EP0809487A1 - Solid active agent preparations containing hydroxypropyl cellulose - Google Patents

Solid active agent preparations containing hydroxypropyl cellulose

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Publication number
EP0809487A1
EP0809487A1 EP96902968A EP96902968A EP0809487A1 EP 0809487 A1 EP0809487 A1 EP 0809487A1 EP 96902968 A EP96902968 A EP 96902968A EP 96902968 A EP96902968 A EP 96902968A EP 0809487 A1 EP0809487 A1 EP 0809487A1
Authority
EP
European Patent Office
Prior art keywords
hydroxypropyl cellulose
preparations
mixture
acid
active
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Withdrawn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
EP96902968A
Other languages
German (de)
French (fr)
Inventor
Joerg Rosenberg
Sven Grabowski
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.)
BASF SE
Original Assignee
BASF SE
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 BASF SE filed Critical BASF SE
Publication of EP0809487A1 publication Critical patent/EP0809487A1/en
Withdrawn legal-status Critical Current

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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
    • A61K9/205—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
    • A61K9/2095—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

Definitions

  • the present invention relates to solid preparations containing active ingredients, obtainable by melt extrusion of a mixture of
  • the invention relates to a method for producing such preparations and pharmaceutical forms from them
  • JP-A 58-79915 and JP-A 58-192817 disclose the production of rod-shaped dosage forms by melt extrusion of water-soluble polymers such as, for example
  • HPC Hydroxypropyl cellulose
  • EP-A 596 203 describes active substance-containing preparations which are obtained by mixing the active substance with a water-soluble melt of two polymers with different viscosities, for example polymer mixtures of hydroxypropyl cellulose and hydroxypropyl methyl cellulose.
  • Known active ingredient preparations generally have relatively high polymer contents. High polymer contents result in good processability, but the inevitably resulting lower active substance contents, that is to say a low active substance dose with a high tablet weight, can make the entire production process uneconomical. For example, if the active substance content of one tablet is originally 40% by weight, the tablet weight could be halved with the same dosage when the active substance content was doubled. With a given melt output of an extruder, the production capacity of the extruder could be doubled.
  • Dosage form would be difficult. In such cases, however, it would also make sense to limit the proportion of the relatively high-priced polymers. In order not to fall below the minimally sensible weight of the pharmaceutical forms, it would make sense to replace a part of the more expensive polymer component by inexpensive, not necessarily meltable, auxiliary substances.
  • the object of the present invention was to find preparations which, with a low polymer content, permit thermoplastic processing of the preparation, so that the highest possible proportion of the preparation can consist of active ingredient or active ingredient and inexpensive auxiliaries.
  • a water-soluble, thermoplastically processable hydroxypropyl cellulose is used as component A), which preferably has a molar degree of substitution of 3.0 to 4.4.
  • “Molar degree of substitution” refers to the average number of moles of propylene oxide converted per glucose unit of the cellulose.
  • the hydroxypropyl celluloses can have melt viscosities according to DIN 53735 in the range from 0.075 to 54.8 g / 10 mm.
  • the molecular weight of the hydroxypropyl cellulose can be varied within a wide range, depending on whether a slower or a faster release of active ingredient is desired.
  • High molecular weight hydroxypropyl cellulose with molecular weights in the range from 200,000 to 1,500,000 is particularly suitable for the production of pharmaceutical forms in which slow release of active ingredients is desired, for example in the case of sustained release forms, since the high molecular weight polymers dissolve less well and only with swelling in water .
  • the use of low molecular weight polymers that are readily water-soluble is recommended, in which case hydroxypropyl celluloses with a molecular weight of 60,000 to 200,000, preferably 60,000 to 100,000, can be used.
  • the preparation of the hydroxypropyl celluloses used according to the invention is generally known.
  • the proportion of hydroxypropyl cellulose in the total amount of the preparation is 10 to 30% by weight, preferably 20 to 30% by weight.
  • component B) of the preparations active substances or mixtures of active substances are considered which are thermally stable under the processing conditions.
  • suitable active ingredients are, for example:
  • Plant protection agents are also suitable as active ingredients.
  • the amount of active ingredient component B) in the overall preparation can vary within wide limits depending on the effectiveness.
  • the content of B) can be from 0.1 to 90% by weight, based on the overall preparation.
  • preparations according to the invention can also contain conventional pharmaceutical auxiliaries as components C), provided that they are thermally stable under the processing conditions, e.g. Fillers or extenders, lubricants, plasticizers, stabilizers, dyes or pigments, disintegrants, preservatives or
  • Suitable fillers are, for example, organic compounds such as lactose or mannitol or inorganic Substances such as silica or silicates, oxides of magnesium, aluminum or titanium.
  • Well water-soluble fillers such as lactose or mannitol are suitable, for example, for the preparation of preparations with accelerated release of active ingredients.
  • the proportion of fillers in the preparation depends on the dosage of the active ingredient. In the case of active ingredients with a low dosage, a higher tablet weight can be achieved according to the invention by means of higher filler contents without the thermoplastic processability being impaired. In the case of active ingredients to be dosed very low, the amount of filler can be up to approximately 90% by weight.
  • glidant can the long-chain fatty acids such as C ⁇ 2, such as the mono-, di- and triglycerides -, C ⁇ 4 -, C ⁇ 6 - and Ci ß fatty acid or waxes such as carnauba wax are used in the usual amounts.
  • C ⁇ 2 such as the mono-, di- and triglycerides -, C ⁇ 4 -, C ⁇ 6 - and Ci ß fatty acid or waxes such as carnauba wax are used in the usual amounts.
  • plasticizers e.g. in addition to low molecular weight
  • Polyalkylene oxides such as polyethylene glycol, polypropylene glycol and polyethylene propylene glycol also called polyhydric alcohols such as propylene glycol, glycerin, pentaerythritol and sorbitol as well as sodium diethylsulfosuccinate, mono-, di- and triacetate of glycerol and polyethyleneglycol stearic acid ester.
  • the amount of plasticizer is about 0.5 to 15, preferably 0.5 to 5 parts by weight.
  • lubricants e.g. Stearates of aluminum or calcium, as well as talc and silicones, the amount of which is approximately 0.1 to 5, preferably 0.1 to 3% by weight.
  • Stabilizers which may be mentioned are, for example, light stabilizers, antioxidants, radical scavengers and stabilizers against microbial attack which can be used in the customary amounts.
  • the active ingredient component can either be melted directly in the form of a physical mixture with the polymer A) or mixed with the polymer melt already present.
  • the component is mixed with the melt in a manner known per se in extruders, preferably in single- or twin-screw extruders, in a temperature range between 50 and 200.degree.
  • the shaping of the polymer melt containing the active substance into the preparations according to the invention can for example, by calendering the extrudate according to the method described in EP-A 240 906 and according to the processing method known from DE-A 38 30 355 by comminuting the extrudate with rotating knives into equal-volume - still deformable - pieces.
  • the cooled melt can also be processed into granules.
  • auxiliaries can be incorporated into the polymer melt together with the active ingredient. Mixtures of auxiliaries, the active ingredient and the polymer A) can also be melted directly. In general, it is common to fuse together a physical mixture of auxiliaries, active ingredients and polymers.
  • preparations according to the invention are used as pharmaceuticals in the form of tablets, granules or as pellets in capsules.
  • the solid pharmaceutical form can also be provided with a conventional coating to improve the appearance and / or taste (dragee) or to delay the release of the active ingredient.
  • the present invention makes it possible to produce solid active substance preparations by melt extrusion in a simple manner, the proportion of polymer being able to be kept low by using a special polymer component without impairing the thermoplastic processability of the preparation.
  • a large proportion of the recipe can consist of an active ingredient and inexpensive auxiliary substances.
  • medicament sizes which are easy to handle according to the invention can be produced by melt extrusion of the preparations without having to use a relatively large proportion of the comparatively high-priced polymer.
  • the throughput was 20 kg / h (feed weigher feed).
  • the hard, homogeneous melt was pressed directly into tablets weighing 500 mg in a molding calender located in front of the extruder head.

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  • 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)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Preparations containing active agents obtainable by the melt extrusion of A) a water-soluble thermoplastic hydroxypropyl cellulose, B) one or more active agents, C) if desired, pharmaceutical auxiliaries, in which the proportion of A) is 10 to 30 % wt. in relation to the entire preparation.

Description

Feste WirkstoffZubereitungen enthaltend HydroxypropylcelluloseSolid active substance preparations containing hydroxypropyl cellulose
Beschreibungdescription
Die vorliegende Erfindung betrifft feste, wirkstoffhaltige Zubereitungen, erhältlich durch Schmelzextrusion einer Mischung ausThe present invention relates to solid preparations containing active ingredients, obtainable by melt extrusion of a mixture of
A) einer wasserlöslichen thermoplastischen Hydroxypropylcellulose,A) a water-soluble thermoplastic hydroxypropyl cellulose,
B) einem oder mehreren Wirkstoffen, undB) one or more active ingredients, and
C) gewünschtenfalls üblichen pharmazeutischen Hilfsstoffen,C) if desired, customary pharmaceutical auxiliaries,
wobei der Anteil der Komponente A) 10 bis 30 Gew.-%, bezogen auf das Gesamtgewicht der Mischung, beträgt.wherein the proportion of component A) 10 to 30 wt .-%, based on the total weight of the mixture.
Weiterhin betrifft die Erfindung ein Verfahren zur Herstellung solcher Zubereitungen sowie Arzneiformen aus diesenFurthermore, the invention relates to a method for producing such preparations and pharmaceutical forms from them
Zubereitungen, die Schmelzextrusion und ihr Einsatz in der pharmazeutischen Technologie ist allgemein bekannt.Preparations, melt extrusion and their use in pharmaceutical technology are generally known.
In der US-A 4 801 460 wird die Herstellung von festen Arzneiformen durch Schmelzextrusion von Mischungen aus Wirkstoff und thermoplastischen N-Vinylpyrrolidon-Polymeren beschrieben.US Pat. No. 4,801,460 describes the production of solid dosage forms by melt extrusion of mixtures of active ingredient and thermoplastic N-vinylpyrrolidone polymers.
Aus der JP-A 58-79915 und der JP-A 58-192817 ist die Herstellung stabförmiger Arzneiformen durch Schmelzextrusion von wasserlöslichen POlymeren wie beispielsweiseJP-A 58-79915 and JP-A 58-192817 disclose the production of rod-shaped dosage forms by melt extrusion of water-soluble polymers such as, for example
Hydroxypropylcellulose (HPC) oder Gemischen von HPC mit anderen Polymeren bekannt.Hydroxypropyl cellulose (HPC) or blends of HPC with other polymers are known.
In der EP-A 596 203 sind wirkstoffhaltige Zubereitungen beschrieben, die durch Vermischen des Wirkstoffs mit einer wasserlöslichen Schmelze zweier Polymeren mit unterschiedlicher Viskosität erhalten werden, beispielsweise Polymermischungen aus Hydroxypropylcellulose und Hydroxypropylmethylcellulose .EP-A 596 203 describes active substance-containing preparations which are obtained by mixing the active substance with a water-soluble melt of two polymers with different viscosities, for example polymer mixtures of hydroxypropyl cellulose and hydroxypropyl methyl cellulose.
Bisher bekannte WirkstoffZubereitungen weisen in der Regel relativ hohe Polymergehalte auf. Hohe Polymergehalte bewirken zwar eine gute Verarbeitbar eit, aber die sich zwangsläufig daraus ergebenden niedrigeren Wirkstoffgehalte, also eine niedrige Wirkstoffdosis bei hohem Tablettengewicht, können das gesamte Herstellverfahren unwirtschaftlich werden lassen. Liegt beispielsweise be einer Tablette der Wirkstoffgehalt ursprünglich bei 40 Gew.-«, so konnte bei gleicher Dosierung das Tablettengewicht bei Verdoppelung des Wirkstoffgehalts halbiert werden. Bei einer gegebenen Schmelze-Ausstoßleistung eines Extruders konnte somit die Produktionskapazität des Extruders verdoppelt werden.Known active ingredient preparations generally have relatively high polymer contents. High polymer contents result in good processability, but the inevitably resulting lower active substance contents, that is to say a low active substance dose with a high tablet weight, can make the entire production process uneconomical. For example, if the active substance content of one tablet is originally 40% by weight, the tablet weight could be halved with the same dosage when the active substance content was doubled. With a given melt output of an extruder, the production capacity of the extruder could be doubled.
Andererseits wurde bei niedrig zu dosierenden Wirkstoffen ein hoher Wirkstoffgehalt zu Arzneiformen fuhren, deren Gesamtgewicht so niedrig läge, daß die Handhabung einer solch kleinenOn the other hand, with active substances to be dosed low, a high active substance content led to pharmaceutical forms, the total weight of which was so low that the handling of such a small one
Arzneiform schwierig wäre. In solchen Fallen wäre es aber genauso sinnvoll den Anteil an den relativ hochpreisigen Polymeren zu begrenzen. Um das minimal sinnvolle Gewicht der Arzneiformen nicht zu unterschreiten, wäre es sinnvoll einen Teil der teureren Polymerkomponente durch preiswerte, nicht notwendigerweise schmelzbare Hilfsstoffe zu ersetzen.Dosage form would be difficult. In such cases, however, it would also make sense to limit the proportion of the relatively high-priced polymers. In order not to fall below the minimally sensible weight of the pharmaceutical forms, it would make sense to replace a part of the more expensive polymer component by inexpensive, not necessarily meltable, auxiliary substances.
Aufgabe der vorliegenden Erfindung war es, Zubereitungen zu finden, die bei einem niedrigen Polymeranteil eine thermoplastische Verarbeitung der Zubereitung erlauben, so daß e n möglichst hoher Anteil der Zubereitung aus Wirkstoff beziehungsweise Wirkstoff und preiswerten Hilfsstoffen bestehen kann.The object of the present invention was to find preparations which, with a low polymer content, permit thermoplastic processing of the preparation, so that the highest possible proportion of the preparation can consist of active ingredient or active ingredient and inexpensive auxiliaries.
Demgemäß wurde die eingangs definierten Zubereitungen sowie ein Verfahren zu deren Herstellung und deren Verwendung gefunden.Accordingly, the preparations defined at the outset and a process for their preparation and their use have been found.
Als Komponente A) wird erfindungsgemaß eine wasserlösliche thermoplastisch verarbeitbare Hydroxypropylcellulose verwendet, die vorzugsweise einen molaren Substitutionsgrad von 3,0 bis 4,4, aufweist. "Molarer Substitutionsgrad" bezieht sich auf die durchschnittliche Anzahl von Molen Propylenoxid, die pro Glucoseeinheit der Cellulose umgesetzt sind.According to the invention, a water-soluble, thermoplastically processable hydroxypropyl cellulose is used as component A), which preferably has a molar degree of substitution of 3.0 to 4.4. "Molar degree of substitution" refers to the average number of moles of propylene oxide converted per glucose unit of the cellulose.
Die Hydroxypropylcellulosen können Schmelzviskositaten nach DIN 53735 im Bereich von 0,075 bis 54,8 g/10 mm aufweisen.The hydroxypropyl celluloses can have melt viscosities according to DIN 53735 in the range from 0.075 to 54.8 g / 10 mm.
Das Molekulargewicht der Hydroxypropylcellulose kann in breiten Bereichen variiert werden, e nachdem ob eine langsamere oder eine schnellere Wirkstoff-Freisetzung gewünscht ist.The molecular weight of the hydroxypropyl cellulose can be varied within a wide range, depending on whether a slower or a faster release of active ingredient is desired.
Hochmolekulare Hydroxypropylcellulose mit Molekulargewichten im Bereich von 200.000 bis 1.500.000 eignet sich insbesondere zur Herstellung von Arzneiformen, bei denen eine langsame Wirkstoff-Freisetzung erwünscht ist, z.B. bei Retard-Formen, da sich die hohermolekularen Polymere weniger gut und nur unter Quellung in Wasser losen. Will man jedoch Arzneiformen mit einer schnelleren Wirkstoff-Freisetzung herstellen, so empfiehlt sich die Verwendung niedermolekularer Polymere, die gut wasserlöslich sind, wobei in diesem Falle Hydroxypropylcellulosen mit einem Molekulargewicht von 60.000 bis 200.000, bevorzugt 60.000 bis 100.000 eingesetzt werden können.High molecular weight hydroxypropyl cellulose with molecular weights in the range from 200,000 to 1,500,000 is particularly suitable for the production of pharmaceutical forms in which slow release of active ingredients is desired, for example in the case of sustained release forms, since the high molecular weight polymers dissolve less well and only with swelling in water . However, if one wants to manufacture pharmaceutical forms with a faster release of active substance, the use of low molecular weight polymers that are readily water-soluble is recommended, in which case hydroxypropyl celluloses with a molecular weight of 60,000 to 200,000, preferably 60,000 to 100,000, can be used.
Die Herstellung der erfindungsgemäß verwendeten Hydroxypropylcellulosen ist allgemein bekannt.The preparation of the hydroxypropyl celluloses used according to the invention is generally known.
Der Anteil der Hydroxypropylcellulose an der Gesamtmenge der Zubereitung beträgt 10 bis 30 Gew.-%, bevorzugt 20 bis 30 Gew.-%.The proportion of hydroxypropyl cellulose in the total amount of the preparation is 10 to 30% by weight, preferably 20 to 30% by weight.
Als Komponente B) der Zubereitungen kommen Wirkstoffe oder Wirkstoff-Gemische in Betracht, die unter den Verarbeitungsbedingungen thermisch stabil sind.As component B) of the preparations, active substances or mixtures of active substances are considered which are thermally stable under the processing conditions.
Geeignete Wirkstoffe sind erfindungsgemäß beispielsweise:According to the invention, suitable active ingredients are, for example:
Acebutolol, Acetylcysteine, Acetylsalicylsäure, Aciclovir, Alprazolam, Albumin, Alfacalcidol, Allantoin, Allopurinol, Ambroxol, Amikacin, Amiloride, Aminoacetic Acid, Amiodarone, Amitriptyline, Amlodipine, Amoxicillin, Ampicillin, Ascorbinsäure, Aspartam, Astemizole, Atenolol, Beclometasone, Benserazid, Benzalkonium Hydroxid, Benzocaine, Benzoesäure, Betametasone, Bezafibrate, Biotin, Biperiden, Bisoprolol, Bromazepam, Bromhexine, Bromocriptine, Budesonide, Bufexamac, Buflomedil, Buspirone, Coffein, Campher, Captopril, Carbamazepine, Carbidopa, Carboplatin, ß-Carotin und andere ~- -otinoide, Cefachlor, Cefalexin, Cefadroxil, Cefazolin, _xime, Cefotaxime, Ceftazidine, Ceftriaxone, Cefuroxime Axetil, Chloramphenicol, Chlorhexidine, Chlorpheniramine, Chlortalidone, Choline, Ci losporin, Cilastatin, Cimetidine, Ciprofloxacin, CisapriJe, Cisplatin, Clarithromycin, Clavulansäure, Clomibr _τ:ne, -Tlonazepam, Clonidine, Clotrimazole, Clozapine, Codeine, Z ,l^sf ramme, Cromoglicinsäure, Cyanocobalamin, Cyprcterone, Desogestrel, Dexamethasone, Dexpanthenol, Dexthrcr.e ϊ-.orp an, Dextropropoxiphene, Diazepam, Diclofenac, Digoxin, 2; ydrccodeine, Dihydroergotamine, Diltiazem, Diphenhydramine, Dipyridamole, Dipyrone, Disopyramide, Domperidone, Dopamine, Enalapril, Ephedrine, Epinephrine, Ergocalciferol, Ergotamine, Erythromycin, Estradiσl, Ethinylestradiol, Etoposide, Eucalyptus Globulus, Famotidine, Felodipine, Fenofibrate, Fenoterol, Fentanyl, Flavin Mononucleotide, Fluconazole, Flunarizine, Fluorouracil,Acebutolol, Acetylcysteine, Acetylsalicylic acid, Aciclovir, Alprazolam, Albumin, Alfacalcidol, Allantoin, Allopurinol, Ambroxol, Amikacin, Amiloride, Aminoacetic, Astitriptyline, Amlodipin, Amoxicinolonol, Asoxicinolone Hydroxide, benzocaine, benzoic acid, betametasone, bezafibrate, biotin, biperiden, bisoprolol, bromazepam, bromhexine, bromocriptine, budesonide, bufexamac, buflomedil, buspirone, caffeine, camphor, captopril, carbamazepine, carbidopa - caratin - carbotin - other - carboplatin otinoids, Cefachlor, Cefalexin, Cefadroxil, Cefazolin, _xime, Cefotaxime, Ceftazidine, Ceftriaxone, Cefuroxime Axetil, Chloramphenicol, Chlorhexidine, Chlorpheniramine, Chlortalidone, Choline, Ci losporin, Cilastatin, Crofapritin, Crofapritin, Crofapritin, Crofapritin, Crofinoxin : ne, -Tlonazepam, Clonidine, Clotrimazole, Clozapine, Codeine, Z, l ^ sf ramme, Cromoglicinsäure, Cyanocobalamin, cyprcterone, desogestrel, dexamethasone, dexpanthenol, dexthrcr.e ϊ-.orp an, dextropropoxiphene, diazepam, diclofenac, digoxin, 2; ydrccodeine, Dihydroergotamine, diltiazem, diphenhydramine, dipyridamole, Dipyrone, Disopyramide, Domperidone, Dopamine, enalapril, ephedrine, epinephrine, ergocalciferol, ergotamine, erythromycin, Estradiσl, ethinylestradiol, etoposide, Eucalyptus globulus, famotidine, felodipine, fenofibrate, fenoterol, fentanyl, flavin Mononucleotides, fluconazoles, flunarizines, fluorouracil,
Fluoxetine, Flurbiprofen, Furosemide, Gemfibrozil, Gentamicin, Ginkgo Biloba, Glibenclamide, Glipizide, Glycyrrhiza Glabra, Guaifenesin, Haloperidol, Heparin, Hyaluronsäure, Hydrochlorothiazide, Hydrocodone, Hydrocortisone, Hydromorphon, Ipratropium Hydroxide, Ibuprofen, Imipenem, Indomethacin, Iohexol, Iopamidol, Isosorbide Dinitrate, Isosorbide Mononitrate, Isotretinoin, Ketotifen, Ketoconazole, Ketoprofen, Ketorolac, Labetaloe, Lactulose, Lecithin, Levocarnitine, Levodopa, Levoglutamide, Levonorgestrel, Levothyroxine, Lidocaine, Lipase, Lisinopril, Loperamide, Lorazepam, Lovastatin, Medroxyprogesterone, Menthol, Methotrexate, Methyldopa, Methylprednisolone, Metoclopramide, Metoprolol, Miconazole, Midazolam, Minocycline, Minoxidil, Misoprostol, Morphine, Multivitamine und Mineralien, Nystatin, N-Methylephedrine, Naftidrofuril, Naproxen, Neomycin, Nicardipine, Nicergoline, Nicotinamide, Nicotine, Nicotinsäure, Nifedipine, Nimodipine, Nitrendipine, Nizatidine, Norethisterone, Norfloxacin,Fluoxetine, Flurbiprofen, Furosemide, Gemfibrozil, Gentamicin, Ginkgo Biloba, Glibenclamide, Glipizide, Glycyrrhiza Glabra, Guaifenesin, Haloperidol, Heparin, Hyaluronic Acid, Hydrochlorothiazide, Hydrocodone, Hydrocortisone, Hydromorphone, Ipratropium Hydroxide, Ibuprofen, Imipenem, Indomethacin, Iohexol, Iopamidol, Isosorbide Dinitrate, Isosorbide Mononitrin, Lactophenoletophenoletophenoletophenoletophenoletone , Lecithin, levocarnitine, levodopa, levoglutamide, levonorgestrel, levothyroxine, lidocaine, lipase, lisinopril, loperamide, lorazepam, lovastatin, medroxyprogesterone, menthol, methotrexate, methyldopa, methylprednisolone, metoclopramon, minazolopolol, minazolopololine, minazolopololine, minazolopololine, minazolopololine, minazolopololine, minazolopololine, minopololine, minopololine, minopololine, minopolol, minopololol, minoprolol, minazolopolol, minoprolol, minopolol, minopolol, minopolol , Multivitamins and minerals, nystatin, N-methylephedrine, naftidrofuril, naproxen, neomycin, nicardipine, nicergoline, nicotinamide, nicotine, nicotinic acid, nifedipine, nimodipine, nitrendipine, nizatidine, norethisterone, norfloxacin,
Norgestrel, Nortriptyline, Ofloxacin, Omeprazole, Ondansetron, Pancreatin, Panthenol, Pantothensäure, Paracetamol, Penicillin G, Penicillin V, Phenobarbital, Pentoxifylline, Phenylephrine, Phenylpropanola in, Phenytoin, Piroxicam, Polymyxin B, Povidone-Iod, Pravastatin, Prazosim, Prednisolone, Propafenone, Propranolol, Pseudoephedrine, Pyridoxine, Quinidine, Ramipril, Ranitidine, Reserpine, Retinol, Riboflavin, Rifampicin, Rutoside, Saccharin, Salbutamol, Salcatonin, Salicylsäure, Selegilin, Simvastatin, Somatropin, Sotalol, Spironolactone, Sucralfate, Sulbactam, Sulfamethoxazole, Sulpiride, Tamoxifen, Tegafur, Teprenone, Terazosin, Terbutaline, Terfenadine, Theophylline, Thiamine, Ticlopi.dine, Timolol, Tranexamsäure, Tretinoin, Triamcinolone Acetonide, Triamterene, Trimethoprim, Troxerutin, Uracil, Valproinsäure, Vancomycin, Verapamil, Vitamin E, Volinic Acid, Zidovudine.Norgestrel, nortriptyline, ofloxacin, omeprazole, ondansetron, pancreatin, panthenol, pantothenic acid, paracetamol, penicillin G, penicillin V, phenobarbital, pentoxifylline, phenylephrine, phenylpropanola in, phenytoin, piroxicam, prodinoxinamone, polymyidone Propafenone, propranolol, pseudoephedrine, pyridoxine, quinidine, ramipril, ranitidine, reserpine, retinol, riboflavin, rifampicin, rutoside, saccharin, salbutamol, salcatonin, salicylic acid, selegiline, simvastatin, somatropin, sotalolamone sulfate, sotalol Tamoxifen, Tegafur, Teprenone, Terazosin, Terbutaline, Terfenadine, Theophylline, Thiamine, Ticlopi.dine, Timolol, Tranexamic Acid, Tretinoin, Triamcinolone Acetonide, Triamterene, Trimethoprim, Troxerutin, Uracil, Accinid, Vercinomine, Volcinic Acid, Vanproinic Acid, Vanproinic Acid, Vanproinic Acid, Vancinic Acid, Volcinic Acid, Vancinic Acid, Vanicinic Acid, Vanicinic Acid, Valcinic Acid, Vanicinic Acid, Valcinic Acid, Vanicinic Acid, Valproic Acid, Vanine Acid .
Weiterhin kommen als Wirkstoffe auch Pflanzenschutzmittel in Betracht.Plant protection agents are also suitable as active ingredients.
Die Menge der Wirkstoff omponente B) in der Gesamtzubereitung kann je nach Wirksamkeit in weiten Grenzen variieren. So kann der Gehalt an B) von 0,1 bis 90 Gew.-%, bezogen auf die gesamte Zubereitung, betragen.The amount of active ingredient component B) in the overall preparation can vary within wide limits depending on the effectiveness. The content of B) can be from 0.1 to 90% by weight, based on the overall preparation.
Weiterhin können die erfindungsgemäßen Zubereitungen als Komponenten C) noch übliche pharmazeutische Hilfsstoffe enthalten, sofern sie unter den Verarbeitungsbedingungen thermisch stabil sind, z.B. Füllstoffe bzw. Streckmittel, Schmiermittel, Weichmacher, Stabilisatoren, Farbstoffe oder Pigmente, Sprengmittel, Konservierungsmittel oderFurthermore, the preparations according to the invention can also contain conventional pharmaceutical auxiliaries as components C), provided that they are thermally stable under the processing conditions, e.g. Fillers or extenders, lubricants, plasticizers, stabilizers, dyes or pigments, disintegrants, preservatives or
Geschmacksstoffe. Geeignet Füllstoffe sind beispielsweise organische Verbindungen wie Lactose oder Mannit oder anorganische Stoffe wie Kieselsäure oder Silicate, Oxide von Magnesium, Aluminium oder Titan. Gut wasserlösliche Füllstoffe wie Lactose oder Mannit eignen sich beispielsweise zur Herstellung von Zubereitungen mit beschleunigter Wirkstoff-Freisetzung.Flavorings. Suitable fillers are, for example, organic compounds such as lactose or mannitol or inorganic Substances such as silica or silicates, oxides of magnesium, aluminum or titanium. Well water-soluble fillers such as lactose or mannitol are suitable, for example, for the preparation of preparations with accelerated release of active ingredients.
Der Anteil an Füllstoffen in der Zubereitung richtet sich nach der Wirkstoff-Dosierung. Bei Wirkstoffen mit niedriger Dosierung kann erfindungsgemäß durch höhere Füllstoffanteile ein höheres Tablettengewicht erzielt werden, ohne daß die thermoplastische Verarbeitbarkeit beeinträchtigt wird. Bei sehr niedrig zu dosierenden Wirkstoffen kann die Füllstoffmenge bis zu circa 90 Gew.-% betragen.The proportion of fillers in the preparation depends on the dosage of the active ingredient. In the case of active ingredients with a low dosage, a higher tablet weight can be achieved according to the invention by means of higher filler contents without the thermoplastic processability being impaired. In the case of active ingredients to be dosed very low, the amount of filler can be up to approximately 90% by weight.
Als weitere pharmazeutische Hilfsstoffe können Fließregulierungsmittel wie beispielsweise die Mono-, Di- und Triglyceride der langkettigen Fettsäuren wie Cι2-, Cι4-, Cι6- und Ciß-Fettsäure oder Wachse wie Carnaubawachs in den üblichen Mengen verwendet werden.As further pharmaceutical excipients glidant can the long-chain fatty acids such as Cι 2, such as the mono-, di- and triglycerides -, Cι 4 -, Cι 6 - and Ci ß fatty acid or waxes such as carnauba wax are used in the usual amounts.
Als Weichmacher seien z.B. neben niedermolekularenAs plasticizers e.g. in addition to low molecular weight
Polyalkylenoxiden wie Polyethylenglykol, Polypropylenglykol und Polyethylenpropylenglykol auch mehrwertige Alkohole wie Propylenglykol, Glycerin, Pentaerythrit und Sorbit sowie Natriumdiethylsulfosuccinat, Mono-, Di- und Triacetat des Glycerins und Polyet ylenglykolstearinsäureester genannt. Dabei liegt die Menge an Weichmacher bei ca. 0,5 bis 15, vorzugsweise 0, 5 bis 5 Gew.- .Polyalkylene oxides such as polyethylene glycol, polypropylene glycol and polyethylene propylene glycol also called polyhydric alcohols such as propylene glycol, glycerin, pentaerythritol and sorbitol as well as sodium diethylsulfosuccinate, mono-, di- and triacetate of glycerol and polyethyleneglycol stearic acid ester. The amount of plasticizer is about 0.5 to 15, preferably 0.5 to 5 parts by weight.
Als Schmiermittel seien z.B. Stearate von Aluminium oder Calcium sowie Talkum und Silikone genannt, wobei ihre Menge bei ca. 0,1 bis 5, vorzugsweise 0,1 bis 3 Gew.-% liegt.As lubricants e.g. Stearates of aluminum or calcium, as well as talc and silicones, the amount of which is approximately 0.1 to 5, preferably 0.1 to 3% by weight.
Als Stabilisatoren seien beispielsweise Lichtstabilisatoren, Antioxidantien, Radikalfänger und Stabilisatoren gegen mikrobiellen Befall genannt, die in den üblichen Mengen eingesetzt werden können.Stabilizers which may be mentioned are, for example, light stabilizers, antioxidants, radical scavengers and stabilizers against microbial attack which can be used in the customary amounts.
Um die erfindungsgemäßen Zubereitungen herzustellen, kann die Wirkstoffkomponente entweder direkt in Form einer physikalischen Mischung mit dem Polymeren A) verschmolzen werden oder mit der bereits vorliegenden Polymerschmelze gemischt werden.In order to produce the preparations according to the invention, the active ingredient component can either be melted directly in the form of a physical mixture with the polymer A) or mixed with the polymer melt already present.
Im übrigen erfolgt die Vermischung der Komponente mit der Schmelze in an sich bekannter Weise in Extrudern, vorzugsweise in Ein- oder Doppelschneckenextrudern in einem Temperaturbereich zwischen 50 und 200°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 Verarbeitungsverfahren durch Zerkleinerung des Extrudates mit rotierenden Messern in volumengleiche - noch verformbare - Stücke. Man kann die erkaltete Schmelze auch zu Granulaten verarbeiten.Otherwise, the component is mixed with the melt in a manner known per se in extruders, preferably in single- or twin-screw extruders, in a temperature range between 50 and 200.degree. The shaping of the polymer melt containing the active substance into the preparations according to the invention can for example, by calendering the extrudate according to the method described in EP-A 240 906 and according to the processing method known from DE-A 38 30 355 by comminuting the extrudate with rotating knives into equal-volume - still deformable - pieces. The cooled melt can also be processed into granules.
Es ist möglich, die Hilfsstoffe in die Schmelze aus Wirkstoffen und dem Polymer A) zu mischen. Ferner können die Hilfsstoffe zusammen mit dem Wirkstoff in die Polymerschmelze eingearbeitet werden. Außerdem können Gemische aus Hilfsstoffen, dem Wirkstoff und dem Polymer A) direkt verschmolzen werden. Im allgemeinen ist es üblich, eine physikalische Mischung aus Hilfsstoffen, Wirkstoffen und Polymeren gemeinsam zu verschmelzen.It is possible to mix the auxiliary substances into the melt of active substances and polymer A). Furthermore, the auxiliaries can be incorporated into the polymer melt together with the active ingredient. Mixtures of auxiliaries, the active ingredient and the polymer A) can also be melted directly. In general, it is common to fuse together a physical mixture of auxiliaries, active ingredients and polymers.
Die erfindungsgemäßen Zubereitungen werden als Arzneimittel verwendet in Form von Tabletten, Granulaten oder als Pellets in Kapseln eingesetzt.The preparations according to the invention are used as pharmaceuticals in the form of tablets, granules or as pellets in capsules.
Falls gewünscht, kann die feste pharmazeutische Form auch mit einem üblichen Überzug zur Verbesserung des Aussehens und/oder des Geschmacks (Dragee) oder zwecks Verzögerung der Wirkstofffreigäbe versehen werden.If desired, the solid pharmaceutical form can also be provided with a conventional coating to improve the appearance and / or taste (dragee) or to delay the release of the active ingredient.
Die vorliegende Erfindung ermöglicht es, auf einfache Weise feste WirkstoffZubereitungen durch Schmelzextrusion herzustellen, wobei durch den Einsatz einer speziellen Polymerkomponente der Anteil an Polymer niedrig gehalten werden kann, ohne daß die thermoplastische Verarbeitbarkeit der Zubereitung beeinträchtigt wird. Auf diese Weise kann ein großer Anteil der Rezeptur aus Wirkstoff und preiswerten Hilfsstoffen bestehen. Dies ermöglicht eine besonders kostengünstige Herstellung von festen Arzneiformen. Vor allem bei niedrig zu dosierenden Wirkstoffen können erfindungsgemäß gut handhabbare Arzneimittelgrößen durch Schmelzextrusion der Zubereitungen hergestellt werden, ohne daß ein größerer Anteil des vergleichsweise hochpreisigen Polymers eingesetzt werden muß.The present invention makes it possible to produce solid active substance preparations by melt extrusion in a simple manner, the proportion of polymer being able to be kept low by using a special polymer component without impairing the thermoplastic processability of the preparation. In this way, a large proportion of the recipe can consist of an active ingredient and inexpensive auxiliary substances. This enables a particularly cost-effective production of solid dosage forms. Particularly in the case of active ingredients to be dosed at low levels, medicament sizes which are easy to handle according to the invention can be produced by melt extrusion of the preparations without having to use a relatively large proportion of the comparatively high-priced polymer.
Beispiel 1example 1
8,0 kg Ambasilide (INN) werden mit 2,0 kg einer8.0 kg Ambasilide (INN) becomes one with 2.0 kg
Hydroxypropylcellulose mit einem Substitutionsgrad von 3,0 - 4,4, einer Schmelzviskosität nach DIN 53735 von 0,076 g/10 min in einem Doppelschneckenextruder (ZSK-40 der Fa. Werner + Pfleiderer, Stuttgart) unter folgenden Verfahrensbedingungen extrudiert: Schuß 1 90°CHydroxypropyl cellulose with a degree of substitution of 3.0 - 4.4, a melt viscosity according to DIN 53735 of 0.076 g / 10 min in a twin screw extruder (ZSK-40 from Werner + Pfleiderer, Stuttgart) extruded under the following process conditions: Shot 1 90 ° C
Schuß 2 120°CShot 2 120 ° C
Schuß 3 110°CShot 3 110 ° C
Schuß 4 110°C Kopf: 120°CShot 4 110 ° C head: 120 ° C
Düsen: 120°CNozzles: 120 ° C
Der Durchsatz lag bei 20 kg/h (Dosierwaagen-Zuführung) . Die harte, homogene Schmelze wurde in einem vor dem Extruderkopf befindlichen Formkalander direkt zu 500 mg schweren Tabletten verpreßt .The throughput was 20 kg / h (feed weigher feed). The hard, homogeneous melt was pressed directly into tablets weighing 500 mg in a molding calender located in front of the extruder head.
Beispiel 2Example 2
Die Freisetzung des Wirkstoffs aus den Tabletten gemäß Beispiel wurde im Wirkstofffreisetzungsmodell gemäß USP XXI ("Paddle-Methode") unter den folgenden Verfahrensbedingungen untersucht :The release of the active ingredient from the tablets according to the example was investigated in the active ingredient release model according to USP XXI ("paddle method") under the following process conditions:
Rührerdrehzahl 75 UpmStirrer speed 75 rpm
Freisetzungsmedium künstlicher Magensaft (USP) pH 1,0Release medium artificial gastric juice (USP) pH 1.0
Temperatur 37°CTemperature 37 ° C
Wirkstoffgehaltsbestimmungen durch UV-Spektroskopie imActive substance content determination by UV spectroscopy in
FreisetzungsmediumRelease medium
Gemessene Wirkstoff-Freisetzung:Measured drug release:
Zeit [min] Wirkstoff-Freisetzung (in [%])Time [min] drug release (in [%])
0 00 0
15 9,015 9.0
30 13,630 13.6
45 17,545 17.5
60 21,160 21.1
270 60,0 270 60.0

Claims

Patentansprüche claims
1. Wirkstoffhaltige Zubereitungen, erhaltlich durch Schmelzextrusion einer Mischung aus1. Active ingredient-containing preparations, obtainable by melt extrusion of a mixture
A) einer wasserlöslichen thermoplastischenA) a water-soluble thermoplastic
Hydroxypropylcellulose,Hydroxypropyl cellulose,
B) einem oder mehreren Wirkstoffen, undB) one or more active ingredients, and
C) gewünschtenfalls üblichen pharmazeutischen Hilfsstoffen,C) if desired, customary pharmaceutical auxiliaries,
wobei der Anteil an A) 10 bis 30 Gew. -%, bezogen auf das Gesamtgewicht der Mischung, betragt.the proportion of A) being 10 to 30% by weight, based on the total weight of the mixture.
2. Zubereitungen nach Anspruch 1, enthaltend Hydroxypropylcellulose mit einem molaren Substitutionsgrad von 3,0 bis 4,4.2. Preparations according to claim 1, containing hydroxypropyl cellulose with a molar degree of substitution of 3.0 to 4.4.
3. Verfahren zur Herstellung von wirkstoffhaltigen Zubereitungen gemäß anspruch 1 oder 2, dadurch gekennzeichnet, daß man eine Mischung aus3. Process for the preparation of active substance-containing preparations according to claim 1 or 2, characterized in that a mixture of
A) einer wasserlöslichen thermoplastischen Hydroxypropylcellulose,A) a water-soluble thermoplastic hydroxypropyl cellulose,
B) einem oder mehreren Wirkstoffen, undB) one or more active ingredients, and
C) gewünschtenfalls üblichen pharmazeutischen Hilfsstoffen,C) if desired, customary pharmaceutical auxiliaries,
wobei der Anteil an A) 10 bis 30 Gew. %, bezogen auf die Gesamtmenge der Mischung, betragt, zu einer Schmelze und unter Formgebung zu Teilchen weiterverarbeitet.wherein the proportion of A) is 10 to 30% by weight, based on the total amount of the mixture, further processed into a melt and shaped into particles.
4. Verwendung der Zubereitungen gemäß Anspruch 1 oder 2 als Arzneimittel .4. Use of the preparations according to claim 1 or 2 as a medicament.
5. Feste Arzneiformen aus den Zubereitungen gemäß Anspruch 1 oder 2.5. Solid dosage forms from the preparations according to claim 1 or 2.
6. Verwendung der Zubereitungen gemäß Anspruch 1 oder 2 als Mittel zur Nahrungsmittelerganzung. Feste WirkstoffZubereitungen enthaltend Hydroxypropylcellulose6. Use of the preparations according to claim 1 or 2 as a food supplement. Solid active substance preparations containing hydroxypropyl cellulose
ZusammenfassungSummary
Wirkstoffhaltige Zubereitungen, erhältlich durch Schmelzextrusion einer Mischung ausPreparations containing active ingredient, obtainable by melt extrusion of a mixture of
A) einer wasserlöslichen thermoplastischen Hydroxypropylcellulose,A) a water-soluble thermoplastic hydroxypropyl cellulose,
B) einem oder mehreren Wirkstoffen,B) one or more active ingredients,
C) gewünschtenfalls pharmazeutischen Hilfsstoffen,C) if desired, pharmaceutical auxiliaries,
wobei der Anteil an A) 10 bis 30 Gew.-%, bezogen auf die gesamte Zubereitung, beträgt. wherein the proportion of A) 10 to 30 wt .-%, based on the entire preparation.
EP96902968A 1995-02-14 1996-02-01 Solid active agent preparations containing hydroxypropyl cellulose Withdrawn EP0809487A1 (en)

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DE19504831A DE19504831A1 (en) 1995-02-14 1995-02-14 Solid active substance preparations containing hydroxypropyl cellulose
DE19504831 1995-02-14
PCT/EP1996/000418 WO1996025149A1 (en) 1995-02-14 1996-02-01 Solid active agent preparations containing hydroxypropyl cellulose

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CN1174502A (en) 1998-02-25
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