Continuous preparation process of enteric coated pill containing flow-aiding anti-blocking agent

Abstract

The invention relates to the technical field of preparation of enteric-coated materials, and discloses a continuous preparation process of enteric-coated pills containing a flow-aiding anti-blocking agent, which comprises the following steps: S1, premixing pill core raw materials according to a prescription, then adding purified water to form a wet material, preparing the wet material into pills, and drying at 50-60 DEG C to obtain pill cores; and S2, coating the pill core obtained in the step S1 by using an isolating layer coating solution, coating by using an enteric layer coating solution after the weight of a coating is increased by 3-6%, finishing coating after the weight of the coating is increased by 8-12%, and screening out oversized or undersized pills to obtain the enteric coated pill containing the flow-aiding anti-blocking agent. According to the invention, a material system is simplified and the production cost is reduced through multi-layer application of an auxiliary material, the whole-process continuous production from pellet core forming to multi-layer coating is realized through structural design and process adaptation, and a technical scheme is provided for preparation of high-difficulty enteric-coated preparations such as pantoprazole sodium preparations sensitive to humidity and heat.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of enteric material preparation, in particular to a continuous preparation process of enteric coated pellets containing flow-aiding and anti-blocking agents. BACKGROUND

[0002] As a common oral sustained-release preparation, enteric coated pellets can protect active ingredients from damage by gastric acid through an enteric coating layer, achieve targeted release in the intestine, and are widely used in the development of preparations of acid-labile drugs such as proton pump inhibitor pantoprazole sodium.

[0003] However, the preparation process of existing enteric coated pellets still faces many challenges: in the preparation of pellet cores, due to the poor flowability of commonly used excipients, they are prone to adhere to the equipment, especially in the continuous extrusion-spheronization process, which can cause hole blockage, wall sticking, irregular pellet shape, and other problems, resulting in low production efficiency and poor batch consistency. In the coating process, the traditional coating liquid often causes problems such as clogging of the spray system, uneven coating, and coating film defects due to the sedimentation and agglomeration of solid particles, affecting the integrity and functionality of the enteric coating layer, and further leading to a decrease in the acid resistance of the preparation and unstable release behavior.

[0004] In addition, the existing process often uses different types of flow agents for pellet cores and coating layers, resulting in a complex excipient system and single functionality, which makes it difficult to achieve multi-level synergistic optimization, increases production costs, and further increases the difficulty of process control. Especially for pantoprazole sodium, which is sensitive to moisture, heat, and light, the existing process often cannot simultaneously ensure the stability of the drug and the performance of the preparation in continuous production, limiting the further improvement of industrial production efficiency and product quality.

[0005] Therefore, there is an urgent need for a new preparation process for enteric coated pellets that can integrate pellet formation and multi-layer coating processes, has good anti-blocking and flow-enhancing functions, and is suitable for continuous production, to solve the common problems of material adhesion, uneven coating, process interruption, and quality fluctuations in existing technology, and meet the efficient and stable production needs of high-difficulty enteric preparations.

[0006] Based on this, the present application provides a continuous preparation process of enteric coated pellets containing flow-aiding and anti-blocking agents. SUMMARY

[0007] Technical problems solved To solve the problems raised in the background art, the present application provides a continuous preparation process of enteric coated pellets containing flow-aiding and anti-blocking agents.

[0008] Technical scheme To achieve the above-mentioned purpose, the present application provides the following technical scheme: A continuous preparation process of enteric coated pellets containing flow-aiding and anti-blocking agents, comprising the following steps: S1, premix the core material according to the prescription, then add purified water to form a wet material, dry the wet material after it is made into a pill, and obtain the pill core; S2, coat the pill core obtained in step S1 with the isolation layer coating liquid, coat with the enteric layer coating liquid after the coating weight is increased by 3-6%, and complete the coating after the coating weight is increased by 8-12%, and screen out the oversized or undersized pellets, thereby obtaining an enteric coated pellet containing a flow-aiding and anti-blocking agent; The pill core, the isolation layer coating liquid, and the enteric layer coating liquid all contain the flow-aiding and anti-blocking agent.

[0009] Further, a continuous preparation process of an enteric coated pellet containing a flow-aiding and anti-blocking agent includes the following steps: S1, premix the core material according to the prescription in a continuous mixer, then add 8-10wt% of purified water to form a wet material, send the wet material into an extruder to be extruded into a strip, and then send it into a rounder to be made into a pellet, dry it at 50-60℃ until the moisture content is less than or equal to 3%, and obtain the pill core; S2, coat the pill core obtained in step S1 with the isolation layer coating liquid, coat with the enteric layer coating liquid after the coating weight is increased by 3-6%, and complete the coating after the coating weight is increased by 8-12%, and screen out the oversized or undersized pellets, thereby obtaining an enteric coated pellet containing a flow-aiding and anti-blocking agent; The pill core, the isolation layer coating liquid, and the enteric layer coating liquid all contain the flow-aiding and anti-blocking agent.

[0010] Further, the core material includes the following ingredients: 40-60 parts of raw material, 300-400 parts of microcrystalline cellulose, 200-300 parts of lactose, 10-20 parts of hydroxypropyl cellulose, and 8-10 parts of flow-aiding and anti-blocking agent.

[0011] Further, the flow-aiding and anti-blocking agent is prepared by the following steps: Disperse the inorganic flow-aiding agent in a solvent to form a 5-10wt% dispersion, then add the organic flow-aiding agent into a fluidized bed, spray the dispersion onto the surface of the organic flow-aiding agent, dry it with hot air at 40-50℃, and then pass it through a 80-100 mesh screen to obtain the flow-aiding and anti-blocking agent.

[0012] In the above technical solution, the organic flow-aiding agent has good hydrophobicity and lubricity, and is easy to form a uniform particle bed in the fluidized bed. The inorganic flow-aiding agent is dispersed in ethanol to form a mist, which is sprayed onto the surface of the organic flow-aiding agent. Since ethanol volatilizes quickly, the mist droplets spread quickly on the surface of the organic flow-aiding agent and dry. The inorganic flow-aiding agent adheres to the surface of the organic flow-aiding agent by van der Waals force and electrostatic force, forming a flow-aiding and anti-blocking agent with a core-shell structure.

[0013] Further, the solvent is an ethanol solution or anhydrous ethanol.

[0014] Further, the inorganic glidant is at least one of colloidal silicon dioxide, microfine silica, talc, and titanium dioxide.

[0015] Further preferably, the inorganic glidant is colloidal silicon dioxide.

[0016] Further, the organic glidant is at least one of magnesium stearate, polyethylene glycol, microcrystalline cellulose, and sodium stearyl fumarate.

[0017] Further preferably, the organic glidant is sodium stearyl fumarate.

[0018] Further, the mass ratio of the inorganic glidant to the organic glidant is (1-3):25.

[0019] Further, in the S2 step, the separating layer coating liquid is specifically prepared by the following steps: The separating layer auxiliary material is mixed with the glidant and anti-blocking agent at a mass ratio of 10-20:1, and the mixture is mixed with a 60-80 wt% ethanol solution at a mass ratio of 1:5-10. A wetting agent is added to the system and high-speed shearing is performed at room temperature for 10-20 minutes to obtain the separating layer coating liquid.

[0020] Further, the amount of the wetting agent added in the separating layer coating liquid is 1.0-1.2% of the total weight of the solids.

[0021] Further, in the S2 step, the specific parameters for coating using the separating layer coating liquid are: an inlet air temperature of 40-50℃, a pellet bed temperature of 35-45℃, an atomization pressure of 0.2-0.3 MPa, and a liquid spraying rate of 20-40 mL / min.

[0022] Further, in the S2 step, the enteric layer coating liquid is specifically prepared by the following steps: The enteric coating auxiliary material is mixed with the glidant and anti-blocking agent at a mass ratio of 15-25:1, and the mixture is mixed with purified water at a mass ratio of 1:4-8. A wetting agent is added to the system and shearing is performed at room temperature for 10-20 minutes to obtain the enteric layer coating liquid.

[0023] Further, the amount of the wetting agent added in the enteric layer coating liquid is 0.8-1.0% of the total weight of the solids.

[0024] Further, in the S2 step, the specific parameters for coating using the enteric layer coating liquid are: an inlet air temperature of 35-45℃, a pellet bed temperature of 30-40℃, an atomization pressure of 0.25-0.35 MPa, and a liquid spraying rate of 30-50 mL / min.

[0025] Beneficial technical effects In the technical scheme of the present application, the same flow-aiding and anti-blocking agent is applied in the pellet core, the isolation layer and the enteric layer material, which significantly improves the production efficiency, process stability and product quality of the enteric preparation. In the pellet core preparation stage, the flow-aiding and anti-blocking agent with core-shell structure can be uniformly dispersed in the granulation process, the organic core provides lubrication and anti-sticking, and the inorganic shell enhances the flowability and reduces adhesion and blocking in the extrusion and spheronization process. By compounding the flow-aiding and anti-blocking agent and the wetting agent in the isolation layer and the enteric layer material, the particle settling in the coating liquid is reduced, the spraying uniformity is improved, the compactness and isolation effect of the coating layer are improved, and the nozzle blocking caused by solid settling or agglomeration in the conveying and atomization process of the coating liquid is effectively prevented, and the surface smoothness and anti-sticking property of the enteric coating are improved.

[0026] In the technical scheme of the present application, the flow-aiding and anti-blocking agent and the wetting agent are compounded and applied in the isolation layer and the enteric layer coating liquid in the coating process, the flow-aiding and anti-blocking agent can effectively prevent the settling and agglomeration of solid particles in the coating liquid, maintain the stability of the coating system, avoid nozzle blocking in the spraying process, and ensure the smooth operation of the continuous coating process. At the same time, the wetting agent improves the wetting and spreading ability of the coating liquid on the surface of the pellet core, combined with the flow-enhancing effect of the flow-aiding and anti-blocking agent, the coating layer is more uniform and compact, and the surface smoothness is significantly improved, thereby enhancing the protection effect of the isolation layer and the anti-sticking property of the enteric coating. The process further ensures the accurate control of the coating weight gain and the stability of the release behavior by optimizing the coating parameters and material ratio, so that the final product exhibits excellent performance in acid resistance, release rate and storage stability. BRIEF DESCRIPTION OF DRAWINGS

[0027] In order to more clearly illustrate the technical scheme of the embodiments of the present application, the drawings required for the description of the embodiments will be briefly introduced. Obviously, the drawings described below are only some embodiments of the present application, and those skilled in the art can obtain other drawings according to these drawings without creative labor.

[0028] Figures 1-7 The dissolution curve of the samples in Examples 1-3 and Comparative Examples 1-4 of the present application. DETAILED DESCRIPTION

[0029] In order to make the purpose, technical scheme and advantages of the embodiments of the present application more clear, the technical scheme in the embodiments of the present application is described clearly and completely. Obviously, the described embodiments are part of the embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0030] The colloidal nanosilica used in the examples and comparative examples of the present application is Aerosil® 200, Wacker, Germany.

[0031] Sodium stearyl fumarate: pharmaceutical grade, particle size D50 20-40 μm, Mallinckrodt, USA.

[0032] Pantoprazole sodium: pharmaceutical grade, purity ≥ 99.0%.

[0033] Hydroxypropyl methylcellulose (hereinafter referred to as HPMC): Pharmacoat® 606.

[0034] Hydroxypropyl cellulose (hereinafter referred to as HPC): EF grade, Dacoh, Japan.

[0035] Eudragit® L30 D-55: Wacker, Germany.

[0036] Examples 1-3 A continuous preparation process of enteric-coated pellets containing flow-aiding and anti-blocking agents is provided in Examples 1-3, taking pantoprazole sodium as an example of the raw material drug. The general process includes the following steps: S1, the core raw materials are premixed in a continuous mixer for 5 minutes according to the prescription, and then 10 wt% purified water is added to form a wet material; the wet material is sent to an extruder to be extruded into a strip, the extruder aperture is 1.0 mm, and the extrusion speed is 50 rpm; the strip-shaped material is immediately sent to a rounder to be made into pellets, the rounder disc rotates at 1200 rpm, and the rounder time is 5 minutes; the pellet-shaped material is transferred to a fluidized bed dryer, dried at 60°C to a moisture content of ≤3%, and the core pellets are obtained; The core prescription used (per 1000 g of pellets) is shown in Table 1 below: Table 1

[0037] S2, the HPMC and flow-aiding and anti-blocking agents are mixed in a mass ratio of 10-20:1, the mixture is mixed with an 80 wt% ethanol solution in a mass ratio of 1:10, Tween-80 is added to the system and sheared at a speed of 800 rpm at room temperature for 20 minutes to obtain an isolation layer coating solution; the amount of Tween-80 added in the isolation layer coating solution is 1.0-1.2% of the total weight of solids.

[0038] The Eudragit® L30 D-55 flow-aiding and anti-blocking agent is mixed in a mass ratio of 15-25:1, the mixture is mixed with purified water in a mass ratio of 1:8, Tween-80 is added to the system and sheared at a speed of 300 rpm at room temperature for 15 minutes, and the amount of Tween-80 added is 0.8-1.0% of the total weight of solids, to obtain an enteric layer coating solution.

[0039] The pellet core obtained in step S1 is coated with an isolation layer coating liquid, and the specific parameters of the coating are as follows: the inlet air temperature is 40°C, the pellet bed temperature is 35°C, the atomization pressure is 0.2 MPa, and the liquid spraying rate is 20 mL / min; after the coating weight is increased by 3-6%, an enteric layer coating liquid is used for coating, and the specific parameters of the coating are as follows: the inlet air temperature is 35°C, the pellet bed temperature is 30°C, the atomization pressure is 0.25 MPa, and the liquid spraying rate is 30 mL / min; after the coating weight is increased by 8-12%, the coating is completed, and the obtained pellets are transported to a vibrating sieve machine to screen out oversized or undersized pellets, thereby obtaining an enteric coated pellet containing a flow-aiding and anti-blocking agent. In steps S1 and S2, the flow-aiding and anti-blocking agent is prepared by the following steps: The colloidal silicon dioxide is configured into a 10 wt% dispersion liquid using anhydrous ethanol, then sodium stearyl fumarate is added to the fluidized bed, and the mass ratio of colloidal silicon dioxide to sodium stearyl fumarate is (1-3):25, then the dispersion liquid is atomized and sprayed onto the surface of the organic flow-aiding agent, dried with hot air at 50°C, and then sieved through a 100 mesh sieve to obtain the flow-aiding and anti-blocking agent.

[0040] The specific process for preparing the enteric coated pellets in Examples 1-3 is shown in Table 2 below.

[0041] Table 2

[0042] Comparative Example 1 The difference between this comparative example and Example 2 is that no flow-aiding and anti-blocking agent is used in the coating process. Specifically, the isolation layer is coated with pure HPMC without Tween-80, and the coating weight is increased by 5%; the enteric layer is coated with Eudragit® L30 D-55 without Tween-80, and the coating weight is increased by 10%.

[0043] Comparative Example 2 The difference between this comparative example and Example 2 is that the flow-aiding and anti-blocking agent used in this comparative example is obtained by physically mixing colloidal silicon dioxide and sodium stearyl fumarate, rather than a core-shell structure. Specifically, in this comparative example, the flow-aiding and anti-blocking agent is prepared by the following steps: The colloidal silicon dioxide and sodium stearyl fumarate are mixed according to a mass ratio of 2:25, dried with hot air at 50°C, and then sieved through a 100 mesh sieve to obtain the flow-aiding and anti-blocking agent.

[0044] Comparative Example 3 The difference between this comparative example and Example 2 is that the content of inorganic flow-aiding agent in the flow-aiding and anti-blocking agent used in this comparative example is increased. Specifically, in this comparative example, the flow-aiding and anti-blocking agent is prepared by the following steps: The colloidal silicon dioxide was configured into a 10wt% dispersion solution using anhydrous ethanol, then sodium stearyl fumarate was added into the fluidized bed, the mass ratio of colloidal silicon dioxide and sodium stearyl fumarate was 1:10, then the dispersion solution was atomized and sprayed onto the surface of the organic flow aid, dried with hot air at 50°C, then sieved through a 100 mesh screen to obtain the flow-aiding and anti-blocking agent.

[0045] Comparative Example 4 The difference between this comparative example and Example 2 is that the content of inorganic flow aid in the flow-aiding and anti-blocking agent used in this comparative example is increased. Specifically, in this comparative example, the flow-aiding and anti-blocking agent was prepared by the following steps: The colloidal silicon dioxide was configured into a 10wt% dispersion solution using anhydrous ethanol, then sodium stearyl fumarate was added into the fluidized bed, the mass ratio of colloidal silicon dioxide and sodium stearyl fumarate was 1:50, then the dispersion solution was atomized and sprayed onto the surface of the organic flow aid, dried with hot air at 50°C, then sieved through a 100 mesh screen to obtain the flow-aiding and anti-blocking agent.

[0046] Now the performance of the enteric-coated pellets prepared in the examples and comparative examples is tested. The specific test methods are as follows: 1. Acid resistance test: according to the method for checking the acid resistance of enteric preparations in the 2020 edition of the Chinese Pharmacopoeia, Chapter IV, 0931, an appropriate amount of sample was placed in 900 mL of 0.1 mol / L hydrochloric acid solution at 37±0.5°C and 100 rpm for 2 hours. After 2 hours, the sample was filtered, and the content of pantoprazole sodium in the filtrate was determined by HPLC to calculate the acid release rate.

[0047] 2. Dissolution test: according to the second method (slurry method) in the 2020 edition of the Chinese Pharmacopoeia, Chapter IV, 0931. The dissolution medium was 900 mL of pH 6.8 phosphate buffer at 37±0.5°C, and the rotation speed was 100 rpm. At 10, 20, 30, 40, 50, and 60 minutes, 5 mL of sample was taken, and an equal volume of fresh medium was added. After filtration, the filtrate was taken, and the content of pantoprazole sodium was determined by HPLC to calculate the cumulative release rate at each time point.

[0048] 3. Stability test: the sample was placed in a stability test box at 40°C and 75% relative humidity for 30 days. Samples were taken at 0 days and 30 days, and the dissolution rate change (Δ%) was determined by the above method, and the total impurity increase was determined by HPLC.

[0049] The specific test results are shown in Tables 3, 4, 5, and Figures 1-7 .

[0050] Table 3 Acid resistance test

[0051] Table 4 Dissolution test

[0052] Table 5 Stability test

[0053] Figures 1-7 The dissolution curves of the samples in Examples 1-3 and Comparative Examples 1-4 of the present application are shown in Figure 1. Figures 1-7 From the above test results, the enteric-coated pellets prepared in the three examples have good acid resistance and stability. From the results in Comparative Example 1, without the use of the flow-aiding and anti-blocking agent, the performance of the pellets is significantly reduced, indicating that the flow-aiding and anti-blocking agent in the technical solution of the present application has a good quality improvement effect. From the results in Comparative Example 2, after physical mixing of the flow-aiding agent, the release behavior of the pellets is lower than that of the examples, indicating that the formation of the core-shell structure has a significant effect on the improvement of the particle dispersion and uniformity of the coating layer. From the results in Comparative Examples 3 and 4, the ratio of the inorganic shell to the organic core needs to be optimized, and too high or too low may affect the balance of the flow-aiding and anti-blocking effects.

[0054] It should be noted that in this document, the terms "comprising", "containing", or any other variant thereof are intended to cover non-exclusive inclusion, so that processes, methods, articles, or devices that include a series of elements not only include those elements, but also include other elements not explicitly listed, or inherent to such processes, methods, articles, or devices. Without more limitations, the element defined by the statement "comprising a" does not exclude the presence of additional identical elements in the process, method, article, or device that includes the element.

[0055] The above examples are only used to illustrate the technical solutions of the present application, and not to limit them; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that they can still modify the technical solutions recorded in the foregoing examples, or make equivalent replacements for part of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present application.

[0056] Those skilled in the art should understand that the above only describes several specific embodiments of the present application, rather than all embodiments.

Claims

1. A continuous preparation process for enteric-coated pills containing a flow aid and anti-clogging agent, characterized in that, Includes the following steps: S1. Premix the pellet core raw materials according to the prescription, then add purified water to form a wet material. After the wet material is made into pellets, it is dried to obtain the pellet core. S2. Coat the pellet core obtained in step S1 with an isolation layer coating solution. After the coating weight increases by 3-6%, coat it with an enteric coating solution. After the coating weight increases by 8-12%, the coating is completed. Screen out pellets that are too large or too small to obtain an enteric coated pellet containing a flow aid and anti-blocking agent. The pellet core, the separator coating solution, and the enteric coating solution all contain flow aids and anti-clogging agents.

2. The continuous preparation process of enteric-coated pills containing a flow aid and anti-clogging agent according to claim 1, characterized in that, The core material consists of the following ingredients by weight: 40-60 parts of active pharmaceutical ingredient, 300-400 parts of microcrystalline cellulose, 200-300 parts of lactose, 10-20 parts of hydroxypropyl cellulose, and 8-10 parts of flow aid and anti-blocking agent.

3. The continuous preparation process of enteric-coated pills containing a flow aid and anti-clogging agent according to claim 1, characterized in that, The flow-aiding and anti-clogging agent is prepared by the following steps: The inorganic flow aid is prepared into a 5-10 wt% dispersion using a solvent. Then, the organic flow aid is added to a fluidized bed, and the dispersion is atomized and sprayed onto the surface of the organic flow aid. The mixture is then dried with hot air at 40-50℃ and sieved to obtain the flow aid and anti-clogging agent.

4. The continuous preparation process of enteric-coated pills containing a flow aid and anti-clogging agent according to claim 3, characterized in that, The inorganic flow aid is at least one of colloidal silica, micronized silica, talc, and titanium dioxide; the organic flow aid is at least one of magnesium stearate, polyethylene glycol, microcrystalline cellulose, and sodium stearate fumarate.

5. The continuous preparation process of enteric-coated pills containing a flow aid and anti-clogging agent according to claim 3, characterized in that, The inorganic flow aid is colloidal silica, and the organic flow aid is sodium stearate fumarate.

6. The continuous preparation process of enteric-coated pills containing a flow aid and anti-clogging agent according to claim 1, characterized in that, In step S2, the isolation layer coating liquid is specifically prepared by the following steps: Mix the isolation layer additive and the flow aid and anti-blocking agent at a mass ratio of 10-20:

1. Then mix the mixture with a 60-80wt% ethanol solution at a mass ratio of 1:5-10. Add a wetting agent to the system and shear at room temperature for 10-20 minutes to obtain the isolation layer coating solution.

7. The continuous preparation process of enteric-coated pills containing a flow aid and anti-clogging agent according to claim 1, characterized in that, In step S2, the specific parameters for coating with the isolation layer coating solution are: inlet air temperature of 40-50℃, pellet bed temperature of 35-45℃, atomization pressure of 0.2-0.3MPa, and spraying rate of 20-40mL / min.

8. The continuous preparation process of enteric-coated pills containing a flow aid and anti-clogging agent according to claim 1, characterized in that, In step S2, the enteric coating solution is specifically prepared by the following steps: The enteric coating excipient and the flow aid and anti-blocking agent are mixed at a mass ratio of 15-25:

1. The mixture is then mixed with purified water at a mass ratio of 1:4-8. A wetting agent is added to the system and sheared at room temperature for 10-20 minutes to obtain the enteric coating solution.

9. The continuous preparation process of enteric-coated pills containing a flow aid and anti-clogging agent according to claim 1, characterized in that, In step S2, the specific parameters for coating with enteric coating solution are: inlet air temperature of 35-45℃, pellet bed temperature of 30-40℃, atomization pressure of 0.25-0.35MPa, and spraying rate of 30-50mL / min.

10. The continuous preparation process of enteric-coated pills containing a flow aid and anti-clogging agent according to claim 1, characterized in that, The amount of wetting agent added to the isolation layer coating solution is 1.0-1.2% of the total solid weight, and the amount of wetting agent added to the enteric coating solution is 0.8-1.0% of the total solid weight.

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