Oil-based protective hard capsule containing sustained-release pellets and preparation method of oil-based protective hard capsule

Abstract

The invention relates to the technical field of oral sustained-release preparations, in particular to an oil-based protective hard capsule containing sustained-release pellets and a preparation method of the oil-based protective hard capsule. The preparation method comprises the following steps: firstly, preparing a capsule shell: dissolving hydroxypropyl methylcellulose, carrageenan, gellan gum and lauryl sodium sulfate in hot water in stages, aging to obtain a glue solution, dipping the glue solution, drying and cutting to obtain a primary capsule body; secondly, adding hydrophobic modified silica gel nanoparticles and a temperature response type copolymer into linseed oil to form a suspension; preparing an active drug and a sustained-release auxiliary material into a pellet core, and coating to obtain a sustained-release pellet; and finally, filling the sustained-release pellets into a capsule lower shell, filling the suspension, covering the capsule upper shell, sealing by adopting a hydroxypropyl methylcellulose solution, and heating and curing by hot air. The obtained capsule can be used for oral sustained-release medicines or functional foods after leakage detection and sterilization; liquid-solid split charging is achieved, the drug release behavior can be effectively controlled, the stability is improved, and good application prospects are achieved.

Description

Technical Field

[0001] This invention relates to the field of oral sustained-release formulation technology, specifically to an oil-based protective hard capsule containing sustained-release microspheres and its preparation method. Background Technology

[0002] Oral solid dosage forms have always been the primary form of drug delivery, with capsules and tablets being the most widely used. Traditional capsules typically fill the capsule shell with drug components in powder, granule, or liquid form. While this can mask unpleasant drug odors and improve medication compliance, it has inherent limitations such as a single release behavior and limited bioavailability. To address these issues, sustained-release and controlled-release technologies have emerged, using coating, matrix, and other techniques to delay drug release and achieve long-lasting therapeutic effects. However, conventional sustained-release formulations often have a slow onset of action, failing to meet the clinical need for rapid action. Although some studies have attempted to combine immediate-release and sustained-release units in the same dosage form, such as bilayer tablets and capsules containing microspheres, these formulations still suffer from complex manufacturing processes, interference between immediate-release and sustained-release units, and poor stability. In particular, oil-based protective hard capsules containing sustained-release microspheres, which combine liquid and solid units, present even greater technical challenges. Ensuring that the liquid medium does not leak during long-term storage and does not affect the drug release characteristics of the solid unit remains a technical problem that has not been well resolved in this field.

[0003] In recent years, liquid-filled capsule technology has offered a new approach to solving the aforementioned problems. This technology dissolves or suspends active ingredients in a liquid matrix and fills the capsule, improving the dissolution and bioavailability of poorly soluble drugs. However, conventional liquid-filled capsules have a single function and still cannot achieve a combination of immediate and sustained release. Although some existing technologies have attempted to incorporate solid units into liquid-filled capsules, these designs often suffer from drawbacks such as interference between the liquid and solid units, poor stability, and uncontrollable drug release behavior. In particular, the liquid matrix may permeate into the solid units, affecting their drug release characteristics; or the solid units may have poor suspension stability in the liquid, easily settling and agglomerating, resulting in uneven content; at the same time, existing capsule technologies have insufficient sealing, allowing liquid to leak easily, leading to poor product stability. These technological bottlenecks severely limit the practical application of oil-based protective hard capsules containing sustained-release microspheres.

[0004] Therefore, there is an urgent need in this field to develop a novel oil-based protective hard capsule containing sustained-release microspheres and its preparation method, which can effectively integrate the advantages of both liquid rapid release and solid sustained release, while solving problems such as poor stability, uncontrollable drug release behavior, and complex preparation processes in existing technologies. An ideal oil-based protective hard capsule containing sustained-release microspheres should possess excellent sealing performance to ensure no leakage during long-term storage; good compatibility between the liquid matrix and the solid unit, with no interference between them; the solid sustained-release unit should maintain physical and chemical stability in the liquid, preserving the expected drug release characteristics; and the preparation process should be simple and feasible, suitable for industrial production. Such a technological breakthrough will greatly expand the application range of liquid-filled capsules and provide important technical support for the development of novel drug delivery systems. Summary of the Invention

[0005] The purpose of this invention is to provide an oil-based protective hard capsule containing sustained-release microparticles and its preparation method, which solves the technical problems of existing hard capsules being unable to stably encapsulate liquid and solid contents at the same time, making it difficult to achieve synergistic sustained-release of drugs, and being prone to leakage during storage.

[0006] The present invention achieves the above objectives through the following technical solutions: A method for preparing an oil-based protective hard capsule containing sustained-release microspheres includes the following steps: S1. Add water to a container, stir and heat to 70-80℃, add hydroxypropyl methylcellulose; cool to 50-60℃, add carrageenan, gellan gum and sodium dodecyl sulfate, stir at a constant temperature to obtain a glue solution; cool the glue solution to 45-55℃, let it stand and age to obtain a capsule shell preparation solution; then dip the capsule in the glue, shape it, dry it, and cut it to obtain an unlocked capsule shell. S2, heat flaxseed oil to 40-50℃, add hydrophobically modified silica nanoparticles and temperature-responsive copolymer, and stir to obtain a suspension; prepare microcapsule cores with active pharmaceutical ingredients and sustained-release excipients; then coat the microcapsule cores with acrylic resin to obtain sustained-release microcapsules; fill the lower shell of capsules with sustained-release microcapsules; S3. Fill the lower shell of the capsule containing the sustained-release microspheres with the suspension prepared in step S2; cover with the upper shell of the capsule, add hydroxypropyl methylcellulose solution at the capsule locking point, heat to seal, and then perform leak testing, visual inspection, packaging and sterilization.

[0007] Preferably, the above preparation method specifically includes: S1. Deionized water is added to a heat-insulated dissolving tank, and stirring is started while heating to raise the water temperature to 70-80℃. Then hydroxypropyl methylcellulose is added. Subsequently, the temperature is lowered to 50-60℃, and carrageenan, gellan gum, and sodium dodecyl sulfate are added. The temperature is maintained and stirring is continued to obtain a glue solution. Finally, the temperature of the glue solution is lowered to 45-55℃ and allowed to stand for aging to obtain a capsule shell preparation solution. The capsule shell preparation solution is dipped in glue, shaped, and then sent to a drying oven for drying. After drying, it is cut to obtain unlocked capsule shells. S2, heat flaxseed oil to 40-50℃, add hydrophobically modified silica nanoparticles and temperature-responsive copolymer, stir evenly to form a suspension; prepare microcapsule cores by fluidized bed pelleting technology with active drug ingredients and sustained-release excipients; then coat the microcapsule cores with acrylic resin to obtain sustained-release microcapsules; fill the lower shell of capsules with sustained-release microcapsules; S3, the suspension prepared in step S2 is filled into the lower shell of the capsule containing the sustained-release microspheres through a precision pumping system; the upper shell of the capsule is closed, hydroxypropyl methylcellulose solution is added to the capsule locking point, and the capsule is sealed by hot air heating; the sealed capsule is subjected to a vacuum leak test; finally, the appearance is inspected, packaged and sterilized.

[0008] In this invention, the active pharmaceutical ingredient can be selected from drugs with poor water solubility and requiring improved bioavailability, such as nonsteroidal anti-inflammatory drugs (e.g., ibuprofen, diclofenac), statins (e.g., simvastatin, atorvastatin), certain antihypertensive drugs (e.g., nifedipine), or antipsychotic drugs (e.g., olanzapine). Before being mixed with the sustained-release excipients, it needs to undergo necessary pretreatment, such as pulverization and sieving, to ensure that its particle size distribution meets the requirements for subsequent pelleting, typically reaching the micron level (e.g., 1-100 μm) to ensure uniform content. The sustained-release excipients include matrix materials for constructing the sustained-release framework and necessary molding excipients. Matrix materials include, but are not limited to, water-insoluble framework materials (e.g., ethyl cellulose, microcrystalline cellulose), erodible framework materials (e.g., hydrogenated vegetable oil, glyceryl monostearate), and hydrophilic gel framework materials (e.g., hydroxypropyl methylcellulose, sodium alginate). Molding excipients include binders (such as povidone K30 and aqueous hydroxypropyl methylcellulose), fillers (such as lactose and mannitol), and lubricants (such as magnesium stearate and talc). The mass ratio of the active pharmaceutical ingredient to the sustained-release excipient can be adjusted within a wide range, for example, from 1:10 to 1:1, depending on the required dosage and release kinetic profile.

[0009] In this invention, the micro-pellet core is prepared using fluidized bed bottom spray pelletizing technology. The specific steps are as follows: First, the active pharmaceutical ingredient in the prescribed amount is thoroughly mixed with some sustained-release excipients (such as fillers and matrix materials). If necessary, dry granulation and pre-flattening are performed to obtain a mixture powder with good flowability. The above mixture powder is fed into the hopper of a fluidized bed granulator as the parent core (starting pellet). The fluidized bed is turned on, and an appropriate inlet air temperature (e.g., 40-60℃) and air volume are set to ensure that the parent core is in a stable suspended fluidized state within the fluidized bed. A binder (such as a pure water or ethanol aqueous solution of povidone K30) is sprayed into the fluidized bed in an atomized form through a spray gun to wet the surface of the parent core. At the same time, the remaining prescription mixture powder is simultaneously added to the fluidized bed through a powder feeding device, and the powder adheres to the wetted parent core surface. Through an intermittent or continuous "spray-powder-drying" process, the particle size of the parent core gradually increases, forming the micro-pellet core. This process requires precise control of parameters such as spray rate, atomization pressure, inlet air temperature, and material temperature to ensure that the pellet cores have good sphericity, suitable particle size distribution (usually between 0.5-1.2 mm), and a solid internal structure. After preparation, the micro pellet cores are initially dried in a fluidized bed, then removed and placed in a drying oven for further drying to constant weight. They are then sieved to remove fine powder and excessively large particles, resulting in micro pellet cores with uniform particle size.

[0010] In this invention, the coating process is performed using a fluidized bed bottom spray coating method. The coating material is acrylic resin, which is purchased from Evonik Specialty Chemicals (Shanghai) Co., Ltd. as Eudragit type (such as Eudragit RL 100 or RS 100). This type of resin is insoluble in water but can form a water-permeable film. First, the acrylic resin is dissolved in a suitable organic solvent (such as ethanol or acetone) or a mixture of it and water to prepare a uniformly dispersed coating solution, with the solid content typically controlled between 5% and 15% (w / w). To improve the adjustability of drug release characteristics, plasticizers (such as triethyl citrate or diethyl phthalate) can be added to the coating solution to enhance the flexibility of the coating film. Pore-forming agents (such as polyethylene glycol or hydroxypropyl cellulose) can also be added to adjust the water permeation rate. The prepared microsphere cores are fed into a fluidized bed coating apparatus, and suitable inlet air temperature, airflow, and material temperature (e.g., 30-40℃) are set to ensure full fluidization of the cores. The coating solution is atomized through a spray gun and uniformly sprayed onto the surface of the fluidized microspheres. By controlling parameters such as the spraying rate of the coating solution (e.g., 5-20 mL / min), atomization pressure (e.g., 0.8-1.5 bar), and fluidized airflow, it is ensured that the coating film uniformly and continuously coats the surface of each microsphere core, preventing adhesion between microspheres. Coating weight gain is a key process parameter, typically controlled within the range of 3%-15% of the microsphere core weight, depending on the target release rate. After coating, the microspheres are dried in the fluidized bed for a period of time to completely remove residual solvent, ultimately obtaining coated sustained-release microspheres.

[0011] In this invention, the overall preparation and functional mechanism of the oil-based protective hard capsule containing sustained-release microspheres is an integrated embodiment of the aforementioned material mechanisms and precision processes. The success of the entire system depends on the orderly combination and interaction of its various components in space and time. The capsule shell is prepared through a complex gelation and hydrogen bond network formed between hydroxypropyl methylcellulose, carrageenan, and gellan gum. After aging, a capsule with suitable mechanical strength and solubility is obtained, providing physical separation and protection for the sustained-release contents. During the filling process, the sustained-release microspheres are first placed in the lower shell of the capsule, with an acrylic resin coating. The release mechanism relies on the osmotic pressure formed by the permeation of gastrointestinal water into the coating membrane, thereby driving the drug to be released slowly and constantly from laser-perforated or intramembrane channels. Subsequently, a suspension filled with hydrophobically modified nanoparticles and temperature-responsive polymers is precisely pumped in. Due to its excellent physical stability, it ensures that the solid nanoparticles do not settle during the liquid filling process and subsequent storage period, maintaining a clear interface with the upper microsphere compartment. The final sealing step uses hydroxypropyl methylcellulose solution as an adhesive. Under instantaneous heating with hot air, moisture evaporates rapidly, and the polymer chains diffuse and entangle to form a strong seal. Vacuum leak testing ensures its integrity. After ingestion, the capsule shell dissolves rapidly in the stomach or intestines, releasing the contents. The temperature-responsive copolymer in the liquid suspension undergoes a phase transition upon body temperature stimulation, regulating the demulsification of the lipid carrier and the drug release rate. Meanwhile, the sustained-release microparticles continuously release the drug over several hours according to their pre-programmed osmotic pump mechanism. These two mechanisms complement each other in time and space, achieving a synergistic therapeutic effect of rapid onset and long-lasting maintenance, greatly improving drug bioavailability and patient compliance.

[0012] According to a preferred embodiment of the present invention, in step S1, the aging time is 1-3 hours and the drying time is 4-5 hours.

[0013] According to a preferred embodiment of the present invention, in step S2, the amount of suspension filling is 70-80% of the capsule capacity.

[0014] According to a preferred embodiment of the present invention, in step S3, the hot air heating time is 0.3-0.8s.

[0015] According to a preferred embodiment of the present invention, the preparation steps of the hydrophobically modified silica nanoparticles include: dispersing silica nanoparticles in anhydrous toluene to form a suspension, subjecting the suspension to ultrasonic treatment to obtain silica nanogel; then adding octyltriethoxysilane and refluxing at 108-112°C; after the reaction is completed, separating by centrifugation, washing repeatedly with ethanol, and vacuum drying at 58-62°C.

[0016] In this invention, the preparation of hydrophobically modified silica nanoparticles is a typical surface silanization modification process, the mechanism of which involves a combination of physical dispersion and chemical bonding. Initially, silica nanoparticles are ultrasonically treated in anhydrous toluene. The purpose is to use the energy of ultrasound to break down the aggregates between silica particles, allowing them to be fully dispersed and reach a nanoscale gel state. This process provides a large specific surface area and abundant surface silanol active sites for subsequent chemical reactions. Octyltriethoxysilane is then added as a modifier. Its ethoxy groups undergo hydrolysis under reflux heating to generate silanol bonds. These newly generated silanol bonds condense with the silanol groups on the surface of the silica nanogel, forming stable siloxane bonds, thereby firmly grafting the long-chain octyl alkane onto the silica particle surface in the form of covalent bonds. The essence of this chemical reaction is the hydrolysis and condensation of the silane coupling agent, resulting in the transformation of the originally hydrophilic silica surface into a hydrophobic surface. After centrifugation, washing, and vacuum drying, the resulting hydrophobically modified silica nanoparticles, due to their low surface energy, significantly reduce their compatibility with aqueous environments and exhibit high affinity for fat-soluble linseed oil. When dispersed in the oil phase, they effectively prevent oil droplet aggregation through steric hindrance, forming an extremely stable nanoemulsion. This is the fundamental reason why the suspension remains homogeneous and does not undergo phase separation during storage.

[0017] According to a preferred embodiment of the present invention, the reflux reaction time at 108-112°C is 12-14 h; the vacuum drying time at 58-62°C is 12-24 h.

[0018] According to a preferred embodiment of the present invention, the preparation steps of the temperature-responsive copolymer include: A1, adding isophorone diisocyanate and polyethylene glycol to a reactor under nitrogen protection, adding N,N-dimethylformamide, and heating to 68-72°C for reaction; A2, cooling the system to 48-52°C, adding octadecylamine and dibutyltin dilaurate, and maintaining the temperature for reaction; after the reaction is completed, cooling to room temperature, adding ice-cold diethyl ether to precipitate, collecting the precipitate and washing it with diethyl ether, and finally vacuum drying at 38-42°C.

[0019] In this invention, the synthesis of temperature-responsive copolymers is a stepwise polymerization process. The mechanism involves the reaction of isocyanates with hydroxyl and amino groups to construct a smart, responsive block copolymer structure. The reaction begins with the reaction of isophorone diisocyanate with polyethylene glycol (PEG). The isophorone diisocyanate molecule contains two highly reactive isocyanate groups. Under catalytic and heating conditions, one of these isocyanate groups preferentially undergoes an addition reaction with the hydroxyl group at the end of the PEG chain to form a urethane bond, thus forming a prepolymer with one end capped by isocyanate. Subsequently, the system is cooled and octadecylamine is added. The primary amino group at the end of the octadecylamine molecule further reacts with the remaining isocyanate groups on the prepolymer to form urea bonds. At this point, a complete ABA-type triblock copolymer molecule is constructed: the middle segment is a hydrophilic, flexible PEG segment, while the segments at both ends are strongly hydrophobic segments composed of long carbon chains of isophorone and octadecylamine. This unique molecular structure endows the copolymer with distinctive temperature-responsive properties. At lower temperatures, hydrophilic polyethylene glycol segments extend in an aqueous environment, causing the molecules to dissolve in water. When the temperature rises to near its minimum critical dissolution temperature, hydration weakens, while interactions between hydrophobic segments strengthen, leading to chain collapse and aggregation, and precipitation from the water. In flaxseed oil suspensions, this copolymer is distributed at the oil-water interface. Its phase transition behavior dynamically alters the properties of the interfacial film, thereby creating a synergistic stabilizing effect with hydrophobic silica nanoparticles, ultimately regulating drug release triggered by body temperature.

[0020] According to a preferred embodiment of the present invention, in step A1, the reaction time at 68-72°C is 2-4 hours.

[0021] According to a preferred embodiment of the present invention, in step A2, the heat preservation reaction time is 3-5 hours.

[0022] The present invention also provides an oil-based protective hard capsule containing sustained-release microparticles, wherein the oil-based protective hard capsule containing sustained-release microparticles is prepared according to the preparation method of the oil-based protective hard capsule containing sustained-release microparticles.

[0023] The beneficial effects of this invention are as follows: The oil-based protective hard capsule containing sustained-release microspheres and its preparation method, as disclosed in this invention, possess significant technological advancements and numerous positive effects. This preparation method, through unique process design and material combination, successfully achieves a structure that separately accommodates a liquid suspension medium and solid sustained-release microspheres within the same capsule. This not only improves drug stability and bioavailability but also provides a new solution for oral drug delivery systems. Its technological advantages are mainly reflected in three aspects: the innovation of the dosage form structure, the controllability of drug release, and the feasibility of the production process.

[0024] In terms of dosage form structure, this method utilizes a carefully designed gel formulation and aging process to prepare capsule shells with excellent mechanical properties and sealing properties, effectively protecting the internal drug from external environmental influences. Simultaneously, the suspension system, stabilized by hydrophobically modified silica nanoparticles and temperature-responsive copolymers, significantly improves the dispersion uniformity and physical stability of the lipid-soluble active ingredients, preventing stratification or precipitation during storage. Furthermore, through an independent sustained-release microsphere preparation process combined with permeation-type coating technology, timed and quantitative drug release in vivo is achieved. The two formulation forms are separately filled without interference, maintaining the rapid absorption characteristics of the liquid component while leveraging the long-lasting sustained-release advantages of the solid microspheres, thus achieving a combined function within a single dosage form.

[0025] In terms of drug release behavior control, this invention exhibits superior precision and environmental responsiveness. The introduction of temperature-responsive copolymers allows the liquid capsule contents to undergo phase transitions according to changes in human digestive tract temperature, further regulating the drug release rate; while the coating layer of the sustained-release microspheres achieves sustained release through osmotic pressure mechanisms. The synergistic effect of both significantly improves the in vivo pharmacokinetic properties of the drug. This multimodal release characteristic is particularly suitable for complex treatment regimens that require both immediate and sustained release, not only improving patient compliance but also providing a new technological pathway for the development of personalized drug delivery systems.

[0026] From the perspective of production process and quality control, this preparation method has promising prospects for industrialization. The entire process encompasses multiple stages, including capsule molding, microcapsule preparation, stepwise filling, precision sealing, and leak detection. The process parameters are clear and controllable, facilitating large-scale production. In particular, the use of hot air instantaneous sealing combined with vacuum leak detection technology significantly improves the sealing reliability of the capsules and the consistency of product quality. Furthermore, this method has a wide range of applications, not only for the formulation development of chemical and biotechnological drugs, but also for functional foods, health products, and other fields, demonstrating significant technical versatility and market application potential. Detailed Implementation

[0027] The following detailed embodiments are only used to further illustrate this application and should not be construed as limiting the scope of protection of this application. Those skilled in the art can make some non-essential improvements and adjustments to this application based on the above application content.

[0028] The following is information on domestic suppliers of key related equipment and materials: The hydroxypropyl methylcellulose was purchased from Shandong Heda Group Co., Ltd.

[0029] The carrageenan was purchased from Qingdao Mingyue Seaweed Group Co., Ltd.

[0030] The gellan gum was purchased from Shanghai Zhongxuan Biotechnology Co., Ltd.

[0031] The sodium dodecyl sulfate was purchased from Guangzhou Xingye Technology Co., Ltd.

[0032] The acrylic resin was purchased from Evonik Specialty Chemicals (Shanghai) Co., Ltd. as Eudragit RL 100.

[0033] The silica nanopowder was purchased from Fujian Yuanxiang New Materials Co., Ltd.

[0034] The octyltriethoxysilane was purchased from Jingzhou Jianghan Fine Chemical Co., Ltd.

[0035] The isophorone diisocyanate was purchased from Zhejiang Huangma Technology Co., Ltd.

[0036] The polyethylene glycol was purchased from Shandong Chuangying Chemical Co., Ltd. as PEG-400.

[0037] The octadecylamine was purchased from Hangzhou Kainuo Chemical Co., Ltd.

[0038] The dibutyltin dilaurate was purchased from the Beijing Additives Research Institute.

[0039] Example 1 A method for preparing an oil-based protective hard capsule containing sustained-release microparticles includes the following steps: S1, 1000g of deionized water is added to a heat-insulating dissolving tank, stirring is started and the water temperature is raised to 75℃; then 10g of hydroxypropyl methylcellulose is added; subsequently, the temperature is lowered to 55℃, 5g of carrageenan, 5g of gellan gum and 1g of sodium dodecyl sulfate are added, the temperature is kept constant and stirring is continued to obtain a glue solution; finally, the temperature of the glue solution is lowered to 50℃ and allowed to stand for 2 hours to obtain a capsule shell preparation solution; the capsule shell preparation solution is dipped in glue, shaped, and then sent to a drying oven for drying for 4.5 hours, and then cut to obtain an unlocked capsule shell; S2, 50g of flaxseed oil is heated to 45℃, 5g of hydrophobically modified silica nanoparticles and 5g of temperature-responsive copolymer are added, and the mixture is stirred evenly to form a suspension. The preparation steps of hydrophobically modified silica nanoparticles include: dispersing 10g of silica nanoparticles in 100g of anhydrous toluene to form a suspension; ultrasonicating the suspension to obtain silica nanogels; then adding 5g of octyltriethoxysilane and refluxing at 110℃ for 13h; after the reaction, centrifuging, washing repeatedly with ethanol, and vacuum drying at 60℃ for 18h. The preparation steps of the temperature-responsive copolymer include: adding 5g of isophorone diisocyanate and 10g of polyethylene glycol to a reactor under nitrogen protection, adding 50g of N,N-dimethylformamide, and heating to 70℃ for 3h; cooling the system to 50℃, adding 3g of octadecylamine and 0.5g of dibutyltin dilaurate, and maintaining the temperature for 4h; after the reaction, cooling to room temperature, adding ice-cold diethyl ether to precipitate, collecting the precipitate and washing with diethyl ether, and finally vacuum drying at 40℃. Microsphere cores were prepared by fluidized bed pelleting technology using 10g of active pharmaceutical ingredient and 5g of sustained-release excipient. Then, the microsphere cores were coated with 2g of acrylic resin to obtain sustained-release microspheres. These sustained-release microspheres were then filled into the lower shell of a capsule. In step S3, the suspension prepared in step S2 was filled into the lower shell of the capsule containing the sustained-release microspheres using a precision pumping system, with the suspension filling volume being 75% of the capsule capacity. The upper shell of the capsule was then closed, and hydroxypropyl methylcellulose solution was added to the capsule locking point. The capsule was then sealed using hot air for 0.5s. The sealed capsules underwent a vacuum leak test. Finally, the capsules were inspected for appearance, packaged, and sterilized.

[0040] Example 2 The specific implementation method is the same as in Example 1, except that the preparation method of an oil-based protective hard capsule containing sustained-release microspheres includes the following steps: S1, 800g of deionized water is added to a heat-insulating dissolving tank, stirring is started and the water temperature is raised to 70°C; then 8g of hydroxypropyl methylcellulose is added; then the temperature is lowered to 50°C, 4g of carrageenan, 4g of gellan gum and 0.8g of sodium dodecyl sulfate are added, the temperature is kept constant and stirring is continued to obtain a glue solution; finally, the temperature of the glue solution is lowered to 45°C and allowed to stand for 1 hour to obtain a capsule shell preparation solution; after dipping and shaping the capsule shell preparation solution, it is sent to a drying oven and dried for 4 hours, and then cut to obtain an unlocked capsule shell; S2, take 40g of flaxseed oil was heated to 40℃, and 4g of hydrophobically modified silica nanoparticles and 4g of temperature-responsive copolymer were added and stirred until a suspension was formed. The preparation steps of the hydrophobically modified silica nanoparticles included: dispersing 8g of silica nanoparticles in 80g of anhydrous toluene to form a suspension, and ultrasonically treating the suspension to obtain silica nanogels; then adding 4g of octyltriethoxysilane and refluxing at 108℃ for 12h; after the reaction, centrifuging was performed, and the mixture was repeatedly washed with ethanol and vacuum dried at 58℃ for 12h. The preparation steps of the temperature-responsive copolymer included: adding 4g of isophorone diisocyanate and 8g of polyethylene glycol to a reactor under nitrogen protection, and adding 40g of... N,N-Dimethylformamide was heated to 68℃ and reacted for 2 hours. The system was then cooled to 48℃, and 2.4 g of octadecylamine and 0.4 g of dibutyltin dilaurate were added. The reaction was maintained at this temperature for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, and ice-cold ether was added to precipitate the product. The precipitate was collected and washed with ether, and finally dried under vacuum at 38℃. 8 g of the active pharmaceutical ingredient and 4 g of the sustained-release excipient were used to prepare microcapsule cores using fluidized bed pelleting technology. Then, 1.6 g of acrylic resin was used to coat the microcapsule cores to obtain sustained-release microcapsules. The sustained-release microcapsules were filled into the lower shell of a capsule. In step S3, the suspension prepared in step S2 was filled into the lower shell of the capsule containing the sustained-release microcapsules using a precision pumping system, with the suspension filling volume being 70% of the capsule capacity. The upper shell of the capsule was then closed, and hydroxypropyl methylcellulose solution was added to the capsule locking point. The capsule was sealed using hot air heating for 0.3 seconds. The sealed capsules underwent a vacuum leak test. Finally, the capsules were inspected for appearance, packaged, and sterilized.

[0041] Example 3 The specific implementation method is the same as in Example 1, except that the preparation method of an oil-based protective hard capsule containing sustained-release microspheres includes the following steps: S1, 1200g of deionized water is added to a heat-insulating dissolving tank, stirring is started and the water temperature is raised to 80℃; then 12g of hydroxypropyl methylcellulose is added; then the temperature is lowered to 60℃, 6g of carrageenan, 6g of gellan gum and 1.2g of sodium dodecyl sulfate are added, the temperature is kept constant and stirring is continued to obtain a glue solution; finally, the temperature of the glue solution is lowered to 55℃ and allowed to stand for 3 hours to obtain a capsule shell preparation solution; after dipping and shaping the capsule shell preparation solution, it is sent to a drying oven and dried for 5 hours, and then cut to obtain an unlocked capsule shell; S2, take 60g of flaxseed oil was heated to 50℃, and 6g of hydrophobically modified silica nanoparticles and 6g of temperature-responsive copolymer were added and stirred until a suspension was formed. The preparation steps of the hydrophobically modified silica nanoparticles included: dispersing 12g of silica nanoparticles in 120g of anhydrous toluene to form a suspension, and ultrasonically treating the suspension to obtain silica nanogels; then adding 6g of octyltriethoxysilane and refluxing at 112℃ for 14h; after the reaction, centrifuging was performed, and the mixture was repeatedly washed with ethanol and vacuum dried at 62℃ for 24h. The preparation steps of the temperature-responsive copolymer included: adding 6g of isophorone diisocyanate and 12g of polyethylene glycol to a reactor under nitrogen protection, and adding 60g of... N,N-Dimethylformamide was heated to 72℃ and reacted for 4 hours. The system was then cooled to 52℃, and 3.6g of octadecylamine and 0.6g of dibutyltin dilaurate were added. The reaction was maintained at this temperature for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, and ice-cold ether was added to precipitate the product. The precipitate was collected and washed with ether, and finally dried under vacuum at 42℃. 12g of the active pharmaceutical ingredient and 6g of the sustained-release excipient were used to prepare microcapsule cores using fluidized bed pelleting technology. Then, 2.4g of acrylic resin was used to coat the microcapsule cores to obtain sustained-release microcapsules. The sustained-release microcapsules were filled into the lower shell of a capsule. In step S3, the suspension prepared in step S2 was filled into the lower shell of the capsule containing the sustained-release microcapsules using a precision pumping system. The filling volume of the suspension was 80% of the capsule capacity. The upper shell of the capsule was closed, and hydroxypropyl methylcellulose solution was added to the capsule locking point. The capsule was sealed by heating with hot air for 0.8s. The sealed capsule was subjected to a vacuum leak test. Finally, the capsule was inspected for appearance, packaged, and sterilized.

[0042] Comparative Example 1 The specific implementation method is the same as in Example 1, except that the preparation method of an oil-based protective hard capsule containing sustained-release microspheres includes the following steps: S1, 1000g of deionized water is added to a heat-insulating dissolving tank, stirring is started and the water temperature is raised to 75°C; then 10g of hydroxypropyl methylcellulose is added; subsequently, the temperature is lowered to 55°C, 5g of carrageenan, 5g of gellan gum and 1g of sodium dodecyl sulfate are added, the temperature is kept constant and stirring is continued to obtain a glue solution; finally, the temperature of the glue solution is lowered to 50°C, and it is allowed to stand for 2 hours to obtain a capsule shell preparation solution; after dipping and shaping the capsule shell preparation solution, it is sent to a drying oven and dried for 4.5 hours, and then cut to obtain an unlocked capsule shell; S2, 50g of flaxseed oil is heated to 45°C, and added Add 5g of temperature-responsive copolymer and stir until a suspension is formed; the preparation steps of the temperature-responsive copolymer are the same as in Example 1; prepare microcapsule cores by using fluidized bed pelleting technology with 10g of active pharmaceutical ingredient and 5g of sustained-release excipient; then coat the microcapsule cores with 2g of acrylic resin to obtain sustained-release microcapsules; fill the lower shell of the capsule with the sustained-release microcapsules; S3, fill the lower shell of the capsule containing the sustained-release microcapsules into the lower shell of the capsule with a precision pumping system, the filling amount of the suspension is 75% of the capsule capacity; cover the upper shell of the capsule, add hydroxypropyl methylcellulose solution at the capsule locking point, and seal the capsule with hot air for 0.5s; perform vacuum leak testing on the sealed capsule; finally, perform appearance inspection, packaging and sterilization.

[0043] Comparative Example 2 The specific implementation method is the same as in Example 2, except that the preparation method of an oil-based protective hard capsule containing sustained-release microspheres includes the following steps: S1, 1000g of deionized water is added to a heat-insulating dissolving tank, stirring is started and the water temperature is raised to 75°C; then 10g of hydroxypropyl methylcellulose is added; then the temperature is lowered to 55°C, 5g of carrageenan, 5g of gellan gum and 1g of sodium dodecyl sulfate are added, the temperature is kept constant and stirring is continued to obtain a glue solution; finally, the temperature of the glue solution is lowered to 50°C and allowed to stand for 2 hours to obtain a capsule shell preparation solution; the capsule shell preparation solution is dipped in glue, shaped, and then sent to a drying oven for drying for 4.5 hours, and then cut to obtain an unlocked capsule shell; S2, 50g of flaxseed oil is heated to 45°C, and 5g of carrageenan, 5g of gellan gum and 1g of sodium dodecyl sulfate are added. g of hydrophobic modified silica nanoparticles were stirred evenly to form a suspension; the preparation steps of the hydrophobic modified silica nanoparticles were the same as in Example 1; 10g of active pharmaceutical ingredient and 5g of sustained-release excipient were prepared into microcapsule cores using fluidized bed pelleting technology; then, 2g of acrylic resin was used to coat the microcapsule cores to obtain sustained-release microcapsules; the sustained-release microcapsules were filled into the lower shell of a capsule; S3, the suspension prepared in step S2 was filled into the lower shell of the capsule containing the sustained-release microcapsules using a precision pumping system, with the suspension filling volume being 75% of the capsule capacity; the upper shell of the capsule was closed, hydroxypropyl methylcellulose solution was added to the capsule locking point, and the capsule was sealed by heating with hot air for 0.5s; the sealed capsule was subjected to a vacuum leak test; finally, the appearance was inspected, packaged, and sterilized.

[0044] Comparative Example 3 The specific implementation method is the same as in Example 3, except that the preparation method of an oil-based protective hard capsule containing sustained-release microparticles includes the following steps: S1, 1000g of deionized water is added to a heat-insulating dissolving tank, stirring is started and the water temperature is raised to 75°C; then 10g of hydroxypropyl methylcellulose is added; then the temperature is lowered to 55°C, 5g of carrageenan, 5g of gellan gum and 1g of sodium dodecyl sulfate are added, the temperature is kept constant and stirring is continued to obtain a glue solution; finally, the temperature of the glue solution is lowered to 50°C and allowed to stand for 2 hours to obtain a capsule shell preparation solution; the capsule shell preparation solution is dipped in glue, shaped and then sent to a drying oven for 4.5 hours to dry, and then cut to obtain an unlocked capsule shell; S2, 50g of flaxseed oil is heated to 45°C, and 5g of hydrophobic modified sodium silicate is added. Rice grains and 5g of temperature-responsive copolymer were stirred evenly to form a suspension; the preparation steps of hydrophobically modified silica nanoparticles were the same as in Example 1; the preparation steps of temperature-responsive copolymers were the same as in Example 1; 10g of active pharmaceutical ingredient and 5g of sustained-release excipient were prepared into microcapsule cores using fluidized bed pelleting technology; without coating, the microcapsule cores were obtained directly; the microcapsule cores were filled into the lower shell of capsules; S3, the suspension prepared in step S2 was filled into the lower shell of capsules containing microcapsule cores using a precision pumping system, with the suspension filling amount being 75% of the capsule capacity; the upper shell of the capsule was closed, hydroxypropyl methylcellulose solution was added to the capsule locking point, and the capsule was sealed by heating with hot air for 0.5s; the sealed capsules were subjected to vacuum leak testing; finally, the appearance was inspected, packaged, and sterilized.

[0045] Performance testing The following tests were performed on the samples obtained in Examples 1-3 and Comparative Examples 1-3: To comprehensively evaluate the performance of the oil-based protective hard capsules containing sustained-release microparticles prepared in this invention, the physical stability of their contents, drug release behavior, and capsule shell sealing integrity were tested. Suspension stability was evaluated using a centrifugation acceleration experiment: A precise amount of the suspensions prepared in the examples and comparative examples was placed in centrifuge tubes and centrifuged at 10,000 r / min for 30 min in a high-speed centrifuge. The tubes were then removed to observe for oil phase separation, stratification, or precipitation. The volume of the precipitated oil phase was measured to calculate the oil separation rate. A lower oil separation rate indicates a more stable suspension system. Drug release behavior was determined in vitro using the slurry method specified in the General Chapters of the Chinese Pharmacopoeia: 900 mL of 0.1% sodium dodecyl sulfate solution was used as the release medium, the temperature was maintained at 37 ± 0.5℃, and the stirring speed was 50 r / min; 5 mL samples were taken at specified time points (e.g., 1h, 2h, 4h, 6h, 8h, 12h) (with an equal volume of fresh release medium added at the same temperature), and the samples were filtered through a 0.45 μm microporous membrane. The drug concentration was determined by high performance liquid chromatography, and the cumulative release percentage was calculated. Each sample was measured in parallel 6 times to evaluate its sustained-release effect. The integrity of the capsule seal was tested using the vacuum staining method: the sealed capsule was completely immersed in a container containing 1% methylene blue staining solution, the container was placed in a vacuum desiccator, and the vacuum was drawn to -90 kPa and maintained for 30 minutes; then the pressure was restored to normal, the capsule was removed, rinsed with clean water and dried, the capsule shell was manually broken open, and the inside was observed to see if the staining solution had seeped in. No staining inside indicated good seal.

[0046] Performance test results: Table 1: Performance test results of each embodiment and comparative example

[0047] As shown in Table 1, Examples 1-3 comprehensively solved the three core problems faced by existing hard capsule technology compared to Comparative Examples 1-3. Firstly, regarding content stability, Examples 1-3, through the synergistic stabilizing effect of hydrophobically modified silica nanoparticles and temperature-responsive copolymers, formed an extremely stable Pickering emulsion system with an oil separation rate of less than 3%, achieving long-term physical stability of the liquid suspension phase and successfully encapsulating the liquid contents stably within the capsule chamber. In contrast, Comparative Examples 1 (lacking nanoparticles) and 2 (lacking copolymers) exhibited oil separation rates as high as 35.7% and 28.4%, respectively, demonstrating that a single component cannot effectively stabilize the system, resulting in severe phase separation and the inability to achieve stable liquid-solid coexistence.

[0048] Secondly, regarding the control of drug release behavior, Examples 1-3 achieved slow and near-complete drug release (cumulative release rate of 97.8-99.2%) within 12 hours by coating the microsphere core with acrylic resin. The release curve was stable with no burst release, achieving a precise synergistic sustained-release effect. In contrast, the drug in Comparative Example 3 (uncoated) was rapidly and completely released within 4 hours, showing no sustained-release function. Although Comparative Examples 1 and 2 had similar final release rates, their release curves showed initial burst release. This was due to the rapid breakdown of the unstable suspension in the release medium, which disrupted the expected release kinetics, proving that unstable contents directly affect drug release behavior.

[0049] Finally, regarding the reliability of the encapsulation, all capsule shells of the embodiments and comparative examples passed the vacuum dyeing test at -90 kPa for 30 minutes, with a sealing qualification rate of 100%. This proves that the capsule shell preparation process, aging parameters and hot air sealing technology adopted in this invention can form a highly complete sealing system, completely solving the risk of leakage during storage and ensuring the absolute isolation and stability of the liquid and solid contents during the shelf life.

[0050] In summary, this invention, through material innovation (synergistic combination of hydrophobic nanoparticles and thermosensitive copolymers), structural innovation (liquid-solid compartmentalization), and process innovation (fluidized bed coating and precision sealing), has successfully achieved simultaneous, efficient, and stable encapsulation of liquid and solid contents, synergistic sustained-release control of drugs, and zero leakage during long-term storage, comprehensively solving problems that existing technologies cannot overcome.

[0051] The embodiments described above are merely examples 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 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.

Claims

1. A process for the preparation of an oil-based, enteric-coated hard capsule containing sustained-release pellets, characterized in that, The method comprises the following steps: S1, water is added into a container, stirred and heated to 70-80℃, and hydroxypropyl methyl cellulose is added; the temperature is lowered to 50-60℃, and carrageenan, gellan gum and sodium dodecyl sulfate are added, and constant temperature stirring is performed to obtain a glue solution; the glue solution is cooled to 45-55℃, and is left to stand and age to obtain a capsule shell preparation liquid; then dipping, shaping, drying and cutting are performed to obtain an unsealed capsule shell; S2, flaxseed oil is heated to 40-50℃, and hydrophobically modified silica gel nanoparticles and temperature-responsive copolymer are added, and stirring is performed to obtain a suspension; an active pharmaceutical ingredient and a sustained-release excipient are prepared into a pellet core; then the pellet core is coated with acrylic resin to obtain a sustained-release pellet; the sustained-release pellet is filled into the capsule lower shell; S3, the suspension prepared in step S2 is filled into the capsule lower shell filled with the sustained-release pellet; The upper capsule shell is covered, and hydroxypropyl methyl cellulose solution is added at the capsule sealing position, and then heating is performed for sealing, followed by leakage test, appearance inspection, packaging and sterilization treatment.

2. The process for the preparation of oil-based, enteric-coated hard gelatin capsules containing sustained-release pellets according to claim 1, characterized in that, In step S1, the standing and aging time is 1-3h, and the drying time is 4-5h.

3. The process for the preparation of oil-based protected hard gelatin capsules containing sustained-release pellets according to claim 1, characterized in that, In step S2, the filling amount of the suspension is 70-80% of the capsule capacity.

4. The process for the preparation of oil-based, enteric-coated hard gelatin capsules containing sustained-release pellets according to claim 1, characterized in that, In step S3, the heating time is 0.3-0.8s.

5. The process for the preparation of oil-based, time release micro-pellet containing hard gelatin capsules as claimed in claim 1, wherein, The preparation steps of the hydrophobically modified silica gel nanoparticles comprise: dispersing silica nano powder in anhydrous toluene to form a suspension, and performing ultrasonic treatment on the suspension to obtain a silica gel nanogel; then adding octyl triethoxysilane, and refluxing at 108-112℃; after the reaction is completed, centrifugal separation is performed, and repeated washing with ethanol is performed, and vacuum drying is performed at 58-62℃.

6. The process for the preparation of oil-based protected hard gelatin capsules containing sustained-release pellets according to claim 5, characterized in that, The refluxing reaction time at 108-112℃ is 12-14h, and the vacuum drying time at 58-62℃ is 12-24h.

7. The process for the preparation of oil-based protected hard gelatin capsules containing sustained-release pellets according to claim 1, characterized in that, The preparation steps of the temperature-responsive copolymer comprise: A1, adding isophorone diisocyanate and polyethylene glycol into a reactor under nitrogen protection, adding N,N-dimethylformamide, and reacting at 68-72℃; A2, lowering the system to 48-52℃, adding octadecylamine and dibutyltin dilaurate, and performing incubation reaction; after the reaction is completed, cooling to room temperature, adding ice ether for precipitation, collecting the precipitate and washing with ether, and finally vacuum drying at 38-42℃.

8. The process for the preparation of oil-based protected hard gelatin capsules containing sustained-release pellets according to claim 7, characterized in that, In step A1, the reaction time at 68-72℃ is 2-4h.

9. The process for the preparation of oil-based protected hard gelatin capsules containing sustained-release pellets according to claim 7, characterized in that, In step A2, the incubation reaction time is 3-5h.

10. An oil-based, enteric-coated hard capsule containing sustained-release pellets, characterized in that, The oil-based protective hard capsule containing sustained-release pellets is prepared according to the preparation method of the oil-based protective hard capsule containing sustained-release pellets according to any one of claims 1-9.

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