Avibactam and cefamandole complex powder injection and preparation method thereof

Abstract

The application relates to a compound cefoperazone and avibactam powder injection and a preparation method thereof. The compound powder injection is obtained by uniformly mixing cefoperazone hydrochloride and avibactam sodium, tabletting and crushing. When the powder injection is prepared into an injection solution, the powder injection is easy to disperse and dissolve, is convenient to use, ensures the content of cefoperazone, is not prone to produce beta-lactamase bacterial drug resistance, and has a good market application prospect.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of compound powder injection, and particularly relates to an avibactin cefmenoxime compound powder injection for injection and a preparation method thereof. BACKGROUND

[0002] Cefmenoxime hydrochloride is difficult to dissolve in water. Generally, sodium carbonate or sodium bicarbonate is added for solubilization (such as patent 201310383089.X cefmenoxime powder injection adding sodium carbonate, ethylenediamine). Sodium carbonate and sodium bicarbonate are alkaline soluble in water. Studies have shown that the content of cefmenoxime in an alkaline solution is reduced. There is also a preparation of cefmenoxime particle size as small as possible (patent 201110040597.9) to facilitate its dissolution in water, but the particle size is too small, and it is easy to aggregate after long storage, thereby affecting the dissolution in use. Liu Jiajian et al. (patent 03117380.2) use alkaline amino acids instead of sodium carbonate in cefmenoxime powder injection, but the reason is that it is also an alkaline solution in water, which can affect the content of cefmenoxime.

[0003] In addition, with the large amount of use and abuse of antibacterial drugs, the problem of bacterial drug resistance is becoming increasingly serious. Bacteria can produce beta-lactamase, and the phenomenon of beta-lactamase-resistant bacteria is increasingly prominent. More than 200 kinds of beta-lactamase have been found. Therefore, the combination of antibiotics and lactamase inhibitors is a good way to solve the problem of drug-resistant bacteria. SUMMARY

[0004] The technical problem to be solved by the present application is to provide an avibactin cefmenoxime compound powder injection for injection and a preparation method thereof. The powder injection is easy to disperse and dissolve when preparing an injection solution, is convenient to use, ensures the content of cefmenoxime, and is not prone to produce beta-lactamase bacterial drug resistance, and has a good market application prospect.

[0005] The present application provides an avibactin cefmenoxime compound powder injection for injection, which is obtained by mixing cefmenoxime hydrochloride and avibactin sodium, tabletting and crushing.

[0006] In some embodiments, the weight ratio of cefmenoxime hydrochloride to avibactin sodium is 5-10:1-5.

[0007] The present application also provides a preparation method of an avibactin cefmenoxime compound powder injection for injection, which comprises the following steps:

[0008] Mixing cefmenoxime hydrochloride and avibactin sodium in a weight ratio of 5-10:1-5, adding them into a dry granulator for twice tabletting and granulation, and finally crushing to obtain an avibactin cefmenoxime compound powder injection for injection.

[0009] In some embodiments, the roller pressure of the dry granulator is 9-12 MPa, and the roller rotation speed is 90-110 rpm. In some embodiments, the roller pressure of the dry granulator is 9-12 MPa, and the roller rotation speed is 90-110 rpm.

[0010] In some embodiments, the pulverization is to a powder of more than 60 mesh.

[0011] The classic beta-lactamase inhibitors all belong to beta-lactam compounds, and the enzyme inhibition mechanisms are basically the same. A non-covalent Michaelis complex is formed with beta-lactamase, a serine nucleophile attacks the amide bond, the beta-lactam ring is opened, and the enzyme is inactivated through rearrangement, and the structure is also destroyed, so it is also called a suicidal enzyme inhibitor.

[0012] Avibactam is a new type of beta-lactamase inhibitor, which has the characteristics of long-acting, broad-spectrum enzyme inhibition, and does not induce the production of beta-lactamase. The essential difference between avibactam and the classic beta-lactamase is that the beta-lactamase serine nucleophile binds to the amide bond of avibactam to form a covalent compound, and the enzyme inhibitor complex is obtained, which is the form of enzyme inhibition and does not hydrolyze. After cyclization to form a lactam ring, avibactam can recover activity again. In this process, the structure of avibactam itself can be restored by reverse reaction, so it has a long-acting enzyme inhibition effect. Therefore, the present application selects avibactam sodium and cefmenoxime to prepare a compound preparation.

[0013] Beneficial effects

[0014] The powder injection of the present application is easy to disperse and dissolve when preparing an injection solution, is convenient to use, ensures the content of cefmenoxime, and is not easy to produce beta-lactamase bacterial drug resistance; both cefmenoxime hydrochloride and avibactam sodium have injection raw materials, and the compound powder injection can realize regular large-scale commercial production; the dry granulator is used for twice tabletting to mix the molecules of cefmenoxime hydrochloride and avibactam sodium uniformly, the process is simple, does not affect the content of the material, and has a good market application prospect. DETAILED DESCRIPTION

[0015] The present application will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not used to limit the scope of the present application. In addition, it should be understood that after reading the content taught by the present application, those skilled in the art can make various modifications or changes to the present application, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

[0016] Example 1

[0017] Under B class clean environment condition, 10 kg of cefmenoxime hydrochloride powder and 5 kg of avibactam sodium powder were mixed, added into a dry granulator, rolled at a pressure of 10.2 MPa and a roller speed of 95 rpm to compress into flakes. The flakes were crushed into granules, and then compressed into flakes again under the same condition, crushed into granules, and then crushed by a high-speed crusher to obtain 13.621 kg of powder (60 mesh or more), which was divided into 13406 bottles (1 g per bottle). HPLC detection showed that the content of cefmenoxime hydrochloride was 60.6%, and the content of avibactam sodium was 32.9%. The sample was prepared with water for injection, and the dissolution was completed in 1 minute and 38 seconds.

[0018] Example 2

[0019] Under B class clean environment condition, 10 kg of cefmenoxime hydrochloride powder and 5 kg of avibactam sodium powder were mixed, added into a dry granulator, rolled at a pressure of 10.2 MPa and a roller speed of 95 rpm to compress into flakes. The flakes were crushed into granules, and then compressed into flakes again under the same condition, crushed into granules, and then crushed by a high-speed crusher to obtain 13.621 kg of powder (60 mesh or more), which was divided into 13406 bottles (1 g per bottle). HPLC detection showed that the content of cefmenoxime hydrochloride was 60.6%, and the content of avibactam sodium was 32.9%. The sample was prepared with water for injection, and the dissolution was completed in 1 minute and 38 seconds.

[0020] Example 3

[0021] Under B class clean environment condition, 10 kg of cefmenoxime hydrochloride powder and 5 kg of avibactam sodium powder were mixed, added into a dry granulator, rolled at a pressure of 10.2 MPa and a roller speed of 95 rpm to compress into flakes. The flakes were crushed into granules, and then compressed into flakes again under the same condition, crushed into granules, and then crushed by a high-speed crusher to obtain 13.621 kg of powder (60 mesh or more), which was divided into 13406 bottles (1 g per bottle). HPLC detection showed that the content of cefmenoxime hydrochloride was 60.6%, and the content of avibactam sodium was 32.9%. The sample was prepared with water for injection, and the dissolution was completed in 1 minute and 38 seconds.

[0022] Example 4

[0023] Under B class clean environment condition, 10 kg of cefmenoxime hydrochloride powder and 5 kg of avibactam sodium powder were mixed, added into a dry granulator, rolled at a pressure of 10.2 MPa and a roller speed of 95 rpm to compress into flakes. The flakes were crushed into granules, and then compressed into flakes again under the same condition, crushed into granules, and then crushed by a high-speed crusher to obtain 13.621 kg of powder (60 mesh or more), which was divided into 13406 bottles (1 g per bottle). HPLC detection showed that the content of cefmenoxime hydrochloride was 60.6%, and the content of avibactam sodium was 32.9%. The sample was prepared with water for injection, and the dissolution was completed in 1 minute and 38 seconds.

[0024] Example 5

[0025] Under B class clean environment condition, 20 kg of cefmenoxime hydrochloride powder and 7 kg of avibactam sodium powder were mixed, added into a dry granulator, rolled at a pressure of 11.9 MPa and a speed of 109 rpm to compress into flakes. The flakes were crushed into granules, and then compressed into flakes again under the same condition, crushed into granules, and then crushed by a high-speed crusher to obtain 25.989 kg of powder (60 mesh or more), which was divided into 25129 bottles (1 g per bottle). HPLC detection showed that the content of cefmenoxime hydrochloride was 72.8% and the content of avibactam sodium was 34.6%. The sample was prepared with water for injection, and the dissolution was completed in 1 minute and 40 seconds.

[0026] Example 6

[0027] Under B class clean environment condition, 10 kg of cefmenoxime hydrochloride powder and 2 kg of avibactam sodium powder were mixed, added into a dry granulator, rolled at a pressure of 9.8 MPa and a speed of 95 rpm to compress into flakes. The flakes were crushed into granules, and then compressed into flakes again under the same condition, crushed into granules, and then crushed by a high-speed crusher to obtain 11.9 kg of powder (60 mesh or more), which was divided into 21387 bottles (0.5 g per bottle). HPLC detection showed that the content of cefmenoxime hydrochloride was 82.1% and the content of avibactam sodium was 16.3%. The sample was prepared with water for injection, and the dissolution was completed in 1 minute and 45 seconds.

[0028] Comparative Example

[0029] Under B class clean environment condition, 10 kg of cefmenoxime hydrochloride powder and 5 kg of potassium clavulanate powder were mixed, added into a dry granulator, rolled at a pressure of 10.2 MPa and a speed of 95 rpm to compress into flakes. The flakes were crushed into granules, and then compressed into flakes again under the same condition, crushed into granules, and then crushed by a high-speed crusher to obtain 13.608 kg of powder (60 mesh or more), which was divided into 13385 bottles (1 g per bottle). The sample was prepared with water for injection, and the dissolution was completed in 6 minutes and 19 seconds.

[0030] Table 1: Change in content in accelerated stability test (40°C, relative humidity 75%)

[0031]

[0032]

[0033] Table 2: Change in dissolution time in water for injection in accelerated stability test (40°C, relative humidity 75%)

[0034] No. January February March April May June Example 1 1 minute 37 seconds 1 minute 36 seconds 1 minute 39 seconds 1 minute 38 seconds 1 minute 38 seconds 1 minute 38 seconds Example 2 1 minute 03 seconds 1 minute 03 seconds 1 minute 03 seconds 1 minute 03 seconds 1 minute 03 seconds 1 minute 03 seconds Example 3 1 minute 58 seconds 1 minute 59 seconds 2 minutes 01 seconds 1 minute 58 seconds 1 minute 57 seconds 1 minute 58 seconds Example 4 1 minute 43 seconds 1 minute 42 seconds 1 minute 44 seconds 1 minute 43 seconds 1 minute 43 seconds 1 minute 43 seconds Example 5 1 minute 40 seconds 1 minute 40 seconds 1 minute 41 seconds 1 minute 40 seconds 1 minute 40 seconds 1 minute 40 seconds Example 6 1 minute 45 seconds 1 minute 46 seconds 1 minute 45 seconds 1 minute 47 seconds 1 minute 45 seconds 1 minute 45 seconds Comparative Example 6 minutes 20 seconds 6 minutes 22 seconds 6 minutes 23 seconds 6 minutes 21 seconds 6 minutes 24 seconds 6 minutes 25 seconds

[0035] As shown in the results of Table 1 and Table 2, the compound powder injection of the present application is easy to disperse and dissolve when prepared, is convenient to use, and has long-acting effect.

Claims

1. A method for preparing a compound powder of avibactam and cefotaxime for injection, comprising: The raw materials for the avibactam-cefotaxime compound powder for injection consist of 10 kg of cefotaxime hydrochloride powder and 10 kg of avibactam sodium powder; characterized in that... The cefotaxime hydrochloride and avibactam sodium were mixed and added to a dry granulator for two tableting and granulation processes. Finally, the mixture was pulverized into a powder of 60 mesh or higher to obtain avibactam-cefotaxime compound powder for injection. Among them, 10 kg of cefotaxime hydrochloride powder and 10 kg of avibactam sodium powder; The roll pressure is 11.6 MPa and the roll speed is 105 rpm.

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