WO2019021143A1 - Hydrogel à base de molécules de l-histidine - Google Patents
Hydrogel à base de molécules de l-histidine Download PDFInfo
- Publication number
- WO2019021143A1 WO2019021143A1 PCT/IB2018/055448 IB2018055448W WO2019021143A1 WO 2019021143 A1 WO2019021143 A1 WO 2019021143A1 IB 2018055448 W IB2018055448 W IB 2018055448W WO 2019021143 A1 WO2019021143 A1 WO 2019021143A1
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- WIPO (PCT)
- Prior art keywords
- product
- parts
- histidine
- silver nitrate
- viscosity
- Prior art date
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- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 title claims abstract description 193
- 239000000017 hydrogel Substances 0.000 title claims abstract description 25
- 229960002885 histidine Drugs 0.000 claims abstract description 94
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 230000000845 anti-microbial effect Effects 0.000 claims abstract description 16
- 229920000642 polymer Polymers 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- FOIXSVOLVBLSDH-UHFFFAOYSA-N Silver ion Chemical compound [Ag+] FOIXSVOLVBLSDH-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002121 nanofiber Substances 0.000 claims abstract description 8
- 229910052751 metal Inorganic materials 0.000 claims abstract description 7
- 239000002184 metal Substances 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 167
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 83
- 230000003013 cytotoxicity Effects 0.000 claims description 22
- 231100000135 cytotoxicity Toxicity 0.000 claims description 22
- 230000003833 cell viability Effects 0.000 claims description 21
- 230000000844 anti-bacterial effect Effects 0.000 claims description 4
- 241000894006 Bacteria Species 0.000 claims description 3
- 241000588724 Escherichia coli Species 0.000 claims description 2
- 241000191967 Staphylococcus aureus Species 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims 28
- 239000004599 antimicrobial Substances 0.000 abstract description 8
- 239000000126 substance Substances 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 122
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 54
- 239000000499 gel Substances 0.000 description 28
- 239000000203 mixture Substances 0.000 description 28
- 239000000243 solution Substances 0.000 description 20
- 230000015572 biosynthetic process Effects 0.000 description 17
- 231100000433 cytotoxic Toxicity 0.000 description 15
- 230000001472 cytotoxic effect Effects 0.000 description 15
- 230000009257 reactivity Effects 0.000 description 15
- 238000004458 analytical method Methods 0.000 description 14
- 239000012153 distilled water Substances 0.000 description 14
- 238000000034 method Methods 0.000 description 14
- 230000008569 process Effects 0.000 description 13
- 125000002066 L-histidyl group Chemical group [H]N1C([H])=NC(C([H])([H])[C@](C(=O)[*])([H])N([H])[H])=C1[H] 0.000 description 10
- 229940024606 amino acid Drugs 0.000 description 9
- 235000001014 amino acid Nutrition 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 150000001413 amino acids Chemical class 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- -1 9-fluorenylmethyl Chemical group 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 238000004630 atomic force microscopy Methods 0.000 description 5
- 238000000527 sonication Methods 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 206010052428 Wound Diseases 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000001879 gelation Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000000178 monomer Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000008929 regeneration Effects 0.000 description 3
- 238000011069 regeneration method Methods 0.000 description 3
- 229910052709 silver Inorganic materials 0.000 description 3
- 239000004332 silver Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- 230000004580 weight loss Effects 0.000 description 3
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 239000012456 homogeneous solution Substances 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000002054 inoculum Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000008707 rearrangement Effects 0.000 description 2
- 238000000518 rheometry Methods 0.000 description 2
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- PNUVRHGTSSHFEL-JEDNCBNOSA-N (2S)-2-amino-3-(1H-imidazol-5-yl)propanoic acid silver Chemical compound N[C@@H](CC1=CNC=N1)C(=O)O.[Ag] PNUVRHGTSSHFEL-JEDNCBNOSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- ODHCTXKNWHHXJC-UHFFFAOYSA-N 5-oxoproline Chemical compound OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical class NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000013043 cell viability test Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000001332 colony forming effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 238000002189 fluorescence spectrum Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 230000002070 germicidal effect Effects 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 210000003041 ligament Anatomy 0.000 description 1
- 150000002632 lipids Chemical group 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000006241 metabolic reaction Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 108090000765 processed proteins & peptides Chemical group 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 238000004544 sputter deposition Methods 0.000 description 1
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- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/38—Silver; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/10—Silver compounds
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- Proteins are high polymers classified as polyamides. The monomers from which they are derived are called alpha amino carboxylic acids. There are about 23 amino acids found in proteins, a-amino acids are required by human and animal body for growth and metabolism. L- histidine is one such amino acid. But histidine is not synthesized in the human or animal body and hence has to be injected or consumed through L-histidine rich food. L-histidine is required for formation of protein and for various metabolic reactions in the body. L-histidine is especially required for growing young children. It influences several growth-related actions in the body.
- L-histidine in wound healing were also conducted and it revealed that L- histidine had a prominent role in the regeneration of skin and improves regenerating skin- breaking strength in rats.
- hydrogel is prepared using amino acid with the tag of 9-fluorenylmethyl (Fmoc), Bolaamphiphilic, lipids, peptide form and with polymers like PMMA(Poly(methyl methacrylate)).
- fluorenylmethyl Frac
- Bolaamphiphilic Bolaamphiphilic
- lipids lipids
- peptide form and with polymers like PMMA(Poly(methyl methacrylate)
- organic solvents are required for preparing hydrogel.
- hydrogel is prepared using only distilled water and L-histidine without any organic solvent polymers.
- JP2000256365A teaches a water soluble silver complex having anti-microbial and antifungal property obtained by the reaction of silver oxide with 2-pyrrolidone-5-carboxylic acid or L-histidine.
- the resultant product is a milky white powder.
- PCT/JP2009/000337 is for a liquid composition comprising a silver L-histidine complex with germicidal activity, in which L-histidine co-ordinates with silver ion along with a hydrocarboxylic acid and polycarboxylic acid and their salts.
- JP2010198479A pertains to an anti-microbial composition containing a polyalcohol based anti-bacterial agent and silver based anti microbial agent, where a number of polyalcohol based anti-microbial agents have been claimed.
- JP2011195582A pertains to a composition having a silver amino acid complex. It also contains hydro-carboxylic acid and at least one member selected from polycarboxylic acid groups. It also contains glucuronic acid including citric acid groups.
- the said prior arts have certain limitations and cannot be used where gel form of the product is required. They do not teach the process of making hydrogel i.e. as a gel. The ingredients used in the present invention are also different from those mentioned in the prior art. The process of production is also totally different.
- the present invention pertains to L-histidine molecule based hydrogel, which has a high antimicrobial activity for domestic and industrial use, including in the health care industry.
- L-histidine molecule based hydrogel is prepared by this inventive process, which consists of four steps.
- the first step pertains to the preparation of L-histidine stock solution.
- the 2 nd step consists of preparation of silver nitrate stock solution. These two steps are performed simultaneously but separately.
- the 3 step pertains to the mixing of the two solutions prepared in step 1 and 2.
- the 4 th step is the final step which pertains to gelation from the above process, to obtain a metal organic coordinated compound in gel form.
- the detailed process is as described below.
- Proteins are natural polymers. They are derived from a-amino acids which are monomers that makeup the entire protein structure.
- Proteins are found in all living cells. They are the principal constituents of skin, muscle, tendons, ligaments, nerve cells, blood cells, enzymes, antibodies and many hormones. There are about 23 aminoacids found in proteins of which some of them are essential for the proper growth of young animals and children. These aminoacids cannot be synthesised by the animal/human body but have to be supported externally as a supplement. L-histidine is one such essential aminoacid.
- Step-1 The first step of this inventive process involves the dissolution of L-histidine in distilled water in the presence of sodium hydroxide (NaOH) which provides the alkaline pH medium.
- NaOH sodium hydroxide
- An alkaline pH medium is required to increase the formation of carboxylate ion which is required to enhance the dissociation of L-histidine in distilled water.
- the solution is then sonicated for 5 minutes.
- About 0.10 to 2 parts of L-histidine, which are a white color powder is dissolved in 9 to
- Step-2 In this step silver nitrate stock solution is prepared by dissolving 0.25 to 1 parts of silver nitrate (AgN0 3 ) which is a white color crystal, in 6 to 10 parts of water and then sonicating the solution for 5 minutes. Sonication is done to ensure complete dissolution of silver nitrate in distilled water. Within this time of 5 minutes, complete dissolution takes place.
- silver nitrate stock solution is prepared by dissolving 0.25 to 1 parts of silver nitrate (AgN0 3 ) which is a white color crystal, in 6 to 10 parts of water and then sonicating the solution for 5 minutes. Sonication is done to ensure complete dissolution of silver nitrate in distilled water. Within this time of 5 minutes, complete dissolution takes place.
- the L-histidine solution prepared in step-1 is mixed with the silver nitrate solution prepared in step-2 in the ratio of 1: 1. Constant stirring of the solution for 8 to 15 minutes does the mixing. The rate of stirring is maintained at 300 rpm during the said time. Here mixing by stirring is done and not sonications as there are any undissolved solids.
- Sodium hydroxide is used to increase the solubility of L-histidine in water. By the addition of sodium hydroxide, the pH of the solution goes up to 7.5 to 8. The solubility of L- histidine increases at high pH value. Any other monovalent non-toxic alkali metal hydroxides such as potassium hydroxide can also be used instead of sodium hydroxide. Sodium hydroxide is preferred to other said hydroxide because it is cost effective.
- the use of sodium hydroxide within the quantity specified in step-2 plays a critical role in the formation of a hydrogel. If the quantity of sodium hydroxide used is less than that specified in step-2 then no gel is formed and the resultant product is only a liquid form. Similarly if sodium hydroxide is used above quantity specified in step-2 then the resultant product will be in solid form and not in gel form.
- the hydroxyl ion such as in sodium hydroxide plays a critical role in the gel formation only when used in step 1 and not in step 3 or 2.
- the addition of the hydroxyl ion in step 1 is to ensure complete solubility of L-Histidine before it reacts with silver nitrate in step-3. Therefore, this aspect is a prime factor in the gel formation.
- the carboxylate ion in L-histidine has a hydrophobic aromatic region and a hydrophilic carboxylate end.
- This metal organic coordinated compound consists of one silver ion sandwiched between two L-histidine molecules. This acts like a monomer to form a polymer like structure. In the resultant reaction n-number of metal organic coordinated compounds, propagate to form a polymer like structure, where a silver ion is sandwiched between two L-histidine molecules.
- step 3 gelation is done, whereby the polymer like structure obtained in step-3 above is left undistributed for 15 hours at room temperature and normal atmospheric pressure.
- the polymer like structure undergoes rearrangement of the comprising metal organic coordinated compounds.
- the aromatic region of the L- histidine molecule in the said compound undergoes ⁇ - ⁇ stacking in the upper side as well as lower side and linear attachment on the other side with a silver ion in a sandwiched manner.
- This is due to the self-assembling of these said compounds leading to the formation of multiple thread-like nano-fibres of thickness varying from 185nm to 195nm. Therefore the self- assembling of the said compound and the resultant propagation of the thread like nano-fibers entrapping water molecules in between the nanofibre threads during the self-assembling of the nano-fiber threads leads to the formation of hydrogel in gel form.
- the color of the hydrogel obtained varies from black to transparent depending upon the quantity of L-histidine used in the range of 0.10 to 2 parts. If the quantity of L-histidine used is less than 0.10 parts then no gel is obtained and the resultant product is a turbid colloidal liquid. Similarly, if the quantity of L-histidine used is above 2 parts than the resultant product is turbid colloidal precipitate and not a gel. Further, if the quantity of L-histidine used is between 0.1 parts to 0.24 parts then the black color gel is obtained. Whereas if the quantity of L-histidine used in 0.25 to 2 parts then a transparent gel is obtained.
- Table- 1 illustrates the above. Varying the quantity of L-histidine:
- the use of silver nitrate in the said specified quantity also affects the hydrogel formation. If no silver nitrate is used then no gel is formed and no antimicrobial activity is obtained. If the quantity of silver nitrate used is less than 0.25 parts then the resultant product is colloidal and not a gel. Similarly, if the quantity of silver nitrate used is more than 1 part then the resultant product is a turbid precipitate and not a gel. The use of silver nitrate between 0.25 to 0.99 parts results in the formation of hydrogel in a transparent form. Whereas the use of silver nitrate in 1 part leads to the formation of a black gel.
- Table-2 illustrates the above. Varying the quantity of Silver nitrate:
- step-1 also directly affects the hydrogel formation as already detailed above.
- the hydrogel (referred to as, 'the product') thus obtained by the above-said the process has thermal, physical, chemical and biological properties, in particular antimicrobial properties.
- the said product has the fluorescence thermal reversibility of 30 to 9 minutes for use of silver nitrate in the specified quantity of 0.25 to 1 parts respectively.
- thermo gravimetric analyzer This analysis was done to determine the weight loss of the product and to thereby confirm that one of the ingredients is water.
- the product is heated in the analyzer at, 100 C.
- the thermo gravimetric data collected from the thermal reaction is compiled into a graph.
- the X-axis shows the temperature and Y- axis shows the initial mass of the product.
- This percentage is graphically represented by a TGA curve as in fig- 1.
- the data obtained reveals that when the product is heated, it losses about 95% of its weight, during temperature between 40 to 100°C. This is the evaporation range of water, thereby confirming that 95% of the content of the product is water.
- This analysis is done by using atomic force microscopy (AFM) to ascertain the surface morphology of the product.
- AFM atomic force microscopy
- the product with the specific composition of L-histidine 0.5g and silver nitrate 0.25g is used in the AFM imaging studies. Initially a small amount of the product was pickled on the Highly Ordered Pyrolytic Graphite (HOPG) substrate by using a needle. Then this substrate is dried at room temperature for about 48 hours without any interference of dust particles. After drying the substrate is mounted on the AFM sample holder. Then the distance between the substrate and AFM scanning tip is maintained constant during the imaging process. This analysis reveals the surface morphology of the product. The test revealed the 2D and 3D surface morphology of the product as in fig-3 & 4 showing multiple intertwined thread like nanofibers of thickness varying from 180nm to 195nm, on the surface.
- the product with the composition of silver nitrate 0.75 g and L-histidine 0.5g showed the shear stress of 92 Pa at the shear rate of 965 per second.
- the said product showed the viscosity of 5770 Pa.S.
- the product with the composition of silver nitrate 1.0 g and L-histidine 0.5g showed the shear stress of 61 Pa at the shear rate of 965 per second.
- the said product showed the viscosity of 1810 Pa.S.
- the product with the composition of silver nitrate 0.75 g and L-histidine 0.5g showed the shear stress of 88.3 Pa at the shear rate of 965 per second.
- the said product showed the viscosity of 6450 Pa.S.
- the product with the composition of silver nitrate 1.0 g and L-histidine 0.5g showed the shear stress of 69.8 Pa at the shear rate of 965 per second.
- the said product showed the viscosity of 1330 Pa.S.
- the product with the composition of silver nitrate 0.75 g and L- histidine 0.5g showed the shear stress of 96.5 Pa at the shear rate of 965 per second.
- the said product showed the viscosity of 27300 Pa.S.
- the product with the composition of silver nitrate 1.0 g and L-histidine 0.5g showed the shear stress of 55.6 Pa at the shear rate of 965 per second.
- the said product showed the viscosity of 19500 Pa.S.
- the product with the composition of L-histidine 0.75g and silver nitrate 0.25 g showed the shear stress of 10 Pa at the shear rate of 965 per second.
- the said product showed the viscosity of 649 Pa.S.
- the product with the composition of L-histidine 1.0 g and silver nitrate 0.25 g showed the shear stress of 8.33 Pa at the shear rate of 965 per second.
- the said product showed the viscosity of 287 Pa.S.
- the said product showed the viscosity of 1610 Pa.S
- the product with the composition of L-histidine 0.75g and silver nitrate 0.25 g (blue color in the graph) showed the shear stress of 5.04 Pa at the shear rate of 965 per second.
- the said product showed the viscosity of 6000 Pa.S.
- the product with the composition of L-histidine 1.0 g and silver nitrate 0.25 g (pink color in the graph) showed the shear stress of 4.17 Pa at the shear rate of 965 per second.
- the said product showed the viscosity of 4220 Pa.S.
- the product sample used for the said test is from 5 to 100 ⁇ g.
- Each serial number corresponding to one sample code which inturn pertains to specific quantity of silver nitrate and L-histidine used as shown in Table-5.
- Serial number 1 to 4 of Table-5 pertains to analysis using a fixed amount of L-histidine for varying the silver nitrate quantity.
- serial number 5, 6, 7 pertains to analysis using fixed amount of silver nitrate but by varying quantity of L-histidine.
- the antimicrobial analysis reveals that the inventive product has 97% reactivity to Escherichia coli (E.Coli) and Staphylococcus aureus (S. aureus) and 98% for other microbes.
- the following Table-7 illustrates the same: Antimicrobial activity of the product:
- a bacterial inoculum of 10 5 (Colony-forming unit) CFU / ml concentration of 24 h culture was kept as positive control.
- To the other set of said inoculum 1 ml of product sample was added.
- the sterile nutrient broth was kept as negative control/ blank. All the above-mentioned sets were incubated at 37°C for 24 hr. Post incubation Optical Density (OD) values were measured at 625 nm. Antibacterial activity was determined using the formula.
- % non-viable bacteria (l-(OD625 Sample/OD625 Control))* 100
- the product being in gel form can directly be used in healthcare as an anti-microbial as a disinfectant, wound cleaning and as a curative in view of its anti-microbial properties.
- the product gel has antimicrobial properties making it useful for varied activities where anti-microbial product that too in gel form is required.
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Abstract
L'invention concerne un hydrogel antimicrobien comprenant un nombre n de composés organiques métalliques coordonnés avec un ion argent pris en sandwich entre deux molécules de L-histidine, disposées de manière particulière, avec un empilement π-π du côté supérieur et inférieur et un ion argent pris en sandwich au milieu, prenant la forme de multiples nanofibres de type fil entrelacé d'épaisseur variable entre 180 nm et 195 nm, et avec plus de 95 % de molécules d'eau piégées et un peu d'alcalis dissous, donnant une structure de type polymère, présentant une activité antimicrobienne et des propriétés physiques et chimiques telles que décrites et revendiquées dans la description.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000002999A2 (fr) * | 1998-07-10 | 2000-01-20 | Encelle, Inc. | Milieu et matrice pour proliferation de cellules a long terme |
WO2009098850A1 (fr) * | 2008-02-08 | 2009-08-13 | Nippon Soda Co., Ltd. | Composition liquide comprenant un complexe histidine-argent, composition d'un agent germicide et procédé de stabilisation d'un complexe histidine-argent |
WO2012144475A1 (fr) * | 2011-04-18 | 2012-10-26 | 株式会社ネオス | Procédé de conservation du pouvoir bactéricide d'un complexe histidine-argent dans une solution comprenant des ions chlore, et composition antibactérienne liquide |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000002999A2 (fr) * | 1998-07-10 | 2000-01-20 | Encelle, Inc. | Milieu et matrice pour proliferation de cellules a long terme |
WO2009098850A1 (fr) * | 2008-02-08 | 2009-08-13 | Nippon Soda Co., Ltd. | Composition liquide comprenant un complexe histidine-argent, composition d'un agent germicide et procédé de stabilisation d'un complexe histidine-argent |
WO2012144475A1 (fr) * | 2011-04-18 | 2012-10-26 | 株式会社ネオス | Procédé de conservation du pouvoir bactéricide d'un complexe histidine-argent dans une solution comprenant des ions chlore, et composition antibactérienne liquide |
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