[go: up one dir, main page]

WO2017092630A1 - 一种硫肽环素的新用途 - Google Patents

一种硫肽环素的新用途 Download PDF

Info

Publication number
WO2017092630A1
WO2017092630A1 PCT/CN2016/107404 CN2016107404W WO2017092630A1 WO 2017092630 A1 WO2017092630 A1 WO 2017092630A1 CN 2016107404 W CN2016107404 W CN 2016107404W WO 2017092630 A1 WO2017092630 A1 WO 2017092630A1
Authority
WO
WIPO (PCT)
Prior art keywords
thiopeptide
acid
cyclin
sodium
group
Prior art date
Application number
PCT/CN2016/107404
Other languages
English (en)
French (fr)
Inventor
陈依军
钱军建
吴旭日
Original Assignee
南京碧迪可医药科技有限公司
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 南京碧迪可医药科技有限公司 filed Critical 南京碧迪可医药科技有限公司
Priority to US15/781,048 priority Critical patent/US20190231844A1/en
Priority to EP16869940.3A priority patent/EP3384921A4/en
Publication of WO2017092630A1 publication Critical patent/WO2017092630A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • 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
    • A61K9/0007—Effervescent
    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/08—Solutions
    • 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
    • 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
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • 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
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
    • 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
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/2873—Proteins, e.g. gelatin
    • 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
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • 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
    • A61K9/485—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • 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

Definitions

  • the invention belongs to the field of novel antibiotics and application thereof, and particularly relates to a novel use of thiopeptide cyclosin against C. difficile and its resistant strain and an oral preparation of thiopeptide cyclin.
  • Clostridium difficile is a Gram-positive anaerobic bacillus, and about 3% of the common population has intestinal parasites in the intestine.
  • C. difficile belongs to a conditional pathogen. Under normal circumstances, other bacteria in the human body will not endanger human health.
  • Clostridium difficile infection (CDI) is usually caused by excessive or unreasonable use of broad-spectrum antibiotics (clindamycin, ampicillin, cephalosporin, lincomycin, etc.) to cause intestinal flora imbalance. And with the emergence of drug-resistant strains, CDI is increasing. The study found that CDI is mainly caused by the cytotoxic effects of toxins A and B produced by the toxin-producing C.
  • CDI diseases include not only common pseudomembranous colitis and antibiotic-associated diarrhea, but also pyelonephritis, meningitis, abdominal and vaginal infections, bacteremia and gas gangrene.
  • the clinical manifestations of these diseases vary in severity, and can be asymptomatic carriers, diarrhea, congestion, edema, erosion, fulminant enteritis, etc. In severe cases, sepsis or even shock death.
  • CDI Crohn's disease
  • metronidazole and vancomycin are the drugs of choice for the treatment and treatment of CDI (see: Am J Gastroenterol 2013, 108: 478), for patients with mild to moderate infections with initial onset, can be treated with metronidazole, severe or recurrent Patients can choose vancomycin for oral therapy, but the recurrence rate of treatment is as high as 15% to 35%, and strains or resistant strains have been found to be sensitive to these two therapeutic agents (see: Clin Infect Dis 2012, 55:71) . In order to obtain better therapeutic effects, in 2011, the US FDA approved a new antibiotic for the treatment of CDI, which is equivalent to vancomycin. The recurrence rate is also low, but for the difficult chlamydia.
  • Thiopeptcin also known as nocafloxacin
  • Thiopeptcin is a secondary metabolite of thiopeptides produced by Amycolaptosis sp. or Nocardia sp. Its structure contains a unique structure of thiazole ring, pyridine ring, anthracene ring and dehydrogenated amino acid, dimethyl glucosamine and tricyclic ring, which is the most clinically promising member of thiopeptide antibiotics (see: J Antibiot 2003, 26:232).
  • the thiopeptide cyclin forms a complex with 23S rRNA and L11 protein in the 50S large subunit of the bacterial ribosome, thereby inhibiting the conformational transition of the L11 protein, thereby affecting the transposition of the peptide chain during protein synthesis to achieve an antibacterial effect. See: Nat Prod Rep, 1999, 16: 249).
  • In vitro activity studies have shown that thiopeptide cyclin can kill Gram-positive aerobic bacteria at very low concentrations (ng/mL), but no thiopeptide cyclins have been shown to exert anti-anaerobic bacteria, especially C. difficile activity and activity. Report.
  • the object of the present invention is to provide an antibiotic with novel structure and unique mechanism for treating C. difficile infectious diseases and complications (CDI), and provide an oral preparation of thiopeptide cyclin according to the characteristics of CDI and intestinal administration and corresponding Formulation process.
  • CDI C. difficile infectious diseases and complications
  • thiopeptide cyclin for the preparation of a medicament for treating C. difficile infectious diseases and their complications.
  • C. difficile infectious diseases and their complications include pseudomembranous colitis, colitis, toxic colitis, diarrhea, pseudomembranous colitis, and pyelonephritis, meningitis, abdominal and vaginal infections caused by Clostridium difficile infection, Bacteremia and gas gangrene, antibiotic-related diseases, and complications.
  • thiopeptide cyclin can be used for C. difficile, including sensitive strains and infections caused by C. difficile resistant to antibiotics.
  • the antibiotic is one or more of ampicillin, cephalosporin, lincomycin, clindamycin, erythromycin, tetracycline, vancomycin, and metronidazole.
  • the thiopeptide cyclin is administered by enema, nasogastric tube, rectal or oral route, preferably orally.
  • Another object of the present invention is to provide a pharmaceutical preparation for treating a C. difficile infectious disease and a complication thereof, wherein the pharmaceutically active ingredient is thiopeptide cycline.
  • the above pharmaceutical preparation is preferably a thiopeptide cyclic oral preparation selected from the group consisting of a tablet, a capsule, a film coated tablet, a chewable tablet, a dragee, a suspension, a syrup, an emulsion, an oral lyophilized powder, an oral solution, A sizing agent, an effervescent agent, a granule or an elixir and related slow release preparations.
  • thiopeptide cyclin comprising thiopeptide cyclin and a pharmaceutically acceptable pharmaceutical auxiliary
  • the auxiliary agent comprising a binder, a disintegrating agent, a filler, a lubricant, a dispersing agent, a glidant, a coloring agent
  • emulsifiers stabilizers, solubilizers, latent solvents, pH adjusters, antioxidants, flavoring agents, preservatives, sustained release materials, controlled release materials, and the like.
  • thiopeptide cyclin selected from the group consisting of polyvinylpyrrolidone, starch, hypromellose, hydroxypropylcellulose, microcrystalline cellulose, methylcellulose, ethylcellulose, carboxymethyl One or more of cellulose and its sodium salt, gelatin, gum arabic, guar gum, tragacanth, sodium alginate, etc.; disintegrating agent selected from croscarmellose sodium, cross-linked polycondensation One or more of ketene, starch, sodium carboxymethyl starch, carboxypropyl starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, etc.; filler is selected from the group consisting of lactose, sucrose, starch, modified starch , one or more of mannitol, sorbitol, dextrin derivatives (such as dextrin, maltodextrin), cellulose derivatives (such as microcrystalline cellulose, cellulose), calcium sul
  • the emulsifier is selected from the group consisting of SLS, Tween, poloxamer, povidone, lecithin, stearic acid, gelatin, methylcellulose, hydroxypropylcellulose, polyoxyethylene, castor oil, beeswax, cetyl alcohol
  • the stabilizer is one or more selected from the group consisting of poloxamers, polyethylene glycols, and polysorbates
  • the solubilizing agent is selected from the group consisting of polyethylene glycol and fatty acid.
  • the latent solvent is selected from the group consisting of ethanol, propylene glycol, DMSO, glycerol or polyethylene glycol Or several;
  • the pH adjusting agent is selected from one or more of hydrochloric acid, acetic acid, phosphoric acid, carbonic acid, citric acid, phosphoric acid, lactic acid, tartaric acid, malic acid, succinic acid, sodium hydroxide, triethanolamine, ethylenediamine or a buffer composed of the corresponding acid and its salt;
  • the antioxidant is selected from the group consisting of sodium metabisulfite, sodium hydrogen sulfite, sodium sulfite, sodium thiosulfate, dibutyl phenol, vitamins One or more of C;
  • the flavoring agent is selected from the group consisting of saccharin, monosaccharide syrup, juice syrup, disodium glycyrrhizinate
  • C. difficile infection is the excessive or unreasonable use of broad-spectrum antibiotics, which breaks the balance of the intestinal flora, resulting in a large number of C. difficile accumulation, resulting in a large number Exotoxins A and B, and excessive or unreasonable use of broad-spectrum antibiotics, C. difficile has reduced sensitivity to therapeutic drugs, and even produces strains resistant to antibiotics.
  • a large number of clinical studies have found that C. difficile is resistant to ampicillin, cephalosporin, lincomycin, clindamycin, erythromycin and tetracycline in the treatment of C. difficile infection.
  • the present invention is directed to Clostridium difficile ATCC 9689, clinical isolates and drug-resistant strains of C. difficile.
  • the antibacterial activity of thiopeptide cyclin is determined by CLSI-recommended broth dilution method, and the MIC value (minimum inhibitory concentration) is used as an evaluation index.
  • the antibacterial activity of thiopeptide cyclosin against C. difficile and its resistant strains was evaluated. The results showed that the bactericidal activity of thiopeptide cycline against C. difficile and its resistant strains was significantly better than vancomycin and metronidazole.
  • Oral pharmaceutical preparations of the thiopeptide cyclins of the present invention can be prepared by conventional techniques in the art.
  • the therapeutic dose of the thiopeptide cyclin used in the present invention is from 0.001 mg/kg to 10,000 mg/kg per day, preferably from 0.001 to 1000 mg/kg per day.
  • the oral preparation of the thiopeptide cyclin is from 0.001 to 10000 mg, preferably from 0.01 to 100 mg per unit dose.
  • the present invention selects an oral preparation for the treatment of C. difficile infection, and studies the oral bioavailability of thiopeptide cyclin.
  • the results show that the rats are administered with thiopeptide cyclin by intragastric administration. No drug enters the blood circulation, and the combined concentration of the systemic circulation is lower than the lower limit of quantitation (1 ng/mL), indicating that the thiopeptide cyclin does not enter the human circulatory system, and can directly act on the intestinal tract, and the safety risk of the drug is small.
  • the present invention has the following advantages over existing CDI therapeutic drugs and technical means.
  • the thiopeptide antibiotic thiopeptide cyclin has unique structure, novel mechanism of action and strong antibacterial activity.
  • the results of the present invention indicate that thiopeptide cyclin shows superior inhibition to intestinal anaerobic bacteria C. difficile and resistant strains. Bacterial activity.
  • the antibacterial activity (MIC value) of thiopeptide cycline on sensitivity and drug resistance C. difficile is superior to antibiotic drugs such as vancomycin in clinical treatment of CDI.
  • Oral thiopeptide ringin intestinal absorption is not absorbed, it will not enter the human circulatory system, will not cause systemic side effects, and the safety hazard is small.
  • oral thiopeptide cycline preparations which are convenient for patients to choose the appropriate oral preparation type and mode of administration.
  • thiopeptide cyclin has the activity of inhibiting C. difficile and can be used for the development and treatment of CDI-related oral preparations, and has important clinical application value.
  • the thiopeptide cyclin was tested against the C. difficile sensitive strain Clostridium difficile ATCC 9689, the clinical isolate strain Clostridium difficile LCN 001, and the clinically isolated resistant strain, and compared with vancomycin.
  • the minimum inhibitory concentration (MIC) of thiopeptide cyclin was determined according to the broth dilution method recommended by CLSI M11-A7. According to the measurement, the Brucella broth supplemented with Hemin (5mg/ml), vitamin K1 (1 ⁇ g/ml), lysed horse blood (5%) and oxidase (1:25v/v) was divided into different measurement groups, and then Add thiopeptide cyclin or vancomycin in DMSO.
  • the concentration of the test drug ranged from 0.025 ⁇ g/ml to 128 ⁇ g/ml.
  • the concentration of the test drug ranged from 0.025 ⁇ g/ml to 128 ⁇ g/ml.
  • the minimum antibacterial concentration of the non-growth of the experimental bacteria is the desired MIC.
  • Table 1 the bactericidal activity of thiopeptide cycline against C. difficile and its resistant strains. Significantly better than vancomycin.
  • Mobile phase A 10 mM ammonium acetate + 0.02% aqueous ammonia solution
  • mobile phase B methanol
  • Preparation method of thiopeptide cyclosin solution take a certain amount of thiopeptide cyclin and mix it in a mixed solvent of pH 5.0 containing 10% PEG400, 1% Tween 80, 5mg/ml citric acid, shake it to clarify to obtain thiopeptide cyclin Stomach solution.
  • N.D. means below the detection limit.
  • the oral tablet formulation of thiopeptide cyclin is a formulation of all commonly used and usable formulations in the field of pharmaceutical preparations, and the examples cited in this patent are for illustrative purposes only and do not limit the scope of application of the invention.
  • the formulation of the example formulation is as follows:
  • thiopeptide cyclin and corn starch are mixed through a 100 mesh sieve and uniformly mixed.
  • the binder solution was prepared by heating with water and PEG 400 at 45 ° C under continuous stirring.
  • the cement solution was sprayed onto the mixture of thiopeptide cycline and starch, dried at an inlet air temperature of 60 ° C, and finally talc and magnesium stearate were added.
  • the above powder was tableted to obtain a thiopeptide cyclin tablet.
  • Preparation method thiopeptide cyclin and micro-powder silica gel are mixed through a 100 mesh sieve and mixed uniformly. Lactose, microcrystalline cellulose, low extraction The hydroxypropyl cellulose and aspartame are uniformly mixed. The above two kinds of powders are passed through a 80 mesh sieve, and uniformly mixed. Tween-80 and magnesium stearate are added and thoroughly mixed in the mixing machine for more than 10 minutes to adjust the pressure and tablet weight of the tableting machine. A thiopeptide cyclin dispersible tablet was obtained.
  • the preparation method of the thiopeptide cyclin tablet is the same as the sustained release tablet.
  • the oral chewing tablet formulation of thiopeptide cyclin is a commonly used and usable formulation for the formulation of pharmaceutical preparations, as listed in this patent.
  • the examples are intended to be illustrative only and not limiting of the scope of application of the invention.
  • the formulation of the example formulation is as follows:
  • thiopeptide cyclin and auxiliary materials respectively pass through a 100 mesh sieve.
  • the thiopeptide cyclin, lactose, cyclamate, and aspartame are uniformly mixed and added to ethanol to make a soft material.
  • the granules are sieved through 20-50 mesh, dried under vacuum at 50 ° C, and then passed through a 20 mesh sieve. grain. Finally add magnesium stearate and fresh milk flavor and mix well.
  • the above powder was tableted to obtain a thiopeptide cyclin chewable tablet.
  • the capsule formulation of thiopeptide cyclin is a formulation of all commonly used and usable formulations in the field of pharmaceutical preparations.
  • the examples cited in this patent are for illustrative purposes only and do not limit the scope of application of the invention.
  • the formulation of the example formulation is as follows:
  • Preparation method the thiopeptide cyclin and the above-mentioned raw materials are separately pulverized and passed through a 100 mesh sieve for use.
  • the thiopeptide cyclin was uniformly mixed with the pregelatinized starch, and then an aqueous solution of polyvinylpyrrolidone (8%) was added as a binder to prepare a soft material.
  • the talc powder and magnesium stearate are added, the pellets are prepared by extrusion rounding, the moisture content of the pellets is controlled to be below 4.0%, and the obtained pellets are filled into the capsule shell to obtain a thiopeptide cycline capsule.
  • the preparation method comprises the following steps: dissolving povidone in PEG400 and Tween 80, stirring uniformly, adding 100 mesh thiopeptide cyclin to stir and dissolving, and then forming the capsule into capsules to obtain thiopeptide cyclin soft capsule.
  • sustained-release capsules Take a prescription of methacrylic acid copolymer, talc, sodium lauryl sulfate, polyethylene glycol, mix and stir as a coating liquid, and set aside. 500 g of 20-mesh drug-containing pellets was placed in a centrifugal coating granulator for coating. The above-mentioned drug-containing coated pellets are filled with ordinary capsules as prescribed to obtain a thiopeptide cyclin sustained-release capsule.
  • the saccharide peptide formulation of thiopeptide cyclin is a formulation of all commonly used and usable formulations in the field of pharmaceutical preparations, and the examples exemplified in this patent are for illustrative purposes only and do not limit the scope of application of the present invention.
  • the formulation of the example formulation is as follows:
  • the preparation method comprises the following steps: mixing 80 mesh thiopeptide cyclin, microcrystalline cellulose, sodium carboxymethyl starch and lactose in a high-efficiency wet process machine, adding appropriate water and stirring to prepare a soft material, and extruding with a pore plate of 0.8 mm aperture. It is spheronized in a rounding machine with a rotational speed of 800-2000 rpm and dried at 50-55 ° C to obtain a thiopeptide cycline pellet.
  • thiopeptide cyclin pellet is placed in a coating pan, the inlet air temperature is adjusted to 40-60 ° C, the atomization pressure and the liquid supply speed are adjusted, and the coating liquid is uniformly wrapped on the surface of the pellet.
  • the thiopeptide cycline dragee can be obtained by drying after the coating is completed for about 30 minutes.
  • the dry suspension formulation of thiopeptide cyclin is a formulation of all commonly used and usable formulations in the field of pharmaceutical preparations.
  • the examples cited in this patent are for illustrative purposes only and do not limit the scope of application of the present invention.
  • the formulation of the example formulation is as follows:
  • Preparation method 120 mesh thiopeptide cyclin and mannitol, cyclamate, hydroxypropylmethyl cellulose are uniformly mixed and passed through a 120 mesh sieve. Then, ethanol was added and mixed uniformly to prepare a soft material, which was passed through a 30 mesh sieve. After drying, the thiopeptide cyclosine dry suspension is obtained by dispensing.
  • Preparation method 120 mesh thiopeptide cyclin and povidone are uniformly mixed, and added to 95% ethanol to stir to obtain a suspension.
  • the blank pellets were placed in a fluidized bed and sprayed with a thiopeptide cyclin solution, and dried to obtain a thiopeptide cycline-loaded pellet.
  • Tween 80 and hydroxypropylmethylcellulose were added to 75% ethanol, stirred until completely dissolved to obtain a coating liquid, and sprayed into a fluidized bed to prepare a thiopeptide cyclin coated pellet.
  • Ethyl cellulose, povidone and polyethylene glycol 4000 were completely dissolved in 95% ethanol under stirring to prepare a sustained-release layer coating solution, which was sprayed into a fluidized bed to prepare a sustained release of thiopeptide cyclin. Pellet. Finally, the drug-loaded sustained-release pellets are mixed with sodium phosphate, sucrose and sodium carboxymethylcellulose to form a thiopeptide cyclic slow-release dry suspension.
  • the syrup formulation of thiopeptide cyclin is a formulation of all commonly used and usable formulations in the field of pharmaceutical preparations, and the examples exemplified in this patent are for illustrative purposes only and do not limit the scope of application of the invention.
  • the formulation of the example formulation is as follows:
  • Preparation method adding sucrose to 300 ml of purified water, stirring and heating to boiling, completely dissolving sucrose into syrup, cooling and filtering for use (solution A).
  • the food coloring matter was added to 1 ml of water and stirred to dissolve (solution B).
  • solution B After boiling 230 ml of purified water, add ⁇ -cyclodextrin, thiourea, EDTA-2Na, benzoic acid and hydroxyethyl ester, stir until completely dissolved, and reduce the temperature to below 60 ° C, add thiopeptide cyclin and glutamine
  • the acid was stirred and dissolved (solution C).
  • Add solution B to solution C stir evenly and slowly add to solution A through a 300 mesh sieve, stir evenly. When cooling to below 40 °C, add strawberry flavor, stir evenly, then add the remaining purified water through 300 mesh.
  • the thiopeptide cyclosporin syrup is obtained after screening through a sieve.
  • the oral emulsion formulation of thiopeptide cyclin is a formulation of all commonly used and usable formulations in the field of pharmaceutical preparations, and the examples cited in this patent are for illustrative purposes only and do not limit the scope of application of the invention.
  • the formulation of the example formulation is as follows:
  • Preparation method Disperse the prescription amount of poloxamer in 0.9% sodium chloride solution, and then add the dissolved sulfur peptide and the lecithin oil phase, stir vigorously to make colostrum, add saccharin and flavor. Thereafter, the colostrum is diluted with a 0.9% sodium chloride solution to obtain a uniformly dispersed emulsion.
  • the oral lyophilized powder formulation of thiopeptide cyclin is a formulation of all commonly used and usable formulations in the field of pharmaceutical preparations.
  • the examples cited in this patent are for illustrative purposes only and do not limit the scope of application of the present invention.
  • the formulation of the example formulation is as follows:
  • Preparation method mixing 100 mesh thiopeptide cyclin with PEG400, stirring and dissolving (solution A); dissolving citric acid, dextran and saccharin with purified water, stirring until completely dissolved (solution B); mixing both A and B solutions uniformly With 0.5N
  • the citric acid or sodium hydroxide solution is adjusted to a pH of 5.0; diluted with water and then dispensed, and then lyophilized to obtain a thiopeptide cyclin oral lyophilized powder.
  • the formulation of the thiopeptide cyclin is a formulation of all the commonly used and usable formulations in the field of pharmaceutical preparations.
  • the examples cited in this patent are for illustrative purposes only and do not limit the scope of application of the present invention.
  • the formulation of the example formulation is as follows:
  • Preparation method 100 mesh thiopeptide cyclin is dissolved in purified water, and then glycerin, propylene glycol, polyoxyethylene polyoxypropylene copolymer and polyethylene oxide 8000 are added, and stirred until the material dissolves into a colloidal solution (solution A) ).
  • solution A colloidal solution
  • the chlorhexidine acetate and EDTA-2Na were dissolved in 200 ml of water and added to the solution A, and the mixture was thoroughly mixed, and the pH was adjusted to 5-6 to obtain a finished thiopeptide cycline cement.
  • the effervescent formulation of thiopeptide cyclin is a formulation of all commonly used and usable formulations in the field of pharmaceutical preparations, and the examples exemplified in this patent are for illustrative purposes only and do not limit the scope of application of the present invention.
  • the formulation of the example formulation is as follows:
  • Preparation method The amount of each excipient is calculated according to the above ratio, and weighed. Thiopeptide cyclin, diatomaceous earth, carboxymethyl Sodium cellulose, citric acid and fumaric acid are mixed evenly. After adding the azone, stir and mix well. Finally, add all other remaining auxiliary materials, crush them through the micro-powder, pass through 200 sieves, and put them into the granulator (or tablet press). One-shot extrusion granulation (or tableting), after drying, is a thiopeptide cyclin granule (or tablet).
  • the granule formulation of thiopeptide cyclin is a formulation of all commonly used and usable formulations in the field of pharmaceutical preparations, and the examples exemplified in this patent are for illustrative purposes only and do not limit the scope of application of the invention.
  • the formulation of the example formulation is as follows:
  • sucrose, pregelatinized starch, sodium saccharin, sodium carboxymethylcellulose are uniformly mixed in a wet mixing granulator, mixed with povidone (4%) aqueous solution, uniformly mixed, and then added to 80-100 mesh
  • the thiopeptide cyclin and the sweet orange flavor are mixed and granulated in a granulating machine to obtain a thiopeptide cyclin oral granule.
  • the oral liquid formulation of thiopeptide cyclin is a formulation of all commonly used and usable formulations in the field of pharmaceutical preparations, and the examples exemplified in this patent are for illustrative purposes only and do not limit the scope of application of the present invention.
  • the formulation of the example formulation is as follows:
  • thiopeptide cyclin, cosolvent and preservative are dissolved in 100 ml of purified water, stirred until completely dissolved (solution A), and used.
  • the flavoring agent is honored in 500 ml of water, then the solution A is added, and then pure water is added to 1000 ml, and the mixture is filtered to obtain a thiopeptide cyclic oral solution.
  • the thiol cyclin tanning agent formulation is all commonly used and usable formulation formulations in the field of pharmaceutical preparations, and the examples listed in this patent are for illustrative purposes only and do not limit the scope of application of the invention.
  • the formulation of the example formulation is as follows:
  • the preparation method comprises the following steps: dissolving thiopeptide cyclin, fatty acid sorbitan and food flavor in edible white wine, mixing uniformly, and filtering to obtain thiopeptide cyclin tanning agent.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nutrition Science (AREA)
  • Inorganic Chemistry (AREA)
  • Physiology (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Communicable Diseases (AREA)
  • Dispersion Chemistry (AREA)
  • Oncology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Dermatology (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明提供了硫肽环素在制备治疗艰难梭菌感染性疾病及其并发症的药物中的用途，以及治疗艰难梭菌感染性疾病及其并发症的含硫肽环素的药物制剂。

Description

一种硫肽环素的新用途 技术领域
本发明属于新型抗生素及其应用领域，具体涉及硫肽环素抗艰难梭菌及其耐药菌株的新用途以及硫肽环素口服制剂。
背景技术
艰难梭菌(Clostridium difficile)为一种革兰氏阳性厌氧芽孢杆菌，普通人群中约有3％人的肠道都有该菌的寄生。艰难梭菌属于一种条件致病菌，在正常情况下，受制于人体内的其他细菌，不会危害人体健康。艰难梭菌感染(Clostridium difficile infection，CDI)通常是由于过度或不合理使用广谱抗生素(克林霉素、氨苄西林、头孢菌素、林可霉素等)造成肠道菌群失调所致，并且随着耐药菌株的不断出现，CDI日益增多。研究发现，CDI主要是由于产毒素性艰难梭菌产生的毒素A和B引起的细胞毒性效应而发病，(参见：Expert Rev Anti Infect Ther 2012,10:1405；Am J Med Sci,2010,340:247)。CDI疾病不仅包括常见的伪膜性肠炎和抗生素相关性腹泻，还会造成肾盂肾炎、脑膜炎、腹腔及阴道感染、菌血症和气性坏疽等。这些疾病临床表现轻重不一，可以是无症状的携带者、腹泻、充血、水肿、糜烂、爆发性肠炎等，严重时亦会败血症甚至休克死亡。
自1978年证实艰难梭菌是抗生素相关性腹泻的病因以来，CDI的发病率和严重程度逐年升高，尤其是加拿大魁北克高毒力型CDI爆发以来15年，CDI发病率提高了4倍。据加拿大医院感染监测中心估计，世界范围内的成人CDI发病率约为4.6/1000个入院患者，死亡率约为2.6/100个CDI患者(参见：Expert Rev Gastroenterol Hepatol 2010,4:409)。近年来，中国CDI亦呈现出日益增长趋势，据黄海辉等对华山医院的调查结果显示，2007-2009医院获得性CDI发病率约为13-17.1/10000个入院病人(Clin Infect Dis 2008,47:1606)。目前，甲硝唑和万古霉素是对抗和治疗CDI的首选药物(参见：Am J Gastroenterol 2013,108:478)，对于初次发病的轻、中度感染患者可用甲硝唑治疗，重度或复发的患者可选择万古霉素口服治疗，但治疗的复发率高达15％～35％，而且已经发现对这两种治疗药敏感性降低菌株或耐药菌株(参见：Clin Infect Dis 2012,55:71)。为获得更好的治疗效果，2011年美国FDA批准了一种治疗CDI新型的抗生素---非达霉素，其治疗效果与万古霉素相当，复发率也较低，但对艰难梭菌剧毒菌株NAP1/BI/027，复发率仍然高达24％(参见：N Engl J Med 2011,364:422)，且临床上已经出现敏感性降低菌株。虽然一些制药公司已经在开发新型的治疗CDI药物，但至今未见上市如瑞士Actelion公司开发的新药--卡达唑胺 (Cadazolid)。因此，不断增加的CDI治疗复发威胁和出现的艰难梭菌耐药问题，以及CDI的治疗规范化要求等，促使亟需开发结构新颖、活性独特、复发率低、不易耐药的CDI治疗的新型一线药物。
硫肽环素(Thiopeptcin，又称诺卡沙星)，是一种由东方拟无枝酸菌(Amycolaptosis sp.)或诺卡氏菌(Nocardia sp.)产生的硫肽类次生代谢产物，其结构中含有噻唑环、吡啶环、吲哚环和脱氢氨基酸、二甲氨基葡萄糖和三环的独特结构，是硫肽类抗生素中最具有临床应用前景的一员(参见：J Antibiot 2003,26:232)。硫肽环素是通过与细菌核糖体50S大亚基中23S rRNA以及L11蛋白结合形成复合物，从而抑制L11蛋白的构象转变，进而影响了蛋白质合成过程中肽链的转座而达到抗菌效果(参见：Nat Prod Rep,1999,16:249)。体外活性研究表明，硫肽环素在极低浓度下(ng/mL)即能杀死革兰氏阳性需氧菌，但是，至今未见硫肽环素发挥抗厌氧菌特别是艰难梭菌作用及活性的报道。
Figure PCTCN2016107404-appb-000001
发明内容
本发明的目的在于为治疗艰难梭菌感染性疾病及其并发症(CDI)提供一种结构新颖、机制独特的抗生素，并根据CDI和肠道给药特点提供硫肽环素的口服制剂以及相应制剂工艺。
本发明的具体技术方案如下：
硫肽环素在制备治疗艰难梭菌感染性疾病及其并发症的药物中的应用。
上述艰难梭菌感染性疾病及其并发症包含伪膜性结肠炎、结肠炎、中毒性巨肠炎、腹泻、伪膜性肠炎以及艰难梭菌感染引起的肾盂肾炎、脑膜炎、腹腔及阴道感染、菌血症和气性坏疽、抗生素相关性疾病以及并发症。
上述应用，硫肽环素可用于艰难梭菌，包括敏感型菌株以及对抗生素耐药的艰难梭菌引起的感染。所述抗生素为氨苄西林、头孢菌素、林可霉素、克林霉素、红霉素、四环素、万古霉素、甲硝唑中的一种或多种。
本发明所述的应用，硫肽环素通过灌肠、鼻胃管、直肠或者口服途径给药，优选口服给药。
本发明的另一目的在于提供一种治疗艰难梭菌感染性疾病及其并发症的药物制剂，其药物活性成分为硫肽环素。
上述药物制剂，优选硫肽环素口服制剂，所述制剂选自片剂、胶囊剂、薄膜包衣片、咀嚼片、糖衣丸、混悬剂、糖浆、乳剂、口服冻干粉、口服液、胶浆剂、泡腾剂、颗粒剂或酊剂及其相关缓控释制剂。
上述硫肽环素口服制剂，包括硫肽环素和药学上可接受的药用辅料，所述辅料包括粘合剂、崩解剂、填充剂、润滑剂、分散剂、助流剂、着色剂、乳化剂、稳定剂、增溶剂、潜溶剂、pH调节剂、抗氧化剂、矫味剂、防腐剂、缓释材料、控释材料等中的一种或几种。
上述硫肽环素口服制剂，所述粘合剂选自聚乙烯吡咯烷酮、淀粉、羟丙甲纤维素、羟丙基纤维素、微晶纤维素、甲基纤维素、乙基纤维素、羧甲基纤维素及其钠盐、明胶、阿拉伯胶、瓜尔胶、黄耆胶、海藻酸钠等中的一种或几种；崩解剂选自交联羧甲基纤维素钠、交联聚维酮、淀粉、羧甲基淀粉钠、羧丙基淀粉、微晶纤维素、低取代羟丙基纤维素等中的一种或几种；填充剂选自乳糖、蔗糖、淀粉、改性淀粉、甘露醇、山梨醇、糊精衍生物(如糊精、麦芽糊精)、纤维素衍生物(如微晶纤维素、纤维素)、硫酸钙等中的一种或几种；润滑剂选自硬脂酸、硬脂酸钙、硬脂酸镁、氢化植物油、巴西棕榈酸蜡、滑石粉、聚乙二醇、硬酯酰富马酸钠等中的一种或几种；助流剂选自微粉硅胶、滑石粉等；分散剂选自微晶纤维素、乳糖、甘露醇、磷酸氢钙等中的一种或几种。乳化剂选自SLS、吐温、泊洛沙姆、聚维酮、卵磷脂、硬脂酸类、明胶、甲基纤维素、羟丙纤维素、聚氧乙烯、蓖麻油、蜂蜡，鲸蜡醇、蛋黄磷脂或大豆磷脂等中的一种或几种；稳定剂选自泊洛沙姆、聚乙二醇、聚山梨酯中的一种或几种；增溶剂选自聚乙二醇、脂肪酸山梨坦、聚山梨酯、聚维酮、泊洛沙姆、环糊精和卵磷脂中的一种或几种；潜溶剂选自乙醇、丙二醇、DMSO、甘油或聚乙二醇中的一种或几种；pH调节剂选自盐酸、醋酸、磷酸、碳酸、柠檬酸、磷酸、乳酸、酒石酸、苹果酸、琥珀酸、氢氧化钠、三乙醇胺、乙二胺中的一种或几种或相应的酸及其盐所组成的缓冲液；抗氧化剂选自焦亚硫酸钠、亚硫酸氢钠、亚硫酸钠、硫代硫酸钠、二丁基苯酚、维生素 C中的一种或几种；矫味剂选自糖精、单糖浆、果汁糖浆、甘草酸二钠、蔗糖、三氯蔗糖、阿斯巴甜、甜菊素、麦芽糖醇、山梨醇、木糖醇、乳糖醇、甘露醇、天然香料或人工香料的一种或几种；防腐剂选自苯甲酸、苯甲酸钠、对羟基苯甲酸酯类、山梨酸/山梨酸钾中的一种或几种；缓释材料选自PLGA、PLA、壳聚糖、甲基丙烯酸共聚物、乳酸-赖氨酸聚合物、羟丙基甲基纤维素、明胶、聚丙烯酸、蜂蜡等中的一种或几种；控释材料选自高分子凝胶、壳聚糖及其共混物、环糊精及其衍生物、白蛋白、聚乳酸及其共聚物、海藻酸钠、纤维素等中的一种或几种。
与普通的细菌感染性疾病不同，产生艰难梭菌感染的原因是由于过度或不合理使用广谱抗生素后，打破了肠内菌群的平衡，从而导致艰难梭菌累计了大量的数量，产生大量的外毒素A和B，并且过度或不合理使用广谱抗生素后，艰难梭菌对治疗药物的敏感性降低，甚至产生对抗生素耐药的菌株。已有大量的临床研究发现在治疗艰难梭菌感染的过程中，艰难梭菌对氨苄西林、头孢菌素、林可霉素、克林霉素、红霉素、四环素出现耐药，目前临床上能够用于艰难梭菌感染药物非常有限，多使用万古霉素和甲硝唑进行治疗，但是随着这两种治疗药敏感性降低菌株和耐药菌株的出现，现有技术下艰难梭菌感染的治疗面临很大的挑战，目前尚无理想的抗菌药能够有效的治疗艰难梭菌感染。
本发明针对艰难梭菌敏感菌株Clostridium difficile ATCC 9689、临床分离菌株以及耐药菌株，采用CLSI推荐的肉汤稀释法测定硫肽环素的抗菌活性，以MIC值(最低抑菌浓度)为评价指标进行硫肽环素抗艰难梭菌及其耐药菌株的抗菌活性评价。结果表明硫肽环素对艰难梭菌及其耐药菌株的杀菌活性明显优于万古霉素和甲硝唑。
本发明所述的硫肽环素的口服药物制剂可以采用本领域常规技术手段进行制备。
本发明所述使用硫肽环素的治疗剂量为每天0.001mg/Kg–10000mg/Kg，优选每天使用量为0.001–1000mg/Kg。硫肽环素口服制剂的每单位剂量为0.001–10000mg，优选0.01–100mg。
由于艰难梭菌存在于人体肠道，本发明选择口服制剂用于艰难梭菌感染治疗，对硫肽环素的口服生物利用度进行了研究，研究结果表明大鼠灌胃给予硫肽环素后，无药物进入血液循环，体循环汇总浓度低于定量下限(1ng/mL)，表明硫肽环素不进入人体循环系统，能够直接作用于肠道部位，服药安全隐患小。
与现有CDI治疗药物和技术手段相比，本发明具有如下优点。
1.硫肽类抗生素硫肽环素结构独特、作用机制全新、抗菌活性极强，本发明研究结果表明硫肽环素对肠道厌氧菌艰难梭菌和耐药菌株均表现出超强抑菌活性。
2.硫肽环素对敏感性和耐药性艰难梭菌的抗菌活性(MIC值)优于临床治疗CDI的抗生素药物如万古霉素。
3.口服硫肽环素肠道不吸收，也不会进入人体循环系统，不会导致全身副作用，安全隐患小。此外，硫肽环素口服制剂种类多，便于病人选择合适的口服制剂类型和用药方式。
综上所述，硫肽环素具有抑制艰难梭菌的活性，可用于开发治疗CDI相关口服制剂，具有重要的临床应用价值。
具体实施方式
以下进一步提供实施实例，这些实施实例有助于理解本发明，仅用作说明而不限制本发明的应用范围。
实施例1 硫肽环素的体外抗艰难梭菌及其耐药菌株活性
硫肽环素针对艰难梭菌敏感菌株Clostridium difficile ATCC 9689、临床分离菌株Clostridium difficile LCN 001以及临床分离的耐药菌株进行了体外抗菌活性测试，且与万古霉素进行比较。依据CLSI M11-A7推荐的肉汤稀释法测定硫肽环素的最低抑菌浓度(MIC)。根据测定需要将补充了Hemin(5mg/ml)、维生素K1(1μg/ml)、裂解马血(5％)和氧化酶(1:25v/v)的布氏肉汤分成不同的测定组，然后加入用DMSO的硫肽环素或万古霉素。测试药物的浓度范围为0.025μg/ml-128μg/ml。检查各培养基中艰难梭菌的生长情况，实验菌不生长的最低抗菌药物浓度即为该要的MIC，如表1所示，硫肽环素对艰难梭菌及其耐药菌株的杀菌活性明显优于万古霉素。
表1艰难梭菌对硫肽环素的敏感性(MIC)
Figure PCTCN2016107404-appb-000002
实施例2 硫肽环素LC-MS/MS检测方法
30μl血样或尿样加入90μl含5ng/ml维拉帕米的甲醇，涡旋振荡3min后14 000rpm离 心5min，取上清80μl，进样LC-MS/MS分析。
高效液相色谱：色谱柱：Waters Symmetry 300C18 3.5μm 2.1*100mm；
流动相A：10mM乙酸铵+0.02％氨水溶液；流动相B：甲醇；
分析时间：5.2min进样量：5μL柱温：25℃；
梯度洗脱：
时间(min) 流速(mL/min) B％
0.00 0.4 67
2.40 0.4 67
2.45 0.4 90
3.80 0.4 90
3.85 0.4 67
5.20 0.4 67
质谱：正离子模式(Agilent6460B)
检测离子对：硫肽环素：1437.3→172.0，fragmentor＝135，CE＝22；
维拉帕米(内标)：455.2→165.1，fragmentor＝135，CE＝25；
质谱参数：Gas Temp＝350℃，Gas Flow＝10L/min，Nebulizer＝40psi，Sheath Gas Flow＝10L/min，Sheath Gas Heater＝400℃。
实施例3 口服硫肽环素药代动力学研究
硫肽环素药液配制方法：取一定量硫肽环素置于pH 5.0含10％PEG400、1％吐温80、5mg/ml柠檬酸的混合溶剂中，摇晃至澄清即得硫肽环素灌胃溶液。
根据实验目的将雄性大鼠分成高、中、低剂量组。其中高剂量组为50mg/Kg、中剂量组为25mg/Kg、低1剂量组为5mg/Kg、低2剂量组为1mg/Kg。在给药后约15min，30min，45min，1，2，4，6、8和24h各时间点采集血样约0.3ml供测定生物利用度使用，方法见实施例2。
表2大鼠口服给药硫肽环素后血浆中硫肽环素的浓度-时间数据(ng/ml)
Figure PCTCN2016107404-appb-000003
N.D.指低于检测限度。
从表2可以看出大鼠灌胃给予硫肽环素后，无药物进入血液循环，体循环汇总浓度低于定量下限(1ng/mL)，表明硫肽环素肠道不吸收，口服安全隐患小。
实施例4 硫肽环素片剂
硫肽环素的口服片剂处方为药物制剂领域所有常用及可以使用的制剂配方，本专利所列举的实施例仅用作说明而不限制本发明的应用范围。实施例制剂处方如下：
普通片剂
成分 用量(g/1000片剂)
硫肽环素 0.01-250g
玉米淀粉 60g
滑石粉 25g
PEG 400 2g
硬脂酸镁 3g
制备方法：硫肽环素与玉米淀粉混合过100目筛并混合均匀。在连续搅拌下，用水和PEG400于45℃下加热制备黏结剂溶液。向硫肽环素与淀粉混合物喷洒黏结剂溶液，在60℃的输入空气温度下干燥，最后添加滑石粉和硬脂酸镁。取上述粉末进行压片即得硫肽环素片剂。
分散片剂
成分 用量(g/1000片剂)
硫肽环素 0.01-250g
乳糖 30g
微晶纤维素 90g
低取代-羟丙基纤维素 25g
吐温-80 5.0g
微粉硅胶 15g
硬脂酸镁 9g
阿斯巴甜 2g
制备方法：取硫肽环素与微粉硅胶混合过100目筛并混合均匀。将乳糖、微晶纤维素、低取 代-羟丙基纤维素和阿斯巴甜混合均匀。将以上两种粉末过80目筛，混合均匀，加入吐温-80和硬脂酸镁在混匀机种充分混匀10min以上，调节压片机压力和片重，取上述粉末进行压片即得硫肽环素分散片。
缓释片剂
Figure PCTCN2016107404-appb-000004
制备方法：
1)将聚乙烯吡咯烷酮溶解于乙醇溶液中，假扮成均匀溶液。将80-100目的硫肽环素、羟丙基甲基纤维素、柠檬酸、乳糖混合均匀，加入聚乙烯吡咯烷酮醇溶液，制得软材。上述软材干燥后加入硬脂酸镁、滑石粉，混合均匀，压片获得硫肽环素片剂。
2)将滑石粉过筛后加入到含羟丙基甲基纤维素、蓖麻油、丙二醇、吐温-80的醇溶液中，搅拌均匀后加入柠檬黄、食用香精的水溶液，制得缓释包衣液。
3)将硫肽环素素片加入包衣锅中，调节好进风量，素片预热后，将温度在30-50℃进行包衣，干燥后即得硫肽环素缓释包衣片。
控释片剂(肠溶片)
Figure PCTCN2016107404-appb-000005
制备方法：
1)硫肽环素素片制备方法同缓释片剂。
2)取聚丙烯酸树脂II加入至乙醇中，搅拌溶解后加入邻苯二钾酸二乙酯、吐温-80和蓖麻油，搅拌均匀，过筛，备用。
3)采用纯化水将蔗糖溶解至糖浆状，趁热过滤备用。
4)将硫肽环素素片加入包衣锅中，调节好进风量，素片预热后，将温度控制在30-50℃，加入糖浆适量使片芯表面均匀湿润，加入滑石粉均匀包裹与片芯表面，吹干备用。然后再重复上述操作进行肠溶包衣即得硫肽环素肠溶控释片。
实施例5 硫肽环素咀嚼片
硫肽环素的口服咀嚼片剂处方为药物制剂领域所有常用及可以使用的制剂配方，本专利所列 举的实施例仅用作说明而不限制本发明的应用范围。实施例制剂处方如下：
咀嚼片
成分 用量(g/1000片剂)
硫肽环素 0.01-250g
乳糖 200g
甜蜜素 50g
阿斯巴甜 20g
硬脂酸镁 50g
鲜奶香精 100g
乙醇 20g
制备方法：硫肽环素与辅料分别过100目筛。把硫肽环素、乳糖、甜蜜素、阿斯巴甜混合均匀后加入乙醇制成软材，过20-50目筛制粒，在50℃真空条件下干燥，然后再过20目筛进行整粒。最后加入硬脂酸镁和鲜奶香精，混合均匀。取上述粉末进行压片即得硫肽环素咀嚼片。
实施例6 硫肽环素胶囊剂
硫肽环素的胶囊剂处方为药物制剂领域所有常用及可以使用的制剂配方，本专利所列举的实施例仅用作说明而不限制本发明的应用范围。实施例制剂处方如下：
普通胶囊剂
成分 用量(g/1000粒剂)
硫肽环素 0.01-250g
预胶化淀粉 200g
聚乙烯吡咯烷酮水溶液(8％) 15g
滑石粉 75g
硬脂酸镁 37.5g
制备方法：将硫肽环素与上述原辅料分别粉碎并过100目筛子，以备用。硫肽环素与预胶化淀粉混合均匀，然后加入聚乙烯吡咯烷酮水溶液(8％)作为粘合剂，制备软材。加入滑石粉和硬脂酸镁，使用挤出抛圆法制备微丸，控制微丸水分在4.0％以下，将所得微丸填充到胶囊壳中即得硫肽环素胶囊剂。
软胶囊剂
成分 百分比含量或用量(g/1000粒剂)
硫肽环素 0.01-250g
明胶 46％
PEG400 0.1L
甘油 17.8％
吐温80 0.02L
水 36.2％
聚维酮K30 30g
制备方法：将聚维酮溶于PEG400和吐温80中，搅拌均匀后加入100目硫肽环素搅拌使其溶解，然后将该溶液制成胶囊即得硫肽环素软胶囊。
缓释胶囊剂
Figure PCTCN2016107404-appb-000006
制备方法：
1)空心微丸芯制备：采用市售的空白微丸即可或自己制备；
2)缓释胶囊制备：取处方量甲基丙烯酸共聚物、滑石粉、十二烷基硫酸钠、聚乙二醇，混合搅拌后作为包衣液，备用。取20目含药微丸500g置于离心包衣造粒机进行包衣。将上述含药包衣微丸按规定填充普通胶囊即得硫肽环素缓控释胶囊剂。
实施例7 硫肽环素糖衣丸剂
硫肽环素的糖丸剂处方为药物制剂领域所有常用及可以使用的制剂配方，本专利所列举的实施例仅用作说明而不限制本发明的应用范围。实施例制剂处方如下：
糖衣丸剂
成分 百分比含量或用量(g/1000丸)
硫肽环素 10g
微晶纤维素 25g
羧甲淀粉钠 6g
乳糖 1.5g
乙醇(95％) 85g
聚丙烯酸树脂 4.4g
聚乙二醇6000 0.9g
硬脂酸镁 1.5g
蔗糖 25g
香精 适量
水 适量
制备方法：将80目硫肽环素、微晶纤维素、羧甲淀粉钠、乳糖于高效湿法制机中混合均匀，加入适当的水搅拌，制成软材，用孔径0.8mm孔板挤出，在转速800-2000rpm的滚圆机中滚圆，50-55℃干燥，即得硫肽环素丸剂。
取乙醇置于容器中边搅拌边加入聚丙烯酸树脂、聚乙二醇6000、香精、蔗糖，加入适量水混合均匀，再加入硬脂酸镁，搅拌混悬包衣液备用。然后将硫肽环素丸剂置于包衣锅中，调节进风温度40-60℃，调节雾化压力和供液速度，使包衣液均匀包裹在丸剂表面。包衣完成后干燥30分钟左右即可获得硫肽环素糖衣丸剂。
实施例8 硫肽环素干混悬剂
硫肽环素的干混悬剂处方为药物制剂领域所有常用及可以使用的制剂配方，本专利所列举的实施例仅用作说明而不限制本发明的应用范围。实施例制剂处方如下：
普通干混悬剂
成分 用量(g)
硫肽环素 0.01-250g
甘露醇 20g
甜蜜素 40g
羟丙甲基纤维素 30g
乙醇(50％) 2g
制备方法：将120目硫肽环素与甘露醇、甜蜜素、羟丙甲基纤维素混合均匀后过120目筛， 然后加入乙醇混合均匀后制备软材，过30目筛。干燥后分装即得硫肽环素干混悬剂。
缓释干混悬剂
成分 用量(g)
硫肽环素 0.01-250g
空白微丸 0.1g
聚维酮 1.8g
羟丙甲基纤维素 1g
吐温80 0.08g
聚乙二醇4000 0.1g
乙基纤维素 0.6g
磷酸钠 0.3g
蔗糖 2g
羧甲基纤维素钠 0.06g
制备方法：将120目硫肽环素与聚维酮混合均匀，并加至95％乙醇中搅拌获得混悬液。将空白微丸置于流化床中并喷入硫肽环素溶液，干燥制得硫肽环素载药微丸。然后将吐温80和羟丙甲基纤维素加入到75％乙醇中，搅拌至完全溶解即得包衣液，喷入流化床中制备硫肽环素包衣微丸。在搅拌状态下将乙基纤维素、聚维酮和聚乙二醇4000加入到95％乙醇中完全溶解，制得缓释层包衣液，喷入流化床中制备硫肽环素缓释微丸。最后将载药缓释微丸与磷酸钠、蔗糖、羧甲基纤维素钠混合装袋后即得硫肽环素缓释干混悬剂。
实施例9 硫肽环素糖浆剂
硫肽环素的糖浆剂处方为药物制剂领域所有常用及可以使用的制剂配方，本专利所列举的实施例仅用作说明而不限制本发明的应用范围。实施例制剂处方如下：
糖浆剂
成分 用量(g)
硫肽环素 0.01-250g
谷氨酸 8g
β-环糊精 35g
硫脲 1g
EDTA-2Na 0.3g
苯甲酸 2g
羟苯乙酯 0.5g
草莓香精 1g
食用色素 0.005g
蔗糖 650g
水 1000ml
制备方法：将蔗糖加入到300ml纯化水中，搅拌加热至沸腾，使蔗糖完全溶解成糖浆，降温过滤后备用(溶液A)。将食用色素加入至1ml水中，搅拌溶解(溶液B)。取230ml纯化水加热沸腾后，加入β-环糊精、硫脲、EDTA-2Na、苯甲酸和羟苯乙酯，搅拌至完全溶解，降温至60℃以下时，加入硫肽环素和谷氨酸搅拌溶解(溶液C)。将溶液B加入到溶液C中，搅拌均匀后经300目筛缓慢加入至溶液A中，搅拌均匀，降温至40℃以下时，加入草莓香精，搅拌均匀，然后加入剩余的纯化水，经300目筛过滤后即得硫肽环素糖浆剂。
实施例10 硫肽环素口服乳剂
硫肽环素的口服乳剂处方为药物制剂领域所有常用及可以使用的制剂配方，本专利所列举的实施例仅用作说明而不限制本发明的应用范围。实施例制剂处方如下：
口服乳剂
成分 用量(g/1000ml)
硫肽环素 0.01-250g
大豆油 200ml
卵磷脂 10g
泊洛沙姆 20g
0.9％氯化钠溶液 800ml
糖精 2g
橙味香精 2g
制备方法：将处方量的泊洛沙姆分散于0.9％的氯化钠溶液中研匀，再将溶解的硫肽环素和卵磷脂的油相加入，用力搅拌制成初乳，加入糖精和香精后，用0.9％氯化钠溶液将初乳稀释定量即得均匀分散的乳剂。
实施例11 硫肽环素口服冻干粉剂
硫肽环素的口服冻干粉剂处方为药物制剂领域所有常用及可以使用的制剂配方，本专利所列举的实施例仅用作说明而不限制本发明的应用范围。实施例制剂处方如下：
口服冻干粉剂
成分 百分比含量或用量(g)
硫肽环素 0.01-250g
PEG400 10％
右旋糖酐 5％
柠檬酸 0.5％
糖精 1％
制备方法：将100目硫肽环素与PEG400混合，搅拌溶解(溶液A)；用纯化水溶解柠檬酸、右旋糖酐和糖精，搅拌至完全溶解(溶液B)；将A和B两种溶液混合均匀，用0.5N 的柠檬酸或氢氧化钠溶液调节pH至5.0；加水稀释定量后分装，然后冻干即得硫肽环素口服冻干粉剂。
实施例12 硫肽环素胶浆剂
硫肽环素的胶浆剂处方为药物制剂领域所有常用及可以使用的制剂配方，本专利所列举的实施例仅用作说明而不限制本发明的应用范围。实施例制剂处方如下：
胶浆剂
成分 用量(g)
硫肽环素 0.01-250g
丙三醇 40g
丙二醇 10g
聚氧乙烯聚氧丙烯共聚物 10g
聚环氧乙烷8000 30g
醋酸氯己定 0.7g
EDTA-2Na 0.1g
水 适量
制备方法：将100目硫肽环素用纯化水溶解，然后加入丙三醇、丙二醇、聚氧乙烯聚氧丙烯共聚物和聚环氧乙烷8000，搅拌至物料溶解成胶体状溶液(溶液A)。将醋酸氯己定和EDTA-2Na用200ml水溶解后加入到溶液A中，充分混合均匀，pH调至5-6，即得硫肽环素胶浆剂成品。
实施例13 硫肽环素泡腾颗粒或片剂
硫肽环素的泡腾剂处方为药物制剂领域所有常用及可以使用的制剂配方，本专利所列举的实施例仅用作说明而不限制本发明的应用范围。实施例制剂处方如下：
泡腾颗粒剂或片剂
成分 百分比含量或用量(g)
硫肽环素 0.01-250g
碳酸氢钠 4.3％
碳酸钠 5.8％
柠檬酸 8.5％
富马酸 1.8％
聚乙二醇 15％
十二烷基苯磺酸钠 6％
羧甲基纤维素钠 6％
氮酮 6％
硅藻土 余量
制备方法：按照上述比例计算每种辅料的下料量，并称取。将硫肽环素、硅藻土、羧甲基 纤维素钠、柠檬酸、富马酸混合均匀，再加入氮酮后搅拌混合均匀，最后加入其它所有剩余辅料，经过微粉机粉碎一边，过200筛，装入造粒机(或压片机)一次成型挤压造粒(或压片)，干燥后即为硫肽环素颗粒剂(或片剂)。
实施例14 硫肽环素颗粒剂
硫肽环素的颗粒剂处方为药物制剂领域所有常用及可以使用的制剂配方，本专利所列举的实施例仅用作说明而不限制本发明的应用范围。实施例制剂处方如下：
颗粒剂
成分 用量(g)
硫肽环素 1g
蔗糖 20g
预胶化淀粉 2g
糖精钠 0.1g
羧甲基纤维素钠 0.1g
聚维酮(4％) 15ml
甜橙香精 0.1g
制备方法：将蔗糖、预胶化淀粉、糖精钠、羧甲基纤维素钠在湿法混合制粒机中混合均匀，加入聚维酮(4％)水溶液后混合均匀，然后加入80-100目硫肽环素和甜橙香精在颗粒机中混合制粒，即得硫肽环素口服颗粒剂。
实施例15 硫肽环素口服液
硫肽环素的口服液处方为药物制剂领域所有常用及可以使用的制剂配方，本专利所列举的实施例仅用作说明而不限制本发明的应用范围。实施例制剂处方如下：
口服液
成分 用量(g/1000ml)
硫肽环素 0.01-250g
磷酸二氢钠 30g
苯甲酸钠 3g
糖精钠 0.1g
枸橼酸 1.5g
蔗糖 350g
水 余量
制备方法：将硫肽环素、助溶剂和防腐剂溶于100ml纯化水中，搅拌至完全溶解(溶液A)，备用。将矫味剂荣誉500ml水中，然后加入溶液A，再加入纯水至1000ml，混匀过滤后即得硫肽环素口服液。
实施例16 硫肽环素酊剂
硫肽环素的酊剂处方为药物制剂领域所有常用及可以使用的制剂配方，本专利所列举的实施例仅用作说明而不限制本发明的应用范围。实施例制剂处方如下：
酊剂
成分 用量(g)
硫肽环素 0.01-250g
30-70％食用白酒 硫肽环素质量的4-20倍
脂肪酸山梨坦 食用白酒量的1％
食用香精 食用白酒量的0.1％
制备方法：将硫肽环素、脂肪酸山梨坦和食用香精溶解于食用白酒，混合均匀后过滤即得硫肽环素酊剂。

Claims (9)

  1. 硫肽环素在制备治疗艰难梭菌感染性疾病及其并发症的药物中的应用。
  2. 如权利要求1所述的应用，其特征在于所述艰难梭菌感染性疾病及其并发症包含伪膜性结肠炎、结肠炎、中毒性巨肠炎、腹泻、伪膜性肠炎以及艰难梭菌感染引起的肾盂肾炎、脑膜炎、腹腔及阴道感染、菌血症和气性坏疽、抗生素相关性疾病以及并发症。
  3. 如权利要求1或2所述的应用，其特征在于所述艰难梭菌包括敏感型降低菌株以及对抗生素耐药的艰难梭菌株。
  4. 如权利要求3所述的应用，其特征在于所述抗生素为氨苄西林、头孢菌素、林可霉素、克林霉素、红霉素、四环素、万古霉素、甲硝唑中的一种或多种。
  5. 如权利要求1所述的应用，其特征在于硫肽环素通过灌肠、鼻胃管、直肠或者口服途径给药。
  6. 一种治疗艰难梭菌感染性疾病及其并发症的药物制剂，其特征在于药物活性成分为硫肽环素。
  7. 如权利要求6所述的药物制剂，其特征在于所述药剂为硫肽环素口服制剂，所述制剂选自片剂、胶囊剂、薄膜包衣片、咀嚼片、糖衣丸、混悬剂、糖浆、乳剂、口服冻干粉、口服液、胶浆剂、泡腾剂、颗粒剂或酊剂及其相关缓控释制剂。
  8. 如权利要求7所述的药物制剂，其特征在于包括硫肽环素和药学上可接受的药用辅料，所述辅料包括粘合剂、崩解剂、填充剂、润滑剂、分散剂、助流剂、着色剂、乳化剂、稳定剂、增溶剂、潜溶剂、pH调节剂、抗氧化剂、矫味剂、防腐剂、缓释材料、控释材料中的一种或几种。
  9. 如权利要求8所述的药物制剂，其特征在所述粘合剂选自聚乙烯吡咯烷酮、淀粉、羟丙甲纤维素、羟丙基纤维素、微晶纤维素、甲基纤维素、乙基纤维素、羧甲基纤维素及其钠盐、明胶、阿拉伯胶、瓜尔胶、黄耆胶、海藻酸钠中的一种或几种；崩解剂选自交联羧甲基纤维素钠、交联聚维酮、淀粉、羧甲基淀粉钠、羧丙基淀粉、微晶纤维素、低取代羟丙基纤维素中的一种或几种；填充剂选自乳糖、蔗糖、淀粉、改性淀粉、甘露醇、山梨醇、糊精衍生物、纤维素衍生物、硫酸钙中的一种或几种；润滑剂选自硬脂酸、硬脂酸钙、硬脂酸镁、氢化植物油、巴西棕榈酸蜡、滑石粉、聚乙二醇、硬酯酰富马酸钠中的一种或几种；助流剂选自微粉硅胶、滑石粉；分散剂选自微晶纤维素、乳糖、甘露醇、磷酸氢钙中的一种或几种；乳化剂选自SLS、吐温、泊洛沙姆、聚维酮、卵磷脂、硬脂酸类、明胶、甲基纤维素、羟丙纤维素、聚氧乙烯、蓖麻油、蜂蜡，鲸蜡醇、蛋黄磷脂或大豆磷脂中的一种或几种；稳定剂选自泊洛沙姆、聚乙二醇、聚山梨酯中的一种或几种；增溶剂选自聚乙二醇、脂肪酸山 梨坦、聚山梨酯、聚维酮、泊洛沙姆、环糊精和卵磷脂中的一种或几种；潜溶剂选自乙醇、丙二醇、DMSO、甘油或聚乙二醇中的一种或几种；pH调节剂选自盐酸、醋酸、磷酸、碳酸、柠檬酸、磷酸、乳酸、酒石酸、苹果酸、琥珀酸、氢氧化钠、三乙醇胺、乙二胺中的一种或几种或相应的酸及其盐所组成的缓冲液；抗氧化剂选自焦亚硫酸钠、亚硫酸氢钠、亚硫酸钠、硫代硫酸钠、二丁基苯酚、维生素C中的一种或几种；矫味剂选自糖精、单糖浆、果汁糖浆、甘草酸二钠、蔗糖、三氯蔗糖、阿斯巴甜、甜菊素、麦芽糖醇、山梨醇、木糖醇、乳糖醇、甘露醇、天然香料或人工香料的一种或几种；防腐剂选自苯甲酸、苯甲酸钠、对羟基苯甲酸酯类、山梨酸/山梨酸钾中的一种或几种；缓释材料选自PLGA、PLA、壳聚糖、甲基丙烯酸共聚物、乳酸-赖氨酸聚合物、羟丙基甲基纤维素、明胶、聚丙烯酸、蜂蜡中的一种或几种；控释材料选自高分子凝胶、壳聚糖及其共混物、环糊精及其衍生物、白蛋白、聚乳酸及其共聚物、海藻酸钠、纤维素中的一种或几种。
PCT/CN2016/107404 2015-12-02 2016-11-28 一种硫肽环素的新用途 WO2017092630A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US15/781,048 US20190231844A1 (en) 2015-12-02 2016-11-28 Oral application of thiopeptcin
EP16869940.3A EP3384921A4 (en) 2015-12-02 2016-11-28 NEW USE OF THIOPEPTIN

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201510870586.1 2015-12-02
CN201510870586 2015-12-02
CN201510896693.1 2015-12-08
CN201510896693.1A CN105363018B (zh) 2015-12-02 2015-12-08 一种硫肽环素的新用途

Publications (1)

Publication Number Publication Date
WO2017092630A1 true WO2017092630A1 (zh) 2017-06-08

Family

ID=55365972

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/107404 WO2017092630A1 (zh) 2015-12-02 2016-11-28 一种硫肽环素的新用途

Country Status (4)

Country Link
US (1) US20190231844A1 (zh)
EP (1) EP3384921A4 (zh)
CN (1) CN105363018B (zh)
WO (1) WO2017092630A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112007002A (zh) * 2020-08-05 2020-12-01 河北君临药业有限公司 一种质量稳定的甲硝唑片剂组合物及其制备方法

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2017327369A1 (en) 2016-09-13 2019-05-02 Allergan, Inc. Stabilized non-protein Clostridial toxin compositions
CN109528652B (zh) * 2019-01-24 2021-07-13 成都迈科康生物科技有限公司 一种注射用自乳化药物乳剂及其制备方法和应用
CN111068099B (zh) * 2019-12-11 2021-04-06 杭州千芝雅卫生用品有限公司 高分子吸收聚合体、制备方法及其用途
CN113413368A (zh) * 2021-07-15 2021-09-21 佛山市隆信医药科技有限公司 一种微丸或颗粒的制备工艺
CN116098864B (zh) * 2023-04-11 2023-06-09 北京普诺旺康医药科技有限公司 一种利那洛肽干混悬剂及其制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102018953A (zh) * 2010-11-18 2011-04-20 陈依军 含诺卡沙星抗生素的药物组合物

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6287827B1 (en) * 1999-05-05 2001-09-11 Bristol-Myers Squibb Company Halo- or hydroxy-substituted nocathiacin antibiotics
CN102028933A (zh) * 2010-11-18 2011-04-27 中国药科大学 含脂质材料的诺卡沙星抗生素的药物组合物
CN103040770B (zh) * 2013-02-05 2016-08-17 南京碧迪可医药科技有限公司 一种诺卡沙星冻干粉针剂的制备方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102018953A (zh) * 2010-11-18 2011-04-20 陈依军 含诺卡沙星抗生素的药物组合物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LV , RUIXUE ET AL.: "Activity of Thiopeptide Antibiotic Nocathiacin against Gram-Positive Bacteria", JOURNAL OF PHARMACEUTICAL RESEARCH, vol. 22, no. 4, 31 August 2014 (2014-08-31), XP055491880 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112007002A (zh) * 2020-08-05 2020-12-01 河北君临药业有限公司 一种质量稳定的甲硝唑片剂组合物及其制备方法

Also Published As

Publication number Publication date
CN105363018A (zh) 2016-03-02
US20190231844A1 (en) 2019-08-01
CN105363018B (zh) 2019-08-30
EP3384921A1 (en) 2018-10-10
EP3384921A4 (en) 2019-08-14

Similar Documents

Publication Publication Date Title
WO2017092630A1 (zh) 一种硫肽环素的新用途
JP6234412B2 (ja) リファキシミンの固溶体
US6764997B2 (en) Stabilized azithromycin compositions
US20070231368A1 (en) Pharmaceutical formulations of 6-11 bicyclic macrolide derivative known as edp-182 and methods for preparation thereof
CN105748499A (zh) 两个抗病毒化合物的联用制剂
US8921416B2 (en) Dronedarone solid dispersion and preparation method thereof
BRPI0608853B1 (pt) composições farmacêuticas e processo para a fabricação de microgrânulos de rifaximina gastrorresistentes
EP3468555B1 (en) Compositions for use in treating bacterial infections
CN104719910B (zh) 具有热稳定性的egcg固体分散体组合物及其制备方法和应用
JP2013521273A (ja) リファキシミン粉体、その調製方法、及び長期持続効果を得るために有用な前記リファキシミン含有徐放性組成物
TW201019938A (en) Pharmaceutical formulations of an HCV protease inhibitor in a solid molecular dispersion
CZ286051B6 (cs) Farmaceutický prostředek a způsob jeho použití pro dasažení projímavého účinku
HUE028671T2 (en) Stable tiacumicin compositions
CN101541309A (zh) 包含神经激肽拮抗剂的药物制剂
CN101340917A (zh) 用替加环素治疗胃肠道感染的方法
KR101157486B1 (ko) 경구용 항미생물성 제약학적 조성물
CN112423751A (zh) 包含Fab I抑制剂的口服给药的药物组合物及制备其的方法
US20070199856A1 (en) Methods of stabilizing azithromycin
WO2017103631A1 (en) Oral pharmaceutical composition in the form of granules comprising metronidazole or derivatives thereof and a taste-masking agent
WO2022083636A1 (zh) 盐酸决奈达隆药物组合物、其制备方法及应用
US10350293B2 (en) Compositions and methods for treating symptoms associated with multiple sclerosis
WO2012113594A1 (en) Use of nifuratel to treat infections caused by clostridium species
CN109776573A (zh) 头孢羟氨苄制剂治疗女性生殖系统感染的新适应症
HK1175114B (zh) 利福昔明固體分散體

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: 16869940

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2016869940

Country of ref document: EP