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EP1143936A2 - MEDICINAL FORMULATIONS CONTAINING AN OPIOID AND AN $g(a)-ANTAGONIST - Google Patents

MEDICINAL FORMULATIONS CONTAINING AN OPIOID AND AN $g(a)-ANTAGONIST

Info

Publication number
EP1143936A2
EP1143936A2 EP00901108A EP00901108A EP1143936A2 EP 1143936 A2 EP1143936 A2 EP 1143936A2 EP 00901108 A EP00901108 A EP 00901108A EP 00901108 A EP00901108 A EP 00901108A EP 1143936 A2 EP1143936 A2 EP 1143936A2
Authority
EP
European Patent Office
Prior art keywords
formulation according
pharmaceutical formulation
opioid
cellulose
release
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP00901108A
Other languages
German (de)
French (fr)
Inventor
Johannes Bartholomäus
Jürgen Betzing
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gruenenthal GmbH
Original Assignee
Gruenenthal 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 Gruenenthal GmbH filed Critical Gruenenthal GmbH
Publication of EP1143936A2 publication Critical patent/EP1143936A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • 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
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect

Definitions

  • the invention relates to pharmaceutical formulations containing an opioid, an ⁇ -agonist and / or in each case its physiologically tolerable salt, from which at least one drug active ingredient is released with a delay.
  • opioids are used to relieve medium-weight and severe acute pain.
  • a major disadvantage of using opioids is the strong side effects associated with them. So side effects often occur on the gastrointestinal tract, such. B. constipation. Respiratory depression also arises as well as with repeated administration a dependency that can lead to abuse. Another disadvantage is the rapid development of tolerance.
  • opioids and ⁇ -agonists as monopreparations using various pharmaceutical formulations is known.
  • retard systems with opioids as described in WO95 / 14460 or EP-A-0 647 448, in which butyrates, ketobemidones, codeins and the like are also used, among others.
  • EP-B-0 271 193 discloses a retard system that uses only hydromorphone.
  • Retardation systems with ⁇ -agonists are disclosed in EP-A-0 805 677 or US 5,484,607. In both cases, only clonidine is used as the ⁇ -agonist.
  • the object of the present invention was therefore to provide a pharmaceutical formulation which is suitable for the treatment of severe to very severe pain, which does not have the typical side effects of the opioids, and which in particular delays the development of an opioid tolerance for a very long time or completely prevents it .
  • this object is achieved by the provision of pharmaceutical formulations which contain an opioid, an ⁇ -agonist and / or in each case its physiologically compatible salt, from which at least one active pharmaceutical ingredient is released with a delay.
  • the opioid is preferably released with a delay from the pharmaceutical formulation according to the invention.
  • the delayed release of the opioid preferably takes place over a period of 8 hours, especially during preferably 12 hours and very particularly preferably over 24 hours.
  • Both pharmaceutical active ingredients are also preferably released with a delay from the pharmaceutical formulation according to the invention.
  • the pharmaceutical formulation according to the invention preferably contains morphine, hydromorphone, codeine, oxycodone, dihydrocodeine, dextropropoxyphene, buprenorphine, levomethadone, fentanyl, sufentanil, etorphin, pentazocin, tilidine, tramadol, levorphanol, methadone and piridone or piridone, dihydromine or dihydromine as opioid physiologically acceptable salt of the opioids mentioned.
  • the pharmaceutical formulation according to the invention particularly preferably contains morphine, tramadol and / or a physiologically tolerable salt thereof as opioids.
  • the pharmaceutical formulation according to the invention preferably contains, as ⁇ -agonists, clonidine, guanfacin, guanabenz, lofexidine, adrenaline, methyldopa, noradrenaline, methoxamine, oxymetazoline, xylometazoline, teryzoline, ST-91, medetomidine, dexmedetomidine, agmatine, UK 14,304-paronidine U-47,476A, DJ-741, ICI-106270, xylazine, talipexol (BHT-920), naphazoline, tizanidine and / or a physiologically acceptable salt of the said ⁇ -agonists.
  • ⁇ -agonists clonidine, guanfacin, guanabenz, lofexidine, adrenaline, methyldopa, noradrenaline, methoxamine, oxymetazoline, xylometazoline, tery
  • the pharmaceutical formulation according to the invention particularly preferably contains clonidine, guanfacin and / or a physiologically tolerable salt thereof as ⁇ -agonists.
  • the pharmaceutical formulation according to the invention very particularly preferably contains morphine and / or tramadol as the opioid and clonidine and / or its physiologically tolerable salt in each case as the ⁇ -agonist.
  • Acetates, tatrates, sulfates, hydrochlorides, phosphates and additionally salicylates and acetylsalicylates for the group of opioids are preferably used as physiologically compatible salts of the active ingredients.
  • the weight ratio of the opioid to the ⁇ -agonist in the pharmaceutical formulations according to the invention is preferably 200 to 1 to 10 to 1. In a particularly preferred embodiment, the weight ratio of the opioid to the ⁇ -agonist is 100 to 1 to 10 to 1.
  • the pharmaceutical formulation according to the invention is preferably administered orally.
  • Preferred oral medicament formulations are tablets, dragees or capsules, particularly preferably tablets, very particularly preferably multilayer tablets.
  • the pharmaceutical formulation according to the invention can also be present in multiparticulate form, such as, for. B. in the form of microtables, microcapsules, ion exchangers, granules, active ingredient crystals or pellets.
  • the pharmaceutical formulation according to the invention can preferably also be in the form of a pellet tablet, which particularly preferably disintegrates quickly.
  • the respective active ingredients can be retarded preferably by means of a retarding coating, fixation to an ion exchange resin, embedding in a retarding matrix or a combination thereof.
  • Suitable sustained release coatings preferably include water-insoluble waxes or polymers such as acrylic resins Poly (meth) acrylates, or water-insoluble celluloses, preferably ethyl cellulose. These materials are known from the prior art, for example Bauer, Lehmann, Osterwald, Rothgang “Coated Pharmaceutical Formulas,ticianliche Verlagsgesellschaft mbH Stuttgart, 1988, page 69 ff. They are hereby introduced as a reference.
  • the sustained release coatings can also be non-retarding, preferably water-soluble polymers in amounts of up to 30% by weight, such as polyvinylpyrrolidone or water-soluble celluloses, preferably hydroxypropylmethyl cellulose or hydroxypropyl cellulose, and / or hydrophilic pore formers , such as sucrose, sodium chloride or mannitol and / or the known plasticizers.
  • Colestyramine is preferably used as the anionic ion exchange resin
  • polystyrene sulfonates are preferably used as the cationic ion exchange resins.
  • the active ingredients can also be present in a retarding matrix, preferably evenly distributed therein.
  • 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.
  • Particularly preferred matrix materials are ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, poly (meth) acrylic acid and / or their derivatives, such as their salts, amides or esters.
  • Matrix materials made of hydrophobic materials such as hydrophobic polymers, waxes, fats, long-chain fatty acids, fatty alcohols or corresponding esters or ethers or mixtures thereof, are likewise preferred.
  • Mono- or diglycerides of C12-C30 fatty acids and / or C12-C30 fatty alcohols and / or waxes or mixtures thereof are particularly preferably used as hydrophobic materials.
  • sustained-release pharmaceutical formulations can also contain both active ingredients in a delayed form.
  • the pharmaceutical formulation according to the invention can also contain at least one of the active ingredients in addition to its retarded form in the non-retarded form. By combining it 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. It is particularly preferred to set the release of the active ingredients in such a way that the sustained-release pharmaceutical formulation has to be administered at most twice, preferably only once a day. Because of the effect of the analgesics, the person skilled in the art knows in which mixing ratios they are to be used so that the desired release of the active compounds is achieved.
  • the pharmaceutical formulations according to the invention can have further coatings. Coatings that dissolve depending on the pH can also be present as coatings. In this way it can be achieved that the subunits pass through the gastrointestinal tract unresolved and are only released in the intestinal tract. Coatings can also be used to improve the taste.
  • the pharmaceutical formulations according to the invention can be prepared by the various methods known to the person skilled in the art, for example Tablets are produced by the customary processes, such as, for example, by extrusion, build-up processes, wet granulation, fluidized bed processes, dry mixtures or pressing processes. If the pharmaceutical formulation according to the invention, e.g. the tablet has coatings, these can be made using conventional methods, e.g. Drying, spraying on solutions, dispersions or suspensions, by melt processes or by powder application processes.
  • the amount of active ingredient to be administered depends on the active ingredients to be used and on the route of administration.
  • clonidine is particularly preferably in an amount between 1 ⁇ g and 500 ⁇ g, particularly preferably between 10 ⁇ g and 50 ⁇ g, in each case based on the base, and guanfacin preferably in an amount between 5 ⁇ g and 900 ⁇ g between 100 ⁇ g and 500 ⁇ g, based in each case on the base.
  • morphine is preferably used in an amount between 0.1 mg and 20 mg, particularly preferably in an amount between 0.5 mg and 5 mg, in each case based on the base, and tramadol preferably in an amount between 1 mg and 50 mg, particularly preferably in an amount between 1 mg and 20 mg, based in each case on the base.
  • the pharmaceutical formulations according to the invention are preferably administered orally, parenterally or transdermally, particularly preferably orally.
  • Transdermal slow release formulations can e.g. B. in the form of plasters with one or more drug matrices or one or more drug depots and a control membrane.
  • the pharmaceutical formulations according to the invention can contain, in addition to an opioid, an ⁇ -agonist and / or in each case its physiologically compatible salt, further active pharmaceutical ingredients and / or auxiliaries.
  • the pharmaceutical auxiliaries are preferably binders, fillers, lubricants, carrier materials, disintegrants, solvents, diluents, dyes, retarding auxiliaries and / or mixtures thereof.
  • the choice of excipients and the megnen to be used depend on whether the slow-release medicinal forms according to the invention are used orally, parenterally or transdermally.
  • fillers is understood to mean, inter alia, starch, microcrystalline cellulose, dextrose, mannitol or mixtures thereof.
  • Hydroxypropyl methyl celluloses polyvinyl pyrrolidines, hydroxypropyl celluloses, starch paste or mixtures thereof can preferably be used as binders.
  • Low-substituted hydroxypropyl celluloses crosspovidones, Crosscarmellose, starches, pectins, alginates, surfactants or mixtures thereof are used.
  • Magnesium tearat, stearic acid, calcium stearate, fatty alcohols or mixtures thereof are examples of the group of the lubricants that are used.
  • Another object of the present invention is. also the use of the pharmaceutical formulations according to the invention for combating moderate to very severe pain.
  • the pharmaceutical formulations according to the invention show a marked increase in the analgesic effect. This means that with the same analgesic effect, the amount of opioid used can be significantly reduced. In addition, the dependency potential caused by opioids and the constipating effect compared to the sole use of an opioid are significantly reduced.
  • a particular advantage of the slow-release pharmaceutical formulations according to the invention is that the development of a tolerance to the opioid is very much delayed or completely avoided.
  • the following examples serve to explain the invention, but do not restrict the general idea of the invention.
  • the granulation was carried out in a Lödiger high-speed mixer FM 5 and the tablets were produced with a fat eccentric press.
  • PVP polyvinylpyrrolidones
  • morphine HCl in the context of the present invention means morphine HCl trihydrate.
  • tramadol HCl means tramadol HCl trihydrate.
  • RPM revolutions per minute
  • the two-layer tablet produced consisted of a retarded layer containing the active ingredient morphine HCl and an unretarded layer containing the active ingredient clonidine.
  • Morphine HCl, part of the lactose, hydroxyethyl cellulose and cetostearyl alcohol were processed in a suitable mixer for the retarded granules. The mixture was heated to 80 ° C and granulated. After cooling, the granules were sieved and mixed with magnesium stearate and talc.
  • the remaining lactose and corn starch were granulated with a solution of clonidine HCl, PVP 30 and purified water in a suitable mixer. Magnesium stearate and PVP Cl were added to the dried granulate. The two granules were pressed into two-layer tablets.
  • the two-layer tablets produced consisted of a retarded layer containing the active ingredient morphine HCl and an unretarded layer containing the active ingredient clonidine.
  • Morphine HCl part of the lactose, hydroxethyl cellulose and cetostearyl were used for the retarded granules.
  • alcohol processed in a suitable mixer. The mixture was heated to 80 ° C and granulated. After cooling, the granules were sieved and mixed with magnesium stearate and talc.
  • the remaining lactose and corn starch were granulated with a solution of clonidine HCl, PVP 30 and purified water in a suitable mixer. Magnesium stearate and PVP Cl were added to the dried granulate. The two granules were pressed into two-layer tablets.
  • the two-layer tablets produced consisted of a delayed-release layer with the active ingredient Tramadol HCl and a further delayed-release layer which contained the active ingredient clonidine HCL.
  • Tramadol HCl was mixed with microcrystalline cellulose, methyl hydroxypropyl cellulose, part of the highly disperse silicon dioxide and magnesium stearate and pressed into tablets. After that, the tab Lithuanian sifted, mixed with the remaining magnesium stearate and highly disperse silicon dioxide.
  • Lactose and hydroxyethyl cellulose were placed in a suitable mixer and mixed.
  • the mixture was moistened with a solution of clonidine HCl in water. After drying, the mixture was mixed with cetostearyl alcohol, heated to 80 ° C. and then granulated. The cooled granules were sieved and mixed with talc and magnesium stearate and the two granules were compressed into two-layer tablets.
  • the two-layer tablets produced consisted of a delayed-release layer with the active ingredient Tramadol HCl and a further delayed-release layer which contained the active ingredient clonidine HCL.
  • HCl was mixed with microcrystalline cellulose, methylhydroxypropyl cellulose, part of the highly disperse silicon dioxide and magnesium stearate and pressed into tablets. After that, the tablets were broken screened, mixed with the remaining magnesium stearate and the highly disperse silicon dioxide.
  • Lactose and hydroxyethyl cellulose were placed in a suitable mixer and mixed. The mixture was moistened with an aqueous solution of clonidine HCl. After drying, it was mixed with cetostearyl cellulose, heated to 80 ° C. and then granulated. The cooled granules were sieved and mixed with talc and magnesium stearate and the two granules pressed into two-layer tablets.
  • the active ingredient clonidine was applied to slow-release morphine pellets as an ⁇ -agonist using a suitable coating system.
  • the pellets produced were filled into capsules or pressed into tablets.
  • the components of the delayed pellets contained:
  • Neutral starter cores were placed in a paint shop and moistened with an ethanolic polyethylene glycol 4000 solution. A mixture of morphine sulfate and lactose was applied several times to the wet cores and the cores were dried. This process was repeated until the morphine sulfate / lactose mixture was completely applied.
  • the total amount per capsule was 31.98 mg.
  • Microcrystalline cellulose and low-substituted hydroxypropyl cellulose were moistened with an aqueous solution of hydroxypropyl methyl cellulose and clonidine HCl.
  • the mixture was extruded through a 0.5 mm perforated disk with a Pharmatex 35 T extruder, rounded in a Spheromat and dried in the fluidized bed.
  • the coated tramadol and clonidine pellets were filled into capsules and compressed into tablets.
  • the matrix tablet contained the following composition
  • Morphine HCl, lactose, hydroxyethyl cellulose and cetostearyl alcohol were mixed.
  • the mixture was moistened with aqueous clonidine HCl.
  • the resulting mixture was dried, then heated to 80 ° C. and granulated. After cooling, the granules were sieved, mixed with magnesium stearate and tableted.
  • the total amount of starting materials was 200 g.
  • the components were sieved (0.63 mm), then mixed in a small cube mixer for 10 minutes and compressed on a Korsch EK 0 eccentric tablet press to tablets of 10 mm diameter with a radius of curvature of 8.5 mm and an average weight of 300 mg .

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Abstract

The invention relates to medicinal formulations containing an opioid, an α-antagonist and/or their physiologically compatible salts, from which at least one medicinal active ingredient is released in a sustained manner.

Description

Arzneiformulierungen enthaltend ein Opioid und einen α-Agonisten Drug formulations containing an opioid and an α-agonist

Die Erfindung betrifft Arzneiformulierungen enthaltend ein Opioid, einen α-Agonisten und/oder jeweils dessen physiologisch verträgliches Salz, aus denen wenigstens ein Arz eimittelwirkstoff verzögert freigesetzt wird.The invention relates to pharmaceutical formulations containing an opioid, an α-agonist and / or in each case its physiologically tolerable salt, from which at least one drug active ingredient is released with a delay.

Opioide werden aufgrund ihrer starken analgetischen Wirkung zur Linderung πiittelschwerer und starker akuter Schmerzen eingesetzt. Ein großer Nachteil bei der Verwendung von Opioiden liegt jedoch in den damit verbun- denen starken Nebenwirkungen. So treten häufig Nebenwirkungen auf den Gastrointestinaltrakt, wie z. B. Obstipation, auf. Weiterhin stellen sich Atemdepression sowie bei wiederholter Gabe eine Abhängigkeit ein, die zu Mißbrauch führen kann. Ein weiterer Nachteil ist die schnell eintretende Toleranzentwicklung.Because of their strong analgesic effect, opioids are used to relieve medium-weight and severe acute pain. A major disadvantage of using opioids, however, is the strong side effects associated with them. So side effects often occur on the gastrointestinal tract, such. B. constipation. Respiratory depression also arises as well as with repeated administration a dependency that can lead to abuse. Another disadvantage is the rapid development of tolerance.

Die Gabe von Opioiden und α-Agonisten als Monopräparate unter Einsatz verschiedener Arzneiformulierungen ist bekannt. Es existieren neben bekannten nicht retardierten Systemen auch Retardsysteme mit Opioiden, wie in der WO95/14460 oder EP-A-0 647 448 beschrieben, in denen unter anderen auch Butyrate, Ketobemidone, Codeine und ähnliche verwendet werden. Die EP-B- 0 271 193 offenbart ein Retardsystem, daß ausschließlich Hydromorphon verwendet. Retardsysteme mit α-Agonisten sind in der EP-A-0 805 677 oder US 5,484,607 offenbart. In beiden Fällen wird als α-Agonist ausschließlich Clonidin verwendet.The administration of opioids and α-agonists as monopreparations using various pharmaceutical formulations is known. In addition to known non-retarded systems, there are also retard systems with opioids, as described in WO95 / 14460 or EP-A-0 647 448, in which butyrates, ketobemidones, codeins and the like are also used, among others. EP-B-0 271 193 discloses a retard system that uses only hydromorphone. Retardation systems with α-agonists are disclosed in EP-A-0 805 677 or US 5,484,607. In both cases, only clonidine is used as the α-agonist.

Aufgabe der vorliegenden Erfindung war es daher, eine Arzneiformulierung zur Verfügung zu stellen, die zur Behandlung starker bis sehr starker Schmerzen geeignet ist, die die typischen Nebenwirkungen der Opioide nicht aufweist, und die insbesondere die Entwicklung einer Opioidtoleranz sehr lange herauszögert bzw. diese vollständig verhindert.The object of the present invention was therefore to provide a pharmaceutical formulation which is suitable for the treatment of severe to very severe pain, which does not have the typical side effects of the opioids, and which in particular delays the development of an opioid tolerance for a very long time or completely prevents it .

Erfindungsgemäß wird diese Aufgabe durch die Bereitstellung von Arzneiformulierungen gelöst, die ein Opioid, einen α-Agonisten und/oder jeweils dessen physiologisch verträgliches Salz enthalten, aus denen wenigstens ein Arzneimittelwirkstoff verzögert freigesetzt wird.According to the invention, this object is achieved by the provision of pharmaceutical formulations which contain an opioid, an α-agonist and / or in each case its physiologically compatible salt, from which at least one active pharmaceutical ingredient is released with a delay.

Vorzugsweise wird aus der erfindungsgemäßen Arzneiformulierung das Opioid verzögert freigesetzt.The opioid is preferably released with a delay from the pharmaceutical formulation according to the invention.

Die verzögerte Freisetzung des Opioids erfolgt vorzugsweise über einen Zeitraum von 8 Stunden, besonders be- vorzugt 12 Stunden und ganz besonders bevorzugt über 24 Stunden.The delayed release of the opioid preferably takes place over a period of 8 hours, especially during preferably 12 hours and very particularly preferably over 24 hours.

Ebenfalls bevorzugt werden aus der erfindungsgemäßen Arzneiformulierung beide Arzneimittelwirkstoffe verzögert freigesetzt.Both pharmaceutical active ingredients are also preferably released with a delay from the pharmaceutical formulation according to the invention.

Vorzugsweise enthält die erfindungsgemäße Arzneiformulierung als Opioid Morphin, Hydromorphon, Codein, Oxycodon, Dihydrocodein, Dextropropoxyphen, Buprenor- phin, Levomethadon, Fentanyl, Sufentanil, Etorphin, Pentazocin, Tilidin, Tramadol, Levorphanol, Methadon, Dihydromorphin, Pethidin, Piritramid und/oder ein physiologisch verträgliches Salz der genannten Opioide.The pharmaceutical formulation according to the invention preferably contains morphine, hydromorphone, codeine, oxycodone, dihydrocodeine, dextropropoxyphene, buprenorphine, levomethadone, fentanyl, sufentanil, etorphin, pentazocin, tilidine, tramadol, levorphanol, methadone and piridone or piridone, dihydromine or dihydromine as opioid physiologically acceptable salt of the opioids mentioned.

Besonders bevorzugt enthält die erfindungsgemäße Arzneiformulierung als Opioide Morphin, Tramadol und/oder ein physiologisch verträgliches Salz davon.The pharmaceutical formulation according to the invention particularly preferably contains morphine, tramadol and / or a physiologically tolerable salt thereof as opioids.

Als α-Agonisten enthält die erfindungsgemäße Arzneiformulierung vorzugsweise Clonidin, Guanfacin, Guanabenz, Lofexidin, Adrenalin, Methyldopa, Noradrenalin, Methoxamin, Oxymetazolin, Xylometazolin, Teryzolin, ST- 91, Medetomidin, Dexmedetomidin, Agmatin, UK 14,304, Para-Amino-Clonidin, U-47,476A, DJ-741, ICI-106270, Xylazin, Talipexol (BHT-920) , Naphazolin, Tizanidin und/oder ein physiologisch verträgliches Salz der genannten α-Agonisten.The pharmaceutical formulation according to the invention preferably contains, as α-agonists, clonidine, guanfacin, guanabenz, lofexidine, adrenaline, methyldopa, noradrenaline, methoxamine, oxymetazoline, xylometazoline, teryzoline, ST-91, medetomidine, dexmedetomidine, agmatine, UK 14,304-paronidine U-47,476A, DJ-741, ICI-106270, xylazine, talipexol (BHT-920), naphazoline, tizanidine and / or a physiologically acceptable salt of the said α-agonists.

Besonders bevorzugt enthält die erfindungsgemäße Arzneiformulierung als α-Agonisten Clonidin, Guanfacin und/oder ein physiologisch verträgliches Salz davon.The pharmaceutical formulation according to the invention particularly preferably contains clonidine, guanfacin and / or a physiologically tolerable salt thereof as α-agonists.

Ganz besonders bevorzugt enthält die erfindungsgemäße Arzneiformulierung als Opioid Morphin und/oder Tramadol und als α-Agonisten Clonidin und/oder jeweils dessen physiologisch verträgliches Salz. Als physiologisch verträgliche Salze der Wirkstoffe werden vorzugsweise Acetate, Tatrate, Sulfate, Hydro- chloride, Phosphate sowie zusätzlich Salicylate und Acetylsalicylate für die Gruppe der Opioide eingesetzt.The pharmaceutical formulation according to the invention very particularly preferably contains morphine and / or tramadol as the opioid and clonidine and / or its physiologically tolerable salt in each case as the α-agonist. Acetates, tatrates, sulfates, hydrochlorides, phosphates and additionally salicylates and acetylsalicylates for the group of opioids are preferably used as physiologically compatible salts of the active ingredients.

Das Gewichtsverhältnis des Opioids zu dem α-Agonisten beträgt in den erfindungsgemäßen Arzneiformulierungen vorzugsweise 200 zu 1 bis 10 zu 1. In einer besonders bevorzugten Ausführungsform beträgt das Gewichtsverhältnis des Opioids zu dem α-Agonisten 100 zu 1 bis 10 zu 1.The weight ratio of the opioid to the α-agonist in the pharmaceutical formulations according to the invention is preferably 200 to 1 to 10 to 1. In a particularly preferred embodiment, the weight ratio of the opioid to the α-agonist is 100 to 1 to 10 to 1.

Vorzugsweise wird die erfindungsgemäße Arzneiformulie- rung oral verabreicht. Bevorzugte orale Arzneiformulierungen sind Tabletten, Dragees, oder Kapseln, besonders bevorzugt Tabletten, ganz besonders bevorzugt Mehr- schichttabletten.The pharmaceutical formulation according to the invention is preferably administered orally. Preferred oral medicament formulations are tablets, dragees or capsules, particularly preferably tablets, very particularly preferably multilayer tablets.

Die erfindungsgemäße Arzneiformulierung kann aucli in multipartikulärer Form vorliegen, wie z. B. in Form von Mikrotable ten, Mikrokapseln, Ionenaustauscher esina- ten, Granulaten, Wirkstoffkristallen oder Pellets. Vorzugsweise kann die erfindungsgemäße Arzneiformulierung auch als Pellettablette vorliegen, die besonders bevorzugt schnell zerfällt.The pharmaceutical formulation according to the invention can also be present in multiparticulate form, such as, for. B. in the form of microtables, microcapsules, ion exchangers, granules, active ingredient crystals or pellets. The pharmaceutical formulation according to the invention can preferably also be in the form of a pellet tablet, which particularly preferably disintegrates quickly.

Die Retardierung der jeweiligen Wirkstoffe kann vorzugsweise durch einen retardierenden Überzug, Fixierung an einem Ionenaustauscherharz, Einbettung in eine retardierende Matrix oder einer Kombination daraus erfolgen.The respective active ingredients can be retarded preferably by means of a retarding coating, fixation to an ion exchange resin, embedding in a retarding matrix or a combination thereof.

Vorzugsweise wird die Retardierung mit Hilfe von retar- dierenden Überzügen erreicht. Geeignete, retardierende Überzüge umfassen wasserunlösliche Wachse oder Polymere, wie z.B. Acrylharze, vorzugsweise Poly (meth) acrylate, oder wasserunlösliche Cellulosen, vorzugsweise Ethylcellulose . Diese Materialien sind aus dem Stande der Technik, z.B. Bauer, Lehmann, Osterwald, Rothgang „Überzogene Arzneiformeln , Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, 1988, Seite 69 ff., bekannt. Sie werden hiermit als Referenz eingeführt.The retardation is preferably achieved with the aid of retarding coatings. Suitable sustained release coatings preferably include water-insoluble waxes or polymers such as acrylic resins Poly (meth) acrylates, or water-insoluble celluloses, preferably ethyl cellulose. These materials are known from the prior art, for example Bauer, Lehmann, Osterwald, Rothgang “Coated Pharmaceutical Formulas, Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, 1988, page 69 ff. They are hereby introduced as a reference.

Neben den wasserunlöslichen Polymeren können gegebenenfalls zur Einstellung der Freisetzungsgeschwindigkeit des Wirkstoffes die Retardüberzüge auch nicht retardierende, vorzugsweise wasserlösliche Polymere in Mengen bis 30 Gew.?,, wie Polyvinylpyrrolidon oder wasserlösliche Cellulosen, vorzugsweise Hydroxypropylmethyl- cellulose oder Hydroxypropylcellulose, und/oder hydro- phile Porenbildner, wie Saccharose, Natriumchlorid oder Mannitol und/oder die bekannten Weichmacher enthalten.In addition to the water-insoluble polymers, in order to adjust the rate of release of the active ingredient, the sustained release coatings can also be non-retarding, preferably water-soluble polymers in amounts of up to 30% by weight, such as polyvinylpyrrolidone or water-soluble celluloses, preferably hydroxypropylmethyl cellulose or hydroxypropyl cellulose, and / or hydrophilic pore formers , such as sucrose, sodium chloride or mannitol and / or the known plasticizers.

Eine weitere übliche Verfahrensweise der Retardierung ist die Fixierung der Wirkstoffe an Ionenaustauscher- harzen. Als anionisches Ionenaustauscherharz wird vorzugsweise Colestyramin, als kationische Ionenaustau- scherharze werden vorzugsweise Polystyrolsulfonate eingesetzt .Another common method of retardation is to fix the active ingredients to ion exchange resins. Colestyramine is preferably used as the anionic ion exchange resin, and polystyrene sulfonates are preferably used as the cationic ion exchange resins.

Zur Retardierung können die Wirkstoffe auch in einer retardierenden Matrix, vorzugsweise gleichmäßig darin verteilt, vorliegen.For retardation, the active ingredients can also be present in a retarding matrix, preferably evenly distributed therein.

Als Matrixmaterialien können physiologisch verträg- liehe, hydrophile Materialien verwendet werden, welche dem Fachmann bekannt sind. Vorzugsweise werden als hydrophile Matrixmaterialien Polymere, besonders bevorzugt Celluloseether, Celluloseester und/oder Acrylharze verwendet. Ganz besonders bevorzugt werden als Matrix- materialien Ethylcellulose, Hydroxypropylmethyl- cellulose, Hydroxypropylcellulose, Hydroxymethyl- cellulose, Poly (meth) acrylsäure und/oder deren Derivate, wie deren Salze, Amide oder Ester eingesetzt.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. Particularly preferred matrix materials are ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, poly (meth) acrylic acid and / or their derivatives, such as their salts, amides or esters.

Ebenfalls bevorzugt sind Matrixmaterialien aus hydro- phoben Materialien, wie hydrophobe Polymere, Wachse, Fette, langkettigen Fettsäuren, Fettalkohole oder entsprechenden Ester oder Ether oder deren Gemische. Besonders bevorzugt werden als hydrophobe Materialien Mono- oder Diglyceride von C12-C30-Fettsäuren und/oder C12-C30-Fettalkohole und/oder Wachse oder deren Gemische eingesetzt.Matrix materials made of hydrophobic materials, such as hydrophobic polymers, waxes, fats, long-chain fatty acids, fatty alcohols or corresponding esters or ethers or mixtures thereof, are likewise preferred. Mono- or diglycerides of C12-C30 fatty acids and / or C12-C30 fatty alcohols and / or waxes or mixtures thereof are particularly preferably used as hydrophobic materials.

Es ist auch möglich, Mischungen der genannten hydrophilen und hydrophoben Materialien als retardierendes Matrixmaterial einzusetzen.It is also possible to use mixtures of the hydrophilic and hydrophobic materials mentioned as retarding matrix material.

In einer weiteren bevorzugten Ausführungsform können die retardierten Arzneiformulierungen auch beide Wirkstoffe in retardierter Form enthalten.In a further preferred embodiment, the sustained-release pharmaceutical formulations can also contain both active ingredients in a delayed form.

Die erfindungsgemäße Arzneiformulierung kann auch mindestens einen der Wirkstoffe zusätzlich zu seiner retardierten Form auch in der nicht retardierten Form enthalten. Durch Kombination mit dem sofort freigesetz- ten Wirkstoff läßt sich eine hohe Initialdosis zur schnellen Schmerzlinderung erzielen. Die langsame Freisetzung aus der retardierten Form verhindert dann ein Abklingen der analgetischen Wirkung. Besonders bevorzugt wird die Freisetzung der Wirkstoffe so einzustel- len sein, daß die retardierte Arzneiformulierung höchstens zweimal, vorzugsweise nur einmal täglich verabreicht werden muß. Dem Fachmann ist aufgrund der Wirkung der Analgetika bekannt, in welchen Mischungsverhältnissen diese einzusetzen sind, damit die gewünschte Freisetzung der Wirkstoffe erreicht wird. Außerdem können die erfindungsgemäßen Arzneiformulierungen noch weitere Überzüge aufweisen. Als Überzüge können auch solche vorhanden sein, die sich pH-abhängig auflösen. So kann erreicht werden, daß die Untereinhei- ten den Magentrakt unaufgelöst passieren und erst im Darmtrakt zur Freisetzung gelangen. Es können auch Überzüge verwendet werden, die der Verbesserung des Geschmackes dienen.The pharmaceutical formulation according to the invention can also contain at least one of the active ingredients in addition to its retarded form in the non-retarded form. By combining it 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. It is particularly preferred to set the release of the active ingredients in such a way that the sustained-release pharmaceutical formulation has to be administered at most twice, preferably only once a day. Because of the effect of the analgesics, the person skilled in the art knows in which mixing ratios they are to be used so that the desired release of the active compounds is achieved. In addition, the pharmaceutical formulations according to the invention can have further coatings. Coatings that dissolve depending on the pH can also be present as coatings. In this way it can be achieved that the subunits pass through the gastrointestinal tract unresolved and are only released in the intestinal tract. Coatings can also be used to improve the taste.

Die Herstellung der erfindungsgemäßen Arzneiformulierungen kann nach den verschiedenen dem Fachmann bekannten Methoden erfolgen, so werden z.B. Tabletten durch die üblichen Verfahren, wie beispielsweise durch Extru- sion, Aufbauverfahren, Naßgranulation, Wirbelbettver- fahren, Trockenmischungen oder Preßverfahren hergestellt. Sofern die erfindungsgemäße Arzneiformulierung, wie z.B. die Tablette Überzüge aufweist, können diese nach üblichen Verfahren, wie z.B. Dragieren, Aufsprühen von Lösungen, Dispersionen oder Suspensionen, durch Schmelzverfahren oder durch Pulverauftragsverfahren aufgebracht werden.The pharmaceutical formulations according to the invention can be prepared by the various methods known to the person skilled in the art, for example Tablets are produced by the customary processes, such as, for example, by extrusion, build-up processes, wet granulation, fluidized bed processes, dry mixtures or pressing processes. If the pharmaceutical formulation according to the invention, e.g. the tablet has coatings, these can be made using conventional methods, e.g. Drying, spraying on solutions, dispersions or suspensions, by melt processes or by powder application processes.

Die zu verabreichende Wirkstoffmenge hängt von den zu verwendenden Wirkstoffen sowie von dem Applikationsweg ab. Für eine orale Applikation wird beispielsweise Clonidin vorzugsweise in einer Menge zwischen 1 μg und 500 μg, besonders bevorzugt zwsichen 10 μg und 50 μg, jeweils bezogen auf die Base, und Guanfacin vorzugsweise in einer Menge zwischen 5 μg und 900 μg, beson- ders bevorzugt zwischen 100 μg und 500 μg, jeweils bezogen auf die Base, eingesetzt.The amount of active ingredient to be administered depends on the active ingredients to be used and on the route of administration. For oral administration, for example, clonidine is particularly preferably in an amount between 1 μg and 500 μg, particularly preferably between 10 μg and 50 μg, in each case based on the base, and guanfacin preferably in an amount between 5 μg and 900 μg between 100 μg and 500 μg, based in each case on the base.

Für eine orale Verabreichung der zu verwendenden Kombination wird beispielsweise Morphin vorzugsweise in einer Menge zwischen 0, 1 mg und 20 mg, besonders bevorzugt in einer Menge zwischen 0,5 mg und 5 mg, jeweils bezogen auf die Base, und Tramadol vorzugsweise in einer Menge zwischen 1 mg und 50 mg, besonders bevorzugt in einer Menge zwischen 1 mg und 20 mg, jeweils bezogen auf die Base, eingesetzt.For oral administration of the combination to be used, for example, morphine is preferably used in an amount between 0.1 mg and 20 mg, particularly preferably in an amount between 0.5 mg and 5 mg, in each case based on the base, and tramadol preferably in an amount between 1 mg and 50 mg, particularly preferably in an amount between 1 mg and 20 mg, based in each case on the base.

Die erfindungsgemäßen Arzneiformulierungen werden vorzugsweise oral, parenteral oder transdermal, besonders bevorzugt oral verabreicht.The pharmaceutical formulations according to the invention are preferably administered orally, parenterally or transdermally, particularly preferably orally.

Transdermale Retardformulierungen können z. B. in Form von Pflastern mit einer oder mehreren Wirkstoffmatrices oder einem oder mehreren Wirkstoffdepots und einer Steuermembran hergestellt werden.Transdermal slow release formulations can e.g. B. in the form of plasters with one or more drug matrices or one or more drug depots and a control membrane.

Die erfindungsgemäßen Arzneiformulierungen können neben einem Opioid, einem α-Agonisten und/oder jeweils dessen physiologisch verträgliches Salz weitere pharmazeutische Wirkstoffe und/oder Hilfsstoffe enthalten. Vorzugsweise handelt es sich bei den pharmazeutischen Hilfsstoffen um Bindemittel, Füllstoffe, Schmiermittel, Trägermaterialien, Zerfallsförderer, Lösemittel, Verdünnungsmittel, Farbstoffe, retardierende Hilfsstoffe und/oder deren Mischungen. Die Auswahl der Hilfsstoffe sowie die einzusetzenden Megnen hängen davon ab, ob die erfindungsgemäßen retardierten Arzneiformen oral, parenteral oder transdermal eingesetzt werden.The pharmaceutical formulations according to the invention can contain, in addition to an opioid, an α-agonist and / or in each case its physiologically compatible salt, further active pharmaceutical ingredients and / or auxiliaries. The pharmaceutical auxiliaries are preferably binders, fillers, lubricants, carrier materials, disintegrants, solvents, diluents, dyes, retarding auxiliaries and / or mixtures thereof. The choice of excipients and the megnen to be used depend on whether the slow-release medicinal forms according to the invention are used orally, parenterally or transdermally.

Unter dem Ausdruck „Füllstoffe" werden unter anderem Stärke, mikrokristalline Cellulose, Dextrose, Mannitol oder Mischungen davon verstanden.The term “fillers” is understood to mean, inter alia, starch, microcrystalline cellulose, dextrose, mannitol or mixtures thereof.

Als Bindemittel können vorzugsweise Hydroxypropyl- methylcellulosen, Polyvinylpyrrolidine, Hydroxypropyl- cellulosen, Stärkekleister oder Mischungen davon eingesetzt werden.Hydroxypropyl methyl celluloses, polyvinyl pyrrolidines, hydroxypropyl celluloses, starch paste or mixtures thereof can preferably be used as binders.

Als Zerfallsförderer werden vorzugsweise niedrig substituierte Hydroxypropylcellulosen, Crosspovidone, Crosscarmellose, Stärken, Pektine, Alginate, Tenside oder Mischungen davon eingesetzt.Low-substituted hydroxypropyl celluloses, crosspovidones, Crosscarmellose, starches, pectins, alginates, surfactants or mixtures thereof are used.

Zur Gruppe der Schmj er ittel, die verwendet werden, seien beispielhaft Magnesiums tearat, Stearinsäure, Calciumstearat, Fettalkohole oder Mischungen davon aufgeführt .Magnesium tearat, stearic acid, calcium stearate, fatty alcohols or mixtures thereof are examples of the group of the lubricants that are used.

Ein weiterer Gegenstand der vorliegenden Erfindung ist. auch die Verwendung der erfindungsgemäßen Arzneiformulierungen zur Bekämpfung von mittelstarken bis sehr starken Schmerzen.Another object of the present invention is. also the use of the pharmaceutical formulations according to the invention for combating moderate to very severe pain.

Die erfindungsgemäßen Arzneiformulierungen zeigen gegenüber der alleinigen Verwendung eines Opioids eine deutliche Verstärkung der analgetischen Wirkung. Dies bedeutet, daß bei gleicher analgetischer Wirkung die eingesetzte Menge des Opioids deutlich reduziert werden kann. Darüber hinaus wird das durch Opioide hervorgeru- fene Abhängigkeitspotentential sowie die obstipierende Wirkung gegenüber dem alleinigen Einsatz eines Opioids deutlich reduziert.Compared to the use of an opioid alone, the pharmaceutical formulations according to the invention show a marked increase in the analgesic effect. This means that with the same analgesic effect, the amount of opioid used can be significantly reduced. In addition, the dependency potential caused by opioids and the constipating effect compared to the sole use of an opioid are significantly reduced.

Diese Verminderung der Nebenwirkungen wird dadurch noch verbessert, daß aufgrund der verzögerten Freisetzung jeweils nur eine relativ geringe Menge der Wirkstoffe freigesetzt wird.This reduction in side effects is further improved in that only a relatively small amount of the active ingredients is released due to the delayed release.

Ein besonderer Vorteil der erfindungsgemäßen retardier- ten Arzneimittelformulierungen ist, daß die Entwicklung einer Toleranz gegenüber dem Opioid sehr stark hinausgezögert bzw. vollständig vermieden wird. Die nachfolgenden Beispiele dienen der Erläuterunu der Erfindung, schränken aber den allgemeinen Erfindungsgedanken nicht ein. A particular advantage of the slow-release pharmaceutical formulations according to the invention is that the development of a tolerance to the opioid is very much delayed or completely avoided. The following examples serve to explain the invention, but do not restrict the general idea of the invention.

BeispieleExamples

Die Granulation erfolgte in einem Lödiger Schnellmischer FM 5 und die Tablettenherstellung mit einer Fette Exzenterpresse.The granulation was carried out in a Lödiger high-speed mixer FM 5 and the tablets were produced with a fat eccentric press.

Unter dem Begriff „PVP" sind im Rahmen der vorliegenden Erfindung Polyvinylpyrrolidone zu verstehen.In the context of the present invention, the term “PVP” is understood to mean polyvinylpyrrolidones.

Der Ausdruck „Morphin HCl" bedeutet im Rahmen der vorliegenden Erfindung Morphin HCl Trihydrat.The term “morphine HCl” in the context of the present invention means morphine HCl trihydrate.

Der Ausdruck „Tramadol HCl" bedeutet im Rahmen der vorliegenden Erfindung Tramadol HCl Trihydrat.In the context of the present invention, the expression “tramadol HCl” means tramadol HCl trihydrate.

Der Ausdruck „min." bedeutet MinuteThe expression "min." Means minute

Der Ausdruck „UpM" bedeutet Umdrehungen pro Minute,The term "RPM" means revolutions per minute,

Beispiel 1example 1

Herstellung von Zweischichttablette mit retardiertem Opioid und unretardiertem α-AgonistenProduction of two-layer tablet with retarded opioid and unretarded α-agonist

Die hergestellten Zweischichttablette bestanden aus einer retardierten, den Wirkstoff Morphin HCl enthaltenden Schicht und einer unretardierten, den Wirkstoff Clonidin enthaltenden Schicht. Für das retardierte Granulat wurde Morphin HCl, ein Teil der Lactose, Hydroxyethylcellulose und Cetostearylalkohol in einem geeigneten Mischer verarbeitet. Die Mischung wurde auf 80° C erhitzt und granuliert. Das Granulat wurde nach dem Abkühlen gesiebt und mit Magnesiu stearat und Talkum vermischt. The two-layer tablet produced consisted of a retarded layer containing the active ingredient morphine HCl and an unretarded layer containing the active ingredient clonidine. Morphine HCl, part of the lactose, hydroxyethyl cellulose and cetostearyl alcohol were processed in a suitable mixer for the retarded granules. The mixture was heated to 80 ° C and granulated. After cooling, the granules were sieved and mixed with magnesium stearate and talc.

Für das unretardierte Granulat wurde die restliche Lactose und Maisstärke mit einer Lösung aus Clonidin HCl, PVP 30 und gereinigtem Wasser in einem geeigneten Mischer granuliert. Dem getrockneten Granulat wurde Magnesiumstearat und PVP Cl hinzugemischt. Die beiden Granulate wurden zu Zweischicht-tabletten verpreßt.For the unretarded granules, the remaining lactose and corn starch were granulated with a solution of clonidine HCl, PVP 30 and purified water in a suitable mixer. Magnesium stearate and PVP Cl were added to the dried granulate. The two granules were pressed into two-layer tablets.

Die in-vitro-Freisetzungsuntersuchung erfolgte in einer Blattrührerapparatur mit einem Volumen von 600 ml verdünnter Salzsäure, einem pH von 1,2 und einer Geschwindigkeit von 75 UpM. Die Untersuchung der Zweischichttablette lieferte über einen Zeitraum von 480 min. fol- gendes Freisetzungsprofil (Mittelwert n = 6) .The in vitro release study was carried out in a blade stirrer apparatus with a volume of 600 ml of dilute hydrochloric acid, a pH of 1.2 and a speed of 75 rpm. The examination of the two-layer tablet delivered over a period of 480 min. following release profile (mean n = 6).

- Freisetzung von Morphin HCl- Release of morphine HCl

- Freisetzung von Clonidin HCl - Release of clonidine HCl

Beispiel 2Example 2

Herstellung von Zweischichttablette mit retardiertem Opioid und unretardiertem α-AgonistenProduction of two-layer tablet with retarded opioid and unretarded α-agonist

Die hergestellten Zweischichttabletten bestanden aus einer retardierten, den Wirkstoff Morphin HCl enthaltenden Schicht und einer unretardierten, den Wirkstoff Clonidin enthaltenden Schicht.The two-layer tablets produced consisted of a retarded layer containing the active ingredient morphine HCl and an unretarded layer containing the active ingredient clonidine.

Für das retardierte Granulat wurde Morphin HCl, ein Teil der Lactose, Hydroxethylcellulose und Cetostearyl- alkohol in einem geeigneten Mischer verarbeitet. Die Mischung wurde auf 80° C erhitzt und granuliert. Das Granulat wurde nach dem Abkühlen gesiebt und mit Magnesiumstearat und Talkum vermischt.Morphine HCl, part of the lactose, hydroxethyl cellulose and cetostearyl were used for the retarded granules. alcohol processed in a suitable mixer. The mixture was heated to 80 ° C and granulated. After cooling, the granules were sieved and mixed with magnesium stearate and talc.

Für das unretardierte Granulat wurde die restliche Lactose und Maisstärke mit einer Lösung aus Clonidin HCl, PVP 30 und gereinigtem Wasser in einem geeigneten Mischer granuliert. Dem getrockneten Granulat wurde Magnesiumstearat und PVP Cl hinzugemischt. Die beiden Granulate verpreßte man zu Zweischichttabletten.For the unretarded granules, the remaining lactose and corn starch were granulated with a solution of clonidine HCl, PVP 30 and purified water in a suitable mixer. Magnesium stearate and PVP Cl were added to the dried granulate. The two granules were pressed into two-layer tablets.

Die in-vitro-Freisetzungsuntersuchung erfolgte in einer Blattrührerapparatur mit einem Volumen von 600 ml ver- dünnter Salzsäure, einem pH von 1,2 und einer Geschwindigkeit von 75 UpM. Die Untersuchung der Zweischichttablette lieferte über einen Zeitraum von 480 min. folgendes Freisetzungsprofil (Mittelwert n = 6) .The in vitro release study was carried out in a blade stirrer apparatus with a volume of 600 ml of dilute hydrochloric acid, a pH of 1.2 and a speed of 75 rpm. The examination of the two-layer tablet delivered over a period of 480 min. following release profile (mean n = 6).

- Freisetzung von Morphin HCl- Release of morphine HCl

- Freisetzung von Clonidin HCl - Release of clonidine HCl

Beispiel 3Example 3

Herstellung von Zweischichttablette mit retardiertem Opioid und retardiertem α-AgonistenProduction of two-layer tablet with delayed opioid and delayed α-agonist

Die hergestellten Zweischichttabletten bestanden aus einer retardierten Schicht mit dem Wirkstoff Tramadol HCl und einer weiteren retardierten Schicht die den Wirkstoff Clonidin HCL enthielt.The two-layer tablets produced consisted of a delayed-release layer with the active ingredient Tramadol HCl and a further delayed-release layer which contained the active ingredient clonidine HCL.

Herstellung der ersten Schicht mit Tramadol HClProduction of the first layer with Tramadol HCl

Tramadol HCl wurde mit mikrokristalliner Cellulose, Methylhydroxypropylcellulose, einem Teil des hochdispersen Ξiliciumdioxids und Magnesiumstearat gemischt und zu Tabletten vorgepreßt. Hiernach wurden die Tab- letten gebrochen gesiebt, mit dem restlichen Magnesiumstearat und hochdispersen Siliciumdioxid gemischt.Tramadol HCl was mixed with microcrystalline cellulose, methyl hydroxypropyl cellulose, part of the highly disperse silicon dioxide and magnesium stearate and pressed into tablets. After that, the tab Latvian sifted, mixed with the remaining magnesium stearate and highly disperse silicon dioxide.

- Herstellung der zweiten Schicht mit Clonidin HCl- Production of the second layer with clonidine HCl

Lactose und Hydroxyethylcellulose wurden in einem geeigneten Mischer vorgelegt und vermischt. Der Mischung wurde mit einer Lösung aus Clonidin HCl in Wasser durchfeuchtet. Nach der Trocknung vermischte man mit Cetostearylalkohol, erhitzte auf 80° C und granulierte anschließend. Das abgekühlte Granulat siebte man und versetzte mit Talkum und Magnesiumstearat und verpreßte die beiden Granulate zu Zweischichttabletten.Lactose and hydroxyethyl cellulose were placed in a suitable mixer and mixed. The mixture was moistened with a solution of clonidine HCl in water. After drying, the mixture was mixed with cetostearyl alcohol, heated to 80 ° C. and then granulated. The cooled granules were sieved and mixed with talc and magnesium stearate and the two granules were compressed into two-layer tablets.

Die in-vitro-Freisetzungsuntersuchung erfolgte in einer Blattrührerapparatur mit einem Volumen von 600 ml verdünnter Salzsäure, einem pH von 1,2 und einer Geschwindigkeit von 75 UpM. Die Untersuchung der Zweischicht- tablette lieferte über einen Zeitraum von 600 min. folgendes Freisetzungsprofil (Mittelwert n = 6) . Freisetzung von Tramadol HClThe in vitro release study was carried out in a blade stirrer apparatus with a volume of 600 ml of dilute hydrochloric acid, a pH of 1.2 and a speed of 75 rpm. The two-layer tablet was examined over a period of 600 minutes. following release profile (mean n = 6). Release of Tramadol HCl

Freisetzung von Clonidin HClRelease of clonidine HCl

Beispiel 4Example 4

Herstellung einer Zweischicht ablette mit retardiertem Opioid und α-ΛgonistenProduction of a two-layer ablette with a retarded opioid and α-Λgonist

Die hergestellten Zweischichttabletten bestanden aus einer retardierten Schicht mit dem Wirkstoff Tramadol HCl und einer weiteren retardierten Schicht die den Wirkstoff Clonidin HCL enthielt.The two-layer tablets produced consisted of a delayed-release layer with the active ingredient Tramadol HCl and a further delayed-release layer which contained the active ingredient clonidine HCL.

- Herstellung der ersten Schicht mit Tramadol HCl - Production of the first layer with Tramadol HCl

Tramadol. HCl wurde mit mikrokristalliner Cellulose, Methylhydroxypropylcellulose, einem Teil des hochdispersen Siliciumdioxids und Magnesiumstearat gemischt und zu Tabletten vorgepreßt. Hiernach wurden die Tabletten gebrochen gesiebt, mit dem restlichen Magnesiumstearat und dem hochdispersen Siliciumdioxid gemischt.Tramadol. HCl was mixed with microcrystalline cellulose, methylhydroxypropyl cellulose, part of the highly disperse silicon dioxide and magnesium stearate and pressed into tablets. After that, the tablets were broken screened, mixed with the remaining magnesium stearate and the highly disperse silicon dioxide.

- Herstellung der zweiten Schicht mit Clonidin HCl.- Production of the second layer with clonidine HCl.

Lactose und Hydroxyethylcellulose wurden in einem geeigneten Mischer vorgelegt und vermischt. Die Mischung durchfeuchtete man mi einer wässrigen Lösung aus Clonidin HCl. Nach der Trocknung wurde mit Cetostearyl- cellulose vermischt, auf 80° C erhitzt und anschließend granuliert. Das abgekühlte Granulat wurde gesiebt und mit Talkum und Magnesiumstearat vermischt und die beiden Granulate zu Zweischichttabletten verpreßt. Die in-vitro-Freisetzungsuntersuchung wurde in einer Blattrührerapparatur mit einem Volumen von 600 ml verdünnter Salzsäure, einem pH von 1,2 und einer Geschwindigkeit von 75 UpM durchgeführt. Die Untersuchung der Zweischichttablette lieferte über einen Zeitraum von 600 min. folgendes Freiset∑ungsprofil (Mittelwert n = 6) .Lactose and hydroxyethyl cellulose were placed in a suitable mixer and mixed. The mixture was moistened with an aqueous solution of clonidine HCl. After drying, it was mixed with cetostearyl cellulose, heated to 80 ° C. and then granulated. The cooled granules were sieved and mixed with talc and magnesium stearate and the two granules pressed into two-layer tablets. The in vitro release study was carried out in a blade stirrer apparatus with a volume of 600 ml of dilute hydrochloric acid, a pH of 1.2 and a speed of 75 rpm. The examination of the two-layer tablet delivered over a period of 600 minutes. following release profile (mean n = 6).

- Freisetzung von Tramadol HCl- Release of Tramadol HCl

- Freisetzung von Clonidin HCl- Release of clonidine HCl

Beispiel 5 Example 5

Herstellung von unterschiedlichen Pellet ArzneiformulierungenProduction of different pellet pharmaceutical formulations

5.1 Schnellfreisetzender Wirkstoff, der auf ein retardiertes Pellet aufgezogen wird5.1 Rapid-release active ingredient that is drawn onto a retarded pellet

Auf retardierte Morphin-Pellets wurde als α-Agonist der Wirkstoff Clonidin mit Hilfe einer geeigneten Lackieranlage aufgetragen. Die hergestellten Pellets wurden in Kapseln gefüllt oder zu Tabletten verpreßt.The active ingredient clonidine was applied to slow-release morphine pellets as an α-agonist using a suitable coating system. The pellets produced were filled into capsules or pressed into tablets.

Die Bestandteile der retardierten Pellets enthielten:The components of the delayed pellets contained:

Neutrale Starterkerne wurden in einer Lackieranlage gegeben und mit einer ethanolischen Polyethylenglykol 4000 Lösung befeuchtet. Auf die feuchten Kerne wurde mehrfach ein Gemisch aus Morphinsulfat und Lactose aufgetragen und die Kerne getrocknet. Dieser Vorgang wurde solange wiederholt bis das Morphinsulfat/Lactose- Gemisch vollständig aufgetragen war.Neutral starter cores were placed in a paint shop and moistened with an ethanolic polyethylene glycol 4000 solution. A mixture of morphine sulfate and lactose was applied several times to the wet cores and the cores were dried. This process was repeated until the morphine sulfate / lactose mixture was completely applied.

Auf die so hergestellten Morphinpellets wurde in einer Lackieranlage eine Suspension aus Clonidin HCl, Hy- droxypropylmethylcellulose, Polyethylenglykol 4000 und Propylenglykol aufgetragen. Der Auftrag hatte folgende Zusammensetzung :A suspension of clonidine HCl, hy- droxypropylmethylcellulose, polyethylene glycol 4000 and propylene glycol applied. The order had the following composition:

Die Gesamtmenge pro Kapsel betrug 31,98 mg.The total amount per capsule was 31.98 mg.

Die in-vitro-Freisetzungsuntersuchung wurden in einer Drehkörbchenapparatur mit einem Volumen von 600 ml verdünnter Salzsäure und einem pH von 1,2 und einer Geschwindigkeit von 100 UpM durchgeführt. Die Untersuchung der Formulierung lieferte über den Zeitraum folgendes Freisetzungsprofil (Mittelwert n = 6) .The in vitro release study was carried out in a rotating basket apparatus with a volume of 600 ml of dilute hydrochloric acid and a pH of 1.2 and a speed of 100 rpm. Examination of the formulation gave the following release profile over the period (mean n = 6).

- Freisetzung von Morphinsulfat- Release of morphine sulfate

Freisetzung von Clonidin Hcl Release of clonidine Hcl

5.2 Gemischte Pellets in Kapseln5.2 Mixed pellets in capsules

- Herstellung der Tramadol Pellets- Production of the Tramadol pellets

Tramadolhydrochlorid, mikrokristalline Cellulose, Calciumhydrogenphosphat und die niedrig substituierte Hydroxypropylcellulose wurden mit einer wässrigen Lösung aus Hydroypropylmethylcellulose durchfeuchtet und in einem Pharmatex 35 T Extruder durch eine 0,5 mm Loch- Scheibe extrudiert. Das Extrudat wurde in einem Sphero- mat gerundet, in der Wirbelschicht getrocknet und daran anschließend mit einer wässrigen Dispersion von Ethylcellulose und Dibutylsebacat retardiert überzogen. - Herstellung von Clonidin PelletsTramadol hydrochloride, microcrystalline cellulose, calcium hydrogen phosphate and the low-substituted hydroxypropyl cellulose were moistened with an aqueous solution of hydroypropyl methyl cellulose and extruded in a Pharmatex 35 T extruder through a 0.5 mm perforated disc. The extrudate was rounded in a spheromat, dried in the fluidized bed and then coated with an aqueous dispersion of ethyl cellulose and dibutyl sebacate. - Production of clonidine pellets

Mikrokristalline Cellulose und niedrig substituierte Hydroxypropylcellulose wurden mit einer wässrigen Lösung von Hydroxypropylmethylcellulose und Clonidin HCl durchfeuchtet. Die Mischung wurde mit einem Pharmatex 35 T Extruder durch eine 0, 5 mm Lochscheibe extrudiert, in einem Spheromat gerundet und in der Wirbelschicht getrocknet. Die überzogenen Tramadol und Clonidin Pellets wurden in Kapseln gefüllt und zu Tabletten verpreßt .Microcrystalline cellulose and low-substituted hydroxypropyl cellulose were moistened with an aqueous solution of hydroxypropyl methyl cellulose and clonidine HCl. The mixture was extruded through a 0.5 mm perforated disk with a Pharmatex 35 T extruder, rounded in a Spheromat and dried in the fluidized bed. The coated tramadol and clonidine pellets were filled into capsules and compressed into tablets.

Die in-vi ro-Freisetzungsuntersuchung wurden in einer Drehkörbchenapparatur mit einem Volumen von 600 ml verdünnter Salzsäure, einem pH von 1,2 und einer Geschwindigkeit von 100 UpM durchgeführt. Die Untersuchung der Kapseln lieferte über den Zeitraum folgendes Freisetzungsprofil (Mittelwert n - 6) .The in vitro release studies were carried out in a rotating basket apparatus with a volume of 600 ml of dilute hydrochloric acid, a pH of 1.2 and a speed of 100 rpm. Examination of the capsules gave the following release profile (mean n - 6).

- Freisetzung von Tramadol HCl- Release of Tramadol HCl

- Freisetzung von Clonidin HCl - Release of clonidine HCl

Beispiel 6Example 6

Die Matrixtablette enthielt folgende ZusammensetzungThe matrix tablet contained the following composition

Morphin HCl, Lactose, Hydroxyethylcellulose und Cetostearylalkohol wurden vermischt. Die Mischung durchfeuchtete man mit wässriger Clonidin HCl. Die entstandene Mischung wurde getrocknet, hiernach auf 80° C erhitzt und granuliert. Nach dem Abkühlen wurde das Granulat gesiebt mit Magnesiumstearat gemischt und tablettiert.Morphine HCl, lactose, hydroxyethyl cellulose and cetostearyl alcohol were mixed. The mixture was moistened with aqueous clonidine HCl. The resulting mixture was dried, then heated to 80 ° C. and granulated. After cooling, the granules were sieved, mixed with magnesium stearate and tableted.

Die in-vitro-Freisetzungsuntersuchung wurde in einer Blattrührerapparatur mit einem Volumen von 600 ml verdünnter Salzsäure, einem pH von 1,2 und einer Geschwin- digkeit von 75 UpM durchgeführt. Die Untersuchung der Matrixtablette lieferte über einen Zeitraum von 480min. folgendes Freisetzungsprofil (Mittelwert n - 6) .The in vitro release study was carried out in a blade stirrer apparatus with a volume of 600 ml of dilute hydrochloric acid, a pH of 1.2 and a speed of speed of 75 rpm. The examination of the matrix tablet delivered over a period of 480 minutes. following release profile (mean n - 6).

Freisetzung von Morphin HClRelease of morphine HCl

- Freisetzung von Clonidin HCl- Release of clonidine HCl

Bei spiel 7In game 7

Herstellung einer Matrixtablette mit folgender Zusammensetzung :Production of a matrix tablet with the following composition:

Die Gesamtmenge an Ausgangsstoffen betrug 200 g. Die Bestandteile wurden gesiebt (0,63 mm), hiernach in einem kleinen Kubusmischer 10 Minuten gemischt und auf einer Korsch EK 0 Excentertablettenpresse zu Tabletten von 10 mm Durchmes-ser mit einem Wölbungsradius von 8,5 mm und einem mittleren Gewicht von 300 mg verpreßt.The total amount of starting materials was 200 g. The components were sieved (0.63 mm), then mixed in a small cube mixer for 10 minutes and compressed on a Korsch EK 0 eccentric tablet press to tablets of 10 mm diameter with a radius of curvature of 8.5 mm and an average weight of 300 mg .

Die in-vitro-Freisetzungsuntersuchung wurde in einer Blattrührerapparatur mit einem Volumen von 600 ml verdünnter Salzsäure, einem pH von 1,2 und einer Geschwindigkeit von 75 UpM durchgeführt. Die Untersuchung der Matrixtablette lieferte über einen Zeitraum von 480min. folgendes Freisetzungsprofil (Mittelwert n = 6) . -Freisetzung von Tramadol HClThe in vitro release study was carried out in a blade stirrer apparatus with a volume of 600 ml of dilute hydrochloric acid, a pH of 1.2 and a speed of 75 rpm. The examination of the matrix tablet delivered over a period of 480 minutes. following release profile (mean n = 6). Release of Tramadol HCl

Freisetzung von Clonidin HClRelease of clonidine HCl

Claims

Patentansprücheclaims 1. Arzneiformulierung enthaltend ein Opioid, einen α-Agonisten und/oder jeweils dessen physiologisch verträgliches Salz, aus der wenigstens ein Arzneimittelwirkstoff verzögert freigesetzt wird.1. Drug formulation containing an opioid, an α-agonist and / or in each case its physiologically compatible salt, from which at least one active pharmaceutical ingredient is released with a delay. 2. Arzneiformulierung gemäß Anspruch 1, dadurch ge- kennzeichnet, daß das Opioid verzögert freigesetzt wird.2. Pharmaceutical formulation according to claim 1, characterized in that the opioid is released with a delay. 3. Arzneiformulierung gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, daß das Opioid über einen Zeitraum von 8 Stunden, vorzugsweise 12 Stunden, besonders bevorzugt 24 Stunden freigesetzt wird.3. Pharmaceutical formulation according to claim 1 or 2, characterized in that the opioid is released over a period of 8 hours, preferably 12 hours, particularly preferably 24 hours. 4. Arzneimittel formulierung gemäß einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, daß beide Wirk- stoffe verzögert freigesetzt werden.4. Medicament formulation according to one of claims 1 to 3, characterized in that both active substances are released with a delay. 5. Arzneiformulierung gemäß einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß als Opioid Morphin, Hydromorphon , Codein, Oxycodon, Dihydrocodein, Dextropropoxyphen, Buprenorphin, Levυmethadon, Fentanyl, Sufentanil, Etorphin, Pentazocin, Tilidin, Tramadol, Levorphanol, Methadon, Dihydro- orphin, Pethidin, Piritra id und/oder ein physiologisch verträgliches Salz davon vorliegt.5. Pharmaceutical formulation according to one of claims 1 to 4, characterized in that as the opioid morphine, hydromorphone, codeine, oxycodone, dihydrocodeine, dextropropoxyphene, buprenorphine, levu methadone, fentanyl, sufentanil, etorphin, pentazocin, tilidine, tramadol, levorphanol, methorphanol - Orphin, pethidine, Piritra id and / or a physiologically acceptable salt thereof. Arzneiformulierung nach Anspruch 5, dadurch gekennzeichnet, daß als Opioid Morphin, Tramadol und/oder ein physiologisch verträgliches Salz davon vorliegt.Pharmaceutical formulation according to claim 5, characterized in that morphine, tramadol and / or a physiologically acceptable salt thereof is present as the opioid. Arzneiformulierung gemäß einem der Ansprüche 1 bis 6, dadurch gekennzeichnet, daß als α-Agonist Clonidin, Guanfacin, Guanabenz, Lofexidin, Adrenalin, Methyldopa, Noradrenalin, Methoxamin, Oxymetazolin, Xylo etazolin, Teryzolin, ST-91, Medetomidin, Dex edeto idin, Agmatin, UK14,304, Para-A ino-Clonidin, U-47, 476A, DJ-741, ICI-Pharmaceutical formulation according to one of claims 1 to 6, characterized in that as an α-agonist Clonidine, guanfacin, guanabenz, lofexidine, adrenaline, methyldopa, noradrenaline, methoxamine, oxymetazoline, xylo etazolin, teryzoline, ST-91, medetomidine, dex edeto idin, agmatine, UK14,304, para-a ino-clonidine, U-47, 476A, DJ-741, ICI- 106270, Xylazin, Talipexol (BHT-920), Naphazolin, Tizanidin und/oder ein physiologisch verträgliches Salz davon vorliegt.106270, xylazine, talipexole (BHT-920), naphazoline, tizanidine and / or a physiologically acceptable salt thereof. 8. Arzneiformulierung nach einem der Anspruch 7, dadurch gekennzeichnet, daß als α-Agonist8. Pharmaceutical formulation according to one of claim 7, characterized in that as an α-agonist Clonidin, Guanfacin und/oder ein physiologisch verträgliches Salz davon vorliegt.Clonidine, guanfacin and / or a physiologically acceptable salt thereof is present. 9. Arzneiformulierung nach einem der Ansprüche 1 bis9. Pharmaceutical formulation according to one of claims 1 to 8, dadurch gekennzeichnet, daß das Gewichtsverhältnis von Opioid zu α-Agonist 200 zu 1 bis 10 zu 1, vorzugsweise 100 zu 1 bis 10 zu 1 beträgt.8, characterized in that the weight ratio of opioid to α-agonist is 200 to 1 to 10 to 1, preferably 100 to 1 to 10 to 1. 10 Arzneiformulierung nach einem der Ansprüche 1 bis10 drug formulation according to any one of claims 1 to 9, dadurch gekennzeichnet, daß sie als Tablette, Kapsel oder Dragee, vorzugsweise als Mehrschicht- talette vorliegt.9, characterized in that it is in the form of a tablet, capsule or dragee, preferably a multi-layer talette. 11. Λrzneifor ulierung nach einem der Ansprüche 1 bis 9, dadurch gekennzeichnet, daß sie in multipartikulärer Form, vorzugsweise in Form von Mikrotablet- ten, Mikrokapseln, Ionenaustauscherresinaten, Granulaten, Wirkstoffkristallen oder Pellets vor- liegt.11. nerzneifor ulierung according to any one of claims 1 to 9, characterized in that it is in multiparticulate form, preferably in the form of microtablets, microcapsules, ion exchange resinates, granules, active ingredient crystals or pellets. 12. Arzneiformulierung nach einem der Ansprüche 1 bis 11, dadurch gekennzeichnet, daß die Retardierung durch einen retardierenden Überzug, Fixierung an einem Ionenaustauscherharz, Einbettung in eine retardierende Matrix oder einer Kombination daraus erfolgt ist. 12. Pharmaceutical formulation according to one of claims 1 to 11, characterized in that the retardation is carried out by a retarding coating, fixation to an ion exchange resin, embedding in a retarding matrix or a combination thereof. 13. Arzneiformulierung nach Anspruch 12, dadurch gekennzeichnet, daß der Überzug auf einem wasserunlöslichen Polymeren oder Wachs basiert.13. Pharmaceutical formulation according to claim 12, characterized in that the coating is based on a water-insoluble polymer or wax. 14. Arzneiformulierung nach Anspruch 13, dadurch gekennzeichnet, daß als wasserunlösliches Polymeres ein Polyacrylharz oder Cellulosederivat, vorzugsweise Alkylcellulose, eingesetzt ist.14. Pharmaceutical formulation according to claim 13, characterized in that a polyacrylic resin or cellulose derivative, preferably alkyl cellulose, is used as the water-insoluble polymer. 15. Arzneiformulierung nach Anspruch 14, dadurch gekennzeichnet, daß Ethylcellulose und/oder ein Poly(meth)acrylat als Polymeres eingesetzt ist.15. Pharmaceutical formulation according to claim 14, characterized in that ethyl cellulose and / or a poly (meth) acrylate is used as the polymer. 16. Arzneiformulierung nach Anspruch 12, dadurch gekennzeichnet, daß die Matrix wenigstens ein Polymeres, ein Wachs, ein Fett, eine Fettsäure, einen Fettalkohol oder einen entsprechenden Ester oder Ether aufweist.16. Pharmaceutical formulation according to claim 12, characterized in that the matrix has at least one polymer, a wax, a fat, a fatty acid, a fatty alcohol or a corresponding ester or ether. 17. Arzneiformulierung nach Anspruch 16, dadurch gekennzeichnet, daß als Polymere Celluloseether, Celluloseester und/oder Acrylharze eingesetzt werden.17. Pharmaceutical formulation according to claim 16, characterized in that cellulose ethers, cellulose esters and / or acrylic resins are used as polymers. 18. Arzneiformulierung nach Anpruch 12, dadurch gekennzeichnet, daß als Matrixmaterial Ethylcellulose, Hydroxyethylcellulose, Hydroxypropylcellulose, Hydroxypropylmethylcellulose, Mono- und Diglyceride von Fettsäuren mit C12 bis C30 und/oder Fettalkoholen mit C12-C30 oder deren Gemische eingesetzt werden.18. Drug formulation according to claim 12, characterized in that ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, mono- and diglycerides of fatty acids with C12 to C30 and / or fatty alcohols with C12-C30 or mixtures thereof are used as matrix material. 19. Arzneiformulierung nach einem der Ansprüche 1 bis 18, dadurch gekennzeichnet, daß mindestens einer der Arzneimittelwirkstoffe in retardierter und nicht retardierter Form vorliegt. 19. Pharmaceutical formulation according to one of claims 1 to 18, characterized in that at least one of the active pharmaceutical ingredients is in retarded and non-retarded form. 20. Arzneiformulierung nach einem der Ansprüche 1 bis 19, dadurch gekennzeichnet, daß sie oral, parenteral oder transdermal, vorzugsweise oral verabreicht wird .20. Pharmaceutical formulation according to one of claims 1 to 19, characterized in that it is administered orally, parenterally or transdermally, preferably orally. 21. Verwendung der Arzneimittelformulierung nach einem der Ansprüche 1 bis 20 zur Behandlung von mittelschweren bis schweren akuten oder chronischen Schmerzzuständen. 21. Use of the pharmaceutical formulation according to one of claims 1 to 20 for the treatment of moderate to severe acute or chronic pain conditions.
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Families Citing this family (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10179130B2 (en) 1999-10-29 2019-01-15 Purdue Pharma L.P. Controlled release hydrocodone formulations
ES2374717T3 (en) 1999-10-29 2012-02-21 Euro-Celtique S.A. FORMULATIONS OF CONTROLLED RELEASE HYDROCODONE.
CA2424021A1 (en) * 2000-09-29 2002-04-04 Board Of Trustees Operating Michigan State University Catecholamine compositions and uses thereof
KR100968128B1 (en) 2000-10-30 2010-07-06 유로-셀티크 소시에떼 아노뉨 Sustained Release Hydrocodone Formulations
US6287599B1 (en) * 2000-12-20 2001-09-11 Shire Laboratories, Inc. Sustained release pharmaceutical dosage forms with minimized pH dependent dissolution profiles
WO2002096368A2 (en) * 2001-05-31 2002-12-05 Skyepharma Inc. Encapsulation of nanosuspensions in liposomes and microspheres
AU2002316582B2 (en) * 2001-07-06 2007-03-15 Endo Pharmaceuticals, Inc. Oral administration of 6-hydroxy-oxymorphone for use as an analgesic
US8329216B2 (en) * 2001-07-06 2012-12-11 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations
DE10141650C1 (en) 2001-08-24 2002-11-28 Lohmann Therapie Syst Lts Safe transdermal therapeutic system for administration of fentanyl or analogous analgesics, having matrix layer of carboxy group-free polyacrylate adhesive providing high permeation rate
CA2459976A1 (en) * 2001-09-26 2003-04-03 Penwest Pharmaceuticals Company Opioid formulations having reduced potential for abuse
US7854230B2 (en) * 2001-10-22 2010-12-21 O.R. Solutions, Inc. Heated medical instrument stand with surgical drape and method of detecting fluid and leaks in the stand tray
US8487002B2 (en) * 2002-10-25 2013-07-16 Paladin Labs Inc. Controlled-release compositions
TWI319713B (en) * 2002-10-25 2010-01-21 Sustained-release tramadol formulations with 24-hour efficacy
US7648981B2 (en) * 2003-02-28 2010-01-19 Ym Biosciences Inc. Opioid delivery system
US7648982B2 (en) * 2003-02-28 2010-01-19 Ym Biosciences Inc. Opioid delivery system
US20060172006A1 (en) * 2003-10-10 2006-08-03 Vincent Lenaerts Sustained-release tramadol formulations with 24-hour clinical efficacy
US20050100594A1 (en) * 2003-11-12 2005-05-12 Nilendu Sen Pharmaceutical formulation containing muscle relaxant and COX-II inhibitor
DE102005013726A1 (en) * 2005-03-22 2006-09-28 Grünenthal GmbH Transdermal therapeutic system for transdermal application of opioid containing analgesics, especially using a plaster for application to permit long-term, pain-free application
US7485323B2 (en) * 2005-05-31 2009-02-03 Gelita Ag Process for making a low molecular weight gelatine hydrolysate and gelatine hydrolysate compositions
NZ565649A (en) * 2005-07-28 2011-03-31 Shire Llc Pharmaceutical formulations/composition of guanfacine suitable for single dose form administration daily
BRPI0615860B8 (en) 2005-09-09 2021-05-25 Labopharm Barbados Ltd solid monolithic extended release pharmaceutical composition
US20070212414A1 (en) * 2006-03-08 2007-09-13 Penwest Pharmaceuticals Co. Ethanol-resistant sustained release formulations
US20080069891A1 (en) 2006-09-15 2008-03-20 Cima Labs, Inc. Abuse resistant drug formulation
US8445018B2 (en) 2006-09-15 2013-05-21 Cima Labs Inc. Abuse resistant drug formulation
US20100172991A1 (en) * 2007-06-08 2010-07-08 Henry Joseph Horacek Extended Release Formulation and Methods of Treating Adrenergic Dysregulation
JP2010529142A (en) 2007-06-08 2010-08-26 アドレネクス・ファーマシューティカルズ，インコーポレイテッド Sustained release formulations and methods for treating adrenergic dysregulation
US20090124650A1 (en) * 2007-06-21 2009-05-14 Endo Pharmaceuticals, Inc. Method of Treating Pain Utilizing Controlled Release Oxymorphone Pharmaceutical Compositions and Instructions on Effects of Alcohol
EP2265259A1 (en) * 2008-04-25 2010-12-29 Cadila Healthcare Limited Rapidly disintegrating oral compositions of tramadol
US20110097393A1 (en) * 2008-06-25 2011-04-28 US WorldMeade, LLC Skin Patches and Sustained-Release Formulations Comprising Lofexidine for Transdermal and Oral Delivery
EP2363147B1 (en) * 2008-10-30 2016-02-24 National University Corporation Okayama University Composition for local anesthesia
JP5894717B2 (en) * 2009-12-17 2016-03-30 シマ ラブス インク． Abuse deterrent preparation
WO2011143120A1 (en) 2010-05-11 2011-11-17 Cima Labs Inc. Alcoholres i stant metoprolol - containing extended - release oral dosage forms
CA2991217C (en) 2010-12-22 2020-06-09 Purdue Pharma L.P. Encased tamper resistant controlled release dosage forms
WO2013052770A1 (en) 2011-10-05 2013-04-11 Sanders Jennifer L Methods and compositions for treating foot or hand pain
US20130096170A1 (en) 2011-10-14 2013-04-18 Hospira, Inc. Methods of treating pediatric patients using dexmedetomidine
US8242158B1 (en) 2012-01-04 2012-08-14 Hospira, Inc. Dexmedetomidine premix formulation
RU2648449C2 (en) 2013-10-07 2018-03-26 ТЕЙКОКУ ФАРМА ЮЭсЭй, ИНК. Methods and compositions for transdermal delivery of a non-sedative amount of dexmedetomidine
CA2924233C (en) 2013-10-07 2018-10-23 Teikoku Pharma Usa, Inc. Methods and compositions for treating attention deficit hyperactivity disorder, anxiety and insomnia using dexmedetomidine transdermal compositions
TWI704933B (en) 2013-10-07 2020-09-21 美商帝國製藥美國股份有限公司 Dexmedetomidine transdermal delivery devices and methods for using the same
US20150118300A1 (en) 2013-10-31 2015-04-30 Cima Labs Inc. Immediate Release Abuse-Deterrent Granulated Dosage Forms
US20220062200A1 (en) 2019-05-07 2022-03-03 Clexio Biosciences Ltd. Abuse-deterrent dosage forms containing esketamine
US11324707B2 (en) 2019-05-07 2022-05-10 Clexio Biosciences Ltd. Abuse-deterrent dosage forms containing esketamine
CN112494486B (en) * 2020-12-07 2022-01-21 深圳善康医疗健康产业有限公司 Pharmaceutical composition for relieving or eliminating opium withdrawal syndrome and application thereof

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4946848A (en) * 1985-10-29 1990-08-07 Baker Cumins Dermatologicals, Inc. Method of treating pruritus with nalmefene and clonidine
PT99629A (en) * 1991-11-28 1993-05-31 Antonio Feria Reis Valle Method for detoxification of opiates
US5635204A (en) * 1994-03-04 1997-06-03 Montefiore Medical Center Method for transdermal induction of anesthesia, analgesia or sedation
DE19749724A1 (en) * 1997-11-11 1999-06-10 Gruenenthal Gmbh Use of a combination of opioid and alpha-adrenergic agonist in pain relievers

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0041681A2 *

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JP2002534458A (en) 2002-10-15
PE20001396A1 (en) 2000-12-23
CA2359273A1 (en) 2000-07-20
AR022252A1 (en) 2002-09-04
SK10012001A3 (en) 2002-01-07
BR0000578A (en) 2001-08-14
AU2109000A (en) 2000-08-01
CO5160243A1 (en) 2002-05-30
HU0000139D0 (en) 2000-03-28
US20020044966A1 (en) 2002-04-18
NZ513501A (en) 2003-11-28
UY25936A1 (en) 2001-07-31
NO20013302D0 (en) 2001-07-03
WO2000041681A2 (en) 2000-07-20
HUP0105043A2 (en) 2002-06-29
NO20000225D0 (en) 2000-01-17
NO20013302L (en) 2001-07-03
WO2000041681A3 (en) 2000-12-07
HUP0105043A3 (en) 2005-06-28
AU772886B2 (en) 2004-05-13

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