daily dose of naltrexone is at least 30 mg, preferably least 40 mg and most preferred least 50 mg. The upper limit is set mainly by economic considerations to up to 300 mg preferably 250 mg and especially 200 mg per day. Suitable doses are 30- 300 mg body weight, preferably 40-250 mg, especially 50-200 mg per day.

The term "pharmaceutically acceptable excipients", as used herein, includes any physiologically inert, pharmacologically inactive material known to one skilled in the art, which is compatible with the physical and chemical characteristics of the particular buprenorphine compound active ingredient selected for use. Pharmaceutically acceptable excipients include, but are not limited to, polymers, resins, plasti- cizers, fillers, binders, lubricants, glidants, disintegrates, solvents, co-solvents, buffer systems, surfactants, preservatives, sweetening agents, flavouring agents, pharmaceutical grade dyes or pigments, and viscosity agents.

The buprenorphine compounds of the present invention may be administered to humans or other mammals by a variety of routes, including, but not limited to, topical, oral and parenteral (i.e. intravenous, intramuscular, intraperitoneal and subcutaneous injections) and dosage forms, including but not limited to those described in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Company, 1990 (i.e. liquids, suspensions and tablets). Numerous other dosage forms containing the novel ketoamide compounds of the present invention can be readily formulated by one skilled in the art, utilising the suitable pharmaceutical excipients as defined above. For considerations of patient compliance, oral dosage forms are generally most preferred.

The invention also relates to a method for preventing alcohol dependence or excessive alcohol use comprising identifying an individual at risk for developing alcohol dependence or excessive alcohol use and administering a pharmaceutically effective amount of a buprenorphine compound according to the invention to the individual possibly together with an opiate receptor antagonist.

The invention also relates to a method for treating alcohol dependence or excessive alcohol use comprising identifying an individual suffering from alcohol dependence or excessive alcohol use and administering a pharmaceutically effective amount of a buprenorphine compound according to the invention to the individual possibly together with an opiate receptor antagonist. The invention will now be described with reference to the included figures of which:

Fig 1 shows the ethanol intake as a function of different dosages of buprenorphine,

Fig 2 shows the ethanol intake as a function of different dosages of the opiate receptor antagonist naltrexone,

Fig 3 shows the ethanol intake as a function of different dosages of the N/OFQ re- ceptor antagonist UFP- 101,

Fig 4 shows the effect of i.p. injections of naltrexone on buprenorphine-induced increased alcohol intake,

Fig 5 shows the effect of i.p. injections of naltrexone on buprenorphine-induced decreased alcohol intake

Fig 6 shows the effect of pre-treatment with the N/OFQ receptor antagonist UFP- 101 on buprenorphine.induced decreased ethanol intake.

The inventions will now be further described by way of the following non-limiting examples. All references mentioned herein are incorporated by reference.

Examples

Methods

Animals

Male genetically selected alcohol-preferring rats were employed. They were bred in the Department of Pharmacological Sciences and Experimental Medicine of the University of Camerino (Marche, Italy) for 53 generations from Sardinian alcohol- preferring (sP) rats of the 13^th generation, provided by the Department of Neuro- sciences of the University of Cagliari, Italy (Agabio R 1996; Colombo G 1997; Lo- bina C 1997). These animals are referred to as Marchigian Sardinian alcohol- preffering (msP) rats. At the time of the experiments their body weight ranged between 400 and 450 g. They were kept in a room with a reverse 12:12 h light/dark cycle (lights off at 9:00 a.m.), temperature of 20-22°C and humidity of 45-55%. Rats were offered free access to tap water and food pellets (4RF18, Mucedola, Set- timo Milanese, Italy). Experiments took place at 9:30 a.m., that is during the dark phase of the cycle. All the procedures were conducted in adherence to the European Community Council Directive for Care and Use of Laboratory.

Intracranial surgery

For intracranial surgery msP rats were anaesthetised by intramuscular injection of 100-150 μl/rat of a solution containing tiletamine cloridrate (58.17 mg/ml) and zo- lazepam cloridrate (57.5 mg/ml). A guide cannula for mtracerebroventricular (ICV) injections into the lateral cerebroventricle was stereotaxically implanted and cemented to the skull. The following coordinates, taken from the atlas of Paxinos and Watson (1986), were used: antero-posterior = 1 mm behind the bregma, lateral = 1.8 mm from the sagittal suture, ventral = 2 mm from the surface of the skull.

Drug injections

Buprenorphine and Naltrexone were purchased from Tocris while, UFP-101 and Nociceptin/orphanin FQ were a generous gift of Dr. G. Calo, Department of Pharmaceutical Sciences of the University of Ferrara, Italy. Naltrexone and UFP-101 were dissolved in sterile isotonic saline. Naltrexone was given by intraperitoneal (IP) injection, whereas, UFP-101 was ICV injected in a volume of 1 μl/rat by means of a stainless-steel injector 2.5 mm longer than the guide cannula, so that its tip protruded into the ventricle. Immediately before the rat sacrifice, 1 ml of black India ink was ICV injected and ink diffusion into the ventricles was evaluated. Buprenorphine was diluted with distilled water and was given by IP injection.

Experimental Procedures

At the age of three months msP rats were selected for their preference for 10% etha- nol solution (w/v), offering them free choice between water and 10% ethanol 24 h a day for 10 days. Water and 10% ethanol were offered in graduated drinking tubes equipped with metallic drinking spouts. The rats employed in the following experiments had a 24-h ethanol intake of 6-7 g/kg with a percent of ethanol preference [ml of ethanol solution/ml of total fluids (water + 10% ethanol) ingested in 24 h x 100] higher than 90.

Starting on day 11 rats had water and food available during the entire day, while 10% ethanol was offered for 2 h/day, at the beginning of the dark phase (9:30 a.m.) of the reverse light/dark cycle. Operated animals received only water and food during the entire day for 5 days after surgery. Then 10% ethanol was offered for 2 h/day.

All the experiments were carried out according to a within-subject design, in which each animal received, in a counterbalanced order, all doses and compounds tested. All animals received 3-4 IP or ICV injections before initiation of the experiments to familiarise them with the injection procedure.

Water and ethanol intakes were measured by reading the volume consumed from the graduated burettes and were always recorded 30, 60, 90 and 120 min after ethanol was offered to the animals. Food intake was measured by weighing the food containers and taking into account spillage and was only measured at 30, 60 and 120 min. Ethanol, water and food and intakes are expressed as g/kg to reduce the influ- ence of differences in body weight.

Statistical analysis

Statistical analysis of data was performed by means of two-way analysis of variance with repeated measures, one factor for treatment and one factor for time. Post-hoc comparisons were carried out by Newman-Keuls test. Statistical significance was set at/? < 0.05.

Example 1 : Effect of acute IP injections of Buprenorphine on Voluntary Alcohol Intake

To evaluate the effect of Buprenorphine on voluntary 10% ethanol intake, 10 msP rats were injected IP with different doses of Buprenorphine (0.03, 0.3, 3.0 and 6.0 mg/kg) or its vehicle (controls) at intervals of 3-4 days, 90 min before access to alcohol. Baseline ethanol drinking was re-established between different dose- treatments.

Results

The overall analysis of variance revealed a highly significant treatment effect [F(4,9) = 22,31;/? < 0.001]. Statistical analysis showed a significant biphasic effect with an increase of ethanol consumption following administration of 0.03 and 0.3 mg/kg of Buprenorphine (PO.01) and a decrease of drinking after treatment with 3.0 and 6.0 mg/kg of the drug (PO.05). As shown in Fig. 1 A, post-hoc comparisons demonstrated that at the two lower doses ethanol drinking significantly increased throughout the 2-h of observation, whereas, injection of 6.0 mg/kg of Buprenor- phine resulted in a significant decrease of drinking for all time point recorded. Similarly, administration of 3.0 mg/kg of the drug induced a significant inhibition of drinking at 30,60 and 120 min. Difference from controls was barely above statistical significance at 60 min (P=0.1). Buprenorphine treatment, elicited a significant decreased of food intake [F(4,9) = 5.15;/? < 0.001]. As shown in Fig. I , post-hoc test revealed a significant decrease only at the highest dose (6.0 mg/kg) tested. Water intake was not modified by drug treatment (data not shown).

Example 2: Effect of acute IP injections of Naltrexone on Voluntary Alcohol Intake To evaluate the effect of Naltrexone on voluntary 10% ethanol intake, according to a within subject design 10 animals received 95 min before access to ethanol Naltrexone (0.25, 1.0 and 2.5 mg/Kg, IP) or vehicle (controls) at intervals of 3-4 days. Baseline ethanol drinking was re-established between different dose-treatments.

Results

The overall ANOVA revealed a significant effect of Naltrexone [F(3,27) = 4.257;/? < 0.05]. As Shown in Fig. 2 Tpost-hoc comparisons showed a significant inhibition of ethanol intake following administration of 1.0 or 2.5 mg/kg of Naltrexone. Con- versely, injection of 0.25 mg/kg of the drug did not significantly modify alcohol consumption. Neither food intake nor water intake were modified by Naltrexone (data not shown).

Example 3: Effect of acute ICV injections of UFP-101 on Voluntary Alcohol Intake

To evaluate the effect of the N/OFQ receptor antagonist UFP-101 on voluntary 10% ethanol intake, at intervals of 3-4 days, 7 msP rats were ICV injected in a counterbalanced order with 5.0, 10.0, and 20.0 μg/rat or its vehicle given twice at 95 and 15 min before access to ethanol (10% w/v).

Results

The overall ANOVA showed that treatment with UFP-101 (5.0, 10.0 or 20.0 μg/rat) given twice at 95 and 15 min before access to ethanol (Fig. 3) did not modified ethanol drinking in msP rats [F(3,6) = 2.264; NS]. Neither food intake nor water intake were modified by UFP-101 treatment (data not shown).

Example 4: Effect of IP injections of Naltrexone on Buprenorphine induced increased Ethanol Intake To evaluate the effect of Naltrexone on Buprenoφhine-induced increased ethanol intake, a group of 13 rats was treated IP with Naltrexone (0.25 mg/kg) or its vehicle. Five minutes later, animals received an IP injection of 0.03 mg/kg of Buprenoφhine or its vehicle. Ethanol was given to the animals 90 min. after Buprenoφhine injection, and alcohol, water and food intake were measured for 2 hours. Rats received all drug treatments at intervals of 3-4 days. Baseline ethanol drinking was reestablished between different dose-treatments.

Results

The overall ANOVA revealed a highly significant treatment effect [F(3,12) = 11.208; /? < 0.001]. Buprenoφhine alone increased ethanol drinking (PO.01). This effect was completely abolished by pre-treatment with 0.25 mg/kg of Naltrexone. Rats treated with naltrexone alone did not differ from controls (Fig. 4). Water and food intake were not influenced by drug treatments (data not shown).

Example 5: Effect of IP injections of Naltrexone on Buprenoφhine-induced de- creased Ethanol Intake

To evaluate the effect of Naltrexone on the reduction of ethanol drinking induced by Buprenoφhine 8 rats were IP injected with 0.25 mg/kg Naltrexone or its vehicle. After 5 min, rats were treated IP with 3.0 mg/kg Buprenoφhine or its vehicle. Rats were offered access to 10% ethanol 90 min after Buprenoφhine injection. All drug treatments were made at intervals of 3-4 days. Baseline ethanol drinking was reestablished between different dose-treatment.

Results

Overall ANOVA showed a significant effect of treatment [F(3,7) = 5.90; /? < 0.01]. As shown in Fig. 5 administration of Buprenorphine 3.0 mg/kg significantly reduced ethanol drinking (P<0.05). Pre-treatment with Naltrexone (0.25 mg/kg, IP) did not significantly modify Buprenoφhine-induced decreased ethanol intake that remained significantly lower compared to control (P<0.01). Administration of Naltrexone alone slightly but not significantly reduced ethanol drinking. Water and food intake were never modified by drug treatments. Example 6: Effect of ICV injections of UFP-101 on Buprenoφhine-induced decreased Ethanol Intake

To evaluate the effect of UFP101 on the reduction of ethanol drinking induced by Buprenoφhine, according to a within subject design, a group of 10 rats was ICV treated with UFP-101 at the doses of 10 and 20 μg/rat or its vehicle, 95 and 15 min before access to 10%) ethanol. Buprenoφhine (3.0 mg/kg) or its vehicle was given 90 min before access to ethanol. Two injections of the peptidic ORL1 antagonist (UFP-101) were given, in an attempt to better antagonise the effects of the non- peptidic, long lasting opioidergic agent (Buprenoφhine). Rats received all drug treatments at intervals of 4-5 days. Baseline ethanol drinking was re-established between different dose-treatment.

Results

Overall ANOVA showed a significant effect of treatment [F(3,9) = 9.16;/? < 0.001]. Administration of Buprenoφhine at the dose of 3.0 mg/kg of significantly reduced alcohol intake (PO.05). Pre-treatment with UFP-101 at the dose of 10.0 μg/rat completely blocked the effect of Buprenoφhine. Administration of 20.0 μg/rat, of the N/OFQ antagonist not only reversed the reduction of ethanol intake by Buprenoφhine but compared to controls resulted in a significant increase of drinking (P<0.05). As shown in Fig. 6 significant differences from controls were observed throughout the entire period of observation. Water and food intake were never modified by drug treatments. References

1. Agabio R, Cortis G, Fadda F, Gessa GL, Lobina C, Reali R, Colombo G. Cir- cadian drinking pattern of Sardinian alcohol-preferring rats. Alcohol Alcohol 1996; 31: 385-8. 2. Colombo G. Ethanol drinking behaviour in Sardinian alcohol-preferring rats. Alcohol Alcohol 1997; 32: 443-53.

3. Lobina C, Agabio R, Diaz G, Fa M, Fadda F, Gessa GL, Reali R, Colombo G. Constant absolute ethanol intake by Sardinian alcohol preferring rats independent of ethanol concentrations. Alcohol Alcohol 1997; 32: 19-22. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 2^nd edition. North Ryde, N.S.W., Australia: Academic Press, 1986.

Claims

1. Use of a compound of the formula:

and its non-toxic pharmaceutically-acceptable salts, wherein:

R is hydrogen or methyl,

Rl is hydrogen, allcyl, alkenyl or alkynyl of up to 8 carbon atoms or cycloalkyl methyl of 4-6 carbon atoms,

R2 is hydrogen, alkyl or alkenyl of up to 3 carbon atoms, phenyl or tolyl and R3 is cycloallcyl of 5-7 carbon atoms, allcyl or alkenyl of up to 8 carbon atoms or alkyl or alkenyl of up to 8 carbon atoms substituted on one of the carbon atoms numbered 1-4 (the carbon atom numbered 1 being adjacent to the carbon atom bearing the alcoholic hydroxy group) by cycloallcyl of 5-7 carbon atoms, phenyl, tolyl, alk- oxy of 1-3 carbon atoms, phenoxy or tetrahydrofuryl or a pharmaceutical acceptable salt or ester thereof for the preparation of a pharmaceutical composition for preventing or treating alcohol dependence and excessive alcohol use.

2. Use of a compound according to claim 1, wherein the compounds is buprenorphine.

3. Use according to any of claims 1-2, wherein the pharmaceutical composition further comprises a pharmaceutical acceptable carrier or excipient.

4. Use according to any of claims 1 -3, wherein the composition further comprises, opiate receptor antagonists.

5. Use according claim 4, wherein the opiate receptor antagonists is naltrexone.

6. A method for preventing or treating alcohol dependence or excessive alcohol use comprising identifying an individual at risk for developing or an invdividual suffering from alcohol dependence or excessive alcohol use and administering a pharmaceutically effective amount of a compound of the formula:

Rl is hydrogen, allcyl, alkenyl or allcynyl of up to 8 carbon atoms or cycloalkyl methyl of 4-6 carbon atoms,

R2 is hydrogen, allcyl or alkenyl of up to 3 carbon atoms, phenyl or tolyl and R3 is cycloallcyl of 5-7 carbon atoms, allcyl or alkenyl of up to 8 carbon atoms or allcyl or alkenyl of up to 8 carbon atoms substituted on one of the carbon atoms numbered 1-4 (the carbon atom numbered 1 being adjacent to the carbon atom bearing the alcoholic hydroxy group) by cycloallcyl of 5-7 carbon atoms, phenyl, tolyl, allcoxy of 1-3 carbon atoms, phenoxy or tetrahydrofuryl or a pharmaceutical acceptable salt or ester thereof.