Montelukast sodium chewable tablet and preparation method and application thereof

Abstract

The application discloses a kind of montelukast sodium chewable tablets and preparation method and application thereof, the chewable tablet includes montelukast sodium, stabilizer consisting of alginate and / or trehalose, food-grade antioxidant and pharmaceutically acceptable adjuvant.The stabilizer is 0.5%~10%, and the food-grade antioxidant is 0.00025%~0.025%.It is prepared by using powder direct compression technology, and can be completed by only pre-mixing and total mixing after compression.The application utilizes the synergistic effect of stabilizer and antioxidant, effectively inhibits the photodegradation and oxidative degradation of montelukast sodium, significantly reduces the increase of related substances, and improves the stability of preparation.Meanwhile, the powder direct compression technology used in the application has a short process, does not need granulation and drying, has high production efficiency, low cost, is easy to industrialize, has good dissolution of the prepared chewable tablet, good taste, high safety, and is especially suitable for children patients.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a montelukast sodium chewable tablet, its preparation method, and its application. Background Technology

[0002] Montelukast Sodium is a highly selective and potent oral leukotriene receptor antagonist developed by Merck & Co., Inc. It competitively antagonizes the binding of leukotriene D4 (LTD4) to cysteyl leukotriene (Cys-LT1) receptors, thereby effectively improving airway inflammation. It has significant efficacy in the prevention and long-term treatment of asthma, and is particularly suitable for pediatric patients.

[0003] However, the chemical instability of montelukast sodium presents significant challenges to its formulation development. First, this compound is extremely sensitive to light, readily undergoing photodegradation under illumination, producing photodegradation impurities such as cis isomers. Second, the active groups in its molecular structure are unstable under high temperature, high humidity, and oxidative conditions, easily being oxidized and degraded into oxidative impurities such as montelukast methyl ketone. While the metabolic pathway of montelukast methyl ketone in vivo is similar to that of montelukast sodium, it has been reported to have higher potential for hepatotoxicity and nephrotoxicity, significantly increasing the safety risks associated with clinical use. Therefore, effectively inhibiting the photodegradation and oxidative degradation of montelukast sodium during production and storage is a core issue in ensuring its formulation efficacy and safety.

[0004] Currently, the following technical solutions have been proposed in this field to improve the stability of montelukast sodium preparations, but all of them have limitations to varying degrees: (1) Using a specific crystal form: For example, Chinese patent CN116509810A improves the photostability of montelukast sodium by preparing and using a new crystal form D. Although this solution improves photostability to a certain extent, its technical focus is on the crystal form itself and does not specifically address the problem of impurity (such as montelukast methyl ketone) growth in montelukast sodium under heat and oxidation conditions. At the same time, this solution does not optimize the dissolution behavior of chewable tablets. (2) Adding functional excipients as protective agents: For example, Chinese patent CN105193743A discloses a montelukast sodium granule, which uses a mixture of dodecyl dimethylamine oxide and ammonium oxalate as a protective agent. Dodecyl dimethylamine oxide, as a synthetic surfactant, has a solubilizing effect on the main drug, but it may pose potential irritation and safety hazards to the human body, especially the gastrointestinal tract of children, which does not conform to the basic principle of prioritizing the safety of children's medication. (3) Adjusting conventional excipients and processes: Most other existing technical solutions mainly improve stability by adjusting the types and amounts of fillers and disintegrants, or by optimizing the wet granulation process (such as using anhydrous ethanol as a binder to reduce the effects of damp heat). However, these methods often fail to systematically solve the degradation problems caused by multiple factors such as light, heat, and oxygen at the same time, resulting in limited improvement in stability, or sacrificing solubility and taste for the sake of stability.

[0005] In summary, existing technologies lack a chewable tablet formulation that can simultaneously and efficiently address the photodegradation and oxidative degradation issues of montelukast sodium, while ensuring good dissolution, palatability, and high safety, particularly suitable for pediatric patients. Therefore, developing a novel, high-performance montelukast sodium chewable tablet formulation and process to meet the higher clinical requirements for drug stability, safety, and efficacy has become a pressing technical challenge in this field. Summary of the Invention

[0006] To address the shortcomings of existing technologies, this invention provides a montelukast sodium chewable tablet, its preparation method, and its application. Through a synergistic stabilizing system of alginate and food-grade antioxidants, the degradation of oxidative impurities in the active ingredient of montelukast sodium is effectively inhibited, thereby improving the stability of montelukast sodium.

[0007] This invention is achieved through the following technical solution:

[0008] A montelukast sodium chewable tablet comprises, by weight percentage, the following components:

[0009] Montelukast sodium 0.5%~0.6%;

[0010] Stabilizers selected from alginate and / or trehalose: 0.5%–10%;

[0011] Food-grade antioxidants: 0.00025%~0.025%;

[0012] Filler 5%~30%;

[0013] Disintegrant 1%~8%;

[0014] Lubricant 0.1%~1%;

[0015] Adhesive 0.1%~1%;

[0016] Flavoring agent: 0.01%~0.05%.

[0017] Preferably, the stabilizer is an alginate, preferably selected from one or more of alginate, sodium alginate, potassium alginate, and sodium calcium alginate; more preferably, the stabilizer is sodium alginate.

[0018] Preferably, the food-grade antioxidant is selected from one or more of propyl gallate, butylated hydroxytoluene, tocopherol, ascorbic acid and its salts, and tert-butyl-p-hydroxyanisole; more preferably, the food-grade antioxidant is propyl gallate.

[0019] Preferably, the filler is mannitol; the disintegrant is one or more of microcrystalline cellulose and croscarmellose sodium; the lubricant is one or more of sodium dodecyl sulfate and magnesium stearate; and the binder is hydroxypropyl cellulose.

[0020] Preferably, the device further includes a flow aid, wherein the flow aid is colloidal silica, and the amount used is 0.01% to 0.5%.

[0021] Preferably, the hardness of the chewing tablet is 30~80 N.

[0022] The above-mentioned method for preparing montelukast sodium chewable tablets includes the following steps:

[0023] Step 1) Pass sodium montelukast, a stabilizer selected from alginate and / or trehalose, a food-grade antioxidant, and excipients through an 80-mesh sieve respectively;

[0024] Step 2) Premix the sieved raw materials from Step 1) at 5-30 rpm for 10-40 min to obtain a mixed powder;

[0025] Step 3) Add lubricant to the mixed powder obtained in Step 2) and mix for 1-10 minutes at 5-30 rpm.

[0026] Step 4) Compress the granules after the total mixing in step 3) into tablets to obtain the final product.

[0027] Preferably, the excipients in step 1) include mannitol, microcrystalline cellulose, aspartame, croscarmellose sodium cellulose, hydroxypropyl cellulose, sodium dodecyl sulfate, and colloidal silica; and the lubricant in step 3) is magnesium stearate.

[0028] The application of a combination of alginate and / or trehalose with a food-grade antioxidant in the preparation of montelukast sodium solid dosage forms, wherein the combination is used to improve the stability of montelukast sodium and inhibit the formation of oxidative and photolytic impurities during storage; wherein the alginate is selected from one or more of alginic acid, sodium alginate, potassium alginate, and calcium sodium alginate; and wherein the food-grade antioxidant is selected from one or more of propyl gallate, butylated hydroxytoluene, tocopherol, ascorbic acid and its salts, and tert-butyl-p-hydroxyanisole.

[0029] Preferably, the montelukast sodium solid dosage form is a chewable tablet.

[0030] The beneficial effects of this invention are as follows:

[0031] (1) This invention creatively selects alginate (such as sodium alginate, potassium alginate, etc.) and / or trehalose as stabilizers, and uses them in combination with food-grade antioxidants (such as propyl gallate, tocopherol, etc.). The two exhibit an unexpected synergistic effect in inhibiting the degradation of montelukast sodium. On the one hand, the stabilizer can form a physical protective barrier on the surface of drug particles, effectively blocking the invasion of moisture and light, and significantly slowing down the hydrolysis and photodegradation process. On the other hand, the antioxidant can actively scavenge oxygen free radicals in the system, efficiently blocking the oxidation reaction pathway of montelukast sodium, and fundamentally inhibiting the generation of key degradation impurities (such as sulfoxide, ketone methanol, etc.). Stability data fully demonstrate that this invention effectively inhibits the degradation pathways caused by multiple factors such as light, heat, and oxygen through this composite stabilization system. Based on the stability study data of the system, it can be scientifically determined that the shelf life of this invention can reach 3 years, which is superior to conventional formulations, and has a longer shelf life and higher storage and transportation adaptability.

[0032] (2) The stable system constructed in this invention uses excipients with high safety and good biocompatibility. Alginate and trehalose are both of natural origin, while propyl gallate and tocopherol are internationally recognized safe food-grade antioxidants. This completely avoids the potential irritation risks associated with the use of synthetic surfactants, greatly improving the safety of medication for children. Clinical trials have confirmed that this invention can still effectively inhibit the formation of impurities in the human body, significantly reducing the risk of exposure to potentially toxic impurities, and is safer to take compared to commercially available formulations (such as Singulair). ® It has superior safety and tolerability.

[0033] (3) Clinical studies have shown that the flavoring system and excellent formulation texture of this invention have been highly recognized by subjects, especially pediatric patients. The excellent taste and reliable safety ensure the smooth implementation of the treatment plan and the stable performance of clinical efficacy.

[0034] (4) Clinical studies have shown that formulations lacking stabilizers, antioxidants, or both exhibit significantly reduced stability, safety, and patient compliance. This, in turn, demonstrates that the combination of alginate and food-grade antioxidants in this invention forms an indispensable whole, and the synergistic effect produced is the core technology for achieving comprehensive and excellent results in this invention.

[0035] (5) Guided by the core synergistic effect, the stabilizers (alginate, trehalose) and antioxidants (propyl gallate, butylated hydroxytoluene, etc.) in the formulation of this invention can be flexibly selected and combined from a group of safe and effective substances. This design gives the formulation great adaptability and adjustability, and can be optimized and adjusted according to different batches of raw materials, different production equipment or specific cost control requirements without affecting the core stabilizing effect, which is convenient for industrial application. The direct powder compression process adopted in this invention, while achieving excellent clinical and stability effects, always maintains its core advantages of extremely simple process, high efficiency and energy saving, and easy industrialization, providing a solid guarantee for the uniformity and stability of product quality and large-scale production. Detailed Implementation

[0036] The present invention will be further described in detail below with reference to specific embodiments.

[0037] Unless otherwise specified, the technical means used in the following embodiments are all conventional means well known to those skilled in the art, and the experimental methods without specific conditions are all conventional methods in the art.

[0038] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0039] A montelukast sodium chewable tablet, the composition of which is shown in Table 1, is prepared by the following steps:

[0040] (1) Sieving: Montelukast sodium, stabilizer (sodium alginate), antioxidant (propyl gallate), mannitol, microcrystalline cellulose, aspartame, croscarmellose sodium, hydroxypropyl cellulose, sodium dodecyl sulfate, and colloidal silica are sieved through an 80-mesh sieve.

[0041] (2) Mixing: Place the sieved raw material into a mixer at a speed of 5-30 rpm and premix for 10-40 min to obtain a mixed powder; then add magnesium stearate to the mixed powder and mix for 0-10 min.

[0042] (3) Tableting: The mixed granules are added to a tablet press for tableting to obtain montelukast sodium chewable tablets.

[0043] (4) Aluminum-plastic packaging (optional): Use an aluminum-plastic blister packaging machine to package montelukast sodium chewable tablets in aluminum-plastic packaging and put them into an outer packaging box with an inner aluminum foil bag.

[0044] Table 1. Ingredients of Montelukast Sodium Chewable Tablets (1000 tablets, each tablet contains 5 mg of Montelukast Sodium)

[0045]

[0046] Example 1 (Optimal Ingredient Ratio)

[0047] A montelukast sodium chewable tablet, the composition of which is shown in Table 2, is prepared by the following steps:

[0048] Montelukast sodium, stabilizer (sodium alginate), antioxidant (propyl gallate), mannitol, microcrystalline cellulose, aspartame, croscarmellose sodium, hydroxypropyl cellulose, sodium dodecyl sulfate, and colloidal silica were each passed through an 80-mesh sieve. The sieved raw materials were placed in a mixer at 20 rpm and premixed for 20 minutes to obtain a mixed powder. Magnesium stearate was then added to the mixed powder and mixed for a final 5 minutes. The resulting granules were then compressed into tablets (hardness controlled at 30-80 N) using a tablet compressor to obtain montelukast sodium chewable tablets.

[0049] Table 2. Ingredients of Montelukast Sodium Chewable Tablets (1000 tablets, each tablet contains 5 mg of Montelukast Sodium)

[0050]

[0051] Example 2 (Adjustment of sodium alginate content)

[0052] A montelukast sodium chewable tablet, the composition of which is shown in Table 3, and the specific preparation steps are the same as in Example 1.

[0053] The tablets prepared in this embodiment have good stability and low levels of oxidative impurities.

[0054] Table 3. Ingredients of Montelukast Sodium Chewable Tablets (1000 tablets, each tablet contains 5 mg of Montelukast Sodium)

[0055]

[0056] Example 3 (Adjustment of propyl gallate content)

[0057] A montelukast sodium chewable tablet, the composition of which is shown in Table 4, and the specific preparation steps are the same as in Example 1.

[0058] The dissolution behavior of the tablets prepared in this embodiment is similar to that of the reference formulation (Singulair). ® It is consistent with the 5 mg specification and its stability meets the requirements.

[0059] Table 4. Ingredients of Montelukast Sodium Chewable Tablets (1000 tablets, each tablet contains 5 mg of Montelukast Sodium)

[0060]

[0061] Example 4 (using trehalose as a stabilizer and tocopherol as an antioxidant)

[0062] A montelukast sodium chewable tablet, the composition of which is shown in Table 5, is prepared by the following steps:

[0063] Montelukast sodium, stabilizer (trehalose), antioxidant (tocopherol), mannitol, microcrystalline cellulose, aspartame, croscarmellose sodium, hydroxypropyl cellulose, sodium lauryl sulfate, and colloidal silica were each passed through an 80-mesh sieve. The sieved raw materials were placed in a mixer at 20 rpm and premixed for 20 minutes to obtain a mixed powder. Magnesium stearate was then added to the mixed powder and mixed for a final 5 minutes. The resulting granules were then compressed into tablets (hardness controlled at 30-80 N) using a tablet compressor to obtain montelukast sodium chewable tablets.

[0064] The tablets prepared in this embodiment exhibit excellent stability and dissolution performance.

[0065] Table 5. Ingredients of Montelukast Sodium Chewable Tablets (1000 tablets, each tablet contains 5 mg of Montelukast Sodium)

[0066]

[0067] Example 5 (using alginate as a stabilizer)

[0068] A montelukast sodium chewable tablet, the composition of which is shown in Table 6, is prepared by the following steps:

[0069] Montelukast sodium, stabilizer (alginic acid), antioxidant (propyl gallate), mannitol, microcrystalline cellulose, aspartame, croscarmellose sodium, hydroxypropyl cellulose, sodium lauryl sulfate, and colloidal silica were each passed through an 80-mesh sieve. The sieved raw materials were placed in a mixer at 20 rpm and premixed for 20 minutes to obtain a mixed powder. Magnesium stearate was then added to the mixed powder and mixed for a final 5 minutes. The resulting granules were then compressed into tablets (hardness controlled at 30-80 N) using a tablet compressor to obtain montelukast sodium chewable tablets.

[0070] The tablets prepared in this embodiment exhibited good dissolution uniformity, and the growth of oxidative impurities was slow during the stability test.

[0071] Table 6. Ingredients of Montelukast Sodium Chewable Tablets (1000 tablets, each tablet contains 5 mg of Montelukast Sodium)

[0072]

[0073] Example 6 (using tert-butyl-p-hydroxyanisole as an antioxidant)

[0074] A montelukast sodium chewable tablet, the composition of which is shown in Table 7, is prepared by the following steps:

[0075] Montelukast sodium, stabilizer (sodium alginate), antioxidant (tert-butylhydroquinone), mannitol, microcrystalline cellulose, aspartame, croscarmellose sodium, hydroxypropyl cellulose, sodium lauryl sulfate, and colloidal silica were each sieved through an 80-mesh sieve. The sieved raw materials were placed in a mixer at 20 rpm and premixed for 20 minutes to obtain a mixed powder. Magnesium stearate was then added to the mixed powder and mixed for a final 5 minutes. The mixed granules were then added to a tablet press for tableting (hardness controlled at 30-80 N) to obtain montelukast sodium chewable tablets.

[0076] The tablets prepared in this embodiment exhibit excellent stability and very good palatability.

[0077] Table 7. Ingredients of Montelukast Sodium Chewable Tablets (1000 tablets, each tablet contains 5 mg of Montelukast Sodium)

[0078]

[0079] Example 7 (using ascorbic acid as an antioxidant)

[0080] A montelukast sodium chewable tablet, the composition of which is shown in Table 8, is prepared by the following steps:

[0081] Montelukast sodium, stabilizer (sodium alginate), antioxidant (ascorbic acid), mannitol, microcrystalline cellulose, aspartame, croscarmellose sodium, hydroxypropyl cellulose, sodium lauryl sulfate, and colloidal silica were each passed through an 80-mesh sieve. The sieved raw materials were placed in a mixer at 20 rpm and premixed for 20 minutes to obtain a mixed powder. Magnesium stearate was then added to the mixed powder and mixed for a final 5 minutes. The resulting granules were then compressed into tablets (hardness controlled at 30-80 N) using a tablet compressor to obtain montelukast sodium chewable tablets.

[0082] The tablets prepared in this embodiment exhibit excellent stability and good taste, with a cumulative dissolution rate of over 93% within 15 minutes.

[0083] Table 8. Ingredients of Montelukast Sodium Chewable Tablets (1000 tablets, each tablet contains 5 mg of Montelukast Sodium)

[0084]

[0085] Example 8 (using potassium alginate as a stabilizer)

[0086] A montelukast sodium chewable tablet, the composition of which is shown in Table 9, is prepared by the following steps:

[0087] Montelukast sodium, stabilizer (potassium alginate), antioxidant (propyl gallate), mannitol, microcrystalline cellulose, aspartame, croscarmellose sodium, hydroxypropyl cellulose, sodium dodecyl sulfate, and colloidal silica were each sieved through an 80-mesh sieve. The sieved raw materials were placed in a mixer at 20 rpm and premixed for 20 minutes to obtain a mixed powder. Magnesium stearate was then added to the mixed powder and mixed for a final 5 minutes. The resulting granules were then compressed into tablets (hardness controlled at 30-80 N) using a tablet compressor to obtain montelukast sodium chewable tablets.

[0088] The tablets prepared in this embodiment have a delicate chewing texture, disintegrate rapidly, and achieve a cumulative dissolution rate of over 95% within 15 minutes.

[0089] Table 9. Ingredients of Montelukast Sodium Chewable Tablets (1000 tablets, each tablet contains 5 mg of Montelukast Sodium)

[0090]

[0091] Example 9 (using sodium calcium alginate as a stabilizer)

[0092] A montelukast sodium chewable tablet, the composition of which is shown in Table 10, is prepared by the following steps:

[0093] Montelukast sodium, stabilizer (sodium calcium alginate), antioxidant (propyl gallate), mannitol, microcrystalline cellulose, aspartame, croscarmellose sodium, hydroxypropyl cellulose, sodium lauryl sulfate, and colloidal silica were each passed through an 80-mesh sieve. The sieved raw materials were placed in a mixer at 20 rpm and premixed for 20 minutes to obtain a mixed powder. Magnesium stearate was then added to the mixed powder and mixed for a final 5 minutes. The resulting granules were then compressed into tablets (hardness controlled at 30-80 N) using a tablet compressor to obtain montelukast sodium chewable tablets.

[0094] The tablets prepared in this embodiment have uniform hardness and a friability of <0.8%, which meets the quality standards for chewable tablets.

[0095] Table 10. Ingredients of Montelukast Sodium Chewable Tablets (1000 tablets, each tablet contains 5 mg of Montelukast Sodium)

[0096]

[0097] Example 10 (Other combinations of stabilizers and antioxidants)

[0098] A montelukast sodium chewable tablet, the composition of which is shown in Table 11, is prepared by the following steps:

[0099] Montelukast sodium, stabilizer (potassium alginate and trehalose mixed at a mass ratio of 1:1), antioxidant (butylated hydroxytoluene and tocopherol mixed at a mass ratio of 2:1), mannitol, microcrystalline cellulose, aspartame, croscarmellose sodium, hydroxypropyl cellulose, sodium lauryl sulfate, and colloidal silica were each sieved through an 80-mesh sieve. The sieved raw materials were placed in a mixer at 20 rpm and premixed for 20 minutes to obtain a mixed powder. Magnesium stearate was then added to the mixed powder and mixed for a total of 5 minutes. The mixed granules were then added to a tablet press for tableting (hardness controlled at 30-80 N) to obtain montelukast sodium chewable tablets.

[0100] The tablets prepared in this embodiment exhibit excellent stability and dissolution performance.

[0101] Table 11. Ingredients of Montelukast Sodium Chewable Tablets (1000 tablets, each tablet contains 5 mg of Montelukast Sodium)

[0102]

[0103] Comparative Example 1 (without stabilizer)

[0104] A montelukast sodium chewable tablet, the composition of which is shown in Table 12, is prepared by the following steps:

[0105] Montelukast sodium, antioxidant (propyl gallate), mannitol, microcrystalline cellulose, aspartame, croscarmellose sodium, hydroxypropyl cellulose, sodium lauryl sulfate, and colloidal silica were each passed through an 80-mesh sieve. The sieved raw materials were placed in a mixer at 20 rpm and premixed for 20 minutes to obtain a mixed powder. Magnesium stearate was then added to the mixed powder and mixed for a final 5 minutes. The resulting granules were then compressed into tablets (hardness controlled at 30-80 N) using a tablet compressor to obtain montelukast sodium chewable tablets.

[0106] Table 12 Ingredients of Montelukast Sodium Chewable Tablets (1000 tablets, each tablet contains 5 mg of Montelukast Sodium)

[0107]

[0108] Comparative Example 2 (without antioxidants)

[0109] A montelukast sodium chewable tablet, the composition of which is shown in Table 13, is prepared by the following steps:

[0110] Montelukast sodium, stabilizer (sodium alginate), mannitol, microcrystalline cellulose, aspartame, croscarmellose sodium, hydroxypropyl cellulose, sodium lauryl sulfate, and colloidal silica were each sieved through an 80-mesh sieve. The sieved raw materials were placed in a mixer at 20 rpm and premixed for 20 minutes to obtain a mixed powder. Magnesium stearate was then added to the mixed powder and mixed for a final 5 minutes. The resulting granules were then compressed into tablets (hardness controlled at 30-80 N) using a tablet compressor to obtain montelukast sodium chewable tablets.

[0111] Table 13 Ingredients of Montelukast Sodium Chewable Tablets (1000 tablets, each tablet contains 5 mg of Montelukast Sodium)

[0112]

[0113] Comparative Example 3 (without stabilizers and antioxidants)

[0114] A montelukast sodium chewable tablet, the composition of which is shown in Table 14, is prepared by the following steps:

[0115] Montelukast sodium, mannitol, microcrystalline cellulose, aspartame, croscarmellose sodium, hydroxypropyl cellulose, sodium lauryl sulfate, and colloidal silica were each sieved through an 80-mesh sieve. The sieved raw materials were placed in a mixer at 20 rpm and premixed for 20 minutes to obtain a mixed powder. Magnesium stearate was then added to the mixed powder and mixed for a final 5 minutes. The resulting granules were then compressed into tablets using a tablet compressor to obtain montelukast sodium chewable tablets.

[0116] Table 14. Ingredients of Montelukast Sodium Chewable Tablets (1000 tablets, each tablet contains 5 mg of Montelukast Sodium)

[0117]

[0118] Test Example 1: Stability Experiment

[0119] 1. Experimental Design

[0120] (1) Samples: Tablets prepared in Example 1 and commercially available formulations (Singulair) ® (5 mg specification).

[0121] (2) Conditions

[0122] Accelerated testing: 40℃, 75% RH, for 0, 1, 3, and 6 months;

[0123] High temperature test: 60℃, placed for 0, 5, and 15 days;

[0124] Long-term experiment: 30℃, 65% RH, placed for 0, 6, and 12 months.

[0125] (3) Test items: related substances, total impurities, dissolution rate, and content uniformity.

[0126] 2. Experimental Results and Analysis

[0127] Table 15 Stability results under accelerated conditions (related substances and total impurities)

[0128]

[0129] Table 16 Stability results under high temperature conditions (related substances and total impurities)

[0130]

[0131] Table 17. Stability results under long-term conditions (related substances and total impurities)

[0132]

[0133] Table 18 Stability results under accelerated conditions (dissolution rate and content uniformity)

[0134]

[0135] As shown in Tables 15-18, the montelukast sodium chewable tablets prepared in Example 1 have better stability and higher safety under accelerated and high-temperature conditions compared with commercially available formulations. Based on the stability test data, the shelf life of the sample is determined to be 3 years.

[0136] Test Example 2: Clinical Trial

[0137] 1. Experimental Objective

[0138] Comparative Examples 1 and 1-3: Tablets prepared with commercially available formulations (Singulair) ® The clinical application effects of the 5 mg specification were used to verify the superiority of the present invention.

[0139] 2. Subject Information

[0140] Two hundred subjects aged 3–45 years who required long-term use of montelukast sodium were selected, including 102 males and 98 females; 80 children aged 3–12 years and 120 adults aged 13–45 years. All subjects were excluded if they had severe hepatic or renal insufficiency or were allergic to montelukast sodium or its excipients.

[0141] 3. Experimental Grouping

[0142] The participants were randomly divided into 5 groups of 40 each. The age and gender ratios of the groups were balanced (P > 0.05), ensuring comparability. The grouping details are as follows:

[0143] Example 1 group: taking the chewable tablets prepared in Example 1;

[0144] Comparative Example 1: The chewable tablets prepared in Comparative Example 1 were taken;

[0145] Comparative Example 2: The chewable tablets prepared in Comparative Example 2 were taken;

[0146] Comparative Example 3: The chewable tablets prepared in Comparative Example 3 were taken;

[0147] Control group: those taking commercially available Singulair ® Chewable tablets.

[0148] 4. Experimental Methods

[0149] All subjects in each group received the corresponding formulation at a dose of 5 mg once daily for 12 weeks. During this period, the subjects' taste rating (using a scale of 1-10, with 10 being the best), medication adherence (on-time medication rate), the content of oxidative impurities in the formulation after 12 weeks of medication, and the occurrence of adverse reactions were recorded.

[0150] 5. Experimental Results and Analysis

[0151] Table 19 Clinical Trial Results

[0152]

[0153] The results of the clinical trial are shown in Table 19, and the specific analysis is as follows:

[0154] (1) Taste score: The average score of Example 1 group was 8.7 points, which was significantly higher than that of Comparative Example 1 (7.2 points), Comparative Example 2 (7.3 points), Comparative Example 3 (6.8 points) and Control Group (7.5 points). The pediatric subjects showed particularly high acceptance of the formulation of Example 1.

[0155] (2) Medication adherence: The on-time medication rate in Example 1 group was 95%, which was higher than that in Comparative Example 1 (82%), Comparative Example 2 (83%), Comparative Example 3 (78%) and the control group (85%).

[0156] (3) Oxidized impurity content: After 12 weeks of medication, the oxidized impurity content in the Example 1 group was only 0.03%, which was much lower than that in the Comparative Example 1 group (0.12%), Comparative Example 2 group (0.15%), Comparative Example 3 group (0.21%) and the control group (0.08%).

[0157] (4) Incidence of adverse reactions: The incidence of adverse reactions in Example 1 group was 2.5% (1 case of mild gastrointestinal discomfort), which was lower than that in Comparative Example 1 (10%), Comparative Example 2 (12.5%), Comparative Example 3 (15%) and the control group (7.5%).

[0158] The above experimental results show that the montelukast sodium chewable tablets prepared in Example 1 of this invention are significantly superior to comparative examples 1-3 and commercially available formulations in terms of taste, medication adherence, stability (control of oxidative impurities) and safety, and have obvious advantages in clinical application.

[0159] The embodiments described above are only some, not all, of the embodiments of the present invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments. The scope of protection of the present invention is determined by the scope claimed in the claims. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

Claims

1. A montelukast sodium chewable tablet, characterized in that, Each 1000 of the chewable tablets contains the following components: Montelukast sodium 5.186 g; Mannitol 157 g; 26 g of microcrystalline cellulose; 11.7 g of croscarmellose sodium cellulose; Hydroxypropyl cellulose 2.8 g; Sodium dodecyl sulfate 2.3 g; 0.78 g of colloidal silica; Magnesium stearate 2.6 g; Aspartame 0.26 g; And any of the following combinations: Combination 1: Sodium alginate 50 g and propyl gallate 0.025 g; Combination 2: Sodium alginate 23.5 g and propyl gallate 0.025 g; Combination 3: Sodium alginate 50 g and propyl gallate 0.04 g; Combination 4: Trehalose 50 g and tocopherol 0.025 g; Combination 5: Alginic acid 50 g and propyl gallate 0.025 g; Combination 6: Sodium alginate 50 g and tert-butyl-p-hydroxyanisole 0.025 g; Combination 7: Sodium alginate 50 g and ascorbic acid 0.025 g; Combination 8: Potassium alginate 50 g and propyl gallate 0.025 g; Combination Nine: 50 g of sodium calcium alginate and 0.025 g of propyl gallate; Combination 10: 50 g of a mixture of potassium alginate and trehalose in a 1:1 mass ratio, and 0.025 g of a mixture of butylated hydroxytoluene and tocopherol in a 2:1 mass ratio.

2. The montelukast sodium chewable tablet according to claim 1, characterized in that, The hardness of the chewable tablet is 30~80 N.

3. A method for preparing montelukast sodium chewable tablets as described in claim 1 or 2, characterized in that, Includes the following steps: Step 1) Pass each component of montelukast sodium, mannitol, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, sodium lauryl sulfate, colloidal silica, aspartame, and any combination of combination one to combination ten through an 80-mesh sieve. Step 2) Premix the sieved raw materials from Step 1) at 5-30 rpm for 10-40 min to obtain a mixed powder; Step 3) Add magnesium stearate to the mixed powder obtained in Step 2) and mix at 5-30 rpm for 1-10 min. Step 4) Compress the granules after the total mixing in step 3) into tablets to obtain the final product.

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