WO2012075744A1 - Pharmaceutical composition comprising pyrazolopyrimidinone-like compound - Google Patents

Pharmaceutical composition comprising pyrazolopyrimidinone-like compound Download PDF

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WO2012075744A1
WO2012075744A1 PCT/CN2011/071510 CN2011071510W WO2012075744A1 WO 2012075744 A1 WO2012075744 A1 WO 2012075744A1 CN 2011071510 W CN2011071510 W CN 2011071510W WO 2012075744 A1 WO2012075744 A1 WO 2012075744A1
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Prior art keywords
streptococcus
cycloheximide
pharmaceutical composition
resistant
maleate
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PCT/CN2011/071510
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French (fr)
Chinese (zh)
Inventor
徐利锋
张克坚
周云鹏
刘举
王洋
刘革萍
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辽宁利锋科技开发有限公司
广东华南新药创制中心
陈烨
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Publication of WO2012075744A1 publication Critical patent/WO2012075744A1/en

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of pharmacy, and in particular to novel aromatic heterocyclic pyrimidine derivatives and analogs thereof, and cyclopyrene tablets or stereoisomers, prodrugs, pharmaceutically acceptable salts, double salts or solvents thereof
  • the pharmaceutical composition of the cycloheximide complex as an active ingredient pharmaceutical complex as an active ingredient and a pharmaceutically acceptable pharmaceutical carrier, and the pharmaceutical composition preparation is a Gram-positive bacteria in the treatment of bacteria: Staphylococcus, pneumococci, Enterococcus faecalis, Streptococcus, Streptococcus bovis, Streptococcus pneumoniae, Streptococcus pneumoniae, Streptococcus pneumoniae, Streptococcus pneumoniae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus mutans, Bovine Streptococcus, Streptococcus agal
  • the aromatic heterocyclic pyrimidine derivative and the analog A ring of the compound represented by the general formula II of the present invention are heterocyclic rings, wherein the hetero atom and X 2 form a pyrimidine ring, the ring and A heterocyclic ring form a condensed ring, and wherein hetero atoms Patent chemical structure and X 3 is connected via the system retrieves and reports only see a patent: US Patent, US 4546181 triazole-aromatic heterocyclic pyrimidine having anticancer activity, and reported (See Document 1; Document 2.: Allen et al, Journal of Organic Chemistry, 24, 1959, 787; Document 3: Sako, Magoichi, et al, Chemical and Pharmaceutical Bulletin, 42, 4, 1994, 806; Lewin et al" J.
  • the technical problem to be solved by the present invention is to represent an active ingredient of a cycloheteropyrimidine derivative and the like, a cycloheximide or a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a double salt or a solvated cyclopyrimidine.
  • the drug-repellent system using the compound as an active ingredient is studied, and a system suitable for its safe drug delivery system is obtained, which solves the technical problems of very narrow therapeutic window and poor clinical application safety, and is a heterocyclic pyrimidine derivative and the like.
  • the chemical structure of the compound was modified to obtain cyclopyrine, which was better than vancomycin and ciprofloxacin after the safety and efficacy of cycloheximin, and the inhibition spectrum was better than vancomycin and ciprofloxacin. Wide, the solubility is significantly increased.
  • a novel pharmaceutical composition comprising a cycloheximide medicinal compound as an active ingredient and a pharmaceutically acceptable pharmaceutical carrier is prepared, which can be used for Gram-positive bacteria: staphylococcus, pneumococcal, feces Enterococcus, Streptococcus, Streptococcus bovis, Streptococcus pneumoniae, Streptococcus pneumoniae, Streptococcus pneumoniae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus mutans, Streptococcus bovis, Streptococcus agalactiae B, group of Streptococcus mutans, diphtheria, tetanus, erysipelas, Bacillus anthracis, tetanus, Bacillus cereus, Bacillus subtilis, Clostridium, Bacillus cereus, Bacillus subtilis
  • a cycloheximide or a stereoisomer a prodrug, a pharmaceutically acceptable salt, a double salt or a solvate having the structure of the general formula (I)
  • the compound of cycloheximide as a active ingredient is used as an active ingredient
  • the drug is formulated into a pharmaceutical composition.
  • the salt may be a mineral acid group and a d-Cw organic acid or an amino acid; and the prodrug may be a d-Cw amide, an ester or the like.
  • the pharmaceutically acceptable pharmaceutical carrier refers to a pharmaceutical carrier in the pharmaceutical field, and the pharmaceutical carrier is selected from the group consisting of: a diluent; an excipient; water; a filler such as starch, sucrose, lactose and/or microcrystalline cellulose; Such as sodium hydroxymethyl starch, hydroxypropyl cellulose, croscarmellose, agar, calcium carbonate and / or sodium bicarbonate; binders such as cellulose derivatives, alginate, gelatin and / or poly Vinyl pyrrolidone; wetting agent such as Tween and / or glycerin; surfactants such as cetyl alcohol and / or sodium lauryl sulfate; adsorption carriers such as kaolin and / or soap clay; lubricants such as talc, calcium stearate Or magnesium, micronized silica gel and / or polyethylene glycol; solubilizers such as polyoxyethylene ether castor oil, Tween and / or
  • the pharmaceutical composition preparation of the present invention may be in the form of any one of pharmaceutically acceptable dosage forms, including tablets, capsules, soft capsules, sprays, gels, gel aerosols, and mixtures. Suspensions, granules, patches, ointments, pills, powders, emulsions, injections, infusion solutions, lyophilized injections, liposome injections, targeted administration injections, suppositories, sustained release preparations and controlled release preparations.
  • composition preparation of the present invention preferably, the cycloheximide pharmaceutical complex is combined with a filler and/or a disintegrating agent to form a tablet or a capsule; or a cycloheximide medicinal compound and
  • the filler and/or hypromellose are formulated into a sustained release preparation or capsule.
  • composition preparation of the present invention preferably, the cycloheximide pharmaceutical complex and filler, hydroxypropyl methylcellulose ester, ethyl cellulose, polyvinyl alcohol, methyl silicone resin, hydroxypropyl group Sustained release of cellulose, polyethylene glycol 600, methacrylic acid acrylate resin, ethoxyethyl cellulose, glyceryl palmitate, sodium polyphosphate-chitosan and/or PEG1500 Formulation or controlled release preparation.
  • the pharmaceutical composition preparation of the present invention preferably, the cycloheximide pharmaceutical complex is mixed with an oil phase such as soybean oil, polyethylene glycol 400, cottonseed oil, peanut oil, sesame oil, corn oil and/or olive oil.
  • an injection or an oral emulsion is prepared; a solubilizing agent or a latent solvent or an antioxidant may also be added to the oil phase.
  • the pharmaceutical composition preparation of the present invention can be administered to a patient in need of such treatment by oral or parenteral administration.
  • a conventional solid preparation such as a tablet, a capsule, a powder or a granule, or a liquid preparation such as an aqueous solution or an oil suspension or other liquid preparation such as a syrup, an oral solution or a tincture.
  • a liquid preparation such as an aqueous solution or an oil suspension or other liquid preparation such as a syrup, an oral solution or a tincture.
  • parenteral administration it can be prepared as a solution for injection, a powder, an aqueous solution or an oily suspension.
  • Preferred forms are tablets, coated tablets, capsules, granules, oral solutions and injections.
  • the preparation method of cyclopyrene maleate comprises the following steps:
  • the solid preparation of tablets, capsules, granules, powders and the like may usually contain 0.1 to 99% (w/w) of the active ingredient, preferably 0.1 to 50% (w/w) of the active ingredient.
  • injections may usually contain 0.01 to 50% (w/w) of the active ingredient, preferably 0.5 to 5% (w/w) of the active ingredient.
  • a dosage form of a suspension, a syrup or the like which is orally administered may usually contain 0.5 to 10% (w/w) of an active ingredient.
  • the preferred amount of the compound of the present invention can be administered depending on the kind of the compound to be used, the kind of the composition to be compounded, the frequency of application, the specific site to be treated, the severity of the condition, the age of the patient, the diagnosis of the doctor, the type of the tumor, and the like.
  • the daily dose of the adult can be in the range of 0.01 to 400 mg at the time of oral administration, and, in the case of parenteral administration, at the time of intravenous injection, it is preferably daily. 0.01 to 100 mg range.
  • the number of administrations varies depending on the administration method and symptoms, but it is 1 to 4 times per day.
  • an administration method such as intermittent administration such as administration every other day or administration for two days may be used.
  • the pharmaceutical composition preparation of the present invention contains the filler and the filler contained in the examples in an amount of from 1% to 90% by weight of the prescription.
  • This product is a sterile aqueous solution of cocaine hydrochloride.
  • the cycloheximide containing maleic acid should be 95% ⁇ 105% of the labeled amount.
  • This product is a sterile oil solution of cyclopyrine, containing cycloheximide should be 90% ⁇ 110% of the labeled amount.
  • Sodium chloride was dissolved in about 4% of the total volume of water for injection, filtered through a G 3 fused glass funnel, and placed in a sealed glass container. Take another half of the above 1 solution, heat on a water bath, add sodium chloride solution and polysorbate 80, stir well, wait until the water bath is boiled, add cyclopyrene tablets and stir well, continue heating for 30min, take out and cool to Leave at room temperature overnight.
  • Example 7 submicron emulsion for cyclopyrine injection
  • Soybean oil 20g water for injection to 100ml
  • Example 8 submicron emulsion for intravenous injection of cyclopyrine
  • ⁇ Method ⁇ Heat the water for injection to boiling, add the prescribed amount of cycloheximide maleate, stir to dissolve, prepare 12% ⁇ 15% solution, add 1.5% activated carbon, keep boiling for l ⁇ 2h, The sulphuric acid is added to the sulphuric acid, and the sulphuric acid is added to the 6%, and then the solution is added to the solution. 0.5%, heated to 70 ⁇ 80 °C, filtered until the liquid is clear and filled, and sterilized at 112 ° C for 30 minutes.
  • This product is a sterile lyophilized preparation of cycloheximide maleate.
  • the potency of cyclopyrimidine maleate should be more than 90% of the labeled amount.
  • This product is a sterile white loose powder of cycloheximide maleate, which is dissolved in water for injection when it is used. Each contains 50mg.
  • ⁇ Method ⁇ Take methylparaben and propyl ester, dissolve in boiling water, dissolve cycloheximide maleate and sodium chloride at 60 °C, filter, add steamed water to a sufficient amount, and irrigate Packed, 100], 30min sterilization.
  • Cycloheximide maleate fine powder or very fine crystal
  • Hard fat broken magnesium 1.5mg [Preparation method] Mix maleic acid cyclohexine, starch and dextrin into a stainless steel electric mixer. In addition, the tartaric acid is dissolved in 50% ethanol, and the mixed powder of cycloheximide maleate is added once, uniformly mixed, and made into a soft material, and 20 ⁇ 40 mesh wet granules are prepared once by a nylon mesh sieve, and the drying box is placed. Medium drying, the temperature does not exceed 60 ° C at the beginning, the temperature can be raised to below 70 ° C when drying, to accelerate drying, but the temperature should not be too high to avoid discoloration. The dry granules are passed through a 20 mesh sieve, and the magnesium stearate is added and mixed to form a tablet.
  • Preparation method Mix the microcrystalline fine powder of cycloheximide maleate with starch and powdered sugar, make soft material with 12% starch slurry, granulate through 12 mesh sieve, and dry the wet pellet at 60 ⁇ 65 °C. The dry granules are sieved through a 12-mesh sieve, and after mixing with magnesium stearate, the tablets are obtained.
  • Each tablet contains cycloheximide maleate 0.25g.
  • Preparation method pulverize maleic acid cyclohexine to 80 mesh fine powder, add starch, aluminum hydroxide, stir evenly, use starch slurry to make soft material, granulate, ventilate and dry at 80 °C, add hard fat Magnesium, whole, mixed, compressed.
  • 4% hydroxypropyl methylcellulose is a film-forming material; the ratio of ethanol to water in the solvent is 50:50; castor oil is selected as a plasticizer.
  • the intestine solution was added to the formulation and stirred, and then propylene glycol and talc powder 300 g were added, and the mixture was further stirred and then used.
  • Cycloheximide maleate was passed through a 120 mesh sieve, and the proportion of the formulation of cycloheximide maleate, acrylic resin III, HPMC, microcrystalline cellulose was uniformly mixed, and 2% PVP ethanol solution was used. Made into suitable soft materials. The granules were sieved with an 18-mesh sieve, magnesium stearate was added, and the mixture was mixed, tableted, and coated.
  • Acrylic resin appropriate amount, 12% starch slurry, proper amount
  • the sustained-release part is prepared by taking a fine powder of ethyl cellulose and acrylic resin, dissolving it with an appropriate amount of ethanol, adding cycloalthene maleate fine powder, and making it into a soft material. Wet granules, dry, sieved and sized. In the immediate release part, weigh the cycloheximide maleate and starch, mix it with 12% starch slurry, mix it, make it into soft material, sieve it to wet grain, dry it, and sieve it. Tableting, will release sustained release and immediate release particles Mix well, weigh, add appropriate amount of talcum powder, and compress.
  • sustained-release tablets Weigh cycloheximide maleate, hydroxypropyl methylcellulose and lactose in chyle according to the prescription, mix them, add 80% ethanol solution to make soft materials, over 18 The mesh is granulated, the wet granules are dried at 50-60 ° C, dried and sieved through a 16 mesh sieve, weighed and added with magnesium stearate, mixed, and tableted.
  • tablet preparation tablet granules consist of two parts, one part is immediate release granules, prepared by ordinary tablet granulation method (containing 17.6%); the other part is sustained release part, from the above solid dispersion, starch , dextrin, gum arabic and the like are obtained by granulating with dilute ethanol (containing about 40%); the two are mixed in a certain ratio, and then a disintegrant and a lubricant are pressed.
  • the raw materials are respectively passed through a 40 mesh sieve, and weighed according to the prescription amount and uniformly mixed.
  • Add 95% ethanol soft material pass 20 mesh sieve granules, dry at 40 °C for 2 hours, and add 18 mesh sieves to the appropriate amount.
  • the core was placed in a coating pan, and hot air was blown in. After the bed temperature was 50 ° C, the coating was carried out.
  • the solution contained PEG400 with CA and 40% CA, the solvent was acetone-isopropyl alcohol (9:1), the input speed of the coating liquid was 4.6 ml/min, the pressure was 24 kPa, and the coating weight gain was 10%.
  • the coated film was dried at 40 ° C for 24 hours, and the remaining solvent was removed. A small hole was formed on one side of the sheet, and the pore diameter was 0.4 mm.
  • the outer layer is made of cellulose acetate, hydroxypropylmethylcellulose and polyethylene glycol (PEG3350), and the laser is used on the semipermeable membrane near the drug layer. Release the small holes.
  • Preparation method Take triethanolamine, glycerin, and paraben dissolved in water, and heat to 75 °C on a water bath; another stearic acid is melted on a water bath, lanolin and white vanel are added and the temperature is maintained at 75 °C.
  • the oil melt is gradually added to the above-mentioned isothermal aqueous solution under constant stirring, and simultaneously removed from the water bath, and stirred until solidified into a paste form, and finally the flavor is added, and the mixture is stirred to obtain a cream.
  • [Method] Boil the appropriate amount of steamed water, add propylene glycol to mix, cool to 50 ⁇ 60 ° C, add hyaluronic acid, carbomer 941 under stirring, let stand for 24h (sufficient swelling) (A); Dissolve cycloheximide maleate in ethanol in another container, add benzyl alcohol to mix (B); add B to A, add triethanolamine to neutralize (to pH6), add steamed water to the foot The amount is stirred until it is even.
  • This product is a sterile aqueous solution of cocaine hydrochloride.
  • the cycloheximide containing maleic acid should be 95% ⁇ 105% of the labeled amount.
  • Cycloheximide maleate (fine powder or very fine crystal) 260.0mg
  • Vre vancomycin resistant
  • MRSA Staphylococcus aureus
  • VRE Enterococcus faecium
  • Example 38 In vivo antibacterial test (therapeutic effect of cycloheximide maleate on a mouse model of systemic infection in mice) Kunming mice were used to isolate methicillin-resistant Staphylococcus aureus and S. pneumoniae Infected mice to prepare abdominal cavity The infection model was tested with vancomycin as a positive control. The test results show that the protective effect of the present invention on cyclopanning maleate is superior to the control vancomycin.

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Abstract

The present invention discloses a pharmaceutical composition comprising a compound of formula (I) or stereoisomer, prodrug, pharmaceutically acceptable salt, double salt and/or solvate thereof as an active ingredient, as well as pharmaceutically acceptable carriers. The dosage form of said pharmaceutical composition is one of the pharmaceutically acceptable dosage forms. The present invention also discloses use of the pharmaceutical composition for treatment of bacterial infections, wherein said bacteria are Gram positive bacteria, including Staphylococcus, Micrococcus pneumoniae, Enterococcus faecalis, Streptococcus, Streptococcus bovis, Streptococcus pneumoniae, Peptostreptococcus, suppurative Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus riridans, Streptococcus agalactiae B and Bacillus diphtheriae, etc.

Description

说 明 书  Description
含有吡唑并嘧啶酮样化合物的药物组合物  Pharmaceutical composition containing pyrazolopyrimidinone-like compound
技术领域 Technical field
本发明属于药学领域， 尤其涉及以新颖的芳杂环并嘧啶衍生物和类似物， 及其代表的的环嘧耐平药或 立体异构体、 前药、 药用盐、 复盐或和溶剂化的环嘧耐平用复合物作为有效成分药用复合物作为有效成分 与药学上可接受的药物载体形成的药物组合物制剂， 以及该药物组合物制剂在治疗细菌为革兰氏阳性菌： 葡萄球菌、 肺炎球菌、 粪肠球菌、 链球菌、 牛链球菌， 肺炎链球菌、 消化链球菌、 化脓肺炎链球菌、 化脓 肺炎链球菌、 化脓性链球菌、 无乳链球菌、 绿色链球菌、 牛链球菌、 无乳链球菌 B、 组绿色链球菌、 白喉 杆菌、 破伤风杆菌、 丹毒杆菌、 炭疽杆菌、 破伤风杆菌、 蜡样芽孢杆菌、 枯草芽胞杆菌、 梭状芽孢杆菌、 蜡样芽孢杆菌、 枯草芽胞杆菌、 炭疽杆菌、 白喉杆菌、 梭状芽孢杆菌、 破伤风杆菌、 产气荚膜杆菌、 产气 荚膜杆菌螺旋体、 放线菌、 结核菌， 其中该细菌为革兰氏阳性耐药菌， 耐甲氧西林葡萄球菌、 耐万古霉素 金葡菌、 葡萄球菌属诱导型克林霉素耐药、 耐万古霉素肠球菌、 肠球菌高水平耐氨基糖苷类、 耐青霉素肺 炎链球菌、 多重耐药鲍曼不动杆菌、 耐药与多重耐药结核杆菌与结核分枝杆菌、 链球菌、 粪肠球菌、 铜绿 假单胞菌、 大肠埃希氏菌及鲍氏不动杆菌等、 耐药流感嗜血杆菌、 耐药淋球菌、 耐药脑膜炎奈瑟菌、 耐药 肠杆菌科细菌、 耐药铜绿假单胞菌感染中应用。  The present invention belongs to the field of pharmacy, and in particular to novel aromatic heterocyclic pyrimidine derivatives and analogs thereof, and cyclopyrene tablets or stereoisomers, prodrugs, pharmaceutically acceptable salts, double salts or solvents thereof The pharmaceutical composition of the cycloheximide complex as an active ingredient pharmaceutical complex as an active ingredient and a pharmaceutically acceptable pharmaceutical carrier, and the pharmaceutical composition preparation is a Gram-positive bacteria in the treatment of bacteria: Staphylococcus, pneumococci, Enterococcus faecalis, Streptococcus, Streptococcus bovis, Streptococcus pneumoniae, Streptococcus pneumoniae, Streptococcus pneumoniae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus mutans, Bovine Streptococcus, Streptococcus agalactia B, Group Streptomyces, Diphtheria, Tetanus, Escherichia, Bacillus anthracis, Tetanus, Bacillus cereus, Bacillus subtilis, Clostridium, Bacillus cereus, Bacillus subtilis, Bacillus anthracis, diphtheria, Clostridium, tetanus, Clostridium perfringens, gas production Clostridium spp., actinomycetes, tuberculosis, wherein the bacteria are Gram-positive bacteria, methicillin-resistant Staphylococcus, vancomycin-resistant Staphylococcus aureus, Staphylococcus-induced clindamycin resistance , vancomycin-resistant enterococci, enterococci high-level aminoglycoside-resistant, penicillin-resistant Streptococcus pneumoniae, multidrug-resistant Acinetobacter baumannii, drug-resistant and multi-drug resistant tuberculosis with Mycobacterium tuberculosis, streptococcus, feces Enterococcus, Pseudomonas aeruginosa, Escherichia coli and Acinetobacter baumannii, drug-resistant Haemophilus influenzae, drug-resistant gonococcal bacteria, resistant Neisseria meningitidis, resistant Enterobacteriaceae bacteria, resistant Application in the drug Pseudomonas aeruginosa infection.
背景技术 Background technique
自 1929年， 弗来明 (Alexander Fleming)发现青霉素以来， 大量抗菌药品临床用药表明， 所用有效的抗 菌药物都有可能出现耐药菌株,而且很多致病菌还会对多种抗菌药物呈现耐药性， 即"多重耐药性"， 如产生 了称之为"超级细菌"的甲氧西林耐药金黄色葡萄球菌 (MRSA), 耐万古霉素肠球菌（VRE )等。 感染"超级 细菌"的人数也在越来越多， 其蔓延已构成对人类健康的严重威胁， 因此研发出新的对耐药菌具有活性的 抗菌药已经是迫在眉睫。  Since 1929, after the discovery of penicillin by Alexander Fleming, the clinical use of a large number of antibacterial drugs has shown that effective antibacterial drugs are likely to have drug-resistant strains, and many pathogenic bacteria will also be resistant to various antibiotics. Sex, that is, "multi-drug resistance", such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), etc., called "super bacteria". The number of people infected with "super bacteria" is also increasing, and its spread has become a serious threat to human health. Therefore, it is urgent to develop new antibacterial drugs that are active against drug-resistant bacteria.
涉及嘧啶结构的研究多为单环嘧啶， 而芳杂环并嘧啶类化合物的专利和报道很少。 文献检索发现， 有 关芳杂环并嘧啶类似物和衍生物的专利和文章与本发明具有抗菌和抗真菌活性用途的结构式 I所表示的化 合物结构无关。 其它活性研究发明专利： US 20060160831吡咯并嘧啶酮具有抗癌活性、 US 20030100572 吡啶并嘧啶酮具有抗癌活性、 US 7262187五元脂环并嘧啶酮具有抗癌活性、 US 6531477吡唑并嘧啶酮具 有抗癌活性、 US 20030100572喹啉并氨基嘧啶用于抗癌治疗、 20030220345喹啉并氨基嘧啶用于抗癌治疗、 抗癌研究发表文章 (文献 1： Kano et al. Chemical and Pharmaceutical Bulletin, 7, 1959, 903)、 US 4581171合成 含硫芳杂环并嘧啶用于治疗心理疾病、 US 20060264624合成咪唑杂环并嘧啶用于性功能调解、 US 4482556 异喹啉并嘧啶酮用于抗高血压疾病、 US 5346901合成吡唑并嘧啶酮用于治疗高血压、 US 5158952哌啶并 嘧啶酮用于治疗心理疾病、 US 4507300哌啶并吡嗪酮用于抗过敏治疗、 US 6790850五元杂环并氨基取代 嘧啶用于治疗哮喘和免疫系统疾病、 US 5008268五元杂环并取代嘧啶用于抗组织胺治疗、 US 20070167423 苯并氨基嘧啶用于治疗神经系统紊乱、 US 7132427苯并氨基嘧啶用于抗癌治疗，然而对芳杂环并嘧啶类似 物和衍生物的抗菌和抗真菌生物活性的专利发明和文章还没见报道。
Figure imgf000004_0001
通式 π Studies involving pyrimidine structures are mostly monocyclic pyrimidines, and there are few patents and reports on aromatic heterocyclic pyrimidine compounds. The literature search found that the patents and articles relating to the aromatic heterocyclic pyrimidine analogs and derivatives are independent of the structure of the compound represented by Structural Formula I for the antibacterial and antifungal activity of the present invention. Other active research invention patents: US 20060160831 pyrrolopyrimidicone has anticancer activity, US 20030100572 pyridopyrimidinone has anticancer activity, US 7262187 5-membered alicyclic pyrimidinone has anticancer activity, and US 6531477 pyrazolopyrimidinone has Anticancer activity, US 20030100572 quinoline aminopyrimidine for anticancer therapy, 20030220345 quinoline pyrimidine for anticancer therapy, anticancer research published (Document 1: Kano et al. Chemical and Pharmaceutical Bulletin, 7, 1959 , 903), US 4581171 Synthesis of Sulfur-containing Aromatic Heterocyclic Pyrimidines for the Treatment of Mental Illness, US 20060264624 Synthetic Imidazole Heterocyclic Pyrimidine for Sexual Function Mediation, US 4482556 Isoquinobenzopyrimidinone for Antihypertensive Diseases, US 5346901 Synthetic pyrazolopyrimidone for the treatment of hypertension, US 5158952 piperidinopyrimidinone for the treatment of mental illness, US 4507300 piperidinopyrazinone for anti-allergy therapy, US 6790850 5-membered heterocyclic amino substituted pyrimidine For the treatment of asthma and immune system diseases, US 5008268 five-membered heterocyclic and substituted pyrimidine for antihistamine treatment, US 20070167423 benzoammonium The use of pyrimidines for the treatment of neurological disorders, US 7132427 benzoaminopyrimidines for anticancer treatment, however, patented inventions and articles on the antibacterial and antifungal biological activities of aromatic heterocyclic pyrimidine analogs and derivatives have not been reported.
Figure imgf000004_0001
General formula π
在化学结构和合成方面，本发明以通式 II所表示的化合物结构的芳杂环并嘧啶衍生物和类似物 A环为 杂环， 其中杂原子 与 或 X2形成嘧啶环、 该环与 A环杂环形成稠环并且其中杂原子与 X3连接的化学 结构的专利和报道经系统检索仅见到一项专利： 美国专利， US 4546181 合成三唑芳香杂环并嘧啶具有抗 癌活性， 及报道 (见文献 1 ; 文献 2.： Allen et al, Journal of Organic Chemistry, 24, 1959, 787; 文献 3 : Sako, Magoichi, et al, Chemical and Pharmaceutical Bulletin, 42, 4, 1994, 806; 文献 4: Lewin et al" J. Gen. Chem. USSR (Engl. Transl.), 33, 1963, 2603; 文献 5: Zhurnal Obshchei Khimii, 33, 1963, 2673; 文献 6: Guerret et al., Bulletin de la Societe Chimique de France, 1972, 3503, Brady,Herbst. Journal of Organic Chemistry, 24, 1959, 922. 924)， 并且它们都没有涉及抗菌和抗真菌活性及其研究。 综上说述， 在活性研究方面， 到目前为止系统检索国内外的专利和文献还没有发现本发明以结构式 ΙΠ所表 示的化合物结构的芳杂环并嘧啶衍生物和类似物具有抗菌活性和抗真菌的发明专利和报道。 化合物 I和 II 是通式 III所包含的结构， 由通式 III所申请的专利名称为芳杂环并嘧啶衍生物和类似物， 公开号 CN 101671336A。 发明内容 In terms of chemical structure and synthesis, the aromatic heterocyclic pyrimidine derivative and the analog A ring of the compound represented by the general formula II of the present invention are heterocyclic rings, wherein the hetero atom and X 2 form a pyrimidine ring, the ring and A heterocyclic ring form a condensed ring, and wherein hetero atoms Patent chemical structure and X 3 is connected via the system retrieves and reports only see a patent: US Patent, US 4546181 triazole-aromatic heterocyclic pyrimidine having anticancer activity, and reported (See Document 1; Document 2.: Allen et al, Journal of Organic Chemistry, 24, 1959, 787; Document 3: Sako, Magoichi, et al, Chemical and Pharmaceutical Bulletin, 42, 4, 1994, 806; Lewin et al" J. Gen. Chem. USSR (Engl. Transl.), 33, 1963, 2603; Document 5: Zhurnal Obshchei Khimii, 33, 1963, 2673; Document 6: Guerret et al., Bulletin de la Societe Chimique De France, 1972, 3503, Brady, Herbst. Journal of Organic Chemistry, 24, 1959, 922. 924), and none of them involve antibacterial and antifungal activity and its research. In summary, in the area of activity research, System retrieval so far The patents and literature have not found that the aromatic heterocyclic pyrimidine derivatives and analogs of the compound structure represented by the structural formula of the present invention have antibacterial activity and antifungal invention patents and reports. Compounds I and II are encompassed by Formula III. Structure, the patent name applied for by the general formula III is an aromatic heterocyclic pyrimidine derivative and the like, and the publication number is CN 101671336A.
本发明所要解决的技术问题是针对芳杂环并嘧啶衍生物和类似物的代表活性成分环嘧耐平药或立体 异构体、 前药、 药用盐、 复盐或和溶剂化的环嘧耐平用复合物作为有效成分的给药系统进行研究， 获得适 合其安全给药系统， 解决了治疗窗非常窄， 临床应用安全性较差等技术问题， 对芳杂环并嘧啶衍生物和类 似物化学结构进行修饰得到环嘧耐平， 经过对环嘧耐平的安全性和有效性研究， 均好于万古霉素和环丙沙 星， 且抑菌谱较万古霉素和环丙沙星广、 溶解度明显增加。 从而研制一种新颖的以环嘧耐平药用复合物作 为有效成分与药学上可接受的药物载体形成药物组合物制剂，该药物制剂可用于革兰氏阳性菌：葡萄球菌、 肺炎球菌、 粪肠球菌、 链球菌、 牛链球菌， 肺炎链球菌、 消化链球菌、 化脓肺炎链球菌、 化脓肺炎链球菌、 化脓性链球菌、 无乳链球菌、 绿色链球菌、 牛链球菌、 无乳链球菌 B、 组绿色链球菌、 白喉杆菌、 破伤风 杆菌、 丹毒杆菌、 炭疽杆菌、 破伤风杆菌、 蜡样芽孢杆菌、 枯草芽胞杆菌、 梭状芽孢杆菌、 蜡样芽孢杆菌、 枯草芽胞杆菌、 炭疽杆菌、 白喉杆菌、梭状芽孢杆菌、 破伤风杆菌、 产气荚膜杆菌、 产气荚膜杆菌螺旋体、 放线菌、 结核菌， 其中该细菌为革兰氏阳性耐药菌， 耐甲氧西林葡萄球菌、 耐万古霉素金葡菌、 葡萄球菌 属诱导型克林霉素耐药、 耐万古霉素肠球菌、 肠球菌高水平耐氨基糖苷类、 耐青霉素肺炎链球菌、 多重耐 药鲍曼不动杆菌、 耐药与多重耐药结核杆菌与结核分枝杆菌、 链球菌、 粪肠球菌、 铜绿假单胞菌、 大肠埃 希氏菌及鲍氏不动杆菌等、 耐药流感嗜血杆菌、 耐药淋球菌、 耐药脑膜炎奈瑟菌、 耐药肠杆菌科细菌、 耐 药铜绿假单胞菌感染中的治疗。 本发明所要解决的技术问题是通过以下的技术方案来实现的： 将具有通式 （ I ) 结构的环嘧耐平药或 立体异构体、 前药、 药用盐、 复盐或和溶剂化的环嘧耐平用复合物作为有效成分的用复合物作为有效成分 和药 制成药物组合物制剂。 The technical problem to be solved by the present invention is to represent an active ingredient of a cycloheteropyrimidine derivative and the like, a cycloheximide or a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a double salt or a solvated cyclopyrimidine. The drug-repellent system using the compound as an active ingredient is studied, and a system suitable for its safe drug delivery system is obtained, which solves the technical problems of very narrow therapeutic window and poor clinical application safety, and is a heterocyclic pyrimidine derivative and the like. The chemical structure of the compound was modified to obtain cyclopyrine, which was better than vancomycin and ciprofloxacin after the safety and efficacy of cycloheximin, and the inhibition spectrum was better than vancomycin and ciprofloxacin. Wide, the solubility is significantly increased. Thus, a novel pharmaceutical composition comprising a cycloheximide medicinal compound as an active ingredient and a pharmaceutically acceptable pharmaceutical carrier is prepared, which can be used for Gram-positive bacteria: staphylococcus, pneumococcal, feces Enterococcus, Streptococcus, Streptococcus bovis, Streptococcus pneumoniae, Streptococcus pneumoniae, Streptococcus pneumoniae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus mutans, Streptococcus bovis, Streptococcus agalactiae B, group of Streptococcus mutans, diphtheria, tetanus, erysipelas, Bacillus anthracis, tetanus, Bacillus cereus, Bacillus subtilis, Clostridium, Bacillus cereus, Bacillus subtilis, Bacillus anthracis, Diphtheria, Clostridium, Tetanus, Clostridium perfringens, Clostridium perfringens, Actinomycetes, Mycobacterium tuberculosis, wherein the bacterium is a Gram-positive resistant bacterium, methicillin-resistant Staphylococcus , vancomycin-resistant Staphylococcus aureus, Staphylococcus inducible clindamycin resistance, vancomycin-resistant enterococci, intestine High levels of bacteria resistant to aminoglycosides, penicillin-resistant Streptococcus pneumoniae, multi-drug resistant Acinetobacter baumannii, drug-resistant and multi-drug resistant Mycobacterium tuberculosis and Mycobacterium tuberculosis, Streptococcus, Enterococcus faecalis, Pseudomonas aeruginosa, Escherichia coli and Acinetobacter baumannii, drug-resistant Haemophilus influenzae, drug-resistant gonococcal bacteria, resistant Neisseria meningitidis, drug-resistant Enterobacteriaceae, and drug-resistant Pseudomonas aeruginosa infection treatment. The technical problem to be solved by the present invention is achieved by the following technical solutions: a cycloheximide or a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a double salt or a solvate having the structure of the general formula (I) The compound of cycloheximide as a active ingredient is used as an active ingredient The drug is formulated into a pharmaceutical composition.
Figure imgf000005_0001
Figure imgf000005_0001
( I )  (I)
通式（ I )中，表示盐可以是无机酸根以及含 d-Cw有机酸或氨基酸等； 前药可以是含 d-Cw酰胺、酯等。 In the formula (I), the salt may be a mineral acid group and a d-Cw organic acid or an amino acid; and the prodrug may be a d-Cw amide, an ester or the like.
所述的药学上可接受的药物载体是指药学领域的药物载体， 药物载体选自： 稀释剂； 赋形剂； 水； 填 充剂如淀粉、 蔗糖、 乳糖和 /或微晶纤维素； 崩解剂如羟甲基淀粉钠、 羟丙纤维素、 交联羧甲基纤维素、 琼 脂、 碳酸钙和 /或碳酸氢钠； 粘合剂如纤维素衍生物、 藻酸盐、 明胶和 /或聚乙烯吡咯烷酮； 润湿剂如吐温 和 /或甘油； 表面活性剂如十六烷醇和 /或十二烷基硫酸钠； 吸附载体如高岭土和 /或皂粘土； 润滑剂如滑石 粉、 硬脂酸钙或镁、 微粉硅胶和 /或聚乙二醇； 增溶剂如聚氧乙烯醚蓖麻油， 吐温和 /或普流罗尼 F-68; 助 溶剂如精氨酸、 葡甲胺、 二乙胺、 乙二胺、 尿素、 烟酰胺、 脯氨酸、 葡萄糖和 /或枸橼酸及其钠盐。 另外还 可以在组合物中加入其它辅剂如香味剂和 /或甜味剂等。  The pharmaceutically acceptable pharmaceutical carrier refers to a pharmaceutical carrier in the pharmaceutical field, and the pharmaceutical carrier is selected from the group consisting of: a diluent; an excipient; water; a filler such as starch, sucrose, lactose and/or microcrystalline cellulose; Such as sodium hydroxymethyl starch, hydroxypropyl cellulose, croscarmellose, agar, calcium carbonate and / or sodium bicarbonate; binders such as cellulose derivatives, alginate, gelatin and / or poly Vinyl pyrrolidone; wetting agent such as Tween and / or glycerin; surfactants such as cetyl alcohol and / or sodium lauryl sulfate; adsorption carriers such as kaolin and / or soap clay; lubricants such as talc, calcium stearate Or magnesium, micronized silica gel and / or polyethylene glycol; solubilizers such as polyoxyethylene ether castor oil, Tween and / or Pluronic F-68; cosolvents such as arginine, meglumine, diethylamine, Ethylenediamine, urea, nicotinamide, valine, glucose and/or citric acid and its sodium salt. Further, other adjuvants such as flavoring agents and/or sweeteners and the like may be added to the composition.
本发明所述的药物组合物制剂， 其剂型可以是药剂学上所说的任何一种剂型， 包括片剂、 胶囊剂、 软 胶囊剂、 喷雾剂、 凝胶剂、 凝胶气雾剂、 混悬剂、 冲剂、 贴剂、 软膏、 丸剂、 散剂、 乳剂、 注射剂、 输液 剂、 冻干注射剂、 脂质体注射剂， 靶向给药注射剂、 栓剂、 缓释制剂和控释制剂。  The pharmaceutical composition preparation of the present invention may be in the form of any one of pharmaceutically acceptable dosage forms, including tablets, capsules, soft capsules, sprays, gels, gel aerosols, and mixtures. Suspensions, granules, patches, ointments, pills, powders, emulsions, injections, infusion solutions, lyophilized injections, liposome injections, targeted administration injections, suppositories, sustained release preparations and controlled release preparations.
本发明所述的药物组合物制剂，优选的，环嘧耐平药用复合物与填充剂和 /或崩解剂组配制成片剂或胶 囊剂； 或者是环嘧耐平药用复合物与填充剂和 /或羟丙甲纤维素组配制成缓释制剂或者胶囊剂。  The pharmaceutical composition preparation of the present invention, preferably, the cycloheximide pharmaceutical complex is combined with a filler and/or a disintegrating agent to form a tablet or a capsule; or a cycloheximide medicinal compound and The filler and/or hypromellose are formulated into a sustained release preparation or capsule.
本发明所述的药物组合物制剂， 优选的， 环嘧耐平药用复合物与填充剂、 羟丙甲基纤维酸酯、 乙基纤 维素、 聚乙烯醇、 甲基硅树脂、 羟丙基纤维素、 聚乙二醇一 600、 丙烯酸一甲基丙烯酯树脂、 乙氧基乙基 纤维素、 甘油棕榈酸硬酯酸酯、 聚磷酸钠-脱乙酰壳多糖和 /或 PEG1500制成缓释制剂或控释制剂。  The pharmaceutical composition preparation of the present invention, preferably, the cycloheximide pharmaceutical complex and filler, hydroxypropyl methylcellulose ester, ethyl cellulose, polyvinyl alcohol, methyl silicone resin, hydroxypropyl group Sustained release of cellulose, polyethylene glycol 600, methacrylic acid acrylate resin, ethoxyethyl cellulose, glyceryl palmitate, sodium polyphosphate-chitosan and/or PEG1500 Formulation or controlled release preparation.
本发明所述的药物组合物制剂， 优选的， 环嘧耐平药用复合物与油相如大豆油、 聚乙二醇 400、 棉籽 油、 花生油、 麻油、 玉米油和 /或橄榄油混合， 制成注射剂或口服乳剂； 在所述的油相中还可加入增溶剂或 潜溶剂或抗氧剂。  The pharmaceutical composition preparation of the present invention, preferably, the cycloheximide pharmaceutical complex is mixed with an oil phase such as soybean oil, polyethylene glycol 400, cottonseed oil, peanut oil, sesame oil, corn oil and/or olive oil. An injection or an oral emulsion is prepared; a solubilizing agent or a latent solvent or an antioxidant may also be added to the oil phase.
本发明的药用组合物制剂可通过口服或非肠胃给药的方式施用于需要这种治疗的患者。 用于口服时， 可将其制成常规的固体制剂如片剂、 胶囊剂、 粉剂或颗粒剂等， 或制成液体制剂如水溶液或油悬浮剂或其 它液体制剂如糖浆、 口服液或酏剂等； 用于肠胃外给药时， 可将其制成注射用的溶液、 粉剂、 水溶液或油 性悬浮剂等。 优选的形式是片剂、 包衣片剂、 胶囊、 颗粒剂、 口服液和注射剂。  The pharmaceutical composition preparation of the present invention can be administered to a patient in need of such treatment by oral or parenteral administration. When used orally, it can be prepared into a conventional solid preparation such as a tablet, a capsule, a powder or a granule, or a liquid preparation such as an aqueous solution or an oil suspension or other liquid preparation such as a syrup, an oral solution or a tincture. For parenteral administration, it can be prepared as a solution for injection, a powder, an aqueous solution or an oily suspension. Preferred forms are tablets, coated tablets, capsules, granules, oral solutions and injections.
本发明中， 马来酸环嘧耐平的制备方法包括以下步骤：  In the present invention, the preparation method of cyclopyrene maleate comprises the following steps:
于 25 ml的茄形瓶， 加入 5-甲基 -4-(4- (三氟甲基)苯基) -4-氢吡唑 -3-胺 723 mg， 二羰基化合物 882 mg， 100 °C 反应 2小时，过滤固体得白色目标产物。 IR(KBr, cm— 3434, 3055, 2774, 1691, 1632, 1585, 1571, 1521, 1494, 1448, 1326, 1172, 1129, 1065; !H NMR (DMSO-d6) δ 12.30 (s, 1H), 7.93 (br, 4H), 7.56 (s, 1H), 7.53 (br, 2H), 6.10 (s, 1H), 2.19 (s, 3H)。 目标产物 I与马来酸乙醇溶液回流 30min， 结晶的目标产物 II。 本发明药用组合物制剂的各种剂型的制备方法是， 用环嘧耐平及其药用复合物为活性成分与以上所述 的一种或多种药学上可接受的药物载体混合， 然后将其制成所需的剂型。 In a 25 ml eggplant-shaped flask, add 723 mg of 5-methyl-4-(4-(trifluoromethyl)phenyl)-4-hydropyrazol-3-amine, 882 mg of dicarbonyl compound. The reaction was carried out at 100 ° C for 2 hours, and the solid was filtered to give a white product. IR (KBr, cm-3474, 3055, 2774, 1691, 1632, 1585, 1571, 1521, 1494, 1448, 1326, 1172, 1129, 1065; ! H NMR (DMSO-d 6 ) δ 12.30 (s, 1H) , 7.93 (br, 4H), 7.56 (s, 1H), 7.53 (br, 2H), 6.10 (s, 1H), 2.19 (s, 3H). The desired product I was refluxed with a solution of maleic acid in ethanol for 30 min. Target product II. Various dosage forms of the pharmaceutical composition preparation of the present invention are prepared by using cyclopyrine and a medicinal compound thereof as an active ingredient together with one or more pharmaceutically acceptable drugs as described above. The carrier is mixed and then formulated into the desired dosage form.
片剂、 胶囊剂、 颗粒剂和粉末等的固形制剂中， 通常可含有 0.1〜99 % (w/w) 的有效成分， 优选的是 0.1〜50 % (w/w) 的有效成分。  The solid preparation of tablets, capsules, granules, powders and the like may usually contain 0.1 to 99% (w/w) of the active ingredient, preferably 0.1 to 50% (w/w) of the active ingredient.
除了预先溶解的注射剂之外， 也可作成加有粉末或适当的添加剂的在使用时溶解的形态。 这些注射液 通常可含有 0.01〜50 % (w/w) 的有效成分、 优选的是 0.5〜5 % (w/w) 的有效成分。  In addition to the pre-dissolved injection, it is also possible to form a form which is dissolved at the time of use with a powder or a suitable additive. These injections may usually contain 0.01 to 50% (w/w) of the active ingredient, preferably 0.5 to 5% (w/w) of the active ingredient.
另外， 经口给药的悬浮剂、 糖浆剂等的剂型， 通常可含 0.5〜10 % (w/w) 的有效成分。  Further, a dosage form of a suspension, a syrup or the like which is orally administered may usually contain 0.5 to 10% (w/w) of an active ingredient.
本发明化合物优选的给药量， 可根据使用的化合物的种类、 配合的组合物种类、 适用频度和应该治疗 的特定部位、 病情的轻重、 患者的年龄、 医生的诊断、 肿瘤的种类等而变化， 但作为大致目标， 例如每天 成人的给药量， 在经口给药时， 可在 0.01〜400mg范围内， 另外， 在非经口给药时， 在静脉注射时， 优选 的是每天在 0.01〜100mg范围内。 另外， 给药次数， 根据给药方法和症状而不同， 但 1天是 1〜4次。 另 外， 也可使用隔日给药、 隔二日给药等间歇给药等给药方法。  The preferred amount of the compound of the present invention can be administered depending on the kind of the compound to be used, the kind of the composition to be compounded, the frequency of application, the specific site to be treated, the severity of the condition, the age of the patient, the diagnosis of the doctor, the type of the tumor, and the like. Change, but as a general target, for example, the daily dose of the adult can be in the range of 0.01 to 400 mg at the time of oral administration, and, in the case of parenteral administration, at the time of intravenous injection, it is preferably daily. 0.01 to 100 mg range. Further, the number of administrations varies depending on the administration method and symptoms, but it is 1 to 4 times per day. Further, an administration method such as intermittent administration such as administration every other day or administration for two days may be used.
本发明的药物组合物制剂， 其所含的填充剂及实施例中所含的填充剂的量为处方中量的 1%至 90%。  The pharmaceutical composition preparation of the present invention contains the filler and the filler contained in the examples in an amount of from 1% to 90% by weight of the prescription.
具体实施方式 detailed description
下面的实施例可以使本专业技术人员更全面地理解本发明， 但不以任何方式限制本发明。  The following examples are intended to provide a fuller understanding of the invention, but are not intended to limit the invention in any way.
实施例 1、 马来酸环嘧耐平注射液  Example 1. Cycloheximide maleate injection
【处方】  [prescription]
马来酸环嘧耐平 125g  Cycloheximide maleate 125g
葡萄糖 50g  Glucose 50g
注射用水 加至 1000ml  Water for injection added to 1000ml
【制法】  【Method】
①将葡萄糖粉溶于注射用水中， 配成 50 %〜60 %左右的溶液， 以 10 %HC1调 pH值至 4.2〜4.6左右 后， 加热煮沸 10〜20min， 投入活性炭 0.05 %， 搅匀， 冷却至室温， 滤除活性炭， 测定含量， 备用。  1 Dissolve the glucose powder in water for injection, prepare a solution of about 50%~60%, adjust the pH value to about 4.2~4.6 with 10% HC1, boil for 10~20min, add 0.05% activated carbon, stir well, cool At room temperature, the activated carbon was filtered off, and the content was determined and used.
②取配液量葡萄糖（按含量计算成容积）， 加入马来酸环嘧耐平， 加热至 40〜50°C， 搅拌溶解， 稀释 成配液量， 冷至室温， 测定 pH值在 4.2〜4.8左右， 精滤至澄明， 灌封于 2ml安瓿中， 100°C流通蒸汽灭菌 30min， 即得。 实施例 2、 马来酸环嘧耐平注射液 2 Take the amount of dosing solution of glucose (calculated according to the content), add cycloheximide maleate, heat to 40~50 ° C, stir to dissolve, dilute to the amount of liquid, cool to room temperature, determine the pH value of 4.2~ 4.8 or so, finely filter to clear, potted in 2ml ampoule, steam sterilization at 100 °C for 30min, that is. Example 2, cycloheximide maleate injection
本品为盐酸刊多卡因的灭菌水溶液。 含马来酸环嘧耐平应为标示量的 95 %〜105 %。  This product is a sterile aqueous solution of cocaine hydrochloride. The cycloheximide containing maleic acid should be 95%~105% of the labeled amount.
【处方】  [prescription]
马来酸环嘧耐平 125g  Cycloheximide maleate 125g
氯化钠 9g  Sodium chloride 9g
注射用水 加至 1000ml  Water for injection added to 1000ml
【制法】取氯化钠溶于注射用水中， 加马来酸环嘧耐平搅拌溶解后， 稀释至全量， 用稀盐酸调整 pH ¾ 3.5-5.0, 加活性炭， 过滤， 灌封， 100°C流通蒸汽灭菌 3min， 即得。  [Preparation method] Take sodium chloride dissolved in water for injection, add cycloheximide maleate and stir to dissolve, dilute to full amount, adjust pH 3⁄4 3.5-5.0 with dilute hydrochloric acid, add activated carbon, filter, potting, 100° C steam sterilization for 3 min, that is.
实施例 3、 环嘧耐平注射液  Example 3, cyclopyrine injection
【处方】  [prescription]
环嘧耐平 1250g 甘油 500g  Cycloheximide 1250g glycerin 500g
乙醇 (95%) 1000ml 注射用水 加至 10000ml  Ethanol (95%) 1000ml water for injection added to 10000ml
【制法】将乙醇用注射用水稀释成 70 %左右， 加去乙酸毛花苷丙， 不断搅拌溶解后， 加甘油， 以注射 用水稀释至总量， 过滤至澄明， 灌封于 2ml安瓿中， 100°C流通蒸汽灭菌 30min,即得。  [Preparation method] Diluted ethanol with water for injection to about 70%, add acetaminophen acetate, stir and dissolve, add glycerin, dilute with water for injection to the total amount, filter to clear, potting in 2ml ampoules, Steam sterilization at 100 ° C for 30 min, that is.
实施例 4、 环嘧耐平注射液 Example 4, cyclopyrine injection
【处方】  [prescription]
环嘧耐平 125g  Cyclopyrine 125g
苯甲酸苄酯 192g  Benzyl benzoate 192g
注射用油 加至 1000ml  Injection oil added to 1000ml
【制法】取注射用油， 干热至 150°C灭菌 lh， 放冷。 另取苯甲酸苄酯加环嘧耐平搅拌溶解， 然后加入 上述放冷的注射用油中， 搅匀。 待温度降至 60°C时， 用干燥 G3垂熔玻璃漏斗滤， 灌封时充氮气， 100°C流 通蒸汽灭菌 30min， 即得。 [Preparation method] Take the injection oil, dry heat to 150 ° C for 1 h, let cool. Further, benzyl benzoate and cycloheximide were stirred and dissolved, and then added to the above-mentioned cold-injected oil for injection, and stirred. When the temperature is lowered to 60 ° C, it is filtered with a dry G 3 fused glass funnel, filled with nitrogen at the time of potting, and steam sterilized at 100 ° C for 30 min.
实施例 5、 环嘧耐平注射液 Example 5, cyclopyrine injection
本品为环嘧耐平的灭菌油溶液， 含环嘧耐平应为标示量的 90%〜110 %。  This product is a sterile oil solution of cyclopyrine, containing cycloheximide should be 90%~110% of the labeled amount.
【处方】  [prescription]
环嘧耐平 125g  Cyclopyrine 125g
苯甲醇 150g  Benzyl alcohol 150g
注射用油 加至 1000ml  Injection oil added to 1000ml
【制法】取注射用油加热至 15 0°C灭菌 2h， 放置过夜， 次日加温至 60°C左右， 加环嘧耐平、苯甲醇， 搅拌溶解， 以干燥的 3号垂熔玻璃漏斗过滤， 通氮气. 灌封， 100°C流通蒸汽灭菌 30min， 即得。 实施例 6、 环嘧耐平注射液 [Preparation method] Take the injection oil and heat it to 150 °C for 2h, place it overnight, heat it to 60 °C the next day, add cyclohexine, benzyl alcohol, stir and dissolve, dry the No. 3 Filtration of glass funnel, nitrogen gas. Potting, steam sterilization at 100 ° C for 30 min, that is. Example 6, cyclopyrine injection
【处方】  [prescription]
环嘧耐平 （微粒结晶）  Cycloheximide (particle crystallization)
羧甲基纤维素钠 （300〜600cP)  Sodium Carboxymethyl Cellulose (300~600cP)
氯化钠  Sodium chloride
聚山梨酯 80  Polysorbate 80
注射用水 加至 1000ml  Water for injection added to 1000ml
【制法】  【Method】
①取马来酸环嘧耐平加入总体积约 30 %的注射用水中， 并加入羧甲基纤维素钠扰匀放置过夜， 用布 氏漏斗垫以 200目尼龙筛布抽滤后， 放于适宜密闭容器内备用。  1 Take cycloheximide maleate and add it to the total volume of about 30% of water for injection, add carboxymethylcellulose sodium and stir it overnight, use a Buchner funnel pad to filter with 200 mesh nylon sieve cloth, and put it on Suitable for use in a closed container.
②取氯化钠溶于总体积约 4 %的注射用水中， 并用 G3垂熔玻璃漏斗滤过， 装入密塞玻璃容器中。 另 取上述①溶液的二分之一， 置水浴上加热， 同时加入氯化钠溶液及聚山梨酯 80搅匀， 待水浴煮沸， 加入 环嘧耐平微粒搅匀， 继续加热 30min， 取出冷却至室温， 再放置过夜。 2 Sodium chloride was dissolved in about 4% of the total volume of water for injection, filtered through a G 3 fused glass funnel, and placed in a sealed glass container. Take another half of the above 1 solution, heat on a water bath, add sodium chloride solution and polysorbate 80, stir well, wait until the water bath is boiled, add cyclopyrene tablets and stir well, continue heating for 30min, take out and cool to Leave at room temperature overnight.
③将①与②的全部溶液， 分别经 200目尼龙筛在搅拌下过筛一次， 筛入适宜的容器内， 然后取滤过 的注射用水， 反复冲洗筛子等， 并加至总体积量， 经搅拌均匀后. 复核重量应符合配制全置要求。  3 sift all the solutions of 1 and 2, respectively, through a 200 mesh nylon sieve, and sieve them into a suitable container, then take the filtered water for injection, repeatedly rinse the sieve, etc., and add to the total volume. After mixing evenly, the weight of the review should meet the requirements for full configuration.
④将上项初筛过的全部混悬液， 再经 200目尼龙筛过筛一次， 筛入搅拌桶内， 边搅拌边装入 5ml瓶 内， 盖塞轧口密闭， 经 100°C流通蒸汽灭菌 30min， 即得。  4 All the suspensions which were sieved in the previous item were sieved once through a 200 mesh nylon sieve, sieved into a mixing tank, and filled into a 5 ml bottle while stirring. The sealing plug was sealed and steamed at 100 °C. Sterilize for 30 minutes, that is.
实施例 7、 环嘧耐平注射用亚微乳 Example 7, submicron emulsion for cyclopyrine injection
【处方】  [prescription]
环嘧耐平 250mg 大豆磷脂 1.2g  Cycloheximide 250mg Soybean phospholipid 1.2g
大豆油 20g 注射用水 加至 100ml  Soybean oil 20g water for injection to 100ml
【制法】将处方中的各成分混合均匀后，在乳匀压力 133Mpa下乳匀 3次，用 0.2mol I LNaOH调节 pH 至 8 .5， 高压灭菌， 充氮， 熔封贮存。  [Preparation method] After mixing the ingredients in the prescription, the emulsion was uniformly immersed at 133 MPa for 3 times, adjusted to pH 8.5 with 0.2 mol of I L NaOH, autoclaved, nitrogen-filled, and sealed.
实施例 8、 环嘧耐平静脉注射用亚微乳  Example 8, submicron emulsion for intravenous injection of cyclopyrine
【处方】  [prescription]
环嘧耐平 250mg 精制豆油 15g  Cycloheximide 250mg refined soybean oil 15g
Poloxamerl08 4g 甘油 2.5g  Poloxamerl08 4g Glycerin 2.5g
精制豆磷脂 0.3g 注射用水 加至 100g  Refined Soy Phospholipid 0.3g Water for Injection Add to 100g
【制法】将精制豆磷脂、 环嘧耐平溶入精制豆油中作油相， 将 Poloxamer108和甘油溶入注射用水中 作水相， 油相与水相加热至 60°C， 倾入组织捣碎机中捣 9min得粗乳， 将粗乳转入高压乳匀机中循环 3次， 过滤、 分装、 灭菌即得。 [Preparation method] The purified soybean phospholipid and cyclopyrazine are dissolved in refined soybean oil as an oil phase, and Poloxam er 108 and glycerin are dissolved in water for injection as an aqueous phase, and the oil phase and the aqueous phase are heated to 60 ° C, poured into The tissue was crushed in a masher for 9 minutes to obtain a crude milk, and the crude milk was transferred to a high-pressure milk homogenizer for 3 times. Filter, dispense, and sterilize.
实施例 9、 马来酸环嘧耐平葡萄糖注射液  Example 9. Cycloheximide maleate glucose injection
【处方】  [prescription]
马来酸环嘧耐平 2.5g  Maleic acid cycloheximide 2.5g
氯化钠 9g  Sodium chloride 9g
注射用水 加至 1000ml  Water for injection added to 1000ml
【制法】将注射用水加热至沸，加入处方量的马来酸环嘧耐平，搅拌使溶解，配制成 12 %~15 %的溶液， 加入 1.5 %的活性炭， 保持微沸 l~2h， 加压过滤脱炭， 加注射用水稀释成 6 %的浓度， 然后加入氯化钠使溶 解， 冷却至室温， 测定含量和 pH值， pH值应控制在 4. 4-4. 9， 再加活性炭 0.5 %， 加热至 70〜80°C， 过滤至药液澄明后灌装， 112°C、 30min灭菌即得。  【Method】 Heat the water for injection to boiling, add the prescribed amount of cycloheximide maleate, stir to dissolve, prepare 12%~15% solution, add 1.5% activated carbon, keep boiling for l~2h, The sulphuric acid is added to the sulphuric acid, and the sulphuric acid is added to the 6%, and then the solution is added to the solution. 0.5%, heated to 70~80 °C, filtered until the liquid is clear and filled, and sterilized at 112 ° C for 30 minutes.
实施例 10、 注射用马来酸环嘧耐平 Example 10, cycloheximide maleate for injection
本品为马来酸环嘧耐平的无菌冻干制剂， 含马来酸环嘧耐平的效价应为标示量的 90 %以上。  This product is a sterile lyophilized preparation of cycloheximide maleate. The potency of cyclopyrimidine maleate should be more than 90% of the labeled amount.
【处方】  [prescription]
马来酸环嘧耐平 250mg 葡萄糖酸钙 lmg  Cycloheximide maleate 250mg calcium gluconate lmg
水解明胶 5mg 半胱氨酸 0.5mg  Hydrolyzed gelatin 5mg cysteine 0.5mg
甘露醇 10mg  Mannitol 10mg
【制法】将上述各成分用适量注射用水溶解后， 无菌过滤， 分装于安瓿中， 每支 0.5ml， 冷冻干燥后 封口， 漏气检査即可。  [Method] Dissolve each of the above ingredients in an appropriate amount of water for injection, aseptically filter, and dispense in ampoules, 0.5 ml each, freeze-dry and seal, and check for leaks.
实施例 11、 注射用马来酸环嘧耐平  Example 11. Cycloheximide maleate for injection
本品为马来酸环嘧耐平的无菌白色疏松状粉末， 临用时用注射用水溶解。 每支内含 50mg。  This product is a sterile white loose powder of cycloheximide maleate, which is dissolved in water for injection when it is used. Each contains 50mg.
【处方】  [prescription]
马来酸环嘧耐平 2.5g  Maleic acid cycloheximide 2.5g
50 %氢氧化钠液 适量  50% sodium hydroxide solution
注射用水 加至 1000ml  Water for injection added to 1000ml
【制法】在无菌操作室内，称取马来酸环嘧耐平 500g，置适当灭菌容器中，加灭菌注射用水约 9500ml， 搅拌使溶解， 测定 pH值（约为 2)， 加 50 %氢氧化钠溶液调节 pH至 6.3〜6. 7， 补加灭菌注射用水至全 量， 然后加入 0.02 %的活性炭， 搅拌 5~10min， 用灭菌布氏漏斗铺 2层灭菌滤纸过滤， 再用灭菌的 06垂 熔玻璃漏斗抽滤， 半成品送检合格后， 无菌条件下灌注于安瓿中， 低温冷冻干燥约 36h， 熔封， 即得。 实施例 12、 马来酸环嘧耐平滴眼液 [Preparation method] In the aseptic operation room, weigh 500g of cycloheximide maleate, place it in a suitable sterilization container, add about 9500ml of sterile water for injection, stir to dissolve, determine the pH value (about 2), plus 50% sodium hydroxide solution to adjust the pH to 6.3~6. 7, add sterile water for injection to the full amount, then add 0.02% activated carbon, stir for 5~10min, filter with 2 layers of sterile filter paper by sterilized Brinell funnel. Then, it is filtered with a sterilized 0 6 fused glass funnel. After passing the semi-finished product, it is poured into an ampoule under aseptic conditions, freeze-dried at a low temperature for about 36 hours, and sealed. Example 12, cycloheximide maleate eye drops
【处方】 马来酸环嘧耐平 lg 氯化钠 2.8g 【prescription】 Maleic acid cyclopyridamole lg sodium chloride 2.8g
硼酸 6.8g 硼砂 8.6g  Boric acid 6.8g Borax 8.6g
注射用水 加至 1000ml  Water for injection added to 1000ml
【制法】取约 800ml注射用水， 加热， 加入马来酸环嘧耐平、硼酸、硼砂、氯化钠及马来酸环嘧耐平， 搅拌使溶解， 过滤， 加注射用水至全量， 搅匀， 灌封， 100°C流通蒸汽灭菌 30min。 无菌分装， 即得。 实施例 13、 马来酸环嘧耐平滴眼液  [Preparation method] Take about 800ml of water for injection, heat, add cycloheximide maleate, boric acid, borax, sodium chloride and cycloheximide maleate, stir to dissolve, filter, add water for injection to full amount, stir Uniform, potting, steam sterilization at 100 ° C for 30 min. Aseptic dispensing, that is. Example 13. Cycloheximide maleate eye drops
【处方】  [prescription]
马来酸环嘧耐平 lOOmg 尼泊金丙酯 O.Ollg  Cycloheximide maleate lOOmg propylparaben O.Ollg
氯化钠 0.9g 蒸熘水 加至 100ml  Sodium chloride 0.9g Steamed water added to 100ml
尼泊金甲酯 0.023g  Methylparaben 0.023g
【制法】取尼泊金甲酯、 丙酯， 加沸蒸熘水溶解， 于 60 °C时溶入马来酸环嘧耐平和氯化钠， 过滤， 加 蒸熘水至足量， 灌装， 100】、 30min灭菌。  【Method】 Take methylparaben and propyl ester, dissolve in boiling water, dissolve cycloheximide maleate and sodium chloride at 60 °C, filter, add steamed water to a sufficient amount, and irrigate Packed, 100], 30min sterilization.
实施例 14、 马来酸环嘧耐平胶囊剂 Example 14. Cycloheximide maleate capsule
【处方】  [prescription]
马来酸环嘧耐平胶 250mg  Maleic acid cycloheximide gel 250mg
乳精 25mg  Creamer 25mg
微晶纤维素 35mg  Microcrystalline cellulose 35mg
乙醇 （70 % ) 适量  Ethanol (70%)
淀粉 34mg  Starch 34mg
【制法】按处方量称取微晶纤维素、 淀粉和乳糖， 混匀； 按处方量称取马来酸环嘧耐平并用少量 70 %乙醇溶解， 加入上述已混匀的粉末中制软材， 过 28目筛制粒， 60°C烘干， 20目筛整粒， 装入 2号空胶 囊， 即得。  [Method] Weigh microcrystalline cellulose, starch and lactose according to the prescription, mix well; weigh cycloheximide maleate and dissolve it with a small amount of 70% ethanol according to the prescription, add it to the mixed powder to make soft The material is sieved through a 28 mesh sieve, dried at 60 ° C, and sieved through a 20 mesh sieve, and filled into an empty capsule No. 2, which is obtained.
实施例 15、 马来酸环嘧耐平片 Example 15. Cycloheximide maleate tablets
【处方】  [prescription]
马来酸环嘧耐平 （细粉或极细小结晶） 250.0mg  Cycloheximide maleate (fine powder or very fine crystal) 250.0mg
酒石酸 l.Omg  Tartaric acid l.Omg
淀粉 20.0mg。  Starch 20.0 mg.
乙醇 50 % 适量  Ethanol 50%
糊精 30.0 mg  Dextrin 30.0 mg
硬脂破镁 1.5mg 【制法】将马来酸环嘧耐平、 淀粉、 糊精置不锈钢电动混合机中混匀。 另收酒石酸溶于 50 %乙醇中， 一次加入马来酸环嘧耐平的混合粉末中， 混合均匀， 制成软材， 通过如目尼龙筛一次制成 20〜40目湿粒， 置干燥箱中干燥， 开始时温度不超过 60°C， 将近干燥时温度可升至 70°C以下， 以加速干燥， 但温度不宜 过高， 以免变色。 干粒通过 20目筛， 加入硬脂酸镁拌匀， 即可压片。 Hard fat broken magnesium 1.5mg [Preparation method] Mix maleic acid cyclohexine, starch and dextrin into a stainless steel electric mixer. In addition, the tartaric acid is dissolved in 50% ethanol, and the mixed powder of cycloheximide maleate is added once, uniformly mixed, and made into a soft material, and 20~40 mesh wet granules are prepared once by a nylon mesh sieve, and the drying box is placed. Medium drying, the temperature does not exceed 60 ° C at the beginning, the temperature can be raised to below 70 ° C when drying, to accelerate drying, but the temperature should not be too high to avoid discoloration. The dry granules are passed through a 20 mesh sieve, and the magnesium stearate is added and mixed to form a tablet.
实施例 16、 马来酸环嘧耐平片 Example 16. Cycloheximide maleate tablets
【处方】每 100万片用量 ( 0.25g/片）  [Prescription] per 1 million tablets (0.25g / tablet)
马来酸环嘧耐平 100kg 淀粉 （冲浆） 8kg  Cycloheximide maleate 100kg starch (slurry) 8kg
淀粉 50kg 硬脂酸镁 2kg  Starch 50kg magnesium stearate 2kg
糖粉 50kg  Powdered sugar 50kg
【制法】将马来酸环嘧耐平微晶细粉与淀粉、糖粉混合均匀，用 12 %淀粉浆制成软材，过 12目筛制粒， 湿粒在 60〜65°C干燥， 干粒过 12目筛整粒， 加硬脂酸镁混匀后， 压片， 即得。  [Preparation method] Mix the microcrystalline fine powder of cycloheximide maleate with starch and powdered sugar, make soft material with 12% starch slurry, granulate through 12 mesh sieve, and dry the wet pellet at 60~65 °C. The dry granules are sieved through a 12-mesh sieve, and after mixing with magnesium stearate, the tablets are obtained.
实施例 17、 马来酸环嘧耐平片 Example 17. Cycloheximide maleate tablets
【处方】每 1000片用量  [prescription] for every 1000 tablets
马来酸环嘧耐平 250g Avicel PH-101 (美国产微晶纤维素） 60g  Cycloheximide maleate 250g Avicel PH-101 (microcrystalline cellulose produced in the United States) 60g
淀粉 9.85g 硬脂酸钙 5.9g  Starch 9.85g calcium stearate 5.9g
PVP-K30 ( 8%醇溶液） 18.1g  PVP-K30 (8% alcohol solution) 18.1g
【制法】将药物和淀粉混合， 用 PVP醇溶液湿润制粒、 干燥， 过 16目筛， 然后加 Avicel PH-101和硬 脂酸钙 （预先过 40目筛）， 一起混合压片。  [Method] The drug and starch were mixed, wetted with PVP alcohol solution, dried, passed through a 16 mesh sieve, and then Avicel PH-101 and calcium stearate (previously passed through a 40 mesh sieve) were added and mixed together.
实施例 18、 马来酸环嘧耐平阴道片 Example 18, Cycloheximide vaginal tablets of maleic acid
常用制品： 每片含马来酸环嘧耐平 0.25g。  Commonly used products: Each tablet contains cycloheximide maleate 0.25g.
【处方】每 10万片用量 （0.25g/片）  [Prescription] for every 100,000 tablets (0.25g / tablet)
马来酸环嘧耐平 25.00kg 淀粉 （冲浆 10%) 0.70kg  Cycloheximide maleate 25.00kg starch (10% pulping) 0.70kg
淀粉 5.00kg 硬脂酸镁 0.24kg  Starch 5.00kg magnesium stearate 0.24kg
氢氧化铝 0.50kg  Aluminum hydroxide 0.50kg
【制法】将马来酸环嘧耐平粉碎成 80目细粉， 加入淀粉、 氢氧化铝， 搅拌均匀， 用淀粉浆制成软材， 制粒， 80°C左右通风干燥， 加入硬脂酸镁， 整粒， 混匀， 压片。  [Preparation method] pulverize maleic acid cyclohexine to 80 mesh fine powder, add starch, aluminum hydroxide, stir evenly, use starch slurry to make soft material, granulate, ventilate and dry at 80 °C, add hard fat Magnesium, whole, mixed, compressed.
实施例 19、 马来酸环嘧耐平薄膜衣片 Example 19: Cycloheximide film of maleic acid film
【片心处方 】  [Piece prescription]
马来酸环嘧耐平 250mg  Cycloheximide maleate 250mg
淀粉与糊精配比 （质量分数） 4: 1 羧甲基淀粉钠 4% Starch and dextrin ratio (mass fraction) 4: 1 Carboxymethyl starch sodium 4%
12%淀粉浆 适量  12% starch slurry
【包衣液处方】 4 %的羟丙基甲基纤维素为成膜材料； 溶剂中乙醇与水的配比为 50:50; 选蓖麻油作为 增塑剂。  [Prescription of coating liquid] 4% hydroxypropyl methylcellulose is a film-forming material; the ratio of ethanol to water in the solvent is 50:50; castor oil is selected as a plasticizer.
【制法】  【Method】
①取处方量主药和辅料， 分别过筛混匀， 制软材， 于 20 U网筛制温颗粒， 60°C干燥至适宜水分， 按 0.5%加入硬脂酸镁， 混合过筛整粒， 于 Φ 6mm冲压片， 待用。  1 Take the prescription of the main drug and auxiliary materials, separately sieve and mix, make soft materials, filter the temperature particles in 20 U mesh, dry to 60 ° C to the appropriate moisture, add 0.5% magnesium stearate, mix and sieve the whole grain , Φ 6mm stamping sheet, ready to use.
②配制包衣浆液， 称取片心适量， 置包衣锅内预热 2〜3min， 待片心温度 35〜40°C时， 开始喷液包 衣。 记录用浆量， 停止喷液后继续鼓风干燥 5min取出， 置干燥器内待用。  2 Prepare the coating slurry, weigh the right amount of the tablets, preheat in the coating pot for 2~3min, and start the liquid coating when the core temperature is 35~40°C. Record the amount of pulp, stop the spray and continue to blow dry for 5 minutes, and set it in the desiccator for use.
实施例 20、 马来酸环嘧耐平肠溶片 Example 20: Cycloheximide maleate enteric coated tablets
【肠溶液处方】每 1万片用量  [Intestinal solution prescription] every 10,000 tablets
马来酸环嘧耐  Cycloheximide maleate
聚丙烯酸 II号树酯 邻苯二甲酸二乙酯 20g  Polyacrylic acid II resin diethyl phthalate 20g
聚丙烯酸 III号树酯 蓖麻油 30g  Polyacrylic acid III resin castor oil 30g
聚山梨酯 80 95%乙醇 1000g  Polysorbate 80 95% Ethanol 1000g
【配制】  [Preparation]
别称取聚丙烯酸 II、 III号树酯各 40g， 邻苯二甲酸二乙酯 20g， 加入 95%乙醇 1000g， 搅拌均匀密 闭静置 24h， 临用前加蓖麻油 30g、 聚山梨酯 80 15g， 搅拌均匀， 过四号筛， 称定总量备用。 【保护液处方】 3 %羟内基甲基纤维素溶液 lkg、 肠溶液 0.24kg、 丙二醇 40g、 滑石粉  Weigh 40g of polyacrylic acid II and III resin, 20g of diethyl phthalate, add 1000g of 95% ethanol, stir evenly and let stand for 24h, add 30g of castor oil and 80g of polysorbate before use. Stir well, pass through the No. 4 sieve, and weigh the total amount. [Protective solution] 3 % hydroxymethyl cellulose solution lkg, intestinal solution 0.24kg, propylene glycol 40g, talcum powder
配成 3 %羟内基中基纤维素溶液后， 将肠溶液接处方量加入搅匀， 再将丙二醇、 滑石粉 300g， 加入， 继续搅拌均匀后备用。  After formulating a 3% hydroxylactone medium-based cellulose solution, the intestine solution was added to the formulation and stirred, and then propylene glycol and talc powder 300 g were added, and the mixture was further stirred and then used.
【工艺】取马来酸环嘧耐平的片心， 先包几层粉衣， 喷肠溶液， 喷保护波， 然后， 包加有羟丙基甲基纤 维素的粉糖衣。  [Process] Take the core of cycloheximide maleate, first pack several layers of powder coat, spray the intestine solution, spray the protective wave, and then add the powdered sugar coating with hydroxypropyl methylcellulose.
实施例 21、 马来酸环嘧耐平分散片 Example 21: Cycloheximide Maleate Dispersible Tablets
【处方】  [prescription]
马来酸环嘧耐平 250mg PVPP lOOmg  Cycloheximide maleate 250mg PVPP lOOmg
乳糖 50m g CMC-Na 25mg  Lactose 50m g CMC-Na 25mg
淀粉 （starch) 1500 lOOmg 阿斯巴甜  Starch 1500 lOOmg aspartame
十二烷基硫酸钠 40mg  Sodium lauryl sulfate 40mg
【制法】将马来酸环嘧耐平过 100目筛后加入乳糖、淀粉 1500、 PVPP、阿斯巴甜混匀， 以 5%PVPK30 乙醇液作黏合剂， 制成软材， 过筛制粒， 60°C鼓风干燥， 整粒后羧甲基淀粉纳和硬脂酸镁， 混匀， 干颗粒 中喷入适量草莓香精， 放置过夜使香精匀化， 压片. 即得。 【Method】 Add cyclohexane maleate to 100 mesh sieve and add lactose, starch 1500, PVPP and aspartame to mix 5% PVPK30 Ethanol solution is used as a binder, made into soft material, sieved and granulated, dried at 60 °C, granulated with sodium carboxymethyl starch and magnesium stearate, mixed, and sprayed with appropriate amount of strawberry flavor in dry granules. Allow the essence to homogenize overnight and compress.
实施例 11、 马来酸环嘧耐平亲水性凝胶骨架片  Example 11, cyclopyrene maleic acid hydrophilic gel matrix sheet
【处方】  [prescription]
马来酸环嘧耐平 400mg HPMC 400mg  Cycloheximide maleate 400mg HPMC 400mg
PEG 200mg 乳糖 75mg  PEG 200mg Lactose 75mg
【制法】称取适量 NFP与适量 PEG (固体）， 采用熔融法或溶剂法制成固体分散物， 再与 HPMC；、 乳糖等混匀， 制粒. 压片， 每片含 NFP20mg。  [Method] Weigh an appropriate amount of NFP and an appropriate amount of PEG (solid), use a melt method or solvent method to make a solid dispersion, and then mix with HPMC;, lactose, etc., granulation. Tablets, each containing NFP20mg.
实施例 23、 马来酸环嘧耐平缓释片  Example 23, cycloheximide maleic acid sustained release tablets
【处方】  [prescription]
基片 每 1000片用量 包衣液 1000片用  Substrate for 1000 tablets, coating solution for 1000 tablets
马来酸环嘧耐平 400g HPMC 5g  Cycloheximide maleate 400g HPMC 5g
丙烯酸树脂 in号 180g 聚乙二醇 400g  Acrylic resin in number 180g polyethylene glycol 400g
HPMC 100g 滑石粉 1.5g  HPMC 100g talcum powder 1.5g
微晶纤维素 80g 蒸熘水 30ml  Microcrystalline cellulose 80g steamed water 30ml
2%PVP 100ml 80%乙醇溶液 加至 100ml  2% PVP 100ml 80% ethanol solution added to 100ml
4g  4g
【制法】将马来酸环嘧耐平过 120目筛，称取处方比例的马来酸环嘧耐平、丙烯酸树脂 III号、 HPMC, 微晶纤维素混合均匀，用 2 %PVP乙醇溶液制成适宜软材。用 18目筛网整粒，加入硬脂酸镁，混匀、压片、 包衣， 即得。  [Preparation method] Cycloheximide maleate was passed through a 120 mesh sieve, and the proportion of the formulation of cycloheximide maleate, acrylic resin III, HPMC, microcrystalline cellulose was uniformly mixed, and 2% PVP ethanol solution was used. Made into suitable soft materials. The granules were sieved with an 18-mesh sieve, magnesium stearate was added, and the mixture was mixed, tableted, and coated.
实施例 24、 马来酸环嘧耐平缓释片 Example 24, cycloheximide maleate sustained-release tablets
【处方】  [prescription]
缓释部分 每片用量 速释部分 每片用量  Sustained release part per tablet amount of immediate release part per tablet
马来酸环嘧耐平细粉 0.40g  Maleic acid cycloheximide fine powder 0.40g
乙基纤维素 适量 淀粉 0.027g  Ethyl cellulose amount of starch 0.027g
丙烯酸树脂 适量 12%淀粉浆 适量  Acrylic resin, appropriate amount, 12% starch slurry, proper amount
稳定剂 适量 滑石粉 适量  Stabilizer, appropriate amount, talcum powder, proper amount
【制法】缓释部分， 取乙基纤维素和丙烯酸树脂的细粉状匀， 用适量浓度的乙醇溶解后， 加入马来酸 环嘧耐平细粉， 制成软材， 过筛， 制湿颗粒， 干燥， 过筛整粒。 速释部分， 称取马来酸环嘧耐平、 淀粉混 匀， 加入 12%淀粉浆适量， 混匀， 制成软材， 过筛制湿粒， 干燥， 过筛整粒。 压片， 将缓释与速释颗粒充 分混匀， 称重， 加适量滑石粉混匀， 压片。 [Preparation method] The sustained-release part is prepared by taking a fine powder of ethyl cellulose and acrylic resin, dissolving it with an appropriate amount of ethanol, adding cycloalthene maleate fine powder, and making it into a soft material. Wet granules, dry, sieved and sized. In the immediate release part, weigh the cycloheximide maleate and starch, mix it with 12% starch slurry, mix it, make it into soft material, sieve it to wet grain, dry it, and sieve it. Tableting, will release sustained release and immediate release particles Mix well, weigh, add appropriate amount of talcum powder, and compress.
实施例 25、 马来酸环嘧耐平缓释片的组成 Example 25 Composition of Cycloheximide Maleate Sustained Release Tablets
【处方】  [prescription]
马来酸环嘧耐平 400mg 80 %乙醇溶液 适量  Cycloheximide maleate 400mg 80% ethanol solution
羟丙基甲基纤维素 （K100M) 40mg 硬脂酸镁 2.3mg  Hydroxypropyl methylcellulose (K100M) 40mg Magnesium stearate 2.3mg
乳糖 50mg  Lactose 50mg
【制法】  【Method】
①将马来酸环嘧耐平、 乳糖粉碎过 100目筛。  1 The cyclosporine maleate and lactose were pulverized through a 100 mesh sieve.
②羟丙基甲基纤维素过 80目筛。  2 hydroxypropyl methylcellulose passed through a 80 mesh sieve.
③ 80 %乙醇溶液的配制： 取 95 %乙醇溶液加蒸熘水稀释， 即得。  3 80% ethanol solution preparation: Take 95% ethanol solution and dilute with distilled water to obtain.
④缓释片的制备： 按处方量称取马来酸环嘧耐平、 羟丙基甲基纤维素及乳糖于乳钵中， 将其混匀， 加 80 %乙醇溶液制软材， 过 18目筛制粒， 湿颗粒在 50~60°C干燥， 干燥经 16目筛整粒， 称重加硬脂酸镁 ， 混匀， 压片， 即得。  4 Preparation of sustained-release tablets: Weigh cycloheximide maleate, hydroxypropyl methylcellulose and lactose in chyle according to the prescription, mix them, add 80% ethanol solution to make soft materials, over 18 The mesh is granulated, the wet granules are dried at 50-60 ° C, dried and sieved through a 16 mesh sieve, weighed and added with magnesium stearate, mixed, and tableted.
实施例 26、 马来酸环嘧耐平缓释片 Example 26: Cycloheximide maleate sustained-release tablets
【处方】 马来酸环嘧耐平、 硬脂酸、 PEG6000等。  [Prescription] Cycloheximide maleate, stearic acid, PEG6000, etc.
【制法】  【Method】
① 固体分散体的制备： 取硬脂酸一聚乙二醇 6000 ( 3: 1 ) 以水浴加热依熔触， 加入与上达等量的马来 酸环嘧耐平， 充分搅匀， 然后迅速冷却使之固化。 低温放置一定时间后粉碎， 过 40目筛。  1 Preparation of solid dispersion: Take stearic acid-polyethylene glycol 6000 (3: 1), heat it in a water bath, add the same amount of cyclopyrene maleate, stir well, then quickly Cool to solidify. After chilling for a certain period of time, it is pulverized and passed through a 40 mesh sieve.
②片剂制备： 片剂颗粒由两部分组成， 一部分是速释颗粒， 按普通片剂制粒办法制备（含药 17. 6% )； 另一部分为缓释部分， 由上述固体分散体、 淀粉、 糊精、 阿拉伯胶等用稀乙醇制粒而得 （含约 40 % ) ; 两 者按一定比例混合后加崩解剂、 润滑剂压片。  2 tablet preparation: tablet granules consist of two parts, one part is immediate release granules, prepared by ordinary tablet granulation method (containing 17.6%); the other part is sustained release part, from the above solid dispersion, starch , dextrin, gum arabic and the like are obtained by granulating with dilute ethanol (containing about 40%); the two are mixed in a certain ratio, and then a disintegrant and a lubricant are pressed.
实施例 27、 马来酸环嘧耐平骨架缓释片 Example 27: Cycloheximide maleate sustained-release tablet
【处方】  [prescription]
马来酸环嘧耐平 400g 羟丙基甲基纤维素 25g  Cycloheximide maleate 400g Hydroxypropyl methylcellulose 25g
氢化植物油 5g 硬脂酸镁 2g  Hydrogenated vegetable oil 5g magnesium stearate 2g
【制法】将马来酸环嘧耐平氢化植物油、 羟丙基甲基纤维素等辅料混匀， 制粒， 干燥， 整粒， 加入硬 脂酸镁混匀， 压片， 即得。  [Method] Mix the cycloheximide hydrogenated vegetable oil, hydroxypropyl methylcellulose and other auxiliary materials, granulate, dry, whole, add magnesium stearate and mix, and compress.
实施例 28、 环嘧耐平单室单层渗透泵片 Example 28, cyclopyrine flat single-chamber single-layer osmotic pump sheet
【片心处方】  [Piece prescription]
环嘧耐平 lOOmg PEO(Mr 500000) 120mg PEO(Mr 200000) 5160mg 氯化钠 lOOmg Cycloheximide lOOmg PEO (Mr 500000) 120mg PEO (Mr 200000) 5160mg sodium chloride lOOmg
【制法】将原料分别过 40目筛，按处方量称取后均匀混合.加 95 %乙醇制软材，过 20目筛制粒， 40°C 干燥 2h， 18目筛整粒， 加适量硬脂酸镁混匀， 适量填允于 9mm浅凹冲模内压片， 即得片心。 将片心置 于包衣锅内， 吹入热空气， 待片床温度为 50°C后， 进行包衣。 包在液含 CA与 40%CA量的 PEG400, 溶 剂为丙酮一异丙醇 （9 : 1 )， 包衣液输入速度为 4.6ml/min， 压力为 24kPa， 包衣增重 10%。 将包衣完毕的 片子在 40°C干燥 24h， 除去剩余溶剂， 在片子的一侧打一小孔， 孔径 0. 4mm ， 即得。  [Preparation method] The raw materials are respectively passed through a 40 mesh sieve, and weighed according to the prescription amount and uniformly mixed. Add 95% ethanol soft material, pass 20 mesh sieve granules, dry at 40 °C for 2 hours, and add 18 mesh sieves to the appropriate amount. Mix the magnesium stearate, and fill it in the 9mm shallow concave die. The core was placed in a coating pan, and hot air was blown in. After the bed temperature was 50 ° C, the coating was carried out. The solution contained PEG400 with CA and 40% CA, the solvent was acetone-isopropyl alcohol (9:1), the input speed of the coating liquid was 4.6 ml/min, the pressure was 24 kPa, and the coating weight gain was 10%. The coated film was dried at 40 ° C for 24 hours, and the remaining solvent was removed. A small hole was formed on one side of the sheet, and the pore diameter was 0.4 mm.
实施例 29、 马来酸环嘧耐平渗透泵片 Example 29: Cyclonepine maleate osmotic pump sheet
【处方】每片用量  [prescription] per tablet
片心层 灘 Jl  Heart layer beach Jl
马来酸环嘧耐平 250 mg 聚氧乙烯 （相对分子质 7000000 ) 80.9 mg 聚氧乙烯 （相对分子质 300000 ) 100.7 mg NaCl 22.0 mg Cycloheximide maleate 250 mg polyoxyethylene (relative molecular mass 7000000 ) 80.9 mg polyoxyethylene (relative molecular weight 300000 ) 100.7 mg NaCl 22.0 mg
PVP K29-K39 16.5 mg HPMC E-5 5.0 mgPVP K29-K39 16.5 mg HPMC E-5 5.0 mg
NaCl 13.2 mg Fe203 1.0 mg 硬脂酸镁 1.7mg 硬脂酸镁 0.5mgNaCl 13.2 mg Fe 2 0 3 1.0 mg Magnesium stearate 1.7 mg Magnesium stearate 0.5 mg
【制法】按处方压制成片心和渗透层后，外层用醋酸纤维素、羟丙基甲基纤维素和聚乙二醇（PEG3350 ), 用激光在靠近药物层的半透膜上打释药小孔。 [Preparation method] After pressing into a core and a permeation layer according to the prescription, the outer layer is made of cellulose acetate, hydroxypropylmethylcellulose and polyethylene glycol (PEG3350), and the laser is used on the semipermeable membrane near the drug layer. Release the small holes.
实施例 30、 马来酸环嘧耐平漂浮片  Example 30. Cycloheximide floatation film of maleic acid
【处方】  [prescription]
马来酸环嘧耐平 200mg PVP 200mg  Cycloheximide maleate 200mg PVP 200mg
MC(4000mPa.s) 70mg EC(10m Pa.s) 80.6mg  MC (4000mPa.s) 70mg EC (10m Pa.s) 80.6mg
25mg 滑石粉 lOmg  25mg talcum powder lOmg
CMC-Na lOmg 硬脂酸镁 3mg  CMC-Na lOmg magnesium stearate 3mg
HPMC(4000mPa.s) 60mg  HPMC (4000mPa.s) 60mg
【制法】将药物与 CMC-Na混合， 用 10%的乙醇溶液作为黏合剂制粒， 其余物料 （滑 石粉、 硬脂 酸镁除外） 混合后干法制粒， 然后将两种颗粒混匀， 加润滑剂， 压片 （压力 4~6kgf/m2'不超过 lO kgf/cm2) 实施例 31、 马来酸环嘧耐平软膏 （乳化法， 乳剂型基质） [Method] Mix the drug with CMC-Na, granulate with 10% ethanol solution as binder, and mix the other materials (except talc powder and magnesium stearate) for dry granulation, then mix the two particles. Add lubricant, compress (pressure 4~6kgf/m 2 ' does not exceed lO kgf/cm 2 ) Example 31, cyclopropazine maleate ointment (emulsification method, emulsion type matrix)
【处方】每 lOOOg  [prescription] every lOOOOg
马来酸环嘧耐平 50g 白凡士林 250.0g  Cycloheximide maleate 50g white petrolatum 250.0g
三乙醇胺 20.0g 尼泊金 l.Og  Triethanolamine 20.0g paraben l.Og
甘油 50.0g 香料 适量 硬脂酸 150.0g 蒸熘水 510.0g Glycerin 50.0g Stearic acid 150.0g distilled water 510.0g
羊毛脂 20.0g  Lanolin 20.0g
【制法】取三乙醇胺、 甘油、 尼泊金溶于水中， 并在水浴上加热至 75°C ; 另取硬脂酸在水浴上熔化， 加入羊毛脂和白凡林并保持温度在 75°C。在不断搅拌下将此油熔融物逐渐加入到上述等温的水溶液中， 同 时自水浴上移下， 并搅拌一直到凝固呈膏状， 最后加入香料， 搅匀， 即得乳膏。 取马来酸环嘧耐平与乳膏 按冷研法制备， 即得。  [Preparation method] Take triethanolamine, glycerin, and paraben dissolved in water, and heat to 75 °C on a water bath; another stearic acid is melted on a water bath, lanolin and white vanel are added and the temperature is maintained at 75 °C. The oil melt is gradually added to the above-mentioned isothermal aqueous solution under constant stirring, and simultaneously removed from the water bath, and stirred until solidified into a paste form, and finally the flavor is added, and the mixture is stirred to obtain a cream. Take the maleic acid cyclopyrine and the cream prepared according to the cold research method.
实施例 32、 马来酸环嘧耐平软膏 Example 32. Cycloheximide maleate ointment
【处方】  [prescription]
马来酸环嘧耐平 50.0g 甘油 lOO.Og  Cycloheximide maleate 50.0g glycerol lOO.Og
交联型聚丙烯酸钠 ( SDB-L-400 ) lO.Og 苯扎溴铵 10.0ml  Crosslinked sodium polyacrylate ( SDB-L-400 ) lO.Og benzalkonium bromide 10.0ml
PEG4000 80.0g 蒸熘水 加至 1000g  PEG4000 80.0g steamed water added to 1000g
【制法】称取 PEG4000、 甘油置烧杯中微热至完全熔解， 加入马来酸环嘧耐平混匀， 交联型聚丙烯酸 钠 （SDB-L-400 ) 加入 800ml水 （60°C ) 于研体中研匀后， 将基质与 PEG4000、 甘油、 马来酸环嘧耐平混 匀， 加水至 1000g即得。  【Method】 Weigh PEG4000 and glycerin in a beaker and heat it to complete melting. Add cyclopropane maleate and mix well. Cross-linked sodium polyacrylate (SDB-L-400) should be added to 800ml water (60°C). After grinding in a mortar, the matrix is mixed with PEG4000, glycerin, and cycloheximide maleate, and water is added to 1000 g.
实施例 33、 马来酸环嘧耐平透明质酸凝胶  Example 33, Cycloheximide Maleate Hyaluronic Acid Gel
【处方】  [prescription]
马来酸环嘧耐平 5g 丙二醇 5g  Cycloheximide maleate 5g propylene glycol 5g
透明质酸 2.5g 乙醇 20ml  Hyaluronic acid 2.5g ethanol 20ml
卡波姆 941 0.5g 三乙醇胺 0.5g  Carbomer 941 0.5g Triethanolamine 0.5g
苯甲醇 0.5g 蒸熘水 加至 100g  Benzyl alcohol 0.5g distilled water added to 100g
【制法】将适量蒸熘水煮沸， 加入丙二醇混匀， 冷却至 50~60°C后， 在搅拌下加人透明质酸、 卡波姆 941， 静置 24h (充分溶胀） （A) ; 在另一容器中用乙醇溶解马来酸环嘧耐平， 加入苯甲醇混匀 （B ) ; 将 B 加入到 A中， 滴入三乙醇胺中和 （至 pH6左右）， 加蒸熘水至足量， 搅拌至均匀即得。  [Method] Boil the appropriate amount of steamed water, add propylene glycol to mix, cool to 50 ~ 60 ° C, add hyaluronic acid, carbomer 941 under stirring, let stand for 24h (sufficient swelling) (A); Dissolve cycloheximide maleate in ethanol in another container, add benzyl alcohol to mix (B); add B to A, add triethanolamine to neutralize (to pH6), add steamed water to the foot The amount is stirred until it is even.
实施例 34、 马来酸环嘧耐平甲酰胺注射液 Example 34. Cycloheximide maleate injection of maleic acid
本品为盐酸刊多卡因的灭菌水溶液。 含马来酸环嘧耐平应为标示量的 95 %〜105 %。  This product is a sterile aqueous solution of cocaine hydrochloride. The cycloheximide containing maleic acid should be 95%~105% of the labeled amount.
【处方】  [prescription]
马来酸环嘧耐平甲酰胺 150g  Cycloheximide maleic acid maleate 150g
氯化钠 9g  Sodium chloride 9g
注射用水 加至 1000ml  Water for injection added to 1000ml
【制法】取氯化钠溶于注射用水中， 加马来酸环嘧耐平搅拌溶解后， 稀释至全量， 用稀盐酸调整 pH 为 3.5〜5.0， 加活性炭， 过滤， 灌封， 100°C流通蒸汽灭菌 3min， [Preparation method] Take sodium chloride dissolved in water for injection, add cycloheximide maleate and stir to dissolve, dilute to full amount, adjust pH with dilute hydrochloric acid For 3.5~5.0, add activated carbon, filter, potting, steam sterilization at 100 °C for 3 min,
实施例 35、 马来酸环嘧耐平甲酰胺胶囊剂 Example 35. Cycloheximide maleate capsule of maleic acid
【处方】  [prescription]
马来酸环嘧耐平甲酰胺 260mg  Cycloheximide maleate 260mg
乳精 30mg  Creamer 30mg
微晶纤维素 40mg  Microcrystalline cellulose 40mg
乙醇 （70 % )  Ethanol (70%)
淀粉 40mg  Starch 40mg
【制法】按处方量称取微晶纤维素、 淀粉和乳糖， 混匀； 按处方量称取马来酸环嘧耐平并用少量 70 %乙醇溶解， 加入上述已混匀的粉末中制软材， 过 28目筛制粒， 60°C烘干， 20目筛整粒， 装入 2号空胶 囊， 即得。  [Method] Weigh microcrystalline cellulose, starch and lactose according to the prescription, mix well; weigh cycloheximide maleate and dissolve it with a small amount of 70% ethanol according to the prescription, add it to the mixed powder to make soft The material is sieved through a 28 mesh sieve, dried at 60 ° C, and sieved through a 20 mesh sieve, and filled into an empty capsule No. 2, which is obtained.
实施例 36、 马来酸环嘧耐平甲酰胺片  Example 36: Cycloheximide maleate tablets of maleic acid
【处方】  [prescription]
马来酸环嘧耐平甲酰胺 （细粉或极细小结晶） 260.0mg  Cycloheximide maleate (fine powder or very fine crystal) 260.0mg
酒石酸 l.Omg  Tartaric acid l.Omg
淀粉 20.0mg。  Starch 20.0 mg.
乙醇 50 % 适量  Ethanol 50%
糊精 30.0 mg  Dextrin 30.0 mg
硬脂破镁 1.5mg  Hard fat broken magnesium 1.5mg
【制法】将马来酸环嘧耐平甲酰胺、 淀粉、 糊精置不锈钢电动混合机中混匀。 另收酒石酸溶于 50 %乙 醇中，一次加入马来酸环嘧耐平甲酰胺的混合粉末中，混合均匀，制成软材，通过如目尼龙筛一次制成 20〜 40目湿粒， 置干燥箱中干燥， 开始时温度不超过 60°C， 将近干燥时温度可升至 70°C以下， 以加速干燥， 但温度不宜过高， 以免变色。 干粒通过 20目筛， 加入硬脂酸镁拌匀， 即可压片。  [Method] Mix maleic acid cyclamate, starch, and dextrin into a stainless steel electric mixer. In addition, tartaric acid is dissolved in 50% ethanol, and a mixed powder of cyclopropanone maleic acid maleate is added at a time, and uniformly mixed to obtain a soft material, and 20 to 40 mesh wet granules are prepared by using a nylon mesh sieve once. Dry in the drying oven, the temperature should not exceed 60 °C at the beginning, the temperature can be raised to below 70 °C when drying, to accelerate drying, but the temperature should not be too high to avoid discoloration. The dry granules are passed through a 20 mesh sieve, and the magnesium stearate is added and mixed well to be tableted.
实施例 37、 体外抗菌试验 Example 37, in vitro antibacterial test
研究表明， 马来酸环嘧耐平对革兰氏阳性菌具有明显的抑制作用， 对蜡样芽孢杆菌、 枯草芽胞杆菌、 肺炎链球菌、 化脓肺炎链球菌、 金黄色葡萄球菌、 金黄色葡萄球菌 （MRSA)、 粪肠球菌、 粪肠球菌（VRE ) 的 MIC范围在 0.006〜4.(^g/ml好于万古霉素的 0.125〜16 g/ml和环丙沙星的 0.125〜16 g/ml， 其中环丙 沙星对粪肠球菌 （VRE ) 的 MIC范围大于 250 g/ml。 马来酸环嘧耐平对金黄色葡萄球菌 （MRSA)和粪肠 球菌 （VRE ) 均有很好的抑制作用。 表 1 马来酸环嘧耐平及对照药对 24种实验菌的 MlC^g/ml)统计结果
Figure imgf000018_0001
MRS
Figure imgf000019_0001
Studies have shown that cyclopyrene maleate has a significant inhibitory effect on Gram-positive bacteria, against Bacillus cereus, Bacillus subtilis, Streptococcus pneumoniae, Streptococcus pneumoniae, Staphylococcus aureus, Staphylococcus aureus The MIC range of (MRSA), Enterococcus faecalis, and Enterococcus faecalis (VRE) is 0.006~4. (^g/ml is better than vancomycin 0.125~16 g/ml and ciprofloxacin is 0.125~16 g/ Ml, wherein the MIC range of ciprofloxacin against Enterococcus faecalis (VRE) is greater than 250 g/ml. Cycloheximide maleate is excellent for both Staphylococcus aureus (MRSA) and Enterococcus faecalis (VRE). Inhibition. Table 1 Statistical results of MlC^g/ml of 24 experimental bacteria of cyclopropene and maleate
Figure imgf000018_0001
MRS
Figure imgf000019_0001
Vre: 耐万古霉素菌  Vre: vancomycin resistant
马来酸环嘧耐平及对照药对 158株临床分离实验菌的 MlC^g/ml)统计结果  Statistic results of MlC^g/ml of 158 clinical isolates from cycloheximide maleate and reference drug
Figure imgf000019_0002
Figure imgf000020_0001
马来酸环嘧耐平对蜡样芽孢杆菌、 枯草芽胞杆菌、 肺炎链球菌、 化脓肺炎链球菌、 金黄色葡萄球菌、 金黄色葡萄球菌 （MRSA)、 粪肠球菌、 粪肠球菌 （VRE ) 的 MBC范围为 0.125〜1.0 g/ml。 马来酸环嘧耐平对 80株实验菌的 MIC和 MBC值比较 ^g/ml)
Figure imgf000019_0002
Figure imgf000020_0001
Cycloheximide maleate against Bacillus cereus, Bacillus subtilis, Streptococcus pneumoniae, Streptococcus pneumoniae, Staphylococcus aureus, Staphylococcus aureus (MRSA), Enterococcus faecalis, Enterococcus faecium (VRE) The MBC range is from 0.125 to 1.0 g/ml. Comparison of MIC and MBC values of 80 strains of experimental bacteria with cycloheximide maleate^g/ml)
Figure imgf000020_0002
实施例 38、 体内抗菌试验 （马来酸环嘧耐平对小鼠全身感染小鼠模型的治疗作用） 采用昆明种小白鼠， 以临床分离耐甲氧西林金黄色葡萄菌、化脓性肺炎链球菌分别感染小鼠制备腹腔 感染模型， 并以万古霉素为阳性对照药进行体内保护试验。 试验结果表明， 本发明马来酸环嘧耐平对感染 小鼠的保护作用均优于对照品万古霉素。
Figure imgf000020_0002
Example 38, In vivo antibacterial test (therapeutic effect of cycloheximide maleate on a mouse model of systemic infection in mice) Kunming mice were used to isolate methicillin-resistant Staphylococcus aureus and S. pneumoniae Infected mice to prepare abdominal cavity The infection model was tested with vancomycin as a positive control. The test results show that the protective effect of the present invention on cyclopanning maleate is superior to the control vancomycin.
表 4 口服马来酸环嘧耐平及对照药物对感染小鼠的 ED5()及 95%可信限 Table 4 ED 5() and 95% confidence limits for oral administration of cycloheximide maleate and control drugs to infected mice
Figure imgf000021_0001
Figure imgf000021_0001

Claims

权利 要 求 书 Claim
1、 含有环嘧耐平药用复合物的药物组合物制剂， 其特征在于： 是将具有通式 （ I ) 结构的环嘧耐平 或立体异构体、 前药、 药用盐、 复盐或和溶剂化的环嘧耐平药用复合物作为有效成分， 与药学上可接受的 药物载体混合制成的药物组合物制剂；  A pharmaceutical composition preparation containing a cycloheximide medicinal complex, which is characterized in that it is a cyclopyrine or stereoisomer having a structure of the general formula (I), a prodrug, a pharmaceutically acceptable salt, a double salt Or a pharmaceutical composition preparation prepared by mixing a pharmaceutically acceptable cycloheximide medicinal complex as an active ingredient with a pharmaceutically acceptable pharmaceutical carrier;
Figure imgf000022_0001
通式（ I )中， 表示盐可以是无机酸根以及含 CrC16有机酸或氨基酸等； 前药可以是含（ Cw酰胺、酯等。
Figure imgf000022_0001
In the formula (I), the salt may be a mineral acid group and a C r C 16 organic acid or an amino acid; and the prodrug may be a Cw amide, an ester or the like.
2、 根据权利要求 1所述的药物组合物制剂， 其特征在于： 所述的药学上可接受的药物载体选自稀释 剂、 赋形剂、 水、 填充剂、 崩解剂、 粘合剂、 润湿剂、 表面活性剂、 吸附载体、 润滑剂、 增溶剂和 /或助 溶剂。  2. The pharmaceutical composition formulation according to claim 1, wherein: the pharmaceutically acceptable pharmaceutical carrier is selected from the group consisting of a diluent, an excipient, water, a filler, a disintegrant, a binder, Wetting agents, surfactants, adsorption carriers, lubricants, solubilizers and/or cosolvents.
3、 根据权利要求 1或 2所述的药物组合物制剂， 其特征在于： 药物组合物制剂的剂型包括片剂、 胶 囊剂、 软胶囊剂、 喷雾剂、 凝胶剂、 凝胶气雾剂、 混悬剂、 冲剂、 贴剂、 软膏、 丸剂、 散剂、 乳剂、 注射 剂、 输液剂、 冻干注射剂、 脂质体注射剂、 靶向给药注射剂、 栓剂、 缓释制剂和控释制剂。  The pharmaceutical composition preparation according to claim 1 or 2, wherein the pharmaceutical composition preparation comprises a tablet, a capsule, a soft capsule, a spray, a gel, a gel aerosol, Suspensions, granules, patches, ointments, pills, powders, emulsions, injections, infusion solutions, lyophilized injections, liposome injections, targeted administration injections, suppositories, sustained release preparations, and controlled release preparations.
4、 根据权利要求 3所述的药物组合物制剂， 其特征在于： 是环嘧耐平或立体异构体、 前药、 药用盐、 复盐或和溶剂化的环嘧耐平用复合物作为有效成分及其药用复合物作为有效成分与填充剂和 /或崩解剂制 成片剂或胶囊剂； 或者是环嘧耐平及其药用复合物作为有效成分与填充剂和 /或羟丙甲纤维素制成缓释制 剂； 或者是环嘧耐平及其药用复合物作为有效成分与填充剂、羟丙甲基纤维酸酯、 乙基纤维素、聚乙烯醇、 甲基硅树脂、 羟丙基纤维素、 聚乙二醇一 600、 丙烯酸一甲基丙烯酯树脂、 乙氧基乙基纤维素、 甘油棕榈 酸硬酯酸酯、 聚磷酸钠-脱乙酰壳多糖和 /或 PEG1500制成缓释制剂或控释制剂。  The pharmaceutical composition preparation according to claim 3, which is characterized in that it is a cycloheximide or a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a double salt or a solvated cyclopyrene complex As an active ingredient and a medicinal compound thereof as an active ingredient and a filler and/or a disintegrating agent, a tablet or a capsule; or a cycloheximide and a medicinal compound thereof as an active ingredient and a filler and/or Hypromellose is made into a sustained release preparation; or cyclopyrine and its medicinal compound are used as active ingredients and fillers, hydroxypropyl methylcellulose ester, ethyl cellulose, polyvinyl alcohol, methyl silicon Resin, hydroxypropylcellulose, polyethylene glycol-600, monomethacrylate resin, ethoxyethylcellulose, glyceryl palmitate, sodium polyphosphate-chitosan and/or PEG 1500 is formulated as a sustained release preparation or a controlled release preparation.
5、 根据权利要求 3所述的药物组合物制剂， 其特征在于： 是环嘧耐平或立体异构体、 前药、 药用盐、 复盐或和溶剂化的环嘧耐平药用复合物作为有效成分与油相组合， 制成注射剂或口服乳剂， 所述的油相是 大豆油、 聚乙二醇 400、 棉籽油、 花生油、 麻油、 玉米油和 /或橄榄油。  The pharmaceutical composition preparation according to claim 3, which is characterized in that it is a cycloheximide or a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a double salt or a solvated cyclopyrine medicinal compound. The active ingredient is combined with an oil to prepare an injection or an oral emulsion, and the oil phase is soybean oil, polyethylene glycol 400, cottonseed oil, peanut oil, sesame oil, corn oil and/or olive oil.
6、 根据权利要求 5所述的药物组合物制剂， 其特征在于： 在油相中还可加入增溶剂或潜溶剂或抗氧 剂。  6. The pharmaceutical composition preparation according to claim 5, characterized in that a solubilizing agent or a latent solvent or an antioxidant is further added to the oil phase.
7、 根据权利要求 2或 4所述的药物组合物制剂， 其特征在于： 所述的填充剂是蔗糖、 乳糖、 微晶纤 维素、 糊精、 淀粉和 /或磷酸钙； 所述的崩解剂是羟丙基甲基纤维素、 羧甲基淀粉钠、 交联聚维酮和 /或交 联羧甲基纤维素。  The pharmaceutical composition preparation according to claim 2 or 4, wherein the filler is sucrose, lactose, microcrystalline cellulose, dextrin, starch and/or calcium phosphate; The agent is hydroxypropyl methylcellulose, sodium carboxymethyl starch, crospovidone and/or croscarmellose.
8、 根据权利要求 1所述的药物组合物制剂， 其特征在于： 所述的药物组合物制剂可通过口服或非肠 胃给药的方式施用于患者； 用于口服时， 可将其制成常规的固体制剂或液体制剂， 所述的固体制剂是片剂、 胶囊剂、 粉剂或颗粒剂， 所述的液体制剂是水溶液、 油悬浮剂、 糖桨或酏剂； 用于非肠胃给药时， 可将其 制成注射用的溶液、 粉剂或油性悬浮剂等。 8. The pharmaceutical composition preparation according to claim 1, wherein: the pharmaceutical composition preparation can be administered to a patient by oral or parenteral administration; when used orally, it can be made into a conventional one. Solid preparation or liquid preparation, the solid preparation is a tablet, a capsule, a powder or a granule, and the liquid preparation is an aqueous solution, an oil suspension, a sugar paddle or an elixir; Can be It is prepared as a solution for injection, a powder or an oily suspension.
9、 根据权利要求 4、 5、 6或 7所述的药物组合物制剂， 其特征在于： 其所含的填充剂及实施例中所 含的填充剂的量为处方中量的 1%至 90%。  The pharmaceutical composition preparation according to Claim 4, 5, 6 or 7, wherein the filler and the filler contained in the examples are in an amount of from 1% to 90% by weight of the prescription. %.
10、 以上任意权利要求所述的药物组合物制剂在治疗细菌为革兰氏阳性菌： 葡萄球菌、 肺炎球菌、 粪 肠球菌、 链球菌、 牛链球菌， 肺炎链球菌、 消化链球菌、 化脓肺炎链球菌、 化脓肺炎链球菌、 化脓性链球 菌、 无乳链球菌、 绿色链球菌、 牛链球菌、 无乳链球菌 B、 组绿色链球菌、 白喉杆菌、 破伤风杆菌、 丹毒 杆菌、 炭疽杆菌、 破伤风杆菌、 蜡样芽孢杆菌、 枯草芽胞杆菌、 梭状芽孢杆菌、 蜡样芽孢杆菌、 枯草芽胞 杆菌、 炭疽杆菌、 白喉杆菌、 梭状芽孢杆菌、 破伤风杆菌、 产气荚膜杆菌、 产气荚膜杆菌螺旋体、 放线菌、 结核菌， 其中该细菌为革兰氏阳性耐药菌， 耐甲氧西林葡萄球菌、 耐万古霉素金葡菌、 葡萄球菌属诱导型 克林霉素耐药、 耐万古霉素肠球菌、 肠球菌高水平耐氨基糖苷类、 耐青霉素肺炎链球菌、 多重耐药鲍曼不 动杆菌、 耐药与多重耐药结核杆菌与结核分枝杆菌、 链球菌、 粪肠球菌、 铜绿假单胞菌、 大肠埃希氏菌及 鲍氏不动杆菌等、 耐药流感嗜血杆菌、 耐药淋球菌、 耐药脑膜炎奈瑟菌、 耐药肠杆菌科细菌、 耐药铜绿假 单胞菌感染中的应用。  10. The pharmaceutical composition preparation according to any of the preceding claims, wherein the bacterium is Gram-positive: staphylococcus, pneumococci, Enterococcus faecalis, streptococcus, Streptococcus bovis, Streptococcus pneumoniae, Streptococcus pneumoniae, pus pneumonia Streptococcus, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus mutans, Streptococcus bovis, Streptococcus agalactia B, Group Streptococcus mutans, Diphtheria, Tetanus, Escherichia coli, Bacillus anthracis, Tetanus, Bacillus cereus, Bacillus subtilis, Clostridium, Bacillus cereus, Bacillus subtilis, Bacillus anthracis, Diphtheria, Clostridium, Tetanus, Clostridium perfringens, gas production Clostridium spp., actinomycetes, tuberculosis, wherein the bacteria are Gram-positive bacteria, methicillin-resistant Staphylococcus, vancomycin-resistant Staphylococcus aureus, Staphylococcus-induced clindamycin resistance , vancomycin-resistant enterococci, enterococci high-level aminoglycoside-resistant, penicillin-resistant Streptococcus pneumoniae, multidrug resistance Acinetobacter baumannii, drug-resistant and multi-drug resistant Mycobacterium tuberculosis and Mycobacterium tuberculosis, Streptococcus, Enterococcus faecalis, Pseudomonas aeruginosa, Escherichia coli and Acinetobacter baumannii, drug-resistant influenza bloodthirsty Use of Bacillus, drug-resistant Neisseria gonorrhoeae, resistant Neisseria meningitidis, Enterobacteriaceae-resistant bacteria, and drug-resistant Pseudomonas aeruginosa infections.
PCT/CN2011/071510 2010-12-08 2011-03-04 Pharmaceutical composition comprising pyrazolopyrimidinone-like compound WO2012075744A1 (en)

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