WO2008075997A1 - Procédé de traitement du syndrome de sevrage aux opioïdes - Google Patents

Procédé de traitement du syndrome de sevrage aux opioïdes Download PDF

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Publication number
WO2008075997A1
WO2008075997A1 PCT/RU2006/000685 RU2006000685W WO2008075997A1 WO 2008075997 A1 WO2008075997 A1 WO 2008075997A1 RU 2006000685 W RU2006000685 W RU 2006000685W WO 2008075997 A1 WO2008075997 A1 WO 2008075997A1
Authority
WO
WIPO (PCT)
Prior art keywords
opioid
withdrawal syndrome
antagonist
peripherally restricted
iodide
Prior art date
Application number
PCT/RU2006/000685
Other languages
English (en)
Inventor
Sergey Konstantinovich Sudakov
Igor Anatolievich Pomytkin
Original Assignee
Sergey Konstantinovich Sudakov
Igor Anatolievich Pomytkin
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sergey Konstantinovich Sudakov, Igor Anatolievich Pomytkin filed Critical Sergey Konstantinovich Sudakov
Priority to PCT/RU2006/000685 priority Critical patent/WO2008075997A1/fr
Publication of WO2008075997A1 publication Critical patent/WO2008075997A1/fr

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of peripherally restricted antagonists of opioid receptors for the treatment of opioid withdrawal syndrome.
  • Unpleasant opioid withdrawal syndrome can occur when the opioid is discontinued or rapidly reduced in dosage.
  • Acute opioid withdrawal syndrome can occur following administration of an opioid receptor antagonist such as naloxone or naltrexone.
  • Signs and symptoms of opioid withdrawal syndrome may include: sweating, malaise, anxiety, depression, persistent and intense penile erection in males (priapism), extra sensitivity of the genitals in females, general feeling of heaviness, cramp-like pains in the limbs, yawning and lacrimation, sleep difficulties, cold sweats, chills, severe muscle and bone aches not precipitated by any physical trauma, nausea and vomiting, diarrhea, goose bumps, cramps, fever, painful conditions, muscle spasms in the legs of the user (restless leg syndrome).
  • the first approach is to substitute a longer-acting opioid such as methadone or buprenorphine for heroin or another short-acting opioid and then slowly taper the dose.
  • this approach can not be realized in some countries due to legal restriction on the use of methadone or buprenorphine for such purposes.
  • benzodiazepines also have a great addiction potential and should be used with care.
  • Naloxone and naltrexone are opioid receptor antagonists which capable to block both central and peripheral opioid receptors. Administering naloxone or naltrexone to a subject which regularly used of an opioid for any reason can induce acute opioid withdrawal syndrome in this subject. Surprisingly, we discovered that administering of peripherally restricted antagonists of opioid receptors to a subject which regularly used of an opioid does not induce withdrawal syndrome and, in contrast, is useful for the treatment of the opioid withdrawal syndrome.
  • the peripherally restricted antagonists are capable to block peripheral opioid receptors and do not block central opioid receptors.
  • peripherally restricted antagonists are quaternary derivatives of naloxone and naltrexone, which block peripheral opioid receptors and do not capable to block central opioid receptors due to decreased transport of quaternary derivatives of naloxone and naltrexone through blood brain barrier.
  • It is an object of the present invention to provide a method for treating opioid withdrawal syndrome comprising administering to a mammal in need thereof an effective amount of a peripherally restricted antagonist of an opioid receptor. It is an object of the present invention to provide the use of a peripherally restricted antagonist of an opioid receptor for manufacturing a medicament for the treatment of opioid withdrawal syndrome.
  • the present invention provides a method for treating opioid withdrawal syndrome comprising administering to a mammal in need thereof an effective amount of a peripherally restricted antagonist of an opioid receptor.
  • a mammal is a human.
  • opioid refers to any agent that activates opioid receptors.
  • opioids include endogenous opioid peptides, opium alkaloids (e.g. morphine), semi-synthetic opioids (e.g. heroin), and fully synthetic opioids (e.g. methadone).
  • opioid withdrawal syndrome refers to a syndrome characterized by signs and symptoms that appear when an opioid that causes physical dependence is regularly used for a long time and then suddenly discontinued or decreased in dosage.
  • Such signs and symptoms may include, but are not limited to, sweating, malaise, anxiety, depression, persistent and intense penile erection in males (priapism), extra sensitivity of the genitals in females, general feeling of heaviness, cramp-like pains in the limbs, yawning and lacrimation, sleep difficulties, cold sweats, chills, severe muscle and bone aches not precipitated by any physical trauma, nausea and vomiting, diarrhea, goose bumps, cramps, fever, painful conditions, muscle spasms in the legs of the user (restless leg syndrome).
  • the term "antagonist” refers to a molecule that prevents the activation of a receptor.
  • peripheral opioid receptors refers to a molecule that prevents the activation of peripheral opioid receptors and does not prevent the activation of central opioid receptors.
  • opioid receptors include ⁇ (mu), K (kappa), and ⁇ (delta) opioid receptors.
  • Term “treating” refers to preventing opioid withdrawal syndrome from occurring hi a subject that may be predisposed to the withdrawal syndrome due to regular use of opioids; and/or inhibiting or slowing opioid withdrawal syndrome, e.g. arresting its development.
  • the peripherally restricted antagonist of an opioid receptor is a compound of formula (I):
  • R is chosen from the cyclopropylmethyl and allyl, and X is a pharmaceutically acceptable anion.
  • the term "pharmaceutically acceptable anion” means an anion substantially non-toxic and substantially non-deleterious to the mammal, preferably human.
  • the pharmaceutically acceptable anion is iodide.
  • the respective compound of formula (I) can be prepared by methods well- known from the art, for example, by the reaction of methyliodide with tertiary morphinan, wherein the morphinan is naloxone or naltrexone.
  • the compound of formula (I) is selected from the group consisting of 4, 5 alpha-Epoxy-3 , 14-dihydroxy- 17-methyl-6-oxo- 17-(2- propenyl)morphinanium iodide and 17-(Cyclopropylmethyl)-4,5alpha-epoxy- 3 , 14-dihydroxy- 17-methyl-6-oxomorphinanium iodide.
  • 4,5alpha-Epoxy-3, 14-dihydroxy- 17-methyl-6-oxo- 17-(2- propenyl)morphinanium iodide is quaternary derivative of naloxone well known from the art, CAS Registry Number 73232-50-5.
  • the synonyms are N- methylnaloxone and methylnaloxonium.
  • 17-(Cyclopropylmethyl)-4,5alpha-epoxy-3,14-dihydroxy-17-methyl-6- oxomorphinanium iodide is quaternary derivative of naltrexone well known from the art, CAS Registry Number 83387-25-1.
  • the synonyms are N- methylnaltrexone and methylnaltrexonium.
  • Methylnaloxonium and methylnaltrexonium iodides can be prepared by methods well-known from the art, for example, by a reaction of methyliodide with naloxone and naltrexone respectively.
  • the term "effective amount" means an amount of the peripherally restricted antagonist of an opioid receptor, the amount is useful for preventing, inhibiting or slowing opioid withdrawal syndrome, e.g. arresting its development.
  • the particular dosage of the peripherally restricted antagonist of an opioid receptor required for treating opioid withdrawal syndrome according to this invention will depend upon the particular circumstances of the conditions to be treated. Considerations such as dosage, route of administration, and frequency of dosing are best decided by the attending physician.
  • the effective amount of the peripherally restricted antagonist of an opioid receptor is from 0.001 mg per kg to 10 mg per kg body weight of the mammal.
  • the present invention provides the use of a peripherally restricted antagonist of an opioid receptor for manufacturing a medicament for the treatment of opioid withdrawal syndrome.
  • the peripherally restricted antagonist of an opioid receptor is a compound of formula (I). More preferably, the compound of formula (I) is selected from the group consisting of 4,5alpha- Epoxy-3, 14-dihydroxy- 17-methyl-6-oxo- 17-(2-propenyl)morphinanium iodide and 17-(Cyclopropylmethyl)-4, 5 alpha-epoxy-3 , 14-dihydroxy- 17-methyl-6- oxomorphinanium iodide.
  • the peripherally restricted antagonist of an opioid receptor can be administered by a route selected from a group consisting of oral, intranasal, sublingual, intramuscular, intravenous, subcutaneous, parenteral, or topical.
  • the peripherally restricted antagonist of an opioid receptor is administered parenterally.
  • the medicament of the invention can be prepared by known procedures using well-known ingredients.
  • the active ingredients will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, tablet, paper or other container.
  • the carrier serves as a diluent, it may be a solid, semisolid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient.
  • the medicaments can be in the form of tablets, pills, powders, elixirs, suspensions, emulsions, solutions, syrups, sprays, soft and hard gelatin capsules, aerosols, suppositories, sterile injectable solutions, eye drops, eye gels, and sterile packaged powders.
  • suitable carriers include lactose, dextrose, sorbitol, mannitol, calcium phosphate, alginates, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, stearic acid, and mineral oil.
  • the medicaments can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents.
  • peripherally restricted antagonists of an opioid receptor are well suited to formulation as sustained release dosage forms.
  • the formulations can also be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time.
  • Such formulations would involve coatings, envelopes, or protective matrices which may be made from polymeric substances or waxes.
  • treating of withdrawal syndrome with the peripherally restricted antagonist of an opioid receptor can be a part of a complex therapy for treating opioid withdrawal syndrome.
  • peripherally restricted antagonist of an opioid receptor can be used in combination with antidepressants, neuroleptics, anxiolytics, and the like.
  • This example shows the efficacy of the peripherally restricted antagonist of opioid receptors for treating opioid withdrawal syndrome.
  • Wistar male rats were made morphine-dependent over 16 days with two daily (8 a.m. and 8 p.m.) i.p. injections of morphine in doses from 5 to 80 mg/kg, by increasing doses by 5 mg/kg per day.
  • the table shows significant decrease in withdrawal index in the morphine-dependent rats administered with 2 mg/kg of methylnaloxonium iodide as compared to the Control.
  • methylnaloxonium iodide the peripherally restricted antagonist of opioid receptors
  • Example 2 This example shows medicaments comprising the peripherally restricted antagonist of opioid receptors for treating opioid withdrawal syndrome (Table 2 and 3).
  • the compound of formula I, lactose and some of the corn starch are mixed together.
  • the mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried.
  • the granules, the remaining corn starch and the magnesium stearate are screened and mixed together.
  • the mixture is compressed to produce tablets of suitable shape and size.
  • the compound of formula I is dissolved in water at its own pH and sodium chloride is added to make it isotonic.
  • the solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilized and sealed by fusion.
  • the each ampoule contains 50 mg of active substance.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Addiction (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne l'utilisation d'un antagoniste périphériquement restreint d'un récepteur opioïde dans le traitement du syndrome de sevrage aux opioïdes. De préférence, l'antagoniste périphériquement restreint d'un récepteur opioïde est sélectionné dans le groupe constitué de 4,5alpha-époxy-3,14-dihydroxy-17-méthyle-6-oxo-17-(2-propényle)iodure de morphinanium et de 17-(cyclopropylméthyle)-4,5alpha-époxy-3,14-dihydroxy-17-méthyle-6-iodure d'oxomorphinanium.
PCT/RU2006/000685 2006-12-21 2006-12-21 Procédé de traitement du syndrome de sevrage aux opioïdes WO2008075997A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/RU2006/000685 WO2008075997A1 (fr) 2006-12-21 2006-12-21 Procédé de traitement du syndrome de sevrage aux opioïdes

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/RU2006/000685 WO2008075997A1 (fr) 2006-12-21 2006-12-21 Procédé de traitement du syndrome de sevrage aux opioïdes

Publications (1)

Publication Number Publication Date
WO2008075997A1 true WO2008075997A1 (fr) 2008-06-26

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020142644A1 (fr) * 2019-01-04 2020-07-09 Aether Therapeutics Inc. Procédé de traitement de la dépendance aux médicaments ou à l'alcool

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004005294A2 (fr) * 2002-07-03 2004-01-15 Alcasynn Pharmaceuticals Gmbh Derives de morphinane et leurs sels d'ammonium quaternaire substitues en position 14, procede de production de ces composes et leur utilisation
WO2004091623A1 (fr) * 2003-04-08 2004-10-28 Progenics Pharmaceuticals. Inc. Formulations pharmaceutiques contenant de la methylnaltrexone

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004005294A2 (fr) * 2002-07-03 2004-01-15 Alcasynn Pharmaceuticals Gmbh Derives de morphinane et leurs sels d'ammonium quaternaire substitues en position 14, procede de production de ces composes et leur utilisation
WO2004091623A1 (fr) * 2003-04-08 2004-10-28 Progenics Pharmaceuticals. Inc. Formulations pharmaceutiques contenant de la methylnaltrexone

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
A. HAMLIN, K. M. BULLER, T. A. DAY, P.B. OSBORNE: "Peripheral withdrawal recruits distinct central nuclei in morphine-dependent rats", NEUROPHARMACOLOGY, vol. 41, 2001, pages 574 - 581, XP002456346 *
LEWANOWITSCH ET AL: "Reversal of morphine, methadone and heroin induced effects in mice by naloxone methiodide", LIFE SCIENCES, PERGAMON PRESS, OXFORD, GB, vol. 78, no. 7, 11 January 2006 (2006-01-11), pages 682 - 688, XP005221164, ISSN: 0024-3205 *
YUAN C-S ET AL: "METHYLNALTREXONE FOR REVERSAL OF CONSTIPATION DUE TO CHRONIC METHADONE USE", 19 January 2000, JAMA THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, CHICAGO,IL, US, PAGE(S) 367-372, ISSN: 0098-7484, XP008065666 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020142644A1 (fr) * 2019-01-04 2020-07-09 Aether Therapeutics Inc. Procédé de traitement de la dépendance aux médicaments ou à l'alcool

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