A fast-dissolving nicorandil tablet and a method for preparing the same

Abstract

The present application belongs to the technical field of pharmaceutical preparation, and provides a quick-dissolving nicorandil tablet and a preparation method thereof. The tablet is composed of an active ingredient nicorandil, hydroxypropyl methylcellulose acetate stearate, maltodextrin powder, a disintegrating agent and a lubricant. The product of the present application has good performances in moisture and heat stability and dissolution rate. In particular, the dissolution rate still has the performance of quick dissolution after accelerated investigation, which is beneficial to the emergency treatment of angina pectoris.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a rapidly dissolving nicorandil tablet and its preparation method. Background Technology

[0002] Nicorandil, chemically named N-(2-hydroxyethyl)nicotinamide nitrate, CAS number 65141-46-0, molecular formula C8H9N3O4, molecular weight 211.18, has the following structural formula:

[0003]

[0004] Nicorandil, a nitrate compound, is the first ATP-sensitive potassium channel opener used clinically. Clinical studies have confirmed that nicorandil is suitable for all types of angina, including exertional angina and spasmodic angina, and can significantly reduce the risk of cardiovascular events and improve prognosis. Nicorandil inhibits intracellular calcium ion ion release, increases cell membrane permeability to potassium ions, dilates coronary vessels, sustainably increases coronary blood flow, and inhibits coronary artery spasm. While dilating coronary vessels, it does not affect blood pressure, heart rate, myocardial contractility, or myocardial oxygen consumption. It also inhibits platelet aggregation and prevents thrombosis.

[0005] Nicorandil has a bitter taste and is slightly soluble in water. Currently available tablets have a long disintegration time, poor dissolution rate and dissolution degree, poor absorption and low bioavailability.

[0006] CN85109190A (a patent in China held by the original Japanese manufacturer) discloses a method for preparing a stable pharmaceutical formulation containing the active ingredient nicorandil. This stable formulation is produced by mixing nicorandil, one or more finely pulverized sugars, and one or more powdered organic acids. The finely pulverized sugars are required to have an average particle size of no more than 10 μm. While this patent can improve drug stability to some extent, the stability is still not entirely satisfactory. Furthermore, the fine sugars require air jet milling, which imposes extremely stringent particle size requirements, resulting in high production costs. Very few manufacturers on the market can achieve this particle size, and their products are expensive.

[0007] CN115429763A discloses a nicorandil tablet and its preparation method. This method involves freeze-drying the nicorandil tablets under vacuum, and the moisture content after drying must be less than 0.5%. This method can improve the stability of the product to a certain extent. However, the freeze-drying method is time-consuming and complicated. The dried tablets need to be packaged in a vacuum drying oven, which increases the difficulty of production and is not conducive to commercial production.

[0008] CN115317456A discloses a nicorandil composition and its preparation method. The composition includes nicorandil, carboxymethyl cellulose alkali metal salt, lactose, sodium dodecyl sulfate, and hydrogenated vegetable oil. The sample is prepared by a wet granulation process, and the prepared wet granules are dried by fluidized bed drying, then atomized and added to a hydrogenated vegetable oil solution, dried, granulated, mixed, and compressed into tablets. The advantage of this patent is that it can improve the stability of the product and avoid special packaging forms and packaging equipment, as conventional aluminum blister packaging can be used. However, the production process is complex, the production cycle is long, and special excipients are added, resulting in high production cycle and direct material costs, making it unsuitable for commercial production.

[0009] CN100591356C discloses a pharmaceutical composition containing nicorandil and its preparation method. The pharmaceutical composition includes nicorandil, a higher saturated fatty acid and its salts and / or higher alcohols (such as palmitic acid, stearic acid, hexadecyl alcohol, octadecyl alcohol, etc.) as a lubricant and not micronized, which are solid at ambient temperature, a cross-linked carboxymethyl cellulose sodium as a disintegrant, and mannitol as a diluent. The preparation method involves direct compression of the powder into tablets. The advantage of this patented technology is its simple production process, which is conducive to commercial production. However, compared with existing commercial products, its stability has not been significantly improved.

[0010] CN115282123A discloses a method for preparing a stable nicorandil formulation. This method involves grinding higher alcohols into a mixed powder and then directly compressing it into a tablet. While this method can improve the stability of the drug to some extent, the packaging still requires additional desiccants and moisture-proof bags. Furthermore, the particle size control of the stabilizer octadecyl alcohol and the filler is too fine, making it difficult to industrialize. Additionally, the grinding, sieving, mixing, and direct compression processes generate significant dust, which is detrimental to worker safety and unsuitable for commercial production.

[0011] CN114732792A discloses a nicorandil orally disintegrating tablet and its preparation method. By using stearic acid / stearyl as a lubricant in the nicorandil orally disintegrating tablet, this lubricant makes the tablet more brittle during compression, thus protecting the integrity of the nicorandil crystals and effectively improving the stability of nicorandil. By adding nicorandil with a specific particle size for tableting, this particle size helps maintain the stability of nicorandil, and the nicorandil with this specific particle size, combined with a specific compression pressure, can better maintain the crystal size of nicorandil, thereby maintaining the stability of the formulation.

[0012] In summary, the preparation of nicorandil formulations is currently not convenient, and the chemical properties of nicorandil are extremely unstable during the preparation process, easily affected by tableting processes and humid and hot environments, leading to reduced drug activity and increased toxic side effects. Furthermore, some tablets have slow absorption and onset of action, and low bioavailability, making them unsuitable for the emergency treatment of angina pectoris. The safety of patient use and the effectiveness of the formulation cannot be guaranteed. Summary of the Invention

[0013] This invention provides a rapidly dissolving nicorandil tablet with excellent stability, high dissolution rate, and a simple preparation process.

[0014] In researching nicorandil tablet formulations, this invention discovered that hydroxypropyl methylcellulose acetate stearate can function as a binder, filler, dispersant, carrier, and viscosity enhancer. The inventors used it as an excipient in nicorandil tablets and found that it could control the stability of nicorandil, but its dissolution performance was unsatisfactory. Further research revealed that adding maltodextrin powder (Glucidex IT series) and reducing the amount of hydroxypropyl methylcellulose acetate stearate could solve the stability problem of nicorandil while ensuring the long-term dissolution stability of nicorandil tablets. The inventors further screened its dosage and tablet preparation methods.

[0015] Specifically, the technical solution used in this invention is as follows: The nicorandil tablet composition includes the following components: nicorandil, hydroxypropyl methylcellulose acetate stearate, maltodextrin powder, disintegrant, and lubricant.

[0016] Preferably, based on the total weight of the tablet composition, it contains 2.5-7.5% nicorandil, 2.5-7.5% hydroxypropyl methylcellulose acetate stearate, 65-80% maltodextrin powder, 6-9% disintegrant, and 5-9% lubricant.

[0017] Preferably, the maltodextrin powder is one of Glucidex IT 12, Glucidex IT 19, and Glucidex IT 33. Glucidex IT 19 is preferred.

[0018] Preferably, the disintegrant is crospovidone and / or crospovidone sodium carboxymethyl cellulose, with crospovidone being more preferred.

[0019] Preferably, the lubricant is stearic acid and / or stearyl alcohol, with stearic acid being preferred.

[0020] Preferably, based on the total weight of the tablet composition, it comprises 5% nicorandil, 5% hydroxypropyl methylcellulose acetate stearate, 75% maltodextrin powder, 8% disintegrant, and 7% lubricant.

[0021] Preferably, a method for preparing the above-mentioned nicorandil tablets includes the following steps:

[0022] 1) Sift nicorandil and hydroxypropyl methylcellulose acetate stearate together and mix thoroughly in a three-dimensional motion mixer;

[0023] 2) Add the maltodextrin powder and disintegrant to the three-dimensional motion mixer and continue mixing;

[0024] 3) Add the lubricant to the three-dimensional motion mixer from step 2) and continue mixing;

[0025] 4) Compress the material obtained in step 3) into tablets using a tablet press.

[0026] Preferably, the obtained material is compressed into tablets under a pressure of 10–15 kN. The hardness of the resulting tablets is 30–50 N.

[0027] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0028] The nicorandil tablets provided by this invention have high dissolution rate and a simple preparation process. The preparation method uses a mixed powder compression method, avoiding operations such as wet granulation and heat drying, thus reducing the impact on drug stability. The product of this invention exhibits excellent wet-heat stability and dissolution rate. In particular, the dissolution rate remains rapid even after accelerated dissolution testing, which is beneficial for the emergency treatment of angina pectoris. Detailed Implementation

[0029] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection claimed by the present invention.

[0030] Example 1

[0031] prescription:

[0032]

[0033] Preparation method:

[0034] 1) Sift nicorandil and hydroxypropyl methylcellulose acetate stearate together and mix thoroughly in a three-dimensional motion mixer;

[0035] 2) Add Glucidex IT 19 and crospovidone to the three-dimensional motion mixer and continue mixing;

[0036] 3) Add the lubricant stearic acid to the three-dimensional motion mixer in step 2) and continue mixing;

[0037] 4) Compress the material obtained in step 3) into tablets under a pressure of 10-15 kN on a tablet press. The tablet hardness is 30-50 N.

[0038] Example 2

[0039] prescription:

[0040]

[0041] Preparation method: Same as in Example 1.

[0042] Example 3

[0043] prescription:

[0044]

[0045]

[0046] Preparation method: Same as in Example 1.

[0047] Example 4

[0048] prescription:

[0049]

[0050] Preparation method: Same as in Example 1.

[0051] Example 5

[0052] prescription:

[0053]

[0054] Preparation method: Same as in Example 1.

[0055] Example 6

[0056] prescription:

[0057]

[0058] Preparation method:

[0059] All components, except the lubricant, are added to a mixer according to the prescribed amounts and mixed. Then, the prescribed amount of lubricant is added, and the mixtures are mixed thoroughly. Finally, tablets are compressed using a tablet press under a pressure of 10–15 kN. The tablet hardness is 30–50 N.

[0060] Comparative Example 1

[0061] prescription:

[0062]

[0063] Preparation method:

[0064] 1) Sift nicorandil and hydroxypropyl methylcellulose acetate stearate together and mix thoroughly in a three-dimensional motion mixer;

[0065] 2) Add crosslinked polyvinyl chloride to the three-dimensional motion mixer and continue mixing;

[0066] 3) Add the lubricant stearic acid to the three-dimensional motion mixer in step 2) and continue mixing;

[0067] 4) Compress the material obtained in step 3) into tablets under a pressure of 10-15 kN on a tablet press. The tablet hardness is 30-50 N.

[0068] Comparative Example 2

[0069] prescription:

[0070]

[0071]

[0072] Preparation method:

[0073] 1) Sift nicoridil and Glucidex IT 19 together and mix thoroughly in a three-dimensional motion mixer;

[0074] 2) Add crosslinked polyvinyl chloride to the three-dimensional motion mixer and continue mixing;

[0075] 3) Add the lubricant stearic acid to the three-dimensional motion mixer in step 2) and continue mixing;

[0076] 4) Compress the material obtained in step 3) into tablets under a pressure of 10-15 kN on a tablet press. The tablet hardness is 30-50 N.

[0077] Verification Implementation Examples

[0078] 1. Dissolution test

[0079] Dissolution conditions: determined according to the method for determination of dissolution and release (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II).

[0080] For the samples from the above examples and control examples, 1000 ml of 0.01 mol / L hydrochloric acid solution or pH 6.8 phosphate buffer was used as the dissolution medium, and the rotation speed was 50 rpm. The dissolution rate was measured at 5 minutes, 10 minutes, and 15 minutes in this medium. The results are shown in Table 1.

[0081] Table 1 Dissolution rate of tablets in each example

[0082]

[0083]

[0084] The results showed that the nicorandil tablets prepared using the formulation and method of this invention had a dissolution rate greater than 95% at 5 minutes. This indicates that the synergistic effect of hydroxypropyl methylcellulose acetate stearate and Glucidex IT 12, Glucidex IT 19, and Glucidex IT 33 ensures rapid dissolution of nicorandil, which is beneficial for the emergency treatment of angina pectoris.

[0085] 2. Accelerated testing

[0086] The samples from each embodiment and the comparative embodiment were placed at 40℃±2℃ and RH 75%±5% for 6 months. Samples were taken at 0, 3, and 6 months, and the test results are shown in Table 2. 1000 ml of 0.01 mol / L hydrochloric acid solution was used as the dissolution medium, and the rotation speed was 50 rpm. The dissolution rate was measured in this medium for 5 minutes according to the prescribed procedure.

[0087] Table 2 Tablet data for each embodiment

[0088]

[0089]

[0090] The stability test results show that the formulation samples of this invention have good stability, solving the problem of the extreme instability of the active pharmaceutical ingredient's physicochemical properties. It also ensures rapid dissolution of nicorandil tablets.

Claims

1. A nicorandil tablet, characterized in that, The nicorandil tablet composition comprises the following components: nicorandil, hydroxypropyl methylcellulose acetate stearate, maltodextrin powder, disintegrant, and lubricant; The nicorandil tablets, by weight of the total tablet composition, contain 2.5-7.5% nicorandil, 2.5-7.5% hydroxypropyl methylcellulose acetate stearate, 65-80% maltodextrin powder, 6-9% disintegrant, and 5-9% lubricant. The disintegrant is crospovidone and / or crospovidone sodium carboxymethyl cellulose.

2. The nicorandil tablet according to claim 1, characterized in that, The maltodextrin powder is one of GlucidexIT 12, GlucidexIT 19, and GlucidexIT 33.

3. The nicorandil tablet according to claim 2, characterized in that, The maltodextrin powder is GlucidexIT 19.

4. The nicorandil tablet according to claim 1, characterized in that, The disintegrant is crospovidone.

5. The nicorandil tablet according to claim 1, characterized in that, The lubricant is stearic acid and / or stearyl alcohol.

6. The nicorandil tablet according to claim 5, characterized in that, The lubricant is stearic acid.

7. The nicorandil tablet according to claim 1, characterized in that, Based on the total weight of the tablet composition, it contains 5% nicorandil, 5% hydroxypropyl methylcellulose acetate stearate, 75% maltodextrin powder, 8% disintegrant, and 7% lubricant.

8. A method for preparing nicorandil tablets according to any one of claims 1 to 7, characterized in that, Includes the following steps: 1) Sift nicorandil and hydroxypropyl methylcellulose acetate stearate together and mix thoroughly in a three-dimensional motion mixer; 2) Add the maltodextrin powder and disintegrant to the three-dimensional motion mixer and continue mixing; 3) Add the lubricant to the three-dimensional motion mixer from step 2) and continue mixing; 4) Compress the material obtained in step 3) into tablets using a tablet press.

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