Thermally-induced slow-release magnetic targeting drug microcapsule based on electromagnetic induction and application of thermally-induced slow-release magnetic targeting drug microcapsule

Abstract

The invention discloses a thermally-induced slow-release magnetic targeted drug microcapsule based on electromagnetic induction and application thereof, and relates to the technical field of microcapsule drug loading, the thermally-induced slow-release magnetic targeted drug microcapsule comprises a capsule shell and a core material, the capsule shell is prepared by blending polycaprolactone and hydroxypropylated modified starch, the mass ratio of the polycaprolactone to the modified starch is 60: 40, and the core material is a mixture of polycaprolactone and hydroxypropylated modified starch. When the capsule shell is prepared, 5-8% of glycerol is added as a plasticizer, and the core material comprises ferroferric oxide nanoparticles and a medicine loaded on the outer surfaces of the ferroferric oxide nanoparticles. The medicine property is released through heating of the electrified coil, active control over the medicine release rate is achieved, the problem that the treatment effect is affected by large fluctuation of the medicine concentration is solved, and it is effectively guaranteed that the release of the medicine property is matched with the rapid and slow degree of the illness state.

Description

Technical Field

[0001] The present invention relates to the technical field of microcapsule drug delivery, in particular to a thermally induced sustained-release magnetic targeted drug microcapsule based on electromagnetic induction and application thereof. Background Art

[0002] Microcapsules refer to a type of microscopic storage container or packaging with a hollow structure that is made by using polycaprolactone as an outer shell to encapsulate core materials of various properties. The size is usually 50-100 nanometers. Microcapsules have protective and controlled-release functions, which can protect the integrity of the embedded material and control its release rate and amount. In the medical field, targeted technology usually refers to making drugs or treatments act specifically on specific parts or diseased areas in the body to reduce the impact on healthy cells or tissues. However, in actual practice, traditional drugs are rapidly distributed throughout the body, and poor compliance cannot achieve good therapeutic effects. At the same time, there are problems such as drugs acting on healthy cells and long drug effectiveness periods.

[0003] Patent CN119074685B discloses a puerarin microcapsule with intestinal targeted release, as well as its preparation method and application. The above patent selects medicinal and edible substances as raw materials without introducing toxic and harmful chemical agents such as cross-linking agents, thus avoiding chemical pollution and potential health risks. The puerarin microcapsules of the present invention have good intestinal sustained-release effect and antioxidant properties.

[0004] The aforementioned patent utilizes a natural polysaccharide complex system of yeast β-glucan and sodium alginate, prepared through physical encapsulation and sharp-pore coagulation. This process avoids the use of chemical cross-linking agents, offering significant advantages in terms of gentle preparation and safe, non-toxic raw materials. However, in the field of clinical treatment, particularly for localized lesions in deep tissues, existing microencapsulation technology still suffers from limitations such as insufficient targeting accuracy and a single release trigger mechanism.

[0005] To this end, the present application proposes a microcapsule that uses polycaprolactone as an outer shell wrapping layer to encapsulate core materials of various properties, and contains drug-loaded ferroferric oxide nanoparticles inside, which further acts on specific parts or diseased areas in the body. A self-made circular ring heating coil surrounds the inflamed and injured area, and controls the release of drugs in the microcapsule by heating, which is based on electromagnetic induction and its application. Summary of the Invention

[0006] The purpose of the present invention is to provide a thermally induced sustained-release magnetic targeted drug microcapsule based on electromagnetic induction and its application, so as to solve the technical problems proposed in the above background technology that the drug is rapidly distributed throughout the body, the compliance is poor and it is impossible to achieve a good therapeutic effect, and at the same time, there is the problem that the drug acts on healthy cells and the drug has a long effective period.

[0007] To achieve the above objectives, the present invention provides the following technical solution: a thermally induced sustained-release magnetic targeted drug microcapsule based on electromagnetic induction, comprising a capsule shell and a core material, wherein the capsule shell is made by blending polycaprolactone and hydroxypropyl modified starch, the mass ratio of the polycaprolactone to the modified starch being 60:40, 5-8% glycerol is added as a plasticizer during the preparation of the capsule shell, and the core material comprises ferroferric oxide nanoparticles and a drug loaded on the outer surface of the ferroferric oxide nanoparticles; The size of the microcapsules is 50-100 nanometers and has a spherical structure; The capsule shell is heated by an external electromagnetic induction heating coil and melts to release the medicine in the core material.

[0008] Preferably, the surface of the capsule shell is treated with plasma, and an inner membrane composed of ferroferric oxide nanoparticles is provided inside the capsule shell, and the melting point of the inner membrane is 40-60°C.

[0009] Preferably, the outer wall of the microcapsule is coated with an oral capsule shell made of enteric material shellac.

[0010] Preferably, the coil is made of gallium-tin alloy with a conductivity of 3×10 6 S / m, elongation ≥50%, power frequency range 20kHz-500kHz.

[0011] Preferably, the coil includes a spiral winding segment and a ring winding segment to form a closed magnetic field surrounding the human body. The coil is woven with multiple strands of enameled wire, each strand of enameled wire has a diameter of 0.05-0.2 mm, and a weaving density of 80-120 strands per square centimeter, forming a flexible structure. The outer wall of the coil is covered with an induction conversion layer, which uses a nanocrystalline alloy film. The induction conversion layer heats the human body through heat conduction. The contact surface between the induction conversion layer and the human body is provided with an insulating protective layer, which uses silicone rubber with a thickness of 0.5-1mm. The side of the coil that does not contact the human body is wrapped with an electromagnetic shielding layer, which is composed of a Permalloy sheet with a thickness of 0.2-0.5mm.

[0012] Preferably, the drug loaded on the outer surface of the ferrosoferric oxide nanoparticles comprises at least one of a chemotherapy drug, a biological agent and a gene drug.

[0013] Preferably, the preparation method of the capsule shell includes the following steps: S1. Raw material selection: Weigh PCL with a moderate molecular weight and hydroxypropyl modified starch, with the mixing ratio of PCL and modified starch being 60:40, and 5-8% plasticizer glycerol; S2. Material pretreatment: Dry the starch at 60-80°C for 4-6 hours to remove moisture; dry the PCL particles at 50°C for 2-4 hours; S3, mixing: dissolving PCL in an organic solvent such as chloroform or dichloromethane, and dispersing starch in water to form a suspension, mixing the two solutions and stirring, and then removing the solvent by evaporation; S4, injection molding: Add the mixed material particles into the injection molding machine, set the temperature at 90-120 ° C, inject the molten material into the capsule mold, and demould after cooling; S5. Post-processing: Plasma surface treatment is performed on the capsule shell, followed by gamma ray sterilization.

[0014] Preferably, the preparation method of the hydroxypropylated modified starch comprises the following steps: S1, starch selection: corn starch, tapioca starch and potato starch; S2. Reagent preparation: propylene oxide, sodium hydroxide, anhydrous sodium sulfate and auxiliary reagents; Propylene oxide: as an etherifying agent, introducing hydroxypropyl groups, 20%-30% by weight of starch; Sodium hydroxide: as a catalyst, 0.5%-2% of starch weight; Anhydrous sodium sulfate: 15%-30% of starch weight; Auxiliary reagents: ethanol, cyclohexane, to disperse starch and adjust reaction conditions; S3. Amorphization pretreatment: Starch is mixed with 50% ethanol solution to prepare a starch milk with a concentration of 0.25g / ml. The starch milk is then heated at 78°C for 35 minutes until the degree of amorphization of the starch reaches more than 90%; S4. Etherification reaction: The starch after amorphization pretreatment is dispersed in water, sodium hydroxide solution is added to the dispersion, the pH value of the reaction system is adjusted to strong alkalinity, and propylene oxide is slowly added. The reaction tank is then sealed, the temperature is raised to 40-50 ° C, and the reaction is stirred for 12 hours. S5. Post-treatment: After the reaction is completed, the pH is adjusted to neutral with dilute hydrochloric acid, and the starch is washed with ethanol to remove unreacted reagents and by-products. The washed starch is dehydrated, dried, and sieved to obtain hydroxypropyl starch.

[0015] Preferably, the microcapsules are used in the preparation of local solid tumor drugs.

[0016] Preferably, the microcapsules are also used in the preparation of drugs for the local treatment of chronic inflammation and postoperative conditions.

[0017] Compared with the prior art, the present invention has the following beneficial effects: 1. This invention releases the drug properties by heating the coil with electricity, realizing active control of the drug release rate, solving the problem of large fluctuations in drug concentration affecting the therapeutic effect, and effectively ensuring that the release of drug potency is adapted to the severity of the disease; 2. The present invention uses ferroferric oxide nanoparticles to form an inner membrane within the capsule shell, achieving both magnetic targeting and induction heating auxiliary functions. This solves the problem of low thermal conductivity efficiency of a single capsule shell material, shortens the effective drug release temperature, and increases the local drug concentration peak. 3. The present invention combines an electromagnetically triggered release mechanism with oral administration by coating the nano-microcapsules with a shellac enteric shell, thereby solving the problem of low oral bioavailability of traditional targeted drugs, improving intestinal absorption rate, and preventing gastric acid from damaging the drug. 4. The present invention achieves the thermal response characteristics of the capsule shell by blending polycaprolactone with hydroxypropyl modified starch, solves the problem of delayed thermal response or uncontrollable decomposition of traditional polymer capsule shells, and improves the synchronization of drug release and external heating signals. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 Schematic diagram of the microcapsule structure of the present invention; Figure 2 Schematic diagram of the microcapsule preparation process of the present invention; Figure 3 Schematic diagram of the coil structure of the present invention; Figure 4 This is a schematic diagram of the coil of the present invention surrounding a part of the human body. DETAILED DESCRIPTION

[0019] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0020] See also Figure 1 、 Figure 2 、 Figure 3 and Figure 4 The present invention provides an embodiment of a thermally sustained-release magnetic targeted drug microcapsule based on electromagnetic induction, comprising a capsule shell and a core material, wherein the capsule shell is made of a blend of polycaprolactone and hydroxypropyl modified starch, the mass ratio of the polycaprolactone to the modified starch being 60:40, 5-8% glycerol is added as a plasticizer during the preparation of the capsule shell, and the core material comprises ferroferric oxide nanoparticles and a drug loaded on the outer surface of the ferroferric oxide nanoparticles; the microcapsule has a size of 50-100 nanometers and a spherical structure; the capsule shell is heated by an external electromagnetic induction heating coil and then melts, releasing the drug in the core material; The outer wall of the microcapsule is coated with an oral capsule shell made of enteric material shellac; The coil is made of gallium-tin alloy with a conductivity of 3×106 S / m, elongation ≥ 50%, power frequency range 20kHz-500kHz; Furthermore, firstly, gallium-tin alloy is selected as the main material of the coil, and the conductivity of gallium-tin alloy is 3×10 6 S / m, with an elongation of ≥50%. A spiral winding segment with a diameter of 5 cm and a pitch of 2 mm is combined with a ring winding segment with an inner diameter of 8 cm and an outer diameter of 10 cm. Multiple strands of enameled wire are woven together to form a closed flexible coil that can wrap around human joints. Each strand of the enameled wire has a diameter of 0.1 mm and a braiding density of 100 strands per square centimeter. Wire connectors are reserved at both ends of the segment. The wires are led out through the edge of the coil and soldered to the STM32 circuit board of the micro control box. The Bluetooth module is integrated on the circuit board. The Bluetooth module is connected to a mobile phone and the heating mode is adjusted through an app. The PT100 sensor is attached to the inside of the sensing layer. The micro control box has a built-in lithium battery. The outer side of the winding is then covered with a 5μm-thick nanocrystalline alloy film, which converts electromagnetic energy into heat energy through the magnetoelectric induction effect, preventing strong electromagnetic fields from directly affecting biological tissue. A 0.8mm-thick silicone rubber layer is applied to the surface of the induction layer that contacts the human body. Medical-grade insulation material is used to prevent users from directly contacting the coil, which could cause burns or electrical leakage. A 0.3mm-thick permalloy sheet is wrapped around the non-human contact side of the winding to reduce electromagnetic radiation to ≤10μT. A PT100 temperature sensor collects real-time temperature signals from the heating zone. The microcontroller receives the temperature sensor data and adjusts the coil current. Finally, a 20kHz alternating current was applied, and the coil was heated to 45°C and stabilized within 30 seconds. The surface temperature uniformity error was ≤2%, and the resistance change rate was ≤5% when stretched 50%, verifying the compatibility of flexibility and conductivity. The microcapsules were placed in 37°C saline, and the coil was started to heat to 45°C. The drug release rate reached 80% within 10 minutes, and the 24-hour release rate was <5% without heating. In a rat arthritis model, the coil was wrapped around the affected knee joint, and microcapsules wrapped with shellac enteric shells were orally administered. The enteric shell dissolved after 4 hours. The "Targeted Temperature Control" APP was opened, the Bluetooth search device was searched, and the "Arthritis Mode" was selected after connection. The preset settings were 45°C and 20kHz. The coil heated the local microcapsule shell to melt, releasing the anti-inflammatory drug loaded with ferroferric oxide nanoparticles, targeting the inflammatory site. After heating the coil for 5 minutes, the drug concentration on the affected side was 10 times that of normal tissue, and the drug in the non-heated area was excreted through metabolism without obvious accumulation.

[0021] See also Figure 1 、 Figure 2 and Figure 3The present invention provides an embodiment of a thermally sustained-release magnetic targeted drug microcapsule based on electromagnetic induction, comprising a capsule shell and a core material, wherein the capsule shell is made of a blend of polycaprolactone and hydroxypropyl modified starch, the mass ratio of the polycaprolactone to the modified starch being 60:40, 5-8% glycerol is added as a plasticizer during the preparation of the capsule shell, and the core material comprises ferroferric oxide nanoparticles and a drug loaded on the outer surface of the ferroferric oxide nanoparticles; the microcapsule has a size of 50-100 nanometers and a spherical structure; the capsule shell is heated by an external electromagnetic induction heating coil and then melts, releasing the drug in the core material; The surface of the capsule shell is treated with plasma, and an inner membrane composed of ferroferric oxide nanoparticles is provided inside the capsule shell, and the melting point of the inner membrane is 40-60°C; The drug loaded on the outer surface of the ferroferric oxide nanoparticles comprises at least one of a chemotherapy drug, a biological agent and a gene drug; Furthermore, first, 6-8 week old female nude mice weighing 18-22 g were selected and housed in a specific pathogen-free environment at a temperature of 22±2°C, a humidity of 50±5%, a 12 h light / dark cycle, and free access to food and water. Human breast cancer MCF-7 cells were cultured in DMEM medium containing 10% fetal bovine serum and 1% penicillin-streptomycin and passaged in a 37°C, 5% CO2 incubator. Cells in the logarithmic growth phase were obtained, trypsinized, centrifuged, and resuspended in PBS to make 1×10 7 cells / mL cell suspension, 100 μL of cell suspension was subcutaneously injected into the right forelimb axilla of nude mice. The long and short diameters of the tumors were measured weekly with a vernier caliper. Tumors were included in the experiment when the volume reached 200±20 mm³, approximately 7-10 days after inoculation. Then, 6g of PCL, 4g of hydroxypropyl modified starch, and 0.6g of glycerol were weighed, the starch was dried at 70℃ for 5 hours, and the PCL was dried at 50℃ for 3 hours. PCL was dissolved in 50mL of dichloromethane, and the starch was dispersed in 50mL of deionized water. After the two were mixed, they were magnetically stirred at 30℃ for 4 hours, and the solvent was removed by rotary evaporation. The obtained particles were injection molded at 90℃, cooled and demolded, and plasma treated for 5 minutes, and sterilized by γ rays. After oleic acid modification, the ferroferric oxide nanoparticles were ultrasonically dispersed with paclitaxel in PBS with pH=7.4, centrifuged to remove the unloaded drug, and assembled with the capsule after freeze-drying. The outer layer was coated with a 30μm thick shellac enteric coating. The dosage was calculated according to the body weight of nude mice, 10mg / kg, and the microcapsules were suspended in 0.5% carboxylic acid. Sodium methylcellulose solution was administered orally via gavage, and patients were fasted for 4 hours after administration to prevent premature dissolution of the enteric coating. A 4 cm × 4 cm flexible coil was prepared, and the center of the spiral winding segment was aligned with the tumor projection on the body surface using medical breathable tape. The annular winding segment was wrapped around the limb to form a closed magnetic field, ensuring that the induction conversion layer was in close contact with the skin and the electromagnetic shielding layer was facing outward to reduce external electromagnetic radiation. A high-frequency power supply was connected, with a power frequency of 150 kHz and an initial power of 30 W, which was gradually adjusted to 50 W. The coil current and voltage were monitored in real time. After heating was started, the tumor area was scanned with an infrared thermal imager every 5 minutes. The coil position was adjusted to stabilize the local temperature at 47 ± 1°C. Heating was continued for 6 hours, during which time physiological saline was replenished every 30 minutes to prevent dehydration. Finally, during the heating process, the central temperature of the tumor was maintained at 46.5-47.5°C, and the temperature of the surrounding normal tissue was ≤39°C. One hour after the heating ended, the nude mice were sacrificed, and the tumor and liver tissues were obtained. After homogenization and methanol extraction, the paclitaxel concentration was detected by HPLC. The results showed that the concentration in tumor tissue reached 8.5±0.8μg / g and the concentration in liver was 0.3±0.1μg / g, indicating that targeted release significantly reduced systemic toxicity. Tumor volume was measured every 2 days during treatment, and a growth curve was drawn. The control group was given the same dose of paclitaxel microcapsules but the coil heating was not activated. After 14 days, the tumor volume in the treatment group shrank from 200±20mm³ to 70±15mm³, and the tumor volume in the control group shrank to 160±25mm³.

[0022] See also Figure 1 、 Figure 2 and Figure 3 The present invention provides an embodiment of a thermally induced sustained-release magnetic targeted drug microcapsule based on electromagnetic induction, wherein the coil includes a spiral winding segment and a ring winding segment to form a closed magnetic field surrounding the human body. The coil is woven with multiple strands of enameled wire, each strand of enameled wire having a diameter of 0.05-0.2 mm and a weaving density of 80-120 strands per square centimeter, forming a flexible structure. The outer wall of the coil is covered with an induction conversion layer made of a nanocrystalline alloy film. The induction conversion layer heats the human body through heat conduction. The surface of the induction conversion layer in contact with the human body is provided with an insulating protective layer made of silicone rubber with a thickness of 0.5-1mm. The side of the coil that does not contact the human body is wrapped with an electromagnetic shielding layer made of a permalloy sheet with a thickness of 0.2-0.5mm. Furthermore, targeted therapy for chronic arthritis was tested: First, a rat arthritis model was established. Six-week-old female SD rats weighing 200±20g were selected. After anesthesia, 0.1ml of Freund's complete adjuvant was injected into the right knee joint cavity. The joint circumference was measured daily after injection. When the swelling reached grade 3 and lasted for more than 48 hours, the model was considered successful. A total of 12 rats were established and randomly divided into a treatment group of 8 rats and a control group of 4 rats. Then, 6g of polycaprolactone and 4g of hydroxypropyl modified starch were weighed, and 0.5g of glycerol was added. After dissolution in chloroform, dispersion in aqueous phase, solvent evaporation, injection molding at 90°C, and plasma surface treatment, dexamethasone was loaded to produce 80nm spherical microcapsules. After γ-ray sterilization, the microcapsule suspension was injected into the tail vein of rats in the treatment group. After 30 minutes, the flexible coil device was attached to the knee joint. The parameters were adjusted by an external power supply: frequency 80kHz, power 30W, and treatment was carried out twice a day for 60 minutes each time for 7 days. The control group was injected with an equal amount of normal saline and received the same coil no-load treatment. Finally, on the third day of treatment, after injection of gadopentetate dimeglumine contrast agent via the tail vein, the knee joint was scanned using 3.0T magnetic resonance imaging. T2-weighted images showed that the signal intensity of the microcapsules in the joint cavity enriched area in the treatment group was 85% higher than that in the contralateral side, and the enrichment rate was 82% calculated by image analysis software. There was no significant signal difference in the control group. On the seventh day of treatment, synovial fluid was obtained and IL-6 concentration was measured by enzyme-linked immunosorbent assay. The treatment group decreased by 75% (from 210 pg / ml to 52 pg / ml) compared with the pre-modeling level, while the control group decreased by 30% (from 205 pg / ml to 143 pg / ml), with significant differences between the groups. The rats were killed, and the knee joint synovial tissue was obtained and observed after HE staining. The number of synovial cell layers in the treatment group decreased from 8-10 layers after modeling to 3-4 layers, the amount of vascular pannus formation decreased by 60%, and the cartilage surface was smooth and without erosion. In the control group, synovial hyperplasia was obvious, and fibrosis and destruction of the cartilage were visible.

[0023] See also Figure 1 、 Figure 2 and Figure 3 The present invention provides an embodiment of a thermally induced sustained-release magnetic targeted drug microcapsule based on electromagnetic induction, wherein the preparation method of the capsule shell comprises the following steps: S1. Raw material selection: Weigh PCL with a moderate molecular weight and hydroxypropyl modified starch, with the mixing ratio of PCL and modified starch being 60:40, and 5-8% plasticizer glycerol; S2. Material pretreatment: Dry the starch at 60-80°C for 4-6 hours to remove moisture; dry the PCL particles at 50°C for 2-4 hours; S3, mixing: dissolving PCL in an organic solvent such as chloroform or dichloromethane, and dispersing starch in water to form a suspension, mixing the two solutions and stirring, and then removing the solvent by evaporation; S4, injection molding: Add the mixed material particles into the injection molding machine, set the temperature at 90-120 ° C, inject the molten material into the capsule mold, and demould after cooling; S5. Post-treatment: Plasma surface treatment of the capsule shell, followed by gamma ray sterilization; The microcapsules are used in the preparation of local solid tumor drugs; Further, first, prepare hydroxypropyl modified starch: Weigh 100 g of corn starch and mix it with 50% ethanol solution to prepare a starch emulsion with a concentration of 0.25 g / ml and a total solution volume of 400 ml. Heat the starch emulsion in a constant temperature water bath at 78°C for 35 minutes. The degree of amorphization is measured to be 92%. Add the starch emulsion to a reactor, add 1.5 g of sodium hydroxide and 25 g of anhydrous sodium sulfate, stir and disperse, slowly add 25 g of propylene oxide, seal the reactor, heat to 45°C, and stir at 200 rpm for 12 hours. After the reaction, adjust the pH to 6.8 with dilute hydrochloric acid, wash with ethanol three times, filter, dry, and pass through a 100-mesh sieve to obtain hydroxypropyl modified starch. Then, prepare the polycaprolactone / modified starch capsule shell: Weigh 60 g of polycaprolactone and 40 g of hydroxypropylated modified starch, add 6 g of glycerol, dissolve the polycaprolactone in 200 ml of dichloromethane, and disperse the modified starch in 100 ml of deionized water to form a suspension. The two solutions are mixed and stirred at 500 rpm for 1 hour. The solvent is evaporated to obtain a uniform mixed material. The mixed material is added to an injection molding machine, set to 110°C, and injected into a spherical mold with a diameter of 80 nm. The mold is cooled and demolded. The capsule shell is plasma treated at a power of 50 W for 5 minutes and sterilized with 25 kGy of gamma rays. Finally, verify the microcapsule structure: Scanning electron microscopy showed that the capsule shell thickness was 70±10nm, the surface was smooth, and the sphericity was >95%. Differential scanning calorimetry measured the melting point of the inner membrane of ferroferric oxide to be 48°C, which met the 40-60°C requirement. In vitro simulated release experiments showed that the drug release rate was 0.2 mg / h at 45°C, and there was no release at room temperature.

[0024] See also Figure 1 、 Figure 2 and Figure 3The present invention provides an embodiment: a thermally induced sustained-release magnetic targeted drug microcapsule based on electromagnetic induction, wherein the preparation method of the hydroxypropylated modified starch comprises the following steps: S1, starch selection: corn starch, tapioca starch and potato starch; S2. Reagent preparation: propylene oxide, sodium hydroxide, anhydrous sodium sulfate and auxiliary reagents; Propylene oxide: as an etherifying agent, introducing hydroxypropyl groups, 20%-30% by weight of starch; Sodium hydroxide: as a catalyst, 0.5%-2% of starch weight; Anhydrous sodium sulfate: 15%-30% of starch weight; Auxiliary reagents: ethanol, cyclohexane, to disperse starch and adjust reaction conditions; S3. Amorphization pretreatment: Starch is mixed with 50% ethanol solution to prepare a starch milk with a concentration of 0.25g / ml. The starch milk is then heated at 78°C for 35 minutes until the degree of amorphization of the starch reaches more than 90%; S4. Etherification reaction: The starch after amorphization pretreatment is dispersed in water, sodium hydroxide solution is added to the dispersion, the pH value of the reaction system is adjusted to strong alkalinity, and propylene oxide is slowly added. The reaction tank is then sealed, the temperature is raised to 40-50 ° C, and the reaction is stirred for 12 hours. S5. Post-treatment: After the reaction is completed, the pH is adjusted to neutral with dilute hydrochloric acid, and the starch is washed with ethanol to remove unreacted reagents and by-products. The washed starch is dehydrated, dried, and sieved to obtain hydroxypropyl starch; The microcapsules are also used in the preparation of drugs for the treatment of chronic inflammation and postoperative local diseases; Furthermore, a postoperative local anti-infection treatment experiment was conducted: First, to simulate a postoperative infection scenario, 2.5 kg New Zealand white rabbits were selected. After shaving and disinfecting the back, a 1 cm incision was made along the spine, deep into the subcutaneous tissue. 0.1 ml of Staphylococcus aureus solution was inoculated at the incision site and the incision was sutured. 24 hours after the operation, redness, swelling, and purulent exudate were observed at the incision site, confirming the formation of an infection focus. A total of 10 rabbits were modeled and randomly divided into a treatment group of 6 New Zealand white rabbits and a control group of 4 New Zealand white rabbits. Then, 6% glycerol was added, the shell surface was plasma-treated, coated with a shellac enteric layer, and the core material was loaded with vancomycin to produce 100 nm microcapsules. The treatment group received injections of the microcapsule suspension at three points around the infection site at a concentration of 2 mg / ml, a dose of 2 mg / cm² of infected area. The control group received an equal volume of saline. A 2 cm × 2 cm flexible coil covered the infected incision and was connected to a microcontroller with the following parameters: frequency 200 kHz, power 20 W, and heating three times daily for 60 minutes each time for five days. During the heating process, the local temperature was monitored in real time with an infrared thermometer and maintained at 50 ± 1°C. Finally, infrared thermal imaging showed that the temperature of the infected site in the treatment group rose to 50°C within 10 minutes after heating and dropped to 37°C within 30 minutes after heating was stopped. A single heating could maintain the effective drug release temperature for 6 hours. High-performance liquid chromatography detection showed that the vancomycin concentration in the wound tissue 24 hours after treatment was 12 μg / g, which was significantly higher than that in the control group. On the third day of treatment, incision secretions were collected, diluted 10-fold in a gradient, and inoculated on blood agar plates. The colony-forming units were counted at 37°C for 24 hours. The CFU in the treatment group was 8×10², and that in the control group was 1.2×10 5 The wound healing was observed every day. The incisions in the treatment group were completely scabbed and fell off on the 7th day; the incisions in the control group healed on the 12th day. Histopathological sections showed that the amount of inflammatory cell infiltration in the treatment group was reduced by 70% compared with the control group, and the collagen fibers were arranged more neatly.

[0025] Working Principle: First, when the external electromagnetic induction heating coil is energized, the coil's spiral and toroidal winding sections form a closed alternating magnetic field surrounding the targeted area of the human body. The coil is constructed from multiple strands of enameled wire woven into a flexible structure that conforms to the curves of the human body. A nanocrystalline alloy thin film induction conversion layer on the coil's outer wall converts electrical energy into thermal energy through electromagnetic induction, transferring heat to human tissue via thermal conduction. Simultaneously, a 0.5-1mm thick silicone rubber insulating protective layer isolates the coil from direct electrical contact with the human body. A 0.2-0.5mm thick permalloy sheet electromagnetic shielding layer on the non-human contact side suppresses magnetic field leakage, minimizing interference with surrounding tissue.

[0026] Then, when the heat transferred by the inductive conversion layer raises the local temperature to the melting point of the shell material, the shell begins to soften; at the same time, the inner membrane composed of ferroferric oxide nanoparticles within the shell preferentially melts, forming the initial drug release channel. As the core material component, ferroferric oxide nanoparticles have inherent magnetic response properties. In an alternating magnetic field, they can assist in heat generation through hysteresis loss, accelerating the melting process of the shell and inner membrane. As the temperature further increases to the melting point of the main shell material, the shell structure is destroyed, and the loaded drug encapsulated in the core material is released through the outer surface of the nanoparticles.

[0027] Finally, the microcapsules, spherical structures measuring 50-100 nm, can be targeted and enriched at the lesion site via intravenous or oral administration. When the coil precisely heats the lesion, the capsule shell melts, releasing the drug directly into the target area, avoiding the toxic side effects of systemic administration. The magnetic properties of the ferroferric oxide nanoparticles can also assist in guiding the directional migration of the microcapsules using an external magnetic field.

[0028] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the invention can be embodied in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as illustrative and non-restrictive, and the scope of the invention is defined by the appended claims, not the foregoing description, and all variations within the meaning and range of equivalents of the claims are intended to be included therein. Any reference sign in a claim should not be construed as limiting the claim to which it relates.

Claims

1. A thermally induced sustained-release magnetic targeted drug microcapsule based on electromagnetic induction, characterized by: The capsule shell comprises a capsule shell and a core material. The capsule shell is made by blending polycaprolactone and hydroxypropyl modified starch. The mass ratio of the polycaprolactone to the modified starch is 60:

40. 5-8% glycerol is added as a plasticizer during the preparation of the capsule shell. The core material comprises ferroferric oxide nanoparticles and a drug loaded on the outer surface of the ferroferric oxide nanoparticles. The size of the microcapsules is 50-100 nanometers and has a spherical structure; The capsule shell is heated by an external electromagnetic induction heating coil and melts to release the medicine in the core material.

2. The electromagnetic induction-based thermal sustained-release magnetic targeted drug microcapsule according to claim 1, characterized in that: The surface of the capsule shell is treated with plasma, and an inner membrane composed of ferroferric oxide nanoparticles is provided inside the capsule shell, and the melting point of the inner membrane is 40-60°C.

3. The electromagnetic induction-based thermal sustained-release magnetic targeted drug microcapsule according to claim 1, characterized in that: The outer wall of the microcapsule is wrapped with an oral capsule shell made of enteric material shellac.

4. The electromagnetic induction-based thermal sustained-release magnetic targeted drug microcapsule according to claim 1, characterized in that: The coil is made of gallium-tin alloy with a conductivity of 3×10 6 S / m, elongation ≥50%, power frequency range 20kHz-500kHz.

5. The electromagnetic induction-based thermal sustained-release magnetic targeted drug microcapsule according to claim 1, characterized in that: The coil includes a spiral winding section and a ring winding section, forming a closed magnetic field surrounding the human body. The coil is woven with multiple strands of enameled wire, each strand of enameled wire has a diameter of 0.05-0.2 mm, and a weaving density of 80-120 strands per square centimeter, forming a flexible structure. The outer wall of the coil is covered with an induction conversion layer, which uses a nanocrystalline alloy film. The induction conversion layer heats the human body through heat conduction. The contact surface between the induction conversion layer and the human body is provided with an insulating protective layer, which uses silicone rubber with a thickness of 0.5-1mm. The side of the coil that does not contact the human body is wrapped with an electromagnetic shielding layer, which is composed of a Permalloy sheet with a thickness of 0.2-0.5mm.

6. The electromagnetic induction-based thermal sustained-release magnetic targeted drug microcapsule according to claim 1, characterized in that: The medicine loaded on the outer surface of the ferrosoferric oxide nanoparticles comprises at least one of chemotherapy drugs, biological agents and gene drugs.

7. The electromagnetic induction-based thermal sustained-release magnetic targeted drug microcapsule according to claim 1, characterized in that: The preparation method of the capsule shell comprises the following steps: S1. Raw material selection: Weigh PCL with a moderate molecular weight and hydroxypropyl modified starch, with the mixing ratio of PCL and modified starch being 60:40, and 5-8% plasticizer glycerol; S2. Material pretreatment: Dry the starch at 60-80°C for 4-6 hours to remove moisture; dry the PCL particles at 50°C for 2-4 hours; S3, mixing: dissolving PCL in an organic solvent such as chloroform or dichloromethane, and dispersing starch in water to form a suspension, mixing the two solutions and stirring, and then removing the solvent by evaporation; S4, injection molding: Add the mixed material particles into the injection molding machine, set the temperature at 90-120 ° C, inject the molten material into the capsule mold, and demould after cooling; S5. Post-processing: Plasma surface treatment is performed on the capsule shell, followed by gamma ray sterilization.

8. The electromagnetic induction-based thermal sustained-release magnetic targeted drug microcapsule according to claim 1, characterized in that: The preparation method of the hydroxypropylated modified starch comprises the following steps: S1, starch selection: corn starch, tapioca starch and potato starch; S2. Reagent preparation: propylene oxide, sodium hydroxide, anhydrous sodium sulfate and auxiliary reagents; Propylene oxide: as an etherifying agent, introducing hydroxypropyl groups, 20%-30% by weight of starch; Sodium hydroxide: as a catalyst, 0.5%-2% of starch weight; Anhydrous sodium sulfate: 15%-30% of starch weight; Auxiliary reagents: ethanol, cyclohexane, to disperse starch and adjust reaction conditions; S3. Amorphization pretreatment: Starch is mixed with 50% ethanol solution to prepare a starch milk with a concentration of 0.25g / ml. The starch milk is then heated at 78°C for 35 minutes until the degree of amorphization of the starch reaches more than 90%; S4. Etherification reaction: The starch after amorphization pretreatment is dispersed in water, sodium hydroxide solution is added to the dispersion, the pH value of the reaction system is adjusted to strong alkalinity, and propylene oxide is slowly added. The reaction tank is then sealed, the temperature is raised to 40-50 ° C, and the reaction is stirred for 12 hours. S5. Post-treatment: After the reaction is completed, the pH is adjusted to neutral with dilute hydrochloric acid, and the starch is washed with ethanol to remove unreacted reagents and by-products. The washed starch is dehydrated, dried, and sieved to obtain hydroxypropyl starch.

9. An application of a thermally induced sustained-release magnetic targeted drug microcapsule based on electromagnetic induction, applicable to the thermally induced sustained-release magnetic targeted drug microcapsule based on electromagnetic induction according to any one of claims 1 to 6, characterized in that: The microcapsule is used in preparing local solid tumor medicine.

10. The use of a thermally induced sustained-release magnetic targeted drug microcapsule based on electromagnetic induction according to claim 9, characterized in that: The microcapsules are also used in the preparation of drugs for treating chronic inflammation and post-operative local diseases.

Images