Microcapsules prepared from crosslinkable polysaccharides, polycations and/or lipids and use therefor

• US 5,705,270 A
• Filed: 06/07/1995
• Issued: 01/06/1998
• 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: Heintz, Roswitha A., DeSai, Neil P., Sojomihardjo, Soebianto, Soon-Shiong, Patrick, Sandford, Paul A.
• Primary Examiner(s): Berman, Susan W.
• Application Number:
  US08/482,970
• Time in Patent Office: 944 Days
• Field of Search: 424/451, 424/493, 424/497, 522/87, 522/88, 522/89, 522/75, 522/74, 527/313, 527/314, 428/402.2
• US Class Current: 428/402.2
• 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
• 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. Microcapsules comprising biologically active material encapsulated in a modified biocompatible material which has been subjected to free radical polymerization under biocompatible conditions in an aqueous media that is free of organic solvents, wherein said material has the formula:

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

wherein;

A is selected from the group consisting of polysaccharides, polycations and lipids,

X is a moiety containing a carbon-carbon double bond or triple bond capable of free radical polymerization; 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 the largest physical dimension of said microcapsule, including the encapsulated material, does not exceed 1 mm.

2. The microcapsules 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.

3. The microcapsules of claim 2 wherein said living cells comprise islets of Langerhans.

4. The microcapsules of claim 1, wherein A is further covalently 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 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.

5. The microcapsules of claim 4, 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.

6. The microcapsules of claim 5, wherein said polysaccharide is sulfonated.

7. The microcapsules of claim 4, 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(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.

8. The microcapsules of claim 4, wherein A is a lipid selected from the group consisting of phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol and dilaurylphosphatidic acid.

9. The microcapsules of claim 4, wherein said modified biocompatible material is ionically and covalently crosslinked.

10. The microcapsules 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.

11. The microcapsules of claim 10, wherein said polysaccharide is sulfonated.

12. The microcapsules 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(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.

13. The microcapsules of claim 1, wherein A is a lipid selected from the group consisting of phosphatidylethanolamine, phsphatidylserine, phosphatidylinositol, phosphatidylglycerol and dilaurylphosphatidic acid.

14. The microcapsules of claim 1, wherein said modified biocompatible material is ionically and covalently crosslinked.

15. The microcapsules of claim 1, wherein said modified biocompatible material is produced by chemically modifying a biocompatible material having a reactive functionality thereon with a reactive species capable of free radical polymerization.

16. The microcapsules of claim 15, wherein said reactive functionality is a hydroxyl, carboxyl, primary or secondary amine, aldehyde, ketone or ester group.

17. The microcapsules of claim 15, wherein said reactive species is an alkenoic acid or the corresponding acid chloride or acid anhydride, alkenol, alkenyl halide or organometallic alkenyl compound.

18. The microcapsules of claim 17, wherein said reactive species is an alkenoic acid anhydride.

19. The microcapsules of claim 15, 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.

20. A drug delivery system comprising the microcapsules of claim 1.

21. A method of making a microcapsule containing biologically active material encapsulated therein, said method comprising:

a) suspending said biologically active material in aqueous media that is free of organic solvents, along with a mixture of a modified biocompatible polymerizable material capable of undergoing free radical polymerization and a free radical initiating system, wherein said modified biocompatible material has the formula;

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

wherein;

A is selected from the group consisting of polysaccharides, polycations and lipids, and

X is a moiety containing a carbon-carbon double bond or triple bond capable of free radical polymerization; 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;

b) forming discrete particles comprising said biologically active material surrounded by the modified biocompatible polymerizable material, wherein the largest physical dimension of said discrete particles, including the biologically active material, does not exceed 1 mm; and

c) subjecting the modified biocompatible polymerizable material to free radical generating conditions.

22. The method according to claim 21, further comprising adding a comonomer in the suspending step.

23. The method according to claim 21, wherein said free radical initiating system comprises a photosensitizing agent and a cocatalyst.

24. The method according to claim 23, wherein said photosensitizing agent is a dye selected from ethyl eosin, eosin, erythrosin, riboflavin, fluoroscein, rose bengal, methylene blue, or thionine;

and

said cocatalyst is triethanolamine, arginine, methyldiethanol amine, or triethylamine.

25. The method according to claim 23, wherein said mixture further comprises at least one comonomer.

26. The method according to claim 25, wherein said comonomer is selected from vinyl pyrrolidinone, acrylamide, methacrylamide, acrylic acid, methacrylic acid, sodium acrylate, sodium methacrylate, hydroxyethyl acrylate, hydroxyethyl methacrylate (HEMA), ethylene glycol diacrylate, ethylene glycol dimethacrylate, pentaerythritol triacrylate, pentaerythritol trimethacrylate, trimethylol propane triacrylate, trimethylol propane trimethacrylate, tripropylene glycol diacrylate, tripropylene glycol dimethacrylate, glyceryl acrylate, glyceryl methacrylate, or combinations of any two or more thereof.

27. The method according to claim 21, wherein said modified biocompatible polymerizable material is further covalently linked thereto Y, wherein Y is selected from alkylene glycols, polyalkylene glycols, or hydrophobic onium cations, wherein said modified biocompatible material has the formula

28. The method according to claim 21, further comprising subjecting said modified biocompatible polymerizable material to ionic crosslinking conditions.