Nicodil tablet and preparation method thereof

Abstract

The invention relates to a Nicodil tablet and a preparation method thereof. The Nicodil tablet comprises the following components in percentage by mass: 5-15% of Nicodil, 70-90% of a filler, 2-10% of a disintegrating agent, 0.5-5% of an adhesive and 0.2-10% of a lubricant, and the filling agent is micronized mannitol. During preparation, the mannitol, the adhesive and the internally added disintegrating agent are prepared into blank dry particles, and then the blank dry particles are mixed with the nicodil, the externally added disintegrating agent and the lubricant step by step. According to the invention, the stability of the Nicodil tablet is improved, the granulation process is improved, the obtained Nicodil tablet is superior to a reference preparation in related substance level under the influence factor condition, meets the long-term stability requirement, and is stable in product quality, free of obvious change in content and small in impurity growth under the condition of accelerating at 40 DEG C for 3 months, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical production, and specifically relates to a nicorandil tablet and a preparation method thereof. Background Art

[0002] Nicorandil, whose chemical name is N-(2-hydroxyethyl) nicotinamide nitrate, has the following structural formula:

[0003]

[0004] Nicorandil is an ATP-sensitive potassium channel opener for the treatment of heart disease. It is a vasodilator with the effect of nitrate drugs. It can dilate coronary blood vessels, continuously increase coronary blood flow, and inhibit coronary artery spasm. It is mainly used clinically to treat angina pectoris.

[0005] The stability of solid-form nicorandil pharmaceutical compositions is generally unsatisfactory, especially under acid, high temperature, high humidity, light and oxygen conditions, the active ingredient degrades and the impurities increase significantly. Therefore, special protective measures are required during the preparation and storage of solid products containing nicorandil to inhibit or delay the process that may cause the degradation of the active ingredient.

[0006] Chinese patent application CN115429763A discloses a nicorandil tablet and a preparation method thereof, comprising: mixing nicorandil and excipients to obtain nicorandil tablets, and freeze-drying the nicorandil tablets in a vacuum to ensure that the impurity content of the product is at a low level, extend the shelf life of nicorandil, and meet the long-term stability requirements of nicorandil tablets. However, the process of freeze-drying the tablets is complicated and the production cost is high, which is not conducive to commercial production.

[0007] Chinese patent application CN1839836A discloses a method for preparing Nicorandil tablets. However, after the prepared product was placed under accelerated conditions (40°C, 75% RH) for 4 weeks, the content of the product decreased by more than 15%. It can be seen that the method still fails to solve the problem of poor product stability of Nicorandil tablets. Summary of the invention

[0008] The purpose of the present invention is to provide a nicorandil tablet and a preparation method thereof, so as to improve the stability of the nicorandil tablet, wherein the level of related substances is better than that of a reference preparation, and the long-term stability requirement is met. Under accelerated conditions of 40° C. for 3 months, the product quality is stable, the content does not change significantly, and the growth of impurities is smaller than that of the reference preparation, so as to simplify the commercial production process, reduce the cost, and be suitable for large-scale industrial production.

[0009] In order to meet the above objectives, the present invention provides the following technical solutions:

[0010] A nicorandil tablet comprises, by mass percentage, 5-15% of nicorandil, 70-90% of a filler, 2-10% of a disintegrant, 0.5-5% of a binder and 0.2-10% of a lubricant; the filler is micronized mannitol.

[0011] Preferably, the particle size of the micronized mannitol is D90≤15 μm, more preferably D90=6-12 μm.

[0012] Furthermore, the disintegrant is divided into an internally added part and an externally added part, wherein the internally added part accounts for 25-100% of the total amount of the disintegrant.

[0013] Furthermore, the disintegrant is sodium carboxymethylcellulose and / or calcium carboxymethylcellulose, and the binder is corn starch and / or povidone.

[0014] Preferably, the lubricant includes 0.2-5% of lubricant one and 0.2-5% of lubricant two; lubricant one is magnesium stearate, calcium stearate or octadecyl alcohol; lubricant two is magnesium stearate, calcium stearate or talc.

[0015] Furthermore, in the Nicorandil tablets, the Nicorandil content is 8-12%, the micronized mannitol content is 75-85%, the carboxymethylcellulose calcium content is 5-8%, the corn starch content is 1-3%, the octadecyl alcohol content is 0.2-5%, and the calcium stearate content is 0.2-5%.

[0016] The present invention provides a method for preparing the nicorandil tablets, comprising the following steps:

[0017] 1) performing air flow grinding on mannitol to obtain a particle size of D90≤15 μm to obtain micronized mannitol;

[0018] 2) Weighing the prescribed amount of corn starch according to the mass fraction percentage of Nicorandil tablets to prepare a starch slurry with a mass fraction of 8 to 15%;

[0019] 3) mixing the prescribed amount of micronized mannitol and the prescribed amount of disintegrant uniformly, stirring with the starch slurry prepared in step 2) to form a soft material, and granulating to obtain wet granules;

[0020] 4) drying the wet granules from step 3) until the moisture content of the granules is no more than 1.0%, and performing dry granulation to obtain blank dry granules;

[0021] 5) Weigh 10-20% of the total amount of blank dry particles and mix them evenly with the prescribed amount of lubricant 1; then add 20-30% of the total amount of blank dry particles, the prescribed amount of nicorandil and the additional prescribed amount of disintegrant, and mix them evenly; then add all the remaining blank dry particles and mix them evenly; then add the prescribed amount of lubricant 2 and mix them evenly to obtain intermediate particles;

[0022] 6) The intermediate granules obtained in step 5) are tableted and packaged to obtain Nicorandil tablets.

[0023] Preferably, in step 1), mannitol is air-flow-pulverized to a particle size of D90≤12 μm, and the portion added to the disintegrant accounts for 25-100% of the total amount of the disintegrant.

[0024] More preferably, in step 1), mannitol is air flow-pulverized to a particle size D90 of 8 to 10 μm, and the portion of the disintegrant added accounts for 25 to 75% of the total amount of the disintegrant.

[0025] Furthermore, in step 4), the drying temperature is 50-70°C.

[0026] Furthermore, in step 3), the mesh size of the sieve is 40 meshes during granulation, and in step 4), the mesh size of the sieve is 60 to 80 meshes during dry granulation.

[0027] Preferably, the obtained Nicorandil tablets are packaged in an aluminum-plastic blister package with an aluminum foil bag, and a silica gel desiccant is placed in the aluminum foil bag.

[0028] The inventors unexpectedly discovered that in Nicorandil tablets, micronized mannitol is used as a filler, which is first prepared into blank dry granules with a binder and all or part of a disintegrant as an added part, and then the blank dry granules are mixed with the added part in sequence and step by step to prepare intermediate granules. The intermediate granules have good mixing uniformity, which effectively improves the compressibility and product hardness during the tableting process, reduces the degradation risk of the Nicorandil raw material, and improves the stability of the Nicorandil tablet product.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] The present invention adopts micronized mannitol to reduce the impurity content in the nicorandil tablet preparation and improve the stability of the nicorandil tablet; the nicorandil tablet of the present invention has a hardness of 2 to 4 kg and a disintegration time of 1 to 3 min, and the samples all reach 100% dissolution within 5 min, and the related substances and contents all meet the requirements of the 2020 edition of the "Chinese Pharmacopoeia"; after being placed under accelerated conditions of 40°C±2°C and relative humidity RH75%±5% for 3 months, the content is greater than 96%, and the total impurities are ≤1%. Under the same conditions, the impurity content change of the product of the present invention is much smaller than that of the commercially available reference preparation.

[0031] The invention improves the compressibility and hardness of the tablets by optimizing the preparation method, the moisture content of the obtained product is not higher than 1.0%, the stability of the product is effectively improved, the quality of the nicorandil tablets is optimized, the preparation process is simple, the production cost is controllable, and the tablets are suitable for large-scale industrial production. DETAILED DESCRIPTION

[0032] The present invention is further described below in conjunction with specific embodiments.

[0033] The experimental methods in the following examples without specifying specific conditions are selected according to conventional methods and conditions, or according to the product specifications. The reagents and raw materials used in the examples of the present invention are all commercially available.

[0034] Nicorandil tablet reference preparation 23B020Z was purchased from Chugai Pharmaceutical Co. Ltd, with a specification of 5 mg.

[0035] Example 1

[0036] The composition of prescription 1 is shown in Table 1:

[0037] Table 1

[0038]

[0039] Preparation method of prescription 1:

[0040] Step 1: air flow pulverizing mannitol to obtain a particle size of D90≤15 μm to obtain micronized mannitol;

[0041] Step 2: Weigh the prescribed amount of corn starch, add 10-20% of the total amount of purified water, stir evenly, then add 80-90% of the total amount of boiling water to make a starch slurry with a mass fraction of 10%, and cool it to 40-60°C;

[0042] Step 3: weigh the prescribed amount of micronized mannitol and the prescribed amount of carboxymethylcellulose calcium, mix them evenly in a wet granulator, add the starch slurry prepared in step 3), and granulate them through a 40-mesh screen of a swing granulator to obtain wet granules;

[0043] Step 4: Place the wet granules from step 2 into a drying oven for drying at 60°C until the moisture content of the granules is no more than 1.0%, and use an 80-mesh sieve to dry the granules to obtain blank dry granules;

[0044] Step 5: Weigh 10-20% of the total amount of blank dry particles and the prescribed amount of octadecyl alcohol, and mix them evenly; then add 20-30% of the total amount of blank dry particles, the prescribed amount of nicorandil and the additional prescribed amount of carboxymethylcellulose calcium, and mix them evenly; then add all the remaining particles, and mix them evenly; then add the prescribed amount of calcium stearate, and mix them evenly to obtain intermediate particles;

[0045] Step 6: Take the intermediate particles obtained in step 4 and compress them into tablets. Each tablet weighs about 50 mg and is packaged in aluminum-plastic blister packs.

[0046] Example 2

[0047] The composition of prescription 2 is shown in Table 2:

[0048] Table 2

[0049]

[0050] Preparation method of prescription 2:

[0051] The preparation method is the same as that of Example 1 except that the particle size D90 is crushed to 8-10 μm and the second lubricant is magnesium stearate.

[0052] Example 3

[0053] The composition of prescription 3 is shown in Table 3:

[0054] Table 3

[0055]

[0056]

[0057] Preparation method of prescription 3:

[0058] The preparation method is the same as Example 1.

[0059] Example 4

[0060] The composition of prescription 4 is shown in Table 4:

[0061] Table 4

[0062]

[0063] Preparation method of prescription 4:

[0064] The preparation method is the same as that of Example 1, except that the mass fraction of the corn starch slurry prepared in step 2 is 8% and the drying temperature in step 4 is 50°C.

[0065] Example 5

[0066] The composition of prescription 5 is shown in Table 5:

[0067] Table 5

[0068]

[0069]

[0070] Preparation process of prescription 5:

[0071] The preparation method is the same as that of Example 1 except that the mass fraction of the corn starch prepared in step 2 is 12% and the drying temperature in step 4 is 70°C.

[0072] Example 6

[0073] The composition of prescription 6 is shown in Table 6:

[0074] Table 6

[0075]

[0076] Preparation process of prescription 6:

[0077] Except that the granules are sieved through a 60-mesh sieve during dry granulation in step 4, the remaining steps are the same as those of Example 1.

[0078] Example 7

[0079] The composition of prescription 7 is shown in Table 7:

[0080] Table 7

[0081]

[0082]

[0083] Preparation method of prescription 7:

[0084] Step 1: air flow pulverizing mannitol to obtain a particle size of D90≤15 μm to obtain micronized mannitol;

[0085] Step 2: Weigh the prescribed amount of corn starch, add 10-20% of the total amount of purified water, stir evenly, then add 80-90% of the total amount of boiling water to make a starch slurry, and cool it to 40-60°C;

[0086] Step 3: weigh the prescribed amount of micronized mannitol and the prescribed amount of carboxymethylcellulose calcium, mix them evenly in a wet granulator, add 10% starch slurry to make a soft material, and granulate them through a 40-mesh screen of a swing granulator to obtain wet granules;

[0087] Step 4: Place the wet granules from step 2 into a drying oven for drying at 60°C until the moisture content of the granules is no more than 1.0%, and use an 80-mesh sieve to dry the granules to obtain blank dry granules;

[0088] Step 5: Weigh 10-20% of the total amount of blank dry particles and the prescribed amount of octadecyl alcohol, mix evenly; then add 20-30% of the total amount of blank dry particles and the prescribed amount of nicorandil, mix evenly; then add all the remaining particles, mix evenly; then add the prescribed amount of calcium stearate, mix evenly, and obtain intermediate particles;

[0089] Step 6: Take the intermediate particles obtained in step 4 and compress them into tablets. Each tablet weighs about 50 mg and is packaged in aluminum-plastic blister packs.

[0090] Comparative Example 1

[0091] The composition of prescription 8 is shown in Table 8:

[0092] Table 8

[0093]

[0094]

[0095] Preparation process of prescription 8:

[0096] Step 1: Grind the mannitol by air flow to a particle size of D90≤15μm;

[0097] Step 2: Weigh the prescribed amount of corn starch, add 10-20% of the total amount of purified water, stir evenly, then add 80-90% of the total amount of boiling water to make a starch slurry, and cool it to 40-60°C;

[0098] Step 3: Weigh the prescribed amount of mannitol, mix it evenly in a wet granulator, add 10% starch slurry to make a soft material, and granulate it through a 40-mesh screen of a swing granulator to obtain wet granules;

[0099] Step 4: Place the wet granules from step 2 into a drying oven for drying at 60°C until the moisture content of the granules is no more than 1.0%, and use an 80-mesh sieve to dry the granules to obtain blank dry granules;

[0100] Step 5: Weigh 10-20% of the total amount of blank dry particles and the prescription amount of octadecyl alcohol, and mix them evenly; then add 20-30% of the total amount of blank dry particles, the prescription amount of nicorandil and the prescription amount of carboxymethylcellulose calcium, and mix them evenly; then add all the remaining particles, and mix them evenly; then add the prescription amount of calcium stearate, and mix them evenly to obtain intermediate particles;

[0101] Step 6: Take the intermediate particles obtained in step 4 and compress them into tablets. Each tablet weighs about 50 mg and is packaged in aluminum-plastic blister packs.

[0102] Comparative Example 2

[0103] The composition of prescription 9 is shown in Table 9:

[0104] Table 9

[0105]

[0106]

[0107] Preparation process:

[0108] The preparation method is the same as that in Example 1, except that in step 1, mannitol is pulverized by air flow to a particle size D90 distributed in the range of 90 to 110 μm.

[0109] Comparative Example 3

[0110] The composition of prescription 10 is shown in Table 10:

[0111] Table 10

[0112]

[0113] Preparation process:

[0114] Except for drying to a moisture content of 4-6% in step 4, the rest of the preparation method is the same as that of Example 1.

[0115] Comparative Example 4

[0116] The composition of prescription 11 is shown in Table 11:

[0117] Table 11

[0118]

[0119]

[0120] Preparation process:

[0121] Step 1: Weigh the prescribed amount of corn starch, add 10-20% of the total amount of purified water, stir evenly, then add 80-90% of the total amount of boiling water to make a starch slurry with a mass fraction of 10%, and cool it to 40-60°C;

[0122] Step 2: Weigh the prescribed amount of lactose and the prescribed amount of carboxymethylcellulose calcium, mix them evenly in a wet granulator, add 10% starch slurry to make a soft material, and granulate them through a 40-mesh screen of a swing granulator to obtain wet granules;

[0123] Step 3: Place the wet granules from step 2 into a drying oven for drying at 60°C until the moisture content of the granules is no more than 1.0%, and use an 80-mesh sieve to dry the granules to obtain blank dry granules;

[0124] Step 4: Weigh 10-20% of the total amount of blank dry particles and the prescribed amount of octadecyl alcohol, and mix them evenly; then add 20-30% of the total amount of blank dry particles, the prescribed amount of nicorandil and the additional prescribed amount of carboxymethylcellulose calcium, and mix them evenly; then add all the remaining particles, and mix them evenly; then add the prescribed amount of calcium stearate, and mix them evenly to obtain intermediate particles;

[0125] Step 5: Take the intermediate particles obtained in step 4 and compress them into tablets. Each tablet weighs about 50 mg and is packaged in aluminum-plastic blister packs.

[0126] Comparative Example 5

[0127] The composition of prescription 12 is shown in Table 12:

[0128] Table 12

[0129]

[0130] Preparation process:

[0131] Except step 5, the rest of the preparation method is the same as that in Example 1.

[0132] In step 5 of this comparative example, all blank dry particles, the prescribed amount of octadecyl alcohol and the additional prescribed amount of carboxymethylcellulose calcium are mixed uniformly; then the prescribed amount of calcium stearate is added and mixed uniformly to obtain intermediate particles.

[0133] The soft materials and mixing uniformity that vary with the conditions during the preparation of each embodiment and comparative example are shown in Table 13, where the mixing uniformity is the RSD value of 5 sampling points:

[0134] Table 13 Soft materials and mixing uniformity

[0135] serial number Soft material status Mixing uniformity % Example 1 The humidity is moderate, it can be held in the hand into a ball and will fall apart when pressed lightly. 2.4 Example 2 The humidity is moderate, it can be held in the hand into a ball and will fall apart when pressed lightly. 1.9 Example 3 The humidity is moderate, it can be held in the hand into a ball and will fall apart when pressed lightly. 1.2 Example 4 The soft material is moist, can be held in the hand into a ball, and will fall apart when pressed lightly. 2.1 Example 5 The soft material is relatively dry, can be held in the hand into a ball, and will fall apart when pressed lightly. 1.9 Example 6 The humidity is moderate, it can be held in the hand into a ball and will fall apart when pressed lightly. 2.9 Example 7 The soft material is relatively dry and difficult to form into a ball by hand. 2.3 Comparative Example 1 The soft material is moist and has more large particles. 2.8 Comparative Example 2 The soft material is relatively dry, can be held in the hand into a ball, and will fall apart when pressed lightly. 4.1 Comparative Example 3 The humidity is moderate, it can be held in the hand into a ball and will fall apart when pressed lightly. 9.4 Comparative Example 4 The soft material is moist and contains many large particles. 6.7 Comparative Example 5 The humidity is moderate, it can be held in the hand into a ball and will fall apart when pressed lightly. 2.3

[0136] As can be seen from Table 13, the soft material state of Examples 1 to 6 is good, the mixing uniformity is good, and the RSD values ​​of the mixing uniformity are all less than 3.0%. The soft material state of Example 7 is slightly worse, but the uniformity can still meet the requirements.

[0137] Stability test of the products prepared in each embodiment and comparative example:

[0138] The preparations of Examples 1 to 7, the preparations of Comparative Examples 1 to 5 and the reference preparation were subjected to stability tests, and the stability was investigated under accelerated conditions of 40°C ± 2°C and relative humidity RH75% ± 5% for 3 months. The changes in hardness, disintegration time, content and total impurities were mainly investigated. The solubility met the requirements of the 2020 edition of the "Chinese Pharmacopoeia". The results are shown in Table 14.

[0139] Table 14 Stability test results

[0140]

[0141] It can be seen from Table 14 that the hardness of the preparations in Examples 1 to 7 is higher than that of Comparative Examples 2-4 and the reference preparations, and the disintegration time of Comparative Examples 1 and 3 is too short. After 3 months of testing, the hardness and disintegration time of the example products did not change significantly, which improved the stability of the products; the solubility of all preparations tested complies with the provisions of the 2020 edition of the "Chinese Pharmacopoeia"; after 3 months of stability testing conditions, the content of the products in Examples 1 to 7 is all above 96%, and the total impurity content is rounded off to ≤1%, which meets the requirements. The total impurities in Comparative Examples 2-5 and the reference preparations are far more than 1%.

[0142] Through the analysis of the stability results of Examples 1 to 7, Comparative Examples 1 to 5 and the reference preparation, it can be seen that the present invention uses micronized mannitol to reduce the impurity content in the Nicorandil tablet preparation, and the product stability of the Nicorandil tablet is significantly improved.

[0143] The nicorandil tablets prepared by the preparation method of the present invention have stable quality, are conducive to long-term storage of the product, are suitable for industrial production, and ensure the safety and effectiveness of clinical medication.

Claims

1. A Nicorandil tablet, characterized in that: The mass fraction includes nicorandil 5-15%, filler 70-90%, disintegrant 2-10%, binder 0.5-5% and lubricant 0.2-10%; The filler is micronized mannitol.

2. The Nicorandil tablet according to claim 1, characterized in that: The particle size of the micronized mannitol is D90≤15 μm, preferably D90=6-12 μm.

3. The Nicorandil tablet according to claim 1, characterized in that: The disintegrant is divided into an internal added part and an external added part, wherein the internal added part accounts for 25-100% of the total amount of the disintegrant.

4. The Nicorandil tablet according to claim 3, characterized in that: The disintegrant is sodium carboxymethylcellulose and / or calcium carboxymethylcellulose; the binder is corn starch and / or povidone.

5. The Nicorandil tablet according to any one of claims 1 to 4, characterized in that: The lubricant comprises lubricant one 0.2-5% and lubricant two 0.2-5%; lubricant one is magnesium stearate, calcium stearate or octadecyl alcohol; lubricant two is magnesium stearate, calcium stearate or talc.

6. The Nicorandil tablet according to claim 5, characterized in that: The nicorandil tablets contain 8-12% nicorandil, 75-85% micronized mannitol, 5-8% carboxymethylcellulose calcium, 1-3% corn starch, 0.2-5% octadecyl alcohol and 0.2-5% calcium stearate.

7. The method for preparing Nicorandil tablets according to claim 1, comprising the following steps: 1) performing air flow grinding on mannitol to obtain a particle size of D90≤15 μm to obtain micronized mannitol; 2) Weighing the prescribed amount of corn starch according to the mass fraction percentage of Nicorandil tablets to prepare a starch slurry with a mass fraction of 8 to 15%; 3) mixing the prescribed amount of micronized mannitol and the prescribed amount of disintegrant uniformly, stirring with the starch slurry prepared in step 2) to form a soft material, and granulating to obtain wet granules; 4) drying the wet granules from step 3) until the moisture content of the granules is no more than 1.0%, and performing dry granulation to obtain blank dry granules; 5) Weigh 10-20% of the total amount of blank dry particles and mix them evenly with the prescribed amount of lubricant 1; then add 20-30% of the total amount of blank dry particles, the prescribed amount of nicorandil and the additional prescribed amount of disintegrant, and mix them evenly; then add all the remaining blank dry particles and mix them evenly; then add the prescribed amount of lubricant 2 and mix them evenly to obtain intermediate particles; 6) The intermediate granules obtained in step 5) are tableted and packaged to obtain Nicorandil tablets.

8. The method for preparing Nicorandil tablets according to claim 7, characterized in that: In step 1), mannitol is pulverized by air flow to a particle size of D90≤12 μm, and the portion added to the disintegrant accounts for 25-100% of the total amount of the disintegrant.

9. The method for preparing Nicorandil tablets according to claim 7, characterized in that: In step 1), mannitol is air-flow-pulverized to a particle size of D90=8-10 μm, and the portion added to the disintegrant accounts for 25-75% of the total amount of the disintegrant.

10. The method for preparing Nicorandil tablets according to claim 7, characterized in that: In step 4), the drying temperature is 50-70° C., and the mesh size of the sieve is 60-80 meshes during the dry granulation.

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