High-stability montelukast sodium granular formulation and preparation method therefor

Abstract

The present invention relates to a high-stability montelukast sodium granular formulation and a preparation method therefor. The preparation method adopts a preparation process of wet granulation followed by drying. Firstly, docusate sodium as a protective agent is added and completely dissolved, followed by standing to remove foam. Then, montelukast sodium continues to be added for dissolution in a dark place. Finally, CMC-Na as a binder is added, and stirring is continued until complete dissolution. The protective agent in a specific ratio to the active pharmaceutical ingredient is added in a specific sequence in the granulation process, thereby reducing the impurity levels of various impurities, and mitigating the problem of reduced dissolution rate of the granules under stability testing conditions.

Description

A high-stability montelukast sodium granule preparation and preparation method thereof Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations and relates to an antiasthmatic drug, montelukast sodium granules, and in particular to a high-stability montelukast sodium granule preparation and a preparation method thereof. Background Art

[0002] Montelukast sodium granules are antiasthmatic drugs, the main ingredient of which is montelukast sodium, with the molecular formula C 35 H 35 ClNNaO3S has a high affinity and selectivity for the type I cysteinyl leukotriene receptor, effectively inhibiting the cysteinyl leukotriene (CysLT1) receptor in the airways, thereby improving airway inflammation and effectively controlling asthma symptoms. It is suitable for the prevention and long-term treatment of asthma in adults and children, including preventing daytime and nighttime asthma symptoms, treating aspirin-sensitive asthma patients, and preventing exercise-induced bronchoconstriction.

[0003] At present, the preparation time of the conventional fluidized bed process is long because the main drug montelukast sodium accounts for a low proportion in montelukast sodium granules. In addition, montelukast sodium has poor stability and is unstable to light, moisture and heat, so the uniformity of the granule content and related substances are poor. For example, the public patent WO2009153305A2 uses a fluidized bed process with nitrogen as a carrier gas, but it cannot be implemented domestically due to its harsh equipment cost conditions. For example, the montelukast sodium granules of the public patent CN02821212.6 did not study the impurity level of the product. The impurities (montelukast cis isomer) produced after oral administration for 15 minutes are toxic and have a certain impact on the health of patients. At the same time, the montelukast sodium granules also have the problem of reduced solubility as the storage time increases.

[0004] For example, patent CN202111483337.9 provides a method for preparing montelukast sodium granules, which also uses a fluidized bed granulation process. Hydroxypropyl cellulose is first slowly added to water, dissolved, and then montelukast sodium is added and stirred until dissolved. Magnesium stearate is then added and dispersed. The coating suspension is then coated on mannitol, dried, and granulated. However, this process has the problem of a large RSD of the dissolution rate of montelukast sodium granules and a decrease in the dissolution rate of the granules with prolonged storage time.

[0005] For example, patent CN202111035149.X provides a montelukast sodium granule and its preparation method, which first prepares mannitol blank granules, then adds the prepared mannitol blank granules to a fluidized bed granulation coating machine, and sprays a montelukast sodium ethanol solution into the fluidized bed granulation coating machine. However, this process has the problem that the granulation and drying time are still long, just like the traditional process, which increases the time that montelukast sodium is in contact with moist heat, and the use of ethanol in the granulation solution further increases the preparation cost of montelukast sodium granules.

[0006] For example, patent CN202010012196.1 provides a montelukast sodium chewable tablet and a method for preparing the same. Montelukast sodium, a mixed solution of a first binder and water, mixed with pharmaceutical excipients, is granulated and dried. However, this process involves drying under harsh conditions at 80°C, which may further increase the content of related substances in the finished product. Furthermore, no research has been conducted on the growth trends of related substances in the finished product or in stability samples.

[0007] In addition, research revealed that the published patent CN201510747141.4 discloses a montelukast sodium granule composition and a preparation method thereof, which uses dodecyldimethylamine oxide and ammonium glycyrrhizate as protective agents. Although dodecyldimethylamine oxide can solubilize the main drug and has low physiological toxicity, as an artificial synthetic surfactant, it still poses a safety hazard to the human body, especially the gastrointestinal tract of children. Summary of the Invention

[0008] The present invention provides a high-stability montelukast sodium granule preparation and a preparation method thereof to solve the problems of impurity levels in current montelukast sodium granules and decreased solubility during stability testing.

[0009] To achieve the above object, the present invention adopts the following technical solutions:

[0010] The first aspect of the present invention is to provide a method for preparing a highly stable montelukast sodium granular preparation, comprising the steps of:

[0011] (1) Pretreatment: Micronize mannitol and low-substituted hydroxypropyl cellulose and set aside:

[0012] (2) Preparation of granulation solution: Under dark conditions, dissolve docusate sodium in purified water, then add montelukast sodium and stir until dissolved, and finally slowly add carboxymethylcellulose sodium (CMC-Na) until completely dissolved to obtain the granulation solution;

[0013] (3) Mixing granulation excipients: adding the mannitol, low-substituted hydroxypropyl cellulose and red iron oxide pretreated in step (1) into a wet mixing granulator and mixing them thoroughly to obtain granulation excipients;

[0014] (4) preparing a soft material: adjusting the speed of the wet mixing granulator and adding the granulation solution prepared in step (2) to prepare a soft material;

[0015] (5) Wet granulation: The soft material prepared in step (4) was granulated by a rocking granulator equipped with a 16-mesh steel wire screen to obtain montelukast sodium wet granules;

[0016] (6) Drying: The wet granules prepared in step (5) are transferred to a fluidized bed or electric blast drying oven for drying at a temperature of 60° C. until the moisture content of the dry granules is less than 0.5%, thereby obtaining montelukast sodium dry granules;

[0017] (7) Dry granulation: The dry granular material after the drying treatment in step (6) is passed through a mobile dry and wet granulation machine equipped with a 1.5 mm screen for granulation;

[0018] (8) Total mixing: weigh the materials, calculate the yield and convert the content of the added excipients, add the granulated materials from step (7) and magnesium stearate into a hopper mixer and mix at 15 rpm for 10 min to obtain montelukast sodium granules;

[0019] (9) Content detection: Detect the content of the main drug in the montelukast sodium granules after the total mixing in step (8);

[0020] (10) Packaging: Calculate the amount of packaging based on the content detected in step (9) and perform subpackaging to obtain the finished product.

[0021] Preferably, in step (1), the mannitol is passed through a 60-mesh sieve, and the low-substituted hydroxypropyl cellulose is passed through a 40-mesh sieve.

[0022] Preferably, in step (2), the mass ratio of docusate sodium to montelukast sodium is (0.8-0.9): (0.4-1.8).

[0023] Preferably, in step (2), the specific order of preparing the granulation solution is:

[0024] First, add the protective agent docusate sodium and dissolve it completely and let it stand to remove foam. Then, continue to add montelukast sodium and dissolve it in the dark. Finally, add the adhesive CMC-Na and continue to stir to dissolve it completely.

[0025] Preferably, in step (3), the stirring speed of the wet mixing granulator is 50 to 500 rpm, and the cutting speed is 50 to 500 rpm.

[0026] Preferably, in step (3), the mass ratio of the mannitol, the low-substituted hydroxypropyl cellulose and the red iron oxide is (90-92): (3-5): (0.1-0.6).

[0027] Preferably, in step (4), the stirring speed of the wet mixing granulator is adjusted to 50-500 rpm and the cutting speed is 1000-2000 rpm.

[0028] Preferably, in step (4), the granulation solution addition time is controlled to be 1 to 3 minutes, and the shearing time is controlled to be 1 to 3 minutes.

[0029] The second aspect of the present invention is to provide a high-stability montelukast sodium granular preparation prepared by the above-mentioned method, which comprises the following components by mass percentage:

[0030] Preferably, the following components are included by weight percentage and mass percentage:

[0031] The present invention adopts the above technical solution, which has the following technical effects compared with the prior art:

[0032] The method of the present invention adopts a preparation process of wet granulation followed by drying, which not only significantly reduces the amount of wetting agent in the granulation solution during the granulation process, but also significantly reduces the time the drug is in contact with unstable conditions by adjusting the order and proportion of protective agents added to prepare the granulation solution. This not only reduces the increasing trend of impurity levels in the finished product during the stability test, but also improves the problem of reduced dissolution during the stability test. DETAILED DESCRIPTION

[0033] The present invention will be described in detail and specifically below through specific examples to provide a better understanding of the present invention, but the following examples do not limit the scope of the present invention.

[0034] Example 1

[0035] A highly stable montelukast sodium granule preparation, comprising a 1:1 dosage ratio of montelukast sodium API to solubilizer docusate sodium. The specific formulation is shown in Table 1 below.

[0036] Table 1: Example 1 Montelukast sodium prescription 4mg / 500mg (API: solubilizer 1:1)

[0037] Note: Purified water is not included in the recipe weight as it is removed during the drying process.

[0038] Based on the prescription ratio shown in Table 1, the preparation method of the high-stability montelukast sodium granules specifically includes the following steps:

[0039] (1) Pretreatment: Pass mannitol through a 60-mesh sieve and low-substituted hydroxypropyl cellulose through a 40-mesh sieve for later use;

[0040] (2) Preparation of granulation solution: Dissolve docusate sodium in purified water in a dark place, then add montelukast sodium and stir until dissolved. Finally, slowly add carboxymethylcellulose sodium (CMC-Na) and completely dissolve to prepare the granulation solution.

[0041] (3) Mixing of granulation auxiliary materials: Add the material pretreated in step (1) and red iron oxide into a wet mixing granulator and mix (stirring speed 50-500 rpm, cutting speed 50-500 rpm);

[0042] (4) Preparation of soft material: Adjust the speed of the wet mixing granulator (stirring speed 50-500 rpm, cutting speed 1000-2000 rpm), and add the granulation solution prepared in step (2) to prepare the soft material (liquid addition time 1-3 min, shearing time 1-3 min);

[0043] (5) Wet granulation: the soft material prepared in step (4) was granulated by a rocking granulator equipped with a 16-mesh steel wire screen;

[0044] (6) Drying: The wet granules prepared in step (5) are transferred to a fluidized bed or electric blast drying oven for drying at a drying temperature of 60° C. until the moisture content of the dry granules is less than 0.5%;

[0045] (7) Dry granulation: The material after drying in step (6) is passed through a mobile dry and wet granulator equipped with a 1.5 mm screen for granulation;

[0046] (8) Total mixing: Weigh the materials, calculate the yield and convert the content of the added excipients; add the dry granulated materials and magnesium stearate into the hopper mixer and mix at 15 rpm for 10 min;

[0047] (9) Content detection: Detect the content of the main drug in the montelukast sodium granules after the total mixing in step (8);

[0048] (10) Packaging: Calculate the amount of packaging based on the content detected in step (9) and perform subpackaging to obtain the finished product.

[0049] Example 2

[0050] A highly stable montelukast sodium granule preparation, wherein the dosage ratio of montelukast sodium API to solubilizer docusate sodium is 1:2, and the specific formulation is shown in Table 2 below.

[0051] Table 2: Example 2 Montelukast Sodium Prescription 4 mg / 500 mg (API: Solubilizer Ratio 1:2)

[0052] Note: Purified water is not included in the recipe weight as it is removed during the drying process.

[0053] Based on the prescription ratio shown in Table 2, the preparation method of the high-stability montelukast sodium granules specifically includes the following steps:

[0054] (1) Pretreatment: Pass mannitol through a 60-mesh sieve and low-substituted hydroxypropyl cellulose through a 40-mesh sieve for later use;

[0055] (2) Preparation of granulation solution: Protect from light, add montelukast sodium and stir until dissolved, and finally slowly add carboxymethylcellulose sodium (CMC-Na) and completely dissolve to prepare the granulation solution;

[0056] (3) Mixing of granulation auxiliary materials: Add the material pretreated in step (1) and red iron oxide into a wet mixing granulator and mix (stirring speed 50-500 rpm, cutting speed 50-500 rpm);

[0057] (4) Preparation of soft material: Adjust the speed of the wet mixing granulator (stirring speed 50-500 rpm, cutting speed 1000-2000 rpm), and add the granulation solution prepared in step (2) to prepare the soft material (liquid addition time 1-3 min, shearing time 1-3 min);

[0058] (5) Wet granulation: the soft material prepared in step (4) was granulated by a rocking granulator equipped with a 16-mesh steel wire screen;

[0059] (6) Drying: The wet granules prepared in step (5) are transferred to a fluidized bed or electric blast drying oven for drying at a drying temperature of 60° C. until the moisture content of the dry granules is less than 0.5%;

[0060] (7) Dry granulation: The material after the drying treatment in step (6) is granulated by a mobile dry and wet granulator equipped with a 1.5 mm screen to obtain montelukast sodium granules;

[0061] (8) Total mixing: weigh the materials, calculate the yield and convert the content of the added excipients; add the dry granulated materials from step (7) and magnesium stearate into a hopper mixer and mix at 15 rpm for 10 minutes;

[0062] (9) Content detection: Detect the content of the main drug in the montelukast sodium granules after the total mixing in step (8);

[0063] (10) Packaging: Calculate the amount of packaging based on the content detected in step (9) and perform subpackaging to obtain the finished product.

[0064] Example 3

[0065] A highly stable montelukast sodium granule preparation, comprising a 1:1 dosage ratio of montelukast sodium API to solubilizer docusate sodium. The specific formulation is shown in Table 3 below.

[0066] Table 3: Example 3 Montelukast Sodium Prescription 4 mg / 500 mg (API: Solubilizer Ratio 2:1)

[0067] Note: Purified water is not included in the recipe weight as it is removed during the drying process.

[0068] Based on the prescription ratio shown in Table 3, the preparation method of the high-stability montelukast sodium granules specifically includes the following steps:

[0069] (1) Pretreatment: Pass mannitol through a 60-mesh sieve and low-substituted hydroxypropyl cellulose through a 40-mesh sieve.

[0070] (2) Preparation of granulation solution: Protect from light, add montelukast sodium and stir until dissolved, and finally slowly add carboxymethylcellulose sodium (CMC-Na) and completely dissolve to prepare the granulation solution;

[0071] (3) Mixing of granulation auxiliary materials: Add the material pretreated in step (1) and red iron oxide into a wet mixing granulator and mix (stirring speed 50-500 rpm, cutting speed 50-500 rpm);

[0072] (4) Preparation of soft material: Adjust the speed of the wet mixing granulator (stirring speed 50-500 rpm, cutting speed 1000-2000 rpm), and add the granulation solution prepared in step (2) to prepare the soft material (liquid addition time 1-3 min, shearing time 1-3 min);

[0073] (5) Wet granulation: the soft material prepared in step (4) was granulated by a rocking granulator equipped with a 16-mesh steel wire screen;

[0074] (6) Drying: The wet granules prepared in step (5) are transferred to a fluidized bed or electric blast drying oven for drying at a drying temperature of 60° C. until the moisture content of the dry granules is less than 0.5%;

[0075] (7) Dry granulation: The material after drying in step (6) is passed through a mobile dry and wet granulator equipped with a 1.5 mm screen for granulation;

[0076] (8) Total mixing: Weigh the materials, calculate the yield and convert the content of the added excipients; add the dry granulated materials and magnesium stearate into the hopper mixer and mix at 15 rpm for 10 min;

[0077] (9) Content detection: Detect the content of the main drug in the montelukast sodium granules after the total mixing in step (8);

[0078] (10) Packaging: Calculate the amount of packaging based on the content detected in step (9) and perform subpackaging to obtain the finished product.

[0079] Comparative Example 1

[0080] A montelukast sodium granule preparation, the specific prescription formula is shown in Table 4 below.

[0081] Table 4: Comparative Example 1 Montelukast Sodium Prescription 4mg / 500mg

[0082] Note: Purified water is not included in the recipe weight as it is removed during the drying process.

[0083] Based on the prescription ratio shown in Table 4, the preparation method of the montelukast sodium granules comprises the following steps:

[0084] (1) Pretreatment: sieve mannitol through a 40-mesh sieve to remove lumps;

[0085] (2) Weighing: Weigh the raw materials and auxiliary materials in the prescribed amount separately, and prepare purified water;

[0086] (3) Preparation of the coating suspension: slowly add the prescribed amount of hydroxypropyl cellulose to the prescribed amount of purified water to dissolve, then add montelukast sodium and stir until dissolved, defoam and set aside;

[0087] (4) Drug coating: Mannitol is placed in a fluidized bed, and the drug coating suspension is coated onto the mannitol in the fluidized bed using a peristaltic pump;

[0088] (5) Drying: Drying is carried out in a fluidized bed, and the moisture content is controlled to 0.5% and then stopped;

[0089] (6) Granulation: The dried granules were sieved with a 20-mesh oscillating sieve;

[0090] (7) Total mixing: Weigh the materials, calculate the yield and the amount of the added excipient (magnesium stearate), and mix the dried materials and magnesium stearate evenly using a hopper mixer (15 rpm, 10 min);

[0091] (8) Content detection: Detect the content of the main drug in the montelukast sodium granules after total mixing;

[0092] (9) Packaging: Calculate the amount of packaging based on the detected content and then package the product to obtain the finished product.

[0093] Comparative Example 2

[0094] A montelukast sodium granule preparation, the specific prescription formula is shown in Table 5 below.

[0095] Table 5: Comparative Example 1 Montelukast Sodium Prescription 4mg / 500mg

[0096] Note: Purified water is not included in the recipe weight as it is removed during the drying process.

[0097] Based on the prescription ratio shown in Table 5, the preparation method of the montelukast sodium granules comprises the following steps:

[0098] (1) Pretreatment: sieve mannitol through a 40-mesh sieve to remove lumps;

[0099] (2) Weighing: Weigh the raw materials and auxiliary materials in the prescribed amount separately, and prepare purified water;

[0100] (3) Preparation of the coating suspension: slowly add the prescribed amount of hydroxypropyl cellulose to the prescribed amount of purified water to dissolve, then add montelukast sodium and stir until dissolved, defoam and set aside;

[0101] (4) Drug coating: Mannitol is placed in a fluidized bed, and the drug coating suspension is coated onto the mannitol in the fluidized bed using a peristaltic pump;

[0102] (5) Drying: Drying is carried out in a fluidized bed, and the moisture content is controlled to 0.5% and then stopped;

[0103] (6) Granulation: The dried granules were sieved with a 20-mesh oscillating sieve;

[0104] (7) Total mixing: Weigh the materials, calculate the yield and the amount of the added excipient (magnesium stearate), and mix the dried materials and magnesium stearate evenly using a hopper mixer (15 rpm, 10 min);

[0105] (8) Content detection: Detect the content of the main drug in the montelukast sodium granules after total mixing;

[0106] (9) Packaging: Calculate the amount of packaging based on the detected content and then package the product to obtain the finished product.

[0107] Comparative Example 3

[0108] A montelukast sodium granule preparation, wherein the dosage ratio of montelukast sodium API to solubilizer docusate sodium is 1:1, and the order of adding the granulation solution is changed. The specific prescription is shown in Table 6 below.

[0109] Table 6: Comparative Example 3 Montelukast Sodium Prescription 4 mg / 500 mg (API: solubilizer 1:1, changing the order of addition)

[0110] Note: Purified water is not included in the recipe weight as it is removed during the drying process.

[0111] Based on the prescription ratio shown in Table 6, the preparation method of the montelukast sodium granules comprises the following steps:

[0112] (1) Pretreatment: Pass mannitol through a 60-mesh sieve and low-substituted hydroxypropyl cellulose through a 40-mesh sieve.

[0113] (2) Preparation of granulation solution: In a dark place, dissolve docusate sodium in purified water, then slowly add carboxymethylcellulose sodium (CMC-Na) and dissolve it, and finally add montelukast sodium and stir until it is completely dissolved to prepare the granulation solution.

[0114] (3) The material pretreated in step (1) and red iron oxide are added to a wet mixing granulator for mixing (stirring speed 50-500 rpm, cutting speed 50-500 rpm).

[0115] (4) Preparation of soft material: Adjust the speed of the wet mixing granulator (stirring speed 50-500 rpm, cutting speed 1000-2000 rpm), and add the solution prepared in step (2) to prepare the soft material (liquid addition time 1-3 min, shearing time 1-3 min).

[0116] (5) Wet granulation: The soft material prepared in step (4) was granulated by a rocking granulator equipped with a 16-mesh steel wire screen.

[0117] (6) Drying: The wet granules prepared in step (5) are transferred to a fluidized bed or electric blast drying oven for drying at a drying temperature of 60° C. until the moisture content of the dry granules is less than 0.5%.

[0118] (7) Dry granulation: The material is granulated through a mobile dry and wet granulator equipped with a 1.5 mm screen.

[0119] (8) Total mixing: Weigh the materials, calculate the yield and convert the content of the added excipients. Add the dry granulated materials and magnesium stearate to the hopper mixer and mix at 15 rpm for 10 minutes.

[0120] (9) Content detection: Detect the content of the main drug in the montelukast sodium granules after total mixing;

[0121] (10) Packaging: Calculate the amount of packaging based on the detected content and then package the product to obtain the finished product.

[0122] Comparative Example 3 only changes the order of adding the three solutes when preparing the granulation solution compared to Example 1.

[0123] Comparative Example 4

[0124] A montelukast sodium granule preparation, wherein the dosage ratio of montelukast sodium API to solubilizer docusate sodium is 1:1, and the order of addition of the granulation solution is changed. The specific formulation is shown in Table 7 below.

[0125] Table 7: Comparative Example 4 Montelukast Sodium Prescription 4 mg / 500 mg (API: solubilizer 1:1, changing the order of addition)

[0126] Note: Purified water is not included in the recipe weight as it is removed during the drying process.

[0127] Based on the prescription ratio shown in Table 7, the preparation method of the montelukast sodium granules comprises the following steps:

[0128] (1) Pretreatment: Pass mannitol through a 60-mesh sieve and low-substituted hydroxypropyl cellulose through a 40-mesh sieve.

[0129] (2) Preparation of granulation solution: In a dark place, slowly add sodium carboxymethylcellulose (CMC-Na) to purified water, then add docusate sodium to dissolve it, and finally add montelukast sodium and continue stirring until it is completely dissolved to prepare the granulation solution.

[0130] (3) The material pretreated in step (1) and red iron oxide are added to a wet mixing granulator for mixing (stirring speed 50-500 rpm, cutting speed 50-500 rpm).

[0131] (4) Preparation of soft material: Adjust the speed of the wet mixing granulator (stirring speed 50-500 rpm, cutting speed 1000-2000 rpm), and add the solution prepared in (1) and (2) to prepare the soft material (liquid addition time 1-3 min, shearing time 1-3 min).

[0132] (5) Wet granulation: The soft material prepared in step (4) was granulated by a rocking granulator equipped with a 16-mesh steel wire screen.

[0133] (6) Drying: The wet granules prepared in step (5) are transferred to a fluidized bed or electric blast drying oven for drying at a drying temperature of 60° C. until the moisture content of the dry granules is less than 0.5%.

[0134] (7) Dry granulation: The material is granulated through a mobile dry and wet granulator equipped with a 1.5 mm screen.

[0135] (8) Total mixing: Weigh the materials, calculate the yield and convert the content of the added excipients. Add the dry granulated materials and magnesium stearate to the hopper mixer and mix at 15 rpm for 10 minutes.

[0136] (9) Content detection: Detect the content of the main drug in the montelukast sodium granules after total mixing;

[0137] (10) Packaging: Calculate the amount of packaging based on the detected content and then package the product to obtain the finished product.

[0138] Comparative Example 4 only changes the order of adding the three solutes when preparing the granulation solution compared to Example 1.

[0139] Stability test method:

[0140] Results of key test items at day 0 of the finished product and the results of the accelerated test (the accelerated test is performed on commercially available packaging - aluminum-plastic composite film packaging - at a temperature of 40±2°C and a humidity of 75±5% RH for 6 months. The equipment used can control the temperature by ±2°C and the humidity by ±5%, and can also detect the actual temperature and humidity. Samples are collected at the 1st, 2nd, 3rd and 6th month of the test and tested according to the key stability inspection items)

[0141] The information of each known impurity is as follows:

[0142] (1) Impurity B

[0143] [1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolyl)-vinyl]phenyl]-3-[2-(1-methylvinyl)phenyl]propenyl]thio]methyl]cyclopropyl]acetic acid

[0144] (2) Impurity C

[0145] [1-[[[1-[3-[(1E)-2-(7-chloro-2-quinolyl)-vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfinyl]methyl]cyclopropyl]acetic acid

[0146] (3) Impurity G

[0147] [1-[[[(1R)-1-[3-[(Z)-2-(7-chloro-2-quinolyl)-vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropyl]acetic acid

[0148] (4) Montelukast ketone impurities

[0149] [1-[3-[(1E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]-1-propanone

[0150] Table 8: Test results of products in Examples 1 to 3 and Comparative Examples 1 to 4

[0151] Summary of stability test results:

[0152] Examples 1 through 3 used API:protectant ratios of (1:1 / 1:2 / 2:1), respectively. Comparative Examples 1 and 2 used a conventional fluidized bed one-step granulation process (with varying ratios of magnesium stearate). Comparative Examples 3 and 4 followed the same formulation as Example 1, differing only in the order of addition of the API, protective agent, and binder to the wet granulation solution.

[0153] According to the table above, in the growth trend of impurity G, it can be clearly seen that Comparative Example 1 and Comparative Example 2 do not contain a sunscreen (red iron oxide), so the base level of impurity G in the finished product (0 day) is higher than that of other batches, and eventually exceeds the limit by >0.1% during the stability test. For impurity C, the levels of Example 1, Example 2, and Example 3 are significantly lower than those of Comparative Examples 1, 2, 3, and 4, wherein Comparative Example 1 and Comparative Example 2 have exceeded the limit, and Comparative Example 3 and Comparative Example 4, although not yet exceeded, have exceeded the limit by >1.7% due to the impurity C level approaching the limit >1.0%. For impurity B, Comparative Examples 3 and Comparative Example 4 have exceeded the limit by >0.3% during the stability test, and Example 3 has also approached the limit. From the perspective of dissolution change trend, Example 1 and Example 2 are slightly reduced during the stability test, while the reduction trend of other batches is very significant, and the final acceleration of 6 months is less than 90%.

[0154] Based on the data summarized above, the API:protective agent ratio is within the range of (1:1-1:2). A specific sequence is required for preparing the wet granulation solution: first, add the protective agent (docusate sodium), dissolve it completely, and let it stand to remove foam. Then, add the API (montelukast sodium) in the dark and dissolve it. Finally, add the binder (CMC-Na) and continue stirring until it dissolves completely. The finished product prepared from this granulation solution has the advantages of low impurity levels and its solubility does not decrease with storage time during stability testing.

[0155] In summary, unlike existing solutions that use dodecyldimethylamine oxide and ammonium glycyrrhizate as protective agents, the process of the present invention uses docusate sodium as a protective agent. The protective principle is mainly based on the following two points. First, amorphous docusate sodium is first dissolved in purified water, and then amorphous montelukast sodium is dissolved. The dissolution rate of montelukast sodium is related to its crystal form and wettability in the formulation. During drying, docusate sodium coats montelukast sodium to produce a crystal-repressing effect, maintaining the amorphous form of montelukast sodium, preventing drug reaggregation and facilitating dissolution. Second, docusate sodium has a wetting effect. Docusate sodium dissolves first in the gastrointestinal tract, increasing the wetting effect of montelukast sodium, which in turn may increase the dissolution rate and absorption rate of montelukast sodium. At the same time, this method further reduces the impurity level of montelukast sodium particles, and the solubility does not decrease with storage time.

[0156] While the specific embodiments of the present invention have been described in detail above, these are merely exemplary and the present invention is not limited thereto. For those skilled in the art, any equivalent modifications and substitutions to the present invention are also within the scope of the present invention. Therefore, any equivalent changes and modifications made without departing from the spirit and scope of the present invention are intended to be encompassed within the scope of the present invention.

Claims

1. A method for preparing a highly stable montelukast sodium granule preparation, characterized in that: The steps include: (1) Pretreatment: micronize mannitol and low-substituted hydroxypropyl cellulose for standby use: (2) Preparation of granulation solution: Under light-shielded operation, docusate sodium was first dissolved in purified water, and then montelukast sodium was added and stirred until dissolved, and finally carboxymethylcellulose sodium (CMC-Na) was slowly added until completely dissolved to obtain a granulation solution; (3) Mixing granulation auxiliary materials: adding the mannitol, low-substituted hydroxypropyl cellulose and red iron oxide pretreated in step (1) into a wet mixing granulator and mixing them thoroughly to obtain granulation auxiliary materials; (4) preparing a soft material: adjusting the speed of the wet mixing granulator and adding the granulation solution prepared in step (2) to prepare a soft material; (5) Wet granulation: the soft material prepared in step (4) is granulated by a rocking granulator equipped with a 16-mesh steel wire screen to obtain montelukast sodium wet granules; (6) Drying: transferring the wet granules prepared in step (5) to a fluidized bed or electric heated blast drying oven for drying at a temperature of 60° C. until the moisture content of the dry granules is less than 0.5%, thereby obtaining montelukast sodium dry granules; (7) Dry granulation: The dry granular material after the drying treatment in step (6) is granulated by a mobile dry and wet granulator equipped with a 1.5 mm screen; (8) Total mixing: weigh the material, calculate the yield and convert the content of the added excipients, add the granulated material in step (7) and magnesium stearate into a hopper mixer and mix at 15 rpm for 10 min to obtain montelukast sodium granules; (9) Content detection: detecting the content of the main drug in the montelukast sodium granules after the total mixing in step (8); (10) Packaging: Calculate the amount of packaging based on the content detected in step (9) to obtain a finished product.

2. The method for preparing the highly stable montelukast sodium granules according to claim 1, characterized in that: In step (1), the mannitol is passed through a 60-mesh sieve, and the low-substituted hydroxypropyl cellulose is passed through a 40-mesh sieve.

3. The method for preparing the highly stable montelukast sodium granules according to claim 1, characterized in that: In step (2), the mass ratio of docusate sodium to montelukast sodium is (0.8-0.9):(0.4-1.8).

4. The method for preparing the highly stable montelukast sodium granules according to claim 1, characterized in that: In step (2), the specific order of preparing the granulation solution is: First, add the protective agent docusate sodium to dissolve completely and let stand to remove foam, then continue to add montelukast sodium in a dark environment to dissolve, and finally add the binder CMC-Na and continue to stir to dissolve completely.

5. The method for preparing the highly stable montelukast sodium granules according to claim 1, characterized in that: In step (3), the stirring speed of the wet mixing granulator is 50 to 500 rpm, and the cutting speed is 50 to 500 rpm.

6. The method for preparing the highly stable montelukast sodium granules according to claim 1, characterized in that: In step (3), the mass ratio of mannitol, low-substituted hydroxypropyl cellulose and red iron oxide is (90-92): (3-5): (0.1-0.6).

7. The method for preparing the highly stable montelukast sodium granules according to claim 1, characterized in that: In step (4), the stirring speed of the wet mixing granulator is adjusted to 50-500 rpm and the cutting speed is adjusted to 1000-2000 rpm.

8. The method for preparing the highly stable montelukast sodium granules according to claim 1, characterized in that: In step (4), the granulation solution addition time is controlled to be 1 to 3 minutes, and the shearing time is controlled to be 1 to 3 minutes.

9. A highly stable montelukast sodium granular preparation prepared by the method according to any one of claims 1 to 8, characterized in that: Calculated by mass percentage, it includes the following components:

10. The highly stable montelukast sodium granules according to claim 9, characterized in that: By weight percentage, by mass percentage, it includes the following components:

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