WO2001091733A2 - Combinaison de principes actifs contenant de la montireline et un compose a effet opioide - Google Patents

Combinaison de principes actifs contenant de la montireline et un compose a effet opioide Download PDF

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Publication number
WO2001091733A2
WO2001091733A2 PCT/EP2001/005345 EP0105345W WO0191733A2 WO 2001091733 A2 WO2001091733 A2 WO 2001091733A2 EP 0105345 W EP0105345 W EP 0105345W WO 0191733 A2 WO0191733 A2 WO 0191733A2
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WO
WIPO (PCT)
Prior art keywords
active ingredient
medicament
ingredient combination
compound
combination according
Prior art date
Application number
PCT/EP2001/005345
Other languages
German (de)
English (en)
Other versions
WO2001091733A3 (fr
Inventor
Boris Chizh
Thomas Christoph
Babette-Yvonne Kögel
Achim SCHÜTTLER
Wolfgang Strassburger
Original Assignee
Grünenthal GmbH
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 Grünenthal GmbH filed Critical Grünenthal GmbH
Priority to AU2001274020A priority Critical patent/AU2001274020A1/en
Publication of WO2001091733A2 publication Critical patent/WO2001091733A2/fr
Publication of WO2001091733A3 publication Critical patent/WO2001091733A3/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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the present invention relates to a combination of active ingredients containing montirelin and a compound with opioid activity and / or in each case their physiologically tolerable salts, pharmaceutical compositions containing this combination of active ingredients, pharmaceutical formulations containing this combination of active ingredients and the use of this combination of active ingredients for the production of a pharmaceutical.
  • Classic opioids such as the morphine
  • Classic opioids are effective in the treatment of severe to very severe pain, but have undesirable side effects such as Respiratory depression, nausea, vomiting, addiction, sedation, constipation or tolerance development.
  • the object underlying the invention was therefore to provide analgesic drugs which are suitable for the treatment of severe to very severe pain.
  • these drugs should have as few side effects of the known opioid analgesics as breathing depression, nausea, vomiting, dependency, sedation, constipation or tolerance development.
  • this object is achieved by providing a new combination of active ingredients
  • This combination of active substances according to the invention surprisingly has a pronounced analgesic activity, the undesirable side effects which occur when opioids are administered alone no longer or only very weakly.
  • hydrochloride, hydrobromide, sulfate, sulfonate, phosphate, tartrate, embonate, formate, acetate, propionate, benzoate, oxalate, succinate, citrate, glutamate, fumarate, aspartate, glutarate, stearate, butyrate, malonate can preferably be used as the physiologically compatible salt of montireline , Lactate, mesylate or a mixture of at least two of these salts.
  • Codeine, dextropropoxyphene, dihydrocodeine, diphenoxylate, ethylmorphine, meptazinol, nalbuphin, pethidine (Mepe ⁇ ' din), tilidine, tramadol or viminol are preferably used as compounds with weak opioid activity, butorphanol, dextrinoramid, decocin are preferred as compounds with strong opioid activity
  • Diacetylmorphine (heroin) hydrocodone, hydromorphone, ketobemidone, levomethadone, levomethadyl acetate, levorphanol, morphine, nalorphine, oxycodone, pentazocine or piritramide and as compounds with a very strong opioid activity, preferably alfentanil, buprenorphentanil, etuprofinilentinil, etupernorphentanil ,
  • the hydrochloride, hydrobromide, sulfate, sulfonate, phosphate, tartrate, embonate, formate, acetate, propionate, benzoate, oxalate, succinate, citrate, glutamate, fumarate, aspartate, glutarate can preferably be used as the physiologically tolerable salt of the compound with opioid activity.
  • Stearate, butyrate, malonate, lactate, mesylate or a mixture of at least two of these salts can be used.
  • the active compound combination according to the invention contains morphine or fentanyl and / or at least one corresponding physiologically tolerated salt as a compound with opioid activity.
  • the active ingredient combination according to the invention contains a component with weakly opioid activity as component b), this should be the case
  • Weight ratio of components a): b) are preferably in the range from 1:10 to 1: 2000, particularly preferably in the range from 1:50 to 1: 1500 and very particularly preferably in the range from 1: 100 to 1: 1000. If component b) is a compound with strong opioid activity, the weight ratio of components a): b) should preferably be in
  • the weight ratio of components a): b) in the active ingredient combination should preferably be in the range from 1: 0.1 to 1:20, particularly preferably in the range from 1: 0.5 to 1 : 15, most preferably in the range from 1: 1 to 1:10.
  • the invention further also relates to medicaments containing the active compound combination according to the invention and, if appropriate, further active compounds and / or auxiliaries. These medicaments according to the invention are preferably used to combat pain, in particular to combat chronic and / or acute pain.
  • the invention also relates to pharmaceutical formulations in various dosage forms which contain the active compound combination according to the invention and, if appropriate, further active compounds and / or auxiliaries.
  • Preferred pharmaceutical formulations are tablets, chewable tablets, chewing gums, dragées, capsules, drops, juices, syrups, suppositories, transmucal therapeutic systems, transdermal therapeutic systems, easily reconstitutable dry preparations, solutions, emulsions, suspensions, powders or sprays.
  • Pharmaceutical formulations in the form of tablets, capsules, drops or solutions are particularly preferred.
  • the pharmaceutical formulations according to the invention are in multiparticulate form, particularly preferably as microtablets, microcapsules, microspheroids, ion exchange resinates, granules, active ingredient crystals or pellets, very particularly preferably as microtablets, granules or pellets.
  • Pellets in the sense of the present invention also include pellets or build-up pellets produced by extrusion and / or spheronization.
  • the pharmaceutical formulations according to the invention are preferably suitable for oral, intravenous, intramuscular, subcutaneous, intrathecal, epidural, buccal, sublingual, pulmonary, rectal, transdermal, nasal or intracerebroventricular administration, pharmaceutical formulations for oral or intravenous administration being particularly preferred.
  • Preparations in the form of tablets, chewable tablets, chewing gums, dragees, capsules, granules, are preferably suitable for oral administration.
  • a transmucal therapeutic system is preferably suitable for buccal application. Solutions are preferably suitable for parenteral, topical and inhalation administration,
  • Suspensions, emulsions, easily reconstitutable Dry preparations, microspheroids, sprays, suppositories or plasters eg transdermal therapeutic systems.
  • Suppositories or solutions are particularly preferred for parenteral administration, transdermal therapeutic systems for topical administration and powders or solutions for inhalation administration.
  • carrier materials In addition to an active ingredient combination according to the invention, carrier materials, fillers, solvents, and
  • Diluents, colorants, flavorings, binders or mixtures of at least two of these materials can be used.
  • the selection of these auxiliaries and their amounts depend on the manner in which the medicament is to be applied. The person skilled in the art is aware of the auxiliaries suitable for the particular form of application and their amounts.
  • the pharmaceutical formulations according to the invention can be prepared by the customary methods known to those skilled in the art.
  • the pharmaceutical formulations according to the invention can also contain at least one active ingredient component a) or b) in retarded form.
  • the respective active substance is preferably retarded by a retarding coating, by fixation to an ion exchange resin, by embedding in a retarding matrix or by a combination of these retardations.
  • Suitable retarding coatings include water-insoluble waxes or polymers such as acrylic resins, preferably poly (meth) acrylates, or water-insoluble celluloses, preferably ethyl cellulose. These materials are from the prior art, for example Bauer, Lehmann, Osterwald, Rothgang “coated drug forms", scientific Verlagsgesellschaft mbH Stuttgart, 1988, page 69 ff. They are hereby introduced as a reference and are therefore considered part of the disclosure.
  • the retarding coatings can optionally also be non-retarding, preferably water-soluble polymers in amounts of up to 30 wt , Sodium chloride or mannitol and / or the known plasticizers.
  • the active ingredient combination according to the invention can have further coatings. Coatings that dissolve depending on the pH can also be present as coatings. It can thus be achieved that the pharmaceutical formulation passes through the gastrointestinal tract undissolved and the active substance combination according to the invention is only released in the intestinal tract. Coatings can also be used to improve the taste.
  • Cation exchange resins preferably polystyrene sulfonates, can be used to retard both component a) and component b).
  • the active ingredient combination according to the invention can also be present in a retarding matrix, preferably evenly distributed.
  • Physiologically compatible, hydrophilic materials which are known to the person skilled in the art can be used as matrix materials.
  • Polymers, particularly preferably cellulose ethers, cellulose esters and / or acrylic resins, are preferably used as the hydrophilic matrix materials.
  • Matrix materials are very particularly preferred
  • Matrix materials made of hydrophobic materials such as hydrophobic polymers, waxes, fats, long-chain fatty acids, are also preferred.
  • Fatty alcohols or corresponding esters or ethers or their mixtures Fatty alcohols or corresponding esters or ethers or their mixtures.
  • Mono- or diglycerides of C 2 -C 3 -fatty acids and / or C 2 -C 3 o-fatty alcohols and / or waxes or mixtures thereof are particularly preferably used as hydrophobic materials.
  • the pharmaceutical formulation according to the invention contains at least one of the active ingredient components a) or b) in addition to its retarded form and also in its unretarded form. Combined with the immediately released active ingredient, a high initial dose can be achieved for quick pain relief. The slow release from the retarded form then prevents the analgesic effect from subsiding.
  • the amount of the active compound combination according to the invention to be administered to the patient varies, for example, depending on the weight of the patient, the type of application, the indication and the severity of the disease.
  • the amount to be administered and the release of the active compound combination according to the invention are preferably adjusted so that they have to be applied at most twice, preferably only once a day.
  • the active compound combinations according to the invention preferably contain 0.1 to 50 mg, particularly preferably 1 to 5 mg montirelin and 0.1 to 2000 mg, preferably 0.5 mg to 1000 mg of a compound with opioid activity.
  • the active compound combinations according to the invention preferably contain 0.05 to 25 mg, preferably 0.5 to 2.5 mg montirelin and 0.05 to 1000 mg, preferably 0.25 to 500 mg of a compound with opioid activity.
  • Another object of the invention is the use of an active ingredient combination according to the invention for the manufacture of a medicament, preferably for the manufacture of a medicament for combating pain, particularly preferably for combating chronic and / or acute pain, since the active substance combinations according to the invention have a very good action in combating from severe to very severe pain, especially when fighting chronic and / or acute pain.
  • the active ingredient combination according to the invention surprisingly shows an improved analgesic activity compared to the opioid active ingredient alone. In addition, there are fewer undesirable side effects.
  • the increased antinociceptive effect has the advantage that the dose of the compound with opioid activity required for effective pain control can be reduced compared to the sole administration of this compound.
  • the rats were placed individually in a test cage and the tail base was exposed to the focused heat radiation from an electric lamp (tail-flick type 50/08 / 1.bc, Labtec, Dr. Hess). The lamp intensity was adjusted so that the time from switching on the lamp until the tail suddenly jerked away (pain latency) was 3 to 5 seconds in untreated rats. Before the solutions of the active compound combinations according to the invention and the comparison solutions were applied, the rats were pretested twice within five minutes and the mean value of these measurements was calculated as the pretest mean. The solution of the active compound combinations according to the invention and the comparison solutions were then administered intravenously. The pain measurement was carried out 10, 20, 40 and 60 minutes after the intravenous application. The analgesic effect was determined as an increase in pain latency (% of the maximum possible antinociceptive effect) according to the following formula:
  • the time To is the latency before application
  • the time Ti is the latency after application of the active ingredient combination
  • the time T 2 is the maximum exposure time (12 seconds).
  • a 0.9% saline solution containing only 1.46 mg morphine per kg body weight of the rat was administered intravenously to a second group of 10 rats.
  • FIG. 1 shows that the comparison solution, which contains the morphine alone, already has good analgesic activity.
  • the application of the solution containing the active ingredient combination of montirelin and morphine has a very much improved analgesic effect compared to the sole application of morphine.

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

Abstract

L'invention concerne une combinaison de principes actifs contenant de la montiréline et un composé à effet opioïde et/ou respectivement leurs sels physiologiquement tolérables. Elle concerne également des médicaments contenant cette combinaison de principes actifs, des formulations de médicaments contenant ladite combinaison, ainsi que l'utilisation de cette combinaison pour produire un médicament.
PCT/EP2001/005345 2000-05-26 2001-05-10 Combinaison de principes actifs contenant de la montireline et un compose a effet opioide WO2001091733A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001274020A AU2001274020A1 (en) 2000-05-26 2001-05-10 Combination of active substances containing montirelin and compound having an opioid effect

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10025947.2 2000-05-26
DE10025947A DE10025947A1 (de) 2000-05-26 2000-05-26 Wirkstoffkombination enthaltend Montirelin und eine Verbindung mit opioider Wirksamkeit

Publications (2)

Publication Number Publication Date
WO2001091733A2 true WO2001091733A2 (fr) 2001-12-06
WO2001091733A3 WO2001091733A3 (fr) 2002-04-04

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PCT/EP2001/005345 WO2001091733A2 (fr) 2000-05-26 2001-05-10 Combinaison de principes actifs contenant de la montireline et un compose a effet opioide

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AR (1) AR029096A1 (fr)
AU (1) AU2001274020A1 (fr)
DE (1) DE10025947A1 (fr)
PE (1) PE20011272A1 (fr)
WO (1) WO2001091733A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102770127A (zh) * 2010-02-24 2012-11-07 思玛化验室公司 抗滥用制剂
US10076499B2 (en) 2006-08-25 2018-09-18 Purdue Pharma L.P. Tamper resistant dosage forms

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4426378A (en) * 1981-04-09 1984-01-17 The United States Of America As Represented By The Secretary Of The Army Thyrotropin releasing hormone in therapy of shock and as a central nervous system stimulant

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4426378A (en) * 1981-04-09 1984-01-17 The United States Of America As Represented By The Secretary Of The Army Thyrotropin releasing hormone in therapy of shock and as a central nervous system stimulant

Non-Patent Citations (6)

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Title
BHARGAVA HEMENDRA N ET AL: "Effect of thyrotropin releasing hormone on U-50,488H-induced pharmacological responses in mice." BRAIN RESEARCH, Bd. 625, Nr. 1, 1993, Seiten 120-124, XP001029522 ISSN: 0006-8993 *
ITOH YOSHINORI ET AL: "Enhancement of brain noradrenaline and dopamine turnover by thyrotropin-releasing hormone and its analogue NS-3 in mice and rats." PHARMACOLOGY & TOXICOLOGY, Bd. 78, Nr. 6, 1996, Seiten 421-428, XP001029649 ISSN: 0901-9928 *
UKAI YOJIRO ET AL: "Effects of montirelin hydrate (NS-3), a TRH analog, on the cerebral glucose utilization and high affinity choline uptake in rats." OYO YAKURI, Bd. 51, Nr. 3, 1996, Seiten 147-153, XP001022252 ISSN: 0300-8533 *
WANG G-L ET AL: "EFFECTS OF THYROTROPIN-RELEASING HORMONE ON ACUTE EXPERIMENTAL TRAUMATIC HEAD INJURY IN CATS" CHINESE MEDICAL JOURNAL (ENGLISH EDITION), Bd. 104, Nr. 11, 1991, Seiten 939-944, XP001022253 ISSN: 0366-6999 *
YAMAMOTO M ET AL: "EFFECTS OF YM-14673 A NEW TRH ANALOGUE ON RESPONSES TO MORPHINE IN RODENTS" ARCHIVES INTERNATIONALES DE PHARMACODYNAMIE ET DE THERAPIE, Bd. 300, 1989, Seiten 29-36, XP001029545 ISSN: 0003-9780 *
ZHUKOV V N ET AL: "HYPERTHERMIA AND ANTINOCICEPTIVE ACTIVITY OF TRH AND MORPHINE FOLLOWING CENTRAL ADMINISTRATION IN RATS" ACTA PHYSIOLOGICA ET PHARMACOLOGICA BULGARICA, Bd. 14, Nr. 2, 1988, Seiten 18-23, XP001022256 ISSN: 0323-9950 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10076499B2 (en) 2006-08-25 2018-09-18 Purdue Pharma L.P. Tamper resistant dosage forms
US10076498B2 (en) 2006-08-25 2018-09-18 Purdue Pharma L.P. Tamper resistant dosage forms
US11298322B2 (en) 2006-08-25 2022-04-12 Purdue Pharma L.P. Tamper resistant dosage forms
US11304909B2 (en) 2006-08-25 2022-04-19 Purdue Pharma L.P. Tamper resistant dosage forms
US11304908B2 (en) 2006-08-25 2022-04-19 Purdue Pharma L.P. Tamper resistant dosage forms
US11826472B2 (en) 2006-08-25 2023-11-28 Purdue Pharma L.P. Tamper resistant dosage forms
US11904055B2 (en) 2006-08-25 2024-02-20 Purdue Pharma L.P. Tamper resistant dosage forms
US11938225B2 (en) 2006-08-25 2024-03-26 Purdue Pharm L.P. Tamper resistant dosage forms
US11964056B1 (en) 2006-08-25 2024-04-23 Purdue Pharma L.P Tamper resistant dosage forms
CN102770127A (zh) * 2010-02-24 2012-11-07 思玛化验室公司 抗滥用制剂

Also Published As

Publication number Publication date
AU2001274020A1 (en) 2001-12-11
AR029096A1 (es) 2003-06-04
DE10025947A1 (de) 2001-11-29
PE20011272A1 (es) 2002-01-26
WO2001091733A3 (fr) 2002-04-04

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