DE19536394A1 - Feste Arzneiformen, erhältlich durch Extrusion einer Isomalt enthaltenden Polymer-Wirkstoff-Schmelze - Google Patents
Feste Arzneiformen, erhältlich durch Extrusion einer Isomalt enthaltenden Polymer-Wirkstoff-SchmelzeInfo
- Publication number
- DE19536394A1 DE19536394A1 DE19536394A DE19536394A DE19536394A1 DE 19536394 A1 DE19536394 A1 DE 19536394A1 DE 19536394 A DE19536394 A DE 19536394A DE 19536394 A DE19536394 A DE 19536394A DE 19536394 A1 DE19536394 A1 DE 19536394A1
- Authority
- DE
- Germany
- Prior art keywords
- weight
- extrusion
- polymer
- solid dosage
- obtainable
- 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- Withdrawn
Links
- 238000001125 extrusion Methods 0.000 title claims abstract description 16
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- 230000002378 acidificating effect Effects 0.000 description 2
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- 235000020944 retinol Nutrition 0.000 description 1
- 239000011607 retinol Substances 0.000 description 1
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- 239000002151 riboflavin Substances 0.000 description 1
- 235000019231 riboflavin-5'-phosphate Nutrition 0.000 description 1
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- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 229960004555 rutoside Drugs 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- JZWFDVDETGFGFC-UHFFFAOYSA-N salacetamide Chemical group CC(=O)NC(=O)C1=CC=CC=C1O JZWFDVDETGFGFC-UHFFFAOYSA-N 0.000 description 1
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- 239000003381 stabilizer Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- 229950006156 teprenone Drugs 0.000 description 1
- 229960001693 terazosin Drugs 0.000 description 1
- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 description 1
- 229960000195 terbutaline Drugs 0.000 description 1
- 229960000351 terfenadine Drugs 0.000 description 1
- OFVLGDICTFRJMM-WESIUVDSSA-N tetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O OFVLGDICTFRJMM-WESIUVDSSA-N 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
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- 235000019157 thiamine Nutrition 0.000 description 1
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
- 229960005001 ticlopidine Drugs 0.000 description 1
- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 229960000401 tranexamic acid Drugs 0.000 description 1
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
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- 229960002117 triamcinolone acetonide Drugs 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
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- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- 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
- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
-
- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
Description
Die vorliegende Erfindung betrifft feste Arzneiformen, erhältlich
durch Extrusion und anschließender Formgebung einer lösungs
mittelfreien Schmelze, enthaltend neben einem oder mehreren Wirk
stoffen
- A) 10 bis 90 Gew.-% eines thermoplastisch verarbeitbaren Polymers,
- B) 5 bis 89,9 Gew.-% Isomalt, und
- C) 0 bis 5 Gew.-% Lecithin,
wobei die angegebenen Mengen auf das Gesamtgewicht der
Arzneiform bezogen sind.
Weiterhin betrifft die Erfindung ein Verfahren zur Herstellung
solcher Arzneiformen.
Wirkstoffhaltige Zubereitungen, die durch Schmelzextrusion herge
stellt werden, sind allgemein bekannt.
Das Extrudieren von wirkstoffhaltigen Schmelzen wasserlöslicher
Polymeren, vorzugsweise von Copolymeren des Vinylpyrrolidons, ist
beispielsweise in der EP-A 240 904 und der EP-A 240 906 beschrie
ben.
Das Verfahren der Schmelzextrusion ist für eine Vielzahl von
Wirkstoffen anwendbar. Durch Einsatz unterschiedlicher Hilfs
stoffe können die Eigenschaften der hergestellten Formulierungen
wie beispielsweise die Auflösegeschwindigkeit der Arzneiform im
Gastrointestinaltrakt gezielt beeinflußt werden.
Will man schnell freisetzende, feste Arzneiformen herstellen, so
muß man Hilfsstoffe mit großer Lösegeschwindigkeit nach ent
sprechend hoher Wasserlöslichkeit verwenden, die zudem die ther
moplastische Verarbeitbarkeit der wirkstoffhaltigen Polymer
schmelze nicht beeinträchtigen dürfen. Bisher wurden dazu im
allgemeinen Zuckeralkohole wie Mannitol oder Sorbitol oder Zucker
wie beispielsweise Lactose eingesetzt.
Nachteilig an bekannten Zusammensetzungen ist aber, daß diese
teilweise eine schlechte Verarbeitbarkeit, verursacht durch eine
starke Klebeneigung bei der Formgebung, vor allem bei der Kalan
drierung aufweisen. Außerdem lassen diese Zusammensetzungen häu
fig noch hinsichtlich der Freisetzungsgeschwindigkeit zu wünschen
übrig. Hinzu kommt, daß auch die mangelnde mechanische Belast
barkeit der Tabletten wegen starker Versprödung und damit auf
tretender Rißbildung noch Anlaß zu Verbesserungen gibt.
Aufgabe der vorliegenden Erfindung war es, Arzneiformen zu fin
den, die eine schnelle Wirkstoff-Freisetzung bei gleichzeitig
sehr guter Verarbeitbarkeit und guter Stabilität der Arzneiform
aufweisen.
Demgemäß wurden die eingangs definierten Arzneiformen gefunden.
Als Wirkstoffe kommen erfindungsgemäß alle solchen in Betracht,
die unter den Verarbeitungsbedingungen der Schmelzextrusion eine
ausreichende thermische Stabilität aufweisen.
Geeignete Wirkstoffe sind beispielsweise
Acebutolol, Acetylcysteine, Acetylsalicylsäure, Aciclovir, Albra zolam, Alfacalcidol, Allantoin, Allopurinol, Ambroxol, Amikacin, Amiloride, Aminoacetic Acid, Amiodarone, Amitriptyline, Amlodi pine, Amoxicillin, Ampicillin, Ascorbic Acid, Aspartam, Astemi zole, Atenolol, Beclometasone, Benserazide, Benzalconium Hydro drochlorid, Benzocaine, Benzoesäure, Betametasone, Bezafibrate, Biotin, Biperiden, Bisoprolol, Bromacepam, Bromhexine, Bromocrip tine, Budesonide, Bufexamac, Buflomedil, Buspirone, Caffeine, Camphor, Captopril, Carbamazepine, Carbidopa, Carboplatin, Cefaclor, Cefalexin, Cefatroxil, Cefazolin, Cefixime, Cefotaxime, Ceftazidine, Ceftriaxone, Cefuroxime, Celediline, Chlor amphenicol, Chlorhexidine, Chlorpheniramine, Chlortalidone, Cho line, Ciclosporin, Cilastatin, Cimetidine, Ciprofloxacin, Cisa pride, Cisplatin, Clarithromycin, Clavulanic Acid, Clomibramine, Clonazepam, Clonidine, Clotrimazole, Codeine, Colestyramine, Cro moglicinsäure, Cyanocobalamin, Cyproterone, Desogestrel, Dexame thasone, Dexpanthenol, Dexthromethorphan, Dextropropoxiphene, Diazepam, Diclofenac, Digoxin, Dihydrocodeine, Dihydroergotamine, Dihydroergotoxin, Diltiazem, Diphenhydramine, Dipyridamole, Dipy rone, Disopyramide, Domperidone, Dopamine, Doxocyclin, Enalapril, Ephedrine, Epinephrine, Ergocalciferol, Ergotamine, Erythromycin, Estradiol, Ethinylestradinol, Etoposide, Eucalyptus Globulus, Fa motidine, Felodipine, Fenofibrate, Fenoterol, Fentanyl, Flavin Mononucleotide, Fluconazole, Flunarizine, Fluorouracil, Fluoxe tine, Flurbiprofen, Furosemide, Gallopamil, Gemfibrozil, Genta mincin, Ginkgo Biloba, Glibenclamid, Glipizide, Glozapine, Gly cyrrhiza Glabra, Griseofulvin, Guaifenesin, Haloperidol, Heparin, Hyaluronsäure, Hydrochlorothiazide, Hydrocodone, Hydrocortisone, Hydromorphon, Ibratropium Hydroxide, Ibuprofen, Imipenem, Indome thacin, Iohexol, Iopamidol, Isosorbide Dinitrate, Isosorbide Mo nonitrate, Isotretionin, Ketotifen, Ketoconazole, Ketoprofen, Ke torolac, Labatalon, Lactulose, Lecithin, Levocarnitine, Levodopa, Levoglutamide, Levonorgestrel, Levothyroxine, Lidocaine, Lipase, Lipramin, Lisinopril, Loperamide, Lorazepam, Lovastatin, Medroxy progesterone, Menthol, Methotrexate, Methyldopa, Methylpredniso lone, Metoclopramide, Metoprolol, Miconazole, Midazolam, Minocy cline, Minoxidil, Misoprostol, Morphine, Multivitamin and Mine rals, N-Methylephedrine, Naftidrofuril, Naproxen, Neomycin, Ni cardipine, Nicergoline, Nicotinamide, Nicotine, Nicotinic Acid, Nifedipine, Nimodipine, Nitrazepam, Nitrendipine, Nizatidine, No rethisterone, Norfloxacin, Norgestrel, Nortriptyline, Nystatin, Ofloxacin, Omeprazole, Ondansetron, Pancreatin, Panthenol, Panto thenic Acid, Paracetamol, Penicillin G, Penicillin V, Phenobarbi tal, Phenoxifylline, Phenoxymethylpenicillin, Phenylephrine, Phe nylpropanolamin, Phenytoin, Piroxicam, Polymyxin B, Povidone-Iod, Pravastatin, Prazepam, Prazosin, Prednisolone, Prednison, Promo criptine, Propafenone, Propranolol, Proxyphyllin, Pseudoephe drine, Pyridoxine, Quinidine, Ramipril, Ranitidine, Reserpine, Retinol, Riboflavin, Rifampicin, Rutoside, Saccharin, Salbutamol, Salcatonin, Salicyl Acid, Simvastatin, Somatropin, Sotalol, Spi ronolactone, Sucralfate, Sulbactam, Sulfamethoxazole, Sulfasala zin, Sulpiride, Tamoxifen, Tegafur, Teprenone, Terazosin, Terbu taline, Terfenadine, Tetracyclin, Theophylline, Thiamine, Ticlo pidine, Timolol, Tranexamsäure, Tretinoin, Triamcinolone Aceto nide, Triamterene, Trimethoprim, Troxerutin, Uracil, Valproic Acid, Vancomycin, Verapamil, Vitamine E, Volinic Acid, Zidovu dine.
Acebutolol, Acetylcysteine, Acetylsalicylsäure, Aciclovir, Albra zolam, Alfacalcidol, Allantoin, Allopurinol, Ambroxol, Amikacin, Amiloride, Aminoacetic Acid, Amiodarone, Amitriptyline, Amlodi pine, Amoxicillin, Ampicillin, Ascorbic Acid, Aspartam, Astemi zole, Atenolol, Beclometasone, Benserazide, Benzalconium Hydro drochlorid, Benzocaine, Benzoesäure, Betametasone, Bezafibrate, Biotin, Biperiden, Bisoprolol, Bromacepam, Bromhexine, Bromocrip tine, Budesonide, Bufexamac, Buflomedil, Buspirone, Caffeine, Camphor, Captopril, Carbamazepine, Carbidopa, Carboplatin, Cefaclor, Cefalexin, Cefatroxil, Cefazolin, Cefixime, Cefotaxime, Ceftazidine, Ceftriaxone, Cefuroxime, Celediline, Chlor amphenicol, Chlorhexidine, Chlorpheniramine, Chlortalidone, Cho line, Ciclosporin, Cilastatin, Cimetidine, Ciprofloxacin, Cisa pride, Cisplatin, Clarithromycin, Clavulanic Acid, Clomibramine, Clonazepam, Clonidine, Clotrimazole, Codeine, Colestyramine, Cro moglicinsäure, Cyanocobalamin, Cyproterone, Desogestrel, Dexame thasone, Dexpanthenol, Dexthromethorphan, Dextropropoxiphene, Diazepam, Diclofenac, Digoxin, Dihydrocodeine, Dihydroergotamine, Dihydroergotoxin, Diltiazem, Diphenhydramine, Dipyridamole, Dipy rone, Disopyramide, Domperidone, Dopamine, Doxocyclin, Enalapril, Ephedrine, Epinephrine, Ergocalciferol, Ergotamine, Erythromycin, Estradiol, Ethinylestradinol, Etoposide, Eucalyptus Globulus, Fa motidine, Felodipine, Fenofibrate, Fenoterol, Fentanyl, Flavin Mononucleotide, Fluconazole, Flunarizine, Fluorouracil, Fluoxe tine, Flurbiprofen, Furosemide, Gallopamil, Gemfibrozil, Genta mincin, Ginkgo Biloba, Glibenclamid, Glipizide, Glozapine, Gly cyrrhiza Glabra, Griseofulvin, Guaifenesin, Haloperidol, Heparin, Hyaluronsäure, Hydrochlorothiazide, Hydrocodone, Hydrocortisone, Hydromorphon, Ibratropium Hydroxide, Ibuprofen, Imipenem, Indome thacin, Iohexol, Iopamidol, Isosorbide Dinitrate, Isosorbide Mo nonitrate, Isotretionin, Ketotifen, Ketoconazole, Ketoprofen, Ke torolac, Labatalon, Lactulose, Lecithin, Levocarnitine, Levodopa, Levoglutamide, Levonorgestrel, Levothyroxine, Lidocaine, Lipase, Lipramin, Lisinopril, Loperamide, Lorazepam, Lovastatin, Medroxy progesterone, Menthol, Methotrexate, Methyldopa, Methylpredniso lone, Metoclopramide, Metoprolol, Miconazole, Midazolam, Minocy cline, Minoxidil, Misoprostol, Morphine, Multivitamin and Mine rals, N-Methylephedrine, Naftidrofuril, Naproxen, Neomycin, Ni cardipine, Nicergoline, Nicotinamide, Nicotine, Nicotinic Acid, Nifedipine, Nimodipine, Nitrazepam, Nitrendipine, Nizatidine, No rethisterone, Norfloxacin, Norgestrel, Nortriptyline, Nystatin, Ofloxacin, Omeprazole, Ondansetron, Pancreatin, Panthenol, Panto thenic Acid, Paracetamol, Penicillin G, Penicillin V, Phenobarbi tal, Phenoxifylline, Phenoxymethylpenicillin, Phenylephrine, Phe nylpropanolamin, Phenytoin, Piroxicam, Polymyxin B, Povidone-Iod, Pravastatin, Prazepam, Prazosin, Prednisolone, Prednison, Promo criptine, Propafenone, Propranolol, Proxyphyllin, Pseudoephe drine, Pyridoxine, Quinidine, Ramipril, Ranitidine, Reserpine, Retinol, Riboflavin, Rifampicin, Rutoside, Saccharin, Salbutamol, Salcatonin, Salicyl Acid, Simvastatin, Somatropin, Sotalol, Spi ronolactone, Sucralfate, Sulbactam, Sulfamethoxazole, Sulfasala zin, Sulpiride, Tamoxifen, Tegafur, Teprenone, Terazosin, Terbu taline, Terfenadine, Tetracyclin, Theophylline, Thiamine, Ticlo pidine, Timolol, Tranexamsäure, Tretinoin, Triamcinolone Aceto nide, Triamterene, Trimethoprim, Troxerutin, Uracil, Valproic Acid, Vancomycin, Verapamil, Vitamine E, Volinic Acid, Zidovu dine.
Bevorzugter Wirkstoff ist Verapamil oder dessen physiologisch
vertragliche Salze, besonders bevorzugt Verapamil-Hydrochlorid.
Als thermoplastisch verarbeitbare, wasserlosliche Polymerkompo
nenten A) seien genannt:
- - Alkylcellulosen wie Methylcellulose,
- - Hydroxyalkylcellulosen wie Hydroxymethyl-, Hydroxyethyl-, Hydroxypropyl- und Hydroxybutylcellulose,
- - Hydroxyalkylcellulosen wie Hydroxyethylmethyl- und Hydroxy propylmethylcellulose,
- - Polyvinylpyrrolidon,
- - Copolymere aus N-Vinylpyrrolidon und Vinylacetat mit bis zu 50 Gew.-% Vinylacetat,
- - Carboxyalkylcellulosen wie Carboxymethylcellulosen,
- - Polysaccharide wie Alginsäure und deren Alkali- und Ammonium salze,
- - Polyethylenglykole
sowie Gemische solcher wasserlöslichen Polymeren.
Die Komponente A) soll in der Gesamtmischung aller Komponenten im
Bereich von 50 bis 180°C, vorzugsweise 80 bis 140°C erweichen oder
schmelzen, so daß die Masse extrudierbar ist. Gegebenenfalls kann
eine Verarbeitbarkeit bei diesen Temperaturen durch Zugabe von
Weichmachern erzielt werden.
"Wasserlöslich" bedeutet, daß sich in 100 g Wasser von 20°C minde
stens 0,5 g, vorzugsweise mindestens 2 g des Polymeren lösen,
gegebenenfalls auch kolloidal.
Bevorzugte Polymerkomponenten A) sind neben Polyvinylpyrrolidon
die Polyethylenglykole und besonders bevorzugt ein Copolymer,
welches durch radikalische Polymerisation von 60 Gew.-% N-Vinyl
pyrrolidon und 40 Gew.-% Vinylacetat erhalten wird.
Als Hilfsstoff enthalten die Arzneiformen Isomalt, das auch unter
dem Markennamen Palatinit® bekannt ist. Isomalt ist eine hy
drierte Isomaltulose, die in etwa aus gleichen Teilen der Iso
meren 1-O-α-D-Glucopyranosyl-D-mannit Dihydrat (1,1-GPM Dihydrat)
und 6-O-α-D-flucopyranosyl-D-Sorbit (1,6-GPS) besteht.
Die Korngröße des Isomalts kann in weiten Bereichen variieren,
bevorzugt sind Korngrößen im Bereich von 0,1 bis 0,8 mm.
Das kommerziell erhältliche Isomalt wird hergestellt, indem in
einem ersten Schritt Saccharose enzymatisch zu Isomaltulose (6-O-
α-D-Glucopyranosyl-D-Fructose) umgelagert wird und anschließend
diese Isomaltulose mit Wasserstoff/Raney-Nickel hydriert wird.
Die erfindungsgemaßen Arzneiformen enthalten die Polymer
komponenten A) in Mengen von 10 bis 90 Gew.-%, bevorzugt 10 bis
50 Gew.-%. Isomalt wird in Mengen von 5 bis 89,9 Gew.-%, bevor
zugt 10 bis 70 Gew.-%, besonders bevorzugt 20 bis 60 Gew.-%, ein
gesetzt.
Die Menge des Wirkstoffs richtet sich auch nach der therapeu
tischen Wirksamkeit. Er kann in Mengen von 0,1 bis 70, bevorzugt
10 bis 60 Gew.-%, besonders bevorzugt 20 bis 50 Gew.-% einge
arbeitet werden.
Die Mengenangaben beziehen sich jeweils auf das Gesamtgewicht der
Arzneiform (= 100 Gew.-%).
Zur weiteren Verbesserung der Verarbeitungseigenschaften können
die Arzneiformen noch bis zu 5 Gew.-%, bevorzugt 2 bis 5 Gew.-%
Lecithin enthalten.
Die erfindungsgemäßen Zubereitungen können weiterhin die üblichen
pharmazeutischen Hilfsstoffe wie Füllstoffe, Schmiermittel,
Formentrennmittel, Fließregulierungsmittel, Weichmacher, Farb
stoffe und Stabilisatoren in Mengen bis zu ca. 50 Gew.-% ent
halten.
Um die erfindungsgemäßen Arzneiformen herzustellen, kann die
Wirkstoffkomponente entweder direkt in Form einer physikalischen
Mischung mit den Polymeren A) verschmolzen werden oder mit der
bereits vorliegenden Polymerschmelze gemischt werden.
Im übrigen erfolgt die Vermischung der Wirkstoffe mit der
Schmelze in an sich bekannter Weise in Extrudern, vorzugsweise in
Ein- oder Doppelschneckenextrudern in einem Temperaturbereich
zwischen 50 und 180°C, bevorzugt 80 bis 140°C. Die Formgebung der
wirkstoffhaltigen Polymerschmelze zu den erfindungsgemäßen
Zubereitungen kann beispielsweise durch Kalandrierung des
Extrudates nach der in der EP-A 240 906 beschriebenen Methode
sowie nach dem aus der DE-A 38 30 355 bekannten Verarbeitungsver
fahren durch Zerkleinerung des Extrudates mit rotierenden Messern
in volumengleiche - noch verformbare - Stücke mit erstarrter
Oberfläche und anschließendes Verpressen zu Tabletten in den
üblichen Tablettiermaschinen erfolgen.
Es ist möglich, die Hilfsstoffe in die Schmelze oder Lösung aus
Wirkstoffen und Polymeren A) zu mischen. Ferner können die Hilfs
stoffe zusammen mit dem Wirkstoff in die Polymerschmelze einge
arbeitet werden. Außerdem können Gemische aus Hilfsstoffen, dem
Wirkstoff und den Polymeren direkt verschmolzen werden. Im allge
meinen ist es üblich, eine physikalische Mischung aus Hilfs
stoffen, Wirkstoffen und den Polymeren gemeinsam zu verschmelzen.
Die erfindungsgemäßen Zubereitungen werden als Arzneimittel
verwendet und in Form von Tabletten, Pellets, Granulaten oder
Kapseln oder anderen oral applizierbaren Arzneiformen eingesetzt.
Vorzugsweise werden mit dem erfindungsgemäßen Zubereitungen
Arzneiformen mit schneller Wirkstofffreisetzung hergestellt.
Falls gewünscht, kann die feste pharmazeutische Form auch mit
einem üblichen Überzug zur Verbesserung des Aussehens und/oder
des Geschmacks (Dragee) versehen werden.
Durch die Zusammensetzung der erfindungsgemäßen Arzneiformen kann
nicht nur eine schnelle Freisetzung des Wirkstoffs erzielt wer
den, sondern auch eine hervorragende Verarbeitbarkeit.
Die besonders bei zum Kleben neigenden Wirkstoffen, wie
beispielsweise dem Verapainil-Hydrochlorid auftretenden Probleme
bei der Handhabung der Schmelze und bei der Formgebung werden
durch die erfindungsgemäßen Zubereitungen vermieden.
Extrusion/Kalandrierung - Allgemeines:
Extrudertyp: Zweischneckenextruder
Anzahl der Schüsse: 4 + Kopf
3 Tablettenformen: rund, Linsenform, ca. 300 mg schwer
Massenfluß: 20-25 kg/h
Bestimmung der Wirkstoff-Freisetzung
Paddle-Methode - USP XXIII (Verapamil-HCI tablets) Seite 1625
Drehzahl: 50 upm
Paddle-Medium: 0,1 mol HCI.
Extrudertyp: Zweischneckenextruder
Anzahl der Schüsse: 4 + Kopf
3 Tablettenformen: rund, Linsenform, ca. 300 mg schwer
Massenfluß: 20-25 kg/h
Bestimmung der Wirkstoff-Freisetzung
Paddle-Methode - USP XXIII (Verapamil-HCI tablets) Seite 1625
Drehzahl: 50 upm
Paddle-Medium: 0,1 mol HCI.
Als Polymer A) wurde ein Copolymerisat hergestellt aus 60 Gew.-%
N-Vinylpyrrolidon und 40 Gew.-% Vinylacetat ("Copolyvidon" nach
DAB) verwendet.
Die Prüfung der Wirkstoff-Freisetzung ergab, daß nach 30 min
52,4% des Wirkstoffs freigesetzt war.
Die Prüfung der Wirkstoff-Freisetzung ergab, daß nach 30 min
91,5% des Wirkstoffs freigesetzt war.
Die Prüfung der Wirkstoff-Freisetzung ergab, daß nach 20 min
65,4% des Wirkstoffs freigesetzt war.
Die Prüfung der Wirkstoff-Freisetzung ergab, daß nach 20 min
77,0% des Wirkstoffs freigesetzt war.
Die Prüfung der Wirkstoff-Freisetzung ergab, daß nach 20 min
85,8% des Wirkstoffs freigesetzt war.
Die Prüfung der Wirkstoff-Freisetzung ergab, daß nach 30 min
93,2% des Wirkstoffs freigesetzt war.
Die Prüfung der Wirkstoff-Freisetzung ergab, daß nach 30 min
93,7% des Wirkstoffs freigesetzt war.
Claims (7)
1. Feste Arzneiformen, erhältlich durch Extrusion mit an
schließender Formgebung einer lösungsmittelfreien Schmelze,
enthaltend neben einem oder mehreren Wirkstoffen
- A) 10 bis 90 Gew.-% eines thermoplastisch verarbeitbaren, wasserlöslichen Polymers,
- B) 5 bis 89,9 Gew.-% Isomalt, und
- C) 0 bis 5 Gew.-% Lecithin,
wobei die Summe aller Inhaltsstoffe gleich 100 Gew.-%
sein soll.
2. Feste Arzneiformen nach Anspruch 1, enthaltend als Polymer A)
ein Homo- oder Copolymer eines N-Vinyllactams.
3. Feste Arzneiformen nach Anspruch 2, enthaltend ein Copolymer
aus N-Vinylpyrrolidon und Vinylacetat.
4. Feste Arzneiform nach einem der Ansprüche 1 bis 3, enthaltend
als Wirkstoff Verapamil oder dessen physiologisch verträg
liche Salze.
5. Feste Arzneiform nach einem der Ansprüche 1 bis 4 enthaltend
zusätzlich übliche pharmazeutische Hilfsstoffe.
6. Verfahren zur Herstellung von Arzneiformen gemäß einem der
Ansprüche 1 bis 5, dadurch gekennzeichnet, daß man die Kom
ponenten bei Temperaturen von 50 bis 180°C zu einer Schmelze
verarbeitet.
Priority Applications (23)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19536394A DE19536394A1 (de) | 1995-09-29 | 1995-09-29 | Feste Arzneiformen, erhältlich durch Extrusion einer Isomalt enthaltenden Polymer-Wirkstoff-Schmelze |
TW085111773A TW438599B (en) | 1995-09-29 | 1996-09-26 | Solid drug forms obtainable by extrusion of an isomalt-containing polymer/active ingredient melt |
ZA9608130A ZA968130B (en) | 1995-09-29 | 1996-09-27 | Solid drug forms obtainable by extrusion of an isomalt-containing polymer/active ingredient melt. |
KR1019980702324A KR19990063853A (ko) | 1995-09-29 | 1996-09-30 | 이성맥아 함유 중합체-활성 물질 용융물의 압출에 의해 수득되는 고형 약제 |
DE59609923T DE59609923D1 (de) | 1995-09-29 | 1996-09-30 | Feste arzneiformen, erhältlich durch extrusion einer isomalt enthaltenden polymer-wirkstoff-schmelze |
IL12325096A IL123250A (en) | 1995-09-29 | 1996-09-30 | Solid drug forms obtainable by extrusion |
HU9903384A HUP9903384A3 (en) | 1995-09-29 | 1996-09-30 | Solid medicaments obtained by extrusion of an isomalt-containing polymer-active substance melt |
PCT/EP1996/004262 WO1997012603A1 (de) | 1995-09-29 | 1996-09-30 | Feste arzneiformen, erhältlich durch extrusion einer isomalt enthaltenden polymer-wirkstoff-schmelze |
US09/029,362 US6187342B1 (en) | 1995-09-29 | 1996-09-30 | Solid medicaments obtained by extrusion of an isomalt-containing polymer-active substance melt |
CZ98959A CZ95998A3 (cs) | 1995-09-29 | 1996-09-30 | Pevné lékové formy získatelné vytlačením taveniny polymerů a účinných látek s obsahem izomaltu |
ES96934494T ES2187678T3 (es) | 1995-09-29 | 1996-09-30 | Formas farmaceuticas solidas, obtenibles mediante extrusion de una funsion de polimero-principio activo que contiene isomalta. |
JP51396597A JP4041163B2 (ja) | 1995-09-29 | 1996-09-30 | イソマルト含有ポリマー/活性物質溶融物の押出により得られる固形薬剤 |
EP96934494A EP0854707B1 (de) | 1995-09-29 | 1996-09-30 | Feste arzneiformen, erhältlich durch extrusion einer isomalt enthaltenden polymer-wirkstoff-schmelze |
AU72828/96A AU7282896A (en) | 1995-09-29 | 1996-09-30 | Solid medicaments obtained by extrusion of an isomalt-containing polymer-active substance melt |
DK96934494T DK0854707T3 (da) | 1995-09-29 | 1996-09-30 | Faste lægemiddelformer, som opnåes ved ekstrusion af en isomalt indeholdende smeltet masse af en polymer og et biologisk virksomt stof |
RU98108536/14A RU2197228C2 (ru) | 1995-09-29 | 1996-09-30 | Твердые лекарственные формы, получаемые экструзией содержащего изомальт расплава полимера и активного вещества |
CNB961972637A CN1200694C (zh) | 1995-09-29 | 1996-09-30 | 通过挤出含氢化异麦芽糖的聚合物/活性成分熔体可得到的固体剂型 |
AT96934494T ATE228355T1 (de) | 1995-09-29 | 1996-09-30 | Feste arzneiformen, erhältlich durch extrusion einer isomalt enthaltenden polymer-wirkstoff- schmelze |
CA002230950A CA2230950C (en) | 1995-09-29 | 1996-09-30 | Solid drug forms obtainable by extrusion of an isomalt-containing polymer/active ingredient melt |
BR9610799A BR9610799A (pt) | 1995-09-29 | 1996-09-30 | Forma de medicamento sólida e processo para sua produção |
MX9801988A MX9801988A (es) | 1995-09-29 | 1998-03-13 | Formas solidas de medicamentos obtenibles por extrusion de una masa fundida de polimero que contiene isomalta y el ingrediente activo. |
BG102346A BG102346A (bg) | 1995-09-29 | 1998-03-24 | Твърди лекарствени форми, получени чрез екструзияна стопилка, включваща изомалт, активно вещество и полимер |
NO981394A NO981394D0 (no) | 1995-09-29 | 1998-03-27 | Faste legemiddelformer som kan oppnås ved ekstrudering av en isomaltholdig polymersmelte som inneholder virkestoff |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19536394A DE19536394A1 (de) | 1995-09-29 | 1995-09-29 | Feste Arzneiformen, erhältlich durch Extrusion einer Isomalt enthaltenden Polymer-Wirkstoff-Schmelze |
Publications (1)
Publication Number | Publication Date |
---|---|
DE19536394A1 true DE19536394A1 (de) | 1997-04-03 |
Family
ID=7773633
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE19536394A Withdrawn DE19536394A1 (de) | 1995-09-29 | 1995-09-29 | Feste Arzneiformen, erhältlich durch Extrusion einer Isomalt enthaltenden Polymer-Wirkstoff-Schmelze |
DE59609923T Expired - Lifetime DE59609923D1 (de) | 1995-09-29 | 1996-09-30 | Feste arzneiformen, erhältlich durch extrusion einer isomalt enthaltenden polymer-wirkstoff-schmelze |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE59609923T Expired - Lifetime DE59609923D1 (de) | 1995-09-29 | 1996-09-30 | Feste arzneiformen, erhältlich durch extrusion einer isomalt enthaltenden polymer-wirkstoff-schmelze |
Country Status (22)
Country | Link |
---|---|
US (1) | US6187342B1 (de) |
EP (1) | EP0854707B1 (de) |
JP (1) | JP4041163B2 (de) |
KR (1) | KR19990063853A (de) |
CN (1) | CN1200694C (de) |
AT (1) | ATE228355T1 (de) |
AU (1) | AU7282896A (de) |
BG (1) | BG102346A (de) |
BR (1) | BR9610799A (de) |
CA (1) | CA2230950C (de) |
CZ (1) | CZ95998A3 (de) |
DE (2) | DE19536394A1 (de) |
DK (1) | DK0854707T3 (de) |
ES (1) | ES2187678T3 (de) |
HU (1) | HUP9903384A3 (de) |
IL (1) | IL123250A (de) |
MX (1) | MX9801988A (de) |
NO (1) | NO981394D0 (de) |
RU (1) | RU2197228C2 (de) |
TW (1) | TW438599B (de) |
WO (1) | WO1997012603A1 (de) |
ZA (1) | ZA968130B (de) |
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Publication number | Priority date | Publication date | Assignee | Title |
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DE3612211A1 (de) | 1986-04-11 | 1987-10-15 | Basf Ag | Kontinuierliches verfahren zum tablettieren |
DE3826946C1 (de) * | 1988-08-09 | 1990-03-15 | A. Nattermann & Cie Gmbh, 5000 Koeln, De | |
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-
1995
- 1995-09-29 DE DE19536394A patent/DE19536394A1/de not_active Withdrawn
-
1996
- 1996-09-26 TW TW085111773A patent/TW438599B/zh not_active IP Right Cessation
- 1996-09-27 ZA ZA9608130A patent/ZA968130B/xx unknown
- 1996-09-30 CN CNB961972637A patent/CN1200694C/zh not_active Expired - Lifetime
- 1996-09-30 IL IL12325096A patent/IL123250A/xx not_active IP Right Cessation
- 1996-09-30 DE DE59609923T patent/DE59609923D1/de not_active Expired - Lifetime
- 1996-09-30 RU RU98108536/14A patent/RU2197228C2/ru active
- 1996-09-30 ES ES96934494T patent/ES2187678T3/es not_active Expired - Lifetime
- 1996-09-30 JP JP51396597A patent/JP4041163B2/ja not_active Expired - Lifetime
- 1996-09-30 WO PCT/EP1996/004262 patent/WO1997012603A1/de not_active Application Discontinuation
- 1996-09-30 CZ CZ98959A patent/CZ95998A3/cs unknown
- 1996-09-30 AT AT96934494T patent/ATE228355T1/de active
- 1996-09-30 DK DK96934494T patent/DK0854707T3/da active
- 1996-09-30 AU AU72828/96A patent/AU7282896A/en not_active Abandoned
- 1996-09-30 CA CA002230950A patent/CA2230950C/en not_active Expired - Lifetime
- 1996-09-30 EP EP96934494A patent/EP0854707B1/de not_active Expired - Lifetime
- 1996-09-30 HU HU9903384A patent/HUP9903384A3/hu unknown
- 1996-09-30 US US09/029,362 patent/US6187342B1/en not_active Expired - Lifetime
- 1996-09-30 KR KR1019980702324A patent/KR19990063853A/ko not_active Application Discontinuation
- 1996-09-30 BR BR9610799A patent/BR9610799A/pt active Search and Examination
-
1998
- 1998-03-13 MX MX9801988A patent/MX9801988A/es not_active IP Right Cessation
- 1998-03-24 BG BG102346A patent/BG102346A/bg unknown
- 1998-03-27 NO NO981394A patent/NO981394D0/no unknown
Also Published As
Publication number | Publication date |
---|---|
EP0854707A1 (de) | 1998-07-29 |
DK0854707T3 (da) | 2002-12-16 |
CA2230950C (en) | 2007-12-04 |
BG102346A (bg) | 1998-10-30 |
RU2197228C2 (ru) | 2003-01-27 |
HUP9903384A3 (en) | 2001-04-28 |
HUP9903384A2 (hu) | 2000-10-28 |
NO981394L (no) | 1998-03-27 |
ZA968130B (en) | 1998-03-27 |
NO981394D0 (no) | 1998-03-27 |
WO1997012603A1 (de) | 1997-04-10 |
TW438599B (en) | 2001-06-07 |
JPH11512729A (ja) | 1999-11-02 |
IL123250A0 (en) | 1998-09-24 |
JP4041163B2 (ja) | 2008-01-30 |
CN1198094A (zh) | 1998-11-04 |
EP0854707B1 (de) | 2002-11-27 |
CA2230950A1 (en) | 1997-04-10 |
US6187342B1 (en) | 2001-02-13 |
AU7282896A (en) | 1997-04-28 |
IL123250A (en) | 2000-08-31 |
ES2187678T3 (es) | 2003-06-16 |
BR9610799A (pt) | 1999-07-13 |
CZ95998A3 (cs) | 1998-08-12 |
MX9801988A (es) | 1998-08-30 |
DE59609923D1 (de) | 2003-01-09 |
KR19990063853A (ko) | 1999-07-26 |
CN1200694C (zh) | 2005-05-11 |
ATE228355T1 (de) | 2002-12-15 |
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