TW201626987A - Process for producing a lyophilized preparation - Google Patents

Abstract

The present invention addresses the main problem of providing a novel method for producing a freeze-dried preparation (combination drug) for injection that comprises tazobactam sodium and piperacillin sodium. An example of the production method according to the present invention is as follows. A method for producing a freeze-dried preparation for injection, said method being characterized by comprising: (a) a step for blowing carbon dioxide gas into an aqueous sodium hydroxide solution; and (b) a step for dissolving tazobactam and piperacillin in the solution obtained in step (a). According to the present invention, a freeze-dried preparation showing good defoaming performance after redissolution can be obtained.

Description

Method for manufacturing freeze-dried preparation

The present invention relates to a novel method for the manufacture of a freeze-dried preparation for injection containing Tazobactam Sodium and Piperacillin Sodium.

The admixture of tazobactam and piperacillin is widely used in the form of a freeze-dried preparation for intravenous injection under the trade name "Zosyn".

In order to produce the freeze-dried preparation for injection containing tazobactam and piperacillin, it is necessary to react the epirubic form of tazobactam and piperacillin in a solution before freeze-drying with sodium ions. The sodium salt of each of tazobactam and piperacillin. However, both tazobactam and piperacillin have low stability in an alkaline solution, and it is not possible to use a strong base such as a sodium hydroxide solution used for pH adjustment or sodiumation in the production of an injection.

In order to solve the above problems, it is known that tazobactam free acid and piperacillin hydrate are dissolved in an aqueous solution of sodium bicarbonate, and added slowly. A method in which a solution of a granule (such as citrate) and an aminocarboxylic chelating agent (EDTA or the like) is freeze-dried and produced (see Patent Document 1). Further, similarly, it is known that a solution of tazobactam free acid and piperacillin hydrate is dissolved in an aqueous solution of sodium bicarbonate, and the dissolved carbon dioxide content is degassed until a certain amount of the solution is freeze-dried. A method of manufacturing (refer to Patent Document 2). In this method, since piperacillin is used instead of using a buffer or an aminocarboxylic acid chelating agent to carry out pH adjustment, the content of the final active ingredient cannot be accurately aggregated.

[Previous Technical Literature]

[Patent Literature]

[Patent Document 1] International Publication No. 2004/091666

[Patent Document 2] International Publication No. 2007/065862

An object of the present invention is to provide a novel method for producing a freeze-dried preparation for injection containing a tazobactam sodium and piperacillin sodium (a blending agent).

In the manufacture of freeze-dried preparations, it is self-evident that the amount of liquid to be dried is as small as possible. Therefore, it is expected to be in a small amount When a sodium hydroxide solution capable of pH adjustment and sodiumation is used, since sodium hydroxide is a strong alkali, there is a fear that the active ingredient is decomposed when a sodium hydroxide solution is used.

Further, the freeze-dried preparation must be re-dissolved with water or the like before intravenous administration of the freeze-dried preparation. When the freeze-dried preparation for injection in which tazobactam and piperacillin are blended is dissolved in water or the like, since the solubility is low, an operation such as stirring is required. Generally, when a foam is produced in a stirred solution, it is preferred to cause the foam to quickly disappear in a medical field.

As a result of intensive review, the present inventors have found that the above problems can be solved by a simple method of blowing carbonic acid gas into a strong alkaline sodium hydroxide aqueous solution, and the present invention has been completed.

As the present invention, for example, the following may be mentioned.

[1] A method for producing a freeze-dried preparation for injection (hereinafter referred to as "the method for producing the present invention"), which comprises the steps described in the following (a) and (b): (a) in an aqueous sodium hydroxide solution a step of blowing in a carbonic acid gas; (b) a step of dissolving tazobactam and piperacillin in the solution obtained in the above step (a).

[2] The method for producing a freeze-dried preparation according to the above [1], which comprises adjusting the aqueous sodium hydroxide solution to a pH of 7.0 to 9.2 by blowing a carbonic acid gas in the step (a). Inside.

[3] The method for producing a freeze-dried preparation according to the above [1] or [2], which further comprises: dissolved tazobactam and piperacillin The aqueous sodium hydroxide solution which was blown into the carbonic acid gas was adjusted to pH 5.5 to 6.8 with an acid.

[4] The method for producing a freeze-dried preparation according to the above [3], wherein the acid is hydrochloric acid, citric acid or phosphoric acid.

[5] The method for producing a freeze-dried preparation according to any one of the above [1] to [4], which further comprises the step of (c): (c) a step of blowing an inert gas.

[6] The method for producing a freeze-dried preparation according to the above [5], wherein the inert gas is nitrogen.

The present invention is characterized in that tazobactam and piperacillin are dissolved in a sodium carbonate aqueous solution which is blown into a carbonic acid gas in the production of a freeze-dried preparation for injection containing tazobactam sodium and piperacillin sodium. Thereby, even if a strong alkaline sodium hydroxide aqueous solution is used, the decomposition of tazobactam and piperacillin can be suppressed as much as possible, and the sodiumation of the active ingredient can be carried out without any problem.

According to the production method of the present invention, even if a strong alkaline sodium hydroxide aqueous solution is used, since the pH of the solution is prevented from being excessively increased by blowing carbonic acid gas into the solution, the decomposition of tazobactam and piperacillin can be suppressed. The admixture (freeze-dried preparation for injection) was produced. Further, when water for injection is added to the freeze-dried preparation obtained by the process of the present invention and re-dissolved, the so-called defoaming property is good.

Fig. 1 is a photograph showing the state before and after redissolution. Individually, the left container of each photograph represents a commercial sample, and the right container represents a sample of the freeze-dried preparation obtained by the method of the present invention. Individually, the upper left photograph indicates the state before re-dissolution, and the upper right photograph indicates the state immediately after re-dissolution with water for injection. The left middle photograph indicates the state after standing for 30 seconds, and the right middle photograph indicates standing. After 1 minute, the lower left photograph indicates the state after standing for 2 minutes, and the lower right photograph indicates the state after standing for 6 minutes.

Hereinafter, the present invention will be described in detail.

I. For the method of the present invention

(a) a step of blowing carbonic acid gas into an aqueous sodium hydroxide solution

This step is a step of blowing carbonic acid gas into an aqueous sodium hydroxide solution.

The aqueous sodium hydroxide solution can be prepared by adding sodium hydroxide to water and dissolving it. The concentration of the sodium hydroxide in the aqueous solution is, for example, 1 to 20% by mass, preferably 2 to 10% by mass, and more preferably 3 to 5% by mass. Examples of the water for preparing the aqueous solution include water for injection, purified water, distilled water, and physiological saline, and water for injection is preferred.

In addition, the city can be used as it is or diluted with water as it is. Aqueous sodium hydroxide solution is sold.

Then, carbonic acid gas was blown into the aqueous sodium hydroxide solution to prepare an aqueous solution of sodium hydroxide in which carbonic acid was dissolved. As a method of blowing a carbonic acid gas, a general gas injection method is mentioned, for example. Specifically, for example, a method in which a sodium carbonate aqueous solution is stirred by a stirrer or the like and a carbon dioxide gas injection tube is inserted and a carbon dioxide gas is blown at a pressure that does not cause a sudden boiling is exemplified. The pressure of the carbon dioxide gas to be blown is suitably 0.5 to 2.0 bar, preferably 0.5 to 1.0 bar.

In the present invention, the aqueous solution is adjusted to a pH of 7.0 to 9.2 (preferably, pH 7.5 to 8.0) by blowing a carbonic acid gas into an aqueous sodium hydroxide solution. The aqueous solution may be finely adjusted to a pH within a range of an appropriate acid after blowing carbonic acid gas into the aqueous solution, or while blowing. Examples of such an acid for pH fine adjustment include hydrochloric acid, citric acid, and phosphoric acid. Among these, hydrochloric acid is particularly suitable.

(b) a step of dissolving tazobactam and piperacillin in the solution obtained in the above step (a)

This step is a step of dissolving tazobactam and piperacillin in an aqueous solution of sodium hydroxide blown into a carbonic acid gas. It is a step of obtaining an aqueous solution in which tazobactam and piperacillin are dissolved.

The concentration of tazobactam in the aqueous solution is not particularly limited, and is, for example, 1 to 20% by mass, preferably 3 to 7% by mass. If it is less than 1% by mass, it is not convenient to obtain the freeze-drying method of the determined price. Agent. If it is more than 20% by mass, stirring at the time of dissolution is difficult. The concentration of piperacillin in the aqueous solution is not particularly limited, and is, for example, 10 to 50% by mass, preferably 20 to 30% by mass. If it is less than 10% by mass, it is inconvenient to obtain a freeze-dried preparation having a predetermined strength. If it is more than 50% by mass, dissolution is difficult. In addition, the strength of tazobactam and piperacillin in the aqueous solution is preferably 1:8 (tazobactam: piperacillin).

The dissolved tazobactam and piperacillin may also be hydrates. For piperacillin, hydrates are generally used.

The order in which tazobactam and piperacillin are dissolved in the aqueous solution is not particularly limited. Either one of them may be dissolved first, or both may be dissolved at the same time.

The dissolution can be carried out by a conventional method. Specifically, for example, tazobactam and piperacillin hydrate are added to an aqueous sodium hydroxide solution to which a carbonic acid gas is blown, and the solution is dissolved while stirring with a stirrer or the like. The dissolution temperature is, for example, 3 to 15 °C. More preferably 4 to 10 ° C. If it is less than 3 ° C, it takes time to dissolve, and if it is higher than 15 ° C, there is a concern that the decomposition of tazobactam and piperacillin is promoted.

In the process of the present invention, it is preferred to adjust the acid to pH 5.5-6.8 (preferably pH 5.7-6.6) by adding an aqueous solution of sodium hydroxide blown into the carbonic acid gas dissolved in tazobactam and piperacillin. The steps within the scope. As such an acid for pH adjustment, the same acid as mentioned above can be mentioned. Among these, hydrochloric acid is particularly suitable.

The tazobactam and piperacillin are dissolved, and the pH is adjusted as needed, and the amount of water can be adjusted as needed. As used for liquid volume The water to be adjusted may, for example, be water for injection, purified water, distilled water or physiological saline, and is preferably water for injection.

(c) the step of blowing in an inert gas

This step is a step of blowing an inert gas into an aqueous solution of sodium hydroxide which is blown into a carbonic acid gas in which tazobactam and piperacillin are dissolved.

Examples of the inert gas include nitrogen gas and argon gas. There is no particular limitation as long as it is generally used as an inert gas, and it is more appropriate to use nitrogen which is easy and inexpensive.

The blowing of the inert gas may be carried out after dissolving tazobactam and piperacillin in the solution obtained in the above step (a), or by dissolving tazobactam and piperacillin in the foregoing ( a) The solution obtained in the step is simultaneously carried out in a pH adjustment stage or a liquid amount adjustment stage after dissolving tazobactam and piperacillin in the solution obtained in the above step (a).

The time of blowing the inert gas and the amount of the inert gas to be blown, regardless of the inert gas, is not particularly limited, and it is more appropriate to, for example, blow the inert gas until the amount of carbon dioxide in the solution obtained in the above step (a) becomes 200 mg / L or less (preferably 75 mg / L or less), and the amount of oxygen is 10 ppm or less (preferably 1 ppm or less).

The carbon dioxide or oxygen in the aqueous solution can be removed by blowing an inert gas into the solution obtained in the above step (b). If carbon dioxide remains in the aqueous solution, there is a fear that the pH value changes during freeze-drying. In addition, if there is residual oxygen in the aqueous solution, there will be a promotion of oxazolidine. Doubts about the decomposition of Batan and piperacillin.

The solution obtained in the above step (b) after the inert gas is blown is preferably subjected to filtration sterilization by a usual method. As a method of filtration sterilization, for example, filtration sterilization using a 0.22 μm membrane filter can be mentioned.

(d) the step of freezing and drying

The solution obtained in the above step (c) is dispensed into a sterile container and freeze-dried by a usual method. Then, in general, the inside of the vial after freeze-drying is replaced with nitrogen and smashed to obtain a freeze-dried preparation for injection according to the present invention (hereinafter referred to as "the preparation of the present invention").

It is generally believed that in the formulation of the present invention, tazobactam and piperacillin are present in the form of a sodium salt.

Preferably, the preparation of the present invention contains tazobactam sodium 0.25 g (force price) or 0.5 g (force price), piperacillin sodium 2.0 g (force price) or 4.0 g (force price) (in terms of power price ratio) For 1:8).

II. Formulations for the present invention

The preparation of the present invention can generally be redissolved and used by adding any suitable solution (redissolved solution). Examples of such a re-dissolution liquid include water for injection, physiological saline, 5% (w/v) glucose injection, and other general infusion solutions. The liquid amount of the re-dissolving solution varies depending on the use and the like, and is not particularly limited, and is preferably 0.5 to 5 times or 500 mL or less of the amount of the liquid filled in the vial before freeze-drying.

The reconstituted preparation of the present invention can be administered to the vein, for example, in the form of an injection or a drip.

The dosage of the preparation of the present invention varies depending on the state of the patient such as age or body weight, the nature and degree of the disease, and the like, which is more suitable for the individual as the tazobactam sodium/piperacillin sodium. It is 4.5g (power price). The state or condition of the patient such as the age or the body weight may be administered once or twice a day, preferably once or four times a day, at an appropriate interval.

[Examples]

The invention is further illustrated by the following examples, but the invention is not limited by the examples.

[Example 1]

2.4 kg of sodium hydroxide was dissolved in 56.25 L of water for injection, and carbonic acid gas was blown in to adjust the pH to about 7.7. After the sodium hydroxide aqueous solution which was blown into the carbonic acid gas was finely adjusted to a pH of 7.7 with a 0.5 M aqueous hydrochloric acid solution, while bubbling with nitrogen gas, 2.976 kg of tazobactam and 23.81 kg of piperacillin hydrate were added, and then Further, 0.1 M aqueous hydrochloric acid and water for injection were added to obtain 125 L of an aqueous solution of pH 6.5. The prepared solution was filtered and sterilized, and after being dispensed into a sterile container, freeze-drying was carried out according to a usual method to obtain oxazobactam sodium 0.25 g (force price) / piperacillin sodium 2.0 g (force) in each container. The preparation of the present invention, which is valence, or tazobactam sodium 0.5 g (force price) / piperacillin sodium 4.0 g (force price).

Hereinafter, the preparation of the present invention containing tazobactam sodium 0.25 g (force price) / piperacillin sodium 2.0 g (force price) is respectively referred to as the preparation of the invention 2.25, and will contain tazobactam sodium 0.5 g (the price) The formulation of the invention of piperacillin sodium 4.0 g (force price) is referred to as formulation 4.5 of the invention.

[Test Example 1] Change in pH over time

The time-dependent change in the pH of the preparation of the present invention obtained in Example 1 was compared with a commercial product (Zosyn (registered trademark) for 2.25, the same as 4.5) and observed. The results are shown in Table 1. In addition, the numerical value of the parentheses is the result of the pH measurement method described in the interview form of Zosyn (registered trademark), and the numerical value of the parentheses is the second correction of the Japanese Pharmacopoeia. The results of the pH measurement method described in the item for the injection of tazobactam/piperacillin for injection were included.

It is apparent that the tendency to decrease with time is observed, and the change with time of the pH of the preparation of the present invention is equivalent to the change with time of the pH of the commercial product.

[Test Example 2] Purity test of tazobactam and piperacillin

The product obtained in Example 1 was carried out by a usual method in the same manner as in the commercial product (Zosyn (registered trademark) for 2.24, the same 4.5) under the conditions of 40 ° C / 75% RH or 60 ° C / 75% RH. Purity test of tazobactam and piperacillin in the formulation of the invention. The results are shown in Table 2 and Table 3. In addition, the contents of tazobactam and piperacillin were carried out by the purity test method described in the item of the tazobactam for injection/piperacillin for injection in the 16th correction of the Japanese Pharmacopoeia.

It is apparent that by using the production method of the present invention, a formulation which is equivalent in quality to a commercially available product can be obtained.

[Test Example 3] Defoaming test

20 mL of water for injection was added to each of the preparation 4.5 of the present invention obtained in Example 1 and a commercially available product (Zosyn (registered trademark) 4.5), and dissolved by inversion mixing until the freeze-dried product was dissipated and allowed to stand. The defoaming state at this time is shown in Fig. 1.

After standing for 1 minute, the commercially available product was clear in the upper part of the foam, while in the formulation of the present invention, it was difficult to see the upper foam, and fine foam was observed throughout the middle portion. After standing for 2 minutes, the foam of the formulation of the present invention all disappeared, and in the case of the commercial product, foam was observed at the liquid level. Finally, after standing for 7 minutes and 30 seconds, the foam on the commercial side also disappeared.

Thus, it is apparent that the preparation of the present invention is excellent in defoaming properties after reconstitution with water for injection.

[Industrial availability]

The production method of the present invention is useful in the production of a commercially available product, Zosyn (registered trademark), which is equivalent in quality and has a good defoaming property.

Claims (2)

A method for producing a freeze-dried preparation for injection, which comprises the steps described in the following (a) and (b): (a) a step of blowing a carbonic acid gas into an aqueous sodium hydroxide solution; (b) a step of injecting a tazobactam The step of dissolving Tazobactam and Piperacillin in the solution obtained in the above step (a). The method for producing a freeze-dried preparation according to claim 1, which comprises adjusting the aqueous sodium hydroxide solution to a pH of 7.0 to 9.2 by blowing a carbonic acid gas in the step (a).