Nifedipine biphase sustained release preparation and preparation method thereof

Abstract

The invention belongs to the technical field of medical drugs, and discloses a nifedipine biphase sustained release preparation and a preparation method thereof. The nifedipine biphase sustained-release preparation consists of a double-layer tablet core and a film coating, wherein the double-layer tablet core consists of a drug-containing quick-release layer and a drug-containing sustained-release layer; nifedipine is respectively dispersed in the sustained-release layer and the quick-release layer according to a certain proportion. The biphasic sustained release preparation provided by the invention can take effect quickly, has stable and lasting drug effect, is safe and reliable, and is simple and efficient in preparation process.

Description

Technical Field

[0001] This invention belongs to the field of medical and pharmaceutical technology, specifically relating to a nifedipine biphasic sustained-release formulation and its preparation method. Background Technology

[0002] Nifedipine, chemically known as dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydro-3,5-pyridine-dicarboxylate, has the molecular formula C2. 17 H 18 N2O6 is a dihydropyridine calcium channel blocker that can be used to prevent and treat angina pectoris in coronary heart disease, especially variant angina and angina pectoris caused by coronary artery spasm. It is also suitable for various types of hypertension and has a good effect on refractory and severe hypertension.

[0003] Currently, my country has a huge number of oral nifedipine preparations, but their quality varies greatly, and there are still many problems in their clinical application and formulation development. ① Nifedipine, as a short-acting calcium channel blocker, has a rapid onset of action, but its effect is short-lived and requires multiple administrations throughout the day; ②Ordinary immediate-release formulations are difficult to maintain efficacy for a long time, and the release rate is unstable, resulting in large fluctuations in blood drug concentration in users, which can easily lead to adverse reactions such as hypotension and sympathetic nerve excitation. ③ Existing nifedipine slow-release systems cannot take effect quickly and also have drawbacks such as complex technology, high production costs, and low production efficiency. Summary of the Invention

[0004] To address the above problems, the present invention aims to provide a nifedipine sustained-release formulation with a dual-phase release mechanism. The dual-phase sustained-release formulation provided by the present invention exhibits rapid onset of action, stable and sustained efficacy, safety and reliability, and a simple and low-cost manufacturing process.

[0005] The technical solution of this invention is: a nifedipine biphasic sustained-release formulation, which comprises a bilayer tablet core consisting of a drug-containing immediate-release layer and a drug-containing sustained-release layer, and a film coating. The weight ratio of the drug-containing immediate-release layer to the drug-containing sustained-release layer of nifedipine is 1:8 to 1:10, preferably 1:9. The drug-containing immediate-release layer includes a therapeutically effective amount of nifedipine and pharmaceutically acceptable immediate-release layer excipients. The immediate-release layer excipients include one or more of fillers, disintegrants, and lubricants, with the following mass percentages: 1-4 parts nifedipine, 85-95 parts filler, 5-15 parts disintegrant, and 0.1-0.5 parts lubricant.

[0006] Furthermore, the filler is selected from one or more of sucrose, lactose, mannitol, microcrystalline cellulose, dicalcium phosphate, and starch; the disintegrant is selected from one or more of corn starch, microcrystalline cellulose, croscarmellose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose; and the lubricant is selected from one or more of colloidal silica, magnesium stearate, and calcium stearate.

[0007] The drug-containing sustained-release layer includes a therapeutically effective amount of nifedipine and pharmaceutically acceptable sustained-release layer excipients. The sustained-release layer excipients include one or more of the following: hydrophilic gel matrix material, binder, filler, disintegrant, and lubricant. The mass fractions of each component are as follows: 5-10 parts of nifedipine, 20-40 parts of hydrophilic gel matrix material, 7-12 parts of binder, 30-50 parts of filler, 2-5 parts of disintegrant, and 0.1-0.5 parts of lubricant.

[0008] Furthermore, the hydrophilic gel skeleton material is selected from one or more of xanthan gum, sodium alginate, sodium carboxymethyl cellulose, carbomer, and hydroxymethyl cellulose; the binder is selected from one or more of povidone, pregelatinized starch, and gelatin; the filler is selected from one or more of sucrose, lactose, microcrystalline cellulose, dextrin, and starch; the disintegrant is selected from one or more of corn starch, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose; and the lubricant is selected from one or more of colloidal silica, magnesium stearate, and talc.

[0009] Furthermore, the hydrophilic gel skeleton material containing the drug-releasing layer is composed of sodium alginate and sodium carboxymethyl cellulose in a mass ratio of 1-4:3-6.

[0010] Furthermore, the filler of the above-mentioned drug-containing sustained-release layer is composed of lactose and microcrystalline cellulose in a mass ratio of 1-4:10-16.

[0011] Furthermore, the filler for the aforementioned drug-containing quick-release layer is composed of corn starch and lactose in a mass ratio of 7-10:3-5.

[0012] The present invention also aims to provide a method for preparing the aforementioned nifedipine biphasic sustained-release formulation, the method comprising the following steps: 1. Preparation of sustained-release granules (1) Add the required amount of nifedipine, hydrophilic gel skeleton material, filler and disintegrant for the sustained-release layer into the granulation pot and stir continuously until the materials are evenly mixed. (2) Add the amount of binder required for the sustained-release layer formulation to water and stir continuously until completely dissolved to form a uniform aqueous suspension for later use. (3) Add the aqueous suspension described in step (2) to the uniformly mixed material, stir and granulate, dry the obtained granules, and granulate the dried granules with a round hole sieve for later use. (4) Add the amount of lubricant required for the sustained-release layer formulation to the particles described in step (3), mix evenly, and set aside.

[0013] 2. Preparation of Immediate-Release Granules (1) Add the required amount of nifedipine, filler and disintegrant for the immediate release layer into the granulation pot and stir continuously until the materials are evenly mixed. (2) Add water as a binder to the well-mixed material, stir and granulate, dry the granules, and then granulate the dried granules through a round hole sieve for later use. (3) Add the amount of lubricant required for the quick-release layer formulation to the particles described in step (2), mix evenly, and set aside.

[0014] 3. Tableting A double-layer tablet press is used to compress sustained-release particles and immediate-release particles into a double-layer tablet core.

[0015] 4. Coating A film-coating premix was prepared into an aqueous solution with a solid content of 13%, and the double-layer tablet core was coated to obtain a nifedipine biphasic sustained-release formulation.

[0016] This invention employs a bilayer tablet core containing a sustained-release layer and an immediate-release layer, and coats the bilayer tablet core with a thin film to obtain a nifedipine biphasic sustained-release formulation. Upon entering the body, the immediate-release layer rapidly disintegrates upon contact with water, quickly reaching an effective blood drug concentration. Then, the active drug in the sustained-release layer is released slowly and stably. This invention combines the immediate-release effect of the immediate-release layer with the sustained-release effect of the sustained-release layer, achieving both rapid and long-lasting drug action, reducing the frequency of medication administration and improving patient adherence. Attached Figure Description

[0017] Figure 1 The dissolution curve is shown in Example 1 of this invention; Figure 2 The dissolution curve is shown in Example 2 of this invention; Figure 3 The dissolution curves are for Example 1, Example 2 of the present invention, and commercially available nifedipine sustained-release tablets. Detailed Implementation

[0018] The following is in conjunction with the appendix Figure 1-3 The present invention will be further illustrated by the embodiments.

[0019] Example 1: Preparation of nifedipine biphasic sustained-release formulation (1000 tablets, g / tablet)

[0020] The preparation steps are as follows: Sustained-release layer (1) Add the required amount of nifedipine, hydrophilic gel skeleton material, filler and disintegrant to the granulation pot and stir at a stirring speed of 60-100r / min for 4-7min to mix the materials evenly. (2) Add the adhesive to the water, with a mass ratio of adhesive to water of 1-3:4-13, and stir until completely dissolved to form a uniform aqueous suspension; (3) Add the prepared water suspension to the mixed material, granulate for 1-4 min, wet granulate the prepared particles through a 5-mesh sieve, dry with forced air at 60℃-80℃ until the particle moisture content is ≤4%, and granulate the dried particles through a 1.5mm round hole sieve. (4) Add the lubricant to the granulated particles and mix for 3-5 minutes at a speed of 10 r / min.

[0021] Immediate release layer (1) Add the required amount of nifedipine, filler and disintegrant for the immediate release layer to the granulation pot and stir at a stirring speed of 60-100 r / min for 4-7 min to mix the materials evenly; (2) Add water as a binder to the well-mixed material, granulate for 1-4 minutes, dry the obtained granules at a drying temperature of 60-80℃ until the moisture content of the granules is ≤4%, and granulate the dried granules through a 1.5 mm round hole sieve. (4) Add the lubricant to the granulated particles and mix for 3-5 minutes at a speed of 10 r / min.

[0022] Tableting A double-layer tablet press is used to compress two parts of granules into a double-layer tablet core.

[0023] Film coating The prescribed amount of film-coating premix was added to water and stirred until completely dissolved. The double-layer tablet core was then coated to obtain the nifedipine biphasic sustained-release formulation.

[0024] Example 2: Preparation of nifedipine biphasic sustained-release formulation (1000 tablets, g / tablet)

[0025] The preparation steps are as follows: Sustained-release layer (1) Add the required amount of nifedipine, hydrophilic gel skeleton material, filler and disintegrant to the granulation pot and stir at a stirring speed of 60-100r / min for 4-7min to mix the materials evenly. (2) Add the adhesive to the water, with a mass ratio of adhesive to water of 1-3:4-13, and stir until completely dissolved to form a uniform aqueous suspension; (3) Add the prepared water suspension to the mixed material, granulate for 1-4 min, wet granulate the prepared particles through a 5-mesh sieve, dry with forced air at 60℃-80℃ until the particle moisture content is ≤4%, and granulate the dried particles through a 1.5mm round hole sieve. (4) Add the lubricant to the granulated particles and mix for 3-5 minutes at a speed of 10 r / min.

[0026] Immediate release layer (1) Add the required amount of nifedipine, filler and disintegrant for the immediate release layer to the granulation pot and stir at a stirring speed of 60-100 r / min for 4-7 min to mix the materials evenly; (2) Add water as a binder to the well-mixed material, granulate for 1-4 minutes, dry the obtained granules at a drying temperature of 60-80℃ until the moisture content of the granules is ≤4%, and granulate the dried granules through a 1.5 mm round hole sieve. (4) Add the lubricant to the granulated particles and mix for 3-5 minutes at a speed of 10 r / min.

[0027] Tableting A double-layer tablet press is used to compress two parts of granules into a double-layer tablet core.

[0028] Film coating The prescribed amount of film-coating premix was added to water and stirred until completely dissolved. The double-layer tablet core was then coated to obtain the nifedipine biphasic sustained-release formulation.

[0029] Drug release performance test (1) Chromatographic conditions: Column: Octadecylsilane bonded silica column (Inertsil ODS-3 4.6mm×33mm, 3μm or equivalent column); Mobile phase: Water-methanol (30:70); Flow rate: 1.0mL / min; Injection volume: 5μL; Column temperature: 30℃; Detection wavelength: 235nm.

[0030] (2) Dissolution test: operation in the dark Six tablets of nifedipine biphasic sustained-release tablets prepared in Examples 1 and 2 were taken respectively, and their dissolution and release were determined according to the method of determination of dissolution and release (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II). 900 mL of phosphate buffer solution (pH 6.8, containing 0.3% Tween 80) was used as the release medium, and the rotation speed was 75 r / min. 5 mL of the solution was collected at 5 min, 15 min, 30 min, 1 h, 2 h, 8 h, and 12 h, respectively. 5 mL of the solution was added to the buffer, and the mixture was filtered. The filtrate was used as the test solution. 5 μL each of the test solution and the reference solution were accurately measured and injected into the liquid chromatograph for determination. The dissolution amounts at 0.5 h, 1 h, and 12 h should be 10%–30%, 20%–40%, and above 70% of the labeled amount, respectively, all of which should meet the requirements.

[0031] The dissolution test results of Example 1 are shown in the table below: Example 1 Sample Dissolution Test Results Table

[0032] The dissolution test results of Example 2 are shown in the table below: Example 2 Sample Dissolution Test Results Table

[0033] The dissolution test results of commercially available nifedipine sustained-release tablets are shown in the table below.

[0034] Dissolution test results of commercially available nifedipine sustained-release tablets

[0035] The above experimental results show that, compared with commercially available nifedipine sustained-release tablets, the nifedipine biphasic sustained-release formulation prepared in this invention can achieve both rapid and slow sustained release of the drug, ultimately achieving the goal of rapid onset of action and long-term stable effectiveness in vivo.

[0036] The technical features of the embodiments described above can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are listed here. However, as long as the combination of these technical features does not contradict each other, it should be considered within the scope of this specification. Those skilled in the art should understand that the present invention is not limited to the above embodiments, and the scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims

1. A nifedipine biphasic sustained-release formulation, comprising a bilayer tablet core consisting of a drug-containing immediate-release layer and a drug-containing sustained-release layer, and a film coating, characterized in that, Includes the following components and their mass fractions: The weight ratio of nifedipine in the immediate-release layer to the sustained-release layer is 1:8 to 1:10; Drug-containing immediate-release layer: 1-4 parts nifedipine, 85-95 parts filler, 5-15 parts disintegrant, 0.1-0.5 parts lubricant; Drug-containing sustained-release layer: 5-10 parts nifedipine, 20-40 parts hydrophilic gel matrix material, 7-12 parts adhesive, 30-50 parts filler, 2-5 parts disintegrant, and 0.1-0.5 parts lubricant.

2. The nifedipine biphasic sustained-release formulation according to claim 1, characterized in that, Includes the following components and their mass fractions: Drug-containing immediate-release layer: 1 part nifedipine, 92 parts filler, 6 parts disintegrant, 0.3 parts lubricant; Drug-containing sustained-release layer: 9 parts nifedipine, 35 parts hydrophilic gel matrix material, 10 parts adhesive, 43 parts filler, 3 parts disintegrant, and 0.4 parts lubricant.

3. A nifedipine biphasic sustained-release formulation according to claim 1 or 2, characterized in that, The hydrophilic gel framework material of the drug-containing sustained-release layer is composed of sodium alginate and sodium carboxymethyl cellulose in a mass ratio of 1-4:3-6.

4. A nifedipine biphasic sustained-release formulation according to claim 1 or 2, characterized in that, The filler of the drug-containing sustained-release layer is composed of lactose and microcrystalline cellulose in a mass ratio of 1-4:10-16.

5. A nifedipine biphasic sustained-release formulation according to claim 1 or 2, characterized in that, The filler for the drug-containing fast-release layer is composed of corn starch and lactose in a mass ratio of 7-10:3-5.

6. The method for preparing a nifedipine biphasic sustained-release formulation according to claim 1 or 2, characterized in that, Includes the following steps: (1) Preparation of sustained-release layer particles: The prescribed amount of nifedipine, hydrophilic gel skeleton material, filler and disintegrant are mixed evenly in a granulation pot, a soft material is prepared with binder, wet granulation is performed through a 5-mesh sieve, drying is performed at 60℃-80℃, granulation is performed through a 1.5mm round hole sieve, lubricant is added and mixed evenly to obtain sustained-release layer particles. (2) Preparation of immediate-release layer particles: The prescribed amount of nifedipine, filler and disintegrant are mixed evenly in a granulation pot, and soft material is prepared with water as binder. The soft material is wet-granulated through a 5-mesh sieve, dried by forced air at 60℃-80℃, granulated through a 1.5mm round hole sieve, and lubricant is added and mixed evenly to obtain sustained-release layer particles. (3) Tableting: The sustained-release layer particles and the immediate-release layer particles are compressed into a double-layer tablet core; (4) Coating: The double-layer core is coated using a film coating machine, and the coating increases the weight by 3%-5%.

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