KR20210056359A - Dantrolene aqueous preparation and preparation method thereof - Google Patents

Abstract

As a technology for quickly and conveniently preparing an aqueous formulation of dantrolene or a pharmacologically acceptable salt thereof, it contains dantrolene or a pharmacologically acceptable salt thereof, a cyclodextrin derivative, and There is provided an aqueous dantrolene formulation in which the blending amount of the cyclodextrin derivative with respect to 1 mole of ene or a pharmacologically acceptable salt thereof is 0.5 moles or more and less than 2 moles.

Description

Dantrolene aqueous preparation and preparation method thereof

The present invention relates to an aqueous dantrolene formulation and a preparation method thereof.

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 by general anesthesia using volatile inhalation anesthetics (halotan, etc.) or muscle relaxants (samethonium, etc.). The characteristic symptoms of malignant hyperthermia are muscle stiffness, tachycardia, and a sudden rise in body temperature.

Dantrolene injection formulation is the only treatment for malignant hyperthermia. Dantrolene is one of the muscle relaxants. It blocks the rianodine receptor and blocks the transfer of excitation from the transverse canal to the muscle vesicles, thereby inhibiting the release of calcium ions from the muscle vesicles, and muscle relaxation. Causes.

Dantrolene injection formulations are used as preparations for use. Since dantrolene has a short shelf life as an aqueous composition, the aqueous composition is dried and powdered, dissolved immediately before use, and reconstituted to be used. Dantrolene injection formulation is used after adding water for injection to a vial, shaking and mixing, and confirming that the solution is clear. However, since dantrolene is very poorly soluble in water, there is a problem that a large amount of solvent is required for dissolution and it takes time, and it is difficult to prepare it quickly in an emergency.

In Patent Document 1, an attempt has been made to improve the solubility of dantrolene by using a cyclodextrin derivative. The dantrolene aqueous composition described in Patent Document 1 is a mixture of 2 to 30 moles of a cyclodextrin derivative with respect to 1 mole of dantrolene or a pharmacologically acceptable salt thereof. On the other hand, cyclodextrin derivatives are concerned about nephrotoxicity.

In addition, it is known that dantrolene undergoes hydrolysis in an alkaline solution and is decomposed by hydantoin ring opening to produce a ring-opening compound (5-(p-nitrophenyl)-2-furaldehyde-2-carboxymethyl-semicarbazone). Decomposition accelerates with an increase in the pH value and is enhanced at high temperatures.

In Patent Document 2, it is proposed to prevent decomposition of dantrolene by using a pure salt or a hydrogen salt of an alkali metal.

In connection with the present invention, Non-Patent Document 1 reports that the hydroxypropyl-β-cyclodextrin inclusion complex of dantrolene improved the bioavailability of dantrolen by oral administration. In this document, dantrolene and hydroxypropyl-β-cyclodextrin are stirred at 45° C. for 3 hours to form an inclusion complex, but here, a large amount of hydroxypropyl-β- is 10 g per 250 mg of dantrolene. Cyclodextrin is being used (refer to “2.2 Preparation of Da-HP-β-CD complex” on the right side of page 154).

International Publication No. 2017/067980 Japanese Patent Laid-Open Publication No. 53-20413

(Patent Document 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

The main object of the present invention is to provide a technique for quickly and conveniently preparing an aqueous formulation of dantrolene or a pharmacologically acceptable salt thereof.

In order to solve the said subject, this invention provides the following [1]-[15].

[1] containing dantrolene or a pharmacologically acceptable salt thereof, and a cyclodextrin derivative,

Dantrolene aqueous formulation, wherein the blending amount of the cyclodextrin derivative with respect to 1 mole of dantrolene or a pharmacologically acceptable salt thereof is 0.5 moles or more and less than 2 moles.

[2] The dantrolene aqueous formulation of [1], wherein the compounding amount of the cyclodextrin derivative with respect to 1 mole of dantrolene or a pharmacologically acceptable salt thereof is 0.7 moles or more and 1.3 moles or less.

[3] The aqueous dantrolene formulation 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. .

[4] The dantrolene aqueous formulation according to any one of [1] to [3], which is an intravenous injection formulation.

[5] comprising dantrolene or a pharmacologically acceptable salt thereof, a cyclodextrin derivative, and an aqueous solvent,

Dantrolene aqueous formulation preparation kit, wherein the amount of the cyclodextrin derivative per 1 mole of dantrolene or a pharmacologically acceptable salt thereof is 0.5 moles or more and less than 2 moles.

[6] The kit for preparing an aqueous dantrolene formulation according to [5], wherein the amount of the cyclodextrin derivative per 1 mole of dantrolene or a pharmacologically acceptable salt thereof is 0.7 moles or more and 1.3 moles or less.

[7] The aqueous dantrolene formulation of [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. Preparation kit.

[8] The dantrolene aqueous preparation kit according to any one of [5] to [7], which is an intravenous injection preparation kit.

[9] As a method for preparing an aqueous dantrolene formulation,

Dantrolene or a pharmacologically acceptable salt thereof and a procedure of dissolving a cyclodextrin derivative in an aqueous solvent at 40°C or higher and 45°C or lower, wherein in 1 mol of dantrolene or a pharmacologically acceptable salt thereof A preparation method comprising, wherein the amount of the cyclodextrin 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 to 10.5 in the above procedure.

[11] The preparation method of [10], wherein the pH of the preparation is adjusted to 9.3 to 10.0 in the above procedure.

[12] The method for preparing any one of [9] to [11], wherein the amount of the cyclodextrin derivative per 1 mol of dantrolene or a pharmacologically acceptable salt thereof is 0.7 mol or more and 1.3 mol or less.

[13] The preparation method of [9] to [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 for preparing any one of [9] to [13], wherein the aqueous dantrolene formulation is an intravenous injection formulation.

[15] As a method for preparing an intravenous injection formulation for dantrolene,

Procedure for obtaining a formulation having a pH of 9.0 to 10.0 by dissolving sodium dantrolene and hydroxypropyl-β-cyclodextrin in water at 40°C or higher and 45°C or lower, wherein hydroxypropyl-β for 1 mole of sodium dantrolene -The amount of cyclodextrin is 0.73 mol or more and 1.31 mol or less, A preparation method containing.

The main object of the present invention is to provide a technique for quickly and conveniently preparing an aqueous formulation of dantrolene or a pharmacologically acceptable salt thereof.

Hereinafter, preferred embodiments for carrying out the present invention will be described. In addition, the embodiment described below shows an example of a typical embodiment of the present invention, and the scope of the present invention is not narrowly interpreted by this.

The aqueous dantrolene formulation according to the present invention contains dantrolene or a pharmacologically acceptable salt thereof, and a cyclodextrin derivative, per mole of dantrolene or a pharmacologically acceptable salt thereof. The blending amount of the cyclodextrin derivative is 0.5 mol or more and less than 2 mol.

In addition, the kit for preparing an aqueous dantrolene formulation according to the present invention comprises dantrolene or a pharmacologically acceptable salt thereof, a cyclodextrin derivative, and an aqueous solvent optionally, and dantrolene or its pharmacology The amount of the cyclodextrin derivative with respect to 1 mole of the salt that can be acceptable is 0.5 moles or more and less than 2 moles.

The structure of dantrolene is shown below.

[Formula 1]

The pharmacologically 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 quinolinium salts, and substituted or unsubstituted pyridinium salts. Any one or more salts selected from the group consisting of may be used.

The pharmacologically acceptable salt of dantrolene is preferably a sodium salt, a potassium salt, an ammonium salt, a calcium salt, and a magnesium salt, and particularly preferably a sodium salt.

The aqueous solvent is water or a mixture of a physiologically acceptable solvent and water, preferably water.

As a physiologically acceptable solvent, C1-6 alcohol (especially ethanol), polyethylene glycol, propylene glycol, glycerol, dimethylacetamide, dimethylisosorbide, dimethylsulfoxide, 1-methyl-2-2 pyrrolidone and 1-ethyl-2-pyrrolidone is mentioned.

In addition, the aqueous solvent does not become an essential component of the kit according to the present invention, and may be obtained separately from the kit from the manufacturer.

Cyclodextrin is a cyclic (α-1,4) bonded oligosaccharide having a hydrophobic central cavity and a hydrophilic outer surface.

Cyclodextrin derivatives introduce a substituent selected from the group consisting of alkyl, hydroxyalkyl, carboxyalkyl, sulfoalkyl, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl and hydroxy-(mono or poly)alkyl groups to cyclodextrin. It was done.

The cyclodextrin derivative may be any one or more selected from the group consisting of hydroxypropyl-β-cyclodextrin, β-cyclodextrin, and α-cyclodextrin. Among these, hydroxypropyl-β-cyclodextrin is particularly preferred.

The blending amount of dantrolene or a pharmacologically acceptable salt thereof in the aqueous formulation is 0.1 to 10 mg/ml, preferably 0.2 to 7.0 mg/ml, more preferably 0.3 to 4.0 mg/ml.

Further, the blending amount of dantrolene or a pharmacologically acceptable salt thereof in the aqueous formulation is 0.25 to 25.0 mM, more preferably 0.50 to 17.50 mM, more preferably 0.75 to 10.0 mM.

The compounding amount of the cyclodextrin derivative in the aqueous preparation is 3.4 to 13.7 mg/ml, preferably 5 to 9.5 mg/ml.

Moreover, the compounding amount of the cyclodextrin derivative in the aqueous preparation is 25 to 99 mM, preferably 36 to 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.

In Test Example 1 to be described later, it has been found that good solubility of dantrolene and turbidity of the formulation are obtained by blending about 0.7 moles or more of a cyclodextrin derivative with respect to 1 mole of dantrolene or a pharmacologically acceptable salt thereof. . Since the cyclodextrin derivative is suspected of nephrotoxicity, the amount of the cyclodextrin derivative is preferably minimized in order to achieve satisfactory solubility of dantrolene and turbidity of the formulation. 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 in the above blending ratio range, the solubility of dantrolene can be improved and a clear formulation can be obtained. Therefore, according to the aqueous dantrolene formulation and its preparation kit according to the present invention, it is effective because it provides a dantrolene intravenous injection formulation quickly and simply in the clinical trial of malignant hyperthermia.

The dantrolene aqueous preparation and its preparation kit may contain a pH adjuster, an osmotic pressure adjuster, and/or a surfactant.

The pH adjusting agent 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 formulation within the above range.

The osmotic pressure regulator is 2 to 10 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 aliphatic polyhydroxyalkanols having carbon atoms and mixtures thereof. Among these, mannitol is particularly preferred. The osmotic pressure modifier is used in an amount suitable for adjusting and maintaining the osmotic pressure of the formulation to about 1 (ratio to the physiological saline solution).

Although it does not specifically limit as surfactant, 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 Industry Co., Ltd.), polyoxyethylene fatty acid Monoester (Ionet MO-400 or MS-400, Sanyo Chemical Industry Co., Ltd.) and glyceryl monostearate (TG-C, Sanyo Chemical Industry Co., Ltd.) are illustrated.

Dantrolene aqueous formulation preparation kit can be reconstituted as a dantrolene aqueous formulation by adding and dissolving an aqueous solvent to dantrolene or a pharmacologically acceptable salt thereof and a cyclodextrin derivative contained in a container such as a vial. I can.

The temperature at the time of dissolution is preferably 40°C or more and 45°C or less. By setting the dissolution temperature in the above range, the solubility of dantrolene can be further improved, and a clearer formulation can be obtained (Test Example 2). For this reason, compared to the usual dissolution at room temperature, good solubility of dantrolene and turbidity of the formulation can be achieved while suppressing the blending amount of the cyclodextrin derivative with dantrolene or its pharmacologically acceptable salt. There is a possibility.

In addition, when the temperature range is exceeded, there is a concern that generation of impurities due to hydrolysis of dantrolene may increase.

The pH of the preparation after dissolution is adjusted to 9.0 to 10.5, preferably 9.3 to 10.0. By setting the pH of the formulation in the above range, it becomes possible to suppress generation of impurities while maintaining good solubility of dantrolene (Test Example 3).

Example

[Test Example 1: Examination of the effect of the molar ratio of dantrolene and cyclodextrin derivative on the solubility of dantrolene and turbidity of the formulation]

20 mg (50 mM) of sodium dantrolene, hydroxypropyl-β-cyclodextrin (HPβCD) and 800 mg of mannitol were dissolved in 10 ml of 45°C water, and stirred for 15 minutes to prepare a formulation.

By varying the molar amount of HPβCD added, the solubility of dantrolene and the turbidity of the formulation were measured.

The measurement of the solubility of dantrolene was carried out as follows.

1 ml of a sample was separated, filtered through a 0.22 µm filter, and diluted with pure water to 0.02 µg/ml. The absorbance (390 nm) of the diluent was measured with an ultraviolet visible spectrophotometer. The solubility was calculated from the measured absorbance based on the calibration curve prepared in advance.

The turbidity of the formulation was measured with a turbidimeter by putting 5 ml of a sample into a vial.

The results are shown in "Table 1".

It was found that by adding 0.73 moles or more of HPβCD to 1 mole of sodium dantrolene, good solubility of dantrolene and turbidity of the formulation were obtained.

[Test Example 2: Examination of the effect of the dissolution temperature on the solubility of dantrolene and the turbidity of the formulation]

20 mg of sodium dantrolene, 75 mg of HPβCD, and 800 mg of mannitol were dissolved in 10 ml of water, followed by stirring for 15 minutes to prepare a formulation.

While changing the dissolution temperature, the solubility of dantrolene and the turbidity of the formulation were measured in the same manner as in Test Example 1.

The results are shown in "Table 2".

At the dissolution temperature of 35°C, the turbidity of the formulation was poor. It was found that satisfactory solubility of dantrolene and turbidity of the formulation were obtained by setting the dissolution temperature to 40°C (preferably 45°C).

[Test Example 3: Examination of the effect of pH at the time of preparation on the solubility of dantrolene and the turbidity and impurity concentration of the 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, followed by stirring for 24 hours to prepare a formulation.

The pH of the preparation after preparation was changed by changing the pH range of water to be maintained at the time of preparation, and the solubility of dantrolene was measured in the same manner as in Test Example 1.

The results are shown in "Table 3".

Next, 20 mg of dantrolene sodium, 75 mg of HPβCD, and 800 mg of mannitol were dissolved in 10 ml of water, followed by stirring for about 30 to 50 seconds to prepare a formulation.

By changing the pH range of the water to be 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 formulation was measured in the same manner as in Test Example 1.

Impurity (5-(p-nitrophenyl)-2-furaldehyde-2-carboxymethyl-semicarbazone: F-524) is a decomposition product produced by changes over time from the original dantrolene. The measurement of the concentration of F-524 was performed under the following conditions using a liquid chromatograph.

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

Diluted solution: 60% acetonitrile

Buffer: Ammonium acetate buffer, pH 4.5 ± 0.1

Mobile phase A: A mixed solution of 840 ml of buffer, 560 ml of acetonitrile and 49 ml of acetic acid

Mobile phase B: A mixture of 350 ml of acetonitrile and 150 ml of pure water

Gradient condition: It is shown in "Table 4".

The results are shown in "Table 5".

From the results of the solubility shown in "Table 3", it was found that the pH of the formulation is preferably prepared to be 9.0 or higher. Moreover, from the results shown in "Table 5", it is predicted that when the pH is low, the turbidity increases, and as the pH increases, the impurity concentration increases. From these results, it is considered that the pH of the formulation is preferably about 9.3 to 10.0.

Claims (8)

It contains dantrolene or a pharmacologically acceptable salt thereof, and a cyclodextrin derivative,
Dantrolene aqueous formulation, wherein the blending amount of the cyclodextrin derivative to 1 mole of dantrolene or a pharmacologically acceptable salt thereof is 0.5 moles or more and less than 2 moles. The method of claim 1,
Dantrolene aqueous formulation, wherein the blending amount of the cyclodextrin derivative with respect to 1 mole of dantrolene or a pharmacologically acceptable salt thereof is 0.7 moles or more and 1.3 moles or less. The method according to claim 1 or 2,
The said cyclodextrin derivative is any one or more selected from the group consisting of hydroxypropyl-β-cyclodextrin, β-cyclodextrin, and α-cyclodextrin, wherein the aqueous dantrolene formulation. Consisting of dantrolene or a pharmacologically acceptable salt thereof, a cyclodextrin derivative, and an aqueous solvent,
Dantrolene aqueous formulation preparation kit, wherein the amount of the cyclodextrin derivative per 1 mole of dantrolene or a pharmacologically acceptable salt thereof is 0.5 moles or more and less than 2 moles. As a method of preparing an aqueous dantrolene formulation,
Dantrolene or a pharmacologically acceptable salt thereof and a procedure of dissolving a cyclodextrin derivative in an aqueous solvent at 40° C. or higher and 45° C. or lower, wherein in 1 mol of dantrolene or a pharmacologically acceptable salt thereof A preparation method comprising, wherein the amount of the cyclodextrin derivative is 0.5 mol or more and less than 2 mol. The method of claim 5,
The preparation method in which the pH of the preparation is adjusted to 9.0 to 10.5 in the above procedure. The method of claim 6,
The preparation method in which the pH of the preparation is adjusted to 9.3 to 10.0 in the above procedure. As a method of preparing an intravenous injection formulation for dantrolene,
Procedure for obtaining a formulation having a pH of 9.0 to 10.0 by dissolving sodium dantrolene and hydroxypropyl-β-cyclodextrin in water at 40°C or higher and 45°C or lower, wherein hydroxypropyl-β for 1 mole of sodium dantrolene -The amount of cyclodextrin is 0.73 mol or more and 1.31 mol or less, A preparation method containing.