CN107823143B - Preparation method of bone morphogenetic protein microspheres - Google Patents
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Abstract
The invention relates to a method for preparing microspheres by using a novel carrier material methoxy polyethylene glycol-polycaprolactone (MPEG-PCL) to entrap bone morphogenetic protein (BMP-2), which comprises the following steps: dispersing BMP-2 solution in the emulsion phase of dichloromethane with dissolved MPEG-PCL to prepare initial emulsion; adding the primary emulsion into a dispersion medium (polyvinyl alcohol solution) to prepare a multiple emulsion stage; and (4) volatilizing the organic solvent to prepare BMP-2 microspheres. The novel carrier material MPEG-PCL used in the invention is used for encapsulating BMP-2, and the prepared microsphere preparation can be locally injected for administration, so that the BMP-2 can stably act on an application part for a long term, the bone growth is promoted, the action time of the medicament can be prolonged, the treatment effect is improved, the toxic and side effects are reduced, the purpose of improving the treatment effect is achieved, the administration times are greatly reduced, and the compliance of patients is improved.
Description
Technical Field
The invention relates to a preparation method of a bone morphogenetic protein microsphere, in particular to a method for preparing the microsphere by using a novel carrier material methoxy polyethylene glycol-polycaprolactone (MPEG-PCL) to entrap bone morphogenetic protein (BMP-2).
Background
With the development of modern society, more and more bone-defect patients are caused by trauma, infection, tumor and the like every year in China. The bone defect repair research is a research hotspot of orthopedics and is also one of the problems which are addressed by orthopedics doctors. Bone morphogenetic protein (BMP-2) is an important factor preferred for promoting bone repair, and a series of cytokines such as bone morphogenetic protein, vascular endothelial cell growth factor, platelet-derived growth factor and the like are required to be jointly regulated and controlled in the processes of formation, absorption and reconstruction of bones in bone defect repair.
BMP-2 is a starting factor in fracture repair, and can induce bone marrow mesenchymal stem cells to directionally proliferate and differentiate into chondroblasts and osteoblasts, thereby promoting the formation of cartilage and bone. However, BMP-2 has a short half-life in vivo, is diluted and metabolized quickly by systemic and local application, does not achieve the expected biological effect, needs to be repeatedly and massively administered, is used in a dosage far higher than a physiological level, is easy to cause a series of complications such as local soft tissue edema, spinal cord radiculitis, ectopic ossification, bone resorption around the implant and cancer, and also increases the physical pain and economic burden of a patient due to repeated administration. In order to overcome the defects of the traditional BMP-2 preparation, a drug sustained-release carrier is prepared to continuously and slowly release the drug so as to maintain the concentration of the local drug, thereby improving the curative effect of the drug.
The microsphere is used as a drug carrier, and great research progress is made in the aspect of sustained and controlled release drugs. Has the following advantages:
(1) Controlling the release rate of the drug;
(2) Increase the permeability of the drug to cell membranes;
(3) Protecting protein medicine from being degraded and inactivated by protease;
(4) The stability of the medicine is improved;
(5) Prolonging the curative effect of the medicine and targeting administration.
In terms of the manufacturing method, the current methods for preparing the drug microspheres are many, such as a 3D printing method, an emulsion solvent volatilization method, a phase separation method, an emulsion solvent extraction method, a spray drying method, a melting method and the like. But all have disadvantages, e.g. in
In the organic solvent volatilization stage, the microspheres prepared by ultrasonic treatment have the defects of large particle size difference and less drug bearing. The method of preparing colostrum by ultrasonic emulsification also causes the influence of overheating denaturation on bone morphogenetic protein, for example, the Chinese patent application 'BMP-2/PLLA/nHA sustained release microsphere and the preparation method thereof' (CN 201710009319.4) prepares the drug microsphere with good biocompatibility, good absorbability, high mechanical strength, good degradability and good stability, but local overheating caused by ultrasound may cause the problems of overheating denaturation and inactivation on the bone morphogenetic protein, thereby influencing the use effect of the drug microsphere.
As for the selected drug carrier materials, the commonly used carrier materials for preparing microspheres at present are poly (acetic acid) (PLA) and poly (lactic-co-glycolic acid) (PLGA), which are widely used as drug carriers because of good biocompatibility and biodegradability, and the final metabolites in vivo are water and carbon dioxide. However, the carrier materials generate acidic degradation byproducts in the in vivo environment, which are easy to cause inflammation and affect the stability and the overall treatment effect of BMP-2.
Therefore, there is a need to provide a new carrier material and a manufacturing method thereof to solve the above problems and improve the administration method.
Disclosure of Invention
Aiming at the prior art, the invention provides a preparation method of bone morphogenetic protein (BMP-2) microspheres, wherein the selected carrier material is methoxy polyethylene glycol-polycaprolactone (MPEG-PCL) copolymer, which is not reported at present as a novel carrier material for preparing BMP-2 microspheres, and the copolymer has good histocompatibility and abundant sources because of no toxicity, no pyrogenicity, no sensitization and no teratogenic carcinogenesis, and is different from other carrier materials.
The invention is realized by the following technical scheme:
(1) Dissolving MPEG-PCL in organic solvent dichloromethane to prepare MPEG-PCL solution;
(2) Dispersing the BMP-2 solution in the MPEG-PCL solution;
(3) Placing the MPEG-PCL solution dissolved with BMP-2 in a homogenizer, stirring and emulsifying for the first time to obtain primary emulsion;
(4) Slowly adding the primary emulsion into a dispersion medium (polyvinyl alcohol solution), continuously shearing, and carrying out second emulsification to obtain a multiple emulsion;
(5) And (3) placing the multiple emulsion on a magnetic stirrer, stirring, volatilizing the organic solvent, and freeze-drying to obtain the BMP-2 microspheres.
In the method, the organic solvent dichloromethane is easy to volatilize and needs to be prepared at present.
In the above method, the concentration of the BMP-2 solution dispersed in the MPEG-PCL solution is preferably 550. Mu.g/ml.
In the above method, the volume ratio of BMP-2 solution/MPEG-PCL solution is: 1: (4 to 10), preferably, the volume ratio of the BMP-2 solution to the MPEG-PCL solution is as follows: 1:5.
In the method, the concentration of the dispersion medium polyvinyl alcohol solution ranges from 2% to 4%, and preferably, the concentration is 2%.
In the above method, the volume ratio of the MPEG-PCL solution to the polyvinyl alcohol solution is as follows: 1, (10 to 15), preferably, the volume ratio of the MPEG-PCL solution to the polyvinyl alcohol solution is as follows: 1:12.
In the method, the BMP-2/MPEG-PCL microspheres are prepared from the following raw material medicines and auxiliary materials in parts by weight: preferably, methoxypolyethylene glycol-polycaprolactone (MPEG-PCL) concentration: 100mg/ml, polyvinyl alcohol (PVA) concentration: 2%, volume ratio of BMP-2 solution/MPEG-PCL solution: 1, MPEG-PCL solution/polyvinyl alcohol solution volume ratio: 1:12.
In the method, a homogenizer is used for carrying out primary emulsification in an ice bath environment, and the shearing rotating speed is 5000-15000r/min. The time is as follows: preparing primary emulsion for 30 to 90 seconds; preferably, the shearing rotating speed is 10000r/min, and the shearing time is 0.5min.
In the method, the colostrum is added into the PVA solution, and the colostrum is added into the PVA solution for the second emulsification by a homogenizer under the ice bath condition, wherein the use speed is 5000 to 15000r/min, and the stirring time is as follows: and (5) obtaining compound emulsion from 30 to 120s. Preferably, the shearing speed of the refiner is 5000r/min, and the shearing time is 1min.
In the method, the multiple emulsion is placed on a magnetic stirrer, the organic solvent is volatilized for 3 to 6 hours at a speed of 300 to 700r/min, preferably for 4 hours at a speed of 400r/min, and the organic solvent is removed.
In the method, the BMP-2/MPEG-PCL microspheres are obtained by volatilizing the organic solvent of the multiple emulsion, then centrifugally washing for three times and freeze-drying.
The BMP-2/MPEG-PCL microsphere prepared by the invention has the average grain diameter of 6.17 mu m.
The invention has the beneficial effects that:
(1) The carrier material is an important part of the microsphere, and the good protein carrier material has the following characteristics that firstly, the good biocompatibility is required, and the rejection reaction cannot occur in vivo; secondly, the good protein carrier material should also be degradable in vivo, the degraded product should not harm human body, and the previous microsphere carrier material can generate acidic substances after being degraded in human body to trigger inflammation to have adverse effect on the treatment effect of the affected part; finally, the good protein carrier material should have proper slow release time and degradation speed, and the treatment effect can be influenced by too fast or too slow;
(2) The invention adopts the multiple emulsion solvent volatilization method to prepare the microspheres, and the microspheres prepared by the method have uniform particle size distribution and high quality;
(3) The shearing speed and time also have great influence on the grain diameter of the microspheres, a great deal of experiments are carried out on the shearing speed and time of primary emulsion and multiple emulsion in the process of preparing the microspheres, and the optimal shearing time of the primary emulsion is 0.5min, the shearing speed is 10000r/min, the optimal shearing time of the multiple emulsion is 1min and the shearing speed is 5000r/min through optimization, so that the microspheres with more uniform grain diameter distribution can be obtained by adopting the shearing speed and time;
(4) The microsphere prepared by the invention has uniform particle size distribution, non-rough surface, high stability and simple and easy preparation method, can be locally injected and administered, ensures that BMP-2 acts on an application part stably for a long time, promotes bone growth, can prolong the action time of the medicament, improves the treatment effect, slowly releases, reduces toxic and side effects, improves the treatment effect, greatly reduces the administration times and improves the compliance of patients.
Drawings
FIG. 1 is a distribution diagram of the particle size of BMP-2/MPEG-PCL microspheres.
FIG. 2 is a scanning electron microscope image of BMP-2/MPEG-PCL microspheres.
FIG. 3 is the release profile of BMP-2/MPEG-PCL microspheres in pH4 acetate buffer using dynamic membrane dialysis.
Detailed Description
The present invention is described in detail below by way of examples, it should be noted that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention, and that some insubstantial modifications and adaptations by those skilled in the art based on the following descriptions are within the scope of the present invention.
Example 1 preparation of BMP-2/MPEG-PCL microspheres: 100mgMPEG-PCL is weighed and placed in 1ml of organic solvent dichloromethane, vortex is carried out to accelerate the dissolution of the MPEG-PCL, the dichloromethane is easy to volatilize, and the MPEG-PCL is prepared for use. 0.24mg of polyvinyl alcohol (PVA) was weighed out and dissolved in 12ml of ultrapure water to obtain a 2% concentration PVA solution. Adding 0.2ml BMP-2 solution into MPEG-PCL solution, and shearing with a homogenizer at ice bath condition of 10000r/min for 0.5min to obtain colostrum. Adding the primary emulsion into PVA solution, and shearing for 1min at 5000r/min by a homogenizer under the ice bath condition to obtain the multiple emulsion. And (3) placing the multiple emulsion on a magnetic stirrer, stirring for 4h at the speed of 400r/min, volatilizing the organic solvent, centrifugally washing for three times, and freeze-drying to obtain the BMP-2/MPEG-PCL microspheres. The average particle size of the prepared microspheres is 6.17 μm, as shown in FIG. 1, and the scanning electron micrograph is shown in FIG. 2.
Example 2 release profile of BMP-2/MPEG-PCL microspheres in pH4 acetate buffer: BMP-2/MPEG-PCL microspheres were prepared as in example 1. The release profile of the drug in acetate buffer pH4 was examined by dynamic membrane dialysis and shown in FIG. 3.
As can be seen from FIG. 3, at about 50h, the release rate of BMP-2 is relatively fast, but with the time being prolonged, the microsphere gradually slows down the release rate of the drug, about 42% of the drug is released at day 16, and the microsphere preparation can prolong the action time of the drug, improve the treatment effect, greatly reduce the administration times and improve the compliance of patients.
The above description is only a preferred embodiment of the present application and is not intended to limit the present application, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims (13)
1. A preparation method of bone morphogenetic protein microspheres is characterized in that the bone morphogenetic protein microspheres are used for encapsulating BMP-2 by taking MPEG-PCL as a carrier material, and comprises the following steps:
(1) Dissolving MPEG-PCL in dichloromethane which is an organic solvent to prepare MPEG-PCL solution;
(2) Dispersing the BMP-2 solution in the MPEG-PCL solution;
(3) Placing the MPEG-PCL solution dissolved with BMP-2 in a homogenizer, stirring and emulsifying for the first time to obtain primary emulsion;
(4) Slowly adding the primary emulsion into a dispersion medium polyvinyl alcohol solution, continuously shearing, and carrying out second emulsification to obtain a multiple emulsion;
(5) And (3) placing the multiple emulsion on a magnetic stirrer, stirring, volatilizing the organic solvent, and freeze-drying to obtain the BMP-2 microspheres.
2. The method of claim 1, wherein the MPEG-PCL solution is at a concentration of 100 mg/ml.
3. The preparation method according to claim 1, wherein the first emulsification is carried out by a homogenizer in an ice bath environment, and the shearing speed is 5000 to 15000r/min, and the time is as follows: 30 to 90s.
4. The method of claim 3, wherein the shear rate is 10000r/min and the shear rate is 0.5min.
5. The method according to claim 1, wherein the colostrum is emulsified for a second time by a homogenizer in an ice bath at a shear rate of 5000 to 15000r/min for a time of: 30 to 120s.
6. The method of claim 5, wherein the refiner has a shear rate of 5000r/min and a shear rate of 1min.
7. The method according to any one of claims 4 to 6, wherein the concentration of the polyvinyl alcohol solution is 2% to 4%.
8. The method of claim 7, wherein the polyvinyl alcohol solution is present at a concentration of 2%.
9. The preparation method according to claim 1, wherein the multiple emulsion is placed on a magnetic stirrer at a speed of 300 to 700r/min for the following time: and volatilizing the organic solvent for 3 to 6 hours, centrifuging, washing for three times, and freeze-drying to obtain the BMP-2/MPEG-PCL microspheres.
10. The method according to claim 9, wherein the magnetic stirrer is operated at a stirring speed of 400r/min for 4 hours.
11. The method according to claim 1, wherein the ratio of the BMP-2 solution to the MPEG-PCL solution by volume is: 1, (5 to 10); volume ratio of MPEG-PCL solution to polyvinyl alcohol solution: 1, (10 to 15).
12. The method according to claim 11, wherein the ratio of the BMP-2 solution to the MPEG-PCL solution is 1; the volume ratio of the MPEG-PCL solution to the polyvinyl alcohol solution is 1.
13. BMP-2/MPEG-PCL microspheres prepared by the method of any one of claims 1 to 12.
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