A nifedipine sustained-release preparation and preparation method thereof

Abstract

The present invention belongs to the technical field of pharmaceutical preparations, and specifically relates to a nifedipine sustained-release tablet and a preparation method thereof. The nifedipine sustained-release tablet of the present invention contains 20g of nifedipine, 2-6g of tributyl acetyl citrate, 18-24g of povidone, 17-25g of microcrystalline cellulose, 10-16g of hypromellose, 3-7g of polyvinyl alcohol, and 1g of magnesium stearate per 1000 tablets. Among them, nifedipine exists in the form of a solid dispersion. The present invention provides a sustained-release tablet suitable for industrial production, which has stable drug release during placement and is bioequivalent to the original formulation, and a preparation method thereof.

Description

Technical Field

[0001] The invention relates to a nifedipine sustained-release preparation composition and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. Background Art

[0002] Nifedipine is a dihydropyridine calcium ion antagonist with rapid onset of action. It is the first choice for variant angina pectoris and is also widely used in various types of hypertension. Pharmacokinetic research data show that nifedipine has a short biological half-life, large fluctuations in blood drug concentration, and obvious adverse reactions. Domestic and foreign experts recommend the use of nifedipine sustained-release preparations to better ensure the safety of patients' medication and improve compliance.

[0003] The original patent of Bayer (US526646) of Nifedipine sustained-release tablets was obtained by strictly controlling the specific surface area of ​​the raw material (1.0-4.0m 2 / g) to achieve the sustained-release effect of the preparation, but ordinary mechanical crushing equipment is difficult to accurately control the particle size of the raw materials, which will cause a large amount of raw material loss and increase the production cost of the drug. Chinese patents CN104138363B and CN103301083B both disclose the use of nifedipine and polyvinylpyrrolidone (PVP) co-dissolved in an organic solvent and then combined with specific excipients to prepare sustained-release tablets, but the strong hygroscopicity of PVP causes the solid dispersion using it as a carrier excipient to easily age during storage, thereby affecting the drug release in vivo. The present invention utilizes tributyl acetyl citrate, povidone and nifedipine bulk drug to dissolve together, thereby improving the solubility of nifedipine and significantly reducing the hygroscopicity of PVP, while retaining the good water solubility, adhesion and film-forming properties of PVP, thereby overcoming the problems of difficult particle size control and aging of solid dispersions after conventional bulk drugs are crushed, and then combined with a composition such as polyvinyl alcohol and hydroxypropyl methylcellulose with a specific molecular weight to ensure the slow erosion of the water-soluble skeleton and the steady release of nifedipine in the dispersion. Summary of the invention

[0004] In view of the problem that the nifedipine sustained-release tablets prepared by the prior art require precise control of the particle size of the raw material (crushing or recrystallization) and that the drug release of the solid dispersion is unstable after aging, the purpose of the present invention is to provide a sustained-release tablet and preparation method suitable for industrial production, which has stable drug release during storage and is bioequivalent to the original formulation by optimizing the composition and process.

[0005] The technical solution of the present invention is:

[0006] A stable nifedipine sustained-release tablet composition, each 1000 tablets containing 20g of nifedipine, 2-6g of acetyl tributyl citrate, 18-24g of povidone, 17-25g of microcrystalline cellulose, 10-16g of hypromellose, 3-7g of polyvinyl alcohol and 1g of magnesium stearate.

[0007] Preferably, the nifedipine sustained-release tablet composition of the present invention contains 20 g of nifedipine, 3-5 g of acetyl tributyl citrate, 20-22 g of povidone, 19-23 g of microcrystalline cellulose, 12-14 g of hypromellose, 4-6 g of polyvinyl alcohol, and 1 g of magnesium stearate per 1,000 tablets.

[0008] Preferably, the nifedipine sustained-release tablet composition of the present invention contains 20 g of nifedipine, 4 g of acetyl tributyl citrate, 21 g of povidone, 21 g of microcrystalline cellulose, 13 g of hypromellose, 5 g of polyvinyl alcohol, and 1 g of magnesium stearate per 1,000 tablets.

[0009] Preferably, in the nifedipine sustained-release tablet composition of the present invention, the molecular weight of the polyvinyl alcohol is 130-200 kDa.

[0010] The preparation method of the composition of the present invention comprises the following steps:

[0011] The first step is to prepare a dispersion solution: dissolve nifedipine, tributyl acetyl citrate and povidone in a certain amount of acetone for later use;

[0012] The second step is fluidized bed one-step granulation: adding the prescribed amount of microcrystalline cellulose, hypromellose, and polyvinyl alcohol into the fluidized bed, and granulating with the dispersion solution prepared in the first step;

[0013] The third step is mixed tableting: the above granules are granulated and mixed evenly with the prescribed amount of magnesium stearate, and tableted using a φ6mm round die;

[0014] The fourth step is film coating: use 12% aqueous solution of film coating premix (gastric soluble type) for coating, and the coating weight gain is 1%-3% to obtain nifedipine sustained-release tablets.

[0015] The beneficial effects of the present invention are:

[0016] (1) The preparation process of the nifedipine sustained-release tablets of the present invention avoids the process and equipment limitations brought about by conventional pulverization, does not require control of the particle size of the API, increases the selectivity of API suppliers, reduces API loss and dust pollution, and reduces production costs.

[0017] (2) The technical solution of the present invention ensures good release of the sustained-release tablets by reasonable component selection and combined use in a specific proportion, while overcoming the aging phenomenon of the solid dispersion with PVP as a carrier excipient during storage. The sustained-release tablets of the present invention are stored under accelerated conditions of high temperature and high humidity at 40°C / 75%RH for 6 months, and have a release stability that is better than that of the original preparation.

[0018] (3) The nifedipine sustained-release tablets prepared by the present invention have been confirmed to be bioequivalent to the original formulation in vivo, providing a new option for domestic substitution of imported drugs in the future. DETAILED DESCRIPTION

[0019] Example 1

[0020] Prescription: nifedipine 20g, acetyl tributyl citrate 4g, povidone 21g, microcrystalline cellulose 21g, hypromellose 13g, polyvinyl alcohol 5g, magnesium stearate 1g, film coating premix (gastric soluble) 2.5g.

[0021] Preparation method: 1000 tablets were prepared according to the following preparation method. The specific steps are as follows:

[0022] The first step is to prepare the dispersion solution: dissolve nifedipine, tributyl acetyl citrate and povidone in a certain amount of acetone and set aside;

[0023] The second step is fluidized bed one-step granulation: adding the prescribed amount of microcrystalline cellulose, hypromellose, and polyvinyl alcohol into the fluidized bed, and granulating with the dispersion solution prepared in the first step;

[0024] The third step is mixed tableting: the above granules are granulated and mixed evenly with the prescribed amount of magnesium stearate, and tableted using a φ6mm round die;

[0025] The fourth step is film coating: use 12% aqueous solution of film coating premix (gastric soluble type) for coating, and the coating weight gain is 1%-3% to obtain nifedipine sustained-release tablets.

[0026] Example 2

[0027] Prescription: nifedipine 20g, acetyl tributyl citrate 6g, povidone 18g, microcrystalline cellulose 21g, hypromellose 16g, polyvinyl alcohol 3g, magnesium stearate 1g, film coating premix (gastric soluble) 2.5g.

[0028] Preparation method: Prepare 1000 tablets according to the preparation method in Example 1.

[0029] Example 3

[0030] Prescription: nifedipine 20g, acetyl tributyl citrate 2g, povidone 24g, microcrystalline cellulose 21g, hypromellose 10g, polyvinyl alcohol 7g, magnesium stearate 1g, film coating premix (gastric soluble) 2.5g.

[0031] Preparation method: Prepare 1000 tablets according to the preparation method in Example 1.

[0032] Comparative Example 1

[0033] Prescription: nifedipine 20g, povidone 25g, microcrystalline cellulose 21g, hypromellose 13g, polyvinyl alcohol 5g, magnesium stearate 1g, film coating premix (gastric soluble) 2.5g.

[0034] Preparation method: 1000 tablets were prepared according to the following preparation method. The specific steps are as follows:

[0035] The first step is to prepare a dispersion solution: dissolve nifedipine and povidone in a certain amount of acetone for later use;

[0036] The second step is fluidized bed one-step granulation: adding the prescribed amount of microcrystalline cellulose, hypromellose, and polyvinyl alcohol into the fluidized bed, and granulating with the dispersion solution prepared in the first step;

[0037] The third step is mixing and tableting: the above granules are granulated and mixed evenly with the prescribed amount of magnesium stearate, and tableted using a φ6mm round die;

[0038] The fourth step is film coating: use 12% aqueous solution of film coating premix (gastric soluble type) for coating, and the coating weight gain is 1%-3% to obtain nifedipine sustained-release tablets.

[0039] Comparative Example 2

[0040] Prescription: nifedipine 20g, acetyl tributyl citrate 7g, povidone 17g, microcrystalline cellulose 22g, hypromellose 13g, polyvinyl alcohol 5g, magnesium stearate 1g, film coating premix (gastric soluble) 2.5g.

[0041] Preparation method: Prepare 1000 tablets according to the preparation method in Example 1.

[0042] Comparative Example 3

[0043] Prescription: nifedipine 20g, acetyl tributyl citrate 1g, povidone 25g, microcrystalline cellulose 20g, hypromellose 13g, polyvinyl alcohol 5g, magnesium stearate 1g, film coating premix (gastric soluble) 2.5g.

[0044] Preparation method: Prepare 1000 tablets according to the preparation method in Example 1.

[0045] Comparative Example 4

[0046] Prescription: nifedipine 20g, acetyl tributyl citrate 4g, povidone 21g, microcrystalline cellulose 23g, hypromellose 8g, polyvinyl alcohol 8g, magnesium stearate 1g, film coating premix (gastric soluble) 2.5g.

[0047] Preparation method: Prepare 1000 tablets according to the preparation method in Example 1.

[0048] Comparative Example 5

[0049] Prescription: nifedipine 20g, acetyl tributyl citrate 4g, povidone 21g, microcrystalline cellulose 19g, hypromellose 18g, polyvinyl alcohol 2g, magnesium stearate 1g, film coating premix (gastric soluble) 2.5g.

[0050] Preparation method: Prepare 1000 tablets according to the preparation method in Example 1.

[0051] Test Example 1 In vitro release study

[0052] According to the dissolution and release determination method (Method 2 of Part IV of the Chinese Pharmacopoeia 2020 Edition, General Rules 0931), the release of the original preparation, Examples 1-3 and Control Examples 1-5 products at 0.5h, 1h, and 12h was determined, and the dissolution similarity factor f2 was calculated. The data are recorded in Tables 1 and 2.

[0053] Release dissolution conditions: 900 mL of 0.3% polysorbate 80 aqueous solution as dissolution medium, paddle method 75 rpm. Chromatographic conditions: octadecylsilane bonded silica gel as filler; methanol-0.01 mol / L disodium hydrogen phosphate solution (55:45, pH adjusted to 6.1 with phosphoric acid) as mobile phase; detection wavelength 230 nm; column temperature 40 °C; flow rate 1.2 mL per minute; injection volume 20 µL.

[0054] Table 1 0-day dissolution results of Examples 1-3 and Comparative Examples 1-5 (compared with original preparation f2, n=12)

[0055]

[0056] Note: f2 is the dissolution curve similarity factor. When the f2 value is not less than 50, the dissolution curves can be considered similar.

[0057] From the 0-day dissolution results in Table 1, the release rates of Examples 1-3 are all similar to the original formulation; the release rate of Control Example 1 is similar to the original formulation, but significantly faster than that of Example 1. The reason is that Control Example 1 does not contain the water-insoluble stabilizer tributyl acetyl citrate, and the separate water-soluble solid dispersion material povidone is more conducive to the rapid release of the nifedipine bulk drug; the amount of the solid dispersion material povidone in the prescription of Control Example 2 is relatively small, which cannot disperse the nifedipine bulk drug well, and the amount of the water-insoluble stabilizer is relatively high, so the dissolution is slow and not similar to the original formulation; on the contrary, the dissolution of Control Example 3 is fast and also not similar to the original formulation; the amounts of the sustained-release skeleton material hydroxypropyl methylcellulose and the solubilizer polyvinyl alcohol in the prescriptions of Control Examples 4-5 deviate from the protection range, so the dissolution is fast and slow, respectively, and is not similar to the original formulation. Based on the data of the above embodiments and comparative examples, it can be found that the dosage of excipients such as the solid dispersion material povidone and the stabilizer tributyl acetyl citrate, the sustained-release skeleton material hydroxypropyl methylcellulose and the solubilizer polyvinyl alcohol has an important influence on the 0-day dissolution of the sustained-release preparation.

[0058] From the results of accelerated dissolution in 6 months in Table 2, it can be seen that the release of Control Example 1 is not similar to that of its own 0-day release. The reason is that the solid dispersion material of Control Example 1 does not contain a stabilizer. After aging under high temperature and high humidity conditions, the single polyvidone is prone to cause some nifedipine raw material molecules to re-aggregate, thereby causing a significant decrease in dissolution; similarly, the amount of stabilizer used in Control Example 3 is relatively small, so the accelerated dissolution in 6 months is not similar to that of its own 0 day; while the amount of stabilizer used in the solid dispersion materials of Examples 1-3, Control Examples 2, 4, and 5 is within the protection range, and tributyl acetyl citrate can effectively inhibit the formation and growth of nifedipine crystal nuclei while reducing the hygroscopicity of polyvidone, so the accelerated dissolution in 6 months is similar to that of its own 0 day.

[0059] Test Example 2 In vivo bioequivalence study

[0060] A two-preparation, two-period crossover design was used with a washout period of at least 3 days.

[0061] Healthy subjects who meet the inclusion criteria were selected: (1) aged ≥18 years, both males and females; (2) male volunteers weighed ≥50.0 kg, female volunteers weighed ≥45.0 kg, and body mass index (BMI) was between 19 and 26 kg / m 2 The number of subjects was 36, who were randomly divided into 2 groups, 18 in each group, and the nifedipine sustained-release tablets produced in Example 1 were used as the test preparation, and compared with the reference preparation nifedipine sustained-release tablets (II) (trade name: Adalat-L20, specification: 20 mg) certified by Bayer Pharmaceuticals Co., Ltd. Japan to study the bioequivalence of the two preparations in humans under fasting and postprandial conditions.

[0062]

[0063] Table 3 Data Description: Main pharmacokinetic parameters (AUC 0-t , AUC 0-∞ The 90% confidence intervals of the geometric mean ratios of Cmax and Cmax all meet the requirements of the technical guidelines for human bioequivalence studies (80.00%-125.00%), indicating that Example 1 is equivalent to the reference preparation and can achieve clinical substitution for the reference preparation.

Claims

1. A stable nifedipine sustained-release tablet composition, characterized in that: Each 1000 tablets contains 20g of nifedipine, 2-6g of tributyl acetyl citrate, 18-24g of povidone, 17-25g of microcrystalline cellulose, 10-16g of hypromellose, 3-7g of polyvinyl alcohol, and 1g of magnesium stearate, wherein the molecular weight of the polyvinyl alcohol is 130-200kDa.

2. The nifedipine sustained-release tablet composition according to claim 1, characterized in that: Each 1000 tablets contains 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, characterized in that: Each 1000 tablets contains 20g of nifedipine, 4g of acetyl tributyl citrate, 21g of povidone, 21g of microcrystalline cellulose, 13g of hypromellose, 5g of polyvinyl alcohol, and 1g of magnesium stearate.

4. A method for preparing the nifedipine sustained-release tablet composition according to claim 1, characterized in that The following steps are involved: The first step is to prepare the dispersion solution: dissolve nifedipine, tributyl acetyl citrate and povidone in a certain amount of acetone and set aside; The second step is fluidized bed one-step granulation: adding the prescribed amount of microcrystalline cellulose, hypromellose, and polyvinyl alcohol into the fluidized bed, and granulating with the dispersion solution prepared in the first step; The third step is mixing and tableting: the above granules are granulated and mixed evenly with the prescribed amount of magnesium stearate, and tableted using a φ6mm round die; The fourth step is film coating: use 12% aqueous solution of film coating premix (gastric soluble type) for coating, and the coating weight gain is 1%-3% to obtain nifedipine sustained-release tablets.

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