A high flowability N-acetyl-L-cysteine ethyl ester granule and a preparation method thereof

Abstract

The application discloses a kind of high fluidity N-acetyl-L-cysteine ethyl ester granules and preparation method, the granule includes the following components: N-acetyl-L-cysteine ethyl ester, porous adsorption carrier and film-forming barrier agent;N-acetyl-L-cysteine ethyl ester granule is obtained by first using porous adsorption carrier and N-acetyl-L-cysteine ethyl ester melt granulation, then using film-forming barrier agent to melt granulation material secondary wet granulation;Porous adsorption carrier is the combination of silicified microcrystalline cellulose and at least one selected from methyl cellulose or hydroxypropyl methyl cellulose;Film-forming barrier agent is ethyl cellulose.The method can improve the fluidity of N-acetyl-L-cysteine ethyl ester, process operation is simple, energy consumption is low, and granule is good in good, it has certain anti-conclusion effect in normal temperature environment, convenient to use.

Description

Technical Field

[0001] This invention belongs to the field of food processing technology, and specifically relates to a highly fluid N-acetyl-L-cysteine ​​ethyl ester particle and its preparation method. Background Technology

[0002] N-acetyl-L-cysteine ​​ethyl ester is an esterified form of N-acetyl-L-cysteine ​​(NAC). As a prodrug of N-acetyl-L-cysteine ​​(NAC), it has promising applications in the pharmaceutical and food industries. In the pharmaceutical field, N-acetyl-L-cysteine ​​ethyl ester possesses antioxidant and mucolytic properties, and can be used to treat diseases such as acetaminophen overdose and chronic obstructive pulmonary disease. In the food additive field, it can be used as an antioxidant and preservative, scavenging free radicals in food, preventing food oxidation and discoloration, and inhibiting bacterial growth, thus helping to extend the shelf life of food. However, N-acetyl-L-cysteine ​​ethyl ester is a white crystalline solid with a melting point of around 44°C. Due to its low melting point, it usually needs to be refrigerated at 2-8°C; otherwise, clumping may occur, affecting the accurate addition and uniformity of the product. In hard capsule filling, it can easily lead to unstable fill volume and material blockage; in tablet applications, it can easily cause tablet weight discrepancies, thus limiting its application.

[0003] Therefore, it is necessary to adopt new technologies and methods to solve the problem of N-acetyl-L-cysteine ​​ethyl ester easily clumping during transportation, avoid the need for cold chain transportation, reduce transportation costs, and improve product quality. Summary of the Invention

[0004] The purpose of this invention is to overcome the shortcomings of the prior art and provide a highly fluid N-acetyl-L-cysteine ​​ethyl ester particle and its preparation method.

[0005] To achieve the above objectives, the present invention adopts the following technical solution: The first aspect of this application provides highly fluid N-acetyl-L-cysteine ​​ethyl ester particles, comprising the following components: N-acetyl-L-cysteine ​​ethyl ester, a porous adsorbent support, and a film-forming barrier agent. The N-acetyl-L-cysteine ​​ethyl ester particles are obtained by first melt granulation using the porous adsorption carrier and the N-acetyl-L-cysteine ​​ethyl ester, and then performing secondary wet granulation on the melt granulated material using the film-forming barrier agent. The porous adsorption carrier is a combination of silanized microcrystalline cellulose and at least one selected from methylcellulose or hydroxypropyl methylcellulose; the film-forming barrier agent is ethyl cellulose. The mass ratio of the porous adsorbent carrier, the N-acetyl-L-cysteine ​​ethyl ester, and the film-forming barrier agent is 1:(1~1.2):(0.02~0.05).

[0006] Preferably, the mass fraction of the silanized microcrystalline cellulose in the porous adsorption carrier is 95-98%.

[0007] A second aspect of this application provides a method for preparing the highly fluid N-acetyl-L-cysteine ​​ethyl ester particles as described above, comprising the following steps: S1. Heat N-acetyl-L-cysteine ​​ethyl ester until it melts; S2. The porous adsorption support is mixed with the molten N-acetyl-L-cysteine ​​ethyl ester and granulated to form a semi-fluid soft material; S3. Cool the soft material to obtain solid microparticles; S4. Mix the solid microparticles and the film-forming barrier agent, and then perform secondary granulation using a wet granulation method to obtain the finished product.

[0008] Preferably, the melting temperature in step S1 is 45~55℃.

[0009] Preferably, step S2 is performed in a high-speed stirring shear granulator.

[0010] Preferably, step S3 involves air cooling to below 25°C.

[0011] Preferably, after cooling in step S3, the process further includes granulation and initial sieving; the initial sieving mesh size is 10-30 mesh.

[0012] Preferably, the film-forming barrier agent in step S4 is dissolved in an ethanol solution with a volume fraction of 90-98%, and the mass fraction of the film-forming barrier agent in the dissolved solution is 5-15%, and then mixed with the solid particles.

[0013] Preferably, step S4 further includes a drying step after wet granulation.

[0014] Preferably, the drying process further includes a secondary sieving step; the secondary sieving mesh size is 10-30 mesh.

[0015] This invention utilizes silicified microcrystalline cellulose (SMCC), which possesses advantages such as high specific surface area, multi-pore size, and high flowability, along with one or a combination of methylcellulose and hydroxypropyl methylcellulose, as a porous adsorption carrier. N-acetyl-L-cysteine ​​solid microparticles are prepared via melt granulation. Then, using ethyl cellulose as a film-forming barrier agent, highly flowable N-acetyl-L-cysteine ​​ethyl ester particles are prepared via wet granulation. This method improves the flowability of N-acetyl-L-cysteine ​​ethyl ester, is simple to operate, has low energy consumption, produces particles with good dispersibility, exhibits a certain anti-caking effect at room temperature, and is convenient to use. Detailed Implementation

[0016] Currently, there are no N-acetyl-L-cysteine ​​ethyl ester granules on the market, and the products are usually made to order and transported via cold chain.

[0017] To address this problem, this application provides highly fluid N-acetyl-L-cysteine ​​ethyl ester particles, comprising the following components: N-acetyl-L-cysteine ​​ethyl ester, a porous adsorbent support, and a film-forming barrier agent. The porous adsorption carrier is a combination of silanized microcrystalline cellulose and at least one selected from methylcellulose or hydroxypropyl methylcellulose; the film-forming barrier agent is ethyl cellulose; The mass ratio of porous adsorbent carrier, N-acetyl-L-cysteine ​​ethyl ester, and film-forming barrier agent is 1:(1~1.2):(0.02~0.05).

[0018] This product is obtained through a two-stage granulation method. First, a porous adsorption carrier and N-acetyl-L-cysteine ​​ethyl ester are melt-granulated, and then a film-forming barrier agent is used to perform a second wet granulation on the melt-granulated material.

[0019] Specifically, the preparation method of this product includes the following steps: S1. Heat N-acetyl-L-cysteine ​​ethyl ester until it melts to form a flowable liquid; the heating temperature should be higher than the melting point, but should not be too high to avoid wasting resources. Preferably, the melting temperature is 45~55℃.

[0020] S2. The porous adsorption carrier is mixed with molten N-acetyl-L-cysteine ​​ethyl ester and granulated. During the granulation process, the porous adsorption carrier is adsorbed onto the surface of the flowing N-acetyl-L-cysteine ​​ethyl ester liquid to form a semi-fluid soft material. Granulation is preferably carried out in a high-speed stirring and shearing granulator.

[0021] S3. Cool the soft material below its melting point to obtain solid microparticles with a certain hardness and uniform particle size; cooling methods such as air cooling and water cooling can be used. Air cooling to below 25°C is preferred. Preferably, after cooling, the process further includes granulation and initial sieving to ensure uniform particle size. Preferably, the initial sieving mesh size is 10-30 mesh.

[0022] S4. Mix the solid microparticles and the film-forming barrier agent, and then perform a second granulation using a wet granulation method to obtain the finished product. Since wet granulation is used, the film-forming barrier agent is preferably dissolved in an ethanol solution with a volume fraction of 90-98% before being mixed with the solid microparticles to increase the material's moisture content, enabling wet granulation and allowing ethyl cellulose to quickly spread on the surface of the microparticles to form a protective layer; the mass fraction of the film-forming barrier agent in the solution is 5-15%.

[0023] Ethyl cellulose has good solubility in ethanol. Using 90-98% ethanol can fully dissolve ethyl cellulose, so that it can better wet, spread and form a film on the surface of the microparticles in wet granulation.

[0024] The porous adsorbent carrier is composed of one or two of silanized microcrystalline cellulose (SMCC) and methylcellulose or hydroxypropyl methylcellulose. SMCC has a large number of microporous structures on its surface, with many "channels" within the molecule that can absorb molten oil. The colloidal silica on the surface can form silanol groups through hydrolysis, which can lock in lipids and prevent aggregation. At the same time, the orderly arrangement of cellulose chains within the cellulose molecules can effectively control the precipitation crystal form of solid lipids, making them firmly locked in the "channels" during cooling. Subsequently, uniform solid particles can be formed through granulation. However, silanized microcrystalline cellulose has short chains and weak intermolecular bonding. Therefore, this application uses long-chain macromolecules such as methylcellulose and hydroxypropyl methylcellulose combined with silanized microcrystalline cellulose. These two types of cellulose have high polymerization degree and strong intermolecular bonding, which can compensate for the short chains and weak intermolecular bonding of silanized microcrystalline cellulose.

[0025] Then, after secondary granulation using a film-forming barrier agent, the film-forming barrier agent ethyl cellulose can quickly spread on the surface of the microparticles to form a uniform and dense polymer film, which blocks the aggregation between the main materials. Compared with other similar compounds, the film formed by ethyl cellulose is completely unaffected by pH, has the strongest barrier effect, and is not prone to recrystallization and deformation during long-term storage, thus fully solving the problem of N-acetyl-L-cysteine ​​ethyl ester having a low melting point and hardening and clumping during storage.

[0026] Therefore, this invention utilizes silicified microcrystalline cellulose (SMCC), which possesses advantages such as high specific surface area, multi-pore size, and high flowability, along with one or a combination of methylcellulose and hydroxypropyl methylcellulose, as a porous adsorption carrier. N-acetyl-L-cysteine ​​solid microparticles are prepared via melt granulation. Then, using ethyl cellulose as a film-forming barrier agent, highly flowable N-acetyl-L-cysteine ​​ethyl ester particles are prepared via wet granulation. This method improves the flowability of N-acetyl-L-cysteine ​​ethyl ester, is simple to operate, has low energy consumption, exhibits good particle dispersibility, demonstrates a certain anti-caking effect at room temperature, and is convenient to use.

[0027] The N-acetyl-L-cysteine ​​ethyl ester granules provided by this invention have a content of up to about 54%, good flowability and a certain degree of hardness, and can be used in dosage forms such as hard capsules and powders. They have lower costs and a wider range of applications than existing raw materials.

[0028] Preferably, the mass fraction of silanized microcrystalline cellulose in the porous adsorption carrier is 95-98%. That is, the porous adsorption carrier is mainly composed of silanized microcrystalline cellulose, supplemented with a small amount of other celluloses, which can give full play to the advantages of silanized microcrystalline cellulose such as high specific surface area, multiple pore sizes and high fluidity.

[0029] Preferably, step S4, after wet granulation, further includes a drying step to allow the ethyl cellulose ethanol solvent to fully evaporate. More preferably, the drying temperature is 25-35°C, lower than that of N-acetyl-L-cysteine ​​ethyl ester, to prevent it from remelting.

[0030] After drying, a secondary sieving step is included to remove large particles and obtain a finished product with uniform particle size. The mesh size of the secondary sieving is 10~30 mesh.

[0031] Example 1 N-acetyl-L-cysteine ​​ethyl ester particles were prepared using silicified microcrystalline cellulose and methylcellulose as porous adsorbent supports. The mass ratio of porous adsorbent support: N-acetyl-L-cysteine ​​ethyl ester: ethyl cellulose was 1:1:0.02. The mass ratio of silicified microcrystalline cellulose to methylcellulose in the porous adsorbent support was 98:2.

[0032] The preparation method includes the following steps: (1) Heat N-acetyl-L-cysteine ​​ethyl ester at 45°C until completely melted; (2) Then, siliconized microcrystalline cellulose and methylcellulose are put into a high-speed stirring shear granulator, and the melted N-acetyl-L-cysteine ​​ethyl ester is slowly added and stirred until completely adsorbed to form a semi-fluid soft material. (3) Spread the soft material flat in the tray, circulate cold air until the material is cooled to below 25°C, granulate it using a granulator, and then sieve it using a 20-mesh national standard sieve to obtain solid microparticles. (4) Prepare a 10% ethyl cellulose solution (the solvent is a 95% ethanol aqueous solution). Put the solid particles into the wet granulator, turn on the stirring and shearing, and slowly add the ethyl cellulose solution through the spray head. After adding the slurry, granulate for 5 seconds and discharge the material. (5) Spread the material evenly in the tray, place it in a hot air circulating oven at 30°C, dry until the ethanol is completely evaporated, and then sieve it with a 20-mesh national standard sieve to obtain high-flowability N-acetyl-L-cysteine ​​ethyl ester particles.

[0033] To verify its stability, it was placed in a warehouse at 30℃ and 75% relative humidity, and samples were taken every three months to test its physicochemical properties and observe whether the product clumped. The physicochemical properties and stability of the prepared N-acetyl-L-cysteine ​​ethyl ester are shown in Table 1: Table 1. Physicochemical properties and accelerated stability test results of Sample 1

[0034]

[0035] Example 2 N-acetyl-L-cysteine ​​ethyl ester particles were prepared using silicified microcrystalline cellulose and hydroxypropyl methylcellulose as porous adsorption supports. The mass ratio of porous adsorption support: N-acetyl-L-cysteine ​​ethyl ester: ethyl cellulose was 1:1:0.05. The mass ratio of silicified microcrystalline cellulose to hydroxypropyl methylcellulose in the porous adsorption support was 98:2.

[0036] The preparation method includes the following steps: (1) Heat N-acetyl-L-cysteine ​​ethyl ester at 45°C until completely melted; (2) Then, siliconized microcrystalline cellulose and hydroxypropyl methylcellulose are put into a high-speed stirring shear granulator, and the melted N-acetyl-L-cysteine ​​ethyl ester is slowly added and stirred until completely adsorbed to form a semi-fluid soft material. (3) Spread the soft material flat in the tray, circulate cold air until the material is cooled to below 25°C, granulate it using a granulator, and then sieve it using a 20-mesh national standard sieve to obtain solid microparticles. (4) Prepare a 10% ethyl cellulose solution (the solvent is a 98% ethanol aqueous solution). Put the solid particles into a wet granulator, turn on the stirring and shearing, and slowly add the ethyl cellulose solution through the spray nozzle. After adding the slurry, granulate for 5 seconds and discharge the material. (5) Spread the material evenly in the tray, place it in a hot air circulating oven at 30°C, dry until the ethanol is completely evaporated, and then sieve it with a 20-mesh national standard sieve to obtain high-flowability N-acetyl-L-cysteine ​​ethyl ester particles.

[0037] To verify its stability, it was placed in a warehouse at 30℃ and 75% relative humidity, and samples were taken every three months to test its physicochemical properties and observe whether the product clumped. The physicochemical properties and stability of the prepared N-acetyl-L-cysteine ​​ethyl ester are shown in Table 2: Table 2. Physicochemical properties and accelerated stability test results of sample 2

[0038]

[0039] Example 3 N-acetyl-L-cysteine ​​ethyl ester particles were prepared using silanized microcrystalline cellulose, methylcellulose, and hydroxypropyl methylcellulose as porous adsorbent supports. The mass ratio of porous adsorbent to N-acetyl-L-cysteine ​​ethyl ester to ethyl cellulose was 1:1.2:0.05. The mass ratio of the porous adsorbents silanized microcrystalline cellulose to methylcellulose and hydroxypropyl methylcellulose was 97:2:1.

[0040] The preparation method includes the following steps: (1) Heat N-acetyl-L-cysteine ​​ethyl ester at 45°C until completely melted; (2) Then, siliconized microcrystalline cellulose, methyl cellulose, and hydroxypropyl methyl cellulose are put into a high-speed stirring shear granulator, and the melted N-acetyl-L-cysteine ​​ethyl ester is slowly added and stirred until completely adsorbed to form a semi-fluid soft material. (3) Spread the soft material flat in the tray, circulate cold air until the material is cooled to below 25°C, granulate it using a granulator, and then sieve it using a 20-mesh national standard sieve to obtain solid microparticles. (4) Prepare a 15% ethyl cellulose solution (the solvent is a 95% ethanol aqueous solution). Put the solid particles into the wet granulator, turn on the stirring and shearing, and slowly add the ethyl cellulose solution through the spray head. After adding the slurry, granulate for 5 seconds and discharge the material. (5) Spread the material evenly in the tray, place it in a hot air circulating oven at 35°C, dry until the ethanol is completely evaporated, and then sieve it with a 20-mesh national standard sieve to obtain high-flowability N-acetyl-L-cysteine ​​ethyl ester particles.

[0041] To verify its stability, it was placed in a warehouse at 30℃ and 75% relative humidity, and samples were taken every three months to test its physicochemical properties and observe whether the product clumped. The physicochemical properties and stability of the prepared N-acetyl-L-cysteine ​​ethyl ester are shown in Table 3: Table 3. Physicochemical properties and accelerated stability test results of sample 3

[0042]

[0043] Comparative Example 1 N-acetyl-L-cysteine ​​ethyl ester particles were prepared directly using ethyl cellulose as a binder without the addition of a porous adsorption carrier. The mass ratio of ethyl cellulose to N-acetyl-L-cysteine ​​ethyl ester was 5:95. The preparation method included the following steps: N-acetyl-L-cysteine ​​ethyl ester was added directly to a wet granulator in solid form. A 10% (w / w) ethyl cellulose solution (95% (v / v) ethanol aqueous solution) was slowly added through a spray nozzle. After the slurry was added, the granulation process lasted 5 seconds. The granules were then discharged, dried, and sieved to obtain N-acetyl-L-cysteine ​​ethyl ester granules.

[0044] N-acetyl-L-cysteine ​​ethyl ester granules were dry-mixed with microcrystalline cellulose at a 1:1 ratio to ensure consistent content. The mixture was then stored in a warehouse at 30℃ and 75% relative humidity. Samples were taken every three months to test physicochemical properties and observe for clumping. The physicochemical properties and stability of the prepared N-acetyl-L-cysteine ​​ethyl ester are shown in Table 4. Table 4. Comparative Example 1: Physicochemical properties and accelerated stability test results

[0045] Comparative Example 2 Using silicified microcrystalline cellulose as a porous adsorption carrier, without secondary granulation of ethyl cellulose, silicified microcrystalline cellulose and N-acetyl-L-cysteine ​​ethyl ester were mixed at a mass ratio of 1.2:1.

[0046] The preparation method includes the following steps: (1) Heat N-acetyl-L-cysteine ​​ethyl ester at 45°C until completely melted; (2) Then, the siliconized microcrystalline cellulose is put into a high-speed stirring shear granulator, and the melted N-acetyl-L-cysteine ​​ethyl ester is slowly added and stirred until it is completely adsorbed to form a semi-fluid soft material. (3) Spread the soft material flat in the tray, circulate cold air until the material is cooled to below 25°C, granulate it using a granulator, and then sieve it using a 20-mesh national standard sieve.

[0047] The product was placed in a warehouse at 30℃ and 75% relative humidity, and samples were taken every three months to test its physicochemical properties and observe whether it clumped. The physicochemical properties and stability of the product prepared in Comparative Example 2 are shown in Table 5. Table 5. Physicochemical properties and accelerated stability test results of Comparative Example 2

[0048]

[0049] Comparative Example 3 N-acetyl-L-cysteine ​​ethyl ester particles were prepared using methylcellulose and hydroxypropyl methylcellulose as porous adsorbent supports. The mass ratio of porous adsorbent support: N-acetyl-L-cysteine ​​ethyl ester: ethyl cellulose was 1:1:0.02. The mass ratio of methylcellulose to hydroxypropyl methylcellulose in the porous adsorbent support was 2:1.

[0050] The preparation method includes the following steps: (1) Heat N-acetyl-L-cysteine ​​ethyl ester at 45°C until completely melted; (2) Then put methylcellulose and hydroxypropyl methylcellulose into a high-speed stirring shear granulator, slowly add the melted N-acetyl-L-cysteine ​​ethyl ester, and stir until completely adsorbed to form a semi-fluid soft material; Since the N-acetyl-L-cysteine ​​ethyl ester melted in step (2) was not completely adsorbed into the porous adsorption carrier, most of the material adhered to the pot wall and could not be used for subsequent production, resulting in the final particles not being formed.

[0051] Although preferred embodiments of the invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including both the preferred embodiments and all changes and modifications falling within the scope of the invention. Clearly, those skilled in the art can make various alterations and modifications to the invention without departing from its spirit and scope. Thus, if these modifications and modifications of the invention fall within the scope of the claims and their equivalents, the invention is also intended to include these modifications and modifications.

Claims

1. A highly flowable N-acetyl-L-cysteine ​​ethyl ester particle, characterized in that, It includes the following components: N-acetyl-L-cysteine ​​ethyl ester, porous adsorbent support, and film-forming barrier agent; The N-acetyl-L-cysteine ​​ethyl ester particles are obtained by first melt granulation using the porous adsorption carrier and the N-acetyl-L-cysteine ​​ethyl ester, and then performing secondary wet granulation on the melt granulated material using the film-forming barrier agent. The porous adsorption carrier is a combination of silanized microcrystalline cellulose and at least one selected from methylcellulose or hydroxypropyl methylcellulose; the film-forming barrier agent is ethyl cellulose. The mass ratio of the porous adsorbent carrier, the N-acetyl-L-cysteine ​​ethyl ester, and the film-forming barrier agent is 1:(1~1.2):(0.02~0.05).

2. The highly fluid N-acetyl-L-cysteine ​​ethyl ester particles as described in claim 1, characterized in that, The mass fraction of the silanized microcrystalline cellulose in the porous adsorbent carrier is 95-98%.

3. A method for preparing highly fluid N-acetyl-L-cysteine ​​ethyl ester particles as described in any one of claims 1 to 2, characterized in that, Includes the following steps: S1. Heat N-acetyl-L-cysteine ​​ethyl ester until it melts; S2. The porous adsorption support is mixed with the molten N-acetyl-L-cysteine ​​ethyl ester and granulated to form a semi-fluid soft material; S3. Cool the soft material to obtain solid microparticles; S4. Mix the solid microparticles and the film-forming barrier agent, and then perform secondary granulation using a wet granulation method to obtain the finished product.

4. The method for preparing highly fluid N-acetyl-L-cysteine ​​ethyl ester particles as described in claim 3, characterized in that, The melting temperature in step S1 is 45~55℃.

5. The method for preparing highly fluid N-acetyl-L-cysteine ​​ethyl ester particles as described in claim 3, characterized in that, Step S2 is carried out in a high-speed stirring shear granulator.

6. The method for preparing highly fluid N-acetyl-L-cysteine ​​ethyl ester particles as described in claim 3, characterized in that, Step S3 involves air cooling to below 25°C.

7. The method for preparing highly fluid N-acetyl-L-cysteine ​​ethyl ester particles as described in claim 3, characterized in that, After cooling in step S3, the process also includes granulation and initial sieving; the initial sieving mesh size is 10-30 mesh.

8. The method for preparing highly fluid N-acetyl-L-cysteine ​​ethyl ester particles as described in claim 3, characterized in that, In step S4, the film-forming barrier agent is dissolved in an ethanol solution with a volume fraction of 90-98%, and the mass fraction of the film-forming barrier agent in the dissolved solution is 5-15%, which is then mixed with the solid particles.

9. The method for preparing highly fluid N-acetyl-L-cysteine ​​ethyl ester particles as described in claim 3, characterized in that, Step S4, following wet granulation, also includes a drying step.

10. The method for preparing highly fluid N-acetyl-L-cysteine ​​ethyl ester particles as described in claim 9, characterized in that, The drying process also includes a secondary sieving step; the secondary sieving mesh size is 10~30 mesh.

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