WO1996029994A1 - Mechanically stable solid formulations of active substances - Google Patents

Mechanically stable solid formulations of active substances Download PDF

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Publication number
WO1996029994A1
WO1996029994A1 PCT/EP1996/001156 EP9601156W WO9629994A1 WO 1996029994 A1 WO1996029994 A1 WO 1996029994A1 EP 9601156 W EP9601156 W EP 9601156W WO 9629994 A1 WO9629994 A1 WO 9629994A1
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WO
WIPO (PCT)
Prior art keywords
coating
active ingredient
plasticizer
active substances
acid
Prior art date
Application number
PCT/EP1996/001156
Other languages
German (de)
French (fr)
Inventor
Reinhard Spengler
Joerg Rosenberg
Jörg Breitenbach
Original Assignee
Basf Aktiengesellschaft
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 Aktiengesellschaft filed Critical Basf Aktiengesellschaft
Priority to AU51453/96A priority Critical patent/AU5145396A/en
Publication of WO1996029994A1 publication Critical patent/WO1996029994A1/en

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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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer

Definitions

  • the present invention relates to mechanically stable, solid active substance preparation forms which have a coating.
  • an active ingredient preparation form e.g. a tablet, a capsule, a pellet, a granulate or also crystals
  • an active ingredient preparation form e.g. a tablet, a capsule, a pellet, a granulate or also crystals
  • Protection against moisture e.g. can accelerate a decomposition reaction of the active ingredient
  • a functional varnish can e.g. transfer the following properties to the painted product:
  • Production of a diffusion-controlled system which releases the active substance into the environment of the gastrointestinal tract in a time-controlled manner through the undestroyed lacquer membrane.
  • Production of a quickly soluble coating which should not impair the absorption of the active ingredient as far as possible, but instead protects the product until it is taken, for example from light, oxygen, access to moisture or for other reasons.
  • a lubricious coating also makes it easier to swallow the dosage form.
  • coatings must have the following basic properties so that the function is preserved:
  • the coating must have a certain flexibility so that it can be used in the storage process of the dosage form, e.g. Temperature change, moisture change, mech. Stress when filling in containers, no mechanical damage and e.g. Cracks. Cracks or generally defects would override the function of a protective lacquer or at least severely interfere with it. In the case of diffusion coating, it would mean the risk of a dose dumping effect and thus serious damage to the patient through immediate release of an excessive amount of active ingredient.
  • the varnish must not move on a drug surface or be pressed together so that its mechanical integrity is guaranteed.
  • the layer thickness of the lacquer must remain constant over the storage time of the dosage form, so that desired and set properties, such as Diffusion permeability for the active ingredient or the dissolution rate of the lacquer are maintained.
  • the solution or dispersion of a lacquer substance has a complex composition so that the aforementioned properties are achieved and are preserved over the planned / tested storage time of the medication.
  • Solid oral pharmaceutical forms in particular are produced by mixing the active ingredient together with one or more polymers and optionally other pharmaceutically customary auxiliaries and tabletting them by extrusion and shaping or compacting.
  • the group of active ingredient preparation forms mentioned include, for example Tablets, pellet, granules.
  • the coating can be one or more layers.
  • the active substance is preferably in the form of a molecularly disperse distribution in a polymer matrix (“solid solution”).
  • the proportion of plasticizer in the coating is preferably 0 to 10% by weight, in particular 0 to 5% by weight, very preferably 0 to 20 3% by weight.
  • the active ingredient is in particular a pharmaceutical ingredient, but it can also be other active compounds such as e.g. Trade vitamins. 25
  • the active substance preparation form can also have one or more functional coatings over the first, plasticizer-free or low-plasticizer coating.
  • the active substance preparations are in the form of "solid solutions"
  • the pharmacologically acceptable polymers can be used, for example: polyvinylpyrrolidone (PVP), Copolymers of
  • N-vinylpyrrolidone (NVP) and vinyl esters in particular vinyl acetate, copolymers of vinyl acetate and crotonic acid, partially saponified polyvinyl acetate, polyvinyl alcohol, ethylene / vinyl acetate, copolymers, polyhydroxyethyl methacrylate, copolymers of methyl methacrylate and acrylic acid, cellulose esters, cellulose ethers,
  • hydroxypropyl cellulose especially hydroxypropyl cellulose, polyethylene glycol or polyethylene, preferably NVP copolymers with vinyl acetate, hydroxypropyl cellulose and polyethylene glycols / polyethylene oxides.
  • the K values (according to H Fikentscher, Cellulose-Chemie 13 (1932), pages 58 to 64 and 71 and 74) of the polymers are in the range from 10 to
  • the polymeric binder must soften or melt in the range from 50 to 180, preferably 60 to 130 ° C., so that the composition can be extruded.
  • the glass transition temperature of the mixture must in any case be below 180, preferably below 130 ° C.
  • plasticizing auxiliaries such as long-chain alcohols, ethylene glycol, propylene glycol, trimethylolpropane, triethylene glycols, butanediols, pentanols, hexanols, polyethylene glycols, silicones, aromatic carboxylic acid esters (for example dialkyl phthalate, benzoic acid ester). Terephthalic acid ester) or aliphatic dicarboxylic acid esters (eg dialkyl adipates, sebacic acid esters, azelaic acid esters, citric and tartaric acid esters) or fatty acid esters.
  • aromatic carboxylic acid esters for example dialkyl phthalate, benzoic acid ester.
  • Terephthalic acid ester or aliphatic dicarboxylic acid esters (eg dialkyl adipates, sebacic acid esters, azelaic acid esters, citric and tartaric acid esters) or fatty acid esters.
  • Active ingredients that can be used in the manufacture of solid solutions include:
  • Metildigoxin o- (beta-hydroxyethyl) rutoside, propicillin, acicovir mononitrate, paracetamol, naftidrofuryl, pentoxyfylline, propafenone, acebutolol, L-thyroxine, tramadol, bromocriptine, loperamide, ketotifen, fenoterol, pro-phenol , Minocycline, nicergoline, ambroxol, metoprolol, beta-sitosterol, enalaprilhy- drug maleate, bezafibrate, ISDN, gallopamil, xantinol nicotinate, digitoxin, flunitrazepan, bencyclan, dexapanthenol, pindolol, lorazepam, diltiazem, furamamzepinamomethylaminomamzepam, pirolamamapin
  • Vitamins can also be formulated according to the invention. These include the vitamins of the A group and the B group, whereby besides B1, B2, B6 and B12 and nicotinic acid and nicotinamide, compounds with vitamin B properties are also understood, such as Adenine, choline, pantothenic acid, biotin, adenylic acid, folic acid, orotic acid, pangamic acid, carnitine, p-aminobenzoic acid, myo-ionite and ⁇ -lipoic acid. Furthermore vitamins of the C group, D group, E group, F group, H group, I and J group, K group and P group.
  • active ingredients for the preparation of solid solutions are ibuprofen, acetylsalicylic acid, para-cetamol, phenazone, flurbiprofen, captopril, nifedipine, acetylcystone, naftidrofuryl, verapamil and furosemide.
  • Combinations of active ingredients can also be used.
  • the amount of active ingredient, based on the solid pharmaceutical form, can be varied within wide limits depending on the effectiveness and rate of release.
  • the active ingredient content can be in the range from 0.1 to 90, preferably 0.5 to 60,% by weight.
  • the mechanical stabilization of moldings such as tablets, granules or pellets on the basis of the abovementioned polymers is successful if these have been processed into solid solutions with the abovementioned active substances or if these polymers have been processed with softening active substances, e.g. Acetylsalicylic acid, fenofibrate, naftidofuryl, furosemide, ibuprofen, anipamil, benzoic acid, indomethacin. Otherwise, the products are deformed, bonded and also melt away, so that individual removal from a container is no longer possible and that if individual moldings are stored separately, they are in a form which is no longer suitable for consumption.
  • softening active substances e.g. Acetylsalicylic acid, fenofibrate, naftidofuryl, furosemide, ibuprofen, anipamil, benzoic acid, indomethacin.
  • the coatings for the active substance preparations according to the invention can be produced in the following way:
  • Suitable coating polymers are:
  • plasticizers if they are used, the following can be used:
  • These polymers include:
  • the moldings are coated with a coating as described under 1 or 2 and thus sufficiently solidified.
  • a plasticizer-containing coating possibly a functional coating, is applied, which contains plasticizer components, as are common in pharmaceutics.
  • a stronger mechanical solidification is achieved and it is also possible to cover the forming with a functional coating (enteric coating, diffusion coating, saliva-resistant coating).
  • the functional covering is represented by the 2nd layer.
  • the functional cover is protected against additional, migrating, softening components from the molding and can thus retain its function and quality over the intended storage period.
  • the coating layers are applied in the known manner.
  • Macrogol 6000 polyethylene glycol 0.070 mg
  • Titanium dioxide E 171 1.840 mg
  • the mechanical stability is guaranteed with a coating over 3 years at ⁇ .30 ° C. At 30 ° C, the tablet is deformed after 4 months of storage if no lacquer coating is used.
  • Klucel EF hydroxypropylmethyl 200 mg cellulose
  • the mechanical stability of the coated pellets can be guaranteed for 3 years at up to + 30 ° C. Without coating, the pellets deform and stick after 2 months, stored at + 30 ° C. With a triethyl citrate content of 22 mg (to 80 mg ethyl cellulose dispersion), this corresponds to the pharmaceutically Chen concentration in the processing of the paint, the
  • the mechanical stability is given with a varnish coating for> 3 years at up to + 30 ° C. Without a coating, the tablet deforms at + 30 ° C after 7 months.
  • Titanium dioxide 1.8 mg iron oxide yellow 0.015 mg
  • the mechanical stability with the stabilizing coating is given at a storage temperature of ⁇ + 30 ° C for> 3 years, without the stabilizing coating only 1.5 months.
  • Titanium dioxide 1.8 mg
  • the mechanical stability with the stabilizing coating is at a storage temperature of ⁇ . + 30 ° C for> 3 years.
  • the uncoated tablet dissolves within a week at + 30 ° C.
  • Aerosil o. 005 mg gastro-resistant function lsöü LubJe ⁇ Srzug
  • the stability of the coated indomethacin tablet is guaranteed for 3 years at a storage temperature of up to + 30 ° C. Without a coating, the tablet dissolves within 3 weeks of storage at + 30 ° C.

Abstract

The invention concerns mechanically stable solid formulations of active substances, containing at least one active substance and at least one polymer and provided with a coating containing a proportion of softener equal to 0-16 wt. %. With the formulations of active substances proposed, it is possible to achieve mechanical stabilisation of moulded articles such as tablets, granules or pellets based on the above polymers when the latter are treated to produce solid solutions with the above active substances or when those polymers are treated with softening active substances such as acetylsalicylic acid, fenofibrate, naftidrofuryl, furosemide, ibuprofen, anipamil, benzoic acid, or indomethacin.

Description

Mechanisch stabile feste WirkstoffZubereitungsformenMechanically stable solid active ingredient preparation forms
Beschreibungdescription
Die vorliegende Erfindung betrifft mechanisch stabile, feste WirkstoffZubereitungsformen, die einen Überzug aufweisen.The present invention relates to mechanically stable, solid active substance preparation forms which have a coating.
Nach dem Stand der pharmazeutisch-technologischen Technik ist es bekannt und aus vielerlei Gründen notwendig, feste orale Darrei¬ chungsformen mit einem Schutz- oder Funktionsüberzug zu versehen. Gründe für das Überziehen einer WirkstoffZubereitungsform (z.B. eine Tablette, eine Kapsel, ein Pellet, ein Granulat oder auch Kristalle) sind z.B.:According to the state of pharmaceutical technology, it is known and for many reasons necessary to provide solid oral dosage forms with a protective or functional coating. Reasons for coating an active ingredient preparation form (e.g. a tablet, a capsule, a pellet, a granulate or also crystals) include:
- Schutz vor Luftsauerstoff bzw. Oxidation- Protection against atmospheric oxygen or oxidation
Schutz vor Feuchtigkeit, die z.B. eine Zersetzungsreaktion des Wirkstoffes beschleunigen kannProtection against moisture, e.g. can accelerate a decomposition reaction of the active ingredient
Schutz vor Lichteinwirkung auf einen photolabilen WirkstoffProtection against exposure to light on a photolabile agent
Schutz vor unangenehmen GeschmackProtection against unpleasant taste
- Schutz des Mundes, der Speiseröhre und des Magens vor aggres¬ siven Wirkstoffen- Protection of the mouth, esophagus and stomach from aggressive agents
Schutz vor Ankleben der Arzneiform im RachenraumProtection against sticking of the dosage form in the pharynx
- Schutz vor Verwechselung durch charakteristische Einfärbung.- Protection against confusion by characteristic coloring.
Umgekehrt kann ein Funktionslack z.B. folgende Eigenschaften auf das lackierte Produkt übertragen:Conversely, a functional varnish can e.g. transfer the following properties to the painted product:
- Herstellung einer speichelresistenten Zubereitung, die sich nicht im Mund auflöst.- Production of a saliva-resistant preparation that does not dissolve in the mouth.
Herstellung einer magensaftresistenten Zubereitung, die sich ab einem bestimmten pH-Wert nach der Magenpassage auflöst.Production of an enteric preparation that dissolves after a certain pH value after passage through the stomach.
Herstellung eines diffusionskontrollierten Systems, das den Wirkstoff zeitlich gesteuert durch die unzerstörte Lackmem¬ brane in das Milieu des Magen-Darπt-Traktes abgibt. Herstellung eines schnell löslichen Überzugs, der möglichst keine Beeinträchtigung der Resorption des Wirkstoffes bewir¬ ken soll, aber dafür das Produkt bis zur Einnahme, z.B. vor Licht, Sauerstoff, Zutritt von Feuchtigkeit oder aus anderen Gründen schützt. Ein gleitfähiger Überzug erleichtert auch das Schlucken der Arzneiform.Production of a diffusion-controlled system which releases the active substance into the environment of the gastrointestinal tract in a time-controlled manner through the undestroyed lacquer membrane. Production of a quickly soluble coating, which should not impair the absorption of the active ingredient as far as possible, but instead protects the product until it is taken, for example from light, oxygen, access to moisture or for other reasons. A lubricious coating also makes it easier to swallow the dosage form.
Aus dieser übergreifenden Betrachtung über bekannte Funktionen der Überzüge geht hervor, daß Überzüge folgende Grundeigenschaf- ten haben müssen, damit die Funktion gewahrt bleibt:From this overarching consideration of known functions of the coatings, it can be seen that coatings must have the following basic properties so that the function is preserved:
Der Überzug muß eine gewisse Flexibilität besitzen, damit er beim Lagerprozeß der Arzneiform, das meint z.B. Temperatur¬ wechsel, Feuchtewechsel, mech. Beanspruchung beim Abfüllen in Gebinde, keinen mechanischen Schaden erleidet und z.B. Risse bekommt. Risse oder allgemein Defektstellen würden in der Re¬ gel die Funktion eines Schutzlackes außer Kraft setzen oder zumindest stark stören. Im Fall eines Diffusionscoatings würde es die Gefahr eines Dose-dumping-Effekts und damit eine ernste Schädigung des Patienten durch sofortige Freisetzung einer zu großen Wirkstoffmenge bedeuten.The coating must have a certain flexibility so that it can be used in the storage process of the dosage form, e.g. Temperature change, moisture change, mech. Stress when filling in containers, no mechanical damage and e.g. Cracks. Cracks or generally defects would override the function of a protective lacquer or at least severely interfere with it. In the case of diffusion coating, it would mean the risk of a dose dumping effect and thus serious damage to the patient through immediate release of an excessive amount of active ingredient.
Der Lack darf sich auf einer Arzneiformenoberfläche nicht verschieben oder sich zusammendrücken lassen, damit seine me- chanische Intaktheit gewährleistet bleibt.The varnish must not move on a drug surface or be pressed together so that its mechanical integrity is guaranteed.
Die Schichtdicke des Lackes muß über die Lagerzeit der Arzneiform konstant bleiben, damit gewünschte und einge¬ stellte Eigenschaften, wie z.B. Diffusions-Durchlässigkeit für den Wirkstoff oder die Auflösegewindigkeit des Lackes er¬ halten bleiben.The layer thickness of the lacquer must remain constant over the storage time of the dosage form, so that desired and set properties, such as Diffusion permeability for the active ingredient or the dissolution rate of the lacquer are maintained.
Die Lösung oder eine Dispersion einer Lacksubstanz ist komplex zusammengesetzt, damit vorgenannte Eigenschaften erzielt werden und über die geplante/geprüfte Lagerzeit des Medikaments erhalten bleiben.The solution or dispersion of a lacquer substance has a complex composition so that the aforementioned properties are achieved and are preserved over the planned / tested storage time of the medication.
Als Bestandteile sind insbesondere zu nennen:The following are particularly important components:
1. Polymer: Zur Erzielung der gewünschten Funktion des1. Polymer: To achieve the desired function of the
ÜberzugsCoating
2. Weichmacher: Zur Erzielung einer gewissen Flexibilität des2. Plasticizer: To achieve a certain flexibility of the
Lacks und zum Schutz vor allzu leichter mecha- nischer Zerstörung und Versprödung. 3. Füllstoffe: Zur Erhöhung der Masse oder Schichtdicke einesLacquers and to protect against too easy mechanical destruction and embrittlement. 3. Fillers: To increase the mass or layer thickness of one
LacküberzugesLacquer coating
4. Antiklebemittel: Zur Verhinderung des Zusammenbackens von Arzneiformen während und nach dem Überziehen mit Lack4. Anti-adhesive: To prevent caking of drug forms during and after coating with varnish
5. Farbmittel: Zur farblichen Kennzeichnung/Identifizierung des Arzneimittels5. Colorant: For the color coding / identification of the drug
6. Aromastoffe: Zur Harmonisierung oder Antagonisierung des6. Flavorings: To harmonize or antagonize the
Geschmackseindruckes des WirkstoffesTaste impression of the active ingredient
Diese Aussagen gelten für zu überziehende Massen/Wirkstofformen, die in der Regel selbst formstabil sind und keine oder keine nen¬ nenswerte Weichmachereigenschaften besitzen.These statements apply to the masses / active ingredient forms to be coated, which are generally dimensionally stable themselves and have no or no significant plasticizer properties.
Insbesondere feste orale Arzneiformen werden dadurch hergestellt, daß der Wirkstoff zusammen mit einem oder mehreren Polymeren und gegebenenfalls weiteren pharmazeutisch üblichen Hilfsstoffen ver¬ mischt und durch Extrusion und Formgebung oder Kompaktierung ta¬ blettiert wird.Solid oral pharmaceutical forms in particular are produced by mixing the active ingredient together with one or more polymers and optionally other pharmaceutically customary auxiliaries and tabletting them by extrusion and shaping or compacting.
Zu der genannten Gruppe von WirkstoffZubereitungsformen gehören z.B. Tabletten, Pellet, Granulat.The group of active ingredient preparation forms mentioned include, for example Tablets, pellet, granules.
Wenn nun in diesem Fall der Wirkstoff mit dem Polymer eine feste Lösung bildet oder der Wirkstoff auf das Polymer als Weichmacher wirkt, oder das Polymer als solches eine Neigung zu "kaltem Fluß" zeigt, so ist in allen vorgenannten Fällen mit keiner formstabi¬ len Zubereitung während der empfohlenen Lagerzeit/Lagertemperatur zu rechnen.In this case, if the active ingredient forms a solid solution with the polymer or if the active ingredient acts on the polymer as a plasticizer, or if the polymer as such shows a tendency to "cold flow", there is no dimensionally stable preparation in all of the above cases to be calculated during the recommended storage period / temperature.
Wenn die vorgenannte Gruppe von form-instabilen Wirkstofformen mit einem polymeren, konventionellen Lack überzogen werden, so kann mit einer kurzzeitigen mechanischen Stabilisierung der äuße¬ ren Form und Beschaffenheit gerechnet werden. Die mechanische Stabilisierung hält aber nur so lange an, bis auch der aufge¬ brachte Lack durch die weichmachende Komponente in der Arznei- form, z.B. der Wirkstoff in die Lackhülle migriert ist und diese ebenfalls erweicht. Gute konventionelle Lacküberzüge sind relativ flexibel durch ihren hohen Weichmacheranteil und eignen sich vom Prinzip her nicht zur mechanischen Stabilisierung von formstabi¬ len Tabletten. Aufgabe der vorliegenden Erfindung war es daher, feste Wirkstoff¬ zubereitungsformen mit einer höheren mechanischen Stabilität zur Verfügung zu stellen.If the aforementioned group of form-unstable active ingredient forms are coated with a polymeric, conventional lacquer, then a brief mechanical stabilization of the outer form and nature can be expected. However, the mechanical stabilization only lasts until the lacquer applied has also migrated through the softening component in the pharmaceutical form, for example the active ingredient, into the lacquer shell and also softens it. Good conventional lacquer coatings are relatively flexible due to their high plasticizer content and are in principle not suitable for the mechanical stabilization of dimensionally stable tablets. The object of the present invention was therefore to provide solid active substance preparation forms with a higher mechanical stability.
5 Diese Aufgabe wird durch mechanisch stabile, feste Wirkstoffzube- reitungsformen, die mindestens einen Wirkstoff und mindestens ein Polymer enthalten und die mit einem Überzug versehen sind, ge¬ löst, die dadurch gekennzeichnet sind, daß der Überzug einen Weichmacheranteil von 0 bis 15 Gew.-% aufweist. Die Gew.-% an 10 Weichmacheranteil sind jeweils auf das Gesamtgewicht des Überzugs bezogen.5 This object is achieved by mechanically stable, solid active substance preparation forms which contain at least one active substance and at least one polymer and which are provided with a coating, which are characterized in that the coating has a plasticizer content of 0 to 15% by weight. -% having. The% by weight of plasticizer content is in each case based on the total weight of the coating.
Der Überzug kann ein oder mehrschichtig sein.The coating can be one or more layers.
15 Der Wirkstoff liegt bevorzugt in Form einer molekulardispersen Verteilung in einer Polymermatrix ("feste Lösung") vor.The active substance is preferably in the form of a molecularly disperse distribution in a polymer matrix (“solid solution”).
Der Weichmacheranteil im Überzug beträgt bevorzugt 0 bis 10 Gew.-%, insbesondere 0 bis 5 Gew.-%, ganz bevorzugt 0 bis 20 3 Gew.-%.The proportion of plasticizer in the coating is preferably 0 to 10% by weight, in particular 0 to 5% by weight, very preferably 0 to 20 3% by weight.
Der Wirkstoff ist insbesondere ein Pharmawirkstoff, es kann sich aber auch um andere aktive Verbindungen, wie z.B. Vitamine han¬ deln. 25The active ingredient is in particular a pharmaceutical ingredient, but it can also be other active compounds such as e.g. Trade vitamins. 25
Die Wirkstoffzubereitungsform kann über dem ersten, weichmacher¬ freien oder weichmacherarmen Überzug noch einen oder mehrere Funktionsüberzuge aufweisen.The active substance preparation form can also have one or more functional coatings over the first, plasticizer-free or low-plasticizer coating.
30 Liegen die Wirksto fZubereitungen als "feste Lösungen" vor, kön¬ nen als pharmakologisch akzeptablen Polymere (wobei die Glas¬ temperatur der Polymere bzw. ihrer Mischungen unter der Zerset¬ zungstemperatur aller Mischungskomponenten liegt) , beispielsweise eingesetzt werden: Polyvinylpyrrolidon (PVP), Copolymerisate vonIf the active substance preparations are in the form of "solid solutions", the pharmacologically acceptable polymers (the glass temperature of the polymers or their mixtures being below the decomposition temperature of all mixture components) can be used, for example: polyvinylpyrrolidone (PVP), Copolymers of
35 N-Vinylpyrrolidon (NVP) und Vinylestern, insbesondere Vinyl- acetat, Copolymerisate von Vinylacetat und Crotonsäure, teilver¬ seiftes Polyvinylacetat, Polyvinylalkohol, Ethylen/Vinylacetat, Copolymerisate, Polyhydroxyethylmethacrylat, Copolymerisate von Methylmethacrylat und Acrylsäure, Celluloseester, Celluloseether,35 N-vinylpyrrolidone (NVP) and vinyl esters, in particular vinyl acetate, copolymers of vinyl acetate and crotonic acid, partially saponified polyvinyl acetate, polyvinyl alcohol, ethylene / vinyl acetate, copolymers, polyhydroxyethyl methacrylate, copolymers of methyl methacrylate and acrylic acid, cellulose esters, cellulose ethers,
40 insbesondere Hydroxypropylcellulose, Polyethylenglykol oder Poly- ethylen, bevorzugt NVP-Copolymerisate mit Vinylacetat, Hydroxy¬ propylcellulose und Polyethalenglykole/Polyethylenoxide. Die K- Werte (nach H Fikentscher, Cellulose-Chemie 13 (1932), Seiten 58 bis 64 und 71 und 74) der Polymeren liegen im Bereich von 10 bis40 especially hydroxypropyl cellulose, polyethylene glycol or polyethylene, preferably NVP copolymers with vinyl acetate, hydroxypropyl cellulose and polyethylene glycols / polyethylene oxides. The K values (according to H Fikentscher, Cellulose-Chemie 13 (1932), pages 58 to 64 and 71 and 74) of the polymers are in the range from 10 to
45 100, vorzugsweise 12 bis 70, insbesondere 12 bis 35, für PVP vor¬ zugsweise bei 12 bis 35, insbesondere bei 12 bis 17. Das polymere Bindemittel muß zur Herstellung der "festen Lösun¬ gen" in der Gesamtmischung aller Komponenten im Bereich von 50 bis 180, vorzugsweise 60 bis 130°C erweichen oder schmelzen, so daß die Masse extrudierbar ist. Die Glasübergangstemperatur der Mischung muß also auf jeden Fall unter 180, vorzugsweise unter 130°C liegen. Erforderlichenfalls wird sie durch übliche pharmako- logisch akzeptable weichmachende Hilfsstoffe wie langkettige Al¬ kohole, Ethylenglykol, Propylenglykol, Trimethylolpropan Tri- ethylenglykol, Butandiole, Pentanole, Hexanole, Polyethlengly- kole, Silicone, aromatische Carbonsäurester (z.B. Dialkylphtha- late, Trimellithsäureester, Benzoesäureester, Terephthalsäure- ster) oder aliphatische Dicarbonsäureester (z.B. Dialkyladipate, Sebacinsäureester, Azelainsäureester, Zitronen- und Weinsäure¬ ester) oder Fettsäureester herabgesetzt. Die Herstellung solcher "festen Lösungen" ist an sich bekannt, siehe z.B. EP 240 904.45 100, preferably 12 to 70, in particular 12 to 35, for PVP preferably 12 to 35, in particular 12 to 17. To produce the “solid solutions” in the total mixture of all components, the polymeric binder must soften or melt in the range from 50 to 180, preferably 60 to 130 ° C., so that the composition can be extruded. The glass transition temperature of the mixture must in any case be below 180, preferably below 130 ° C. If necessary, it is supplemented by customary pharmacologically acceptable plasticizing auxiliaries such as long-chain alcohols, ethylene glycol, propylene glycol, trimethylolpropane, triethylene glycols, butanediols, pentanols, hexanols, polyethylene glycols, silicones, aromatic carboxylic acid esters (for example dialkyl phthalate, benzoic acid ester). Terephthalic acid ester) or aliphatic dicarboxylic acid esters (eg dialkyl adipates, sebacic acid esters, azelaic acid esters, citric and tartaric acid esters) or fatty acid esters. The preparation of such "solid solutions" is known per se, see for example EP 240 904.
Wirkstoffe, die bei der Herstellung fester Lösungen eingesetzt werden können, sind beispielsweise:Active ingredients that can be used in the manufacture of solid solutions include:
Betamethason, Thioctsäure, Sotalol, Salbutamol, Norfenefrin,Betamethasone, thioctic acid, sotalol, salbutamol, norfenefrin,
Silymarin, Dihydroergotamin, Buflomedil, Etofibrat, Indometacin, Oxazepam, beta-Acetyldigoxim, Piroxicam, Haloperidol, ISMN, Ami- triptylin, Diclofenac, Nifedipin, Verapamil, Pyritinol, Nitrendipin, Doxycyclin, Bromhexin, Methylprednisolon, Clonidin, Fenofibrat, Allopurinol, Pirenzepin, Levothyroxin, Tamoxifen,Silymarin, dihydroergotamine, buflomedil, etofibrate, indomethacin, oxazepam, beta-acetyldigoxim, piroxicam, haloperidol, ISMN, amitiptytylin, diclofenac, nifedipine, verapamil, pyritinol, nitrendipin, fenofonolonopinidol, pyridolinidol, pyridolinidol, pyridolinid, methyloxinprinid, methyloxinprinid, methyloxin Levothyroxine, tamoxifen,
Metildigoxin, o-(beta-Hydroxyethyl)rutosid, Propicillin, Aciclo- vir-mononitrat, Paracetamol, Naftidrofuryl, Pentoxyfyllin, Propa- fenon, Acebutolol, L-Thyroxin, Tramadol, Bromocriptin, Loperamid, Ketotifen, Fenoterol, Ca-Dobelisat, Propranolol, Minocyclin, Nicergolin, Ambroxol, Metoprolol, beta-Sitosterin, Enalaprilhy- drogenmaleat, Bezafibrat, ISDN, Gallopamil, Xantinolnicotinat, Digitoxin, Flunitrazepan, Bencyclan, Dexapanthenol, Pindolol, Lorazepam, Diltiazem, Piracetam, Phenoxymethylpenicillin, Furose- mid, Bromazepam, Flunarizin, Erythromycin, Metoclopramid, Acemetacin, Ranitidin, Biperiden, Metamizol, Doxepin, Dikalium- Chlorazepat, Tetrazepam, Estramustinphosphat, Terbutalin, Capto- pril, Maprotilin, Prazosin, Atenolol, Glibenclamid, Cefaclor, Etilefrin, Cimetidin, Theophyllin, Hydromorphon, Ibuprofen, Primidon, Clobazam, Oxaceprol, Medroxyprogesteron, Flecainid, Mg-Pyridoxal-5-phosphatglutaminat, Hymechromon, Etofyllinclofi- brat, Vincamin, Cinnarizin, Diazepam, Ketoprofen, Flupentixol, Molsidomin, Glibornurid, Dimetinden, Melperon, Soqüinolol, Di- hydrocodein, Clomethiazol, Clemastin, Glisoxepid, Kallidino- genase, Oxyfedrin, Baclofen, Carboxymethylcystein, Thioridacin, Betahistin, L-Tryptophan, Myrtol, Bromalaine, Prenylamin, Salazo- sulfa pyridin, Astemizol, Sulpirid, Benzerazid, Dibenzepin, Ace- tylsalicylsäure, Miconazol, Nystatin, Ketoconazol, Na-Picosulfat, Colestyramin, Gemfibrocil, Rifampicin, Fluorcortolon, Mexiletin, Amoxicillin, Terfenadrin, Mucopolysaccharidpolyschwefelsäuree- ster, Triazolam, Mianserin, Tiaprofensäure, Ameziniummetilsulfat, Mefloquin, Probucol, Chinidin, Carbamazepin, Mg-L-aspartat, Pen- butolol, Piretanid, Amitriptylin, Cyproteron, Na-Valproinat, Me- beverin, Bisacodyl, 5-Amino-Salicylsäure, Dihydralazin, Magal- drat, Phenprocoumon, Amantadin, Naproxen, Carteolol, Famotidin, Methyldopa, Auranofin, Estriol, Nadolol, Levomepromazin, Doxoru- bicin, Medofenoxat, Azathioprin, Flutamid, Norfloxacin, Fendilin, Prajmaliumbitartrat, Aescin.Metildigoxin, o- (beta-hydroxyethyl) rutoside, propicillin, acicovir mononitrate, paracetamol, naftidrofuryl, pentoxyfylline, propafenone, acebutolol, L-thyroxine, tramadol, bromocriptine, loperamide, ketotifen, fenoterol, pro-phenol , Minocycline, nicergoline, ambroxol, metoprolol, beta-sitosterol, enalaprilhy- drug maleate, bezafibrate, ISDN, gallopamil, xantinol nicotinate, digitoxin, flunitrazepan, bencyclan, dexapanthenol, pindolol, lorazepam, diltiazem, furamamzepinamomethylaminomamzepam, pirolamamapinamethylaminomamzepam, pirolamamapinamethylpiramamzepam, pirolamamethylpiramamzepinam, pirolamamethylpiramamzepam, pentololamin, pentolamamethenomamethylpiramamzepin , Erythromycin, metoclopramide, acemetacin, ranitidine, biperiden, metamizole, doxepin, dipotassium chlorazepate, tetrazepam, estramustine phosphate, terbutaline, captopril, maprotiline, prazosin, atenolol, glibenclamide, ceforphophylin, e , Clobazam, oxaceprol, medroxyprogesterone, flecainide, Mg-pyridoxal-5-phosphate glutaminate, hymechromone, etofyllinclofibrate, vincamine, cinnarizine, diazepam, ketoprofen, Fl upentixol, Molsidomin, Glibornurid, Dimetinden, Melperon, Soqüinolol, Dihydrocodein, Clomethiazol, Clemastin, Glisoxepid, Kallidino- genase, Oxyfedrin, Baclofen, Carboxymethylcysteine, Thioridacin, Betahistin, Sal-tryptylophidine, L-tryol- phenylamine, L-tryol- phenylamine , Astemizole, sulpiride, benzerazide, dibenzepine, acetylsalicylic acid, miconazole, nystatin, ketoconazole, sodium picosulfate, Cholestyramine, ster, triazolam, mianserin, tiaprofenic acid, Ameziniummetilsulfat, mefloquine, probucol, quinidine, carbamazepine, Mg-L-aspartate gemfibrocil, rifampicin, fluocortolone, mexiletine, amoxicillin, Terfenadrin, Mucopolysaccharidpolyschwefelsäuree-, pen butolol, piretanide, amitriptyline, cyproterone, Na valproinate, meververin, bisacodyl, 5-amino-salicylic acid, dihydralazine, maglarate, phenprocoumon, amantadine, naproxen, carteolol, famotidine, methyldopa, auranofin, estriol, nadolol, levomepromazine, doxorubate, azathrinoxinoxinobrin, medofen Flutamide, norfloxacin, fendilin, prajmalium bitartrate, aescin.
Acetaminophen (= Paracetamol) , Acetohexamid, Acetyldigoxim, Ace- tylsalicylsäure, Acromycin, Anipamil, Benzocain, beta-Carotin, Chloramphenicol, Chlordiazepoxid, Chlormadinoacetat, Chlorthia- zid, Cinnarizin, Clonazepam, Codein, Dexamethason, Diazepam, Di- cumarol, Digitoxin, Digoxin, Dihydroergotamin, Drotaverin, Fluni- trazepam, Furosemid, Gramicidin, Griseofulvin, Hexobarbital, Hy- drochlorothiazid, Hydrocortison, Hydroflumethazid, Ibuprofen, In- dimethazin, Ketoprofen, Lonetil, Medazepam, Mefrusid, Methandro- stenolon, Methylprednisolon, Methylsulfadiazin (= Sulfaperin) , Nalidixinsäure, Nifedipin, Nitrazepam, Nitrofurantoin, Nystatin, Östradiol, Papaverin, Phenacetin, Phenobarbital, Phenylbutazon, Phenytoin, Prednison, Reserpin, Spironolacton, Streptomycin, Sul- fadimidin (= Sulfamethazin) , Sulfamethizol, Sulfamethoxazol (= Sulfameter) , Sulfaperin, Sulfathiazol, Sulfisoxazol, Testosteron, Tolazamid, Tolbutamid, Trimethoprim, Tyrothricin.Acetaminophen (= paracetamol), acetohexamide, acetyldigoxime, acetylsalicylic acid, acromycin, anipamil, benzocaine, beta-carotene, chloramphenicol, chlordiazepoxide, chlormadinoacetate, chlorthiazide, cinnarizine, donazepametham, codon, doxin, codonoxin, codonoxin, codonoxin, codonoxin, codonoxin, codonoxin, codonoxin, codonoxin, codonoxin, codonoxin, codonoxin, codonoxin, codonoxin, codon, digoxin, dihydroergotamine, drotaverine, Fluni- trazepam, furosemide, gramicidin, griseofulvin, hexobarbital, hybrid drochlorothiazid, hydrocortisone, hydroflumethazide, ibuprofen, dimethazin home, ketoprofen, Lonetil, medazepam, mefruside, Methandro- Stenolon, methylprednisolone, Methylsulfadiazin (= Sulfaperin ), nalidixic acid, nifedipine, nitrazepam, nitrofurantoin, nystatin, estradiol, papaverine, phenacetin, phenobarbital, phenylbutazone, phenytoin, prednisone, reserpine, spironolactone, streptomycin, sulfonic fadimidin (= sulfamethazine), sulfamethizole, sulfamethoxazole (= sulfameter), Sulfaperin, Sulfathiazole, sulfisoxazole, testosterone, tolazamide, tolbutamide, trimethoprim, tyrothricin.
Auch Vitamine lassen sich erfindungsgemäß formulieren. Dazu gehö¬ ren die Vitamine der A-Gruppe, der B-Gruppe, wobei neben Bl, B2, B6 und B12 sowie Nicotinsäure und Nicotinamid auch Verbindungen mit Vitamin B-Eigenschaften verstanden werden, wie z.B. Adenin, Cholin, Pantothensäure, Biotin, Adenylsäure, Folsäure, Orotsäure, Pangamsäure, Carnitin, p-Aminobenzoesäure, myo-Ionsit und α-Li- ponsäure. Weiterhin Vitamine der C-Gruppe, D-Gruppe, E-Gruppe, F- Gruppe, H-Gruppe,I- und J-Gruppe, K-Gruppe und P-Gruppe.Vitamins can also be formulated according to the invention. These include the vitamins of the A group and the B group, whereby besides B1, B2, B6 and B12 and nicotinic acid and nicotinamide, compounds with vitamin B properties are also understood, such as Adenine, choline, pantothenic acid, biotin, adenylic acid, folic acid, orotic acid, pangamic acid, carnitine, p-aminobenzoic acid, myo-ionite and α-lipoic acid. Furthermore vitamins of the C group, D group, E group, F group, H group, I and J group, K group and P group.
Ganz besonders bevorzugte Wirkstoffe zur Herstellung fester Lö¬ sungen sind erfindungsgemäß Ibuprofen, Acetylsalicylsäure, Para¬ cetamol, Phenazon, Flurbiprofen, Captopril, Nifedipin, Acetylcy- stein, Naftidrofuryl, Verapamil und Furosemid.According to the invention, very particularly preferred active ingredients for the preparation of solid solutions are ibuprofen, acetylsalicylic acid, para-cetamol, phenazone, flurbiprofen, captopril, nifedipine, acetylcystone, naftidrofuryl, verapamil and furosemide.
Es können auch Kombinationen von Wirkstoffen verwendet werden. Die Wirkstoffmenge, bezogen auf die feste Arzneiform, kann je nach Wirksamkeit und Freisetzungsgeschwindigkeit in weiten Gren¬ zen variiert werden. So kann der Wirkstoffanteil im Bereich von 0,1 bis 90, vorzugsweise 0,5 bis 60 Gew.-% liegen.Combinations of active ingredients can also be used. The amount of active ingredient, based on the solid pharmaceutical form, can be varied within wide limits depending on the effectiveness and rate of release. The active ingredient content can be in the range from 0.1 to 90, preferably 0.5 to 60,% by weight.
Mit den erfindungsgemäßen WirkstoffZubereitungsformen gelingt die mechanische Stabilisierung von Formungen wie Tabletten, Granulat oder Pellet auf der Basis der obengenannten Polymeren, wenn diese verarbeitet sind zu festen Lösungen mit den obengenannten Wirk- Stoffen oder wenn diese Polymere mit weichmachenden Wirkstoffen verarbeitet sind, wie z.B. Acetylsalicylsäure, Fenofibrat, Nafti- dofuryl, Furosemid, Ibuprofen, Anipamil, Benzoesäure, Indo- metacin. Andernfalls kommt es bei den Produkten zu Verformungen, Verklebungen und auch zum Zerfließen, so daß eine Einzelentnahme aus einem Behältnis nicht mehr möglich ist und daß, falls ein¬ zelne Formlinge getrennt gelagert werden, diese in einer nicht mehr einnahmegerechten Form vorliegen.With the active substance preparation forms according to the invention, the mechanical stabilization of moldings such as tablets, granules or pellets on the basis of the abovementioned polymers is successful if these have been processed into solid solutions with the abovementioned active substances or if these polymers have been processed with softening active substances, e.g. Acetylsalicylic acid, fenofibrate, naftidofuryl, furosemide, ibuprofen, anipamil, benzoic acid, indomethacin. Otherwise, the products are deformed, bonded and also melt away, so that individual removal from a container is no longer possible and that if individual moldings are stored separately, they are in a form which is no longer suitable for consumption.
Im einzelnen können die Überzüge für die erfindungsgemäßen Wirk- stoffZubereitungen auf folgende Weise hergestellt werden:In particular, the coatings for the active substance preparations according to the invention can be produced in the following way:
1. Einsatz eines Polymer-Coatingmaterials, daß nur einen minima¬ len oder keinen Weichmacherzusatz enthält.1. Use of a polymer coating material that contains only a minimal or no plasticizer additive.
Geeignete Coating-Polymere sind:Suitable coating polymers are:
Ethylcellulose, Hydroxypropylcellulose, Hydroxypropylmethyl- cellulose, Methylcellulose, Carboxymethylcellulose, Hydroxy- ethylcellulose, Methacrylsäure-Ethacrylat-1:1-Copolymer Methacrylsäure-Methylmethacrylat-1:1-Copolymer Methacrylsäure-Methylmethacrylat-1:2-Copolymer Dimethylaminoethylmethycrylat-Coplymer Methylmethacrylat-Ethylacrylat-2:1-Copolymer Methylmethacrylat-2: 1-Copolymer Ethylacrylat-Methylmethacrylat-2:1-CopolmerEthyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxy ethyl cellulose, methacrylic acid-ethacrylate-1: 1 copolymer methacrylic acid-methyl methacrylate-1: 1 copolymer methacrylic acid-methyl methacrylate-1: 2-copolymer dimethylaminoethyl methycrylate copolymer ethyl methyl acrylate 2: 1 copolymer methyl methacrylate 2: 1 copolymer ethyl acrylate methyl methacrylate 2: 1 copolymer
Als Weichmacher, sofern diese eingesetzt werden, können verwendet werden:As plasticizers, if they are used, the following can be used:
Diethylphthalat, Dibutylphthalat, Acetyltributylcitrat, Trie- thylcitrat, Glyceroltinacetat, Glycerol, Rizinusöl, 1,2-Propylenglykol, Polyethylenglykol. Auch Mischungen dieser Weichmacher sind möglich. 2. Einsatz eines Coatingpolymers, welches in Abhängigkeit von der Weichmacherkonzentration kaum an Flexibilität zunimmt, so daß die Lackierung ohne Weichmacher durchgeführt werden kann.Diethyl phthalate, dibutyl phthalate, acetyl tributyl citrate, triethyl citrate, glycerol acetate, glycerol, castor oil, 1,2-propylene glycol, polyethylene glycol. Mixtures of these plasticizers are also possible. 2. Use of a coating polymer, which hardly increases in flexibility depending on the plasticizer concentration, so that the coating can be carried out without a plasticizer.
Zu diesen Polymeren gehören:These polymers include:
Gelatine, Pektin, Traganth, Gummi arabicum, MethylcelluloseGelatin, pectin, tragacanth, gum arabic, methyl cellulose
3. Bei Arzneiformulierungen, die einen derart starken kalten Fluß aufweisen, daß eine Formstabilität nicht über den Zeit¬ raum 1 Woche oder 1 Monat gegeben ist, wurde folgende Vorge¬ hensweise zur mechanischen Stabilisierung gefunden:3. The following procedure for mechanical stabilization has been found in pharmaceutical formulations which have such a strong cold flow that there is no dimensional stability over a period of 1 week or 1 month:
Im ersten Schritt werden die Formlinge mit einem Coating wie unter 1 oder 2 beschrieben überzogen und somit ausreichend verfestigt.In the first step, the moldings are coated with a coating as described under 1 or 2 and thus sufficiently solidified.
In einem zweiten Arbeitschritt wird ein weichmacherhaltiges Coating, ggf. ein Funktionsüberzug, aufgetragen, das Weichma- cheranteile enthält, wie sie pharmazeutisch üblich sind.In a second step, a plasticizer-containing coating, possibly a functional coating, is applied, which contains plasticizer components, as are common in pharmaceutics.
Durch das Aufbringen eines solchen Doppelcoatings werden 2 wesentliche Effekte erzielt.By applying such a double coating, 2 essential effects are achieved.
Zunächst wird eine insgesamt stärkere mechanische Verfesti- gung erzielt und außerdem wird es möglich, den Formung mit einem Funktionüberzug (magensaftresistentes Coating, Diffu- sionscoating, speichelresistentes Coating) zu überziehen. Der Funktionsüberzug wird durch die 2. Schicht repräsentiert. Der Funktionsüberzug ist vor zusätzlich einmigrierenden weichma- chenden Komponenten aus dem Formung geschützt und kann so über die vorgesehene Lagerzeit seine Funktion und Qualität bewahren.First of all, a stronger mechanical solidification is achieved and it is also possible to cover the forming with a functional coating (enteric coating, diffusion coating, saliva-resistant coating). The functional covering is represented by the 2nd layer. The functional cover is protected against additional, migrating, softening components from the molding and can thus retain its function and quality over the intended storage period.
Die Aufbringung der Coating-Schichten erfolgt in der bekannten Weise. The coating layers are applied in the known manner.
Beispiel 1example 1
Extrusionstablette:Extrusion tablet:
Acetylsalicylsäure 500 mg Kollidon VA 64* 400 mgAcetylsalicylic acid 500 mg Kollidon VA 64 * 400 mg
Mannitol 100 mgMannitol 100 mg
* Copolymerisat aus N-Vinylpyrrolidon und Vinylacetat * Copolymer of N-vinyl pyrrolidone and vinyl acetate
mechn. stabilisierender Lacküberzug, 1-schichtig:mechan. stabilizing lacquer coating, 1-layer:
HydroxypropylmethylcelluloseHydroxypropylmethyl cellulose
(Pharmacoat 603) 7 mg Hydroxypropylmethylcellulose(Pharmacoat 603) 7 mg hydroxypropylmethyl cellulose
(Pharmacoat 615) 0,7 mg(Pharmacoat 615) 0.7 mg
Macrogol 6000 (Polyethylenglykol) 0,070 mgMacrogol 6000 (polyethylene glycol) 0.070 mg
Docusat-Natrium (Na-Laurylsulfat) 0,018 mgDocusate sodium (Na lauryl sulfate) 0.018 mg
Titandioxid E 171 1,840 mgTitanium dioxide E 171 1.840 mg
Eisenoxidgelb E 172 0,012 mgIron oxide yellow E 172 0.012 mg
Talcum 0, 492 mgTalcum 0.492 mg
Aerosil 0,018 mgAerosil 0.018 mg
Die mechanische Stabilität ist mit Überzug gewährleistet über 3 Jahre bei <.30°C. Bei 30°C ist die Tablette nach 4 Monaten Lagerzeit verformt, wenn kein Lacküberzug verwendet wird.The mechanical stability is guaranteed with a coating over 3 years at <.30 ° C. At 30 ° C, the tablet is deformed after 4 months of storage if no lacquer coating is used.
Beispiel 2Example 2
Extrusionstablette:Extrusion tablet:
Fenofibrat 250 mgFenofibrate 250 mg
Kollidon VA 64 150 mgKollidon VA 64 150 mg
Klucel EF (Hydroxypropylmethyl¬ 200 mg cellulose)Klucel EF (hydroxypropylmethyl 200 mg cellulose)
mechn. stabilisierender Lacküberzug, 1-schichtig als Difussions- barriere Ethylcellulose Dispersion 30 mg (Feststoffanteil) Triethylcitrat 24 % 1,2 mgmechan. stabilizing lacquer coating, 1-layer as diffusion barrier ethyl cellulose dispersion 30 mg (solid content) triethyl citrate 24% 1.2 mg
Die mechanische Stabilität der überzogenen Pellets kann für 3 Jahre bei bis + 30°C garantiert werden. Ohne Lacküberzug verfor- men sich die Pellets und verkleben nach 2 Monaten, gelagert bei + 30°C. Bei einem Triethylcitratgehalt von 22 mg (zu 80 mg Ethyl¬ cellulose Dispersion), dies entspricht der pharmazeutisch übli- chen Konzentration bei der Verarbeitung des Lacks, erfolgt dieThe mechanical stability of the coated pellets can be guaranteed for 3 years at up to + 30 ° C. Without coating, the pellets deform and stick after 2 months, stored at + 30 ° C. With a triethyl citrate content of 22 mg (to 80 mg ethyl cellulose dispersion), this corresponds to the pharmaceutically Chen concentration in the processing of the paint, the
Verformung der Pellets nach 4,5 Monaten bei + 30°C.Deformation of the pellets after 4.5 months at + 30 ° C.
Beispiel 3Example 3
Extrusionstablette:Extrusion tablet:
Naftidrofuryl 100 mgNaftidrofuryl 100 mg
Kollidon VA 64 30 mgKollidon VA 64 30 mg
Klucel EF 50 mgKlucel EF 50 mg
mechn. stabilisierender Lacküberzug, 1-schichtig als Diffusionsbarrieremechan. stabilizing lacquer coating, 1-layer as diffusion barrier
Ethylcellulose 11 mg Talcum 15 mgEthylcellulose 11 mg Talcum 15 mg
Dibutylphthalat 0,35 mgDibutyl phthalate 0.35 mg
Die mechanische Stabilität ist mit Lacküberzug für > 3 Jahre bei bis + 30°C gegeben. Ohne Lacküberzug verformt sich die Tablette bei + 30°C nach 7 Monaten.The mechanical stability is given with a varnish coating for> 3 years at up to + 30 ° C. Without a coating, the tablet deforms at + 30 ° C after 7 months.
Beispiel 4Example 4
Extrusionstablette:Extrusion tablet:
Ibuprofen 200 mgIbuprofen 200 mg
Kollidon VA 64 500 mgKollidon VA 64 500 mg
D(-)-Mannit 300 mgD (-) - mannitol 300 mg
1. Stabilisierender Lacküberzug1. Stabilizing lacquer coating
Schicht HPMC-Lack, weichmacherfrei Hydroxypropylmethylcellulose (Pharmacoat 603) 3,5 mgLayer of HPMC lacquer, plasticizer-free hydroxypropylmethyl cellulose (Pharmacoat 603) 3.5 mg
Hydroxypropylmethylcellulose (Pharmacoat 615) 0,35 mgHydroxypropylmethyl cellulose (Pharmacoat 615) 0.35 mg
Docusat-Natrium 0,018 mgDocusate sodium 0.018 mg
Aerosil 0,018 mg 2. FunktionsüberzugAerosil 0.018 mg 2. Functional covering
Schicht HPMC-Lack, weichmacherhaltigLayer of HPMC lacquer, contains plasticizer
HydroxypropylmethylcelluloseHydroxypropylmethyl cellulose
(Pharmacoat 603) 3,5 mg(Pharmacoat 603) 3.5 mg
HydroxypropylmethylcelluloseHydroxypropylmethyl cellulose
(Pharmacoat 615) 0,350 mg(Pharmacoat 615) 0.350 mg
Hydroxypropylcellulose 0,700 mg Macrogol 400 1,08 mgHydroxypropyl cellulose 0.700 mg macrogol 400 1.08 mg
Macrogol 6000 0,190 mgMacrogol 6000 0.190 mg
Docusat Natrium 0,018 mgDocusat sodium 0.018 mg
Titandioxid 1,8 mg Eisenoxidgelb 0,015 mgTitanium dioxide 1.8 mg iron oxide yellow 0.015 mg
Talcum 0,500 mgTalcum 0.500 mg
Aerosil 0,02 mgAerosil 0.02 mg
Die mechanische Stabilität mit dem stabilisierenden Überzug ist bei einer Lagertemperatur von < + 30°C für > 3 Jahre gegeben, ohne den stabilisierenden Überzug lediglich 1,5 Monate.The mechanical stability with the stabilizing coating is given at a storage temperature of <+ 30 ° C for> 3 years, without the stabilizing coating only 1.5 months.
Beispiel 5 Extrusionstablette:Example 5 Extrusion Tablet:
Furosemid 500 mgFurosemide 500 mg
Kollidon VA 64 400 mgKollidon VA 64 400 mg
Mannitol 50 mgMannitol 50 mg
mechn. stabilisierender Lacküberzug, 1-schichtig:mechan. stabilizing lacquer coating, 1-layer:
Methylcellulose 18 mgMethyl cellulose 18 mg
Docusat-Natrium 0,01 mg Titandioxid 2,00 mgDocusate sodium 0.01 mg titanium dioxide 2.00 mg
Talcum 0, 85 mgTalcum 0.85 mg
Aerosil 0,01 mgAerosil 0.01 mg
Die mit Methylcellulose überzogenen Tabletten sind mehr als 3 Jahre stabil bei einer Lagertemperatur bis + 30°C. Ohne Lack¬ überzug sind die Tabletten bereits nach 2 1/2 Wochen stark ver¬ formt. Beispiel 6The tablets coated with methyl cellulose are stable for more than 3 years at a storage temperature of up to + 30 ° C. Without a lacquer coating, the tablets are severely deformed after just 2 1/2 weeks. Example 6
Extrusionstablette:Extrusion tablet:
Anipamil 80 mg Kollidon VA 64 100 mg Klucel EF 70 mgAnipamil 80 mg Kollidon VA 64 100 mg Klucel EF 70 mg
mechn. stabilisierender Lacküberzugmechan. stabilizing lacquer coating
Methylcellulose 6 mg Docusat-Natrium 0,005 mg Aerosil 0,005 mg 2 Weichmacherhaltiger FunktionsüberzugMethyl cellulose 6 mg docusate sodium 0.005 mg Aerosil 0.005 mg 2 Functional coating containing plasticizer
HydroxypropylmethylcelluloseHydroxypropylmethyl cellulose
Pharmacoat 603 7 mg HydroxypropylmethylcellulosePharmacoat 603 7 mg hydroxypropylmethyl cellulose
Pharmacoat 615 0,7 mgPharmacoat 615 0.7 mg
Hydroxypropylcellulose 0,7 mgHydroxypropyl cellulose 0.7 mg
Macrogol 400 1,08 mgMacrogol 400 1.08 mg
Macrogol 6000 0,190 mgMacrogol 6000 0.190 mg
Docusat Natrium 0,018 mgDocusat sodium 0.018 mg
Titandioxid 1,8 mgTitanium dioxide 1.8 mg
Eisenoxidgelb 0,015 mgIron oxide yellow 0.015 mg
Talcum 0,500 mgTalcum 0.500 mg
Aerosil 0,02 mgAerosil 0.02 mg
Die mechanische Stabilität mit dem stabilisierenden Überzug ist bei einer Lagertemperatur von <. + 30°C für > 3 Jahre gegeben. Die nichtüberzogene Tablette zerfließt innerhalb einer Woche bei +30°C.The mechanical stability with the stabilizing coating is at a storage temperature of <. + 30 ° C for> 3 years. The uncoated tablet dissolves within a week at + 30 ° C.
Beispiel 7 Extrusionstablette:Example 7 Extrusion Tablet:
Indometacin 50 mg Kollidon VA 64 110 mg Klucel EF 80 mg Mannit 50 mg 1. mechn. stabilisierender LacküberzugIndomethacin 50 mg Kollidon VA 64 110 mg Klucel EF 80 mg mannitol 50 mg 1. mechan. stabilizing lacquer coating
Methylcellulose 6 mg Docusat-Natrium o, , 005 mgMethyl cellulose 6 mg docusate sodium o. 005 mg
Aerosil o, , 005 mg magensaftresistenter Funtion lsöü LubJeτSrzugAerosil o., 005 mg gastro-resistant function lsöü LubJeτSrzug
Eudragit L30D 20 mg Triethylcitrat 6 mg Titandioxid 2 , 68 mg Talcum 10 mgEudragit L30D 20 mg triethyl citrate 6 mg titanium dioxide 2, 68 mg talcum 10 mg
Antischaumemulsion 0 , 56 mg Aromastoff 0 , 76 mgAntifoam emulsion 0.56 mg aroma 0.76 mg
Die Stabilität der mit Lack überzogenen Indometacin-Tablette ist bei einer Lagertemperatur bis + 30°C über 3 Jahre garantiert. Ohne Lacküberzug zerfließt die Tablette innerhalb von 3 Wochen Lager¬ zeit bei + 30°C. The stability of the coated indomethacin tablet is guaranteed for 3 years at a storage temperature of up to + 30 ° C. Without a coating, the tablet dissolves within 3 weeks of storage at + 30 ° C.

Claims

Patentansprüche claims
1. Mechanisch stabile, feste WirkstoffZubereitungsformen, die mindestens einen Wirkstoff und mindestens ein Polymer enthal¬ ten und die mit einem Überzug versehen sind, dadurch gekenn¬ zeichnet, daß der Überzug einen Weichmacheranteil von 0 bis 15 Gew.-% aufweist.1. Mechanically stable, solid active substance preparation forms which contain at least one active substance and at least one polymer and which are provided with a coating, characterized in that the coating has a plasticizer content of 0 to 15% by weight.
2. WirkstoffZubereitungsformen nach Anspruch 1, dadurch gekenn¬ zeichnet, daß der Überzug ein- oder mehrschichtig ist.2. active ingredient preparation forms according to claim 1, characterized gekenn¬ characterized in that the coating is one or more layers.
3. WirkstoffZubereitungsformen nach Anspruch 1, dadurch gekenn¬ zeichnet, daß der Wirkstoff in Form einer molekulardispersen Verteilung in einer Polymermatrix vorliegt .3. active ingredient preparation forms according to claim 1, characterized gekenn¬ characterized in that the active ingredient is in the form of a molecularly disperse distribution in a polymer matrix.
4. WirkstoffZubereitungsformen nach Anspruch 1, dadurch gekenn¬ zeichnet, daß der Weichmacheranteil im Überzug 0 bis4. active ingredient preparation forms according to claim 1, characterized gekenn¬ characterized in that the plasticizer content in the coating 0 to
10 Gew.-% beträgt.Is 10% by weight.
5. WirkstoffZubereitungsformen nach Anspruch 1, dadurch gekenn¬ zeichnet, daß der Wirkstoff ein Pharmawirkstoff ist.5. active ingredient preparation forms according to claim 1, characterized gekenn¬ characterized in that the active ingredient is a pharmaceutical ingredient.
6. WirkstoffZubereitungsformen nach Anspruch 1, dadurch gekenn- zeichnet, daß sie über dem ersten, weichmacherfreien oder weichmacherarmen Überzug einen oder mehrere Funktionsüberzüge aufweisen. 6. Active ingredient preparation forms according to claim 1, characterized in that they have one or more functional coatings over the first, plasticizer-free or low-plasticizer coating.
Mechanisch stabile feste WirkstoffZubereitungsformenMechanically stable solid active ingredient preparation forms
ZusammenfassungSummary
Mechanisch stabile, feste WirkstoffZubereitungsform mit einem weichmacherfreien oder weichmacherarmen Überzug. Mechanically stable, solid active ingredient preparation form with a plasticizer-free or low-plasticizer coating.
PCT/EP1996/001156 1995-03-27 1996-03-18 Mechanically stable solid formulations of active substances WO1996029994A1 (en)

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DE19511131.1 1995-03-27
DE1995111131 DE19511131A1 (en) 1995-03-27 1995-03-27 Mechanically stable solid active substance preparation forms

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WO1998056355A1 (en) * 1997-06-12 1998-12-17 Hexal Ag Controlled release pharmaceutical preparation with ace inhibitor as active agent
US5902632A (en) * 1995-01-31 1999-05-11 Mehta; Atul M. Method of preparation of controlled release nifedipine formulations
US9089492B2 (en) 2000-11-20 2015-07-28 Warner Chilcott Company, Llc Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures

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IT1311915B1 (en) * 1999-04-12 2002-03-20 Pharmexcel S R L RANITIDINE HYDROCHLORIDE ANHYDROUS TABLET WITH DOUBLE-LAYER COATING AND ITS COMPOSITION.
WO2008110534A1 (en) * 2007-03-13 2008-09-18 Sandoz Ag Pharmaceutical compositions of poorly soluble drugs

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5902632A (en) * 1995-01-31 1999-05-11 Mehta; Atul M. Method of preparation of controlled release nifedipine formulations
WO1998056355A1 (en) * 1997-06-12 1998-12-17 Hexal Ag Controlled release pharmaceutical preparation with ace inhibitor as active agent
AU736357B2 (en) * 1997-06-12 2001-07-26 Hexal Ag Controlled-release pharmaceutical preparation comprising an ACE inhibitor as active ingredient
US6267990B1 (en) 1997-06-12 2001-07-31 Hexal Ag Controlled-release pharmaceutical preparation comprising an ACE inhibitor as active ingredient
US9089492B2 (en) 2000-11-20 2015-07-28 Warner Chilcott Company, Llc Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures

Also Published As

Publication number Publication date
AU5145396A (en) 1996-10-16
DE19511131A1 (en) 1996-10-02

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