A pharmaceutical composition containing carbocisteine and a preparation method thereof

Abstract

The present invention discloses a pharmaceutical composition containing carbocisteine, which comprises carbocisteine, a filler, a binder, a disintegrant, a lubricant and a surfactant. The particle size of the carbocisteine is 50 μm ≤ D90 ≤ 95 μm, and the bulk density is 1.00 - 1.10 g / cm 3 , and the tapped density is 1.10 - 1.30 g / cm 3 . The mass ratio of the filler to the binder is 1:0.7 - 1. When the mass portion of carbocisteine is 1, the dosage of the surfactant is 0.003 - 0.005 portions. The carbocisteine raw material prepared by the method of the present invention meets the requirements of subsequent formulation processes, and its powder properties are beneficial to realizing the direct powder compression process, and there are no phenomena such as sticking to the punch and capping during the tabletting process. The quality is qualified and stable. The process of the present invention is simple in operation, suitable for commercial scale production, and has great application value.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations. In particular, the present invention relates to a pharmaceutical composition containing carbocysteine and a preparation method thereof. Background Art

[0002] Carbocysteine is an expectorant and antitussive drug used for treating cough and expectoration caused by diseases such as chronic bronchitis and bronchial asthma. In addition, it can be used for non-suppurative otitis media in children to prevent deafness. The chemical name of carbocysteine is S-(carboxymethyl)cysteine, with the molecular formula C5H9NO4S and a molecular weight of 179.19. The structural formula of carbocysteine is:

[0003]

[0004] Currently, the commercially available carbocysteine is mainly in the form of tablets, oral solutions, and granules. Among them, carbocysteine tablets are widely used in clinical practice due to their convenience in carrying, taking, and high oral bioavailability.

[0005] Chinese Patent CN202010346870.X published on September 8, 2020, discloses a preparation process and equipment for carbocysteine tablets. Its prescription is: 1000 parts of carbocysteine, 120 parts of corn starch, 200 parts of pregelatinized starch, 2800 parts of powdered sugar, 200 parts of low-substituted hydroxypropyl cellulose, 500 parts of 30% ethanol, 16.5 parts of magnesium stearate, 120 parts of sodium carboxymethyl starch, 120 parts of microcrystalline cellulose, 15 parts of steviol glycoside, and 3 parts of pineapple essence. The preparation method is wet granulation.

[0006] Lu Dan et al. published "Process Research on Rapid-Release Carbocysteine Tablets". This literature discloses a rapid-release carbocysteine tablet with the following prescription: 250 g of carbocysteine, 12.8 g of sodium carboxymethyl starch, 2.56 g of sodium dodecyl sulfate, 7.5 g of polyvinylpyrrolidone, 43.94 g of other excipients, and 3.2 g of magnesium stearate, and a total of 1000 tablets are prepared. The preparation method is wet granulation.

[0007] Chinese Patent CN202110353601.0 discloses a preparation method for carbocysteine raw material medicine. The carbocysteine raw material medicine prepared by this method meets the requirements of subsequent preparation processes in terms of particle size, density, and fluidity. The particle size range of the particles in the prepared carbocysteine raw material medicine is 50μm ≤ D90 ≤ 95μm, and it can be used in subsequent preparation processes only by simple sieving.

[0008] At present, most of the preparation process patents and literatures on carbocisteine tablets mainly focus on wet granulation and tableting, rather than direct compression. The wet granulation and tableting process is a traditional process commonly used in tablets, but its process steps are more than those of powder direct compression, and the humid and hot factors in the granulation and drying links are likely to affect the physical and chemical stability of the active pharmaceutical ingredient, and even cause crystal form transformation. Powder direct compression is also one of the dry preparation processes. The process operation is simple, without granulation, drying and sizing required, the process flow is short, the production efficiency is high, the energy consumption is low, and the tablets obtained have a smooth surface and a short disintegration time limit. However, compared with the traditional preparation methods, powder direct compression also has some disadvantages, such as the fluidity of the material is not as good as that of the wet granulation process, and it is easy to have problems with unqualified content uniformity. In addition, powder direct compression is also prone to problems such as poor compressibility and difficulty in forming. Therefore, the direct compression process needs to consider multiple process parameters, such as the ratio of raw and auxiliary materials, powder uniformity, fluidity, tableting pressure, etc. in the preparation prescription. Any one of these parameters can affect the quality of the preparation product. The implementation difficulty of the powder direct compression technology is greater than that of dry granulation and wet granulation. Therefore, whether it is a specific parameter or as a whole, the powder direct compression process will affect the quality of the final pharmaceutical composition, and its formation requires a large amount of creative labor. This is also the reason why the existing carbocisteine tablets mostly adopt the wet granulation and tableting process. Summary of the Invention

[0009] In view of the deficiencies of the prior art, the purpose of the present invention is to provide a pharmaceutical composition containing carbocisteine and its preparation method. The tablet prescription composition is simple, has good compressibility, the prepared carbocisteine tablets have good dissolution performance, stability and mechanical strength, the powder direct compression is used in the preparation process, and there are no phenomena such as tablet loosening, capping and sticking during long-term tableting, which is suitable for large-scale production.

[0010] To achieve the above purpose, through a large number of experimental studies and improvements on the existing preparation prescription and process, the present invention has obtained the following technical solution: A pharmaceutical composition containing carbocisteine, comprising carbocisteine, filler, binder, disintegrant, lubricant and surfactant, characterized in that the particle size of the carbocisteine is 50μm ≤ D90 ≤ 95μm, and the bulk density is 1.00 - 1.10 g / cm 3 , and the tapped density is 1.10 - 1.30 g / cm 3 , the mass ratio of the filler to the binder is 1:0.7 - 1, and when the mass portion of the carbocisteine is 1, the dosage of the surfactant is 0.003 - 0.005 parts.

[0011] In the present invention, the powder form of the carbocisteine is an important technical key to achieve the technical effect. When the particle size of the carbocisteine is 50μm ≤ D90 ≤ 95μm, and the bulk density is 1.00 - 1.10 g / cm 3 , and the tapped density is 1.10 - 1.30 g / cm3 When it is in this state, its fluidity is moderate and it is suitable for use in the direct powder compression process. Specifically, the particle size, bulk density, and tapped density of carbocisteine need to simultaneously meet the above ranges, and its powder properties can only meet the requirements of fluidity and compressibility, and the direct powder compression process can be achieved. More specifically, as is well known to those skilled in the art, there is no necessary connection between the particle size of drug powders and their bulk density and tapped density. Even powders with similar particle size ranges may correspond to very different bulk densities and tapped densities. For the carbocisteine crystal form of the present invention, its actual particle morphology can be flakes, granular materials, etc. During detection, they can all exhibit the same / similar particle size range, thus showing similar fluidity, but can exhibit very different bulk densities and tapped densities, and there are also obvious differences in their performance during the actual formulation process. When the bulk density and tapped density are too small, the direct compression powder and the punch have a relatively long contact time under relatively high pressure, and adhere to the punch surface when the punch temperature is high, manifested as the phenomenon of "punch sticking" after the direct compression process has been carried out for a period of time; while when the bulk density and tapped density are too large, uneven mixing is likely to occur during the mixing process of the direct compression powder, and the raw and auxiliary materials are prone to layering, which is not conducive to the control of product quality. Preferably, the particle size of carbocisteine is 50μm ≤ D90 ≤ 95μm, and the bulk density is 1.00 - 1.10 g / cm 3 , and the tapped density is 1.10 - 1.30 g / cm 3 , more preferably, the particle size of carbocisteine is 60μm ≤ D90 ≤ 80μm, and the bulk density is 1.01 - 1.05 g / cm 3 , and the tapped density is 1.15 - 1.20 g / cm 3 .

[0012] In the present invention, the types and proportions of the filler and the binder are important technical keys to achieving the technical effects. The filler can increase the compressibility of the raw materials, and the binder can increase the compressibility of the tablets while solving the problem of easy lamination during the tableting process. When the filler and the binder are in a suitable proportion, while increasing the compressibility of carbocisteine, the phenomena of sticking to the punch and lamination of the raw and auxiliary materials can be reduced. Preferably, the mass ratio of the filler to the binder is 1:0.7 - 1, and more preferably, the mass ratio of the filler to the binder is 1:0.8 - 1. Preferably, the filler is one or more mixtures of starch, pregelatinized starch, lactose, and calcium hydrogen phosphate, and the binder is one or more mixtures of microcrystalline cellulose, methylcellulose, and hydroxypropyl cellulose. More preferably, the filler is pregelatinized starch and the binder is microcrystalline cellulose. When the filler is pregelatinized starch, it can increase the fluidity, compressibility, self-lubricity, and dry adhesiveness of the raw materials, and does not have a good disintegration effect. However, the inventor found that when using only pregelatinized starch as the filler, although the tablets are easy to form and have a low friability, the disintegration performance still fails to meet the requirements, and during long-term tableting, there are still prone to problems of sticking to the punch and lamination of the raw and auxiliary materials. At this time, when using microcrystalline cellulose as the binder, while increasing the compressibility of the tablets, the problem of easy lamination during the tableting process can be solved. When pregelatinized starch and microcrystalline cellulose are in a suitable proportion, while increasing the compressibility of carbocisteine, the phenomena of sticking to the punch and lamination of the raw and auxiliary materials can be reduced.

[0013] In the present invention, the types and proportions of the surfactant are important technical keys to achieving the technical effects. The inventor found that during the tableting process, when using a lubricant, a large amount of the lubricant will interfere with the adhesion of the materials during tableting, reduce the hardness of the tablets, and slow down the dissolution of the product, thus affecting the stability of the carbocisteine tablets. After adding a small amount of the surfactant, the problem of sticking to the punch can be effectively solved while reducing the use of the lubricant, thereby ensuring the hardness and dissolution of carbocisteine. Preferably, the surfactant is sodium dodecyl sulfate. When the mass portion of carbocisteine is 1, the dosage of the surfactant is 0.003 - 0.005 portions, and more preferably, when the mass portion of carbocisteine is 1, the dosage of the surfactant is 0.004 portions.

[0014] In the present invention, the selection of the formulation is one of the key factors for achieving the technical effects. Specifically, an increase in the amount of excipients is beneficial for enhancing compressibility and reducing the possibility of sticking to the punch, but an increase in the amount of excipients will result in a relatively large tablet weight, which is not conducive to patient administration. Unless otherwise specified, the amount of the active ingredient in the formulation of the present invention is calculated based on carbocisteine. Preferably, the lubricant is one or a mixture of two or more of magnesium stearate, sodium stearyl fumarate, colloidal silicon dioxide, and talc powder, and the disintegrant is one or a mixture of two or more of low-substituted hydroxypropyl methylcellulose, crospovidone, and sodium carboxymethyl starch. More preferably, the lubricant is magnesium stearate and the disintegrant is sodium carboxymethyl starch.

[0015] Further, when the mass part of carbocisteine is 1, the amount of the filler is 0.1 - 0.15 parts, the amount of the binder is 0.08 - 0.1 parts, the amount of the lubricant is 0.025 - 0.035 parts, and the amount of the disintegrant is 0.030 - 0.035 parts. Even further, when the mass part of carbocisteine is 1, the amount of the filler is 0.12 parts, the amount of the binder is 0.096 parts, the amount of the lubricant is 0.0308 parts, and the amount of the disintegrant is 0.0336 parts.

[0016] The carbocisteine raw material used in the formulation of the present invention only needs to meet the above description of particle size and bulk density. A preferred technical solution of the present invention is that the used carbocisteine raw material is prepared by the following process:

[0017] a) Add the crude carbocisteine to water, control the temperature at 35 - 50 °C, dropwise add concentrated hydrochloric acid at a dropping rate of 0.3 - 0.7 L / min, stir for 20 - 40 min at a stirring speed of 50 - 100 revolutions per minute until the pH = 0.5 - 1.0 and the solid dissolves to prepare a carbocisteine solution with a concentration range of 0.15 - 0.25 g / mL;

[0018] b) Control the temperature at 25 - 35 °C, dropwise add sodium hydroxide solution at a dropping rate of 0.1 - 0.5 L / min until the pH = 2.0 - 2.5, and stop dropping the sodium hydroxide solution;

[0019] c) Control the temperature to 15 - 25 °C, stir at a stirring speed of 60 - 90 revolutions per minute for 25 - 35 min;

[0020] d) Continue to dropwise add sodium hydroxide solution, adjust the pH = 2.8 - 3.0 at 10 - 15 °C, stir at a stirring speed of 40 - 80 revolutions per minute for 20 - 30 min, filter, wash with water, and dry to obtain the refined carbocisteine.

[0021] The carbocisteine raw material medicine obtained by this method has fine products in granular form with uniform particle size distribution. Its bulk density, morphology, etc. all meet the requirements of subsequent formulation processes, and the yield is relatively high.

[0022] The carbocisteine raw material medicine prepared by the method of the present invention meets the requirements of subsequent formulation processes. Specifically, the fine products of the carbocisteine raw material medicine achieve the preset purpose, that is, to improve fluidity and compressibility, which can be reflected by particle size, bulk density and tapped density. The bulk density of the powder is measured by a conventional detection method in the art such as the graduated cylinder method, and the tapped density is also measured by a conventional detection method in the art such as the graduated cylinder tapping method (from Ph.Eur 2.9.34 Bulk density and Tapped density).

[0023] The second object of the present invention is to provide a method for preparing the aforementioned pharmaceutical composition containing carbocisteine raw material medicine and further pressing it into an oral preparation containing carbocisteine by direct powder compression process. The method comprises the following steps:

[0024] (1) Pass each of the raw and auxiliary materials in the prescription through a 13-mesh sieve (Φ1.5 mm) and set aside.

[0025] (2) Weigh the raw and auxiliary materials according to the prescription composition.

[0026] (3) Premix carbocisteine and microcrystalline cellulose for 3 - 5 min.

[0027] (4) Place pregelatinized starch, cross-linked sodium carboxymethyl cellulose and sodium lauryl sulfate in a three-dimensional swing mixer, set the rotation speed at 10 - 15 rpm, and mix for 10 - 20 min to obtain an intermediate.

[0028] (5) Add magnesium stearate and mix for 3 - 5 min.

[0029] (6) Press the tablet core according to an average hardness of 30 - 60 N. During the pressing process, examine the appearance of the tablet core and observe whether there is sticking to the punch, loose tablets and cracked tablets.

[0030] (7) Coating the tablet core with qualified appearance and hardness with hydroxypropyl methylcellulose in a coating pan.

[0031] The present invention provides carbocisteine direct compression tablets prepared from the above-mentioned carbocisteine composition. The carbocisteine direct compression tablets can be uncoated plain tablets or coated tablets, and the coating can use any acceptable coating material in the pharmaceutical field. Preferably, the coating material is a film coating material. In the specific embodiments of the present invention, a rapid-release film coating material, preferably hydroxypropyl methylcellulose, is used. The coating solution is prepared at a concentration of 10%, and the weight gain of the coating solution is 2.0% - 3.0%.

[0032] The present invention also provides a carbocisteine pharmaceutical composition. Specifically, the preparation contains the following components:

[0033]

[0034] Compared with the prior art, the present invention has the following outstanding advantages and beneficial effects:

[0035] 1) The carbocisteine pharmaceutical composition provided by the present invention has powder properties that are conducive to realizing the direct powder compression process, and there are no phenomena such as sticking to the punch and capping during the tabletting process, and the quality is qualified and stable.

[0036] 2) The carbocisteine pharmaceutical composition provided by the present invention adds a surfactant, which while increasing the compressibility of the tablets, ensures its dissolution rate and helps to improve the bioavailability.

[0037] 3) The process of the present invention is simple in operation, suitable for commercial scale production, and has great application value. Specific Embodiments

[0038] The present invention will be further described in detail below in conjunction with the embodiments, but the embodiments of the invention are not limited thereto.

[0039] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

[0040] The carbocisteine used as the raw material drug in the embodiments of the present invention can be prepared according to the preparation method of the carbocisteine raw material drug in Chinese Patent CN202110353601.0.

[0041] Example 1 Preparation of Carbocisteine Tablets

[0042] Prescription composition of 1000 tablets of the carbocisteine tablets

[0043]

[0044] Preparation method:

[0045] (1) Pass each of the raw and auxiliary materials in the prescription through a 13-mesh sieve (Φ1.5 mm) and set aside;

[0046] (2) Weigh the raw and auxiliary materials according to the prescription composition;

[0047] (3) Premix the carbocisteine and microcrystalline cellulose for 3 - 5 minutes;

[0048] (4) placing pregelatinized starch, cross-linked sodium carboxymethyl cellulose and sodium dodecyl sulfate in a three-dimensional oscillating mixer, setting the speed to 10-15 rpm, and mixing for 10-20 minutes to obtain an intermediate;

[0049] (5) Add magnesium stearate and mix for 3-5 minutes;

[0050] (6) Compressing the tablet core at an average hardness of 30-60N. During the pressing process, inspect the appearance of the tablet core to see if it is sticky, loose, or cracked;

[0051] (7) The tablet cores that meet the requirements of appearance and hardness are coated with hypromellose in a coating pan.

[0052] Example 2 Preparation of Carbocisteine ​​Tablets

[0053] Prescription composition of 1000 tablets of carbocystine tablets

[0054]

[0055] The preparation method is the same as Example 1.

[0056] Example 3 Preparation of Carbocisteine ​​Tablets

[0057] Prescription composition of 1000 tablets of carbocystine tablets

[0058]

[0059] The preparation method is the same as Example 1.

[0060] Example 4 Preparation of Carbocisteine ​​Tablets

[0061] Prescription composition of 1000 tablets of carbocystine tablets

[0062]

[0063]

[0064] The preparation method is the same as Example 1.

[0065] Example 5 Preparation of Carbocysteine ​​Tablets Prescription Composition of 1000 Tablets of Carbocysteine ​​Tablets

[0066]

[0067] The preparation method is the same as Example 1.

[0068] Comparative Example 1 Preparation of Carbocysteine ​​Tablets Prescription Composition of 1000 Tablets of Carbocysteine ​​Tablets

[0069]

[0070] The preparation method is as in Example 1.

[0071] Preparation of Carbocisteine Tablets for Comparative Example 2 Prescription composition of 1000 tablets of the said Carbocisteine Tablets

[0072]

[0073] The preparation method is as in Example 1.

[0074] Preparation of Carbocisteine Tablets for Comparative Example 3 Prescription composition of 1000 tablets of the said Carbocisteine Tablets

[0075]

[0076] The preparation method is as in Example 1.

[0077] Preparation of Carbocisteine Tablets for Comparative Example 4 Prescription composition of 1000 tablets of the said Carbocisteine Tablets

[0078]

[0079]

[0080] The preparation method is as in Example 1.

[0081] Preparation of Carbocisteine Tablets for Comparative Example 5

[0082] Prescription composition of 1000 tablets of the said Carbocisteine Tablets

[0083]

[0084] Preparation method:

[0085] (1) Pass each of the raw and auxiliary materials in the prescription through a 13-mesh sieve (Φ1.5 mm) and set aside.

[0086] (2) Weigh the raw and auxiliary materials according to the prescription composition.

[0087] (3) Premix carbocisteine and microcrystalline cellulose for 3 - 5 min.

[0088] (4) Place pregelatinized starch and cross-linked carboxymethyl cellulose sodium in a three-dimensional swing mixer, set the rotation speed at 10 - 15 rpm, and mix for 10 - 20 min to obtain an intermediate.

[0089] (5) Add magnesium stearate and mix for 3 - 5 min.

[0090] (6) Press the tablet cores according to an average hardness of 30 - 60 N. During the pressing process, inspect the appearance of the tablet cores and observe whether there is sticking to the punch, loose tablets, and chipping.

[0091] (7) Coating the tablet cores with qualified appearance and hardness with hydroxypropyl methylcellulose in a coating pan.

[0092] Example 7

[0093] Take the carbocisteine direct compression tablets prepared in Examples 1-5 and Comparative Examples 1-4 for quality inspection. The results are as follows:

[0094] Table 1 Quality inspection of carbocisteine direct compression tablets

[0095]

[0096]

[0097] From the above results, the carbocisteine direct compression tablets prepared in Examples 1-5 and Comparative Examples 1-5 are all white or off-white tablets after removing the coating. However, for the carbocisteine tablets in Comparative Examples 1 and 2, during the tableting process, partial sticking to the punch occurred. Through analysis, it can be seen that due to the too small bulk density and tapped density of the carbocisteine raw materials used in Comparative Examples 1 and 2, the direct compression powder and the punch have a relatively long contact time under relatively high pressure, and adhere to the punch surface when the punch temperature is relatively high, resulting in sticking to the punch during a certain period of the direct compression process. Moreover, since the content of the filler pregelatinized starch and the binder microcrystalline cellulose in Comparative Example 1 is relatively low, during the tableting process, some tablets show the phenomena of loose tablets or cracked tablets. In Comparative Example 4, fillers, binders, lubricants and disintegrants that are not the preferred ones in this solution are used. Therefore, during the tableting process, some tablets also show the phenomena of sticking to the punch, loose tablets or cracked tablets. In terms of content uniformity, Examples 1-5 and Comparative Examples 1, 2, 4 and 5 all meet the requirements, while the content uniformity of Comparative Example 3 exceeds the limit. Through analysis, it can be seen that due to the too large bulk density and tapped density of the carbocisteine raw materials, uneven mixing and easy stratification of the raw and auxiliary materials occur during the mixing process of the direct compression powder, resulting in the problem of exceeding the limit of content uniformity.

[0098] Example 9

[0099] The carbocisteine tablets prepared in Examples 1-5 and Comparative Example 5 and the commercially available carbocisteine tablets (Guangdong South China Pharmaceutical Group Co., Ltd., specification 0.25 g) were operated according to the dissolution determination method of carbocisteine tablets in the second part of the Chinese Pharmacopoeia (2020 Edition). Using 1000 mL of phosphate buffer solution (pH 6.6) as the dissolution medium and a rotation speed of 100 revolutions per minute, 10 mL of the solution was taken at 5 min, 10 min, 20 min, 30 min, and 60 min respectively, filtered, and the subsequent filtrate was taken as the test solution; another 12.5 mg of carbocisteine reference substance was accurately weighed, placed in a 50 mL volumetric flask, dissolved with the dissolution medium and diluted to the mark, shaken well, and used as the reference solution. Accurately measure 5 mL of the test solution and 2 mL of the reference solution, place them in 50 mL volumetric flasks respectively, accurately add 2 mL of 2% ninhydrin solution and 2 mL of the dissolution medium, shake well, heat in a water bath for 15 minutes, take out, cool, dilute to the mark with water, shake well, and measure the absorbance at a wavelength of 567 nm according to the ultraviolet-visible spectrophotometry method, and calculate the dissolution of each tablet. The results are as follows:

[0100] Table 2 Results of dissolution determination of carbocisteine tablets

[0101]

[0102] According to the dissolution determination results in Table 2, it can be seen that the carbocisteine tablets prepared in Examples 1-5 and the commercially available carbocisteine tablets can dissolve more than 80% in 20 min, and are basically completely dissolved at 60 min. However, for the carbocisteine tablets prepared in Comparative Example 5, the dissolution rate is much lower than that of other groups. It can be analyzed that a large amount of lubricant was used in the tabletting process of Comparative Example 5, which would interfere with the adhesion of the materials during the tabletting process, reduce the tablet hardness, and slow down the product dissolution. After adding a small amount of surfactant sodium dodecyl sulfate in Examples 1-5, the problem of sticking to the punch can be effectively solved while reducing the use of lubricant, thus ensuring the hardness and dissolution of carbocisteine.

[0103] Example 10

[0104] The carbocisteine tablets of Examples 1-5 and the commercially available carbocisteine tablets (Guangdong South China Pharmaceutical Group Co., Ltd., specification 0.25 g) were packaged in aluminum-plastic blister packs and placed under the conditions of 40°C ± 2°C and RH 75% ± 5% for investigation. Samples were taken at the end of January, February, March, and June respectively, and the changes in appearance, dissolution, related substances, and content were determined. The test results are shown in Table 3.

[0105] Table 3 Investigation results of appearance, dissolution, related substances, and content of carbocisteine tablets

[0106]

[0107]

[0108] As can be seen from Table 3, the samples of the embodiments of the present invention were placed for 6 months under the conditions of 40°C ± 2°C and 75% ± 5%. Compared with the 0-month data, the related substances slightly increased, and there were no significant changes in other indicators. This shows that after being packaged in aluminum-plastic blister packs, the product is relatively stable after being placed for 6 months under the conditions of 40°C ± 2°C and 75% ± 5%. Compared with the commercially available carbocisteine tablets, the stability effect is similar. All the various parameters in Example 1, including the particle size, bulk density, tapped density of the carbocisteine raw material, and the types and dosages of other various excipients, etc., are all the most preferred. The overall combination of the above conditions enables the obtained carbocisteine tablets to be prepared by the direct powder compression process without sticking to the punch and also ensures its dissolution performance and stability, achieving the optimal overall performance.

[0109] In summary, the carbocisteine tablets prepared by this solution can not only implement the direct powder compression process, without phenomena such as sticking to the punch and tablet splitting during the tableting process, with qualified and stable quality, but also ensure its dissolution performance and stability.

[0110] The above embodiments are the preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. A pharmaceutical composition containing carbocisteine, comprising carbocisteine, filler, binder, disintegrant, lubricant and surfactant, characterized in that, The particle size of the carbocisteine is 50 μm ≤ D90 ≤ 95 μm, and the bulk density is 1.00 - 1.10 g / cm 3 , and the tapped density is 1.10 - 1.30 g / cm 3 , the mass ratio of the filler to the binder is 1:0.7 - 1. When the mass portion of the carbocisteine is 1, the dosage of the surfactant is 0.003 - 0.005 portions. The surfactant is sodium dodecyl sulfate. The filler is one or more mixtures of starch, pregelatinized starch, and lactose; the binder is one or more mixtures of microcrystalline cellulose, methylcellulose, and hydroxypropyl cellulose; the lubricant is one or more mixtures of magnesium stearate, colloidal silica, and talc powder; the disintegrant is one or more mixtures of low-substituted hydroxypropyl cellulose, crospovidone, and cross-linked sodium carboxymethyl cellulose; When the mass portion of carbocisteine is 1, the dosage of the filler is 0.1 - 0.15 portions, the dosage of the binder is 0.08 - 0.1 portion, the dosage of the lubricant is 0.025 - 0.035 portion, and the dosage of the disintegrant is 0.030 - 0.035 portion.

2. The pharmaceutical composition according to claim 1, wherein The particle size of the carbocisteine is 60μm ≤ D90 ≤ 80μm, and the bulk density is 1.01 - 1.05 g / cm 3 , and the tapped density is 1.15 - 1.20 g / cm 3 . The mass ratio of the filler to the binder is 1:0.8 - 1. When the mass portion of the carbocisteine is 1, the dosage of the surfactant is 0.004 portions.

3. The pharmaceutical composition according to claim 1, characterized in that, The filler is pregelatinized starch, the binder is microcrystalline cellulose, the lubricant is magnesium stearate, and the disintegrant is croscarmellose sodium.

4. The pharmaceutical composition according to claim 1, characterized in that, When the mass portion of carbocisteine is 1, the dosage of the filler is 0.12 portion, the dosage of the binder is 0.096 portion, the dosage of the lubricant is 0.0308 portion, and the dosage of the disintegrant is 0.0336 portion.

5. The pharmaceutical composition according to any one of claims 1-4, characterized in that The carbocisteine is prepared by the following method: a) Add the crude carbocisteine to water, control the temperature at 35 - 50 °C, dropwise add concentrated hydrochloric acid at a dropping rate of 0.3 - 0.7 L / min, stir for 20 - 40 min at a stirring speed of 50 - 100 revolutions per minute until the pH = 0.5 - 1.0 and the solid dissolves to prepare a carbocisteine solution with a concentration range of 0.15 - 0.25 g / mL; b) Control the temperature at 25 - 35 °C, dropwise add sodium hydroxide solution at a dropping rate of 0.1 - 0.5 L / min until the pH = 2.0 - 2.5, and stop dropping the sodium hydroxide solution; c) Control the temperature to 15 - 25 °C, stir at a stirring speed of 60 - 90 revolutions per minute for 25 - 35 min; d) Continue to dropwise add sodium hydroxide solution, adjust the pH = 2.8 - 3.0 at 10 - 15 °C, stir at a stirring speed of 40 - 80 revolutions per minute for 20 - 30 min, filter, wash with water and dry to obtain the high-quality carbocisteine.

6. A pharmaceutical composition containing carbocisteine, characterized in that, It contains the following components: Among them, the particle size of the carbocisteine is 60μm ≤ D90 ≤ 80μm, and the bulk density is 1.01 - 1.05 g / cm 3 , and the tapped density is 1.15 - 1.20 g / cm 3 .

7. A method for preparing the pharmaceutical composition according to claim 6, characterized in that, This method includes the following steps: (1) Pass each of the raw and auxiliary materials in the prescription through a 13-mesh sieve and set aside; (2) Weigh the raw and auxiliary materials according to the prescription composition; (3) Premix the carbocisteine and microcrystalline cellulose for 3 - 5 min; (4) Place the pregelatinized starch, croscarmellose sodium and sodium lauryl sulfate in a three-dimensional swing mixer, set the rotation speed at 10 - 15 rpm, and mix for 10 - 20 min to obtain the intermediate; (5) Add magnesium stearate and mix for 3 - 5 min; (6) Press the tablet core according to an average hardness of 30 - 60 N, and during the pressing process, inspect the appearance of the tablet core to observe whether there is sticking to the punch, loose tablets and cracked tablets; (7) Coat the tablet cores with qualified appearance and hardness with hydroxypropyl methylcellulose in a coating pan.

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