DE19857766A1 - Delayed pain reliever containing tilidine - Google Patents
Delayed pain reliever containing tilidineInfo
- Publication number
- DE19857766A1 DE19857766A1 DE19857766A DE19857766A DE19857766A1 DE 19857766 A1 DE19857766 A1 DE 19857766A1 DE 19857766 A DE19857766 A DE 19857766A DE 19857766 A DE19857766 A DE 19857766A DE 19857766 A1 DE19857766 A1 DE 19857766A1
- Authority
- DE
- Germany
- Prior art keywords
- tilidine
- pain reliever
- hours
- maximum
- reliever according
- 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- Withdrawn
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- WDEFBBTXULIOBB-WBVHZDCISA-N dextilidine Chemical compound C=1C=CC=CC=1[C@@]1(C(=O)OCC)CCC=C[C@H]1N(C)C WDEFBBTXULIOBB-WBVHZDCISA-N 0.000 title claims abstract description 52
- 229960001402 tilidine Drugs 0.000 title claims abstract description 41
- 229940124641 pain reliever Drugs 0.000 title claims description 20
- 230000003111 delayed effect Effects 0.000 title 1
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims abstract description 36
- 229960005181 morphine Drugs 0.000 claims abstract description 18
- 239000005557 antagonist Substances 0.000 claims abstract description 16
- 239000008139 complexing agent Substances 0.000 claims abstract description 15
- 239000007787 solid Substances 0.000 claims abstract description 12
- 150000001768 cations Chemical class 0.000 claims abstract description 8
- 238000000338 in vitro Methods 0.000 claims abstract description 8
- 229910052751 metal Inorganic materials 0.000 claims abstract description 8
- 239000002184 metal Substances 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 239000011159 matrix material Substances 0.000 claims description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 229920002678 cellulose Polymers 0.000 claims description 7
- 239000001913 cellulose Substances 0.000 claims description 7
- 235000010980 cellulose Nutrition 0.000 claims description 7
- RGPDIGOSVORSAK-STHHAXOLSA-N naloxone hydrochloride Chemical group Cl.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C RGPDIGOSVORSAK-STHHAXOLSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 229920013821 hydroxy alkyl cellulose Polymers 0.000 claims description 5
- 229920013820 alkyl cellulose Polymers 0.000 claims description 4
- 229960005250 naloxone hydrochloride Drugs 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 3
- -1 hydroxyalkyl radical Chemical class 0.000 claims description 3
- 229920000609 methyl cellulose Polymers 0.000 claims description 3
- 239000001923 methylcellulose Substances 0.000 claims description 3
- 235000010981 methylcellulose Nutrition 0.000 claims description 3
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 235000010944 ethyl methyl cellulose Nutrition 0.000 claims description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 229920003087 methylethyl cellulose Polymers 0.000 claims description 2
- 150000007524 organic acids Chemical group 0.000 claims description 2
- 235000005985 organic acids Nutrition 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 150000003628 tricarboxylic acids Chemical class 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 2
- 150000007513 acids Chemical class 0.000 claims 1
- 230000000144 pharmacologic effect Effects 0.000 claims 1
- 235000011007 phosphoric acid Nutrition 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 5
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229920001477 hydrophilic polymer Polymers 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229960001502 tilidine hydrochloride Drugs 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 206010031009 Oral pain Diseases 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- MUWDJVKYGSDUSH-KALLACGZSA-N ethyl (1s,2r)-2-(dimethylamino)-1-phenylcyclohex-3-ene-1-carboxylate;hydron;chloride Chemical compound Cl.C=1C=CC=CC=1[C@@]1(C(=O)OCC)CCC=C[C@H]1N(C)C MUWDJVKYGSDUSH-KALLACGZSA-N 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229960004127 naloxone Drugs 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
- TXMZWEASFRBVKY-IOQDSZRYSA-N (4r,4as,7ar,12bs)-4a,9-dihydroxy-3-prop-2-enyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;dihydrate;hydrochloride Chemical compound O.O.Cl.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C TXMZWEASFRBVKY-IOQDSZRYSA-N 0.000 description 1
- 229920003084 Avicel® PH-102 Polymers 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241001440269 Cutina Species 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000005250 alkyl acrylate group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- OPNPQXLQERQBBV-UHFFFAOYSA-N carbromal Chemical compound CCC(Br)(CC)C(=O)NC(N)=O OPNPQXLQERQBBV-UHFFFAOYSA-N 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-M fumarate(1-) Chemical compound OC(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-M 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000010309 melting process Methods 0.000 description 1
- 229960004088 naloxone hydrochloride dihydrate Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000000014 opioid analgesic Substances 0.000 description 1
- 229940124583 pain medication Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Gegenstand der Erfindung sind feste, peroral applizierbare, Retardiermittel aufweisende Schmerzmittel enthaltend Tilidin. DOLLAR A Diese enthalten Tilidin als Salz eines Komplexbildners für 2- oder 3-wertige Metallkationen oder übliche Tilidinsalze in Kombination mit einem Komplexbildner für 2- oder 3-wertige Metallkationen und einen Morphinantagonisten, wobei die invitro Freisetzungsrate des Tilidins und des Morphinantagonisten im wesentlichen gleich sind.The invention relates to solid, orally administrable, slow release painkillers containing tilidine. DOLLAR A These contain tilidine as the salt of a complexing agent for 2- or 3-valent metal cations or conventional tilidine salts in combination with a complexing agent for 2- or 3-valent metal cations and a morphine antagonist, the in vitro release rate of the tilidine and the morphine antagonist being essentially the same .
Description
Gegenstand der Erfindung sind feste, peroral applizierbare, Retardiermittel aufweisende Schmerzmittel enthaltend Tilidin.The invention relates to solid retardants which can be applied orally Painkillers containing tilidine.
Tilidin, [(±)-Ethyl-(trans-2-dimethylamino-phenyl-3-cyclohexan-trans-1-carboxylat)] ist ein entfernt mit Morphin verwandtes Opioidanalgetikum, das enteral rasch resorbiert wird und sich dementsprechend in der Schmerztherapie hervorragend eignet.Tilidine, [(±) -ethyl- (trans-2-dimethylaminophenyl-3-cyclohexane-trans-1-carboxylate)] is an opioid analgesic remotely related to morphine, which is enterally rapid is absorbed and accordingly excellent in pain therapy is suitable.
In der EP 0 665 830 B1 wird beschrieben, daß vornehmlich Salze des basischen Wirkstoffs in Frage kommen, da die Base als solche keine ausreichende Stabilität über einen längeren Zeitraum aufweist. Es wird weiterhin festgehalten, daß alle Anstrengungen, brauchbare feste Arzneimittelformen des Wirkstoffs Tilidin bereitzustellen, an Stabilitätsproblemen gescheitert sind. Es wird angenommen, daß nur über eine feste Formulierung eine steuerbare Retardierung des Tilidins realisierbar sein dürfte. So wird in der genannten EP 0 665 830 B1 festgehalten, daß Tilidindihydrogenorthophosphat eine hervorragende Stabilität aufweist und sich als bisher einziges Salz für die Herstellung von festen Arzneimittelformen eignet, weil es in fester Form, d. h. in Verbindung mit festen Hilfsstoffen praktisch keine Zersetzung erleidet. Auch soll das Phosphatsalz überraschend pharmazeutisch technologische Eigenschaften haben, die die Eigenschaften vergleichbarer Tilidinsalze, wie zum Beispiel das Tilidinhydrogensulfat oder das Tilidinhydrogen fumarat übertreffen.EP 0 665 830 B1 describes that primarily salts of the basic Active substance come into question because the base as such does not have sufficient stability over a longer period of time. It is also stated that all Efforts to use usable solid drug forms of the active ingredient tilidine to provide, have failed due to stability problems. It is believed, that a controllable retardation of tilidine can only be achieved through a fixed formulation should be feasible. For example, EP 0 665 830 B1 states that that tilidine dihydrogen orthophosphate has excellent stability and as the only salt suitable so far for the production of solid pharmaceutical forms, because it is in solid form, i.e. H. practically none in connection with solid auxiliaries Suffered decomposition. The phosphate salt is also said to be surprisingly pharmaceutical have technological properties that make the properties more comparable Tilidine salts, such as, for example, the tilidine bisulfate or the tilidine hydrogen surpass fumarate.
Tilidin wird im Handel üblicherweise zusammen mit einem Morphinantagonisten, beispielsweise Naloxon-Hydrochlorid eingesetzt.Tilidine is usually sold together with a morphine antagonist, for example, naloxone hydrochloride used.
Es bestand daher die Aufgabe, feste, peroral applizierbare, Retardiermittel aufweisende Schmerzmittel zur Verfügung zu stellen, bei denen die in-vitro Freisetzungsrate des Tilidins und des Morphinantagonisten im wesentlichen gleich sind.There was therefore the task of solid, orally applicable, retardants to have available pain relievers in which the in vitro Release rate of tilidine and morphine antagonist are substantially the same are.
Die vorgenannte Aufgabe wurde gelöst durch feste peroral applizierbare, Schmerzmittel enthaltend Tilidin als Salz eines nicht toxischen Komplexbildners für 2- oder 3-wertige Metallkationen und einen Morphinantagonisten in einer Cellulosederivatmatrix als Retardiermittel.The above-mentioned task was solved by fixed oral application, Pain reliever containing tilidine as salt of a non-toxic complexing agent for 2- or 3-valent metal cations and a morphine antagonist in one Cellulose derivative matrix as a retardant.
Eine weitere Ausführungsform der vorliegenden Erfindung betrifft feste peroral applizierbare Schmerzmittel enthaltend ein pharmakologisch unbedenkliches Tilidinsalz, einen Komplexbildner für 2- oder 3-wertige Metallkationen und einen Morphinantagonisten in einer Cellulosederivatmatrix als Retardiermittel.Another embodiment of the present invention relates to fixed oral Applicable pain relievers containing a pharmacologically harmless Tilidine salt, a complexing agent for 2- or 3-valent metal cations and one Morphine antagonists in a cellulose derivative matrix as a retardant.
Erfindungsgemäß wurde somit gefunden, daß ausgewählte Tilidinsalze von Komplexbildnern für 2- oder 3-wertige Metallkationen nicht nur eine hohe Stabilität im Vergleich zu festen, Tilidin enthaltenden Schmerzmitteln des Standes der Technik aufweisen, sondern daß darüber hinaus auch bei Einsatz der genannten Komplexbildnern in der genannten Matrix die in-vitro Freisetzungsraten des Tilidins und des Morphinantagonisten im wesentlichen gleich sind.According to the invention, it was found that selected tilidine salts of Complexing agents for 2- or 3-valent metal cations not only have a high stability compared to solid pain medications containing tilidine of the prior art Have technology, but also that when using the above Complexing agents in the matrix mentioned the in vitro release rates of tilidine and the morphine antagonist are substantially the same.
Während es bisher üblich war, feste perorale Schmerzmittel zu retardieren, die nur einen Wirkstoff enthalten, werden erfindungsgemäß zwei Wirkstoffe mit unterschiedlichen chemischen Strukturen und physikalischen Eigenschaften in einer Matrix miteinander kombiniert. Diese Kombination ergibt üblicherweise zwei verschiedene Freisetzungsprofile der beiden Wirkstoffe. Die gleiche Matrix ist aber bei einem festen peroralen Schmerzmittel hoch erwünscht, da beispielsweise die Tablette teilbar und somit eine individuelle Dosierung ermöglicht werden kann. Aus medizinischer Sicht ist für eine retardierte Tilidin/Naloxon-Zubereitung eine vergleichbare, d. h. im wesentlichen gleiche Freisetzung beider Wirkstoffe und eine Teilbarkeit der Darreichungsform hoch erwünscht. Überraschenderweise wurde gefunden, daß in einer Cellulosederivatmatrix Tilidin und Naloxon-Hydrochlorid mit im wesentlichen gleichen Freisetzungsraten freigesetzt werden.While it has so far been common to retard fixed oral pain relievers, only contain an active ingredient, two active ingredients according to the invention different chemical structures and physical properties in one Matrix combined together. This combination usually results in two different release profiles of the two active substances. The same matrix is however highly desirable with a fixed oral pain reliever, for example because the Tablet divisible and thus an individual dosage can be made possible. Out From a medical point of view, one is for a retarded tilidine / naloxone preparation comparable, d. H. essentially the same release of both active ingredients and one Divisibility of the dosage form is highly desirable. Surprisingly found that in a cellulose derivative matrix with tilidine and naloxone hydrochloride essentially the same release rates are released.
Erfindungsgemäß werden somit insbesondere Tilidinsalze von Komplexbildnern 2- oder 3-wertiger Metallkationen eingesetzt. Besonders bevorzugt in diesem Sinne sind organische Säuren, insbesondere Dicarbonsäuren und/oder Tricarbonsäuren, gegebenenfalls hydroxysubstituiert, beispielsweise Citronensäure und/oder Weinsäure bedingt durch die fehlende Toxizität. Wenn die Komplexbildner neben den Tilidinsalzen als weiterer Bestandteil des Schmerzmittels enthalten sind, so können diese selbstverständlich auch in Form der Alkali- und/oder Erdalkalimetallsalze enthalten sein. According to the invention, tilidine salts of complexing agents are thus 2- or 3-valent metal cations used. Particularly preferred in this sense are organic acids, especially dicarboxylic acids and / or tricarboxylic acids, optionally hydroxy-substituted, for example citric acid and / or Tartaric acid due to the lack of toxicity. If the complexing agent next to the tilidine salts are included as a further component of the pain reliever, so can of course also in the form of alkali and / or Alkaline earth metal salts may be included.
Die genannten Komplexbildner wirken offensichtlich stabilisierend auf das Gesamtsystem und sind in Kombination mit geeigneten Retardiermitteln geeignet, die in-vitro Freisetzungsrate des Tilidins und des Morphinantagonisten im wesentlichen gleichzusetzen. Somit ist es im Sinne der vorliegenden Erfindung möglich, Tilidinhydrochlorid-Semihydrat, Tilidinhydrogenfumarat und Tildinhydro gensulfat jeweils mit Naloxonhydrochlorid-Dihydrat und üblicherweise pharmazeutisch eingesetzten Hilfsstoffen in eine stabile Zubereitung einzubringen. Auch ohne den Zusatz von Komplexbildnern ist in der Gellulosederivat-Matrix eine stabile pharmazeutische Zusammensetzung auf der Basis von Tilidinhydrochloridsemihydrat erhältlich. Gleiches gilt selbstverständlich auch für das in der EP 0 665 830 B1 genannte Tilidinhydrogenorthophospat.The complexing agents mentioned obviously have a stabilizing effect on the Overall system and are suitable in combination with suitable retardants, the in vitro release rate of the tilidine and the morphine antagonist in the essentially equate. It is therefore within the meaning of the present invention possible, tilidine hydrochloride semihydrate, tilidine hydrogen fumarate and tildin hydro gene sulfate each with naloxone hydrochloride dihydrate and usually to incorporate pharmaceutically used excipients into a stable preparation. Even without the addition of complexing agents, there is one in the cellulose derivative matrix stable pharmaceutical composition based on Tilidine hydrochloride semihydrate available. The same naturally applies to that Tilidine hydrogen orthophosphate mentioned in EP 0 665 830 B1.
Setzt man den vorgenannten Tilidinsalzen von Komplexbildnern in einer Menge von 0,2 bis 30 Gew.-%, insbesondere 2 bis 6 Gew.-%, bezogen auf die Masse der Gesamtzubereitung zu, so ist auch bei Lagerversuchen bei erhöhter Temperatur keine Instabilität und insbesondere kein aggressives Korrosionsverhalten erkennbar.If you set the aforementioned tilidine salts of complexing agents in an amount of 0.2 to 30 wt .-%, in particular 2 to 6 wt .-%, based on the mass of the Total preparation, so is also in storage tests at elevated temperature no instability and in particular no aggressive corrosion behavior recognizable.
Der neben Tilidin eingesetzte Morphinantagonist ist im Sinne der vorliegenden Erfindung besonders bevorzugt ausgewählt aus Naloxonhydrochlorid-Semihydrat.The morphine antagonist used in addition to tilidine is in the sense of the present Invention particularly preferably selected from naloxone hydrochloride semihydrate.
Zur Herstellung retardierter fester Arzneimittelformen des Tilidins kommen prinzipiell alle üblichen Retardierverfahren in Frage, die die Stabilität des Wirkstoffs aufgrund ihrer Zusammensetzung nicht negativ beeinflussen. So sind in der EP 0 043 254 B durch ein Schmelzverfahren retardierte Tabletten beschrieben. Als Retardiermittel eignen sich aber auch prinzipiell schwerlösliche Stoffe, wie zum Beispiel Lipide oder lipoide Substanzen, wie Stearinsäure und insbesondere hydriertes Rizinusöl (Cutina®HR) (DE 16 17 657 A, US-4,123,753 A) oder hydrophile Polymere, die als Quellstoffe die Freigabe des Wirkstoffs retardieren (J. Pharm. Sci. S. 974 (1966)). Zur gezielten Steuerung der Freisetzung von Tilidin wird in der EP 0 068 446 B ein Verfahren beschrieben, bei dem die Freigabe der Geschwindigkeit des Wirkstoffs aus einer mittels schwerlöslicher Substanzen retardierten Wirkstoffzubereitung durch die Viskosität eines zugegebenen hydrophilen Polymeren, wie zum Beispiel Methylcellulose oder Carboxymethylcellulose, eingestellt wird, ausgehend von der Erkenntnis, daß die Freigabegeschwindigkeit mit steigender Viskosität zunimmt. In principle, retarded solid pharmaceutical forms of tilidine are used all usual retardation methods in question, which are due to the stability of the active substance do not negatively affect their composition. For example, EP 0 043 254 B Retarded tablets described by a melting process. As a retardant In principle, however, sparingly soluble substances such as lipids or are also suitable lipoid substances such as stearic acid and especially hydrogenated castor oil (Cutina®HR) (DE 16 17 657 A, US-4,123,753 A) or hydrophilic polymers, which as Swell substances delay the release of the active substance (J. Pharm. Sci. S. 974 (1966)). EP 0 068 446 B describes a method for controlling the release of tilidine Process described in which the release of the speed of the active substance from an active ingredient preparation retarded by means of poorly soluble substances by the viscosity of an added hydrophilic polymer, such as Methyl cellulose or carboxymethyl cellulose, is adjusted starting from the Realization that the release rate increases with increasing viscosity.
Im Sinne der vorliegenden Erfindung sind daher die Retardiermittel ausgewählt aus hydrophilen oder hydrophoben Polymeren, d. h. Cellulosederivaten, insbesondere Alkylcellulosen oder Hydroxyalkylcellulosen mit 1 bis 6 C-Atomen im Alkyl- oder Hydroxyalkylrest. Besonders bevorzugt im Sinne der vorliegenden Erfindung sind daher die Alkylcellulosen ausgewählt aus Methylcellulose oder Ethylcellulose. In gleicher Weise sind die Hydroxyalkylcellulosen besonders bevorzugt ausgewählt aus Hydroxyethylcellulose oder Hydroxypropylcellulose.For the purposes of the present invention, the retardants are therefore selected from hydrophilic or hydrophobic polymers, i. H. Cellulose derivatives, in particular Alkyl celluloses or hydroxyalkyl celluloses with 1 to 6 carbon atoms in the alkyl or Hydroxyalkyl group. Are particularly preferred for the purposes of the present invention hence the alkyl celluloses selected from methyl cellulose or ethyl cellulose. In in the same way, the hydroxyalkyl celluloses are particularly preferably selected from hydroxyethyl cellulose or hydroxypropyl cellulose.
Wenn im Sinne der vorliegenden Erfindung definiert wird, daß die in-vitro Freisetzungsraten des Tilidins und des Morphinantagonisten im wesentlichen gleich sind, so bedeutet dies, daß die Freisetzungsraten wie folgt bestimmt worden sind:If it is defined in the sense of the present invention that the in vitro Release rates of tilidine and morphine antagonist are substantially the same , it means that the release rates have been determined as follows:
Die in-vitro Freisetzung von Tilidinsalz und Morphinantagonist aus den Arzneimittelzubereitungen wurde nach DAB10 (Deutsches Arzneibuch, 10. Auflage) in einer Blattrührerapparatur bestimmt. Die Temperatur des Lösungsmediums betrug 37°C und die Umdrehungsgeschwindigkeit des Rührers 100 U/min. Zu Beginn der Untersuchung wurde jede Tablette in 900 ml künstlichen Magensaft gegeben. Die zu dem vorbestimmten Zeitpunkt im Lösungsmedium befindliche freigesetzte kombinierte Wirkstoffmenge wurde mittels HPLC bestimmt.The in vitro release of tilidine salt and morphine antagonist from the Pharmaceutical preparations were made according to DAB10 (German Pharmacopoeia, 10th edition) determined in a blade stirrer apparatus. The temperature of the solution medium was 37 ° C and the speed of rotation of the stirrer was 100 rpm. To At the start of the study, each tablet was placed in 900 ml of artificial gastric juice given. The one in the solution medium at the predetermined time The combined amount of active substance released was determined by means of HPLC.
Besonders bevorzugt im Sinne der vorliegenden Erfindung wird die in-vitro
Freisetzungsrate demgemäß eingestellt, daß die Freisetzungsgeschwindigkeit des
Tilidins nach
1 Stunde 15 bis 30 Gew.-%,
2 Stunden 25 bis 40 Gew.-%,
4 Stunden 50 bis 70 Gew.-%
6 Stunden 60 bis 80 Gew.-% und
8 Stunden 70 bis 90 Gew.-% beträgt.In the sense of the present invention, the in-vitro release rate is particularly preferably adjusted in such a way that the release rate of the tilidine decreases
1 hour 15 to 30% by weight,
2 hours 25 to 40% by weight,
4 hours 50 to 70% by weight
6 hours 60 to 80 wt .-% and
8 hours is 70 to 90 wt .-%.
Darüber hinaus ist es im Sinne der vorliegenden Erfindung besonders bevorzugt,
daß sich die Freisetzungsraten von Tilidin und Morphinantagonist nach
1 Stunde um höchstens 25%, bezogen auf Tilidin,
2 Stunden um höchstens 20%, bezogen auf Tilidin,
4 Stunden um höchstens 15%, bezogen auf Tilidin,
6 Stunden um höchstens 12%, bezogen auf Tilidin und
8 Stunden um höchstens 10%, bezogen auf Tilidin unterscheiden.
In addition, it is particularly preferred for the purposes of the present invention that the release rates of tilidine and morphine antagonist follow
1 hour by a maximum of 25%, based on tilidine,
2 hours by a maximum of 20%, based on tilidine,
4 hours by a maximum of 15%, based on tilidine,
6 hours by a maximum of 12%, based on tilidine and
Differ by 8%, based on tilidine, for 8 hours.
Neben der Retardiermatrix können die erfindungsgemäßen Schmerzmittel auch übliche im Stand der Technik bekannte pharmazeutische Hilfsstoffe enthalten, wie beispielsweise Fette, Fettalkohole, Fettsäuren, Acrylate, Alkylacrylate, Tenside, mikrokristalline Cellulose, Stärken, Milchzucker, Zuckeralkohole, Zucker allgemein oder auch Magnesiumstearat. Das erfindungsgemäße Präparat kann gege benenfalls auch oberflächenbeschichtet werden.In addition to the retardation matrix, the pain relievers according to the invention can also Contain customary pharmaceutical auxiliaries known in the prior art, such as for example fats, fatty alcohols, fatty acids, acrylates, alkyl acrylates, surfactants, microcrystalline cellulose, starches, milk sugar, sugar alcohols, sugar in general or magnesium stearate. The preparation according to the invention can be used if necessary also be surface coated.
Die Herstellung der festen, peroral applizierbaren Arzneimittelform, insbesondere Tabletten, kann nach üblichen im Stand der Technik bekannten Verfahren erfolgen. Hierbei ist beispielsweise die Direktpressung der nicht-vorbehandelten Hilfs- und Wirkstoffe zu nennen. Darüber hinaus ist selbstverständlich auch die Granulierung einzelner oder mehrerer Rezepturbestandteile vor der Verpreßung möglich.The production of the solid, orally administrable pharmaceutical form, in particular Tablets can be made by conventional methods known in the art. Here, for example, is the direct pressing of the non-pretreated auxiliary and To name active ingredients. In addition, of course, the granulation single or multiple recipe components possible before pressing.
Aus 102,9 mg Tilidin × HCl, 8,8 mg Naloxon × HCl, 16 mg Citronensäure, 199,3 mg einer Hydroxyalkylcellulose (Metocell® K 100 M), 50 mg mikrokristalline Cellulose (Avicel® PH 102) und 4,0 mg Magnesiumstearat wurde durch Direktpressung eine Tablette hergestellt.From 102.9 mg tilidine × HCl, 8.8 mg naloxone × HCl, 16 mg citric acid, 199.3 mg a hydroxyalkyl cellulose (Metocell® K 100 M), 50 mg microcrystalline cellulose (Avicel® PH 102) and 4.0 mg magnesium stearate was directly pressed into a Tablet made.
Die Freisetzungsraten wurden entsprechend der Beschreibung wie folgt bestimmt:
The release rates were determined as follows as described:
Claims (12)
1 Stunde 30 Gew.-%,
2 Stunden 25 bis 40 Gew.-%,
4 Stunden 50 bis 70 Gew.-%,
6 Stunden 60 bis 80 Gew.-% und
8 Stunden 70 bis 90 Gew.-%
beträgt.10. Pain reliever according to one of claims 1 to 9, characterized in that the release rates of the tilidine after
1 hour 30% by weight,
2 hours 25 to 40% by weight,
4 hours 50 to 70% by weight,
6 hours 60 to 80 wt .-% and
8 hours 70 to 90% by weight
is.
1 Stunde um höchstens 25%, bezogen auf Tilidin,
2 Stunden um höchstens 20%, bezogen auf Tilidin,
4 Stunden um höchstens 15%, bezogen auf Tilidin,
6 Stunden um höchstens 12%, bezogen auf Tilidin und
8 Stunden um höchstens 10%, bezogen auf Tilidin
unterscheiden.12. Pain reliever according to one of claims 1 to 10, characterized in that the release rates of tilidine and morphine antagonist after
1 hour by a maximum of 25%, based on tilidine,
2 hours by a maximum of 20%, based on tilidine,
4 hours by a maximum of 15%, based on tilidine,
6 hours by a maximum of 12%, based on tilidine and
8 hours by a maximum of 10%, based on tilidine
differentiate.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19857766A DE19857766A1 (en) | 1998-05-28 | 1998-12-15 | Delayed pain reliever containing tilidine |
| AT99109927T ATE261302T1 (en) | 1998-05-28 | 1999-05-20 | SUSTAINED RELEASE PAIN MEDICINE CONTAINING TILIDINE |
| EP99109927A EP0960619B1 (en) | 1998-05-28 | 1999-05-20 | Sustained release analgesic compositions comprising tilidine |
| DE59908792T DE59908792D1 (en) | 1998-05-28 | 1999-05-20 | Delayed pain reliever containing tilidine |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19823778 | 1998-05-28 | ||
| DE19857766A DE19857766A1 (en) | 1998-05-28 | 1998-12-15 | Delayed pain reliever containing tilidine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE19857766A1 true DE19857766A1 (en) | 1999-12-02 |
Family
ID=7869131
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19857766A Withdrawn DE19857766A1 (en) | 1998-05-28 | 1998-12-15 | Delayed pain reliever containing tilidine |
| DE59908792T Expired - Fee Related DE59908792D1 (en) | 1998-05-28 | 1999-05-20 | Delayed pain reliever containing tilidine |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE59908792T Expired - Fee Related DE59908792D1 (en) | 1998-05-28 | 1999-05-20 | Delayed pain reliever containing tilidine |
Country Status (1)
| Country | Link |
|---|---|
| DE (2) | DE19857766A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8518925B2 (en) | 2004-06-08 | 2013-08-27 | Euro-Celtique S.A. | Opioids for the treatment of the chronic obstructive pulmonary disease (COPD) |
| US8673355B2 (en) | 1997-12-22 | 2014-03-18 | Purdue Pharma L.P. | Opioid agonist/antagonist combinations |
| US8822487B2 (en) | 1997-12-22 | 2014-09-02 | Purdue Pharma L.P. | Opioid agonist/opioid antagonist/acetaminophen combinations |
| US8846091B2 (en) | 2002-04-05 | 2014-09-30 | Euro-Celtique S.A. | Matrix for sustained, invariant and independent release of active compounds |
| US8969369B2 (en) | 2001-05-11 | 2015-03-03 | Purdue Pharma L.P. | Abuse-resistant controlled-release opioid dosage form |
| US10258235B2 (en) | 2005-02-28 | 2019-04-16 | Purdue Pharma L.P. | Method and device for the assessment of bowel function |
-
1998
- 1998-12-15 DE DE19857766A patent/DE19857766A1/en not_active Withdrawn
-
1999
- 1999-05-20 DE DE59908792T patent/DE59908792D1/en not_active Expired - Fee Related
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| US9205082B2 (en) | 1997-12-22 | 2015-12-08 | Purdue Pharma L.P. | Opioid agonist/antagonist combinations |
| US8936808B1 (en) | 1997-12-22 | 2015-01-20 | Purdue Pharma L.P. | Opioid agonist/opioid antagonist/acetaminophen combinations |
| US8822487B2 (en) | 1997-12-22 | 2014-09-02 | Purdue Pharma L.P. | Opioid agonist/opioid antagonist/acetaminophen combinations |
| US9474750B2 (en) | 1997-12-22 | 2016-10-25 | Purdue Pharma L.P. | Opioid agonist/opioid antagonist/acetaminophen combinations |
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| US9480685B2 (en) | 2001-05-11 | 2016-11-01 | Purdue Pharma L.P. | Abuse-resistant controlled-release opioid dosage form |
| US8969369B2 (en) | 2001-05-11 | 2015-03-03 | Purdue Pharma L.P. | Abuse-resistant controlled-release opioid dosage form |
| US9358230B1 (en) | 2001-05-11 | 2016-06-07 | Purdue Pharma L.P. | Abuse-resistant controlled-release opioid dosage form |
| US8846091B2 (en) | 2002-04-05 | 2014-09-30 | Euro-Celtique S.A. | Matrix for sustained, invariant and independent release of active compounds |
| US9655855B2 (en) | 2002-04-05 | 2017-05-23 | Purdue Pharma L.P. | Matrix for sustained, invariant and independent release of active compounds |
| US9555000B2 (en) | 2002-04-05 | 2017-01-31 | Purdue Pharma L.P. | Pharmaceutical preparation containing oxycodone and naloxone |
| US8846090B2 (en) | 2002-04-05 | 2014-09-30 | Euro-Celtique S.A. | Matrix for sustained, invariant and independent release of active compounds |
| US9907793B2 (en) | 2002-04-05 | 2018-03-06 | Purdue Pharma L.P. | Pharmaceutical preparation containing oxycodone and naloxone |
| US10420762B2 (en) | 2002-04-05 | 2019-09-24 | Purdue Pharma L.P. | Pharmaceutical preparation containing oxycodone and naloxone |
| US8518925B2 (en) | 2004-06-08 | 2013-08-27 | Euro-Celtique S.A. | Opioids for the treatment of the chronic obstructive pulmonary disease (COPD) |
| US10258235B2 (en) | 2005-02-28 | 2019-04-16 | Purdue Pharma L.P. | Method and device for the assessment of bowel function |
Also Published As
| Publication number | Publication date |
|---|---|
| DE59908792D1 (en) | 2004-04-15 |
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