EP1124538A2 - Composition pour administration parenterale de principes actifs - Google Patents

Composition pour administration parenterale de principes actifs

Info

Publication number
EP1124538A2
EP1124538A2 EP99948917A EP99948917A EP1124538A2 EP 1124538 A2 EP1124538 A2 EP 1124538A2 EP 99948917 A EP99948917 A EP 99948917A EP 99948917 A EP99948917 A EP 99948917A EP 1124538 A2 EP1124538 A2 EP 1124538A2
Authority
EP
European Patent Office
Prior art keywords
composition according
composition
microparticles
water
polysaccharide
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Withdrawn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
EP99948917A
Other languages
German (de)
English (en)
Inventor
Jürgen Grande
Silke Schuth
Gitte Böhm
Holger Bengs
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.)
Suedzucker AG
Original Assignee
Celanese GmbH
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 Celanese GmbH filed Critical Celanese GmbH
Publication of EP1124538A2 publication Critical patent/EP1124538A2/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Withdrawn legal-status Critical Current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
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • composition for the parenteral application of active ingredients are provided.
  • the present invention relates to a composition for the parenteral application of active ingredients comprising a particulate carrier material based on polysaccharide and a stable suspension thereof.
  • active substance carriers are of importance which meet the requirements of the respective
  • Administration form are optimally adapted, which can be applied gently and which can have a targeted influence on the biodistribution, bioavailability or absorption of an active ingredient.
  • the active substance carriers in the organism should disintegrate in a controlled manner, on the one hand to enable controlled release of the active substance over a longer period of time if necessary and on the other hand to ensure the biocompatible degradation of the carrier.
  • an active ingredient carrier For parenteral application e.g. B. by means of injection, an active ingredient carrier must be selected which can form a stable suspension and has excellent cannula mobility, in particular with a very small cannula diameter. From the point of view of biocompatibility, the suspension stability should also be guaranteed without the addition of dispersing agents.
  • US Pat. No. 4,451,452 describes a composition for parenteral administration, the polymer used being a biodegradable carrier material which is naturally water-soluble and contains hydroxyl groups and which has been rendered water-insoluble by partial esterification.
  • Various compounds such as polyvinyl alcohol or amylose are mentioned as examples of the water-soluble polymer.
  • the carrier material for the injection as a suspension it is proposed to use the carrier material in the form of particles together with an emulsifying aid such as low molecular weight polyvinyl alcohol.
  • WO 96/39464 describes suspensions of particles made of a crosslinked water-soluble polymer suitable for injection, which can still pass cannulas with a comparatively small diameter of 20 gauge (corresponding to a diameter of 0.9 mm and a length of 40 mm).
  • water-soluble polymers examples include a. called natural polysaccharides like amylose.
  • US Patent No. 1, 143,219 describes a process for making a stable suspension from an amylose material obtained from an amylose-rich starch.
  • the amylose-rich starch is first degraded by acid hydrolysis and the water-insoluble degradation products obtained are then mechanically comminuted until the material is distributed so finely that it can form a stable suspension.
  • the particles obtained are very inconsistent in size and shape and therefore have to be subjected to additional classification processes. There is also no indication of a potential suitability for parenteral use.
  • composition for parenteral administration which contains a carrier material which can form a stable suspension even without the addition of appropriate auxiliaries, has a high cannula compatibility and has excellent biocompatibility.
  • the carrier material should have a depot effect and be suitable for the controlled release of active ingredient.
  • composition for the parenteral administration of active substances which is a carrier material and at least one Contains active ingredient, wherein the carrier material contains spherical microparticles with an average diameter of 1 nm to 100 microns, which consist entirely or partially of at least one water-insoluble linear polysaccharide.
  • spherical microparticles according to the invention which consist wholly or partly of water-insoluble linear polysaccharides is essential for solving this problem.
  • Microparticles of this type are distinguished by a high degree of uniformity in size and shape and therefore have excellent cannula mobility even with a very small cannula diameter. In addition, they form slightly stable suspensions even without the addition of dispersing agents.
  • microparticles used according to the invention are distinguished by high biocompatibility.
  • Biodegradation is understood to mean any process that takes place in vivo, which leads to a degradation or destruction of the compounds, in particular the polysaccharides. This includes z. B. hydrolytic or enzymatic
  • the spherical microparticles used as carrier material have an average diameter dn (number average) of 1 nm to 100 ⁇ m, preferably 100 nm to 10 ⁇ m, and particularly preferably 1 ⁇ m to 5 ⁇ m.
  • Spherical microparticles are to be understood as microparticles which have approximately spherical shape.
  • a sphere is described by axes of the same length that start from a common origin and are directed into space Define the radius of the sphere in all spatial directions, the spherical particles can deviate from the ideal length of the sphere by 1% to 40%. The deviation is preferably 25% or less, particularly preferably 15% or less.
  • the surface of the spherical particles can be compared macroscopically with a raspberry, the depth of irregularities on the particle surface, such as indentations or cuts, being at most 20%, preferably 10%, of the mean diameter of the spherical microparticles.
  • the specific surface area of the microparticles is generally from 1 m 2 / g to 100 m 2 / g, preferably 1.5 m 2 / g to 20 m 2 / g and particularly preferably 3 m 2 / g to 10 m 2 / g.
  • the mean values used here are defined as follows:
  • the spherical microparticles are prepared by dissolving the water-insoluble linear polysaccharide or a mixture of several of these and, if appropriate, further biocompatible polymers in a solvent, for. B. DMSO, introducing the solution into a precipitant, e.g. B. water, preferably at a temperature of 20 ° C to 60 ° C, if necessary cooling the solution to a temperature of minus 10 ° C to plus 10 ° C and separating the particles formed.
  • a precipitant e.g. B. water
  • the dissolving process of the poiysaccharide used as the starting material can take place at room temperature or higher temperatures.
  • the properties of the microparticles such as size, surface structure, porosity, etc., as well as the process control can be influenced.
  • Suitable additives are e.g. surfactants such as sodium dodecyl sulfate,
  • Alkyl polyglycol ether ethylene oxide-propylene oxide block copolymers (e.g. Pluronic
  • alkyl polyglycol ether sulfates generally alkyl sulfates and fatty acid glycol esters
  • sugars such as e.g. Fructose, sucrose, glucose, water-soluble cellulose or hot-water-soluble poly-alpha-D-glucan such as e.g. native or chemically modified starches, poly-alpha-D-glucans obtained from these starches and starch-analogous compounds.
  • additives are usually added to the precipitant.
  • the amount used depends on the individual case and the desired
  • crosslinking agents in the production of the particles can be dispensed with.
  • Linear water-insoluble polysaccharides for the purposes of the present invention
  • Polysaccharides which are made up of Monosaccharide ⁇ , Disacchariden or other monomeric building blocks in such a way that the individual building blocks are always linked in the same way.
  • Each basic unit or building block defined in this way has exactly two links, one each to a different monomer. The only exception are the two basic units that form the beginning and the end of the polyaccharide. These have only one link to another monomer and form the end groups of the linear polyaccharide.
  • the linear water-insoluble polysaccharides have a maximum degree of branching of 8%, i.e. they have a maximum of 8 branches per 100 basic units.
  • the degree of branching is preferably less than 4% and in particular a maximum of 2.5%.
  • the degree of branching in the 6-position is less than 4%, preferably a maximum of 2% and in particular a maximum of 0.5% and the degree of branching in the other positions, e.g. B. in 2- or 3-position, is preferably a maximum of 2% and in particular 1%.
  • polysaccharides in particular polyglycans such as poly-alpha-D-glucans, which have no branches or whose degree of branching is so minimal that it can no longer be detected using conventional methods
  • Examples of preferred water-insoluble linear polysaccharides are linear poly-D-glucans, the type of linkage being immaterial as long as there is linearity in the sense of the invention.
  • Examples are poly (1 ! 4-alpha-D-glucan) and poly (1, 3- beta-D-glucan), with poly (1,4-alpha-D-glucan) being particularly preferred.
  • sparingly soluble to practically insoluble compounds in particular very sparingly soluble to practically insoluble compounds, are preferred.
  • they can be obtained from natural plant or animal sources by isolation and / or purification.
  • Sources can also be used which have been genetically manipulated in such a way that they contain a higher proportion of unbranched or comparatively slightly branched polysaccharides compared to the unmanipulated source.
  • Biotechnical methods include biocatalytic, also biotransformatory, or fermentative processes.
  • Modified water-insoluble linear polysaccharides can also be used, it being possible for the polysaccharides to have been chemically modified, for example by esterification and / or etherification, in one or more positions which are not involved in the linear linkage.
  • the modification can take place in the 2-, 3- and / or 6-position. Measures for such modifications are well known to the person skilled in the art.
  • Linear polysaccharides such as pullulans, pectins, mannans or polyfructans, which are water-soluble per se, can be water-insoluble by modification be made.
  • alpha-amylase-resistant polysaccharides can be used, such as, B. are described in German Patent Application No. 19830618.0.
  • water-insoluble linear polysaccharides are preferably used which have been produced in a biotechnical, in particular in a biocatalytic or a fermentative, process.
  • the polysaccharides obtained in this way have a particularly homogeneous profile of properties, e.g. B. in relation to the molecular weight distribution, they contain no or at most only in very small amounts of unwanted by-products that have to be separated in a complex manner, and can be reproduced in a precisely specified manner.
  • water-insoluble linear polysaccharides can be obtained with biotechnological methods, such as. B. poly-1, 4-alpha-D-glucans, which contain no branches, or whose degree of branching is below the detection limit of conventional analytical methods.
  • the molecular weights M w (weight average, determined by means of gel permeation chromatography in comparison with a calibration using pullulan standard) of the linear polysaccharides used according to the invention can vary within a wide range from 0.75 ⁇ 10 2 g / mol to 10 7 g / mol.
  • the molecular weight M w is preferably in a range from 10 3 g / mol to 10 6 g / mol and particularly preferably from 10 3 g / mol to 10 5 g / mol.
  • Another advantageous range is from 2 x 10 3 to 8 x 10 3 .
  • Corresponding ranges apply to the preferred poly (1,4-D-glucan).
  • the molecular weight distribution or polydispersity M w / M ⁇ can also vary widely depending on the production process of the polysaccharide. Preferred values are from 1.01 to 50, in particular from 1.5 to 15.
  • the Polydispersity with a bimodal distribution of molecular weights are from 1.01 to 50, in particular from 1.5 to 15.
  • a single linear polysaccharide substance in particular linear poly (1,4-D-glucan), or mixtures of two or more representatives can be used.
  • a water-insoluble branched polysaccharide preferably a polyglucan, in particular a poly (1, 4-alpha-D-glucan) or a poly (1, 3-beta-D-glucan), can be added. Mixtures of two or more branched polysaccharides can also be added.
  • the branched polysaccharides can be of any origin.
  • Preferred sources are starch and starch analogs such as glycogen. If necessary, the proportion of linear structures in the branched polysaccharides can be increased by suitable enrichment processes.
  • the molecular weight can also be higher for the branched polysaccharides, e.g. B. values up to preferably 10 9 g / mol and more.
  • biocompatible or biodegradable polymers can also be added.
  • the amount of the other polymer (s) that are added without changing the spherical shape and / or other properties of the microparticles to be produced always depends on the polymer added.
  • the proportion of linear polysaccharide should be at least 70% by weight, in particular 80% by weight and preferably 90% by weight, based on the total content of polysaccharide and optionally further polymer.
  • the microparticles consist of 100% by weight of linear polysaccharide.
  • microparticles used according to the invention as carrier material for parenteral use can also contain other auxiliaries customary for this purpose in customary amounts.
  • the active substance or the active substance for the composition according to the invention can be any solid, liquid or gaseous substance which is to be administered parenterally, in particular by means of injection, to a living organism or to an inanimate object.
  • biologically active substances or combinations of substances are also understood in the broadest sense.
  • LHRH analogs such as Busereiin (registered trademark of Hoechst Marrion Roussel) for use against prostate cancer, endometriosis and other tumor-like diseases of the genital organs; Erythropoietin (EPO) to stimulate the growth of red blood cells, analgesic agents, antiallergics, growth hormones, Steroids for hormone treatment and birth control, biphosphonates, calcitonin (e.g. cibacalcin from Ciba-Geigy) for the treatment of osteoporosis, psychotropic drugs, generally active substances, e.g. proteins or peptides, which are broken down in the gastrointestinal tract and therefore not orally can be administered, or active ingredients that require parenteral administration, etc.
  • LHRH analogs such as Busereiin (registered trademark of Hoechst Marrion Roussel) for use against prostate cancer, endometriosis and other tumor-like diseases of the genital organs; Erythropoietin (
  • the active substances or combinations of active substances which can be used can be chosen as desired for the desired field of use and, insofar as they can be administered parenterally, are not subject to any restrictions either with regard to the nature of the active substance, with regard to the preparation of the active substance or with the field of use.
  • So-called macromolecules, in particular peptides, proteins or nucleotides, which z. B. by biotechnical or by modern biotechnology based methods can be produced or synthesized.
  • the active ingredient or combination of active ingredients is brought into contact with the carrier material in the required amount.
  • the active ingredient can be added to the starting compounds used for the production of the microparticles, such as the water-insoluble linear polysaccharides, so that the microparticles consist of a mixture of starting compounds and active ingredient.
  • the active substance can be encapsulated in the microparticles, it being possible to use conventional encapsulation techniques. Suitable examples are emulsion processes or spray drying processes. Thereby fall under the last The term also applies to spray processes in which the particles are sprayed with a solution of the active substance in a fluidized bed or in an analogous process.
  • the active ingredient can be absorbed and / or adsorbed on the microparticle surface by, for. B. the active ingredient and the microparticles suspended in a suitable medium, allowed to stand until equilibrium is reached and then the particles loaded with active ingredient are separated.
  • composition according to the invention is particularly suitable for the controlled release of active ingredient, but is not restricted to this.
  • Controlled release of active substance is understood to mean that the active substance is not released immediately and all at once, but that the release takes place over a certain period of time and / or after a certain period of time has elapsed.
  • the release rate can be chosen arbitrarily depending on the intended use. It can be constant over time or it can be large initially followed by a slower release.
  • the rate of release and the rate of degradation of the microparticles in an organism depend strongly on the type of starting materials, the type of active ingredient used, the particle size and the production process. Depending on requirements, the person skilled in the art can create a system tailored to his specific purpose by simply varying these parameters, which is familiar per se.
  • Parenteral administration is understood to mean the administration of any active ingredient via injection or infusion, for which good dispersibility and cannulability of the composition to be administered is particularly advantageous.
  • composition according to the invention is suitable because of the excellent cannula mobility of the microparticles used according to the invention especially for administration by injection.
  • the injection can be arbitrary, it can be administered intravenously, intramuscularly, intraarterially, subcutaneously or intralumbally.
  • a high cannula passage means that the composition according to the invention can also easily pass through injection needles such as syringes with small needle diameters.
  • the composition is suspended in a suitable medium. It has been shown that the composition according to the invention, even without the addition of other auxiliaries such as dispersants, forms a stable suspension which remains unchanged even over a longer period of time.
  • the suspension of settling of the microparticles can be generated again by a simple brief shaking, usually several seconds, a stable suspension.
  • sterile salt solutions such. B. a physiological NaCI solution.
  • concentration ranges Up to 25% solids can be present in the suspension. This corresponds to a proportion of 250 mg particles per 1 ml of solvent, e.g. B. Physiological saline. Preferred concentration ranges are 1% to 18%. A range from 5% to 10% solids content is particularly preferred. This corresponds to amounts of 50 mg to 100 mg drug-loaded microparticles, a value that can only be achieved with alternative formulations even with a suspension aid with great experimental effort becomes.
  • the very good suspendability and the ability to pass cannulas can be supported by the observation that 500 mg of the particulate carrier can be suspended in only 3 ml of water and can be applied without problems through a cannula with a diameter of 0.6 mm.
  • auxiliaries such as Pluronic (brand from BASF AG), Haemaccel (brand from Behringwerke), sodium dodecyl sulfate etc., i.e. auxiliaries that are generally suitable for such pharmaceutical application forms are recognized and used.
  • the microparticles themselves can be effective as an active ingredient.
  • the microparticles used according to the invention can be used as contrast agents, e.g. B. for ultrasound diagnosis.
  • the composition according to the invention can be applied with or without a further active ingredient.
  • Possible other active ingredients are e.g. B. gases
  • the type of gas can vary within wide ranges (z. B. nitrogen, air, argon, helium, chlorofluorocarbons, fluorocarbons).
  • Aspirin or NO-releasing compounds can also be used, which are particularly important in cardiovascular diseases.
  • microparticles used according to the invention are particularly suitable for parenteral administration on account of their excellent dispersibility and high cannulability.
  • microparticles from poly (1,4- ⁇ -D-glucan 500 mg of poly (1,4-D-glucan) are dissolved in 2.5 ml of dimethyl sulfocide (DMSO, pa from Riedel-de-Haen) at approx. 70 ° C.
  • DMSO dimethyl sulfocide
  • the DMSO solution is added dropwise in 100 ml of double-distilled water with stirring and the solution is kept at 5 ° C. overnight.
  • the fine milky suspension is centrifuged for 15 minutes at 3500 revolutions per minute and the supernatant is decanted off.
  • the sediment is slurried with double-distilled water and centrifuged again. The process is repeated two more times.
  • the suspension is then freeze-dried. 311 mg of white poly (1,4- ⁇ -D-glucan) particles are obtained. This corresponds to a yield of 62% colorless microparticles.
  • Example 1 100 mg of microparticles obtained according to Example 1 are suspended in 1 ml of double-distilled water.
  • the particles can be separated by simply shaking the closed container by hand.
  • the suspension is drawn through a septum using a syringe and a cannula with a diameter of 0.5 mm (or larger).
  • the particles are then pressed out through the cannula to be tested.
  • the assessment of the individual cannulas is summarized in the following tables.
  • a cross symbolizes the cannula passage of the suspension.
  • the cannulas used are from Braun Petzold GmbH (Melsungen).
  • Comparative materials comparative examples
  • the experiments with comparative substances were carried out as in Example 1.
  • the systems used are known biodegradable polymers made from lactic and glycolic acid or from tartaric acid or from aspartic acid (see Table 3).
  • the microparticles, or agglomerates, made of poly (- ⁇ -D-glucan) are loaded with active ingredient by a suspension process.
  • 250 mg Busereiin * are dissolved in 10 ml distilled water. 100 mg of particles are added.
  • the suspension is stirred for 3 hours.
  • the suspension is centrifuged.
  • the centrifugate is washed with water.
  • the particulate solid is separated off using a centrifuge (3000 rpm) and the centrifugate is freeze-dried.
  • the loading with Busereiin can be calculated at 3.28% based on the total mass of the particles using a calibration curve.
  • the solvent e.g. As alcohol
  • the solubility and thus the loading of the particles with active ingredients can be influenced.
  • the microparticles are suspended in distilled water or a mixture of water and a volatile component such as acetone or ethanol.
  • 10 g of the solid are added to 1000 ml of the solvent.
  • Solvent had previously been dissolved in 0.5 g of theophylline.
  • the spray dryer (mini spray dryer 191 from Büchi) is operated as follows: atomizing air flow 700 liters per hour, inlet temperature 200 ° C., nozzle cooling switched on, nozzle diameter 0.5 mm, aspirator 70%, pump 10%.
  • the spectroscopic examination of the load shows a degree of loading of 4.8%. This value corresponds to the theoretically achievable value of 5.0% within the error limits.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Physics & Mathematics (AREA)
  • Biomedical Technology (AREA)
  • Nanotechnology (AREA)
  • Optics & Photonics (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne une composition pour administration parentérale de principes actifs, contenant un excipient et au moins un principe actif. L'excipient contient des microparticules sphériques de diamètre moyen compris entre 1 nm et 100 mu m, qui se composent entièrement ou en partie d'au moins un polysaccharide linéaire non soluble dans l'eau, notamment un polyglucane linéaire. L'invention concerne en outre une suspension contenant ladite composition, ainsi que son utilisation.
EP99948917A 1998-10-15 1999-10-02 Composition pour administration parenterale de principes actifs Withdrawn EP1124538A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19847593 1998-10-15
DE1998147593 DE19847593A1 (de) 1998-10-15 1998-10-15 Zusammensetzung für die parenterale Applikation von Wirkstoffen
PCT/EP1999/007300 WO2000021505A2 (fr) 1998-10-15 1999-10-02 Composition pour administration parenterale de principes actifs

Publications (1)

Publication Number Publication Date
EP1124538A2 true EP1124538A2 (fr) 2001-08-22

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP99948917A Withdrawn EP1124538A2 (fr) 1998-10-15 1999-10-02 Composition pour administration parenterale de principes actifs

Country Status (8)

Country Link
EP (1) EP1124538A2 (fr)
JP (1) JP2002527376A (fr)
AU (1) AU6198999A (fr)
CA (1) CA2346670A1 (fr)
DE (1) DE19847593A1 (fr)
NO (1) NO20011670L (fr)
PL (1) PL347770A1 (fr)
WO (1) WO2000021505A2 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10022095B4 (de) * 2000-05-08 2005-07-14 Südzucker AG Mannheim/Ochsenfurt Gel aus einem Poly-α-1,4-Glucan und Stärke
DE10119522A1 (de) * 2001-04-20 2002-12-05 Innovacell Biotechnologie Gmbh Herstellung und Anwendung einer Suspensionszusammensetzung mit einem Ultraschall-Kontrastmittel
ES2899590T3 (es) 2004-01-23 2022-03-14 Eden Research Plc Métodos de eliminación de nematodos que comprenden la aplicación de un componente terpénico
EP2338332B1 (fr) 2004-05-20 2014-02-12 Eden Research Plc Particule creuse de glucane ou de paroi cellulaire encapsulant un composant de terpene
US20080227805A1 (en) 2007-02-28 2008-09-18 Abbott Laboratories Sustained release parenteral formulations of buprenorphine

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2646879A1 (de) * 1975-10-21 1977-05-05 Takeda Chemical Industries Ltd Matrix aus einem in wasser unloeslichen beta-1,3-glucangel und verfahren zu ihrer herstellung
DE3045135A1 (de) * 1980-11-29 1982-06-09 Sandoz-Patent-GmbH, 7850 Lörrach Pharmazeutische kompositionen enthaltende bioabbaubare polymere
PT759993E (pt) * 1994-05-18 2007-08-10 Bayer Bioscience Gmbh ''sequências de dna que codificam para enzimas capazes de facilitar a síntese de alfa-1,4-glucanos lineares em plantas, fungos e microrganismos''
DE19737481A1 (de) * 1997-08-28 1999-03-04 Hoechst Ag Sphärische lineare Polysaccharide enthaltende Mikropartikel
JP2002511399A (ja) * 1998-04-09 2002-04-16 セラニーズ ベンチャーズ ゲー・エム・ベー・ハー 肺投与のための粒状賦形剤
DE19839216C1 (de) * 1998-08-28 2000-01-20 Aventis Res & Tech Gmbh & Co Verfahren zur Herstellung von sphärischen Mikropartikeln, die ganz oder teilweise aus mindestens einem wasserunlöslichen Verzweigungen enthaltenden Polyglucan bestehen, sowie mit diesem Verfahren erhältliche Mikropartikel und die Verwendung

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0021505A3 *

Also Published As

Publication number Publication date
DE19847593A1 (de) 2000-04-20
NO20011670L (no) 2001-06-12
CA2346670A1 (fr) 2000-04-20
PL347770A1 (en) 2002-04-22
WO2000021505A3 (fr) 2000-09-21
NO20011670D0 (no) 2001-04-03
WO2000021505A2 (fr) 2000-04-20
JP2002527376A (ja) 2002-08-27
AU6198999A (en) 2000-05-01

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