WO2021044608A1 - Dantrolene aqueous formulation and method for preparing same - Google Patents

Dantrolene aqueous formulation and method for preparing same Download PDF

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Publication number
WO2021044608A1
WO2021044608A1 PCT/JP2019/035122 JP2019035122W WO2021044608A1 WO 2021044608 A1 WO2021044608 A1 WO 2021044608A1 JP 2019035122 W JP2019035122 W JP 2019035122W WO 2021044608 A1 WO2021044608 A1 WO 2021044608A1
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dantrolene
preparation
aqueous
acceptable salt
agent
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PCT/JP2019/035122
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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/JP2019/035122 priority Critical patent/WO2021044608A1/en
Publication of WO2021044608A1 publication Critical patent/WO2021044608A1/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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps

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 is a serious complication with the highest mortality rate. Malignant hyperthermia develops in patients with a genetic predisposition to general anesthesia with volatile inhalational anesthetics (such as halothane) or muscle relaxants (such as suxamethonium). Characteristic symptoms of malignant hyperthermia are muscle rigidity, tachycardia and a rapid increase in body temperature.
  • Dantrolene injectable preparation is the only therapeutic drug for malignant hyperthermia.
  • Dantrolene is a muscle relaxant that suppresses the release of calcium ions from the sarcoplasmic reticulum by blocking the ryanodine receptor and blocking the transmission process of excitement from the transverse tubule to the sarcoplasmic reticulum. Causes relaxation.
  • Dantrolene is hydrolyzed in an alkaline solution and decomposed by hydantoin ring-opening to produce a ring-opening compound (5- (p-nitrophenyl) -2-furaldehyde-2-carboxymethyl-semicarbazone), so that it is used as an aqueous composition.
  • a ring-opening compound (5- (p-nitrophenyl) -2-furaldehyde-2-carboxymethyl-semicarbazone), so that it is used as an aqueous composition.
  • a ring-opening compound (5- (p-nitrophenyl) -2-furaldehyde-2-carboxymethyl-semicarbazone)
  • Patent Document 1 proposes to prevent the decomposition of dantrolene by using a positive salt or a hydrogen salt of an alkali metal.
  • a main object of the present invention is to provide a technique for suppressing the formation of impurities in an aqueous preparation of dantrolene or a pharmacologically acceptable salt thereof.
  • an aqueous preparation of dantrolene containing dantrolene or a pharmacologically acceptable salt thereof and mannitol comprises a first agent containing a dry powder of dantrolene or a pharmacologically acceptable salt thereof and a second agent consisting of an aqueous composition containing mannitol.
  • the first agent and the second agent are prepared at the time of use, Dantrolene aqueous formulation.
  • the aqueous preparation of dantrolene according to [1] which further comprises a dry powder of a cyclodextrin derivative as a first agent.
  • cyclodextrin derivative is at least one selected from the group consisting of hydroxypropyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin and ⁇ -cyclodextrin.
  • Dextrin aqueous formulation [6] The aqueous dantrolene preparation according to any one of [1]-[5], wherein the second agent contains mannitol in an amount such that the osmotic pressure ratio of the aqueous dantrolene preparation to the physiological saline solution is 0.8-1.2.
  • a preparation containing a dry powder of dantrolene or a pharmacologically acceptable salt thereof A preparation used for the preparation of an aqueous dantrolene preparation containing mannitol and dantrolene or a pharmacologically acceptable salt thereof in combination with a preparation consisting of an aqueous composition containing mannitol.
  • the preparation of [8] further comprising a dry powder of a cyclodextrin derivative.
  • the preparation of [9] wherein the amount of the cyclodextrin derivative to be blended with respect to 1 mol of dantrolene or a pharmacologically acceptable salt thereof is 0.5 mol or more and less than 2 mol.
  • a preparation comprising an aqueous composition containing mannitol.
  • the blending amount of mannitol in the preparation is an amount such that the osmotic pressure ratio of the aqueous dantrolene preparation to the physiological saline solution is 0.8-1.2.
  • a method for preparing an aqueous preparation of dantrolene at the time of use which comprises dantrolene or a pharmacologically acceptable salt thereof and mannitol.
  • a method comprising a procedure of mixing in use a first agent comprising a dry powder of dantrolene or a pharmacologically acceptable salt thereof and a second agent comprising an aqueous composition containing mannitol.
  • the first agent further comprises a dry powder of a cyclodextrin derivative.
  • the present invention provides a technique for suppressing the formation of impurities in an aqueous preparation of dantrolene or a pharmacologically acceptable salt thereof.
  • the aqueous dantrolene preparation according to the present invention is a dantrolene aqueous preparation containing dantrolene or a pharmacologically acceptable salt thereof and mannitol, and the first dantrolene aqueous preparation containing a dry powder of dantrolene or a pharmacologically acceptable salt thereof. It comprises an agent and a second agent composed of an aqueous composition containing mannitol, and the first agent and the second agent are prepared at the time of use.
  • Cyclodextrin by preparing an aqueous preparation of dantrolene by mixing a first agent containing a dry powder of dantrolene or a pharmacologically acceptable salt thereof and a second agent containing an aqueous composition containing mannitol at the time of use. It is possible to suppress the decomposition of dantrolene that occurs when mannitol and dantrolene coexist as a freeze-dried product in the presence of a derivative, and to obtain an aqueous preparation of dantrolene containing less impurities.
  • the pharmacologically acceptable salts of dantrolene are alkali metal salts, alkaline earth metal salts, ammonium salts, alkylammonium salts, polyalkylammonium salts, arylammonium salts, substituted or unsubstituted quinolidinium salts, and substituted or unsubstituted quinolidinium salts. It may be any one or more salts selected from the group consisting of pyridinium salts.
  • the pharmacologically acceptable salt of dantrolene is preferably a sodium salt, a potassium salt, an ammonium salt, a calcium salt, a magnesium salt, and particularly preferably a sodium salt.
  • the first agent may further contain a dry powder of a cyclodextrin derivative in addition to a dry powder of dantrolene or a pharmacologically acceptable salt thereof.
  • Cyclodextrin is a cyclic ( ⁇ -1,4) -linked oligosaccharide with a hydrophobic central cavity and a hydrophilic outer surface.
  • a cyclodextrin derivative is obtained by introducing a substituent selected from the group consisting of alkyl, hydroxyalkyl, carboxyalkyl, sulfoalkyl, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl and hydroxy- (mono or poly) alkyl groups 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 preferable.
  • the amount of dantrolene or a pharmacologically acceptable salt thereof in the aqueous preparation is 0.1-10 mg / ml, preferably 0.2-7.0 mg / ml, more preferably 0.3-4.0 mg. / Ml.
  • the amount of dantrolene or a pharmacologically acceptable salt thereof in the aqueous preparation is 0.25-25.0 mM, more preferably 0.50-17.50 mM, more preferably 0.75-10. It is 0 mM.
  • the blending 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 blending amount of the cyclodextrin derivative with respect to 1 mol of dantrolene or a pharmacologically acceptable salt thereof is 0.5 mol or more and less than 2 mol, preferably 0.7 mol or more and 1.3 mol or less.
  • good dantrolene solubility and turbidity of the preparation can be obtained. Since cyclodextrin derivatives are suspected to be nephrotoxic, it is desirable that the amount of cyclodextrin derivatives be minimized to achieve good dantrolene solubility and formulation turbidity.
  • the blending amount of the cyclodextrin derivative with respect to 1 mol of dantrolene or a pharmacologically acceptable salt thereof is preferably 0.7 mol or more and 1.3 mol or less.
  • Mannitol contained in the second agent can function as an osmotic pressure regulator. Mannitol promotes the production of dantrolene degradation product F-524 (5- (p-nitrophenyl) -2-furaldehyde-2-carboxymethyl-semicarbazone) when present as a lyophilized product with dantrolene and cyclodextrin derivatives. Has been clarified (see Examples).
  • the amount of mannitol blended in the aqueous dantrolene preparation is preferably an amount such that the osmotic pressure ratio of the aqueous dantrolene preparation to the physiological saline solution is 0.8-1.2.
  • the blending amount of mannitol is appropriately set so as to realize the osmotic pressure ratio according to the reconstituted volume of the aqueous dantrolene preparation.
  • the amount of mannitol contained in the second agent is 800 mg.
  • the amount of mannitol contained in the second agent is 3000 mg.
  • the second agent is preferably provided as an aqueous composition containing mannitol.
  • the second agent is provided as a frozen powder of mannitol, and an aqueous solvent provided together with the second agent or an aqueous composition containing mannitol is used by mixing the aqueous solvent separately obtained by the preparer with the second agent. May be prepared at times.
  • the aqueous solvent is water or a mixture of a physiologically acceptable solvent and water, preferably water.
  • Physiologically acceptable solvents include C1-6 alcohols (particularly ethanol), polyethylene glycol, propylene glycol, glycerol, dimethylacetamide, dimethylisosorbide, dimethylsulfoxide, 1-methyl-2-2pyrrolidone and 1-ethyl-2-. Pyrrolidone can be mentioned.
  • the aqueous dantrolene preparation according to the present invention may contain a pH adjuster, an osmotic pressure adjuster and / or a surfactant.
  • the osmotic pressure regulator is a fat having 2-10 carbon atoms selected from the group consisting of mannitol, fructose, glucose, gluconolactone, gluconate, sucrose, lactose, trehalose, dextrose, dextran, and hydroxyethyl starch. It is selected from the group consisting of group polyhydroxyalkanols and mixtures thereof.
  • the pH regulator is used in an amount suitable for adjusting and maintaining the osmotic pressure of the formulation to about 1 (ratio to saline).
  • the osmotic pressure adjusting agent is particularly preferably mannitol, and when mannitol is used as the osmotic pressure adjusting agent, mannitol is contained only in the second agent. That is, in the aqueous dantrolene preparation according to the present invention, the first agent does not contain mannitol.
  • the osmotic pressure adjusting agent can be blended with any one or more of the first agent and the second agent.
  • the pH regulator is selected from the group consisting of citrate, carbonate, phosphate, arginine, lysine, meglumin, tromethamine, histidine and mixtures thereof.
  • the pH regulator is used in an amount suitable for adjusting and maintaining the pH of the formulation within the range described below.
  • the surfactant is not particularly limited, but is 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.
  • NIKKOL HCO-60 Nikko Chemicals Co., Ltd.
  • Polysolvate 20 NIKKOL TL-10, Nikko Chemicals Co., Ltd.
  • Polyethylene glycol Macrogol 400, Sanyo Kasei Kogyo Co., Ltd.
  • Polyoxyethylene fatty acid examples thereof include monoester (ionet MO-400 or MS-400, Sanyo Kasei Kogyo Co., Ltd.) and glyceryl monostearate (TG-C, Sanyo Kasei Kogyo Co., Ltd.).
  • the pH adjuster and the surfactant can be blended in any one or more of the first agent and the second agent.
  • the aqueous dantrolene preparation according to the present invention is reconstituted at the time of use by adding the second agent also contained in a container such as a vial to the first agent contained in a container such as a vial to dissolve the first agent.
  • “during use” is immediately before use (for example, intravenous injection), and examples thereof include 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, and 30 minutes before use, and in some cases, before use. It means about 45 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours. It is preferable to use a shorter time before use in order to suppress the formation of dantrolene decomposition products.
  • the melting temperature is preferably 40 ° C. or higher and 45 ° C. or lower.
  • the pH of the preparation after dissolution is adjusted to 9.0-10.5, preferably 9.3-10.0.
  • the amount of dantrolene decomposition product F-524 (5- (p-nitrophenyl) -2-furaldehyde-2-carboxymethyl-semicarbazone) in the redissolved solution was measured using a liquid chromatograph. As a control, the same measurement was performed under the condition that mannitol was not added.
  • the ratio of the impurity F-524 to the amount of dantrolene initially added was in the range of 43.13-48.72%, and remarkable decomposition of dantrolene occurred.
  • the ratio of the impurity F-524 to the amount of dantrolene initially added was 0.60%. It was revealed that mannitol promotes the decomposition of dantrolene in a lyophilized product containing mannitol and dantrolene in the presence of a cyclodextrin derivative.

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Abstract

As a technique for suppressing the generation of impurities in an aqueous formulation of dantrolene or a pharmacologically acceptable salt thereof, there is provided a dantrolene aqueous formulation including dantrolene or a pharmacologically acceptable salt thereof and mannitol, wherein the dantrolene aqueous formulation comprises a first agent including a dry powder of dantrolene or a pharmacologically acceptable salt thereof, and a second agent composed of an aqueous composition including mannitol, the first agent and the second agent being prepared at the time of use.

Description

ダントロレン水性製剤及びその調製方法Aqueous dantrolene preparation and its preparation method
　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 is a serious complication with the highest mortality rate. Malignant hyperthermia develops in patients with a genetic predisposition to general anesthesia with volatile inhalational anesthetics (such as halothane) or muscle relaxants (such as suxamethonium). Characteristic symptoms of malignant hyperthermia are muscle rigidity, tachycardia and a rapid increase in body temperature.
　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 injectable preparation is the only therapeutic drug for malignant hyperthermia. Dantrolene is a muscle relaxant that suppresses the release of calcium ions from the sarcoplasmic reticulum by blocking the ryanodine receptor and blocking the transmission process of excitement from the transverse tubule to the sarcoplasmic reticulum. Causes relaxation.
　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）を生成するため、水性組成物としての貯蔵寿命が短い。分解は、ｐＨ値の増加とともに加速され、高温で増強される。不純物の生成を抑制するため、ダントロレン注射製剤は、ダントロレンの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。 Dantrolene is hydrolyzed in an alkaline solution and decomposed by hydantoin ring-opening to produce a ring-opening compound (5- (p-nitrophenyl) -2-furaldehyde-2-carboxymethyl-semicarbazone), so that it is used as an aqueous composition. Has a short shelf life. Degradation is accelerated with increasing pH value and enhanced at elevated temperatures. In order to suppress the formation of impurities, the dantrolene injection preparation is used by dissolving and reconstitution of an aqueous composition of dantrolene which has been dried and powdered immediately before use.
　特許文献１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。 Patent Document 1 proposes to prevent the decomposition of dantrolene by using a positive salt or a hydrogen salt of an alkali metal.
特開昭５３－２０４１３号公報Japanese Unexamined Patent Publication No. 53-20413
　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において不純物の生成を抑制するための技術を提供することを主な目的とする。 A main object of the present invention is to provide a technique for suppressing the formation of impurities in an aqueous preparation of dantrolene or a pharmacologically acceptable salt thereof.
　上記課題解決のため、本発明は、以下の［１］－［２１］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マンニトールとを含むダントロレン水性製剤であって、
ダントロレン又はその薬理学的に許容され得る塩の乾燥粉末を含む第１剤と、マンニトールを含む水性組成物からなる第２剤と、を含んでなり、
第１剤と第２剤とが用時調製される、
ダントロレン水性製剤。
［２］　第１剤に、シクロデキストリン誘導体の乾燥粉末をさらに含む、［１］のダントロレン水性製剤。
［３］　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、［２］のダントロレン水性製剤。
［４］　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、［３］のダントロレン水性製剤。
［５］　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、［２］－［４］のいずれかのダントロレン水性製剤。
［６］第２剤が、マンニトールを、ダントロレン水性製剤の生理食塩液に対する浸透圧比を０．８－１．２とする量で含む、［１］－［５］のいずれかのダントロレン水性製剤。
［７］　静注用注射製剤である、［１］－［６］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]-[21].
[1] An aqueous preparation of dantrolene containing dantrolene or a pharmacologically acceptable salt thereof and mannitol.
It comprises a first agent containing a dry powder of dantrolene or a pharmacologically acceptable salt thereof and a second agent consisting of an aqueous composition containing mannitol.
The first agent and the second agent are prepared at the time of use,
Dantrolene aqueous formulation.
[2] The aqueous preparation of dantrolene according to [1], which further comprises a dry powder of a cyclodextrin derivative as a first agent.
[3] The aqueous preparation of dantrolene according to [2], wherein the amount of the cyclodextrin derivative to be blended with respect to 1 mol of dantrolene or a pharmacologically acceptable salt thereof is 0.5 mol or more and less than 2 mol.
[4] The aqueous preparation of dantrolene according to [3], wherein the amount of the cyclodextrin derivative to be blended with respect to 1 mol of dantrolene or a pharmacologically acceptable salt thereof is 0.7 mol or more and 1.3 mol or less.
[5] Any one of [2]-[4], wherein the cyclodextrin derivative is at least one selected from the group consisting of hydroxypropyl-β-cyclodextrin, β-cyclodextrin and α-cyclodextrin. Dextrin aqueous formulation.
[6] The aqueous dantrolene preparation according to any one of [1]-[5], wherein the second agent contains mannitol in an amount such that the osmotic pressure ratio of the aqueous dantrolene preparation to the physiological saline solution is 0.8-1.2.
[7] An aqueous dantrolene preparation according to any one of [1] to [6], which is an injection preparation for intravenous injection.
［８］　ダントロレン又はその薬理学的に許容され得る塩の乾燥粉末を含む製剤であって、
マンニトールを含む水性組成物からなる製剤と組み合わせて、ダントロレン又はその薬理学的に許容され得る塩とマンニトールとを含むダントロレン水性製剤の用時調製に用いられる、製剤。
［９］　シクロデキストリン誘導体の乾燥粉末をさらに含む、［８］の製剤。
［１０］　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、［９］の製剤。
［１１］　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、［１０］の製剤。
［１２］　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、［８］－［１１］のいずれかの製剤。 [8] A preparation containing a dry powder of dantrolene or a pharmacologically acceptable salt thereof.
A preparation used for the preparation of an aqueous dantrolene preparation containing mannitol and dantrolene or a pharmacologically acceptable salt thereof in combination with a preparation consisting of an aqueous composition containing mannitol.
[9] The preparation of [8] further comprising a dry powder of a cyclodextrin derivative.
[10] The preparation of [9], wherein the amount of the cyclodextrin derivative to be blended with respect to 1 mol of dantrolene or a pharmacologically acceptable salt thereof is 0.5 mol or more and less than 2 mol.
[11] The preparation of [10], wherein the amount of the cyclodextrin derivative to be blended with respect to 1 mol of dantrolene or a pharmacologically acceptable salt thereof is 0.7 mol or more and 1.3 mol or less.
[12] Any one of [8]-[11], wherein the cyclodextrin derivative is at least one selected from the group consisting of hydroxypropyl-β-cyclodextrin, β-cyclodextrin and α-cyclodextrin. Formulation.
［１３］　マンニトールを含む水性組成物からなる製剤であって、
ダントロレン又はその薬理学的に許容され得る塩の乾燥粉末を含む製剤と組み合わせて、ダントロレン又はその薬理学的に許容され得る塩とマンニトールとを含むダントロレン水性製剤の用時調製に用いられる、製剤。
［１４］　製剤におけるマンニトールの配合量が、ダントロレン水性製剤の生理食塩液に対する浸透圧比を０．８－１．２とする量である、［１３］の製剤。 [13] A preparation comprising an aqueous composition containing mannitol.
A preparation used for the preparation of an aqueous dantrolene preparation containing dantrolene or a pharmacologically acceptable salt thereof and mannitol in combination with a preparation containing a dry powder of dantrolene or a pharmacologically acceptable salt thereof.
[14] The preparation of [13], wherein the blending amount of mannitol in the preparation is an amount such that the osmotic pressure ratio of the aqueous dantrolene preparation to the physiological saline solution is 0.8-1.2.
［１５］　ダントロレン又はその薬理学的に許容され得る塩とマンニトールとを含む、ダントロレン水性製剤の用時調製方法であって、
ダントロレン又はその薬理学的に許容され得る塩の乾燥粉末を含む第１剤と、マンニトールを含む水性組成物を含む第２剤と、用時に混合する手順を含む、方法。
［１６］　第１剤が、シクロデキストリン誘導体の乾燥粉末をさらに含む、［１５］の方法。
［１７］　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、［１６］の方法。
［１８］　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、［１７］の方法。
［１９］　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、［１６］－［１８］のいずれかの方法。
［２０］　第２剤が、マンニトールを、ダントロレン水性製剤の生理食塩液に対する浸透圧比を０．８－１．２とする量で含む、［１５］－［１９］のいずれかの方法。
［２１］　ダントロレン水性製剤が、静注用注射製剤である、［１５］－［２０］のいずれかの方法。 [15] A method for preparing an aqueous preparation of dantrolene at the time of use, which comprises dantrolene or a pharmacologically acceptable salt thereof and mannitol.
A method comprising a procedure of mixing in use a first agent comprising a dry powder of dantrolene or a pharmacologically acceptable salt thereof and a second agent comprising an aqueous composition containing mannitol.
[16] The method of [15], wherein the first agent further comprises a dry powder of a cyclodextrin derivative.
[17] The method of [16], wherein the amount of the cyclodextrin derivative to be blended with respect to 1 mol of dantrolene or a pharmacologically acceptable salt thereof is 0.5 mol or more and less than 2 mol.
[18] The method of [17], wherein the amount of the cyclodextrin derivative to be blended with respect to 1 mol of dantrolene or a pharmacologically acceptable salt thereof is 0.7 mol or more and 1.3 mol or less.
[19] Any one of [16]-[18], wherein the cyclodextrin derivative is at least one selected from the group consisting of hydroxypropyl-β-cyclodextrin, β-cyclodextrin and α-cyclodextrin. the method of.
[20] The method according to any one of [15] to [19], wherein the second agent contains mannitol in an amount such that the osmotic pressure ratio of the aqueous dantrolene preparation to the physiological saline solution is 0.8-1.2.
[21] The method according to any one of [15] to [20], wherein the aqueous dantrolene preparation is an injectable preparation for intravenous injection.
　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において不純物の生成を抑制するための技術が提供される。 The present invention provides a technique for suppressing the formation of impurities in an aqueous preparation of dantrolene or a pharmacologically 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, a suitable mode for carrying out the present invention will be described. It should be noted that the embodiments described below show an example of typical embodiments of the present invention, and the scope of the present invention is not narrowly interpreted by this.
　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マンニトールとを含むダントロレン水性製剤であって、ダントロレン又はその薬理学的に許容され得る塩の乾燥粉末を含む第１剤と、マンニトールを含む水性組成物からなる第２剤とを含んでなり、第１剤と第２剤とが用時調製されることを特徴とする。ダントロレン又はその薬理学的に許容され得る塩の乾燥粉末を含む第１剤と、マンニトールを含む水性組成物を含む第２剤とを用時に混合してダントロレン水性製剤を調製することにより、シクロデキストリン誘導体の存在下でマンニトールとダントロレンとが凍結乾燥物として共在する場合において生じるダントロレンの分解を抑制して、不純物の含有がより少ないダントロレン水性製剤を得ることができる。 The aqueous dantrolene preparation according to the present invention is a dantrolene aqueous preparation containing dantrolene or a pharmacologically acceptable salt thereof and mannitol, and the first dantrolene aqueous preparation containing a dry powder of dantrolene or a pharmacologically acceptable salt thereof. It comprises an agent and a second agent composed of an aqueous composition containing mannitol, and the first agent and the second agent are prepared at the time of use. Cyclodextrin by preparing an aqueous preparation of dantrolene by mixing a first agent containing a dry powder of dantrolene or a pharmacologically acceptable salt thereof and a second agent containing an aqueous composition containing mannitol at the time of use. It is possible to suppress the decomposition of dantrolene that occurs when mannitol and dantrolene coexist as a freeze-dried product in the presence of a derivative, and to obtain an aqueous preparation of dantrolene containing less impurities.
　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。 The pharmacologically acceptable salts of dantrolene are alkali metal salts, alkaline earth metal salts, ammonium salts, alkylammonium salts, polyalkylammonium salts, arylammonium salts, substituted or unsubstituted quinolidinium salts, and substituted or unsubstituted quinolidinium salts. It may be any one or more salts selected from the group consisting of pyridinium salts.
The pharmacologically acceptable salt of dantrolene is preferably a sodium salt, a potassium salt, an ammonium salt, a calcium salt, a magnesium salt, and particularly preferably a sodium salt.
　第１剤は、ダントロレン又はその薬理学的に許容され得る塩の乾燥粉末に加えて、シクロデキストリン誘導体の乾燥粉末をさらに含んでいてもよい。 The first agent may further contain a dry powder of a cyclodextrin derivative in addition to a dry powder of dantrolene or a pharmacologically acceptable salt thereof.
　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。 Cyclodextrin is a cyclic (α-1,4) -linked oligosaccharide with a hydrophobic central cavity and a hydrophilic outer surface.
A cyclodextrin derivative is obtained by introducing a substituent selected from the group consisting of alkyl, hydroxyalkyl, carboxyalkyl, sulfoalkyl, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl and hydroxy- (mono or poly) alkyl groups 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 preferable.
　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 pharmacologically acceptable salt thereof in the aqueous preparation is 0.1-10 mg / ml, preferably 0.2-7.0 mg / ml, more preferably 0.3-4.0 mg. / Ml.
The amount of dantrolene or a pharmacologically acceptable salt thereof in the aqueous preparation is 0.25-25.0 mM, more preferably 0.50-17.50 mM, more preferably 0.75-10. It is 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 blending 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。
　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。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、かつ澄明な水性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 blending amount of the cyclodextrin derivative with respect to 1 mol of dantrolene or a pharmacologically acceptable salt thereof is 0.5 mol or more and less than 2 mol, preferably 0.7 mol or more and 1.3 mol or less.
By blending about 0.7 mol or more of the cyclodextrin derivative with 1 mol of dantrolene or a pharmacologically acceptable salt thereof, good dantrolene solubility and turbidity of the preparation can be obtained. Since cyclodextrin derivatives are suspected to be nephrotoxic, it is desirable that the amount of cyclodextrin derivatives be minimized to achieve good dantrolene solubility and formulation turbidity. Therefore, the blending amount of the cyclodextrin derivative with respect to 1 mol of dantrolene or a pharmacologically 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 within the above compounding ratio range, the solubility of dantrolene can be improved and a clear aqueous preparation can be obtained. Therefore, the aqueous dantrolene preparation according to the present invention is effective for promptly and easily providing an intravenous dantrolene injection preparation in the clinical setting of malignant hyperthermia.
　第２剤に含まれるマンニトールは、浸透圧調整剤として機能し得るものである。マンニトールは、ダントロレン及びシクロデキストリン誘導体とともに凍結乾燥物として存在する場合に、ダントロレンの分解産物Ｆ－５２４（5-(p-nitrophenyl)-2-furaldehyde-2-carboxymethyl-semicarbazone）の生成を促進することが明らかとなっている（実施例参照）。 Mannitol contained in the second agent can function as an osmotic pressure regulator. Mannitol promotes the production of dantrolene degradation product F-524 (5- (p-nitrophenyl) -2-furaldehyde-2-carboxymethyl-semicarbazone) when present as a lyophilized product with dantrolene and cyclodextrin derivatives. Has been clarified (see Examples).
　ダントロレン水性製剤におけるマンニトールの配合量は、ダントロレン水性製剤の生理食塩液に対する浸透圧比を０．８－１．２とする量とされることが好ましい。マンニトールの配合量は、ダントロレン水性製剤の再構成容量に応じて上記浸透圧比を実現するように適宜設定されるものである。例えば、ダントロレン水性製剤が容量20 mLで再構成される場合、第２剤に含まれるマンニトールの配合量は800 mgとされる。ダントロレン水性製剤が容量60 mLで再構成される場合、第２剤に含まれるマンニトールの配合量は3000 mgとされる。 The amount of mannitol blended in the aqueous dantrolene preparation is preferably an amount such that the osmotic pressure ratio of the aqueous dantrolene preparation to the physiological saline solution is 0.8-1.2. The blending amount of mannitol is appropriately set so as to realize the osmotic pressure ratio according to the reconstituted volume of the aqueous dantrolene preparation. For example, when the aqueous dantrolene preparation is reconstituted in a volume of 20 mL, the amount of mannitol contained in the second agent is 800 mg. When the aqueous dantrolene preparation is reconstituted with a volume of 60 mL, the amount of mannitol contained in the second agent is 3000 mg.
　第２剤はマンニトールを含む水性組成物として提供されることが好ましい。しかし、第２剤がマンニトールの凍結粉末として提供され、これと供に提供される水性溶媒あるいは調製者において別途入手された水性溶媒と第２剤とが混合されてマンニトールを含む水性組成物が用時調製されてもよい。
　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。 The second agent is preferably provided as an aqueous composition containing mannitol. However, the second agent is provided as a frozen powder of mannitol, and an aqueous solvent provided together with the second agent or an aqueous composition containing mannitol is used by mixing the aqueous solvent separately obtained by the preparer with the second agent. May be prepared at times.
The aqueous solvent is water or a mixture of a physiologically acceptable solvent and water, preferably water.
Physiologically acceptable solvents include C1-6 alcohols (particularly ethanol), polyethylene glycol, propylene glycol, glycerol, dimethylacetamide, dimethylisosorbide, dimethylsulfoxide, 1-methyl-2-2pyrrolidone and 1-ethyl-2-. Pyrrolidone can be mentioned.
　本発明に係るダントロレン水性製剤は、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 according to the present invention may contain a pH adjuster, an osmotic pressure adjuster and / or a surfactant.
　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。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。
　浸透圧調整剤は特にマンニトールが好ましく、浸透圧調整剤にマンニトールが用いられる場合には、マンニトールは第２剤のみに含有される。すなわち、本発明に係るダントロレン水性製剤において、第１剤は、マンニトールを含まない。マンニトール以外の浸透圧調整剤が用いられる場合には、浸透圧調整剤は第１剤及び第２剤のいずれか１以上に配合できる。 The osmotic pressure regulator is a fat having 2-10 carbon atoms selected from the group consisting of mannitol, fructose, glucose, gluconolactone, gluconate, sucrose, lactose, trehalose, dextrose, dextran, and hydroxyethyl starch. It is selected from the group consisting of group polyhydroxyalkanols and mixtures thereof. The pH regulator is used in an amount suitable for adjusting and maintaining the osmotic pressure of the formulation to about 1 (ratio to saline).
The osmotic pressure adjusting agent is particularly preferably mannitol, and when mannitol is used as the osmotic pressure adjusting agent, mannitol is contained only in the second agent. That is, in the aqueous dantrolene preparation according to the present invention, the first agent does not contain mannitol. When an osmotic pressure adjusting agent other than mannitol is used, the osmotic pressure adjusting agent can be blended with any one or more of the first agent and the second agent.
　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を後述する範囲内に調整し維持するのに適した量で用いられる。
　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。
　ｐＨ調節剤及び界面活性剤は、第１剤及び第２剤のいずれか１以上に配合できる。 The pH regulator is selected from the group consisting of citrate, carbonate, phosphate, arginine, lysine, meglumin, tromethamine, histidine and mixtures thereof. The pH regulator is used in an amount suitable for adjusting and maintaining the pH of the formulation within the range described below.
The surfactant is not particularly limited, but is 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.), Polysolvate 20 (NIKKOL TL-10, Nikko Chemicals Co., Ltd.), Polyethylene glycol (Macrogol 400, Sanyo Kasei Kogyo Co., Ltd.), Polyoxyethylene fatty acid Examples thereof include monoester (ionet MO-400 or MS-400, Sanyo Kasei Kogyo Co., Ltd.) and glyceryl monostearate (TG-C, Sanyo Kasei Kogyo Co., Ltd.).
The pH adjuster and the surfactant can be blended in any one or more of the first agent and the second agent.
　本発明に係るダントロレン水性製剤は、バイアル等の容器に収容された第１剤に、同じくバイアル等の容器に収容された第２剤を加えて第１剤を溶解させることにより用時に再構成される。 The aqueous dantrolene preparation according to the present invention is reconstituted at the time of use by adding the second agent also contained in a container such as a vial to the first agent contained in a container such as a vial to dissolve the first agent. To.
　ここで、「用時」とは、使用（例えば静脈注射）の直前であって、例えば使用前1分、5分、10分、15分、20分、30分が例示され、場合によって使用前45分、60分、2時間、3時間、4時間、5時間、6時間程度を意味する。ダントロレンの分解産物の生成を抑制するため、使用前のより短い時間であることが好ましい。 Here, "during use" is immediately before use (for example, intravenous injection), and examples thereof include 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, and 30 minutes before use, and in some cases, before use. It means about 45 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours. It is preferable to use a shorter time before use in order to suppress the formation of dantrolene decomposition products.
　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。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 melting temperature is preferably 40 ° C. or higher and 45 ° C. or lower. By setting the dissolution temperature in the above range, the solubility of dantrolene can be further improved and a clearer preparation can be obtained. Therefore, good solubility of dantrolene and turbidity of the preparation can be achieved while suppressing the amount of the cyclodextrin derivative to be blended with dantrolene or a pharmacologically acceptable salt thereof as compared with the usual dissolution at room temperature. there is a possibility.
If the temperature exceeds the above temperature range, there is a concern that the production of impurities due to the 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。 The pH of the preparation 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 formation of impurities while maintaining good solubility of dantrolene.
［試験例１：乾燥粉末中においてマンニトールがダントロレンの安定性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）８０ｍｇ（５２ｍＭ）及びマンニトール８００ｍｇを水１０ｍｌに添加し、４５℃に加熱して溶解させた。溶液を２５℃まで冷却した後、凍結乾燥した。乾燥粉末を６０℃で１週間静置した後に水１２ｍｌに再溶解した。再溶解液中のダントロレンの分解産物Ｆ－５２４（5-(p-nitrophenyl)-2-furaldehyde-2-carboxymethyl-semicarbazone）の量を、液体クロマトグラフを用いて測定した。
　対照として、マンニトールを添加しない条件でも同様の測定を行った。 [Test Example 1: Examination of the effect of mannitol on the stability of dantrolene in dry powder]
20 mg (50 mM) of dantrolene sodium, 80 mg (52 mM) of hydroxypropyl-β-cyclodextrin (HPβCD) and 800 mg of mannitol were added to 10 ml of water and heated to 45 ° C. to dissolve them. The solution was cooled to 25 ° C. and then lyophilized. The dry powder was allowed to stand at 60 ° C. for 1 week and then redissolved in 12 ml of water. The amount of dantrolene decomposition product F-524 (5- (p-nitrophenyl) -2-furaldehyde-2-carboxymethyl-semicarbazone) in the redissolved solution was measured using a liquid chromatograph.
As a control, the same measurement was performed under the condition that mannitol was not added.
液体クロマトグラフ測定条件
　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１」に示す。 Liquid chromatograph measurement conditions Column: ZORBAX ODS, 4.6 mm x 150 mm, 5 μm
Diluted solution: 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 1".
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　マンニトールの添加条件では、当初添加したダントロレンの量に占める不純物Ｆ－５２４の割合は４３．１３－４８．７２％の範囲であり、ダントロレンの顕著な分解が生じた。一方、マンニトールの非添加条件では、当初添加したダントロレンの量に占める不純物Ｆ－５２４の割合は０．６０％であった。シクロデキストリン誘導体の存在下、マンニトールとダントロレンとを含む凍結乾燥物において、マンニトールがダントロレンの分解を促進することが明らかとなった。 Under the conditions for adding mannitol, the ratio of the impurity F-524 to the amount of dantrolene initially added was in the range of 43.13-48.72%, and remarkable decomposition of dantrolene occurred. On the other hand, under the non-additional condition of mannitol, the ratio of the impurity F-524 to the amount of dantrolene initially added was 0.60%. It was revealed that mannitol promotes the decomposition of dantrolene in a lyophilized product containing mannitol and dantrolene in the presence of a cyclodextrin derivative.

Claims (9)

  1. 　ダントロレン又はその薬理学的に許容され得る塩とマンニトールとを含むダントロレン水性製剤であって、
    ダントロレン又はその薬理学的に許容され得る塩の乾燥粉末を含む第１剤と、マンニトールを含む水性組成物からなる第２剤と、を含んでなり、
    第１剤と第２剤とが用時調製される、
    ダントロレン水性製剤。     An aqueous preparation of dantrolene containing dantrolene or a pharmacologically acceptable salt thereof and mannitol.
    It comprises a first agent containing a dry powder of dantrolene or a pharmacologically acceptable salt thereof and a second agent consisting of an aqueous composition containing mannitol.
    The first agent and the second agent are prepared at the time of use,
    Dantrolene aqueous formulation.
  2. 　第１剤に、シクロデキストリン誘導体の乾燥粉末をさらに含む、請求項１記載のダントロレン水性製剤。 The aqueous dantrolene preparation according to claim 1, further comprising a dry powder of a cyclodextrin derivative in the first agent.
  3. 　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、請求項２記載のダントロレン水性製剤。 The aqueous preparation of dantrolene according to claim 2, wherein the amount of the cyclodextrin derivative to be blended with respect to 1 mol of dantrolene or a pharmacologically acceptable salt thereof is 0.5 mol or more and less than 2 mol.
  4. 　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３記載のダントロレン水性製剤。 The aqueous dantrolene preparation according to claim 3, wherein the amount of the cyclodextrin derivative to be blended with respect to 1 mol of dantrolene or a pharmacologically acceptable salt thereof is 0.7 mol or more and 1.3 mol or less.
  5. 　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２－４のいずれか一項に記載のダントロレン水性製剤。 The invention according to any one of claims 2-4, wherein the cyclodextrin derivative is at least one selected from the group consisting of hydroxypropyl-β-cyclodextrin, β-cyclodextrin and α-cyclodextrin. Dextrin aqueous formulation.
  6. 　第２剤が、マンニトールを、ダントロレン水性製剤の生理食塩液に対する浸透圧比を０．８－１．２とする量で含む、請求項１－５のいずれか一項に記載のダントロレン水性製剤。 The aqueous dantrolene preparation according to any one of claims 1-5, wherein the second agent contains mannitol in an amount such that the osmotic pressure ratio of the aqueous dantrolene preparation to the physiological saline solution is 0.8-1.2.
  7. 　ダントロレン又はその薬理学的に許容され得る塩の乾燥粉末を含む製剤であって、
    マンニトールを含む水性組成物からなる製剤と組み合わせて、ダントロレン又はその薬理学的に許容され得る塩とマンニトールとを含むダントロレン水性製剤の用時調製に用いられる、製剤。     A preparation containing a dry powder of dantrolene or a pharmacologically acceptable salt thereof.
    A preparation used for the preparation of an aqueous dantrolene preparation containing mannitol and dantrolene or a pharmacologically acceptable salt thereof in combination with a preparation consisting of an aqueous composition containing mannitol.
  8. 　マンニトールを含む水性組成物からなる製剤であって、
    ダントロレン又はその薬理学的に許容され得る塩の乾燥粉末を含む製剤と組み合わせて、ダントロレン又はその薬理学的に許容され得る塩とマンニトールとを含むダントロレン水性製剤の用時調製に用いられる、製剤。     A preparation consisting of an aqueous composition containing mannitol.
    A preparation used for the preparation of an aqueous dantrolene preparation containing dantrolene or a pharmacologically acceptable salt thereof and mannitol in combination with a preparation containing a dry powder of dantrolene or a pharmacologically acceptable salt thereof.
  9. 　ダントロレン又はその薬理学的に許容され得る塩とマンニトールとを含む、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の乾燥粉末を含む第１剤と、マンニトールを含む水性組成物を含む第２剤と、用時に混合する手順を含む、方法。     A method for preparing an aqueous preparation of dantrolene, which comprises dantrolene or a pharmacologically acceptable salt thereof and mannitol.
    A method comprising a procedure of mixing in use a first agent comprising a dry powder of dantrolene or a pharmacologically acceptable salt thereof and a second agent comprising an aqueous composition containing mannitol.
PCT/JP2019/035122 2019-09-06 2019-09-06 Dantrolene aqueous formulation and method for preparing same WO2021044608A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018531268A (en) * 2015-10-20 2018-10-25 ベー．ブラウン メルスンゲン アクチェンゲゼルシャフト Aqueous composition containing dantrolene
JP2019505571A (en) * 2015-12-18 2019-02-28 ヴィヴォルックス アーベー Pharmaceutical composition comprising an indole derivative, process for its preparation and use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018531268A (en) * 2015-10-20 2018-10-25 ベー．ブラウン メルスンゲン アクチェンゲゼルシャフト Aqueous composition containing dantrolene
JP2019505571A (en) * 2015-12-18 2019-02-28 ヴィヴォルックス アーベー Pharmaceutical composition comprising an indole derivative, process for its preparation and use thereof

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