WO2002087572A1 - Preparations de solutions contenant un derive triazole - Google Patents

Preparations de solutions contenant un derive triazole Download PDF

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Publication number
WO2002087572A1
WO2002087572A1 PCT/JP2002/004246 JP0204246W WO02087572A1 WO 2002087572 A1 WO2002087572 A1 WO 2002087572A1 JP 0204246 W JP0204246 W JP 0204246W WO 02087572 A1 WO02087572 A1 WO 02087572A1
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WO
WIPO (PCT)
Prior art keywords
triazole derivative
solution preparation
acid
salt
surfactant
Prior art date
Application number
PCT/JP2002/004246
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English (en)
Japanese (ja)
Inventor
Katunori Sato
Emi Hashimoto
Original Assignee
Nippon Kayaku Kabushiki Kaisha
Ssp Co., Ltd.
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 Nippon Kayaku Kabushiki Kaisha, Ssp Co., Ltd. filed Critical Nippon Kayaku Kabushiki Kaisha
Publication of WO2002087572A1 publication Critical patent/WO2002087572A1/fr

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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
    • A61K9/08—Solutions
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the present invention relates to a solution preparation of a triazole derivative which is useful as an antifungal agent for deep mycosis.
  • Deep mycosis is a fatal disease for immunosuppressed patients such as cancer, organ transplants, and acquired immunodeficiency syndrome, and is increasing in recent years.
  • Japanese Patent Application Laid-Open No. H11-24071 discloses that the triazole derivative SS750 has an excellent antibacterial activity against fungi including Aspergillus and Candida compared to known similar compounds. It is disclosed that the seaweed is highly secure.
  • the publication discloses an injection as a solution formulation.
  • Examples include hydrogenated castor oil, propylene glycol, glucose, and distilled water for injection as a carrier.
  • the injection solution designated as L is described.
  • the hardened castor oil contained in the preparation of the injection disclosed in Japanese Patent Application Laid-Open No. H11-240871 does not dissolve in water, and can be dissolved and emulsified in the formulation of Example. Was unsuitable.
  • the solubility of the triazole derivative SS750 in water at 25 ° C is as small as about 0.5 mg / mL, and a high-concentration solution preparation has not been obtained by the conventional method.
  • an injection having a concentration of 10 mg L or more is preferred.
  • oils and fats and organic solvents are generally used.
  • the use of poorly water-soluble fats and organic solvents requires special emulsification techniques. There is a problem that it cannot be easily manufactured by the method.
  • a water-soluble organic solvent is used, there is a problem that the drug precipitates out when mixed with an infusion solution.
  • the additive is also highly safe, stable for a long period of time, and 10 mg
  • a propellant that can be produced by a conventional method with a concentration of at least mL (lw / v% or more) and appropriate viscosity.
  • the present inventors have conducted intensive studies with the aim of obtaining a clinically applicable and easy-to-use formulation of the triazole derivative SS750 or a salt thereof as an injection or the like, and as a result, a high-concentration solution formulation using a surfactant and alcohol as a solvent.
  • a surfactant and alcohol as a solvent.
  • the addition of an acidic substance can withstand the heat load in the manufacturing process such as heat dissolution, high-pressure steam sterilization, and the like, and obtain a solution preparation with further improved storage stability, and completed the present invention. That is, the present invention relates to the following (1) to (16).
  • Triazole derivative SS 750 (Chemical name: 2- (2,4-difluoropheninole) -1-1- (Ethylsulfonyl) -1-1,1-difluoro-3 _ (1H-1,2,4-triazole-1 Solution preparation of tritriazole derivative containing 1-f)-2-propanol) or its salt, surfactant and alcohol.
  • Triazole derivative SS750 or 100 parts by weight of a salt thereof contains 300 to 4,000 parts by weight of a surfactant and 200 to 5,000 parts by weight of alcohol.
  • the surfactant is at least one surfactant selected from polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oils and polyoxyethylene polyoxypropylene glycols.
  • the surfactant is at least one surfactant selected from polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oils and polyoxyethylene polyoxypropylene glycols.
  • Triazole derivative SS 750 or its salt ! ⁇ 25 w / v% polysorbate 80 or polyoxyethylene castor oil 10 ⁇ 80 w / v% ethanol;! ⁇ 70 w / v% water balance
  • Triazole derivative SS750 or a salt thereof ! ⁇ 25 w / v% polysorbate 80 or polyoxyethylene castor oil 10 ⁇ 80 wZvO / o Etanomono:! ⁇ 70 w / v% cunic acid, phosphoric acid, Maleic acid or hydrochloric acid 0;; ⁇ 12 w / V% Water balance
  • the triazole derivative SS750 used in the present invention has a chemical name of 2- (2,4-diphenolophenyl) 1-1- (ethylsulfonyl) 1,1-difluoro-3- (1H-1,2,4triazole). 1_yl) — 2-propanol, which can be obtained by the production method described in Japanese Patent Application Laid-Open No. H11-240871.
  • the salt of the triazole derivative SS750 is not particularly limited as long as it is a pharmacologically acceptable salt. As the pharmacologically acceptable salt, an acid addition salt is preferable.
  • acid addition salts include inorganic acid salts such as hydrochloride, nitrate, and hydrobromide, and organic acids such as p-toluenesulfonate, methanesulfonate, fumarate, succinate, and lactate. Acid salts.
  • the triazole derivative SS750 used in the present invention and its salt have stereoisomers based on asymmetric carbon atoms, and the present invention includes these stereoisomers and a mixture of isomers such as racemic isomers. Is done. Further, the triazole derivative SS750 or a salt thereof may exist in the form of a solvate represented by a hydrate. In these, these are also included.
  • the solution preparation refers to a liquid preparation for internal use, a liquid preparation for external use, and an injection.
  • injectables include forms such as intravenous injection, including intravenous dilution, intramuscular injection and subcutaneous injection.
  • Liquid preparations for internal use include those in the form of syrups, elixirs, sprays and the like.
  • the liquid for external use includes a lotion, a spray and the like.
  • the liquid preparation for internal use and the liquid preparation for external use can be applied to the solution preparation of the present invention as it is or by adding appropriate additives.
  • the injection can be applied by sterilizing the solution preparation of the present invention, filling in vials or ampoules, and sealing. If necessary, it can be applied after sterilization such as high pressure steam sterilization after filling and sealing. In the present invention, it is preferably applied as an injection.
  • the effective dose of the triazole derivative SS750 depends on the age and weight of the individual being treated, the fungus infected and the symptoms, but is usually 1% for adults.
  • administration of 100 to 1000 mg, preferably 40 to 30 Omg is required.
  • the mixing ratio of the triazole derivative SS 750 or a salt thereof in the solution formulation is 1 wZv% or more, preferably 2 wZvO / o or more, more preferably 4 wZv% or more, and the upper limit is 25 w / vo / o or less, preferably 15 wZv% or less, more preferably 8 w / v% or less.
  • any surfactant can be used as long as it is a nonionic surfactant and can be dissolved in alcohol.
  • polyoxyethylene sorbitan fatty acid esters (generic names: polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, etc.), natural fats and oils, and polyoxyethylene which is a polyoxyethylene derivative of liposomes Ethylene castor oils (trade names: Cremo Fornore RH40, Cremo Fornore RH60, Cremo Fornole EL (all manufactured by BPSF), etc.), polyoxyethylene polyoxypropylene glycols (generic name: Poloxamer 1) 88 etc.), alone or multiple It can be used in combination. More preferred are polysorbate 80 or polyoxyethylene castor oil, which is a polyoxyethylene sonorevitan fatty acid ester.
  • the mixing ratio of the surfactant is desirably set variously in accordance with the dose of the triazole derivative SS750 or a salt thereof.
  • the mixing ratio of the surfactant is 10 wZV% or more, preferably 20 wZv% or more, more preferably 3 OwZv% or more, based on the total amount of the preparation, and the upper limit is 80 w / v. % Or less, preferably 70 wZ v% or less, more preferably 60 wZ v% or less.
  • the alcohol lower alcohols and polyethylene dalicols can be used.
  • As the lower alcohol a chain alcohol having 1 to 5 carbon atoms can be used.
  • polyethylene glycols preference is given to ethanol, glycerin and propylene glycol.
  • polyethylene dalicols any polyethylene glycols can be used as long as they are liquid.
  • Injections are usually used in the solution preparation of the present invention by diluting with an aqueous phase at the time of use.
  • physiological saline physiological saline, glucose injection, fructose injection, maltose injection, xylitol injection, sorbitol injection, fructose mannitol injection, Ringer's solution, dextran injection, high Dilute and administer to the aqueous phase such as the basic solution for caloric infusion and the infusion such as water.
  • ethanol is most preferred as the alcohol for the purpose of reducing the viscosity of the solution, making it easier to withdraw with a syringe needle, improving the usability, and suppressing the foaming property upon dilution.
  • the mixing ratio of the alcohol be variously set according to the dose of the triazole derivative SS750 or a salt thereof and the type and amount of the surfactant, for example, 1 wZ v O / o with respect to the total amount of the preparation.
  • the above is more preferably 20 wZv O / o or more, and the upper limit is 70 wZv% or less, more preferably 60 w / v% or less.
  • Injectables can be manufactured by aseptic procedures, but terminal sterilization is preferred. Good.
  • the triazole derivative SS 750 or its salt is thermally unstable in solution, and most of it decomposes under normal high-pressure steam sterilization at 121 ° C for 20 minutes.
  • 1,2-elimination reaction was initiated by proton extraction with a base catalyst.
  • the stability is drastically improved by adding an acidic substance, and the stability is maintained even after autoclaving. I found out.
  • an inorganic acid or an organic acid may be used, and furthermore, a salt showing such acidity may be used.
  • the addition of these acidic substances is usually one kind, but two or more kinds may be used in combination.
  • the inorganic acid include phosphoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and nitric acid.
  • the organic acid include citric acid, maleic acid, acetic acid, lactic acid, oxalic acid, malonic acid, succinic acid, and fumaric acid.
  • carboxylic acids such as tartaric acid
  • sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid
  • amino acids such as aspartic acid and glutamic acid.
  • the most preferred acidic substance for use in the present invention is phosphoric acid, citric acid, maleic acid or hydrochloric acid. The more acidic substance is added, the more the decomposition can be suppressed under severe conditions.However, it is physiologically unfavorable that the diluted solution used for clinical use is extremely acidic.
  • the total amount of the preparation is at least 0.1 wZv%, preferably at least 0.2 wZv%, more preferably at least 0.4 wZv%, and the upper limit thereof is at most 12 w / v%, preferably at most 8 wZv%, more preferably Is less than 4 wZv%. That is, when diluted with an infusion solution having no buffering capacity, such as distilled water for injection or physiological saline, the pH is 2 or more, preferably 3 or more.
  • water is preferably not added because it is a poor solvent for the triazole derivative SS 750 or a salt thereof, but water may be added in a small amount.
  • the upper limit is 60% or less, preferably 20% or less, based on the total amount.
  • the compounding ratio of the solution preparation of the triazole derivative SS 750 or a salt thereof according to the present invention is as follows.
  • Surfactant generally 300 parts by weight or more, preferably 500 parts by weight or more, more preferably 650 parts by weight or more, and the upper limit is generally 4000 parts by weight or less, preferably 2000 parts by weight or less. Preferably it is 1000 parts by weight or less.
  • the amount is from 00 to 2,000 parts by weight, and more preferably from 650 to 1,000 parts by weight.
  • Alcohol generally at least 200 parts by weight, preferably at least 700 parts by weight, the upper limit of which is generally at most 5,000 parts by weight, preferably at most 2,000 parts by weight.
  • Acidic substance When an acidic substance is further added, it is generally at least 2 parts by weight, preferably at least 5 parts by weight, more preferably at least 10 parts by weight, and the upper limit is generally at most 200 parts by weight.
  • an acidic substance is generally at least 2 parts by weight, preferably at least 5 parts by weight, more preferably at least 10 parts by weight, and the upper limit is generally at most 200 parts by weight.
  • the amount is generally 2 to 200 parts by weight, preferably 5 to 100 parts by weight, and more preferably 10 to 50 parts by weight.
  • it is 1 w / v% or more, preferably 2 wZvO / o or more, more preferably 4 wZV% or more, and the upper limit is generally 25 w / v% or less, preferably 15 w / v% or less. / V% or less, more preferably 8 w / v% or less.
  • Surfactant Generally, 10 wZv% or more, preferably 20 w / v% or more, more preferably 3 OwZvO / o or more, and the upper limit is generally 80 w / v% or less, preferably 70 w / v% or less. v% or less, more Preferably it is 60 wZv% or less.
  • Alcohol generally 1 wZv% or more, preferably 20 wZv% or more, and its upper limit is generally 70 wZv% or less, preferably
  • it is generally 1 to 70 w / v%, preferably 20 to 60 wZv%.
  • Acidic substance When an acidic substance is further added, it is generally at least 0.1 lw / v%, preferably at least 0.2 V%, more preferably at least 0.2 v%.
  • the solution preparation of the present invention is an injection
  • the injection can be produced by an ordinary method without employing any special method. That is, for example, a surfactant and an alcohol are mixed, an acidic substance is added as necessary, then a triazole derivative SS750 or a salt thereof is added, and the mixture is dissolved with heating if necessary. If necessary, add distilled water for injection and mix. The solution is then sterilized by filtration, filled into vials or ampoules, sealed, and formulated. If necessary, sterilize by high-pressure steam to prepare a preparation.
  • a solution preparation of the triazole derivative SS750 or a salt thereof can be formulated into an injection, an internal liquid and an external liquid, and in the case of an internal liquid and an external liquid, in addition to the above components, In addition, flavoring agents, sweetening agents, fragrances and preservatives can be added.
  • the method for producing the liquid preparation for internal use and the liquid preparation for external use of the present invention can be prepared by an ordinary method without employing a special method. That is, for example, a surfactant and an alcohol are mixed, and if necessary, an acidic substance such as citric acid is added. Add the derivative SS750 or a salt thereof and dissolve with heating if necessary. If necessary, add preservatives such as methyl paraoxybenzoate and propyl paraoxybenzoate. Add a flavoring agent such as lemon essence and make up to the total volume with water for injection. Fill the appropriate container according to the application and stopper. In addition, high-pressure steam sterilization is performed if necessary.
  • 3 g of the triazole derivative (SS750) was dissolved in a mixed solution of 20 g of polysorbate 80 and 30 mL (24 g) of ethanol to make a total volume of about 50 mL. After sterilizing by filtration with a 0.2 / m membrane filter, the vial was filled with 5 mL and sealed. An injection having a triazole derivative concentration of about 60 mg / mL was obtained.
  • 3 g of the triazole derivative (SS 750) was added to a mixed solution of polysorbate 802 Og, 30 mL of ethanol (24 g) and 0.3 g of citric acid and dissolved, and about 1 OmL of water for injection was added. OmL was used. After sterilizing by filtration with a 0.2 // m membrane filter, the vial was filled with 6 mL and sealed. An injection with a triazole derivative concentration of 50 mg L was obtained.
  • 3 g of the triazole derivative (SS750) was added to a mixed solution of 20 g of polysorbate 80, 30 mL (24 g) of ethanol, and 200 mg of maleic acid, and dissolved to a total volume of about 50 mL. After sterilization by filtration through a 0.2 ⁇ m membrane filter, 5 mL of the vial was filled and sealed. An injection having a triazole derivative concentration of about 60 mg / mL was obtained.
  • 0.5 g of the triazole derivative (SS750) was dissolved in a mixed solution of 800 g of polysorbate, 20 mL (16 g) of ethanol and 0.3 g of citric acid, and then about 2 OmL of water for injection was added. The total volume was 5 OmL. After sterilization by filtration with a 0.2 ⁇ membrane filter, the vial was filled with 5 mL, sealed, and subjected to high-pressure steam sterilization. An injection with a triazole derivative concentration of 10 mg L was obtained.
  • 6.4 g of the triazole derivative (SS750) was added to a mixed solution of 20 g of polysorbate 80, 2 OmL (16 g) of ethanol and 85 Omg of phosphoric acid, and dissolved to make a total volume of about 40 mL. After sterilization by filtration through a 0.2 / m membrane filter, 4 ml of the noial was filled, sealed, and subjected to high-pressure steam sterilization. An injection with a triazonole derivative concentration of about 160 mg / mL was obtained.
  • 3 g of the triazole derivative (SS750) was dissolved in a mixed solution of 20 g of polyoxyethylene castor oil and 30 mL (24 g) of ethanol to make the total amount about 5 OmL. After sterilization by filtration with a 0.2 ⁇ membrane filter, the vial was filled with 5 mL and sealed. An injection having a triazole derivative concentration of about 60 mg ZmL was obtained.
  • 3 g of the triazole derivative (SS750) was dissolved in a mixed solution of 60 20 g of polyoxyethylene hydrogenated castor oil and 3 OmL (24 g) of ethanol to make the total amount about 5 OmL. After sterilization by filtration through a 0.2-m membrane filter, the vial was filled with 5 mL and sealed. An injection with a triazole derivative concentration of about 60 mg L was obtained. Was.
  • 3 g of the triazole derivative (SS750) was dissolved in a mixed solution of 20 g of poloxamer 188 and 30 mL (24 g) of ethanol, and the total amount was adjusted to about 50 mL. 0.2; After sterilizing by filtration with a um membrane filter, the vial was filled with 5 mL and sealed. An injection having a triazole derivative concentration of about 60 mg ZmL was obtained.
  • Triazole derivative Syrup preparation with SS750 concentration of 1 SmgZmL is obtained.
  • the solubility and the viscosity were also excellent and were judged to be B or more.
  • the combination in which the alcohol is ethanol is a triazole derivative SS750 solution that enables a high dose of the determination A in a preferable mixing ratio even when water or an acidic substance is added. Obtained.
  • the triazole derivative (SS750) 0.6 mg / mL diluted solution was prepared from the solution preparations of the present invention in Examples 3 and 4 using 500 mL of physiological saline (infusion), and 25 The solution was stored at 24 ° C for 24 hours, and the appearance was observed to confirm the presence or absence of crystal precipitation. The results are shown in Table 2.
  • the solution formulation of the triazole derivative SS750 of the present invention was stable without crystal precipitation even after dilution by infusion as an injection.
  • Example 3 Clear and colorless, no crystal precipitation Clear and colorless, no crystal precipitation Example 4 Clear and colorless, no crystal deposition Clear and colorless, no crystal precipitation
  • Table 3 shows the results.
  • the solution formulation of the triazonole derivative SS750 of the present invention was stable for a long time under an environment of 40 ° C. or less without adding an acidic substance.
  • Example 4 100. 0% 100. 2% (1 20 minutes)
  • the solution formulation of the triazole derivative SS750 of the present invention is a high-concentration formulation excellent in solubility, viscosity, etc., and also has storage stability and stability under high temperature conditions. The nature is enough. Furthermore, even when diluted with an infusion solution or the like during use as an injection, no crystal precipitation occurs, and a product that can be applied clinically has been provided.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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Abstract

L'invention concerne des préparations de solutions contenant un dérivé triazole SS750 ou un sel de ce dérivé pouvant servir d'agent antifongique contre une mycose profonde, ainsi qu'un tensioactif, un alcool et de préférence une substance acide. Lesdites préparations peuvent être cliniquement employées, sont faciles d'utilisation et présentent une excellente stabilité à la chaleur.
PCT/JP2002/004246 2001-04-27 2002-04-26 Preparations de solutions contenant un derive triazole WO2002087572A1 (fr)

Applications Claiming Priority (2)

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JP2001-130677 2001-04-27
JP2001130677A JP2002322056A (ja) 2001-04-27 2001-04-27 トリアゾール誘導体の溶液製剤

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WO2002087572A1 true WO2002087572A1 (fr) 2002-11-07

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JP6086539B2 (ja) * 2010-12-16 2017-03-01 プラットフォーム ブライトワークス トゥー， リミテッド 非経口投与のためのアゾール医薬製剤ならびにその調製方法およびアゾール化合物に対して感受性の疾患の処置としてのその使用方法
CN103635179B (zh) 2011-04-28 2017-12-29 普拉福姆五金器具第二有限公司 亲脂性药剂的改进的胃肠外制剂以及制备和使用其的方法
UY36570A (es) * 2015-02-26 2016-10-31 Merial Inc Formulaciones inyectables de acción prolongada que comprenden un agente activo isoxazolina, métodos y usos de las mismas

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0927719A1 (fr) * 1997-12-26 1999-07-07 SSP Co., Ltd. Dérivés de triazole et leurs sels, leurs procédés de préparation et compositions pharmaceutiques les contenant
JP2000063363A (ja) * 1998-08-12 2000-02-29 Yamanouchi Pharmaceut Co Ltd 新規なトリアゾール誘導体
EP1054005A1 (fr) * 1998-02-05 2000-11-22 Takeda Chemical Industries, Ltd. Derives de sulfamide, leur procede de production et leur utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0927719A1 (fr) * 1997-12-26 1999-07-07 SSP Co., Ltd. Dérivés de triazole et leurs sels, leurs procédés de préparation et compositions pharmaceutiques les contenant
EP1054005A1 (fr) * 1998-02-05 2000-11-22 Takeda Chemical Industries, Ltd. Derives de sulfamide, leur procede de production et leur utilisation
JP2000063363A (ja) * 1998-08-12 2000-02-29 Yamanouchi Pharmaceut Co Ltd 新規なトリアゾール誘導体

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