A montelukast sodium dry suspension formulation and a method of preparing the same

Abstract

The present application relates to a kind of dry suspension preparations of montelukast sodium, belong to the field of pharmaceutical pharmacy.The dry suspension preparation component is composed of montelukast sodium, carbomer, fumed silica, corn starch, sucrose, cherry powder essence, banana powder essence.By montelukast sodium and carbomer primary coating, again with fumed silica coating, enhanced protective layer, avoid the continued destruction of external light, oxygen, good stability effect is obtained.Through accelerated test, long-term test investigation, appearance, dissolution, content, related substances are superior to prior art.Preparation process uses large particle size solid drug substance, avoids the loss of raw material in preparation process, product preparation process is simple, easy to operate, quality meets the requirements, facilitate commercial production.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to a montelukast sodium dry suspension and its preparation method. Background Technology

[0002] According to my country's "Guidelines for the Prevention and Treatment of Bronchial Asthma," leukotriene modifiers are the only long-term control medications, besides inhaled corticosteroids, that can be used alone. They can be used as an alternative treatment for mild asthma and as a combination therapy for moderate to severe asthma. Montelukast sodium, as an oral leukotriene receptor antagonist, is a non-steroidal anti-inflammatory drug suitable for the prevention and long-term treatment of asthma in adults and children over 1 year of age, as well as for the treatment of allergic rhinitis. Montelukast sodium oral formulations were first approved in Mexico on July 31, 1997, under the brand name Singulair R. It was subsequently approved by the U.S. Food and Drug Administration (FDA) on February 20, 1998. Marketed dosage forms include film-coated tablets, chewable tablets, and granules in strengths of 10mg, 5mg, and 4mg. It was subsequently marketed in 71 countries, including Canada, Italy, Spain, Sweden, Switzerland, Germany, and France. In the late 1990s, Merck Sharp & Dohme (MDS)'s montelukast tablets entered the Chinese market, followed by its oral granules and chewable tablets. Montelukast sodium granules are indicated for the prevention and long-term treatment of childhood asthma, including the prevention of daytime and nighttime asthma symptoms, treatment of aspirin-sensitive asthma patients, and prevention of exercise-induced bronchoconstriction. It received approval from the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on January 25, 2008.

[0003] Montelukast sodium is chemically unstable and sensitive to humidity, heat, and light. It readily absorbs moisture in humid air, decomposes upon exposure to light, and is readily soluble in methanol, ethanol, and chloroform. It also degrades under conditions of oxidation, light, and high temperature.

[0004] To improve product stability, commercially available products incorporate pigments into their formulations, employ light-shielding coatings for tablets, and undergo strict light-avoidance processes during manufacturing to reduce light instability. Due to their dosage forms, film-coated tablets and chewable tablets present swallowing compliance issues for younger children. While granules effectively address swallowing compliance in younger children, the Chinese Pharmacopoeia imposes particle size requirements (the total percentage of particles that cannot pass through a No. 1 sieve and those that can pass through a No. 5 sieve must not exceed 15%), necessitating granules with a specific particle size and placing certain demands on the manufacturing process.

[0005] To reduce its oxidative impurities, patent WO2009153305A2 uses nitrogen as the fluidized bed carrier gas, which avoids contact between particles and oxygen, resulting in fewer oxidative impurities. However, it requires high-end equipment, which is difficult to achieve with existing domestic technology. At the same time, the manufacturing cost is high, which is not conducive to commercial production.

[0006] Patent CN107998091A utilizes the unique cavity structure of β-cyclodextrin to protect montelukast sodium from the effects of light and oxygen due to the inclusion complex of cyclodextrin, thus improving the stability of montelukast tablets. However, montelukast sodium is readily soluble in alcoholic aqueous solutions, making it difficult to effectively guarantee the inclusion rate of β-cyclodextrin; furthermore, the process requires the use of large amounts of ethanol to dissolve montelukast sodium and β-cyclodextrin, posing a safety risk.

[0007] Patents with publication numbers CN115770222A and 114425040A both disclose a montelukast sodium granule and its preparation method, both involving preparing montelukast sodium into a solution and using it as a binder for fluidized bed granulation. This preparation process carries risks such as raw material loss and large batch-to-batch variations in content during granulation. Summary of the Invention

[0008] To address the aforementioned problems, the present invention aims to provide a single-dose montelukast sodium dry suspension formulation, which possesses advantages such as high stability, good dissolution rate, and low impurity content. Furthermore, the Chinese Pharmacopoeia does not impose particle size requirements on dry suspensions. In addition, the present invention further provides a method for preparing this montelukast sodium dry suspension formulation.

[0009] The technical problem described in this invention is solved by the following technical solution:

[0010] A montelukast sodium dry suspension formulation is prepared by montelukast sodium, carbomer, fumed silica, corn starch, sucrose, cherry powder flavoring, and banana powder flavoring.

[0011] Preferably, the montelukast sodium dry suspension is prepared from the following components in parts by weight: 5 parts montelukast sodium, 5-15 parts carbomer, 3-5 parts fumed silica, 10 parts corn starch, 60 parts sucrose, 8 parts cherry powder flavoring, 12 parts banana powder flavoring, appropriate amount of purified water, and appropriate amount of ethanol. More preferably, the montelukast sodium dry suspension is prepared from the following components in parts by weight: 5 parts montelukast sodium, 10 parts carbomer, 4 parts fumed silica, 10 parts corn starch, 60 parts sucrose, 8 parts cherry powder flavoring, 12 parts banana powder flavoring, appropriate amount of purified water, and appropriate amount of ethanol.

[0012] A method for preparing the above-mentioned montelukast sodium dry suspension includes the following steps:

[0013] S1: Weigh the prescribed amount of raw and auxiliary materials and set aside.

[0014] S2: Add carbomer and sodium montelukast to a centrifugal granulator / coating machine. Set the turntable speed to 250-400 r / min, the inlet air temperature to 40℃, and the liquid supply speed to 25-40 r / min. Spray in purified water for coating and granulation. Control the particle moisture content to 15%~20% during granulation.

[0015] S3: After spraying the purified water, set the powder feeding speed to 10-20 r / min, add fumed silica, and continue coating.

[0016] S4: Add corn starch to the mixture, spray ethanol solution at an air inlet temperature of 40℃ and a liquid supply speed of 25-40 r / min, and dry.

[0017] S5: Add sucrose to the mixture and mix for 10 minutes.

[0018] S6: Add cherry powder flavoring and banana powder flavoring to the mixture and mix for 5 minutes.

[0019] S7: Dispense the mixture into smaller portions.

[0020] The beneficial effects of the montelukast sodium dry suspension formulation described in this invention are as follows:

[0021] This invention innovatively uses carbomer and fumed silica as coating materials to coat montelukast sodium in a sequential manner. First, carbomer absorbs water and slightly gels, adhering to the surface of the montelukast sodium particles to form a gel coating layer. Simultaneously, extremely fine-particle-size fumed silica is innovatively used as a coating material to further coat the montelukast sodium and carbomer spheres, thereby enhancing the protective layer and preventing further damage from external light and oxygen, achieving excellent stability. Furthermore, carbomer molecules act as carboxyl donors, forming hydrogen bonds with the hydroxyl groups in the montelukast sodium molecule, protecting the hydroxyl groups and preventing oxidation, thus inhibiting the growth of oxidative impurities in montelukast sodium. Accelerated and long-term testing showed that the appearance, dissolution rate, content, and related substances are superior to existing technologies. The preparation process uses large-particle-size solid active pharmaceutical ingredient (API), avoiding API loss during preparation. The product preparation process is simple, easy to operate, and meets quality requirements, facilitating commercial production.

[0022] During the preparation of this product, by controlling the moisture content of the particles during granulation, the carbomer is able to undergo slight gelation, allowing it to bind more tightly with sodium montmorillonite and fumed silica, thus ensuring the stability and density of the protective layer.

[0023] Therefore, the montelukast sodium dry suspension formulation of the present invention has achieved good technical results with a specific formulation ratio and a specific preparation process, providing a different technical solution for the preparation of montelukast sodium dry suspension formulation, which can better meet clinical needs.

[0024] The preparation process of montelukast sodium dry suspension described in this invention is simple to operate and has low production cost compared with other existing oral solid dosage form technologies, while greatly improving the stability of montelukast sodium formulations. Attached Figure Description

[0025] Figure 1 Microscopic state of the sample in Example 2;

[0026] Figure 2 Microscopic state of sample 2 in Comparative Example Implementation

[0027] The invention will be described in more detail below by way of examples, but it should be understood that these examples are merely illustrative and not limiting. Unless otherwise stated, all materials used are commercially available.

[0028] The following examples are only used to further illustrate the present invention, but do not limit the present invention.

[0029] Example

[0030]

[0031] The preparation method is as follows:

[0032] S1: Weigh the prescribed amount of raw and auxiliary materials and set aside;

[0033] S2: Add carbomer and sodium montelukast to a centrifugal granulator / coating machine. Set the rotary table speed to 250-400 rpm, the inlet air temperature to 40°C, and the liquid supply speed to 25-40 rpm. Spray in purified water for coating and granulation. Control the particle moisture content to 15%~20% during granulation.

[0034] S3: After spraying the purified water, set the powder feeding speed to 10-20 r / min, add fumed silica, and continue coating;

[0035] S4: Add corn starch to the mixture, spray ethanol solution at an air inlet temperature of 40℃ and a liquid supply speed of 25-40 r / min, and dry.

[0036] S5: Add sucrose to the mixture and mix for 10 minutes;

[0037] S6: Add cherry powder flavoring and banana powder flavoring to the mixture and mix for 5 minutes;

[0038] S7: Dispense the mixture into smaller portions.

[0039] Comparative Example

[0040]

[0041] The preparation method of Comparative Example 1 is as follows:

[0042] S1: Weigh out the prescribed amount of raw and auxiliary materials and set aside.

[0043] S2: Add sodium montelukast to a centrifugal granulator / coating machine. Set the turntable speed to 250-400 r / min, the inlet air temperature to 40℃, and the powder feeding speed to 10-20 r / min. Add fumed silica and spray purified water at a liquid feeding speed of 25-40 r / min for coating and granulation. Control the moisture content of the particles to 15%~20% during granulation.

[0044] S3: Add corn starch to the mixture, spray ethanol solution at an air inlet temperature of 40℃ and a liquid supply speed of 25-40 r / min, and dry.

[0045] S4: Add the sucrose and the mixture from step 3 to mixer 2 and mix for 10 minutes. The mixer speed is 10 rpm.

[0046] S5: Add cherry powder flavoring and banana powder flavoring to the mixture and mix for 5 minutes. Mixer speed: 10 rpm.

[0047] S6: Pack the mixture into individual bags.

[0048] The preparation methods for Comparative Examples 2 and 3 are the same as those in the Examples.

[0049] The preparation methods of Comparative Examples 4 and 5 are the same as those of the Examples, but the moisture content of the particles is controlled at about 5% during the granulation process of Comparative Example 4 and about 25% during the granulation process of Comparative Example 5.

[0050] Comparison under a microscope Figure 1 and Figure 2 It can be seen that in Example 2, a ring of carbomer particles was wrapped around the sodium montmorillonite raw material crystals; while in Comparative Example 2, the carbomer content was insufficient, resulting in a loose wrapping.

[0051] According to the requirements of the General Rules for Preparations, Part IV, of the 2020 edition of the Chinese Pharmacopoeia, the samples of the examples and comparative examples, as well as commercially available montelukast sodium chewable tablets, were tested as follows. Stability tests were performed on the samples under accelerated conditions (temperature 40℃±2℃, relative humidity 75%±5%). The properties, content, related substances, and dissolution curves in pH 6.8 medium were also tested for the samples. The results are shown in the table below. During the coating and granulation process of Comparative Example 5, due to the high moisture content of the granules, the material agglomerated into large clumps.

[0052] Table 3 Detection results of drug compositions

[0053]

[0054] Note: The limit for related substances is 1.5%, and f2≥50 indicates that the dissolution curve is similar to that of the original formulation.

[0055] Stability tests showed that the original product approached the limit requirements for related substances after 6 months of accelerated stability, while Comparative Examples 1, 2, and 4 exceeded the limit. The dissolution curves of Comparative Examples 1 and 3 in pH 6.8 medium were not similar to those of the original formulation. The related substances in Examples 1-3 were significantly better than those of the original formulation and the comparative products. Their dissolution curves were similar to those of the original formulation and showed a smaller trend of change compared to their own 0-day values, indicating greater overall stability.

[0056] The above are merely preferred embodiments of the present invention. The scope of protection of the present invention is not limited to the above embodiments. All technical solutions falling within the scope of the present invention's concept are within the scope of protection of the present invention. It should be noted that for those skilled in the art, any improvements and modifications made without departing from the principles of the present invention should be considered within the scope of protection of the present invention.

Claims

1. A dry suspension formulation of montelukast sodium characterized in that, It is prepared from sodium montelukast, carbomer, fumed silica, corn starch, sucrose, cherry powder flavoring, and banana powder flavoring, wherein there are 5 parts sodium montelukast, 5-15 parts carbomer, 3-5 parts fumed silica, 10 parts corn starch, 60 parts sucrose, 8 parts cherry powder flavoring, and 12 parts banana powder flavoring.

2. The dry suspension formulation according to claim 1, characterized in that, Montelukast sodium dry suspension is prepared from the following components in parts by weight: 5 parts montelukast sodium, 10 parts carbomer, 4 parts fumed silica, 10 parts corn starch, 60 parts sucrose, 8 parts cherry powder flavoring, and 12 parts banana powder flavoring.

3. A process for the preparation of a dry suspension formulation of montelukast sodium as claimed in claim 1, characterized in that, Includes the following steps: S1: Weigh the prescribed amount of raw and auxiliary materials and set aside; S2: Add carbomer and sodium montelukast to a centrifugal granulator and coating machine, spray in purified water, and granulate. Control the moisture content of the particles to 15%~20% during the granulation process. S3: After spraying the purified water, add fumed silica and continue coating; S4: Add corn starch to the above mixture, spray with ethanol solution, and dry; S5: Add the sucrose to the mixture above and mix. S6: Add cherry powder flavoring and banana powder flavoring to the mixture and mix. S7: Dispense the mixture into smaller portions.

4. A process for the preparation of the montelukast sodium dry suspension formulation according to claim 3, characterized in that, Includes the following steps: S1: Weigh the prescribed amount of raw and auxiliary materials and set aside; S2: Add carbomer and sodium montelukast to a centrifugal granulator and coating machine, set the turntable speed to 250-400 r / min, the inlet air temperature to 40℃, the liquid supply speed to 25-40 r / min, spray in purified water, and perform coating and granulation. During the granulation process, control the moisture content of the particles to 15%~20%. S3: After spraying the purified water, set the powder feeding speed to 10-20 r / min, add fumed silica, and continue coating; S4: Add corn starch to the mixture, spray ethanol solution at an air inlet temperature of 40℃ and a liquid supply speed of 25-40 r / min, and dry. S5: Add sucrose to the mixture and mix for 10 minutes; S6: Add cherry powder flavoring and banana powder flavoring to the mixture and mix for 5 minutes; S7: Dispense the mixture into smaller portions.

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