Oral controlled-release pharmaceutical preparation and preparation method thereof

Abstract

The invention discloses an oral controlled-release medicinal preparation and a preparation method thereof. According to the invention, by adopting multiple controlled release mechanisms such as the temperature-sensitive polymer, the pH-sensitive polymer and the sustained-release polymer, the fixed-point release of the medicine in the intestinal tract can be realized, so that the bioavailability and the treatment effect of the medicine are remarkably improved. According to the intelligent release system, the drug release rate can be adjusted according to small changes of the in-vivo environment, release of drugs at non-target parts is reduced, side effects are reduced, and the medication safety and comfort of patients are improved. The components such as the nano-hydroxyapatite and the enzyme-sensitive cross-linking agent can enhance the mechanical strength and stability of the pharmaceutical preparation, and further control of drug release is realized through enzyme-sensitive degradation. By means of the design, the stability of the medicine in the storage and transportation process is guaranteed, the medicine can be accurately released under the action of specific enzyme in the body, the requirement for personalized treatment is met, and a more accurate medicine treatment scheme is provided for patients.

Description

Technical Field

[0001] The invention belongs to the technical field of controlled-release drugs, and specifically relates to an oral controlled-release drug preparation and a preparation method thereof. Background Art

[0002] Oral controlled-release drug preparations are an advanced drug delivery system that is specially designed to release drugs at a predetermined constant rate in the body, thereby maintaining stable blood drug concentrations, reducing the number of dosing times, and improving patient compliance and therapeutic effects. This preparation usually contains a drug core, a controlled-release coating layer, and an optional immediate-release layer, of which the controlled-release coating layer is the key. It is composed of water-insoluble or slow-soluble materials, and the drug release rate is controlled by precise processes. Oral controlled-release drug preparations have the advantages of small fluctuations in blood drug concentrations, reduced side effects, and ease of use for patients. They are particularly suitable for diseases that require long-term treatment, such as hypertension, diabetes, heart disease, etc. In addition, controlled-release preparations can also improve the bioavailability of drugs and reduce drug irritation to the gastrointestinal tract, which is of great significance for improving the quality of life of patients and the safety of drug treatment.

[0003] However, many controlled-release preparations in the prior art rely on a single controlled-release mechanism, such as a sustained-release polymer coating or an enteric material, which may not be able to adapt to the complex environmental changes in the body, resulting in unstable drug release. In addition, existing preparations still need to be improved in terms of improving drug bioavailability and reducing side effects. Summary of the invention

[0004] The object of the present invention is to provide an oral controlled-release pharmaceutical preparation and a method for preparing the same in order to solve the above-mentioned problems.

[0005] The technical solution adopted by the present invention is as follows: an oral controlled-release pharmaceutical preparation comprising:

[0006] Active pharmaceutical ingredient (API) microparticles 50-80 parts by weight, temperature-sensitive polymer 10-20 parts by weight, pH-sensitive polymer 5-10 parts by weight, sustained-release polymer 15-20 parts by weight, nano-hydroxyapatite 5-10 parts by weight, enzyme-sensitive cross-linking agent 2-5 parts by weight, enteric material 10-15 parts by weight, color and taste modifier 2-5 parts by weight, probiotics 2-5 parts by weight, natural flavor 2-5 parts by weight and tracking agent 1-5 parts by weight;

[0007] The temperature sensitive polymer is one of polyethylene oxide-polyacrylic acid copolymer or polyethylene glycol-polylactic acid copolymer.

[0008] The pH sensitive polymer is one of polyacrylic acid, chitosan or polymethyl methacrylate.

[0009] The sustained-release polymer is one of polylactic acid-glycolic acid copolymer, polylactic acid or polycaprolactam.

[0010] The nano-hydroxyapatite is one of pure nano-hydroxyapatite, surface-modified nano-hydroxyapatite or nano-hydroxyapatite composite material.

[0011] The enzyme sensitive cross-linking agent is one of a glucose oxidase cross-linking polymer, a lipase cross-linking polymer or a protease cross-linking polymer.

[0012] The enteric material is one of hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate or acrylic resin Eudragit L100.

[0013] The color and taste modifier is one of food coloring, natural flavoring or food coloring.

[0014] The probiotic is one of Bifidobacterium lactis, Lactobacillus acidophilus or Lactobacillus rhamnosus.

[0015] The natural flavor is one of peppermint oil, lemon oil or orange oil.

[0016] The tracer is one of edible blue pigment, fluorescent marker or quantum dots.

[0017] In a preferred embodiment, a method for preparing an oral controlled-release pharmaceutical preparation comprises the following steps:

[0018] S1: Dissolve the API in an appropriate solvent and prepare it into microcapsules or microparticles by emulsification solvent diffusion method or spray drying technology. Use supercritical fluid technology or mechanical grinding method to further refine the API particles to ensure that they have uniform particle size;

[0019] S2: dissolving the temperature-sensitive polymer in an appropriate solvent to form a solution. Mixing the API particles with the temperature-sensitive polymer solution to form composite particles by spray drying or freeze drying technology;

[0020] S3: dissolving the pH sensitive polymer in a buffer solution and adjusting the pH value to adapt to the intestinal environment. Adding the temperature sensitive polymer composite microparticles into the pH sensitive polymer solution and coating them by dropwise addition or spin coating technology;

[0021] S4: dissolving a slow-release polymer (such as PLGA) in an organic solvent to prepare a coating solution. Immersing the microparticles coated with the pH-sensitive polymer in the slow-release polymer solution, and then centrifuging or drying to form a slow-release layer;

[0022] S5: Dispersing nHA nanoparticles in water and ensuring uniform dispersion by ultrasonic treatment. Mixing the sustained-release polymer-coated microparticles with the nHA suspension and attaching nHA to the surface of the microparticles by mechanical stirring or electrostatic adsorption technology;

[0023] S6: adding an enzyme-sensitive crosslinking agent (such as glucose oxidase) to the suspension containing the microparticles. Under appropriate conditions (such as specific pH and temperature), the crosslinking agent reacts with the functional groups on the surface of the microparticles to enhance the stability of the microparticles;

[0024] S7: dissolving the enteric material (such as CAP) in a suitable solvent to form a coating solution. Using fluidized bed coating technology, the enteric material solution is evenly coated on the cross-linked particles to form a final enteric coating;

[0025] S8: Mix color and taste modifiers (such as food coloring and flavoring) into the filling of the capsule. Add probiotics and natural flavorings to the filling in a certain proportion. Finally, add an appropriate amount of tracking agent (such as food coloring) to ensure that the preparation can be tracked throughout the preparation process. The mixed filling is loaded into the capsule to complete the preparation of the oral controlled release drug preparation.

[0026] In a preferred embodiment, in step S1, the active pharmaceutical ingredient particles are dissolved in a non-aqueous solvent, dimethylformamide (DMF), to ensure that the concentration of the API is 10% to 20% (w / v). Subsequently, the API solution is slowly added dropwise to the aqueous phase containing the emulsifier using an emulsified solvent diffusion method while stirring to form a primary emulsion. The emulsion is transferred to a high-pressure homogenizer and homogenized at a pressure of 100-200 MPa to obtain uniform API particles. Thereafter, the solvent is removed by rotary evaporation to obtain dry API particles. The particle size of the particles is detected by a particle size analyzer, and the target particle size is 1-5 microns.

[0027] In a preferred embodiment, in step S2, the temperature-sensitive polymer PNIPAm is dissolved in ethyl acetate at a concentration of 5% to 10% (w / v) to form a transparent solution. Then, the API particles prepared in step S1 are added to the PNIPAm solution and stirred at a low speed using a magnetic stirrer to ensure uniform mixing. Then, the mixture is dried in a spray dryer at an inlet temperature of 40-50°C and an outlet temperature of 25-30°C to form temperature-sensitive API composite particles. The inlet and outlet air velocities during the spray drying process are set to 0.8-1.2 m / s and 1.5-2.0 m / s, respectively.

[0028] In a preferred embodiment, in step S3, the pH-sensitive polymer PAA is dissolved in a phosphate buffer at a concentration of 2% to 5% (w / v), and the pH is adjusted to 6.8-7.4 to simulate the intestinal environment. Then, the temperature-sensitive polymer composite microparticles prepared in step S2 are added to the PAA solution, and a peristaltic pump is used to drip at a constant rate while stirring at a low speed with a magnetic stirrer. Spin coating technology is used to coat at a low speed (100-200 rpm), and then dried at room temperature overnight to form composite microparticles with pH responsiveness.

[0029] In a preferred embodiment, in step S4, the pH-sensitive polymer-coated microparticles prepared in step S3 are immersed in a PLGA solution and coated using a vacuum rotary evaporator under mild reduced pressure conditions (30-50 mbar) to form a sustained-release layer. The coated microparticles are centrifuged (3000 rpm, 5 minutes) to remove excess polymer solution and dried in a freeze dryer for 24 hours to remove residual solvent.

[0030] In a preferred embodiment, in step S5, the nHA nanoparticles are dispersed in deionized water and treated with an ultrasonic cell disruptor at a power of 400-600 W for 30 minutes to ensure uniform dispersion of nHA. Subsequently, the sustained-release polymer-coated microparticles prepared in step S4 are added to the nHA suspension and stirred at room temperature for 2 hours using a mechanical stirrer (500 rpm) to promote electrostatic adsorption and physical adsorption of nHA to the surface of the microparticles, thereby integrating nHA to the surface of the microparticles.

[0031] In a preferred embodiment, in step S6, a magnetic stirrer is used to stir at a low speed for 4-6 hours at a pH value of 6.0-7.0 and a temperature of 37° C. to promote the cross-linking reaction between the cross-linking agent and the functional groups on the surface of the microparticles. During the cross-linking process, the cross-linking efficiency is optimized by adjusting the pH and temperature, and the morphological changes of the microparticles are observed under a microscope to confirm the cross-linking effect.

[0032] In a preferred embodiment, in step S7, a fluidized bed coating technique is used, the cross-linked microparticles in step S6 are placed in a fluidized bed, and the CAP solution is sprayed at a constant flow rate (5-10 mL / min), while the inlet air temperature is maintained at 30-40° C. and the outlet air temperature is maintained at 25-35° C. During the coating process, the microparticles are uniformly coated with the enteric material in a fluidized state to form a final enteric coating.

[0033] In a preferred embodiment, in step S8, probiotics (such as freeze-dried powder) are added to the mixture in an amount of 100 million to 500 million CFU per capsule. Then, natural flavors (such as peppermint oil) are added to the mixture at a ratio of 0.05% to 0.2% (w / v) to improve the taste of the capsules. Finally, a tracer (such as fluorescein sodium salt) is added to the mixture at a ratio of 0.01% to 0.05% (w / v) to facilitate subsequent drug tracking and release studies. After all additives are mixed evenly, they are evenly sprayed or mixed onto the enteric coated particles prepared in step S7.

[0034] In summary, due to the adoption of the above technical solution, the beneficial effects of the present invention are:

[0035] 1. In the present invention, by adopting multiple controlled release mechanisms such as temperature-sensitive polymers, pH-sensitive polymers and sustained-release polymers, the drug can be released at a fixed point in the intestine, thereby significantly improving the bioavailability and therapeutic effect of the drug. This intelligent release system can adjust the drug release rate according to slight changes in the body environment, reduce the release of drugs in non-target areas, reduce side effects, and improve the safety and comfort of patients.

[0036] 2. In the present invention, nano-hydroxyapatite and enzyme-sensitive cross-linking agents can enhance the mechanical strength and stability of the drug preparation, and further control the drug release through enzyme-sensitive degradation. This design not only ensures the stability of the drug during storage and transportation, but also can accurately release the drug under the action of specific enzymes in the body, meet the needs of personalized treatment, and provide patients with a more accurate drug treatment plan.

[0037] 3. In the present invention, the addition of color and taste modifiers, probiotics and natural flavors not only improves the taste of the preparation and the patient's compliance, but also the addition of probiotics helps maintain intestinal health and enhance the body's immune capacity. In addition, the use of tracers allows the behavior and release path of drugs in the body to be monitored in real time, providing valuable data support for the development and application of drugs, and further promoting the optimization and innovation of drug preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 It is a schematic diagram of the process principle of the present invention. DETAILED DESCRIPTION

[0039] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0040] Embodiment 1:

[0041] Reference Figure 1 , an oral controlled-release pharmaceutical preparation comprising:

[0042] Active pharmaceutical ingredient (API) microparticles 50 parts by weight, temperature-sensitive polymer 10 parts by weight, pH-sensitive polymer 5 parts by weight, sustained-release polymer 15 parts by weight, nano-hydroxyapatite 5 parts by weight, enzyme-sensitive cross-linking agent 2 parts by weight, enteric material 10 parts by weight, color and taste modifier 2 parts by weight, probiotics 2 parts by weight, natural flavor 2 parts by weight and tracer 1 part by weight;

[0043] The temperature sensitive polymer is one of polyethylene oxide-polyacrylic acid copolymer or polyethylene glycol-polylactic acid copolymer.

[0044] The pH sensitive polymer is one of polyacrylic acid, chitosan or polymethyl methacrylate.

[0045] The sustained-release polymer is one of polylactic acid-glycolic acid copolymer, polylactic acid or polycaprolactam.

[0046] The nano-hydroxyapatite is one of pure nano-hydroxyapatite, surface-modified nano-hydroxyapatite or nano-hydroxyapatite composite material.

[0047] The enzyme sensitive cross-linking agent is one of a glucose oxidase cross-linking polymer, a lipase cross-linking polymer or a protease cross-linking polymer.

[0048] The enteric material is one of hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate or acrylic resin Eudragit L100.

[0049] The color and taste modifier is one of food coloring, natural flavoring or food coloring.

[0050] The probiotic is one of Bifidobacterium lactis, Lactobacillus acidophilus or Lactobacillus rhamnosus.

[0051] The natural flavor is one of peppermint oil, lemon oil or orange oil.

[0052] The tracer is one of edible blue pigment, fluorescent marker or quantum dots.

[0053] The manufacturing method comprises the following steps:

[0054] S1: Dissolve the API in an appropriate solvent and prepare it into microcapsules or microparticles by emulsification solvent diffusion method or spray drying technology. Use supercritical fluid technology or mechanical grinding method to further refine the API particles to ensure that they have uniform particle size;

[0055] S2: dissolving the temperature-sensitive polymer in an appropriate solvent to form a solution. Mixing the API particles with the temperature-sensitive polymer solution to form composite particles by spray drying or freeze drying technology;

[0056] S3: dissolving the pH sensitive polymer in a buffer solution and adjusting the pH value to adapt to the intestinal environment. Adding the temperature sensitive polymer composite microparticles into the pH sensitive polymer solution and coating them by dropwise addition or spin coating technology;

[0057] S4: dissolving a slow-release polymer (such as PLGA) in an organic solvent to prepare a coating solution. Immersing the microparticles coated with the pH-sensitive polymer in the slow-release polymer solution, and then centrifuging or drying to form a slow-release layer;

[0058] S5: Dispersing nHA nanoparticles in water and ensuring uniform dispersion by ultrasonic treatment. Mixing the sustained-release polymer-coated microparticles with the nHA suspension and attaching nHA to the surface of the microparticles by mechanical stirring or electrostatic adsorption technology;

[0059] S6: adding an enzyme-sensitive crosslinking agent (such as glucose oxidase) to the suspension containing the microparticles. Under appropriate conditions (such as specific pH and temperature), the crosslinking agent reacts with the functional groups on the surface of the microparticles to enhance the stability of the microparticles;

[0060] S7: dissolving the enteric material (such as CAP) in a suitable solvent to form a coating solution. Using fluidized bed coating technology, the enteric material solution is evenly coated on the cross-linked particles to form a final enteric coating;

[0061] S8: Mix color and taste modifiers (such as food coloring and flavoring) into the filling of the capsule. Add probiotics and natural flavorings to the filling in a certain proportion. Finally, add an appropriate amount of tracking agent (such as food coloring) to ensure that the preparation can be tracked throughout the preparation process. The mixed filling is loaded into the capsule to complete the preparation of the oral controlled release drug preparation.

[0062] In step S1, the active pharmaceutical ingredient particles are dissolved in the non-aqueous solvent dimethylformamide DMF to ensure that the concentration of the API is 10% to 20% (w / v). Subsequently, the API solution is slowly added dropwise to the aqueous phase containing the emulsifier using an emulsified solvent diffusion method while stirring to form a primary emulsion. The emulsion is transferred to a high-pressure homogenizer and homogenized at a pressure of 100-200 MPa to obtain uniform API particles. Thereafter, the solvent is removed by rotary evaporation to obtain dry API particles. The particle size of the particles is detected by a particle size analyzer, and the target particle size is 1-5 microns.

[0063] In step S2, the temperature-sensitive polymer PNIPAm is dissolved in ethyl acetate at a concentration of 5% to 10% (w / v) to form a transparent solution. Next, the API particles prepared in step S1 are added to the PNIPAm solution and stirred at a low speed using a magnetic stirrer to ensure uniform mixing. Then, the mixture is dried in a spray dryer at an inlet temperature of 40-50°C and an outlet temperature of 25-30°C to form temperature-sensitive API composite particles. The inlet and outlet air velocities during the spray drying process are set to 0.8-1.2 m / s and 1.5-2.0 m / s, respectively.

[0064] In step S3, the pH-sensitive polymer PAA is dissolved in a phosphate buffer at a concentration of 2% to 5% (w / v), and the pH is adjusted to 6.8-7.4 to simulate the intestinal environment. Next, the temperature-sensitive polymer composite microparticles prepared in step S2 are added to the PAA solution, and a peristaltic pump is used to drip at a constant rate while stirring at a low speed with a magnetic stirrer. Spin coating technology is used to coat at a low speed (100-200 rpm), and then dried at room temperature overnight to form pH-responsive composite microparticles.

[0065] In step S4, the pH-sensitive polymer-coated microparticles prepared in step S3 are immersed in a PLGA solution and coated using a vacuum rotary evaporator under mild reduced pressure conditions (30-50 mbar) to form a sustained-release layer. The coated microparticles are centrifuged (3000 rpm, 5 minutes) to remove excess polymer solution and dried in a freeze dryer for 24 hours to remove residual solvent.

[0066] In step S5, nHA nanoparticles are dispersed in deionized water and treated with an ultrasonic cell disruptor at a power of 400-600 W for 30 minutes to ensure uniform dispersion of nHA. Subsequently, the sustained-release polymer-coated microparticles prepared in step S4 are added to the nHA suspension and stirred at room temperature for 2 hours using a mechanical stirrer (500 rpm) to promote electrostatic adsorption and physical adsorption of nHA to the microparticle surface, thereby integrating it onto the microparticle surface.

[0067] In step S6, a magnetic stirrer is used to stir at a low speed for 4-6 hours at a pH value of 6.0-7.0 and a temperature of 37° C. to promote the cross-linking reaction between the cross-linking agent and the functional groups on the surface of the particles. During the cross-linking process, the cross-linking efficiency is optimized by adjusting the pH and temperature, and the morphological changes of the particles are observed under a microscope to confirm the cross-linking effect.

[0068] In step S7, the cross-linked microparticles in step S6 are placed in a fluidized bed using fluidized bed coating technology, and the CAP solution is sprayed at a constant flow rate (5-10 mL / min), while maintaining the inlet air temperature at 30-40° C. and the outlet air temperature at 25-35° C. During the coating process, the microparticles are evenly coated with the enteric material in a fluidized state to form the final enteric coating.

[0069] In step S8, probiotics (such as freeze-dried powder) are added to the mixture in an amount of 100 million to 500 million CFU per capsule. Next, natural flavors (such as peppermint oil) are added to the mixture at a ratio of 0.05% to 0.2% (w / v) to improve the taste of the capsules. Finally, a tracer (such as fluorescein sodium salt) is added to the mixture at a ratio of 0.01% to 0.05% (w / v) to facilitate subsequent drug tracking and release studies. After all additives are mixed evenly, they are evenly sprayed or mixed onto the enteric coated particles prepared in step S7.

[0070] From the above, it can be seen that in the present invention, by adopting multiple controlled release mechanisms such as temperature-sensitive polymers, pH-sensitive polymers and sustained-release polymers, it is possible to achieve targeted release of drugs in the intestine, thereby significantly improving the bioavailability and therapeutic effect of the drugs. This intelligent release system can adjust the drug release rate according to slight changes in the body environment, reduce the release of drugs in non-target areas, reduce side effects, and improve the safety and comfort of patients.

[0071] In the present invention, nano-hydroxyapatite (nHA) and enzyme-sensitive cross-linking agents can enhance the mechanical strength and stability of the drug preparation, while further controlling the drug release through enzyme-sensitive degradation. This design not only ensures the stability of the drug during storage and transportation, but also enables precise release of the drug under the action of specific enzymes in the body, meeting the needs of personalized treatment and providing patients with a more accurate drug treatment plan.

[0072] In the present invention, the addition of color and taste modifiers, probiotics and natural flavors not only improves the taste of the preparation and the patient's compliance, but also the addition of probiotics helps maintain intestinal health and enhance the body's immune capacity. In addition, the use of tracers allows the behavior and release path of drugs in the body to be monitored in real time, providing valuable data support for the development and application of drugs, and further promoting the optimization and innovation of drug preparations.

[0073] Embodiment 2:

[0074] An oral controlled-release pharmaceutical preparation comprising:

[0075] 80 parts by weight of active pharmaceutical ingredient (API) microparticles, 20 parts by weight of temperature-sensitive polymer, 10 parts by weight of pH-sensitive polymer, 20 parts by weight of sustained-release polymer, 10 parts by weight of nano-hydroxyapatite, 5 parts by weight of enzyme-sensitive cross-linking agent, 15 parts by weight of enteric material, 5 parts by weight of color and taste modifier, 5 parts by weight of probiotics, 5 parts by weight of natural flavor and 5 parts by weight of tracer;

[0076] The temperature sensitive polymer is one of polyethylene oxide-polyacrylic acid copolymer or polyethylene glycol-polylactic acid copolymer.

[0077] The pH sensitive polymer is one of polyacrylic acid, chitosan or polymethyl methacrylate.

[0078] The sustained-release polymer is one of polylactic acid-glycolic acid copolymer, polylactic acid or polycaprolactam.

[0079] The nano-hydroxyapatite is one of pure nano-hydroxyapatite, surface-modified nano-hydroxyapatite or nano-hydroxyapatite composite material.

[0080] The enzyme sensitive cross-linking agent is one of a glucose oxidase cross-linking polymer, a lipase cross-linking polymer or a protease cross-linking polymer.

[0081] The enteric material is one of hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate or acrylic resin Eudragit L100.

[0082] The color and taste modifier is one of food coloring, natural flavoring or food coloring.

[0083] The probiotic is one of Bifidobacterium lactis, Lactobacillus acidophilus or Lactobacillus rhamnosus.

[0084] The natural flavor is one of peppermint oil, lemon oil or orange oil.

[0085] The tracer is one of edible blue pigment, fluorescent marker or quantum dots.

[0086] The manufacturing method comprises the following steps:

[0087] S1: Dissolve the API in an appropriate solvent and prepare it into microcapsules or microparticles by emulsification solvent diffusion method or spray drying technology. Use supercritical fluid technology or mechanical grinding method to further refine the API particles to ensure that they have uniform particle size;

[0088] S2: dissolving the temperature-sensitive polymer in an appropriate solvent to form a solution. Mixing the API particles with the temperature-sensitive polymer solution to form composite particles by spray drying or freeze drying technology;

[0089] S3: dissolving the pH sensitive polymer in a buffer solution and adjusting the pH value to adapt to the intestinal environment. Adding the temperature sensitive polymer composite microparticles into the pH sensitive polymer solution and coating them by dropwise addition or spin coating technology;

[0090] S4: dissolving a slow-release polymer (such as PLGA) in an organic solvent to prepare a coating solution. Immersing the microparticles coated with the pH-sensitive polymer in the slow-release polymer solution, and then centrifuging or drying to form a slow-release layer;

[0091] S5: Dispersing nHA nanoparticles in water and ensuring uniform dispersion by ultrasonic treatment. Mixing the sustained-release polymer-coated microparticles with the nHA suspension and attaching nHA to the surface of the microparticles by mechanical stirring or electrostatic adsorption technology;

[0092] S6: adding an enzyme-sensitive crosslinking agent (such as glucose oxidase) to the suspension containing the microparticles. Under appropriate conditions (such as specific pH and temperature), the crosslinking agent reacts with the functional groups on the surface of the microparticles to enhance the stability of the microparticles;

[0093] S7: dissolving the enteric material (such as CAP) in a suitable solvent to form a coating solution. Using fluidized bed coating technology, the enteric material solution is evenly coated on the cross-linked particles to form a final enteric coating;

[0094] S8: Mix color and taste modifiers (such as food coloring and flavoring) into the filling of the capsule. Add probiotics and natural flavorings to the filling in a certain proportion. Finally, add an appropriate amount of tracking agent (such as food coloring) to ensure that the preparation can be tracked throughout the preparation process. The mixed filling is loaded into the capsule to complete the preparation of the oral controlled release drug preparation.

[0095] In step S1, the active pharmaceutical ingredient particles are dissolved in the non-aqueous solvent dimethylformamide DMF to ensure that the concentration of the API is 10% to 20% (w / v). Subsequently, the API solution is slowly added dropwise to the aqueous phase containing the emulsifier using an emulsified solvent diffusion method while stirring to form a primary emulsion. The emulsion is transferred to a high-pressure homogenizer and homogenized at a pressure of 100-200 MPa to obtain uniform API particles. Thereafter, the solvent is removed by rotary evaporation to obtain dry API particles. The particle size of the particles is detected by a particle size analyzer, and the target particle size is 1-5 microns.

[0096] In step S2, the temperature-sensitive polymer PNIPAm is dissolved in ethyl acetate at a concentration of 5% to 10% (w / v) to form a transparent solution. Next, the API particles prepared in step S1 are added to the PNIPAm solution and stirred at a low speed using a magnetic stirrer to ensure uniform mixing. Then, the mixture is dried in a spray dryer at an inlet temperature of 40-50°C and an outlet temperature of 25-30°C to form temperature-sensitive API composite particles. The inlet and outlet air velocities during the spray drying process are set to 0.8-1.2 m / s and 1.5-2.0 m / s, respectively.

[0097] In step S3, the pH-sensitive polymer PAA is dissolved in a phosphate buffer at a concentration of 2% to 5% (w / v), and the pH is adjusted to 6.8-7.4 to simulate the intestinal environment. Next, the temperature-sensitive polymer composite microparticles prepared in step S2 are added to the PAA solution, and a peristaltic pump is used to drip at a constant rate while stirring at a low speed with a magnetic stirrer. Spin coating technology is used to coat at a low speed (100-200 rpm), and then dried at room temperature overnight to form pH-responsive composite microparticles.

[0098] In step S4, the pH-sensitive polymer-coated microparticles prepared in step S3 are immersed in a PLGA solution and coated using a vacuum rotary evaporator under mild reduced pressure conditions (30-50 mbar) to form a sustained-release layer. The coated microparticles are centrifuged (3000 rpm, 5 minutes) to remove excess polymer solution and dried in a freeze dryer for 24 hours to remove residual solvent.

[0099] In step S5, nHA nanoparticles are dispersed in deionized water and treated with an ultrasonic cell disruptor at a power of 400-600 W for 30 minutes to ensure uniform dispersion of nHA. Subsequently, the sustained-release polymer-coated microparticles prepared in step S4 are added to the nHA suspension and stirred at room temperature for 2 hours using a mechanical stirrer (500 rpm) to promote electrostatic adsorption and physical adsorption of nHA to the microparticle surface, thereby integrating it onto the microparticle surface.

[0100] In step S6, a magnetic stirrer is used to stir at a low speed for 4-6 hours at a pH value of 6.0-7.0 and a temperature of 37° C. to promote the cross-linking reaction between the cross-linking agent and the functional groups on the surface of the particles. During the cross-linking process, the cross-linking efficiency is optimized by adjusting the pH and temperature, and the morphological changes of the particles are observed under a microscope to confirm the cross-linking effect.

[0101] In step S7, the cross-linked microparticles in step S6 are placed in a fluidized bed using fluidized bed coating technology, and the CAP solution is sprayed at a constant flow rate (5-10 mL / min), while maintaining the inlet air temperature at 30-40° C. and the outlet air temperature at 25-35° C. During the coating process, the microparticles are evenly coated with the enteric material in a fluidized state to form the final enteric coating.

[0102] In step S8, probiotics (such as freeze-dried powder) are added to the mixture in an amount of 100 million to 500 million CFU per capsule. Next, natural flavors (such as peppermint oil) are added to the mixture at a ratio of 0.05% to 0.2% (w / v) to improve the taste of the capsules. Finally, a tracer (such as fluorescein sodium salt) is added to the mixture at a ratio of 0.01% to 0.05% (w / v) to facilitate subsequent drug tracking and release studies. After all additives are mixed evenly, they are evenly sprayed or mixed onto the enteric coated particles prepared in step S7.

[0103] From the above, it can be seen that in the present invention, by adopting multiple controlled release mechanisms such as temperature-sensitive polymers, pH-sensitive polymers and sustained-release polymers, it is possible to achieve targeted release of drugs in the intestine, thereby significantly improving the bioavailability and therapeutic effect of the drugs. This intelligent release system can adjust the drug release rate according to slight changes in the body environment, reduce the release of drugs in non-target areas, reduce side effects, and improve the safety and comfort of patients.

[0104] In the present invention, nano-hydroxyapatite (nHA) and enzyme-sensitive cross-linking agents can enhance the mechanical strength and stability of the drug preparation, while further controlling the drug release through enzyme-sensitive degradation. This design not only ensures the stability of the drug during storage and transportation, but also enables precise release of the drug under the action of specific enzymes in the body, meeting the needs of personalized treatment and providing patients with a more accurate drug treatment plan.

[0105] In the present invention, the addition of color and taste modifiers, probiotics and natural flavors not only improves the taste of the preparation and the patient's compliance, but also the addition of probiotics helps maintain intestinal health and enhance the body's immune capacity. In addition, the use of tracers allows the behavior and release path of drugs in the body to be monitored in real time, providing valuable data support for the development and application of drugs, and further promoting the optimization and innovation of drug preparations.

[0106] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the term "comprise" or any other variant thereof is intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In the absence of further restrictions, the elements defined by the sentence "comprise a ..." do not exclude the existence of other identical elements in the process, method, article or device including the elements.

[0107] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. An oral controlled-release pharmaceutical preparation, characterized in that: include: 50-80 parts by weight of active pharmaceutical ingredient microparticles, 10-20 parts by weight of temperature-sensitive polymer, 5-10 parts by weight of pH-sensitive polymer, 15-20 parts by weight of sustained-release polymer, 5-10 parts by weight of nano-hydroxyapatite, 2-5 parts by weight of enzyme-sensitive cross-linking agent, 10-15 parts by weight of enteric material, 2-5 parts by weight of color and taste modifier, 2-5 parts by weight of probiotics, 2-5 parts by weight of natural flavor and 1-5 parts by weight of tracking agent; The temperature sensitive polymer is one of polyethylene oxide-polyacrylic acid copolymer or polyethylene glycol-polylactic acid copolymer; The pH sensitive polymer is one of polyacrylic acid, chitosan or polymethyl methacrylate; The sustained-release polymer is one of polylactic acid-co-glycolic acid, polylactic acid or polycaprolactam; The nano-hydroxyapatite is one of pure nano-hydroxyapatite, surface-modified nano-hydroxyapatite or nano-hydroxyapatite composite material; The enzyme sensitive cross-linking agent is one of a glucose oxidase cross-linked polymer, a lipase cross-linked polymer or a protease cross-linked polymer; The enteric material is one of hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate or acrylic resin Eudragit L100; The color and taste modifier is one of a food coloring, a natural flavoring, or a food coloring; The probiotic is one of Bifidobacterium lactis, Lactobacillus acidophilus or Lactobacillus rhamnosus; The natural flavor is one of peppermint oil, lemon oil or orange oil; The tracer is one of edible blue pigment, fluorescent marker or quantum dots.

2. The method for producing an oral controlled-release pharmaceutical preparation according to claim 1, characterized in that: The manufacturing method comprises the following steps: S1: Dissolve the API in an appropriate solvent and prepare it into microcapsules or microparticles by emulsification solvent diffusion method or spray drying technology; use supercritical fluid technology or mechanical grinding method to further refine the API particles to ensure that they have uniform particle size; S2: dissolving the temperature-sensitive polymer in a suitable solvent to form a solution; mixing the API microparticles with the temperature-sensitive polymer solution to form composite microparticles by spray drying or freeze drying technology; S3: dissolving the pH-sensitive polymer in a buffer solution and adjusting the pH value to adapt to the intestinal environment; adding the temperature-sensitive polymer composite microparticles to the pH-sensitive polymer solution and coating them by dropwise addition or spin coating technology; S4: dissolving the sustained-release polymer in an organic solvent to prepare a coating solution; immersing the microparticles coated with the pH-sensitive polymer in the sustained-release polymer solution, and then centrifuging or drying to form a sustained-release layer; S5: Disperse nHA nanoparticles in water and ensure uniform dispersion by ultrasonic treatment; mix the sustained-release polymer-coated microparticles with the nHA suspension and attach nHA to the surface of the microparticles by mechanical stirring or electrostatic adsorption technology; S6: adding an enzyme-sensitive cross-linking agent to a suspension containing microparticles; under appropriate conditions, allowing the cross-linking agent to undergo a cross-linking reaction with functional groups on the surface of the microparticles to enhance the stability of the microparticles; S7: dissolving the enteric material in a suitable solvent to form a coating solution; using a fluidized bed coating technique, uniformly coating the enteric material solution on the cross-linked particles to form a final enteric coating; S8: Mix the color and taste modifiers into the filling of the capsule; add the probiotics and natural flavors into the filling in a certain proportion; finally, add an appropriate amount of tracking agent to ensure that the preparation can be tracked throughout the preparation process; load the mixed filling into the capsule to complete the preparation of the oral controlled-release drug preparation.

3. The method for producing an oral controlled-release pharmaceutical preparation according to claim 2, characterized in that: In the step S1, the active pharmaceutical ingredient particles are dissolved in a non-aqueous solvent, dimethylformamide (DMF), to ensure that the concentration of the API is 10% to 20%; then, the API solution is slowly added dropwise to the aqueous phase containing the emulsifier by an emulsified solvent diffusion method, while stirring to form a primary emulsion; The emulsion is transferred to a high-pressure homogenizer and homogenized at a pressure of 100-200 MPa to obtain uniform API particles; thereafter, the solvent is removed by rotary evaporation to obtain dry API particles; the particle size of the particles is detected by a particle size analyzer, and the target particle size is 1-5 microns.

4. The method for producing an oral controlled-release pharmaceutical preparation according to claim 2, characterized in that: In the step S2, the temperature-sensitive polymer PNIPAm is dissolved in ethyl acetate at a concentration of 5% to 10% (w / v) to form a transparent solution; then the API particles prepared in step S1 are added to the PNIPAm solution, and a magnetic stirrer is used to stir at a low speed to ensure uniform mixing; The mixture is then dried in a spray dryer at an inlet temperature of 40-50°C and an outlet temperature of 25-30°C to form temperature-sensitive API composite microparticles; The air inlet velocity and air outlet velocity during the spray drying process were set to 0.8-1.2 m / s and 1.5-2.0 m / s, respectively.

5. The method for producing an oral controlled-release pharmaceutical preparation according to claim 2, characterized in that: In the step S3, the pH-sensitive polymer PAA is dissolved in a phosphate buffer at a concentration of 2% to 5% (w / v), and the pH is adjusted to 6.8-7.4 to simulate the intestinal environment; then, the temperature-sensitive polymer composite microparticles prepared in step S2 are added to the PAA solution, and are dripped at a constant rate using a peristaltic pump while stirring at a low speed using a magnetic stirrer; a spin coating technique is used to coat the microparticles at a rotation of 100-200 rpm, and then dried at room temperature overnight to form composite microparticles with pH responsiveness.

6. The method for producing an oral controlled-release pharmaceutical preparation according to claim 2, characterized in that: In step S4, the pH-sensitive polymer-coated microparticles prepared in step S3 are immersed in a PLGA solution and coated using a vacuum rotary evaporator under mild reduced pressure conditions of 30-50 mbar to form a sustained-release layer; the coated microparticles are centrifuged at 3000 rpm for 5 minutes to remove excess polymer solution, and are dried in a freeze dryer for 24 hours to remove residual solvent.

7. The method for producing an oral controlled-release pharmaceutical preparation according to claim 2, characterized in that: In the step S5, the nHA nanoparticles are dispersed in deionized water and treated with an ultrasonic cell disruptor at a power of 400-600 W for 30 minutes to ensure uniform dispersion of the nHA; Subsequently, the sustained-release polymer-coated microparticles prepared in step S4 were added to the nHA suspension and stirred at room temperature for 2 hours using a mechanical stirrer (500 rpm) to promote electrostatic adsorption and physical adsorption of nHA to the surface of the microparticles, thereby integrating nHA onto the surface of the microparticles.

8. The method for producing an oral controlled-release pharmaceutical preparation according to claim 2, characterized in that: In the step S6, under the conditions of pH 6.0-7.0 and temperature 37° C., a magnetic stirrer is used to stir at a low speed for 4-6 hours to promote the cross-linking reaction between the cross-linking agent and the functional groups on the surface of the particles; During the cross-linking process, the pH and temperature were adjusted to optimize the cross-linking efficiency, and the changes in the particle morphology were observed under a microscope to confirm the cross-linking effect.

9. The method for producing an oral controlled-release pharmaceutical preparation according to claim 2, characterized in that: In the step S7, a fluidized bed coating technique is used to place the cross-linked microparticles in the step S6 in a fluidized bed, and the CAP solution is sprayed at a constant flow rate of 5-10 mL / min, while maintaining the inlet air temperature at 30-40° C. and the outlet air temperature at 25-35° C. During the coating process, the microparticles are uniformly coated with the enteric material in a fluidized state to form a final enteric coating.

10. The method for producing an oral controlled-release pharmaceutical preparation according to claim 2, characterized in that: In step S8, probiotics are added to the mixture in an amount of 100 million to 500 million CFU per capsule; then, natural flavors are added to the mixture at a ratio of 0.05% to 0.2% to improve the taste of the capsules; finally, tracers are added to the mixture at a ratio of 0.01% to 0.05% to facilitate subsequent drug tracking and release studies; after all additives are evenly mixed, they are evenly sprayed or mixed onto the enteric coated particles prepared in step S7.

Images