Nicodil sublingual tablet and preparation method thereof

Abstract

The invention relates to the technical field of medicines, in particular to a Nicodil sublingual tablet and a preparation method thereof. The preparation method comprises the following steps: dissolving a stabilizer in absolute ethyl alcohol, pretreating Nicodil, then adding a filling agent, a disintegrating agent, a lubricating agent, a wetting agent and a flavoring agent, mixing, and directly pressing powder to prepare the Nicodil sublingual tablet. The stability of the Nicodil sublingual tablet prepared by the method disclosed by the invention is greatly improved. The product is suitable for preventing and rapidly relieving angina pectoris attack caused by coronary artery diseases.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a nicorandil sublingual tablet and a preparation method thereof. Background Art

[0002] Nicorandil is a nitrate compound that can prevent the release of intracellular calcium ions, increase the permeability of cell membranes to potassium ions, dilate coronary blood vessels, continuously increase coronary blood flow, and inhibit coronary artery spasm. When dilating coronary blood vessels, it does not affect blood pressure, heart rate, myocardial contractility, and myocardial oxygen consumption. This product also has the effect of inhibiting platelet aggregation and preventing thrombosis, and is a new choice for the treatment of angina pectoris. Nicorandil is the first ATP-sensitive potassium ion channel opener used in clinical practice. Clinical studies have confirmed that it is suitable for all types of angina pectoris, including exertional angina pectoris and spasmodic angina pectoris, and can significantly reduce the risk of cardiovascular events and improve prognosis. The launch of Nicorandil will become a new choice for patients with angina pectoris.

[0003] Nicorandil was successfully trial-produced by Chugai Pharmaceutical and Mitsubishi Petrochemical in Japan in 1978, used in clinical research in 1981, and had its international generic name Nicorandil in 1982. It was included in the first volume of the American New Drug Yearbook "Cardiovascular Drugs" in 1983. It has completed a number of research works such as animal experiments, pharmacological toxicity tests and clinical trials, and has reached the practical stage. It was launched in Japan in early 1984. The trade names of Nicorandil currently sold on the market include: Ikorel, Dancor, Zynicor, Aprior, and Sigmart.

[0004] Nicorandil tablets are available in two specifications in Japan: 2.5mg and 5mg. In my country, only the 5mg specification is available. The drug in ordinary tablets takes a long time to dissolve, and the drug takes effect slowly. So far, no Nicorandil sublingual tablets have been marketed.

[0005] Sublingual tablets are a way of administering drugs under the tongue. The drugs are directly absorbed through the sublingual mucosa to exert systemic effects, which can avoid the destruction of drugs by gastrointestinal digestive enzymes and first-pass metabolism in the liver, improve bioavailability, and enable rapid absorption of drugs to quickly exert their efficacy.

[0006] Nicorandil, chemically known as N-(2-hydroxyethyl) nicotinamide nitrate, is a white or off-white crystalline powder. Nicorandil is easily soluble in anhydrous ethanol, slightly soluble in water, and almost insoluble in n-heptane. The critical relative humidity (CRH) of Nicorandil is above 90%, and it is almost non-hygroscopic below RH90%. Nicorandil is unstable under high temperature and high humidity conditions and is easily degraded. According to literature reports, under high temperature and high humidity conditions, the content of Nicorandil is significantly reduced and the degradation products increase.

[0007] In order to improve the stability of Nicorandil sublingual tablets, we can start from two aspects: first, start from packaging, such as using brown glass bottles, using smaller bottles as much as possible, using aluminum gaskets and metal bottle caps, and using internal desiccant, etc.; second, start from prescription and process, such as adding appropriate stabilizers, choosing to dry below 40°C as much as possible, and using processes such as direct powder compression. As people's understanding of Nicorandil gradually deepens, manufacturers have adopted countermeasures in packaging. If we want to fundamentally solve the stability problem of Nicorandil sublingual tablets, we also need to start from prescription and process.

[0008] Therefore, it is particularly important to find a stabilizer with good fluidity and low moisture absorption in the industrial production process. During the development of Nicorandil sublingual tablets, the inventors of the present application added a stabilizer and used a fluidized bed to pretreat the Nicorandil raw material, overcoming the defects of the prior art. The prepared Nicorandil sublingual tablets meet the quality requirements, and after accelerated stability test research, its content, properties, dissolution, and related substances meet the standards; in vitro dissolution tests show that the dissolution curves of the Nicorandil sublingual tablets prepared by the preparation method provided by the present invention in four different pH media of water, pH 1.2, pH 4.5, and pH 6.8 are similar to those of the original Nicorandil tablets. At the same time, the disintegration time of the Nicorandil sublingual tablets provided by the present invention is no more than 1 minute, preferably no more than 30 seconds. Summary of the invention

[0009] In view of the above problems, the present invention provides a stable Nicorandil sublingual tablet and a preparation method thereof. The Nicorandil sublingual tablet provided by the present invention has better stability, faster disintegration, less irritation to the digestive tract mucosa, more options for clinical use, easy administration, rapid absorption, and increased patient compliance.

[0010] A stable nicorandil sublingual tablet comprises the following main drugs and auxiliary materials in parts by weight: 0.5-10 parts of nicorandil, 0.5-3 parts of stabilizer, 18.15-90 parts of filler, 0.25-10 parts of disintegrant, 0.05-3 parts of lubricant, 0.05-1 parts of wetting agent and 0.01-1 parts of flavoring agent.

[0011] Preferably, the nicorandil sublingual tablet comprises the following main drugs and auxiliary materials in parts by weight: 5-10 parts of nicorandil, 0.5-3 parts of stabilizer, 75-90 parts of filler, 1-5 parts of disintegrant, 0.05-3 parts of lubricant, 0.05-1 part of wetting agent, and 0.05-1 part of flavoring agent.

[0012] More preferably, the nicorandil sublingual tablet comprises the following main drugs and auxiliary materials in parts by weight: 10 parts of nicorandil, 2 parts of stabilizer, 81 parts of filler, 5 parts of disintegrant, 1 part of lubricant, 0.5 parts of wetting agent, and 0.5 parts of flavoring agent.

[0013] The filler is selected from one of microcrystalline cellulose, lactose, starch, sucrose, mannitol, and sorbitol, preferably mannitol, and the best is 200SD direct compression mannitol, which further enhances the stability of the Nicorandil sublingual tablet, reduces the related substances and total impurities of the Nicorandil sublingual tablet, and improves the fluidity and compressibility. The present invention uses a lubricant and a filler in a specific mass ratio, which can significantly improve the compressibility and further improve the taste.

[0014] The stabilizer is selected from one or more of saturated higher alcohols (referring to monohydric alcohols containing more than six carbon atoms), polyoxyethylene (40) hydrogenated castor oil, maleic acid rosin glyceride, hydrogenated rosin glyceride, caprylic acid capric acid polyethylene glycol glyceride, triacetin, caprylic acid capric acid mono- and diglycerides, monolinoleic acid glyceride, and tricaprylic acid glyceride, preferably saturated higher alcohols, and most preferably octadecyl alcohol. The present invention uses stearyl alcohol (octadecyl alcohol) as the stabilizer in the nicorandil sublingual tablet, and the stabilizer can improve the stability of the product.

[0015] The disintegrant is selected from one of low-substituted hydroxypropyl cellulose (L-HPC), pregelatinized starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, carboxymethyl cellulose, sodium carboxymethyl cellulose, and calcium carboxymethyl cellulose, preferably calcium carboxymethyl cellulose. The present invention has been found through research that when the disintegrant is calcium carboxymethyl cellulose, the disintegration and stability of the Nicorandil sublingual tablet are better.

[0016] The lubricant is selected from one of calcium stearate, magnesium stearate, sodium stearyl fumarate, talc, and polyethylene glycol, preferably calcium stearate. In addition to its inherent lubricating effect, it can also play a good role as a protective agent for nicorandil. By selecting a specific amount of lubricant, it can be used in combination with nicorandil and other excipients to improve the stability and comprehensive performance of the nicorandil sublingual tablet.

[0017] The wetting agent is selected from one of polysorbate 80 and sodium lauryl sulfate, preferably sodium lauryl sulfate. The present invention has found that the wetting agent can accelerate the disintegration of Nicorandil sublingual tablets.

[0018] The flavoring agent is selected from one of stevioside, aspartame and citric acid, preferably aspartame. The flavoring agent is used in combination with other auxiliary materials to further improve the taste of the Nicorandil sublingual tablet.

[0019] The present invention also provides a method for preparing a nicorandil sublingual tablet, wherein a stabilizer is dissolved in anhydrous ethanol, nicorandil is subjected to fluidized bed pretreatment, a filler, a disintegrant, a lubricant, a wetting agent and a flavoring agent are added, mixed and then the powder is directly compressed to prepare the nicorandil sublingual tablet, which specifically comprises the following steps:

[0020] (1) Preparation

[0021] Nicorandil is passed through a 40-mesh sieve and weighed according to the theoretical feed amount; the stabilizer is weighed according to the theoretical feed amount; the filler, disintegrant, lubricant, wetting agent and flavoring agent are weighed after the yield of the raw material pretreatment material is calculated.

[0022] (2) Nicorandil pretreatment

[0023] Preparation of stabilizer solution: Pour anhydrous ethanol into an electrically heated stirring insulation tank, set the heating temperature to 40℃~70℃, turn on stirring, pour in the stabilizer, stir until there is no solid insoluble matter visible to the naked eye in the anhydrous ethanol, and then turn off stirring.

[0024] Pour Nicorandil into the fluidized bed pot, set the air inlet temperature to 30℃~50℃, and turn on the fan for preheating. When the material temperature reaches 30℃~40℃, set the peristaltic pump speed to 15~30rpm and start spraying the stabilizer solution. During the spraying process, keep the temperature of the stabilizer solution at 40℃~70℃.

[0025] After the stabilizer solution is sprayed, set the air inlet temperature to 30°C and start drying until the material has a drying weight loss of no more than 1% before removing from the pot. Sieve the removed material to size the particles, weigh it, and calculate the yield of the raw material pretreatment material and the amount of other auxiliary materials. Weigh the filler, disintegrant, lubricant, wetting agent and flavoring agent and set aside.

[0026] The yield of raw material pretreatment material = 100% * weight of raw material pretreatment material / (theoretical feeding amount of Nicorandil + theoretical feeding amount of octadecanol).

[0027] Remaining auxiliary material usage = theoretical feed amount * raw material pretreatment material yield.

[0028] (3) Whole grain

[0029] The filler and disintegrant are mixed with the raw material pretreatment material obtained in step (2), and the mixture is granulated using a granulator.

[0030] (4) Mixing

[0031] The material obtained in step (3) is mixed with a lubricant, a wetting agent and a flavoring agent.

[0032] (5) Particle inspection

[0033] The properties, moisture content and nicorandil content of the total mixed granules obtained in step (4) were tested according to the following standards and methods:

[0034] This product contains Nicorandil (C 8 H 9 N 3 O 4 ) should be 9.7% to 10.3%.

[0035]

Properties

[0036] [Inspection] Water content: Take this product and determine it according to the water content determination method (Chinese Pharmacopoeia 2020 Edition Part 4 General Rules 0832 Method 1 1), the water content shall not exceed 1.0%.

[0037] [Content Determination] Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0512).

[0038] Test solution: Take an appropriate amount of this product, grind it into powder, accurately weigh an appropriate amount (equivalent to 10 mg of Nicorandil), put it in a 100 ml volumetric flask, add an appropriate amount of mobile phase, sonicate in an ice-water bath to dissolve Nicorandil, dilute to the scale with mobile phase, shake well, filter, and take the filtrate.

[0039] Reference solution: Take about 10 mg of Nicorandil reference substance, weigh accurately, place in a 100 ml volumetric flask, add appropriate amount of mobile phase to dissolve and dilute to the scale, and shake well.

[0040] System suitability solution: Take appropriate amount of Nicorandil reference substance and Impurity A reference substance, add mobile phase to dissolve and quantitatively dilute to make a mixed solution containing approximately 250 μg Nicorandil and 50 μg Impurity A per 1 ml.

[0041] Chromatographic conditions: end-capped octadecylsilane bonded silica gel is used as the filler (Agilent EclipseXDB-C18 4.6mm*250mm*5μm or a chromatographic column with similar performance is recommended); [trifluoroacetic acid-triethylamine-tetrahydrofuran-water (volume ratio of 3:5:10:982) (pH adjusted to 2.50±0.20 with 10% (v / v) trifluoroacetic acid or triethylamine)]-methanol (95:5) is used as the mobile phase, with a flow rate of 1.0 ml per minute; column temperature is 30°C; detection wavelength is 254nm; injection volume is 20μl; injection plate temperature is 10°C.

[0042] System suitability requirements: In the system suitability solution chromatogram, the separation between the Nicorandil peak and the impurity A peak should be no less than 3.0, and the theoretical plate number calculated based on the Nicorandil peak should be no less than 2000.

[0043] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate the peak area according to the external standard method.

[0044] (6) Tablet pressing

[0045] Install the tablet press mold, adjust the tablet weight, tablet main pressure (4-12 kN), tablet press speed (10-30 rpm), control the hardness to 10N-40N, and tablet the particles that have passed the inspection in step (5).

[0046] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0047] The present invention pre-treats the nicorandil raw material, adds a specific amount of stabilizer, filler, disintegrant, lubricant, wetting agent and flavoring agent, and compresses the tablet under a certain pressure to obtain a nicorandil sublingual tablet with higher stability and better comprehensive performance; the product has higher quality, better stability, rapid disintegration, less irritation to the digestive tract mucosa, provides more choices in clinical use, is easy to take, quickly absorbed, has a good taste, and enhances patient adaptability.

[0048] The Nicorandil sublingual tablet provided by the present invention is more stable to humidity, and after accelerated stability test, its content still meets the standard after 6 months; and mannitol in the auxiliary material during the preparation process improves the fluidity and compressibility of the particles. The Nicorandil sublingual tablet prepared by the present invention has an optimal disintegration time of less than 30 seconds. DETAILED DESCRIPTION

[0049] In order to enable those skilled in the art to better understand the technical solution of the present invention, the present invention is further described in detail below in conjunction with specific examples. However, it should be understood that the following examples are only used to illustrate the present invention, and are not used to limit the scope of protection claimed in the claims of the present invention. The experimental methods used in the following examples are conventional methods unless otherwise specified; the materials, reagents, etc. used, unless otherwise specified, can all be obtained from commercial channels.

[0050] Example 1: Production of Nicorandil Sublingual Tablets (Prescription 1)

[0051] This embodiment provides a nicorandil sublingual tablet and a preparation method thereof. The prescription composition of each 2000 nicorandil sublingual tablet is:

[0052] Table 1: Target prescription

[0053] Name of raw materials Function Theoretical feed amount (g) Nicorandil Active ingredients 10 Octadecanol Stabilizer 2 200SD Direct Pressed Mannitol Fillers 81 Carboxymethylcellulose calcium Disintegrants 5 Sodium Lauryl Sulfate Wetting Agents 0.5 Aspartame Flavoring agents 0.5 Calcium stearate Lubricants 1 Anhydrous ethanol Solvent (removed during production) 20

[0054] The preparation method of the Nicorandil sublingual tablet comprises the following steps:

[0055] (1) Nicorandil is passed through a 40-mesh sieve and weighed according to the theoretical feed amount; the stabilizer octadecyl alcohol is weighed according to the theoretical feed amount; the filler, disintegrant, lubricant, wetting agent and flavoring agent are weighed after the yield of the raw material pretreatment material is calculated.

[0056] (2) Preparation of stabilizer solution: Pour anhydrous ethanol into an electrically heated stirring insulated tank, set the heating temperature to 40°C to 70°C, turn on stirring, pour in the stabilizer, stir until there is no solid insoluble matter visible to the naked eye in the anhydrous ethanol, and then turn off stirring.

[0057] Pour Nicorandil into the fluidized bed pot, set the inlet air temperature to 30℃~50℃, and turn on the fan for preheating. When the material temperature reaches 30℃~40℃, set the peristaltic pump speed to 10~30rpm, and start spraying the stabilizer solution (during the spraying process, the temperature of the stabilizer solution is maintained at 40℃~70℃). After the stabilizer solution is sprayed, set the inlet air temperature to 30℃, start drying, and end drying until the material loss on drying is less than 1%, and then discharge the material. The material discharged from the pot is sieved through a 40-mesh sieve, weighed, and the weight of the raw material pretreatment material is recorded, and the yield of the raw material pretreatment material and the amount of remaining excipients are calculated. Weigh the filler, disintegrant, lubricant, wetting agent and flavoring agent for later use.

[0058] The yield of raw material pretreatment material = 100% * weight of raw material pretreatment material / (theoretical feeding amount of Nicorandil + theoretical feeding amount of octadecanol).

[0059] Remaining auxiliary material usage = theoretical feed amount * raw material pretreatment material yield.

[0060] (3) Mixing the filler, disintegrant and the pre-treated raw material obtained in step (2), and granulating the mixture using a granulator.

[0061] (4) The material obtained in step (3) is mixed with a lubricant, a wetting agent and a flavoring agent.

[0062] (5) Testing the properties, moisture content, and nicorandil content of the total mixed granules obtained in step (4) according to the following standards and methods:

[0063] This product contains Nicorandil (C 8 H 9 N 3 O 4 ) should be 9.7% to 10.3%;

[0064] Properties: This product is white to off-white granules or powder;

[0065] Moisture content: Take this product and determine it according to the moisture determination method (Chinese Pharmacopoeia 2020 Edition Part 4 General Rules 0832 First Method 1), the moisture content shall not exceed 1.0%;

[0066] Content determination:

[0067] Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0512);

[0068] Test solution: Take an appropriate amount of this product, grind it finely, accurately weigh an appropriate amount (equivalent to 10 mg of Nicorandil), put it in a 100 ml volumetric flask, add an appropriate amount of mobile phase, sonicate in an ice-water bath to dissolve Nicorandil, dilute to the scale with mobile phase, shake well, filter, and take the filtrate;

[0069] Reference solution: Take about 10 mg of Nicorandil reference substance (China Food and Drug Administration, batch number: 101079-202103, content 99.6%), accurately weigh, place in a 100 ml volumetric flask, add appropriate amount of mobile phase to dissolve and dilute to the scale, shake well;

[0070] System suitability solution: Take appropriate amounts of Nicorandil reference substance and Impurity A reference substance (TLC, batch number: 1736-008A9, content 99.5%), add mobile phase to dissolve and quantitatively dilute to prepare a mixed solution containing approximately 250 μg Nicorandil and 50 μg Impurity A per 1 ml;

[0071] Chromatographic conditions: Agilent Eclipse XDB-C18 (4.6*250mm, 5μm); [trifluoroacetic acid-triethylamine-tetrahydrofuran-water (volume ratio of 3:5:10:982) (pH adjusted to 2.50 with 10% (v / v) trifluoroacetic acid)]-methanol (95:5) as mobile phase, flow rate of 1.0 ml per minute; column temperature of 30°C; detection wavelength of 254nm; injection volume of 20μl; injection plate temperature of 10°C;

[0072] System suitability requirements: In the system suitability solution chromatogram, the separation between the Nicorandil peak and the impurity A peak should be no less than 3.0, and the theoretical plate number calculated based on the Nicorandil peak should be no less than 2000;

[0073] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate the peak area according to the external standard method.

[0074] (6) Install the tablet press die, adjust the tablet weight, control the hardness to 20N-40N, the tablet press speed to 10-30rpm, and the main pressure range to 4-6kN. After the test run is completed and the qualified particles in step (5) are confirmed to be qualified, the tablets are normally pressed. The qualified tablets after tableting are placed in a material barrel covered with a double-layer PE bag, weighed, and filled in the material weighing label, and transferred to the intermediate station for storage in the dark.

[0075] Example 2: Production of Nicorandil Sublingual Tablets (Prescription 2)

[0076] This embodiment provides a nicorandil sublingual tablet and a preparation method thereof. The prescription composition of each 2000 nicorandil sublingual tablet is:

[0077] Table 2: Mannitol model investigation

[0078] Name of raw materials Function Theoretical feed amount (g) Nicorandil Active ingredients 10 Octadecanol Stabilizer 2 Mannitol Fillers 81 Carboxymethylcellulose calcium Disintegrants 5 Sodium Lauryl Sulfate Wetting Agents 0.5 Aspartame Flavoring agents 0.5 Calcium stearate Lubricants 1 Anhydrous ethanol Solvent (removed during production) 20

[0079] The mannitol used in this example was purchased from Shijiazhuang Huaxu Pharmaceutical Co., Ltd. with batch number 210905.

[0080] The preparation method of Nicorandil sublingual tablets of this embodiment is the same as that of Example 1, except that the hardness in step (6) is controlled to be 5N to 15N and the main pressure range is 8 to 10 kN.

[0081] Example 3: Production of Nicorandil Sublingual Tablets (Prescription 3)

[0082] This embodiment provides a nicorandil sublingual tablet and a preparation method thereof. The prescription composition of each 2000 nicorandil sublingual tablet is:

[0083] Table 3: Disintegrant Carboxymethylcellulose calcium (1%)

[0084]

[0085]

[0086] The preparation method of Nicorandil sublingual tablets in this example is the same as that in Example 1.

[0087] Example 4: Production of Nicorandil Sublingual Tablets (Prescription 4)

[0088] This embodiment provides a nicorandil sublingual tablet and a preparation method thereof. The prescription composition of each 2000 nicorandil sublingual tablet is:

[0089] Table 4: Disintegrant Crospovidone (5%)

[0090] Name of raw materials Function Theoretical feed amount (g) Nicorandil Active ingredients 10 Octadecanol Stabilizer 2 200SD Direct Pressed Mannitol Fillers 81 Crospovidone Disintegrants 5 Sodium Lauryl Sulfate Wetting Agents 0.5 Aspartame Flavoring agents 0.5 Calcium stearate Lubricants 1 Anhydrous ethanol Solvent (removed during production) 20

[0091] The preparation method of Nicorandil sublingual tablets in this example is the same as that in Example 1.

[0092] Comparative Example 1: Production of Nicorandil Sublingual Tablets (Prescription 5)

[0093] This comparative example provides a nicorandil sublingual tablet and a preparation method thereof. The prescription composition of each 2000 tablets of nicorandil sublingual tablet is:

[0094] Table 5: Stabilizer Octadecanol (5%)

[0095] Name of raw materials Function Theoretical feed amount (g) Nicorandil Active ingredients 10 Octadecanol Stabilizer 5 200SD Direct Pressed Mannitol Fillers 78 Carboxymethylcellulose calcium Disintegrants 5 Sodium Lauryl Sulfate Wetting Agents 0.5 Aspartame Flavoring agents 0.5 Calcium stearate Lubricants 1 Anhydrous ethanol Solvent (removed during production) 20

[0096] The preparation method of Nicorandil sublingual tablets of this embodiment is the same as that of Example 1, except that the hardness in step (6) is controlled to be 5N to 15N and the main pressure range is 8 to 10 kN.

[0097] Comparative Example 2: Production of Nicorandil Sublingual Tablets (Prescription 6)

[0098] This comparative example provides a nicorandil sublingual tablet and a preparation method thereof. The prescription composition of each 2000 tablets of nicorandil sublingual tablet is:

[0099] Table 6: Lubricant calcium stearate (5%)

[0100] Name of raw materials Function Theoretical feed amount (g) Nicorandil Active ingredients 10 Octadecanol Stabilizer 2 200SD Direct Pressed Mannitol Fillers 77 Carboxymethylcellulose calcium Disintegrants 5 Sodium Lauryl Sulfate Wetting Agents 0.5 Aspartame Flavoring agents 0.5 Calcium stearate Lubricants 5 Anhydrous ethanol Solvent (removed during production) 20

[0101] The preparation method of Nicorandil sublingual tablets of this embodiment is the same as that of Embodiment 1 except that the hardness in step (6) is controlled to be 5N to 15N and the main pressure range is 7 to 9kN.

[0102] Example 5: In vitro dissolution test of Nicorandil sublingual tablets

[0103] Take the Nicorandil sublingual tablets produced in Example 1 and the original Nicorandil tablets imported and marketed in my country (developed by Chugai Pharmaceutical Co., Ltd., the English trade name is Sigmart, the Chinese trade name is Xigemai, and the specification is 5 mg), and operate according to the dissolution test method (the second method of dissolution and release test method of the fourth general rule of the 2020 edition of the Chinese Pharmacopoeia 0931): measure 900 mL of dissolution medium (including water, pH 1.2 hydrochloric acid medium, pH 4.5 acetate solution, pH 6.8 phosphate solution), the speed is 50 revolutions per minute, operate according to the law, and pass 1 m At in, 2min, 3min, 5min, and 10min, 10mL of the solution was taken respectively, and the dissolution medium of the same temperature and volume was supplemented at the same time. Filter, accurately measure an appropriate amount of the filtrate, add the dissolution medium and quantitatively dilute it to make a solution containing approximately 5.5μg of nicorandil per 1mL, and detect it according to the high performance liquid chromatography (General Rules 0512 High Performance Liquid Chromatography of Part IV of the 2020 Edition of the Chinese Pharmacopoeia) using an octadecylsilane bonded silica gel column, the mobile phase was methanol-water (30:70), the flow rate was 1.0mL / min, the column temperature was 30°C, and the detection wavelength was 262nm. Under this chromatographic condition, 50 μl of the test solution was accurately measured and injected into the liquid chromatograph to record the chromatogram; another appropriate amount of Nicorandil reference substance (China National Institute for Food and Drug Control, batch number: 101079-202103, content 99.6%) was accurately weighed, dissolved in 80% methanol and quantitatively diluted to prepare a solution containing about 5.5 μg of Nicorandil per 1 mL, and the solution was determined in the same way, and the dissolution amount of each tablet at different time points was calculated by the external standard method using the peak area. The determination results are shown in Table 7.

[0104] Table 7: Average cumulative dissolution of Nicorandil sublingual tablets (Formulation 1) produced in Example 1

[0105]

[0106] From the results in Table 7, it can be seen that the dissolution behavior of the Nicorandil sublingual tablets (Formulation 1) produced by the method of the present invention in four different pH media of water, pH 1.2, pH 4.5, and pH 6.8 is basically consistent with the original Nicorandil tablets imported and marketed in my country, and the dissolution curve is similar to the original product. This shows that the key quality attributes of the dissolution curve of the Nicorandil sublingual tablets (Formulation 1) produced by the production process of the present invention are basically consistent with the original product.

[0107] Example 6: Compressibility study of Nicorandil sublingual tablets

[0108] During the production of Nicorandil sublingual tablets in Examples 1 to 4 and Comparative Examples 1 to 2, the main compression, hardness measurement, and whether there was a cover-lifting phenomenon during the tableting process were investigated, as shown in Table 8.

[0109] Table 8: Compressibility study of Nicorandil sublingual tablets produced

[0110]

[0111] From the results in Table 8, it can be seen that the compressibility of the Nicorandil sublingual tablets (Formulation 1) produced by the method of the present invention is basically consistent with that of the original product. With the change of the mannitol type, the increase of the amount of stabilizer octadecyl alcohol and the increase of the amount of lubricant, the compressibility of the prescription becomes worse.

[0112] Example 7: Disintegration time study of Nicorandil sublingual tablets

[0113] The disintegration phenomenon of the Nicorandil sublingual tablets produced in Examples 1 to 4 and Comparative Examples 1 to 2 was investigated, and the disintegration time was recorded as shown in Table 9.

[0114] Determination method: According to the disintegration time limit test method (Disintegration time limit test method of Part IV of the 2020 edition of the Chinese Pharmacopoeia, 0921). Hang the hanging basket on the bracket through the stainless steel shaft at the upper end, immerse it in a 1000mL beaker, and adjust the position of the hanging basket so that when it drops to the lowest point, the screen is 25mm away from the bottom of the beaker. The beaker is filled with water at a temperature of 37℃±1℃. Adjust the water level so that when the hanging basket rises to the highest point, the screen is 15mm below the water surface. The top of the hanging basket cannot be immersed in the solution. Take 6 tablets of the test sample and place them in the glass tubes of the above-mentioned hanging baskets respectively. Start the disintegration instrument for inspection. All tablets should be completely disintegrated and dissolved within 5 minutes. If one tablet cannot be completely disintegrated or dissolved, another 6 tablets should be taken for retesting, and all should meet the requirements.

[0115] Table 9: Disintegration time of Nicorandil sublingual tablets produced

[0116]

[0117] As shown in Table 9, the disintegration time of Nicorandil sublingual tablets (Formulation 1) produced by the method of the present invention is faster than that of the original product. With the change of mannitol type, the increase of the amount of stabilizer octadecyl alcohol and the increase of lubricant, the change of disintegrant type and the decrease of disintegrant amount, the disintegration of the formulation is slower than that of formulation 1.

[0118] Example 8: Accelerated stability test of Nicorandil sublingual tablets produced in various examples and Nicorandil original tablets

[0119] Nicorandil sublingual tablets produced in Examples 1 to 4 and Comparative Examples 1 to 2 were placed in 30-70 ml brown glass bottles, 30 tablets per bottle, with a built-in molecular sieve desiccant, and tightened with an aluminum gasket and an iron cap. Another original product imported and marketed in my country (developed by Chugai Pharmaceutical Co., Ltd., with an English trade name of Sigmart and a Chinese trade name of Xigemai, with a specification of 5 mg) was taken. The properties, content, solubility and related substances were investigated at 0, 1, 2, 3 and 6 months under accelerated test conditions (40°C ± 2°C, RH 75% ± 5%). The results are shown in Table 12.

[0120] (1) Dissolution determination method:

[0121] The dissolution method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931 Dissolution and Release Determination Method 2) was used: the dissolution medium was aqueous medium, the rotation speed was 50 revolutions per minute, and the sampling time was 15 minutes. Take 10 mL of the solution, and at the same time add the dissolution medium of the same temperature and volume, filter, accurately measure the appropriate amount of the filtrate, add the dissolution medium and quantitatively dilute to make a solution containing about 5.5 μg of nicorandil per 1 mL, and detect according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512 High Performance Liquid Chromatography), octadecylsilane bonded silica gel chromatographic column, mobile phase methanol-water (30:70), flow rate of 1.0 mL / min, column temperature of 30 ° C, detection wavelength of 262 nm. Under this chromatographic condition, accurately measure 50 μl of the test solution, inject it into the liquid chromatograph, and record the chromatogram; accurately weigh an appropriate amount of Nicorandil reference substance (China National Institute for Food and Drug Control, batch number: 101079-202103, content 99.6%), dissolve it in 80% methanol and quantitatively dilute it to make a solution containing approximately 5.5 μg of Nicorandil per 1 mL. Determine it in the same way and calculate the dissolution amount of each tablet by the peak area according to the external standard method.

[0122] (2) Content determination method:

[0123] Determined by high performance liquid chromatography (High Performance Liquid Chromatography, General Chapter 0512, Part IV, 2020 Edition of the Chinese Pharmacopoeia).

[0124] Test solution: Take 20 tablets of this product, accurately weigh, grind, accurately weigh an appropriate amount (equivalent to 10 mg of Nicorandil), place in a 100 ml volumetric flask, add an appropriate amount of mobile phase [(trifluoroacetic acid: triethylamine: tetrahydrofuran: water, volume ratio = 3:5:10:982) - methanol (95:5)], sonicate in an ice-water bath to dissolve Nicorandil, dilute to the scale with mobile phase, shake well, filter, and take the filtrate.

[0125] Reference solution: Take about 10 mg of Nicorandil reference substance, weigh accurately, add an appropriate amount of mobile phase [(trifluoroacetic acid: triethylamine: tetrahydrofuran: water in a volume ratio of 3:5:10:982) - methanol (95:5)] to dissolve and quantitatively dilute to make a solution containing about 100 μg per 1 ml.

[0126] Chromatographic conditions: Agilent Eclipse XDB-C18 (4.6*250mm, 5μm); [trifluoroacetic acid-triethylamine-tetrahydrofuran-water (volume ratio of 3:5:10:982) (pH adjusted to 2.50 with 10% (v / v) trifluoroacetic acid)]-methanol (95:5) as mobile phase, flow rate of 1.0 ml per minute; column temperature of 30°C; detection wavelength of 254nm; injection volume of 20μl; injection plate temperature of 10°C.

[0127] Accurately measure the test solution and reference solution, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate by peak area according to the external standard method.

[0128] (3) Determination method of related substances:

[0129] Determined by high performance liquid chromatography (High Performance Liquid Chromatography, General Chapter 0512, Part IV, 2020 Edition of the Chinese Pharmacopoeia).

[0130] Test solution: Prepare freshly before use. Take an appropriate amount of fine powder of this product (equivalent to about 20 mg of Nicorandil), accurately weigh it, put it in a 10 ml volumetric flask, add an appropriate amount of mobile phase A [trifluoroacetic acid-triethylamine-tetrahydrofuran-water (volume ratio of 3:5:2:990)], sonicate in an ice-water bath to dissolve Nicorandil, dilute to scale with mobile phase A, shake well, filter, and take the filtrate.

[0131] Reference solution: Take about 40 mg of Nicorandil reference substance, weigh accurately, place in a 10 ml volumetric flask, add mobile phase A to dissolve and dilute to the scale, shake well, as the Nicorandil reference substance stock solution, accurately measure an appropriate amount, add mobile phase A to quantitatively dilute to make a solution containing about 4 μg per 1 ml.

[0132] Accurately measure the test solution and reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram. If there are impurity peaks in the chromatogram of the test solution, calculate by the external standard method based on the nicorandil peak area in the reference solution, impurity B shall not exceed 0.2% of the labeled amount, impurity C shall not exceed 0.5% of the labeled amount, impurity D shall not exceed 0.5% of the labeled amount, nicorandil dimer shall not exceed 0.5% of the labeled amount, other individual impurities shall not exceed 0.2% of the labeled amount, and total impurities shall not exceed 2.0% of the labeled amount; chromatographic peaks in the chromatogram of the test solution that are less than 0.5 times the main peak area of ​​the reference solution are ignored (0.1%).

[0133] Chromatographic conditions: Use octadecylsilane bonded silica gel column, mobile phase A is [trifluoroacetic acid-triethylamine-tetrahydrofuran-water (volume ratio is 3:5:2:990)], mobile phase B is [trifluoroacetic acid-triethylamine-tetrahydrofuran-water (volume ratio is 8:5:8:979)], gradient elution is performed according to Table 10, flow rate is 0.8 ml / min, column temperature is 30°C, detection wavelength is 254 nm, injection volume is 20 μl.

[0134] Table 10

[0135] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 100 0 27 100 0 40 0 100 50 0 100 80 100 0 90 100 0

[0136] System suitability requirements: In the system suitability solution chromatogram, the order of peaks is impurity B, impurity C, impurity D, impurity A, nicorandil, and nicorandil dimer, and the separation of each chromatographic peak should meet the requirements.

[0137] Table 11: Impurity codes and chemical structures

[0138]

[0139]

[0140] (4) Disintegration time determination method:

[0141] The determination method is the same as in Example 7.

[0142] Table 12: Accelerated test data of Nicorandil sublingual tablets produced in various examples and the original product

[0143]

[0144]

[0145]

[0146] The results in Table 12 show that the Nicorandil sublingual tablets (prescription 1) produced by the method of the present invention were placed under accelerated conditions for 6 months, and no significant changes were found in the properties, content, solubility and related substances of the product, indicating that the quality of the Nicorandil sublingual tablets produced by the method of the present invention is stable and basically consistent with the original product, but the disintegration time is significantly better than the original product, and the effect is faster.

Claims

1. A Nicorandil sublingual tablet, characterized in that: The nicorandil sublingual tablet comprises the following main drugs and auxiliary materials in parts by weight: 0.5-10 parts of nicorandil, 0.5-3 parts of stabilizer, 18.15-90 parts of filler, 0.25-10 parts of disintegrant, 0.05-3 parts of lubricant, 0.05-1 parts of wetting agent and 0.01-1 parts of flavoring agent.

2. The nicorandil sublingual tablet according to claim 1, characterized in that The nicorandil sublingual tablet comprises the following main drugs and auxiliary materials in parts by weight: 5-10 parts of nicorandil, 0.5-3 parts of stabilizer, 75-90 parts of filler, 1-5 parts of disintegrant, 0.05-3 parts of lubricant, 0.05-1 parts of wetting agent and 0.05-1 parts of flavoring agent.

3. The nicorandil sublingual tablet according to claim 2, characterized in that: The nicorandil sublingual tablet comprises the following main drugs and auxiliary materials in parts by weight: 10 parts of nicorandil, 2 parts of stabilizer, 81 parts of filler, 5 parts of disintegrant, 1 part of lubricant, 0.5 parts of wetting agent and 0.5 parts of flavoring agent.

4. The Nicorandil sublingual tablet according to any one of claims 1 to 3, characterized in that: The filler is selected from one of microcrystalline cellulose, lactose, starch, sucrose, mannitol and sorbitol, preferably mannitol.

5. The Nicorandil sublingual tablet according to any one of claims 1 to 3, characterized in that: The stabilizer is selected from one or more of saturated higher alcohols, polyoxyethylene (40) hydrogenated castor oil, maleic acid rosin glycerol ester, hydrogenated rosin glycerol ester, caprylic acid capric acid polyethylene glycol glyceride, triacetin, caprylic acid capric acid mono- and di-glycerides, monolinoleic acid glyceride, and tricaprylic acid glyceride, preferably saturated higher alcohols.

6. The Nicorandil sublingual tablet according to any one of claims 1 to 3, characterized in that: The disintegrant is selected from one of low-substituted hydroxypropyl cellulose, pregelatinized starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, carboxymethyl cellulose, sodium carboxymethyl cellulose, and calcium carboxymethyl cellulose, preferably calcium carboxymethyl cellulose.

7. The Nicorandil sublingual tablet according to any one of claims 1 to 3, characterized in that: The lubricant is selected from one of calcium stearate, magnesium stearate, sodium stearyl fumarate, talc, and polyethylene glycol, preferably calcium stearate.

8. The Nicorandil sublingual tablet according to any one of claims 1 to 3, characterized in that: The wetting agent is selected from one of polysorbate 80 and sodium lauryl sulfate, preferably sodium lauryl sulfate; The flavoring agent is selected from one of stevioside, aspartame and citric acid, preferably aspartame.

9. A method for preparing the Nicorandil sublingual tablet according to any one of claims 1 to 8, characterized in that: The stabilizer is dissolved in anhydrous ethanol, nicorandil is pretreated in a fluidized bed, and after removing the anhydrous ethanol, a filler, a disintegrant, a lubricant, a wetting agent and a flavoring agent are added and mixed, and then the powder is directly compressed to prepare a nicorandil sublingual tablet.

10. The preparation method according to claim 9, characterized in that: The following steps are involved: (1) Preparation of materials Nicorandil is passed through a 40-mesh sieve and weighed according to the theoretical feed amount; the stabilizer is weighed according to the theoretical feed amount; the filler, disintegrant, lubricant, wetting agent, and flavoring agent are weighed after the yield of the raw material pretreatment material is calculated; (2) Nicorandil pretreatment Preparation of stabilizer solution: Pour anhydrous ethanol into an electrically heated stirring insulation tank, set the heating temperature to 40℃~70℃, turn on stirring, pour in stabilizer, stir until there is no solid insoluble matter visible to the naked eye in the anhydrous ethanol, and then turn off stirring; Pour Nicorandil into the fluidized bed pot, set the air inlet temperature to 30°C~50°C, and start the fan for preheating; when the material temperature reaches 30°C~40°C, set the peristaltic pump speed to 15~30rpm, start spraying the stabilizer solution, and during the spraying process, keep the temperature of the stabilizer solution at 40°C~70°C; after the stabilizer solution is sprayed, set the air inlet temperature to 30°C, start drying, and remove the material from the pot after the drying weight loss is no more than 1%; sieve the material out of the pot, weigh it, and calculate the yield of the raw material pretreatment material and the amount of other auxiliary materials; weigh the filler, disintegrant, lubricant, wetting agent, and flavoring agent for use; (3) Whole grain Mixing the filler, disintegrant and the raw material pre-treated material obtained in step (2), and granulating the mixture using a granulator; (4) Mixing Mixing the material obtained in step (3) with a lubricant, a wetting agent, and a flavoring agent; (5) Particle inspection Testing the properties, moisture content, and nicorandil content of the total mixed granules obtained in step (4); (6) Tableting Install the tablet press mold, adjust the tablet weight, set the tablet main pressure to 4-12 kN, the tablet press speed to 10-30 rpm, and the hardness to 20N-40N, and tablet the granules that have passed the inspection in step (5).

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