EP1223960A2 - Preparations de principes actifs pharmaceutiques - Google Patents

Preparations de principes actifs pharmaceutiques

Info

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Withdrawn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)
English (en)
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/fr
Withdrawn legal-status Critical Current

Links

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)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Nanotechnology (AREA)
  • Physics & Mathematics (AREA)
  • Biomedical Technology (AREA)
  • Optics & Photonics (AREA)
  • Pulmonology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des formes galéniques pharmaceutiques solides contenant un principe actif sous forme de mélange physique d'au moins deux préparations différentes en termes d'état physique du principe actif.
EP00972786A 1999-10-26 2000-10-17 Preparations de principes actifs pharmaceutiques Withdrawn EP1223960A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19951617 1999-10-26
DE19951617A DE19951617A1 (de) 1999-10-26 1999-10-26 Zubereitungen pharmazeutische Wirkstoffe
PCT/EP2000/010205 WO2001030372A2 (fr) 1999-10-26 2000-10-17 Preparations de principes actifs pharmaceutiques

Publications (1)

Publication Number Publication Date
EP1223960A2 true EP1223960A2 (fr) 2002-07-24

Family

ID=7926968

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00972786A Withdrawn EP1223960A2 (fr) 1999-10-26 2000-10-17 Preparations de principes actifs pharmaceutiques

Country Status (7)

Country Link
EP (1) EP1223960A2 (fr)
JP (1) JP2004500343A (fr)
CN (1) CN1384753A (fr)
CA (1) CA2388614A1 (fr)
DE (1) DE19951617A1 (fr)
PL (1) PL354991A1 (fr)
WO (1) WO2001030372A2 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7255877B2 (en) 1996-08-22 2007-08-14 Jagotec Ag Fenofibrate microparticles
US6465016B2 (en) * 1996-08-22 2002-10-15 Research Triangle Pharmaceuticals Cyclosporiine particles
US6979456B1 (en) 1998-04-01 2005-12-27 Jagotec Ag Anticancer compositions
DE69912441T2 (de) 1998-08-19 2004-08-19 Skyepharma Canada Inc., Verdun Injizierbare wässerige propofoldispersionen
AR033711A1 (es) * 2001-05-09 2004-01-07 Novartis Ag Composiciones farmaceuticas
DE102005026755A1 (de) * 2005-06-09 2006-12-14 Basf Ag Herstellung von festen Lösungen schwerlöslicher Wirkstoffe durch Kurzzeitüberhitzung und schnelle Trocknung

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0816053B2 (ja) * 1986-12-04 1996-02-21 大正製薬株式会社 貼付剤の製造方法
JPH0436237A (ja) * 1990-06-01 1992-02-06 Taiho Yakuhin Kogyo Kk 抗腫瘍性複合製剤
ES2085656T3 (es) * 1991-12-05 1996-06-01 Alfatec Pharma Gmbh Forma de administracion peroral de medicamentos peptidicos, en particular insulina.
GB9325445D0 (en) * 1993-12-13 1994-02-16 Cortecs Ltd Pharmaceutical formulations
JP4189044B2 (ja) * 1997-07-01 2008-12-03 大正製薬株式会社 マルチプルユニットタイプ徐放性錠剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0130372A2 *

Also Published As

Publication number Publication date
JP2004500343A (ja) 2004-01-08
CN1384753A (zh) 2002-12-11
CA2388614A1 (fr) 2001-05-03
WO2001030372A3 (fr) 2001-11-01
DE19951617A1 (de) 2001-05-03
PL354991A1 (en) 2004-03-22
WO2001030372A2 (fr) 2001-05-03

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