KR20140119363A - Stable compositions of voriconazole - Google Patents

Abstract

The present invention relates to a stabilized voriconazole composition, wherein a non-reducing sugar as a stabilizer is added to a composition containing voriconazole and a solubilizer, thereby improving the stability of the composition containing voriconazole; a method for preparing same; and to a stabilized composition. The use of a non-reducing sugar as a stabilizer can improve the stability of a composition containing voriconazole which is difficult to solubilize and unstable in moisture and heat even if solubilized, thus generating voriconazole related compound B ((2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol) or triazole acetophenone (1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone), which are decomposition products. Therefore, the composition containing voriconazole can be stored for a long time without concerns about side effects caused by the decomposition products. Furthermore, in the case where the composition according to the present invention is formulated into a freeze-dried form, the time for re-suspension or dissolution of the composition in an injectable solvent can be reduced, and the preparation into an injection composition is convenient since a precipitate is not generated during dilution.

Description

[0001] Stable compositions of voriconazole [0002]

The present invention relates to a composition comprising a boricone sol, and more particularly to a stabilized boricone sol composition which is improved in the stability of a composition containing a boricone sol by adding a stabilizing composition in a composition comprising a boricone sol and a solubilizing agent A process for producing the same, and a stabilizing composition.

Recently, the incidence of highly fatal mycotic fungi such as invasive Aspergillus infection, candidiasis, and Candida infection is increasing. The reason for this is that the number of patients who have weakened immunity due to cancer treatment of various malignant tumors, immunosuppressive treatment for immune diseases, organ transplantation and the spread of AIDS has increased rapidly. Originally, fungal spores survive for several months in a dry environment and float in the air, which is mainly infused into the human body through the respiratory tract and can enter the human body through damaged skin, wound, cornea or ear. Fungi that enter the body cause allergic or general fungal infections in people with normal immune mechanisms, while fatal fungal infections in patients with impaired immune function.

Amphotericin B has been used as a gold standard for the treatment of this mycotic fungus. It has been reported that the overall response rate is as low as 34% on average. Furthermore, nephrotoxicity of amphotericin B is a serious problem, and itraconazole (itraconazole) has recently been recommended, but the success rate of treatment is not so high.

On the other hand, Voriconazole CAS No. 137234-62-9, a compound of formula I disclosed in European Patent EP 0 440 372 B, is a new second-generation synthetic broad-range trizaole antifungal agent, which is useful for treating orcopathogenic candidiasis, It is widely used to treat fungal infections caused by Gillosis and various filamentous fungi.

(I)

Its mechanism of action is to inhibit the biosynthesis of ergosterol by inhibiting the demethylation of 14a-lanosterol mediated by cytochrome P-450 in the fungus.

In clinical practice, voriconazole is administered intravenously and orally in formulations such as lyophilized powder injections, tablets, and dry suspensions to show general systemic action. Commercially available formulations containing voriconazole were first approved in Europe in May 2002 based on the composition described in European patent EP 1001813B and sold as "Vfend Lyphilized Powder for Injection (" Vfend ™ LV) and "Vfend Tablet" . More specifically, Vfend ™ LV, an intravenous injection, is a formulation containing 30 mg of lyophilized powder containing 30 mg of Type I clear glass vial containing 200 mg of voriconazole and 3200 mg of sulfobutyl ether cyclodextrin sodium. The formulation was dissolved in distilled water for injection once at a concentration of 10 mg / ml, diluted to a concentration of 5 mg / ml or less before administration, and administered intravenously at a rate of 3 mg / kg per hour for 1 hour to 2 hours .

Because of their low water solubility (0.2 mg / ml at pH 3) and the semi-polar nature of the compound (log D = 1.8), voriconazole is an oil, surfactant or water miscible common It is very difficult to be solubilized by a conventional means such as a foaming agent. In addition, as a decomposition product in an aqueous solution, an inert enantiomer such as Voriconazole related Compound B ((2S, 3R) -2- (2,4-Difluorophenyl) -3- (5-fluoropyrimidin- ) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol)) is formed from the recombination of the hydrolyzate retroalloy product and is unstable to moisture and heat, It is known that triazole acetophenone (1- (2,4-Difluorophenyl) -2- (1H-1,2,4-triazol-1-yl) ethanone) Therefore, it is difficult to develop aqueous intravenous formulations having a sufficient shelf life during the storage period.

International application WO 1998/58677 discloses a lyophilized pharmaceutical composition solubilized by a sulfoalkyl ether cyclodextrin derivative which is a novel excipient as a solubilizing agent. However, recently, a 1,4-cyclohexanecarboxylic acid derivative, which is a by-product of a novel sulfoalkyl ether cyclodextrin derivative, Genotoxic risk for butane sultone (1,4-butane sultone) has been reported. According to the European Union's CHMP Guideline, the maximum daily allowable dose of this genotoxic drug substance is 1.5 μg. However, it is not easy to control quality of 3200 mg of sulfoalkyl ether cyclodextrin derivative contained in Vfend (TM) LV to 0.47 ppm or less, so that only a few producers can be manufactured, and commercial use is limited as a highly expensive excipient.

In Korean Patent Laid-Open No. 10-2011-0094138, the solubility of voriconazole is increased by using the "monomethoxy polyethylene glycol-poly (D, L-lactic acid) block copolymer mPEG-PDLLA" Although mPEG-PDLLA used as a solubilizing agent has been disclosed as a novel polymer, clinical safety has not been established and its commercial use is limited.

European Patent Publication No. EP2409699A1 discloses a composition containing hydroxypropylcyclodextrin as a solubilizing agent and glycine as an auxiliary agent to ensure aqueous liquid stability. However, only the short-term stability of 96 hours during the manufacturing process is solved, but the fundamental problem of long-term stability taking into account the distribution and storage time is not solved.

In addition to the pharmaceutical compositions disclosed in the above patents, other pharmaceutical compositions disclosed in other prior art also have a disadvantage of being insufficient in stability and becoming unsuitable for producing and consuming impurities exceeding the pharmaceutical limit beyond a certain period of time. Thus, considering all of these disadvantages, stable formulations over a long period of time are required.

Accordingly, the technical problem to be solved by the present invention is to provide a Voriconazole related Compound B ((2S, 3R) -2- (2,4-Difluorophenyl 2-ol)) or triazole acetophenone (1- (4-fluoropyrimidin-4-yl) (2,4-Difluorophenyl) -2- (1H-1,2,4-triazol-1-yl) ethanone)) and stabilizers capable of improving the stability of unstable boricone- Which comprises a stabilized boricone sol. Particularly, the composition according to the present invention can reduce resuspension or dissolution time of the composition into a solvent for use in injection, and does not cause precipitation during dilution, and thus has ease of preparation into a composition for injection.

In order to accomplish the above object, the present invention provides a stabilizing composition for a voriconazole solution containing non-reducing sugar and a method for stabilizing a solution of voriconazole by treating non-reducing sugar.

In addition, the present invention provides a composition comprising a voriconazole and a solubilizing agent, wherein the composition contains a non-reducing sugar as a stabilizer and a method for producing the same.

The present inventors have found that the addition of non-reducing sugar as a stabilizer to a solution of voriconazole remarkably reduces the production rate of decomposition products of voriconazole during storage over a long period of time, thus completing the present invention.

Accordingly, in one aspect, the present invention provides a stabilizing composition for a voriconazole solution comprising a non-reducing sugar and a method for treating a non-reducing sugar to stabilize the solution of the voriconazole.

In the context of the present invention, the term "stabilization" means minimizing decomposition of bioricone sol during the production, storage or distribution of the composition, as well as maintaining its biological structure and maintaining its biological structure do. The term "storage stability" means to be chemically and / or physically stable for a period of time after storage at a temperature between 5 ° C and 50 ° C, and the term " Chemical and / or physical stability "relates to what physical and / or chemical changes of the boricone sol are formed under accelerated or harsh storage conditions, such as degradation or oxidation, and in particular by thermal or moisture, A decomposition product such as a sol-related compound B or triazole aceptophenone can be produced.

By treating the non-reducing sugar according to the present invention, the voriconazole composition of the lyophilized powder formulation is stabilized to produce decomposition products of equal or lesser extent than Vfend ™ LV under accelerated or harsh storage conditions, 0.3%, 0.2%, 0.1%, 0.08%, and most preferably less than 0.05% of triazolezeptophenone (PAR) after 16 days at an acceleration condition of a temperature of + 2 ° C and a humidity of 75% , 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, and most preferably 0.5% after lapse of 16 days at 60 ° C ± 2 ° C. (PAR,%). ≪ / RTI > Further, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.25%, and the like were measured after 16 days at an acceleration condition of a temperature of 40 ° C ± 2 ° C and a humidity of 75% , 6%, 5% and 4% after 16 days in harsh storage conditions of 60 ° C ± 2 ° C, indicating a value of total soft matter (PAR,%) of not more than 0.1% %, 3%, 2%, 1.5%, 1% and most preferably less than 1%.

The non-reducing sugar means a saccharide having no reducing functional group, and various non-reducing sugars known in the art can be used. Examples thereof include sucrose, trehalose, lactose, raffinose, mannitol, Xylitol, sorbitol, maltitol, isomalt, lactitol and monohydrate, but preferably sucrose or trehalose may be used, more preferably sucrose may be used.

In the embodiment according to the present invention, when sucrose is used as a stabilizer (corresponding to Example 4), 16 days elapsed under acceleration conditions of a temperature of 40 ° C ± 2 ° C and humidity of 75% ± 5% , No triazolezeptophenone was produced at all, and it was confirmed that the value of total solids (PAR,%) was less than 1% even after 16 days of storage at 60 ° C ± 2 ° C.

In addition, when trehalose was used as a stabilizer (corresponding to Example 7), no triazole acepthophenone was generated at room temperature, and a temperature of 40 캜 2 캜 and an acceleration of humidity of 75% 5% RH (PAR,%) was produced even after 16 days in the condition, and less than 2% of the total suppositories (PAR,%) was formed even after 16 days under the harsh storage condition of 60 ° C ± 2 ° C. ) Value of the product.

From this it can be seen that sucrose and trehalose exert a stabilizing effect of the voricinazole composition which is significantly superior to the use of other excipients known in the art, such as povidone K17, It is expected that the non-reducing sugar in addition to the haloose will similarly exhibit an excellent stabilizing effect.

In another aspect, the present invention provides a composition comprising a voriconazole and a solubilizing agent, wherein the composition contains a non-reducing sugar as a stabilizer and a method for producing the same.

In the specification of the present invention, the term " boriconazole "includes the boriconazole represented by the above formula (I) and pharmaceutically acceptable salts thereof such as hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, Maleate, fumarate, benzenesulfonate or p-toluenesulfonate; Acid esters acceptable in the pharmacological context of the invention, such as phosphate esters, and the like. (W / V), 0.05 to 8% (W / V), 0.1 to 7% (W / V), 0.5 to 5% (W / V) based on the total boricone sol- V), 0.5 to 4% (W / V), 0.5 to 3% (W / V), 0.8 to 2% (W / V), or 0.8 to 1.5% And preferably 0.9 to 1.2% (W / V).

(W / V), 1 to 15% (W / V), 5 to 15% (W / V), 5 to 12% (W / V) based on the total boricone sol- ), 5 to 11% (W / V), and most preferably 6 to 10% (W / V). When the content is less than 0.05% (W / V) based on the total boriconazole-containing composition, it is difficult to expect the stabilization effect of the voriconazole and it is uneconomical when the content exceeds 15% (W / V).

(W / V), 5 to 15% (W / V), 8 to 14% (W / V), and 9 to 14% (W / V) based on the total boricone sol- To 13% (W / V), or 9 to 12% (W / V), and most preferably 9 to 11% (W / V).

(W / V), 3 to 13% (W / V), 4 to 9% (W / V) based on the total boricone sol containing composition when trehalose is selected as the non- ), Or 5 to 8% (W / V), and even more preferably 5 to 7% (W / V).

The solubilizing agent is added to dissolve the voriconazole in a solvent, particularly water. The solubilizing agent is not limited as long as it can be used to solubilize the voriconazole, but it is preferably a hydroxypropyl betacyclocyclin -β-cyclodextrin) can be used.

(W / V), 7 to 15% (W / V), 8 to 14% (W / V), or 9 to 14% (W / V) based on the total boricone sol- V), and most preferably from 10 to 13% (W / V). When the content is less than 5% (W / V) based on the total boriconazole-containing composition, the solubilization effect of boricone is hardly expected, and it is uneconomical when the content exceeds 15% (W / V).

The active ingredient, isotonizing agent, buffer or bulking agent commonly used in the art may be additionally included in the composition containing the voriconazole according to the present invention without limitation.

The isotonic agent refers to an agent that, when dissolved in the composition, causes the osmotic pressure of the composition to be within the physiological range of blood, peritoneal fluid or other body fluids, including but not limited to sodium acetate, sodium lactate, potassium chloride, Calcium chloride may be used.

The bulking agent refers to an agent that imparts lyophilized cake characteristics and overcomes various stresses during cutting or freezing associated with the lyophilization process and helps maintain the activity of the voriconazole. Examples thereof include, but are not limited to, mannitol , Glycine, or lactose may be used.

The voriconazole composition according to the present invention may be in the form of a liquid or solid, preferably in the form of a powder, more preferably in the form of a lyophilized powder. Both the liquid and solid phase of the voriconazole composition have excellent stability. When formulated in the form of a lyophilized powder, it is advantageous for storage and distribution. In particular, the voriconazole formulation formulated with the freeze-dried powder according to the present invention can be resuspended or dissolved in the solvent for use in a short time, There is an advantage that it is easy to formulate into the injectable composition.

The composition containing the voriconazole according to the present invention is an antifungal composition which exhibits the antimicrobial effect which is conventionally expected in the art by voriconazole and which is effective for the treatment of diseases such as invasive Aspergillus infection, Or a serious fungal infection caused by Scedosporium apiospermum (asexual type of Pseudallescheria boydii) or Fusarium spp. (Including Fusarium solani), and can be used as a composition for the treatment or prevention of these diseases, diseases and symptoms.

When a voriconazole pharmaceutical composition is formulated as a lyophilized powder, it needs to be reconstituted into a liquid phase prior to use in order to be administered to a patient as an injection. However, the present invention does not exclude that the voriconazole pharmaceutical composition can be administered to a patient in solid form.

The pharmaceutical composition according to the present invention can be preferably used for parenteral administration, such as, for example, intravenous, intramuscular, subcutaneous administration, and the like, most preferably for intravenous administration.

The pharmaceutical composition containing the voriconazole according to the present invention may further comprise a pH adjusting agent, a osmotic agent, a stabilizer or a diluent commonly used in the art.

The method for preparing a composition containing a boricone sol according to the present invention includes the following steps.

(S1) adding the boricone sol to the solubilizing agent-containing solution; And

(S2) adding non-reducing sugar as a stabilizer to the solution.

Additionally, (S3) filtration, dispensing, and lyophilization may additionally be included.

Each step will be described in detail as follows.

(S1) adding the boricone sol to the solubilizing agent-containing solution

After solubilizing the solubilizing agent in a solvent, preferably water, and more preferably purified water for injectable use, the solution is added with boricone sol and mixed with stirring. If necessary, a bulking agent or the like may be added.

(S2) adding non-reducing sugar as a stabilizer to the solution

To this solution is added non-reducing sugar as a stabilizer and dissolved.

Then, the concentration of the composition can be suitably adjusted in consideration of the route of administration, the administration rate, or the purpose of administration by adding a solvent, preferably water, more preferably injectable purified water thereto. For example, a final concentration suitable for transfer to an injection bag for use in intravenous administration can be adjusted to a concentration of about 5.0 mg / mL.

In some cases, a pH adjusting agent, an osmotic agent, a stabilizer, a filler, a lubricant, a disintegrant, a binder, a diluent or a lubricant may be added.

(S3) filtration, dispensing, and lyophilization

The solution prepared through step (S2) may be filtered by various methods known in the art.

The filtered solution is dispensed into an appropriate container. For example, glass containers commonly used in the pharmaceutical field, especially standard USP type I borosilicate glass containers, can be used.

It may be subjected to a sterile filtration process prior to lyophilization. To freeze the vessel and solution, a temperature below the critical product temperature is applied to the shelf of the freeze-dryer. Water is removed by introducing vacuum conditions and water condensation is emitted on the ice-condenser of the freeze-dryer. The lyophilization can be carried out, for example, by freezing at about -60 to -40 占 폚, lyophilizing the frozen formulation at -30 to -20 占 폚, and secondary drying at 10 to 20 占 폚.

When the lyophilized product prepared through the above process is lyophilized, it becomes a cake form of the composition, and the container can be sealed and sealed and stored at room temperature before use.

As described above, when a non-reducing sugar is used as a stabilizer, it is difficult to be solubilized, and even if it is solubilized, Voriconazole related Compound B ((2S, 3R) 2- (2,4-Difluorophenyl) -3- (5-fluoropyrimidin-4-yl) -1- (1H-1,2,4-triazol- The stability of the unstable boriconazole-containing composition such as triazole acetophenone (1- (2,4-Difluorophenyl) -2- (1H-1,2,4-triazol-1-yl) ethanone) So that the composition containing the voriconazole can be stored for a long period of time without fear of side effects due to decomposition products. In addition, when the composition according to the present invention is formulated in a lyophilized form, it is possible to reduce the resuspension time or dissolution time of the composition into a solvent for use, and it is easy to prepare into a composition for injection without causing sedimentation during dilution.

Fig. 1 shows the XRD measurement results for Comparative Example 1 and Example 4. Fig.

Hereinafter, embodiments of the present invention will be described in more detail. However, the embodiments according to the present invention can be modified into various other forms, and the scope of the present invention should not be construed as being limited to the embodiments described below.

<Examples>

Ingredient Amount (mg) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Comparative Example 1 Voriconazole 500 500 500 500 500 500 500 500 500 500 Hydroxypropyl-β-cyclodextrin 6000 4500 6000 6000 6000 6000 6000 6000 6000 - Sulphobutylether β-cyclodextrin, sodium salts - - - - - - - - - 8000 Glycine - - 1040 - - - - - - - Sucrose - - - 5000 - - - - - - D-Mannitol - - - - 5000 - - - - - Poloxamer
188 - - - - - 250 - - - - Trehalose - - - - - - 3000 - - - Edetate disodium dihydrate - - - - - - - 250 - - Povidone K17 - - - - - - - - 250 - Water for injection to 50.0ml to 50.0ml to 50.0ml to 50.0ml to 50.0ml to 50.0ml to 50.0ml to 50.0ml to 50.0ml to 50.0ml

Approximately 40 ml of purified water was dissolved in hydroxypropyl-β-cyclodextrin (Kleptose ^® HPB, Roquette) according to the amounts shown in the above table in Examples 1 to 9, To this solution, Voriconazole (MSN, India) was added and stirred at a constant rate of about 35 ° C to prepare a transparent solution. To this solution were added the additional excipients Glycine, Sucrose, D-Mannitol, Poloxamer 188, Trehalose (D-Mannitol), which correspond to Examples 3 to 9 Trehalose, Edtate disodium dehydrate and Povidone K17 were added in amounts corresponding to the above-mentioned amounts, and dissolved. Then, distilled water for injection was added to a final volume of 50 ml. The resulting solution was filtered through a Millex ™ -GP syringe-driven filter unit with a diameter of 0.22 μm and packed into 20 ml glass vials, 5 ml each. The vial was partially capped by a lyophilization stopper available from Helvoet Pharma and lyophilized until the cake was formed at the bottom of the vial.

Comparative Example 1 In the case of, sulfo-butyl-ether-beta-cyclo dextrin, sodium salt (Sulphobutylether β-cyclodextrin, sodium salts) was ^(? Captisol Research grade, Cydex社) a state dissolved the use of purified water of about 40ml, barley To this solution Voriconazole (MSN, India) was added, and the mixture was stirred at a constant rate of about 35 ° C to prepare a transparent solution. The same procedure as in Example 1 was followed by filtration, dispensing and freeze-drying to prepare a lyophilized powder Respectively.

The lyophilization process was performed as follows.

1) Freezing: -40 ° C, 3 hours

2) Chamber vaccum: 0.05 mba

3) Primary drying: -20 ℃, 24 hours, 0.01 mba

4) Temperature rise at ramp rate of 1 K / min

5) Secondary drying: 20 ℃, 8 hours

< Experimental Example  1> Property evaluation

The dissolution time required for diluting the solution to a concentration of 10 mg / ml of Voriconazole was measured by adding purified water to each of the lyophilized powders prepared in each of the Examples and Comparative Examples, and the osmotic pressure of the diluted solution (OSMOMAT 030- D, Gonotec GmbH) and pH (SevenEasy, Mettler toledo). The diluted solution was diluted to a concentration of 5 mg / ml using purified water for injection, left to stand for 24 hours in a refrigerated state, and subjected to dilution stability evaluation by confirming whether it was precipitated visually. The above results are shown in Table 2.

Evaluation items Example 3 Example 4 Example 5 Example 7 Comparative Example 1 Dissolution time Within a minute Within a minute In two minutes Within a minute Within a minute Dilution stability No settling No settling No settling No settling No settling Osmotic pressure 0.209 0.230 0.388 0.148 0.230 pH 4.69 6.43 4.81 6.15 5.49

As shown in Table 2 above, when compared with Comparative Example 1, which is the same formulation as the commercially available product VFEND Lyophilized powder, it dissolved in completely transparent solution within 2 minutes in all the examples, and was diluted, And the osmolality and pH range of the body fluid (pH 3.5 to 7) are shown. Therefore, in Examples 3, 4, 5, and 7, no specific discomfort was found .

&Lt; Experimental Example 2 >

The lyophilized powders prepared in Examples 1 to 9 and Comparative Example 1 were subjected to a stability test under the following conditions. The degree of decomposition products of boraniconazole was evaluated and the stability was compared. The results are shown in Table 3 below.

[Stability test conditions]

1) Acceleration test

- Temperature and humidity: 40 ℃ ± 2 ℃ / 75% ± 5% RH

- Sample storage Packing: 30ml Type I transparent glass vial

2) Temperature Harsh Test

- Temperature: 60 ° C ± 2 ° C

- Sample storage Packing: 30ml Type I transparent glass vial

[Organic flexible substance analysis conditions]

1) Prepare standard solution of flexible substance

5 mg of triazole acetophenone (TAP) standard is placed in a 50 ml volumetric flask and diluted with acetonitrile. (100 ug / ml)

2) Preparation of standard solution

20.0 mg of Voriconazole standard is precisely weighed into a 10 ml volumetric flask and diluted with acetonitrile. (2000ug / ml)

3) Preparation of test liquid

Precisely take samples of 20 mg of voriconazole and place in a 10 ml volumetric flask and dilute with acetonitrile. (2000ug / ml)

4) Operation

Test and test 20 μl of each of the sample solution and standard solution according to the liquid chromatography method in the General Test Methods under the following conditions.

5) Equipment condition

Column: Symmetry C8, 250 x 4.6 mm, 5 um

Diluent: 7.8 g of sodium dihydrogen phosphate dehydrate was dissolved in 1000 ml of purified water and adjusted to pH 5.5 with 10% sodium hydroxide.

Mobile phase: Gradient system of diluent and acetonitrile (8: 2 ratio) mixture (A), diluent and acetonitrile (2: 8 ratio)

Detector: Ultraviolet absorptiometer (measuring wavelength 254 nm)

Flow rate: 1 mL / min

Temperature: 40 ° C

6) Calculation

Result (PAR,%) = (At / Av) X (F) X 100

At = Peak area of the individual flexible substances from the test solution

Av = Peak area of voriconazole from the sample solution

F = relative response coefficient

* Reporting threshold: 0.05%

Test items Test condition Test period Example 4 Example 5 Example 6 Example 7 Example 9 Comparative Example 1 TAP ^*
(PAR ^* ,%) Ambient Temperature Initial 0.00 0.00 0.08 0.00 0.06 0.05 40 ° C / 75% RH 7 days 0.00 0.19 0.40 0.05 0.30 16 days 0.00 0.38 0.64 0.08 0.45 0.06 60 ° C 7 days 0.17 1.79 2.68 0.46 2.63 16 days 0.37 3.59 4.85 0.87 3.81 0.56 Total impurites (PAR ^* ,%) Ambient Temperature Initial 0.11 0.29 0.11 0.11 0.20 0.25 40 ° C / 75% RH 7 days 0.10 0.43 0.95 0.20 0.71 16 days 0.07 0.87 1.38 0.25 0.97 0.28 60 ° C 7 days 0.41 3.46 5.35 1.08 5.32 16 days 0.89 6.93 9.58 1.97 7.58 1.42

TAP ^* : Triazole acetophenone

PAR ^* : Percent area ratio, sum of the ratio of the peak area of each impurity to the area of the main peak.

As shown in Table 3, the lyophilized powder formulations of Examples 4 and 7 containing non-reducing sugars as excipients showed significantly higher values than those of Comparative Example 1 comprising the same formulation as the commercially available formulation VFEND Lyophilized powder under accelerated or harsh storage conditions It was confirmed that triazole acetophenone, which is a flexible substance derived from conazole, is remarkably reduced or produced to a similar extent.

<Experimental Example 3> XRD measurement

XRD measurements were made for Comparative Examples 1 and 4, and the results are shown in FIG. XRD measurement was performed under the following conditions.

- Maker Bruker AXS, D8 Advance

- 40 kV, 30 mA, 2θ / θ scan, 3 ° to 50 °

As shown in FIG. 1, the freeze-dried formulation prepared in Example 4 did not show a specific crystalline peak of boricone sol on XRD in the same manner as in Comparative Example 1, indicating that boriconazole was stabilized in cyclodextrin It was confirmed that it was enclosed.

Accordingly, the present invention relates to a method for preparing a pharmaceutical composition containing a compound of formula (I), which is a decomposition product of water and heat by using a non-reducing sugar as a stabilizer of a second-generation synthetic triazole antifungal drug- 3-yl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol) and Triazole (1, 2,4-Difluorophenyl) -2- (1H-1,2,4-triazol-1-yl) ethanone in the distilled water for injection It is possible to reduce the resuspension or dissolution time of the composition and improve the stability of the precipitate upon dilution, thereby remarkably improving the convenience of the preparation, which is highly likely to be used industrially.

Claims (12)

A stabilizing composition for a voriconazole solution comprising non-reducing sugar. A composition comprising a voriconazole and a solubilizing agent, wherein the composition contains a non-reducing sugar as a stabilizer. The method according to claim 2, wherein the non-reducing sugar is selected from the group consisting of sucrose, trehalose, lactose, raffinose, mannitol, xylitol, sorbitol, maltitol, isomalt, lactitol, 1 &lt; / RTI &gt; or more is selected. The composition according to claim 2, wherein the non-reducing sugar comprises 0.05 to 15% (W / V) based on the total boricone sol containing composition. 3. The method of claim 2, wherein the non-reducing sugar comprises sucrose in an amount of 3 to 15% (w / v) based on the total boricone sol containing composition, or wherein the non-reducing sugar trehalose is added to the total boricone sol- By weight, based on the total weight of the composition, of from 3 to 15% (W / V). The composition according to claim 2, wherein the solubilizing agent is hydroxypropyl-beta-cyclodextrin. The composition according to claim 2, wherein the solubilizing agent comprises 6 to 15% (W / V) based on the total boricone sol containing composition. The composition according to claim 2, wherein the composition containing voriconazole is a pharmaceutical composition for treating or preventing invasive Aspergillus infection, candidiasis, Candida infection, or severe fungal infection. The composition according to claim 2, wherein the composition containing voriconazole is in the form of a lyophilized powder. Wherein the non-reducing sugar is treated to stabilize the solution of the boriconazole. In the method for producing a composition containing voriconazole,
(S1) adding the boricone sol to the solubilizing agent-containing solution; And
(S2) adding non-reducing sugar as a stabilizer to the solution. 12. The method according to claim 11, further comprising the step of (S2) followed by filtration, dispensing, and lyophilization.

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