WO2020073844A1 - 一种有效成分包含银杏萜内酯的滴丸及其制备方法 - Google Patents

一种有效成分包含银杏萜内酯的滴丸及其制备方法 Download PDF

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Publication number
WO2020073844A1
WO2020073844A1 PCT/CN2019/108918 CN2019108918W WO2020073844A1 WO 2020073844 A1 WO2020073844 A1 WO 2020073844A1 CN 2019108918 W CN2019108918 W CN 2019108918W WO 2020073844 A1 WO2020073844 A1 WO 2020073844A1
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Prior art keywords
filler
ginkgo terpene
lactose
terpene lactone
cellulose
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PCT/CN2019/108918
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English (en)
French (fr)
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陈彦
杨勇
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成都百裕制药股份有限公司
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Priority to EP19871224.2A priority Critical patent/EP3834821A4/en
Priority to KR1020217007958A priority patent/KR102648910B1/ko
Publication of WO2020073844A1 publication Critical patent/WO2020073844A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and in particular relates to a dropping pill containing ginkgo terpene lactone as an effective component and a preparation method thereof.
  • Ginkgo terpene lactones belong to terpenoids, mainly including ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide M, ginkgolide J and ginkgolide, etc.
  • the chemical structure is as follows:
  • ginkgo terpene lactone is a natural PAF receptor antagonist, a powerful and selective antagonist of glycine receptors (GlyRs), and a peripheral benzodiazepine receptor antagonist. Therefore, ginkgo terpene lactones can play a role in the above-mentioned receptor-related diseases, such as dilating coronary blood vessels, improving cerebral circulation, inhibiting platelet aggregation, preventing atherosclerosis, antagonizing the increase of vascular permeability, alleviating bronchoconstriction, etc.
  • Role protects the central nervous system from heart and brain ischemic injury; anti-aging, anti-shock, anti-allergy, antibacterial, anti-inflammatory, anti-tumor, anti-organ transplant rejection, and also has certain damage to liver and kidney damage Efficacy.
  • ginkgo terpene lactone has very broad clinical application prospects.
  • ginkgo terpene lactone is a water-insoluble drug, and the bioavailability of absorption in the body is low, which brings certain difficulties to drug development.
  • Most existing ginkgo terpene lactone preparations are oral preparations and injections. Among them, ordinary oral preparations have limited bioavailability, which affects the clinical efficacy of drugs.
  • the ginkgo terpene lactone dripping pills disclosed in recent years have partially solved the problem of drug solubility, but there is still a technical problem of limited dissolution rate.
  • Chinese patent CN101422456B actually discloses a preparation method and quality detection method of ginkgolide drop pills, which solves the technical problems of preparation of ginkgolide drop pills and identification of effective ingredients, content determination, etc., but it is disclosed from the patent specification Content can not determine whether to solve the problem of drug dissolution rate.
  • Chinese patent CN 106924197A discloses a ginkgolide drop pill and its preparation method. This patent solves the aging phenomenon of dripping pill formulations by optimizing the formulation of dripping pill formulations, but still has the technical problems of limited dissolution rate of active ingredients and low bioavailability.
  • the present invention provides a dropping pill containing ginkgo terpene lactone as an active ingredient and a preparation method thereof.
  • the dropping pill can achieve rapid dissolution and good bioavailability.
  • the present invention provides a dripping pill containing ginkgo terpene lactone as an active ingredient, containing a rigid molecular filler and / or a filler with a porous surface.
  • the ginkgo terpene lactone according to the present invention may be in the form of an extract of ginkgo biloba leaves, or it may be a high-purity monomer compound or a combination thereof.
  • the rigid molecular filler is selected from microcrystalline cellulose, methyl cellulose, ethyl cellulose, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium carbonate, calcium sulfate dihydrate, lactose, mannitol, cellulose One or more of lactose.
  • the bulk density of the microcrystalline cellulose is 0.21 g / cm 3 to 0.42 g / cm 3 .
  • the microcrystalline cellulose is one or more selected from the group consisting of siliconized microcrystalline cellulose SMCC 50, microcrystalline cellulose UF711, and microcrystalline cellulose PH302.
  • the loose and porous filler is selected from one or more of lactose, mannitol and cellulose lactose.
  • the lactose and mannitol are prepared by spray drying method.
  • the dropping pills include the following parts by weight of components: 5-15 parts of ginkgo terpene lactone, 20-40 parts of base, and 1-20 parts of filler.
  • the filler is a rigid molecular filler as defined above and / or a filler with a porous surface.
  • the base is preferably PEGs, polyvinylpyrrolidone, polyoxyethylene stearate, poloxamer, hydrogenated vegetable oil, insect wax, glyceryl monostearate or / and gelatin.
  • the dropping pills of the present invention also include 0.1-4 parts by weight of surfactant.
  • the surfactant is preferably polysorbate-80, lecithin or / and carbomer.
  • the surfactant is more preferably polysorbate-80.
  • the dropping pills of the present invention also include 0.1-2.5 parts by weight of disintegrant.
  • the disintegrant is preferably sodium carboxymethyl cellulose, dry starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone or / and croscarmellose sodium.
  • the disintegrant is more preferably sodium carboxymethyl cellulose.
  • the dropping pill filler is a mixture of microcrystalline cellulose and lactose.
  • the weight ratio of the microcrystalline cellulose to lactose is preferably (4 to 1): (1 to 4).
  • the present invention provides a method for preparing the dropping pills, including the following steps:
  • step b) Mix the matrix and other ingredients, heat to melt, add the fine powder obtained in step a) with stirring, and get the mixture for use;
  • step b) The mixture obtained in step b) is dripped by a dripper, and the condensate is cooled and shaped.
  • the crushing in step a) is airflow impact crushing and / or mechanical shear crushing.
  • gas pressure of the impact crushing of the air flow is 0.5-0.8 MPa.
  • the ginkgo terpene lactone and the filler are crushed together, which is more conducive to the rapid dissolution of ginkgo terpene lactone.
  • the beneficial technical effects of the present invention the dropping pills disclosed by the present invention have a rapid dissolution rate of the active ingredient ginkgo terpene lactone; animal test results show that the active ingredients of the dropping pills disclosed by the present invention can be Quickly enter the bloodstream, so that the effect can be played faster and the therapeutic effect can be achieved.
  • Figure 1 is the dissolution curve of ginkgo terpene lactone (pH1.0);
  • Figure 2 is the dissolution curve of ginkgo terpene lactone (pH2.5);
  • Figure 3 is the time curve of ginkgo terpene lactone (rabbit).
  • the raw materials and equipment mentioned in the specific embodiments of the present invention are known products and can be obtained by purchasing commercially available products.
  • the dripping pills of the present invention solve the problems of the prior art through the selection of auxiliary materials such as fillers.
  • the dissolution rate of ginkgo terpene lactone is significantly accelerated.
  • Subsequent animal experiments further confirmed that the dripping pills prepared with the above ginkgo terpene lactone are more conventional
  • the ginkgo terpene lactone dropping pills obtained by the preparation formula and the preparation method reach the highest blood drug concentration faster, that is, the Tmax is earlier.
  • the inventors observed that the above-mentioned beneficial effects also exist in the dripping pill formulation in which the active ingredient contains ginkgo terpene lactone and one or more other active ingredients.
  • the examples of the present invention only list the dissolution curve and drug-time curve of the ginkgo terpene lactone-containing dripping pill formulation and its active ingredient ginkgo terpene lactone. It should not be understood that the active ingredient of the dropping pills according to the present invention contains only ginkgo terpene lactone. It should be understood that the active ingredient of the dropping pills of the present invention contains at least ginkgo terpene lactone.
  • the ginkgo terpene lactone in the present invention may be an extract of ginkgo biloba leaves, or a high-purity monomer compound or a combination thereof.
  • the ginkgo terpene lactone of the present invention can be separated and purified by the prior art. Further, it can be solvent extraction method, column extraction method, solvent extraction-column extraction method, supercritical extraction method, chromatography or column chromatography purification method, etc. .
  • the ginkgo terpene lactone of the present invention is obtained by the method disclosed in WO2013159412A1.
  • the ginkgo terpene lactone of the present invention can also be obtained through commercial purchase.
  • Filler also known as diluent, is mainly used to increase the weight and volume of tablets in the prior art, and is an auxiliary material that is beneficial to molding and dosage.
  • Commonly used fillers for solid preparations include starch, compressible starch, powdered sugar, lactose, microcrystalline cellulose, inorganic salts, absorbents, sugar alcohols and the like.
  • bulk density is also called “bulk density”, and in micronology, refers to the mass per unit volume.
  • the filler in the present invention refers to a filler having a rigid molecular structure.
  • it may be one of microcrystalline cellulose, methyl cellulose, ethyl cellulose, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium carbonate, calcium sulfate dihydrate, lactose, mannitol, cellulose lactose Or more.
  • the bulk density of the microcrystalline cellulose is 0.21 g / cm 3 to 0.42 g / cm 3 , and it is preferably selected from one of siliconized microcrystalline cellulose SMCC 50, microcrystalline cellulose UF711, and microcrystalline cellulose PH302 or Two or more.
  • the filler according to the present invention also refers to a filler having a structure with a porous surface.
  • it may be one or more of lactose, mannitol and cellulose lactose.
  • lactose, mannitol and cellulose lactose with loose and porous fillers described in the present invention can be purchased through commercial products, or according to It can be prepared by prior art, such as lactose and mannitol prepared by spray drying method. Ginkgo terpene lactone itself is hard to dissolve in water, disperse it on the loose and porous surface of the filler.
  • the filler dissolves quickly, leaving the ginkgo terpene lactone with a very high degree of dispersion, which is The beneficial effect of increasing the dissolution rate of ginkgo terpene lactone.
  • the present invention found that the use of a mixture of microcrystalline cellulose and lactose in a ratio of (4 to 1): (1 to 4) as a filler can achieve the fastest in vitro dissolution rate of ginkgo lactone and the smallest Tmax.
  • Microcrystalline cellulose bulk density is based on Asahi Kasei Chemicals Corporation (UF711, UF702, PH series) and JRS (J. RETTENMAIER & GROUP) (silicified microcrystalline cellulose SMCC 50) as an example.
  • the filler of the present invention may be microcrystalline cellulose UF711 (bulk density 0.22g / cm 3 ) (Example 7), microcrystalline cellulose UF702 (bulk density 0.29g / cm 3 ) ( Prescription 2), microcrystalline cellulose PH101 (bulk density 0.29g / cm 3 ) (prescription 3), microcrystalline cellulose PH103 (bulk density 0.31g / cm 3 ) (prescription 4), microcrystalline cellulose PH-F20JP ( Bulk density 0.23g / cm 3 ) (prescription 5), microcrystalline cellulose PH302 (bulk density 0.42g / cm 3 ) (Example 1), silicified microcrystalline cellulose SMCC 50 (bulk density 025-0.37g / cm 3 ) (Example 5), microcrystalline cellulose KG802 (bulk density 0.21g / cm 3 ) (prescription 3) and other fillers with a rigid molecular structure, may also be lactose (Exa
  • the inorganic salt with a molecular structure may also be other fillers such as cellulose lactose (prescription 1, prescription 2) which have both a rigid molecular structure and a porous surface. In a specific embodiment, it may also be a combination of one or more fillers (such as Example 7, Example 8, and Example 9).
  • the dropping pills according to the present invention also contain a matrix, such as PEGs, polyvinylpyrrolidone (PVP), polyoxyethylene stearate, poloxamer, hydrogenated vegetable oil, insect wax, glyceryl monostearate or gelatin, etc. .
  • a matrix such as PEGs, polyvinylpyrrolidone (PVP), polyoxyethylene stearate, poloxamer, hydrogenated vegetable oil, insect wax, glyceryl monostearate or gelatin, etc.
  • the dropping pills according to the present invention may also contain surfactants, such as polysorbate-80, lecithin, or carbomer.
  • the dropping pills according to the present invention may also contain disintegrants, such as sodium carboxymethyl cellulose (CMC-Na), dry starch, low-substituted hydroxypropyl cellulose (L-HPC), cross-linked polyvinylpyrrolidone ( Crosslinked PVP), croscarmellose sodium (CCNa), etc.
  • disintegrants such as sodium carboxymethyl cellulose (CMC-Na), dry starch, low-substituted hydroxypropyl cellulose (L-HPC), cross-linked polyvinylpyrrolidone ( Crosslinked PVP), croscarmellose sodium (CCNa), etc.
  • the condensed liquid may be an aqueous condensate, such as water, ethanol with different concentrations, etc., or an oily condensate, such as liquid paraffin Methyl silicone oil, vegetable oil, gasoline or mixtures thereof.
  • Examples of prescriptions for dripping pills that are equivalent to or close to the technical effects of Examples 1-9 (dissolution rate in vitro or Tmax value).
  • the specific model of microcrystalline cellulose is the product model of Asahi Kasei Chemicals Corporation (UF711, UF702, PH series) as an example.
  • microcrystalline cellulose PH-302 and UF711 in the following Examples 1-9 were purchased from Asahi Kasei Chemicals Corporation.
  • the bulk density was 0.42 g / cm 3 and 0.22 g / cm 3
  • the silicified microcrystalline cellulose was JRS (J. RETTENMAIER & GROUP) product SMCC 50, bulk density is 0.25-0.37g / cm 3 .
  • Preparation process Pass the ginkgo terpene lactone through a 60 mesh sieve and other auxiliary materials through a 100 mesh sieve and set aside; take 1 kg of ginkgo terpene lactone and mix with 1 kg of microcrystalline cellulose PH302 in a tank mixer for 10 minutes, and pass the mixture through the airflow Pulverizer, the air pressure is set to 0.5MPa, to prepare a fine powder with d90 less than 20 ⁇ m; take 3kg polyethylene glycol 4000 and 0.2kg polysorbate-80, heat to melt at 80 °C, and slowly add the previously prepared fine powder under stirring Powder; then the whole mixture was dripped with a 2.4mm dripper, and cooled and shaped in liquid paraffin at 15 ° C to obtain 100,000 dripping pills, 52mg per pill.
  • the ginkgo terpene lactone and the filler microcrystalline cellulose are crushed together, and the particle size of the raw material is reduced by crushing, which is beneficial to the rapid dissolution of the ginkgo terpene lactone.
  • the lactose in the prescription of this example is prepared by spray drying.
  • Preparation process pass the ginkgo terpene lactone through a 60 mesh sieve, and other auxiliary materials through a 100 mesh sieve, and set aside; pass the ginkgo terpene lactone through a jet mill, the air pressure is set to 0.5MPa, and prepare a fine powder with d90 less than 50 ⁇ m; take 1kg ginkgo Terpene lactone fine powder is mixed evenly with 1kg of lactose, and the two are fully contacted; take 3kg polyethylene glycol 6000 and 0.2kg polysorbate-80, heat to melt at 80 °C, slowly add the previously prepared fines under stirring Powder; then the whole mixture was dripped with a 2.4mm dripper, and cooled and shaped in liquid paraffin at 15 ° C to obtain 100,000 dripping pills, 52mg per pill.
  • Preparation process Pass the ginkgo terpene lactone through a 60 mesh sieve and other auxiliary materials through a 100 mesh sieve for standby; take 0.5kg ginkgo terpene lactone and mix with 1kg methyl cellulose in a trough mixer for 10 minutes, and pass the mixture through the airflow Pulverizer, the air pressure is set to 0.6MPa, and a fine powder with a d90 of less than 20 ⁇ m is prepared; add 0.2kg polyethylene glycol 400 to the mixture, mix well, and make the two fully contact; take 3kg polyethylene glycol 4000 and 0.2kg Polysorbate-80, heated to melt at 80 °C, slowly add the previously prepared fine powder under stirring; then the whole mixture was dripped with a 2.4mm dripper, and cooled and formed in dimethyl silicone oil 100 # at 15 °C to prepare 50,000 drops of pills, 98mg per pill.
  • Preparation process Pass the ginkgo terpene lactone through a 60 mesh sieve and other auxiliary materials through a 100 mesh sieve and set aside; take 15kg ginkgo terpene lactone and mix with 0.6kg calcium hydrogen phosphate in a trough mixer for 10 minutes, and crush the mixture by air flow Machine, the air pressure is set to 0.8MPa, and a fine powder with a d90 of less than 20 ⁇ m is prepared; 0.2kg polysorbate-80 is added to the mixture to mix evenly, and the two are fully contacted; take 3kg polyethylene glycol 4000 and heat to 80 °C to Melt and slowly add the previously prepared fine powder under stirring; then the whole mixture is dripped with a 2.2mm dripper, and cooled and shaped in 15 ° C dimethicone 100 # to produce 150,000 dropping pills, 125.3mg per pill .
  • Preparation process Ginkgo terpene lactone is passed through a 60 mesh sieve, other auxiliary materials are passed through a 100 mesh sieve, and used; 1kg of ginkgo terpene lactone is mixed with 0.5kg siliconized microcrystalline cellulose SMCC 50 and 0.1kg methyl cellulose in a trough Mix in the machine for 10 minutes, pass the mixture through a jet mill, the air pressure is set to 0.5MPa, and prepare a fine powder with d90 less than 20 ⁇ m; add 0.2kg of polyethylene glycol 400 to the mixture to mix evenly and make the two fully contact; 3kg polyethylene glycol 4000, 0.1kg hypromellose K4 and 0.2kg polysorbate-80, heated to melt at 80 °C, slowly add the previously prepared fine powder under stirring; then the whole mixture was dropped through 2.4mm It was prepared by head-dropping, and cooled and shaped in liquid paraffin at 15 ° C to obtain 100,000 dropping pills, each with 51mg.
  • the mannitol in the prescription of this example is prepared by spray drying.
  • Preparation process pass the ginkgo terpene lactone through a 60 mesh sieve, and other auxiliary materials through a 100 mesh sieve, and set aside; crush the ginkgo terpene lactone through a universal crusher to prepare a fine powder with d90 less than 50 ⁇ m; take 1 kg of ginkgo terpene lactone fine powder Mix well with 1kg of mannitol and make the two fully contact; take 3kg of polyethylene glycol 6000 and 0.2kg of lecithin, heat to melt at 80 ° C, and slowly add the previously prepared fine powder under stirring; 2.4mm dripper is made by dripping, cooling and forming in 15 °C liquid paraffin, 100,000 dripping pills are prepared, 52mg per pill.
  • Preparation process Pass the ginkgo terpene lactone through a 60 mesh sieve, and other auxiliary materials through a 100 mesh sieve, and set aside; crush ginkgo terpene lactone, 0.8 kg microcrystalline cellulose UF711, and 0.2 kg calcium hydrogen phosphate through a universal crusher to obtain d90 fine powder less than 50 ⁇ m; take 2.8kg polyethylene glycol 4000 and 0.4kg polyethylene glycol 6000, heat to melt at 80 °C, slowly add the previously prepared fine powder under stirring; then drop the whole mixture through 2.4mm It was prepared by head-dropping, and cooled and shaped in liquid paraffin at 15 ° C to obtain 100,000 dropping pills, 52 mg per pill.
  • Preparation process Pass the ginkgo terpene lactone through a 60 mesh sieve, and other auxiliary materials through a 100 mesh sieve, and set aside; take 1 kg of ginkgo terpene lactone and mix with 0.6 kg of microcrystalline cellulose PH302 in a tank mixer for 10 minutes, and pass the mixture through Air pulverizer, the air pressure is set to 0.5MPa, to prepare a fine powder with d90 less than 20 ⁇ m; take the fine powder and 0.4kg lactose to mix evenly, and make the two fully contact; take 2.8kg polyethylene glycol 4000, and heat to 80 °C Melt and slowly add the previously prepared fine powder under stirring; then the whole mixture is dropped through a 2.4mm dripper, cooled and shaped in 15 ° C liquid paraffin to produce 100,000 dropping pills, 48mg per pill.
  • Preparation process Pass the ginkgo terpene lactone through a 60 mesh sieve and other auxiliary materials through a 100 mesh sieve for standby; take 1kg of ginkgo terpene lactone and mix with 0.4kg of microcrystalline cellulose PH302 in a trough mixer for 10 minutes, and pass the mixture through Jet mill, the air pressure is set to 0.5MPa, to prepare a fine powder with d90 less than 20 ⁇ m; take the fine powder and 0.6kg of lactose to mix evenly, and make the two fully contact; take 2.7kg polyethylene glycol 4000, heat at 80 °C to Melt, slowly add the previously prepared fine powder, 0.1kg polysorbate-80 and 0.2kg CMC-Na under stirring; after fully stirring, the whole mixture is dripped with a 2.4mm dripper and liquid at 15 ° C It is cooled and molded in paraffin to obtain 100,000 pills, 50mg per pill.
  • Preparation process Pass the ginkgo terpene lactone through a 60-mesh sieve, and other auxiliary materials through a 100-mesh sieve, set aside; take 3kg polyethylene glycol 4000 and 1kg polyethylene glycol 6000, heat to melt at 80 °C, slowly add ginkgo under stirring Terpene lactone fine powder; then the whole mixture was dripped with a 2.4mm dripper, cooled and formed in liquid paraffin at 15 ° C, and 100,000 dripping pills were prepared, each with 51mg.
  • the detection method is HPLC detection of "2010 Edition Pharmacopoeia”.
  • the content of each ginkgolide A, B, C and ginkgolide is 2.5mg, 1.0mg, 1.5mg, 5.0mg, respectively.
  • Example 1 ginkgo terpene lactone dripping pills, in vitro dissolution test in pH1.0 hydrochloric acid solution (intragastric pH before meals), respectively at 3min, 6min, 10min, 15min, Samples were taken at 20min, 25min and 30min, and the dissolution curve was measured. The results are shown in Table 1 and Figure 1.
  • the dissolution amount is calculated as the percentage of the total amount of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide M, ginkgolide J and ginkgolide.
  • the above test results indicate that the ginkgo terpene lactone drop pills prepared in the examples of the present invention are prepared by the conventional formula and method (Comparative Example 1, Example 4 of patent CN 106924197A) in the in vitro dissolution test.
  • the pills dissolve faster.
  • the in vitro dissolution rate of the ginkgo terpene lactone dripping pills prepared in Example 8 and Example 9 using two fillers (microcrystalline cellulose + lactose) is significantly faster than that in Example 2, Example 4, and Example 6, Exceeded the inventor's expectations.
  • Plasma samples were directly collected into EDTA-Monovette blood collection tubes (Sust), and centrifuged to prepare plasma. Take 30 ⁇ L of plasma, add 500 ⁇ L of tetrahydrofuran, 30 ⁇ Ll.S. solution (180 ng / mL) and 50 ⁇ L of 2M hydrochloric acid and mix well. The reaction mixture was vortexed for 20 seconds, and then centrifuged at 3700 g for 10 minutes. Transfer 830 ⁇ L of supernatant to Extraction column. Thereafter, the compound was extracted with 6 mL of methyl tert-butyl ether and evaporated to dryness with nitrogen.
  • the centrifuged precipitate was added to a 50/50 methanol / water (0.1% formic acid) mixed solution and vortexed, and then placed in an ultrasonic generator for 15 minutes; then it was centrifuged again at 3700 g for 10 minutes. The supernatant was transferred to an HPLC sample tube and analyzed.
  • the drug time curve is based on the blood concentration of bilobalide (the highest content). The results are shown in Table 3, Table 4 and Figure 3.
  • Peak concentration (Cmax) and time to peak (Tmax) refer to the highest concentration value and appearance time of the drug in plasma after extravascular administration, respectively representing the degree and speed of drug absorption.
  • the above test results indicate that the ginkgo terpene lactone dripping pills prepared in the examples of the present invention are prepared in animal experiments by a more conventional formula and method (Comparative Example 1, ie, CN Patent No. 106924197A Example 4).
  • the highest blood drug concentration is reached faster, the peak time Tmax is earlier, and the peak concentration Cmax value is higher. Therefore, the active ingredient of the ginkgo terpene lactone dropping pills disclosed in the present invention is easier to absorb and can exert the drug effect faster.
  • Example 9 Compared with Example 1 and Example 2, the ginkgo terpene lactone dripping pills prepared with Examples 8 and 9 using two fillers (microcrystalline cellulose + lactose) had significantly earlier Tmax values than the inventors expected.
  • the Cmax value of Example 9 is significantly higher than that of Example 1, Example 2 and Example 8, which is the most preferred example.
  • the present invention provides a ginkgo terpene lactone dripping pill preparation and a preparation method thereof.
  • the preparation can dissolve faster and enter the bloodstream in vivo and outside, and can achieve a therapeutic effect faster.

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Abstract

一种包含银杏萜内酯的滴丸及其制备方法，所述滴丸包含银杏萜内酯、基质、具有刚性分子结构的填充剂、和/或表面疏松多孔的填充剂。

Description

一种有效成分包含银杏萜内酯的滴丸及其制备方法
交叉引用
本申请要求在2018年10月8日提交中国专利局、申请号为201811165409.3、发明名称为“一种有效成分包含银杏萜内酯的滴丸及其制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于药物制剂领域，具体涉及一种有效成分包含银杏萜内酯的滴丸及其制备方法。
背景技术
银杏萜内酯属于萜类化合物，主要包含银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯M、银杏内酯J及白果内酯等，其化学结构如下所示：
Figure PCTCN2019108918-appb-000001
药理研究结果显示，银杏萜内酯是人天然的PAF受体拮抗剂，是甘氨酸受体(GlyRs)的强力和选择性拮抗剂，还是外周苯二氮卓受体拮抗剂。因此，银杏萜内酯可在上述受体相关的疾病中发挥功效，起到扩张冠状血管、改善脑循环、抑制血小板聚集、防止动脉粥样硬化、拮抗血管通透性增加、缓解支气管收缩等药理作用；对心、脑缺血损伤，中枢神经系统具有保护作用；可抗衰老、抗休克、抗过敏、抗菌抗炎、抗肿瘤、抗器官移植中的排斥反应，同时对肝、肾损伤也有一定的疗效。
综上所述，银杏萜内酯具有非常广阔的临床应用前景。但是银杏萜内酯为水难溶性药物，体内吸收生物利用度低，给药物开发带来一定难度。现有银杏萜内酯制剂以口服制剂和注射剂居多。其中，普通的口服制剂生物利用度有限，影响药物临床疗效。近年 来公开的银杏萜内酯滴丸剂部分解决了药物溶解度的问题，但是依然存在溶解速度有限的技术问题。比如中国专利CN 101422456B实际公开了一种银杏内酯滴丸的制备方法和质量检测方法，解决了银杏内酯滴丸的制备和有效成分的鉴别、含量测定等技术问题，但是从该专利说明书公开的内容无法确定是否解决了药物溶出速度的问题。再比如中国专利CN 106924197A公开了一种银杏内酯滴丸及其制备方法。该专利通过优化滴丸制剂配方，解决了滴丸制剂老化现象，但是依然存在活性成分溶出速度有限、生物利用度不高的技术问题。
同时因为滴丸制剂配方具有独特性，因此存在根据银杏萜内酯本身的特性研究其辅料配伍及制备方法的需要。
发明内容
为解决上述技术问题，本发明提供一种有效成分包含银杏萜内酯的滴丸及其制备方法，该滴丸能达到快速溶出，生物利用度好的效果。
本发明解决上述技术问题所采用的技术方案：
一方面，本发明提供一种有效成分包含银杏萜内酯的滴丸，包含刚性分子填充剂和/或表面疏松多孔的填充剂。
本发明所述的银杏萜内酯，可以是银杏叶提取物的形式，也可是纯度高的单体化合物或其组合物。
进一步地，所述刚性分子填充剂选自微晶纤维素、甲基纤维素、乙基纤维素、磷酸氢钙、磷酸二氢钙、碳酸钙、二水硫酸钙、乳糖、甘露醇、纤维素乳糖中的一种或两种以上。
进一步地，所述微晶纤维素松密度为0.21g/cm 3～0.42g/cm 3。
在具体的实施方式中，所述微晶纤维素选自硅化微晶纤维素SMCC 50、微晶纤维素UF711、微晶纤维素PH302中的一种或两种以上。
进一步地，所述表面疏松多孔的填充剂选自乳糖、甘露醇、纤维素乳糖中的一种或两种以上。
优选地，所述乳糖、甘露醇通过喷雾干燥法制备得到。
进一步地，所述滴丸包含下述重量份的组分：银杏萜内酯5-15份，基质20-40份，填充剂1-20份。
所述填充剂为上文定义的刚性分子填充剂和/或表面疏松多孔的填充剂。
所述基质优选PEG类、聚乙烯吡咯烷酮、聚氧乙烯硬脂酸酯、泊洛沙姆、氢化植物油、虫蜡、单硬脂酸甘油酯或/和明胶。
本发明所述滴丸还包括表面活性剂0.1-4份重量份。
所述表面活性剂优选聚山梨酯-80、卵磷脂或/和卡波姆。
所述表面活性剂更优选聚山梨酯-80。
本发明所述滴丸还包括0.1-2.5重量份的崩解剂。
所述崩解剂优选羧甲基纤维素钠、干淀粉、低取代基羟丙基纤维素、交联聚乙烯吡咯烷酮或/和交联羧甲基纤维素钠。
所述崩解剂更优选羧甲基纤维素钠。
进一步地，所述滴丸填充剂为微晶纤维素和乳糖的混合物。
更进一步地，所述微晶纤维素与乳糖的重量比优选为(4～1)∶(1～4)。
另一方面，本发明提供一种所述滴丸的制备方法，包括如下步骤：
a)将银杏萜内酯与填充剂共同破碎或混合；
b)将基质和其他成分混合，加热至熔融，搅拌加入步骤a)所得细粉，得混合物备用；
c)步骤b)所得混合物经滴头滴制、冷凝液冷却成型。
进一步地，步骤a)所述破碎为气流冲击粉碎和/或机械剪切破碎。
更进一步地，所述气流冲击粉碎的气压为0.5-0.8MPa。
本发明工艺中，将银杏萜内酯与填充剂共同破碎，更有利于银杏萜内酯的快速溶出。与现有技术相比，本发明的有益技术效果：本发明公开的滴丸其有效成分银杏萜内酯溶出速度快；动物试验结果表明，本发明公开的滴丸的有效成分银杏萜内酯能快速进入血液，从而能够更快发挥疗效，达到治疗效果。
附图说明
图1为银杏萜内酯溶出曲线(pH1.0)；
图2为银杏萜内酯溶出曲线(pH2.5)；
图3为银杏萜内酯药时曲线(家兔)。
具体实施方式
除非特别注明，本发明具体实施例方式中述及的原辅料、设备均为已知产品，均可 通过购买市售产品获得。
本发明的滴丸通过对填充剂等辅料选择，解决了现有技术的问题，银杏萜内酯的溶出速度明显加快，后续动物试验进一步证实，用上述银杏萜内酯制备得到的滴丸剂较常规制剂配方、制备方法得到的银杏萜内酯滴丸剂更快达到最高血药浓度，即Tmax更早。发明人观察到上述有益效果同样存在于有效成分包含银杏萜内酯和一种或多种其他有效成分的滴丸制剂中。
为了简明、直观地说明上述有益效果，本发明实施例中仅列出了有效成分包含银杏萜内酯的滴丸制剂及其有效成分银杏萜内酯的溶出曲线和药时曲线。不应理解为本发明所述滴丸的有效成分仅仅包含银杏萜内酯。应理解为，本发明所述滴丸的有效成分至少包含银杏萜内酯。
本发明所述银杏萜内酯可以是银杏叶提取物，也可以是纯度高的单体化合物或其组合物。
本发明所述银杏萜内酯可以通过现有技术分离纯化得到，进一步的，可以是溶剂萃取法、柱提取法、溶剂萃取-柱提取法、超临界提取法及色谱或柱层析纯化法等。优选地，本发明所述银杏萜内酯通过WO2013159412A1公开的方法得到。
本发明所述银杏萜内酯也可以通过市售购买的方式得到。
填充剂，又称稀释剂，现有技术中主要用以增加片剂的重量与体积，是利于成型和分剂量的辅料。固体制剂的常用填充剂包括淀粉、可压性淀粉、糖粉、乳糖、微晶纤维素、无机盐类、吸收剂、糖醇类等。
如本发明所用，术语“松密度”又称“堆密度”，在微粉学中，指单位容积的质量。
本发明所述的填充剂，指具有刚性分子结构的填充剂。任选地，可以是微晶纤维素、甲基纤维素、乙基纤维素、磷酸氢钙、磷酸二氢钙、碳酸钙、二水硫酸钙、乳糖、甘露醇、纤维素乳糖中的一种或多种。具体地，所述微晶纤维素松密度为0.21g/cm 3～0.42g/cm 3，优选自硅化微晶纤维素SMCC 50、微晶纤维素UF711、微晶纤维素PH302中的一种或两种以上。
本发明所述的填充剂，还指具备表面疏松多孔的结构的填充剂。任选地，可以是乳糖、甘露醇、纤维素乳糖中的一种或多种本发明所述的具备疏松多孔的填充剂乳糖、甘露醇、纤维素乳糖可通过购买市售产品，也可以根据现有技术制备得到，比如喷雾干燥法制得的乳糖、甘露醇。银杏萜内酯本身难溶于水，将其分散在填充剂疏松多孔的表面， 当药物制剂接触(消化液)之后，填充剂迅速溶解，留下分散度极高的银杏萜内酯，进而实现提高银杏萜内酯的溶解速度的有益效果。
本发明发现采用微晶纤维素与乳糖以(4～1)∶(1～4)比例的混合物作为填充剂，能使银杏内酯的体外溶出速度达到最快、Tmax值最小。
微晶纤维素松密度以旭化成株式会社(Asahi Kasei Chemicals Corporation)(UF711、UF702、PH系列)和JRS公司(J.RETTENMAIER &
Figure PCTCN2019108918-appb-000002
GROUP)(硅化微晶纤维素SMCC 50)的产品为例。在具体实施方式中，本发明所述的填充剂可以是微晶纤维素UF711(松密度0.22g/cm 3)(实施例7)、微晶纤维素UF702(松密度0.29g/cm 3)(处方2)、微晶纤维素PH101(松密度0.29g/cm 3)(处方3)、微晶纤维素PH103(松密度0.31g/cm 3)(处方4)、微晶纤维素PH-F20JP(松密度0.23g/cm 3)(处方5)、微晶纤维素PH302(松密度0.42g/cm 3)(实施例1)、硅化微晶纤维素SMCC 50(松密度025-0.37g/cm 3)(实施例5)、微晶纤维素KG802(松密度0.21g/cm 3)(处方3)等具有刚性分子结构的填充剂，还可以是乳糖(实施例2、实施例8等)、甘露醇(实施例6)等具有疏松多孔表面的填充剂，还可以是磷酸氢钙(实施例4)、磷酸二氢钙、碳酸钙(处方4)、二水硫酸钙(处方5)等具有刚性分子结构的无机盐类，还可以是纤维素乳糖(处方1、处方2)等同时具有刚性分子结构和疏松多孔表面的其他填充剂。在具体的实施例中，也可以是上述一种或多种填充剂的组合(如实施例7、实施例8、实施例9)。
本发明所述的滴丸还包含基质，比如PEG类、聚乙烯吡咯烷酮(PVP)、聚氧乙烯硬脂酸酯、泊洛沙姆、氢化植物油、虫蜡、单硬脂酸甘油酯或明胶等。
本发明所述的滴丸还可以包含表面活性剂，比如聚山梨酯-80、卵磷脂或卡波姆等。
本发明所述的滴丸还可以包含崩解剂，比如羧甲基纤维素钠(CMC-Na)、干淀粉、低取代基羟丙基纤维素(L-HPC)、交联聚乙烯吡咯烷酮(交联PVP)、交联羧甲基纤维素钠(CCNa)等。
本发明所述的有效成分包含银杏萜内酯的滴丸的制备方法，其中，冷凝液体可以是水性冷凝液，比如水、不同浓度的乙醇等，也可以是油性冷凝液，比如液体石蜡、二甲基硅油、植物油、汽油或其混合物等。
与实施例1-9技术效果(体外溶出速度或Tmax值)相当或接近的滴丸处方举例。微晶纤维素具体型号以旭化成株式会社(Asahi Kasei Chemicals Corporation)(UF711、UF702、PH系列)的产品型号为例。
处方1：
Figure PCTCN2019108918-appb-000003
处方2：
Figure PCTCN2019108918-appb-000004
处方3
Figure PCTCN2019108918-appb-000005
处方4
Figure PCTCN2019108918-appb-000006
处方5
Figure PCTCN2019108918-appb-000007
处方6
Figure PCTCN2019108918-appb-000008
Figure PCTCN2019108918-appb-000009
处方7
Figure PCTCN2019108918-appb-000010
处方8
Figure PCTCN2019108918-appb-000011
以下通过较佳实施例对本发明的上述内容作进一步说明。但不应将此理解为本发明上述主题的范围仅限于以下具体实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
如未特别说明，以下实施例中使用的原料、设备均为已知产品，通过购买市售产品的方式获得。以下实施例1-9中的微晶纤维素PH-302、UF711购买自旭化成株式会社(Asahi Kasei Chemicals Corporation)，松密度为0.42g/cm 3、0.22g/cm 3，硅化微晶纤维素为JRS公司(J.RETTENMAIER &
Figure PCTCN2019108918-appb-000012
GROUP)的产品SMCC 50型，松密度为0.25-0.37g/cm 3。
实施例1
处方：
Figure PCTCN2019108918-appb-000013
制备工艺：将银杏萜内酯过60目筛，其他辅料过100目筛，备用；取1kg银杏萜内酯，与1kg微晶纤维素PH302在槽型混合机中混合10分钟，将混合物通过气流粉碎机，气压设为0.5MPa，制得d90小于20μm的细粉；取3kg聚乙二醇4000 与0.2kg聚山梨酯-80，80℃加热至熔融，慢慢在搅拌下加入之前制备的细粉；再将全部混合物经2.4mm滴头滴制，在15℃液态石蜡中冷却成型，制得10万粒滴丸，每丸52mg。
在本实施例制备工艺中，将银杏萜内酯与填充剂微晶纤维素共同破碎，通过破碎，减小原料粒径，有利于银杏萜内酯的快速溶出。
实施例2
处方：
Figure PCTCN2019108918-appb-000014
本实施例处方中的乳糖通过喷雾干燥法制得。
制备工艺：将银杏萜内酯过60目筛，其他辅料过100目筛，备用；将银杏萜内酯通过气流粉碎机，气压设为0.5MPa，制得d90小于50μm的细粉；取1kg银杏萜内酯细粉与1kg乳糖混合均匀，并使二者充分接触；取3kg聚乙二醇6000与0.2kg聚山梨酯-80，80℃加热至熔融，慢慢在搅拌下加入之前制备的细粉；再将全部混合物经2.4mm滴头滴制，在15℃液态石蜡中冷却成型，制得10万粒滴丸，每丸52mg。
实施例3
处方：
Figure PCTCN2019108918-appb-000015
制备工艺：将银杏萜内酯过60目筛，其他辅料过100目筛，备用；取0.5kg银杏萜内酯，与1kg甲基纤维素在槽型混合机中混合10分钟，将混合物通过气流粉碎机，气压设为0.6MPa，制得d90小于20μm的细粉；向混合物中加入0.2kg聚乙二醇400，混合均匀，并使二者充分接触；取3kg聚乙二醇4000与0.2kg聚山梨酯-80，80℃加热至熔融，慢慢在搅拌下加入之前制备的细粉；再将全部混合物经2.4mm滴头滴制，在15℃二甲硅油100#中冷却成型，制得5万粒滴丸，每丸98mg。
实施例4
处方：
Figure PCTCN2019108918-appb-000016
制备工艺：将银杏萜内酯过60目筛，其他辅料过100目筛，备用；取15kg银杏萜内酯，与0.6kg磷酸氢钙在槽型混合机中混合10分钟，将混合物通过气流粉碎机，气压设为0.8MPa，制得d90小于20μm的细粉；向混合物中加入0.2kg聚山梨酯-80混合均匀，并使二者充分接触；取3kg聚乙二醇4000，80℃加热至熔融，慢慢在搅拌下加入之前制备的细粉；再将全部混合物经2.2mm滴头滴制，在15℃二甲硅油100#中冷却成型，制得15万粒滴丸，每丸125.3mg。
实施例5
处方：
Figure PCTCN2019108918-appb-000017
制备工艺：将银杏萜内酯过60目筛，其他辅料过100目筛，备用；取1kg银杏萜内酯，与0.5kg硅化微晶纤维素SMCC 50、0.1kg甲基纤维素在槽型混合机中混合10分钟，将混合物通过气流粉碎机，气压设为0.5MPa，制得d90小于20μm的细粉；向混合物中加入0.2kg聚乙二醇400混合均匀，并使二者充分接触；取3kg聚乙二醇4000、0.1kg羟丙甲纤维素K4与0.2kg聚山梨酯-80，80℃加热至熔融，慢慢在搅拌下加入之前制备的细粉；再将全部混合物经2.4mm滴头滴制，在15℃液态石蜡中冷却成型，制得10万粒滴丸，每丸51mg。
实施例6
处方：
Figure PCTCN2019108918-appb-000018
Figure PCTCN2019108918-appb-000019
本实施例处方中的甘露醇通过喷雾干燥法制得。
制备工艺：将银杏萜内酯过60目筛，其他辅料过100目筛，备用；将银杏萜内酯通过万能粉碎机破碎，制得d90小于50μm的细粉；取1kg银杏萜内酯细粉与1kg甘露醇混合均匀，并使二者充分接触；取3kg聚乙二醇6000与0.2kg卵磷脂，80℃加热至熔融，慢慢在搅拌下加入之前制备的细粉；再将全部混合物经2.4mm滴头滴制，在15℃液态石蜡中冷却成型，制得10万粒滴丸，每丸52mg。
实施例7
处方：
Figure PCTCN2019108918-appb-000020
制备工艺：将银杏萜内酯过60目筛，其他辅料过100目筛，备用；将银杏萜内酯，与0.8kg微晶纤维素UF711、0.2kg磷酸氢钙通过万能粉碎机破碎，制得d90小于50μm的细粉；取2.8kg聚乙二醇4000与0.4kg聚乙二醇6000，80℃加热至熔融，慢慢在搅拌下加入之前制备的细粉；再将全部混合物经2.4mm滴头滴制，在15℃液态石蜡中冷却成型，制得10万粒滴丸，每丸52mg。
实施例8
处方：
Figure PCTCN2019108918-appb-000021
制备工艺：将银杏萜内酯过60目筛，其他辅料过100目筛，备用；取1kg银杏萜内酯，与0.6kg微晶纤维素PH302在槽型混合机中混合10分钟，将混合物通过气流粉碎机，气压设为0.5MPa，制得d90小于20μm的细粉；取该细粉与0.4kg乳糖混合均匀，并使二者充分接触；取2.8kg聚乙二醇4000，80℃加热至熔融，慢慢在搅拌下加入之前制备的细粉；再将全部混合物经2.4mm滴头滴制，在15℃液态石蜡中冷却成型，制得10万粒滴丸，每丸48mg。
实施例9
处方：
Figure PCTCN2019108918-appb-000022
制备工艺：将银杏萜内酯过60目筛，其他辅料过100目筛，备用；取1kg银杏萜内酯，与0.4kg微晶纤维素PH302在槽型混合机中混合10分钟，将混合物通过气流粉碎机，气压设为0.5MPa，制得d90小于20μm的细粉；取该细粉与0.6kg乳糖混合均匀，并使二者充分接触；取2.7kg聚乙二醇4000，80℃加热至熔融，慢慢在搅拌下加入之前制备的细粉，以及0.1kg聚山梨酯-80和0.2kg CMC-Na；经过充分搅拌后，再将全部混合物经2.4mm滴头滴制，在15℃液态石蜡中冷却成型，制得10万粒滴丸，每丸50mg。
对比例1(专利CN 106924197A实施例4)
处方：
Figure PCTCN2019108918-appb-000023
制备工艺：将银杏萜内酯过60目筛，其他辅料过100目筛，备用；取3kg聚乙二醇4000与1kg聚乙二醇6000，80℃加热至熔融，慢慢在搅拌下加入银杏萜内酯细粉；再将全部混合物经2.4mm滴头滴制，在15℃液态石蜡中冷却成型，制得10万粒滴丸，每丸51mg。
含量测定：检测方法采用《2010年版药典》HPLC检测，每粒银杏内酯A、B、C及白果内酯的含量分别为2.5mg、1.0mg、1.5mg、5.0mg。
以下通过试验例来进一步说明本发明的有益效果。
试验例1
取上述实施例1、3、7、9，对比例1银杏萜内酯滴丸，在pH1.0盐酸溶液(餐前胃 内pH)进行体外溶出试验，分别在3min、6min、10min、15min、20min、25min、30min取样，测定溶出曲线，结果见表1及图1。溶出量按银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯M、银杏内酯J及白果内酯总量百分比计。
表1 本发明银杏萜内酯滴丸在pH1.0盐酸溶液中的药物溶出实验
Figure PCTCN2019108918-appb-000024
上述试验结果表示，本发明的实施例制备得到的银杏萜内酯滴丸在体外溶出试验中较常规配方、方法(对比例1，即专利CN 106924197A实施例4)制备得到的银杏萜内酯滴丸溶出速度更快。使用两种填充剂(微晶纤维素+乳糖)的实例8、实例9制备得到的银杏萜内酯滴丸的体外溶出速度与实施例1、实施例3、实例5、实例7相比，明显更快，超出发明人预期。
试验例2
取上述实验例2、4、8、9，对比例1银杏萜内酯滴丸，在pH2.5磷酸盐缓冲溶液(餐后胃内pH)进行体外溶出试验，分别在3min、6min、10min、15min、20min、25min、30min取样，测定溶出曲线，结果见表2及图2。溶出量按银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯M、银杏内酯J及白果内酯总量百分比计。
表2 本发明银杏萜内酯滴丸在pH2.5磷酸盐缓冲溶液中的药物溶出实验
Figure PCTCN2019108918-appb-000025
上述试验结果表示，本发明的实施例制备得到的银杏萜内酯滴丸在体外溶出试验中较常规配方、方法(对比例1，即专利CN 106924197A实施例4)制备得到的银 杏萜内酯滴丸溶出速度更快。使用两种填充剂(微晶纤维素+乳糖)的实例8、实例9制备得到的银杏萜内酯滴丸的体外溶出速度与实施例2、实施例4、实例6相比，明显更快，超出发明人预期。
试验例3
取上述实验例1(单用一种刚性分子填充剂微晶纤维素)、2(单用一种表面疏松多孔的填充剂乳糖)、8(微晶纤维素、乳糖)、9(微晶纤维素+乳糖+崩解剂+表面活性剂)，对比例1(无填充剂)银杏萜内酯滴丸，按500mg/kg的剂量通过灌胃喂给动物，分别在家兔服用滴丸后5min、10min、15min、20min、30min、45min、60min、2h、4h、8h采集血液样品。直接将血液样本采集至EDTA-Monovette采血管(莎斯特公司)中，离心分离制备血浆。取30μL血浆，加入500μL四氢呋喃、30μLI.S.溶液(180ng/mL)和50μL 2M盐酸混匀。将反应混合物漩涡振荡20秒，然后3700g离心10分钟。取830μL上清液转移至
Figure PCTCN2019108918-appb-000026
萃取柱。此后，用6mL甲基叔丁基醚提取化合物并用氮蒸发干燥。将离心沉淀加入至50/50甲醇/水(0.1％甲酸)混合液中漩涡振荡，之后放入超声波发生器15分钟；然后再次3700g离心10分钟。将上清液转移至HPLC样品管中并进行分析。药时曲线以白果内酯(含量最高)的血药浓度计，结果见表3、表4及图3。
表3 本发明银杏萜内酯滴丸在家兔体内各个时间的药物浓度
Figure PCTCN2019108918-appb-000027
表4 本发明银杏萜内酯滴丸在家兔体内的峰浓度和达峰时间
检测指标 实施例1 实施例2 实施例8 实施例9 对比例1
Tmax(min) 30 20 15 15 45
Cmax(ng/ml) 121.82 115.47 120.72 125.64 106.18
峰浓度(Cmax)和达峰时间(Tmax)指血管外给药后药物在血浆中的最高浓度值和出现时间，分别代表药物吸收的程度和速度。
上述试验结果表示，本发明的实施例制备得到的银杏萜内酯滴丸在动物试验中较常规配方、方法(对比例1，即专利CN 106924197A实施例4)制备得到的银杏萜内酯滴丸更快达到最高血药浓度，达峰时间Tmax更早，同时峰浓度Cmax值更高。因此，本发明公开的银杏萜内酯滴丸的有效成分银杏萜内酯更易吸收、能更快发挥药效。
使用两种填充剂(微晶纤维素+乳糖)的实例8、实例9制备得到的银杏萜内酯滴丸与实施例1、实例2相比，Tmax值明显更早，超出发明人预期。其中实施例9的Cmax值明显高于实施例1、实施例2和实施例8，为最优选实施例。
综上所述，本发明提供了一种银杏萜内酯滴丸制剂及其制备方法，该制剂在体内外能够更快的溶出并且进入血液，能够更快达到治疗效果。
以上内容仅仅为本发明的较佳实施例，对于本领域的普通技术人员，依照本发明的思路，在具体实施例方式及其应用范围上均会有所改变之处，本说明书内容不应理解为对本发明的限制。

Claims (12)

  1. 一种有效成分包含银杏萜内酯的滴丸，其特征在于，包含刚性分子填充剂和/或表面疏松多孔的填充剂。
  2. 根据权利要求1所述的滴丸，其特征在于，所述刚性分子填充剂选自微晶纤维素、甲基纤维素、乙基纤维素、磷酸氢钙、磷酸二氢钙、碳酸钙、二水硫酸钙、乳糖、甘露醇、纤维素乳糖中的一种或两种以上。
  3. 根据权利要求2所述的滴丸，其特征在于，所述微晶纤维素松密度为0.21g/cm 3～0.42g/cm 3。
  4. 根据权利要求1所述的滴丸，其特征在于，所述表面疏松多孔的填充剂选自乳糖、甘露醇、纤维素乳糖中的一种或两种以上。
  5. 根据权利要求1～4任意一项所述的滴丸，其特征在于，包含下述重量份的组分：银杏萜内酯5-15份，基质20-40份，填充剂1-20份。
  6. 根据权利要求5所述的滴丸，其特征在于，还包括表面活性剂0.1-4重量份，所述表面活性剂为聚山梨酯-80、卵磷脂或/和卡波姆。
  7. 根据权利要求6所述的滴丸，其特征在于，还包括0.1-2.5重量份的崩解剂，所述崩解剂为羧甲基纤维素钠、干淀粉、低取代基羟丙基纤维素、交联聚乙烯吡咯烷酮或/和交联羧甲基纤维素钠。
  8. 根据权利要求7所述的滴丸，其特征在于，所述填充剂为微晶纤维素和乳糖的混合物。
  9. 根据权利要求8所述的滴丸，其特征在于，所述微晶纤维素与乳糖的重量比为(4～1)∶(1～4)。
  10. 权利要求1～9任意一项所述的滴丸的制备方法，其特征在于，包括如下步骤：
    a)将银杏萜内酯与填充剂共同破碎或混合；
    b)将基质和其他组分混合，加热至熔融，搅拌加入步骤a)所得细粉，得混合物备用；
    c)步骤b)所得混合物经滴头滴制、冷凝液冷却成型。
  11. 根据权利要求10所述的制备方法，其特征在于，步骤a)所述破碎为气流冲击粉碎和/或机械剪切破碎。
  12. 根据权利要求11所述的制备方法，其特征在于，所述气流冲击粉碎的气压为0.5-0.8MPa。
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KR20210047319A (ko) 2021-04-29
KR102648910B1 (ko) 2024-03-15
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CN111000807A (zh) 2020-04-14
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