Macrocapsules prepared from crosslinkable polysaccharides, polycations and/or lipids and uses therefor

• US 5,846,530 A
• Filed: 06/07/1995
• Issued: 12/08/1998
• Est. Priority Date: 10/29/1991
• Status: Expired due to Term

• Current Assignee: ReNeuron Limited (ReNeuron Group Plc)
• Original Assignee: American Bioscience, Inc. (Bristol-Myers Squibb Company)
• Inventors: Soon-Shiong, Patrick, Desai, Neil P., Sandford, Paul A., Heintz, Roswitha A., Sojomihardjo, Soebianto
• Primary Examiner(s): Berman, Susan W.
• Application Number:
  US08/475,175
• Time in Patent Office: 1,280 Days
• Field of Search: 428/321.5, 522/87, 522/88, 424/460, 424/461, 424/462, 424/93.7, 424/486, 424/487, 424/488
• US Class Current: 424/93.7
• CPC Class Codes: A61F 13/02 Adhesive bandages or dressings
• CPC Class Codes: A61F 2013/00157 for burns or skin transplants A61F2013/00187 takes precedence; not adhering to the wound A61F2013/00217
• CPC Class Codes: A61F 2013/00229 with alginate
• CPC Class Codes: A61F 2013/00574 shaped as a body part A61F2013/00187 take precedence; use of plasters A61F2013/00365; containing means for different purposes A61F2013/00902
• CPC Class Codes: A61F 2013/00625 in situ
• CPC Class Codes: A61F 2013/00638 Gel
• CPC Class Codes: A61F 2013/0068 cross-linked by radiations, e.g. electron beam
• CPC Class Codes: A61F 2013/00748 with hydrocolloids or superabsorbers wound bandages with alginate A61F2013/00229; plasters with cyano-acrylic adhesive A61F2013/00459; plasters for treating burn with hydrogel A61F2013/00523; adhesive for plasters, with hydrogel A61F2013/00676; water-based A61F2013/00689; for use on mucosae A61F2013/00714; for use on wounds A61F2013/00719; with absorbent adhesives A61F2013/00757; with fumed silica A61F2013/00787; with viscoelastic oil-elastomer gel A61F2013/00893
• CPC Class Codes: A61F 2013/00876 vapour permeability >500 g/mg/24h
• CPC Class Codes: A61F 2013/00906 for transcutaneous or transdermal drugs application
• CPC Class Codes: A61F 2013/0091 with disinfecting or anaesthetics means, e.g. anti-mycrobic
• CPC Class Codes: A61K 9/1273 Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances polymers grafted or coated on phosphatidyl liposomes A61K9/1271, on non-phosphatidyl liposomes A61K9/1272
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61L 24/04 containing macromolecular materials
• CPC Class Codes: A61L 24/08 Polysaccharides A61L24/043 takes precedence
• CPC Class Codes: A61L 26/0009 containing macromolecular materials
• CPC Class Codes: A61L 26/0023 Polysaccharides
• CPC Class Codes: A61L 27/3804 characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C08B 37/00 : Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof cellulose D21; microbiological processes C12P
• CPC Class Codes: C08B 37/003 : Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
• CPC Class Codes: C08B 37/0072 : Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
• CPC Class Codes: C08B 37/0084 : Guluromannuronans, e.g. alginic acid, i.e. D-mannuronic acid and D-guluronic acid units linked with alternating alpha- and beta-1,4-glycosidic bonds; Derivatives thereof, e.g. alginates
• CPC Class Codes: C08F 290/00 : Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups
• CPC Class Codes: C08F 290/08 : on to polymers modified by introduction of unsaturated side groups
• CPC Class Codes: C08F 290/10 : Polymers provided for in subclass C08B
• CPC Class Codes: Y10T 428/2984 : Microcapsule with fluid core [includes liposome]

Abstract

The present invention relates to a new form of biocompatible materials (e.g., lipids, polycations, polysaccharides) which are capable of undergoing free radical polymerization, e.g., by using certain sources of light; methods of modifying certain synthetic and naturally occurring biocompatible materials to make polymerizable microcapsules containing biological material coated with said polymerizable materials, composites of said polymerizable materials, methods of making microcapsules and encapsulating biological materials therein, and apparatus for making microcapsules containing biological cells (particularly islets of Langerhans) coated with polymerizable alginate or with a composite thereof (e.g., alginate and PEG). The present invention also relates to drug delivery systems relating to the foregoing, as well as bioadhesives and wound dressings made utilizing the foregoing technology.

Claims

1. Macrocapsules comprising biologically active material encapsulated in an ionically and covalently crosslinked biocompatible material, wherein said material, prior to being crosslinked, has the formula:

space="preserve" listing-type="equation">A--X

wherein;

A is a polysaccharide, polycation or lipid;

X is a moiety capable of forming a covalent crosslink; and

A and X are linked covalently through linkages selected from the group consisting of ester, ether, thioether, disulfide, amide, secondary amines, tertiary amines, direct C--C linkages, sulfate esters, sulfonate esters, phosphate esters, urethanes, and carbonates, and

wherein at least one physical dimension of said macrocapsule is greater than 1 mm.

2. The macrocapsules of claim 1 further comprising individual cells or groups of cells.

3. A drug delivery system comprising the macrocapsules of claim 1.

4. The macrocapsules of claim 1, wherein A is a polysaccharide selected from the group consisting of alginate, high M-content alginate, polymannuronic acid, polymannuronate, hyaluronic acid, chitosan, chitin, cellulose, starch, glycogen, guar gum, locust bean gum, dextran, levan, inulin, cyclodextrin, agarose, xanthan gum, carageenan, heparin, pectin, gellan gum, and scleroglucan.

5. The macrocapsules of claim 4, wherein said polysaccharide is sulfonated.

6. The macrocapsules of claim 1, wherein A is a polycation selected from the group consisting of polyhistidine, polylysine, polyornithine, polyarginine, polyalanine-polylysine, poly(histidine, glutamic acid)-polyalanine-polylysine, poly(phenylalanine, glutamic acid)-polyalanine-polylysine, poly(phenylalanine, glutamic acid)-polyalanine-polylysine, poly(tyrosine, glutamic acid)-polyalanine-polylysine, collagen, gelatin;

random copolymers of;

arginine with tryptophan, tyrosine, or serine;

glutamic acid with lysine;

glutamic acid with lysine, ornithine; and

mixtures of any two or more thereof.

7. The macrocapsules of claim 1, wherein A is a lipid selected from the group consisting of phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol and dilaurylphosphatidic acid.

8. The macrocapsules of claim 1, wherein said crosslinked biocompatible material is produced by subjecting said biocompatible material to ionic crosslinking and free radical polymerization conditions.

9. The macrocapsules of claim 1, wherein A has a reactive functionality thereon and X is a reactive species capable of free radical polymerization.

10. The macrocapsules of claim 9, wherein said reactive functionality is a hydroxyl, carboxyl, primary or secondary amine, aldehyde, ketone or ester group.

11. The macrocapsules of claim 9, wherein said reactive species is an alkenoic acid or the corresponding acid chloride or acid anhydride, alkenol, alkenyl halide or organometallic alkenyl compound.

12. The macrocapsules of claim 11, wherein said reactive species is an alkenoic acid anhydride.

13. The macrocapsules of claim 9, wherein said reactive species is an acryloyl chloride, methacryloyl chloride, acrylic acid, methacrylic acid, acrylic anhydride, methacrylic anhydride, allyl alcohol, allyl chloride, or vinyl magnesium bromide.

14. The macrocapsules of claim 1, wherein said biologically active material is:

individual living cells or groups of living cells;

at least one pharmacologically active drug;

or

at least one diagnostic agent.

15. The macrocapsules of claim 14, wherein said living cells comprise islets of Langerhans.

16. The macrocapsules of claim 14, wherein said cells are encapsulated within microcapsules wherein the largest physical dimension of each microcapsule does not exceed 1 mm.

17. The macrocapsules of claim 1, wherein A is further linked to Y, wherein Y is an alkylene glycol, polyalkylene glycol, or hydrophobic onium cation, wherein the linkage between Y and A is selected from the group consisting of the covalent linkages ester, ether, thioether, disulfide, amide, secondary amines, tertiary amines, direct C--C linkages, sulfate esters, sulfonate esters, phosphate esters, urethanes, and carbonates;

or, when Y is an onium cation, said linkage between Y and A is the ionic linkage ##STR9## wherein Q is nitrogen or phosphorus, and R is hydrogen, an alkyl radical, an aryl radical, an alkaryl radical, or an aralkyl radical.

18. The macrocapsules of claim 17, wherein A is a polysaccharide selected from the group consisting of alginate, high M-content alginate, polymannuronic acid, polymannuronate, hyaluronic acid, chitosan, chitin, cellulose, starch, glycogen, guar gum, locust bean gum, dextran, levan, inulin, cyclodextrin, agarose, xanthan gum, carageenan, heparin, pectin, gellan gum, and scleroglucan.

19. The macrocapsules of claim 18, wherein said polysaccharide is sulfonated.

20. The macrocapsules of claim 17, wherein A is a polycation selected from the group consisting of polyhistidine, polylysine, polyornithine, polyarginine, polyalanine-polylysine, poly(histidine, glutamic acid)-polyalanine-polylysine, poly(phenylalanine, glutamic acid)-polyalanine-polylysine, poly(phenylalanine, glutamic acid)-polyalanine-polylysine, poly(tyrosine, glutamic acid)-polyalanine-polylysine, collagen, gelatin;

random copolymers of;

arginine with tryptophan, tyrosine, or serine;

glutamic acid with lysine;

glutamic acid with lysine, ornithine; and

mixtures of any two or more thereof.

21. The macrocapsules of claim 17, wherein A is a lipid selected from the group consisting of phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol and dilaurylphosphatidic acid.

22. The macrocapsules of claim 17, wherein said crosslinked biocompatible material is produced by subjecting said biocompatible material to ionic crosslinking and free radical polymerization conditions.