CN112121022A - Fenofibrate tablet composition and preparation method thereof - Google Patents

Abstract

The invention relates to a fenofibrate composition, which belongs to the technical field of pharmaceutical preparations. The technical scheme of the present invention is as follows: a fenofibrate tablet composition, in every 1000 tablets, contains: 1 g of fenofibrate with a particle size of 6-10 microns, 36-60 g of food-grade chitosan oligosaccharides, microcrystalline fibers 30-50g of vegetarian food, 20-30g of hydroxypropyl cellulose E5, 8-16g of polysorbate-80, 6-12g of micropowder silica gel, and 1-2g of magnesium stearate. The invention provides a norfibrate composition with uniform content and low incidence of adverse reactions.

Description

A kind of fenofibrate tablet composition and preparation method thereof

technical field

The invention relates to a fenofibrate tablet composition, which belongs to the technical field of pharmaceutical preparations.

Background technique

Fenofibrate was first used clinically in 1975. It is mainly used to treat hyperlipidemia in adults with unsatisfactory dietary control therapy. It is one of the first-choice drugs for lowering triglycerides. It has a more obvious effect than cholesterol, and can also reduce the level of blood uric acid. It also has a good effect on the treatment of type 2 diabetes and metabolic syndrome. It is one of the most commonly used fibrates and has a good effect and tolerance.

According to the biopharmaceutical classification system, fenofibrate is a typical class II drug. The insoluble properties of fenofibrate and the poor dissolution rate make fenofibrate low in bioavailability, and its oral bioavailability is only 35%. Most of the current literature describes how to improve the bioavailability of fenofibrate preparations.

It was clinically found that some patients had abdominal discomfort, diarrhea, and constipation, the most common adverse reactions after taking commercially available fenofibrate, which increased the discomfort of patients and seriously affected the clinical promotion and application of the drug.

SUMMARY OF THE INVENTION

The purpose of the invention is to solve the common adverse reactions such as abdominal discomfort, diarrhea and constipation after taking the existing fenofibrate tablets, and improve the comfort of patients after taking the medicine.

The technical scheme of the present invention is: a fenofibrate tablet composition, each 1000 tablets contains: 1 g of fenofibrate with a particle size of 6-10 microns, 36-60 g of food-grade chitosan oligosaccharides, microcrystalline fibers Vegetarian 30-50g, hydroxypropyl cellulose E5 20-30g, polysorbate-80 8-16g, micropowder silica gel 6-12g, magnesium stearate 1-2g.

In the technical solution of the present invention, polysorbate-80 plays a positive role in improving the dissolution of fenofibrate; the combined effect of food-grade chitosan oligosaccharide, microcrystalline cellulose and hypromellose E5 not only overcomes the fenofibrate Abdominal discomfort, diarrhea, constipation and other common adverse reactions caused by fibrate to patients can meet the requirements of dissolution consistency evaluation. The addition of micropowder silica gel solves the problem of the content uniformity of fenofibrate.

The preferred technical solution of the present invention is: a fenofibrate tablet composition, each 1000 tablets contains: 1 g of fenofibrate with a particle size of 8-9 microns, 45-55 g of food-grade chitosan oligosaccharide, microcrystalline Cellulose 38-45g, hydroxypropyl cellulose E5 25-28g, polysorbate-80 12-15g, micropowder silica gel 8-10g, magnesium stearate 1.5g.

The molecular weight of the food-grade chitosan oligosaccharide of the present invention is 1800-2200.

The preferred technical solution of the present invention is: a fenofibrate tablet composition, each 1000 tablets contains: 1 g of fenofibrate with a particle size of 8.5 microns, 50 g of food-grade chitosan oligosaccharides, 42 g of microcrystalline cellulose, Hypromellose E5 26g, polysorbate-8014g, micropowder silica gel 9g, magnesium stearate 1.5g.

The preparation method of the fenofibrate tablet composition of the present invention comprises the following steps:

Step 1. The fenofibrate API is pulverized to the required particle size, and other solid excipients are passed through an 80-mesh sieve;

Step 2. Mix the recipe amount of fenofibrate, polysorbate-80, and micropowder silica gel evenly, and then mix with the recipe amount of food-grade chitosan oligosaccharide, microcrystalline cellulose, and hypromellose E5 in a fluidized bed. uniform;

Step 3. To the obtained in step 2, spray 30-45% aqueous ethanol solution, and granulate;

Step 4. Whole grain, dry at 60℃;

Step 5. Add the prescribed amount of magnesium stearate and compress.

Beneficial effects:

According to the preparation method of the present invention, fenofibrate is firstly mixed with micropowder silica gel, and then mixed with other auxiliary materials for granulation, which can improve the content uniformity of the tablet; 30% ethanol aqueous solution is used for granulation, which can improve the dissolution of the tablet Spend. Using the method of spraying 30-45% ethanol aqueous solution, the viscosity of chitosan oligosaccharide is used for granulation, preferably 35-40% ethanol aqueous solution.

If the granulation is sprayed with water or an ethanol solution with a concentration of less than 30%, the hardness of the resulting tablet is too large, which will affect the dissolution of the drug. If the concentration of the ethanol aqueous solution is too large, it is not conducive to production safety control. Therefore, choose to spray 30-45% ethanol aqueous solution for granulation.

Beneficial effects: The present invention provides a fenofibrate tablet composition, which can reduce the adverse reactions of patients after taking the composition while meeting the stipulations of the Pharmacopoeia.

Example 1. 2 g of fenofibrate with a particle size of 6 microns, 72 g of food-grade chitosan oligosaccharide, 100 g of microcrystalline cellulose, 40 g of hypromellose E5, 32 g of polysorbate-80, 12 g of micropowder silica gel, stearic acid Magnesium 2g. It is prepared according to the preparation method described in the technical scheme of the manual, and 30% ethanol aqueous solution is used for spray granulation to prepare 2000 tablets.

Example 2. 2 g of fenofibrate with a particle size of 10 microns, 120 g of food-grade chitosan oligosaccharide, 60 g of microcrystalline cellulose, 60 g of hypromellose E5, 16 g of polysorbate-80, 24 g of micropowder silica gel, stearic acid Magnesium 4g. According to the preparation method described in the technical scheme of the manual, 45% ethanol aqueous solution was used for spray granulation, and 2000 tablets were prepared.

Example 3. 2 g of fenofibrate with a particle size of 8.5 microns, 100 g of food-grade chitosan oligosaccharide, 84 g of microcrystalline cellulose, 52 g of hypromellose E5, 28 g of polysorbate-80, 18 g of micropowder silica gel, stearic acid Magnesium 3g. According to the preparation method described in the technical scheme of the manual, spray 35% ethanol aqueous solution for granulation, and prepare 2000 tablets.

Comparative Example 1. The prescription was the same as that of Example 3, and 1000 tablets were prepared according to the following method.

The preparation method of the fenofibrate tablet composition of the present invention comprises the following steps:

Step 1. The fenofibrate API is pulverized to the required particle size, and other solid excipients are passed through an 80-mesh sieve;

Step 2. Take fenofibrate, polysorbate-80, micropowder silica gel, food-grade chitosan oligosaccharide, microcrystalline cellulose, and hypromellose E5 in the prescribed amount, and place it in a fluidized bed to mix evenly.

Step 3. To the obtained in step 2, spray 12-16g of 30-45% ethanol aqueous solution, and granulate.

Step 4. Whole grains, drying at 60℃.

Step 5. Add the prescribed amount of magnesium stearate and compress.

Comparative Example 2. Adjustment with reference to the prescription of Example 3

2g of fenofibrate with a particle size of 8.5 microns, 20g of food-grade chitosan oligosaccharide, 144g of microcrystalline cellulose, 572g of hydroxypropylcellulose E572g, 28g of polysorbate-80, 18g of micropowder silica gel, and 3g of magnesium stearate. According to the preparation method described in the technical scheme of the manual, spray 35% ethanol aqueous solution for granulation, and prepare 2000 tablets.

Comparative Example 3. Adjustment with reference to the prescription of Example 3

2g of fenofibrate with a particle size of 8.5 microns, 120g of food-grade chitosan oligosaccharide, 40g of microcrystalline cellulose, 596g of hypromellose E, 28g of polysorbate-80, 18g of micropowder silica gel, and 3g of magnesium stearate. According to the preparation method described in the technical scheme of the manual, spray 35% ethanol aqueous solution for granulation, and prepare 2000 tablets.

Comparative Example 4. Adjustment with reference to the prescription of Example 3

2g of fenofibrate with a particle size of 8.5 microns, 100g of food-grade chitosan oligosaccharide, 120g of microcrystalline cellulose, 580g of hypromellose, 28g of polysorbate-80, 18g of micropowder silica gel, 3g of magnesium stearate, spray 35% ethanol aqueous solution was granulated to prepare 2000 tablets.

Comparative Example 5. The recipe was the same as that of Example 3, and 2000 tablets were prepared by spraying purified water and granulating according to the preparation method described in the technical solution of the specification.

Test Example 1. Take the products of Examples 1-3 and Comparative Example 1 respectively, and measure the content uniformity according to the content uniformity determination method stipulated in the 2015 edition of the Pharmacopoeia. The data are recorded in Table 1.

Content uniformity: Take 1 tablet of this product, put it in a 100ml measuring bottle, add 50ml of water, ultrasonicate for 15min to dissolve, let cool, dilute to the mark with water, shake well, filter, precisely measure 5ml of the subsequent filtrate and put it in a 50ml measuring bottle , diluted with water to the mark, shake well, as the test solution. Precisely measure 20μl and inject it into the liquid chromatograph to record the chromatogram; another appropriate amount of fenofibrate reference substance is taken, accurately weighed, dissolved in water and quantitatively diluted to make a solution containing about 100μg of fenofibrate per 1ml, as a control product solution. Determined by the same method, calculated by the peak area according to the external standard method. The results are recorded in Table 1.

Table 1

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The data in Table 1 shows that the content uniformity of the tablets prepared by the preparation method of the present invention meets the standard requirements. In contrast, in Comparative Example 1, the adjuvant was directly mixed, and the content uniformity was not up to the standard. It shows that the preparation method of the present invention has a positive effect on the content uniformity.

Test Example 2. According to the second method of the dissolution measurement method specified in Appendix XC of the 2015 edition of the Pharmacopoeia, the paddle method, the dissolution medium is 900ml, the temperature is set to (37±0.5°C) and the rotation speed is 75 r/min to measure Examples 1-3 respectively , The dissolution rate of the products of Comparative Example 2-5 in pH1.0 medium (0.025 mol/ SDS (sodium dodecyl sulfate)), pH4.0 medium, pH6.8 medium, and water medium, respectively at 10min and 15min , 30min, 45min, 60min, 90min sampling to detect dissolution, the data are recorded in Table 2-Table 6.

The reference preparation market was purchased by Beijing Yimin Pharmaceutical Co., Ltd., and the specification is 0.1g.

Table 2 Summary of cumulative dissolution data of 0.025 mol/ SDS pH 1.0 hydrochloric acid solution medium (Examples 1-3)

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Table 3 Summary of cumulative dissolution data of 0.025 mol/ SDS pH 1.0 hydrochloric acid solution medium (Comparative Example 2-5)

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Table 2, Table 3 data description: compared with the reference preparation, the dissolution rate of the sample of the present invention is greater than 50, and meets the requirements of consistency evaluation in the pH 1.0 hydrochloric acid solution medium; while the product f ₂ of the comparative example _2-5 is greater than 50. All are less than 50, which do not meet the requirements for consistency evaluation.

Therefore, in the subsequent pH4.0 medium, pH6.8 medium, and water medium, the dissolution studies of the products of Comparative Examples 2-5 were not carried out.

Table 4 Summary of cumulative dissolution data in pH4.0 acetate buffer medium (Examples 1-3)

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The data in Table 4 shows that the dissolution behavior of the fenofibrate tablets obtained in Examples 1-3 in a pH 4.0 acetate buffer medium is consistent with the reference.

Table 5 Summary of cumulative dissolution data in pH6.8 phosphate buffer medium (Examples 1-3)

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The data in Table 5 shows that the dissolution behavior of the fenofibrate tablets obtained in Examples 1-3 in a pH 6.8 phosphate buffer medium is consistent with the reference.

Table 6 Summary of Cumulative Dissolution Data in Aqueous Medium (Examples 1-3)

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The data in Table 6 shows that the dissolution behavior of the fenofibrate tablets obtained in Examples 1-3 in an aqueous medium is consistent with the reference.

The above dissolution results show that the dissolution behavior of the final formulation and the reference preparation in water, pH4.0 acetate buffer and pH6.8 phosphate buffer dissolution medium are similar, which are in line with the product development goals.

Test example 3. 210 patients with mild hyperlipidemia (no other diseases), aged 38-65 years old, were admitted to the outpatient clinic and were randomly divided into 7 groups, 30 people in each group, respectively taking commercially available fenofibrate tablets, Example 1- 3 fenofibrate tablets, control examples 2-4 fenofibrate tablets, in order to reduce stomach discomfort, the doctor ordered to take it with the diet. On the first day, take orally, 1 tablet at a time, 3 times a day. From the second day onwards, take 1 tablet each time, 1 time a day, together with the morning. The period was 30 days. During the experiment, they ate a normal diet, and did not eat cold, spicy food, and recorded their feelings after taking the medicine. On day 30, summary data were collected and recorded in Table 7.

Table 7 Summary of feelings after taking the drug

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The data in Table 7 shows that the product prepared by the technical solution of the present invention has well overcome the adverse reactions such as abdominal discomfort, diarrhea, and constipation after the patient takes it, and has greatly improved the comfort of the patient after taking the medicine.

Claims (4)

1. a fenofibrate tablet composition is characterized in that, in every 1000 pieces, containing: particle diameter is the fenofibrate 1g of 6-10 microns, food grade chitosan oligosaccharide 36-60g, microcrystalline cellulose 30-50g, hydroxypropyl cellulose E5 20-30g, polysorbate-80 8-16g, micropowder silica gel 6-12g, magnesium stearate 1-2g. 2. fenofibrate tablet composition according to claim 1 is characterized in that, in every 1000 pieces, containing: particle diameter is 8-9 micron fenofibrate 1g, food grade chitosan oligosaccharide 45-55g, Microcrystalline cellulose 38-45g, hydroxypropyl cellulose E5 25-28g, polysorbate-80 12-15g, micropowder silica gel 8-10g, magnesium stearate 1.5g. 3. fenofibrate tablet composition according to claim 1, is characterized in that, in every 1000 pieces, containing: particle diameter is 8.5 microns fenofibrate 1g, food grade chitosan oligosaccharide 50g, microcrystalline cellulose 42g, hydroxypropyl cellulose E5 26g, polysorbate-8014g, micropowder silica gel 9g, magnesium stearate 1.5g. 4. the preparation method of the described fenofibrate tablet composition of claim 1, is characterized in that, comprises the following steps: Step 1. The fenofibrate API is pulverized to the required particle size, and other solid excipients are passed through an 80-mesh sieve; Step 2. Mix the recipe amount of fenofibrate, polysorbate-80, and micropowder silica gel evenly, and then mix with the recipe amount of food-grade chitosan oligosaccharide, microcrystalline cellulose, and hypromellose E5 in a fluidized bed. uniform; Step 3. To the obtained in step 2, spray 30-45% aqueous ethanol solution, and granulate; Step 4. Whole grain, dry at 60℃; Step 5. Add the prescribed amount of magnesium stearate and compress.