WO2017117881A1 - Pharmaceutical composition of ampicillin sodium and sulbactam sodium - Google Patents

Abstract

The present invention discloses a pharmaceutical composition of ampicillin sodium and sulbactam sodium, wherein a sulbactam sodium is combined with an ampicillin sodium with a specific rotation of +264° to +269°, wherein the ampicillin sodium and the sulbactam sodium have a mass ratio of 2:1. The invention is produced by combining the sulbactam sodium with an ampicillin sodium with a selected specific rotation, thereby improving pharmaceutical stability and user safety of the pharmaceutical composition.

Description

Medicinal composition of ampicillin sodium and sulbactam sodium Technical field

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

Background technique

Ampicillin sodium and sulbactam sodium are medically injectable drugs. The aliases are sultacillin, Youlixin, Shuoxinxin, Youlixin, Shuxicillin, Ampicillin-Sulbactam. Its antibacterial mechanism is the same as that of penicillin G. It binds to the main penicillin binding protein (PBPs) of bacteria and interferes with the synthesis of bacterial cell wall to play an antibacterial role. Its action is characterized by a broad spectrum and is not resistant to penicillinase. It is suitable for the treatment of sensitive bacteria, including respiratory infections caused by β-lactamase producing strains, hepatobiliary infections, urinary tract infections, and skin and soft tissue infections. Treatment of aerobic and anaerobic mixed infections, especially abdominal infections and pelvic infections.

However, ampicillin sodium and sulbactam sodium are unstable during production and storage, and are easy to introduce impurities. For example, there are residual solvents in the production process, and other polymers are degraded during storage. These impurities may cause allergies in clinical use. Adverse reactions, which have a serious impact on the safety of medication, are not conducive to safe clinical use.

Summary of the invention

The invention provides a pharmaceutical composition of ampicillin sodium and sulbactam sodium, which is prepared by using ampicillin sodium and sulbactam sodium with specific specific rotation, can improve the stability of the drug and improve the safety of the drug. .

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

Medicinal composition of ampicillin sodium and sulbactam sodium, comprising sulbactam sodium and specific rotation It is composed of ampicillin sodium of +264° to +269°, wherein the mass ratio of ampicillin sodium to sulbactam sodium is 2:1.

The pharmaceutical composition of the invention is uniformly mixed with sulbactam sodium and ampicillin sodium with a specific rotation of +264° to +269°, and the process of mixing the powder is carried out in an existing preparation laboratory. The existing process is not repeated here.

When the inventors studied the stability test of ampicillin sodium and sulbactam sodium, it was found that the stability of ampicillin sodium and sulbactam sodium, which differed in specific rotation, was different, and the degradation efficiency was also different. The content and purity of ampicillin sodium and sulbactam sodium composed of ampicillin sodium and sulbactam sodium with a specific rotation of +264° to +269° are high, and the stability of the drug, especially the stability of the clarification, can be improved. Compared with the commercially available ampicillin sodium and sulbactam sodium, the clarity is more stable.

The specific rotation of ampicillin sodium is +266° to +269°.

The specific rotation of ampicillin sodium is +267°.

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

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

The preparation method of ampicillin sodium comprises the following steps: (1) dissolving ampicillin in acetone at 0-5 ° C, adding triethylamine with stirring to obtain ampicillin salt solution, and the molar ratio of ampicillin to triethylamine is 1 (1) at 0-5 ° C, the sodium acetate solution was added dropwise to the ampicillin salt solution, and stirring was continued; (3) After the sodium acetate solution was added dropwise, the ampicillin salt solution was heated to 10 -15 ° C, dropwise addition of sodium bicarbonate solution, and constantly Stirring for 30-60 min, washing and drying by suction filtration to obtain ampicillin sodium crystals. The total moles of sodium acetate and sodium hydrogencarbonate are equal to the moles of ampicillin sodium.

The factors affecting the stability of ampicillin sodium are mainly the temperature, particle size and packaging materials of the drug in the production process. The existing unstable factors for the production of ampicillin sodium may be that the product contains various chemical residues, and the residue may interact with ampicillin sodium to produce a water-insoluble, opalescent substance, resulting in unstable product clarity; Or it may be that the chemical residues contained in the product interact with the product package to produce a substance that is insoluble in water and opalescent.

The ampicillin sodium obtained by the preparation method of ampicillin sodium of 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. It can reach 92% or more, and the prepared specificity of ampicillin sodium can be controlled within +264° to +269°.

In the preparation process, the method uses acetone as a solvent, triethylamine as a reaction alkali agent, sodium acetate and sodium hydrogencarbonate as a salt forming agent, acetone is easily recovered as a solvent, and sodium acetate is first selected as a first salt forming agent, carbonic acid. As a second salt-forming agent, sodium hydrogen can obtain a high content (92% or more) and a low degradation product (0.5-2%) under certain temperature conditions. The role of sodium acetate as the first salt-forming agent is to control the crystal grain size of the starting ampicillin sodium. It is found that sodium acetate can be used as a salt-forming agent to obtain large particles of ampicillin sodium crystal under certain conditions, but The yield is not high, so in the present invention, the first step is to use sodium acetate as the first salt-forming agent, and after standing, to obtain a crystal nucleus which produces large crystal particles, and then sodium hydrogencarbonate as a second salt-forming salt. Agent, and finally, during crystallization, crystal particles are obtained due to the induction of the nucleus of the large crystal particles. Large ampicillin sodium, the product has high purity, and the yield can reach above 92%, and the specific rotation is within +264°~+269°.

By this method, in the crystallization process, it is also possible to increase the crystal grain size and increase the crystallization rate without adding additional seed crystals. Of course, on the basis of this law, the choice of additional seed crystals will also play a certain auxiliary role, and this technical solution naturally falls within the scope of protection of the present invention.

The number of moles of sodium acetate is 1-10% of the moles of ampicillin sodium.

The stirring speed in the step (2) was 30-60 r/min, and the dropping rate was 1-2 ml/min.

The stirring speed in the step (3) was 30-60 r/min, and the dropping rate was 1-2 ml/min. Regardless of the agitation in step (2) or the agitation in step (3), the agitation speed has an effect on the formation of crystal nuclei. Appropriate agitation speed can promote the growth of crystal nuclei, while faster, it will produce many fine crystals, which is not conducive to the formation of large particle crystals. The drop acceleration has a certain influence on the stability of the supersaturation of the crystallization solution. The drop acceleration in the present invention may also be a gradient drop acceleration, that is, at the beginning, it may be 1 ml/min, and the drop is added to the solution. In the case of two doses, the speed rose to 1.5 ml/min and the dropping rate was increased to 2 ml/min when added to the last third of the solution. This gradient drip acceleration promotes the formation of more and larger particles and also contributes to the stability of the final product.

In the step (3), 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 purpose of standing is to raise the crystal. Of course, when the crystallization is carried out until the final stage of the addition of the sodium hydrogencarbonate solution, it may be left to stand and stirred for another 30 to 60 minutes.

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 reaction solution to be 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 fraction of sodium acetate is 10-10 of sulbactam 15%, the molar fraction of sodium bicarbonate 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 and a pharmaceutically acceptable carrier.

It is a pharmaceutically acceptable type of preparation. The type of preparation may be an injection, a tablet, a capsule, or the like.

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

1. The pharmaceutical composition of ampicillin sodium and sulbactam sodium of the present invention can improve the stability of the drug, particularly the clarity of the drug, and improve the safety of the drug.

2. The product yield (92% or more) of ampicillin sodium prepared by the invention is high, the specific rotation is +264°~+269°, the crystal grain size is large, the stability is high, and the product can be stored for a long time, and has high The clarity of the solution is clear.

3. The product yield (92.8% or more) of the sulbactam sodium of the invention is high, the specific rotation is +223° to +228°, the crystal grain size is large, the stability is high, and the product can be stored for a long time, and has a high Solution clarity stability.

detailed description

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

The following chemical products are commercially available.

Example 1

A pharmaceutical composition of ampicillin sodium and sulbactam sodium, which is prepared by mixing sulbactam sodium and ampicillin sodium with a specific rotation of +264°, wherein the mass ratio of ampicillin sodium to sulbactam sodium is 2 :1.

Example 2

A pharmaceutical composition of ampicillin sodium and sulbactam sodium, which is prepared by mixing sulbactam sodium with ampicillin sodium having a specific rotation of +269°, wherein ampicillin sodium and sulbactam sodium are The ratio is 2:1.

Example 3

A pharmaceutical composition of ampicillin sodium and sulbactam sodium, which is prepared by mixing sulbactam sodium with ampicillin sodium having a specific rotation of +267°, wherein the mass ratio of ampicillin sodium to sulbactam sodium is 2 :1.

Example 4

The invention relates to a pharmaceutical composition of ampicillin sodium and sulbactam sodium, which is prepared by mixing sulbactam sodium and ampicillin sodium with a specific rotation degree of +266°, wherein the mass ratio of ampicillin sodium to sulbactam sodium is 2 :1.

Example 5

A pharmaceutical composition of ampicillin sodium and sulbactam sodium, which is prepared by mixing sulbactam sodium with a specific rotation of +223° and ampicillin sodium with a specific rotation of +264°, wherein ampicillin sodium and sulbac The mass ratio of Tan Sodium is 2:1.

Example 6

A pharmaceutical composition of ampicillin sodium and sulbactam sodium, which is prepared by mixing sulbactam sodium with a specific rotation of +225° and ampicillin sodium with a specific rotation of +269°, wherein ampicillin sodium and sulbac The mass ratio of Tan Sodium is 2:1.

Example 7

A pharmaceutical composition of ampicillin sodium and sulbactam sodium, which is prepared by mixing sulbactam sodium with a specific rotation of +228° and ampicillin sodium with a specific rotation of +265°, wherein ampicillin sodium and sulbac The mass ratio of Tan Sodium is 2:1.

Example 8

A pharmaceutical composition of ampicillin sodium and sulbactam sodium, which is prepared by mixing sulbactam sodium with a specific rotation of +225° and ampicillin sodium with a specific rotation of +267°, wherein ampicillin sodium and sulbac The mass ratio of Tan Sodium is 2:1.

Example 9

The preparation method of ampicillin sodium comprises the following steps: (1) dissolving ampicillin in acetone at 0-5 ° C, adding triethylamine with stirring to obtain ampicillin salt solution, and the molar ratio of ampicillin to triethylamine is 1 :1; (2) at 0-5 ° C, add sodium acetate solution to the ampicillin salt solution, the dropping rate is 1-2ml / min, and stirring constantly, the stirring speed is 30-60r / min; (3) After the sodium acetate solution is added dropwise, the ampicillin salt solution is heated to 10-15 ° C, sodium bicarbonate solution is added dropwise, and stirring is continued for 30-60 min, and washed with suction to obtain ampicillin sodium crystals, sodium acetate and The total moles of sodium bicarbonate are equal to the number of moles of ampicillin sodium.

The number of moles of sodium acetate may be 1%, 6% or 10% of the moles of ampicillin sodium.

The stirring speed in the step (3) was 30-60 r/min, and the dropping rate was 1-2 ml/min. In the step (3), 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 specific rotation of ampicillin sodium prepared by this method is between +264° and +269°, and the yield is above 92%. Ampicillin sodium with a specific rotation of +266° to +269° can be obtained by changing the process parameters. For example, adjust the concentration of sodium acetate solution to 8%, 5%, etc., adjust the stirring speed to 45r/min, 50r/min, and the drip acceleration can be adjusted stepwise with the crystallization process by 1/1.5/2ml/min.

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 reaction solution to be 5.5-6.0; After the reaction is completed, ethanol is added and stirred for 10 minutes, and then irradiated with infrared rays for 3-5 minutes, and stirring is continued for 30-60 minutes to obtain crystals, wherein the molar fraction of sodium acetate may be 10%, 12% or 15% of sulbactam acid. The molar fraction of sodium bicarbonate is 90%, 88% or 85% of sulbactam acid. 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.

The specific rotation of the sulbactam sodium prepared by the present invention is between +223° and +228°, and the yield obtained is 92.8% or more.

A pharmaceutical preparation comprising a pharmaceutical composition of ampicillin sodium and sulbactam sodium as in the previous examples. A pharmaceutically acceptable formulation type of the above pharmaceutical 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.

Performance test: Accelerate the experimental method, investigate the stability of the pharmaceutical composition in the humidity-protected glass rubber stopper at room temperature for 0 months, January, June, and December, and the content of related substances, and examine the clarity of the injectable agent. Stabilization experiment (ie, ampicillin sodium and sulbactam sodium were prepared as injections, and the clarity was examined at room temperature after 0 months, January, June, December, and 18 months).

Table 1 formula:

Experimental results:

Table 2: Content stability of ampicillin sodium (%)

project	0 month	January	June	December
Example 1	100.1	99.8	99.4	99.0
Example 2	99.8	99.7	99.5	99.2
Example 3	99.9	99.9	99.7	99.5
Example 4	99.8	99.6	99.3	99.0
Example 5	100.0	99.7	99.4	99.1
Example 6	99.7	99.7	99.5	99.1
Example 7	99.8	99.6	99.2	98.6
Example 8	99.9	99.9	99.7	99.6
Comparative example 1	99.8	99.5	98.5	97.2
Comparative example 2	100.0	99.4	98.1	96.8
Comparative example 3	99.8	99.1	97.9	96.2
Comparative example 4	99.9	99.2	98.3	96.1
Comparative example 5	99.7	99.1	98.3	95.9

Table 3: Stability of sulbactam sodium content (%)

project	0 month	January	June	December
Example 1	100.0	99.8	99.3	99.0
Example 2	99.7	99.7	99.2	98.7
Example 3	99.8	99.6	99.2	98.9
Example 4	99.9	99.7	99.4	99.0
Example 5	100.0	99.8	99.5	99.1
Example 6	99.8	99.8	99.6	99.2
Example 7	99.7	99.6	99.1	98.6
Example 8	100.1	99.9	99.7	99.3
Comparative example 1	100.0	99.8	98.7	97.3
Comparative example 2	99.8	99.5	98.5	97.1
Comparative example 3	99.9	99.6	98.3	96.8
Comparative example 4	99.8	99.7	98.6	97.5
Comparative example 5	99.6	99.2	98.1	96.7

Table 4: Relevant substance content (%)

project	0 month	January	June	December
Example 1	1.48	1.48	1.51	1.53
Example 2	1.47	1.49	1.50	1.53

Example 3	1.47	1.48	1.48	1.50
Example 4	1.49	1.50	1.52	1.58
Example 5	1.46	1.47	1.48	1.51
Example 6	1.52	1.53	1.54	1.57
Example 7	1.56	1.56	1.57	1.59
Example 8	1.47	1.47	1.49	1.52
Comparative example 1	1.63	1.65	1.68	0.75
Comparative example 2	3.68	3.70	4.20	5.12
Comparative example 3	3.63	3.63	4.11	5.10
Comparative example 4	3.69	3.72	4.86	5.72
Comparative example 5	3.73	3.76	4.92	5.97

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

Example 7	clarify	clarify	clarify	clarify	clarify
Example 8	clarify	clarify	clarify	clarify	clarify
Comparative example 1	clarify	clarify	clarify	turbid	turbid
Comparative example 2	clarify	clarify	clarify	turbid	turbid
Comparative example 3	clarify	clarify	clarify	turbid	turbid
Comparative example 4	clarify	clarify	clarify	turbid	turbid
Comparative example 5	clarify	clarify	clarify	turbid	turbid

It can be seen from the above Table 2 - Table 4 that both ampicillin sodium and sulbactam sodium prepared by the present invention have good drug stability, and the content of ampicillin sodium is 98.6% - 99.6% after storage for 12 months. The content of sulbactam sodium is 98.6%-99.3%, and the content of related substances is less than 1.59%. Compared with the comparative examples 1-5, it has higher stability and less content of related substances. Further, it can be seen from the results of the clarity test of Table 5 that the ampicillin sodium and sulbactam sodium of the present invention have high stability in production and storage, and can be stored 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 ampicillin sodium and sulbactam sodium, characterized by comprising sulbactam sodium and ampicillin sodium having a specific rotation of +264° to +269°, wherein ampicillin sodium and sulbactam sodium The mass ratio is 2:1.
2. The pharmaceutical composition according to claim 1, wherein the specific rotation of ampicillin sodium is from +266° to +269°.
3. The pharmaceutical composition according to claim 1, wherein the specific rotation of ampicillin sodium is +267°.
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 any one of claims 1 to 5, characterized in that the method for preparing ampicillin sodium comprises the following steps: (1) dissolving ampicillin in acetone at 0-5 ° C, stirring to add triethyl The amine is obtained as an ampicillin salt solution, and the molar ratio of ampicillin to triethylamine is 1:1; (2) at 0-5 ° C, the sodium acetate solution is added dropwise to the ampicillin salt solution, and stirring is continued; 3) After adding sodium acetate solution, the ampicillin salt solution is heated to 10-15 ° C, sodium bicarbonate solution is added dropwise, and stirring is continued for 30-60 min, and washed with suction to obtain ampicillin sodium crystals, acetic acid. The total moles of sodium and sodium bicarbonate are equal to the number of moles of ampicillin sodium.
7. The pharmaceutical composition according to claim 6, wherein the number of moles of sodium acetate is from 1 to 10% of the moles of ampicillin sodium.
8. The pharmaceutical composition according to claim 6, wherein the stirring speed in the step (2) and the step (3) is 30-60 r/min, and the dropping rate is 1-2 ml/min.
9. 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.
10. A pharmaceutical preparation comprising the pharmaceutical composition according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.