CN113081988A

CN113081988A - Cefradine dispersible tablet and preparation method thereof

Info

Publication number: CN113081988A
Application number: CN202110507598.3A
Authority: CN
Inventors: 律涛; 刘彦; 李程; 杨少坤; 薛忠; 王嫚; 张静岩
Original assignee: Hebei Medical University
Current assignee: Hebei Medical University
Priority date: 2021-05-10
Filing date: 2021-05-10
Publication date: 2021-07-09
Anticipated expiration: 2041-05-10
Also published as: CN113081988B

Abstract

The invention provides a cefradine dispersible tablet and a preparation method thereof, wherein the cefradine dispersible tablet comprises the following components in parts by weight: 250 parts of cefradine, 37-41 parts of mannitol, 8-12 parts of carboxymethyl starch sodium, 8 parts of taura, 5 parts of guar gum, 8-12 parts of microcrystalline cellulose, 22-28 parts of carboxymethyl starch sodium and 2 parts of magnesium stearate. After 6 months of accelerated stability tests, the content of specific impurities, friability and dissolution rate of the cefradine dispersible tablet prepared by the invention meet the standards, and the treatment effect of the medicine during storage is ensured.

Description

Cefradine dispersible tablet and preparation method thereof

Technical Field

The invention relates to the field of pharmaceutical preparations, in particular to a cefradine dispersible tablet and a preparation method thereof.

Background

Chemical name of cefradine: (6R,7R) -7- [ (R) -2-amino-2- (1, 4-cyclohexadien-1-yl) acetylamino ] -3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid of formula: C16H19N3O4S, molecular weight: 349.40. the structural formula is as follows:

cefradine is a beta-lactam antibiotic and is used for treating respiratory tract infection, genitourinary tract infection, skin and soft tissue infection and the like caused by sensitive bacteria, such as acute pharyngitis, tonsillitis, otitis media, bronchitis, pneumonia and the like; the cefradine has wide market application, but has unstable chemical property, high impurity content, easy hydrolysis and other problems in the storage process, thereby not only influencing the quality of products, but also bringing potential safety hazards to clinical application.

The dispersible tablet is an excellent new formulation developed in recent years and has the reputation of solid oral liquid. It integrates the advantages of tablet and liquid preparation, and overcomes the disadvantages of both. Has the following characteristics: 1. the disintegration time is short, and the dispersion state is good; 2. the medicine is dissolved out quickly and absorbed quickly; 3. the oral liquid is convenient to take and various in taking method, can be directly swallowed or dispersed in water for taking, and is particularly suitable for old, young and dysphagia patients; 5. the dispersible tablet has simple production process, and can be produced by using common tablet production equipment.

Disclosure of Invention

The invention aims to solve the problems of poor stability, easy generation of degradation impurities and the like of the cefradine dispersible tablet in storage, can effectively reduce the content of specific degradation impurities such as cefalexin, 7-aminodesacetoxycephalosporanic acid, cefradine polymer and the like in the preparation by controlling the weight ratio of mannitol, taurine and guar gum in a prescription, can keep the specific degradation impurities slowly growing after the medicine is placed for a long time, is favorable for the long-term stability of the preparation, and ensures the safety of the medicine.

Firstly, the invention provides a cefradine dispersible tablet which comprises the following components in parts by weight:

further, the microcrystalline cellulose is microcrystalline cellulose with the density of 0.35-0.46mg/ml and the average grain diameter of 50-60 microns, and preferably the microcrystalline cellulose is PH 301.

Adding adjuvants, and mixing with active ingredients or other adjuvants by "internal addition method" to make into granule.

Further, mannitol: taurine: guar gum ═ (7.4-8.2): 1.6: 1; preferably, the ratio of mannitol: taurine: guar gum-8: 1.6:1

Furthermore, the cefradine dispersible tablet contains 500mg, preferably 250mg of cefradine 125-.

Further, the invention provides a cefradine dispersible tablet which comprises the following components in percentage by weight:

further, the invention provides a preparation method of the cefradine dispersible tablet composition.

A preparation method of a cefradine dispersible tablet is characterized by comprising the following steps:

(1) preparation of adhesive solution: dissolving guar gum serving as a binding agent into water to prepare a guar gum solution with the concentration of 4.5-5.5% (w/w);

(2) premixing and wet granulation: firstly adding the cefradine and the internally added auxiliary materials into a wet mixing granulator for premixing, then adding the adhesive solution under the stirring condition, and carrying out wet granulation;

(3) and (3) drying: drying the wet granules with a boiling granulator, wherein the moisture content is not higher than 1.5%.

(4) Straightening: adding the dried granules into a granulating machine for granulating;

(5) mixing: adding microcrystalline cellulose and sodium carboxymethyl starch into the granules, mixing for 10-15 minutes, adding magnesium stearate, and mixing for 3-5 minutes.

(6) Tabletting: tabletting under 9-12KN to obtain the cefradine dispersible tablet.

In the preparation method, in the drying in the step (3), the wet granules are dried by a boiling granulator, and a low-temperature drying technology is adopted, wherein the air inlet temperature is set to be 45 ℃, the air outlet temperature is set to be 38 ℃, the material temperature is 41 ℃, and the moisture is measured by sampling, and reaches below 1.5%.

In the preparation method, the concentration of the guar gum solution in the preparation of the binder solution in the step (1) is 5.0%.

In the preparation method, in the step (6), the tabletting pressure is 10 KN.

The inventor screens a better prescription proportion of a dispersible tablet preparation and a preparation process thereof through a large number of experiments, (1) by controlling the dosage of mannitol, a stabilizer taurine and an adhesive guar gum with a specific proportion are added to form mannitol: taurine: guar gum ═ (7.4-8.2): 1.6:1, the addition of taurine and guar gum plays a role in protecting cefradine raw materials, the cefradine dispersible tablet prepared by the method effectively controls specific degradation impurities such as cephalexin, 7-aminodesacetoxycephalosporanic acid, cefradine polymer and the like through the synergistic effect of the three components, and (2) the brittleness and the dissolution rate of the prepared cefradine dispersible tablet meet the standard through controlling the concentration of guar gum serving as a binding agent and the density and the particle size of microcrystalline cellulose, and the dissolution rate meets the standard through an accelerated stability test for 6 months, so that the treatment effect of the medicine during storage is ensured.

Detailed Description

The invention discloses a cefradine dispersible tablet and a preparation method thereof, and the cefradine dispersible tablet can be realized by combining the relevant principles of pharmaceutical preparations and properly improving the process parameters by taking the contents of the invention as reference. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the scope of the invention. While the invention has been described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations may be applied, or changes and combinations may be made, in the methods and applications described herein to achieve and use the inventive techniques without departing from the spirit, scope, and content of the invention.

For a better understanding of the invention, and not as a limitation on the scope thereof, all numbers expressing quantities, percentages, and other numerical values used in this application are to be understood as being modified in all instances by the term "about". At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

The cefradine and the auxiliary materials are all sold in the market.

The present invention is further illustrated by the following examples, which are not intended to limit the invention in any way.

Content uniformity: the content uniformity was measured by the method of examining the content uniformity in four parts of the year 2015, which is the "Chinese pharmacopoeia" (general rule 0941).

Friability: the measurement was carried out according to the friability test method for four parts (general rule 0923) of the year 2015 version, China pharmacopoeia.

Cephalexin, 7-aminodesacetoxycephalosporanic acid, cephradine polymer: the quality standard of cefradine is determined according to the second part of cefradine in the year 2015 of Chinese pharmacopoeia.

(1) Dissolution medium:

ph1.2 hydrochloric acid solution: 7.65ml of concentrated hydrochloric acid was taken out from a measuring cylinder and diluted to 1000ml with water.

(2) A dissolution device: a paddle method; rotating speed: 50 revolutions per minute; volume of medium: 900 ml; temperature: 37.0 +/-0.5 ℃; sampling volume: 7 ml;

(3) the standard is as follows: and the dissolution rate is not lower than 80% in 45 min.

Dispersion uniformity: the measurement is carried out according to "disintegration time limit inspection method" (0921 in the four general guidelines of the pharmacopoeia 2015 edition of China). The method specifically comprises the following steps: checking according to disintegration time limit method, hanging the hanging basket on a metal bracket through a stainless steel shaft at the upper end, immersing the hanging basket in a 1000ml beaker, adjusting the position of the hanging basket to enable the hanging basket to fall to a low point, wherein the screen is 25mm away from the bottom of the beaker, and the water temperature is 15-25 ℃; the inner diameter of a sieve pore of the stainless steel screen is 710 microns; the screen is 15mm below the liquid level when the liquid level is adjusted to enable the basket to rise, and the top of the basket cannot be immersed in the solution. Taking 6 tablets of the product, respectively placing the tablets in glass tubes of the hanging baskets, immediately starting a disintegration tester for checking, and completely disintegrating each tablet within 3.0 minutes and passing through a screen mesh.

Test example 1: prescription screening

1. The prescription composition is as follows:

2. the preparation method comprises the following steps:

(1) preparation of adhesive solution: dissolving guar gum serving as a binding agent in water to prepare a guar gum solution with the concentration of 5.0% (w/w);

(3) and (3) drying: drying wet granules by a boiling granulator by adopting a low-temperature drying technology, wherein the air inlet temperature is set to be 45 ℃, the air outlet temperature is set to be 38 ℃, the material temperature is 41 ℃, sampling is carried out to measure the moisture content, the moisture content reaches below 1.5 percent, and the drying time is about 35min after the drying is finished;

(6) Tabletting: tabletting under 10KN pressure to obtain cefradine dispersible tablet;

samples with different prescription ratios are subjected to an accelerated stability test under the conditions of 40 ℃ and 75% +/-5% relative humidity, and the specific degradation impurity condition is detected at 6 months, and the results are shown in table 1.

TABLE 1 Table of specific impurity levels at 6 months of accelerated stability testing for samples produced according to different recipes

As shown in Table 1, through an accelerated stability test for 6 months, a more optimal formula ratio of the preparation is screened, the content of taurine is found to have great influence on the stability of the cephradine dispersible tablets, and in addition, the formula is further optimized by adding a filler mannitol and an adhesive guar gum in a specific ratio, so that specific degradation impurities such as cephalexin, 7-aminodesacetoxycephalosporanic acid, cephradine polymer and the like are effectively controlled. The optimal prescription range obtained finally is 37-41 parts of mannitol, 8 parts of taurine and 5 parts of guar gum, namely the mannitol is formed: taurine: guar gum ═ (7.4-8.2): 1.6:1, the cefradine dispersible tablet prepared by the method meets the standard of each specific impurity through an accelerated stability test for 6 months.

Example 1: cefradine dispersible tablet

1. The prescription composition is as follows:

1000 tablets are dosed according to the prescription to prepare the cefradine dispersible tablets, the same applies below

2. The preparation method comprises the following steps:

(2) premixing and wet granulation: firstly adding cefradine, mannitol, sodium carboxymethyl starch and taurine into a wet mixing granulator for premixing, then adding an adhesive solution under the stirring condition, and carrying out wet granulation;

(3) and (3) drying: drying wet granules by using a boiling granulator, adopting a low-temperature drying technology, setting the air inlet temperature to be 45 ℃, the air outlet temperature to be 38 ℃, the material temperature to be 41 ℃, sampling and measuring the moisture, wherein the moisture reaches 1.2 percent, and after drying, the drying time is about 35 min;

(5) mixing: the microcrystalline cellulose and sodium carboxymethyl starch were added to the granules, mixed for 12 minutes, then added with magnesium stearate, and mixed for 4 minutes.

3. and (3) detection results:

the friability, dispersion uniformity and dissolution of the prepared cefradine dispersible tablets were measured, and the results are shown in table 2.

Table 2: EXAMPLE 1 friability, Dispersion uniformity, dissolution results for dispersible tablets of cefradine

Example 2: cefradine dispersible tablet

1. The prescription composition is as follows:

2. the preparation method comprises the following steps: the same as in example 1.

3. And (3) detection results:

the friability, dispersion uniformity and dissolution of the prepared cefradine dispersible tablets were measured, and the results are shown in table 3.

Table 3: example 2 results of friability, dispersion uniformity, dissolution of cefradine dispersible tablets

Example 3: cefradine dispersible tablet

1. The prescription composition is as follows:

3. And (3) detection results:

the friability, dispersion uniformity and dissolution of the prepared dispersible tablets of cephradine were measured, and the results are shown in table 43.

Table 4: example 3 results of friability, dispersion uniformity, dissolution of cefradine dispersible tablets

Example 4: cefradine dispersible tablet

1. The prescription composition is as follows:

2. the preparation method comprises the following steps:

(1) preparation of adhesive solution: dissolving guar gum serving as a binding agent in water to prepare a guar gum solution with the concentration of 4.5% (w/w);

(5) mixing: the microcrystalline cellulose and sodium carboxymethyl starch are added into the granules, mixed for 12 minutes, then added with magnesium stearate, and mixed for 5 minutes.

(6) Tabletting: tabletting under 11KN pressure to obtain cefradine dispersible tablet;

3. and (3) detection results:

the friability, dispersion uniformity and dissolution of the prepared cefradine dispersible tablets were measured, and the results are shown in table 5.

Table 5: example 4 results of friability, dispersion uniformity, dissolution of cefradine dispersible tablets

Example 5: cefradine dispersible tablet

1. The prescription composition is as follows:

2. the preparation method comprises the following steps:

(1) preparation of adhesive solution: dissolving guar gum serving as a binding agent in water to prepare a guar gum solution with the concentration of 5.5% (w/w);

(3) and (3) drying: drying wet granules by using a boiling granulator, adopting a low-temperature drying technology, setting the air inlet temperature to be 45 ℃, the air outlet temperature to be 38 ℃, the material temperature to be 41 ℃, sampling and measuring the moisture, wherein the moisture reaches 1.3 percent, and after drying, the drying time is about 35 min;

(5) mixing: adding microcrystalline cellulose and sodium carboxymethyl starch into the granules, mixing for 10 min, adding magnesium stearate, and mixing for 5 min.

(6) Tabletting: tabletting under the pressure of 9KN to obtain the cefradine dispersible tablet;

3. and (3) detection results:

the friability, dispersion uniformity and dissolution of the prepared cefradine dispersible tablets were measured, and the results are shown in table 6.

Table 6: example 5 results of friability, dispersion uniformity, dissolution of cefradine dispersible tablets

Comparative example 1: effect of guar concentration on dissolution

1. The prescription composition is as follows: the same as in example 1.

2. The preparation method comprises the following steps: the procedure of step (1) is as follows, and the rest of the procedure is the same as in example 1.

3. And (3) detection results:

the friability, dispersion uniformity and dissolution of the prepared cefradine dispersible tablets were measured, and the results are shown in table 7.

Table 7: comparative example 1 results of friability, dispersion uniformity and dissolution of cefradine dispersible tablets

As can be seen from Table 7: comparative analysis examples 1-5 and comparative examples 1-1 and 1-2, the concentration of the binder guar gum affects the friability and dissolution of the cephradine dispersible tablets. When the concentration of the adhesive is lower, for example, lower than 4.5% (for example, 4%), the dissolution of the dispersible tablet is slow, and the dissolution rate in 45min is only 75.1%, which is not satisfactory. ② when the concentration of the binder is higher, for example higher than 5.5% (for example 6%), the friability of the dispersible tablet is not satisfactory.

In conclusion, the concentration of the guar gum is 4.5% -5.5%.

Comparative example 2: effect of microcrystalline cellulose Density and particle size

1. The prescription composition is as follows: microcrystalline cellulose of various densities and particle sizes was used as shown in the following table, and the procedure was otherwise the same as in example 1.

3. The result of the detection

The friability, dispersion uniformity and dissolution of the prepared cefradine dispersible tablets were measured, and the results are shown in table 8.

Table 8: comparative example 2 results of friability, dispersion uniformity and dissolution of cefradine dispersible tablet

As can be seen from Table 8: comparative analysis examples 1-5 and comparative example 2, the dissolution of the dispersible tablet of cefradine is affected by different types of microcrystalline cellulose with density of 0.35-0.46mg/ml and average particle size of 50-60 μm, preferably microcrystalline cellulose pH 301.

Comparative example 3: influence of drying Process in step (3)

1. The prescription composition is as follows: the same as in example 1.

2. The preparation method comprises the following steps: the procedure (3) is as follows, and the rest of the procedure is the same as in example 1.

3. The result of the detection

The friability, dispersion uniformity and dissolution of the prepared cefradine dispersible tablets were measured, and the results are shown in table 9.

Table 9: comparative example 3 results of friability, dispersion uniformity and dissolution of cefradine dispersible tablets

From table 9 in combination with example 6: comparative analysis examples 1-5 and comparative example 3, the drying process affects the content of polymer impurities in the cephradine tablet, and the cephradine dispersible tablet prepared in comparative example 3 is accelerated to stand for 6 months, and the content of the cephradine polymer is significantly increased, which is not satisfactory (see example 6).

Example 6: stability survey

The cefradine dispersible tablets prepared in the examples 1-5 and the comparative example 3 are selected respectively to be examined by an accelerated stability test, and after being placed for 6 months under the long-term conditions of the temperature of 40 ℃ and the relative humidity of 75% +/-5%, the specific impurities and the dissolution rate are tested, and the test results are shown in table 10.

Table 10: accelerated stability survey data

As can be seen from table 3: compared with the comparative example 3, the content of specific impurities prepared in the examples 1 to 5 of the present invention is lower, especially the content of the cephradine polymer, the cefradine polymer is not detected at 6 months, the content of other impurities is also obviously lower than the comparative example 3, and the above results show that the cefradine dispersible tablets prepared in the examples 1 to 5 of the present invention have better stability.

The above is only a preferred embodiment of the present invention, and it should be understood that the present invention is not limited thereto, and those skilled in the art can make various modifications, decorations and equivalents without departing from the principle of the present invention, and therefore, the present invention is to be covered within the protection scope of the present invention.

Claims

1. A cefradine dispersible tablet comprises the following components in parts by weight:

the microcrystalline cellulose is microcrystalline cellulose with the density of 0.35-0.46mg/ml and the average grain diameter of 50-60 microns, and the microcrystalline cellulose PH301 is preferred.

2. The dispersible tablet according to claim 1, comprising the following components in parts by weight:

。

3. the dispersible tablet according to claim 1, wherein the dispersible tablet comprises 250mg of cefradine 125-.

4. The dispersible tablet according to claim 3, comprising 250mg of cefradine.

5. A process for the preparation of a dispersible tablet of cefradine according to any one of claims 1 to 4, comprising the steps of:

(3) and (3) drying: drying the wet granules by using a boiling granulator, wherein the water content is not higher than 1.5%;

(5) mixing: adding microcrystalline cellulose and sodium carboxymethyl starch into the granules, mixing for 10-15 minutes, adding magnesium stearate, and mixing for 3-5 minutes;

(6) tabletting: tabletting under the pressure of 9-12KN to obtain cefradine dispersible tablets;

the step (3) is drying: drying wet granules by a boiling granulator by adopting a low-temperature drying technology, wherein the air inlet temperature is set to be 45 ℃, the air outlet temperature is set to be 38 ℃, the material temperature is 41 ℃, and sampling is carried out to measure the moisture content, so that the moisture content is below 1.5 percent.

6. The method of claim 5, wherein the guar gum solution is prepared at a concentration of 5.0% in the step (1) of preparing the binder solution.

7. The process according to claim 5, wherein in the tabletting of step (6), the tabletting pressure is 10 KN;

。

8. the method of claim 6, wherein the step (1) is performed to prepare a 6% strength binder solution.

9. The preparation method according to claim 6, wherein in the step (6), when the specification of the glimepiride dispersible tablet is 1mg, the compression pressure is 8-14 KN.

10. The preparation method according to claim 6, wherein in the step (6), when the specification of the glimepiride dispersible tablet is 2mg, the compression pressure is 10-16 KN.