A nifedipine controlled-release tablet and its preparation method

Abstract

The present invention discloses a method for preparing nifedipine controlled-release tablets. The method micronizes the raw material nifedipine in the controlled-release tablets, ensuring stable process and product quality. Specifically, the method includes steps such as preparing drug-containing layer particles, preparing booster layer particles, double-layer tableting, semipermeable membrane coating, and film coating. The process described in the present invention can effectively improve process stability and product quality.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a method for preparing nifedipine controlled-release tablets. Background Art

[0002] Nifedipine is a yellow crystalline powder; odorless; unstable in light, easily soluble in acetone or chloroform, slightly soluble in ethanol, and almost insoluble in water. Its chemical name is: 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylic acid dimethyl ester, and its molecular formula is: C 17 H 18 N2O6, its chemical structure is:

[0003]

[0004] Nifedipine is a first-generation dihydropyridine calcium antagonist that selectively inhibits transmembrane transport of calcium ions into cardiomyocytes and smooth muscle cells and inhibits calcium ion release from the cells. This blocks excitation-contraction coupling in cardiomyocytes, weakens myocardial contractility, and reduces myocardial energy and oxygen consumption. It directly protects myocardial cells by preventing calcium overload. It also inhibits excitation-contraction coupling in vascular, bronchial, and uterine smooth muscle, dilating systemic vasculature (including the pulmonary, hepatic, renal, cerebral, femoral, and mesenteric arteries) and coronary arteries without altering plasma calcium concentrations. It can dilate coronary arteries in both normal and ischemic territories, antagonize coronary artery spasm, increase myocardial oxygen delivery in patients with coronary artery spasm, and relieve and prevent coronary artery spasm. It is clinically used to prevent and treat angina pectoris caused by coronary heart disease, particularly variant angina and angina due to coronary artery spasm. It is also indicated for various types of hypertension and has shown efficacy in refractory and severe hypertension. Because it reduces afterload, it is also effective in treating refractory congestive heart failure and is suitable for long-term use. The drug has a rapid onset of action, a high peak-to-trough ratio, and neurohumoral activation. Its efficacy has been well-established through years of clinical use. However, nifedipine also has drawbacks such as a short duration of action, large blood pressure fluctuations, and negative inotropic and transductive effects.

[0005] Ordinary nifedipine tablets require three daily doses, which cannot effectively maintain stable blood drug concentrations and daily blood pressure. Currently available sustained-release and controlled-release preparations include nifedipine sustained-release and controlled-release tablets. Among them, the controlled-release preparation, Bayer, produced by Bayer AG in Germany, is taken once daily and releases drugs at a near-constant rate. Bayer is an osmotic pump tablet. The tablet core consists of a drug-containing layer and a booster layer. The tablet core is coated with a semipermeable membrane. Water penetrates the tablet core through the semipermeable membrane. In the drug-containing layer, the drug and polymer material form a suspension with a certain viscosity. In the booster layer, the polymer material absorbs water and expands, pushing the suspension in the drug-containing layer out of the small holes, thereby achieving quantitative drug release.

[0006] Nifedipine is a BCS class II drug with poor solubility, resulting in significant individual variability in absorption. Furthermore, due to the poor solubility, high permeability, and instability of the raw material used in nifedipine, the quality of nifedipine controlled-release tablets is subject to numerous factors during the manufacturing process, impacting product quality and industrial production. Summary of the Invention

[0007] The present invention develops a nifedipine controlled-release tablet and a preparation method thereof, which can ensure stable process and product quality and better absorbability by optimizing various parameters.

[0008] The present invention provides a nifedipine controlled-release tablet, which comprises D 90 In the particle size range of 8μm-25μm, D 50 Nifedipine API in the particle size range of 1 μm-8 μm.

[0009] In some embodiments, the formulation comprises D 90 Nifedipine API in the particle size range of 10 μm-20 μm, such as D 90 It may be 10μm, 10.5μm, 11μm, 11.5μm, 12μm, 12.5μm, 13μm, 13.5μm, 14μm, 14.5μm, 15μm, 15.5μm, 16μm, 16.5μm, 17μm, 17.5μm, 18μm, 18.5μm, 19μm, 19.5μm, 20μm or any range therebetween, including but not limited to 11μm-20μm, 12μm-20μm, 13μm-20μm, 14μm-20μm, 15μm-20μm, 15.5μm-19.5μm, 16μm-20μm, 16μm-19μm, 16.5μm-19μm, 16.5μm-18.5μm, etc.

[0010] In some examples, the nifedipine raw material of the preparation is further D 10 In the particle size range of 0.5 μm-1.1 μm, in some more specific examples, D 10 In the particle size range of 0.6μm-1μm.

[0011] In some examples, the nifedipine raw material of the preparation is further D 50 In the particle size range of 2μm-5μm.

[0012] In some examples, the nifedipine controlled-release tablets of the present application include a drug-containing layer, a booster layer, a semipermeable membrane coating layer, and a film coating layer, wherein the formulation of each layer is as follows:

[0013]

[0014]

[0015] The weight percentages are based on the total mass of the tablet.

[0016] In some embodiments, the content of nifedipine in the drug-containing layer of the present invention is 10-15% (w / w).

[0017] In some embodiments, in the drug-containing layer of the present invention, the content of the adhesive HPMC E5 is 2-5% (w / w).

[0018] In some embodiments, the content of the suspending agent polyoxyethylene in the drug-containing layer of the present invention is 35-45% (w / w). The polyoxyethylene in the drug-containing layer mainly plays a suspending role. Commercially available products such as Colorcon's POLYOX® can be used. TM , model PEO N80.

[0019] The polyoxyethylene in the boosting layer of the present invention mainly plays an expansion role, and a commercially available product can be selected, for example, the PEO Coagulant model of POLYOX™ produced by Colorcon Company.

[0020] In some embodiments, the boosting layer of the present invention contains 5-10% sodium chloride as an osmotic pressure regulator.

[0021] In some embodiments, the boost layer of the present invention has a red iron oxide content of 0.1-1.0% (w / w).

[0022] In some embodiments, in the semipermeable membrane coating layer of the present invention, the semipermeable membrane coating material is 9-12% (w / w) of cellulose acetate full formula coating powder. Furthermore, the weight ratio of cellulose acetate to polyethylene glycol is 90:10 to 99:1, preferably 95:5.

[0023] In some embodiments, the film layer of the present invention comprises 3-8% (w / w) Opadry.

[0024] The present invention also provides a method for preparing the nifedipine controlled-release tablets of the present invention, wherein the raw material nifedipine in the controlled-release tablets is micronized to make D 90 In the particle size range of 8μm-25μm, D 50 In the particle size range of 1μm-8μm.

[0025] In some embodiments, the raw material nifedipine in the controlled release tablet is micronized to make D 90 In the particle size range of 10μm-20μm, for example, D 90It may be 10μm, 10.5μm, 11μm, 11.5μm, 12μm, 12.5μm, 13μm, 13.5μm, 14μm, 14.5μm, 15μm, 15.5μm, 16μm, 16.5μm, 17μm, 17.5μm, 18μm, 18.5μm, 19μm, 19.5μm, 20μm or any range therebetween, including but not limited to 11μm-20μm, 12μm-20μm, 13μm-20μm, 14μm-20μm, 15μm-20μm, 15.5μm-19.5μm, 16μm-20μm, 16μm-19μm, 16.5μm-19μm, 16.5μm-18.5μm, etc.

[0026] In some examples, further micronization allows D 10 In the particle size range of 0.5 μm-1.1 μm, in some more specific examples, D 10 In the particle size range of 0.6μm-1μm.

[0027] In some examples, further micronization allows D 50 In the particle size range of 2μm-5μm.

[0028] In some examples, the method for preparing the nifedipine controlled-release tablets of the present invention is carried out under red light or yellow light, preferably under yellow light.

[0029] In some specific examples, the method for preparing the nifedipine controlled-release tablets of the present invention comprises the following steps:

[0030] (1) Preparation of drug-layered granules: The formulated amount of nifedipine was micronized, half of the polyoxyethylene was added to a wet granulator, and the formulated amount of polyoxyethylene, nifedipine, HPMC E5, and the other half of the polyoxyethylene were added to the wet granulator in sequence and preliminarily mixed. Ethanol was sprayed and granulated for 50-70 seconds. The formulated amount of magnesium stearate was added and mixed uniformly to obtain drug-layered granules.

[0031] (2) Preparation of boost layer granules: The sieved formula amount of polyethylene oxide, red iron oxide, HPMC E5, and sodium chloride are added to the wet granulation equipment in order and mixed evenly, and ethanol is sprayed into the granulation for 50-70 seconds. The formula amount of magnesium stearate is added and mixed evenly to obtain the boost layer granules;

[0032] (3) Double-layer tableting, semipermeable membrane coating, laser drilling and film coating are performed to form nifedipine controlled-release tablets.

[0033] The wet granulation equipment in step (1) and step (2) of the present invention can be a commonly used wet granulation equipment in the art, such as a fluidized bed or a high-efficiency wet granulator. The ethanol sprayed in is usually 90-100% ethanol as a binder, preferably 95% ethanol.

[0034] In some embodiments, the time for the preliminary mixing in step (1) is 2-10 minutes.

[0035] In some embodiments, the mixing time in step (2) is 2-10 minutes.

[0036] In some embodiments, the semipermeable membrane coating has a weight gain of 9% to 14%.

[0037] In some examples, the film coating weight gain is 3% to 7%.

[0038] In step (3) of the present invention, tableting, semipermeable membrane coating, laser drilling and film coating can be performed using conventional methods and conventional operations in the art, wherein the solvent of the semipermeable membrane coating solution can be a 90-100% (w / w) acetone aqueous solution, or further a 94-96% (w / w) acetone aqueous solution.

[0039] Beneficial effects of the present invention: The process method of the present invention can effectively improve the process and product quality stability, and has better absorption than the original drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 is the dissolution rate of samples of micronized and non-micronized API. DETAILED DESCRIPTION

[0041] The following examples are provided to facilitate a better understanding of the present invention, but are not intended to limit the present invention. The experimental methods in the following examples, unless otherwise specified, are conventional methods. The test materials used in the following examples, unless otherwise specified, were purchased from conventional biochemical reagent stores.

[0042] Example 1

[0043] The API was crushed using a jet mill to obtain nifedipine API of three different particle sizes (Table 1):

[0044] Table 1 Particle sizes of different prescriptions

[0045] serial number D10 D50 D90 Prescription 1 1.25 9.366 32.45 Prescription 2 0.764 3.026 17.31 Prescription 3 0.871 3.186 7.072

[0046] The above three kinds of raw materials with different particle sizes were used to prepare nifedipine osmotic pump tablets according to the prescription and process in Table 2.

[0047] Table 2 Prescription

[0048]

[0049] Process

[0050] (1) Crushing: nifedipine is crushed by a jet mill to obtain the target particle size of the raw material;

[0051] (2) Granulation of the drug-containing layer: Weigh the prescribed amount of nifedipine, hypromellose, and polyoxyethylene, add them to a high-efficiency wet granulator and mix them evenly. Spray 95% ethanol water into the granules. After finishing, transfer them to a fluidized bed dryer at 35°C until the moisture content is less than 0.5%. Pass the dried granules through a 20-mesh sieve. Mix the sieved dry granules with magnesium stearate to obtain the product.

[0052] (3) Boosting layer: Weigh the prescribed amount of hypromellose, polyoxyethylene, sodium chloride, and red iron oxide, add them to a high-efficiency wet granulator and mix them evenly. Spray 95% ethanol water into the granules. After finishing, transfer them to a fluidized bed dryer at 35°C until the moisture content is less than 0.5%. Pass the dried granules through a 20-mesh sieve. Mix the sieved dry granules with magnesium stearate to obtain the product.

[0053] (3) Double-layer tableting: Use a 9mm shallow round punch to press the drug-containing layer granules and the booster layer granules into a double-layer tablet core.

[0054] (4) Semipermeable membrane coating layer: slowly add cellulose acetate full formula coating powder into acetone aqueous solution and stir to dissolve, with air inlet temperature of 30-40°C and material temperature of 20-30°C, coat until weight gain reaches 9-14%, and dry at 40°C for 6 hours.

[0055] (5) Laser drilling: Use a laser drilling machine to drill holes on the surface of the drug-containing layer, with a hole diameter (outer diameter) of 1.0 mm ± 0.1 mm, a hole diameter (inner diameter) of 0.8 mm ± 0.1 mm, and a hole depth of 0.5 mm ± 0.1 mm.

[0056] (6) Film coating: Slowly add the film coating premix containing the light-shielding material into water and stir until uniform. The inlet air temperature is 50-60°C and the material temperature is 40-50°C. The film coating is applied until the weight gain is 3-6%. Nifedipine osmotic pump tablets, i.e., nifedipine controlled-release tablets, are obtained.

[0057] Experimental results:

[0058] (1) The in vitro release results in pH 6.8 medium are shown in Table 3. The in vitro release of the preparations prepared with different particle sizes of APIs is not much different and is also close to that of the original formulation Baixintong.

[0059] Table 3 In vitro release of formulations using different particle sizes of raw materials in pH 6.8 medium (%)

[0060] Time (h) Original preparation Prescription 1 Prescription 2 Prescription 3 2 0.8 0.0 0.2 1.2 4 12.2 11.8 11.9 13.1 6 23.9 22.3 23.6 24.5 8 36.1 34.6 35.1 36.2 10 48.1 47.6 48.7 49.1 12 59.8 58.0 58.1 59.5 16 79.3 77.2 78.8 79.4 20 94.2 92.8 94.1 95.4 24 103.4 99.5 103.3 103.6

[0061] (2) A randomized, open-label, two-sequence, two-period, double-crossover pharmacokinetic study was conducted on 16 healthy subjects who received a single oral dose of nifedipine controlled-release tablets, including the original and formulations 1-3, on an empty stomach. The results are shown in Table 4. The results showed that the AUC of formulation 2 was higher than that of the original formulation, indicating that formulation 2 was better absorbed.

[0062] Table 4 Results of human pharmacokinetic studies

[0063]

[0064]

[0065] Example 2

[0066] The raw material components of this embodiment are shown in Table 5:

[0067] Table 5 Raw material components

[0068]

[0069] The process of this embodiment is as follows:

[0070] 1. Preparation of drug-layered granules

[0071] a) Weighing and sieving

[0072] Weigh all materials according to the prescription except nifedipine, set aside; micronize nifedipine D 90 In 8μm-25μm, D 50 In 1μm-8μm;

[0073] b) Dry mix

[0074] PEO N80, nifedipine, and HPMC E5 were added to a wet granulator in sequence and mixed uniformly to obtain a dry blend, and the mixing uniformity and drying loss were measured;

[0075] c) Wet granulation

[0076] 95% ethanol was sprayed into the wet granulator at a certain rate, and granulation was continued for about 60 seconds after the spraying was completed;

[0077] d) Wet granulation

[0078] Use a 12-mesh or 16-mesh sieve for wet granulation;

[0079] e) Drying

[0080] Use fluidized bed to dry, with air inlet temperature of 40±5℃, and dry to the same moisture content as the material during dry mixing;

[0081] f) Dry granulation

[0082] Use a 24-mesh or 30-mesh sieve to dry granulate to obtain drug-containing dry granules;

[0083] g) Mixing

[0084] Add the prescribed amount of magnesium stearate to the drug-containing layer dry granules and mix them evenly to obtain drug-containing layer granules.

[0085] 2. Preparation of boost layer particles

[0086] a) Weighing and sieving

[0087] Weigh all materials according to the prescription and set aside;

[0088] b) Dry mix

[0089] Add PEO coagulant, red iron oxide, sodium chloride, and HPMC E5 into a wet granulator in order and mix evenly to obtain a dry blend. Visually inspect the appearance for uniformity.

[0090] c) Wet granulation

[0091] 95% ethanol was sprayed into the wet granulator at a certain rate, and granulation was continued for about 60 seconds after the spraying was completed;

[0092] d) Wet granulation

[0093] Wet granulation with a 12-mesh or 16-mesh sieve

[0094] e) Drying

[0095] Use fluidized bed to dry, with air inlet temperature of 40±5℃, and dry to the same moisture content as the material during dry mixing;

[0096] f) Dry granulation

[0097] Use a 24-mesh sieve or a 30-mesh sieve to dry granulate to obtain booster layer dry granules;

[0098] g) Mixing

[0099] The prescribed amount of magnesium stearate is added to the push layer dry granules and mixed evenly to obtain push layer granules.

[0100] 3. Double-layer tableting

[0101] Use a double-layer tablet press to press double-layer tablets to control the weight of the drug-containing layer, the core weight and the hardness of the tablet.

[0102] 4. Semipermeable membrane coating

[0103] Preparation of coating solution: Slowly add the coating powder into the continuously stirred acetone solution, and continue stirring until the solution is clear and transparent.

[0104] Use a high-efficiency coating machine for coating, with an atomization pressure of 1.5 bar and a tablet bed temperature of 23±3℃. Stop spraying when the wet coating weight gain is about 14%, then set the inlet air temperature to 40±5℃ and dry until the acetone residue is ≤1% for more than 24 hours.

[0105] 5. Laser drilling

[0106] Use a laser punch to punch holes with a diameter of 0.8 mm and a depth of about 0.5 mm just enough to penetrate the film.

[0107] 6. Film coating

[0108] Film coating was performed using a high-efficiency coating machine with a coating weight gain of 5%.

[0109] According to the formula and process of Example 2, production is carried out under yellow light, red light, white light or natural light, wherein white light refers to fluorescent lamps and natural light refers to a place in the laboratory that is not directly exposed to sunlight.

[0110] Table 6 Impurity content produced under different light conditions

[0111]

[0112] The results are shown in Table 6. (1) Impurity I was not detected in all samples; (2) Impurity I did not increase in the yellow light sample within 48 hours; (3) Impurity I did not increase in the red light sample within 24 hours; (4) Impurity I was stable under natural light for 1 hour, but increased with prolonged exposure, exceeding the limit at 2 hours; (5) Impurity I was not stable under white light, but increased with prolonged exposure. It can be seen that during the approximately 24-hour exposure time of the API in the production process, the red light or yellow light selected in this application has good stability. However, considering that operators may feel uncomfortable under red light, yellow light is preferred for light protection during production and inspection.

[0113] Example 3

[0114] The formulation and process of Example 3 are the same as those of Example 2, wherein nifedipine is micronized (D 90 In 8μm-25μm, D 50 in the range of 1 μm-8 μm) and non-micronized.

[0115] The results are as follows Figure 1 As shown in Figure 3, the dissolution rate of samples prepared with micronized API was significantly faster than that of non-micronized samples.

[0116] Example 4

[0117] The formulation and process of Example 4 are the same as those of Example 2, the only difference being the coating weight gain.

[0118] Table 7 In vitro release results of semipermeable membrane coating in pH 6.8 medium

[0119]

[0120] The cumulative dissolution results are shown in Table 7. When the coating weight gain is 10% to 14%, the in vitro release meets the requirements of an hourly release rate of 4 to 7% and an f2 greater than 50% of the original drug.

[0121] Example 5

[0122] The formulation and process of Example 5 are the same as those of Example 2, with the only difference being the feeding and dry mixing time of the drug-containing layer: PEO N80 (1) is first fed into the wet granulator, and then nifedipine, HPMC E5 (1), and PEO N80 (2) are fed into the wet granulator in that order. The lid is closed, the stirring paddle and granulating knife are turned on, and after dry mixing for 3 min, 5 min, and 7 min, 1 g of samples are taken from the upper, middle, and lower layers of the wet granulator to determine the content uniformity.

[0123] Table 8 Content uniformity

[0124] Dry mixing time 3min 5min 7min Content average (%) 109.2 109.9 107.0 RSD (%) 0.8 0.3 0.4 A+2.2S<15.0 2.6 0.9 4.1

[0125] The results are shown in Table 8. All results meet the requirements that the mean content should be 104.5% to 115.5% of the labeled amount, the RSD should not exceed 4.0%, and A+2.2S < 15.0.

[0126] Example 6

[0127] The formula and process of Example 6 are the same as those of Example 2, except for the mixing time of the boosting layer: PEO Coagulant, red iron oxide, HPMC E5 (2), and sodium chloride are sequentially put into the wet granulator, the lid is closed, the stirring paddle and granulating knife are turned on, and the mixture is mixed for 3 min, 5 min, and 7 min. The lid is opened to visually observe whether the appearance and color of the dry mixed powder of the boosting layer are uniform.

[0128] Table 9 Visual appearance and color of booster layer dry mix powder

[0129] Dry mixing time 3min 5min 7min Is the appearance and color uniform? yes yes yes

[0130] The results are shown in Table 9. The dry mixing times of the booster layer for 3 min, 5 min, and 7 min all meet the requirements.

[0131] Example 7

[0132] The formulation and process of Example 7 are the same as those of Example 2, the only difference being the weight gain of the semipermeable membrane coating.

[0133] Table 10 In vitro release results in pH 6.8 medium after investigation of weight gain range of semipermeable membrane coating

[0134]

[0135]

[0136] The cumulative dissolution is shown in Table 10. When the coating weight gain is 9% to 14%, the in vitro release meets the requirements of an hourly release rate of 4 to 7% and f2 greater than 50%.

Claims

1. A nifedipine controlled-release tablet, characterized in that: It includes drug-containing layer, booster layer, semipermeable membrane coating layer and film coating layer, among which nifedipine raw material D 90 17.31μm, D 50 3.026μm, D 10 The thickness is 0.764 μm, and the formula of each layer is as follows: The weight percentages are based on the total mass of the tablet.

2. The method for preparing the nifedipine controlled-release tablets according to claim 1, wherein: The preparation method is carried out under red light or yellow light and comprises the following steps: (1) Preparation of drug-containing layer particles: The formulated amount of nifedipine is micronized to make D 90 17.31μm, D 50 3.026μm, D 10 The particle size is 0.764 μm. The formulated amount of polyethylene oxide, nifedipine, and HPMC E5 are added to the wet granulator in order and mixed uniformly. Ethanol is sprayed into the granulator for 50 to 70 seconds. The formulated amount of magnesium stearate is added and mixed uniformly to obtain drug-layered granules. (2) Preparation of boost layer granules: Polyoxyethylene, red iron oxide, sodium chloride, and HPMC E5 in the formula amount are added to the wet granulation equipment in order and mixed evenly, ethanol is sprayed into the granulation for 50-70 seconds, and magnesium stearate in the formula amount is added and mixed evenly to obtain boost layer granules; (3) Double-layer tableting, semipermeable membrane coating, laser drilling and film coating, the weight gain of the semipermeable membrane coating is 9% to 14%; the weight gain of the film coating is 3% to 7%, to form nifedipine controlled-release tablets.

3. The method for preparing nifedipine controlled-release tablets according to claim 2, wherein: The mixing time in step (1) is 2-10 min.

4. The method for preparing nifedipine controlled-release tablets according to claim 2, wherein: The mixing time of step (2) is 2-10 min.

5. The method for preparing nifedipine controlled-release tablets according to claim 2, wherein: The preparation method is carried out under yellow light.

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