KR20170067709A - Method for producing freeze-dried preparation - Google Patents

Abstract

Disclosure of the Invention The present invention provides a novel method for preparing a lyophilized preparation for free use (compounding agent) containing sodium tazobactam and piperacillin sodium. As the present invention, for example, the following production methods can be mentioned. A method for producing a freeze-dried preparation for injection, which comprises the steps of (a) and (b) below. (a) a step of blowing carbonic acid gas into an aqueous solution of sodium hydroxide (b) a step of dissolving tazobactam and piperacillin in the solution obtained in the step (a)
INDUSTRIAL APPLICABILITY According to the present invention, it is possible to obtain a lyophilized preparation having good bubble removal of a solution after redissolution.

Description

METHOD FOR PRODUCING FREEZE-DRIED PREPARATION [0002]

The present invention relates to a novel process for preparing a freeze-dried preparation for injection use containing tazobactam sodium and Piperacillin sodium.

The combination of tazobactam and piperacillin is commercially available under the trade name of "Zosyn" (registered trademark) in the form of a freeze-dried preparation for intravenous administration and widely used in the world.

In order to prepare a lyophilized preparation for injection for use in combination with tazobactam and piperacillin, it is preferred that the free form of tazobactam and piperacillin in the form of a free form are reacted with sodium ions in a solution before lyophilization, It is necessary to generate a sodium salt. However, both tazobactam and piperacillin have low stability in an alkaline solution, so that it is not possible to use a strong alkali such as sodium hydroxide solution used for pH adjustment, sodiumation or the like in the preparation of an injection.

In order to solve the above problems, a method of preparing a solution by dissolving tazobactam free acid and piperacillin hydrate in an aqueous solution of sodium bicarbonate and lyophilizing a solution containing a buffer (citrate or the like) and an aminocarboxylic acid chelating agent (EDTA or the like) (See Patent Document 1). Similarly, a method is known in which tazobactam free acid and piperacillin hydrate are dissolved in an aqueous solution of sodium bicarbonate and the dissolved carbon dioxide content is degassed to a certain amount to prepare a solution by freeze-drying (Patent Document 2). In this method, since the pH is adjusted using piperacillin instead of using a buffering agent or an aminocarboxylic acid chelating agent, the final effective ingredient content can not be precisely adjusted.

International Publication No. 2004/091666 International Publication No. 2007/065862

It is an object of the present invention to provide a novel method for preparing a lyophilized preparation for free use (formulation) containing mainly tazobactam sodium and piperacillin sodium.

It goes without saying that, in the production of the freeze-dried preparation, the liquid amount to be dried is advantageously reduced as much as possible. Therefore, a sodium hydroxide solution capable of pH adjustment and sodiumation can be used in a small amount, but since sodium hydroxide is a strong alkali, use of a sodium hydroxide solution may cause decomposition of the active ingredient.

In addition, prior to intravenous administration of the lyophilized preparation, it is necessary to reuse the lyophilized preparation with water or the like. When a lyophilized preparation for injection use containing a combination of tazobactam and piperacillin is dissolved in water or the like, the solubility thereof is low, so that an operation such as stirring is required. Since bubbles are usually generated in the solution after stirring, it is preferable that the bubbles disappear rapidly in a medical field.

As a result of intensive studies, the inventors of the present invention have found that the above problems can be solved by a simple method of blowing carbon dioxide gas into a strongly alkaline aqueous solution of sodium hydroxide.

Examples of the present invention include the following.

[1] A method for producing a freeze-dried preparation for injection, which comprises the steps of (a) and (b) below (hereinafter referred to as "the present invention production method").

(a) Bring carbon dioxide gas into an aqueous solution of sodium hydroxide

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

[2] The method for producing a freeze-dried preparation according to the above [1], which comprises adjusting carbon dioxide gas in the step (a) to adjust the sodium hydroxide aqueous solution to a pH within the range of 7.0 to 9.2.

[3] The method according to the above [1] or [2], further comprising a step of adjusting an aqueous solution of sodium hydroxide in which carbonic acid gas is blown in which tazobactam and piperacillin are dissolved to pH 5.5 to 6.8 with acid ≪ / RTI >

[4] The method for producing a freeze-dried preparation according to [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 [1] to [4], further comprising the step of (c)

(c) Injection of inert gas

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

The present invention is characterized in that tazobactam and piperacillin are dissolved in an aqueous sodium hydroxide solution in which carbon dioxide gas is blown in the preparation of a lyophilized preparation for injection, which contains sodium tazobactam and piperacillin sodium. Thus, even when an aqueous solution of sodium hydroxide of a strong alkali is used, sodium hydroxide of the active ingredient is prevented without any problem, while the decomposition of tazobactam and piperacillin is suppressed as much as possible.

According to the process of the present invention, even when a strong alkaline aqueous solution of sodium hydroxide is used, since the pH of the solution can be prevented from being excessively increased by blowing carbon dioxide gas into the solution, it is possible to suppress the decomposition of the ozone bactam and piperacillin (Freeze-dried preparation for injection) can be prepared. In addition, when the solution for injection is added to the lyophilized preparation obtained by the production method of the present invention and redissolved, the so-called bubble elimination is favorable.

1 is a photograph showing the state before and after the redissolution. The left container of each photograph represents a commercially available sample, and the right container represents a freeze-dried preparation sample obtained by the present invention. The upper left photograph shows the state before redissolution, the upper right photograph shows the state immediately after reuse with the injection water, the left middle photograph shows the state after 30 seconds, the right middle photograph shows the state after 1 minute, The state after 2 minutes from the standstill, and the image on the lower right side shows the state after 6 minutes from standstill.

Hereinafter, the present invention will be described in detail.

I. About the process of the present invention

(a) Bring carbon dioxide gas into an aqueous solution of sodium hydroxide

This step is a step of blowing carbon dioxide gas into an aqueous solution of sodium hydroxide.

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

It is also possible to use a commercially available sodium hydroxide aqueous solution as it is or diluted with water as appropriate.

Subsequently, carbon dioxide gas is blown into the aqueous solution of sodium hydroxide to prepare an aqueous solution of sodium hydroxide in which carbonic acid is dissolved. As a method for blowing carbon dioxide gas, for example, a general gas blowing method can be mentioned. Specifically, for example, there can be mentioned a method of injecting a carbonic acid gas injection tube while stirring an aqueous solution of sodium hydroxide with a stirrer or the like, and blowing carbon dioxide gas at a pressure not to cause boiling. 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, a pH of 7.5 to 8.0) by blowing a carbonic acid gas into an aqueous solution of sodium hydroxide. If necessary, the carbonic acid gas can be finely adjusted within the pH range by blowing the carbonic acid gas into the aqueous solution or blowing the aqueous solution with a suitable acid. Examples of acids for such fine pH adjustment include hydrochloric acid, citric acid and phosphoric acid. Of these, hydrochloric acid is particularly suitable.

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

This step is a step of dissolving tazobactam and piperacillin in an aqueous sodium hydroxide solution into which carbon dioxide gas is blown. Tazobactam and piperacillin are dissolved in the aqueous solution.

The concentration of tazobactam in the aqueous solution is not particularly limited and may be, for example, 1 to 20 mass%, preferably 3 to 7 mass%. If it is less than 1% by mass, it is inconvenient to obtain a lyophilized preparation having a predetermined activity. When 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 may be, for example, 10 to 50 mass%, preferably 20 to 30 mass%. If it is less than 10% by mass, it is inconvenient to obtain a lyophilized preparation having a predetermined activity. If it is more than 50% by mass, dissolution is difficult. Further, the ratio of inverse ratio of tazobactam to piperacillin in the aqueous solution is preferably 1: 8 (tazobactam: piperacillin).

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

There is no particular limitation on the order of dissolving tazobactam and piperacillin in the aqueous solution. Either one can be dissolved first, or both can be dissolved at the same time.

This dissolution can be carried out by a usual method. Specifically, for example, tazobactam and piperacillin hydrate may be added to an aqueous solution of sodium hydroxide in which carbon dioxide gas is blown, and the mixture may be dissolved by stirring with a stirrer or the like. The melting temperature is, for example, 3 to 15 占 폚. More preferably 4 to 10 ° C. If it is lower than 3 ° C, it takes time to dissolve. If it is higher than 15 ° C, the decomposition of tazobactam and piperacillin may be accelerated.

In the process of the present invention, it is preferable to include a step of adjusting an aqueous solution of sodium hydroxide in which carbonic acid gas is blown in which tazobactam and piperacillin are dissolved to pH 5.5 to 6.8 (preferably pH 5.7 to 6.6) with acid Do. As such an acid for pH adjustment, the same acid as mentioned above can be mentioned. Of these, hydrochloric acid is particularly suitable.

Tazobactam and piperacillin may be dissolved, and after adjusting the pH as occasion demands, the amount of the liquid may be adjusted with water as necessary. Water for adjusting the amount of liquid includes, for example, water for injection, purified water, distilled water and physiological saline, but water for injection is preferable.

(c) Injection of inert gas

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

Examples of the inert gas include nitrogen gas and argon gas. Is not particularly limited as long as it is generally used as an inert gas, but nitrogen gas which is easy to handle and is inexpensive is suitable.

Blowing of the inert gas can be carried out after dissolving tazobactam and piperacillin in the solution obtained in the step (a), in addition to dissolving the tazobactam and the piperacillin in the solution obtained in the step (a) Also, the step of pH adjustment after the dissolution of the tazobactam and the piperacillin in the solution obtained in the step (a) and the adjustment of the amount of the liquid can be carried out.

There is no particular limitation on the time for blowing the inert gas and the amount of blowing inert gas. For example, the amount of carbon dioxide in the solution obtained in the step (a) is 200 mg / L or less (preferably 75 mg / L or less), and an inert gas is blown until the amount of oxygen becomes 10 ppm or less (preferably 1 ppm or less).

By blowing an inert gas into the solution obtained in the step (b), carbon dioxide and oxygen in the aqueous solution can be removed. If carbon dioxide remains in the aqueous solution, the pH may fluctuate during lyophilization. Further, if oxygen remains in the aqueous solution, there is a fear that the decomposition of tazobactam and piperacillin may be promoted.

The solution obtained in the step (b) after the inert gas is blown is preferably subjected to filtration sterilization by a usual method. Filtration sterilization is, for example, filtration sterilization by a membrane filter of 0.22 占 퐉.

(d) lyophilization process

The solution obtained in the above step (c) is dispensed into an aseptic container and lyophilized by a conventional method. In general, the vial after lyophilization is replaced with nitrogen gas, and the vial is plugged to obtain a lyophilized preparation for main use (hereinafter referred to as "the present invention preparation") according to the present invention.

In the formulation of the present invention, it is considered that tazobactam and piperacillin are present as a sodium salt.

It is preferable that 0.25 g (titer) or 0.5 g (titer) of tazobactam sodium in the preparation of the present invention and 2.0 g (potency) or 4.0 g (potency) of piperacillin sodium are contained .

II. For the present invention formulation

In general, the preparation of the present invention can be used by redissolution by the addition of any appropriate solution (redissolving solution). Examples of such a remedial solution include water for injection, physiological saline, 5% (w / v) glucose injection solution, and other common liquid solutions. The amount of this redissolving solution varies depending on the use and the like, and is not particularly limited, but 0.5 to 5 times, or 500 mL or less, of the volume of the solution filled in the vial before freeze-drying is suitable.

The redissolved agent of the present invention can be administered intravenously, for example, as an injection or a drip agent.

The dosage of the present invention varies depending on the condition of the patient such as age and body weight, the nature and severity of the disease, etc., but 4.5 g (potency) of tazobactam sodium / piperacillin sodium is appropriate per adult. This amount can be administered at appropriate intervals of 1 to 5 times per day, preferably 1 to 4 times per day depending on the condition or disease of the patient such as age or body weight.

Example

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited at all by these Examples.

[Example 1]

2.4 kg of sodium hydroxide was dissolved in 56.25 liters of water for injection, carbon dioxide gas was blown into the solution, and the pH was adjusted to about 7.7. The sodium hydroxide aqueous solution in which the carbon dioxide gas was blown was finely adjusted to pH 7.7 with a 0.5M hydrochloric acid aqueous solution and then added with 2.976 kg of tazobactam and 23.81 kg of piperacillin hydrate while bubbling with nitrogen gas, Aqueous hydrochloric acid solution and injection water were further added to obtain 125 L of an aqueous solution having a pH of 6.5. After the preparation, the solution was sterilized by filtration, dispensed in an aseptic container, and lyophilized according to a conventional method. In each container, 0.25 g (potency) of sodium tazobactam, 2.0 g (potency) of piperacillin sodium, And 0.5 g (potency) of piperacillin sodium and 4.0 g (potency) of piperacillin sodium.

Hereinafter, the formulation of the present invention containing 0.25 g of tazobactam sodium (potency) and 2.0 g (potency) of piperacillin sodium was referred to as the present invention preparation 2.25, and 0.5 g of tazobactam sodium (potency), 4.0 g of piperacillin sodium ) Is referred to as the present invention preparation 4.5, respectively.

[Test Example 1] Change in pH over time

The change with time of the pH of the preparation of the present invention obtained in Example 1 was observed in comparison with a commercially available product (Joshin (registered trademark) intravenous injection 2.25, 4.5). The results are shown in Table 1. The numerical values in parentheses in the tables indicate results obtained by the pH measurement method described in the Joshin (registered trademark) interview form, and the values without parentheses are the values obtained by the method described in the Japanese Pharmacopoeia No. 16, And the results obtained by the pH measurement method described in the section on silane.

All of them showed a tendency to deteriorate with time, but it is clear that the change with time of pH of the preparation of the present invention is equivalent to that of a commercial product.

[Test Example 2] Purity test of tazobactam and piperacillin

The purity test of tazobactam and piperacillin in the preparation of the present invention obtained in Example 1 was carried out under the conditions of 40 占 폚 / 75% RH or 60 占 폚 / 75% RH in a commercially available product (Joshin (registered trademark) intravenous injection 2.25, ) Was carried out by a conventional method. The results are shown in Tables 2 and 3. In addition, the content of tazobactam and piperacillin was determined by the method of purity test described in the paragraph of the 16th Japanese Pharmacopoeia, Second Prospectus, the section of the injection-use tazobactam piperacillin.

It is clear that the use of the process of the present invention makes it possible to produce an equivalent product with a commercial product.

[Test Example 3] Bubbling test

20 mL of water for injection was added to each of the formulation 4.5 of the present invention obtained in Example 1 and commercial product (Joshin (registered trademark) intravenous injection 4.5), and dissolved by conduction and mixing until the freeze-dried product disappeared. The state of bubble removal at that time is shown in Fig.

After one minute of standing, clear bubbles were observed on the upper side of the commercial product, but the bubbles on the upper side of the product of the present invention were invisible and fine bubbles were observed in the middle to upper part. After 2 minutes from the standstill, all of the bubbles were lost on the preparation of the present invention, but bubbles were observed on the liquid surface of the commercial product. Finally, after 7 minutes and 30 seconds from the standstill, air bubbles also disappeared on the market.

Therefore, it is clear that the preparation of the present invention is excellent in bubble removal after redissolving with water for injection.

The production method of the present invention is equivalent to a commercial product Josin (registered trademark) in quality and is useful in producing a lyophilized preparation having excellent bubble elimination.

Claims (2)

A method for producing a freeze-dried preparation for injection, which comprises the steps of (a) and (b) below.
(a) Bring carbon dioxide gas into an aqueous solution of sodium hydroxide
(b) a step of dissolving tazobactam and piperacillin in the solution obtained in the step (a) The method for producing a freeze-dried preparation according to claim 1, which comprises adjusting the sodium hydroxide aqueous solution to a pH within the range of 7.0 to 9.2 by blowing carbon dioxide gas in the step (a).

Images