WO2015037659A1 - 水溶液製剤及びその製造方法 - Google Patents

水溶液製剤及びその製造方法 Download PDF

Info

Publication number
WO2015037659A1
WO2015037659A1 PCT/JP2014/074065 JP2014074065W WO2015037659A1 WO 2015037659 A1 WO2015037659 A1 WO 2015037659A1 JP 2014074065 W JP2014074065 W JP 2014074065W WO 2015037659 A1 WO2015037659 A1 WO 2015037659A1
Authority
WO
WIPO (PCT)
Prior art keywords
aqueous solution
compound represented
compound
diseases
producing
Prior art date
Application number
PCT/JP2014/074065
Other languages
English (en)
French (fr)
Inventor
板井　昭子
亮一 冨田
智行 ▲藤▼川
Original Assignee
株式会社医薬分子設計研究所
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 株式会社医薬分子設計研究所 filed Critical 株式会社医薬分子設計研究所
Priority to US14/917,638 priority Critical patent/US9974860B2/en
Priority to EP14844160.3A priority patent/EP3045169B1/en
Priority to JP2015536623A priority patent/JP6083770B2/ja
Priority to CN201480050141.2A priority patent/CN105636583B/zh
Publication of WO2015037659A1 publication Critical patent/WO2015037659A1/ja

Links

Classifications

    • 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
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • 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
    • A61P31/12—Antivirals
    • 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
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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

Definitions

  • the present invention relates to an aqueous solution preparation containing N- [3,5-bis (trifluoromethyl) phenyl] -5-chloro-2-hydroxybenzamide as an active ingredient and a method for producing the same.
  • Formula (I) It is known that the compound represented by the formula (hereinafter referred to as Compound (I)) is useful for preventing or ameliorating various diseases and useful as various preparations (Patent Documents 1 to 40). And non-patent documents 1 to 35).
  • An object of the present invention is to provide an aqueous solution preparation containing compound (I) and a method for producing the same.
  • the present inventors have dissolved the compound (I) and the compound represented by the following general formula (II), (III) or (IV) in an organic solvent. Thereafter, by removing the organic solvent from this solution, it was found that the obtained residue could be dissolved in water or an aqueous solution, that is, an aqueous solution preparation containing Compound (I) could be produced, and the present invention was completed.
  • a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof and a compound represented by any one of the following general formulas (II) to (IV) are dissolved in an organic solvent.
  • a first step of preparing a dissolving solution; a second step of removing the organic solvent from the dissolving solution; and a third step of dissolving the residue by adding a solution to the residue obtained by the second step A method for producing an aqueous solution preparation comprising a step; [2] The method for producing an aqueous solution preparation according to the above [1], wherein n of the compound represented by the general formula (II) is 14 or 37; [3] The method for producing an aqueous solution preparation according to the above [1], wherein n of the compound represented by the general formula (III) is 46; [4] The method for producing an aqueous solution preparation according to the above [1], wherein n of the compound represented by the general formula (IV) is 46; [5] An
  • an aqueous solution preparation containing Compound (I) and a method for producing the same can be provided.
  • the aqueous solution preparation of the present invention i.e., the aqueous solution preparation containing compound (I) as an active ingredient, compound (I) or a pharmacologically acceptable salt, and general formulas (II) and (III) Or a first step of preparing a solution in which the compound represented by (IV) is dissolved, a second step of removing the organic solvent from the solution, and a solution in the residue obtained by the second step. And a third step of dissolving the residue.
  • Compound (I) can be produced, for example, based on the method described in US Patent Application Publication No. 2004/0259877. Moreover, the pharmacologically acceptable salt of compound (I) can be produced by a method widely used in the art. Examples of the pharmacologically acceptable salt of compound (I) include metal salts such as lithium salt, sodium salt, potassium salt, magnesium salt and calcium salt, or ammonium salt, methylammonium salt, dimethylammonium salt and trimethyl. Mention may be made of ammonium salts such as ammonium salts and dicyclohexylammonium salts.
  • the compound represented by the general formula (II) has an average molecular weight of 1000 to 2000, that is, n (average number of units of polyethylene glycol (PEG) contained in the compound) is an integer of 14 to 37. Although it will not be restrict
  • the compound represented by the general formula (III) is not particularly limited as long as the average molecular weight of polyethylene glycol is 1000 to 2000, that is, n is an integer of 22 to 46. It is preferable to use one having an average molecular weight of polyethylene glycol of 2000, that is, n of 46.
  • the compound represented by the general formula (III) can be produced according to the method described in US Pat. No. 6,679,822.
  • the compound represented by the general formula (IV) is not particularly limited as long as the average molecular weight of polyethylene glycol is 1000 to 2000, that is, n is an integer of 22 to 46. It is preferable to use one having an average molecular weight of polyethylene glycol of 2000, that is, n of 46.
  • the organic solvent is not particularly limited as long as it can dissolve the compound (I) or a pharmacologically acceptable salt and the compound represented by the general formula (II), (III) or (IV).
  • primary alcohols such as methanol, ethanol, isopropanol, tert-butanol, dimethyl sulfoxide (DMSO), methyl tert-butyl ether, N, N-dimethylacetamide, N, N-dimethylformamide, acetone, N -Methyl-2-pyrrolidone, tetrahydrofuran, acetonitrile or ethyl acetate, or a mixture thereof can be used, and a pharmaceutically acceptable organic solvent such as ethanol, N-methyl-2-pyrrolidone, dimethyl sulfoxide can be used. preferable.
  • the temperature at which compound (I) or a pharmacologically acceptable salt, and a compound represented by general formula (II), (III) or (IV) is dissolved in an organic solvent may be compound (I) or a drug.
  • the salt is not particularly limited as long as it is a temperature at which a physically acceptable salt and the compound represented by the general formula (II), (III) or (IV) can be dissolved in an organic solvent.
  • the melting temperature is, for example, a temperature range of 50 to 60 ° C.
  • the solution added to the residue obtained by removing the organic solvent from the solution is not particularly limited as long as it is a pharmaceutically acceptable solution.
  • a pharmaceutically acceptable solution for example, water for injection (water), physiological saline A glucose aqueous solution, Ringer's solution, lactated Ringer's solution, or the like can be used.
  • the temperature at which this solution is added to the residue to dissolve the residue is not particularly limited as long as the temperature can dissolve the residue in the solution.
  • the melting temperature of the residue is, for example, a temperature range of 0 to 60 ° C., preferably a temperature range of 4 to 55 ° C., and more preferably a temperature range of room temperature (23 to 25 ° C.) to 55 ° C.
  • the aqueous solution preparation obtained by the method for producing an aqueous solution preparation of the present invention has any concentration range that can be used as a preparation such as an injection, that is, any concentration as long as 1 mg or more of Compound (I) is dissolved in 1 mL of the solution. However, a high concentration is preferable in that the dose can be reduced.
  • the aqueous solution preparation of the present invention produced as described above can be used for the prevention (including suppression of progression / deterioration) or improvement of the diseases described in Patent Documents 1 to 40 or Non-Patent Documents 1 to 35, for example. Useful for treatment, prolongation of life, etc.).
  • Diseases include, for example, autoimmune diseases, inflammatory diseases, allergic diseases, tumors, cancers, carcinomas, sarcomas, blood diseases, cardiovascular diseases, respiratory diseases, digestive diseases, liver diseases, lung diseases, urological diseases, Endocrine diseases, metabolic diseases, eye diseases, otolaryngology diseases, skin diseases, neurological diseases, brain diseases, connective tissue diseases, musculoskeletal diseases, viral diseases, bacterial diseases, thrombosis and the like can be mentioned.
  • the above diseases include rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, systemic scleroderma, polymyositis, Sjogren's syndrome, vasculitis syndrome, antiphospholipid antibody syndrome, Still's disease, Behcet's disease , Periarteritis nodosa, ulcerative colitis, Crohn's disease, active chronic hepatitis, glomerulonephritis, chronic nephritis, chronic pancreatitis, gout, atherosclerosis, multiple sclerosis, intimal thickening, psoriasis, psoriatic Arthritis, contact dermatitis, atopic dermatitis, eczema, hay fever, hives, vasculitis, rhinitis, gastroenteropathy, diarrhea, neuritis, otitis media, granulomatosis, cystitis, laryngitis, purpur
  • the injectable composition of the present invention can also be used as an organ deterioration preventive agent when pre-transplant organ preservation.
  • prevention and / or improvement of tumor or its synonyms include tumoricidal action or anticancer action, tissue or cell canceration inhibiting action, tumor metastasis inhibiting action, existing antitumor agent Intensive action of drugs, action to overcome drug resistance to existing antitumor agents, cancer epidemic improvement action, prevention of recurrence, life-prolonging action of tumor patients, etc.
  • prevention or improvement of Alzheimer's disease includes amyloid ⁇ protein accumulation inhibitory effect, nerve cell death inhibitory effect, brain atrophy inhibitory effect, neurofibrillary tangle change inhibitory effect, dementia improving effect, and the like.
  • epilepsy includes epileptic seizure suppression (eg, tonic-clonic seizure, absence seizure, myoclonic seizure, etc.), cerebral nerve cell abnormal excitation suppression, hippocampal neuronal cell death suppression, etc. including.
  • the aqueous solution preparation of the present invention may further contain one or two or more additives that are acceptable as components of the aqueous solution preparation, in addition to the residue and the solution.
  • the additive include a buffer such as sodium phosphate; a stabilizer such as sodium pyrosulfite; an osmotic pressure regulator such as sodium chloride, mannitol and glycerin; a soothing agent such as lidocaine; and a preservative such as phenol.
  • a buffer such as sodium phosphate
  • a stabilizer such as sodium pyrosulfite
  • an osmotic pressure regulator such as sodium chloride, mannitol and glycerin
  • a soothing agent such as lidocaine
  • a preservative such as phenol.
  • the necessary amount of the injectable composition of the present invention may be administered to the administration subject at one time, intermittently, or continuously.
  • Examples of the continuous administration method include infusion administration.
  • the injectable composition of the present invention can be suitably used for the improvement of acute diseases requiring urgent administration of a therapeutic agent.
  • diseases include cerebrovascular disorders such as stroke, ischemic heart disease such as acute myocardial infarction, and the like.
  • the injectable composition of the present invention can be suitably used for the improvement of diseases that require continuous administration of a therapeutic agent.
  • SUNBRIGHT registered trademark
  • CS-010 and CS-020 are used as examples of the compound represented by the general formula (II), and the compound represented by the general formula (III) is used.
  • SUNBRIGHT registered trademark
  • DSPE-020CN NOF Co., Ltd.
  • SUNBRIGHT registered trademark
  • DSPE-020GL2U NOF Corporation
  • Example 1 to Example 7 Preparation of aqueous solution containing compound (I) Drug [Compound (I)], the compound shown in the table below and ethanol were added to a vial and heated to 55-60 ° C. And the compound was completely dissolved in ethanol (colorless and transparent without causing precipitation and precipitation) to prepare each dissolution solution.
  • Each lysis solution was warmed at 60 ° C. for 1.5 hours, and the contents were evaporated to dryness.
  • a predetermined amount of physiological saline or water was added to the resulting residue, and the mixture was heated to 55 ° C. (incubated at room temperature for 24 hours in Example 6. Incubated at 4 ° C. for 72 hours in Example 7) for dissolution. It was.
  • the storage stability is excellent without being clouded or producing precipitates or precipitates at 4 ° C. or at room temperature for at least 2 months.
  • I was able to confirm.
  • the aqueous solution of Example 3 was excellent in storage stability without becoming cloudy or producing precipitates or precipitates at 4 ° C. for at least 2 months.
  • the aqueous solution of Example 7 was excellent in storage stability without becoming cloudy or producing precipitates or precipitates at 4 ° C. for at least one month.
  • Example 1 Pharmacokinetic test using the aqueous solution obtained in Example 1 The aqueous solution obtained in Example 1 was filtered and sterilized with Millex (registered trademark) -GV (0.22 ⁇ m; Nippon Millipore Corporation / Merck Millipore). Then, it was intravenously administered to male and female Sprague-Daweley IGS rats (6 weeks old), and the kinetics of compound (I) was examined.
  • Millex registered trademark
  • ⁇ Test method> As the animal group, male and female Sprague-Daweley IGS rats (Charles River Japan) were used. The rats were 6 weeks old and weighed 166-189 g for males and 123-145 g for females. The rats were quarantined and acclimatized for 7 days in a SPF (Specific pathogen free) animal laboratory, and at the same time the health condition was observed. Rats were housed one in each gauge in a sterilized stainless steel gauge. In the SPF animal laboratory, the room temperature was maintained at 20.6-22.5 ° C. and the relative humidity was maintained at 44-60%. Ventilation in the SPF animal laboratory was performed 15 times per hour. The lighting in the SPF animal laboratory was switched between bright and dark every 12 hours.
  • SPF Standard pathogen free
  • the animal sample used was a rod-shaped dry basic sample (component analysis completed).
  • the drinking water was tap water that was confirmed to be within the reference value by analysis, and rats were allowed to ingest freely.
  • the quarantined rats were randomly divided into the following 3 groups (4 males and 4 females per group) according to body weight.
  • Group 3 Group to administer 3 mL / kg of the aqueous solution obtained in Example 1 After the quarantined rats were fasted overnight (about 16 hours), the aqueous solution obtained in Example 1 was intravenously administered.
  • Blood was collected 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 4 hours, and 24 hours after administration, and the blood concentration of compound (I) was measured. From the measured blood concentration of compound (I) at each sampling time, the maximum blood concentration C 0 (ng / mL) immediately after intravenous administration of the injectable composition, and the compound (I ) AUC 0-24 (ng ⁇ h / mL) under the blood concentration curve was calculated.
  • Example 1 From the results of the present confirmation example, it is clear that the aqueous solution obtained in Example 1 can be exposed in a dose-dependent and sufficient amount, as an active ingredient, by intravenous administration into the living body. It became. Further, in this confirmed example, there were no deaths in the rats, and no toxicological findings that could cause serious disability were observed.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Neurology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Diabetes (AREA)
  • Biomedical Technology (AREA)
  • Pulmonology (AREA)
  • Neurosurgery (AREA)
  • Immunology (AREA)
  • Hematology (AREA)
  • Pain & Pain Management (AREA)
  • Oncology (AREA)
  • Cardiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Urology & Nephrology (AREA)
  • Dermatology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Communicable Diseases (AREA)
  • Obesity (AREA)
  • Molecular Biology (AREA)
  • Virology (AREA)
  • Biophysics (AREA)
  • Endocrinology (AREA)

Abstract

　有機溶媒に下式(I)で表される化合物又は薬理学的に許容されるその塩、及び下記の一般式(II)～(IV)のいずれかで表される化合物を溶解した溶解液を調製する第１の工程と、前記溶解液から前記有機溶媒を取り除く第２の工程と、第２の工程によって得られた残留物に溶液を加えて前記残留物を溶解する第３の工程を行うことにより、化合物(I)を含有する水溶液製剤を製造することができる。

Description

水溶液製剤及びその製造方法
　本発明は、N-[3,5-ビス(トリフルオロメチル)フェニル]-5-クロロ-2-ヒドロキシベンズアミドを有効成分として含む水溶液製剤及びその製造方法に関する。
　下式(I)：
Figure JPOXMLDOC01-appb-C000002
 で表される化合物（以下、化合物(I)と称する）は、様々な疾患の予防又は改善に有用であり、また、様々な製剤として有用であることが知られている（特許文献１～４０及び非特許文献１～３５を参照）。
米国特許第3331874号明細書 米国特許第3332996号明細書 米国特許出願公開第2004/0259877号明細書 米国特許出願公開第2008/0318956号明細書 米国特許出願公開第2010/0274051号明細書 米国特許出願公開第2008/0249071号明細書 米国特許出願公開第2006/0122243号明細書 米国特許出願公開第2008/0090779号明細書 米国特許出願公開第2007/0185110号明細書 米国特許出願公開第2007/0185059号明細書 米国特許出願公開第2006/0111409号明細書 米国特許出願公開第2006/0019958号明細書 米国特許出願公開第2006/0100257号明細書 米国特許出願公開第2006/0089395号明細書 米国特許出願公開第2008/0311074号明細書 米国特許出願公開第2006/0014811号明細書 米国特許出願公開第2006/0035944号明細書 米国特許出願公開第2008/0234233号明細書 米国特許出願公開第2007/0042997号明細書 米国特許出願公開第2007/0042997号明細書 米国特許出願公開第2007/0254956号明細書 米国特許出願公開第2009/0239868号明細書 米国特許出願公開第2006/0094718号明細書 米国特許出願公開第2010/0113770号明細書 国際公開第2008/041066号パンフレット 国際公開第2008/094410号パンフレット 国際公開第2008/133884号パンフレット 国際公開第2009/006555号パンフレット 国際公開第2009/074809号パンフレット 国際公開第2009/082514号パンフレット 国際公開第2010/000903号パンフレット 国際公開第2010/048273号パンフレット 国際公開第2010/096574号パンフレット 国際公開第2010/096574号パンフレット 国際公開第2010/099731号パンフレット 国際公開第2010/106082号パンフレット 国際公開第2011/133879号パンフレット 国際公開第2012/019284号パンフレット 国際公開第2012/024612号パンフレット 国際公開第2006/013873号パンフレット
Cardiovasc. Res.,63(1), p.51-59(2004). Biochem. Biophys. Res.Commun., 323(1), p.242-248(2004). Blood, 105(6), p.2324-2331(2005). Cancer Res., 66(1), p.419-426(2006). Am. J. Respir. Crit. Care Med., 173(9), p.1016-1022(2006). Am. J. Physiol. Heart Circ. Physiol., 292(1), H530-538(2007). J. Invest. Dermatol., 127(4), p.855-863(2007). Infect. Immun., 76(2), p.781-787(2008). J. Med. Dent. Sci., 55(1), p.49-59(2008). J. Gastroenterol., 44(9), p.935-943(2009). Int. Arch. Allergy Immunol., 148(3), p.186-198(2009). Res. Vet. Sci., 89(3), p.378-382(2010). Clin. Exp. Allergy, 41(1), p.104-115(2011). Clin. Exp. Nephrol., 15(1), p.41-49(2011). Expert. Opim. Investig. Drugs,20(3), p.395-405(2011). Cancer Sci., 103(1), p.100-106(2012). Cadiovasc. Res., 63(1), p.8-10(2004). Cancer Res., 67(7), p.3220-3228(2007). Curr. Cancer Drug Targets, 7(5), p.492-503(2007). Mod. Rheumatol., 17(6), p.459-463(2007). Basic Clin. Pharmacol. Toxicol., 101(6), p.401-406(2007). Spine (phila Pa 1976), 33(23), p.2489-2494(2008). Radiat. Res., 171(1), p.9-21(2009). Glycobiology, 19(7), p.776-788(2009). Am. J. Physiol. Lung Cell Mol. Physiol., 298(2), L197-209(2010). Histochem. Cell Biol., 133(3), p.339-348(2010). Eur. J. Pharmacol., 637(1-3), p.148-154(2010). Scientific World Journal, 10, p.2139-2156(2010). Toxicol. Appl. Pharmacol., 249(1), p.25-32(2010). Cytokine, 54(2), p.161-166(2011). J. Neuroinflammation, 8, 107(2011). J. Viral Hepat., 18(10), e439-446(2011). World J. Gastroenterol., 17(47), p.5203-5213(2011). Drug Metab. Dispos., 40(1), p.205-211(2012). Toxicol. Lett., 209(2), p.107-112(2012).
　しかしながら、上記化合物(I)は難水溶性の化合物であるため、化合物(I)を含有する水溶液製剤の製造が困難である。
　本発明は、化合物(I)を含有する水溶液製剤及びその製造方法を提供することを目的とする。
　本発明者らは上記課題を解決すべく鋭意研究を行った結果、化合物(I)、及び下記の一般式(II)、(III)又は(IV)で表される化合物を有機溶媒に溶解した後、この溶解液から有機溶媒を取り除くことにより、得られた残留物を水又は水溶液に溶解できること、すなわち、化合物(I)を含有する水溶液製剤を製造できることを見出し、本発明を完成した。
　すなわち、本発明は、
[1] 有機溶媒に下式(I)で表される化合物又は薬理学的に許容されるその塩、及び下記の一般式(II)～(IV)のいずれかで表される化合物を溶解した溶解液を調製する第１の工程と、前記溶解液から前記有機溶媒を取り除く第２の工程と、第２の工程によって得られた残留物に溶液を加えて前記残留物を溶解する第３の工程を含むことを特徴とする水溶液製剤の製造方法；
Figure JPOXMLDOC01-appb-C000003
 [2] 一般式(II)で表される化合物のnが14又は37である上記[1]に記載の水溶液製剤の製造方法;
[3] 一般式(III)で表される化合物のnが46である上記[1]に記載の水溶液製剤の製造方法;
[4] 一般式(IV)で表される化合物のnが46である上記[1]に記載の水溶液製剤の製造方法;
[5] 上記[1]～[4]のいずれかに記載の水溶液製剤の製造方法により得られる水溶液製剤などである。
　本発明によれば、化合物(I)を含有する水溶液製剤及びその製造方法を提供することができる。
　以下、上記知見に基づき完成した本発明の実施の形態を、実施例を挙げながら詳細に説明する。実施例において特に説明がない場合には、市販の試薬キットや測定装置はそれらに添付のプロトコールを用いる。
　なお、本発明の目的、特徴、利点、及びそのアイデアは、本明細書の記載により、当業者には明らかであり、当業者であれば本明細書の記載から容易に本発明を再現できる。以下に記載された発明の実施の形態及び具体的な実施例などは、本発明の好ましい実施態様を示すものであり、例示又は説明のために示されているものであって、本発明をそれらに限定するものではない。本明細書で開示されている本発明の意図並びに範囲内で、本明細書の記載に基づき、様々な改変並びに修飾ができることは、当業者にとって明らかである。
　本発明の水溶液製剤、すなわち、化合物(I)を有効成分として含有する水溶液製剤は、有機溶媒に、化合物(I)又は薬理学的に許容される塩、及び一般式(II)、(III)又は(IV)で表される化合物を溶解した溶解液を調製する第１の工程と、前記溶解液から前記有機溶媒を取り除く第２の工程と、第２の工程によって得られた残留物に溶液を加えて前記残留物を溶解する第３の工程を含む方法によって製造することができる。
　化合物(I)は、例えば米国特許出願公開第2004/0259877号明細書に記載の方法に基づいて製造することができる。また、化合物(I)の薬理学的に許容される塩は、当業界で汎用されている方法により製造することができる。化合物(I)の薬理学的に許容される塩としては、例えば、リチウム塩、ナトリウム塩、カリウム塩、マグネシウム塩、カルシウム塩などの金属塩、又はアンモニウム塩、メチルアンモニウム塩、ジメチルアンモニウム塩、トリメチルアンモニウム塩、ジシクロヘキシルアンモニウム塩などのアンモニウム塩を挙げることができる。
　一般式(II)で表される化合物としては、平均分子量が１０００～２０００であるもの、すなわち、ｎ（該化合物に含まれるポリエチレングリコール（ＰＥＧ）の平均ユニット数）が１４～３７の整数であるものであれば特に制限されるものではないが、平均分子量が１０００又は２０００であるもの、すなわち、ｎが１４又は３７であるものを用いることが好ましい。
　一般式(III)で表される化合物としては、ポリエチレングリコールの平均分子量が１０００～２０００であるもの、すなわち、ｎが２２～４６の整数であるものであれば特に制限されるものではないが、ポリエチレングリコールの平均分子量が２０００であるもの、すなわち、ｎが４６であるものを用いることが好ましい。なお、一般式(III)で表される化合物は、米国特許第6679822号明細書に記載の方法に従って製造することができる。
　一般式(IV)で表される化合物としては、ポリエチレングリコールの平均分子量が１０００～２０００であるもの、すなわち、ｎが２２～４６の整数であるものであれば特に制限されるものではないが、ポリエチレングリコールの平均分子量が２０００であるもの、すなわち、ｎが４６であるものを用いることが好ましい。
　有機溶媒としては、化合物(I)又は薬理学的に許容される塩、及び一般式(II)、(III)又は(IV)で表される化合物を溶解できるものであれば特に制限されるものではないが、例えば、メタノール、エタノール、イソプロパノール、tert-ブタノール等の第１級アルコール、ジメチルスルホキシド（ＤＭＳＯ）、メチルtert-ブチルエーテル、N,N-ジメチルアセトアミド、N,N-ジメチルホルムアミド、アセトン、N-メチル-2-ピロリドン、テトラヒドロフラン、アセトニトリル若しくは酢酸エチル、又はこれらの混合物を用いることができ、エタノール、N-メチル-2-ピロリドン、ジメチルスルホキシドなどの医薬的に許容される有機溶媒を用いることが好ましい。
　有機溶媒に、化合物(I)又は薬理学的に許容される塩、及び一般式(II)、(III)又は(IV)で表される化合物を溶解させる温度としては、化合物(I)又は薬理学的に許容される塩、及び一般式(II)、(III)又は(IV)で表される化合物が有機溶媒に溶解できる温度であれば特に制限されるものではない。溶解温度としては、例えば、５０～６０℃の温度範囲である。
　化合物(I)又は薬理学的に許容される塩、及び一般式(II)、(III)又は(IV)で表される化合物を溶解した溶解液から有機溶媒を取り除く方法としては、例えば、蒸発乾固、乾燥、減圧留去などの公知の方法を用いることができる。
　上記溶解液から有機溶媒を取り除いて得られた残留物に加える溶液としては、医薬的に許容される溶液であれば特に制限されるものではないが、例えば、注射用水（水）、生理食塩水、グルコース水溶液、リンゲル溶液、乳酸加リンゲル溶液などを用いることができる。なお、この溶液を残留物に加えて残留物を溶解させる温度としては、溶液に残留物が溶解できる温度であれば特に制限されるものではない。残留物の溶解温度としては、例えば、０～６０℃の温度範囲、好ましくは４～５５℃の温度範囲、より好ましくは室温（２３～２５℃）～５５℃の温度範囲である。
　本発明の水溶液製剤の製造方法により得られる水溶液製剤は、注射剤等の製剤として使用することができる濃度範囲、すなわち溶液１mL中に化合物(I)が1mg以上溶解していればいかなる濃度であってもよいが、投与量を少なくすることができる点で高濃度のものであることが好ましい。
　上述のように製造された本発明の水溶液製剤は、例えば、上記特許文献１～４０又は上記非特許文献１～３５に記載された疾患の予防（進行／悪化の抑制を含む。）又は改善（治療、延命化などを含む。）に有用である。疾患としては、例えば、自己免疫疾患、炎症性疾患、アレルギー性疾患、腫瘍、癌、癌腫、肉腫、血液疾患、心血管疾患、呼吸器疾患、消化器疾患、肝疾患、肺疾患、泌尿器疾患、内分泌疾患、代謝疾患、眼疾患、耳鼻咽喉疾患、皮膚疾患、神経疾患、脳疾患、結合組織疾患、筋骨格疾患、ウィルス性疾患、細菌性疾患、血栓症などを挙げることができる。
　上記疾患として、より具体的には、関節リウマチ、変形性関節症、全身性エリテマトーデス、全身性強皮症、多発性筋炎、シェーグレン症候群、血管炎症候群、抗リン脂質抗体症候群、スティル病、ベーチェット病、結節性動脈周囲炎、潰瘍性大腸炎、クローン病、活動性慢性肝炎、糸球体腎炎、慢性腎炎、慢性膵炎、痛風、アテローム硬化症、多発性硬化症、血管内膜肥厚、乾癬、乾癬性関節炎、接触性皮膚炎、アトピー性皮膚炎、湿疹、花粉症、蕁麻疹、血管炎、鼻炎、胃腸症、下痢、神経炎、中耳炎、肉芽腫症、膀胱炎、喉頭炎、紫斑病、食物アレルギー、昆虫アレルギー、薬物アレルギー、金属アレルギー、アナフィラキシーショック、喘息、気管支炎、間質性肺炎、慢性閉塞性肺疾患、慢性肺血栓塞栓症、炎症性大腸炎、インスリン抵抗性、肥満症、糖尿病、糖尿病合併症、腎症、網膜症、白内障、神経症、壊疽、高インスリン血症、動脈硬化症、高血圧症、末梢血管閉塞、昏睡、高脂血症、肺炎、アルツハイマー症、パーキンソン病、ハンチントン病、脳脊髄炎、てんかん、反復性肩関節脱臼、急性肝炎、慢性肝炎、薬物中毒性肝障害、アルコール性肝炎、ウィルス性肝炎、黄疸、肝硬変、肝不全、心房粘液腫、キャッスルマン症候群、メサンギウム増殖性腎炎、腫瘍、固形癌、腎臓癌、肺癌、肝癌、乳癌、子宮癌、膵癌、前立腺癌、大腸癌、皮膚癌、卵巣癌、子宮頸癌、黒色腫、肉腫、骨肉腫、腫瘍転移、腫瘍浸潤、癌性悪液質、白血病、多発性骨髄腫、レンネルトリンパ腫、悪性リンパ腫、薬剤耐性腫瘍、脳腫瘍、神経腫瘍、サルコイドーシス、エンドトキシンショック、敗血症、サイトメガロウィルス性肺炎、サイトメガロウィルス性網膜症、アデノウィルス性感冒、アデノウィルス性プール熱、アデノウィルス性眼炎、眼炎、結膜炎、後天性免疫不全症候群、ぶどう膜炎、全身炎症症候群、血行再建術（例えば、経皮的冠状動脈血管形成術など）後の再狭窄又は再閉塞、虚血再灌流障害、組織移植後拒絶反応、歯周病、脱毛症、食欲不振、倦怠感、慢性疲労症候群、骨粗鬆症、癌性疼痛、臓器障害、心筋炎、筋炎、ステント留置後の再狭窄、関節炎、皮膚炎、子宮内膜症、子宮筋腫、心リモデリング、血管リモデリング、気管支リモデリング、心筋梗塞、腎炎、線維症（例えば、肺線維症、肝線維症、嚢胞性線維症など）、鬱病、ケロイド、皮膚色素沈着、血栓形成、肝障害、脳血栓症、脳塞栓症、脳梗塞、一過性脳虚血発作、脳卒中、脳血管性痴呆（脳血管性認知症）、虚血性脳血管障害、狭心症、心房細動による心房内血栓症、心不全、虚血性心疾患、肺血栓症、肺塞栓症、血栓性肺疾患、深部静脈血栓症（DVT）、血栓性静脈炎、閉塞性静脈疾患、急性動脈閉塞症、慢性動脈閉塞症、閉塞性末梢動脈疾患、バイパス血管移植後血栓、播種性血管内凝固症候群（DIC）、血管障害、腎血栓症、腎塞栓症、血栓性腎疾患、血栓性疾患、血液凝固、虚血性疾患、心臓発作、深在性血栓症、静脈血栓塞栓症、腎硬化症、メタボリック症候群、アルドステロン性組織障害、臓器不全、間質性膀胱炎、前立腺肥大、筋萎縮症、記憶障害、加齢黄斑変性症、リンパ浮腫、脳浮腫、排尿障害、血管イベント、エコノミークラス症候群、非細菌性血栓性心内膜炎、感染症（例えば、Staphylococcus aureus、S. choleraesuis、Escherichia coliなどの細菌感染症など）、高コレステロール血症、多嚢胞性腎症、創傷、褥瘡、疼痛（例えば、腰痛、関節痛、神経痛、歯痛など）、治療抵抗性高血圧症、慢性腎臓病（CKD）、筋ジストロフィー、中皮腫、発熱、水頭症、高血糖疾患、、記憶形成不全、緑内障、心原性脳塞栓症、動脈瘤、原田病、非アルコール性肝炎、網膜静脈閉塞症、中心性漿液性網膜脈絡膜症、早産などを挙げることができる。また、本発明の注射用組成物は、移植前臓器保存時の臓器の劣化防止剤としても利用可能である。
　なお、本明細書において「腫瘍の予防及び／又は改善」あるいはその類義語は、殺腫瘍作用又は制癌作用の他、組織又は細胞の癌化阻害作用、腫瘍の転移阻害作用、既存の抗腫瘍剤の作用増強、既存の抗腫瘍剤に対する薬剤耐性の克服作用、癌性悪疫質改善作用、再発防止作用、腫瘍患者の延命作用などを含む。また、「アルツハイマー症の予防又は改善」は、アミロイドβ蛋白の蓄積抑制作用、神経細胞死抑制作用、脳萎縮抑制作用、神経原線維変化抑制作用、痴呆改善作用などを含む。さらに、「てんかんの予防又は改善」は、てんかん発作抑制作用（例えば、強直間代発作、欠神発作、ミオクロニー発作など）、大脳の神経細胞の異常興奮抑制作用、海馬の神経細胞死抑制作用などを含む。
　本発明の水溶液製剤は、上記残留物及び溶液のほかに、水溶液製剤の成分として許容される1又は2種以上の添加剤をさらに含有してもよい。該添加剤としては、例えば、リン酸ナトリウムなどの緩衝剤；ピロ亜硫酸ナトリウムなどの安定化剤；塩化ナトリウム、マンニトール、グリセリンなどの浸透圧調整剤；リドカインなどの無痛化剤；フェノールなどの保存剤を挙げることができる。
　本発明の注射用組成物は、投与対象に対して、必要量を一度に投与されてもよいし、間歇的に投与されてもよいし、持続的に投与されてもよい。持続的な投与方法としては、例えば、点滴投与を挙げることができる。
　本発明の注射用組成物は、治療薬の緊急投与が必要な急性疾患の改善のために好適に用いることができる。該疾患としては、例えば、脳卒中などの脳血管障害、急性心筋梗塞などの虚血性心疾患などを挙げることができる。また、本発明の注射用組成物は、治療薬の持続的な投与が必要となる疾患の改善のために好適に用いることができる。
　以下、実施例により本発明をさらに具体的に説明するが、本発明の範囲は下記の実施例に限定されるものではない。なお、本実施例においては、一般式(II)で表される化合物の例として、SUNBRIGHT(登録商標) CS-010及びCS-020（日油株式会社）を用い、一般式(III)で表される化合物の例として、SUNBRIGHT(登録商標) DSPE-020CN（日油株式会社）を用い、一般式(IV)で表される化合物の例として、SUNBRIGHT(登録商標) DSPE-020GL2U（日油株式会社）を用いた。
実施例１～実施例７：化合物(I)を含有する水溶液の調製
　バイアルに、薬剤［化合物(I)］と下表に示される化合物とエタノールを加えて55～60℃に加温し、薬剤及び化合物をエタノールに完全に（析出物及び沈殿物が生じることなく、無色透明に）溶解させ、各溶解溶液を調製した。各溶解溶液を60℃で1.5時間加温し、内容物を蒸発乾固させた。得られた残渣に生理食塩水又は水を所定量加えて55℃に加温し（実施例６では室温にて２４時間インキュベーションした。実施例７では４℃で７２時間インキュベーションした。）、溶解させた。バイアル内の水溶液をそれぞれ目視したところ、水溶液は析出物及び沈殿物がなく、無色澄明であったことから、薬剤が完全に溶解し、少なくとも1mg/mlの濃度で化合物(I)を含有する水溶液をそれぞれ調製できることが確認できた。なお、下表に示される化合物以外の化合物を用いて、1mg/mlの濃度で化合物(I)を含有する水溶液を調製することを試みたが、下表に示される化合物以外では、薬剤が完全に溶解した水溶液を調製できなかった。
Figure JPOXMLDOC01-appb-T000004
　なお、実施例１、２、５及び６の水溶液においては、４℃又は室温で少なくとも２カ月の間、白濁したり、析出物や沈殿物が生じたりすることなく、保存安定性に優れていることが確認できた。また、実施例３の水溶液においては、４℃で少なくとも２カ月の間、白濁したり、析出物や沈殿物が生じたりすることなく、保存安定性に優れていることが確認できた。さらに、実施例７の水溶液においては、４℃で少なくとも１カ月の間、白濁したり、析出物や沈殿物が生じたりすることなく、保存安定性に優れていることが確認できた。
確認例１：実施例１により得られた水溶液を用いた薬物動態試験
　実施例１で得られた水溶液をMillex(登録商標)-GV（0.22μm; 日本ミリポア株式会社／メルクミリポア）で濾過、滅菌し、雌雄Sprague-Daweley系IGSラット（6週齢）に静脈内投与し、化合物(I)の動態を調べた。
＜試験方法＞
　動物群は、雌雄Sprague-Daweley系IGSラット（チャールズリバージャパン）を用いた。前記ラットは6週齢であり、体重は、雄が166～189g、雌が123～145gであった。
　前記ラットをSPF（Specific pathogen free）動物実験室で7日間検疫、馴化し、同時に健康状態を観察した。ラットは、滅菌済ステンレス製ゲージ内で、各ゲージに1匹ずつ飼育した。SPF動物実験室内は、室内温度を20.6～22.5℃に、相対湿度を44～60％に維持した。SPF動物実験室内の換気は、1時間あたり15回実施した。SPF動物実験室内の照明は、12時間ごとに明るい状態と暗い状態に切り替えた。
　動物試料は、棒状の乾燥した基礎試料（成分分析済）を用いた。飲水用の水は、分析によって基準値内であることが確認された水道水を用い、ラットに自由摂取させた。
　前記の検疫済ラットを体重によってランダムに、下記の3群（1群あたり雌雄各4匹）に群分けした。
(1) グループ1：実施例１で得られた水溶液を1mL/kg投与する群
(2) グループ2：実施例１で得られた水溶液を2mL/kg投与する群
(3) グループ3：実施例１で得られた水溶液を3mL/kg投与する群
　前記検疫済ラットを一夜（約16時間）空腹にした後、実施例１で得られた水溶液を静脈内投与し、投与から0.083時間、0.25時間、0.5時間、1時間、4時間、及び24時間後に血液を採取し、化合物(I)の血中濃度を測定した。測定した各採取時間における化合物(I)の血中濃度から、注射用組成物を静脈内投与した直後の最大血中濃度C0(ng/mL)、及び投与後0～24時間における化合物(I)の血中濃度曲線下面積AUC0-24(ng・h/mL)を算出した。
＜試験結果＞
　各投与群において選択された雄各3匹のラットにおけるC0及びAUC0-24の平均値を下表に示す。
Figure JPOXMLDOC01-appb-T000005
　各投与群において選択された雌各3匹のラットにおけるC0及びAUC0-24の平均値を下表に示す。
Figure JPOXMLDOC01-appb-T000006
　本確認例の結果から、実施例１により得られた水溶液を生体内に静脈内投与することによって、有効成分である化合物(I)を用量依存的かつ十分な量で暴露させることができることが明らかとなった。また、本確認例において、ラットに死亡例は認められず、重篤な障害等を引き起こす可能性を示すような毒性所見も認められなかった。

Claims (5)

  1. 　有機溶媒に下式(I)で表される化合物又は薬理学的に許容されるその塩、及び下記の一般式(II)～(IV)のいずれかで表される化合物を溶解した溶解液を調製する第１の工程と、前記溶解液から前記有機溶媒を取り除く第２の工程と、第２の工程によって得られた残留物に溶液を加えて前記残留物を溶解する第３の工程を含むことを特徴とする水溶液製剤の製造方法。
    Figure JPOXMLDOC01-appb-C000001
  2. 　一般式(II)で表される化合物のnが14又は37である請求項１に記載の水溶液製剤の製造方法。
  3. 　一般式(III)で表される化合物のnが46である請求項１に記載の水溶液製剤の製造方法。
  4. 　一般式(IV)で表される化合物のnが46である請求項１に記載の水溶液製剤の製造方法。
  5. 　請求項１～４のいずれかに記載の水溶液製剤の製造方法により得られる水溶液製剤。
PCT/JP2014/074065 2013-09-13 2014-09-11 水溶液製剤及びその製造方法 WO2015037659A1 (ja)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US14/917,638 US9974860B2 (en) 2013-09-13 2014-09-11 Aqueous solution formulation and method for manufacturing same
EP14844160.3A EP3045169B1 (en) 2013-09-13 2014-09-11 Aqueous solution formulation, and manufacturing method for same
JP2015536623A JP6083770B2 (ja) 2013-09-13 2014-09-11 水溶液製剤及びその製造方法
CN201480050141.2A CN105636583B (zh) 2013-09-13 2014-09-11 水溶液制剂及其制造方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2013191192 2013-09-13
JP2013-191192 2013-09-13

Publications (1)

Publication Number Publication Date
WO2015037659A1 true WO2015037659A1 (ja) 2015-03-19

Family

ID=52665759

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2014/074065 WO2015037659A1 (ja) 2013-09-13 2014-09-11 水溶液製剤及びその製造方法

Country Status (5)

Country Link
US (1) US9974860B2 (ja)
EP (1) EP3045169B1 (ja)
JP (1) JP6083770B2 (ja)
CN (1) CN105636583B (ja)
WO (1) WO2015037659A1 (ja)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9827253B2 (en) 2013-11-06 2017-11-28 Aeromics, Inc. Prodrug salts
US9994514B2 (en) 2012-05-08 2018-06-12 Aeromics, Inc. Methods of treating cerebral edema and spinal cord edema

Citations (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3331874A (en) 1962-05-29 1967-07-18 Herbert C Stecker Bistrifluoromethyl anilides
US3332996A (en) 1961-03-25 1967-07-25 Cassella Farbwerke Mainkur Ag Trifluoromethyl-substituted salicylanilides
US6679822B2 (en) 2001-03-02 2004-01-20 Nof Corporation Polyalkylene oxide-modified phospholipid and production method thereof
US20040259877A1 (en) 2000-12-18 2004-12-23 Susumu Muto Inhibitors against the production and release of inflammatory cytokines
US20060014811A1 (en) 2002-06-10 2006-01-19 Susumu Muto Medicament for treatment of cancer
US20060019958A1 (en) 2002-06-05 2006-01-26 Susumu Muto Immunity-related protein kinase inhibitors
WO2006013873A1 (ja) 2004-08-05 2006-02-09 Institute Of Medicinal Molecular Design. Inc. シクロオキシゲナーゼ阻害作用を有する医薬
US20060035944A1 (en) 2002-06-11 2006-02-16 Susumu Muto Remedies for neurodegenerative diseases
US20060089395A1 (en) 2002-06-10 2006-04-27 Susumu Muto Nf-kb activation inhibitors
US20060094718A1 (en) 2002-06-06 2006-05-04 Susumu Muto O-substituted hydroxyaryl derivatives
US20060100257A1 (en) 2002-06-05 2006-05-11 Susumu Muto Inhibitors against the activation of ap-1 and nfat
US20060111409A1 (en) 2002-06-05 2006-05-25 Susumu Muto Medicament for treatment of diabetes
US20060122243A1 (en) 2002-06-06 2006-06-08 Susumu Muto Antiallergic
JP2006160696A (ja) * 2004-12-09 2006-06-22 Nof Corp 難水溶性薬剤用可溶化剤組成物
US20070042997A1 (en) 2003-07-16 2007-02-22 Akiko Itai Medicament for treatment of dermal pigmentation
US20070254956A1 (en) 2003-10-29 2007-11-01 Koichi Shudo Medicament for Therapeutic and/or Preventive Treatment of Restenosis or Reocclusion After Vascular Recanalization Operation
WO2008041066A1 (en) 2006-10-02 2008-04-10 Clipper Windpower Technology, Inc. Wind turbine with blade pitch control to compensate for wind shear and wind misalignment
WO2008094410A2 (en) 2007-02-01 2008-08-07 Albert Einstein College Of Medicine Of Yeshiva University Parallel profiling of signaling pathways
WO2008133884A2 (en) 2007-04-23 2008-11-06 Combinatorx, Incorporated Methods and compositions for the treatment of neurodegenerative disorders
WO2009006555A2 (en) 2007-07-02 2009-01-08 Yu, Ming Methods, composition, targets for combinational cancer treatments
WO2009074809A1 (en) 2007-12-13 2009-06-18 University Of Dundee Sigma ligands and ikk / nf - kb inhibitors for medical treatment
WO2009082514A1 (en) 2007-12-21 2009-07-02 University Of Rochester Molecular targets for treatment of inflammation
US20090239868A1 (en) 2007-10-23 2009-09-24 Institute Of Medical Molecular Design, Inc. Inhibitor of pai-1 production
WO2010000903A2 (es) 2008-06-30 2010-01-07 Centro De Investigaciones Energéticas, Medioambientales Y Tecnológicas (Ciemat) Composición capaz de modular la actividad de ikkalpha para el tratamiento de enfermedades que cursan con acantolisis
WO2010048273A2 (en) 2008-10-21 2010-04-29 President And Fellows Of Harvard College Methods and compounds for treatment of neurodegenerative disorders
WO2010096574A1 (en) 2009-02-20 2010-08-26 Lisanti Michael P A method of diagnosis or prognosis of a neoplasm comprising determining the level of expression of a protein in stromal cells adjacent to the neoplasm
WO2010099731A1 (en) 2009-03-01 2010-09-10 Ming Yu Compounds, compositions and use for anticancer therapy
WO2010106082A1 (en) 2009-03-16 2010-09-23 Genmedica Therapeutics Sl Anti-inflammatory and antioxidant conjugates useful for treating metabolic disorders
JP2011140470A (ja) * 2010-01-08 2011-07-21 Toray Ind Inc 親水性生理活性物質含有微粒子の製造方法
WO2011133879A2 (en) 2010-04-22 2011-10-27 University Of Massachusetts Combination therapies with mitochondrial-targeted anti-tumor agents
WO2012019284A1 (en) 2010-08-11 2012-02-16 Universite De Montreal Combinatory cancer treatment
WO2012024612A1 (en) 2010-08-20 2012-02-23 Pangea Biosciences, Inc. Cancer diagnostic and cancer therapeutic
JP2012102107A (ja) * 2004-06-30 2012-05-31 Centre National De La Recherche Scientifique ゲムシタビン誘導体ナノ粒子
WO2012148799A1 (en) * 2011-04-28 2012-11-01 Board Of Regents, The University Of Texas System Improved parenteral formulations of lipophilic pharmaceutical agents and methods for preparing and using the same
JP2013199476A (ja) * 2012-02-23 2013-10-03 Canon Inc 粒子、及び、それを有する光イメージング用造影剤

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102133172B (zh) * 2011-01-24 2012-11-14 北京大学 一种紫杉醇纳米胶束及其应用
CN102293736B (zh) * 2011-08-31 2013-06-05 兰州大学 紫杉醇-聚合物载药胶束制备工艺

Patent Citations (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3332996A (en) 1961-03-25 1967-07-25 Cassella Farbwerke Mainkur Ag Trifluoromethyl-substituted salicylanilides
US3331874A (en) 1962-05-29 1967-07-18 Herbert C Stecker Bistrifluoromethyl anilides
US20040259877A1 (en) 2000-12-18 2004-12-23 Susumu Muto Inhibitors against the production and release of inflammatory cytokines
US20100274051A1 (en) 2000-12-18 2010-10-28 Institute Of Medicinal Molecular Design. Inc. Inflammatory cytokine release inhibitor
US20080318956A1 (en) 2000-12-18 2008-12-25 Institute Of Medicinal Molecular Design. Inc. Inflammatory cytokine release inhibitor
US20080249071A1 (en) 2000-12-18 2008-10-09 Institute Of Medicinal Molecular Design. Inc. Inflammatory cytokine release inhibitor
US6679822B2 (en) 2001-03-02 2004-01-20 Nof Corporation Polyalkylene oxide-modified phospholipid and production method thereof
US20060111409A1 (en) 2002-06-05 2006-05-25 Susumu Muto Medicament for treatment of diabetes
US20060100257A1 (en) 2002-06-05 2006-05-11 Susumu Muto Inhibitors against the activation of ap-1 and nfat
US20060019958A1 (en) 2002-06-05 2006-01-26 Susumu Muto Immunity-related protein kinase inhibitors
US20070185059A1 (en) 2002-06-06 2007-08-09 Institute Of Medicinal Molecular Design, Inc. Antiallergic agents
US20060122243A1 (en) 2002-06-06 2006-06-08 Susumu Muto Antiallergic
US20060094718A1 (en) 2002-06-06 2006-05-04 Susumu Muto O-substituted hydroxyaryl derivatives
US20070185110A1 (en) 2002-06-06 2007-08-09 Institute Of Medicinal Molecular Design, Inc. Antiallergic agents
US20100113770A1 (en) 2002-06-06 2010-05-06 Institute Of Medicinal Molecular Design, Inc. O-substituted hydroxyaryl derivatives
US20080090779A1 (en) 2002-06-06 2008-04-17 Institute Of Medicinal Molecular Design, Inc. Antiallergic agents
US20060089395A1 (en) 2002-06-10 2006-04-27 Susumu Muto Nf-kb activation inhibitors
US20080311074A1 (en) 2002-06-10 2008-12-18 Institute Of Medical Molecular Design Inc. Inhibitors against activation of NF-kappaB
US20060014811A1 (en) 2002-06-10 2006-01-19 Susumu Muto Medicament for treatment of cancer
US20080234233A1 (en) 2002-06-11 2008-09-25 Institute Of Medicinal Molecular Design Inc. Medicament for treatment of neurodegenerative diseases
US20060035944A1 (en) 2002-06-11 2006-02-16 Susumu Muto Remedies for neurodegenerative diseases
US20070042997A1 (en) 2003-07-16 2007-02-22 Akiko Itai Medicament for treatment of dermal pigmentation
US20070254956A1 (en) 2003-10-29 2007-11-01 Koichi Shudo Medicament for Therapeutic and/or Preventive Treatment of Restenosis or Reocclusion After Vascular Recanalization Operation
JP2012102107A (ja) * 2004-06-30 2012-05-31 Centre National De La Recherche Scientifique ゲムシタビン誘導体ナノ粒子
WO2006013873A1 (ja) 2004-08-05 2006-02-09 Institute Of Medicinal Molecular Design. Inc. シクロオキシゲナーゼ阻害作用を有する医薬
JP2006160696A (ja) * 2004-12-09 2006-06-22 Nof Corp 難水溶性薬剤用可溶化剤組成物
WO2008041066A1 (en) 2006-10-02 2008-04-10 Clipper Windpower Technology, Inc. Wind turbine with blade pitch control to compensate for wind shear and wind misalignment
WO2008094410A2 (en) 2007-02-01 2008-08-07 Albert Einstein College Of Medicine Of Yeshiva University Parallel profiling of signaling pathways
WO2008133884A2 (en) 2007-04-23 2008-11-06 Combinatorx, Incorporated Methods and compositions for the treatment of neurodegenerative disorders
WO2009006555A2 (en) 2007-07-02 2009-01-08 Yu, Ming Methods, composition, targets for combinational cancer treatments
US20090239868A1 (en) 2007-10-23 2009-09-24 Institute Of Medical Molecular Design, Inc. Inhibitor of pai-1 production
WO2009074809A1 (en) 2007-12-13 2009-06-18 University Of Dundee Sigma ligands and ikk / nf - kb inhibitors for medical treatment
WO2009082514A1 (en) 2007-12-21 2009-07-02 University Of Rochester Molecular targets for treatment of inflammation
WO2010000903A2 (es) 2008-06-30 2010-01-07 Centro De Investigaciones Energéticas, Medioambientales Y Tecnológicas (Ciemat) Composición capaz de modular la actividad de ikkalpha para el tratamiento de enfermedades que cursan con acantolisis
WO2010048273A2 (en) 2008-10-21 2010-04-29 President And Fellows Of Harvard College Methods and compounds for treatment of neurodegenerative disorders
WO2010096574A1 (en) 2009-02-20 2010-08-26 Lisanti Michael P A method of diagnosis or prognosis of a neoplasm comprising determining the level of expression of a protein in stromal cells adjacent to the neoplasm
WO2010099731A1 (en) 2009-03-01 2010-09-10 Ming Yu Compounds, compositions and use for anticancer therapy
WO2010106082A1 (en) 2009-03-16 2010-09-23 Genmedica Therapeutics Sl Anti-inflammatory and antioxidant conjugates useful for treating metabolic disorders
JP2011140470A (ja) * 2010-01-08 2011-07-21 Toray Ind Inc 親水性生理活性物質含有微粒子の製造方法
WO2011133879A2 (en) 2010-04-22 2011-10-27 University Of Massachusetts Combination therapies with mitochondrial-targeted anti-tumor agents
WO2012019284A1 (en) 2010-08-11 2012-02-16 Universite De Montreal Combinatory cancer treatment
WO2012024612A1 (en) 2010-08-20 2012-02-23 Pangea Biosciences, Inc. Cancer diagnostic and cancer therapeutic
WO2012148799A1 (en) * 2011-04-28 2012-11-01 Board Of Regents, The University Of Texas System Improved parenteral formulations of lipophilic pharmaceutical agents and methods for preparing and using the same
JP2013199476A (ja) * 2012-02-23 2013-10-03 Canon Inc 粒子、及び、それを有する光イメージング用造影剤

Non-Patent Citations (36)

* Cited by examiner, † Cited by third party
Title
AM. J. PHYSIOL. HEART CIRC. PHYSIOL., vol. 292, no. 1, 2007, pages H530 - 538
AM. J. PHYSIOL. LUNG CELL MOL. PHYSIOL., vol. 298, no. 2, 2010, pages L197 - 209
AM. J. RESPIR. CRIT. CARE MED., vol. 173, no. 9, 2006, pages 1016 - 1022
BASIC CLIN. PHARMACOL. TOXICOL., vol. 101, no. 6, 2007, pages 401 - 406
BIOCHEM. BIOPHYS. RES. COMMUN., vol. 323, no. 1, 2004, pages 242 - 248
BLOOD, vol. 105, no. 6, 2005, pages 2324 - 2331
CADIOVASC. RES., vol. 63, no. 1, 2004, pages 8 - 10
CANCER RES., vol. 66, no. 1, 2006, pages 419 - 426
CANCER RES., vol. 67, no. 7, 2007, pages 3220 - 3228
CANCER SCI., vol. 103, no. 1, 2012, pages 100 - 106
CARDIOVASC. RES., vol. 63, no. 1, 2004, pages 51 - 59
CLIN. EXP. ALLERGY, vol. 41, no. 1, 2011, pages 104 - 115
CLIN. EXP. NEPHROL., vol. 15, no. 1, 2011, pages 41 - 49
CURR. CANCER DRUG TARGETS, vol. 7, no. 5, 2007, pages 492 - 503
CYTOKINE, vol. 54, no. 2, 2011, pages 161 - 166
DRUG METAB. DISPOS., vol. 40, no. 1, 2012, pages 205 - 211
EUR. J. PHARMACOL., vol. 637, no. 1-3, 2010, pages 148 - 154
EXPERT. OPIN. INVESTIG. DRUGS, vol. 20, no. 3, 2011, pages 395 - 405
GLYCOBIOLOGY, vol. 19, no. 7, 2009, pages 776 - 788
HISTOCHEM. CELL BIOL., vol. 133, no. 3, 2010, pages 339 - 348
INFECT. IMMUN., vol. 76, no. 2, 2008, pages 781 - 787
INT. ARCH. ALLERGY IMMUNOL., vol. 148, no. 3, 2009, pages 186 - 198
J. GASTROENTEROL., vol. 44, no. 9, 2009, pages 935 - 943
J. INVEST. DERMATOL., vol. 127, no. 4, 2007, pages 855 - 863
J. MED. DENT. SCI., vol. 55, no. 1, 2008, pages 49 - 59
J. NEUROINFLAMMATION, vol. 8, 2011, pages 107
J. VIRAL HEPAT., vol. 18, no. 10, 2011, pages E439 - 446
MOD. RHEUMATOL., vol. 17, no. 6, 2007, pages 459 - 463
RADIAT. RES., vol. 171, no. 1, 2009, pages 9 - 21
RES. VET. SCI., vol. 89, no. 3, 2010, pages 378 - 382
SCIENTIFIC WORLD JOURNAL, vol. 10, 2010, pages 2139 - 2156
SPINE (PHILA PA 1976, vol. 33, no. 23, 2008, pages 2489 - 2494
TANAKA A. ET AL.: "A novel NF-KB inhibitor, IMD- 0354, suppresses neoplastic proliferation of human mast cells with constitutively activated c-kit receptors.", BLOOD, vol. 105, no. 6, 2005, pages 2324 - 2331, XP055326674 *
TOXICOL. APPL. PHARMACOL., vol. 249, no. 1, 2010, pages 25 - 32
TOXICOL. LETT., vol. 209, no. 2, 2012, pages 107 - 112
WORLD J. GASTROENTEROL., vol. 17, no. 47, 2011, pages 5203 - 5213

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9994514B2 (en) 2012-05-08 2018-06-12 Aeromics, Inc. Methods of treating cerebral edema and spinal cord edema
US11084778B2 (en) 2012-05-08 2021-08-10 Aeromics, Inc. Methods of treating cardiac edema, neuromyelitis optica, and hyponatremia
US11873266B2 (en) 2012-05-08 2024-01-16 Aeromics, Inc. Methods of treating or controlling cytotoxic cerebral edema consequent to an ischemic stroke
US9827253B2 (en) 2013-11-06 2017-11-28 Aeromics, Inc. Prodrug salts
US9949991B2 (en) 2013-11-06 2018-04-24 Aeromics, Inc. Methods of treating aquaporin-mediated conditions
US10258636B2 (en) 2013-11-06 2019-04-16 Aeromics, Inc. Prodrug salts
US10894055B2 (en) 2013-11-06 2021-01-19 Aeromics, Inc. Pharmaceutical compositions, methods of making pharmaceutical compositions, and kits comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}4-chlorophenyl dihydrogen phosphate
US11071744B2 (en) 2013-11-06 2021-07-27 Aeromics, Inc. Prodrug salts
US11801254B2 (en) 2013-11-06 2023-10-31 Aeromics, Inc. Pharmaceutical compositions and methods of making pharmaceutical compositions comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate

Also Published As

Publication number Publication date
CN105636583A (zh) 2016-06-01
EP3045169A4 (en) 2017-04-26
CN105636583B (zh) 2019-08-20
US20160220680A1 (en) 2016-08-04
JP6083770B2 (ja) 2017-02-22
EP3045169B1 (en) 2018-05-02
EP3045169A1 (en) 2016-07-20
JPWO2015037659A1 (ja) 2017-03-02
US9974860B2 (en) 2018-05-22

Similar Documents

Publication Publication Date Title
JP5480804B2 (ja) リポ酸誘導体を含有する医薬製剤
WO2018003857A1 (ja) 非経口投与用医薬組成物
JP6083770B2 (ja) 水溶液製剤及びその製造方法
WO2008087461B1 (en) Use of kynurenic acid and derivatives thereof in the treatment of conditions of the gastrointestinal tract accompanied by hypermotility and inflammation or gout or multiple sclerosis
US8202898B1 (en) Pharmaceutical composition
JP2017519020A (ja) コハク酸脱水素酵素阻害剤（ＳＤＨｉ’ｓ）
Assis et al. Synthesis, hypolipidemic, and anti-inflammatory activities of arylphthalimides
JP2007269769A (ja) 神経変性疾患関連蛋白質凝集線維化抑制剤
JP2021105061A (ja) アミロイド線維形成の抑制又は阻害剤
JP7430879B2 (ja) アルブミン結合性を有するｎｏラジカル放出型抗がん剤としてのニトロ化フェニルカルボン酸誘導体
FR3108502A1 (fr) Dérivés de nicotinamide mononucléotides dans le traitement et la prévention des infections bactériennes
US20130084330A1 (en) Composition for the treatment of arthritis containing a dibenzo-p-dioxin derivative as the active ingredient
EP3237015B1 (fr) Derives hydroxybisphosphoniques hydrosolubles de la doxorubicine
RU2663848C1 (ru) 5-Фтор-2-(4-этоксикарбонилпиперазин-1-ил)-1,3-бензотиазин-4-он, обладающий противотуберкулезной активностью
US11730712B2 (en) Functionalized long-chain hydrocarbon mono- and di-carboxylic acids and derivatives thereof, and their use for the prevention or treatment of disease
US11111219B2 (en) Polysubstituted pyrimidines inhibiting the formation of prostaglandin E2, a method of production thereof and use thereof
WO2024133757A1 (en) Cyclodextrin derivatives for the treatment of gout and hyperuricemia
JP2021165241A (ja) 細胞内コレステロール輸送障害治療薬及び予防薬
RAY et al. COMPOUNDS FOR CANCER RESEARCH. II. 1 FLUORENE-2-CARBOXAMIDINE
WO2022251382A1 (en) Modulating expression level of a gene encoding an uncoupling protein by treating a human subject with a nitroxide
JPH0532550A (ja) 血小板凝集阻害剤

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: 14844160

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 14917638

Country of ref document: US

ENP Entry into the national phase

Ref document number: 2015536623

Country of ref document: JP

Kind code of ref document: A

REEP Request for entry into the european phase

Ref document number: 2014844160

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2014844160

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE