WO2007124668A1 - Composition pharmaceutique comportant un concentré élevé de polydatine - Google Patents

Composition pharmaceutique comportant un concentré élevé de polydatine Download PDF

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Publication number
WO2007124668A1
WO2007124668A1 PCT/CN2007/001233 CN2007001233W WO2007124668A1 WO 2007124668 A1 WO2007124668 A1 WO 2007124668A1 CN 2007001233 W CN2007001233 W CN 2007001233W WO 2007124668 A1 WO2007124668 A1 WO 2007124668A1
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WIPO (PCT)
Prior art keywords
polydatin
cyclodextrin
aqueous solution
pharmaceutical composition
composition according
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PCT/CN2007/001233
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English (en)
Chinese (zh)
Inventor
Guanghui Yao
Jinhua Zhao
Hui Kang
Wei Qu
Yong Li
Lijuan Zhang
Jing Li
Lin Yu
Kesen Zhao
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Shenzhen Neptunus Pharmaceutical Co., Ltd.
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Application filed by Shenzhen Neptunus Pharmaceutical Co., Ltd. filed Critical Shenzhen Neptunus Pharmaceutical Co., Ltd.
Priority to AU2007246046A priority Critical patent/AU2007246046B2/en
Publication of WO2007124668A1 publication Critical patent/WO2007124668A1/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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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 present invention relates to a pharmaceutical composition containing a high concentration of polydatin, and more particularly to a pharmaceutical composition comprising the pharmaceutically active ingredient polydatin and the cosolvent glucosamine and/or cyclodextrin.
  • Polydatin ie, 3,4,5-trihydroxystilbene-3- ⁇ -indole-glucoside (C 2 .H 22 0 8 ) can be found in the literature and patents as a pharmaceutical ingredient, basic pharmacological studies have shown , Polydatin has the pharmacological activities of improving microcirculation, lowering blood fat and anti-tumor.
  • Chinese patent application CN 1709269A pointed out: In the basic pharmacology research literature of polydatin, in vivo studies often use intravenous route to give polydatin, and the test samples are mostly prepared with water or physiological saline to prepare a concentration of 2-5 mg/ml of polydatin, but The literature does not further explain the feasible preparation method of the solution; according to the literature, the clinical effective dose of polydatin (adult) should be above 112mg/time, under the standard of 1 ⁇ 20ml conventional injection, the concentration of polydatin in clinical injection should not be low.
  • the pH of the injection solution should generally be in the range of 4.0 to 9.0, it is difficult to obtain an aqueous solution of polydatin with a pharmacodynamic concentration only by pH adjustment; the method of heating and dissolving is obviously not suitable for preparation into a pharmaceutical preparation; pH adjustment method and/or The addition of a surfactant (Tween 80) to prepare a higher concentration of the polydatin solution for injection has defects in drug storage due to difficulty in achieving refrigerated storage.
  • a surfactant Teween 80
  • Chinese patent application CN 1709269 A proposes an injection solution containing a high concentration of polydatin, using ethanol and/or propylene glycol as a solvent, and a preparation method thereof, and the patent realizes the preparation of an injection for clinical use for the first time.
  • the polydatin injection provided by the patent is a concentrated solution for injection, that is to say, the polydatin extract provided by the patent needs to be diluted with water for injection or physiological saline to be used for injection, because the injection is The injection is not suitable for direct injection because of the high concentration of organic solvent.
  • the high concentration of polydatin can meet the needs of clinical use of polydatin, and its composition can be free of organic cosolvents such as ethanol, so it is especially suitable for clinical direct injection.
  • the pharmaceutical composition containing the polydatin of the present invention uses glucosamine and/or cyclodextrin as a co-solvent, and the dosage form is an aqueous solution or a lyophilized product prepared by using water or physiological saline before use, and the aqueous solution of polydatin In the aqueous solution prepared by using the lyophilized product, the concentration of polydatin can reach 5 mg/ml or more.
  • the glucosamine is 1-deoxy small (nonylamino) sorbitol
  • the cyclodextrin refers to ⁇ -cyclodextrin or a derivative thereof, particularly ⁇ -cyclodextrin, hydroxypropyl ⁇ - cyclodextrin and succinyl ether- ⁇ -cyclodextrin, etc.
  • the high concentration of polydatin solution means that the concentration of polydatin in the solution reaches about 5 mg/ml or more.
  • the present invention first provides a high concentration aqueous solution of polydatin having meglumine as a solubilizing agent.
  • the solution may contain about 5 mg/ml to 20 mg/ml of polydatin, and the content of the cosolvent glucosamine may be about 7.5 mg/ml to 60 mg/mL.
  • a pH adjuster can be used to improve the water solubility of polydatin, but it is difficult to prepare a high concentration of polydatin in a clinically acceptable injection pH range (4.0 9.0) using a conventional acid-base regulator alone.
  • the solubility of polydatin in an aqueous solution of NaOH having a pH of 7 to 10 is less than 0.5 mg/ml.
  • glucosamine has a good effect of enhancing the dissolution of polydatin, for example, at room temperature, in a 10 mg/ml aqueous solution of glucosamine, the solubility of polydatin can reach about 5.69 mg/ml, and the pH of the solution is About 8.9; In a 20 mg/ml aqueous solution of glucosamine, the solubility of Polygonum cuspidatum can reach about 9.68 mg/ml at room temperature, and the pH of the solution is about 9.5; and the preparation of 20 mg/ml glucosamine is prepared with phosphate buffer. In aqueous solution of pH 9.0, the saturation solubility of polydatin can reach about 7.2 mg/ml. Obviously, the solubilization of scutella by glucosamine is not only achieved by adjusting the pH.
  • the present invention provides a high concentration polydatin aqueous solution using ⁇ -cyclodextrin as a co-solvent.
  • the aqueous solution may contain about 5 mg/ml to 15 mg/ml of polydatin, and the content of the cosolvent ⁇ -cyclodextrin may be about 20 mg/ml to 60 mg/ml.
  • the solubility of polydatin can exceed 5 mg/ml.
  • a ⁇ -cyclodextrin solution prepared in pH 9.0 phosphate buffer when the concentration of cyclodextrin is about 20 mg/ml, the solubility of polydatin can exceed 5 mg/ml; when the cyclodextrin concentration is about 60 mg/ml. In time, the solubility of polydatin can exceed 20 mg/ml.
  • ⁇ -cyclodextrin can be used to prepare clathrates of various chemical compositions.
  • the preparation of the clathrate generally requires drying to obtain a solid matter; and generally has a certain inclusion ratio.
  • the present invention adopts ⁇ -cyclodextrin or the like as a cosolvent to prepare a polydatin solution, and the basic physical and chemical principles and the inclusion complexes should have the same, but the polydatin solution obtained by the present invention is a clear solution, without going through a solid process. There is also no inclusion rate problem.
  • the solubility of polydatin increases with the concentration of ⁇ -cyclodextrin, there is no obvious linear relationship between the two, which is different from the dissolution behavior of the inclusion compound.
  • the present invention has other unexpected effects when preparing a polydatin solution by using ⁇ -cyclodextrin as a solubilizing agent. Effects: For example, both the literature and the results of the present inventors have shown that the solubility of ⁇ -cyclodextrin in pure water is about 18 mg/ml at room temperature; using pure water as a solvent, in the presence of polydatin, ⁇ -cyclodextrin The maximum solubility of sperm at room temperature can reach about 60mg/ml, that is, the self-solubility of ⁇ -cyclodextrin can be significantly increased by about 3 times; the solubility of polydatin in 18mg/ml ⁇ -cyclodextrin aqueous solution is only about 2.5 mg. /ml; The solubility of polydatin can be close to 20mg/mL in a solution containing cyclodextrin containing about 60mg/ml in pH buffer.
  • Hydroxypropyl- ⁇ -cyclodextrin or sulfobutylether- ⁇ -cyclodextrin has an approximation that is slightly stronger than that of ⁇ -cyclodextrin. Since hydroxypropyl- ⁇ -cyclodextrin or sulfobutylether- ⁇ -cyclodextrin itself has better water solubility, it is more suitable for preparing a high concentration aqueous solution of polydatin. Thus, the present invention also provides a high concentration aqueous solution of polydatin having hydroxypropyl- ⁇ -cyclodextrin or sulfobutylether- ⁇ -cyclodextrin as a co-solvent.
  • the solution may contain about 5 mg/ml to 60 mg/ml of polydatin, and the concentration of hydroxypropyl- ⁇ -cyclodextrin or sulfobutylether- ⁇ -cyclodextrin may be from about 25 mg/ml to 500 mg/ml.
  • concentration of hydroxypropyl- ⁇ -cyclodextrin or sulfobutylether- ⁇ -cyclodextrin may be from about 25 mg/ml to 500 mg/ml.
  • the aqueous solution of hydroxypropyl- ⁇ -cyclodextrin or sulfobutylether- ⁇ -cyclodextrin at a concentration of not less than 25 mg/ml can dissolve about 5 mg/ml or more of polydatin. .
  • the solubility of polydatin in the range of pH 6 ⁇ 9 can be increased with the increase of the concentration of hydroxypropyl- ⁇ -cyclodextrin or sulfobutylether- ⁇ -cyclodextrin, and there is no obvious between the two.
  • the linear relationship In a solution prepared in pH 9.0 buffer, when the hydroxypropyl- ⁇ -cyclodextrin or sulfobutylether- ⁇ -cyclodextrin is 300 mg/ml, the solubility of polydatin can reach about 60 mg/ml.
  • glucosamine 5 mg/ml can increase the solubility of polydatin to about 3.17 mg/ml
  • ⁇ -cyclodextrin 15 mg/ml can increase the solubility of polydatin to about 2.72 mg/ml, and the sum is 5.89 mg. /ml
  • the solubility of polydatin increased by 7.64 mg/ml, which is about 30% higher than the single addition value.
  • the solubilization effect of glucosamine and ⁇ -cyclodextrin on polydatin is greater than the single addition of solubilization when the two are used alone.
  • the present invention further provides a high concentration aqueous solution of polydatin comprising ⁇ -cyclodextrin and glucosamine as a co-solvent.
  • concentration of polydatin in the solution may be about 5 mg/ml to 40 mg/ml, and the concentration of ⁇ -cyclodextrin may be in the range of about 10 mg/ml to 60 mg/ml, and the concentration of paclitaxel may be about 2.5. In the range of mg/ml ⁇ 45mg/ml.
  • the synergistic solubilization of polydatin by a combination of hydroxypropyl- ⁇ -cyclodextrin or sulfobutyl- ⁇ -cyclodextrin and glucosamine as a solubilizing agent also provides a high concentration aqueous solution of polydatin having hydroxypropyl- ⁇ -cyclodextrin or sulfobutylether- ⁇ -cyclodextrin and glucosamine as a co-solvent.
  • the concentration of polydatin in the aqueous solution may be about 5 mg/ml to 100 mg/ml, and the aqueous solution contains hydroxypropyl- ⁇ -cyclodextrin or sulfobutylether- ⁇ -cyclodextrin from about 10 mg/ml to 300 mg/ Ml, containing glucosamine from about 2.5mg/ml ⁇ lOOmg/mL
  • the high-concentration polydatin aqueous solution of the present invention can be prepared by using pure water, physiological saline or a buffer of pH 7.0 to 9.0 as a solvent, for example, 0.9% aqueous sodium chloride solution, 5% glucose solution, carbonate buffer. Liquid, phosphate buffer, Tris buffer and Hepes buffer.
  • glucosamine Since the solubilization of glucosamine is not equivalent to a general acid-base regulator, glucosamine is used.
  • the pH value exceeds 9 the pH can be adjusted back to pH 6 ⁇ 9 by using a pharmaceutically acceptable acid reduction regulator, thereby preparing for clinical use, especially High concentration of polydatin injection for injection.
  • the high concentration of polydatin in the aqueous solution of the present invention may contain, in addition to the active ingredient polydatin and the co-solvent, other pharmaceutically acceptable excipients such as antioxidants, osmotic pressure regulators, pH adjusters. Wait.
  • the pH adjusting agent may be an alkali metal or an alkaline earth metal hydroxide, a pharmaceutically acceptable inorganic base such as sodium carbonate or sodium phosphate, a pharmaceutically acceptable inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid, or may be A pharmaceutically acceptable organic base such as a reduced amino acid, a pharmaceutically acceptable organic acid such as citric acid or fumaric acid.
  • the high concentration polydatin may also contain other active ingredients which can be used in combination with polydatin.
  • the high-concentration aqueous solution of the aglycone of the present invention can be easily obtained as a pharmaceutical preparation suitable for administration in a liquid preparation, and these preparations may be liquid oral preparations or liquid preparations for administration by injection or topical administration.
  • the high concentration aqueous solution of the saponin of the present invention is preferably an injection suitable for parenteral administration such as intravenous injection, intramuscular injection or subcutaneous injection.
  • the present invention further provides a method for preparing a high concentration aqueous solution of polydatin, which comprises: using pure water, physiological saline or a buffered aqueous solution as a solvent, and preparing with stoichiometric polydatin, glucosamine and/or cyclodextrin.
  • the mixed aqueous solution of the high concentration polydatin of the present invention may optionally further contain other pharmaceutically acceptable excipients such as antioxidants, etc., and the solution is filled in an injection container such as an ampoule by sterilizing and/or heatless treatment well known in the art. bottle.
  • the sterilized and/or athermal-free treatment can be microfiltration ultrafiltration, autoclaving, and the like.
  • the high-concentration polydatin solution which meets the needs of clinical application provided by the present invention may be free of organic solvents, and thus the solution may be used for further preparation of lyophilized products, such as lyophilized powder needles.
  • the present invention further provides a lyophilized preparation which is reconstituted with a high concentration of polydatin aqueous solution by using water for injection or physiological saline before use.
  • the lyophilized product of the present invention may be a pharmaceutical preparation obtained by freeze-drying an aqueous solution of polydatin, prepared by using a cosolvent glucosamine and/or cyclodextrin at a concentration of about 5 mg/ml to 100 mg/ml, for example, frozen. Dry powder needle.
  • a pharmaceutically acceptable filler, an antifreeze, an osmotic pressure adjusting agent, a pH adjusting agent and the like may be optionally added to the aqueous solution of the polydatin in the lyophilization.
  • the solvent amount of the solution before lyophilization may be appropriately higher than the amount of solvent required for preparing the aforementioned high concentration of polydatin solution, that is, The concentration of polydatin in the prepared lyophilized solution may be lower than the concentration of polydatin in the aqueous solution prepared before use.
  • the concentration of polydatin in the aqueous solution prepared by the lyophilized product of the present invention may be from about 5 mg/ml to 100 mg/ml; obviously, if necessary, the aqueous solution prepared from the lyophilized product of the present invention may be subjected to an optional ratio. dilution.
  • the saponin lyophilized product of the present invention may be a pharmaceutical preparation prepared by freeze-drying an aqueous solution of polydatin from a concentration of about 5 mg/ml to 15 mg/ml, prepared by using glucosamine as a co-solvent. Since the concentration of meglumine in the aqueous solution of polydatin can be about 7.5 mg/ml to 60 mg/ml, the ratio of polydatin to glucosamine in the lyophilized preparation can be between about 1:1.5 1:12; In the present invention, the ratio can be further preferably Between 1:1.5 ⁇ 1:3.
  • the saffron lyophilized product of the present invention may also be a pharmaceutical preparation obtained by freeze-drying an aqueous solution of polydatin, which is prepared by using ⁇ -cyclodextrin as a co-solvent at a concentration of about 5 mg/ml to 20 mg/ml.
  • concentration of ⁇ -cyclodextrin in the aqueous solution of polydatin can be about 20 mg/ml to 60 mg/ml, so the ratio of polydatin to ⁇ -cyclodextrin in the frozen product can be about 1:3 ⁇ 1 :12 Further, according to the present invention, the ratio is still further preferably between 1:3 and 1:8.
  • the saponin lyophilized product of the present invention may also be an aqueous solution of polydatin composed of hydroxypropyl- ⁇ -cyclodextrin or sulfobutylether- ⁇ -cyclodextrin as a co-solvent at a concentration of about 5 mg/ml to 60 mg/ml.
  • the resulting pharmaceutical preparation is freeze-dried.
  • the concentration of ⁇ -cyclodextrin in the aqueous solution of polydatin can be about 20 mg/ml to 300 mg/ml, so the ratio of polydatin to glucosamine in the frozen product can be between about 1:4 and 1:60. According to the invention, the ratio is still further preferably between 1:4 and 1:8.
  • the saponin lyophilized product of the present invention may also be a pharmaceutical preparation obtained by freeze-drying an aqueous solution of polydatin having a concentration of about 5 mg/ml to 40 mg/ml, which is prepared by using ⁇ -cyclodextrin and glucosamine as a co-solvent.
  • the concentration of ⁇ -cyclodextrin may be about 10 mg/ml to 60 mg/ml, and the concentration of meglumine may be about 2.5 mg/ml to 45 mg/ml, so that the freeze-dried product thereof
  • the ratio of polydatin to meglumine and ⁇ -cyclodextrin may be between about 1:0.5:1.5 1 :9:12; according to the invention, the ratio is still further preferably 1:0.5:4 ⁇ 1 : Between 2: 8.
  • the lycopene lyophilized product of the present invention may also be prepared by using hydroxypropyl- ⁇ -cyclodextrin or sulfobutylether- ⁇ -cyclodextrin and glucosamine as a co-solvent at a concentration of about 5 mg/ml to 100 mg/ml.
  • a pharmaceutical preparation obtained by subjecting an aqueous solution of polydatin to lyophilization.
  • 3-cyclodextrin or sulfobutylether- ⁇ -cyclodextrin in the aqueous solution of lycopene before lyophilization may be about 10 mg/ml to 300 mg/ml, and the concentration of glucosamine may be about 2.5.
  • Mg/ml ⁇ 100mg/ml, so in its lyophilized product, the ratio of polydatin to glucosamine, hydroxypropyl- ⁇ -cyclodextrin or sulfobutylether- ⁇ -cyclodextrin can be about 1:0.5: Between 2 and 1:20:60; according to the invention, the ratio is preferably between 1:0.5:4 and 1:2:8.
  • the present invention further provides a method for preparing the above lyophilized powder injection, which comprises formulating a stoichiometric amount of polydatin, glucosamine and/or cyclodextrin using pure water, physiological saline or a buffered aqueous solution as a solvent.
  • the high-concentration polydatin aqueous solution may further contain a medicinal auxiliary agent such as a pharmaceutically acceptable filler, and the obtained solution is subjected to ultrafiltration to remove the heat source, and is aseptically packaged in Xilin, and after cold-drying, the product is obtained, that is, the polydatin Lyophilized mixture.
  • a suitable filler may be advantageous for lyophilization of the saponin lyophilized product of the present invention.
  • Preferred fillers of the present invention include mannitol, NaCl, and the like.
  • the lyophilized product containing the high concentration of polydatin of the present invention may be a divided sterile powder or a directly freeze-dried lyophilized powder needle, of which a lyophilized powder injection is preferred.
  • the lyophilized product containing the high concentration of polydatin of the present invention can be administered by a parenteral route such as intravenous injection, intravenous drip, intramuscular injection, subcutaneous injection or topical administration.
  • the lyophilized product containing "high concentration" polydatin according to the present invention means that the concentration of the polydatin in the solution can be up to 5 mg/ml or more after the lyophilized product is formulated into an aqueous solution by means of pure water or physiological saline.
  • the polydatin-containing pharmaceutical composition provided by the present invention can be used for the preparation of a therapeutic drug for a microcirculatory disorder-related disease.
  • the polydatin pharmaceutical composition of the present invention has significant expansion and dredging: blood vessels, It can reduce blood viscosity in microvessels and inhibit blood cell adhesion, so it can be used to treat or prevent shock and other diseases related to microcirculation disorders such as myocardial ischemia, cerebral ischemia, and circulatory disorders.
  • Chinese patent application CN 1709269A provides a pharmaceutical preparation which can provide a therapeutic dose of polydatin by intravenous drip. Since the preparation contains a relatively high concentration of organic solvent and cannot be used for direct injection, it has not been clinically available.
  • a pharmaceutical preparation of polydatin which can be administered by direct injection.
  • the present invention provides a high concentration aqueous solution of polydatin which may be free of organic solvents, which may be further prepared as a lyophilized product. These aqueous polydatin and their lyophilized preparations can be used for direct injection administration because they can be free of organic solvents.
  • the high-concentration polydatin aqueous solution of the present invention may contain no organic solvent, but does not exclude the use of an organic solvent.
  • the aqueous solution may include a small amount of ethanol, propylene glycol or the like without affecting the specific administration mode and the molding conditions of the preparation.
  • the invention provides for the first time a polydatin preparation which can be directly injected and administered with practical clinical application value, which not only provides a more convenient way for clinical application of polydatin, but also can further broaden the knotweed.
  • the clinical application range of glycosides provides conditions.
  • the pharmaceutical composition of the present invention has an intrinsic improvement over the state of the art.
  • polydatin can be used for the treatment of critical illnesses such as traumatic shock due to its remarkable microcirculation improvement.
  • Direct injection is undoubtedly of great significance for the rescue treatment of these critical diseases.
  • the animal test and the solution stability test show that the scutellarin pharmaceutical composition provided by the invention is safe, effective and stable, and therefore, the solution has good clinical application prospect.
  • Figure 1 shows the effect of polydatin on mean arterial pressure in hemorrhagic shock dogs
  • Figure 2 shows the effect of polydatin on coronary blood flow in hemorrhagic shock dogs.
  • Polydatin provided by Shenzhen Haiwang Technology Center, with a purity of 99.63%, batch number 20050819.
  • Glucosamine Pharmaceutical Excipients, Shanghai Fucan Chemical Co., Ltd.; ⁇ -cyclodextrin, Pharmaceutical Excipients, Yongguang Cyclodextrin Co., Ltd.; Hydroxypropyl- ⁇ -cyclodextrin, First Class of Accessories, Xi'an Deli Biochemical Co., Ltd.; sulfobutylether- ⁇ -cyclodextrin, pharmaceutical excipients, Shanghai Fucan Chemical Co., Ltd.; Freon F12, Zhejiang Fluorescent Chemical Co., Ltd. Water for injection, Haiwang Industrial City; 0.9% sodium chloride solution, prepared with water for injection; Na2HP04-NaH2P04 buffer, water for injection.
  • test materials used in the present invention are commercially available products unless otherwise stated.
  • the condensation temperature reaches -40 °C, and the vacuum is applied.
  • the temperature of the plate slowly rises to 40 °C, and the temperature of the product rises and is dried.
  • the lyophilized material is opened out of the box, and the stopper is rolled and rolled.
  • Formulation molding After the vial is placed in the freeze-drying box, the temperature of the plate drops to -35 °C, the temperature of the product drops to -30 ⁇ for 3 hours, the condensation temperature reaches -40 °C, the vacuum is applied, and the plate temperature rises slowly to 4 CTC. It is then raised, dried, and the lyophilizer is unpacked, the vial is stoppered, and the lid is rolled.
  • Preparation of the preparation After the vial is placed in the freeze-drying box, the temperature of the plate drops to -35 °C, the temperature of the product drops to -30 °C for 3 hours, the condensation temperature reaches -40 °C, the vacuum is applied, and the temperature of the plate rises slowly to 40. °C, the temperature of the product rises and is dried, the lyophilizer is unpacked, the vial is stoppered, and the lid is rolled.
  • Preparation of the preparation After the vial is placed in the freeze-drying box, the temperature of the plate is lowered to -35 ° C, the temperature of the product is reduced to 3 hours, the condensation temperature is -40 ° C, the vacuum is applied, and the temperature of the plate is slowly raised to 40 ° C. It is then raised, dried, and the lyophilizer is unpacked, the vial is stoppered, and the lid is rolled.
  • Formulation molding After the vial is placed in a frozen box, the temperature of the plate drops to -50 °C, the temperature of the product drops to -45 °C for 3 hours, the condensation temperature reaches -55 °C, the vacuum is applied, and the temperature of the plate rises slowly to - 20 After °C, then freeze and then heat up. After 3 times, the plate temperature is slowly raised to 40. C, the product is thus dried and formed. The lyophilizer is unpacked, the vial is stoppered, and the car L is covered.
  • Formulation molding After the vial is placed in the freeze-drying box, the temperature of the plate drops to -50 °C, the temperature of the product drops to -45 °C for 3 hours, the condensation temperature reaches -55 °C, the vacuum is applied, and the plate temperature rises slowly to - 20 After °C, then freeze and then heat up. After 3 times, the plate temperature is slowly raised to 40. C, the product is thus dried and formed. The lyophilizer is unpacked, the vial is stoppered, and the lid is rolled.
  • a solution of glucosamine at a concentration of 7.5 mg/ml is prepared, and a saturated solution of polydatin is prepared by the above method.
  • the solubility of the polydatin in the solution is about 5.12 mg/ml, and the pH is about 8.7; .5 Phosphate buffer solution
  • a solution of 60 mg/ml of glucosamine was prepared.
  • the saturated solution of polydatin was prepared by the above method.
  • the solubility of polydatin in the solution was about 14.83 mg/ml, and the pH was about 8.94.
  • the cyclodextrin may not be completely dissolved, that is, the beta-cyclodextrin in the filtrate may not reach the calculated concentration of ⁇ -cyclodextrin listed in Table 2; in addition, the pH value of the above-mentioned polydatin suspension solution is detected, and the result is Its ⁇ is lower than 7.
  • the obtained solution was unfiltered as a clear solution, indicating that ⁇ -cyclodextrin and polydatin can be completely dissolved in the preparation solution, and the solubility of ⁇ -cyclodextrin can be above 60 mg/ml.
  • the water solubility of polydatin can be increased with the increase of the amount of ⁇ -cyclodextrin, but there is no obvious linear relationship between the two concentrations; (2) in the presence of polydatin, ⁇ -cyclodextrin The self-solubility can also be greatly increased, which constitutes the basic conditions for the preparation of a high-concentration polydatin solution with clinical application value by using ⁇ -cyclodextrin; (3) ⁇ -cyclodextrin with a concentration of 20-60 mg/ml An aqueous solution of polydatin in a concentration of up to 5-20 mg/ml within pH 9.0 can be prepared.
  • the water solubility of polydatin can be increased with the increase of the amount of hydroxypropyl- ⁇ -cyclodextrin, but there is no obvious linear relationship between the two concentrations.
  • concentration of hydroxypropyl- ⁇ -cyclodextrin reaches 30mg/ml
  • solubility of polydatin can exceed 6mg/ml
  • concentration of hydroxypropyl- ⁇ -cyclodextrin reaches 300mg/ml
  • the solubility of polydatin can exceed 50mg/ml.
  • a solution of not less than 5 mg/ml of polydatin can be prepared with a solution of hydroxypropyl- ⁇ -cyclodextrin as low as 20 mg/ml; a solution of hydroxypropyl- ⁇ -cyclodextrin can be prepared at pH 9.0. Polydatin solution at a concentration of 60 mg/ml. The test also showed that sulphur Butyl ether- ⁇ -cyclodextrin produces a similar solubilizing effect on polydatin.
  • Glucosamine 0, 50, 100 and 150 mg were added, respectively, 0, 150, 300 and 450 mg were added, 200 mg of polydatin, and 10 ml of steamed water were added. After sonication for 30 min, it was placed at room temperature for 3 hr, filtered through a 0.20 ⁇ microporous membrane, and the concentration of polydatin in the filtrate was determined by HPLC. The results are shown in Table 4.
  • ⁇ -cyclodextrin dosage 0 15 30 45 0 15 30 45
  • 15. 30 and 45 mg/ml of ⁇ -cyclodextrin The solubility of polydatin can be increased by 2.72, 5.48 and 9.48 mg/ml, respectively; in the absence of ⁇ -cyclodextrin 4, 5, 10 and 15 mg/ml glucosamine can increase the solubility of polydatin by 3.17, 5.44 and 6.99 mg/ Ml.
  • glucosamine 5 mg/ml can increase the solubility of polydatin to about 3.17 mg/ml
  • ⁇ -cyclodextrin 15 mg/ml can increase the solubility of polydatin to about 2.72 mg/ml, and the sum is 5.89 mg/ml
  • the solubility of polydatin increased by 7.64 mg/ml, which was about 30% higher than the single addition value.
  • hydroxypropyl- ⁇ -cyclodextrin, sulfobutyl- ⁇ -cyclodextrin and glucosamine produce a stronger synergistic solubilization of polydatin.
  • glucosamine and 600mg of p-cyclodextrin taking 450mg of glucosamine and 600mg of p-cyclodextrin, adding 400mg of polydatin, and adding 10ml of pH 8.5 phosphate buffer to dissolve, can obtain a clear aqueous solution of polydatin, indicating that combined with glucosamine and ⁇ -ring Dextrin can be formulated with an aqueous solution of polydatin (pH below 9) at a concentration of up to 40 mg/ml.
  • test samples were stored at 30 in the dark. C incubator and 4. C refrigerator.
  • Clarity check Check the clarity of the test sample before storage and after storage for three months.
  • the freeze-dried powder is diluted with the designed volume (5ml or 10ml) saline and checked.
  • Content detection High performance liquid chromatography. Chromatographic conditions: Agilent 1100 High Performance Liquid Chromatograph; Agilent DAD Detector; Dalian Elite YWG C18 ⁇ 4.6 ⁇ 250 mm column; mobile phase sterol-6% acetic acid solution (25:75); flow rate of 1.0 ml/ Min; detection wavelength is 306 nm; column temperature is 30. C; The injection volume is 20 ⁇ l.
  • Example 1 Injection qualified and qualified 4.953 4.743 4.951
  • Example 2 Injectable qualified Qualified 9.883 9.664 9.823
  • Example 3 Injection qualified and qualified 20.07 19.29 20.10
  • Example 4 Injection qualified and qualified 14.96 14.91 14.95
  • Example 5 Injection Qualified pass qualified 15.02 14.22 15.00
  • Example 6 Injection qualified and qualified 79.51 75.40 79.52
  • Example ⁇ Freeze-dried powder Qualified qualified 4.893 4.682 4.886
  • Example 8 lyophilized powder needle qualified qualified 7.492 7.403 7.429
  • Example 9 freeze-dried powder needle Qualified pass qualified 14.75 14.60 14.77
  • Example 10 freeze-dried powder needle qualified pass 9.832 9.731 9.826
  • Example 11 freeze-dried powder needle qualified pass qualified 10.16 *** 10.23
  • Example 12 freeze-dried powder needle qualified pass qualified 58.63 55.36 57.98
  • Sample 2 Example 11 Polydatin freeze-dried powder needle. Dissolve in 5 ml of normal saline before use.
  • Hemolysis test New Zealand rabbit ear vein blood was collected, washed with defibrinogen and physiological salt, and diluted with physiological saline to a 2% suspension for testing.
  • Systemic allergy test 24 healthy guinea pigs (250-350 g), randomized into groups of 6 rats. Each group of animals was intraperitoneally injected with normal saline (negative control), polydatin or lyophilized powder reconstituted water every other day. Solution and egg white (positive control) 1ml / only, a total of 3 times. On the 14th day after the first injection, 3 rats in each group were again given a control solution or a test solution of 2.5 ml/mouse, and the reaction of the test animals after the injection was observed. The remaining 3 guinea pigs in each group were injected with the control solution or the test solution 2.5 ml/mouse on the 21st day after the first injection, and the animals were observed for anti-disease conditions.
  • vascular irritation test 6 New Zealand rabbits, ? ⁇ Each half, according to the 5mg/kg ear vein intravenous injection of polydatin or lyophilized powder reconstituted aqueous solution, once a day, for 3 times, observe the changes of blood vessels and surrounding tissues after injection, 30 minutes after the last injection
  • the carotid artery was exsanguinated and sacrificed.
  • the rabbit ear was fixed at the injection site, and the opposite part of the rabbit ear was cut and fixed as a normal control. Pathological sections were used to examine the pathological changes of rabbit ear vessels.
  • Hemolysis test The hemolysis phenomenon occurred in the aqueous solution of polydatin and lyophilized powder reconstituted at 30, 60, and 180 min, and red blood cell agglutination occurred.
  • Vascular stimulation test After the rabbit ear vein injection of polydatin and the lyophilized powder reconstituted aqueous solution, no venous dilatation, hyperemia, and no edema in the surrounding tissues. Pathological examination showed no damage to the skin of rabbit ears or subcutaneous tissue congestion, edema, no expansion and congestion of the ear veins, no changes in vascular endothelial cells, no wall thrombus and inflammatory cell infiltration in the vessel wall, no bleeding around the blood vessels.
  • Test article Example 5 of polydatin, Shenzhen Haiwang Pharmaceutical Co., Ltd.
  • Test method Animals were anesthetized with 3% sodium pentobarbital and fixed on the back of the large animal operating table. Intubation, ventilator (ElOOi type, Newport Ven, USA) Maintain breathing (15 times / min, 300 ⁇ 400 ml / min). Bilateral femoral artery cannula, used to record blood pressure (US Marquette Eagle 4000 physiological recorder) and bloodletting, femoral vein cannula for drug administration. Open the chest between the 2 ⁇ 4 intercostals on the left side, expose the heart, cut the happy capsule, and record the blood flow of the anterior descending coronary artery by ultrasonic blood flow meter (T206 type, American transonic systems company).
  • Bleeding was performed through a femoral artery cannula and flowed into a sterile infusion bottle containing heparin saline to adjust the amount of blood loss, and the mean arterial pressure was reduced to 40 mmHg within 15 min, maintaining the mean arterial pressure at this level.
  • Min then administered, polydatin injection was dissolved in physiological saline with a volume of 1/3 blood loss and was injected into the body by the femoral vein within 120 min, and the dose was 5.0 mg/kg.
  • Coronary blood flow before and after administration was recorded.
  • the test used physiological saline as a control. Standardize the blood flow data with 100% normal blood flow, and use SPSS13.0 statistical software package. Factor analysis of variance (ANO VA) for statistical analysis.
  • ANO VA Factor analysis of variance
  • Control group 100 ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • the invention provides a scutellarin pharmaceutical composition which can be directly injected and administered with practical clinical application value, which is safe, effective and stable, and can provide a more convenient use for the clinical application of polydatin.
  • the route can also provide conditions for further broadening the clinical application range of polydatin.

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Abstract

La présente invention concerne une composition pharmaceutique comportant un concentré élevé de polydatine. La composition contient de la polydatine, la méglumine et/ou la cyclodextrine. Ladite composition se présente sous une forme de solution aqueuse ou lyophilisée qui doit être préparée avant l'utilisation.
PCT/CN2007/001233 2006-04-28 2007-04-16 Composition pharmaceutique comportant un concentré élevé de polydatine WO2007124668A1 (fr)

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EP2832348A4 (fr) * 2012-03-31 2015-09-02 Kunming Pharmaceutical Corp Procédé de dissolution d'un composé flavonoïde, d'un composé de glycoside carboné ou d'un composé de stilbène, et procédé de préparation d'une injection ou d'une poudre pour injection
US10624830B2 (en) 2017-11-30 2020-04-21 L'oreal Aqueous compositions with mangiferin for cosmetic applications
US10898420B2 (en) 2016-10-31 2021-01-26 L'oreal Compositions containing phenolic compounds having synergistic antioxidant benefits

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CN101791292A (zh) * 2010-04-13 2010-08-04 江庆澜 虎杖苷喷雾剂在作为哮喘治疗药物中的应用
CN107638571B (zh) * 2016-07-15 2021-07-06 中国人民解放军军事医学科学院毒物药物研究所 一种特考韦瑞口服药物组合物及其制备方法
CN107625967B (zh) * 2016-07-15 2021-07-06 中国人民解放军军事医学科学院毒物药物研究所 一种特考韦瑞注射用药物组合物及其制备方法
CN108670950B (zh) * 2018-06-29 2020-10-02 深圳海王医药科技研究院有限公司 一种不含有机溶剂的虎杖苷药物组合物及其制备方法
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CN1709269A (zh) * 2005-07-08 2005-12-21 深圳海王药业有限公司 一种含虎杖苷的药物组合物及其应用

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CN1220486C (zh) * 2002-11-15 2005-09-28 董英杰 白藜芦醇类化合物的β－环糊精或其衍生物的包合物及其制备方法

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CN1557297A (zh) * 2004-01-14 2004-12-29 江苏康缘药业股份有限公司 一种银杏内酯粉针剂及其制备方法
CN1709269A (zh) * 2005-07-08 2005-12-21 深圳海王药业有限公司 一种含虎杖苷的药物组合物及其应用

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2832348A4 (fr) * 2012-03-31 2015-09-02 Kunming Pharmaceutical Corp Procédé de dissolution d'un composé flavonoïde, d'un composé de glycoside carboné ou d'un composé de stilbène, et procédé de préparation d'une injection ou d'une poudre pour injection
US10898420B2 (en) 2016-10-31 2021-01-26 L'oreal Compositions containing phenolic compounds having synergistic antioxidant benefits
US10624830B2 (en) 2017-11-30 2020-04-21 L'oreal Aqueous compositions with mangiferin for cosmetic applications

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