TW202010495A - Aqueous product of dantrolene and preparation method thereof having 0.5 mole or more but less than 2 moles of cyclodextrin derivatives relative to 1 mole of dantrolene or a pharmacologically acceptable salt thereof - Google Patents

Abstract

As a technique for quickly and simply preparing an aqueous product of dantrolene or a pharmacologically acceptable salt thereof, the present invention provides an aqueous product of dantrolene, which includes dantrolene or a pharmacologically acceptable salt thereof, and cyclodextrin derivatives, wherein the mole ratio of the aqueous product is 0.5 mole or more but less than 2 moles of cyclodextrin derivatives relative to 1 mole of dantrolene or a pharmacologically acceptable salt thereof.

Description

丹曲林水性製劑及其調製方法 Dantrolene aqueous preparation and its preparation method

本發明係關於丹曲林(Dantrolene)水性製劑及其調製方法。 The invention relates to an aqueous formulation of Dantroline and its preparation method.

惡性高熱症為全身麻醉之併發症，為死亡率最高的嚴重併發症。惡性高熱症係由於使用揮發性吸入***(哈樂仙(halothane)等)或肌肉鬆弛劑(琥珀膽鹼(suxamethonium)等)之全身麻醉，而於具有遺傳素因之患者中發病。惡性高熱症之特徴性症狀為肌肉僵硬、心搏過速及急速的體溫上升。 Malignant hyperthermia is a complication of general anesthesia and the most serious complication of mortality. Malignant hyperthermia is caused by general anesthesia using volatile inhalation anesthetics (halothane, etc.) or muscle relaxants (suxamethonium, etc.), and it develops in patients with genetic factors. The characteristic symptoms of malignant hyperthermia are stiff muscles, tachycardia, and rapid temperature rise.

丹曲林(Dantrolene)注射製劑為對惡性高熱症之唯一治療藥。丹曲林為肌肉鬆弛劑之一，藉由遮斷雷諾丁(ryanodine)受體，遮斷從橫小管至肌質網(sarcoplasmic reticulum)之興奮的傳達過程，而抑制來自肌質網之鈣離子的游離，引起肌肉鬆弛。 Dantroline (Dantrolene) injection preparation is the only treatment for malignant hyperthermia. Dantrolene is one of the muscle relaxants, by blocking the ryanodine receptor, blocking the transmission of excitement from the lateral tubule to the sarcoplasmic reticulum, and inhibiting calcium ions from the sarcoplasmic reticulum The dissociation of muscles causes muscle relaxation.

丹曲林注射製劑係以使用時調製的方式來使用。丹曲林由於作為水性組成物之儲藏壽命短，故係將水性組成物乾燥而作成粉末者於即將使用前進行溶解、再構成而使用。丹曲林注射製劑係於小瓶中添加注射用水而搖勻，確認溶液變得澄清後再使用。然而，丹曲林 由於對水為極難溶性，為了溶解需要大量的溶媒，耗費工夫，有所謂的緊急時難以迅速地調製之問題。 Dantraline injection formulations are used in a manner that is prepared at the time of use. Dantrolene has a short shelf life as an aqueous composition. Therefore, the dried aqueous composition is powdered and dissolved and reconstituted before use. Dantrolene injection preparation is added to the vial with water for injection and shaken to confirm that the solution becomes clear before use. However, dantrolene is extremely insoluble in water, so a large amount of solvent is required to dissolve it, which takes a lot of time and has a problem that it is difficult to prepare quickly in an emergency.

專利文獻1中，嘗試使用環糊精衍生物來改善丹曲林之溶解度。專利文獻1中所記載之丹曲林水性組成物，係作成相對於1莫耳之丹曲林或其藥理學上可容許之鹽，摻合2-30莫耳之環糊精衍生物者。另一方面，環糊精衍生物有腎毒性的疑慮。 In Patent Document 1, attempts are made to use cyclodextrin derivatives to improve the solubility of dantrolene. The aqueous composition of dantrolene described in Patent Document 1 is prepared by blending 2 to 30 moles of cyclodextrin derivative with respect to 1 mole of dantrolene or a pharmacologically acceptable salt thereof. On the other hand, cyclodextrin derivatives have doubts about nephrotoxicity.

又，已知丹曲林於鹼溶液中受到水解，藉由乙內醯脲(hydantoin)開環而分解，生成開環化合物(5-(對硝基苯基)-2-糠醛-2-羧甲基-縮胺脲)。分解係隨著pH值之增加而加速，於高溫增強。 Furthermore, it is known that dantrolene is hydrolyzed in an alkaline solution and decomposes by hydantoin ring opening to generate a ring-opening compound (5-(p-nitrophenyl)-2-furaldehyde-2-carboxy Methyl-semicarbazone). The decomposition is accelerated with the increase of pH value and enhanced at high temperature.

專利文獻2中，提案使用鹼金屬之正鹽或氫鹽來防止丹曲林之分解。 In Patent Document 2, it is proposed to use a positive salt or a hydrogen salt of an alkali metal to prevent the decomposition of dantrolene.

與本發明相關地，非專利文獻1中，報導丹曲林之羥丙基-β-環糊精包合錯合物(clathrate complex)改善利用經口投與之丹曲林的生體可用率。同一文獻係將丹曲林與羥丙基-β-環糊精於45℃攪拌3小時而形成包合錯合物，但其中相對於250mg之丹曲林，使用10g之大量的羥丙基-β-環糊精(參照154頁右欄「2.2 Preparation of Da-HP-β-CD complex」)。 In connection with the present invention, Non-Patent Document 1 reports that the hydroxypropyl-β-cyclodextrin inclusion complex of dantrolene improves the bioavailability of dantrolene administered orally . In the same literature, Dantraline and hydroxypropyl-β-cyclodextrin were stirred at 45°C for 3 hours to form inclusion complexes. However, compared with 250mg of Dantraline, a large amount of 10g of hydroxypropyl- β-cyclodextrin (refer to “2.2 Preparation of Da-HP-β-CD complex” on the right column on page 154).

[先前技術文獻] [Prior Technical Literature] [專利文獻] [Patent Literature]

[專利文獻1]國際公開第2017/067980號 [Patent Literature 1] International Publication No. 2017/067980

[專利文獻2]日本特開昭53-20413號公報 [Patent Document 2] Japanese Unexamined Patent Publication No. 53-20413

[非專利文獻] [Non-patent literature]

[專利文獻1]「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 [Patent Literature 1] "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

本發明之主要目的係提供用以迅速且簡便地調製丹曲林或其藥理學上可容許之鹽之水性製劑的技術。 The main object of the present invention is to provide a technique for quickly and easily preparing an aqueous preparation of dantrolene or a pharmacologically acceptable salt thereof.

為了解決上述課題，本發明提供以下之[1]至[15]。 In order to solve the above problems, the present invention provides the following [1] to [15].

[1]一種丹曲林水性製劑，其包含丹曲林或其藥理學上可容許之鹽、及環糊精衍生物，相對於1莫耳之丹曲林或其藥理學上可容許之鹽，環糊精衍生物之摻合量為0.5莫耳以上且小於2莫耳。 [1] An aqueous formulation of dantrolene, comprising dantrolene or a pharmacologically acceptable salt thereof, and a cyclodextrin derivative, relative to 1 mole of dantrolene or a pharmacologically acceptable salt thereof The blending amount of cyclodextrin derivatives is 0.5 mole or more and less than 2 moles.

[2]如[1]之丹曲林水性製劑，其中相對於1莫耳之丹曲林或其藥理學上可容許之鹽，環糊精衍生物之摻合量為0.7莫耳以上1.3莫耳以下。 [2] The aqueous formulation of dantrolene of [1], wherein the blending amount of the cyclodextrin derivative is 0.7 mole or more and 1.3 mole relative to 1 mole of dantrolene or a pharmacologically acceptable salt thereof. Below the ear.

[3]如[1]或[2]之丹曲林水性製劑，其中前述環糊精衍生物係選自包含羥丙基-β-環糊精、β-環糊精及α-環糊精之群組中的任一種以上。 [3] The dantrolene aqueous preparation according to [1] or [2], wherein the cyclodextrin derivative is selected from the group consisting of hydroxypropyl-β-cyclodextrin, β-cyclodextrin and α-cyclodextrin More than one of the groups.

[4]如[1]至[3]中任一項之丹曲林水性製劑，其為靜脈注射用注射製劑。 [4] The dantrolene aqueous preparation according to any one of [1] to [3], which is an injection preparation for intravenous injection.

[5]一種丹曲林水性製劑調製套組，其係包含丹曲林或其藥理學上可容許之鹽、環糊精衍生物及水性溶媒而成，相對於1莫耳之丹曲林或其藥理學上可容許之鹽，環糊精衍生物之量為0.5莫耳以上且小於2莫耳。 [5] A dantrolene aqueous formulation preparation kit comprising dantrolene or a pharmacologically acceptable salt thereof, a cyclodextrin derivative, and an aqueous solvent, which is 1 mole of dantrolene or The amount of its pharmacologically acceptable salt and cyclodextrin derivative is more than 0.5 mol and less than 2 mol.

[6]如[5]之丹曲林水性製劑調製套組，其中相對於1莫耳之丹曲林或其藥理學上可容許之鹽，環糊精衍生物之量為0.7莫耳以上1.3莫耳以下。 [6] The dantrolene aqueous preparation kit of [5], wherein the amount of cyclodextrin derivative is 0.7 mole or more relative to 1 mole of dantrolene or its pharmacologically acceptable salt Moore below.

[7]如[5]或[6]之丹曲林水性製劑調製套組，其中前述環糊精衍生物係選自包含羥丙基-β-環糊精、β-環糊精及α-環糊精之群組中的任一種以上。 [7] The dantrolene aqueous preparation kit of [5] or [6], wherein the cyclodextrin derivative is selected from the group consisting of hydroxypropyl-β-cyclodextrin, β-cyclodextrin and α- More than one of the cyclodextrin group.

[8]如[5]至[7]中任一項之丹曲林水性製劑調製套組，其為靜脈注射用注射製劑調製套組。 [8] The dantrolene aqueous preparation preparation kit according to any one of [5] to [7], which is an injection preparation preparation kit for intravenous injection.

[9]一種調製方法，其係丹曲林水性製劑之調製方法，其包含於40℃以上45℃以下，使丹曲林或其藥理學上可容許之鹽、及環糊精衍生物溶解於水性溶媒中的步驟，其中相對於1莫耳之丹曲林或其藥理學上可容許之鹽，環糊精衍生物之量為0.5莫耳以上且小於2莫耳。 [9] A preparation method, which is a method for preparing an aqueous formulation of dantrolene, which is contained above 40°C and below 45°C, so that dantrolene or its pharmacologically acceptable salt, and cyclodextrin derivative are dissolved in A step in an aqueous vehicle in which the amount of cyclodextrin derivative is 0.5 mole or more and less than 2 moles relative to 1 mole of dantrolene or a pharmacologically acceptable salt thereof.

[10]如[9]之調製方法，其中在前述步驟中，製劑之Ph係調製成9.0-10.5。 [10] The preparation method according to [9], wherein in the aforementioned step, the Ph of the preparation is adjusted to 9.0-10.5.

[11]如[10]之調製方法，其中在前述步驟中，製劑之pH係調製成9.3-10.0。 [11] The preparation method according to [10], wherein in the aforementioned step, the pH of the preparation is adjusted to 9.3-10.0.

[12]如[9]至[11]中任一項之調製方法，其中相對於1莫耳之丹曲林或其藥理學上可容許之鹽，環糊精衍生物之量為0.7莫耳以上1.3莫耳以下。 [12] The preparation method according to any one of [9] to [11], wherein the amount of the cyclodextrin derivative is 0.7 mol relative to 1 mol of dantrolene or a pharmacologically acceptable salt thereof Above 1.3 moles and below.

[13]如[9]至[12]之調製方法，其中前述環糊精衍生物係選自包含羥丙基-β-環糊精、β-環糊精及α-環糊精之群組中的任一種以上。 [13] The preparation method as described in [9] to [12], wherein the aforementioned cyclodextrin derivative is selected from the group consisting of hydroxypropyl-β-cyclodextrin, β-cyclodextrin and α-cyclodextrin More than one of them.

[14]如[9]至[13]中任一項之調製方法，其中丹曲林水性製劑係靜脈注射用注射製劑。 [14] The preparation method according to any one of [9] to [13], wherein the aqueous formulation of dantrolene is an injection preparation for intravenous injection.

[15]一種調製方法，其係丹曲林靜脈注射用注射製劑之調製方法，其包含於40℃以上45℃以下，使丹曲林鈉(Dantrolene sodium)、及羥丙基-β-環糊精溶解於水中而得到pH9.0-10.0之製劑的步驟，其中相對於1莫耳之丹曲林鈉，羥丙基-β-環糊精之量為0.73莫耳以上1.31莫耳以下。 [15] A preparation method, which is a preparation method of an injectable preparation for dantrolene intravenous injection, which comprises at 40°C or more and 45°C or less, dantrolene sodium (Dantrolene sodium) and hydroxypropyl-β-cyclodextrin The step of dissolving sperm in water to obtain a formulation of pH 9.0-10.0, wherein the amount of hydroxypropyl-β-cyclodextrin is 0.73 mol or more and 1.31 mol or less relative to 1 mol of dantrolene sodium.

本發明之主要目的係提供用以迅速且簡便地調製丹曲林或其藥理學上可容許之鹽之水性製劑的技術。 The main object of the present invention is to provide a technique for quickly and easily preparing an aqueous preparation of dantrolene or a pharmacologically acceptable salt thereof.

[實施發明之形態] [Forms for carrying out the invention]

以下，針對用以實施本發明之適當形態加以說明。此外，以下所說明之實施形態係顯示本發明之代表性實施形態之一例者，本發明之範圍並不因此而被狹 隘地解釋。 Hereinafter, suitable forms for implementing the present invention will be described. In addition, the embodiment described below shows an example of a representative embodiment of the present invention, and the scope of the present invention is not therefore narrowly interpreted.

本發明之丹曲林水性製劑，包含丹曲林或其藥理學上可容許之鹽、及環糊精衍生物，相對於1莫耳之丹曲林或其藥理學上可容許之鹽，環糊精衍生物之摻合量係設為0.5莫耳以上且小於2莫耳。 The aqueous formulation of dantrolene of the present invention comprises dantrolene or a pharmacologically acceptable salt thereof and a cyclodextrin derivative. With respect to 1 mole of dantrolene or a pharmacologically acceptable salt thereof, the ring The blending amount of the dextrin derivative is set to 0.5 mol or more and less than 2 mol.

又，本發明之丹曲林水性製劑調製套組，係包含丹曲林或其藥理學上可容許之鹽、環糊精衍生物並任意地包含水性溶媒而成，相對於1莫耳之丹曲林或其藥理學上可容許之鹽，環糊精衍生物之量係設為0.5莫耳以上且小於2莫耳。 In addition, the dantrolene aqueous formulation preparation kit of the present invention contains dantrolene or a pharmacologically acceptable salt thereof, a cyclodextrin derivative, and optionally contains an aqueous solvent. The amount of Qu Lin or its pharmacologically acceptable salt, and the amount of cyclodextrin derivative is set to 0.5 mole or more and less than 2 mole.

以下顯示丹曲林之構造。 The following shows the structure of Danqulin.

丹曲林之藥理學上可容許之鹽，可為選自包含鹼金屬鹽、鹼土金屬鹽、銨鹽、烷基銨鹽、多烷基銨鹽、芳基銨鹽、取代或非取代喹

鎓(quinolizinium)鹽、及取代或非取代吡啶鎓(pyridinium)鹽之群組中的任一種以上之鹽。 The pharmacologically acceptable salt of dantrolene can be selected from the group consisting of alkali metal salts, alkaline earth metal salts, ammonium salts, alkyl ammonium salts, polyalkyl ammonium salts, aryl ammonium salts, substituted or unsubstituted quinoline

Any one or more salts in the group of quinolizinium salts and substituted or unsubstituted pyridinium salts.

丹曲林之藥理學上可容許之鹽，較佳為鈉鹽、鉀鹽、銨鹽、鈣鹽、鎂鹽，特佳為鈉鹽。 The pharmacologically acceptable salt of dantrolene is preferably sodium salt, potassium salt, ammonium salt, calcium salt, magnesium salt, particularly preferably sodium salt.

水性溶媒為水、或生理學上容許之溶媒與水之混合物，較佳為水。 The aqueous solvent is water, or a mixture of physiologically acceptable solvent and water, preferably water.

就生理學上容許之溶媒而言，可列舉C1-6醇(尤其乙醇)、聚乙二醇、丙二醇、甘油、二甲基乙醯胺、二甲基異山梨醇酯(dimethyl isosorbide)、二甲基亞碸、1-甲基-2-2吡咯啶酮及1-乙基-2-吡咯啶酮。 Examples of physiologically acceptable solvents include C1-6 alcohols (especially ethanol), polyethylene glycol, propylene glycol, glycerin, dimethylacetamide, dimethyl isosorbide, and dimethyl isosorbide. Methyl sulfoxide, 1-methyl-2-2pyrrolidone and 1-ethyl-2-pyrrolidone.

此外，水性溶媒並非本發明之套組的必須構成要素，可為調製者從套組以外取得者。 In addition, the aqueous solvent is not an essential component of the kit of the present invention, and may be obtained from outside the kit by the modulator.

環糊精為具有疏水性中心空洞及親水性外表面之環狀(α-1,4)鍵結寡糖。 Cyclodextrin is a cyclic (α-1,4) bonded oligosaccharide with a hydrophobic central cavity and a hydrophilic outer surface.

環糊精衍生物為對環糊精導入選自包含烷基、羥基烷基、羧基烷基、磺酸基烷基(sulfoalkyl)、烷基羰氧基烷基、烷氧基羰基烷基及羥基-(單或多)烷基之群組中的取代基者。 The cyclodextrin derivative is selected from the group consisting of alkyl, hydroxyalkyl, carboxyalkyl, sulfoalkyl, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, and hydroxyl groups. -Substituents in the group of (single or multiple) alkyl groups.

環糊精衍生物可為選自包含羥丙基-β-環糊精、β-環糊精及α-環糊精之群組中的任一種以上。其中，特佳為羥丙基-β-環糊精。 The cyclodextrin derivative may be any one or more selected from the group consisting of hydroxypropyl-β-cyclodextrin, β-cyclodextrin, and α-cyclodextrin. Among them, particularly preferred is hydroxypropyl-β-cyclodextrin.

丹曲林或其藥理學上可容許之鹽於水性製劑中之摻合量為0.1-10mg/ml，較佳為0.2-7.0mg/ml，更佳為0.3-4.0mg/ml。 The blending amount of dantrolene or its pharmacologically acceptable salt in an aqueous preparation is 0.1-10 mg/ml, preferably 0.2-7.0 mg/ml, and more preferably 0.3-4.0 mg/ml.

又，丹曲林或其藥理學上可容許之鹽於水性製劑中之摻合量為0.25-25.0mM，較佳為0.50-17.50mM，更佳為0.75-10.0mM。 In addition, the blending amount of dantrolene or its pharmacologically acceptable salt in the aqueous preparation is 0.25-25.0 mM, preferably 0.50-17.50 mM, more preferably 0.75-10.0 mM.

環糊精衍生物於水性製劑中之摻合量為3.4-13.7mg/ml，較佳為5-9.5mg/ml。 The blending amount of the cyclodextrin derivative in the aqueous preparation is 3.4-13.7 mg/ml, preferably 5-9.5 mg/ml.

又，環糊精衍生物於水性製劑中之摻合量為25-99mM，較佳為36-69mM。 In addition, the blending amount of the cyclodextrin derivative in the aqueous preparation is 25-99 mM, preferably 36-69 mM.

相對於1莫耳之丹曲林或其藥理學上可容許之鹽，環糊精衍生物之摻合量係設為0.5莫耳以上且小於2莫耳，較佳設為0.7莫耳以上1.3莫耳以下。 The blending amount of the cyclodextrin derivative is set to 0.5 mol or more and less than 2 mol, preferably 0.7 mol or more with respect to 1 mol of dantrolene or its pharmacologically acceptable salt. Moore below.

在後述之試驗例1中可知，藉由相對於1莫耳之丹曲林或其藥理學上可容許之鹽而摻合約0.7莫耳以上之環糊精衍生物，可得到良好的丹曲林之溶解度及製劑之濁度。環糊精衍生物由於有腎毒性之疑慮，其摻合量期望設為用以達成良好的丹曲林之溶解度及製劑之濁度的必要最小限度。因此，相對於1莫耳之丹曲林或其藥理學上可容許之鹽，環糊精衍生物之摻合量較佳為0.7莫耳以上1.3莫耳以下。 As can be seen in Test Example 1 described later, by blending a cyclodextrin derivative of 0.7 mole or more with respect to 1 mole of dantrolene or a pharmacologically acceptable salt thereof, good dantrolene can be obtained The solubility and turbidity of the preparation. The cyclodextrin derivative is suspected of nephrotoxicity, and its blending amount is desirably the minimum necessary to achieve good solubility of dantrolene and turbidity of the preparation. Therefore, the blending amount of the cyclodextrin derivative is preferably 0.7 mol or more and 1.3 mol or less with respect to 1 mol of dantrolene or its pharmacologically acceptable salt.

藉由在丹曲林或其藥理學上可容許之鹽中以上述摻合比率範圍添加環糊精衍生物，可使丹曲林之溶解度提高，且得到澄清之製劑。因此，若依據本發明之丹曲林水性製劑及其調製套組，則在惡性高熱症之臨床中，對於用以迅速且簡便地提供丹曲林靜脈注射用注射製劑係有效的。 By adding cyclodextrin derivatives in the above-mentioned blending ratio range to dantrolene or its pharmacologically acceptable salt, the solubility of dantrolene can be improved and a clear formulation can be obtained. Therefore, according to the Dantraline aqueous preparation and its preparation kit according to the present invention, it is effective for quickly and simply providing an injection preparation for intravenous administration of Dantraline in the clinical malignant hyperthermia.

丹曲林水性製劑及其調製套組，亦可包含pH調節劑、滲透壓調整劑及/或界面活性劑。 The dantrolene aqueous preparation and its preparation kit may also contain a pH adjusting agent, an osmotic pressure adjusting agent and/or a surfactant.

pH調節劑係選自包含檸檬酸鹽、碳酸鹽、磷酸鹽、精胺酸、離胺酸、葡甲胺(meglumine)、胺丁三醇(tromethamine)、組胺酸及彼等之混合物的群組。pH調節劑係以適於將製劑之pH調整並維持於上述範圍內的 量來使用。 The pH adjusting agent is selected from the group consisting of citrate, carbonate, phosphate, arginine, lysine, meglumine, tromethamine, histidine, and mixtures thereof group. The pH adjusting agent is used in an amount suitable for adjusting and maintaining the pH of the preparation within the above range.

滲透壓調整劑係選自包含具有2~10個碳原子之脂肪族多羥基烷醇及彼等之混合物的群組，該具有2~10個碳原子之脂肪族多羥基烷醇係選自包含甘露醇、果糖、葡萄糖、葡萄糖酸內酯、葡萄糖酸鹽、蔗糖、乳糖、海藻糖、右旋糖、葡聚糖、羥乙基澱粉之群組。其中，特佳為甘露醇。pH調節劑係以適於將製劑之滲透壓調整並維持於約1(相對於生理食鹽水之比)的量來使用。 The osmotic pressure adjusting agent is selected from the group containing aliphatic polyhydroxyalkanols having 2 to 10 carbon atoms and mixtures thereof, the aliphatic polyhydroxyalkanol having 2 to 10 carbon atoms is selected from The group of mannitol, fructose, glucose, gluconolactone, gluconate, sucrose, lactose, trehalose, dextrose, dextran, hydroxyethyl starch. Among them, particularly good is mannitol. The pH adjusting agent is used in an amount suitable for adjusting and maintaining the osmotic pressure of the preparation at about 1 (ratio to physiological saline).

就界面活性劑而言，無特別限定，但可例示PEG-40氫化蓖麻油(NIKKOL HCO-40，Nikko Chemicals股份有限公司)、PEG-50氫化蓖麻油(NIKKOL HCO-50，Nikko Chemicals股份有限公司)、PEG-60氫化蓖麻油(NIKKOL HCO-60，Nikko Chemicals股份有限公司)、聚山梨醇酯20(NIKKOL TL-10，Nikko Chemicals股份有限公司)、聚乙二醇(Macrogol 400，三洋化成工業股份有限公司)、聚氧伸乙基脂肪酸單酯(IONET MO-400或MS-400，三洋化成工業股份有限公司)及單硬脂酸甘油酯(TG-C，三洋化成工業股份有限公司)。 The surfactant is not particularly limited, but examples include PEG-40 hydrogenated castor oil (NIKKOL HCO-40, Nikko Chemicals Co., Ltd.) and 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 Industry Co., Ltd.), polyoxyethylene ethyl fatty acid monoester (IONET MO-400 or MS-400, Sanyo Chemical Industry Co., Ltd.) and glyceryl monostearate (TG-C, Sanyo Chemical Industry Co., Ltd.).

丹曲林水性製劑調製套組，藉由在收容於小瓶等容器中之丹曲林或其藥理學上可容許之鹽及環糊精衍生物中添加水性溶媒，使其溶解，可再構成而作成丹曲林水性製劑。 Dantrolene aqueous formulation preparation kit is prepared by adding an aqueous solvent to dantrolene or its pharmacologically acceptable salt and cyclodextrin derivative contained in a container such as a vial to dissolve it and reconstitute it. Make an aqueous formulation of dantrolene.

溶解時之溫度較佳為40℃以上45℃以下。藉由將溶解溫度設定於上述範圍，可進一步使丹曲林之溶 解度提高，且得到更澄清之製劑(試驗例2)。因此，與通常室溫下之溶解相比，有抑制相對於丹曲林或其藥理學上可容許之鹽之環糊精衍生物的摻合量，同時可達成良好的丹曲林溶解度及製劑濁度的可能性。 The temperature during dissolution is preferably 40°C or higher and 45°C or lower. By setting the dissolution temperature within the above range, the solubility of dantrolene can be further improved, and a clearer preparation can be obtained (Test Example 2). Therefore, compared with the normal room temperature dissolution, the blending amount of cyclodextrin derivative with respect to dantrolene or its pharmacologically acceptable salt is suppressed, and at the same time, good dantrolene solubility and preparation can be achieved The possibility of turbidity.

此外，若超過上述溫度範圍，有增強因丹曲林之水解所造成之雜質生成的疑慮。 In addition, if the above temperature range is exceeded, there is a concern that the generation of impurities due to the hydrolysis of dantrolene may be enhanced.

溶解後之製劑的pH係調製成9.0-10.5，較佳調製成9.3-10.0。藉由將製劑之pH設定於上述範圍，可維持丹曲林之良好的溶解度，同時亦抑制雜質之生成(試驗例3)。 The pH of the dissolved preparation is adjusted to 9.0-10.5, preferably 9.3-10.0. By setting the pH of the preparation within the above range, the good solubility of dantrolene can be maintained while also suppressing the formation of impurities (Test Example 3).

[實施例] [Example]

[試驗例1：丹曲林與環糊精衍生物之莫耳比對丹曲林之溶解度及製劑之濁度所造成之影響的檢討] [Test Example 1: Review of the effect of the molar ratio of dantrolene and cyclodextrin derivatives on the solubility of dantrolene and the turbidity of the preparation]

將20mg(50mM)之丹曲林鈉、羥丙基-β-環糊精(HPβCD)及800mg之甘露醇溶解於10ml之45℃之水中，攪拌15分鐘而製劑化。 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 prepare a formulation.

使HPβCD之添加莫耳量變化而測定丹曲林之溶解度及製劑之濁度。 The molar amount of HPβCD added was changed to determine the solubility of dantrolene and the turbidity of the preparation.

丹曲林之溶解度的測定係以如以下之方式進行。 The measurement of the solubility of dantrolene was carried out as follows.

分取1mL之樣本，以0.22μm之過濾器過濾後，以純水稀釋成0.02μg/mL。以紫外-可見光分光光度計測定稀釋液之吸光度(390nm)。基於預先作成之校正曲線，從所測定之吸光度算出溶解度。 A 1 mL sample was taken, filtered with a 0.22 μm filter, and diluted with pure water to 0.02 μg/mL. The absorbance (390nm) of the diluted solution was measured with an ultraviolet-visible light spectrophotometer. Based on the calibration curve prepared in advance, the solubility was calculated from the measured absorbance.

製劑之濁度係將5mL之樣本裝入小瓶中，以 濁度計測定。 The turbidity of the formulation was measured by measuring the turbidity by filling a 5 mL sample into a vial.

將結果示於「表1」。 The results are shown in "Table 1."

可知藉由相對於1莫耳之丹曲林鈉添加0.73莫耳以上之HPβCD，可得到良好的丹曲林之溶解度及製劑之濁度。 It can be seen that by adding more than 0.73 moles of HPβCD to 1 mole of dantrolene sodium, good dantrolene solubility and turbidity of the preparation can be obtained.

[試驗例2：溶解溫度對丹曲林之溶解度及製劑之濁度所造成之影響的檢討] [Test Example 2: Review of the effect of dissolution temperature on the solubility of dantrolene and the turbidity of the preparation]

將20mg之丹曲林鈉、75mg之HPβCD及800mg之甘露醇溶解於10ml之水中，攪拌15分鐘而製劑化。 20 mg of dantrolene sodium, 75 mg of HPβCD, and 800 mg of mannitol were dissolved in 10 ml of water, stirred for 15 minutes, and formulated.

使溶解溫度變化，以與試驗例1同樣的方式測定丹曲林之溶解度及製劑之濁度。 The dissolution temperature was changed, and the solubility of dantrolene and the turbidity of the preparation were measured in the same manner as in Test Example 1.

將結果示於「表2」。 The results are shown in "Table 2."

當溶解溫度為35℃時製劑之濁度不良。可知藉由將溶解溫度設為40℃(較佳為45℃)，可得到良好的丹曲林之溶解度及製劑之濁度。 When the dissolution temperature is 35°C, the turbidity of the preparation is poor. It can be seen that by setting the dissolution temperature to 40°C (preferably 45°C), good dantrolene solubility and turbidity of the preparation can be obtained.

[試驗例3：調製時之pH對丹曲林之溶解度以及製劑之濁度及雜質濃度所造成之影響的檢討] [Test Example 3: Review of the effect of pH during preparation on the solubility of dantrolene and the turbidity and impurity concentration of the preparation]

將20mg之丹曲林鈉、200mg之HPβCD及800mg之甘露醇於室溫下溶解於10ml之水中，攪拌24小時而製劑化。 20 mg of dantrolene sodium, 200 mg of HPβCD, and 800 mg of mannitol were dissolved in 10 ml of water at room temperature, stirred for 24 hours, and formulated.

藉由變更調製時所維持的水之pH範圍，而使調製後之製劑的pH變化，以與試驗例1同樣的方式測定丹曲林之溶解度。 By changing the pH range of the water maintained at the time of preparation, the pH of the prepared preparation was changed, and the solubility of dantrolene was measured in the same manner as in Test Example 1.

將結果示於「表3」。 The results are shown in "Table 3."

繼而，將20mg之丹曲林鈉、75mg之HPβCD及800mg之甘露醇溶解於10ml之水中，攪拌約30~50秒而製劑化。 Then, 20 mg of dantrolene sodium, 75 mg of HPβCD and 800 mg of mannitol were dissolved in 10 ml of water and stirred for about 30 to 50 seconds to prepare a formulation.

藉由變更調製時所維持的水之pH範圍，而使調製後之製劑的pH變化，測定製劑之濁度及雜質濃度。製劑之濁度係以與試驗例1同樣的方式測定。 By changing the pH range of the water maintained at the time of preparation, the pH of the preparation after preparation was changed, and the turbidity and impurity concentration of the preparation were measured. The turbidity of the preparation was measured in the same manner as in Test Example 1.

雜質(5-(對硝基苯基)-2-糠醛-2-羧甲基-縮胺脲：F-524)係從丹曲林原體因經時變化所生成之分解物。F-524之濃度的測定係使用液體層析，藉由以下之條件進行。 Impurity (5-(p-nitrophenyl)-2-furaldehyde-2-carboxymethyl-semicarbazone: F-524) is a decomposed product formed from the original dantrolene body due to changes over time. The concentration of F-524 was measured using liquid chromatography under the following conditions.

管柱：ZORBAX ODS,4.6mm×150mm,5μm Column: ZORBAX ODS, 4.6mm×150mm, 5μm

稀釋液：60%乙腈 Diluent: 60% acetonitrile

緩衝液：乙酸銨緩衝液，pH4.5±0.1 Buffer: Ammonium acetate buffer, pH4.5±0.1

移動相A：840mL之緩衝液、560mL之乙腈及49mL之乙酸的混合液 Mobile phase A: a mixture of 840 mL of buffer, 560 mL of acetonitrile, and 49 mL of acetic acid

移動相B：350mL之乙腈與150mL之純水的混合液 Mobile phase B: a mixture of 350mL of acetonitrile and 150mL of pure water

梯度條件：示於「表4」。 Gradient conditions: shown in "Table 4".

將結果示於「表5」。 The results are shown in "Table 5."

從「表3」所示的溶解度之結果可知，製劑 之pH較佳為調製成9.0以上。又，從「表5」所示之結果，若pH低則濁度變高，可預測隨著pH變高而雜質濃度上升。從此等結果，可認為製劑之pH期望為約9.3-10.0。 From the results of the solubility shown in "Table 3", the pH of the preparation is preferably adjusted to 9.0 or more. Furthermore, from the results shown in "Table 5", if the pH is low, the turbidity becomes high, and it can be predicted that the impurity concentration increases as the pH becomes high. From these results, it can be considered that the pH of the formulation is expected to be about 9.3-10.0.

Claims (8)

一種丹曲林(Dantrolene)水性製劑，其包含丹曲林或其藥理學上可容許之鹽、及環糊精衍生物，相對於1莫耳之丹曲林或其藥理學上可容許之鹽，環糊精衍生物之摻合量為0.5莫耳以上且小於2莫耳。 An aqueous formulation of Dantroline (Dantrolene) comprising Dantroline or a pharmacologically acceptable salt thereof and a cyclodextrin derivative, relative to 1 mol of Dantraline or a pharmacologically acceptable salt thereof The blending amount of cyclodextrin derivatives is 0.5 mole or more and less than 2 moles. 如請求項1之丹曲林水性製劑，其中相對於1莫耳之丹曲林或其藥理學上可容許之鹽，環糊精衍生物之摻合量為0.7莫耳以上1.3莫耳以下。 The aqueous formulation of dantrolene according to claim 1, wherein the blending 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. 如請求項1或2之丹曲林水性製劑，其中該環糊精衍生物係選自包含羥丙基-β-環糊精、β-環糊精及α-環糊精之群組中的任一種以上。 The dantrolene aqueous formulation of claim 1 or 2, wherein the cyclodextrin derivative is selected from the group consisting of hydroxypropyl-β-cyclodextrin, β-cyclodextrin and α-cyclodextrin Any one or more. 一種丹曲林水性製劑調製套組，其係包含丹曲林或其藥理學上可容許之鹽、環糊精衍生物、及水性溶媒而成，相對於1莫耳之丹曲林或其藥理學上可容許之鹽，環糊精衍生物之量為0.5莫耳以上且小於2莫耳。 A dantrolene aqueous formulation preparation kit, which comprises dantrolene or its pharmacologically acceptable salt, cyclodextrin derivative, and aqueous solvent, relative to 1 dmol of dantrolene or its pharmacology The amount of salt that can be tolerated in science, the amount of cyclodextrin derivative is more than 0.5 mole and less than 2 mole. 一種調製方法，其係丹曲林水性製劑之調製方法，其包含於40℃以上45℃以下，使丹曲林或其藥理學上可容許之鹽、及環糊精衍生物溶解於水性溶媒中的步驟，其中相對於1莫耳之丹曲林或其藥理學上可容許之鹽，環糊精衍生物之量為0.5莫耳以上且小於2莫耳。 A preparation method, which is a preparation method of an aqueous formulation of dantrolene, which is contained at a temperature of 40°C or more and 45°C or less, so that dantrolene or a pharmacologically acceptable salt thereof, and a cyclodextrin derivative are dissolved in an aqueous solvent Wherein the amount of cyclodextrin derivative is 0.5 mole or more and less than 2 moles relative to 1 mole of dantrolene or its pharmacologically acceptable salt. 如請求項5之調製方法，其中在該步驟中，製劑之pH係調製成9.0-10.5。 The preparation method according to claim 5, wherein in this step, the pH of the preparation is adjusted to 9.0-10.5. 如請求項6之調製方法，其中在該步驟中，製劑之pH 係調製成9.3-10.0。 The preparation method according to claim 6, wherein in this step, the pH of the preparation is adjusted to 9.3-10.0. 一種調製方法，其係丹曲林靜脈注射用注射製劑之調製方法，其包含於40℃以上45℃以下，使丹曲林鈉(Dantrolene sodium)、及羥丙基-β-環糊精溶解於水中而得到pH9.0-10.0之製劑的步驟，其中相對於1莫耳之丹曲林鈉，羥丙基-β-環糊精之量為0.73莫耳以上1.31莫耳以下。 A preparation method, which is a preparation method of an injectable preparation for intravenous injection of dantrolene, which is contained at a temperature above 40°C and below 45°C, so as to dissolve Dantroline sodium (Dantrolene sodium) and hydroxypropyl-β-cyclodextrin in The step of obtaining a preparation of pH 9.0-10.0 in water, wherein the amount of hydroxypropyl-β-cyclodextrin is 0.73 mol or more and 1.31 mol or less relative to 1 mol of dantrolene sodium.