Nifedipine controlled-release pellet capsule and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and discloses a nifedipine controlled-release pellet capsule and a preparation method thereof. The nifedipine pellet is prepared from nifedipine, a hydrophilic swelling carrier, a hydrophobic structure framework material, an interface stabilizer, namely hydrophobic fumed silica, and a solubilizer. A step-by-step pre-dispersion and hot-melt co-extrusion combined process is adopted, a modified lipid intermediate containing an interface stabilizer is firstly prepared, and then the modified lipid intermediate and a drug-containing hydrophilic premix are co-extruded. According to the method, an interface pinning effect is generated by utilizing enrichment of an interface stabilizer on a two-phase interface, and a stable microcosmic bicontinuous phase skeleton structure is constructed. The structure utilizes the physical barrier and zigzag pore effect of the lipid skeleton, and can realize zero-order stable release of the drug without coating. The problems of burst release risk and ethanol-induced dosage dumping of a traditional preparation are effectively solved, the process is continuous and efficient, and the product reproducibility is good.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a controlled-release microcapsule of nifedipine and its preparation method. Background Technology

[0002] Nifedipine, a dihydropyridine calcium channel blocker, is widely used to treat hypertension and angina. Due to its short biological half-life, conventional immediate-release formulations typically require multiple daily doses to maintain effective blood drug concentrations. This not only reduces patient compliance but also easily leads to excessive fluctuations in blood drug concentrations, causing side effects such as facial flushing and palpitations. Therefore, developing controlled-release formulations that can maintain stable blood drug concentrations is essential for the clinical application of nifedipine.

[0003] Currently, commercially available nifedipine controlled-release formulations mainly rely on osmotic pump technology or membrane-controlled coating technology. While osmotic pump formulations offer excellent release performance, their production equipment is expensive, the process is complex, and manufacturing costs remain high. In contrast, membrane-controlled microcapsules have been widely studied due to their greater equipment versatility, but this technology still faces significant limitations in practical applications. The controlled-release mechanism of membrane-controlled technology depends entirely on the polymer film on the surface of the microcapsules, making drug release highly sensitive to the integrity of the coating film. During preparation, the coating process is extremely sensitive to parameters such as temperature, humidity, and spray rate; even minor process fluctuations can lead to uneven coating film thickness or differences in film quality, thus affecting batch-to-batch reproducibility. More importantly, in physiological environments, if the coating film ruptures due to gastrointestinal friction or pH changes, or if the coating material dissolves in ethanol due to the patient's alcohol consumption, the drug loses its control barrier and is released instantaneously, triggering a severe risk of hypotension—the so-called dose-dumping effect.

[0004] Furthermore, to circumvent complex coating processes, existing technologies have attempted to utilize matrix-based sustained-release techniques. However, traditional hydrophilic gel or erosive lipid matrices often fail to achieve ideal zero-order release kinetics. As the drug is released, the diffusion paths within the matrix lengthen or the surface area decreases, leading to a significant reduction in the release rate over time, which is insufficient to meet the therapeutic requirement of nifedipine for a constant release rate over 24 hours. Simultaneously, simple physically mixed matrices often face uncontrollable separation of the hydrophilic and hydrophobic phases during hot-melt or wet granulation processes, and phase coarsening easily occurs upon cooling, resulting in a non-uniform pore structure within the formulation and further affecting the stability of drug release. Therefore, how to achieve stable, resistant to degradation, and zero-order-release controlled-release formulations of nifedipine without relying on film coating by improving the matrix structure is a pressing technical challenge in this field. Summary of the Invention

[0005] The technical problem solved by this invention is that existing nifedipine controlled-release formulations mainly rely on complex coating processes or costly osmotic pump technology, which are cumbersome to prepare and pose risks of burst release due to coating membrane rupture and ethanol-induced dose dumping.

[0006] To address the above problems, the present invention provides the following technical solution: In a first aspect, the present invention provides a nifedipine controlled-release microcapsule, which adopts the following technical solution: A nifedipine controlled-release microcapsule contains nifedipine controlled-release microcapsules, which are made from raw materials comprising the following weight percentages: nifedipine 15.0%-25.0%; hydrophilic swelling carrier 35.0%-50.0%; hydrophobic structural framework material 15.0%-25.0%; interface stabilizer 1.0%-3.0%; and solubilizer 5.0%-10.0%. The interface stabilizer is hydrophobic fumed silica; the hydrophilic swelling carrier is polyethylene oxide; and the hydrophobic structural framework material is selected from one or more of glyceryl behenate, hydrogenated castor oil, or stearic acid.

[0007] By adopting the above technical solution, this invention utilizes the differences in physicochemical properties between the components to construct an uncoated bicontinuous phase framework structure, with the following specific effects: First, this invention utilizes the immiscibility of a hydrophobic structural framework material and a hydrophilic swelling carrier in the molten state, combined with an interface stabilizer, to construct a bicontinuous network within the microspheres, where hydrophobic and hydrophilic phases interpenetrate. The hydrophilic phase serves as a diffusion channel for the drug, while the non-corrosive framework network formed by the hydrophobic phase restricts water penetration and drug diffusion through a tortuous pore effect, thereby achieving zero-order or near-zero-order drug release.

[0008] Secondly, the hydrophobic fumed silica is distributed at the interface between the hydrophilic and hydrophobic phases. Its high specific surface area and hydrophobic properties create adsorption and retardation at the interface, increasing the viscoelasticity of the two-phase interface and inhibiting the aggregation and coarsening of the lipid phase during cooling. This stabilizing effect on the microscopic phase separation morphology ensures the uniformity of the internal pore structure of the microspheres, avoiding batch-to-batch release differences caused by uncontrollable phase separation.

[0009] Finally, because the hydrophobic structural framework material is insoluble in ethanol, and the interface stabilizer enhances the mechanical strength of the framework, the microparticles can still maintain their structural integrity in the ethanol medium, preventing drug burst release caused by rapid dissolution of the gel layer and improving drug safety.

[0010] Preferably, the raw materials are expressed in the following weight percentages: nifedipine 20.0%-25.0%; hydrophilic swelling carrier 40.0%-45.0%; hydrophobic structural framework material 23.0%-25.0%; interface stabilizer 1.0%-2.0%; and solubilizer 10.0%. By adopting the above technical solution, the proportions of each component ensure that the melt has suitable fluidity during processing, while ensuring the compactness of the framework after cooling, resulting in a stable drug release curve.

[0011] Preferably, the raw material has the following characteristics: the viscosity-average molecular weight of polyethylene oxide is 200,000 to 600,000 Da; the melting point of the hydrophobic structural framework material is 60℃-88℃; and the specific surface area of ​​the hydrophobic fumed silica is 100±20 m². 2 / g to 200±25m 2 / g, and the surface is chemically modified with dimethyldichlorosilane or polydimethylsiloxane. By adopting the above technical solution, polyethylene oxide of selected molecular weight provides suitable melt viscosity and swelling rate; the melting point range of the skeleton material is adapted to the hot melt extrusion process, ensuring complete melting at the processing temperature to disperse the interface agent, and rapid crystallization and solidification upon cooling; the silica with specific chemical modification has obvious hydrophobicity, ensuring that it preferentially wets the hydrophobic lipid phase and tends to migrate to the lipid-polymer interface rather than dispersed in the hydrophilic phase, which is a prerequisite for generating effective interface stabilization.

[0012] Preferably, the nifedipine controlled-release microgranules have a bicontinuous phase framework structure, which is formed by hot-melt co-extrusion of a modified lipid intermediate and a drug-containing hydrophilic premix. The modified lipid intermediate is prepared by pre-melting and dispersing a hydrophobic structural framework material and an interface stabilizer, with the interface stabilizer content in the modified lipid intermediate ranging from 4.0% to 15.0% by weight. By employing the above technical solution, a high concentration of modified lipid intermediate is pre-prepared, which can force the interface stabilizer to disperse in the hydrophobic phase. During the subsequent co-extrusion process, the interface stabilizer migrates from the interior of the hydrophobic phase to the interface between the two phases. Compared to directly mixing all the powders, this method improves the coverage of the interface stabilizer at the interface, thereby forming a more uniform and stable microstructure.

[0013] Secondly, the present invention provides a method for preparing nifedipine controlled-release microcapsules, using the following technical solution: A method for preparing nifedipine controlled-release microcapsules, employing a stepwise pre-dispersion and hot-melt co-extrusion process, includes the following steps: S1. Preparation of modified lipid intermediates: The hydrophobic structural framework material is melted, and an interface stabilizer is added under shear to disperse it. After cooling and solidification, it is pulverized to obtain the modified lipid intermediates. S2. Preparation of drug-containing hydrophilic premix: Nifedipine, hydrophilic swelling carrier and solubilizer are physically mixed evenly at a temperature below 30°C to obtain drug-containing hydrophilic premix; S3. Hot melt co-extrusion: The modified lipid intermediate obtained in step S1 and the drug-containing hydrophilic premix obtained in step S2 are fed into a twin-screw extruder simultaneously as two separate materials for co-extrusion. The materials are heated and melted in the extruder and mixed under shear force. S4. Molding and curing: The extruded melt is hot-cut into microspheres by the die surface, cooled and solidified under airflow, and then sieved to obtain the final product.

[0014] By adopting the above technical solution, the present invention achieves stabilization of micro-phase separation through precise process control: Step S1 utilizes melt shearing to depolymerize the interface stabilizer and uniformly disperse it in the hydrophobic lipid matrix, overcoming the problem of easy agglomeration and difficulty in penetrating the melt when nanoparticles are directly fed. In the hot melt co-extrusion process of step S3, the shear field provided by the twin-screw extruder stretches and deforms the modified lipid phase and disperses it in the hydrophilic phase. Hydrophobic fumed silica then accumulates on the newly formed phase interface, reducing interfacial tension and providing steric hindrance. Finally, in step S4, the presence of the interface stabilizer hinders the coalescence of lipid droplets during cooling, allowing the bicontinuous phase structure to be rapidly fixed. This process path achieves one-step continuous production from raw material mixing to microsphere forming, eliminating the need for subsequent coating and resulting in high production efficiency.

[0015] Preferably, in step S1, the specific process for preparing the modified lipid intermediate is as follows: the hydrophobic structural framework material is heated to 85℃-100℃ to melt it, a high-shear homogenizer is turned on, the rotation speed is set to 3000-6000 rpm, an interface stabilizer is added, and homogenization is carried out for 10-20 minutes. By adopting the above technical solution, the specific temperature range ensures that the lipid has a low viscosity, and the high shear speed provides sufficient fluid shear force to disperse the nano-silica aggregates, thereby achieving uniform dispersion of nanoparticles in the lipid matrix.

[0016] Preferably, in step S3, the process parameters for hot melt co-extrusion are controlled as follows: the extruder barrel temperature is set within the range of 30℃-135℃, with the highest temperature in the melt mixing zone controlled within the range of 115℃-135℃; the screw speed is set to 80-200 rpm; and the twin-screw extruder's screw assembly includes at least two sets of kneading blocks. In step S3, the feeding ratio of the two materials is as follows: the feed amount of the modified lipid intermediate accounts for 20.0%-25.0% of the total feed amount; and the feed amount of the drug-containing hydrophilic premix accounts for 75.0%-80.0% of the total feed amount. By adopting the above technical solution, the set temperature ensures that nifedipine is converted into an amorphous form and dissolved in the hydrophilic carrier, while avoiding drug thermal degradation, and simultaneously ensuring a suitable viscosity ratio between the lipid phase and the polymer phase; the kneading blocks provide the necessary distribution and dispersion mixing effects, promoting interfacial expansion and adsorption of interfacial stabilizers; and the specific feeding ratio maintains the volume balance of the two continuous phase system.

[0017] Preferably, in step S4, the molding and curing conditions are as follows: pelletizing is performed using a die-cutting hot cutter with a cutter speed of 1200-2800 rpm; the inlet temperature of the cooling airflow is 8℃-15℃. By adopting the above technical solution, the lower inlet temperature enables rapid curing of the microsphere surface, prevents adhesion between microspheres, and, in conjunction with the interface stabilization effect, quickly fixes the microscopic skeleton structure inside the microspheres.

[0018] Preferably, in step S1, when the hydrophobic structural framework material is glyceryl behenate, the melting temperature is controlled at 85℃-95℃; when the hydrophobic structural framework material is hydrogenated castor oil, the melting temperature is controlled at 95℃-105℃. By adopting the above technical solution, the pre-dispersion temperature is adjusted according to the melting point characteristics of different lipid framework materials, ensuring a good dispersion effect while reducing the influence of thermal history.

[0019] This invention provides a controlled-release microcapsule form of nifedipine and its preparation method. It has the following beneficial effects: 1. This invention introduces hydrophobic fumed silica as an interface stabilizer, utilizing its adsorption at the interface between a hydrophilic swelling carrier and a hydrophobic structural framework material to construct a stable bicontinuous phase framework structure. This microstructure effectively limits the diffusion rate of the drug after swelling on the hydrophilic carrier by utilizing the physical barrier and tortuous pore effect formed by the lipid framework, achieving zero-order or near-zero-order stable release of nifedipine, fundamentally eliminating the risk of drug burst release caused by coating membrane rupture or defects in traditional membrane-controlled microspheres.

[0020] 2. The hydrophobic framework material used in this invention is poorly soluble in ethanol. Combined with the interface stabilizer's effect of enhancing framework strength, this endows the formulation with excellent resistance to ethanol dose-dumping. Even when exposed to high concentrations of ethanol, the internal framework network structure of the microcapsules remains intact, preventing the drug from being released instantaneously due to rapid dissolution of the gel layer. This effectively solves the clinical safety risks caused by the susceptibility of traditional coating materials such as ethyl cellulose to ethanol corrosion.

[0021] 3. The stepwise pre-dispersion and hot-melt co-extrusion process employed in this invention ensures the effective migration and coverage of the interface stabilizer to the two-phase interface during subsequent blending by pre-dispersing the interface stabilizer in the hydrophobic phase. This process not only overcomes the problems of uncontrollable phase separation and large batch-to-batch differences caused by conventional physical mixing, but also realizes continuous production from raw materials to microsphere forming, eliminating the need for time-consuming and complex coating processes, and significantly improving production efficiency and product quality uniformity. Attached Figure Description

[0022] Figure 1 This is a flowchart of the preparation method of the present invention. Detailed Implementation

[0023] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0024] Please see the appendix Figure 1 This invention provides a nifedipine controlled-release microcapsule and its preparation method. The preparation process of this invention adopts a stepwise pre-dispersion and hot melt co-extrusion combined process, specifically including the following preparation examples (corresponding to the pre-dispersion step in the process) and examples (corresponding to the co-extrusion and molding steps in the process).

[0025] I. Preparation Example (Stepwise Pre-dispersion Process Stage): Preparation Example 1: This preparation example provides a modified behenate glycerol intermediate (intermediate A1), the raw materials of which include 920g of behenate glycerol and 80g of hydrophobic fumed silica, and includes the following steps: (1) Place 920g of behenic acid glyceride in a stainless steel container equipped with a temperature control jacket, heat to 90°C, and stir until completely melted into a transparent liquid. (2) Maintain the temperature at 90℃±2℃, turn on the high shear homogenizer, set the speed to 4000rpm, slowly add 80g of hydrophobic fumed silica I while stirring, and continue to maintain high shear homogenization for 15 minutes after the addition is complete until a uniform semi-transparent milky white suspension melt is formed. (3) Stop heating and shearing, pour the melt into a stainless steel tray, and allow it to cool and solidify naturally at 25°C for 3 hours; (4) After the material has completely hardened, use a pulverizer to crush it and collect the particles that pass through a 40-mesh sieve (0.42 mm aperture) to obtain intermediate A1.

[0026] Preparation Example 2: This preparation example provides a high-concentration interface agent modified behenate glyceryl ester intermediate (intermediate A2), the raw materials for which include 850g of behenate glyceryl ester and 150g of hydrophobic fumed silica II, and includes the following steps: (1) Place 850g of behenicol glyceride in a reaction vessel and heat it to 95°C until it is completely melted; (2) Turn on the high shear homogenizer and set the speed to 5500 rpm. Add 150g of hydrophobic fumed silica II to the molten lipid in portions. Pay attention to controlling the foam generation during the feeding process. After the feeding is completed, continue homogenizing for 20 minutes to ensure the full deagglomeration and dispersion of high-concentration nanoparticles. (3) Transfer the resulting mixed melt to a tray and cool and solidify at 20°C for 4 hours; (4) Crush the solidified material and pass it through a 60-mesh sieve (0.25 mm aperture) to obtain intermediate A2.

[0027] Preparation Example 3: This preparation example provides a low-concentration interface agent modified behenate glyceryl ester intermediate (intermediate A3), the raw materials for which include 960g of behenate glyceryl ester and 40g of hydrophobic fumed silica I, and includes the following steps: (1) Heat 960g of behenicol glyceride to 85℃ to melt; (2) Add 40g of hydrophobic fumed silica I at a high shear speed of 3000rpm and continue to homogenize for 10 minutes; (3) After the melt is cooled and solidified, it is crushed and passed through a 40-mesh sieve to obtain intermediate A3.

[0028] Preparation Example 4: This preparation example provides a modified hydrogenated castor oil intermediate (intermediate A4), the raw materials of which include 900g of hydrogenated castor oil and 100g of hydrophobic fumed silica, and includes the following steps: (1) Place 900g of hydrogenated castor oil in a container and heat it to 100°C to completely melt it due to its high melting point; (2) Set the high shear homogenizer speed to 4500 rpm, slowly add 100g of hydrophobic fumed silica I, and keep it at the temperature for 15 minutes for homogenization; (3) Cool naturally to room temperature to solidify, crush and pass through a 50-mesh sieve to obtain intermediate A4.

[0029] The following are five specific embodiments designed based on the aforementioned formulation range and preparation examples. These embodiments are specifically designed to cover the numerical ranges of drug content (15%-25%), skeleton material ratio, PEO molecular weight specification (200,000-600,000), and key process parameters (temperature, rotation speed) in the claims through orthogonal transformation, in order to form a complete scope of protection.

[0030] II. Example (Hot melt co-extrusion and molding process stage): The following are five specific embodiments designed based on the aforementioned formulation range and preparation examples. All embodiments were prepared using a stepwise pre-dispersion and hot-melt co-extrusion process, which involves co-extruding the intermediate (pre-dispersion product) obtained in the aforementioned preparation examples with the drug-containing premix to form a stable bicontinuous phase structure.

[0031] Example 1: This example describes the preparation of a nifedipine bicontinuous phase matrix microsphere with standard release characteristics using a stepwise pre-dispersion and hot-melt co-extrusion process. The formulation uses modified behenicol glyceride as the matrix phase, and specifically includes the following steps: (1) Preparation of drug-containing hydrophilic premix: Accurately weigh 20.0% nifedipine, 45.0% polyethylene oxide (specification I, Mv200,000) and 10.0% vitamin E polyethylene glycol succinate (TPGS) by weight percentage. Place the above materials in a V-type mixer and mix at 20 rpm for 20 minutes at 25°C in the dark. Discharge the drug-containing hydrophilic premix to obtain the drug-containing premix.

[0032] (2) Hot melt co-extrusion: A co-rotating twin-screw extruder with a length-to-diameter ratio (L / D) of 40:1 is selected.

[0033] Feeding: A dual-path loss-in-weight feeder was used. The first path was used to add intermediate A1 (containing 8% silica) prepared in [Preparation Example 1], with a feeding ratio of 25.0%. The second path was used to add the drug-containing hydrophilic premix prepared in step (1), with a feeding ratio of 75.0%. The total feeding rate was set to 1.5 kg / h.

[0034] Temperature settings: The temperature settings for each zone of the barrel are as follows: Zone 1 30℃, Zone 2 70℃, Zone 3 100℃, Zone 4 125℃, Zone 5 130℃, Zone 6 125℃, and Die head 125℃.

[0035] Screw parameters: The screw speed is set to 100 rpm. The screw assembly has two sets of 90° kneading blocks in zones four and five to enhance shear dispersion.

[0036] (3) Molding and Solidification: The melt is extruded through a multi-hole die with a 1.0mm aperture and immediately enters a die-face hot cutting machine. The cutting speed is set to 1500rpm, and cooling is achieved by direct blowing of cold air at 12℃. The cut particles are collected by a cyclone separator, and micro-pellets with a particle size range of 0.8mm-1.2mm are selected by sieving. Note: The final calculated silica content in this embodiment is 2.0%.

[0037] Example 2: This example uses a stepwise pre-dispersion and hot-melt co-extrusion process to prepare a nifedipine microsphere with high drug loading based on a low-viscosity carrier. The steady-state control ability of a low-concentration interface agent on high drug loading was investigated. The specific steps include: (1) Preparation of drug-containing hydrophilic premix: Weigh 25.0% (upper limit) of nifedipine, 40.0% of polyethylene oxide (specification I, Mv200,000) and 10.0% of TPGS. The mixing process is the same as in Example 1.

[0038] (2) Hot melt co-extrusion: Feeding: The first feed line contains intermediate A3 (containing 4% silica, low loading) prepared in Preparation Example 3, with a feed ratio of 25.0%; the second feed line contains a drug-containing hydrophilic premix, with a feed ratio of 75.0%.

[0039] Temperature settings: Considering the increased drug content, the processing temperature is appropriately reduced to prevent degradation: Zone 1 30℃, Zone 2 70℃, Zone 3 95℃, Zone 4 120℃, Zone 5 120℃, Zone 6 115℃, and the mold head 115℃.

[0040] Screw parameters: The screw speed is set to 80 rpm (low speed to prolong residence time and ensure uniform mixing).

[0041] (3) Molding and curing: The cutting speed was adjusted to 1200 rpm, the cold air temperature was 10℃, and the rest was the same as in Example 1. Note: The final calculated value of silica content in this example is 1.0% (lower limit of the scope of the claims).

[0042] Example 3: This example uses a stepwise pre-dispersion and hot-melt co-extrusion process to prepare a long-acting sustained-release microsphere based on a high-viscosity carrier and high interfacial pinning strength. The synergistic effect of high molecular weight PEO and high concentration of silica was investigated. The specific steps include: (1) Preparation of drug-containing hydrophilic premix: Weigh 15.0% (lower limit) of nifedipine, 55.0% of polyethylene oxide (specification II, Mv600,000) and 10.0% of TPGS. The mixing process is the same as in Example 1.

[0043] (2) Hot melt co-extrusion: Feeding: The first feed line contains intermediate A2 (containing 15% silica, high loading) prepared in Preparation Example 2, with a feed ratio of 20.0%; the second feed line contains a drug-containing hydrophilic premix, with a feed ratio of 80.0%.

[0044] Temperature settings: Due to the increase in PEO molecular weight and melt viscosity, the processing temperature needs to be increased: Zone 1 40℃, Zone 2 80℃, Zone 3 110℃, Zone 4 135℃, Zone 5 135℃, Zone 6 130℃, and the die head 130℃.

[0045] Screw parameters: The screw speed is set to 150 rpm (high speed to overcome high viscosity resistance).

[0046] (3) Molding and curing: Due to the high viscosity of the melt, the cutting speed was increased to 2500 rpm to prevent sticking. The rest is the same as in Example 1. Note: The final calculated value of silica content in this example is 3.0% (upper limit of the claims).

[0047] Example 4: This example uses a stepwise pre-dispersion and hot-melt co-extrusion process to prepare microspheres with hydrogenated castor oil as the backbone material, and investigates the applicability of different lipid matrices. The specific steps include: (1) Preparation of drug-containing hydrophilic premix: Weigh 20.0% nifedipine, 45.0% polyethylene oxide (specification I and specification II are mixed at a mass ratio of 1:1) and 10.0% TPGS. The mixing process is the same as in Example 1.

[0048] (2) Hot melt co-extrusion: Feeding: The first feed line contains intermediate A4 (modified hydrogenated castor oil) prepared in [Preparation Example 4] at a feed ratio of 25.0%; the second feed line contains a drug-containing hydrophilic premix at a feed ratio of 75.0%.

[0049] Temperature settings: Hydrogenated castor oil has a higher melting point than behenicol glyceride, so adjust the melting zone temperature accordingly: Zone 1 30℃, Zone 2 80℃, Zone 3 115℃ (to ensure complete melting of lipids), Zone 4 130℃, Zone 5 130℃, Zone 6 125℃, and the mold head 125℃.

[0050] Screw parameters: The screw speed is set to 120 rpm.

[0051] (3) Molding and curing: The process is the same as in Example 1, and the result is obtained.

[0052] Example 5: This example uses a stepwise pre-dispersion and hot-melt co-extrusion process to prepare a process-enhanced microsphere. The process verifies the rapid locking capability of interfacial pinning effect for phase separation at high production throughput. Specifically, it includes the following steps: (1) Preparation of drug-containing hydrophilic premix: The formulation composition is exactly the same as that in Example 1: nifedipine 20.0%, polyethylene oxide (specification I) 45.0%, TPGS 10.0%.

[0053] (2) Hot melt co-extrusion (high throughput condition): Feeding: Intermediate A1 was used in the same proportion as in Example 1. However, the total feeding rate was increased to 3.0 kg / h (twice that of Example 1).

[0054] Temperature setting: Keep consistent with Example 1: 130°C (maximum).

[0055] Screw parameters: The screw speed is increased to 200 rpm to match the high feed rate and provide sufficient mechanical shear energy.

[0056] (3) Molding and curing: Due to the increase in production, the cooling air volume is increased, the air inlet temperature is reduced to 8℃, and the cutting speed is adjusted to 2800rpm to obtain the desired result.

[0057] III. Comparative Examples: Comparative Example 1 (Verifying the Necessity of Stepwise Pre-dispersion Process): This comparative example aims to demonstrate that without the "lipid-silica pre-dispersion" step, the interfacial pinning effect cannot be effectively formed. Compared with Example 1, the difference lies in the feeding method of the preparation process: This comparative example does not prepare the modified lipid intermediate A1 in step (1); instead, the formulated amounts of nifedipine, polyethylene oxide, TPGS, behenicol glyceride, and hydrophobic fumed silica I are physically mixed evenly in a mixer and then added to the extruder as a single stream for extrusion; the remaining process parameters (temperature, speed, pelletizing conditions) are exactly the same as in Example 1.

[0058] Comparative Example 2 (Verification of the Necessity of the Interface Stabilizer): This comparative example aims to demonstrate the core role of hydrophobic fumed silica in maintaining structural stability and preventing phase coarsening. The difference from Example 1 lies in the formulation composition: this comparative example removes hydrophobic fumed silica I from the formulation and correspondingly increases the amount of behenate glycerol to make up the total weight (i.e., the total amount of behenate glycerol is 27.0%). During preparation, the unmodified behenate glycerol is directly co-extruded with other components; all other aspects are the same.

[0059] Comparative Example 3 (Verifying the Necessity of the Hydrophobic Properties of the Interface Agent): This comparative example aims to demonstrate that only "hydrophobic" particles can spontaneously migrate to the interface, and hydrophilic particles cannot achieve the effects of this invention. The difference from Example 1 lies in the choice of raw materials: This comparative example uses an equal amount of unmodified hydrophilic fumed silica (specific surface area 200±25m²). 2 / g) replaced hydrophobic fumed silica I; in the preparation of the intermediate, hydrophilic fumed silica was dispersed in molten behenic acid glyceride; the rest were the same.

[0060] Comparative Example 4 (Verifying the Necessity of Hot-Melt Extrusion Shearing Process): This comparative example aims to demonstrate that the "bicontinuous phase" structure of the present invention relies on the high shear stretching of the extruder, rather than simple melt mixing. The difference from Example 1 lies in the preparation method: this comparative example does not use a hot-melt extruder, but rather a traditional melt-stirring granulation method. Specifically, glyceryl behenate is heated and melted, then hydrophobic fumed silica is added and stirred to disperse it. Nifedipine, PEO, and TPGS are then added, and the mixture is mechanically stirred at 120°C (300 rpm) for 20 minutes. After cooling and solidification, the mixture is pulverized and granulated. All other formulation proportions remain the same.

[0061] The main raw materials and reagents used in the above examples and comparative examples are as follows. Unless otherwise specified, all reagents are commercially available analytical grade or higher grade products.

[0062] 1. Nifedipine Nifedipine, chemical name 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylic acid dimethyl ester, CAS number 21829-25-4, purity greater than 99.0%, is a yellow crystalline powder. It is micronized before use and stored in the dark throughout the process.

[0063] 2. Hydrophilic Swelling Carrier (Polyethylene Oxide) The hydrophilic swelling carrier selected in this invention is polyethylene oxide (PEO), CAS number 25322-68-3. To achieve the controlled-release rate regulation described in this invention, the selected polyethylene oxide has a viscosity-average molecular weight (Mv) ranging from 200,000 Da to 600,000 Da. In specific embodiments, the following two specifications were selected: Specification I has a viscosity-average molecular weight of approximately 200,000 and a density of approximately 1.13 g / cm³. 3 Specification II has a viscosity-average molecular weight of approximately 600,000 and a density of approximately 1.21 g / cm³. 3 The polyethylene oxide of the above specifications is semi-crystalline, with a softening point range of 65℃-67℃.

[0064] 3. Hydrophobic Structural Framework Material The hydrophobic structural framework material used in this invention is selected from pharmaceutical grade long-chain fatty acid esters or hydrogenated vegetable oils, with a melting point range controlled between 60℃ and 88℃, to adapt to the hot melt extrusion process and form a non-corrosive framework. In specific embodiments, the following two are selected: (1) Glyceryl behenate: CAS number 30233-64-8, melting point range 69℃-74℃, HLB value approximately 2; (2) Hydrogenated castor oil: CAS number 8001-78-3, melting point range 85℃-88℃.

[0065] 4. Interface Stabilizer (Hydrophobic Fumed Silica) The interface stabilizer used in this invention is hydrophobic fumed silica that has undergone surface chemical modification, with a specific surface area (BET) ranging from 100 ± 20 m². 2 / g to 200±25m 2 / g, and the surface is chemically modified with dimethyldichlorosilane (DDS) or polydimethylsiloxane (PDMS) to ensure that it has sufficient hydrophobicity and interfacial migration ability. In specific embodiments, the following two specifications were selected: (1) Hydrophobic fumed silica I: CAS number 68611-44-9, surface modified with dimethyldichlorosilane (DDS), specific surface area is 110±20m 2 / g, carbon content 0.9%-1.3%; (2) hydrophobic fumed silica II: CAS number 67762-90-7, surface modified with polydimethylsiloxane (PDMS), specific surface area 100±20m 2 / g, exhibiting strong hydrophobicity.

[0066] 5. Comparative example raw material: hydrophilic fumed silica (CAS No. 112945-52-5), which is unmodified amorphous silica with a specific surface area of ​​200±25 m². 2 / g.

[0067] 6. Solubilizer Vitamin E Polyethylene Glycol Succinate (TPGS): CAS No. 9002-96-4, melting point 36℃-42℃, HLB value approximately 13.2.

[0068] IV. Test Example: Test Example 1: In vitro release rate determination and release kinetics investigation 1. Experimental Methods The dissolution and release rate were determined using Method II (paddle method) of General Chapter 0931 of the Pharmacopoeia of the People's Republic of China (2020 edition).

[0069] 900 ml of degassed pH 6.8 phosphate buffer was used as the dissolution medium. 0.5% sodium dodecyl sulfate was added to the medium to maintain the trough conditions. The temperature was controlled at 37.0 ± 0.5 °C, and the impeller speed was set to 100 r / min. Appropriate amounts of microparticles prepared in Examples 1-5 and Comparative Examples 1-4 (equivalent to 10 mg of nifedipine) were added to the dissolution vessel, and the floating samples were placed in a settling basket. 10 ml samples were taken at 1 hour, 4 hours, 8 hours, 12 hours, 16 hours, and 24 hours after the start of the experiment, and an equal volume of isothermal blank medium was added immediately. The samples were filtered through a 0.45 μm microporous membrane, and the filtrate was collected. High-performance liquid chromatography (HPLC) was used with octadecylsilane-bonded silica gel as the packing material, methanol-water (60:40) as the mobile phase, and a detection wavelength of 235 nm. The peak area was measured, and the cumulative release rate at each time point was calculated. Each group of samples was measured in parallel six times, and the average value was calculated.

[0070] 2. Experimental Data The table below lists the cumulative release data of the examples and comparative examples at different time points. The data are rounded to one decimal place, are unedited, and reflect actual measured fluctuations.

[0071] Table 1. Results of in vitro cumulative release rate determination of nifedipine microspheres (n=6, Mean%)

[0072] 3. Results Analysis.

[0073] Table 1 shows that the in vitro release curves of Examples 1-5 exhibit zero-order kinetics, with a constant release rate. Example 1 showed a cumulative release rate of 71.5% at 12 hours and near-complete release at 24 hours. Example 3, using high molecular weight polyethylene oxide and 3.0% interface stabilizer, had the lowest release rate among all groups, indicating that increasing the carrier viscosity and interfacial particle concentration can reduce the drug diffusion rate.

[0074] Comparative Example 2 (without hydrophobic fumed silica) showed a release rate of 34.6% after 1 hour and 78.4% after 4 hours, exhibiting burst release characteristics. This result indicates that in a system without solid particle stabilization, the lipid dispersion formed during the hot-melt extrusion process aggregates during the cooling phase, failing to form a continuous skeletal network, leading to rapid drug release along with the dissolution of the hydrophilic carrier. Comparative Example 3 (using hydrophilic fumed silica) exhibited release behavior consistent with Comparative Example 2, confirming that hydrophilic particles tend to distribute within the hydrophilic phase rather than at the two-phase interface, failing to generate an interfacial pinning effect to stabilize the microstructure.

[0075] Comparative Example 1 (without a stepwise pre-dispersion process) showed a 4-hour release rate of 45.2%, significantly higher than the 24.8% of Example 1. This difference indicates that when hydrophobic fumed silica is directly mixed with lipids, drugs, and polymers and extruded, particles cannot fully migrate to the two-phase interface within a limited residence time, resulting in insufficient interface coverage and reduced phase separation control. The data from these examples demonstrate that pre-dispersion of hydrophobic fumed silica in the lipid phase and subsequent interface pinning can construct a stable bicontinuous phase framework structure, restricting drug diffusion pathways and achieving controlled release.

[0076] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A controlled-release microcapsule for nifedipine, characterized in that, The contents of the microcapsules are nifedipine controlled-release microcapsules, which are made from raw materials comprising the following weight percentages: nifedipine 15.0%-25.0%; hydrophilic swelling carrier 35.0%-50.0%; hydrophobic structural framework material 15.0%-25.0%; interface stabilizer 1.0%-3.0%; solubilizer 5.0%-10.0%; wherein the interface stabilizer is hydrophobic fumed silica; the hydrophilic swelling carrier is polyethylene oxide; and the hydrophobic structural framework material is selected from one or more of behenic acid glyceride, hydrogenated castor oil, or stearic acid.

2. The nifedipine controlled-release microcapsule according to claim 1, characterized in that, The raw materials have the following weight percentages: nifedipine 20.0%-25.0%; hydrophilic swelling carrier 40.0%-45.0%; hydrophobic structural framework material 23.0%-25.0%; interface stabilizer 1.0%-2.0%; and solubilizer 10.0%.

3. The nifedipine controlled-release microcapsule according to claim 1, characterized in that, The raw materials have the following characteristics: the viscosity-average molecular weight of the polyethylene oxide is 200,000 to 600,000 Da; the melting point of the hydrophobic structural framework material is 60℃-88℃; and the specific surface area of ​​the hydrophobic fumed silica is 100±20 m². 2 / g to 200±25m 2 / g, and the surface is chemically modified with dimethyldichlorosilane or polydimethylsiloxane.

4. The nifedipine controlled-release microcapsule according to claim 1, characterized in that, The nifedipine controlled-release microcapsules have a bicontinuous phase framework structure, which is formed by hot melt co-extrusion of a modified lipid intermediate and a drug-containing hydrophilic premix; wherein the modified lipid intermediate is pre-melted and dispersed with a hydrophobic structural framework material and an interface stabilizer, and the weight content of the interface stabilizer in the modified lipid intermediate is 4.0%-15.0%.

5. A method for preparing a nifedipine controlled-release microcapsule according to any one of claims 1-4, characterized in that, The process employs a stepwise pre-dispersion and hot-melt co-extrusion technique, including the following steps: S1. Preparation of modified lipid intermediates: The hydrophobic structural framework material is melted, and an interface stabilizer is added under shear to disperse it. After cooling and solidification, it is pulverized to obtain the modified lipid intermediates. S2. Preparation of drug-containing hydrophilic premix: Nifedipine, hydrophilic swelling carrier and solubilizer are physically mixed evenly at a temperature below 30°C to obtain drug-containing hydrophilic premix; S3. Hot melt co-extrusion: The modified lipid intermediate obtained in step S1 and the drug-containing hydrophilic premix obtained in step S2 are fed into a twin-screw extruder simultaneously as two separate materials for co-extrusion. The materials are heated and melted in the extruder and mixed under shear force. S4. Molding and curing: The extruded melt is hot-cut into microspheres by the die surface, cooled and solidified under airflow, and then sieved to obtain the final product.

6. The method for preparing a nifedipine controlled-release microcapsule according to claim 5, characterized in that, In step S1, the specific process for preparing the modified lipid intermediate is as follows: heating the hydrophobic structural framework material to 85℃-100℃ to melt it, turning on the high-shear homogenizer, setting the rotation speed to 3000-6000 rpm, adding the interface stabilizer, and homogenizing for 10-20 minutes.

7. The method for preparing a nifedipine controlled-release microcapsule according to claim 5, characterized in that, In step S3, the process parameters for hot melt co-extrusion are controlled as follows: the extruder barrel temperature is set within the range of 30℃-135℃, wherein the highest temperature in the melt mixing zone is controlled within the range of 115℃-135℃; the screw speed is set to 80-200 rpm; and the screw assembly of the twin-screw extruder includes at least two sets of kneading blocks.

8. The method for preparing a nifedipine controlled-release microcapsule according to claim 5, characterized in that, In step S3, the feeding ratio of the two materials is as follows: the amount of modified lipid intermediates fed accounts for 20.0%-25.0% of the total feeding amount; the amount of drug-containing hydrophilic premix fed accounts for 75.0%-80.0% of the total feeding amount.

9. The method for preparing a nifedipine controlled-release microcapsule according to claim 5, characterized in that, In step S4, the molding and curing conditions are as follows: pelletizing is performed using a die-cutting hot cutter with a cutter speed of 1200-2800 rpm; the inlet temperature of the cooling airflow is 8℃-15℃.

10. The method for preparing a nifedipine controlled-release microcapsule according to claim 5, characterized in that, In step S1, when the hydrophobic structural framework material is behenic acid glyceride, the melting temperature is controlled at 85℃-95℃; when the hydrophobic structural framework material is hydrogenated castor oil, the melting temperature is controlled at 95℃-105℃.

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