Preparation method of double-phase release capsule preparation

Abstract

The invention discloses a preparation method of a two-phase release capsule preparation, and belongs to the field of capsule preparation. The method mainly comprises the following steps: dispersing meso-porous silicon nanoparticles in a drug solution, stirring, adsorbing the loaded drug, filtering, drying, sequentially adding a modified sodium alginate solution, a pore-foaming agent and a dichloromethane solution of cyclodextrin acyl chloride, and reacting to obtain a composite functionalized meso-porous silicon nano loaded drug; the preparation method comprises the following steps: dissolving sodium alginate and gelatin in deionized water according to a mass ratio of 3: 2, adding adamantane isocyanate for reaction, then adding a temperature-sensitive polymer, a pH responsive polymer, a cross-linking agent and an initiator, and uniformly stirring to obtain a precursor solution; by constructing an innovative two-phase release system, fusing a release regulation and control mechanism adaptive to multiple physiological environments, adopting an integrated preparation process and matching with a moisture-proof coating technology, the precision and the structural stability of two-phase release are remarkably improved, quick effect of a quick release phase and long-acting stable release of a slow release phase are realized, and the fluctuation range of blood concentration is greatly reduced.

Description

Technical Field

[0001] This invention relates to the field of capsule preparation technology, and in particular to a method for preparing a biphasic release capsule formulation. Background Technology

[0002] Capsule formulations are a common oral medication dosage form, widely used because they can mask taste and improve patient compliance. For many chronic diseases that require long-term administration (such as hypertension, diabetes, and mental illnesses), capsules are crucial for maintaining stable and sustained blood drug concentrations. Biphasic-release capsule formulations aim to take effect rapidly after administration and then maintain effective blood drug concentrations for a long time, thereby reducing the frequency of dosing and reducing the toxic side effects caused by fluctuations in blood drug concentration.

[0003] The prior art patent document CN120899669A discloses "a loxoprofen sodium dual-release capsule microplate and its preparation method." Through the synergistic effect of immediate-release and sustained-release microplates, the immediate-release microplates achieve rapid release and absorption, while the sustained-release microplates maintain a relatively stable blood drug concentration over a long period. This not only reduces the frequency of dosing but also ensures that postprandial medication requirements are coordinated with dietary habits, reducing the occurrence of gastrointestinal adverse reactions. The formulation of this application conforms to chronopharmacology dosage form design. Dosing twice daily allows for rapid onset of action while maintaining blood drug concentrations during the peak nocturnal disease period, avoiding the drawbacks of needing to take medication after meals during nocturnal disease attacks, ensuring sleep quality, and improving overall therapeutic efficacy.

[0004] Patent document CN104739808B discloses "A troxyl chloride dual-release capsule and its preparation method." This troxyl chloride dual-release capsule is composed of 2090% troxyl chloride sustained-release microspheres and 1080% troxyl chloride delayed-release microspheres by weight. Both the sustained-release and delayed-release microspheres are obtained by coating troxyl chloride immediate-release microspheres. This invention mixes sustained-release and delayed-release microspheres in a specific ratio, which on the one hand allows for slow drug release, maintains a stable blood drug concentration, and improves medication safety; on the other hand, it rationally controls the drug release rate in the small intestine, increases bioavailability, improves therapeutic effect, and saves costs.

[0005] While existing technologies can reduce the frequency of drug administration through the synergistic effect of immediate-release and sustained-release components, achieving rapid drug onset to meet immediate treatment needs while maintaining relatively stable blood drug concentrations over a long period, reducing adverse reactions caused by fluctuations in blood drug concentrations, and adapting to postprandial medication habits and chronopharmacology design to improve patient medication adherence, some technologies can also improve drug bioavailability, save costs, improve the treatment effect of specific diseases, and ensure medication safety. However, existing technologies rely on the underlying logic of physical mixing or layered coating, which is a simple stacking of technologies with a single release regulation mechanism. They lack precise adaptation to multiple physiological environments such as body temperature, gastrointestinal pH, and intestinal enzyme systems. Their structural stability is poor, and layering and aggregation are prone to occur during storage, leading to release curve drift. The process steps are redundant, with high substitutability and large batch-to-batch differences. Drug compatibility is limited, with insufficient adaptability to drugs with different solubilities, a high proportion of release from non-target sites, and room for improvement in bioavailability. Summary of the Invention

[0006] Purpose of the invention: The purpose of this invention is to provide a method for preparing biphasic release capsule formulations to solve the problems mentioned in the background art.

[0007] Technical solution: A method for preparing a biphasic-release capsule formulation, comprising the following steps: S1. Disperse mesoporous silica nanoparticles in a drug solution, stir to adsorb the drug, filter and dry, then add modified sodium alginate solution, pore-forming agent, and dichloromethane solution of cyclodextrin acyl chloride in sequence to obtain composite functionalized mesoporous silica nanoparticles for drug loading. S2. Dissolve sodium alginate and gelatin in deionized water at a mass ratio of 3:2, add adamantane isocyanate to react, then add thermosensitive polymer, pH-responsive polymer, crosslinking agent and initiator, and stir evenly to obtain precursor solution. S3. Disperse the composite functionalized mesoporous silica nanoparticles in the precursor solution at a mass ratio of 1:4, adjust the pH to 6.0, purge with nitrogen for protection, and stir at 35°C for 30 minutes to form an interlocking gel dispersion. S4. Spray dry the interlocking gel dispersion, controlling the inlet air temperature to 120℃ and the outlet air temperature to 60℃, to prepare microspheres with a particle size of 100-200µm. S5. Microparticles are coated with an ultra-thin protective film of 5-10µm by electrospinning, and then filled into hollow capsules. The capsules are then cured in an environment of 30℃ and 40% relative humidity for 2 hours to obtain a biphasic release capsule formulation.

[0008] Preferably, in step S1, the mesoporous silicon nanoparticles have a pore size of 2-5 nm and a specific surface area of ​​800-1000 m². 2 / g; the drug solution is an aqueous solution of water-soluble drugs or an ethanol-water solution of lipid-soluble or poorly soluble drugs; the stirring and adsorption temperature for drug loading is 30℃ for 4 hours; the reaction temperature is 40℃ for 6 hours; the modified sodium alginate is hydroxypropylated modified sodium alginate, the pore-forming agent is gelatin-chitosan graft, and the cyclodextrin acyl chloride is β-cyclodextrin acyl chloride.

[0009] Preferably, in step S2, the concentration of the aqueous solution of sodium alginate and gelatin is 5%; the reaction temperature after adding adamantane isocyanate is 50°C, and the reaction time is 2 hours; the thermosensitive polymer is N-isopropylacrylamide, the pH-responsive polymer is dimethylaminoethyl methacrylate, and the molar ratio of the two is 3:2; the crosslinking agent is a β-glucosidase-responsive crosslinking agent, which accounts for 8% of the total mass of sodium alginate and gelatin; and the initiator is ammonium persulfate.

[0010] Preferably, in step S3, the composite functionalized mesoporous silica nanocarrier forms a 1:1 host-guest inclusion complex with adamantane covalently grafted onto the gelatin molecular chain in the precursor solution via β-cyclodextrin. Simultaneously, the amino groups on the surface of the composite functionalized mesoporous silica nanocarrier are covalently linked with the carboxyl groups in the precursor solution via amide bonds, thereby achieving in-situ interlocking.

[0011] Preferably, in step S5, the material of the ultrathin protective film is PLGA, the coating method is electrospinning, and the thickness of the protective film is 5-10µm.

[0012] Preferably, in step S1, the stirring speed for adsorbing and loading the drug is 200-300 r / min, and the concentration of the dichloromethane solution of β-cyclodextrin acyl chloride is 5-8 mg / mL.

[0013] Preferably, in step S3, the flow rate of nitrogen gas introduced is 0.5-1.0 L / min.

[0014] Preferably, in step S4, the atomization pressure of the spray drying is 0.2-0.4 MPa, and the bulk density of the microparticles is controlled at 0.6-0.8 g / cm³. 3 .

[0015] Beneficial Effects: This invention, by constructing an innovative biphasic release system and integrating release regulation mechanisms adapted to multiple physiological environments, employs an integrated preparation process combined with moisture-proof coating technology. This significantly improves the accuracy and structural stability of biphasic release, achieving rapid onset of action in the immediate-release phase and long-lasting, stable release in the sustained-release phase, greatly reducing fluctuations in blood drug concentration. Simultaneously, it enhances broad compatibility with water-soluble, lipid-soluble, and poorly soluble drugs, adapting to complex physiological environments in vivo, improving bioavailability, and reducing drug release from off-target sites. Furthermore, the optimized integrated process reduces production steps and energy consumption, minimizes batch-to-batch variability, and improves preparation efficiency. Accelerated testing confirms significantly improved storage stability and extended shelf life, while the process is environmentally friendly. This invention not only solves the common problems of traditional biphasic capsule formulations, such as single release regulation, easy structural stratification and aggregation, process redundancy, and poor drug compatibility, but also provides a highly efficient and sustainable technical path for the large-scale preparation of precision-drug-directed capsule formulations through multi-technology integration and innovation. Attached Figure Description

[0016] Figure 1 This is a schematic diagram of the method flow of the present invention. Detailed Implementation

[0017] To make the technical solution of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

[0018] Example 1 A method for preparing a biphasic-release capsule formulation includes: 1. A pore size of 2 nm and a specific surface area of ​​800 m² are selected. 2 / g of mesoporous silica nanoparticles were dispersed in an aqueous solution of a water-soluble drug (such as ibuprofen). The drug was adsorbed and loaded at 30°C for 4 hours with a stirring speed of 200r / min. After filtration and drying, hydroxypropylated modified sodium alginate solution, gelatin-chitosan graft porogen, and β-cyclodextrin acyl chloride dichloromethane solution with a concentration of 5mg / mL were added sequentially. The reaction was carried out at 40°C for 6 hours to obtain composite functionalized mesoporous silica nanoparticles loaded with drugs.

[0019] 2. Dissolve sodium alginate and gelatin in deionized water at a mass ratio of 3:2 to prepare a 5% aqueous solution. Add adamantane isocyanate and react at 50°C for 2 hours. Then add N-isopropylacrylamide (thermosensitive polymer) and dimethylaminoethyl methacrylate (pH-responsive polymer) in a molar ratio of 3:2, along with β-glucosidase-responsive crosslinking agent and ammonium persulfate initiator accounting for 8% of the total mass of sodium alginate and gelatin. Stir until homogeneous to obtain the precursor solution.

[0020] 3. Disperse the composite functionalized mesoporous silica nanoparticles prepared in step S1 into the precursor solution in step S2 at a mass ratio of 1:4. Adjust the pH to 6.0, introduce nitrogen gas at a flow rate of 0.5 L / min for protection, and stir at 35°C for 30 minutes. Through host-guest recognition between β-cyclodextrin and adamantane and covalent linkage between amino and carboxyl groups, an interlocking gel dispersion is formed.

[0021] 4. Spray-dry the interlocking gel dispersion, setting the inlet air temperature to 120℃, the outlet air temperature to 60℃, and the atomization pressure to 0.2MPa, to produce particles with a diameter of 100µm and a bulk density of 0.6g / cm³. 3 Microparticles.

[0022] 5. The microparticles were coated with a 5µm thick PLGA ultrathin protective film by electrospinning, and then filled into hollow capsules. The capsules were then cured in an environment of 30℃ and 40% relative humidity for 2 hours to obtain a biphasic release capsule formulation.

[0023] Example 2 A method for preparing a biphasic-release capsule formulation includes: 1. A pore size of 3.5 nm and a specific surface area of ​​900 m² are selected. 2 / g of mesoporous silica nanoparticles were dispersed in an ethanol-water solution of a lipid-soluble drug (such as vitamin E). The drug was adsorbed and loaded at 30°C for 4 hours with a stirring speed of 250r / min. After filtration and drying, hydroxypropylated modified sodium alginate solution, gelatin-chitosan graft porogen, and β-cyclodextrin acyl chloride dichloromethane solution with a concentration of 6.5mg / mL were added sequentially. The reaction was carried out at 40°C for 6 hours to obtain composite functionalized mesoporous silica nanoparticles loaded with drugs.

[0024] 2. Dissolve sodium alginate and gelatin in deionized water at a mass ratio of 3:2 to prepare a 5% aqueous solution. Add adamantane isocyanate and react at 50°C for 2 hours. Then add N-isopropylacrylamide and dimethylaminoethyl methacrylate in a molar ratio of 3:2, β-glucosidase-responsive crosslinking agent and ammonium persulfate initiator accounting for 8% of the total mass of sodium alginate and gelatin, and stir until homogeneous to obtain the precursor solution.

[0025] 3. The composite functionalized mesoporous silica nanoparticles were dispersed in the precursor solution at a mass ratio of 1:4. The pH was adjusted to 6.0, and nitrogen gas was introduced at a flow rate of 0.75 L / min for protection. The mixture was stirred at 35 °C for 30 minutes. An interlocking gel dispersion was formed through host-guest recognition between β-cyclodextrin and adamantane and covalent linkage between amino and carboxyl groups.

[0026] 4. Spray-dry the interlocking gel dispersion, setting the inlet air temperature to 120℃, the outlet air temperature to 60℃, and the atomization pressure to 0.3MPa, to produce particles with a diameter of 150µm and a bulk density of 0.7g / cm³.3 Microparticles.

[0027] 5. The microparticles were coated with a 7.5µm thick PLGA ultrathin protective film by electrospinning, and then filled into hollow capsules. The capsules were then cured in an environment of 30℃ and 40% relative humidity for 2 hours to obtain a biphasic release capsule formulation.

[0028] Example 3 A method for preparing a biphasic-release capsule formulation includes: 1. A pore size of 5 nm and a specific surface area of ​​1000 m² are selected. 2 / g of mesoporous silica nanoparticles were dispersed in an ethanol-water solution of a poorly soluble drug (such as artemisinin). The drug was adsorbed and loaded at 30°C for 4 hours with a stirring speed of 300r / min. After filtration and drying, hydroxypropylated modified sodium alginate solution, gelatin-chitosan graft porogen, and β-cyclodextrin acyl chloride dichloromethane solution with a concentration of 8mg / mL were added sequentially. The reaction was carried out at 40°C for 6 hours to obtain composite functionalized mesoporous silica nanoparticles loaded with drugs.

[0029] 2. Dissolve sodium alginate and gelatin in deionized water at a mass ratio of 3:2 to prepare a 5% aqueous solution. Add adamantane isocyanate and react at 50°C for 2 hours. Then add N-isopropylacrylamide and dimethylaminoethyl methacrylate in a molar ratio of 3:2, β-glucosidase-responsive crosslinking agent and ammonium persulfate initiator accounting for 8% of the total mass of sodium alginate and gelatin, and stir until homogeneous to obtain the precursor solution.

[0030] 3. The composite functionalized mesoporous silica nanoparticles were dispersed in the precursor solution at a mass ratio of 1:4. The pH was adjusted to 6.0. Nitrogen gas was introduced at a flow rate of 1.0 L / min for protection. The mixture was stirred at 35 °C for 30 minutes. An interlocking gel dispersion was formed through host-guest recognition between β-cyclodextrin and adamantane and covalent linkage between amino and carboxyl groups.

[0031] 4. Spray-dry the interlocking gel dispersion, setting the inlet air temperature to 120℃, the outlet air temperature to 60℃, and the atomization pressure to 0.4MPa, to produce particles with a diameter of 200µm and a bulk density of 0.8g / cm³. 3 Microparticles.

[0032] 5. The microparticles were coated with a 10µm thick PLGA ultrathin protective film by electrospinning, and then filled into hollow capsules. The capsules were then cured in an environment of 30℃ and 40% relative humidity for 2 hours to obtain a biphasic release capsule formulation.

[0033] Comparative Example 1 The difference between Comparative Example 1 and Examples 1-3 is that Comparative Example 1 uses a traditional process of "layer coating of immediate-release microplates and sustained-release microplates + physical mixing" (refer to the prior art document CN120899669A in the background section above). It relies on physical barriers to achieve release differences and lacks molecular-level interlocking and covalent bond anchoring structures. The process includes the following steps: Weigh out 10%-45% loxoprofen sodium, 25%-75% filler (lactose + microcrystalline cellulose), 0.5%-10% binder (povidone K30), 2%-20% disintegrant (sodium carboxymethyl starch), 0.02%-5% glidant (silica), and 0.05%-5% lubricant (magnesium stearate) by weight ratio. Mix them and add 30%-70% ethanol aqueous solution to make a soft mass. Sieve to make wet granules, dry and compress into tablets (1-3 mm in diameter). Then, use Opadry® for film coating (weight gain of 5%-20%) to obtain immediate-release microtablets.

[0034] Weigh out 10%-50% loxoprofen sodium, 5%-45% filler (microcrystalline cellulose), 10%-70% release inhibitor (hydroxypropyl methylcellulose K4M+K100M), 0.05%-10% binder (povidone K30), 0.02%-5% glidant (silica), and 0.05%-5% lubricant (magnesium stearate) according to the following weight ratios: mix and add 60%-95% ethanol aqueous solution to prepare a soft mass. After tableting, sequentially coat with an isolation layer (Opadry®, weight gain 5%-20%) and an enteric coating layer (Acryl-EZE®, weight gain 10%-30%) to obtain sustained-release microtablets.

[0035] Mix the immediate-release microcapsules and the sustained-release microcapsules at a ratio of 1:(0.8-3.5) to obtain a total drug content of 90mg, and fill the mixture into empty capsules to complete the preparation of the formulation.

[0036] Comparative Example 2 The difference between Comparative Example 2 and Examples 1-3 is that Comparative Example 2 uses a process of "immediate-release microcapsules as a base + layered coating to prepare sustained-release / delayed-release microcapsules + physical mixing" (refer to the prior art CN104739808B in the background section above). It relies solely on pH-responsive coating to achieve release regulation, without temperature-sensitive or enzyme-responsive mechanisms, and includes the following steps: Take 40%-80% of 30-35 mesh blank pellet cores (sucrose type / starch type / microcrystalline cellulose type), and use an ethanol aqueous solution (0%-80%) containing 10%-50% tromethorphan chloride, 1%-10% binder (hydroxypropyl methylcellulose), and 1%-10% anti-adhesion agent (magnesium stearate) as the drug-loaded coating solution. The drug is loaded using a fluidized bed cutting-spray process (inlet air temperature 40-80℃, atomization pressure 0.1-0.3MPa) to obtain drug-loaded micro pellets.

[0037] A 5%-15% separating layer coating solution is prepared using an ethanol-water solution of polyvinyl alcohol (1%-10%), and the drug-loaded microspheres are coated to obtain immediate-release microspheres.

[0038] Take 45%-90% immediate-release microspheres, 5%-50% sustained-release coating material (ethyl cellulose aqueous dispersion), 1%-5% pore-forming agent (polyethylene glycol), and 1%-5% sustained-release protective layer (hydroxypropyl methylcellulose) to prepare a 5%-20% sustained-release coating solution. After fluidized bed coating, dry the solution to prepare sustained-release microspheres.

[0039] Take 45%-75% immediate-release microcapsules, 20%-50% delayed-release coating material (Utec FS30D), 1%-5% plasticizer (polysorbate), and 1%-5% delayed-release protective layer (Opadry®) to prepare a 5%-30% delayed-release coating solution. After fluidized bed coating, dry the solution to prepare delayed-release microcapsules.

[0040] Mix 20%-90% sustained-release microcapsules and 10%-80% delayed-release microcapsules by weight, fill them into empty capsules (20-100mg specification), and complete the preparation of the formulation.

[0041] Comparative Example 3 The difference between Comparative Example 3 and Examples 1-3 is that Comparative Example 3 uses a "stepwise preparation of capsule material and coating layer + physical bonding" process (refer to comparative document CN112826115A), without in-situ polymerization and specific intermolecular binding, and achieves targeted release only through mechanical mixing and coating, including the following steps: Add purified water to the sol tank, heat to 95℃, add hydroxypropyl methylcellulose and carrageenan, stir for 20 minutes until uniform, then add the excipients and stir evenly. Stir at high temperature and remove air bubbles under vacuum for 60 minutes, cool to 50℃ and stir at a constant temperature for 60 minutes. After correcting the viscosity (2200-2400cps), release the gel and keep it at a temperature of 53℃ for the body and 51℃ for the cap.

[0042] Weigh out 2400-4400g of acetone, 700-900g of hydroxypropyl methylcellulose phthalate, 100-300g of pharmaceutical-grade polyacrylic acid resin, 2400-4400g of 95% ethanol, 50-150g of polyethylene glycol, 6.5-8.5g of triethyl citrate, 6.5-8.5g of glycerol, and 50-150g of diethyl phthalate. Stir for 24 hours, then filter and seal for 24 hours before use.

[0043] Hydroxypropyl methylcellulose empty capsules were prepared by a dipping process, followed by two stages of enteric coating dipping (coating chamber temperature 22-24℃, relative humidity 35-45%), and then dried to obtain intestinal-targeted empty capsules. These capsules were then filled with conventional drug particles (without a special drug delivery system) to complete the formulation preparation.

[0044] To illustrate the preparation of the biphasic-release capsule formulation described in this invention, tests were conducted on the capsules prepared in Examples 1-3 and Comparative Examples 1-3. These tests included the release rate of the immediate-release phase at 15 minutes, the cumulative release rate of the sustained-release phase over 24 hours, the fluctuation range of blood drug concentration, the drug retention rate after 6 months of accelerated testing, batch-to-batch differences, and the proportion of release from non-target sites. Release rate was determined using dissolution assay, blood drug concentration was determined using high-performance liquid chromatography (HPLC), drug retention rate was determined using headspace chromatography (HGC), and batch-to-batch differences were calculated through parallel testing of multiple batches of samples. The test results are shown in the table below: Test Project Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Immediate-release phase release rate at 15 minutes (%) 88.2 90.5 91.8 75.3 82.1 78.6 Cumulative release rate of sustained-release phase over 24 hours (%) 95.1 96.3 95.8 82.4 86.7 84.2 Fluctuation range of blood drug concentration (%) 11.8 10.3 11.2 38.5 25.7 28.3 Drug retention rate (%) after 6 months in accelerated testing 96.2 97.5 96.8 83.7 89.4 87.1 Inter-batch variation (%) 3.8 3.2 3.5 12.6 9.8 11.5 Percentage of release from non-target sites (%) 3.8 3.2 3.5 26.4 18.7 21.2 As can be seen from the comparison of the examples and comparative examples, the present invention significantly improves the release accuracy and structural stability of the formulation by constructing a molecular-level interlocking-covalent bond anchoring structure, integrating a triple physiological response mechanism and an integrated preparation process, reducing blood drug concentration fluctuations and batch-to-batch variability, reducing drug release from non-target sites, broadening drug compatibility, and optimizing the overall performance of biphasic-release capsules. Traditional methods often rely on simple stacking logic of physical mixing or layered coating, resulting in a single release regulation mechanism, lacking precise adaptation to multiple physiological environments in vivo, and exhibiting inherent defects such as easy structural layering and aggregation, large batch-to-batch variability, and limited drug compatibility. The technical solution of the present invention has significant advantages in release accuracy, structural stability, bioavailability, and production efficiency, providing an innovative technical path for the preparation of biphasic-release capsule formulations.

[0045] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. 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 modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A process for the preparation of a biphasic release capsule formulation, characterized in that, The method comprises the following steps: S1, dispersing mesoporous silica nanoparticles in a drug solution, stirring to adsorb the drug, and then filtering and drying, and then sequentially adding a modified sodium alginate solution, a porogen, and a dichloromethane solution of cyclodextrin acyl chloride to obtain a composite functionalized mesoporous silica nanoparticle drug carrier; S2, dissolving sodium alginate and gelatin in deionized water at a mass ratio of 3:2, adding adamantane isocyanate to react, and then adding a temperature-sensitive polymer, a pH-responsive polymer, a crosslinking agent, and an initiator to obtain a precursor solution; S3, dispersing the composite functionalized mesoporous silica nanoparticle drug carrier in the precursor solution at a mass ratio of 1:4, adjusting the pH to 6.0, passing nitrogen gas for protection, and stirring at 35°C for 30 minutes to form an interlocking gel dispersion; S4, spray drying the interlocking gel dispersion, controlling the inlet air temperature to be 120°C and the outlet air temperature to be 60°C, and preparing micro-pellets with a particle size of 100-200µm; S5, electrospinning a 5-10µm ultra-thin protective film on the micro-pellets, and then filling the micro-pellets into a hollow capsule and solidifying the capsule in an environment at 30°C and a relative humidity of 40% for 2 hours to obtain a dual-phase release capsule preparation.

2. A process for the preparation of a biphasic release capsule formulation according to claim 1, characterized in that, The pore size of the mesoporous silica nanoparticles is 2-5 nm, and the specific surface area is 800-1000 m 2 / g; the drug solution is a water-soluble drug aqueous solution or an ethanol-water solution of a fat-soluble and poorly soluble drug; the temperature for stirring and loading the drug is 30 DEG C, and the duration is 4 hours; the reaction temperature is 40 DEG C, and the duration is 6 hours; the modified sodium alginate is hydroxypropylated modified sodium alginate, the pore-forming agent is a gelatin-chitosan graft, and the cyclodextrin acyl chloride is beta-cyclodextrin acyl chloride.

3. A process for the preparation of a biphasic release capsule formulation according to claim 1, characterized in that, In S2, the concentration of the sodium alginate and gelatin aqueous solution is 5%; the reaction temperature after adding adamantane isocyanate is 50°C, and the duration is 2 hours; the temperature-sensitive polymer is N-isopropyl acrylamide, the pH-responsive polymer is dimethylaminoethyl methacrylate, and the molar ratio of the two is 3:2; the crosslinking agent is a β-glucosidase-responsive crosslinking agent, and the mass of the crosslinking agent accounts for 8% of the total mass of sodium alginate and gelatin; and the initiator is ammonium persulfate.

4. A process for the preparation of a biphasic release capsule formulation according to claim 1, characterized in that, In S3, the composite functionalized mesoporous silica nanoparticle drug carrier forms a 1:1 host-guest inclusion compound with adamantane covalently grafted on the gelatin molecular chain in the precursor solution through β-cyclodextrin, and the amino groups on the surface of the composite functionalized mesoporous silica nanoparticle drug carrier are covalently connected to the carboxyl groups in the precursor solution through amide bonds to realize in-situ interlocking.

5. A process for the preparation of a biphasic release capsule formulation according to claim 1, characterized in that, In S5, the material of the ultra-thin protective film is PLGA, the coating method is electrospinning, and the thickness of the protective film is 5-10µm.

6. A process for the preparation of a biphasic release capsule formulation according to claim 2, characterized in that, In S1, the stirring speed for stirring and adsorbing the drug is 200-300r / min, and the concentration of the dichloromethane solution of β-cyclodextrin acyl chloride is 5-8mg / mL.

7. A process for the preparation of a biphasic release capsule formulation according to claim 1, characterized in that, In S3, the flow rate of the nitrogen gas is 0.5-1.0L / min.

8. A process for the preparation of a biphasic release capsule formulation according to claim 1, characterized in that, In the S4, the spray-drying atomization pressure is 0.2-0.4 MPa, and the bulk density of the pellets is controlled at 0.6-0.8 g / cm 3 .

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