JP2002322056A - Solution preparation of triazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a solution preparation of a triazole derivative SS750 useful as an antifungal agent for profound mycosis or its salt. SOLUTION: This solution preparation of the triazole derivative SS750 or its salt is characterized by comprising the triazole derivative SS750 or its salt, a surfactant and an alcohol. The solution preparation of the triazole derivative SS750 or its salt having excellent thermal stability, clinically applicable and easily usable can be provided by further including an acidic substance.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a solution preparation of a triazole derivative useful as an antifungal agent for deep mycosis.

[0002]

2. Description of the Related Art Deep mycosis is a fatal disease for patients who have a suppressed immunity such as cancer, organ transplantation and acquired immunodeficiency syndrome, and has been increasing in recent years. JP-A-11-
No. 240871 discloses a triazole derivative SS750.
Has an excellent antibacterial activity against fungi including Aspergillus and Candida compared to known similar compounds,
Moreover, it is disclosed that the security is high. The publication discloses an injection as a solution preparation, for example, as examples, hydrogenated castor oil, propylene glycol, glucose,
Triazole derivative SS using distilled water for injection as carrier
An injection with a 7500 concentration of 5 mg / mL is described.

[0003]

However, the hardened castor oil contained in the formulation of the injection disclosed in JP-A-11-240871 is not soluble in water, and cannot be dissolved or emulsified by the formulation of the example. Was unsuitable. The solubility of the triazole derivative SS750 in water at 25 ° C. is about 0.5 m.
g / mL, which is small, and a high-concentration solution preparation has not been obtained by the conventional method. In the case of the triazole derivative SS750, an injection having a concentration of 10 mg / mL or more is preferable.

In order to improve the solubility of a drug which is hardly soluble in water, fats and oils and organic solvents are generally used. However, in order to use fats and oils and organic solvents which are hardly soluble in water, a special emulsification technique is required. There is a problem that it cannot be easily manufactured by an ordinary method. Further, when a water-soluble organic solvent is used, there is a problem that the drug is easily precipitated when the compound is incorporated into an infusion.

[0005] Therefore, as an injection of the triazole derivative SS750, a formulation which is clinically applicable and easy to use, that is, an additive is also highly safe, stable for a long time, and
Injectables having a concentration of g / mL or more (1 w / v% or more) and appropriate viscosity and which can be produced by a conventional method are desired.

[0006]

DISCLOSURE OF THE INVENTION The present inventors have conducted intensive studies with the aim of obtaining a triazole derivative SS750 or a salt thereof as an injection or the like which is clinically applicable and easy to use. A high concentration solution preparation as a solvent was found. Furthermore, the present inventors have found that by adding an acidic substance, a solution preparation which can withstand the heat load in the production process such as heat dissolution and high-pressure steam sterilization and has more improved storage stability can be obtained, and completed the present invention.

That is, the present invention provides the following (1) to (16)
It is about. (1) Triazole derivative SS750 (chemical name: 2-
(2,4-difluorophenyl) -1- (ethylsulfonyl) -1,1-difluoro-3- ( 1H- 1,2,4
-Triazol-1-yl) -2-propanol) or a solution preparation of a triazole derivative containing a salt thereof, a surfactant and an alcohol. (2) A solution preparation of the triazole derivative according to (1), further comprising an acidic substance. (3) Triazole derivative SS750 or a salt thereof 100
With respect to parts by weight, 300 to 4000 parts by weight of a surfactant,
A solution preparation of the triazole derivative according to (1) or (2), comprising 200 to 5,000 parts by weight of alcohol.

(4) A solution preparation of the triazole derivative according to (2) or (3), comprising 2 to 200 parts by weight of the acidic substance with respect to 100 parts by weight of the triazole derivative SS750 or a salt thereof. (5) The surfactant is at least one surfactant selected from polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oils and polyoxyethylene polyoxypropylene glycols, (1) to (4).
A solution preparation of the triazole derivative according to any one of the above. (6) The solution preparation of a triazole derivative according to (5), wherein the surfactant is polysorbate 80 or polyoxyethylene castor oil.

(7) The solution preparation of a triazole derivative according to any one of (1) to (6), wherein the alcohol is at least one alcohol selected from lower alcohols and polyethylene glycols. (8) The solution preparation of the triazole derivative according to (7), wherein the alcohol is ethanol. (9) The solution preparation of the triazole derivative according to any of (2) to (8), wherein the acidic substance is citric acid, phosphoric acid, maleic acid, or hydrochloric acid.

(10) The solution preparation of the triazole derivative according to (1), wherein the concentration of each component is as follows. Triazole derivative SS750 or a salt thereof 1 to 25 w / v% Surfactant 10 to 80 w / v% Alcohol 1 to 70 w / v% Water balance (11) The concentration of each component is as follows: Solution preparation of a triazole derivative. Triazole derivative SS750 or its salt 1 to 25 w / v% polysorbate 80 or polyoxyethylene castor oil 10 to 80 w / v% ethanol 1 to 70 w / v% water balance

(12) The solution preparation of a triazole derivative according to (2), wherein the concentration of each component is as follows. Triazole derivative SS750 or salt thereof 1 to 25 w / v% Surfactant 10 to 80 w / v% Alcohol 1 to 70 w / v% Acid 0.1 to 12 w / v% Water balance (13) The concentration of each component is as follows: A solution preparation of the triazole derivative according to (2), which comprises a ratio. Triazole derivative SS750 or its salt 1-25 w / v% polysorbate 80 or polyoxyethylene castor oil 10-80 w / v% ethanol 1-70 w / v% citric acid, phosphoric acid, maleic acid or hydrochloric acid 0.1-12 w / v % Water balance

(14) The solution preparation is an injection (1) to
(13) A solution preparation of the triazole derivative according to any one of (1) to (3). (15) An injection of a triazole derivative in which the concentration of each component is as follows: Triazole derivative SS750 or salt thereof 1 to 25 w / v% polysorbate 80 or polyoxyethylene castor oil 20 to 70 w / v% ethanol 20 to 60 w / v% water balance (16) Triazole in which the concentration of each component is as follows: Derivative injections. Triazole derivative SS750 or a salt thereof 1 to 25 w / v% polysorbate 80 or polyoxyethylene castor oil 20 to 70 w / v% ethanol 20 to 60 w / v% citric acid, phosphoric acid, maleic acid or hydrochloric acid 0.2 to 8 w / v % Water balance

[0013]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The triazole derivative SS750 used in the present invention has a chemical name of 2- (2,4-difluorophenyl) -1- (ethylsulfonyl) -1,1-difluoro-3- ( 1H- 1). , 2,4-triazol-1-yl) -2-propanol and disclosed in JP-A-11-2408.
It can be obtained by using the production method described in JP-A-71.
The salt of the triazole derivative SS750 is not particularly limited as long as it is a pharmacologically acceptable salt. As the pharmacologically acceptable salt, an acid addition salt is preferable. Examples of the acid addition salt include inorganic acid salts such as hydrochloride, nitrate and hydrobromide, and organic acid salts such as p-toluenesulfonate, methanesulfonate, fumarate, succinate and lactate. Is mentioned.

The triazole derivative SS7 used in the present invention
50 and its salts have stereoisomers based on asymmetric carbon atoms, and the present invention includes these stereoisomers and isomer mixtures such as racemates. The triazole derivative SS750 or a salt thereof may exist in the form of a solvate represented by a hydrate, and these are included in the present invention.

[0015] In the present invention, the solution preparation is a liquid preparation for internal use,
Shows external preparations and injections. Injectables include those in the form of intravenous injection, including those diluted at the time of use, intramuscular injection, and subcutaneous injection. Liquid preparations for internal use include those in the form of syrups, elixirs, sprays and the like. The liquid for external use includes a form such as a lotion, a spray and the like. The liquid preparation for internal use and the liquid preparation for external use can be applied with the solution preparation of the present invention as it is or by adding appropriate additives. The injection can be applied by sterilizing the solution preparation of the present invention, filling and sealing in vials or ampoules. In addition, after filling and sealing as necessary, sterilization such as high-pressure steam sterilization can be performed and applied. In the present invention, it is preferably applied as an injection.

[0016] For patients with deep mycosis, the effective dosage of the triazole derivative SS750 depends on the age and weight of the individual to be treated, the fungus infected and the condition, but usually the adult will be treated with the triazole derivative SS750. About 0.1 to 1000 mg, preferably 1 to 30 as a daily dose
A dose of 0 mg is required. Moreover, 10 to 1000 mg, preferably 40 to 300 mg for aspergillosis.
mg administration is required.

Triazole derivative SS7 in solution formulation
The mixing ratio of 50 or a salt thereof is 1 w /
v% or more, preferably 2 w / v% or more, more preferably 4 w / v% or more, the upper limit of which is 25 w / v% or less,
Preferably 15 w / v% or less, more preferably 8 w / v%
It is as follows.

In the present invention, any surfactant can be used as long as it is a non-ionic surfactant or a surfactant which can be dissolved in alcohol. For example, preferred are polyoxyethylene sorbitan fatty acid esters (generic names: polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, etc.),
Polyoxyethylene castor oils (trade names: Cremophor RH40, Cremophor RH60, Cremophor E) which are polyoxyethylene derivatives of natural fats and oils and waxes
L (all manufactured by BFSF) and polyoxyethylene polyoxypropylene glycols (general name: poloxamer 188) can be used alone or in combination of two or more. More preferred are polysorbate 80 and polyoxyethylene castor oil, which are polyoxyethylene sorbitan fatty acid esters.

The mixing ratio of the surfactant is desirably variously set according to the dose of the triazole derivative SS750 or a salt thereof. For example, the following mixing ratio is preferable. The mixing ratio of the surfactant was 10 w /
v% or more, preferably 20 w / v% or more, more preferably 30 w / v% or more, and the upper limit thereof is 80 w / v% or less, preferably 70 w / v% or less, more preferably 60 w / v% or less.
w / v% or less.

As the alcohol, lower alcohols and polyethylene glycols can be used. As the lower alcohol, a chain alcohol having 1 to 5 carbon atoms can be used. For example, preferred are ethanol, glycerin and propylene glycol. Any polyethylene glycol can be used as long as it is a liquid. For example, preferred are those having an average molecular weight of 200,
300, 400 or 600 polyethylene glycols. These alcohols can be used alone or in combination of two or more.

[0021] In the solution preparation of the present invention, an injection is usually used by diluting it with an aqueous phase at the time of use. For clinical use of injections, physiological saline, glucose injection, fructose injection, maltose injection, xylitol injection, sorbitol injection, fructose / mannitol injection, Ringer's solution, dextran injection, high calorie infusion It is diluted and administered in an aqueous phase such as a basic solution or an infusion solution such as water.

Therefore, in the case of an injection, ethanol is the most preferred alcohol for the purpose of lowering the viscosity of the solution, making it easier to withdraw with a syringe needle, improving the usability, and suppressing the foaming property upon dilution. preferable. The blending ratio of the alcohol is desirably set variously in accordance with the dose of the triazole derivative SS750 or a salt thereof and the type and amount of the surfactant, for example, 1 w / v% based on the total amount of the preparation.
As described above, it is more preferably at least 20 w / v%, and the upper limit is at most 70 w / v%, more preferably at most 60 w / v%.

Although the injection can be produced by an aseptic operation, it is preferable that the injection be terminally sterilized. The triazole derivative SS750 or a salt thereof is unstable to heat in a solution, and is almost completely decomposed by treatment at 121 ° C. for 20 minutes under a normal autoclaving condition. As a result of the study of the thermal decomposition mechanism, it was considered that a 1,2-elimination reaction in which proton extraction by a base catalyst was initiated was caused. In the present invention, it has been found that in order to suppress the thermal decomposition of the triazole derivative SS750 or a salt thereof, the stability is drastically improved by adding an acidic substance, and that it is stable even after high-pressure steam sterilization. .

The acidic substance as the stabilizer may be an inorganic acid or an organic acid, or a salt exhibiting the acidity. The addition of these acidic substances is usually one, but
Any combination of more than one species is acceptable. As the inorganic acid, for example, phosphoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid,
Examples of the organic acid include carboxylic acids such as citric acid, maleic acid, acetic acid, lactic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, and tartaric acid; and methanesulfonic acid and p-toluenesulfonic acid. Examples include sulfonic acids and amino acids such as aspartic acid and glutamic acid. The most preferred acidic substance used in the present invention is phosphoric acid, citric acid, maleic acid or hydrochloric acid. The more the amount of the acidic substance added, the more the decomposition can be suppressed under severe conditions.However, it is physiologically unfavorable that the diluted solution for clinical use is extremely unbalanced toward the acidic side. 0.1 w / v% or more, preferably 0.2 w / v% or more, more preferably 0.4 w / v% or more based on the total amount of the preparation.
/ V% or more, and the upper limit thereof is 12 w / v% or less, preferably 8 w / v% or less, more preferably 4 w / v% or less. That is, when diluted with a buffered infusion such as distilled water for injection or physiological saline, the pH is 2 or more, preferably 3 or more.

In the solution preparation of the present invention, water is preferably not added because it is a poor solvent for the triazole derivative SS750 or a salt thereof, but water may be added in a small amount. The upper limit when adding water is 6
0% or less, preferably 20% or less.

The triazole derivative SS75 of the present invention
The mixing ratio of a solution preparation of 0 or a salt thereof is as follows. Triazole derivative SS750 or its salt 10
0 parts by weight of surfactant: generally 300 parts by weight or more, preferably 500 parts by weight or more, more preferably 650 parts by weight or more, and the upper limit is generally 4000 parts by weight or less,
Preferably not more than 2000 parts by weight, more preferably 100 parts by weight
0 parts by weight or less. Therefore, in general, 300 to 40
00 parts by weight, preferably 500 to 2000 parts by weight, more preferably 650 to 1000 parts by weight. Alcohol: generally 200 parts by weight or more, preferably 700 parts by weight or more, and the upper limit is generally 5 parts by weight.
It is at most 2,000 parts by weight, preferably at most 2,000 parts by weight. Therefore, it is generally 200 to 5000 parts by weight, preferably 700 to 2000 parts by weight. Acidic substance: When an acidic substance is further added, it is generally at least 2 parts by weight, preferably at least 5 parts by weight, more preferably at least 10 parts by weight, and the upper limit is generally at most 200 parts by weight, Preferably it is 100 parts by weight or less, more preferably 50 parts by weight or less. Therefore, it is generally 2 to 200 parts by weight, preferably 5 to 100 parts by weight, more preferably 10 to 50 parts by weight.

The compounding ratio of each component to the total amount of the preparation is triazole derivative SS750 or a salt thereof: generally 1 w / v% or more, preferably 2 w / v% or more, more preferably 4 w / v%. The upper limit is generally 2
It is at most 5 w / v%, preferably at most 15 w / v%, more preferably at most 8 w / v%. Therefore, in general, 1
２５25 w / v%, preferably 2-15 w / v%, more preferably 4-8 w / v%. Surfactant: generally at least 10 w / v%, preferably at least 20 w / v%, more preferably at least 30 w / v%, and the upper limit is generally at most 80 w / v%, preferably at least 70 w / v%. v% or less, more preferably 60 w / v
% Or less. Therefore, generally 10 to 80 w / v
%, Preferably 20-70% w / v, more preferably 3%
0 to 60 w / v%. Alcohol: generally at least 1 w / v%, preferably at least 20 w / v%, and the upper limit is generally 70%.
w / v% or less, preferably 60 w / v% or less. Therefore, it is generally 1 to 70 w / v%, preferably 20 to 70 w / v%.
60% w / v. Acidic substance: When an acidic substance is further added, it is generally 0.1 w / v% or more, preferably 0.2 w / v%.
The above is more preferably 0.4 w / v% or more, and the upper limit is generally 12 w / v% or less, preferably 8 w / v%.
v% or less, more preferably 4 w / v% or less. Therefore, it is generally 0.1 to 12 w / v%, preferably 0.1 to 12 w / v%.
It is 2-8 w / v%, more preferably 0.4-4 w / v%.

When the solution preparation of the present invention is an injection, an injection can be produced by an ordinary method without employing any special method. That is, for example, a surfactant and an alcohol are mixed, an acidic substance is added if necessary, and then the triazole derivative SS7 is added.
Add 50 or its salt, optionally heating,
Dissolve. Further, if necessary, distilled water for injection is added and mixed. Next, the solution is sterilized by filtration, filled in a vial or an ampoule, and sealed to prepare a preparation. If necessary, the product is subjected to high-pressure steam sterilization to prepare a preparation. In the present invention, a solution preparation of the triazole derivative SS750 or a salt thereof can be formulated into an injection and a liquid for internal use and a liquid for external use. Agents, sweeteners, flavors and preservatives can be added.

The liquid preparation for internal use and the liquid preparation for external use of the present invention can be prepared by an ordinary method without employing a special method. That is, for example, a surfactant and an alcohol are mixed, an acidic substance such as citric acid is added as necessary, and a triazole derivative SS750 or a salt thereof is added, and the mixture is dissolved with heating as necessary.
If necessary, a preservative such as methyl paraoxybenzoate and propyl paraoxybenzoate is added. Further, a flavoring agent such as lemon essence is added, and the whole is made up with water for injection. Fill and plug in an appropriate container according to the application. If necessary, sterilize by high-pressure steam.

[0030]

EXAMPLES The effects of the present invention will be specifically described below with reference to examples and test examples, but the present invention is not limited to these examples. Example 1 3 g of a triazole derivative (SS750) was dissolved in a mixed solution of 20 g of polysorbate 80 and 30 mL (24 g) of ethanol to make the total amount about 50 mL. After sterilization by filtration through a 0.2 μm membrane filter, 5 m
L and sealed. Triazole derivative concentration about 60m
g / mL injection was obtained.

Example 2 After dissolving 3 g of the triazole derivative (SS750) in a mixed solution of 20 g of polysorbate 80 and 30 mL (24 g) of ethanol, about 10 mL of water for injection was added, and the total amount was reduced to 6%.
It was 0 mL. After sterilization by filtration through a 0.2 μm membrane filter, the vial was filled with 6 mL and sealed. An injection having a triazole derivative concentration of 50 mg / mL was obtained.

Example 3 3 g of a triazole derivative (SS750) was added to polysorbate 8
0 20 g of ethanol, 30 mL (24 g) of ethanol and 0.3 g of citric acid were added to dissolve the mixture, and then about 1 g of water for injection was added.
0 mL was added to bring the total volume to 60 mL. After sterilizing by filtration with a 0.2 μm membrane filter, 6 m
L and sealed. Triazole derivative concentration 50mg
/ ML injection was obtained.

Example 4 3 g of a triazole derivative (SS750) was added to polysorbate 8.
0 20 g, ethanol 30 mL (24 g) and phosphoric acid 1
After adding and dissolving in 50 mg of the mixed solution, about 1 ml of water for injection was added.
0 mL was added to bring the total volume to 60 mL. After sterilizing by filtration with a 0.2 μm membrane filter, 6 m
L and sealed. Triazole derivative concentration 50mg
/ ML injection was obtained.

Example 5 3 g of triazole derivative (SS750) was added to polysorbate 8
0 20 g, ethanol 30 mL (24 g) and maleic acid 200 mg were added to a mixed solution and dissolved.
mL. After sterilization by filtration through a 0.2 μm membrane filter, the vial was filled with 5 mL and sealed. An injection having a triazole derivative concentration of about 60 mg / mL was obtained.

Example 6 0.5 g of a triazole derivative (SS750) was added to a mixed solution of 10 g of polysorbate 80, 20 mL (16 g) of ethanol and 0.3 g of citric acid and dissolved, and about 20 mL of water for injection was added to make a total volume of 50 mL. And 0.2 μm
After filtration sterilization with a membrane filter, the vial was filled with 5 mL, sealed, and subjected to high-pressure steam sterilization. An injection having a triazole derivative concentration of 10 mg / mL was obtained.

Example 7 6.4 g of a triazole derivative (SS750) was added to a mixed solution of 20 g of polysorbate 80, 20 mL (16 g) of ethanol and 850 mg of phosphoric acid, and dissolved.
mL. After sterilizing by filtration with a 0.2 μm membrane filter, 4 mL was filled into a vial, the vial was sealed, and then subjected to high-pressure steam sterilization. Triazole derivative concentration about 160mg /
mL injections were obtained.

Example 8 3 g of the triazole derivative (SS750) was dissolved in a mixed solution of 20 g of polyoxyethylene castor oil and 30 mL (24 g) of ethanol to make the total amount about 50 mL. 0.2 μm
After filtration sterilization with a membrane filter, the vial was filled with 5 mL and sealed. Triazole derivative concentration about 6
0 mg / mL injection was obtained.

EXAMPLE 9 3 g of a triazole derivative (SS750) was mixed with 6020 g of polyoxyethylene hydrogenated castor oil and 30 mL of ethanol (24 mL).
g) to make a total volume of about 50 mL.
After filtration sterilization with a 0.2 μm membrane filter,
The vial was filled with 5 mL and sealed. An injection having a triazole derivative concentration of about 60 mg / mL was obtained.

Example 10 3 g of a triazole derivative (SS750) was added to poloxamer 18
8 Dissolved in a mixed solution of 20 g and ethanol 30 mL (24 g) to make the total amount about 50 mL. After sterilization by filtration through a 0.2 μm membrane filter, 5 mL
Filled and stoppered. Triazole derivative concentration about 60mg
/ ML injection was obtained.

Example 11 After 15 mg of methyl paraoxybenzoate and 5 mg of propyl paraoxybenzoate were dissolved in 2 mL (1.6 g) of ethanol, 6 g of polysorbate 80, 5 g of propylene glycol and 0.3 g of lemon essence were mixed,
600 mg of a triazole derivative (SS750) is added and dissolved. Furthermore, 1 g of citric acid and 25 mL of simple syrup (33
g), make up to 50 mL with purified water, and fill the container. Triazole derivative SS750 concentration 12mg / mL
To obtain a syrup.

Example 12 6 g of polysorbate 80 and 5 g of propylene glycol
After mixing 0.3 g of lemon essence and 0.6 g of a triazole derivative (SS750), the mixture is dissolved. 1 g of citric acid and 25 mL of simple syrup (33 g) were added to this solution.
And make up to a total volume of 50 mL with purified water, fill a sterile bottle, and sterilize with high pressure steam. A syrup having a triazole derivative SS750 concentration of 12 mg / mL is obtained.

Test Example 1 Solubility and Viscosity in Various Solvent Compositions 5 to 10 mL of the solvent compositions shown in Table 1 were prepared, and a supersaturated amount of the triazole derivative SS750 was added to each solvent composition, followed by stirring at 25 ° C. for 24 hours. did. Then
Filtering, measuring the concentration of the triazole derivative SS750 using liquid chromatography on the filtered solution,
The solubility was evaluated. Further, the filtered solution was sucked and discharged with a syringe having an 18 G needle, and the viscosity was evaluated based on the easiness of the operation. From the evaluation of these solubility and viscosity, the triazole derivative SS750 solution was determined. The results are shown in Table 1.

[0043]

[Table 1] Table 1 Composition (weight ratio) Solubility Viscosity Judgment ―――――――――――――――――――――――――――――――――― Water only-+++ C PS80 only +++-C EtOH only +++ ++ A (* C) POECO only +++-C PS80: water = 10:90-++ C POECO: water = 10:90-++ C PEG: water = 50: 50-++ CPG: water = 50: 50-++ CPS80: EtOH = 40: 60 ++++ APS80: EtOH = 45: 55 ++++++ POECO: EtOH = 45: 55 ++++++ APOEHCO: EtOH = 45: 55 ++++ A PS80: PEG: water = 20: 30: 50 ++++ B PS80: EtOH: water = 20: 30: 50 ++++ BPOECO: EtOH: water = 2 0:30:50 +++++ B PS80: EtOH: water = 45: 55: 23 ++++++ A PS80: EtOH: water: CA = 45: 55: 23: 1 ++++ A PS80: EtOH: water: CA = 45: 55: 23: 3 ++++ APS80: EtOH: CA = 45: 55: 3 ++++++ APS80: EtOH: PA = 45: 55: 23 ++++ APS80: EtOH: PA = 45: 55: 0.5 ++++ ++ A ―――――――――――――――――――――――――――――― ＊ EtOH only has crystal precipitation due to dilution with infusion solution etc. Unpleasant

Evaluation of PA solubility; [0044] Abbreviations polysorbate 80 in the table; PS80 ethanol; EtOH polyethylene glycol 300; PEG propylene glycol; PG polyoxyethylene castor oil; POECO polyoxyethylene hardened castor oil 60; POEHCO citrate; CA phosphate -; Less than 1 w / v% +; 1 w / v% or more ++; 2 w / v% or more +++; 4 w / v% or more

Evaluation of viscosity- : Inhalation and discharge operations cannot be performed smoothly with an 18G injection needle. +; Inhalation and discharge operations can be performed smoothly with an 18G injection needle. ++; Inhalation and discharge operations can be performed with an 18G injection needle. Smooth judgment A: more preferable as a solution preparation (five + under evaluation) B; preferable as a solution preparation (four or less during evaluation) C; unfavorable as a solution preparation (− during evaluation) is there)

As shown in Table 1, in the case of water alone, a surfactant alone, or a combination of water and a surfactant, or a combination of water and an alcohol, it was unsuitable for either solubility or viscosity and was judged to be C. Undesired triazole derivative SS
Only 750 solutions were obtained. When the solvent was ethanol alone, the solution was excellent in solubility and viscosity as a concentrated solution, but when mixed with an infusion solution shown in Test Example 2 described below, the concentration of ethanol was reduced and crystals were precipitated, which was not preferable. In the case of the combination containing the surfactant and the alcohol, which is the composition of the solution preparation of the present invention, the solubility and the viscosity were also excellent and were judged to be B or more. Especially in these,
In the case of the combination in which the alcohol was ethanol, a triazole derivative SS750 solution which enables a high dose of the judgment A was obtained in the case of the preferable mixing ratio even when water or an acidic substance was added.

Test Example 2 Crystal Precipitation Property in Diluted Infusion The solution preparation of the present invention of Examples 3 and 4 was treated with 500 mL of physiological saline (infusion) in 0.6 of the triazole derivative (SS750).
Prepare a dilution of mg / mL, store at 25 ° C for 24 hours,
The appearance was observed, and the presence or absence of crystal precipitation was confirmed. Table 2 shows the results
It was shown to. The solution preparation of the triazole derivative SS750 of the present invention was stable without crystal deposition even after being diluted by infusion as an injection.

[0048]

[Table 2] Table 2 Immediately after dilution After 24 hours at 25 ° C ――――――――――――――――――――――――――――――― Example 3 Colorless Clear, no crystal precipitation Colorless, clear, no crystal deposition Example 4 Colorless, clear, no crystal deposition Colorless, clear, no crystal precipitation ―――――――――――――――――――――――― ―――――――――

Test Example 3 Storage stability The solution preparation of the present invention of Example 1 was stored at 40 ° C. for 10 months.
The content was measured as the residual ratio by liquid chromatography. The results are shown in Table 3. Triazole derivative of the present invention
The solution formulation of SS750 can be used without adding any acidic substance.
It was stable for a long time under an environment of less than ° C.

[0050]

[Table 3] Table 3 Immediately after production 40 ° C for 10 months ――――――――――――――――――――――――――― Example 1 100.0% 96.8% ―――――――――――――――――――――――――――――

Test Example 4 Stability Under High-Temperature Conditions The solution preparations of the present invention of Examples 1 and 3 to 5 were subjected to high-pressure steam sterilization, and the content was measured as a residual ratio by liquid chromatography. The results are shown in Table 4. Solution formulations of the triazole derivative SS750 of the present invention, as in Examples 3-5,
Addition of an acidic substance hardly caused decomposition even in autoclaving and was stable against heat. By adding an acidic substance, a solution formulation of the present invention that can withstand the heat load in the manufacturing process such as heat dissolution and high-pressure steam sterilization and has improved storage stability has been completed.

[0052]

[Table 4] Table 4 Immediately after production High-pressure steam sterilization 122 ° C ―――――――――――――――――――――――――――― Example 1 100.0% 33.9% (30 minutes) Example 3 100.0% 99.8% (120 minutes) Example 4 100.0% 100.2% (120 minutes) Example 5 100.0% 98.5% ( 30 minutes) ――――――――――――――――――――――――――――――

[0053]

As shown in the above Examples and Test Examples, the solution preparation of the triazole derivative SS750 of the present invention is a high concentration preparation excellent in solubility, viscosity, etc.
In addition, storage stability and stability under high temperature conditions are also sufficient. Furthermore, even when diluted with an infusion solution or the like at the time of use as an injection, crystal precipitation does not occur, and a clinically applicable product can be provided.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (reference) A61P 31/10 A61P 31/10 F term (reference) 4C076 AA12 AA22 BB11 CC31 DD01 DD09 DD22 DD37 DD38 DD42 DD43 EE23 EE53 FF15 FF36 FF63 4C086 AA02 BC60 MA03 MA05 MA17 MA23 MA66 NA02 NA03 ZB35

Claims (16)

[Claims] 1. A triazole derivative SS750 (chemical name:
2- (2,4-difluorophenyl) -1- (ethylsulfonyl) -1,1-difluoro-3- ( 1H- 1,
A solution preparation of a triazole derivative containing 2,4-triazol-1-yl) -2-propanol) or a salt thereof, a surfactant and an alcohol. 2. The solution preparation of a triazole derivative according to claim 1, further comprising an acidic substance. 3. A surfactant of 300 to 4000 per 100 parts by weight of the triazole derivative SS750 or a salt thereof.
The solution preparation of a triazole derivative according to claim 1 or 2, comprising 200 to 5000 parts by weight of an alcohol. 4. The solution preparation of a triazole derivative according to claim 2, wherein the solution preparation contains 2 to 200 parts by weight of the acidic substance based on 100 parts by weight of the triazole derivative SS750 or a salt thereof. 5. The surfactant according to claim 1, wherein the surfactant is at least one selected from polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oils and polyoxyethylene polyoxypropylene glycols. A solution preparation of the triazole derivative according to any one of the above. 6. The solution preparation of a triazole derivative according to claim 5, wherein the surfactant is polysorbate 80 or polyoxyethylene castor oil. 7. The solution preparation of a triazole derivative according to claim 1, wherein the alcohol is at least one alcohol selected from lower alcohols and polyethylene glycols. 8. The solution preparation of a triazole derivative according to claim 7, wherein the alcohol is ethanol. 9. The solution preparation of a triazole derivative according to claim 2, wherein the acidic substance is citric acid, phosphoric acid, maleic acid or hydrochloric acid. 10. The solution preparation of a triazole derivative according to claim 1, wherein the concentration of each component is as follows. Triazole derivative SS750 or a salt thereof 1 to 25 w / v% Surfactant 10 to 80 w / v% Alcohol 1 to 70 w / v% Water balance 11. The solution preparation of a triazole derivative according to claim 1, wherein the concentration of each component is as follows. Triazole derivative SS750 or its salt 1 to 25 w / v% polysorbate 80 or polyoxyethylene castor oil 10 to 80 w / v% ethanol 1 to 70 w / v% water balance 12. The solution preparation of a triazole derivative according to claim 2, wherein the concentration of each component is as follows. Triazole derivative SS750 or a salt thereof 1 to 25 w / v% Surfactant 10 to 80 w / v% Alcohol 1 to 70 w / v% Acid 0.1 to 12 w / v% Water balance 13. The solution preparation of a triazole derivative according to claim 2, wherein the concentration of each component is as follows. Triazole derivative SS750 or a salt thereof 1 to 25 w / v% polysorbate 80 or polyoxyethylene castor oil 10 to 80 w / v% ethanol 1 to 70 w / v% citric acid, phosphoric acid, maleic acid or hydrochloric acid 0.1 to 12 w / v % Water balance 14. The solution preparation according to claim 1, wherein the solution preparation is an injection.
3. A solution preparation of the triazole derivative according to any one of 3. 15. An injection of a triazole derivative in which the concentration of each component is as follows. Triazole derivative SS750 or a salt thereof 1 to 25 w / v% polysorbate 80 or polyoxyethylene castor oil 20 to 70 w / v% ethanol 20 to 60 w / v% water balance 16. An injection of a triazole derivative in which the concentration of each component is as follows. Triazole derivative SS750 or a salt thereof 1 to 25 w / v% polysorbate 80 or polyoxyethylene castor oil 20 to 70 w / v% ethanol 20 to 60 w / v% citric acid, phosphoric acid, maleic acid or hydrochloric acid 0.2 to 8 w / v % Water balance