Montelukast sodium granules and preparation method thereof

Abstract

The present invention provides montelukast sodium granules and a preparation method thereof. The granules are prepared from mannitol granules, montelukast sodium, a binder, a lubricant, ethanol, and purified water. The mannitol granules are composed of mannitol 200 sd, hydroxypropyl cellulose, and purified water in parts by weight. The granule preparation has good stability and solubility, and the content of related substances is superior to that of the prior art. The present invention also discloses a preparation process of the montelukast sodium granules. The preparation process is simple, easy to operate, and suitable for industrial production.

Description

Technical Field

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

[0002] Montelukast is an anti-asthma drug developed by Merck in the United States. It is a selective leukotriene receptor antagonist that can specifically inhibit the cysteinyl leukotriene (CysLT1) receptor. Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are inflammatory mediators released by a variety of cells including mast cells and eosinophils. These important pro-asthma mediators bind to the cysteinyl leukotriene (CysLT) receptor. Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are inflammatory mediators released by a variety of cells including mast cells and eosinophils. These important pro-asthma mediators bind to the cysteinyl leukotriene (CysLT) receptor.

[0003] Cysteinyl leukotriene (CysLT1) receptors are distributed throughout the human airways (including airway smooth muscle cells and airway macrophages) and other proinflammatory cells (including eosinophils and certain bone marrow stem cells). CysLTs are implicated in the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include a range of airway responses, such as bronchoconstriction, mucus secretion, increased vascular permeability, and eosinophil accumulation. In allergic rhinitis, CysLTs, which are associated with allergic rhinitis symptoms, are released from the nasal mucosa during both the immediate and delayed phases following allergen exposure. Intranasal CysLT challenge increases nasal airway resistance and symptoms of nasal obstruction. Montelukast sodium improves markers of asthma inflammation. Montelukast sodium has a high affinity and selectivity for the CysLT1 receptor, effectively inhibiting the physiological effects of LTC4, LTD4, and LTE4 binding to the CysLT1 receptor without any receptor agonist activity.

[0004] Montelukast sodium oral formulation was first approved in Mexico on July 31, 1997, under the trade name It was subsequently approved by the U.S. Food and Drug Administration (FDA) on February 20, 1998, with the following dosage forms: film-coated tablets, chewable tablets, and granules, with strengths of 10 mg, 5 mg, and 4 mg, respectively. It was subsequently launched in 71 countries, including Canada, Italy, Spain, Sweden, Switzerland, Germany, and France. In the late 1990s, Merck Sharp & Dohme (MDS)'s montelukast tablets began to enter 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 prevention of daytime and nighttime asthma symptoms, treatment of aspirin-sensitive asthma patients, and prevention of exercise-induced bronchoconstriction. It was approved by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on January 25, 2008.

[0005] Montelukast sodium is chemically unstable and sensitive to moisture, heat, and light. It readily absorbs moisture in moist air and decomposes in the presence of light. It is readily soluble in methanol, ethanol, and chloroform, and degrades under conditions of oxidation, light, and high temperature. Most R&D efforts aim to enhance its stability by adding antioxidants or shielding the preparation process from light. This increases the number of excipients and production costs.

[0006] The preparation processes for montelukast sodium granules are disclosed in CN 201210026670.1, CN 200610151038.4, and CN02821212.6. However, the granules in these processes degrade into the cis-isomer and montelukast sulfoxide within 15 minutes of administration. Both the cis-isomer and montelukast are harmful to humans, especially children, and pose a significant safety risk.

[0007] WO2003035036A1 discloses the formula and preparation process of the commercially available montelukast sodium granules. The fluidized bed granulation method is used, and the loose granules prepared further increase the dissolution rate of montelukast sodium and ensure bioavailability in the body. However, montelukast sodium easily reacts with oxygen under high temperature conditions, and the oxidative impurities (sulfoxides) increase significantly. To reduce its oxidative impurities, patent WO2009153305A2 uses nitrogen as the fluidized bed carrier gas, avoiding contact between the particles and oxygen, resulting in fewer oxidative impurities, but the equipment requirements are high, which is difficult to achieve with existing domestic technology.

[0008] Patent CN201510747141.4 discloses a montelukast sodium granule composition and its preparation method, using 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

[0009] In response to the above-mentioned problems, the present invention aims to provide a montelukast sodium granule preparation having the advantages of high stability, good solubility, and low impurity content. In addition, the present invention further provides a method for preparing the montelukast sodium granule preparation.

[0010] The technical problem of the present invention is achieved by the following technical solutions:

[0011] A montelukast sodium granule preparation is prepared from montelukast sodium, mannitol granules, a lubricant, ethanol and purified water.

[0012] A montelukast sodium granule preparation, which is prepared from the following components in parts by weight:

[0013]

[0014]

[0015] Preferably, the montelukast sodium granule preparation is prepared from the following components in parts by weight:

[0016]

[0017] The mannitol granules are prepared from the following components in parts by weight:

[0018] Mannitol 200sd 480.23-485.63 parts

[0019] Adhesive 11.56-12.05 parts

[0020] Purified water 225.56-230.41 parts;

[0021] Preferably, the mannitol granules are prepared from the following components in parts by weight:

[0022] Mannitol 200sd 482.63 parts

[0023] 11.96 parts of adhesive

[0024] 227.24 parts of purified water;

[0025] The binder is hydroxypropyl cellulose, methyl cellulose and hypromellose, more preferably hydroxypropyl cellulose; the lubricant is magnesium stearate.

[0026] A method for preparing the above-mentioned montelukast sodium granules comprises the following steps:

[0027] (1) Preparation of Montelukast Sodium Mannitol Blank Granules

[0028] ① Weigh 200 sd of mannitol according to the prescribed amount and pass it through a 40-mesh sieve for later use.

[0029] ② Weigh the prescribed amount of hydroxypropyl cellulose to prepare a 5% hydroxypropyl cellulose solution. Slowly disperse the hydroxypropyl cellulose in stirred purified water until it is completely dissolved.

[0030] ③ Add 200 sd of prepared mannitol to the preheated fluidized bed granulator and spray the prepared hydroxypropyl cellulose solution into the fluidized bed granulator. Set parameters such as inlet air temperature, fan frequency, and atomization pressure to control the material temperature and humidity. Begin spraying the hydroxypropyl cellulose solution at a constant rate to prepare the mannitol granules. After spraying, dry the granules.

[0031] (2) Preparation of Montelukast Sodium Granules

[0032] ① Weigh ethanol and purified water according to the prescribed amount to prepare a 40% ethanol solution, mix well under stirring, and set aside.

[0033] ② Weigh the prescribed amount of montelukast sodium raw material and slowly disperse it into the completely dissolved 40% ethanol solution mentioned above, stirring until the montelukast sodium is completely dissolved. (Avoid light during weighing and subsequent operations)

[0034] ③ Add the prepared mannitol blank granules to the fluidized bed granulator and spray the montelukast sodium ethanol solution into the fluidized bed granulator. Set parameters such as inlet air temperature, fan frequency, and atomization pressure to control the material temperature and humidity. Begin spraying the montelukast sodium ethanol solution at a constant rate. After spraying is complete, dry the granules.

[0035] Preferably, in step (1), the material temperature is controlled to be generally below 40° C. during the preparation of the montelukast sodium mannitol granules;

[0036] Preferably, in step (2), the material temperature is controlled to be lower than 36° C. and the drying temperature is controlled to be lower than 60° C. during the preparation of the montelukast sodium granular preparation.

[0037] The montelukast sodium granule preparation of the present invention has the following beneficial effects:

[0038] The prescription was prepared by using montelukast sodium mannitol granules, which achieved good stability effects. After accelerated tests and long-term tests, the appearance, particle size, dissolution, content, and related substances were superior to the existing technology. After zero-day and six-month accelerated tests, the quality had obvious advantages. The process was simple, easy to operate, met the quality requirements, and was easy to scale up.

[0039] Therefore, the montelukast sodium granule preparation described in the present invention achieves good technical effects with a specific prescription ratio and a specific preparation process, providing a different technical solution for the preparation of montelukast sodium granule preparation, which can better meet clinical needs. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 Similarity evaluation diagram of pH 1.2 dissolution curve using f2 factor method

[0041] Figure 2 Similarity evaluation diagram of pH 4.5 dissolution curve using f2 factor method

[0042] The self-made preparations in the figure refer to the montelukast sodium granules prepared in Examples 1-3. DETAILED DESCRIPTION

[0043] The present invention provides a montelukast sodium granule and a preparation method thereof, which are used to solve the problems of unstable product quality and large differences between batches in the prior art.

[0044] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0045] Example 1

[0046] (1) Preparation of Montelukast Sodium Mannitol Granules

[0047] Montelukast sodium mannitol granules ratio:

[0048] Name of raw materials Prescription quantity (㎎) effect Mannitol 200sd 482.63 diluent Hydroxypropylcellulose 11.96 Adhesives purified water 227.24 solvent

[0049] ① Weigh 200 sd of mannitol according to the prescribed amount and pass it through a 40-mesh sieve for later use.

[0050] ② Weigh the prescribed amount of hydroxypropyl cellulose to prepare a 5% hydroxypropyl cellulose solution. Slowly disperse the hydroxypropyl cellulose in stirred purified water until the hydroxypropyl cellulose is completely dissolved.

[0051] ③ Add the prepared mannitol 200sd to the preheated fluidized bed granulator. Use side spray granulation. Set parameters such as inlet air temperature, fan frequency, and atomization pressure to control material temperature and humidity. Begin spraying the binder at a constant rate to form granules. After spraying is complete, dry the granules.

[0052] (2) Preparation of Montelukast Sodium Granules

[0053] The ratio of montelukast sodium granules:

[0054] Name of raw materials Prescription quantity (㎎) effect Mannitol granules 494.59 diluent Montelukast sodium 4.16 Active substances ethanol 39.94 solvent purified water 59.9 solvent magnesium stearate 1.25 lubricant

[0055] ① Weigh ethanol and purified water according to the prescribed amount to prepare a 40% ethanol solution, mix well under stirring, and set aside.

[0056] ② Weigh the prescribed amount of montelukast sodium raw material and slowly disperse it into the completely dissolved 40% ethanol solution mentioned above. Continue stirring until the montelukast sodium is completely dissolved. (Protect from light during weighing and subsequent operations)

[0057] ④ Add the prepared mannitol granules to the fluidized bed granulator and spray the montelukast sodium solution into the fluidized bed granulator. Adjust the inlet air temperature, fan frequency, atomization pressure, and other parameters to control the material temperature and humidity. Begin spraying the montelukast sodium ethanol solution at a constant rate. After spraying, dry the granules to control the moisture content to no more than 0.5%.

[0058] Example 2

[0059] (1) Preparation of Montelukast Sodium Mannitol Granules

[0060] Montelukast sodium mannitol granules ratio:

[0061] Name of raw materials Prescription quantity (㎎) effect Mannitol 200sd 480.23 diluent Hydroxypropylcellulose 11.26 Adhesives purified water 225.56 solvent

[0062] ① Weigh 200 sd of mannitol according to the prescribed amount and pass it through a 40-mesh sieve for later use.

[0063] ② Weigh the prescribed amount of hydroxypropyl cellulose to prepare a 5% hydroxypropyl cellulose solution. Slowly disperse the hydroxypropyl cellulose in stirred purified water until the hydroxypropyl cellulose is completely dissolved.

[0064] ③ Add the prepared mannitol 200sd to the preheated fluidized bed granulator. Use side spray granulation. Set parameters such as inlet air temperature, fan frequency, and atomization pressure to control material temperature and humidity. Begin spraying the binder at a constant rate to form granules. After spraying is complete, dry the granules.

[0065] (2) Preparation of Montelukast Sodium Granules

[0066] The ratio of montelukast sodium granules:

[0067] Name of raw materials Prescription quantity (㎎) effect Mannitol granules 490.07 diluent Montelukast sodium 4.05 Active substances ethanol 38.04 solvent purified water 58.66 solvent magnesium stearate 1.11 lubricant

[0068] ① Weigh ethanol and purified water according to the prescribed amount to prepare a 40% ethanol solution, mix well under stirring, and set aside.

[0069] ② Weigh the prescribed amount of montelukast sodium raw material and slowly disperse it into the completely dissolved 40% ethanol solution mentioned above. Continue stirring until the montelukast sodium is completely dissolved. (Protect from light during weighing and subsequent operations)

[0070] ④ Add the prepared mannitol granules to the fluidized bed granulator and spray the montelukast sodium solution into the fluidized bed granulator. Adjust the inlet air temperature, fan frequency, atomization pressure, and other parameters to control the material temperature and humidity. Begin spraying the montelukast sodium ethanol solution at a constant rate. After spraying, dry the granules to control the moisture content to no more than 0.5%.

[0071] Example 3

[0072] (1) Preparation of Montelukast Sodium Mannitol Granules

[0073] Montelukast sodium mannitol granules ratio:

[0074] Name of raw materials Prescription quantity (㎎) effect Mannitol 200sd 485.63 diluent Hydroxypropylcellulose 12.05 Adhesives purified water 230.41 solvent

[0075] ① Weigh 200 sd of mannitol according to the prescribed amount and pass it through a 40-mesh sieve for later use.

[0076] ② Weigh the prescribed amount of hydroxypropyl cellulose to prepare a 5% hydroxypropyl cellulose solution. Slowly disperse the hydroxypropyl cellulose in stirred purified water until the hydroxypropyl cellulose is completely dissolved.

[0077] ③ Add the prepared mannitol 200sd to the preheated fluidized bed granulator. Use side spray granulation. Set parameters such as inlet air temperature, fan frequency, and atomization pressure to control material temperature and humidity. Begin spraying the binder at a constant rate to form granules. After spraying is complete, dry the granules.

[0078] (2) Preparation of Montelukast Sodium Granules

[0079] The ratio of montelukast sodium granules:

[0080] Name of raw materials Prescription quantity (㎎) effect Mannitol granules 499.26 diluent Montelukast sodium 4.20 Active substances ethanol 40.08 solvent purified water 62.15 solvent magnesium stearate 1.45 lubricant

[0081] ① Weigh ethanol and purified water according to the prescribed amount to prepare a 40% ethanol solution, mix well under stirring, and set aside.

[0082] ② Weigh the prescribed amount of montelukast sodium raw material and slowly disperse it into the completely dissolved 40% ethanol solution mentioned above. Continue stirring until the montelukast sodium is completely dissolved. (Protect from light during weighing and subsequent operations)

[0083] ④ Add the prepared mannitol granules to the fluidized bed granulator and spray the montelukast sodium solution into the fluidized bed granulator. Adjust the inlet air temperature, fan frequency, atomization pressure, and other parameters to control the material temperature and humidity. Begin spraying the montelukast sodium ethanol solution at a constant rate. After spraying, dry the granules to control the moisture content to no more than 0.5%.

[0084] Verification test example

[0085] Accelerated testing:

[0086] The montelukast sodium granules prepared in Example 1 of the present invention, the original research (Singulair, Merck Sharp & Dohme Corp.), and the commercially available (montelukast sodium granules, Changchun Haiyue Pharmaceutical Co., Ltd., production batch number: CA200104) were placed at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% to investigate changes in properties, dissolution, and related substances. The test results are shown in Table 1 below.

[0087] Table 1 Montelukast sodium granule accelerated test results

[0088]

[0089]

[0090] The results showed that the montelukast sodium granules prepared in Example 1 were comparable to or even better than the original drug in terms of properties, dissolution, and changes in related substances, and were significantly better than similar commercially available products.

Claims

1. A montelukast sodium granule preparation, characterized in that: The montelukast sodium granule preparation is prepared by using montelukast sodium, mannitol granules, lubricant, ethanol and purified water; the montelukast sodium granule preparation is prepared by using the following components in parts by weight: 4.05-4.20 parts of Montelukast sodium Mannitol granules 490.07-499.26 parts 1.11-1.45 parts of lubricant 38.04-40.08 parts of ethanol 58.66-62.15 parts of purified water; The mannitol granules are prepared from the following components in parts by weight: Mannitol 200sd 480.23-485.63 parts Adhesive 11.56-12.05 parts Purified water 225.56-230.41 parts; The binder is hydroxypropyl cellulose, and the lubricant is magnesium stearate; The preparation method of the montelukast sodium granule preparation comprises the following steps: (1) Preparation of mannitol blank particles ① Weigh 200 sd of mannitol according to the prescription and pass it through a 40-mesh sieve for later use; ② Weigh hydroxypropyl cellulose according to the prescribed amount and prepare a 5% hydroxypropyl cellulose solution. Slowly disperse the hydroxypropyl cellulose in stirred purified water until it is completely dissolved. ③ Add the prepared mannitol 200sd to the preheated fluidized bed granulator, spray the prepared hydroxypropyl cellulose solution into the fluidized bed granulator, set the air inlet temperature, fan frequency, atomization pressure, control the material temperature and humidity, start spraying the hydroxypropyl cellulose solution at a certain rate to prepare mannitol granules, and dry the granules after the spraying is completed; (2) Preparation of Montelukast Sodium Granules ① Weigh ethanol and purified water according to the prescribed amount to prepare a 40% ethanol solution, mix well under stirring, and set aside; ② Weigh the prescribed amount of montelukast sodium raw material and slowly disperse it in the completely dissolved 40% ethanol solution mentioned above until the montelukast sodium is completely dissolved; ③ Add the prepared mannitol blank particles into a fluidized bed granulation coating machine, spray the montelukast sodium ethanol solution into the fluidized bed granulation coating machine, set the air inlet temperature, fan frequency, atomization pressure, control the material temperature and humidity, start spraying the montelukast sodium ethanol solution at a certain rate, and dry the particles after the spraying is completed; in the step (1), the material temperature is controlled to be lower than 40°C during the preparation of the montelukast sodium mannitol particles, and in the step (2), the material temperature is controlled to be lower than 36°C and the drying temperature is controlled to be lower than 60°C during the preparation of the montelukast sodium granule preparation.

2. The montelukast sodium granules according to claim 1, characterized in that The montelukast sodium granule preparation is prepared from the following components in parts by weight: 4.16 parts of Montelukast sodium 494.59 portions of mannitol granules 1.25 parts lubricant 39.94 parts of ethanol 59.90 parts of purified water.

3. The montelukast sodium granules according to claim 1, wherein The mannitol granules are prepared from the following components in parts by weight: Mannitol 200sd 482.63 parts 11.96 parts of adhesive 227.24 parts of purified water.

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