JPWO2020049670A1 - Dantrolene aqueous preparation and its preparation method - Google Patents

Abstract

As a technique for quickly and easily preparing an aqueous preparation of dantrolene or a pharmacologically acceptable salt thereof, dantrolene or a pharmacologically acceptable salt thereof and a cyclodextrin derivative are included, and dantrolene or a pharmacologically acceptable salt thereof is included. Provided is an aqueous dantrolene preparation in which the amount of the cyclodextrin derivative to be blended with respect to 1 mol of a pharmacologically acceptable salt is 0.5 mol or more and less than 2 mol.

Description

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 the most 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 formulation is the only treatment 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.

The dantrolene injectable preparation is used in the preparation at the time of use. Since dantrolene has a short shelf life as an aqueous composition, it is used by dissolving and reconstitution of a dried aqueous composition into a powder immediately before use. The dantrolene injection preparation is used after adding water for injection to the vial and shaking it to confirm that the solution is clear. However, since dantrolene is extremely sparingly soluble in water, it requires a large amount of solvent to dissolve it, which is troublesome and difficult to prepare quickly in an emergency.
In Patent Document 1, an attempt is made to improve the solubility of dantrolene by using a cyclodextrin derivative. The aqueous composition of dantrolene described in Patent Document 1 is obtained by blending 2 to 30 mol of a cyclodextrin derivative with 1 mol of dantrolene or a pharmacologically acceptable salt thereof. On the other hand, cyclodextrin derivatives are of concern for nephrotoxicity.

It is also known that 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). Has been done. Degradation is accelerated with increasing pH value and enhanced at high temperatures.
Patent Document 2 proposes to prevent the decomposition of dantrolene by using a positive 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 dantrolene by oral administration. In the same 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-cyclodextrin of 10 g per 250 mg of dantrolene is used. It is used (see “2.2 Preparation of Da-HP-β-CD complex” on page 154, right column).

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

"Preparation, characterization and in vivo evaluation of a formulation of dantrolene sodium with hydroxypropyl-β-cyclodextrin", Journal of Pharmaceutical and Biomedical Analysis, 2017, Vol.135, p.153-159

An 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.

In order to solve the above problems, the present invention provides the following [1]-[15].
[1] Containing dantrolene or a pharmacologically acceptable salt thereof, and a cyclodextrin derivative.
The amount of the cyclodextrin derivative compounded with respect to 1 mol of dantrolene or a pharmacologically acceptable salt thereof is 0.5 mol or more and less than 2 mol.
Dantrolene aqueous preparation.
[2] The aqueous dantrolene preparation according to [1], 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.
[3] The dantrolene aqueous solution of [1] or [2], wherein the cyclodextrin derivative is at least one selected from the group consisting of hydroxypropyl-β-cyclodextrin, β-cyclodextrin and α-cyclodextrin. pharmaceutical formulation.
[4] The aqueous dantrolene preparation according to any one of [1]-[3], which is an injection preparation for intravenous injection.

[5] It comprises dantrolene or a pharmacologically acceptable salt thereof, a cyclodextrin derivative, and an aqueous solvent.
The amount of cyclodextrin derivative per mol of dantrolene or a pharmacologically acceptable salt thereof is 0.5 mol or more and less than 2 mol.
Dantrolene aqueous preparation preparation kit.
[6] The aqueous preparation preparation kit for dantrolene according to [5], 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.
[7] The dantrolene aqueous solution 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. Formulation preparation kit.
[8] The dantrolene aqueous preparation preparation kit according to any one of [5]-[7], which is an injection preparation preparation kit for intravenous injection.

[9] A method for preparing an aqueous dantrolene preparation.
The procedure for dissolving dantrolene or a pharmacologically acceptable salt thereof and a cyclodextrin derivative in an aqueous solvent at 40 ° C. or higher and 45 ° C. or lower, where cyclone to 1 mol of dantrolene or a pharmacologically acceptable salt thereof. A preparation method comprising an amount of dextrin derivative of 0.5 mol or more and less than 2 mol.
[10] The preparation method of [9], wherein the pH of the pharmaceutical product is adjusted to 9.0-10.5 in the above procedure.
[11] The preparation method of [10], wherein the pH of the pharmaceutical product is adjusted to 9.3-10.0 in the above procedure.
[12] The preparation method according to any one of [9]-[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 method for preparing [9]-[12], wherein the cyclodextrin derivative is at least one selected from the group consisting of hydroxypropyl-β-cyclodextrin, β-cyclodextrin and α-cyclodextrin. ..
[14] The preparation method according to any one of [9]-[13], wherein the aqueous dantrolene preparation is an injection preparation for intravenous injection.

[15] A method for preparing an injectable preparation for intravenous dantrolene.
The procedure for dissolving sodium dantrolene and hydroxypropyl-β-cyclodextrin in water at 40 ° C. or higher and 45 ° C. or lower to obtain a preparation having a pH of 9.0-10.0, wherein the hydroxypropyl-β with respect to 1 mol of dantrolene sodium is obtained. -A preparation method comprising an amount of cyclodextrin of 0.73 mol or more and 1.31 mol or less.

An 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.

Hereinafter, suitable embodiments 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.

The aqueous dantrolene preparation according to the present invention contains dantrolene or a pharmacologically acceptable salt thereof and a cyclodextrin derivative, and the amount of the cyclodextrin derivative to be blended with 1 mol of dantrolene or a pharmacologically acceptable salt thereof. Is 0.5 mol or more and less than 2 mol.

Further, the dantrolene aqueous preparation preparation kit according to the present invention comprises dantrolene or a pharmacologically acceptable salt thereof, a cyclodextrin derivative, and optionally an aqueous solvent, and dantrolene or a pharmacologically acceptable salt thereof. The amount of the cyclodextrin derivative per 1 mol of the possible salt is 0.5 mol or more and less than 2 mol.

The structure of dantrolene is shown below.

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 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 solvent is not an essential component of the kit according to the present invention, and may be obtained separately from the kit by the preparer.

Cyclodextrin is a cyclic (α-1,4) -linked oligosaccharide with a hydrophobic central cavity and a hydrophilic outer surface.
Cyclodextrin derivatives are introduced into cyclodextrin with substituents selected from the group consisting of alkyl, hydroxyalkyl, carboxyalkyl, sulfoalkyl, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl and hydroxy- (mono or poly) alkyl groups. 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.

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 to 25.0 mM, more preferably 0.50 to 17.50 mM, and 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 blending 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.
In Test Example 1, which will be described later, by blending about 0.7 mol or more of a cyclodextrin derivative with 1 mol of dantrolene or a pharmacologically acceptable salt thereof, good dantrolene solubility and turbidity of the preparation can be obtained. It is clear that it can be obtained. Since the cyclodextrin derivative is suspected to be nephrotoxic, it is desirable that the amount of the cyclodextrin derivative to be the minimum necessary to achieve good dantrolene solubility and turbidity of the preparation. 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-mentioned compounding ratio range, the solubility of dantrolene can be improved and a clear preparation can be obtained. Therefore, the aqueous dantrolene preparation and the preparation kit thereof according to the present invention are effective for promptly and easily providing the intravenous dantrolene injection preparation in the clinical setting of malignant hyperthermia.

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

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 pharmaceutical product within the above range.

The osmotic pressure regulator is a fat having 2 to 10 carbon atoms selected from the group consisting of mannitol, fructose, glucose, gluconolactone, gluconate, sucrose, lactoose, trehalose, dextrose, dextran, and hydroxyethyl starch. It is selected from the group consisting of group polyhydroxyalkanols and mixtures thereof. Of these, mannitol is particularly preferable. The pH regulator is used in an amount suitable for adjusting and maintaining the osmotic pressure of the pharmaceutical product to about 1 (ratio to saline solution).

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 Chemical Industries, Ltd.), Polyoxyethylene fatty acids Examples thereof include monoester (ionet MO-400 or MS-400, Sanyo Chemical Industries, Ltd.) and glyceryl monostearate (TG-C, Sanyo Chemical Industries, Ltd.).

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

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 formulation can be obtained (Test Example 2). Therefore, good solubility of dantrolene and turbidity of the preparation can be achieved while suppressing the blending amount of the cyclodextrin derivative with respect to dantrolene or a pharmacologically acceptable salt thereof as compared with the dissolution at normal 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.

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

[Test Example 1: Examination of the effect of the molar ratio of dantrolene and cyclodextrin derivative on the solubility of dantrolene and the turbidity of the preparation]
20 mg (50 mM) of dantrolene sodium, hydroxypropyl-β-cyclodextrin (HPβCD) and 800 mg of mannitol were dissolved in 10 ml of water at 45 ° C., and the mixture was formulated by stirring for 15 minutes.
The solubility of dantrolene and the turbidity of the pharmaceutical product were measured by changing the amount of added moles of HPβCD.

The solubility of dantrolene was measured as follows.
1 mL of the 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 diluted solution 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 preparation was measured by placing 5 mL of the sample in a vial and measuring it with a turbidity meter.

The results are shown in "Table 1".

It was clarified that good solubility of dantrolene and turbidity of the preparation can be obtained by adding 0.73 mol or more of HPβCD to 1 mol of sodium dantrolene.

[Test Example 2: Examination of the effect of dissolution temperature on dantrolene solubility and pharmaceutical turbidity]
20 mg of dantrolene sodium, 75 mg of HPβCD and 800 mg of mannitol were dissolved in 10 ml of water, and the mixture was formulated by stirring for 15 minutes.
The solubility of dantrolene and the turbidity of the pharmaceutical product were measured in the same manner as in Test Example 1 by changing the dissolution temperature.

The results are shown in "Table 2".

When the dissolution temperature was 35 ° C., the turbidity of the preparation was poor. It was clarified that good solubility of dantrolene and turbidity of the preparation can be 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, and the mixture was formulated by stirring for 24 hours.
The solubility of dantrolene was measured in the same manner as in Test Example 1 by changing the pH of the prepared preparation by changing the pH range of the water maintained at the time of preparation.

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, and the mixture was formulated by stirring for about 30 to 50 seconds.
The turbidity and impurity concentration of the preparation were measured by changing the pH of the prepared preparation by changing the pH range of the water maintained at the time of preparation. The turbidity of the pharmaceutical product was measured in the same manner as in Test Example 1.

Impurities (5- (p-nitrophenyl) -2-furaldehyde-2-carboxymethyl-semicarbazone: F-524) are decomposition products produced from the drug substance of dantrolene over time. The concentration of F-524 was measured using a liquid chromatograph under the following 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 4".

The results are shown in "Table 5".

From the results of the solubility shown in "Table 3", it was clarified that the pH of the pharmaceutical product is preferably adjusted to 9.0 or higher. Further, from the results shown in "Table 5", it is predicted that the turbidity increases when the pH is low, and the impurity concentration increases as the pH increases. From these results, it was considered that the pH of the pharmaceutical product is preferably about 9.3-10.0.

Claims (8)

Containing dantrolene or a pharmacologically acceptable salt thereof and a cyclodextrin derivative,
The amount of the cyclodextrin derivative compounded with respect to 1 mol of dantrolene or a pharmacologically acceptable salt thereof is 0.5 mol or more and less than 2 mol.
Dantrolene aqueous preparation. The aqueous dantrolene preparation according to claim 1, 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. The aqueous dantrolene preparation according to claim 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. It comprises dantrolene or a pharmacologically acceptable salt thereof, a cyclodextrin derivative, and an aqueous solvent.
The amount of cyclodextrin derivative per mol of dantrolene or a pharmacologically acceptable salt thereof is 0.5 mol or more and less than 2 mol.
Dantrolene aqueous preparation preparation kit. A method for preparing an aqueous dantrolene preparation,
The procedure for dissolving dantrolene or a pharmacologically acceptable salt thereof and a cyclodextrin derivative in an aqueous solvent at 40 ° C. or higher and 45 ° C. or lower, where cyclone to 1 mol of dantrolene or a pharmacologically acceptable salt thereof. A preparation method comprising an amount of dextrin derivative of 0.5 mol or more and less than 2 mol. The preparation method according to claim 5, wherein the pH of the preparation is adjusted to 9.0-10.5 in the above procedure. The preparation method according to claim 6, wherein the pH of the preparation is adjusted to 9.3-10.0 in the above procedure. A method for preparing an injectable preparation for intravenous dantrolene.
The procedure for dissolving sodium dantrolene and hydroxypropyl-β-cyclodextrin in water at 40 ° C. or higher and 45 ° C. or lower to obtain a preparation having a pH of 9.0-10.0, wherein the hydroxypropyl-β with respect to 1 mol of dantrolene sodium is obtained. -A preparation method comprising an amount of cyclodextrin of 0.73 mol or more and 1.31 mol or less.