WO2014157989A1

WO2014157989A1 - Stabilized composition containing voriconazole

Info

Publication number: WO2014157989A1
Application number: PCT/KR2014/002666
Authority: WO
Inventors: 김관영; 신동철; 신호철; 김훈택
Original assignee: 에스케이케미칼 주식회사
Priority date: 2013-03-29
Filing date: 2014-03-28
Publication date: 2014-10-02
Also published as: KR20140119363A

Abstract

The present invention relates to: a stabilized voriconazole composition, wherein the stability of a composition containing voriconazole is improved by adding a non-reducing sugar as a stabilizer to a composition comprising voriconazole and a solubilizing agent; a preparation method therefor; and the stabilized composition. When using a non-reducing sugar as a stabilizer, it is possible to improve the stability of a composition containing voriconazole which is difficult to be solubilized and unstable in the presence of moisture and heat even if solubilized, and thus is unstable in 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, and the like, thereby enabling the storage of a composition containing voriconazole for a long time without concerns about side effects caused by the decomposition products. In addition, it is possible to reduce the time required for re-suspension or dissolution of an injectable solvent and to prevent the generation of a precipitate during dilution if the composition according to the present invention is formulated into a freeze-dried form, and thus preparation into an injection composition is convenient.

Description

Stabilized Compositions Containing Boleyconazole

The present invention relates to a voriconazole-containing composition, and more particularly, to a stabilized boroconazole composition in which a stabilizing composition is added in a voriconazole-containing composition to improve the stability of the voriconazole-containing composition, a preparation method thereof, and the above. It relates to a stabilizing composition.

Recently, the incidence of very deadly cardiac fungi, such as invasive Aspergillus infection, candidiasis and Candida infection, is increasing. The reason for this is that the number of patients with weakened immunity increased rapidly due to chemotherapy of various malignancies, immunosuppressive treatment for immune diseases, organ transplantation and AIDS. Originally, fungal spores can survive for months in a dry environment, float in the air, and enter the body primarily through the respiratory system, which can also enter the body through damaged skin, surgical wounds, corneas or ears. Fungi that enter the body cause allergic or normal fungal infections in people with normal immune mechanisms, while fatal fungal infections in patients with reduced immune function.

Amphotericin B has been used as a gold standard for the treatment of cardiac fungal disease, and the overall response rate is reported to have a very low response rate of 34% on average. Moreover, the nephrotoxicity of amphotericin B is a serious problem. Recently, the treatment of itraconazole is recommended, but the success rate of the treatment is not so high.

Meanwhile, voriconazole CAS No.:137234-62-9, a compound of formula I, disclosed in European Patent EP0440372B, is a new second generation synthetic broad-range trizaole antifungal agent, oropharyngeal candidiasis, invasive asthma It is widely used to treat fungal infections caused by Pergillosis and various filamentous fungi.

[Formula I]

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

In the clinical practice, voriconazole is administered intravenously and orally in the form of lyophilized powder injections, tablets, dry suspensions, and the like to have systemic effects. Commercial 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"). It is becoming. More specifically, Vfend ™ LV, an intravenous injectable formulation, is a formulation containing a white lyophilized powder comprising 200 mg of barleyconazole and 3200 mg sulfobutylethercyclodextrin sodium in a 30 ml Type I clear glass vial. The formulation is once dissolved at 10 mg / ml in distilled water for injection, then diluted to a concentration of 5 mg / ml or less prior to administration, and administered intravenously in droplets at a rate of up to 3 mg / kg per hour over 1 to 2 hours. It is supposed to be done.

Boleyconazole has a low aqueous solubility (0.2 mg / ml at pH 3), and due to the semi-polar nature of the compound (log D = 1.8), oil, surfactant or water miscibility commonly used in the development of injectables It is very difficult to solubilize by conventional means such as falcons. In addition, the inert enantiomer, boriconazole related Compound B ((2S, 3R) -2- (2,4-Difluorophenyl) -3- (5-fluoropyrimidin-4-yl) as an decomposition product in an aqueous solution. ) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol)) is formed from the recombination of the hydrolyzate retroaldol product, which is unstable to moisture and heat and is therefore a triazole as a decomposition product. Triazole acetophenone (1- (2,4-Difluorophenyl) -2- (1H-1,2,4-triazol-1-yl) ethanone) is known to have poor stability. Therefore, it is difficult to develop an aqueous intravenous preparation having a sufficient shelf life during the shelf life.

International application WO 1998/58677 discloses lyophilized pharmaceutical compositions solubilized by sulfoalkylethercyclodextrin derivatives, which are novel excipients as solubilizers, but recently 1,4- which are by-products of novel sulfoalkylethercyclodextrin derivatives. Genotoxic risks for 1,4-butane sultone have been reported. According to the European Union's CHMP Guidelines, the maximum daily dose for these genotoxic analogs is 1.5 µg. However, quality control of less than 0.47 ppm of 3200 mg of sulfoalkylethercyclodextrin derivatives contained in Vfend ™ LV is not easy, and very few manufactures are available, and the commercial use is limited due to the extremely expensive excipients.

In Korean Patent Laid-Open Publication No. 10-2011-0094138, a monomethoxy polyethyleneglycol-poly (D, L-lactic acid) block copolymer mPEG-PDLLA is used as an adjuvant to increase the solubility of voriconazole and to improve the water solubility of voriconazole. Although improved drug formulations are disclosed, mPEG-PDLLA, used as a dissolution aid, is a novel polymer with limited clinical safety and has limited commercial use.

European Patent Publication EP2409699A1 discloses a composition containing hydroxypropylcyclodextrin as a solubilizer, and glycine added as an adjuvant to secure aqueous phase stability. However, only short-term stability for 96 hours during the manufacturing process is solved, and the fundamental problem of long-term stability in consideration of distribution and storage time has not been solved.

In addition to the pharmaceutical compositions disclosed in the above patents, the pharmaceutical compositions disclosed in other prior arts also lack the stability and have a fatal disadvantage that they become inadequate to produce and consume impurities exceeding the pharmaceutical limit beyond a certain period of time. Therefore, in view of all these drawbacks, there is a need for a stable formulation over a long period of time.

Accordingly, the technical problem to be solved by the present invention is difficult to solubilize and unstable to moisture and heat even if solubilized, the boric azole 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- Stabilizers capable of improving the stability of unstable boronazole-containing compositions, such as (2,4-Difluorophenyl) -2- (1H-1,2,4-triazol-1-yl) ethanone) To provide a stabilized voriconazole containing composition. In particular, the composition according to the present invention can reduce the resuspension or dissolution time in the solvent for injection, and does not produce a precipitate upon dilution, and thus has ease of preparation into the composition for injection.

In order to achieve the above technical problem, the present invention provides a stabilizing composition and a non-reducing sugar for stabilizing the boroconazole solution to stabilize the voriconazole solution containing a non-reducing sugar (Non-reducing sugar).

In addition, the present invention provides a composition containing a voriconazole, characterized in that it comprises a non-reducing sugar as a stabilizer and a method for producing the same.

In addition, the present invention provides a pharmaceutical composition for preventing and / or treating fungal infections comprising a composition containing voriconazole, a method for preventing and / or treating a fungal infection by administering to a subject a composition comprising a voriconazole-containing composition, and a fungal infection prevention and And / or the use of a voriconazole comprising composition for the manufacture of a pharmaceutical formulation for treatment.

The present inventors have found that the addition of non-reducing sugar as a stabilizer to the voriconazole solution significantly reduces the production rate of voriconazole decomposition products during long-term storage.

Therefore, in one aspect, the present invention provides a stabilizing composition for stabilizing a voriconazole solution containing non-reducing sugar and a method for stabilizing a voriconazole solution by treating the non-reducing sugar.

In the context of the present invention, the term "stabilization" refers to minimizing degradation of voriconazole and maintaining its intrinsic structure to maintain its biological activity during the production, storage, or distribution of the voriconazole containing composition. it means. In particular, the stabilization is meant to include "storage stability" and the term "storage stability" means chemically and / or physically stable for a period of time after being stored at a temperature between 5 ° C and 50 ° C, and the term " Chemical and / or physical stability "refers to what physical and / or chemical changes of voriconazole are formed under accelerated or harsh storage conditions, which physical and / or chemical changes may cause degradation or oxidation, for example, In particular, it refers to a decomposition product such as boleyconazole-related compound B or triazole acetophenone may be produced by heat or moisture.

Upon treatment of the non-reducing sugars according to the invention, the voricoconazole composition of the lyophilized powder formulation can be stabilized to produce an equivalent or less amount of degradation products compared to Vfend ™ LV under accelerated or harsh storage conditions, for example Triazolceptetophenone of 0.4%, 0.3%, 0.2%, 0.1%, 0.08%, most preferably less than 0.05% after 16 days at accelerated conditions of 40 ° C ± 2 ° C and humidity of 75% ± 5% RH (PAR,%), and 3.5%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, most preferably after 16 days under severe storage conditions of 60 ° C ± 2 ° C. Less than 0.5% triazoleacetophenone (PAR,%) can be produced. Further, for example, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.25% after 16 days at accelerated conditions of a temperature of 40 ° C ± 2 ° C and a humidity of 75% ± 5% RH. , 0.2%, 0.1%, most preferably less than 0.1% total lead (PAR,%) value, 7%, 6%, 5%, 4 after 16 days under severe storage conditions of 60 ° C ± 2 ° C. Total soft matter (PAR,%) values of%, 3%, 2%, 1.5%, 1%, most preferably less than 1%.

The non-reducing sugar refers to a sugar having no reducing functional group, and various non-reducing sugars known in the art may be used, such as sucrose, trehalose, lactose, raffinose, mannitol, One or more may be selected from the group consisting of xylitol, sorbitol, maltitol, isomalt, lactitol and monohydrate, but sucrose or trehalose may be preferably used, and more preferably sucrose may be used.

In an embodiment according to the invention, when sucrose is used as a stabilizer (corresponding to example 4), 16 days have elapsed at room temperature as well as at accelerated conditions of a temperature of 40 ° C. ± 2 ° C. and a humidity of 75% ± 5% RH. Triazol aceptophenone was not produced at all, and after 16 days under severe storage conditions of 60 ° C. ± 2 ° C., it was confirmed that the total analog (PAR,%) value was less than 1%.

In addition, when trehalose was used as a stabilizer (corresponding to Example 7), no triazole acetophenone was produced at room temperature, and acceleration of a temperature of 40 ° C. ± 2 ° C. and a humidity of 75% ± 5% RH was observed. Less than 1% of triazoleacetophenone (PAR,%) was produced even after 16 days under conditions, and less than 2% of total lead (PAR,%) after 16 days under severe storage conditions of 60 ° C ± 2 ° C. ) Value.

From this, it can be seen that sucrose and trehalose exhibit a significantly better stabilizing effect of the voriconazole composition than when using other excipients known in the art, such as povidone K17, and sucrose and tre Non-reducing sugars other than halose are also expected to show excellent stabilizing effects.

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

In the context of the present invention, the term "voriconazole" includes voriconazole represented by the following formula (I) and pharmaceutically acceptable salts thereof, such as hydrochloride, hydrobromide, sulfate, phosphate, methane sulfonate, Maleate, fumarate, benzene sulfonate or p-toluenesulfonate; Or pharmaceutically acceptable acid esters thereof, such as phosphate esters. The voriconazole is 0.01 to 10% (W / V), 0.05 to 8% (W / V), 0.1 to 7% (W / V), 0.5 to 5% (W / V), 0.5-4% (W / V), 0.5-3% (W / V), 0.8-2% (W / V), or 0.8-1.5% (W / V), most Preferably 0.9 to 1.2% (W / V).

[Formula I]

The non-reducing sugar is 0.05 to 15% (W / V), 1 to 15% (W / V), 5 to 15% (W / V), 5 to 12% (W / V) based on the total barleyconazole-containing composition. ), 5 to 11% (W / V), most preferably 6 to 10% (W / V). When it is included in less than 0.05% (W / V) based on the total voriconazole-containing composition, it is difficult to expect a voriconazole stabilizing effect, it is uneconomical when included in more than 15% (W / V).

More specifically, when sucrose is selected as the non-reducing sugar, 3 to 15% (W / V), 5 to 15% (W / V), 8 to 14% (W / V) based on the total voriconazole-containing composition , 9 to 13% (W / V), or 9 to 12% (W / V), and most preferably 9 to 11% (W / V).

Alternatively, when trehalose is selected as the non-reducing sugar, 3 to 15% (W / V), 3 to 13% (W / V), and 4 to 9% (W / V) based on the total voriconazole-containing composition ), Or 5 to 8% (W / V), even more preferably 5 to 7% (W / V).

The composition containing boleyconazole according to the present invention may additionally include a solubilizer. The solubilizer is a substance added to dissolve voriconazole in a solvent, preferably an aqueous solvent, more preferably water, and may be included without limitation as long as it is a substance usable for solubilizing voriconazole. Hydroxypropyl beta cyclotextrin (Hydroxypropyl-β-cyclodextrin) can be used.

The solubilizer may be 6 to 15% (W / V), 7 to 15% (W / V), 8 to 14% (W / V), or 9 to 14% (W / V) based on the total voriconazole containing composition. V), most preferably 10 to 13% (W / V). If it contains less than 5% (W / V) based on the total voriconazole containing composition, it is difficult to expect the voriconazole solubilization effect, it is uneconomical to include more than 15% (W / V).

The boleyconazole-containing composition according to the present invention may additionally include, without limitation, active ingredients, isotonic agents, buffers or bulking agents commonly used in the art.

By tonicity agent is meant an agent that, when dissolving the composition, causes the composition to have an osmotic pressure within the physiological range of blood, peritoneal fluid or other body fluids, including but not limited to, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride or Calcium chloride can be used.

The bulking agent refers to an agent that imparts lyophilized cake characteristics, helps to overcome various stresses occurring during cleavage or freezing associated with the lyophilization process and maintains the activity of voriconazole, including but not limited to mannitol , Glycine, or lactose may be used.

The voriconazole composition according to the present invention may be liquid or solid, preferably in powder form, and more preferably in lyophilized powder form. Irrespective of the properties, all of the compositions containing borosiconazole according to the present invention have excellent stability. When formulated in the form of a lyophilized powder, it is advantageous for storage and distribution. Especially, the voriconazole composition formulated with the lyophilized powder according to the present invention can be resuspended or dissolved in a solvent for injection in a short time and the precipitate is diluted upon dilution. There is an advantage that it does not occur and has ease of preparation into an injectable composition.

The boleyconazole-containing composition according to the present invention is an antifungal composition, which exhibits the antifungal effect commonly expected in the art by voriconazole, such as invasive Aspergillus infection, Candidiasis, Candida infection, Or scedosporium apiospermum (asexual reproduction of Pseudallescheria boydii) or Fusarium genus (including Fusarium solani).

Accordingly, the voriconazole containing composition according to the present invention can be used for the treatment and / or prevention of fungal infections.

Accordingly, in another aspect, the present invention provides a pharmaceutical composition for preventing and / or treating fungal infections comprising a composition containing voriconazole, a method for preventing and / or treating a fungal infection by administering to a subject a composition comprising a voriconazole-containing composition, and Provided is the use of a voriconazole containing composition for the manufacture of a pharmaceutical formulation for the prophylaxis and / or treatment of fungal infections.

The composition containing voriconazole can be administered by various routes such as oral, subcutaneous, parenteral, intravenous, peritoneal or intramuscular, and most preferably can be used for intravenous administration.

The voriconazole containing composition may be formulated in solid or liquid form, and in the solid phase, may be administered dissolved in a sterile injectable solvent for administration in a subject. If the composition containing voriconazole is solid, such as formulated as a lyophilized powder, it needs to be reconstituted in liquid form prior to use in order to be administered to the patient as an injection. However, the present invention does not exclude that the voriconazole pharmaceutical composition may be administered to the patient in a solid state.

The composition containing boleyconazole for the prophylaxis and / or treatment of fungal infections according to the present invention may additionally include pH adjusting agents, osmotic agents, stabilizers or diluents commonly used in the art.

In addition, the method for producing a composition containing a boleyconazole according to the present invention includes the following steps.

(S1) adding voriconazole to a solution containing a solubilizer; And

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

Additionally, (S3) may include filtration, dispensing, and / or lyophilization.

It will be described in detail for each step, as follows.

(S1) adding voriconazole to a solution containing a solubilizer

The solubilizer is dissolved in a solvent, preferably an aqueous solvent, more preferably water, such as sterile injectable purified water, and then the solution is added with voriconazole and stirred and mixed. In some cases, bulking agents and the like may be added.

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

Non-reducing sugars are added to the solution as stabilizers and dissolved.

Then, a solvent, preferably an aqueous solvent, more preferably water, such as sterile injectable purified water, may be added to suitably adjust the concentration of the composition in consideration of the route of administration, rate of administration, or purpose of administration. For example, it may be adjusted to a final concentration suitable for transfer to an infusion bag for use in a patient for intravenous administration, a concentration of about 5.0 mg / mL.

If desired, pH adjusters, osmotic agents, stabilizers, fillers, lubricants, disintegrants, binders, diluents or glidants may be added.

(S3) filtration, dispensing, and / or lyophilization

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

Dispense the filtered solution into an appropriate container. For example, glass containers commonly used in the pharmaceutical art, in particular standard USP type I borosilicate glass containers, can be used.

Prior to lyophilization, a sterile filtration process may be performed. A temperature below the critical product temperature is applied to the shelf of the freeze-dryer to freeze the vessel and solution. Water is removed by introducing vacuum conditions and condensation of water is diverted on the ice-condenser of the freeze-dryer. Lyophilization may be carried out, for example, by freezing at about −60 to −40 ° C., lyophilizing the freeze formulation at −30 to −20 ° C., and secondary drying at 10 to 20 ° C.

When lyophilized through the above process, the composition becomes a cake form, and the container may be sealed and sealed and stored at room temperature until use.

As described above, when non-reducing sugar is used as a stabilizer, it is difficult to solubilize and is unstable to moisture and heat even when solubilized, and thus, 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 Stability of unstable boriconazole-containing compositions, such as the generation of aceptophenone (Triazole acetophenone (1- (2,4-Difluorophenyl) -2- (1H-1,2,4-triazol-1-yl) ethanone)) It can be improved, and the composition containing the voriconazole can be stored for a long time without concern about the side effects caused by the degradation products. In addition, when the composition according to the present invention is formulated in a lyophilized form, it is possible to reduce the resuspension or dissolution time in the solvent for injection, and there is no precipitate upon dilution, thereby having ease of preparation into the composition for injection.

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

Hereinafter, the present invention will be described with reference to Examples in order to describe the present invention in more detail. However, embodiments according to the present invention may be modified in many different forms, the scope of the present invention should not be construed as limited to the embodiments described below.

<실시예> <Example>

Table 1

Ingredient	Amount (mg)
Ingredient	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	-	-	-	-	-
Poloxamer188	-	-	-	-	-	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

In Examples 1 to 9, hydroxypropyl betacyclotextrin (Kleptose ^® HPB, Roquette) was dissolved in about 40 ml of injectable water according to the amount shown in the above table. After the addition of voriconazole (Voriconazole) (MSN, India) was stirred at a constant rate at about 35 ℃ to prepare a transparent solution. Additional excipients corresponding to Examples 3-9 were Glycine, Sucrose, D-Mannitol, Poloxamer 188 and Trehalose. Trehalose), Edtate disodium dehydrate and Povidone K17 were added in an amount corresponding to the above table, dissolved, and then purified water for injection was added to the final 50 ml. The resulting solution was filtered through a Millex ™ -GP syringe-driven filter unit having a diameter of 0.22 μm and filled in 20 ml glass vials of 5 ml each. The vial was partially capped by a lyophilized stopper sold by Helvoet Pharma and lyophilized until the cake formed at the bottom of the vial.

In Comparative Example 1, sulfobutylether beta-cyclodextrin and sodium salts (Captisol ^? Research grade, Cydex) were dissolved in about 40 ml of injectable purified water, and barley was dissolved in the solution. After adding Conazole (MSN, India) and stirring at a constant rate at about 35 ℃ to prepare a transparent liquid, as described in the Example through the filtration, dispensing and lyophilization process to prepare a lyophilized powder It was.

The freeze drying process was performed as follows.

1) Freezing: -40 ℃, 3 hours

2) Chamber vaccum: 0.05 mba

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

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

5) Secondary drying: 20 ℃, 8 hours

<실험예 1> 물성 평가Experimental Example 1 Physical Property Evaluation

Purified water was added to the lyophilized powders prepared in each of Examples and Comparative Examples, and the dissolution time required for dilution to 10 mg / ml of boriconazole solution was measured, and the osmotic pressure of the diluted solution (OSMOMAT 030- D, Gonotec GmbH) and pH (SevenEasy, Mettler toledo) were measured. In addition, the solution was diluted to a concentration of 5 mg / ml using purified water for injection, and left for 24 hours in a refrigerated state, followed by dilution stability evaluation by visually confirming precipitation. The results are shown in Table 2.

TABLE 2

Evaluation item	Example 3	Example 4	Example 5	Example 7	Comparative Example 1
Dissolution time	Within 1 minute	Within 1 minute	Within 2 minutes	Within 1 minute	Within 1 minute
Dilution Stability	No precipitation	No precipitation	No precipitation	No precipitation	No precipitation
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, when compared to Comparative Example 1 composed of the same formulation as the commercial formulation VFEND Lyophilized powder, dissolved in a completely clear solution within 2 minutes in all the examples, diluted to precipitate even in the cold storage for 24 hours This did not occur, and the osmotic pressure and pH range of the body fluid (pH 3.5-7), so that the characteristics of the product to be diluted and administered intravenously, all of Examples 3, 4, 5, and 7 do not have any specific discomfort. It was expected.

<실험예 2> 안정성 시험Experimental Example 2 Stability Test

The lyophilized powders prepared in Examples 1 to 9 and Comparative Example 1 were subjected to stability tests under the following conditions. The degree of formation of degradation products of voriconazole was evaluated to compare the stability. The results are shown in Table 3 below.

[Stability Test Conditions]

1) accelerated test

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

-Sample Storage Package: 30ml Type I Clear Glass Vial

2) Temperature Severity Test

Temperature: 60 ℃ ± 2 ℃

-Sample Storage Package: 30ml Type I Clear Glass Vial

[Organic Flexible Material Analysis Conditions]

1) Preparation of Standard Solution

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

2) Standard Solution

Accurately weigh 20.0 mg of voriconazole standard into a 10 ml volumetric flask and dilute with acetonitrile. (2000ug / ml)

3) Preparation of Test Solution

A sample of 20 mg of voriconazole is precisely taken and placed in a 10 ml volumetric flask and diluted with acetonitrile. (2000ug / ml)

4) operation

20 μl of the sample solution and standard solution are tested according to the Liquid Chromatograph Method in the Pharmacopoeia General Test Methods under the following conditions.

5) Equipment condition

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

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) and diluent and acetonitrile (2: 8 ratio) mixture (B)

Detector: ultraviolet absorption photometer (wavelength 254nm)

Flow rate: 1mL / min

Temperature: 40 ℃

6) Calculation

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

At = peak area of individual lead substances from the sample solution

Av = peak area of voriconazole from the sample solution

F = relative response coefficient

* Reporting threshold: 0.05%

TABLE 3

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 ℃ / 75% RH	7 days	0.00	0.19	0.40	0.05	0.30
	40 ℃ / 75% RH	16 days	0.00	0.38	0.64	0.08	0.45	0.06
	60 ℃	7 days	0.17	1.79	2.68	0.46	2.63
	60 ℃	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 ℃ / 75% RH	7 days	0.10	0.43	0.95	0.20	0.71
	40 ℃ / 75% RH	16 days	0.07	0.87	1.38	0.25	0.97	0.28
	60 ℃	7 days	0.41	3.46	5.35	1.08	5.32
	60 ℃	16 days	0.89	6.93	9.58	1.97	7.58	1.42

TAP ^* : Triazole acetophenone

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

As shown in Table 3, the lyophilized powder formulations of Examples 4 and 7 including non-reducing sugars as excipients were compared to Comparative Example 1, which was composed of the same formulation as the commercially available VFEND Lyophilized powder under accelerated or harsh storage conditions. It was confirmed that triazole acetophenone, a softener derived from Konazole, was produced in a markedly reduced or similar degree.

<실험예 3> XRD 측정Experimental Example 3 XRD Measurement

XRD was measured for Comparative Example 1 and Example 4, and the results are shown in FIG. XRD measurements were 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 lyophilized formulation prepared in Example 4 does not show a specific crystalline peak of barleyconazole on XRD as in Comparative Example 1, and thus, barleyconazole is stable to Cyclodextrin. It was confirmed that it was included.

Accordingly, the present invention provides a decomposed product of Voriconazole related Compound B ((2S, which is produced by water and heat) by using a non-reducing sugar as a stabilizer of a second-generation synthetic triazole antifungal agent-containing pharmaceutical composition. 3R) -2- (2,4-Difluorophenyl) -3- (5-fluoropyrimidin-4-yl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol) and Triazole It significantly improved the storage stability of acetophenone (1- (2,4-Difluorophenyl) -2- (1H-1,2,4-triazol-1-yl) ethanone) and greatly improved the storage stability of the product. It is highly industrially available because it significantly reduces the resuspension or dissolution time of the composition and improves the ease of preparation by diluting the stability upon dilution.

Claims

Stabilizing composition for stabilizing barleyconazole solution containing non-reducing sugar
A composition comprising barleyconazole, comprising a non-reducing sugar as a stabilizer.
The non-reducing sugar of claim 2, wherein the non-reducing sugar is selected from the group consisting of sucrose, trehalose, lactose, raffinose, mannitol, xylitol, sorbitol, maltitol, isomalt, lactitol and monohydrate. A composition comprising voriconazole, wherein at least one is selected.
3. The composition of claim 2, wherein the non-reducing sugar comprises 0.05 to 15% (W / V) based on the total voriconazole-containing composition.
The composition according to claim 2, wherein the non-reducing sugar comprises 3-15% (W / V) of sucrose as the total voriconazole-containing composition, or the trehalose-containing total voriconazole-containing composition as the non-reducing sugar. 3 to 15% (W / V) on the basis of the composition comprising a voriconazole.
The composition of claim 2, wherein the composition comprises a solubilizer in addition to the composition containing voriconazole.
7. The composition of claim 6, wherein the solubilizer is hydroxypropyl betacyclotextrin (Hydroxypropyl-β-cyclodextrin).
3. The composition of claim 2, wherein the solubilizer comprises 6 to 15% (W / V) based on the total voriconazole-containing composition.
The composition of claim 2, wherein the composition containing boleyconazole is a pharmaceutical composition for treating and / or preventing fungal infections.
The composition of claim 2, wherein the composition containing voriconazole is in the form of a lyophilized powder.
A method of treating a non-reducing sugar to stabilize a barleyconazole solution.
In the method for producing a composition containing boleyconazole,

(S1) adding voriconazole to a solution containing a solubilizer; And

(S2) A method for producing a composition comprising a voriconazole comprising the step of adding a non-reducing sugar as a stabilizer to the solution.
13. The method of claim 12, further comprising the step of (S2) followed by filtration, dispensing, and / or lyophilization.
A method of treating and / or preventing fungal infections by administering to a subject a pharmaceutically effective amount of a composition comprising a voriconazole of claim 2.
Use of the voriconazole containing composition of claim 2 for the manufacture of a pharmaceutical preparation for the treatment and / or prophylaxis of fungal infections.
A pharmaceutical composition for treating and / or preventing fungal infections, comprising the composition comprising the boleyconazole of claim 2.