WO2015129800A1 - Dioctyl sodium sulfosuccinate otolaryngological solution - Google Patents

Dioctyl sodium sulfosuccinate otolaryngological solution Download PDF

Info

Publication number
WO2015129800A1
WO2015129800A1 PCT/JP2015/055590 JP2015055590W WO2015129800A1 WO 2015129800 A1 WO2015129800 A1 WO 2015129800A1 JP 2015055590 W JP2015055590 W JP 2015055590W WO 2015129800 A1 WO2015129800 A1 WO 2015129800A1
Authority
WO
WIPO (PCT)
Prior art keywords
solution
weight
parts
buffer
doss
Prior art date
Application number
PCT/JP2015/055590
Other languages
French (fr)
Japanese (ja)
Inventor
一 金澤
文也 平野
Original Assignee
セオリアファーマ株式会社
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 セオリアファーマ株式会社 filed Critical セオリアファーマ株式会社
Priority to JP2016505290A priority Critical patent/JPWO2015129800A1/en
Publication of WO2015129800A1 publication Critical patent/WO2015129800A1/en

Links

Classifications

    • 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
    • A61K9/0046—Ear
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • 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
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals

Definitions

  • the present invention relates to an otolaryngological solution containing dioctylsodium sulfosuccinate as an active ingredient.
  • DOSS Dioctylsodiumsulfosuccinate
  • Bis (2-ethylhexyl) sodiumsulfosuccinate Used as an ingredient.
  • a solution containing glycerin added to DOSS has been sold as a prescription drug since 1970 (trade name “Waxnate”, manufactured by Kotobuki Pharmaceutical Co., Ltd., sold by Zeria Shinyaku Kogyo Co., Ltd.). Sales have been discontinued.
  • DOSS is a white waxy or resinous substance and has adhesiveness
  • various attempts have been made in its formulation.
  • a fine powder is added as an excipient to DOSS in a pulverizing mixer equipped with a cooling facility, and the powder is doubled and granulated.
  • JP-A-58-152809 contains sodium dihydrogen phosphate as a foaming agent and polyethylene glycol for promptly neutralizing body fluids.
  • a foaming vaginal suppository having a contraceptive effect using DOSS as a foaming aid is disclosed.
  • the inventors of the present invention have evaluated the stability of ⁇ waxnate '' (a solution obtained by adding glycerin to DOSS), which has been commercially available, in providing an otolaryngological solution containing DOSS as an active ingredient. It has been found that the content of DOSS, which is an active ingredient, decreases as the pH of the product decreases. Such a problem has never been reported so far, and is a problem found for the first time by the present inventors.
  • an object of the present invention is to provide an otolaryngological solution containing dioctylsodium sulfosuccinate as an active ingredient, which has improved storage stability. More specifically, it is an object of the present invention to provide a preparation that does not lower the content of DOSS as an active ingredient without lowering the pH of the solution during storage.
  • the present inventors have added a buffer to a liquid agent containing DOSS and a polyhydric alcohol (such as glycerin), thereby storing a liquid agent containing DOSS as an active ingredient. It was found that a decrease in pH and a decrease in DOSS content can be remarkably suppressed. In addition, it has been found that by adding a diol (such as propylene glycol) as a solubilizing agent in combination with a buffering agent, it is possible to provide a preparation having excellent stability and uniform dispersibility. The present invention has been completed based on the above findings.
  • a diol such as propylene glycol
  • an otolaryngological solution for removing foreign matter of the external auditory canal for example, an otic solution for removing foreign matter of the external auditory canal
  • a dissolution aid A solution comprising an agent and a buffer
  • the buffer is an alkanolamine, preferably triethanol
  • the above liquid agent that is an amine is an amine
  • the above liquid agent that the buffer is a phosphate buffer
  • the above liquid agent that is a combination of a glycerin and propylene glycol as a solubilizing agent and the phosphate buffer is provided.
  • the above liquid preparation comprising 100 to 1,000 parts by weight of a solubilizing agent and 50 to 200 parts by weight of a buffering agent with respect to 100 parts by weight of dioctylsodium sulfosuccinate; And / or the above solution containing propylene glycol and a phosphate buffer; the above solution containing a combination of glycerin and propylene glycol and a phosphate buffer; pH of 6.5 when prepared and stored at 60 ° C. for 2 weeks; The above liquid preparation in the range of ⁇ 8.0; the above-mentioned liquid preparation having a residual ratio of active ingredients of 96% or more when stored at 60 ° C. for 2 weeks is provided.
  • a method for stabilizing an otolaryngological solution for example, an otologic solution for removing foreign matter of the external auditory canal
  • an otolaryngological solution for example, an otologic solution for removing foreign matter of the external auditory canal
  • a stabilizer for an otolaryngological solution containing dioctylsodium sulfosuccinate as an active ingredient for example, an otologic solution for removing foreign matter of the external auditory canal.
  • a stabilizer comprising a combination of solubilizer and buffer is provided.
  • the otolaryngological solution of the present invention which contains a solubilizing agent and a buffer together with dioctylsodium sulfosuccinate, which is an active ingredient, is stable over a long period of time because the decrease in pH and the decrease in DOSS content during storage are suppressed. is there.
  • a liquid preparation containing a combination of glycerin and propylene glycol as a solubilizing agent the decrease in pH and DOSS content is remarkably suppressed, and the viscosity is further reduced, so it is suitable for application to the outer ear. .
  • the liquid agent of this invention since the uniformly mixed dispersion state is maintained over a long period of time, it can be stored and distributed as a stable liquid agent.
  • the otolaryngological solution of the present invention can be used as, for example, an otolaryngological solution for removing foreign matter in the external auditory canal or nasal cavity, and preferably can be used as an otic solution for removing foreign matter in the external auditory canal. It is a liquid and contains dioctylsodium sulfosuccinate as an active ingredient, and further contains a solubilizing agent and a buffer.
  • Dioctyl sodium sulfosuccinate which is an active ingredient, is sometimes called chemical name: bis (2-ethylhexyl) sodium sulfosuccinate. This substance has been conventionally used as an active ingredient in constipation drugs and earwax removal agents, and is readily available to those skilled in the art.
  • the solubilizing agent only needs to have an action of improving the solubility of dioctyl sodium sulfosuccinate, which is a poorly soluble drug, in water.
  • polyhydric alcohol polyhydric alcohol such as divalent or trivalent
  • examples of the polyhydric alcohol include diols (such as water-soluble polypropylene glycol such as ethylene glycol, diethylene glycol, polyethylene glycol (PEG), propylene glycol, and dipropylene glycol), trihydric or higher polyhydric alcohols such as glycerin and polyglycerin, and the like. Can be illustrated.
  • glycerin can be used, but propylene glycol can be used together with or in place of glycerin.
  • other additives described as a solubilizing agent in the pharmaceutical additive dictionary for example, medium-chain fatty acid triglyceride, castor oil, macrogol, or isopropyl myristate can be used.
  • solubilizers glycerin, propylene glycol, or combinations thereof are preferred.
  • An embodiment in which glycerin and propylene glycol are used in combination is particularly preferable.
  • the type of the buffer is not particularly limited.
  • phosphoric acid trisodium phosphate, sodium hydrogen phosphate hydrate, dipotassium phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, anhydrous monohydrogen phosphate
  • phosphate buffers such as sodium and anhydrous sodium dihydrogen phosphate, acetate buffers, citrate buffers, borate buffers, tartaric acid buffers, and tris buffers
  • sodium hydroxide, hydrogen carbonate examples include sodium, alkanolamine (for example, triethanolamine, diethanolamine, monoethanolamine, etc.), trishydroxymethylaminomethane (trometamol), acid or base such as lactic acid, anhydrous citric acid, anhydrous sodium acetate, or salts thereof. .
  • buffering agents may be used alone or in combination of two or more.
  • phosphoric acid trisodium phosphate, sodium hydrogen phosphate hydrate, dipotassium phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, anhydrous sodium monohydrogen phosphate, anhydrous A phosphate buffer such as sodium dihydrogen phosphate is preferred.
  • Two or more phosphate buffer solutions may be used in combination.
  • the proportion of DOSS in the liquid preparation can be appropriately selected according to the purpose of use, the number of administrations, the administration method, etc., but 0.1 to 10 parts by weight, preferably 0.3 to 7 parts by weight with respect to the total mass of the liquid preparation More preferably, it can be selected from the range of about 5 parts by weight.
  • the ratio of the solubilizing agent is selected from the range of 5 to 50 parts by weight, preferably 10 to 40 parts by weight, more preferably about 15 to 30 parts by weight (for example, 20 to 25 parts by weight) with respect to the total mass of the liquid agent. can do.
  • the ratio of the other solubilizer is, for example, 10 to 500 parts by weight, preferably 15 to 400 parts by weight, with respect to 100 parts by weight of one solubilizer.
  • the range is preferably from 25 to 300 parts by weight, particularly preferably from about 25 to 150 parts by weight.
  • a diol such as propylene glycol
  • a trihydric or higher polyhydric alcohol such as glycerin
  • the amount can be about 20 to 30 parts by weight, more preferably about 25 parts by weight with respect to the total mass of the liquid agent.
  • solubilizing agent 100 to 1000 parts by weight, preferably 300 to 700 parts by weight, more preferably 400 to 600 parts by weight, particularly preferably about 450 to 550 parts by weight, of the solubilizing agent is used for 100 parts by weight of the active ingredient DOSS®. can do.
  • the proportion of the buffer should be appropriately selected according to the type of buffer used so that the pH of the solution does not decrease after long-term storage, but in general, for example, when using a phosphate buffer, 5 to 1000 parts by weight (eg 10 to 1000 parts by weight), preferably 10 to 700 parts by weight (eg 30 to 700 parts by weight), more preferably 15 to 500 parts by weight (eg 50 to 500 parts by weight) per 100 parts by weight of DOSS Parts by weight), more preferably 20 to 200 parts by weight (eg 70 to 200 parts by weight), and particularly preferably about 20 to 35 parts by weight.
  • the buffering agent can be added to the liquid agent and stored at 60 ° C. for several weeks to select an amount that does not cause a decrease in pH.
  • the liquid preparation of the present invention includes water (purified or sterile water, distilled water for injection, etc.), physiological saline, glucose solution, water-soluble organic solvents (ethanol, isopropanol and other lower aliphatic alcohols and ethylene glycol as necessary.
  • Polyalkylene glycols such as diethylene glycol and polyethylene glycol
  • animal and vegetable oils vegetable oils
  • vegetable oils vegetable oils
  • vegetable oils vegetable oils
  • mineral oils liquid paraffin, Silicone oils
  • waxes beeswax, carnauba wax, lanolin, paraffin, petrolatum, etc.
  • long chain fatty acid esters saturated or unsaturated fatty acid alkyl esters, fatty acids and polyhydric alcohols (poly C2-4 alkylene glycol, glycerin or Polyglycerol, etc.) and esters
  • hydrogenated oil high grade Alcohol (saturated aliphatic such as stearyl alcohol alcohols, and unsaturated fatty alcohols such as oleyl alcohol), higher fatty acids (stearic acid, oleic acid) and the like can also be added.
  • preservatives or preservatives such as parabens such as methyl paraben and butyl paraben
  • flavoring agents or fragrances such as fragrances such as menthol
  • cooling agents such as cooling agents
  • soothing agents such as local anesthetics such as lidocaine
  • active ingredients antibacterial agents, antibiotics, anti-inflammatory agents, etc.
  • active ingredients for the treatment of infectious diseases and inflammation can be added. These additives may be added singly or in combination of two or more.
  • the liquid preparation of the present invention can be produced by conventional means such as mixing, dissolution, suspension, or emulsification using the above components, and is generally provided as a viscous liquid preparation.
  • propylene glycol together with glycerin, it is possible to prepare a solution suitable for application to the ear canal or nasal cavity by reducing the viscosity.
  • the liquid preparation of the present invention is used to remove foreign substances existing in the ear canal or the nasal cavity (usually those in which the earwax or earwax has solidified, or an artificial product mistakenly taken into the ear canal).
  • the application method of the liquid preparation of the present invention is not particularly limited, but in general, it can be administered by dropping (earing) or spraying into the ear canal or nasal cavity, or can be applied to the outer ear with a cotton swab or the like. Earwax can be applied either dry or viscous. In the case of earwax that is difficult to remove, it can be washed at a slight temperature of about 37 ° C. 5 to 20 minutes after instilling a few drops.
  • liquid preparation of the present invention can be used not only for humans but also for mammals other than humans (mouse, rat, rabbit, dog, cat, cow, horse, pig, monkey, etc.).
  • Test example 1 ⁇ Formulation method> DOSS and glycerin were added to a 0.1 mol / L phosphate buffer solution at pH 7.5 at the concentrations shown in the table below, heated to 60-70 ° C. to dissolve DOSS, and water was added to produce a solution ( % In the table indicates the concentration in the solution).
  • Example 3 As compared with Example 1 and Example 2 (respectively Comparative Examples), in the liquid preparation of Example 3, the decrease in pH and DOSS content was suppressed by adding a phosphate buffer. About Example 4 which added sodium hydroxide as a buffering agent, pH fell compared with Example 3.
  • Example 10 and Example 11 as in Example 6, the decrease in pH and DOSS content was suppressed. Even when triethanolamine was used as a buffering agent, the decrease in pH and DOSS content was markedly suppressed.
  • Example 12 containing propylene glycol and phosphate buffer, the viscosity was lower than that in Example 6, and administration to the outer ear was easy. Further, in this liquid preparation, the suppression of the decrease in pH and the decrease in the DOSS content was more remarkable than in Example 6.
  • Test example 2 Stability test (acceleration test) In accordance with the guidelines of the Yakuhin No. 165 stability test implementation method dated February 15, 1991, pH and content changes over time were observed over 6 months under accelerated conditions of 40 ° C and relative humidity of 75%.
  • Example 18 was prepared in the same manner as Example 3.
  • Example 6 in which glycerin and propylene glycol were added as a solubilizing agent, and phosphate buffer (anhydrous sodium monohydrogen phosphate and anhydrous sodium dihydrogen phosphate) was added as a buffering agent.
  • phosphate buffer anhydrous sodium monohydrogen phosphate and anhydrous sodium dihydrogen phosphate

Abstract

　An otolaryngological solution used in an ear wax remover or the like and having dioctyl sodium sulfosuccinate (DOSS) as an effective ingredient, said solution including a buffer such as a phosphate buffer solution, and a solubilizer formed from a combination of glycerin and propylene glycol, for example, wherein during storage there is no decrease in the pH of said solution and no decrease in the content of DOSS, that is, the effective ingredient.

Description

ジオクチルソジウムスルホサクシネート耳鼻科用液剤Dioctyl sodium sulfosuccinate otolaryngological solution
　本発明は、ジオクチルソジウムスルホサクシネートを有効成分とする耳鼻科用液剤に関する。 The present invention relates to an otolaryngological solution containing dioctylsodium sulfosuccinate as an active ingredient.
　ジオクチルソジウムスルホサクシネート(Dioctyl sodium sulfosuccinate: 以下、「DOSS」と略す場合がある。この物質はBis(2-ethylhexyl)sodium sulfosuccinateと表される場合もある)は便秘薬や耳垢除去剤の有効成分として使用されている。耳垢除去剤としてはDOSSにグリセリンを添加した液剤が1970年より医療用医薬品として販売されていたが(商品名「ワックスネート」、寿製薬株式会社製造、ゼリア新薬工業株式会社販売)、2006年に販売が中止されている。 Dioctylsodiumsulfosuccinate (hereinafter sometimes abbreviated as “DOSS”. This substance is sometimes referred to as Bis (2-ethylhexyl) sodiumsulfosuccinate). Used as an ingredient. As an earwax remover, a solution containing glycerin added to DOSS has been sold as a prescription drug since 1970 (trade name “Waxnate”, manufactured by Kotobuki Pharmaceutical Co., Ltd., sold by Zeria Shinyaku Kogyo Co., Ltd.). Sales have been discontinued.
　DOSSは、白色のろう状又は樹脂状物質であり粘着性を有することから、その製剤化においては様々な試みが行われている。例えば、特開平2-255613号公報(特許文献1、請求項1)には、冷却設備を備えた粉砕混合機中でDOSSに賦形剤として微細粉末を加え、倍散末化して造粒することにより打錠性の改善された製剤が開示されている。また、特開昭58-152809号公報(特許文献2、請求項1～4)には、発泡剤としてリン酸二水素ナトリウム及び体液に対して速やかな中和反応を進めるためのポリエチレングリコールを含有し、DOSSを発泡助剤として使用した避妊効果を有する発泡性膣坐剤が開示されている。 Since DOSS is a white waxy or resinous substance and has adhesiveness, various attempts have been made in its formulation. For example, in Japanese Patent Application Laid-Open No. H2-255613 (Patent Document 1, Claim 1), a fine powder is added as an excipient to DOSS in a pulverizing mixer equipped with a cooling facility, and the powder is doubled and granulated. Thus, a formulation with improved tabletability is disclosed. In addition, JP-A-58-152809 (Patent Document 2, claims 1 to 4) contains sodium dihydrogen phosphate as a foaming agent and polyethylene glycol for promptly neutralizing body fluids. A foaming vaginal suppository having a contraceptive effect using DOSS as a foaming aid is disclosed.
特開平2-255613号公報Japanese Patent Laid-Open No. 2-255613 特開昭58-152809号公報JP 58-152809 A
　本発明者らは、DOSSを有効成分として含む耳鼻科用液剤を提供するにあたり、従来市販されていた「ワックスネート」(DOSSにグリセリンを添加した液剤)の安定性を評価したところ、保存時に液剤のpHが低下するとともに、有効成分であるDOSSの含有量が低下することを見出した。このような問題点は従来全く報告されておらず、本発明者が初めて見出した問題点である。 The inventors of the present invention have evaluated the stability of `` waxnate '' (a solution obtained by adding glycerin to DOSS), which has been commercially available, in providing an otolaryngological solution containing DOSS as an active ingredient. It has been found that the content of DOSS, which is an active ingredient, decreases as the pH of the product decreases. Such a problem has never been reported so far, and is a problem found for the first time by the present inventors.
　従って、本発明の課題は、ジオクチルソジウムスルホサクシネートを有効成分とする耳鼻科用液剤であって、保存安定性が改善された製剤を提供することにある。より具体的には、保存時に液剤のpHが低下することなく、有効成分であるDOSSの含有量低下のない製剤を提供することが本発明の課題である。 Therefore, an object of the present invention is to provide an otolaryngological solution containing dioctylsodium sulfosuccinate as an active ingredient, which has improved storage stability. More specifically, it is an object of the present invention to provide a preparation that does not lower the content of DOSS as an active ingredient without lowering the pH of the solution during storage.
　本発明者らは上記の課題を解決すべく鋭意検討した結果、DOSSと多価アルコール（グリセリン等）とを含む液剤に緩衝剤を添加することによりDOSSを有効成分として含む液剤を保存した際のpHの低下及びDOSS含有量の低下を顕著に抑制できることを見出した。また、緩衝剤と組み合わせて溶解補助剤としてジオール（プロピレングリコール等）を添加することにより、安定性に優れるとともに、均一に混合された分散性に優れた製剤を提供できることを見いだした。本発明は上記の知見に基づいて完成されたものである。 As a result of intensive studies to solve the above-mentioned problems, the present inventors have added a buffer to a liquid agent containing DOSS and a polyhydric alcohol (such as glycerin), thereby storing a liquid agent containing DOSS as an active ingredient. It was found that a decrease in pH and a decrease in DOSS content can be remarkably suppressed. In addition, it has been found that by adding a diol (such as propylene glycol) as a solubilizing agent in combination with a buffering agent, it is possible to provide a preparation having excellent stability and uniform dispersibility. The present invention has been completed based on the above findings.
　すなわち、本発明により、有効成分であるジオクチルソジウムスルホサクシネートを含む外耳道異物を除去するための耳鼻科用液剤（例えば、外耳道異物を除去するための耳科用液剤）であって、溶解補助剤及び緩衝剤を含む液剤が提供される。 That is, according to the present invention, there is an otolaryngological solution for removing foreign matter of the external auditory canal (for example, an otic solution for removing foreign matter of the external auditory canal) containing dioctylsodium sulfosuccinate as an active ingredient, and a dissolution aid A solution comprising an agent and a buffer is provided.
　本発明の好ましい態様によれば、溶解補助剤が多価アルコール、例えばグリセリン、プロピレングリコール、又はそれらの組み合わせから選択される多価アルコールである上記の液剤；緩衝剤がアルカノールアミン、好ましくはトリエタノールアミンである上記の液剤；緩衝剤がリン酸緩衝液である上記の液剤；及び、溶解補助剤がグリセリン及びプロピレングリコールの組み合わせであり、緩衝剤がリン酸緩衝液である上記の液剤が提供される。
が提供される。 According to a preferred embodiment of the present invention, the solution as described above, wherein the solubilizer is a polyhydric alcohol such as glycerin, propylene glycol, or a combination thereof; the buffer is an alkanolamine, preferably triethanol There is provided the above liquid agent that is an amine; the above liquid agent that the buffer is a phosphate buffer; and the above liquid agent that is a combination of a glycerin and propylene glycol as a solubilizing agent and the phosphate buffer. The
Is provided.
　本発明のさらに好ましい態様によれば、ジオクチルソジウムスルホサクシネート100重量部に対して、溶解補助剤を100～1,000重量部、緩衝剤を50～200重量部の割合で含む上記の液剤；グリセリン及び/又はプロピレングリコールとリン酸緩衝液とを含む上記の液剤；グリセリン及びプロピレングリコールの組み合わせとリン酸緩衝液とを含む上記の液剤；調製時及び60℃で2週間保存した場合のpHが6.5～8.0の範囲である上記の液剤；60℃で2週間保存した場合の有効成分の残存率が96％以上である上記の液剤が提供される。 According to a further preferred embodiment of the present invention, the above liquid preparation comprising 100 to 1,000 parts by weight of a solubilizing agent and 50 to 200 parts by weight of a buffering agent with respect to 100 parts by weight of dioctylsodium sulfosuccinate; And / or the above solution containing propylene glycol and a phosphate buffer; the above solution containing a combination of glycerin and propylene glycol and a phosphate buffer; pH of 6.5 when prepared and stored at 60 ° C. for 2 weeks; The above liquid preparation in the range of ˜8.0; the above-mentioned liquid preparation having a residual ratio of active ingredients of 96% or more when stored at 60 ° C. for 2 weeks is provided.
　別の観点からは、本発明により、有効成分であるジオクチルソジウムスルホサクシネートを含む耳鼻科用液剤（例えば外耳道異物を除去するための耳科用液剤）の安定化方法であって、該液剤に溶解補助剤及び緩衝剤を添加する方法；及び、有効成分であるジオクチルソジウムスルホサクシネートを含む耳鼻科用液剤（例えば外耳道異物を除去するための耳科用液剤）の安定化剤であって、溶解補助剤及び緩衝剤の組み合わせを含む安定化剤が提供される。 From another point of view, according to the present invention, there is provided a method for stabilizing an otolaryngological solution (for example, an otologic solution for removing foreign matter of the external auditory canal) containing dioctylsodium sulfosuccinate as an active ingredient, the solution And a stabilizer for an otolaryngological solution containing dioctylsodium sulfosuccinate as an active ingredient (for example, an otologic solution for removing foreign matter of the external auditory canal). Thus, a stabilizer comprising a combination of solubilizer and buffer is provided.
　有効成分であるジオクチルソジウムスルホサクシネートとともに溶解補助剤及び緩衝剤を含む本発明の耳鼻科用液剤は、保存時におけるpHの低下及びDOSS含有量の低下が抑制されており、長期にわたって安定である。特に、グリセリンとプロピレングリコールとの組み合わせを溶解補助剤として含む液剤では、pH及びDOSS含有量の低下が顕著に抑制されており、さらに粘性が低下していることから外耳への適用に好適である。また、本発明の液剤では、均一に混合された分散状態が長期にわたって維持されることから、安定な液剤として保存及び流通させることができる。 The otolaryngological solution of the present invention, which contains a solubilizing agent and a buffer together with dioctylsodium sulfosuccinate, which is an active ingredient, is stable over a long period of time because the decrease in pH and the decrease in DOSS content during storage are suppressed. is there. In particular, in a liquid preparation containing a combination of glycerin and propylene glycol as a solubilizing agent, the decrease in pH and DOSS content is remarkably suppressed, and the viscosity is further reduced, so it is suitable for application to the outer ear. . Moreover, in the liquid agent of this invention, since the uniformly mixed dispersion state is maintained over a long period of time, it can be stored and distributed as a stable liquid agent.
　本発明の耳鼻科用液剤は、例えば外耳道又は鼻腔内異物を除去するための耳鼻科用液剤として使用することができ、好ましくは外耳道異物を除去するための耳科用液剤として使用することができる液剤であって、有効成分としてジオクチルソジウムスルホサクシネートを含み、さらに溶解補助剤及び緩衝剤を含むことを特徴としている。 The otolaryngological solution of the present invention can be used as, for example, an otolaryngological solution for removing foreign matter in the external auditory canal or nasal cavity, and preferably can be used as an otic solution for removing foreign matter in the external auditory canal. It is a liquid and contains dioctylsodium sulfosuccinate as an active ingredient, and further contains a solubilizing agent and a buffer.
　有効成分であるジオクチルソジウムスルホサクシネート(DOSS)は化学名：ビス(2-エチルヘキシル)ソディウム・スルホサクシネートと呼ばれる場合もある。この物質は従来より便秘薬や耳垢除去剤の有効成分として使用されており、当業者に容易に入手可能である。 Dioctyl sodium sulfosuccinate (DOSS), which is an active ingredient, is sometimes called chemical name: bis (2-ethylhexyl) sodium sulfosuccinate. This substance has been conventionally used as an active ingredient in constipation drugs and earwax removal agents, and is readily available to those skilled in the art.
　溶解補助剤は、難溶性薬物であるジオクチルソジウムスルホサクシネートの水に対する溶解性を改善する作用を有するものであればよい。例えば、多価アルコール(二価または三価などの多価アルコール)を用いることができるが、これらに限定されることはない。多価アルコールとしては、例えば、ジオール(エチレングリコール、ジエチレングリコール、ポリエチレングリコール(PEG)、プロピレングリコール、ジプロピレングリコールなどの水溶性ポリプロピレングリコール等）、グリセリン、ポリグリセリンなどの三価以上の多価アルコールなどが例示できる。一般的にはグリセリンを用いることができるが、グリセリンとともに、あるいはグリセリンに代えてプロピレングリコールを用いることができる。また、医薬品添加物事典に溶解補助剤として記載されている他の添加物、例えば、中鎖脂肪酸トリグリセリド、ヒマシ油、マクロゴール、又はミリスチン酸イソプロピルなどを用いることもできる。これらの溶解補助剤のうち、グリセリン、プロピレングリコール、又はそれらの組み合わせが好ましい。グリセリンおよびプロピレングリコールを組み合わせて使用する態様は特に好ましい。 The solubilizing agent only needs to have an action of improving the solubility of dioctyl sodium sulfosuccinate, which is a poorly soluble drug, in water. For example, polyhydric alcohol (polyhydric alcohol such as divalent or trivalent) can be used, but is not limited thereto. Examples of the polyhydric alcohol include diols (such as water-soluble polypropylene glycol such as ethylene glycol, diethylene glycol, polyethylene glycol (PEG), propylene glycol, and dipropylene glycol), trihydric or higher polyhydric alcohols such as glycerin and polyglycerin, and the like. Can be illustrated. In general, glycerin can be used, but propylene glycol can be used together with or in place of glycerin. In addition, other additives described as a solubilizing agent in the pharmaceutical additive dictionary, for example, medium-chain fatty acid triglyceride, castor oil, macrogol, or isopropyl myristate can be used. Of these solubilizers, glycerin, propylene glycol, or combinations thereof are preferred. An embodiment in which glycerin and propylene glycol are used in combination is particularly preferable.
　緩衝剤の種類は特に限定されないが、例えば、リン酸、リン酸三ナトリウム、リン酸水素ナトリウム水和物、リン酸二カリウム、リン酸ニ水素カリウム、リン酸ニ水素ナトリウム、無水リン酸一水素ナトリウム、無水リン酸ニ水素ナトリウム等のリン酸緩衝液、酢酸緩衝液、クエン酸緩衝液、ホウ酸緩衝液、酒石酸緩衝液、又はトリス緩衝剤などの緩衝剤のほか、水酸化ナトリウム、炭酸水素ナトリウム、アルカノールアミン(例えば、トリエタノールアミン、ジエタノールアミン、モノエタノールアミンなど)、トリスヒドロキシメチルアミノメタン(トロメタモール)、乳酸、無水クエン酸、無水酢酸ナトリウムなどの酸又は塩基、あるいはそれらの塩が挙げられる。 The type of the buffer is not particularly limited. For example, phosphoric acid, trisodium phosphate, sodium hydrogen phosphate hydrate, dipotassium phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, anhydrous monohydrogen phosphate In addition to phosphate buffers such as sodium and anhydrous sodium dihydrogen phosphate, acetate buffers, citrate buffers, borate buffers, tartaric acid buffers, and tris buffers, sodium hydroxide, hydrogen carbonate Examples include sodium, alkanolamine (for example, triethanolamine, diethanolamine, monoethanolamine, etc.), trishydroxymethylaminomethane (trometamol), acid or base such as lactic acid, anhydrous citric acid, anhydrous sodium acetate, or salts thereof. .
　これらの緩衝剤は単独で用いてもよいが、二種以上を組み合わせて使用してもよい。これらの緩衝剤のうち、特に、リン酸、リン酸三ナトリウム、リン酸水素ナトリウム水和物、リン酸二カリウム、リン酸ニ水素カリウム、リン酸ニ水素ナトリウム、無水リン酸一水素ナトリウム、無水リン酸ニ水素ナトリウム等のリン酸緩衝液が好ましい。また、2種以上のリン酸緩衝液を組み合わせて使用してもよい。 These buffering agents may be used alone or in combination of two or more. Among these buffers, phosphoric acid, trisodium phosphate, sodium hydrogen phosphate hydrate, dipotassium phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, anhydrous sodium monohydrogen phosphate, anhydrous A phosphate buffer such as sodium dihydrogen phosphate is preferred. Two or more phosphate buffer solutions may be used in combination.
　本発明の液剤において、液剤中のDOSSの割合は使用目的や投与回数、投与方法などに応じて適宜選択できるが、液剤の全質量に対して0.1～10重量部、好ましくは0.3～7重量部、さらに好ましくは5重量部程度の範囲から選択できる。 In the liquid preparation of the present invention, the proportion of DOSS in the liquid preparation can be appropriately selected according to the purpose of use, the number of administrations, the administration method, etc., but 0.1 to 10 parts by weight, preferably 0.3 to 7 parts by weight with respect to the total mass of the liquid preparation More preferably, it can be selected from the range of about 5 parts by weight.
　溶解補助剤の割合は、液剤の全質量に対して5～50重量部、好ましくは10～40重量部、さらに好ましくは15～30重量部程度（例えば、20～25重量部）の範囲から選択することができる。例えば2種の溶解補助剤を使用する場合には、一方の溶解補助剤100重量部に対して、他方の溶解補助剤の割合を例えば10～500重量部、好ましくは15～400重量部、さらに好ましくは25～300重量部、特に好ましくは25～150重量部程度の範囲とすることができる。具体的には、グリセリンなどの3価以上の多価アルコール100重量部に対して、プロピレングリコール等のジオールを5～50重量部、好ましくは10～40重量部、さらに好ましくは15～35重量部、特に好ましくは20～30重量部程度の範囲とすることができる。より具体的には、溶解補助剤としてグリセリン及び/又はプロピレングリコールを用いる場合には、液剤の全質量に対して20～30重量部程度、より好ましくは25重量部程度とすることができる。有効成分であるDOSS 100重量部に対して、溶解補助剤を100～1000重量部、好ましくは300～700重量部、さらに好ましくは400～600重量部、特に好ましくは450～550重量部程度で使用することができる。 The ratio of the solubilizing agent is selected from the range of 5 to 50 parts by weight, preferably 10 to 40 parts by weight, more preferably about 15 to 30 parts by weight (for example, 20 to 25 parts by weight) with respect to the total mass of the liquid agent. can do. For example, when two types of solubilizers are used, the ratio of the other solubilizer is, for example, 10 to 500 parts by weight, preferably 15 to 400 parts by weight, with respect to 100 parts by weight of one solubilizer. The range is preferably from 25 to 300 parts by weight, particularly preferably from about 25 to 150 parts by weight. Specifically, 5 to 50 parts by weight of a diol such as propylene glycol, preferably 10 to 40 parts by weight, more preferably 15 to 35 parts by weight with respect to 100 parts by weight of a trihydric or higher polyhydric alcohol such as glycerin. Particularly preferably, it can be in the range of about 20 to 30 parts by weight. More specifically, when glycerin and / or propylene glycol is used as a solubilizing agent, the amount can be about 20 to 30 parts by weight, more preferably about 25 parts by weight with respect to the total mass of the liquid agent. 100 to 1000 parts by weight, preferably 300 to 700 parts by weight, more preferably 400 to 600 parts by weight, particularly preferably about 450 to 550 parts by weight, of the solubilizing agent is used for 100 parts by weight of the active ingredient DOSS®. can do.
　緩衝剤の割合は長期保存後に液剤のpHが低下しないように使用する緩衝剤の種類に応じて適宜選択すべきであるが、一般的には、例えばリン酸緩衝剤を用いる場合などにおいては、DOSS 100重量部に対して5～1000重量部(例えば10～1000重量部)、好ましくは10～700重量部(例えば30～700重量部)、より好ましくは15～500重量部(例えば50～500重量部)、さらに好ましくは20～200重量部(例えば70～200重量部)、特に好ましくは20～35重量部程度の範囲から選択することができる。緩衝剤の量の選択にあたっては、例えば、液剤に緩衝剤を添加して60℃で数週間保存して、pHの低下が生じないような量を選択することができる。 The proportion of the buffer should be appropriately selected according to the type of buffer used so that the pH of the solution does not decrease after long-term storage, but in general, for example, when using a phosphate buffer, 5 to 1000 parts by weight (eg 10 to 1000 parts by weight), preferably 10 to 700 parts by weight (eg 30 to 700 parts by weight), more preferably 15 to 500 parts by weight (eg 50 to 500 parts by weight) per 100 parts by weight of DOSS Parts by weight), more preferably 20 to 200 parts by weight (eg 70 to 200 parts by weight), and particularly preferably about 20 to 35 parts by weight. In selecting the amount of the buffering agent, for example, the buffering agent can be added to the liquid agent and stored at 60 ° C. for several weeks to select an amount that does not cause a decrease in pH.
　本発明の液剤には、必要に応じて、水(精製又は無菌水、注射用蒸留水など)や生理食塩水、ブドウ糖液、水溶性有機溶媒(エタノール、イソプロパノールなどの低級脂肪族アルコールやエチレングリコール、ジエチレングリコール、ポリエチレングリコールなどのポリアルキレングリコール類など)、動植物系油剤(ホホバ油、オリーブ油、やし油、綿実油などの植物系油剤；スクアランなどの動物系油剤など)や鉱物系油剤(流動パラフィン、シリコーンオイルなど)、ワックス類(蜜ろう、カルナウバロウ、ラノリン、パラフィン、ワセリンなど)、長鎖脂肪酸エステル(飽和又は不飽和脂肪酸アルキルエステル、脂肪酸と多価アルコール(ポリＣ２－４アルキレングリコール、グリセリン又はポリグリセリンなど)とのエステルなど）、硬化油、高級アルコール(ステアリルアルコールなどの飽和脂肪族アルコール、オレイルアルコールなどの不飽和脂肪族アルコールなど)、高級脂肪酸(ステアリン酸、オレイン酸など)などを添加することもできる。さらに、防腐剤又は保存剤(メチルパラベン、ブチルパラベンなどのパラベン類など)、矯臭剤又は香料(メントールなどの芳香剤など)、清涼化剤、無痛化剤(リドカインなどの局所麻酔剤など)のほか、感染症や炎症に対する治療のための有効成分(抗菌剤、抗生物質、抗炎症剤など)を配合することもできる。これらの添加剤は単独で添加してもよいが、二種以上組み合わせて使用してもよい。 The liquid preparation of the present invention includes water (purified or sterile water, distilled water for injection, etc.), physiological saline, glucose solution, water-soluble organic solvents (ethanol, isopropanol and other lower aliphatic alcohols and ethylene glycol as necessary. , Polyalkylene glycols such as diethylene glycol and polyethylene glycol), animal and vegetable oils (vegetable oils such as jojoba oil, olive oil, palm oil and cottonseed oil; animal oils such as squalane) and mineral oils (liquid paraffin, Silicone oils), waxes (beeswax, carnauba wax, lanolin, paraffin, petrolatum, etc.), long chain fatty acid esters (saturated or unsaturated fatty acid alkyl esters, fatty acids and polyhydric alcohols (poly C2-4 alkylene glycol, glycerin or Polyglycerol, etc.) and esters), hydrogenated oil, high grade Alcohol (saturated aliphatic such as stearyl alcohol alcohols, and unsaturated fatty alcohols such as oleyl alcohol), higher fatty acids (stearic acid, oleic acid) and the like can also be added. In addition to preservatives or preservatives (such as parabens such as methyl paraben and butyl paraben), flavoring agents or fragrances (such as fragrances such as menthol), cooling agents, soothing agents (such as local anesthetics such as lidocaine). In addition, active ingredients (antibacterial agents, antibiotics, anti-inflammatory agents, etc.) for the treatment of infectious diseases and inflammation can be added. These additives may be added singly or in combination of two or more.
　本発明の液剤は上記成分を用いて混合、溶解、懸濁、又は乳化などの慣用の手段により製造することができ、一般的には粘稠な液剤として提供される。グリセリンとともにプロピレングリコールを用いることにより粘度を低下させて外耳道又は鼻腔内への適用に適した液剤を調製することもできる。 The liquid preparation of the present invention can be produced by conventional means such as mixing, dissolution, suspension, or emulsification using the above components, and is generally provided as a viscous liquid preparation. By using propylene glycol together with glycerin, it is possible to prepare a solution suitable for application to the ear canal or nasal cavity by reducing the viscosity.
　本発明の液剤は、外耳道又は鼻腔内に存在する異物(通常は耳垢や耳垢が固化したものなどのほか、外耳道に誤って取り込まれた人工物など)を除去するために用いられる。本発明の液剤の適用方法は特に限定されないが、一般的には外耳道又は鼻腔内に滴下(点耳)又は噴霧などの方法により投与するか、綿棒などで外耳に塗布することができる。耳垢は乾燥性又は粘稠性のいずれにも適用可能である。除去困難な耳垢の場合には、数滴を点耳してから5分～20分後に37℃程度の微温にて洗浄を行うことができる。また、高度の耳垢塞栓の場合には一日あたり数回、一日から数日にわたり連続点耳した後、37℃程度の微温湯での洗浄を行うこともできる。
　本発明の液剤は、ヒトのみならず、ヒト以外の哺乳類動物(マウス、ラット、ウサギ、イヌ、ネコ、ウシ、ウマ、ブタ、サルなど)に対しても使用できる。 The liquid preparation of the present invention is used to remove foreign substances existing in the ear canal or the nasal cavity (usually those in which the earwax or earwax has solidified, or an artificial product mistakenly taken into the ear canal). The application method of the liquid preparation of the present invention is not particularly limited, but in general, it can be administered by dropping (earing) or spraying into the ear canal or nasal cavity, or can be applied to the outer ear with a cotton swab or the like. Earwax can be applied either dry or viscous. In the case of earwax that is difficult to remove, it can be washed at a slight temperature of about 37 ° C. 5 to 20 minutes after instilling a few drops. In the case of advanced earwax embolism, it can be rinsed several times a day for several days to several days, and then rinsed with slightly warm water at about 37 ° C.
The liquid preparation of the present invention can be used not only for humans but also for mammals other than humans (mouse, rat, rabbit, dog, cat, cow, horse, pig, monkey, etc.).
　以下、実施例により本発明をさらに具体的に説明するが、本発明の範囲はこれらの実施例によって限定されるものではない。 Hereinafter, the present invention will be described more specifically by way of examples. However, the scope of the present invention is not limited by these examples.
試験例1
＜製剤化方法＞
　pH7.5の0.1mol/Lリン酸緩衝液に下表に示す濃度でDOSSおよびグリセリンを加えて、60～70℃に加温してDOSSを溶解し、水を加えて、液剤を製造した（表中の％は液剤中の濃度を示す）。 Test example 1
<Formulation method>
DOSS and glycerin were added to a 0.1 mol / L phosphate buffer solution at pH 7.5 at the concentrations shown in the table below, heated to 60-70 ° C. to dissolve DOSS, and water was added to produce a solution ( % In the table indicates the concentration in the solution).
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　例1及び例2(それぞれ比較例)と比較して、例3の液剤ではリン酸緩衝液を加えることによりpH及びDOSS含有量の低下が抑制されていた。緩衝剤として水酸化ナトリウムを加えた例4については、pHが例3と比較して低下していた。 As compared with Example 1 and Example 2 (respectively Comparative Examples), in the liquid preparation of Example 3, the decrease in pH and DOSS content was suppressed by adding a phosphate buffer. About Example 4 which added sodium hydroxide as a buffering agent, pH fell compared with Example 3.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　リン酸緩衝液の濃度について検討した結果、例3、例5、及び例6ではいずれもpH及びDOSS含有量の低下が顕著に抑制されていた。 As a result of examining the concentration of the phosphate buffer, in Examples 3, 5, and 6, the decrease in pH and DOSS content was remarkably suppressed.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　例10及び例11では例6と同様にpH及びDOSS含有量の低下が抑制されていた。緩衝剤としてトリエタノールアミンを用いた場合にもpH及びDOSS含有量の低下の抑制が顕著であった。 In Example 10 and Example 11, as in Example 6, the decrease in pH and DOSS content was suppressed. Even when triethanolamine was used as a buffering agent, the decrease in pH and DOSS content was markedly suppressed.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　プロピレングリコール及びリン酸緩衝液を配合した例12では、例6と比較して粘性が低下しており、外耳への投与が容易であった。また、この液剤は例6と比較してpH低下及びDOSS含有量の低下の抑制がさらに顕著であった。 In Example 12 containing propylene glycol and phosphate buffer, the viscosity was lower than that in Example 6, and administration to the outer ear was easy. Further, in this liquid preparation, the suppression of the decrease in pH and the decrease in the DOSS content was more remarkable than in Example 6.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　リン酸緩衝液0.05mol/Lの存在下においてグリセリン単独、プロピレングリコール単独、及びグリセリンとプロピレングリコールとの組み合わせを用いることにより、pH低下が顕著に抑制された。 By using glycerin alone, propylene glycol alone, or a combination of glycerin and propylene glycol in the presence of 0.05 mol / L of phosphate buffer, pH reduction was remarkably suppressed.
試験例2：安定性試験(加速試験)
　平成3年2月15日付薬発第165号安定性試験実施方法のガイドラインに従い、40℃、相対湿度75％の加速条件のもと、6ヶ月にわたりpHおよび含量の経時変化をみた。例18は例3と同様の方法にて製造した。 Test example 2: Stability test (acceleration test)
In accordance with the guidelines of the Yakuhin No. 165 stability test implementation method dated February 15, 1991, pH and content changes over time were observed over 6 months under accelerated conditions of 40 ° C and relative humidity of 75%. Example 18 was prepared in the same manner as Example 3.
　その結果、表6に示すとおり、溶解補助剤としてグリセリン及びプロピレングリコール、緩衝剤としてリン酸緩衝液(無水リン酸一水素ナトリウム及び無水リン酸二水素ナトリウム)を加えた例18では6ヶ月目においてもpH及び含量がまったく変化することがなく、例1(比較例)と比較して極めて安定な製剤であった。 As a result, as shown in Table 6, in Example 6 in which glycerin and propylene glycol were added as a solubilizing agent, and phosphate buffer (anhydrous sodium monohydrogen phosphate and anhydrous sodium dihydrogen phosphate) was added as a buffering agent. The pH and content did not change at all, and the preparation was extremely stable as compared with Example 1 (Comparative Example).
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006

Claims (8)

  1. 有効成分であるジオクチルソジウムスルホサクシネートを含む耳鼻科用液剤であって、溶解補助剤及び緩衝剤を含む液剤。 An otolaryngological solution containing dioctylsodium sulfosuccinate as an active ingredient, the solution containing a solubilizing agent and a buffer.
  2. 溶解補助剤が多価アルコールである請求項１に記載の液剤。 The solution according to claim 1, wherein the solubilizing agent is a polyhydric alcohol.
  3. 溶解補助剤がグリセリン、プロピレングリコール、又はそれらの組み合わせである請求項１又は２に記載の液剤。 The solution according to claim 1 or 2, wherein the solubilizer is glycerin, propylene glycol, or a combination thereof.
  4. 緩衝剤がアルカノールアミンである請求項１ないし３のいずれかに記載の液剤。 The liquid agent according to any one of claims 1 to 3, wherein the buffer is an alkanolamine.
  5. 緩衝剤がトリエタノールアミンである請求項１ないし４のいずれかに記載の液剤。 The liquid preparation according to any one of claims 1 to 4, wherein the buffer is triethanolamine.
  6. 緩衝剤がリン酸緩衝液である請求項１ないし３のいずれかに記載の液剤。 The liquid agent according to any one of claims 1 to 3, wherein the buffer is a phosphate buffer.
  7. 溶解補助剤がグリセリン及びプロピレングリコールの組み合わせであり、緩衝剤がリン酸緩衝液である請求項１に記載の液剤。 The solution according to claim 1, wherein the solubilizer is a combination of glycerin and propylene glycol, and the buffer is a phosphate buffer.
  8. 耳垢除去剤である請求項１ないし７のいずれか１項に記載の液剤。 The liquid preparation according to any one of claims 1 to 7, which is an earwax removing agent.
PCT/JP2015/055590 2014-02-26 2015-02-26 Dioctyl sodium sulfosuccinate otolaryngological solution WO2015129800A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2016505290A JPWO2015129800A1 (en) 2014-02-26 2015-02-26 Dioctyl sodium sulfosuccinate otolaryngological solution

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2014-035357 2014-02-26
JP2014035357 2014-02-26
JP2014-160603 2014-08-06
JP2014160603 2014-08-06

Publications (1)

Publication Number Publication Date
WO2015129800A1 true WO2015129800A1 (en) 2015-09-03

Family

ID=54009114

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2015/055590 WO2015129800A1 (en) 2014-02-26 2015-02-26 Dioctyl sodium sulfosuccinate otolaryngological solution

Country Status (2)

Country Link
JP (1) JPWO2015129800A1 (en)
WO (1) WO2015129800A1 (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58152809A (en) * 1982-03-05 1983-09-10 Eisai Co Ltd Stable foaming vaginal suppository
JPH0418018A (en) * 1990-05-10 1992-01-22 Senju Pharmaceut Co Ltd Aqueous solution
JPH09157157A (en) * 1995-12-01 1997-06-17 Pola Chem Ind Inc Medicine composition
JP2002519330A (en) * 1998-06-29 2002-07-02 ラボラトワール・ゴエマー・ソシエテ・アノニム Isoosmotic saline solution, method for producing the same, and earwax dissolving agent based on the solution
JP2007532490A (en) * 2004-04-08 2007-11-15 ダームケア−ヴェット ピーティーワイ リミテッド Antimicrobial compositions and methods for their use

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58152809A (en) * 1982-03-05 1983-09-10 Eisai Co Ltd Stable foaming vaginal suppository
JPH0418018A (en) * 1990-05-10 1992-01-22 Senju Pharmaceut Co Ltd Aqueous solution
JPH09157157A (en) * 1995-12-01 1997-06-17 Pola Chem Ind Inc Medicine composition
JP2002519330A (en) * 1998-06-29 2002-07-02 ラボラトワール・ゴエマー・ソシエテ・アノニム Isoosmotic saline solution, method for producing the same, and earwax dissolving agent based on the solution
JP2007532490A (en) * 2004-04-08 2007-11-15 ダームケア−ヴェット ピーティーワイ リミテッド Antimicrobial compositions and methods for their use

Also Published As

Publication number Publication date
JPWO2015129800A1 (en) 2017-03-30

Similar Documents

Publication Publication Date Title
DE602004002201T2 (en) DISPERSIBLE PHARMACEUTICAL COMPOSITION OF AN INFLAMMATORY HEATER
AU2011234492B2 (en) Thermogelling anaesthetic compositions
JP5616228B2 (en) Topical composition
JP2005523267A5 (en)
JP5113323B2 (en) Injectable pharmaceutical composition comprising diclofenac sodium and β-cyclodextrin
JP6538920B2 (en) Aqueous solution
BR0317104B1 (en) stable dispersible pharmaceutical composition comprising an antibacterial substance and article of manufacture containing said composition
KR20000048812A (en) Use of Mupirocin for the Manufacture of a Medicament for the Treatment of Bacterial Infections Associated with Colonisation of the Nasopharynx by Pathogenic Organisms
JP2011231082A (en) External preparation composition for pimple
JP2017519568A5 (en)
TW201350107A (en) Topical pharmaceutical compositions
US20140066481A1 (en) Water-Free Pharmaceutical Compositions Suitable for Local Anaesthetics
JP2017081902A (en) Oil-in-water emulsion composition
JP5176132B2 (en) Ophthalmic agent
JP6888180B1 (en) Pharmaceutical composition containing an antifungal drug as an active ingredient
JP2009073788A (en) Isopropyl unoprostone-containing ophthalmic composition
JP5682005B2 (en) Aqueous composition containing tranilast
WO2015129800A1 (en) Dioctyl sodium sulfosuccinate otolaryngological solution
JP2007169232A (en) Ophthalmic composition
JP5434981B2 (en) Eye drops
KR102482158B1 (en) gel composition for disinfection and manufacturing method thereof
JP2004238346A (en) Stable aqueous solution preparation of tranilast
JP2020002046A (en) External pharmaceutical composition
JP2007291073A (en) Nebulization pharmaceutical formulation for hemorrhoid
JP4961671B2 (en) Eye drops

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: 15754474

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2016505290

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15754474

Country of ref document: EP

Kind code of ref document: A1