Preparation method of montelukast orally disintegrating tablet

Abstract

The invention relates to the technical field of medicines, in particular to a montelukast orally disintegrating tablet and a preparation method thereof. The orally disintegrating tablet adopts a freeze drying process, the montelukast sodium orally disintegrating tablet prepared by the process method provided by the invention is uniform and bright in appearance color, relatively good in stability, high in dissolution speed and high in bioavailability, and the preparation process is simple and stable.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, in particular to a method for preparing a montelukast sodium orally disintegrating tablet. Background Art

[0002] Montelukast sodium salt (CAS: 151767-02-1), chemical name is [R-(E)]-1-ff[1-[3-[2-[7-chloro-2-quinolinyl)vinyl]phenyl-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid sodium, structural formula is

[0003]

[0004] Montelukast sodium is an oral leukotriene receptor antagonist that can specifically inhibit cysteinyl leukotriene (CysLT1) receptors in the airways, thereby improving airway inflammation and effectively controlling asthma symptoms.

[0005] Montelukast sodium is a non-hormonal anti-inflammatory drug, suitable for the prevention and long-term treatment of asthma in adults and children over 1 year old and the treatment of allergic rhinitis, with three different specifications. According to the 2008 edition of my country's "Guidelines for the Prevention and Treatment of Bronchial Asthma", leukotriene modifiers are the only long-term control drugs that can be used alone except inhaled hormones. They can be used as an alternative treatment for mild asthma and a combination treatment for moderate to severe asthma.

[0006] Montelukast sodium was developed by Merck and has been approved for marketing in the United States, Europe and other countries since 1998. The dosage form is tablets. In 2001, Japan approved the marketing of Montelukast sodium tablets. In October 2007, Montelukast sodium granules were first approved for marketing in Japan. It is used to treat children aged 1-5 years. In December 2015, Montelukast sodium chewable tablets were approved for marketing. Marketing status in my country: Merck's granules were approved for marketing in China in 2010, and Merck's tablets and chewable tablets were approved for marketing in China in August 2012.

[0007] Currently, the commercially available dosage forms of montelukast sodium include tablets, chewable tablets, and granules. However, during acute asthma attacks, it is inconvenient for patients to take medication due to their air-blocking state, and most asthma patients are elderly people, children, and other groups with weak swallowing ability. Freeze-dried orally disintegrating tablets have the advantages of rapid disintegration and good taste due to their rich pores and soluble matrix, which can greatly improve patients' compliance with medication. Some drugs can be absorbed through the sublingual mucosa, avoiding the first-pass effect of drugs and improving bioavailability. Summary of the invention

[0008] The present invention has found a method for preparing a montelukast sodium orodisintegrating tablet. The preparation method adopted by the present invention has simple process, low cost, controllable quality, and is easy to industrialize. The prepared orodisintegrating tablet has uniform and bright appearance, good stability, fast disintegration speed, rapid dissolution, and high bioavailability. The in vitro dissolution rate of the montelukast sodium orodisintegrating tablet prepared by the present invention can be significantly improved, and the dissolution behavior similar to that of the original control drug Singulair can be achieved in different media, ensuring the bioequivalence with the original product.

[0009] Specifically, the montelukast sodium orally disintegrating tablet provided by the present invention is composed of the following composition: montelukast sodium, a filler, a binder, a sweetener, and a lyophilized solution, wherein the lyophilized solution uses purified water as a solvent.

[0010] The filler of the present invention is selected from one or more of sugars and sugar alcohols, such as sucrose, fructose, lactose, maltose, xylose, mannitol, xylitol, etc. In the present invention, mannitol is preferably used as the filler.

[0011] The adhesive of the present invention is selected from one or more of povidone, water-soluble fiber and gelatin. These adhesives can greatly improve the properties of orally disintegrating tablets. In the present invention, gelatin is preferably used as the adhesive, and the gelatin can be selected from biogenic gelatin, or hydrolyzed or partially hydrolyzed gelatin. Considering the solubility characteristics of gelatin, gelatin is first dissolved during the preparation process. To accelerate this process, in the present invention, gelatin is dissolved with warm water or hot water, preferably at a concentration of 0.01% to 5%.

[0012] The sweetener of the present invention is selected from one or more of aspartame, sucralose and sucralose. The addition of the sweetener effectively improves the taste of the product and improves the compliance of the applicable population of the product, namely, children with asthma and allergic rhinitis. In the present invention, sucralose is preferably used as the sweetener.

[0013] More preferably, the components of the above-mentioned montelukast sodium orally disintegrating tablets and their proportions in parts by weight are:

[0014] Montelukast sodium 4-6 parts;

[0015] 20-40 parts of filler;

[0016] 4-12 parts of adhesive;

[0017] Sweetener 0.004-5 parts:

[0018] 300-600 parts of purified water.

[0019] The preparation process of the montelukast sodium orally disintegrating tablets of the present invention is a freeze-drying process.

[0020] The method for preparing the montelukast sodium orally disintegrating tablets of the present invention comprises the following steps:

[0021] 1) Weigh the raw materials according to claim 5, add the binder and filler in the raw materials to a proper amount of warm water or hot water, stir until a solution is formed, cool to room temperature, add the sweetener and stir until it is completely dissolved;

[0022] 2) Take an appropriate amount of water and stir to dissolve montelukast sodium.

[0023] 3) Add the montelukast sodium solution in 2) into 1) and stir to mix evenly.

[0024] 4) Fill the prepared solution in 3) into a sheet-shaped mold, freeze it, and then vacuum dry it.

[0025] The disintegration time of the tablets prepared by the preparation process of the montelukast sodium orally disintegrating tablets of the present invention is less than 40 seconds, and the dissolution rate in 20 minutes is more than 90%. DETAILED DESCRIPTION

[0026] The embodiments described below are exemplary and are only used to explain the present invention, but should not be construed as limiting the present invention.

[0027] Reference example

[0028] The formulation and preparation of montelukast sodium orally disintegrating tablets;

[0029] Montelukast sodium 4.15 g;

[0030] Mannitol 27.85g;

[0031] Gelatin 7g;

[0032] Sucralose 0.008 g;

[0033] 400g purified water.

[0034] The preparation process is as follows: (the preparation process should be carried out in a dark environment)

[0035] 1) Weigh gelatin and add it to an appropriate amount of 50℃ water, stir until it becomes a solution, cool it to room temperature, then add mannitol and sucralose, and stir until they are completely dissolved;

[0036] 2) Take an appropriate amount of water and stir to dissolve montelukast sodium.

[0037] 3) Add the montelukast sodium solution in 2) into 1) and stir to mix evenly.

[0038] 4) Degas the product obtained in 3).

[0039] 5) The product obtained in 4) is divided into tablet blister molds, and is quickly frozen in a quick freezer at a freezing temperature of -40°C to -100°C, and placed in a freeze dryer. The plate temperature is set to -5°C during feeding, the heat transfer oil temperature is set to -40°C for pre-freezing and maintained for 90 minutes, the heat transfer oil temperature is set to 10°C for sublimation, and the temperature is raised to 10°C in 240 minutes, and maintained for 200 minutes, and the vacuum degree is 0.60±0.05mbar, and the heat transfer oil temperature is set to 30°C for analytical drying, and the temperature is raised to 30°C in 60 minutes, and maintained for 180 minutes, and the vacuum degree is 0.20±0.05mbar.

[0040] 6) Take out the product and store it in an aluminum-plastic sealed container.

[0041] Example 1

[0042] Dissolution Determination

[0043] The dissolution curve of this product was measured under light-proof conditions, and compared with the original comparative preparation product Singulair (4 mg, batch number: X000002, X010188). 0.5% sodium dodecyl sulfate aqueous solution, pH 6.8 phosphate buffer (containing 0.5% sodium dodecyl sulfate), pH 4.5 acetate buffer (containing 2.0% sodium dodecyl sulfate) were used as dissolution media, respectively. According to the dissolution determination method (Appendix XC Method 2 of Part II of the 2010 edition of the Chinese Pharmacopoeia), the volume of the dissolution medium was 900 mL, the rotation speed was 50 revolutions per minute (75 revolutions for pH 4.5 medium), and the water temperature was 37°C. According to the method, 5 ml of samples were taken at 5 min, 10 min, 15 min, 20 min and 30 min, respectively, and filtered. The filtrate was taken and the dissolution medium of the same temperature and volume was replenished in time.

[0044] Reference substance solution: Accurately weigh about 15.7 mg of montelukast dicyclohexylamine reference substance, place it in a 50 ml volumetric flask, add methanol-water (3:1) to dissolve and dilute to make a solution containing about 0.24 mg of montelukast per 1 ml, shake well, and use it as the reference substance stock solution. Take 2 ml of the reference substance stock solution, place it in a 100 ml volumetric flask, add dissolution medium to dissolve and dilute to make a solution containing about 0.0045 mg of montelukast per 1 ml, shake well, and use it as the reference substance solution.

[0045] The chromatographic conditions were determined in accordance with high performance liquid chromatography (General Rule 0512), using phenyl bonded silica gel (recommended chromatographic column: Welch Ultimate XB-Phenyl, 3.0×100mm, 5μm or a chromatographic column with equivalent performance) as the filler; 0.07g / L sodium dihydrogen phosphate solution-acetonitrile (45:55) (add 1.33ml / L triethylamine and adjust the pH to 6.7 with phosphoric acid) as the mobile phase; the flow rate was 1.0ml per minute; the detection wavelength was 225nm; the column temperature was 35℃; the running time was about 10min; and the injection volume was 100μl.

[0046] Determination method: Accurately measure 100 μl of the test solution and the reference solution, respectively, and inject them into the liquid chromatograph, record the chromatogram, and calculate the peak area according to the external standard method.

[0047] Table 1 Dissolution test results in reference example dissolution medium

[0048]

[0049]

[0050] Table 2 Dissolution test results of the original comparative preparations in dissolution medium

[0051]

[0052] Note: “N / A” means no sample was taken at that time point

[0053] It can be seen from the results in Tables 1 and 2 that the dissolution curves of different batches of the reference sample formulations in the three dissolution media have good reproducibility, which can reach more than 85% in 15 minutes, which is consistent with the dissolution behavior of the original comparative preparations, and exhibits rapid-release in vitro dissolution characteristics in the three media.

[0054] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A montelukast sodium orally disintegrating tablet, characterized in that: The invention is prepared from the following raw materials in parts by weight: montelukast sodium, a filler, a binder, a sweetener and a freeze-dried solution, wherein the freeze-dried solution uses purified water as a solvent.

2. The orally disintegrating tablet of montelukast sodium according to claim 1, characterized in that The filler is one or more of sugars and sugar alcohols.

3. The orodisintegrating tablet of montelukast sodium according to claim 1, characterized in that The adhesive is one or more of polyvidone, water-soluble fiber and gelatin.

4. The orodisintegrating tablet of montelukast sodium according to claim 1, characterized in that The sweetener is one or more of aspartame, sucralose and sucralose.

5. The montelukast sodium orally disintegrating tablet according to claim 1, characterized in that: It is made of the following raw materials in parts by weight: Montelukast sodium 4-6 parts; 20-40 parts of filler; 4-12 parts of adhesive; Sweetener 0.004-5 parts: 300-600 parts of purified water.

6. A method for preparing montelukast sodium orally disintegrating tablets, characterized in that: The following steps are involved: 1) Weigh the raw materials according to claim 5, add the binder and filler in the raw materials to a proper amount of warm water or hot water, stir until a solution is formed, cool to room temperature, add the sweetener and stir until it is completely dissolved; 2) Take an appropriate amount of water and stir to dissolve montelukast sodium. 3) Add the montelukast sodium solution in 2) into 1) and stir to mix evenly. 4) Fill the prepared solution in 3) into a sheet-shaped mold, freeze it, and then vacuum dry it.

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