Montelukast sodium granular preparation and preparation method thereof

Abstract

The invention discloses a montelukast sodium granular preparation and a preparation method thereof, and the preparation method comprises the following steps: dissolving montelukast sodium and mannitol in purified water in proportion to obtain a liquid medicine; and spraying the liquid medicine on the surface of spray-dried mannitol in a fluidized state, drying, and finishing to obtain the montelukast sodium granules. The montelukast sodium granular preparation prepared by the preparation method has the characteristics of good stability, few types of auxiliary materials, low production cost, high production efficiency, high bioavailability and the like, and is more suitable for children to use and industrial production.

Description

Technical Field

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

[0002] The statements herein merely provide background information related to the present invention and do not necessarily constitute prior art.

[0003] Montelukast sodium is a selective, oral leukotriene receptor antagonist. Its core pharmacological action is to effectively block leukotriene signaling in airway smooth muscle. This mechanism significantly inhibits the release of inflammatory mediators, reduces vascular permeability, alleviates airway spasm, and reduces eosinophil infiltration, thereby improving lung function parameters. It plays a key role in the prevention and symptom control of childhood asthma, including daytime and nighttime symptoms, aspirin-sensitive asthma, and exercise-induced bronchoconstriction. Additionally, the drug is approved for the relief of symptoms associated with seasonal and perennial allergic rhinitis in children aged 2 to 5 years.

[0004] Given the prevalence of tablet swallowing difficulties in young children, montelukast sodium is often used in granular dosage forms. Its clinical dosage must be strictly individualized based on the child's age and weight.

[0005] However, montelukast sodium API is extremely sensitive to a variety of environmental factors and is prone to degradation reactions under conditions of oxidation, light, high temperature and high humidity. The impurities produced by the oxidation pathway are particularly difficult to effectively control.

[0006] The current mainstream production process relies on fluidized bed coating technology, which is generally prepared using the following method: the binder solution and the montelukast sodium API solution are sprayed separately and sequentially onto the surface of mannitol carrier particles, accompanied by multiple spraying and drying cycles; or the binder and API are dissolved in purified water to form a single solution, which is then sprayed onto the mannitol carrier. Therefore, existing fluidized bed coating methods all require the addition of binders and lubricants, or stabilizers. The increased number of excipients leads to increased material costs and a more complex process. However, without the addition of these excipients, it is difficult to prepare qualified montelukast sodium granules, and the stability of the granules is also affected.

[0007] Furthermore, the addition of some excipients may have varying degrees of impact on children's developing organs. Therefore, in the pharmaceutical development of pediatric medicines, the minimum number and lowest amount of excipients should be used, while minimizing risk and ensuring product efficacy and stability. Summary of the Invention

[0008] In view of the shortcomings of the existing technology, the purpose of the present invention is to provide a montelukast sodium granule preparation and a preparation method thereof. The montelukast sodium granule preparation prepared by this preparation method has the characteristics of good stability, fewer types of excipients, low production cost, high production efficiency, greater suitability for children, suitability for industrial production, and high bioavailability.

[0009] In order to achieve the above object, the present invention is implemented through the following technical solutions: In a first aspect, the present invention provides a method for preparing a montelukast sodium granule preparation, comprising the following steps: dissolving montelukast sodium and mannitol in purified water in proportion to obtain a drug solution; The drug solution is sprayed onto the surface of the fluidized mannitol, and after drying and granulation, montelukast sodium granules are obtained.

[0010] The preparation method of the montelukast sodium granules of the present invention does not add a binder, a lubricant, or a stabilizer. The raw material drug and mannitol are dissolved in purified water at a certain ratio, and the solution is coated on the surface of the spray-dried mannitol. The prepared granules have excellent stability and fluidity, and no lubricant is required, thereby reducing costs and simplifying the process. In addition, fewer types of excipients are required for children's use, making the granules more suitable for children's use.

[0011] Spray-dried mannitol is in the form of a sphere composed of a rod-like structure. The API and part of the mannitol are dissolved in purified water in a certain proportion. The drug solution is coated on the surface of the spray-dried mannitol. After drying, the mannitol blended with the API can effectively wrap the API and embed the API in the rod-like structure of the spray-dried mannitol.

[0012] In some embodiments, the mannitol is spray-dried mannitol.

[0013] Spray-dried mannitol is prepared by spray-drying an aqueous solution of mannitol or a solution containing mannitol.

[0014] In the present invention, as the fluidized bed impinges, the spray-dried mannitol embedded with the API forms a smoother, denser spherical shell with fewer pores. This effectively encapsulates the API and, protected by the denser shell, reduces the API's contact area with oxygen. Furthermore, the smoother, denser spherical shell reduces the particle's specific surface area and pore volume, thereby helping to reduce the particle's oxygen load, lowering the oxygen content within the packaging bag after packaging, reducing the generation of oxidative impurities, and improving the stability of the montelukast sodium particles.

[0015] In some embodiments, montelukast sodium and mannitol are dissolved in purified water at a mass ratio of 1-2:4-8 to obtain a pharmaceutical solution.

[0016] Too little mannitol will prevent the API from being embedded in its rod-like structure during the spraying and drying process, and will not protect the API from contact with oxygen and moisture. Too much mannitol will exceed its solubility in water, preventing complete dissolution.

[0017] Preferably, after dissolving montelukast sodium and mannitol in purified water in proportion, the process further includes standing to eliminate bubbles.

[0018] Preferably, the mass percentage of montelukast sodium in the medicinal solution is 1-3%.

[0019] If the concentration of montelukast sodium is too low, the water consumption increases, the total amount of solution during the spraying process increases, the spraying time is prolonged, and the efficiency decreases. When the total amount of solution increases, it may also cause the wetting efficiency of the fluidized bed to exceed the drying efficiency, resulting in material sticking to the wall, material clumping, and material bed collapse.

[0020] Preferably, during the spraying process, the inlet air temperature for the fluidization is 45-55°C. Excessively high inlet air temperatures result in high temperatures within the fluidized bed chamber, which in turn increases the material temperature. Montelukast sodium is unstable at high temperatures, and high temperatures can cause the growth of related substances. Excessively low inlet air temperatures can lead to low drying efficiency after spraying, and the material can easily stick to the wall, clumping, or collapse.

[0021] More preferably, the spray pressure of the liquid medicine is 0.3-0.5 MPa.

[0022] In some embodiments, the sieve used for granulation is a 30-mesh sieve.

[0023] In some embodiments, during the process of spraying the liquid medicine on the surface of mannitol in the fluidized bed, the inlet air temperature of the fluidized bed is 45-55°C, the inlet air volume is 800-1000m 3 / h, the spray rate of the liquid medicine is 80-100g / min, and the spray pressure is 0.3-0.5Mpa.

[0024] In some embodiments, during the fluidized bed spraying process, the temperature of the material reaches equilibrium at 15-21°C.

[0025] In addition, the setting of specific process parameters ensures a lower material temperature, but the fluidized bed does not collapse, the drying efficiency is higher, the temperature and time that the raw materials experience in a hot and humid environment are reduced, and the tendency of impurities to grow in a hot and humid environment is reduced.

[0026] The invention uses fewer types and amounts of auxiliary materials, does not add adhesives, lubricants and stabilizers, is more suitable for children to take, and reduces material costs.

[0027] In a second aspect, the present invention provides a montelukast sodium granular preparation prepared by the preparation method.

[0028] In some embodiments, the montelukast sodium granule preparation comprises the following components, by mass: 1-2 parts of montelukast sodium, 4-8 parts of mannitol, and 90-95 parts of spray-dried mannitol.

[0029] The beneficial effects achieved by one or more embodiments of the present invention are as follows: The invention uses fewer types and amounts of auxiliary materials, does not add adhesives, lubricants and stabilizers, is more suitable for children to take, and reduces material costs.

[0030] The preparation method of the present invention has simple procedures and is convenient for production operation.

[0031] After the liquid medicine is sprayed on the surface of the mannitol particles and then dried, the mannitol undergoes boiling, fluidization and collision in the fluidized bed cavity, eventually forming spherical particles. The particles are non-adhesive, dense and compact, with good fluidity, so there is no need to add lubricants, the stability is good, and the growth of oxidized impurities is reduced.

[0032] Furthermore, appropriate process parameter settings ensured a low material temperature without fluidized bed collapse, resulting in high drying efficiency and reduced impurity growth in hot and humid environments. Furthermore, the dissolution profile showed no downward trend, and all test parameters were excellent. Bioavailability was high, demonstrating bioequivalence to the reference formulation. DETAILED DESCRIPTION

[0033] It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs.

[0034] The present invention will be further described below with reference to the embodiments.

[0035] Example 1 The formulation of this embodiment is shown in Table 1: Table 1

[0036] The preparation method is: (1) Pretreatment: Pass the prescribed amount of mannitol through a 30-mesh sieve for later use.

[0037] (2) Preparation of the drug solution: Dissolve the API and mannitol (internal) in purified water at a ratio of 1:4, stir to dissolve, and let stand for 15 minutes to defoam to obtain the drug solution. The concentration of the API in the drug solution is 2%, and the concentration of mannitol is 8%, where % is the mass percentage.

[0038] (3) Granulation: Place the prescribed amount of spray-dried mannitol (external) in a fluidized bed for preheating, set the inlet air temperature to 50°C, and the fan frequency to 800m / s. 3 / After preheating for 10 minutes, spray the API solution onto the surface of the mannitol granules at a spray rate of 80 g / min and a spray pressure of 0.3 MPa. The material temperature reaches equilibrium at 15-18°C.

[0039] (4) Drying: After spraying, dry until the moisture content is ≤ 0.5%.

[0040] (5) Granulation: The dried granules are sieved through a 30-mesh sieve for granulation.

[0041] (6) Packaging: Calculate the amount of particles according to their content and pack them into finished products.

[0042] Example 2 The formulation of this embodiment is shown in Table 2: Table 2

[0043] The preparation method is: (1) Pretreatment: Pass the prescribed amount of mannitol through a 30-mesh sieve for later use.

[0044] (2) Preparation of the drug solution: Dissolve the API and mannitol (internal) in purified water at a ratio of 1:7, stir to dissolve, and let stand for 15 minutes to defoam to obtain the drug solution. The concentration of the API in the drug solution is 2%, and the concentration of mannitol is 14%.

[0045] (3) Granulation: Place the remaining mannitol (external) in the fluidized bed for preheating, set the inlet air temperature to 55°C, and the fan frequency to 1000m / s. 3 / After preheating for 10 minutes, spray the API solution onto the surface of the mannitol granules at a spray rate of 100 g / min and a spray pressure of 0.5 MPa. The material temperature reaches equilibrium at 17-20°C.

[0046] (4) Drying: After spraying, dry until the moisture content is ≤ 0.5%.

[0047] (5) Granulation: The dried granules are sieved through a 30-mesh sieve for granulation.

[0048] (6) Packaging: Calculate the amount of particles according to their content and pack them into finished products.

[0049] Example 3 The formulation of this embodiment is shown in Table 3: Table 3

[0050] The preparation method is: (1) Pretreatment: Pass the prescribed amount of mannitol through a 30-mesh sieve for later use.

[0051] (2) Preparation of the drug solution: Dissolve the API and mannitol (internal) in purified water at a ratio of 1:5, stir to dissolve, and let stand for 15 minutes to defoam to obtain the drug solution. The API concentration in the drug solution is 2%, and the mannitol concentration is 10%.

[0052] (3) Granulation: Place the prescribed amount of spray-dried mannitol (external) in a fluidized bed for preheating, set the inlet air temperature to 45°C, and the fan frequency to 900m / s. 3 / h. After preheating for 10 minutes, the API solution was sprayed onto the surface of the spray-dried mannitol granules at a spray rate of 90 g / min and a spray pressure of 0.4 MPa. The material temperature reached equilibrium at 16-19°C.

[0053] (4) Drying: After spraying, dry until the moisture content is ≤ 0.5%.

[0054] (5) Granulation: The dried granules are sieved through a 30-mesh sieve for granulation.

[0055] (6) Packaging: Calculate the amount of particles according to their content and pack them into finished products.

[0056] Example 4 The formulation of this embodiment is shown in Table 4: Table 4

[0057] The preparation method is: (1) Pretreatment: Pass the prescribed amount of mannitol through a 30-mesh sieve for later use.

[0058] (2) Preparation of the drug solution: Dissolve the API and mannitol (internal) in purified water at a ratio of 1:5, stir to dissolve, and let stand for 15 minutes to defoam to obtain the drug solution. The concentration of the API in the drug solution is 2%, and the concentration of mannitol is 10%.

[0059] (3) Granulation: Place the prescribed amount of spray-dried mannitol (external) in a fluidized bed for preheating, set the inlet air temperature to 55°C, and the fan frequency to 1000m / s. 3 / h. After preheating for 10 minutes, the API solution was sprayed onto the surface of the spray-dried mannitol granules at a spray rate of 90 g / min and a spray pressure of 0.5 MPa. The material temperature reached equilibrium at 18-21°C.

[0060] (4) Drying: After spraying, dry until the moisture content is ≤ 0.5%.

[0061] (5) Granulation: The dried granules are sieved through a 30-mesh sieve for granulation.

[0062] (6) Packaging: Calculate the amount of particles according to their content and pack them into finished products.

[0063] Comparative Example 1 The difference from Example 3 is that the ratio of the raw material drug: mannitol (internal) is adjusted to 1:3.

[0064] The formulation of this embodiment is shown in Table 5: Table 5

[0065] The preparation method is: (1) Pretreatment: Pass the prescribed amount of mannitol through a 30-mesh sieve for later use.

[0066] (2) Preparation of the drug solution: Dissolve the API and mannitol (internal) in purified water at a ratio of 1:3, stir to dissolve, and let stand for 15 minutes to defoam to obtain the drug solution. The concentration of the API in the drug solution is 2%, and the concentration of mannitol is 6%.

[0067] (3) Granulation: Place the prescribed amount of spray-dried mannitol (external) in a fluidized bed for preheating, set the inlet air temperature to 45°C, and the fan frequency to 900m / s. 3 / h. After preheating for 10 minutes, spray the liquid onto the surface of the mannitol particles at a spray rate of 90 g / min and a spray pressure of 0.4 MPa. The material temperature reaches equilibrium at 16-19°C.

[0068] (4) Drying: After spraying, dry until the moisture content is ≤ 0.5%.

[0069] (5) Granulation: The dried granules are sieved through a 30-mesh sieve for granulation.

[0070] (6) Packaging: Calculate the amount of particles according to their content and pack them into finished products.

[0071] Comparative Example 2 The difference from Example 1 is that only the API solution (API dissolved in purified water, without adding mannitol) is used for fluidized bed spraying on the surface of the spray-dried mannitol.

[0072] The formulation of this embodiment is shown in Table 6: Table 6

[0073] The preparation method is: (1) Pretreatment: Pass the prescribed amount of mannitol through a 30-mesh sieve for later use.

[0074] (2) Preparation of the drug solution: Dissolve the API in purified water, stir to dissolve, and let stand for 15 minutes to eliminate foaming to obtain the drug solution. The API concentration in the drug solution is 2%.

[0075] (3) Granulation: Place the prescribed amount of mannitol in a fluidized bed for preheating, set the inlet air temperature to 55°C, and the fan frequency to 1000m / s.3 / After preheating for 10 minutes, spray the API solution onto the surface of the mannitol granules at a spray rate of 100 g / min and a spray pressure of 0.5 MPa. The material temperature reaches equilibrium at 18-21°C.

[0076] (4) Drying: After spraying, dry until the moisture content is ≤ 0.5%.

[0077] (5) Granulation: The dried granules are sieved through a 30-mesh sieve for granulation.

[0078] (6) Packaging: Calculate the amount of particles according to their content and pack them into finished products.

[0079] Comparative Example 3 The ratio of the raw material drug to mannitol and the process parameters are different from those in Examples 1-4.

[0080] The prescription of this comparative example preparation is shown in Table 7: Table 7

[0081] The preparation method is: (1) Pretreatment: Pass the prescribed amount of mannitol through a 30-mesh sieve for later use.

[0082] (2) Preparation of the drug solution: Dissolve the API and mannitol (internal) in purified water at a ratio of 1:1, stir to dissolve, and let stand for 15 minutes to defoam. The concentration of the API is 2%, and the concentration of mannitol is 2%.

[0083] (3) Granulation: Place the prescribed amount of spray-dried mannitol (external) in a fluidized bed for preheating, set the inlet air temperature to 60°C, and the fan frequency to 1100m / s. 3 / After preheating for 10 minutes, the API solution was sprayed onto the surface of the spray-dried mannitol particles at a spray rate of 110 g / min and a spray pressure of 0.6 MPa. The material temperature reached equilibrium at 19-22°C.

[0084] (4) Drying: After spraying, dry until the moisture content is ≤ 0.5%.

[0085] (5) Granulation: The dried granules are sieved through a 30-mesh sieve for granulation.

[0086] (6) Packaging: Calculate the amount of particles according to their content and pack them into finished products.

[0087] Comparative Example 4 The difference from Example 3 is that the ratio of the raw material drug: mannitol (internal) is adjusted to 1:8.

[0088] The formulation of this embodiment is shown in Table 8: Table 8

[0089] The preparation method is: (1) Pretreatment: Pass the prescribed amount of mannitol through a 30-mesh sieve for later use.

[0090] (2) Preparation of the drug solution: Dissolve the API and mannitol (internal) in purified water at a ratio of 1:8. The API concentration is 2% and the mannitol concentration is 16%. The dissolution phenomenon is that some mannitol remains undissolved in the solution. The amount of mannitol used is too high, exceeding its solubility.

[0091] Preparation stability test: Examples 1-4, the original formulation (trade name: Singulair, manufacturer: Organon LLC), and Comparative Examples 1-3 were subjected to stability testing under conditions consistent with the 2025 edition of the Chinese Pharmacopoeia Guidelines 9001 and ICH Q1. The formulations were stored in commercial packaging at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% for six months. Samples were collected at the end of the third and sixth months to assess changes in sample quality. The results are shown in Table 9.

[0092] Table 9-1 Summary of stability test results

[0093] Table 9-2 Summary of stability test results

[0094] Analysis of Table 9-1 and Table 9-2 shows that for the 0-day samples of Examples 1 to 4, the impurity C is ≤0.15%, the other impurities are ≤0.05%, and the total impurities are ≤0.2%, which are far less than the limit requirements for each impurity and total impurities. Compared with the reference preparation 0 day, the impurity C, impurity B and total impurities are better than the reference preparation.

[0095] For Examples 1 to 4, from 0 days to 3 months of acceleration, the increase in each impurity and total impurities was small, with an increase of ≤0.1%; from 3 months of acceleration to 6 months, the increase in each impurity and total impurities was smaller than that from 0 days to 3 months of acceleration, with an increase of ≤0.5%. The samples were relatively stable. It is considered that the oxygen in the packaging bag was depleted and the impurity growth tended to be stable (impurity C is an oxidized impurity).

[0096] In the samples of Comparative Examples 1 and 3 at day 0, impurity C, impurity B, and total impurities were significantly higher than those in Examples 1-4. From day 0 to 3 months of accelerated reaction, impurity C and total impurities were close to the limit and increased significantly. From 3 months to 6 months of accelerated reaction, impurity C and total impurities were close to the limit and increased significantly, indicating poor sample stability.

[0097] In Comparative Example 2, the impurity C, impurity B and total impurities in the 0-day sample exceeded the limits. The increases from 0 days to 3 months of acceleration and from 3 months of acceleration to 6 months were large. The related substances were poor. It was considered that the raw material was directly sprayed on the surface of mannitol, lacked a protective agent or stabilizer, and was fully in contact with oxygen, resulting in poor stability.

[0098] Compared with Comparative Examples 1-3, during the stability test, from 0 days to 3 months of accelerated testing, and from 3 months of accelerated testing to 6 months of accelerated testing, the content of Examples 1-4 decreased less, the samples were relatively stable, there was no obvious downward trend in dissolution, the moisture content was qualified, and the content uniformity was better than that of the comparative examples.

[0099] Detection of particle repose angle: The angles of repose of Examples 1-4, the reference preparations, and Comparative Examples 1-3 were tested using an intelligent powder property tester. The results are summarized in Table 10: Table 10 Comparison of the angle of repose of particles in Examples and Comparative Examples

[0100] The results show that the angles of repose of the particles of Examples 1-4 are all less than 35°, and the samples have good fluidity, which is better than the reference preparation and the comparative example, so there is no need to add lubricants to improve fluidity.

[0101] Bioequivalence evaluation: The bioequivalence of the homemade montelukast sodium granules prepared in Example 1 and the original formulation was evaluated in healthy subjects. The main PK parameters (C max , AUC 0-t and AUC 0-∞ ) of the geometric mean ratio (homemade preparation / original preparation) with a 90% confidence interval ( CI ), the results are shown in Table 11, the results show that the C max , AUC 0-t and AUC 0-∞ 90% of the geometric mean ratio CI The bioequivalence rates were both within the range of 80.00% to 125.00%, meeting the bioequivalence standard. This indicates that the homemade preparation of montelukast sodium granules prepared in Example 1 and the original preparation are bioequivalent to each other after single oral administration under fasting conditions and can be used interchangeably.

[0102] Table 11 Geometric mean ratios of pharmacokinetic parameters between homemade and original preparations and 90% confidence interval

[0103] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A method for preparing a montelukast sodium granule preparation, characterized in that: The steps include: dissolving montelukast sodium and mannitol in purified water in proportion to obtain a drug solution; The drug solution is sprayed onto the surface of the fluidized mannitol, and after drying and granulation, montelukast sodium granules are obtained.

2. The method for preparing the montelukast sodium granules according to claim 1, wherein: The drug solution is sprayed onto the surface of the spray-dried mannitol in a fluidized state.

3. The method for preparing the montelukast sodium granules according to claim 1, wherein: Montelukast sodium and mannitol are dissolved in purified water in a mass ratio of 1-2:4-8 to obtain a medicinal solution.

4. The method for preparing the montelukast sodium granules according to claim 1, wherein: After dissolving montelukast sodium and mannitol in purified water in proportion, the method also includes a process of standing to eliminate bubbles.

5. The method for preparing the montelukast sodium granules according to claim 1, wherein: In the medicinal solution, the mass percentage of montelukast sodium is 1-3%.

6. The method for preparing the montelukast sodium granules according to claim 1, wherein: During the spraying process, the inlet air temperature of the fluidization is 45-55℃.

7. The method for preparing the montelukast sodium granules according to claim 6, wherein: The spray pressure of the liquid medicine is 0.3-0.5MPa.

8. The method for preparing the montelukast sodium granules according to claim 1, wherein: During the process of spraying the liquid on the surface of mannitol in the fluidized bed, the inlet air temperature of the fluidized bed is 45-55℃ and the inlet air volume is 800-1000m 3 / h, the spray rate of the liquid is 80-100g / min, and the spray pressure is 0.3-0.5Mpa; Preferably, during the fluidized bed spraying process, the temperature of the material reaches equilibrium at 15-21°C.

9. A montelukast sodium granular preparation, characterized in that: Prepared by the preparation method according to any one of claims 1 to 8.

10. The montelukast sodium granules according to claim 9, characterized in that: The preparation comprises the following components in parts by mass: 1-2 parts of montelukast sodium, 4-8 parts of mannitol, and 90-95 parts of spray-dried mannitol.

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