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WO1988000237A1 - Membranes covalentes - Google Patents

Membranes covalentes Download PDF

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Publication number
WO1988000237A1
WO1988000237A1 PCT/US1987/001495 US8701495W WO8800237A1 WO 1988000237 A1 WO1988000237 A1 WO 1988000237A1 US 8701495 W US8701495 W US 8701495W WO 8800237 A1 WO8800237 A1 WO 8800237A1
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WO
WIPO (PCT)
Prior art keywords
cells
tissue
membrane
core material
substance
Prior art date
Application number
PCT/US1987/001495
Other languages
English (en)
Inventor
Franklin Lim
Lloyd Thomas Hall, Iii
Original Assignee
Damon Biotech, Inc.
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 Damon Biotech, Inc. filed Critical Damon Biotech, Inc.
Publication of WO1988000237A1 publication Critical patent/WO1988000237A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N11/00—Carrier-bound or immobilised enzymes; Carrier-bound or immobilised microbial cells; Preparation thereof
    • C12N11/02—Enzymes or microbial cells immobilised on or in an organic carrier
    • C12N11/04—Enzymes or microbial cells immobilised on or in an organic carrier entrapped within the carrier, e.g. gel or hollow fibres
    • 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
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; 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
    • A61K9/48—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
    • A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/06—Making microcapsules or microballoons by phase separation
    • B01J13/10—Complex coacervation, i.e. interaction of oppositely charged particles

Definitions

  • the present invention relates to microcapsules of semipermeable membrane, and more particularly to membranes which are formed covalently.
  • U.S. Patent No. 4,352,883 to Franklin Lim discloses a microencapsulation technique which can be used to encapsulate solid or liquid material within semipermeable or substantially impermeable capsule membranes.
  • the process disclosed in the '883 patent begins by suspending the core material in a solution of a water-soluble substance which can be reversibly gelled. The resulting solutio is formed into droplets which are gelled to produce discrete shape-retaining temporary capsules. A polyionically bonded semipermeable membrane is then formed around the temporary capsules, followed by reliquifying the gel within the capsules.
  • Core materials discussed in the '883 patent include living cells and finely divided living tissue which are suspended in an aqueous medium which is physiologically compatible with the cells or tissue.
  • the preferred water-soluble substance therein for forming the temporary capsules is a gum, a preferred gum being sodium alginate.
  • the temporary capsules are formed by subjecting the droplets to a solution of ultivalent cations, such as an aqueous solution of calcium chloride.
  • the capsular membrane is formed by contacting the temporary capsules with a polymer of a molecular weigh between 3000 and 100,000 daltons which has free amino groups which react with the free carboxyl groups of the alginate.
  • crosslinking polymers are polylysine and other cationic polyamino acids.
  • sodium alginate is the water- soluble substance
  • the gelled core material is reliquified by removal of the calcium ions contained in the capsules, thereby resolubilizing their interior.
  • Other patents relating to this same general system of forming membranes of the polyelectrolyte complex type and various modifications thereof are U.S. Patents 4,391,909; 4,407,957; 4,409,331; and 4,495,288 to Franklin Lim, all incorporated herein by reference.
  • the present invention is a process for encapsulating a gel bead containing core material within a permanent, covalently cross-linked semipermeable membrane.
  • the process includes the steps of: activating a first compound possessing multiple functional groups by reaction of the first compound with a polyfunctional activating agent; placing a core material in a solution of a water- soluble substance which can be reversibly gelled, and which will covalently react with the activated first compound; forming a resulting solution into droplets; gelling the droplets to produce discrete shape retaining gel beads; and dropping the beads into a solution of the activated first compound to substantially instantaneously form a permanent covalent semipermeable membrane about the beads.
  • the process of the present invention employs the polyelectrolyte complex capsules or gelled material of the prior art (for example, of the type described in U.S. Patent No. 4,352,883).
  • the polyelectrolyte complex capsule or gelled material is modified at its outer surface by means of reaction with an activated polymer such as polyacrylic acid modified with
  • Woodward's Reagent K polymeric dextran modified with sulfoSANPAH (sulfosuccinimidyl 6-(4'-azido-2'- nitrophenylamino) hexanoate) , or other appropriately chosen activated polymer.
  • sulfoSANPAH sulfosuccinimidyl 6-(4'-azido-2'- nitrophenylamino) hexanoate
  • the result of the process is to produce a bila inar, i.e., two-layer, capsule membrane, the inner region of which is characterized by polyionic bonding, and the outer region of which is characterized by covalent bonding.
  • the inner, polyionic region of this bilaminar structure may subsequently be disrupted as necessary by treatment with appropriately chosen polyvalent ions or low molecular weight ionic species.
  • low molecular weight is meant under about 1000 daltons.
  • the outer membrane due to its covalent character, will be substantially unaffected by this treatment and will therefore serve to maintain the overall structure of the capsule.
  • the permeability of the resultant membrane may, however, differ substantially from the permeability of the original bilaminar system.
  • the relative thicknesses and permeabilities of the two regions of the bilaminar membrane may be controlled by altering the nature, concentrations and exposure times of the reacting species. It should be recognized, though, that the inner polyionic region acts as a reactant in the formation of the outer, covalent region of the bilayered membrane structure. For this reason, increases in the thickness of the covalent region may occur to some extent at the expense of the inner, polyionic layer.
  • a unilaminar covalent membrane surrounding the gelled material is produced.
  • Two means of generating such a unilaminar membrane are described below.
  • the gelled material to be encapsulated for example, chitosan acetate gelled with sodium citrate
  • an activated polymer solution for example, polyacrylic acid derivatized with Woodward's Reagent K
  • the required conditions are that the gelled material possess sites at which chemical reaction can occur under the available conditions of pH, temperature, and solvent composition, and further that the activated polymer possess moieties capable of covalently bonding to the reactive sites on the gelled material.
  • the permeability of the resulting membrane varies according to the concentration of the reactants, the reaction time, and the abundance of reactive sites present on the reactive species.
  • the gelled material to be encapsulated is itself activated in such a manner as to allow its covalent reaction with an appropriately chosen polymeric reactant.
  • an appropriately chosen polymeric reactant for example, beads of sodium alginate gelled in calcium chloride are derivatized with Woodward's Reagent K, and the resulting activated surface is treated with polylysine. The result of this process is the production of a gel bead surrounded by a covalently crosslinked polymer membrane.
  • the degree of crosslinking, and therefore the permeability of the resulting membrane can be controlled by altering the concentrations and reaction times of the reactants, or by varying other experimental conditions in a manner appropriate to the reactive species in use. Examples of these other conditions are temperature, ionic composition of the medium and light intensity at the site of polymerization.
  • the gelled core of the product capsule may be reliquified if desired by the addition of appropriate ungelling agents.
  • suitable ungelling agents would be calcium chloride and sodium citrate, respectively.
  • microcapsules of the polyelectrolyte complex type can be prepared such that their core contains enzyme-antigen complexes having a unit molecular weight of about 5000 daltons.
  • the polyelectrolyte complex membrane of such capsules would be prepared in such a way as to prevent the escape by diffusion of the core material.
  • a covalent membrane is then placed around the polyelectrolyte complex membrane.
  • the outer covalent membrane can be produced in such a way that it is permeable to the enzyme- antigen complexes contained in the core.
  • To the outer covalent membranes can then be coupled antibody molecules which specifically bind the antigen portion of the enzyme-antigen complex of the core material.
  • the capsules produced would be exposed to free specific antigen in aqueous medium, and binding of the antigen to the immobolized antibody would be allowed to occur.
  • the microcapsules would then be removed and washed.
  • the capsule would then be treated with a solution capable of disintegrating the inner polyelectrolyte complex membrane.
  • the enzyme-antigen complexes of the core material are free to diffuse out of the capsule.
  • the antigen moiety of such complexes can then bind to any unfilled binding sites of the immobilized antibody on the outer surface of the capsule.
  • this binding process is substantially complete the capsules are again washed leaving bound enzyme on the surface of the capsules and only washing solution in the core.
  • a chromogenic substrate can then be added to the system and the color change measured after the defined incubation period.
  • the amount of color change can then be related to the amount of the free antigen originally added to the system.
  • a test system based on this sort of approach but utilizing radiolabeled antigen rather than an enzyme-antigen complex could also be utilized. In either case, a simple, extremely sensitive, assay system results.
  • the activated compound employed in the present invention certain compounds can be used without modification, for example, polymeric aryl azides or n-hydroxy succinimide esters. In other cases, the compound may require activation or derivitization to produce reactive chemical groups capable of covalent bond formation with the functional groups of the other reacting compound or membrane surface. Typical examples of covalent bonds formed in this manner are ester bonds, peptide bonds, disulfide bonds, and bonds formed by free radical reactions.
  • Activation of functional groups may be accomplished by initiators or activators such as light or temperatures or by specific cross-linking reagents which functionally possess at least two types of reactive groups, hereafter referred to as "polyfunctional activating agents".
  • Membrane pore size can be controlled by choosing or adjusting the density (number) and distribution of the reactive groups in the reactants, adjusting the concentration of the reactants, or adjusting the reaction conditions, such as time or temperature.
  • the process of the present invention produces microcapsules substantially instantaneously with a true covalently linked polymeric membrane, about a reversible polyelectrolyte complex type of membrane of the prior art.
  • substantially instantaneously is meant, in fewer than about five seconds.
  • production of the covalently linked polymeric membrane is complete in one second or less, particularly when living material is involved. Otherwise, the chemicals and conditions used may adversely affect its viability.
  • the tissues, organelles, or cells to be encapsulated in accordance with the process of the present invention are prepared in accordance with well- known prior art techniques.
  • the material to be encapsulated is suspended in a solution of a water- soluble substance which can be reversibly gelled.
  • a medium is utilized which is suitable for maintenance and for supporting the ongoing metabolic processes of the particular material involved.
  • Media suitable for these purposes are available commercially.
  • the average diameter of the material being encapsulated can vary widely between less than a micron to several millimeters.
  • samples of materials as divergent in size as mammalian Islets of Langerhans 50-200 micrometers in diameter
  • Herpes simplex virus (30-40 nanometers in diameter
  • onomeric immunoglobulins molecular weight approximately 150,000 daltons
  • the core material to be encapsulated can be discrete living cells, viable tissue of plant or animal origin, or Protista such as viruses.
  • individual cells such as fibroblasts, leukocytes, pancreatic beta cells, alpha cells, delta cells, or various ratios thereof.
  • Islets of Langerhans, individual hepatocytes, organelles, or other tissue units may be encapsulated as desired.
  • Other cells which can be encapsulated include thymic cells, thyroid cells, liver cells (e.g., hepatocytes), adrenal cells, blood cells, lymphoid cells, and pituitary cells.
  • microorganisms may be encapsulated as well as non-living materials of biological or non-biological origin.
  • the process of the present invention includes the in situ formation of a membrane on the surface of a capsule. This surface, if necessary, may be modified during the process, for example, by activation or by the addition of reactive sites.
  • one of the reactants is polyacrylic acid
  • the carboxylic acid moieties of the polyacrylic acid can be activated, for example, by reaction with Woodward's Reagent K (N-ethyl-5- phenylisoxazolium-3'-sulfonate) . While in this case the activating group does not form a part of the final product membrane, it is acceptable for the activating species to be incorporated into the final product membrane.
  • Woodward's Reagent K is a well known material for enzyme immobilization by the formation of water- soluble enzyme-polymer conjugates. Typical of such prior art enzyme immobilization conjugates are alpha- chymotrypsin on polyacrylic acid, carboxymethyl cellulose, or poly-L-glutamic acid. Although a preferred polyfunctional activating agent is Woodward's Reagent K, numerous other polyfunctional activating agents are known which will, for the purposes of the present invention, act in the same manner as Woodward's Reagent K, provided suitable reactants are chosen.
  • polyfunctional activating agents examples include m-maleimidobenzoyl-N-hydroxysuccinimide ester, m-maleimidobenzoylsulfosuccinimide ester, N- succinimidyl-(4-iodoacetyl)aminobenzoate, succinimidyl 4-(N-maleimidomethyl)-cy ⁇ lohexane-1-carboxylate, sulfosuccinimidyl(4-iodoacetyl)aminobenzoate, and sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-1- carboxylate.
  • a hydroxyl group-containing polymer is activated by reaction with the photoactivated cross- linking agent sulfoSANPAH and then the amino groups of the temporary chitosan capsule surface react with the activated groups on the dextran polymer.
  • photoactivation is typically accomplished over a period of 5 - 45 minutes.
  • dextran polymers and chitosan acetate are only being used as examples of suitable polyfunctional reactants.
  • the present invention is applicable generally to reactions between a wide variety of covalently reactive species, including, but not limited to, polyamino and polysulfhydryl compounds, polycarboxylic acids, polymeric aryl azides, and polymeric n- hydroxysuccinimide esters.
  • the solution containing the core material is formed into droplets of a desired size.
  • the drop formation may be conducted by known methods. An exemplary procedure follows.
  • a receiving vessel of a selected volume which vessel contains one of the reactants, e.g., calcium chloride, is fitted with a stopper which holds a drop-forming apparatus.
  • the apparatus consists of a housing having an upper air intake nozzle and an elongate hollow body friction fitted into the stopper.
  • a 10 cc syringe equipped with a syringe pump is mounted atop the housing with, e.g., a 20G by 1-1/2" needle squared off at the end which passes through the length of the housing.
  • the interior of the housing is designed such that the tip of the needle is subjected to a constant air flow which acts as an air knife.
  • the syringe pump In use, with the syringe full of solution or suspension containing the material to be encapsulated, e.g., cells in a sodium alginate suspension, the syringe pump is actuated to incrementally force droplets of solution or suspension from the tip of the needle. Each drop is "cut off" by the air stream and falls approximately 2 to 10 cm into the vessel containing the gelling solution, e.g. aqueous calcium chloride. The distance between the tip of the needle and the surface of the solution in the vessel is great enough, in this instance, to allow the solution or suspension to assume the most physically favorable shape; i.e., a sphere
  • Capsules formed by the process of the present invention have essentially the same utilities as those of the prior art, and thus also the same advantages, and are in fact useful in applications where material encapsulated solely by the polyelectrolyte complex type microcapsules of the prior art would not be useful because of potential adverse ionic interactions, or lack of permanency of the polyelectrolyte complex membrane.
  • the process of the present invention is useful for the encapsulation of biologically active material such as enzymes, hormones, and antibodies.
  • the process of the present invention is also useful for the encapsulation of viable Islets of Langerhans.
  • the resulting capsules when placed in a medium containing the nutrients and other materials necessary to maintain viability and support in_Vitro metabolism of the tissue will maintain their complete physiological functional integrity.
  • Other types of cells similarly can be encapsulated in a physiologically active state.
  • the capsules of the present invention would also be useful for tissue implantation into a mammalian body. Another use for the present invention would be in the manufacture of an artificial or bioartificial organ.
  • the capsules of the present invention can be used in the culturing of anchorage dependent cells according to the method described in U.S. Patent 4,495,288, incorporated herein by reference.
  • Cell cultures encapsulated as described above may be suspended in culture media designed specifically to satisfy all of the requirements of the particular cell type involved and will continue to carry out normal metabolic processes in the capsules.
  • Nutrients required by the cells will normally be of sufficiently low molecular weight so that their diffusion into the microcapsule will be substantially unimpeded by the membrane.
  • the membrane may be constructed in such a way as to limit the escape of the cells' high molecular weight metabolic products, thereby allowing the isolation of these products from the relatively smaller volume of the intracapsular medium rather than the larger volume of the extracapsular medium. This concentrating effect of microcapsular membranes is an advantage that the present invention shares with the microcapsules of the prior art.
  • the encapsulated cells may be cultured under conditions of, e.g., temperature, pH, and ionic environment, identical to conventional cultures.
  • cell-produced products may be harvested from the extracapsular medium or from within the capsules by conventional techniques. Examples of cell produced products which may be harvested include insulin, glucagon, antibodies, prolactin, somatostatin, thyroxin, steroid hormones, pituitary hormones, interferons, FSH, and PTH.
  • EXAMPLE 1 In 20 ml of saline is dissolved 0.2 g of T40 dextran (m.w. 40,000). To this is added 5 mg of SulfoSANPAH (sulfosuccinimidyl 6-(4'-azido-2'- nitrophenylamino)hexanoate) (a product sold by Pierce Chemical Company, P. 0. Box 117, Rockford, Illinois 61105) . The resulting solution is placed in a closed container with a high pressure mercury light source. The solution is irradiated for about 30 minutes while maintaining a temperature in the container of about
  • SulfoSANPAH sulfosuccinimidyl 6-(4'-azido-2'- nitrophenylamino)hexanoate
  • the resulting activated dextran is rehydrated to 1% by volume of dextran by the addition of saline.
  • chitosan acetate is readily prepared by suspending 2 grams of chitosan in 200 ml of deionized water, adding 0.62 ml of acetic acid, mixing until the chitosan dissolves, and filtering to remove undissolved material.
  • the cell-containing chitosan acetate solution is added dropwise to a three percent by weight solution of sodium citrate (pH 6.8) to form polyionically bonded temporary capsules.
  • the resulting temporary capsules are removed from the citrate solution, followed by the addition of an aliquot of activated dextran solution, and mixing for about 1 minute to produce a covalently bonded membrane around the polyionically bonded membrane.
  • the cores of the capsuled are then ungelled by placing the capsules in a 0.65% by weight solution of calcium chloride (pH 6.2). However, the capsules remain intact, thereby demonstrating that the outer membrane is covalently bonded, since the interior ionically bonded layer disintegrates under these conditions.
  • EXAMPLE 2 A one mM solution of T40 dextran (m.w. 40,000) in saline is prepared. Approximately 5 mg of SANPAH (N-succinimidyl-6-(4'-azido-2'- nitrophenylamino)hexanoate) are suspended in approximately 20 ml of the dextran solution.
  • SANPAH N-succinimidyl-6-(4'-azido-2'- nitrophenylamino)hexanoate
  • the resulting solution is irradiated for 15 minutes under a UV light source, and the resulting solid is redissolved in saline to approximately one percent by volume, and then the debris removed by centrifuging.

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Abstract

Le procédé décrit permet d'encapsuler une perle de gel contenant un matériau noyau a l'intérieur d'une membrane semi-perméable, permanente, à réticulation covalente. Le procédé comprend les étapes suivantes: activation d'un premier composé ayant des groupes fonctionnels multiples par réaction de ce premier composé avec un agent d'activation polyfonctionnel; introduction d'un matériau noyau dans une solution d'une substance hydrosoluble qui peut être gélifiée de manière réversible et qui peut réagir de manière covalente avec le premier composé activé; transformation d'une solution résultante en gouttelettes; gélification des gouttelettes pour produire des perles de gel gardant leur forme; et immersion des perles dans une solution du premier composé activé pour former presque instantanément une membrane semi-perméable covalente et permanente autour des perles.
PCT/US1987/001495 1986-06-27 1987-06-29 Membranes covalentes WO1988000237A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US879,605 1978-02-21
US87960586A 1986-06-27 1986-06-27

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WO1988000237A1 true WO1988000237A1 (fr) 1988-01-14

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PCT/US1987/001495 WO1988000237A1 (fr) 1986-06-27 1987-06-29 Membranes covalentes

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989010786A3 (fr) * 1988-04-22 1990-03-08 Microdrop Inc Procede de formation et d'utilisation de microgouttelettes
US4915301A (en) * 1988-11-15 1990-04-10 International Flavors & Fragrances, Inc. Container with sorbent member and microporous membrane for dispensing vapor from volatile liquid
WO1992006678A1 (fr) 1990-10-15 1992-04-30 Board Of Regents, The University Of Texas System Microcapsules biocompatibles
EP0588707A1 (fr) * 1992-09-18 1994-03-23 Rhone-Poulenc Nutrition Animale Compositions nutritives ou médicamenteuses pour l'administration aux ruminants à base de chitosane
EP0663951A1 (fr) * 1992-09-28 1995-07-26 Brown University Research Foundation Matrices en chitosan pour cellules encapsulees
US5462990A (en) * 1990-10-15 1995-10-31 Board Of Regents, The University Of Texas System Multifunctional organic polymers
US5531735A (en) * 1994-09-27 1996-07-02 Hercules Incorporated Medical devices containing triggerable disintegration agents
US5798113A (en) * 1991-04-25 1998-08-25 Brown University Research Foundation Implantable biocompatible immunoisolatory vehicle for delivery of selected therapeutic products
US5800829A (en) * 1991-04-25 1998-09-01 Brown University Research Foundation Methods for coextruding immunoisolatory implantable vehicles with a biocompatible jacket and a biocompatible matrix core
WO2001047624A1 (fr) * 1999-12-23 2001-07-05 Henkel Kommanditgesellschaft Auf Aktien Preparations aqueuses multiphases

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DE3931432A1 (de) * 1989-09-21 1991-04-04 Hoechst Ag Pyrimidin-4,6-dicarbonsaeurediamide, verfahren zu deren herstellung sowie verwendung derselben sowie arzneimittel auf basis dieser verbindungen

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US4409331A (en) * 1979-03-28 1983-10-11 Damon Corporation Preparation of substances with encapsulated cells
US4518693A (en) * 1982-11-01 1985-05-21 Research Corporation Immobilized biocatalysts
EP0173915A2 (fr) * 1984-09-07 1986-03-12 Joachim Prof. Dr. Klein Biocatalyseur et son procédé de préparation
WO1987004367A1 (fr) * 1986-01-23 1987-07-30 Ltl Associates Membranes covalentes

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Publication number Priority date Publication date Assignee Title
US4409331A (en) * 1979-03-28 1983-10-11 Damon Corporation Preparation of substances with encapsulated cells
US4518693A (en) * 1982-11-01 1985-05-21 Research Corporation Immobilized biocatalysts
EP0173915A2 (fr) * 1984-09-07 1986-03-12 Joachim Prof. Dr. Klein Biocatalyseur et son procédé de préparation
WO1987004367A1 (fr) * 1986-01-23 1987-07-30 Ltl Associates Membranes covalentes

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Title
Chemtech, January 1974, American Chemical Society, (Washington, US), W.R. VIETH et al.: "Enzyme Engineering Part II. Materials for Immobilized Enzyme Reactors", pages 47-54 see page 48 *

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989010786A3 (fr) * 1988-04-22 1990-03-08 Microdrop Inc Procede de formation et d'utilisation de microgouttelettes
US4915301A (en) * 1988-11-15 1990-04-10 International Flavors & Fragrances, Inc. Container with sorbent member and microporous membrane for dispensing vapor from volatile liquid
US5462990A (en) * 1990-10-15 1995-10-31 Board Of Regents, The University Of Texas System Multifunctional organic polymers
EP0553195A1 (fr) * 1990-10-15 1993-08-04 Univ Texas Microcapsules biocompatibles.
EP0553195A4 (en) * 1990-10-15 1993-09-29 Board Of Regents The University Of Texas System Biocompatible microcapsules
WO1992006678A1 (fr) 1990-10-15 1992-04-30 Board Of Regents, The University Of Texas System Microcapsules biocompatibles
US5820882A (en) * 1990-10-15 1998-10-13 Board Of Regents, The University Of Texas System Biocompatible microcapsules
US6231892B1 (en) 1990-10-15 2001-05-15 The Board Of Regents, The University Of Texas System Compositions for coating microcapsules and other surfaces
US5874099A (en) * 1991-04-25 1999-02-23 Brown University Research Foundation Methods for making immunoisolatary implantable vehicles with a biocompatible jacket and a biocompatible matrix core
US5869077A (en) * 1991-04-25 1999-02-09 Brown University Research Foundation Methods for treating diabetes by delivering insulin from biocompatible cell-containing devices
US5871767A (en) * 1991-04-25 1999-02-16 Brown University Research Foundation Methods for treatment or prevention of neurodegenerative conditions using immunoisolatory implantable vehicles with a biocompatible jacket and a biocompatible matrix core
US5798113A (en) * 1991-04-25 1998-08-25 Brown University Research Foundation Implantable biocompatible immunoisolatory vehicle for delivery of selected therapeutic products
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