WO2020049670A1 - Dantrolene aqueous formulation and method for preparing same - Google Patents

Dantrolene aqueous formulation and method for preparing same Download PDF

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WO2020049670A1
WO2020049670A1 PCT/JP2018/032953 JP2018032953W WO2020049670A1 WO 2020049670 A1 WO2020049670 A1 WO 2020049670A1 JP 2018032953 W JP2018032953 W JP 2018032953W WO 2020049670 A1 WO2020049670 A1 WO 2020049670A1
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dantrolene
mol
preparation
cyclodextrin
acceptable salt
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PCT/JP2018/032953
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French (fr)
Japanese (ja)
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裕幸 川嶋
政博 高栖
億霖 陳
育勝 劉
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シミックホールディングス株式会社
株式会社オーファンパシフィック
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Priority to PCT/JP2018/032953 priority Critical patent/WO2020049670A1/en
Priority to JP2020540932A priority patent/JPWO2020049670A1/en
Priority to CN201880097128.0A priority patent/CN112770744A/en
Priority to KR1020217008679A priority patent/KR20210056359A/en
Publication of WO2020049670A1 publication Critical patent/WO2020049670A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • 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
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

  • the present invention relates to an aqueous dantrolene preparation and a method for preparing the same.
  • Malignant hyperthermia is a complication of general anesthesia and the most severe mortality complication. Malignant hyperthermia develops in patients with a genetic predisposition due to general anesthesia with volatile inhaled anesthetics (such as halothane) or muscle relaxants (such as suxamethonium).
  • volatile inhaled anesthetics such as halothane
  • muscle relaxants such as suxamethonium
  • Dantrolene injection is the only treatment for malignant hyperthermia.
  • Dantrolene is a muscle relaxant that blocks the release of calcium ions from the sarcoplasmic reticulum by blocking the ryanodine receptor and blocking the transmission of excitability from transverse tubules to the sarcoplasmic reticulum. Causes relaxation.
  • Dantrolene injectable preparations are used in preparation for use. Since dantrolene has a short shelf life as an aqueous composition, it is used by dissolving and reconstituting a powder obtained by drying the aqueous composition immediately before use. The dantrolene injection preparation is used after adding water for injection to a vial and shaking to confirm that the solution has become clear. However, since dantrolene is extremely insoluble in water, a large amount of solvent is required for dissolution, which is troublesome, and there is a problem that it is difficult to rapidly prepare it in an emergency. In Patent Document 1, an attempt has been made to improve the solubility of dantrolene using a cyclodextrin derivative.
  • aqueous dantrolene composition described in Patent Document 1 contains 2 to 30 mol of a cyclodextrin derivative per 1 mol of dantrolene or a pharmacologically acceptable salt thereof.
  • cyclodextrin derivatives are concerned about nephrotoxicity.
  • Patent Document 2 proposes using a normal salt or a hydrogen salt of an alkali metal to prevent the decomposition of dantrolene.
  • Non-Patent Document 1 reports that a hydroxypropyl- ⁇ -cyclodextrin inclusion complex of dantrolene improved dantrolene bioavailability by oral administration.
  • dantrolene and hydroxypropyl- ⁇ -cyclodextrin are stirred at 45 ° C. for 3 hours to form an inclusion complex.
  • the main object of the present invention is to provide a technique for quickly and easily preparing an aqueous preparation of dantrolene or a pharmaceutically acceptable salt thereof.
  • the present invention provides the following [1] to [15].
  • [1] comprising dantrolene or a pharmacologically acceptable salt thereof, and a cyclodextrin derivative
  • the compounding amount of the cyclodextrin derivative is 0.5 mol or more and less than 2 mol per 1 mol of dantrolene or a pharmaceutically acceptable salt thereof, Dantrolene aqueous formulation.
  • [2] The aqueous dantrolene preparation according to [1], wherein the amount of the cyclodextrin derivative is 0.7 mol or more and 1.3 mol or less per mol of dantrolene or a pharmaceutically acceptable salt thereof.
  • dantrolene or a pharmacologically acceptable salt thereof, a cyclodextrin derivative, and an aqueous solvent The amount of the cyclodextrin derivative is 0.5 mol or more and less than 2 mol per 1 mol of dantrolene or a pharmaceutically acceptable salt thereof, Dantrolene aqueous preparation preparation kit.
  • a method for preparing an aqueous dantrolene preparation A procedure of dissolving dantrolene or a pharmaceutically acceptable salt thereof and a cyclodextrin derivative in an aqueous solvent at a temperature of 40 ° C. or more and 45 ° C. or less, wherein dantrolene or a pharmaceutically acceptable salt thereof is added to 1 mole of The amount of the dextrin derivative is 0.5 mol or more and less than 2 mol.
  • the preparation method of [9] wherein the pH of the preparation is adjusted to 9.0-10.5 in the above procedure.
  • the preparation method of [10] wherein the pH of the preparation is adjusted to 9.3-10.0 in the above procedure.
  • a method for preparing an intravenous dantrolene injection formulation Procedure of dissolving dantrolene sodium and hydroxypropyl- ⁇ -cyclodextrin in water at a temperature of 40 ° C. or more and 45 ° C. or less to obtain a formulation having a pH of 9.0-10.0, wherein hydroxypropyl- ⁇ is added to 1 mol of dantrolene sodium. -A process wherein the amount of cyclodextrin is from 0.73 mol to 1.31 mol;
  • the main object of the present invention is to provide a technique for quickly and easily preparing an aqueous preparation of dantrolene or a pharmaceutically acceptable salt thereof.
  • the aqueous dantrolene preparation according to the present invention comprises dantrolene or a pharmacologically acceptable salt thereof and a cyclodextrin derivative, and a blending amount of the cyclodextrin derivative per 1 mol of dantrolene or a pharmacologically acceptable salt thereof. Is 0.5 mol or more and less than 2 mol.
  • the kit for preparing an aqueous dantrolene preparation comprises dantrolene or a pharmaceutically acceptable salt thereof, a cyclodextrin derivative, and optionally an aqueous solvent, and comprises dantrolene or a pharmaceutically acceptable salt thereof.
  • the amount of the cyclodextrin derivative is 0.5 mol or more and less than 2 mol per 1 mol of the salt that can be obtained.
  • Pharmaceutically acceptable salts of dantrolene include alkali metal salts, alkaline earth metal salts, ammonium salts, alkyl ammonium salts, polyalkyl ammonium salts, aryl ammonium salts, substituted or unsubstituted quinolidinium salts, and substituted or unsubstituted Any one or more salts selected from the group consisting of pyridinium salts may be used.
  • the pharmacologically acceptable salts of dantrolene are preferably the sodium, potassium, ammonium, calcium, and magnesium salts, particularly preferably the sodium salt.
  • the aqueous solvent is water or a mixture of a physiologically acceptable solvent and water, preferably water.
  • Physiologically acceptable solvents include C1-6 alcohols (especially ethanol), polyethylene glycol, propylene glycol, glycerol, dimethylacetamide, dimethylisosorbide, dimethylsulfoxide, 1-methyl-2-pyrrolidone and 1-ethyl-2-. Pyrrolidone.
  • the aqueous solvent is not an essential component of the kit according to the present invention, and may be obtained by the preparer separately from the kit.
  • Cyclodextrins are cyclic ( ⁇ -1,4) -linked oligosaccharides having a hydrophobic central cavity and a hydrophilic outer surface.
  • a substituent selected from the group consisting of alkyl, hydroxyalkyl, carboxyalkyl, sulfoalkyl, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl and hydroxy- (mono or poly) alkyl is introduced into cyclodextrin. It is a thing.
  • the cyclodextrin derivative may be any one or more selected from the group consisting of hydroxypropyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin, and ⁇ -cyclodextrin. Of these, hydroxypropyl- ⁇ -cyclodextrin is particularly preferred.
  • the amount of dantrolene or a pharmaceutically acceptable salt thereof in the aqueous preparation is 0.1 to 10 mg / ml, preferably 0.2 to 7.0 mg / ml, more preferably 0.3 to 4.0 mg. / Ml.
  • the amount of dantrolene or a pharmaceutically acceptable salt thereof in the aqueous preparation is 0.25 to 25.0 mM, more preferably 0.50 to 17.50 mM, and still more preferably 0.75 to 10.5 mM. 0 mM.
  • the compounding amount of the cyclodextrin derivative in the aqueous preparation is 3.4-13.7 mg / ml, preferably 5-9.5 mg / ml.
  • the amount of the cyclodextrin derivative in the aqueous preparation is 25-99 mM, preferably 36-69 mM.
  • the amount of the cyclodextrin derivative per 1 mol of dantrolene or a pharmacologically acceptable salt thereof is from 0.5 mol to less than 2 mol, preferably from 0.7 mol to 1.3 mol.
  • Test Example 1 described below by blending about 0.7 mol or more of cyclodextrin derivative with respect to 1 mol of dantrolene or a pharmacologically acceptable salt thereof, good dantrolene solubility and turbidity of the preparation can be obtained. It is clear that it can be obtained.
  • the amount of the cyclodextrin derivative to be mixed with 1 mol of dantrolene or a pharmaceutically acceptable salt thereof is preferably 0.7 mol or more and 1.3 mol or less.
  • the aqueous dantrolene preparation and its preparation kit may contain a pH adjuster, an osmotic adjuster and / or a surfactant.
  • the pH adjuster is selected from the group consisting of citrate, carbonate, phosphate, arginine, lysine, meglumine, tromethamine, histidine and mixtures thereof.
  • the pH adjusting agent is used in an amount suitable for adjusting and maintaining the pH of the preparation within the above range.
  • the osmotic pressure adjusting agent is a fat having 2 to 10 carbon atoms selected from the group consisting of mannitol, fructose, glucose, gluconolactone, gluconate, sucrose, lactose, trehalose, dextrose, dextran, and hydroxyethyl starch. Selected from the group consisting of Group III polyhydroxyalkanols and mixtures thereof. Of these, mannitol is particularly preferred.
  • the pH adjuster is used in an amount suitable to adjust and maintain the osmotic pressure of the formulation at about 1 (ratio to saline).
  • surfactant examples include, but are not particularly limited to, PEG-40 hydrogenated castor oil (NIKKOL @ HCO-40, Nikko Chemicals Co., Ltd.), PEG-50 hydrogenated castor oil (NIKKOL @ HCO-50, Nikko Chemicals Co., Ltd.), PEG -60 hydrogenated castor oil (NIKKOL @ HCO-60, Nikko Chemicals Co., Ltd.), polysorbate 20 (NIKKOL @ TL-10, Nikko Chemicals Co., Ltd.), polyethylene glycol (Macrogol 400, Sanyo Chemical Industries, Ltd.), polyoxyethylene fatty acid Monoesters (Ionette MO-400 or MS-400, Sanyo Chemical Industries, Ltd.) and glyceryl monostearate (TG-C, Sanyo Chemical Industries, Ltd.) are exemplified.
  • PEG-40 hydrogenated castor oil NIKKOL @ HCO-40, Nikko Chemicals Co., Ltd.
  • PEG-50 hydrogenated castor oil NIKKOL @ HCO-50, Nikko
  • the dantrolene aqueous preparation preparation kit can be reconstituted as a dantrolene aqueous preparation by adding an aqueous solvent to dantrolene or a pharmaceutically acceptable salt thereof and a cyclodextrin derivative contained in a container such as a vial and dissolving the dantrolene aqueous preparation. .
  • the temperature at the time of dissolution is preferably from 40 ° C to 45 ° C.
  • the solubility of dantrolene can be further improved and a clearer preparation can be obtained (Test Example 2). For this reason, it is possible to achieve good solubility of dantrolene and turbidity of the preparation while suppressing the compounding amount of the cyclodextrin derivative with respect to dantrolene or a pharmacologically acceptable salt thereof, as compared with normal dissolution at room temperature. there is a possibility.
  • the temperature exceeds the above-mentioned temperature range, there is a concern that generation of impurities due to hydrolysis of dantrolene is enhanced.
  • the pH of the formulation after dissolution is adjusted to 9.0-10.5, preferably 9.3-10.0.
  • the solubility of dantrolene was measured as follows. A 1 mL sample was collected, filtered through a 0.22 ⁇ m filter, and then diluted with pure water to 0.02 ⁇ g / mL. The absorbance (390 nm) of the diluted solution was measured with an ultraviolet-visible spectrophotometer. Based on the calibration curve created in advance, the solubility was calculated from the measured absorbance.
  • the turbidity of the preparation was measured by placing a 5 mL sample in a vial and using a turbidimeter.
  • Test Example 2 Examination of the influence of the dissolution temperature on the solubility of dantrolene and the turbidity of the preparation] 20 mg of dantrolene sodium, 75 mg of HP ⁇ CD and 800 mg of mannitol were dissolved in 10 ml of water, and the mixture was stirred for 15 minutes to prepare a formulation. By changing the dissolution temperature, the solubility of dantrolene and the turbidity of the preparation were measured in the same manner as in Test Example 1.
  • Test Example 3 Influence of pH at the time of preparation on solubility of dantrolene and turbidity and impurity concentration of preparation
  • 20 mg of dantrolene sodium, 200 mg of HP ⁇ CD and 800 mg of mannitol were dissolved in 10 ml of water at room temperature and stirred for 24 hours to prepare a formulation.
  • the solubility of dantrolene was measured in the same manner as in Test Example 1 by changing the pH of the formulation after preparation by changing the pH range of water maintained during preparation.
  • the impurity (5- (p-nitrophenyl) -2-furaldehyde-2-carboxymethyl-semicarbazone: F-524) is a decomposed product generated from the dantrolene raw material over time.
  • the concentration of F-524 was measured using a liquid chromatograph under the following conditions.

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Abstract

Provided as a technique for preparing an aqueous formulation of dantrolene or a pharmacologically acceptable salt thereof quickly and easily is a dantrolene aqueous formulation containing dantrolene or a pharmacologically acceptable salt thereof and a cyclodextrin derivative in which the amount of cyclodextrin derivative blended is from 0.5 mol to less than 2 mol per mol of dantrolene or pharmacologically acceptable salt thereof.

Description

ダントロレン水性製剤及びその調製方法Dantrolene aqueous preparation and method for preparing the same
　本発明は、ダントロレン水性製剤及びその調製方法に関する。 The present invention relates to an aqueous dantrolene preparation and a method for preparing the same.
　悪性高熱症は、全身麻酔の合併症であり、最も死亡率が高い重篤な合併症である。悪性高熱症は、揮発性吸入麻酔薬（ハロタンなど）あるいは筋弛緩薬（スキサメトニウムなど）を用いた全身麻酔によって遺伝的素因のある患者で発症する。悪性高熱症の特徴的な症状は、筋硬直、頻脈及び急激な体温上昇である。 Malignant hyperthermia is a complication of general anesthesia and the most severe mortality complication. Malignant hyperthermia develops in patients with a genetic predisposition due to general anesthesia with volatile inhaled anesthetics (such as halothane) or muscle relaxants (such as suxamethonium). The characteristic symptoms of malignant hyperthermia are muscle stiffness, tachycardia, and rapid temperature rise.
　ダントロレン（Dantrolene）注射製剤は、悪性高熱症に対する唯一の治療薬である。ダントロレンは、筋弛緩薬の一つであり、リアノジン受容体を遮断して横行小管から筋小胞体への興奮の伝達過程を遮断することにより筋小胞体からのカルシウムイオンの遊離を抑制し、筋弛緩を引き起こす。 Dantrolene injection is the only treatment for malignant hyperthermia. Dantrolene is a muscle relaxant that blocks the release of calcium ions from the sarcoplasmic reticulum by blocking the ryanodine receptor and blocking the transmission of excitability from transverse tubules to the sarcoplasmic reticulum. Causes relaxation.
　ダントロレン注射製剤は、用時の調製で用いられる。ダントロレンは、水性組成物としての貯蔵寿命が短いため、水性組成物を乾燥して粉末としたものを使用直前に溶解し再構成して使用されている。ダントロレン注射製剤は、バイアルに注射用水を加えて振り混ぜ、溶液が澄明になったことを確認した後に使用される。しかしながら、ダントロレンは水に極めて難溶性であるため、溶解に多量の溶媒が必要となって手間がかかり、緊急時に迅速に調製することが難しいという問題がある。
　特許文献１では、シクロデキストリン誘導体を用いてダントロレンの溶解度を改善する試みがなされている。特許文献１に記載されるダントロレン水性組成物は、ダントロレン又はその薬理学的に許容され得る塩１モルに対して、シクロデキストリン誘導体を２－３０モル配合したものとされている。一方で、シクロデキストリン誘導体は腎毒性が懸念されている。 Dantrolene injectable preparations are used in preparation for use. Since dantrolene has a short shelf life as an aqueous composition, it is used by dissolving and reconstituting a powder obtained by drying the aqueous composition immediately before use. The dantrolene injection preparation is used after adding water for injection to a vial and shaking to confirm that the solution has become clear. However, since dantrolene is extremely insoluble in water, a large amount of solvent is required for dissolution, which is troublesome, and there is a problem that it is difficult to rapidly prepare it in an emergency.
In Patent Document 1, an attempt has been made to improve the solubility of dantrolene using a cyclodextrin derivative. The aqueous dantrolene composition described in Patent Document 1 contains 2 to 30 mol of a cyclodextrin derivative per 1 mol of dantrolene or a pharmacologically acceptable salt thereof. On the other hand, cyclodextrin derivatives are concerned about nephrotoxicity.
　また、ダントロレンは、アルカリ溶液中で加水分解を受けて、ヒダントイン開環により分解して開環化合物（5-(p-nitrophenyl)-2-furaldehyde-2-carboxymethyl-semicarbazone）を生成することが知られている。分解は、ｐＨ値の増加とともに加速され、高温で増強される。
　特許文献２では、アルカリ金属の正塩又は水素塩を用いてダントロレンの分解を防止することが提案されている。 It is also known that dantrolene is hydrolyzed in an alkaline solution and decomposed by opening the hydantoin to form a ring-opened compound (5- (p-nitrophenyl) -2-furaldehyde-2-carboxymethyl-semicarbazone). Have been. Degradation is accelerated with increasing pH value and is enhanced at elevated temperatures.
Patent Document 2 proposes using a normal salt or a hydrogen salt of an alkali metal to prevent the decomposition of dantrolene.
　本発明に関連して、非特許文献１には、ダントロレンのヒドロキシプロピル－β－シクロデキストリン包摂錯体が、経口投与によるダントロレンのバイオアベイラビリティを改善したことが報告されている。同文献は、ダントロレンとヒドロキシプロピル－β－シクロデキストリンを４５℃で３時間攪拌して包摂錯体を形成させているが、ここではダントロレン２５０ｍｇに対して１０ｇという大量のヒドロキシプロピル－β－シクロデキストリンが用いられている（１５４頁右欄「2.2 Preparation of Da-HP-β-CD complex」参照）。 In connection with the present invention, Non-Patent Document 1 reports that a hydroxypropyl-β-cyclodextrin inclusion complex of dantrolene improved dantrolene bioavailability by oral administration. According to the reference, dantrolene and hydroxypropyl-β-cyclodextrin are stirred at 45 ° C. for 3 hours to form an inclusion complex. (Refer to “2.2 Preparation of Da-HP-β-CD complex” on page 154, right column).
国際公開第２０１７／０６７９８０号International Publication No. WO 2017/067980 特開昭５３－２０４１３号公報JP-A-53-20413
"Preparation, characterization and in vivo evaluation of a formulation of dantrolene sodium with hydroxypropyl-β-cyclodextrin", Journal of Pharmaceutical and Biomedical Analysis, 2017, Vol.135, p.153-159"Preparation, characterization and in vivo evaluation of the aformation of dantrolene sodium with hydroxypropyl-β-cyclodextrin", Journal of Pharmaceutical and Biomedical Analysis, 2017, Vol. 135, pp. 153-159
　本発明は、ダントロレン又はその薬理学的に許容され得る塩の水性製剤を迅速かつ簡便に調製するための技術を提供することを主な目的とする。 主 The main object of the present invention is to provide a technique for quickly and easily preparing an aqueous preparation of dantrolene or a pharmaceutically acceptable salt thereof.
　上記課題解決のため、本発明は、以下の［１］－［１５］を提供する。
［１］　ダントロレン又はその薬理学的に許容され得る塩と、シクロデキストリン誘導体と、を含み、
ダントロレン又はその薬理学的に許容され得る塩１モルに対するシクロデキストリン誘導体の配合量が０．５モル以上２モル未満である、
ダントロレン水性製剤。
［２］　ダントロレン又はその薬理学的に許容され得る塩１モルに対するシクロデキストリン誘導体の配合量が０．７モル以上１．３モル以下である、［１］のダントロレン水性製剤。
［３］　前記シクロデキストリン誘導体が、ヒドロキシプロピル－β－シクロデキストリン、β－シクロデキストリン及びα－シクロデキストリンからなる群から選択されるいずれか１以上である、［１］又は［２］のダントロレン水性製剤。
［４］　静注用注射製剤である、［１］－［３］のいずれかのダントロレン水性製剤。 In order to solve the above problems, the present invention provides the following [1] to [15].
[1] comprising dantrolene or a pharmacologically acceptable salt thereof, and a cyclodextrin derivative,
The compounding amount of the cyclodextrin derivative is 0.5 mol or more and less than 2 mol per 1 mol of dantrolene or a pharmaceutically acceptable salt thereof,
Dantrolene aqueous formulation.
[2] The aqueous dantrolene preparation according to [1], wherein the amount of the cyclodextrin derivative is 0.7 mol or more and 1.3 mol or less per mol of dantrolene or a pharmaceutically acceptable salt thereof.
[3] The dantrolene aqueous solution of [1] or [2], wherein the cyclodextrin derivative is at least one selected from the group consisting of hydroxypropyl-β-cyclodextrin, β-cyclodextrin, and α-cyclodextrin. Formulation.
[4] The dantrolene aqueous preparation according to any one of [1] to [3], which is an intravenous injection preparation.
［５］　ダントロレン又はその薬理学的に許容され得る塩と、シクロデキストリン誘導体と、水性溶媒と、を含んでなり、
ダントロレン又はその薬理学的に許容され得る塩１モルに対するシクロデキストリン誘導体の量が０．５モル以上２モル未満である、
ダントロレン水性製剤調製キット。
［６］　ダントロレン又はその薬理学的に許容され得る塩１モルに対するシクロデキストリン誘導体の量が０．７モル以上１．３モル以下である、［５］のダントロレン水性製剤調製キット。
［７］　前記シクロデキストリン誘導体が、ヒドロキシプロピル－β－シクロデキストリン、β－シクロデキストリン及びα－シクロデキストリンからなる群から選択されるいずれか１以上である、［５］又は［６］のダントロレン水性製剤調製キット。
［８］　静注用注射製剤調製キットである、［５］－［７］のいずれかのダントロレン水性製剤調製キット。 [5] dantrolene or a pharmacologically acceptable salt thereof, a cyclodextrin derivative, and an aqueous solvent,
The amount of the cyclodextrin derivative is 0.5 mol or more and less than 2 mol per 1 mol of dantrolene or a pharmaceutically acceptable salt thereof,
Dantrolene aqueous preparation preparation kit.
[6] The kit for preparing an aqueous dantrolene preparation according to [5], wherein the amount of the cyclodextrin derivative is 0.7 mol or more and 1.3 mol or less relative to 1 mol of dantrolene or a pharmacologically acceptable salt thereof.
[7] The dantrolene aqueous solution according to [5] or [6], wherein the cyclodextrin derivative is at least one selected from the group consisting of hydroxypropyl-β-cyclodextrin, β-cyclodextrin, and α-cyclodextrin. Formulation preparation kit.
[8] The kit for preparing an aqueous dantrolene preparation according to any one of [5] to [7], which is a kit for preparing an injection preparation for intravenous injection.
［９］　ダントロレン水性製剤の調製方法であって、
ダントロレン又はその薬理学的に許容され得る塩と、シクロデキストリン誘導体と、を４０℃以上４５℃以下で水性溶媒に溶解させる手順、ここでダントロレン又はその薬理学的に許容され得る塩１モルに対するシクロデキストリン誘導体の量が０．５モル以上２モル未満である、を含む調製方法。
［１０］　前記手順において製剤のｐＨが９．０－１０．５に調製される、［９］の調製方法。
［１１］　前記手順において製剤のｐＨが９．３－１０．０に調製される、［１０］の調製方法。
［１２］　ダントロレン又はその薬理学的に許容され得る塩１モルに対するシクロデキストリン誘導体の量が０．７モル以上１．３モル以下である、［９］－［１１］のいずれかの調製方法。
［１３］　前記シクロデキストリン誘導体が、ヒドロキシプロピル－β－シクロデキストリン、β－シクロデキストリン及びα－シクロデキストリンからなる群から選択されるいずれか１以上である、［９］－［１２］の調製方法。
［１４］　ダントロレン水性製剤が、静注用注射製剤である、［９］－［１３］のいずれかの調製方法。 [9] A method for preparing an aqueous dantrolene preparation,
A procedure of dissolving dantrolene or a pharmaceutically acceptable salt thereof and a cyclodextrin derivative in an aqueous solvent at a temperature of 40 ° C. or more and 45 ° C. or less, wherein dantrolene or a pharmaceutically acceptable salt thereof is added to 1 mole of The amount of the dextrin derivative is 0.5 mol or more and less than 2 mol.
[10] The preparation method of [9], wherein the pH of the preparation is adjusted to 9.0-10.5 in the above procedure.
[11] The preparation method of [10], wherein the pH of the preparation is adjusted to 9.3-10.0 in the above procedure.
[12] The method according to any one of [9] to [11], wherein the amount of the cyclodextrin derivative is from 0.7 mol to 1.3 mol per 1 mol of dantrolene or a pharmaceutically acceptable salt thereof.
[13] The method for preparing [9]-[12], wherein the cyclodextrin derivative is at least one selected from the group consisting of hydroxypropyl-β-cyclodextrin, β-cyclodextrin, and α-cyclodextrin .
[14] The method of any of [9] to [13], wherein the dantrolene aqueous preparation is an intravenous injection preparation.
［１５］　ダントロレン静注用注射製剤の調製方法であって、
ダントロレンナトリウムと、ヒドロキシプロピル－β－シクロデキストリンと、を４０℃以上４５℃以下で水に溶解させてｐＨ９．０－１０．０の製剤を得る手順、ここでダントロレンナトリウム１モルに対するヒドロキシプロピル－β－シクロデキストリンの量が０．７３モル以上１．３１モル以下である、を含む調製方法。 [15] A method for preparing an intravenous dantrolene injection formulation,
Procedure of dissolving dantrolene sodium and hydroxypropyl-β-cyclodextrin in water at a temperature of 40 ° C. or more and 45 ° C. or less to obtain a formulation having a pH of 9.0-10.0, wherein hydroxypropyl-β is added to 1 mol of dantrolene sodium. -A process wherein the amount of cyclodextrin is from 0.73 mol to 1.31 mol;
　本発明は、ダントロレン又はその薬理学的に許容され得る塩の水性製剤を迅速かつ簡便に調製するための技術を提供することを主な目的とする。 主 The main object of the present invention is to provide a technique for quickly and easily preparing an aqueous preparation of dantrolene or a pharmaceutically acceptable salt thereof.
　以下、本発明を実施するための好適な形態について説明する。なお、以下に説明する実施形態は、本発明の代表的な実施形態の一例を示したものであり、これにより本発明の範囲が狭く解釈されることはない。 Hereinafter, preferred embodiments for carrying out the present invention will be described. The embodiment described below is an example of a typical embodiment of the present invention, and the scope of the present invention is not construed as being narrow.
　本発明に係るダントロレン水性製剤は、ダントロレン又はその薬理学的に許容され得る塩と、シクロデキストリン誘導体と、を含み、ダントロレン又はその薬理学的に許容され得る塩１モルに対するシクロデキストリン誘導体の配合量が０．５モル以上２モル未満とされる。 The aqueous dantrolene preparation according to the present invention comprises dantrolene or a pharmacologically acceptable salt thereof and a cyclodextrin derivative, and a blending amount of the cyclodextrin derivative per 1 mol of dantrolene or a pharmacologically acceptable salt thereof. Is 0.5 mol or more and less than 2 mol.
　また、本発明に係るダントロレン水性製剤調製キットは、ダントロレン又はその薬理学的に許容され得る塩と、シクロデキストリン誘導体と、任意に水性溶媒と、を含んでなり、ダントロレン又はその薬理学的に許容され得る塩１モルに対するシクロデキストリン誘導体の量が０．５モル以上２モル未満とされる。 The kit for preparing an aqueous dantrolene preparation according to the present invention comprises dantrolene or a pharmaceutically acceptable salt thereof, a cyclodextrin derivative, and optionally an aqueous solvent, and comprises dantrolene or a pharmaceutically acceptable salt thereof. The amount of the cyclodextrin derivative is 0.5 mol or more and less than 2 mol per 1 mol of the salt that can be obtained.
　ダントロレンの構造を以下に示す。 The structure of dantrolene is shown below.
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
　ダントロレンの薬理学的に許容され得る塩は、アルカリ金属塩、アルカリ土類金属塩、アンモニウム塩、アルキルアンモニウム塩、ポリアルキルアンモニウム塩、アリールアンモニウム塩、置換または非置換キノリジニウム塩、及び置換又は非置換ピリジニウム塩からなる群から選択されるいずれ一以上の塩であってよい。
　ダントロレンの薬理学的に許容され得る塩は、好ましくは、ナトリウム塩、カリウム塩、アンモニウム塩、カルシウム塩、マグネシウム塩であり、特に好ましくはナトリウム塩である。 Pharmaceutically acceptable salts of dantrolene include alkali metal salts, alkaline earth metal salts, ammonium salts, alkyl ammonium salts, polyalkyl ammonium salts, aryl ammonium salts, substituted or unsubstituted quinolidinium salts, and substituted or unsubstituted Any one or more salts selected from the group consisting of pyridinium salts may be used.
The pharmacologically acceptable salts of dantrolene are preferably the sodium, potassium, ammonium, calcium, and magnesium salts, particularly preferably the sodium salt.
　水性溶媒は、水または生理学的に許容される溶媒と水との混合物であり、好ましくは水である。
　生理学的に許容される溶媒としては、Ｃ１－６アルコール（特にエタノール）、ポリエチレングリコール、プロピレングリコール、グリセロール、ジメチルアセトアミド、ジメチルイソソルビド、ジメチルスルホキシド、１－メチルー２－２ピロリドン及び１－エチル－２－ピロリドンが挙げられる。
　なお、水性溶媒は、本発明に係るキットの必須の構成要素とはならず、調製者においてキットとは別に入手されものであってもよい。 The aqueous solvent is water or a mixture of a physiologically acceptable solvent and water, preferably water.
Physiologically acceptable solvents include C1-6 alcohols (especially ethanol), polyethylene glycol, propylene glycol, glycerol, dimethylacetamide, dimethylisosorbide, dimethylsulfoxide, 1-methyl-2-pyrrolidone and 1-ethyl-2-. Pyrrolidone.
The aqueous solvent is not an essential component of the kit according to the present invention, and may be obtained by the preparer separately from the kit.
　シクロデキストリンは、疎水性中心空洞および親水性外表面を有する環状（α－１，４）結合オリゴ糖である。
　シクロデキストリン誘導体は、シクロデキストリンに、アルキル、ヒドロキシアルキル、カルボキシアルキル、スルホアルキル、アルキルカルボニルオキシアルキル、アルコキシカルボニルアルキル及びヒドロキシ－（モノまたはポリ）アルキル基からなる群から選択される置換基が導入されたものである。
　シクロデキストリン誘導体は、ヒドロキシプロピル－β－シクロデキストリン、β－シクロデキストリン及びα－シクロデキストリンからなる群から選択されるいずれか１以上であってよい。このうち、特にヒドロキシプロピル－β－シクロデキストリンが好ましい。 Cyclodextrins are cyclic (α-1,4) -linked oligosaccharides having a hydrophobic central cavity and a hydrophilic outer surface.
In the cyclodextrin derivative, a substituent selected from the group consisting of alkyl, hydroxyalkyl, carboxyalkyl, sulfoalkyl, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl and hydroxy- (mono or poly) alkyl is introduced into cyclodextrin. It is a thing.
The cyclodextrin derivative may be any one or more selected from the group consisting of hydroxypropyl-β-cyclodextrin, β-cyclodextrin, and α-cyclodextrin. Of these, hydroxypropyl-β-cyclodextrin is particularly preferred.
　ダントロレン又はその薬理学的に許容され得る塩の水性製剤中の配合量は、０．１－１０ｍｇ／ｍｌ、好ましくは０．２－７．０ｍｇ／ｍｌ、より好ましくは０．３－４．０ｍｇ／ｍｌである。
　また、ダントロレン又はその薬理学的に許容され得る塩の水性製剤中の配合量は、０．２５－２５．０ｍＭ、より好ましくは０．５０－１７．５０ｍＭ、より好ましくは０．７５－１０．０ｍＭである。 The amount of dantrolene or a pharmaceutically acceptable salt thereof in the aqueous preparation is 0.1 to 10 mg / ml, preferably 0.2 to 7.0 mg / ml, more preferably 0.3 to 4.0 mg. / Ml.
The amount of dantrolene or a pharmaceutically acceptable salt thereof in the aqueous preparation is 0.25 to 25.0 mM, more preferably 0.50 to 17.50 mM, and still more preferably 0.75 to 10.5 mM. 0 mM.
　シクロデキストリン誘導体の水性製剤中の配合量は、３．４－１３．７ｍｇ／ｍｌ、好ましくは５－９．５ｍｇ／ｍｌである。
　また、シクロデキストリン誘導体の水性製剤中の配合量は、２５－９９ｍＭ、好ましくは３６－６９ｍＭである。 The compounding amount of the cyclodextrin derivative in the aqueous preparation is 3.4-13.7 mg / ml, preferably 5-9.5 mg / ml.
The amount of the cyclodextrin derivative in the aqueous preparation is 25-99 mM, preferably 36-69 mM.
　ダントロレン又はその薬理学的に許容され得る塩１モルに対するシクロデキストリン誘導体の配合量は、０．５モル以上２モル未満とされ、好ましくは０．７モル以上１．３モル以下とされる。
　後述する試験例１では、ダントロレン又はその薬理学的に許容され得る塩１モルに対して約０．７モル以上のシクロデキストリン誘導体を配合することで、良好なダントロレンの溶解度と製剤の濁度が得られることが明らかになっている。シクロデキストリン誘導体は、腎毒性が疑われているため、その配合量は、良好なダントロレンの溶解度と製剤の濁度を達成するために必要最小限とされることが望ましい。したがって、ダントロレン又はその薬理学的に許容され得る塩１モルに対するシクロデキストリン誘導体の配合量は、０．７モル以上１．３モル以下が好ましい。
　ダントロレン又はその薬理学的に許容され得る塩にシクロデキストリン誘導体を上記配合比率範囲で添加することで、ダントロレンの溶解度を向上させ、かつ澄明な製剤を得ることができる。したがって、本発明に係るダントロレン水性製剤及びその調製キットによれば、悪性高熱症の臨床においてダントロレン静注用注射製剤を迅速かつ簡便に提供するために有効である。 The amount of the cyclodextrin derivative per 1 mol of dantrolene or a pharmacologically acceptable salt thereof is from 0.5 mol to less than 2 mol, preferably from 0.7 mol to 1.3 mol.
In Test Example 1 described below, by blending about 0.7 mol or more of cyclodextrin derivative with respect to 1 mol of dantrolene or a pharmacologically acceptable salt thereof, good dantrolene solubility and turbidity of the preparation can be obtained. It is clear that it can be obtained. Since the cyclodextrin derivative is suspected of nephrotoxicity, it is desirable that the amount of the cyclodextrin derivative be minimized to achieve good dantrolene solubility and turbidity of the preparation. Therefore, the amount of the cyclodextrin derivative to be mixed with 1 mol of dantrolene or a pharmaceutically acceptable salt thereof is preferably 0.7 mol or more and 1.3 mol or less.
By adding a cyclodextrin derivative to dantrolene or a pharmacologically acceptable salt thereof in the above-mentioned mixing ratio range, the solubility of dantrolene can be improved and a clear preparation can be obtained. Therefore, the aqueous dantrolene preparation and the preparation kit thereof according to the present invention are effective for quickly and easily providing an injection preparation for intravenous dantrolene in a clinical setting of malignant hyperthermia.
　ダントロレン水性製剤及びその調製キットは、ｐＨ調節剤、浸透圧調整剤及び／又は界面活性剤を含んでいてもよい。 The aqueous dantrolene preparation and its preparation kit may contain a pH adjuster, an osmotic adjuster and / or a surfactant.
　ｐＨ調節剤は、クエン酸塩、炭酸塩、リン酸塩、アルギニン、リジン、メグルミン、トロメタミン、ヒスチジン及びそれらの混合物からなる群から選択される。ｐＨ調節剤は、製剤のｐＨを上記範囲内に調整し維持するのに適した量で用いられる。 The pH adjuster is selected from the group consisting of citrate, carbonate, phosphate, arginine, lysine, meglumine, tromethamine, histidine and mixtures thereof. The pH adjusting agent is used in an amount suitable for adjusting and maintaining the pH of the preparation within the above range.
　浸透圧調整剤は、マンニトール、フルクトース、グルコース、グルコノラクトン、グルコン酸塩、スクロース、ラクトース、トレハロース、デキストロース、デキストラン、ヒドロキシエチルデンプンからなる群から選択される2～10個の炭素原子を有する脂肪族ポリヒドロキシアルカノールおよびそれらの混合物からなる群から選択される。このうち、特にマンニトールが好ましい。ｐＨ調節剤は、製剤の浸透圧を約１（生理食塩液に対する比）に調整し維持するのに適した量で用いられる。 The osmotic pressure adjusting agent is a fat having 2 to 10 carbon atoms selected from the group consisting of mannitol, fructose, glucose, gluconolactone, gluconate, sucrose, lactose, trehalose, dextrose, dextran, and hydroxyethyl starch. Selected from the group consisting of Group III polyhydroxyalkanols and mixtures thereof. Of these, mannitol is particularly preferred. The pH adjuster is used in an amount suitable to adjust and maintain the osmotic pressure of the formulation at about 1 (ratio to saline).
　界面活性剤としては、特に限定されないが、PEG-40水添ヒマシ油（NIKKOL HCO-40、日光ケミカルズ株式会社）、PEG-50水添ヒマシ油（NIKKOL HCO-50、日光ケミカルズ株式会社）、PEG-60水添ヒマシ油（NIKKOL HCO-60、日光ケミカルズ株式会社）、ポリソルベート２０（NIKKOL TL-10、日光ケミカルズ株式会社）、ポリエチレングリコール（マクロゴール400、三洋化成工業株式会社）、ポリオキシエチレン脂肪酸モノエステル（イオネットMO-400又はMS-400、三洋化成工業株式会社）及びモノステアリン酸グリセリル（TG-C、三洋化成工業株式会社）が例示される。 Examples of the surfactant include, but are not particularly limited to, PEG-40 hydrogenated castor oil (NIKKOL @ HCO-40, Nikko Chemicals Co., Ltd.), PEG-50 hydrogenated castor oil (NIKKOL @ HCO-50, Nikko Chemicals Co., Ltd.), PEG -60 hydrogenated castor oil (NIKKOL @ HCO-60, Nikko Chemicals Co., Ltd.), polysorbate 20 (NIKKOL @ TL-10, Nikko Chemicals Co., Ltd.), polyethylene glycol (Macrogol 400, Sanyo Chemical Industries, Ltd.), polyoxyethylene fatty acid Monoesters (Ionette MO-400 or MS-400, Sanyo Chemical Industries, Ltd.) and glyceryl monostearate (TG-C, Sanyo Chemical Industries, Ltd.) are exemplified.
　ダントロレン水性製剤調製キットは、バイアル等の容器に収容したダントロレン又はその薬理学的に許容され得る塩とシクロデキストリン誘導体に水性溶媒を加えて溶解させることにより、ダントロレン水性製剤として再構成することができる。 The dantrolene aqueous preparation preparation kit can be reconstituted as a dantrolene aqueous preparation by adding an aqueous solvent to dantrolene or a pharmaceutically acceptable salt thereof and a cyclodextrin derivative contained in a container such as a vial and dissolving the dantrolene aqueous preparation. .
　溶解時の温度は、４０℃以上４５℃以下とすることが好ましい。溶解温度を上記範囲に設定することで、ダントロレンの溶解度をさらに向上させ、かつより澄明な製剤を得ることができる（試験例２）。このため、通常の室温での溶解に比して、ダントロレン又はその薬理学的に許容され得る塩に対するシクロデキストリン誘導体の配合量を抑制しつつ、良好なダントロレンの溶解度と製剤の濁度を達成できる可能性がある。
　なお、上記温度範囲を超えると、ダントロレンの加水分解による不純物の生成が増強される懸念がある。 The temperature at the time of dissolution is preferably from 40 ° C to 45 ° C. By setting the dissolution temperature in the above range, the solubility of dantrolene can be further improved and a clearer preparation can be obtained (Test Example 2). For this reason, it is possible to achieve good solubility of dantrolene and turbidity of the preparation while suppressing the compounding amount of the cyclodextrin derivative with respect to dantrolene or a pharmacologically acceptable salt thereof, as compared with normal dissolution at room temperature. there is a possibility.
When the temperature exceeds the above-mentioned temperature range, there is a concern that generation of impurities due to hydrolysis of dantrolene is enhanced.
　溶解後の製剤のｐＨは、９．０－１０．５、好ましくは９．３－１０．０に調製される。製剤のｐＨを上記範囲に設定することで、ダントロレンの良好な溶解度を維持しつつ、不純物の生成も抑制することが可能となる（試験例３）。 製 剤 The pH of the formulation after dissolution is adjusted to 9.0-10.5, preferably 9.3-10.0. By setting the pH of the preparation in the above range, it is possible to suppress the generation of impurities while maintaining good solubility of dantrolene (Test Example 3).
［試験例１：ダントロレンとシクロデキストリン誘導体のモル比がダントロレンの溶解度と製剤の濁度に及ぼす影響の検討］
　ダントロレンナトリウム２０ｍｇ（５０ｍＭ）、ヒドロキシプロピル－β－シクロデキストリン（ＨＰβＣＤ）及びマンニトール８００ｍｇを４５℃の水１０ｍｌに溶解し、１５分攪拌して製剤化した。
　ＨＰβＣＤの添加モル量を変化させて、ダントロレンの溶解度と製剤の濁度を測定した。 [Test Example 1: Investigation of the effect of the molar ratio of dantrolene and cyclodextrin derivative on the solubility of dantrolene and the turbidity of the preparation]
20 mg (50 mM) of dantrolene sodium, hydroxypropyl-β-cyclodextrin (HPβCD) and 800 mg of mannitol were dissolved in 10 ml of water at 45 ° C. and stirred for 15 minutes to form a formulation.
The solubility of dantrolene and the turbidity of the preparation were measured by changing the molar amount of HPβCD added.
　ダントロレンの溶解度の測定は、以下のようにして行った。
　サンプル１ｍＬを分取し、０．２２μｍのフィルターでろ過後、純水で０．０２μｇ／ｍＬに希釈した。希釈液の吸光度（３９０ｎｍ）を紫外可視分光光度計で測定した。あらかじめ作成した検量線に基づき、測定された吸光度から溶解度を算出した。 The solubility of dantrolene was measured as follows.
A 1 mL sample was collected, filtered through a 0.22 μm filter, and then diluted with pure water to 0.02 μg / mL. The absorbance (390 nm) of the diluted solution was measured with an ultraviolet-visible spectrophotometer. Based on the calibration curve created in advance, the solubility was calculated from the measured absorbance.
　製剤の濁度は、サンプル５ｍＬをバイアルに入れ、濁度計で測定した。 濁 The turbidity of the preparation was measured by placing a 5 mL sample in a vial and using a turbidimeter.
　結果を「表１」に示す。 The results are shown in Table 1.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　ダントロレンナトリウム１モルに対して０．７３モル以上のＨＰβＣＤを添加することで、良好なダントロレンの溶解度と製剤の濁度を得られることが明らかとなった。 It was revealed that by adding 0.73 mol or more of HPβCD to 1 mol of dantrolene sodium, favorable dantrolene solubility and turbidity of the preparation can be obtained.
［試験例２：溶解温度がダントロレンの溶解度と製剤の濁度に及ぼす影響の検討］
　ダントロレンナトリウム２０ｍｇ、ＨＰβＣＤ７５ｍｇ及びマンニトール８００ｍｇを水１０ｍｌに溶解し、１５分攪拌して製剤化した。
　溶解温度を変化させて、ダントロレンの溶解度と製剤の濁度を試験例１と同様にして測定した。 [Test Example 2: Examination of the influence of the dissolution temperature on the solubility of dantrolene and the turbidity of the preparation]
20 mg of dantrolene sodium, 75 mg of HPβCD and 800 mg of mannitol were dissolved in 10 ml of water, and the mixture was stirred for 15 minutes to prepare a formulation.
By changing the dissolution temperature, the solubility of dantrolene and the turbidity of the preparation were measured in the same manner as in Test Example 1.
　結果を「表２」に示す。 The results are shown in Table 2.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　溶解温度を３５℃では製剤の濁度が不良であった。溶解温度を４０℃（好ましくは４５℃）とすることで、良好なダントロレンの溶解度と製剤の濁度得られることが明らかとなった。 で は When the dissolution temperature was 35 ° C., the turbidity of the preparation was poor. It was clarified that by setting the dissolution temperature to 40 ° C. (preferably 45 ° C.), good dantrolene solubility and turbidity of the preparation were obtained.
［試験例３：調製時のｐＨがダントロレンの溶解度並びに製剤の濁度及び不純物濃度に及ぼす影響の検討］
　ダントロレンナトリウム２０ｍｇ、ＨＰβＣＤ２００ｍｇ及びマンニトール８００ｍｇを室温で水１０ｍｌに溶解し、２４時間攪拌して製剤化した。
　調製時に維持する水のｐＨ範囲を変更させることにより調製後の製剤のｐＨを変化させて、ダントロレンの溶解度を試験例１と同様にして測定した。 [Test Example 3: Influence of pH at the time of preparation on solubility of dantrolene and turbidity and impurity concentration of preparation]
20 mg of dantrolene sodium, 200 mg of HPβCD and 800 mg of mannitol were dissolved in 10 ml of water at room temperature and stirred for 24 hours to prepare a formulation.
The solubility of dantrolene was measured in the same manner as in Test Example 1 by changing the pH of the formulation after preparation by changing the pH range of water maintained during preparation.
　結果を「表３」に示す。 The results are shown in Table 3.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　次に、ダントロレンナトリウム２０ｍｇ、ＨＰβＣＤ７５ｍｇ及びマンニトール８００ｍｇを水１０ｍｌに溶解し、約３０～５０秒攪拌して製剤化した。
　調製時に維持する水のｐＨ範囲を変更させることにより調製後の製剤のｐＨを変化させて、製剤の濁度及び不純物濃度を測定した。製剤の濁度は試験例１と同様にして測定した。 Next, 20 mg of dantrolene sodium, 75 mg of HPβCD and 800 mg of mannitol were dissolved in 10 ml of water, and the mixture was stirred for about 30 to 50 seconds to form a formulation.
The turbidity and impurity concentration of the preparation were measured by changing the pH of the preparation after preparation by changing the pH range of water maintained during preparation. The turbidity of the preparation was measured in the same manner as in Test Example 1.
　不純物（5-(p-nitrophenyl)-2-furaldehyde-2-carboxymethyl-semicarbazone：Ｆ－５２４）はダントロレン原体から経時変化によって生成する分解物である。Ｆ－５２４の濃度の測定は、液体クロマトグラフを用いて以下の条件で行った。
　カラム：ZORBAX ODS, 4.6 mm × 150 mm, 5 μm
　希釈液：６０％アセトニトリル
　バッファー：酢酸アンモニウムバッファー、ｐＨ４．５±０．１
　移動相Ａ：バッファー８４０ｍＬ、アセトニトリル５６０ｍＬ及び酢酸４９ｍＬの混合液
　移動相Ｂ：アセトニトリル３５０ｍＬと純水１５０ｍＬの混合液
　グラジエント条件：「表４」に示す。 The impurity (5- (p-nitrophenyl) -2-furaldehyde-2-carboxymethyl-semicarbazone: F-524) is a decomposed product generated from the dantrolene raw material over time. The concentration of F-524 was measured using a liquid chromatograph under the following conditions.
Column: ZORBAX ODS, 4.6 mm × 150 mm, 5 μm
Diluent: 60% acetonitrile Buffer: Ammonium acetate buffer, pH 4.5 ± 0.1
Mobile phase A: Mixed solution of 840 mL of buffer, 560 mL of acetonitrile and 49 mL of acetic acid Mobile phase B: Mixed solution of 350 mL of acetonitrile and 150 mL of pure water Gradient conditions: shown in Table 4.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　結果を「表５」に示す。 The results are shown in Table 5.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
　「表３」に示す溶解度の結果から、製剤のｐＨは９．０以上に調製されることが好ましいことが明らかとなった。また、「表５」に示す結果から、ｐＨが低いと濁度が高くなり、ｐＨが高くなるにしたがって不純物濃度が上がることが予測される。これらの結果から、製剤のｐＨは９．３－１０．０程度が望ましいと考えられた。
  From the results of the solubility shown in "Table 3," it became clear that the pH of the preparation is preferably adjusted to 9.0 or more. From the results shown in Table 5, it is predicted that the turbidity increases when the pH is low, and that the impurity concentration increases as the pH increases. From these results, it was considered that the pH of the preparation was desirably about 9.3-10.0.

Claims (8)

  1. 　ダントロレン又はその薬理学的に許容され得る塩と、シクロデキストリン誘導体と、を含み、
    ダントロレン又はその薬理学的に許容され得る塩１モルに対するシクロデキストリン誘導体の配合量が０．５モル以上２モル未満である、
    ダントロレン水性製剤。     Comprising dantrolene or a pharmaceutically acceptable salt thereof, and a cyclodextrin derivative,
    The compounding amount of the cyclodextrin derivative is 0.5 mol or more and less than 2 mol per 1 mol of dantrolene or a pharmaceutically acceptable salt thereof,
    Dantrolene aqueous formulation.
  2. 　ダントロレン又はその薬理学的に許容され得る塩１モルに対するシクロデキストリン誘導体の配合量が０．７モル以上１．３モル以下である、請求項１記載のダントロレン水性製剤。 2. The aqueous dantrolene preparation according to claim 1, wherein the compounding amount of the cyclodextrin derivative per 0.7 mol of dantrolene or a pharmaceutically acceptable salt thereof is 0.7 mol or more and 1.3 mol or less.
  3. 　前記シクロデキストリン誘導体が、ヒドロキシプロピル－β－シクロデキストリン、β－シクロデキストリン及びα－シクロデキストリンからなる群から選択されるいずれか１以上である、請求項１又は２記載のダントロレン水性製剤。 3. The aqueous dantrolene preparation according to claim 1, wherein the cyclodextrin derivative is at least one selected from the group consisting of hydroxypropyl-β-cyclodextrin, β-cyclodextrin, and α-cyclodextrin.
  4. 　ダントロレン又はその薬理学的に許容され得る塩と、シクロデキストリン誘導体と、水性溶媒と、を含んでなり、
    ダントロレン又はその薬理学的に許容され得る塩１モルに対するシクロデキストリン誘導体の量が０．５モル以上２モル未満である、
    ダントロレン水性製剤調製キット。     Dantrolene or a pharmacologically acceptable salt thereof, a cyclodextrin derivative, and an aqueous solvent,
    The amount of the cyclodextrin derivative is 0.5 mol or more and less than 2 mol per 1 mol of dantrolene or a pharmaceutically acceptable salt thereof,
    Dantrolene aqueous preparation preparation kit.
  5. 　ダントロレン水性製剤の調製方法であって、
    ダントロレン又はその薬理学的に許容され得る塩と、シクロデキストリン誘導体と、を４０℃以上４５℃以下で水性溶媒に溶解させる手順、ここでダントロレン又はその薬理学的に許容され得る塩１モルに対するシクロデキストリン誘導体の量が０．５モル以上２モル未満である、を含む調製方法。     A method for preparing an aqueous dantrolene formulation,
    A procedure of dissolving dantrolene or a pharmaceutically acceptable salt thereof and a cyclodextrin derivative in an aqueous solvent at 40 ° C. or more and 45 ° C. or less, wherein dantrolene or a pharmaceutically acceptable salt thereof is added to 1 mol of The amount of the dextrin derivative is 0.5 mol or more and less than 2 mol.
  6. 　前記手順において製剤のｐＨが９．０－１０．５に調製される、請求項５記載の調製方法。 (6) The preparation method according to (5), wherein the pH of the preparation is adjusted to 9.0-10.5 in the procedure.
  7. 　前記手順において製剤のｐＨが９．３－１０．０に調製される、請求項６記載の調製方法。 (7) The preparation method according to the above (6), wherein the pH of the preparation is adjusted to 9.3-10.0 in the procedure.
  8. 　ダントロレン静注用注射製剤の調製方法であって、
    ダントロレンナトリウムと、ヒドロキシプロピル－β－シクロデキストリンと、を４０℃以上４５℃以下で水に溶解させてｐＨ９．０－１０．０の製剤を得る手順、ここでダントロレンナトリウム１モルに対するヒドロキシプロピル－β－シクロデキストリンの量が０．７３モル以上１．３１モル以下である、を含む調製方法。
          A method of preparing an injection preparation for intravenous dantrolene,
    Procedure of dissolving dantrolene sodium and hydroxypropyl-β-cyclodextrin in water at a temperature of 40 ° C. or more and 45 ° C. or less to obtain a formulation having a pH of 9.0-10.0, wherein hydroxypropyl-β is added to 1 mol of dantrolene sodium. -A process wherein the amount of cyclodextrin is from 0.73 mol to 1.31 mol;
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011500570A (en) * 2007-10-09 2011-01-06 ユーエス ワールドメッズ リミテッド ライアビリティ カンパニー Co-solvent compositions and methods for improving delivery of dantrolene therapeutics
WO2017067980A1 (en) * 2015-10-20 2017-04-27 B. Braun Melsungen Ag Aqueous composition comprising dantrolene
WO2018146187A1 (en) * 2017-02-09 2018-08-16 Sapiotec Gmbh Pharmaceutical formulation

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JPS5822011B2 (en) 1976-08-10 1983-05-06 山之内製薬株式会社 Stable dantrolene sodium formulation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011500570A (en) * 2007-10-09 2011-01-06 ユーエス ワールドメッズ リミテッド ライアビリティ カンパニー Co-solvent compositions and methods for improving delivery of dantrolene therapeutics
WO2017067980A1 (en) * 2015-10-20 2017-04-27 B. Braun Melsungen Ag Aqueous composition comprising dantrolene
WO2018146187A1 (en) * 2017-02-09 2018-08-16 Sapiotec Gmbh Pharmaceutical formulation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
C HEN M. ET AL.: "Preparation, characterization and in vivo evaluation of a formulation of dantrolene sodium with hydroxypropyl- beta -cyclodextrin", JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, vol. 135, 19 December 2017 (2017-12-19), pages 153 - 159, XP029879694, DOI: 10.1016/j.jpba.2016.12.022 *
TANAKA, RYO ET AL.: "Non-official translation: Pharmaceutical Research on Dantrolene Sodium. Anesthesia and Resuscitation. Special Volume: Advances in Malignant Hyperthermia Research II", PROCEEDINGS OF THE 2ND JAPANESE SYMPOSIUM ON MALIGNANT HYPERTHERMIA, vol. 15, no. 2, 1979, pages 101 - 108 *

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