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WO1991009119A1 - Microcapsules d'alginate ameliorees et procedes pour leur fabrication et leur utilisation - Google Patents

Microcapsules d'alginate ameliorees et procedes pour leur fabrication et leur utilisation Download PDF

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Publication number
WO1991009119A1
WO1991009119A1 PCT/US1990/007275 US9007275W WO9109119A1 WO 1991009119 A1 WO1991009119 A1 WO 1991009119A1 US 9007275 W US9007275 W US 9007275W WO 9109119 A1 WO9109119 A1 WO 9109119A1
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WO
WIPO (PCT)
Prior art keywords
alginate
poly
barium
layer
lysine
Prior art date
Application number
PCT/US1990/007275
Other languages
English (en)
Inventor
Gudmund Skjak-Braek
Olav Smidsrod
Terje Espevik
Marit Otterlei
Original Assignee
Trancel Corporation
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 Trancel Corporation filed Critical Trancel Corporation
Publication of WO1991009119A1 publication Critical patent/WO1991009119A1/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
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0676—Pancreatic cells
    • C12N5/0677—Three-dimensional culture, tissue culture or organ culture; Encapsulated cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/37—Digestive system
    • A61K35/39—Pancreas; Islets of Langerhans
    • 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
    • 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

Definitions

  • This invention relates to the fields of polymer chemistry, immunology and transplantation, and more particularly to the field of materials for use in conjunction with transplantation and implantation of foreign cells and biological materials.
  • islet transplantation can cure the diabetic animal of the need for insulin therapy.
  • the major obstacle preventing clinical success in islet transplantation as a therapy for diabetes to date has been immunogenicity of the cell and rejection of the transplanted graft.
  • Survival of islet allografts and or xenografts has been achieved by various methods of immunosuppression and/or related immunological techniques.
  • immunosuppression and/or related immunological techniques have had only limited success in that the transplanted islet cells survive only a short while before rejection occurs.
  • the extended use of immunosuppressive agents often results in severe complications, such as renal damage and even cancer in the transplant recipient.
  • Microencapsulation is a process in which small, discrete materials, viable biological tissue or cells, liquid droplets, or gases are completely enveloped by an intact membrane which is preferably compatible with the biological system in which it is placed.
  • the function of the microcapsule membrane is to protect the material within from immunological recognition by the host and to control the flow of materials inside and outside the microcapsule across the membrane.
  • islet cells In addition to islet cells, other materials such as microbial cells, other mammalian cells, yeasts, chloroplasts, plant protoplasts, mitochondria and enzymes have been immobilized and entrapped using microencapsulation techniques.
  • the Lim and Sun capsules are usually made by first forming a negatively charged alginate bead around purified and isolated islet cells by cross-linking alginate with calcium chloride, then creating a positively charged membrane on the outer surface by forming an ionic bond with a cation such as poly-L-lysine. Additionally, a second negatively charged outer layer of alginate is usually formed around the outside of the poly-L-lysine layer, ionically bonded thereto. Finally, the inner bead of alginate is degelled, leaving a capsule surrounded by a layer of poly-L-lysine-alginate gel and an outer layer of alginate. This prior art capsule is depicted in Figure 1 and described in more detail below.
  • Capsules formed according to the foregoing procedure are difficult to make, requiring many steps, which is not advantageous in light of the consideration that live cells are involved. Also, it is desirable to minimize handling time and moderate handling conditions. Even more significant, however, is the fact that these prior art capsules often fail in vivo as a result of the release of substances which stimulate cytokine release, which in turn cause the microcapsules to be attacked by immunoglobulins.
  • the immunoglobulins may either, or in combination, penetrate the microcapsule and destroy the enclosed islet cells, cause fibroblast formation around the microcapsule thereby choking off nutrients to the cells and preventing the cell products from being released into the host; and/or stimulate the destruction of the microcapsule via the host's immunological system.
  • Alginate the principal material of the microcapsules, is a heterogeneous group of linear binary copolymers of 1-4 linked ⁇ -D-mannuronic acid (M) and its C-5 epimer ⁇ -L-guluronic acid (G) .
  • the monomers are arranged in a blockwise pattern along the polymeric chain where homopolymeric regions are interspaced with sequences containing both monomers.
  • the proportion and sequential arrangement of the uronic acids in alginate depend upon the species of algae and the kind of algal tissue from which the material is prepared. Various properties of different types of alginates are based upon the guluronic acid makeup of the particular alginate.
  • viscosity depends mainly upon the molecular size, whereas the affinity for divalent ions essential for the gel-forming properties are related to the guluronic acid content. Specifically, two consecutive di-axially linked G residues provide binding sites for calcium ions and long sequences of such sites form cross-links with similar sequences in other alginate molecules, giving rise to gel networks.
  • M 1-4 linked /3-D-mannuronic acid
  • These M blocks do not bind with calcium when the gel is formed in the inner bead, and it is believed that some of this M alginate leaches out after the microcapsule is formed.
  • microcapsules form an effective barrier against immunoglobulin penetration by having a sufficiently small diameter porosity that large proteins are excluded.
  • the negative charge of the alginate bead plays a more significant role in excluding negatively charged proteins, such as immunoglobulins.
  • the present invention overcomes the deficiencies of the prior art by providing a microcapsule of the type described herein in accordance with the following description, as well as ancillary materials and methods relating thereto.
  • the present invention provides a successful approach to microencapsulation and implantation which has not heretofore been discovered. It is one object of the present invention to provide a material which may be implanted or transplanted in vivo which is non-immunogenic and non-fibroblast inducing.
  • the present invention comprises a new encapsulation material comprised of alginate gelled by barium salt, the material being useful in vivo for implantation and transplantation in mammalian bodies.
  • the material may take many forms, such as sheets, organ capsulation and the like, but is preferably used for microencapsulation of living cells which are foreign to the host in which they are implanted.
  • the present invention also protects the islets of Langerhans or other transplanted tissue from immunological cell rejection.
  • the present invention also provides a microencapsulation system which limits fibroblast overgrowth.
  • the present invention relates to encapsulation of cells or other biological material with a coating of alginate gelled with barium salt, preferably, barium chloride.
  • a second layer of poly-L-lysine, and a third outermost layer of alginate may be added to the capsule.
  • the alginate in the outer coating is preferably comprised of substantially guluronic acid, with minor amounts of mannuronic acid blocks.
  • the alginate portion of either of the former embodiments is gelled with a combination of barium and calcium.
  • the inner layer of the microcapsule is comprised of barium gelled or barium plus calcium gelled alginate, which is then coated with a poly-L-lysine and an outer layer of hyaluronic acid.
  • FIGURE 1 is an illustration of a cross-section of the prior art microcapsule depicting the various layers and one example of the potential contents of the microcapsule.
  • FIGURE 2 is an illustration of a cross-section of one embodiment of the present invention.
  • FIGURE 3 is an illustration of a cross-section of another embodiment of the present invention.
  • FIGURE 4 is an illustration of a cross-section of the preferred embodiment of the present invention.
  • FIGURE 5 is an illustration of a cross-section of another embodiment of the present invention. Detailed Description of the Invention
  • the present invention comprises material which can be implanted or transplanted in vivo into mammals without inducing any substantial immunogenic reaction or fibroblast formation.
  • the present invention also comprises materials for encapsulation of biological materials.
  • the present invention is also a process for microencapsulating biological cells and other materials for use in implantation or transplantation as a drug or biological material delivery system.
  • biological materials includes prokaryotic and eukaryotic cells which are either naturally occurring or genetically engineered, drugs or pharmaceuticals, enzymes, parts of cells such as mitochondria and protoplasts or any other naturally occurring or synthesized material which may be implanted.
  • the material used in the present invention is alginate cross-linked with barium salt, and preferably barium chloride.
  • the alginate may be any alginate solution capable of forming microcapsules, as is known in the art.
  • the alginate may be comprised substantially of ⁇ -L-guluronic acid (G) which may be referred to herein as guluronic acid alginate or high G.
  • high guluronic acid alginate is described in our copending patent application Serial No. 446,462.
  • Small amounts of mannuronic acid j8-D-mannuronic acid
  • Alginate so comprised elicits a very low response from monocytes in the production of tumor necrosis factor (TNF) and IL-1 and IL- 6, and, as a result, does not elicit fibrosis.
  • TNF tumor necrosis factor
  • IL-1 and IL- 6 do not elicit fibrosis.
  • Such alginate may be obtained from Protan A/S, Drammen, Norway.
  • High G alginate is the preferred alginate used on the outside of microcapsules because of its property of not inducing fibroblast formation.
  • Figure 1 shows the prior art capsule of Lim and Sun.
  • such prior art microcapsules comprise islets of Langerhans 12 or other substance for transplantation or implantation contained in a liquid bead or capsule of alginate 14 which was gelled with calcium chloride during the making of the microcapsule and then ungelled to return it to a liquid state.
  • Surrounding the calcium-alginate liquid bead is a layer of poly-L-lysine 16 which forms a membrane by bonding ionically with the alginate core.
  • On the outside is another layer of alginate 20.
  • the present invention in one embodiment, comprises islets of Langerhans 12 or other transplantation or implantation material, coated with a bead of alginate 22 gelled with a barium salt, preferably barium chloride.
  • the islet of Langerhans 12 may be surrounded by a barium alginate gel coating 22, as in Figure 2, which in turn is surrounded by a poly-L-lysine layer 16, which in turn is surrounded by an outer layer of alginate 24, preferably high G alginate.
  • the islet of Langerhans 12 may be surrounded by an alginate gel coating 26, that is gelled with both calcium and barium, which in turn is surrounded by a poly-L-lysine layer 16, which in turn is surrounded by an outer layer of alginate 24, preferably high G alginate.
  • the islet of Langerhans 12 may be surrounded by a barium alginate bead 22 or an alginate bead gelled with both calcium and barium 26, which in turn is surrounded by a poly-L-lysine layer 16, which in turn is surrounded by an outer layer of hyaluronic acid 30.
  • the barium alginate capsule may be used alone or in conjunction with other layers to form a microcapsule.
  • a 1.0% to 1.5% by weight alginate solution is formed around purified islets of Langerhans and is treated with a solution in the range of 2 to 20 mM barium chloride to form a gelled microcapsule.
  • an alginate bead having a concentration of 1.0 to 1.5% alginate is first treated with a solution of 80 to 100 mM calcium chloride, to bind the G-blocks, and then with a second solution of 1 to 20 mM barium chloride to bind the blocks of the alginate composition.
  • the microcapsule of the immediately foregoing embodiment is further treated with a solution of 0.5% poly-L-lysine (20,000 M ) .
  • An outer coating of 1.1% alginate, preferably high G alginate, is then formed therearound.
  • poly-L-lysine is the preferred material.
  • poly-L-ornithine and chitosan may be used in place of poly-L-lysine, and that other cationic compounds with similar properties may also be used.
  • hyaluronic acid as a component of the present invention inhibits the formation of fibroblasts when applied as an outside coating on the microcapsule.
  • barium alginate tends to be a more rugged and hardy material than prior art calcium alginate. Also, fewer steps are required in the manufacture of barium alginate microcapsules, first because multiple layers are not required, and also, if as many layers are used, there is no need for a de-gelling step as is used in the prior art.
  • alginate beads When alginate beads are treated with both barium chloride and calcium chloride, the bead is first dropped in a solution of calcium chloride, and then in a solution of barium chloride.
  • the calcium is believed to cross-link with the guluronic acid blocks of he alginate molecules, and the barium cross-links both with the M-block portions of the alginate and the G-block portions which have not previously been cross-linked with the calcium chloride.
  • the resulting microcapsules of the present invention have improved kinetics of insulin release.
  • the barium chloride gel material has a greater negative charge because it is in a gel form, rather than a liquid form, and also because over time, the liquid calcium alginate of the prior art microcapsules leaches out so there is less negatively charged material in prior art microcapsules.
  • the negatively charged portion repels the negatively charged insulin, or other negatively charged material thereby forcing said insulin or other material out of the microcapsule.
  • the negative charge would also repel immunoglobulin molecules produced by the host, thereby safely protecting the contents of the microcapsule.
  • the composition comprising alginate having a high G content may be used in the form of organ capsulation, sheets of alginate for implantation, hollow fibers and membranes formed of the subject composition.
  • Cultured rat islets of Langerhans (2 X 10 3 islets in 0.2 ml medium) may be suspended uniformly in 2 ml of a 1.5% (w/w) sodium alginate solution (viscosity 51 cps) in physiological saline.
  • Spherical droplets containing islets were produced by syringe pump/air jet extrusion through a 22-gauge needle and collected in 1.5% (w/w) barium chloride solution. The supernatant was decanted and the gelled spherical alginate droplets, containing islets, were washed with dilute CHES (2-cyclohexylamino- ethane sulfonic acid) solution and 1.1% barium chloride solution.
  • the microcapsules are found to be generally spherical and each to contain from 1 to 2 viable islets.
  • the microcapsules have a diameter of 500 ⁇ 50 ⁇ m and wall thicknesses of about 3-4 ⁇ m.
  • the microcapsules may be suspended in nutrient medium at 37°C.
  • Example 2 Mutliple-laver Microencapsulation of Islets of Langerhans Cultured rat islets of Langerhans (2 X 10 3 islets in 0.2 ml medium) may be suspended uniformly in 2 ml of a 1.5% (w/w) sodium alginate solution (viscosity 51 cps) in physiological saline. Spherical droplets containing islets were produced by syringe pump/air jet extrusion through a 22-gauge needle and collected in 1.5% (w/w) barium chloride solution. The supernatant was decanted and the gelled spherical alginate droplets, containing islets, were washed with dilute CHES solution and 1.1% barium chloride solution.
  • a 1.5% (w/w) sodium alginate solution viscosity 51 cps
  • the gelled droplets were incubated for 6 minutes in 0.05% (w/w) polylysine having a molecular weight of 17,000.
  • the supernatant was decanted and the polylysine capsules were washed with dilute CHES, 1.1% calcium chloride solution and physiological saline.
  • the washed polylysine capsules were incubated for 4 minutes in 30 ml of 0.03% sodium alginate to permit he formation of an outer alginate membrane on the initial polylysine membrane, by ionic interaction between the negatively charged alginate and the positively charged polylysine.
  • the alginate used in the outer coating, and if desired, the inner coating as well is poly G alginate (Protan) produced as described above.
  • the microcapsules are found to be perfectly spherical and each to contain from 1 to 2 viable islets.
  • the microcapsules have a diameter of 700 ⁇ 50 ⁇ m and wall thicknesses of about 5 ⁇ m.
  • the microcapsules may be suspended in nutrient medium at 37°C.
  • the gelled droplets were incubated for 6 minutes in 0.05% (w/w) polylysine having a molecular weight of 17,000.
  • the supernatant was decanted and the polylysine capsules were washed with dilute CHES, 1.1% calcium chloride solution and physiological saline.
  • the washed polylysine capsules were incubated for 4 minutes in 30 ml of 0.03% sodium alginate to permit the formation of an outer alginate membrane on the initial polylysine membrane, by ionic interaction between the negatively charged alginate and the positively charged polylysine.
  • the alginate used in the outer coating, and if desired, the inner coating as well, is poly G alginate produced as described above.
  • the microcapsules are found to be perfectly spherical and each to contain from 1 to 2 viable islets.
  • microcapsules would have a diameter of 700 ⁇ 50 ⁇ m and wall thicknesses of about 5 ⁇ m.
  • the microcapsules may be suspended in nutrient medium at 37° C. It will be obvious to a person of ordinary skill in the art that the present invention is not limited in its application to specific biological materials to be encapsulated, such as the islet cells described in detail above, or by the specifically described other inner layers of microcapsule discussed herein. The only limitations of the present invention are set forth in the claims appended hereto and any equivalents thereof.

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  • Engineering & Computer Science (AREA)
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  • Cell Biology (AREA)
  • General Engineering & Computer Science (AREA)
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Abstract

Une composition permettant de contenir un matériau biologique destiné à l'implantation in vivo et la transplantation comprenant de l'alginate réticulé avec du sel de baryum, de préférence du chlorure de baryum. La microcapsule est susceptible de comporter facultativement comme ses autres couches de l'acide hyaluronique et de la poly-L-lysine. On peut également utiliser de l'alginate réticulé avec du chlorure de calcium aussi bien que du chlorure de baryum. La microcapsule décrite est rugueuse et conserve une forte charge négative, améliorant la libération de protéines et limitant l'invasion par des immunoglobulines. La microcapsule peut être utilisée de préférence pour l'encapsulation des îlots de Langerhans en vue de la production d'insuline.
PCT/US1990/007275 1989-12-13 1990-12-10 Microcapsules d'alginate ameliorees et procedes pour leur fabrication et leur utilisation WO1991009119A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US44998389A 1989-12-13 1989-12-13
US449,983 1989-12-13

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WO1991009119A1 true WO1991009119A1 (fr) 1991-06-27

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Cited By (36)

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EP0651996A1 (fr) * 1993-11-08 1995-05-10 Giovanni Brotzu Equipement et méthode pour la préparation de microcapsules polymériques contenant des cellules productrices d'hormones
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EP1025869A1 (fr) * 1999-02-05 2000-08-09 ZIMMERMANN, Ulrich Procédé pour la fabrication d'un matériau stable à base d'alginate
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EP1224259A4 (fr) * 1999-09-27 2005-04-27 Univ Florida Inversion de diabetes dependant de l'insuline par des cellules souches insulaires, des cellules insulaires progenitrices et des structures de type insulaire
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WO2012130567A1 (fr) 2011-03-29 2012-10-04 Beta-Cell Nv Procédé destiné à des produits thérapeutiques encapsulés et leurs utilisations
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WO2014057203A1 (fr) 2012-10-09 2014-04-17 Societe D'exploitation De Produits Pour Les Industries Chimiques Seppic Compositions pharmaceutiques comprenant des capsules obtenues par coacervation ne mettant pas en oeuvre de reticulant toxique
WO2016086020A1 (fr) * 2014-11-24 2016-06-02 Cytostormrx Llc Cellules souches encapsulées pour le traitement d'une maladie inflammatoire
CN107073176A (zh) * 2014-06-09 2017-08-18 康奈尔大学 可植入治疗递送系统及其方法
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US20200323784A1 (en) * 2017-09-20 2020-10-15 The General Hospital Corporation Use of cxcl12 to promote survival, function, and immunoisolation of stem cell-derived beta cells
JPWO2020209273A1 (fr) * 2019-04-09 2020-10-15
USRE48523E1 (en) 2012-03-19 2021-04-20 Algae To Omega Holdings, Inc. System and method for producing algae
CN114190363A (zh) * 2021-12-24 2022-03-18 大连大学 一种ε-聚赖氨酸微球载体及在少量精子冷冻保存中的应用

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