BR102020005876A2 - PHARMACEUTICAL COMPOSITION BASED ON METAL IONS - Google Patents
PHARMACEUTICAL COMPOSITION BASED ON METAL IONS Download PDFInfo
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- silver
- pharmaceutical composition
- metal ions
- ions
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- 229910021645 metal ion Inorganic materials 0.000 title claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 35
- 229910052709 silver Inorganic materials 0.000 claims description 12
- 239000004332 silver Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- -1 silver ions Chemical class 0.000 claims description 8
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 8
- ONDPHDOFVYQSGI-UHFFFAOYSA-N zinc nitrate Chemical compound [Zn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ONDPHDOFVYQSGI-UHFFFAOYSA-N 0.000 claims description 8
- 229940071575 silver citrate Drugs 0.000 claims description 6
- QUTYHQJYVDNJJA-UHFFFAOYSA-K trisilver;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Ag+].[Ag+].[Ag+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QUTYHQJYVDNJJA-UHFFFAOYSA-K 0.000 claims description 6
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 claims description 5
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 4
- 150000001455 metallic ions Chemical class 0.000 claims description 3
- WGIWBXUNRXCYRA-UHFFFAOYSA-H trizinc;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Zn+2].[Zn+2].[Zn+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O WGIWBXUNRXCYRA-UHFFFAOYSA-H 0.000 claims description 2
- 229940068475 zinc citrate Drugs 0.000 claims description 2
- 235000006076 zinc citrate Nutrition 0.000 claims description 2
- 239000011746 zinc citrate Substances 0.000 claims description 2
- 210000004027 cell Anatomy 0.000 abstract description 12
- 241001465754 Metazoa Species 0.000 abstract description 6
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 6
- 229940121375 antifungal agent Drugs 0.000 abstract description 4
- 210000000987 immune system Anatomy 0.000 abstract description 4
- 238000010521 absorption reaction Methods 0.000 abstract description 3
- 230000000843 anti-fungal effect Effects 0.000 abstract description 3
- 230000000840 anti-viral effect Effects 0.000 abstract description 3
- 239000002738 chelating agent Substances 0.000 abstract description 3
- 230000035755 proliferation Effects 0.000 abstract description 3
- 230000002195 synergetic effect Effects 0.000 abstract description 3
- 210000002865 immune cell Anatomy 0.000 abstract description 2
- 210000004698 lymphocyte Anatomy 0.000 abstract description 2
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 7
- FOIXSVOLVBLSDH-UHFFFAOYSA-N Silver ion Chemical compound [Ag+] FOIXSVOLVBLSDH-UHFFFAOYSA-N 0.000 description 6
- 241000282412 Homo Species 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 241000700605 Viruses Species 0.000 description 3
- 230000000845 anti-microbial effect Effects 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 206010006326 Breath odour Diseases 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000002730 additional effect Effects 0.000 description 2
- 239000004599 antimicrobial Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002484 inorganic compounds Chemical class 0.000 description 2
- 229910010272 inorganic material Inorganic materials 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-L 2-(carboxymethyl)-2-hydroxysuccinate Chemical compound [O-]C(=O)CC(O)(C(=O)O)CC([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-L 0.000 description 1
- FZIPCQLKPTZZIM-UHFFFAOYSA-N 2-oxidanylpropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O FZIPCQLKPTZZIM-UHFFFAOYSA-N 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 208000001840 Dandruff Diseases 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000001398 Granzyme Human genes 0.000 description 1
- 108060005986 Granzyme Proteins 0.000 description 1
- 206010053759 Growth retardation Diseases 0.000 description 1
- 208000032139 Halitosis Diseases 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010022971 Iron Deficiencies Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- 229910021607 Silver chloride Inorganic materials 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 102100031988 Tumor necrosis factor ligand superfamily member 6 Human genes 0.000 description 1
- 108050002568 Tumor necrosis factor ligand superfamily member 6 Proteins 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- FNBULQHGNNELGY-UHFFFAOYSA-K [Ag+3].C(CC(O)(C(=O)[O-])CC(=O)[O-])(=O)[O-] Chemical class [Ag+3].C(CC(O)(C(=O)[O-])CC(=O)[O-])(=O)[O-] FNBULQHGNNELGY-UHFFFAOYSA-K 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 229940045985 antineoplastic platinum compound Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229940064004 antiseptic throat preparations Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 150000001622 bismuth compounds Chemical class 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- XEYBHCRIKKKOSS-UHFFFAOYSA-N disodium;azanylidyneoxidanium;iron(2+);pentacyanide Chemical compound [Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].[O+]#N XEYBHCRIKKKOSS-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000005989 gallbladder dysfunction Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 231100000001 growth retardation Toxicity 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 238000007210 heterogeneous catalysis Methods 0.000 description 1
- 238000007172 homogeneous catalysis Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 244000000056 intracellular parasite Species 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- XKLJHFLUAHKGGU-UHFFFAOYSA-N nitrous amide Chemical compound ON=N XKLJHFLUAHKGGU-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229930192851 perforin Natural products 0.000 description 1
- 150000003058 platinum compounds Chemical class 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 235000019624 protein content Nutrition 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 210000003935 rough endoplasmic reticulum Anatomy 0.000 description 1
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 1
- 229960003600 silver sulfadiazine Drugs 0.000 description 1
- UEJSSZHHYBHCEL-UHFFFAOYSA-N silver(1+) sulfadiazinate Chemical compound [Ag+].C1=CC(N)=CC=C1S(=O)(=O)[N-]C1=NC=CC=N1 UEJSSZHHYBHCEL-UHFFFAOYSA-N 0.000 description 1
- 229940083618 sodium nitroprusside Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000004753 textile Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000003253 viricidal effect Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
composição farmacêutica à base de íons metálicos. é descrita uma composição farmacêutica que compreende a associação sinérgica de íons metálicos e ácido cítrico, formando complexos hidrossolúveis, onde o íon metálico é envolvido por ligações covalentes do agente quelante, obtendo resultados mais eficazes de absorção pelas células e biodisponibilidade, atuando no sistema imunológico mediante a proliferação de linfócitos t e inúmeras outras células imunológicas e apresentando, adicionalmente, propriedades antifúngicas, antivirais e antibactericidas, potencialmente útil para a administração oral a humanos e animais.pharmaceutical composition based on metal ions. a pharmaceutical composition is described that comprises the synergistic association of metal ions and citric acid, forming water-soluble complexes, where the metal ion is involved by covalent bonds of the chelating agent, obtaining more effective results of absorption by cells and bioavailability, acting on the immune system through proliferation of lymphocytes and numerous other immune cells and additionally having antifungal, antiviral and antibacterial properties, potentially useful for oral administration to humans and animals.
Description
[01] A presente patente de invenção descreve uma composição farmacêutica que compreende a associação sinérgica de íons metálicos e ácido cítrico, formando complexos hidrossolúveis, onde o íon metálico é envolvido por ligações covalentes do agente quelante, obtendo resultados mais eficazes de absorção pelas células e biodisponibilidade, atuando no sistema imunológico mediante a proliferação de linfócitos T e inúmeras outras células imunológicas e apresentando, adicionalmente, propriedades antifúngicas, antivirais e antibactericidas, potencialmente útil para a administração oral a humanos e animais.[01] The present invention patent describes a pharmaceutical composition that comprises the synergistic association of metallic ions and citric acid, forming water-soluble complexes, where the metallic ion is involved by covalent bonds of the chelating agent, obtaining more effective results of absorption by the cells and bioavailability, acting on the immune system through the proliferation of T lymphocytes and countless other immune cells and presenting, in addition, antifungal, antiviral and antibacterial properties, potentially useful for oral administration to humans and animals.
[02] Os íons metálicos são necessários para muitas das funções vitais do organismo humano. A ausência de alguns deles pode ocasionar sérias doenças, tais como: anemia, por deficiência de ferro; retardamento do crescimento de crianças, por falta de zinco; e má formação óssea em crianças, por falta de cálcio.[02] Metal ions are necessary for many of the vital functions of the human body. The absence of some of them can cause serious diseases, such as: anemia, due to iron deficiency; growth retardation in children due to lack of zinc; and poor bone formation in children, due to lack of calcium.
[03] As atividades exercidas por íons metálicos nos meios biológicos têm estimulado a pesquisa e o desenvolvimento de compostos inorgânicos como agentes terapêuticos. Devido ao sucesso dos compostos de platina no tratamento do câncer, muitos pesquisadores têm direcionado esforços no sentido de desenvolver novas drogas à base de metais e, como consequência, atualmente há vários compostos inorgânicos sendo utilizados na clínica médica, dentre os quais podemos citar os complexos de ouro, empregados no tratamento da artrite reumatoide; o nitroprussiato de sódio, um complexo de ferro(III) eficaz no tratamento da hipertensão; o carbonato de lítio, que tem ação antidepressiva; a sulfadiazina de prata, que previne e trata infecções em pacientes queimados e os compostos de bismuto utilizados na erradicação do Helicobacter pylori [Cohen, S. M.; Curr. Op. Chem. Biol. 2007, 11, 115.], [Fricker, S. P.; Dalton Trans. 2007, 43, 4903;Rodrigues, M. A.; Ruggiero, R.; Guerra, W.; Bol. SPQ 2009, 115, 25; Orvig, C.; Abrams, M. J.; Chem. Rev. 1999, 99, 2201; Garoufis, A.; Hadjikakou, S. K.; Hadjiliadis, N.; Coord. Chem. Rev. 2009, 253, 1384. ] e [Bruijnincx, P. C. A.; Sadler, P. J.; Curr. Op. Chem. Biol. 2008, 12, 197.].[03] The activities exerted by metal ions in biological media have stimulated the research and development of inorganic compounds as therapeutic agents. Due to the success of platinum compounds in the treatment of cancer, many researchers have directed efforts to develop new drugs based on metals and, as a consequence, there are currently several inorganic compounds being used in clinical medicine, among which we can mention the complexes gold, used in the treatment of rheumatoid arthritis; sodium nitroprusside, an iron(III) complex effective in the treatment of hypertension; lithium carbonate, which has antidepressant action; silver sulfadiazine, which prevents and treats infections in burn patients, and bismuth compounds used in the eradication of Helicobacter pylori [Cohen, S. M.; Curr. Op. Chem. Biol. 2007, 11, 115.], [Fricker, S.P.; Dalton Trans. 2007, 43, 4903;Rodrigues, M.A.; Ruggiero, R.; Guerra, W.; ball SPQ 2009, 115, 25; Orvig, C.; Abrams, M.J.; Chem. Rev. 1999, 99, 2201; Garoufis, A.; Hadjikakou, S.K.; Hadjiliadis, N.; coordinate Chem. Rev. 2009, 253, 1384.] and [Bruijnincx, P.C.A.; Sadler, P.J.; Curr. Op. Chem. Biol. 2008, 12, 197.].
[04] De acordo com artigo da Faculdade Médica da Universidade de Aachen, na Alemanha, os íons de zinco têm a capacidade de estimular a proliferação de linfócitos T.[04] According to an article from the Medical Faculty of the University of Aachen, Germany, zinc ions have the ability to stimulate the proliferation of T lymphocytes.
[05] O linfócito T citotóxico, CD8+, tem como função principal a eliminação de células infectadas por parasitas intracelulares, nominalmente os vírus. Dentro dessas células, a produção de proteínas não pertencentes ao indivíduo são, em parte, processadas pelo proteassoma, produzindo peptídeos exógenos, que, após envio ao Retículo Endoplasmático Rugoso, com auxílio da proteína TAP, são expostos na parte de fora da célula. Ao reconhecer um antígeno como não próprio, o linfócito citotóxico libera grânulos contendo perforinas e granzimas que causam dano direto às células adjacentes, além de fatores como o ligante de Fas e TNFα que induzem apoptose na célula alvo, prevenindo o espalhamento da infecção [Roitt, I., Brostoff, J., Maled, D; Immunology, Sixth edition, Mosby, 2001].[05] The cytotoxic T lymphocyte, CD8+, has as its main function the elimination of cells infected by intracellular parasites, namely viruses. Inside these cells, the production of proteins not belonging to the individual are, in part, processed by the proteasome, producing exogenous peptides, which, after being sent to the Rough Endoplasmic Reticulum, with the aid of the TAP protein, are exposed outside the cell. Upon recognizing an antigen as non-self, the cytotoxic lymphocyte releases granules containing perforins and granzymes that cause direct damage to adjacent cells, in addition to factors such as the Fas ligand and TNFα that induce apoptosis in the target cell, preventing the spread of infection [Roitt, I., Brostoff, J., Maled, D; Immunology, Sixth edition, Mosby, 2001].
[06] Em 2016 pesquisadores da Holanda e da Noruega usaram células T do sistema imunológico de um doador saudável e constataram o ataque ao câncer de um paciente, o experimento deu resultados e as células T foram capazes de reconhecer as células anômalas (cancerígenas) [Stronen, Erlend; Mireille (19 de maio de 2016). «Targeting of cancer neoantigens with donor-derived T cell receptor repertoires». Science (em inglês): aaf2288. ISSN 0036-8075. PMID 27198675. doi:10.1126/science.aaf2288].[06] In 2016 researchers from the Netherlands and Norway used T cells from the immune system from a healthy donor and found a patient's cancer attack, the experiment gave results and the T cells were able to recognize the abnormal (cancerous) cells [06] Stronen, Erlend; Mireille (May 19, 2016). "Targeting cancer neoantigens with donor-derived T cell receptor repertoires". Science: aaf2288. ISSN 0036-8075. PMID 27198675. doi:10.1126/science.aaf2288].
[07] Compostos contendo prata vêm sendo investigados, uma vez que, na concentração aplicável, os íons de prata não exibem toxicidade e atividade carcinogênica [Stillman MJ, Presta A, Gui Z, Jiang DT. Spectroscopic studies of copper, silver and gold-metallothioneins. Metal-Based Drugs. 1994;1(5-6):375-394].[07] Compounds containing silver have been investigated since, at the applicable concentration, silver ions do not exhibit toxicity and carcinogenic activity [Stillman MJ, Presta A, Gui Z, Jiang DT. Spectroscopic studies of copper, silver and gold-metallothioneins. Metal-Based Drugs. 1994;1(5-6):375-394].
[08] A prata é um metal conhecido pela sua ampla atividade biocida contra bactérias Gram-positivas e Gram-negativas, fungos, protozoários e certos vírus, incluindo espécies resistentes a antibióticos. Segundo Monteiro et al. (MONTEIRO, D. R. et al. The growing importance of materials that prevent microbial adhesion: antimicrobial effect of medical devices containing silver. International Journal of Antimicrobial Agents, v. 34, p. 103-110, 2009.), a prata pode ser usada na redução de infecções em áreas queimadas, para prevenir a colonização bactericida sobre dispositivos médicos, assim como nas fábricas têxteis e para o tratamento de água. A prata, como um agente antisséptico, tem sido eficaz em uma variedade de materiais, incluindo vidro, titânio e polímeros.[08] Silver is a metal known for its broad biocidal activity against Gram-positive and Gram-negative bacteria, fungi, protozoa and certain viruses, including antibiotic-resistant species. According to Monteiro et al. (MONTEIRO, DR et al. The growing importance of materials that prevent microbial adhesion: antimicrobial effect of medical devices containing silver. International Journal of Antimicrobial Agents, v. 34, p. 103-110, 2009.), silver can be used in reducing infections in burnt areas, to prevent bactericidal colonization on medical devices, as well as in textile factories and for water treatment. Silver, as an antiseptic agent, has been effective on a variety of materials, including glass, titanium, and polymers.
[09] Um estudo de 2013 publicado na revista Biomaterials demonstrou que a prata possui propriedades de combate ao câncer, especificamente no tratamento da leucemia.[09] A 2013 study published in the journal Biomaterials demonstrated that silver has cancer-fighting properties, specifically in the treatment of leukemia.
[010] Um estudo de 2010 publicado no Journal of Clinical and Experimental Research concluiu: “a prata coloidal pode ser um potencial agente alternativo para a terapia de tratamento do câncer de mama em humanos”. Estudos também têm demonstrado benefícios na luta contra o câncer cervical, câncer de fígado e câncer de pulmão.[010] A 2010 study published in the Journal of Clinical and Experimental Research concluded, “colloidal silver may be a potential alternative agent for human breast cancer treatment therapy.” Studies have also shown benefits in fighting cervical cancer, liver cancer and lung cancer.
[011] De acordo com a publicação Colloidal Silver, The Natural Antibiotic, de 2013, a prata coloidal também tem sido usada com sucesso para tratar diarréia, excesso de gases, disfunção da vesícula biliar, mau hálito (Halitose), síndrome do intestino irritável (SCI), conjuntivite, asma, resfriado, acne, queimaduras, caspa e eczema.[011] According to the 2013 publication Colloidal Silver, The Natural Antibiotic, colloidal silver has also been used successfully to treat diarrhea, excess gas, gallbladder dysfunction, bad breath (Halitosis), irritable bowel syndrome (SCI), conjunctivitis, asthma, cold, acne, burns, dandruff and eczema.
[012] Astruc et al. (Astruc et al. Nanoparticles as recycable catalysis: the frontier between homogeneous and heterogeneous catalysis. V. 44, p. 7852-7872, 2005) descrevem que as nanopartículas de prata apresentam diversas aplicações como antissépticos, antibacterianos, antifúngicos, entre outros.[012] Astruc et al. (Astruc et al. Nanoparticles as recyclable catalysis: the frontier between homogeneous and heterogeneous catalysis. V. 44, p. 7852-7872, 2005) describe that silver nanoparticles have several applications as antiseptics, antibacterials, antifungals, among others.
[013] O mecanismo de ação das nanopartículas de prata não é completamente esclarecido. No entanto, sua atuação resulta em inibição do crescimento e perda da infectividade, ao impedir os processos que ocorrem na superfície e no interior da célula dos microrganismos. A diminuta dimensão da nanoprata é essencial para sua melhor penetração à membrana celular, podendo assim, prejudicar o funcionamento celular, retardando a velocidade de suas atividades vitais, podendo então, ocasionar danos celulares (SHARMA, V. K.; YNGARD, R. A.; e LIN, Y. Silver nanoparticles: Green synthesis and their antimicrobial activities. Chemistry Department, Florida Institute of Technology, 150 West University Boulevard, Melbourne, Florida 32901, USA, v. 154, setembro, 2008. P. 83-96.).[013] The mechanism of action of silver nanoparticles is not completely understood. However, its action results in growth inhibition and loss of infectivity, by preventing the processes that occur on the surface and inside the cell of microorganisms. The tiny dimension of nanosilver is essential for its better penetration into the cell membrane, which may impair cell functioning, slowing down the speed of its vital activities, and thus causing cell damage (SHARMA, VK; YNGARD, RA; and LIN, Y Silver nanoparticles: Green synthesis and their antimicrobial activities. Chemistry Department, Florida Institute of Technology, 150 West University Boulevard, Melbourne, Florida 32901, USA, v. 154, September, 2008. P. 83-96.).
[014] As nanopartículas de prata são capazes de invadir as células, interagindo com ligações dissulfeto dos conteúdos de glicoproteína/proteína de microrganismos tais como vírus, bactérias e fungos, ou seja, é nociva às proteínas, e consequentemente afeta negativamente o DNA (dificulta sua replicação) e o RNA (impossibilita sua transcrição) (LARA, H. H.; GARZA-TREVINO E. N.; IXTEPAN-TURRENT L.; e SINGH D. K.; Silver nanoparticles are broad-spectrum bactericidal and virucidal compounds. v. 9, agosto, 2011).[014] Silver nanoparticles are capable of invading cells, interacting with disulfide bonds of the glycoprotein/protein contents of microorganisms such as viruses, bacteria and fungi, that is, it is harmful to proteins, and consequently negatively affects DNA (impairs replication) and RNA (impairs its transcription) (LARA, HH; GARZA-TREVINO EN; IXTEPAN-TURRENT L.; and SINGH DK; Silver nanoparticles are broad-spectrum bactericidal and virucidal compounds. v. 9, August, 2011) .
[015] A associação de íons metálicos, mais especificamente citrato de prata e ácido cítrico, é relatada por DJOKIC [DJOKIC, Stojan. Synthesis and Antimicrobial Activity of Silver Citrate Complexes. doi: 10.1155/2008/436458] com o objetivo de alcançar a solubilidade do citrato de prata que, na sua forma livre, é minimamente solúvel em água, conforme descrito na patente US6197814 que ensina que, sob condições fisico-químicas normais, 1 parte de citrato de prata é solúvel em 3500 partes de água, o que corresponde a 285 ppm de íon de prata na solução.[015] The association of metal ions, more specifically silver citrate and citric acid, is reported by DJOKIC [DJOKIC, Stojan. Synthesis and Antimicrobial Activity of Silver Citrate Complexes. doi: 10.1155/2008/436458] with the objective of achieving the solubility of silver citrate which, in its free form, is minimally soluble in water, as described in patent US6197814 which teaches that, under normal physicochemical conditions, 1 part of silver citrate is soluble in 3500 parts of water, which corresponds to 285 ppm of silver ion in the solution.
[016] O ácido cítrico ou citrato de hidrogênio, de nome oficial ácido 2-hidroxi-1, 2,3-propanotricarboxílico, é um ácido orgânico fraco, que pode ser encontrado nos citrinos. A acidez do ácido cítrico é devida aos três grupos carboxilas -COOH que podem perder um próton em soluções. Como consequência, forma-se um íon citrato que pode quelar íons metálicos, complexando e inativando os íons metálicos e neutralizando sua ação tóxica.[016] Citric acid or hydrogen citrate, officially called 2-hydroxy-1, 2,3-propanetricarboxylic acid, is a weak organic acid that can be found in citrus fruits. The acidity of citric acid is due to the three carboxyl groups -COOH that can lose a proton in solutions. As a consequence, a citrate ion is formed that can chelate metal ions, complexing and inactivating the metal ions and neutralizing their toxic action.
[017] O estado da técnica revela o documento PI0513520 que descreve uma composição quelante de íon metálico para aplicação tópica em humanos e animais para o tratamento de vários estados de queimadura.[017] The state of the art discloses document PI0513520 which describes a metal ion chelating composition for topical application in humans and animals for the treatment of various burn conditions.
[018] No entanto, o estado da técnica não descreve nem sugere uma composição para administração oral a humanos e animais onde, a associação sinérgica de íons metálicos e ácido cítrico, gera a formação de íons citratos, formando complexos hidrossolúveis, onde o íon metálico é envolvido por ligações covalentes do agente quelante, obtendo resultados mais eficazes de absorção pelas células e biodisponibilidade, atuando no sistema imunológico e apresentando, adicionalmente, propriedades antifúngicas, antivirais e antibactericidas. Adicionalmente, conforme a literatura técnica, o ácido cítrico, afora permitir a solubilidade do citrato de prata, apresenta características anti-oxidantes para bloquear a transformação de nitrato em nitrito no estômago de humanos e animais, eliminando o risco de conversão em nitrosamina e dificultando a conversão em cloreto de prata no suco gastrico.[018] However, the state of the art does not describe or suggest a composition for oral administration to humans and animals where the synergistic association of metal ions and citric acid generates the formation of citrate ions, forming water-soluble complexes, where the metal ion it is involved by covalent bonds of the chelating agent, obtaining more effective results of absorption by cells and bioavailability, acting on the immune system and presenting, in addition, antifungal, antiviral and antibacterial properties. Additionally, according to the technical literature, citric acid, in addition to allowing the solubility of silver citrate, has antioxidant characteristics to block the transformation of nitrate into nitrite in the stomach of humans and animals, eliminating the risk of conversion to nitrosamine and making it difficult to conversion to silver chloride in gastric juice.
[019] A composição farmacêutica à base de íons metálicos, objeto da presente patente de invenção, compreende a diluição em soluto de 0,1 a 50 ppm de íons de zinco, de 0,1 a 500 ppm de íons de prata e ácido cítrico (ácido 2-hidroxi-1,2,3-propanotricarboxílico) entre 1,0 a 500 ppm, provendo uma composição para administração oral a humanos e animais.[019] The pharmaceutical composition based on metal ions, object of the present invention patent, comprises the dilution in solute of 0.1 to 50 ppm of zinc ions, from 0.1 to 500 ppm of silver ions and citric acid (2-hydroxy-1,2,3-propanetricarboxylic acid) between 1.0 to 500 ppm, providing a composition for oral administration to humans and animals.
[020] Os íons de zinco são selecionados dentre nitrato de zinco e citrato de zinco, isoladamente ou em associação.[020] Zinc ions are selected from zinc nitrate and zinc citrate, alone or in association.
[021] Os íons de prata são selecionados dentre nitrato de prata e citrato de prata, isoladamente ou em associação.[021] Silver ions are selected from silver nitrate and silver citrate, alone or in association.
[022] Preferentemente, o ácido cítrico é misturado em etapa posterior à mistura dos íons metálicos, para conversão total ou parcial de íons nitratos para íons citratos.[022] Preferably, citric acid is mixed in a subsequent step to the mixture of metal ions, for total or partial conversion of nitrate ions to citrate ions.
[023] Um exemplo de formulação preferida inclui 70 ppm de nitrato de prata, 0,1 ppm de nitrato de zinco e 30 ppm de ácido cítrico diluídos em água purificada ou destilada em q.s.p para a dissolução em 1 litro.[023] An example of a preferred formulation includes 70 ppm silver nitrate, 0.1 ppm zinc nitrate and 30 ppm citric acid diluted in purified or distilled water q.s.p. for dissolution in 1 liter.
[024] Um segundo exemplo de formulação preferida compreende 200 ppm de nitrato de prata, 10 ppm de nitrato de zinco e 200 ppm de ácido cítrico diluídos em água purificada ou destilada em q.s.p. para a dissolução em 1 litro.[024] A second preferred formulation example comprises 200 ppm silver nitrate, 10 ppm zinc nitrate and 200 ppm citric acid diluted in purified or distilled water q.s.p. for dissolution in 1 liter.
[025] A dosagem recomendada para a formulação mais diluída varia de uma a duas doses diárias de 10 ml da solução diluída em 200 ml de água filtrada, sendo a posologia dependente da enfermidade, podendo ser administrada por até 15 dias.[025] The recommended dosage for the most diluted formulation varies from one to two daily doses of 10 ml of the solution diluted in 200 ml of filtered water, the dosage being dependent on the disease, and can be administered for up to 15 days.
Claims (3)
- a) de 0,1 a 50 ppm de íons de zinco;
- b) de 0,1 a 500 ppm de íons de prata
- c) entre 1 a 500 ppm de ácido cítrico;
- d) água em q.s.p.
- a) from 0.1 to 50 ppm of zinc ions;
- b) from 0.1 to 500 ppm of silver ions
- c) from 1 to 500 ppm citric acid;
- d) water in qsp
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