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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Prior art keywords
polydatin
cyclodextrin
aqueous solution
pharmaceutical composition
composition according
Prior art date
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Ceased
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PCT/CN2007/001233
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English (en)
French (fr)
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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Shenzhen Neptunus Pharmaceutical Co Ltd
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Priority to AU2007246046A priority Critical patent/AU2007246046B2/en
Publication of WO2007124668A1 publication Critical patent/WO2007124668A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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 9.635 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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Description

一种含高浓度虎杖苷的药物组合物
技术领域
本发明涉及一种含高浓度虎杖苷的药物组合物，具体地说涉及含有药用活 性成分虎杖苷和助溶剂葡曱胺和 /或环糊精的药物组合物。
背景技术
虎杖苷， 即 3,4，, 5-三羟基二苯乙烯 -3-β-ϋ-葡萄糖苷（C2。H2208 )作为药用 成分可见于文献及专利报道， 基础药理学研究表明， 虎杖苷具有改善微循环、 降血脂、 抗肿瘤等药理活性。
中国专利申请 CN 1709269A指出： 虎杖苷基础药理学研究文献中， 在体 试验研究多采用静脉内途径给予虎杖苷， 试验样品多采用水或生理盐水配制 2 - 5mg/ml 浓度的虎杖苷溶液， 但文献对溶液的可行配制方法均无进一步说 明；根据文献测算，虎杖苷临床有效剂量 (成人)应在 112mg/次以上，在 1 ~ 20ml 常规注射剂规格下， 临床用注射剂中虎杖苷浓度应不低于 5.6 mg/ml; 虎杖苷 在纯水或生理盐水溶液中的溶解度有限，其常规水溶液难以达到文献所述的药 物浓度： 室温下， 虎杖苷在水及生理盐水中的饱和浓度均低于 0.5mg/ml, 远 低于上述 2 - 5mg/ml给药浓度。
调节 pH值、 加热、 添加表面活性剂等方法， 都是提高化合物溶解度的常 用方法， 但是， 研究表明， 对于制备临床所需药效浓度的稳定的虎杖苷药物组 合物，这些方法的价值有限。例如，调节溶液 pH值可以增加虎杖苷的溶解度， 但是， 室温下以 NaOH调节 pH配制虎杖苷水溶液时， 当虎杖苷溶解度达到 3mg/ml时， 其水溶液 pH值需达 12以上。 鉴于注射液之 pH值一般应在 4.0 ~ 9.0范围内， 因此仅通过 pH调节难以获得药效浓度的虎杖苷水溶液； 加热溶 解的方法显然并不适合制备成药物制剂；采用 pH调节法和 /或添加表面活性剂 (吐温 80)制备较高浓度的虎杖苷注射用溶液因难以实现冷藏保存而存在药物 储存方面的缺陷。
如中国专利申请 CN 1709269A所述， 在临床制剂允许的范围内， 通过调 节 pH值、 添加吐温类表面活性剂等常规制剂方法难以获得理想的临床用虎杖 苷注射液的制剂方案。
中国专利申请 CN 1709269 A提出了一种以乙醇和 /或丙二醇作为溶剂的含 高浓度虎杖苷的注射用溶液及其制备方法，该专利首次实现了可供临床使用的 注射剂的制备。 但该专利所提供的虎杖苷注射液是注射用浓溶液， 也就是说， 该专利所提供的虎杖苷注射液需经注射用水或生理盐水稀释至一定程度后方 可用于注射给药，其原因在于， 其注射液因含较高浓度的有机溶剂而不适合直 接注射给药。
毫无疑问，含高浓度虎杖苷的注射用制剂对于实现虎杖苷的临床应用价值 具有至关重要的现实意义。
发明内容
本发明的目的在于提供一种含高浓度虎杖苷的药物组合物，该药物组合物 所含高浓度的虎杖苷可满足虎杖苷临床用药的需要，其组合物中可不含乙醇等 有机助溶剂， 因此尤其适合于临床直接注射给药使用。
本发明之含虎杖苷药用组合物采用葡曱胺和 /或环糊精作为助溶剂， 其剂 型为水溶液或临用前用水或生理盐水配制成水溶液的冻干制品，所述虎杖苷水 溶液以及用冻干制品配制的水溶液中， 其虎杖苷浓度可达 5mg/ml以上。
本发明中，所述葡曱胺是 1-脱氧小 (曱氨基) 山梨醇；所述环糊精是指 β- 环糊精或其衍生物， 特别是 β-环糊精、羟丙基 β-环糊精以及碩丁醚 -β-环糊精 等； 所述高浓度虎杖苷溶液是指其溶液中的虎杖苷的浓度达到约 5mg/ml 或 5mg/ml以上。
本发明首先提供一种以葡甲胺作为增溶剂的高浓度虎杖苷水溶液。该溶液 中可以含虎杖苷约 5mg/ml ~ 20mg/ml , 助溶剂葡曱胺的含量可以为约 7.5mg/ml ~ 60mg/mL
已知 pH调节剂可用于提高虎杖苷的水溶性， 但是， 单用常规酸碱调节剂 难以在临床允许的注射剂 pH值范围 (4.0 9.0)内制备高浓度的虎杖苷溶液。如 中国专利申请 CN 1709269A所述，虎杖苷在 pH 7〜 10的 NaOH水溶液中的溶 解度均低于 0.5mg/ml。 本发明人发现， 葡曱胺具有良好的增强虎杖苷的溶解 作用， 例如， 室温下， 在 10mg/ml 的葡曱胺水溶液中， 虎杖苷饱和溶解度可 达约 5.69mg/ml, 其溶液 pH值约 8.9; 在 20mg/ml的葡曱胺水溶液中， 室温下 虎杖苦饱和溶解度可达约 9.68 mg/ml,其溶液 pH值约 9.5; 而以磷酸緩冲液配 制含 20mg/ml葡曱胺的 pH 9.0水溶液，则虎杖苷饱和溶解度可达约 7.2 mg/ml。 显然， 葡曱胺对虎杖苷的增溶作用并非只是通过调节 pH值来实现的。
采用純水以及緩冲溶液作为溶剂保持葡曱胺水溶液之 pH值在约 7.5 ~ 9.0 范围内， 当葡甲胺所用浓度在约 7.5mg/ml ~ 60mg/ml范围内时，可制备虎杖苷 浓度约 5mg/ml - 15mg/ml的水溶液。
另一方面， 本发明提供一种以 β-环糊精作为助溶剂的高浓度虎杖苷水溶 液。 该水溶液中可以含虎杖苷约 5 mg/ml ~ 15 mg/ml, 其中助溶剂 β-环糊精的 含量可以为约 20 mg/ml ~ 60 mg/ml。
以纯水配制的 β-环糊精溶液中， 当环糊精浓度为约 25mg/ml时， 其虎杖苷 的溶解度即可超过 5mg/ml。 在以 pH 9.0磷酸緩冲液配制的 β-环糊精溶液中 , 当环糊精浓度为约 20mg/ml时， 其虎杖苷溶解度可超过 5mg/ml; 当环糊精浓 度为约 60mg/ml时， 则虎杖苷溶解度可超过 20mg/ml。
已知 β-环糊精类可用于制备多种化学成分的包合物。 包合物的制备一般都 需要经干燥制得固形物； 并且一般都存在一定的包合率。 本发明采用 β-环糊 精等作为助溶剂制备的虎杖苷溶液，其基本物理化学原理与包合物应当有相同 之处， 但本发明所得虎杖苷溶液均为澄明溶液， 无需经过固体过程， 也不存在 包合率问题。本发明中，虎杖苷的溶解度虽然随 β-环糊精类浓度的增加而升高， 但两者之间并不呈现明显的线性关系， 此与包合物的溶解行为有所不同。
本发明釆用 β-环糊精作为增溶剂制备虎杖苷溶液时还有其它意想不到的 效果： 例如， 文献以及本发明人实测结果均表明， 室温下， β-环糊精在純水中 的溶解度约为 18mg/ml; 以纯水作为溶剂， 在虎杖苷存在下， β-环糊精在室温 中的最大溶解度可以达到约 60mg/ml, 即 β-环糊精的自身溶解度可显著提高 约 3倍； 虎杖苷在 18mg/ml β-环糊精水溶液中的溶解度仅为约 2.5 mg/ml; 而 在 pH緩冲液配制的含环糊精约 60mg/ml 的溶液中， 虎杖苷溶解度可接近 20mg/mL
羟丙基 -β-环糊精或磺丁醚 -β-环糊精对虎杖苷具有近似而略强于 β-环糊精 的助溶作用。 由于羟丙基 -β-环糊精或磺丁醚 -β-环糊精自身具有更好水溶性， 因此更适合于制备高浓度的虎杖苷水溶液。 由此， 本发明还提供一种以羟丙基 -β-环糊精或磺丁醚 -β-环糊精作为助溶剂的高浓度虎杖苷水溶液。 该溶液中可 以含虎杖苷约 5mg/ml ~ 60mg/ml, 所采用的羟丙基 -β-环糊精或磺丁醚 -β-环糊 精的浓度可以在约 25mg/ml ~ 500mg/ml范围内。
室温下， 在 pH约 6 ~ 9范围内， 浓度不低于 25mg/ml的羟丙基 -β-环糊精 或磺丁醚 -β-环糊精水溶液可以溶解约 5mg/ml以上的虎杖苷。
室温下， 在 pH 6 ~ 9范围内， 虎杖苷的溶解度可以随着羟丙基 -β-环糊精 或磺丁醚 -β-环糊精浓度的提高而提高， 两者之间也没有明显的线性关系。 以 pH 9.0緩冲液配制的溶液中， 当羟丙基 -β-环糊精或磺丁醚 -β-环糊精为 300 mg/ml时， 虎杖苷的溶解度可以达到约 60mg/ml。
本发明还发现联合采用 β-环糊精和葡曱胺作为助溶剂可以对虎杖苷产生 意想不到的协同增溶作用。 举例来说， 例如， 葡曱胺 5mg/ml可使虎杖苷溶解 度提高约 3.17mg/ml, β-环糊精 15mg/ml可使虎杖苷溶解度提高约 2.72mg/ml， 其加和为 5.89 mg/ml; 而对应浓度的葡曱胺、 β-环糊精混合溶液中， 虎杖苷的 溶解度增加了 7.64mg/ml, 此值较筒单加和值提高约 30%。 显然， 葡曱胺、 β- 环糊精对虎杖苷的增溶作用大于两者单独使用时的增溶作用的筒单加和。
由此本发明进一步提供一种以 β-环糊精以及葡曱胺作为助溶剂的高浓度 虎杖苷水溶液。所述溶液中虎杖苷的浓度可以为约 5mg/ml ~ 40 mg/ml, β-环糊 精的浓度可以在约 10mg/ml ~ 60mg/ml 范围内，' 葡曱胺的浓度可以在约 2.5mg/ml ~ 45mg/ml范围内。
类似地， 联合采用羟丙基 -β-环糊精或磺丁醚 -β-环糊精和葡曱胺作为助溶 剂亦可对虎杖苷产生协同增溶作用。 因此， 本发明还提供一种以羟丙基 -β-环 糊精或磺丁醚 -β-环糊精以及葡曱胺作为助溶剂的高浓度虎杖苷水溶液。 所述 水溶液中虎杖苷的浓度可以为约 5mg/ml ~ 100 mg/ml,所述水溶液含羟丙基 -β- 环糊精或磺丁醚 -β-环糊精约 10mg/ml ~ 300mg/ml, 含葡曱胺约为 2.5mg/ml ~ lOOmg/mL
本发明所述之高浓度虎杖苷水溶液可采用纯水、 生理盐水或 pH 7.0〜 9.0 的緩冲液作为溶剂进行配制， 例如， 0.9%氯化钠水溶液、 5%葡萄糖溶液、 碳 酸盐緩冲液、 磷酸盐緩沖液、 Tris緩冲液和 Hepes緩冲液等。
由于葡曱胺的助溶作用并不等同于一般的酸碱调节剂， 因此， 采用葡曱胺 配制的高浓度虎杖苷水溶液时， 当其 pH值超过 9时， 可采用药学上可接受的 酸减调节剂将其 pH回调至 pH 6~9, 由此制备可供临床使用， 特别是可供注射 给药的高浓度虎杖苷注射液。
显而易见，本发明之高浓度虎杖苷水溶液中， 除活性成分虎杖苷以及所述 助溶剂外， 还可以含有药学上可接受的其它药用辅料， 例如抗氧剂、 渗透压调 节剂、 pH调节剂等。 其中， 所述 pH调节剂可以是碱金属、 碱土金属的氢氧 化物以及碳酸钠、 磷酸钠等药学上可接受的无机碱， 盐酸、 硫酸、 磷酸等药学 上可接受的无机酸， 也可以是减性氨基酸等药学上可接受的有机碱， 柠檬酸、 富马酸等药学上可接受的有机酸。此外， 所述高浓度虎杖苷水溶液中也可以含 有可以与虎杖苷联合用药的其它活性成分。
本发明之高浓度杖苷水溶液可作为适合以液体制剂给药的药物制剂，显而 易见， 这些制剂可以是液体口服制剂， 也可以是通过注射给药、局部给药的液 体制剂。 本发明之高浓度杖苷水溶液优选作为适合静脉注射、 肌肉注射、 皮下 注射等胃肠外途径给药的注射剂。
本发明进一步提供本发明之高浓度虎杖苷水溶液的制备方法， 该方法包 括： 采用纯水、 生理盐水或緩冲水溶液作为溶剂， 以化学计量的虎杖苷、 葡曱 胺和 /或环糊精配制本发明所述高浓度虎杖苷的混合水溶液， 还可以任选含有 其它药用辅料如抗氧化剂等， 该溶液经本领域熟知的无菌和 /或无热源处理后 灌装于注射液容器如安瓿瓶。 举例来说， 其无菌和 /或无热源处理可以是微孔 超滤、 热压灭菌等。
本发明所提供的满足临床应用需要的高浓度虎杖苷溶液中可以不含有机 溶剂， 因此该溶液可以用于进一步制备冻干制品， 例如冻干粉针。 由此， 本发 明进一步提供一种在使用前以注射用水或生理盐水等重新配制成高浓度虎杖 苷水溶液的冻干制剂。
显然， 本发明之冻干制品可以是用助溶剂葡曱胺和 /或环糊精配制的浓度 约为 5mg/ml ~ lOOmg/ml的虎杖苷水溶液经冷冻干燥处理所得的药用制剂， 例 如冻干粉针。 冻干前虎杖苷水溶液可以任选添加药学上可接受的填充剂、防冻 剂、 渗透压调节剂、 pH调节剂等。
容易理解， 本发明之虎杖苷冻干制品的制备过程中， 为使冻干前溶液容易 处理，冻干前溶液之溶剂用量可以适当高于配制前述高浓度虎杖苷溶液所需的 溶剂量，即所配制的冻干前溶液中的虎杖苷浓度可以低于使用前配制水溶液中 的虎杖苷浓度。 一般地， 以本发明之冻干制品配制的水溶液中， 虎杖苷浓度可 达约 5mg/ml ~ 100mg/ml; 显而易见， 如有必要， 本发明之冻干制品配制的水 溶液可以进行任选比例的稀释。
本发明之虎杖苷冻干制品可以是用葡曱胺作为助溶剂配制的浓度约为 5mg/ml ~ 15mg/ml虎杖苷水溶液经冷冻干燥所得的药用制剂。由于所述虎杖苷 水溶液中葡甲胺的浓度可以为约 7.5mg/ml ~ 60mg/ml， 因此其冻干制剂中虎杖 苷与葡曱胺的比例可以在约 1:1.5 1:12之间； 本发明中， 该比例可进一步优选 在 1 :1.5〜1:3之间。
本发明之虎杖苷冻干制品还可以是用 β-环糊精作为助溶剂配制的浓度约 为 5mg/ml ~ 20mg/ml虎杖苷水溶液经冷冻干燥处理所得的的药用制剂。 所述 虎杖苷水溶液中 β-环糊精的浓度可以约为 20mg/ml ~ 60mg/ml , 因此其冻千制 品中虎杖苷与 β-环糊精的比例可以在约 1:3 ~ 1 :12之间； 根据本发明， 该比例 还进一步优选在 1:3 ~ 1:8之间。
本发明之虎杖苷冻干制品还可以是用羟丙基 -β-环糊精或磺丁醚 -β-环糊精 作为助溶剂配制的浓度约 5mg/ml ~ 60mg/ml的虎杖苷水溶液经冷冻干燥处理 所得的药用制剂。 所述虎杖苷水溶液中 β-环糊精的浓度可以约为 20mg/ml ~ 300mg/ml,因此其冻千制品中虎杖苷与葡曱胺的比例可以在约 1 :4〜 1:60之间； 根据本发明， 该比例还进一步优选在 1:4 ~ 1 :8之间。
本发明之虎杖苷冻干制品还可以是联用 β-环糊精和葡曱胺作为助溶剂配 制的浓度约 5mg/ml ~ 40mg/ml的虎杖苷水溶液经冷冻干燥处理所得的药用制 剂。 所述冻干前虎杖苷水溶液中， β-环糊精的浓度可以为约 10mg/ml ~ 60mg/ml, 葡甲胺的浓度可以为约 2.5mg/ml ~ 45mg/ml, 因此其冻干制品中， 虎杖苷与葡甲胺、 β-环糊精的比例可以在约 1 : 0.5:1.5 1 : 9:12之间；根据本发 明， 该比例还进一步优选在 1: 0.5: 4〜 1 : 2: 8之间。
本发明之虎杖苷冻干制品还可以是用羟丙基 -β-环糊精或磺丁醚 -β-环糊精 以及葡曱胺作为助溶剂配制的浓度约 5mg/ml ~ lOOmg/ml的虎杖苷水溶液经冷 冻干燥处理所得的药用制剂。 所述冻干前虎杖苷水溶液中羟丙基 -|3-环糊精或 磺丁醚 -β-环糊精浓度可以为约 10mg/ml ~ 300mg/ml， 葡曱胺的浓度可以为约 2.5mg/ml ~ 100mg/ml, 因此其冻干制品中， 虎杖苷与葡曱胺、 羟丙基 -β-环糊 精或磺丁醚 -β-环糊精的比例可以在约 1： 0.5： 2 ~ 1： 20： 60之间；根据本发明， 该比例优选 1 : 0.5: 4〜 1: 2: 8之间。
本发明进一步提供上述冻干粉针剂的制备方法， 该方法包括， 采用纯水、 生理盐水或緩冲水溶液作为溶剂以化学计量的虎杖苷、 葡曱胺和 /或环糊精配 制本发明所述高浓度虎杖苷水溶液，可以另含药学上可接受的填充剂等药用辅 料， 所得溶液经超滤法除热源， 无菌分装于西林瓿， 冷干成型后， 得到制品， 即含虎杖苷的冻干混合物。适当的填充剂可以有利于本发明之虎杖苷冻干制品 的冻干成型， 本发明优选的填充剂包括甘露醇、 NaCl等。
本发明之含高浓度虎杖苷的冻干制品可以是分装的无菌粉末，也可以是直 接冻干成型的冻干粉针， 其中优选冻干粉针剂。本发明之含高浓度虎杖苷的冻 干制品可以通过静脉注射、静脉滴注、肌肉注射、 皮下注射以及局部给药等胃 肠外途径给药。 本发明所述之含 "高浓度"虎杖苷的冻干制品意思是指该冻干 制品经纯水或生理盐水等配制成水溶液后， 该溶液中的虎杖苷浓度可达 5mg/ml以上。
本发明所提供的含虎杖苷的药物组合物可以用于制备微循环障碍相关性 疾病的治疗药物。 本发明之虎杖苷药物組合物具有显著的扩张和疏通^:血管、 降低微血管内血液黏度、抑制血细胞黏附作用， 因而可以用于治疗或预防休克 以及其它与微循环障碍有关的疾病如心肌缺血、 脑缺血、 肢端循环障碍等。
中国专利申请 CN 1709269A提供了一种可通过静脉滴注提供有效治疗剂 量虎杖苷的药用制剂，由于该制剂含较高浓度有机溶剂而不能用于直接注射给 药， 因此， 迄今尚无具有临床实际应用价值的、 可通过直接注射给药的虎杖苷 药用制剂。本发明提供了一种可以不含有机溶剂的高浓度虎杖苷水溶液，该水 溶液还可以进一步被制备成冻干制品。 由于可以不含有机溶剂，这些虎杖苷水 溶液及其冻干制剂可以用于直接注射给药。
显然， 本发明之高浓度虎杖苷水溶液可以不含有机溶剂，但并不排斥使用 有机溶剂， 例如在不影响特定给药方式及制剂成型条件下， 其水溶液亦可包括 少量乙醇、 丙二醇等。
本发明首次提供了一种具有实际临床应用价值的、可以直接注射给药的虎 杖苷制剂， 这不仅可以为虎杖苷的临床应用提供了一种更为便捷的使用途径 , 又可以为进一步拓宽虎杖苷的临床应用范围提供了条件。与现有的技术水平相 比， 本发明之药物组合物具有本质上的进步。
举例来说，虎杖苷由于其显著的微循环改善作用而可以应用于创伤性休克 等危重疾病的治疗，直接注射给药无疑对于这些危重疾病的抢救治疗具有极为 重要的意义。
动物试验及溶液稳定性试验表明，本发明提供的虎杖苷药物组合物安全有 效、 稳定性良好， 因此， 该溶液具有良好的临床应用前景。
为了更好地理解本发明的本质， 下面结合附图，通过对部分较佳实施方式 所进行的描述， 详细说明但不限制本发明。
附图的简要说明
图 1表示虎杖苷注射液对失血性休克犬平均动脉压的影响；
图 2表示虎杖苷治疗对失血性休克犬冠脉血流的影响。
发明的具体实施方式
以下实施例中所采用的材料包括：
虎杖苷， 由深圳海王技术中心提供， 纯度 99.63%, 批号 20050819。
葡曱胺， 药用辅料， 上海富蔗化工有限公司； β-环糊精， 药用辅料， 永光 环糊精有限公司； 羟丙基 -β-环糊精， 辅料第一类， 西安德立生物化工有限公 司； 磺丁醚 -β-环糊精， 药用辅料， 上海富蔗化工有限公司； 氟里昂 F12, 浙江 荧光化工有限公司。 注射用水， 海王工业城； 0.9%氯化钠溶液， 以注射用水配 制； Na2HP04-NaH2P04緩冲液， 注射用水配制。
本发明所用其它试验材料， 如无特别说明， 均为市售购买产品。
虎杖苷注射液的制备
【实施例 1】
1.处方
原料 用 量 虎杖苷 25.0 g 葡曱胺 50.0 g
pH 8.0 Na2HP04-NaH2P04緩冲液 至 5.0 L
制成 1000支
2.制法 Na2HP04-Na¾P04緩冲液 4.8L, 加入虎杖苷 25.0g, 葡曱胺 50.0g, 40。C超声促溶， 加 Na2HP04-Na¾P04緩冲液定容至 5.0 L, 0.2μηι微 孔滤膜超滤， 灌封于 1000支安瓿瓶中。
【实施例 2】
1. 处方
原料 用 量
虎杖苷 50.0 g
β-环糊精 250.0 g
pH 9.0 Na2HP04-NaH2P04緩冲液 至 5.0 L
制成 1000支
2.制法 Na2HP04-NaH2P04緩冲液 4.8L, 加入虎杖苷 50.0g , β-环糊精
250.0g, 40。C超声促溶， 加 Na2HP04-NaH2P04緩冲液定容至 5.0 L, 0.2μιη微 孔滤膜超滤， 灌封于 1000支安瓿瓶中。
【实施例 3】
1. 处方
原料 用 量
虎杖苷 100.0 g
羟丙基 -β-环糊精 600.0 g
pH 7.5 Na2HP04-NaH2P04緩冲液 至 5.0 L
制成 1000支
2.制法 Na2HP04-Na¾P04緩冲液 4.8L, 加入虎杖苷 lOO.Og, 羟丙基 -β- 环糊精 600.0g, 40。C超声促溶,加 Na2HP04-Na¾P04緩冲液定容至 5.0 L, 0.2μιη 微孔滤膜超滤， 灌封于 1000支安瓿瓶中。
【实施例 4】
1.处方
原料 用 量
虎杖苷 75.0 g
磺丁醚 -β-环糊精 400.0 g
pH 8.0 Na2HP04-Na¾P04缓冲液 至 5.0 L
制成 1000支
2.制法 Na2HP04- NaH2P04緩冲液 4.8L, 加入虎杖苷 75.0g， 磺丁醚 -β- 环糊精 400.0g, 40。C超声促溶,加 Na2HP04-Na¾P04緩冲液定容至 5.0 L, 0.2μιη 微孔滤膜超滤， 灌封于 1000支安瓿瓶中。
【实施原虎羟原甘虎葡 .葡 .例 5】
1. 处处处杖料料杖露丙曱甲方
方方}胺苷胺苷醇
原料 用 量
虎杖苷 75.0 g
葡曱胺 75.0 g
β-环糊精 250.0 g
Η 8.0 Na2HP04-NaH2P04緩冲液 至 5.0 L
制成 1000支
2.制法 Na2HP04-Na¾P04緩冲液 4.8L,加入虎杖苷 75.0g,葡曱胺 100.0 g, β-环糊精 200.0g, 40。C超声促溶，加 Na2HP04-Na¾P04緩冲液定容至 5.0L, 0.45μιη的微孔滤膜粗滤， 续滤液过 0.22μιη的微孔滤膜， 配备 1万截留分子量 的 PES膜的板框式超滤器除热原， 棕色瓶充氮气灌封。
【实施例 6】 用 量
400.0 g
400.0 g
β-环糊精 1500.0 g pH 7.5 Na2HP04-NaH2P04緩冲液 至 5.0 L
制成 1000支
2. 制法 Na2HP04-NaH2P04緩冲液 4.8L, 加入虎杖苷 400.0g, 葡曱胺
400.0g, 羟丙基 -β-环糊精 1250.0g, 40。C超声促溶， 加 Na2HP04-NaH2P04緩 冲液定容至 5.0L, 0.45μιη的 孔滤膜粗滤， 续滤液过 0.22μιη的微孔滤膜， 1 万截留分子量的 PES膜超滤除热原， 棕色瓶充氮气灌封。
虎杖苷冻干粉针的制备
【实施例 7】 用 量
25.0 g
50.0 g
50.0 g
pH 8.0 Na2HP04-NaH2P04緩冲液 至 5.0 L
制成 1000支
2.制法 冻干前溶液配制： Na2HP04-Na¾P04緩冲液 4.8L, 加入虎杖苷 25.0g, 葡曱胺 50.0g, 甘露醇 50.0g, 40。C超声促溶， 加 Na2HP04- Na¾P04 緩冲液定容至 5.0 L, 0.2μπι微孔滤膜超滤，分装到 1000支冻干专用西林瓶中。 制剂成型： 西林瓶放入冻干箱后板温降至 -35 °C，品温降至 -30 °C冷冻三小 时， 冷原甘虎- ώ .凝温度达 -40°C , 抽真空， 板温緩慢升至 40°C , 制品温度随之升高、 干 燥， 冻干处环料杖露机开箱， 西林瓶压塞， 轧盖。
糊方苷醇
【实施例 8】 用 量
75.0 g
400.0 g
100.0 g
pH 9.0 Na2HPO4-Na¾PO4緩冲液 至 10.0 L
制成 1000支
2. 制法 冻干前溶液配制： Na2HP04-NaH2P04緩冲液 9.5L,加入虎杖苷 75.0g, β-环糊精 400.0g,甘露醇 lOO.Og, 40。C超声促溶，加 Na2HP04-Na¾P04 緩冲液定容至 10.0 L, 0.2μπι微孔滤膜超滤， 分装到 1000支冻干专用西林瓶 中。
制剂成型： 西林瓶放入冻干箱后板温降至 -35 °C , 品温降至 -30Ό冷冻 3小 时， 冷凝温度达 -40°C , 抽真空， 板温缓慢升至 4CTC , 制品温度随之升高、 干 燥， 冻干机开箱， 西林瓶压塞， 轧盖。
【实施例 9】
1. 处方
原料 用 量
虎杖苷 75.0 g
羟丙基 -β-环糊精 500.0 g
甘露醇 50.0 g
pH 7.5 Na2HP04-NaH2P04緩冲液 至 5.0 L
制成 1000支
2. 制法 冻干前溶液配制： Na2HP04-NaH2P04緩冲液 4.8L, 加入虎杖 苷 750.0g, 羟丙基 -β-环糊精 500.0g, 甘露醇 50.0 g , 40。C 超声促溶， 加 Na2HP04-NaH2P04緩冲液定容至 5.0 L, 0.2μηι微孔滤膜超滤后分装到 1000支 冻干专用西林瓶中。
制剂成型： .西林瓶放入冻干箱后板温降至 -35 °C , 品温降至 -30°C冷冻 3小 时， 冷凝温度达 -40°C , 抽真空， 板温緩慢升至 40°C , 制品温度随之升高、 干 燥， 冻干机开箱， 西林瓶压塞， 轧盖。
【实施例 10]
1. 处方
原料 ' 用 量
虎杖苷 100.0 g 磺丁醚 -β-环糊精
甘原甘虎原甘葡虎 .葡 . 露醇
ρΗ处环处杖料露料杖曱丁露甲 8.0 Na2HP04-NaH2P04緩冲液
制成糊方方胺苷醇胺苷醚醇 1000支
2. 制法 冻干前溶液配制： Na2HP04- NaH2P04緩冲液 9.5L,加入虎杖苷 50.0g,磺丁醚 -β-环糊精 400.0g, 甘露醇 lOO.Og, 40。C超声促溶， 力 P Na2HP04- Na¾P04緩冲液定容至 10.0L, 0.2μπι微孔滤膜超滤后分装到 1000支冻干专用 西林瓶中。
制剂成型： 西林瓶放入冻干箱后板温降至 -35°C ,品温降至 冷冻 3 小 时， 冷凝温度达 -40°C , 抽真空， 板温缓慢升至 40°C , 制品温度随之升高、 干 燥， 冻干机开箱， 西林瓶压塞， 轧盖。
【实施例 11】 用 量
50.0 g
50.0 g
200.0 g
50.0 g
pH 8.5 Na2HP04-NaH2P04緩冲液 至 5.0 L
制成 1000支
2.制法 冻干前溶液配制： Na2HP04-NaH2P04緩冲液 4.5L, 加入虎杖 苷 50.0g, 葡曱胺 50.0g, β-环糊精 200.0g, 甘露醇 100.0g， 40。C超声促溶， 加 Na2HP04- NaH2P04缓 液定容至 5.0L, 0.2μηι微孔滤膜超滤后分装到 1000 支冻干专用西林瓶中。
制剂成型： 西林瓶放入冻千箱后板温降至 -50°C， 品温降至 -45°C冷冻 3小 时， 冷凝温度达 -55 °C , 抽真空， 板温緩慢升至 - 20°C , 之后再冷冻、 再升温, 如此 3次后， 再使板温緩慢升至 40。C, 制品由此干燥成型。 冻干机开箱， 西 林瓶压塞， 车 L盖。
【实施例 12】 用 量
300.0 g
300.0 g
β-环糊精 1500.0 g
50.0 g
pH 7.5 Na2HP04-NaH2P04緩冲液 5.0 L
制成 1000支
2.制法 冻干前溶液配制： Na2HP04-Na¾P04緩冲液 4.5L, 加入虎杖 苷 300.0g, 葡曱胺 300.0g, 磺丁醚 -β-环糊精 lOOO.Og, 甘露醇 50.0g, 40。C超 声促溶原虎. ώ葡 .， 加 Na2HP04- NaH2P04緩冲液定容至 5.0L, 0.45μιη的微孔滤膜粗滤， 续滤液过处环料杖曱 0.22μιτι的微孔滤膜， 1万截留分子量的 PES膜超滤除热原后分装到 1000支冻干专用西林瓶中。
制剂成型： 西林瓶放入冻干箱后板温降至 -50°C , 品温降至 -45°C冷冻 3小 时， 冷凝温度达 -55 °C , 抽真空， 板温緩慢升至 - 20°C， 之后再冷冻、 再升温， 如此 3次后， 再使板温緩慢升至 40。C, 制品由此干燥成型。 冻干机开箱， 西 林瓶压塞， 轧盖。
虎杖苷口服溶液的制备
【实施例 13】
1. 处方
原料
虎杖苷
葡曱胺
β-环糊精
ρΗ 8.5 Na2HP04-Na¾P04緩冲液
制成 1000瓶
2. 制法 Na2HP04-NaH2P04緩冲液 9.5L, 加入虎杖苷 100.0g, 葡甲胺 100.0g, β-环糊精 450.0g, 40。C超声促溶， 加 Na2HP04- NaH2P04缓冲液定容 至 10.0L, 0.45μιη微孔滤膜超滤后分装到 1000支口服液玻璃瓶中。
虎杖苷喷雾剂的制备
【实施例 14]
方
用 量
苷 500.0 g
胺 500.0 g
糊精 3000.0 g
pH 8.0 Na2HP04-NaH2P04緩冲液 至 20.0 L
制成 1000支
2. 制法 Na2HP04-NaH2P04缓冲液 19L, 加入虎杖苷 500g, 葡曱胺 500g, β-环糊精 3000g, 40。C超声促溶， 加 Na2HP04- NaH2P04緩冲液定容至 20.0L, 0.45μιη微孔滤膜粗滤， 续以 0.22μηι的微孔滤膜过滤后， 滤液灌于超 声波雾化器内即得虎杖苷喷雾剂。 雾粒直径大部分在 5μηι以下， 可吸入呼吸 支气管和肺泡内。
虎杖苷气雾剂的制备
【实施例 15】
1. 处方
原料 用 量 虎杖苷 100.0 g 羟丙基 -β-环糊精 600.0 g
pH 7.5 Na2HP04-NaH2P04 3.5 L
氟利昂 F12 至 5000.0 g
制成 1000瓶
2. 制法 Na2HP04-Na¾P04緩冲液 3.5L, 加入虎杖苷 100g， β-环糊精 600g, 40。C超声促溶， 0.45μπι微孔滤膜粗滤， 滤液续以 0.22μηι的微孔滤膜 过滤， 滤液分剂量灌装， 封接剂量阀门系统， 然后再加压注入 F12， 摇勾， 即 得虎杖苷气雾剂。
葡甲胺及环糊精对虎杖苷的助溶作用
【实施例 16】 葡曱胺对虎杖苷的助溶作用
配制浓度为 0、 2.5、 5、 10、 20、 40、 80mg/ml的葡甲胺溶液各 10ml, 每 份溶液中分别加入虎杖苷至 50ml, 40°C超声促溶 30min后， 室温放置 3hr, 0.20μπι微孔滤膜过滤， HPLC法检测滤液中虎杖苷浓度， 检测结果如表 1所 示。
表 1 虎杖苷在不同浓度葡曱胺溶液中的饱和溶解度 (mg/ml) 葡甲胺溶液 0 2.5 5 10 20 40 80 虎杖苷溶解度 0.25 2.51 5.69 6.51 9.68 16.82 22.68 当葡曱胺浓度高于 10mg/ml时，所配制的虎杖苷饱和溶液 pH值可在 9 ~ 12 之间， 但是， 虎杖苷在葡曱胺溶波中的溶解度比在相同 pH值下的 NaOH溶液 中的溶解度高数十倍不等 （参见中国专利申请 CN 1709269 A )。
此外， 配制浓度 7.5mg/ml的葡曱胺溶液， 以上述方法制备虎杖苷 ο饱和溶 液，经检测，该溶液中虎杖苷溶解度约为 5.12mg/ml,其 pH值约 8.7; 以 p寸H7.5 磷酸緩冲液配制浓度 60mg/ml 的葡曱胺溶液， 以上述方法制备虎杖苷饱和溶 液， 经检测， 该溶液中虎杖苷溶解度约为 14.83mg/ml, 其 pH值约 8.94。
显然： （1) 葡曱胺对虎杖苷的增溶作用不能归因于 pH调节作用； （2)采用 7.5~60mg/ml的葡曱胺溶液可以配制 pH在 9以下而虎杖苷浓度在 5~15mg/ml 范围内的虎杖苷水溶液。
【实施例 17】 虎杖苷在 β-环糊精溶液中的溶解度
分別取 β-环糊精 0、 25、 50、 100、 200、 300、 450mg, 加入虎杖苷 lOOmg, 加蒸馏水 10ml, 40。C超声促溶 30min后， 室温放置 3hr， 0.20μπι微孔滤膜过 滤， HPLC法检测滤液中虎杖苷浓度, 检测结果如表 2所示。
表 2 虎杖苷在不同浓度 β-环糊精溶液中的饱和溶解度 （mg/ml) β-环糊精用量 0 2.5 5.0 10.0 20.0 30.0 45.0 虎杖苷溶解度 0.25 0.91 1.35 2.35 3.76
结果表明， 当溶液中 β-环糊精浓度高于 30mg/ml时， 虎杖苷溶解度即可超 过 5mg/ml。 鉴于文献及实验室实测结果均表明， β-环糊精在室温下的純水中 的溶解度约为 18mg/ml, 因此上述操作中， 高浓度 β-环糊精溶液配制中， 所加 入的 β-环糊精可能不完全溶解， 也就是说， 滤液中 β-环糊精可能达不到表 2所 列的 β-环糊精计算浓度； 此外，检测上述虎杖苷饱和溶液之 ρΗ值， 结果其 ρΗ 均低于 7。 为检测虎杖苷存在下的 β-环糊精实际溶解性以及不同 ρΗ值下 β-环 糊精对虎杖苷溶解度的影响， 试验进一步采用 ρΗ 9.0磷酸緩冲液配制下列溶 液： 取 β-环糊精 200, 400, 600mg, 分别加入虎杖苷 50, 100, 200mg, 加磷酸緩 冲液 10ml, 40。C超声促溶后， 室温放置 3hr。 经检查， 所得溶液未经过滤均 为澄明溶液， 说明 β-环糊精和虎杖苷在配制溶液均可完全溶解， 其中 β-环糊精 溶解度可在 60mg/ml以上。
由上述结果可见， （1) 虎杖苷水溶性可随 β-环糊精存在量的增加而提高， 但两者浓度没有明显的线性关系； （2)在虎杖苷存在下， β-环糊精的自身溶解 度也可以大幅度升高，这构成了利用 β-环糊精制备具有临床应用价值的高浓度 虎杖苷溶液的基础条件； （3)采用浓度 20 ~ 60mg/ml的 β-环糊精可以制备浓度 可达 5 ~ 20mg/ml的 pH 9.0以内的虎杖苷水溶液。
【实施例 18】 虎杖苷在羟丙基 -β-环糊精溶液中的溶解度
分别取羟丙基 -β-环糊精 0、 25、 50、 100、 200、 300、 400、 500、 700、 900、 1200、 1500、 2000、 3000、 5000mg, 加入虎杖苷至过饱和， 加蒸馏水 10ml, 40。C超声促溶 30min后， 室温放置 3hr， 0.20μπι微孔滤膜过滤， HPLC法检 测滤液中虎杖苷浓度， 检测结果如表 3所示。
虎杖苷在不同浓度羟丙基 -β-环糊精中的饱和溶解度 (mg/ml) 环糊精用量 0 2.5 5.0 10.0 30.0 60.0 虎杖苷溶解度 0.25 0.83 1.56 2.88 6.25 11.53 环糊精用量 90 120 150 200 300 500 虎杖苷溶解度 16.34 22.60 29.12 39.18 50.12 56.32 结果表明， 羟丙基 -β-环糊精可产生近似于 β-环糊精的虎杖苷增溶活性， 由 于其自身水溶性较好而可以形成更高浓度的虎杖苷水溶液。虎杖苷水溶性可随 羟丙基 -β-环糊精存在量的增加而提高， 但两者浓度增长亦无明显的线性关系。 当羟丙基 -β-环糊精浓度至 30mg/ml时， 虎杖苷溶解度即可超过 6mg/ml; 当羟 丙基 -β-环糊精浓度至 300mg/ml时， 虎杖苷溶解度即可超过 50mg/ml。 试验 进一步采用 pH 9.0磷酸緩冲液配制下列两种溶液： 取羟丙基 -β-环糊精 200、 4500mg，分别加入虎杖苷 50、 600mg,加磷酸緩冲液 10ml, 40。C超声促溶后， 室温放置 3hr。 经检查， 所得溶液未经过滤均为澄明溶液， 说明羟丙基 -β-环糊 精和虎杖苷在配制溶液均可完全溶解。 试验表明， 可以采用低至 20mg/ml 的 羟丙基 -β-环糊精溶液配制不低于 5mg/ml的虎杖苷溶液；在 pH 9.0以内可以采 用羟丙基 -β-环糊精溶液配制浓度达 60mg/ml的虎杖苷溶液。 试验还表明， 磺 丁醚 -β-环糊精可对虎杖苷产生类似的助溶作用。
【实施例 19】 葡甲胺和 β-环糊精对虎杖苷的协同增溶作用
分别取葡曱胺 0、 50、 100和 150mg, 分别加入 0、 150、 300和 450mg, 加入虎杖苷 200mg, 加蒸偬水 10ml, 40。C超声促溶 30min后， 室温放置 3hr, 0.20μιη微孔滤膜过滤， HPLC法检测滤液中虎杖苷浓度， 检测结果如表 4所 示。
表 4虎杖苷在不同浓度葡曱胺、 β-环糊精溶液中的溶解度 (mg/ml)
ο
葡曱胺用量 0 5
β-环糊精用量 0 15 30 45 0 15 30 45 虎杖苷溶解度 3.42 7.89 11.25 15.46 葡曱胺用量 10 15
β-环糊精用量 0 15 30 45 0 15 30 45 虎杖苷溶解度 5.69 10.09 13.11 17 p.86 7.24 12.25 15.92 19.37 显然， 无葡曱胺存在时， 15、 30和 45mg/ml的 β-环糊精可以使虎杖苷溶解 度分別提高 2.72、 5.48和 9.48mg/ml; 无 β-环糊 4青存在时， 5、 10和 15mg/ml葡 曱胺可以使虎杖苷溶解度分别提高 3.17、 5.44和 6.99mg/ml。 显然， 不同浓度葡 曱胺和 β-环糊精共同存在时，其对虎杖苷的增溶作用均高于对应浓度下单独存在 的葡曱胺和 β-环糊精对虎杖苷增溶作用的简单加和。 例如， 葡曱胺 5mg/ml可使 虎杖苷溶解度提高约 3.17mg/ml, β-环糊精 15mg/ml可使虎杖苷溶解度提高约 2.72mg/ml, 其加和为 5.89 mg/ml; 而对应浓度的葡曱胺、 β-环糊精混合溶液中， 虎杖苷的溶解度增加了 7.64mg/ml, 此值较筒单加和值提高约 30%。 类似地， 羟 丙基 -β-环糊精、磺丁醚 -β-环糊精与葡曱胺可对虎杖苷产生更强的协同增溶作用。
此外， 取 450mg葡曱胺和 600mg p-环糊精， 加 400mg虎杖苷后， 加 10ml pH 8.5磷酸緩冲液溶解， 可得澄明的虎杖苷水溶液， 说明， 联用葡曱胺和 β- 环糊精可以配制浓度高达 40mg/ml的虎杖苷水溶液 (pH低于 9)。 取 lg葡曱胺 和 3g羟丙基 -β-环糊精， 加 lg虎杖苷后， 再加 10ml pH 8.5磷酸缓冲液溶解， 亦可获得澄明的虎杖苷水溶液， 说明， 联用葡曱胺和羟丙基 -β-环糊精可以配 制浓度高达 100mg/ml的虎杖苷水溶液（pH低于 9)。
虎杖苷药物组合物的安全性、 稳定性研究
【实施例 20】 虎杖苷注射液及冻干粉针之储存稳定性考察
1. 试验样品
实施例 1 ~ 12制备的虎杖苷注射液及冻干粉针。
2. 试验方法
存在条件： 供试样品分别避光储存于 30。C恒温箱和 4。C冰箱。
澄明度检查：检查供试样品于储存前和储存三个月后的溶液澄明度，其中， 冻干粉针以设计容量 (5ml或 10ml)生理盐水稀释后检查。 含量检测： 高效液相色谱法。 色谱条件： Agilent 1100 高效液相色谱仪； Agilent DAD检测器； 大连依利特 YWG C18 ΙΟμιπ 4.6 χ 250mm色谱柱； 流动 相为曱醇 -6%醋酸溶液 (25:75); 流速为 l.Oml/min; 检测波长为 306nm; 柱温为 30。C; 进样量为 20 μ1。
3. 结果
考察结果见表 5。 结果表明， 虎杖苷注射液以及冻干粉针复溶的水溶液的 澄明度检查均合格； 受试样品在 30。C或 4。C下储存 3个月， 其有效成分含量 可保持稳定 （变化不超过土 10%)。
表 4 虎杖苷注射液及冻干粉针的储存稳定性 (mg/ml)
澄明度检查 含量检测
供试品 储存 3个月 储存 3个月
储存前 储存前
30°C 4°C 30°C 4。C 实施例 1注射液 合格 合格 合格 4.953 4.743 4.951 实施例 2注射液 合格 合格 合格 9.883 9.664 9.823 实施例 3注射液 合格 合格 合格 20.07 19.29 20.10 实施例 4注射液 合格 合格 合格 14.96 14.91 14.95 实施例 5注射液 合格 合格 合格 15.02 14.22 15.00 实施例 6注射液 合格 合格 合格 79.51 75.40 79.52 实施例 Ί冻干粉针 合格 合格 合格 4.893 4.682 4.886 实施例 8冻干粉针 合格 合格 合格 7.492 7.403 7.429 实施例 9冻干粉针 合格 合格 合格 14.75 14.60 14.77 实施例 10冻干粉针 合格 合格 合格 9.852 9.731 9.826 实施例 11冻干粉针 合格 合格 合格 10.16 9.635 10.23 实施例 12冻干粉针 合格 合格 合格 58.63 55.36 57.98
【实施例 21】 虎杖苷注射液及冻干粉针之溶血、 过敏及血管刺激性检查
1.供试品
样品 1， 实施例 3之虎杖苷注射液。
样品 2, 实施例 11虎杖苷冻干粉针。 临用前以 5ml生理盐水溶解。
2. 方法
溶血试验： 新西兰兔耳静脉采血， 经去纤维蛋白原， 生理盐洗涤后， 以生 理盐水稀释成 2%的混悬液供试验用。
分别取虎杖苷注射液或冻干粉针复溶的水溶液 0(对照)、 0.1、 0.2、 0.3、 0.4、 0.5ml后， 分别加生理盐水至 2.5ml, 混匀后加上述 2%血细胞混悬液， 轻摇混 匀后， 置 27°C室温中， 观察、 记录 30、 60、 180min的溶血结果。
全身过敏试验： 健康豚鼠 24只 (250-350g), 随机分组， 每组 6只。 各组动 物隔日分别腹腔注射生理盐水 (阴性对照)、 虎杖苷注射液或冻干粉针复溶的水 溶液及鸡蛋清 (阳性对照） 1ml/只， 共 3次。 首次注射后的第 14天， 每组取 3 只再次分别对照溶液或供试品溶液 2.5ml/只， 观察注射后试验动物的反应情 况。 各组余下 3只豚鼠于首次注射后的第 21天同法分别注射对照溶液或供试 品溶液 2.5ml/只并观察动物反症情况。
血管刺激性试验： 新西兰兔 6只， ？ ί各半， 按 5mg/kg耳缘静脉注射虎 杖苷注射液或冻干粉针复溶的水溶液， 每天一次， 连续 3次， 观察注射后血管 及其周围组织的变化情况， 末次注射后 30分钟， 颈动脉放血处死动物， 剪下 兔耳注射部位固定，对侧兔耳同一部位剪下固定作为正常对照， 病理切片检查 兔耳血管病理变化情况。
2. 结果
溶血试验： 虎杖苷注射液及冻干粉针复溶的水溶液在 30、 60、 180min均 未发生溶血现象， 出现红细胞凝集反应。
全身过敏试验： 注射虎杖苷注射液及冻干粉针复溶的水溶液末次给药后， 与阴性对照一样， 仅少数动物出现轻微抓鼻反应， 未见颤抖、 呼吸困难、 痉挛 等过敏症状， 阳性对照组则见试验动物因强烈过敏反应而死亡。
血管刺激试验：兔耳静脉注射虎杖苷注射液及冻干粉针复溶的水溶液后均 未引起静脉扩张、 充血， 周围组织未见水肿。 病理检查未见兔耳皮肤破坏或皮 下组织充血、 水肿， 耳缘静脉未见扩张、 充血， 血管内皮细胞未见改变， 血管 壁未见附壁血栓及炎性细胞浸润， 血管周围未见出血。
结论: (1)供试的虎杖苷注射液及冻干粉针没有体外溶血作用和凝集反 应。 (2)供试的虎杖苷注射液及冻干粉针兔耳血管无刺激作用。 (3)供试的 虎杖苷注射液及冻干粉针不引起全身过敏反应。
虎杖苷药物组合物的药效学研究
【实施例 22】虎杖苷注射液对失血性休克犬心肌血流量的的影响
供试品： 实施例 5之虎杖苷注射液， 深圳海王药业有限公司。
动物: Beagle犬，体重 8〜12 kg。合格证号 001321 ,许可证号 SYXK (粤） 2003 - 0007。 第一军医大学动物所。
试验方法： 动物用 3% 戊巴比妥钠麻醉后， 仰卧固定于大动物手术台。 行气管插管， 呼吸机 (ElOOi型， 美国 Newport Ven公司产品） 维持呼吸（15次 /min、 300~400 ml/min)。 双侧股动脉插管， 分别用于记录血压 （美国 Marquette Eagle4000生理记录仪）和放血， 行股静脉插管用于给药。 左侧 2~4肋间开胸， 暴露心脏， 剪开心包膜， 超声血流量计 (T206型， 美国 transonic systems公司 产品)记录冠脉前降支血流量。 通过一侧股动脉插管放血并使之流入装有肝素 生理盐水的无菌输液瓶内， 调节放血量， 使平均动脉压在 15min 内降至 40 mmHg, 使平均动脉压维持在该水平 120 min, 然后给药, 虎杖苷注射液混溶 于容量为 1/3失血量的生理盐水并在 120min内由股静脉输入体内， 给药剂量 5.0 mg/kg。记录给药前后的冠脉血流量。 试验采用生理盐水作为对照。 以正常 血流量为 100%对血流量数据进行标准化处理，采用 SPSS13.0统计软件包的多 因素方差分析 ( ANO VA)进行统计学分析。
试验结果： 实验中， 犬失血量约占全血量的 60 %。 试验结果显示， 犬失 血性休克期间， 冠脉血流量明显减少。 给予虎杖苷注射液进行复苏抢救后， 犬 平均动脉压显著升高 （见图 1 ), 给药后冠脉血流量得到明显恢复， 给药开始 60 min后冠脉血流达到了正常的 62.92±8.76 %； 在随后的观察时间内， 虎杖苷 组的冠脉血流量维持在较高水平，给药开始后 120 min时甚至达到正常水平（正 常的 101.96±15.87 % )。 虎杖苷组增加冠脉血流量的程度从给药 60分钟开始， 各时间点均显著高于生理盐水对照组（见表 5, 图 2 )。
表 5 虎杖香治疗对 H- 失血性休克犬心脏冠脉血流量的影响 (%, x±s)
休克 给药过程 给药后
分組 正常-
Γ 60' 120' 30' 60' 120' 30' 60' 120'
31.86 32.11 35.62 48.20 59.31 60.87 51.06 52.04
对照組 100 ± 士 ± ± ± 士 ± ± 士
7.31* 11.10* 16.46* 9.85* 9.89* 9.73* 5.96*
27.09 30.12 32.98 62.92 91.09 101.96 85.92 78.97 82.00 虎杖組 100 士 士 ± 士 士
2.87* 8.76 24.02# 15.87Λ 6.66Λ 3.12Λ# 5.25# 自身比较： * 与正常时相比， ρ<0.05; Λ与休克 120，相比， ρ<0.05。
组间比较： # 与对照组相比， <0.05ο 工业应用性
本发明提供了一种具有实际临床应用价值的， 可以直接注射给药的虎杖苷 药物组合物， 其安全有效、稳定性良好， 不仅可以为虎杖苷的临床应用提供了 一种更为便捷的使用途径，又可以为进一步拓宽虎杖苷的临床应用范围提供了 条件。

Claims

权利要求书
1、 一种含高浓度虎杖苷的药物组合物 , 所述药物组合物含有药用活性成 分虎杖苷及助溶剂葡曱胺和 /或环糊精， 所述药物组合物为水溶液或使用前配 制成水溶液的冻干制品，在所述水溶液以及用冻干制品配制的水溶液中虎杖苷 浓度能够达到 5mg/ml ~ 100mg/ml。
2、 权利要求 1所述的药物組合物， 虎杖苷与助溶剂葡甲胺和 /或环糊精的 质量比为 1 :0.5:1.5〜1 :20:100。
3、 杈利要求 2所述的药物组合物， 其特征在于所述组合物为虎杖苷水溶 液。
4、 权利要求 3所述药物组合物， 其特征在于： 所述虎杖苷水溶液中含有 虎杖苷 5mg/ml ~ 15mg/ml以及葡甲胺 7.5mg/ml ~ 60mg/ml。
5、 权利要求 3所述药物组合物, 其特征在于： 所述虎杖苷水溶液中含有 虎杖苷 5mg/ml ~ 20mg/ml以及 β-环糊精 20mg/ml ~ 60mg/ml。
6、 权利要求 3所述药物组合物， 其特征在于： 所述虎杖苷水溶液中含有 虎杖苷 5mg/ml ~ 60mg/ml 以及羟丙基 β-环糊精或磺丁醚 -β-环糊精 20mg/ml ~ 500mg/mL
7、 权利要求 3所述药物组合物， 其特征在于： 所述虎杖苷水溶液中含有 虎杖苷 5mg/ml - 40mg/ml、 β-环糊精 10mg/ml ~ 60mg/ml 以及葡曱胺 2.5mg/ml ~ 45mg/ml。
8、 权利要求 3所述药物组合物， 其特征在于： 所述虎杖苷水溶液中含有 虎杖苷 5mg/ml ~ 100 mg/ml、 羟丙基 β-环糊精或磺丁醚 -β-环糊精 10mg/ml ~ 300mg/ml以及葡甲胺 2.5mg/ml ~ 1 OOmg/mL
9、权利要求 3 ~ 8所述药物組合物, 其特征在于： 所述虎杖苷水溶液采用 注射用水、 生理盐水或 pH 7.0〜 9.0的缓冲液作为溶剂配制。
10、权利要求 3所述药物组合物， 其特征在于： 所述虎杖苷水溶液是虎杖 苷注射液。
11、权利要求 3所述药物组合物的制备方法： 采用注射用水、 生理盐水或 pH 7.0〜 9.0的缓冲液配制所需浓度的助溶剂葡甲胺和 /或环糊精及所述高浓度 虎杖苷的水溶液， 所得虎杖苷水溶液经无菌和 /或无热源处理后灌装于安飯瓶。
12、权利要求 2所述的药物組合物，其特征在于所述的组合物为冻干药物 制剂，该冻干药物制剂以注射用水或注射用生理盐水配制成水溶液后 ,其水溶 液中的虎杖苷的浓度能够达到 5mg/ml ~ 100mg/ml。
13、 权利要求 12所述药物组合物， 其特征在于所述制剂中含有活性成分 虎杖苷、 助溶剂葡曱胺， 虎杖苷与助溶剂葡甲胺的质量比为 1:1.5〜1:12； 所述 冻干药物制剂以注射用水或注射用生理盐水配制成水溶液后，其虎杖苷浓度为 5mg/ml ~ 15mg/ml。
14、 权利要求 13所述的药物組合物， 其特征在于： 其中虎杖苦与葡曱胺 的质量比为 1 :1.5 1 :3。
15、 权利要求 12所述药物组合物， 其特征在于所述冻干药物制剂中含有 虎杖苷、助溶剂 β-环糊精， 虎杖苷与助溶剂 β-环糊精的质量比为 1:3 ~ 1:12; 所 述冻干药物制剂以注射用水或注射用生理盐水配制成水溶液后，其虎杖苷浓度 达 5mg/ml ~ 20mg/ml。
16、 权利要求 15所述药物组合物， 其特征在于： 其中虎杖苷与助溶剂 β- 环糊精的质量比为 1:3〜 1:8。
17、 权利要求 12所述药物组合物， 其特征在于： 所述冻千药物制剂中含 有虎杖苷、 羟丙基 -β-环糊精或磺丁醚 -β-环糊精， 虎杖苷与羟丙基 -β-环糊精或 磺丁醚 -β-环糊精的质量比为 1:4 ~ 1:60； 该冻干药物制剂以注射用水或注射用 生理盐水配制成水溶液后， 其虎杖苷浓度可达 5mg/ml ~ 60mg/mL
18、 权利要求 17所述药物组合物， 其特征在于： 其中虎杖苷与羟丙基 -β- 环糊精或磺丁醚 -β-环糊精的质量比为 1:4〜 1:8。
19、 权利要求 12所述药物组合物， 其特征在于： 所述冻干制品中含有虎 杖苷、 助溶剂 β-环糊精以及葡曱胺， 虎杖苷与葡曱胺、 β-环糊精的质量比为 1:0.5:1.5-1 :9:12; 该冻干药物制剂以注射用水或注射用生理盐水配制成水溶液 后， 其虎杖苷浓度可达 5mg/ml - 40mg/ml。
20、 权利要求 19所述药物组合物， 其特征在于： 其中虎杖苷与助溶剂葡 甲胺、 β-环糊精的质量比为 1 :0.5:3~1 :2:8。
21、 权利要求 12所述药物组合物， 其特征在于: 所述冻干药物制剂中含 有虎杖苷、羟丙基 -β-环糊精或磺丁醚 -β-环糊精以及葡曱胺， 虎杖苷与葡曱胺、 羟丙基 -β-环糊精或磺丁醚 -β-环糊精的质量比在 1： 0.5： 2〜 1： 20： 60之间； 该 冻干药物制剂以注射用水或注射用生理盐水配制成水溶液后 ,其虎杖苷的浓度 可达 5mg/ml ~ 100mg/ml。
22、 权利要求 21所述药物组合物， 其特征在于: 其中虎杖苷与葡曱胺、 羟丙基 -β-环糊精或璜丁醚 -β-环糊精的质量比为 1： 0.5： 4 ~ 1： 2： 8。
23、 权利要求 12 ~ 22所述药物组合物， 其特征在于： 所述冻干药物制剂 是注射用冻干粉针。
24、 权利要求 12所述药物组合物, 其特征在于： 所述冻干药物制剂中进 一步含有药学上可接受的填充剂。
25、 权利要求 12所述药物组合物的制备方法： 采用注射用水、 生理盐水 或 ρΗ 7.0〜 9.0的緩冲液配制所需浓度的助溶剂葡甲胺和 /或环糊精及所述高浓 度虎杖苷的水溶液， 其中任选加入药学上可接受的填充剂， 所得溶液经超滤法 除热源后， 无菌分装于西林飯， 冷干成型后， 封瓶。
26、 权利要求 1所述药物组合物， 其特征在于： 其水溶液以及用冻干制品 配制的水溶液可以通过口服或静脉注射、静脉滴注、 肌肉注射、 皮下注射以友 局部给药等胃肠外途径给药。
27、 权利要求 1 所述药物组合物在制备预防和 /或治疗心血管疾病的药物 中的应用。
PCT/CN2007/001233 2006-04-28 2007-04-16 Composition pharmaceutique comportant un concentré élevé de polydatine Ceased WO2007124668A1 (fr)

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CN118415904A (zh) * 2024-05-06 2024-08-02 赣州华汉生物科技有限公司 一种包含虎杖苷的稳定组合物及其制备方法

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