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 PDFInfo
- Publication number
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- silicic acid
- ortho
- solution
- acid
- carnitine
- Prior art date
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- 150000007513 acids Chemical class 0.000 claims abstract description 12
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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.
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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 |
CN113853202A (zh) * | 2019-02-15 | 2021-12-28 | 生物矿物股份有限公司 | 预防和治疗肌肉痉挛的硅镁组合 |
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 |
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IL277892B2 (en) * | 2018-04-06 | 2024-10-01 | Bio Minerals Nv | Silicic acid formulation and use thereof |
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 |
AU2019247705B2 (en) * | 2018-04-06 | 2024-07-11 | Bio Minerals N.V. | Silicic acid formulation and use thereof |
US11878031B2 (en) | 2018-10-05 | 2024-01-23 | Bio Minerals N.V. | Silicic acids for use in the treatment of periodontitis |
CN113853202A (zh) * | 2019-02-15 | 2021-12-28 | 生物矿物股份有限公司 | 预防和治疗肌肉痉挛的硅镁组合 |
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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