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WO2004078178A1 - Composes de buprenorphine pour le traitement de la dependance a l'alcool et de la consommation excessive d'alcool - Google Patents

Composes de buprenorphine pour le traitement de la dependance a l'alcool et de la consommation excessive d'alcool Download PDF

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Publication number
WO2004078178A1
WO2004078178A1 PCT/SE2004/000293 SE2004000293W WO2004078178A1 WO 2004078178 A1 WO2004078178 A1 WO 2004078178A1 SE 2004000293 W SE2004000293 W SE 2004000293W WO 2004078178 A1 WO2004078178 A1 WO 2004078178A1
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WIPO (PCT)
Prior art keywords
carbon atoms
alcohol
alkenyl
buprenorphine
ethanol
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Ceased
Application number
PCT/SE2004/000293
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English (en)
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WO2004078178B1 (fr
Inventor
Markus Heilig
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Individual
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Individual
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Publication of WO2004078178A1 publication Critical patent/WO2004078178A1/fr
Publication of WO2004078178B1 publication Critical patent/WO2004078178B1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine

Definitions

  • Buprenorphine compounds for treatment of alcohol dependence and excessive alcohol use are Buprenorphine compounds for treatment of alcohol dependence and excessive alcohol use.
  • 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.
  • 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.
  • 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.
  • the present invention relates to the use of buprenorphine compounds of the formula:
  • 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
  • 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.
  • 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.
  • bupreno ⁇ hine 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.
  • 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).
  • 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.
  • a buprenorphine compound together with an opiate receptor antagonist.
  • naltrexone is used as opiate receptor antagonist.
  • pharmaceutical composition 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.
  • an effective amount 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.
  • pharmaceutically acceptable excipients 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).
  • 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.
  • 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.
  • 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.
  • msP rats were anaesthetised by intramuscular injection of 100-150 ⁇ l/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.
  • 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 ⁇ l/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.
  • 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.
  • 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.
  • 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.
  • Example 1 Effect of acute IP injections of Buprenorphine on Voluntary Alcohol Intake
  • 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.
  • Example 4 Effect of IP injections of Naltrexone on Buprenorphine 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 Bupreno ⁇ hine or its vehicle. Ethanol was given to the animals 90 min. after Bupreno ⁇ hine 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.
  • Example 5 Effect of IP injections of Naltrexone on Bupreno ⁇ hine-induced de- creased Ethanol Intake

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne un composé de buprenorphine ou un sel ou ester pharmaceutiquement acceptable de celui-ci pour la préparation d'une composition pharmaceutique permettant de prévenir ou de traiter la dépendance à l'alcool et la consommation excessive d'alcool. Elle se rapporte aussi à l'utilisation d'un composé de buprenorphine avec un antagoniste récepteur d'opiacé, ainsi qu'à un procédé de traitement ou de prévention de la dépendance à l'alcool et de la consommation excessive d'alcool.
PCT/SE2004/000293 2003-03-03 2004-03-03 Composes de buprenorphine pour le traitement de la dependance a l'alcool et de la consommation excessive d'alcool Ceased WO2004078178A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US31998803P 2003-03-03 2003-03-03
US60/319,988 2003-03-03

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WO2004078178A1 true WO2004078178A1 (fr) 2004-09-16
WO2004078178B1 WO2004078178B1 (fr) 2005-01-27

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7511054B2 (en) 2006-09-22 2009-03-31 Alltranz Inc. Transdermally deliverable opioid prodrugs, abuse-resistant compositions and methods of using opioid prodrugs
US9051334B2 (en) 2011-07-08 2015-06-09 The University Of Bath Orvinol and thevinol derivatives useful in the treatment of drug and alcohol abuse

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0346830A2 (fr) * 1988-06-13 1989-12-20 Alko Limited Utilisation des antagonistes des opiates pour obtenir une composition pharmaceutique de traitement de l'alcoolisme
WO2001015699A1 (fr) * 1999-08-27 2001-03-08 Southern Research Institute Compositions injectables de microparticules de buprenorphine et leurs utilisations

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0346830A2 (fr) * 1988-06-13 1989-12-20 Alko Limited Utilisation des antagonistes des opiates pour obtenir une composition pharmaceutique de traitement de l'alcoolisme
WO2001015699A1 (fr) * 1999-08-27 2001-03-08 Southern Research Institute Compositions injectables de microparticules de buprenorphine et leurs utilisations

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7511054B2 (en) 2006-09-22 2009-03-31 Alltranz Inc. Transdermally deliverable opioid prodrugs, abuse-resistant compositions and methods of using opioid prodrugs
US9051334B2 (en) 2011-07-08 2015-06-09 The University Of Bath Orvinol and thevinol derivatives useful in the treatment of drug and alcohol abuse
US9259422B2 (en) 2011-07-08 2016-02-16 The University Of Bath Orvinol and thevinol derivatives useful in the treatment of depression

Also Published As

Publication number Publication date
WO2004078178B1 (fr) 2005-01-27

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