CN112656769B

CN112656769B - Cefdinir dispersible tablet

Info

Publication number: CN112656769B
Application number: CN202110075227.2A
Authority: CN
Inventors: 刘遵利; 李彤彤; 孟宪娣; 张曦; 赵凤; 闫崇国; 邢刚; 孙金龙
Original assignee: Tianjin Central Pharmaceutical Co ltd
Current assignee: Tianjin Central Pharmaceutical Co ltd
Priority date: 2021-01-20
Filing date: 2021-01-20
Publication date: 2022-08-23
Anticipated expiration: 2041-01-20
Also published as: CN112656769A

Abstract

A cefdinir dispersible tablet comprises the following components: 80-120 parts of cefdinir, 0.5-1 part of a flavoring agent, 50-80 parts of pretreated crospovidone serving as a disintegrating agent, 100-150 parts of microcrystalline cellulose serving as a filler, 3-8 parts of a lubricant and 3-8 parts of a flow aid; the preparation method of the pretreated crospovidone comprises the following steps: dissolving polyvidone K30 and polyethylene glycol 4000 in anhydrous ethanol to obtain a solution, mixing the solution with crospovidone, and spray drying to obtain pretreated crospovidone.

Description

Cefdinir dispersible tablet

Technical Field

The invention relates to an oral preparation, in particular to an oral preparation taking cefdinir as an active ingredient.

Background

Cefdinir (CAS: 91832-40-5) is an oral third-generation cephalosporin, has the advantages of wide antibacterial spectrum, low toxicity and the like, is insoluble in water and is slightly soluble in 0.1mol/L hydrochloric acid and phosphate buffer solution. The existing cefdinir oral preparations mainly comprise capsules and dispersible tablets, wherein the dispersible tablet is the key point of the research of the existing cefdinir preparations because of convenient taking, quick disintegration, quick absorption and high bioavailability. Cefdinir belongs to beta-lactam antibiotics, and is prepared by a powder direct compression technology in order to avoid generating impurities by decomposition under a damp-heat condition and influence the content of related substances of a product and meet the requirement that a dispersible tablet formulation needs to be rapidly disintegrated. However, in practical use, the existing cefdinir dispersible tablets prepared by adopting a powder direct compression mode can absorb moisture after being taken out from a sealed package in a damp and hot environment and placed for a short time, and when the moisture absorption and weight increase of the tablet body exceed 5%, the tablet body obviously swells, and the strength of the tablet body is obviously reduced and even dispersed. Under the condition of damp-heat weather, the user takes out the medicine and then temporarily does not take the medicine for some reason, and the taken medicine is discarded due to moisture absorption. The traditional damp-proof measures are that auxiliary materials for preventing deliquescence, such as cyclodextrin and the like, are added or coating is carried out after granulation is carried out, but the measures can increase the process complexity of the preparation and can generate adverse effects on the disintegration speed and the dissolution rate of the dispersible tablets. Therefore, the problem to be solved in the prior art is to provide an improved cefdinir dispersible tablet which can avoid the deliquescence of the tablet body in a damp and hot environment as much as possible on the premise of high disintegration and high dissolution speed.

Disclosure of Invention

In the research, the inventors unexpectedly found that the ability of the prepared cefdinir dispersible tablet to resist the damp-heat environment can be remarkably improved by treating the crosslinked polyvinylpyrrolidone (crosslinked PVP) serving as the disintegrant with polyvinylpyrrolidone (PVP) and polyethylene glycol ethanol solution. Based on this, in order to solve the aforementioned technical problems, the technical solution adopted by the present invention is:

the cefdinir dispersible tablet is characterized by comprising the following components in parts by weight: 80-120 parts of cefdinir, 0.5-1 part of a flavoring agent, 50-80 parts of pretreated crospovidone serving as a disintegrating agent, 100-150 parts of microcrystalline cellulose serving as a filler, 3-8 parts of a lubricant and 3-8 parts of a flow aid; the preparation method of the pretreated crospovidone comprises the following steps: dissolving polyvidone K30 and polyethylene glycol 4000 in anhydrous ethanol to obtain a solution, mixing the solution with crospovidone, and spray drying to obtain pretreated crospovidone.

The cefdinir dispersible tablet is characterized in that the weight ratio of the povidone K30 to the polyethylene glycol 4000 is 2-5: 1, preferably 3-4: 1; the weight ratio of the povidone K30 to the crospovidone is 1: 12-20, and preferably 1: 14-16.

The cefdinir dispersible tablet is further preferably prepared from the following components in parts by weight:

98-102 parts of cefdinir, 0.3-0.8 part of a flavoring agent, 55-65 parts of pretreated crospovidone serving as a disintegrating agent, 120-125 parts of microcrystalline cellulose serving as a filling agent, 4-6 parts of a lubricant and 4-6 parts of a flow aid.

100 parts of cefdinir, 0.3-0.8 part of flavoring agent, 60 parts of pretreated crospovidone serving as a disintegrating agent, 120-125 parts of microcrystalline cellulose serving as a filler, 4.5 parts of lubricant and 6 parts of glidant, wherein the weight ratio of povidone K30 to polyethylene glycol 4000 is (3-4): 1; the weight ratio of the polyvidone K30 to the pre-treated crospovidone is 1: 15.

The cefdinir dispersible tablet is characterized in that the flavoring agent is aspartame, the lubricant is magnesium stearate, and the glidant is aerosil.

The cefdinir dispersible tablet is further prepared by respectively sieving the pretreated crospovidone and the rest raw materials, mixing, and tabletting by a powder direct tabletting method to obtain the cefdinir dispersible tablet.

According to the cefdinir dispersible tablet provided by the invention, through a preferable formula and a preferable process, the anhydrous ethanol solution of povidone K30 and polyethylene glycol in a preferable proportion is used as a pretreatment solution, the crospovidone serving as a disintegrant is subjected to spray drying pretreatment, and then the powder is directly tabletted, so that the wet heat resistance of the obtained dispersible tablet can be remarkably improved. Compared with a reference medicament, the cefdinir dispersible tablet provided by the invention keeps a lower level of moisture absorption and weight increase and still keeps higher tablet body quality after being taken out from a sealed package and exposed in a damp and hot environment for a period of time. And can maintain high disintegration rate and dissolution rate of effective components. Thereby solving the problem of poor damp-proof thermal performance of the cefdinir dispersible tablet provided by the prior art.

Detailed Description

The preparation process of the cefdinir dispersible tablet provided by the invention comprises the following steps:

preparation of pretreated crospovidone: dissolving povidone (PVP) K30 and polyethylene glycol (PEG4000) in anhydrous ethanol according to the weight ratio of A to 1 to prepare a solution with the weight percentage concentration of 2%, and mixing the PVP and the PVPP according to the weight ratio of 1: b, mixing the solution with PVPP, and then carrying out spray drying to obtain pretreated cross-linked povidone (pretreated PVPP);

sieving: the raw and auxiliary materials are screened by a screen of 40 meshes for standby, so that the caking phenomenon of the raw and auxiliary materials in the placing process is prevented

Mixing: sequentially putting the pre-treated crospovidone, the cefdinir, the micropowder silica gel, the aspartame and the microcrystalline cellulose according to the prescription into a pyramid mixer, mixing for 20 minutes, then adding the magnesium stearate according to the prescription, and continuously mixing for 15 minutes.

Tabletting: and tabletting the mixed materials in a tabletting machine.

After preparation, the dissolution curve of the sample in pH6.8 phosphate buffer, water, hydrochloric acid solution, pH4.0 acetate buffer is determined. The dissolution profile results are as follows.

The examples and comparative examples are formulated in the following table: (unit: parts by weight)

According to the prescription of the examples and comparative examples, 100 mg/tablet of cefdinir dispersible tablets were prepared, and each tablet was tested for dissolution and disintegration, and commercially available cefdinir dispersible tablets (trade name: cefdinir, 100 mg/tablet, manufactured by Tianjin Central pharmaceutical industry Co., Ltd.) were received as reference drug

Pharmacological example 1 test for Dispersion uniformity

The test method comprises the following steps: 6 cefdinir dispersible tablets prepared in reference drugs, examples and comparative examples are respectively put into 100mL of water in a 250mL beaker to be shaken, and all the cefdinir dispersible tablets are disintegrated and reach a uniform dispersion state within 3 minutes at the temperature of about 20 ℃, and pass through a No. 2 sieve, and the test results are shown in the following table.

The experimental results show that all the drugs in the examples, the comparative examples and the provided reference drugs can be disintegrated within 3min, but the dispersion time of the comparative example 1/2 is obviously longer than that of the other examples, which shows that the PVP or PEG pretreatment of crospovidone alone can have adverse effects on the disintegration speed and the dispersion uniformity of the cefdinir dispersible tablets. The crospovidone of comparative example 3 was not subjected to the pretreatment operation, and its disintegration rate was similar to that of the reference drug.

Pharmacological example 2 dissolution test

According to a dissolution determination method (appendix X C second method of the second part of the year edition of Chinese pharmacopoeia 2015), respectively taking 900mL of hydrochloric acid solution (diluted hydrochloric acid (appendix XV B of the second part of the year edition of Chinese pharmacopoeia 2015) 24mL to 1000mL) as a dissolution medium, rotating at 50 revolutions per minute, operating according to the method, and taking a proper amount of solution and supplementing the solution after 5 minutes, 10 minutes, 15 minutes and 30 minutes; filtering the solution, precisely measuring appropriate amount of the filtrate, placing in brown bottle, diluting with the above hydrochloric acid solution to obtain solution containing 10 μ g per 1ml, and measuring absorbance at 280nm wavelength by spectrophotometry; and precisely weighing a proper amount of cefdinir reference substance, placing the cefdinir reference substance into a brown measuring flask, adding phosphate buffer solution (pH7.0) to dissolve and dilute the cefdinir reference substance to prepare a solution containing 250 mu g of cefdinir in each 1ml, filtering the solution, precisely weighing a proper amount of subsequent filtrate, placing the filtrate into the brown measuring flask, diluting the filtrate with a proper amount of hydrochloric acid solution to prepare a solution containing 10 mu g of cefdinir in each 1ml, and measuring by the same method to calculate the dissolution rate of each tablet. The dissolution rate test results are shown in the following table

The experimental results show that example 2/3, comparative example 3 and the reference drug can complete dissolution within 15 min.

Pharmacological example 3 high temperature high humidity Environment test

Taking 20 dispersible tablets prepared in the examples and the comparative examples, placing each group of 20 dispersible tablets in a watch glass, and calculating the average moisture absorption weight gain rate of each sample by 5 sampling tablets under the condition of high humidity RH 90% (40 ℃) for 1h, 2h, 4h and 8h respectively, wherein in the prior experiment, when the dispersible tablets absorb moisture until the weight gain exceeds 5%, the expansion of tablets is obvious, the strength is obviously reduced, and therefore, the weight gain rate exceeding 5% is taken as the experiment termination condition. The results of the experiments are given in the following table (in%):

experimental results show that the weight gain of the dispersible tablets obtained in examples 1-5 is lower than 5% in 8 hours. While the weight gain of the dispersible tablet and the reference drug obtained in the comparative example 3 is over 5% in 2h respectively.

Combining the results of pharmacological example 1 and pharmacological example 2, it can be seen that the cefdinir dispersible tablets obtained in examples 1 to 5 can maintain a fast dispersion speed and a high dissolution rate, and can also maintain a long time in a humid and hot environment, and particularly, the cefdinir dispersible tablets obtained in example 3 can not only maintain a fast dispersion speed and a high dissolution rate, but also show a good ability to withstand a humid and hot environment. The comparative example 3 and the reference drug, although having a high dispersion speed, could not withstand long-term storage in moist heat storage, and could not achieve a good moist heat resistance. Comparative examples 1 and 2 have a strong moist heat resistant environment, but the dispersion time reached 60 seconds.

Claims

1. A cefdinir dispersible tablet is characterized in that the prescription of the cefdinir dispersible tablet is as follows: 98-102 parts of cefdinir, 0.3-0.8 part of a flavoring agent, 55-65 parts of pretreated crospovidone serving as a disintegrating agent, 120-125 parts of microcrystalline cellulose serving as a filler, 4-6 parts of a lubricant and 4-6 parts of a flow aid; the preparation method of the pretreated crospovidone comprises the following steps: dissolving polyvidone K30 and polyethylene glycol 4000 in anhydrous ethanol to obtain a solution, mixing the solution with crospovidone, and spray-drying to obtain pretreated crospovidone; the weight ratio of the povidone K30 to the polyethylene glycol 4000 is 3-4: 1; the weight ratio of the povidone K30 to the crospovidone is 1: 14-16.

2. A cefdinir dispersible tablet according to claim 1, wherein the cefdinir dispersible tablet is formulated as follows: 100 parts of cefdinir, 0.3-0.8 part of flavoring agent, 60 parts of pretreated crospovidone serving as a disintegrating agent, 120-125 parts of microcrystalline cellulose serving as a filler, 4.5 parts of lubricant and 6 parts of glidant, wherein the weight ratio of povidone K30 to polyethylene glycol 4000 is (3-4): 1; the weight ratio of the povidone K30 to the crospovidone is 1: 15.

3. A cefdinir dispersible tablet according to any one of claims 1 to 2, wherein the flavoring agent is aspartame, the lubricant is magnesium stearate, and the glidant is aerosil.

4. A cefdinir dispersible tablet according to claim 3, wherein the dispersible tablet is prepared by sieving pre-treated crospovidone and the rest of the raw materials respectively, mixing, and tabletting by direct powder compression to obtain the cefdinir dispersible tablet.