EP4366760A1 - Complex based on lactoferrin and/or a hydrolyzate thereof, process for producing the same, and uses thereof - Google Patents
Complex based on lactoferrin and/or a hydrolyzate thereof, process for producing the same, and uses thereofInfo
- Publication number
- EP4366760A1 EP4366760A1 EP22743589.8A EP22743589A EP4366760A1 EP 4366760 A1 EP4366760 A1 EP 4366760A1 EP 22743589 A EP22743589 A EP 22743589A EP 4366760 A1 EP4366760 A1 EP 4366760A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- lactoferrin
- hydrolyzate
- complex according
- complex
- pullulan
- 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
- 108010063045 Lactoferrin Proteins 0.000 title claims abstract description 56
- 102000010445 Lactoferrin Human genes 0.000 title claims abstract description 56
- CSSYQJWUGATIHM-IKGCZBKSSA-N l-phenylalanyl-l-lysyl-l-cysteinyl-l-arginyl-l-arginyl-l-tryptophyl-l-glutaminyl-l-tryptophyl-l-arginyl-l-methionyl-l-lysyl-l-lysyl-l-leucylglycyl-l-alanyl-l-prolyl-l-seryl-l-isoleucyl-l-threonyl-l-cysteinyl-l-valyl-l-arginyl-l-arginyl-l-alanyl-l-phenylal Chemical compound C([C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 CSSYQJWUGATIHM-IKGCZBKSSA-N 0.000 title claims abstract description 56
- 229940078795 lactoferrin Drugs 0.000 title claims abstract description 56
- 235000021242 lactoferrin Nutrition 0.000 title claims abstract description 56
- 238000000034 method Methods 0.000 title claims description 10
- 230000008569 process Effects 0.000 title claims description 7
- 239000000203 mixture Substances 0.000 claims abstract description 29
- 229920001218 Pullulan Polymers 0.000 claims abstract description 25
- 239000004373 Pullulan Substances 0.000 claims abstract description 25
- 235000019423 pullulan Nutrition 0.000 claims abstract description 25
- 230000002265 prevention Effects 0.000 claims abstract description 14
- 230000000699 topical effect Effects 0.000 claims abstract description 11
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 10
- 230000000968 intestinal effect Effects 0.000 claims abstract description 7
- 230000003612 virological effect Effects 0.000 claims abstract description 7
- 206010061218 Inflammation Diseases 0.000 claims abstract description 5
- 230000004054 inflammatory process Effects 0.000 claims abstract description 5
- 210000004400 mucous membrane Anatomy 0.000 claims abstract description 5
- 208000035143 Bacterial infection Diseases 0.000 claims abstract description 4
- 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 4
- 206010040840 Skin erosion Diseases 0.000 claims abstract description 3
- 208000036142 Viral infection Diseases 0.000 claims abstract description 3
- 230000007170 pathology Effects 0.000 claims abstract description 3
- 206010040882 skin lesion Diseases 0.000 claims abstract description 3
- 231100000444 skin lesion Toxicity 0.000 claims abstract description 3
- 231100000397 ulcer Toxicity 0.000 claims abstract description 3
- 208000025865 Ulcer Diseases 0.000 claims abstract 2
- 210000002229 urogenital system Anatomy 0.000 claims abstract 2
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 230000001580 bacterial effect Effects 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 4
- 239000002417 nutraceutical Substances 0.000 claims description 4
- 235000021436 nutraceutical agent Nutrition 0.000 claims description 4
- 206010017533 Fungal infection Diseases 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000001694 spray drying Methods 0.000 claims description 3
- 241000222122 Candida albicans Species 0.000 claims description 2
- 206010007134 Candida infections Diseases 0.000 claims description 2
- 206010046914 Vaginal infection Diseases 0.000 claims description 2
- 201000008100 Vaginitis Diseases 0.000 claims description 2
- 201000003984 candidiasis Diseases 0.000 claims description 2
- 210000001215 vagina Anatomy 0.000 claims description 2
- 208000010266 Aggressive Periodontitis Diseases 0.000 claims 1
- 201000006727 periodontosis Diseases 0.000 claims 1
- 230000003078 antioxidant effect Effects 0.000 abstract description 5
- 230000003385 bacteriostatic effect Effects 0.000 abstract description 4
- 230000005923 long-lasting effect Effects 0.000 abstract description 2
- FXYZDFSNBBOHTA-UHFFFAOYSA-N 2-[amino(morpholin-4-ium-4-ylidene)methyl]guanidine;chloride Chemical compound Cl.NC(N)=NC(=N)N1CCOCC1 FXYZDFSNBBOHTA-UHFFFAOYSA-N 0.000 abstract 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000002245 particle Substances 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 230000000845 anti-microbial effect Effects 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 229910052742 iron Inorganic materials 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 102000057297 Pepsin A Human genes 0.000 description 3
- 108090000284 Pepsin A Proteins 0.000 description 3
- 239000003125 aqueous solvent Substances 0.000 description 3
- 238000000889 atomisation Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 229940111202 pepsin Drugs 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 230000001790 virustatic effect Effects 0.000 description 3
- -1 viscosity regulators Substances 0.000 description 3
- 101000798100 Bos taurus Lactotransferrin Proteins 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 241000186660 Lactobacillus Species 0.000 description 2
- 101800004361 Lactoferricin-B Proteins 0.000 description 2
- 206010040943 Skin Ulcer Diseases 0.000 description 2
- 125000003275 alpha amino acid group Chemical group 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 108010038047 apolactoferrin Proteins 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 229940072440 bovine lactoferrin Drugs 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- CFFMZOZGXDAXHP-HOKBLYKWSA-N lactoferricin Chemical compound C([C@H](NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CSSC[C@@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CO)C(=O)N[C@H](C(N[C@H](C(=O)N1)[C@@H](C)O)=O)[C@@H](C)CC)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 CFFMZOZGXDAXHP-HOKBLYKWSA-N 0.000 description 2
- 239000002324 mouth wash Substances 0.000 description 2
- 229940051866 mouthwash Drugs 0.000 description 2
- 201000001245 periodontitis Diseases 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 229960001957 stomatological preparations Drugs 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 229940034610 toothpaste Drugs 0.000 description 2
- 239000000606 toothpaste Substances 0.000 description 2
- 239000002544 virustatic Substances 0.000 description 2
- 241000223678 Aureobasidium pullulans Species 0.000 description 1
- 208000001528 Coronaviridae Infections Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 208000006389 Peri-Implantitis Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000003082 abrasive agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 230000002882 anti-plaque Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000013060 biological fluid Substances 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
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- 230000008859 change Effects 0.000 description 1
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- 230000000536 complexating effect Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
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- 235000015872 dietary supplement Nutrition 0.000 description 1
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- 201000010099 disease Diseases 0.000 description 1
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- 238000004043 dyeing Methods 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
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- 235000003599 food sweetener Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000007970 homogeneous dispersion Substances 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000009878 intermolecular interaction Effects 0.000 description 1
- 230000010438 iron metabolism Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940039696 lactobacillus Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000009993 protective function Effects 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- BMVUIWJCUQSHLZ-YFZGBAIXSA-N sn-Glycero-3-phosphoinositol Chemical compound OC[C@@H](O)COP(O)(=O)OC1[C@H](O)[C@@H](O)C(O)[C@@H](O)[C@H]1O BMVUIWJCUQSHLZ-YFZGBAIXSA-N 0.000 description 1
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- 239000008107 starch Substances 0.000 description 1
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- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 210000001138 tear Anatomy 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- KDSWDGKIENPKLB-QJDQKFITSA-N verbascoside Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](OC(=O)CCC=2C=C(O)C(O)=CC=2)[C@@H](CO)O[C@@H](OCCC=2C=C(O)C(O)=CC=2)[C@@H]1O KDSWDGKIENPKLB-QJDQKFITSA-N 0.000 description 1
- QFRYQWYZSQDFOS-UHFFFAOYSA-N verbascoside Natural products CC1OC(COC2C(O)C(COC3OC(C(O)C(O)C3O)C(=O)O)OC(Oc4cc(O)cc5OC(=CC(=O)c45)c6ccc(O)c(O)c6)C2O)C(O)C(O)C1O QFRYQWYZSQDFOS-UHFFFAOYSA-N 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- FYGDTMLNYKFZSV-BYLHFPJWSA-N β-1,4-galactotrioside Chemical group O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@H](CO)O[C@@H](O[C@@H]2[C@@H](O[C@@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-BYLHFPJWSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/719—Pullulans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/01—Hydrolysed proteins; Derivatives thereof
- A61K38/012—Hydrolysed proteins; Derivatives thereof from animals
- A61K38/018—Hydrolysed proteins; Derivatives thereof from animals from milk
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
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- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/0063—Periodont
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
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- A61Q19/00—Preparations for care of the skin
Definitions
- the present invention relates to a complex based on lactoferrin and/or a hydrolyzate thereof, a process for its production, and uses thereof.
- Lactoferrin is an antimicrobial and iron-carrying glycoprotein, naturally present in various biological fluids of mammals, such as milk, saliva, tears. It is also present in neutrophil granulocytes, which are immune cells with defence functions against bacterial and fungal infections. Lactoferrin is considered a particularly useful product for its antioxidant, immunomodulatory and anti-infective properties.
- lactoferrin Several scientific papers have recently been published demonstrating the antiviral properties of lactoferrin. See for example the article by E. Campione et al, published in Int. J. Mol. Sci. 2020, 21(14), 4903; https;//doi.org/10.3390/ i ms21144903, where the protective effect exerted by lactoferrin in cases of coronavirus infections and inflammations is demonstrated, acting both as a natural barrier for respiratory and intestinal mucous membranes and to counteract disorders in iron metabolism due to viral colonisation.
- lactoferrin Through pepsin digestion of lactoferrin, it is possible to obtain peptides, which are commonly indicated as lactoferrin hydrolyzates or even, more simply, as lactoferricin which, although having a rather lower molecular weight with respect to the starting protein, contain the N-terminal sequence of lactoferrin and maintain the biological activity thereof; in some cases such activity is even reinforced.
- lactoferricin which, although having a rather lower molecular weight with respect to the starting protein, contain the N-terminal sequence of lactoferrin and maintain the biological activity thereof; in some cases such activity is even reinforced.
- lactoferricin and its antimicrobial, antiviral, antitumor and immunological properties are described.
- Patent application WO 2016/046108 describes a composition containing a lactoferrin hydrolyzate and glycerophosphoinositol or salts thereof and/or verbascoside or extracts that contain it, and the use thereof for the prevention and/or treatment of dermatological, otologic and stomatological inflammations and infections.
- Such composition can be applied for the treatment of different infections, especially in the veterinary field, which can cause diseases of the ears, skin or of the stomatological type.
- Lactoferrin and hydrolyzates thereof have not yet been widely used, mainly because of their poor stability and compatibility with excipients normally used in the pharmaceutical or para-pharmaceutical field (e.g. toothpaste, mouthwash, dietary supplements and the like). Lactoferrin and hydrolyzates thereof also have relatively low bioavailability when applied topically and are subject to oxidative degradation phenomena.
- the Applicant has therefore faced the problem of obtaining a lactoferrin and/or a hydrolyzate thereof in a physiologically acceptable form with high stability and bioavailability, so as to exert a bacteriostatic, virustatic and/or antioxidant action that is effective and long-lasting.
- the present invention thus relates to a complex between at least one lactoferrin and/or a hydrolyzate thereof with at least one pullulan.
- the present invention relates to a pharmaceutical or nutraceutical composition, which comprises said complex and at least one physiologically acceptable excipient.
- the pharmaceutical composition is for oral use or for topical use.
- the present invention relates to a composition for oral hygiene, which comprises said complex and at least one physiologically acceptable excipient.
- the present invention relates to a complex as defined above for use, by topical application, in the prevention or treatment of pathologies of dental apparatus, in particular for use in the prevention or treatment of periodontitis or perimplantitis .
- the present invention relates to a complex as defined above for use, by topical application, in the prevention or treatment of viral and/or bacterial infections of nasal, oral and/or ocular mucous membranes.
- This complex is indeed able to effectively exert a barrier effect on these mucous membranes, so as to inhibit viral and/or bacterial proliferation.
- the present invention relates to a complex as defined above for use, by topical application or oral administration, in the prevention or treatment of inflammations of urogenital apparatus, in particular of vagina, such as vaginosis or vaginitis of bacterial or viral origin, or yeast infections (candidiasis).
- the present invention relates to a complex as defined above for use, by oral administration, in the prevention or treatment of intestinal dismicrobism, i.e. for restoring the balance of the intestinal microbiome.
- the present invention relates to a complex as defined above for use, by topical application, in the treatment of skin lesions, in particular skin sores, ulcers or erosions.
- complex refers to an association between two different molecules in which intermolecular interactions (of electrostatic or van der Waals type) are established that modify release and biological activity characteristics of the molecules.
- pullulan interacts with lactoferrin and/or a hydrolyzate thereof so as to modulate their release over time, as thus to prolong their effectiveness.
- pullulan is a water-soluble polysaccharide formed by the repetition of maltotriose units, connected to each other by an -1,6 glycosidic bond, having the following structural formula:
- the pullulan has a number average molecular weight (M n) comprised between 30,000 and 800,000 g/mol, more preferably between 50,000 and 200,000 g/mol.
- M n number average molecular weight
- lactoferrin this can be of natural or synthetic origin, and can include different forms, both monomeric and oligomeric, possibly already bound to iron (ololactoferrin) or not bound to iron (apolactoferrin) .
- lactoferrin hydrolyzates they are products well known in the art, which can be prepared according to known techniques, in particular through treatment of a lactoferrin with a proteolitic enzyme, e.g. pepsin.
- the starting lactoferrin can be of natural or synthetic origin, and can include different forms, both monomeric and oligomeric, possibly already bound to iron (ololactoferrin) or not bound to iron (apolactoferrin) . Further details on lactoferrin hydrolyzates and on the preparation thereof are reported, for example, in the following articles: Wakabayashi H., et al, Current Pharm.
- the peptides resulting from lactoferrin proteolysis generally have a number of amino acid units from 5 to 30, preferably from 5 to 15.
- the weight ratio between lactoferrin and/or its hydrolyzate and pullulan is from 0.01:1 to 1:1, more preferably from 0.04:1 to 0.4:1.
- the complex according to the present invention comprises a mixture of at least one lactoferrin and at least one lactoferrin hydrolyzate, the weight ratio between said at least one lactoferrin and said at least one lactoferrin hydrolyzate being between 5:95 and 95:5, preferably between 50:50 and 90:10.
- the Applicant has found that the combination of a lactoferrin and/or a hydrolyzate thereof with a pullulan as defined above, which is belived to be in the form of a stable complex in which the lactoferrin and/or its hydrolyzate are incorporated into a pullulan matrix, allows to obtain an improved antibacterial and antioxidant effect compared to the lactoferrin and/or its derivative used alone at the same concentrations, which is exerted for longer periods of time, so that the effect is prolonged without having to repeat the application of the composition too often.
- pullulan is able to perform a protective function for lactoferrin and/or its derivative, so as to hinder or prevent any degradation of the protein structure due to, for instance, pH changes.
- a protective function for lactoferrin and/or its derivative so as to hinder or prevent any degradation of the protein structure due to, for instance, pH changes.
- Such variations may be caused, for example, by the addition of particular excipients suitable for particular formulations.
- the complex can be formulated to have a pH value from 4 to 7.
- the complex according to the present invention is preferably prepared through a process which comprises: preparing an aqueous solution of at least one pullulan; mixing the aqueous solution of at least one pullulan with at least one lactoferrin and/or a hydrolyzate thereof; subjecting the mixture thus obtained to a drying step.
- the concentration of pullulan in the aqueous solution is preferably comprised between 0.1% and 10% by weight, more preferably between 0.3% and 5% by weight.
- the aqueous solution may comprise water alone as a solvent or a mixture of water with a water-soluble organic solvent, in particular with glycerol.
- Mixing between the aqueous solution of pullulan and the lactoferrin and/or its hydrolyzate is preferably accomplished by gradual addition of the lactoferrin and/or its hydrolyzate to the solution until a homogeneous dispersion of the lactoferrin and/or its hydrolyzate in the aqueous phase is achieved.
- the mixing temperature is generally maintained between 15°C and 50°C.
- the drying phase is carried out by atomisation (spray drying), according to known techniques.
- atomisation spray drying
- the mixture between pullulan and lactoferrin and/or its hydrolyzate in aqueous solvent is introduced into a high-pressure atomiser, which comprises a distribution ring provided with a plurality of nozzles through which the mixture exits in the form of tiny droplets (spray) in order to promote heat exchange due to increase in specific surface area.
- the droplets come into contact with a hot air flow, which causes the aqueous solvent to evaporate very quickly, which is then removed in the form of vapour, while the solid components form dried particles, which generally have an average size (dm) varying from 20 pm to 200 pm, which depends mainly on sizes of the nozzle holes and characteristics of the atomiser.
- the dried particles generally contain an amount of residual moisture from 1% to 8% by weight, preferably from 3% to 5% by weight.
- the oral hygiene composition according to the present invention comprises, in addition to the complex, at least one physiologically acceptable excipient. This is in order to obtain a product for oral hygiene in different forms, for example toothpaste, mouthwash, gel, chewing gum, orodispersible tablet, gingival dyeing, and the like.
- composition according to the present invention can comprise ingredients commonly used in the field of dental hygiene products, such as for example: abrasive agents in particulate form, humectants, binders, thickeners, viscosity regulators, surfactants, sweeteners, flavourings, preservatives, anti-plaque agents, dyes, etc.
- ingredients commonly used in the field of dental hygiene products such as for example: abrasive agents in particulate form, humectants, binders, thickeners, viscosity regulators, surfactants, sweeteners, flavourings, preservatives, anti-plaque agents, dyes, etc.
- compositions which include the complex according to the present invention may be presented in different forms, such as tablets, capsules, powders, aqueous suspensions, syrups, suppositories, and contain the common excipients used for such products.
- nutraceutical compositions including the complex according to the present invention may be in the form of capsules, tablets, liquid formulations, bars, gels, powders, and the like.
- they can include water and other products with nutritional value such as carbohydrates, lipids, proteins, vitamins, minerals and the like.
- the complex in accordance with the present invention may be combined with other biologically active products in order to increase, for example, bacteriostatic and/or virustatic effect.
- nutraceutical compositions particularly suitable in the prevention or treatment of intestinal dismicrobism, they may contain, in addition to the complex, one or more microorganism strains useful for intestinal microbiome, such as Lactobacilli and the like (e.g. Lactobacillus easel).
- the complex may be formulated in the form of a suspension, gel, tincture, cream and the like, with excipients commonly used for such products.
- the formulation may possibly contain a pH adjuster, in order to guarantee a physiological pH, e.g. lactic acid which provides a pH around 3.4/4, typical of vaginal environment.
- a solution of a pullulan in water at a concentration of 1% by weight was prepared.
- the weight ratio of (lactoferrin + hydrolyzate) to pullulan was equal to 0.08:1.
- the weight ratio of lactoferrin to hydrolyzate was equal to 80:20.
- the resulting mixture was subjected to atomisation (spray drying) in order to obtain the complex between pullulan and (lactoferrin + hydrolyzate) (PLL - Example 1), in the form of particles with an average diameter (d 9 o) equal to 100 pm.
- the particles were dispersed in water at a concentration of either 1% by weight or 10% by weight.
- compositions were tested to verify antimicrobial activity with respect to E. coli.
- An amount equal to 9 g of the composition was added to 1 ml of inoculum of E. coli (ATCC 8739) so as to obtain a final charge of about 10 5 CFU.
- 0.5 ml of the suspension was taken to carry out plate count (surface spatulation method). Percentage variation of the bacterial load was therefore determined with respect to the initial one.
- the PLL complex both in 1% solution and in 10% solution, has an antibacterial activity that grows more slowly but is prolonged over time and remains at higher values even 24 hours after application, compared to the LL mixture.
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IT102021000018008A IT202100018008A1 (it) | 2021-07-08 | 2021-07-08 | Complesso a base di lattoferrina e/o un suo idrolizzato, processo di produzione dello stesso, e relativi usi. |
PCT/IB2022/056274 WO2023281430A1 (en) | 2021-07-08 | 2022-07-07 | Complex based on lactoferrin and/or a hydrolyzate thereof, process for producing the same, and uses thereof |
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