High-stability carbocisteine particles and preparation method thereof

Abstract

The invention provides a high-stability carbocisteine particle and a preparation method thereof. The high-stability carbocisteine particle comprises the following raw materials: modified carbocisteine microparticles, mannitol, croscarmellose sodium, an adhesive and a sweetening agent. Carbocisteine and polysorbate 80 are mixed and stirred to prepare the modified carbocisteine microparticles. The preparation method comprises the following steps: granulating the modified carbocisteine microparticles I in two parts, mixing the modified carbocisteine microparticles I with mannitol, mixing the modified carbocisteine microparticles II with croscarmellose sodium, respectively carrying out wet granulation, and then carrying out mixing and swinging granulation, drying, size stabilization and packaging. According to the technical scheme, the stability and uniformity of the medicine can be effectively improved, meanwhile, the method is easy to operate, the use amount of auxiliary materials is reduced, the utilization rate of the auxiliary materials is increased, the production efficiency is high, and the consistency of product quality can be guaranteed.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to high-stability carbocysteine ​​granules and a preparation method thereof. Background Art

[0002] As a commonly used drug ingredient, carbocysteine ​​is widely used in the treatment of respiratory diseases. The traditional preparation method of carbocysteine ​​granules has problems such as poor stability and uneven mixing, which leads to unstable drug efficacy and affects the therapeutic effect. In the prior art, the preparation methods of carbocysteine ​​granules mainly include the following: single mixing method: carbocysteine ​​is mixed with other excipients at one time, and then granulated. This method is simple to operate, but the mixing is uneven, resulting in poor stability of the granules and unstable drug efficacy. Batch mixing method: carbocysteine ​​is mixed with other excipients in batches and then granulated. Although this method can improve the uniformity of mixing, it is cumbersome to operate, has low production efficiency, and the mixing effect between different batches varies greatly, affecting the consistency of product quality. Mechanical mixing method: carbocysteine ​​is mixed with other excipients by mechanical stirring, and then granulated. This method can improve the mixing efficiency, but due to the large shear force of mechanical stirring, it is easy to cause the damage of carbocysteine ​​granules, affecting the drug efficacy. In contrast, the modified carbocysteine ​​granules are granulated separately and have better stability. This technical solution adopts a method for preparing high-stability carbocysteine ​​particles, wherein carbocysteine ​​is modified and then mixed in two parts, which can prevent the reaction between the auxiliary materials and between the auxiliary materials and carbocysteine ​​powder after being damp, and can effectively improve the uniformity of the drug and the stability of the drug. At the same time, the method is simple to operate, has high production efficiency, can ensure the consistency of product quality, and has obvious advantages. Summary of the invention

[0003] In view of this, the present invention provides a high-stability carbocysteine ​​granule and a preparation method thereof.

[0004] The technical solution of the present invention is achieved in this way:

[0005] A high-stability carbocysteine ​​granule and a preparation method thereof, comprising the following raw materials in parts by weight: 90-100 parts of modified carbocysteine ​​microgranules, 50-60 parts of mannitol, 0.5-2 parts of cross-linked sodium carboxymethyl cellulose, 1-3 parts of a binder, and 3-6 parts of a sweetener, and comprising the following steps:

[0006] S1. Dividing the modified carbocysteine ​​microparticles into two parts, namely, modified carbocysteine ​​microparticles I and modified carbocysteine ​​microparticles II;

[0007] S2, mixing the modified carbocisteine ​​microgranules I and mannitol, and wet granulating the mixture to obtain a mixture I;

[0008] S3, mixing the modified carbocisteine ​​microparticles II and cross-linked sodium carboxymethyl cellulose, and wet granulating the mixture to obtain a mixture II;

[0009] S4, mixing mixture I, mixture II, a binder, a sweetener and ethanol to obtain a total mixture;

[0010] S5. The total mixture is shaken to granulate, dried, granulated, and packaged to obtain the finished product.

[0011] Furthermore, the preparation method of the modified carbocysteine ​​microparticles comprises: mixing carbocysteine ​​and polysorbate 80 to obtain a modified carbocysteine ​​mixture, vacuum drying the modified carbocysteine ​​mixture, crushing, and granulating to obtain modified carbocysteine ​​microparticles.

[0012] Furthermore, the mass ratio of carbocysteine ​​to polysorbate is 10:0.5-0.8.

[0013] Furthermore, the mixing and stirring is performed at a mixing temperature of 35-40° C., a mixing time of 25-30 minutes, and a stirring speed of 130-150 rpm.

[0014] Furthermore, the vacuum drying has a vacuum degree of -0.08MPa to -0.06MPa, a drying temperature of 55-60°C, a drying time of 3-4 hours, and the pulverization has a pulverized particle size range of 100 to 500μm.

[0015] Furthermore, in step S1, the mass ratio of the modified carbocysteine ​​microparticles I and the modified carbocysteine ​​microparticles II is 1:1-1.2.

[0016] Furthermore, in step S2 and step S3, the wet granulation has a stirring speed of 20-25 Hz, a cutting speed of 8-10 Hz, and a stirring and cutting time of 4-6 minutes.

[0017] Furthermore, in step S4, the mass fraction of the ethanol is 80%; the binder is at least one of hydroxypropyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl methyl cellulose; and the sweetener is at least one of sucralose, acesulfame potassium, aspartame, and maltitol.

[0018] Furthermore, in step S4, the mixing is performed at a rotation speed of 15-20 rpm and a mixing time of 8-12 minutes; in step S5, the swing granulation is performed by pouring the total mixture into a granulator and swinging the granules through a 24-mesh screen for 10-20 minutes.

[0019] Furthermore, in step S5, the drying is performed at a temperature of 50-65° C. and a drying time of 2-3 hours, and the moisture content of the particles after drying is controlled at 1%-3%.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] 1) The present invention reduces the hygroscopicity of the drug by modifying carbocysteine ​​and separately granulating the carbocysteine.

[0022] 2) The batch mixing method of the present invention reduces the contact area between the excipients, and can continuously maintain the uniformity and stability of the drug when the external environment changes.

[0023] 3) The operation method of the present invention is simple, the usage of auxiliary materials is reduced, and the utilization rate of auxiliary materials is improved. DETAILED DESCRIPTION

[0024] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0025] Unless otherwise specified, the experimental methods used in the examples of the present invention are all conventional methods, and the reagents used in the examples are all available from commercial sources.

[0026] Preparation Example 1

[0027] The preparation method of modified carbocysteine ​​microparticles comprises: mixing carbocysteine ​​with a purity of 99.9% and polysorbate 80 in a mass ratio of 10:0.5, the mixing temperature is 35° C., the mixing time is 25 minutes, the stirring speed is 130 rpm, to obtain a modified carbocysteine ​​mixture, vacuum drying the modified carbocysteine ​​mixture, wherein the vacuum degree is -0.08 MPa, the drying temperature is 55° C., the drying time is 3 hours, and after drying, the mixture is crushed to a particle size of 200 μm, and the particles are granulated to obtain the modified carbocysteine ​​microparticles of Preparation Example 1.

[0028] Preparation Example 2

[0029] The preparation method of modified carbocysteine ​​microparticles includes: mixing carbocysteine ​​with a purity of 99.9% and polysorbate 80 in a mass ratio of 10:0.6, the mixing temperature is 40°C, the mixing time is 30 minutes, and the stirring speed is 150 rpm to obtain a modified carbocysteine ​​mixture, vacuum drying the modified carbocysteine ​​mixture, wherein the vacuum degree is -0.06MPa, the drying temperature is 60°C, and the drying time is 4 hours. After drying, the mixture is crushed to a particle size of 300μm, and the particles are granulated to obtain the modified carbocysteine ​​microparticles of Preparation Example 2.

[0030] Preparation Example 3

[0031] The preparation method of modified carbocysteine ​​microparticles includes: mixing carbocysteine ​​with a purity of 99.9% and polysorbate 80 in a mass ratio of 10:0.7, the mixing temperature is 38°C, the mixing time is 28 minutes, and the stirring speed is 140 rpm to obtain a modified carbocysteine ​​mixture, vacuum drying the modified carbocysteine ​​mixture, wherein the vacuum degree is -0.07MPa, the drying temperature is 57°C, and the drying time is 3.5 hours. After drying, the mixture is crushed to a particle size of 250μm, and the particles are granulated to obtain the modified carbocysteine ​​microparticles of Preparation Example 3.

[0032] Example 1

[0033] A high-stability carbocysteine ​​granule and a preparation method thereof, comprising the following raw materials in parts by weight: 100 parts of modified carbocysteine ​​microgranules prepared in Preparation Example 1, 50 parts of mannitol, 0.8 parts of cross-linked sodium carboxymethyl cellulose, 1 part of a binder, and 3 parts of a sweetener, comprising the following steps:

[0034] Step (1), dividing the modified carbocysteine ​​microparticles into two parts, namely, modified carbocysteine ​​microparticles I and modified carbocysteine ​​microparticles II, wherein the mass ratio of the modified carbocysteine ​​microparticles I to the modified carbocysteine ​​microparticles II is 1:1;

[0035] Step (2), mixing the modified carbocisteine ​​microparticles I and mannitol and wet granulating them, wherein the stirring speed during granulation is 20 Hz, the cutting speed is 8 Hz, and the stirring and cutting time is 4 minutes, to obtain a mixture I;

[0036] Step (3), the modified carbocisteine ​​microparticles II and cross-linked sodium carboxymethyl cellulose are mixed and granulated in another wet granulator with a stirring speed of 20 Hz, a cutting speed of 8 Hz, and a stirring and cutting time of 4 minutes.

[0037] The mixture II is obtained;

[0038] Step (4), mixing mixture I, mixture II, a binder, a sweetener and an ethanol solution with a mass fraction of 80%, wherein the binder is hydroxyethyl cellulose, and the sweeteners are sucralose and maltitol, at a mixing speed of 15 rpm and a mixing time of 8 minutes to obtain a total mixture;

[0039] Step (5), pouring the total mixture into a granulator, shaking and granulating through a 24-mesh screen, the granulation time is 10 minutes, drying after granulation, the drying temperature is 50° C., the drying time is 2 hours, the moisture content of the granules after drying is controlled to be 1%, and after drying, the granules are granulated and packaged to obtain the finished product.

[0040] Example 2

[0041] A high-stability carbocysteine ​​granule and a preparation method thereof, comprising the following raw materials in parts by weight: 98 parts of modified carbocysteine ​​microgranules prepared in Preparation Example 2, 60 parts of mannitol, 2 parts of cross-linked sodium carboxymethyl cellulose, 3 parts of a binder, and 6 parts of a sweetener, comprising the following steps:

[0042] Step (1), dividing the modified carbocysteine ​​microparticles into two parts, namely, modified carbocysteine ​​microparticles I and modified carbocysteine ​​microparticles II, wherein the mass ratio of the modified carbocysteine ​​microparticles I to the modified carbocysteine ​​microparticles II is 1:1;

[0043] Step (2), mixing the modified carbocisteine ​​microparticles I and mannitol, wet granulating, stirring at a speed of 25 Hz, a cutting speed of 10 Hz, and a stirring and cutting time of 6 minutes, to obtain a mixture I;

[0044] Step (3), the modified carbocisteine ​​microparticles II and cross-linked sodium carboxymethyl cellulose are mixed and granulated in another wet granulator with a stirring speed of 25 Hz, a cutting speed of 10 Hz, and a stirring and cutting time of 6 minutes.

[0045] The mixture II is obtained;

[0046] Step (4), mixing mixture I, mixture II, a binder, a sweetener and an ethanol solution with a mass fraction of 80%, wherein the binder is hydroxypropyl methylcellulose, and the sweeteners are acesulfame potassium and maltitol, at a mixing speed of 20 rpm and a mixing time of 12 minutes; obtaining a total mixture;

[0047] Step (5), pouring the total mixture into a granulator, shaking granulating through a 24-mesh screen, the granulating time is 20 minutes, drying after granulation, the drying temperature is 65° C., the drying time is 3 hours, the moisture content of the granules after drying is controlled to be 3%, and after drying, granulating and packaging to obtain a finished product.

[0048] Example 3

[0049] A high-stability carbocysteine ​​granule and a preparation method thereof, comprising the following raw materials in parts by weight: 96 parts of modified carbocysteine ​​microgranules prepared in Preparation Example 3, 55 parts of mannitol, 1 part of cross-linked sodium carboxymethyl cellulose, 2 parts of a binder, and 5 parts of a sweetener, comprising the following steps:

[0050] Step (1), dividing the modified carbocysteine ​​microparticles into two parts, namely, modified carbocysteine ​​microparticles I and modified carbocysteine ​​microparticles II, wherein the mass ratio of the modified carbocysteine ​​microparticles I to the modified carbocysteine ​​microparticles II is 1:1;

[0051] Step (2), the modified carbocisteine ​​microparticles I and mannitol are mixed and wet granulated, the stirring speed is 23 Hz, the cutting speed is 9 Hz, and the stirring and cutting time is 5 minutes to obtain a mixture I;

[0052] Step (3), the modified carbocisteine ​​microparticles II and cross-linked sodium carboxymethyl cellulose are mixed and granulated in another wet granulator with a stirring speed of 23 Hz, a cutting speed of 9 Hz, and a stirring and cutting time of 5 minutes.

[0053] The mixture II is obtained;

[0054] Step (4), mixing mixture I, mixture II, a binder, a sweetener and an ethanol solution with a mass fraction of 80%, wherein the binder is hydroxypropyl cellulose, and the sweeteners are sucralose and maltitol, at a mixing speed of 18 rpm and a mixing time of 10 minutes; obtaining a total mixture;

[0055] Step (5), pouring the total mixture into a granulator, shaking and granulating through a 24-mesh screen, the granulation time is 15 minutes, drying after granulation, the drying temperature is 60° C., the drying time is 2.5 hours, the moisture content of the granules after drying is controlled to be 2%, and after drying, the granules are granulated and packaged to obtain the finished product.

[0056] Comparative Example 1

[0057] The main difference between Comparative Example 1 and Example 3 is that the modified carbocysteine ​​microparticles are replaced with carbocysteine ​​powder, and other drug raw materials, proportions and steps are not changed.

[0058] Comparative Example 2

[0059] The main difference between Comparative Example 2 and Example 3 is that step (1) is removed, and the modified carbocysteine ​​microparticles are divided into two parts and replaced by modified carbocysteine ​​microparticles mixed and added as a whole, and other drug raw materials, proportions and steps are unchanged.

[0060] Step (1), mixing modified carbocisteine ​​microgranules, mannitol and cross-linked sodium carboxymethyl cellulose, and wet granulating the mixture, with a stirring speed of 23 Hz, a cutting speed of 9 Hz, and a stirring and cutting time of 5 minutes.

[0061] A mixture is obtained;

[0062] Step (2), mixing the mixture, a binder, a sweetener and an ethanol solution with a mass fraction of 80%, wherein the binder is hydroxypropyl cellulose, and the sweeteners are sucralose and maltitol, at a mixing speed of 18 rpm and a mixing time of 10 minutes; obtaining a total mixture;

[0063] Step (3), pouring the total mixture into a granulator, shaking granulating through a 24-mesh screen, the granulating time is 15 minutes, drying after granulation, the drying temperature is 60° C., the drying time is 2.5 hours, the moisture content of the granules after drying is controlled to be 2%, and after drying, the granules are granulated and packaged to obtain the finished product.

[0064] Comparative Example 3

[0065] The main differences between Comparative Example 3 and Example 3 are that in step (4), "an ethanol solution with a mass fraction of 80%" is replaced by "an ethanol solution with a mass fraction of 50%", and in step (5), "the drying temperature is 60°C, the drying time is 2.5 hours, and the moisture content of the particles after drying is controlled to be 2%" is replaced by "the drying temperature is 45°C, the drying time is 2.5 hours, and the moisture content of the particles after drying is controlled to be 4%", and other drug raw materials, proportions and steps are unchanged.

[0066] Comparison

[0067] An equal amount of commercially available carbocysteine ​​granules was used, and the manufacturer was Meiji Pharmaceutical (Xiamen) Co., Ltd.

[0068] 1. Uniformity test

[0069] The uniformity of the carbocisteine ​​pharmaceutical composition granule samples of Examples 1-3, Comparative Examples 1-3 and the control was tested respectively. The results are shown in Table 1. The uniformity detection method was determined in accordance with the "General Rules of the Four Parts of the 2020 Edition of the Chinese Pharmacopoeia 0941". The content uniformity requires A+2.2S≤15.0, RSD<5%. The test results show that the RSD% of the carbocisteine ​​granules prepared by the method of the present invention is less than 2%, A+2.2S≤6, and the uniformity is high, which meets the national standards (see Table 1).

[0070] Table 1 Uniformity Change Table

[0071] Group RSD(%) A+2.2S Example 1 1.10 5.2 Example 2 1.23 4.9 Example 3 1.08 4.8 Comparative Example 1 1.92 6.7 Comparative Example 2 1.83 7.0 Comparative Example 3 2.39 7.9 Comparison 2.04 6.2

[0072] 2. Hygroscopicity test

[0073] The carbocysteine ​​granules prepared by the methods of Examples 1-3 and Comparative Examples 1-3 and the control were subjected to hygroscopicity tests. According to the guidance of the drug hygroscopicity test of the "General Rules 9103 of the Four Parts of the Chinese Pharmacopoeia 2020 Edition", the test results are shown in Table 2. The hygroscopicity of the carbocysteine ​​granules prepared by the preparation methods of Examples 1-3 is significantly lower than that of Comparative Examples 1-3 and the control, and the method of the present invention reduces the hygroscopicity of the carbocysteine ​​granules (see Table 2).

[0074] Table 2 Humidity change table (g)

[0075] Group Average value before moisture absorption Average after moisture absorption Average weight gain Examples 1-3 1.0001-1.0004 1.0004-1.0008 0.0002-0.0004a Comparative Example 1 1.0003 1.0016 0.0013b Comparative Example 2 1.0002 1.0014 0.0012b Comparative Example 3 1.0001 1.0018 0.0017c Comparison 1.0003 1.0013 0.0010b

[0076] Note: a, b, c indicate significant difference with P < 0.05

[0077] 3. Stability value test

[0078] The carbocisteine ​​granules prepared by the methods of Examples 1-3 and Comparative Examples 1-3 and the control test were observed for changes in appearance properties. The test conditions were RH80% high humidity conditions, 55°C high temperature conditions, and 4500LX+500LX strong light. The sampling and data recording time were the initial time day 0 and day 7 (see Table 3). The powder spectrophotometer was used to measure the color change. The determination of carbocisteine ​​content was carried out by spectrophotometry. The test sample and the reference substance were added with phosphate buffer (pH 6.6) to prepare a solution containing 200 micrograms of carbocisteine ​​per 1 ml. Then, the solution was measured, 2% ninhydrin aqueous solution and phosphate buffer were added, and the mixture was heated in a boiling water bath for 15 minutes. After cooling, the solution was diluted to the specified scale, shaken up, and the absorbance was measured at a wavelength of 567 nanometers using a UV-visible spectrophotometer to calculate the carbocisteine ​​content (see Table 4).

[0079] Table 3 Appearance Observation Table

[0080]

[0081] The carbocysteine ​​granules prepared by the methods of Examples 1-3 and Comparative Examples 1-3 and the control were subjected to stability test results. The results showed that the carbocysteine ​​granules prepared by the methods of Examples 1-3 had a significant change in appearance color after 7 days. The carbocysteine ​​granules were more resistant to high temperature, high humidity and strong light than the comparative examples and the control, indicating that the carbocysteine ​​granules prepared by the method of the examples had higher stability.

[0082] Table 4 Changes in mass ratio (%)

[0083]

[0084] Note: a, b, c indicate significant difference with P < 0.05

[0085] In summary, the modified carbocisteine ​​granules of the present invention are wet granulated twice and then mixed in the preparation method, the contact between carbocisteine ​​raw materials and auxiliary materials is avoided, the contact between auxiliary materials and auxiliary materials is avoided, the negative reaction between the drug component and the auxiliary materials and between the auxiliary materials is significantly reduced, and the stability and uniformity of the drug are improved. After the modified carbocisteine ​​microgranules are replaced with carbocisteine ​​powder by comparative example 1, the carbocisteine ​​mass ratio decreases, and the color is yellowish after high temperature; after the modified carbocisteine ​​microgranules are mixed and added as a whole by comparative example 2, the stability of the finished product decreases, the color turns yellow under strong light and high humidity conditions, and the carbocisteine ​​granule mass ratio decreases; when comparative example 3 changes the ethanol solution mass fraction and the preparation conditions, the stability of the finished product is also reduced. Therefore, the carbocisteine ​​granules prepared by the raw material of the present invention in combination with the preparation method of the present invention have higher stability, and reduce the amount of auxiliary materials, and improve production efficiency.

[0086] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing high-stability carbocysteine ​​granules, characterized in that: The method comprises the following raw materials in parts by weight: 90-100 parts of modified carbocisteine ​​microparticles, 50-60 parts of mannitol, 0.5-2 parts of cross-linked sodium carboxymethyl cellulose, 1-3 parts of a binder, and 3-6 parts of a sweetener, and comprises the following steps: S1. Dividing the modified carbocysteine ​​microparticles into two parts, namely, modified carbocysteine ​​microparticles I and modified carbocysteine ​​microparticles II; S2, mixing the modified carbocisteine ​​microgranules I and mannitol, and wet granulating the mixture to obtain a mixture I; S3, mixing the modified carbocisteine ​​microparticles II and cross-linked sodium carboxymethyl cellulose, and wet granulating the mixture to obtain a mixture II; S4, mixing mixture I, mixture II, a binder, a sweetener and ethanol to obtain a total mixture; S5. The total mixture is shaken to granulate, dried, granulated, and packaged to obtain the finished product.

2. The method for preparing a high-stability carbocysteine ​​granule according to claim 1, characterized in that: The preparation method of the modified carbocysteine ​​microparticles comprises: mixing carbocysteine ​​and polysorbate 80 to obtain a modified carbocysteine ​​mixture, vacuum drying the modified carbocysteine ​​mixture, crushing and granulating to obtain the modified carbocysteine ​​microparticles.

3. The method for preparing a high-stability carbocysteine ​​granule according to claim 2, characterized in that: The mass ratio of carbocysteine ​​to polysorbate is 10:0.5-0.

8.

4. The method for preparing a high-stability carbocysteine ​​granule according to claim 2, characterized in that: The mixing and stirring process has a mixing temperature of 35-40° C., a mixing time of 25-30 minutes, and a stirring speed of 130-150 rpm.

5. The method for preparing a high-stability carbocysteine ​​granule according to claim 2, characterized in that: The vacuum drying has a vacuum degree of -0.08MPa to -0.06MPa, a drying temperature of 55-60°C, and a drying time of 3-4 hours. The crushing has a crushing particle size range of 100-500μm.

6. The method for preparing a high-stability carbocysteine ​​granule according to claim 1, characterized in that: Step S1, the mass ratio of the modified carbocysteine ​​microparticles I to the modified carbocysteine ​​microparticles II is 1:1-1.

2.

7. The method for preparing a high-stability carbocysteine ​​granule according to claim 1, characterized in that: In step S2 and step S3, the wet granulation has a stirring speed of 20-25 Hz, a cutting speed of 8-10 Hz, and a stirring and cutting time of 4-6 minutes.

8. The method for preparing a high-stability carbocysteine ​​granule according to claim 1, characterized in that: Step S4, the mass fraction of the ethanol is 80%; the binder is at least one of hydroxypropyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl methyl cellulose; the sweetener is at least one of sucralose, acesulfame potassium, aspartame, and maltitol.

9. The method for preparing a high-stability carbocysteine ​​granule according to claim 1, characterized in that: Step S4, the mixing, the rotation speed is 15-20 rpm, the mixing time is 8-12 minutes; Step S5, the swing granulation, the total mixture is poured into a granulator, and the granulation is swing-granulated through a 24-mesh screen, and the granulation time is 10-20 minutes.

10. The method for preparing high-stability carbocysteine ​​granules according to claim 1, characterized in that: Step S5, the drying, the drying temperature is 50-65°C, the drying time is 2-3 hours, and the moisture content of the particles after drying is controlled at 1%-3%.

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