CN115844845A - Nifedipine sustained release preparation and preparation method thereof - Google Patents

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a nifedipine sustained-release tablet and a preparation method thereof. Every 1000 tablets of the nifedipine sustained-release tablet contain 20g of nifedipine, 2-6g of acetyl tributyl citrate, 18-24g of povidone, 17-25g of microcrystalline cellulose, 10-16g of hydroxypropyl methylcellulose, 3-7g of polyvinyl alcohol and 1g of magnesium stearate. Wherein the nifedipine is in the form of a solid dispersion. The invention provides a sustained-release tablet which is suitable for industrial production, releases drug stably in the placement process and is bioequivalent to the original preparation and a preparation method thereof.

Description

Nifedipine sustained release preparation and preparation method thereof

Technical Field

The invention relates to a nifedipine sustained-release preparation composition and a preparation method thereof, belonging to the technical field of pharmaceutical preparations.

Background

Nifedipine is a dihydropyridine calcium ion antagonist, has quick response, is a first choice drug for variant angina, and is also widely applied to various types of hypertension. The pharmacokinetic research data show that the biological half-life period of nifedipine is short, the blood concentration fluctuation is large, the adverse reaction is obvious, and experts at home and abroad recommend the sustained-release preparation of nifedipine to better ensure the medication safety of patients and improve the compliance.

The nifedipine sustained release tablet is prepared by strictly controlling the specific surface area (1.0-4.0 m) of raw materials (US 526646) ² The/g) achieves the slow release effect of the preparation, but the common mechanical crushing equipment is difficult to accurately control the granularity of the raw materials, so that more raw material medicine loss is caused, and the production cost of the medicine is increased. Chinese patents CN104138363B and CN103301083B both disclose that nifedipine and povidone (PVP) are dissolved in an organic solvent together and then combined with specific auxiliary materials to prepare a sustained release tablet, but the problem of aging of solid dispersion taking the PVP as a carrier auxiliary material is easily caused in the storage process due to strong hygroscopicity of the PVP, so that drug release in vivo is influenced. The raw material medicines of the acetyltributyl citrate, the povidone and the nifedipine are jointly dissolved, so that the solubility of the nifedipine is improved, the hygroscopicity of the PVP is obviously reduced, and the good water solubility, cohesiveness and film forming property of the PVP are kept, so that the problems of difficult control of granularity and aging of solid dispersoid after the conventional raw material medicines are crushed are solved, and the slow corrosion of a water-soluble framework and the stable release of the nifedipine in the dispersoid are ensured by combining the crushed raw material medicines with the compositions of polyvinyl alcohol, hydroxypropyl methylcellulose and the like with specific molecular weight.

Disclosure of Invention

In view of the problems that the nifedipine sustained-release tablet prepared by the prior art needs to accurately control the granularity (crushing or recrystallization) of the raw material drug and the drug release is unstable after the solid dispersion is aged, the invention aims to provide the sustained-release tablet which is suitable for industrial production, releases drug stably in the placement process and is bioequivalent to the original preparation and the preparation method thereof by optimizing the composition and the process.

The technical scheme of the invention is as follows:

every 1000 tablets of the stable nifedipine sustained-release tablet composition contain 20g of nifedipine, 2-6g of acetyl tributyl citrate, 18-24g of povidone, 17-25g of microcrystalline cellulose, 10-16g of hydroxypropyl methylcellulose, 3-7g of polyvinyl alcohol and 1g of magnesium stearate.

Preferably, each 1000 tablets of the nifedipine sustained-release tablet composition contain 20g of nifedipine, 3-5g of acetyl tributyl citrate, 20-22g of povidone, 19-23g of microcrystalline cellulose, 12-14g of hydroxypropyl methylcellulose, 4-6g of polyvinyl alcohol and 1g of magnesium stearate.

Preferably, each 1000 tablets of the nifedipine sustained-release tablet composition contain 20g of nifedipine, 4g of acetyl tributyl citrate, 21g of povidone, 21g of microcrystalline cellulose, 13g of hydroxypropyl methylcellulose, 5g of polyvinyl alcohol and 1g of magnesium stearate.

Preferably, the nifedipine sustained-release tablet composition provided by the invention is used, wherein the molecular weight of the polyvinyl alcohol is 130-200kDa.

The preparation method of the composition comprises the following steps:

first step preparation of dispersion solution: dissolving nifedipine, acetyl tributyl citrate and povidone in a certain amount of acetone for later use;

and secondly, fluidized bed one-step granulation: adding microcrystalline cellulose, hydroxypropyl methylcellulose and polyvinyl alcohol in the formula amount into a fluidized bed, and granulating by using the dispersion solution prepared in the first step;

thirdly, mixing and tabletting: granulating the granules, mixing with magnesium stearate in a prescription amount uniformly, and tabletting by using a round punch die with the diameter of 6 mm;

fourthly, film coating: coating with 12% water solution of film coating premix (gastric soluble type) to increase the coating weight by 1% -3% to obtain nifedipine sustained release tablets.

The beneficial effects of the invention are:

(1) The preparation process of the nifedipine sustained-release tablet avoids the process and equipment limitation caused by conventional crushing, does not need to control the granularity of the raw material medicine, increases the selectivity of raw material medicine suppliers, reduces the loss and dust pollution of the raw material medicine, and reduces the production cost.

(2) The technical scheme of the invention ensures the good release of the sustained-release tablet by reasonable component selection and combined use of specific proportion, simultaneously overcomes the aging phenomenon of solid dispersion taking PVP as a carrier auxiliary material in the storage process, and the sustained-release tablet of the invention is stored for 6 months under the condition of 40 ℃/75 percent RH high temperature and high humidity acceleration, and has the release stability superior to the original developing agent.

(3) The nifedipine sustained-release tablet prepared by the invention is proved to be equivalent to the original preparation in vivo biology, and provides a new choice for realizing domestic substitution of imported drugs in the future.

The specific implementation mode is as follows:

example 1

Prescription: 20g of nifedipine, 4g of acetyl tributyl citrate, 21g of povidone, 21g of microcrystalline cellulose, 13g of hydroxypropyl methylcellulose, 5g of polyvinyl alcohol, 1g of magnesium stearate and 2.5g of a film coating premix (gastric soluble).

The preparation method comprises the following steps: 1000 tablets are prepared according to the following preparation method, and the specific steps are as follows:

first step preparation of dispersion solution: dissolving nifedipine, acetyl tributyl citrate and povidone in a certain amount of acetone for later use;

and secondly, fluidized bed one-step granulation: adding the microcrystalline cellulose, hydroxypropyl methylcellulose and polyvinyl alcohol in the formula amount into a fluidized bed, and granulating by using the dispersion solution prepared in the first step;

thirdly, mixing and tabletting: after finishing the granules, uniformly mixing the granules with magnesium stearate in a prescription amount, and tabletting by using a round punch die with the diameter of 6 mm;

fourthly, film coating: coating with 12% water solution of film coating premix (gastric soluble type) to obtain nifedipine sustained release tablet with coating weight increased by 1% -3%.

Example 2

Prescription: 20g of nifedipine, 6g of tributyl acetylcitrate, 18g of povidone, 21g of microcrystalline cellulose, 16g of hydroxypropyl methylcellulose, 3g of polyvinyl alcohol, 1g of magnesium stearate and 2.5g of a film coating premix (gastric soluble).

The preparation method comprises the following steps: 1000 tablets were prepared according to the preparation method of example 1.

Example 3

Prescription: 20g of nifedipine, 2g of tributyl acetylcitrate, 24g of povidone, 21g of microcrystalline cellulose, 10g of hydroxypropyl methylcellulose, 7g of polyvinyl alcohol, 1g of magnesium stearate and 2.5g of a film-coated premix (gastric-soluble).

The preparation method comprises the following steps: 1000 tablets were prepared according to the preparation method of example 1.

Comparative example 1

Prescription: 20g of nifedipine, 25g of povidone, 21g of microcrystalline cellulose, 13g of hydroxypropyl methylcellulose, 5g of polyvinyl alcohol, 1g of magnesium stearate and 2.5g of a film coating premix (gastric soluble type).

The preparation method comprises the following steps: 1000 tablets are prepared by the following preparation method, which comprises the following steps:

first step preparation of dispersion solution: dissolving nifedipine and povidone in a certain amount of acetone for later use;

and secondly, fluidized bed one-step granulation: adding the microcrystalline cellulose, hydroxypropyl methylcellulose and polyvinyl alcohol in the formula amount into a fluidized bed, and granulating by using the dispersion solution prepared in the first step;

thirdly, mixing and tabletting: granulating the granules, mixing with magnesium stearate in a prescription amount uniformly, and tabletting by using a round punch die with the diameter of 6 mm;

fourthly, film coating: coating with 12% water solution of film coating premix (gastric soluble type) to obtain nifedipine sustained release tablet with coating weight increased by 1% -3%.

Comparative example 2

Prescription: 20g of nifedipine, 7g of acetyl tributyl citrate, 17g of povidone, 22g of microcrystalline cellulose, 13g of hydroxypropyl methylcellulose, 5g of polyvinyl alcohol, 1g of magnesium stearate and 2.5g of a film coating premix (gastric soluble).

The preparation method comprises the following steps: 1000 tablets were prepared according to the preparation method of example 1.

Comparative example 3

Prescription: 20g of nifedipine, 1g of acetyl tributyl citrate, 25g of povidone, 20g of microcrystalline cellulose, 13g of hydroxypropyl methylcellulose, 5g of polyvinyl alcohol, 1g of magnesium stearate and 2.5g of a film coating premix (gastric soluble).

The preparation method comprises the following steps: 1000 tablets were prepared according to the preparation method of example 1.

Comparative example 4

Prescription: 20g of nifedipine, 4g of acetyl tributyl citrate, 21g of povidone, 23g of microcrystalline cellulose, 8g of hydroxypropyl methylcellulose, 8g of polyvinyl alcohol, 1g of magnesium stearate and 2.5g of a film coating premix (gastric soluble).

The preparation method comprises the following steps: 1000 tablets were prepared according to the preparation method of example 1.

Comparative example 5

Prescription: 20g of nifedipine, 4g of acetyl tributyl citrate, 21g of polyvidone, 19g of microcrystalline cellulose, 18g of hydroxypropyl methylcellulose, 2g of polyvinyl alcohol, 1g of magnesium stearate and 2.5g of a film coating premix (gastric-soluble type).

The preparation method comprises the following steps: 1000 tablets were prepared according to the preparation method of example 1.

Test example 1 in vitro Release degree study

According to the dissolution and release determination method (second method of 0931 in the four general guidelines of the 2020 edition of Chinese pharmacopoeia), the release rates of the original preparation, the products of examples 1-3 and comparative examples 1-5 at 0.5h, 1h and 12h were determined, respectively, and the dissolution similarity factor f2 was calculated and the data are recorded in tables 1 and 2.

Release dissolution conditions: 900mL of 0.3% polysorbate 80 aqueous solution is used as a dissolution medium, and the paddle method is carried out for 75 revolutions. Chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent; methanol-0.01 mol/L disodium hydrogen phosphate solution (55, pH adjusted to 6.1 with phosphoric acid) as mobile phase; the detection wavelength is 230nm; the column temperature is 40 ℃; the flow rate was 1.2mL per minute; sample injection volume is 20 muL.

TABLE 1 dissolution results on day 0 of examples 1 to 3 and comparative examples 1 to 5 (f 2, n =12 in comparison with the original preparation)

Note: f2 is a dissolution curve similarity factor, and when the value of f2 is not less than 50, the dissolution curves are considered to be similar.

From the day 0 dissolution results of table 1: the release degree of the examples 1-3 can be similar to that of the original preparation; the release degree of the comparative example 1 is similar to that of the original preparation, but is obviously faster than that of the example 1, the reason is that the comparative example 1 does not contain water-insoluble stabilizer acetyl tributyl citrate, and the single water-soluble solid dispersion material povidone is more beneficial to the rapid release of the nifedipine bulk drug; in the prescription of the comparative example 2, the dosage of the solid dispersion material povidone is less, the nifedipine bulk drug cannot be well dispersed, and the dosage of the water-insoluble stabilizer is higher, so the dissolution is slow and is not similar to the original preparation; on the contrary, the dissolution of the comparative example 3 is faster and is not similar to the original preparation; in the comparison examples 4-5, the dosage of the slow-release skeleton material hypromellose and the solubilizer polyvinyl alcohol in the formula deviates from the protection range, so the dissolution is respectively faster and slower, which are not similar to the original preparation. By combining the data of the above examples and comparative examples, it can be found that the dosage of the solid dispersion material povidone, the stabilizer acetyltributyl citrate, the sustained release framework material hypromellose, the solubilizer polyvinyl alcohol and other auxiliary materials has an important influence on the 0-day dissolution of the sustained release preparation.

From the accelerated 6 month dissolution results of table 2: the release rate of the comparative example 1 in 0 day is not similar to that of the comparative example 1, and the reason is that the solid dispersion material of the comparative example 1 does not contain a stabilizer, and after the single povidone is aged under the conditions of high temperature and high humidity, part of nifedipine raw material drug molecules are easy to re-aggregate, so that the dissolution is remarkably reduced; similarly, the amount of the stabilizer used in comparative example 3 is small, so that the dissolution rate accelerated for 6 months is not similar to that in 0 day per se; the dosage of the stabilizer in the solid dispersion materials of examples 1-3 and comparative examples 2, 4 and 5 is within the protection range, and the acetyltributyl citrate can effectively inhibit the nucleation and growth of nifedipine while reducing the hygroscopicity of povidone, so that the dissolution in 6 months is accelerated to be similar to that in 0 day per se.

Test example 2 in vivo bioequivalence study

The two-preparation double-period cross design is adopted, and the cleaning period is at least 3 days.

Screening healthy subjects meeting inclusion criteria: (1) the age is more than or equal to 18 years old, and the male and the female can both use the health care product; (2) The weight of a male volunteer is more than or equal to 50.0kg, the weight of a female volunteer is more than or equal to 45.0kg, and the Body Mass Index (BMI) is 19 to 26kg/m ² Between (including boundary values). The test subjects were 36 persons and randomly divided into 2 groups of 18 persons, and the nifedipine sustained-release tablets produced in example 1 were used as test preparations, and the bioequivalence of the two preparations in fasting and postprandial conditions was investigated in comparison with a reference preparation nifedipine sustained-release tablet (II) (trade name: adalat-L20, specification: 20 mg) certified by Japanese Bayer drug Co.

Table 3 data illustrates: example 1 and reference formulations the respective major pharmacokinetic parameters (AUC) under fasting and postprandial test conditions before meal _0-t 、AUC _0-∞ And Cmax) the 90% confidence interval of the geometric mean ratio meets the technical guidance principle requirement (80.00% -125.00%) of human bioequivalence research, which shows that the embodiment 1 is equivalent to the reference preparation and can realize clinical substitution of the reference preparation.

Claims (5)

1. The stable nifedipine sustained-release tablet composition is characterized in that each 1000 tablets contain 20g of nifedipine, 2-6g of acetyl tributyl citrate, 18-24g of povidone, 17-25g of microcrystalline cellulose, 10-16g of hydroxypropyl methylcellulose, 3-7g of polyvinyl alcohol and 1g of magnesium stearate.

2. A nifedipine sustained-release tablet composition according to claim 1, wherein each 1000 tablets contain 20g of nifedipine, 3-5g of acetyl tributyl citrate, 20-22g of povidone, 19-23g of microcrystalline cellulose, 12-14g of hypromellose, 4-6g of polyvinyl alcohol and 1g of magnesium stearate.

3. The nifedipine sustained-release tablet composition according to claim 1, wherein each 1000 tablets contain 20g of nifedipine, 4g of acetyl tributyl citrate, 21g of povidone, 21g of microcrystalline cellulose, 13g of hydroxypropyl methylcellulose, 5g of polyvinyl alcohol and 1g of magnesium stearate.

4. Nifedipine sustained release tablet composition according to claim 1, wherein the molecular weight of the polyvinyl alcohol is 130-200kDa.

5. A method for preparing a nifedipine sustained-release tablet composition is characterized by comprising the following steps:

first step preparation of dispersion solution: dissolving nifedipine, acetyl tributyl citrate and povidone in a certain amount of acetone for later use;

the second step is fluidized bed one-step granulation: adding microcrystalline cellulose, hydroxypropyl methylcellulose and polyvinyl alcohol in the formula amount into a fluidized bed, and granulating by using the dispersion solution prepared in the first step;

thirdly, mixing and tabletting: granulating the granules, mixing with magnesium stearate in a prescription amount uniformly, and tabletting by using a round punch die with the diameter of 6 mm;

fourthly, film coating: coating with 12% water solution of film coating premix (gastric soluble type) to increase the coating weight by 1% -3% to obtain nifedipine sustained release tablets.