Method for preparing modified hydroxyapatite gel drug sustained-release material

Abstract

The invention provides a method for preparing a modified hydroxyapatite gel drug sustained-release material, and belongs to the field of hydroxyapatite application. The preparation method comprises the following steps: firstly, carrying out ball milling on a high-molecular polymer and hydroxyapatite to carry out structure modification on the hydroxyapatite, so as to improve the load rate of the hydroxyapatite on a medicine and improve the wettability of the hydroxyapatite in a PVP (Polyvinyl Pyrrolidone) aqueous solution, thereby preparing a high-stability modified hydroxyapatite dispersion liquid; and then adding PVA (Polyvinyl Alcohol) to obtain the modified hydroxyapatite composite gel drug sustained-release material. PVP and PVA are cross-linked to form a gel system, coating of hydroxyapatite is achieved, the stability of hydroxyapatite in an acid environment is improved, and stable release of drugs is achieved. The technology is simple, efficient, low in comprehensive cost and suitable for industrial production.

Description

Technical Field

[0001] The invention discloses a modified hydroxyapatite composite gel with drug sustained-release function and a preparation method thereof, belonging to the field of hydroxyapatite and drug sustained-release. Background Art

[0002] Hydroxyapatite is a calcium phosphate, its English name is Hydroxyapatite, referred to as HAP, and its chemical composition is Ca 10 (PO4)6(OH)2. The HAP unit cell contains 10 Ca 2+ , 2 OH - , 6 PO4 3- HAP is the most thermally stable calcium phosphate salt. It is slightly soluble in water, easily soluble in acid, and weakly alkaline. HAP is also an important component of human bones and teeth, accounting for 65% in bones, 70% in dentin, and 97% in enamel. HAP is non-toxic, non-irritating and non-immunogenic, and has good biocompatibility and bioactivity, so it is widely used in the field of biomedicine.

[0003] Hydroxyapatite has been widely used in the biomedical field due to its excellent biocompatibility. The nano-hydroxyapatite composites obtained by modification and modification have outstanding performance in bioimaging, drug delivery and tumor treatment. + Will react with OH in hydroxyapatite - The groups react, causing them to dissolve. This causes structural changes, such as lattice distortion or phase transition. These changes may affect its compatibility with biological tissues and its biological activity. The drug release behavior of hydroxyapatite will be changed in an acidic environment. For example, increased solubility may lead to premature release of drugs, thus affecting the therapeutic effect. Although hydroxyapatite can be used as a drug carrier, its drug release kinetics may be difficult to accurately control. As a material with good biological activity and drug carrier, the development of hydroxyapatite in the field of biomedicine is limited by factors such as pH.

[0004] The Chinese patent with application number 202210583429.2, entitled "A method for preparing drug sustained-release microspheres", prepares W / O emulsion by emulsification, which can effectively disperse nHAP inside the dissolved oil phase, then emulsify it with polyvinyl alcohol solution, and then precipitate it into spheres by solvent volatilization. nHAP is compounded in PLGA microspheres, which can effectively buffer the acidic environment during degradation when the PLGA microspheres degrade, thereby reducing the impact on the released protein drugs. The prepared microspheres are used for drug loading and sustained release, and hydroxyapatite is not used as the main drug loading material.

[0005] The Chinese patent with application number 202110670160.7, named "A pH-responsive dual-drug sustained-release particle", achieves control of drug loading and release under different pH environments by modifying mesoporous hydroxyapatite with PDBA. In an acidic environment, PDBA is hydrophilic, the chain segments are stretched, and a large amount of drugs can freely enter the MHA mesopores. In a neutral environment, PDBA is hydrophobic, the chain segments are curled up, and coated on the MHA surface, blocking a large amount of drug leakage, thereby increasing the drug loading rate of MHA and achieving sustained release of drugs in the human body environment (pH=about 7.4). However, the stability of hydroxyapatite in an acidic environment and the sustained release in an acidic environment are not involved.

[0006] The Chinese patent application number is 202011098297.1, entitled "A drug sustained-release hydrogel semi-embedded composite scaffold and its preparation method". A hydroxyapatite three-dimensional scaffold is constructed by 3D printing technology, which is immersed in alendronate sodium drug solution to achieve drug loading, and then a composite hydrogel is prepared based on photoinitiated polymerization. However, the application field of this material cannot guarantee stable drug sustained release in an acidic environment.

[0007] Therefore, there is an urgent need for a modified hydroxyapatite to achieve stable drug release in an acidic environment. Summary of the invention

[0008] In view of this, the object of the present invention is to provide a method for preparing a modified hydroxyapatite gel drug sustained-release material, wherein the method uses hydroxyapatite as the main drug carrier and sustained-release body, firstly modifies the hydroxyapatite to increase the drug loading, improves the stability of the hydroxyapatite in an acidic environment through gel modification, avoids the occurrence of drug burst release, and expands the application environment and field of hydroxyapatite with excellent biocompatibility as a drug carrier. The method has simple preparation process, low cost, good biocompatibility, and is suitable for industrial production.

[0009] In order to achieve the above object, the technical solution of the present invention is as follows: 1) First, hydroxyapatite and polycationic polymer or polyanionic polymer are ball-milled to prepare modified hydroxyapatite material; 2) Using modified hydroxyapatite materials for drug loading; 3) mixing the composite material loaded with the drug with the PVP solution and performing ultrasonic dispersion to obtain a modified hydroxyapatite dispersion; 4) Take an appropriate amount of PVA and heat and stir to dissolve at 90°C to obtain a PVA solution; 5) adding the modified hydroxyapatite dispersion described above into the PVA solution and stirring to obtain a mixed solution; 6) The mixed solution is frozen and thawed three times and then freeze-dried to obtain a gel material.

[0010] The present invention provides a method for preparing a modified hydroxyapatite gel drug sustained-release material, wherein the surface of hydroxyapatite is structurally modified by using polyanionic and cationic polymer materials, so as to increase the adsorption of drugs by hydroxyapatite, increase the drug loading amount, and improve the dispersion stability of hydroxyapatite in water. The hydroxyapatite is dispersed in a PVP aqueous solution by ultrasonic technology, and finally the dispersion is added to a PVA solution and stirred evenly so that the hydroxyapatite is evenly dispersed in the gel. This technology realizes drug sustained release in different environments while increasing the drug loading.

[0011] First, hydroxyapatite and polycationic polymer or polyanionic polymer are ball-milled to prepare modified hydroxyapatite material. In the method of the present invention, the polycationic polymer in step 1) includes one or more of chitosan, carboxymethyl chitosan, gelatin, and polyethyleneimine. The polyanionic polymer includes one or more of sodium alginate, sodium carboxymethyl cellulose, hyaluronic acid, and polyacrylic acid. The polyanion / cationic polymer accounts for 0.1% to 10% by weight, preferably 0.5% to 5%.

[0012] In the method of the present invention, the preparation of hydroxyapatite in step 1) adopts coprecipitation method and sol-gel method. The hydroxyapatite accounts for 0.1% to 10% by weight, preferably 1% to 8%.

[0013] In the method of the present invention, the ball milling beads used in the ball milling technology in step 1) are made of agate, the ball milling time is 0.5-10 h, and the ball milling speed is 100-700 r / min. Preferably, the ball milling time is 2-6 h, and the ball milling speed is 300-600 r / min.

[0014] In the method of the present invention, the drug involved in the drug loading in the composite material in step 2) includes one of ibuprofen, acetylsalicylic acid, curcumin, acetaminophen, vancomycin, and cephalexin.

[0015] In the method of the present invention, the specific steps of step 2) loading the modified hydroxyapatite with the drug are to prepare a 10 mg / mL drug solution (water or ethanol), take 10 mL of the drug solution, put 1 g of the modified hydroxyapatite in a test tube, place it in a constant temperature water bath shaker to test the absorbance of the solution until the absorbance no longer changes, that is, the drug loading reaches saturation. The drug loading amount is determined by the change in the solution absorbance.

[0016] In the method of the present invention, the concentration of the PVP solution used in step 3) is 5% to 20%, preferably 10% to 20%.

[0017] In the method of the present invention, the ultrasonic power of the ultrasonic dispersion in step 3) is 40%W~80%W, and the ultrasonic time is 0.5~10h, preferably the ultrasonic power is 50%W~70%W, and the ultrasonic time is 3~5h.

[0018] In the method of the present invention, the concentration of the PVA solution used in step 4) is 1% to 30%, preferably 5% to 25%.

[0019] Compared with the prior art, the beneficial effects of the present invention are at least: The present invention aims at the main raw material of hydroxyapatite with excellent biocompatibility. After being modified by a polymer material, the drug loading amount of hydroxyapatite is not only increased, but also the stability of hydroxyapatite in a PVP solution is improved. The basis is provided for the subsequent uniform dispersion of hydroxyapatite in a PVA gel. The entire technical process is simple and feasible, and the raw materials used are non-toxic and are all medical-grade raw materials. The prepared modified hydroxyapatite gel can achieve sustained release of drugs in different pH environments, expanding the application field of hydroxyapatite as a drug carrier. BRIEF DESCRIPTION OF THE DRAWINGS In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for describing the embodiments are briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work. The modified hydroxyapatite gel drug sustained-release material prepared in the above experimental example 1 was tested for sustained-release effect under pH 3.4 and 7.4. The test results are shown in Figure 1 and Figure 2 . Attached photos Figure 1 This is a diagram showing the drug release of modified hydroxyapatite gel drug sustained-release material under a pH of 3.4. Attached photos Figure 2 This is a diagram showing the drug release of modified hydroxyapatite gel drug sustained-release material under a pH of 7.4. By comparing the sustained-release concentration of drugs under different pH environments, it can be seen that in an acidic environment, the drug concentration change curve is close to the drug concentration change curve in a neutral environment, and no sudden release of drug concentration occurs. The fitting results of sustained-release time and drug concentration show that the composite material after gelation effectively alleviates the sudden release phenomenon caused by the dissolution of hydroxyapatite. In summary, the modified hydroxyapatite gel drug sustained-release material prepared by the present invention has good drug loading and drug release performance in different pH environments, and can be used as a good drug carrier material. DETAILED DESCRIPTION

[0020] The present invention will be described in detail below by specific examples. These examples are provided in order to enable a more thorough understanding of the present invention and to fully convey the scope of the present invention to those skilled in the art. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art. The test methods in the following examples, unless otherwise specified, are conventional methods. Unless otherwise specified, the reagents and materials used can all be obtained through commercial channels. Example

[0021] This embodiment provides a method for preparing a modified hydroxyapatite gel drug sustained-release material, comprising the following steps: 1) Weigh 1 g of hydroxyapatite and 1 g of sodium carboxymethyl cellulose, mix them evenly and put them in a ball mill, the ball-to-material ratio is,, the ball mill speed is 600 r / min, and the ball milling time is 3 h. After the reaction is completed, modified hydroxyapatite is obtained; 2) Prepare a 10 mg / mL ibuprofen ethanol solution, weigh 1 g of modified hydroxyapatite and place it in the ibuprofen ethanol solution, place it on a shaker until the absorbance no longer changes, and filter and dry the hydroxyapatite loaded with the drug; 3) mixing the drug-loaded hydroxyapatite with 10% PVP solution and performing ultrasonic dispersion to obtain a hydroxyapatite-polymer dispersion; 4) Prepare 20% PVA and heat and stir to dissolve at 90°C to obtain a PVA solution; 5) adding the hydroxyapatite-polymer dispersion liquid described above into the PVA solution and stirring to obtain a mixed solution; 6) The mixed solution is frozen and thawed three times and then freeze-dried to obtain a gel material. Example

[0022] This embodiment provides a method for preparing a modified hydroxyapatite gel drug sustained-release material, comprising the following steps: 1) Weigh 0.5 g hydroxyapatite and 1 g sodium carboxymethyl cellulose, mix them evenly and put them in a ball mill, the ball-to-material ratio is,, the ball mill speed is 600 r / min, and the ball milling time is 3 h. After the reaction is completed, modified hydroxyapatite is obtained; 2) Prepare a 10 mg / mL ibuprofen ethanol solution, weigh 1 g of modified hydroxyapatite and place it in the ibuprofen ethanol solution, place it on a shaker until the absorbance no longer changes, and filter and dry the hydroxyapatite loaded with the drug; 3) mixing the drug-loaded hydroxyapatite with 10% PVP solution and performing ultrasonic dispersion to obtain a hydroxyapatite-polymer dispersion; 4) Prepare 20% PVA and heat and stir to dissolve at 90°C to obtain a PVA solution; 5) adding the hydroxyapatite-polymer dispersion liquid described above into the PVA solution and stirring to obtain a mixed solution; 6) The mixed solution is frozen and thawed three times and then freeze-dried to obtain a gel material. Example

[0023] This embodiment provides a method for preparing a modified hydroxyapatite gel drug sustained-release material, comprising the following steps: 1) Weigh 1 g of hydroxyapatite and 1 g of chitosan, mix them evenly and put them in a ball mill with a ball-to-material ratio of ,, a ball mill speed of 600 r / min, and a ball milling time of 3 h. After the reaction is completed, modified hydroxyapatite is obtained; 2) Prepare a 10 mg / mL curcumin ethanol solution, weigh 1 g of modified hydroxyapatite and put it into the ibuprofen ethanol solution, place it on a shaker until the absorbance no longer changes, and filter and dry the hydroxyapatite loaded with the drug; 3) mixing the drug-loaded hydroxyapatite with 10% PVP solution and performing ultrasonic dispersion to obtain a hydroxyapatite-polymer dispersion; 4) Prepare 20% PVA and heat and stir to dissolve at 90°C to obtain a PVA solution; 5) adding the hydroxyapatite-polymer dispersion liquid described above into the PVA solution and stirring to obtain a mixed solution; 6) The mixed solution is frozen and thawed three times and then freeze-dried to obtain a gel material. Example

[0024] This embodiment provides a method for preparing a modified hydroxyapatite gel drug sustained-release material, comprising the following steps: 1) Weigh 1 g of hydroxyapatite and 1 g of chitosan, mix them evenly and put them in a ball mill with a ball-to-material ratio of ,, a ball mill speed of 600 r / min, and a ball milling time of 3 h. After the reaction is completed, modified hydroxyapatite is obtained; 2) Prepare a 10 mg / mL curcumin ethanol solution, weigh 1 g of modified hydroxyapatite and put it into the ibuprofen ethanol solution, place it on a shaker until the absorbance no longer changes, and filter and dry the hydroxyapatite loaded with the drug; 3) mixing the drug-loaded hydroxyapatite with 10% PVP solution and performing ultrasonic dispersion to obtain a hydroxyapatite-polymer dispersion; 4) Prepare 20% PVA and heat and stir to dissolve at 90°C to obtain a PVA solution; 5) adding the hydroxyapatite-polymer dispersion liquid described above into the PVA solution and stirring to obtain a mixed solution; 6) The mixed solution is frozen and thawed three times and then freeze-dried to obtain a gel material. Example

[0025] This embodiment provides a method for preparing a modified hydroxyapatite gel drug sustained-release material, comprising the following steps: 1) Weigh 1 g of hydroxyapatite and 1 g of chitosan, mix them evenly and put them in a ball mill with a ball-to-material ratio of ,, a ball mill speed of 600 r / min, and a ball milling time of 3 h. After the reaction is completed, modified hydroxyapatite is obtained; 2) Prepare a 10 mg / mL curcumin ethanol solution, weigh 1 g of modified hydroxyapatite and put it into the ibuprofen ethanol solution, place it on a shaker until the absorbance no longer changes, and filter and dry the hydroxyapatite loaded with the drug; 3) mixing the drug-loaded hydroxyapatite with 10% PVP solution and performing ultrasonic dispersion to obtain a hydroxyapatite-polymer dispersion; 4) Prepare 20% PVA and heat and stir to dissolve at 90°C to obtain a PVA solution; 5) adding the hydroxyapatite-polymer dispersion liquid described above into the PVA solution and stirring to obtain a mixed solution; 6) The mixed solution is frozen and thawed three times and then freeze-dried to obtain a gel material. Example

[0026] This embodiment provides a method for preparing a modified hydroxyapatite gel drug sustained-release material, comprising the following steps: 1) Weigh 1 g of hydroxyapatite and 1 g of chitosan, mix them evenly and put them in a ball mill with a ball-to-material ratio of ,, a ball mill speed of 600 r / min, and a ball milling time of 3 h. After the reaction is completed, modified hydroxyapatite is obtained; 2) Prepare a 10 mg / mL curcumin ethanol solution, weigh 1 g of modified hydroxyapatite and put it into the ibuprofen ethanol solution, place it on a shaker until the absorbance no longer changes, and filter and dry the hydroxyapatite loaded with the drug; 3) mixing the drug-loaded hydroxyapatite with 10% PVP solution and performing ultrasonic dispersion to obtain a hydroxyapatite-polymer dispersion; 4) Prepare 20% PVA and heat and stir to dissolve at 90°C to obtain a PVA solution; 5) adding the hydroxyapatite-polymer dispersion liquid described above into the PVA solution and stirring to obtain a mixed solution; 6) The mixed solution is frozen and thawed three times and then freeze-dried to obtain a gel material.

[0027] Comparative Example 1 provides a method for preparing a modified hydroxyapatite gel drug sustained-release material. The specific preparation method is basically the same as that of Example 1, except that hydroxyapatite is directly used for the drug loading experiment.

[0028] The hydroxyapatite in Examples 1-6 and Comparative Example 1 was subjected to drug loading test and loading rate calculation, and the test results are shown in Table 1.

[0029] Table 1: Test table of drug loading rate of modified hydroxyapatite Drug loading rate% Example 1 77 Example 2 73 Example 3 75 Example 4 86 Example 5 85 Example 6 81 Comparative Example 1 24 Experimental Example 7 This Example 7 provides a method for preparing a modified hydroxyapatite gel drug sustained-release material. The specific drug sustained-release experiment is as follows: The modified hydroxyapatite gel drug sustained-release material prepared in the above experimental example 1 was tested for sustained-release effect under pH 3.4 and 7.4. The test results are shown in Figure 1 .

[0030] By comparing the sustained-release concentration of drugs under different pH environments, it can be seen that in an acidic environment, the drug concentration change curve is close to the drug concentration change curve in a neutral environment, and no sudden release of drug concentration occurs. The fitting results of sustained-release time and drug concentration show that the composite material after gelation effectively alleviates the sudden release phenomenon caused by the dissolution of hydroxyapatite. In summary, the modified hydroxyapatite gel drug sustained-release material prepared by the present invention has good drug loading and drug release performance in different pH environments, and can be used as a good drug carrier material.

[0031] The above description is only the preferred embodiment of the present application and is not intended to limit the present application. For those skilled in the art, the present application may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing a modified hydroxyapatite gel drug sustained-release material, characterized in that: The preparation of modified hydroxyapatite gel comprises the following steps: 1) Firstly, hydroxyapatite and polycationic polymer or polyanionic polymer are ball-milled to prepare a modified hydroxyapatite composite material; 2) Using modified hydroxyapatite composites for drug loading; 3) mixing the composite material loaded with the drug with the PVP solution and performing ultrasonic dispersion to obtain a modified hydroxyapatite dispersion; 4) Take an appropriate amount of PVA and heat and stir to dissolve at 90°C to obtain a PVA solution; 5) adding the modified hydroxyapatite dispersion described above into the PVA solution and stirring to obtain a mixed solution; 6) The mixed solution is frozen and thawed three times and then freeze-dried to obtain a gel material.

2. A method for preparing a modified hydroxyapatite gel drug sustained-release material according to claim 1, characterized in that: In the step 1), the sources of hydroxyapatite include hydroxyapatite prepared by co-precipitation method, sol-gel method and hydroxyapatite extracted from discarded animal bones, and the weight percentage of hydroxyapatite in the composite material is 0.1% to 10%.

3. The method for preparing a modified hydroxyapatite gel drug sustained-release material according to claim 1, characterized in that: In the step 1), the polycationic polymer or polyanionic polymer accounts for 0.1% to 10% by weight, wherein the polycationic polymer includes one or more of chitosan, carboxymethyl chitosan, gelatin, and polyethyleneimine; the polyanionic polymer includes one or more of sodium alginate, sodium carboxymethyl cellulose, hyaluronic acid, and polyacrylic acid.

4. The method for preparing a modified hydroxyapatite gel drug sustained-release material according to claim 1, characterized in that: In the step 1), the modified hydroxyapatite composite material is prepared, and the ratio of hydroxyapatite to polycationic / anionic polymer is 0.1-10.

5. The method for preparing a modified hydroxyapatite gel drug sustained-release material according to claim 1, characterized in that: In the step 1), the ball milling technology uses agate beads, the ball milling time is 0.5-10 h, and the ball milling speed is 100-700 r / min.

6. The method for preparing a modified hydroxyapatite gel drug sustained-release material according to claim 1, characterized in that: The drug involved in the drug loading in the composite material in step 2) includes one of ibuprofen, acetylsalicylic acid, curcumin, acetaminophen, vancomycin, and cephalexin.

7. The method for preparing a modified hydroxyapatite gel drug sustained-release material according to claim 1, characterized in that: The concentration of the PVP solution used in step 3) is 5% to 20%.

8. The method for preparing a modified hydroxyapatite gel drug sustained-release material according to claim 1, characterized in that: The ultrasonic power of the ultrasonic dispersion in step 3) is 40%W-80%W, and the ultrasonic time is 0.5-10 h.

9. The method for preparing a modified hydroxyapatite gel drug sustained-release material according to claim 1, characterized in that: The concentration of the PVA solution used in step 4) is 1% to 30%.

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