WO2011120339A1 - Formulation de microémulsion contenant de l'arctigénine - Google Patents

Formulation de microémulsion contenant de l'arctigénine Download PDF

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WO2011120339A1
WO2011120339A1 PCT/CN2011/000574 CN2011000574W WO2011120339A1 WO 2011120339 A1 WO2011120339 A1 WO 2011120339A1 CN 2011000574 W CN2011000574 W CN 2011000574W WO 2011120339 A1 WO2011120339 A1 WO 2011120339A1
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microemulsion
emulsifier
oil
polyoxyethylene
mixture
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PCT/CN2011/000574
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English (en)
Chinese (zh)
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赵志全
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鲁南制药集团股份有限公司
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Publication of WO2011120339A1 publication Critical patent/WO2011120339A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention belongs to the field of medicine and relates to a microemulsion preparation.
  • the present invention relates to a microemulsion formulation of arctigenin. Background technique
  • Burdock is a dry and mature fruit of the burdock of the Compositae. It is a commonly used traditional Chinese medicine. It has the functions of evacuating wind and heat, venting the lungs, and detoxifying and pharynx. It is used for wind-heat, cold, cough, measles, rubella, sore throat. Itchy erysipelas, swollen sores.
  • the traditional Chinese medicine contains lignan compounds, mainly arctiin and arctigenin.
  • burdock aglycone also known as arctigenin
  • its precursor burdock is high in Chinese burdock and burdock fruit, so a large number of burdock can be obtained by transformation of burdock glycosides.
  • Aglycone According to reports in the literature, burdock is decomposed into burdock aglycon in the body and produces numerous pharmacological effects, and burdock aglycone has stronger biological activity than burdock, such as significant antibacterial, antiviral, antitumor, anti-PAF receptors and Calcium antagonistic activity.
  • the burdock aglycone is a white powder or a colorless block crystal. It is easily soluble in an organic solvent such as chloroform, methanol or ethanol. It is poorly soluble in petroleum ether and has a melting point of 111-112 °C. It is not volatile, it is not easily oxidized in the air, and its physical and chemical properties are relatively stable. However, the burdock aglycone is difficult to dissolve in water, and its bioavailability is low, which limits its application as a new drug to some extent.
  • the molecular structure of bovine glycosides is as follows:
  • Bovine aglycone (Arctigenin)
  • the bioavailability of intragastric administration in rabbits was only 9.5%.
  • the main reason for the analysis was that the burdock aglycone was a fat-soluble compound with poor water solubility, which led to low oral bioavailability.
  • the invention patent application publication CN 101036644A discloses a pharmaceutical composition containing arctigenin, which comprises an anthraquinone in a cyclodextrin derivative to solve the poor water solubility and bioavailability of arctigenin. Low problem.
  • the invention patent application publication CN101036643A also discloses a pharmaceutical composition containing arctigenin, which comprises an alloin, an oil, an emulsifier and water, and specifically provides an oral or intravenous emulsion.
  • the average particle size of the emulsion is more than 100 nm, and the emulsion contains 0.05-2.0 g of burdock aglycone, 5-20 g of oil, 0.5-5.0 g of emulsifier, 0.02-0.2 g of oleic acid, and the balance is water.
  • the microemulsion drug delivery system is a mixture of a drug, an oil phase (ie, an oil phase component), water, an emulsifier, and a co-emulsifier in an appropriate ratio, and has an average particle diameter of 10 to 100 nm, which is thermodynamically stable in vitro.
  • the system is stabilized by an emulsifier and a co-emulsifier; it has good solubility for water-soluble, fat-soluble and poorly soluble drugs, and has high physical stability; it is easy to penetrate the stomach and intestine due to low surface tension.
  • the hydration layer of the wall the drug can directly contact with the gastrointestinal epithelial cells, promote drug absorption, improve bioavailability; can be absorbed by lymphatics after oral administration, overcoming the first-pass effect and obstacles when the macromolecule passes through the gastrointestinal epithelial cell membrane .
  • microemulsions also has many difficulties. Since a large amount of emulsifier is required in the microemulsion, the emulsifier content increases and its accumulation in the body tends to produce certain toxicity, and the co-emulsifier, the oil phase and the ratio between them will all affect the microemulsion. The diameter and its stability have a major impact. Summary of the invention
  • the present invention provides a novel microemulsion preparation of arctigenin.
  • the microemulsion of the present invention has a uniform particle size, generally 10-100 nm.
  • the invention prepares the burdock aglycone microemulsion concentrate by using the microemulsion as a pharmaceutical carrier of the burdock aglycone, and can also prepare the microemulsion preparation containing the burdock aglycone by adding an excipient, including the solid micro Milk preparations and liquid microemulsion preparations.
  • the microemulsion preparation of the arctigenin of the present invention comprises an arctigenin microemulsion carrier comprising an oil phase and an emulsifier, and the microemulsion preparation has an average particle diameter of 10 to 90 nm.
  • the burdock aglycone and the microemulsion carrier constitute a microemulsion concentrate of burdock aglycone.
  • a microemulsion preparation of arctigenin according to the present invention, wherein the microemulsion carrier may further contain an excipient.
  • the burdock aglycone microemulsion concentrate of the present invention may be liquid, solid or semi-solid at room temperature.
  • the microemulsion preparation of the present invention comprises an arctigenin and a microemulsion carrier, the microemulsion carrier comprising an oil phase and an emulsifier, and may further comprise a co-emulsifier, preferably, the bovine aglycone in the microemulsion preparation of the present invention,
  • the weight ratio of the oil phase, the emulsifier and the co-emulsifier is: 1-10 parts of burdock aglycone, 5-85 parts of an oil phase, 20-60 parts of an emulsifier, and 5-60 parts of a co-emulsifier.
  • the present invention also preferably optimizes the oil phase, the emulsifier and the co-emulsifier, respectively.
  • Oil is one of the essential components relative to the burdock aglycone microemulsion preparation.
  • the oil phase can promote the transport of drugs in the body, enhance the absorption of the body, and improve the bioavailability of the drug.
  • the larger the molecular volume of the oil phase the stronger the solubility of the drug, but the molecular volume of the oil phase is too large to form a microemulsion.
  • the oil phase compatible with the drug should be selected.
  • the oil phase of the above microemulsion preparation is a solid or semi-solid oil phase component selected from one or more of a fatty acid glyceride, an alcohol ester, a fatty alcohol, and a polysaccharide-derived saturated glyceride.
  • the fatty acid glyceride is selected from one or more of hydrogenated cocoglyceride, hydrogenated palm oil PEG-6 ester and hydrogenated palm oil PEG-6 ester
  • the alcohol ester is selected from propylene glycol stearate.
  • PEG-2-stearate and cetyl palmitate the fatty alcohol is myristyl alcohol
  • the polysaccharide-saturated glyceride is lauroyl polyethylene glycol-32- Glyceride.
  • the oil phase of the above microemulsion preparation is a liquid oil phase component selected from one or more of glycerides, natural vegetable oils and their fractions, essential oils, volatile oils and synthetic oils.
  • the glyceride is a mixture of a monoglyceride and a diglyceride, a caprylic acid glyceride, a medium chain fatty acid glyceride, a monolinoleic acid glyceride or a glyceryl caprylate, and the natural vegetable oil and the fraction thereof are safflower oil.
  • the preference for the above oil phase is mainly to increase the solubility of the burdock aglycone in the oil phase and to increase the area in which the microemulsion is formed. All of the above "preferred” means that the oil phase having a larger area of microemulsion formation is selected as much as possible while ensuring greater solubility of the arctigenin. The preferred component has a stronger solubility of arctigenin. Ability and ability to form a 3 ⁇ 4 ⁇ large microemulsion area.
  • the emulsifier is one of the essential components of the burdock aglycone microemulsion preparation.
  • the emulsifier is generally a surface active material and a mixture thereof, and may be an ionic, nonionic or zwitterionic surfactant having a reduced interfacial tension to form an interfacial film to promote microemulsion formation. Not all surfactants are suitable as components of the microemulsions of the present invention.
  • the emulsification agent used in the present invention is preferably a nonylphenol ethoxylate, Polyoxyethylene fatty acid ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, sorbitan derivative, polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene nonyl ether, polyglycerin fatty acid ester and sub One or more of the mercapto polyol esters.
  • the polyoxyethylene fatty acid ester is polyoxyethylene stearate, PEG-40-stearate or a mixture thereof, and the sorbitan derivatives are Tween-20, Tween-40, Tween-60, and spit.
  • the polyoxyethylene-polyoxypropylene copolymer is poloxamer
  • the polyoxyethylene decyl ether is polyoxyethylene-2-cetyl ether, polyoxyethylene-10-whale wax Ether, polyoxyethylene-20-cetyl ether, polyoxyethylene-23-lauryl ether, polyoxyethylene-20-oleyl ether, polyoxyethylene-2-stearyl ether, polyoxyethylene-10 - stearyl ether, polyoxyethylene-20-stearyl ether or a mixture thereof
  • polyglycerol fatty acid ester is decaglyceryl monostearate, hexaglycerol monostearate, tetraglyceryl monostearate Or a mixture thereof
  • the alkylene polyol ester is stearyl, lauroyl polyethylene glycol-32-glyceride or a mixture thereof.
  • the above polyoxyethylene alkyl ether is polyoxyethylene-23-lauryl ether or polyoxyethylene-20-oleyl ether.
  • Self-emulsifying drug delivery systems require self-emulsifying and maintaining the state of the emulsion in the gastrointestinal tract.
  • a large amount of emulsifier is required in the formulation, but a large emulsifier may irritate the gastrointestinal tract, so the safety of the emulsion should be fully considered. Therefore, it is preferred for the emulsifier to combine pharmaceutics and pharmacological toxicology studies to select an emulsifier which is less toxic, irritating and hemolytic, and which has a stronger ability to lower the interfacial tension.
  • the "preferred" of the above emulsifiers indicates the screening of the emulsifier safety and emulsifying ability. Preferred components have greater safety and emulsifying capabilities.
  • the burdock aglycone microemulsion formulation of the invention further comprises a co-emulsifier.
  • Co-emulsifiers are generally surface active materials.
  • the co-emulsifier can not only increase the flexibility of the film, but also facilitate the formation of the microemulsion droplet interface film, increase the dissolution of the emulsifier, further reduce the interfacial tension, and is beneficial to the stability of the microemulsion.
  • the emulsifier used in the present invention is a medium chain length alcohol or a nonionic surfactant polar organic substance having a suitable HLB value.
  • the co-emulsifier of the present invention is one of the following components or any mixture thereof: short-chain alcohol, organic ammonia, mercapto acid, glyceryl mono-dimercaptoate, and polyoxyethylene fatty acid ester.
  • the co-emulsifier is a short chain alcohol selected from one or more of polyethylene glycol, n-butanol, n-hexanol, ethanol, ethylene glycol, propylene glycol, and glycerin.
  • the co-emulsifier is ethanol, glycerin, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400 or 1, 2-propanediol.
  • the preferred preference for the co-emulsifier is to consider the effect of the addition of the co-emulsifier on the stability and emulsification of the microemulsion.
  • the length of the co-emulsifier chain has a certain influence on the auxiliary emulsification effect.
  • the linear chain is superior to the branched chain, and the long chain is superior to the short chain.
  • the "preferred" of the above co-emulsifiers means the screening of the emulsifying ability and stability of the co-emulsifier.
  • the preferred components are more powerful in ensuring microemulsion stability and emulsifying ability to the drug.
  • the microemulsion region can be identified by the ternary phase diagram to determine it. Their usage. At the same time, it is necessary to consider the safety of the emulsifier, the stability of the co-emulsifier to the microemulsion and their solubilizing effect on the arctiin. Minimize the amount of emulsifier in the case of ensuring the preparation of microemulsions to ensure the lowest possible toxicity.
  • the weight ratio of the oil phase, the emulsifier and the co-emulsifier of the microemulsion is preferred, and the weight ratio of the oil phase, the emulsifier and the co-emulsifier is: 5-85 parts of the oil phase, 20-60 of the emulsifier 5 to 60 parts of co-emulsifier. Further preferably, the weight ratio of the oil phase, the emulsifier, and the co-emulsifier is: 20-40 parts of the oil phase, 35-55 parts of the emulsifier, and 15-45 parts of the co-emulsifier. '
  • Most of the microemulsion concentrate of the bovine aglycone prepared above has a liquid state, and in order to make the above microemulsion concentrate solid or semi-solid at room temperature, a hydrophilic component is added to the above microemulsion concentrate.
  • the hydrophilic component is preferably polyethylene glycol, polyethylene oxide or a mixture thereof.
  • the polyethylene glycol is polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400 or a mixture thereof.
  • the microemulsion concentrate formed in accordance with the present invention comprises components in the following weight ratios: 1-10 parts of arctigenin, 5-85 parts of oil phase, 20-60 parts of emulsifier, co-emulsifier 5-60 parts, hydrophilic component 20-70 parts.
  • the microemulsion concentrate comprises components in the following weight ratio: 1-10 parts of burdock aglycone, 20-40 parts of oil phase, 35-55 parts of emulsifier, 15-45 parts of co-emulsifier, hydrophilic group 30-50 parts. It is preferred for the kind and weight of the hydrophilic component to indicate that the crystal structure of the preferred hydrophilic component is not affected or less affected.
  • microemulsion preparation can be used as a self-emulsifying drug delivery system, and the microemulsion concentrate containing the medicine enters the gastrointestinal tract and automatically forms microemulsion after contact with the water in the stomach and intestine for absorption by the human body. It is also possible to prepare the microemulsion preparation by adding the microemulsion concentrate to the excipient. To increase the patient's choice of drug route and dosage form preferences for the drug microemulsion formulation.
  • the excipient is a preservative, a filler, a pH adjuster, an isotonicity adjuster, an acidulant, water or a mixture thereof.
  • the excipients range from 0.05% to 80% by weight of the microemulsion.
  • the above preservative is ascorbic acid and its derivatives, tocopherol and its derivatives, butylated hydroxyanisole, butylhydroxytoluene or any mixture thereof.
  • Fillers are microcrystalline cellulose, silica, starch and its derivatives, lactose, dicalcium dihydrate, mannitol or any mixture thereof.
  • the acidifying agent is citric acid, succinic acid, fumaric acid, ascorbic acid, phosphoric acid, citric acid, oleic acid, cellulose acetate, acetic acid-1,2,4-benzenetricarboxylic acid cellulose, hydroxypropyl methylcellulose Acid ester, carboxymethyl ethyl cellulose, carbomer or any mixture thereof.
  • the pH adjusting agent is a buffer solution of phosphate, sodium hydroxide, hydrochloric acid or any mixture thereof.
  • the isotonicity adjusting agent is a sodium chloride solution, a potassium chloride solution or a mixture thereof.
  • the above microemulsion concentrate of bovine aglycone and an excipient can be prepared into an oral microemulsion preparation and a intravenous microemulsion preparation.
  • Oral microemulsion formulations include tablets, granules and oral solutions. Due to the natural formation and thermodynamic stability, the preparation process of the burdock aglycone microemulsion preparation is simple.
  • the burdock aglycone microemulsion preparation can be prepared into a water-in-oil type (W/0 type) or an oil-in-water type (0/W type), and the present invention is preferably prepared into a 0/W type microemulsion preparation.
  • the preparation process of the burdock aglycone microemulsion preparation comprises the following steps:
  • microemulsion concentrate of burdock aglycone is added to the above excipient to prepare a microemulsion oral preparation and a microemulsion intravenous preparation.
  • the present invention provides a process for the preparation of the burdock aglycone microemulsion formulation of the present invention, the method comprising the steps of:
  • microemulsion preparation (4) The above microemulsion is added to an excipient to prepare a microemulsion preparation.
  • the present invention provides a process for the preparation of the burdock aglycone microemulsion formulation of the present invention, the method comprising the steps of:
  • microemulsion preparation (4) The above microemulsion is added to an excipient to prepare a microemulsion preparation.
  • the method for preparing the burdock aglycone microemulsion preparation of the present invention comprising the steps of:
  • microemulsion is added to an excipient to prepare a microemulsion preparation.
  • the present invention provides a method of preparing the burdock aglycone microemulsion preparation of the present invention, the method Including the following steps:
  • microemulsion is added to an excipient to prepare a microemulsion preparation.
  • the preparation process of the burdock aglycone microemulsion preparation may further comprise diluting the microemulsion concentrate into an appropriate amount of an aqueous medium to prepare a naturally dispersible microemulsion clarified concentrate, thereby preparing a microemulsion oral solution which becomes bovine aglycone.
  • an aqueous medium to a dilution of 1: 1 to 300, preferably 1 : 10-70, more preferably 1: 10
  • the naturally dispersible microemulsion preconcentrate forms a 0/W microemulsion.
  • the microemulsion concentrate of the burdock aglycone of the present invention may also be mixed and heated with the above excipients and stirred until melted. It may be prepared into granules, or the obtained granules may be further refined and then placed in a capsule shell to form a soft capsule or a hard capsule. When the granules or capsules are contacted with an aqueous medium, including gastric juice, the bovine aglycone microemulsion concentrate can be diluted into naturally dispersible microemulsions.
  • the invention provides a method for treating a condition or disease, such as a viral infection, a bacterial infection, a tumor, etc., the method comprising administering to a subject in need thereof an effective amount of an aglycone of the invention Microemulsion preparation.
  • a condition or disease such as a viral infection, a bacterial infection, a tumor, etc.
  • viral infections include, but are not limited to, influenza viruses, parainfluenza viruses, herpes viruses, mumps viruses, and the like.
  • bacterial infections include, but are not limited to, Staphylococcus aureus, pneumococci, streptococci, and the like.
  • the tumor includes sarcoma and cancer, such as lung cancer, liver cancer, esophageal cancer, gastric cancer, breast cancer and the like.
  • the burdock aglycone microemulsion preparation of the present invention can also be used for the treatment of cardiovascular diseases and senile dementia and the like.
  • the burdock aglycone microemulsion preparation of the present invention may be combined with other drugs which enhance its pharmacological effects, and examples of the other drugs include, but are not limited to, antiviral drugs, antibiotics, antineoplastic agents, immunopotentiators, and the like. Therapeutic agent.
  • the present invention provides the use of the burdock aglycone microemulsion preparation of the present invention for the preparation of a medicament for treating a viral infection, a bacterial infection, a tumor or the like.
  • the invention describes the burdock aglycone microemulsion preparation of the invention and the preparation method thereof by the embodiment 1-30, and all the microemulsion preparations diluted by the microemulsion preparation or the microemulsion concentrate of the invention meet the quality standard of the microemulsion preparation. . After the centrifugation test, the microemulsion was still clear and transparent, and no delamination or turbidity occurred. The results of particle size and particle size distribution of the burdock aglycone microemulsion concentrate and diluent showed that the average particle size was 10-90 nm, which did not exceed 100 nm, and the distribution range was narrow and uniform, which was consistent with the distribution requirements of particle size and particle size of microemulsion. .
  • the present invention investigates the oral bioavailability of the burdock aglycone microemulsion preparation, and as a result, finds the burdock glycosides provided by the present invention.
  • the micro-milk preparation (including Example 1-31) significantly increased the oral bioavailability of the bovine glycoside emulsion disclosed in CN101036643A by 1.39-4.73 times.
  • the invention also finds that the microemulsion preparation of the burdock aglycone provided by the invention has the effect of significantly improving the anti-mouse S180 tumor of the burdock aglycone emulsion disclosed by the invention according to CN101036643A.
  • Yuan's microemulsion preparation has significant advantages over the bovine glucoside aglycone emulsion disclosed in CN101036643A in inhibiting H22 hepatocarcinoma and mouse Lewis lung cancer solid tumor; in combination with the burdock aglycone emulsion and tegafur at the same dose
  • the combination of the burdock aglycone microemulsion preparation of the present invention and tegafur has a significant advantage in inhibiting H22 liver cancer solid tumors and mouse Lewis lung cancer solid tumors, and the tumor inhibition rate is significantly improved.
  • microemulsions improve drug delivery, which increases drug loading, enhances permeability, reduces particle size, improves particle size uniformity, increases drug dissolution rates, and increases bioavailability compared to emulsions and conventional formulations. Reduce inter- and intra-individual differences in pharmacokinetics.
  • the microemulsion formulations of the present invention exhibit advantageous properties such as high levels of bioavailability obtained in standard bioavailability assays.
  • the microemulsion concentrate obtained above was diluted with water to a clear solution in a weight ratio of 1:10-20 to obtain a microemulsion.
  • a small amount of burdock aglycone microemulsion concentrate was added to the methylene blue and Sudan red solution respectively to observe the diffusion rate of the two different color solutions in the microemulsion.
  • the burdock aglycone microemulsion was centrifuged at 30 mii in a DT5-3 centrifuge to observe the phenomenon and examine its physical stability. 3.4 Study on particle size and particle size distribution
  • burdock aglycone microemulsion determines its particle size and particle size distribution by laser granulometry; take appropriate amount of burdock aglycone microemulsion, dilute 50 times with water; determine the particle size and particle size distribution of the diluent by laser granulometry .
  • burdock aglycone microemulsion Take 1 ml of burdock aglycone microemulsion, place it in a 100 ml volumetric flask, dilute to the mark with methanol, and measure the content of arctigenin. 4. Investigation of physical and chemical properties of burdock aglycones and its quality evaluation results
  • microemulsion is still clear and transparent, no precipitation occurs, and no delamination or turbidity occurs. It shows that its physical stability is good, which can indirectly indicate that it can maintain good stability after standing for a long time.
  • the results of particle size and particle size distribution of the burdock aglycone microemulsion concentrate and diluent showed that the average particle size of the prepared bovine aglycone microemulsion was 25 nm, and the polydispersity coefficient was 0.105.
  • Preparation process Weigh the prescription amount of caprylic acid glyceride, polyoxyethylene castor oil EL-40, 1, 2-propanediol, mix and stir evenly, then add the burdock aglycone to dissolve, sonicate to accelerate the dissolution, to obtain a clear concentrate, ie is arctigenin ⁇ microemulsion concentrate obtained above microemulsion concentrate with water in a 1: 10-20 ratio by weight was diluted to a clear solution to obtain a microemulsion. The particle size was measured by a laser granulometer, and the average particle diameter was 15 nm.
  • Example 3 Microemulsion concentrate
  • Example 4 Laser particle size analyzer using a particle diameter, an average particle diameter of 35nm £ microemulsion concentrate of Example 4
  • Example 5 Microemulsion concentrate
  • Preparation process Weigh the prescribed amount of octanoic acid ethyl oleate, Tween-80, 1, 2-propanediol, polyethylene glycol 3350, mix and mix evenly, then add the burdock aglycone dissolved, sonicated to accelerate the dissolution, to clarify
  • the concentrate is the burdock aglycone microemulsion concentrate.
  • the microemulsion concentrate obtained above was diluted with water to a clear solution in a weight ratio of 1:10-20 to obtain a microemulsion.
  • the particle size was measured by a laser granulometer, and the average particle diameter was 40 nm.
  • the preparation process was the same as in Example 6.
  • the particle size was measured by a laser granulometer, and the average particle diameter was 35 nm.
  • the preparation process was the same as in Example 6.
  • the particle size was measured by a laser granulometer, and the average particle diameter was 40 nm.
  • Example 10 Microemulsion concentrate
  • Example 11 Microemulsion concentrate
  • Example 12 Microemulsion concentrate
  • Example 14 Microemulsion concentrate
  • Example 15 Microemulsion concentrate
  • Example 16 Microemulsion concentrate
  • Example 18 Microemulsion concentrate
  • Example 19 Laser particle size analyzer using a particle diameter, an average particle diameter of 27nm t microemulsion concentrate of Example 19
  • Example 21 Microemulsion concentrate
  • Example 22 Microemulsion concentrate
  • Example 24 Microemulsion concentrate
  • Example laser particle size analyzer using the same preparation process embodiment the particle size, the average particle diameter of 25 Example embodiment microemulsion concentrate 80nm t Component weight / g
  • Example 26 Microemulsion concentrate
  • Example 27 Microemulsion concentrate
  • Example 28 Microemulsion injection of arctigenin.
  • Example 30 Capsules containing burdock aglycone microemulsion
  • Preparation process Weigh the prescribed amount of hydrogenated coconut glyceride, polyoxyethylene castor oil EL-40, 1, 2-propanediol, mix and stir evenly, then add the burdock aglycone to dissolve, ultrasonic treatment to accelerate the dissolution, to obtain a clear concentrate , that is, the burdock aglycone microemulsion concentrate.
  • the microemulsion concentrate obtained above was diluted with water to a clear solution in a weight ratio of 1:10-20 to obtain a microemulsion.
  • the particle size was measured by a laser granulometer, and the average particle diameter was 80 nm.
  • microemulsion concentrate or microemulsion preparation of the arctigenin prepared in Example 2-31 was repeated, and the "investigation and quality evaluation of the physicochemical properties of the burdock aglycone microemulsion" in Example 1 was repeated, and all the microemulsion preparations were found or The microemulsion preparations diluted by the microemulsion concentrates all meet the quality standards of the microemulsion preparations. After the centrifugation test, the microemulsion was still clear and transparent, and no delamination or turbidity occurred.
  • the results of particle size distribution and particle size distribution of the burdock aglycone microemulsion concentrate and the diluent showed that the average particle size of the burdock aglycone microemulsion prepared in Example 2-31 was 10-90 nm, and the distribution range was not more than 100 nm, and the distribution range was narrow and uniform. It meets the requirements for the distribution of particle size and particle size of microemulsion.
  • the microemulsion concentrate or microemulsion preparation of the arctigenin prepared in Example 1-31 was subjected to an accelerated test at 40 ° C under 75% RH, and sampled at 1, 2, 3, and 6 months, using laser particle size.
  • the analyzer was used to detect the particle size, and the results are shown in Table 1 (bit nm). It can be seen from Table 1 that the burdock aglycone microemulsion prepared by the invention has good stability, especially the stability of the burdock aglycone microemulsion concentrate or the microemulsion preparation prepared in Examples 1-18 is more The path is smaller.
  • Test Example 1 Oral bioavailability of bovine aglycone microemulsion preparation
  • the burdock aglycone emulsion the formulation and the preparation process are the same as the embodiment 3 of the CN101036643A specification, and the formulation of the burdock aglycone emulsion: burdock aglycone 1.0 g + egg yolk phospholipid 3.0 g + medium chain oil 15 g + oleic acid 0.08 g + glycerol 3.0 g. Bork aglycone microemulsion: the microemulsion prepared in Example 1 of the present invention;
  • Anthraquinone reference substance (purity 99.5%); heparin sodium, normal saline, methanol, acetonitrile (all chromatographic reagents), others are analytical reagents.
  • LC-10A high performance liquid chromatography SPD-10AV UV detector: ShimazuClass-vp Version 5.03 working station; KQ-100 ultrasonic cleaner; desktop centrifuge TGL-16C; manual homogenizer.
  • New Zealand rabbits weighing 1400-1500g, both male and female, are provided by Shandong New Age Pharmaceutical Animal Center.
  • 0.5 ml of the sample was placed in a separatory funnel, 5 ml of dichloromethane was added, shaken, and extracted twice. The dichloromethane layer was separated and combined, and the dichloromethane solution was evaporated to dryness in a 40-inch water bath. The residue was dissolved in 0.5 ml of acetonitrile, and used as a test solution, placed in a refrigerator (-20 ° C) to be tested, and 10 ⁇ l was injected. .
  • the plasma of the experimental animals was treated as described above, and then injected into a high performance liquid chromatograph.
  • the blank plasma sample was processed in the same way.
  • the peak of bovine aglycone has a good separation from other peaks, and the resolution of the adjacent peak is R: 2.5, and the number of theoretical plates is 3566 pieces/meter.
  • the blank plasma has no interference with its analysis.
  • the low detection of arctigenin in plasma was 9.58x10 g/ml based on the peak height as a baseline noise of 3 times.
  • Plasma samples need to be removed from impurities such as proteins before injection into the column to prevent clogging of the column, resulting in reduced column efficiency.
  • a water-soluble organic solvent such as methanol, acetonitrile, or a strong acid such as 10% trichloroacetic acid is added to remove the protein. Or extract with an organic solvent.
  • a biological sample was extracted from dichloromethane with good solubility of arctigenin. Considering the high volatility of dichloromethane, the dichloromethane solution was evaporated and then stabilized with acetonitrile to dissolve. Injection.
  • the blood drug concentration-time curve was processed by the 3 ⁇ 87 practical pharmacokinetics program prepared by the Chinese Pharmaceutical Association's Committee of Mathematics and Pharmacology, and the curve was fitted by computer to obtain the main pharmacokinetic parameters.
  • Microemulsion group 30 4.6520 0.1550 45.21
  • microemulsion concentrate or microemulsion preparation of the arctigenin prepared in Examples 2 to 31 was substituted for the microemulsion preparation of the bovine aglycone of Example 1 used in Test Example 1, and the description of the examples 1 to 7 was replaced with the test example of CN101036643A.
  • the emulsion in 1 was repeated in Test Example 1, and as a result, it was found that the oral bioavailability of the emulsion of the Example 1 to 7 burdock aglycone disclosed in the specification of CN101036643A was 9.60% to 16.23%, and the oral bioavailability of the microemulsion preparation of the burdock aglycone of the present invention.
  • S180 cells were cultured in 1640 medium, n. C, under 5% C0 2 were cultured, passaged on average once every 2 days to the preparation with physiological saline to a density of logarithmic growth phase was 3.0xl0 7 / mL single cell suspension, under sterile conditions in mice inoculated intraperitoneally Within (about 5 mice, both male and female), the mice were obviously swollen in the abdominal cavity about 10 days after inoculation. At this time, the mice were sacrificed by cervical dislocation and soaked in a beaker containing 75% ethanol for 2 to 3 minutes.
  • mice Place the sterilized mice on the ultra-clean workbench, use the tweezers to clip the skin in the middle of the abdomen, cut the skin with the surgical scissors in the lower abdomen, expose the abdomen, and pass through the sterile syringe. Ascites was taken from the abdominal muscles and placed in a sterile reagent bottle for later use.
  • the above ascites fluid extracted by trypan blue exclusion, using tumor cells> 95% of the graft was diluted with physiological saline to adjust the cell number 2 ⁇ 10 7 ⁇ 6 ⁇ 10 7 / ml, and obtained tumor cell suspension.
  • the rats were weighed the next day after inoculation.
  • the healthy mice were randomly divided into 4 groups, 1Q each, male and female, and each weighing was recorded.
  • the cells were inoculated 24 hours after inoculation of the tumor cells. 0.2 mL each, once a day for 14 days.
  • the tumor inhibition rate (%) (the average tumor weight of the negative control group - the average tumor weight of the experimental group) / the average tumor weight of the negative control group ⁇ %, and the tumor was taken for pathological examination.
  • the excised tissue is tumor tissue, and the tissue type is less.
  • the inhibition rate of the burdock aglycone emulsion group was only 17.0%, while the inhibition rate of the burdock aglycone microemulsion group was 46.4%. This indicates that the effect of the burdock aglycone microemulsion formulation against the mouse S180 tumor was significantly improved relative to the emulsion group.
  • the microemulsion concentrate or microemulsion preparation of 6 bursin aglycone was prepared in Example 2 to 31 instead of the microemulsion preparation of the burdock aglycone of Example 1 used in Test Example 2, using CN101036643A
  • the specification discloses the use of the emulsion of Example 2 to 7 in the replacement of Example 33, and the test example 2 was repeated.
  • the microemulsion preparation of the arctiin of the present invention has a tumor inhibition rate of 35.60% to 53.82%, and CN101036643A discloses the embodiment 2
  • the tumor inhibition rate of the ⁇ 7 emulsion was 10.5% to 18.3%, which indicates that the effect of the emulsion of the burdock aglycone microemulsion provided by the present invention is significantly higher than that of the emulsion disclosed by CN101036643A against the mouse S180 tumor.
  • Test Example 3 Inhibition test of burdock aglycone on KM mouse H22 liver cancer
  • the burdock aglycone microemulsion was weighed with caprylic acid glyceryl ester, nonylphenol ethoxylate and propylene glycol according to the prescription amount, and evenly mixed.
  • the prescription amount of burdock aglycone was ultrasonicated to dissolve, and then the burdock aglycone microemulsion concentrate was obtained. . Autoclave treatment is required before use. Determination of burdock aglycone microemulsion: Take the burdock aglycone microemulsion lg and add it to 100g of water, stir until the emulsification is complete, and measure the particle size, the average is 25nm, which meets the requirement of microemulsion (less than 100nm).
  • mouse group 1 2 3 4 5 6 stained part 'white head back tail left front left middle
  • Cage Name and Specifications Cage Name and Specifications: Squirrel Cage (LxWxH 1450 mmx400 mmx l500 mm) Mouse Cartridge (LxWxH 300 mmx lOOmmx 150mm)
  • the cage is wet-disinfected every day.
  • the disinfectant is 0.1% chlorpheniramine and 75% ethanol solution.
  • the disinfectant is used alternately every week.
  • Dosage design The dosage design of the drug administration group is shown in Table 5.
  • mice were randomly divided into 6 groups, 10 in each group, half male and half female.
  • Mouse H22 cells were cultured in 1640 medium, routinely cultured at 37 ° C under 5 % CO 2 , subcultured every two days, and prepared to a density of 3.0 ⁇ 10 7 /ml single cells with physiological saline in the logarithmic growth phase.
  • the suspension was injected into the abdominal cavity of the mice under aseptic conditions.
  • the abdominal cavity of the mice was swollen 7 days after inoculation.
  • the neck was sacrificed and placed in a beaker containing 75% ethanol for 2 3 minutes.
  • the sterilized mice were placed in a clean bench, exposed to the abdomen, and ascites was taken with a sterile syringe and placed in a sterile reagent bottle for use.
  • the ascites was counted with trypan blue, diluted with physiological saline, and the number of cells was adjusted to ⁇ . ⁇ 7 /ml, and inoculated into the right axilla of the mouse, each 0.2 ml.
  • the animals were administered on the fourth day after inoculation of the tumor, and were administered once a day according to Table 6 (administered every morning) at a dose of 10 ml 'kg -1 ; the model group was given an equal amount of physiological saline. Continuous administration for 10 days.
  • Detection frequency Weighed animals were weighed before and before anatomy.
  • Detection frequency The test was terminated 10 days after administration, and the blood was sacrificed and the necropsy was performed.
  • Anatomy Intraperitoneal injection of 2% sodium pentobarbital (0.3 ml.kg) anesthesia, after the main abdominal vein was taken, the abdominal aorta was cut and sacrificed, and then the tumor was routinely removed.
  • test data is expressed in ⁇ s and data processing was performed using SPSS 11.5 statistical software.
  • the present invention also investigates the combination of burdock aglycon and tegafur, and finds that, at the same dose, the burdock aglycone is compared with the combination of burdock aglycone and tegafur.
  • ⁇ The combination of preparation and tegafur has a significant advantage in inhibiting H22 solid tumors of liver cancer, and the tumor inhibition rate is significantly improved.
  • Table 7 Effect of burdock aglycone on tumor weight and tumor inhibition rate in KM mice (s) s group dose tumor tumor inhibition rate model group - 2.05 ⁇ 0.89 - emulsion low dose group 15 mg / kg 1.92 ⁇ 1.55 6.3 emulsion high Dosage group 45 mg/kg 1.85 ⁇ 0.96 9.8 Microemulsion low dose group 15 mg/kg 1.69 ⁇ 1.55 AA 17.6 Microemulsion high dose group 45 mg/kg 1.56 ⁇ 0.96 AA 23.9
  • Test Example 4 Effect of burdock aglycone on tumor inhibition rate of transplanted Lewis lung cancer
  • the glyceryl caprylate, nonylphenol ethoxylate and propylene glycol were weighed according to the prescription amount, and the mixture was mixed.
  • the prescription amount of burdock aglycone was ultrasonicated to dissolve, and the burdock aglycone microemulsion concentrate was obtained. Autoclave treatment is required before use. Determination of burdock aglycone microemulsion: Take burdock aglycone microemulsion lg to 100g water, stir until the emulsification is complete, and measure the particle size, the average is 25nm, which meets the requirements of microemulsion (less than 100nm).
  • Mouse group 1 2 3 4 5 6 Dyeing site White head Back tail Left front Left middle
  • Cage Name and Specifications Cage Name and Specifications: Squirrel Cage (LxWxH 1450 mmx400 mmxl500 mm) Mouse Cartridge (LxWxH 300 mmx lOOmmx 150mm)
  • Frequency of replacement The mouse case is replaced every two days. Cleaning and disinfection: The cage is wet-disinfected every day. The disinfectant is 0.1% of benzalkonium chloride and 75% of ethanol solution. The disinfectant is used alternately every week.
  • Dosage design The dosage design of the drug administration group is shown in Table 5.
  • mice were randomly divided into 6 groups, 10 in each group, half male and half female.
  • Mouse lung cancer Lewis tumor cells were cultured in 1640 medium, routinely cultured at 37 ° C under 5 % CO 2 , subcultured every two days, and prepared to a density of 3.0 ⁇ 10 7 with physiological saline in the logarithmic growth phase.
  • Ml single cell suspension was injected into the peritoneal cavity of mice under aseptic conditions.
  • the abdominal cavity of the mice was swollen 7 days after inoculation.
  • the neck was sacrificed and placed in a beaker containing 75% ethanol. 2 3
  • the sterilized mice were placed in a clean bench, the abdomen was exposed, and ascites was taken with a sterile syringe and placed in a sterile reagent bottle for use.
  • the above ascites was counted with trypan blue, diluted with physiological saline, and the number of cells was adjusted to 1.0 ⁇ 10 7 cells/ml, and inoculated into the right axilla of the mouse, each 0.2 ml.
  • the animals were administered on the fourth day after the tumor was inoculated, and administered once a day according to Table 6 (administered every morning) at a dose of 10 ml 'kg - the same amount of normal saline was administered to the model group. Continuous administration for 10 days.
  • Detection frequency Weighed animals were weighed before and before anatomy.
  • Equipment ACS-3A-a type electronic scale, Shanghai Dahua Electronic Scale Factory
  • Detection frequency The test was terminated 10 days after administration, and the blood was sacrificed and the necropsy was performed.
  • Anatomy Intraperitoneal injection of 2% sodium pentobarbital (0.3 ml * kg) anesthesia, after the main abdominal vein was taken, the abdominal aorta was cut and sacrificed, and then the tumor was routinely removed.
  • test data is represented by ⁇ s s, and data processing is performed using SPSS 11.5 statistical software.
  • the present invention also investigates the combination of burdock aglycon and tegafur, and finds that, at the same dose, the burdock aglycone is compared with the combination of the burdock aglycone and tegafur.
  • the combination of a milk preparation and tegafur has a significant advantage in inhibiting Lewis solid tumors of lung cancer, and the tumor inhibition rate is significantly improved.
  • microemulsion preparation of burdock aglycone has a better antitumor effect than the emulsifier of arctigenin, which may improve oral utilization with the emulsifier of burdock aglycone.

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Abstract

L'invention concerne une formulation de microémulsion contenant de l'arctigénine et des supports de microémulsion, lesdits supports de microémulsion comprenant une phase huileuse et un émulsifiant, et la microémulsion ayant une dimension moyenne de particule de 10 à 90 nm.
PCT/CN2011/000574 2010-04-03 2011-04-01 Formulation de microémulsion contenant de l'arctigénine WO2011120339A1 (fr)

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CN102440986B (zh) * 2010-10-08 2014-12-03 鲁南制药集团股份有限公司 牛蒡子苷元在制备防治辐射或化学品引起的骨髓抑制的药物中的用途
CN103371995A (zh) * 2012-04-13 2013-10-30 山东新时代药业有限公司 牛蒡子苷元在制备肿瘤免疫增强剂中的用途
CN108498575B (zh) * 2018-05-30 2021-06-22 南阳市中心医院 一种治疗食管鳞癌的药物及其制备方法
CN112823798A (zh) * 2019-11-21 2021-05-21 中国科学院上海药物研究所 牛蒡子苷与牛蒡子苷元在制备治疗和/或预防皮肤炎症的药物中的应用
CN111887264A (zh) * 2020-07-15 2020-11-06 上海驰纺材料科技有限公司 一种天然植物精油微乳液抗菌喷雾及制备方法

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CN101036643A (zh) * 2006-03-13 2007-09-19 海南盛科天然药物研究院有限公司 含牛蒡子苷元的药物组合物及其制备方法
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CN101036643A (zh) * 2006-03-13 2007-09-19 海南盛科天然药物研究院有限公司 含牛蒡子苷元的药物组合物及其制备方法
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