CN105581989B - Pharmaceutical composition containing fenofibric acid - Google Patents

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical composition containing fenofibric acid. The product of the invention has good stability, complete dissolution and more excellent product quality; the product of the invention has simple and easy production operation and is suitable for industrial production.

Description

A pharmaceutical composition containing fenofibric acid

technical field

The invention belongs to the technical field of medicines, and in particular relates to a pharmaceutical composition containing fenofibric acid and a preparation method of tablets thereof.

Background technique

Fenofibric acid (English name Fenofibric Acid), its chemical name is: 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropionic acid. Molecular formula: C ₁₇ H ₁₅ ClO ₄ , molecular weight: 318.75, and its structural formula is as follows:

Fenofibric acid is a second-generation phenoxyaromatic acid drug used to treat hypercholesterolemia and hypertriglyceridemia. It is the metabolite and active ingredient of fenofibrate in the human body. Therefore, it has better bioavailability than fenofibrate, and the bioavailability is not affected by food.

Chinese patent CN102172347A discloses a preparation process of fenofibric acid enteric-coated sustained-release capsules, by granulating and pressing tablets to form micro-tablets, each micro-tablet has a diameter of about 3mm, and then coats the micro-tablets with an enteric coating, and then packs The microtablets behind the coat are packed into capsules to make enteric-coated sustained-release capsules. However, the use of microtablet technology also requires further processing and filling of the microtablets into capsules for the convenience of patients to take after the preparation is completed, and also requires the use of special molds and tablet pressing equipment, the production efficiency is relatively low and time-consuming.

Chinese patent CN101780049A discloses a preparation method of fenofibric acid enteric-coated preparations. The active ingredient of fenofibric acid is coated on the pellets, and then coated with an isolation coat and an enteric-coated layer to make an enteric-coated suspension. However, the micropellet process requires fluidized bed bottom spray coating technology, multiple coatings on the micropellets, long processing time, and the prepared suspension is not conducive to patient administration, and the dosage is difficult to control.

None of the above information mentioned fenofibric acid and its physiologically acceptable salt ordinary tablet and its preparation method. Although the dissolution rate can be improved by adopting the wet granulation process, the related substances are relatively high. Therefore, preparing a common fenofibric acid tablet, which has the characteristics of less related substances, complete dissolution and stable quality, to ensure the stability and safety of clinical efficacy, is a technical problem that needs to be solved by those skilled in the art.

Contents of the invention

Based on the above reasons, the applicant has discovered a new pharmaceutical composition of fenofibric acid through research, which contains erythritol and methyl cellulose, and on the basis of ensuring dissolution, it is effective for promoting fenofibric acid. impurity spectrum stability.

The purpose of the present invention is to provide a new pharmaceutical composition containing fenofibric acid, which is prepared into a preparation and has the advantages of good dissolution rate and stable impurity spectrum.

Another object of the present invention is to provide a preparation method of a pharmaceutical composition containing fenofibric acid, which is suitable for industrial production.

Specifically, the present invention provides:

A pharmaceutical composition containing fenofibric acid, comprising: fenofibric acid, lubricant, methylcellulose and erythritol.

The pharmaceutical composition containing fenofibric acid is a tablet.

The weight ratio of the methylcellulose to erythritol is (2-2.3):1.

Described pharmaceutical composition containing fenofibric acid, the weight ratio of each component is:

Fenofibric acid 1~4 parts by weight

3~8 parts by weight of methyl cellulose

Erythritol 1~5 parts by weight

Filler 30~60 parts by weight

1-5 parts by weight of lubricant.

The filler is selected from one or more of starch, lactose, powdered sugar, mannitol, microcrystalline cellulose, and pregelatinized starch.

The lubricant is selected from one or more of micropowder silica gel, talcum powder and magnesium stearate.

The described pharmaceutical composition containing fenofibric acid is prepared into tablet, and its preparation method comprises the following steps: sieving respectively fenofibric acid, methylcellulose, erythritol, filler, lubricant, mixing homogeneously, sieved, mixed evenly, and compressed into tablets to obtain fenofibric acid tablets.

Compared with the prior art, the present invention has the following advantages and positive effects:

1. The product of the present invention has good stability and complete dissolution.

2. The production operation of the product of the present invention is simple and easy, and is suitable for industrial production.

Detailed ways

The present invention will be further described below through the description of specific embodiment, but this is not limitation to the present invention, those skilled in the art can make various modifications or improvements according to the basic idea of the present invention, but as long as not departing from the basic principle of the present invention Thoughts are all within the scope of the present invention.

experiment method

Dissolution Take this product, according to the dissolution determination method (Chinese Pharmacopoeia 2010 edition two appendix XC second method), with pH6.8 phosphate buffer (take 0.2mol/L potassium dihydrogen phosphate solution 250ml, add 0.2mol/L 112ml of sodium hydroxide solution, dilute to 1000ml with water, shake well, to get) 900ml is the dissolution medium, the speed is 75 revolutions per minute, operate according to the law, after 15 minutes, take 10ml of the solution, filter, and the filtrate is used as the test sample solution; take about 10 mg of fenofibric acid reference substance, weigh it accurately, put it in a brown measuring bottle, add pH 6.8 phosphate buffer to dissolve and dilute to make a solution containing 0.04 mg per 1 ml, shake well, and use it as a control product solution. Use water (adjust the pH value to 2.5 with phosphoric acid)-acetonitrile (50:50) as the mobile phase, and the detection wavelength is 286nm. Precisely measure 10 μl each of the test solution and the reference solution, inject them into the liquid chromatograph, and record the chromatograms. The dissolution rate of each tablet was calculated by the peak area according to the external standard method.

For the relevant substance, take an appropriate amount of fine powder (approximately equivalent to 50 mg of fenofibric acid) under the content determination item of this product, accurately weigh it, put it in a 100ml brown measuring bottle, add solvent ((adjust the pH value to 2.5 with phosphoric acid)-acetonitrile (30 :70)) appropriate amount, sonicate (or shake) for 10 minutes to dissolve, dilute to the mark with solvent, centrifuge (or filter) and take supernatant (or continued filtrate) as the test solution; accurately measure appropriate amount, use solvent Dilute to make a solution containing about 1 μg per 1ml, as a control solution; take an appropriate amount of the test solution, add impurity IV at 0.1%, mix well, take this solution and light it for 5 to 10 minutes, and use it as a system suitability test solution. According to high performance liquid chromatography (Chinese Pharmacopoeia 2010 edition two appendix Ⅴ D), use octadecylsilane bonded silica gel (recommended TC-C18, 5μm, 4.6×250mm) as filler; water (adjusted with phosphoric acid) pH value to 2.5) is the mobile phase A, acetonitrile is the mobile phase B, and the linear gradient elution is performed in the following table; the detection wavelength is 286nm. Take 10 μl of the system suitability test solution and inject it into the liquid chromatograph, record the chromatogram, the retention time of the fenofibric acid peak is about 16-18 minutes, the fenofibric acid peak and the impurity II peak (the relative retention time is about 0.9), The resolution of impurity III peak (relative retention time is about 2.36) and impurity IV peak (relative retention time is about 2.42) should meet the requirements. Take 10 μl of the control solution, inject it into the liquid chromatograph, and adjust the detection sensitivity so that the peak height of the main component chromatographic peak is about 10% of the full scale; Instrument, record the chromatogram.

Impurity Ⅰ (RRT=0.65)

Chinese name: 4-Chloro-4`hydroxybenzophenone

English name: 4-Chloro-4'-hydroxybenzophenone

Impurity II (RRT=0.9)

Chinese name: (4-chlorophenyl)[4-(2-hydroxypropyl-2-yl)phenyl]methanone

English name: (4-chlorophenyl)(4-(2-hydroxypropan-2-yl)phenyl)methanone

Impurity Ⅲ (RRT=2.36)

Chinese name: ethyl 2-[4-(4-chlorophenyl)phenoxy]-2-methylpropionate

English name: Ethyl 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoate

Impurity Ⅳ (RRT=2.42)

Chinese name: (4-chlorophenyl)[4-(1-methoxy)phenyl]-methanone

English name: (4-chlorobenzoyl)[4-(1-methylthoxy)phenyl]-methanone

Determination of content Determination according to high performance liquid chromatography (Chinese Pharmacopoeia 2010 edition two appendix V D) determination.

Chromatographic conditions and system suitability test Octadecylsilane bonded silica gel was used as filler; water (adjust pH value to 2.5 with phosphoric acid)-acetonitrile (50:50) was used as mobile phase, and the detection wavelength was 286nm. Take an appropriate amount of fine powder of this product (approximately equivalent to fenofibric acid 10mg), put it in a 100ml measuring bottle, add solvent to dissolve and dilute to the mark, shake well, light for 5 to 10 minutes, accurately measure 10μl and inject it into the liquid chromatograph, The number of theoretical plates calculated based on the fenofibric acid peak should not be less than 3000, and the separation between the fenofibric acid peak and adjacent impurity peaks should meet the requirements.

Determination method Take 20 tablets of this product, accurately weigh, grind finely, accurately weigh an appropriate amount (approximately equivalent to fenofibric acid 10mg), put it in a 100ml brown measuring bottle, add solvent [water (use phosphoric acid to adjust the pH value to 2.5) -Acetonitrile (30:70)] appropriate amount, sonicate (or shake) for 10 minutes to dissolve and dilute to the mark, shake well, centrifuge (or filter), take 10 μl of supernatant (or continued filtrate) according to fenofibric acid Determination under chromatographic conditions under the item of content determination; take another fenofibric acid reference substance about 10mg, weigh it accurately, put it in a 100ml brown measuring bottle, add solvent to dissolve and dilute to the scale, shake well, and measure in the same way. According to the external standard method to calculate the peak area, that is.

Test Example 1: Prescription Screening Test

Take fenofibric acid 3g (content 99.9%, total impurities 0.09%), starch 35g, micropowder silica gel 1.8g respectively, make tablets containing fenofibric acid according to the following prescription, test related substances and dissolution rate, the results are shown in Table 2:

Table 1 Prescription Screening

Table 2 Test results of related substances

The test results show that the related substances prepared by dissolving fenofibric acid and methylcellulose in erythritol and their dissolution rate are better than other methods.

Test Example 2: Influencing Factor Test

Get embodiment 3,5,6,8 product and carry out influence factor test, the results are shown in Table 3.

Table 3 Influencing factors test data

Conclusion: As can be known from the above table, the product prepared by the method of the present invention has better stability under high temperature and light than the comparative example.

Test Example 3: Accelerated Test

Get embodiment 5,6,8 product and carry out accelerated test, the results are shown in Table 4.

Table 4 Accelerated test data

Packaging: commercially available packaging, inspection conditions: temperature 40°C, humidity 75%

Conclusion: As can be known from the above table, the product prepared by the method of the present invention has better stability under high temperature and light than the comparative example.

Preparation example

Example 1

prescription

Fenofibric Acid 1.0g

Methylcellulose 7.2g

Erythritol 3.6g

Starch 35g

Micronized silica gel 1.8g.

Preparation method: sieve fenofibric acid, methylcellulose, erythritol, starch, and micropowdered silica gel respectively, mix, sieve, mix evenly, and press into tablets to obtain fenofibric acid tablets.

Example 2

prescription

Fenofibric Acid 1.5g

Methylcellulose 4.5g

Erythritol 2.0g

Lactose 38g

Talc powder 2.8g.

Preparation method: sieve fenofibric acid, methylcellulose, erythritol, lactose, and talcum powder respectively, mix evenly, sieve, mix evenly, and press into tablets to obtain fenofibric acid tablets.

Example 3

prescription

Fenofibric Acid 2.0g

Methylcellulose 6.2g

Erythritol 2.8g

45g powdered sugar

Micronized silica gel 2.5g.

Preparation method: sieve and mix fenofibric acid, methylcellulose, erythritol, powdered sugar, and micronized silica gel respectively, pass through a 20-mesh sieve, mix for 20 minutes, and press into tablets to obtain fenofibric acid tablets .

Example 4

prescription

Fenofibric Acid 2.5g

Methylcellulose 7.5g

Erythritol 3.6g

Mannitol 54g

Magnesium Stearate 2.5g.

Preparation method: sieve and mix fenofibric acid, methylcellulose, erythritol, mannitol and magnesium stearate respectively, pass through a 20-mesh sieve, mix for 20 minutes, and press into tablets to obtain fenofibric acid tablet.

Example 5

prescription

Fenofibric Acid 3.0g

Methylcellulose 6.8g

Erythritol 3.2g

Microcrystalline Cellulose 37g

Micronized silica gel 1.2g

Magnesium Stearate 0.5g.

Preparation method: sieve fenofibric acid, methylcellulose, erythritol, microcrystalline cellulose, micropowder silica gel and magnesium stearate respectively, mix them evenly, pass through a 20-mesh sieve, mix for 20 minutes, and press into tablets. Fenofibric acid tablets.

Example 6

prescription

Fenofibric Acid 3.5g

Methylcellulose 5.0g

Erythritol 1.8g

Microcrystalline Cellulose 85g

Talc powder 0.8g

Magnesium Stearate 0.5g.

Preparation method: sieve fenofibric acid, methylcellulose, erythritol, microcrystalline cellulose, talcum powder, and magnesium stearate, mix them evenly, pass through a 20-mesh sieve, mix for 20 minutes, and press into tablets. Fenofibric acid tablets.

Example 7

prescription

Fenofibric Acid 4.0g

Methylcellulose 3.0g

Erythritol 1.3g

Pregelatinized starch 53g

Micronized silica gel 4g.

Preparation method: sieve and mix fenofibric acid, methylcellulose, erythritol, pregelatinized starch, and micropowdered silica gel respectively, pass through a 20-mesh sieve, mix for 20 minutes, and press into tablets to obtain fenofibric acid tablet.

Example 8

prescription

Fenofibric Acid 1.0g

Methylcellulose 8.0g

Erythritol 3.5g

Microcrystalline Cellulose 48g

Micronized silica gel 1.5g.

Preparation method: sieve and mix fenofibric acid, methylcellulose, erythritol, crystalline cellulose, and micropowdered silica gel respectively, pass through a 20-mesh sieve, mix for 20 minutes, and press into tablets to obtain fenofibric acid tablets agent.

Example 9

prescription

Fenofibric Acid 2.0g

Methylcellulose 3.0g

Erythritol 1.2g

Mannitol 60g

Talc powder 3g.

Preparation method: sieve fenofibric acid, methylcellulose, erythritol, mannitol, and talcum powder respectively, mix them evenly, pass through a 20-mesh sieve, mix for 20 minutes, and press into tablets to obtain fenofibric acid tablets .

Example 10

prescription

Fenofibric Acid 4.0g

Methylcellulose 7.1g

Erythritol 3.1g

Mannitol 10g

Micronized silica gel 5g.

Preparation method: sieve fenofibric acid, methylcellulose, erythritol, mannitol, and micropowdered silica gel respectively, mix them evenly, pass through a 20-mesh sieve, mix for 20 minutes, and press into tablets to obtain fenofibric acid tablets .

Claims (6)

1. A pharmaceutical composition containing fenofibric acid, characterized in that the composition and weight ratio of each component of the pharmaceutical composition are: 2. The pharmaceutical composition containing fenofibric acid according to claim 1, characterized in that the pharmaceutical composition is prepared into a tablet. 3. The pharmaceutical composition containing fenofibric acid according to claim 1, characterized in that: the weight ratio of methylcellulose to erythritol is 2-2.3:1. 4. the pharmaceutical composition containing fenofibric acid according to claim 1, is characterized in that described filler is selected from starch, lactose, powdered sugar, mannitol, microcrystalline cellulose, pregelatinized starch one or several. 5. The pharmaceutical composition containing fenofibric acid according to claim 1, characterized in that said lubricant is selected from one or more of micropowdered silica gel, talcum powder, and magnesium stearate. 6. the pharmaceutical composition containing fenofibric acid according to claim 2, is characterized in that the preparation method of tablet is: with fenofibric acid, methylcellulose, erythritol, filler, lubricant Sieve separately, mix evenly, sieve, mix evenly, and compress into tablets to obtain fenofibric acid tablets.