CN107670024A - A kind of sustained-release micro-spheres for being loaded with bone morphogenetic protein - Google Patents
A kind of sustained-release micro-spheres for being loaded with bone morphogenetic protein Download PDFInfo
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- CN107670024A CN107670024A CN201711106516.4A CN201711106516A CN107670024A CN 107670024 A CN107670024 A CN 107670024A CN 201711106516 A CN201711106516 A CN 201711106516A CN 107670024 A CN107670024 A CN 107670024A
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- Prior art keywords
- bmp
- sustained
- mpeg
- pcl
- spheres
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1875—Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
Abstract
The present invention relates to a kind of new carrier material methoxy poly (ethylene glycol) polycaprolactone（MPEG‑PCL）For containing bone morphogenetic protein（BMP‑2）The sustained-release micro-spheres of preparation.The novel carriers material MPEG PCL that the present invention uses are used for containing BMP 2, prepare microball preparation can local injection administration, make 2 long-acting stabilizations of BMP acts on application site, promote bone uptake, the action time of medicine can be extended, therapeutic effect is improved and be sustained, reduce toxic side effect, improve the purpose of therapeutic effect, greatly reduce administration number of times, improve patient's compliance.
Description
Technical field
The present invention relates to the preparing technical field of bone renovating material, one kind is loaded with bone morphogenetic protein（BMP-2）It is slow
Release microballoon.
Background technology
Startup factor when BMP-2 is repair of fractured bones, can be with inducing bone mesenchymal stem cell to thin into cartilage, skeletonization
Born of the same parents' directional proliferation breaks up, so as to promote the formation of cartilage and bone.But the half-life shorts of BMP-2 in vivo, whole body and part
Using being diluted being metabolized quickly, do not reach desired biological effect, need repeatedly a large amount of administrations, dosage is far above physiological water
It is flat, easily trigger such as local soft tissue oedema, spinal cord radiculitis, ectopic ossification, bone regeneration around implant bone information and initiation cancer
The a series of complication such as disease, repetitively administered also increase the pain on patient body and burden economically.Passed to overcome
The defects of BMP-2 preparations of system, go out medicine come Continuous slow release to maintain the dense of topical remedy by preparing slow releasing carrier of medication
Degree, it is one of approach solved the effect of so as to improve medicine.
MPEG2000-PCL2000（MPEG-PCL）It is a kind of block copolymer, one end is hydrophilic segment-methoxy
Base polyethylene glycol, one end are oleophylic segment-polycaprolactones.By adjusting molecular weight or hydrophilic/lipophilic segment ratio, methoxyl group
PEG-PCL can be as the carrier material of variety classes medicine, and improves the water solubility and envelop rate of medicine
And drugloading rate.MPEG2000-PCL2000 can be made into microballoon, micro-capsule, vesica, the micella for carrying medicine, for realizing medicine
Slow-release controlled-release, can also be used as into the preferable tissue engineering bracket material of hydrophily.
The content of the invention
For above-mentioned prior art, the invention provides one kind to be loaded with bone morphogenetic protein（BMP-2）Sustained-release micro-spheres,
Carrier material selected by the present invention is MPEG2000-PCL2000（MPEG-PCL）Copolymer, it is as preparation
The carrier material of BMP-2 microballoons has not yet to see report, have it is non-toxic, without it is pyrogenicity, without sensitization, without teratogenesis carcinogenicity
The advantages of advantage, has a good histocompatbility, abundance, and it is different from other carrier materials is to be nearly free from acid
Property degradation by-products, reduce the generation of inflammatory reaction.This is loaded with bone morphogenetic protein（BMP-2）Sustained-release micro-spheres can reach
To sustained release, whole body toxic side effect is reduced, improves the purpose of therapeutic effect.
It is an object of the invention to provide one kind to be loaded with bone morphogenetic protein（BMP-2）Sustained-release micro-spheres.Microballoon utilizes
Dynamic Membrane dialysis, the BMP-2 of the 400h releasable 40% in pH4 acetate buffers, and there is bioactivity such as Fig. 1.
Technical scheme is as follows.
One kind is loaded with bone morphogenetic protein（BMP-2）Sustained-release micro-spheres construction method, comprise the following steps：Will be appropriate
MPEG-PCL be dissolved in dichloromethane, and a certain amount of a certain proportion of BMP-2 solution is dispersed therein, uses refiner
Colostrum is prepared, colostrum is then slowly added into decentralized medium（Poly-vinyl alcohol solution）In, continue to shear, obtain emulsion.By this
Emulsion is placed on magnetic stirring apparatus stirs 4h, volatile organic solvent with 400r/min, and centrifugation washing three times, freezes, produces this
It is loaded with bone morphogenetic protein（BMP-2）Sustained-release micro-spheres.
In the above method, organic solvent dichloromethane is volatile, needs matching while using.
In the above method, the concentration for the BMP-2 solution being distributed in MPEG-PCL solution is 550 μ g/ml.
In the above method, the volume ratio of BMP-2 solution/MPEG-PCL solution：1：（4~10）, it is preferred that BMP-2 solution/
The volume ratio of MPEG-PCL solution：1:5.
In the above method, the concentration range 2% ~ 4% of decentralized medium poly-vinyl alcohol solution, preferable concentration is 2%.
In the above method, MPEG-PCL solution/poly-vinyl alcohol solution volume ratio：1:（10~15）, it is preferred that MPEG-PCL
Solution/poly-vinyl alcohol solution volume ratio：1:12.
In the above method, bone morphogenetic protein is loaded with（BMP-2）Sustained-release micro-spheres, be by the bulk drug of following parts by weight
Made of auxiliary material：Preferably, MPEG2000-PCL2000（MPEG-PCL）Concentration：100mg/ml, polyvinyl alcohol
（PVA）Concentration：The volume ratio of 2%, BMP-2 solution/MPEG-PCL solution：1:5, MPEG-PCL solution/poly-vinyl alcohol solution volume
Than：1:12.
In the above method, first time emulsification is carried out in the environment of ice bath using refiner, shearing rotating speed is 5000 ~
15000r/min.Time is：30 ~ 90 seconds, colostrum is prepared；Preferably, shearing rotating speed 10000r/min, shear time
0.5min。
In the above method, colostrum is added in PVA solution, with refiner under condition of ice bath, colostrum is added to PVA solution
Middle second of emulsification of progress, uses 5000 ~ 15000r/min of rotating speed, mixing time：30 ~ 120s, obtain emulsion.Preferably, it is even
Pulp grinder shear rate 5000r/min, shear 1min.
In the above method, emulsion is placed on magnetic stirring apparatus, 300 ~ 700r/min stirring 3 ~ 6h volatile organic solvents are excellent
Choosing, 400r/min stirring 4h, remove organic solvent.
In the above method, after the organic solvent for the emulsion that volatilizees, then centrifuge washing three times, freeze, produce this and be loaded with bone shape
Albumen occurs for state（BMP-2）Sustained-release micro-spheres.
Bone morphogenetic protein is loaded with by what the present invention was prepared（BMP-2）Sustained-release micro-spheres, the average grain of microballoon
Footpath is 6.17 μm.
Beneficial effects of the present invention：
（1）Carrier material is the pith of microballoon, and good protein carrier material should have the characteristics that, first have to have
There is good biocompatibility, rejection cannot occur in vivo；Secondly, good protein carrier material should also be in body
Interior degradable, product should not produce harm to human body after degraded, and microspherical carrier material before can produce after being degraded in human body
Acidic materials trigger inflammation to affected part therapeutic effect harmful effect；Finally, good protein carrier material should also have suitable delay
Release time and degradation speed, it is too fast or can all influence therapeutic effect slowly excessively;
（2）The present invention employs double emulsion solvent volatility process and prepared when preparing microballoon, the microspherulite diameter obtained by this method point
Cloth is uniform, and quality is high;
（3）Shearing rotating speed can also have a significant impact with the time to the particle diameter of microballoon, and the present invention is during microballoon is prepared, to colostrum
Many experiments are done with the time with the shear rate of emulsion, by preferred, it is 0.5min to draw the optimal shear time of colostrum, is cut
Cutting speed degree is 10000r/min, and the optimal shear time of emulsion is 1min, shear rate 5000r/min, using this shear rate with
Time can obtain the more uniform microballoon of particle diameter distribution;
（4）The microspherulite diameter of the present invention is evenly distributed, and surface is not coarse, and stability is high, and preparation method is simple to operation, can be local
Drug administration by injection, make the application site that acts on of the long-acting stabilizations of BMP-2, promote bone uptake, the action time of medicine can be extended, carried
High therapeutic effect and it is sustained, reduces toxic side effect, improve the purpose of therapeutic effect, greatly reduce administration number of times, improves patient
Compliance.
One kind of the present invention is loaded with bone morphogenetic protein（BMP-2）Sustained-release micro-spheres, preparation method is simple, can reach slow
Release, reduce whole body toxic side effect, improve the purpose of therapeutic effect.
Brief description of the drawings
Fig. 1 is that microballoon utilizes Dynamic Membrane dialysis, the release profiles in pH4 acetate buffers.
Fig. 2 is the scanning electron microscope (SEM) photograph of microballoon.
Fig. 3 is the grain size distribution of microballoon.
Embodiment
The present invention is specifically described below by embodiment, it is necessary to be pointed out that following embodiments are served only for this
Invention is described further, it is impossible to is interpreted as limiting the scope of the invention, person skilled in art states under
It is all within the scope of the present invention that bright content makes some nonessential modifications and adaptations.
The one kind of embodiment 1 is loaded with bone morphogenetic protein（BMP-2）Sustained-release micro-spheres produce:Weigh 100mgMPEG-
PCL is placed in 1ml organic solvent dichloromethanes, is vortexed and is accelerated its dissolving, dichloromethane is volatile, should be now with the current.Weigh
0.24mg polyvinyl alcohol（PVA）, it is dissolved in 12ml ultra-pure waters, obtains the PVA solution that concentration is 2%.0.2mlBMP-2 solution is taken to add
Into MPEG-PCL solution, with refiner under condition of ice bath, 10000r/min, 0.5min is sheared, obtains colostrum.By colostrum plus
Into PVA solution, with refiner under condition of ice bath, 5000r/min, 1min is sheared, obtains emulsion.The emulsion is placed in magnetic force
4h, volatile organic solvent are stirred with 400r/min on agitator, centrifugation washing three times, freezes, produces this and be loaded with Bones morphology
Albumen（BMP-2）Sustained-release micro-spheres.Obtained microsphere average grain diameter is 6.17 μm, as shown in Fig. 2 the ESEM for microballoon
Photo, Fig. 3 are the grain size distribution of microballoon.
Embodiment 2 is loaded with bone morphogenetic protein（BMP-2）Release of the sustained-release micro-spheres in pH4 acetate buffers
Curve:It is made by embodiment 1 and is loaded with bone morphogenetic protein（BMP-2）Sustained-release micro-spheres.Using Dynamic Membrane dialysis, it is investigated
Release rule in pH4 acetate buffers, gained release profiles are as shown in Figure 1.
As shown in Figure 1, in about preceding 50h, BMP-2 rate of release is relatively fast, but with the extension of time, microballoon discharges
The speed of medicine is slowed down gradually, and about 42% medicine was released at the 16th day, and microball preparation can extend the action time of medicine,
Therapeutic effect is improved, greatly reduces administration number of times, improves patient's compliance.
Claims (7)
1. one kind is loaded with bone morphogenetic protein（BMP-2）Sustained-release micro-spheres, it is characterised in that the sustained-release micro-spheres are by methoxy
Base polyethylene glycol polycaprolactone（MPEG-PCL）As carrier, the carrier carries bone morphogenetic protein（BMP-2）, MPEG-
BMP-2 is wrapped among microballoon by PCL.
2. it is loaded with bone morphogenetic protein as claimed in claim 1（BMP-2）Sustained-release micro-spheres, it is characterised in that the sustained release is micro-
The preparation method of ball comprises the following steps：
（1）MPEG-PCL is dissolved in the MPEG-PCL solution for being made that concentration is 100mg/ml in organic solvent dichloromethane；
（2）BMP-2 solution is scattered in MPEG-PCL solution；
（3）Stirred refiner is placed under condition of ice bath dissolved with BMP-2 MPEG-PCL solution, shearing rotating speed 5000 ~
15000r/min, time are that emulsification obtains colostrum for the first time for 30 ~ 90s progress；
（4）Colostrum is slowly added into decentralized medium（Solution concentration is 2% ~ 4% poly-vinyl alcohol solution）In with 5000 ~
15000r/min rotating speed continues 30 ~ 120s of shearing, carries out second and emulsifies, obtains emulsion；
（5）This emulsion is placed on magnetic stirring apparatus 3 ~ 6h, volatile organic solvent, centrifugation are stirred with 300 ~ 700r/min rotating speed
Washing three times, freezes, produces the bone morphogenetic protein（BMP-2）Sustained-release micro-spheres.
3. preparation method as claimed in claim 2, it is characterised in that in step（2）In, BMP-2 solution and MPEG-PCL are molten
The volume ratio of liquid：1:（5~10）；The volume ratio of MPEG-PCL solution and poly-vinyl alcohol solution：1:（10~15）.
4. preparation method as claimed in claim 2, it is characterised in that in step（4）In, the solution concentration of poly-vinyl alcohol solution
For 2% ~ 4%.
5. one kind as claimed in claim 1 is loaded with bone morphogenetic protein（BMP-2）Sustained-release micro-spheres, it is characterised in that this is micro-
Ball is shaped as the spherical of rounding.
6. one kind as claimed in claim 1 is loaded with bone morphogenetic protein（BMP-2）Sustained-release micro-spheres, it is characterised in that this is micro-
The size distribution of ball is uniform, average grain diameter 6.5um.
7. one kind as claimed in claim 1 is loaded with bone morphogenetic protein（BMP-2）Sustained-release micro-spheres, it is characterised in that this is micro-
It is MPEG-PCL outside ball, bone morphogenetic protein（BMP-2）It is evenly distributed in inside microballoon.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711106516.4A CN107670024A (en) | 2017-11-10 | 2017-11-10 | A kind of sustained-release micro-spheres for being loaded with bone morphogenetic protein |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711106516.4A CN107670024A (en) | 2017-11-10 | 2017-11-10 | A kind of sustained-release micro-spheres for being loaded with bone morphogenetic protein |
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| CN107670024A true CN107670024A (en) | 2018-02-09 |
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| CN201711106516.4A Pending CN107670024A (en) | 2017-11-10 | 2017-11-10 | A kind of sustained-release micro-spheres for being loaded with bone morphogenetic protein |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014093836A1 (en) * | 2012-12-13 | 2014-06-19 | University Of Georgia Research Foundation, Inc. | Ossification-inducing composition and methods of use thereof |
| TW201714610A (en) * | 2015-04-06 | 2017-05-01 | Lg Household & Health Care Ltd | Soluble microneedle for protein or peptide |
| CN106620654A (en) * | 2017-01-25 | 2017-05-10 | 山东大学 | BMP-2/PPLA (bone morphogenetic protein-2/polylactic acid and polyethylene glycol block copolymer) microspheres and preparation method thereof |
-
2017
- 2017-11-10 CN CN201711106516.4A patent/CN107670024A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014093836A1 (en) * | 2012-12-13 | 2014-06-19 | University Of Georgia Research Foundation, Inc. | Ossification-inducing composition and methods of use thereof |
| TW201714610A (en) * | 2015-04-06 | 2017-05-01 | Lg Household & Health Care Ltd | Soluble microneedle for protein or peptide |
| CN106620654A (en) * | 2017-01-25 | 2017-05-10 | 山东大学 | BMP-2/PPLA (bone morphogenetic protein-2/polylactic acid and polyethylene glycol block copolymer) microspheres and preparation method thereof |
Non-Patent Citations (4)
| Title |
|---|
| 丁婷婷: ""负载BMP-2的MPEG-PCL微球的制备及成骨活性评价"", 《中国学位论文全文数据库》 * |
| 傅顺等: "聚（ε-己内酯）-聚乙二醇-聚（ε-己内酯）两亲三嵌段共聚物蛋白大分子药物微球的研究"", 《中国药房》 * |
| 刘丽波等: ""O/O乳化-溶剂挥发法制备mPEG-PCL微球的形成过程及影响因素"", 《上海交通大学学报》 * |
| 唐见茂: "《绿色复合材料》", 31 December 2016, 中国铁道出版社 * |
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