Montelukast Sodium Chewable Tablets and Preparation Method Thereof

Abstract

The present invention relates to a montelukast sodium chewable tablet and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. The montelukast sodium chewable tablet of the present invention comprises: montelukast sodium, starch, dextrin, calcium sulfate, menthol, sucrose, sodium carboxymethyl starch, and magnesium stearate. By optimizing the excipients and upgrading the preparation method, the problem that montelukast sodium is easily decomposed by light is solved, the content stability of the montelukast sodium chewable tablet is improved, the content of related substances in the montelukast sodium chewable tablet is reduced, and the medication safety of the montelukast sodium chewable tablet is improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a montelukast sodium chewable tablet and a preparation method thereof. Background Art

[0002] Disclosing the information of this background art section is only intended to enhance the overall understanding of the present invention, and it is not necessarily regarded as an admission or an implication in any form that this information constitutes the prior art already known to those of ordinary skill in the art.

[0003] Asthma is a common chronic airway inflammatory disease with a large number of patients worldwide. According to the data of the World Health Organization (WHO), approximately 300 million people globally suffer from asthma. The pathogenesis of asthma is complex, and the condition can be intermittent or persistent, with varying degrees of severity. The goal of treating asthma is to control symptoms, improve quality of life, and reduce the risk of acute exacerbations and airway inflammation.

[0004] Montelukast sodium, as a commonly used anti-allergy drug, belongs to long-acting non-chromaffin cell releasers. By blocking the activity of histamine H1 receptors, it can relieve the symptoms caused by allergic reactions, and has antihistamine, anti-inflammatory and anti-allergy effects. It can reduce vascular permeability, inhibit the activation of inflammatory cells and alleviate allergic reactions. Clinically, it is used for the prevention and long-term treatment of asthma in adults and children, including the prevention of asthma symptoms during the day and at night, the treatment of asthma patients sensitive to aspirin, and the prevention of exercise-induced bronchoconstriction. Its indications are relatively extensive, including: ① Asthma: applicable to mild to moderate asthma patients, and can be used for long-term control of asthma symptoms and prevention of asthma attacks; ② Allergic rhinitis: used to relieve symptoms such as nasal congestion, runny nose, and sneezing caused by allergic rhinitis; ③ Skeletal muscle dystonia: can be used to treat symptoms related to skeletal muscle dystonia, such as bronchospasm.

[0005] Montelukast sodium was first developed by the French pharmaceutical company Sanofi-Aventis and was launched in Europe in 1993. Currently, the commercially available montelukast sodium preparations include dosage forms such as chewable tablets, tablets, oral solutions, etc. Montelukast sodium chewable tablets are oral tablets for chewing in the mouth and then swallowing. The specifications are usually 5 mg or 10 mg, and they have the convenience of chewing and then swallowing, especially suitable for children and the elderly.

[0006] Chinese Patent with Publication No. CN103494785A discloses a montelukast sodium chewable tablet and a preparation method thereof. The montelukast sodium chewable tablet is composed of montelukast sodium, diluent, lubricant, binder, disintegrant, colorant, sweetener, and flavoring agent. The preparation process is to use absolute ethanol as a solvent to prepare the binder, and then mix it with the powders of the remaining raw and auxiliary materials, carry out wet granulation. After the wet granules are dried, they are mixed with the flavoring agent and lubricant and then pressed into tablets. The entire preparation process requires light protection operation.

[0007] Chinese Patent with Publication No. CN111000813A discloses a montelukast sodium chewable tablet and its preparation method. Under light-shielded conditions, montelukast sodium, a first binder, and water are mixed to obtain a montelukast sodium solution; the montelukast sodium solution is mixed with pharmaceutical excipients and granulated to obtain wet granules; the wet granules are dried to obtain dried granules; and the dried granules are formed to obtain the montelukast sodium chewable tablet.

[0008] During the preparation process of the above montelukast sodium chewable tablet, light-shielded operation is required, which has high requirements for the preparation process conditions and does not solve the problem of the instability of montelukast sodium upon exposure to light. Summary of the Invention

[0009] Aiming at the deficiencies of the prior art, the present invention overcomes the defect of the instability of montelukast sodium upon exposure to light by optimizing the formulation and improving the preparation process, and provides a montelukast sodium chewable tablet with high stability and qualified quality.

[0010] Specifically, the technical solution of the present invention is as follows:

[0011] The first object of the present invention is to provide a montelukast sodium chewable tablet composed of the following raw materials:

[0012] Montelukast sodium 5 - 10 parts by weight

[0013] Starch 150 - 220 parts by weight

[0014] Dextrin 30 - 80 parts by weight

[0015] Calcium sulfate 6 - 20 parts by weight

[0016] Menthol 3 - 10 parts by weight

[0017] Sucrose 10 - 25 parts by weight

[0018] Sodium carboxymethyl starch 3 - 18 parts by weight

[0019] Magnesium stearate 0.3 - 5 parts by weight.

[0020] In multiple embodiments of the present invention, the montelukast sodium chewable tablet may further be added with flavors, such as lemon flavor, strawberry flavor, orange flavor, apple flavor, etc., and the weight parts of the added flavor are 0.15 - 0.36 parts.

[0021] In one embodiment of the present invention, the montelukast sodium chewable tablet is composed of the following raw materials:

[0022] Montelukast sodium 5 parts by weight

[0023] Starch 180 parts by weight

[0024] Dextrin 60 parts by weight

[0025] Calcium sulfate 8 parts by weight

[0026] Menthol 4 parts by weight

[0027] Sucrose 14 parts by weight

[0028] Sodium carboxymethyl starch 10 parts by weight

[0029] Magnesium stearate 2 parts by weight.

[0030] In one embodiment of the present invention, the montelukast sodium chewable tablets are composed of the following raw materials:

[0031] Montelukast sodium 10 parts by weight

[0032] Starch 200 parts by weight

[0033] Dextrin 50 parts by weight

[0034] Calcium sulfate 16 parts by weight

[0035] Menthol 8 parts by weight

[0036] Sucrose 18 parts by weight

[0037] Sodium carboxymethyl starch 14 parts by weight

[0038] Magnesium stearate 3 parts by weight.

[0039] Furthermore, the weight ratio of calcium sulfate to menthol in the montelukast sodium chewable tablets is 6-20:3-10 to solve the problem that montelukast sodium is easily decomposed by light.

[0040] The second object of the present invention is to provide a preparation method of the above-mentioned montelukast sodium chewable tablets, including the following steps:

[0041] (1) Dissolve sucrose in water, add calcium sulfate and menthol to make a solution for standby;

[0042] (2) Crush, sieve and mix montelukast sodium, starch and dextrin, add the solution in step (1), carry out wet granulation, drying and sizing to obtain coarse granules;

[0043] (3) Mix the crushed and sieved magnesium stearate and sodium carboxymethyl starch with the coarse granules in step (2), and press tablets to obtain the product.

[0044] Specifically, step (1) is: dissolve sucrose in 5-10 times of water, add calcium sulfate and menthol to make a solution for standby.

[0045] Specifically, the mesh number of the auxiliary materials sieved in the preparation method of the present invention is 80 mesh.

[0046] Furthermore, the flavoring agent is added at step (3), and it can be added together with magnesium stearate and sodium carboxymethyl starch.

[0047] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0048] The present invention preferably uses calcium sulfate and menthol as excipients, adjusts the weight ratio of calcium sulfate to menthol to 6 - 20:3 - 10, and upgrades the preparation method. Calcium sulfate and menthol are pre - formulated with the binder sucrose solution, and then wet granulation is used to prepare montelukast sodium chewable tablets. This solves the problem that montelukast sodium is easily decomposed by light, improves the content stability of montelukast sodium chewable tablets, reduces the related substance content of montelukast sodium chewable tablets, and improves the medication safety of montelukast sodium chewable tablets. Description of the Drawings

[0049] Figure 1 It is the change curve of the related substance content of montelukast sodium chewable tablets in Examples 1 - 2 and Comparative Examples 1 - 3 during the accelerated test.

[0050] Figure 2 It is the change curve of the related substance content of montelukast sodium chewable tablets in Examples 3 - 4, Comparative Examples 3 - 5, and commercially available montelukast sodium chewable tablets during the accelerated test.

[0051] Figure 3 It is the change curve of the montelukast sodium content of montelukast sodium chewable tablets in Examples 1 - 4, Comparative Examples 1 - 5, and commercially available montelukast sodium chewable tablets during the light exposure test. Detailed Embodiments

[0052] In order to make the objectives and technical solutions of the present invention clearer, the following further describes the present invention with reference to the embodiments. However, the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. Those skilled in the art should understand that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0053] Example 1 Montelukast Sodium Chewable Tablets

[0054] Formulation:

[0055] Montelukast Sodium 5g

[0056] Starch 180g

[0057] Dextrin 60g

[0058] Calcium Sulfate 8g

[0059] Menthol 4g

[0060] 14 g of sucrose

[0061] 10 g of sodium carboxymethyl starch

[0062] 2 g of magnesium stearate

[0063] Preparation method:

[0064] (1) Dissolve sucrose in 5 - 10 times of water, add calcium sulfate and menthol to make a solution for standby;

[0065] (2) Grind montelukast sodium, starch and dextrin, sieve through 80 - mesh sieve, mix them, add the solution in step (1), carry out wet granulation, drying and sizing to obtain coarse granules;

[0066] (3) Mix the magnesium stearate and sodium carboxymethyl starch after grinding and sieving through 80 - mesh sieve with the coarse granules in step (2), and press tablets to obtain the product.

[0067] Example 2 Montelukast Sodium Chewable Tablets

[0068] Formulation:

[0069] 10 g of montelukast sodium

[0070] 200 g of starch

[0071] 50 g of dextrin

[0072] 16 g of calcium sulfate

[0073] 8 g of menthol

[0074] 18 g of sucrose

[0075] 14 g of sodium carboxymethyl starch

[0076] 3 g of magnesium stearate

[0077] Preparation method:

[0078] (1) Dissolve sucrose in 5 - 10 times of water, add calcium sulfate and menthol to make a solution for standby;

[0079] (2) Grind montelukast sodium, starch and dextrin, sieve through 80 - mesh sieve, mix them, add the solution in step (1), carry out wet granulation, drying and sizing to obtain coarse granules;

[0080] (3) Mix the magnesium stearate and sodium carboxymethyl starch after grinding and sieving through 80 - mesh sieve with the coarse granules in step (2), and press tablets to obtain the product.

[0081] Example 3 Montelukast Sodium Chewable Tablets

[0082] Formulation:

[0083] Montelukast Sodium 5g

[0084] Starch 150g

[0085] Dextrin 30g

[0086] Calcium Sulfate 6g

[0087] Menthol 3g

[0088] Sucrose 10g

[0089] Sodium Carboxymethyl Starch 3g

[0090] Magnesium Stearate 0.3g

[0091] Preparation Method:

[0092] (1) Dissolve sucrose in 5 - 10 times of water, add calcium sulfate and menthol to make a solution for standby;

[0093] (2) Crush montelukast sodium, starch and dextrin, sieve through 80 - mesh sieve, mix them, add the solution in step (1), carry out wet granulation, drying and sizing to obtain coarse granules;

[0094] (3) Mix the crushed magnesium stearate and sodium carboxymethyl starch sieved through 80 - mesh sieve with the coarse granules in step (2), and press tablets to obtain.

[0095] Example 4 Montelukast Sodium Chewable Tablets

[0096] Formulation:

[0097] Montelukast Sodium 10g

[0098] Starch 220g

[0099] Dextrin 80g

[0100] Calcium Sulfate 20g

[0101] Menthol 10g

[0102] Sucrose 25g

[0103] Sodium Carboxymethyl Starch 18g

[0104] Magnesium Stearate 5g

[0105] Preparation Method:

[0106] (1) Dissolve sucrose in 5 - 10 times of water, add calcium sulfate and menthol to make a solution for standby;

[0107] (2) Crush montelukast sodium, starch and dextrin, sieve through 80 - mesh sieve, mix them, add the solution in step (1), carry out wet granulation, drying and sizing to obtain coarse granules;

[0108] (3) Mix the magnesium stearate and sodium carboxymethyl starch that have been crushed and passed through an 80-mesh sieve with the coarse granules from step (2), and press into tablets to obtain the product.

[0109] Examples 5 - 8 Montelukast Sodium Chewable Tablets

[0110] Formulation:

[0111] Preparation method:

[0112] (1) Dissolve sucrose in 5 - 10 times the amount of water, add calcium sulfate and menthol, and make into a solution for standby.

[0113] (2) Crush montelukast sodium, starch, and dextrin, pass through an 80-mesh sieve, mix, add the solution from step (1), perform wet granulation, dry, and size the granules to obtain coarse granules.

[0114] (3) Mix the magnesium stearate, sodium carboxymethyl starch, and essence that have been crushed and passed through an 80-mesh sieve with the coarse granules from step (2), and press into tablets to obtain the product.

[0115] Comparative Example 1 Montelukast Sodium Chewable Tablets

[0116] Formulation:

[0117] Montelukast Sodium 5 g

[0118] Starch 180 g

[0119] Dextrin 60 g

[0120] Menthol 4 g

[0121] Sucrose 14 g

[0122] Sodium Carboxymethyl Starch 10 g

[0123] Magnesium Stearate 2 g

[0124] Preparation method:

[0125] (1) Dissolve sucrose in 5 - 10 times the amount of water, add menthol, and make into a solution for standby.

[0126] (2) Crush montelukast sodium, starch, and dextrin, pass through an 80-mesh sieve, mix, add the solution from step (1), perform wet granulation, dry, and size the granules to obtain coarse granules.

[0127] (3) Mix the magnesium stearate and sodium carboxymethyl starch that have been crushed and passed through an 80-mesh sieve with the coarse granules from step (2), and press into tablets to obtain the product.

[0128] Comparative Example 2 Montelukast Sodium Chewable Tablets

[0129] Formulation:

[0130] Montelukast Sodium 5g

[0131] Starch 180g

[0132] Dextrin 60g

[0133] Calcium Sulfate 8g

[0134] Sucrose 14g

[0135] Sodium Carboxymethyl Starch 10g

[0136] Magnesium Stearate 2g

[0137] Preparation Method:

[0138] (1) Dissolve sucrose in 5 - 10 times of water, add calcium sulfate, and make a solution for standby;

[0139] (2) Crush montelukast sodium, starch, and dextrin, pass through an 80 - mesh sieve, mix them, add the solution from step (1), carry out wet granulation, drying, and sizing to obtain coarse granules;

[0140] (3) Mix the crushed magnesium stearate and sodium carboxymethyl starch passed through an 80 - mesh sieve with the coarse granules from step (2), and press tablets to obtain the product.

[0141] Comparative Example 3 Montelukast Sodium Chewable Tablets

[0142] Formulation:

[0143] Montelukast Sodium 5g

[0144] Starch 180g

[0145] Dextrin 60g

[0146] Calcium Sulfate 3g

[0147] Menthol 5g

[0148] Sucrose 14g

[0149] Sodium Carboxymethyl Starch 10g

[0150] Magnesium Stearate 2g

[0151] Preparation Method:

[0152] (1) Dissolve sucrose in 5 - 10 times of water, add calcium sulfate and menthol, and make a solution for standby;

[0153] (2) Crush montelukast sodium, starch, and dextrin, pass through an 80 - mesh sieve, mix them, add the solution from step (1), carry out wet granulation, drying, and sizing to obtain coarse granules;

[0154] (3) Mix the magnesium stearate and sodium carboxymethyl starch that have been crushed and passed through an 80-mesh sieve with the coarse granules from step (2), and press into tablets to obtain the product.

[0155] Comparative Example 4 Montelukast Sodium Chewable Tablets

[0156] Formula:

[0157] Montelukast Sodium 5 g

[0158] Starch 180 g

[0159] Dextrin 60 g

[0160] Calcium Carbonate 8 g

[0161] Menthol 4 g

[0162] Sucrose 14 g

[0163] Sodium Carboxymethyl Starch 10 g

[0164] Magnesium Stearate 2 g

[0165] Preparation Method:

[0166] (1) Dissolve sucrose in 5 - 10 times the amount of water, add calcium carbonate and menthol to make a solution, and set aside.

[0167] (2) Crush montelukast sodium, starch, and dextrin, pass through an 80-mesh sieve, mix, add the solution from step (1), carry out wet granulation, dry, and size the granules to obtain coarse granules.

[0168] (3) Mix the magnesium stearate and sodium carboxymethyl starch that have been crushed and passed through an 80-mesh sieve with the coarse granules from step (2), and press into tablets to obtain the product.

[0169] Comparative Example 5 Montelukast Sodium Chewable Tablets

[0170] Formula:

[0171] Montelukast Sodium 5 g

[0172] Starch 180 g

[0173] Dextrin 60 g

[0174] Calcium Sulfate 8 g

[0175] Menthol 4 g

[0176] Sucrose 14 g

[0177] Sodium Carboxymethyl Starch 10 g

[0178] Magnesium Stearate 2 g

[0179] Preparation Method:

[0180] (1) Dissolve sucrose in 5 - 10 times the amount of water to make a solution for later use.

[0181] (2) Crush montelukast sodium, starch, dextrin, calcium sulfate, and menthol, sieve through an 80 - mesh sieve, mix them, add the solution from step (1), carry out wet granulation, drying, and sizing to obtain coarse granules.

[0182] (3) Mix the magnesium stearate and sodium carboxymethyl starch which have been crushed and sieved through an 80 - mesh sieve with the coarse granules from step (2), and press tablets to obtain the product.

[0183] Commercially available montelukast sodium chewable tablets: Approval number for drugs in China: J20130054.

[0184] Quality evaluation of montelukast sodium chewable tablets

[0185] 1. Appearance shape, weight variation of tablets, and friability of montelukast sodium chewable tablets

[0186] Appearance shape: It should be complete, smooth, with uniform color, no mottles, no foreign matters, and remain unchanged after 6 - month accelerated test. The accelerated test conditions are: Place in the commercial package at a temperature of 40 ± 2°C and a relative humidity of 75% ± 5% for 6 months. Samples are taken for inspection at the end of the 0th month, 1st month, 3rd month, and 6th month during the test period.

[0187] Weight variation of tablets: Take 20 tablets of the test sample, accurately weigh the total weight, calculate the average tablet weight, then accurately weigh each tablet separately. Compare the weight of each tablet with the average weight. The weight variation limit is ±5%. No more than 2 tablets shall exceed the weight variation limit, and no single tablet shall exceed the limit by more than 1 time.

[0188] Friability: Determine with a friability tester. A friability less than 1% indicates a qualified tablet.

[0189] Table 1 Appearance shape, weight variation of tablets, and friability of montelukast sodium chewable tablets

[0190] Table 1 shows that the montelukast sodium chewable tablets provided in Examples 1 - 8 of the present invention are qualified and stable in quality, and meet the standards of the Chinese Pharmacopoeia in terms of appearance shape, weight variation of tablets, friability, etc.

[0191] 2. Stability of montelukast sodium chewable tablets

[0192] Determine the related substances of montelukast sodium tablets by the method of the United States Pharmacopoeia. According to the accelerated test, place the montelukast sodium chewable tablets of Examples 1 - 8 and Comparative Examples 1 - 5 in the commercial package at a temperature of 40 ± 2°C and a relative humidity of 75% ± 5% for 6 months. Samples are taken for inspection of the related substances of montelukast sodium at the end of the 0th month, 1st month, 3rd month, and 6th month during the test period.

[0193] Figure 1 Curves showing the changes in the related substance contents of montelukast sodium chewable tablets of Examples 1 - 2 and montelukast sodium chewable tablets of Comparative Examples 1 - 3 during the accelerated test. Figure 2 Curves showing the changes in the related substance contents of montelukast sodium chewable tablets of Examples 3 - 4, montelukast sodium chewable tablets of Comparative Examples 3 - 5, and commercially available montelukast sodium chewable tablets during the accelerated test. The montelukast sodium chewable tablets of Examples 5 - 8 also underwent the same experiment, showing that the change in the related substance content was similar to that of the montelukast sodium chewable tablets of Example 1, indicating that the addition of the essence did not affect the stability of the montelukast sodium chewable tablets. The montelukast sodium chewable tablets of Examples 1 - 8 of the present invention have low related substance contents and high stability.

[0194] Determination of montelukast sodium content: Place the test sample in a light box equipped with fluorescent lamps and expose it for 30 days under the condition of an illuminance of 4500 lx ± 500 lx. Sampling is carried out on the 0th day, 10th day, 20th day, and 30th day. The content of montelukast sodium is detected by high - performance liquid chromatography. Take 10 montelukast sodium chewable tablets, weigh them precisely, grind them finely, take an appropriate amount of the fine powder (equivalent to 2.5 mg of montelukast), weigh it precisely, transfer it to a 25 - ml volumetric flask, add an appropriate amount of the mobile phase, sonicate for 5 minutes, dilute to the mark, shake well, filter, precisely measure 20 μl of the continued filtrate, inject it into the high - performance liquid chromatograph, and record the chromatogram; take an appropriate amount of montelukast sodium reference substance and determine it in the same way. Calculate according to the external standard method using the peak area, and you will get the result. Chromatographic conditions: Use octadecylsilane - bonded silica gel as the filler; water - acetonitrile (33∶67) adjusted to a pH value of 3.0 with phosphoric acid is used as the mobile phase; the flow rate is 2.0 ml / min; the detection wavelength is 283 nm.

[0195] Figure 3 Curves showing the changes in the montelukast sodium contents of montelukast sodium chewable tablets of Examples 1 - 4, montelukast sodium chewable tablets of Comparative Examples 1 - 5, and commercially available montelukast sodium chewable tablets during the light exposure test. It should be noted that the change in the content of the montelukast sodium chewable tablets of Examples 5 - 8 of the present invention during the light exposure test is similar to that of Example 1 and can remain basically unchanged. Overall, the montelukast sodium chewable tablets of the present invention effectively solve the problem that montelukast sodium is easily decomposed by light, and the content is stable.

Claims

1. A montelukast sodium chewable tablet, characterized in that, The montelukast sodium chewable tablets are composed of the following raw materials: Montelukast sodium 5 parts by weight Starch 180 parts by weight Dextrin 60 parts by weight Calcium sulfate 8 parts by weight Menthol 4 parts by weight Sucrose 14 parts by weight Sodium carboxymethyl starch 10 parts by weight Magnesium stearate 2 parts by weight The preparation method of the montelukast sodium chewable tablets is as follows: (1) Dissolve sucrose in water, add calcium sulfate and menthol to make a solution for standby; (2) Crush, sieve and mix montelukast sodium, starch and dextrin, add the solution in step (1), carry out wet granulation, drying and sizing to obtain coarse granules; (3) Mix the crushed and sieved magnesium stearate and sodium carboxymethyl starch with the coarse granules in step (2), and press tablets to obtain the product.

2. A montelukast sodium chewable tablet, characterized in that, The montelukast sodium chewable tablets are composed of the following raw materials: Montelukast sodium 10 parts by weight Starch 200 parts by weight Dextrin 50 parts by weight Calcium sulfate 16 parts by weight Menthol 8 parts by weight Sucrose 18 parts by weight Sodium carboxymethyl starch 14 parts by weight Magnesium stearate 3 parts by weight The preparation method of the montelukast sodium chewable tablets is as follows: (1) Dissolve sucrose in water, add calcium sulfate and menthol to make a solution for standby; (2) Crush, sieve and mix montelukast sodium, starch and dextrin, add the solution in step (1), carry out wet granulation, drying and sizing to obtain coarse granules; (3) Mix the crushed and sieved magnesium stearate and sodium carboxymethyl starch with the coarse granules in step (2), and press tablets to obtain the product.

3. The montelukast sodium chewable tablets according to any one of claims 1 or 2, characterized in that Step (1) is: dissolve sucrose in 5 - 10 times of water, add calcium sulfate and menthol to make a solution for standby.

4. The montelukast sodium chewable tablets according to any one of claims 1 or 2, characterized in that, The sieving is through a 80 - mesh sieve.

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