CN111499658A

CN111499658A - New indications of cefoperazone medicinal preparation for treating endometritis and other gynecological genital tract infections

Info

Publication number: CN111499658A
Application number: CN202010336043.2A
Authority: CN
Inventors: 薛晓斌; 傅苗青; 周白水; 王丽霞; 吴丰喆; 马庆双; 俞玉萍; 李秋荣; 应鹏
Original assignee: Guangdong Saifaluo Pharmaceutical Co ltd
Current assignee: GUANGDONG JINCHENG JINSU PHARMACY Co.,Ltd.
Priority date: 2020-04-25
Filing date: 2020-04-25
Publication date: 2020-08-07
Anticipated expiration: 2040-04-25
Also published as: CN111499658B

Abstract

The invention discloses a new indication of a pharmaceutical preparation of cefperazone and cefperazone for treating endometritis and other gynecological genital tract infections. The cefoperazone sodium provided by the invention through a specific raw material production process has extremely low impurity content and obvious drug effect, is beneficial to improving the quality of preparation products, ensures the safety and effectiveness of the preparation products, and has the application in preparing medicines for treating endometritis and other gynecological genital tract infections.

Description

New indications of cefoperazone medicinal preparation for treating endometritis and other gynecological genital tract infections

Technical Field

The invention relates to a preparation technology of a medicament, in particular to a novel indication that a cefperazone medicinal preparation and a cefperazone medicinal preparation are used for treating endometritis and other gynecological genital tract infections.

Background

Cefoperazone sodium (Cefobid, C)₂₅H₂₆N₉NaO₈S₂) Is the third generation cephalosporin antibacterial drug. The chemical name is 7- (((4-ethyl-2, 3-dioxo-1-piperazinyl) carboxamido) (4-hydroxyphenyl) acetamido) -3- ((1-methyl-1H-tetrazol-5-yl) thiomethyl) -8-oxo-5-thio-1-azabicyclo (4.2.0) oct-2-ene-2-carboxylic acid sodium salt. The chemical structural formula is as follows:

cefoperazone sodium, marketed in 1988 by Pfizer, inc, which is currently available from Brand Name: pioneb CEFOBID is a third generation cephalosporin antibiotic, and the antibacterial action mechanism of the cephalosporin antibiotic is that the cephalosporin antibiotic achieves the bactericidal action by inhibiting the biosynthesis of sensitive bacterial cell wall mucopeptide in the bacterial reproduction period. Similar to other cephalosporins, the product can inhibit transpeptidation of transpeptidase in the final step of cell wall synthesis, so that cross-linking can not be formed, thereby affecting cell wall synthesis and leading to bacterial lysis and death.

The cefoperazone sodium has high stability to β lactamase generated by gram-positive bacteria and gram-negative bacteria, has high antibacterial activity to staphylococcus aureus, staphylococcus epidermidis, streptococcus pneumoniae, streptococcus pyogenes, streptococcus agalactiae, most hemolytic streptococcus, enterococcus and the like, has wide clinical application and good treatment effect, has high medical value, has the following indications and new application, is approved by the general administration of food and drug supervision and management in 2017, and obtains new increased indications by the first company, specifically as follows:

the single medicine use:

the product can be used for treating the following infections caused by sensitive bacteria:

upper and lower respiratory tract infections;

peritonitis, cholecystitis, cholangitis and other intra-abdominal infections;

sepsis;

meningitis;

skin and soft tissue infections;

pelvic inflammation, endometritis, gonorrhea and other genital tract infections;

upper and lower urinary tract infections;

bone and joint infections.

And (3) infection prevention:

the product can be used for preventing postoperative infection of patients with abdominal, gynecological, cardiovascular and orthopedic surgery.

Combined medication:

the product has wide antibacterial spectrum, and can be used alone to treat most infections. It can also be used in combination with other antibiotics when necessary. If combined with aminoglycoside antibiotics, the renal function of the patient should be monitored during the course of treatment.

Because cefoperazone sodium is used for injection, a plurality of adverse reactions are also generated. Although the cefoperazone sodium injection is a sterile preparation, the adverse reaction is greatly reduced, but the cefoperazone sodium stability is deteriorated and polymers are increased due to the residue or introduction of impurities in the synthesis, purification and preparation of the cefoperazone sodium, and finally the anaphylactic reaction is caused. In addition, some impurities can cause pharmacological harm to human bodies and are not beneficial to human health.

In view of the above problems, the present inventors have conducted quality studies on cefoperazone sodium, thereby providing a safe, effective and quality-controllable cefoperazone sodium and its formulation.

Disclosure of Invention

The inventor of the invention has conducted extensive research, and through improving the raw material synthesis process, provides cefoperazone sodium with high effective content and low impurity content, which is beneficial to the stability of the raw material and the improvement of the medication safety and the clinical treatment effect of the corresponding preparation, thereby completing the invention.

The invention aims to provide the following technical scheme:

in a first aspect, a preparation method of cefoperazone sodium is provided, which comprises the following steps:

step 1), dissolving 7-ACA (7-aminocephalosporanic acid) and MTT (1-methyl-5-mercaptotetrazole) in a reaction solvent, reacting under the action of a catalyst, adding ammonia water to an isoelectric point after the reaction is finished, and crystallizing to obtain 7-ACT (3- [ (1-methyl-1H-4-oxazole) -5-mercapto ] -7-aminocephalosporanic acid);

step 2), 7-ACT reacts with oxypiperazine acid chloride (namely D- (-) -2- [ (4-ethyl-2, 3-dioxo-1-piperazinyl) amido ] -2- (4-hydroxyphenyl) acetic acid chloride) to synthesize cefoperazone acid;

step 3), reacting cefoperazone acid with sodium salt, and obtaining cefoperazone sodium by elution and crystallization

In a second aspect, the present invention also provides cefoperazone sodium prepared by the above method, wherein the weight content of the effective components is more than 98.00%, and the cefoperazone sodium comprises impurity a:

the weight content is not higher than 0.2%; and/or the presence of a gas in the gas,

the impurity B is a nitrogen-containing impurity,

the weight content is not higher than 0.2%.

In a third aspect, the single preparation of cefoperazone sodium comprises cefoperazone sodium or cefoperazone sodium prepared by the above preparation method as an active ingredient, and the preparation types comprise injection, granule, tablet, dripping pill and capsule, preferably injection.

In a fourth aspect, the compound preparation of cefoperazone sodium comprises cefoperazone sodium or cefoperazone sodium prepared by the preparation method as an active ingredient, and the compound preparation is prepared from the following raw material ingredients in parts by mass:

10 parts of cefoperazone sodium;

1-10 parts of a synergist;

wherein the synergist is abamectin, sulbactam, tazobactam or sodium salt thereof;

optionally, the compound preparation can also comprise pharmaceutically acceptable auxiliary materials and/or pharmaceutically active substances without incompatibility, wherein the auxiliary materials are preferably one or more of osmotic pressure regulator, pH regulator and antioxidant.

In a fifth aspect, the cefoperazone sodium prepared by the preparation method, the single preparation of the cefoperazone sodium, or the compound preparation of the cefoperazone sodium are used in the aspect of medicines for treating endometritis and other new indications of gynecological genital tract infection.

The cefperazone pharmaceutical preparation for treating endometritis and other new indications of gynecological genital tract infection provided by the invention has the following beneficial effects:

(1) according to the synthesis method of cefoperazone sodium provided by the invention, the high content and low impurity of the raw material are effectively ensured, the stability of the raw material is high, and the use safety and the clinical treatment effect of the corresponding preparation are favorably improved;

(2) the cefoperazone sodium and the preparation thereof provided by the invention have good stability, are beneficial to long-term storage and placement, and reduce various impurities generated by degradation, thereby reducing the clinical sensitization risk;

(3) according to the preparation method of cefoperazone sodium, the prepared cefoperazone sodium has good fluidity and is beneficial to uniformly mixing with auxiliary materials or other medicines;

(4) the cefoperazone sodium and the preparation thereof provided by the invention have the application of effectively preparing the medicines for treating endometritis and other gynecological genital tract infections.

Detailed Description

The present invention is further described below in terms of specific embodiments, and features and advantages of the present invention will become apparent as the description proceeds.

The invention aims to provide cefoperazone sodium, and requires an effective component of cefoperazone sodium (C)₂₅H₂₆N₉NaO₈S₂) The content of (b) is not less than 98.00%, preferably not less than 99.00%, more preferably not less than 99.50%, most preferably not less than 99.90% by mass. Therefore, the inventor of the invention has conducted long-term intensive research on a synthesis process of cefoperazone sodium, so as to improve the effective content of cefoperazone sodium in cefoperazone sodium by obtaining cefoperazone sodium with low impurity content, and further facilitate solving the problems of stability and medication safety of related preparations.

The inventor carries out a great deal of analysis and summary on sample impurities in cefoperazone sodium for injection produced by a plurality of manufacturers, and finds that the impurities which are more commonly present in the product comprise:

the impurity A is a nitrogen-containing impurity,

which is the residue of the raw material 7-ACA (7-aminocephalosporanic acid) in the product. The reason for the residue in the product may be: (a)7-ACT can not completely react with MTT (1-methyl-5-mercapto tetrazole) to generate 7-ACT; (b) the purification effect of the final product is not ideal.

The impurity B is a nitrogen-containing impurity,

it is an impurity generated by the reaction of 7-ACA and MTT

Reacting with the chloride of the oxypiperazine acid.

The impurity A and the impurity B have the same mother nucleus structure as the cefoperazone sodium, and have higher possibility of biological activity. It has been proved that the relatively strong sensitization of the impurity a to guinea pigs results in a very high probability of developing sensitization to the human body, whereas the current studies on the toxic and side effects of the impurity B are very few, and although the effect on the organism is not clear, it is still of practical significance to reduce the residue of the impurity B due to the high residual content (higher than the residue of the impurity a).

Therefore, the invention improves the synthesis process of cefoperazone sodium, and comprises the following steps:

and 3) reacting the cefoperazone acid with a sodium salt, and performing elution crystallization to obtain cefoperazone sodium.

In step 1) of the present invention, the reaction formula is represented by the following formula (1):

it was found that an anhydrous environment was advantageous for the reaction in step 1). In the presence of moisture, the conversion of 7-ACA is reduced and the yield of 7-ACT product is suppressed. In order to solve the defect, a dehydrating agent can be added into the reaction system, and the dehydrating agent can be one or more of inorganic salt dehydrating agents such as anhydrous magnesium chloride, anhydrous magnesium sulfate or anhydrous sodium sulfate, pyridine, or a combination of pyridine and the inorganic salt dehydrating agents.

In the presence of a dehydrating agent, in the step 1), the reaction solvent and the dehydrating agent are mixed in advance, and then the 7-ACA, the MTT and the catalyst are added into the reaction solvent for reaction. This mode is in advance to the reaction solvent dewatering, and the reaction raw materials is in anhydrous environment all the time, does benefit to the improvement of reaction efficiency.

As is clear from the formula (1), 7-ACA and MTT are equivalent reactions, and it is preferable that one of the raw materials is in excess in order to promote the reaction. Since 7-ACA has been proved to have strong sensitization to guinea pigs, the possibility of generating sensitization to human body is very high, and meanwhile, if the reaction speed is slow and the 7-ACA is excessive in the reaction process, 7-ACA self-condensation (amino and ester group reaction) is easily caused, and the possibility of generating high molecular polymer is generated, and the high molecular polymer is one of the main reasons for causing anaphylactic reaction, so that the degree and dosage of 7-ACA reaction are related to the post-treatment difficulty, the safety of products and the possibility of derivative side reaction. Therefore, the present invention selects a slight excess of MTT.

In combination with reaction conditions such as the selection of a reaction solvent and a catalyst, in order to realize high-efficiency conversion of a reaction product and reduce the residual amount of reaction raw materials in the product, the molar ratio of the 7-ACA to the MTT is determined to be 1: (1.05-1.30), preferably 1 (1.10-1.20).

Research shows that boron trifluoride (BF) is commonly used as the catalyst for the reaction in the step 1)₃) The yield of the-diethyl ether complex can reach 82 percent, but the obtained 7-ACT is light yellow and has poor quality, and the crude product is difficult to refine when the compound is used for preparing cefoperazone. If concentrated sulfuric acid is used as a catalyst, although the obtained 7-ACT is white crystals and has good quality, the yield of the 7-ACT is only about 65% due to instability of the quaternary ring to strong acid, and the production loss is large.

To balance the yield and quality of 7-ACT,the inventor conducts re-screening on the catalyst, and after a large number of experiments, the catalyst adopts TiCl₄Tetrabutyl titanate compositions, in which TiCl₄And tetrabutyl titanate in a molar ratio of 1: (0.05 to 0.25), preferably 1: (0.1-0.2). The TiCl₄The selection of the tetrabutyl titanate composite catalyst has the following characteristics compared with boron trifluoride-diethyl ether complex or concentrated sulfuric acid:

(a) the 7-ACT has good quality and high yield: with TiCl₄The obtained 7-ACT is white crystal, has good quality, is easy to separate from liquid phase and is beneficial to the purification of final products; the yield is high and reaches more than 90 percent;

(b) solve the problem of BF₃The pollution problem of (2): BF (BF) generator₃-diethyl ether complex, BF₃The catalyst is extremely toxic, explosive, highly corrosive and difficult to store, is not consumed when used as a catalyst for reaction, and is finally discharged out of a reaction system in the form of wastewater. The prior art method for treating fluorine-containing wastewater (calcium salt method, high-price metal coagulation method or magnesium hydroxide adsorption treatment method) can not be used for BF-containing wastewater at all₃Treatment of waste water (due to BF-containing)₃F in the waste water is not equal to F^-In the form of ions). The existing normal temperature and pressure method for removing BF₃Although the treatment cost is low, the period is long and the occupied area is large; the high-temperature high-pressure method has high treatment efficiency, but the treatment cost is high.

TiCl₄The price is low, and the catalyst has catalytic action on the reaction; containing TiCl₄The wastewater treatment method is simple; albeit TiCl₄The autocatalytic properties are not good, but TiCl₄When the titanium dioxide is used in combination with tetrabutyl titanate, TiCl can be greatly improved₄The catalyst performance of the catalyst is better to promote the reaction, and the reaction efficiency of the combination of the catalyst and the catalyst is even higher than that of BF₃The efficiency of the reaction as a catalyst.

TiCl compared to conventional boron trifluoride-diethyl ether complexes or concentrated sulfuric acid₄The tetrabutyl titanate catalyst has higher catalytic efficiency and is expressed by high conversion rate and high reaction rate of reaction raw materials, which is equivalent to improving the stability of the reaction raw materials and avoiding the self-condensation product of 7-ACAHigh molecular polymer impurities are generated, and the residue of reaction raw materials is reduced.

The inventors have also found that when pyridine is included in the dehydrating agent, it reacts with TiCl₄The tetrabutyl titanate composite catalyst has a synergistic effect:

(a)TiCl₄hydrochloric acid gas is easily generated through decomposition, the reaction is influenced, the generated HCl enables 7-ACT to generate ring-opening degradation impurities, pyridine can be used as an acid-binding agent to be complexed with the hydrochloric acid gas, and the amount of the hydrochloric acid in a reaction system is reduced;

(b) the reaction of the 7-ACA and the MTT is nucleophilic substitution reaction, sulfydryl (-SH) and adjacent N in the MTT resonate, and the existence of pyridine is favorable for capturing hydrogen on the-SH, so that S is exposed and carries negative charges, and the adjacent C of an ester group on the 7-ACA is more easily attacked, thereby improving the reaction efficiency, correspondingly improving the conversion rate of the 7-ACA and reducing the generation of impurities B.

In the present invention, the amount of the catalyst is TiCl in the catalyst₄In terms of molar ratio to 7-ACA, TiCl is added to ensure the catalytic effect and to effectively control the amount of catalyst added₄The molar ratio of the compound to 7-ACA is (1.0-1.2): 1, preferably 1.1: 1.

When the dehydrating agent contains pyridine, the dosage of the pyridine is (1.05-1.25) by the molar ratio of the pyridine to 7-ACT: 1, preferably (1.1-1.2): 1.

in the step 1), after the 7-ACA and the MTT completely react, filtering the reaction system, cooling the filtered system to below 5 ℃, dropwise adding ammonia water (preferably 5-10% ammonia water) to an isoelectric point, crystallizing, performing suction filtration, and drying to obtain the 7-ACT.

Inorganic dehydrating agent or salified pyridine is filtered by filtering operation, then ammonia water is adopted to adjust pH to isoelectric point at low temperature, 7-ACT can be separated out without precipitating other impurities, and weak base does not affect the stability of the four-membered ring in 7-ACT.

In step 1), the reaction solvent is acetonitrile. Acetonitrile is used as a reaction solvent, when 7-ACT is crystallized and separated out, the acetonitrile-water system is beneficial to precipitation and separation, and the obtained precipitate is white particles, is free from agglomeration and adhesion and is convenient to filter.

And step 2), reacting the 7-ACT with the oxypiperazine acid chloride to synthesize the cefoperazone acid. The reaction formula is shown as the following formula (2):

in the step 2), 7-ACT is added to the oxypiperazine acid chloride in batches at the temperature of-20 to-25 ℃, or the 7-ACT is dissolved in a solvent and then added in a dropwise manner, the dropwise addition time is 0.5 to 1.0 hour, the reaction is carried out for 3.0 to 4.0 hours under the condition of heat preservation after the dropwise addition is finished, and trimethylchlorosilane is introduced into a reaction system to remove water contained in the reaction system. After the reaction is finished, heating to 15-20 ℃, adding sodium bicarbonate for neutralization reaction, and then adding water for continuous reaction for 1-2 hours. And (3) dropwise adding the reacted system into ice water at 0-5 ℃, separating out white solid, and filtering to obtain a cefoperazone acid crude product.

Further comprises a purification step of the crude cefoperazone acid: dissolving the cefoperazone acid crude product in N, N-dimethylformamide, adding water into the system, wherein the water addition amount is about 1/2 volume of the N, N-dimethylformamide, uniformly stirring, adding a salt forming agent sodium bicarbonate for reaction, acidifying by hydrochloric acid after the reaction is finished, adding water (reducing the solubility of the cefoperazone acid), cooling to 0-5 ℃ for crystallization, filtering, washing with water, and drying to obtain a white high-purity cefoperazone acid crystal.

And 3) reacting the cefoperazone acid with a sodium salt, and performing elution crystallization to obtain cefoperazone sodium. The reaction formula is shown as the following formula (3):

in the step 3), dissolving cefoperazone acid in a crystallization solvent (such as acetone), dropwise adding a sodium salt water solution until the pH value is stabilized at 6.0-7.0, adding activated carbon for decoloring after the sodium salt is added, filtering, cooling the filtrate, dropwise adding a solvent (crystallization solvent) for reducing the solubility of a solute, and performing dissolution crystallization to obtain the final cefoperazone sodium.

The quality of cefoperazone sodium is mainly embodied by the aspects of clarity, main content, granularity of crystal, crystal form and the like of the product. The quality of the product depends not only on the synthesis method of cefoperazone sodium, but also on the implementation of the final crystallization method. The domestic crystallization method for cefoperazone sodium mainly comprises a freeze-drying method, a dissolution crystallization method and a reaction crystallization method (few literature reports): the freeze-drying method is simple to operate, the yield is high, but the product is amorphous powder and has poor stability (generally, gradual degradation phenomenon occurs in three months), so that manufacturers adopting the method in China are fewer and fewer; the cefoperazone sodium obtained by the elution crystallization method is a crystal, is mostly a needle-shaped crystal, and has good stability (the content is still stable in one year). Therefore, the invention adopts the elution crystallization to obtain the cefoperazone sodium.

The cefoperazone sodium which is a marketed drug is often combined with a synergist such as sulbactam sodium, the mixing uniformity of the cefoperazone sodium and the synergist can also influence the medication effect, and the mixing uniformity is related to the crystal form and the crystal grains of the cefoperazone sodium. The cefoperazone sodium crystal obtained by the solvent crystallization method sometimes has the problem that the mixing uniformity is influenced by small particle size or serious agglomeration.

In order to obtain cefoperazone sodium with higher purity and being beneficial to mixing, the invention carries out experimental research on a dissolution crystallization method. For the sodium salt which reacts with cefoperazone acid to generate cefoperazone sodium, the alkalinity of the sodium salt cannot be too strong so as to avoid the problems of product four-membered ring opening, generation of colloidal substances and reduction of product yield; if cefoperazone is precipitated with sodium acetate or sodium bicarbonate, crystals can be produced, but the clarity of the final product is not good. The inventor tries to use sodium isooctanoate, and finds that the use of sodium isooctanoate is easy to obtain product crystals, and the clarity and the yield of the obtained product are high.

The invention further adopts a gradient cooling crystallization method. The crystallization process is as follows:

cooling the filtrate to 15-20 ℃, and dripping 1/3 crystallization solvent ethanol at the stirring speed of 150-200 revolutions per minute for 0.5-1.0 h, wherein no crystal grains are generated;

cooling the filtrate to 5-10 ℃, adding sodium chloride crystals to induce crystallization, dropwise adding the residual crystallization solvent ethanol again, wherein the dropwise adding time is 2.0-2.5 h, and the stirring speed is 80-100 r/min, so that crystals are gradually precipitated;

cooling to-5-0 ℃, stopping stirring, and growing crystals for 1.5-2.5 h to provide enough time for crystal growth and crystal form adjustment;

the ratio of the total volume of the crystallization solvent ethanol to the mass of the cefoperazone sodium is (4-5): 1.

in the crystallization process, the nucleation and growth of particles can be greatly influenced by fluid conditions, the stirring speed is low, trace mixing is insufficient, the local supersaturation degree is too high, and the distribution in the solution is limited; too high stirring speed increases the turbulence shear stress in the suspension, easily causes the crushing of particles, and leads to uneven particle size distribution of the product. At the temperature of 15-20 ℃, in order to form a supersaturation stage, the stirring speed is faster at 150-200 r/min, so that a uniform solution is obtained; at the temperature of 5-10 ℃, in order to generate crystals, the stirring speed is reduced to 80-100 r/min, and at a lower stirring speed, the crystals can be prevented from being broken, so that the crystals with larger particles and narrower particle size distribution can be obtained.

In the absence of crystals (spontaneous nucleation), the generation of crystal nuclei is particularly sensitive to the change of supersaturation degree, and a large amount of crystal nuclei are generated and are easy to form aggregates when the addition speed of a crystallization solvent is too high; if the addition speed of the crystallization solvent is too slow, the crystal particle size is too large, and the crystallization efficiency is affected. Therefore, in the crystallization stage, sodium chloride crystals are added as seed crystals, the induction period is shortened, the sensitivity of crystal nucleus generation to supersaturation is reduced, crystallization is performed at low saturation, crystals with larger and uniform particles are obtained, the dropping time (2.0-2.5 h) of the crystallization solvent is determined on the premise of setting the concentration of cefoperazone and the dosage of the crystallization solvent, the aggregation of the crystal nucleus is avoided, and the crystallization efficiency is improved.

The smaller the particle size and the larger the surface area due to the same mass of seed crystals, the more growth points are provided and the smaller the primary particle size of the product. Therefore, the sodium chloride with the particle size of 30-60 meshes is selected, the seed crystal particles are favorable for avoiding the problems of agglomeration and poor fluidity caused by undersize crystal particles of the product, difficulty in later-stage mixing and low stability, and the problem of large difference among bottles after bottling caused by oversize crystal particles can be avoided by combining the dropping speed and the stirring speed.

More than 50% of cefoperazone sodium obtained in the condition range is granular crystals with the grain diameter of 40-86 mu m, the grain size uniformity is high, and the cefoperazone sodium is favorably mixed with a synergist.

The inventor carries out impurity analysis on cefoperazone sodium prepared by the method, wherein the impurity A is residual raw material 7-ACA, and the content of the impurity A is not higher than 0.2% by weight, or not higher than 0.1% by weight, preferably not higher than 0.05% by weight, and more preferably not higher than 0.01% by weight;

the impurity B is generated by the reaction of 7-ACA and MTT

And the content of the compound is not higher than 0.2 percent, or not higher than 0.1 percent, or not higher than 0.05 percent by weight.

In the invention, as for the impurity A, the MTT is selected to be in slight excess, the moisture in a system is reduced, the selection of a catalyst is improved, the reaction is promoted, and the impurity A is controlled by combining with the final purification step;

as for the impurity B, the reaction is promoted and the reaction selectivity of the 7-ACA is improved at the same time by selecting the catalyst and matching the catalyst with an organic base dehydrating agent (pyridine), so that the generation of the impurity B is inhibited.

In the invention, the cefoperazone sodium crystal obtained by the method is used for preparing a single preparation, which can be any pharmaceutically acceptable preparation type, including injections, granules, tablets, dripping pills, capsules and the like, or other medically usable carriers, preferably injections.

In the invention, the cefoperazone sodium obtained by the method can be combined with a synergist to prepare a compound preparation, which can be any pharmaceutically acceptable preparation type, including injections, tablets, capsules and the like or loaded on other pharmaceutically usable carriers, preferably injections.

In a preferred embodiment, the compound preparation is prepared from the following raw material ingredients in parts by weight:

10 parts of cefoperazone sodium;

1-10 parts of a synergist.

Wherein the synergist is abamectin, sulbactam, tazobactam or sodium salt thereof.

Preferably, the compound preparation can also comprise auxiliary materials and/or pharmaceutically active substances without incompatibility in pharmacy, wherein the auxiliary materials are preferably one or more of osmotic pressure regulators, pH regulators and antioxidants. The osmotic pressure regulator is sodium chloride or glucose; the pH regulator comprises one or more of sodium hydroxide, sodium chloride, phosphoric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate and sodium acetate; the antioxidant is one or more of vitamin C, sodium sulfite and sodium pyrosulfite.

In the invention, the cefoperazone sodium compound preparation is obtained by a mixed crystal method, and comprises the following steps: accurately weighing cefoperazone sodium according to the formula, or mixing with adjuvants to obtain cefoperazone sodium mixture, accurately weighing synergist according to the formula, mixing well, metering according to set specification based on cefoperazone, sealing and packaging.

According to the cefoperazone sodium and the single preparation or the compound preparation of the cefoperazone sodium provided by the invention, the application in preparing the medicine for treating endometritis and other gynecological genital tract infection is provided.

In the present invention, the other gynecological genital tract infections include vaginitis.

Examples

The invention is further illustrated by the following specific preferred examples. These examples are illustrative only and should not be construed as limiting the invention.

Example 1 Synthesis of cefoperazone sodium

Step 1), 272g (1.0mol, M ═ 272.28)7-ACA, 122g (1.05mol, M ═ 116.14) MTT were dissolved in acetonitrile (820M L) containing 83.1g pyridine (1.05mol, M ═ 79.10), the temperature was reduced to 5 ℃, 208.6g TiCl was added₄(1.1mol, M. cndot. 189.68) -37.4 g of tetrabutyl titanate (0.11mol, M. cndot. 340.3) as catalyst, the temperature was raised to 30 ℃ and stirring was carried outAnd after the reaction is finished for 3 hours, filtering, cooling the filtrate to 0-5 ℃, dropwise adding 10% ammonia water to an isoelectric point while stirring, allowing crystallization to occur, continuously stirring for 1 hour, performing suction filtration, washing with acetone, and drying to obtain white solid powder 7-ACT (M is 328.37)327.4g, wherein the yield is 98.0%, and the content of HP L C is more than 98.3%.

Step 2), 353.8g of oxypiperazine acid chloride (1.0mol, M is 353.76) is dissolved in 1100M L N, N-dimethylformamide, the mixture is stirred and cooled to-20 ℃, the prepared 7-ACT is dissolved in 1100M L N, N-dimethylformamide, 34M L of trimethylchlorosilane is added under ice-bath cooling to remove water contained in the mixture, the mixture is stirred for 1h, the mixture is dropwise added into the oxypiperazine acid chloride within 40min, the temperature is kept between minus 20 ℃ and minus 25 ℃, the reaction is continued for 3h, after the reaction is finished, the temperature is increased to 15 ℃, sodium bicarbonate (252g, 3.0mol) is added, the mixture is stirred uniformly, 1200M L of water is added within 15min, the mixture is stirred for 2h, the system after the reaction is dropwise added into ice water at 0-5 ℃, white solid is separated out, and a crude product of the cefoperazone acid is obtained after filtering.

Dissolving the crude cefoperazone acid in a mixed solution of 1000M L N, N-dimethylformamide and 500M L of water, adding 458g (5.4mol) of sodium bicarbonate while stirring until the solution is dissolved, heating to 30 ℃, adjusting the pH value to 2 with hydrochloric acid, keeping the temperature and stirring for 1h, adding 1100M L of water after the temperature is kept, cooling to 0-5 ℃ for crystallization, performing suction filtration, washing with water, and drying to obtain white crystals, namely 484.5g (M645.67) of purified cefoperazone acid.

Step 3), dissolving the prepared cefoperazone acid in 500m L acetone, dropwise adding 10.0 wt% sodium isooctanoate solution at 25 ℃ under stirring until the pH value is stabilized at 6.6, adding 7.5g of activated carbon for decolorization after the addition is finished, filtering, cooling the filtrate to 15 ℃, dropwise adding 800m L ethanol under the stirring speed of 200r/min, wherein the dropwise adding time is 0.5 h;

then the temperature is reduced to 5 ℃, 1600m L ethanol is added dropwise, the dropwise adding time is 2.0h, and the stirring speed is 80 r/min;

and finally, cooling to-5-0 ℃, stopping stirring, growing crystals for 1.5h, filtering, washing the product with 240M of L acetone for three times, and drying in vacuum to obtain 481.4g of white cefoperazone sodium (M ═ 667.65) blocky crystal particles, wherein the particle size of more than 50% of the particles is 40-86 mu M, the yield is 71.80% based on 7-ACA, and the purity is 99.58%.

Example 2 Synthesis of cefoperazone sodium

The same synthesis as in example 1, except that: in step 1), step 1) was performed using 139.4g (1.20mol) of MTT, i.e., the molar ratio of 7-ACA to MTT was 1: 1.20.

Example 3 Synthesis of cefoperazone sodium

The same synthesis as in example 1, except that: in step 1), MTT 151g (1.30mol), i.e., the molar ratio of 7-ACA to MTT, was 1: 1.30.

Example 4 Synthesis of cefoperazone sodium

The same synthesis as in example 1, except that: in the step 1), TiCl is added dropwise to the reaction system in the step 1)₄189.7g (1.0mol), 68.1g (0.2mol) of tetrabutyl titanate, i.e. TiCl₄The mol ratio of the catalyst to the 7-ACA is 1:1, and TiCl is contained in the catalyst₄And tetrabutyl titanate in a molar ratio of 1: 0.2.

example 5 Synthesis of cefoperazone sodium

The same synthesis as in example 1, except that: in the step 3), in the step 1), the crystallization solvent in the dissolution crystallization process is acetone, and the obtained product is needle-shaped crystals.

Example 6 Synthesis of cefoperazone sodium

The same synthesis as in example 1, except that: in the step 3), in the step 1), sodium chloride seed crystals are not introduced in the elution crystallization process, and the obtained product is needle crystals.

Example 7 Synthesis of cefoperazone sodium

The same synthesis as in example 1, except that: in the step 3), in the step 1), the sodium chloride seed crystal introduced in the elution crystallization process is 100-200 meshes.

EXAMPLE 8 cefoperazone sodium-sulbactam sodium powder injection

The raw materials used were as follows:

300g of cefoperazone sodium based on cefoperazone;

sulbactam sodium Based on sulbactam 300g；

600 bottles, 1.0 g/bottle (based on cefoperazone)

The cefoperazone sodium-sulbactam sodium powder injection is prepared by the following production process:

accurately weighing cefoperazone sodium and sulbactam sodium according to the formula, mixing uniformly, loading according to the set specification, sealing and packaging to obtain the cefoperazone sodium sulbactam sodium tablet.

Example 9 Cefoperazone sodium-sulbactam sodium powder injection

The raw materials used were as follows:

300g of cefoperazone sodium based on cefoperazone;

sulbactam sodium Based on sulbactam meter 150g；

300 bottles, 1.0 g/bottle (based on cefoperazone)

The preparation method of cefoperazone sodium-sulbactam sodium powder injection is the same as that in example 8.

Comparative example

Comparative example 1 Synthesis of cefoperazone sodium

The same synthesis as in example 1, except that: in step 1), BF will be used₃-an ether catalyst obtained by reacting BF₃To saturation in diethyl ether, to give 282.9g of 7-ACT (M ═ 328.37) as a pale yellow solid, in 85.2% yield and with an HP L C content of greater than 98.9%.

Comparative example 2 Synthesis of cefoperazone sodium

The method is the same as the synthesis process of the embodiment 1, and is different from the synthesis process of the embodiment 1 only in that in the step 3), a conventional crystallization method is adopted, namely, the prepared cefoperazone acid is dissolved in 500m L acetone, 8 wt% of sodium bicarbonate solution is dropwise added under the stirring at 25 ℃, the pH value is always kept to be 6.6-6.8, the molar weight of the added sodium bicarbonate is 1.5 times of that of the cefoperazone acid, after the addition is finished, the temperature is reduced to 5 ℃, 5400m L acetone is dropwise added, the dropwise adding time is 1h, the stirring speed is 350r/min, the filtering is carried out, the washing is carried out by 250m L acetone, and the white cefoperazone sodium needle-shaped crystals are obtained after the vacuum drying.

Examples of the experiments

Experimental example 1 quality measurement of cefoperazone sodium

1.1) Long term test

According to the 2015 pharmacopoeiaCefoperazoneSodium under-test the results of examples 1, 2, 5, 6, 7, and comparative example 2CefoperazoneSodium content and related substances, storage conditions were 25. + -. 2 ℃ and relative humidity 60. + -. 10%, the results are given in Table 1 below

TABLE 1

Note: "not detected" means that the content is less than 0.01% by weight.

1.2 accelerated test)

Samples of examples 1, 2, 5, 6, 7 and comparative example 2 were taken and stored in commercial packages at a temperature of 40. + -. 2 ℃ and a relative humidity of 75. + -. 5% at the end of months 1, 3, 6 and 12 respectively, and the results are shown in Table 2 below.

TABLE 2

Experimental example 2 mixing uniformity determination

Cefoperazone sodium-sulbactam sodium formulations were prepared according to the method of example 8 using samples of cefoperazone sodium prepared in examples 1, 2, 5, 6, 7 and comparative example 2, respectively, and sulbactam sodium prepared by the zilutamide pharmaceutical manufacturer, according to the provisions set out in pharmacopeia mixing uniformity term of the 2015 edition.

The determination method comprises the following steps:

the feeding amount of the sulbactam sodium and the cefoperazone sodium is calculated according to the ratio of 1:1 of the sulbactam and the cefoperazone. The maximum mixing amount is 6kg and the rotating speed is 17r min based on 2/3 which is not more than the volume of the V-shaped high-efficiency mixer^-1. The mixing time is 20min, 15min is taken as a starting point, and if the result does not meet the regulation, the mixing time is increased by 5 min. After mixing, sampling at 3 different points for content determination, and calculating an average value.

The determination standard is as follows:

mixing the two raw materialsAfter the mixing, the content of the cefoperazone after the mixing (calculated according to anhydrous substance) is calculated to be not lower than the specification of 2015 edition of Chinese pharmacopoeia, and each lmg contains the cefoperazone C₂₅H₂₇N₉O₈S₂) And sulbactam (C)₈H₁₁N₅Good S) respectively should not be less than 435 μ g and 445 μ g (ratio of 1:1) or respectively should not be less than 588 μ g and 294 μ g (ratio of 2: 1); calculated according to the average loading, the cefoperazone content is 90.0-110.0% of the marked amount.

The results of the measurement are shown in table 3 below:

TABLE 3

Examples/comparative examples	Cefoperazone content
		Example 1	97.6％
Example 2	96.9％
		Example 5	92.3％
Example 6	93.1％
		Example 7	95.2％
Comparative example 2	90.7％

Experimental example 3 insoluble microparticle assay

The cefoperazone sodium preparation prepared in examples 1-7 was subjected to insoluble particle study according to the 2015 pharmacopoeia, and the results are shown in table 4 below:

TABLE 4

Experimental example 4 pharmacological study

Experimental example 4.1 therapeutic Effect test in mice

Healthy female mice (4 weeks old, 18-20g in weight) were inoculated with Escherichia coli 1 x 10 in the vagina and uterus, respectively⁶Model mice with vaginal or endometrial infections were obtained by constructing mouse vaginitis and endometritis models.

60 vaginally infected mice were selected and divided into placebo and observation groups, each of which contained 30 mice. Endometrium-infected mice were 60, divided into placebo and observation groups, and 30 mice were used per group.

The product prepared in example 1 was administered to the observation groups of vaginal infection and endometrial infection by tail vein injection with a body weight of 100mg/kg, respectively, at a frequency of 24 hours, while the placebo group was administered by tail vein injection (saline) at a frequency of 24 hours; after 3 days of treatment, mice were sacrificed, dissected, and vaginal and intrauterine infections were examined

Wherein, the judgment standard of healing, improvement, obvious effect and ineffectiveness of vaginal infection is as follows:

and (3) healing: vaginal secretion is not obvious, and vaginal mucosa has no hyperemia phenomenon;

improvement: the vaginal secretion is greatly reduced, and the vaginal mucosa is slightly congested;

the effect is shown: vaginal secretion reduction, vaginal mucosal congestion;

and (4) invalidation: vaginal secretion is increased and massive, and congestion of vulva and vaginal mucosa is obvious.

The treatment results for vaginally infected mice were:

observation group: 21 patients are cured, 5 patients are improved, 2 patients are obviously effective, and 2 patients are ineffective.

Placebo group: 2 patients are cured, 3 patients are improved, 7 patients are obviously effective, and 18 patients are ineffective.

The criteria for the recovery, improvement, obvious effect and ineffectiveness of the endometrium infection are as follows:

and (3) healing: the epithelial cells of the endometrial cavity are intact, and no inflammatory cells are gathered;

improvement: the epithelial cells in the endometrial cavity are mostly intact, and a small amount of inflammatory cells are gathered;

the effect is shown: the epithelial cells in the endometrial cavity are partially intact, and inflammatory cells aggregate;

and (4) invalidation: the endometrium has uterine injury phenomena such as epithelial cell deletion, sparseness, inflammatory cell aggregation and the like.

The therapeutic results for endometrium infected mice were:

observation group: the medicine is prepared by 20 healings, 4 improvement, 4 obvious effects and 2 ineffective effects.

Placebo group: 3 patients are cured, 3 patients are improved, 7 patients are obviously effective, and 17 patients are ineffective.

Experimental example 4.2 therapeutic Effect test on rats

Healthy female SD rats (190-⁷After injection, the abdomen was closed in layers to obtain model SD rats with endometrial infection.

100 endometrium-infected SD rats were selected and divided into placebo and observation groups, 50 rats each. The product prepared in example 1 was administered to the observation group of endometrial infection by tail vein injection at a body weight of 100mg/kg at a frequency of 24 hours, and to the placebo group by tail vein injection (saline) at a frequency of 24 hours; after 18 days of treatment, the rats were sacrificed, dissected and examined for intrauterine infection.

Wherein, the judgment criteria of recovery, improvement, obvious effect and ineffectiveness of the endometrium infection are as follows:

The therapeutic results for endometriotic SD rats were:

observation group: 37 patients are cured, 5 patients are improved, 2 patients are obviously effective, and 6 patients are ineffective.

Placebo group: 5 patients are cured, 7 patients are improved, 7 patients are obviously effective, and 31 patients are ineffective.

In conclusion, the observed group had significantly better efficacy than the placebo group.

EXAMPLE 4.3 sensitization test

300 healthy mice were used, and the product obtained in example 1 was administered by tail vein injection at a dose of 500mg/kg, and the mice were observed for symptoms such as agitation, flaring of nasal wings, nasal grasping, shortness of breath, shrugging of hair, limb spasm, and jumping, and whether or not they died was recorded.

The results are shown statistically as follows:

the total of 7 mice showing the above symptoms, and no mice died. The product obtained in example 1 is shown to be highly safe and less allergenic.

The invention has been described in detail with reference to specific embodiments and illustrative examples, but the description is not intended to be construed in a limiting sense. Those skilled in the art will appreciate that various equivalent substitutions, modifications or improvements may be made to the technical solution of the present invention and its embodiments without departing from the spirit and scope of the present invention, which fall within the scope of the present invention. The scope of the invention is defined by the appended claims.

Claims

1. A preparation method of cefoperazone sodium comprises the following steps:

2. The preparation method according to claim 1, wherein in step 1), a dehydrating agent is added to the reaction system, and the dehydrating agent can be an inorganic salt dehydrating agent, or pyridine, or a combination of an inorganic salt dehydrating agent and pyridine;

in the step 1), on the premise of existence of a dehydrating agent, a reaction solvent and the dehydrating agent are mixed in advance, and then the 7-ACA, the MTT and the catalyst are added into the reaction solvent for reaction.

3. The method according to claim 1, wherein the amount of 7-ACA to MTT used in step 1) is 1: (1.05-1.30), preferably 1 (1.10-1.20).

4. The preparation method according to claim 1, wherein in the step 3), the cefoperazone acid is dissolved in a crystallization solvent acetone, a sodium salt aqueous solution is added dropwise until the pH value is stabilized at 6.0-7.0, after the sodium salt is added, activated carbon is added for decolorization, the filtration is carried out, the filtrate is cooled, a crystallization solvent ethanol is added dropwise, and the final cefoperazone sodium is obtained by elution and crystallization.

5. Cefoperazone sodium, characterized in that it is prepared by the process according to any one of claims 1 to 4.

6. Cefoperazone sodium according to claim 5, wherein the content by weight of cefoperazone sodium as active ingredient is more than 98.00%, and comprises impurity A:

the weight content is not higher than 0.2%.

7. The cefoperazone sodium according to claim 5, further comprising:

the impurity B is a nitrogen-containing impurity,

the weight content is not higher than 0.2%.

8. A single preparation of cefoperazone sodium, which comprises cefoperazone sodium of any one of claims 5 to 7 or cefoperazone sodium prepared by the preparation method of any one of claims 1 to 4 as an active ingredient, wherein the preparation types comprise injections, granules, tablets, dripping pills and capsules, and preferably injections.

9. A compound preparation of cefoperazone sodium, which comprises cefoperazone sodium as an active ingredient in any one of claims 5 to 7 or prepared by the preparation method in any one of claims 1 to 4, wherein the compound preparation is prepared from the following raw materials in parts by mass:

10 parts of cefoperazone sodium;

1-10 parts of a synergist;

10. Use of cefoperazone sodium according to any one of claims 5 to 7, cefoperazone sodium prepared by the preparation method according to any one of claims 1 to 4, the single preparation of cefoperazone sodium according to claim 8, or the compound preparation of cefoperazone sodium according to claim 9 in the preparation of medicaments for treating endometritis and other new indications of gynecological genital tract infections.