WO2012035364A1 - Solution stabilisée d'acide ortho-silicique, sa préparation et son utilisation - Google Patents

Solution stabilisée d'acide ortho-silicique, sa préparation et son utilisation Download PDF

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WO2012035364A1
WO2012035364A1 PCT/HR2011/000036 HR2011000036W WO2012035364A1 WO 2012035364 A1 WO2012035364 A1 WO 2012035364A1 HR 2011000036 W HR2011000036 W HR 2011000036W WO 2012035364 A1 WO2012035364 A1 WO 2012035364A1
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silicic acid
ortho
solution
acid
carnitine
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PCT/HR2011/000036
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English (en)
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Ivica Cepanec
Antonio Lelas
Marijan Ramljak
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Creogen D.O.O.
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Publication of WO2012035364A1 publication Critical patent/WO2012035364A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • 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
    • A61K31/695—Silicon compounds
    • 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
    • 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
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/20—Halogens; Compounds 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
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/24—Phosphorous; Compounds 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
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/25—Silicon; Compounds 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
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/345—Alcohols containing more than one hydroxy group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/42—Amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • 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
    • A61K8/60—Sugars; Derivatives 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
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/86—Polyethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q3/00—Manicure or pedicure preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

  • the present invention relates to a stabilized solution of ortho- silicic acid (H 4 Si0 4 ) , which is used as nutritional and therapeutic source of silicon (Si) in nutrition, medicine, cosmetic, veterinary and agriculture.
  • the present invention solves the technical problem of stabilization of ortho-silicic acid (H 4 Si0 4 ) solution, and procedure for production of such stabilized solution.
  • the solution is consisting of:
  • X CI, H 2 P0 4 , HS0 4 , N0 3 , CH 3 S0 3 , C fi H 5 S0 3 , 1 , -CH 3 C 6 H 4 S0 3 from 7-40% w/w;
  • auxiliary stabilizer of H 4 Si0 4 selected from the group comprising glycerol, 1 , 2-propylene glycol, d-panthenol, glucosamine, or their mixtures, from 10-50% w/w; and
  • diluent selected from the group consisting of purified water, ethanol or their mixtures, in amounts of up to 100% w/w of overall formulation.
  • Silicon (Si) is important biogenic microelement which exhibits several roles in human and animal organism:
  • Jugdaohsingh Orthosilicic acid stimulates collagen type I synthesis and osteoblast-like cells in vitro, Bone 32 (2003) 127; S. Spripanyakorn, R. Jungdaohsingh, R. P. H. Thompson, J. J. Powell: Dietary silicon and bone health, Nutr. Bull. 30 (2005) 222];
  • ortho-silicic acid H 4 Si0 4
  • silicic acid in its monomeric form, ortho-silicic acid (H Si0 4 ) is not stable, but at higher concentrations undergoes polymerization yielding dimeric (H 6 Si 2 0 7 ) , trimeric (H 8 Si 3 Oi 0 ) , as well as linear unbranched oligomers (SI) which are all water soluble.
  • Linear polymers of silicic acid (SI) undergo further polymerization giving tridimensional, branched polymers (S2) which are of very low water solubility and give opalescent gel.
  • the process of polymerization proceeds further with generation of hydrated silicon dioxide (silica gel; Si0 2 -xH 2 0) .
  • the course of polymerization of silicic acid is given in Scheme 1, at the end of the specification.
  • Beside monomeric ortho-silicic acid (H Si0 4 ) biologically available forms are also its lower oligomers that are soluble in water; they release starting H 4 Si0 by hydrolysis (oligomerization is reversible) . In other words, at certain concentrations, an equilibrium between monomeric ortho-silicic acid and its lower oligomers is established.
  • Branched polymers of silicic acid are not biologically available [H. Yokoi, S. Enomoto: Effect of degree of polymerization of silicic acid on the gastrointestinal absorption of silicate in rats, Chem. Pharm. Bull. 27 (1979) 1733; K. Van Dyck, R. Van Cauwenbergh, H. Robberecht: Bioavailability of silicon from food and food supplements, Fresenius J. Anal. Chem. 363 (1999) 541] .
  • Such products can be used as effective food supplements or therapeutic agents at such diseases or disorders.
  • Such products can be used as effective food supplements or therapeutic agents at such diseases or disorders.
  • Partially polymerized forms of silicic acid (of nano-sized particles) were stabilized with strong inorganic acids in the presence of methyl sulfonilmethane (CH 3 S0 2 CH 3 ) or dimethylsulfoxide (CH 3 SOCH 3 ) and humectants like 1 , 2-propylene glycol or polyethyene glycol 400 (PEG-400) [I. Suvee, G. Tourgis: Hydronium stabilized and dissoluble silicic acid nanoparticles : Preparation, stabilization and use, WO 2009/127256 Al (2008)].
  • CH 3 S0 2 CH 3 methyl sulfonilmethane
  • CH 3 SOCH 3 dimethylsulfoxide
  • PEG-400 polyethyene glycol 400
  • Beside choline chloride-stabilized ortho-silicic acid (H 4 Si0 4 )
  • the latter is also called Trophocic acid", despite the fact that it is actually an anhydride of silicic acid.
  • Such products are characterized by very low bioavailability [R. Jugdaohsingh : Silicon and bone health, J. Nutr. Health Aging 11 (2007) 99] .
  • the present invention involves improved formulation of stabilized solution of ortho-silicic acid (H 4 Si0 4 ) which is used in nutrition, medicine, cosmetic, veterinary, or agriculture as effective source of highly bioavailable silicon (Si) .
  • the solution is consisting of the following ingredients:
  • X CI, H 2 P0 4 , HSOstance, N0 3 , CH 3 SO 3 , C 6 H 5 S0 3 , 1 , 4 -CH 3 C 5 H 4 S0 3 from 7-40% w/w;
  • auxiliary stabilizer of H 4 Si0 4 selected from the group comprising: glycerol, 1 , 2-propylene glycol, d-panthenol, glucosamine, or their mixtures, from 10-50% w/w; and
  • diluent selected from the group consisting of purified water, ethanol or their mixtures, in amounts of up to 100% w/w of overall formulation.
  • salts can be derivatives of racemic DL-carnitine or enantiomerically pure L- or D-carnitine.
  • Pharmaceutically acceptable acid which is used in the solution from the present invention is selected from the same group, where the advantage is given to phosphoric acid (H 3 P0 4 ) , because it was found that H3PO 4 additionally stabilizes ortho-silicic acid (H 4 Si0 4 ), presumably by inhibition of its polymerization (see Table 1) .
  • Glucosamine as auxiliary stabilizer is used either in the form of free base, or corresponding salt of pharmaceutically acceptable acid such as sulphuric (H 2 S0 4 ) , phosphoric (H 3 P0 4 ) , hydrochloric (HC1) , or other above-mentioned acid.
  • sulphuric H 2 S0 4
  • phosphoric H 3 P0 4
  • hydrochloric HC1
  • carnitine salts like carnitine hydrochloride (la) , effectively act as stabilizers of ortho-silicic acid (H 4 Si0 ) at low pH values (acidic medium) .
  • solutions of ortho-silicic acid of concentration of 2-4% w/w prepared by hydrochloric acid (HC1 ) -catalysed hydrolysis of tetraethyl orthosilicate [TEOS; Si(OC 2 H 5 ) 4 ], are stable at room temperature (20-25 °C) for 2-3 months.
  • HC1 hydrochloric acid
  • TEOS tetraethyl orthosilicate
  • Si(OC 2 H 5 ) 4 tetraethyl orthosilicate
  • carnitine hydrochloride (la) in concentration from 7- 40% w/w does act as stabilizer of ortho-silicic acid (H 4 S0 4 ) due to the fact that solutions of analogous concentrations do not undergo gelling, e.g. polymerization, even after 2 years storage at room temperature .
  • choline chloride (2) destabilizes ortho-silicic acid (H 4 Si0 4 ) at pH conditions that are close to physiological (around 7) . Moreover, choline chloride in these conditions does catalyze polymerization of H Si0 (see Table 1), what actually decreasing its bioavailability .
  • phase of solution which is, at the begining, clear and then opalescent
  • phase of (opalescent) gel is relatively fast, so it can be employed for analytical purpose for determination of gelling (polymerization) rate of H 4 Si0 4 .
  • crankRelative stability expressed as numerical parameter, coefficient which describes stability of ortho-silicic acid in the given sample in comparison with the standard (solution of H «jSi0 4 ) . Shows stabilizing or destabilizing effect on ortho-silicic acid, and its polymerization (gelling) .
  • the standard was prepared by addition of TEOS (1.2 mL; 1.12 g; 0.0054 mol) to a solution of 85% phosphoric acid (0.2 mL; 0.34 g; 0.289 g H 3 P0 4 ; 0.0029 mol; 0.55 mol. equiv.) in distilled water (10.00 g) followed by stirring at room temperature for 3 h, with subsequent dilution with distilled water up to the total weight of 15.00 g [contains 150 mg (1% w/w) of Si] .
  • Sample solutions were prepared by addition of 0.0054 mol of choline chloride (2; 0.75 g) , or DL- ( ⁇ ) -carnitine hydrochloride (la; 1.06 g) , and then TEOS (1.2 mL; 1.12 g; 0.0054 mol) to a solution of 85% phosphoric acid (0.2 mL; 0.34 g; 0.289 g H 3 P0 4 ; 0.0029 mol; 0.55 mol. equiv.) in distilled water (10.00 g) . Reaction mixture was stirred at room temperature for 3 h, and then diluted with distilled water to overall weight of 15.00 g [contains 150 mg (1% w/w) of Si] .
  • DL- ( ⁇ ) -carnitine hydrokloride (la) does not influence significantly on rate of polymerization of ortho-silicic acid (H 4 S1O 4 ) , where observed gelling time was only 3% shorter than for the standard (Experiment 3 against Experiment 1), what can be considered as acceptable difference within the limits of experimental error which are normally for this method up to approx. 5% .
  • crankRelative stability expressed as numerical parameter, coefficient which describes stability of ortho-silicic acid in the given sample in comparison with the standard (solution of H 4 Si0 4 ) . Shows stabilizing or destabilizing effect on ortho-silicic acid, and its polymerization (gelling) .
  • auxiliary stabilizer glycerol, glucosamine, d-panthenol, and 1 , 2-propylene glycol;
  • curbanRelative stability expressed as numerical parameter, coefficient which describes stability of ortho-silicic acid in the given sample in comparison with the standard (solution of H 4 Si0 ) . It shows stabilizing or destabilizing effect on ortho-silicic acid, and its polymerization (gelling) .
  • the solution of analogous composition like the product answeringBioSil R " was prepared by addition of TEOS (1.2 mL; 1.12 g; 0.0054 mol) to a solution of 85% phosphoric acid (0.2 mL; 0.34 g; 0.289 g H 3 P0 4 ; 0.0029 mol; 0.55 mol.
  • the best version of the solution from the present invention is based on the combination of carnitine salt (like carnitine hydrochloride), 1 , 2-propylene glycol and phosphoric acid (Table 4, Experiment 5) .
  • Analogous solution with glycerol and d-panthenol showed somewhat weaker stabilizing effect.
  • the version of the formulation with glucosamine (as sulfate) showed the weakest effect, but even this was 20x stronger than is the case at the solution based on choline chloride from the prior art.
  • composition of the sample solutions (%, w/w) : 3.5% H 4 Si0 4 (1% Si); 5.8% carnitine base; 1.5 molar equiv. / Si of corresponding acid (Experiment 1: HC1; Experiment 2: H 3 P0 4 ; Experiment 3: H 2 S0 4 ); 6.6% ethanol; and up to 100% distilled water.
  • composition of the sample solution in the Experiment 4 (%, w/w) : 3.5% H 4 Si0 4 (1% Si); 7% carnitin hydrochloride; 1.9% H 3 P0 4 (0.5 mol. equiv. / H 4 Si0 4 ); 6.6% ethanol, up to 100% distilled water.
  • carnitine salts like DL- ( ⁇ ) -carnitine hydrochloride, not only act as stabilizers of ortho-silicic (H 4 Si0 4 ) in acidic pH medium of the formulation from the present invention, but they do not cause its destabilization at physiological conditions.
  • carnitine salts do not catalyze polymerization of H 4 Si0 under physiological conditions, and subsequently, cannot exhibit negatively on (decreasing) of its bioavailability .
  • H 4 Si0 4 ortho-silicic acid
  • choline chloride can act as bidentate ligand for H 4 Si0 4
  • carnitine salts act as tetradentate ligands. Because of this, carnitine hydrochloride (la) forms far more stable complex 3a than choline chloride (2) which gives the corresponding complex with less hydrogen bonds.
  • less stable complex e.g. with choline chloride
  • higher equilibrium concentration of free H Si0 4 because the formation of the complex is a reversible process
  • Unwanted polymerization causes shift of the equilibrium of formation of the complex into the left (to the degradation direction) .
  • the solution from the present invention is prepared by addition of precursor of silicic acid ( PSA) of tetraethyl orthosilicate [TEOS; Si(OC 2 H 5 ) ] in previously prepared solution of carnitine salt like DL- ( ⁇ ) -carnitine hydrochloride ( la ) , pharmaceutically acceptable acid, and auxiliary stabilizer of H 4 Si0 4 according to the invention with vigorous stirring at temperatures between -10 °C to +40 °C, preferably at +15 °C to +30 °C (room temperature conditions) during 1-24 h.
  • PSA silicic acid
  • TEOS tetraethyl orthosilicate
  • Si(OC 2 H 5 ) tetraethyl orthosilicate
  • PSA the followings can be employed:
  • TEOS tetraethyl orthosilicate
  • hydrochloric acid released during its hydrolysis (4 mol of HC1 per single mol of SiCl 4 ) .
  • HC1 hydrochloric acid released during its hydrolysis (4 mol of HC1 per single mol of SiCl 4 ) .
  • Excess of HC1 is neutralized by addition of corresponding amounts of pharmaceutically acceptable base such as sodium or potassium hydroxide (NaOH, KOH) , calcium or magnesium hydroxide or carbonate [Ca(OH) 2 , Mg(OH) 2 , CaC0 3 , MgC0 3 ] , etc.
  • corresponding salts of used bases are generated, e.g. NaCl, KC1, CaCl 2 , MgCl 2 .
  • These salts do not alter stability of ortho- silicic acid in the solution from the present invention; these are leaved in the final product or, if precipitate, removed by filtration .
  • generated ortho-silicic acid in status nascendi forms complex with carnitine (e.g. carnitine hydrochloride) .
  • Hydrolysis of tetraethyl orthosilicate can be carried out in the presence of pharmaceutically acceptable acid in purified water (only) , whereas all other ingredients (carnitine salt, auxiliary stabilizer) can be added afterwards.
  • the solution from the present invention can be prepared by the same manners, with the use of free carnitine mecanical base" or its zwitter-ionic form), however, then pharmaceutically acceptable acid (e.g. H 3 P0 4 ) is used in excess of one molar equivalent; this is because one equivalent is spent on neutralization of carnitine base.
  • pharmaceutically acceptable acid e.g. H 3 P0 4
  • the product is subjected to dilution with water up to declared concentration of silicon (Si), filtration, and packaging into plastic bottles.
  • Si silicon
  • the solution from the present invention is employed as food supplement or as therapeutic agent for humans and animals, and for plant nutrition.
  • the solution is diluted with water to a concentration suitable for application:
  • (ii) takes part in structure of arterial, vein, and capillary walls, increases their elasticity and hardness of blood vessels, decreases their permeability; also takes part in structure of connective tissue and formation of functional tertiary structure of building proteins of soft organs like liver, lung, and brain;
  • antiinflammatory effect the therapy of various acute and chronic inflammatory diseases, e.g. positively acts at various skin diseases such as psoriasis, seborrheic dermatitis, neurodermitis , eczema, skin irritations, burns, wound healing, soothes decubitus, then at dandruff, and other skin diseases and disorders; helps also in other inflammatory diseases like rheumatoid arthritis;
  • (v) acts as cross-linking agent for glucosaminoglycans and mucopolysaccharides and thus helps in function of joints, ligaments and formation of sinovial fluid;
  • (ix) acts as antioxidant; prevents development of atherosclerosis and other diseases which are caused by prolonged exposure to oxidative stress like diabetes and diabetes complications.
  • silicon nutrition provides:
  • the present solution is diluted with water to the final concentration of 0.005-0.1% and used by foliar application by all common spraying equipments.
  • Lower concentrations (0.005-0.05% of Si) are used preventively for stimulation of growth and against development of fungal diseases (e.g. at grape), whilst higher concentrations (0.05-0.1% of Si) are employed in stressful conditions at drought or after hail.
  • Dosing rates are between 10-100 g of silicon per hectare (ha), or 1-10 L of the formulation from the present invention in concentration of 1% w/w of Si to the sprayer with 200-400 L of water, applied on area of 1 ha.
  • the solution from the present invention can be used as raw material (intermediate) for production of other pharmaceutical products, cosmetics, food supplements, veterinary, and agrochemical products with content of highly bioavailable silicon (Si) .
  • Si highly bioavailable silicon
  • room temperature means the temperature interval: 20-25 °C . All portions (%) of ingredients are expressed as weight percentages (w/w) . Relative ratio of reactants in reaction mixtures are expressed as molar equivalents (mol. equiv.) .
  • TEOS 1.2 mL; 1.12 g; 0.0054 mol
  • the reaction mixtures were stirred at room temperature for 3 h, and then diluted with distilled water (0.79 g) up to the total weight of the reaction mixtures of 15.00 g [contain 10 mg/g (1% w/w) of Si] .
  • reaction mixture was stirred at temperatures between -5 °C and room temperature during 1 h. Afterwards, purified water (approx. 28-30 g) was added up to the total weight of the reaction mixture of 1000.00 g. Content of silicon (Si) in thus prepared solution was 5.84 mg/g (0.58% w/w of Si) .
  • the reaction mixture was stirred at temperatures from 0 °C to room temperature during 1 h. Then, purified water (14.60 g) was added up to the total weight of the reaction mixture of 1000.00 g.
  • the content of silicon (Si) in thus prepared solution was 5.84 mg/g (0.58% w/w of Si) .
  • TEOS tetraethyl orthosilicate

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Abstract

La présente invention concerne une solution stabilisée d'acide ortho- silicique qui sert de source hautement biodisponible de silicium (Si) consistant en : (i) acide ortho-silicique (H4SiO4), de 0,01-8% p/p ; (ii) sel de carnitine (1) d'acides pharmaceutiquement acceptables, formule (1), X= Cl, H2PO4, HSO4, NO3, CH3SO3, C6H5SO3, 1,4-CH3C6H4SO3 de 7-40% p/p ; (iii) acide pharmaceutiquement acceptable, de 0,05-4 équivalents molaires par rapport à H4SiO4 ; (iv) stabilisant auxiliaire de H4SiO4, sélectionné parmi le groupe comprenant : glycérol, 1,2-propylèneglycol, d-panthénol, glucosamine, ou leurs mélanges, de 10-50% p/p ; et (v) diluant, sélectionné parmi le groupe consistant en eau purifiée, éthanol, ou leurs mélanges, dans des quantités allant jusqu'à 100% p/p de la formulation globale. La présente invention concerne la préparation et l'utilisation de la formulation qui fournit tous les effets thérapeutiques positifs connus de l'acide ortho-silicique chez l'homme et les animaux, et les bénéfices de l'utilisation pour les plantes.
PCT/HR2011/000036 2010-09-15 2011-09-13 Solution stabilisée d'acide ortho-silicique, sa préparation et son utilisation WO2012035364A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014185794A1 (fr) * 2013-05-15 2014-11-20 Przedsiębiorstwo INTERMAG Sp. z o.o. Formulation de silicium dotée de propriétés de stimulation de croissance de plantes, procédé de préparation d'une formulation de silicium dotée de propriétés de stimulation de croissance de plantes et son utilisation
EP3549578A1 (fr) * 2018-04-06 2019-10-09 Bio Minerals N.V. Formulation d'acide silicique et son utilisation
WO2021012062A1 (fr) * 2019-07-23 2021-01-28 Kehr Duhart Marcia Eugenia Procédé d'obtention d'une solution acide et homogène de chitosane-silice stable à court terme comprenant la préparation d'une solution acide de chitosane dans une concentration en poids de 2-20% de chitosane et une solution solide de silice dans une concentration de 2-30% de silice
US11878031B2 (en) 2018-10-05 2024-01-23 Bio Minerals N.V. Silicic acids for use in the treatment of periodontitis
WO2024028039A1 (fr) 2022-08-02 2024-02-08 Barlaa B.V. Solutions d'acide silicique stabilisé

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2577485A (en) 1950-09-08 1951-12-04 Du Pont Process of making stable silica sols and resulting composition
US2630410A (en) 1949-04-19 1953-03-03 Union Carbide & Carbon Corp Nongelling aqueous silica sols stabilized with boron compounds
GB1335783A (en) * 1971-07-06 1973-10-31 Labaz Anti-seborrhoeic compositions
WO1995021124A1 (fr) 1994-02-07 1995-08-10 Bio Pharma Sciences B.V. Composition renfermant de l'acide ortho-silicique stabilise, et composition biologique
US5707970A (en) 1997-02-12 1998-01-13 Nutrition 21 Arginine silicate complex and use thereof
US6335457B1 (en) 1999-10-15 2002-01-01 Exsymol S.A.M. Complex containing biologically assimilable orthosilicic acid, which is under solid form, stable and concentrated, and a process for preparation of said complex
WO2003077657A1 (fr) 2002-03-20 2003-09-25 Bio Minerals N.V. Complexe d'acide choline-silicique contenant des osmolytes ainsi que des elements divalents a l'etat de traces
WO2004016551A1 (fr) 2002-08-12 2004-02-26 Bio Minerals N.V. Procede pour la preparation d'un acide siliceux comprenant un extrudat, extrudat, son utilisation et composition pharmaceutique comprenant ledit extrudat
WO2004017913A2 (fr) 2002-08-22 2004-03-04 Nutrition 21, Inc. Complexe d'arginine-silicate-inositol et son utilisation
US20060178268A1 (en) 2002-05-31 2006-08-10 Sabalo N.V. Aqueous solution of non-colloidal silicic acid and boric acid
WO2009115827A1 (fr) * 2008-03-20 2009-09-24 The Nottingham Trent University Complément alimentaire
WO2009127256A1 (fr) 2008-04-17 2009-10-22 Jisbrey, S.A Nanoparticules d'acide silicique dissolubles et stabilisées à l’hydronium : préparation, stabilisation et utilisation

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2630410A (en) 1949-04-19 1953-03-03 Union Carbide & Carbon Corp Nongelling aqueous silica sols stabilized with boron compounds
US2577485A (en) 1950-09-08 1951-12-04 Du Pont Process of making stable silica sols and resulting composition
GB1335783A (en) * 1971-07-06 1973-10-31 Labaz Anti-seborrhoeic compositions
WO1995021124A1 (fr) 1994-02-07 1995-08-10 Bio Pharma Sciences B.V. Composition renfermant de l'acide ortho-silicique stabilise, et composition biologique
US5922360A (en) 1994-02-07 1999-07-13 Bio Pharma Sciences B.V. Stabilized orthosilicic acid comprising preparation and biological preparation
US5707970A (en) 1997-02-12 1998-01-13 Nutrition 21 Arginine silicate complex and use thereof
US6335457B1 (en) 1999-10-15 2002-01-01 Exsymol S.A.M. Complex containing biologically assimilable orthosilicic acid, which is under solid form, stable and concentrated, and a process for preparation of said complex
EP1371289A1 (fr) 2002-03-20 2003-12-17 Bio Minerals N.V. Complexe choline-acide silicique
WO2003077657A1 (fr) 2002-03-20 2003-09-25 Bio Minerals N.V. Complexe d'acide choline-silicique contenant des osmolytes ainsi que des elements divalents a l'etat de traces
US20060178268A1 (en) 2002-05-31 2006-08-10 Sabalo N.V. Aqueous solution of non-colloidal silicic acid and boric acid
WO2004016551A1 (fr) 2002-08-12 2004-02-26 Bio Minerals N.V. Procede pour la preparation d'un acide siliceux comprenant un extrudat, extrudat, son utilisation et composition pharmaceutique comprenant ledit extrudat
WO2004017913A2 (fr) 2002-08-22 2004-03-04 Nutrition 21, Inc. Complexe d'arginine-silicate-inositol et son utilisation
US7576132B2 (en) 2002-08-22 2009-08-18 Nutrition 21, Inc. Arginine silicate inositol complex and use thereof
WO2009115827A1 (fr) * 2008-03-20 2009-09-24 The Nottingham Trent University Complément alimentaire
WO2009127256A1 (fr) 2008-04-17 2009-10-22 Jisbrey, S.A Nanoparticules d'acide silicique dissolubles et stabilisées à l’hydronium : préparation, stabilisation et utilisation
WO2009144087A2 (fr) * 2008-04-17 2009-12-03 Jisbrey, S.A Suspension contenant des nanoparticules d'acide silicique colloïdales stabilisées à l'hydronium, formulation obtenue à partir de ladite suspension diluée, poudre obtenue à partir de ladite suspension déshydratée, compositions obtenues à partir de ladite poudre, préparation et utilisation

Non-Patent Citations (31)

* Cited by examiner, † Cited by third party
Title
A. LASSUS: "Colloidal silicic acid for oral and topical treatment of aged skin, fragile hair and brittle nails in females", J. INT. MED. RES., vol. 21, 1993, pages 209, XP055182916
A. LASSUS: "Colloidal silicic acid for oral and topical treatment of aged skin, fragile hair and brittle nails in females", J. INT. PLED. RES., vol. 21, 1993, pages 209, XP055182916
A. LASSUS: "Colloidal silicic acid for the treatment of psoriatic skin lesions, arthropathy and onychopathy", A PILOT STUDY. J. INT. MED. RES., vol. 25, 1997, pages 206
A. P. ABBOTT, D. BOOTHBY, G. CAPPER, D. L. DAVIES, R. K. RASHEED: "Deep Eutectic Solvents Formed between Choline Chloride and Carboxylic acids: Versatile Alternatives to Ionic Liquids", J. AM. CHEM. SOC., vol. 126, 2004, pages 9142 - 9147, XP055254619, DOI: doi:10.1021/ja048266j
A. SCHIANO, F. EISINGER, P. DETOLLE: "Silicium, tissu osseux et immunite", REVUE DU RHUMATISME, vol. 46, 1979, pages 483
C. D. SEABORN, F. H. NIELSEN: "Silicon deprivation decreases collagen formation in wounds and bone, and ornithine transaminase enzyme activity in liver", BIOL. TRACE ELEMENT RES., vol. 89, 2002, pages 251
D. KUSTRAK: "Pharmacognosy and phytopharmacy", GOLDEN MARKETING-TEHNICKA KNJIGA, 2005
D. M. REFFITT, N. OGSTON, R. JUGDAOHSINGH: "Orthosilicic acid stimulates collagen type I synthesis and osteoblast-like cells in vitro", BONE, vol. 32, 2003, pages 127
D. M. REFFITT, R. JUGDAOHSINGH, R. P. H. THOMPSON: "Silicic acid: its gastrointestinal uptake and urinary excretion in man and effects on aluminium excretion", J. INORG. BIOCHEM., vol. 76, 1999, pages 141
E. M. CARLISLE, C. SUCHIL: "Silicon and ascorbate interaction in cartilage formation in culture", FED. PROC., vol. 42, 1983, pages 398
E. M. CARLISLE, D. L. GARVEY: "The effect of silicon on formation of extra-cellular matrix components by chondrocytes in culture", FED. PROC., vol. 41, 1982, pages 461
E. M. CARLISLE: "A relation between silicon and calcium in bone formation", FED. PROC., vol. 29, 1970, pages 265
E. M. CARLISLE: "A requirement for silicon for bone growth in culture", FED. PROC., vol. 37, 1978, pages 1123
E. M. CARLISLE: "Silicon: a requirement in bone formation independent of vitamin D", CALCIF. TISSUE INT., vol. 33, 1981, pages 27, XP009036273
H. A. CURRIE, C. C. PERRY: "Silica in Plants: Biological, Biochemical and Chemical Studies", ANN. BOTANY, vol. 100, 2007, pages 1383 - 1389
H. YOKOI, S. ENOMOTO: "Effect of degree of polymerization of silicic acid on the gastrointestinal absorption of silicate in rats", CHEM. PHARM. BULL., vol. 27, 1979, pages 1733
J. D. BIRCHALL, J. S. CHAPPELL: "The chemistry of aluminium and silicon in relation to Alzheimer's disease", CLIN. CHEM., vol. 34, 1980, pages 265
J. LOEPER, J. EMERIT, J'. GOY, L. ROZENSZTAJN, M. FRAGNY: "Fatty acids and lipid peroxidation in experimental atheroma in the rabbit. Role played by silicon", PATHOL. BIOL., vol. 32, 1984, pages 693 - 697
J. LOEPER, J. GOY, M. FRAGNY, R. TRONIOU, 0. BEDU: "Study of fatty acids in atheroma induced in rabbits by an atherogenic diet with or wihout silicon i.v. treatment", LIFE SCI., vol. 42, 1988, pages 2105 - 2112
J. LOEPER, J. GOY-LOEPER, L. ROZENSZTAJN, M. FRAGNY: "The antiatheromatous action of silicon", ATHEROSCLEROSIS, vol. 33, 1979, pages 397 - 408, XP000612679, DOI: doi:10.1016/0021-9150(79)90032-7
J. LOEPER, J. GOY-LOEPER, L. ROZENSZTAJN, M. FRAGNY: "The antiatheromatous action of silicon", BULL. ACAD. NATL. MED., vol. 163, 1979, pages 530 - 534
K. SCHWARTZ: "A bound form of silicon in glycosaminoglycans and polyuronides", PROC. NAT. ACAD. SCI. USA, vol. 70, 1973, pages 1608, XP002524735, DOI: doi:10.1073/pnas.70.5.1608
K. VAN DYCK, R. VAN CAUWENBERGH, H. ROBBERECHT: "Bioavailability of silicon from food and food supplements, Fresenius", J. ANAL. CHEM., vol. 363, 1999, pages 541
M. FIGUEIREDO, C. GOMES, R. COSTA, A. MARTINS, C. M. PEREIRA, F. SILVA: "Differential capacity of deep eutectic solvent based on choline chloride and glycerol on solid electrodes", ELECTROCHIM. ACTA, vol. 54, 2009, pages 2630 - 2634, XP026000656, DOI: doi:10.1016/j.electacta.2008.10.074
M. R. CALOMME, D. A. V. BERGHE: "Supplementation of calves with stabilised orthosilicic acid effect on the Si, Ca, Mg and P concentration in serum and the collagen concentration in skin and cartilage", BIOL. TRACE ELEMENT RES., vol. 56, 1997, pages 153, XP000925562
R. JUGDAOHSINGH, D. M. REFFITT, C. OLDHAM: "Oligomeric but not monomeric silica prevents aluminium absorption in human", AM. J. CLIN. NUTR., vol. 71, 2000, pages 944
R. JUGDAOHSINGH, S. H. ANDERSON, K. L. TUCKER: "Dietary silicon intake and absorption", AM. J. CLIN. NUTR., vol. 75, 2002, pages 887
R. JUGDAOHSINGH: "Silicon and bone health", J. NUTR. HEALTH AGING, vol. 11, 2007, pages 99 - 110
R. JUGDAOHSINGH: "Silicon and bone health", J. NUTR. HEALTH AGING, vol. 11, 2007, pages 99, XP055189787
R. JUGDAOHSINGH: "Soluble silica and aluminium bioavailability", PHD THESIS, 1999
S. SPRIPANYAKORN, R. JUNGDAOHSINGH, R. P. H. THOMPSON, J. J. POWELL: "Dietary silicon and bone health", NUTR. BULL., vol. 30, 2005, pages 222

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014185794A1 (fr) * 2013-05-15 2014-11-20 Przedsiębiorstwo INTERMAG Sp. z o.o. Formulation de silicium dotée de propriétés de stimulation de croissance de plantes, procédé de préparation d'une formulation de silicium dotée de propriétés de stimulation de croissance de plantes et son utilisation
EP3549578A1 (fr) * 2018-04-06 2019-10-09 Bio Minerals N.V. Formulation d'acide silicique et son utilisation
WO2019193200A1 (fr) * 2018-04-06 2019-10-10 Name: Bio Minerals N.V. Formulation d'aide silicique et son utilisation
CN112261936A (zh) * 2018-04-06 2021-01-22 生物矿物股份有限公司 硅酸制剂及其用途
JP2021523219A (ja) * 2018-04-06 2021-09-02 バイオ・ミネラルズ・エヌ・ヴェー ケイ酸配合物及びその使用
JP7315654B2 (ja) 2018-04-06 2023-07-26 バイオ・ミネラルズ・エヌ・ヴェー ケイ酸配合物及びその使用
US11878031B2 (en) 2018-10-05 2024-01-23 Bio Minerals N.V. Silicic acids for use in the treatment of periodontitis
WO2021012062A1 (fr) * 2019-07-23 2021-01-28 Kehr Duhart Marcia Eugenia Procédé d'obtention d'une solution acide et homogène de chitosane-silice stable à court terme comprenant la préparation d'une solution acide de chitosane dans une concentration en poids de 2-20% de chitosane et une solution solide de silice dans une concentration de 2-30% de silice
WO2024028039A1 (fr) 2022-08-02 2024-02-08 Barlaa B.V. Solutions d'acide silicique stabilisé

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