EP1223960A2 - Pharmaceutical agent preparations - Google Patents

Pharmaceutical agent preparations

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Publication number
EP1223960A2
EP1223960A2 EP00972786A EP00972786A EP1223960A2 EP 1223960 A2 EP1223960 A2 EP 1223960A2 EP 00972786 A EP00972786 A EP 00972786A EP 00972786 A EP00972786 A EP 00972786A EP 1223960 A2 EP1223960 A2 EP 1223960A2
Authority
EP
European Patent Office
Prior art keywords
active ingredient
component
dosage form
solid dosage
form according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00972786A
Other languages
German (de)
French (fr)
Inventor
Robert Heger
Jörg Breitenbach
Gunther Berndl
Rudolf Binder
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BASF SE
Original Assignee
BASF SE
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by BASF SE filed Critical BASF SE
Publication of EP1223960A2 publication Critical patent/EP1223960A2/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • the present invention relates to solid dosage forms of a pharmaceutical active substance in which there is a physical mixture of at least two preparations of the active substance which differ in terms of the physical state of the active substance.
  • the invention further relates to dosage forms which contain a third preparation which is different with regard to the physical state of the active ingredient.
  • a whole series of highly effective pharmaceutical active substances 15 causes great problems with regard to the bioavailability of the dosage forms, in particular if, in the context of long-term therapy, uniform blood plasma concentrations are desired, but excessively high blood plasma levels have to be avoided because of the strong side effects. This applies, for example, to many 20 immunosuppressants, HIV therapeutics or CNS-active substances.
  • Cyclosporins a series of non-polar, cyclic oligopeptides, are characterized by their unsuppressive effect. Among them, the cyclosporin A, obtained from fermentation and consisting of 25 11 amino acids, has gained therapeutic importance.
  • cyclosporin formulations have been developed for both oral and intravenous use, oral administration of cyclosporin is preferred because it ensures better patient compliance.
  • cyclosporin A which is quite large, has a high lipophilicity, which is
  • Peroral forms currently available on the market are accordingly either emulsion concentrates for administration as solutions or microemulsions filled in capsules. In both In some cases, solvents such as ethanol and / or oil are used to solubilize the cyclosporin.
  • the bioavailability can, however, be subject to strong fluctuations in the range from 10 to 60%. These fluctuations are related to the galenic form and the condition of the preparation in the gastrointestinal tract. Furthermore, natural fat digestion has a significant influence on the absorption of the cyclosporin administered orally.
  • WO 97/07787 also describes cyclosporin formulations which, in addition to the active ingredient, contain an alkanol solvent such as ethanol or propylene glycol and a nonionic polyoxyalkylene derivative as a surface-active substance.
  • an alkanol solvent such as ethanol or propylene glycol
  • a nonionic polyoxyalkylene derivative as a surface-active substance.
  • a disadvantage of such forms is, on the one hand, that they contain solvents, especially ethanol, and, on the other hand, that the cyclosporin tends to recrystallize at low temperatures, which is problematic in terms of storage stability. Such precipitates are largely not absorbed, so that even bioavailability may not be guaranteed.
  • EP-A 425 892 discloses a process for improving the bioavailability of active pharmaceutical ingredients with peptide bonds, a solution of the active ingredient in a water-miscible organic solvent being rapidly mixed with an aqueous colloid, so that the active ingredient is in a colloidally dispersed form fails.
  • WO 93/10767 describes oral administration forms for peptide medicaments in which the medicament is incorporated into a gelatin matrix in such a way that the colloidal particles which form are present in a charge-neutral manner.
  • a disadvantage of such forms, however, is their tendency to flocculate.
  • the dosage forms defined at the outset were found in which the active ingredient is in the form of a physical mixture of at least two preparations of the active ingredient which differ in terms of the physical state of the active ingredient. Furthermore, pharmaceutical forms have been found in which a third physically different form of the active ingredient is additionally present.
  • the active ingredient is present in a first preparation (component 1) in the form of solid, X-ray amorphous particles in a colloidally dispersed distribution in a matrix of a polymeric coating material.
  • a second preparation (component 2), the active ingredient is present in a molecularly dispersed form in an auxiliary matrix.
  • a third physically different form (component 3), the active ingredient is in the form of crystalline particles.
  • the dosage form according to the invention is suitable in principle for all poorly water-soluble and poorly bioavailable active ingredients, but in particular for cyclosporin.
  • Cyclosporin A has a melting point of 148 to 151 ° C. and is used as a colorless, crystalline substance.
  • the active substance in the form of X-ray amorphous particles is colloidally embedded in an envelope matrix consisting of one or more polymeric stabilizers.
  • Suitable polymeric stabilizers are swellable protective colloids such as, for example, cattle, pork or fish gelatin, starch, dextrin, pectin, gum arabic, lignin sulfonates, chitosan, polystyrene sulfonate, alginates, casein, caseinate, methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, milk pulp, hydroxypropyl cellulose, milk pulp or skimmed milk or mixtures of these protective colloids.
  • Homopolymers and copolymers based on the following monomers are also suitable: ethylene oxide, propylene oxide, acrylic acid, maleic anhydride, lactic acid, N-vinylpyrrolidone, vinyl acetate, ⁇ - and ⁇ -aspartic acid.
  • gelatin types mentioned is particularly preferably used, in particular acidic or basic degraded gelatin with Bloom numbers in the range from 0 to 250, very particularly preferably gelatin A 100, A 200, B 100 and B 200 as well as low molecular weight, enzymatically degraded gelatin types the Bloom number 0 and molecular weights from 15000 to 25000 D such as Collagel A and Gelitasol P (from Stoess, Eberbach) and mixtures of these types of gelatin. These preparations also contain low molecular weight surface-active compounds. As such, amphiphilic compounds or mixtures of such compounds are particularly suitable. Basically, all surfactants with an HLB value of 5 to 20 can be used.
  • esters of long-chain fatty acids with ascorbic acid mono- and diglycerides of fatty acids and their oxyethylation products
  • esters of mono-fatty acid glycerides with acetic acid, citric acid, lactic acid or diacetyl tartaric acid polyglycerol fatty acid esters such as the monostearate of tritlyglycerol acid sorbet, sorbet acid , 2- (2 '-stearoyllactyl) lactic acid salts and lecithin.
  • Ascorbyl palmitate is preferably used.
  • the amounts of the various components are chosen according to the invention so that the preparations 0.1 to 70% by weight, preferably 1 to 40% by weight, of active ingredient, 1 to 80% by weight, preferably 10 to 60% by weight. %, one or more polymeric stabilizers and 0 to 50% by weight, preferably 0.5 to 20% by weight, of one or more low molecular weight stabilizers.
  • the percentages by weight relate to a dry powder.
  • a solution of the active ingredient is first prepared in a suitable solvent, the solution in this context meaning a real molecularly disperse solution or a melt emulsion.
  • suitable solvents are organic, water-miscible solvents which are volatile and thermally stable and contain only carbon, hydrogen, nitrogen and oxygen. Appropriately, they are at least 10% by weight miscible with water and have a boiling point below 200 ° C. and / or have less than 10 carbon atoms.
  • Corresponding alcohols, esters, ketones and acetals are preferred. In particular, ethanol, n-propanol, isopropanol 1, 2-butanedio-1-methyl ether, 1, 2-propanediol-1-n-propyl ether or acetone are used.
  • a molecularly disperse solution of the active ingredient in the selected solvent is dissolved at temperatures in the range from preferably 20 to 150 ° C., within a period of less than 120 seconds, optionally with an excess pressure of up to 100 bar, preferably 30 bar.
  • the active ingredient solution is prepared in such a way that the mixture of active ingredient and solvent is raised to 150 to within a period of less than 10 seconds above the melting point of the active ingredient Heated 240 ° C, which can optionally work at an excess pressure of up to 100 bar, preferably 30 bar.
  • the concentration of the active ingredient solution thus prepared is generally 10 to 500 g of active ingredient per 1 kg of solvent.
  • the low molecular weight stabilizer is added directly to the active ingredient solution.
  • the active ingredient solution is mixed with an aqueous solution of the polymeric shell material.
  • concentration of the solution of the polymeric coating material is 0.1 to 200 g / 1, preferably 1 to 100 g / 1.
  • a high mechanical energy input is recommended when mixing the active ingredient solution with the solution of the coating material.
  • Such energy input can take place, for example, by vigorous stirring or shaking in a suitable device, or by injecting the two components into a mixing chamber with a hard jet, so that vigorous mixing occurs.
  • the mixing process can be carried out batchwise or, preferably, continuously.
  • the active ingredient is precipitated in the form of solid, X-ray amorphous particles.
  • the colloidal suspension obtained in this way can then be converted into a dry powder in a manner known per se, for example by spray drying, freeze drying or drying in a fluidized bed.
  • the preparation of the preparations according to the invention is carried out by adjusting the pH of the solution of the coating material, in particular gelatin, and a solution of the active ingredient in such a way that the active ingredient particles which form do not have any charge neutrality, that is to say that the Do not adjust the pH value of the gelatin solution to such a value that a charge-neutral state results when the particles are formed.
  • the particles are preferably produced at pH values greater than 7.
  • the average particle diameter of the solid active ingredient particles in the matrix of the polymeric coating material is 20 to 1000 nm, preferably 100 to 600 nm.
  • the spherical active ingredient particles are completely X-ray amorphous.
  • X-ray amorphous means the absence of crystal interference in X-ray powder diagrams (cf. HP Klug, LE Alexander, "X-Ray Diffraction procedures for Polycristalline and Amorphous Materials, John Wiley, New York, 1959).
  • the active substance particles are distinguished by the fact that after redispersion they are negatively charged in an aqueous medium at a pH greater than 5.
  • the active ingredient is present in a molecularly dispersed form in an auxiliary matrix.
  • Such molecularly disperse distributions of an active ingredient in a matrix are also referred to as "solid solutions" (cf. Chiou and Riegelman, J. Pharm. Sei., 60, 1281-1300).
  • Such solid solutions can be prepared by the solution process by dissolving the active ingredient together with the components forming the auxiliary matrix in a suitable solvent and then removing the solvent.
  • suitable solvents are water, ethanol, isopropanol, acetone, chlorinated hydrocarbons such as methylene chloride or chloroform, tetrahydrofuran, toluene or methyl ethyl ketone. The solvent is usually evaporated in vacuo.
  • Such solid solutions can be produced by the melt process, the active ingredient and the starting materials forming the auxiliary matrix being intimately mixed in the melt.
  • 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, 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. Double-screw extruders rotating in the same direction are particularly preferred.
  • processing is generally carried out at temperatures of 40 to 260 ° C., preferably 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.
  • the liquid or oily surface-active substance can be mixed with another feed material to form a free-flowing granulate.
  • the surface-active substance in liquid form, for example via liquid pumps, which are preferably heated in the case of semi-solid substances. 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.
  • 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.
  • the second preparation forms can contain, for example, thermoplastically processable water-soluble or water-swellable polymers as suitable matrix formers.
  • Water-soluble means that at 25 ° C at least 1 g of the polymer dissolve in 10 ml of water.
  • Water-swellable means that the water absorption at 25 ° C. and 75% relative air humidity is more than 1% by weight without the polymer dissolving.
  • Suitable polymers are, for example, homopolymers and copolymers of N-vinylpyrrolidone with K values according to Fikentscher from 19 to 100.
  • Comonomers which are particularly suitable are N-vinyl acetate, and also vinyl propionate, vinyl caprolactam or vinyl imidazole.
  • Cellulose derivatives are also suitable, for example, hydroxyalkyl celluloses such as hydroxypropyl cellulose, alkyl celluloses or alkyl hydroxyalkyl celluloses such as hydroxypropyl methyl celluloses.
  • hydroxyalkyl celluloses such as hydroxypropyl cellulose, alkyl celluloses or alkyl hydroxyalkyl celluloses such as hydroxypropyl methyl celluloses.
  • Polyethylene glycols with molecular weights of 1500 to 10 million D or polyoxyethylene-polyoxypropylene block copolymers are also suitable.
  • Sugar alcohols such as erythritol, isomalt, mannitol, sorbitol, xylitol or mixtures of such sugar alcohols are also suitable as matrix formers.
  • the matrix can also contain pharmaceutically acceptable auxiliaries such as fillers, lubricants, mold release agents, flow regulators, plasticizers, colorants, flavorings and / or stabilizers in the amounts customary for this.
  • auxiliaries such as fillers, lubricants, mold release agents, flow regulators, plasticizers, colorants, flavorings and / or stabilizers in the amounts customary for this.
  • the active ingredient dosage forms can contain a third formulation (component 3).
  • the active ingredient is in the form of particles, the active ingredient in the particles having a degree of crystallinity of at least 20%.
  • the degree of crystallinity denotes the proportion of the active substance that is not amorphous.
  • the active ingredient can also be present in component 3 in various crystal modifications.
  • the active ingredient in this preparation form is in the form of a pure crystalline substance without further auxiliaries.
  • the particles have average diameters in the range from 0.05 to 200 ⁇ m, preferably 0.1 to 50 ⁇ m.
  • the crystalline particles can be obtained from crystalline raw materials by grinding processes known per se. Suitable grinding processes are, for example, dry or wet grinding. Suitable devices are, for example, ball mills, pin mills or air jet mills.
  • the dosage forms according to the invention are obtained by physically mixing components 1, 2 and 3.
  • the total proportion of active ingredient of component 1 is in the range from 10 to 70% by weight, particularly preferably from 20 to 60% by weight, of component 2 in the range from 10 to 70% by weight, particularly preferably from 20 to 60% by weight, and component 3 in the range from 0 to 30% by weight.
  • the physical properties of the individual components are unchanged after mixing.
  • the physical mixtures according to the invention of two or three preparations of the active ingredient, in which the active ingredient is in a different physical form, can be used in all oral dosage forms suitable for this purpose. So you can, for example, in hard or soft gelatin Fill capsules or under known conditions
  • the dosage forms according to the invention have bioavailability which is higher than that of the individual components. Such a synergistic effect was not to be expected for the person skilled in the art.
  • this molecularly disperse solution was fed to a mixing chamber at 25 ° C. There, the mixture was mixed with 537 g of an aqueous solution of 14.4 g of gelatin B 100 Bloom and 12.6 g of lactose in demineralized water, which had been adjusted to pH 9.2 using 1 N NaOH. The entire process was carried out with a pressure limit of 30 bar. After mixing, a colloidally disperse cyclosporin A dispersion was obtained with a white cloudy color.
  • this molecularly disperse solution was fed to a mixing chamber at 135 ° C. There, the mixture was mixed with 393.9 g of an aqueous solution of 9.2 g of gelatin A 100 Bloom and 6.1 g of lactose in demineralized water, which had been adjusted to pH 9.2 using 1 N NaOH. The process was carried out under pressure limitation to 30 bar to prevent the water from evaporating. After mixing, a colloidally disperse cyclosporin A dispersion with a white, cloudy shade was obtained.
  • Spray drying the dispersion resulted in a nanoparticulate dry powder.
  • the active substance content in the dry powder was determined by chromatography to be 15.9% by weight.
  • the dry powder dissolves in drinking water to form a white cloudy dispersion.
  • the active substance content in the powder was determined by chromatography to be 16.1% by weight of cyclosporin.
  • a colloidally disperse cyclosporin A dispersion was prepared from 4.5 g of cyclosporin A, 0.9 g of ascorbyl palmitate, 9.6 g of gelatin A 100 Bloom and 7.2 g of lactose.
  • a nanoparticulate dry powder with a cyclosporin A content (determined by chromatography) of 19.9% by weight was obtained by spray drying.
  • the dry powder dissolved in drinking water to form a white, cloudy dispersion (hydrosol).
  • a preparation was produced in the same way as in production example 3, in which fish gelatin with molecular weight fractions of 10 3 to 10 7 D was used as the coating matrix material.
  • Preparation example 5
  • the calendered molds were ground using an air jet mill, so that 95% of the particles had a diameter of ⁇ 10 ⁇ m.
  • Example 5 Analogously to Example 5, a mixture of 80% by weight of a copolymer of 60% by weight of N-vinylpyrrolidone and 40% by weight of vinyl acetate and 20% by weight of cyclosporin was processed. Shot temperature: 55, 110, 140, 137, 136, 141 ° C; Nozzle: 140 ° C.
  • Cyclosporin was administered in the corresponding preparation to beagle dogs with a weight in the range from 8 to 12 kg either orally as a solid form or by gavage in liquid forms. Liquid forms were placed in 50 ml of water and rinsed with a further 50 ml of water. Solid forms were administered without water. The feed was withdrawn from the animals 16 h before the substance was administered, and the animals were fed again 4 h after the substance was administered. Blood was drawn from the jugular vein or the antebrachial vein in heparinized vessels from the dogs before administration of the substance and in a time interval of up to 32 hours after administration of the substance. The blood was frozen and stored at -20 ° C until analytical processing. Blood levels were determined using a validated, internally standardized GC-MS method. Form 1 (for comparison):
  • Form 2 5 dry powder according to preparation example 2, active ingredient dose 100 mg; Administration as a hydrosol

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  • Health & Medical Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to solid pharmaceutical galenic forms comprising an agent in the form of a physical mixture of two different preparations with regard to the physical state of the agent.

Description

Zubereitungen pharmazeutischer Wirkstoffe Preparations of active pharmaceutical ingredients
Beschreibung 5Description 5
Die vorliegende Erfindung betrifft feste Darreichungsformen eines pharmazeutischen Wirkstoffs, in denen eine physikalische Mischung mindestens zweier hinsichtlich des physikalischen Zustands des Wirkstoffs verschiedenen Zubereitungen des Wirkstoffs vorliegt. 10 Weiterhin betrifft die Erfindung Darreichungsformen, welche eine dritte hinsichtlich des physikalischen Zustands des Wirkstoffs verschiedene Zubereitung enthalten.The present invention relates to solid dosage forms of a pharmaceutical active substance in which there is a physical mixture of at least two preparations of the active substance which differ in terms of the physical state of the active substance. The invention further relates to dosage forms which contain a third preparation which is different with regard to the physical state of the active ingredient.
Eine ganze Reihe von hoch wirksamen pharmazeutischen Wirkstoffen 15 bereitet hinsichtlich der Bioverfügbarkeit der Darreichungsformen große Probleme, insbesondere dann wenn im Rahmen einer Langzeittherapie gleichmäßige Blutplasmakonzentrationen erwünscht sind, aber zu hohe Blutplasmaspiegel wegen der starken Nebenwirkungen vermieden werden müssen. Dies gilt beispielsweise für viele 20 Immunsuppressiva, HIV-Therapeutika oder ZNS-aktive Substanzen.A whole series of highly effective pharmaceutical active substances 15 causes great problems with regard to the bioavailability of the dosage forms, in particular if, in the context of long-term therapy, uniform blood plasma concentrations are desired, but excessively high blood plasma levels have to be avoided because of the strong side effects. This applies, for example, to many 20 immunosuppressants, HIV therapeutics or CNS-active substances.
Cyclosporine, eine Reihe von unpolaren, cyclischen Oligopeptiden, zeichnen sich durch ihre im unsuppressive Wirkung aus. Unter ihnen hat vor allem das durch Fermentation gewonnene, aus 25 11 Aminosäuren bestehende, Cyclosporin A therapeutische Bedeutung gewonnen .Cyclosporins, a series of non-polar, cyclic oligopeptides, are characterized by their unsuppressive effect. Among them, the cyclosporin A, obtained from fermentation and consisting of 25 11 amino acids, has gained therapeutic importance.
Obwohl Cyclosporinformulierungen sowohl für orale als auch für intravenöse Anwendung entwickelt wurden, wird die orale 30 Verabreichung von Cyclosporin bevorzugt, da sie eine bessere Patientencompliance gewährleistet .Although cyclosporin formulations have been developed for both oral and intravenous use, oral administration of cyclosporin is preferred because it ensures better patient compliance.
Allerdings weist das mit einem Molekulargewicht von 1202 g/mol recht große Cyclosporin A eine hohe Lipophilie auf, welche sichHowever, with a molecular weight of 1202 g / mol, cyclosporin A, which is quite large, has a high lipophilicity, which is
35 gleichzeitig in einer sehr geringen Wasserlöslichkeit äußert (<0,004 % m/V) . Durch eine gewisse Löslichkeit in Ölen wie Olivenöl sowie in Ethanol wurde es möglich, Emulsionskonzentrate zu entwickeln, welche bei peroraler Verabreichung zu einer, wenn auch relativ variablen, Bioverfügbarkeit von circa 30 % führen35 expressed at the same time in a very low water solubility (<0.004% m / V). A certain solubility in oils such as olive oil and in ethanol made it possible to develop emulsion concentrates which, when administered orally, lead to an albeit relatively variable bioavailability of approximately 30%
40 (Vgl. R.H. Müller et al . in "Pharmazeutische Technologie: Moderne Arzneiformen" , Wissenschaftliche Verlagsgesellschaft, Stuttgart, 1997, S. 118-125) .40 (Cf. R.H. Müller et al. In "Pharmaceutical Technology: Modern Pharmaceutical Forms", Wissenschaftliche Verlagsgesellschaft, Stuttgart, 1997, pp. 118-125).
Derzeitig am Markt erhältliche perorale Formen sind dement- 45 sprechend entweder Emulsionskonzentrate zur Verabreichung als Lösungen oder in Kapseln gefüllte Mikroemulsionen. In beiden Fällen werden Lösungsmittel wie Ethanol und/oder Öl zur Solu- bilisierung des Cyclosporins eingesetzt.Peroral forms currently available on the market are accordingly either emulsion concentrates for administration as solutions or microemulsions filled in capsules. In both In some cases, solvents such as ethanol and / or oil are used to solubilize the cyclosporin.
Dabei kann die Bioverfügbarkeit allerdings starken Schwankungen im Bereich von 10 bis 60 % unterworfen sein. Diese Schwankungen stehen im Zusammenhang mit der galenischen Form und dem Zustand der Zubereitung im Gastrointestinaltrakt . Weiterhin hat die natürliche Fettverdauung einen signifikanten Einfluß auf die Absorption des peroral verabreichten Cyclosporins.The bioavailability can, however, be subject to strong fluctuations in the range from 10 to 60%. These fluctuations are related to the galenic form and the condition of the preparation in the gastrointestinal tract. Furthermore, natural fat digestion has a significant influence on the absorption of the cyclosporin administered orally.
Auch in der WO 97/07787 werden Cyclosporinformulierungen beschrieben, die neben dem Wirkstoff ein alkanolisches Lösungsmittel wie Ethanol oder Propylenglycol sowie ein nichtionisches Polyoxyalkylenderivat als oberflächenaktive Substanz enthalten.WO 97/07787 also describes cyclosporin formulations which, in addition to the active ingredient, contain an alkanol solvent such as ethanol or propylene glycol and a nonionic polyoxyalkylene derivative as a surface-active substance.
Nachteilig an solchen Formen ist jedoch zum einen, daß sie Lösungsmittel, vor allem Ethanol, enthalten, zum anderen, daß das Cyclosporin bei niedrigen Temperaturen dazu neigt, zu rekristallisieren, was hinsichtlich der Lagerstabilität problematisch ist. Solche Präzipitate werden nämlich weitest- gehend nicht absorbiert, so daß eine gleichmäßige Bioverfügbarkeit unter Umständen nicht gewährleistet ist .A disadvantage of such forms is, on the one hand, that they contain solvents, especially ethanol, and, on the other hand, that the cyclosporin tends to recrystallize at low temperatures, which is problematic in terms of storage stability. Such precipitates are largely not absorbed, so that even bioavailability may not be guaranteed.
Aus der EP-A 425 892 ist ein Verfahren zur Verbesserung der Bioverfügbarkeit von pharmazeutischen Wirkstoffen mit Peptid- bindungen bekannt, wobei eine Lösung des Wirkstoffs in einem mit Wasser mischbaren organischen Lösungsmittel mit einem wäßrigen Kolloid schnell vermischt wird, so daß der Wirkstoff in kolloiddisperser Form ausfällt.EP-A 425 892 discloses a process for improving the bioavailability of active pharmaceutical ingredients with peptide bonds, a solution of the active ingredient in a water-miscible organic solvent being rapidly mixed with an aqueous colloid, so that the active ingredient is in a colloidally dispersed form fails.
In der WO 93/10767 sind perorale Applikationsformen für Peptid- arzneimittel beschrieben, in denen das Arzneimittel in der Weise in eine Gelatinematrix eingebaut wird, daß die sich bildenden kolloidalen Teilchen ladungsneutral vorliegen. Nachteilig an solchen Formen ist jedoch deren Neigung zum Ausflocken.WO 93/10767 describes oral administration forms for peptide medicaments in which the medicament is incorporated into a gelatin matrix in such a way that the colloidal particles which form are present in a charge-neutral manner. A disadvantage of such forms, however, is their tendency to flocculate.
Weiterhin ist beispielsweise aus der EP-A 240 904 bekannt, daß molekulardisperse Verteilungen eines Wirkstoffs in einer Polymermatrix durch Schmelzextrusion erhalten werden können.Furthermore, it is known, for example from EP-A 240 904, that molecularly disperse distributions of an active ingredient in a polymer matrix can be obtained by melt extrusion.
Aufgabe der vorliegenden Erfindung war es, für die orale Verabreichung geeignete Darreichungsformen von schwer bioverfügbaren Wirkstoffen wie beispielsweise Cyclosporin zu finden, die frei von Lösungsmitteln sind und hinsichtlich ihrer Bioverfügbarkeit mit den Mikroemulsionen vergleichbar sind. Demgemäß wurden die eingangs definierten Darreichungsformen gefunden, in denen der Wirkstoff in Form einer physikalischen Mischung mindestens zweier hinsichtlich des physikalischen Zustands des Wirkstoffs verschiedenen Zubereitungen des Wirk- Stoffs vorliegt. Weiterhin wurden Arzneiformen gefunden, in denen zusätzlich eine dritte physikalisch verschiedene Form des Wirkstoffs vorliegt.It was an object of the present invention to find dosage forms of poorly bioavailable active substances, such as cyclosporin, which are suitable for oral administration and which are free from solvents and whose bioavailability is comparable to that of the microemulsions. Accordingly, the dosage forms defined at the outset were found in which the active ingredient is in the form of a physical mixture of at least two preparations of the active ingredient which differ in terms of the physical state of the active ingredient. Furthermore, pharmaceutical forms have been found in which a third physically different form of the active ingredient is additionally present.
Erfindungsgemäß liegt der Wirkstoff in einer ersten Zubereitung (Komponente 1) in Form fester, röntgenamorpher Partikel kolloidaldispers verteilt in einer Matrix eines polymeren Hüllmaterials vor. In einer zweiten Zubereitung (Komponente 2) liegt das Wirkstoff molekulardispers verteilt in einer Hilfsstoffmatrix vor. In einer dritten physikalisch verschiedenen Form (Komponente 3) liegt das Wirkstoff in Form kristalliner Partikel vor.According to the invention, the active ingredient is present in a first preparation (component 1) in the form of solid, X-ray amorphous particles in a colloidally dispersed distribution in a matrix of a polymeric coating material. In a second preparation (component 2), the active ingredient is present in a molecularly dispersed form in an auxiliary matrix. In a third physically different form (component 3), the active ingredient is in the form of crystalline particles.
Die erfindungsgemäße Darreichungsform eignet sich prinzipiell für alle schwer wasserlöslichen und schwer bioverfügbaren Wirkstoffe, insbesondere aber für Cyclosporin.The dosage form according to the invention is suitable in principle for all poorly water-soluble and poorly bioavailable active ingredients, but in particular for cyclosporin.
Erfindungsgemäß lassen sich alle Cyclosporine verarbeiten, bevorzugt ist jedoch Cyclosporin A. Cyclosporin A weist einen Schmelzpunkt von 148 bis 151°c auf und wird als farblos kristalline Substanz eingesetzt.According to the invention, all cyclosporins can be processed, but cyclosporin A is preferred. Cyclosporin A has a melting point of 148 to 151 ° C. and is used as a colorless, crystalline substance.
In der Komponente 1 ist der Wirkstoff in Form röntgenamorpher Partikel kolloidal in eine aus einem oder mehreren polymeren Stabilisatoren bestehende Hüllmatrix eingebettet. Als polymere Stabilisatoren eignen sich quellbare Schutzkolloide wie bei- spielsweise Rinder-, Schweine- oder Fischgelatine, Stärke, Dextrin, Pektin, Gummiarabicum, Ligninsulfonate, Chitosan, Polystyrolsulfonat, Alginate, Kasein, Kaseinat, Methylcellulose, Carboxymethylcellulose, Hydroxypropylcellulose, Milchpulver, Dextran, Vollmilch oder Magermilch oder Mischungen dieser Schutz- kolloide. Weiterhin eignen sich Homo- und Copolymere auf Basis folgender Monomeren: Ethylenoxid, Propylenoxid, Acrylsäure, Maleinsäureanhydrid, Milchsäure, N-Vinylpyrrolidon, Vinylacetat, α- und ß-Asparaginsäure . Besonders bevorzugt wird eine der genannten Gelatine-Typen eingesetzt, insbesondere sauer oder basisch abgebaute Gelatine mit Bloom-Zahlen im Bereich von 0 bis 250, ganz besonders bevorzugt Gelatine A 100, A 200, B 100 und B 200 sowie niedermolekulare, enzymatisch abgebaute Gelatinetypen mit der Bloom-Zahl 0 und Molekulargewichten von 15000 bis 25000 D wie zum Beispiel Collagel A und Gelitasol P (Firma Stoess, Eberbach) sowie Mischungen dieser Gelatine-Sorten. Weiterhin enthalten diese Zubereitungen niedermolekulare oberflächenaktive Verbindungen. Als solche eignen sich vor allem amphiphile Verbindungen oder Gemische solcher Verbindungen. Grundsätzlich kommen alle Tenside mit einem HLB-Wert von 5 bis 20 in Betracht. Als entsprechende oberflächenaktive Substanzen kommen beispielsweise in Betracht: Ester langkettiger Fettsäuren mit Ascorbinsäure , Mono- und Diglyceride von Fettsäuren und deren Oxyethylierungsprodukte, Ester von Monofettsäureglyceriden mit Essigsäure, Zitronensäure, Milchsäure oder Diacetylweinsäure, Polyglycerinfettsäureester wie z.B. das Monostearat des Tri- glycerins , Sorbitanfettsäureester , Propylenglykolfettsäureester , 2- ( 2 ' -stearoyllactyl) -milchsaure Salze und Lecithin. Bevorzugt wird Ascorbylpalmitat eingesetzt.In component 1, the active substance in the form of X-ray amorphous particles is colloidally embedded in an envelope matrix consisting of one or more polymeric stabilizers. Suitable polymeric stabilizers are swellable protective colloids such as, for example, cattle, pork or fish gelatin, starch, dextrin, pectin, gum arabic, lignin sulfonates, chitosan, polystyrene sulfonate, alginates, casein, caseinate, methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, milk pulp, hydroxypropyl cellulose, milk pulp or skimmed milk or mixtures of these protective colloids. Homopolymers and copolymers based on the following monomers are also suitable: ethylene oxide, propylene oxide, acrylic acid, maleic anhydride, lactic acid, N-vinylpyrrolidone, vinyl acetate, α- and β-aspartic acid. One of the gelatin types mentioned is particularly preferably used, in particular acidic or basic degraded gelatin with Bloom numbers in the range from 0 to 250, very particularly preferably gelatin A 100, A 200, B 100 and B 200 as well as low molecular weight, enzymatically degraded gelatin types the Bloom number 0 and molecular weights from 15000 to 25000 D such as Collagel A and Gelitasol P (from Stoess, Eberbach) and mixtures of these types of gelatin. These preparations also contain low molecular weight surface-active compounds. As such, amphiphilic compounds or mixtures of such compounds are particularly suitable. Basically, all surfactants with an HLB value of 5 to 20 can be used. Examples of suitable surface-active substances are: esters of long-chain fatty acids with ascorbic acid, mono- and diglycerides of fatty acids and their oxyethylation products, esters of mono-fatty acid glycerides with acetic acid, citric acid, lactic acid or diacetyl tartaric acid, polyglycerol fatty acid esters such as the monostearate of tritlyglycerol acid sorbet, sorbet acid , 2- (2 '-stearoyllactyl) lactic acid salts and lecithin. Ascorbyl palmitate is preferably used.
Die Mengen der verschiedenen Komponenten werden erfindungsgemäß so gewählt, daß die Zubereitungen 0,1 bis 70 Gew.-%, vorzugsweise 1 bis 40 Gew.-%, an Wirkstoff, 1 bis 80 Gew.-%, bevorzugt 10 bis 60 Gew.-%, eines oder mehrerer polymerer Stabilisatoren und 0 bis 50 Gew.-%, bevorzugt 0,5 bis 20 Gew.-%, eines oder meh- rerer niedermolekularer Stabilisatoren enthält. Die Gewichtsprozentangaben beziehen sich auf ein Trockenpulver.The amounts of the various components are chosen according to the invention so that the preparations 0.1 to 70% by weight, preferably 1 to 40% by weight, of active ingredient, 1 to 80% by weight, preferably 10 to 60% by weight. %, one or more polymeric stabilizers and 0 to 50% by weight, preferably 0.5 to 20% by weight, of one or more low molecular weight stabilizers. The percentages by weight relate to a dry powder.
Zur Herstellung der ersten Zubereitungsform wird zunächst eine Lösung des Wirkstoffs in einem geeigneten Lösungsmittel her- gestellt, wobei die Lösung in diesem Zusammenhang eine echte molekulardisperse Lösung oder eine Schmelzeemulsion bedeutet. Als Lösungsmittel geeignet sind organische, mit Wasser mischbare Lösungsmittel, welche flüchtig und thermisch stabil sind und nur Kohlenstoff, Wasserstoff, Stickstoff und Sauerstoff enthalten. Zweckmäßigerweise sind sie zu mindestens 10 Gew.-% mit Wasser mischbar und weisen einen Siedepunkt von unter 200°C auf und/oder haben weniger als 10 Kohlenstoffatome . Bevorzugt sind entsprechende Alkohole, Ester, Ketone und Acetale. Insbesondere verwendet man Ethanol, n-Propanol, Isopropanol 1, 2-Butandio-l-methyl- ether, 1 , 2-Propandiol-l-n-propylether oder Aceton.To produce the first preparation form, a solution of the active ingredient is first prepared in a suitable solvent, the solution in this context meaning a real molecularly disperse solution or a melt emulsion. Suitable solvents are organic, water-miscible solvents which are volatile and thermally stable and contain only carbon, hydrogen, nitrogen and oxygen. Appropriately, they are at least 10% by weight miscible with water and have a boiling point below 200 ° C. and / or have less than 10 carbon atoms. Corresponding alcohols, esters, ketones and acetals are preferred. In particular, ethanol, n-propanol, isopropanol 1, 2-butanedio-1-methyl ether, 1, 2-propanediol-1-n-propyl ether or acetone are used.
Gemäß einer Ausführungsform der Erfindung wird eine molekulardisperse Lösung des Wirkstoffs in dem gewählten Lösungsmittel bei Temperaturen im Bereich von vorzugsweise 20 bis 150°C, innerhalb eines Zeitraums von weniger als 120 Sekunden, gelöst, wobei man gegebenenfalls bei einem Überdruck von bis zu 100 bar, vorzugsweise 30 bar, arbeiten kann.According to one embodiment of the invention, a molecularly disperse solution of the active ingredient in the selected solvent is dissolved at temperatures in the range from preferably 20 to 150 ° C., within a period of less than 120 seconds, optionally with an excess pressure of up to 100 bar, preferably 30 bar.
Gemäß einer weiteren bevorzugten Ausführungsform wird die Wirk- stoff-Lösung so hergestellt, daß man die Mischung aus Wirkstoff und Lösungsmittel innerhalb eines Zeitraums von weniger als 10 Sekunden über den Schmelzpunkt des Wirkstoffs auf 150 bis 240°C erwärmt, wobei gegebenenfalls bei einem Überdruck von bis zu 100 bar, vorzugsweise 30 bar, arbeiten kann.According to a further preferred embodiment, the active ingredient solution is prepared in such a way that the mixture of active ingredient and solvent is raised to 150 to within a period of less than 10 seconds above the melting point of the active ingredient Heated 240 ° C, which can optionally work at an excess pressure of up to 100 bar, preferably 30 bar.
Die Konzentration der so hergestellten Wirkstoff-Lösung beträgt im allgemeinen 10 bis 500 g Wirkstoff pro 1 kg Lösungsmittel. In einer bevorzugten Ausführungsform des Verfahrens wird der niedermolekulare Stabilisator direkt zu der Wirkstoff-Lösung gegeben.The concentration of the active ingredient solution thus prepared is generally 10 to 500 g of active ingredient per 1 kg of solvent. In a preferred embodiment of the method, the low molecular weight stabilizer is added directly to the active ingredient solution.
In einem sich daran anschließenden Verfahrensschritt wird die Wirkstoff-Lösung mit einer wäßrigen Lösung des polymeren Hüll- materialS vermischt. Die Konzentration der Lösung des polymeren Hüllmaterials beträgt 0,1 bis 200 g/1, vorzugsweise 1 bis 100 g/1.In a subsequent process step, the active ingredient solution is mixed with an aqueous solution of the polymeric shell material. The concentration of the solution of the polymeric coating material is 0.1 to 200 g / 1, preferably 1 to 100 g / 1.
Um beim Mischvorgang möglichst kleine Teilchengrößen zu erzielen, empfiehlt sich ein hoher mechanischer Energieeintrag beim Vermischen der Wirkstoff-Lösung mit der Lösung des Hüllmaterials. Ein solcher Energieeintrag kann beispielsweise durch starkes Rühren oder Schütteln in einer geeigneten Vorrichtung erfolgen, oder dadurch, daß man die beiden Komponenten mit hartem Strahl in eine Mischkammer einspritzt, so daß es zu einer heftigen Vermischung kommt .In order to achieve the smallest possible particle sizes during the mixing process, a high mechanical energy input is recommended when mixing the active ingredient solution with the solution of the coating material. Such energy input can take place, for example, by vigorous stirring or shaking in a suitable device, or by injecting the two components into a mixing chamber with a hard jet, so that vigorous mixing occurs.
Der Mischvorgang kann diskontinuierlich oder, bevorzugt, konti- nuierlich erfolgen. Als Folge des Mischvorgangs kommt es zu einer Präzipitation des Wirkstoffs in Form fester, röntgenamorpher Partikel. Die so erhaltene kolloidale Suspension kann dann auf an sich bekannte Weise in ein Trockenpulver überführt werden, beispielsweise durch Sprühtrocknung, Gefriertrocknung oder Trocknung im Wirbelbett .The mixing process can be carried out batchwise or, preferably, continuously. As a result of the mixing process, the active ingredient is precipitated in the form of solid, X-ray amorphous particles. The colloidal suspension obtained in this way can then be converted into a dry powder in a manner known per se, for example by spray drying, freeze drying or drying in a fluidized bed.
Bei der Herstellung der erfindungsgemäßen Zubereitungen verfährt man so, daß man den pH-Wert der Lösung des Hüllmaterials, insbesondere von Gelatine, und einer Lösung des Wirkstoffs so einstellt, daß bei den sich bildenden Wirkstoff-Partikeln keine Ladungsneutralität auftritt, d.h., man darf den pH-Wert der Gelatinelösung nicht auf einen solchen Wert einstellen, daß sich bei Bildung der Partikel ein ladungsneutraler Zustand einstellt. Vorzugsweise stellt man die Partikel bei pH-Werten größer 7 her.The preparation of the preparations according to the invention is carried out by adjusting the pH of the solution of the coating material, in particular gelatin, and a solution of the active ingredient in such a way that the active ingredient particles which form do not have any charge neutrality, that is to say that the Do not adjust the pH value of the gelatin solution to such a value that a charge-neutral state results when the particles are formed. The particles are preferably produced at pH values greater than 7.
Der mittlere Teilchendurchmesser der festen Wirkstoffpartikel in der Matrix des polymeren Hüllmaterials beträgt 20 bis 1000 nm, vorzugsweise 100 bis 600 nm. Die sphärischen Wirkstoff-Partikel sind völlig röntgenamorph. Röntgenamorph bedeutet in diesem Zusammenhang das Fehlen von Kristallinterferenzen bei Röntgen- pulverdiagrammen (vgl. H.P. Klug, L.E. Alexander, "X-Ray Diffraction procedures for Polycristalline and Amorphous Materials, John Wiley, New York, 1959). Die Wirkstoff-Partikel zeichnen sich dadurch aus, daß sie nach Redispergieren bei einem pH-Wert größer 5 in wäßrigem Milieu negativ geladen sind.The average particle diameter of the solid active ingredient particles in the matrix of the polymeric coating material is 20 to 1000 nm, preferably 100 to 600 nm. The spherical active ingredient particles are completely X-ray amorphous. In this context, X-ray amorphous means the absence of crystal interference in X-ray powder diagrams (cf. HP Klug, LE Alexander, "X-Ray Diffraction procedures for Polycristalline and Amorphous Materials, John Wiley, New York, 1959). The active substance particles are distinguished by the fact that after redispersion they are negatively charged in an aqueous medium at a pH greater than 5.
In der zweiten Zubereitungsform liegt der Wirkstoff molekulardispers verteilt in einer Hilfsstoffmatrix vor. Solche molekulardispersen Verteilungen eines Wirkstoffs in einer Matrix werden auch als "feste Lösungen" bezeichnet (Vgl. Chiou and Riegelman, J. Pharm. Sei., 60, 1281-1300). Solche festen Lösungen können nach dem Lösungsverfahren hergestellt werden, indem der Wirkstoff zusammen mit den die Hilfsstoffmatrix bildenden Komponenten in einem geeigneten Lösungsmittel gelöst werden und anschließend das Lösungsmittel entfernt wird. Als Lösungsmittel kommen beispielsweise Wasser, Ethanol, Isopropanol, Aceton, chlorierte Kohlenwas- serstoffe wie Methylenchlorid oder Chloroform, Tetrahydrofuran, Toluol oder Methylethylketon in Betracht. Üblicherweise wird das Lösungsmittel im Vakuum verdampft.In the second form of preparation, the active ingredient is present in a molecularly dispersed form in an auxiliary matrix. Such molecularly disperse distributions of an active ingredient in a matrix are also referred to as "solid solutions" (cf. Chiou and Riegelman, J. Pharm. Sei., 60, 1281-1300). Such solid solutions can be prepared by the solution process by dissolving the active ingredient together with the components forming the auxiliary matrix in a suitable solvent and then removing the solvent. Examples of suitable solvents are water, ethanol, isopropanol, acetone, chlorinated hydrocarbons such as methylene chloride or chloroform, tetrahydrofuran, toluene or methyl ethyl ketone. The solvent is usually evaporated in vacuo.
Weiterhin können solche festen Lösungen nach dem Schmelze- verfahren hergestellt werden, wobei der Wirkstoff und die die Hilfsstoffmatrix bildenden Einsatzstoffe in der Schmelze innig vermischt werden. Bevorzugt wird das Verfahren ohne Zugabe von Lösungsmitteln durchgeführt .Furthermore, such solid solutions can be produced by the melt process, the active ingredient and the starting materials forming the auxiliary matrix being intimately mixed in the melt. 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 Kneter der Firmen Haake oder Farrell.The melting process is carried out in a kneader or a screw extruder. Suitable kneaders are, for example, 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. 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. 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 bis 260°C, bevorzugt 50 bis 200°C.Depending on the composition, processing is generally carried out at temperatures of 40 to 260 ° C., preferably 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 kann 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 ebenfalls 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.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. In this way, the liquid or oily surface-active substance can be 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. 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.
Als geeignete Matrixbildner können die zweiten Zubereitungsformen beispielsweise thermoplastisch verarbeitbare wasserlösliche oder wasserquellbare Polymere enthalten. Wasserlöslich bedeutet, daß sich bei 25°C mindestens 1 g des Polymeren in 10 ml Wasser lösen. Wasserquellbar bedeutet, daß die Wasseraufnahme bei 25°C und 75 % relativer Luftfeuchte mehr als 1 Gew.-% beträgt, ohne daß sich das Polymer auflöst.The second preparation forms can contain, for example, thermoplastically processable water-soluble or water-swellable polymers as suitable matrix formers. Water-soluble means that at 25 ° C at least 1 g of the polymer dissolve in 10 ml of water. Water-swellable means that the water absorption at 25 ° C. and 75% relative air humidity is more than 1% by weight without the polymer dissolving.
Geeignete Polymere sind beispielsweise Homo- und Copolymere des N-Vinylpyrrolidons mit K-Werten nach Fikentscher von 19 bis 100. Als Comonomere kommt insbesondere N-Vinylacetat in Betracht, weiterhin auch Vinylpropionat , Vinylcaprolactam oder Vinyl- imidazol.Suitable polymers are, for example, homopolymers and copolymers of N-vinylpyrrolidone with K values according to Fikentscher from 19 to 100. Comonomers which are particularly suitable are N-vinyl acetate, and also vinyl propionate, vinyl caprolactam or vinyl imidazole.
Ebenso eignen sich auch Cellulosederivate beispielsweise Hydroxyalkylcellulosen wie Hydroxypropylcellulose, Alkyl- cellulosen oder Alkyl-Hydroxyalkylcellulosen wie Hydroxypropyl- methylcellulosen. Weiterhin eignen sich Polyethylenglykole mit Molekulargewichten von 1500 bis 10 Mio D oder Polyoxyethylen-polyoxypropylen-Block- copolymere .Cellulose derivatives are also suitable, for example, hydroxyalkyl celluloses such as hydroxypropyl cellulose, alkyl celluloses or alkyl hydroxyalkyl celluloses such as hydroxypropyl methyl celluloses. Polyethylene glycols with molecular weights of 1500 to 10 million D or polyoxyethylene-polyoxypropylene block copolymers are also suitable.
Selbstverständlich können auch Mischungen aus den genannten Poly- meren eingesetzt werden.Mixtures of the polymers mentioned can of course also be used.
Als Matrixbildner kommen weiterhin Zuckeralkohole wie Erythritol, Isomalt, Mannit, Sorbit, Xylit oder Gemische solcher Zuckeralkohole in Betracht.Sugar alcohols such as erythritol, isomalt, mannitol, sorbitol, xylitol or mixtures of such sugar alcohols are also suitable as matrix formers.
Weiterhin kann die Matrix noch pharmazeutisch akzeptable Hilfsstoffe wie Füllstoffe, Schmiermittel, Formentrennmittel, Fließregulierungsmittel, Weichmacher, Farbstoffe, Aromastoffe und/oder Stabilisatoren in den hierfür üblichen Mengen enthalten.Furthermore, the matrix can also contain pharmaceutically acceptable auxiliaries such as fillers, lubricants, mold release agents, flow regulators, plasticizers, colorants, flavorings and / or stabilizers in the amounts customary for this.
Nach einer weiteren Ausgestaltung der Erfindung können die Wirkstoff-Darreichungsformen eine dritte Zubereitungsform (Komponente 3) enthalten. In dieser Zubereitungsform liegt der Wirkstoff in Form von Partikeln vor, wobei der Wirkstoff in den Par- tikeln einen Kristallinitätsgrad von mindestens 20 % aufweist. Der Kristallinitätsgrad bezeichnet den Anteil der WirkstoffSubstanz, der nicht amorph vorliegt. Der Wirkstoff kann in Komponente 3 auch in verschiedenen Kristallmodifikationen vorliegen.According to a further embodiment of the invention, the active ingredient dosage forms can contain a third formulation (component 3). In this form of preparation, the active ingredient is in the form of particles, the active ingredient in the particles having a degree of crystallinity of at least 20%. The degree of crystallinity denotes the proportion of the active substance that is not amorphous. The active ingredient can also be present in component 3 in various crystal modifications.
Insbesondere liegt das Wirkstoff in dieser Zubereitungsform als kristalline Reinsubstanz ohne weitere Hilfsstoffe vor. Die Partikel weisen mittlere Durchmesser im Bereich von 0,05 bis 200 μm, bevorzugt 0,1 bis 50 μm, auf. Die kristallinen Partikel können durch an sich bekannte Mahlprozesse aus kristalliner Roh- wäre erhalten werden. Geeignete Mahlprozesse sind beispielsweise Trocken- oder Naßvermahlung. Geeignete Vorrichtungen sind beispielsweise Kugelmühlen, Stiftmühlen oder LuftStrahlmühlen.In particular, the active ingredient in this preparation form is in the form of a pure crystalline substance without further auxiliaries. The particles have average diameters in the range from 0.05 to 200 μm, preferably 0.1 to 50 μm. The crystalline particles can be obtained from crystalline raw materials by grinding processes known per se. Suitable grinding processes are, for example, dry or wet grinding. Suitable devices are, for example, ball mills, pin mills or air jet mills.
Die erfindungsgemäßen Darreichungsformen werden durch physi- kalisches Mischen der Komponenten 1, 2 und 3 erhalten. Bevorzugt liegt der Gesamtanteil an Wirkstoff der Komponente 1 im Bereich von 10 bis 70 Gew.-%, besonders bevorzugt von 20 bis 60 Gew.-%, der Komponente 2 im Bereich von 10 bis 70 Gew.-%, besonders bevorzugt von 20 bis 60 Gew.-%, und der Komponente 3 im Bereich von 0 bis 30 Gew.-%. Die physikalischen Eigenschaften der einzelnen Komponenten sind nach dem Mischen unverändert.The dosage forms according to the invention are obtained by physically mixing components 1, 2 and 3. The total proportion of active ingredient of component 1 is in the range from 10 to 70% by weight, particularly preferably from 20 to 60% by weight, of component 2 in the range from 10 to 70% by weight, particularly preferably from 20 to 60% by weight, and component 3 in the range from 0 to 30% by weight. The physical properties of the individual components are unchanged after mixing.
Die erfindungsgemäßen physikalischen Mischungen zweier oder dreier Zubereitungen des Wirkstoffs, in denen das Wirkstoff jeweils in einer anderen physikalischen Form vorliegt, lassen sich in allen hierfür geeigneten oralen Arzneiformen einsetzen. So kann man sie beispielsweise in Hart- oder Weichgelatine- Kapseln füllen oder unter an sich bekannten Bedingungen zuThe physical mixtures according to the invention of two or three preparations of the active ingredient, in which the active ingredient is in a different physical form, can be used in all oral dosage forms suitable for this purpose. So you can, for example, in hard or soft gelatin Fill capsules or under known conditions
Tabletten verpressen.Press tablets.
Überraschenderweise weisen die erfindungsgemäßen Darreichungs- formen Bioverfügbarkeiten auf, die über denen der Einzelkomponenten liegen. Ein solcher synergistischer Effekt war für den Fachmann nicht zu erwarten.Surprisingly, the dosage forms according to the invention have bioavailability which is higher than that of the individual components. Such a synergistic effect was not to be expected for the person skilled in the art.
Die Ergebnisse einer Hundestudie belegen die gute Bioverfüg- barkeit der Darreichungsform im Vergleich zu einem Marktprodukt.The results of a dog study demonstrate the good bioavailability of the dosage form compared to a market product.
Herstellbeispiel 1Production Example 1
Herstellung eines Wirkstoff-Trockenpulvers mit einem Wirkstoff- gehalt im Bereich von 10 Gew.-%Production of an active ingredient dry powder with an active ingredient content in the range of 10% by weight
a) Herstellung des Mikronisatsa) Production of the micronizate
3 g Cyclosporin A wurden in eine Lösung von 0,6 g Ascorbyl- palmitat in 36 g Isopropanol bei 25°C eingerührt, wobei eine klare Lösung entstand.3 g of cyclosporin A were stirred into a solution of 0.6 g of ascorbyl palmitate in 36 g of isopropanol at 25 ° C., a clear solution being formed.
Zur Ausfällung des Cyclosporin A in kolloiddisperser Form wurde diese molekulardisperse Lösung bei 25°C einer Misch- kammer zugeführt. Dort erfolgte die Vermischung mit 537 g einer mittels 1 N NaOH auf pH 9,2 eingestellten wäßrigen Lösung von 14,4 g Gelatine B 100 Bloom und 12,6 g Lactose in vollentsalztem Wasser. Der gesamte Prozeß erfolgte unter Druckbegrenzung auf 30 bar. Nach dem Mischen wurde eine kolloiddisperse Cyclosporin A-Dispersion mit einem weißtrüben Farbton erhalten.To precipitate cyclosporin A in a colloidally dispersed form, this molecularly disperse solution was fed to a mixing chamber at 25 ° C. There, the mixture was mixed with 537 g of an aqueous solution of 14.4 g of gelatin B 100 Bloom and 12.6 g of lactose in demineralized water, which had been adjusted to pH 9.2 using 1 N NaOH. The entire process was carried out with a pressure limit of 30 bar. After mixing, a colloidally disperse cyclosporin A dispersion was obtained with a white cloudy color.
Durch quasielastische Lichtstreuung wurde die mittlere Teilchengröße zu 256 nm bei einer Varianz von 31 % bestimmt. Mittels Fraunhofer-Beugung wurde der Mittelwert der Volumenverteilung zu D(4,3) = 0,62 μm bei einem Feinanteil der Verteilung von 99,2 <1,22 μm bestimmt.The mean particle size was determined to be 256 nm with a variance of 31% by quasi-elastic light scattering. Using Fraunhofer diffraction, the mean value of the volume distribution was determined to be D (4.3) = 0.62 μm with a fine fraction of the distribution of 99.2 <1.22 μm.
b) Trocknung der Dispersion a) zu einem nanopartikulären Trockenpulverb) drying the dispersion a) to a nanoparticulate dry powder
Sprühtrocknung des Produktes la) ergab ein nanopartikuläres Trockenpulver. Der Wirkstoffgehalt im Pulver wurde chromatographisch zu 9,95 Gew.-% bestimmt. Das Trockenpulver löst sich in Trinkwasser unter Ausbildung einer weiß-trüben Dispersion (Hydrosol). Herstellbeispiel 2Spray drying of the product la) gave a nanoparticulate dry powder. The active ingredient content in the powder was determined by chromatography to be 9.95% by weight. The dry powder dissolves in drinking water to form a white, cloudy dispersion (hydrosol). Preparation example 2
Herstellung eines Cyclosporin-Trockenpulvers mit einem Wirkstoffgehalt im Bereich von 15 Gew.-%Production of a cyclosporin dry powder with an active substance content in the range of 15% by weight
a) Herstellung des Mikronisatsa) Production of the micronizate
3 g Cyclosporin A wurden in eine Lösung von 0,6 g Ascorbyl- palmitat in 18 g Isopropanol und 18 g vollentsalztem Wasser bei 25°C eingerührt. Diese Lösung wurde durch Erhitzen in einem Wärmeaustauscher in den molekular gelösten Zustand überführt. Die Verweilzeit der Cyclosporin-Lösung im Wärmeaustauscher betrug 90 sec, wobei eine Temperatur von maximal 135°C nicht überschritten wurde.3 g of cyclosporin A were stirred into a solution of 0.6 g of ascorbyl palmitate in 18 g of isopropanol and 18 g of deionized water at 25 ° C. This solution was converted into the molecularly dissolved state by heating in a heat exchanger. The residence time of the cyclosporin solution in the heat exchanger was 90 seconds, a temperature of a maximum of 135 ° C. not being exceeded.
Zur Ausfällung des Cyclosporin A in kolloiddisperser Form wurde diese molekulardisperse Lösung bei 135°C einer Mischkammer zugeführt. Dort erfolgte die Vermischung mit 393,9 g einer mittels 1 N NaOH auf pH 9,2 eingestellten wäßrigen Lösung von 9,2 g Gelatine A 100 Bloom und 6,1 g Lactose in vollentsalztem Wasser. Der Prozeß erfolgte unter Druckbegrenzung auf 30 bar, um ein Verdampfen des Wassers zu verhindern. Nach dem Vermischen wurde eine kolloiddisperse Cyclosporin A-Dispersion mit einem weiß-trüben Farbton erhalten.To precipitate cyclosporin A in a colloidally dispersed form, this molecularly disperse solution was fed to a mixing chamber at 135 ° C. There, the mixture was mixed with 393.9 g of an aqueous solution of 9.2 g of gelatin A 100 Bloom and 6.1 g of lactose in demineralized water, which had been adjusted to pH 9.2 using 1 N NaOH. The process was carried out under pressure limitation to 30 bar to prevent the water from evaporating. After mixing, a colloidally disperse cyclosporin A dispersion with a white, cloudy shade was obtained.
Durch quasi-elastische Lichtstreuung wurde die mittlere Teilchengröße zu 285 nm bei einer Varianz von 48 % bestimmt. Mittels Fraunhofer-Beugung wurde der Mittelwert der Volumen- Verteilung zu D(4,3) = 0,62 μm bei einem Feinanteil der Verteilung von 99,8 % <1,22 μm bestimmtThe mean particle size was determined to be 285 nm with a variance of 48% by quasi-elastic light scattering. Using Fraunhofer diffraction, the mean value of the volume distribution was determined to be D (4.3) = 0.62 μm with a fine fraction of the distribution of 99.8% <1.22 μm
b) Trocknung der Dispersion 2a) zu einem Trockenpulverb) drying the dispersion 2a) to a dry powder
Sprühtrocknung der Dispersion führte zu einem nanopartiku- lären Trockenpulver. Der Wirkstoffgehalt im Trockenpulver wurde chromatographisch zu 15,9 Gew.-% bestimmt. Das Trockenpulver löst sich in Trinkwasser unter Ausbildung einer weißtrüben Dispersion.Spray drying the dispersion resulted in a nanoparticulate dry powder. The active substance content in the dry powder was determined by chromatography to be 15.9% by weight. The dry powder dissolves in drinking water to form a white cloudy dispersion.
Durch uasielastische Lichtstreuung wurde die mittlere Teilchengröße sofort nach dem Redispergieren zu 376 nm bei einer Varianz von 38 % bestimmt. Mittels Fraunhofer Beugung wurde der Mittelwert der Volumenverteilung zu D(4,3) = 0,77 μm bei einem Feinanteil der Verteilung von 84,7 % <1,22 μm bestimmt. Gefriertrocknung des Produktes führte zu einem nanopartiku- lären Trockenpulver. Der Wirkstoffgehalt im Pulver wurde chromatographisch zu 16,1 Gew.-% Cyclosporin bestimmt. DasThe average particle size was determined immediately after redispersion to be 376 nm with a variance of 38% by uasielastic light scattering. Using Fraunhofer diffraction, the mean value of the volume distribution was determined to be D (4.3) = 0.77 μm with a fine fraction of the distribution of 84.7% <1.22 μm. Freeze drying of the product resulted in a nanoparticulate dry powder. The active substance content in the powder was determined by chromatography to be 16.1% by weight of cyclosporin. The
Trockenpulver löste sich in Trinkwasser zu einem weiß-trüben Hydrosol .Dry powder dissolved in drinking water to form a white, cloudy hydrosol.
Durch quasi-elastische Lichtstreuung wurde die mittlere Teilchengröße sofort nach dem Redispergieren zu 388 nm bei einer Varianz von 32 % bestimmt. Mittels Fraunhofer-Beugung wurde der Mittelwert der Volumenverteilung zu D(4,3) = 0,79 μm bei einem Feinanteil der Verteilung von 82,4 % <1,22 μm bestimmt.The average particle size was determined by quasi-elastic light scattering immediately after redispersion to be 388 nm with a variance of 32%. Using Fraunhofer diffraction, the mean value of the volume distribution was determined to be D (4.3) = 0.79 μm with a fine fraction of the distribution of 82.4% <1.22 μm.
Herstellbeispiel 3Preparation example 3
Analog Beispiel 2a) wurde eine kolloiddisperse Cyclosporin A-Dispersion aus 4,5 g Cyclosporin A, 0,9 g Ascorbylpalmitat , 9,6 g Gelatine A 100 Bloom und 7,2 g Lactose hergestellt.Analogously to example 2a), a colloidally disperse cyclosporin A dispersion was prepared from 4.5 g of cyclosporin A, 0.9 g of ascorbyl palmitate, 9.6 g of gelatin A 100 Bloom and 7.2 g of lactose.
Durch quasi-elastische Lichtstreuung wurde die mittlere Teilchengröße zu 280 nm bei einer Varianz von 21 % bestimmt. Mittels Fraunhofer-Beugung wurde der Mittelwert der Volumenverteilung zu D(3,4) = 0,62 μm bei einem Feinanteil der Verteilung von 99,2 % <1,2 μm bestimmt.The mean particle size was determined to be 280 nm with a variance of 21% by quasi-elastic light scattering. Using Fraunhofer diffraction, the mean value of the volume distribution was determined to be D (3.4) = 0.62 μm with a fine fraction of the distribution of 99.2% <1.2 μm.
b) Trocknung der Dispersion 3a) zu einem nanopartikulären Trockenpulverb) drying the dispersion 3a) to a nanoparticulate dry powder
Durch Sprühtrocknung wurde ein nanopartikuläres Trockenpulver mit einem Cyclosporin A-Gehalt (chromatographisch bestimmt) von 19,9 Gew.-% erhalten. Das Trockenpulver löste sich in Trinkwasser unter Ausbildung einer weiß-trüben Dispersion (Hydrosol) .A nanoparticulate dry powder with a cyclosporin A content (determined by chromatography) of 19.9% by weight was obtained by spray drying. The dry powder dissolved in drinking water to form a white, cloudy dispersion (hydrosol).
Durch quasi-elastische Lichtstreuung wurde die die mittlere Teilchengröße sofort nach dem Redispergieren zu 377 nm bei einer Varianz von 45 % bestimmt. Mittels Fraunhofer Beugung wurde der Mittelwert der Volumenverteilung zu D(4,3) = 0,62 μm bei einem Feinanteil der Verteilung von 83,3 % <1,2 μm bestimmt.The mean particle size was determined immediately after redispersion to be 377 nm with a variance of 45% by quasi-elastic light scattering. Using Fraunhofer diffraction, the mean value of the volume distribution was determined to be D (4.3) = 0.62 μm with a fine fraction of the distribution of 83.3% <1.2 μm.
Herstellbeispiel 4Preparation example 4
Analog Herstellbeispiel 3 wurde eine Zubereitung hergestellt, bei der als Hüllmatrixmaterial Fischgelatine mit Molgewichtsanteilen von 103 bis 107 D eingesetzt wurde. Herstellbeispiel 5A preparation was produced in the same way as in production example 3, in which fish gelatin with molecular weight fractions of 10 3 to 10 7 D was used as the coating matrix material. Preparation example 5
Herstellung einer festen Lösung von Cyclosporin durch Schmelz- extrusionPreparation of a solid solution of cyclosporin by melt extrusion
Die Herstellung erfolgte in einem Doppelschneckenextruder ZKS30 der Fa. Werner & Pfleiderer bei einem Durchsatz von 2 kg/Stunde. Die Formgebung des noch plastischen Extrudats erfolgte wie in der EP-A 240 960 beschrieben durch Kalandrierung . Verarbeitet wurde eine Mischung aus 65 Gew.-% eines Polyvinylpyrrolidons mit dem K-Wert 12, 15 Gew.-% Poloxamer 407 und 20 Gew.-% Cyclosporin. Temperatur der Schüsse: 50, 88, 128, 131, 127, 126°C; Düse: 120°C.It was produced in a ZKS30 twin-screw extruder from Werner & Pfleiderer at a throughput of 2 kg / hour. The still plastic extrudate was shaped as described in EP-A 240 960 by calendering. A mixture of 65% by weight of a polyvinylpyrrolidone with a K value of 12, 15% by weight of Poloxamer 407 and 20% by weight of cyclosporin was processed. Shot temperature: 50, 88, 128, 131, 127, 126 ° C; Nozzle: 120 ° C.
Die kalandrierten Formen wurden mittels einer Luftstrahlmühle vermählen, so daß 95 % der Teilchen einen Durchmesser <10 μm aufwies .The calendered molds were ground using an air jet mill, so that 95% of the particles had a diameter of <10 μm.
Herstellbeispiel 6Preparation example 6
Analog zu Beispiel 5 wurde eine Mischung aus 80 Gew.-% eines Copolymerisats aus 60 Gew.-% N-Vinylpyrrolidon und 40 Gew.-% Vinylacetat sowie 20 Gew.-% Cyclosporin verarbeitet. Temperatur der Schüsse: 55, 110, 140, 137, 136, 141°C; Düse: 140°C.Analogously to Example 5, a mixture of 80% by weight of a copolymer of 60% by weight of N-vinylpyrrolidone and 40% by weight of vinyl acetate and 20% by weight of cyclosporin was processed. Shot temperature: 55, 110, 140, 137, 136, 141 ° C; Nozzle: 140 ° C.
Pharmakokinetische Eigenschaften der ZubereitungsformenPharmacokinetic properties of the preparation forms
Blutspiegelkinetik am Hund: Allgemeine MethodeBlood level kinetics in dogs: general method
Cyclosporin wurde in der entsprechenden Zubereitung Beagle-Hunden mit einem Gewicht im Bereich von 8 bis 12 kg entweder oral als feste Form oder mittels Schlundsonde bei flüssigen Formen verabreicht. Flüssige Formen wurden in 50 ml Wasser gegeben und mit weiteren 50 ml Wasser nachgespült. Feste Formen wurden ohne Wasser verabreicht. Den Tieren wurde 16 h vor der Substanzgabe das Futter entzogen, eine erneute Fütterung erfolgte 4 h nach Substanzgabe. Den Hunden wurde vor Substanzgabe und im Zeitraster bis 32 h nach Substanzgabe aus der Vena jugularis oder der Vena cephalica antebrachii in heparinisierten Gefäßen Blut entnommen. Das Blut wurde tiefgefroren und bis zur analytischen Aufarbeitung bei -20°C aufbewahrt. Die Blutspiegelbestimmung erfolgte durch eine validierte, intern standardisierte GC-MS-Methode . Form 1 (zum Vergleich) :Cyclosporin was administered in the corresponding preparation to beagle dogs with a weight in the range from 8 to 12 kg either orally as a solid form or by gavage in liquid forms. Liquid forms were placed in 50 ml of water and rinsed with a further 50 ml of water. Solid forms were administered without water. The feed was withdrawn from the animals 16 h before the substance was administered, and the animals were fed again 4 h after the substance was administered. Blood was drawn from the jugular vein or the antebrachial vein in heparinized vessels from the dogs before administration of the substance and in a time interval of up to 32 hours after administration of the substance. The blood was frozen and stored at -20 ° C until analytical processing. Blood levels were determined using a validated, internally standardized GC-MS method. Form 1 (for comparison):
Sandimmun Optoral, Kapsel, 100 mg WirkstoffSandimmun Optoral , capsule, 100 mg active ingredient
Form 2 : 5 Trockenpulver gemäß Herstellbeispiel 2, Wirkstoffdosis 100 mg; Verabreichung als HydrosolForm 2: 5 dry powder according to preparation example 2, active ingredient dose 100 mg; Administration as a hydrosol
Form 3 :Form 3:
Extrudat gemäß Herstellbeispiel 5, Wirkstoffdosis 100 mg; 10 Verabreichung als TabletteExtrudate according to preparation example 5, active ingredient dose 100 mg; 10 Administration as a tablet
Form 4 :Form 4:
Kombination aus Trockenpulver gemäß Beispiel 2 und Extrudat gemäß Beispiel 5, Wirkstoffdosis im Trockenpulver 50 mg und im Extrudat 15 50 mgCombination of dry powder according to Example 2 and extrudate according to Example 5, active ingredient dose in dry powder 50 mg and in extrudate 15 50 mg
Flächen unter den Blutspiegelkurven und relative BioverfügbarkeitAreas under the blood level curves and relative bioavailability
Tabelletable
2020
Form 1 (Sandimmun Optoral)Form 1 (Sandimmun Optoral)
2525
30 30
AUC: Area under the curveAUC: Area under the curve
BV: Bioverfügbarkeit tmax: [h]BV: Bioavailability tmax: [h]
35 Cmax: [ng/ml]35 Cmax: [ng / ml]
Form 2Form 2
4040
45 Form 345 Form 3
Form 4Form 4

Claims

Patentansprüche claims
1. Feste pharmazeutische Darreichungsform, enthaltend einen Wirkstoff in Form einer physikalischen Mischung mindestens zweier hinsichtlich des physikalischen Zustands des Wirkstoffs verschiedener Zubereitungen.1. Solid pharmaceutical dosage form containing an active ingredient in the form of a physical mixture of at least two preparations which differ in terms of the physical state of the active ingredient.
2. Feste Darreichungsform nach Anspruch 1, enthaltend eine erste Zubereitung (Komponente 1) , in der der Wirkstoff in Form fester röntgenamorpher Partikel kolloidaldispers in eine Hüllmatrix eingebettet ist, und eine zweite Zubereitung (Komponente 2), in der der Wirkstoff molekulardispers in einer Hilfsstoffmatrix vorliegt.2. Solid dosage form according to claim 1, containing a first preparation (component 1), in which the active ingredient in the form of solid X-ray amorphous particles is colloidally dispersed in an envelope matrix, and a second preparation (component 2), in which the active ingredient is molecularly dispersed in an auxiliary matrix is present.
3. Feste Darreichungsform nach Anspruch 1 oder 2, enthaltend ein dritte hinsichtlich des physikalischen Zustands des Wirkstoffs verschiedene Zubereitung (Komponente 3).3. Solid dosage form according to claim 1 or 2, containing a third preparation with respect to the physical state of the active ingredient (component 3).
4. Feste Darreichungsform nach einem der Ansprüche 1 bis 3, enthaltend als Komponente 3 Wirkstoffpartikel , in denen der Wirkstoff einen Kristallinitätsgrad von mindestens 20 % aufweist.4. Solid dosage form according to one of claims 1 to 3, containing as component 3 active ingredient particles in which the active ingredient has a degree of crystallinity of at least 20%.
5. Feste Darreichungsform nach einem der Ansprüche 1 bis 3, in der die Wirkstoffpartikel der Komponente 1 einen mittleren Teilchendurchmesser von 0,02 bis 1 μm aufweisen.5. Solid dosage form according to one of claims 1 to 3, in which the active ingredient particles of component 1 have an average particle diameter of 0.02 to 1 μm.
6. Feste Darreichungsform nach einem der Ansprüche 1 bis 4, in der die Hüllmatrix der Komponente 1 aus einem oder mehreren polymeren Schutzkolloiden besteht .6. Solid dosage form according to one of claims 1 to 4, in which the shell matrix of component 1 consists of one or more polymeric protective colloids.
7. Feste Darreichungsform nach einem der Ansprüche 1 bis 5, in der die Hilfsstoffmatrix der Komponente 2 ein oder mehreren wasserlösliches Polymer enthält.7. Solid dosage form according to one of claims 1 to 5, in which the auxiliary matrix of component 2 contains one or more water-soluble polymer.
8. Feste Darreichungsform nach einem der Ansprüche 1 bis 7, enthaltend 10 bis 90 Gew.-% des Wirkstoffs in Komponente 1 und 10 bis 90 Gew.-% des Wirkstoffs in Komponente 2. 8. Solid dosage form according to one of claims 1 to 7, containing 10 to 90 wt .-% of the active ingredient in component 1 and 10 to 90 wt .-% of the active ingredient in component 2.
9. Feste Darreichungsform nach einem der Ansprüche 1 bis 4, wobei die Komponente 3 in verschiedenen Kristallmodifikationen vorliegt.9. Solid dosage form according to one of claims 1 to 4, wherein component 3 is present in various crystal modifications.
5 10. Feste Darreichungsform nach einem der Ansprüche 1 bis 8, enthaltend 20 bis 60 Gew.-% des Wirkstoffs in Komponente 1, 20 bis 60 Gew.-% des Wirkstoffs in Komponente 2 und 0 bis 30 Gew.-% des Wirkstoffs in Komponente 3.5 10. Solid dosage form according to one of claims 1 to 8, containing 20 to 60 wt .-% of the active ingredient in component 1, 20 to 60 wt .-% of the active ingredient in component 2 and 0 to 30 wt .-% of the active ingredient in Component 3.
10 11. Feste Darreichungsform nach einem der Ansprüche 1 bis 9, enthaltend als Wirkstoff Cyclosporin.11. Solid dosage form according to one of claims 1 to 9, containing cyclosporin as active ingredient.
1515
2020
55
00
55
00
5 5
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US6465016B2 (en) * 1996-08-22 2002-10-15 Research Triangle Pharmaceuticals Cyclosporiine particles
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DE102005026755A1 (en) * 2005-06-09 2006-12-14 Basf Ag Production of solid solutions of sparingly soluble active ingredients by short-term overheating and rapid drying

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CA2125284C (en) * 1991-12-05 2000-06-20 Jens-Christian Wunderlich Peroral administration form for peptidic medicaments, in particular insulin
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