KR101314500B1 - Oxacephem preparations with improved stability and preparation method thereof - Google Patents

Abstract

PURPOSE: A freeze dried preparation containing flomoxef or the salt thereof pharmaceutically allowed is provided to prolong the expiration date of the final product drastically by rapidly improving long term stability. CONSTITUTION: A manufacturing method of a freeze dried preparation containing flomoxef or the salt thereof pharmaceutically allowed comprises: a step of preparing 7β-difluoromethylthio acetamino-7a-methoxy-3 [1-(2-hydroxy alkyl)-1H-tetrazole-5-yl] thiomethyl1-dethia-1-oxa-3-cephem-4-carboxylic acid as a starting material; a step of adjusting pH by dissolving a weak basic pH adjusting agent in aqueous solvent; a step of dissolving the starting material in the above aqueous solvent; and a step of quick freezing the liquid from the previous step and adjusting water activity to be 0.020-0.050 while supplying heat of sublimation. The moisture activity of the freeze dried preparation containing flomoxef or the salt thereof pharmaceutically allowed is 0.020-0.050. [Reference numerals] (AA,HH) Initial stage; (BB) Example 1; (CC) Example 2; (DD) Example 3; (EE) Example 4; (FF) Example 5; (GG,PP) 3rd week; (II) Comparative example 1; (JJ) Comparative example 2; (KK) Comparative example 3; (LL) Comparative example 4; (MM) Comparative example 5; (NN) Comparative example 6; (OO) Comparative example 7

Description

OXACEPHEM PREPARATIONS WITH IMPROVED STABILITY AND PREPARATION METHOD THEREOF

The present invention relates to a novel oxasefem formulation having improved stability and a method for preparing the same. More specifically, the present invention relates to a method for producing a lyophilized preparation of oxacefem, which is simple compared to a process used in the past and has dramatically increased stability of the final lyophilized preparation.

Flomoxef of the following formula (I) is an oxasefem antibacterial agent.

Plomoxef is a compound disclosed by Japanese Patent Application No. 57-234472, exhibits strong antimicrobial activity against Gram-positive and negative bacteria, and is used to treat various infectious diseases including sepsis and infective endocarditis. Flomoxef is generally administered by intravenous or drip intravenous injection, and lyophilized formulations are commercially available.

On the other hand, when flomoxef is made into a lyophilized formulation by a conventional method, a phenomenon in which the titer decreases at the same time as the color of yellowish brown gradually decreases due to long-term standing.

Therefore, Japanese Patent Laid-Open No. 3-70688 has stabilized flomoxef using glucose, fructose, maltose, an inorganic acid alkali metal salt or a carboxylic acid alkali metal salt as a colorant and a stabilizer. That is, although the above patent is generally known that sugars are used to stabilize the lyophilized preparations of β-lactam compounds, in the case of flomoxef, only glucose, fructose and maltose show stabilizing effects among sugars. Doing.

More specifically, according to the above literature, as a method of making lyophilized preparation of flomoxef, the following compound

(Wherein R is a 2-hydroxyalkyl group and M represents an alkali metal atom)

And the stabilizer was dissolved in an aqueous medium to obtain a mixed solution, the pH was adjusted to 5-8, cooled, and rapidly frozen at -10 ° C to -60 ° C for several minutes to 10 hours, while supplying sublimation heat. Subsequently, water was sublimated and removed until a predetermined water content was maintained while maintaining the time at 0.005 to 1 mb, an inert gas such as nitrogen, or dry air was filled and sealed. That is, in the prior art, a compound in which an alkali metal atom is substituted at the carboxy group 4 of the cefemo nucleus is used as a starting material for making lyophilized preparation of flomoxef.

By the way, the alkali metal salt of flomoxef as the raw material, for example, flomoxef sodium, is prepared by reacting the same amount of alkali metal salt as the carboxylic acid of flomoxef and then lyophilizing. Therefore, when the lyophilized preparation is prepared using the alkali metal salt of flomoxef as a raw material, two lyophilizations should be performed as a result, in which case a lot of physical stress is applied to the compound. Therefore, it can not but seriously affect the stability of the final formulation.

That is, in the preparation of the lyophilized formulation of flomoxef according to the prior art, it was necessary to use a stabilizer and an anti-coloring agent due to the above stability problems, but unless the physical stress applied in the manufacturing method is reduced, There could not be a satisfactory effect, and therefore there is a need for providing a freeze-dried formulation with increased stability as a lyophilized formulation of Flomoxef and a need for a new method of making the same.

Japan Special Place 57-234472 Japanese Patent Publication Hei 3-70688

The present invention is a method for producing a lyophilized formulation of flomoxef, cost reduction effect through the simplification of the process while preparing a freeze-drying agent with increased stability than the lyophilized formulation of flomoxef prepared by the prior art An object of the present invention is to provide an excellent method for producing a freeze-dried preparation.

In addition, an object of the present invention is to provide a lyophilized formulation having significantly improved stability by having a specific water activity as a lyophilized formulation of flomoxef prepared by the above method.

In order to solve the above problems, in the present invention,

A process for the preparation of an increased stability lyophilized formulation comprising flomoxef or a pharmaceutically acceptable salt thereof, comprising: (a) 7β-difluoromethylthioacet amino-7a-methoxy-3 as starting material; Providing [1- (2-hydroxyalkyl) -1H-tetrazol-5-yl] thiomethyl-1-dethia-1-oxa-3-cepem-4-carboxylic acid; (b) dissolving the weakly basic pH adjuster in an aqueous solvent to adjust the pH; (c) dissolving the starting material of step (a) in the aqueous solvent of step (b); And (d) is disclosed a method for producing a flomokse lyophilized preparation comprising the step of (c) rapidly cooling the solution and supplying the sublimation heat, the water activity (Aw) of 0.020 ~ 0.050.

In addition, in the above method, the pH of step (b) is disclosed in the manufacturing method, characterized in that to adjust to 7.0 to 7.5.

In addition, in the above method, a weakly basic pH adjuster in step (b) is disclosed, characterized in that the production method is selected from the group of alkali donors consisting of sodium bicarbonate, sodium carbonate, sodium hydroxide.

Also in the above method, a production method is characterized in that the weakly basic pH adjuster is sodium hydrogen carbonate.

Also disclosed is a method of producing a process, characterized in that the stabilizer is further dissolved in step (b) or (C) of the process.

Further, in the above method, a stabilizing agent is disclosed, wherein the production method is selected from the group consisting of sodium chloride and potassium chloride.

Lastly, the lyophilized formulation having increased stability, which comprises flomoxef prepared by the above method or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the lyophilized formulation has a water activity of 0.020 to 0.050. I begin.

The lyophilized formulation comprising flomoxef or a pharmaceutically acceptable salt thereof according to the present invention has an effect of significantly extending the shelf life of the final product by significantly increasing stability, particularly long-term stability. In addition, as compared to the conventional method, it is possible to produce a higher quality lyophilized formulation while simplifying the process.

1 is a view showing the degree of coloring during storage of Examples and Comparative Examples.
2 is a diagram showing the results of the harsh stability test of the comparative example.

The present invention provides a method and a lyophilized formulation for preparing a lyophilized formulation comprising flomoxef or a pharmaceutically acceptable salt thereof having improved potency retention and stability under storage conditions.

More specifically, in the production method of the present invention, 7β-difluoromethylthioacet amino-7a-methoxy-3 [1- (2-hydroxyalkyl) -1H represented by the following general formula (I) as a starting material -Tetrazol-5-yl] thiomethyl-1-dethia-1-oxa-3-cefe-4-carboxylic acid.

(I)

Conventional lyophilized preparations of flomoxef are prepared using alkali metal salts of the above substances, that is, compounds in which alkali metal salts are substituted in the carboxylic acid 3 of the cefemonucle of the above compounds, for example, flomoxef sodium. There has been no report of preparation of lyophilized preparations using the above compounds as direct starting materials.

However, according to the research of the present inventors, as described above, when preparing a lyophilized formulation using a compound of the formula (I) as a starting material through a specific production conditions, surprisingly, the stability of the lyophilized formulation of flomoxep is greatly improved. The inventors have found that the shelf life of products can be significantly extended, leading to the present invention.

That is, the production method of the present invention is compared with the production method of the prior art using the alkali metal salt of flomoxef as a starting material, and the production method of the present invention using flomoxef carboxylic acid as the starting material. In this case, as a result of the reduction of physical stress applied during the manufacturing process, the long-term storage stability of the final lyophilized formulation is dramatically increased, and furthermore, the cost itself can be reduced by simplifying the process itself.

Specifically, the present invention provides a method for preparing a lyophilized formulation having increased stability, comprising flomoxef or a pharmaceutically acceptable salt thereof, which comprises: (a) 7β-difluoromethylthioacetamino as starting material; -7a-methoxy-3 [1- (2-hydroxyalkyl) -1H-tetrazol-5-yl] thiomethyl-1-dethia-1-oxa-3-cepem-4-carboxylic acid Making; (b) dissolving the weakly basic pH adjuster in an aqueous solvent to adjust the pH; (c) dissolving the starting material of step (a) in the aqueous solvent of step (b); And (d) adjusting the water activity (Aw) to 0.020 to 0.050 while rapidly cooling the solution of step (d) and supplying sublimation heat. This will be described in detail.

In the present invention, the compound of formula (I) is used as starting material. The compound is in the form of a carboxylic acid, and may exist as a solvate or nonsolvate, but in the preparation method of the present invention, compound (I) may be used regardless of the specific crystalline form. The use of compounds of formula (I) as starting materials in the present invention is due to the novel finding that the stability of the final product is increased by changing the starting materials, unlike when using alkali metal salts as starting materials, as in the conventional manner. . That is, in the conventional method, the alkali metal salt of flomoxef was dissolved as a starting material in a solvent, and lyophilization was performed by adding a stabilizer, but stability, in particular, long-term storage stability could not be secured. For this reason, the shelf life of currently available products is about 24 months, which is short. However, according to the research of the present inventors, when the lyophilized formulation is prepared using the starting material in the form of carboxylic acid, an effective period of 30 months to 36 months can be secured.

In particular, the core of the technical features of the production method of the present invention, an aqueous solvent prepared in advance to satisfy specific conditions as an aqueous solvent for dissolving the starting material, as well as using the compound of formula (I) as a starting material Is to use

More specifically, in the production method of the present invention, while using the compound of the formula (I) as a starting material, it is prepared as an aqueous solvent, that is, a weakly basic pH adjuster dissolved in advance to meet specific conditions. It is a technical feature to dissolve in an aqueous solvent whose pH is adjusted to 7.0 to 7.5.

That is, in the prior art, the lyophilized preparation was prepared by dissolving the alkali metal salt of flomoxef in an aqueous solvent together with a stabilizer and then cooling it. It was found that stability could not be ensured when only the starting material was changed to fluoromoxef carboxylic acid while maintaining it as it was, and the preliminary preparation of the aqueous solvent was satisfied to satisfy specific conditions. It was surprising to find that stability was increased only by adding acid.

Accordingly, the present invention simplifies the process by combining the two requirements: (1) changing the starting material and (2) using an aqueous solvent prepared to meet certain conditions in advance. It should be understood as a technical idea that the stability of the

The aqueous solvent used in the present invention can be used without limitation as long as it is an aqueous solvent usable in the field of formulation, but it is preferable to use sterile distilled water for injection. Moreover, in this invention, it is necessary to put a pH adjuster into an aqueous solvent, and to adjust pH of an aqueous solvent to 7.0-7.5.

In the case of pH adjustment, a weakly basic pH adjuster should be used, for example, it is preferable to adjust the pH to 7.0-7.5 using a weakly basic adjuster selected from alkali-imparting agents. Here, the use of the weakly basic pH regulator as described above, in the present invention uses a compound of formula (I), for example, when using a strong base regulator is difficult to adjust the target pH compared to the same aqueous solvent, at the target pH This is because there is a risk that the compound decomposes toward alkali.

Examples of the weakly basic pH adjuster usable in the present invention include, but are not limited to, an alkali-imparting agent selected from the group consisting of sodium hydrogen carbonate, sodium carbonate and sodium hydroxide. In addition, the amount of the weakly basic pH adjuster may be appropriately selected, but an amount such that the final pH of the aqueous solvent is 7.0 to 7.5 may be added.

In addition, in the present invention, it is possible to dissolve the stabilizer together with the weakly basic pH adjuster in an aqueous solvent, alternatively, when dissolving the stabilizer together when dissolving the compound of formula (I) in the aqueous solvent having completed pH adjustment It is also possible. As the stabilizer, alkali metal salts and sugars can be used. Examples of the stabilizer include sodium chloride, potassium chloride, glucose, fructose, maltose, sodium sulfate, sodium hydrogen sulfate, Na succinate, Na fumarate, Na maleate, and the like. Can be used, but is not limited thereto. The amount of the above stabilizer is preferably 1.25 to 7.5 w / v% of the aqueous solvent.

As described above, the compound of formula (I) is dissolved in an aqueous solvent having a pH adjusted in advance.

In this case, unlike the present invention, when dissolving pH adjuster and / or stabilization together with the compound of formula (I) in an aqueous solvent from the beginning, the pH is adjusted to 7.0 to 7.5 as in the present invention. In addition, it should be noted that an increase in stability, which is an effect of the present invention, is not achieved, and in this regard, a combination of two technical ideas of pre-preparation of an aqueous solvent that satisfies specific conditions as well as a change of starting material is provided. It can be seen that the characteristic technical idea of.

After dissolving the weakly basic pH adjuster in the aqueous solvent and adjusting the pH to 7.0 to 7.5, the compound of formula (I) is dissolved to obtain a solution having a final pH of 4.0 to 5.5. After rapidly cooling the above solution at -40 ° C to -80 ° C, by sublimating the solvent at 1 to 100 millitorr for 30 to 80 hours until the desired water activity, ie, 0.020 to 0.050, is reached while supplying sublimation heat. To dry. Lyophilization may use a conventional lyophilization method such as trays, vials, and the like.

On the other hand, in the present invention, the above water activity is introduced, because the new knowledge that the water activity is affected in relation to the long-term stability of the flow moxef. That is, the water activity (Aw) is expressed as the ratio of the maximum water vapor pressure (Po) of pure water to the water vapor pressure (Ps) of the freeze-drying agent at any temperature, which is the free water contained in the freeze-drying agent. It serves as a measure of how much is contained in the. According to the research of the present inventors, in the case of the lyophilized preparation according to the present invention, when the water activity is 0.020 to 0.050, it was found that the long-term safety inertia is extremely excellent, thereby limiting the conditions of such water activity. .

In particular, the inventor's research confirms that the stability of the lyophilized formulation is more affected by the free water than by the water content including both the combined and free water present in the formulation. For this reason, the concept of water activity is linked with the stability of the preparation. There has been no report on the correlation between the stability of the preparation and the water activity.

On the other hand, the control of the water activity can be carried out by controlling the drying process, it will be possible to select the drying conditions for each process while measuring the water activity.

The resultant product thus dried can be sealed and, if necessary, stored in a container filled with an inert gas, for example nitrogen, or dry air, to produce the final product. Hereinafter, the present invention will be described through examples. However, the following examples illustrate specific aspects of the present invention by way of example, and are not intended to limit the scope of the present invention, the present invention may be modified in various ways within the scope of the technical spirit described in the claims. Care must be taken.

Example 1

After the dissolution, and by degassing the NaHCO ₃ and the stabilizer using an appropriate amount sterile distilled water, 2ml of NaCl 0.05g as a main agent to adjust the pH to 7.0 as a PH adjusting agent, dissolving the compound (I) 0.5g, placed in a 10ml vial in the refrigerator and then Rapid cooling to -40 ° C. After holding at −40 ° C. for 3 hours, the cooled material is lyophilized by sublimation of the contained water through a 55 hour elevated temperature at 40 mTorr up to 30 ° C. to obtain a stable freeze-dried formulation.

Example 2

After adjusting the pH to 7.3 by dissolving and degassing 0.05 g NaHCO ₃ as a pH adjuster and NaCl as a stabilizer in sterile distilled water (2 ml) for injection, 0.5 g of Compound (I) was dissolved and placed in a 10 ml vial, followed by a refrigerator Rapid cooling to -40 ° C at. After holding at −40 ° C. for 3 hours, the cooled material is lyophilized by sublimation of the contained water at 30 ° C. over 30 hours at elevated temperature up to 30 ° C. to obtain a stable freeze-dried formulation.

Example 3

After dissolving and degassing 0.05 g NaHCO ₃ as a pH adjuster and NaCl as a stabilizer in sterile distilled water (2 ml) for injection, adjusting the pH to 7.5, 0.5 g of Compound (I) was dissolved and placed in a 10 ml vial Cool rapidly to -80 ℃ in the refrigerator. After holding at −80 ° C. for 3 hours, the cooled material is lyophilized by sublimation of the contained water through 30 hours of elevated temperature at 1 to 3 mTorr up to 30 ° C. to obtain a stable freeze-dried formulation.

Example 4

After NaHCO ₃ as a primary stabilizer, and a suitable amount of NaCl 0.05g use sterile distilled water (2ml) was adjusted to the pH 7.1 dissolution and degassing in a PH adjusting agent, dissolving the compound (I) 0.5g, and then placed in a 10ml vial Cool rapidly to -40 ° C in a refrigerator. After holding at −40 ° C. for 3 hours, the cooled material is lyophilized by sublimation of the contained water through elevated temperature at 100 mTorr to 80 ° C. over 80 hours to obtain a stable freeze-dried formulation.

Example 5

After dissolving and degassing NaHCO ₃ as a pH adjuster in sterile distilled water (2 ml) for injection, adjusting the pH to 7.3, dissolving 0.5 g of compound (I) and 0.05 g of NaCl as a stabilizer, and placing it in a 10 ml vial Rapid cooling to -40 ° C in a refrigerator. After holding at −40 ° C. for 3 hours, the cooled material is lyophilized by sublimation of the contained water through a 55 hour elevated temperature at 40 mTorr up to 30 ° C. to obtain a stable freeze-dried formulation.

Comparative Example 1

0.5 g of compound (I) and a proper amount of NaHCO ₃ as a pH adjuster, 0.05 g of NaCl as a stabilizer were dissolved in sterile distilled water for injection (2 ml) to adjust the pH to 7.3, then placed in a 10 ml vial and then -40 ° C. in a freezer. Rapid cooling After holding at −40 ° C. for 3 hours, the cooled material is lyophilized by sublimation of the contained water through a 55 hour elevated temperature at 40 mTorr up to 30 ° C. to obtain a lyophilized formulation.

Comparative Example 2

NaHCO ₃ titration as a pH adjuster and NaCl as a stabilizer were dissolved and degassed in 0.05 ml of injectable sterile distilled water, and after adjusting the pH to 8.5, 0.5 g of flomoxe sodium was dissolved in a 10 ml vial. Rapid cooling to -40 ° C in a refrigerator. After holding at −40 ° C. for 3 hours, the cooled material is lyophilized by sublimation of the contained water through a 55 hour elevated temperature at 40 mTorr up to 30 ° C. to obtain a stable freeze-dried formulation.

Comparative Example 3

NaHCO ₃ titration as a pH adjuster and NaCl as a stabilizer were dissolved and degassed in 2 ml of sterile distilled water for injection, and after adjusting the pH to 6.5, 0.5 g of flomoxe sodium was dissolved in a 10 ml vial, Rapid cooling to -40 ° C in a refrigerator. After holding at −40 ° C. for 3 hours, the cooled material is lyophilized by sublimation of the contained water through a 55 hour elevated temperature at 40 mTorr up to 30 ° C. to obtain a stable freeze-dried formulation.

Comparative Example 4

After the dissolution, and by degassing the NaHCO ₃ and the stabilizer using an appropriate amount sterile distilled water, 2ml of NaCl 0.05g as a main agent to adjust the pH to 7.0 as a PH adjusting agent, dissolving the compound (I) 0.5g, placed in a 10ml vial in the refrigerator and then Rapid cooling to -40 ° C. After holding at −40 ° C. for 3 hours, the cooled material was lyophilized by sublimation of water contained at 100 mTorr through 55 hours at 100 mTorr to obtain a freeze-dried formulation, except that its water activity was 0.0612.

Comparative Example 5

After the dissolution, and by degassing the NaHCO ₃ and the stabilizer using an appropriate amount sterile distilled water, 2ml of NaCl 0.05g as a main agent to adjust the pH to 7.0 as a PH adjusting agent, dissolving the compound (I) 0.5g, placed in a 10ml vial in the refrigerator and then Rapid cooling to -40 ° C. After holding at −40 ° C. for 3 hours, the cooled material was lyophilized by sublimation of the contained water at 100 mTorr to 24 ° C. for 24 hours at elevated temperature to obtain a lyophilized formulation, with the water activity being 0.0894.

Comparative Example 6

1 g of phlomoxef sodium, 0.3 g of glucose as a stabilizer is dissolved in sterile distilled water for injection (4 ml) to adjust the pH to 7.3, then placed in a 10 ml vial and rapidly cooled to -35 ° C in a freezer. Freeze at -35 ° C for 3 hours. The cooled material is kept below 0.1 mb for 20 hours and 0.05 mb for 6 hours while warming to maintain below -20 ° C. to sublimate moisture to obtain a lyophilized formulation.

Comparative Example 7

After the dissolution, and by degassing the NaHCO ₃ and the stabilizer using an appropriate amount sterile distilled water, 2ml of NaCl 0.05g as a main agent to adjust the pH to 7.0 as a PH adjusting agent, dissolving the flow neck chef sodium 0.5g, and then placed in a 10ml vial in the refrigerator Rapid cooling to -40 ° C. After holding at −40 ° C. for 3 hours, the cooled material is lyophilized by sublimation of the contained water through a 55 hour elevated temperature at 40 mTorr up to 30 ° C. to obtain a stable freeze-dried formulation.

Experimental Example 1

Water activity in the freeze-dried preparations finally obtained using a water activity meter_AQUA LAB equipment at 25 ℃ ± 2, relative humidity 10% ± 2 conditions with the freeze-dried preparation prepared in Examples 1-5 and Comparative Examples 1-7 Aw) was measured. The results are shown in Table 1 below.

Water activity (Aw) Example 1 0.0256 Example 2 0.0203 Example 3 0.0249 Example 4 0.0254 Example 5 0.0258 Comparative Example 1 0.0279 Comparative Example 2 0.0303 Comparative Example 3 0.0582 Comparative Example 4 0.0612 Comparative Example 5 0.0894 Comparative Example 6 0.0353 Comparative Example 7 0.0362

Experimental Example 2

The lyophilized preparations prepared in Examples 1 to 5 and Comparative Examples 1 to 7 were subjected to a stability test under severe conditions at 60 ° C. The results are shown in Table 2 below and FIG. 2.

Preparation of standard solution

Accurately weigh about 50.0 mg of the standard product and add water to make exactly 100 mL. (0.5 mg / mL)

Preparation of Samples

About 50.0 mg of Flomoxef lyophilized preparation is precisely weighed with water and accurately diluted to 100 mL (0.5 mg / mL).

Equipment condition

Detector: ultraviolet absorbance photometer (wavelength 246 nm)

Column: Hypersil ODS (5 um, 200 × 4.0 mm)

Column temperature: 25 ℃

Mobile phase: 6.94 g of potassium dihydrogen phosphate, 3.22 g of disodium hydrogen phosphate (12-hydrate) and 1.60 g of tetra n-butyl ammonium bromide are dissolved in water to make 1000 mL. 250 mL of methanol is added to 750 mL of this solution.

Flow rate: retention time about 9 minutes

Main volume: 5 uL

content(%) Leading material (%) Early Three weeks Early Three weeks Example 1 99.37 79.10 0.298 2.063 Example 2 99.58 80.94 0.281 1.566 Example 3 99.88 81.72 0.306 1.635 Example 4 102.28 84.44 0.291 2.070 Example 5 99.65 80.34 0.293 2.014 Comparative Example 1 80.54 25.11 0.709 18.094 Comparative Example 2 22.94 - 19.375 - Comparative Example 3 99.56 70.492 0.737 2.925 Comparative Example 4 99.47 61.753 0.826 7.241 Comparative Example 5 98.00 54.247 0.813 10.102 Comparative Example 6 99.47 71.06 1.241 2.897 Comparative Example 7 81.43 62.81 0.684 9.472

From the above experiments, in the case of the lyophilized preparations prepared according to the present invention, the degree of decrease in titer and the formation of 1- (2-hydroxyethyl) -1H-tetrazol-5-thiol, which is a flexible substance, are very small. It was confirmed that the stability was very good. However, when fluoromox sodium is used as a starting material, or when the pH of an aqueous solvent is adjusted and the stabilizer is dissolved and the compound is not dissolved but the stabilizer is dissolved together with the compound from the beginning, the compound (I) is started. It was confirmed that the stability is not good even when used as a material. In addition, it was confirmed that even if the conditions of the present invention satisfies the stability when the water activity is out of the scope of the present invention.

Experimental Example 3

The lyophilized preparations prepared in Examples 1 to 4 and Comparative Examples 1 to 5 were observed for coloration at 60 ° C. under severe conditions. The results are shown in Table 3 below and FIG. 1.

Early Three weeks Example 1 white pale yellow Example 2 white pale yellow Example 3 white pale yellow Example 4 white pale yellow Comparative Example 1 pale yellow brown Comparative Example 2 yellow brown Comparative Example 3 white yellow Comparative Example 4 white yellow Comparative Example 5 white yellow Comparative Example 6 white yellow Comparative Example 7 pale yellow yellow

As can be seen from the above table, the freeze-dried preparation according to the present invention was confirmed that the less the color phenomenon in storage than the comparative example.

According to the present invention, it is possible to provide a freeze-dried preparation having increased stability than the freeze-dried preparation of Flomoxef prepared by a conventional method, and further, compound (I), a pH adjuster, and a stabilizer once in an aqueous solvent. By dissolving it is possible to prepare a lyophilized formulation, thus simplifying the process.

Claims (8)

A method of preparing a lyophilized formulation having increased stability, comprising flomoxef or a pharmaceutically acceptable salt thereof,
(a) 7β-difluoromethylthioacet amino-7a-methoxy-3 [1- (2-hydroxyalkyl) -1H-tetrazol-5-yl] thiomethyl-1-dethia- as starting material Providing 1-oxa-3-cefe-4-carboxylic acid;
(b) dissolving the weakly basic pH adjuster in an aqueous solvent to adjust the pH;
(c) dissolving the starting material of step (a) in the aqueous solvent of step (b); And
(d) a method of producing a flomokse freeze-dried preparation comprising the step of rapidly cooling the solution of step (c) and supplying heat of sublimation to adjust the water activity (Aw) to 0.020 to 0.050. The method according to claim 1, wherein the pH in step (b) is adjusted to 7.0 to 7.5. The method according to claim 1, wherein the weakly basic pH adjusting agent in step (b) is selected from the group of alkali-imparting agents consisting of sodium hydrogen carbonate, sodium carbonate and sodium hydroxide. 4. The process according to claim 3, wherein the weakly basic pH adjuster is sodium hydrogen carbonate. The method according to claim 1, wherein the stabilizing agent is further dissolved in step (b) or (C). The method of claim 5, wherein the stabilizer is selected from the group consisting of sodium chloride and potassium chloride. A lyophilized formulation having increased stability, which comprises flomoxef or a pharmaceutically acceptable salt thereof prepared by the method of claim 1 as an active ingredient, wherein the water activity of the formulation is 0.020 to 0.050. Lyophilized preparations. delete

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