Stimulus-responsive antioxidant crystals and method for their preparation

Patent metadata

Field	Value
Publication number	US-2021308100-A1
Application number	US-202117217524-A
Country	US
Kind code	A1
Filing date	Mar 30, 2021
Priority date	Apr 3, 2020
Publication date	Oct 7, 2021
Grant date	—

Abstract

Compositions comprising an active oxygen-responsive antioxidant crystal, methods of making them, and methods for controlling the dissolution rate and/or altering the crystallization behavior of an antioxidant are disclosed. The crystals comprise an antioxidant and a disulfide- or diselenide-crosslinked polymer that is adsorbed onto a surface of the antioxidant. Upon exposure to an active-oxygen stimulus, the polymer de-crosslinks to release the antioxidant from the composition in an amount effective to counteract the stimulus. While prior approaches to altering dissolution rates have relied on passive zero- or first-order kinetics that are independent of ROS levels, the inventive compositions actively respond by releasing antioxidant in an amount proportional to the concentration of active-oxygen species present. The crystallization methods are simple and scalable. The antioxidant balances ROS concentration and allows formulators of nutritional supplements, drug therapies, and other applications to more effectively use antioxidants while avoiding undesirable levels of antioxidative stress.

First claim

We claim:

1 . A composition comprising an active oxygen-responsive antioxidant crystal, the crystal comprising:
(a) an antioxidant; and (b) a disulfide- or diselenide-crosslinked polymer that is adsorbed onto a surface of the antioxidant; wherein the polymer, upon exposure to an active-oxygen stimulus, de-crosslinks to release the antioxidant from the composition in an amount effective to counteract the stimulus.

2 . The composition of claim 1 wherein the antioxidant is water-soluble.

3 . The composition of claim 1 wherein the antioxidant is a phenolic, a vitamin, or a carotenoid.

4 . The composition of claim 3 wherein the antioxidant is a phenolic selected from the group consisting of phenolic acids, phenolate esters, flavonoids, and stilbenes,

5 . The composition of claim 1 wherein the antioxidant is selected from the group consisting of p-coumaric acid, ferulic acid, ellagic acid, caffeic acid, gallic acid, hydroxybenzoic acids, flavonones, catechins, isoflavonoids, resveratrol, pterostilbene, lignans, apigenin, luteolin, tangertin, isorhamnetin, kaempferol, myrcetin, condensed tannins, quercetin, eriodictyol, hesperetin, naringenin, cyanidin, delphinidin, malvidin, pelargonidin, peonidin, petunidin, L-ascorbic acid, vitamin A, vitamin E, chromans, tocopherols, tocotrienols, beta-carotene, alpha-carotene, lycopene, lutein, zeaxanthin, N-acetylcysteine, glutathione, coenzyme Q10, melatonin, erythorbic acid, and lipoic acid.

6 . The composition of claim 1 wherein the antioxidant is catechin, L-ascorbic acid, or N-acetylcysteine.

7 . The composition of claim 1 wherein the polymer is water-soluble.

8 . The composition of claim 1 wherein the polymer is selected from the group consisting of polyethylenimines, polyethylene glycols, polyglucosides, polysaccharides, hyaluronic acid polysaccharides, dopamine conjugates of polysaccharides, polyglycerols, hydroxyalkylcelluloses, polyvinyl acetates, polyvinyl alcohols, acrylic polymers, polyacrylamides, N-vinylpyrrolidone polymers, block copolymers thereof, and mixtures thereof.

9 . The composition of claim 1 wherein the polymer is a diselenide-crosslinked, branched polyethylenimine.

10 . The composition of claim 9 wherein the antioxidant is catechin.

11 . The composition of claim 1 wherein the polymer is a diselenide-crosslinked hyaluronic acid grafted with dopamine (HA-DOPA) and the antioxidant is N-acetylcysteine.

12 . The composition of claim 1 comprising 1 to 20 wt. % of the disulfide- or diselenide-crosslinked polymer based on the combined amounts of antioxidant and disulfide- or diselenide-crosslinked polymer.

13 . The composition of claim 1 wherein the active-oxygen stimulus is selected from the group consisting of hydroxy radicals, hydrogen peroxide, superoxide anions, hypochlorous acid, peroxynitrite, and singlet oxygen-containing species.

14 . A method which comprises crystallizing an antioxidant in the presence of a disulfide- or diselenide-crosslinked polymer to produce an active oxygen-responsive antioxidant crystal, wherein at least a portion of the polymer is adsorbed onto a surface of the antioxidant, and wherein upon exposure to an active-oxygen stimulus, the polymer can de-crosslink to release the antioxidant from the composition in an amount effective to counteract the stimulus.

15 . The method of claim 14 wherein the antioxidant is selected from the group consisting of phenolics, vitamins, and carotenoids.

16 . The method of claim 14 wherein the antioxidant is water-soluble.

17 . The composition of claim 14 wherein the antioxidant is selected from the group consisting of p-coumaric acid, ferulic acid, ellagic acid, caffeic acid, gallic acid, hydroxybenzoic acids, flavonones, catechins, isoflavonoids, resveratrol, pterostilbene, lignans, apigenin, luteolin, tangertin, isorhamnetin, kaempferol, myrcetin, condensed tannins, quercetin, eriodictyol, hesperetin, naringenin, cyanidin, delphinidin, malvidin, pelargonidin, peonidin, petunidin, L-ascorbic acid, vitamin A, vitamin E, chromans, tocopherols, tocotrienols, beta-carotene, alpha-carotene, lycopene, lutein, zeaxanthin, N-acetylcysteine, glutathione, coenzyme Q10, melatonin, erythorbic acid, and lipoic acid.

18 . The composition of claim 14 wherein the antioxidant is catechin, L-ascorbic acid, or N-acetylcysteine.

19 . The method of claim 14 wherein the polymer is selected from the group consisting of polyethylenimines, polyethylene glycols, polyglucosides, polysaccharides, hyaluronic acid polysaccharides, dopamine conjugates of polysaccharides, polyglycerols, hydroxyalkylcelluloses, polyvinyl acetates, polyvinyl alcohols, acrylic polymers, polyacrylamides, N-vinyl pyrrolidone polymers, block copolymers thereof, and mixtures thereof.

20 . A method which comprises controlling the dissolution rate, altering the crystallization behavior, or both, of a water-soluble antioxidant by crystallizing the antioxidant in water in the presence of a disulfide- or diselenide-crosslinked polymer to produce a crystallized composition, wherein at least a portion of the polymer is adsorbed onto a surface of the antioxidant.

21 . The method of claim 20 wherein upon exposure to an active-oxygen stimulus, the polymer can de-crosslink to release the antioxidant from the composition in an amount effective to counteract the stimulus.

Assignees

• Univ Illinois

Inventors

• Kong Hyunjoon
• Kim Byoungsoo
• Lee Jonghwi
• Kim Youngjun
• Miller Ryan Cree

Classifications

• A61K47/61

  the organic macromolecular compound being a polysaccharide or a derivative thereof · CPC title

• A61K47/59

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes · CPC title

• A61K9/146 Primary

  with organic macromolecular compounds · CPC title

• A61K31/353

  3,4-Dihydrobenzopyrans, e.g. chroman, catechin · CPC title

• A61K47/34

  Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence) · CPC title