EP4396192A1 - Compound in the form of particles functionalized with high percentage ionic metal, and its use as an antimicrobial - Google Patents
Compound in the form of particles functionalized with high percentage ionic metal, and its use as an antimicrobialInfo
- Publication number
- EP4396192A1 EP4396192A1 EP22777315.7A EP22777315A EP4396192A1 EP 4396192 A1 EP4396192 A1 EP 4396192A1 EP 22777315 A EP22777315 A EP 22777315A EP 4396192 A1 EP4396192 A1 EP 4396192A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- formula
- moles
- present
- composition
- 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.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 107
- 229910052751 metal Inorganic materials 0.000 title claims abstract description 35
- 239000002184 metal Substances 0.000 title claims abstract description 35
- 239000002245 particle Substances 0.000 title claims description 30
- 230000000845 anti-microbial effect Effects 0.000 title abstract description 12
- 239000004599 antimicrobial Substances 0.000 title description 4
- 239000000203 mixture Substances 0.000 claims abstract description 46
- 238000000034 method Methods 0.000 claims abstract description 19
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 16
- 230000000699 topical effect Effects 0.000 claims abstract description 12
- 230000000843 anti-fungal effect Effects 0.000 claims abstract description 11
- 230000000840 anti-viral effect Effects 0.000 claims abstract description 11
- 206010017533 Fungal infection Diseases 0.000 claims abstract description 10
- 208000031888 Mycoses Diseases 0.000 claims abstract description 10
- 208000036142 Viral infection Diseases 0.000 claims abstract description 10
- 230000001580 bacterial effect Effects 0.000 claims abstract description 10
- 230000003612 virological effect Effects 0.000 claims abstract description 10
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 36
- AUVSUPMVIZXUOG-UHFFFAOYSA-N (4-sulfanylphenyl)boronic acid Chemical compound OB(O)C1=CC=C(S)C=C1 AUVSUPMVIZXUOG-UHFFFAOYSA-N 0.000 claims description 26
- 125000000524 functional group Chemical group 0.000 claims description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 20
- FOIXSVOLVBLSDH-UHFFFAOYSA-N Silver ion Chemical compound [Ag+] FOIXSVOLVBLSDH-UHFFFAOYSA-N 0.000 claims description 20
- 239000003093 cationic surfactant Substances 0.000 claims description 15
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 13
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 13
- 239000000725 suspension Substances 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 239000008119 colloidal silica Substances 0.000 claims description 9
- 125000005210 alkyl ammonium group Chemical group 0.000 claims description 8
- 239000002537 cosmetic Substances 0.000 claims description 8
- 241000700605 Viruses Species 0.000 claims description 6
- 229940121375 antifungal agent Drugs 0.000 claims description 6
- 239000000377 silicon dioxide Substances 0.000 claims description 6
- 229910052681 coesite Inorganic materials 0.000 claims description 5
- 229910052906 cristobalite Inorganic materials 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 210000004400 mucous membrane Anatomy 0.000 claims description 5
- 229910052682 stishovite Inorganic materials 0.000 claims description 5
- 229910052905 tridymite Inorganic materials 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 4
- 241000222122 Candida albicans Species 0.000 claims description 4
- 206010007134 Candida infections Diseases 0.000 claims description 4
- 241000700588 Human alphaherpesvirus 1 Species 0.000 claims description 4
- 208000031650 Surgical Wound Infection Diseases 0.000 claims description 4
- 206010000496 acne Diseases 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 4
- 201000003984 candidiasis Diseases 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- 208000035874 Excoriation Diseases 0.000 claims description 3
- 238000005299 abrasion Methods 0.000 claims description 3
- 239000006071 cream Substances 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 241000228245 Aspergillus niger Species 0.000 claims description 2
- 241000271566 Aves Species 0.000 claims description 2
- 206010010741 Conjunctivitis Diseases 0.000 claims description 2
- 241000194032 Enterococcus faecalis Species 0.000 claims description 2
- 241000991587 Enterovirus C Species 0.000 claims description 2
- 241000588724 Escherichia coli Species 0.000 claims description 2
- 208000001688 Herpes Genitalis Diseases 0.000 claims description 2
- 241000589242 Legionella pneumophila Species 0.000 claims description 2
- 241000186779 Listeria monocytogenes Species 0.000 claims description 2
- 208000007027 Oral Candidiasis Diseases 0.000 claims description 2
- 206010067152 Oral herpes Diseases 0.000 claims description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims description 2
- 241000607142 Salmonella Species 0.000 claims description 2
- 206010040880 Skin irritation Diseases 0.000 claims description 2
- 206010072170 Skin wound Diseases 0.000 claims description 2
- 241000191967 Staphylococcus aureus Species 0.000 claims description 2
- 241000287411 Turdidae Species 0.000 claims description 2
- 206010046914 Vaginal infection Diseases 0.000 claims description 2
- 201000008100 Vaginitis Diseases 0.000 claims description 2
- 208000000558 Varicose Ulcer Diseases 0.000 claims description 2
- 208000002399 aphthous stomatitis Diseases 0.000 claims description 2
- 208000010217 blepharitis Diseases 0.000 claims description 2
- 229940095731 candida albicans Drugs 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 229940032049 enterococcus faecalis Drugs 0.000 claims description 2
- 239000006260 foam Substances 0.000 claims description 2
- 239000000499 gel Substances 0.000 claims description 2
- 201000004946 genital herpes Diseases 0.000 claims description 2
- 210000004392 genitalia Anatomy 0.000 claims description 2
- 208000007565 gingivitis Diseases 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 201000001371 inclusion conjunctivitis Diseases 0.000 claims description 2
- 230000007794 irritation Effects 0.000 claims description 2
- 229940115932 legionella pneumophila Drugs 0.000 claims description 2
- 230000000144 pharmacologic effect Effects 0.000 claims description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 2
- 208000024891 symptom Diseases 0.000 claims description 2
- 206010044325 trachoma Diseases 0.000 claims description 2
- 241000701161 unidentified adenovirus Species 0.000 claims description 2
- 208000010484 vulvovaginitis Diseases 0.000 claims description 2
- 239000003446 ligand Substances 0.000 abstract description 34
- 229910052709 silver Inorganic materials 0.000 abstract description 25
- 239000004332 silver Substances 0.000 abstract description 25
- 239000011859 microparticle Substances 0.000 abstract description 19
- 208000035143 Bacterial infection Diseases 0.000 abstract description 3
- 208000022362 bacterial infectious disease Diseases 0.000 abstract description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 22
- 239000000194 fatty acid Substances 0.000 description 22
- 229930195729 fatty acid Natural products 0.000 description 22
- 150000004665 fatty acids Chemical class 0.000 description 22
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 21
- 230000001588 bifunctional effect Effects 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 229910021645 metal ion Inorganic materials 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 9
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- 210000003491 skin Anatomy 0.000 description 7
- 239000004408 titanium dioxide Substances 0.000 description 7
- 244000005700 microbiome Species 0.000 description 6
- 239000002105 nanoparticle Substances 0.000 description 6
- -1 silver ions Chemical class 0.000 description 6
- 150000002500 ions Chemical class 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 4
- 230000035508 accumulation Effects 0.000 description 4
- 238000009825 accumulation Methods 0.000 description 4
- 239000003125 aqueous solvent Substances 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 235000012239 silicon dioxide Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XOLBLPGZBRYERU-UHFFFAOYSA-N tin dioxide Chemical compound O=[Sn]=O XOLBLPGZBRYERU-UHFFFAOYSA-N 0.000 description 4
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 4
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 206010052428 Wound Diseases 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 125000005621 boronate group Chemical group 0.000 description 3
- 150000007942 carboxylates Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 150000004668 long chain fatty acids Chemical class 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 150000002739 metals Chemical class 0.000 description 3
- 210000004877 mucosa Anatomy 0.000 description 3
- RVTZCBVAJQQJTK-UHFFFAOYSA-N oxygen(2-);zirconium(4+) Chemical compound [O-2].[O-2].[Zr+4] RVTZCBVAJQQJTK-UHFFFAOYSA-N 0.000 description 3
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229910001928 zirconium oxide Inorganic materials 0.000 description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- GWOLZNVIRIHJHB-UHFFFAOYSA-N 11-mercaptoundecanoic acid Chemical compound OC(=O)CCCCCCCCCCS GWOLZNVIRIHJHB-UHFFFAOYSA-N 0.000 description 2
- CFPHMAVQAJGVPV-UHFFFAOYSA-N 2-sulfanylbutanoic acid Chemical compound CCC(S)C(O)=O CFPHMAVQAJGVPV-UHFFFAOYSA-N 0.000 description 2
- VMKYTRPNOVFCGZ-UHFFFAOYSA-N 2-sulfanylphenol Chemical compound OC1=CC=CC=C1S VMKYTRPNOVFCGZ-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- CMNQZZPAVNBESS-UHFFFAOYSA-N 6-sulfanylhexanoic acid Chemical compound OC(=O)CCCCCS CMNQZZPAVNBESS-UHFFFAOYSA-N 0.000 description 2
- JWWGTYCXARQFOT-UHFFFAOYSA-N 6-sulfanylidene-1h-pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=C(S)N=C1 JWWGTYCXARQFOT-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- 208000002109 Argyria Diseases 0.000 description 2
- 241001554566 Argyria Species 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 210000004207 dermis Anatomy 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000009881 electrostatic interaction Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 235000020778 linoleic acid Nutrition 0.000 description 2
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229910044991 metal oxide Inorganic materials 0.000 description 2
- 150000004706 metal oxides Chemical class 0.000 description 2
- 229910052752 metalloid Inorganic materials 0.000 description 2
- 150000002738 metalloids Chemical class 0.000 description 2
- 239000002086 nanomaterial Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 229910001887 tin oxide Inorganic materials 0.000 description 2
- 239000010936 titanium Substances 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- 239000011787 zinc oxide Substances 0.000 description 2
- 208000025721 COVID-19 Diseases 0.000 description 1
- 241001678559 COVID-19 virus Species 0.000 description 1
- 229920000049 Carbon (fiber) Polymers 0.000 description 1
- 208000032544 Cicatrix Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000711573 Coronaviridae Species 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000031439 Striae Distensae Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 229960004150 aciclovir Drugs 0.000 description 1
- 239000012445 acidic reagent Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007961 artificial flavoring substance Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- DLGYNVMUCSTYDQ-UHFFFAOYSA-N azane;pyridine Chemical compound N.C1=CC=NC=C1 DLGYNVMUCSTYDQ-UHFFFAOYSA-N 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 239000004917 carbon fiber Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000007596 consolidation process Methods 0.000 description 1
- 229910001431 copper ion Inorganic materials 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000011810 insulating material Substances 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 235000010935 mono and diglycerides of fatty acids Nutrition 0.000 description 1
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000021315 omega 9 monounsaturated fatty acids Nutrition 0.000 description 1
- 235000020660 omega-3 fatty acid Nutrition 0.000 description 1
- 229940012843 omega-3 fatty acid Drugs 0.000 description 1
- 235000020665 omega-6 fatty acid Nutrition 0.000 description 1
- 229940033080 omega-6 fatty acid Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000007331 pathological accumulation Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000037387 scars Effects 0.000 description 1
- 239000004065 semiconductor Substances 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 description 1
- 229940071536 silver acetate Drugs 0.000 description 1
- LMEWRZSPCQHBOB-UHFFFAOYSA-M silver;2-hydroxypropanoate Chemical compound [Ag+].CC(O)C([O-])=O LMEWRZSPCQHBOB-UHFFFAOYSA-M 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- NJRXVEJTAYWCQJ-UHFFFAOYSA-N thiomalic acid Chemical compound OC(=O)CC(S)C(O)=O NJRXVEJTAYWCQJ-UHFFFAOYSA-N 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 229910001428 transition metal ion Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Abstract
The present invention relates to a compound in the form of a microparticle comprising a support or carrier to which is bound, via an "n" number of ligands, a large number of moles of a metal in ionic form (preferably silver), wherein said compound exhibits high antimicrobial, antibacterial, antiviral and antifungal activity. Further, the present invention relates to said compound based on a metal in ionic form and compositions thereof for topical dermatological, gynecological, oral, oromucosal and/or ocular use in methods of treatment of bacterial, viral and/or fungal infections.
Description
"Compound in the form of particles functionalized with high percentage ionic metal, and its use as an antimicrobial"
The present invention relates to a compound in the form of a microparticle comprising a support or carrier to which is bound, via an "n" number of ligands, a large number of moles of a metal in ionic form (preferably silver), wherein said compound exhibits at least a high activity selected from antimicrobial activity, antibacterial activity, antiviral activity and/or antifungal activity.
Further, the present invention relates to said compound based on a metal in ionic form and compositions thereof for topical dermatological, gynecological, oral, oromucosal and/or ocular use in methods of treatment of bacterial, viral and/or fungal infections.
In addition, the present invention relates to the nontherapeutic topical use, such as a cosmetic use, of said compound based on a metal in ionic form and compositions thereof.
Finally, a process for the preparation of said compound in microparticle form comprising a high percentage of a metal in ionic form, preferably silver (Ag-), using of a high-purity ligand, preferably from 90% to 99%, is also described.
A wide variety of microbes, such as bacteria, viruses, and fungi, are often the causes of skin diseases (e.g., acne, slow healing or infection of wounds, ulcers or burns, etc.) and mucosal diseases (e.g., gynecological diseases from Herpes or Candida).
The antimicrobial or antibacterial activity of some metal ions is known (oligodynamic effect). Among the metal ions with greater antimicrobial or antibacterial activity are known to be silver (Ag ) and copper (Cu**) ions. For example, the incorporation of such metals, particularly silver ions, into plastic, ceramic or carbon fiber materials enables the elimination or reduction of microbial or bacterial colony growth. In addition, the use of silver for the control of skin infections has been known since ancient times.
The antimicrobial or antibacterial effect of silver (e.g., silver in the oxidation state (+1)) may be advantageous considering the compatibility of Ag- ions with the human organism and the increasing resistance to synthetic antibiotic compounds of many pathogenic bacteria infecting human and animal subjects.
WO 2008/135093 A1 document refers to a product containing a nanomaterial compound having general formula AOx-(L-Me<n+>)i(FA)j, wherein AOx denotes a metal or metalloid oxide, x denotes the number of oxygen atoms bonded to the metal atoms (A); Me<n+> is a metal ion; L denotes a bifunctional molecule that binds the metal or metalloid oxide (AOx) and the metal ion (Me<n+>); I is a parameter that indicates the number of groups (L-Me<n+>) that bind the metal oxide AOx; (FA) is a fatty acid that binds to the AOx
nanoparticles; j is an additional parameter that indicates the number of fatty acid (FA) molecules that bind the AOx nanoparticles. The product containing said nanomaterial compound having general formula AOx- (L-Me<n+>) i (FA) j described in WO 2008/135093 A1 is obtained by a time-consuming and laborious preparation method because it necessarily involves the formation of the bond with said fatty acid (FA)j.
Patent documents WO 2007/122651 A1 and WO 2008/043396 A1 describe a nanocrystalline or nanoparticle ((nano)compound) with antimicrobial activity having formula "AOx(L-Men+)j ", wherein an "i" number of ions of a metal (in ionic form) "Men+" such as Ag- or Cu++, are bound via "i" bifunctional ligands "L" (e.g. 4- mercaptophenyl boronic acid) homogeneously on the surface of a metal or semimetal oxide nanoparticle "AOx " (e.g. TiO2, SiO2 , ZnO, etc.). The metal in ionic form present in the nanocompound performs its antimicrobial function and is used both in the medical field and for coating various surfaces to make them sterile or to prevent the proliferation of microbes on said surfaces. Said (nano)compound of the known art AOx(L-Men+)j has a particle size (/.e., mean geometric diameter) of less than 40 nm, preferably less than 15 nm.
As is well known, topically acting compounds (e.g., compounds for dermatological or gynecological use) having an average particle diameter of less than 100 nm, i.e., so-called nanoparticles, can be directly absorbed as such by tissues, such as skin (or dermis) and mucosa.
In contrast, topically acting compounds having an average particle diameter greater than 100 nm are not directly absorbed as such by the skin (or dermis) and mucosa.
Prolonged use of metal-based compounds, such as silver or copper, for the treatment of skin or mucous membranes can lead to accumulation in tissues of said metals, particularly if said metals are formulated in particles smaller than 100 nm in size (either solubilized in aqueous solvents or insoluble in aqueous solvents), as said particles are absorbed by the body.
In the case of a wound or ulcer, accumulation of silver in tissues can cause damage to the wound bed by hindering and delaying the healing process. In addition, accumulation of silver in tissues can lead to bluegray discolorations of the skin or eyes (argyria and argyrosis).
In addition, the nanocompounds of formula "AOx(L-Men+)j" described in patent documents WO 2007/122651 A1 and WO 2008/043396 A1 comprise an amount of (L-Men+) or Men+ of about 2.0-2.3 x 105 moles per gram of "AOX" support.
The technical problem that the present invention addresses and solves is to make available compounds with antibacterial, antiviral, and/or antifungal action based on metal ions, preferably silver, having greater
efficacy (e.g., at the same dosage unit) and greater safety than compounds in the known art, particularly compared to compounds described in patent documents WO 2007/122651 A1 and WO 2008/043396 A1 , as well as a method of preparation that is simple, and less time-consuming and laborious than that described in WO 2008/135093 A1.
The Applicant addresses and solves the above technical problems and those that will be clear from this description by providing a compound of the formula "AOx(L-Men+)j " (Figure 1) having a particle mean geometric diameter ranging from about 1 pm to 10 pm (microparticles) and having an "I" number of groups (L-Men+) bound on the surface of each metal or semimetal oxide particle "AOX" (in short support, e.g., TIO2, SiO2 , or ZnO) higher than the known art, such as WO 2007/122651 A1 and WO 2008/043396 A1 , as detailed and quantified below in the present invention.
In the formula "AOx(L-Men+)j", L is a bifunctional ligand capable of both binding to the metal oxide by strong electrostatic interaction (by sharing the same atomic electrons) and binding to the metal (preferably silver) by a bond almost as strong as a covalent dative bond, allowing the metal to remain in the ionic form "Men+", e.g. Ag- . The preparation of said compound according to the present invention of the formula "AOx(L-Men+)j" in the form of microparticles and having a large number of groups (L-Men+) bound on the surface of each microparticle is made possible by using a ligand L of high purity (approximately from 90% to 99% w/w) compared with the use of a ligand L of lower purity.
In addition, the Applicant provides a process for the preparation of said compound of formula "AOx(L-Men+)j" according to the invention (process of the invention). Specifically, said process of the invention provides for the use of a high-purity (about 95%-98% w/w) ligand L that allows binding on the surface area of each microparticle support "AOX" a large number of "L" ligands so as to obtain a final product "AOx(L-Men+)j" with a high degree of groups (L-Men+), and thus of metal ions "Men+" (e.g. Ag+), bound to the surface area of said support. Said number of groups (L-Men+) per unit of support "AOX" in the compound of the present invention results advantageously higher (e.g., by 20%-30%) than products of the known art, such as WO 2007/122651 A1 and WO 2008/043396 A1.
The compound of the present invention AOx(L-Men+)j has a particle mean geometric diameter in the range of a few microns (about from 1 pm to about 10 pm, preferably from about 2 pm to about 8 pm, even more preferably from about 4 pm to about 6 pm, e.g., about 5 pm) that ensures its nonabsorption into tissues (e.g., skin or mucosa) to which it is applied to exert topical antimicrobial action. Said nonabsorption ensures the absence of accumulation of the "Me" metal, preferably silver, into said tissue and, consequently, the
absence of undesirable side effects from irreversible pathological accumulation of metal in tissues (argyria and argyrosis).
Further, having, for the same surface unit, the compound of the present invention AOx(L-Men+)j a greater number of groups (L-Men+) and, therefore, of bound Men+ metal ions (e.g., Ag- ) homogeneously on surface units of the microparticle support AOX than compounds of formula (I) of the known art, said compound of the invention proves to be more effective as a broad-spectrum antibacterial, antiviral, and/or antifungal than compounds of formula (I) of the known art (e.g., WO 2007/122651 A1 and WO 2008/043396 A1).
In addition, as a result of the increased and surprising proximity of silver ions per surface unit, the compound of formula (I) of the present invention is more effective (antiseptic activity) against small sized microorganisms (such as, small bacteria, yeasts, and viruses) than compounds of formula (I) of the known art (e.g., WO 2007/122651 A1 and WO 2008/043396 A1) because the Men+ metal ions (e.g., Ag-) are more closely distributed with each other for the same surface area of support and thus more easily intercept at least one spot of a small-sized microorganism.
A "small-sized" microorganism is preferably means a microorganism with size (e.g., average diameter or average length) from about 20 nanometers to 300 nanometers; for example, coronavirus measures from 60 nanometers to 140 nanometers.
The compounds of the invention and compositions thereof show a high safety profile and can be used by a wide category of subjects, such as, adults, elderly and pediatric subjects.
The compounds of the invention and compositions thereof are easy to prepare and cost-effective. In particular, the use of a ligand L of higher purity than the known art mentioned above allows for a compound of formula (I) having a greater number of moles of groups (L-Me+) per gram of AOX support than the known art, for the same amount by weight of ligand L used.
These purposes, and others that will become clear from the detailed description that follows, are achieved by the compounds, compositions, and processes of the present invention due to of the technical features in the description and the attached claims.
DESCRIPTION OF THE FIGURES
Figure 1 represents a schematic representationof the compound of formula "AOX(L-Men+)" wherein the groups (L-Men+) are bound to the surface of the metal or semimetal oxide particle "AOX".
Figure 2 represents a thermogravimetric graph of 4-mercaptophenylboronic acid subjected to heating up to 150°C (chromatogram of residual solvent weight loss).
SUMMARY OF THE INVENTION
A first aspect of the present invention relates to a compound of formula AOx(L-Men+)j as described in the known art having, however, a particle mean geometric diameter ranging from 1 m to 10 m but especially a high "I" number per surface unit (higher than the known art), wherein AOX is a microparticle of metal or semimetal oxide that serves as a support, wherein L is a bifunctional ligand that binds the metal in ionic form Men+ to said support AOX, and wherein "I" represents the number of groups (L-Men+) bound to the surface of the support microparticle AOX.
A second aspect of the present invention relates to a more effective composition comprising n moles of compound of formula AOx(L-Men+)j and additives and/or excipients, such as a composition formulated for dermatological or gynecological topical use or a composition formulated for surface coating.
A third aspect of the present invention relates to the compound of formula AOx(L-Men+)j and compositions thereof for more specific medical use against microorganisms, such as that for use as an antimicrobial, antibacterial, antiviral and/or antifungal, preferably for dermatological or gynecological use.
A fourth aspect of the present invention relates to the cosmetic (non-therapeutic) use of a compound of formula AOx(L-Men+)j and compositions thereof in the treatment of acne and the prevention of the consolidation of skin blemishes such as stretch mark abrasions and scars.
A fifth aspect of the present invention relates to a process for the preparation of a compound of formula AOx(L-Men+)i .
A sixth aspect of the present invention relates to a compound of formula AOx(L-Men+)j obtainable by the process of the present invention.
A seventh aspect of the present invention relates to a method of treatment of dermatological or gynecological diseases or symptoms caused by bacteria, viruses or fungi by administering a therapeutically effective amount of a compound of formula AOx(L-Men+)j or compositions thereof to a subject in a state of need.
DETAILED DESCRIPTION OF THE INVENTION
It is an object of the present invention a compound of formula (I),
AOx(L-Men+)i (I), wherein
- AOX (or support) is a metal or semimetal oxide particle, wherein A denotes the metal and X the number of oxygens bound to A, x= 1 or 2;
- Men+ is a transition metal ion, preferably a silver ion (Ag+);
- L (or ligand) is a bifunctional molecule, organic or organometallic molecule, comprising at one end a first functional group bound to said AOX support and with considerable affinity for it and at its other end a second functional group binding said metal ion Men+;
- i is a number of groups (L-Men+) bonded to an AOX support particle ; wherein said compound AOx(L-Men+)j is in the form of a particle having an average diameter from about 1 pm to 10 pm (e.g., 2 pm, 3 pm, 4 pm, 5 pm, 6 pm, 7 pm, 8 pm, or 9 pm) or greater than 10 pm, such as 20 pm, 30 pm, 40 pm, or 50 pm; preferably wherein said AOX particle has an average diameter approximately from 1 pm to 10pm and said L and Men+ for example have each an average diameter of the order of picometers.
Said compound of formula (I) according to the present invention theoretically comprises for 1 g of AOx from about 2.8 x 10 5 moles to 5 x 105 moles of Men+ (e.g., 2.9 or 3.0 or 3.1 3,2 or 3.3 or 3.4 or 3.5 or 3.6 or 3.7 or 3.8 or 3.9 or 4.0 or 4.5 x 105 moles), preferably from 2.8 x 105 moles to 3.5 x 105 moles of Men+, more preferably about 3.0±0.2 x 105 moles of Men+; preferably wherein Men+ is a silver ion (Ag+).
Said metal or semimetal oxides AOX (or supports) of the invention are insulating or semiconducting materials (e.g., titanium oxide (TiC>2 ), colloidal silica (SiC>2 ), zinc oxide (ZnO), zirconium oxide (ZrCh) or tin oxide (SnC>2)), which can be produced in the form of particles with diameters (particle diameter or particle mean geometric diameter or particle size) of the order of microns, approximately from 1 pm to 10 pm (e.g., 2 pm, 3 pm, 4 pm, 5 pm, 6 pm, 7 pm, 8 pm, or 9 pm) or slightly smaller from 1 pm to 10 pm. On the surface of said metal or semimetal oxides AOX (supports of the invention), molecules having at least one suitable functional group (e.g., a ligand L), such as a carboxyl or carboxylic (-COOH) (or carboxylate), or phosphonic (-PO3H2) (or phosphonate), or boronic (-B(OH)2) (or boronate) group, can bind. Said bonding between AOx and L occurs through strong electrostatic interaction (by sharing the same atomic electrons).
In addition, said metal or semimetal oxides AOX of the invention are materials that can be used in the medical or cosmetic field as materials that are safe for humans.
Said ligand L is a bifunctional organic or organometallic molecule (e.g., a transition metal complex) comprising a first functional group bound to (or absorbed on) the AOX support and a second functional group bound to the metal ion Men+. Said first functional group may be selected from the group comprising or alternatively consisting of: boronic group (-B(OH)2) (or boronate group), phosphonic group (-PO3H2) (or phosphonate group), carboxyl or carboxylic group (-COOH) (or carboxylate group), dipyridyl group, and terpyridyl group; preferably (-B(OH)2). Preferably, said dipyridyl or terpyridyl group is substituted with a carboxylic group, more preferably in the para position with respect to the pyridine nitrogen.
Said second functional group can be selected from the group that comprises or, alternatively, consists of: - Cl, -Br, -I, -S, -CNS, -NH2, -N, -CN and -NCS, preferably -S.
The organic-type bifunctional ligand L can be selected from a group that comprises or alternatively consists of:
- C6 -C18 nitrogen-containing heterocycle, preferably pyridine, dipyridyl or terpyridyl, optionally substituted with at least one substituent selected from: carboxyl or carboxylic (-COOH), boronic (-B(OH)2), phosphonic (-PO3H2), mercaptan (-SH) and hydroxyl (-OH);
- C6-C18 aryl, preferably phenyl, naphthyl or biphenyl, optionally substituted with at least one substituent selected from: carboxyl or carboxylic (-COOH), boronic (-B(OH)2), phosphonic (-PO3H2), mercaptan (-SH) and hydroxyl (-OH);
- C2-C18 monocarboxylic or dicarboxylic acid, optionally substituted with at least one mercaptan group (- SH) and/or at least one hydroxyl group (-OH).
- pyridine, dipyridyl, or terpyridyl functionalized with at least one carboxylic group, boronic group, or phosphonic group;
- mercaptosuccinic acid, 11-mercaptoundecanoic acid, mercaptophenol, 6-mercaptonicotinic acid, 5- carboxypentanethiol, mercaptobutyric acid, and 4-mercaptophenylboronic acid.
In the context of the present invention, the compound of formula (I) AOx(L-Men+)i of the present invention does not provide at all the presence of an additional fatty acid (FA)j as described in formula AOx-(L-Men+)i (FA)j of patent application W02008/135093. In the context of the present invention, L does not have the meaning and function of fatty acid (FA) in the formula AOx-(L-Men+)i (FA)j described in patent application W02008/ 135093. In the context of the present invention, the bifunctional ligand L used in the compound of formula (I) AOx(L-Men+)i of the present invention is not, for example, a fatty acid (FA)j, is not, for example, a long-chain fatty acid (FA)j, is not, for example, a saturated long-chain fatty acid (FA)j such as, for example, butyric acid, lauric acid, myristic acid, palmitic acid, or stearic acid, is not, for example, an unsaturated long- chain fatty acid (FA)j such as, for example, oleic acid or linoleic acid; L is also not an Omega-3 fatty acid
(FA)j such as, for example, alpha-linolenic acid (ALA) 18:3, or an Omega-6 fatty acid (FA)j such as, for example, linoleic acid 18:2, or an Omega-9 fatty acid (FA)j such as, for example, oleic acid 18:1.
According to one aspect of the present invention, the ligand L is a bifunctional organic molecule wherein said second functional group is -S (which binds L to Men+), preferably selected from: mercaptosuccinic acid, 11-mercaptoundecanoic acid, mercaptophenol, 6-mercaptonicotinic acid, 5-carboxypentanethiol, mercaptobutyric acid, and 4-mercaptophenylboronic acid.
According to one aspect of the present invention, ligand L is a bifunctional organic molecule comprising at least a first functional group linked to said AOX , and at least a second functional group linked to said Men+, wherein said first functional group comprises a boronic (-B (OH)2) or phosphonic (-PO3H2) functionality, and wherein said second functional group is -S.
Advantageously, the ligand L is a bifunctional organic molecule wherein said first functional group is the (- B(OH)2) group (which binds L to AOX), and wherein said second functional group is -S (which binds L to Men+), preferably L is a 4-mercaptophenylboronic acid (MPB for short, e.g with CAS nr 237429-33-3) or an ion (or anion) thereof.
According to one aspect of the invention, the compound of the present invention of formula (I) (AOx(L-Men+)j) is a compound wherein
- "AOX" is selected from the group comprising or alternatively consisting of: titanium oxide (TiO2), colloidal silica (SiO2), zinc oxide (ZnO), zirconium oxide (ZrO2), tin oxide (SnO2);
- Men+ is selected from a silver ion (Ag+) or a copper ion (Cu**);
- L is a bifunctional molecule, preferably an organic molecule, wherein said first functional group comprises or, alternatively, consists of a boronic (-B(OH)2) (or boronate group) or phosphonic (-PO3H2) (or phosphonate group) functionality, or carboxyl (-COOH) (or carboxylic or carboxylate group), preferably (-B(OH)2), and wherein said second functional group comprises or, alternatively, consists of: -Cl, -Br, -I, -S, -CNS, -NH2, - N, -CN and -NCS, preferably -S; wherein said AOX (L-Men+)j particle has a mean geometric diameter approximately from 1 pm to 10 pm (e.g., 2 pm, 3 pm, 4 pm, 5 pm, 6 pm, 7 pm, 8 pm, or 9 pm or greater than 10 pm); preferably wherein said AOX particle has an average diameter approximately from 1 pm to 10 pm and said L and Men+ have, for example, each an average diameter of the order of picometers; and wherein for 1 g of AOX are comprised from 2.8 x 105 moles to 5 x 105 moles of Men+, preferably from 2.8 x 105 moles to 3.5 x 105 moles of Men+, even more preferably from 3.0±0.2 x 105 moles of Me n+ to 3.5 x 10’5 moles of Men+, e.g. 3.0±0.2 x 105 moles of Men+. The presence of a higher density of silver ions (Ag+)
on the AOx surface realized through the selection of the ligand L, such as 4-mercaptophenyl boronic acid (MPB), allows for a smaller distance (smaller volume) between a first silver ion and a second (contiguous to the first) silver ion resulting in a higher probability of intercepting microorganisms and pathogens that have a size or hindrance smaller than the said distance, such as in the case of viruses that have a size or hindrance smaller than bacteria.
According to a preferred aspect of the invention, the compound of the present invention of formula (I) (AOX(L- Men+)j ) is a compound wherein
- "AOX" is selected from the group comprising or alternatively consisting of: titanium oxide (TIO2), colloidal silica (SIO2), zinc oxide (ZnO), preferably titanium oxide (TiO2) or colloidal silica (SIO2);
- Men+ is the monovalent silver ion (Ag+);
- L is a bifunctional organic molecule, wherein said first functional group is (-B(OH)2 ) (binding L to AOX), and whereinh said second functional group is -S (binding L to Men+), preferably L is a 4-mercaptophenylboronic acid or an ion thereof; wherein said AOx(L-Men+)j particle has a mean geometric diameter approximately from 1 pm to 10 pm (e.g., 2 pm, 3 pm, 4 pm, 5 pm, 6 pm, 7 pm, 8 pm, or 9 pm or greater than 10 pm); preferably wherein said AOX particle has an average diameter approximately from 1 pm to 10 pm and said L and Men+ have, for example, each an average diameter of the order of picometers; and wherein for 1 g of AOX are comprised from 2.8 x 105 moles to 5 x 105 moles of Men+, preferably from 2.8 x 105 moles to 3.5 x 105 moles of Men+, even more preferably from 3.0±0.2 x 10 5 moles of Men+ to 3.5 x 10’5 moles of Men+, e.g. 3.0±0.2 x 10’5 moles of Men+.
According to a further preferred aspect of the invention, the compound of the present invention of formula (I) (AOx(L-Men+)j ) is a compound wherein
- "AOX" is titanium oxide (TiO2) or colloidal silica (SIO2), preferably titanium oxide (TIO2);
- Men+ is the monovalent silver ion (Ag+);
- L is 4-mercaptophenylboronic acid or an ion thereof; wherein said AOx(L-Men+)j particle has a mean geometric diameter approximately from 1 pm to 10 pm (e.g., 2 pm, 3 pm, 4 pm, 5 pm, 6 pm, 7 pm, 8 pm, or 9 pm or greater than 10 pm); preferably wherein said AOX particle has an average diameter approximately from 1 pm to 10 pm and said L and Men+ have, for example, each an average diameter of the order of picometers; and wherein for 1 g of AOX are comprised from 2.8 x 105 moles to 5 x 105 moles of Men+, preferably from 2.8 x 105 moles to 3.5 x 105 moles of Men+, even more preferably from 3.0±0.2 x 10 5 moles of Men+ to 3.5 x 10’5 moles of Men+, e.g. 3.0±0.2 x 10’5 moles of Men+.
Compounds of the present invention of formula (I) in the form of positively charged microparticles can give rise to stable suspensions in both aqueous and polar solvents of organic nature.
According to one aspect of the present invention, said compound of formula (I) of the present invention (according to any described embodiment) may optionally be combined with a cationic surfactant; preferably wherein said cationic surfactant is selected from a group of alkylammonium salts comprising or alternatively consisting of: quaternary ammonium, alkylammonium chloride, benzalkonium chloride (BZC); more preferably said cationic surfactant is benzalkonium chloride (BZC).
Said cationic surfactant (e.g., an alkylammonium salt, such as BZC) enhances the bactericidal activity of the compound of formula (I) of the invention, as said cationic surfactants exhibit bactericidal activity that can be complementary to that of metal ions, such as that of the silver ion.
Said cationic surfactant (e.g., an alkylammonium salt, such as BZC) and the compound of formula (I) of the invention can form a combination, such as a mixture of two solids or a suspension in aqueous solvent or a polar solvent of organic nature of the two components.
Surprisingly, alkylammonium salts (e.g., benzalkonium chloride), which tend to precipitate in a basic medium or in the presence of high concentrations of anions, are stable in the presence of formed positively charged suspensions of the compound of formula (I) of the invention.
According to one aspect, said cationic surfactants (e.g., an alkylammonium salt, such as BZC) can be adsorbed on compounds of formula (I) of the invention under near-neutral pH conditions, particularly on compounds of formula (I) wherein the support is titanium dioxide. This offers the additional advantage of reducing the volatility of alkylammonium salts after they have been applied on a tissue.
It is an object of the present invention a composition comprising a compound of formula (I), according to any one of the described embodiments (e.g., the compound of formula (I) alone or the combination of compound of formula (I) and cationic surfactant), and additives and/or excipients of acceptable pharmacological or cosmetic grade.
Said composition according to the present invention may be in solid, liquid, or semi-liquid form, for example formulated as cream, gel, foam, oil-water emulsions, suspensions, powder (or spray powder), or granules
(or microgranules). Preferably, a composition according to the present invention comprising the compound of formula (I) is formulated as a cream-gel for topical use.
According to one aspect, said composition of the invention comprising the compound of formula (I) may further comprise at least one additional compound having antiviral and/or antibacterial and/or antimicrobial and/or antifungal properties known to the person skilled in the art and selected according to the specific use for which the composition of the present invention is intended.
Alternatively, the compound of formula (I) of the present invention or a composition thereof can be added to known products on the market for topical treatment having antiviral properties (for example, non-limiting, Acyclovir, Ritonavir and the like) and/or antibacterial and/or antifungal properties (for example, products active against Candida), increasing their efficacy.
Said at least one additive and/or excipient of pharmaceutical or cosmetic grade, included in the composition of the invention together with the compound of formula (I), consists of a substance without therapeutic activity suitable for pharmaceutical or cosmetic use selected from auxiliary substances known to the person skilled in the art such as, e.g., diluents, solvents (e.g., water, glycerin, ethyl alcohol), solubilizers, binders, polymeric and nonpolymeric thickeners and viscosifiers, sweeteners, flavoring agents, colorants, lubricants, surfactants, antimicrobials, antioxidants, preservatives, pH-stabilizing buffers and mixtures thereof, and tonicity agents. Non-limiting examples of such substances are phosphate buffers (e.g., dicalcium phosphate), stearate of an alkaline or alkaline earth metal (e.g., magnesium), silicon dioxide, mono- and diglycerides of fatty acids, microcrystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, starch or corn starch, natural or artificial flavors.
Said composition of the invention can be a pharmaceutical composition, a medical device composition (Medical Device Regulation (EU) 2017/745 (MDR)) and/or a cosmetic composition.
It is an object of the present invention a compound of formula (I) or a composition containing it, according to any one of the described embodiments (e.g., the compound of formula (I) alone or the combination of compound of formula (I) and cationic surfactant), for use as a medicament.
It is an object of the present invention a compound of formula (I) or a composition containing it, according to any one of the described embodiments (e.g., the compound of formula (I) alone or the combination of compound of formula (I) and cationic surfactant), for use as an antibacterial or antiviral or antifungal, preferably wherein said use is a dermatological or gynecological or oromucosal (or buccal area) or ocular use, more preferably a topical (or local) use.
According to one aspect, said compound of formula (I) or a composition thereof, according to any one of the embodiments described in the present invention, is for use in a method of treatment, preferably topical, of acne, venous ulcers, oral or genital herpes, skin wounds or irritations or abrasions, burns, surgical site infections (SSIs), bacterial or viral or fungal infections of the skin, bacterial or viral or fungal infections of the genital mucous membranes (e.g., candidiasis, vaginitis, vulvovaginitis, vaginosis, bacterial or viral or fungal infections of the mucous membranes of the buccal area (e.g., aphthae, thrush, gingivitis, bacterial infections) or viral or fungal infections of the ocular surface (e.g., conjunctivitis, blepharitis, trachoma).
According to a further aspect, said compound of formula (I) or a composition thereof, according to any one of the embodiments described in the present invention, is for use in the treatment, preferably topical, of diseases caused by at least one of the following microbes: HSV-1 (Herpes Simplex Virus-1), Coronavirus SARS-CoV-2 (Covid-19), Adenovirus, Poliovirus, Avian virus, Legionella pneumophila, Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus faecalis, Escherichia Coli, Salmonella enteridis D1, Listeria monocytogenes, Candida albicans, and Aspergillus niger.
A composition comprising compound of formula (I) according to the present invention can be administered topically or more specifically dermatologically (e.g., in cream and/or gel form) in a dosage form comprising said compound of formula (I) in a concentration ranging from 0.05% to 4.0% (concentration as a mass/volume percentage, mg/100 mL).
The administration of said dosage form at the above concentration can be applied on the subject in a state of need several times a day (once, twice, three or four times a day) depending on the type of treatment and the condition of the subject.
An example of a process for preparing the compound of formula (I) of the present invention, in any one of the embodiments described above, comprises the following steps: step (1) organize or prepare a suspension in water and alcohol (e.g., ethanol) of microparticles of metal or semimetal oxide "AOX" according to the invention (preferably Ti O2 or SIC>2), wherein said microparticles have a particle mean geometric diameter ranging from 1 pm to 10 pm, wherein said suspension has a concentration (g/mL) from 0.5% to 30% (e.g., 1 %, 2%, 5%, 10%, 15%, or 20%, preferably about 1.5% or 15%), and wherein said suspension has a concentration (kg/L) of alcohol from 10% to 50% (e.g., 20%, 30%, or 40%, preferably 25%), obtaining a step 1 AOX microparticles suspension , preferably a suspension from about 10 kg to 150 kg of AOX microparticles;
step (2) add to 1 volume (e.g., 100 mL) of step 1 AOX microparticles suspension having a concentration (g/mL) of 15% 1 volume of water, and add a solution in alcohol (e.g., ethanol) of a bifunctional ligand L according to the invention (e.g., 4-mercaptophenyl boronic acid (MPB)), wherein said ligand L has a purity from 90% to 99% (weight/weight percentage, determined by HPLC; e.g. 91 %, 92%, 93%, 94%, 95%, 96%, 97%, or 98%, preferably about 98%), wherein for each gram from AOX 2.8 x 105 moles to 5 x 105 moles of ligand "L" are added (preferably about 3.0±0.2 x 105 moles), preferably wherein said solution in alcohol of ligand "L" has a concentration (moles/mL) ranging from 1 x 105 moles to 30 x 105 moles per 100 mL (e.g., 10, 15 or 20 x 105 moles, preferably about 15 x 10~5 moles per 100 mL), obtaining a step 2 suspension; step (3) stir the step 2 suspension from 12 to 36 hours (preferably about 24 hours) at a room temperature from 12°C to 35°C (preferably 20°C), until complete binding of the ligands L to the surface of the AOX microparticles, preferably wherein the amount of reaction progress is monitored by spectrophotometry, to obtain a step 4 mixture; step (4) add to the step 4 mixture under stirring a stoichiometric amount or in slight excess with respect of the ligand L of a salt of a metal "Me" according to the invention (e.g., silver lactate or silver acetate) and keep stirring for a time from 30 min to 12 hr (e.g., 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, or 10 hours, preferably about from 1 to 2 hours) at a room temperature from 12°C to 35°C (preferably 20°C) until complete binding of the metal in the form of the cation "Men+" (e.g., Ag+), to give a mixture of compound of formula (I) AOx(L-Men+)j of the present invention.
According to an aspect of the said process of the present invention, step (4) is followed by step (5) of adding to the mixture of compound of formula (I) AOx(L-Men+)j obtained from step (4) an aqueous solution of cationic surfactant (preferably benzalkonium chloride), e.g., an about 50% (w/v) solution and stir for a time from 30 minutes to 2 hours (preferably about 1 hour) at a room temperature from 12°C to 35°C (preferably 20°C), to give a mixture comprising the compound of formula (I) AOx(L-Men+)j and the cationic surfactant according to the present invention.
Examples of components that can be used in the context of the present invention for the preparation of the composition of formula (I) are given below.
An example of titanium oxide (Ti O2) that can be used in the context of the present invention has the following characteristics: titanium dioxide, cas nr 13463-67-7, typical density (bulk) 0.4-0.62 g/cm3 (tapped) 0.625- 0.830 g/cm3 ; dielectric constant 48 for anatase, 114 for rutile; hardness 5-6 for anatase, 6-7 for rutile; loss on drying <=0.5% (test: JP XV or USP 32); loss on ignition <=13% (test: USP 32); melting point 185.5 °C; specific surface area 9.90-10.77 m2 /g.
Titanium dioxide (TiO2 ) is naturally occurring (rutile, anatase, brookite) or can be commercially prepared by methods and equipment known to the skilled person, such as the sulfate or chloride process.
An example of colloidal silica (SIC>2) that can be used in the context of the present invention is a common colloidal silica known to the person skilled in the art and commercially prepared according to methods and equipment known to the skilled person, such as by polymerization of silicic acid in an acidic environment at controlled pH.
Table 1 shows an HPLC analysis of purity of a ligand "L" that can be used in the process for the preparation of a compound of formula (I) according to the present invention; the ligand "L" 4-mercaptophenyl boronic acid (MPB) is found to have a purity as weight percentage greater than or equal to 95 % (about 98 %) with respect to the total weight of the ligand sample (HPLC measurement vs reference standard, average value over 3 experiments, Table 1).
4-Mercaptophenyl boronic acid is known to be an unstable compound, and to date it has never been used at a purity from 90% to 99%, preferably from 95% to 99% (w/w %).
Table 1
With reference to the 4-mercaptophenylboronic acid reagent with purity 97-98±0.50 % (w/w) in Table 1 , the amounts for reaching 100 % are confirmed to be about 1.5 % by thermogravimetric graph up to 150°C (Figure 3), obtained by heating the industrial sample to dryness.
Until now, for the preparation of a compound of formula (I) according to the known art (not according to the present invention), such as patent documents WO 2007/122651 A1 and WO 2008/043396 A1, the ligand "L" 4-mercaptophenyl boronic acid (MPB) (e.g., commercial product manufactured by Sigma Aldrich) having a weight percent purity of about 70% with respect of the total sample weight (HPLC measurement, average value over 3 experiments, Table 2) was used.
Table 2
In the compound of formula (I) according to the known art (not according to the present invention), for the preparation of which 4-mercaptophenyl boronic acid having about 70% (w/w) purity was used as ligand "L," for each gram of titanium dioxide about 0.0025 g of silver is bound (equal to 2.31 x 10 5 moles of silver, molecular weight of Ag equal to 107.8683).
Considering that titanium dioxide in the form of a microparticle with a mean diameter of about 2 microns (pm) has a surface area of about 10 m2/g, using as ligand "L" 4-mercaptophenyl boronic acid having about 70% (w/w) purity, a compound of formula (I) is obtained (not according to the present invention) in which 0.0025 g silver (equal to 2.31 x 105 moles of silver) is bound on 10 m2 of titanium dioxide, which is equivalent to say that 4000 m2 of support surface of the compound of formula (I) binds 1 g silver in ionic form.
According to one aspect of the present invention, considering that titanium dioxide in the form of a microparticle with a mean diameter of about 2 microns (pm) has a surface area of about 10 m2 /g, using a ligand "L" 4-mercaptophenyl boronic acid having about 98% (w/w) purity, a compound of formula (I) is obtained (according to the present invention) in which 0.0035 g silver (equal to 3.23 x 10 5 moles of silver) is bound on 10 m2 of titanium dioxide, which is equivalent to saying 2857 m2 of support surface of compound of formula (I) binds 1 g silver in ionic form or, similarly, that 4000 m2 of support surface of compound of formula (I) binds 1 .4 g silver in ionic form.
The term "subject(s)" in the context of the present invention refers to mammals (animal and human), preferably human subjects.
The term "therapeutically effective amount" refers to the amount of mixture or compound or formulation that elicits biological or medicinal response in a tissue, system, or subject that is researched and defined by an expert in the field.
Unless otherwise specified, the expression mixture or composition comprises a component in an amount "comprised in a range from x to y" means that said component may be present in the composition in all amounts present in said range, even if not made explicit, extremes of the range included.
Claims
1 . A compound of formula (I):
AOx(L-Me"+)i (I) wherein
AOx is a metal or semimetal oxide particle selected from the group comprising or alternatively consisting of: TiO2 , SiO2 (colloidal silica) and ZnO;
Men+ is silver ion Ag+;
L is a molecule comprising at least a first functional group bound to said AOX, and at least a second functional group bound to said Men+; i is a number of groups (L-Men+) bound to an AOX particle ; wherein said compound AOx(L-Men+)j is in the form of a particle having a mean geometric diameter ranging from 1 m to 10 pm, and wherein from 2.8 x 105 moles to 5 x 105 moles of Men+ are bound to 1 g of AOX.
2. The compound of formula (I) according to claim 1 , wherein from 2.8 x 105 moles to 3.5 x 105 moles of (L-Men+) or Men+, preferably from 3.0±0.2 x 10'5 moles of Men+ to 3.5 x 10'5 moles of Men+, even more preferably about 3.0±0.2 x 105 moles, are bound to 1 g of AOx.
3. The compound of formula (I) according to claim 1 or 2, wherein said first functional group of the molecule L includes a boronic (-B(OH)2) or phosphonic (-PO3H2) or carboxylic (-COOH) functionality; preferably wherein L is 4-mercaptophenyl boronic acid (MPB).
4. The compound of formula (I) according to any one of claims 1-3, wherein
AOX is TiO2 or SiO2 (colloidal silica),
Men+ is silver ion Ag+, and
L is 4-mercaptophenyl boronic acid (MPB).
5. The compound of formula (I) according to any one of claims 1-4, wherein said compound of formula (I) is in combination with a cationic surfactant;
preferably wherein said cationic surfactant is selected from a group of alkylammonium salts comprising or alternatively consisting of: quaternary ammonium, Cl-alkylammonium chloride, benzalkonium chloride (BZC); more preferably wherein said cationic surfactant is benzalkonium chloride (BZC).
6. A composition comprising the compound formula (I) according to any one of claims 1-5 and additives and/or excipients of pharmacological or cosmetic grade; preferably wherein said composition is in the form of cream, gel, foam, oil-water emulsions, suspensions, powder, granules.
7. The compound of formula (I) or composition according to any of the preceding claims for use as a medicament.
8. The compound of formula (I) or composition according to any of the preceding claims for use as an antibacterial or antiviral or antifungal; preferably, wherein said use is a topical dermatological or gynecological or oromucosal or ocular use.
9. The compound of formula (I) or composition for use according to claim 8, wherein said use as an antibacterial or antiviral or antifungal is a use in a method of topical treatment of acne, venous ulcers, oral or genital herpes, skin wounds or irritations or abrasions or excoriations, burns, surgical site infections (SSIs), bacterial or viral or fungal infections of the skin, bacterial or viral or fungal infections of the genital mucous membranes, candidiasis, vaginitis, vulvovaginitis, vaginosis, bacterial or viral or fungal infections of the mucous membranes of the buccal area, aphthae, thrush, gingivitis, bacterial or viral or fungal infections of the ocular surface, conjunctivitis, blepharitis, and trachoma.
10. The compound of formula (I) or composition for use according to claim 8, wherein said use as an antibacterial or antiviral or antifungal is a use in a method of treating diseases and/or symptoms caused by at least one of the following microbes: HSV-1 (Herpes Simplex Virus-1), Adenovirus, Poliovirus, Avian virus, Legionella pneumophila, Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Salmonella enteridis D1, Listeria monocytogenes, Candida albicans, and Aspergillus niger.
Publications (1)
Publication Number | Publication Date |
---|---|
EP4396192A1 true EP4396192A1 (en) | 2024-07-10 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3285759B1 (en) | Antibacterial compositions comprising copper oxo-hydroxide nanoparticles and their preparation | |
EP2024117B1 (en) | Functional nanomaterials with antibacterial and antiviral activity | |
US10016525B2 (en) | Antimicrobial compositions for use in wound care products | |
TWI250969B (en) | Colloidal nanosilver solution and method for making the same | |
CA2889423A1 (en) | Metastable silver nanoparticle composites | |
WO2012017349A2 (en) | An improved topical pharmaceutical composition comprising nanonized silver sulfadiazine | |
JP2017512189A (en) | Materials and methods related to stabilized polymeric silicate compositions | |
Mahmoudabadi et al. | Effectiveness of green synthesis of silver/kaolinite nanocomposite using Quercus infectoria galls aqueous extract and its chitosan-capped derivative on the healing of infected wound | |
EP4396192A1 (en) | Compound in the form of particles functionalized with high percentage ionic metal, and its use as an antimicrobial | |
WO2023031822A1 (en) | Compound in the form of particles functionalized with high percentage ionic metal, and its use as an antimicrobial | |
EP2887936B1 (en) | Antimicrobial titanium dioxide nanoparticles functionalized with cationic silver ions | |
US9108987B2 (en) | Silver/polydiguanide complex, preparation method thereof, and antibacterial composition containing the same as an active ingredient | |
KR20080112405A (en) | Functional nanomaterials with antibacterial and antiviral activity | |
WO2009144711A1 (en) | Compositions comprising red microalgae polysaccharides and metals | |
KR101796141B1 (en) | Multifunctional therapeutic silver and vitamin B6 complex, preparation method thereof, and wound healing pharmaceutical composition containing the same as active ingredient | |
RU2404988C2 (en) | Functional nanomaterials with antibacterial and antiviral activity | |
EP3516960A1 (en) | Composition comprising silver (ag+) ion clusters | |
EP3003251B1 (en) | Antibacterial powders based on anionic silicon or titanium dioxide adsorbed with pharmaceutically active cations | |
Ogli et al. | Obtaining and properties of the implant film made with carboxymethylcellulose containing silver nanoparticles used for treatment of burn wounds | |
Sekar et al. | Smart Nanomaterials for Antiseptic Application | |
DE102005012888B4 (en) | Use of a compound for the manufacture of a substance for eliminating biomolecule-based microorganisms | |
WO2021237094A1 (en) | Antimicrobial compositions and methods of use and for making same | |
DE112008001612B4 (en) | Antimicrobial cosmetic and / or pharmaceutical compositions for topical use, process for their preparation and their use in the treatment of diseases | |
CZ16515U1 (en) | A preparation with fungicidal, bactericidal and possibly viricidal effects |