WO2001000175A1 - Mechanically stable pharmaceutical dosage forms, containing liquid or semi-solid surface-active substances - Google Patents
Mechanically stable pharmaceutical dosage forms, containing liquid or semi-solid surface-active substances Download PDFInfo
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- WO2001000175A1 WO2001000175A1 PCT/EP2000/005494 EP0005494W WO0100175A1 WO 2001000175 A1 WO2001000175 A1 WO 2001000175A1 EP 0005494 W EP0005494 W EP 0005494W WO 0100175 A1 WO0100175 A1 WO 0100175A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
Definitions
- the present invention relates to preparations in the form of solid solutions of active pharmaceutical ingredients in an excipient matrix, the excipient matrix containing as a polymer component a homo- or copolymer of N-vinylpyrrolidone, and 2 to 40% by weight of a surface-active substance with an HLB value of 2 to 18, which is liquid at 20 ° C, or has a dropping point in the range from 20 to 50 ° C.
- a polymer component a homo- or copolymer of N-vinylpyrrolidone
- EP-A 240 904 or EP-A 240 906 enables targeted control of the properties of the formulations to be produced by targeted selection or defined blends of the auxiliaries used.
- suitable matrix polymers it is possible, for example, to prepare preparations that continuously release the active ingredient over a longer period of time. On the other hand, it may be desirable e.g. to achieve a rapid dissolution with rapid release of the active substance in pain relievers.
- the melt extrusion process has proven to be suitable for the production of both quick-release and slow-release preparation forms.
- the absorption of the active substance is only possible if it is present in solution, since only dissolved active substances can pass through the intestinal wall. In the case of poorly soluble active ingredients, this can lead to insufficient absorption and the associated low bioavailability.
- solid dispersions only has a positive influence on the bioavailability of the active ingredient if the active ingredient is also rapidly absorbable.
- the poorly soluble active ingredient recrystallizes in the aqueous environment of the intestinal lumen, since a supersaturated active ingredient solution can result from the dissolution of the pharmaceutical form. For this reason, unsatisfactory bioavailability can often only be achieved with solid dispersions.
- the present invention was therefore based on the object of finding mechanically stable solid preparation forms for oral use which, in particular in the case of poorly soluble active ingredients, can serve for a rapid and nevertheless long-lasting solubilization after their liberation from the pharmaceutical form.
- a solid solution is present when the active substance is essentially molecularly dispersed in the polymer matrix (J. Pharm. Sei. 60, 1281-1302, 1971).
- Suitable active substances are, in particular, antidiabetic agents, anti-asthmatics, hormones, in particular steroid hormones, immunosuppressants, protease inhibitors, reverse transcriptase inhibitors, cytostatics or antifungals, and also CNS-active substances or dihydropyrimidine derivatives.
- poorly soluble or difficultly bioavailable active ingredients can be formulated according to the invention.
- Slightly soluble means that the solubility in water at 25 ° C is below 1 mg / ml.
- active ingredients are also referred to as hardly soluble or practically insoluble.
- Poorly soluble active ingredients are, for example, esupron, nifedipine, nimodipine, ciclosporin or taxol.
- Suitable surface-active substances are preferably low-molecular substances which are liquid at 20 ° C. or have a dropping point in the range from above 20 ° C. to 50 ° C., preferably up to 40 ° C. Substances with an HLB value of 7 to 18, particularly preferably 10 to 15, are preferred.
- Suitable surface-active substances are, for example, saturated and unsaturated polyglycolized glycerides, semisynthetic glycerides, fatty acid esters or ethers of fatty alcohols, provided that they have the properties indicated above.
- sorbitan fatty acid esters or ethoxylated sorbitan fatty acid esters such as, for example, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, are particularly suitable.
- Macrogol-6-cetylstearyl ether or are also suitable
- Polyoxyethylene glycerol ricinoleate-35 are particularly preferred.
- the surface-active substances are contained in the preparations in amounts of at least 2% by weight, based on the total weight of the preparation, and up to 40% by weight, preferably 5 to 25% by weight and particularly preferably 10 to 25% by weight. -%.
- the preparations according to the invention also contain at least one thermoplastically processable polymeric matrix auxiliary.
- thermoplastically processable polymeric matrix auxiliary water-soluble homo- and copolymers of N-vinylpyrrolidone such as polyvinylpyrrolidone with K values according to Fikentscher from 12 to 100, in particular K 17 to K 30, or copolymers with carboxylic acid vinyl esters such as vinyl acetate or vinyl propionate, particularly preferably copovidones (VP / VAc-60/40), a copolymer of 60% by weight of N-vinylpyrrolidone and 40% by weight of vinyl acetate.
- N-vinylpyrrolidone such as polyvinylpyrrolidone with K values according to Fikentscher from 12 to 100, in particular K 17 to K 30, or copolymers with carboxylic acid vinyl esters such as vinyl acetate or vinyl propionate, particularly preferably copovidones (VP / VAc-60/40), a copoly
- the preparations can also contain up to 10% by weight of hydroxyalkyl-alkylcelluloses which swell in water, for example hydroxypropylmethylcellulose (HPMC), preferably those with degrees of methoxy substitution in the range of 22% and degrees of hydroxypropoxy in the range of 8%, especially preferred HPMC types with viscosities of 4000 mPas, lbUUU mpas or 100000 mPas, measured at 20 ° C in 2 wt .-% aqueous solution. HPMC types with degrees of methoxy substitution in the range from 28 to 29% and hydroxypropoxy degrees of substitution in the range from 5 to 8.5% are also suitable.
- HPMC hydroxypropylmethylcellulose
- polymeric matrix auxiliary The amounts of polymeric matrix auxiliary depend on the amount of active ingredient and surface-active substance used.
- the preparations may also contain conventional pharmaceutical auxiliaries such as flavors, antioxidants, silicas, mold release agents or colorants in the amounts customary for this.
- Preparations containing 15 to 65% by weight of copovidones, 5 to 25% by weight of polyoxyethylene glycerol trihydroxystearate, 0 to 10% by weight of hydroxypropylmethyl cellulose and 5 to 65% by weight of active compound are particularly preferred according to the invention.
- the preparations according to the invention are produced by a melt process.
- the process is preferably carried out without the addition of solvents.
- the melting process is carried out in a kneader or a screw extruder.
- Suitable kneaders are, for example, 25 kneaders from Haake or Farrell.
- the melt is preferably produced in a screw extruder, particularly preferably a twin-screw extruder with and without kneading disks or similar mixing elements. 30 Double-screw extruders rotating in the same direction are particularly preferred.
- processing is generally carried out at temperatures of 40 ° C. to 260 ° C., preferably 35 50 to 200 ° C.
- the feed materials can be fed to the extruder or kneader individually or as a premix.
- the addition is preferably in the form of powdered or granulated premixes. So can
- the liquid or oily surface-active substance is previously mixed with another feed material to form a free-flowing granulate. It is also possible to add the surface-active substance in liquid form, for example via liquid pumps, which are preferably heated in the case of semi-solid substances
- the starting materials are accordingly processed together to form a melt, which is processed into a homogeneous mass by introducing mechanical energy, in particular in the form of shear forces.
- the homogeneous melt is then extruded through a die or perforated plate and subjected to shaping.
- This can be done by knocking off the extrudate emerging in the form of a strand using the usual knock-off techniques, for example using rotating knives or by knocking off compressed air, resulting in pellets or granules.
- the shaping can be carried out as described in EP-A 240 906, in that the extrudate emerging in the form of a strand is guided between two counter-rotating calender rolls and shaped directly into tablets.
- the melt can be drawn out via the open extruder head and, if necessary, can be ground after solidification or can be further processed by suitable granulating devices such as roller mills or compacting units.
- Granules or pellets can then be processed into tablets in conventional tablet presses. It is also possible to subject the preparations already obtained in the form of mechanically stable tablets to a milling process and then to compress them into tablets in a conventional manner. If desired, the tablets can then be provided with a conventional coating.
- tablets can be obtained according to the invention which have good mechanical stability even with high proportions of liquid or semi-solid surface-active substances and do not tend to stickiness or softening.
- Filling into capsules can be dispensed with according to the invention due to the good dimensional stability of the preparations.
- the resulting pharmaceutical forms contain the active ingredient in the form of solid solutions in which the active ingredient is present in molecularly dispersed form.
- the pharmaceutical forms according to the invention make it possible to sufficiently solubilize even poorly soluble active ingredients or to disperse them stably in the auxiliary matrix in an aqueous medium.
- the preparations according to the invention After dissolving in an aqueous medium, in particular at a pH of 1, the preparations according to the invention form a stable solubilizate or a stable dispersion for at least one hour, in which the active ingredient is preferably non-crystalline. Due to their better solubility compared to conventional formulations, the preparations have an improved bioavailability.
- a powder mixture of nimodipine and copovidone was placed in a Diosna mixer and mixed with polyoxyethylene trihydroxy stearate-40.
- the mixture obtained in this way which consisted of 12% by weight of nimodipine, 78% by weight of copovidone and 10% by weight of polyoxyethylene glycerol trihydroxystearate-40, was fed via a metering scale into a twin-screw extruder of the type ZKS-30 (Werner & Pfleiderer ) with heated shots.
- a vacuum of 200 mbar was applied in the penultimate shot.
- the strand emerging from the nozzle was passed between two counter-rotating calender rolls provided with lenticular depressions and calendered into lenticular tablets weighing 250 mg.
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Abstract
Description
Mechanisch stabile pharmazeutische Darreichungsformen, enthaltend flüssige oder halbfeste oberflächenaktive SubstanzenMechanically stable pharmaceutical dosage forms containing liquid or semi-solid surface-active substances
Beschreibungdescription
Die vorliegende Erfindung betrifft Zubereitungen in Form fester Lösungen von pharmazeutischen Wirkstoffen in einer Hilfsstoffmatrix, wobei die Hilfsstoffmatrix als polymeren Bestandteil ein Homo- oder Copolymer des N-Vinylpyrrolidons enthält, sowie 2 bis 40 Gew.-% einer oberflächenaktiven Substanz mit einem HLB-Wert von 2 bis 18, welche bei 20°C flüssig ist, oder einen Tropfpunkt im Bereich von 20 bis 50°C aufweist. Weiterhin wurde ein Verfahren zur Herstellung solcher Formen gefunden.The present invention relates to preparations in the form of solid solutions of active pharmaceutical ingredients in an excipient matrix, the excipient matrix containing as a polymer component a homo- or copolymer of N-vinylpyrrolidone, and 2 to 40% by weight of a surface-active substance with an HLB value of 2 to 18, which is liquid at 20 ° C, or has a dropping point in the range from 20 to 50 ° C. We have also found a method for producing such molds.
Die Herstellung pharmazeutischer Zubereitungen nach dem Schmelzextrusionsverfahren ist an sich bekannt. So ermöglicht das beispielsweise in der EP-A 240 904 oder der EP-A 240 906 beschriebene Verfahren durch gezielte Auswahl bzw. definierte Abmischungen der eingesetzten Hilfsstoffe eine gezielte Steuerung der Eigenschaften der herzustellenden Formulierungen.The production of pharmaceutical preparations by the melt extrusion process is known per se. For example, the method described in EP-A 240 904 or EP-A 240 906 enables targeted control of the properties of the formulations to be produced by targeted selection or defined blends of the auxiliaries used.
Durch Auswahl geeigneter Matrixpolymere lassen sich zum Beispiel Zubereitungen herstellen, die den Wirkstoff über einen längeren Zeitraum kontinuierlich freisetzen. Andererseits kann es erwünscht sein, z.B. bei Schmerzmitteln eine rasche Auflösung mit schneller Freisetzung des Wirkstoffs zu erzielen. Sowohl für die Herstellung von schnell freisetzenden wie auch von langsam freisetzenden Zubereitungsformen hat sich das Schmelzextrusions- verfahren als geeignet erwiesen.By selecting suitable matrix polymers, it is possible, for example, to prepare preparations that continuously release the active ingredient over a longer period of time. On the other hand, it may be desirable e.g. to achieve a rapid dissolution with rapid release of the active substance in pain relievers. The melt extrusion process has proven to be suitable for the production of both quick-release and slow-release preparation forms.
Eine Grundvoraussetzung ist allerdings ein ausreichendes Auflösungsvermögens des Wirkstoffs im wäßrigen Milieu des Verdauungstrakts. Die Resorption des Wirkstoffs ist nur dann möglich, wenn dieser gelöst vorliegt, da nur gelöste Wirkstoffe die Darmwand passieren können. Im Falle schwerlöslicher Wirkstoffe kann dies zu ungenügender Resorption und damit verbundener niedriger Bioverfügbarkeit führen.A basic requirement, however, is a sufficient dissolution capacity of the active substance in the aqueous environment of the digestive tract. The absorption of the active substance is only possible if it is present in solution, since only dissolved active substances can pass through the intestinal wall. In the case of poorly soluble active ingredients, this can lead to insufficient absorption and the associated low bioavailability.
Es hat nicht an Versuchen gefehlt, die Bioverfügbarkeit schwerlöslicher Wirkstoffe zu verbessern (vgl. R. Voigt; "Pharmazeutische Technologie", Verlag Ullstein Mosby, 7. Auflage, 1993, Seiten 80-85) . Insbesondere die Herstellung von Coevaporaten oder sogenannten festen Dispersionen, in denen der Wirkstoff mole- kulardispers in einer Hilfsstoffmatrix verteilt vorliegt, hat sich häufig als vorteilhaft für die Erhöhung der Bioverfügbarkeit erwiesen. Bei der Aurlösung der Arzneiform im Körper Kann αer Wirkstoff aus solchen festen Dispersionen direkt und ohne Aufbringen von Solvatationsenergie molekular freigesetzt werden.There has been no lack of attempts to improve the bioavailability of poorly soluble active ingredients (cf. R. Voigt; "Pharmaceutical Technology", Verlag Ullstein Mosby, 7th edition, 1993, pages 80-85). In particular, the production of coevaporates or so-called solid dispersions, in which the active substance is present in a molecularly dispersed manner in an auxiliary matrix, has often proven advantageous for increasing the bioavailability proved. When the pharmaceutical form is dissolved in the body, the active substance can be released molecularly from such solid dispersions directly and without applying solvation energy.
Einen positiven Einfluß auf die Bioverfügbarkeit des Wirkstoffs hat die Anwendung von festen Dispersionen aber nur, wenn der Wirkstoff auch schnell resorbierbar ist. Ist der Resorptionsvorgang aber langsam, kommt es zu einer Rekristallisation des schwerlöslichen Wirkstoffs im wäßrigen Milieu des Darmlumens, da bei der Auflösung der Arzneiform eine übersättigte Wirkstofflösung entstehen kann. Aus diesem Grund sind auch mit festen Dispersionen häufig nur unbefriedigende Bioverfügbarkeiten zu erzielen.However, the use of solid dispersions only has a positive influence on the bioavailability of the active ingredient if the active ingredient is also rapidly absorbable. However, if the resorption process is slow, the poorly soluble active ingredient recrystallizes in the aqueous environment of the intestinal lumen, since a supersaturated active ingredient solution can result from the dissolution of the pharmaceutical form. For this reason, unsatisfactory bioavailability can often only be achieved with solid dispersions.
Oft scheitert die ausreichende Resorption des Wirkstoffs auch daran, daß der Wirkstoff zu langsam aus der Tablette freigesetzt wird. Die Resorption in die Blutzirkulation findet für den überwiegenden Teil aller Wirkstoffe in den oberen Dünndarm- Abschnitten statt, d.h. relativ kurz nach Passage des Magens. Wirkstoffe, die in diesem Bereich des Dünndarms noch nicht ausreichend solubilisiert wurden, können nur noch begrenzt resorbiert werden.Sufficient absorption of the active ingredient often fails because the active ingredient is released from the tablet too slowly. The absorption into the blood circulation takes place for the majority of all active substances in the upper sections of the small intestine, i.e. relatively shortly after passage of the stomach. Active substances that have not yet been sufficiently solubilized in this area of the small intestine can only be absorbed to a limited extent.
Zur Erzielung optimaler Resorptionsraten ist es daher ent- scheidend, insbesondere bei schwerlöslichen, leicht kristallisierenden Wirkstoffen eine schnelle und genügend lang andauernde Solubilisierung im wäßrigen Milieu des Verdauungstrakts zu erreichen, ohne daß dabei eine Rekristallisation eintritt.To achieve optimal absorption rates, it is therefore crucial, especially with poorly soluble, easily crystallizing active ingredients, to achieve rapid and sufficiently long-lasting solubilization in the aqueous environment of the digestive tract without recrystallization occurring.
Hierzu bietet sich der Zusatz oberflächenaktiver Substanzen an. Die Zugabe von oberflächenaktiven Substanzen zu Formulierungen schwerlöslicher Wirkstoffe ist an sich allgemein bekannt.The addition of surface-active substances lends itself to this. The addition of surface-active substances to formulations of poorly soluble active substances is generally known.
Aus der US-A 5,834,472 ist beispielsweise bekannt, daß durch Mitverwendung einer nichtionischen oberflächanaktiven Substanz die Bioverfügbarkeit eines Antimykotiku s verbessert werden kann.From US-A 5,834,472 it is known, for example, that the bioavailability of an antifungal can be improved by the use of a nonionic surface-active substance.
Da die meisten der oberflächenaktiven Substanzen bei Raumtemperatur aber flüssig oder halbfest sind, werden daher bisher meist flüssig-ölige oder halbfeste Zubereitungen hergestellt, die dann in Hart- oder Weichgelatine-Kapseln abgefüllt werden. Jedoch treten bei Weichgelatine-Kapseln häufig Wechselwirkungen zwischen Hilfsstoffen und der Gelatinehülle der Kapsel auf, die zum vorzeitigen Auslaufen der Kapsel führen. Auch der Einsatz der oberflächenaktiven Substanzen in Tabletten- Formulierungen ist nicht ohne weiteres möglich, da die flüssigen oder halbfesten oberfächenaktiven Substanzen die Verpreßbarkeit beim konventionellen Tablettierprozeß verhindern, insbesondere dann, wenn zur Solubilisierung des Wirkstoffs größere Mengen an oberflächenaktiven Substanzen benötigt werden.However, since most of the surface-active substances are liquid or semi-solid at room temperature, liquid-oily or semi-solid preparations have so far mostly been produced, which are then filled into hard or soft gelatin capsules. However, soft gelatin capsules often cause interactions between additives and the gelatin shell of the capsule, which lead to premature leakage of the capsule. The use of the surface-active substances in tablet formulations is also not readily possible, since the liquid or semi-solid surface-active substances prevent compressibility in the conventional tabletting process, in particular when larger amounts of surface-active substances are required to solubilize the active substance.
Der vorliegenden Erfindung lag daher die Aufgabe zugrunde, mechanisch stabile feste Zubereitungsformen für die perorale Anwendung zu finden, die insbesondere bei schwerlöslichen Wirkstoffen zu einer schnellen und trotzdem langanhaltenden Solubilisierung nach deren Liberation aus der Arzneiform dienen können.The present invention was therefore based on the object of finding mechanically stable solid preparation forms for oral use which, in particular in the case of poorly soluble active ingredients, can serve for a rapid and nevertheless long-lasting solubilization after their liberation from the pharmaceutical form.
Demgemäß wurden die eingangs definierten pharmazeutischen Zubereitungsformen und ein Verfahren zu deren Herstellung gefunden.Accordingly, the pharmaceutical preparation forms defined at the outset and a process for their preparation have been found.
Eine feste Lösung liegt dann vor, wenn der Wirkstoff im wesentlichen molekulardispers in der Polymermatrix verteilt ist (J. Pharm. Sei. 60, 1281-1302, 1971).A solid solution is present when the active substance is essentially molecularly dispersed in the polymer matrix (J. Pharm. Sei. 60, 1281-1302, 1971).
Als Wirkstoffe können prinzipiell alle pharmazeutischen Substanzen für den Human- wie den Veterinärbereich sowie Wirkstoffe, die in der Nahrungsmittelergänzung Anwendung finden, eingesetzt werden.In principle, all pharmaceutical substances for human and veterinary use as well as active substances used in food supplements can be used as active substances.
Als geeignete Wirkstoffe kommen vor allem Antidiabetika, Antiasthmatika, Hormone, insbesondere Steroidhormone, Immun- suppressiva, Protease-Inhibitoren, Reverse-Transkriptase- Inhibitoren, Cytostatica oder Antimykotika in Betracht, weiterhin auch ZNS-aktive Wirkstoffe oder Dihydropyrimidinderivate .Suitable active substances are, in particular, antidiabetic agents, anti-asthmatics, hormones, in particular steroid hormones, immunosuppressants, protease inhibitors, reverse transcriptase inhibitors, cytostatics or antifungals, and also CNS-active substances or dihydropyrimidine derivatives.
Insbesondere lassen sich erfindungsgemäß schwerlösliche oder schwer bioverfügbare Wirkstoffe formulieren. Schwerlöslich bedeutet, daß die Löslichkeit in Wasser bei 25°C unter 1 mg/ml liegt. Solche Wirkstoffe werden gemäß USP XXII, Seite 8, auch als kaum löslich oder praktisch unlöslich bezeichnet. Schwerlösliche Wirkstoffe sind beispielsweise Esupron, Nifedipin, Nimodipin, Ciclosporin oder Taxol .In particular, poorly soluble or difficultly bioavailable active ingredients can be formulated according to the invention. Slightly soluble means that the solubility in water at 25 ° C is below 1 mg / ml. According to USP XXII, page 8, such active ingredients are also referred to as hardly soluble or practically insoluble. Poorly soluble active ingredients are, for example, esupron, nifedipine, nimodipine, ciclosporin or taxol.
Als oberflächenaktive Substanzen kommen vorzugsweise niedermolekulare Substanzen in Betracht, die bei 20°C flüssig sind oder einen Tropfpunkt im Bereich von über 20°C bis 50°C aufweisen, bevorzugt von bis zu 40°C. Bevorzugt werden Substanzen mit einem HLB-Wert von 7 bis 18, besonders bevorzugt 10 bis 15. Geeignete oberflächenaktive Substanzen sind beispielsweise gesättigte und ungesättigte polyglykolisierte Glyceride, halbsynthetische Glyceride, Fettsäureester oder Ether von Fettalkoholen, sofern sie die oben angegebenen Eigenschaften auf- weisen.Suitable surface-active substances are preferably low-molecular substances which are liquid at 20 ° C. or have a dropping point in the range from above 20 ° C. to 50 ° C., preferably up to 40 ° C. Substances with an HLB value of 7 to 18, particularly preferably 10 to 15, are preferred. Suitable surface-active substances are, for example, saturated and unsaturated polyglycolized glycerides, semisynthetic glycerides, fatty acid esters or ethers of fatty alcohols, provided that they have the properties indicated above.
Insbesondere eignen sich die entsprechenden Sorbitanfettsäure- ester oder ethoxilierte Sorbitanfettsäureester wie beispielsweise Polyoxyethylen(20) sorbitanmonolaurat, Polyoxyethylen(20) sorbitanmonopalmitat,The corresponding sorbitan fatty acid esters or ethoxylated sorbitan fatty acid esters such as, for example, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, are particularly suitable.
Polyoxyethylen(20) sorbitanmonostearat,Polyoxyethylene (20) sorbitan monostearate,
Polyoxyethylen (20 ) sorbitan onooleat ,Polyoxyethylene (20) sorbitan onooleate,
Polyoxyethylen(20) sorbitantristearat,Polyoxyethylene (20) sorbitan tristearate,
Polyoxyethylen (20) sorbitantrioleat, Polyoxyethylen (4) sorbitanmonostearat,Polyoxyethylene (20) sorbitan trioleate, polyoxyethylene (4) sorbitan monostearate,
Polyoxyethylen (4) sorbitanmonolaurat oderPolyoxyethylene (4) sorbitan monolaurate or
Polyoxyethylen(4) sorbitanmonooleat .Polyoxyethylene (4) sorbitan monooleate.
Weiterhin eignen sich Macrogol-6-Cetylstearylether oderMacrogol-6-cetylstearyl ether or are also suitable
Macrogol-25-Cetylstearylether .Macrogol 25 cetyl stearyl ether.
Besonders bevorzugt sind Polyoxyethylenglycerolricinoleat-35,Polyoxyethylene glycerol ricinoleate-35 are particularly preferred.
Polyoxyethylenglyceroltrihydroxystearat-40, PEG-660-12-Hydroxy- stearinsäure (Polyglykolester der 12-Hydroxystearin-säurePolyoxyethylene glycerol trihydroxystearate-40, PEG-660-12-hydroxystearic acid (polyglycol ester of 12-hydroxystearic acid
(70 mol-%) mit 30 mol-% Ethylenglykol) . Ganz besonders bevorzugt ist davon Polyoxyethylenglyceroltrihydroxystearat-40 (Cremophor® (70 mol%) with 30 mol% ethylene glycol). Very particular preference is dependent Polyoxyethylenglyceroltrihydroxystearat-40 (Cremophor ®
RH40, BASF) .RH40, BASF).
Die oberflächenaktiven Substanzen sind in den Zubereitungen in Mengen von mindestens 2 Gew.-%, bezogen auf das Gesamtgewicht der Zubereitung, und bis zu 40 Gew.-% enthalten, bevorzugt 5 bis 25 Gew.-% und besonders bevorzugt 10 bis 25 Gew.-%.The surface-active substances are contained in the preparations in amounts of at least 2% by weight, based on the total weight of the preparation, and up to 40% by weight, preferably 5 to 25% by weight and particularly preferably 10 to 25% by weight. -%.
Weiterhin enthalten die erfindungsgemäßen Zubereitungen noch mindestens einen thermoplastisch verarbeitbaren polymeren Matrix- Hilfsstoff. Als polymerer Matrixhilfsstoff werden erfindungsgemäß wasserlösliche Homo- und Copolymere des N-Vinylpyrrolidons wie Polyvinylpyrrolidon mit K-Werten nach Fikentscher von 12 bis 100, insbesondere K 17 bis K 30, oder Copolymere mit Carbonsäure- vinylestern wie Vinylacetat oder Vinylpropionat, besonders bevorzugt Copovidone (VP/VAc-60/40) , ein Copolymer aus 60 Gew.-% N-Vinylpyrrolidon und 40 Gew.-% Vinylacetat eingesetzt.The preparations according to the invention also contain at least one thermoplastically processable polymeric matrix auxiliary. According to the invention, water-soluble homo- and copolymers of N-vinylpyrrolidone such as polyvinylpyrrolidone with K values according to Fikentscher from 12 to 100, in particular K 17 to K 30, or copolymers with carboxylic acid vinyl esters such as vinyl acetate or vinyl propionate, particularly preferably copovidones (VP / VAc-60/40), a copolymer of 60% by weight of N-vinylpyrrolidone and 40% by weight of vinyl acetate.
Zusätzlich können die Zubereitungen noch bis zu 10 Gew.-% an Hydroxyalkyl-alkylcellulosen, die in Wasser quellen, enthalten, beispielsweise Hydroxypropyl-methylcellulose (HPMC) , bevorzugt solche mit Methoxy-Substitutionsgraden im Bereich von 22 % und Hydroxypropoxy-Substitutionsgraden im Bereich von 8 %, besonders bevorzugt HPMC-Typen mit Viskositäten von 4000 mPas, lbUUU mpas oder 100000 mPas, gemessen bei 20°C in 2 gew.-%iger wäßriger Lösung. Geeignet sind auch HPMC-typen mit Methoxy-Substitutions- graden im Bereich von 28 bis 29 % und Hydroxypropoxy-Substi- 5 tutionsgraden im Bereich von 5 bis 8,5 %.In addition, the preparations can also contain up to 10% by weight of hydroxyalkyl-alkylcelluloses which swell in water, for example hydroxypropylmethylcellulose (HPMC), preferably those with degrees of methoxy substitution in the range of 22% and degrees of hydroxypropoxy in the range of 8%, especially preferred HPMC types with viscosities of 4000 mPas, lbUUU mpas or 100000 mPas, measured at 20 ° C in 2 wt .-% aqueous solution. HPMC types with degrees of methoxy substitution in the range from 28 to 29% and hydroxypropoxy degrees of substitution in the range from 5 to 8.5% are also suitable.
Die Mengen an polymerem Matrixhilfsstoff richten sich nach der Menge an eingesetztem Wirkstoff und oberflächenaktiver Substanz .The amounts of polymeric matrix auxiliary depend on the amount of active ingredient and surface-active substance used.
10 Weiterhin können die Zubereitungen noch übliche pharmazeutische Hilfsstoffe wie Aromen, Antioxidantien, Kieselsäuren, Trennmittel oder Farbstoffe in den hierfür üblichen Mengen enthalten.10 The preparations may also contain conventional pharmaceutical auxiliaries such as flavors, antioxidants, silicas, mold release agents or colorants in the amounts customary for this.
Besonders bevorzugt sind erfindungsgemäß Zubereitungen, ent- 15 haltend 15 bis 65 Gew.-% Copovidone, 5 bis 25 Gew.-% Polyoxy- ethylenglyceroltrihydroxystearat , 0 bis 10 Gew.-% Hydroxypropyl- methylcellulose und 5 bis 65 Gew.-% Wirkstoff.Preparations containing 15 to 65% by weight of copovidones, 5 to 25% by weight of polyoxyethylene glycerol trihydroxystearate, 0 to 10% by weight of hydroxypropylmethyl cellulose and 5 to 65% by weight of active compound are particularly preferred according to the invention.
Die Herstellung der erfindungsgemäßen Zubereitungen erfolgt über 20 ein Schmelzeverfahren. Bevorzugt wird das Verfahren ohne Zugabe von Lösungsmitteln durchgeführt.The preparations according to the invention are produced by a melt process. The process is preferably carried out without the addition of solvents.
Das Schmelzeverfahren wird in einem Kneter oder einem Schneckenextruder durchgeführt. Geeignete Kneter sind beispielsweise 25 Kneter der Firmen Haake oder Farrell .The melting process is carried out in a kneader or a screw extruder. Suitable kneaders are, for example, 25 kneaders from Haake or Farrell.
Bevorzugt erfolgt die Herstellung der Schmelze in einem Schneckenextruder, besonders bevorzugt einem Doppelschneckenextruder mit und ohne Knetscheiben oder ähnlichen Mischelementen. 30 Besonders bevorzugt sind gleichsinnig drehende Doppelschneckenextruder .The melt is preferably produced in a screw extruder, particularly preferably a twin-screw extruder with and without kneading disks or similar mixing elements. 30 Double-screw extruders rotating in the same direction are particularly preferred.
In Abhängigkeit von der Zusammensetzung erfolgt die Verarbeitung im allgemeinen bei Temperaturen von 40°C bis 260°C, bevorzugt 35 50 bis 200°C.Depending on the composition, processing is generally carried out at temperatures of 40 ° C. to 260 ° C., preferably 35 50 to 200 ° C.
Die Einsatzstoffe können dem Extruder oder Kneter einzeln oder als Vormischung zugeführt werden. Die Zugabe erfolgt bevorzugt in Form von pulverförmigen oder granulierten Vormischungen. So kannThe feed materials can be fed to the extruder or kneader individually or as a premix. The addition is preferably in the form of powdered or granulated premixes. So can
40 die flüssige oder ölige oberflächenaktive Substanz zuvor mit einem anderen Einsatzstoff zu einem rieselfähigen Granulat vermengt werden. Eine Zugabe der oberflächenaktiven Substanz in flüssiger Form, beispielsweise über Flüssigkeitspumpen, die bei halbfesten Substanzen vorzugsweise beheizt werden, ist ebenfalls40 the liquid or oily surface-active substance is previously mixed with another feed material to form a free-flowing granulate. It is also possible to add the surface-active substance in liquid form, for example via liquid pumps, which are preferably heated in the case of semi-solid substances
45 möglich. Man kann auch zunächst den Wirkstoff in der oberflächenaktiven Substanz lösen und diese Mischung dann mit dem Polymer granulieren. Dabei muß der Wirkstoff selbst nicht schmelzen.45 possible. You can also first dissolve the active ingredient in the surface-active substance and then granulate this mixture with the polymer. The active ingredient does not have to melt itself.
Bei temperaturempfindlichen Wirkstoffen kann es sich auch empfehlen, zunächst die anderen Einsatzstoffe aufzuschmelzen und dann erst den Wirkstoff zuzugeben.In the case of temperature-sensitive active ingredients, it may also be advisable to first melt the other starting materials and only then add the active ingredient.
Die Einsatzstoffe werden demgemäß gemeinsam zu einer Schmelze verarbeitet, welche durch Eintragen mechanischer Energie, insbesondere in Form von Scherkräften, zu einer homogenen Masse verarbeitet wird.The starting materials are accordingly processed together to form a melt, which is processed into a homogeneous mass by introducing mechanical energy, in particular in the form of shear forces.
Die homogene Schmelze wird anschließend durch eine Düse oder eine Lochplatte extrudiert und der Formgebung unterworfen. Dies kann durch Abschlag des strangförmig austretenden Extrudats mit den üblichen Abschlagtechniken erfolgen, beispielsweise mit Hilfe rotierender Messer oder durch Druckluftabschlag, wobei Pellets oder Granulate entstehen. Weiterhin kann die Formgebung wie in der EP-A 240 906 beschrieben erfolgen, indem das strangförmig austretende Extrudat zwischen zwei gegenläufig rotierende Kalanderwalzen geführt und direkt zu Tabletten ausgeformt wird. Ebenso kann die Schmelze über den offenen Extruderkopf ausgefahren werden und nach Erstarren gegebenenfalls noch gemahlen werden oder durch geeignete Granuliergeräte wie Walzenstühle oder Kompaktiereinheiten weiterverarbeitet werden.The homogeneous melt is then extruded through a die or perforated plate and subjected to shaping. This can be done by knocking off the extrudate emerging in the form of a strand using the usual knock-off techniques, for example using rotating knives or by knocking off compressed air, resulting in pellets or granules. Furthermore, the shaping can be carried out as described in EP-A 240 906, in that the extrudate emerging in the form of a strand is guided between two counter-rotating calender rolls and shaped directly into tablets. Likewise, the melt can be drawn out via the open extruder head and, if necessary, can be ground after solidification or can be further processed by suitable granulating devices such as roller mills or compacting units.
Granulate oder Pellets können dann in konventionellen Tablettenpressen zu Tabletten verarbeitet werden. Es ist auch möglich, die durch Kalandrierung zunächst bereits in Form von mechanisch stabile Tabletten erhaltenen Zubereitungen einem Mahlvorgang zu unterwerfen und dann auf konventionelle Weise zu Tabletten zu verpressen. Gewünschtenfalls können die Tabletten dann mit einem üblichen Überzug versehen werden.Granules or pellets can then be processed into tablets in conventional tablet presses. It is also possible to subject the preparations already obtained in the form of mechanically stable tablets to a milling process and then to compress them into tablets in a conventional manner. If desired, the tablets can then be provided with a conventional coating.
Überraschenderweise lassen sich erfindungsgemäß Tabletten erhalten, die auch bei hohen Anteilen an flüssigen oder halbfesten oberflächenaktiven Substanzen eine gute mechanische Stabilität aufweisen und nicht zur Klebrigkeit oder zum Erweichen neigen. Auf eine Abfüllung in Kapseln kann aufgrund der guten Formstabilität der Zubereitungen erfindungsgemäß verzichtet werden.Surprisingly, tablets can be obtained according to the invention which have good mechanical stability even with high proportions of liquid or semi-solid surface-active substances and do not tend to stickiness or softening. Filling into capsules can be dispensed with according to the invention due to the good dimensional stability of the preparations.
Die resultierenden Arzneiformen enthalten den Wirkstoff in Form fester Lösungen, in denen der Wirkstoff molekulardispers verteilt vorliegt. Die erfindungsgemäßen Arzneiformen ermöglichen es, auch schwerlösliche Wirkstoffe ausreichend zu solubilisieren bzw. in wäßrigem Medium stabil in der Hilfsstoffmatrix zu dispergieren.The resulting pharmaceutical forms contain the active ingredient in the form of solid solutions in which the active ingredient is present in molecularly dispersed form. The pharmaceutical forms according to the invention make it possible to sufficiently solubilize even poorly soluble active ingredients or to disperse them stably in the auxiliary matrix in an aqueous medium.
Die erfindungsgemäßen Zubereitungen bilden nach Auflösen in wäßrigem Medium, insbesondere bei einem pH-Wert von 1, für mindestens eine Stunde ein stabiles Solubilisat oder eine stabile Dispersion, in der der Wirkstoff bevorzugt nicht-kristallin vorliegt . Die Zubereitungen weisen infolge ihrer besseren Löslichkeit gegenüber herkömmlichen Formulierungen eine ver- besserte Bioverfügbarkeit auf.After dissolving in an aqueous medium, in particular at a pH of 1, the preparations according to the invention form a stable solubilizate or a stable dispersion for at least one hour, in which the active ingredient is preferably non-crystalline. Due to their better solubility compared to conventional formulations, the preparations have an improved bioavailability.
Beispiel 1example 1
Eine Pulvermischung aus Nimodipin und Copovidon wurde in einem Diosna-Mischer vorgelegt und mit Polyoxyethylentrihydroxy- stearat-40 versetzt. Die so erhaltene Mischung, die aus 12 Gew.-% Nimodipin, 78 Gew.-% Copovidon und 10 Gew.-% Polyoxyethylen- glyceroltrihydroxystearat-40 bestand, wurde über eine Dosierwaage in einen Doppelschneckenextruder des Typs ZKS-30 (Firma Werner & Pfleiderer) mit beheizbaren Schüssen eingebracht.A powder mixture of nimodipine and copovidone was placed in a Diosna mixer and mixed with polyoxyethylene trihydroxy stearate-40. The mixture obtained in this way, which consisted of 12% by weight of nimodipine, 78% by weight of copovidone and 10% by weight of polyoxyethylene glycerol trihydroxystearate-40, was fed via a metering scale into a twin-screw extruder of the type ZKS-30 (Werner & Pfleiderer ) with heated shots.
Temperaturprofil des Extruders: Schuß 1: 62°C / Schuß 2: 104°C / Schuß 3: 122°C / Schuß 4: 121°C / Schuß 5: 125°C / Düse: 126°CTemperature profile of the extruder: weft 1: 62 ° C / weft 2: 104 ° C / weft 3: 122 ° C / weft 4: 121 ° C / weft 5: 125 ° C / die: 126 ° C
Im vorletzten Schuß wurde ein Vakuum von 200 mbar angelegt. Der aus der Düse austretende Strang wurde zwischen zwei gegenläufige, mit linsenförmigen Vertiefungen versehenen Kalanderwalzen geführt und zu linsenförmigen Tabletten mit einem Gewicht von 250 mg kalandriert . A vacuum of 200 mbar was applied in the penultimate shot. The strand emerging from the nozzle was passed between two counter-rotating calender rolls provided with lenticular depressions and calendered into lenticular tablets weighing 250 mg.
Claims
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1999129361 DE19929361A1 (en) | 1999-06-25 | 1999-06-25 | Mechanically stable pharmaceutical dosage forms containing liquid or semi-solid surface-active substances |
| DE19929361.9 | 1999-06-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2001000175A1 true WO2001000175A1 (en) | 2001-01-04 |
Family
ID=7912675
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2000/005494 Ceased WO2001000175A1 (en) | 1999-06-25 | 2000-06-15 | Mechanically stable pharmaceutical dosage forms, containing liquid or semi-solid surface-active substances |
Country Status (2)
| Country | Link |
|---|---|
| DE (1) | DE19929361A1 (en) |
| WO (1) | WO2001000175A1 (en) |
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| US7364752B1 (en) | 1999-11-12 | 2008-04-29 | Abbott Laboratories | Solid dispersion pharamaceutical formulations |
| WO2010143074A2 (en) | 2009-06-08 | 2010-12-16 | Abbott Gmbh & Co. Kg | Pharmaceutical dosage form for oral administration of a bcl-2 family inhibitor |
| WO2012121758A1 (en) | 2010-10-29 | 2012-09-13 | Abbvie Inc. | Melt-extruded solid dispersions containing an apoptosis-inducing agent |
| US8268349B2 (en) | 2003-08-28 | 2012-09-18 | Abbott Laboratories | Solid pharmaceutical dosage form |
| US8470347B2 (en) | 2000-05-30 | 2013-06-25 | AbbVie Deutschland GmbH and Co KG | Self-emulsifying active substance formulation and use of this formulation |
| WO2014048783A1 (en) | 2012-09-27 | 2014-04-03 | Basf Se | A storage-stable dust-free homogeneous particulate formulation comprising at least one water-soluble vitamin e-derivative and at least one hydrophilic polymer |
| WO2014048782A1 (en) | 2012-09-27 | 2014-04-03 | Basf Se | A storage-stable dust-free homogeneous particulate formulation comprising at least one water-soluble vitamin e-derivative and at least one hydrophilic polymer |
| US8722657B2 (en) | 2010-11-23 | 2014-05-13 | Abbvie Inc. | Salts and crystalline forms of an apoptosis-inducing agent |
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| US9078921B2 (en) | 2006-07-19 | 2015-07-14 | Abbvie Deutschland Gmbh & Co Kg | Pharmaceutically acceptable solubilizing composition and pharmaceutical dosage form containing same |
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| US9107830B2 (en) | 1999-11-12 | 2015-08-18 | Abbvie, Inc. | Inhibitors of crystallization in a solid dispersion |
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| AU2003304242A1 (en) * | 2003-06-27 | 2005-01-13 | Bioprogress S.P.A. | Composite product obtainable by cogrinding of a active principle with a copolymer n-vinyl-2-pyrrolidone/vinyl-acetate |
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| US9616130B2 (en) | 2006-07-19 | 2017-04-11 | Abbvie Deutschland Gmbh & Co Kg | Pharmaceutically acceptable solubilizing composition and pharmaceutical dosage form containing same |
| US8728516B2 (en) | 2009-04-30 | 2014-05-20 | Abbvie Inc. | Stabilized lipid formulation of apoptosis promoter |
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| EP2982366A1 (en) | 2009-06-08 | 2016-02-10 | Abbott GmbH & Co. KG | Pharmaceutical dosage form for oral administration of a bcl-2 family inhibitor |
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| US9096556B2 (en) | 2011-05-27 | 2015-08-04 | Hetero Research Foundation | Amorphous ritonavir co-precipitated |
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| WO2014048782A1 (en) | 2012-09-27 | 2014-04-03 | Basf Se | A storage-stable dust-free homogeneous particulate formulation comprising at least one water-soluble vitamin e-derivative and at least one hydrophilic polymer |
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