WO2017117880A1 - Pharmaceutical composition of cefoperazone sodium and sulbactam sodium - Google Patents

Abstract

Disclosed is a pharmaceutical composition of cefoperazone sodium and sulbactam sodium, comprising cefoperazone sodium and sulbactam sodium. The mass ratio of cefoperazone sodium and sulbactam sodium is 1-2 : 1, the specific rotation of cefoperazone sodium is -20° to -24°, and the specific rotation of sulbactam sodium is +223° to +228°. Same is made from cefoperazone sodium and sulbactam sodium with specific rotations, and can improve drug stability, thereby making the medication clinically safe.

Description

Medicinal composition of cefoperazone sodium and sulbactam sodium Technical field

The present invention relates to the field of medicine, and more particularly to a pharmaceutical composition of cefoperazone sodium and sulbactam sodium.

Background technique

Cefoperazone sodium and sulbactam sodium are complex preparations with higher antibacterial activity than cefoperazone sodium, which was developed by Pfizer Inc. under the trade name of Sulpelazon. Sulbactam is a broad-spectrum enzyme inhibitor with weak antibacterial activity, and has strong irreversible inhibitory effect on Staphylococcus aureus and β-lactamase produced by most negative bacilli, but is chromosomally mediated by certain negative bacilli. The β-lactamase is inactive. Cefoperazone is a third-generation cephalosporin with poor stability to β-lactamase. The combination of the two shows not only significant synergistic antibacterial activity against the negative bacilli, but also the antibacterial effect of the combined cefoperazone. 4 times.

The existing pharmaceutical compositions of cefoperazone sodium and sulbactam sodium have a problem of insufficient stability and clinically impossible to ensure reliable and effective administration, thereby causing considerable safety hazards to patients.

Summary of the invention

The present invention provides a pharmaceutical composition of cefoperazone sodium and sulbactam sodium and a preparation thereof, which are prepared by using cefoperazone sodium and sulbactam sodium having a specific specific rotation, thereby improving drug stability and making it safe for clinical use.

In order to solve the above technical problems, the present invention adopts the following technical solutions:

A pharmaceutical composition of cefoperazone sodium and sulbactam sodium comprising sulbactam sodium and cefoperazone sodium having a specific rotation of -20 ° to -24 °, the mass ratio of cefoperazone sodium and sulbactam sodium is 1 to 2:1.

The pharmaceutical composition of cefoperazone sodium and sulbactam sodium of the invention is uniformly mixed with sulbactam sodium and cefoperazone sodium with a specific rotation of -20 ° ~ 24 °, and the process of mixing powder is in the existing preparation laboratory. It is carried out as an existing process and will not be described again.

Further, the specific rotation of cefoperazone sodium is -22 to -24.

The specific rotation of cefoperazone sodium was -24°, and the mass ratio of cefoperazone sodium to sulbactam sodium was 2:1.

When the inventors studied the stability test of cefoperazone sodium and sulbactam sodium, it was found that the stability of cefoperazone sodium and sulbactam sodium, which differed from the degree of rotation, was different, and the degradation efficiency was also different. Selecting cefoperazone sodium and sulbactam sodium with a specific rotation of -20 ° ~ 24 ° is high in content and purity, and can improve drug stability, especially clarity stability, compared to Commercially available cefoperazone sodium and sulbactam sodium have better clarity.

The specific rotation of sulbactam sodium is +223° to +228°. The inventors have also found that the addition of a certain range of specificity of sulbactam sodium can also help improve drug stability and increase the content and purity of cefoperazone sodium and sulbactam sodium products.

The specific rotation of sulbactam sodium is +223° to +225°.

The preparation method of cefoperazone sodium is as follows: (1) stirring the sodium acetate solution to the cefoperazone acid acetone solution at 0-5 ° C, the pH value is controlled at 6.5-6.9; (2) after the sodium acetate is added, the solution is heated again. To 10-25 degrees Celsius, the sodium bicarbonate solution is stirred into the cefoperazone acid acetone solution, the pH value is controlled at 6.5-6.9; (3) after the reaction is decolorized and filtered, it is divided into three stages, and the first stage is to control the temperature of the filtrate. Add at 18-20 ° C with stirring Acetone, drop 5-10min; second stage, 18-20 ° C stirring 30-60min, after the crystal precipitation, continue to add acetone to add dropwise, 10-15min; 3rd stage, 10-15 ° C stirring 30-60min The crystals are washed by filtration; wherein the total number of moles of sodium acetate and sodium hydrogencarbonate is equal to the number of moles of acetophenone acid.

In the step (2), after the sodium acetate solution is added dropwise, before the temperature rise, the standing step is further included, and the standing time is 20-40 min.

The cefoperazone sodium obtained by the preparation method of cefoperazone sodium used in the invention is stable and not easy to be degraded, and the stability of the solution after storage for a long time is also high, conforms to national standards, and has large particles and high product yield, and can reach 94. Above 100%, the specific rotation of the prepared cefoperazone sodium can be controlled within +264° to +269°.

In the preparation process, the method uses sodium acetate and sodium hydrogencarbonate as a salt forming agent, first selects sodium acetate as the first salt forming agent and sodium hydrogencarbonate as the second salt forming agent, and can obtain high under certain temperature conditions. The content of the product (93.5wt% or more) and the lower degradation product (0.5-2%). The role of sodium acetate as the first salt-forming agent is to control the crystal grain size of the starting cefoperazone sodium. It has been found that under certain conditions, sodium acetate can be used as a salt-forming agent to obtain large particles of cefoperazone sodium crystals, but the yield is obtained. If the product is not high, the clarity of the product is not good. Therefore, in the present invention, the first step is to use sodium acetate as the first salt-forming agent, and then sodium hydrogencarbonate as the second salt-forming agent. Finally, when crystallization, sodium acetate is used as the salt. The salt agent obtains the crystal nucleus of the large crystal grains, and the cefoperazone sodium having a large crystal grain size is obtained by the induction of the large crystal grains, and the product has high purity, and the yield can reach 93.5% or more, and the specific rotation degree is +264° to +269°.

The molar fraction of sodium acetate is 10-15% of cefoperazone acid, and the molar fraction of sodium bicarbonate The number is 85-90% of cephalosporin. Since the yield of the product using sodium acetate as a salt forming agent is not high, the number of moles of sodium acetate is preferably less than the number of moles of sodium hydrogencarbonate.

The stirring speed of the first stage in the step (3) is 300-350 r/min.

The second stage stirring speed in the step (3) is 200-250 r/min.

The stirring speed of the third stage in the step (3) is 100-150 r/min.

The preparation method of sulbactam sodium is as follows: (1) adding sulbactam to a mixed solution of sodium acetate and sodium hydrogencarbonate at 20-25 ° C, stirring constantly, and controlling the pH of the solution to be 5.5-6.0; After the end, add ethanol and stir for 10 minutes, then irradiate with infrared rays for 3-5min, and continue stirring for 30-60min to obtain crystals, wherein the molar fraction of sodium bicarbonate is 10-15% of sulbactam, and the molar of sodium acetate The fraction is 85-90% of sulbactam.

The factors affecting the stability of sulbactam sodium are mainly the control of the process of the production process. In the preparation method of sulbactam sodium, sodium acetate and sodium hydrogencarbonate are alkaline agents. If sodium acetate alone is used, the pH value of the product is low, and the reaction is not sufficient, but the obtained crystal particles are large, and the carbonic acid is used alone. Since sodium hydride obtained a small amount of crystal particles, crystallization was carried out by using a mixed solution of sodium acetate and sodium hydrogencarbonate as an alkali agent. Of course, it is better to first add sodium acetate solution to culture the large crystal nucleus, and then add sodium bicarbonate to continue crystallization to maintain the yield and higher pH. The added ethanol is based on the ability to fully crystallize the crystal. The inventors have found that infrared irradiation can increase the free energy of ions in a solution, and can accelerate crystallization. Appropriate irradiation can promote crystallization, and energy is too high, and many fine crystals are generated.

A small amount of sulbactam sodium crystals may be added after stirring for 10 minutes in step (2). The molar percentage of the sulbactam sodium crystals is 0.1-0.5% of the added sulbactam acid.

A pharmaceutical preparation comprising a pharmaceutical composition as described above.

The pharmaceutical preparation can be of a pharmaceutically acceptable type of preparation. The type of preparation may be an injection, a tablet, a capsule, or the like or may be loaded on other medically usable carriers.

Compared with the prior art, the beneficial effects of the present invention are:

1. The invention is prepared by using cefoperazone sodium and sulbactam sodium with specific specific rotation, and can improve the stability of the drug, especially the clarity, so that the clinical safety can be safely administered.

2. The preparation prepared by the cefoperazone sodium and sulbactam sodium of the present invention has good clarity and can be stored at room temperature for more than 18 months.

detailed description

The present invention will be further described in detail with reference to the preferred embodiments of the present invention. Limited.

Example 1

A pharmaceutical composition of cefoperazone sodium and sulbactam sodium comprising sulbactam sodium and cefoperazone sodium having a specific rotation of -20°, and a mass ratio of cefoperazone sodium to sulbactam sodium of 1:1.

Example 2

A pharmaceutical composition of cefoperazone sodium and sulbactam sodium comprising sulbactam sodium and cefoperazone sodium having a specific rotation of -22°, and a mass ratio of cefoperazone sodium to sulbactam sodium is 1:1.

Example 3

A pharmaceutical composition of cefoperazone sodium and sulbactam sodium comprising sulbactam sodium and cefoperazone sodium having a specific rotation of -24°, a mass ratio of cefoperazone sodium to sulbactam sodium of 2:1.

Example 4

A pharmaceutical composition of cefoperazone sodium and sulbactam sodium comprising sulbactam sodium having a specific rotation of +228° and cefoperazone sodium having a specific rotation of -20°, and a mass ratio of cefoperazone sodium to sulbactam sodium of 1:1.

Example 5

A pharmaceutical composition of cefoperazone sodium and sulbactam sodium comprising sulbactam sodium having a specific rotation of +223° and cefoperazone sodium having a specific rotation of -22°, and a mass ratio of cefoperazone sodium to sulbactam sodium of 1:1.

Example 6

A pharmaceutical composition of cefoperazone sodium and sulbactam sodium comprising sulbactam sodium having a specific rotation of +225° and cefoperazone sodium having a specific rotation of -24°, and a mass ratio of cefoperazone sodium to sulbactam sodium of 2:1.

Example 7

The preparation method of cefoperazone sodium is as follows: (1) stirring the sodium acetate solution to the cefoperazone acid acetone solution at 0-5 ° C, the pH value is controlled at 6.5-6.9; (2) after the sodium acetate is added, the solution is heated again. To 10-25 degrees Celsius, the sodium bicarbonate solution is stirred into the cefoperazone acid acetone solution, the pH value is controlled at 6.5-6.9; (3) after the reaction is filtered, it is divided into three stages, and the first stage is to control the temperature of the filtrate. At 18-20 ° C, add acetone to the mixture and add 5-10 min. In the second stage, stir at 30-20 ° C for 30-60 min. After the crystals are precipitated, add acetone and add dropwise for 10-15 min. In the third stage, Stir at 10-15 ° C for 30-60 min, and finally wash the crystal; the molar fraction of sodium acetate is 10-15% of cefoperazone acid, and the molar fraction of sodium bicarbonate is 85-90 of ceftitone %.

In the first step of step (3), the stirring speed is 300-350r/min, and the second stage is stirred. The speed is 200-250r/min, and the third stage stirring speed is 100-150r/min.

The molar fraction of sodium acetate may be 10%, 12% or 15% of cefoperazone. The molar fraction of sodium bicarbonate is 85%, 88% or 90% of cefoperazone acid.

The specific rotation of cefoperazone sodium prepared by the invention is -20 ° ~ 24 °, and the yield of cefoperazone sodium obtained is 94% or more, and the crystal particles are large.

Example 8

The preparation method of sulbactam sodium is as follows: (1) adding sulbactam to a mixed solution of sodium acetate and sodium hydrogencarbonate at 20-25 ° C, stirring constantly, and controlling the pH of the solution to be 5.5-6.0; After the end, add ethanol and stir for 10 minutes, then irradiate with infrared rays for 3-5min, and continue stirring for 30-60min to obtain crystals, wherein the molar fraction of sodium bicarbonate is 10-15% of sulbactam, and the molar of sodium acetate The fraction is 85-90% of sulbactam.

A small amount of sulbactam sodium crystals may be added after stirring for 10 minutes in step (2). The molar percentage of the sulbactam sodium crystals is 0.1-0.5% of the added sulbactam acid.

The obtained sulbactam sodium has a specific rotation of +223° to +228° and a yield of 92.8% or more, and the crystal particles are large.

Example 9

A pharmaceutical preparation comprising a pharmaceutical composition as described above and a pharmaceutically acceptable carrier.

The pharmaceutical preparation may be in the form of a pharmaceutically acceptable preparation such as an injection, a tablet, a capsule or the like.

Performance test: Accelerate the experimental method, and investigate the stability of the pharmaceutical composition at room temperature and humidity in the dark, and the content of related substances in the month of January, January, June and December, and investigate the injection. The clarity of the injection agent was stabilized (ie, the cefoperazone sodium sulbactam sodium was prepared as an injection and the clarity was examined at room temperature after 0 months, 1 month, 6 months, 12 months, and 18 months).

Table 1 Formulation:

Experimental results:

Table 2 Content of cefoperazone sodium (%)

project	0 month	January	June	December
Example 1	99.9	99.8	99.7	99.5
Example 2	99.8	99.7	99.5	99.3
Example 3	99.9	99.9	99.7	99.6

Example 4	99.7	99.7	99.6	99.4
Example 5	99.9	99.9	99.6	99.5
Example 6	100.1	99.9	99.8	99.7
Comparative example 1	99.8	99.2	98.2	96.4
Comparative example 2	99.7	99.1	98.2	96.1

Table 3 Content of sulbactam sodium (%)

project	0 month	January	June	December
Example 1	99.8	99.8	99.6	99.4
Example 2	99.8	99.8	99.5	99.2
Example 3	99.9	99.8	99.6	99.4
Example 4	99.6	99.6	99.4	99.3
Example 5	99.8	99.8	99.5	99.5
Example 6	99.8	99.8	99.6	99.5
Comparative example 1	99.7	99.3	98.1	96.2
Comparative example 2	99.6	98.9	97.3	96.0

Table 4 Content of related substances (%)

project	0 month	January	June	December
Example 1	0.62	0.62	0.68	0.71
Example 2	0.54	0.55	0.60	0.63

Example 3	0.50	0.51	0.54	0.57
Example 4	0.58	0.60	0.62	0.66
Example 5	0.42	0.43	0.46	0.46
Example 6	0.45	0.45	0.50	0.53
Comparative example 1	4.12	4.89	6.13	7.58
Comparative example 2	4.65	5.03	6.24	7.72

Table 5 clarity

project	0 month	January	June	December	August
Example 1	clarify	clarify	clarify	clarify	turbid
Example 2	clarify	clarify	clarify	clarify	clarify
Example 3	clarify	clarify	clarify	clarify	clarify
Example 4	clarify	clarify	clarify	clarify	clarify
Example 5	clarify	clarify	clarify	clarify	clarify
Example 6	clarify	clarify	clarify	clarify	clarify
Comparative example 1	clarify	clarify	clarify	turbid	turbid
Comparative example 2	clarify	clarify	clarify	turbid	turbid

It can be seen from Table 2 - Table 5 that the stability of cefoperazone sodium and sulbactam sodium of the present invention is good, and the content of cefoperazone sodium can be maintained at 99.3% -99.7% after 12 months, and the content of sulbactam sodium is maintained at 99.2%. -99.5%, the relevant substance content is below 0.71%; while the content of cefoperazone sodium and sulbactam sodium in the comparative examples are all reduced to below 96.5%, and the related substances are up to Up to 7.58% or more; the injection prepared by the cefoperazone sodium and sulbactam sodium prepared by the present invention has good clarity and can be stored at room temperature for more than 18 months.

As described above, it is an embodiment of the present invention. The present invention is not limited to the above embodiments, and any one skilled in the art should be aware of the structural changes made in the light of the present invention. Any technical solutions having the same or similar to the present invention fall within the protection scope of the present invention.

Claims (10)

1. A pharmaceutical composition of cefoperazone sodium and sulbactam sodium, characterized in that the mass ratio of cefoperazone sodium, cefoperazone sodium and sulbactam sodium containing sulbactam sodium and specific rotation of -20 ° to -24 ° is 1-2: 1.
2. The pharmaceutical composition according to claim 1, wherein the cefoperazone sodium has a specific rotation of from -22 to -24.
3. The pharmaceutical composition according to claim 3, wherein the specific rotation of cefoperazone sodium is -24, and the mass ratio of cefoperazone sodium to sulbactam sodium is 2:1.
4. The pharmaceutical composition according to claim 1, wherein the specific rotation of sulbactam sodium is from +223° to +228°.
5. The pharmaceutical composition according to claim 4, wherein the specific rotation of sulbactam sodium is from +223° to +225°.
6. The pharmaceutical composition according to claim 4 or 5, wherein the sulbactam sodium is prepared by: (1) adding sulbactam to a mixed solution of sodium acetate and sodium hydrogencarbonate at 20-25 ° C; Stirring constantly, and controlling the pH of the reaction solution to 5.5-6.0; (2) After the reaction is completed, add ethanol and stir for 10 minutes, then irradiate with infrared rays for 3-5 minutes, and continue stirring for 30-60 minutes to obtain crystals, wherein the molar of sodium acetate The fraction is 10-15% of sulbactam and the molar fraction of sodium bicarbonate is 85-90% of sulbactam.
7. The pharmaceutical composition according to claim 6, wherein a small amount of sulbactam sodium crystals are added after stirring for 10 minutes in the step (2), and the mole percentage of the sulbactam sodium crystals is added to the sulbactam acid. 0.1-0.5%.
8. The pharmaceutical composition according to any one of claims 1 to 5, wherein the cefoperazone sodium is prepared by: (1) stirring the sodium acetate solution to cefoperazone acid acetone at 0-5 ° C; In the liquid, the pH value is controlled at 6.5-6.9; (2) after the sodium acetate is added, the solution is heated to 10-25 degrees Celsius, and the sodium hydrogencarbonate solution is stirred and added to the cefoperazone acid acetone solution, and the pH is controlled. 6.5-6.9; (3) After the reaction is decolorized and filtered, it is divided into three stages. In the first stage, the temperature of the filtrate is controlled at 18-20 ° C, the acetone is added dropwise with stirring, and the mixture is added dropwise for 5-10 min; the second stage is stirred at 18-20 ° C. After 30-60 min, after the crystals are precipitated, the acetone is added dropwise with stirring, and the mixture is added dropwise for 10-15 min; the third stage is stirred at 10-15 ° C for 30-60 min, and the crystals are washed by filtration; the molar amount of sodium acetate and sodium hydrogencarbonate is obtained. The total amount is equal to the number of moles of acetophenone acid, the molar fraction of sodium acetate is 10-15% of cefoperazone acid, and the molar fraction of sodium hydrogencarbonate is 85-90% of cephalosporin acid.
9. The pharmaceutical composition according to claim 8, wherein the stirring speed in the first stage in the step (3) is 300-350 r/min, the stirring speed in the second stage is 200-250 r/min, and the stirring speed in the third stage is 100-150r/min.
10. A pharmaceutical preparation comprising the pharmaceutical composition according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.