A montelukast sodium tablet and a preparation method thereof

Abstract

The application relates to the technical field of pharmaceutical preparations, and discloses a montelukast sodium tablet and a preparation method thereof. The preparation steps are as follows: a binder is added into water, heated and uniformly stirred to obtain a binder mixture; montelukast sodium, a stabilizer, an excipient and a disintegrating agent are added into water, uniformly stirred, then the binder mixture is added, uniformly stirred and sheared and emulsified, water is added again, uniformly stirred and sheared and emulsified, vacuum degassed, injected into a mold, frozen, dried, and the montelukast sodium tablet is obtained; the disintegrating agent is modified tamarind gum, sodium carboxymethyl starch, amino acid modified sodium carboxymethyl starch and crosslinked sodium carboxymethyl starch with a mass ratio of (0.5-1):(1-1.5):(1-1.5):(0.1-0.2). The prepared montelukast sodium tablet is an oral disintegration tablet with good mechanical strength, fast disintegration speed and high stability in a humid environment.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of pharmaceutical preparations and discloses a montelukast sodium tablet and a preparation method thereof. BACKGROUND

[0002] Leukotrienes are one of important mediums of bronchial asthma, and montelukast is a cysteinyl leukotriene receptor antagonist which can block the interaction between cysteinyl leukotrienes and receptors, so as to achieve the purpose of controlling asthma. The montelukast sodium orally disintegrating tablet is a new type of immediate-release drug, has the advantage of disintegrating at the entrance, can shorten the drug onset time, reduce the stimulation of the gastrointestinal tract, and significantly improves the patient's medication compliance, and is a research hotspot at present.

[0003] However, the orally disintegrating tablet still has the following problems to be solved: (1) the hardness and disintegration rate are difficult to balance: the orally disintegrating tablet needs to have certain physical hardness to prevent the tablet from being broken or powdered, however, the increase of the hardness leads to the prolongation of the disintegration time, if the proportion of the disintegrant is increased to ensure the disintegration rate, the tablet structure will be loose and the hardness will be insufficient, which seriously affects the quality stability; (2) the moisture stability of montelukast sodium is poor, when the orally disintegrating tablet is stored in a humid environment, a hydrolysis reaction is prone to occur, leading to the decrease of the drug content. In summary, it is of great significance to study a montelukast sodium orally disintegrating tablet which has good mechanical strength, fast disintegration rate and high stability in a humid environment and a preparation method thereof. SUMMARY

[0004] The application aims to provide a montelukast sodium tablet and a preparation method thereof, so as to solve the problems in the background.

[0005] In order to solve the above technical problems, the application provides the following technical scheme: a preparation method of a montelukast sodium tablet, comprising the following steps:

[0006] The binder is added into water, heated to 55-60 DEG C and uniformly stirred to obtain a binder mixture; the montelukast sodium, the stabilizer, the excipient and the disintegrant are added into water, uniformly stirred, then the binder mixture is added, uniformly stirred and sheared and emulsified, water is added again, uniformly stirred, sheared and emulsified, vacuum degassed, injected into a mold, frozen, dried to obtain the montelukast sodium tablet;

[0007] The disintegrant comprises modified tamarind gum, sodium carboxymethyl starch, amino acid modified sodium carboxymethyl starch and cross-linked sodium carboxymethyl starch.

[0008] More preferably, the montelukast sodium tablet comprises the following raw materials in mass fraction: 0.08-0.1 parts of the binder, 0.08-0.12 parts of the montelukast sodium, 0.01-0.02 parts of the stabilizer, 0.12-0.18 parts of the excipient, 0.03-0.04 parts of the disintegrant and 399.54-399.68 parts of water.

[0009] More preferably, the disintegrating agent is modified tamarind gum, sodium carboxymethyl starch, amino acid modified sodium carboxymethyl starch, and cross-linked sodium carboxymethyl starch in a mass ratio of (0.5-1):(1-1.5):(1-1.5):(0.1-0.2).

[0010] More preferably, the preparation of the modified tamarind gum comprises the following steps: adding sodium hydroxide into water-isopropyl alcohol, mixing uniformly, adding tamarind gum, stirring at 50-55°C for 2-3h, adding chloroacetic acid solution, stirring at 60-65°C for 3-4h, removing the solvent by suction filtration, washing, drying, and obtaining carboxylated tamarind gum; adding the carboxylated tamarind gum into water, adding calcium chloride aqueous solution, stirring until precipitation occurs, taking the precipitate, washing with water, drying, grinding, and sieving to obtain the modified tamarind gum.

[0011] More preferably, the carboxylated tamarind gum comprises the following raw materials in terms of mass fraction: 3-4 parts of sodium hydroxide, 8-12 parts of water, 25-30 parts of isopropyl alcohol, and 1.5-2 parts of tamarind gum; the pH of the chloroacetic acid solution is 3-4, and the chloroacetic acid solution comprises 7-8 parts of chloroacetic acid; the modified tamarind gum comprises the following raw materials in terms of mass fraction: 1.5-2 parts of carboxylated tamarind gum, 15-20 parts of water, and 25-30 parts of 5wt% calcium chloride aqueous solution.

[0012] The carboxymethylation of the modified tamarind gum can enhance its disintegrating performance, and the calcium complexation can improve its absorption capacity, thereby improving the disintegration rate.

[0013] More preferably, the preparation of the amino acid modified sodium carboxymethyl starch comprises the following steps: adding sodium carboxymethyl starch into water, stirring uniformly, adding leucine, stirring and adjusting the pH to 9-10, heating to 70-75°C and stirring for 1-2h, centrifuging to take the precipitate, washing, and freeze-drying to obtain the amino acid modified sodium carboxymethyl starch.

[0014] Leucine is a hydrophilic amino acid, and the additional hydrophilic sites on the starch molecules can also disrupt the original structure of the starch, so that the starch can rapidly swell in a shorter time and produce stronger disintegrating force, thereby improving the disintegration rate.

[0015] More preferably, the amino acid modified sodium carboxymethyl starch comprises the following raw materials in terms of mass fraction: 1.5-2 parts of sodium carboxymethyl starch, 5-6 parts of water, and 0.5-1 part of leucine.

[0016] More preferably, the preparation of the cross-linked sodium carboxymethyl starch comprises the following steps: taking sodium carboxymethyl starch, adding an ethanolic solution of epichlorohydrin, stirring uniformly, heating at 65-75°C for 15-20min, adjusting the pH to 6-7, filtering while hot, washing, drying, grinding, and sieving to obtain the cross-linked sodium carboxymethyl starch.

[0017] The cross-linked sodium carboxymethyl starch comprises the following raw materials in mass fraction: 1.5-2 parts of sodium carboxymethyl starch, 0.01-0.012 parts of epichlorohydrin, and 0.1-0.2 parts of ethanol.

[0018] More preferably, the adhesive is gelatin, the stabilizer is cyclodextrin, and the excipient is mannitol.

[0019] Compared with the prior art, the present application has the following beneficial effects: a special disintegrating agent is selected, which is a combination of modified tamarind gum, sodium carboxymethyl starch, amino acid modified sodium carboxymethyl starch, and cross-linked sodium carboxymethyl starch.

[0020] Tamarind gum is a polysaccharide gum with good biocompatibility. Its disintegration performance can be enhanced by carboxymethylation modification, and its absorption capacity can be improved by calcium complexation, thereby achieving rapid release and disintegration of the tablet. However, the amount of tamarind gum introduced should not be too much, otherwise the hardness and moisture resistance stability of the tablet will decrease, and if the hydrophilicity is too high, it will affect the disintegration rate.

[0021] Sodium carboxymethyl starch is a commonly used disintegrating agent. The disintegration speed and mechanical strength of sodium carboxymethyl starch need to be improved. Therefore, amino acid modified sodium carboxymethyl starch and cross-linked sodium carboxymethyl starch are introduced in the present application.

[0022] The amino acid modified sodium carboxymethyl starch introduces leucine, which increases the hydrophilic sites on the starch molecules and disrupts the original structure of the starch, so that the starch can rapidly swell in a shorter time and produce stronger disintegration force, thereby improving the disintegration speed.

[0023] The cross-linked sodium carboxymethyl starch produces strong mechanical stress by swelling, which rapidly destroys the binding force between particles, thereby facilitating rapid disintegration. In addition, the cross-linked structure can help improve the hardness and moisture resistance stability of the tablet as a whole. Therefore, the amount of each substance in the disintegrating agent needs to be strictly controlled, because too high hydrophilicity or too much cross-linked substance will slow down the disintegration rate.

[0024] In summary, by adding a specially designed disintegrating agent, the present application obtains a montelukast sodium tablet with good mechanical strength, fast disintegration speed, and high stability in a humid environment. DETAILED DESCRIPTION

[0025] The technical solutions in the embodiments of the present application will be described below in a clear and complete manner. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0026] It should be noted that there is no special restriction on the purchase manufacturer of all raw materials involved in the present application, which exemplarily includes: carboxymethyl starch sodium (pharmaceutical grade); tamarind gum (tamarind polysaccharide gum, food grade); gelatin, cyclodextrin, mannitol (pharmaceutical grade);

[0027] Unless otherwise specified, the following are all mass parts, mass ratio;

[0028] Example 1: S1: 1.8 parts of carboxymethyl starch sodium was added to 6 parts of water and stirred uniformly, 0.6 parts of leucine was added, stirred and adjusted to pH 10, heated to 75℃ and stirred for 1h, centrifuged for 10min, the precipitate was taken, washed, freeze-dried to obtain amino acid modified carboxymethyl starch sodium;

[0029] S2: 3 parts of sodium hydroxide, 10 parts of water, 30 parts of isopropyl alcohol were mixed uniformly, 2 parts of tamarind gum was added, stirred at 50℃ for 3h, chloroacetic acid solution (pH 3, containing 7 parts of chloroacetic acid) was added, stirred at 65℃ for 4h, filtered to remove the solvent, washed, 50 parts of water was added, adjusted to neutral pH, filtered to remove the solvent, washed, dried to obtain carboxylated tamarind gum; 1.8 parts of carboxylated tamarind gum was added to 20 parts of water, 26 parts of 5wt% calcium chloride aqueous solution was added, stirred until precipitation occurred, the precipitate was taken, washed with water, dried, ground through an 80 mesh sieve to obtain modified tamarind gum;

[0030] S3: 1.8 parts of carboxymethyl starch sodium was added to 0.01 parts of a mixed solution of epichlorohydrin and 0.2 parts of ethanol in a spray manner, stirred uniformly, heated in a microwave belt reactor at 70℃ for 20min, adjusted to pH 6, filtered while hot, washed with ethanol, dried, and ground through a 120 mesh sieve to obtain cross-linked carboxymethyl starch sodium;

[0031] S4: 0.1 parts of adhesive gelatin, 20 water were mixed, heated to 60℃ and stirred uniformly to obtain an adhesive mixture; 0.1 parts of montelukast sodium, 0.01 parts of stabilizer cyclodextrin, 0.15 parts of excipient mannitol, 0.04 parts of disintegrant, 20 parts of water were stirred uniformly, the adhesive mixture was added, stirred uniformly, sheared and emulsified at 3000r / min for 5min, 359.6 parts of water was added, stirred uniformly, sheared and emulsified at 3000r / min for 8min, vacuum degassed, the liquid medicine was injected into the bubble cap with a pipette, frozen at-60℃ for 10min, vacuum dried to obtain montelukast sodium tablets; the disintegrant is modified tamarind gum, carboxymethyl starch sodium, amino acid modified carboxymethyl starch sodium and cross-linked carboxymethyl starch sodium in a mass ratio of 0.8:1.2:1:0.15.

[0032] Example 2: S1: Take 1.5 parts of sodium carboxymethyl starch, add 6 parts of water and stir until uniform, add 0.5 parts of leucine, stir and adjust the pH to 10, heat to 75°C and stir for 1 h, centrifuge for 10 min and take the precipitate, wash, freeze-dry, and obtain amino acid modified sodium carboxymethyl starch;

[0033] S2: Mix 3 parts of sodium hydroxide, 8 parts of water, and 25 parts of isopropyl alcohol uniformly, add 1.5 parts of tamarind gum, stir at 50°C for 3 h, add a chloroacetic acid solution (pH 3, containing 7 parts of chloroacetic acid), stir at 65°C for 4 h, remove the solvent by suction filtration, wash, add 50 parts of water, adjust the pH to neutral, remove the solvent by suction filtration, wash, dry, and obtain carboxylated tamarind gum; take 1.5 parts of carboxylated tamarind gum, add 20 parts of water, add 25 parts of 5wt% calcium chloride aqueous solution, stir until precipitation occurs, take the precipitate, wash with water, dry, and grind through an 80-mesh sieve to obtain modified tamarind gum;

[0034] S3: Take 1.5 parts of sodium carboxymethyl starch, add a mixed solution of 0.01 parts of epichlorohydrin and 0.1 parts of ethanol in a spray manner, stir until uniform, heat in a microwave belt reactor at 70°C for 20 min, adjust the pH to 6, filter while hot, wash with ethanol, dry, and grind through a 120-mesh sieve to obtain cross-linked sodium carboxymethyl starch;

[0035] S4: Mix 0.1 parts of adhesive gelatin and 20 water, heat to 60°C and stir until uniform to obtain an adhesive mixture; take 0.1 parts of montelukast sodium, 0.01 parts of stabilizer cyclodextrin, 0.15 parts of excipient mannitol, 0.04 parts of disintegrant, 20 parts of water, stir until uniform, add the adhesive mixture, stir until uniform, shear emulsify at 3000 r / min for 5 min, add 359.6 parts of water, stir until uniform, shear emulsify at 3000 r / min for 8 min, vacuum degas, inject the liquid medicine into the bubble cap with a pipette, freeze at -60°C for 10 min, and vacuum dry to obtain montelukast sodium tablets; the disintegrant is a mixture of modified tamarind gum, sodium carboxymethyl starch, amino acid modified sodium carboxymethyl starch, and cross-linked sodium carboxymethyl starch at a mass ratio of 1:1:1:0.1.

[0036] Example 3: S1: Take 2 parts of sodium carboxymethyl starch, add 6 parts of water and stir until uniform, add 1 part of leucine, stir and adjust the pH to 10, heat to 75°C and stir for 1 h, centrifuge for 10 min and take the precipitate, wash, freeze-dry, and obtain amino acid modified sodium carboxymethyl starch;

[0037] S2: 4 parts of sodium hydroxide, 12 parts of water, 30 parts of isopropyl alcohol were mixed uniformly, 2 parts of tamarind gum was added, stirred at 50°C for 3h, chloroacetic acid solution (pH 3, containing 7 parts of chloroacetic acid) was added, stirred at 65°C for 4h, the solvent was removed by suction filtration, washed, 50 parts of water was added, the pH was adjusted to neutral, the solvent was removed by suction filtration, washed, dried, to obtain carboxylated tamarind gum; 2 parts of carboxylated tamarind gum was taken and added to 20 parts of water, 30 parts of 5wt% calcium chloride aqueous solution was added, stirred until precipitation occurred, the precipitate was taken, washed with water, dried, ground through an 80 mesh sieve, to obtain modified tamarind gum;

[0038] S3: 2 parts of carboxymethyl starch sodium was taken, a mixed solution of 0.012 parts of epichlorohydrin and 0.2 parts of ethanol was added in a spray manner, stirred uniformly, heated in a microwave belt reactor at 70°C for 20min, the pH was adjusted to 6, filtered while hot, washed with ethanol, dried, ground through a 120 mesh sieve, to obtain crosslinked carboxymethyl starch sodium;

[0039] S4: 0.1 parts of adhesive gelatin, 20 water were mixed, heated to 60°C and stirred uniformly, to obtain an adhesive mixture; 0.1 parts of montelukast sodium, 0.01 parts of stabilizer cyclodextrin, 0.15 parts of excipient mannitol, 0.04 parts of disintegrant, 20 parts of water were stirred uniformly, the adhesive mixture was added, stirred uniformly, sheared and emulsified at 3000r / min for 5min, 359.6 parts of water was added, stirred uniformly, sheared and emulsified at 3000r / min for 8min, vacuum degassed, the liquid medicine was injected into the bubble cap with a pipette, frozen at -60°C for 10min, vacuum dried, to obtain montelukast sodium tablets; the disintegrant was modified tamarind gum, carboxymethyl starch sodium, amino acid modified carboxymethyl starch sodium, crosslinked carboxymethyl starch sodium at a mass ratio of 1:1.5:1.5:0.1.

[0040] Comparative Example 1 (increasing the proportion of modified tamarind gum, the rest being the same as Example 1): S1: 1.8 parts of carboxymethyl starch sodium was taken, added to 6 parts of water and stirred uniformly, 0.6 parts of leucine was added, stirred and the pH was adjusted to 10, heated to 75°C and stirred for 1h, centrifuged for 10min, the precipitate was taken, washed, freeze-dried, to obtain amino acid modified carboxymethyl starch sodium;

[0041] S2: 3 parts of sodium hydroxide, 10 parts of water, 30 parts of isopropyl alcohol were mixed uniformly, 2 parts of tamarind gum was added, stirred at 50°C for 3h, chloroacetic acid solution (pH 3, containing 7 parts of chloroacetic acid) was added, stirred at 65°C for 4h, the solvent was removed by suction filtration, washed, 50 parts of water was added, the pH was adjusted to neutral, the solvent was removed by suction filtration, washed, dried, to obtain carboxylated tamarind gum; 1.8 parts of carboxylated tamarind gum was taken and added to 20 parts of water, 26 parts of 5wt% calcium chloride aqueous solution was added, stirred until precipitation occurred, the precipitate was taken, washed with water, dried, ground through an 80 mesh sieve, to obtain modified tamarind gum;

[0042] S3: Take 1.8 parts of sodium carboxymethyl starch, add a mixed solution of 0.01 parts of epichlorohydrin and 0.2 parts of ethanol in a spray manner, stir uniformly, heat in a microwave belt reactor at 70°C for 20 min, adjust the pH to 6, filter while hot, wash with ethanol, dry, and grind through a 120 mesh sieve to obtain cross-linked sodium carboxymethyl starch;

[0043] S4: Mix 0.1 parts of adhesive gelatin with 20 parts of water, heat to 60°C and stir uniformly to obtain an adhesive mixture; take 0.1 parts of montelukast sodium, 0.01 parts of stabilizer cyclodextrin, 0.15 parts of excipient mannitol, 0.04 parts of disintegrant, and 20 parts of water, stir uniformly, add the adhesive mixture, stir uniformly, shear emulsify at 3000 r / min for 5 min, add 359.6 parts of water, stir uniformly, shear emulsify at 3000 r / min for 8 min, vacuum degassing, inject the liquid medicine into the bubble cap with a pipette, freeze at -60°C for 10 min, vacuum dry to obtain montelukast sodium tablets; the disintegrant is modified tamarind gum, sodium carboxymethyl starch, amino acid modified sodium carboxymethyl starch, and cross-linked sodium carboxymethyl starch in a mass ratio of 1.2:1:0.8:0.15.

[0044] Comparative Example 2 (reduce the proportion of modified tamarind gum, the rest is the same as Example 1): S1: Take 1.8 parts of sodium carboxymethyl starch, add 6 parts of water and stir uniformly, add 0.6 parts of leucine, stir and adjust the pH to 10, heat to 75°C and stir for 1 h, centrifuge for 10 min to take the precipitate, wash, freeze-dry to obtain amino acid modified sodium carboxymethyl starch;

[0045] S2: Mix 3 parts of sodium hydroxide, 10 parts of water, and 30 parts of isopropyl alcohol uniformly, add 2 parts of tamarind gum, stir at 50°C for 3 h, add a chloroacetic acid solution (pH 3, containing 7 parts of chloroacetic acid), stir at 65°C for 4 h, filter to remove the solvent, wash, add 50 parts of water, adjust the pH to neutral, filter to remove the solvent, wash, dry to obtain carboxylated tamarind gum; take 1.8 parts of carboxylated tamarind gum, add 20 parts of water, add 26 parts of 5wt% calcium chloride aqueous solution, stir until precipitation occurs, take the precipitate, wash with water, dry, and grind through an 80 mesh sieve to obtain modified tamarind gum;

[0046] S3: Take 1.8 parts of sodium carboxymethyl starch, add a mixed solution of 0.01 parts of epichlorohydrin and 0.2 parts of ethanol in a spray manner, stir uniformly, heat in a microwave belt reactor at 70°C for 20 min, adjust the pH to 6, filter while hot, wash with ethanol, dry, and grind through a 120 mesh sieve to obtain cross-linked sodium carboxymethyl starch;

[0047] S4: 0.1 parts of the binder gelatin, 20 water were mixed, heated to 60°C and stirred to uniform, to obtain the binder mixture; 0.1 parts of montelukast sodium, 0.01 parts of stabilizer cyclodextrin, 0.15 parts of excipient mannitol, 0.04 parts of disintegrant, 20 parts of water were stirred to uniform, the binder mixture was added, stirred to uniform, sheared to emulsify at 3000 r / min for 5 min, 359.6 parts of water was added, stirred to uniform, sheared to emulsify at 3000 r / min for 8 min, vacuum degassing, the liquid medicine was injected into the bubble cap with a pipette, frozen at -60°C for 10 min, vacuum dried, to obtain montelukast sodium tablets; the disintegrant was modified tamarind gum, sodium carboxymethyl starch, amino acid modified sodium carboxymethyl starch and cross-linked sodium carboxymethyl starch at a mass ratio of 0.4:1.2:1.4:0.15.

[0048] Comparative Example 3 (increasing the proportion of cross-linked sodium carboxymethyl starch, the rest is the same as Example 1): S1: 1.8 parts of sodium carboxymethyl starch was added to 6 parts of water and stirred to uniform, 0.6 parts of leucine was added, stirred and adjusted to pH 10, heated to 75°C and stirred for 1 h, centrifuged for 10 min to take the precipitate, washed, freeze-dried to obtain amino acid modified sodium carboxymethyl starch;

[0049] S2: 3 parts of sodium hydroxide, 10 parts of water and 30 parts of isopropyl alcohol were mixed to uniform, 2 parts of tamarind gum was added, stirred at 50°C for 3 h, a chloroacetic acid solution (pH 3, containing 7 parts of chloroacetic acid) was added, stirred at 65°C for 4 h, the solvent was removed by suction filtration, washed, 50 parts of water was added, adjusted to neutral pH, the solvent was removed by suction filtration, washed and dried to obtain carboxylated tamarind gum; 1.8 parts of carboxylated tamarind gum was added to 20 parts of water, 26 parts of 5 wt% calcium chloride aqueous solution was added, stirred to precipitate, the precipitate was taken, washed with water, dried and ground to 80 mesh to obtain modified tamarind gum;

[0050] S3: 1.8 parts of sodium carboxymethyl starch was added to a mixed solution of 0.01 parts of epichlorohydrin and 0.2 parts of ethanol in a spray manner, stirred to uniform, heated at 70°C for 20 min in a microwave belt reactor, adjusted to pH 6, filtered while hot, washed with ethanol and dried, ground to 120 mesh to obtain cross-linked sodium carboxymethyl starch;

[0051] S4: 0.1 parts of the binder gelatin, 20 water were mixed, heated to 60℃ and stirred uniformly to obtain a binder mixture; 0.1 parts of montelukast sodium, 0.01 parts of stabilizer cyclodextrin, 0.15 parts of excipient mannitol, 0.04 parts of disintegrant, 20 parts of water were stirred uniformly, the binder mixture was added, stirred uniformly, sheared and emulsified at 3000 r / min for 5 min, 359.6 parts of water was added, stirred uniformly, sheared and emulsified at 3000 r / min for 8 min, vacuum degassing, the liquid medicine was injected into the bubble cap with a pipette, frozen at -60℃ for 10 min, vacuum dried to obtain montelukast sodium tablets; the disintegrant was modified tamarind gum, carboxymethyl starch sodium, amino acid modified carboxymethyl starch sodium and cross-linked carboxymethyl starch sodium in a mass ratio of 0.8:1:1:0.35.

[0052] Comparative Example 4 (remove cross-linked carboxymethyl starch sodium, the rest is the same as Example 1): S1: 1.8 parts of carboxymethyl starch sodium was added into 6 parts of water and stirred uniformly, 0.6 parts of leucine was added, stirred and the pH was adjusted to 10, the temperature was raised to 75℃ and stirred for 1 h, the precipitate was taken after centrifugation for 10 min, washed, freeze-dried to obtain amino acid modified carboxymethyl starch sodium;

[0053] S2: 3 parts of sodium hydroxide, 10 parts of water and 30 parts of isopropyl alcohol were mixed uniformly, 2 parts of tamarind gum was added, stirred at 50℃ for 3 h, chloroacetic acid solution (pH 3, containing 7 parts of chloroacetic acid) was added, stirred at 65℃ for 4 h, the solvent was removed by suction filtration, washed, 50 parts of water was added, the pH was adjusted to neutral, the solvent was removed by suction filtration, washed and dried to obtain carboxylated tamarind gum; 1.8 parts of carboxylated tamarind gum was added into 20 parts of water, 26 parts of 5wt% calcium chloride aqueous solution was added, stirred until the precipitate was produced, the precipitate was taken, washed with water, dried, ground through an 80 mesh sieve to obtain modified tamarind gum;

[0054] S3: 1.8 parts of carboxymethyl starch sodium was added into a mixed solution of 0.01 parts of epichlorohydrin and 0.2 parts of ethanol in a spraying manner, stirred uniformly, heated at 70℃ for 20 min in a microwave belt reactor, the pH was adjusted to 6, filtered while hot, washed with ethanol and dried, passed through a 120 mesh sieve to obtain cross-linked carboxymethyl starch sodium;

[0055] S4: 0.1 parts of adhesive gelatin, 20 water were mixed, heated to 60 DEG C and stirred uniformly to obtain an adhesive mixture; 0.1 parts of montelukast sodium, 0.01 parts of stabilizer cyclodextrin, 0.15 parts of excipient mannitol, 0.04 parts of disintegrant, 20 parts of water were stirred uniformly, the adhesive mixture was added, stirred uniformly, sheared and emulsified at 3000 r / min for 5 min, 359.6 parts of water was added, stirred uniformly, sheared and emulsified at 3000 r / min for 8 min, vacuum degassing, the liquid medicine was injected into the bubble cap with a pipette, frozen at-60 DEG C for 10 min, vacuum dried to obtain montelukast sodium tablets; the disintegrant was modified tamarind gum, carboxymethyl starch sodium and amino acid modified carboxymethyl starch sodium with a mass ratio of 0.8:1.2:1.

[0056] Performance test 1: take the montelukast sodium tablets prepared in examples 1-3 and comparative examples 1-4; (1) according to the fourth part of Chinese Pharmacopoeia 2020, the disintegration time was tested; (2) the hardness was measured with a tablet hardness tester; (3) the tablets were placed in an environment with a relative humidity of 75% for ten days, and the increased mass due to moisture absorption was tested; see table 1 for details;

[0057] Table 1:

[0058]

[0059] In comparative example 1, the proportion of modified tamarind gum was increased, the hardness decreased and the moisture resistance stability decreased; in comparative example 2, the proportion of tamarind gum was reduced, the disintegration rate was slow; in comparative example 3, the proportion of cross-linked carboxymethyl starch sodium was increased, the hardness increased but the disintegration rate was too slow; in comparative example 4, the proportion of cross-linked carboxymethyl starch sodium was reduced, which also affected the disintegration time, and the moisture resistance stability decreased; in summary, the raw materials and their proportions of the disintegrant are important, the montelukast sodium tablets prepared by the present scheme have good mechanical strength, fast disintegration rate and high stability.

[0060] Finally, it should be noted that: the above only describes the preferred embodiments of the present application and is not intended to limit the present application, although the present application has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some technical features. Any modification, equivalent substitution, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing montelukast sodium tablets, characterized in that: Includes the following steps: S1: Mix modified tamarind gum, sodium carboxymethyl starch, amino acid-modified sodium carboxymethyl starch, and cross-linked sodium carboxymethyl starch to obtain a disintegrant; S2: Add the adhesive to water, heat and stir evenly to obtain an adhesive mixture; add montelukast sodium, stabilizer, excipient and disintegrant to water, stir evenly, add the adhesive mixture, stir evenly, shear emulsify, add water again, stir evenly, shear emulsify, vacuum degas, inject into mold, freeze and dry to obtain montelukast sodium tablets. The preparation of the modified tamarind gum includes the following steps: sodium hydroxide is added to water-isopropanol and mixed evenly, tamarind gum is added, and the mixture is stirred at 50-55℃ for 2-3 hours. Then, chloroacetic acid solution is added and stirred at 60-65℃ for 3-4 hours. The solvent is removed by filtration, and the mixture is washed and dried to obtain carboxylated tamarind gum. The carboxylated tamarind gum is added to water, and calcium chloride aqueous solution is added. The mixture is stirred until a precipitate is formed. The precipitate is taken, washed with water, dried, ground, and sieved to obtain modified tamarind gum. The preparation of the amino acid-modified carboxymethyl starch sodium includes the following steps: adding carboxymethyl starch sodium to water and stirring evenly, adding leucine, adjusting the pH to 9-10, heating to 70-75℃ and stirring for 1-2 hours, centrifuging to collect the precipitate, washing, and freeze-drying to obtain amino acid-modified carboxymethyl starch sodium; The disintegrant is composed of modified tamarind gum, sodium carboxymethyl starch, amino acid-modified sodium carboxymethyl starch, and cross-linked sodium carboxymethyl starch in a mass ratio of (0.5~1):(1~1.5):(1~1.5):(0.1~0.2).

2. The method for preparing montelukast sodium tablets according to claim 1, characterized in that: The montelukast sodium tablets comprise the following raw materials, in 400 parts by weight: 0.08-0.1 parts binder, 0.08-0.12 parts montelukast sodium, 0.01-0.02 parts stabilizer, 0.12-0.18 parts excipient, 0.03-0.04 parts disintegrant, with the remainder being water.

3. The method for preparing montelukast sodium tablets according to claim 1, characterized in that: The carboxylated tamarind gum comprises the following raw materials, by mass parts: 3-4 parts sodium hydroxide, 8-12 parts water, 25-30 parts isopropanol, and 1.5-2 parts tamarind gum; the chloroacetic acid solution has a pH of 3-4 and contains 7-8 parts chloroacetic acid; the modified tamarind gum comprises the following raw materials, by mass parts: 1.5-2 parts carboxylated tamarind gum, 15-20 parts water, and 25-30 parts 5 wt% calcium chloride aqueous solution.

4. The method for preparing montelukast sodium tablets according to claim 1, characterized in that: The amino acid-modified sodium carboxymethyl starch comprises the following raw materials, by mass: 1.5-2 parts sodium carboxymethyl starch, 5-6 parts water, and 0.5-1 parts leucine.

5. The method for preparing montelukast sodium tablets according to claim 1, characterized in that: The preparation of the cross-linked carboxymethyl starch sodium includes the following steps: taking carboxymethyl starch sodium, adding epichlorohydrin ethanol solution, stirring evenly, heating at 65~75℃ for 15~20 min, adjusting pH to 6~7, filtering while hot, washing, drying, grinding and sieving to obtain cross-linked carboxymethyl starch sodium; the cross-linked carboxymethyl starch sodium includes the following raw materials, by mass parts: 1.5~2 parts carboxymethyl starch sodium, 0.01~0.012 parts epichlorohydrin, and 0.1~0.2 parts ethanol.

6. The method for preparing montelukast sodium tablets according to claim 1, characterized in that: The adhesive is gelatin, the stabilizer is cyclodextrin, and the excipient is mannitol.

7. Montelukast sodium tablets prepared by the method for preparing montelukast sodium tablets according to any one of claims 1 to 6.

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