KR20180085496A - Lyophilized formulation comprising piperacillin or its salt and tazobactam or its salt - Google Patents

Abstract

The present invention provides a lyophilized formulation comprising piperacillin (or salt thereof), tazobactam (or salt thereof), and dexamethasone phosphate (or salt thereof); or a lyophilized formulation comprising piperacillin (or salt thereof) and tazobactam (or salt thereof), wherein the lyophilized formulation contains sodium chloride as a stabilizer. The lyophilized formulation of the present invention can be used in a form of reconstitutable formulations.

Description

[0001] The present invention relates to a lyophilized formulation comprising piperacillin or its salt and tazobactam or its salt,

The present invention relates to a freeze-dried preparation comprising piperacillin or a salt thereof and tazobactam or a salt thereof; Or a freeze-dried preparation comprising piperacillin or a salt thereof, tazobactam or a salt thereof, and dexamethasone phosphate or a salt thereof.

A pharmaceutical composition containing piperacillin (or piperacillin sodium) and tazobactam (or tazobactam sodium) has been used as Zosyn ^™ . The composition is useful as an in-patient antibiotic for intravenous administration and has a lyophilized injectable form. The lyophilized injectable solution is used by dissolving in water for injection, physiological saline, glucose, etc., and the prepared solution is required to be used within 24 hours in a refrigerated condition (2-8 ° C).

U.S. Patent No. 6,207,661 discloses a liquid premix formulation (Premix formulation) containing sodium piperacillin, tazobactam sodium and sodium citrate as a buffer. The liquid pre-mixture is stored frozen, and after thawing, the diluent is added as needed and then parenterally administered to the patient. In addition, International Patent Publication No. WO 2004/091666 discloses a pharmaceutical composition comprising, in addition to sodium piperazylate and tazobactam sodium, an aminocarboxylic acid chelating agent such as ethylenediaminetetraacetic acid (EDTA) or a salt thereof and a citrate salt as a buffer and optionally an aminoglycoside ≪ / RTI > have been disclosed.

Korean Patent Publication No. 10-2014-0052122 discloses a pharmaceutical composition for topical administration comprising piperacillin or a salt thereof, tazobactam or a salt thereof, dexamethasone phosphate or a salt thereof. When the pharmaceutical composition for topical administration is stored in a refrigerated condition by mixing piperacillin (or a salt thereof), tazobactam (or a salt thereof), and dexamethasone phosphate (or a salt thereof) in an aqueous medium, And the use of acetic acid or acetic acid and its salts as stabilizers in order to solve the problem that it is difficult to reuse in the treatment period. In addition, the pharmaceutical composition for topical administration may contain one or more of piperacillin or a pharmaceutically acceptable salt thereof, tazobactam or a pharmaceutically acceptable salt thereof, and dexamethasone phosphate or a pharmaceutically acceptable salt thereof (and an acetic acid salt, Its salt) in the form of a lyophilizate.

On the other hand, in order to design freeze-dried preparations simultaneously containing piperacillin (or a salt thereof), tazobactam (or a salt thereof), and dexamethasone phosphate (or a salt thereof), stability in the freeze- The lyophilized preparation itself is required to have storage stability during use. That is, in order to formulate a freeze-dried preparation, it is necessary not only to suppress the production of the freeze-drying substance during the freeze-drying process, but also to effectively suppress the production of the freeze-dried substance in the storage of the obtained freeze-dried preparation. However, when the freeze-dried preparation is prepared according to the applicant's prior art, that is, Korean Patent Laid-Open Publication No. 10-2014-0052122, there is a problem in that the free substance exceeds the standard value during the freeze-drying process and storage of the obtained freeze- .

The present inventors have found that piperacillin (or a salt thereof) and tazobactam (or a salt thereof); A variety of studies have been conducted to develop lyophilized preparations comprising piperacillin (or a salt thereof), tazobactam (or a salt thereof), and dexamethasone phosphate (or a salt thereof). Surprisingly, the inventors have found that sodium chloride functions as a stabilizing agent to provide storage stability of lyophilized preparations comprising these drugs.

Accordingly, it is an object of the present invention to provide a freeze-dried preparation comprising piperacillin or a salt thereof, tazobactam or a salt thereof, dexamethasone phosphate or a salt thereof as an active ingredient, and sodium chloride as a stabilizer.

It is still another object of the present invention to provide a freeze-dried preparation containing piperacillin or a salt thereof and tazobactam or a salt thereof as an active ingredient and containing sodium chloride as a stabilizer.

According to one aspect of the present invention, piperacillin or a pharmaceutically acceptable salt thereof; Tazobactam or a pharmaceutically acceptable salt thereof; There is provided a lyophilization agent comprising dexamethasone phosphate or a pharmaceutically acceptable salt thereof and sodium chloride as a stabilizer. In one embodiment, the lyophilized formulation comprises piperacillin sodium; Tazobactam sodium; Dexamethasone phosphate disodium; And sodium chloride as a stabilizer.

According to another aspect of the present invention, piperacillin or a pharmaceutically acceptable salt thereof; Tazobactam or a pharmaceutically acceptable salt thereof; And sodium chloride as a stabilizer. In one embodiment, the lyophilized formulation comprises piperacillin sodium; Tazobactam sodium; And sodium chloride as a stabilizer.

The lyophilized preparation of the present invention may contain the dexamethasone phosphate or a pharmaceutically acceptable salt thereof in a proportion of 1.25 mg to 5.0 mg per 100 mg of piperacillin, for example, 1.25 mg per 100 mg of piperacillin mg, 2.5 mg, or 5.0 mg.

In the lyophilized preparation of the present invention, the sodium chloride may be present in a proportion of not more than 22.5 mg per 100 mg of piperacillin, preferably in a proportion of 5.5 mg to 22.5 mg per 100 mg of piperacillin .

Lyophilized formulations comprising piperacillin (or a salt thereof), tazobactam (or a salt thereof), and dexamethasone phosphate (or a salt thereof); (Or a salt thereof) or tazobactam (or a salt thereof), it is disclosed in the present invention that sodium chloride functions as a stabilizing agent that provides storage stability of the lyophilized preparation. . That is, the freeze-dried preparation according to the present invention can effectively inhibit the production of the soft substance in the lyophilization process, and can secure the storage stability of the obtained freeze-dried preparation.

The present invention relates to piperacillin or a pharmaceutically acceptable salt thereof; Tazobactam or a pharmaceutically acceptable salt thereof; Dexamethasone phosphate or a pharmaceutically acceptable salt thereof, and sodium chloride as a stabilizer. The present invention also relates to piperacillin or a pharmaceutically acceptable salt thereof; Tazobactam or a pharmaceutically acceptable salt thereof; And sodium chloride as a stabilizer.

Lyophilized formulations comprising piperacillin (or a salt thereof), tazobactam (or a salt thereof), and dexamethasone phosphate (or a salt thereof); It has been discovered by the present invention that sodium chloride acts as a stabilizing agent for lyophilized preparations in lyophilized preparations comprising paclitaxel (and its salts) and tazobactam (or its salts). That is, the freeze-dried preparation according to the present invention can effectively inhibit the production of the soft substance in the lyophilization process, and can secure the storage stability of the obtained freeze-dried preparation. The lyophilized preparations according to the present invention can be used in the form of reconstitutable formulations and can be rapidly applied to eyes, ears, nose, skin, etc. by reconditioning with solvents such as water for injection, May be used in the form of an otic formulation to be applied.

In the freeze-dried preparation according to the present invention, the pharmaceutically acceptable salt of piperacillin may be a conventional acid addition salt including a sodium salt, preferably a piperacillin sodium salt. The piperacillin or a pharmaceutically acceptable salt thereof may be used in a therapeutically effective content range, preferably 1.0 to 20.0% (w / v) when reconditioned with a solvent such as purified water Can be used.

The pharmaceutically acceptable salt of tazobactam may be a conventional acid addition salt including a sodium salt, preferably a tazobactam sodium salt. The tazobactam or a pharmaceutically acceptable salt thereof may be used in a therapeutically effective content range, and may preferably be used in a ratio of 12.5 mg as an ostobacam against 100 mg of piperacillin.

In addition, the pharmaceutically acceptable salt of dexamethasone phosphate may be a conventional metal salt including dexamethasone phosphate sodium, preferably dexamethasone phosphate sodium. The dexamethasone phosphate or a pharmaceutically acceptable salt thereof may be used in a proportion of 1.25 mg to 5.0 mg per 100 mg of piperacillin, for example, 1.25 mg, 2.5 mg, or 5.0 mg per 100 mg of piperacillin mg. < / RTI >

In one embodiment, the lyophilized formulation of the present invention comprises piperacillin sodium; Tazobactam sodium; Dexamethasone phosphate disodium; And sodium chloride as a stabilizer. In another embodiment, the lyophilized formulation of the present invention comprises piperacillin sodium; Tazobactam sodium; And sodium chloride as a stabilizer.

As described above, sodium chloride functions as a stabilizer in the lyophilized preparation of the present invention. In the lyophilized preparation of the present invention, the sodium chloride may be present in a proportion of not more than 22.5 mg per 100 mg of piperacillin, preferably in a proportion of 5.5 mg to 22.5 mg per 100 mg of piperacillin .

In one embodiment of the present invention, there is provided a three-component lyophilization agent having the following components and contents.

The three-component lyophilized preparation described above can be rapidly redispersed using 2.5 mL of water for injection, and the concentration of the redispersed solution is 4.0% (w / v) of piperacillin, 0.5% (w / v), dexamethasone phosphate 0.1% (w / v) sodium, and can be administered locally in the form of a solution.

Further, in another embodiment of the present invention, there is provided a two-component lyophilization agent having the following components and contents.

The above two-component freeze-dried preparations can be quickly redispersed using 2.5 mL of water for injection, and the concentration of redispersed solution is 4.0% (w / v) of piperacillin and 0.5% (w / v), and can be administered to a local site in the form of a solution.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrating the present invention, and the present invention is not limited to these examples.

Example  1. Preparation and evaluation of freeze-dried preparations using various additives

41.7 g of piperacillin sodium (40 g as piperacillin) and 5.4 g of tazobactam sodium (5.0 g as tazobactam) were completely dissolved in 900 mL of water for injection. While stirring the obtained solution, 1.0 g of sodium dexamethasone phosphate was added and dissolved completely. While stirring the obtained solution, 7.0 g of an additive (sodium chloride, sodium citrate, sodium acetate, ethylenediamine tetraacetic acid (EDTA)) was added and completely dissolved. The solution was adjusted to 1,000 mL with the injection water, and stirred for about 30 minutes. The resulting solution was aseptically filtered, dispensed into sterile vials, and lyophilized. Each vial was sealed with a rubber stopper and then sealed with an aluminum cap. The components and contents of the lyophilized preparations thus obtained are shown in Table 1 below, and the content thereof is the content of each component relative to 100 mg as piperacillin. The total content of the suppositories after storage for 4 weeks under the conditions of total initial suppository contents and accelerated conditions (conditions of 40 ° C / 75% relative humidity) of the lyophilized preparations were analyzed by high performance liquid chromatography (HPLC) The results are shown in Table 1. In the following Table 1, the total content of the flexible substances means the HPLC area%. The above HPLC analysis was carried out according to the test method for a flexible substance of Test Method 3 in the "injection of piperacillin tazobactam "

ingredient Formulation Example (mg) 1-1 1-2 1-3 1-4 1-5 Sodium piperacillin
(As piperacillin) 104.2
(100) 104.2
(100) 104.2
(100) 104.2
(100) 104.2
(100) Tazobactam sodium
(As an ostrich bactam) 13.4
(12.5) 13.4
(12.5) 13.4
(12.5) 13.4
(12.5) 13.4
(12.5) Dexamethasone phosphate disodium 2.5 2.5 2.5 2.5 2.5 additive Sodium chloride - 17.5 - - - Sodium citrate - - 17.5 - - Sodium acetate - - - 17.5 - Ethylenediaminetetraacetic acid (EDTA) - - - - 17.5 Total Flexible Substance (%) Immediately After Production 1.52 1.32 2.03 1.83 1.49 Total Suspended Substance (%) after 4 weeks storage 2.31 1.70 3.06 5.51 4.68 Increase in Total Flexible Substance (%) 0.79 0.38 1.03 3.68 3.19

From the results of Table 1, it can be seen that Formulation Example 1-2 obtained using sodium chloride is significantly lower in the content of the suppositories immediately after preparation of the lyophilized formulation than that of Formulation Example 1-1. Further, in the case of the freeze-dried preparation (Preparation example 1-1), stability was lowered when stored under accelerated conditions because of the increase in the amount of the flexible substance, and even when sodium citrate, sodium acetate and ethylenediaminetetraacetic acid (EDTA) Respectively. On the contrary, the lyophilized preparation of Preparation Example 1-2 has a small amount of the production of a flexible substance, and thus it can be seen that sodium chloride functions as a stabilizer.

Example  2. Preparation and evaluation of freeze-dried preparations according to sodium chloride content

The freeze-dried preparation was prepared in the same manner as in Example 1, according to the ingredients and contents in Table 2 below. The resulting freeze-dried preparation was analyzed by high performance liquid chromatography (HPLC) in the same manner as in Example 1, and the results are shown in Table 2. In the following Table 2, the total content of the flexible substances means the HPLC area%.

ingredient Formulation Example (mg) 2-1 2-2 2-3 2-4 2-5 Sodium piperacillin
(As piperacillin) 104.2
(100) 104.2
(100) 104.2
(100) 104.2
(100) 104.2
(100) Tazobactam sodium
(As an ostrich bactam) 13.4
(12.5) 13.4
(12.5) 13.4
(12.5) 13.4
(12.5) 13.4
(12.5) Dexamethasone phosphate disodium 2.5 2.5 2.5 2.5 2.5 Sodium chloride 5.5 11.25 22.5 30.0 40.0 Total Flexible Substance (%) Immediately After Production 1.46 1.37 1.44 1.43 1.43 Total Suspended Substance (%) after 4 weeks storage 1.90 1.83 2.20 2.27 2.31 Increase in Total Flexible Substance (%) 0.44 0.46 0.76 0.84 0.88

From the results shown in the above Table 2, the formulation contents 2-1 to 2-5 are significantly lower in the content of the suppositories immediately after preparation of the freeze-dried preparations than those of the formulation 1-1. In addition, when the amount of sodium chloride used was less than 22.5 mg per 100 mg of piperacillin, the amount of increase in the amount of the flexible substance was smaller than that of the freeze-dried preparation without using sodium chloride (Preparation Example 1-1) In the case of 30.0 mg or more, the increase of the amount of the substance was increased. Therefore, it is preferable that sodium chloride is used in an amount of not more than 22.5 mg per 100 mg of piperacillin.

Example  3. Dexamethasone Phosphate Of sodium  Preparation and evaluation of freeze-dried preparations according to contents (1)

The freeze-dried preparation was prepared in the same manner as in Example 1, according to the ingredients and contents in Table 3 below. With respect to the obtained freeze-dried preparation, the total content of the suppositories was analyzed by high performance liquid chromatography (HPLC) in the same manner as in Example 1, and the results are shown in Table 3. In the following Table 3, the total content of the flexible substances means the HPLC area%.

ingredient Formulation Example (mg) 3-1 3-2 3-3 3-4 3-5 3-6 Sodium piperacillin
(As piperacillin) 104.2
(100) 104.2
(100) 104.2
(100) 104.2
(100) 104.2
(100) 104.2
(100) Tazobactam sodium
(As an ostrich bactam) 13.4
(12.5) 13.4
(12.5) 13.4
(12.5) 13.4
(12.5) 13.4
(12.5) 13.4
(12.5) Dexamethasone phosphate disodium 1.25 1.25 1.25 1.25 1.25 1.25 Sodium chloride - 5.5 11.25 17.5 22.5 30.0 Total Flexible Substance (%) Immediately After Production 1.42 1.41 1.35 1.37 1.40 1.39 Total Suspended Substance (%) after 4 weeks storage 2.01 1.73 1.59 1.54 1.73 2.02 Increase in Total Flexible Substance (%) 0.59 0.32 0.24 0.17 0.33 0.63

From the results shown in Table 3, it can be seen that sodium chloride acts as a stabilizer when the amount of sodium chloride used is 22.5 mg or less per 100 mg of piperacillin, as in the results of Examples 1 and 2. [

Example  4. Dexamethasone Phosphate Of sodium  Preparation and evaluation of freeze-dried preparations according to contents (2)

The freeze-dried preparation was prepared in the same manner as in Example 1, according to the ingredients and contents in Table 4 below. The resulting freeze-dried preparation was analyzed by high performance liquid chromatography (HPLC) in the same manner as in Example 1, and the results are shown in Table 4. In the following Table 4, the total content of the flexible substances means the HPLC area%.

ingredient Formulation Example (mg) 4-1 4-2 4-3 4-4 4-5 4-6 Sodium piperacillin
(As piperacillin) 104.2
(100) 104.2
(100) 104.2
(100) 104.2
(100) 104.2
(100) 104.2
(100) Tazobactam sodium
(As an ostrich bactam) 13.4
(12.5) 13.4
(12.5) 13.4
(12.5) 13.4
(12.5) 13.4
(12.5) 13.4
(12.5) Dexamethasone phosphate disodium 5.0 5.0 5.0 5.0 5.0 5.0 Sodium chloride - 5.5 11.25 17.5 22.5 30.0 Total Flexible Substance (%) Immediately After Production 2.17 2.04 2.00 1.99 2.02 2.16 Total Suspended Substance (%) after 4 weeks storage 3.20 2.78 2.58 2.55 2.93 3.25 Increase in Total Flexible Substance (%) 1.03 0.74 0.58 0.56 0.91 1.09

From the results shown in Table 4, it can be seen that sodium chloride functions as a stabilizer when the amount of sodium chloride used is 22.5 mg or less per 100 mg of piperacillin, as in the results of Examples 1 to 3.

Example  5. Dexamethasone Phosphate This sodium  Preparation and evaluation of freeze-dried preparations not included

A freeze-dried preparation was prepared in the same manner as in Example 1, except that sodium dexamethasone phosphate was not used, depending on the ingredients and contents in Table 5 below. After storage for 4 weeks under the conditions of the initial content of 1-Ethylpiperazine-2,3-dione and the acceleration conditions (conditions of 40 ° C / 75% relative humidity) immediately after the preparation of the lyophilized preparation, The content of 1-Ethylpiperazine-2,3-dione was analyzed by high performance liquid chromatography (HPLC). The results are shown in Table 5. In the following Table 5, the total content of the flexible substances means the HPLC area%. The above HPLC analysis was carried out according to the test method for a flexible substance of Test Method 3 in the "injection of piperacillin tazobactam "

ingredient Formulation Example (mg) 4-1 4-2 4-3 4-4 4-5 4-6 Sodium piperacillin
(As piperacillin) 104.2
(100) 104.2
(100) 104.2
(100) 104.2
(100) 104.2
(100) 104.2
(100) Tazobactam sodium
(As an ostrich bactam) 13.4
(12.5) 13.4
(12.5) 13.4
(12.5) 13.4
(12.5) 13.4
(12.5) 13.4
(12.5) Sodium chloride - 5.5 11.25 17.5 22.5 30.0 The Piperacillin Flexible Substance E ((%)) 0.12 0.11 0.11 0.11 0.11 0.12 Piperacillin after 4 weeks storage Flexible substance E (%) 0.54 0.44 0.34 0.38 0.47 0.59 Increase (%) of Piperacillin Flexible E 0.42 0.33 0.23 0.27 0.38 0.47

From the results shown in Table 5, it can be seen that when sodium chloride is used in an amount of 22.5 mg or less with respect to 100 mg of piperacillin even in the lyophilized preparation in which dexamethasone phosphate is not used as in the case of the results of Examples 1 to 4, sodium chloride acts as a stabilizer .

Claims (10)

Piperacillin or a pharmaceutically acceptable salt thereof; Tazobactam or a pharmaceutically acceptable salt thereof; Dexamethasone phosphate or a pharmaceutically acceptable salt thereof, and sodium chloride as a stabilizing agent. Piperacillin or a pharmaceutically acceptable salt thereof; Tazobactam or a pharmaceutically acceptable salt thereof; And sodium chloride as a stabilizer. 2. The composition of claim 1, wherein the piperacillin sodium; Tazobactam sodium; Dexamethasone phosphate disodium; And sodium chloride as a stabilizer. 3. The pharmaceutical composition according to claim 2, further comprising: piperacillin sodium; Tazobactam sodium; And sodium chloride as a stabilizer. The freeze-dried preparation according to claim 1, wherein the dexamethasone phosphate or a pharmaceutically acceptable salt thereof is present in a ratio of 1.25 mg to 5.0 mg based on 100 mg of piperacillin. 6. The freeze-dried preparation according to claim 5, wherein the dexamethasone phosphate or a pharmaceutically acceptable salt thereof is present in a ratio of 1.25 mg to 100 mg of piperacillin. 6. The freeze-dried preparation according to claim 5, wherein the dexamethasone phosphate or a pharmaceutically acceptable salt thereof is present in a ratio of 2.5 mg to 100 mg of piperacillin. The freeze-dried preparation according to claim 5, wherein the dexamethasone phosphate or a pharmaceutically acceptable salt thereof is present in a ratio of 5.0 mg to 100 mg of piperacillin. 9. The freeze-dried preparation according to any one of claims 1 to 8, wherein the sodium chloride is present in a proportion of not more than 22.5 mg per 100 mg of piperacillin. The freeze-dried preparation according to claim 9, wherein the sodium chloride is present in a proportion of 5.5 mg to 22.5 mg per 100 mg of piperacillin.