CN117547534B - Nicorandil sustained release preparation and preparation method thereof - Google Patents

Abstract

The invention provides a nicorandil sustained release preparation and a preparation method thereof, wherein the preparation comprises the following raw materials: nicorandil or its salt derivatives, sustained release agent and other pharmaceutically acceptable excipient; the sustained release preparation is characterized in that the sustained release preparation is at least one of glyceryl behenate, stearyl alcohol, hydrogenated castor oil and ethyl cellulose; the other pharmaceutically acceptable excipients at least comprise a diluent selected from at least one of small particle size sugar alcohols, microcrystalline cellulose and organic acids; and the content of the nicorandil is 1-10%, the content of the sustained release agent is 40-80% and the balance is excipient according to 100% of the mass of the nicorandil sustained release preparation. The sustained release preparation can last 24 hours for sustained release and has good stability. Is obviously superior to the sustained release preparation of nicorandil disclosed in the prior patent and the prior commercial preparation of the Xigemai.

Description

Nicorandil sustained-release preparation and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a nicorandil sustained-release preparation and a preparation method thereof.

Background technique

Nicorandil is a nitrate compound, a nitrate derivative of nicotinamide, and its main function is to dilate blood vessels. Its chemical name is: N-(2-hydroxyethyl) nicotinamide nitrate, its molecular formula is C ₈ H ₉ N ₃ O ₄ , CAS number 65141-46-0, and its structural formula is as follows:

Nicorandil has the appearance of white crystals with a special smell. In the biopharmaceutics classification system, it belongs to BCSⅢ: high solubility, low permeability. Nicorandil is easily soluble in methanol, ethanol, and acetic acid, soluble in anhydrous acetic acid, slightly soluble in water, slightly soluble in ether, and the equilibrium solubility in water at 37°C is 13.5 mg/mL. The melting point of Nicorandil is 92°C (decomposition), and pKa = 3.24±0.01. According to relevant literature reports, Nicorandil has poor physical stability, is sensitive to temperature and humidity, and is prone to degradation under high temperature and high humidity conditions.

Nicorandil is mainly used to treat angina pectoris and coronary heart disease. It not only has the characteristics of nitrate drugs, but is also a potassium channel opener. It is the only drug with a dual mechanism of action among the cardiovascular system drugs currently on the market, and it is also the first ATP-sensitive potassium channel opener used in clinical practice. Nicorandil can dilate coronary arteries, increase blood flow in coronary arteries, and relax vascular smooth muscles; Nicorandil can also promote the outflow of potassium ions in cells, inhibit the influx of calcium ions, and increase the permeability of cell membranes to potassium ions, thereby relaxing vascular smooth muscles and vasodilation.

Currently, the Nicorandil preparations on the market mainly include injections, tablets and freeze-dried powder injections. In 1995, Nicorandil tablets were launched in China. Due to the extremely short half-life of the drug (about 1h), it needs to be taken orally three times a day, which makes patients' medication compliance poor. When taking the drug, it is difficult for the blood drug concentration to reach a steady state due to the influence of individual differences, sleep time and other factors. When the blood drug concentration is too high, it is easy to produce certain toxic and side effects; when the blood drug concentration is low, it may be below the effective therapeutic concentration and cannot show a good therapeutic effect. Therefore, it is urgent to further develop Nicorandil drug preparations that can achieve slow release within a certain period of time to reduce the peak and valley phenomenon of blood drug concentration, improve the efficacy of the drug and reduce toxic and side effects.

The patent for sustained-release preparations related to Nicorandil is CN1994283A, in which the inventor uses a hydrophilic gel skeleton material with a high water content to prepare a sustained-release tablet to achieve a sustained-release effect. Hydroxypropyl methylcellulose, hydroxypropyl cellulose, and carbomer are used in the embodiments, but they can only be sustained-released for 12 hours and cannot achieve a sustained-release effect of 24 hours. In addition, the preparation process adopted by the inventor is dry granulation and wet granulation. The present invention intends to use a powder direct compression process to prepare a Nicorandil sustained-release preparation, which has simple process steps and is easier to scale up industrially. Through comparative studies of the embodiments, it is found that the sustained-release preparation of the present invention has better drug stability than the Nicorandil sustained-release preparation prepared in the patent CN1994283A.

Summary of the invention

In view of this, the object of the present invention is to provide a nicorandil sustained-release preparation and a preparation method thereof, which has a sustained-release effect of up to 24 hours and has good stability, can reduce the peak and valley phenomenon of blood drug concentration, improve drug efficacy, and reduce adverse reactions.

In order to achieve the above technical objectives, the technical solution adopted by the present invention is as follows:

In a first aspect, the present invention provides a nicorandil sustained-release preparation, the raw materials for its preparation comprising: nicorandil or its salt derivatives, a sustained-release agent and other pharmaceutically acceptable excipients; characterized in that the sustained-release agent is selected from at least one of glyceryl behenate, stearyl alcohol, hydrogenated castor oil and ethyl cellulose; the other pharmaceutically acceptable excipients at least include a diluent, and the diluent is selected from at least one of small-particle sugar alcohols, microcrystalline cellulose and organic acids; and based on 100% by mass of the nicorandil sustained-release preparation, the content of nicorandil is 1-10%, the content of the sustained-release agent is 40-80%, and the balance is excipients.

Preferably, the amount of the sustained-release agent is 45-80%, more preferably 45-70%; preferably, the sustained-release agent is selected from at least two of glyceryl behenate, stearyl alcohol, hydrogenated castor oil, and ethyl cellulose; further preferably, the sustained-release agent is a compound of glyceryl behenate and at least one of stearyl alcohol, hydrogenated castor oil, and ethyl cellulose; and/or, the content of glyceryl behenate in the nicorandil sustained-release preparation is 25-35%.

Preferably, in the diluent, the small-particle sugar alcohol is micronized mannitol, and its particle size is <100 μm, preferably <25 μm, and more preferably <10 μm; the organic acid is a small molecule organic acid, preferably at least one of fumaric acid, stearic acid, and palmitic acid; the weight ratio of the diluent in the nicorandil sustained-release preparation is 10-50%, preferably 15-30%.

Preferably, the other pharmaceutically acceptable excipients further include a lubricant, and the lubricant is selected from at least one of magnesium stearate and sodium stearyl fumarate; the weight ratio of the lubricant in the nicorandil sustained-release preparation is 0-2%.

Preferably, the other pharmaceutically acceptable excipients further include a glidant, and the glidant is selected from at least one of colloidal silicon dioxide and talc; the weight ratio of the glidant in the nicorandil sustained-release preparation is 0-2%.

Preferably, the raw materials for preparation comprise, by weight percentage, 1-5% nicorandil, 25-35% glyceryl behenate, 5-10% stearyl alcohol, 15-25% ethyl cellulose, 0-10% hydrogenated castor oil, 35-50% diluent, 1-2% lubricant, and 1-2% glidant.

Preferably, the sustained-release preparation is a tablet with a tablet weight of 400 mg to 700 mg, preferably 600 mg to 700 mg, most preferably 700 mg.

In a second aspect, the present invention provides a method for preparing a nicorandil sustained-release tablet, which adopts a powder direct compression process to prepare a nicorandil sustained-release preparation.

Preferably, the preparation method comprises:

(1) Passing nicorandil or its salt derivative through an 80-mesh sieve, and crushing the remaining solid excipients and passing them through a 60-mesh sieve, and collecting the materials separately;

(2) Blending nicorandil or its salt derivative powder with sustained-release agent and other pharmaceutically acceptable excipients and passing through a 40-mesh sieve, collecting the material and pressing it into tablets to obtain nicorandil sustained-release tablets.

Compared with the prior art, the present invention has the following technical effects:

(1) The present invention prepares a sustained-release preparation with a sustained release of 24 hours by combining nicorandil or its salt derivatives with at least one of glyceryl behenate, stearyl alcohol, hydrogenated castor oil, and ethyl cellulose and excipients such as diluents. The preparation is suitable for oral administration once a day, can reduce the peak and valley phenomenon of blood drug concentration, maintain the steady state of blood drug concentration, improve drug efficacy, reduce adverse reactions, increase drug safety, and improve patient compliance with medication.

(2) The present invention adopts a dry preparation process to obtain a nicorandil sustained-release preparation, which has a simple process and good stability. In addition, through stability test research and comparison, it is found that compared with the nicorandil sustained-release preparation in patent CN1994283A and the existing commercial preparation Sigma, the nicorandil and its salt derivatives sustained-release preparation of the present invention have better stability.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Release curves of Example 13 and Comparative Examples 5 to 6.

Detailed ways

In the description of the present invention, it should be noted that, if the specific conditions are not specified in the examples, the conventional conditions or the conditions recommended by the manufacturer are used. If the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be purchased commercially.

The present invention is further described in detail below in conjunction with the accompanying drawings and specific embodiments, which are intended to explain the present invention rather than to limit it.

In order to better describe the present invention, the chromatographic conditions for measuring the release curve and the chromatographic conditions for measuring the related substances are described.

The test was conducted in accordance with the provisions of the second method of dissolution and release determination in Part IV of the 2020 edition of the Chinese Pharmacopoeia, 0931, using 900 mL of degassed hydrochloric acid solution with a pH of 1.0 as the release medium, the medium temperature was 37°C ± 0.5°C, and the speed was 75 r/min. 10 ml of samples were taken at 1, 2, 4, 6, 8, 12, 16, and 24 hours, and an equal amount of fresh medium at the same temperature was added at the same time. The samples were filtered through a 0.45 μm microporous membrane, and the peak area of the filtrate was determined by high performance liquid chromatography with a detection wavelength of 254 nm. Another appropriate amount of reference substance was accurately weighed and determined in the same way, and the cumulative release was calculated by the external standard method.

Examples 1 to 4, Comparative Examples 1 to 4

Examples 1 to 4 and Comparative Examples 1 to 4 respectively use glyceryl behenate ( 888ATO), stearyl alcohol, ethyl cellulose (T10), hydrogenated castor oil or a mixture of more than one thereof is used as a sustained-release agent, and a powder direct compression preparation process is used to prepare Nicorandil sustained-release tablets. The mass percentage of the raw materials of Examples 1 to 4 and Comparative Examples 1 to 4 is shown in Table 1:

Table 1 Raw material mass percentage ratio of Example 1 to Example 4 and Comparative Example 1 to Comparative Example 4

Preparation:

(1) Pass Nicorandil through an 80-mesh sieve, glyceryl behenate ( 888ATO), stearyl alcohol, ethyl cellulose (T10), hydrogenated castor oil, mannitol (if necessary, crushed) through a 60-mesh sieve and collect the materials separately;

(2) Premix nicorandil and mannitol for 5 min; blend other excipients for 5 min and pass through a 40-mesh sieve;

(3) Blend the above raw and auxiliary materials for 5 minutes, pass through a 40-mesh sieve, collect the materials and press them into tablets.

The release curve of the sustained-release tablets in 900 ml of hydrochloric acid with a pH of 1.0 was measured by high performance liquid chromatography. The experimental results are shown in Table 2.

Table 2 Experimental results of release curves of different examples in Example 1 to Example 4 and Comparative Example 1 to Comparative Example 4

As shown in Table 2, when the tablet weight and the amount of sustained-release matrix material are fixed, glyceryl behenate ( Comparative Examples 1 to 4, which use 888ATO), stearyl alcohol, ethyl cellulose (T10), and hydrogenated castor oil as skeleton materials, show a slower sustained release effect. Since the excipients themselves are insoluble in water, it is difficult for the release medium to enter the tablet core, and the final release is incomplete. In Examples 1 to 4, water-insoluble ethyl cellulose (T10) is used in combination with a waxy skeleton material. The waxy skeleton produces a dissolving and peeling effect in the later stage, and the final release is complete, and the release reaches more than 90% in 16 hours. The release curves of the examples and comparative examples show that the use of glyceryl behenate ( The sustained-release effect of a mixture of two or more of 888ATO, stearyl alcohol, ethyl cellulose (T10), and hydrogenated castor oil as the skeleton material is better than that of a prescription using only one excipient.

Embodiment 5 to Embodiment 8

Examples 5 to 8 use glyceryl behenate ( 888ATO), stearyl alcohol, and ethyl cellulose (T10) were used as sustained-release skeleton materials, and a powder direct compression preparation process was used to prepare nicorandil sustained-release preparations of different tablet weights. The mass percentages of the raw materials of Examples 5 to 8 are shown in Table 3:

Table 3 Raw material mass percentage ratio of Example 5 to Example 8

Preparation:

(1) Pass Nicorandil through an 80-mesh sieve, glyceryl behenate ( 888ATO), stearyl alcohol, ethyl cellulose (T10), mannitol (if necessary, crushed) through a 60-mesh sieve to collect the material;

(2) Premix nicorandil and mannitol for 5 min; blend other excipients for 5 min and pass through a 40-mesh sieve;

(3) Blend the above raw and auxiliary materials for 5 minutes, pass through a 40-mesh sieve, collect the materials and press them into tablets.

The release curve of the sustained-release tablets in 900 ml of hydrochloric acid with a pH of 1.0 was measured by high performance liquid chromatography. The experimental results are shown in Table 4.

Table 4 Experimental results of release curves of different embodiments in Examples 5 to 8

It can be seen from Table 4 that as the tablet weight increases, the sustained release time gradually increases. In the range of tablet weight of 400mg to 700mg, the sustained release time can be 12 to 24h. The reason for the analysis is that the sustained release materials are all water-insoluble. As the tablet weight increases, the diffusion path formed after the raw materials are dissolved becomes longer, thereby slowing down the release rate. When the tablet weight is between 600mg and 700mg, the dissolution rate in 1h is reduced to less than 20%, and the converted dose is approximately equal to 5mg, which is equivalent to the dose of the immediate-release preparation. This means that the release amount within 1h can reach a similar onset dose to the immediate-release preparation and quickly exert its efficacy. Overall, the tablet weight of 700mg has the best effect.

Example 9 to Example 11, Comparative Example 5

Examples 9 to 11 and Comparative Example 5 use glyceryl behenate ( 888ATO), stearyl alcohol, and ethyl cellulose (T10) in different proportions are used as sustained-release skeleton materials, and nicorandil sustained-release preparations are prepared by powder direct compression preparation process. The mass percentages of raw materials in Examples 9 to 11 and Comparative Example 5 are shown in Table 3:

Table 5 Different compositions in Examples 9 to 11 and Comparative Example 5:

Preparation:

(1) Pass Nicorandil through an 80-mesh sieve, glyceryl behenate ( 888ATO), stearyl alcohol, ethyl cellulose (T10), mannitol (if necessary, crushed) through a 60-mesh sieve to collect the material;

(2) Premix nicorandil and mannitol for 5 min; blend other excipients for 5 min and pass through a 40-mesh sieve;

(3) Blend the above raw and auxiliary materials for 5 minutes, pass through a 40-mesh sieve, collect the materials and press them into tablets.

The release curve of the sustained-release tablets in 900 ml of hydrochloric acid with a pH of 1.0 was measured by high performance liquid chromatography. The experimental results are shown in Table 6.

Table 6 Experimental results of release curves of different examples in Examples 9 to 11 and Comparative Example 5

As shown in Table 6, the use of glyceryl behenate ( 888ATO), stearyl alcohol, and ethyl cellulose (T10) in different ratios as the sustained-release matrix material in Examples 9 to 11 can release about 20% in 1 hour, and the converted dose is equivalent to the 5mg specification of the immediate-release preparation, indicating that it can take effect quickly, achieve a blood drug concentration similar to that of the immediate-release preparation, and can be released continuously. The release rate of Comparative Example 5 in 1 hour is 19.3%, indicating that the use of glyceryl behenate ( 888ATO), stearyl alcohol, and ethyl cellulose (T10) all have good hydrophobic effects, delaying the time for water to dissolve and form pores, and the early release is slow. However, the release rate of comparative example 5 is 86.5% in 24h, which does not reach the release platform, indicating that the sustained-release material behenic acid glyceryl ( When the dosage of 888ATO was 40%, the release was incomplete.

Example 12 to Example 13

Examples 12 to 13 use glyceryl behenate ( A mixture of three or more of 888ATO, hydrogenated castor oil and ethyl cellulose (T10) is used as a sustained-release skeleton material, and a nicorandil sustained-release preparation is prepared by a powder direct compression preparation process. The mass percentage of the raw materials of Example 12 to Example 13 is shown in Table 7:

Table 7 Different compositions in Examples 12 to 13:

Preparation:

(1) Pass Nicorandil through an 80-mesh sieve, glyceryl behenate ( 888ATO), hydrogenated castor oil, ethyl cellulose (T10), mannitol (if necessary, crushed) through a 60-mesh sieve to collect the materials;

(2) Premix nicorandil and mannitol for 5 min; blend other excipients for 5 min and pass through a 40-mesh sieve;

(3) Blend the above raw and auxiliary materials for 5 minutes, pass through a 40-mesh sieve, collect the materials and press them into tablets.

The release curve of the sustained-release tablets in 900 ml of hydrochloric acid with a pH of 1.0 was measured by high performance liquid chromatography. The experimental results are shown in Table 8.

Table 8 Experimental results of release curves of different embodiments in Examples 12 to 13

As shown in Table 8, the use of glyceryl behenate ( 888ATO), hydrogenated castor oil, and ethyl cellulose (T10) as the sustained-release skeleton material. Examples 12 to 13 can release about 20% in 1 hour, and the converted dose is equivalent to the 5mg specification of the immediate-release preparation, indicating that it can take effect quickly, achieve a blood drug concentration similar to that of the immediate-release preparation, and can be released continuously. The overall dissolution trend of Example 12 is basically the same as that of Example 10, indicating that at the same ratio, the sustained-release effect of hydrogenated castor oil and stearyl alcohol is equivalent, and has no effect on the target sustained-release. Example 13 has a release rate of 20.0% in 1 hour, and the behenic acid glyceryl ( 888ATO), hydrogenated castor oil, ethyl cellulose (T10), and stearyl alcohol all have good hydrophobic effects. The multi-component composite delays the time for water to dissolve and form pores. The solubility in the later 12 hours is 73%, and the remaining drugs can maintain stable release in the later period, indicating that the nicorandil sustained-release preparation prepared by the powder direct compression process can show good sustained-release ability, and the sustained-release time can reach 24 hours.

Comparative Example 6

At present, the patent for sustained-release preparations related to Nicorandil is CN1994283A, in which the inventor uses a hydrophilic gel skeleton material with a high water content to prepare a sustained-release tablet to achieve a sustained-release effect. Hydroxypropyl methylcellulose, hydroxypropyl cellulose, and carbomer are used in the examples, but the sustained-release effect can only be achieved for 12 hours, and the sustained-release effect for 24 hours cannot be achieved. Comparative Example 6 uses the method described in patent CN1994283A to prepare a Nicorandil sustained-release preparation, and the raw material composition is shown in Table 9.

Table 9 Comparative Examples 6 with different compositions:

Element Comparative Example 6 Nicorandil 5g Hydroxypropyl methylcellulose 15g Hydroxypropylcellulose 50g Carbomer 1g lactose 10g Microcrystalline cellulose 10g Polyethylene glycol 4000 30g Magnesium stearate Moderate

Among them, Comparative Example 6 refers to Example 1 in patent CN1994283A and adopts a dry granulation process; the release curve of the obtained sustained-release tablets in 900 mL of pH 1.0 hydrochloric acid is determined by high performance liquid chromatography, and the experimental results are shown in Table 10.

Table 10 Experimental results of release curves of different comparative examples in comparative example 6

As shown in Table 10, the nicorandil sustained-release preparations prepared by the method described in patent CN1994283A all release more than 85% of the active ingredient within 8 hours. Considering the short half-life of nicorandil, the blood concentration after 8 hours cannot be effectively maintained, and thus the effect of sustained release for 24 hours cannot be achieved. FIG1 shows the release curves of Example 16, Comparative Example 5, and Comparative Example 6. It can be seen that the formulation of Example 16 shows a more stable sustained-release ability.

Embodiment 14

Stability studies

Example 4, Example 8, Example 13, Comparative Examples 4 to 6 and the commercially available preparation Sigma were subjected to stability tests, and the specific method is as follows: Example 4, Example 8, Example 13, Comparative Examples 4 to 6 and the commercially available preparation Sigma were packaged in aluminum-plastic packaging and placed under long-term test conditions (25°C ± 2°C & 60% RH ± 10% RH) for 6 months. The main investigation indicators were related substances. The stability results are shown in Table 11.

Table 11 Stability investigation results (unit: %)

illustrate:

Impurity 1 Chemical name: Pyridine-3-carboxylic acid; Molecular formula: C ₆ H ₅ NO ₂

Impurity B Chemical name: N-(2-hydroxyethyl)nitrothane; Molecular formula: C ₈ H ₁₀ N ₂ O ₂

Impurity C Chemical name: Nicotinate diaminoethyl ester; Molecular formula: C ₁₈ H ₁₀ N ₂ O ₂

Impurity D Chemical name: 2-(3-pyridine)-2-oxazoline; Molecular formula: C ₈ H ₈ N ₂ O

The polymer composition is as follows: ① Impurity 4 chemical name: 3-[[(2-nitrooxy)ethyl]aminomethyl]-1-[2-[(pyridine-3-carbonyl)amino]ethyl]pyridin-1-ium, molecular formula: C ₁₂ H ₂₇ N ₇ O ₆ ;

② Impurity 5 Chemical name: 3-[[(2-nitrooxy)ethyl]carbamoyl]-1-{2-[(1-[2-[(pyridine-3-carbonyl)amino]ethyl]pyridin-1-ium-3-carbonyl)amino]ethyl]pyridin-1-ium, molecular formula: C ₁₂ H ₂₇ N ₇ O ₆ ;

③ Impurity 6 Chemical name: 3-[[2-(Nitrooxy)ethyl]carbamoyl]-1-[2-[(1-[2-[(1-[2-[(pyridine-3-carbonyl)amino]ethyl]pyridin-1-ium-3-carbonyl)amino]ethyl]pyridin-1-ium-3carbonyl)amino]ethyl]pyridin-1-ium, molecular formula: C ₃₂ H ₃₆ N ₉ O ₇ . (Impurities 4, 5, and 6 are recorded in the European Pharmacopoeia)

As can be seen from Table 11, compared with Example 4, the sustained-release preparation of Nicorandil in Example 8 has better stability when the tablet weight is 700 mg compared with 300 mg, which is derived from the selected skeleton material glyceryl behenate ( 888ATO), stearyl alcohol, hydrogenated castor oil and ethyl cellulose (T10) are all hydrophobic and can effectively wrap Nicorandil, thereby delaying the time of oxidative hydrolysis of Nicorandil and improving the stability of the tablet.

In Examples 8 and 13 and Comparative Example 5, under the condition of consistent tablet weight, the stability difference is not obvious. Compared with Sigma, the selection of glyceryl behenate ( Tablets composed of hydrophobic materials such as glycerol (888ATO), stearyl alcohol, hydrogenated castor oil and ethyl cellulose (T10) can provide better high temperature stability.

The total impurities in Comparative Example 6 exceeded 2% after 6 months of storage. The reason for this is that a large amount of hydrophilic gel material is used in the formulation. In the case of outer packaging, the moisture contained in the material will accelerate the degradation of Nicorandil. At the same time, it shows that the hydrophobic skeleton material has low moisture content and can effectively prevent moisture intrusion, thereby improving the stability of the sample.

Therefore, the nicorandil sustained-release preparation of the present invention has better stability than the nicorandil sustained-release preparation prepared by the method described in patent CN1994283A and the existing commercially available preparation Sigma. In addition, the preparation process adopted by the inventor is dry granulation and wet granulation. The present invention adopts a powder direct compression process to prepare the nicorandil sustained-release preparation, which has simple process steps and is easier to scale up industrially.

Another patent related to the stability of Nicorandil is CN85109190A, in which the inventors mixed one or more small-particle sugars and one or more powdered organic acids with Nicorandil to prepare a Nicorandil preparation, which has good stability but does not have good sustained-release ability. The in vitro dissolution and release results show that the longest sustained-release time is 6 hours. The Nicorandil sustained-release preparation of the present invention has a better sustained-release effect in terms of in vitro release than the Nicorandil tablets prepared by the method described in CN85109190A.

In summary, the present invention has studied and investigated a large number of sustained-release materials and found that by using one or more of glyceryl behenate, stearyl alcohol, hydrogenated castor oil and ethyl cellulose (T10) and a mixture thereof, a conventional powder direct compression method can be used to prepare a sustained-release preparation of nicorandil and its salt derivatives, and the sustained-release effect can reach 24 hours and has good stability.

The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims (5)

1. The nicorandil slow release preparation is characterized in that the preparation raw materials comprise: nicorandil or its salt derivatives, sustained release agent and other pharmaceutically acceptable excipient; the slow release agent is a compound of glyceryl behenate, ethyl cellulose and stearyl alcohol, or a compound of glyceryl behenate, ethyl cellulose, stearyl alcohol and hydrogenated castor oil, and the dosage of the slow release agent is 45-70%; the other pharmaceutically acceptable excipients at least comprise a diluent, a lubricant and a glidant, wherein the diluent is at least one of sugar alcohol with small particle size, microcrystalline cellulose and organic acid, the lubricant is at least one of magnesium stearate and sodium stearyl fumarate, the glidant is at least one of colloidal silicon dioxide and talcum powder,

The preparation raw materials comprise the following components in percentage by weight: 1-5% of nicorandil, 25-35% of glyceryl behenate, 5-10% of stearyl alcohol, 15-25% of ethyl cellulose, 0-10% of hydrogenated castor oil, 10-50% of a diluent, 1-2% of a lubricant and 1-2% of a glidant.

2. The sustained release formulation of nicorandil as claimed in claim 1, wherein in the diluent, the small particle size sugar alcohol is micronized mannitol having a particle size < 100 μm; the organic acid is small molecular organic acid, and is at least one of fumaric acid, stearic acid and palmitic acid.

3. The sustained release formulation of nicorandil as claimed in claim 1 or 2, wherein the sustained release formulation is a tablet having a tablet weight of 400mg to 700mg.

4. A method for preparing a sustained release preparation of nicorandil as claimed in claim 3, wherein the preparation of the sustained release preparation of nicorandil is carried out by adopting a powder direct compression process.

5. The method according to claim 4, comprising:

(1) Sieving nicorandil or its salt derivatives with 80 mesh sieve, pulverizing the rest solid adjuvants, sieving with 60 mesh sieve, and collecting materials respectively;

(2) Blending the nicorandil or its salt derivative powder with sustained release agent and other pharmaceutically acceptable excipients, sieving with 40 mesh sieve, collecting material, and tabletting to obtain nicorandil sustained release tablet.