WO2023060749A1 - Cefpodoxime proxetil tablet and preparation method therefor - Google Patents

Abstract

A cefpodoxime proxetil tablet and a preparation method therefor. The preparation comprises the following raw materials in parts by weight: 30-50 parts of cefpodoxime proxetil, 0.1-0.5 part of sodium cellulose, 5-10 parts of ethyl cellulose, 10-20 parts of a plasticizer, 0.1-1 part of magnesium stearate, and 5-15 parts of a flavoring agent.

Description

A kind of cefpodoxime axetil tablet and preparation method thereof technical field

The invention relates to the field of medicine, in particular to a cefpodoxime axetil tablet and a preparation method thereof.

Background technique

Cefpodoximeproxetil (CPDX-PR) is the third-generation oral cephalosporin, which was first launched in Japan in 1990. Its structural feature is that the 7th position of the cephalosporin skeleton is connected with a methoxyiminothiazolyl group, and the 3rd position is connected with a methoxyiminothiazolyl group. The methyl group has a proxetil group on the 4-position carboxylic acid. CPDX-PR is the prodrug of cefpodoxime (CPDX), which itself has no antibacterial activity. It is absorbed through the intestinal tract after oral administration, and is hydrolyzed into CPDX by non-specific esterase in the intestinal wall to exert antibacterial activity.

Organic solvents such as methanol and ethanol are used in the production process of sporoxime proxetil, which may react with hydrochloric acid used in the process to generate genotoxic impurities such as methyl chloride and ethyl chloride. The reactivity of this type of impurity is very active, and it can directly undergo an alkylation reaction with DNA, thereby inhibiting cell growth and initiating programmed cell apoptosis. Although this type of impurity is in a small amount, it may still cause cancer risk. In addition, the poor fluidity of cefpodoxime axetil raw materials is prone to self-agglomeration when it contacts with other materials, which will cause uneven powder mixing and poor content uniformity; cefpodoxime axetil is difficult to dissolve in water, and when in contact with aqueous media, It has the characteristics of forming a gel or gel-like substance, greatly reducing its disintegration and dissolution rate, reducing absorption in the gastrointestinal tract, and low bioavailability.

Contents of the invention

In view of this, the object of the invention is to propose a kind of cefpodoxime axetil tablet and preparation method thereof. Technical scheme of the present invention is realized like this:

A cefpodoxime axetil tablet comprises the following raw materials in parts by weight: 30-50 parts of cefpodoxime axetil, 0.1-0.5 parts of cellulose sodium, 5-10 parts of ethyl cellulose, 10-20 parts of plasticizer, hard 0.1-1 part of magnesium fatty acid and 5-15 parts of flavoring agent.

A further technical solution is that the plasticizer is one of coconut oil, glycerin, and tributyl citrate.

A further technical solution is that the flavoring agent is a mixture of one or more of sucrose, stevioside, β-cyclodextrin, mannitol and sorbitol in any proportion.

A kind of preparation method of above-mentioned cefpodoxime axetil tablet, comprises the following steps:

(1) After cefpodoxime axetil is passed through a 100-150 mesh sieve, it is ultrasonically mixed with cellulose sodium alcohol solution to make granules; 10 mesh sieves, made into tablet cores;

(2) adding ethyl cellulose, plasticizer and flavoring agent into water and ultrasonically mixing to make a premix aqueous dispersion;

(3) Spray the premix aqueous dispersion on the surface of the tablet core, and then sequentially solidify and dry to prepare the cefpodoxime axetil tablet.

The ethyl cellulose described in the present application can improve the smoothness and glossiness of the surface of the coating film, has stable properties, and remains stable even when heated to a softening point temperature of 135°C.

The cellulose sodium alcohol solution is first mixed with cefpodoxime axetil ultrasonically, and the purpose is to further remove the trace impurities contained in cefpodoxime axetil through cellulose sodium, ethyl chloride, methyl chloride, etc., thereby reducing the risk of taking cefpodoxime axetil side effects, and the resulting ethyl cellulose can be used for the coating of cefpodoxime axetil tablets. The magnesium stearate is used as an anti-adhesive agent to increase the fluidity of cefpodoxime axetil and prevent adhesion between tablet cores, making it difficult to carry out subsequent coating operations. Plasticizers can improve the plasticity, flexibility and stretchability of the coating film.

A further technical scheme is that the sodium cellulose alcohol solution in the step (1) is an ethanol solution with a mass concentration of sodium methylcellulose of 0.5-1%; the mass concentration of the magnesium stearate is 2-5%.

A further technical solution is that the drying condition described in step (1) is 50-55°C, and the drying time is 30-45min;

A further technical solution is that the weight of water in the step (2) is 2-10 times of the weight of the plasticizer.

A further technical solution is that the spraying in step (3) is coating pan spraying, the spray speed is 5-10ml/min, the temperature in the coating pan is 45-55°C, and the coating pan rotating speed is 50-60r/min .

A further technical solution is that the curing and drying temperature in step (3) is 20-35° C., and the curing and drying time is 12-36 hours.

A further technical solution is that the temperature of the ultrasonic mixing in the step (1) and the step (2) is 70-80° C., and the ultrasonic time is 5-10 min.

Compared with prior art, the beneficial effect of the present invention is:

(1) This application adopts the spraying method of coating pan for coating, which has the advantages of high solid content of premix, low viscosity, high coating efficiency, and is not easy to generate static electricity, and the coating film of cefpodoxime axetil tablet is dense smooth.

(2) The preparation method of the cefpodoxime axetil tablet described in the present application can further remove impurities in the cefpodoxime axetil raw material, thereby reducing the side effects of the medicine.

(3) The cefpodoxime axetil tablet described in this application, through the preparation method of each raw material proportioning and multiple studies, has guaranteed the stability of cefpodoxime axetil tablet, still has very high stripping when storing for 12 months degree, thereby ensuring bioavailability.

Detailed ways

In order to clearly and completely describe the technical solutions in the present invention, it is obvious that the inventors describe in conjunction with the embodiments, but the following embodiments describe only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

Example 1

A cefpodoxime axetil tablet, comprising the following raw materials in parts by weight: 30 parts of cefpodoxime axetil, 0.1 part of cellulose sodium, 5 parts of ethyl cellulose, 10 parts of plasticizer, 0.1 part of magnesium stearate and flavoring 5 doses. Described plasticizer is coconut oil. The flavoring agent is stevioside.

Example 2

A cefpodoxime axetil tablet, comprising the following raw materials in parts by weight: 50 parts of cefpodoxime axetil, 0.5 parts of sodium cellulose, 10 parts of ethyl cellulose, 15 parts of plasticizer, 1 part of magnesium stearate and flavoring 15 doses. The plasticizer is tributyl citrate. The flavoring agent is sucrose.

Example 3

A cefpodoxime axetil tablet, comprising the following raw materials in parts by weight: 40 parts of cefpodoxime axetil, 0.3 parts of sodium cellulose, 8 parts of ethyl cellulose, 20 parts of plasticizers, 0.5 parts of magnesium stearate and flavoring 10 doses. The plasticizer is glycerin. The flavoring agent is mannitol.

The preparation method of the cefpodoxime axetil tablet described in embodiment 1-3, comprises the following steps:

(1) After passing cefpodoxime axetil through a 100-mesh sieve, ultrasonically mix it with sodium cellulose alcohol solution to make granules; after the granules are dried, add magnesium stearate and mix them, pass through a 10-mesh sieve, and make tablets core;

(2) adding ethyl cellulose, plasticizer and flavoring agent into water and ultrasonically mixing to make a premix aqueous dispersion;

(3) Spray the premix aqueous dispersion on the surface of the tablet core, and then sequentially solidify and dry to prepare the cefpodoxime axetil tablet.

The sodium cellulose alcohol solution described in the step (1) is an ethanol solution with a mass concentration of sodium methylcellulose of 0.5%; the mass concentration of the magnesium stearate is 2%. The drying condition in the step (1) is 50° C., and the drying time is 30 minutes; the weight of the water in the step (2) is twice the weight of the plasticizer. The spraying in step (3) is coating pan spraying, the spray speed is 5ml/min, the temperature inside the coating pan is 45°C, and the rotating speed of the coating pan is 50r/min. In step (3), the curing and drying temperature is 20° C., and the curing and drying time is 36 hours. The temperature of the ultrasonic mixing in the step (1) and the step (2) is 70° C., and the ultrasonic time is 10 min.

Example 4

The preparation method of described cefpodoxime axetil tablet, comprises the following steps:

(1) After passing cefpodoxime axetil through a 150-mesh sieve, ultrasonically mix it with sodium cellulose alcohol solution to make granules; after the granules are dried, add magnesium stearate and mix them, pass through a 10-mesh sieve, and make tablets core;

(2) adding ethyl cellulose, plasticizer and flavoring agent into water and ultrasonically mixing to make a premix aqueous dispersion;

(3) Spray the premix aqueous dispersion on the surface of the tablet core, and then sequentially solidify and dry to prepare the cefpodoxime axetil tablet.

The sodium cellulose alcohol solution described in the step (1) is an ethanol solution with a mass concentration of sodium methylcellulose of 1%; the mass concentration of the magnesium stearate is 5%. The drying condition in the step (1) is 55° C., and the drying time is 45 minutes; the weight of the water in the step (2) is 10 times the weight of the plasticizer. The spraying in step (3) is coating pan spraying, the spray speed is 10ml/min, the temperature inside the coating pan is 55°C, and the rotating speed of the coating pan is 60r/min. In step (3), the curing and drying temperature is 35° C., and the curing and drying time is 12 hours. The temperature of the ultrasonic mixing in the step (1) and the step (2) is 80° C., and the ultrasonic time is 5 min.

Comparative example 1

Sodium cellulose is replaced by sodium croscarmellose, ethyl cellulose is replaced by microcrystalline cellulose, and others are the same as in Example 2.

Comparative example 2

In the preparation method of cefpodoxime axetil tablet, the temperature of ultrasonic mixing is 65 ℃, other is identical with embodiment 2.

Comparative example 3

In the preparation method of cefpodoxime axetil tablet, the temperature of ultrasonic mixing is 85 ℃, and others are identical with embodiment 2.

Comparative example 4

In the preparation method of cefpodoxime axetil tablet, comprise the following steps:

(1) After cefpodoxime axetil is passed through a 100-mesh sieve, it is ultrasonically mixed with cellulose sodium alcohol solution to make granules; after the granules are dried, go through a 10-mesh sieve to make a tablet core;

(2) Ethyl cellulose, magnesium stearate, plasticizer and correctives are added into water and ultrasonically mixed to make a premix aqueous dispersion;

(3) Spray the premix aqueous dispersion on the surface of the tablet core, and then sequentially solidify and dry to prepare the cefpodoxime axetil tablet.

Others are identical with embodiment 2.

Performance Testing

By visually observing the appearance character of cefpodoxime axetil sheet, the cefpodoxime axetil sheet appearance described in embodiment 1-4, comparative example 2-4 is shown smooth by table 1, and the cefpodoxime axetil sheet appearance described in comparative example 1 Slightly rough, indicating that ethyl cellulose can improve the smoothness and gloss of the coating film surface.

Detect the content of ethyl chloride in embodiment 1-4, comparative example 1-3 by HPLC, find that the ethyl chloride content is between 0.02-0.03% in the cefpodoxime axetil tablet described in embodiment 1-4 by table 1, In the cefpodoxime axetil tablet described in comparative example 4, the ethyl chloride content is equivalent to that of Example 2, showing that in the preparation method of the cefpodoxime axetil tablet, the mixing order of magnesium stearate does not affect the reaction of sodium cellulose and ethyl chloride . The content of ethyl chloride in the cefpodoxime axetil tablet described in Comparative Examples 3 and 4 is higher than that in Example 2, indicating that the control of the ultrasonic temperature for raw material mixing will affect the reaction of sodium cellulose and ethyl chloride. In the cefpodoxime axetil tablet described in comparative example 1, the ethyl chloride content is significantly higher than

Example 2 shows that croscarmellose sodium cannot react with ethyl chloride, that is, croscarmellose sodium does not have the same impurity removal effect as cellulose sodium.

By simulating the market packaging (aluminum-plastic) of the samples of the test group, placing them for 12 months under the conditions of temperature 40°C and relative humidity 75%, the dissolution rate of cefpodoxime axetil tablets was determined. Table 1 shows that the dissolution rates of Examples 1-4 are higher than those of Comparative Examples 1-4, but are all within the limits of the 2010 edition of "Chinese Pharmacopoeia". From the comparison of Example 2 and Comparative Example 1, it can be seen that ethyl cellulose, as the main material for the coating of cefpodoxime axetil tablet, has higher stability than microcrystalline cellulose.

Table 1

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of the present invention. within the scope of protection.

Claims (10)

A cefpodoxime axetil tablet is characterized in that: it comprises the following raw materials in parts by weight: 30-50 parts of cefpodoxime axetil, 0.1-0.5 parts of cellulose sodium, 5-10 parts of ethyl cellulose, 10-50 parts of plasticizer 20 parts, 0.1-1 part of magnesium stearate and 5-15 parts of flavoring agent. A kind of cefpodoxime axetil tablet according to claim 1, is characterized in that: described plasticizer is the one in coconut oil, glycerin, tributyl citrate. A kind of cefpodoxime axetil tablet according to claim 1, is characterized in that: described flavoring agent is one or more arbitrary ratios in sucrose, stevioside, β-cyclodextrin, mannitol, sorbitol mix. The preparation method of a kind of cefpodoxime axetil tablet according to any one of claims 1-3, is characterized in that: comprises the following steps: (1) After cefpodoxime axetil is passed through a 100-150 mesh sieve, it is ultrasonically mixed with cellulose sodium alcohol solution to make granules; after the granules are dried, magnesium stearate is added and mixed, and then passed through a 10 mesh sieve to prepare into a core; (2) adding ethyl cellulose, plasticizer and flavoring agent into water and ultrasonically mixing to make a premix aqueous dispersion; (3) Spray the premix aqueous dispersion on the surface of the tablet core, and then sequentially solidify and dry to prepare the cefpodoxime axetil tablet. The preparation method of a kind of cefpodoxime axetil tablet according to claim 4, is characterized in that: the cellulose sodium alcohol solution described in step (1) is the ethanol solution that methylcellulose sodium mass concentration is 0.5-1% ; The mass concentration of the magnesium stearate is 2-5%. The preparation method of a kind of cefpodoxime axetil tablet according to claim 4, is characterized in that: the drying condition described in step (1) is 50-55 ℃, and drying time is 30-45min; The preparation method of a kind of cefpodoxime axetil tablet according to claim 4, is characterized in that: the weight of water in the described step (2) is 2-10 times of plasticizer weight. The preparation method of a kind of cefpodoxime axetil tablet according to claim 4, is characterized in that: in step (3), spraying is coating pot spraying, and described spray speed is 5-10ml/min, and coating pot inner temperature 45-55°C, the rotating speed of the coating pan is 50-60r/min. A preparation method of cefpodoxime axetil tablet according to claim 4, characterized in that: in step (3), the curing and drying temperature is 20-35°C, and the curing and drying time is 12-36h. The preparation method of a kind of cefpodoxime axetil tablet according to claim 4, is characterized in that: the temperature of the ultrasonic mixing in described step (1) and step (2) is 70-80 ℃, and ultrasonic time is 5- 10min.