WO2000020005A1 - Compositions pharmaceutiques renfermant un analgesique opiace et une substance synergique - Google Patents

Compositions pharmaceutiques renfermant un analgesique opiace et une substance synergique Download PDF

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Publication number
WO2000020005A1
WO2000020005A1 PCT/HU1998/000090 HU9800090W WO0020005A1 WO 2000020005 A1 WO2000020005 A1 WO 2000020005A1 HU 9800090 W HU9800090 W HU 9800090W WO 0020005 A1 WO0020005 A1 WO 0020005A1
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Prior art keywords
dimethoxy
benzodiazepine
methyl
styryl
composition according
Prior art date
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PCT/HU1998/000090
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English (en)
Inventor
József Székely
Ferenc ANDRÁSI
Györgyné MÁTÉ
Katalin HORVÁTH
Edit HORVÁTH
Cecília HASKÁNÉ SALAMON
Péter ARÁNYI
Gábor Gigler
Pál FEKETE
Márton Fekete
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EGIS Gyógyszergyár Rt.
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Priority to PCT/HU1998/000090 priority Critical patent/WO2000020005A1/fr
Priority to AU95538/98A priority patent/AU9553898A/en
Publication of WO2000020005A1 publication Critical patent/WO2000020005A1/fr

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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
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0031—Rectum, anus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • This invention relates to synergistic analgesic pharmaceutical compositions and a process for the preparation thereof.
  • Morphine and chemically related analgesics of similar action of mechanism - known as opiate analgesic agents - are well-spreadly used as medicine for a long time.
  • the use of such analgesics has the advantage that said agents are suitable for the efficient relief of pain of any kind, e.g. pain caused by serious injuries, surgical interventions; spasm of the intestines, gall bladder and kidney; vessel occlusion of organs or serious decrease of blood supply; malignant tumors etc.
  • the administration of opiate agents is accompanied by the drawback that in the course of dose dependent repeated administration the activity is continuously decreased, a so-called state of tolerance takes place and on stopping the addition of the opiate agents withdrawal symptoms may be observed.
  • Any intervention which increases the efficiency of morphine or other opiate analgesic agents and decreases the dose of said opiate agent alter the applicability of opiate analgesics in a preferred and desirable manner.
  • Such intervention may be the simultaneous use of medicines which strengthens the analgesic effect of morphine or other opiate agents without exhibiting any specific activity being similar to the effect of opiate analgesic agents.
  • the above object is achieved with the aid of the present invention by preparing pharmaceutical preparations of a definite composition.
  • the pharmaceutical preparation of the present invention strengthens the efficiency of morphine or other opiate analgesic agents whereby the synergizing compound of the compositions exhibits no specific effect being similar to the activity of said opiate analgesic agent.
  • a synergistic analgesic pharmaceutical composition comprising an opiate analgesic agent (component A) and a substance synergizing the analgesic effect of said opiate (component B) an admixture with suitable inert solid or liquid pharmaceutical carriers and/or diluents.
  • a process for the preparation of a synergistic analgesic pharmaceutical composition which comprises admixing an opiate analgesic agent (component A) and a substance synergizing said opiate analgesic agent (component B) with suitable inert solid or liquid pharmaceutical carriers and/or auxiliary agents and bringing said mixture into galenic form.
  • the present invention is based on the recognition that certain 2,3-benzodiazepine derivatives and other compounds, a significant part thereof binding with high affinity to the specific binding sites of said compounds [FEBS Letters 308, 215-217 (1992)] increase the analgesic effect and also the affinity of morphine and other opiate analgesic agents to the opiate receptor to a significant extent.
  • component B increases the binding of morphine and other opiate analgesic agents.
  • component B becomes inactive in the opiate receptor binding test.
  • composition according to the present invention comprises as opiate analgesic agent preferably morphine, codeine, dihydrocodeine, noscapine, ethyl morphine, methadone, pethidine, phentanyl, meperidine, loperamide, sufentanyl, alfentanyl or pentazocine or an endogenic opiode peptide formed in the organism.
  • opiate analgesic agent preferably morphine, codeine, dihydrocodeine, noscapine, ethyl morphine, methadone, pethidine, phentanyl, meperidine, loperamide, sufentanyl, alfentanyl or pentazocine or an endogenic opiode peptide formed in the organism.
  • composition of the present invention may comprise as component A also endogenic opioid peptides formed in the organism, derivatives of said compounds effective on the opiate receptors and compounds which increase the concentration of said peptides by enhancing the synthesis of said peptides or inhibiting the decomposition thereof.
  • endogenous peptides are the following substances: methionine-encefaline, leucine- encefaline, beta-endorphine and dinorphines.
  • composition of the present invention comprises as component B preferably an 1-aryl-2,3-benzodiazepine, 1- ethenyl-aryl-2,3-benzodiazepine, 1 ,4-benzoquinone, 1 ,2,3,4- tetrahydroisoquinoline, isoquinoline, pyrimido[6, 1 -a]isoquinoline or pyrrolo[2,1 -ajisoquinoline.
  • 1 -aryl-2,3-benzodiazepines preferably 1-(3,4-dimethoxy-phenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H- 2,3-benzodiazepine (tofisopam); 1-(3-chloro-phenyl)-4-methyl-7,8-dimethoxy-5H-2,3- benzodiazepine (girisopam); 1-(4-amino-phenyl)-4-methyl-7,8-dimethoxy-5H-2,3- benzodiazepine (nerisopam);
  • 1-(4-acetylamino-phenyl)-4-methyl-7,8-dimethoxy-5H-2,3- benzodiazepine 1-ethenyl-aryl-2,3-benzodiazepines, preferably 1-(E)-(4- hyd roxy-sty ryl)-4-methyl-7 , 8-d imethoxy-5H-2 , 3- benzodiazepine;
  • Isoquinolines and 1 ,2,3,4-tetrahydroisoquinolines preferably drotaverine or racemic 2-(N-ethyl-pyrrolidine-2-yl)- methyl-4-hydroxy-6,7-methylenedioxy-1 , 2,3,4- tetrahydroisoquinoline; papaverine; perparine;
  • Pyrrolo[2,1-a]isoquinolines preferably 2,3,5,6- tetrahydro-8,9-dimethoxy-3-(3'-carbomethoxy-pyridyl-6'- methyl)-2-oxo-pyrrolo[2, 1 -ajisoquinoline.
  • the animals received various 2,3-benzodiazepine derivatives intraperitoneally.
  • the dose of morphine was 0.5-10 mg/kg s.c.
  • the animals of the control group received physiological saline in the place of the 2,3-benzodiazepine derivative.
  • Compound B 20 mg/kg i.p. 0.10 mg/kg
  • mice were treated with varying doses of morphine, whereupon pain reaction was measured during an hour following administration every 15 th minute. Pain reaction was induced by placing the mice on a hot plate (temperature 56°C). Mice reacted on pain within 5 seconds by a typical foot licking reaction. An animal was regarded as free of pain if no pain reaction was observed within a period of time being 2.5 times longer than the control time of the untreated group. The dose which caused painfree state in 50 % of the animals was determined by methods of statistical mathematics [J. Pharm. exptl. Therm. 96:99 (1949)]. The results are summarized in Table 2.
  • test compounds significantly increase the affinity of morphine to " ⁇ " (mu) receptors; (the IC5 0 values became 2-8 times lower).
  • This increase of the morphine affinity is an explanation and a further proof of the morphine potentiating effect observed on measuring the in vivo analgesic effect.
  • the test compounds cause an increase of the opiate efficiency without modifying the biological properties of the receptor protein. This recognition constitutes and opens a new therapeutical applicability for all compounds which are capable of enhancing DADLE competition.
  • O 1-[2-(3-indolyl)-ethenyl]-4-methyl-7,8-dimethoxy-5H-2,3- benzodiazepine
  • P 1-(4-acetylamino-styryl)-4-methyl-7,8-dimethoxy-5H-2,3- benzodiazepine
  • R 1-(4-acetylamino-styryl)-3-acetyl-4-methyl-7,8- dimethoxy-5H-2,3-benzodiazepine
  • S 1-(2-methoxy-3,4-methylenedioxy-styryl)-4-methyl-7,8- dimethoxy-5H-2,3-benzodiazepine
  • T 1-(3,4,5-trimethoxy-styryl)-4-methyl-7,8-dimethoxy-5H-
  • V papaverine
  • W drotaverine
  • Y 1-phenyl-6,7-dimethoxy-isoquinoline-hydrobromide
  • compositions of the present invention the ratio of the opiate analgesic agent (component A) and the synergizing component B may vary between wide ranges.
  • the compositions of the present invention may contain preferably 0.05-100 mg of component A and 5-1000 mg of component B per dosage unit.
  • compositions of the present invention may be prepared by methods of pharmaceutical industry known p_er se.
  • the combination of active ingredients according to the present invention may be used in therapy by simultaneous administration of two separate commercially available compositions containing one active ingredient each.
  • the improvement of the quality of life and simplification of the administration of the active ingredients it is preferably to prepare and use a combined composition comprising both components A and B.
  • compositions according to the present invention may be suitable for oral (e.g. tablets, pills, coated pills, capsules, hard or soft gelatine capsules, solutions, suspensions, syrups), parenteral (e.g. subcutaneous, intramuscular, intravenous injections and infusions), rectal (e.g. suppositories) or nasal (e.g. aerosol) administration.
  • parenteral e.g. subcutaneous, intramuscular, intravenous injections and infusions
  • rectal e.g. suppositories
  • nasal e.g. aerosol
  • the compositions may be of the immediate release type, wherein the duration of the therapeutical effect is determined solely by the activity and action of the active ingredient, and of the sustained release type in which case the duration of therapeutical activity is influenced by the additives and the formulation too (sustained release or retardized compositions).
  • the combination compositions may be prepared according to methods generally used in the manufacture of the above enumerated types of pharmaceutical compositions, whereby experiences obtained by the preparation of the mono-compositions containing only one of the active ingredients may be utilized as well.
  • the tablets may contain fillers e.g. lactose (monohydrate, anhydrate, pulverized-dried etc.), mannitol, types of cellulose (e.g. powdered, microcrystalline etc.), inorganic salts (e.g. secondary calcium phosphate, calcium sulfate, calcium carbonate etc.).
  • fillers e.g. lactose (monohydrate, anhydrate, pulverized-dried etc.), mannitol, types of cellulose (e.g. powdered, microcrystalline etc.), inorganic salts (e.g. secondary calcium phosphate, calcium sulfate, calcium carbonate etc.).
  • binder e.g. gelatine, polyvinyl pyrrolidone (various molecular weight), various cellulose ethers (e.g. hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose etc.), hydrolysed starch, vegetable gums (e.g.
  • gum arabicum, guar gum etc. may be used in solutions formed with water or C1- aliphatic alcohols or mixtures thereof.
  • disintegrating agent e.g. starch (potato starch, maize starch, wheat starch) or so-called super disintegrants, such as carboxymethyl cellulose (commercial product sold under the tradename Ac-di-sol), carboxymethyl starch sodium (commercial product sold under the tradename Primojel, Ultraamilopectine or Explo-Tab), polyvinyl pyrrolidone (tradename Poliplasdone) etc.
  • starch potato starch, maize starch, wheat starch
  • super disintegrants such as carboxymethyl cellulose (commercial product sold under the tradename Ac-di-sol), carboxymethyl starch sodium (commercial product sold under the tradename Primojel, Ultraamilopectine or Explo-Tab), polyvinyl pyrrolidone (tradename Poliplasdone) etc.
  • carboxymethyl cellulose commercial product sold under
  • alkali stearates magnesium-calcium stearate
  • fatty acids stearic acid
  • glycerides tradename Precirol, Cutina-H
  • paraffine oil silicon oils, silicon oil emulsions, talc, silicium dioxide etc.
  • the active ingredients and auxiliary agents may be prepared for tabletting by wet or dry granulation procedure.
  • Directly pressable auxiliary agents e.g. microcrystalline cellulose, powdered dried lactose, Tablettose, Cellactose etc.
  • auxiliary agents e.g. microcrystalline cellulose, powdered dried lactose, Tablettose, Cellactose etc.
  • Granules or powdered homogenizates may be filled instead of tablets into hard gelatine capsules too and thus hard gelatine capsules can be prepared.
  • Controlled release (retardized) solid pharmaceutical compositions may be prepared by any known method of pharmaceutical industry.
  • matrix tablets may be prepared comprising as retardizing matrix material a hydrophilic polymer (e.g. hydroxypropyl cellulose, hydroxypropylmethyl cellulose), polyacrylic acid derivatives, polysaccharose (e.g. guar gum, xanthane gum etc.) or a mixture thereof.
  • Hydrophobic polymers e.g. ethyl cellulose, methacrylic esters, copolymers, polyvinyl acetate, polyvinyl butyral etc. or mixtures thereof
  • a hydrophilic polymer e.g. hydroxypropyl cellulose, hydroxypropylmethyl cellulose
  • polyacrylic acid derivatives e.g. guar gum, xanthane gum etc.
  • Hydrophobic polymers e.g. ethyl cellulose, methacrylic esters, copolymers, polyvinyl acetate, poly
  • the matrix which retardizes release of the active ingredient may be formed with the aid of a mixture of hydrophilic and hydrophobic polymers or a mixture of polymeric and fatty substances.
  • Matrix tablets can also be prepared as multilayer tablets wherein each active ingredient is embedded in a different layer and accordingly the release profile of the active ingredient can be more readily adjusted to the individual pharmacokinetical properties.
  • the combined pharmaceutical compositions of the present invention can also be prepared in the form of a coated pellet type retardized composition.
  • Pellets can be prepared from the individual active ingredients each or from a mixture of said active ingredients. Such pellets may be prepared by extrusion spheronification, rotogranulation methods or by applying onto placebo pellets. Said procedures can be performed in rotating layer or fluidization equipment.
  • coating agent solutions of water-insoluble polymers formed with organic solvents e.g. lower C ⁇ -3 aliphatic alcohols and/or C 1-2 polychlorinated hydrocarbons and/or acetone and/or ethyl acetate or a mixture thereof
  • aqueous dispersion thereof can be used.
  • compositions of the present invention can also be prepared in the form of osmotic or diffusion-osmotic . preparations.
  • Such preparations are manufactured by preparing tablets which comprise the active ingredients and hydrophilic polymers (e.g. hydroxypropylmethyl cellulose), coating said tablets with a layer being semipermeable (e.g. cellulose acetate) or permeable (e.g. aminomethacrylate copolymer) to the active ingredient and drilling a bore through said layer, whereby the active ingredient is osmotically pressed through said bore.
  • hydrophilic polymers e.g. hydroxypropylmethyl cellulose
  • a layer being semipermeable (e.g. cellulose acetate) or permeable (e.g. aminomethacrylate copolymer) to the active ingredient and drilling a bore through said layer, whereby the active ingredient is osmotically pressed through said bore.
  • the velocity of the release of the active ingredient is preferably adjusted to such a value that according to assays performed as described in the Pharmacopoeia at least 80 % of the active ingredient is set free within 2-24 hours.
  • the pH of the composition is to be adjusted to a value below 5 or to an even more acidic value.
  • a pharmaceutical acceptable co-solvent e.g. ethanol, propylene glycol, polyethylene glycol, sorbitol, cyclodextrines, surfactants, polyethylene glycol/polypropyleneglycol copolymers etc. may be used.
  • injections are generally prepared in the form of compositions containing organic co- solvents, too.
  • the compositions may contain further components, e.g. benzyl alcohol, dimethyl acetamide, methyl pyrrolidone etc.
  • the injection may also be finished in the form of an emulsion composition.
  • Such compositions are prepared by dissolving the active ingredient in the form the base in a fatty auxiliary agent (e.g. soya oil) and emulsifying said oily liquid solution in an aqueous medium with the aid of a surfactant (e.g. lecitines).
  • a surfactant e.g. lecitines
  • Suppositories are generally prepared by using methods known per se. One may proceed by dissolving or suspending the active ingredients in a melt suppository base, filling the still liquid mass into suppository moulds or into conical containers pre-formed from a polymer film and solidifying said mixture by cooling.
  • suppository base natural (e.g. cocoa butter) or synthetic fatty substances (e.g. Witepsol - tradename) can be used.
  • the active ingredient is applied into the respiratory system in the form of atomized drops and/or a powder/air suspension.
  • the active ingredient components of the present invention are suitable for clawal administration.
  • Such compositions are prepared by filling a solution or suspension of the active ingredients in the presence or absence of a propellant into containers closed by a metered valve.
  • propellant a compressed gas (e.g. hydrocarbons) can be used.
  • a nozzle equipped with a pump is used.
  • analgesic active ingredients used in the combinations of the present invention and the single dose thereof are shown in Table 4.
  • Pentozocine 20-60 600 The 2,3-benzodiazepines used as synergistic component B and also the single and maximal doses thereof are summarized in Table 5.
  • sustained release compositions comprising 60 mg of codeine hydrochloride and 50 mg of girisopam.
  • suppositories having an average weight of 6 g and containing 20 mg of morphine hydrochloride and 50 mg of tofisopam are obtained.

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Abstract

L'invention concerne une composition pharmaceutique analgésique synergique renfermant un analgésique opiacé (composant A) et une substance qui assure la synergie de l'effet analgésique de l'opiacé en question (composant B) en admixtion avec des vecteurs pharmaceutiques inertes appropriés, solides ou liquides, et/ou des diluants.
PCT/HU1998/000090 1998-10-01 1998-10-01 Compositions pharmaceutiques renfermant un analgesique opiace et une substance synergique WO2000020005A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/HU1998/000090 WO2000020005A1 (fr) 1998-10-01 1998-10-01 Compositions pharmaceutiques renfermant un analgesique opiace et une substance synergique
AU95538/98A AU9553898A (en) 1998-10-01 1998-10-01 Pharmaceutical compositions containing an opiate analgesic and a synergizing substance

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/HU1998/000090 WO2000020005A1 (fr) 1998-10-01 1998-10-01 Compositions pharmaceutiques renfermant un analgesique opiace et une substance synergique

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Cited By (8)

* Cited by examiner, † Cited by third party
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EP2460804A1 (fr) * 2010-12-03 2012-06-06 Laboratorios Del Dr. Esteve, S.A. Dérivés de 5-méthyl-1-(naphthalen-2-yl)-1h-pyrazole et leur utilisation dans la potentialisation de l'effet des analgésiques opioïdes
US9757358B2 (en) 2010-02-04 2017-09-12 Laboratorios Del Dr. Esteve, S.A. Sigma ligands for potentiating the analgesic effect of opioids and opiates in post-operative pain and attenuating the dependency thereof
US9782483B2 (en) 2010-05-21 2017-10-10 Laboratories Del Dr. Esteve, S.A. Sigma ligands for the prevention and/or treatment of emesis induced by chemotherapy or radiotherapy
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US9914705B2 (en) 2008-04-25 2018-03-13 Laboratorios Del Dr. Esteve, S.A. 1-aryl-3-aminoalkoxy pyrazoles as sigma ligands enhancing analgesic effect of opioids and attenuating the dependency thereof
US9757358B2 (en) 2010-02-04 2017-09-12 Laboratorios Del Dr. Esteve, S.A. Sigma ligands for potentiating the analgesic effect of opioids and opiates in post-operative pain and attenuating the dependency thereof
US9844516B2 (en) 2010-02-04 2017-12-19 Laboratorios De Dr. Esteve Sigma ligands for use in the prevention and/or treatment of post-operative pain
US9782483B2 (en) 2010-05-21 2017-10-10 Laboratories Del Dr. Esteve, S.A. Sigma ligands for the prevention and/or treatment of emesis induced by chemotherapy or radiotherapy
US9789115B2 (en) 2010-08-03 2017-10-17 Laboratorios Del Dr. Esteve, S.A. Use of sigma ligands in opioid-induced hyperalgesia
CN103261192B (zh) * 2010-12-03 2016-08-10 埃斯特韦实验室有限公司 5-甲基-1-(萘-2-基)-1h-吡唑衍生物及其在增强阿片类镇痛剂之作用中的用途
US8729073B2 (en) 2010-12-03 2014-05-20 Laboratorios Del Dr. Esteve, S.A. 5-methyl-1-(naphthalen-2-yl)-1H-pyrazole derivatives and their use in potentiating the effect of opioid analgesics
JP2013544270A (ja) * 2010-12-03 2013-12-12 ラボラトリオス・デル・ドクトル・エステベ・ソシエダッド・アノニマ ５−メチル−１−（ナフタレン−２−イル）−１ｈ−ピラゾール誘導体
EP2460804A1 (fr) * 2010-12-03 2012-06-06 Laboratorios Del Dr. Esteve, S.A. Dérivés de 5-méthyl-1-(naphthalen-2-yl)-1h-pyrazole et leur utilisation dans la potentialisation de l'effet des analgésiques opioïdes
CN103261192A (zh) * 2010-12-03 2013-08-21 埃斯特韦实验室有限公司 5-甲基-1-(萘-2-基)-1h-吡唑衍生物及其在增强阿片类镇痛剂之作用中的用途
WO2012072781A1 (fr) * 2010-12-03 2012-06-07 Laboratorios Del Dr. Esteve, S.A. Dérivés du 5-méthyl-1-(naphtalén-2-yle)-1h-pyrazole et leur utilisation dans la potentialisation de l'effet d'analgésiques opioïdes
US9789117B2 (en) 2011-05-18 2017-10-17 Laboratorios Del Dr. Esteve, S.A. Use of sigma ligands in diabetes type-2 associated pain
US9931346B2 (en) 2013-12-17 2018-04-03 Laboratorios Del Dr. Esteve S.A. Serotonin-norepinephrine reuptake inhibitors (SNRIs) and Sigma receptor ligands combinations

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