WO1998058258A1 - Formulation pour systemes reactionnels immunologiques - Google Patents

Formulation pour systemes reactionnels immunologiques Download PDF

Info

Publication number
WO1998058258A1
WO1998058258A1 PCT/EP1998/003616 EP9803616W WO9858258A1 WO 1998058258 A1 WO1998058258 A1 WO 1998058258A1 EP 9803616 W EP9803616 W EP 9803616W WO 9858258 A1 WO9858258 A1 WO 9858258A1
Authority
WO
WIPO (PCT)
Prior art keywords
formulation
formulation according
anspmch
providing compound
functional group
Prior art date
Application number
PCT/EP1998/003616
Other languages
German (de)
English (en)
Inventor
Elvira Schecklies
Frank Weber
Original Assignee
Elvira Schecklies
Frank Weber
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
Priority claimed from DE19725766A external-priority patent/DE19725766B4/de
Application filed by Elvira Schecklies, Frank Weber filed Critical Elvira Schecklies
Priority to DE29824000U priority Critical patent/DE29824000U1/de
Priority to EP98933618A priority patent/EP0988550A1/fr
Publication of WO1998058258A1 publication Critical patent/WO1998058258A1/fr

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54353—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals with ligand attached to the carrier via a chemical coupling agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit

Definitions

  • the invention relates to formulations for the production of biological, in particular immunological, enzymatic and chemical test systems, in which compounds containing reactive functional groups are incorporated in the polymer matrix, processes for their preparation, and their use in the form of adjuvants and as materials for affinity chromatography or cell culture relates in particular to formulations based on renewable raw materials, in which reactive functional group-providing compounds are incorporated, and their use as adjuvants.
  • the material for adjuvants or column material is preferably in powder form
  • Immunological test systems which are produced with the help of the various antibodies, are an integral part of modern analysis and research.
  • the tests are usually carried out as solid phase assays, whereby one of the reactants involved in the test (e.g. antigen, antibodies, their conjugates or Substances that react with them) are bound to a solid matrix.
  • the solid phases are shaped bodies made of polymeric compounds in the form of, for example, beads (spheres), immunotubes, sticks or microtitre plates renewable raw materials such as polyhydroxybutyric acid, polylactide (racemate or L-form), modified starch, modified cellulose
  • a reaction partner is bound to the surface of the shaped body by methods known per se.
  • the binding is generally adhesive, although statistically different parts of the reactant can be bound, since the adhesive binding is not specific for an adhesive binding.
  • only molecules with a molecular weight greater than 2000 are suitable. Smaller molecules are not fixed or cannot be reproducibly fixed.
  • haptens or peptides e.g. with a normal sequence of 10-15 Amino acids
  • the invention is therefore based on the object of providing formulations which can be used in immunological reaction systems.
  • these formulations should be suitable for use in immunological test systems, as adjuvants in immunization reactions in vivo, and as materials for affinity chromatography and cell culture.
  • Even low-molecular substances are defined to bind covalently to the matrix, whereby, among other things, the material has a sufficient shelf life for test kits, adjuvants and column material. It should be possible to covalently bind different functional groups to the matrix by means of different inclusions in the polymer formulations Above all, an increased shelf life and shelf life of the formulations should be achieved.
  • matrix effects according to the invention are to be minimized in immunological test systems and the specificity of the binding is to be increased.
  • the formulations are intended to be an inexpensive, easy-to-apply and well-tolerated adjuvant that stimulates antibody production even in low doses (especially for Production in egg-laying animals, for example Huhner), and as a material for affinity chromatography, this object is achieved according to the invention by a formulation for immunological reaction systems, comprising a polymer matrix in which one or more compounds providing functional groups are incorporated.
  • This formulation is preferably in Powdery form before the subject of the invention are also produced with this formulation biological test systems and adjuvants.
  • molecules can be stored, which defined functional groups Contain in the form of oligo- or poly suppliers of these groups, to which various molecules can be bound. It is also possible to store long-chain fatty acids with suitable functional groups, via which covalent bonds to other molecules can also be produced, in particular amino serving as functional groups -, Carboxy or SH groups By incorporating suppliers of these functional groups into the matrix of the materials used for immunological processes, it is possible to bind substances in a defined manner.
  • the molecular weight of the compounds can be between 100 and 200,000.
  • the carriers of the functional groups are chosen as required so that after
  • Polyamino acids in which a free functional group is available for covalent binding to a reactant are preferably suitable for this purpose
  • a polyamino group supplier is stored in its matrix.
  • This can be, for example, oligo- or polylysine or the oligomer of the polymer matrix with introduced amino groups.
  • the COOH group of the reactant is coupled with carbodiimide via an acid amide bond to the amino groups, for example of polylysine.
  • reactants with their amino group can be covalently bound by incorporation of carboxy group suppliers of glutamic acid or aspartic acid, a derivatized oligomer of the polymer matrix or terephthalic acid can be used.
  • Suitable oligomers or polymers of cysteine derivatives can be used to form disulfide bridges. It is thus ensured that a suitable functional group of the substance to be bound is fixed to the molded article via other functional ones Couplings that can still be in the molecule cannot be coupled. This leads to improved standardization of the immunological test systems, as well as to the selective and specific binding of the molecules to adjuvant or Saulenm atrix
  • the amino acids which carry the functional groups for a covalent bond can also be bound to various oligomeric or polymeric structures, provided that it is ensured that only the respective desired functional group in the total molecule can bind the reactant
  • the reactive group-providing substances can also be used in the form of their salts, for example as hydrobromides.
  • fatty acids with suitable functional groups molecules with a lower molecular weight can also be used, since the polarity of the polymer matrix means that the fatty acid residue is stored inside while the part with the reactive groups on the surface is available for a chemical reaction
  • the proportion of inclusions in the polymer matrix can be between 0.05% and 5% based on the weight of the polymer matrix. If it is technically possible, higher concentrations can be used, but it has been shown that the technical and financial outlay for this in poor relation to an improved matrix. Lower concentrations of inclusions are conceivable, but in most cases this deteriorates the test quality.
  • the preferred range is between 0J% and 1% proportion of inclusions in the polymer structure, the particularly preferred range between 0. 2% and 0.5%
  • the type of polymer matrix depends on the concentrations of
  • the areas can generally apply to any polymer matrix.
  • the polymers e.g. polystyrene, PHB or PLA - depending on the need for processability or type of application, different concentrations of other substances such as low and high molecular weight plasticizers, nucleating agents , Dyes, technical auxiliaries, etc., unless they are used as in the case of PHB or PLA adjuvants for immunization purposes.
  • these substances are individual and known per polymer and are added by a person skilled in the art depending on the desired end product
  • the starting granules of the polymers - preferably polystyrene, PHB and PLA - are produced by processes known per se. These processes are known from the prior art. A suitable amount of functional groups is then supplied to the granules in an extruder
  • various shaped bodies for example immunosticks, immunotubes, spheres or microtiter plates, can be used for the use in tests based on the binding of a substance, in particular immunological, enzymatic or Chemical test systems can be produced.
  • the raw matrix with the inclusions can also be used for the coating of shaped bodies (eg modified cellulose or modified starch) by technical processes - for example immersion or coinjection.
  • Adjuvants are an indispensable ingredient in formulations for generating an immune response, ie for inducing antibody production.
  • Antibodies are proteins that react in a highly specific manner with foreign substances. Due to the specific reaction, you can use it to trace foreign substances within the scope of diagnostic methods.
  • Antibodies can be produced in animals (e.g. suckers or birds) according to known methods. In mammals, the antibodies are obtained from the blood, in chickens from the egg yolk. In order to achieve a good immune response, the immune system of the animal in question must be stimulated. This can be done either via the antigen itself (e.g. bacteria, Viruses) or, as in most cases, by coupling particularly low-molecular substances to carrier proteins (e.g. bovine serum albumin) in conjunction with a special adjuvant, which is also intended to stimulate the immune system.
  • Adjuvant and conjugated antigen are applied together. This stimulates the immune system to produce antibodies
  • Freund's oil-based adjuvant is usually used as the standard adjuvant.
  • Antigen Three components are involved in the generation of antibodies, in particular against small antigens, haptens, etc.
  • Antigen, carrier molecule and adjuvant According to the prior art, at least two steps are necessary for immunization and the maintenance of a ready-to-use antigen
  • PHB227 and PLA L1021 from the company Biomer, with various inclusions on substances bearing functional groups, which surprisingly offer the possibility of covalently binding antigens, can be comminuted to a powdery consistency and then for application in animals with the aim of producing antibodies Particularly good results of the formulations are achieved by pulverization.
  • the particle size is 0.04 to 400 ⁇ m, preferably 0.06 to 200 ⁇ m, more preferably 0.08 to 100 ⁇ m, most preferably 0J to 50 ⁇ m.
  • molecules with amino or amino groups are suitable as functional groups
  • Carboxy groups where, for example, an oligolysin can be used as the amino group supplier, for example terephthalic acid (especially when used for column material) can be used as the carboxy group supplier
  • the pulverization is carried out according to methods known per se by mechanical comminution or spraying techniques. In mechanical comminution, cutting or ball mills are particularly preferred. Microdisembrator or ultracentrif galmuhle
  • the adjuvant formulations according to the invention enable the production of such a small particle size (0.04 - 400 ⁇ m) that after suspension in physiological buffer it can be administered by means of a syringe.
  • a larger particle size for application in principle is conceivable, but the powder sediments too much in the syringe.
  • the disadvantage of the structure of the polymer is that the embedded carriers of the functional groups can at least partially dissolve during the coupling process of the antigen and an inadequate coupling rate is thus achieved.
  • the particularly preferred range of particle size is 0.1-200 ⁇ m
  • the embedded functional groups enable a covalent binding of antigens to the polymer matrix. It is also advantageous that, for example, PHB or PLA show immunostimulatory properties due to the base material resulting from the isolation from the producing bacteria.
  • formulations made from renewable raw materials such as PHB or PLA -preferably the formulation PHB 227 or PLA L1021 from Biomer - which are suitable for the production of a sufficiently small particle size and which contain functional groups can be provided, innovative adjuvants represent the administered adjuvants achieve a depot effect, since they are in suspension and gradually takes place through the body's own enzymes metabolism, so that the formation of abscesses can be avoided.
  • the powdered adjuvant is only suspended and applied in PBS (physiological saline solution).
  • the adjuvants according to the invention are carrier molecule and immunostimulant in one
  • any antigens can be coupled to the substances bearing functional groups in the polymer structure, for example steroids, prostaglandins or pesticides, selected from the group of chlorinated phenols by way of methods known per se.
  • the adjuvants according to the invention could also be used for vaccinations in humans or animals Find The previously usual procedure of first producing a hapten-carrier conjugate, which must subsequently be mixed with an adjuvant, is simplified in that the hapten is coupled directly to the adjuvant, which is also an immunostimulant, since the adjuvants according to the invention are not water-soluble , purification of the reaction product is also simplified. Column chromatography or dialysis are no longer necessary.
  • the corresponding conjugate is poured into a small column and all undesired unbound molecules are simply washed away with physiological buffer
  • the polymers used for the preparation of the adjuvant can also be sterilized, it is also ensured that there is no infection by contaminated material during the immunization
  • the advantages of the prototype therefore lie in the good physiological tolerance of the polymers and above all in the fact that the adjuvant is also the carrier molecule for substances to be coupled.This also leads to a minimal need for anti genes, since the controllable type and number of functional groups in the matrix are one Enable economical use of antigen
  • the non-specific production of antibodies can be reduced and allergic / inflammatory reactions can be contained.
  • the adjuvant according to the invention is also economical importance If the formulations according to the invention are used for biological test systems, beads, immunotubes, microtiter plates or sticks for use in immunological, enzymatic and chemical test systems or powdery products (adjuvant, column material) are preferably produced. After processing into the respective end products, they have a sufficient shelf life also for their use in test kits, cell culture, as adjuvants or column material.
  • the functional groups of suppliers, which are embedded in the polymer matrix are made according to known processes and chemical reactions - e.g.
  • Oligosaccharides or low-molecular haptens should be bound to the surface.
  • blood substances, pesticides in water, toxins or pharmaceuticals in feed and food, bacteria and viruses are detected, coupled for immunization or bound to columns for affinity chromatography.
  • Another area of application is the detection of peptides or nucleotides, their immunization or purification, as required, for example, for medicine or genetic research. Due to the defined covalent bond to the formulations according to the invention with inclusions, it is possible to achieve sufficient standardization even with haptens
  • the covalent bond additionally enables the minimization of matrix effects which often occur in immunological processes. Since the tests are carried out with antibodies, the environment in which the antibody is located has an influence on binding capacity, since the structure of the antibody protein (IgG) is influenced by the pH or ionic strength of the sample to be examined. However, if the antigen is covalently bound, unwanted accompanying substances can be removed by washing steps before the actual test reaction itself can be carried out by adding IgG introduces known methods It is also possible if there are different substances in a sample, according to previous methods all were bound adhesively, selectively only coupling those that have a corresponding functional group. This significantly increases the specificity of the test systems.
  • IgG antibody protein
  • polystyrene granules together with 5%, 2.5% J%, 0.5% and 0J% o polyaspartate (potassium salt, 93% polymer content from Rohm and Haas) are metered into an extruder, extruded and processed into beads.
  • the screw temperatures are 145 Degrees C (Zone 1), 190 Degrees C (Zone 2), 165 Degrees C (Zone 3) and 135 Degrees C (Nozzle).
  • Beads of uniform size are produced, which can be used in the tests either directly or after processing into shaped bodies
  • polystyrene granules together with 1%> and 0.1% polylysine (HBr salt, molecular weight up to 50,000 Da from Bachem) are metered into an extruder, extruded and processed into beads.
  • the screw temperatures are 145 degrees C (zone 1), 190 Degree C (Zone 2), 165 Degree C (Zone 3) and 135 Degree C (Nozzle). Beads of uniform size are formed, which can be used in the tests either directly or after processing into shaped bodies
  • Biomer PHB formulation P 152 is metered in different batches together with 5%, 2.5%, 1%, 0.5% and 0.1% terephthalic acid into an extruder, extruded and processed into beads.
  • the screw temperatures are 165 degrees C (zone 1), 180 degrees C (zone 2), 155 degrees C (zone 3) and 1 10 degrees C (nozzle) can be used in the tests either directly or after processing into molded bodies
  • Biomer PHB formulation P 152 is metered in various batches together with 2.5%> and 0.25% polylysine (HBr salt, molecular weight up to 50,000 Da, Bachem) into an extruder, extruded and processed into beads.
  • the screw temperatures are 165 degrees C (Zone 1), 180 degrees C (Zone 2), 155 degrees C (Zone 3) and 1 10 degrees C (nozzle) Beads of uniform size are formed, which can be used in the tests either directly or after processing to form shaped bodies
  • Lacty type 1012 is metered in different batches together with 5%, 2.5%, 1%, 0.5% and 0.1% terephthalic acid into an extruder, extruded and processed into beads
  • Screw temperatures are 200 degrees C (zone 1), 210 degrees C (zone 2), 165 degrees C (zone 3) and 155 degrees C (nozzle). Beads of uniform size are produced, which are used in the tests either directly or after processing into molded bodies can be
  • Lacty type 1012 is metered into an extruder together with 1% and 0.1% polylysine (HBr salt, molecular weight up to 50,000 Da, Bachem), extruded and processed into beads.
  • the screw temperatures are 200 degrees C (zone 1), 210 degrees C (zone 2), 165 degrees C (zone 3) and 155 degrees C (nozzle). Beads of uniform size are produced which can be used in the tests either directly or after processing into molded bodies
  • Beads made from polymers of polystyrene, biomer P152 and lacty type 1012, each with 1% storage of polylysine, are coated by incubating 10 ⁇ g MCPA in phosphate-buffered physiological saline (PBS) with carbodiimide (EDC) overnight in the refrigerator. After removing the solution, block by adding Free binding sites from 1% Tween 20 solution in PBS (2 hours at room temperature). The blocking solution is then removed and an anti-MCPA-IgG-alkaline phosphatase conjugate in PBS is added. After an hour of incubation at room temperature, the beads are washed
  • NuncCovalink are commercially available microtiter plates made of polystyrene, the surface of which has been modified so that molecules with carboxy groups can be conjugated via amino groups.
  • Biomer P 152 / 0.25% polylysine matrix, lacty type 1012/1% polyaspartate and NuncCovalink are each coated with 10 ⁇ g MCPA Carrying out the experiment is analogous to example
  • a stick of Biomer P 152/1% terephthalic acid is coated in a tube with 0.3 ml (corresponds to about 1/3 of the stick length) of PBS, which contains 10 ⁇ g phenylurea and carbodiimide (EDC), overnight in a refrigerator. Then the stick is washed under running water and 1 ml of 1% tween solution in PBS is added to block free binding sites. After 2 hours of incubation at room temperature, the blocking solution is removed and 1 ml of anti-phenylurea-IgG-alkaline phosphatase conjugate in PBS is added. After a further hour of incubation at room temperature, the stick is washed under running water.
  • the stick is incubated for approx. 30 minutes in 1 ml of the substrate solution.
  • the substrate precipitates on the stick and remains attached.
  • Example 11 Analytical determination of the pesticide mecoprop using a stick test according to the invention
  • a stick of PHB / 0.25% polylysine from Biomer is coated in a tube with 0.3 ml (corresponds to approximately 1/3 of the stick length) of a water sample which contains 10 ⁇ g of mecoprop and carbodiimide (EDC), and is washed overnight in the refrigerator then the stick under running water and gives 1 ml of 1% l to block free binding sites Tween solution in PBS after this. After 2 hours of incubation at room temperature, the block solution is removed and 1 ml of anti-mecoprop-IgG-alkaline phosphatase conjugate in PBS is added. The further course of the experiment is analogous to Example 10
  • EDC mecoprop and carbodiimide
  • the conjugate can now be used directly for immunization
  • conjugate 15 mg conjugate are suspended in 0.3 ml physiological saline (PBS) and drawn on a disposable syringe. The suspension is administered subcutaneously to a rabbit. The immunization is repeated twice every one week. After a further 10 days, 20 mg conjugate in 0.5 ml PBS is administered intramuscularly. The first blood sample is taken one week after this boost injection.
  • PBS physiological saline
  • the serum is obtained by methods known per se.
  • the check is carried out by binding MCPA to Nunc covalink (according to the manufacturer's instructions) and then incubating with diluted serum.
  • the bound antibodies are detected by protein A alkaline phasphatase followed by a substrate reaction.
  • an anti-MCPA rabbit serum produced under conventional conditions is also tested under identical conditions.
  • the titer is comparable in both methods.
  • the serum produced with the adjuvant according to the invention advantageously has a significantly lower background.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Hematology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • Food Science & Technology (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Cell Biology (AREA)
  • Epidemiology (AREA)
  • Microbiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne une formulation pour systèmes réactionnels immunologiques, comprenant une matrice polymère dans laquelle sont insérés des composés fournissant un ou plusieurs groupes fonctionnels, ainsi que les systèmes de tests biologiques qui en découlent, et des formulations additionnelles à phase solide, caractérisée en ce que les composés fournissant les groupes fonctionnels réactifs sont insérés dans la phase solide. Les composés fournisseurs de groupes fonctionnels renferment, par exemple, des groupes amino, carboxy ou sulhydryle, par l'intermédiaire desquels des molécules covalentes peuvent être liées.
PCT/EP1998/003616 1997-06-18 1998-06-16 Formulation pour systemes reactionnels immunologiques WO1998058258A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DE29824000U DE29824000U1 (de) 1998-01-20 1998-06-16 Stick-System für Küvetten zur Durchführung immunologischer Verfahren
EP98933618A EP0988550A1 (fr) 1997-06-18 1998-06-16 Formulation pour systemes reactionnels immunologiques

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE19725766.6 1997-06-18
DE19725766A DE19725766B4 (de) 1997-06-18 1997-06-18 Formulierung zur Herstellung von Testsystemen und Herstellung der Formulierung
DE19801888A DE19801888A1 (de) 1997-06-18 1998-01-20 Adjuvans-Formulierungen aus nachwachsenden Rohstoffen mit Einlagerungen an funktionellen Gruppen tragenden Substanzen, an die Antigene kovalent gebunden werden und deren Verwendung
DE19801888.6 1998-01-20

Publications (1)

Publication Number Publication Date
WO1998058258A1 true WO1998058258A1 (fr) 1998-12-23

Family

ID=26037543

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/003616 WO1998058258A1 (fr) 1997-06-18 1998-06-16 Formulation pour systemes reactionnels immunologiques

Country Status (2)

Country Link
EP (1) EP0988550A1 (fr)
WO (1) WO1998058258A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0363921A2 (fr) * 1988-10-12 1990-04-18 Juridical Foundation The Chemo-Sero-Therapeutic Research Institute Particules de support synthétiques et leur procédé de préparation
DE19529250C1 (de) * 1995-08-09 1996-08-14 Elvira Schecklies Hapten-Träger-Konjugate mit hoher, definierter Kopplungsrate
WO1996032419A1 (fr) * 1995-04-14 1996-10-17 The General Hospital Corporation Polymeres de polyacetals biodegradables, formation et utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0363921A2 (fr) * 1988-10-12 1990-04-18 Juridical Foundation The Chemo-Sero-Therapeutic Research Institute Particules de support synthétiques et leur procédé de préparation
WO1996032419A1 (fr) * 1995-04-14 1996-10-17 The General Hospital Corporation Polymeres de polyacetals biodegradables, formation et utilisation
DE19529250C1 (de) * 1995-08-09 1996-08-14 Elvira Schecklies Hapten-Träger-Konjugate mit hoher, definierter Kopplungsrate

Also Published As

Publication number Publication date
EP0988550A1 (fr) 2000-03-29

Similar Documents

Publication Publication Date Title
DE69433523T2 (de) Makromolekulare Mikropartikel und Verfahren zur ihrer Herstellung
DE69122828T2 (de) Hydroxyapatit-antigen-konjugate und verfahren zur auslösung einer poly-ig-immunantwort
DE69826452T2 (de) Stellenspezifische proteinmodifizierung
DE69103755T2 (de) Wachstumshormonkristalle und verfahren zu deren herstellung.
EP2164949B1 (fr) Biomatériau à base d'un support polymère hydrophile
DE3224837A1 (de) Traegergebundenes immunosorptionsmittel
DE102006011507A1 (de) Wirkstoffbeladene Nanopartikel auf Basis hydrophiler Proteine
DE3876997T2 (de) Konjugate von superoxiddismutase.
DE69921636T2 (de) Medikamentöse verabreichung von proteinen aus polymergemischen
DE3738228A1 (de) Verfahren zur herstellung von bioabbaubaren mikrokapseln wasserloeslicher peptide und proteine sowie nach diesem verfahren erhaltene mikrokapseln
DE1961541A1 (de) Immunologisches Indikatorreagens
WO1994020521A1 (fr) Elements de synthese et de selection de sequences d'elements constitutifs lies par covalence
DE69306243T2 (de) Zusammensetzungen mit verzögerter wirkstoffabgabe
DE69219913T2 (de) Ergänzung von Oberflächenrezeptoren
WO1998058258A1 (fr) Formulation pour systemes reactionnels immunologiques
EP2214733B1 (fr) Matériau composite biologique pour la libération contrôlée d'agents actifs
DE19529250C1 (de) Hapten-Träger-Konjugate mit hoher, definierter Kopplungsrate
EP1282695B1 (fr) Surfaces de polymere hemocompatibles
DE19725766B4 (de) Formulierung zur Herstellung von Testsystemen und Herstellung der Formulierung
DE3239863C2 (de) Verfahren zur Herstellung eines subkultivierbaren Lymphokin-bildenden Human-T-Zell-Hybridoms
EP0306473B1 (fr) Structure pharmaceutique avec agents liés à des supports protéiniques
DE60023324T2 (de) Zusammensetzung zur in-vitro befruchtung
DE60305940T2 (de) Modifizierte therapeutische mittel
WO2000017232A2 (fr) Proteine regulatrice issue de keratinocytes humains
DE19513659A1 (de) Polypeptid-enthaltende pharmazeutische Darreichungsformen in Form von Mikropartikeln und Verfahren zu deren Herstellung

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): BR JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1998933618

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: JP

Ref document number: 1999503722

Format of ref document f/p: F

WWP Wipo information: published in national office

Ref document number: 1998933618

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1998933618

Country of ref document: EP