A preparation process of mesalazine sustained-release granules

Abstract

The invention discloses a preparation process of mesalazine sustained-release granules, comprising the following steps: mixing a mesalazine main drug, a diluent and an anti-adhesive agent to obtain a drug-containing mixed powder; granulating the drug-containing mixed powder, polyacrylic acid resin, an anti-adhesive agent and water to obtain a drug-containing soft material; extruding the drug-containing soft material by an extrusion device to obtain a drug-containing strip; spheronizing the drug-containing strip to obtain drug-containing wet granules; drying the drug-containing wet granules to obtain drug-containing dry granules; sieving the drug-containing dry granules to obtain mesalazine sustained-release granules; wherein the mesalazine main drug includes mesalazine or a pharmaceutically acceptable salt thereof, and the discharge end of the extrusion device is provided with a flat sieve plate for extruding the drug-containing soft material. The mesalazine sustained-release granules prepared by the preparation process have a good sustained-release effect.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparation production, and in particular to a preparation process of mesalazine sustained-release granules. Background Art

[0002] Mesalazine is a local gastrointestinal drug, and its efficacy is not related to its concentration in the systemic circulation, but to the concentration of mesalazine in the intestinal inflammation site. After oral administration of mesalazine sustained-release granules, mesalazine released too quickly will be rapidly absorbed by the human body and enter the systemic circulation, thereby reducing its concentration in the intestinal inflammation site and reducing the efficacy. Therefore, it is urgently needed to provide a mesalazine sustained-release granule with a better function of delaying and prolonging drug release. Summary of the invention

[0003] The main purpose of the present invention is to provide a preparation process of mesalazine sustained-release granules, aiming to obtain mesalazine sustained-release granules with good delayed and prolonged drug release function.

[0004] To achieve the above object, the present invention provides a preparation process of mesalazine sustained-release granules, comprising the following steps:

[0005] Mixing the main drug of mesalazine, a diluent and an anti-adhesive agent to obtain a drug-containing mixed powder;

[0006] Granulating the drug-containing mixed powder, polyacrylic acid resin, anti-adhesive agent and water to obtain a drug-containing soft material;

[0007] The drug-containing soft material is extruded into a shape by using an extrusion device to obtain a drug-containing strip;

[0008] Spheronizing the drug-containing strips to obtain drug-containing wet granules;

[0009] Drying the drug-containing wet granules to obtain drug-containing dry granules;

[0010] Screening the drug-containing dry particles to obtain mesalazine sustained-release particles;

[0011] Wherein, the mesalazine main drug includes mesalazine or a pharmaceutically acceptable salt thereof, and the discharge end of the extrusion device is provided with a flat screen plate for extruding the drug-containing soft material.

[0012] Optionally, the extrusion device is a screw extruder, and the discharge end of the screw extruder is provided with the flat screen plate.

[0013] Optionally, the sieve hole diameter of the planar sieve plate is 0.5 to 1.5 mm;

[0014] Optionally, the thickness of the flat sieve plate is 1.5 to 5.0 mm.

[0015] Optionally, the polyacrylic acid resin includes at least one of ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride.

[0016] Optionally, the polyacrylic acid resin includes Eudragit NM 30D, Eudragit NM 40D, Eudragit NE 30D or Eudragit NE 40D.

[0017] Optionally, the step of granulating the drug-containing mixed powder, polyacrylic acid resin, anti-adherent agent and water to obtain the drug-containing soft material comprises:

[0018] The drug-containing mixed powder, adhesive, polyacrylic acid resin, anti-adhesive agent and water are granulated to obtain the drug-containing soft material.

[0019] Optionally, the binder comprises hypromellose, hydroxypropyl cellulose or polyvinyl pyrrolidone.

[0020] Optionally, the step of spheronizing the drug-containing strip to obtain drug-containing wet granules comprises:

[0021] The drug-containing strip is spheronized at a rotation speed of 100-500 rpm for 1-10 min, then spheronized at a rotation speed of 1000-1600 rpm for 1-10 min, and finally spheronized at a rotation speed of 1600-2000 rpm for 1-10 min.

[0022] The preparation process of mesalazine sustained-release granules provided by the present invention comprises the following steps: the drug-containing soft material is extruded through a flat screen plate of an extrusion device, and compared with an existing basket extruder and a spherical screw extruder, the obtained drug-containing strips are more compact, the surface will not be cracked, and the overall strips are longer, so that the obtained mesalazine sustained-release granules have a better effect of delaying and prolonging drug release; and, compared with an existing basket extruder and a spherical screw extruder, the flat screen plate extrusion finally obtains granules with a larger bulk density, further improving the sustained-release effect of the mesalazine sustained-release granules, so that the granules have a stable and repeatable drug release mode. In addition, since the obtained mesalazine sustained-release granules have a good sustained-release effect, no additional sustained-release functional coating is required, which helps to simplify the process steps; by adding a diluent to the material, and combining granulation, extrusion molding and spheronization, the diluent is better attached to the surface of the mesalazine sustained-release granules, so that the surface of the mesalazine sustained-release granules is relatively smooth, and the enteric functional coating and the taste-masking layer coating can be directly performed without additional isolation layer coating to obtain the subsequent product mesalazine enteric sustained-release granules, which is convenient for commercial application; polyacrylic acid resin is used as a skeleton material in the mesalazine sustained-release granules to further optimize the sustained-release effect; through spheronization, drug-containing wet granules with a better particle size are obtained, thereby improving the yield of the mesalazine sustained-release granules; the granulation process combined with extrusion molding and spheronization can prepare mesalazine sustained-release granules with a higher drug loading amount compared to the existing main drug spraying granulation method; the preparation process is simple, efficient and energy-saving and is conducive to commercial application. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without paying creative work.

[0024] Figure 1 This is a schematic flow chart of an embodiment of a process for preparing mesalazine sustained-release granules proposed in the present invention;

[0025] Figure 2 is the cumulative release rate of the mesalazine sustained-release granules of Example 1-2 of the present invention in a pH 6.8 medium;

[0026] Figure 3 It is the cumulative release rate of the mesalazine enteric-coated sustained-release granules of Example 7 and Comparative Examples 1-2 of the present invention in a medium of pH 6.8.

[0027] The realization of the purpose, functional features and advantages of the present invention will be further explained in conjunction with embodiments and with reference to the accompanying drawings. DETAILED DESCRIPTION

[0028] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0029] It should be noted that if the embodiments of the present invention involve directional indications (such as up, down, left, right, front, back, etc.), the directional indications are only used to explain the relative position relationship, movement status, etc. between the components under a certain specific posture (as shown in the accompanying drawings). If the specific posture changes, the directional indication will also change accordingly.

[0030] In addition, if there are descriptions involving "first", "second", etc. in the embodiments of the present invention, the descriptions of "first", "second", etc. are only used for descriptive purposes and cannot be understood as indicating or implying their relative importance or implicitly indicating the number of technical features indicated. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In addition, the meaning of "and / or" appearing in the full text includes three parallel schemes. Taking "A and / or B" as an example, it includes scheme A, or scheme B, or a scheme that satisfies both A and B. In addition, the technical solutions between the various embodiments can be combined with each other, but it must be based on the ability of ordinary technicians in the field to implement. When the combination of technical solutions is contradictory or cannot be implemented, it should be deemed that such a combination of technical solutions does not exist and is not within the scope of protection required by the present invention.

[0031] Mesalazine is a local gastrointestinal drug, and its efficacy is not related to its concentration in the systemic circulation, but to the concentration of mesalazine in the intestinal inflammation site. After oral administration of mesalazine sustained-release granules, mesalazine released too quickly will be rapidly absorbed by the human body and enter the systemic circulation, thereby reducing its concentration in the intestinal inflammation site and reducing the efficacy. Therefore, it is urgently needed to provide a mesalazine sustained-release granule with a better function of delaying and prolonging drug release.

[0032] In view of this, the present invention proposes a preparation process of mesalazine sustained-release granules. Figure 1 The present invention is a schematic flow chart of an embodiment of a process for preparing mesalazine sustained-release granules.

[0033] Please refer to Figure 1 The preparation process of the mesalazine sustained-release granules comprises the following steps:

[0034] Step S10, mixing the main drug of mesalazine, the diluent and the anti-adhesive agent to obtain a drug-containing mixed powder. The main drug of mesalazine includes mesalazine or a pharmaceutically acceptable salt thereof.

[0035] By adding the diluent, after subsequent processing, the diluent will eventually adhere to the surface of the mesalazine sustained-release granules, thereby improving the smoothness of the surface of the mesalazine sustained-release granules, making it easier to prepare the subsequent product, the mesalazine enteric-coated sustained-release granules.

[0036] The diluent includes but is not limited to microcrystalline cellulose, sucrose and starch; the anti-adherent of step S10 includes but is not limited to stearic acid, pharmaceutically acceptable metal salts of stearic acid, stearyl fumaric acid, pharmaceutically acceptable metal salts of stearyl fumaric acid, silicon dioxide, talc, glyceryl monostearate and glyceryl distearate.

[0037] Furthermore, the present invention does not limit the specific manner of mixing in step S10, which may be tumbling mixing or stirring shearing mixing. The present invention also does not limit the specific equipment used for mixing, such as a square cone mixer and a multi-directional mixer (tumbling mixing), and a high-efficiency wet mixing granulator (stirring shearing mixing).

[0038] Step S20, granulating the drug-containing mixed powder, polyacrylic acid resin, anti-adhesive agent and water to obtain a drug-containing soft material.

[0039] The sustained-release effect was further optimized by adding polyacrylic acid resin as the skeleton material in the mesalazine sustained-release granules.

[0040] The polyacrylic acid resin includes at least one of ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride. When the polyacrylic acid resin is a combination of multiple of ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride, the polyacrylic acid resin includes Eudragit NM 30D, Eudragit NM 40D, Eudragit NE 30D or Eudragit NE 40D.

[0041] Furthermore, an additional adhesive may be added in step S20 to make the materials more firmly bonded by the adhesive, so that the drug-containing soft material is more compact, which is beneficial to the sustained-release effect of the mesalazine sustained-release granules obtained later. When an adhesive is added in step S20, step S20 specifically includes: granulating the drug-containing mixed powder, adhesive, polyacrylic acid resin, anti-adhesive agent and water to obtain the drug-containing soft material. Wherein, the adhesive includes hydroxypropyl methylcellulose, hydroxypropyl cellulose or polyvinyl pyrrolidone.

[0042] The anti-adhesive agent of step S20 includes, but is not limited to, stearic acid, pharmaceutically acceptable metal salts of stearic acid, stearyl fumaric acid, pharmaceutically acceptable metal salts of stearyl fumaric acid, silicon dioxide, talc, glyceryl monostearate and glyceryl distearate.

[0043] It should be noted that the present invention does not limit the specific method of granulation in step S20, for example, stirring shearing granulation, flow granulation, and of course, the present invention does not limit the specific equipment used for granulation in step S20, which may be a high-efficiency wet mixing granulator (stirring shearing granulation) or a fluidized bed (flow granulation).

[0044] Step S30, using an extrusion device to extrude the drug-containing soft material into a shape to obtain a drug-containing strip, wherein a flat sieve plate for extruding the drug-containing soft material is provided at the discharge end of the extrusion device.

[0045] The drug-containing soft material is extruded through the flat screen plate of the extrusion device. Compared with the existing basket extruder and spherical screw extruder, the obtained drug-containing strips are more compact, the surface will not crack, and the overall strips are longer, so that the mesalazine sustained-release granules obtained after subsequent processing have a good effect of delaying and prolonging drug release; and, compared with the existing basket extruder and spherical screw extruder, the flat screen plate extrusion finally obtains a larger bulk density of the granules, further improving the sustained-release effect of the mesalazine sustained-release granules; in addition, since the obtained mesalazine sustained-release granules have a good sustained-release effect, there is no need to perform additional sustained-release functional coating, which helps to simplify the process steps.

[0046] According to the test, the bulk density of the mesalazine sustained-release granules obtained by extrusion using a flat sieve plate is 0.4-1.0 g / mL. When the parameters of the flat sieve plate are well controlled, the bulk density of the mesalazine sustained-release granules can reach 0.6-0.8 g / mL.

[0047] Specifically, the extrusion device is a screw extruder, and the discharge end of the screw extruder is provided with the flat screen plate. Through the effects of screw extrusion, shearing and stirring, the drug-containing soft material is continuously extruded through the flat screen plate, and the extrusion efficiency is high.

[0048] In order to obtain a drug-containing strip with better properties, the thickness of the plane sieve plate is optimized in the embodiment of the present invention, and the thickness of the plane sieve plate is 1.5 to 5.0 mm, and preferably the thickness of the plane sieve plate is 2.0 to 4.0 mm. As the thickness of the plane sieve plate increases, the resistance of the drug-containing soft material passing through the small holes of the sieve plate increases. When the drug-containing soft material is continuously extruded by the extrusion device, the extrusion force between the drug-containing soft materials near the plane sieve plate increases, so that after passing through the plane sieve plate, a drug-containing strip with a smooth surface and no cracks and a tight interior is formed, ensuring the effect of delaying and extending the release of the main drug mesalazine. However, the extrusion surface of the basket extruder and the spherical screw extruder is not a plane, but a stainless steel arc surface. Due to the limitation of the manufacturing process, the thickness of the extrusion sieve plate of the two is mostly 1.0 mm or less, and the resistance of the drug-containing soft material passing through the sieve plate is small, so the extruded drug-containing strip is not tight, easy to break, and the surface is cracked, which makes it difficult to ensure the effect of delaying and extending the release of the main drug mesalazine.

[0049] In addition, the embodiment of the present invention optimizes the sieve hole diameter of the planar sieve plate, and the sieve hole diameter of the planar sieve plate is 0.5-1.5 mm. Preferably, the sieve hole diameter of the planar sieve plate is 0.8-1.2 mm. Within the sieve hole diameter range, the obtained drug-containing strips are more compact, further improving the effect of delaying and extending the release of the main drug mesalazine.

[0050] It is understandable that the parameters of the sieve hole diameter and thickness of the above-mentioned planar sieve plate can be satisfied at the same time, or only one of them can be satisfied. As a preferred embodiment of the present invention, the above conditions are satisfied at the same time, which can make the properties of the drug-containing strips better.

[0051] Step S40: Spheronize the drug-containing strips to obtain drug-containing wet granules.

[0052] The drug-containing wet granules with a better particle size are obtained through spheronization, thereby improving the yield of mesalazine sustained-release granules. The mesalazine sustained-release granules obtained after spheronization are tested, and the mass content of granules with a particle size of 0.5 to 2.5 mm is greater than or equal to 99%. When the parameters of the spheronization are well controlled, the mass content of granules with a particle size of 0.8 to 1.6 mm is greater than or equal to 95%.

[0053] Specifically, step S40 includes: rolling the drug-containing strip at a speed of 100-500 rpm for 1-10 minutes, then rolling at a speed of 1000-1600 rpm for 1-10 minutes, and finally rolling at a speed of 1600-2000 rpm for 1-10 minutes. By using the three-step rolling process with different speed gradients, the drug-containing strip is cut and rolled into drug-containing wet granules with regular shapes.

[0054] The present invention does not limit the specific equipment used for the rounding process in step S40. For example, the rounding process can be performed using a rounding machine, which uses a high-speed rotating toothed turntable in the rounding machine to cut and round the drug-containing strip. Of course, other rounding equipment can also be used, which are not listed here one by one.

[0055] Step S50, drying the drug-containing wet granules to obtain drug-containing dry granules.

[0056] The wet granules containing the drug are dried to evaporate the water therein, and obtain dry granules containing the drug that are dried and easy to screen. The drying equipment used can be a fluidized bed or an oven, or other equipment, which is not limited in the present invention.

[0057] Step S60, sieving the drug-containing dry particles to obtain mesalazine sustained-release particles.

[0058] The particles with larger particle size or broken particles are removed by sieving to finally obtain mesalazine sustained-release granules.

[0059] The specific steps of step S60 are as follows: the drug-containing dry particles are sequentially passed through a first sieve of 8 mesh (corresponding to a particle size of 2.5 mm) and a second sieve of 35 mesh (corresponding to a particle size of 0.5 mm), and the particles passing through the first sieve and retained on the second sieve are collected to obtain mesalazine sustained-release particles.

[0060] Of course, step S60 can also be performed as follows: the drug-containing dry particles are sequentially passed through a first sieve of 12 mesh (corresponding to a particle size of 1.6 mm) and a second sieve of 24 mesh (corresponding to a particle size of 0.8 mm), and the particles that pass through the first sieve and are retained on the second sieve are collected to obtain mesalazine sustained-release particles.

[0061] In addition, step S60 can also be performed as follows: the drug-containing dry particles are sequentially passed through a first sieve of 12 mesh (corresponding to a particle size of 1.6 mm) and a second sieve of 20 mesh (corresponding to a particle size of 0.9 mm), and the particles that pass through the first sieve and are retained on the second sieve are collected to obtain mesalazine sustained-release particles.

[0062] It should be noted that when an adhesive is added in step S20, the raw materials of the mesalazine sustained-release granules are in the following proportions: in terms of mass percentage, the mesalazine sustained-release granules include the following raw materials: 50-80% of the main drug of mesalazine, 10-40% of the diluent, greater than 0 and less than or equal to 2% of the anti-adhesive agent, greater than 0 and less than or equal to 5% of the adhesive, and 4-15% of the polyacrylic acid resin. In this way, combined with extrusion molding and spheronization, mesalazine sustained-release granules with a drug loading of up to 50-80% are obtained, which can further improve patient compliance.

[0063] The obtained mesalazine sustained-release granules were measured in a model system using the paddle method of the second method of the Chinese Pharmacopoeia, with a release medium of pH 6.8 and a stirring paddle speed of 100 rpm, and the following in vitro release characteristics of mesalazine were obtained (based on the mass percentage of mesalazine in the sustained-release granules): 15-40% was released after 30 minutes; 50-70% was released after 120 minutes; 70-85% was released after 240 minutes; and >85% was released after 480 minutes. This indicates that the mesalazine sustained-release granules have a good effect of delaying and prolonging drug release.

[0064] The preparation process of mesalazine sustained-release granules provided by the present invention comprises the following steps: the drug-containing soft material is extruded through a flat screen plate of an extrusion device, and compared with an existing basket extruder and a spherical screw extruder, the obtained drug-containing strips are more compact, the surface will not be cracked, and the overall strips are longer, so that the obtained mesalazine sustained-release granules have a better effect of delaying and prolonging drug release; and, compared with an existing basket extruder and a spherical screw extruder, the flat screen plate extrusion finally obtains granules with a larger bulk density, further improving the sustained-release effect of the mesalazine sustained-release granules, so that the granules have a stable and repeatable drug release mode. In addition, since the obtained mesalazine sustained-release granules have a good sustained-release effect, no additional sustained-release functional coating is required, which helps to simplify the process steps; by adding a diluent to the material, and combining granulation, extrusion molding and spheronization, the diluent is better attached to the surface of the mesalazine sustained-release granules, so that the surface of the mesalazine sustained-release granules is relatively smooth, and the enteric functional coating and the taste-masking layer coating can be directly performed without additional isolation layer coating to obtain the subsequent product mesalazine enteric sustained-release granules, which is convenient for commercial application; polyacrylic acid resin is used as a skeleton material in the mesalazine sustained-release granules to further optimize the sustained-release effect; through spheronization, drug-containing wet granules with a better particle size are obtained, thereby improving the yield of the mesalazine sustained-release granules; the granulation process combined with extrusion molding and spheronization can prepare mesalazine sustained-release granules with a higher drug loading amount compared to the existing main drug spraying granulation method; the preparation process is simple, efficient and energy-saving and is conducive to commercial application.

[0065] The technical solution of the present invention is further described in detail below in conjunction with specific examples and test data. It should be understood that the following examples are only used to explain the present invention and are not intended to limit the present invention.

[0066] Example 1 Preparation of Mesalazine Sustained-Release Granules

[0067] (1) The prescription of mesalazine sustained-release granules is shown in Table 1.

[0068] Table 1 Prescription of Mesalazine Sustained Release Granules of Example 1

[0069]

[0070] In the table, * is calculated based on solid content; ** evaporated during processing.

[0071] (2) Preparation process:

[0072] 1) Mesalazine, microcrystalline cellulose and magnesium stearate were mixed using a high-efficiency wet mixing granulator, with a stirring blade speed of 300 rpm, a cutting blade speed of 1200 rpm, and a mixing time of 5 min to obtain a drug-containing mixed powder.

[0073] 2) Using a mechanical stirrer to stir the aqueous dispersion of ethyl acrylate-methyl methacrylate copolymer, adding colloidal silica, and mixing evenly to obtain a polymer binder solution; adding the drug-containing mixed powder into the pot of the high-efficiency wet mixing granulator, and starting the stirring paddle and cutter of the high-efficiency wet mixing granulator, and then using an atomizing spray gun and a peristaltic pump to spray the polymer binder solution into the pot of the high-efficiency wet mixing granulator, and adding an appropriate amount of purified water to obtain a drug-containing soft material. Among them, the stirring paddle speed is 300rpm, the cutter speed is 1200rpm, the atomization pressure of the atomizing spray gun is 0.06MPa, the speed of the peristaltic pump is 25rpm, and the spraying time is 20min.

[0074] 3) The drug-containing soft material is fed into a screw extruder, the sieve hole diameter of the flat sieve plate of the screw extruder is 1.1 mm, the thickness of the flat sieve plate is 3.5 mm, and the drug-containing soft material is extruded at an extrusion speed of 45 rpm to obtain a full drug-containing strip.

[0075] 4) Use a spheronizer to cut and spheronize the full drug-containing strips, spheronize at 200 rpm for 7 min, then spheronize at 1500 rpm for 3 min, and finally spheronize at 2000 rpm for 10 min to obtain drug-containing wet granules.

[0076] 5) Use a fluidized bed to dry the wet granules containing the drug, with an inlet air temperature of 65°C and an air volume of 60-160m 3 / h, until the LOD (Loss on drying) of the particles is lower than 3.0%, thereby obtaining drug-containing dry particles.

[0077] 6) The drug-containing dry particles are sequentially passed through a first sieve of 12 mesh (corresponding to a particle size of 1.6 mm) and a second sieve of 20 mesh (corresponding to a particle size of 0.9 mm), and the particles that pass through the first sieve and are retained on the second sieve are collected to obtain mesalazine sustained-release particles.

[0078] In the release model of pH 6.8 medium, the release behavior of the mesalazine sustained-release granules prepared in Example 1 is shown in Tables 2 and Figure 2 .

[0079] Table 2 Release of mesalazine sustained-release granules prepared in Example 1

[0080]

[0081] As can be seen from Table 2, mesalazine is not completely released until 8 to 12 hours later, indicating that the mesalazine sustained-release granules have a release period of 8 to 12 hours, proving that the mesalazine sustained-release granules prepared in Example 1 have a good effect of delaying and prolonging drug release and a good sustained-release effect.

[0082] In the release model of pH 6.8 medium, the intra-batch release differences of Example 1 are shown in Table 3 below.

[0083] Table 3 Intra-batch release differences of mesalazine sustained-release granules prepared in Example 1

[0084]

[0085] Table 3 shows that at different time points, the RSD (relative deviation) values ​​of the release of the three parallel samples were all less than 5.0%, indicating that the intra-batch release difference of the mesalazine sustained-release granules prepared in Example 1 was small.

[0086] Example 2 Preparation of Mesalazine Sustained-Release Granules

[0087] (1) The prescription of mesalazine sustained-release granules is shown in Table 4.

[0088] Table 4 Prescription of mesalazine sustained-release granules

[0089]

[0090] In the table, * is calculated based on solid content; ** evaporated during processing.

[0091] (2) Preparation process:

[0092] 1) Mesalazine, microcrystalline cellulose and magnesium stearate were mixed using a high-efficiency wet mixing granulator, with a stirring blade speed of 300 rpm, a cutting blade speed of 1200 rpm, and a mixing time of 5 min to obtain a drug-containing mixed powder.

[0093] 2) Mixing hydroxypropyl methylcellulose and purified water using a magnetic stirrer / mechanical stirrer to obtain a hydroxypropyl methylcellulose aqueous solution; adding colloidal silicon dioxide to an aqueous dispersion of ethyl acrylate-methyl methacrylate copolymer, stirring, and then adding a hydroxypropyl methylcellulose aqueous solution, mixing evenly to obtain a polymer binder solution; adding the drug-containing mixed powder to the pot of a high-efficiency wet mixing granulator, and starting the stirring paddle and cutter of the high-efficiency wet mixing granulator, and then using an atomizing spray gun and a peristaltic pump to spray the polymer binder solution into the pot of the high-efficiency wet mixing granulator, and adding an appropriate amount of purified water to obtain a drug-containing soft material. Among them, the stirring paddle speed is 300rpm, the cutter speed is 1200rpm, the atomization pressure of the atomizing spray gun is 0.06MPa, the peristaltic pump speed is 25rpm, and the spraying time is 20min.

[0094] 3) feeding the drug-containing soft material into a screw extruder, the sieve hole diameter of the flat sieve plate of the screw extruder is 1.0 mm, the thickness of the flat sieve plate is 3.0 mm, and extruding the drug-containing soft material at an extrusion speed of 45 rpm to obtain a full drug-containing strip.

[0095] 4) Use a spheronizer to cut and spheronize the full drug-containing strips, spheronize at 200 rpm for 3 min, then spheronize at 1500 rpm for 4 min, and finally spheronize at 2000 rpm for 8 min to obtain drug-containing wet granules.

[0096] 5) Use a fluidized bed to dry the wet granules containing the drug, with an inlet air temperature of 65°C and an air volume of 60-160m 3 / h until the LOD of the particles is lower than 3.0% to obtain drug-containing dry particles.

[0097] 6) The drug-containing dry particles are sequentially passed through a first sieve of 12 mesh (corresponding to a particle size of 1.6 mm) and a second sieve of 20 mesh (corresponding to a particle size of 0.9 mm), and the particles that pass through the first sieve and are retained on the second sieve are collected to obtain mesalazine sustained-release particles.

[0098] In the release model of pH 6.8 medium, the release behavior of the mesalazine sustained-release granules prepared in Example 2 is shown in Tables 5 and Figure 2 .

[0099] Table 5 Release of mesalazine sustained-release granules prepared in Example 2

[0100]

[0101] As can be seen from Table 5, mesalazine is not completely released until 8 to 12 hours later, indicating that the mesalazine sustained-release granules have a release period of 8 to 12 hours, proving that the mesalazine sustained-release granules prepared in Example 2 have a good effect of delaying and prolonging drug release, and have a good sustained-release effect.

[0102] In the release model of pH 6.8 medium, the intra-batch release differences of Example 2 are shown in Table 6 below:

[0103] Table 6 Intra-batch release differences of mesalazine sustained-release granules prepared in Example 2

[0104]

[0105] Table 6 shows that at different time points, the RSD values ​​of the release of the three parallel samples were all less than 5.0%, indicating that the intra-batch release difference of the mesalazine sustained-release granules prepared in Example 2 was small.

[0106] Example 3 Preparation of Mesalazine Sustained Release Granules

[0107] The difference from Example 2 is that in preparation process 3), the sieve hole diameter of the flat sieve plate is 0.5 mm, and the thickness of the flat sieve plate is 1.5 mm; in preparation process 4), the rolling is carried out at a rotation speed of 150 rpm for 3 min, then at a rotation speed of 1000 rpm for 3 min, and finally at a rotation speed of 1600 rpm for 2 min.

[0108] In the release model of pH 6.8 medium, the release behavior of the mesalazine sustained-release granules prepared in Example 3 is shown in Table 7 below.

[0109] Table 7 Release of mesalazine sustained-release granules prepared in Example 3

[0110]

[0111] As shown in Table 7, mesalazine is not completely released until 8 to 12 hours later, indicating that the mesalazine sustained-release granules have a release period of 8 to 12 hours, proving that the mesalazine sustained-release granules prepared in Example 3 have a good effect of delaying and prolonging drug release, and have a good sustained-release effect.

[0112] In the release model of pH 6.8 medium, the intra-batch release differences of Example 3 are shown in Table 8 below:

[0113] Table 8 Intra-batch release differences of mesalazine sustained-release granules prepared in Example 3

[0114]

[0115]

[0116] Table 8 shows that at different time points, the RSD values ​​of the release of the three parallel samples were all less than 5.0%, indicating that the intra-batch release difference of the mesalazine sustained-release granules prepared in Example 3 was small.

[0117] Example 4

[0118] The difference from Example 2 is that in preparation process 3), the sieve hole diameter of the flat sieve plate is 0.8 mm, and the thickness of the flat sieve plate is 2.5 mm; in preparation process 4), the rolling is performed at a rotation speed of 200 rpm for 3 min, then at a rotation speed of 1500 rpm for 2 min, and finally at a rotation speed of 1800 rpm for 4 min.

[0119] In the release model of pH 6.8 medium, the release behavior of the mesalazine sustained-release granules prepared in Example 4 is shown in Table 9 below.

[0120] Table 9 Release of mesalazine sustained-release granules prepared in Example 4

[0121]

[0122] As shown in Table 9, mesalazine is not completely released until 8 to 12 hours later, indicating that the mesalazine sustained-release granules have a release period of 8 to 12 hours, proving that the mesalazine sustained-release granules prepared in Example 4 have a good effect of delaying and prolonging drug release, and have a good sustained-release effect.

[0123] In the release model of pH 6.8 medium, the intra-batch release differences of Example 4 are shown in Table 10 below:

[0124] Table 10 Intra-batch release differences of mesalazine sustained-release granules prepared in Example 4

[0125]

[0126] Table 10 shows that at different time points, the RSD values ​​of the release of the three parallel samples were all less than 5.0%, indicating that the intra-batch release difference of the mesalazine sustained-release granules prepared in Example 4 was small.

[0127] Example 5

[0128] The difference from Example 2 is that in preparation process 3), the sieve hole diameter of the flat sieve plate is 1.2 mm, and the thickness of the flat sieve plate is 4.0 mm; in preparation process 4), the rolling is performed at a rotation speed of 200 rpm for 3 min, then at a rotation speed of 1600 rpm for 4 min, and finally at a rotation speed of 2000 rpm for 9 min.

[0129] In the release model of pH 6.8 medium, the release behavior of the mesalazine sustained-release granules prepared in Example 5 is shown in Table 11 below.

[0130] Table 11 Release of mesalazine sustained-release granules prepared in Example 5

[0131]

[0132] As can be seen from Table 11, mesalazine is not completely released until 8 to 12 hours later, indicating that the mesalazine sustained-release granules have a release period of 8 to 12 hours, proving that the mesalazine sustained-release granules prepared in Example 5 have a good effect of delaying and prolonging drug release, and have a good sustained-release effect.

[0133] In the release model of pH 6.8 medium, the intra-batch release differences of Example 5 are shown in Table 12 below:

[0134] Table 12 Intra-batch release differences of mesalazine sustained-release granules prepared in Example 5

[0135]

[0136] Table 12 shows that at different time points, the RSD values ​​of the release of the three parallel samples were all less than 5.0%, indicating that the intra-batch release difference of the mesalazine sustained-release granules prepared in Example 5 was small.

[0137] Example 6

[0138] The difference from Example 2 is that in preparation process 3), the sieve hole diameter of the flat sieve plate is 1.5 mm, and the thickness of the flat sieve plate is 5.0 mm; in preparation process 4), the rolling is carried out at a rotation speed of 200 rpm for 3 min, then at a rotation speed of 1600 rpm for 6 min, and finally at a rotation speed of 2000 rpm for 10 min.

[0139] In the release model of pH 6.8 medium, the release behavior of the mesalazine sustained-release granules prepared in Example 6 is shown in Table 13 below.

[0140] Table 13 Release of mesalazine sustained-release granules prepared in Example 6

[0141]

[0142] As can be seen from Table 13, mesalazine is not completely released until 8 to 12 hours later, indicating that the mesalazine sustained-release granules have a release period of 8 to 12 hours, proving that the mesalazine sustained-release granules prepared in Example 6 have a good effect of delaying and prolonging drug release, and have a good sustained-release effect.

[0143] In the release model of pH 6.8 medium, the intra-batch release differences of Example 6 are shown in Table 14 below:

[0144] Table 14 Intra-batch release differences of mesalazine sustained-release granules prepared in Example 6

[0145]

[0146] Table 14 shows that at different time points, the RSD values ​​of the release of the three parallel samples were all less than 5.0%, indicating that the intra-batch release difference of the mesalazine sustained-release granules prepared in Example 6 was small.

[0147] Example 7 Preparation of Mesalazine Enteric-Coated Sustained-Release Granules

[0148] (1) Formulation of Mesalazine Enteric-Coated Sustained-Release Granules The mesalazine sustained-release granules prepared by the process of Example 2 were used as the coated granule cores, and enteric functional coating was performed according to the formulation of Table 15 below, and taste-masking layer coating was performed according to the formulation of Table 16 below, to obtain mesalazine enteric-coated sustained-release granules.

[0149] 1) Enteric functional coating:

[0150] Table 15 Enteric functional coating formulation

[0151]

[0152]

[0153] Mix appropriate amounts of ethanol and water, stir with a magnetic / mechanical stirrer, and slowly add methacrylic acid-methyl methacrylate copolymer (1:1) L100, triethyl citrate, hydroxypropyl methylcellulose, talc, magnesium stearate, titanium dioxide, stir evenly to obtain coating solution. Add the granule core into the fluidized bed, start the fluidized bed, adjust the air volume, so that the granule core is in a fluidized state. Spray the coating solution onto the surface of the granule core according to the target parameters. The air temperature is 20-40℃, and the air volume is 60-160m 3 / h, spray speed 1-8g / min, atomization pressure 0.5-3bar. When the particle core reaches the target weight gain, stop. The target weight gain is 10-20%.

[0154] 2) Taste-masking coating:

[0155] Table 16 Taste masking coating formulation

[0156] Material Name Proportion / % Weight / g Granules after enteric functional coating 96.08 600.0 Sodium Carboxymethyl Cellulose 0-3 NA Titanium Dioxide 0-1 NA Aspartame 0-1 NA Anhydrous citric acid 0-1 NA talcum powder 0-1 NA Polyvinylpyrrolidone 0-1 NA Purified water NA Moderate

[0157] Place purified water in a magnetic / mechanical stirrer, start the stirrer to stir, slowly add sodium carboxymethyl cellulose, aspartame, anhydrous citric acid, talcum powder, polyvinyl pyrrolidone, titanium dioxide, stir evenly to obtain a coating solution. Add the granule core into the fluidized bed, start the fluidized bed, and adjust the air volume to make the granule core fluidized. Spray the coating solution onto the surface of the granule core according to the target parameters. The air inlet temperature is 40-65°C, and the air volume is 60-160m 3 / h, spray speed 1-8g / min, atomization pressure 0.5-3bar. When the particle core reaches the target weight gain, stop. The target weight gain is 2-5%.

[0158] In the release model of pH 6.8 medium, the release behavior of mesalazine sustained-release enteric-coated granules prepared in Example 7 is shown in Table 17 below.

[0159] Table 17 Release of mesalazine sustained-release enteric-coated granules prepared in Example 7

[0160]

[0161] The mesalazine enteric-coated sustained-release granules prepared in Example 2 still have a release period of 8 to 12 hours after being coated with the functional enteric layer and the taste-masking layer. It can be seen that after the mesalazine enteric-coated sustained-release granules are coated to make the mesalazine enteric-coated sustained-release granules, the release period of mesalazine does not change significantly, but has a gastric acid resistance effect to avoid premature release of mesalazine. At the same time, due to the addition of the taste-masking layer coating, the taste of taking is significantly improved, thereby improving the compliance of patients.

[0162] Comparative Example 1 Preparation of Mesalazine Enteric-coated Sustained-release Granules

[0163] This comparative example uses the mesalazine sustained-release granule formula provided in Example 2 of the present invention, but uses a basket extruder to complete the extrusion process, thereby preparing mesalazine sustained-release granules. The sustained-release granules are used as the coated granule cores, and are coated according to the enteric functional coating and taste-masking layer coating process of Example 7 to obtain mesalazine enteric sustained-release granules.

[0164] Comparative Example 2 Preparation of Mesalazine Enteric-coated Sustained-release Granules

[0165] This comparative example uses the mesalazine sustained-release granule formula provided in Example 2 of the present invention, but uses a spherical screw extruder to complete the extrusion process, thereby preparing mesalazine sustained-release granules. The sustained-release granules are used as the coated granule cores, and are coated according to the enteric functional coating and taste-masking layer coating process of Example 7 to obtain mesalazine enteric sustained-release granules.

[0166] In the release model of pH 6.8 medium, the release behaviors of mesalazine enteric-coated sustained-release granules prepared in Example 7, Comparative Example 1 and Comparative Example 2 are shown in Tables 18 and Figure 3 .

[0167] Table 18 Release of mesalazine sustained-release granules prepared in Example 7 and Comparative Example 1-2

[0168]

[0169] Example 7 has a mesalamine release period of 8 to 12 hours; Comparative Example 1 has a mesalamine release period of 4 to 6 hours; Comparative Example 2 has a mesalamine release period of 2 to 3 hours. In combination with Example 7, it can be seen that the mesalamine sustained-release granules prepared by the preparation process of mesalamine sustained-release granules proposed in the present invention have better effects of delaying and prolonging drug release. Generally speaking, the better effect of delaying and prolonging drug release can be reflected in clinical applications as reducing the number of times the drug is taken per day. For mesalamine drugs that act locally in intestinal lesions, better effects of delaying and prolonging drug release can expand their therapeutic range.

[0170] The above are only preferred embodiments of the present invention, and do not limit the patent scope of the present invention. For those skilled in the art, the present invention may have various changes and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the patent protection scope of the present invention.

Claims

1. A preparation process of mesalazine sustained-release granules, characterized in that: The following steps are involved: Mixing the main drug of mesalazine, a diluent and an anti-adhesive agent to obtain a drug-containing mixed powder; Granulating the drug-containing mixed powder, polyacrylic acid resin, anti-adhesive agent and water to obtain a drug-containing soft material; The drug-containing soft material is extruded into a shape by using an extrusion device to obtain a drug-containing strip; Spheronizing the drug-containing strips to obtain drug-containing wet granules; Drying the drug-containing wet granules to obtain drug-containing dry granules; Screening the drug-containing dry particles to obtain mesalazine sustained-release particles; Wherein, the mesalazine main drug includes mesalazine or a pharmaceutically acceptable salt thereof, and the discharge end of the extrusion device is provided with a flat sieve plate for extruding the drug-containing soft material; The extrusion device is a screw extruder, and the discharge end of the screw extruder is provided with the flat screen plate; The sieve hole diameter of the flat sieve plate is 0.5 to 1.5 mm; The thickness of the flat sieve plate is 1.5 to 5.0 mm; The polyacrylic acid resin is selected from Eudragit NM 30D, Eudragit NM 40D, Eudragit NE 30D or Eudragit NE 40D.

2. The preparation process of mesalazine sustained-release granules according to claim 1, characterized in that: The step of granulating the drug-containing mixed powder, polyacrylic acid resin, anti-adhesive agent and water to obtain the drug-containing soft material comprises: The drug-containing mixed powder, adhesive, polyacrylic acid resin, anti-adhesive agent and water are granulated to obtain the drug-containing soft material.

3. The preparation process of mesalazine sustained-release granules according to claim 2, characterized in that: The binder includes hypromellose, hydroxypropyl cellulose or polyvinyl pyrrolidone.

4. The preparation process of mesalazine sustained-release granules according to claim 1, characterized in that: The step of spheronizing the drug-containing strip to obtain drug-containing wet granules comprises: The drug-containing strip is spheronized at a rotation speed of 100-500 rpm for 1-10 min, then spheronized at a rotation speed of 1000-1600 rpm for 1-10 min, and finally spheronized at a rotation speed of 1600-2000 rpm for 1-10 min.

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