WO2015062466A1 - Particle composition, preparation method and formulation therefor - Google Patents

Abstract

A particle composition and a preparation method therefor. The particle composition comprises montelukast sodium particles and levocetirizine particles. The montelukast sodium particles comprise montelukast sodium, a filler, a stabilizer, and an adhesive. The levocetirizine particles comprise levocetirizine, a filler, a stabilizer, and an adhesive. The stabilizers are meglumine, and the adhesives are hydroxypropyl-β-cyclodextrin.

Description

Granule composition and preparation method and preparation thereof

The present application claims priority to Chinese Patent Application No. 201310521523.6, entitled "A granule composition and its preparation method, preparation", which is filed on October 29, 2013, the entire contents of In this application.

Technical field

The invention relates to the field of pharmaceutical preparations, in particular to a granular composition, a preparation method thereof and a preparation.

Background technique

Allergic rhinitis (AR), a multifactorial disease induced by the interaction of genes and the environment, is a medium mainly mediated by IgE after atopic individuals are exposed to allergens. (mainly histamine) release, and a variety of immune-active cells and cytokines involved in the non-infectious inflammatory diseases of the nasal mucosa. There are three necessary conditions for its occurrence: 1 specific antigen is the substance that causes the body's immune response; 2 atopic individual is called individual difference, allergic constitution; 3 specific antigen meets with the atopic individual. Specific antigens are derived from animals, plants, insects, fungi or occupational substances such as alfalfa, pollen, animal dander, fungal allergens, mite allergens, food allergens, etc., and their constituents are proteins or glycoproteins. Very few are polysaccharides. The typical symptoms of allergic rhinitis are paroxysmal sneezing, clear watery nose, nasal congestion and nasal itching, some with olfactory hypothyroidism. Moderate or severe allergic rhinitis can affect the quality of life of patients, which can lead to many other diseases. The patient is incapacitated.

Montelukast is a highly selective cysteine leukotriene (Cys-LT) receptor antagonist developed by Merck in recent years, which competitively antagonizes leukotriene D4 Binding to the Cys-LT1 receptor. It was first used as a new type of non-steroidal anti-asthma drug in clinical practice and has achieved positive results in the clinic. With the deeper understanding of leukotrienes (LT) and its receptor antagonists, it has been found that montelukast sodium can not only improve the lung function of asthma patients, but also has important application value in many aspects such as anti-inflammation and immunity. For example, montelukast sodium can be used for the treatment of allergic rhinitis.

Levocetirizine is a selective H1 receptor antagonist. In vitro binding characteristics studies found that levocetirizine (Xyzal) has twice the affinity for H1 receptor than cetirizine, and levocetirizine is effective in relieving allergic rhinitis in adult and children over 6 years old. symptom. The pharmaceutical form of levocetirizine is levocetirizine hydrochloride. In a randomized, double-blind, placebo-controlled, randomized controlled trial in France, 470 patients with allergic rhinitis were randomized into 4 groups of oral levocetirizine 2.5 mg, 5 mg, 10 mg, and placebo. 2 weeks. The patient recorded the severity of the previous 24h rhinitis every night, including sneezing, involuntary salivation, nasal itching, itchy eyes, and nasal congestion. Studies have shown that the main symptoms of patients in the levocetirizine hydrochloride group improved significantly, except for nasal congestion, the other symptoms were significantly different from placebo (P = 0.001). In addition, levocetirizine hydrochloride tablets were more effective in reducing the severity of the disease (except nasal congestion) than placebo (P = 0.0001). The study also showed that there is a simple curve relationship between the dose-effect relationship of levocetirizine hydrochloride. All patients were well tolerated in all doses of levocetirizine hydrochloride. The incidence of adverse reactions was 10.2% in the 10 mg group and 1.7% in the 5 mg group. There were no serious adverse events in each dose group.

Through the investigation of clinical literature at home and abroad, it can be seen that the combination of montelukast sodium and levocetirizine hydrochloride is more effective than the corresponding unilateral in relieving nasal discharge, sneezing, itchy nose, etc., and montelukast sodium is also mainly used. Relieve the therapeutic effect of nasal congestion, while levocetirizine hydrochloride can only relieve symptoms such as itchy nose and sneezing. It can not relieve the symptoms of nasal congestion in patients with moderate to severe allergic rhinitis with nasal congestion. The compound preparation can play a role in the curative effect. Complementary role. In addition, the combination of montelukast sodium levocetirizine hydrochloride is not as effective as corticosteroids, but it can be used as a long-term treatment for patients with moderate to severe rhinitis who are unwilling to use or are intolerant to corticosteroids.

At present, in the study of the compound preparation of montelukast sodium levocetirizine hydrochloride, there are mainly two factors that hinder the development of the compound preparation. On the one hand, montelukast sodium is very easy to absorb moisture, and it is unstable in light, humidity, heat, oxygen and acid. It is found that montelukast sodium and levocetirizine hydrochloride react quickly after contact. Yellow indicates that there is a contraindication between montelukast sodium and levocetirizine hydrochloride. On the other hand, sugar-free pharmaceutical preparations are very necessary for diabetic patients. Since mannitol is completely non-hygroscopic and has a sweet taste, it can be used instead of glucose or sucrose, so mannitol is used as a filler (or sweetener). A strong advantage is shown in sugar-free pharmaceutical preparations. However, mannitol and levocetirizine hydrochloride were very unstable under high temperature conditions. It was found that the related substances of levocetirizine hydrochloride containing mannitol were significantly increased, indicating that mannitol and hydrochloric acid There is also a contraindication between telizine. In the preparation of a pharmaceutical preparation containing levocetirizine hydrochloride, the use of mannitol is limited. So far, no effective solution has been found for the incompatibility between montelukast sodium and levocetirizine hydrochloride and the limited use of the preferred excipient mannitol in sugar-free preparations.

Summary of the invention

In view of the above, the present invention provides a granular composition, a preparation method thereof, and a preparation. The granular composition solves the incompatibility problem between montelukast sodium and levocetirizine hydrochloride through the addition of meglumine, improves the stability of montelukast sodium, and improves the left oxime hydrochloride. The stability of the alkazine makes mannitol can be used as an auxiliary in the compound preparation; the addition of hydroxypropyl-β-cyclodextrin can improve the stability of montelukast sodium, reduce the production of oxidation products, and improve the drug. The uniformity of the active ingredients.

In order to achieve the above object, the present invention provides the following technical solutions:

The present invention provides a granule composition comprising montelukast sodium granules and levocetirizine hydrochloride granules;

The montelukast sodium granules include montelukast sodium, a filler, a stabilizer, and a binder;

The levocetirizine hydrochloride granules include levocetirizine hydrochloride, a filler, a stabilizer, and a binder;

The stabilizer is meglumine;

The binder is hydroxypropyl-β-cyclodextrin.

In the present invention, studies have shown that meglumine can keep the surrounding of montelukast sodium alkaline, eliminate the effect of levocetirizine hydrochloride on montelukast sodium, and improve the stability of montelukast sodium. Overcome the incompatibility between montelukast sodium and levocetirizine hydrochloride; it can effectively improve the incompatibility between levocetirizine hydrochloride and mannitol, and fully exert the preference of mannitol as a sugar-free preparation. The advantages of accessories.

In the present invention, studies have shown that hydroxypropyl-β-cyclodextrin can effectively improve the stability of montelukast sodium, solve the problem of excessive oxidation of montelukast sodium in general preparations; improve Montelux The degree of dispersion of sodium is greatly improved in the uniformity and dissolution of montelukast sodium; it can effectively improve the bitterness of levocetirizine hydrochloride; the compressibility of mannitol is not good, hydroxypropyl-β - Cyclodextrin can increase the compressibility of the granules, allowing the high mannitol content of the granules to be smoothly compressed.

Preferably, in the granular composition, the montelukast sodium particles include 0.5 to 5 parts of montelukast sodium, 85 to 98 parts of a filler, 0.1 to 1 part of a stabilizer, and 1 to 7.2 of a binder. Share

The levocetirizine hydrochloride granule comprises 0.1 to 5 parts of levocetirizine hydrochloride, 89.96 to 98 parts of a filler, 0.1 to 2.9 parts of a stabilizer, and 1 to 5 parts of a binder;

The mass ratio of montelukast sodium granules to levocetirizine hydrochloride granules was (0.5-2):1.

Preferably, the montelukast sodium particles comprise 0.8 to 3.6 parts of montelukast sodium, 89.1 to 97 parts of a filler, 0.14 to 0.2 parts of a stabilizer, and 2 to 7.2 parts of a binder, in parts by weight;

The levocetirizine hydrochloride granules include 0.5-3.6 parts of levocetirizine hydrochloride, 89.96-97.1 parts of a filler, 0.4-2.9 parts of a stabilizer, and 2-3.6 parts of a binder;

The mass ratio of montelukast sodium granules to levocetirizine hydrochloride granules was (0.99-1.04):1.

In some embodiments provided by the present invention, the montelukast sodium particles in the granular composition comprise 0.8 parts of montelukast sodium, 97 parts of filler, 0.2 parts of stabilizer, 2 parts of binder. ;

The levocetirizine hydrochloride granules include 0.5 parts of levocetirizine hydrochloride, 97.1 parts of a filler, 0.4 parts of a stabilizer, and 2 parts of a binder;

The mass ratio of montelukast sodium granules to levocetirizine hydrochloride granules was 1:1.

In other embodiments provided by the present invention, the montelukast sodium particles in the granular composition comprise 3.6 parts of montelukast sodium, 89.1 parts of filler, 0.14 parts of stabilizer, binder 7.2. Share

The levocetirizine hydrochloride granules include 3.6 parts of levocetirizine hydrochloride, 89.96 parts of a filler, 2.9 parts of a stabilizer, and 3.6 parts of a binder;

The mass ratio of montelukast sodium granules to levocetirizine hydrochloride granules was 0.99:1.

The filler refers to a substance which accounts for a major portion of the preparation in terms of volume, such as mannitol, starch, microcrystalline fibers, sorbitol, and the like. Preferably, the filler in the present invention is one or a mixture of two or more of mannitol, lactose or microcrystalline cellulose.

In some embodiments provided by the present invention, the filler is mannitol, and the mannitol has a good mouthfeel and improves patient compliance.

The invention also provides a preparation method of the granular composition, comprising the following steps:

Mixing montelukast sodium, stabilizer, binder, filler with water to obtain montelukast sodium The solution is granulated, dried, and granulated to obtain montelukast sodium granules;

Taking levocetirizine hydrochloride, a stabilizer, a binder, a filler and water to obtain a levocetirizine hydrochloride solution, which is granulated, dried, and granulated to obtain levocetirizine hydrochloride granules;

The montelukast sodium granules are mixed with the levocetirizine hydrochloride granules, that is, obtained;

The stabilizer is meglumine;

The binder is hydroxypropyl-β-cyclodextrin.

In the preparation method of the granular composition, preferably, the mass ratio of montelukast sodium, filler, stabilizer, binder to water in the montelukast sodium solution is (0.5 to 5): (85~ 98): (0.1 to 1): (1 to 7.2): (8 to 17.2);

In the levocetirizine hydrochloride solution, the mass ratio of levocetirizine hydrochloride, a filler, a stabilizer, a binder to water is (0.1 to 5): (89.96 to 98): (0.1 to 2.9) :(1~5): (5~15);

The mass ratio of montelukast sodium granules to levocetirizine hydrochloride granules was (0.5-2):1.

In the preparation method of the granular composition, preferably, the mass ratio of montelukast sodium, filler, stabilizer, binder to water in the montelukast sodium solution is (0.8 to 3.6): (89.1~ 97): (0.14 to 0.2): (2 to 7.2): (8 to 17.2);

In the levocetirizine hydrochloride solution, the mass ratio of levocetirizine hydrochloride, filler, stabilizer, binder to water is (0.5 to 3.6): (89.96 to 97.1): (0.4 to 2.9): 2 to 3.6): (7.0 to 7.2);

The mass ratio of montelukast sodium granules to levocetirizine hydrochloride granules was (0.99-1.04):1.

In some embodiments provided by the present invention, the mass ratio of montelukast sodium, filler, stabilizer, binder to water in the montelukast sodium solution is 0.8:97:0.2:2:8;

The mass ratio of levocetirizine hydrochloride, filler, stabilizer, binder to water in levocetirizine hydrochloride solution is 0.5:97.1:0.4:2:7;

The mass ratio of montelukast sodium granules to levocetirizine hydrochloride granules was 1:1.

In other embodiments provided by the present invention, the montelukast sodium solution comprises 3.6 parts of montelukast sodium, 89.1 parts of filler, 0.14 parts of stabilizer, 7.2 parts of binder, and 17.2 parts of water in parts by weight. ;

The levocetirizine hydrochloride solution includes 3.6 parts of levocetirizine hydrochloride and 89.96 parts of a filler. 2.9 parts stabilizer, 3.6 parts of binder, 7.2 parts of water;

The mass ratio of montelukast sodium granules to levocetirizine hydrochloride granules was 0.99:1.

In some examples of the preparation methods provided by the present invention, the filler is one or a mixture of two or more of mannitol, lactose or microcrystalline cellulose.

The present invention also provides a combination preparation comprising the granular composition provided by the present invention and a pharmaceutically acceptable excipient composition.

The formulations provided by the present invention are oral formulations, and in some embodiments provided herein, the dosage forms of the combination formulations are granules or tablets. However, the oral preparations which are considered to be feasible by those skilled in the art are all within the scope of the present invention. The type of the oral preparation is not limited thereto, and the present invention is not limited thereto.

In some embodiments provided by the present invention, when the dosage form of the combination preparation is a granule, the pharmaceutically acceptable excipient in the granule is a lubricant.

Lubricant refers to an auxiliary material which can reduce the friction between the particles or the surface of the tablet and the die wall, so as to prevent the friction from being large and the tableting is difficult; the lubricant can make the pressure distribution uniform during tableting and make the density of the tablet uniform; The force required to push the tablet out of the die hole is reduced. In some embodiments provided by the invention, the lubricant is magnesium stearate. However, the lubricants that are considered to be feasible by those skilled in the art are all within the scope of the present invention. The type of the lubricant is not limited thereto, and the present invention is not limited thereto.

Preferably, the mass ratio of the particulate composition to the pharmaceutically acceptable excipient in the granule is (99 to 99.9): (0.1 to 1).

In some embodiments provided herein, the granule composition and the pharmaceutically acceptable excipient (i.e., lubricant) produce granules. In the granules, the mass ratio of the granule composition to the pharmaceutically acceptable excipient is 800:1.

In some embodiments provided by the present invention, when the dosage form of the combination preparation is a tablet, the pharmaceutically acceptable excipient in the tablet is a mixture of a sweetener, a disintegrant, a fragrance, a pigment, and a lubricant. Sweeteners and flavors can improve the taste of the drug and improve the patient's compliance; the disintegrant can increase the dissolution rate of the drug; the pigment can improve the appearance of the drug; the lubricant can reduce the friction and make the tableting smooth.

Preferably, the mass ratio of the granular composition to the pharmaceutically acceptable excipient is (90 to 99): (1 to 10).

In some embodiments provided by the present invention, the granular composition and the pharmaceutically acceptable excipient Chewable tablets are prepared (including sweeteners, disintegrants, flavors, colors, lubricants). In the chewable tablet, the mass ratio of the granular composition to the pharmaceutically acceptable excipient is 18.7:1.

Preferably, in the pharmaceutically acceptable excipient, the mass ratio of the sweetener, the disintegrant, the essence, the pigment and the lubricant is (0.1 to 1): (0.5 to 6): (0.01 to 0.5): (0.1 to 1): (0.1 to 2).

In some embodiments provided herein, the pharmaceutically acceptable excipients have a mass ratio of sweetener, disintegrant, flavor, pigment to lubricant of 1:4.5:0.25:0.25:1.6.

In some embodiments provided by the invention, the sweetener is sucralose. However, the sweeteners that are considered to be feasible by those skilled in the art are all within the scope of the present invention. The type of the sweetener is not limited thereto, and the present invention is not limited thereto.

In some embodiments provided by the present invention, the disintegrant is one of sodium carboxymethyl starch, hydroxypropyl cellulose, crospovidone, croscarmellose sodium, and croscarmellose sodium. Kind or a mixture of two or more. However, the disintegrators which are considered to be feasible by those skilled in the art are all within the scope of the present invention. The type of disintegrant is not limited thereto, and the present invention is not limited thereto.

The method of adding the disintegrating agent may be selected from any one of three ways of adding, adding, and adding the inside and the outside, and the present invention is not limited thereto.

In some embodiments provided by the present invention, the fragrance is a cherry flavor. However, the flavors that are considered to be feasible by those skilled in the art are all within the scope of the present invention, and the types of flavors are not limited thereto, and the present invention is not limited thereto.

In some embodiments provided by the invention, the pigment is red iron oxide. However, the pigments that are considered to be feasible by those skilled in the art are all within the scope of the present invention. The type of the pigment is not limited thereto, and the present invention is not limited thereto.

In some embodiments provided by the invention, the lubricant is magnesium stearate. However, the lubricants that are considered to be feasible by those skilled in the art are all within the scope of the present invention. The type of the lubricant is not limited thereto, and the present invention is not limited thereto.

The invention provides a granular composition, a preparation method thereof and a preparation. The granular composition comprises montelukast sodium particles and levocetirizine hydrochloride particles; montelukast sodium particles include montelukast sodium, a filler, a stabilizer, a binder; levocetirizine hydrochloride particles Including levocetirizine hydrochloride, a filler, a stabilizer, a binder; the stabilizer is meglumine; the binder is hydroxypropyl-β-cyclodextrin. By the stability test under accelerated conditions, the results show that the content of the pharmaceutically active ingredient related substance in the granular composition and the preparation thereof provided by the present invention slightly increases or does not increase, and the content of the related substance in the reference preparation increases greatly. It is indicated that the preparation provided by the invention has stable properties; the stability test by long-term conditions shows that the indexes of the preparations provided by the invention have no significant change, and the impurities in the reference substance of the montelukast sodium particle reference preparation are determined. The increase indicates that the preparation provided by the present invention has good stability; the research further indicates that the pharmaceutical formulation of the present invention solves the incompatibility problem between montelukast sodium and levocetirizine hydrochloride, and improves montelukast sodium. Stability, so that montelukast sodium no longer discolors, and improve the stability of levocetirizine hydrochloride, so that mannitol can be used as an auxiliary in the compound preparation; by the dissolution test results, it is known that the present invention provides After the preparation was left at 60 ° C for 10 days, the dissolution effect was hardly affected, indicating that the granular composition provided by the present invention The dissolution rate of the preparation is not easily affected by high temperature conditions; montelukast sodium and levocetirizine hydrochloride are dissolved in the binder solution for wet granulation, and the uniformity of the active ingredient content of the drug is greatly improved. It can be seen that the granular composition and the preparation thereof provided by the invention have stable properties, and the content uniformity of the active ingredients of the two drugs is improved, and the quality of the medicine fully conforms to the national standard.

DRAWINGS

Figure 1 shows the dissolution profile of montelukast sodium when the granules provided in Example 7 were placed for 0 days;

Figure 2 is a graph showing the dissolution profile of montelukast sodium when the granules provided in Example 7 were placed at 60 ° C for 10 days;

Figure 3 shows the dissolution profile of the commercially available reference formulation Shun Ning;

Figure 4 is a graph showing the dissolution profile of levocetirizine hydrochloride when the granules provided in Example 7 were placed for 0 days;

Figure 5 is a graph showing the dissolution profile of levocetirizine hydrochloride when the granules provided in Example 7 were allowed to stand at 60 ° C for 10 days.

detailed description

The invention discloses a granular composition, a preparation method thereof and a preparation thereof, and those skilled in the art can learn from the contents of the present invention and appropriately improve the process parameters. Special mention is that all classes Such substitutions and modifications will be apparent to those skilled in the art and are considered to be included in the invention. The method and the application of the present invention have been described by the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention. The technique of the present invention is applied.

The granule composition provided by the present invention, a preparation method thereof, and a drug substance or an auxiliary material used in the preparation are commercially available.

The present invention is further illustrated below in conjunction with the embodiments:

Example 1 Preparation of granule composition

The formulation of the granular composition is shown in Table 1.

Table 1 Prescription of the granular composition

Preparation of montelukast sodium granules: Add purified water to a stainless steel tank, add meglumine and stir until dissolved; continue stirring and add hydroxypropyl-β-cyclodextrin to dissolve, and finally add montelukast sodium to stir Dissolved to obtain a first binder solution, which was used. The mannitol was placed in a wet granulator after passing through a 26 mesh sieve, and the prepared first binder solution was placed in a wet granulator to prepare a soft material, and the soft material was sieved through a 26 mesh sieve, and dried at 45 ° C. After a minute, the granules were sieved through a 26 mesh sieve, and drying was continued until the loss on drying was ≤ 2.0% (IR 90 ° C, dried for 10 minutes), and sieved through a 26 mesh sieve to obtain montelukast sodium granules.

Preparation of levocetirizine hydrochloride granules: adding purified water to a stainless steel tank, adding hydroxypropyl-β-cyclodextrin to dissolve until dissolved; stirring and adding levocetirizine hydrochloride to dissolve; finally adding meglumine Stir until dissolved to obtain a second binder solution, which is ready for use. After mannitol has passed through 26 mesh sieve Put it in the wet granulator, put the prepared second binder solution in the wet granulator, make the soft material, soft material through the 26 mesh sieve granules, dry at 45 ° C for 15 minutes and then pass through the 26 mesh sieve The granules were further dried until the loss on drying was ≤2.0% [infrared moisture analyzer (IR) 90 ° C, dried for 10 minutes], and sieved through a 26 mesh sieve to obtain levocetirizine hydrochloride granules.

The montelukast sodium granules and levocetirizine hydrochloride granules were mixed in a mixer for 60 minutes to obtain.

Example 2 Preparation of Granular Composition

The formulation of the granular composition is shown in Table 2.

Table 2 Prescription of the granular composition

Preparation of montelukast sodium granules: Add purified water to a stainless steel tank, add meglumine and stir until dissolved; continue stirring and add hydroxypropyl-β-cyclodextrin to dissolve, and finally add montelukast sodium to stir Dissolved to obtain a first binder solution, which was used. The mannitol and microcrystalline cellulose 101 are respectively passed through a 26 mesh sieve, uniformly mixed, placed in a wet granulator, and the first binder solution is placed in a wet granulator to prepare a soft material and a soft material. The granules were sieved at 26 ° C, dried at 45 ° C for 15 minutes, sieved through a 26 mesh sieve, and dried until the loss on drying was ≤ 2.0% (IR 90 ° C, dried for 10 minutes), and sieved through a 26 mesh sieve to obtain montelukast sodium. Particles.

Preparation of levocetirizine hydrochloride granules: adding purified water to a stainless steel tank, adding hydroxypropyl-β-cyclodextrin to dissolve until dissolved; stirring and adding levocetirizine hydrochloride to dissolve; finally adding meglumine Stir until dissolved to obtain a second binder solution, which is ready for use. The mannitol and microcrystalline cellulose 101 are respectively passed through a 26 mesh sieve, uniformly mixed, placed in a wet granulator, and the prepared second binder solution is placed in a wet granulator to prepare a soft material and a soft material. The granules of 26 mesh sieves were dried at 45 ° C for 15 minutes, then sieved through a 26 mesh sieve, and dried until the loss on drying was ≤ 2.0% (IR 90 ° C, dried for 10 minutes), and sieved through a 26 mesh sieve to obtain levocetirizine hydrochloride. Pyrazine particles.

The montelukast sodium granules and levocetirizine hydrochloride granules were mixed in a mixer for 60 minutes to obtain.

Example 3 Preparation of granule composition

The formulation of the granular composition is shown in Table 3.

Table 3 Prescription of the granular composition

Preparation of montelukast sodium granules: Add purified water to a stainless steel tank, add meglumine and stir until dissolved; continue stirring and add hydroxypropyl-β-cyclodextrin to dissolve, and finally add montelukast sodium to stir Dissolved to obtain a first binder solution, which was used. The mannitol was placed in a wet granulator after passing through a 26 mesh sieve, and the prepared first binder solution was placed in a wet granulator to prepare a soft material, and the soft material was sieved through a 26 mesh sieve, and dried at 45 ° C. After a minute, the granules were sieved through a 26 mesh sieve, and drying was continued until the loss on drying was ≤ 2.0% (IR 90 ° C, dried for 10 minutes), and sieved through a 26 mesh sieve to obtain montelukast sodium granules.

Preparation of levocetirizine hydrochloride granules: adding purified water to a stainless steel tank, adding hydroxypropyl - β-cyclodextrin is stirred until dissolved; stirring is continued and left cetirizine hydrochloride is added until dissolution; finally, meglumine is added and stirred until dissolved to obtain a second binder solution, which is ready for use. The mannitol was placed in a wet granulator after passing through a 26 mesh sieve, and the prepared second binder solution was placed in a wet granulator to prepare a soft material, and the soft material was sieved through a 26 mesh sieve, and dried at 45 ° C. After a minute, the whole mesh was sieved through a 26 mesh sieve, and drying was continued until the loss on drying was less than or equal to 2.0% (IR 90 ° C, dried for 10 minutes), and sieved through a 26 mesh sieve to obtain levocetirizine hydrochloride particles.

The montelukast sodium granules and levocetirizine hydrochloride granules were mixed in a mixer for 60 minutes to obtain.

Example 4 Preparation of granule composition

The formulation of the granular composition is shown in Table 4.

Table 4 Prescription of the granular composition

Preparation of montelukast sodium granules: Add purified water to a stainless steel tank, add meglumine and stir until dissolved; continue stirring and add hydroxypropyl-β-cyclodextrin to dissolve, and finally add montelukast sodium to stir Dissolved to obtain a first binder solution, which was used. Mannitol and lactose were sieved through a 26 mesh sieve, mixed uniformly and placed in a wet granulator. The first binder solution was placed in a wet granulator to make a soft material. The soft material was sieved through a 26 mesh screen. The granules were dried at 45 ° C for 15 minutes and then sieved through a 26 mesh sieve. The granules were further dried to a loss on drying ≤ 2.0% (IR 90 ° C, dried for 10 minutes), and sieved through a 26 mesh sieve. The montelukast sodium granules are obtained.

Preparation of levocetirizine hydrochloride granules: adding purified water to a stainless steel tank, adding hydroxypropyl-β-cyclodextrin to dissolve until dissolved; stirring and adding levocetirizine hydrochloride to dissolve; finally adding meglumine Stir until dissolved to obtain a second binder solution, which is ready for use. Mannitol and lactose were sieved through a 26 mesh sieve, mixed uniformly, placed in a wet granulator, and the second binder solution was placed in a wet granulator to make a soft material. The soft material was sieved through a 26 mesh screen. The granules were dried at 45 ° C for 15 minutes, sieved through a 26 mesh sieve, and dried to a loss on drying ≤ 2.0% (IR 90 ° C, dried for 10 minutes), and sieved through a 26 mesh sieve to obtain levocetirizine hydrochloride granules.

The montelukast sodium granules and levocetirizine hydrochloride granules were mixed in a mixer for 60 minutes to obtain.

Example 5 Preparation of granule composition

The formulation of the granular composition is shown in Table 5.

Table 5 Prescription of the granular composition

Preparation of montelukast sodium granules: Add purified water to a stainless steel tank, add meglumine and stir until dissolved; continue stirring and add hydroxypropyl-β-cyclodextrin to dissolve, and finally add montelukast sodium to stir Dissolved to obtain a first binder solution, which was used. The mannitol was placed in a wet granulator after passing through a 26 mesh sieve, and the prepared first binder solution was placed in a wet granulator to prepare a soft material, and the soft material was sieved through a 26 mesh sieve, and dried at 45 ° C. After a minute, the granules were sieved through a 26 mesh sieve, and drying was continued until the loss on drying was ≤ 2.0% (IR 90 ° C, dried for 10 minutes), and sieved through a 26 mesh sieve to obtain montelukast sodium granules.

Preparation of levocetirizine hydrochloride granules: adding purified water to a stainless steel tank, adding hydroxypropyl-β-cyclodextrin to dissolve until dissolved; stirring and adding levocetirizine hydrochloride to dissolve; finally adding meglumine Stir until dissolved to obtain a second binder solution, which is ready for use. The mannitol was placed in a wet granulator after passing through a 26 mesh sieve, and the prepared second binder solution was placed in a wet granulator to prepare a soft material, and the soft material was sieved through a 26 mesh sieve, and dried at 45 ° C. After a minute, the whole mesh was sieved through 26 mesh, and drying was continued until the loss on drying was less than or equal to 2.0% [infrared moisture analyzer (IR) at 90 ° C, dried for 10 minutes], and sieved through a 26 mesh sieve to obtain levocetirizine hydrochloride particles.

The montelukast sodium granules and levocetirizine hydrochloride granules were mixed in a mixer for 60 minutes to obtain.

Example 6 Preparation of granule composition

The formulation of the granular composition is shown in Table 6.

Table 6 Prescription of the granular composition

Preparation of montelukast sodium granules: Add purified water to a stainless steel tank, add meglumine and stir until dissolved; continue stirring and add hydroxypropyl-β-cyclodextrin to dissolve, and finally add montelukast sodium to stir Dissolved to obtain a first binder solution, which was used. The mannitol and microcrystalline cellulose 101 are respectively passed through a 26 mesh sieve, uniformly mixed, placed in a wet granulator, and the first binder solution is placed in a wet granulator to prepare a soft material and a soft material. 26 mesh sieve granules, dried at 45 ° C for 15 minutes The whole mesh was sieved by 26 mesh, and drying was continued until the loss on drying was less than or equal to 2.0% (IR 90 ° C, dried for 10 minutes), and sieved through a 26 mesh sieve to obtain montelukast sodium particles.

Preparation of levocetirizine hydrochloride granules: adding purified water to a stainless steel tank, adding hydroxypropyl-β-cyclodextrin to dissolve until dissolved; stirring and adding levocetirizine hydrochloride to dissolve; finally adding meglumine Stir until dissolved to obtain a second binder solution, which is ready for use. The mannitol and microcrystalline cellulose 101 are respectively passed through a 26 mesh sieve, uniformly mixed, placed in a wet granulator, and the prepared second binder solution is placed in a wet granulator to prepare a soft material and a soft material. The granules of 26 mesh sieves were dried at 45 ° C for 15 minutes, then sieved through a 26 mesh sieve, and dried until the loss on drying was ≤ 2.0% (IR 90 ° C, dried for 10 minutes), and sieved through a 26 mesh sieve to obtain levocetirizine hydrochloride. Pyrazine particles.

The montelukast sodium granules and levocetirizine hydrochloride granules were mixed in a mixer for 60 minutes to obtain.

Example 7 Preparation of granules

The prescription of granules is shown in Table 7.

Table 7 prescription of granules

kind	Original accessories name	Prescription amount (g/30,000 bags)
			Granular composition	Granular composition prepared in Example 1	30000
Lubricant	Magnesium stearate	37.5

The granule composition obtained in Example 1 was mixed with magnesium stearate in a mixer for 5 minutes, and after the air bag airtightness was confirmed, the filling was started, and the granules were obtained by loading 1 g/bag.

Example 8 Preparation of Chewable Tablets

The prescription for chewing tablets is shown in Table 8.

Table 8 Prescription for chewable tablets

The granule composition prepared in Example 2 was mixed with sucralose, sodium carboxymethyl starch, cherry flavor, red iron oxide, magnesium stearate in a mixer for 5 minutes, and tableted to obtain a chewable tablet.

Example 9 Preparation of granules

The prescription of the granules is shown in Table 9.

Table 9 Prescription of granules

kind	Original accessories name	Prescription amount (g)
			Granular composition	Granular composition prepared in Example 3	17960
Lubricant	Magnesium stearate	18

The granule composition obtained in Example 3 was mixed with magnesium stearate in a mixer for 5 minutes, and after the air bag airtightness was confirmed, the filling was started, and the granules were obtained by loading 1 g/bag.

Example 10 Preparation of Chewable Tablets

The prescription for chewing tablets is shown in Table 10.

Table 10 Prescriptions for chewing tablets

kind	Original accessories name	Prescription amount (g)
			Granular composition	Granular composition prepared in Example 4	20820
Sweetener	Sucralose	34
			Disintegrator	Hydroxypropyl cellulose	2041
essence	Cherry flavor	170
			pigment	Red iron oxide	34
Lubricant	Magnesium stearate	34

The granule composition prepared in Example 4 was mixed with sucralose, hydroxypropylcellulose, cherry flavor, red iron oxide, magnesium stearate in a mixer for 5 minutes, and tableted to obtain a chewable tablet.

Example 11 Preparation of granules

The prescription of the granules is shown in Table 11.

Table 11 prescription of granules

kind	Original accessories name	Prescription amount (g)
			Granular composition	Granular composition prepared in Example 5	30000
Lubricant	Magnesium stearate	303

The granule composition obtained in Example 5 was mixed with magnesium stearate in a mixer for 5 minutes, and after the air bag airtightness was confirmed, the filling was started, and the granules were obtained by loading 1 g/bag.

Example 12 Preparation of Chewable Tablets

The prescription for chewing tablets is shown in Table 12.

Table 12 Prescriptions for chewable tablets

kind	Original accessories name	Prescription amount (g)
			Granular composition	Granular composition prepared in Example 6	28480
Sweetener	Sucralose	36
			Disintegrator	Cross-linked povidone	36
essence	Cherry flavor	0.7
			pigment	Red iron oxide	72
Lubricant	Magnesium stearate	143.3

The granule composition prepared in Example 6 was mixed with sucralose, crospovidone, cherry flavor, red iron oxide, magnesium stearate in a mixer for 5 minutes, and tableted to obtain a chewable tablet.

Example 13 Stability Study

Take the three batches of granules obtained in Example 7 (product batch number: 20121101, 20121102, 20121103) and the commercially available Shun Ning (from Merck East Pharmaceutical Company, the trade name is

The batch number is 0000148425A, which is a reference preparation for the related substances of montelukast sodium, and the stability test is carried out. Stability tests include accelerated tests, long-term tests, and intermediate tests.

The accelerated test was as follows: the granules and the reference preparation prepared in Example 7 were respectively measured at 0, 1, 2 under accelerated test conditions of a temperature of 40 ± 2 ° C and a relative humidity of 75 ± 5% RH for 6 months. At 3 and 6 months, the content of cetirizine hydrochloride, water, dissolution, labeling content and related substances were investigated for stability.

The long-term test is: take the three batches of granules obtained in Example 7 (product batch number: 20121101, 20121102, 20121103) and the commercially available Shun Ning (from Merck East Pharmaceutical Company, the trade name is

Batch number 0000148425A, as a reference preparation for montanukast sodium related substances) stored in a constant temperature and humidity chamber, controlled temperature and relative humidity conditions of 25 ± 2 ° C and 60 ± 10% RH, in 3, 6, 18 Samples were taken after the month and compared with the 0 month data and map. The montelukast sodium fraction was compared with the reference preparation Shun Ning, and levocetirizine hydrochloride was partially compared with its own 0-day data because there was no reference preparation.

The intermediate test was: taking the three batches of granules obtained in Example 7 (product batch number: 20121101, 20121102, 20121103) and the commercially available Shun Ning (from Merck East Pharmaceutical Company, the trade name is

Batch number 0000148425A, as a reference preparation for montelukast sodium related substances) stored in a constant temperature and humidity chamber, controlled temperature and relative humidity conditions of 30 ± 2 ° C and 65 ± 5% RH, in 3, 6, 18 Samples were taken after the month and compared with the 0 month data and map. The montelukast sodium fraction was compared with the reference preparation Shun Ning, and levocetirizine hydrochloride was partially compared with its own 0-day data because there was no reference preparation.

The moisture is determined by the moisture measurement method (Chinese Pharmacopoeia 2010 edition two appendix VIIIM first method A). The content determination, related substances, levocetirizine hydrochloride and dissolution were determined by HPLC. The microbial limit test method is improved according to the Chinese Pharmacopoeia 2010 edition two appendix microbial limit test method.

Montelukast sodium related substance detection method: in the dark operation, take 2500mg of granules prepared in Example 7, add 10mL volumetric flask, montelukast sodium concentration is 1mg / mL, add solvent [methanol-water (9 :1)] Appropriate amount, sonicate for 10 minutes, dilute to the mark with solvent [methanol-water (9:1)], shake well, filter, and take the filtrate as the test solution. According to high performance liquid chromatography (Chinese Pharmacopoeia 2010 edition two appendix V D) test, using phenyl bonded silica as a filler (Agilent SB-PHENYL 4.6*50mm, 1.8μm); flowing with 0.15% aqueous solution of trifluoroacetic acid Phase A, with 0.15% trifluoroacetic acid acetonitrile as mobile phase B, was subjected to gradient elution according to the procedure of Table 13; the flow rate was 1.2 mL per minute, the detection wavelength was 238 nm, and the column temperature was 30 °C. Another precise reference to the appropriate dose of montelukast sodium system 10mg, dissolved in solvent [methanol-water (9:1)] and diluted to make 1mg solution containing 1mg of the applicable standard of montelukast system Place under natural light for 20 minutes, shake well, as a system suitability solution, take 10 μL of the system suitability solution into the liquid chromatograph, record the chromatogram, sulfoxide impurity, cis isomer, montelukast and methyl ketone At the peak, the separation between the cis isomer peak and the montelukast peak should be not less than 2.5, and the separation between the montelukast peak and the methyl ketone peak should be not less than 1.5. Take 10 μL of the control solution into the liquid chromatograph to adjust the detection sensitivity so that the peak height of the main component peak is about 10% to 20% of the full scale; then accurately measure 10 μL of the test solution and inject it into the liquid chromatograph. If there is any impurity in the chromatogram of the test solution Peak, its peak area compared with the main peak area of the control solution, sulfoxide impurities should not exceed 1.0%, cis isomer impurities should not exceed 0.1%, methyl ketone impurities should not exceed 0.1%, other single unknown impurities should not exceed 0.1%, The total impurity should not exceed 1.2%, and any impurity peak in the chromatogram of the test solution that is less than 0.5 times the main peak area of the control solution can be ignored.

Method for detecting levocetirizine hydrochloride related substance: in the dark operation, 1000 mg of the granules prepared in Example 7 was placed in a 10 mL volumetric flask, and the solvent [water-acetonitrile (58:42)] was added in an appropriate amount, and ultrasonication was carried out for 10 minutes. Dilute to the mark, shake well, filter through a 0.22 μm filter, and take the filtrate as the test solution. Another precision weighed di-p-chlorobenzyl piperazine 5mg, p-chlorophenol 10mg and di-p-chlorophenylmethanol 5mg, placed in a 100mL volumetric flask, dissolved in solvent [water-acetonitrile (58:42)] and diluted to the scale Shake well, as a reference substance storage solution for impurities, accurately measure 1 mL of the relevant substance reference solution in a 200 mL volumetric flask, dilute to the mark with water [water-acetonitrile (58:42)], shake well, as a reference Solution. According to high performance liquid chromatography (Chinese Pharmacopoeia 2010 edition two appendix V D) test, using octadecylsilane bonded silica as a filler (CAPCELL PAK C185μm, 4.6 × 250mm); with buffer (sodium heptane sulfonate) 0.3 g of water (580 mL) (diluted sulfuric acid adjusted to pH 2.2) as mobile phase A, acetonitrile as mobile phase B, gradient elution according to the procedure of Table 14; flow rate of 1.0 mL per minute, detection wavelength of 230 nm, column temperature of 30 °C. Another 12.5mg of levocetirizine hydrochloride reference substance plus acetonitrile-water (58:42) to 50ml, prepared into a solution of 0.25mg / mL, take 2mL of this solution, 1mL of the relevant substance reference solution, set the same amount of 200mL In a bottle, dilute to the mark with solvent [water-acetonitrile (58:42)] and shake well as a system suitability solution. 20 μL of the system suitability solution was injected into the liquid chromatograph, and the chromatogram was recorded. Di-p-chlorobenzyl piperazine, levocetirizine, p-chlorophenol and di-p-chlorophenylmethanol were sequentially peaked, and di-p-chlorobenzoyl was obtained. The relative retention times of piperazine, p-chlorophenol and di-p-chlorophenylmethanol are about 0.9, 1.1 and 3.8, respectively. The resolution of di-p-chlorobenzyl piperazine peak and levocetirizine peak should be in accordance with the regulations. Adjust the detection sensitivity so that the peak of di-p-chlorobenzyl piperazine is about 20% of full scale. Then, 20 μL of each of the reference solution, the control solution, and the test solution were accurately weighed and injected into a liquid chromatograph to record a chromatogram. If there is a chromatogram with the retention time of di-p-chlorobenzyl piperazine peak, p-chlorophenol peak and di-p-chlorophenylmethanol peak in the chromatogram of the test solution, the peak area is calculated according to the external standard method. P-chlorobenzyl piperazine, p-chlorophenol and di-p-chlorophenylmethanol should not exceed 0.5% of the labeled amount of levocetirizine hydrochloride. The area of other single unknown impurity peaks should not be greater than the levocetirizine peak in the control solution. Area (0.5%), the total impurities should not exceed 1.0%. The impurity peak in the chromatogram of the test solution which is less than 0.1 times the area of the levocetirizine in the control solution is negligible.

Method for determining the content of montelukast sodium: in the dark operation, 250 mg of the granules prepared in Example 7 was added to a 10 mL volumetric flask, and the concentration of montelukast sodium was 0.1 mg/mL, and the solvent was added [methanol-water (9). :1)] Appropriate amount, sonicate for 10 minutes, dilute to the mark with solvent [methanol-water (9:1)], shake well, filter, and take the filtrate as the test solution. According to high performance liquid chromatography (Chinese Pharmacopoeia 2010 edition two appendix V D) test, using phenyl bonded silica as a filler (Agilent SB-PHENYL 4.6*50mm, 1.8μm); flowing with 0.15% aqueous solution of trifluoroacetic acid Phase A, with 0.15% trifluoroacetic acid acetonitrile as mobile phase B, was subjected to gradient elution according to the procedure of Table 15; the flow rate was 1.2 mL per minute, the detection wavelength was 238 nm, and the column temperature was 30 °C. Another 10ml of montelukast sodium reference substance, dissolved in solvent [methanol-water (9:1)] and diluted to make a solution containing about 0.1mg per 1mL, the same method, according to the external standard method to calculate the peak area That's it.

Determination of levocetirizine hydrochloride content: chromatographic conditions and system suitability test using octadecyl bonded silica as a filler, 0.2% aqueous trifluoroacetic acid as mobile phase A, 0.2% trifluoroacetic acid acetonitrile solution For mobile phase B, the detection wavelength was 230 nm, the flow rate was 1.0 mL per minute, and the gradient elution was performed according to the procedure of Table 16. Specific operation method: 1000 mg of the granules prepared in Example 7 was obtained, which was equivalent to levocetirizine hydrochloride 2.5. Mg, placed in a 25mL volumetric flask, add solvent [water-acetonitrile (58:42)] to the appropriate amount of ultrasound for 10 minutes, dilute to the mark, shake well, filter, accurately measure 20L of the filtrate, inject into the liquid chromatograph, record Chromatogram; take another 12.5mg to 50ml volumetric flask of levocetirizine hydrochloride reference substance, add solvent [water-acetonitrile (58:42)] to dissolve and dilute to make a solution containing about 0.1mg per 1mL, the same method According to the external standard method, the peak area is calculated.

Microbial limit detection method: 10 g of the granules prepared in Example 7 were aseptically weighed, and a pH 7.0 sterile sodium chloride-peptone buffer solution containing 0.3% egg yolk lecithin and 3% polysorbate 80 was added to 100 mL. Shake until the test sample is evenly dispersed to make a 1:10 test solution. Count bacteria, mold and yeast, take 1:10 test solution 1.0mL, evenly dispense into 2 dishes, 0.5mL per dish, check according to law (Chinese Pharmacopoeia 2010 edition second appendix XI J). For Escherichia coli examination, take 10 mL of test solution: 10 mL, add to 100 mL of bile salt lactose medium, and check according to law (Chinese Pharmacopoeia 2010 Edition Part II Appendix XI J). The test standard is: 1g of the test sample, the number of bacteria should not exceed 1000 CFU, the number of molds and yeasts should not exceed 100 CFU, and Escherichia coli should not be detected.

The accelerated test results are shown in Tables 17 and 18. The long-term test results are shown in Tables 19 and 20. The intermediate test results are shown in Table 21 and Table 22.

Table 13 Montelukast sodium related substances detection and elution procedures

Time (min)	Mobile phase A (%)	Mobile phase B (%)
			0	70	30
3	70	30
			16	49	51
25	49	51
			25.1	70	30
30	70	30

Table 14 Determination of elution procedures for levocetirizine hydrochloride related substances

Time (min)	Mobile phase A (%)	Mobile phase B (%)
			0	58	42
30	58	42
			50	20	80
55	20	80
			55.1	58	42
60	58	42

Table 15 Montelukast sodium content detection elution procedure

Time (minutes)	Mobile phase A (%)	Mobile phase B (%)
			0	70	30
3	70	30
			16	49	51
25	49	51
			25.1	70	30
30	70	30

Table 16 Levocitride hydrochloride content detection elution procedure

Time (minutes)	Mobile phase A (%)	Mobile phase B (%)
			0	62	38
6	62	38
			13	20	80
13.1	62	38
			18	62	38

Table 17 Accelerated test results (40 ± 2 ° C, 75 ± 5% RH)

Table 18 Acceleration test related substance determination results (40 ± 2 ° C, 75 ± 5% RH)

Note: ND means not detected.

Table 19 Long-term test results (25 ± 2 ° C, 60 ± 5% RH)

Table 20 Long-term test related substance determination results (25 ± 2 ° C, 60 ± 5% RH)

Note: ND means not detected.

Table 21 Intermediate test results (30 ± 2 ° C, 65 ± 5% RH)

Table 22 Determination results of related substances in the intermediate test (30±2°C, 65±5%RH)

Note: ND means not detected.

From the test results in Tables 17 and 18, it was found that the stability of the accelerated conditions for 6 months showed that the sulfoxide impurities and total impurities were slightly increased in the related substances of montelukast sodium; levocetirizine hydrochloride Among the related substances, the largest single unknown impurity and total impurities increased; there was no significant change in other inspection items. Reference preparation

The increase of sulfoxide impurity and total impurity in the determination of related substances was large, and there was no significant change in the content and dissolution. The results show that the granules provided in Example 7 of the present invention are stable in nature.

From the test results of Tables 19 to 22, it can be seen that after 18 months of stability investigation in the long-term and intermediate conditions, the results showed that in all the investigation items, the granules provided in Example 7 did not change significantly. Sinter sodium particle reference preparation Shun Ning

There was an increase in impurities in the determination of related substances, and there was no significant change in the content and dissolution. The results show that the granules provided in Example 7 of the present invention have good stability.

The three batches of chewable tablets (product lot number: 13050039, 13060051, 13060052) prepared in Example 8 were subjected to a stability test. Stability tests include accelerated tests, long-term and intermediate tests.

The accelerated test was: the chewable tablet prepared in Example 8 and the reference preparation were measured at 0 and 6 months under accelerated test conditions of a temperature of 40 ± 2 ° C and a relative humidity of 75 ± 5% RH for 6 months. The stability of the content of dextrozartrazin hydrochloride, water, dissolution, labeling content and related substances were investigated.

The long-term test was as follows: the three batches of chewable tablets prepared in Example 8 (product batch number: 13050039, 13060051, 13060052) were stored in a constant temperature and humidity chamber, and the controlled temperature and relative humidity conditions were 25 ± 2 ° C and 60 ± 10% RH, sampled after 3, 6, and 12 months and compared with the 0 month data and map.

The intermediate test was as follows: the three batches of chewable tablets prepared in Example 8 (product batch number: 13050039, 13060051, 13060052) were stored in a constant temperature and humidity chamber, and the controlled temperature and relative humidity conditions were 30±2° C. and 65±. 5% RH was sampled after 3, 6, and 12 months and compared with the 0 month data and map.

The test method refers to the test method for detecting the related substances of the granules of the present invention, and the accelerated test results are shown in Table 23 and Table 24. The long-term test results are shown in Table 25 and Table 26. The intermediate condition test results are shown in Table 27 and Table 28. .

Table 23 Accelerated test results (40 ± 2 ° C, 75 ± 5% RH)

Table 24 Acceleration test related substance determination results (40 ± 2 ° C, 75 ± 5% RH)

Note: ND means not detected.

Table 25 Long-term test results (25 ± 2 ° C, 60 ± 5% RH)

Table 26 Test results of related substances in long-term test (25±2°C, 60±5%RH)

Note: ND means not detected.

Table 27 Intermediate test results (30 ± 2 ° C, 65 ± 5% RH)

Table 28 Measurement results of related substances in the intermediate test (30±2°C, 65±5%RH)

Note: ND means not detected.

From the test results of Table 23 and Table 24, it was found that the stability condition of the accelerated condition for 6 months showed that the sulfoxide impurity and the total impurity were slightly in the related substances of the chewing tablet montelukast sodium provided in Example 8. Increase; among the related substances of levocetirizine hydrochloride, the largest single unknown impurity and total impurities increased; no other changes were observed in other inspection items. From the test results of Tables 25 and 26, it can be seen that after 12 months of stability investigation by long-term conditions, the results showed that the evaluation indexes of the chewable tablets provided in Example 8 did not change significantly in all the investigation items.

From the test results of Tables 27 and 28, it was found that the stability of the intermediate condition for 12 months showed that the evaluation indexes of the chewable tablets provided in Example 8 did not change significantly in all the investigation items. The results show that the chewable tablet provided in Example 8 of the present invention is stable in nature.

The preparations prepared in Examples 9 to 12 were subjected to accelerated and long-term stability investigation, and the results were similar to those of the granules prepared in Example 7, indicating that the preparations prepared in Examples 9 to 12 were stable in nature.

It can be seen that the compound preparation provided by the invention has stable properties and can overcome the incompatibility between montelukast sodium and levocetirizine hydrochloride, and can overcome the incompatibility between mannitol and levocetirizine hydrochloride. .

Example 14 Stability investigation under accelerated test conditions

The granules obtained in Example 7 and the chewable tablets prepared in Example 8 were each placed at 60 ° C for 10 days, and the contents of the relevant substances were measured for stability investigation. The results are shown in Tables 29 to 32.

Table 29 Determination results of related substances of montelukast sodium in the granules prepared in Example 7

Table 30 Determination of related substances of levocetirizine hydrochloride in the granules prepared in Example 7

Impurity	P-chlorophenol	Chlorodiphenylmethanol	Chlorodiphenylmethylpiperazine	Unknown impurity	Total impurity
						standard(%)	0.5	0.5	0.5	0.5	1.0
0 days	not detected	not detected	not detected	0.193	0.357
						10 days at 60 ° C	not detected	not detected	not detected	0.335	0.695

Table 31 Results of determination of related substances of montelukast sodium in chewable tablets prepared in Example 8

Table 32 Results of determination of related substances of levocetirizine hydrochloride in chewable tablets prepared in Example 8

Impurity	P-chlorophenol	Chlorodiphenylmethanol	Chlorodiphenylmethylpiperazine	Unknown impurity	Total impurity
						standard(%)	0.5	0.5	0.5	0.5	1.0
0 days	not detected	not detected	not detected	0.087	0.087
						10 days at 60 ° C	not detected	not detected	not detected	0.127	0.671

As can be seen from Table 29, the results show that the montelukast sodium component in the granules provided in Example 7 is very stable under high temperature conditions, the related substances are not substantially increased, and the quality of the drug completely conforms to the national standard; from Table 30, the results show examples. 7 The granules provided in the granules are very stable under high temperature conditions, the related substances are slightly increased, and the quality of the drugs is in full compliance with the national standard. quasi. It can be seen that the granules provided in Example 7 are stable in nature and the quality of the drug is in full compliance with national standards.

As can be seen from Table 31, the results show that the amount of montelukast sodium-related substance in the chewable tablet provided in Example 8 is slightly increased, and the quality of the drug completely conforms to the national standard; as can be seen from Table 32, the results show that hydrochloric acid in the chewable tablet provided in Example 8 The substance related to levocetirizine is slightly increased, and the quality of the drug is in full compliance with national standards. It can be seen that the chewable tablet provided in Example 8 is stable in nature and the quality of the drug is in full compliance with national standards.

The preparations prepared in Examples 9 to 12 were examined for stability, and the results were similar to those of the preparations prepared in Examples 7 and 8, indicating that the preparations prepared in Examples 9 to 12 were stable in nature.

It can be seen that the compound preparation provided by the invention has stable properties and can overcome the incompatibility between montelukast sodium and levocetirizine hydrochloride, and can overcome the incompatibility between mannitol and levocetirizine hydrochloride. .

Example 15 dissolution test

The granules prepared in Example 7 were allowed to stand at 60 ° C for 10 days, and then with the commercially available Shun Ning [from Merck East Pharmaceutical Company, the trade name is

The batch number was 0000148425A, and the dissolution test was carried out as a reference preparation of the dissolution rate (dissolution amount) of the montelukast sodium. The granules obtained in Example 7 were obtained and placed at 0 days and 10 days, montelukast sodium and levocetine hydrochloride. The dissolution of the lizine, as well as the dissolution of Shun Ning. The dissolution method is determined by the paddle method in the second method of Appendix 2C of the Chinese Pharmacopoeia 2010 edition. The dissolution conditions of montelukast sodium are: 0.5% SDS aqueous solution: 5.0 g SDS dissolved in water and diluted to 1000 mL, shake well , that is; medium volume: 900mL; device: paddle method; speed: 50 rpm; medium temperature: 37 ° C; sampling time: 5, 10, 15, 30, 45, 60 min. The dissolution conditions of levocetirizine hydrochloride were: dissolution medium: water; medium volume: 900 mL; device: paddle method; rotation speed: 50 rpm; medium temperature: 37 ° C; sampling time: 5, 10, 15, 30, 45, 60 min .

The test results are shown in Figs. 1 to 5, Table 29, and Table 30, wherein the test data of Figs. 1 to 3 are shown in Table 33, and the test data of Figs. 4 and 5 are shown in Table 34.

Table 33 Montelukast sodium dissolution (%) determination results

Table 34 Determination of dissolution rate (%) of levocetirizine hydrochloride

1 to 3 and Table 33, the granules prepared in Example 7 were left to stand at 60 ° C for 10 days, and the dissolution rate of montelukast sodium was almost unchanged from 0 days, and the dissolution of the reference preparation Shun Ning was observed. The degree is similar. 4, 5, and 34, the granules obtained in Example 7 were left to stand at 60 ° C for 10 days, and the dissolution rate of levocetirizine hydrochloride was almost unchanged from 0 days. From this, it was found that the granules obtained in Example 7 were left unaffected for 10 days under high temperature conditions, and the elution effect was hardly affected, and it was found that the dissolution rate of the granule composition provided in Example 1 was not easily affected by high temperature conditions.

The preparations prepared in Examples 8 to 12 were subjected to a dissolution test, and the results were similar to those of the granules provided in Example 7, indicating that the preparations prepared in Examples 8 to 12 were left to stand under high temperature for 10 days, and the dissolution effect was almost Without being affected, it can be inferred that the dissolution of the granular compositions provided in Examples 2 to 6 is not easily affected by high temperature conditions.

Thus, it can be seen that the dissolution rate of the granular composition and the preparation thereof provided by the present invention is not easily affected by high temperature conditions.

The above description is only a preferred embodiment of the present invention, and it should be noted that those skilled in the art can also make several improvements and retouchings without departing from the principles of the present invention. It should be considered as the scope of protection of the present invention.

Claims (9)

1. A granule composition comprising montelukast sodium granules and levocetirizine hydrochloride granules;

   The montelukast sodium particles include montelukast sodium, a filler, a stabilizer, a binder;

   The levocetirizine hydrochloride granule comprises levocetirizine hydrochloride, a filler, a stabilizer, a binder;

   The stabilizer is meglumine;

   The binder is hydroxypropyl-β-cyclodextrin.
2. The granular composition according to claim 1, wherein the montelukast sodium particles comprise 0.5 to 5 parts of montelukast sodium, 85 to 98 parts of a filler, and 0.1 to a stabilizer in parts by weight. 1 part, 1 to 7.2 parts of the binder;

   The levocetirizine hydrochloride granule comprises 0.1 to 5 parts of levocetirizine hydrochloride, 89.96 to 98 parts of a filler, 0.1 to 2.9 parts of a stabilizer, and 1 to 5 parts of a binder;

   The mass ratio of the montelukast sodium particles to the levocetirizine hydrochloride particles is (0.5 to 2):1.
3. The granular composition according to claim 1, wherein the filler is one or a mixture of two or more of mannitol, lactose or microcrystalline cellulose.
4. A method of preparing a granular composition according to any one of claims 1 to 3, comprising the steps of:

   Taking montelukast sodium, a stabilizer, a binder, a filler and water to obtain a montelukast sodium solution, which is granulated, dried, and granulated to obtain montelukast sodium granules;

   Taking levocetirizine hydrochloride, a stabilizer, a binder, a filler and water to obtain a levocetirizine hydrochloride solution, which is granulated, dried, and granulated to obtain levocetirizine hydrochloride granules;

   Taking the montelukast sodium granules and the levocetirizine hydrochloride granules to be mixed;

   The stabilizer is meglumine;

   The binder is hydroxypropyl-β-cyclodextrin.
5. The preparation method according to claim 4, wherein the montelukast sodium solution, the filler, the stabilizer, the binder and the water are in a mass ratio of the montelukast sodium solution. The ratio is (0.5 to 5): (85 to 98): (0.1 to 1): (1 to 7.2): (8 to 17.2);

   In the levocetirizine hydrochloride solution, the mass ratio of levocetirizine hydrochloride, a filler, a stabilizer, a binder to water is (0.1 to 5): (89.96 to 98): (0.1 to 2.9) :(1~5): (5~15);

   The mass ratio of the montelukast sodium particles to the levocetirizine hydrochloride particles is (0.5 to 2):1.
6. A combination preparation comprising the particulate composition of any one of claims 1 to 3 and a pharmaceutically acceptable adjuvant composition.
7. The combination preparation according to claim 6, wherein the preparation form of the combination preparation is granules or tablets.
8. The combination according to claim 6, wherein in the granule, the pharmaceutically acceptable excipient is a lubricant.
9. The combination according to claim 6, wherein in the tablet, the pharmaceutically acceptable excipient is a mixture of a sweetener, a disintegrant, a fragrance, a pigment, and a lubricant.

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