WO2012032364A1 - Stabilized solution of ortho-silicic acid based on salicylic acid as effective inhibitor of its polymerization, its preparation and use - Google Patents

Stabilized solution of ortho-silicic acid based on salicylic acid as effective inhibitor of its polymerization, its preparation and use Download PDF

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Publication number
WO2012032364A1
WO2012032364A1 PCT/HR2011/000034 HR2011000034W WO2012032364A1 WO 2012032364 A1 WO2012032364 A1 WO 2012032364A1 HR 2011000034 W HR2011000034 W HR 2011000034W WO 2012032364 A1 WO2012032364 A1 WO 2012032364A1
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silicic acid
acid
ortho
silicon
solution
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PCT/HR2011/000034
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English (en)
French (fr)
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Ivica Cepanec
Antonio Lelas
Marijan Ramljak
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Creogen D.O.O.
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Publication of WO2012032364A1 publication Critical patent/WO2012032364A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • 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
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/368—Carboxylic acids; Salts or anhydrides thereof with carboxyl groups directly bound to carbon atoms of aromatic rings
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B33/00—Silicon; Compounds thereof
    • C01B33/113—Silicon oxides; Hydrates thereof
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B33/00—Silicon; Compounds thereof
    • C01B33/20—Silicates
    • C01B33/32—Alkali metal silicates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/10—General cosmetic use

Definitions

  • the present invention relates to the composition of highly bioavailable silicon (Si) which is used in medicine, cosmetics, veterine and agronomy.
  • the present invention solves technical problem of effective stabilization of ortho-silicic acid (H Si0 4 ) , which is used as nutritional and therapeutic source of highly bioavailable silicon
  • Formulation of the product is in the form of a solution comprising:
  • diluent selected from the group consisting of: purified water, 1, 2-propylene glycol, glycerol, ethanol, or their mixtures, in amounts of up to 100% w/w of the formulation.
  • Silicon (Si) is important biogenic microelement which exhibits several important 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];
  • (v) exhibits antiinflammatory effect; e.g. helps at various inflammatory diseases like rheumatoid arthritis, muscle inflammation, skin disorders such as psoriasis, seborrheic dermatitis, neurodermitis, skin irritations, accelerates wound healing, soothes decubitus and other skin disorderds and diseases
  • silicic acid in its monomeric form, ortho-form (H 4 Si0 4 ) is not stable and at higher concentration, but undergoes polymerization with formation of dimer (H 6 Si 2 0 7 ) , trimer (H 8 Si 3 O 10 ) , and linear chain oligomers (SI) which are still water soluble.
  • Linear chain polymers of silicic acid (SI) undergo further polymerization yielding tridimensional, branched polymers (S2) which are not of significant water solubility but form opalescent gel.
  • the polymerization process proceeds further with formation of hydratized silicon dioxide (silica gel; Si0 2 'xH 2 0) .
  • 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].
  • silicic acid For application in pharmacy, cosmetics, and veterinary, only pharmaceutically acceptable forms of silicic acid can be employed. For use in agriculture, also, only non-toxic forms of silicic acid of high bioavailability can be applied.
  • humectants like polyethylene glycol, polysorbates, plant gums, substituted cellulose, 1 , 2-propylene glycol, pectin, ethoxylated derivatives of higher fatty acids, acetylated or hydroxypropyl-derivatized starch, starch phosphate, urea, sorbitol, maltitol, vitamins [W. A. Kros, U.S.
  • Beside choline chloride-stabilized silicic acid on the market exist various food supplements which contain silicon in the forms of amorphous or colloidal silicon dioxide (Si0 2 ) .
  • Si0 2 amorphous or colloidal silicon dioxide
  • such products are characterized by very low bioavailability [R. Jugdaohsingh : Silicon and bone health, J. Nutr. Health Aging 11 (2007) 99] .
  • Somewhat effective (bioavailable) sources of silicic acid are also various plant drugs like extracts of horsetail (Equisetum arvense) , nettle (Urtica dioica) , and some other plants.
  • portions of soluble (and thus bioavailable) silicic acid from these healing plants usually do not exceed 1/10 of total amounts. All remained silicic acid is not soluble and, as such, not bioavailable [D. Kustrak: Pharmacognosy and phytopharmacy (in Wegn) Golden marketing-Tehnicka knjiga, Zagreb, Croatia (2005)].
  • silicon based products are used for only a few years. They are used for increasing resistance of plants to stress (at drought or hail) and against fungal diseases. It seems that they also pasively protect from insect attacks by forming thin hard barrier of silicon dioxide on the plant leaves.
  • the most known product are those based on horsetail ⁇ Equisetum arvense) extract or finelly milled quartz sand (silicon dioxide; Si0 2 ) in organic, and solution of potassium silicate (30% K 2 Si0 3 ) in conventional agriculture (mainly at grape; e.g. perennialSil-Matrix" ) . These products are usually applied by foliar spraying.
  • Salicylic acid (1) is a well known pharmaceutically active substance which, as such, or in forms of its derivatives (e.g. salicylamide, acetylsalicylic acid) , is widely used as antiinflammatoric, analgesic, and antipyretic for decades.
  • salicylamide, acetylsalicylic acid e.g. acetylsalicylic acid
  • keratolytic removes dead top skin layers
  • cosmetic peeling
  • keratoplastic acts as keratoplastic . Beside this, exhibits topical microbiocidal action.
  • the present invention represents improved pharmaceutical, cosmetic, veterinary or agrochemical composition which is effective source of highly bioavailable silicon.
  • the formulation is consisting of:
  • diluent selected from the group consisting of: purified water, 1 , 2-propylene glycol, glycerol, ethanol, or their mixtures, in amounts of up to 100% w/w of the formulation.
  • the following pharmaceutically acceptable acids can be used: hydrochloric (HC1) , sulfuric (H 2 S0 4 ) , nitric (HN0 3 ) , phosphoric (H 3 P0 4 ) , methanesulfonic (CH 3 SO 3 H) , benzenesulfonic (C 6 H 5 S0 3 H) , salicylic ( 1 , 2-C 6 H 4 (OH) COOH) or sulfosalicylic [C 6 H 3 (3- COOH) (4-OH)S0 3 H] acid, mixtures of these acids, or other acids which are not of significant toxicity for human, animal, or plant organism.
  • salicylic acid as pharmaceutically acceptable acid represents the special case of the present invention, because then it is in the same time:
  • Pharmaceutically acceptable base is selected from the group comprising sodium hydroxide (NaOH) , potassium hydroxide (KOH) , ammonium hydroxide (NH OH) , tetramethylammonium hydroxide [N(CH 3 ) 4 OH], tetraethylammonium hydroxide [N (C 2 H 5 ) 4 OH] , mixtures of these bases, or other bases characterized by:
  • salicylic acid (1) acts as effective stabilizer of ortho-silicic acid (H Si0 ) at pH values closed to neutral. In this manner, it inhibits its polymerization into biologically unavailable polymers of silicic acid. Consequently increases its bioavailability after oral administration of the formulation from the present invention.
  • TEOS tetraethyl orthosilicate
  • Samples are prepared by addition of 0.0054 mol of choline chloride (0.75 g) or L-serine (0.57 g) in hydrolyzed solution of sodium silicate (6.00 g distilled water + 0.44 g NaOH + 1.2 mL TEOS), with subsequent dilution with distilled water up to the total weight of 15.00 g [contains 150 mg (1% w/w) of Si].
  • the solution of the complex was prepared by addition of salicylic acid (0.75 g; 0.0054 mol) in previously prepared solution of sodium silicate (6.00 g distilled water + 0.44 g NaOH + 1.2 mL TEOS), with subsequent dilution with distilled water up to the total weight of 15.00 g [contains 150 mg (1% w/w) of Si].
  • Solutions are prepared by mixing previously prepared solution of sodium silicate (6.00 g distilled water + 0.44 g NaOH + 1.2 mL TEOS) and 2.25 g (15% w/w) or 6.00 g (40% w/w) of 1 , 2-propylene glycol with subsequent dilution with distilled water, up to the total weight of 15.00 g [contains 150 mg (1% w/w) of Si].
  • the solution of the complex was prepared by addition of salicylic acid (0.75 g; 0.0054 mol) to previously prepared solution of sodium silicate (6.00 g distilled water + 0.44 g NaOH + 1.2 mL TEOS) . Reaction mixture was stirred at room temperature during 1 h. Then, 1, 2-propilene glycol (2.25 g; 15% w/w) was added, and subsequently diluted with distilled water, up to the total weight of 15.00 g [contains 150 mg (1% w/w) of Si] .
  • Solutions like those of the complex 2 are clear and colourless solutions, stable to the occurence of gelling at room temperature (17-25 °C) , and at temperatures ⁇ 30 °C, during minimally 2 years.
  • the formulation from the present invention can be prepared as complex with ortho-silicic acid (HSi0 4 ) with salicylic acid salts (like disodium salicylate) in molar ratio of 1:2.
  • ortho-silicic acid HSi0 4
  • salicylic acid salts like disodium salicylate
  • the formulation from the present invention can be prepared as stabilized solution of ortho- silicic acid (H 4 Si0 4 ) also in acidic medium, by the influence of one or more above-mentioned pharmaceutically acceptable acid (0.1-4 molar equivalents) in the presence of 1-2 molar equivalents of salicylic acid, calculated to H 4 Si0 .
  • cCloudRelative stability is expressed as numerical parameter, coefficient, which describes stability of ortho-silicic acid in the given sample in comparison with the standard [pure solution of silicic acid (HSi0 4 ) ] . It shows stabilizing or destabilizing effect on ortho-silicic acid, in other words on its polymerization (gelling) .
  • Samples are prepared by addition of 0.0054 mol of choline chloride (0.75 g) or L-serine (0.57 g) to a solution of ortho-silicic acid (H 4 Si0 4 ; 10.00 g destilirana voda + 1.2 mL TEOS + 0.2 mL 85% H 3 P0 4 ; 3 h-stirring / room temperature) with subsequent dilution with distilled water, up to the total weight of 15.00 g [contains 150 mg (1% w/w) of Si] .
  • ortho-silicic acid H 4 Si0 4 ; 10.00 g destilirana voda + 1.2 mL TEOS + 0.2 mL 85% H 3 P0 4 ; 3 h-stirring / room temperature
  • Samples are prepared by addition of salicylic acid (0.75 g; 0.0054 mol) to a solution of tetraethyl orthosilicate (TEOS; 1.2 mL; 1.12 g; 0.0054 mol) in 1 , 2-propylene glycol (10.00 g) .
  • Distilled water (0.4 mL; 0.022 mol; 4.1 mol. equiv.) was added to the reaction mixture, and stirred at room temperature during 5 h. Then, 1,2- propylene glycol was added to the solution up to the total weight of 15.00 g [contains 150 mg (1% w/w) of Si].
  • amino acid serine which is also described in the literature as stabilizer of ortho-silicic acid, does exhibit slight stabilizing effect, indeed. However, this effect is almost negliable because observed increase of gelling time was only 8-10% prolonged against that for the standard (Experiments 3; Tables 2 and 3) .
  • salicylic acid (1) exhibits significant effect of stabilization of ortho-silicic acid (H 4 Si0 4 ) where observed polymerization time was 2.2x longer (Experiments 4; Tables 2 and 3), what suggest on high stability of the complex H 4 Si0 4 -salicylic acid (compound 3) .
  • humectant can be also used glycerol.
  • alternative diluent beside purified water, can be employed ethanol, or mixtures of these substances.
  • Solutions of the complex like compound 3 are also clear, colourless and relatively viscous solutions, stable to occurrence of gelling at room temperature (17-25 °C) , and at temperatures ⁇ 30 °C, during minimally 2 years.
  • formulation of the present invention provides all known positive therapeutic effects of silicic acid on human, animal or plant organism, which are known to those skilled in the art.
  • the present formulation is used in the following medicinal, cosmetic, and veterinary indications:
  • (ii) takes part in structure of arterial, vein, and capillary walls, increases elasticity and hardness of blood vessels, decreases its 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 of silicon and silicic acid therapy of various acute and chronic inflammatory diseases, e.g. positively acts at various inflammations of locomotive system such as muscle inflammations, rheumatoid arthritis, etc; skin diseases like psoriasis, seborrheic dermatitis, neurodermitis, eczema, skin irritations, burns, wound healing, at dandruff, and at other skin disorders and diseases; also positively acts at other inflammatory diseases;
  • (v) acts as cross-linking agent for glucosaminoglycans and mucopolysaccharides, and thus helps function of joints, ligaments, and production of synovial fluid; (vi) inhibits resorption of aluminum (Al 3+ ) from gastrointestinal tract, thus preventively acts on development of neurodegenerative diseases like Alzheimer or Parkinson diseases ;
  • the formulation from the present invention is used as adjuvant in treatment of pain and decreasing of increased body temperature. This is expecially recommended at indications where basic patological condition is consequence of silicon deficiency.
  • the formulation of the present invention due to the content of salicylic acid, shows:
  • microbiocidal effect (iii) microbiocidal effect.
  • the latter effects of salicylic acid are excellently supplemented with basic actions of silicon, where effects of refreshing of the skin are achieved through combination of wrinkle reducing (biosynthesis of collagen and elastin) , keratolytic/keratoplastic, and microbiocidal effects.
  • the formulation from the present invention at topical application provides positive effects in conditions like:
  • the formulation of the present invention provides:
  • the formulation of the present invention intended for medicinal, cosmetic, veterinary, and agrochemical applications is in the dosing form of solution (concentrate) .
  • the solution is diluted with water and administered orally in a dosage which corresponds to the following daily intakes of silicon (Si) :
  • the present formulation is also diluted with water up to the final concentration od silicon from 0.005-0.1% w/w, and applied by foliar application by using all common spraying equipments .
  • the formulation of the present invention can be used as starting material (intermediate) for production of other pharmaceutical products, cosmetics, then veterinary or agrochemical products with content of silicon (Si) of high bioavailability.
  • Basic complexes of ortho-silicic (H 4 Si0 4 ) and salicylic acid are prepared by hydrolysis of precursor of silicic acid ( PSA) tetraethyl orthosilicate (TEOS) :
  • PSA PSA
  • Acidic complexes of salicylic and ortho-silicic acid such as compound 3 are prepared by addition of 0.1-4 molar equivalents of pharmaceutically acceptable acid into previously prepared solution of precursor of silicic acid ( PSA) and salicylic acid in the diluent .
  • diluent or solvent 1 2-propylene glycol, purified water, glycerol, ethanol, or mixtures of these substances can be employed.
  • Reactions are conducted by vigorous stirring at temperatures from - 10 °C to +40 °C, preferably from +15 °C to +30 °C (conditions of room temperature) during 0,5-6 h.
  • TEOS tetraethyl orthosilicate
  • SiCl 4 tetraethyl orthosilicate
  • available commercial products are of very high purity due to the fact that TEOS is readily purified by distillation.
  • final product of very high purity with the content of unwanted heavy metals (Pb, Cd, Hg, As) far under common limits for pharmaceutical products and food supplements can be produced.
  • sodium or potassium silicate are difficult to purify from heavy metals, so, commercial products are not of so high level of chemical purity.
  • ortho-silicic acid (HSi0 ) in status nascendi generated in the reaction, forms the complex with:
  • the formulation of the present invention is clear, colourless, more or less viscous solution.
  • TEOS tetraethyl orthosilicate
  • Si silicon
  • paked into plastic bottles four molar equivalents of ethanol (C 2 H 5 OH) are generated. Since ethanol in this concentration is completely harmless and does not influence negatively on the stability of the present solution, it is not removed but kept in the final product as auxiliary solvent or diluent. It is known to those skilled in the art of pharmaceuticaly technology that ethanol is widely used as pharmaceuticaly excipient, diluent. Alternatively, ethanol can be removed from the final solution of the present invention by evaporation under high vacuum at temperatures ⁇ 40 °C, without negative effect upon its stability. Finally, the reaction product, the solution, is only diluted with water or 1 , 2-propylene glycol up to the nominal concentration of silicon (Si), filtered, and paked into plastic bottles.
  • Si silicon
  • room temperature refers to the temperature interval: 20-25 °C. All percentage (%) portions of ingredients are expressed as weight (w/w) portions.
  • TEOS tetraethyl orthosilicate
  • tetraethyl orthosilicate NaOH; 1.00 g; 0.025 mol; 2 mol. equiv.
  • TEOS tetraethyl orthosilicate
  • the reaction mixture was stirred at room temperature for 6 h.
  • salicylic acid (1.74 g; 0.0126 mol; 1 mol. equiv.) was added to the reaction mixture during 30 minutes with vigorous stirring.
  • the reaction mixture was stirred at room temperature for 1 h.

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PCT/HR2011/000034 2010-09-06 2011-08-31 Stabilized solution of ortho-silicic acid based on salicylic acid as effective inhibitor of its polymerization, its preparation and use WO2012032364A1 (en)

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Cited By (8)

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WO2014185794A1 (en) * 2013-05-15 2014-11-20 Przedsiębiorstwo INTERMAG Sp. z o.o. A silicon formulation with plant growth stimulating properties, a method of the preparation of a silicon formulation with plant growth stimulating properties and its use
EP3549578A1 (en) * 2018-04-06 2019-10-09 Bio Minerals N.V. Silicic acid formulation and use thereof
WO2021014240A1 (en) 2019-07-25 2021-01-28 Upl Limited Novel agrochemical combinations
GB2588213A (en) * 2019-10-16 2021-04-21 Maxstim Ltd Improvements in, and relating to, biostimulants
WO2021259731A1 (fr) * 2020-06-26 2021-12-30 Olmix Utilisation d'une composition organo-minerale par application foliaire pour stimuler le developpement des plantes en presence d'au moins un stress abiotique ou d'un stress biotique
EP4039666A1 (en) 2021-02-05 2022-08-10 Maxstim Limited Liquid plant biostimulant compositions containing silicon
US11878031B2 (en) 2018-10-05 2024-01-23 Bio Minerals N.V. Silicic acids for use in the treatment of periodontitis
WO2024078282A1 (zh) * 2022-10-10 2024-04-18 淄博乐悠悠农业科技有限公司 一种促进创伤面愈合的液体敷料

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