Nicodil tablet preparation and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a Nicodil tablet and a preparation method thereof. The oral Nicodil preparation provided by the invention mainly solves the problems of high difficulty in obtaining original Nicodil auxiliary materials, high cost and poor tablet quality. The nirandil preparation adopts conventional auxiliary materials, is convenient to obtain and relatively low in cost, has the tablet hardness remarkably superior to that of an original developed preparation, and is simple in preparation process.

Description

Technical Field

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

[0002] Nicorandil is a drug that selectively dilates coronary blood vessels and has little effect on hemodynamics. It was first synthesized and developed by the Chugai Pharmaceutical Research Institute in Japan in 1975. The tablets were approved by PMDA on April 3, 1984, with the trade name: Sigmart, and the specifications are 2.5mg and 5mg. The injection was approved in September 1993, with the trade name: Sigmart, and the specifications are 2mg, 12mg, and 48mg. The license holder and manufacturer are both Chugai Pharmaceutical. Both its tablets and injections have generic products on the market in Japan. The European Union first launched Nicorandil tablets on August 12, 1992, with specifications of 10mg and 20mg. The license holders are Merck and Sanofi, and the countries where it is launched include the United Kingdom, France, Portugal, Austria, Denmark, etc.

[0003] Nicorandil is quickly and completely absorbed after oral administration, with a bioavailability of 75%. The blood concentration reaches its peak 0.5 to 1 hour after taking the drug, and the half-life (T1 / 2) is about 1 hour. It is mainly distributed in the liver, heart, kidney, adrenal gland and blood. The nitro group is removed by hydrolysis in the body, and the metabolite has little pharmacological activity and is mainly excreted in the urine.

[0004] According to the Nicorandil tablets marketed in Japan by Chugai Pharmaceutical Co., Ltd. According to the instructions, its prescription composition is mannitol, corn starch, carboxymethylcellulose calcium, octadecyl alcohol, and calcium stearate. Among them, carboxymethylcellulose calcium and calcium stearate are commonly used disintegrants in Japanese medicines. There are few manufacturers of carboxymethylcellulose calcium in my country. Calcium salts have a certain effect on the absorption of drugs in the body and are prone to precipitation when encountering alkaline excipients. Therefore, Chinese medicine often uses cross-linked sodium carboxymethyl cellulose as a disintegrant and magnesium stearate as a lubricant.

[0005] According to the research results of Professor Tu Jiasheng's "Research Progress on the Effects of Traditional Chinese Medicine Excipients in Oral Drugs on Gastrointestinal Permeability", excipients such as mannitol and octadecanol can affect the permeation and absorption of active drug ingredients in the gastrointestinal tract by changing gastrointestinal motility, affecting the efflux mediated by intestinal cell P-glycoprotein and affecting the dissolution of drugs. At the same time, compared with the commonly used fillers lactose and microcrystalline cellulose in the industry, mannitol has poor plasticity and the hardness of the tablets is low. Corn starch is an older filler and has large batch differences due to the source of the material. The high water content of starch (generally between 109% and 18%) can easily lead to excessive microorganisms in the tablets and affect the disintegration and dissolution properties of the tablets. Therefore, lactose and microcrystalline cellulose were selected to replace mannitol, corn starch and cetyl alcohol as fillers for Nicorandil tablets. Summary of the invention

[0006] In view of the deficiencies in the prior art, the present invention provides a nicorandil tablet preparation and a preparation method thereof.

[0007] The technical scheme of the present invention is as follows: a Nicorandil tablet comprises the following components by weight: 5 to 10 parts of Nicorandil, 40 to 70 parts of filler, 4 to 6 parts of disintegrant and 1 to 2 parts of lubricant.

[0008] The filler is selected from one or more of calcium hydrogen phosphate, microcrystalline cellulose, corn starch, dextrin, pregelatinized starch, lactose, hexadecanol or mannitol, preferably lactose and microcrystalline cellulose.

[0009] The disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, and silicified microcrystalline cellulose; preferably cross-linked sodium carboxymethyl cellulose.

[0010] The lubricant is selected from one or more of talc, magnesium stearate, silicon dioxide, polyethylene glycol, sodium lauryl sulfate, and hydrogenated vegetable oil; preferably magnesium stearate.

[0011] Preferably, the nicorandil tablet comprises the following components by weight: 5 parts of nicorandil, 44 parts of filler, 5 parts of disintegrant and 1 part of lubricant.

[0012] More preferably, the nicorandil tablet comprises the following components in parts by weight:

[0013]

[0014] The present invention also provides a method for preparing the Nicorandil tablet, which is characterized by comprising the following steps:

[0015] 1) Weigh the prescribed amount of nicorandil, filler and disintegrant, sieve and premix;

[0016] 2) weighing a prescribed amount of lubricant and adding it to the mixture prepared in step (1) and mixing them to obtain a nicorandil tablet intermediate;

[0017] 3) Compressing the nicorandil tablet intermediate into tablets to obtain nicorandil tablets.

[0018] Beneficial effects of the present invention: The nicorandil oral preparation of the present invention mainly solves the problems of difficulty in obtaining the original research excipients of nicorandil, high cost and tablet quality. The nicorandil preparation of the present invention uses conventional excipients, is easy to obtain, has low cost, and has significantly better tablet hardness than the original research preparation, and has a simple preparation process. DETAILED DESCRIPTION

[0019] The following embodiments can enable those skilled in the art to more fully understand the present invention, but the present invention is not limited to the scope of the embodiments.

[0020] Example 1

[0021] Recipe ratio:

[0022] Element Dosage per tablet (5 mg) Nicorandil 5 lactose 33 Microcrystalline Cellulose 11 Croscarmellose Sodium 5 Magnesium Stearate 1 Tablet weight 55

[0023] Preparation process:

[0024] (1) Weigh the prescribed amount of nicorandil, lactose, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate;

[0025] (2) Mix the prescribed amounts of nicorandil, lactose, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose by sieving through an 80-mesh sieve in equal increments;

[0026] (3) adding the prescribed amount of magnesium stearate and sieving through an 80-mesh sieve to mix;

[0027] (4) tableting is performed according to the theoretical tablet weight to obtain the product.

[0028] Example 2

[0029] Recipe ratio:

[0030] Element Dosage per tablet (5 mg) Nicorandil 5 Mannitol 35 Corn starch 10 Cetyl Alcohol 4 Calcium stearate 1 Tablet weight 55

[0031] Preparation process:

[0032] (1) Weigh the prescribed amount of nicorandil, mannitol, corn starch, cetyl alcohol, and magnesium stearate;

[0033] (2) Mix the prescribed amount of nicorandil, mannitol, corn starch, mannitol, and cetyl alcohol by sieving through an 80-mesh sieve in equal increments;

[0034] (3) adding the prescribed amount of magnesium stearate and sieving through an 80-mesh sieve to mix;

[0035] (4) tableting is performed according to the theoretical tablet weight to obtain the product.

[0036] Example 3

[0037] Element Dosage per tablet (5 mg) Nicorandil 5 dextrin 30 Pregelatinized starch 15 Low substituted hydroxypropyl cellulose 4 Magnesium Stearate 1 Tablet weight 55

[0038] Example 4

[0039] Element Dosage per tablet (5 mg) Nicorandil 5 dextrin 50 Pregelatinized starch 20 Low substituted hydroxypropyl cellulose 6 Magnesium Stearate 2 Tablet weight 83

[0040] Example 5

[0041]

[0042]

[0043] Example 6

[0044] Element Dosage per tablet (5 mg) Nicorandil 5 lactose 30 Microcrystalline Cellulose 15 Crospovidone 4 Magnesium Stearate 1 Tablet weight 55

[0045] Example 7

[0046] Element Dosage per tablet (5 mg) Nicorandil 5 Corn starch 30 Microcrystalline Cellulose 15 Croscarmellose Sodium 4 Magnesium Stearate 1 Tablet weight 55

[0047] Comparative Example 1

[0048] Element Dosage per tablet (5 mg) Nicorandil 5 lactose 42.5 Microcrystalline Cellulose 10 Sodium Carboxymethyl Cellulose 1.6 Micro powder silica gel 0.6 Magnesium Stearate 1 Tablet weight 60

[0049] Comparative Example 2

[0050] Element Dosage per tablet (5 mg) Nicorandil 5 lactose 36 Microcrystalline Cellulose 13 Pregelatinized starch 6.5 Croscarmellose Sodium 1.15 Magnesium Stearate 0.35 Tablet weight 65

[0051] Comparative Example 3

[0052] Element Dosage per tablet (5 mg) Nicorandil 0.25 Calcium Hydrogen Phosphate 11 Microcrystalline Cellulose 21 Pregelatinized starch 16 Sodium Carboxymethyl Cellulose 1.5 Magnesium Stearate 0.25 Tablet weight 50

[0053] Comparative Example 4

[0054] Element Dosage per tablet (5 mg) Nicorandil 2.5 lactose 30 Microcrystalline Cellulose 7 Micro powder silica gel 0.3 Magnesium Stearate 0.2 Tablet weight 40

[0055] Test Example 1 Hardness Evaluation

[0056] 20 pieces of each of Examples 1 to 7 were taken for hardness testing to obtain the average value. The specific evaluation results are shown in Table 1.

[0057] Mannitol has the lowest hardness, while lactose plus microcrystalline cellulose has the highest hardness. Adding microcrystalline cellulose can significantly increase the hardness, while increasing tablet weight does not significantly improve the hardness.

[0058] Test Example 2: Tablet Weight Fluctuation Study

[0059] 50 tablets were taken from each of Examples 1 to 7 to test the tablet weight, and the fluctuation range of the tablet weight was calculated to compare the stability of the solution system.

[0060] The sample weights of Examples 1-7 all meet the requirements, but there are obvious differences

[0061] Experimental Example 3 Single Chip Cost Study

[0062] 1000 pieces of each of Examples 1 to 7 were prepared, and the cost per piece was calculated based on the material cost for comparison.

[0063] The results are as follows:

[0064]

[0065]

[0066] As can be seen from the table above, the sample in Example 1 has the highest hardness, the smallest fluctuation in tablet weight, and the second lowest cost;

[0067] The sample in Example 2 is the most expensive, has the lowest hardness, and has the largest fluctuation in tablet weight;

[0068] Although the sample of Example 3 has the lowest price, its tablet weight fluctuates greatly and its hardness is low;

[0069] The sample in Example 4 increases the tablet weight based on Example 3 to improve the tablet weight fluctuation. Although the price is increased and the tablet weight fluctuation is improved, the hardness is not improved.

[0070] The sample in Example 5 adds microcrystalline cellulose to improve the hardness based on Example 2. It is the most expensive, has a medium hardness, and has a large fluctuation in tablet weight.

[0071] The sample of Example 6 is based on Example 1, except that the disintegrant is replaced with cross-linked polyvinylpyrrolidone, the price is increased, the hardness is medium, and the tablet weight fluctuation is medium.

[0072] The sample of Example 7 is based on Example 1, except that lactose is replaced with corn starch, the price is reduced, the hardness is medium, and the tablet weight fluctuates greatly.

[0073] The sample of Comparative Example 1 has a slightly increased tablet weight and a slightly higher price than that of Example 1, but no significant improvement in tablet weight fluctuation and hardness.

[0074] The sample of Comparative Example 2 further increases the tablet weight and reduces the amount of lactose on the basis of Example 1, with a slightly higher price, no significant improvement in tablet weight fluctuation, and a slightly higher hardness.

[0075] The sample of Comparative Example 3 keeps the tablet weight unchanged on the basis of Example 1, significantly reduces the amount of microcrystalline cellulose, increases the price, keeps the tablet weight unchanged, and significantly reduces the hardness.

[0076] The sample of Comparative Example 4 reduces the tablet weight while keeping the same weight on the basis of Example 1, significantly reduces the amount of microcrystalline cellulose, slightly increases the price, significantly increases the fluctuation of tablet weight, and slightly reduces the hardness.

[0077] Although the prices of Examples 3, 4 and 7 are lower than that of Example 1, the overall quality attributes of the tablets of Example 1 are significantly better than those of Examples 2-6 and Comparative Examples 1-4.

[0078] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not limiting. Although the present invention has been described in detail with reference to the preferred embodiments, ordinary timekeeping personnel in the field should understand that the technical solutions of the present invention can be modified or replaced by equivalents without departing from the purpose and scope of the technical solutions of the present invention, and should be covered by the scope of the claims of the present invention.

Claims

1. A nicorandil tablet comprising the following components by weight: 5 to 10 parts of nicorandil, 40 to 70 parts of a filler, 4 to 6 parts of a disintegrant and 1 to 2 parts of a lubricant.

2. The nicorandil tablet according to claim 1, characterized in that The filler is selected from one or more of calcium hydrogen phosphate, microcrystalline cellulose, corn starch, dextrin, pregelatinized starch, lactose, hexadecanol or mannitol, preferably lactose and microcrystalline cellulose.

3. The nicorandil tablet according to claim 1, characterized in that The disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, and silicified microcrystalline cellulose; preferably cross-linked sodium carboxymethyl cellulose.

4. The nicorandil tablet according to claim 1, characterized in that: The lubricant is selected from one or more of talc, magnesium stearate, silicon dioxide, polyethylene glycol, sodium lauryl sulfate, and hydrogenated vegetable oil; preferably magnesium stearate.

5. The nicorandil tablet according to claim 1, characterized in that: The nicorandil tablet comprises the following components by weight: 5 parts of nicorandil, 44 parts of filler, 5 parts of disintegrant and 1 part of lubricant.

6. The nicorandil tablet according to claim 1, characterized in that: The nicorandil tablet comprises the following components by weight:

7. The method for preparing the Nicorandil tablet according to claim 1, characterized in that: The following steps are involved: 1) Weigh the prescribed amount of nicorandil, filler and disintegrant, sieve and premix; 2) weighing a prescribed amount of lubricant and adding it to the mixture prepared in step (1) and mixing them to obtain a nicorandil tablet intermediate; 3) Compressing the nicorandil tablet intermediate into tablets to obtain nicorandil tablets.

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