Bromhexine hydrochloride direct-take granules and preparation method thereof

Abstract

The present invention provides a bromhexine hydrochloride direct-take granules and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The bromhexine hydrochloride direct-take granules include the following components by weight percentage: the following components by weight percentage: bromhexine hydrochloride 1.3-2.0%; filler 90-95%; disintegrant 2-3%; binder 0.3-0.7%; coating agent 3-4.5%; bulk drug particle size D90 <50 μm; the mass ratio of the disintegrant and the binder is 4-10:1. The present invention provides a bromhexine hydrochloride direct-take granules through a specific raw material ratio and process, which is convenient for patients with difficulty in taking medicine. At the same time, the bromhexine hydrochloride direct-take granules provided by the present invention also have the advantages of high powder quality, good dissolution performance, high content of active ingredients and content uniformity, and good particle stability.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to bromhexine hydrochloride direct-take granules and a preparation method thereof. Background Art

[0002] Bromhexine hydrochloride is an organic compound with the chemical formula C 14 H 21 Br2ClN2 can directly act on bronchial glands, promote the release of lysosomes in mucus-secreting cells, differentiate and lyse mucopolysaccharide fibers in sputum, and inhibit the synthesis of acidic glycoproteins in mucus glands and goblet cells, causing them to secrete small-molecule glycoproteins with lower viscosity, thereby reducing the viscosity of sputum and making it easier to cough up.

[0003] Chinese patent CN117017931A discloses a method for preparing bromhexine hydrochloride tablets, comprising the following steps: S1 beating: dissolving corn starch in water, adding boiling water to make corn starch slurry; the amount of corn starch used is 6-10wt% of the corn starch slurry; S2 material mixing: adding bromhexine hydrochloride, corn starch, powdered sugar, and sodium carboxymethyl starch to mix evenly, and then adding the corn starch slurry prepared in step S1 to mix and stir for granulation; S3 drying: drying the wet granules prepared in step S2 to a temperature of 30-35°C and then discharging the material, and the moisture content of the material is 1.5-3wt%; S4 granulation: the granulation screen uses a 16-18 mesh screen. S5 tableting: the granules after granulation are mixed with a lubricant and tableted to obtain bromhexine hydrochloride tablets; the dissolution rate of the bromhexine hydrochloride tablets obtained by the preparation method is up to 88.43%, which has a high dissolution rate.

[0004] Direct-take granules, also known as water-free swallow granules, are a new type of oral solid dosage form. Unlike common granules or dry suspensions, direct-take granules do not need to be taken with water, but are placed directly in the mouth and taken directly with secreted saliva. The realization of this dosage form requires powerful taste-masking technology and high requirements for excipients. Its advantage is that it is easy to use for children and patients who have difficulty taking medicine.

[0005] Chinese patent CN116785245A discloses a heat-clearing and detoxifying granule that can be directly swallowed. The raw materials for preparation include 800-810 parts of original drug granules, 180-200 parts of coating, and 10-13 parts of mixed granules by weight. The invention can reduce the surface hygroscopicity of the coating agent and improve the stability of the granules in a high temperature and high humidity oral environment by using Eudragit EPO polymethacrylate copolymer and stearic acid. The invention masks the bitterness and astringency by coating, and the prepared granules can be directly swallowed orally, avoiding the inconvenience of using granules, and there is no bitterness within 2 minutes after being put into the mouth. The process has good repeatability and is stable and can be mass-produced.

[0006] However, there are few studies on bromhexine hydrochloride direct-take granules, and therefore there is an urgent need to develop bromhexine hydrochloride direct-take granules and a preparation method thereof to make up for the shortcomings in this field. Summary of the invention

[0007] Based on the deficiencies of the prior art, the present invention aims to provide a bromhexine hydrochloride direct-take granules and a preparation method thereof, and by controlling the type, content and ratio of auxiliary materials, the obtained bromhexine hydrochloride direct-take granules have good stability and high solubility.

[0008] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0009] A bromhexine hydrochloride direct-take granule comprises the following components by weight percentage: 1.3-2.0% bromhexine hydrochloride; 90-95% filler; 2-3% disintegrant; 0.3-0.7% binder; 3-4.5% coating agent; and the particle size D90 of the raw material medicine is less than 50 μm.

[0010] The filler is selected from one or more of lactose monohydrate, mannitol, xylitol, sorbitol, starch, calcium hydrogen phosphate and microcrystalline cellulose;

[0011] Preferably, the filler is a mixture of lactose monohydrate, mannitol, xylitol and sorbitol;

[0012] More preferably, the filler is a mixture of lactose monohydrate, xylitol and mannitol;

[0013] Further preferably, the mass ratio of lactose monohydrate, xylitol and mannitol is 1:1.8-4:1.8-4;

[0014] Still more preferably, the mass ratio of the lactose monohydrate, xylitol and mannitol is 1:2.25:2.5.

[0015] The disintegrant is selected from one or more of pregelatinized starch, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch and polyvinylpyrrolidone;

[0016] Preferably, the disintegrant is one or more of cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone and sodium carboxymethyl starch;

[0017] More preferably, the disintegrant is cross-linked polyvinylpyrrolidone.

[0018] The adhesive is hypromellose.

[0019] The coating agent is hydroxypropyl methylcellulose or hydroxypropyl cellulose.

[0020] As some preferred embodiments, the mass ratio of the disintegrant to the binder is 4-10:1; preferably, the mass ratio of the disintegrant to the binder is 6:1.

[0021] The present invention also provides a method for preparing the bromhexine hydrochloride direct-take granules, comprising the following steps:

[0022] (1) Add the adhesive into hot water and dissolve it to obtain an adhesive solution for later use;

[0023] (2) Pass part of the filler through a 60-mesh sieve and set aside;

[0024] (3) adding bromhexine hydrochloride and the remaining filler into a wet granulator, and then adding the sieved filler and stirring; then adding a disintegrant and continuing to stir to obtain a mixture 1;

[0025] (4) adding the binder solution into the wet granulator and continuing to stir to obtain a mixture 2;

[0026] (5) Transferring the mixture 2 into a swing granulator for granulation, and then drying the mixture to obtain granules to be coated;

[0027] (6) Placing the granules to be coated in a fluidized bed, pumping in a coating liquid for coating, and finally drying to obtain the bromhexine hydrochloride direct-take granules.

[0028] in,

[0029] The hot water temperature in step (1) is 80-100°C;

[0030] The stirring parameters in step (3) are: stirring paddle speed 100-150 rpm, cutting blade speed 250-400 rpm, premixing 5-10 min;

[0031] Preferably, the stirring parameters in step (3) are: stirring paddle speed 120 rpm, cutter speed 300 rpm, and premixing for 5 minutes.

[0032] The stirring parameters in step (4) are: stirring paddle speed 350-420 rpm, cutting blade speed 500-650 rpm, stirring time 10-20 min;

[0033] Preferably, the stirring parameters in step (4) are: stirring paddle speed 400 rpm, cutting blade speed 600 rpm, stirring time 15 min;

[0034] The time for adding the binder solution described in step (4) into the wet granulator should be controlled within 60 seconds.

[0035] The particle size of the swing granulator in step (5) is 18 mesh;

[0036] The drying parameters described in step (5) are: inlet air temperature is 55-75°C, material temperature is 30-40°C, fan frequency is 10-40Hz, and drying is stopped when LOD is less than 2.0%.

[0037] The parameters of the fluidized bed described in step (6) are: inlet air temperature: 55-75°C, material temperature 30-40°C, fan frequency: 10-40Hz, liquid supply speed: 3-12rpm, atomization pressure: 1.5-2bar.

[0038] The drying air inlet temperature in step (6) is 50-70°C and the drying time is 5-20 minutes.

[0039] Compared with the prior art, the present invention has the following beneficial effects:

[0040] (1) The present invention provides bromhexine hydrochloride direct-take granules through a specific raw material ratio and process, which is convenient for patients who have difficulty taking medicine. At the same time, the bromhexine hydrochloride direct-take granules provided by the present invention also have the advantages of high powder quality, good dissolution performance, high active ingredient content and content uniformity, and good particle stability.

[0041] (2) The present invention uses a mixture of lactose monohydrate, xylitol and mannitol as a filler, and controls the mass ratio of the three to be 1:1.5-4:1.5-4, which can effectively mask the bitter taste of bromhexine hydrochloride, so that the obtained bromhexine hydrochloride direct-take granules have a suitable taste and meet the requirements of direct-take granules, and the user satisfaction and comfort are significantly improved; in addition, during the implementation of the present invention, it was unexpectedly found that the use of lactose monohydrate, xylitol and mannitol in a mass ratio of 1:1.8-4:1.8-4 as a filler can significantly improve the stability of bromhexine hydrochloride direct-take granules;

[0042] (3) The present invention can significantly improve the stability and dissolution efficiency of the granules by controlling the mass ratio of the disintegrant to the binder to be 4-10:1, so that the stability of the obtained direct-take granules is significantly improved on the basis of meeting the dissolution requirements;

[0043] (4) In the preparation process of the present invention, various components are added in batches and the rotation speed is reasonably controlled, so that the uniformity of the prepared granules is significantly improved. DETAILED DESCRIPTION

[0044] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly used in the field to which the present invention belongs. For the purpose of interpreting this specification, the following definitions will apply, and where appropriate, terms used in the singular will also include the plural form, and vice versa.

[0045] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with embodiment. If the specific conditions are not specified in the embodiment, it is carried out according to the conditions recommended by normal conditions or manufacturers. If the manufacturer is not specified in all reagents or instruments, they are all conventional products that can be purchased commercially. In order to better illustrate the present invention, numerous specific details are provided in the specific embodiments below. The specific embodiments described herein are only used to explain the present invention and are not intended to constitute any limitation of the present invention. In addition, in the following description, the description of known structures and technologies is omitted to avoid unnecessary confusion of the concept of the present invention. Such structures and technologies are also described in many publications.

[0046] The following raw material types, models, functions and their standards or sources. N / A means no restrictions on the model:

[0047]

[0048] Example 1 A kind of bromhexine hydrochloride direct-take granules and preparation method thereof

[0049] The recipe is as follows:

[0050]

[0051] Preparation method:

[0052] (1) Add the adhesive into 80°C hot water to dissolve it to obtain an adhesive solution for later use;

[0053] (2) Pass xylitol and mannitol through a 60-mesh sieve and set aside;

[0054] (3) Add bromhexine hydrochloride and lactose monohydrate to a wet granulator, then add sieved mannitol and xylitol and stir, the stirring paddle speed is 120 rpm, the premixing shear (cutter) speed is 300 rpm, and the premixing time is 5 minutes; then add a disintegrant and continue stirring, the stirring paddle speed is 120 rpm, the premixing shear (cutter) speed is 300 rpm, and the premixing time is 5 minutes; obtain a mixture 1;

[0055] (4) Add the binder solution into the wet granulator and continue stirring at a stirring speed of 400 rpm and a cutting blade speed of 600 rpm for 15 min to obtain a mixture 2;

[0056] (5) Transfer the mixture 2 into a swing granulator for granulation, and then dry it. The air inlet temperature is 60°C, the material temperature is 30-40°C, and the fan frequency is 30 Hz. Drying is stopped when LOD is less than 2.0% to obtain the granules to be coated.

[0057] (6) Placing the granules to be coated in a fluidized bed, setting the fan frequency to 30 Hz, the material temperature to 30-40°C, the liquid supply speed to 3-12 rpm, the atomization pressure to 2.0 bar, pumping in the coating liquid for coating, and finally drying, with the air inlet temperature at 60°C and the drying time for 10 min. Passing through an 80-mesh sieve, the bromhexine hydrochloride direct-take granules are obtained.

[0058] Example 2 A kind of bromhexine hydrochloride direct-take granules and preparation method thereof

[0059] The recipe is as follows:

[0060]

[0061] Preparation method:

[0062] (1) Add the adhesive into 80°C hot water to dissolve it to obtain an adhesive solution for later use;

[0063] (2) Pass xylitol and mannitol through a 60-mesh sieve and set aside;

[0064] (3) Add bromhexine hydrochloride and lactose monohydrate to a wet granulator, then add sieved mannitol and xylitol and stir, the stirring paddle speed is 120 rpm, the premixing shear (cutter) speed is 300 rpm, and the premixing time is 5 minutes; then add a disintegrant and continue stirring, the stirring paddle speed is 120 rpm, the premixing shear (cutter) speed is 300 rpm, and the premixing time is 5 minutes; obtain a mixture 1;

[0065] (4) Add the binder solution into the wet granulator and continue stirring at a stirring speed of 400 rpm and a cutting blade speed of 600 rpm for 15 min to obtain a mixture 2;

[0066] (5) Transfer the mixture 2 into a swing granulator for granulation, and then dry it. The air inlet temperature is 60°C, the material temperature is 30-40°C, and the fan frequency is 30 Hz. Drying is stopped when LOD is less than 2.0% to obtain the granules to be coated.

[0067] (6) Placing the granules to be coated in a fluidized bed, setting the fan frequency to 30 Hz, the material temperature to 30-40°C, the liquid supply speed to 3-12 rpm, the atomization pressure to 2.0 bar, pumping in the coating liquid for coating, and finally drying, with the air inlet temperature at 60°C and the drying time for 10 min. Passing through an 80-mesh sieve, the bromhexine hydrochloride direct-take granules are obtained.

[0068] Example 3 A Bromhexine Hydrochloride Direct-Oral Granule and Its Preparation Method

[0069] The recipe is as follows:

[0070]

[0071] Preparation method:

[0072] (1) Add the adhesive into 80°C hot water to dissolve it to obtain an adhesive solution for later use;

[0073] (2) Pass xylitol and mannitol through a 60-mesh sieve and set aside;

[0074] (3) Add bromhexine hydrochloride and lactose monohydrate to a wet granulator, then add sieved mannitol and xylitol and stir, the stirring paddle speed is 120 rpm, the premixing shear (cutter) speed is 300 rpm, and the premixing time is 5 minutes; then add a disintegrant and continue stirring, the stirring paddle speed is 120 rpm, the premixing shear (cutter) speed is 300 rpm, and the premixing time is 5 minutes; obtain a mixture 1;

[0075] (4) Add the binder solution into the wet granulator and continue stirring at a stirring speed of 400 rpm and a cutting blade speed of 600 rpm for 15 min to obtain a mixture 2;

[0076] (5) Transfer the mixture 2 into a swing granulator for granulation, and then dry it. The air inlet temperature is 60°C, the material temperature is 30-40°C, and the fan frequency is 30 Hz. Drying is stopped when LOD is less than 2.0% to obtain the granules to be coated.

[0077] (6) Placing the granules to be coated in a fluidized bed, setting the fan frequency to 30 Hz, the material temperature to 30-40°C, the liquid supply speed to 3-12 rpm, the atomization pressure to 2.0 bar, pumping in the coating liquid for coating, and finally drying, with the air inlet temperature at 60°C and the drying time for 10 min. Passing through an 80-mesh sieve, the bromhexine hydrochloride direct-take granules are obtained.

[0078] Example 4 A Bromhexine Hydrochloride Direct-Oral Granule and Its Preparation Method

[0079] The recipe is as follows:

[0080]

[0081] Preparation method:

[0082] (1) Add the adhesive into 80°C hot water to dissolve it to obtain an adhesive solution for later use;

[0083] (2) Pass xylitol and mannitol through a 60-mesh sieve and set aside;

[0084] (3) Add bromhexine hydrochloride and lactose monohydrate to a wet granulator, then add sieved mannitol and xylitol and stir, the stirring paddle speed is 120 rpm, the premixing shear (cutter) speed is 300 rpm, and the premixing time is 5 minutes; then add a disintegrant and continue stirring, the stirring paddle speed is 120 rpm, the premixing shear (cutter) speed is 300 rpm, and the premixing time is 5 minutes; obtain a mixture 1;

[0085] (4) Add the binder solution into the wet granulator and continue stirring at a stirring speed of 400 rpm and a cutting blade speed of 600 rpm for 15 min to obtain a mixture 2;

[0086] (5) Transfer the mixture 2 into a swing granulator for granulation, and then dry it. The air inlet temperature is 60°C, the material temperature is 30-40°C, and the fan frequency is 30 Hz. Drying is stopped when LOD is less than 2.0% to obtain the granules to be coated.

[0087] (6) Placing the granules to be coated in a fluidized bed, setting the fan frequency to 30 Hz, the material temperature to 30-40°C, the liquid supply speed to 3-12 rpm, the atomization pressure to 2.0 bar, pumping in the coating liquid for coating, and finally drying, with the air inlet temperature at 60°C and the drying time for 10 min. Passing through an 80-mesh sieve, the bromhexine hydrochloride direct-take granules are obtained.

[0088] Comparative Example 1

[0089] The difference from Example 3 is that the mass ratio of lactose monohydrate, xylitol and mannitol is 1:1.5:1.5, and the total amount of filler is the same as that in Example 3, namely 22.5% lactose monohydrate, 33.75% xylitol and 33.75% mannitol. The other steps and operations are the same as those in Example 3.

[0090] Comparative Example 2

[0091] The difference from Example 3 is that the mass ratio of disintegrant to binder is 3:1, and the other steps and operations are the same as those in Example 3.

[0092] Comparative Example 3

[0093] The difference from Example 3 is that the mass ratio of disintegrant to binder is 1:11.5, and the other steps and operations are the same as those in Example 3.

[0094] Comparative Example 4

[0095] The difference from Example 3 is that the stirring parameters of step (3) are: the stirring paddle speed is 80 rpm, the premixing shear (cutter) speed is 400 rpm; the stirring parameters of step (4) are: the stirring paddle speed is 200 rpm, the chopper speed is 700 rpm; the other steps and operations are the same as those of Example 3.

[0096] Performance data:

[0097] 1. Dissolution test

[0098] Detection method:

[0099] ① pH4.5, pH6.8 medium: paddle method 50rpm, 900ml;

[0100] ② pH 1.2 medium: add 0.2% NaCl, paddle method 50 rpm, 900 ml;

[0101] The test results are shown in Table 1-2 below.

[0102] Table 1 Dissolution of bromhexine hydrochloride direct-dose granules prepared in Example 1 at pH 1.2, pH 4.5 and pH 6.8

[0103]

[0104] According to the test results in Table 1 above, the bromhexine hydrochloride direct-take granules prepared in Example 1 are rapidly dissolved in pH 1.2 and pH 4.5 media, and are incompletely dissolved in pH 6.8 media. It can be seen that the bromhexine hydrochloride direct-take granules prepared by the present invention can be rapidly dissolved in pH 1.2 and pH 4.5 media, and are incompletely dissolved in pH 6.8 media, so the subsequent examples only detect pH 1.2 media.

[0105] Table 2 Dissolution of bromhexine hydrochloride direct-dose granules prepared in Examples 2-4 and Comparative Examples 1-4 at pH 1.2

[0106]

[0107] According to the test data in Table 2 above, the bromhexine hydrochloride direct-take granules prepared in Examples 2-4 of the present invention can be quickly dissolved in a pH 1.2 medium; the bromhexine hydrochloride direct-take granules prepared in Comparative Example 1 can be quickly dissolved in a pH 1.2 medium, while the bromhexine hydrochloride direct-take granules prepared in Comparative Examples 2-4 cannot be quickly dissolved in a pH 1.2 medium, indicating that the mass ratio of the binder to the disintegrant, and the stirring speed during the preparation process will affect the dissolution efficiency of the bromhexine hydrochloride direct-take granules.

[0108] 2. Stability test

[0109] The conditions of the accelerated experiment are: 40℃±2℃ / 75%RH±5%RH, and the observation period is 6 months.

[0110] Test method: Use high performance liquid chromatography, the chromatographic column is Welch Utimate XB-C18, 4.6mm×150mm, 5μm or chromatographic column of equivalent performance, the mobile phase is acetonitrile: ammonium formate buffer solution (40:60), (ammonium formate buffer preparation: dissolve 1.26g ammonium formate in 950ml water, adjust to pH 4.4 with formic acid, and dilute to 1000mL with water); flow rate is 1.0ml / min, injection volume is 50μl, column temperature is 30℃, detection wavelength is 248nm, and running time is twice the retention time of the main component peak.

[0111] The test results are shown in Table 3 below.

[0112] Table 3

[0113]

[0114] According to the test results in Table 3 above, the bromhexine hydrochloride direct-take granules prepared in Examples 1-4 of the present invention have good stability, and the impurity content after accelerated 6 months still meets the requirements; while changing the mass ratio of the filler in Comparative Example 1 significantly affects the stability of the bromhexine hydrochloride direct-take granules, and the impurity content after accelerated 6 months significantly increases, resulting in the bromhexine hydrochloride direct-take granules not meeting the requirements.

[0115] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A bromhexine hydrochloride direct-take granule, characterized in that: The composition is composed of the following components by weight percentage: bromhexine hydrochloride 1.3-2.0%; filler 90-95%; disintegrant 2-3%; binder 0.3-0.7%; coating agent 3-4.5%, the sum of the weight percentages of the components is 100%; the particle size of the raw material drug D90 is less than 50 μm; The mass ratio of the disintegrant to the binder is 4-10:1; The filler is a mixture of lactose monohydrate, xylitol and mannitol, and the mass ratio of the three is 1:1.8-4:1.8-4; The binder is hypromellose; The disintegrant is cross-linked polyvinylpyrrolidone; The preparation method of the bromhexine hydrochloride direct-take granules comprises the following steps: (1) Add the adhesive into hot water and dissolve it to obtain an adhesive solution for later use; (2) Pass part of the filler through a 60-mesh sieve and set aside; (3) adding bromhexine hydrochloride and the remaining filler into a wet granulator, and then adding the sieved filler and stirring; then adding a disintegrant and continuing to stir to obtain a mixture 1; (4) adding the binder solution into the wet granulator and continuing to stir to obtain a mixture 2; (5) Transferring the mixture 2 into a swing granulator for granulation, and then drying the mixture to obtain granules to be coated; (6) placing the granules to be coated in a fluidized bed, pumping in a coating liquid for coating, and finally drying to obtain the bromhexine hydrochloride direct-take granules; The stirring parameters in step (3) are: stirring paddle speed 100-150 rpm, cutting blade speed 250-400 rpm, premixing 5-10 min; The stirring parameters described in step (4) are: stirring paddle speed 350-420 rpm, cutter speed 500-650 rpm, and stirring time 10-20 min.

2. Bromhexine hydrochloride direct-take granules according to claim 1, characterized in that: The mass ratio of the lactose monohydrate, xylitol and mannitol is 1:2.25:2.

5.

3. Bromhexine hydrochloride direct-take granules according to claim 1, characterized in that: The coating agent is hydroxypropyl methylcellulose or hydroxypropyl cellulose.

4. Bromhexine hydrochloride direct-take granules according to claim 1, characterized in that: The mass ratio of the disintegrant to the binder is 6:

1.

5. Bromhexine hydrochloride direct-take granules according to claim 1, characterized in that: The drying parameters described in step (5) are: inlet air temperature of 55-75°C, material temperature of 30-40°C, fan frequency of 10-40Hz, and drying is stopped when LOD is less than 2.0%. The parameters of the fluidized bed described in step (6) are: inlet air temperature: 55-75°C, material temperature of 30-40°C, fan frequency: 10-40Hz, liquid supply speed: 3-12rpm, and atomization pressure: 1.5-2bar.

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