Tacrolimus multi-layer coated pellet capsule and preparation method thereof
By designing a three-layer coating structure and optimizing process parameters, the multi-stage release characteristics of tacrolimus were achieved, solving the problems of low bioavailability of tacrolimus and instability of existing formulations, and improving the safety and efficacy of drug therapy.
Patent Information
- Application Number
- CN202511346833.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-09-19
- Publication Date
- 2025-12-16
AI Technical Summary
Tacrolimus has low bioavailability, and existing formulations have problems such as large fluctuations in blood drug concentration and the need for frequent dosing. Furthermore, sustained-release formulations have problems such as slow onset of action and incomplete drug release.
The three-layer coating structure is designed with high molecular weight ethyl cellulose in the core microparticles, medium molecular weight ethyl cellulose in the middle coating layer, and low molecular weight ethyl cellulose and release promoter in the outer coating layer. Combined with optimized preparation process parameters, multi-stage drug release characteristics are achieved.
This approach achieves the multi-stage release characteristics of tacrolimus, avoids peak-to-trough fluctuations in blood drug concentration, improves the safety and efficacy of drug therapy, and ensures the stability and reproducibility of the microparticles.
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Abstract
Description
Technical Field
[0001] This application relates to the field of pharmaceutical formulations, specifically to a tacrolimus multilayer coated microcapsule and its preparation method. Background Technology
[0002] Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis, which has the following chemical formula 1.
[0003] Tacrolimus is a white crystalline or crystalline powder, insoluble in water but readily soluble in ethanol. Its solubility in water is extremely low, resulting in very low bioavailability when taken orally, with a wide range of utilization rates, between 5% and 65%. Currently, commercially available tacrolimus formulations mainly include regular capsules and extended-release capsules. However, regular capsules suffer from large fluctuations in blood drug concentrations and require frequent dosing, while extended-release formulations have drawbacks such as slow onset of action and incomplete drug release.
[0004] Therefore, it is necessary to provide a tacrolimus multilayer coated microcapsule capsule and its preparation method. Summary of the Invention
[0005] To address the technical problems of unstable tacrolimus drug release control and poor formulation reproducibility, this application provides a multilayer coated microcapsule tacrolimus capsule and its preparation method.
[0006] The first aspect of this application provides a tacrolimus multilayer coated microcapsule capsule, characterized in that it comprises: a core microcapsule, a middle coating layer, and an outer coating layer; the core microcapsule comprises tacrolimus, high molecular weight ethyl cellulose with a molecular weight of 100,000-300,000 Da, a disintegrant, and a filler; the middle coating layer comprises medium molecular weight ethyl cellulose with a molecular weight of 30,000-50,000 Da; and the outer coating layer comprises low molecular weight ethyl cellulose with a molecular weight of 1,000-10,000 Da and a release promoter.
[0007] This application achieves multi-stage release characteristics of tacrolimus through an innovative three-layer coating structure. The core microcapsule uses high molecular weight ethyl cellulose as the matrix material, providing a basis for sustained drug release; the middle coating layer uses medium molecular weight ethyl cellulose to form a stable membrane-controlled release layer, precisely controlling the drug release rate; the outer coating layer uses low molecular weight ethyl cellulose combined with a release promoter to achieve rapid drug release. This molecular weight gradient design makes the drug release curve more stable and controllable, effectively avoiding peak and trough fluctuations in blood drug concentration, and improving the safety and efficacy of drug therapy. Simultaneously, the selection and optimization of the materials and proportions of each layer ensure the stability and reproducibility of the microcapsule preparation.
[0008] Furthermore, the disintegrant is croscarmellose sodium. Croscarmellose sodium has good water absorption and swelling properties, which can promote the disintegration of the core microspheres in vivo and accelerate drug release. Its dosage can be adjusted as needed, usually accounting for 5-15% of the total weight of the core microspheres.
[0009] Furthermore, the filler is microcrystalline cellulose. Microcrystalline cellulose has good flowability and compressibility, which can improve the formability and mechanical strength of the pellets. Its dosage is usually 20-40% of the total weight of the core pellets.
[0010] Furthermore, the intermediate coating layer also comprises hydroxypropyl methylcellulose and lactose. Hydroxypropyl methylcellulose, as a film-forming aid, improves the film-forming properties of medium molecular weight ethyl cellulose, enhancing the uniformity and integrity of the coating layer; lactose, as a pore-forming agent, regulates the permeability of the coating layer and controls the drug release rate. In the intermediate coating layer, the weight ratio of medium molecular weight ethyl cellulose, hydroxypropyl methylcellulose, and lactose can be 1:(0.1-0.3):(0.2-0.5).
[0011] Furthermore, the outer coating layer also contains lactose. Lactose acts as a pore-forming agent and filler in the outer coating, regulating the pore structure of the coating layer and promoting rapid drug release. In the outer coating layer, the weight ratio of low molecular weight ethyl cellulose, release promoter, and lactose can be 1:0.5-1.5:0.3-0.7.
[0012] The second aspect of this application provides a method for preparing tacrolimus multilayer coated microcapsules, comprising the following steps: core microcapsule preparation, middle layer encapsulation, outer layer encapsulation, and capsule filling. This method, through optimized process parameters and strict control conditions, ensures the quality stability and reproducibility of the multilayer coated microcapsules.
[0013] Furthermore, the preparation of the core microspheres includes: mixing tacrolimus, high molecular weight ethyl cellulose, disintegrant, and filler; adding anhydrous ethanol for granulation; extrusion-spheroidization; drying at 40-50°C for 3-5 hours; and sieving to obtain the core microspheres. This process effectively avoids drug degradation and microsphere deformation by controlling the drying temperature and time, thus ensuring the quality of the core microspheres.
[0014] Furthermore, in the extrusion-spheroidizing step, the extruder sieve aperture diameter is 0.4-0.6 mm, the spheroidizer drum speed is 50-70 rpm, and the spheroidizing time is 6-10 minutes. The optimization of these parameters ensures the sphericity and particle size uniformity of the microspheres, laying a good foundation for subsequent coating processes.
[0015] Furthermore, the intermediate coating comprises: preparing a coating solution by dispersing medium molecular weight ethyl cellulose, hydroxypropyl methyl cellulose, and lactose in anhydrous ethanol, and coating the core microparticles in a fluidized bed, with a coating weight gain of 30-50 wt%. The weight gain ratio of the intermediate coating directly affects the drug release rate; by precisely controlling the coating weight gain, precise regulation of drug release can be achieved.
[0016] Furthermore, the outer coating comprises: preparing a coating solution by dispersing low molecular weight ethyl cellulose, a release promoter, and lactose in anhydrous ethanol; coating the middle-layer coated microspheres in a fluidized bed; and achieving a coating weight gain of 20-40 wt%. The weight gain ratio of the outer coating affects the onset rate of the drug; by optimizing the coating weight gain, rapid drug release and effective absorption can be achieved.
[0017] The present invention has the following beneficial effects: This invention achieves multi-stage release characteristics of tacrolimus through an innovative three-layer coating structure, effectively avoiding peak and trough fluctuations in blood drug concentration and improving the safety and efficacy of drug therapy.
[0018] This invention uses a combination of ethyl cellulose with different molecular weights to precisely control the drug release rate and release time through molecular weight gradient design, thus solving the problem of unstable release in traditional formulations.
[0019] This invention ensures the quality stability and reproducibility of multilayer coated microspheres through optimized preparation process and strict parameter control, solving the problems of insufficient interlayer bonding and poor coating uniformity in traditional methods.
[0020] The tacrolimus multilayer coated microcapsules of the present invention have good stability and bioavailability, can reduce the frequency of administration, improve patient compliance, and have broad clinical application prospects. Detailed Implementation
[0021] To facilitate understanding of this application, a more complete description will be provided below. This application can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a more thorough and complete understanding of the disclosure of this application.
[0022] Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one of that feature. In the description of the application, "multiple" means at least two, such as two, three, etc., unless otherwise explicitly specified. In the description of this application, "several" means at least one, such as one, two, etc., unless otherwise explicitly specified.
[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.
[0024] In this application, the technical features described in an open-ended manner include both closed technical solutions consisting of the listed features and open technical solutions that include the listed features.
[0025] In this application, numerical ranges are referred to as continuous unless otherwise specified, and include the minimum and maximum values of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.
[0026] Unless otherwise specified, the percentage content mentioned in this application refers to mass percentage for solid-liquid mixtures and solid-phase-solid mixtures, and volume percentage for liquid-phase-liquid mixtures.
[0027] Unless otherwise specified, all percentage concentrations mentioned in this application refer to the final concentration. The final concentration refers to the proportion of the added component in the system after the addition of that component.
[0028] Unless otherwise specified, the temperature parameters in this application may be either constant temperature processing or processing within a certain temperature range. The constant temperature processing allows for temperature fluctuations within the precision range controlled by the instrument.
[0029] The term "particle" as used in this application, or a substance with a defined particle size distribution, is not necessarily spherical in shape; it may be irregular and can be either primary or secondary particles. The particle size of irregular particles is calculated as the average of their maximum and minimum diameters.
[0030] Example 1: This example provides a tacrolimus multilayer coated microcapsule capsule and its preparation method.
[0031] Raw materials for the preparation of kernel microcapsules: Tacrolimus (CAS: 104987-11-3), high molecular weight ethyl cellulose (molecular weight approximately 200,000 Da), croscarmellose sodium cellulose (CAS: 74811-65-7), microcrystalline cellulose (CAS: 9004-34-6).
[0032] Preparation method of kernel microgranules: The weighed tacrolimus, high molecular weight ethyl cellulose, croscarmellose sodium, and microcrystalline cellulose were sequentially added to a high-speed mixing granulator and mixed at low speed for 3 minutes. The agitator was started, and anhydrous ethanol was slowly sprayed in until a uniform, well-plasticized wet material was formed. The wet material was fed into an extruder (0.5 mm sieve diameter) and extruded into strips. The extrudate was collected and fed into a pelletizer (60 rpm drum speed, 8 minutes) for pelletizing to obtain spherical microspheres. The wet microspheres were spread on a stainless steel tray and placed in a forced-air drying oven at 45°C for 4 hours, followed by a vacuum drying oven (45°C, -0.008 MPa) for another 4 hours. After drying, the moisture content of the microspheres was tested and required to be ≤4%. Microspheres of the qualified particle size were collected using 65-mesh and 250-mesh sieves for later use.
[0033] Preparation of the intermediate coating solution: Medium molecular weight ethyl cellulose (50,000 Da), hydroxypropyl methylcellulose, and lactose. The powders were added in portions to anhydrous ethanol and magnetically stirred to prepare a uniform coated dispersion.
[0034] Middle layer wrapping method: Place the dried core microspheres into a fluidized bed coating machine, setting the inlet air temperature to 35-40℃, the spray pressure to 0.1-0.2MPa, and the spray rate to 8-15ml / min. Evenly spray the intermediate coating solution until the theoretical weight gain reaches 40%, pausing occasionally to check the coating thickness. After coating, air dry at a low temperature (35℃) for 30 minutes, then remove and dry in a vacuum drying oven (45℃, -0.008MPa) for 2 hours. Sieve to remove any adhered or broken microspheres, retaining only the qualified products.
[0035] Preparation of the outer coating solution: Low molecular weight ethyl cellulose (10000 Da), release promoter, lactose. Add an appropriate amount of anhydrous ethanol and stir magnetically until uniformly dispersed.
[0036] Outer wrapping method: The mid-coated microspheres were fed into a fluidized bed coating machine with an inlet air temperature of 35℃, a spray pressure of 0.1MPa, and a spray rate of 8ml / min. The outer coating solution was sprayed until the theoretical weight gain reached 30%, with multiple samples taken and weighed during the process to control the uniformity of the coating thickness. After coating, the microspheres were air-dried at low temperature for 30 minutes, followed by vacuum drying for 2 hours. The microspheres were then sieved using 65-mesh and 250-mesh sieves to remove any defective products.
[0037] Capsule filling: Weigh out the microcrystalline cellulose and lactose according to the formula and mix them evenly. Slowly mix the multi-layered coated microcapsules with the excipient mixture to prevent delamination and microcapsule breakage. Add magnesium stearate and stir for 10 minutes at a mixing speed of 12 rpm to ensure uniform lubrication. Use an automatic capsule filling machine, set the fill weight to 110 mg / capsule, and the filling speed to 30,000 capsules / hour. Take 20 capsules from the beginning and end of each batch, and weigh them to check the fill weight consistency (RSD ≤ 2%). Seal the capsules and perform initial inspections on appearance, delamination, particle uniformity, and dissolution.
[0038] Example 2: This example provides a tacrolimus multilayer coated microcapsule capsule and its preparation method.
[0039] Compared with Example 1, the difference is that: the core microcapsules use high molecular weight ethyl cellulose with a molecular weight of 100,000 Da; the middle coating uses medium molecular weight ethyl cellulose with a molecular weight of 50,000 Da; and the outer coating uses low molecular weight ethyl cellulose with a molecular weight of 10,000 Da. Other components and process parameters are the same as in Example 1.
[0040] Example 3: This example provides a tacrolimus multilayer coated microcapsule capsule and its preparation method.
[0041] Compared with Example 1, the difference is that the weight gain of the middle coating is 30 wt%. Other components and process parameters are the same as in Example 1.
[0042] Example 4: This example provides a tacrolimus multilayer coated microcapsule capsule and its preparation method.
[0043] Compared with Example 1, the difference is that the outer coating weight gain is 40 wt%. Other components and process parameters are the same as in Example 1.
[0044] Example 5: This example provides a tacrolimus multilayer coated microcapsule capsule and its preparation method.
[0045] Compared with Example 1, the difference is that the content of cross-linked sodium carboxymethyl cellulose in the core microspheres is 5 wt%, and the content of microcrystalline cellulose is 60 wt%. Other components and process parameters are the same as in Example 1.
[0046] Example 6: This example provides a tacrolimus multilayer coated microcapsule capsule and its preparation method.
[0047] Compared with Example 1, the difference is that in the extrusion-spheroidizing step, the extruder sieve diameter is 0.4 mm, the spheroidizer drum speed is 70 rpm, and the spheroidizing time is 6 minutes. Other components and process parameters are the same as in Example 1.
[0048] Comparative Example 1: This comparative example does not include the middle coating layer.
[0049] Compared with Example 1, the difference is that the middle coating step is omitted, and the outer coating is performed directly on the core microgranules, with an outer coating weight gain of 70 wt%. Other components and process parameters are the same as in Example 1.
[0050] Comparative Example 2: This comparative example uses ethyl cellulose with a single molecular weight.
[0051] Compared to Example 1, the difference is that the core pellets, middle coating, and outer coating all use ethyl cellulose with the same molecular weight (approximately 70,000 Da). Other components and process parameters are the same as in Example 1.
[0052] Comparative Example 3: This comparative example does not contain release promoters.
[0053] Compared with Example 1, the difference is that no release promoter is added to the outer coating, and the outer coating composition is low molecular weight ethyl cellulose (70 wt%) and lactose (30 wt%). Other components and process parameters are the same as in Example 1.
[0054] Table 1. Release rate test results of the examples and comparative examples. Examples 1-6 all exhibited good drug release characteristics and physical properties. The drug release curves showed a stable multi-stage release pattern, with a release rate of 10-15% at 0.5 hours, 32-41% at 1.5 hours, and over 94% at 24 hours, meeting the release requirements of sustained-release formulations. The microcapsules had high sphericity (>0.90), low friability (<1.0%), and good content uniformity (RSD<1.5%), indicating that the multi-layer coated microcapsules of the present invention have good reproducibility and stability in preparation.
[0055] Comparative Example 1 lacked a middle coating layer, resulting in excessively rapid drug release. The release rate reached 28.6% at 0.5 hours and 62.3% at 1.5 hours, failing to achieve the multi-stage sustained-release characteristics of the drug. Simultaneously, the sphericity of the microspheres decreased (0.85), friability increased (2.5%), and content uniformity deteriorated (RSD 3.8%), indicating that the middle coating layer plays a crucial role in maintaining the structural integrity of the microspheres and controlling drug release.
[0056] Comparative Example 2 used ethyl cellulose with a single molecular weight. The drug release rate was between that of Example 1 and Comparative Example 1, with a release rate of 18.4% at 0.5 hours and 48.6% at 1.5 hours. However, the release curve was not smooth enough, and precise multi-stage release control could not be achieved. The physical properties of the pellets were also worse than those of Example 1, indicating that the combination of ethyl cellulose with different molecular weights is crucial for achieving precise drug release control.
[0057] Comparative Example 3 did not contain a release promoter, resulting in excessively slow release from the outer coating. The release rate was only 7.2% at 0.5 hours, 20.5% at 1.5 hours, and 85.4% at 24 hours, failing to achieve rapid and complete drug release. This indicates that release promoters play a crucial role in the rapid release characteristics of the outer coating.
[0058] In Example 3, the lower weight gain of the middle coating (30 wt%) resulted in a slightly faster drug release rate than in Example 1, but good multi-stage release characteristics were still maintained. In Example 4, the higher weight gain of the outer coating (40 wt%) resulted in a slightly faster drug release rate than in Example 1, but the release curve remained stable. In Example 5, the lower disintegrant content resulted in a slightly slower drug release rate than in Example 1, but it was still within an acceptable range. In Example 6, changes in process parameters had little impact on the performance of the microcapsules, indicating that the preparation process of the present invention has good adaptability and stability.
[0059] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.
[0060] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.
Claims
1. A tacrolimus multilayer coated microcapsule, characterized in that, It comprises: a core microsphere, a middle coating layer, and an outer coating layer; the core microsphere contains tacrolimus, high molecular weight ethyl cellulose with a molecular weight of 100,000-300,000 Da, a disintegrant, and a filler; the middle coating layer contains medium molecular weight ethyl cellulose with a molecular weight of 30,000-50,000 Da; and the outer coating layer contains low molecular weight ethyl cellulose with a molecular weight of 1,000-10,000 Da and a release promoter.
2. The tacrolimus multilayer coated microcapsule according to claim 1, characterized in that, The disintegrant is croscarmellose sodium.
3. The tacrolimus multilayer coated microcapsule according to claim 1, characterized in that, The filler is microcrystalline cellulose.
4. The tacrolimus multilayer coated microcapsule according to claim 1, characterized in that, The middle coating layer also contains hydroxypropyl methylcellulose and lactose.
5. The tacrolimus multilayer coated microcapsule according to claim 1, characterized in that, The outer coating layer also contains lactose.
6. The method for preparing tacrolimus multilayer coated microcapsules according to any one of claims 1-5, characterized in that, It includes the following steps: core microparticle preparation, middle layer encapsulation, outer layer encapsulation, and capsule filling.
7. The preparation method according to claim 6, characterized in that, The preparation of the core microspheres includes: mixing tacrolimus, high molecular weight ethyl cellulose, disintegrant and filler, adding anhydrous ethanol for granulation, extrusion-spheroidization, drying at 40-50℃ for 3-5 hours and then sieving to obtain core microspheres.
8. The preparation method according to claim 7, characterized in that, In the extrusion-spheroidizing step, the extruder screen diameter is 0.4-0.6 mm, the spheroidizer drum speed is 50-70 rpm, and the spheroidizing time is 6-10 minutes.
9. The preparation method according to claim 6, characterized in that, The middle layer coating comprises: preparing a coating solution by dispersing medium molecular weight ethyl cellulose, hydroxypropyl methyl cellulose and lactose in anhydrous ethanol, coating the core microparticles in a fluidized bed, and the coating weight gain is 30-50 wt%.
10. The preparation method according to claim 6, characterized in that, The outer coating comprises: preparing a coating solution by dispersing low molecular weight ethyl cellulose, a release promoter and lactose in anhydrous ethanol, coating the middle layer of coated microspheres in a fluidized bed, and the coating weight gain is 20-40 wt%.