One-step preparation method of chitosan-coated calcium phosphate drug controlled release carrier material

Abstract

The invention belongs to the technical field of biomedical material preparation, and particularly relates to a one-step preparation method of a chitosan coated calcium phosphate drug controlled release carrier material. Two kinds of PS microsphere primary pulp emulsions with uniform particle sizes from micron-scale particle size to nano-scale particle size are prepared through a one-step emulsion polymerization method, and the two kinds of PS microsphere primary pulp emulsions are directly self-assembled into binary PS colloidal crystals with controllable morphology without subsequent treatment; the particle sizes of the two kinds of PS microspheres are regulated and controlled by controlling the adding amount, the dripping rate, the adding time and the reaction time of KPS; regulating and controlling the proportion of the PS microspheres with two different particle sizes by regulating the mass ratio of the styrene monomer which is added again to the PS microspheres in the primary pulp emulsion; the preparation method comprises the following steps: mixing a calcium phosphate precursor with binary PS colloidal crystals, dipping, carrying out suction filtration, and calcining to obtain a graded ordered porous calcium phosphate material with controllable morphology, thereby obtaining the CS-coated calcium phosphate drug controlled release carrier material. The material can more accurately realize the controllable release of the medicine, effectively treat diseases and reduce the toxic and side effects of the medicine at the same time.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedical material preparation, and particularly relates to a one-step preparation method of a chitosan-coated calcium phosphate drug controlled-release carrier material. Background Art

[0002] Orthopedic surgery is a complex and delicate treatment method. Although it plays a vital role in restoring the patient's bone structure and function, the possible complications after surgery are still a problem that cannot be ignored. Among them, complications caused by bacterial infection are particularly serious. It may not only delay the patient's recovery process, but may even threaten the patient's life safety. In order to effectively prevent such infections and relieve the pain caused by surgery, antibiotics and non-steroidal anti-inflammatory drugs such as ibuprofen (IBU) are widely used.

[0003] However, traditional IBU administration methods, such as oral administration and direct injection, have many limitations and potential risks. Although oral IBU is convenient, it is often accompanied by serious gastrointestinal side effects, such as nausea, vomiting, abdominal pain, etc., which to a certain extent limits its clinical application. Direct injection into the blood, although it can quickly increase the concentration of the drug in the body, may also increase the risk of serious cardiovascular events, such as thrombosis, arrhythmia, etc., which undoubtedly brings new threats to patients' health.

[0004] More importantly, traditional drug administration may also lead to dramatic fluctuations in blood drug concentrations. After entering the body, the drug will quickly reach a peak concentration and then drop rapidly. This "roller coaster" concentration change not only shortens the effective treatment time of the drug, but may also cause excessive fluctuations in drug concentrations due to frequent administration, causing toxic side effects on blood vessels and further increasing the patient's physical burden.

[0005] In view of the many shortcomings of traditional drug delivery methods, researchers have begun to explore new drug delivery routes. Among them, the degradable implantable drug sustained-release system, as an innovative drug delivery method, has shown great potential and advantages. This system can not only effectively reduce the impact of gastrointestinal metabolism on drugs, but also efficiently load and release drugs, thereby extending the effective treatment time of drugs and reducing toxic side effects. More importantly, by precisely controlling the release rate and duration of drugs, the system is expected to achieve targeted drug delivery for orthopedic anti-inflammatory and analgesic purposes, further improve the treatment effect, and reduce the pain of patients. However, although the degradable implantable drug sustained-release system has broad application prospects in orthopedic surgery, it still faces some technical difficulties and challenges. For example, how to ensure the stable release of drugs in the body, how to avoid adverse reactions between implants and surrounding tissues, and how to reduce production costs are all urgent issues to be solved. Summary of the invention

[0006] The object of the present invention is to provide a one-step preparation method of a chitosan-coated calcium phosphate drug controlled-release carrier material for targeted administration of IBU after orthopedic surgery, thereby achieving the purpose of controlled release of IBU drugs and reducing drug toxicity and side effects.

[0007] In order to achieve the above object, the present invention adopts the following technical solutions: In a first aspect, the present invention provides a one-step preparation method of a chitosan-coated calcium phosphate drug controlled-release carrier material, which specifically comprises the following steps: S1: mixing styrene monomer, potassium bicarbonate and sodium p-styrene sulfonate to form a first mixed solution, placing it in a constant temperature water bath, and passing N2 for deoxygenation under continuous stirring; S2: dissolving 1%-3% of KPS by mass in water to form a KPS solution, and adding all of the KPS solution dropwise into the first mixed solution for 15-60 min; reacting in a constant temperature water bath for 7-10 h to form a stock emulsion; S3: taking out a portion of the stock emulsion, measuring the mass ratio of the PS microspheres in the portion of the stock emulsion, and obtaining the mass ratio of the PS microspheres in the stock emulsion, thereby obtaining the mass of the PS microspheres in the stock emulsion; adding styrene monomer to the stock emulsion to form a second mixed solution, placing it in a constant temperature water bath, and passing N2 for deoxygenation under continuous stirring; wherein the mass ratio of the styrene monomer to the PS microspheres in the stock emulsion in S3 is (5-2):1; S4: dissolving 1%-3% of the mass percentage of KPS in the styrene monomer described in S3 in water again to form a KPS solution, and dropping all of the KPS solution into the second mixed solution for 30-90 minutes; after reacting in a constant temperature water bath, pouring the solution into a crystallization dish, and obtaining binary PS colloidal crystals with controllable morphology after ultrasonic dispersion and drying; S5: mixing and stirring the calcium salt and the phosphate to obtain a calcium phosphate precursor; S6: The calcium phosphate precursor and the binary PS colloidal crystal are mixed in a mass ratio of (15-10):1, and a hierarchical ordered porous calcium phosphate material with controllable morphology is obtained after impregnation, filtration and calcination; S7: immersing the hierarchical ordered porous calcium phosphate material in an acetic acid solution of CS for 0.5 to 2 h, and drying to obtain CS-coated hierarchical ordered porous calcium phosphate drug controlled release carrier materials with different morphologies; Wherein, the concentration of the CS acetic acid solution is 0.5%-2% (w / v).

[0008] Preferably, the styrene monomer is extracted with NaOH and water respectively before use.

[0009] Preferably, the mass of potassium bicarbonate in S1 is 1.92% of the styrene monomer in S1; the mass of sodium p-styrene sulfonate in S1 is 0.13% of the styrene monomer in S1.

[0010] Preferably, the temperature of the constant temperature water bath is 70-80°C.

[0011] Preferably, the preparation method of the acetic acid solution of CS is: mixing the acetic acid solution and CS to obtain the acetic acid solution of CS; wherein the solubility of the acetic acid solution is 1%; the deacetylation of the CS is ≥90%; and the molecular weight of the CS is 700,000-800,000.

[0012] Preferably, the constant temperature water bath reaction time in S4 is 16 to 20 hours.

[0013] Preferably, the molar ratio of the calcium salt to the phosphate in S5 is (150-167):100.

[0014] Preferably, the calcination conditions in S6 are: calcination at 600-750° C., with a heating rate of 1-1.5° C. / min.

[0015] In a second aspect, the present invention provides a CS-coated calcium phosphate drug controlled-release carrier material, which is prepared by the preparation method described in the claims above.

[0016] In a third aspect, the present invention provides an application of a CS-coated calcium phosphate drug controlled-release carrier material in the field of biomedical materials.

[0017] Compared with the prior art, the present invention has the following beneficial effects: In the design of material components, the present invention coats CS on the surface of calcium phosphate. Compared with a single drug sustained-release carrier, calcium phosphate has good biocompatibility and biodegradability. The surface of CS contains a large number of functional groups such as hydroxyl, amino and N-acetylamino, which makes it have better adsorption effect on IBU drug molecules. The surface coating modification of CS makes the material have better biocompatibility, biodegradability, higher IBU loading performance and certain antibacterial properties; the one-step polymerization method of the present invention controls the particle size of the two PS microspheres by controlling the addition amount, drop rate, addition time and reaction time of KPS; the ratio of the two PS microspheres with different particle sizes is regulated by adjusting the mass ratio of the secondary added styrene monomer and the PS microspheres in the original emulsion, and two PS microsphere original emulsions with uniform particle sizes of micrometer-scale to nanometer-scale particle grading are obtained. The emulsion does not need subsequent treatment, and directly self-assembles to obtain binary PS colloidal crystals with controllable morphology. Using this as a template, the obtained hierarchical ordered porous structure has the advantages of more flexible pore size matching, higher porosity, larger specific surface area, etc., which enables it to achieve more accurate controlled release of drugs compared with nano drug sustained-release carrier materials and porous drug sustained-release carrier materials with a single pore size, effectively treat diseases while reducing the toxic and side effects of drugs; the preparation process of the method of the present invention is simple, repeatable and has low production cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments are briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without creative work.

[0019] Figure 1 These are the SEM and EDS images of the CS-coated hierarchical ordered porous calcium phosphate drug controlled-release carrier material prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0020] In order to enable those skilled in the art to understand the characteristics and effects of the present invention, the following is a general description and definition of the terms and expressions mentioned in the specification and claims. Unless otherwise specified, all technical and scientific terms used in the text are the common meanings understood by those skilled in the art for the present invention. In the event of a conflict, the definition in this specification shall prevail.

[0021] The theories or mechanisms described and disclosed herein, whether correct or incorrect, should not limit the scope of the present invention in any way, that is, the present invention can be implemented without being limited by any specific theory or mechanism.

[0022] In this article, all features such as values, quantities, contents and concentrations defined in the form of numerical ranges or percentage ranges are for simplicity and convenience only. Accordingly, the description of numerical ranges or percentage ranges should be considered to have included and specifically disclosed all possible sub-ranges and individual values ​​within the range (including integers and fractions).

[0023] In this document, unless otherwise specified, “includes,” “including,” “contains,” “has,” or similar terms cover the meanings of “consisting of” and “mainly consisting of,” for example, “A includes a” covers the meanings of “A includes a and other” and “A only includes a.”

[0024] In this document, in order to make the description concise, not all possible combinations of various technical features in various embodiments or examples are described. Therefore, as long as there is no contradiction in the combination of these technical features, the various technical features in various embodiments or examples can be combined arbitrarily, and all possible combinations should be considered to be within the scope of this specification.

[0025] Calcium phosphate is a ceramic material with good biocompatibility and biodegradability. It is often used as a bone transplant substitute. It has good dispersibility under physiological conditions, is easy to reach the treatment site, and has little toxicity and side effects. It is an ideal sustained-release carrier material for orthopedic drugs. Chitosan (CS), as a natural polymer material, has excellent biocompatibility, bioactivity, biodegradability and antibacterial properties. It is the only positive polysaccharide discovered so far. Its surface contains a large number of hydroxyl groups, amino groups and N-acetylamino groups, which make it have good adsorption effects on a variety of drug molecules. The present invention aims to give full play to the advantages of both and prepare a CS-coated hierarchical ordered porous calcium phosphate-degradable implantable drug controlled release carrier material with controllable pore size.

[0026] The first object of the present invention is to provide a one-step preparation method of a chitosan-coated calcium phosphate drug controlled-release carrier material, which specifically comprises the following steps: S1: Styrene monomer, potassium bicarbonate and sodium p-styrene sulfonate are mixed to form a first mixed solution, and the solution is placed in a constant temperature water bath to maintain the water bath temperature at 70-80° C., and N2 is introduced for deoxygenation under continuous stirring; wherein the mass of the potassium bicarbonate is 1.92% of the styrene monomer described in S1; and the mass of the sodium p-styrene sulfonate described in S1 is 0.13% of the styrene monomer described in S1.

[0027] S2: Dissolve 1%-3% of potassium persulfate (KPS) by mass in hot water at 70-80°C (the temperature of the hot water is consistent with the water bath temperature in S1) to form a KPS solution, and drip all of the KPS solution into the first mixed solution for 15-60 minutes; keep the water bath temperature at 70-80°C, and stop the reaction in a constant temperature water bath after 7-10 hours to form a stock emulsion, and the stock emulsion contains unreacted styrene monomer, potassium bicarbonate, sodium p-styrene sulfonate and KPS, etc.; S3: taking out a portion of the stock emulsion, measuring the mass ratio of polystyrene (PS) microspheres in the portion of the stock emulsion, and obtaining the mass ratio of PS microspheres in the stock emulsion, thereby obtaining the mass of PS microspheres in the stock emulsion; adding styrene monomer to the stock emulsion to form a second mixed solution, maintaining the water bath temperature at 70-80°C, performing a constant temperature water bath, and passing N2 for deoxygenation under continuous stirring; wherein the mass ratio of styrene monomer to PS microspheres in the stock emulsion in S3 is (5-2):1; S4: Dissolve 1%-3% of KPS by mass in hot water at 70-80°C (the temperature of the hot water is consistent with the water bath temperature in S3) to form a KPS solution, and add all of the KPS solution dropwise into the second mixed solution for 30-90 minutes; react in a constant temperature water bath for 16-20 hours, pour into a Φ6 cm crystallization dish, and obtain binary PS colloidal crystals with controllable morphology after ultrasonic dispersion and drying; S5: mixing and stirring the calcium salt and the phosphate in a molar ratio of (150-167):100 to obtain a calcium phosphate precursor; S6: The calcium phosphate precursor and the binary PS colloidal crystal are mixed in a mass ratio of (15-10):1, and a hierarchical ordered porous calcium phosphate material with controllable morphology is obtained after impregnation, filtration and calcination; S7: immersing the hierarchical ordered porous calcium phosphate material in an acetic acid solution of CS for 0.5 to 2 h, and drying to obtain CS-coated hierarchical ordered porous calcium phosphate drug controlled release carrier materials of different morphologies; Wherein, the concentration of the CS acetic acid solution is 0.5%-2% (w / v).

[0028] The styrene monomer is extracted by NaOH and water respectively before use; the preparation method of the acetic acid solution of CS is: mixing the acetic acid solution and CS to obtain the acetic acid solution of CS; wherein the solubility of the acetic acid solution is 1%; the deacetylation of the CS is ≥90%; and the molecular weight of the CS is 700,000-800,000.

[0029] The present invention uses KPS as an initiator, potassium bicarbonate as a pH regulator, and sodium p-styrene sulfonate as an emulsifier, and adopts a one-step polymerization method to prepare two kinds of PS microsphere stock emulsions with uniform particle sizes from micron-level to nanometer-level particle grading. The stock emulsion does not need subsequent treatment and directly self-assembles into binary PS colloidal crystals with controllable morphology. In the process, the particle sizes of the two PS microspheres are regulated by controlling the addition amount, drop rate, addition timing and reaction time of KPS. The ratio of the two PS microspheres with different particle sizes is regulated by adjusting the mass ratio of the styrene monomer added again in S3 to the PS microspheres in the stock emulsion. After mixing the calcium phosphate precursor and the binary PS colloidal crystals in a certain mass ratio, impregnating, filtering and calcining, a hierarchical ordered porous calcium phosphate material with controllable morphology of micron-level and submicron-level, submicron-level and nanometer-level pore sizes prepared by a one-step method is obtained. The material is immersed in a 0.5% to 2% (w / v) CS acetic acid solution for 0.5 to 2 hours and then dried to obtain a morphology-controllable CS-coated hierarchical ordered porous calcium phosphate-degradable implantable drug controlled release carrier material. The preparation process of the invention is simple, repeatable and low in production cost.

[0030] The second object of the present invention is to provide a chitosan-coated calcium phosphate drug controlled release carrier material, which is a hierarchical ordered porous structure calcium phosphate material with different pore sizes from micrometer to nanometer, and a layer of CS coating is coated on the surface of calcium phosphate. In terms of the design of the composition of the material, CS is coated on the surface of calcium phosphate. Compared with a single inorganic drug sustained-release carrier, the surface of CS contains a large number of functional groups such as hydroxyl, amino and N-acetylamino, so that it has a better adsorption effect on IBU drug molecules. At the same time, the surface coating modification of CS makes the material have better biocompatibility, biodegradability, higher IBU loading performance and certain antibacterial properties.

[0031] The third purpose of the present invention is to provide a chitosan-coated calcium phosphate drug controlled-release carrier material for use in the field of biomedical materials, mainly used for targeted delivery of IBU, an anti-inflammatory and analgesic drug after orthopedic surgery. The material can significantly increase the drug loading capacity of IBU, reduce drug burst release and achieve controlled drug release.

[0032] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms fall within the scope limited by the appended claims of the application equally.

[0033] The following examples use conventional instruments and equipment in the art. The experimental methods in the following examples that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. The various raw materials used in the following examples, unless otherwise specified, are conventional commercially available products, and their specifications are conventional specifications in the art. In the specification of the present invention and the following examples, unless otherwise specified, "%" means weight percentage, "part" means weight part, and ratio means weight ratio.

[0034] Example 1 S1: Styrene monomer, potassium bicarbonate and sodium p-styrene sulfonate are mixed to form a first mixed solution, which is placed in a constant temperature water bath, the water bath temperature is maintained at 70° C., and N2 is passed through under continuous stirring for deoxygenation; wherein the mass of potassium bicarbonate is 1.92% of the styrene monomer in S1; and the mass of sodium p-styrene sulfonate in S1 is 0.13% of the styrene monomer in S1.

[0035] S2: dissolving KPS accounting for 1% of the mass percentage of the styrene monomer in S1 in hot water at 70°C to form a KPS solution, and dripping all of the KPS solution into the first mixed solution for 15 minutes; maintaining the water bath temperature at 70°C, and stopping the reaction in a constant temperature water bath after 7 hours to form a stock emulsion, and the stock emulsion contains unreacted styrene monomer, potassium bicarbonate, sodium p-styrene sulfonate and KPS, etc.; S3: taking out part of the stock emulsion, measuring the mass ratio of the PS microspheres in part of the stock emulsion, and obtaining the mass ratio of the PS microspheres in the stock emulsion, thereby obtaining the mass of the PS microspheres in the stock emulsion; adding styrene monomer to the stock emulsion to form a second mixed solution, maintaining the water bath temperature at 70°C, performing a constant temperature water bath, and passing N2 for deoxygenation under continuous stirring; wherein, the mass ratio of styrene monomer to PS microspheres in the stock emulsion in S3 is 2:1; S4: Dissolve 1% KPS by mass of the styrene monomer in S3 in hot water at 70°C to form a KPS solution, and drip all of the KPS solution into the second mixed solution for 30 minutes; react in a constant temperature water bath for 16 hours, pour into a Φ6 cm crystallization dish, and obtain binary PS colloidal crystals with controllable morphology after ultrasonic dispersion and drying; S5: mixing calcium salt and phosphate in a molar ratio of 3:2 and stirring to obtain a calcium phosphate precursor; S6: The calcium phosphate precursor and the binary PS colloidal crystals are mixed in a mass ratio of 10:1, and after impregnation and filtration, they are calcined at 600°C with a heating rate of 1°C / min to obtain a hierarchically ordered porous calcium phosphate material with controllable morphology; S7: mixing the acetic acid solution and CS to obtain an acetic acid solution of CS; wherein the solubility of the acetic acid solution is 1%; the deacetylation of CS is ≥ 90%; and the molecular weight of CS is 700,000; The hierarchical ordered porous calcium phosphate material was immersed in CS acetic acid solution for 0.5 h, and after drying, CS-coated hierarchical ordered porous calcium phosphate drug controlled release carrier materials with different morphologies were obtained; the concentration of CS acetic acid solution was 0.5% (w / v).

[0036] Wherein, styrene monomer was extracted by NaOH and water respectively before use.

[0037] Example 2 S1: Styrene monomer, potassium bicarbonate and sodium p-styrene sulfonate are mixed to form a first mixed solution, which is placed in a constant temperature water bath, the water bath temperature is maintained at 73° C., and N2 is introduced for deoxygenation under continuous stirring; wherein the mass of potassium bicarbonate is 1.92% of the styrene monomer in S1; and the mass of sodium p-styrene sulfonate in S1 is 0.13% of the styrene monomer in S1.

[0038] S2: dissolving KPS accounting for 1.5% of the mass percentage of styrene monomer in S1 in hot water at 73°C to form a KPS solution, and dripping all the KPS solution into the first mixed solution for 30 minutes; keeping the water bath temperature at 73°C, and stopping the reaction in a constant temperature water bath after 8 hours to form a stock emulsion, and the stock emulsion contains unreacted styrene monomer, potassium bicarbonate, sodium p-styrene sulfonate and KPS; S3: taking out part of the stock emulsion, measuring the mass ratio of the PS microspheres in part of the stock emulsion, and obtaining the mass ratio of the PS microspheres in the stock emulsion, thereby obtaining the mass of the PS microspheres in the stock emulsion; adding styrene monomer to the stock emulsion to form a second mixed solution, maintaining the water bath temperature at 73°C, performing a constant temperature water bath, and passing N2 for deoxygenation under continuous stirring; wherein, the mass ratio of styrene monomer to PS microspheres in the stock emulsion in S3 is 3:1; S4: Dissolve KPS accounting for 1.5% of the mass percentage of styrene monomer in S3 in hot water at 73°C to form a KPS solution, and add all the KPS solution dropwise into the second mixed solution for 45 minutes; after reacting in a constant temperature water bath for 18 hours, pour into a Φ6 cm crystallization dish, and obtain binary PS colloidal crystals with controllable morphology after ultrasonic dispersion and drying; S5: mixing and stirring the calcium salt and the phosphate in a molar ratio of 31:20 to obtain a calcium phosphate precursor; S6: The calcium phosphate precursor and the binary PS colloidal crystals were mixed in a mass ratio of 12:1, and after impregnation and filtration, they were calcined at 650°C with a heating rate of 1.2°C / min to obtain a hierarchical ordered porous calcium phosphate material with controllable morphology; S7: Mix the acetic acid solution and CS to obtain an acetic acid solution of CS; wherein the solubility of the acetic acid solution is 1%; the deacetylation of CS is ≥90%; the molecular weight of CS is 730,000; immerse the hierarchical ordered porous calcium phosphate material in the acetic acid solution of CS for 1 hour, and after drying, obtain CS-coated hierarchical ordered porous calcium phosphate drug controlled release carrier materials with different morphologies; the concentration of the acetic acid solution of CS is 1% (w / v).

[0039] Wherein, styrene monomer was extracted by NaOH and water respectively before use.

[0040] Example 3 S1: Styrene monomer, potassium bicarbonate and sodium p-styrene sulfonate are mixed to form a first mixed solution, which is placed in a constant temperature water bath, the water bath temperature is maintained at 75° C., and N2 is introduced for deoxygenation under continuous stirring; wherein the mass of potassium bicarbonate is 1.92% of the styrene monomer in S1; and the mass of sodium p-styrene sulfonate in S1 is 0.13% of the styrene monomer in S1.

[0041] S2: dissolving KPS accounting for 2% of the mass percentage of the styrene monomer in S1 in hot water at 75°C to form a KPS solution, and dripping all of the KPS solution into the first mixed solution for 45 minutes; maintaining the water bath temperature at 75°C, and stopping the reaction in a constant temperature water bath after 9 hours to form a stock emulsion, and the stock emulsion contains unreacted styrene monomer, potassium bicarbonate, sodium p-styrene sulfonate and KPS, etc.; S3: taking out part of the stock emulsion, measuring the mass ratio of the PS microspheres in part of the stock emulsion, and obtaining the mass ratio of the PS microspheres in the stock emulsion, thereby obtaining the mass of the PS microspheres in the stock emulsion; adding styrene monomer to the stock emulsion to form a second mixed solution, maintaining the water bath temperature at 75°C, performing a constant temperature water bath, and passing N2 for deoxygenation under continuous stirring; wherein, the mass ratio of styrene monomer to PS microspheres in the stock emulsion in S3 is 4:1; S4: Dissolve KPS accounting for 2% of the mass percentage of styrene monomer in S3 in hot water at 75°C to form a KPS solution, and add all the KPS solution dropwise into the second mixed solution for 60 minutes; after reacting in a constant temperature water bath for 19 hours, pour into a Φ6 cm crystallization dish, and obtain binary PS colloidal crystals with controllable morphology after ultrasonic dispersion and drying; S5: mixing the calcium salt and the phosphate in a molar ratio of 8:5 and stirring to obtain a calcium phosphate precursor; S6: The calcium phosphate precursor and the binary PS colloidal crystals were mixed in a mass ratio of 13:1, and after impregnation and filtration, they were calcined at 700°C with a heating rate of 1.4°C / min to obtain a hierarchical ordered porous calcium phosphate material with controllable morphology; S7: Mix the acetic acid solution and CS to obtain an acetic acid solution of CS; wherein the solubility of the acetic acid solution is 1%; the deacetylation of CS is ≥90%; the molecular weight of CS is 750,000; immerse the hierarchical ordered porous calcium phosphate material in the acetic acid solution of CS for 1.5 h, and obtain CS-coated hierarchical ordered porous calcium phosphate drug controlled release carrier materials of different morphologies after drying; the concentration of the acetic acid solution of CS is 1.5% (w / v).

[0042] Wherein, styrene monomer was extracted by NaOH and water respectively before use.

[0043] Example 4 S1: Styrene monomer, potassium bicarbonate and sodium p-styrene sulfonate are mixed to form a first mixed solution, which is placed in a constant temperature water bath, the water bath temperature is maintained at 80° C., and N2 is introduced for deoxygenation under continuous stirring; wherein the mass of potassium bicarbonate is 1.92% of the styrene monomer in S1; and the mass of sodium p-styrene sulfonate in S1 is 0.13% of the styrene monomer in S1.

[0044] S2: dissolving KPS accounting for 3% of the mass percentage of the styrene monomer in S1 in hot water at 80°C to form a KPS solution, and dripping all of the KPS solution into the first mixed solution for 60 minutes; keeping the water bath temperature at 80°C, and stopping the reaction in a constant temperature water bath after 10 hours to form a stock emulsion, and the stock emulsion contains unreacted styrene monomer, potassium bicarbonate, sodium p-styrene sulfonate and KPS; S3: taking out part of the stock emulsion, measuring the mass ratio of the PS microspheres in part of the stock emulsion, and obtaining the mass ratio of the PS microspheres in the stock emulsion, thereby obtaining the mass of the PS microspheres in the stock emulsion; adding styrene monomer to the stock emulsion to form a second mixed solution, maintaining the water bath temperature at 80°C, performing a constant temperature water bath, and passing N2 for deoxygenation under continuous stirring; wherein, the mass ratio of styrene monomer to PS microspheres in the stock emulsion in S3 is 5:1; S4: Dissolve KPS accounting for 3% of the mass percentage of styrene monomer in S3 in hot water at 80°C to form a KPS solution, and add all the KPS solution dropwise into the second mixed solution for 90 minutes; after reacting in a constant temperature water bath for 20 hours, pour into a Φ6 cm crystallization dish, and obtain binary PS colloidal crystals with controllable morphology after ultrasonic dispersion and drying; S5: mixing and stirring a calcium salt and a phosphate in a molar ratio of 167:100 to obtain a calcium phosphate precursor; S6: The calcium phosphate precursor and the binary PS colloidal crystals are mixed in a mass ratio of 15:1, and after impregnation and filtration, they are calcined at 750°C with a heating rate of 1.5°C / min to obtain a hierarchically ordered porous calcium phosphate material with controllable morphology; S7: Mix the acetic acid solution and CS to obtain an acetic acid solution of CS; wherein the solubility of the acetic acid solution is 1%; the deacetylation of CS is ≥90%; the molecular weight of CS is 800,000; immerse the hierarchical ordered porous calcium phosphate material in the acetic acid solution of CS for 2 hours, and obtain CS-coated hierarchical ordered porous calcium phosphate drug controlled release carrier materials with different morphologies after drying; the concentration of the acetic acid solution of CS is 2% (w / v).

[0045] Wherein, styrene monomer was extracted by NaOH and water respectively before use.

[0046] like Figure 1 As shown, a is the SEM image of the CS-coated hierarchical ordered porous calcium phosphate drug controlled-release carrier material of different morphologies prepared in Example 1 of the present invention, and b is the EDS image corresponding to the EDS point 1 circled in a. It can be seen that this point contains only C, N, O, P and Ca elements.

[0047] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A one-step preparation method of a chitosan-coated calcium phosphate drug controlled-release carrier material, characterized in that: The specific steps include: S1: mixing styrene monomer, potassium bicarbonate and sodium p-styrene sulfonate to form a first mixed solution, placing it in a constant temperature water bath, and passing N2 for deoxygenation under continuous stirring; S2: dissolving 1%-3% of KPS by mass in water to form a KPS solution, and adding all of the KPS solution dropwise into the first mixed solution for 15-60 min; reacting in a constant temperature water bath for 7-10 h to form a stock emulsion; S3: taking out a portion of the stock emulsion, measuring the mass ratio of the PS microspheres in the portion of the stock emulsion, and obtaining the mass ratio of the PS microspheres in the stock emulsion, thereby obtaining the mass of the PS microspheres in the stock emulsion; adding styrene monomer to the stock emulsion to form a second mixed solution, placing it in a constant temperature water bath, and passing N2 for deoxygenation under continuous stirring; wherein the mass ratio of the styrene monomer to the PS microspheres in the stock emulsion in S3 is (5-2):1; S4: dissolving 1%-3% of the mass percentage of KPS in the styrene monomer described in S3 in water again to form a KPS solution, and dropping all of the KPS solution into the second mixed solution for 30-90 minutes; after reacting in a constant temperature water bath, pouring the solution into a crystallization dish, and obtaining binary PS colloidal crystals with controllable morphology after ultrasonic dispersion and drying; S5: mixing and stirring the calcium salt and the phosphate to obtain a calcium phosphate precursor; S6: The calcium phosphate precursor and the binary PS colloidal crystal are mixed in a mass ratio of (15-10):1, and a hierarchical ordered porous calcium phosphate material with controllable morphology is obtained after impregnation, filtration and calcination; S7: immersing the hierarchical ordered porous calcium phosphate material in an acetic acid solution of CS for 0.5 to 2 h, and drying to obtain CS-coated hierarchical ordered porous calcium phosphate drug controlled release carrier materials with different morphologies; Wherein, the concentration of the CS acetic acid solution is 0.5%-2% (w / v).

2. The one-step preparation method of a chitosan-coated calcium phosphate drug controlled-release carrier material according to claim 1, characterized in that: The styrene monomer was extracted with NaOH and water respectively before use.

3. The one-step preparation method of a chitosan-coated calcium phosphate drug controlled-release carrier material according to claim 1, characterized in that: The mass of potassium bicarbonate described in S1 is 1.92% of the styrene monomer described in S1; the mass of sodium p-styrene sulfonate described in S1 is 0.13% of the styrene monomer described in S1.

4. The one-step preparation method of a chitosan-coated calcium phosphate drug controlled-release carrier material according to claim 1, characterized in that: The temperature of the constant temperature water bath is 70-80°C.

5. The one-step preparation method of a chitosan-coated calcium phosphate drug controlled-release carrier material according to claim 1, characterized in that: The preparation method of CS acetic acid solution is: mixing acetic acid solution and CS to obtain CS acetic acid solution; wherein the solubility of the acetic acid solution is 1%; the deacetylation of the CS is ≥90%; and the molecular weight of the CS is 700,000-800,000.

6. The one-step preparation method of a chitosan-coated calcium phosphate drug controlled-release carrier material according to claim 1, characterized in that: The reaction time in the constant temperature water bath in S4 is 16 to 20 hours.

7. The one-step preparation method of a chitosan-coated calcium phosphate drug controlled-release carrier material according to claim 1, characterized in that: The molar ratio of calcium salt to phosphate in S5 is (150~167):

100.

8. The one-step preparation method of a chitosan-coated calcium phosphate drug controlled-release carrier material according to claim 1, characterized in that: The calcination conditions in S6 are: calcination at 600-750° C., and a heating rate of 1-1.5° C. / min.

9. A chitosan-coated calcium phosphate drug controlled-release carrier material, characterized in that: The method is prepared by the preparation method according to any one of claims 1 to 8.

10. Use of the chitosan-coated calcium phosphate drug controlled-release carrier material according to claim 9 in the field of biomedical materials.

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