WO2015132985A1 - Composition d'émulsion contenant du sévoflurane - Google Patents

Composition d'émulsion contenant du sévoflurane Download PDF

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Publication number
WO2015132985A1
WO2015132985A1 PCT/JP2014/073864 JP2014073864W WO2015132985A1 WO 2015132985 A1 WO2015132985 A1 WO 2015132985A1 JP 2014073864 W JP2014073864 W JP 2014073864W WO 2015132985 A1 WO2015132985 A1 WO 2015132985A1
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emulsion composition
sevoflurane
fatty acid
present
emulsion
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PCT/JP2014/073864
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English (en)
Japanese (ja)
Inventor
文由 石井
夏実 中川
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丸石製薬株式会社
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Priority to JP2014543710A priority Critical patent/JPWO2015132985A1/ja
Publication of WO2015132985A1 publication Critical patent/WO2015132985A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/08—Ethers or acetals acyclic, e.g. paraformaldehyde
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics

Definitions

  • the present invention relates to a sevoflurane-containing emulsion composition.
  • Sevoflurane is widely used as an inhalation anesthetic because it has a low blood / gas partition coefficient of 0.63 due to its fat solubility and volatility, and excellent anesthetic depth controllability can be obtained.
  • it is an inhalation anesthetic that has less respiratory tract irritation than other inhalation anesthetics and can be used to introduce and maintain anesthesia in children. Since intravenous anesthetics are directly administered intravenously, they are generally superior to inhaled anesthetics in terms of airway irritation, rapid induction of anesthesia, and the amount of drug itself used.
  • venous anesthetics do not require the vaporizer required for inhalation anesthetics, and can be managed with a BIS monitor at the depth of anesthesia, and are widely used for induction and maintenance of anesthesia and sedation during artificial respiration in intensive care. ing.
  • direct intravenous administration of volatile gas anesthetics to animals is often lethal, but it is known that fluoropolymer-based emulsions can be delivered intravenously as fluorinated anesthetic formulations ( Patent Document 1).
  • fluoropolymers are feared for carcinogenicity, and histamine releasing action and blood pressure lowering action have been reported.
  • emulsions using Intralipid which is known as the base of fat emulsions, have low solubility of sevoflurane, and a considerable amount of administration is required to obtain an anesthetic effect, and the development and maintenance of the anesthetic effect is achieved. Furthermore, there are still problems in practical use from the viewpoint of safety due to excessive administration of lipids.
  • An object of the present invention is to provide a sevoflurane-containing emulsion composition that is excellent in physical stability over time, has good safety, and can be applied to high concentrations.
  • the composition satisfies all of these conditions.
  • the product was not yet present due to its formulation difficulties.
  • the present inventors have formulated sevoflurane at a high concentration by incorporating hydroxyethyl starch (HES) into a sevoflurane-containing emulsion composition using fatty acid glycerides. And the physical stability over time can be ensured, and further research has been made based on this finding to complete the present invention.
  • HES hydroxyethyl starch
  • An emulsion composition comprising sevoflurane, fatty acid glyceride and hydroxyethyl starch.
  • the present invention can provide an emulsion composition having a small particle size, physical stability over time, and capable of preparing sevoflurane at a high concentration.
  • the emulsion composition of the present invention can be used as a venous anesthetic, and the onset of anesthesia of sevoflurane, that is, the induction of anesthesia is fast, and not only enables the introduction and maintenance of anesthesia with the composition alone,
  • anesthesia management can be performed only by monitoring sevoflurane concentration during expiration Useful.
  • the emulsion composition of the present invention uses HES, which is a plasma expander already used clinically, and has been confirmed to have no side effects such as edema, so it is safer than the prior art. It can be a highly potent formulation.
  • HES a plasma expander already used clinically, and has been confirmed to have no side effects such as edema, so it is safer than the prior art. It can be a highly potent formulation.
  • the emulsion composition of the present invention can be applied to high-concentration sevoflurane, and further has the advantage that the exposure amount of the base to the human body during clinical use can be reduced. Moreover, the emulsion composition of this invention has the effect which prevents also the change of the color tone with time by adding EDTA further.
  • FIG. 1 shows the particle diameter measurement result of the acceleration test of Example 1 emulsion.
  • FIG. 2 shows the particle size measurement results of the acceleration test of Example 1 and Example 2 emulsion.
  • FIG. 3 shows the color tone after 8 weeks in the accelerated emulsion test.
  • (A) shows the result of Example 1, and (b) shows the result of Example 2.
  • FIG. 4 shows the measurement results of the particle sizes at the time of preparation of the emulsions of Examples 1 to 5.
  • the emulsion composition of the present invention contains sevoflurane as an active ingredient.
  • Sevoflurane is produced by the method described in Japanese Patent Publication No. 53-04443, but sevoflurane having a different production method can also be used.
  • sevoflurane it is also possible to obtain a commercially available product. Examples of commercially available products include sevoflurane (registered trademark, manufactured by Maruishi Pharmaceutical Co., Ltd.).
  • the content of sevoflurane is not particularly limited, but is usually 1 to 30% by weight, preferably 13 to 27% by weight, particularly preferably 17 to 23% by weight, based on the entire composition.
  • the emulsion composition of the present invention may contain other active ingredients as long as the effects of the present invention are not impaired.
  • the active ingredient that can be used in combination may be any ingredient that is not contraindicated with sevoflurane.
  • the emulsion composition of the present invention contains a fatty acid glyceride.
  • the fatty acid species constituting the fatty acid glyceride are not particularly limited, and may be a single or plural fatty acid glycerides, or a combination of these plural fatty acid glycerides.
  • Examples of fatty acid glycerides include medium chain fatty acid (about 6 to 12 carbon atoms) monoglyceride, medium chain fatty acid diglyceride, medium chain fatty acid triglyceride, long chain fatty acid (14 to 22 carbon atoms) monoglyceride, long chain fatty acid diglyceride, long chain fatty acid triglyceride and the like.
  • medium chain fatty acid monoglyceride, medium chain fatty acid diglyceride and medium chain fatty acid triglyceride are preferable, and medium chain fatty acid triglyceride is more preferable.
  • the content of the fatty acid glyceride is not particularly limited as long as the effect of the present invention is not hindered, but is usually 2 to 20% by weight, preferably 5 to 15% by weight, particularly preferably 7 to 13% by weight.
  • the fatty acid glyceride can be produced by a known method, and commercially available products such as Coconut (registered trademark) RK (Kao Corporation) and Panacet (registered trademark, NOF Corporation) can be obtained.
  • Hydroxyethyl starch The emulsion composition of the present invention contains hydroxyethyl starch (HES), which makes it possible to provide an emulsion composition that ensures physical stability over time.
  • HES hydroxyethyl starch
  • the molecular weight of hydroxyethyl starch (HES) is not particularly limited, and any of low molecular weight (about 50,000 to 100,000), medium molecular weight (about 130,000 to 390,000), and high molecular weight (about 400,000 to 600,000) is suitable. However, it is preferably about 50,000 to 100,000, more preferably about 70,000.
  • hydroxyethyl starch is not particularly limited as long as the effect of the present invention is not hindered, but is usually 0.1 to 5.0% by weight, preferably 0.2 to 3% based on the entire composition. 0.0 wt%, particularly preferably 0.7 to 2.0 wt%.
  • Hydroxyethyl starch (HES) can be produced by a known method, and commercially available products such as Sarinjes (registered trademark) infusion 6% (Fresenius Kirby Japan) 500 mL can also be obtained.
  • the formulation carrier is suitably blended in the emulsion composition of the present invention as necessary.
  • the pharmaceutical carrier include solvents, solubilizers, emulsifiers, tonicity agents, soothing agents and the like.
  • any known additive or pharmacologically acceptable additive usually used in the pharmaceutical field such as a stabilizer, a preservative, and an antioxidant can be used as necessary.
  • the solvent is not particularly limited, and examples thereof include purified water, ethanol, propylene glycol, polyethylene glycol, macrogol, and edible oil (sesame oil, corn oil, olive oil, etc.).
  • the solubilizing agent is not particularly limited, and examples thereof include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • the emulsifier is not particularly limited.
  • quaternary ammonium salts benzalkonium chloride, benzethonium chloride, etc.
  • carmellose hydroxypropylcellulose, propylene glycol, polyvinylpyrrolidone, methylcellulose, glyceryl monostearate, polyvinyl alcohol, Lecithin (egg yolk lecithin, soybean lecithin), deoxycholic acid, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitan monooleate (polysorbate 80), poly monolaurate poly Examples include oxyethylene sorbitan, lecithin is preferable, and egg yolk lecithin is more preferable.
  • the content of egg yolk lecithin is preferably 0.1 to 3.0% by weight, more preferably 0.5 to 2.0% by weight, and 1.0 to 1.5% by weight based on the whole emulsion composition. Particularly preferred.
  • the isotonizing agent is not particularly limited, and examples thereof include glucose, D-sorbitol, sodium chloride, D-mannitol, glycerin and the like, and glycerin is preferable.
  • the content of glycerin is determined by calculating the amount to be isotonic with respect to the whole emulsion composition.
  • the stabilizer is not particularly limited, and examples thereof include EDTA, sodium oleate, casein, and sodium caseinate.
  • EDTA is preferable because it has an effect of suppressing a change in the color tone of the emulsion composition, and oleic acid Na is preferable because of its surface-active action and atomization effect, but EDTA is particularly preferable.
  • Examples of EDTA include EDTA-2Na and EDTA-4Na.
  • the content of EDTA is preferably 0.001 to 0.1% by weight, more preferably 0.001 to 0.01% by weight, and particularly preferably 0.001 to 0.006% by weight, based on the entire emulsion composition. preferable.
  • preservatives include, but are not limited to, for example, paraoxybenzoic acid esters (ethyl paraoxybenzoate, methyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate), chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid Etc. Although it does not specifically limit as an antioxidant, For example, sodium sulfite, ascorbic acid, etc. are mentioned.
  • antioxidants examples include t-butylhydroquinone, butylhydroxyanisole, butylhydroxytoluene, L-cysteine hydrochloride, sodium bisulfite and ⁇ -tocopherol, polyphenol, ascorbic acid and derivatives thereof.
  • the emulsion composition of the present invention can be used singly or in combination of two or more, depending on the intended preparation form. These can use a commercial item.
  • the content thereof is preferably from 0.01 to 97.00% by weight, more preferably from 10 to 80% by weight, and more preferably from 65 to 75% by weight based on the whole emulsion composition. Particularly preferred. If it is the range of the said content, while being able to fully exhibit the effect
  • the emulsion composition of the present invention is a preferred embodiment that includes, in addition to sevoflurane, fatty acid glycerides, and hydroxyethyl starch (HES), one or more selected from the group consisting of EDTA, reticin and glycerin.
  • HES hydroxyethyl starch
  • the emulsion composition of the present invention is produced , for example, by adding each component other than sevoflurane and fatty acid glyceride to purified water and stirring, further adding sevoflurane and fatty acid glyceride and stirring, and then homogenizing. Can do.
  • the emulsion composition of the present invention may be either W / O type or O / W type, but the O / W type is preferred.
  • Sevoflurane is usually contained in the oil phase. Thereby, the effect
  • the pH of the emulsion composition of the present invention may be within the range normally used as the pH of injections, but among them, about 4 to 7 is preferable, and about 4.5 to 6.5 is more preferable.
  • the emulsion composition of the present invention is obtained when the average particle size of emulsion particles immediately after production and after 4 weeks is measured by a laser Doppler method, for example, when stored at ordinary temperature (range of 15 to 25 ° C.) or under heating and humidification.
  • the increase in average particle diameter over time under accelerated conditions is about 70 to 110 nm.
  • the emulsion composition of the present invention is white brown or slightly yellowish white to bluish white, and preferably white to bluish white.
  • the emulsion composition of the present invention is safe and has low toxicity, for example, for humans and other mammals (for example, rats, mice, rabbits, sheep, pigs, cows, cats, dogs, monkeys, etc.) Can be administered.
  • the dose varies depending on the administration subject, target organ, symptom, administration method and the like. For example, in the case of an injection, it is usually about 0.01 to 30 mg, preferably about 0.1, per day in a human body weight of about 60 kg, for example. It is convenient to administer about 1 to 20 mg, more preferably about 0.1 to 10 mg by a known intravenous administration method.
  • the total daily dose may be a single dose or divided doses.
  • the method of intravenous administration can be varied by those skilled in the art to maximize the therapeutic effect of sevoflurane.
  • the anesthetic effect of sevoflurane contained in the emulsion composition of the present invention can be confirmed by examining whether or not the subject or the animal under test is stimulated to feel pain.
  • the following two methods can be used for the test animals.
  • LORR loss of righting reflex
  • the rat is placed on its back and anesthesia is not returned. It is considered effective.
  • the tail clamp method confirms the response to painful stimuli when the rat ridge is pinched with a clamp (forceps) after the specular reflex disappears due to the administration of the emulsion composition. If no response is seen, such as biting, it is considered as a loss of pain.
  • LORR LORR
  • an anesthetic state is recognized.
  • the tail clamp method is performed on the test animals after the positive OROR, and if the analgesia is observed, it is recognized as a stronger anesthesia state.
  • the blood concentration of sevoflurane can be measured, for example, by gas chromatography.
  • the concentration of anesthetic agent in exhaled breath can be measured by a general method performed with an inhaled anesthetic agent, and the depth of anesthesia can be easily confirmed and controlled.
  • the present invention includes embodiments in which the above configurations are combined in various ways within the technical scope of the present invention as long as the effects of the present invention are exhibited.
  • Example 2 Production of emulsion composition of Example 2 Example 1 except that EDTA-2Na was further added to 0.003 (w / v)% with respect to the whole emulsion composition in Step 1 of Example 1. As well as.
  • Example 3 Production of emulsion composition of Example 3 Example 1 except that EDTA-2Na was further added to 0.01 (w / v)% with respect to the whole emulsion composition in Step 1 of Example 1. As well as.
  • Example 4 Production of emulsion composition of Example 4 Example 1 except that EDTA-2Na was further added to 0.04 (w / v)% with respect to the whole emulsion composition in Step 1 of Example 1. As well as.
  • Example 5 Production of emulsion composition of Example 5 Example 1 except that EDTA-2Na was further added to 0.10 (w / v)% with respect to the whole emulsion composition in Step 1 of Example 1. As well as.
  • Example 1 Production of emulsion composition of Comparative Example 1 The same procedure as in Example 1 was conducted, except that dextran 40 (Tokyo Chemical Industry Co., Ltd.) was used instead of hydroxyethyl starch (HES).
  • dextran 40 Tokyo Chemical Industry Co., Ltd.
  • HES hydroxyethyl starch
  • Example 1 (6-1) ED50 value, LD50 value
  • ED50 50% effective dose
  • the emulsion composition of Example 1 was administered into the tail vein of SD male rats weighing approximately 200 g. confirmed.
  • 9 rats per group 9 rats per group were used, and 6 dose groups of 0.40, 0.45, 0.50, 0.56, 0.63, and 0.71 mL / kg were set and 1 mL / kg was set.
  • the ED50 value using disappearance of right-angled reflection as an index was 0.47 mL / kg
  • the ED50 value by tail clamp method using disappearance of pain sensation as an index was 0.53 mL / kg.
  • the 50% lethal dose was also calculated by administering the emulsion composition of Example 1 to rats.
  • LD50 quantification 6 rats per group were used, and 7 dose groups of 0.95, 1.00, 1.06, 1.12, 1.19, 1.26 and 1.33 mL / kg were set. And administered at 1 mL / min. As a result, the LD50 value was 1.12 mL / kg. Both the ED50 value and the LD50 value were calculated using the probit method.
  • the emulsion composition of the present invention is useful as a intravenous anesthetic containing sevoflurane as an active ingredient.
  • the emulsion composition of the present invention has a rapid introduction of anesthesia, and in particular, when the same drug (sevoflurane) is used in combination with an inhalation anesthetic, and in addition, when sevoflurane during anesthesia or when it is desired to increase the depth of anesthesia, It is useful in that it can be monitored by measuring the concentration and is easy to follow.

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  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

La présente invention concerne une composition d'émulsion ayant une excellente stabilité physique dans le temps et une sécurité appropriée, qui est utilisable dans des applications d'augmentation de concentration, et caractérisée par l'inclusion de sévoflurane, d'un glycéride d'acide gras, et d'un hydroxyéthyl amidon.
PCT/JP2014/073864 2014-03-03 2014-09-10 Composition d'émulsion contenant du sévoflurane WO2015132985A1 (fr)

Priority Applications (1)

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JP2014543710A JPWO2015132985A1 (ja) 2014-03-03 2014-09-10 セボフルラン含有エマルション組成物

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JP2014-040857 2014-03-03

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018164121A1 (fr) 2017-03-06 2018-09-13 丸石製薬株式会社 Composition d'émulsion acide contenant un agent anesthésique local

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003520769A (ja) * 1999-05-27 2003-07-08 アボット・ラボラトリーズ 注射可能な麻酔製剤
JP2007520555A (ja) * 2004-02-05 2007-07-26 バクスター・インターナショナル・インコーポレイテッド 自己安定化剤の使用により調製された分散剤
WO2011145660A1 (fr) * 2010-05-21 2011-11-24 富士フイルム株式会社 Composition d'émulsion d'huile dans l'eau contenant du propofol
JP2013001700A (ja) * 2011-06-21 2013-01-07 Fujifilm Corp プロポフォール含有水中油型エマルション組成物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003520769A (ja) * 1999-05-27 2003-07-08 アボット・ラボラトリーズ 注射可能な麻酔製剤
JP2007520555A (ja) * 2004-02-05 2007-07-26 バクスター・インターナショナル・インコーポレイテッド 自己安定化剤の使用により調製された分散剤
WO2011145660A1 (fr) * 2010-05-21 2011-11-24 富士フイルム株式会社 Composition d'émulsion d'huile dans l'eau contenant du propofol
JP2013001700A (ja) * 2011-06-21 2013-01-07 Fujifilm Corp プロポフォール含有水中油型エマルション組成物

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018164121A1 (fr) 2017-03-06 2018-09-13 丸石製薬株式会社 Composition d'émulsion acide contenant un agent anesthésique local
KR20190121752A (ko) 2017-03-06 2019-10-28 마루이시세이야쿠가부시키가이샤 국소마취약 함유 산성 에멀션 조성물

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