US20150038719A1 - Agent for Ameliorating Chronic Obstructive Pulmonary Disease - Google Patents

Agent for Ameliorating Chronic Obstructive Pulmonary Disease Download PDF

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US20150038719A1
US20150038719A1 US14/385,067 US201314385067A US2015038719A1 US 20150038719 A1 US20150038719 A1 US 20150038719A1 US 201314385067 A US201314385067 A US 201314385067A US 2015038719 A1 US2015038719 A1 US 2015038719A1
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administration
mepenzolate
agent
results
airway
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Toru Mizushima
Hongxing Liu
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LTT Bio Pharma Co Ltd
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Assigned to LTT BIO-PHARMA CO., LTD. reassignment LTT BIO-PHARMA CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LIU, HONGXING, MIZUSHIMA, TORU
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/452—Piperidinium derivatives
    • 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
    • A61K9/0031—Rectum, anus
    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug 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
    • A61K9/2013—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the present invention relates to an agent for ameliorating chronic obstructive pulmonary disease, and specifically to an agent for ameliorating chronic obstructive pulmonary disease that contains mepenzolate bromide (hereinafter may be referred to simply as “mepenzolate”) as an active ingredient.
  • mepenzolate mepenzolate bromide
  • COPD chronic obstructive pulmonary disease
  • Non-Patent Literature 2 ipratropium bromide, which is a muscarinic antagonist, is reported to exhibit a bronchodilator effect by relaxing bronchial smooth muscle.
  • COPD chronic obstructive pulmonary disease
  • a disease previously referred to as pulmonary emphysema (PE) and a disease previously referred to as chronic bronchitis (CB) are often combined in various ratios and developed, and accordingly, the diseases caused by these two diseases came to be collectively referred to as chronic obstructive pulmonary disease (COPD).
  • PE pulmonary emphysema
  • CB chronic bronchitis
  • Non-Patent Literature 3 The primary cause of COPD development is smoking. 90% of COPD patients are smokers (Non-Patent Literature 3) and the risk of smokers developing COPD is six or more times higher than that by nonsmokers. Approximately 10 to 15% of smokers develop COPD and, exclusively in the elderly population, nearly 50% of smokers suffer from COPD. Other causes include indoor air pollution or air pollution, inhalation of chemical substances or dust, genetic factors, pneumonia or bronchitis in childhood, and the like.
  • COPD chronic airway inflammation.
  • Smoking, inhaled substances, and the like cause inflammation in various sites in a lung ranging from a central airway to a peripheral bronchus. It is believed that the inflammation leads to protease-antiprotease imbalance, oxidant-antioxidant imbalance, and the like, which in turn causes alveolar destruction and bronchial mucous gland hypertrophy.
  • COPD is an incurable disease since irreversible destruction of the airway has occurred.
  • Smoking cessation, pharmacotherapy by administration of e.g., a bronchodilator, an expectorant, and an antitussive drug, oxygen therapy, or the like can only relieve symptoms of COPD, and thus COPD is a very troublesome disease.
  • Patent Literatures 1 and 2 various kinds of agents for ameliorating COPD or methods for ameliorating COPD have been proposed so far (for example, Patent Literatures 1 and 2); however, development of an even better agent for ameliorating COPD is currently awaited.
  • the present inventors have worked toward development of an agent for ameliorating COPD by performing a study to search existing commercially available drugs. As a result, the present inventors have confirmed that mepenzolate bromide, which has been used as a therapeutic drug for irritable bowel, exhibited a therapeutic effect on COPD based on a bronchodilator effect and an anti-inflammatory effect thereof, and thus accomplished the present invention.
  • Mepenzolate bromide is known as an anticholinergic drug that has an effect of suppressing movement and contraction in a lower gastrointestinal tract and has been used as a therapeutic drug for irritable bowel in a clinical setting since 1967. However, it is unknown that mepenzolate bromide is effective for COPD treatment.
  • the present invention provides an agent for ameliorating chronic obstructive pulmonary disease that contains mepenzolate bromide as an active ingredient.
  • the present invention provides an agent for ameliorating chronic obstructive pulmonary disease whose mode of administration is airway administration or inhalation administration.
  • the present invention provides an agent for ameliorating chronic obstructive pulmonary disease whose mode of administration is oral administration.
  • the present invention also provides an agent for ameliorating chronic obstructive pulmonary disease whose mode of administration is rectal administration.
  • the present invention provides an agent for ameliorating COPD that contains mepenzolate bromide, which has already been used as a therapeutic drug for irritable bowel and whose safety has been confirmed, as an active ingredient.
  • Mepenzolate bromide which is an active ingredient of the agent for ameliorating COPD provided by the present invention, has an excellent effect of ameliorating COPD, and in particular exhibits a significant effect by airway administration and inhalation administration. Furthermore, mepenzolate bromide showed an excellent effect by oral administration and rectal administration.
  • mepenzolate bromide is based on a bronchodilator effect and an anti-inflammatory effect. Since there has been, until now, no agent for ameliorating COPD that has both of these effects, the agent for ameliorating COPD of the present invention is a very specific agent for ameliorating COPD.
  • mepenzolate bromide which is an active ingredient of the agent for ameliorating COPD provided by the present invention, is that it shows the effects thereof by an action mechanism different from those of a muscarinic antagonistic action and an anticholinergic action.
  • the specific and safe mepenzolate bromide can be administered to ameliorate the symptoms of COPD, and thus, the medical effect thereof is very specific.
  • FIG. 1 shows electron micrographs of the lung tissues dyed with H&E in Test Example 1, in which mepenzolate bromide was administered via the airway.
  • FIG. 2 shows a graph showing the results of measurement of a mean linear intercept in Test Example 1, in which mepenzolate bromide was administered via the airway.
  • FIG. 3 shows graphs representing the results of measurement of total respiratory system elastance and tissue elastance in Test Example 1, in which mepenzolate bromide was administered via the airway.
  • FIG. 4 shows electron micrographs of the lung tissues dyed with H&E in Test Example 1, in which mepenzolate bromide was administered by inhalation.
  • FIG. 5 shows a graph showing the results of measurement of a mean linear intercept in Test Example 1, in which mepenzolate bromide was administered by inhalation.
  • FIG. 6 shows graphs representing the results of measurement of total respiratory system elastance and tissue elastance in Test Example 1, in which mepenzolate bromide was administered by inhalation.
  • FIG. 7 shows electron micrographs of the lung tissues dyed with H&E in Test Example 2.
  • FIG. 8 shows a graph showing the results of measurement of a mean linear intercept in Test Example 2.
  • FIG. 9 shows graphs representing the results of measurement of total respiratory system elastance and tissue elastance in the case of airway administration in Test Example 2.
  • FIG. 10 shows a graph showing the results of measurement of FEV 0.05 /FVC in Test Example 3.
  • FIG. 11 shows a graph showing the results of measurement of airway resistance in the case of different doses of mepenzolate bromide being administered in Test Example 4.
  • FIG. 12 shows a graph showing the results of measurement of airway resistance at different times after administration of mepenzolate bromide at a dose of 38 ⁇ g/kg in Test Example 4.
  • FIG. 13 shows graphs representing the results of measurement of a total cell count and a neutrophil count in Test Example 5.
  • FIG. 14 shows graphs representing the results of measurement of TNF- ⁇ , MIP-2, MCP-1, and KC in Test Example 5.
  • FIG. 15 shows electron micrographs of the lung tissues dyed with H&E in Test Example 6, in which the subjects were subjected to smoking.
  • FIG. 16 shows a graph showing the results of measurement of a mean linear intercept in Test Example 6, in which the subjects were subjected to smoking.
  • FIG. 17 shows graphs representing the results of measurement of total respiratory system elastance and tissue elastance in Test Example 6, in which the subjects were subjected to smoking.
  • FIG. 18 shows electron micrographs of the lung tissues dyed with H&E in the case of oral administration in Test Example 7.
  • FIG. 19 shows a graph showing the results of measurement of a mean linear intercept in the case of oral administration in Test Example 7.
  • FIG. 20 shows graphs representing the results of measurement of total respiratory system elastance and tissue elastance in the case of oral administration in Test Example 7.
  • FIG. 21 shows graphs representing the results of measurement of a total cell count and a neutrophil count in the case of rectal administration in Test Example 8.
  • FIG. 22 shows electron micrographs of the lung tissues dyed with H&E in the case of rectal administration in Test Example 8.
  • FIG. 23 shows a graph showing the results of measurement of a mean linear intercept in the case of rectal administration in Test Example 8.
  • FIG. 24 shows graphs representing the results of measurement of total respiratory system elastance, tissue elastance, and FEV 0.05 /FVC in the case of rectal administration in Test Example 8.
  • FIG. 25 shows a graph showing the results of measurement of airway resistance in the case of different doses of mepenzolate bromide being administered rectally in Test Example 9.
  • Mepenzolate bromide used in the agent for ameliorating COPD provided by the present invention is a quaternary ammonium salt compound having the below-mentioned chemical formula.
  • This agent has already been on the market as a medicine. Therefore, a commercially available product can be used as an active ingredient of the agent for ameliorating COPD of the present invention as it is.
  • the agent for ameliorating COPD provided by the present invention contains mepenzolate bromide represented by the above-mentioned chemical formula as an active ingredient and can be administered preferably by airway administration and inhalation administration. Furthermore, the inventive agent can be effective by oral administration or rectal administration.
  • An airway-administered formulation for the above-mentioned airway administration and an inhalation formulation for the above-mentioned inhalation administration represent a pharmaceutical composition to be delivered to tissues such as a trachea, a bronchus, or a lung, and favorably represent a nasal drop or a composition suitable for transnasal administration or pulmonary administration.
  • These formulations are effective when administered by a nebulizer, an atomizer, a dropper, a pipette, a cannula, and the like.
  • the airway-administered formulation and the inhalation formulation can be prepared in the form of a powder formulation, a solution formulation, or a suspension formulation of mepenzolate bromide.
  • the formulations can be prepared by processing mepenzolate bromide as an active ingredient into fine particles alone or together with a suitable additive such as an excipient, a lubricant, a binder, a disintegrant, a stabilizer, and a flavoring agent.
  • a suitable additive such as an excipient, a lubricant, a binder, a disintegrant, a stabilizer, and a flavoring agent.
  • the formulations can be prepared as follows.
  • the formulations can be prepared by dissolving or suspending mepenzolate bromide in water or a mixture that is a mixed solvent of water and a cosolvent, for example, an alcoholic cosolvent such as ethanol, propylene glycol, or polyethylene glycol.
  • Such solution or suspension may further contain an antiseptic, a solubilizer, a buffering agent, an isotonic agent, an absorption promoter, a thickener, and the like.
  • the airway-administered formulation and the inhalation formulation prepared as described above are administered to a nasal cavity or an oral cavity or directly to a tissue such as a trachea, a bronchus, or a lung by means common in the field of an inhalation formulation.
  • these formulations are administered by using a dropper, a pipette, a cannula, or a sprayer such as an atomizer or a nebulizer to pulverize the formulations.
  • the formulations can be sprayed as an aerosol kept in a container under pressure with a suitable propellant (for example, chlorofluorocarbon such as dichlorofluoromethane, trichlorofluoromethane, or dichlorotetrafluoromethane, or gas such as carbon dioxide) or be administered by using a nebulizer.
  • a suitable propellant for example, chlorofluorocarbon such as dichlorofluoromethane, trichlorofluoromethane, or dichlorotetrafluoromethane, or gas such as carbon dioxide
  • a tablet, a powder, a granule, a capsule, and the like can be produced by adding an additive such as an excipient, a lubricant, a binder, a disintegrant, a stabilizer, and a flavoring agent to mepenzolate bromide as an active ingredient.
  • a tablet can be prepared by using a usual tablet compression machine after adding an excipient such as lactose, starch or derivatives thereof, or cellulose or derivatives thereof; a binder such as carboxymethylcellulose sodium, alginic acid, or gum arabic; a lubricant such as magnesium stearate or talc; and other conventional additives as necessary.
  • an excipient such as lactose, starch or derivatives thereof, or cellulose or derivatives thereof
  • a binder such as carboxymethylcellulose sodium, alginic acid, or gum arabic
  • a lubricant such as magnesium stearate or talc
  • other conventional additives as necessary.
  • the formulation may be in any form such as an aqueous solution form, a suspension form, a sol form, or a gel form.
  • the formulation for rectal administration is prepared by using water, glycerol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, a vegetable oil, and the like as appropriate. Additionally, a thickener, a buffering agent, a preservative, a pH regulator, and the like may be added as appropriate.
  • the dosage of mepenzolate bromide that is an active ingredient of the agent for ameliorating COPD of the present invention varies depending on a method by which the formulation is prepared, a dosage form, a symptom of the disease, the age and weight of a patient, and the like and thus cannot be necessarily specified.
  • an appropriate clinical dosage is 0.5 to 200 mg per day for adults in the case of administration of an airway-administered formulation and an inhalation formulation and 0.5 to 500 mg per day for adults in the case of administration of an oral formulation.
  • the frequency of administration cannot be necessarily specified, either.
  • the frequency of administration can be once or several times a day.
  • an appropriate dosage is 0.01 mg to 100 mg per day for adults.
  • mepenzolate bromide that is an active ingredient of the agent for ameliorating COPD of the present invention can be used more effectively by combined administration with an anticholinergic drug such as ipratropium, scopolamine, pirenzepine, tiotropium, or oxitropium.
  • an anticholinergic drug such as ipratropium, scopolamine, pirenzepine, tiotropium, or oxitropium.
  • Mepenzolate described in the below-mentioned Test Examples and Working Examples refers to mepenzolate bromide.
  • PPE porcine pancreatic elastase
  • Mep mepenzolate
  • PBS alone was administered to a control mouse.
  • a mouse was placed in a chamber. Then, the whole amount of a mepenzolate solution prepared by dissolving mepenzolate in 10 mL of PBS was sprayed onto the mouse over 30 minutes by using an ultrasonic nebulizer (NE-U07, manufactured by OMRON Corporation) that was connected to the chamber.
  • an ultrasonic nebulizer NE-U07, manufactured by OMRON Corporation
  • Lung function and airway resistance were measured by using a computer-controlled small animal ventilator (FlexiVent, SCIREQ Scientific Respiratory Equipment Inc.).
  • a mouse was anesthetized with chloral hydrate, a tracheostomy was performed, and an 8 mm metal tube was inserted into the trachea. Ventilation was performed on the mouse with a volume of 8.7 mL/kg, a positive end-expiratory pressure of 2 to 3 cmH 2 O, and a respiratory rate of 150 times/min.
  • Total respiratory system elastance was measured by a snap shot technique and tissue elastance was measured by a forced oscillation technique.
  • FEV 0.05 /FVC was determined by using the FlexiVent software.
  • a lung damage model for pulmonary emphysema and altered lung function was generated by administering 100 ⁇ g of porcine pancreatic elastase per mouse to 4 to 6 week old ICR mice once via the airway.
  • mice Different doses of mepenzolate were administered to these mice via the airway ( ⁇ g/kg) or by inhalation ( ⁇ g/chamber) once daily for 14 days (Day 0 to Day 13) and the mice were euthanized on Day 14.
  • Sections of the lung tissues were prepared and dyed with H&E (hematoxylin-eosin staining), and stained images were obtained by electron microscopy.
  • FIG. 1 airway administration
  • FIG. 4 inhalation administration
  • the airspace size in the cells in the H&E stained images obtained above was measured as a mean linear intercept (MLI; ⁇ m).
  • mice After 4 to 6 week old ICR mice were used and treated with porcine pancreatic elastase by a similar method to that in Test Example 1, different doses ( ⁇ g/kg) of mepenzolate were administered to these mice via the airway once daily from 14 days to 20 days after the treatment. Then, the mice were euthanized, sections of the lung tissues were prepared and dyed with H&E, and stained images were obtained by electron microscopy.
  • the mean linear intercept was suppressed and damage in the alveolar wall was improved dose-dependently in the case of airway administration of mepenzolate.
  • the mean linear intercept was increased compared to that in the case of coadministration in Test Example 1.
  • Ipra ipratropium, scopolamine, and pirenzepine, respectively.
  • mepenzolate effectively exhibited a recovering effect of vital capacity represented by FEV 0.05 /FVC that had been reduced by PPE administration.
  • ipratropium Ipra
  • scopolamine Scop
  • pirenzepine Pire
  • mepenzolate, ipratropium, scopolamine, and pirenzepine are known to have a muscarinic antagonistic action (an anticholinergic action); however, ipratropium, scopolamine, and pirenzepine had no effect of FEV 0.05 /FVC and only mepenzolate had an effect of FEV 0.05 /FVC. This suggests that mepenzolate improves vital capacity by an action mechanism different from that of a muscarinic antagonistic action (an anticholinergic action).
  • mice were administered to the mice via the airway, and one hour after administration, the mice received five exposures to nebulized methacoline, and then, the airway resistance for each dose was measured.
  • mice were administered to the mice at a dose of 38 ⁇ g/kg. Then, the mice received five exposures to nebulized methacoline at 6 hours, 24 hours, and 48 hours after drug administration. The airway resistance for each time length was measured.
  • mepenzolate reduced the airway resistance almost dose-dependently at doses of 0.04, 0.08, 0.38, 3.8, and 38.0 ⁇ g/kg.
  • mepenzolate reduced the airway resistance even 24 hours after administration thereof.
  • the total number of TNF- ⁇ , MIP-2, MCP-1, or KC in the BALF decreased when 38 ⁇ g/kg of mepenzolate was administered.
  • mepenzolate is effective against inflammatory symptoms caused by porcine pancreatic elastase.
  • mice Three-times-a-day exposure to smoking and once-a-day coadministration of 38 ⁇ g/kg of mepenzolate were performed on 5 week old DBA/2 mice, 5 days a week (Monday to Friday) for 6 weeks. The mice were subjected to only smoking during the final week.
  • mice were subjected to smoking by the method described below. 15 to 20 mice were placed in a 45 L chamber and the chamber was connected to a cigarette smoke generator. Commercially available unfiltered cigarette that produced 28 mg of tar and 2.3 mg of nicotine were used. The mice were exposed to smoke of one cigarette over 35 minutes, which was repeated three times a day for five days a week. This was continued for 6 weeks. The mice were made to inhale the cigarette smoke 15 times over a 5-minute period. Mepenzolate was administered to the mice by inhalation.
  • mice After smoking was completed, the mice were euthanized, sections of the lung tissues were prepared and dyed with H&E, and stained images were obtained by electron microscopy.
  • the airspace size in the cells in the H&E stained images obtained above was measured as a mean linear intercept. The results were shown in FIG. 16 .
  • CS refers to cigarette smoke
  • porcine pancreatic elastase per mouse 100 ⁇ g of porcine pancreatic elastase per mouse was administered to 4 to 6 week old ICR mice once via the airway. Then, different doses (mg/kg) of mepenzolate were administered to the mice orally once daily for 14 days. After administration, sections of the lung tissues were excised. Subsequently, the sections were subjected to H&E dyeing, MLI measurement, and elastance measurement performed by a similar method to that in Test Example 1.
  • porcine pancreatic elastase per mouse 100 ⁇ g of porcine pancreatic elastase per mouse was administered to 4 to 6 week old ICR mice once via the airway to induce damage in the lung.
  • mice intrarectally once daily for 14 days.
  • sections of the lung tissues were excised. Subsequently, the sections were subjected to H&E dyeing, MLI measurement, and elastance measurement performed by a similar method to that in Test Example 1.
  • a liquid formulation for inhalation is prepared by mixing 1% (w/w) of mepenzolate bromide, 0.05% (w/w) of benzalkonium chloride, 10% (w/w) of polyethylene glycol, 20% (w/w) of propylene glycol, and the remaining percentage of purified water.
  • An enema preparation was prepared by dissolving 1 mg of mepenzolate bromide in 1 mL of water and adding adequate amounts of carboxymethylcellulose sodium and tris(hydroxymethyl)aminomethane thereto.
  • the agent for ameliorating COPD provided by the present invention contains mepenzolate bromide, which has already been used in a clinical setting, as an active ingredient.
  • the inventive agent exhibited a remarkable effect of ameliorating COPD by airway administration and inhalation administration, and also exhibited an effect of ameliorating COPD by oral administration and rectal administration.
  • Mepenzolate bromide can be used without concern about side effects and without anxiety since the safety thereof has already been confirmed. Therefore, the medical value thereof is great.
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CN107095885A (zh) * 2017-04-28 2017-08-29 青岛东海药业有限公司 酪酸梭菌在制备预防或治疗慢性阻塞性肺疾病制剂中的应用
JP7000305B2 (ja) 2018-12-26 2022-01-19 ファナック株式会社 工作機械および工具マガジンの原点検出方法

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JP6013450B2 (ja) 2016-10-25
US9539248B2 (en) 2017-01-10
WO2013137009A1 (fr) 2013-09-19
CN104363910A (zh) 2015-02-18
EP2826479B1 (fr) 2019-02-20
EP2826479A4 (fr) 2015-11-11
EP2826479A1 (fr) 2015-01-21
JPWO2013137009A1 (ja) 2015-08-03
KR20140138880A (ko) 2014-12-04

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