[go: up one dir, main page]

WO2012075744A1 - Composition pharmaceutique comprenant un composé de type pyrazolopyrimidinone - Google Patents

Composition pharmaceutique comprenant un composé de type pyrazolopyrimidinone Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
streptococcus
cycloheximide
pharmaceutical composition
resistant
maleate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2011/071510
Other languages
English (en)
Chinese (zh)
Inventor
徐利锋
张克坚
周云鹏
刘举
王洋
刘革萍
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Liaoning Lifeng Scientific & Technology Development Co Ltd
SOUTH CHINA CENTER FOR INNOVATIVE PHARMACEUTICALS(SCCIP)
Original Assignee
Liaoning Lifeng Scientific & Technology Development Co Ltd
SOUTH CHINA CENTER FOR INNOVATIVE PHARMACEUTICALS(SCCIP)
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Liaoning Lifeng Scientific & Technology Development Co Ltd, SOUTH CHINA CENTER FOR INNOVATIVE PHARMACEUTICALS(SCCIP) filed Critical Liaoning Lifeng Scientific & Technology Development Co Ltd
Publication of WO2012075744A1 publication Critical patent/WO2012075744A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Ophthalmology & Optometry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une composition pharmaceutique comprenant un composé de formule (1) ou un stéréo-isomère, promédicament, sel pharmaceutiquement acceptable, sel double et/ou solvate de ce composé, en tant que principe actif, ainsi que des excipients pharmaceutiquement acceptables. La forme galénique de cette composition pharmaceutique est une forme galénique pharmaceutiquement acceptable. L'invention concerne en outre l'utilisation de cette composition pharmaceutique pour traiter des infections bactériennes par des bactéries telles que des bactéries à gram positif parmi lesquelles figurent entre autres Staphylococcus, Micrococcus pneumoniae, Enterococcus faecalis, Streptococcus, Streptococcus bovis, Streptococcus pneumoniae, Peptostreptococcus, suppurative Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus riridans, Streptococcus agalactiae B et Bacillus diphtheriae.
PCT/CN2011/071510 2010-12-08 2011-03-04 Composition pharmaceutique comprenant un composé de type pyrazolopyrimidinone Ceased WO2012075744A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201010577757.9 2010-12-08
CN2010105777579A CN102048738A (zh) 2010-12-08 2010-12-08 含有环嘧耐平药用复合物的药物组合物制剂

Publications (1)

Publication Number Publication Date
WO2012075744A1 true WO2012075744A1 (fr) 2012-06-14

Family

ID=43953755

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2011/071510 Ceased WO2012075744A1 (fr) 2010-12-08 2011-03-04 Composition pharmaceutique comprenant un composé de type pyrazolopyrimidinone

Country Status (2)

Country Link
CN (1) CN102048738A (fr)
WO (1) WO2012075744A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JO3407B1 (ar) 2012-05-31 2019-10-20 Eisai R&D Man Co Ltd مركبات رباعي هيدرو بيرازولو بيريميدين
CN108658991B (zh) * 2017-04-01 2023-12-15 辽宁利锋科技开发有限公司 3,5-二取代甲基吡唑并[1,5-a]嘧啶-7-酚盐类似物和衍生物制备方法和用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101671336A (zh) * 2009-09-23 2010-03-17 辽宁利锋科技开发有限公司 芳杂环并嘧啶衍生物和类似物及其制备方法和用途

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101671336A (zh) * 2009-09-23 2010-03-17 辽宁利锋科技开发有限公司 芳杂环并嘧啶衍生物和类似物及其制备方法和用途

Also Published As

Publication number Publication date
CN102048738A (zh) 2011-05-11

Similar Documents

Publication Publication Date Title
US8586082B2 (en) Solid orally administerable pharmaceutical dosage forms with rapid active principle release
CA2720658C (fr) Formulations ameliorees pour des ingredients pharmaceutiques actifs faiblement permeables
JP6173521B2 (ja) ナルブフィンを含有する製剤及びそれらの使用
CN101616668B (zh) 药用组合物
JP2012501971A (ja) 共結晶および共結晶を含む薬学的処方物
CN105358535A (zh) 恩杂鲁胺制剂
EA010832B1 (ru) Композиция (варианты) и способ для лечения гиперпролиферативных процессов, способ лечения рака (варианты) и способ получения твёрдой дисперсии вещества
TW200534843A (en) Galenic formulations of organic compounds
WO2009135646A2 (fr) Compositions pharmaceutiques stables et procédés de préparation desdites compositions adaptés à l’échelle industrielle
CA2741731A1 (fr) Compositions de modulateurs du recepteur de la serotonine 5-ht2a utilespour le traitement des troubles associesaudit recepteur
MX2008016568A (es) Composiciones farmaceuticas de memantina.
CN116490178A (zh) Sglt-2抑制剂与血管紧张素受体阻滞剂的组合物及用途
US8101207B2 (en) Composition containing medicine extremely slightly soluble in water and method for preparation thereof
JP2018516942A (ja) 生体利用率が改善された含プランルカスト固形製剤の組成物及びその製造方法
CN102088972B (zh) 含有咪唑-5-羧酸类衍生物的药用组合物,其制备方法及用途
CN114585362B (zh) 治疗制剂及其用途
TWI871668B (zh) 醫藥調配物
WO2012075744A1 (fr) Composition pharmaceutique comprenant un composé de type pyrazolopyrimidinone
AU2018230521B2 (en) Pharmaceutical compositions and uses thereof
CN117897174A (zh) 共晶
US20240383892A1 (en) PARTICLES OF IMIDAZO[4,5-b]PYRIDINE COMPOUND, PHARMACEUTICAL COMPOSITIONS, AND THEIR USE IN TREATING MEDICAL CONDITIONS
CN103126994B (zh) 含决奈达隆的固体药物组合物
WO2005016315A1 (fr) Compositions pharmaceutiques de nateglinide
US20070299054A1 (en) Oral pharmaceutical composition of a poorly water-soluble active agent
CN101759599A (zh) 具有氨基肟基的四环素类化合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11846418

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 23-09-2013)

122 Ep: pct application non-entry in european phase

Ref document number: 11846418

Country of ref document: EP

Kind code of ref document: A1