CN104525068B - Preparation method of polylactic acid-based bipolymer hollow microsphere - Google Patents
Preparation method of polylactic acid-based bipolymer hollow microsphere Download PDFInfo
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Abstract
The invention belongs to the technical field of a high-molecular material, and particularly relates to a preparation method of a polylactic acid-based bipolymer hollow microsphere. The bipolymer is formed by copolymerization of lactide having different optical activity with biodegradable materials such as carbonic ester (TMC), glycolide (GA), polycaprolactone (PCL) or polyethylene glycol (PEG). A levorotatory polylactic acid-based bipolymer and a dextrorotatory polylactic acid-based bipolymer are blended in a solution according to a certain ratio and then poured and volatilized to form a film; the prepared film is put into a protease K solution and is degraded in an oven which is at a constant temperature of 37 DEG C; sampling is performed at different time to prepare the polylactic acid-based polymer microsphere with a hollow structure. The polymer microsphere prepared by the method disclosed by the invention is 2 micrometers in diameter, uniform in particle size distribution, capable of being widely applied to the fields such as biological medicine carrying and knee cartilage repair, and wide in application prospect.
Description
Technical field
The invention belongs to technical field of polymer materials is and in particular to a kind of polylactic acid base bipolymer hollow microsphere
Preparation method.
Background technology
Polylactic acid (pla) is that the green that one kind is prepared from Renewable resource (as straw, starch) for raw material is moulded
Material, due to having good biocompatibility and biodegradability so as to carry medicine and knee cartilage reparation etc. in bio-medical
Field has great using value.
The polylactic acid microsphere method of preparing of disclosedization mainly has phase separation method, emulsification-evaporation method, freezing method at present
With nebulization etc..Wherein being most widely used of emulsification-evaporation method.Its operational approach be polymer is dissolved in organic molten
In agent, then under high-speed stirred, organic aqueous phase that is added to is carried out emulsifying again, with the volatilization of solvent, microsphere gradually forms.Specially
Sharp document 1 discloses one kind and prepares coffee acid polylactic acid copolymer nanometer microsphere using above-mentioned emulsification-evaporation method.Should
Method concrete operations are: copolymer of poly lactic acid and caffeic acid are dissolved in organic solvent, as organic faciess；Slow under agitation
Slow addition pva aqueous solution, makes organic solvent volatilize by stirring, and centrifugation, washing, lyophilization obtain pla copolymer microsphere.So
And organic solvent easily causes microsphere that serious volume contraction occurs in volatilization process, lead to Microsphere Size uncontrollable.Additionally,
The microsphere that this technical method prepares mostly is solid construction, seriously reduces drug loading.In addition, patent documentation 2 ~ 4 is equal
Disclose this technology.These preparation methoies all in a large number using organic solvent, are inevitably made in prepared microsphere
Become dissolvent residual, use as pharmaceutical carrier and have serious security hidden trouble.This in preparation technology and environmental conservation all
Constrain the development of this technical method, the organic solvent simultaneously remaining when polylactic acid microsphere uses as pharmaceutical carrier also can carry
Carry out potential safety hazard.For above deficiency, the method using being separated and emulsifying-both solvent volatilizations combine for the patent documentation 5, preparation
Obtain porous polylactic acid microball.But, the porosity of institute's acquisition microsphere is not high, and load capacity still can not reach conventional medicine
Carry medicine to require.In addition, most of microsphere inside and outside hole connect, institute's carrying medicament is easy to run off from hole,
Medicine is led to be unable to reach the effect of accurate slow release.
The present invention is directed in the studies above to be had organic solvent residual, is readily obtained solid microsphere and drug loading is low not
Foot, employs protease k degradation technique, is prepared for that particle diameter distribution is homogeneous, and has the polylactic acid microsphere of hollow structure.The method
Avoid the use of a large amount of organic solvents, be a kind of brand-new preparation side preparing polylactic acid base bipolymer hollow microsphere
Method.
List of references:
Patent documentation 1: Chinese patent, publication number cn101305985a
Patent documentation 2: Chinese patent, publication number cn103834054a
Patent documentation 3: Chinese patent, publication number cn102143996a
Patent documentation 4: Chinese patent, publication number cn102211008a
Patent documentation 5: Chinese patent, publication number cn1586704a.
Content of the invention
Present invention aims to the shortcomings of existing polylactic acid microsphere material preparation process complexity, structure heterogeneity,
There is provided a kind of porosity high, preparation process is simple, particle diameter distribution is homogeneous, and has the preparation side of the polylactic acid microsphere of hollow structure
Method.
The preparation method of the polylactic acid hollow microsphere that the present invention provides, using protease k selective etch technology, using material
Difference on material crystalline region and amorphous area two phase structure, first performs etching to the amorphous area on copolymer surface, subsequent crystalline region is in albumen
Under enzyme k solution effects, degrade in inside, prepares polylactic acid base bipolymer hollow microsphere, concretely comprises the following steps:
(1) prepare polylactic acid bipolymer thin film；
(2) again polylactic acid bipolymer thin film is put in protease k solution and perform etching；
(3) etched thin film is taken out from protease k solution, drying is processed, that is, obtain polylactic acid base binary altogether
Polymers hollow microsphere.
Wherein, described polylactic acid base bipolymer, for having l type lactide (left-handed) (plla) of different optical activitys
With Biodegradable materials such as trimethylene carbonate (tmc), Acetic acid, hydroxy-, bimol. cyclic ester (ga), polycaprolactone (pcl) or Polyethylene Glycol (peg)
The bipolymer that copolymerization is formed: plla-tmc, plla-ga, plla-peg or plla-pcl, and d type lactide (dextrorotation)
(pdla) can drop with biologies such as trimethylene carbonate (tmc), Acetic acid, hydroxy-, bimol. cyclic ester (ga), polycaprolactone (pcl) or Polyethylene Glycol (peg)
The bipolymer that solution material copolymerization is formed: pdla-tmc, pdla-ga, pdla-peg or pdla-pcl.
In bipolymer, plla(or pdla) molar content of unit is 75% ~ 95%；Tmc, ga, pcl or peg unit
Molar content be 5% ~ 25%.Preferably plla(or pdla) unit molar content be 85 ~ 95%；Tmc, ga, pcl or peg unit
Molar content be 5 ~ 15%.
The number-average molecular weight of above-mentioned bipolymer is 1.0 × 104~5.0×105.
In the present invention, described in step (1), prepare polylactic acid bipolymer thin film, be by plla(pdla)-(tmc,
Ga, peg, pcl) (i.e. Poly-L-lactic acid base bipolymer and dextrorotation polylactic acid base bipolymer: plla-tmc and pdla-
Tmc, plla-ga and pdla-ga, plla-peg and pdla-peg, plla-pcl and pdla-pcl) 2 kinds of bipolymers are respectively
It is dissolved in dichloromethane, pour in silica ware together and mixed, then volatilization film forming of casting.Wherein, described solvent dichloro
Methane concentration is 0.1 ~ 200 w/v%, preferably 1 ~ 5 w/v%.The weight proportion of two kinds of described bipolymers is 70:30 ~ 30:
70, preferred weight proportioning is 45:55 ~ 55:45.
In the present invention, described in step (2), polylactic acid bipolymer thin film is put in protease k solution and carved
Erosion, is to put into the thin film preparing in protease k solution, is degraded in 37 DEG C of constant temperature ovens, degradation time 0 ~ 30 day,
Every 6 hours to 3 days of interval time changed a protease k solution, different time sampling during degraded；Preferably degradation time 0 ~
15 days, every 6 ~ 12 hours of interval time changed a protease k solution.
Wherein, the compound method of described protease k solution is as follows: first compound concentration is the tris of 0.01 ~ 0.2mol/l
The hcl solution of solution and 0.01 ~ 0.2mol/l, takes 50 ~ 500mltris solution, adds hcl solution, adjusts ph value to 8.6, is formed
Tris buffer solution.Wherein tris solution concentration preferably 0.05 ~ 0.1mol/l, hcl solution preferably 0.05 ~ 0.1mol/l.
After preparing tris buffer solution, weigh 1.0 ~ 5.0mg protease k respectively, 1.0 ~ 5.0mg Hydrazoic acid,sodium salt is dissolved in
The ph of 5 ~ 50ml is in 8.6 tris buffer solution, is configured to protease k solution.
In the present invention, dried described in step (3), thin film that can be just etched takes from protease k solution
Go out, put into after being dried process in vacuum drying oven.
In the present invention, above-mentioned optimum condition on the basis of with reference to common sense in the field can combination in any, obtain final product the present invention each
Preferred embodiment.
The raw material of the present invention and reagent are all commercially available.
The present invention, due to preparing microsphere using protease k edman degradation Edman, is prepared into using emulsification-evaporation method with traditional
To microsphere compare.The microsphere preparing has hollow structure, is more beneficial for as medicine or cell carrier；And, with breast
Change-solvent evaporation method needs unlike a large amount of organic solvents in operation, prepares polylactic acid hollow using edman degradation Edman micro-
Ball consumption of organic solvent is little, and preparation technology is more environmentally-friendly, and product does not have this potential safety hazard of residual solvent when using；With
When, this complete biodegradable of polylactic acid bipolymer.Therefore, the polylactic acid base bipolymer that the present invention prepares is micro-
Ball has great advantage, can be widely applied to the fields such as bio-medical material, such as can be applicable to bio-medical and carries medicine and knee
Repair of cartilage etc..
Brief description
Fig. 1 is the sem figure of embodiment 1 pla80/ga20 bipolymer hollow microsphere.
Fig. 2 is the load medicine preparation-time graph of embodiment 1 pla80/ga20 bipolymer hollow microsphere.
Fig. 3 is the sem figure of embodiment 2 pla85/peg15 bipolymer hollow microsphere.
Fig. 4 is the sem figure of comparative example 9 pla95/tmc5 bipolymer hollow microsphere.
Fig. 5 is the sem figure of comparative example 10 pla80/ga20 bipolymer hollow microsphere.
Specific embodiment
Example is given below, to be specifically described to the present invention.But the present invention is not intended to be limited thereto, wherein:
The polylactic acid base bipolymer hollow microsphere of present invention preparation, by scanning electron microscope (sem) to microsphere
Surface topography and microscopic pattern are characterized, sem model fegs-4800, accelerate sample surfaces metal spraying, and accelerating potential is 1kv,
Electric current is 14.7 μ a.Using high performance liquid chromatography (hplc), the paclitaxel carried medicine amount of microsphere and envelop rate are characterized, hplc
Model Japan Shimadzu Corporation lc-10a, is equipped with spd-10a ultraviolet uv detector and dionex chromatographic column, Detection wavelength 227nm,
Mobile phase is acetonitrile/water (55:45, volume ratio), and flow velocity is 1.0ml/min.By Malvern zetasizer nano granularity electricity
Position analyser characterizes to the size of microspherulite diameter.
Embodiment 1
(1) weighing molecular weight is 5.0 × 104Plla-ga, pdla-ga bipolymer of g/mol, ga molar content 20%
Each 1.5g is added separately in the dichloromethane of 150ml, and stirring 2h makes it be completely dissolved.Again two kinds of solution are mixed,
Under room temperature, stirring 4h makes its plla-ga solution mix homogeneously with pdla-ga solution, stands 1 week, treat that its solvent is evaporated completely under room temperature
Full film forming.
(2) compound concentration is the hcl solution of the tris solution 0.1mol/l of 0.1mol/l, takes 500ml0.1mol/l's
Tris solution, adds the hcl solution of 0.1mol/l, is settled to 1l, forms the buffer solution of ph value 8.6.Then by 2.0mg albumen
Enzyme k, 2.0mg Hydrazoic acid,sodium salt is dissolved in 10ml buffer solution, is configured to protease k solution.
(3) thin film preparing in step (1) is put in protease k solution, degraded in 37 DEG C of baking ovens, 36 is little
When after sampling, dry, obtain polylactic acid base bipolymer hollow microsphere.
Can see from table 1 hollow microsphere drug loading be 7.0%, envelop rate be 73.0%.Polylactic acid as can be seen from Fig. 1
Base bipolymer hollow microsphere has good hollow structure, and microspherulite diameter is in 2 microns.Fig. 2 is hollow microsphere as purple
The drug accumulation release profiles of China fir alcohol pharmaceutical carrier, it reaches more than 50% in the 4th day release rate as seen from the figure, can be used as property
The excellent pharmaceutical carrier of energy.
Embodiment 2
Weighing molecular weight is 5.0 × 104Plla-peg, pdla-peg bipolymer of g/mol, peg molar content 15%
Each 1.5g is added separately in the dichloromethane of 150ml, and stirring 2h makes it be completely dissolved.Step in preparation process such as embodiment 1
(1) (2) (3) are described.Its drug loading is 6.7%, envelop rate 65.4%.The sem of gained sample schemes as shown in figure 3, microspherulite diameter 2 is micro-
About rice.
Embodiment 3
Weighing molecular weight is 5.0 × 104Plla-pcl, pdla-pcl bipolymer of g/mol, pcl molar content 10%
Each 1.5g is added separately in the dichloromethane of 150ml, and stirring 2h makes it be completely dissolved.Step in preparation process such as embodiment 1
(1) (2) (3) are described.Its drug loading is 6.1%, envelop rate is 61.1%.Gained sample has good hollow structure.
Embodiment 4
Weighing molecular weight is 5.0 × 104Plla-tmc, pdla-tmc bipolymer of g/mol, tmc molar content 10%
Each 1.5g is added separately in the dichloromethane of 150ml, and stirring 2h makes it be completely dissolved.Step in preparation process such as embodiment 1
(1) (2) (3) are described.Its drug loading is 5.8%, envelop rate is 57.2%.The microsphere hollow structure of gained sample is good.
Embodiment 5
(1) weighing molecular weight is 5.0 × 104Plla-ga, pdla-ga bipolymer of g/mol, ga molar content 20%
Each 1.5g is added separately in the dichloromethane of 150ml, and stirring 2h makes it be completely dissolved.Again two kinds of solution are mixed,
Under room temperature, stirring 4h makes its plla-ga solution and pdla-ga solution be sufficiently mixed, and stands 1 week, treat that its solvent is evaporated completely under room temperature
Full film forming.
(2) compound concentration is the hcl solution of the tris solution 0.1mol/l of 0.1mol/l, then takes 500ml0.1mol/l
Tris solution, add 0.1mol/l hcl solution, be settled to 1l.Form the buffer solution of ph value 8.6；Then by 4.0mg egg
White enzyme k, 4.0mg Hydrazoic acid,sodium salt is dissolved in 10ml buffer solution, is configured to protease k solution.
(3) thin film preparing in step (1) is put in protease k solution, degraded in 37 DEG C of baking ovens, 60 is little
When after sampling, dry, obtain polylactic acid base bipolymer hollow microsphere.The structure improvement of gained sample hollow microsphere.From table 1
Data is visible, and microsphere drug loading is 9.2%, envelop rate is 72.3%.
Embodiment 6
Weighing molecular weight is 1.0 × 105Plla-peg, pdla-peg bipolymer of g/mol, peg molar content 20%
Each 1.5g is added separately in the dichloromethane of 150ml, and stirring 2h makes it be completely dissolved.Step in preparation process such as embodiment 5
(1) (2) (3) are described.Gained sample microspheres structural integrity.Its drug loading is 8.7%, envelop rate is 67.8%.
Embodiment 7
Weighing molecular weight is 1.0 × 105Plla-pcl, pdla-pcl bipolymer of g/mol, pcl molar content 15%
Each 1.5g is added separately in the dichloromethane of 150ml, and stirring 2h makes it be completely dissolved.Step in preparation process such as embodiment 5
(1) (2) (3) are described.Gained sample microspheres structural integrity.Its drug loading is 7.7%, envelop rate is 63.2%.
Embodiment 8
Weighing molecular weight is 1.0 × 105Plla-tmc, pdla-tmc bipolymer of g/mol, tmc molar content 5%
Each 1.5g is added separately in the dichloromethane of 150ml, and stirring 2h makes it be completely dissolved.Step in preparation process such as embodiment 4
(1) (2) (3) are described.Gained sample microspheres structural integrity.Its drug loading is 6.5%, envelop rate is 60.1%.
In order to be better understood from the impact that degradation process and degradation time are prepared to hollow microsphere, spy carries out following right
Compare embodiment.
Comparative example 9, weighing molecular weight is 5.0 × 104Plla-tmc, pdla-tmc bis- of g/mol, tmc molar content 5%
The each 1.5g of membered copolymer is added separately in the dichloromethane of 150ml, and stirring 2h makes it be completely dissolved.Again two kinds of solution are mixed
Together, under room temperature, stirring 4h makes its plla-tmc solution and pdla-tmc solution be sufficiently mixed, and stands 1 week, treat it under room temperature
The solvent complete film of volatilization.By the thin film preparing without degraded, directly with sem, it is characterized, acquired results such as Fig. 4 institute
Show.Hollow microsphere is not had to be formed without the thin film of degraded as can be seen from Fig. 4.
Comparative example 10, weighing molecular weight is 1.0 × 105Plla-pcl, pdla-pcl of g/mol, pcl molar content 10%
The each 1.5g of bipolymer is added separately in the dichloromethane of 150ml, and stirring 2h makes it be completely dissolved.Again two kinds of solution are mixed
It is combined, under room temperature, stirring 4h makes its plla-tmc solution and pdla-tmc solution be sufficiently mixed, and stands 1 week, treat under room temperature
Its solvent complete film of volatilization.By the thin film preparing without degraded, directly with sem, it is characterized, acquired results such as Fig. 5
Shown.Identical with comparative example 9, the thin film without degraded does not have hollow microsphere to be formed.
Can be seen that from above-described embodiment and comparative example and polylactic acid base bipolymer is prepared using protease k edman degradation Edman
Hollow microsphere, with respect to traditional methods such as emulsification-evaporation method.It is effectively reduced the usage amount of organic solvent, whole system
Standby technique is more environmentally-friendly.Meanwhile, compared with preparing solid microsphere with emulsification-evaporation method, during the method prepares
Empty microspherulite diameter is less and has hollow structure simultaneously, has extensively in the field such as bio-medical pharmaceutical carrier and knee cartilage reparation
General application prospect.
Table 1 is the test result of the polylactic acid microsphere of different compositions
.
Claims (8)
1. a kind of preparation method of polylactic acid base bipolymer hollow microsphere is it is characterised in that carved using protease k selectivity
Erosion technology, using the difference on material crystalline region and amorphous area two phase structure, first performs etching to the amorphous area on copolymer surface, with
Crystalline region is internal under protease k solution effects afterwards degrades, and prepares polylactic acid base bipolymer hollow microsphere, specifically
Step is:
(1) prepare polylactic acid bipolymer thin film；
(2) polylactic acid bipolymer thin film is put in protease k solution and perform etching；
(3) etched thin film is taken out from protease k solution, drying is processed, that is, obtain polylactic acid base bipolymer
Hollow microsphere.
2. preparation method according to claim 1 it is characterised in that:
Described polylactic acid base bipolymer, the l type lactide for having different optical activitys is handed over trimethylene carbonate, second
The bipolymer that ester, polycaprolactone or Polyethylene Glycol copolymerization are formed, and d type lactide and trimethylene carbonate, Acetic acid, hydroxy-, bimol. cyclic ester,
Polycaprolactone or the bipolymer of Polyethylene Glycol copolymerization formation；
In bipolymer, the molar content of l type lactide or d type lactide unit is 75% ~ 95%；Trimethylene carbonate,
The molar content of Acetic acid, hydroxy-, bimol. cyclic ester, polycaprolactone or Polyethylene Glycol unit is 5% ~ 25%；
The number-average molecular weight of above-mentioned bipolymer is 1.0 × 104~5.0×105.
3. preparation method according to claim 2 it is characterised in that: in bipolymer, l type lactide or d type third
The molar content of lactide unit is 85 ~ 95%；Trimethylene carbonate, Acetic acid, hydroxy-, bimol. cyclic ester, polycaprolactone or Polyethylene Glycol unit mole
Content is 5% ~ 15%.
4. preparation method according to claim 2 it is characterised in that: prepare polylactic acid binary described in step (1) altogether
Homopolymer film, is that Poly-L-lactic acid base bipolymer and dextrorotation polylactic acid base bipolymer are dissolved separately in dichloromethane
In, pour in silica ware together and mixed, then volatilization film forming of casting；Wherein, described methylene chloride concentration be 0.1 ~
200 w/v%, the weight proportion of described Poly-L-lactic acid base bipolymer and dextrorotation polylactic acid base bipolymer be 70:30 ~
30:70.
5. preparation method according to claim 4 it is characterised in that: described Poly-L-lactic acid base bipolymer and the right side
The weight proportion of rotation polylactic acid base bipolymer is 45:55 ~ 55:45.
6. according to claim 2,3 or 4 preparation method it is characterised in that: polylactic acid binary described in step (2)
Copolymer film is put in protease k solution and is performed etching, and is to put in protease k solution by the thin film preparing, at 37 DEG C
Degraded in constant temperature oven, degradation time 0 ~ 30 day, every 6 hours to 3 days of interval time changed a protease k solution, in
Different time sampling during degraded.
7. preparation method according to claim 6 it is characterised in that: the compound method of described protease k solution is such as
Under: first compound concentration is the tris solution of 0.01 ~ 0.2mol/l and the hcl solution of 0.01 ~ 0.2mol/l, takes 50 ~ 500mltris
Solution, adds hcl solution, adjusts ph value to 8.6, forms tris buffer solution；Then, weigh respectively 1.0 ~ 5.0mg protease k,
The ph that 1.0 ~ 5.0mg Hydrazoic acid,sodium salt is dissolved in 5 ~ 50ml is in 8.6 tris buffer solution, is configured to protease k solution.
8. preparation method according to claim 2 it is characterised in that: dried described in step (3), is using true
Empty baking oven is dried process.
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