Reduced and oxidized polysaccharides and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2018326073-A1
Application number	US-201615770937-A
Country	US
Kind code	A1
Filing date	Oct 26, 2016
Priority date	Oct 26, 2015
Publication date	Nov 15, 2018
Grant date	—

Abstract

The present invention is directed to reduced and highly oxidized polysaccharides, such as alginates, that are useful for encapsulating therapeutic or diagnostic agents, or lipid based nanoparticles, e.g., liposomes or virosomes, encapsulating therapeutic or diagnostic agents, prior to their delivery into a subject, as well as methods for making and using them.

First claim

1 . A composition comprising a reduced polysaccharide, wherein
said reduced polysaccharide comprises less than 2% of residual aldehydes; or said reduced polysaccharide comprises less than 3% of residual aldehydes; wherein said reduced polysaccharide is produced by reacting a polysaccharide with a diol specific oxidizing agent, thereby producing an oxidized polysaccharide comprising 0.1% or more oxidation on a molar basis; followed by reacting said oxidized polysaccharide with a water soluble aldehyde specific reducing agent to produce said reduced polysaccharide.

2 - 5 . (canceled)

6 . The composition of claim 1 , wherein said polysaccharide is selected from the group consisting of alginate, agarose, pullulan, scleroglucan, chitosan, elsinan, xanthan gum, dextran, mannose, gellan, levan, cellulose, hyaluronic acid, chondroitin sulfate A, chondroitin sulfate C, chondroitin sulfate E and β-d-glucans.

7 . (canceled)

8 . The composition of claim 1 , wherein said reduced polysaccharide comprises algoxinol having the following structure:

9 . The composition of claim 1 , wherein said aldehyde specific water soluble reducing agent is selected from the group consisting of sodium borohydride (NaBH 4 ); sodium cyanoborohydride (NaCNBH 3 ); hydrogen gas (H 2 ) in the presence of a catalyst; ammonia borane (H 3 NBH 3 ); and a borane complex.

10 . The composition of claim 9 , wherein said aldehyde specific water soluble reducing agent is ammonia borane and wherein said diol specific oxidizing agent is sodium periodate.

11 . (canceled)

12 . The composition of claim 1 , wherein said composition further comprises a cross-linking agent attached to the reduced polysaccharide.

13 . The composition of claim 12 , wherein said cross-linking agent is a click reagent.

14 . (canceled)

15 . A composition comprising a reduced polysaccharide and a cross-linking agent attached to the reduced polysaccharide.

16 . The composition of claim 15 , wherein said reduced polysaccharide is a reduced alginate polymer, wherein said reduced polysaccharide comprises algoxinol having the following structure:

17 . (canceled)

18 . The composition of claim 15 , wherein said reduced polysaccharide is produced by a method comprising the steps of:
reacting the polysaccharide with a diol specific oxidizing agent to produce an aldehyde containing oxidized polysaccharide; and reacting said oxidized polysaccharide with a water soluble aldehyde specific reducing agent to produce said reduced polysaccharide.

19 . The composition of claim 18 , wherein said diol specific oxidizing agent is sodium periodate and wherein said water soluble aldehyde specific reducing agent is ammonia borane.

20 . (canceled)

21 . A composition comprising a highly oxidized polysaccharide and a cross-linking agent attached to the highly oxidized polysaccharide.

22 . The composition of claim 21 , wherein said highly oxidized polysaccharide is an alginate polymer, wherein said highly oxidized polysaccharide comprises algoxalate having the following structure:

23 . (canceled)

24 . The composition of claim 21 , wherein said highly oxidized polysaccharide is produced by a method comprising the steps of:
reacting the polysaccharide with a diol specific oxidizing agent to produce an aldehyde containing oxidized polysaccharide; and reacting said oxidized polysaccharide with a second oxidizing agent which converts aldehydes into carboxylic acids to produce said highly oxidized polysaccharide.

25 . The composition of claim 24 , wherein said diol specific oxidizing agent is sodium periodate and wherein said second oxidizing agent is sodium chlorite.

26 . (canceled)

27 . The composition of claim 15 , wherein said cross-linking agent is a click reagent.

28 - 38 . (canceled)

39 . A hydrogel comprising a plurality of reduced and/or highly oxidized polysaccharides cross-linked to each other, wherein said hydrogel comprises a mesh size of 10 nm or less.

40 . The hydrogel of claim 39 , wherein said highly oxidized polysaccharides are highly oxidized alginate polymers produced by a method comprising the steps of:
reacting an alginate with a diol specific oxidizing agent to produce an aldehyde containing oxidized alginate; and reacting said aldehyde containing oxidized alginate with a second oxidizing agent which converts aldehydes into carboxylic acids, thereby producing said highly oxidized alginate polymers.

41 . (canceled)

42 . The hydrogel of claim 40 , wherein said diol specific oxidizing agent is sodium periodate and wherein said second oxidizing agent is sodium chlorite.

43 - 44 . (canceled)

45 . The hydrogel of claim 39 , wherein said reduced polysaccharides are reduced alginate polymers produced by a method comprising the steps of:
reacting an alginate with a diol specific oxidizing agent to produce an aldehyde containing oxidized alginate; and reacting said aldehyde containing oxidized alginate with a water soluble aldehyde specific reducing agent, thereby producing said reduced alginate polymers.

46 . (canceled)

47 . The hydrogel of claim 45 , wherein said diol specific oxidizing agent is sodium periodate and wherein said water soluble aldehyde specific reducing agent is ammonia borane.

48 - 49 . (canceled)

50 . The hydrogel of claim 39 , further comprising a therapeutic or diagnostic agent selected from the group consisting of a cell, a small molecule and a biologic.

51 - 59 . (canceled)

60 . The hydrogel of claim 39 , wherein said polysaccharides comprise a cross-linking agent attached to the polysaccharides and wherein said cross-linking agent is a click reagent.

61 - 62 . (canceled)

63 . An implantable or injectable device comprising the hydrogel of claim 39 .

64 . A method of producing a reduced polysaccharide, the method comprising the steps of:
reacting a polysaccharide with a diol specific oxidizing agent to produce an aldehyde containing oxidized polysaccharide; and reacting said aldehyde containing oxidized polysaccharide with an aldehyde specific water soluble reducing agent, thereby producing said reduced polysaccharide.

65 - 73 . (canceled)

74 . A method of producing a highly oxidized polysaccharide covalently attached to a cross-linking agent, the method comprising the steps of:
reacting a polysaccharide with a diol specific oxidizing agent to produce an aldehyde containing oxidized polysaccharide; reacting said aldehyde containing oxidized polysaccharide with a second oxidizing agent which converts aldehydes into carboxylic acids, thereby producing said highly oxidized polysaccharide; and reacting said highly oxidized polysaccharide with a cross-linking agent.

75 - 80 . (canceled)

81 . A drug delivery composition comprising
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Assignees

• Harvard College

Inventors

• Mooney David J
• Stafford Alexander
• Desai Rajiv
• Martinick Kathleen

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C08L5/04

  Alginic acid; Derivatives thereof · CPC title

• A61K47/36 Primary

  Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin · CPC title

• A61P27/02

  Ophthalmic agents · CPC title