A kind of high stability carbocisteine ​​granules and preparation method thereof

Abstract

The present invention provides a high-stability carbocysteine ​​granule and a preparation method thereof, comprising raw materials: modified carbocysteine ​​microparticles, mannitol, cross-linked sodium carboxymethyl cellulose, a binder, and a sweetener. Carbocysteine ​​and polysorbate 80 are mixed and stirred to produce the modified carbocysteine ​​microparticles. The modified carbocysteine ​​microparticles are then granulated in two parts: modified carbocysteine ​​microparticles I are mixed with mannitol, and modified carbocysteine ​​microparticles II are mixed with cross-linked sodium carboxymethyl cellulose. The two parts are wet-granulated separately, followed by mixing and shaking granulation, drying, granulation, and packaging. This technical solution can effectively improve the stability and uniformity of the drug. Furthermore, the method is simple to operate, reduces the amount of excipients used, improves excipient utilization, has high production efficiency, and can ensure consistent product quality.

Description

Technical Field

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

[0002] Carbocysteine, a commonly used pharmaceutical ingredient, is widely used in the treatment of respiratory diseases. Traditional methods for preparing carbocysteine ​​granules suffer from poor stability and uneven mixing, resulting in unstable efficacy and affecting therapeutic results. Prior art methods for preparing carbocysteine ​​granules mainly include the following: The single-shot mixing method involves mixing carbocysteine ​​with other excipients at once, followed by granulation. This method is simple to operate, but results in uneven mixing, resulting in poor granule stability and unstable efficacy. The batch mixing method involves mixing carbocysteine ​​with other excipients in batches, followed by granulation. While this method improves mixing uniformity, it is cumbersome, has low production efficiency, and exhibits significant variability in mixing quality between batches, impacting product quality consistency. The mechanical mixing method involves mixing carbocysteine ​​with other excipients using mechanical stirring, followed by granulation. This method improves mixing efficiency, but the high shear forces from mechanical stirring can easily lead to breakage of the carbocysteine ​​granules, affecting efficacy. In contrast, modified carbocysteine ​​granules prepared separately exhibit greater stability. This technical solution adopts a method for preparing highly stable carbocysteine ​​granules. Carbocysteine ​​is modified and then mixed into two parts. This prevents moisture-induced reactions between excipients and between the excipients and carbocysteine ​​powder, effectively improving the uniformity and stability of the drug. Furthermore, this method is simple to operate, has high production efficiency, and can ensure consistent product quality, offering significant 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 as follows:

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

[0006] S1. Dividing the modified carbocisteine ​​microparticles into two parts, namely, modified carbocisteine ​​microparticles I and modified carbocisteine ​​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 includes: 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 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 is carried out with a vacuum degree of -0.08 MPa to -0.06 MPa, a drying temperature of 55-60° C., and a drying time of 3-4 hours. The pulverization is carried out with a pulverized particle size range of 100 to 500 μm.

[0015] Furthermore, in step S1, the mass ratio of the modified carbocisteine ​​microparticles I to the modified carbocisteine ​​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; and in step S5, the swing granulation is performed by pouring the total mixture into a granulator and swing granulating the mixture 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. 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 preparing the granules separately.

[0022] 2) The batch mixing method of the present invention reduces the contact surface 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, which reduces the usage of auxiliary materials and improves the utilization rate of auxiliary materials. DETAILED DESCRIPTION

[0024] In order to better understand the technical content of the present invention, specific examples 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 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 includes: mixing carbocysteine ​​with a purity of 99.9% and polysorbate 80 in a mass ratio of 10:0.5, stirring at a mixing temperature of 35° C., a mixing time of 25 minutes, and a stirring speed of 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., and the drying time is 3 hours. After drying, the mixture is crushed to a particle size of 200 μm, and 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, stirring at a mixing temperature of 40°C, a mixing time of 30 minutes, and a stirring speed of 150 rpm to obtain a modified carbocysteine ​​mixture, vacuum drying the modified carbocysteine ​​mixture, wherein the vacuum degree is -0.06 MPa, the drying temperature is 60°C, and the drying time is 4 hours. After drying, the mixture is crushed to a particle size of 300 μm, and 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, stirring at a mixing temperature of 38° C., a mixing time of 28 minutes, and a stirring speed of 140 rpm to obtain a modified carbocysteine ​​mixture, vacuum drying the modified carbocysteine ​​mixture, wherein the vacuum degree is -0.07 MPa, 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 250 μm, and the particles are granulated to obtain the modified carbocysteine ​​microparticles of Preparation Example 3.

[0032] Example 1

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

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

[0035] Step (2), mixing the modified carbocisteine ​​microparticles I and mannitol and wet granulating them, wherein the stirring speed 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 80% by mass ethanol solution, wherein the binder is hydroxyethyl cellulose, and the sweeteners are sucralose and maltitol, at a mixing speed of 15 rpm for 8 minutes to obtain a total mixture;

[0039] Step (5), pouring the total mixture into a granulator, shaking granulation 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 carbocisteine ​​microparticles into two parts, namely, modified carbocisteine ​​microparticles I and modified carbocisteine ​​microparticles II, wherein the mass ratio of the modified carbocisteine ​​microparticles I to the modified carbocisteine ​​microparticles II is 1:1;

[0043] Step (2), mixing the modified carbocisteine ​​microparticles I and mannitol, and wet granulating them at a stirring 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 80% by mass ethanol solution, 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 to obtain a total mixture;

[0047] Step (5), pouring the total mixture into a granulator, shaking granulation through a 24-mesh screen, the granulation 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, the granules are granulated and packaged to obtain the finished product.

[0048] Example 3

[0049] A high-stability carbocisteine ​​granule and a preparation method thereof, comprising the following raw materials in parts by weight: 96 parts of the modified carbocisteine ​​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 carbocisteine ​​microparticles into two parts, namely, modified carbocisteine ​​microparticles I and modified carbocisteine ​​microparticles II, wherein the mass ratio of the modified carbocisteine ​​microparticles I to the modified carbocisteine ​​microparticles II is 1:1;

[0051] Step (2), the modified carbocisteine ​​microparticles I and mannitol are mixed and wet granulated at a stirring speed of 23 Hz, a cutting speed of 9 Hz, and a stirring and cutting time of 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 80% by mass ethanol solution, wherein the binder is hydroxypropyl cellulose, and the sweeteners are sucralose and maltitol, at a mixing speed of 18 rpm for 10 minutes to obtain a total mixture;

[0055] Step (5), pouring the total mixture into a granulator, shaking granulation 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 unchanged.

[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. Other drug raw materials, proportions and steps remain unchanged.

[0060] Step (1), the modified carbocisteine ​​microparticles, mannitol and cross-linked sodium carboxymethyl cellulose are mixed and wet granulated, the wet granulation is carried out 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 80% by mass ethanol solution, 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 to obtain a total mixture;

[0063] Step (3), pouring the total mixture into a granulator, shaking granulation 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.

[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%". Other drug raw materials, proportions and steps remain unchanged.

[0066] comparison

[0067] An equal amount of commercially available carbocisteine ​​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 Part Four of the Chinese Pharmacopoeia 2020 Edition 0941". The content uniformity requirement is 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 standard (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 a hygroscopicity test. The operation was performed according to the guidance principle of the hygroscopicity test of drugs in the "General Rules 9103 of the Fourth Part 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 was significantly lower than that of Comparative Examples 1-3 and the control. 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 differences at 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 to have different appearance properties. The test conditions were RH80% high humidity, 55°C high temperature, 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 performed 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 milliliter. The solution was then measured, and 2% ninhydrin aqueous solution and phosphate buffer were added. 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 a UV-visible spectrophotometer was used to measure absorbance at a wavelength of 567 nanometers to calculate the carbocisteine ​​content (see Table 4).

[0079] Table 3 Appearance characteristics 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 tests. 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 according to the example methods have higher stability.

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

[0083]

[0084] Note: a, b, c indicate significant differences at P < 0.05

[0085] In summary, the modified carbocisteine ​​granules of the present invention are wet granulated twice and then mixed in a preparation method, which avoids the contact between carbocisteine ​​raw materials and auxiliary materials, avoids the contact between auxiliary materials and auxiliary materials, significantly reduces the negative reaction between the drug component and the auxiliary materials and between the auxiliary materials, and improves the stability and uniformity of the medicine. After comparative example 1 replaces modified carbocisteine ​​microgranules with carbocisteine ​​powder, carbocisteine ​​mass ratio decreases, and color is yellowish after high temperature; after comparative example 2 adds modified carbocisteine ​​microgranules as a whole, the stability of the finished product decreases, and color turns yellow under strong light and high humidity conditions, and carbocisteine ​​granule mass ratio decreases; comparative example 3 also reduces the stability of the finished product when changing ethanol solution mass fraction and preparation conditions. Therefore, the carbocisteine ​​granules obtained by the raw materials of the present invention in combination with the preparation method of the present invention have higher stability, and reduce the amount of auxiliary materials, thereby improving 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 scope of protection of the present invention.

Claims

1. A method for preparing high-stability carbocisteine ​​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 includes the following steps: S1. Dividing the modified carbocisteine ​​microparticles into two parts, namely, modified carbocisteine ​​microparticles I and modified carbocisteine ​​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; the mass fraction of the ethanol is 80%; S5. Shake the total mixture to granulate, dry, granulate, and package to obtain the finished product; the drying temperature is 50-65°C, the drying time is 2-3 hours, and the moisture content of the granules after drying is controlled at 1%-3%; 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.

2. The method for preparing high-stability carbocysteine ​​granules according to claim 1, wherein The mass ratio of carbocysteine ​​to polysorbate is 10:0.5-0.

8.

3. The method for preparing a high-stability carbocysteine ​​granule according to claim 1, wherein 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.

4. The method for preparing a high-stability carbocisteine ​​granule according to claim 1, wherein The vacuum drying process has a vacuum degree of -0.08 MPa to -0.06 MPa, a drying temperature of 55-60° C., and a drying time of 3-4 hours. The crushing process has a crushed particle size range of 100-500 μm.

5. The method for preparing high-stability carbocysteine ​​granules according to claim 1, wherein In step S1, the mass ratio of the modified carbocysteine ​​microparticles I to the modified carbocysteine ​​microparticles II is 1:1-1.

2.

6. The method for preparing high-stability carbocysteine ​​granules according to claim 1, wherein In step S2 and step S3, the wet granulation process 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.

7. The method for preparing high-stability carbocysteine ​​granules according to claim 1, wherein 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.

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

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