WO2019052471A1 - Composition de fullerène et procédé de préparation et utilisation de cette dernière - Google Patents

Composition de fullerène et procédé de préparation et utilisation de cette dernière Download PDF

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WO2019052471A1
WO2019052471A1 PCT/CN2018/105240 CN2018105240W WO2019052471A1 WO 2019052471 A1 WO2019052471 A1 WO 2019052471A1 CN 2018105240 W CN2018105240 W CN 2018105240W WO 2019052471 A1 WO2019052471 A1 WO 2019052471A1
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Prior art keywords
fullerene
oil
emulsion
water
injection
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PCT/CN2018/105240
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English (en)
Chinese (zh)
Inventor
王春儒
李慧
许哲
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北京福纳康生物技术有限公司
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Priority claimed from CN201710817804.4A external-priority patent/CN109481464B/zh
Priority claimed from CN201710817127.6A external-priority patent/CN107411983B/zh
Priority claimed from CN201710818005.9A external-priority patent/CN109481396B/zh
Priority claimed from CN201710817414.7A external-priority patent/CN109481463B/zh
Application filed by 北京福纳康生物技术有限公司 filed Critical 北京福纳康生物技术有限公司
Publication of WO2019052471A1 publication Critical patent/WO2019052471A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/44—Elemental carbon, e.g. charcoal, carbon black
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/92—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants

Definitions

  • the invention relates to the field of fullerenes, in particular to a water-soluble fullerene and a preparation method and application thereof, and to a water-soluble fullerene external composition, an oral fullerene emulsion, and a fullerene emulsion for injection. And their preparation methods and applications.
  • fullerenes A series of molecules having a cage-like carbon cluster structure are collectively referred to as fullerenes, which are another allotrope of carbon other than graphite, diamond, and amorphous carbon.
  • Fullerenes mainly include hollow fullerenes, embedded fullerenes, fullerene derivatives, and heterocyclic fullerenes.
  • the large ⁇ -bond conjugated system composed of multiple P orbitals of fullerenes has a strong ability to accept electrons, and because of its unique structure and physicochemical properties, it has excellent scavenging free radical properties.
  • "Free radical sponge” also exhibits excellent antioxidant properties, making it widely concerned in cosmetic materials, biomedicine and other fields.
  • C60 can still eliminate the reactive oxygen species in the cell, inhibit the depolarization of mitochondria, the activation of cysteine protease, the exposure of phosphatidylserine on the cell membrane and the splitting of DNA.
  • C60 shows Protect cells from oxidative apoptosis.
  • the C60 liposome complex acts as an antioxidant against UVA damage to the skin structure, nucleus and collagen fibers, and penetration into human skin tissue. It is 172 times more potent than vitamin C and is capable of affinity with free radicals.
  • Patent WO2013/025180A1 mixes fullerene powder with vegetable oil, and after ball milling, centrifugation and filtration, obtains fullerene vegetable oil, and treats the disease by directly drinking fullerene vegetable oil.
  • Oral preparations generally have a problem of low bioavailability, so that the preparation of the drug into an injectable form, especially for a disease with a high degree of malignancy such as cancer, can better exert the therapeutic effect on the disease. Due to the fullerene characteristics, solubility in most solvents is very poor, usually dissolved in aromatic solvents such as toluene, chlorobenzene and the like.
  • Fullerenes are hardly soluble in water, and therefore, the characteristic that fullerenes are poorly soluble in water under normal conditions restricts their use in aqueous systems, especially in solution-type injections.
  • covalent modification introduces an amino group on the fullerene molecule by an addition reaction, and the hydroxyl group and/or the polar side chain can improve its solubility in water.
  • CN201210406707A uses an amine group to modify the fullerene to obtain a fullerene derivative.
  • Non-covalent modification on the surface of fullerene refers to the hydrophilic group and the appropriate size of the guest molecule to enhance the dispersion of fullerenes in water.
  • CN101284660A discloses that glucose is used as a solubilizing substance to obtain particles having a particle diameter of about 200 nm
  • CN102674312A discloses that a fullerene is treated with a cosolvent such as polyvinylpyrrolidone, polyethylene glycol or starch to obtain a particle diameter of 100-200 nm. Water soluble fullerene nanoparticles.
  • CN201410088515A discloses adding fullerene powder to water and using a long time magnetic force and mechanical stirring to make the particle size reach 2 nm, but it uses a long time of stirring to make a full amount of water molecules or hydroxyl groups attached to the fullerene. A small amount of dissolved into water, the concentration of fullerenes in water is very low, the highest is 1 / 1000, and precipitation will occur in long-term placement.
  • CN104983676A discloses a water-soluble fullerene injection which directly delivers the fullerene component to the human blood system by injection, so that the human body can absorb more fullerene components more quickly.
  • Fullerene injections are 0.01-8% by weight of sterile fullerenes, 45-60% polyoxyethylated castor oil, 35-50% anhydrous ethanol, polyoxyethylated castor oil and no Water ethanol is used as a solvent to fully dissolve fullerenes.
  • the polyoxyethylene-based castor oil in the patent can be used as an emulsifier to enhance the capacity, and the sensitization rate of the polyoxyethylene-based castor oil is high, and the sensitization mechanism has not been explained yet.
  • the viscosity of the injection is greatly increased, which may cause blood atheroma, which may cause embolism; and it will interact with the commonly used polyvinyl chloride plastic infusion device to leach the dioctyl phthalate, causing toxicity;
  • many solubilizers cause changes in biofilm morphology and tissue damage; the Pharmacopoeia stipulates that the amount of ethanol used is up to 12%. Excessive use of ethanol causes re-precipitation in the drug release and affects drug absorption and utilization.
  • an object of an embodiment of the present invention is to provide an aqueous solution of fullerene which has biosafety, high solubility in water, small particle size, and rapid absorption.
  • Another object of the embodiments of the present invention is to provide a method for preparing the fullerene aqueous solution, which is simple and easy to operate, has high stability, and is easy to be industrially produced.
  • Still another object of the present invention is to provide an injection containing the aqueous solution of fullerene, which is an intravenously injectable preparation having low toxicity, low sensitization, and low hemolytic activity.
  • the embodiment of the invention further provides that the aqueous fullerene solution and the injection thereof have the effects of treating tumor, Parkinson's disease, bone marrow inhibitor or eliminating free radical anti-aging in vivo.
  • the excipient 15-hydroxystearate polyethylene glycol ester has good biotolerance, high solubility to fullerenes, and low toxicity, low sensitization, low hemolytic property, and high content. In case of low viscosity. Direct intravenous injection, rapid action, not affected by pH, enzymes, food, etc., no first-pass effect, fullerene directly acts on human blood, allowing the body to quickly absorb fullerenes, better efficacy Play.
  • Embodiments of the present invention provide a technical solution, an aqueous solution of fullerene, the solute of which comprises fullerene and 15-hydroxystearic acid polyethylene glycol ester, wherein the fullerene and 15-hydroxystearic acid
  • the mass ratio of the polyethylene glycol ester is (0.01-10): (30-60).
  • an aqueous fullerene solution the solute of which comprises fullerene and 15-hydroxystearic acid polyethylene glycol ester, wherein the mass ratio of the fullerene and the 15-hydroxystearic acid polyethylene glycol ester For (1-10): (40-60).
  • an aqueous fullerene solution the solute of which comprises fullerene and 15-hydroxystearic acid polyethylene glycol ester, wherein the mass ratio of the fullerene and the 15-hydroxystearic acid polyethylene glycol ester (4-5): (50-60).
  • the fullerene aqueous solution of the embodiment of the present invention is a brownish yellow transparent liquid in which fullerene has a solubility of up to 3000 ppm and a particle diameter of 10-100 nm.
  • the fullerene is a hollow fullerene and/or a metal fullerene.
  • the fullerene is selected to select one or a mixture of one or more of C60, C70, C76, and C84.
  • Polyethylene glycol 15-hydroxystearate according to the examples of the present invention - in the conventional sense, mainly refers to the ethoxylation of 12-hydroxystearic acid and polyethylene glycol by 12-hydroxystearic acid. A mixture of monoesters and diesters obtained.
  • Polyethylene glycol 15-hydroxystearate is also known as a-hydrogen-omega hydroxy poly(oxy-1,2-ethanediyl); 12-hydroxystearic acid polyethylene glycol copolymer; polyethyl b Glycol 15-hydroxystearate; polyethylene glycol-15-hydroxystearate and polyethylene glycol 12012-hydroxystearate 12-hydroxyoctadecanoic acid polymer.
  • the polyethylene glycol ester of 15-hydroxystearic acid is HS15 (BASF AG, Germany).
  • HS15 consists of a polyethylene glycol monoester and a diester of 12-hydroxystearic acid (i.e., a lipophilic moiety) having about 30% free polyethylene glycol (i.e., hydrophilic). section).
  • Polyethylene glycol 15-hydroxystearate has lower hemolytic property, lower sensitization, higher solubility to fullerenes, lower viscosity of final injection, and higher safety than Tween-80, sesame oil and other co-solvents.
  • the embodiment of the invention also discloses the preparation method of the above fullerene aqueous solution, the fullerene and the 15-hydroxystearic acid polyethylene glycol ester are mixed together, and the mixture is vigorously mixed by a ball mill for 12-48 hours (optional 24h), ball milling During the process, the temperature is controlled at 35-45 degrees, homogenized, and the number of homogenization times is 1-7 times (optional 2-5 times), and finally a clear solution is obtained by filtration.
  • the fullerene aqueous solution according to the embodiment of the present invention can be used for one of active ingredients of health care products or medicines or foods or skin care products or hair products, and the amount thereof is 0.01-99.99%.
  • the aqueous solution according to the embodiment of the present invention may be administered orally, intramuscularly, subcutaneously, intradermally or intraperitoneally, and the suppository is administered rectally or sublingually.
  • the aqueous solution can be made into an acceptable dosage form by a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier may be from 0.1 to 99.9% by weight based on the total weight of the formulation.
  • Fullerene oil is present in a form suitable for pharmaceutical use.
  • Pharmaceutically acceptable preparations are tablets, capsules, granules, pills, powders, ointments, suspensions, injections, powders, suppositories, creams, drops, or patches.
  • the tablet is a sugar-coated tablet, a film-coated tablet, an enteric-coated tablet or a sustained-release tablet;
  • the capsule is a hard capsule, a soft capsule, a sustained release capsule;
  • the powder injection is Freeze-dried powder injection.
  • the pharmaceutically acceptable carrier is selected from the group consisting of: mannitol, sorbitol, sorbic acid or potassium salt, sodium metabisulfite, sodium hydrogen sulfite, sodium thiosulfate, cysteine hydrochloride, thioglycolic acid, methionine, vitamin A, Vitamin C, vitamin E, vitamin D, azone, EDTA disodium, EDTA calcium sodium, monovalent alkali metal carbonate, acetate, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, chlorine Sodium, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and its derivatives, alginate, Gelatin, polyvinylpyrrolidone, glycerin, propylene glycol,
  • the fullerene aqueous solution of the embodiment of the present invention as a preparation form, the effective amount of the fullerene aqueous solution contained in each dose is 0.1-1000 mg, and each dose refers to each preparation unit, such as each tablet Each capsule can also refer to each dose, such as taking 100mg each time. While the amount of active ingredient contained in the dosage unit form can vary, it will generally be in the range of from 1 to 1000 mg, depending on the potency of the active ingredient selected.
  • Liquid formulations of the embodiments of the invention include solutions, suspensions and emulsions.
  • an injection preparation for parenteral administration may be in the form of water or a water-propylene glycol solution, adjusting its isotonicity, pH, etc. to suit physiological conditions of a living body.
  • Liquid preparations can also be prepared in the form of solutions in polyethylene glycol, aqueous solutions.
  • An oral aqueous solution can be prepared by dissolving the active ingredient in water, followed by the addition of a suitable amount of coloring, flavoring, stabilizing and thickening agents.
  • the micronized active ingredient can be dispersed in viscous materials such as natural and synthetic gums, methylcellulose, sodium carboxymethylcellulose, and other known suspending agents to prepare aqueous suspensions suitable for oral administration.
  • Dosage unit form of the formulation refers to physically discrete units suitable as a single dose, each unit containing a calculated predetermined amount of active ingredient that produces the desired therapeutic effect.
  • Such dosage unit forms can be in the form of a package such as a tablet, a capsule or a powder in a vial or vial, or an ointment, gel or cream in a tube or vial.
  • the fullerene aqueous solution may be selected into a fullerene injection, which comprises 30-70% by weight of the fullerene aqueous solution, and the balance water for injection.
  • the fullerene injection of the embodiment of the present invention comprises 50-70% by weight of an aqueous solution of fullerene, and the balance is water for injection.
  • the main solvent of the water for injection according to the embodiment of the present invention is a solute or solute-free solvent which can be used for injection.
  • the aqueous solution for injection is one or more selected from the group consisting of physiological saline, glucose injection, water for injection, and absolute ethanol.
  • the anhydrous ethanol is USP specification absolute ethanol.
  • the water for injection according to the embodiment of the present invention is water for injection and anhydrous ethanol, and the volume ratio thereof is (30-60): (5-15), and the optional ratio is (25-38): (8-10) ).
  • the ratio of fullerenes to polyethylene glycol ester of 15-hydroxystearic acid in the injection has a great influence on the solvent dispersibility of the water for injection, and ensures that the fullerene maintains the nanomorphology in the water or ethanol medium without agglomeration. Can maintain a certain stability. If the ratio of fullerene powder to polyethylene glycol 15-hydroxystearate is too small, the effect of fullerene will be affected, and precipitation or suspension will occur too much.
  • the fullerene injection further includes an excipient for injection, such as a pH adjuster, an antioxidant, a biocompatible substance, and the like.
  • an excipient for injection such as a pH adjuster, an antioxidant, a biocompatible substance, and the like.
  • the pH adjusting agent is selected from the group consisting of citric acid, lactic acid, hydrochloric acid, acetic acid, phosphoric acid, sodium hydrogencarbonate, sodium hydroxide and the like.
  • the antioxidants described in the examples of the present invention include, but are not limited to, one or more of sulfite, ascorbic acid, propyl gallate, and tocopherol.
  • Biocompatible materials according to embodiments of the invention include, but are not limited to, albumin, sorbitol, glycine, dextran, and the like.
  • the injection solution according to the embodiment of the present invention can be administered by intravenous injection, subcutaneous injection, intramuscular injection or the like.
  • the injection can be lyophilized and the like, and the reconstitution does not affect the dispersibility and solubility of the fullerene aqueous solution.
  • the embodiment of the invention has the following beneficial effects:
  • the polyethylene glycol ester of 15-hydroxystearic acid and fullerene are fully dissolved to prepare a clear yellowish brown aqueous solution, which has strong stability, small particle size and uniform distribution, and can enhance free radicals in the human body.
  • the effect enhance the body immunity, anti-aging, inhibit tumors, treat Parkinson and have a significant effect.
  • 15-hydroxystearic acid polyethylene glycol ester is resistant to high temperature and does not deteriorate at 120 ° C.
  • the terminal aqueous solution or injection is sterilized by high temperature sterilization at 121 ° C, which does not require expensive aseptic manufacturing process.
  • Industrial production has a very high promotion value.
  • the embodiment of the present invention fills in the blank of the fullerene aqueous solution, especially the water-soluble injection, which provides more selectivity for clinical application.
  • the aqueous solution of fullerene in the embodiment of the present invention only refers to the non-toxic polyethylene glycol ester of 15-hydroxystearic acid, and the entire operation does not need to add any organic solvent, the fullerene structure is not destroyed, and the original fullerene is retained. Biological activity.
  • HS15 is not sensitizing. After preparation of HS15-fullerene injection, the human body can tolerate higher doses than EL35 injections, and the drug effect is better.
  • the fullerene concentration is 0.1-5 mg/ml, and further optionally 1-5 mg/ml.
  • the water-soluble fullerene external composition has a particle diameter of from 1 to 200 nm and an optional particle diameter of from 10 to 100 nm.
  • the fullerene is one or more of hollow fullerenes, metal fullerenes, heterocyclic fullerenes, and embedded fullerenes.
  • the fullerene is selected to be a mixture of one or more of C60, C70, C76, C84, Gd@C82 and derivatives thereof.
  • the water-soluble adjuvants described in the above composition include, but are not limited to, phospholipids, gelatin, gum arabic, tragacanth, monoglycerin fatty acid esters, triglycerin fatty acid esters, polyglycerin fatty acid esters, sucrose fatty acid esters, Glyceryl monostearate, sorbitan fatty acid, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, polyoxyethylene-polyoxypropylene copolymers, polyoxyethylene-polyoxypropylene block copolymers , sodium stearate, potassium stearate, sodium oleate, potassium oleate, calcium stearate, sodium lauryl sulfate, cetyl sulfated castor oil, gum arabic, scutellaria, xanthan Gum, guar gum, pectin, agar, bentonite, cetyl alcohol, beeswax, glyceryl
  • water-soluble assistants are lauroyl polyoxyethylene glyceride, stearic acid polyoxyethylene glyceride, oleoyl polyoxyethylene glyceride, linoleyl polyoxyethylene glyceride, caprylic acid phthalic acid polyethylene glycol glycerin Ester, diethylene glycol monoethyl ether, polyoxyethylene beeswax, propylene glycol monocaprylate, glyceryl monostearate, polyoxyethylene (75) stearate, three ceteareth-4 -phosphate, ethylene glycol stearate, diethylene glycol stearate, polyethylene glycol-7-stearate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, cetyl stearin Alcohol polyether, sucrose polystearate, polyoxyethylene castor oil, cocopolyether, olive oil ester, polyoxyethylene 2-hard alcohol ether, polyoxyethylene 21-hard alcohol ether, twenty two Carboxyl ether
  • water-soluble auxiliaries are polyethylene glycol glyceride caprylate, polyethylene glycol ester of 15-hydroxystearic acid, polyethylene glycol-7-stearate, polyoxyethylene castor oil, poly One or more of oxyethylene hydrogenated castor oil, olive oil ester, polyoxyethylene sorbitan ester.
  • composition of polyethylene glycol ester of 15-hydroxystearic acid, polyethylene glycol glyceride caprylate, polyoxyethylene castor oil, olive oil ester is particularly preferred.
  • composition of the embodiment of the invention can be used for the cosmetic formula, one of the raw materials of the pharmaceutical external preparation, the dosage is 0.01-99.99%, and other auxiliary materials include oils and fats, surfactants, preservatives, perfumes, binders, thickeners. , complexing agents, pH regulators, and the like.
  • composition of the embodiment of the invention can be combined with a dressing to form an instrument, and can be used with a hyaluronic acid, a non-woven fabric, a plastic model, a gauze, a vaseline oil gauze, a semi-permeable membrane, and a foaming auxiliary device. When applied to the surface of the skin to play a role.
  • the fullerene composition of the embodiment of the present invention is optionally used in the formulation of a water-repellent or emulsion, using a ratio of 0.01% to 5%.
  • composition of the present invention as a liquid preparation may be, for example, an aqueous or oily suspension, a solution, or a dry product which can be formulated with water or other suitable carrier before use.
  • Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate or hydrogenated edible fats; solutions It is usually prepared by dissolving the active substance in a carrier and sterilizing it by filtration before filling it into a suitable vial or ampoule, and then sealing.
  • Optional fullerene composition preparation method the fullerene composition is mixed with water according to the ratio, stirred uniformly, and then homogenized, and a preservative and a fragrance are added to obtain a water agent.
  • compositions of the present invention are in the form of an emulsion which may comprise conventional emulsifiers, emulsions, surfactants and the like.
  • Optional Fullerene Composition Preparation of Emulsion: The fullerene composition is mixed with an emulsifier in proportion, then homogenized, into an emulsion or paste, and a preservative and a perfume are added to obtain an emulsion.
  • Embodiments of the present invention provide a method for preparing a cosmetically active fullerene composition, comprising the following steps:
  • a method for preparing a cosmetically active fullerene composition comprises the following steps:
  • Embodiments of the present invention also provide the use of the fullerene composition for whitening and anti-oxidation wrinkles.
  • the fullerene in the fullerene-containing composition of the embodiment of the present invention is in a molecular state, and the particle size is small, which is more easily released in the formulation and is then absorbed and utilized.
  • the preparation method of the fullerene-containing composition of the embodiment of the present invention is simple and convenient, and is suitable for mass preparation.
  • the fullerene-containing composition of the examples of the present invention is stable in nature and is suitable for the preparation of any external formulation.
  • the fullerene-containing composition of the embodiment of the present invention has a whitening, freckle, and wrinkle effect.
  • the object of the present invention is also to provide a fullerene emulsion for oral use, which is prepared by dissolving fullerenes in vegetable oil by using a high pressure homogenizer or a micro jet to uniformly emulsifier, fullerene oil and deionized water. After being dispersed, an emulsion is formed, and after being used orally, the absorption and efficacy of fullerene can be accelerated, and the bioavailability can be improved, thereby achieving the effects of eliminating free radicals in the human body, reducing body damage, and anti-aging, without any side effects.
  • An oral fullerene emulsion according to an embodiment of the present invention comprises the following components by weight percentage: 10-50% of fullerene oil, 4-30% of emulsifier, 0.1-0.2% of co-emulsifier, deionized Water supplement.
  • an oral fullerene emulsion comprising the following components by weight percentage: 18-40% of fullerene oil, 8-20% of emulsifier, 0.1-0.2% of co-emulsifier, deionized water supplement.
  • the oral fullerene emulsion according to the embodiment of the present invention is an oil-in-water fullerene emulsion, and the emulsion droplet has a particle diameter of 50 to 200 nm. Optional 50-150nm.
  • the fullerene oil according to the examples of the present invention is composed of a fullerene and a vegetable oil in a weight ratio of (0.1-10):(10-40). Further optionally, the fullerene oil is composed of a fullerene and a vegetable oil in a weight ratio of (1-5): (15-25). Most preferably fullerene oil is composed of fullerene and vegetable oil in a weight ratio of 1:20.
  • the fullerene is a hollow fullerene and/or a metal fullerene.
  • the fullerene is selected from a mixture of one or more of C60, C70, C76, C82, C84.
  • the vegetable oil includes, but is not limited to, olive oil, medicinal soybean oil, green thorn oil, linseed oil, sunflower oil, jojoba oil, peanut oil, tea oil, tea tree oil, rose hip oil, nut oil, At least one of avocado oil, castor oil, corn germ oil, and corn oil. Further optional soybean oil, olive oil, castor oil, and tea oil. Further optional soybean oil, in addition to high solubility in fullerenes, contains a large amount of unsaturated fatty acids.
  • the emulsifier according to the embodiment of the invention is selected from the fullerene by an excipient having high emulsifying ability, high temperature resistance and easy storage.
  • Optional emulsifiers include, but are not limited to, polyoxyethylene castor oil, polyglyceryl oleate, oleoyl polyoxyethylene glyceride, caprylic acid phthalate, polyethylene glycol-15-hydroxystearate One or more of lauric acid polyoxyethylene ester, Tween 80, soybean phospholipid, egg yolk lecithin, and hydrogenated soybean phospholipid.
  • the optional emulsifier is selected from soybean phospholipids and polyoxyethylene castor oil. The combination of the two emulsifiers can have better stability and enhanced emulsifying ability.
  • the oil phase and the emulsifier which have the best solubility of fullerenes are selected for the in vivo absorption characteristics of the oral preparation to ensure that the drug content in the oral emulsion is as high as possible.
  • the co-emulsifier includes ethyl oleate, propylene glycol, glycerol, ethanol, sodium citrate, sodium carboxymethylcellulose, sodium dodecylbenzenesulfonate, sodium alginate, povidone, stearic acid , polyethylene glycol 400, polyethylene glycol 600, xanthan gum.
  • the optional co-emulsifier is sodium citrate, which is safe, non-toxic, and has good fluidity, and can rapidly decompose and excrete after entering the human body.
  • the fullerene emulsion water-soluble adjuvant of the embodiment of the present invention includes a fragrance, a preservative, and the like.
  • the fullerene emulsion of the embodiment of the present invention can be used as one of the raw materials of other pharmaceutical compositions in an amount of from 0.1 to 99.9%.
  • the fullerene emulsion of the present invention can be formulated into a pharmaceutically acceptable dosage form with a pharmaceutically acceptable carrier.
  • the dosage form is an oral administration route including, but not limited to, one of a capsule, a tablet, a pill, a granule, a concentrated pill, an oral solution, and a mixture.
  • the orally administered preparation may contain common excipients such as a binder, a filler, a diluent, a tablet, a lubricant, a disintegrant, a coloring agent, and a seasoning. And humectants, if necessary, the tablets can be coated.
  • Suitable fillers include cellulose, mannitol, lactose and other similar fillers.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives (e.g., sodium starch glycolate).
  • Suitable lubricants are, for example, magnesium stearate and the like.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate and the like.
  • the fullerene emulsion of the embodiment of the present invention can be prepared into a solid oral composition by a method commonly used in the art by mixing, filling, tableting, etc., and repeated mixing can be used to uniformly distribute the active material in a composition using a large amount of filler as a whole. .
  • the oral liquid preparation may be in the form of, for example, an aqueous or oily suspension, a solution, a syrup or an elixir, or may be a dry product which may be formulated with water or other suitable carrier before use.
  • Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fat; Solutions are usually prepared by dissolving the active in a carrier and sterilizing the solution before filling it into a suitable vial or ampoule, and then sealing. Excipients such as local anesthetics, preservatives, and buffers can also be dissolved in the carrier. To increase the stability of the liquid unit dosage form, the composition can be frozen after filling the vial and the water removed under vacuum.
  • one or more suitable pharmaceutically acceptable carriers may be optionally added thereto, the pharmaceutically acceptable carrier being selected from the group consisting of: sugar alcohols For example, mannitol, sorbitol, xylitol; amino acids such as cysteine hydrochloride, methionine, glycine; inorganic salts such as monovalent alkali metal carbonates, phosphates or aqueous solutions thereof, sodium chloride, chlorination Potassium, sodium metabisulfite, sodium hydrogen sulfite, sodium thiosulfate, calcium carbonate, calcium hydrogencarbonate; inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid; organic acids such as acetic acid, vitamin C, thioglycolic acid; organic acid salts such as vinegar Acid salts, alginate, sodium lactate, disodium EDTA, calcium EDTA, stearates such as calcium
  • sugar alcohols For example, mannitol, sorbitol, xylit
  • the embodiment of the invention also discloses a preparation method of an oral fullerene emulsion, comprising the following steps:
  • the fullerene powder is sufficiently mixed with the vegetable oil, and then placed in a ball mill, ultrasonically stirred, heated, and the fullerene is sufficiently dissolved in the vegetable oil to obtain a fullerene oil by filtration.
  • step (1) the fullerene powder is ball milled and refined by 0.05-1 ⁇ m, and the refined fullerene powder is mixed with vegetable oil, placed in a ball mill at 500-1000 rpm, and ball milled 8- 20h, a fullerene oil suspension is obtained, and the fullerene oil suspension is heated to 0-60 ° C, protected by nitrogen, stirred for 12-72 hours, centrifuged, and filtered to obtain a fullerene oil solution.
  • step (1) the fullerene powder is ball milled and refined to 0.05-1 ⁇ m, fully mixed with the vegetable oil, placed in a ball mill at 500-700 rpm, and ball milled for 6-10 h to obtain a fullerene oil suspension. Liquid, then the suspension is heated to 0-50 ° C ultrasonic, nitrogen protection, stirring and heating for 10-15h, the fullerenes are fully dissolved in the oil-based adjuvant, centrifuged, filtered to obtain fullerene oil.
  • step (2) the emulsifier, the co-emulsifier, and the fullerene oil are preheated, placed in a dispersing machine, and uniformly stirred to obtain an oil phase.
  • step (2) the emulsifier, co-emulsifier and fullerene oil are preheated at 55-70 ° C, and placed in a dispersing machine and stirred at a speed of 5000-8000 rpm for 8-15 min to be uniformly dispersed, thereby obtaining an oil phase.
  • an aqueous emulsion auxiliary agent such as a fragrance or a preservative may be added to the aqueous phase.
  • the water-soluble auxiliary material, the deionized water, and the preheating are placed in a dispersing machine and stirred to obtain an aqueous phase.
  • step (3) the water-soluble auxiliary material is added to deionized water to be preheated at 50-60 ° C, and placed in a dispersing machine at 3000-7000 rpm for 8-15 minutes to obtain an aqueous phase.
  • step (4) the oil phase is slowly added to the aqueous phase, placed in a dispersing machine, stirred and dispersed uniformly, and homogenized at a high pressure to obtain an oil-in-water fullerene emulsion.
  • step (4) the oil phase is slowly added to the aqueous phase at 50-60 ° C to disperse 7000-12000 rpm, 8-15 min to disperse and emulsifie the colostrum, and the colostrum temperature is naturally lowered to room temperature, and then the high pressure is applied.
  • the homogenizer at a pressure of 50-60 MPa, the mixture is homogenized 4-6 times until the emulsion particle size is 140-150 nm or the micro-jet produces an emulsion particle size of 50-100 nm, that is, the concentrate is obtained.
  • the optional homogenization pressure and the number of homogenization times in the examples of the present invention are selected according to the particle size and stability of the emulsion.
  • the 140-150 nm emulsion was homogeneously obtained, and no aggregation phenomenon was observed.
  • the micro-jet technique in order to obtain a smaller particle size emulsion, the micro-jet technique can solve the problem of small droplet size aggregation, and the micro-jet allows the emulsion droplet to be in a more stable state.
  • the embodiments of the present invention also provide an effect of an oral fullerene emulsion in the preparation of a medicament for treating tumors, especially in the preparation of a medicament for treating myelosuppression.
  • Embodiments of the present invention also provide the use of an oral fullerene emulsion for the preparation of a medicament for treating Parkinson's disease.
  • the embodiment of the invention also provides that the oral fullerene emulsion has the effect of eliminating free radical anti-aging in the body.
  • fullerene emulsions fullerenes, vegetable oils, and emulsifiers are not homogeneously homogeneous, and are always in a suspended state.
  • the above-mentioned defects can be overcome when the fullerene is previously prepared into a fullerene oil and then homogenized with an emulsifier.
  • the emulsion particle size of the examples of the present invention can be monitored by a dynamic dynamic light scattering analyzer to reach 50-300 nm.
  • the first embodiment of the present invention prepares fullerene into an emulsion, selects a suitable vegetable oil emulsifier and the like, and suitable process parameters, etc., and obtains an oral fullerene emulsion with high bioavailability and stability; A olefin emulsion that reduces the side effects of pure fullerene oil as a formulation.
  • the fullerene emulsion is more easily and accurately quantified than the fullerene oil, and the oil adheres to the container wall, and the emulsion does not hang on the wall. If the oil is encapsulated for precise quantification, the patient's intake of too much capsule shell has a side effect.
  • the emulsion can smoothly drink straight, reducing the side effects of excessive pharmaceutical preparations.
  • Fullerene oil + polyoxyethylene castor oil is the key two components in fullerene oral emulsion, especially polyoxyethylene castor oil, which is the best emulsifier for the solubility of fullerenes. .
  • the fullerene emulsion of the embodiment of the invention can eliminate free radicals in the human body, reduce body damage, anti-aging and the like, and has no side effects.
  • the present invention also provides an effect of an oral fullerene emulsion in the preparation of a medicament for treating tumors. In particular, it is used in the preparation of a medicament for treating myelosuppression. In the embodiment of the present invention, the effect of the injection emulsion on the prevention of bone marrow suppression is superior to that of the oral oil.
  • the oral emulsion prepared in the examples of the present invention is excellent in inhibiting tumor, alleviating Parkinson's symptoms and scavenging hydroxyl radicals.
  • the fullerene emulsion of the embodiment of the invention has good dispersion effect, large effective surface area, and is favorable for release, dissolution and absorption of the drug; the emulsion contains an emulsifier, has surface activity, can improve gastrointestinal mucosa performance, and promote drug absorption.
  • the absorption of oil in the emulsion can promote bile secretion, increase the flow rate of blood and lymph, and help the drug to dissolve and absorb; the oil in the emulsion is digested to produce linoleic acid and oleic acid, which can inhibit the gastrointestinal motility.
  • the oily substances in the emulsion may also be transported through the lymphatic system.
  • the fullerene emulsion prepared in the examples of the present invention is dried to form a solid preparation, such as a granule, a capsule, a tablet, etc., and the solid preparation is convenient for storage and transportation, and is convenient to carry, and is more convenient for the patient to use.
  • the emulsion prepared in the examples of the invention has the emulsifier with strong emulsifying ability and low cost, which reduces the production cost and is beneficial to industrial production.
  • the purpose of the embodiments of the present invention is also to provide a fullerene emulsion for injection, which greatly improves the bioavailability of fullerenes, enhances long-term circulation of fullerenes in vivo, and increases the targeting effect.
  • the inventors have found that in the preparation of an injection fullerene emulsion, the fullerene, the injectable oil, and the emulsifier are not uniform in any way, and are always in a suspended state.
  • the above-mentioned defects can be overcome when the fullerene is previously prepared into a fullerene oil and then homogenized with an emulsifier.
  • a fullerene emulsion for injection comprising 15-50% by weight of fullerene oil, 4-17% of emulsifier, 0.3-1% of stabilizer, 2-9% of excipient and water for injection, and not A solvent or cosolvent is included, and the fullerene emulsion is an oil-in-water emulsion stabilized at pH 7.3-7.4.
  • the fullerene emulsion for injection according to the embodiment of the present invention is an oil-in-water type fullerene emulsion for injection, and the emulsion droplet has a particle diameter of 50 to 150 nm.
  • the fullerene oil according to the embodiment of the present invention dissolves fullerenes into an injectable oil, the solubility is 1-10 mg/ml, and the further optional fullerene concentration is 2-7 mg/ml.
  • the fullerene is a hollow fullerene and/or a metal fullerene.
  • the fullerene is selected from a mixture of one or more of C60, C70, C76, C84.
  • the oil for injection is a vegetable oil, including but not limited to olive oil, soybean oil, green thorn oil, linseed oil, sunflower oil, jojoba oil, peanut oil, tea oil, tea tree oil, rosehip oil, At least one of nut oil, avocado oil, castor oil, corn germ oil, and corn oil. Further optional soybean oil, olive oil, green thorn fruit oil, tea oil. Further optional soybean oil, soybean oil in addition to high solubility of fullerenes, while containing a large amount of unsaturated fatty acids, is more suitable for injection.
  • the amount of the fullerene oil in the embodiment of the present invention accounts for 15-40% of the fullerene emulsion for injection.
  • the emulsifier according to the embodiment of the invention selects an auxiliary material with strong emulsifying ability, high temperature resistance and easy storage.
  • Optional emulsifiers include, but are not limited to, polyglycol phthalate, oleic acid ethyl ester, soybean phospholipid, egg yolk lecithin, phosphatidylcholine, poloxamer-188, 15-hydroxystearic acid polyethyl One or more of the glycol esters.
  • the emulsifier is 4-17% of the fullerene emulsion for injection, the emulsifier is 5-13% of the fullerene emulsion for injection, and the optimum emulsifier is 5-7%.
  • Optional poloxamer-188 is used in combination with polyethylene glycol ester of 15-hydroxystearic acid.
  • the weight ratio of the poloxamer-188 to the polyethylene glycol ester of 15-hydroxystearic acid is (0.6-4):1, and further optionally (1-1.6):1.
  • Stabilizers in the examples of the invention include, but are not limited to, sodium citrate, sodium alginate, sodium dodecyl sulfate, and optionally sodium citrate.
  • the sodium citrate is safe, non-toxic, and has good fluidity, and can be rapidly degraded and quickly excreted after entering the human body.
  • the stability is from 0.3 to 1% of the fullerene emulsion for injection.
  • excipients described in the examples of the present invention are acceptable additives in injections, including water-soluble formulations such as osmotic pressure regulators, pH adjusters or other biocompatible materials, and oily excipients such as antioxidants and the like.
  • the osmotic pressure adjusting agent according to the embodiment of the present invention includes, but is not limited to, one or more of glucose, glycerin, sorbitol, and mannitol.
  • the osmotic pressure adjusting agent is used in an amount of from 2 to 8% of the fullerene emulsion for injection. Optional 3-6%.
  • the antioxidants described in the examples of the present invention include, but are not limited to, one or more of sulfite, ascorbic acid, propyl gallate, and tocopherol.
  • the antioxidant is used in an amount of from 0.01 to 0.1% by weight based on the fullerene emulsion for injection.
  • the pH adjusting agent according to the embodiment of the present invention includes, but not limited to, one or more selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide and sodium hydrogencarbonate.
  • Biocompatible materials according to embodiments of the invention include, but are not limited to, albumin, sorbitol, glycine, dextran, and the like.
  • the embodiment of the invention also discloses a preparation method of a fullerene emulsion for injection, comprising the following steps:
  • step (1) the fullerene powder and the oil for injection are sufficiently mixed, and then placed in a ball mill, ultrasonically stirred, heated, and the fullerene is sufficiently dissolved in the oil for injection, and the fullerene oil is obtained by filtration.
  • step (1) the fullerene powder is ball-milled and refined by 0.05-1 ⁇ m, and the refined fullerene powder is mixed with an injection oil, placed in a ball mill at 500-1000 rpm, and ball milled. 8-20h, a fullerene oil suspension is obtained, and the fullerene oil suspension is heated to 40-60 ° C, protected by nitrogen, stirred for 12-72 hours, centrifuged, and filtered to obtain a fullerene oil solution.
  • step (1) the fullerene powder is thoroughly mixed with the injection oil, and then placed in a ball mill at 700 rpm for 8 hours to obtain a fullerene oil suspension, and then the fullerene oil is further obtained.
  • the suspension was heated to 40 ° C for ultrasonic stirring for 12-24 h, centrifuged, and filtered to obtain a fullerene oil solution.
  • step (2) the emulsifier and the fullerene oil are preheated, and an oily excipient is added to the disperser to be uniformly stirred to obtain an oil phase.
  • step (2) the emulsifier and the fullerene oil are preheated at 55-70 ° C, and the oily excipient is placed in a dispersing machine and stirred at a speed of 5000-10000 rpm for 2-10 min to uniformly disperse, thereby obtaining an oil phase.
  • step (2) dispersing machine speed 7000rmp, stirring for 5min.
  • the stabilizer, the aqueous vehicle, the water for injection, and the preheating are placed in a dispersing machine and stirred to obtain an aqueous phase.
  • step (3) the stabilizer, the aqueous vehicle, and the water for injection are preheated at 55-70 ° C, and placed in a dispersing machine and stirred at a speed of 5000-10000 rpm for 2-10 min to uniformly disperse, thereby obtaining an aqueous phase.
  • step (3) dispersing machine speed 7000rmp, stirring for 5min.
  • the oil phase is slowly added to the aqueous phase, placed in a dispersing machine, stirred and dispersed uniformly, and the micro-jet or high-pressure homogenization is obtained, that is, an oil-in-water fullerene emulsion is obtained.
  • step (4) slowly adding the oil phase to the aqueous phase at 60-80 ° C to disperse 7000-10000 rpm, 5-15 min to disperse and emulsifie the crude milk, and after the crude milk temperature is naturally lowered to room temperature, the micro-jet is put into the micro-jet.
  • a high-pressure homogenizer at a pressure of 50-60Mpa, homogenize 5-6 times until the emulsion particle size is 140-150nm or micro-jet to obtain an emulsion particle size of 50-100nm, that is, to obtain a fine milk, adjust the pH to 7.3- 7.4, the injection water to make up, sub-package, nitrogen, sterilization.
  • the optional homogenization pressure and the number of homogenization times of the examples of the present invention are selected according to the particle size and stability of the emulsion.
  • the 140-150 nm emulsion was homogeneously obtained, and no aggregation phenomenon was observed.
  • the micro-jet in order to obtain a smaller particle size emulsion, the micro-jet can solve the problem of small droplet size aggregation, and the micro-jet allows the emulsion droplet to be in a more stable state.
  • Embodiments of the present invention also provide the effect of the fullerene emulsion for injection in the preparation of a medicament for treating tumors.
  • it is used in the preparation of a medicament for treating myelosuppression.
  • the first embodiment of the present invention prepares fullerene into an oil emulsion, selects suitable injection oil, emulsifier and the like, and suitable process parameters, and the obtained fullerene emulsion has high bioavailability and is stable;
  • the sensitization rate of polyoxyethylene-based castor oil is avoided, and the introduction of other solvents or co-solvents such as ethanol is avoided, the side effects are reduced, and the safety is higher.
  • the inventors have found that in the development of injectable emulsions in the field, the drug powder, the injectable oil and the emulsifier are simultaneously stirred or homogenized to obtain an oil phase, and then an emulsion is prepared.
  • the characteristics of fullerenes themselves are not instructed according to the prior art, and the homogeneously stable emulsions are not obtained by uniformly mixing the fullerene powder, the injectable oil and the emulsifier, and are always in a suspended state.
  • the fullerene powder is previously prepared into fullerene oil and then homogeneously prepared with an emulsifier, the above defects can be overcome, the stability is good, and uniformity and non-layering are always maintained.
  • the emulsion prepared in the examples of the invention has the advantages of strong emulsifying ability and good temperature resistance, especially the polyethylene glycol ester of 15-hydroxystearic acid can withstand the high temperature of 120 ° C, and the final emulsion can withstand steam sterilization at 121 ° C. .
  • the relatively low-cost emulsifier selected in the embodiment of the invention reduces the production cost and is advantageous for industrial production.
  • the fullerene emulsion for injection of the embodiment of the present invention does not contain any solvent and/or co-solvent, such as a polar or non-polar solvent such as ethanol, methanol, acetone or chloroform.
  • a polar or non-polar solvent such as ethanol, methanol, acetone or chloroform.
  • the preparation of the present invention prepares an emulsion for injection, directly enters the blood by injection, avoids the first pass effect of the liver, can achieve the drug effect at a lower fullerene concentration, and improves the drug utilization.
  • the embodiment of the invention can prepare the emulsion by the high temperature steam sterilization method, avoids the cumbersome and expensive aseptic process of the use process, is convenient to operate, can rapidly and mass-produce the production, and improves the production capacity, which is beneficial to industrial production.
  • the micro-jet in order to obtain a smaller particle size emulsion, can solve the problem of small droplet size aggregation, and the micro-jet allows the emulsion droplet to be in a more stable state.
  • the emulsion of the present invention has superior protection against myelosuppression compared with the oral oil.
  • the emulsion of the embodiment of the present invention has a high inhibition rate against liver cancer.
  • the emulsion of the embodiment of the present invention can significantly improve the symptoms of Parkinson's disease
  • the emulsion of the embodiment of the invention has high scavenging efficiency against hydroxyl radicals.
  • 1-2 is a microstructure diagram of an aqueous solution of fullerene according to an embodiment of the present invention.
  • 1-3 are particle size distribution diagrams of a fullerene aqueous solution according to an embodiment of the present invention.
  • FIG. 1-4 are diagrams showing the scavenging of hydroxyl radicals in an aqueous solution of fullerene according to an embodiment of the present invention
  • composition DLS is a particle size distribution diagram of a composition DLS according to an embodiment of the present invention.
  • 2-2 is a DLS particle size distribution diagram of a fullerene complex obtained in the form of PVP micelles according to the application number: 200480005008.1;
  • 3-1 is an illustration of the ability of an oral fullerene emulsion to scavenge hydroxyl radicals in accordance with an embodiment of the present invention
  • 3-2 is an illustration of an oral fullerene emulsion protecting cells from oxidation resistance in accordance with an embodiment of the present invention
  • 3-3 is particle size DLS data of an oral fullerene emulsion according to an embodiment of the present invention.
  • Figure 4-1 is particle size DLS data of a fullerene emulsion for injection according to Examples 4-6 of the present invention
  • 4-2 is particle size DLS data of a fullerene emulsion for injection according to Examples 4-7 of the present invention.
  • 4-3 is particle size DLS data of a fullerene emulsion for injection according to Examples 4-8 of the present invention.
  • 4-4 is a graph showing the effect of scavenging free radicals of the emulsion for injection according to Examples 4-7 of the present invention.
  • Example 1-1 Preparation of fullerene aqueous solution according to an embodiment of the present invention
  • Example 1-2 Preparation of fullerene aqueous solution according to an embodiment of the present invention
  • Example 1-3 Preparation of fullerene aqueous solution according to an embodiment of the present invention
  • Example 1-4 Preparation of fullerene aqueous solution according to an embodiment of the present invention
  • Example 1-5 Preparation of fullerene aqueous solution according to an embodiment of the present invention
  • Example 1-6 Preparation of fullerene aqueous solution according to an embodiment of the present invention
  • Example 1-10 Preparation of fullerene injection by an embodiment of the present invention
  • Test Example 1-1 Antitumor effect of fullerene fullerene aqueous solution
  • Animal strain Balb/c female, 5 weeks, weighing between 16-20g;
  • Tumor model mouse liver cancer H22 tumor strain
  • Experimental group randomly divided into drug group A, drug group B and control group C, with 6 rats in each group.
  • Mode of administration (1) A 1 mg/ml fullerene aqueous solution was administered to a mouse of the drug group A, intravenously, at a dose of 200 ul/d, and administered continuously for 10 times; (2) administration to a mouse of the drug group B was 1.2. Mg/ml fullerene oil group (patent WO2013/025180A1), oral, 200ml/kg/d, continuous administration 10 times; (3) control group C: normal saline (Saline);
  • mice 100 ⁇ L of H22 hepatoma cells with a concentration of 5 ⁇ 10 7 /ml were inoculated subcutaneously; the administration was started 24 hours after the inoculation, and the drug was administered continuously for 10 times; the body weight of the mice was weighed every other day during the experiment and the tumor growth was observed. The experiment was terminated 15 days after the inoculation, and the tumor weight of the mice was weighed and the volume was measured to calculate the tumor inhibition rate.
  • Table 1-1 shows the following results by the above anti-cancer method and tumor inhibition rate:
  • the fullerene aqueous solution of the examples of the present invention is superior to the fullerene oil product in suppressing tumors.
  • Test Example 1-2 Chemoprotective efficacy of a fullerene aqueous solution at a living level
  • Animal model 4-5 weeks ICR mice, randomly divided into 4 groups, 6 in each group, drug group A: CTX + 1 mg / ml fullerene aqueous solution group (injection of Example 1-1); drug group B: CTX + 3 mg / ml fullerene oil group (WO 2013 / 025180 A1); control group C: normal saline (Saline), experimental group D; cyclophosphamide (CTX).
  • Oral administration mode group A intravenous injection, dose, 20ul / d: group B, C, D orally administered, the dose of 200ml / kg.
  • mice were subcutaneously inoculated with 10 6 mouse hepatoma cells (H22 cells), and after 5-7 days of inoculation, the tumor was drilled to a diameter of about 5 mm.
  • the amount of CTX administered was 60 mg/kg of mouse body weight.
  • the drug was administered on the seventh day after tumor inoculation, as the first day of the start of the experiment, once a day for 5 consecutive days, on the fourth day, seventh day, tenth day, fourteenth day and seventeenth day, respectively.
  • Blood was collected from the eye of the mouse (20 ⁇ l), and blood routine was detected by an automatic blood cell analyzer.
  • the main indicators related to myelosuppression were white blood cell count (WBC), red blood cell count (RBC), platelet count (PLT), and hemoglobin measurement (HGB). .
  • mice in the CTX+ fullerene fullerene aqueous test group due to the protective effect of fullerenes, their white blood cells, red blood cells, platelets, hemoglobin
  • CTX cyclophosphamide
  • Test Example 1-3 Effect of improving the symptoms of Parkinson's disease in a fullerene fullerene solution
  • Wistar rats weighing 180-200 g The experiment was divided into 5 groups, male and female, and the control group was not modeled. The other groups were administered two weeks after modeling, and were administered continuously for 6 weeks. Fullerene aqueous solution injection was divided into high dose group (0.213mg/ml), middle dose group (0.113mg/ml), low dose group (0.0565mg/ml), administered dose was 2ml, using LPS damage model: Apu Morphine (0.5 mg/kg) can mimic the behavioral and pathological changes of Parkinson's symptoms after subcutaneous injection. The rotation behavior to the healthy side was induced after 5-15 minutes of injection, and the control group was behavioral change. The number of rotations in the PD group increased with the increase of modeling time.
  • the number of rotations of the rats in the drug-administered group decreased with the prolongation of the modeling time, and the number of rotations in the high-dose group decreased more significantly.
  • the number of rotations in the high-dose group and the middle-measurement group was significantly different from that in the PD group at the same time.
  • the number of days of rotation in the 5th and 6th weeks was significantly different (P ⁇ 0.05).
  • the data in Table 1-2 can be used to obtain the richness. Alem aqueous solution has a significant effect on LPS-induced Alzheimer's disease
  • Test Example 1-4 Anti-aging effect of the fullerene aqueous solution of the present invention:
  • the spin removal method was used to determine the radical removal effect.
  • the specific operation is as follows: for the free radical generated by the reaction of hydrogen peroxide with ferrous ions, DMPO (5,5-dimethyl-1-pyrroline-N-oxide) is used as a spin trap to detect the freedom of DMPO and hydroxyl groups. The signal of the product DMPO-OH formed by the base reaction.
  • the concentration of ferrous sulfate heptahydrate was 0.4mmol/L
  • the concentration of hydrogen peroxide was 5%
  • the pH of PBS was 7.4
  • the concentration of C60 in HS15-C60 was 1mg/ML
  • the concentration of DMPO was 0.4mol. /L
  • 50 ⁇ L of each of the above five solutions was mixed and tested. It can be seen from Figures 1-4 that the removal efficiency of the obtained HS15-fullerene to hydroxyl radicals is very high.
  • the embodiment of the invention also relates to the field of daily chemistry, in particular to a cosmetic composition having a cosmetic effect.
  • Fullerene is an allotrope of carbon as well as diamond and graphite.
  • C60 is a spherical molecule composed of 60 carbon atoms. It consists of 12 pentagons and 20 hexagons. Each carbon atom and three adjacent carbon atoms are hybridized by SP2, which is called a football. For "football".
  • SP2 which is called a football. For "football”.
  • a series of molecules having a cage-like carbon cluster structure are collectively referred to as fullerenes, and mainly include hollow fullerenes, inlaid fullerenes, fullerene derivatives, and heterocyclic fullerenes. Common types of C60, C70, C76, C84, etc.
  • the large ⁇ -bond conjugated system composed of multiple P orbitals of fullerenes has a strong ability to accept electrons, and because of its unique structure and physicochemical properties, it has excellent scavenging free radical properties.
  • "Free radical sponge” also exhibits excellent oxidation resistance. It has attracted extensive attention in cosmetic materials, biomedicine and other fields.
  • C60 By embedding C60 in the surfactant, C60 can still eliminate the reactive oxygen species in the cell, inhibit the depolarization of mitochondria, the activation of cysteine protease, the exposure of phosphatidylserine on the cell membrane and the splitting of DNA.
  • C60 shows Protect cells from oxidative apoptosis.
  • the C60 liposome complex acts as an antioxidant against UVA damage to the skin structure, nucleus and collagen fibers, and penetration into human skin tissue. It is 172 times more potent than vitamin C and is capable of affinity with free radicals.
  • C60-PVP fullerene-related products
  • application number: 200480005008.1, 200580049615.2 Due to the preparation process and the limitation of the composite properties of PVP and C60, the content of C60 is not in the composite. More than 1%, combined with PVP has obvious film-forming properties, too much coating on the surface of the skin will play a certain role in hindering the efficacy of certain cosmetics.
  • C60-squalane, application number 201510427642.4 but the solubility of C60 in squalane is limited, and squalane is an oil solution, making the use of this series limited.
  • Fullerenes are non-polar molecules with strong hydrophobicity and are only soluble in non-polar organic solvents harmful to living organisms such as toluene, benzene, cyclohexane and chloroform.
  • the hydrophobic nature of fullerenes directly affects the biological activity of the fullerenes, especially under water-soluble conditions.
  • fullerene has been studied as a small particle size solution type or emulsion type fullerene which is easily absorbed by the skin and which is in a molecular state.
  • the fullerene-containing composition of the embodiment of the present invention ensures that the fullerene is dispersed in a molecular state in the selected water-soluble adjuvant, and the obtained fullerene-containing composition is stable in properties and can be used in any external formulation.
  • the composition of the embodiment of the present invention is different from the micelle-coated fullerene composite, and the particle size of the composition is within 200 nm, which is easier to absorb and utilize, and the effect is more easily exerted.
  • 15-hydroxystearic acid polyethylene glycol ester, octoate phthalic acid polyethylene glycol glyceride, polyoxyethylene castor oil, olive oil ester are mixed uniformly according to the weight ratio of 2:2:5:1, and the volume is obtained. 1 L of the mixture solvent. Then weigh 4 g of fullerene C60, disperse in a mixed solvent, put the mixture of the two in a ball mill, 700 rpm, the temperature of the ball mill is controlled between 20-30 degrees, and after 7 hours of ball milling, the mixture is set.
  • 15-hydroxystearic acid polyethylene glycol ester, octoate phthalic acid polyethylene glycol glyceride, polyoxyethylene castor oil, olive oil ester are mixed uniformly according to the weight ratio of 2:2:5:1, and the volume is obtained. 1 L of the mixture solvent. Then weigh 3 g of fullerene C70, disperse in a mixed solvent, put the mixture of the two in a ball mill, 700 rpm, the temperature of the ball mill is controlled between 20-30 degrees, and after 7 hours of ball milling, the mixture is set.
  • the container In the container, the container is heated, the temperature is controlled at 35-45 degrees, the stirring paddle built in the container is opened, and the stirring is continued for 72 hours, then the solution is taken out, centrifugally filtered, and QXBG-FULLERENE is obtained, and the fullerene C70 standard curve is used to obtain the rich The concentration of the Cenene C70 was 2.5 mg/ml.
  • 15-hydroxystearic acid polyethylene glycol ester, octoate phthalic acid polyethylene glycol glyceride, polyoxyethylene castor oil, olive oil ester are mixed uniformly according to the weight ratio of 2:2:5:1, and the volume is obtained. 1 L of the mixture solvent. Then weigh 1 g of fullerene C76, disperse in a mixed solvent, put the mixture of the two in a ball mill, 800 rpm, the temperature of the ball mill is controlled between 20-30 degrees, and after 7 hours of ball milling, the mixture is set.
  • the container In the container, the container is heated, the temperature is controlled at 30-40 degrees, the stirring pad built in the container is opened, and the stirring is continued for 72 hours, then the solution is taken out, centrifugally filtered, and QXBG-FULLERENE is obtained, and the fullerene C76 standard curve is used to obtain the rich
  • the concentration of lenidine C76 was 0.5 mg/ml.
  • 15-hydroxystearic acid polyethylene glycol ester, octoate phthalic acid polyethylene glycol glyceride, polyoxyethylene castor oil, olive oil ester are mixed uniformly according to the weight ratio of 2:2:5:1, and the volume is obtained. 1 L of the mixture solvent.
  • the mixture is placed in a container, the container is heated, the temperature is controlled at 40-50 degrees, the stirring paddle built in the container is opened, the stirring is continued for 72 hours, the solution is taken out, and the solution is centrifuged to obtain QXBG-FULLERENE, and the concentration of Gd@C82 is obtained by ICP calibration. 0.05 mg/ml.
  • 15-hydroxystearic acid polyethylene glycol ester, caprylic acid phthalic acid polyethylene glycol glyceride, polyoxyethylene castor oil, olive oil ester are mixed uniformly according to the weight ratio of 1:1:8:1, and the volume is obtained. 1 L of the mixture solvent. Then weigh 4 g of fullerene C60, disperse in a mixed solvent, put the mixture of the two in a ball mill, 700 rpm, the temperature of the ball mill is controlled between 20-30 degrees, and after 7 hours of ball milling, the mixture is set.
  • 15-hydroxystearic acid polyethylene glycol ester, octoate phthalic acid polyethylene glycol glyceride, polyoxyethylene castor oil, olive oil ester are mixed uniformly according to the weight ratio of 3:3:7:3, and the volume is obtained. 1 L of the mixture solvent. Then weigh 5 g of fullerene C60, disperse in a mixed solvent, put the mixture of the two in a ball mill, 700 rpm, the temperature of the ball mill is controlled between 20-30 degrees, and after ball milling for 7 hours, the mixture is set.
  • a polyethylene glycol ester of 15-hydroxystearic acid, a polyethylene glycol glyceryl octylate, a polyoxyethylene castor oil, and an olive oil ester were uniformly mixed in a ratio to obtain a solvent mixture of a volume of 1 L. Then weigh 3 g of fullerene C70, disperse in a mixed solvent, put the mixture of the two in a ball mill, 700 rpm, the temperature of the ball mill is controlled between 20-30 degrees, and after 7 hours of ball milling, the mixture is set.
  • the container In the container, the container is heated, the temperature is controlled at 40-50 degrees, the stirring paddle built in the container is opened, the stirring is continued for 72 hours, the solution is taken out, and the solution is centrifuged to obtain QXBG-FULLERENE, which is obtained by using the fullerene C70 standard curve.
  • the concentration of the Cenene C70 was 2.5 mg/ml.
  • a polyethylene glycol ester of 15-hydroxystearic acid, a polyethylene glycol glyceryl octylate, a polyoxyethylene castor oil, and an olive oil ester were uniformly mixed in a ratio to obtain a solvent mixture of a volume of 1 L. Then weigh 5 g of fullerene C60, disperse in a mixed solvent, put the mixture of the two in a ball mill, 700 rpm, the temperature of the ball mill is controlled between 20-30 degrees, and after ball milling for 7 hours, the mixture is set.
  • Test group The fullerene composition of the present invention was prepared according to Example 2-1.
  • Control group application number: 200480005008.1
  • Pig skin was selected as the experimental object, and the fullerene composition and the micelle-coated fullerene complex were respectively subjected to transdermal experiments.
  • Drug permeability analysis was performed using LC-MS.
  • the fullerene-containing composition of the present invention has a particle size of ⁇ 20 nm.
  • the obtained fullerene-containing composition is stable in nature and can be used in any external formulation.
  • the particle size of the micelle-coated fullerene complex is about 1000 nm.
  • the particles are large and cannot be released and absorbed very well. Therefore, the composition of the embodiment of the present invention is different from the micelle-coated fullerene composite, has a small particle size, is very easy to penetrate the stratum corneum of the skin, is more easily absorbed and utilized, and is more easily exerted.
  • Test Example 2-2 the auxiliary material and the ratio screening process of the embodiment of the present invention
  • Polyethylene glycol glyceride caprylate can ensure high content of fullerene in the presence of as little water-soluble co-solvent as possible, and the addition of olive oil ester has good skin absorption and emollient properties.
  • the compounded water-soluble co-solvent does not form a film, has no blocking effect on the skin, and promotes the absorption of fullerene skin.
  • the proportions of the ingredients in the aqueous solvent builder of the examples of the invention are also critical.
  • octoate decanoic acid polyethylene glycol glyceride, polyoxyethylene castor oil, olive oil ester in a weight ratio of 2:2:5:1 can be guaranteed to be as small as possible
  • the composition has a high content of fullerene, and at the same time has good skin absorption and emollient.
  • mice were anesthetized with 2.5% sodium pentobarbital, the model group was intramuscularly injected with 0.4% progesterone injection at a dose of 0.02 g/kg for 6 times a week for 4 weeks.
  • the normal group was intramuscularly injected with 0.02 g/kg of sterile water for injection.
  • Sixty healthy female mice and three dose groups were randomly divided into 6 groups, 10 in each group.
  • the normal group, the model group, and the 2-1 group were externally administered with three dose groups (0.10, 0.20, 0.40 g/g) and 3% hydroquinone positive control group (0.69 g/g).
  • Each of the three dose treatment groups of Example 2-1 was administered topically to the skin on the day of mouse modeling, once a day for 30 days.
  • the normal group and the model group were topically applied with distilled water at the corresponding time; the 3% hydroquinone-positive drug control group started topical administration on the day of modeling, and the time and course of treatment were the same as the fullerene group.
  • the mice were sacrificed by cervical dislocation and the back was depilated. Two pieces of skin tissue of the liver tissue and the application site were quickly taken, one of which was rinsed with ice-cold saline, the blood was removed, the filter paper was blotted, and the liver and skin were excised.
  • Each 0.5g was placed in a 2.0ml pre-cooled physiological beaker, the tissue was cut, and then poured into a test tube, homogenized twice with a high-speed disperser for 10 seconds each time; and then centrifuged at 3500 r/min for 15 minutes. Take the supernatant and test it.
  • composition of the examples of the present invention has significant effects on the model group and the positive control group, and it can be seen that the composition of the embodiment of the present invention has the effect of whitening and freckle.
  • Example 2-2 The composition of Example 2-2 was made into an emulsion.
  • mice 6-week-old nude mice were selected and divided into two groups, 10 in each group.
  • the experimental group applied water-soluble fullerene topical composition milk on the back of the right ear of nude mice twice a day, about 0.5 each time. g, the control group was not administered.
  • the same feed is fed in a clean, ventilated, dry, room temperature 22 ⁇ 2 ° C condition.
  • 8 rats were taken.
  • the drug action site and the corresponding skin of the contralateral side were taken for testing.
  • the effect of the skin-soluble fullerene topical composition on the ratio of skin collagen to the dermal layer area was observed for the 60-day experimental group.
  • the fullerene composition of the embodiment of the invention has a cosmetic effect, acne, eliminates fine lines, and improves the skin spotting effect.
  • Embodiments of the present invention also relate to an oral fullerene emulsion and a method of preparing the same.
  • Patent WO 2013/025180 A1 mixes fullerene powder with vegetable oil, after ball milling, centrifugation, filtration, to obtain a fullerene vegetable oil, which is administered in pure form or as an emulsion in water.
  • the fullerene vegetable oil is directly used to treat the disease.
  • a large amount of vegetable oil is required, and the use of the above three high patients is relatively low, and the patient compliance is relatively low.
  • the emulsion refers to two mutually incompatible liquids, and is prepared into a stable oil-in-water emulsion preparation for oral administration.
  • the emulsion has good dispersion, large effective surface area, and is favorable for release, dissolution and absorption of the drug; the emulsion contains an emulsifier. It has a surface active effect, can improve the performance of gastrointestinal mucosa, and promote drug absorption; the absorption of oil in the emulsion can promote bile secretion, increase the flow rate of blood and lymph, and help the drug to dissolve and absorb; the oil in the emulsion is digested After the formation of linoleic acid and oleic acid, can inhibit the peristalsis of the gastrointestinal tract, prolong the time the drug stays in the small intestine; the oily substances in the emulsion may also be transported through the lymphatic system.
  • the present invention selects an oral fullerene emulsion that has not been studied.
  • the fullerene powder C70 is ball-milled and refined to 0.05-1 ⁇ m, and then 1 g of the refined fullerene powder is mixed with 20 g of soybean oil, placed in a ball mill at 500 rpm, and ball-milled for 8 hours to obtain a fullerene oil mixture.
  • the suspension was heated to 40 ° C with fullerene oil suspension, and protected with nitrogen. After stirring for 12 hours, it was centrifuged and filtered to obtain a fullerene oil solution.
  • the fullerene powder C60 was ball-milled and refined to 0.05-1 ⁇ m, and 5 g of the refined fullerene powder was mixed with 100 g of soybean oil, placed in a ball mill at 700 rpm, and ball-milled for 12 hours to obtain a fullerene oil mixture.
  • the suspension was heated to 50 ° C, and protected with nitrogen. After stirring for 24 hours, it was centrifuged and filtered to obtain a fullerene oil solution.
  • the fullerene powder C76 is ball-milled and refined to 0.05-1 ⁇ m, and the refined fullerene powder 0.1 is mixed with 10 g of green thorn fruit oil, placed in a ball mill at 1000 rpm, and ball-milled for 20 hours to obtain fullerenes.
  • the oil suspension, the fullerene oil suspension was heated to 60 ° C, protected with nitrogen, stirred for 36 h, centrifuged, and filtered to obtain a fullerene oil solution.
  • the fullerene powder Gd@C82 is ball milled and refined to 0.05-1 ⁇ m, and 10 g of the refined fullerene powder is mixed with 40 g of tea oil, placed in a ball mill at 500-1000 rpm, and ball milled for 8-20 h.
  • a fullerene oil suspension is obtained, and the fullerene oil suspension is heated to 40-60 ° C, protected with nitrogen, stirred for 12-72 h, centrifuged, and filtered to obtain a fullerene oil solution.
  • the fullerene powder C60 is ball-milled and refined to 0.05-1 ⁇ m, and then 3 g of the refined fullerene powder is mixed with 3 g of olive oil, placed in a ball mill at 500 rpm, and ball-milled for 80 hours to obtain a fullerene oil mixture.
  • the suspension was heated to 40 ° C with fullerene oil suspension, and protected with nitrogen. After stirring for 12 hours, it was centrifuged and filtered to obtain a fullerene oil solution.
  • the fullerene powder C60 is ball-milled and refined to 0.05-1 ⁇ m, and then 3 g of the refined fullerene powder is mixed with 3 g of olive oil, placed in a ball mill at 500 rpm, and ball-milled for 80 hours to obtain a fullerene oil mixture.
  • the suspension was heated to 40 ° C with fullerene oil suspension, and protected with nitrogen. After stirring for 12 hours, it was centrifuged and filtered to obtain a fullerene oil solution.
  • the fullerene powder C76 was ball-milled and refined to 0.05-1 ⁇ m, and then 3 g of the refined fullerene powder and 45 g of castor oil were mixed, placed in a ball mill at 500 rpm, and ball-milled for 80 hours to obtain a fullerene oil mixture.
  • the suspension was heated to 40 ° C with fullerene oil suspension, and protected with nitrogen. After stirring for 12 hours, it was centrifuged and filtered to obtain a fullerene oil solution.
  • the fullerene powder C60 is ball-milled and refined to 0.05-1 ⁇ m, and 5 g of the refined fullerene powder and 25 g of castor oil are mixed, placed in a ball mill at 500 rpm, and ball-milled for 80 hours to obtain a fullerene oil mixture.
  • the suspension was heated to 40 ° C with fullerene oil suspension, and protected with nitrogen. After stirring for 12 hours, it was centrifuged and filtered to obtain a fullerene oil solution.
  • the fullerene powder C70 is ball-milled and refined to 0.05-1 ⁇ m, and then 1 g of the refined fullerene powder is mixed with 15 g of olive oil, placed in a ball mill at 500 rpm, and ball-milled for 80 hours to obtain a fullerene oil mixture.
  • the suspension was heated to 40 ° C with fullerene oil suspension, and protected with nitrogen. After stirring for 12 hours, it was centrifuged and filtered to obtain a fullerene oil solution.
  • Example 3-15 Fullerene Gd@C82 emulsion
  • Example 3-16 Fullerene C60 Emulsion
  • Example 3-20 Fullerene C70 emulsion
  • Example 3-22 Fullerene solid particle granule
  • Example 23 50 parts of fullerene emulsion particles, 200 g of starch, 200 g of microcrystalline cellulose, 50 g of crospovidone, 1000 g of lactose, 1000 g of purified water, 20 g of magnesium stearate, and made into 10,000 tablets. .
  • Test Example 3-1 Screening of Vegetable Oils in Fullerene Emulsions
  • Fullerene powder was thoroughly mixed with the oil and fat excipients in Table 3-1, placed in a ball mill at 700 rpm, ball milled for 8 h, and then the mixture was heated at 40 ° C for 2 h with stirring to make fullerenes Fully dissolved in oil and fat excipients, and finally filtered to obtain fullerene oil.
  • the vegetable oils shown in Table 3-1 can only be used as an oil phase in the emulsion, and the vegetable oil has a better solubility for various fullerenes, preferably soybean oil, olive oil and tea oil.
  • the solubility is much less than the solubility of vegetable oils to fullerenes.
  • fullerenes are mixed with emulsifiers or co-emulsifiers, and fullerenes cannot be dispersed into the oils of emulsifiers or co-emulsifiers.
  • vegetable oil is the most soluble oil phase of fullerenes, in order to ensure that the drug content in the oral emulsion is as high as possible during the preparation of the emulsion.
  • the formulation does not use a co-emulsifier, the amount of the emulsifier is large and the cost is high, so a co-emulsifier is added on the basis to reduce the amount of the emulsifier.
  • the co-emulsifier generally has no emulsifying ability or is weak, and plays an important role in increasing the stability of the emulsion during the preparation of the emulsion, can increase the viscosity of the emulsion, increase the strength of the emulsion film, thereby increasing the stability of the emulsion, and the potential of the emulsion system is at
  • sodium citrate is preferred.
  • the Ke value is a centrifugal stability parameter, and the smaller the Ke value is, the more stable the emulsion is. It can be seen from Table 3-7 that when the emulsion preparation temperature is 70 ° C, the centrifugal stability parameter is the smallest and the emulsion stability is the best.
  • the high-pressure homogenizer plays the role of emulsification homogenization in the process of preparing the emulsion. Therefore, the emulsion has different particle diameters, which affects the stability of the final emulsion.
  • the homogeneous pressure is screened, and after 5 times of homogenization, the emulsion particles are detected. path.
  • the number of homogenization also affects the size of the emulsion particle size.
  • the number of homogenizations is not significantly different between the 4th and 5th particle sizes.
  • the number of homogenization times is 4 times as the number of preparations.
  • Test Example 3-5 Fullerene oral emulsion at the living level of chemotherapy protection
  • mice 4-5 weeks ICR mice, randomly divided into 4 groups, 6 in each group, drug group A: CTX + 1 mg / ml oral emulsion group, intragastric administration, 100ul each time; drug group B: CTX + 5 mg/ml fullerene oil group, intragastric administration, 100 ul each time; control group C: normal saline (Saline), cyclophosphamide (CTX) experimental group D.
  • the mice were subcutaneously inoculated with 10 6 mouse hepatoma cells (H22 cells), and after 5-7 days of inoculation, the tumor was drilled to a diameter of about 5 mm. The amount of CTX administered was 60 mg/kg of mouse body weight.
  • the drug was administered on the seventh day after tumor inoculation, as the first day of the start of the experiment, once a day for 5 consecutive days, on the fourth day, seventh day, tenth day, fourteenth day and seventeenth day, respectively.
  • Blood was collected from the eye of the mouse (20 ⁇ l), and blood routine was detected by an automatic blood cell analyzer.
  • the main indicators related to myelosuppression were white blood cell count (WBC), red blood cell count (RBC), platelet count (PLT), and hemoglobin measurement (HGB). .
  • WBC white blood cell count
  • RBC red blood cell count
  • PHT platelet count
  • HGB hemoglobin measurement
  • the oral emulsion has a more protective effect on myelosuppression than the oral oil. It is indicated that the fullerene oral emulsion has a more obvious protective effect on the bone marrow suppression induced by the chemotherapy drug CTX.
  • Table 3-10 White blood cell count, red blood cell count, platelet count, hemoglobin measurement data
  • Test Example 3-6 Test of the ability of fullerene emulsion to scavenge hydroxyl radicals in the examples of the present invention
  • Test Example 3-7 Antioxidant effect of fullerene emulsion of the present invention
  • vascular endothelial cells The effect of vascular endothelial cells on the antioxidant protection of fullerene emulsion was evaluated: firstly, intravascular human skin cells and fullerene emulsion, in which the full concentration of fullerene was 20umol/L, were incubated for 5 hours, then centrifuged and discarded. The supernatant was added to the culture dish, then hydrogen peroxide was added at a concentration of 100 umol/L, and incubation was continued for 12 hours, and then the cells were analyzed. As shown in Figure 3-2, the morphology of the cells in the model group (hydrogen peroxide damage group) and the blank control were basically the same, indicating that the fullerene emulsion showed excellent protective effect on the cells.
  • Test Example 3-8 Determination of the particle size of the oral emulsion of the present invention
  • the fullerene emulsion was diluted 100 times with water, and then the particle size was measured by a dynamic light scattering analyzer. As shown in Fig. 3-3, the fullerene emulsion particle size was maintained substantially between 130-180 nm.
  • Test Example 3-9 Efficacy of oral emulsions in inhibiting tumors
  • Animal strain Balb/c female, 5 weeks, weighing between 16-20g;
  • Tumor model mouse liver cancer H22 tumor strain
  • Experimental group randomly divided into drug group A, drug group B and control group C, with 6 rats in each group.
  • Mode of administration (1) Administration of 1 mg/ml fullerene emulsion to mice of drug group A, orally administered at a dose of 200 ul/d for 10 consecutive administrations; (2) Administration to mice of drug group B 1.2mg/ml fullerene oil group (patent WO2013/025180A1), oral, 200ml/kg/d, continuous administration 10 times; (3) control group C: normal saline (Saline);
  • mice 100 ⁇ L of H22 hepatoma cells with a concentration of 5 ⁇ 10 7 /ml were inoculated subcutaneously; the administration was started 24 hours after the inoculation, and the drug was administered continuously for 10 times; the body weight of the mice was weighed every other day during the experiment and the tumor growth was observed. The experiment was terminated 15 days after the inoculation, and the tumor weight of the mice was weighed and the volume was measured to calculate the tumor inhibition rate.
  • Table 3-11 shows the following results by the above anti-cancer method and tumor inhibition rate:
  • the fullerene oral emulsion of the examples of the present invention is superior to the fullerene oil product in suppressing tumors.
  • Test Example 3-10 The beneficial effects of fullerene oral emulsion on Parkinson's symptoms
  • Wistar rats weighing 180-200 g The experiment was divided into 5 groups, male and female, and the control group was not modeled. The other groups were intragastrically administered for two weeks after modeling for 6 weeks. Fullerene oral emulsion is divided into high dose group (0.424mg/ml), middle dose group (0.212mg/ml), low dose group (0.106mg/ml), dose is 2ml, using LPS damage model: Apu Morphine (0.5 mg/kg) can mimic the behavioral and pathological changes of Parkinson's symptoms after subcutaneous injection. The rotation behavior to the healthy side was induced after 5-15 minutes of injection, and the control group was behavioral change. The number of rotations in the PD group increased with the increase of modeling time.
  • the number of rotations of the rats in the drug-administered group decreased with the prolongation of the modeling time, and the number of rotations in the high-dose group decreased more significantly.
  • the number of rotations in the high-dose group and the middle-measurement group was significantly different (P ⁇ 0.05).
  • the data in Table 3-12 can be used to obtain rich. Injectable emulsion has a significant effect on LPS-induced Alzheimer's disease
  • Embodiments of the present invention also relate to a fullerene emulsion for injection and a preparation method thereof.
  • Oral preparations generally have a low bioavailability problem, so the preparation of the drug into an injectable form, especially for a disease with a high degree of malignancy such as cancer, can better exert the efficacy, and the treatment of the disease CN104983676A discloses a fuller
  • the ene shot can directly deliver the fullerene component to the human blood system by injection, so that the human body can absorb more fullerene components more quickly.
  • Fullerene injections are 0.01-8% by weight of sterile fullerenes, 45-60% polyoxyethylated castor oil, 35-50% anhydrous ethanol, polyoxyethylated castor oil and no Water ethanol is used as a solvent to fully dissolve fullerenes.
  • the polyoxyethylene-based castor oil in the patent can be used as an emulsifier to enhance the capacity, and the sensitization rate of the polyoxyethylene-based castor oil is high, and the sensitization mechanism is not explained yet, and the commonly used polychlorinated chlorine
  • the vinyl plastic infusion device interacts to leach the dioctyl phthalate to cause toxicity; the addition of ethanol is used for solubilization, and many solubilizers cause changes in biofilm morphology and tissue damage; the pharmacopoeia specifies the amount of ethanol used. Up to 12%, the use of too much ethanol will cause the drug to release too heavy and re-precipitate, affecting drug absorption and utilization.
  • an embodiment of the present invention has selected a fullerene emulsion which does not contain a solvent or a cosolvent for injection has not been studied.
  • the fullerene powder C70 is ball-milled and refined to 0.05-1 ⁇ m, and then 3 g of the refined fullerene powder is mixed with 100 g of olive oil, placed in a ball mill at 500 rpm, and ball-milled for 80 hours to obtain a fullerene oil mixture.
  • the suspension was heated to 40 ° C with fullerene oil suspension, and protected with nitrogen. After stirring for 12 hours, it was centrifuged and filtered to obtain a fullerene oil solution.
  • the fullerene powder C60 was ball-milled and refined to 0.05-1 ⁇ m, and 5 g of the refined fullerene powder was mixed with 100 g of soybean oil, placed in a ball mill at 700 rpm, and ball-milled for 12 hours to obtain a fullerene oil mixture.
  • the suspension was heated to 50 ° C, and protected with nitrogen. After stirring for 24 hours, it was centrifuged and filtered to obtain a fullerene oil solution.
  • the fullerene powder C76 is ball-milled and refined to 0.05-1 ⁇ m, and the refined fullerene powder 1.5 is mixed with 100 g of green thorn fruit oil, placed in a ball mill at 1000 rpm, and ball-milled for 20 hours to obtain fullerenes.
  • the oil suspension, the fullerene oil suspension was heated to 60 ° C, protected with nitrogen, stirred for 36 h, centrifuged, and filtered to obtain a fullerene oil solution.
  • the fullerene powder Gd@C82 is ball milled and refined to 0.05-1 ⁇ m, and then 0.7 g of the refined fullerene powder is mixed with 100 g of tea oil, placed in a ball mill at 500-1000 rpm, and ball milled for 8-20 h.
  • a fullerene oil suspension is obtained, and the fullerene oil suspension is heated to 40-60 ° C, protected with nitrogen, stirred for 12-72 hours, centrifuged, and filtered to obtain a fullerene oil solution.
  • the fullerene powder C60 is ball-milled and refined to 0.05-1 ⁇ m, and then 3 g of the refined fullerene powder is mixed with 100 g of olive oil, placed in a ball mill at 500 rpm, and ball-milled for 80 hours to obtain a fullerene oil mixture.
  • the suspension was heated to 40 ° C with fullerene oil suspension, and protected with nitrogen. After stirring for 12 hours, it was centrifuged and filtered to obtain a fullerene oil solution.
  • the crude milk After the temperature of the crude milk is naturally lowered to room temperature, it is put into a high-pressure homogenizer, homogenized 5 times at 50 Mpa, pH is 7.3-7.4, and water for injection is supplemented to 1000 ml, and the nitrogen is packed and filled.
  • the fullerene emulsion was obtained by sterilization at 121 ° C for 30 min.
  • the fullerene emulsion for injection was diluted 100 times with water, and then the particle diameter was measured by a dynamic light scattering analyzer. As shown in Fig. 4-1, the fullerene emulsion particle size was kept substantially at 50 nm.
  • the crude milk was naturally lowered to room temperature, it was put into a high-pressure homogenizer, homogenized 5 times at 50 Mpa, adjusted to pH 7.3-7.4, and the water for injection was supplemented to 1200 ml, and the nitrogen was packed and filled.
  • the fullerene emulsion was obtained by sterilization at 121 ° C for 30 min.
  • the fullerene emulsion for injection was diluted 100 times with water, and then the particle size was measured by a dynamic light scattering analyzer. As shown in Fig. 4-2, the fullerene emulsion particle size was maintained at 100 nm.
  • the crude milk temperature is naturally reduced to room temperature, it is put into a high-pressure homogenizer, homogenized 5 times at 50Mpa, adjusted to pH 7.3-7.4, and filled with water to 1000ml, sub-packaging, nitrogen filling,
  • the fullerene emulsion was obtained by sterilization at 121 ° C for 30 min.
  • the fullerene emulsion for injection was diluted 100 times with water, and then the particle size was measured by a dynamic light scattering analyzer. As shown in Fig. 4-3, the fullerene emulsion particle size was maintained at substantially 150 nm.
  • the crude milk temperature is naturally reduced to room temperature, it is put into a high-pressure homogenizer, homogenized 5 times at 50Mpa, adjusted to pH 7.3-7.4, and filled with water to 5000ml, sub-packaging, nitrogen filling, The fullerene emulsion was obtained by sterilization at 121 ° C for 30 min.
  • the crude milk After the temperature of the crude milk is naturally lowered to room temperature, it is put into a high-pressure homogenizer, homogenized 5 times at 50 Mpa, adjusted to pH 7.3-7.4, and the water for injection is supplemented to 1200 ml, and the nitrogen is packed and filled.
  • the fullerene emulsion was obtained by sterilization at 121 ° C for 30 min.
  • the crude milk After the temperature of the crude milk is naturally reduced to room temperature, it is put into the high-pressure homogenizer, homogenized 5 times at 50Mpa, adjusted to pH 7.3-7.4, and the water for injection is supplemented to 400ml.
  • the fullerene emulsion was obtained by nitrogen filling and sterilization at 121 ° C for 30 min.
  • the crude milk temperature is naturally lowered to room temperature, it is put into the high-pressure homogenizer, homogenized 5 times at 50Mpa, adjusted to pH 7.3-7.4, and the injected water is used to make up. 200ml, can be sterilized and dispensed.
  • the crude milk temperature is naturally reduced to room temperature, it is put into the high-pressure homogenizer, homogenized 5 times at 50Mpa, adjusted to pH 7.3-7.4, and the water for injection is supplemented to 400ml. Bacteria, can be packed.
  • the micro-jet is homogenized until the droplet size is 50-100 nm, the pH is 7.3-7.4, the water for injection is supplemented to 1000 ml, and the nitrogen is packed and filled.
  • the fullerene emulsion was obtained by sterilization at 121 ° C for 30 min.
  • the micro-jet is homogenized until the droplet size is 50-100 nm, the pH is adjusted to 7.3-7.4, and the water for injection is supplemented to 1200 ml, and the nitrogen is packed and filled.
  • the fullerene emulsion was obtained by sterilization at 121 ° C for 30 min.
  • Test Example 4-1 Screening of Injection Oil
  • Soybean oil, olive oil, thorn fruit oil and tea oil shown in Table 4-1 have better solubility to various fullerenes, more preferably soybean oil, which contains a large amount of unsaturated fatty acids, and is more suitable as an injection oil. .
  • Emulsifier selection principle excipients with strong emulsifying ability, high temperature resistance and easy storage, non-toxic and safe. Select the medium emulsifier in Table 4-2, investigate the storage conditions of the emulsifier, emulsifying ability, non-toxic (sensitization, hemolysis)
  • Table 4-3 auxiliary materials were prepared for oil-in-water fullerene emulsion, and 20 g of prescription oil was screened to prepare a concentration of 1 mg/ml.
  • the emulsifier can form a uniform emulsion in the range of 5-6.5%, but the sample 7 and 8 use HS-15 or poloxamer alone, although the dosage is 5%, but the emulsifying ability is still weak.
  • the emulsion is unevenly layered, so two or more emulsifiers are selected to prepare the emulsion.
  • Samples 3, 5-6 used HS-15 and poloxamer to solve the emulsification ability and had synergistic effects.
  • the inventors also investigated the ratio of the two and the proportion of the emulsion.
  • the emulsifier was poloxamer and HS-15 ratio (0.6-1.5):1
  • the prepared emulsion was stable and uniform without delamination.
  • the price of HS-15 is higher than that of poloxamer.
  • the dosage of HS-15 is less preferred, and the ratio of poloxamer to HS-15 is further preferred (1-1.5): 1.
  • the stabilizer was selected to be safe, non-toxic, and has good fluidity. It can rapidly decompose and excrete sodium citrate after entering the human body.
  • the Ke value is a centrifugal stability parameter, and the smaller the Ke value is, the more stable the emulsion is. It can be seen from Table 4-5 that the centrifugal stability parameter is the smallest when the emulsion preparation temperature is 60 ° C, and the emulsion stability is the best.
  • the high-pressure homogenizer plays the role of emulsification homogenization in the process of preparing the emulsion. Therefore, the emulsion has different particle diameters, which affects the stability of the final emulsion.
  • the homogeneous pressure is screened, and after 5 times of homogenization, the emulsion particles are detected. path.
  • the number of homogenization also affects the size of the emulsion particle size.
  • Test Example 4-5 Fullerene emulsion at the living level of chemotherapy protection
  • mice randomly divided into 4 groups, 6 in each group, drug group A: CTX + 1 mg / ml injection emulsion group, tail vein injection, 100ul each time; drug group B: CTX + 5mg /ml fullerene oil group, intragastric administration, 100ul each time; control group C: normal saline (Saline), cyclophosphamide (CTX) experimental group D.
  • the mice were subcutaneously inoculated with 10 6 mouse hepatoma cells (H22 cells), and after 5-7 days of inoculation, the tumor was drilled to a diameter of about 5 mm. The amount of CTX administered was 60 mg/kg of mouse body weight.
  • the drug was administered on the seventh day after tumor inoculation, as the first day of the start of the experiment, once a day for 5 consecutive days, on the fourth day, seventh day, tenth day, fourteenth day and seventeenth day, respectively.
  • Blood was collected from the eye of the mouse (20 ⁇ l), and blood routine was detected by an automatic blood cell analyzer.
  • the main indicators related to myelosuppression were white blood cell count (WBC), red blood cell count (RBC), platelet count (PLT), and hemoglobin measurement (HGB). .
  • WBC white blood cell count
  • RBC red blood cell count
  • PHT platelet count
  • HGB hemoglobin measurement
  • mice in the cyclophosphamide (CTX) experimental group white blood cells, Red blood cells, platelets, and hemoglobin have different degrees of reduction in mice, among which white blood cells are most obvious.
  • CTX+ fullerene injection emulsion white blood cells and red blood cells are protected by fullerene.
  • the amount of platelets and hemoglobin was greatly improved compared with the cyclophosphamide (CTX) experimental group, and with the prolongation of time, the relevant indicators were getting closer to the values of normal mice.
  • Table 4-8 White blood cell count, red blood cell count, platelet count, hemoglobin measurement data
  • Test Example 4-6 Antitumor effect of fullerene fullerene injection emulsion
  • Animal strain Balb/c female, 5 weeks, weighing between 16-20g;
  • Tumor model mouse liver cancer H22 tumor strain
  • Experimental group randomly divided into drug group A, drug group B and control group C, with 6 rats in each group.
  • Mode of administration (1) Administration of 1 mg/ml fullerene injection emulsion to mice of drug group A, intravenous injection, at a dose of 200 ul/d, for 10 consecutive administrations; (2) Administration to mice of drug group B 1.2mg/ml fullerene oil group (patent WO2013/025180A1), oral, 200ml/kg/d, continuous administration 10 times; (3) control group C: normal saline (Saline);
  • mice 100 ⁇ L of H22 hepatoma cells with a concentration of 5 ⁇ 10 7 /ml were inoculated subcutaneously; the administration was started 24 hours after the inoculation, and the drug was administered continuously for 10 times; the body weight of the mice was weighed every other day during the experiment and the tumor growth was observed. The experiment was terminated 15 days after the inoculation, and the tumor weight of the mice was weighed and the volume was measured to calculate the tumor inhibition rate.
  • Table 4-9 shows the following results by the above anti-cancer method and tumor inhibition rate:
  • the fullerene injection emulsion of the examples of the present invention is superior to the fullerene oil product in suppressing tumors.
  • Test Example 4-7 Effect of fullerene injection on the improvement of Parkinson's symptoms
  • Wistar rats weighing 180-200 g The experiment was divided into 5 groups, male and female, and the control group was not modeled. The other groups were administered two weeks after modeling, and were administered continuously for 6 weeks. Fullerene injection emulsion was divided into high dose group (0.113mg/ml), middle dose group (0.0565mg/ml), low dose group (0.02820.113mg/ml), dose was 2ml, using LPS damage model: The morphine and pathological changes of Parkinson's symptoms can be well simulated by subcutaneous injection of morphine (0.5 mg/kg). The rotation behavior to the healthy side was induced after 5-15 minutes of injection, and the control group was behavioral change. The number of rotations in the PD group increased with the increase of modeling time.
  • the number of rotations of the rats in the drug-administered group decreased with the prolongation of the modeling time, and the number of rotations in the high-dose group decreased more significantly.
  • the number of rotations in the high-dose group and the middle-measurement group was significantly different (P ⁇ 0.05).
  • the data in Table 4-10 can be used to obtain the rich. Injectable emulsion has a significant effect on LPS-induced Alzheimer's disease
  • fullerene injection emulsion has a significant improvement effect on Parkinson's symptoms compared with the control group.
  • Test Example 4-8 Anti-aging effect of fullerene injection emulsion of the present invention
  • Hydroxyl radicals are an important form of free radicals that harm the human body. For the injection of fullerene emulsions prepared in this patent, the removal of polyhydroxyl radicals was investigated.
  • the radical removal effect was measured by spin capture (ESR).
  • ESR spin capture
  • the specific operation is as follows: for the free radical generated by the reaction of hydrogen peroxide with ferrous ions, DMPO (5,5-dimethyl-1-pyrroline-N-oxide) is used as a spin trap to detect the freedom of DMPO and hydroxyl groups. The signal of the product DMPO-OH formed by the base reaction.
  • the concentration of ferrous sulfate heptahydrate was 0.4 mmol/L
  • the concentration of hydrogen peroxide was 5%
  • the pH of PBS was 7.4
  • the concentration of C60 in the emulsion was 1 mg/ml
  • the concentration of DMPO was 0.4 mol/ L, each of which was mixed with 50 ⁇ L of the above five solutions and tested. It can be seen from Fig. 4-4 that the obtained fullerene injection emulsion has a high scavenging efficiency for hydroxyl radicals.
  • the present invention provides a fullerene composition, a preparation method and application thereof, and an aqueous solution of fullerene, wherein the solute comprises fullerene and 15-hydroxystearic acid polyethylene glycol ester, wherein the fuller
  • the mass ratio of olefin and 15-hydroxystearic acid polyethylene glycol ester is (0.01-10): (30-60)
  • the fullerene aqueous solution has biosafety, high solubility in water and small particle size, and can be quickly absorbed. .
  • the present invention further provides a water-soluble fullerene external composition, and a preparation method thereof, the water-soluble fullerene external composition containing a water-soluble auxiliary agent and fullerene dissolved in the water-soluble auxiliary agent
  • the fullerene concentration is 0.01-10 mg/ml, and the composition has small particle size and fast absorption, and has the effects of whitening and wrinkles.
  • the embodiment of the present invention further provides an oral fullerene emulsion, a preparation method and application thereof, which comprises the following components by weight percentage: 10-50% of fullerene oil, 4-30% of emulsifier, co-emulsifier 0.1-0.2%, deionized water supplement, the emulsion is safe and stable, and has high bioavailability.
  • An embodiment of the present invention further provides a fullerene emulsion for injection and a preparation method thereof, which comprises 15-50% by weight of fullerene oil, 4-17% by weight of emulsifier, and 0.3-1% of stabilizer.
  • the agent is 2-9% and the balance water for injection, and does not include a solvent or a cosolvent.
  • the fullerene emulsion is an oil-in-water emulsion which is stable at pH 7.3-7.4, and the emulsion is safe and stable, and has high bioavailability.

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Abstract

L'invention concerne une solution aqueuse contenant un fullerène et du stéarate de 15-hydroxylpolyéthylène glycol, un procédé de préparation et l'utilisation de cette dernière ; une composition destinée à un usage externe contenant un fullerène et un auxiliaire soluble dans l'eau, et un procédé de préparation et l'utilisation de cette dernière ; une émulsion orale contenant 10 % à 50 % d'une huile de fullerène, 8 % à 20 % d'un émulsifiant, 0,1 % à 0,2 % d'un co-émulsifiant et le complément d'eau désionisée, et un procédé de préparation et l'utilisation de cette dernière ; et une émulsion de type huile dans l'eau contenant 10 % à 50 % d'une huile de fullerène, 4 % à 17 % d'un émulsifiant, 0,3 % à 1 % d'un stabilisant, 2 % à 9 % d'un excipient et le complément d'eau, destinée à être injectée, ladite émulsion de type huile dans l'eau ne contenant ni solvant ni co-solvant, et présentant un pH stable de 7,3 à 7,4, et un procédé de préparation et l'utilisation de cette dernière.
PCT/CN2018/105240 2017-09-12 2018-09-12 Composition de fullerène et procédé de préparation et utilisation de cette dernière WO2019052471A1 (fr)

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CN201710817804.4A CN109481464B (zh) 2017-09-12 2017-09-12 一种注射用富勒烯乳剂及其制备方法
CN201710818005.9 2017-09-12
CN201710817414.7 2017-09-12
CN201710817804.4 2017-09-12
CN201710817127.6A CN107411983B (zh) 2017-09-12 2017-09-12 一种水溶性富勒烯外用组合物
CN201710817127.6 2017-09-12
CN201710818005.9A CN109481396B (zh) 2017-09-12 2017-09-12 一种富勒烯水溶液、注射剂及其制备方法
CN201710817414.7A CN109481463B (zh) 2017-09-12 2017-09-12 一种口服富勒烯乳剂、制备方法及应用

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WO2021167481A1 (fr) * 2020-02-19 2021-08-26 Акционерное Общество "Акванова Рус" Solution micellisée de fullerènes, procédé de production et utilisation

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CN1753968A (zh) * 2003-01-27 2006-03-29 三菱商事株式会社 抗氧化组合物以及外用组合物
WO2008058234A2 (fr) * 2006-11-08 2008-05-15 Memory Pharmaceuticals Corporation Formulations pharmaceutiques pour des composés de 1,4-dihydropyridine ayant une solubilité améliorée
CN105596368A (zh) * 2016-02-01 2016-05-25 北京福纳康生物技术有限公司 一种富勒烯橄榄油组合物及其在治疗帕金森病中的应用
CN105616342A (zh) * 2014-10-28 2016-06-01 北京世纪博康医药科技有限公司 甘草醇的药用组合物、制备方法及用途
CN107411983A (zh) * 2017-09-12 2017-12-01 北京福纳康生物技术有限公司 一种水溶性富勒烯外用组合物

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Publication number Priority date Publication date Assignee Title
CN1753968A (zh) * 2003-01-27 2006-03-29 三菱商事株式会社 抗氧化组合物以及外用组合物
WO2008058234A2 (fr) * 2006-11-08 2008-05-15 Memory Pharmaceuticals Corporation Formulations pharmaceutiques pour des composés de 1,4-dihydropyridine ayant une solubilité améliorée
CN105616342A (zh) * 2014-10-28 2016-06-01 北京世纪博康医药科技有限公司 甘草醇的药用组合物、制备方法及用途
CN105596368A (zh) * 2016-02-01 2016-05-25 北京福纳康生物技术有限公司 一种富勒烯橄榄油组合物及其在治疗帕金森病中的应用
CN107411983A (zh) * 2017-09-12 2017-12-01 北京福纳康生物技术有限公司 一种水溶性富勒烯外用组合物

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021167481A1 (fr) * 2020-02-19 2021-08-26 Акционерное Общество "Акванова Рус" Solution micellisée de fullerènes, procédé de production et utilisation

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