Sustained-release mononitrate isosorbide tablet and preparation method thereof

Abstract

The application belongs to the technical field of direct compression of pharmaceutical preparations, and particularly relates to a sustained-release isosorbide mononitrate tablet and a preparation method thereof. The sustained-release tablet is composed of a sustained-release tablet core and a coating layer. After isosorbide mononitrate, hydroxypropyl cellulose, palm wax, silicon dioxide, microcrystalline cellulose-lactose and talc powder are mixed, the powder is directly compressed into a tablet. The obtained tablet is coated into a film-coated tablet by using a moisture-proof coating material (AMB). The powder direct compression technology is adopted, so that the technical complexity is greatly reduced, and the wet heat unit operation is avoided. The preparation process is simple, and the quality is stable.

Description

Technical Field

[0001] This invention belongs to the field of direct compression technology of pharmaceutical preparations, specifically relating to an isosorbide mononitrate sustained-release tablet and its preparation method. Background Technology

[0002] Isosorbide mononitrate, chemically known as 3,6-didehydro-D-sorbitol-5-nitrate, is the active metabolite of isosorbide nitrate. Oral administration is unaffected by hepatic metabolism, and the drug enters systemic circulation unchanged. It has a long-acting effect, a half-life of approximately 5 hours, and high bioavailability. Clinically, it is used for the prevention and treatment of angina pectoris. It is also used for the long-term treatment of coronary artery disease, prevention of vasospasm and mixed angina, and is suitable for the treatment of post-myocardial infarction and the long-term treatment of chronic heart failure.

[0003] The structural formula of isosorbide mononitrate is:

[0004]

[0005] Direct compression technology was first proposed by Milosovitch in 1962. Before that, raw materials and excipients needed to be granulated before tableting. Isosorbide mononitrate belongs to BCS Class I, a category of highly soluble and highly permeable drugs. Current technology involves wet granulation followed by high-temperature drying. However, humidity during production and storage can affect drug stability, potentially impacting drug safety. Summary of the Invention

[0006] Direct powder compression technology avoids unit operations such as wet heat, significantly reducing the process risks of isosorbide mononitrate sustained-release formulations and further promoting the development of solid oral tablets. This invention addresses the shortcomings and deficiencies of current isosorbide mononitrate sustained-release formulations by providing a simple process for isosorbide mononitrate sustained-release tablets with high drug stability and its preparation method.

[0007] Based on the above objectives, one objective of this invention is to provide an isosorbide mononitrate sustained-release tablet, wherein the tablet adopts the following technical solution: an isosorbide mononitrate sustained-release tablet, comprising a sustained-release tablet core and a coating layer, wherein the sustained-release tablet core is composed of the following raw materials in the following mass percentages:

[0008] Isosorbide mononitrate 10%-20%,

[0009] Hydroxypropyl cellulose 20%-40%,

[0010] Carnauba wax 5%-20%,

[0011] Microcrystalline cellulose - lactose 20%-40%,

[0012] 2%-4% silicon dioxide

[0013] Talc powder 0.5%-5%;

[0014] The obtained tablets were obtained through When coated into film-coated tablets, the tablet weight increases by 2-5% after coating.

[0015] Furthermore, it consists of two parts: a sustained-release tablet core and a coating layer. The sustained-release tablet core is composed of the following raw materials in the indicated mass percentages:

[0016] Isosorbide mononitrate 14%,

[0017] Hydroxypropyl cellulose 33%,

[0018] Carnauba wax 10%,

[0019] Microcrystalline cellulose-lactose 37%,

[0020] 2% silicon dioxide

[0021] 4% talc

[0022] The weight of the sheet increases by 2%-5% after coating.

[0023] Furthermore, the microcrystalline cellulose-lactose composition has a mass ratio of lactose to microcrystalline cellulose of 1:2-3.

[0024] Another object of the present invention is to provide a method for preparing the above-mentioned isosorbide mononitrate sustained-release tablets, comprising the following steps:

[0025] (2) Weigh the prescribed amount of raw materials, grind them, and pass them through a 60-80 mesh sieve for later use;

[0026] (3) Add the prescribed amounts of isosorbide mononitrate, hydroxypropyl cellulose, palm wax, silica, and microcrystalline cellulose-lactose to a mixer, set the speed to 30-40 Hz / min, and the mixing time to 10-20 min. Add talc and mix again for 5-10 min, then compress into tablets to obtain the sustained-release tablet core;

[0027] (4) Weigh the prescription amount The coating solution is obtained by adding 9-11 times the amount of 10% ethanol to the film coating premix and stirring until homogeneous.

[0028] (5) Coating the sustained-release tablet core obtained in step (2) and drying it at 35-40℃ increases the tablet weight by 2-5%, thus obtaining the isosorbide mononitrate sustained-release tablet.

[0029] Compared with the prior art, the beneficial effects achieved by the present invention are as follows:

[0030] The use of powder direct pressing technology greatly reduces technical complexity and avoids unit operations such as damp heat. It features simple preparation process, long shelf life, stable quality, and suitability for large-scale industrial production. Detailed Implementation

[0031] The present invention will be further illustrated below with specific embodiments. It is worth noting that the specific embodiments are only for illustrating the present invention and are not intended to limit the present invention. Therefore, simple improvements made to the method of the present invention are also within the scope of the present invention.

[0032] Example 1

[0033] An isosorbide mononitrate sustained-release tablet has the following composition:

[0034]

[0035] The preparation method includes the following steps:

[0036] (1) Weigh the prescribed amount of raw materials, crush them and pass them through a 60-80 mesh sieve for later use.

[0037] (2) Weigh 60g of isosorbide mononitrate, 140g of hydroxypropyl cellulose, 40g of palm wax, 8g of silicon dioxide, and 154g of microcrystalline cellulose-lactose (2:1). Add them to a mixer and set the speed to 30-40 Hz / min for 10-20 min. Add 2g of talc and mix again for 5-10 min. Then compress the mixture into tablets with a diameter of 9mm and control the hardness to 10-12kg to obtain the sustained-release tablet core.

[0038] (3) Weigh Add 16g of film coating premix to 9-11 times the amount of 10% ethanol and stir until homogeneous to obtain the coating solution.

[0039] (4) Coating the sustained-release tablet core obtained in step (2) and drying it at 35℃-40℃ increases the tablet weight by 2%-5%, thus obtaining the isosorbide mononitrate sustained-release tablet.

[0040] Example 2

[0041] An isosorbide mononitrate sustained-release tablet has the following composition:

[0042]

[0043]

[0044] The preparation method includes the following steps:

[0045] (1) Weigh the prescribed amount of raw materials, crush them and pass them through a 60-80 mesh sieve for later use.

[0046] (2) Weigh 60g of isosorbide mononitrate, 140g of hydroxypropyl cellulose, 40g of palm wax, 8g of silicon dioxide, and 66.5g of microcrystalline cellulose-lactose (2:1). Add them to a mixer, set the speed to 30-40 Hz / min, and the mixing time to 10-20 min. Add 2g of talc and mix again for 5-10 min. Then compress the tablets with a diameter of 9mm and control the hardness to 10kg-12kg to obtain the sustained-release tablet core.

[0047] (3) Weigh Add 16g of film coating premix to 9-11 times the amount of 10% ethanol and stir until homogeneous to obtain the coating solution.

[0048] (4) Coating the sustained-release tablet core obtained in step (2) and drying it at 35℃-40℃ increases the tablet weight by 2%-5%, thus obtaining the isosorbide mononitrate sustained-release tablet.

[0049] Example 3

[0050] An isosorbide mononitrate sustained-release tablet has the following composition:

[0051]

[0052] The preparation method includes the following steps:

[0053] (1) Weigh the prescribed amount of raw materials, crush them and pass them through a 60-80 mesh sieve for later use.

[0054] (2) Weigh 60g of isosorbide mononitrate, 140g of hydroxypropyl cellulose, 40g of palm wax, 8g of silicon dioxide, and 177g of microcrystalline cellulose-lactose (3:1). Add them to a mixer and set the speed to 30-40 Hz / min for 10-20 min. Add 2g of talc and mix again for 5-10 min. Then compress the mixture into tablets with a diameter of 9mm and control the hardness to 10kg-12kg to obtain the sustained-release tablet core.

[0055] (3) Weigh Add 16g of film coating premix to 9-11 times the amount of 10% ethanol and stir until homogeneous to obtain the coating solution.

[0056] (4) Coating the sustained-release tablet core obtained in step (2) and drying it at 35℃-40℃ increases the tablet weight by 2%-5%, thus obtaining the isosorbide mononitrate sustained-release tablet.

[0057] Comparative Example 1

[0058] An isosorbide mononitrate sustained-release tablet has the following composition:

[0059]

[0060] The preparation method includes the following steps:

[0061] (1) Weigh the prescribed amount of raw materials, crush them and pass them through a 60-80 mesh sieve for later use.

[0062] (2) Weigh 60g of isosorbide mononitrate, 140g of hydroxypropyl cellulose, 40g of palm wax, 8g of silicon dioxide, 104g of pregelatinized starch, and 50g of lactose. Add them to a mixer and set the speed to 30-40 Hz / min for 10-20 min. Add 2g of talc and mix again for 5-10 min. Then compress the mixture into tablets with a diameter of 9mm and control the hardness to 10kg-12kg to obtain the sustained-release tablet core.

[0063] (3) Weigh Add 16g of film coating premix to 9-11 times the amount of 10% ethanol and stir until homogeneous to obtain the coating solution.

[0064] (4) Coating the sustained-release tablet core obtained in step (2) and drying it at 35℃-40℃ increases the tablet weight by 2%-5%, thus obtaining the isosorbide mononitrate sustained-release tablet.

[0065] Comparative Example 2

[0066] An isosorbide mononitrate sustained-release tablet has the following composition:

[0067]

[0068]

[0069] The preparation method includes the following steps:

[0070] (1) Weigh the prescribed amount of raw materials, crush them and pass them through a 60-80 mesh sieve for later use.

[0071] (2) Weigh 60g of isosorbide mononitrate, 140g of hydroxypropyl cellulose, 40g of palm wax, 8g of silicon dioxide, 104g of calcium hydrogen phosphate dihydrate, and 50g of lactose. Add them to a mixer and set the speed to 30-40 Hz / min for 10-20 min. Add 2g of talc and mix again for 5-10 min. Then compress the mixture into tablets with a diameter of 9mm and control the hardness to 10kg-12kg to obtain the sustained-release tablet core.

[0072] (3) Weigh Add 16g of film coating premix to 9-11 times the amount of 10% ethanol and stir until homogeneous to obtain the coating solution.

[0073] (4) Coating the sustained-release tablet core obtained in step (2) and drying it at 35℃-40℃ increases the tablet weight by 2%-5%, thus obtaining the isosorbide mononitrate sustained-release tablet.

[0074] Comparative Example 3

[0075] A sustained-release tablet of isosorbide mononitrate has the following composition as shown in the table below:

[0076]

[0077] The preparation method includes the following steps:

[0078] (1) Weigh the prescribed amount of raw materials, crush them and pass them through a 60-80 mesh sieve for later use.

[0079] (2) Weigh 60g of isosorbide mononitrate, 140g of hydroxypropyl cellulose, 40g of palm wax, 8g of silicon dioxide, and 154g of microcrystalline cellulose-lactose (4:1). Add them to a mixer and set the speed to 30-40 Hz / min for 10-20 min. Add 2g of talc and mix again for 5-10 min. Then compress the mixture into tablets with a diameter of 9mm and control the hardness to 10-12kg to obtain the sustained-release tablet core.

[0080] (3) Weigh Add 16g of film coating premix to 9-11 times the amount of 10% ethanol and stir until homogeneous to obtain the coating solution.

[0081] (4) Coating the sustained-release tablet core obtained in step (2) and drying it at 35℃-40℃ increases the tablet weight by 2%-5%, thus obtaining the isosorbide mononitrate sustained-release tablet.

[0082] Comparative Example 4

[0083] A sustained-release tablet of isosorbide mononitrate has the following composition as shown in the table below:

[0084]

[0085] The preparation method includes the following steps:

[0086] (1) Weigh the prescribed amount of raw materials, crush them and pass them through a 60-80 mesh sieve for later use.

[0087] (2) Weigh 60g of isosorbide mononitrate, 140g of hydroxypropyl cellulose, 40g of palm wax, 8g of silicon dioxide, and 154g of microcrystalline cellulose-lactose (1:1). Add them to a mixer and set the speed to 30-40 Hz / min for 10-20 min. Add 2g of talc and mix again for 5-10 min. Then compress the mixture into tablets with a diameter of 9mm and control the hardness to 10-12kg to obtain the sustained-release tablet core.

[0088] (3) Weigh Add 16g of film coating premix to 9-11 times the amount of 10% ethanol and stir until homogeneous to obtain the coating solution.

[0089] (4) Coating the sustained-release tablet core obtained in step (2) and drying it at 35℃-40℃ increases the tablet weight by 2%-5%, thus obtaining the isosorbide mononitrate sustained-release tablet.

[0090] Comparative Example 5

[0091] A sustained-release tablet of isosorbide mononitrate has the following composition as shown in the table below:

[0092]

[0093]

[0094] The preparation method includes the following steps:

[0095] (1) Weigh the prescribed amount of raw materials, crush them and pass them through a 60-80 mesh sieve for later use.

[0096] (2) Weigh 60g of isosorbide mononitrate, 140g of hydroxypropyl cellulose, 40g of hydrogenated castor oil, 8g of silicon dioxide, and 154g of microcrystalline cellulose-lactose (1:1). Add them to a mixer, set the speed to 30-40 Hz / min, and the mixing time to 10-20 min. Add 2g of talc and mix again for 5-10 min. Then compress the mixture into tablets with a diameter of 9mm and control the hardness to 10kg-12kg to obtain the sustained-release tablet core.

[0097] (3) Weigh Add 16g of film coating premix to 9-11 times the amount of 10% ethanol and stir until homogeneous to obtain the coating solution.

[0098] (4) Coating the sustained-release tablet core obtained in step (2) and drying it at 35℃-40℃ increases the tablet weight by 2%-5%, thus obtaining the isosorbide mononitrate sustained-release tablet.

[0099] Comparative Example 6

[0100] A sustained-release tablet of isosorbide mononitrate has the following composition as shown in the table below:

[0101]

[0102] The preparation method includes the following steps:

[0103] (1) Weigh the prescribed amount of raw materials, crush them and pass them through a 60-80 mesh sieve for later use.

[0104] (2) Weigh 60g of isosorbide mononitrate, 140g of hydroxypropyl cellulose, 40g of liquid paraffin, 8g of silica, and 154g of microcrystalline cellulose-lactose (1:1). Add them to a mixer and set the speed to 30-40 Hz / min for 10-20 min. Add 2g of talc and mix again for 5-10 min. Then compress the mixture into tablets with a diameter of 9mm and control the hardness to 10kg-12kg to obtain the sustained-release tablet core.

[0105] (3) Weigh Add 16g of film coating premix to 9-11 times the amount of 10% ethanol and stir until homogeneous to obtain the coating solution.

[0106] (4) Coating the sustained-release tablet core obtained in step (2) and drying it at 35℃-40℃ increases the tablet weight by 2%-5%, thus obtaining the isosorbide mononitrate sustained-release tablet.

[0107] Stability test

[0108] 1. Performance index evaluation under different categories

[0109] Fillers have a significant impact on the bulk density and angle of repose of the material. We first screened different fillers to examine their effects on tableting performance.

[0110] The performance of the product was evaluated by the angle of repose, compressibility and hardness of the obtained powder mixture. The results are shown in Table 1.

[0111] Table 1. Angle of repose and compressibility of powders mixed with different fillers

[0112] batch number Angle of repose (°) Compression Example 1 34.94° 35.91％ Comparative Example 1 37.89° 38.60％ Comparative Example 2 28.32° 30.55％

[0113] Meanwhile, a comparative test on the mixing uniformity of isosorbide mononitrate sustained-release tablets was conducted, and the results are shown in Table 2.

[0114] Table 2. Mixing uniformity of powders using different fillers

[0115]

[0116]

[0117] As can be seen from the table above, Example 1 and Comparative Example 2 have relatively good angle of repose and compressibility, but the mixing uniformity of Comparative Example 2 is poor, and the filler used in the end is microcrystalline cellulose-lactose.

[0118] 2. Dissolution study under different filler ratios

[0119] Lactose has good water solubility, while microcrystalline cellulose is poorly soluble in water. Different proportions of microcrystalline cellulose and lactose in the formulation will affect the dissolution behavior of APIs. We used different proportions of microcrystalline cellulose-lactose to investigate the effect on tablet dissolution, and the results are shown in Table 3.

[0120] Table 3. Dissolution of tablets using different ratios of microcrystalline cellulose-lactose

[0121] time Example 1 Comparative Example 3 Comparative Example 4 1h(15％-35％) 22.09 18.16 16.91 2h(28％-48％) 44.43 38.26 30.50 4h(43％-68％) 67.72 58.04 45.59 8h(65％-95％) 92.76 77.95 62.82 12h(≥80％) 98.41 84.68 76.26

[0122] Table 3 shows that the formulations of Example 1 and Comparative Example 4 meet the requirements, while the formulation of Comparative Example 3 dissolves too slowly and does not meet the requirements. The final determination is that the ratio of microcrystalline cellulose to lactose is 1:(2-3).

[0123] 3. Performance evaluation under different frame selections

[0124] Palm wax in this tablet formulation not only reduces interparticle friction, improves powder flowability, and prevents raw materials and excipients from sticking to the punch surface, but it is also an important component of the sustained-release matrix and thus a crucial part of this tablet. We screened different sustained-release matrices to examine their impact on tableting performance.

[0125] The properties of the product were evaluated by the angle of repose, compressibility, and hardness of the obtained powder mixture. The results are shown in Table 4.

[0126] Table 4. Comparison results using different sustained-release matrix structures

[0127] batch number Angle of repose (°) Compression Tablet hardness (N) Example 1 34.94° 35.91％ 100-120 Comparative Example 5 42.67° 38.60％ 110-130 Comparative Example 6 45.32° 39.55％ 90-130

[0128] Good flowability is a prerequisite and foundation for achieving good mixing uniformity. Good compressibility can reduce tablet brittleness, difficulty in forming, and reduce the risks to tablets caused by mechanical properties. The smaller the angle of repose and the degree of compressibility, the better the tableting performance.

[0129] As shown in the table above, Example 1 exhibits relatively good hardness stability and good tableting performance. Therefore, Example 1 was ultimately determined as the final formulation of the sustained-release tablets of this application.

[0130] 4. Stability test of isosorbide mononitrate sustained-release tablets

[0131] The finished products of Examples 1-3 were subjected to accelerated stability tests for 6 months (test conditions 40℃±2℃, relative humidity 75%±5%) to examine the dissolution at 1h, 2h, 4h, and 8h. The products met the current standards of the Chinese Pharmacopoeia in terms of dissolution, appearance, and related impurities. The results are shown in Table 5.

[0132] Table 5. Accelerated test results of Examples 1-3

[0133]

[0134] As shown in Table 5 above, during the accelerated stability test of Examples 1-3 for 6 months (test conditions 40℃±2℃, relative humidity 75%±5%), the products met the current standards of the Chinese Pharmacopoeia in terms of dissolution, appearance, and related impurities, and met the product quality requirements of sustained-release tablets.

Claims

1. A sustained-release tablet of isosorbide mononitrate, characterized in that, The sustained-release tablet consists of two parts: a sustained-release tablet core and a coating layer. The sustained-release tablet core is composed of the following raw materials in the indicated mass percentages: Isosorbide mononitrate 10%-20%, Hydroxypropyl cellulose 20%-40%, Carnauba wax 5%-20%, Microcrystalline cellulose - lactose 20%-40%, 2%-4% silicon dioxide Talc powder 0.5%-5%; The sustained-release tablets are coated with a moisture-proof coating material to form a film-coated tablet, and the weight of the tablet increases by 2%-5% after the coating layer is applied; The mass ratio of lactose to microcrystalline cellulose in the microcrystalline cellulose-lactose is 1:2-3; The sustained-release tablets are prepared using a powder direct compression method.

2. The isosorbide mononitrate sustained-release tablet as described in claim 1, characterized in that, The sustained-release tablet core is composed of the following raw materials in the following weight percentages: Isosorbide mononitrate 14%, Hydroxypropyl cellulose 33%, Carnauba wax 10%, Microcrystalline cellulose - lactose 37%, 2% silicon dioxide Talc 4%.

3. The method for preparing isosorbide mononitrate sustained-release tablets as described in claim 1, characterized in that, The method includes the following steps: (1) Weigh the prescribed amount of raw materials, crush and sieve them for later use; (2) Add the prescribed amounts of isosorbide mononitrate, hydroxypropyl cellulose, palm wax, silica, and microcrystalline cellulose-lactose to a mixer, add talc powder and mix again, then compress into tablets to obtain sustained-release tablet cores. (3) Weigh the prescribed amount of moisture-proof coating material, add 10% ethanol and stir well to obtain the coating solution; (4) Coating the sustained-release tablet core obtained in step (2) and drying it will yield the isosorbide mononitrate sustained-release tablet.

4. The method for preparing isosorbide mononitrate sustained-release tablets as described in claim 3, characterized in that, The method includes the following steps: (1) Weigh the prescribed amount of raw materials, grind them, and pass them through a 60-80 mesh sieve for later use; (2) Add the prescribed amounts of isosorbide mononitrate, hydroxypropyl cellulose, palm wax, silica, and microcrystalline cellulose-lactose to a mixer, add talc powder and mix again, then compress into tablets to obtain sustained-release tablet cores. (3) Weigh the prescribed amount of moisture-proof coating material, add 9-11 times the amount of 10% ethanol and stir well to obtain the coating solution; (4) Coating the sustained-release tablet core obtained in step (2) and drying it at 35-40℃ increases the tablet weight by 2-5%, thus obtaining the isosorbide mononitrate sustained-release tablet.

5. The method for preparing isosorbide mononitrate sustained-release tablets as described in claim 4, characterized in that, In step (2), the speed of the mixer is 30-40 Hz / min.

6. The method for preparing isosorbide mononitrate sustained-release tablets as described in claim 4, characterized in that, In step (2), the mixing time is 10-20 min.

7. The method for preparing isosorbide mononitrate sustained-release tablets as described in claim 4, characterized in that, In step (2), the talc powder is mixed again for 5-10 minutes.

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