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WO2009133413A1 - Formulation based on micronized clinoptilolite as a therapeutic agent for removal of toxins, bacteria and viruses from organism - Google Patents

Formulation based on micronized clinoptilolite as a therapeutic agent for removal of toxins, bacteria and viruses from organism 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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WO
WIPO (PCT)
Prior art keywords
polyoxyethylene
extract
sodium
acid
clinoptilolite
Prior art date
Application number
PCT/HR2008/000013
Other languages
French (fr)
Inventor
Antonio Lelas
Ivica Cepanec
Original Assignee
Novatech D.O.O.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novatech D.O.O. filed Critical Novatech D.O.O.
Priority to PCT/HR2008/000013 priority Critical patent/WO2009133413A1/en
Publication of WO2009133413A1 publication Critical patent/WO2009133413A1/en

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Classifications

    • 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.

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Abstract

The present invention relates to formulation based on: (i) micronized clinoptilolite (Me-MC) of enhanced mesoporosity of general formula: (Men+)x/n [(A1O2)χ(SiO2)y] • mH2O (Me-MC) where 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 μm, BET total surface area larger than 30 m2/g, total mesoporous surface area larger than 15 m2/g, and with portion of 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. The formulation of the present invention provides more effective elimination of toxins from human or animal organism such as: (i) micotoxins; (ii) polycyclic aromatic hydrocarbons; (iii) nitrosamines; (iv) heavy metals; (v) toxic aliphatic or aromatic amines; (vi) acrylamide; (vii) dioxins; and for removal of (viii) bacteria; and (ix) viruses; which enter through gastrointestinal tract, by breathing, or through skin and/or mucous membranes. In this manner, numerous harmful effects of these toxins, bacteria, and viruses on human or animal organisms can be more effectively prevented.

Description

FORMULATION BASED ON MICRONIZED CLINOPTILOLITE AS A THERAPEUTIC AGENT FOR REMOVAL OF TOXINS, BACTERIA AND VIRUSES FROM ORGANISM
DESCRIPTION
THE FIELD OF THE INVENTION
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.
SUMMARY OF THE INVENTION
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:
(i) micronized clinoptilolite (Me-MC) of enhanced mesoporosity of general formula:
(Men+)x/n [(AlO2) x (SiO2) y] • KiH2O (Me-MC)
where 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 μm, with total surface area larger than 30 m2/g estimated via BET (Brunauer, Emmett, Teller) method, and with total mesoporous surface area larger than 15 m2/g, and with percentage of 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.
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.
PRIOR ART
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)] .
Among recently described application of zeolites, example of S. K. Gupta is given, who described the use of zinc zeolite as cosmetic active substance acting as deodorant [US 2006/0045860] . In this case, deodorant action of this substance is based both on antibiotic and astringent actions of zinc cation, as well as on strong adsorptive action of its aluminosilicate structure.
Among all zeolites, only clinoptilolite is recognized as pharmaceutical active substance. Good example of commercial drug based on clinoptilolite is Enterex which was developed for treatment of diarrhea [G. Rodriguez-Fuentes, M. A. Barrios, A. Iraizoz, I. Perdomo, B. Cedre: Enterex: Anti- diarrheic drug based on purified natural clinoptilolite, Zeolites 19 (1997) 441-448] . Except in therapy of diarrhea, clinoptilolite has been studied as adjuvant in cancer therapy [K. Pavelic, Medical News 26 (1998) 21-22] . It is also widely employed as cosmetic active substance in cosmetic creams.
Preparation of micronized clinoptilolite by similar but not identical manner like in this invention was described in the prior art [T. Lelas, EP 1316530 (2004); J. R. McLaughlin, US 5,704,556 (1998)]. Otherwise it can be micronized by wet milling technic [T. J. C. Arts, T. J. Osinga, EP 0 823 884 (1996)] .
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].
The most common toxins which enter into human or animal organism are:
(i) micotoxins such as aflatoxin Bl (AFBl) ;
(ii) polycyclic aromatic hydrocarbons like pyrene or benzo [α] pyrene; (iii) nitrosamines;
(iv) heavy metals such as mercury, lead, cadmium, or arsenic; (v) harmful amines; aliphatic polyamines such as cadaverine (CAD) and putrescine, and expecially aromatic amines such as aniline; (vi) acrylamide; and
(vii) dioxins like 2, 3, 7, 8-tetrachloro-dibenzo-p-dioxin (Dl)
Some studies of adsorption of these toxins on zeolites are known in the prior art. For example, in scientific literature several studies of adsorption of aflatoxin Bl [A. Dakovic, M. Tomasevic-Canovic, V. Dondur, G. E. Rottinghaus, V. Medakovic, S. Zaric: Adsorption of mycotoxins by organozeolites, Coll. Surf. B: Biointerfaces 46 (2005) 20-25], polycyclic aromatic hydrocarbons [S. Casini, L. Marsili, M. C. Fossi, G. Mori, D. Bucalossi, S. Porcelloni, I. Caliani, G. Stefanini, M. Ferraro, C. Alberti di Catenaja: Use of biomarkers to investigate toxicological effects of produced water treated with conventional and innovative methods, Marine Environ. Res. 62 (2006) S347-S351; J. Schlϋpen, F. -H. Haegel, J. Kuhlmann, H. Geisler, M. J. Schwuger: Sorption hysteresis of pyrene on zeolite, Colloids and Surf. 156 (1999) 335-347], nitrosamines [C. F. Zhou, J. H. Zhu: Adsorption of nitrosamines in acidic solution by zeolites, Chemosphere 58 (2005) 109-114; X. Dong, C. F. Zhou, M. B. Yue, C. Z. Zhang, W. Huang, J. H. Zhu: New application of hierarchical zeolite in life science: Fast trapping nitrosamines in artificial gastric juice by alkaline- tailored HZSM-5, Material Lett. 61 (2007) 3154-3158], heavy metals [S. Shevade, R. G. Ford: Use of synthetic zeolites for arsenate removal from pollutant water, Water Res. 38 (2004) 3197-3204], polyamines [N. Jiang, S. Yuan, J. Wang, Z. Qin, H. Jiao: Amines adsorption on Li- and Na-exchanged MOR: An ONIOM2 Study, J. MoI. Catal. A: Chemical 242 (2005) 105-112], and dioxins [Y. Guan, Y. Liu, W. Wu, K. Sun, Y. Li, P. Ying, Z. Feng, C. Li: Dibenzodioxin Adsorption on Inorganic Materials, Langmuir 21 (2005) 3887-3880] were published.
The structures of most common toxins from food and drink are shown in Figure 1. Additionally, several papers from scientific literature describe applications of zeolites as agents for adsorption of bacterial cells and viruses [M. Kubota, T. Nakabayashi, Y. Matsumoto, T. Shiomi, Y. Yamada, K. Ino, H. Yamanokuchi, M. Matsui, T. Tsunoda, F. Mizukami, K. Sakaguchi: Selective adsorption of bacterial cells onto zeolites, Colloids & Surf. B: Biointerfaces (2008); T. Uchida, N. Maru, M. Furuhata, A. Fujino, S. Muramoto, A. Ishibashi, K. Koshiba, T. Shiba, T. Kikuchi: Anti-bacterial zeolite balloon catheter and its potential for urinary tract infection control, Hinyokika Kiyo . 38 (1992) 973-978; K. I. Chuikova, S. V. Vozhakov: Assessment of efficacy of the drug litovit as a novel pathogenetic modality in acute virus hepatitis, Ter. Arkh. 77 (2005) 29- 31] .
Exposure of human or animal organism to mentioned toxins might result in development of severe diseases. By decreasing concentration of these toxins (from food and drink) in gastrointestinal tract, amounts of these substances absorbed are also decreased. In this manner, by using proper adsorbent, many harmful effects on human or animal health can be prevented.
Additionally, by binding of bacterial cells or viruses in gastrointestinal tract, from skin or mucous membranes, the number of patogenic microorganisms which enter into organism is significantly reduced. Thus, development of bacterial or viral infections can be completely prevented or at least minimized.
In this manner, 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.
Technical problem of more effective removal of toxins, bacterial cells, and viruses from human or animal organism, which enter either through gastrointestinal tract, by breathing, or through skin and/or mucous membranes, by this invention is solved on a new and very efficient way as will be demonstrated in detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Preparation of micronized clinoptilolite (Me-MC) of enhanced mesoporosity
This invention relates to formulation consisting of variable portions of:
(i) micronized clinoptilolite (Me-MC) of enhanced mesoporosity, of general formula:
(Men+)x/n [(AlO2) x (SiO2Jy] ' fflH20 (Me-MC)
where 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 μm, with BET total surface area of at least 30 m2/g, total mesoporous surface area of at least 15 m2/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.
According to the present invention the micronized clinoptilolite (Me-MC) of enhanced mesoporosity is produced by the following procedure that includes phases:
(i) the treatment of natural clinoptilolite (C) which is mainly in calcium form (Ca-C) with suitable acid affording hydrogen (acidic) form of clinoptilolite (H-C) , or with suitable ammonium salt giving ammonium clinoptilolite (NH4-C) ;
(ii) the treatment of such prepared hydrogen form of clinoptilolite (H-C) or ammonium clinoptilolite (NH4-C) , or by treatment of synthetic sodium or potassium clinoptilolite with solution of suitable metal salt of lithium, sodium, potassium, magnesium, calcium, zinc, copper, silver, manganese, or iron affording desired metal form of clinoptilolite, Me-C where Me= Li, Na, K, Mg, Ca, Zn, Cu, Ag, Mn, Fe; and
(iii) the micronization of the said Me-C to the micronized product to achive above-mentioned physical characteristics.
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.
Except removal of calcium (Ca2+) , thus described treatment of natural clinoptilolite allows removal of other metal cations (Na+, K+, Mg2+, Fe3+) present, as well as eventual traces of unwanted heavy metals (Pb2+, Cd2+, Hg2+) what is essential for producing of pharmaceutically pure material. For example, according to current ICH directives of active pharmaceutical substances quality, maximal content of lead cannot exceed 15 ppm. In the case of using natural clinoptilolite as raw material, it is of essential importance to develop effective and reproducible process for production of pure clinoptilolite which will meet current pharmaceutical quality standards. By described treatment with acids, the product was of high purity.
Alternatively, 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 (NH4-C) . In this case, calcium cations from aluminosilicate structure are exchanged with ammonium cations. Such obtained ammonium clinoptilolite (NH4-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.
The conversion of acidic form of clinoptilolite (H-C) or ammonium clinoptilolite (NH4-C) to desired metal form of clinoptilolite is carried out by mixing of these materials with aqueous solution of suitable metal salt consisting of halogenides, nitrates, acetates, perchlorates, or arylsulfonates of general formula MeX, Me1X2 or Me1 1X3; where Me= Li, Na, K, Cu, Ag; Me'= Mg, Ca, Zn, Cu, Mn, Fe; Me1'= Fe; X= Cl, Br, I, NO3, CH3COO, ClO4, or ArSO3 such as p-CH3C6H4SO3. It is clear to those skilled in the art that in this phase, other water soluble metal salts can be used.
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)].
We have found that thus obtained micronized clinoptilolite (Me-MC) , beside very fine level of particles size ranging from 100 nm to 2 μm 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.
One of the most effective manners of producing mineral material of significantly damaged surface with enhanced mesoporosity is by collision of particles of the material being micronized. Micronization via collisions forms the base of the microniser which is used for the preparation of micronized clinoptilolite (Me-MC) according to this invention. For study of adsorption and absorption efficacy, 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:
(i) by classical micronizer where ordinarily micronized clinoptilolite (Ca-mC) was prepared;
whereas by micronization with modified micronizer (improved variant of [T. Lelas, EP 1316530 (2004)]), three samples of micronised clinoptilolite of enhanced mesoporosity were obtained:
(ii) Ca-MCi at duration of micronization process for 1 minute;
(iii) Ca-MC2 at duration of micronization process for 15 minutes; and
(iv) Ca-MC3 at duration of micronization process for 30 minutes .
Analyses showed that calcium clinoptilolites Ca-MCx, Ca-MC2, and Ca-MC3 in comparison with ordinarily micronized clinoptilolite (Ca-mC) were of unexpectedly enhanced mesoporosity (31-69%; Table 1) . In the same time, particles sizes of all samples (Ca-mC, Ca-MCi, Ca-MC2, Ca-MCa) were in range from 100 nm to 2 μm, with Gauss-type of particles size distribution and maximal peak at 0.8-1.2 μm.
Table 1. Results of analysis of clinoptilolites micronized by classical micronizer (Ca-mC) , and by micronizer from this invention Ca-MCi (1 min) , Ca-MC2 (15 min) , Ca-MC3 (30 min) .
Figure imgf000012_0001
1 Calculated as ratio of mesoporous surface area of given sample (Ca-MCi, Ca-MC2, Ca-MCa) and the same value of clinoptilolite (Ca-mC) produced by classical micronization.
So, the key difference between classical micronization, and micronization described in T. Lelas, EP 1316530 (2004) is in the construction of the micronization device.
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 results of micronizaton are not described rigorously, i.e. by using calculation of the paths and the models for the collisions. However, the value of mesoporosity leads to an indirect evidence of the micronization quality.
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. In the said micronization process, the product is characterised by total mesoporous surface area that surprisingly exceed 50% of BET total surface area.
Such obtained clinoptilolite (Ca-MCi, Ca-MC2, Ca-MC3) 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) .
Proper-ties of prepared clinoptilolite
Described samples of clinoptilolites Ca-MCi, Ca-MC2, Ca-MC3 were studied as adsorbents of the following model toxins:
(i) polyamine cadaverine (CAD; 1, 5-pentanediamine) , and (ii) aflatoxin Bl (AFBl) .
The study of adsorption of cadaverine (CAD) was carried out by mixing of sample of cadaverine (100 mg) in double-distilled water (100 mL) in the presence of clinoptilolite (Ca-MCi, Ca- MC2, Ca-MC3; 1.00 g) samples during 1 h. Then, suspended clinoptilolite was filtered; filtrates were collected; and diluted to 100 mL. Aliquot (1 mL) of each filtrate was analysed volumetrically, by classical titration with 0. IM standard solution of hydrochloric acid with methyl orange as indicator. From used volume of 0. IM HCl, amount of cadaverine remained unadsorbed in supernatant was calculated. From this results, and starting amount of cadaverine employed (100 mg) , the amount of cadaverine adsorbed on each sample of clinoptilolite (1.00 g) was calculated. Results are given in Table 2.
Table 2. Determination of adsorption capacity (mg CAD/g C) of cadaverine on clinoptilolites Ca-mC, Ca-MCi, Ca-MC2, Ca-MC3.
Figure imgf000014_0001
1 Calculated as ratio of adsorption capacity of clinoptilolite (Ca-MCi, Ca-MC2, Ca-MC3) of enhanced mesoporosity, and the same value of clinoptilolite (Ca-mC) produced by classical micronization.
It has been shown that clinoptilolite (Ca-MCi, Ca-MC2, Ca-MC3) of enhanced mesoporosity exhibits 32-74% more potent adsorption of cadaverine (CAD) than the same material (Ca-mC) obtained by classical micronization.
In addition, efficiency of adsorption of aflatoxin Bl on clinoptilolite Ca-mC, and on clinoptilolite (Ca-MCi, Ca-MC2, Ca-MC3) of enhanced mesoporosity was studied. Samples of aflatoxin Bl (2 mg) were stirred in distilled water during 1 hour at room temperature with samples of clinoptilolites (100 mg; Ca-mC, Ca-MCi, Ca-MC2, Ca-MC3) . Clinoptilolites were removed by filtration, and concentrations of aflatoxin Bl in thus obtained filtrates were determined by quantitative HPLC analysis. From such obtained results, 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-MC2, and Ca-MC3.
Figure imgf000015_0001
1 Calculated as ratio of adsorption capacity of clinoptilolites (Ca-MCi, Ca-MC2, Ca-MC3) of enhanced mesoporosity, and the same value of clinoptilolite (Ca-mC) produced by classical micronization.
Despite the fact that micronized clinoptilolite (Ca-MCi, Ca- MC2, Ca-MC3) 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.
It is known to those skilled in the art that cadaverine and aflatoxin Bl, and other harmful toxins from food and drinks do bind onto zeolites such as clinoptilolite through reinstatement of:
(i) ionic interactions;
(ii) hydrogen bonds;
(iii) van der Waals interactions; and
(iv) weak interactions (ion-dipole; dipole-dipole; dipole- induced dipole; etc.)
Therefore it is clear that model adsorbates cadaverine and aflatoxin Bl clearly demonstrate wide possibilities of strongly enhanced adsorption of other harmful toxins: (i) polycyclic aromatic hydrocarbons;
(ii) nitrosamines;
(iii) acrylamide; and
(iv) dioxins; which also form the same kinds of interactions with micro- and/or mesopores of zeolite structure.
Thus clinoptilolite (Ca-MCi, Ca-MC2, Ca-MC3) of enhanced mesoporosity is characterised by profoundly enhanced adsorption properties. Although employed method of micronization slightly increases BET total surface area (for approx. 27%; comparison between samples Ca-mC and Ca-MC3), 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.
Study of absorption was performed on mercury (Hg2+) as model heavy metal on classical micronized clinoptilolite (Ca-mC) , and on clinoptilolite (Ca-MCi, Ca-MC2, Ca-MC3) of enhanced mesoporosity. The experiment was conducted by using solution (100 mL) of mercury (II) nitrate [Hg (NO3) 2'H2O] , containing 60 ppb Hg, at pH= 8.1. Filtrates after absorption onto samples of clinoptilolites (0.50 g) , depending on time (5, 10, 15, 20 minutes) , were separated by filtration, and analysed by atomic absorption spectroscopy (AAS). Results are given in Table 4.
Table 4. Results of determination of rate of mercury (Hg2+) absorption on classically micronized clinoptilolite (Ca-mC) , and on clinoptilolite (Ca-MCi, Ca-MC2, Ca-MC3) of enhanced mesoporosity at pH 8.1.
Time Ca-mC Ca-MC1 Increasing of (miπ) Concentration of Hg Concentration of Hg (ppb) rate of (ppb) absorption (%) 1
0 60 60 -
5 38 25 59
10 23 13 27
15 10 9 2
20 8 8 -
Time Ca-mC Ca-MC2 Increasing of (min) Concentration of Hg Concentration of Hg (ppb) rate of (ppb) absorption (%)
0 60 60 -
5 38 23 68
10 23 10 35
15 10 9 1
20 8 8 -
Time Ca-mC Ca-MC3 Increasing of (miπ) Concentration of Hg Concentration of Hg (ppb) rate of (ppb) absorption (%)
0 60 60 -
5 38 21 77
10 23 9 38
15 10 8 4
20 8 8 -
1 Calculated as ratio of absorption rate of mercury onto clinoptilolite (Ca-MCi, Ca-MC2, Ca-MC3) of enhanced mesoporosity, and the same value of clinoptilolite (Ca-mC) produced by classical micronization. Classically micronized clinoptilolite (Ca-mC) showed the same level of ion-exchange capacity like clinoptilolite (Ca-MCi, Ca- MC2, Ca-MC3) of enhanced mesoporosity . All samples of clinoptilolites (1.00 g) absorbed mercury from the solution by decreasing its concentration from starting 60 ppb to 8 ppb. So, all samples examined absorbed 87% of mercury, whilst 13% of mercury remained in supernatant.
This result is expected since total ion-exchange capacity of given sample of zeolite is connected with molar ratio of silicon to aluminum. Therefore, 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.
However, our results showed that clinoptilolite (Ca-MCi, Ca- MC2, Ca-MC3) of enhanced mesoporosity did exhibit faster absorption of mercury from aqueous solution. In other words, it allows faster achieving the state of maximal cation- exchange capacity. The enhancement of the rate was surprisingly 59-77%.
Furthermore, efficacy of adsorption of bacterial cells on micronised clinoptilolite (Ca-mC, Ca-MCi, Ca-MC2, Ca-MC3) was studied by employing Escherichia coli and Bacillus subtilis bacteria. To suspensions of bacterial cells, known amount of each sample of micronized clinoptilolite was added. After incubation at room temperature for 1 hour in buffer (pH 7), absorbances of supernatants were measured. From these results, amounts of adsorbed bacterial cells were calculated. Results are given in Table 5. Table 5. Results of adsorption (%) of bacterial cells E. coli and B. subtilis on classically micronized clinoptilolite (Ca- mC) and on clinoptilolite (Ca-MCi, Ca-MC2, Ca-MC3) of enhanced mesoporosity at pH 7.
Bacterium Ca-mC Ca-MC1 Increasing of adsorption (%)
E. coli 21 29 38
B. subtilis 47 79 68
Bacterium Ca-mC Ca-MC2 Increasing of adsorption (%)
E. coli 21 34 62
B. subtilis 47 83 77
Bacterium Ca-mC Ca-MC3 Increasing of adsorption (%)
E. coli 21 35 67
B. subtilis 47 87 85
Clinoptilolite (Ca-MCi, Ca-MC2, Ca-MC3) 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) .
Furthermore, inhibitory effect of micronized clinoptilolites Ca-mC, Ca-MCi, Ca-MC2, Ca-MC3 on viruses was studied by using herpesvirus type 1 (HSVl) . The study was performed at concentration of Ca-mC, Ca-MCi, Ca-MC2, Ca-MC3 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. Inhibition (%) of proliferation of HSVl at V"1 titre with 5 mg/mL of classically micronized clinoptilolite (Ca-mC) and clinoptilolite (Ca-MC1, Ca-MC2, Ca-MC3) of enhanced mesoporosity.
Sample Inhibition of Increasing of inhibition proliferation (%) of proliferation (%)
Ca-mC 21.4 -
Ca-MC1 31.9 49
Ca~MC2 34.5 61
Ca-MC3 35.7 67
In comparison with classically micronized clinoptilolite (Ca- mC) , micronized clinoptilolite (Ca-MCi, Ca-MC2, Ca-MC3) of enhanced mesoporosity showed 49-67% increased inhibition of proliferation of model viruses HSVl.
From all results obtained, it is clear to those skilled in the art that increasing of mesoporosity of clinoptilolite clearly lead to:
(i) unexpected increasing of adsorption of different molecules which can restitute: ionic interactions; hydrogen bonds; van der Waals interactions; and weak interactions; with aluminosilicate skeleton of clinoptilolite;
(ii) unexpected increasing of adsorption of higher particles such as bacterial cells, or virus particles which can restitute: ionic interactions and/or hydrogen bonds with aluminosilicate skeleton; and
(iii) hastened ion-exchange process of existing metal cations (e.g. calcium) with cations from supernatant which enter into micropores of clinoptilolite. These observed effects of micronized clinoptilolite (Ca-MCi, Ca-MC2, Ca-MCa) of enhanced mesoporosity are unexpected because analogous material (Ca-mC) of the same range of particles size, and only slightly lower BET total surface area, showed significantly less exhibited effects.
Composition of the formulation according to the invention
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:
(i) micronized clinoptilolite (Me-MC) of enhanced mesoporosity where 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
(ii) one or more excipients: from 0,01% to 99,00%.
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. In solid oral forms such as tablets and capsules, 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.
In solid oral forms the following 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.
As disintegrants in oral dosage forms, 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.
As lubricant in oral forms or powders, 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 .
As emollients, 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 (dicyclohexylsiloxane) , other polymeric liquid or semi-solid silicones; liquid, semi-solid, or solid polyethyleneglycols; liquid, semi-solid, or solid polypropyleneglycols; or mixtures of these substances.
In creams, ointments, or liquid dosage forms like lotions, the following 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; etoxylates of higher fatty acids such as polyoxyethylene (2) laurate, polyoxyethylene (10) stearate, polyoxyethylene (23) oleate, where 2, 10 and 23 represent average number of ethyleneglycol units on higher fatty acids; ethoxylates of sorbitan esters of higher fatty acids such as polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan monopalmitate (Tween 40) , polyoxyethylene sorbitan monostearate (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80) , polyoxyethylene sorbitan tristearate (Tween 65), polyoxyethylene sorbitan sesquioleate (Tween 85); castor oil and its etoxylates; or mixtures of these substances.
In solid dosage forms such as powders, liquid powders, or compact powders, the following 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.
As tensides in liquid forms such as lotions in the formulation of this invention, the following excipients can be used: 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 cocoamphodiacetate; polyoxyethylene (10) laurylether, polyoxyethylene (10) laurylether, polyoxyethylene (23) laurylether, polyoxyethylene (10) stearylether, polyoxyethylene (23) stearylether, polyoxyethylene (10) oleylether, polyoxyethylene (23) oleylether, or other ethoxylates of higher fatty alcohols with H. 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. factor ≥ 10; 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 mixtures of these substances.
In formulation of the present invention, 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 malate; diethyl tartarate; diethyl sebacate; diisopropyl adipate; dimethylsulfoxide; triethylhexanoin; or mixtures of these substances.
In formulation of the present invention, the following 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.
In 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.
In formulation of the present invention for providing a long- term microbiological stability, the following preservatives are employed: methyl 4-hydroxybenzoate; ethyl 4- hydroxybenzoate; propyl 4-hydroxybenzoate; butyl 4- hydroxybenzoate; triclosan; chlorhexidine diacetate; chlorhexidine dihydrochloride; chlorhexidine digluconate; chlorobutanol; diimidazolidinyl urea; sorbic and/or benzoic acids or their salts of pharmaceutically acceptable bases; 2- bromo-2-nitropropane-l, 3-diol; 2-hydroxybiphenyl; 4-chloro-in- cresol; thymol; eugenol; eucalyptol; linalool; herbal extracts with significant content of thymol, eugenol, eucalyptol, linalool, pinene, borneol, or related terpenes such as extracts of thyme (Thymus vulgaris) , clove (Syzygium aromaticum) , lavender (Lavandula officinalis) , common juniper (Juniperus communis) , eucalyptus (Eucalyptus globules) , cinnamon (Cinnamomum zeylanicum) , lemon (Citrus limonum) , orange (Citrus aurantium) , peppermint (Mentha piperita) , oregano (Origanum vulgare) , melaleuca (Melaleuca alternifolia) , caraway (Carum carvi) , anise (Pimpinella anisum) ; or mixtures of these substances.
In the formulation of the present invention, the following 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.
As stabilizers in the formulation of the present invention, the following excipients can be employed: disodium ethylenediamine tetraacetate (Na2EDTAx2H2O) , or other salts of EDTA; disodium N- (2-hydroxyethyl) ethylenediamine triacetate [Na2H(HEDTA)], or other salts of HEDTA; disodium diethylenetriamine pentaacetate [Na2H3(DTPA)], or other salts of DTPA; disodium citrate [Na2C(OH) (COOH) (CH2COO)2], or other salts of citric acid; disodium tartarate, or other salts of tartaric acid; or mixtures of these substances. Except all mentioned excipients, 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.
These substances 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 .
These substances 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, β-carotene, niacinamide, d-panthenol, calcium pantothenate, folic acid, riboflavin, pyridoxine or its derivatives, ascorbic acid, ascorbyl palmitate, tocoferol acetate; benzoylperoxide; azelaic acid; resorcinol; resorcinol monoacetate; tars; naphthalan; γ-linolenic acid or plant oils with significant percentage of γ-linolenic acid such as fish oil or soybean oil; allantoin or herbal extracts with significant amounts of allantoin such as extract of comfrey {Symphytum officinale); hypericin or extract of Saint John's worth {Hypericum perforatum) ; azulene or extract of chamomile {Matricaria recutita); extract of marigold {Calendula officinalis) ; extract of arnica {Arnica montana) ; extract of white willow {Salix alba cortex) ; capsaicin or extract of chili pepper {Capsici fruct.) ; extract of white mustard {Brassica alba) ; menthol; essential oil or extract of peppermint {Mentha piperita) ; essential oil or extract of rosemary {Rosmarinus officinalis) ; green tea extract {Camellia sinensis) ; extract of rooibos {Aspalathus linearis) ; nettle extract {Urtica dioica) ; aescin; horse-chestnut extract {Hippocastani sem.); primrose extract {Primula officinalis) ; extract of centaurium {Erythraea centaurium) ; mullein extract {Verbascum phlomoides) ; extract of holly {Ilex aquifolium) ; borage extract {Borago officinalis) ; burdock extract {Arctium lappa); extract of ribwort plantain {Plantago lanceolata) ; extract of leaves and root of century plant {Agave americana) ; extract of ground pine {Lycopodium clavatum) ; extract of common ivy {Hedera helix) ; extracts of herbals with significant contents of silicic acid (H4SiO4) such as field horsetail {Equisetum arvense) , lungwort {Pulmonaria officinalis) , common knotgrass {Polygonum aviculare) , Agropyron {repens) , common agrimony {Agrimonia eupatoria) , oat {Avena sativa) , Taraxaci radix; zinc oxide; zinc tannate; bismuth subnitrate; bismuth subcarbonate; bismuth phosphate; bismuth tannate; calamine; silver proteine; peru balsam; titanium dioxide; tannic acid; albumin tannate; methylene ditannate; herbal extracts with significant contents of tannins such as extracts of oak bark {cortex Quercus ruber, Quercus sessiliflora, Gallae asiaticae) , blackberry {Rubus fruticosus) , bearberry leaves {Arctostaphylos uvae ursi) , common agrimony {Agrimonia eupatoria) , silverweed {Potentilla anserina) , rhizoma Potentilla tormentillae, common bistrot {Polygonum bistorta) , Filipendula ulmaria, or common sage (Salvia officinalis) ; α-hydroxy-acids such as glycolic, lactic, malic, citric, and tartaric acid; urea; coenzyme QlO; betaine; methionine; S-adenozyl-methionine; catechin; quercetin; rutin; citiolone; malotilate; phosphoryl choline; protoporphyrin IX; α-lipoic acid [5- (1, 2-dithiolane-3- il) valeric acid] or its salts with pharmaceutically acceptable bases; timonacic (4-thiazolidine-2-carboxylic acid) or its salts with pharmaceutically acceptable acids and bases; tiopronin; silymarin or milk thistle extract (Silybum marianum) ; cyanidin or extract of Vaccinium myrtillus; hesperidin; diosmin; extract of orange (Citrus aurantium) ; lycopene or extracts with significant amounts of lycopene; resveratrol; tetrahydrocurcumin; rosmarinic acid; chlorogenic acid; oleuropein; extract of olive leaves (Olea europea) ; grape seed extract; pycnogenol; carnosine; glutathione; or compatible mixtures of these substances.
It is clear to those skilled in the art that in the cases of using combinations of relatively reactive pharmaceutical and/or cosmetic excipients or plant extracts, that the main point is their compatibility.
Preparation of the formulation of the present invention
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)].
For example, tablets are produced either by direct compression of homogenized tablet mixture, or by wet granulation followed by compression of granulate into tablets. Anyway, 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.
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.
In the case of preparation of the formulation in the form of creams, micronized clinoptilolite (Me-MC) is added:
(i) into melted fatty phase containing emulsifiers followed by emulsification with slow addition of previously prepared water-phase;
(ii) to previously prepared water-phase followed by emulsification by slow addition of melted fatty phase containing emulsifiers; ;iii) to previously prepared emulsion - cream.
Thus obtained product is emulsion. Depending on emulsifiers employed, cream can be emulsion of oil-in-water (U-V) type, or emulsion of water-in-oil (V-U) type. In U-V creams, ,,inner" phase is fatty phase which is finely dispersed (emulsified) in water phase which is ,,outer" or continuous phase. In 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.
It is clear to those skilled in the art that in the production of emulsions such as creams, several other variants of these three basic methods are possible, but they are within the scope of this invention.
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. 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.
Powders are prepared by dry homogenization of micronized clinoptilolite (Me-MC) with other excipients (fillers for powders such as talc, kaolin, or calcium carbonate) . To thus obtained basic powder mixture, other functional excipients are added (e.g. magnesium stearate) , and if desired, fragrances. The latter are usually 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. In the case of the use of artificial sweeteners, 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.
Preparations of other forms of the formulation of this invention correspond to standard procedures well known to those skilled in the art with several possible variations which are substantially within the scope of this invention.
EXAMPLES
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 0C. Example 1
Preparation of pure micronized calcium clinoptilolite (Ca-MC; CaAl2Si7Oi8) of enhanced mesoporosity from natural clinoptilolite (C; mainly CaAl2Si7Oi8)
Clinoptilolite (C; 1.00 kg; 1.73 mol; mainly calcium form; approx. CaAl2Si7Oi8) was suspended in demineralized water (5000 mL) . To obtained suspension, 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) . The product was dried under high vacuum at 105 0C during 20 h, yielding 934.51 g (93.5%) of acidic (H+) form of clinoptilolite (H-C; H2Al2Si7Oi8) as white to white off powder.
Thus obtained product (500.00 g; 0.928 mol) was suspended in demineralized water (2000 mL) . To this suspension, previously prepared solution of calcium chloride dihydrate (CaCl2 • 2H2O; 272.81 g; 1.86 mol; 2 ekv. ) in demineralized water (1000 mL) was added at once. The suspension was stirred at room temperature during 6 h. Then, the product was filtered, washed with demineralized water (5x500 mL) , and dried at 105 °C under high vacuum during 20 h, giving pure calcium clinoptilolite (Ca-C; CaAl2Si7OiB) as white off powder.
Analysis for CaAl2Si7Oi8; Calculated: CaO 9.69%; Al2O3 17.62%; SiO2 72.69%; Found: CaO 9.41%; Al2O3 17.49%; SiO2 72.29%.
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-MC2 (15 min) and Ca-MC3 (30 min) of particles size ranging from 100 nm to 2 μm (the peak of Gauss-type curve was between 0.8 and 1.2 μm) .
Results of samples surfaces analyses: total porous volume (cm3/g) ; BET total surface area m2/g) ; and total mesoporous surface area (m2/g) are given in Table 1.
Example 2
Preparation of pure micronized magnesium clinoptilolite (Mg- MCi; MgAl2Si7Oi8) of enhanced mesoporosity from natural clinoptilolite (C; mainly CaAl2Si7Oi8)
Clinoptilolite (C; 1.00 kg; 1.73 mol; mainly of calcium form; approx. CaAl2Si7Oi8) 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
(3x500 mL) , and dried at 105 °C under high vacuum during 20 h, giving 949.81 g (95%) of ammonium (NH4 +) form of clinoptilolite
(NH4-C; corresponds to (NH4J2Al2Si7Oi8) as white to greyish powder.
Thus obtained product (500.00 g; 0.928 mol) was suspended in demineralized water (2000 mL) , and previously prepared solution of magnesium chloride hexahydrate (MgCl2* 6H2O; 282.00 g; 1.39 mol; 1.5 ekv. ) in demineralized water (2000 mL) was added. The suspension was stirred at room teemperature for 20 h. Then, the product was separated by filtration, washed with demineralized water (5x500 mL) , and dried at 105 0C under high vacuum during 20 h affording pure magnesium clinoptilolite (Mg-C; MgAl2Si7Oi8) in the form of white off powder. Analysis for MgAl2Si7Oi8; Calculated: MgO 7.16%; Al2O3 18.12%; SiO2 74.72%; Found: MgO 6.97%; Al2O3 17.85%; SiO2 74.13%.
Pure magnesium clinoptilolite was micronized (1 min) in described microniser giving micronized product Mg-MCi of particles size 100 nm to 2 μm (the peak of Gauss-type curve was around 1 μm) ; BET total surface area of 29,1 m2/g; and total mesoporous surface area of 15,8 m2/g.
Example 3
Preparation of pure micronized zinc clinoptilolite (Zn-MCi; ZnAl2Si7OIe) of enhanced mesoporosity from natural clinoptilolite (C; mainly CaAl2Si7Oi8)
Clinoptilolite (C; 100.00 g; 0.173 mol; mainly of calcium form; approx. CaAl2Si7OiS) was suspended in demineralized water (500 mL) . To thus obtained suspension, 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. Then, the crystals were separated by filtration, washed with demineralized water (3x30 mL) , and dried at 105 °C under high vacuum during 20 h, yielding 92.71 g (92.7%) of acidic (H+) form of clinoptilolite (H-C; corresponds to H2Al2Si70iβ) as white off powder.
This product (50.00 g; 0.09 mol) was suspended in demineralized water (200 mL) , and previously prepared solution of zinc sulphate heptahydrate (ZnSO4* 7H2O; 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; ZnAl2Si7Oi8) as white powder.
Analysis for ZnAl2Si7Oi8; Calculated: ZnO 13.48%; Al2O3 16.88%; SiO2 69.64%; Found: ZnO 13.32%; Al2O3 16.83%; SiO2 69.65%.
This product was subjected to micronization in described microniser giving zinc clinoptilolite (Zn-MCi) of enhanced mesoporosity; particles size 100 nm to 2 μm (the peak of Gauss-type curve was around 1 μm) ; BET total surface area of 30.9 m2/g; and total mesoporous surface area of 17.3 m2/g.
Example 4
Study of adsorption of cadaverine (CAD) on classically micronized clinoptilolite (Ca-mC) and on clinoptilolite (Ca- MCi, Ca-MC2, Ca-MC3) of enhanced mesoporosity
The study was conducted by mixing cadaverine (CAD; 100 mg) in double-distilled water (100 mL) in the presence of clinoptilolites (Ca-mC, Ca-MCi, Ca-MC2, Ca-MC3; 1.00 g) during 1 h. Then, samples of clinoptilolites were removed by filtration, and each filtrate was diluted with distilled water to 100 mL. Aliquot (1 mL) of each filtrate was analysed by classical titration with 0. IM standard solution of hydrochloric acid using methyl orange as indicator. From used volume of 0. IM HCl, weight (mg) of cadaverine (Mr= 102.18) remained in supernatant was calculated. From starting amount of CAD employed in the analysis (100 mg) and determined amount of CAD in supernatant, weight of CAD adsorbed on each sample of clinoptilolite was calculated. These results are given in Table 2. Example 5
Study of adsorption of aflatoxin Bl on classically micronized clinoptilolite (Ca-mC) and on clinoptilolite (Ca-MCi, Ca-MC2, Ca-MC3) of enhanced mesoporosity
Accurately weighted sample (20 mg) of aflatoxin Bl was transferred into 100 mL flask, and dissolved in acetonitrile . Aliquots (4x) of 10 mL of such prepared solution were transferred into four flasks. Accurately weighted samples of clinoptilolite (100 mg; Ca-mC, Ca-MCi, Ca-MC2, Ca-MC3) were added into flasks (100 mL) , and distilled water was added up to 100 mL into each flask. Suspensions were stirred at room temperature during 1 h. The mixtures was then filtered, and thus prepared filtrates were analysed by HPLC using the following method: column Hypersil C18 (150 mm x 4.6 mm); MeOH- water-MeCN (25:25:50; V/V/V) as mobile phase; fluorescence detector (366/418 nm) ; injection volume 10 μL; room temperature. From obtained results, weight of aflatoxin Bl in each supernatant was calculated. From these values, weight of aflatoxin Bl adsorbed on each sample of clinoptilolite was calculated. Results given as adsorption capacity (%) are presented in Table 3.
Example 6
Study of mercury absorption on classically micronized clinoptilolite (Ca-mC) and on clinoptilolite (Ca-MCi, Ca-MC2, Ca-MCs) of enhanced mesoporosity
A solution (1000 mL) of mercury (II) nitrate monohydrate (Hg (NO3) 2 0H2O; 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 Hg2+, clinoptilolites (500 mg; Ca-mC, Ca-MCi, Ca-MC2, Ca-MC3) were added. Suspensions were stirred at room temperature during 5, 10, 15 and 20 minutes. At these time points, suspensions were filtered through Bϋchner 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.
Example 7
Study of efficacy of adsorption of bacterial cells of Escherichia coli and Bacillus subtilis on classically micronized clinoptilolite (Ca-mC) and on clinoptilolite (Ca- MCi) of enhanced mesoporosity
Comparative study of absorption of bacterial cells of Escherichia coli (XLl-blue) and Bacillus subtilis (IAM 12118) on samples (25 mg) of classically micronized clinoptilolite (Ca-mC) , and micronized clinoptilolite of enhanced mesoporosity (Ca-MCi, Ca-MC2, Ca-MC3) was performed. The cultivation medium was according to Luria-Bertrani, which contained: 10 g tryptone; 5 g yeast extract; 5 g NaCl; 1000 mL distilled water; pH 7. The cultures were incubated at 37 0C overnight. The starting cultures were transferred onto solid agar plates prepared with the same medium. Samples of bacterial cells of E. coli and B. subtilis were isolated by centrifugation (1500 x g; 4 °C/15 min) , washed with 10 mM 3- morfoline propanesulfonic acid buffer (pH 7) . Thus obtained samples of bacterial cells in the form of pellets were suspended in the same buffer. Aliquot (1 mL) of cell suspension was incubated with 25 mg of each clinoptilolite (Ca-mC, Ca-MCi, Ca-MC2, Ca-MC3) in the presence of 150 mM NaCl. Absorbances of the supernatants were determined at 600 nm. The spectrofotometer was adjusted to 100% absorbancy by using original suspension of bacterial cells without clinoptilolite added. From obtained results, percentage of absorbed cells (%) was calculated. Results are given in Table 5.
Example 8
Study of inhibition of proliferation of HSVl viruses by micronized clinoptilolite (Ca-mC) and by clinoptilolites (Ca- MCi, Ca-MC2, Ca-MC3) of enhanced mesoporosity
The study of inhibition of proliferation of herpesvirus of type 1 (HSVl; ATCC No.: VR-733) by clinoptilolites (Ca-mC, Ca- MCi, Ca-MC2, Ca-MC3) was performed. HSVl were propagated on human cervical carcinoma cells (HeLa) . HeLa cells were propagated in Dulbecco's medium supplemented with: 10% inactivated foetal bovine serum; 1% L-glutamine; 0.3% NaHCO3; at 37 0C and 5% CO2. 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 (2xlθVmL) were infected with viruses after one day. Clinoptilolites (Ca-mC, Ca-MCi, Ca-MC2, Ca-MC3) were added in concentration of 50 mg/mL. After incubation (37 0C; 5% CO2) , 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.
Example 9
Preparation of 250 mg tablets of micronized calcium clinoptilolite (Ca-MCi) Content (100 g of tablet mixture) : (a) Microcrystalline cellulose (40.00 g; 40%), (b) lactose monohydrate (28.00 g; 28%), (c) sodium starch glycolate (3.00 g; 3%), (d) polyvinylpyrrolidone (3.00 g; 3%), (e) magnesium stearate (1.00 g, 1%), (f) micronized calcium clinoptilolite (Ca-MCi; 25.00 g; 25%) ,
Procedure: Ingredients (a), (b) , (c) , (d) and (f) were homogenized in dry homogenizer during 15 minutes. Then, (e) was added and homogenization was continued for 15 minutes. Then, homogeneous mixture was milled, and compressed into tablets yielding 100 tablets (1 g) ; Average tablet weight 993 mg.
Example 10
Preparation of powder with 10% of micronized calcium clinoptilolite (Ca-MCi)
Content (100 g of powder): (a) Talc (54.00 g; 54%), (b) kaolin (20.00 g; 20%), (c) micronized calcium clinoptilolite (Ca-MCi; 10.00 g; 10%), (d) precipitated calcium carbonate (5.00 g; 5%), (e) zinc oxide (5.00 g; 5%), (f) zinc stearate (5.00 g; 5%), (g) heavy mineral oil (1.00 g; 1%) .
Procedure: In a homogenizer (a), (b) and (c) were added, and the mixture was mixed for 10 minutes. Then (d) , (e) , (f) and (g) were added, and the resulting mixture was mixed for 30 minutes, giving white off, fine gentle powder, without dusting tendencies . Example 11
Preparation of ointment with 10% of micronized clinoptilolite (Ca-MCi)
Content (100 g of ointment): (a) Petroleum jelly (40.00 g; 40%), (b) heavy mineral oil (49.50 g; 49.5%), (c) clinoptilolite (Ca-MC1; 10.00 g; 10%), (d) d-panthenol (0.50 g; 0.5%) .
Procedure: (b) was slowly heated to 60 0C, and then (a) and (c) were added with stirring. The mixture was stirred at this temperature until clear oily liquid was formed. Then, (d) was added, and stirring was continued for 15 minutes. Thus obtained mixture was carefully poured into small (25 mL) plastic jars. The product was in the form of fine, white to slightly greenish, odourless, semi-solid ointment.
Example 12
Preparation of cream with 1% of micronized zinc clinoptilolite (Zn-MCi)
Content (100 g of cream): (a) Petroleum jelly (20.00 g; 20%), (b) stearyl alcohol (20.00 g; 20%), (c) lanolin (2.00 g; 2%), (d) isopropyl myristate (1,50 g; 1,5%), (e) sodium laurylsulphate (1.00 g; 1%), (f) methyl 4-hydroxybenzoate (0.20 g; 0.2%), (g) sorbitol (7.00 g; 7%), (h) 1,2- propyleneglycol (3.00 g; 3%), (i) micronized zinc clinoptilolite (Zn-MCi; 1-00 g; 1%), (j) purified water (44.30 g; 44.3%) .
Procedure: (a) and (b) were carefully melted with stirring, and further heated to 80 0C with stirring. Then, (c) , (d) , (e) and (f) were added. The mixture was stirred at this temperature for 15-20 min. Water phase was prepared by dissolution of (g) and (h) in (j), and added drop-wise during 30 min. Thus obtained emulsion was vigorously stirred at temperatures between 80 0C and 50 °C during 15-20 minutes, and then (i) was added. The cream was vigorously stirred at 50 0C for 20-40 minutes, and then carefully cooled to room temperature with constant stirring. The product was additionally homogenized by mixing at room temperature during 15 min. The product was a white, fine, semi-solid cream with only slight smell after lanoline.
Example 13
Preparation of gel with 10% micronized calcium clinoptilolite (Ca-MC1)
Content (100 g of gel): (a) 1, 2-Propyleneglycol (30.00 g; 30%), (b) polypropyleneglycol 425 (1.50 g; 1.5%), (c) glycerol (2.50 g; 2.5%), (d) carbopol 934P (1.00 g; 1%), (e) triethanolamine (q.s.), (f) micronized calcium clinoptilolite (Ca-MCi; 10.00 g; 10%), (g) sodium benzoate (0.20 g; 0.2%), (h) potassium sorbate (0.30 g; 0.30%), (i) anhydrous citric acid (0.50 g; 0.5%), (j) purified water (54.00 g; 54%) .
Procedure: To (j) with vigorous stirring (d) was added, and the mixture was stirred at room temperature during 2 h giving clear viscous liquid. Then, (a) , (b) , (c) , (g) , (h) and (i) were added, and the mixture was stirred at room temperature for additional 10 min. Then, (f) was added and stirred for 10 minutes, and then (e) was added and mixed until white gel was obtained (pH should be between 6-6.5) . The product was in the form of fine, white, odourless semi-solid gel. Example 14
Preparation of cosmetic mask with 20% of micronized calcium clinoptilolite (Ca-MCi)
Content (100 g of mask) : (a) Petroleum jelly (8.50 g; 8.5%), (b) glycerol monostearate (4.00 g; 4%), (c) cetyl alcohol (2.00 g; 2%), (d) cetyl palmitate (0.80 g; 0.8%), (e) beeswax (2.50 g; 2.5%), (f) ceteareth-20 (0.90 g; 0.9%), (g) ceteareth-12 (0.60 g; 0.6%), (h) dimethicone (0.50 g; 0.5%), (i) sweet almond oil (3.00 g; 3%), (j) jojoba oil (1.00 g;
1%), (k) tocoferol acetate (0.50 g; 0.5%), (1) retinol palmitate (0.05 g; 0.05%), (m) nicotinamide (0.20 g; 0.2%), (n) isopropyl myristate (1.20 g; 1.2%), (o) methyl 4- hydroxybenzoate (0.20 g; 0.2%); (p) ethyl 4-hydroxybenzoate (0.03 g; 0.03%), (q) propyl 4-hydroxybenzoate (0.03 g; 0.03%), (r) butyl 4-hydroxybenzoate (0.03 g; 0.03%), (s) carbopol 934P (0.60 g; 0.6%), (t) sodium hydroxide (0.90 g of 20% aqueous solution), (u) 1, 2-propyleneglycol (0.50 g; 0.5%), (v) glycerol (2.50 g; 2.5%), (w) micronized calcium clinoptilolite (Ca-MCi; 20.00 g; 20%), (z) mixture of essential oils of lavender : lemon (1.00 g; 2:1, m/m; 1%), (x) purified water (48.46 g; 48.46%) .
Procedure: (a), (b) , (c) , (d) , (e) , (f) and (g) were carefully melted. Thus obtained melt was further heated to 70-75 0C with constant stirring. Then, (h) , (i) , (j) and (n) were added, followed by (k), (1), (m) , (o) , (p) , (q) and (r) , and stirring was continued during additional 15 min. To this suspension, aqueous phase was added at 70-75 0C drop-wise during 30 min. The aqueous phase was previously prepared by dissolution of (s), (u) and (v) in (x) . Then, (t) was added to the cream. 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 0C during 30 min, and then was cooled to 40 0C. 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.
Therefore, we demonstrated the industrial applicability (i.e. the use) of the present invention, where the core of the invention is defined by the claims.

Claims

1. Formulation based on micronized clinoptilolite (Me-MC), characterized by the ingredients selected from:
(i) Me-MC with increased mesoporosity of general formula (Men+)x/n [ (AlO2) x (SiO2) y] • JnH2O, where Me= H, Li, Na, K, Mg, Ca, Zn, Ag, Cu, Mn, or Fe; wherein the ratio of silicon/aluminum, is between 3/1 to 6/1; with the particles size from 100 nm to 2 μm, with the BET total surface area of at least 30 m2/g, and total mesoporous surface area of at least 15 m2/g, with portion of total mesoporous surface area within BET total surface area of at least 50%; and
(ii) one or more suitable excipients to produce the desired pharmaceutical form; tablets, capsules, ointments, creams, gels, lotions, powders, liquid powders, compact powders, masks, suspensions, syrups, and therapeutic patches.
2. Formulation according to claim 1, characterized by that the excipient is selected from the groups consisting of fillers, binders, disintegrants, lubricants, emollients, emulsifiers, fillers for powders, tensides, solvents, humectants, thickeners, preservatives, antioxidants, stabilizers, colors, fragrances, pH control additives; and additives which promote basic detoxification action of micronized clinoptilolite through faster removal of already occured consequences of toxification.
3. Formulation according to claims 1 and 2, characterized by that the excipient is filler selected from the group consisting of: microcrystalline cellulose; lactose monohydrate; calcium hydrogenphosphate; sucrose; glucose; silicon dioxide; sorbitol; mannitol; starch; modified starches; or mixtures of these substances.
4. Formulation according to claims 1-3, characterized by -that the excipient is binder selected from the group consisting of: polyvinylpyrrolidone; polyvinylpyrrolidone co-polymers; lactose monohydrate; glucose; mannitol; sorbitol; starch; modified starches; carrageenans; gum arabic; alginates; sodium carboxymethylcellulose; sucrose; gelatine; or mixtures of these substances.
5. Formulation according to claims 1-4, characterized by that the excipient is disintegrant selected from the group consisting of: polyvinylpyrrolidone; polyvinylpyrrolidone co-polymers; agar agar; starch; alginic acid; sodium alginate; sodium starch glycolate; or mixtures of these substances .
6. Formulation according to claims 1-5, characterized by that the excipient is lubricant selected from the group consisting of: talc; stearic acid; magnesium stearate; calcium stearate; zinc stearate; solid polyethyleneglycols; solid polypropyleneglycols; sodium laurylsulphate or related substances; or mixtures of these substances.
7. Formulation according to claims 1-6 characterized by that the excipient is emollient 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 like 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 like cetyl alcohol, stearyl alcohols, cetostearyl alcohol, oleyl alcohol; poly (dimethylsiloxane) , poly (dicyclohexylsiloxane) , other polymeric liquid or semisolid silicones; liquid, semi-solid, or solid polyethyleneglycols; liquid, semi-solid, or solid polypropyleneglycols; or mixtures of these substances.
8. Formulation according to claims 1-7, characterized by that the excipient is emulsifier selected from the group consisting of: 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 alcohol; etoxylates of higher fatty acids such as polyoxyethylene (2) laurate, polyoxyethylene (10) stearate, polyoxyethylene (23) oleate, where 2, 10 and 23 represent average number of ethyleneglycol units on higher fatty acids; ethoxylates of sorbitan esters of higher fatty acids such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan sesquioleate; castor oil and its etoxylates; or mixtures of these substances.
9. Formulation according to claims 1-8, characterized by that the excipient is filler for powders selected from the group consisting of: talc; kaolin; bentonite; montmorillonite; calcium carbonate; basic magnesium carbonate; calcium silicate; aluminum hydroxide; silicon dioxide; purified clays; microcrystalline cellulose; or mixtures of these substances .
10. Formulation according to claims 1-9, characterized by that the excipient is tenside selected from the group consisting of: soaps like 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 cocoamphodiacetate; polyoxyethylene (10) laurylether, polyoxyethylene (10) laurylether, polyoxyethylene (23) laurylether, polyoxyethylene (10) stearylether, polyoxyethylene (23) stearylether, polyoxyethylene (10) oleylether, polyoxyethylene (23) oleylether, or other ethoxylates of higher fatty alcohols with H. 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. factor ≥10; sorbitan esters like polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, or polyoxyethylene sorbitan monooleate; 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; tenside-containing plant extracts such as extract of soapwort {Saponaria officinalis) ; or mixtures of these substances .
11. Formulation according to claims 1-10, characterized by that the excipient is solvent 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 malate; diethyl tartarate; diethyl sebacate; diisopropyl adipate; dimethylsulfoxide; triethylhexanoin; or mixtures of these substances.
12. Formulation according to claims 1-11, characterized by -that the excipient is humectant selected from the group consisting of: 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 co-polymers; or mixtures of these substances.
13. Formulation according to claims 1-12, characterized by that the excipient is thickener selected from the group consisting of: 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.
14. Formulation according to claims 1-13, characterized by that the additive for promoting basic detoxification action of clinoptilolite is 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, β-carotene, niacinamide, d-panthenol, calcium pantothenate, folic acid, riboflavin, pyridoxine or its derivatives, ascorbic acid, ascorbyl palmitate, tocoferol acetate; benzoylperoxide; azelaic acid; resorcinol; resorcinol monoacetate; tars; naphthalan; γ-linolenic acid or plant oils with significant percentage of γ-linolenic acid such as fish oil or soybean oil; allantoin or herbal extracts with significant amounts of allantoin such as extract of comfrey {Symphytum officinale) ; hypericin or extract of Saint John's worth (Hypericum perforatum) ; azulene or extract of chamomile {Matricaria recutita) ; extract of marigold {Calendula officinalis) ; extract of arnica (Arnica montana) ; extract of white willow (Salix alba cortex); capsaicin or extract of chili pepper (Capsici fruct.) ; extract of white mustard (Brassica alba) ; menthol; essential oil or extract of peppermint (Mentha piperita) ; essential oil or extract of rosemary (Rosmarinus officinalis) ; green tea extract (Camellia sinensis) ; extract of rooibos (Aspalathus linearis) ; nettle extract (Urtica dioica) ; aescin; horse- chestnut extract (Hippocastani sem.) ; primrose extract (Primula officinalis) ; extract of centaurium (Erythraea centaurium) ; mullein extract (Verbascum phlomoides) ; extract of holly (Ilex aquifolium) ; borage extract (Borago officinalis) ; burdock extract (Arctium lappa) ; extract of ribwort plantain (Plantago lanceolata) ; extract of leaves and root of century plant (Agave americana) ; extract of ground pine {Lycopodium clavatum) ; extract of common ivy {Hedera helix) ; extracts of herbals with significant contents of silicic acid (H4SiO4) such as field horsetail {Equisetum arvense) , lungwort {Pulmonaria officinalis) , common knotgrass (Polygonum aviculare) , Agropyron (repens) , common agrimony {Agrimonia eupatoria) , oat (Avena sativa) , Taraxaci radix; zinc oxide; zinc tannate; bismuth subnitrate; bismuth subcarbonate; bismuth phosphate; bismuth tannate; calamine; silver proteine; peru balsam; titanium dioxide; tannic acid; albumin tannate; methylene ditannate; herbal extracts with significant contents of tannins such as extracts of oak bark (cortex Quercus ruber, Quercus sessiliflora, Gallae asiaticae) , blackberry {Rubus fruticosus) , bearberry leaves (Arctostaphylos uvae ursi) , common agrimony (Agrimonia eupatoria) , silverweed (Potentilla anserina) , rhizoma Potentilla tormentillae, common bistrot (Polygonum bistorta) , Filipendula ulmaria, or common sage (Salvia officinalis) ; α-hydroxy-acids such as glycolic, lactic, malic, citric, and tartaric acid; urea; coenzyme QlO; betaine; methionine; S-adenozyl- methionine; catechin; quercetin; rutin; citiolone; malotilate; phosphoryl choline; protoporphyrin IX; α-lipoic acid [5- (1, 2-dithiolane-3-il) valeric acid] or its salts with pharmaceutically acceptable bases; timonacic (4- thiazolidine-2-carboxylic acid) or its salts with pharmaceutically acceptable acids and bases; tiopronin; silymarin or milk thistle extract (Silybum marianum) ; cyanidin or extract of Vaccinium myrtillus; hesperidin; diosmin; extract of orange (Citrus aurantium) ; lycopene or extracts with significant amounts of lycopene; resveratrol; tetrahydrocurcumin; rosmarinic acid; chlorogenic acid; oleuropein; extract of olive leaves (Olea europea) ; grape seed extract; pycnogenol; carnosine; glutathione; or compatible mixtures of these substances.
15. The use of the formulation according to claims 1-14, as the therapeutic agent for removal of toxins from human or animal organism which enter through gastrointestinal tract, by breathing, or through skin and/or mucous membranes.
16. The use of the formulation according to claim 15, where the toxin is selected from the groups consisting of: micotoxins; polycyclic aromatic hydrocarbons; nitrosamines; heavy metals; aliphatic and aromatic amines; acrylamide; dioxins; or mixtures of these toxins.
17. The use of the formulation according to claims 1-14, as the therapeutic agent for prevention entering of toxins into human or animal organism through gastrointestinal tract, by breathing, or through skin and/or mucous membranes.
18. The use of the formulation according to claims 1-14, as the therapeutic agent for removal of bacteria from human or animal organism which enter through gastrointestinal tract, by breathing, or through skin and/or mucous membranes.
19. The use of the formulation according to claims 1-14, as the therapeutic agent for removal of viruses from human or animal organism which enter through gastrointestinal tract, by breathing, or through skin and/or mucous membranes.
PCT/HR2008/000013 2008-04-28 2008-04-28 Formulation based on micronized clinoptilolite as a therapeutic agent for removal of toxins, bacteria and viruses from organism WO2009133413A1 (en)

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011101340A1 (en) * 2010-02-22 2011-08-25 Biotake Gmbh Zeolite-containing preparations containing clinoptilolite and uses thereof
ITRM20100435A1 (en) * 2010-08-03 2012-02-04 Ecobase Gmbh ZEOLITES WITH NEUROPROTECTIVE ACTION
WO2012156913A1 (en) * 2011-05-18 2012-11-22 Slavko Ivkovic An antioxidant composition
KR20130121899A (en) * 2010-12-02 2013-11-06 온콜리틱스 바이오테크 인코포레이티드 Liquid viral formulations
CN104941675A (en) * 2015-05-21 2015-09-30 河南师范大学 Preparation method of bismuth phosphate photocatalyst with controllable shape
CN106075799A (en) * 2016-07-08 2016-11-09 广西大学 A kind of Chinese medicine composition of degrading polycyclic aromatic hydrocarbons
US20170136060A1 (en) * 2015-11-12 2017-05-18 Glock Health, Science And Research Gmbh Treatment of vaginitis
EP3329926A1 (en) * 2016-12-02 2018-06-06 Hraschan, Jakob Zeolite compositions and method for the production thereof
CN108670897A (en) * 2018-05-29 2018-10-19 安徽省银锂子生物科技发展有限公司 A kind of Efficient antibacterial wet tissue composition and preparation method thereof
CN108671896A (en) * 2018-05-17 2018-10-19 盐城工学院 A kind of modified montmorillonite used and preparation method thereof, heavy metal chelating agent
RU2680832C1 (en) * 2018-01-17 2019-02-28 Талагаева Елена Владимировна Clay masks for face and body
WO2019038782A1 (en) * 2017-08-22 2019-02-28 Rajesh Chandrakant Soni A novel detox with mineral composition and process to balance human hormonce
CN109880175A (en) * 2019-03-06 2019-06-14 江苏申凯包装高新技术股份有限公司 A kind of double template mesoporous supports/light stimulus responsiveness assembly
WO2019179597A1 (en) * 2018-03-19 2019-09-26 Symrise Ag Water-soluble release forms for an active substance
CN111358760A (en) * 2020-05-13 2020-07-03 扬子江药业集团广州海瑞药业有限公司 Ticagrelor tablet pharmaceutical composition and preparation method thereof
CN111529510A (en) * 2020-05-09 2020-08-14 重庆医科大学 Application of nanoparticles as tumor microenvironment responsive drug or imaging agent
CN115254019A (en) * 2022-07-21 2022-11-01 河南农业大学 Silicate functional mycotoxin adsorbent and preparation method thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5443812A (en) * 1989-04-24 1995-08-22 Kanebo Ltd. Stabilized synthetic zeolite and a process for the preparation thereof
WO1998024724A1 (en) * 1996-11-26 1998-06-11 Battelle Memorial Institute Mesoporous-silica films, fibers, and powders by evaporation
WO2005041657A1 (en) * 2003-10-20 2005-05-12 Framework Therapeutics, L.L.C. Zeolite molecular sieves for the removal of toxins
WO2007029208A2 (en) * 2005-09-10 2007-03-15 Kevin Gast Pharmaceutical composition which includes clinoptilolite

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5443812A (en) * 1989-04-24 1995-08-22 Kanebo Ltd. Stabilized synthetic zeolite and a process for the preparation thereof
WO1998024724A1 (en) * 1996-11-26 1998-06-11 Battelle Memorial Institute Mesoporous-silica films, fibers, and powders by evaporation
WO2005041657A1 (en) * 2003-10-20 2005-05-12 Framework Therapeutics, L.L.C. Zeolite molecular sieves for the removal of toxins
US20050106267A1 (en) * 2003-10-20 2005-05-19 Framework Therapeutics, Llc Zeolite molecular sieves for the removal of toxins
WO2007029208A2 (en) * 2005-09-10 2007-03-15 Kevin Gast Pharmaceutical composition which includes clinoptilolite

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
GRCE M ET AL: "Antiviral properties of clinoptilolite", MICROPOROUS AND MESOPOROUS MATERIALS, ELSEVIER SCIENCE PUBLISHING, NEW YORK, US, vol. 79, no. 1-3, 1 April 2005 (2005-04-01), pages 165 - 169, XP004784522, ISSN: 1387-1811 *
NOVIKOVA L A ET AL: "Effect of treatment with acids on the state of the surface of natural clay minerals", RUSSIAN JOURNAL OF PHYSICAL CHEMISTRY, NAUKA/INTERPERIODICA, MO, vol. 80, no. 1, 1 November 2006 (2006-11-01), pages S185 - S188, XP019456560, ISSN: 1531-863X *
SPRYNSKYY ET AL: "Study of the selection mechanism of heavy metal (Pb<2+>, Cu<2+>, Ni<2+>, and Cd<2+>) adsorption on clinoptilolite", JOURNAL OF COLLOID AND INTERFACE SCIENCE, ACADEMIC PRESS, NEW YORK, NY, US, vol. 304, no. 1, 1 December 2006 (2006-12-01), pages 21 - 28, XP005716659, ISSN: 0021-9797 *
SPRYNSKYY M ET AL: "Ammonium sorption from aqueous solutions by the natural zeolite Transcarpathian clinoptilolite studied under dynamic conditions", JOURNAL OF COLLOID AND INTERFACE SCIENCE, ACADEMIC PRESS, NEW YORK, NY, US, vol. 284, no. 2, 15 April 2005 (2005-04-15), pages 408 - 415, XP004787391, ISSN: 0021-9797 *

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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