GB2588748A - Composition for delivering nitric oxide to skin - Google Patents
Composition for delivering nitric oxide to skin Download PDFInfo
- Publication number
- GB2588748A GB2588748A GB1914435.1A GB201914435A GB2588748A GB 2588748 A GB2588748 A GB 2588748A GB 201914435 A GB201914435 A GB 201914435A GB 2588748 A GB2588748 A GB 2588748A
- Authority
- GB
- United Kingdom
- Prior art keywords
- component
- skin
- application composition
- nitric oxide
- skin application
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 62
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 title description 64
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 23
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 22
- 239000002861 polymer material Substances 0.000 claims abstract description 15
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 14
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 14
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 14
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 13
- 239000011343 solid material Substances 0.000 claims abstract description 13
- 239000002738 chelating agent Substances 0.000 claims abstract description 12
- 239000013522 chelant Substances 0.000 claims abstract description 3
- ICRHORQIUXBEPA-UHFFFAOYSA-N thionitrous acid Chemical compound SN=O ICRHORQIUXBEPA-UHFFFAOYSA-N 0.000 abstract description 21
- HYHSBSXUHZOYLX-WDSKDSINSA-N S-nitrosoglutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CSN=O)C(=O)NCC(O)=O HYHSBSXUHZOYLX-WDSKDSINSA-N 0.000 abstract description 7
- 229920000642 polymer Polymers 0.000 abstract description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 abstract description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 abstract description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 abstract description 2
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 abstract description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 abstract description 2
- 150000002500 ions Chemical class 0.000 abstract 2
- 239000000499 gel Substances 0.000 description 22
- 239000000017 hydrogel Substances 0.000 description 17
- 206010052428 Wound Diseases 0.000 description 16
- 208000027418 Wounds and injury Diseases 0.000 description 16
- 239000010410 layer Substances 0.000 description 13
- 239000000463 material Substances 0.000 description 12
- 238000000354 decomposition reaction Methods 0.000 description 9
- MGWGWNFMUOTEHG-UHFFFAOYSA-N 4-(3,5-dimethylphenyl)-1,3-thiazol-2-amine Chemical compound CC1=CC(C)=CC(C=2N=C(N)SC=2)=C1 MGWGWNFMUOTEHG-UHFFFAOYSA-N 0.000 description 6
- 229920001477 hydrophilic polymer Polymers 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 6
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 150000003573 thiols Chemical class 0.000 description 5
- 229920002678 cellulose Polymers 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 230000037317 transdermal delivery Effects 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 210000000416 exudates and transudate Anatomy 0.000 description 3
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 108010001742 S-Nitrosoglutathione Proteins 0.000 description 2
- XOWVFANEOZMPKG-REOHCLBHSA-N S-nitroso-L-cysteine Chemical compound OC(=O)[C@@H](N)CSN=O XOWVFANEOZMPKG-REOHCLBHSA-N 0.000 description 2
- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- UPBDXRPQPOWRKR-UHFFFAOYSA-N furan-2,5-dione;methoxyethene Chemical compound COC=C.O=C1OC(=O)C=C1 UPBDXRPQPOWRKR-UHFFFAOYSA-N 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- -1 polyethylene Polymers 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 235000010289 potassium nitrite Nutrition 0.000 description 2
- 239000004304 potassium nitrite Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000002344 surface layer Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- ABXYOVCSAGTJAC-JGWLITMVSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanethial Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=S ABXYOVCSAGTJAC-JGWLITMVSA-N 0.000 description 1
- HNIULCDUASSKOM-RQJHMYQMSA-N (2s)-1-[(2s)-2-methyl-3-nitrososulfanylpropanoyl]pyrrolidine-2-carboxylic acid Chemical compound O=NSC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O HNIULCDUASSKOM-RQJHMYQMSA-N 0.000 description 1
- XHZPRMZZQOIPDS-UHFFFAOYSA-N 2-Methyl-2-[(1-oxo-2-propenyl)amino]-1-propanesulfonic acid Chemical compound OS(=O)(=O)CC(C)(C)NC(=O)C=C XHZPRMZZQOIPDS-UHFFFAOYSA-N 0.000 description 1
- ZIIQCSMRQKCOCT-UHFFFAOYSA-N 2-acetamido-3-methyl-3-nitrososulfanylbutanoic acid Chemical compound CC(=O)NC(C(O)=O)C(C)(C)SN=O ZIIQCSMRQKCOCT-UHFFFAOYSA-N 0.000 description 1
- VNEAYYCHMUGPDK-UHFFFAOYSA-N 2-nitrososulfanylethanamine Chemical compound NCCSN=O VNEAYYCHMUGPDK-UHFFFAOYSA-N 0.000 description 1
- LHDUMLDMQBPCKN-UHFFFAOYSA-N 3-nitrososulfanylpropane-1,2-diol Chemical compound OCC(O)CSN=O LHDUMLDMQBPCKN-UHFFFAOYSA-N 0.000 description 1
- CJSRFRAVAGCWRN-UHFFFAOYSA-N 3-nitrososulfanylpropanoic acid Chemical compound OC(=O)CCSN=O CJSRFRAVAGCWRN-UHFFFAOYSA-N 0.000 description 1
- IRLPACMLTUPBCL-KQYNXXCUSA-N 5'-adenylyl sulfate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OS(O)(=O)=O)[C@@H](O)[C@H]1O IRLPACMLTUPBCL-KQYNXXCUSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical compound OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- RWSXRVCMGQZWBV-PHDIDXHHSA-N L-Glutathione Natural products OC(=O)[C@H](N)CCC(=O)N[C@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-PHDIDXHHSA-N 0.000 description 1
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 1
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001398 aluminium Chemical class 0.000 description 1
- 239000005030 aluminium foil Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- ZNAAXKXXDQLJIX-UHFFFAOYSA-N bis(2-cyclohexyl-3-hydroxyphenyl)methanone Chemical compound C1CCCCC1C=1C(O)=CC=CC=1C(=O)C1=CC=CC(O)=C1C1CCCCC1 ZNAAXKXXDQLJIX-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 125000004386 diacrylate group Chemical group 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 150000002734 metacrylic acid derivatives Chemical class 0.000 description 1
- XJRBAMWJDBPFIM-UHFFFAOYSA-N methyl vinyl ether Chemical compound COC=C XJRBAMWJDBPFIM-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 150000002826 nitrites Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000011236 particulate material Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000003014 reinforcing effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 229940035024 thioglycerol Drugs 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
- A61K38/063—Glutathione
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/42—Use of materials characterised by their function or physical properties
- A61L15/44—Medicaments
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
- A61K8/447—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof containing sulfur
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
- A61K8/8129—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical; Compositions of hydrolysed polymers or esters of unsaturated alcohols with saturated carboxylic acids; Compositions of derivatives of such polymers, e.g. polyvinylmethylether
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
- A61K8/817—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen; Compositions or derivatives of such polymers, e.g. vinylimidazol, vinylcaprolactame, allylamines (Polyquaternium 6)
- A61K8/8176—Homopolymers of N-vinyl-pyrrolidones. Compositions of derivatives of such polymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
- A61L15/24—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
- A61L2300/114—Nitric oxide, i.e. NO
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Hematology (AREA)
- Birds (AREA)
- Gastroenterology & Hepatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A skin application composition comprising a first component comprising S-nitrosothiol in dry inactive condition. Preferably the application composition is a skin dressing, and preferably the first component is a solid material. Preferably the solid material is a polymer material, such as a polymer comprising polyvinyl alcohol, polyvinyl pyrrolidone, or a mixture thereof. Preferably the solid material is in the form of a sheet, layer, or slab. The first component may comprise a chelating agent. The skin application compositions may comprise a second component comprising a source of water, and may additionally comprise a source of divalent metal ions. A preferred S-nitrosothiol is S-nitrosoglutathione (GSNO). The chelating agent may be EDTA, EGTA, histidine, or citrate. Preferably, the concentration of divalent ions in the second component exceeds the capacity of the chelating agent to chelate divalent ions.
Description
Composition for Delivering Nitric Oxide to Skin
Field of the Invention
The invention relates to a treatment composition, e.g. skin dressings, for application to a part of a human or animal body (for therapeutic or cosmetic purposes).
Background and prior art
Nitric oxide is an essential signalling molecule in mammals and it is known to play a variety of roles, ranging from regulation of blood flow, neurotransmission and immune response. It is so important that a family of special enzymes, called nitric oxide synthases has evolved with the exclusive job of making controlled amounts of nitric oxide when and where it is needed, using the amino acid arginine as the precursor substance.
Nitric oxide is however a very hydrophobic compound and its solubility in water is therefore limited. Maximum solubility in water achievable under normal conditions is approximately 1.7 mM, with the solubility being similar to that of oxygen.
Nitric oxide also reacts rapidly with oxygen to form nitrogen dioxide. Nitrogen dioxide has no known role in maintaining or controlling homeostasis, or ability to respond to important stimuli in biological systems. In fact, nitrogen dioxide is known as a toxin and irritant.
In addition, the biology of mammals (and other vertebrates) is capable of safely managing the logistics of nitric oxide because of the abundance of thiol groups within the tissues, especially the skin. Nitric oxide spontaneously reacts with thiol groups (e.g. on proteins) to form S-nitrosothiol functional groups, in which form the nitric oxide can be safely and efficiently stored or transported. S-Nitrosothiols are compounds capable of releasing nitric oxide. Therefore nitric oxide can also be readily released on demand via the degradation of S-nitrosothiols.
Thus, mammalian biology deals with these problems of nitric oxide, when locked up as Snitrosothiols it can't be oxidised to nitrogen dioxide and its insolubility in water is not a problem.
However, delivery of exogenous raw nitric oxide to a skin site can result in unacceptable losses to the production of nitrogen dioxide. Also, any nitric oxide that gets into the skin can become locked into keratin S-nitrosothiols in the wrong place, or the nitric oxide can't dissolve in the available water of the system being targeted.
Various strategies therefore need to be employed before the effective delivery of the valuable nitric oxide to a skin site can be considered.
US 6,103,275 discloses a biocompatible system for generating nitric oxide by bringing together a nitrite, a reductant and a particular acid. The nitrite and acid are typically kept separate until the moment of use.
As described, S-nitrosothiols can release free nitric oxide by spontaneous decomposition, and are therefore a very convenient delivery means for the reactive and insoluble nitric oxide. However, nitrosothiols spontaneously decompose and therefore have a limited lifetime as a delivery vehicle for nitric oxide.
WO 2006/095193 discloses a skin dressing in an inactive state, but can be made to become active and deliver S-nitrosothiols to a skin site. The dressing is kept inactive either by containing reactants for the nitrosothiols so that they form the nitrosothiols only immediately before use, or by keeping pre-formed nitrosothiols in a dry state, to be activated when needed by addition of water.
The rate of decomposition varies considerably depending on the side chain of the thiol. For example, whilst nitrosocysteine can be totally decomposed within minutes under normal conditions, it takes hours/days to achieve 100% decomposition of nitrosoglutathione. The decomposition is generally accelerated in the presence of Cu24 and Hg24.
Summary of the Invention
The present invention mimics the natural biological process by directly synthesising Snitrosothiols which can safely escort nitric oxide into the target location, without forming nitrogen dioxide, and in a water-soluble form. By their chemical nature, the 5-nitrosothiols can readily exchange their nitric oxide with thiols of the body, thereby efficiently interposing the delivered nitric oxide into the body, harmonising with the nitric oxide logistics of the body.
Thus, the present invention provides a skin application composition comprising a first component comprising S-nitrosothiol in dry inactive condition.
As the S-nitrosothiols are in dry condition the treatment composition is in an inactive state. However, the treatment composition can be activated, by bringing an aqueous composition into contact with the dry S-nitrosothiol immediately prior to use, to allow the active delivery of the S-nitrosothiols to the skin site to be treated.
Dry condition means that there is no free water in the first component, such that no significant or measurable water loss occurs through evaporation under normal ambient conditions of temperature, pressure and humidity. Dry condition includes desiccated condition, which is an extra thoroughly dried condition. Desiccated condition means a condition maintained by storage in an environment enclosed by a moisture impermeable barrier, wherein the material is kept scrupulously free of water by means of an added desiccant.
Nitric oxide has beneficial effects on tissues, and also functions as a vasodilator, causing blood capillaries in the vicinity to open up. This effect can enhance transdermal delivery of materials such as a pharmaceutically active agent, e.g. hormones, analgesics etc, by accelerating delivery and uptake of the materials. The composition can thus be used as an adjuvant for transdermal delivery, typically by having a composite dressing or patch, plaster, bandage, gauze etc. also including material for delivery.
Preferably the skin treatment composition is a skin dressing. The term "skin dressing" covers dressings such as patches, plasters, bandages and gauze etc. for use in connection with transdermal delivery of agents. The term also includes material in amorphous or liquid form. The term covers dressings for application to body surfaces generally, including internal and external tissues, particularly the skin including the scalp.
Suitable S-nitrosothiols include S-nitrosoglutathione (preferably S-nitroso-L-glutathione, as this is the physiologically important version), S-nitrosocysteine, S-nitrosothioglycerol, 5-nitroso-N-acetylcysteine, S-nitrosocaptopril, S-nitrosomercaptoethylamine, S-nitroso-3-mercaptopropanoic acid, S-nitroso-D-thioglucose and S-nitroso-N-acetyl-D, L-penicillamine. S-nitrosoglutathione is currently preferred, because of its relatively slow rate of decomposition to generate nitric oxide, resulting in satisfactory stability of the S-nitrosothiol in the dressing and consequential slow release of nitric oxide at an appropriate rate for skin benefits.
The S-nitrosothiol is typically prepared, e.g. by reaction between a nitrite and a thiol, prior to preparation of the treatment composition. This enables the S-nitrosothiols to be dried down to a suitable degree, to allow them to remain inactive and stable until required. This can be carried out by preparing an aqueous mix comprising a source of nitrite (such as a nitrite salt such as sodium nitrite or potassium nitrite) and a thiol (preferably thioglycerol, thioglucose or glutathione) followed by adjusting the pH of the mixture to less than 5.0, preferably less than 4.5, more preferably between 2.5 and 4.0. Any other additional ingredients can then be added (e.g. a chelating agent as discussed below) before removing water from the mix such as by freeze-drying or spray drying.
The or each treatment component may be in the form of a layer, e.g. in the form of a sheet, slab or film, that may produce from an amorphous material, not having any fixed form or shape, that can be deformed and shaped in three dimensions, including being squeezed through a nozzle.
Because the first component is in dry condition the S-nitrosothiol is in stable condition and available when required. When the S-nitrosothiol is wetted, e.g. by contact with a source of water, the S-nitrosothiol is solubilised and released. Sufficient water is required to form a contact liquid junction between the treatment composition and a water source.
The first component may be provided as a solid material with the dry S-nitrosothiol preferably dispersed in a reasonably homogeneous manner. The solid material preferably comprises a polymer material.
Preferred polymers include water-soluble polymers such as polyvinyl alcohol (PVA), polyvinyl pyrrolidone, cellulose or modified cellulose (such as carboxymethylcellulose). One preferred polymer material comprises PVA. PVA has convenient and acceptable properties for skin treatment use, e.g. being non-toxic. PVA is also easy to handle and use, readily forming a film on drying of a PVA solution in water, with the resulting film being easy to handle. PVA is also readily available and cheap. Cross-linking is not required to form a solid material, e.g. in the form of a film, although cross-linking may optionally be employed. PVA is available in a wide range of grades based on molecular weight and degree of hydrolysis, which affect the physical properties of the material. Appropriate grades of PVA can be readily selected to produce a polymer product having desired properties for a particular intended use. For example, for use in skin dressings, good results have been obtained by use of PVA with a molecular weight in the range 100,000 to 200,000, substantially fully hydrolysed (98-99% hydrolysed), e.g. in the form of code 36,316-2 from Aldrich, in non-cross-linked form.
Another suitable polymer material comprises polyvinylpyrrolidone (PVP). The properties of PVP are very similar to those of PVA, and PVP is also acceptable for skin treatment use. PVP is readily available in a range of different molecular weights. Appropriate grades of PVP can be readily selected. For example, good results have been obtained using a PVP having a molecular weight average of 360,000, e.g. in the form of code PVP360 from Sigma, in a non-crosslinked form.
Mixtures of polymer materials may be used.
The solid material is conveniently in the form of a sheet, layer or film, typically having a thickness in the range 0.01 to 1.0mm, preferably in the range 0.05 to 0.5mm.
The solid material may optionally include a support to provide rigidity when wet.
The solid material of the invention is conveniently made by mixing a solution of a polymer (e.g. an aqueous solution of PVA and/or PVP) and reagent, and drying the mixture to produce a solid material, e.g. forming film by a casting procedure. Suitable techniques are well known to those skilled in the art, and may be combined with the process described above.
The polymer material or materials are suitably used in appropriate amounts that result in formation of a film, with the upper limit of concentration typically being dictated by the limit of solubility (generally in water) and the lower limit of concentration being the point at which a film does not form. For PVA code 36,316-2 from Aldrich, the limit of solubility in water is about 6% w/w, resulting in a concentration of PVA in the film prior to drying of about 5%.
Alternatively, the first component may be provided in the form of a mesh, onto which the Snitrosothiol is provided in dried form. Such a mesh is preferably made from a polymer, e.g. polyethylene, polypropylene, polystyrene and polyamide.
Alternatively, the first component may be provided in the form of a particulate material such as a powder or in granular form. In such an arrangement the first component will generally include a carrier or bulking agent such as sugar or a polyol.
The first component may also comprise a chelating agent, capable of chelating divalent metal ions such as Cu2+, Zn2+ and/or Fe2+. It is known that such metal ions catalyse the decomposition of the S-nitrosothiol into nitric oxide, and therefore the chelating agent ensures that the S-nitrosothiol remains in an inactive state until desired for use. Suitable chelating agents include EDTA, EGTA, histidine and/or citrate.
The first component may also comprise a buffer, to ensure that the pH of any resulting solutions when brought into contact with water is in the range of from 4 to 7, preferably from 5 to 7.
The composition is activated, by bringing the first component into contact with a source of water (e.g. from a wound), resulting in release from the treatment composition of one or more S-nitrosothiols.
The S-nitrosothiol can therefore be released from the composition simply by applying the layer onto a moist surface (e.g. wound bed). Once released, S-nitrosothiol undergoes a slow decomposition to generate nitric oxide. The release of S-nitrosothiol from the layer can be relatively rapid. This can be demonstrated by applying the layer onto a moist skin, which results in rapid (within approximately 1 min) reddening of the skin due to dermal vasodilation. The reddening is totally reversible and disappears within several minutes after removal of the composition.
Alternatively the treatment composition may include a second component comprising a source of water (the aqueous component), separated from the S-nitrosothiol in dry condition.
The aqueous component may be a hydrated hydrogel. A hydrated hydrogel means one or more water-based or aqueous gels, in hydrated form. A hydrated hydrogel thus includes a source of water, for activation of the treatment composition. A hydrated hydrogel can also act to absorb water and other materials exuded from a wound site, enabling the treatment composition to perform a valuable and useful function by removing such materials from a wound site. The hydrated hydrogel also provides a source of moisture that can act in use to maintain a wound site moist, aiding healing.
Suitable hydrated hydrogels are disclosed in WO 03/090800. The hydrated hydrogel conveniently comprises hydrophilic polymer material. Suitable hydrophilic polymer materials include polyacrylates and methacrylates, e.g. as supplied by First Water Ltd in the form of proprietary hydrogels, including poly 2-acrylamido-2-methylpropane sulphonic acid (poly-AMPS) and/or salts thereof (e.g. as described in WO 01/96422), polysaccharides e.g. polysaccharide gums particularly xanthan gum (e.g. available under the Trade Mark Keltrol), various sugars, polycarboxylic acids (e.g. available under the Trade Mark Gantrez AN-169 BF from ISP Europe), poly(methyl vinyl ether co-maleic anhydride) (e.g. available under the Trade Mark Gantrez AN 139, having a molecular weight in the range 20,000 to 40,000), polyvinyl pyrrolidone (e.g. in the form of commercially available grades known as PVP K-30 and PVP K-90), polyethylene oxide (e.g. available under the Trade Mark Polyox WSR-301), polyvinyl alcohol (e.g. available under the Trade Mark Elvanol), cross-linked polyacrylic polymer (e.g. available under the Trade Mark Carbopol EZ-1), celluloses and modified celluloses including hydroxypropyl cellulose (e.g. available under the Trade Mark Klucel EEF), sodium carboxymethyl cellulose (e.g. available under the Trade Mark Cellulose Gum 7LF) and hydroxyethyl cellulose (e.g. available under the Trade Mark Natrosol 250 LR).
Mixtures of hydrophilic polymer materials may be used in a gel.
In a hydrated hydrogel of hydrophilic polymer material, the hydrophilic polymer material is desirably present at a concentration of at least 1%, preferably at least 2%, more preferably at least 5%, yet more preferably at least 10%, or at least 20%, desirably at least 25% and even more desirably at least 30% by weight based on the total weight of the gel. Even higher amounts, up to about 40% by weight based on the total weight of the gel, may be used.
Good results have been obtained with use of a hydrated hydrogel of poly-AMPS and/or salts thereof in an amount of about 30% by weight of the total weight of the gel.
By using a gel comprising a relatively high concentration (at least 2% by weight) of hydrophilic polymer material, the gel can function particularly effectively to take up water in use of the treatment composition, e.g. from serum exudates while in contact with a wound. Because the gel is an aqueous system, use of the treatment composition does not have the effect of inducing an overall dryness of the wound which would be undesirable. This is because water vapour pressure is maintained in the enclosed environment surrounding the skin in use of the treatment composition. The gel thus functions as an absorbent entity for the removal of moisture, e.g. wound exudate, that also provides a helpful background level of excess moisture.
The water-uptake capacity of a hydrated hydrogel, including a high concentration gel, enables the treatment composition to aid wound healing by removing substantial amounts of exudates, swelling-up as it does so. By using a carefully formulated, ready-hydrated gel, the wound is prevented from reaching a state of unhelpful dryness. Ready hydration also ensures the quick formation of an aqueous liquid interface between the treatment composition and the wound, thus preventing adhesion, which otherwise would interfere with easy lifting of the treatment composition when it has to be replaced. A good aqueous liquid interface between the wound and the treatment composition is also important in allowing any beneficial products carried in the gel to enter the wound through all of the available surface.
The hydrated hydrogel material is typically in the form of a solid layer, sheet or film of material that is typically cross-linked, and that may incorporate a mechanical reinforcing structure. The size and shape of the layer, sheet or film can be selected to suit the intended use of the treatment composition. Thicknesses in the range 0.05 to 5 mm, preferably 0.5 to 3 mm are particularly suitable.
Alternatively, the hydrated hydrogel may be in the form of an amorphous gel not having a fixed form or shape that can be deformed and shaped in three dimensions, including being squeezed through a nozzle. Amorphous gels are typically not cross-linked or have low levels of cross-linking. A shear-thinning amorphous gel may be used. Such a gel is liquid when subjected to shear stress (e.g. when being poured or squeezed through a nozzle) but set when static. Thus the gel may be in the form of a pourable or squeezable component that may be dispensed, e.g. from a compressible tube or a syringe-like dispenser, comprising a piston and cylinder, typically with a nozzle of about 3 mm diameter. Such a gel may be applied in the form of a surface layer, or into a wound cavity as a fully conformable gel that fills the available space and contacts the wound surface.
A typical example of an amorphous gel formulation is: 15% w/w AMPS (sodium salt), 0.19% polyethylene glycol diacrylate and 0.01% hydroxycyclohexyl phenyl ketone, with the volume made up to 100% with analytical grade DI water. The reagents are thoroughly mixed and dissolved, then polymerised for between 30-60 seconds, using a UV-A lamp delivering approximately 100 mW/cm2, to form the required hydrogel. This may be contained in plastic syringes from which the amorphous gel may then be dispensed from a syringe to a target site, as a surface layer or to fill a cavity.
The second component may alternatively comprise a hydro-cream carried in a suitable container such as a tub or a squeezable pouch or tube.
The second component may also comprise a buffer, to ensure that the pH of any resulting solutions is in the range of from 4 to 7, preferably from 5 to 7.
The second component may also comprise a source of divalent metal ions, such as Cu2+, Zn2+ and/or Fe2+. It is known that such metal ions catalyse the decomposition of the Snitrosothiol into nitric oxide, and therefore providing them in the second composition can aid the delivery of nitric oxide when the first and second compositions are brought together.
When the first composition includes a chelating agent, it is preferred that the concentration of divalent metal ions in the second component exceeds the capacity of the chelating agent to chelate the divalent metal ions. This is so that, when brought together, any chelating agent in the first component will be capable of only chelating a fraction of the divalent metal ions in the second component. The excess of divalent metal ions can then act to catalyse the decomposition of the S-nitrosothiol to nitric oxide.
Thus, in one preferred embodiment the invention comprises a first component comprising a dry polymeric matrix, preferably dried PVA, containing the S-nitrosothiol and a second component comprising a layer of hydrated hydrogel. The second component may be used in contact with the skin, as the hydrated hydrogel has beneficial properties for skin contact, as discussed above, with the first component being placed on top of the second component. Provided the components are kept separate prior to use, the treatment composition remains in non-activated condition. However, when the two components are brought into contact, this has the effect of activating the treatment composition.
In one preferred embodiment of this type, the treatment composition comprises a layer of dried PVA containing pre-generated S-nitrosothiol. The layer is formed from PVA, a source of nitrite (preferably potassium nitrite) and a thiol (preferably L-glutathione). In a typical example of this embodiment both of these additives are added to the PVA solution prior to drying. S-nitrosothiol (GSNO in the preferred case) is generated within the layer during the drying step. Nitrosothiols are known to be rather unstable in aqueous solutions. Nevertheless, GSNO was found very stable in the dried layer of PVA, especially if stored in a moisture-free atmosphere.
In another embodiment, the treatment composition comprises two components which are amorphous. The components can be in the form of e.g. a gel, semi-solid, paste, cream, lotion or liquid. Hydrated hydrogels may be conveniently employed, as discussed above.
The two amorphous components are kept separate until it is desired to apply the treatment composition to a body surface. Conveniently they are packaged in a container having a nozzle, through which the amorphous components can be delivered. Preferably, the two components are packaged in a two compartment dispenser, preferably being operable to deliver both components simultaneously.
The treatment composition optionally includes, or is used with, a covering or outer layer for adhering a dressing to the skin of a human or animal in known manner.
Treatment compositions in accordance with the invention can be manufactured in a range of different sizes and shapes for treatment of areas of skin e.g. wounds of different sizes and shapes. Appropriate amounts of reagents for a particular dressing can be readily determined by experiment.
Treatment composition components are suitably stored prior to use in sterile, sealed, water-impervious packages, e.g. laminated aluminium foil packages. To ensure a dry condition is maintained, desiccant material is desirably included in the packages.
In use, the treatment composition component or components are removed from their packaging and located in appropriate order on the skin of a human or animal, e.g. over a wound or other region of skin to be treated for cosmetic or therapeutic purposes. The treatment composition may also be used as an adjuvant for transdermal delivery, as noted above.
Claims (10)
- Claims 1. A skin application composition comprising a first component comprising Snitrosothiol in dry inactive condition.
- 2. A skin application composition according to claim 1, wherein the application composition is a skin dressing
- 3. A skin application composition according to any one of the preceding claims, wherein the first component is a solid material.
- 4. A skin application composition according to claim 3, wherein the solid material comprises a polymer material.
- 5. A skin application composition according to claim 4, wherein the polymer material comprises polyvinyl alcohol or polyvinyl pyrrolidone or a mixture thereof.
- 6. A skin application composition according to any one of claims 3 to 5, wherein the solid material is in the form of a sheet, layer or slab.
- 7 A skin application composition according to any one of the preceding claims, wherein the first component comprises a chelating agent capable of chelating divalent metal ions.
- 8. A skin application composition according to any one of the preceding claims, which comprises a second component comprising a source of water.
- 9. A skin application composition according to claim 8, wherein the second component comprises a source of divalent metal ions.
- 10. A skin application composition according to claim 7, 8 and 9, wherein the concentration of divalent metal ions exceeds the capacity of the chelating agent to chelate divalent metal ions.
Priority Applications (17)
Application Number | Priority Date | Filing Date | Title |
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GB1914435.1A GB2588748A (en) | 2019-10-07 | 2019-10-07 | Composition for delivering nitric oxide to skin |
EP23173000.3A EP4233831A3 (en) | 2019-10-07 | 2020-10-06 | Composition for delivering nitric oxide to skin |
PCT/GB2020/052459 WO2021069876A1 (en) | 2019-10-07 | 2020-10-06 | Composition for delivering nitric oxide to skin |
US17/634,471 US20220296532A1 (en) | 2019-10-07 | 2020-10-06 | Composition for delivering nitric oxide to skin |
CN202080071717.9A CN114727915A (en) | 2019-10-07 | 2020-10-06 | Compositions for delivering nitric oxide to skin |
BR112022005166A BR112022005166A2 (en) | 2019-10-07 | 2020-10-06 | Skin application composition |
CN202080071718.3A CN114585347A (en) | 2019-10-07 | 2020-10-06 | Composition for delivering nitric oxide to skin |
US17/634,464 US20220296769A1 (en) | 2019-10-07 | 2020-10-06 | Composition for delivering nitric oxide to skin |
JP2022521037A JP2022552825A (en) | 2019-10-07 | 2020-10-06 | Compositions that deliver nitric oxide to the skin |
EP23172996.3A EP4233830A3 (en) | 2019-10-07 | 2020-10-06 | Composition for delivering nitric oxide to skin |
JP2022521054A JP2022550990A (en) | 2019-10-07 | 2020-10-06 | Compositions that deliver nitric oxide to the skin |
EP20793050.4A EP3986376A1 (en) | 2019-10-07 | 2020-10-06 | Composition for delivering nitric oxide to skin |
PCT/GB2020/052458 WO2021069875A1 (en) | 2019-10-07 | 2020-10-06 | Composition for delivering nitric oxide to skin |
BR112022005129A BR112022005129A2 (en) | 2019-10-07 | 2020-10-06 | Skin application composition |
EP20793051.2A EP3986359A1 (en) | 2019-10-07 | 2020-10-06 | Composition for delivering nitric oxide to skin |
CA3152119A CA3152119A1 (en) | 2019-10-07 | 2020-10-06 | Composition for delivering nitric oxide to skin |
CA3152127A CA3152127A1 (en) | 2019-10-07 | 2020-10-06 | Composition for delivering nitric oxide to skin |
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US20160367492A1 (en) * | 2014-02-28 | 2016-12-22 | Pusan National University Industry-University Cooperation Foundation | Nitric oxide-releasing wound treatment film and preparation method therefor |
WO2019169092A1 (en) * | 2018-03-01 | 2019-09-06 | The Regents Of The University Of Michigan | Two-part nitric oxide generating topical compositions |
WO2019236825A1 (en) * | 2018-06-08 | 2019-12-12 | University Of Georgia Research Foundation, Inc. | Antimicrobial compositions with wound healing properties |
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2019
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US20110287113A1 (en) * | 2009-01-29 | 2011-11-24 | Insense Limited | Treatment of psoriasis |
US20120136323A1 (en) * | 2009-08-21 | 2012-05-31 | Nathan Stasko | Wound Dressings, Methods of Using the Same and Methods of Forming the Same |
US20160367492A1 (en) * | 2014-02-28 | 2016-12-22 | Pusan National University Industry-University Cooperation Foundation | Nitric oxide-releasing wound treatment film and preparation method therefor |
WO2019169092A1 (en) * | 2018-03-01 | 2019-09-06 | The Regents Of The University Of Michigan | Two-part nitric oxide generating topical compositions |
WO2019236825A1 (en) * | 2018-06-08 | 2019-12-12 | University Of Georgia Research Foundation, Inc. | Antimicrobial compositions with wound healing properties |
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