CN108379666B - Gelatin microsphere/magnesium phosphate based bone cement drug sustained-release carrier and preparation method thereof - Google Patents
Gelatin microsphere/magnesium phosphate based bone cement drug sustained-release carrier and preparation method thereof Download PDFInfo
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
- A61L2300/604—Biodegradation
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
- A61L2300/622—Microcapsules
Abstract
The invention discloses a gelatin microsphere/magnesium phosphate based bone cement drug sustained-release carrier and a preparation method thereof, wherein 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride cross-linked drug-loaded gelatin microsphere is prepared; and uniformly mixing the obtained drug-loaded gelatin microspheres with magnesium phosphate-based bone cement powder, and blending and curing the mixture with magnesium phosphate-based bone cement liquid to obtain the gelatin microsphere/magnesium phosphate-based bone cement drug sustained-release carrier. 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride is used as a gelatin crosslinking agent, and the obtained gelatin microsphere has good biocompatibility; the gelatin microspheres can carry various drugs, and the degradation speed of the microspheres can be controlled by the concentration of the cross-linking agent, so that the drug release speed is controlled; the gelatin microsphere/magnesium phosphate based bone cement drug carrier has excellent drug slow release effect, and realizes the sustained release of the drug for several months.
Description
Technical Field
The invention relates to the technical field of preparation of biomedical materials, in particular to a bone filling and repairing material with a drug treatment effect and a method for preparing the material.
Background
In modern society, accidents such as aging of population, production, transportation and the like and diseases such as bone tuberculosis, osteomyelitis, bone tumor and the like cause a large number of patients needing to receive bone tissue defect repair. Conventional bone tissue defect repair is mainly achieved by autologous bone grafting and allogeneic bone grafting. But both methods have defects of different degrees, the former is a method for treating wounds by wounds; the latter often presents problems with disease transmission and immune rejection, and both are of limited origin. The artificial materials are not limited in source, and have been paid attention and studied by many researchers to develop a series of bone repair materials. However, the bone defect is filled with bone filling material alone, which is likely to cause surgical complications, and therefore, the bone defect needs to be treated with medicine for a certain period of time after surgery. The clinical common method is to take oral medicine or inject medicine subcutaneously after operation, however, the methods easily cause the medicine concentration in the body to be unstable, the medicine utilization rate is low, and the bad control can cause toxic and side effects to the body. If the bone repair material is loaded with the medicine and the medicine is slowly released at the defect part, the utilization rate of the medicine is improved, and the toxicity to the body is reduced.
In recent years, many researchers have considered the dual effect of loading drugs into bone cement to repair bone defects and treat bone diseases. Lopez-Heredia et al loaded paclitaxel into injectable calcium phosphate bone cement and performed cell experiments to obtain that the activity of osteosarcoma cells and metastatic breast cancer cells in the drug-loaded group is lower than that of the drug-free group, which indicates that the drug-loaded group in bone cement can achieve a certain drug treatment effect (Lopez-Heredia M A et al. an injectable calcium phosphate moiety for the local delivery of paclitaxel to bone [ J ]. Biomaterials,2011,32(23): 5411-. However, such drug loading has significant disadvantages: the medicine is directly mixed with the bone cement powder phase or the liquid phase to prepare the medicine-carrying bone cement, and the bone cement and the medicine can generate mutual adverse effect in the hydration process; if the solidified bone cement is used for medicine loading, the medicine can be released too fast to achieve the effect of slow release. Therefore, the organic microspheres are used for wrapping the medicine and then compounded into the bone cement, so that the slow release performance of the medicine can be improved while the interaction between the medicine and the bone cement is avoided, and the organic microsphere has potential application value. At present, although the drug-loaded microspheres are researched to be introduced into bone cement, the long-term slow release effect is not obvious. Chinese patent publication No. 101564556A discloses a composite drug-carrying system of gelatin microspheres and calcium phosphate cement, but the drug release rate is high, and the drug release amount is over 90% in 14 days.
Bone defects, particularly those caused by bone diseases such as osteomyelitis, bone tumors, bone tuberculosis, etc., often require several months of continuous drug therapy to achieve complete healing, and too fast drug release does not meet the requirements. Therefore, the exploration of the drug-loaded bone repair material which can load the drug and can slowly release the drug for a long time and the preparation method thereof have profound significance. In addition, as a bone repair material, the system needs to be degradable and have good biocompatibility.
Disclosure of Invention
In view of the above, the invention aims to provide a preparation method of a gelatin microsphere/magnesium phosphate based bone cement drug sustained-release system capable of releasing drugs for a long time. The gelatin microsphere/magnesium phosphate based bone cement drug sustained-release system has good drug sustained-release effect, and meets the long-term continuous drug treatment requirement of bone defect.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a preparation method of a gelatin microsphere/magnesium phosphate based bone cement drug sustained-release carrier comprises the following steps:
(1) preparing 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride cross-linked drug-loaded gelatin microspheres;
(2) and (2) uniformly mixing the drug-loaded gelatin microspheres obtained in the step (1) with magnesium phosphate-based bone cement powder, and then blending and curing the mixture with magnesium phosphate-based bone cement liquid to obtain the gelatin microsphere/magnesium phosphate-based bone cement drug slow-release carrier.
Preferably, the preparation method of the drug-loaded gelatin microsphere comprises the following steps:
1) dissolving gelatin and a medicament in deionized water at the temperature of 40-60 ℃ and uniformly mixing to obtain a gelatin medicament-carrying solution with the gelatin mass fraction of 20-30%, wherein the medicament addition amount is 1-100% of the gelatin mass;
2) taking liquid paraffin as an oil phase and span 80 as a dispersing agent, wherein the volume ratio of the liquid paraffin to the dispersing agent is preferably 10:1, and mixing the liquid paraffin and the dispersing agent and stirring uniformly;
3) dripping gelatin drug-loaded solution into the oil phase at the rotation speed of 100-; then continuing to stir for 5-60min and then dropwise adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride solution; crosslinking for 30-240min, preferably 60-90 min;
4) taking out the microspheres, cleaning the microspheres by using a dehydrating agent, and drying the microspheres at normal temperature to obtain the drug-loaded gelatin microspheres.
Preferably, the dosage of the cross-linking agent 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride is 1-25 wt% of the dosage of the gelatin.
Preferably, the crosslinking agent 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride is used in an amount of 13% by weight of the amount of gelatin.
Preferably, the dehydrating agent in the step 4) is one or more of the following: isopropanol, ethanol, diethyl ether, acetone, and petroleum ether.
Preferably, the magnesium phosphate-based bone cement powder phase component is a mixture of magnesium oxide, calcium dihydrogen phosphate and potassium dihydrogen phosphate; the liquid phase component is citric acid aqueous solution.
Preferably, the ratio of the magnesium phosphate based cement powder phase to the liquid phase is 1.5g/mL to 2.5g/mL, preferably 1.6g/mL to 2.2 g/mL.
Preferably, the mass ratio of the drug-loaded gelatin microspheres to the magnesium phosphate-based bone cement powder is (1-15): 100.
preferably, the magnesium oxide in the magnesium phosphate-based bone cement powder phase component is subjected to calcination treatment: calcining at 1600 deg.C, heating at 3 deg.C/min, maintaining for 1.5h, and ball milling to obtain particle size of 1-3 μm, preferably 1-2 μm.
Preferably, the particle size of the monocalcium phosphate in the magnesium phosphate-based bone cement powder phase component is 0.5-30 μm; the particle size of the potassium dihydrogen phosphate is 1-20 μm.
Preferably, in the magnesium phosphate-based bone cement powder phase component, the ratio of magnesium oxide: potassium dihydrogen phosphate: the mass ratio of the monocalcium phosphate is 1.5:3: 1; the concentration of citric acid in the liquid phase component is 0.01g/mL-0.05 g/mL.
Preferably, the gelatin carries drugs which are one or more of the following: diclofenac sodium, acetaminophen, gentamicin sulfate, isoniazid, pyrazinamide, doxorubicin hydrochloride, dexamethasone, doxycycline hydrochloride, tetracycline hydrochloride, ibuprofen, 5-fluorouracil, rifampin, ethambutol hydrochloride, clofazidine, vancomycin hydrochloride.
A gelatin microsphere/magnesium phosphate based bone cement drug sustained release carrier is prepared by the method.
In the preparation of the gelatin microsphere, the degradation speed of the microsphere can be adjusted by controlling the concentration of the cross-linking agent, so that the release speed of the drug is controlled. Then the drug-loaded gelatin microspheres are compounded with degradable magnesium phosphate-based bone cement with good adhesive property and biological property. The magnesium phosphate-based bone cement can tightly wrap the drug-carrying microspheres by forming magnesium potassium phosphate hexahydrate and free calcium salt to be chelated with the citrate radicals. The drug is released through the cross-linked network of the gelatin microsphere, then is diffused into the bone cement matrix, and is released through the micro-nano gaps of the bone cement, so that the purpose of slow release of the drug is achieved. The gelatin microsphere/magnesium phosphate based bone cement drug sustained-release carrier prepared by the invention can carry various drugs, and has good drug sustained-release effect.
The beneficial effects of the invention are as follows: 1. 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride is used as a gelatin crosslinking agent, the degradation speed of gelatin can be simply controlled by controlling the concentration of the crosslinking agent, and the obtained gelatin microsphere has good biocompatibility; 2. the medicine is wrapped in the gelatin microsphere, so that the medicine can be prevented from participating in the hydration process of bone cement, the adverse reaction possibly generated between the medicine and the gelatin microsphere can be reduced, and the activity of the medicine can be greatly maintained; 3. the gelatin microspheres are compounded with the magnesium phosphate-based bone cement, the medicine needs to break through the release of double media, the medicine release time is prolonged, the effect of medicine slow release treatment is achieved, and the medicine release time is as long as 2-3 months. 4. The gelatin microspheres can form holes in situ in bone cement after being degraded, and provide gaps for promoting the ingrowth of bone tissues at the later stage, so that the gelatin microspheres have the potential capability of promoting bone repair.
Drawings
FIG. 1 is a diagram of a cytotoxicity test of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride crosslinked gelatin microspheres, (which is obtained by dispersing gelatin microspheres crosslinked with 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride in 1640 culture solution at a concentration of 200mg/mL, co-culturing with mesenchymal stem cells for 1 day, adding MTT after 3 days, and then continuing to incubate for 4 hours, wherein the absorbance value is measured to show cell activity, and the larger the absorbance value is, the better the cell activity is, and the microspheres are not added as a control group);
FIG. 2 is a scanning electron micrograph of the diclofenac sodium-loaded gelatin microspheres obtained in example 1;
FIG. 3 is a scanning electron microscope image of the drug-loaded gelatin microsphere/magnesium phosphate-based bone cement obtained in examples 1 and 2, wherein a) shows the morphology of the composite bone cement of example 1, and b) shows the morphology of the composite bone cement of example 2;
fig. 4 is a drug release profile of drug-loaded gelatin microspheres/magnesium phosphate-based bone cement obtained in examples 1, 2 and 3.
Detailed Description
The present invention will be further illustrated by the following examples, but the present invention is not limited to these examples. The following examples are not specifically described, and all reagents used are commercially available chemical reagents of chemical purity.
Example 1
1.5g of gelatin microspheres and 0.03g of diclofenac sodium are weighed and dissolved in distilled water at 50 ℃ to prepare a medicinal gelatin aqueous solution which is uniformly mixed. And adding 30mL of liquid paraffin and 3mL of span 80 into a round-bottom flask, stirring for 10min at the rotation speed of 500r/min and the temperature of 50 ℃, slowly dropwise adding the medicinal gelatin solution into the flask at the rotation speed of 250r/min, stirring for 10min, rapidly using an ice water bath, and adding 1mL of carbodiimide hydrochloride solution with the concentration of 0.5mol/L after 15 min. And continuously stirring and crosslinking for 60min, taking out, washing with isopropanol, and drying at room temperature to obtain the diclofenac sodium-loaded gelatin microspheres. The morphology of the microspheres was observed by scanning electron microscopy as shown in FIG. 2.
The bone cement powder is prepared by uniformly mixing magnesium oxide, monopotassium phosphate and monocalcium phosphate according to the mass ratio of 1.5:3: 1. 4g of bone cement powder was weighed, and 0.4g of the above gelatin microspheres was added. Then preparing a citric acid solution with the concentration of 0.02g/mL, taking 1.8mL of the citric acid solution to be mixed with the powder for 2min, placing the mixture into a mold for curing, and then curing for 48h in an environment with the temperature of 37 ℃ and the humidity of 100%. The strength of the cured bone cement was tested for two days using a universal testing machine. The cured bone cement was placed in a PBS buffer solution with pH 7.4 at a ratio of 1g:20mL for drug release.
The drug-loaded gelatin microsphere has good balling effect, and the particle size is 0-300 μm, as shown in figure 2. The strength of the gelatin microsphere/magnesium phosphate based bone cement drug sustained-release system is 35MPa after curing for two days, the section morphology is shown in figure 3, 53.9 percent of the drug is released in 60 days (as shown in figure 4), and then the drug is also released continuously, so that the gelatin microsphere/magnesium phosphate based bone cement drug sustained-release system has a good drug release effect.
Example 2
1.5g of gelatin microspheres and 0.03g of diclofenac sodium are weighed and dissolved in distilled water at 50 ℃ to prepare a medicinal gelatin aqueous solution which is uniformly mixed. And adding 30mL of liquid paraffin and 3mL of span 80 into a round-bottom flask, stirring for 10min at the rotation speed of 500r/min and the temperature of 50 ℃, slowly dropwise adding the medicinal gelatin solution into the flask at the rotation speed of 350r/min, stirring for 10min, rapidly using an ice water bath, and adding 1mL of carbodiimide hydrochloride solution with the concentration of 1mol/L after 15 min. And continuously stirring and crosslinking for 60min, taking out, washing with isopropanol, and drying at room temperature to obtain the diclofenac sodium-loaded gelatin microspheres. The portion where the gelatin microspheres and the bone cement were combined was the same as in example 1.
The drug-loaded gelatin microsphere has good balling effect and the particle size of 0-250 μm. The strength of the gelatin/magnesium phosphate based bone cement drug slow release system is 32MPa after curing for two days, and 31.9 percent of drug is released in 60 days (as shown in figure 4).
Example 3
1.5g of gelatin microspheres and 0.03g of diclofenac sodium are weighed and dissolved in distilled water at 50 ℃ to prepare a medicinal gelatin aqueous solution which is uniformly mixed. And adding 30mL of liquid paraffin and 3mL of span 80 into a round-bottom flask, stirring for 10min at the rotating speed of 500r/min and the temperature of 50 ℃, slowly dropwise adding the medicinal gelatin solution into the flask at the rotating speed of 350r/min, stirring for 10min, rapidly using an ice water bath, and adding 1mL of carbodiimide hydrochloride solution with the concentration of 0.1mol/L after 15 min. And continuously stirring and crosslinking for 60min, taking out, washing with isopropanol, and drying at room temperature to obtain the diclofenac sodium-loaded gelatin microspheres. The portion where the gelatin microspheres and the bone cement were combined was the same as in example 1.
The drug-loaded gelatin microsphere has good balling effect and the particle size of 0-250 μm. The strength of the gelatin/magnesium phosphate based bone cement drug slow release system is 28MPa after curing for two days, and 70 percent of the drug is released in 60 days (as shown in figure 4).
Example 4
1.5g of gelatin microspheres and 1.5g of acetaminophen are weighed and dissolved in distilled water at 50 ℃, and a medicinal gelatin aqueous solution is prepared and uniformly mixed. And adding 30mL of liquid paraffin and 3mL of span 80 into a round-bottom flask, stirring for 10min at the rotating speed of 600r/min and the temperature of 50 ℃, slowly dropwise adding the medicinal gelatin solution into the flask at the rotating speed of 600r/min, stirring for 10min, rapidly using an ice water bath, and adding 1mL of carbodiimide hydrochloride solution with the concentration of 0.5mol/L after 15 min. And continuously stirring and crosslinking for 120min, taking out, washing with isopropanol, and drying at room temperature to obtain the acetaminophen-loaded gelatin microspheres.
The bone cement powder is prepared by uniformly mixing magnesium oxide, monopotassium phosphate and monocalcium phosphate according to the mass ratio of 1.5:3: 1. 4g of bone cement powder was weighed, and 0.08g of the above gelatin microspheres was added. Then preparing a citric acid solution with the concentration of 0.02g/mL, taking 1.6mL of the citric acid solution to be mixed with the powder for 2min, placing the mixture into a mold for curing, and then curing for 48h in an environment with the temperature of 37 ℃ and the humidity of 100%. The strength of the cured bone cement was tested for two days using a universal testing machine. The cured bone cement was placed in a PBS buffer solution with pH 7.4 at a ratio of 1g:20mL for drug release.
The drug-loaded gelatin microsphere has a general balling effect, the particle size is 0-200 mu m, the strength of the gelatin/magnesium phosphate-based bone cement drug slow release system is 67MPa after two-day curing, and the drug is released by 50 percent after 60 days.
Example 5
1.5g of gelatin microspheres and 0.75g of acetaminophen are weighed and dissolved in distilled water at 50 ℃, and a medicinal gelatin aqueous solution is prepared and uniformly mixed. And adding 30mL of liquid paraffin and 3mL of span 80 into a round-bottom flask, stirring for 10min at the rotating speed of 600r/min and the temperature of 50 ℃, slowly dropwise adding the medicinal gelatin solution into the flask at the rotating speed of 450r/min, stirring for 10min, rapidly using an ice water bath, and adding 1mL of 2mol/L carbodiimide hydrochloride solution after 15 min. And continuously stirring and crosslinking for 60min, taking out, washing with isopropanol, and drying at room temperature to obtain the acetaminophen-loaded gelatin microspheres.
The bone cement powder is prepared by uniformly mixing magnesium oxide, monopotassium phosphate and monocalcium phosphate according to the mass ratio of 1.5:3: 1. 4g of bone cement powder was weighed, and 0.24g of the above gelatin microspheres was added. Then preparing a citric acid solution with the concentration of 0.02g/mL, taking 1.8mL of the citric acid solution to be mixed with the powder for 2min, placing the mixture into a mold for curing, and then curing for 48h in an environment with the temperature of 37 ℃ and the humidity of 100%. The strength of the cured bone cement was tested for two days using a universal testing machine. The cured bone cement was placed in a PBS buffer solution with pH 7.4 at a ratio of 1g:20mL for drug release.
The drug-loaded gelatin microsphere has good balling effect, the particle size is 0-250 mu m, the strength of the gelatin/magnesium phosphate-based bone cement drug slow release system is 50MPa after two-day curing, and the drug is released by 37 percent after 60 days.
Example 6
1.5g of gelatin microspheres and 0.75g of p-isoniazid are weighed and dissolved in distilled water at 50 ℃ to prepare a medicinal gelatin aqueous solution which is uniformly mixed. And adding 30mL of liquid paraffin and 3mL of span 80 into a round-bottom flask, stirring for 10min at the rotation speed of 500r/min and the temperature of 50 ℃, slowly dropwise adding the medicinal gelatin solution into the flask at the rotation speed of 600r/min, stirring for 10min, rapidly using an ice water bath, and adding 1mL of carbodiimide hydrochloride solution with the concentration of 1mol/L after 15 min. And continuously stirring and crosslinking for 60min, taking out, washing with isopropanol, and drying at room temperature to obtain the isoniazid-loaded gelatin microsphere.
The bone cement powder is prepared by uniformly mixing magnesium oxide, monopotassium phosphate and monocalcium phosphate according to the mass ratio of 1.5:3: 1. 4g of bone cement powder was weighed, and 0.32g of the above gelatin microspheres was added. Then preparing a citric acid solution with the concentration of 0.02g/mL, taking 2mL of the citric acid solution to be mixed with the powder for 2min, placing the mixture into a mold for curing, and then placing the mixture in an environment with the temperature of 37 ℃ and the humidity of 100% for curing for 48 h. The strength of the cured bone cement was tested for two days using a universal testing machine. The cured bone cement was placed in a PBS buffer solution with pH 7.4 at a ratio of 1g:20mL for drug release.
The drug-loaded gelatin microsphere has good balling effect, the particle size is 0-150 mu m, the strength of the gelatin/magnesium phosphate-based bone cement drug slow release system is 51MPa after curing for two days, and the drug is released by 55 percent after 60 days.
Example 7
1.5g of gelatin microspheres and 0.15g of pyrazinamide are weighed and dissolved in distilled water at 50 ℃, and a medicinal gelatin aqueous solution which is uniformly mixed is prepared. And adding 30mL of liquid paraffin and 3mL of span 80 into a round-bottom flask, stirring for 10min at the rotation speed of 500r/min and the temperature of 50 ℃, slowly dropwise adding the medicinal gelatin solution into the flask at the rotation speed of 100r/min, stirring for 10min, rapidly using an ice water bath, and adding 1mL of carbodiimide hydrochloride solution with the concentration of 0.5mol/L after 15 min. And continuously stirring and crosslinking for 240min, taking out, washing with isopropanol, and drying at room temperature to obtain the pyrazinamide-loaded gelatin microspheres.
The bone cement powder is prepared by uniformly mixing magnesium oxide, monopotassium phosphate and monocalcium phosphate according to the mass ratio of 1.5:3: 1. 4g of bone cement powder was weighed, and 0.4g of the above gelatin microspheres was added. Then preparing a citric acid solution with the concentration of 0.02g/mL, taking 2.2mL of the citric acid solution to be mixed with the powder for 2min, placing the mixture into a mold for curing, and then curing for 48h in an environment with the temperature of 37 ℃ and the humidity of 100%. The strength of the cured bone cement was tested for two days using a universal testing machine. The cured bone cement was placed in a PBS buffer solution with pH 7.4 at a ratio of 1g:20mL for drug release.
The drug-loaded gelatin microsphere has good balling effect, the particle size is 0-550 mu m, the strength of the gelatin/magnesium phosphate-based bone cement drug slow release system is 25MPa after two-day curing, and the drug is released by 56 percent after 60 days.
Example 8
1.5g of gelatin microspheres and 0.02g of diclofenac sodium are weighed and dissolved in distilled water at 50 ℃ to prepare a medicinal gelatin aqueous solution which is uniformly mixed. And adding 30mL of liquid paraffin and 3mL of span 80 into a round-bottom flask, stirring for 10min at the rotating speed of 500r/min and the temperature of 50 ℃, slowly dropwise adding the medicinal gelatin solution into the flask at the rotating speed of 300r/min, stirring for 10min, rapidly using an ice water bath, and adding 1mL of carbodiimide hydrochloride solution with the concentration of 0.5mol/L after 15 min. And continuously stirring and crosslinking for 30min, taking out, washing with isopropanol, and drying at room temperature to obtain the pyrazinamide-loaded gelatin microspheres.
The bone cement powder is prepared by uniformly mixing magnesium oxide, monopotassium phosphate and monocalcium phosphate according to the mass ratio of 1.5:3: 1. 4g of bone cement powder was weighed, and 0.8g of the above gelatin microspheres was added. Then preparing a citric acid solution with the concentration of 0.02g/mL, taking 2.6mL of the citric acid solution to be mixed with the powder for 2min, placing the mixture into a mold for curing, and then curing for 48h in an environment with the temperature of 37 ℃ and the humidity of 100%. The strength of the cured bone cement was tested for two days using a universal testing machine. The cured bone cement was placed in a PBS buffer solution with pH 7.4 at a ratio of 1g:20mL for drug release.
The drug-loaded gelatin microsphere has good balling effect, the particle size is 0-250 mu m, the strength of the gelatin/magnesium phosphate-based bone cement drug slow release system is 14MPa after two-day curing, and the drug is released by 90 percent after 60 days.
While the foregoing is directed to the preferred embodiment of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow.
Claims (3)
1. A preparation method of a gelatin microsphere/magnesium phosphate based bone cement drug sustained-release carrier is characterized by comprising the following steps:
(1) dissolving gelatin and medicine in deionized water at 40-60 deg.C, and mixing to obtain gelatin medicine-carrying solution with gelatin mass fraction of 20-30%;
(2) mixing liquid paraffin serving as an oil phase and span 80 serving as a dispersing agent, and uniformly stirring;
(3) dripping gelatin drug-loaded solution into the oil phase at the rotation speed of 100-; then continuing to stir for 5-60min and then dropwise adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride solution; wherein the dosage of the cross-linking agent 1-ethyl- (3-dimethyl aminopropyl) carbodiimide hydrochloride is 13wt% of the dosage of the gelatin, and the cross-linking is carried out for 30-240 min;
(4) taking out the microspheres, cleaning the microspheres by using a dehydrating agent, and drying the microspheres at normal temperature to obtain drug-loaded gelatin microspheres;
(5) uniformly mixing the drug-loaded gelatin microspheres obtained in the step (4) with magnesium phosphate-based bone cement powder, and then blending and curing the mixture with magnesium phosphate-based bone cement powder, wherein the magnesium phosphate-based bone cement powder is a mixture of magnesium oxide, potassium dihydrogen phosphate and calcium dihydrogen phosphate in a mass ratio of 1.5:3:1, and the particle size of the calcium dihydrogen phosphate is 0.5-30 mu m; the particle size of the potassium dihydrogen phosphate is 1-20 mu m; the liquid phase component is a citric acid aqueous solution with the concentration of 0.01g/mL-0.05g/mL, and the mass ratio of the drug-loaded gelatin microspheres to the magnesium phosphate-based bone cement powder phase is (1-15): 100, obtaining the gelatin microsphere/magnesium phosphate based bone cement drug sustained release carrier.
2. The method for preparing the magnesium phosphate-based bone cement powder phase component according to claim 1, wherein the magnesium oxide in the magnesium phosphate-based bone cement powder phase component is subjected to calcination treatment: the calcining temperature is 1600 ℃, the heating rate is 3 ℃/min, the heat preservation is 1.5h, and the particle size is 1-3 μm after ball milling.
3. A gelatin microsphere/magnesium phosphate based bone cement drug sustained release carrier, characterized in that it is prepared by the method of any one of claims 1-2.
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| CN112891622A (en) * | 2021-02-04 | 2021-06-04 | 武汉理工大学 | Porous calcium-magnesium dual-phase ceramic microsphere and preparation method thereof |
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