WO2009133413A1 - Formulation à base de clinoptilolite micronisée en tant qu’agent thérapeutique destiné à éliminer des toxines, des bactéries et des virus de l’organisme - Google Patents

Formulation à base de clinoptilolite micronisée en tant qu’agent thérapeutique destiné à éliminer des toxines, des bactéries et des virus de l’organisme Download PDF

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Publication number
WO2009133413A1
WO2009133413A1 PCT/HR2008/000013 HR2008000013W WO2009133413A1 WO 2009133413 A1 WO2009133413 A1 WO 2009133413A1 HR 2008000013 W HR2008000013 W HR 2008000013W WO 2009133413 A1 WO2009133413 A1 WO 2009133413A1
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Prior art keywords
polyoxyethylene
extract
sodium
acid
clinoptilolite
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PCT/HR2008/000013
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English (en)
Inventor
Antonio Lelas
Ivica Cepanec
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Novatech D.O.O.
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Priority to PCT/HR2008/000013 priority Critical patent/WO2009133413A1/fr
Publication of WO2009133413A1 publication Critical patent/WO2009133413A1/fr

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    • 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
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B39/00—Compounds having molecular sieve and base-exchange properties, e.g. crystalline zeolites; Their preparation; After-treatment, e.g. ion-exchange or dealumination
    • C01B39/02—Crystalline aluminosilicate zeolites; Isomorphous compounds thereof; Direct preparation thereof; Preparation thereof starting from a reaction mixture containing a crystalline zeolite of another type, or from preformed reactants; After-treatment thereof
    • C01B39/026—After-treatment

Definitions

  • the present invention relates to a formulation based on micronized clinoptilolite which is used as effective agent for removal of toxins, bacteria, and viruses from organism, and for prevention of toxification.
  • the present invention solves technical problem of improved pharmaceutical product for detoxification of human or animal organism, based on formulation consisting of variable amounts of:
  • micronized clinoptilolite (Me-MC) of enhanced mesoporosity of general formula:
  • Me H, Li, Na, K, Mg, Ca, Zn, Ag, Cu, Mn, or Fe; whereas ratio of silicon to aluminum, y:x is between 3:1 and 6:1; number of crystalline water m is from 0 to >10; which is characterized by particles size from 100 nm to 2 ⁇ m, with total surface area larger than 30 m 2 /g estimated via BET (Brunauer, Emmett, Teller) method, and with total mesoporous surface area larger than 15 m 2 /g, and with percentage of mesoporous surface area within BET total surface area of at least 50%; and
  • excipients which yield in desired pharmaceutical form: tablets, capsules, ointments, creams, gels, lotions, powders, liquid powders, compact powders, masks, suspensions, syrups, and therapeutic patches.
  • the formulation of the present invention provides more effective removal of toxins, bacteria and viruses from human or animal organism which are ordinarily entering through gastrointestinal tract, by breathing, or through skin or mucous membranes.
  • Aluminosilicates such as zeolites have several technical applications where their strong adsorptive and absorptive properties are used [R. T. Yang: Adsorbents , Fundamentals and Applications, John Wiley & Sons. Inc. (2003)] .
  • Aluminosilicates such as zeolites can be employed as medicinal agents for removal of toxins from organism. Similar applications of zeolites were described in the prior art [G. K. Frykman, G. H. Gruett, U.S. 2005/0106267 Al (2005); G. K. Frykman, G. H. Gruett, EP 1679962 (2006)], including clinoptilolite itself [K. Gast, WO 2007029208].
  • effective adsorbent can help in prevention of development or relieve several diseases which can occur due to consumption of low quality food, drinks, by breathing in polluted air, or at common intestinal infections either by bacteria or viruses.
  • This invention relates to formulation consisting of variable portions of:
  • micronized clinoptilolite (Me-MC) of enhanced mesoporosity of general formula:
  • Me H, Li, Na, K, Mg, Ca, Zn, Cu, Ag, Mn, Fe; molar ratio of silicon: aluminum, y:x is between 3:1 to 6:1, m is number of crystalline water which is from 0 to >10; characterized by particles size from 100 nm to 2 ⁇ m, with BET total surface area of at least 30 m 2 /g, total mesoporous surface area of at least 15 m 2 /g, with portion of total mesoporous surface area within BET total surface area of at least 50%; and (ii) one or more excipients which yield in desired pharmaceutical form: tablets, capsules, ointments, creams, gels, lotions, powders, liquid powders, compact powders, masks, suspensions, syrups, and therapeutic patches.
  • micronized clinoptilolite (Me-MC) of enhanced mesoporosity is produced by the following procedure that includes phases:
  • the conversion of natural clinoptilolite (C) which is dominantly in calcium form is performed by treatment with 2-10 molar equivalents of acids which forms corresponding calcium salts of high water solubility. During this treatment, calcium cations from aluminosilicate structure of clinoptilolite undergo exchange process with hydrogen cations. Acidic form of clinoptilolite (H-C) is isolated by filtration, whereas excess of acid is removed by washings.
  • Suitable acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, formic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or mixture of these acids.
  • natural clinoptilolite (C) of mainly calcium form (Ca-C) by treatment with 2-10 molar equivalents of suitable ammonium salts is converted to ammonium clinoptilolite (NH 4 -C) .
  • calcium cations from aluminosilicate structure are exchanged with ammonium cations.
  • Such obtained ammonium clinoptilolite (NH 4 -C) is isolated by filtration, whilst excess of ammonium salt is removed by washings.
  • Suitable ammonium salt is selected from the group consisting of ammonium chloride, ammonium bromide, ammonium formate, ammonium acetate, ammonium nitrate, ammonium perchlorate, ammonium benzenesulfonate, ammonium p- toluenesulfonate, ammonium methanesulfonate, or mixture of these salts.
  • Such prepared pure Me-C is further subjected to micronization process by using slightly modified micronizer already described in patent literature [T. Lelas, EP 1316530 (2004)].
  • micronized clinoptilolite (Me-MC)
  • very fine level of particles size ranging from 100 nm to 2 ⁇ m with Gauss-type of particle size distribution, possess unexpectedly high range of mesoporosity .
  • Mesoporosity describes volume or area of larger pores which were formed during crystallization of given mineral material as defects of crystal structure. In contrast to micropores which are described through parameter of microporosity, mesoporosity occurs in samples which were crystallized under non ideal conditions, or were generated by mechanical means [T. Lelas, EP 1316530 (2004)]. Mesopores are of significantly higher dimensions, e.g. 20-50 A, and they are responsible for increased adsorption of larger organic molecules.
  • micronization via collisions forms the base of the microniser which is used for the preparation of micronized clinoptilolite (Me-MC) according to this invention.
  • Me-MC micronized clinoptilolite
  • the sample of pure calcium clinoptilolite was prepared by described treatment of natural clinoptilolite with hydrochloric acid, followed by treatment with solution of calcium chloride.
  • Such obtained pure calcium clinoptilolite (Ca-C) was subjected to micronization:
  • the process of micronization used by the present invention is almost identical with the process (and device) already disclosed in the EP 1316530 - with the blades geometry slightly changed to enhance the collision occurrence.
  • the enhanced blade geometry has been shown in the Fig. 2A and the number and position of the blades on the main rotor is shown in the Fig 2B.
  • the used microniser has the rotor diameter of approximately 20 cm, and the revolution speed of approximately 21000 rpm.
  • the final shape of the blades, depicted in the figure 2A has been achieved by empirical manner by skillfull engineers (and their know-how) .
  • the above micronization process led to enhanced mesoporosity of the micronized product.
  • the product is characterised by total mesoporous surface area that surprisingly exceed 50% of BET total surface area.
  • Such obtained clinoptilolite (Ca-MCi, Ca-MC 2 , Ca-MC 3 ) exhibits profound and unexpected adsorption and absorption activity. This action is significantly stronger than the action of the same material micronized by classical micronization process (described elsewhere) .
  • CAD adsorption of cadaverine
  • adsorption capacity (mg AFBl/g C) of aflatoxin Bl for all tested clinoptilolites were calculated. Results are given in Table 3. Table 3. Determination of adsorption capacities (mg AFBl/g C) of aflatoxin Bl on clinoptilolites Ca-mC, Ca-MCi, Ca-MC 2 , and Ca-MC 3 .
  • micronized clinoptilolite (Ca-MCi, Ca- MC 2 , Ca-MC 3 ) from this invention is only 5-27% of higher BET total surface area than ordinarily micronized clinoptilolite (Ca-mC) , unexpectedly, in example of adsorption of aflatoxin Bl, it showed 44-79% increasing of adsorption.
  • dioxins which also form the same kinds of interactions with micro- and/or mesopores of zeolite structure.
  • clinoptilolite (Ca-MCi, Ca-MC 2 , Ca-MC 3 ) of enhanced mesoporosity is characterised by profoundly enhanced adsorption properties.
  • employed method of micronization slightly increases BET total surface area (for approx. 27%; comparison between samples Ca-mC and Ca-MC 3 ), the increasing of mesoporosity was 69%, what resulted in unexpectedly increased of adsorption for 74%.
  • Heavy metals such as mercury, lead, or cadmium form ionic interactions with aluminosilicate structure, by entering into micropores.
  • the ion-exchange capacity is directly related to molar ratio of silicon to aluminum. Substitution of silicon with aluminum leads to generation of negative charge which has to be neutralized with metal cation which enters into micropores of given aluminosilicate. Further increasing of portio of aluminum leads to increasing of number of metal cations in micropores, and therefore increasing the ion- exchange capacity as well.
  • ion-exchange capacity is, expectedly connected with chemical structure of zeolite, and not with physical state of the material, e.g. degree of mesoporosity, or range of particles size.
  • Clinoptilolite (Ca-MCi, Ca-MC 2 , Ca-MC 3 ) of enhanced mesoporosity showed for 38-85% increased adsorption of model bacterial cells of E. coli and B. subtilis in comparison to classically micronized clinoptilolite (Ca-mC) .
  • HSVl herpesvirus type 1
  • the study was performed at concentration of Ca-mC, Ca-MCi, Ca-MC 2 , Ca-MC 3 of 5 mg/mL (5%) at V "1 titre of HSVl.
  • the inhibitory effect of viral proliferation was expressed as percentage of cytopathic effect (CPE) and was compared to CPE of HSVl suspension of the same titre without addition of micronized clinoptilolite. Results are given in Table 6. Table 6.
  • micronized clinoptilolite (Ca- mC)
  • micronized clinoptilolite (Ca-MCi, Ca-MC 2 , Ca-MC 3 ) of enhanced mesoporosity showed 49-67% increased inhibition of proliferation of model viruses HSVl.
  • Micronized clinoptilolite (Me-MC) of enhanced mesoporosity can be employed in various forms suitable for the use as therapeutic agent for removal of toxins, or for preventing of toxins intake into the human or animal organism: tablets, capsules, ointments, creams, gels, lotions, powders, liquid powders, compact powders, masks, suspensions, syrups, and therapeutic patches.
  • the formulation of the present invention is consisting of the following components:
  • micronized clinoptilolite (Me-MC) of enhanced mesoporosity
  • Me H, Li, Na, K, Mg, Ca, Zn, Ag, Cu, Mn, Fe of characteristics described in this invention: from 1,0% to 99,99%, and
  • Excipients are selected from the groups of different technological additives which are essential to incorporate powderous substance such as Me-MC into the final pharmaceutical or cosmetic form: fillers; binders; disintegrants; lubricants; fatty emollients; emulgators; fillers for powders; tensides; solvents; humectants; thickeners; preservatives; antioxidants; stabilizers; colors; perfumes; pH control agents; and other functional additives.
  • the following fillers well-known to those skilled in the art are selected: microcrystalline cellulose; lactose monohydrate; calcium hydrogenphosphate; sucrose; glucose; silicium dioxide; sorbitol; mannitol; starch; modified starches; or mixtures of these substances.
  • binders can be employed: polyvinylpyrrolidone; polyvinylpyrrolidone co-polymers; lactose monohydrate; glucose; mannitol; sorbitol; starch; modified starches; carrageenans; alginates; gum arabic; sodium carboxymethylcellulose; sucrose; gelatine; or mixtures of these substances.
  • the following excipients can be used: polyvinylpyrrolidone; polyvinylpyrrolidone co-polymers; agar agar; starch; alginic acid; sodium alginate; sodium starch glycolate; or mixtures of these substances.
  • the following excipients can be employed: talc; stearic acid; magnesium stearate; calcium stearate; zinc stearate; solid polyethyleneglycols; solid polypropyleneglycols; sodium laurylsulphate or related substances; or mixtures of these substances .
  • the major components of fatty phase in semisolid and liquid dosage forms such as ointments, creams, and lotions, excipients are selected from the group consisting of: solid paraffin wax; petroleum jelly; mineral oil; ozokerite; yellow or white beeswax; synthetic esters of higher fatty acids such as isopropyl myristate, isopropyl palmitate, butyl palmitate, trimethylolpropane tristearate, or glyceryl tricaprylate; synthetic waxes such as lauryl laurate; liquid natural waxes such as jojoba oil; different plant oils such as soybean oil, sweet almond oil, sunflower oil, fish oil, olive oil, wheat germ oil, corn germ oil, avocado oil, palm oil, coconut oil, castor oil; higher fatty alcohols such as cetyl alcohol, stearyl alcohol, cetostearyl alcohol, oleyl alcohol; poly (dimethylsiloxane) , poly (dicyclohexylsi
  • emulsifiers can be used: lanolin or lanolin derivatives; lecithin; glyceryl monostearate; cetyl alcohol; stearyl alcohol; cetostearyl alcohol; oleyl alcohol; sodium laurylsulphate; sodium lauryl ethyleneglycolsulphate; sodium lauryl diethyleneglycolsulphate; sodium lauryl triethyleneglycolsulphate; etoxylates of higher fatty alcohols such as polyoxyethylene (2) laurylether, polyoxyethylene (10) laurylether, polyoxyethylene (23) laurylether, polyoxyethylene (2) stearylether, polyoxyethylene (10) stearylether, polyoxyethylene (23) stearylether, polyoxyethylene (2) oleylether, polyoxyethylene (10) oleylether, polyoxyethylene (23) oleylether, where 2, 10 and 23 represent average number of ethyleneglycol units on higher fatty alcohols;
  • fillers can be employed: talc; kaolin; bentonite; montmorillonite; calcium carbonate; basic magnesium carbonate; calcium silicate; aluminum hydroxide; silicon dioxide; purified clays; microcrystalline cellulose; or mixtures of these substances.
  • soaps such as sodium laurate, potassium laurate, sodium myristate, potassium myristate, sodium palmitate, potassium palmitate, sodium stearate, potassium stearate, sodium oleate, potassium oleate, sodium ricinoleate, potassium ricinoleate, sodium abietate, potassium abietate; metal salts of higher fatty alcohols such as sodium laurylsulphate, sodium lauryl ethyleneglycolsulphate, sodium lauryl diethyleneglycolsulphate, potassium laurylsulphate, potassium lauryl ethyleneglycolsulphate, potassium lauryl diethyleneglycolsulphate, ammonium laurylsulphate, ammonium lauryl ethyleneglycolsulphate, ammonium lauryl diethyleneglycolsulphate, sodium or potassium cocoamphopropionate; disodium or dipotassium cocoamph
  • L. B. factor ⁇ IO polyoxyethylene (10) laurate, polyoxyethylene (23) laurate, polyoxyethylene (10) stearate, polyoxyethylene (23) stearate, polyoxyethylene (10) oleate, polyoxyethylene (23) oleate, or other ethoxylates of higher fatty acids with H. L. B.
  • sorbitan esters such as polyoxyethylene sorbitan monolaurate (Tween 20) , polyoxyethylene sorbitan monopalmitate (Tween 40), polyoxyethylene sorbitan monostearate (Tween 60), or polyoxyethylene sorbitan monooleate (Tween 80) ; mono- or di-ethanolamides of higher fatty acids such as cocodiethanolamide; glycosides of higher fatty alcohols such as cocoglucoside; sodium or potassium di(2- ethylhexyl) sulfosuccinate; cocoamidopropyl betaine; cationic tensides such as cetyltrimethylammonium bromide, didecyldimethylammonium chloride, benzalkonium chloride, cetylbenzyldimethylammonium chloride, cetylpyridinium chloride; various tenside-containing plant extracts such as extract of soapwort ⁇ Saponaria officinalis) ; or
  • solvent is selected from the group consisting of: purified water; ethanol; isopropanol; diethyleneglycol monomethylether; diethyleneglycol dimethylether; diethyleneglycol monoethylether; diethyleneglycol diethylether; triethyleneglycol monomethylether; triethyleneglycol dimethylether; triethyleneglycol monoethylether; triethyleneglycol diethylether; glycerol; 1, 2-propyleneglycol; 1, 3-propyleneglycol; 1, 3-butanediol; polyethyleneglycol 400; polyethyleneglycol 600; polyethyleneglycol 1000; polyethyleneglycol 2000; polyethyleneglycol 4000; polyethyleneglycol 6000; polypropyleneglycol 425; polypropyleneglycol 100; other polypropyleneglycols; polyglycerols; isosorbide dimethylether; triethyl citrate; ethyl lactate; diethyl
  • humectants can be employed: glycerol; 1, 2-propyleneglycol; 1, 3-propyleneglycol; hexyleneglycol; 1, 3-butanediol; polyethyleneglycol 400; polyethyleneglycol 600; polyethyleneglycol 1000; polyethyleneglycol 2000; polyethyleneglycol 4000; polyethyleneglycol 6000; polypropyleneglycol 425; polypropyleneglycol 1000; other polypropyleneglycols; polyglycerols; sorbitol; xylitol; sucrose; urea; polyvinylpyrrolidone; polyvinylpyrrolidone copolymers; or mixtures of these substances.
  • liquid or semi-solid dosage forms of formulation of the present invention such as creams, gels, lotions or suspensions
  • the following thickeners can be used: polyacrylic acid or its sodium, potassium or triethanolamine salts; methylcellulose; sodium carboxymethylcellulose; 2- hydroxyethylcellulose; 2-hydroxypropylcellulose; bentonite; montmorillonite; starch; modified starches; gelatine; polyglycerols; polyethyleneglycol 400; polyethyleneglycol 600; polyethyleneglycol 1000; polyethyleneglycol 2000; polyethyleneglycol 4000; polyethyleneglycol 6000; polypropyleneglycol 425; polypropyleneglycol 2000; agar agar; gum arabic; carrageenans; tragacanth; alginic acid; sodium alginate; or mixtures of these substances.
  • antioxidants can be used: 2, 6-di-tert-butyl-4-hydroxytoluene (BHT) ; tert-butylhydroxyanisole (BHA) ; tocoferol; tocoferol acetate; other tocoferol esters; ascorbic acid; ascorbyl palmitate; lecithin; sodium sulfite; sodium metabisulfite; sodium formaldehyde sulfoxylate; sulphur dioxide; thioglycerol; thioglycolic acid; cysteine hydrochloride; N- acetylcysteine; hydroquinone; propyl gallate; or mixtures of these substances.
  • BHT 2, 6-di-tert-butyl-4-hydroxytoluene
  • BHA tert-butylhydroxyanisole
  • the following excipients can be employed: disodium ethylenediamine tetraacetate (Na 2 EDTAx2H 2 O) , or other salts of EDTA; disodium N- (2-hydroxyethyl) ethylenediamine triacetate [Na 2 H(HEDTA)], or other salts of HEDTA; disodium diethylenetriamine pentaacetate [Na 2 H 3 (DTPA)], or other salts of DTPA; disodium citrate [Na 2 C(OH) (COOH) (CH 2 COO) 2 ], or other salts of citric acid; disodium tartarate, or other salts of tartaric acid; or mixtures of these substances.
  • the formulation of the present invention also contains one or more other functional substances which promote detoxification action of micronized clinoptilolite (Me-MC) by relieving hazardous consequences of toxins, bacteria or viruses in cases when the therapy has been started when these unwanted events had already occured.
  • Me-MC micronized clinoptilolite
  • vitamins are known to those skilled in the art as vitamins, anti-inflammatory agents, antioxidants, hepatoprotectives, or astringents at applications through gastrointestinal tract, or as antiphlogistics, topical protectives, astringents, keratolytics, keratoplasties, or hydration agents at topical application on skin. They contribute to faster elimination or relieving of unwanted effects of organism toxification, and/or bacterial or viral infections .
  • salicylic acid or its salts with pharmaceutically acceptable bases are selected from the group consisting of: salicylic acid or its salts with pharmaceutically acceptable bases; salicylamide; methyl salicylate; ethyl salicylate; benzyl salicylate; 2-hydroxyethyl salicylate; acetylsalicylic acid or its salts with pharmaceutically acceptable bases; salsalate; purified turpentine oil; camphor; pinene; bornyl acetate; terpineol; terpenyl acetate; bromelain; glucosamine sulphate; L-histidine; chondroitin sulphate; hyaluronidase; heparin sodium; coumarin; choline chloride; sulphur; chlorophyll; vitamins or pro-vitamins such as retinol palmitate, ⁇ -carotene, niacinamide, d-panthenol, calcium pantothenate, folic acid,
  • the formulation of the present invention is in the following forms: tablets; capsules; ointments; creams; gels; lotions; powders; liquid powders; compact powders; masks; suspensions; syrups; and therapeutic patches.
  • the formulation is produced directly by addition of micronized clinoptilolite (Me-MC) described in this invention, to one or more excipients according to usual methodologies known in the art [S. C. Gad (Ed.) : Pharmaceutical Manufacturing Handbook: Production and Processes, Wiley (2008)].
  • Me-MC micronized clinoptilolite
  • tablets are produced either by direct compression of homogenized tablet mixture, or by wet granulation followed by compression of granulate into tablets.
  • tablets with micronized clinoptilolite (Me-MC) do contain one or more excipients essential for their production: filler; binder; disintegrant ; lubricant; eventually coating agent; etc.
  • Capsules are produced by filling of standard gelatin capsules with homogenized mixture of micronized clinoptilolite (Me-MC) and one or more excipients.
  • Me-MC micronized clinoptilolite
  • the formulation of the present invention in the form of ointment is produced by homogenization of micronized clinoptilolite (Me-MC) and one or more excipients in melted fatty phase consisting of one or more semi-solid (e.g. petroleum jelly), liquid (e.g. mineral oil) or solid (e.g. paraffin wax) emollients, with or without addition of further excipients such as fragrances, emulsifiers, etc.
  • semi-solid e.g. petroleum jelly
  • liquid e.g. mineral oil
  • solid e.g. paraffin wax
  • micronized clinoptilolite (Me-MC) is added:
  • cream can be emulsion of oil-in-water (U-V) type, or emulsion of water-in-oil (V-U) type.
  • U-V creams ,,inner” phase is fatty phase which is finely dispersed (emulsified) in water phase which is ,,outer" or continuous phase.
  • V-U creams water phase is ,,inner” phase in the form of very finely particles emulsified in fatty phase which is in this case ,,outer" or continuous phase.
  • Gel is produced by homogenization of micronized clinoptilolite (Me-MC) and one or more excipients in aqueous-alcoholic lotion, usually with addition of humectants such as glycerol and/or 1, 2-propyleneglycol and suitable thickeners.
  • humectants such as glycerol and/or 1, 2-propyleneglycol and suitable thickeners.
  • the thicking of thus obtained lotion is carried out by addition of certain thickeners (e.g. 2-hydroxyethylcellulose, methylcellulose) , or by neutralization of thickeners (e.g. polyacrylic acid) with suitable bases (e.g. triethanolamine) .
  • Lotion is produced by mixing of micronized clinoptilolite (Me- MC) in aqueous-alcoholic medium followed by addition of one or more excipients.
  • Me- MC micronized clinoptilolite
  • Powders are prepared by dry homogenization of micronized clinoptilolite (Me-MC) with other excipients (fillers for powders such as talc, kaolin, or calcium carbonate) .
  • excipients fillers for powders such as talc, kaolin, or calcium carbonate
  • other functional excipients e.g. magnesium stearate
  • fragrances e.g. oily organic liquids. They are firstly adsorbed on double weight of basic magnesium carbonate. In this manner, obtained material is a solid which can be easily- added to the rest of the powder, followed by final homogenization of whole powder batch.
  • Syrup is produced by homogenization of micronized clinoptilolite (Me-MC) in viscous aqueous solution of sucrose, honey, glucose, glucose syrup, fructose, etc.
  • Me-MC micronized clinoptilolite
  • an aqueous suspension of Me- MC is thickened by addition of standard edible thickeners such as gelatin, pectin, starch, modified starches, sodium carboxymethylcellulose, their mixtures, or other additives.
  • Sweeteners are selected from the group consisting of: sodium saccharin; acesulfame potassium; sucralose; sodium or calcium cyclamate; xylitol; sorbitol; or mixtures of these substances.
  • HPLC analyses were performed on Hewlett-Packard 1050 instrument equipped with autosampler and fluorescence detector.
  • Analyses of clinoptilolites by sorption-desorption of argon according to BET method was conducted on Micrometrics ASAP 2010 instrument.
  • Analyses by atomic absorption spectroscopy were performed on AAnalyst 800 (Perkin-Elmer) instrument with grafite furnace (GFAA) .
  • Analyses of particles size was carried out on Zetasizer NanoZS (Malvern instruments) instrument. The term room temperature means: 18-25 0 C.
  • Clinoptilolite (C; 1.00 kg; 1.73 mol; mainly calcium form; approx. CaAl 2 Si 7 Oi 8 ) was suspended in demineralized water (5000 mL) .
  • demineralized water 5000 mL
  • 37% hydrochloric acid (288 mL; 341.28 g of solution; 126.27 g HCl; 3.46 mol; 2 equiv. ) was added. Suspension was stirred at room temperature for 1 h. Then, the product was separated by filtration, and washed with demineralized water (3x500 mL) .
  • Such prepared pure calcium clinoptilolite was subjected to described micronization process during 1, 15, and 30 minutes affording micronized clinoptilolites Ca-MCi (1 min) , Ca-MC 2 (15 min) and Ca-MC 3 (30 min) of particles size ranging from 100 nm to 2 ⁇ m (the peak of Gauss-type curve was between 0.8 and 1.2 ⁇ m) .
  • Clinoptilolite (C; 1.00 kg; 1.73 mol; mainly of calcium form; approx. CaAl 2 Si 7 Oi 8 ) was suspended in demineralized water (5000 mL) . The suspension was stirred at room temperature for 20 h. The product was filtered, washed with demineralized water
  • Pure magnesium clinoptilolite was micronized (1 min) in described microniser giving micronized product Mg-MCi of particles size 100 nm to 2 ⁇ m (the peak of Gauss-type curve was around 1 ⁇ m) ; BET total surface area of 29,1 m 2 /g; and total mesoporous surface area of 15,8 m 2 /g.
  • Clinoptilolite (C; 100.00 g; 0.173 mol; mainly of calcium form; approx. CaAl 2 Si 7 OiS) was suspended in demineralized water (500 mL) .
  • demineralized water 500 mL
  • 37% hydrochloric acid (30 mL; 35.55 g of solution; 13.15 g HCl; 0.36 mol; 2.1 equiv. ) was added drop-wise during 15 minutes.
  • the reaction mixture was stirred at room temperature during 1 h.
  • This product (50.00 g; 0.09 mol) was suspended in demineralized water (200 mL) , and previously prepared solution of zinc sulphate heptahydrate (ZnSO 4 * 7H 2 O; 38.81 g; 0.135 mol; 1.5 equiv.) in demineralized water (200 mL) was added at once.
  • the reaction mixture was stirred at room temperature for 20 h.
  • the product was filtered, washed with demineralized water (5x500 mL) , and dried at 105 °C under high vacuum for 20 h, affording pure zinc clinoptilolite (Zn-C; ZnAl 2 Si 7 Oi 8 ) as white powder.
  • This product was subjected to micronization in described microniser giving zinc clinoptilolite (Zn-MCi) of enhanced mesoporosity; particles size 100 nm to 2 ⁇ m (the peak of Gauss-type curve was around 1 ⁇ m) ; BET total surface area of 30.9 m 2 /g; and total mesoporous surface area of 17.3 m 2 /g.
  • Zn-MCi zinc clinoptilolite
  • a solution (1000 mL) of mercury (II) nitrate monohydrate (Hg (NO 3 ) 2 0 H 2 O; 102.5 mg; contains 60 mg Hg) was prepared. Aliquot (10 mL) of such prepared solution was accurately- diluted to 1000 mL. For this study, 100 mL (contains 60 ppb Hg) of this solution per sample was used. pH value was corrected to 8.1 by addition of sodium hydroxide solution. To each solution of Hg 2+ , clinoptilolites (500 mg; Ca-mC, Ca-MCi, Ca-MC 2 , Ca-MC 3 ) were added. Suspensions were stirred at room temperature during 5, 10, 15 and 20 minutes. At these time points, suspensions were filtered through B ⁇ chner funnel by using vacuum pump to ensure rapid filtration. Samples of filtrates were analysed by atomic absorption spectroscopy (AAS). These results are given in Table 4.
  • AAS atomic absorption spectroscopy
  • HSVl herpesvirus of type 1
  • HSVl human cervical carcinoma cells
  • HeLa cells were propagated in Dulbecco's medium supplemented with: 10% inactivated foetal bovine serum; 1% L-glutamine; 0.3% NaHCO 3 ; at 37 0 C and 5% CO 2 .
  • the viral suspension was obtained by centrifugation (20 min/4 °C/5000 x g) of infected medium collected at maximal viral proliferation.
  • the viral titre V "1 was prepared.
  • HeLa cells (2xl ⁇ VmL) were infected with viruses after one day.
  • Clinoptilolites (Ca-mC, Ca-MCi, Ca-MC 2 , Ca-MC 3 ) were added in concentration of 50 mg/mL.
  • CPE was monitored by optical microscopy. Each determination was conducted three times. Inhibitory effect was compared with CPE of viral suspension incubated at 4 °C/15 h without addition of micronized clinoptilolite. Results are given in Table 6.
  • micronized calcium clinoptilolite (Ca-MCi) Content 100 g of tablet mixture
  • micronized calcium clinoptilolite (Ca-MCi; 25.00 g; 25%) a) Microcrystalline cellulose (40.00 g; 40%)
  • Obtained emulsion was vigorously stirred at 70-50 °C during 20- 30 min. Then, (w) was added to the cream. The product was vigorously stirred at 50 0 C during 30 min, and then was cooled to 40 0 C. Then, (z) was added, and stirring was continued to room temperature during 30 minutes. The cream was additionally- homogenized by mixing at room temperature for 30 min. The product was obtained in the form of fine, greenish-white, semi-solid creamy mask of pleasant fragrance.

Abstract

La présente invention concerne des formulations à base (i) de clinoptilolite micronisée (Me-MC) avec une mésoporosité améliorée. Ladite clinoptilolite présente une formule générale (Men+)x/n [(A1O2)χ(SiO2)y]•mH2O (Me-MC), avec Me = H, Li, Na, K, Mg, Ca, Zn, Ag, Cu, Mn, ou Fe, et avec un rapport silicium/aluminium y:x situé entre 3:1 et 6:1, et un nombre d’eau cristalline m situé entre 0 et > 10. La clinoptilolite se caractérise par une taille de particule allant de 100 nm à 2 μm, une surface totale BET supérieure à 30 m2/g, une surface mésoporeuse supérieure à 15 m2/g, et une partie de surface mésoporeuse dans la surface totale BET d’au moins 50 %. Lesdites formulations sont également à base (ii) d’un ou de plusieurs excipients qui produisent, sous la forme pharmaceutique désirée, des comprimés, des capsules, des onguents, des crèmes, des gels, des lotions, des poudres, des poudres liquides, des poudres compactes, des masques, des suspensions, des sirops et des timbres thérapeutiques. La formulation de la présente invention permet une élimination plus efficace des toxines depuis des organismes humains ou animaux, par exemple : (i) des mycotoxines ; (ii) des hydrocarbures aromatiques polycycliques ; (iii) des nitrosamines ; (iv) des métaux lourds ; (v) des amines aromatiques ou aliphatiques toxiques ; (vi) de l’acrylamide ; et (vii) des dioxines ; ainsi que (viii) des bactéries et des (ix) virus qui pénètrent dans le tractus gastro-intestinal, par la respiration, ou par la peau et/ou les membranes muqueuses. De cette façon, il est possible de prévenir plus efficacement de nombreux effets nocifs de ces toxines, de ces bactéries et de ces virus sur les organismes humains ou animaux.
PCT/HR2008/000013 2008-04-28 2008-04-28 Formulation à base de clinoptilolite micronisée en tant qu’agent thérapeutique destiné à éliminer des toxines, des bactéries et des virus de l’organisme WO2009133413A1 (fr)

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CN104941675A (zh) * 2015-05-21 2015-09-30 河南师范大学 形貌可控的磷酸铋光催化剂的制备方法
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RU2680832C1 (ru) * 2018-01-17 2019-02-28 Талагаева Елена Владимировна Глиняные маски для лица и тела
CN109880175A (zh) * 2019-03-06 2019-06-14 江苏申凯包装高新技术股份有限公司 一种双模板剂介孔载体/光刺激响应性组装体
WO2019179597A1 (fr) * 2018-03-19 2019-09-26 Symrise Ag Formes à libération soluble dans l'eau pour une substance active
CN111358760A (zh) * 2020-05-13 2020-07-03 扬子江药业集团广州海瑞药业有限公司 一种替格瑞洛片药物组合物及制备方法
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WO2012017402A2 (fr) 2010-08-03 2012-02-09 Ecobase Gmbh Zéolites ayant un effet neuro-protecteur
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