Montelukast sodium tablet composition and preparation method thereof

Abstract

The invention relates to a montelukast sodium tablet composition and a preparation method thereof, and belongs to the field of pharmaceutical preparations. The preparation method comprises the following steps: pressing a montelukast sodium micro-tablet and auxiliary material mixed particle by a chip-coated tablet press, wherein the montelukast sodium micro-tablet is used as a tablet core; compared with the prior art, an opacifying agent and a coloring agent are avoided in the prescription composition, the preparation method is innovated, and the quality stability and medication safety of the product are improved.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a montelukast sodium core-coated tablet and a preparation method thereof. Background Art

[0002] Montelukast sodium is a selective leukotriene receptor antagonist originally developed by Merck & Co., Inc., suitable for the prevention and long-term treatment of asthma in adults and children. Compared to adults, children require a more convenient administration method to improve drug compliance and efficacy. Currently, the approved dosage forms of montelukast sodium in China include ordinary tablets, chewable tablets, granules, and orally disintegrating films. Referring to the drug instructions for each dosage form, the applicable population statistics are as follows:

[0003] However, children aged 2 to 3 years old often encounter incomplete tooth development, lack of chewing cooperation or difficulty swallowing when taking chewable tablets, which increases the risk of choking or suffocation in children and poses a safety hazard; montelukast sodium granules are unstable when exposed to light, moisture and heat. Doctors recommend that they be taken quickly with drinks with a certain light-shielding effect, such as milk, and it is not recommended to be placed in water for a long time; montelukast sodium orally disintegrating film is sensitive to storage conditions such as temperature and humidity, and is prone to moisture, adhesion or failure, and the production process is relatively complex and the cost is high.

[0004] Montelukast sodium API is unstable when exposed to light. Field measurements have shown that after 10 days of exposure, the API's content drops from 100% to approximately 70%, while impurities rapidly increase, far exceeding standard limits. To address these quality challenges, the reference formulation for montelukast sodium tablets uses a film coating with a colorant. The reference formulation for montelukast sodium chewable tablets incorporates colorants such as red iron oxide and titanium dioxide, as well as a light shield, into the tablet core. The improved orally disintegrating film formulation for montelukast sodium released domestically also incorporates a colorant. Patent CN115590827A utilizes direct powder compression technology to prepare orally disintegrating montelukast sodium tablets, but no product stability studies have been conducted.

[0005] On February 18, 2020, the European Union issued Delegated Regulation (EU) 2020 / 217, amending CLP Regulation (EC) No. 1272 / 2008 (Classification, Labelling and Packaging of Substances and Mixtures), which listed titanium dioxide as a Category 2 carcinogen. On December 31, 2020, the National Medical Products Administration (NMPA) issued the "Guiding Principles for the Pharmaceutical Development of Pediatric Medications (Chemical Drugs) (Trial Implementation)," which explicitly stated that colorants are generally not recommended in pediatric medicines, particularly for infants and young children. Azo dyes should not be used in pediatric medicines, and particular attention should be paid to the allergic risks caused by natural colorants.

[0006] In view of the pharmacological properties of montelukast sodium raw materials and the shortcomings of various dosage forms, it is necessary to develop a new formulation that is widely applicable to the population, has good compliance, stable quality and is suitable for industrial production. Summary of the Invention

[0007] The present invention provides a novel method for preparing montelukast sodium tablets, which adopts a core-coated chip design. The specific concept is as follows: the outer layer of the core-coated chip can quickly disintegrate without chewing after contacting oral saliva; the inner layer of micro-tablets slowly releases the drug, is reasonably sized, and does not pose safety risks such as choking or inhalation into the airway, covering the medication needs of people aged 2 and above; the entire tablet formulation does not contain any colorants or light-shielding agents, and the stability of related substances is excellent; the in vitro drug release curve is similar to that of the reference preparation, meeting the in vivo efficacy requirements.

[0008] A review of the literature revealed that the size of oral tablets for children is the basis for whether they can swallow smoothly and is also the most important factor in determining tablet acceptability and compliance. EMA proposed in its draft guidelines for the pharmaceutical development of pediatric medicines that children of different age groups can accept tablets of different sizes, as follows:

[0009] Based on the above scientific guidance, the present invention provides a new montelukast sodium tablet composition and a preparation method thereof, the prescription composition is as follows:

[0010] The preparation method is as follows: Step 1: Mix the montelukast sodium API and microcrystalline cellulose, and then add magnesium stearate and mix; Step 2: Using a round die to compress montelukast sodium microtablets; Step 3: After mixing other excipients, magnesium stearate is added to the mixture to obtain excipient mixed granules; Step 4: Compress the montelukast sodium microtablets and the mixed excipients into pellets, with the microtablets serving as the core tablets.

[0011] Preferably, the particle size of the montelukast sodium bulk drug is 40-80 μm.

[0012] Preferably, the diameter of the montelukast sodium microtablet is φ2~3.5mm and the hardness is 15~40N.

[0013] Preferably, the average hardness of the montelukast sodium tablet is 50-55N.

[0014] Preferably, the relative humidity of the environment during the production process is ≤50%.

[0015] The montelukast sodium tablet composition and preparation method thereof of the present invention meet the above-mentioned requirements and have significant beneficial effects.

[0016] In order to better understand the technical solutions and advantages of the present invention, the present invention is further described below through specific implementation methods, but the examples do not limit the present invention in any way. Example 1

[0017] Prescription composition:

[0018] Note: 4.2 mg of montelukast sodium is equivalent to 4 mg of montelukast.

[0019] Preparation method: Step 1: Add montelukast sodium API (measured particle size D90: 60.5 μm) and microcrystalline cellulose into a blender and mix for 10 minutes. Then add magnesium stearate and mix for 5 minutes. Step 2: Use a φ3 circular punch to press the micro-slice, controlling the average hardness to 25~30N; Step 3: Add mannitol, microcrystalline cellulose, crospovidone, cherry powder flavor, aspartame, and colloidal silicon dioxide to a blender and mix for 10 minutes. Then add magnesium stearate and mix for a total of 5 minutes. Step 4: Add the montelukast sodium microtablets and excipient mixed granules obtained in step 2 to a Romaco Kilian tablet press, and press the tablets to control the average hardness to 50~55N. Example 2

[0020] Prescription composition: same as Example 1.

[0021] Preparation method: The difference from Example 1 is that the particle size of the raw material used in step 1 is different. The details are as follows: Step 1: Add montelukast sodium API (measured particle size D90: 41.2 μm) and microcrystalline cellulose into a blender and mix for 10 minutes. Then add magnesium stearate and mix for 5 minutes. Step 2: Use a φ3 circular punch to press the micro-slice, controlling the average hardness to 25~30N; Step 3: Add mannitol, microcrystalline cellulose, crospovidone, cherry powder flavor, aspartame, and colloid into a mixer and mix for 10 minutes, then add magnesium stearate and mix for a total of 5 minutes; Step 4: Add the montelukast sodium microtablets and excipient mixed granules obtained in step 2 to a Romaco Kilian tablet press, and press the tablets to control the average hardness to 50~55N. Example 3

[0022] Prescription composition: same as Example 1.

[0023] Preparation method: The difference from Example 1 is that the particle size of the raw material used in step 1 is different. The details are as follows: Step 1: Add montelukast sodium API (measured particle size D90: 79.8 μm) and microcrystalline cellulose into a blender and mix for 10 minutes. Then add magnesium stearate and mix for 5 minutes. Step 2: Use a φ3 circular punch to press the micro-slice, controlling the average hardness to 25~30N; Step 3: Add mannitol, microcrystalline cellulose, crospovidone, cherry powder flavor, aspartame, and colloid into a mixer and mix for 10 minutes, then add magnesium stearate and mix for a total of 5 minutes; Step 4: Add the montelukast sodium microtablets and excipient mixed granules obtained in step 2 to a Romaco Kilian tablet press, and press the tablets to control the average hardness to 50~55N. Example 4

[0024] Prescription composition: same as Example 1.

[0025] Preparation method: The difference from Example 1 lies in the diameter and hardness of the microchips obtained in step 2. The details are as follows: Step 1: Add montelukast sodium API (the same batch of API as in Example 1) and microcrystalline cellulose into a mixer and mix for 10 minutes, then add magnesium stearate and mix for 5 minutes; Step 2: Use a φ2 circular punch to press the micro-slice, controlling the average hardness to 35~40N; Step 3: Add mannitol, microcrystalline cellulose, crospovidone, cherry powder flavor, aspartame, and colloid into a mixer and mix for 10 minutes, then add magnesium stearate and mix for a total of 5 minutes; Step 4: Add the montelukast sodium microtablets and excipient mixed granules obtained in step 2 to a Romaco Kilian tablet press, and press the tablets to control the average hardness to 50~55N. Example 5

[0026] Prescription composition: same as Example 1.

[0027] Preparation method: The difference from Example 1 lies in the diameter and hardness of the microchips obtained in step 2. The details are as follows: Step 1: Add montelukast sodium API (the same batch of API as in Example 1) and microcrystalline cellulose into a mixer and mix for 10 minutes, then add magnesium stearate and mix for 5 minutes; Step 2: Use a φ3.5 round punch to press the micro-slice, controlling the average hardness to 15~20N; Step 3: Add mannitol, microcrystalline cellulose, crospovidone, cherry powder flavor, aspartame, and colloidal silicon dioxide to a blender and mix for 10 minutes. Then add magnesium stearate and mix for a total of 5 minutes. Step 4: Add the montelukast sodium microtablets and excipient mixed granules obtained in step 2 to a Romaco Kilian tablet press, and press the tablets to control the average hardness to 50~55N. Comparative Example 1

[0028] Prescription composition: same as Example 1.

[0029] Preparation method: The difference from Example 1 is that no chip package is prepared. The details are as follows: Step 1: Add all raw materials and auxiliary materials except magnesium stearate (the same batch of raw materials as in Example 1) into a mixer and mix for 10 minutes, then add magnesium stearate and mix for 5 minutes; Step 2: Compress the mixture obtained in step 1 into tablets, controlling the average hardness to be 50~55N. Comparative Example 2

[0030] Prescription composition: same as Example 1.

[0031] Preparation method: The difference from Example 1 is that the particle size of the raw material used in step 1 exceeds the lower limit of the protection range. The details are as follows: Step 1: Add montelukast sodium API (measured particle size D90: 35.2 μm) and microcrystalline cellulose into a blender and mix for 10 minutes. Then add magnesium stearate and mix for 5 minutes. Step 2: Use a φ3 circular punch to press the micro-slice, controlling the average hardness to 25~30N; Step 3: Add mannitol, microcrystalline cellulose, crospovidone, cherry powder flavor, aspartame, and colloidal silicon dioxide to a blender and mix for 10 minutes. Then add magnesium stearate and mix for a total of 5 minutes. Step 4: Add the montelukast sodium microtablets and excipient mixed granules obtained in step 2 to a Romaco Kilian tablet press, and press the tablets to control the average hardness to 50~55N. Comparative Example 3

[0032] Prescription composition: same as Example 1.

[0033] Preparation method: The difference from Example 1 is that the particle size of the raw material used in step 1 exceeds the upper limit of the protection range. The details are as follows: Step 1: Add montelukast sodium API (measured particle size D90: 87.3 μm) and microcrystalline cellulose into a blender and mix for 10 minutes. Then add magnesium stearate and mix for 5 minutes. Step 2: Use a φ3 circular punch to press the micro-slice, controlling the average hardness to 25~30N; Step 3: Add mannitol, microcrystalline cellulose, crospovidone, cherry powder flavor, aspartame, and colloidal silicon dioxide to a blender and mix for 10 minutes. Then add magnesium stearate and mix for a total of 5 minutes. Step 4: Add the montelukast sodium microtablets and excipient mixed granules obtained in step 2 to a Romaco Kilian tablet press, and press the tablets to control the average hardness to 50~55N. Comparative Example 4

[0034] Prescription composition: same as Example 1.

[0035] Preparation method: Step 2: The hardness of the micro-slice exceeds the upper limit of the protection range. The details are as follows: Step 1: Add montelukast sodium API (the same batch of API as in Example 1) and microcrystalline cellulose into a mixer and mix for 10 minutes, then add magnesium stearate and mix for 5 minutes; Step 2: Use a φ2 circular punch to press the micro-tablets, controlling the average hardness to 45~50N.

[0036] Step 3: Add mannitol, microcrystalline cellulose, crospovidone, cherry powder flavor, aspartame, and colloidal silicon dioxide to a blender and mix for 10 minutes. Then add magnesium stearate and mix for a total of 5 minutes. Step 4: Add the montelukast sodium microtablets and excipient mixed granules obtained in step 2 to a Romaco Kilian tablet press, and press the tablets to control the average hardness to 50~55N. Comparative Example 5

[0037] Prescription composition: same as Example 1.

[0038] Preparation method: Step 2: The diameter of the microchip exceeds the upper limit of the protection range. The details are as follows: Step 1: Add montelukast sodium API (the same batch of API as in Example 1) and microcrystalline cellulose into a mixer and mix for 10 minutes, then add magnesium stearate and mix for 5 minutes; Step 2: Using a φ4 circular die to press micro-tablets, cracks occurred due to the thickness being too thin. To improve this situation, the amount of auxiliary materials must be increased, which is not optimal, so further investigation is not carried out. Test Example 1 Study on the stability of related substances

[0039] Chromatographic conditions: Phenyl-hexylsilane bonded silica gel as filler (Welch Xtimate Phenyl-Hexyl, 4.6 mm × 250 mm, 3 μm or equivalent performance column); 0.2% trifluoroacetic acid aqueous solution as mobile phase A, methanol-acetonitrile (50:50) as mobile phase B, gradient elution as shown in the table below; detection wavelength, 255 nm; flow rate, 1.0 ml / min; column temperature, 30°C; injection volume, 25 μl.

[0040]

[0041] Investigation of influencing factors: The samples were placed under lighting conditions (illuminance of 4500lx±500lx, and the total illuminance of the light source was not less than 1.2×10 6 lux·hr, near-ultraviolet lamp energy not less than 200W·hr / m 2 ) for 12 days to observe the changes in relevant substances.

[0042]

[0043] Accelerated stability study: After the samples are packaged in aluminum-plastic packaging, they are placed under accelerated conditions (temperature 40℃±2℃, relative humidity 75%±5%) for 3 and 6 months respectively to examine the changes in related substances.

[0044]

[0045]

[0046] Analysis of influencing factors and accelerated stability results: After the comparative example 1 sample was placed under light conditions for 12 days and accelerated for 6 months, the results of the relevant substances no longer met the limit requirements (impurity C ≤ 1.5%, total impurities ≤ 1.8%). The measured values of the remaining samples all met the pharmacopoeia standards of various countries. Test Example 2 Dissolution curve study

[0047] Referencing the apparatus described in Part IV, 0931, Dissolution Method, Method 2 of the 2025 Chinese Pharmacopoeia, using a pH 6.8 solution with 0.05% Tween 80 as the dissolution medium and a rotation speed of 50 rpm, the following samples were sampled and tested for dissolution at 5, 15, 30, and 120 minutes, and the dissolution characteristics of each sample were recorded. A similarity comparison was performed with the reference preparation, montelukast sodium chewable tablets, for a similarity factor f2 ≥ 50, indicating similarity; otherwise, dissimilarities were considered.

[0048]

[0049] Analysis of the results: The dissolution results of Examples 1 to 5 were similar to those of the reference preparation (f2 ≥ 50); the dissolution result of Comparative Example 2 was faster than that of the reference preparation, and the dissolution results of Comparative Examples 3 to 4 were slower than that of the reference preparation, further confirming that the dissolution of the coated microchips was affected by the particle size of the API, the diameter of the microtablets, and the hardness; although the dissolution result of Comparative Example 1 was similar to that of the reference preparation, the related substances were significantly exceeded (see Test Example 1 for details). Test Example 3: Investigation of the Disintegration Time of the Chip Packaging Outer Layer

[0050] The samples of Examples 1-5 were tested according to the orally disintegrating tablet test method under Section 0921 of Part IV of the 2025 Chinese Pharmacopoeia. Timing was stopped from the moment the tablet was dropped into the package until the outer layer completely disintegrated and the microtablet was exposed. Because the relevant substances or dissolution profiles of Comparative Examples 1-5 did not meet the requirements, this study was discontinued.

[0051]

[0052] Result analysis: The outer layers of the chip packages in Examples 1 to 5 all collapsed rapidly within 15 seconds, which was in line with the design expectations.

Claims

1. A montelukast sodium tablet composition, characterized in that The tablet composition is composed of montelukast sodium microtablets and excipient mixed granules, wherein the montelukast sodium particle size D90 is 40-80 μm. The preparation method of the tablet composition is as follows: Step 1: Mix the montelukast sodium API and microcrystalline cellulose, and then add magnesium stearate and mix; Step 2: Using a round die to compress montelukast sodium microtablets; Step 3: After mixing other excipients, magnesium stearate is added to the mixture to obtain excipient mixed granules; Step 4: Compress the montelukast sodium microtablets and the mixed excipients into pellets, with the microtablets serving as the core tablets.

2. The composition according to claim 1, characterized in that The auxiliary material mixed granules are prepared by mixing mannitol, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, cherry powder flavor, aspartame, and colloidal silicon dioxide, and then adding magnesium stearate and mixing the mixture.

3. The composition according to claim 1, characterized in that The diameter of the microchip is φ2~3.5mm.

4. The composition according to claim 1, characterized in that The hardness of the micro-chip is 15~40N.

5. The composition according to claim 1, characterized in that The microtablet weighs 19.2 mg.

6. The method for preparing the composition according to claim 1, wherein In the third step, the montelukast sodium microtablets and the excipient mixed granules were added to the Romaco Kilian tablet press and pressed into tablets with an average hardness of 50~55N.

7. The method for preparing the composition according to claim 1, wherein the production During the process, the relative humidity of the environment must be controlled to ≤50%.

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