CN105982862B - Porous microsphere and preparation method thereof and drug bearing microsphere and its preparation method and application - Google Patents
Porous microsphere and preparation method thereof and drug bearing microsphere and its preparation method and application Download PDFInfo
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- CN105982862B CN105982862B CN201510075508.2A CN201510075508A CN105982862B CN 105982862 B CN105982862 B CN 105982862B CN 201510075508 A CN201510075508 A CN 201510075508A CN 105982862 B CN105982862 B CN 105982862B
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Abstract
The invention discloses a kind of preparation method of porous microsphere, this method is mainly included under electrostatic spinning conditions, and the EFI liquid containing pharmaceutical carrier polymer, the first solvent and the second solvent is carried out EFI.The present invention also provides porous microspheres prepared by the above method, and using the porous microsphere as the drug bearing microsphere of carrier.The present invention also provides a kind of preparation method of drug bearing microsphere and its drug bearing microspheres obtained.The present invention also provides above-mentioned drug bearing microspheres to prepare the application in the drug for treating the relevant disease of mucous membrane.The drug bearing microsphere that the present invention obtains has high mucoadhesive forces and high slow release effect.
Description
Technical field
The present invention relates to porous microspheres and preparation method thereof and drug bearing microsphere and its preparation method and application.
Background technique
In recent years in the relevant lysis for the treatment of human epithelia, nanosphere medicine carrier is as a kind of bioadhesion
Pharmaceutical carrier can carry out the conveying of drug and vaccine, have become one kind of substitution tradition intravenous injection administration mode
Novel approach.Relative to conventional medicament, Bio-adhesive pharmaceutical carrier has many peculiar advantages: on the one hand extending drug viscous
The administration time in attached site, to reduce the frequency of administration；Furthermore the binding force of drug Yu mucous epithelium tissue is enhanced, just
In the conveying of the poor drug of the conveying capacitys such as polypeptide, protein；It is finally that dosage is small, specificity is good, reduces conventional medicament
Side effect.It is emphasized that the lesions position multidigit of people's in-vivo tumour is in epithelial tissue, such as respiratory system, digestion
Road system and urinary system etc., while tumour cell and normal cell coexist on the mucosal tissue of epithelium, are target tumor
The administration of the Bio-adhesive pharmaceutical carrier of cell provides attachment sites, therefore carries out tumour by mucoadhesive delivery system in recent years
Chemotherapy be increasingly becoming hot spot.
Currently in order to the adhesive efficiency of enhancing mucoadhesive delivery system, researchers have attempted the preparation method of variety carrier,
On the one hand hydrophilic polymer, hydrogel, copolymer/interpolymer complex and thiolated polymers are constructed by chemical method
High molecular polymer adhesive systems, another aspect micro-processing technology also can be applied to the viscous of surface modification microtrabeculae or aculea structure
The adhesion strength in unit area can be enhanced in the building of appendix body, the microtrabeculae prepared in this way or aculea structure.In addition it is
The adhesion strength of enhancing and destination organization can use lectin, mercaptan and various other adhesion molecule functional groups to viscous
Film drug-loading system carries out special sex modification.However it is above-mentioned no matter the method for micro-machined method or particular adherence molecular modification all
The design cost for increasing Bio-adhesive pharmaceutical carrier, also makes complex manufacturing process, and the practicality needs to be proved.
Summary of the invention
It is an object of the invention to overcome the design cost of existing Bio-adhesive pharmaceutical carrier high, complex manufacturing process and
The uncontrollable defect of pattern, provide it is a kind of can morphology controllable, relatively easily obtain the porous micro- of Bio-adhesive pharmaceutical carrier
The preparation method of ball and its porous microsphere obtained, and the drug bearing microsphere after load medicine and its preparation are carried out using such carrier
Method.
In recent years, using electrostatic spinneret technology prepare Bio-adhesive pharmaceutical carrier, especially nanosphere medicine carrier be by
The method of pro-gaze.Electrostatic spinneret technology, abbreviation electric jet technology, refer in high voltage electric field conductive fluid generate it is micro-/receive scale
The process of EFI silk or EFI microballoon.And it was found by the inventors of the present invention that when specific pharmaceutical carrier polymeric material will be used
When material, the first solvent and the second solvent carry out mixing resulting mixed liquor as EFI liquid, and guarantee first solvent 20
DEG C saturated vapor pressure be higher than saturated vapor pressure of second solvent at 20 DEG C, and the dosage of first solvent be greater than it is described
The dosage of second solvent；The available porous microsphere especially suitable for carrying medicine, the porous microsphere are antitumor particularly suitable for carrying
The drugs such as medicine, anti-inflammatory drug, anodyne, antibiotic, anticoagulant, antiallergic, antifungal.
For this purpose, the present invention provides a kind of preparation method of porous microsphere, wherein this method comprises: in electrostatic spinning conditions
Under, the EFI liquid containing pharmaceutical carrier polymer, the first solvent and the second solvent is subjected to EFI, wherein described first is molten
Agent is higher than saturated vapor pressure of second solvent at 20 DEG C in 20 DEG C of saturated vapor pressure, and the dosage of first solvent is big
In the dosage of second solvent；The pharmaceutical carrier is polylactic acid, polyurethane, gelatin, polyacrylic acid, carboxylic with polymer material
In sodium carboxymethylcellulose pyce, polycarbophil, chitosan, polyvinylpyrrolidone, poly lactide-glycolide acid and polyvinyl alcohol
It is one or more.
The present invention also provides the porous microspheres obtained by the above method.
The present invention also provides a kind of drug bearing microspheres, wherein the carrier of the drug bearing microsphere is above-mentioned porous microsphere.
The present invention also provides a kind of preparation methods of drug bearing microsphere, wherein the preparation method includes: in electrostatic strand
Under part, the EFI liquid containing drug, pharmaceutical carrier polymer material, the first solvent and the second solvent is subjected to EFI, wherein
First solvent is higher than saturated vapor pressure of second solvent at 20 DEG C in 20 DEG C of saturated vapor pressure, and described first molten
The dosage of agent is greater than the dosage of second solvent；The pharmaceutical carrier with polymer material be polylactic acid, polyurethane, gelatin,
Polyacrylic acid, sodium carboxymethylcellulose, polycarbophil, chitosan, polyvinylpyrrolidone, poly lactide-glycolide acid
With one of polyvinyl alcohol or a variety of.
The present invention also provides drug bearing microspheres obtained by the preparation method as above-mentioned drug bearing microsphere.
The present invention also provides above-mentioned drug bearing microspheres to prepare the application in the drug for treating the relevant disease of mucous membrane.
The present invention by using electrostatic spinneret method, will containing the specific pharmaceutical carrier polymer material of the present invention,
First solvent and the second solvent carry out EFI, have obtained the porous microsphere for being very suitable for carrying drug, and select this using
Under the specific pharmaceutical carrier polymer material of sample, the first solvent and the second solvent, by drug and the specific pharmaceutical carrier
EFI liquid is mixed to get with polymer material, the first solvent and the second solvent and carries out EFI, and obtaining carrier band has having for drug high
The drug bearing microsphere of mucoadhesive forces, high slow release effect.Further, more empty microballoons provided by the invention can be micro- by regulating and controlling
The pore size and distribution of pores of ball surface, enable drug bearing microsphere more specifically to be combined with lesion tissue, to reach
Better drug release effect.
Other features and advantages of the present invention will the following detailed description will be given in the detailed implementation section.
Detailed description of the invention
The drawings are intended to provide a further understanding of the invention, and constitutes part of specification, with following tool
Body embodiment is used to explain the present invention together, but is not construed as limiting the invention.In the accompanying drawings:
Fig. 1 is a kind of electrostatic spinning appts.
Fig. 2 is the SEM figure of porous microsphere made from embodiment 1.
Fig. 3 is the SEM figure of porous microsphere made from comparative example 1.
Fig. 4 is the SEM figure for carrying drug bearing microsphere made from medicine embodiment 1.
Fig. 5 is the SEM figure for carrying drug bearing microsphere made from medicine comparative example 1.
Fig. 6 is the SEM figure for carrying drug bearing microsphere made from medicine embodiment 5.
Fig. 7 is the SEM figure for carrying drug bearing microsphere made from medicine embodiment 6.
Fig. 8 is the SEM figure for carrying drug bearing microsphere made from medicine embodiment 7.
Description of symbols
1 syringe
2 high voltage power supplies
3 syringe needles
4 collecting boards
Specific embodiment
Detailed description of the preferred embodiments below.It should be understood that described herein specific
Embodiment is merely to illustrate and explain the present invention, and is not intended to restrict the invention.
The present invention provides a kind of preparation method of porous microsphere, wherein this method comprises: under electrostatic spinning conditions, it will
EFI liquid containing pharmaceutical carrier polymer, the first solvent and the second solvent carries out EFI, wherein first solvent is 20
DEG C saturated vapor pressure be higher than saturated vapor pressure of second solvent at 20 DEG C, and the dosage of first solvent be greater than it is described
The dosage of second solvent；The pharmaceutical carrier is polylactic acid, polyurethane, gelatin, polyacrylic acid, carboxymethyl fibre with polymer material
Tie up one of plain sodium, polycarbophil, chitosan, polyvinylpyrrolidone, poly lactide-glycolide acid and polyvinyl alcohol
Or it is a variety of.
In the present invention, in order to obtain the porous microsphere for being suitable for carrying drug, the present inventor is by repeatedly attempting
It just finds, when the pharmaceutical carrier is polylactic acid, polyurethane, gelatin, polyacrylic acid, carboxymethyl cellulose with polymer material
One of sodium, polycarbophil, chitosan, polyvinylpyrrolidone, poly lactide-glycolide acid and polyvinyl alcohol are more
When kind, the porous microsphere for being more suitable for carrying medicine can be obtained, the medicine that treatment mucous membrane class there are related disorders can be carried by especially obtaining
The porous microsphere of object, such as antineoplastic, anti-inflammatory drug, anodyne, antibiotic, anticoagulant, antiallergic and antifungal,
For the drugs such as metronidazole, acetylsalicylic acid and 5 FU 5 fluorouracil, when using porous microsphere conduct of the invention
When its carrier, better slow release effect can be obtained.For this purpose, inventor is by the test repeatedly repeatedly attempted, it is found that when adopting
With polylactic acid, polyurethane, gelatin, polyacrylic acid, sodium carboxymethylcellulose, polycarbophil, chitosan, polyvinylpyrrolidone,
When one of poly lactide-glycolide acid and polyvinyl alcohol or a variety of conducts pharmaceutical carrier polymer material,
The above problem can be overcome, particularly preferably using in polylactic acid, polyvinylpyrrolidone and poly lactide-glycolide acid
When one or more conducts pharmaceutical carrier polymer material, it can obtain and carry the more superior porous microsphere of drug effect fruit.
It is highly preferred that weight average molecular weight (the M of the pharmaceutical carrier polymer materialw) it is 15000g/mol or more, more
Preferably 15000-500000g/mol is still more preferably 50000-250000g/mol, is still more preferably 70000-
200000g/mol is still more preferably 70000-150000g/mol.Especially with described in 70000-150000g/mol
Porous microsphere made from pharmaceutical carrier polymer material is capable of the size of more easy regulation microballoon, the aperture and hole of hole
Gap number, more can be convenient for carrying out the pattern appropriate for adjusting porous microsphere for different lesions positions, so as to carry the load after medicine
Medicine microballoon is more suitable for the drug release of specific lesions position.
In the present invention, inventor speculates that the formation of above-mentioned porous microsphere is mainly the process mutually separated according to two steps,
In, it is entered at nozzle (such as when the EFI liquid enters the container (syringe 1 as shown in figure 1) of electrostatic spinneret and flows downward
Syringe needle 3 in Fig. 1) drop is formed, it is sprayed down under electrostatic field, reaches collection device (collecting board 4 as shown in figure 1)
Before, liquid-liquid phase separation will first occur for the first high solvent of saturated vapor pressure；After reaching collection device, saturated vapor pressure is lower
The second solvent then solid-liquid phase separate, to form the cavernous micro-sphere structure in surface layer.
In order to cooperate the pharmaceutical carrier polymer material of the invention, and obtained using the technology of electrostatic spinneret
It is of the invention using the porous microsphere for carrying medicine, present invention employs two kinds of solvents, and first solvent is full at 20 DEG C
It is higher than saturated vapor pressure of second solvent at 20 DEG C with vapour pressure.As described above, in the mistake for forming the porous microsphere
There are the processes that two steps mutually separate in journey, are all more favorable for the more of carrying medicament in order to obtain size, aperture and porosity
Hole microballoon, under preferable case, the difference of first solvent and saturated vapor pressure of second solvent at 20 DEG C is 4-
35kPa, more preferably 5-30kPa.
It is preferably capable dissolving the organic solvent of the pharmaceutical carrier polymer material as such first solvent, more
Preferably methylene chloride (20 DEG C of saturated vapor pressure is 30.77kPa), acetone (20 DEG C of saturated vapor pressure is 24.64kPa),
Tetrahydrofuran (20 DEG C of saturated vapor pressure is 19.3kPa), chloroform (20 DEG C of saturated vapor pressure is 21.2kPa), dichloroethanes
One of (20 DEG C of saturated vapor pressure is 24.34kPa) and n-hexane (20 DEG C of saturated vapor pressure is 17kPa) are a variety of,
It is still more preferably one of tetrahydrofuran, methylene chloride, dichloroethanes and acetone or a variety of.
Under preferable case, second solvent be ethyl alcohol (20 DEG C of saturated vapor pressure is 5.87kPa), acetic acid (20 DEG C
Saturated vapor pressure is 1.5kPa), acetonitrile (20 DEG C of saturated vapor pressure be 11.53kPa), ethyl acetate (20 DEG C of saturated vapor
Pressure is 9.7kPa), methanol (20 DEG C of saturated vapor pressure is 12.3kPa), (20 DEG C of saturated vapor pressure is methyl acetate
10.1kPa), (20 DEG C of saturated vapor pressure is for n-butanol (20 DEG C of saturated vapor pressure is 0.73kPa) and propylene glycol
0.106kPa), more preferably one of ethyl acetate, acetic acid, methanol and ethyl alcohol or a variety of.
In a preferred embodiment of the invention, first solvent is methylene chloride, and second solvent is
Ethyl alcohol and/or propylene glycol.When using such preferred embodiment, porous microsphere of the invention can be obtained more at low cost
And drug bearing microsphere.
In another preferred embodiment of the invention, the pharmaceutical carrier with polymer material be polylactic acid and/
Or poly lactide-glycolide acid, first solvent are tetrahydrofuran, second solvent is propylene glycol.When using this
The preferred embodiment of sample can be controlled by the first solvent of regulation and the second solvent obtained porous more conveniently
The pattern of microballoon, to be more suitable for carrying medicine.
In another preferred embodiment of the invention, the pharmaceutical carrier is polylactic acid with polymer material and gathers
The combination of vinylpyrrolidone, first solvent are acetone, and second solvent is methanol and/or ethyl acetate.Work as use
Such preferred embodiment can substantially more play the synergistic effect of two kinds of pharmaceutical carrier polymer materials, come
Acquisition pattern is more stable and carries drug effect fruit and all more superior porous microsphere of drug release effect and drug bearing microsphere.
In the present invention, the size of the porous microsphere, aperture and porosity can be used by adjusting the pharmaceutical carrier
Polymer material, the type of the first solvent and the second solvent and dosage are regulated and controled.Drug can be preferably carried in order to obtain
Porous microsphere carrier, under preferable case, the volume ratio of first solvent and second solvent is 4-80:1, more preferably
10-60:1, more preferably 20-40:1.
In the present invention, although the pharmaceutical carrier polymer material can obtain institute of the invention by the above method
State porous microsphere, but in order to obtain the porous microsphere that can have medical value, under preferable case, with the gross weight of the EFI liquid
On the basis of amount, the content of pharmaceutical carrier polymer material is 0.5-15 weight %, preferably 1-10 weight %.
Present inventor is it was unexpectedly observed that using certain drug carrier polymer material and the first solvent and the
In the case that two solvents are cooperated, especially mentioned kind, dosage cooperation under, can obtain it is dispersed preferably, and ruler
Very little, aperture and porosity are all very suitable as the porous microsphere of pharmaceutical carrier.
In a kind of particularly preferred embodiment of the invention, the EFI liquid is first to polymerize the pharmaceutical carrier
Object material and first solvent mixing, add obtained by second solvent.Such hybrid mode is taken, than directly by three
For the kind blended together mode of substance, the problem of the second micro solvent evaporates in mixed process is avoided, it can be more preferable
Drop is in microsphere surface pore-forming.
In the present invention, the electrostatic spinneret refers to that electrostrictive polymer hydrojet is made to be atomized to form nanostructure using electrostatic field
Process, wherein the conical drop that suspended on when applying exterior static field to EFI liquid, at nozzle can be made by electrostatic field
It with the surface tension for breaking through drop, sprays, and is arranged on collected by the reception device of lower section, to form nanostructure outward
Polymer.Preferably, the device for the electrostatic spinneret that the present invention uses is as shown in Figure 1, the device of the i.e. described electrostatic spinneret includes:
Syringe 1, syringe needle 3, high voltage power supply 2 and receiver board 4.EFI liquid is fitted into syringe 1, according to certain rate push injection
Device 1 to hang drop at syringe needle 3, which sprays under the action of the electrostatic field provided by high voltage power supply 2 downwards, and
It is collected collected by plate 4.Preferably, the rate of push injection device 1 makes the flow control of EFI liquid in 0.2-1mL/min.
In the case of in the present invention, it is preferred to, the condition of the electrostatic spinneret includes: that voltage is 5-40kV, nozzle to reception
The distance of device is 5-50cm.It is highly preferred that it is 7-25kV that the condition of the electrostatic spinneret, which includes: voltage, nozzle is filled to reception
The distance set is 15-30cm.And to the temperature and humidity of the electrostatic spinneret, there is no any restrictions, as long as can obtain described
Porous microsphere, such as temperature can be 10-40 DEG C, and humidity can be 20-40%.
The present invention also provides porous microspheres made from the preparation method as above-mentioned porous microsphere.
In the case of in the present invention, it is preferred to, the partial size of the porous microsphere is 1-200 μm, more preferably 5-100 μm, more
Preferably 10-50 μm, be still more preferably 10-30 μm.Preferably, every 10 μm of the porous microsphere2Surface on hole
Gap number is 5-200, and preferably 5-150, more preferably 10-110, be still more preferably 30-110.Preferably,
The aperture of the surface pore of the porous microsphere is 50-900nm, more preferably 100-500nm.
The present invention also provides a kind of drug bearing microsphere, the carrier of the drug bearing microsphere is above-mentioned porous microsphere.
For the present invention using the porous microsphere as the carrier of drug release, medicine-carrying method can use the load of this field routine
Prescription method, such as obtained porous microsphere can be carried into mode for drug encapsulation at this using conventional mixing, infiltration etc.
In the porous microsphere of invention.The conventional medicine-carrying method of even now can also obtain the drug bearing microsphere of certain carrying drug ratio, but originally
Inventing preferred drug bearing microsphere is that drug is formed solution with other EFI ingredients or forms drug and other EFI ingredients
Suspension forms drug and other EFI ingredients using the preparation method that porous microsphere is similar after lotion, load medicine is made
Microballoon, and this drug bearing microsphere can obtain higher carrying drug ratio and drug release effect.
In order to obtain preferable drug action, in the present invention, on the basis of the total weight of the drug bearing microsphere, the load
The content for the drug that medicine microballoon is loaded with is preferably 2.5-20 weight % (drug total amount × carrying drug ratio/(pharmaceutical carrier polymeric material
The dosage of material+drug total amount × carrying drug ratio) × 100 weight %), more preferably 4-15 weight % is still more preferably 9-15
Weight %.
As long as although need using carrier drug can porous microsphere through the invention carried, it is preferred that
Ground, the drug are in antineoplastic, anti-inflammatory drug, anodyne, antibiotic, anticoagulant, antiallergic and antifungal
It is one or more.Porous microsphere of the invention is especially suitable for one in carrier band metronidazole, acetylsalicylic acid and 5 FU 5 fluorouracil
Kind is a variety of.When carrier of the use porous microsphere of the invention as these drugs, lesions position can be preferably adhered to,
And can preferably extend the slow releasing function of these drugs, reduce administration number of times.
The present invention also provides a kind of preparation methods of drug bearing microsphere, wherein the preparation method includes: in electrostatic strand
Under part, electricity will be carried out containing the EFI liquid for needing carrying medicament, pharmaceutical carrier polymer material, the first solvent and the second solvent
Spray, wherein first solvent is higher than saturated vapor pressure of second solvent at 20 DEG C in 20 DEG C of saturated vapor pressure；It is described
Pharmaceutical carrier is polylactic acid, polyurethane, gelatin, polyacrylic acid, sodium carboxymethylcellulose, polycarbophil, shell with polymer material
One of glycan, polyvinylpyrrolidone, poly lactide-glycolide acid and polyvinyl alcohol are a variety of.
In the preparation method of drug bearing microsphere of the invention, the type of the pharmaceutical carrier polymer material, described
The type and ratio of one solvent and the second solvent, condition of the electrostatic spinneret etc. can use the preparation side of above-mentioned porous microsphere
The preferred suchlike condition of institute in method, is not stated herein tired.
In a kind of particularly preferred embodiment of the invention, the pharmaceutical carrier with polymer material be polylactic acid and
The combination of polyvinylpyrrolidone, such combination are more advantageous to the medicament slow release of gained drug bearing microsphere.
It, can be using each when using such porous microsphere of the invention as pharmaceutical carrier although as described above
The method of kind this field routine carries out load medicine, but is to be able to preferably play the property of porous microsphere, invention of the invention
People has found also carry out together EFI to carrying medicament as use, by the preparation method of above-mentioned drug bearing microsphere, can obtain
Drug bearing microsphere of the drug as the constituent of porous microsphere, that is to say, that drug be not be simply be adhered to it is porous micro-
On the surface of ball (for example mixing, made from the method for infiltration), but join together with pharmaceutical carrier polymer material and drug
With constitute the structure of porous microsphere.Such drug bearing microsphere can obtain for the drug bearing microsphere simply adhered to
Higher carrying drug ratio, longer slow releasing function and more stable drug action.And the preparation method of drug bearing microsphere of the invention
It can control the pattern of microsphere surface, so as to match with the cell mass of particular surface pattern, realize the spy of drug bearing microsphere
The opposite sex is viscous, to enhance the adhesive attraction with specific lesions position of drug bearing microsphere, further realizes longer slow releasing function
With more stable drug action.
Such as the inflammation of external skin surfaces for, it is preferred to use partial size be 1-10 μm, aperture 50-200nm
Drug bearing microsphere.For the skin surface of cervicitis and vaginitis, it is preferred to use partial size be 5-50 μm, aperture be
The drug bearing microsphere of 100-500nm.For the mucomembranous surface of tumor locus, it is preferred to use partial size be 10-30 μm, aperture be
The drug bearing microsphere of 500-1000nm.
In the present invention, although the drug can be added with any content, load medicine of the invention can be obtained
Microballoon, but it was found by the inventors of the present invention that when the weight ratio of the drug and the pharmaceutical carrier polymer material is 1:
When 5-40, preferably 1:9-25 can obtain the drug bearing microsphere of higher carrying drug ratio.And carrying drug ratio is higher, not only to be added
Drug can more effectively be supported, and the drug bearing microsphere of carrying drug ratio high in this way is being used to prepare into the corresponding disease for the treatment of
When the drug of disease, such as tumour relevant to respiratory mucosa, gastrointestinal mucosal, urinary system mucous membrane or reproductive system mucous membrane,
In epithelial tissue when the drug of the diseases such as lesion or inflammation, gained drug can obtain better slow release effect, to maintain
The long-acting of drug bearing microsphere, and shortened administration number of times.
The preparation method of drug bearing microsphere of the invention can be using various in the preparation method of porous microsphere of the invention
Optimum condition, but in order to preferably match the load of composite medicine, in a preferred embodiment of the invention, relative to 1g
Pharmaceutical carrier polymer material, the dosage of the drug are 0.025-0.2g, more preferably 0.05-0.15g.That is,
Although the preparation method of porous microsphere above-mentioned obtains the porous microsphere for being suitable for pharmaceutical carrier, and in the drug bearing microsphere
In preparation method, it is contemplated that the drug and the pharmaceutical carrier have set up such porous microsphere knot with polymer material jointly
Structure just obtains drug bearing microsphere, needs further to consider the drug, pharmaceutical carrier polymer material, the first solvent and second
Mating reaction between solvent, and it is also contemplated that the drug action of drug bearing microsphere obtained.
In the preferred embodiment of the present invention, relative to pharmaceutical carrier polymer material described in 1g, described
The dosage of one solvent is 10-200mL, and second solvent is 0.1-10mL.
Although drug bearing microsphere can be prepared using the condition for the electrostatic spinneret for preparing porous microsphere, in order to obtain more
Has the drug bearing microsphere of drug action, under preferable case, it is 16-20kV that the condition of the electrostatic spinneret, which includes: voltage, and nozzle is to connecing
The distance of receiving apparatus is 25-40cm.
Therefore, mutual cooperation acts on the medicine with resulting drug bearing microsphere between the substance in view of preparing the drug bearing microsphere
Effect effect, drug of the present invention is preferably antineoplastic, anti-inflammatory drug, anodyne, antibiotic, anticoagulant, antiallergy
One of medicine and antifungal are a variety of, more preferably one of metronidazole, acetylsalicylic acid and 5 FU 5 fluorouracil or
It is a variety of.
According to the present invention, cosolvent can also be added in above-mentioned EFI liquid, which facilitates the dissolution of drug, can be with
It is the solvent of more conducively drug dissolution, such as n,N-Dimethylformamide.There is no special limits for the dosage of such cosolvent
It is fixed, as long as can aid in the dissolution of drug and will not influence the formation of drug bearing microsphere, such as relative to every 100mg medicine
Object, the dosage of the cosolvent are 2-6mL.
The present invention also provides the drug bearing microsphere as obtained by the above method, i.e., a kind of is the structure of porous microsphere for drug
The drug bearing microsphere of ingredient.In the case of in the present invention, it is preferred to, the partial size of above-mentioned drug bearing microsphere is 1-200 μm, more preferably 5-
100 μm, more preferably 10-50 μm are still more preferably 10-30 μm.Preferably, every 10 μm of the drug bearing microsphere2Table
Number of apertures on face is 5-200, and preferably 5-150, more preferably 5-150, more preferably 10-110 is a, more into one
Step is preferably 30-110.Preferably, the aperture of the surface pore of the drug bearing microsphere is 50-900nm, more preferably 100-
500nm。
The present invention also provides above-mentioned drug bearing microspheres to prepare the application in the drug for treating the relevant disease of mucous membrane.
Under preferable case, the relevant disease of the mucous membrane be with respiratory mucosa, gastrointestinal mucosal, urinary system mucous membrane or
Lesion or inflammation in the relevant tumour of reproductive system mucous membrane, epithelial tissue.
As such drug, the medicament forms of this field routine can be used, for example, can be suppository, liquid preparation,
Medicine film, capsule, tablet, drug granule, spray, ointment etc..
As described above, since drug bearing microsphere of the invention is porous structure, aperture is controllable, can be according to disease
Type uses the drug bearing microsphere of different pore size and size, in the case where adhesive attraction enhances, then cooperates load of the invention
The high carrying drug ratio of medicine microballoon and it is long when slow releasing function, can in the less situation of administration number of times, obtain preferably treatment effect
Fruit, especially for lesions position such as respiratory mucosa, gastrointestinal mucosal, urinary system mucous membrane or the life of medicine-feeding part inconvenience
System mucous membrane etc. is grown, even more favorably.
The present invention will be described in detail by way of examples below.
Using electrostatic spinning appts shown in FIG. 1, which includes syringe 1, needle for following embodiment and comparative example
First 3 (internal diameter 0.7mm), high voltage power supply 2 and collecting board 4 (glass plate that surface is covered with aluminium foil), high voltage power supply 2 and syringe needle 3
It is electrically connected with collecting board 4, and collecting board 4 is connect with ground wire, the voltage of high voltage power supply 2 can be set according to different examples
It sets, the distance of collecting board 4 and syringe needle 3 can also be adjusted；
Number of apertures refers to every 10 μm2The number of micropore on surface.
Embodiment 1-3
The present embodiment is for illustrating porous microsphere and preparation method thereof of the invention.
Respectively by the M of 0.99gw(Jinan Dai Gang biotech firm, article No. DG- are purchased from for the l-lactic acid of 80,000 g/mol
L100 it) is dissolved in the methylene chloride (13.2g) of 10mL, is separately added into 0.5mL (0.4g), 0.33mL (0.26g) and 0.25mL
The ethyl alcohol of (0.2g) obtains EFI liquid 1-3, and EFI liquid 1-3 is respectively charged into the syringe 1 of electrostatic spinning appts shown in FIG. 1
In, push injection device 1 make EFI liquid with flow velocity be 0.2mL/min carry out EFI (wherein the condition of EFI includes: collecting board 4
Distance with syringe needle 3 is 20cm, and voltage 13kV, temperature is 20 DEG C, humidity 30%), it is obtained by the collection of collecting board 4 porous
Microballoon A1-A3, wherein scanning electron microscope (SEM) figure of A1 is as shown in Figure 2, partial size, surface void aperture and the number of pores of A1-A3
Mesh is as shown in table 1.
Comparative example 1
According to method shown in embodiment 1, the difference is that gathering oneself using weight average molecular weight for 65000g/mol
Lactone (Sigma, article No. 181609) replaces polylactic acid, obtains porous microsphere B1 by the collection of collecting board 4, SEM figure is as in Fig. 3
Shown, the partial size of B1, surface mesh diameter and porosity are as shown in table 1.
Embodiment 4
The present embodiment is for illustrating porous microsphere and preparation method thereof of the invention.
By the M of 0.8gw(Jinan Dai Gang biotech firm, article No. DG- are purchased from for the l-lactic acid of 80,000 g/mol
It L100 is) polyvinylpyrrolidone (being purchased from the Aladdin company P110607 trade mark) of 58000g/mol with 0.08g weight average molecular weight
It is dissolved in the chloroform (14.8g) of 10mL, and the acetic acid (0.052g) that 0.5mL is added obtains EFI liquid 4, and EFI liquid 4 is distinguished
Be fitted into the syringe 1 of electrostatic spinning appts shown in FIG. 1, push injection device 1 make EFI liquid with flow velocity be 0.5mL/min into
(it is 30cm that wherein the condition of EFI includes: the distance of collecting board 4 and syringe needle 3 to row EFI, and voltage 15kV, temperature is 20 DEG C, wet
30%) degree is, collects by collecting board 4 and obtains porous microsphere A4, in partial size, surface pore aperture and number of apertures such as table 1
It is shown.
Carry medicine embodiment 1-4
The present embodiment is for illustrating drug bearing microsphere and preparation method thereof of the invention.
By the M of 0.99gwIt is molten for the l-lactic acid (being purchased from Jinan Dai Gang biotech firm, article No. DG-L100) of 80,000 g/mol
Solution is in the methylene chloride of three parts of 10mL, then is separately added into the green tea crude extract (GTE, purchased from the green precious science and technology of the Wuxi sun of 0.1g
Co., Ltd), 0.1g metronidazole (be purchased from Aladdin, article No. M109874), 0.1g acetylsalicylic acid (be purchased from Aladdin, article No.
A104180), the ethyl alcohol for being then respectively adding 0.5mL obtains EFI liquid 1'-3'.
In addition, by the M of 0.468gw(Jinan Dai Gang biotech firm, article No. are purchased from for the l-lactic acid of 80,000 g/mol
DG-L100 it) is dissolved in the methylene chloride of 4mL and the n,N-Dimethylformamide of 1mL, adds the 5 FU 5 fluorouracil of 0.023g
(being purchased from Aladdin, article No. F100149), the ethyl alcohol that 0.25mL is then added obtains EFI liquid 4'.
EFI liquid 1'-4' is respectively charged into the syringe 1 of electrostatic spinning appts shown in FIG. 1, push injection device 1 makes
EFI liquid is that 0.2mL/min carries out EFI (wherein the condition of EFI includes: that the distance of collecting board 4 and syringe needle 3 is with flow velocity
30cm, voltage 17kV, temperature are 20 DEG C, humidity 30%), drug bearing microsphere ZA1-ZA4 is obtained by the collection of collecting board 4,
As shown in Figure 4, the partial size of ZA1-ZA4, surface pore aperture and number of apertures are as shown in table 1 for the SEM figure of middle ZA4.
Carry medicine comparative example 1
According to carrying medicine method described in embodiment 1, the difference is that being 65000 to gather oneself using weight average molecular weight
Lactone (Sigma, article No. 181609) replaces polylactic acid, obtains drug bearing microsphere DB1, SEM figure such as Fig. 5 by the collection of collecting board 4
Shown in, the partial size of DB1, surface pore aperture and number of apertures are as shown in table 1.
Carry medicine comparative example 2
After 0.1g porous microsphere A1 made from embodiment 1 is impregnated 3h in the GTE aqueous solution of 5g/L, it is dried to obtain load medicine
Microballoon DB2.
Carry medicine comparative example 3
According to load medicine method described in embodiment 1, the difference is that using the ethyl alcohol of 12mL, as a result, it has been found that, due to non-molten
Agent ethanol content increases, and polymer is precipitated, and can not carry out electrospinning.
Carry medicine embodiment 5
The present embodiment is for illustrating drug bearing microsphere and preparation method thereof of the invention.
By the M of 0.269gwIt is dissolved in for the polyvinylpyrrolidone (being purchased from sigma, article No. V900010) of 360,000 g/mol
In the methylene chloride of 10mL, the ethyl alcohol that 0.5mL is added obtains EFI liquid, by EFI liquid according to carry medicine method described in embodiment 1,
It is collected by collecting board 4 and only obtains the Electrospun structure ZA5 with node, wherein the SEM figure of ZA5 is as shown in Figure 6.
Carry medicine embodiment 6
By the M of 0.442gw(Jinan Dai Gang biotech firm, article No. DG- are purchased from for the polylactic acid of 150,000 g/mol
L150), the M of 0.055gwFor 5.8 ten thousand g/mol polyvinylpyrrolidones (being purchased from Aladdin company, article No. P110607), 0.05g
Metronidazole (being purchased from Aladdin, article No. M109874) is dissolved in the methylene chloride of 5mL, and the ethyl alcohol that 0.25mL is added obtains EFI
Liquid obtains drug bearing microsphere ZA6 by the collection of collecting board 4, wherein ZA6 by EFI liquid according to medicine method described in embodiment 1 is carried
Partial size, surface pore aperture and number of apertures are as shown in table 1, and SEM figure is as shown in Figure 7.
Carry medicine embodiment 7
By 0.665g MwFor 80,000 g/mol poly lactic-co-glycolic acid (PLGA, purchased from be purchased from Jinan Dai Gang biotech firm,
Article No. DG-50DLG 065), the green tea crude extract of 0.066g (GTE is purchased from Wuxi Taiyo Green Power Co., Ltd.) is dissolved in
In the tetrahydrofuran of 10mL, the propylene glycol that 0.5mL is then added obtains EFI liquid, by EFI liquid according to load medicine embodiment 1
Method, drug bearing microsphere ZA7 is obtained by the collection of collecting board 4, wherein the partial size of ZA7, surface pore aperture and number of apertures be such as
Shown in table 1, SEM figure is as shown in Figure 8.
Test case 1
10mg drug bearing microsphere ZA1-ZA4, ZA6-ZA7 and DB1-DB2 are dissolved in respectively in 5mL methylene chloride, then plus
Enter the phosphate buffer (PBS) of 40mL under the conditions of 45 DEG C, stirred with 500 revs/min of revolving speed, until methylene chloride volatilization is dry
Only.
For the drug bearing microsphere for loading GTE, the UV absorption at UV detector measurement 274nm, root are utilized
The content of GTE in 10mg microballoon can be calculated according to the standard curve of GTE UV absorption in PBS, the value and hypothesis GTE are whole
It is carrying drug ratio that the case where load, which calculates the ratio between gained theoretical value, and the results are shown in Table 1；
For the drug bearing microsphere for loading metronidazole, the UV absorption at 320nm is measured using UV detector,
The content of metronidazole in 10mg microballoon, the value and vacation can be calculated according to the standard curve of metronidazole UV absorption in PBS
If it is carrying drug ratio that the case where metronidazole all loads, which calculates the ratio between gained theoretical value, the results are shown in Table 1；
For the drug bearing microsphere for loading acetylsalicylic acid, the acetyl salicylic acid solution in PBS is dissolved in 1:1 body
Product ratio is mixed with the sodium hydroxide solution of 0.2M, after reacting 15 minutes in 60 DEG C of water-baths, is surveyed using UV detector
Determine the UV absorption at 297nm, 10mg microballoon can be calculated according to the standard curve of acetylsalicylic acid UV absorption in PBS
It is load that the case where content of middle acetylsalicylic acid, the value and hypothesis acetylsalicylic acid all load, which calculates the ratio between gained theoretical value,
Medicine rate, the results are shown in Table 1；
For the drug bearing microsphere of 5 FU 5 fluorouracil, the UV absorption at 265nm is measured using UV detector,
The content of 5 FU 5 fluorouracil in 10mg microballoon can be calculated according to the standard curve of 5 FU 5 fluorouracil UV absorption in PBS,
It is carrying drug ratio that the case where value and hypothesis 5 FU 5 fluorouracil all load, which calculates the ratio between gained theoretical value, and the results are shown in Table 1.
Table 1
By the data of analytical table 1 it can be seen that the reduction of the ethanol consumption as the second solvent can reduce microballoon table
The size of face gap, but when ethyl alcohol volume accounts for the 1/30 of total system ratio, every 10 μm can be made2Interior micropore number reaches most
Greatly, therefore the relative area of drug release is increased；The pore size that polycaprolactone microballoon sphere surface is formed is larger, and every 10 μm2It is interior
Micropore number also relatively seldom, therefore the relative area of drug release is also less；Drug packet of the green tea crude extract in microballoon
Carrying capacity is less than metronidazole, acetylsalicylic acid and 5 FU 5 fluorouracil；Although the mode of drug immersion microballoon can make drug by
Carried by porous microsphere of the invention, but the present invention is more preferably still made using the preparation method of drug bearing microsphere of the invention
Obtain the drug bearing microsphere.
Test case 2
Weigh 10mg drug bearing microsphere ZA1-ZA4 and ZA6 be dispersed in 10mL phosphate buffer (PBS) respectively obtain carry medicine
The PBS suspension of microballoon is placed in 37 DEG C, in 100 revs/min of shaking table, measures the drug in solution respectively in different time points
Burst size.Drug release quantity measuring method: point takes out suspension and with 2500 revs/min of centrifuging and taking 1mL supernatant in different times
Then liquid adds 1mL PBS solution,
For drug bearing microsphere (i.e. ZA1, result are as shown in table 2) for loading GTE (green tea crude extract), supernatant is taken
0.2mL in liquid is using the UV absorption at UV detector measurement 274nm, according to the mark of GTE UV absorption in PBS
Directrix curve can calculate the burst size at each time point；
For drug bearing microsphere (i.e. ZA2 and ZA6, result is respectively as shown in table 3 and 4) for loading metronidazole, take
0.2mL in supernatant is ultraviolet in PBS according to metronidazole using the UV absorption at UV detector measurement 320nm
The standard curve of absorption can calculate the burst size at each time point；
For drug bearing microsphere (i.e. ZA3, result are as shown in table 5) for loading acetylsalicylic acid, take in supernatant
1mL, mixed with 1:1 volume ratio with the sodium hydroxide solution of 0.2M, after reacting 15 minutes in 60 DEG C of water-baths, utilization is ultraviolet
UV absorption at spectrophotometric determination 0.2mL reaction solution 297nm, according to the mark of acetylsalicylic acid UV absorption in PBS
Directrix curve can calculate the burst size at each time point；
For drug bearing microsphere (i.e. ZA4, result are as shown in table 6) for loading 5 FU 5 fluorouracil, take in supernatant
0.2mL using UV detector measurement 265nm at UV absorption, according to 5 FU 5 fluorouracil in PBS UV absorption
Standard curve can calculate the burst size at each time point；
Table 2
| Time point/h | It is accumulative that quality/μ g is precipitated |
| 0.5 | 701.13 |
| 1 | 751.78 |
| 2 | 785.36 |
| 3 | 830.56 |
| 4.5 | 843.95 |
| 6 | 863.90 |
Table 3
| Time point/h | Cumulative release amount/μ g |
| 0.5 | 45.95 |
| 1 | 46.04 |
| 1.5 | 49.90 |
| 2.5 | 51.64 |
| 3.5 | 50.87 |
| 4.5 | 54.49 |
| 5.5 | 53.70 |
| 9.5 | 57.57 |
| 13.5 | 59.51 |
| 25.5 | 66.18 |
| 37.5 | 71.78 |
| 49.5 | 73.70 |
| 61.5 | 75.19 |
| 85.5 | 80.41 |
| 109.5 | 83.29 |
| 133.5 | 87.38 |
| 127.5 | 86.96 |
Table 4
| Time point/h | Cumulative release amount/μ g |
| 0.5 | 86.06 |
| 1.5 | 92.92 |
| 3 | 105.83 |
| 5 | 114.04 |
| 7 | 122.34 |
| 21 | 134.67 |
| 33 | 147.14 |
| 57 | 158.04 |
| 81 | 165.93 |
| 105 | 177.02 |
| 129 | 183.83 |
| 177 | 193.60 |
| 225 | 205.13 |
| 273 | 211.56 |
Table 5
| Time point/h | Cumulative release amount/μ g |
| 0.5 | 19.54 |
| 1 | 19.74 |
| 2 | 36.11 |
| 3 | 39.43 |
| 5 | 44.66 |
| 7 | 48.11 |
| 10 | 54.24 |
| 22 | 85.38 |
| 46 | 125.75 |
| 68 | 268.45 |
| 90 | 361.98 |
| 114 | 447.43 |
| 150 | 520.08 |
| 174 | 522.02 |
| 198 | 586.30 |
| 222 | 615.15 |
| 246 | 616.61 |
| 270 | 634.06 |
Table 6
| Time point/h | Cumulative release amount/μ g |
| 0.5 | 305.56 |
| 1 | 340.74 |
| 2 | 372.30 |
| 4 | 391.47 |
| 5 | 394.62 |
| 6 | 405.56 |
| 8 | 405.45 |
| 13 | 416.58 |
| 37 | 446.79 |
| 61 | 447.22 |
| 85 | 432.41 |
By the data of analytical table 2-6 it can be seen that being loaded with the rate of release of the drug bearing microsphere (i.e. ZA1) of green tea crude extract
Comparatively fast, it can reach peak value in six hours；And the load medicine for being loaded with the drug of metronidazole, acetylsalicylic acid and 5 FU 5 fluorouracil is micro-
The rate of release of ball is then more steady, can discharge in a longer period of time, to reach preferably slow release effect.
The preferred embodiment of the present invention has been described above in detail, still, during present invention is not limited to the embodiments described above
Detail within the scope of the technical concept of the present invention can be with various simple variants of the technical solution of the present invention are made, this
A little simple variants all belong to the scope of protection of the present invention.
It is further to note that specific technical features described in the above specific embodiments, in not lance
In the case where shield, can be combined in any appropriate way, in order to avoid unnecessary repetition, the present invention to it is various can
No further explanation will be given for the combination of energy.
In addition, various embodiments of the present invention can be combined randomly, as long as it is without prejudice to originally
The thought of invention, it should also be regarded as the disclosure of the present invention.
Claims (27)
1. a kind of preparation method of porous microsphere, which is characterized in that this method comprises: medicine will be contained under electrostatic spinning conditions
The EFI liquid of object carrier polymer, the first solvent and the second solvent carries out EFI, wherein first solvent is full at 20 DEG C
It is higher than saturated vapor pressure of second solvent at 20 DEG C with vapour pressure, and the dosage of first solvent is molten greater than described second
The dosage of agent；The pharmaceutical carrier is polylactic acid, polyurethane, gelatin, polyacrylic acid, carboxymethyl cellulose with polymer material
One of sodium, polycarbophil, chitosan, polyvinylpyrrolidone, poly lactide-glycolide acid and polyvinyl alcohol are more
Kind, the difference of first solvent and saturated vapor pressure of second solvent at 20 DEG C is 4-35kPa, and first solvent is
The organic solvent of the pharmaceutical carrier polymer material can be dissolved, second solvent is ethyl alcohol, acetic acid, acetonitrile, acetic acid
One of ethyl ester, methanol, methyl acetate, n-butanol and propylene glycol are a variety of.
2. according to the method described in claim 1, wherein, first solvent and saturated vapor of second solvent at 20 DEG C
The difference of pressure is 5-30kPa.
3. according to the method described in claim 1, wherein, the pharmaceutical carrier is polylactic acid, polyethylene pyrrole with polymer material
One of pyrrolidone and poly lactide-glycolide acid are a variety of.
4. according to the method described in claim 1, wherein, first solvent be methylene chloride, acetone, tetrahydrofuran, chloroform,
One of dichloroethanes and n-hexane are a variety of.
5. according to the method described in claim 4, wherein, first solvent be tetrahydrofuran, methylene chloride, dichloroethanes and
One of acetone is a variety of.
6. according to the method described in claim 1, wherein, second solvent is in acetic acid, ethyl acetate, methanol and ethyl alcohol
It is one or more.
7. method according to claim 1 or 2, wherein on the basis of the total weight of the EFI liquid, the pharmaceutical carrier
It is 0.5-15 weight % with the content of polymer material.
8. method according to claim 1 or 2, wherein the volume ratio of first solvent and second solvent is 5-
80:1.
9. according to the method described in claim 8, wherein, the volume ratio of first solvent and second solvent is 10-60:
1。
10. according to the method described in claim 1, wherein, the weight average molecular weight of pharmaceutical carrier polymer material is
15000g/mol or more.
11. according to the method described in claim 10, wherein, the weight average molecular weight of pharmaceutical carrier polymer material is
15000-500000g/mol。
12. according to the method for claim 11, wherein the weight average molecular weight of pharmaceutical carrier polymer material is
50000-250000g/mol。
13. according to the method described in claim 1, wherein, the condition of the electrostatic spinneret includes: that voltage is 5-40kV, nozzle
Distance to reception device is 5-50cm.
14. according to the method described in claim 1, wherein, the EFI liquid is first by the pharmaceutical carrier polymer material
It mixes, is added obtained by second solvent with first solvent.
15. porous microsphere made from the method as described in any one of claim 1-14.
16. porous microsphere according to claim 15, wherein the partial size of the porous microsphere is 1-200 μm.
17. porous microsphere described in any one of 5-16 according to claim 1, wherein at every 10 μm2The porous microsphere
Number of apertures on surface is 5-200.
18. porous microsphere described in any one of 5-16 according to claim 1, wherein the surface pore of the porous microsphere
Aperture be 50-900nm.
19. a kind of drug bearing microsphere, which is characterized in that the carrier of the drug bearing microsphere is described in any one of claim 15-18
Porous microsphere.
20. drug bearing microsphere according to claim 19, wherein on the basis of the total weight of the drug bearing microsphere, the load medicine
The content for the drug that microballoon is loaded with is 2.5-20 weight %.
21. a kind of preparation method of drug bearing microsphere, which is characterized in that the preparation method includes: that will contain under electrostatic spinning conditions
There is the EFI liquid of drug, pharmaceutical carrier polymer material, the first solvent and the second solvent to carry out EFI, wherein described first
Solvent is higher than saturated vapor pressure of second solvent at 20 DEG C, and the dosage of first solvent in 20 DEG C of saturated vapor pressure
Greater than the dosage of second solvent；The pharmaceutical carrier with polymer material be polylactic acid, polyurethane, gelatin, polyacrylic acid,
Sodium carboxymethylcellulose, polycarbophil, chitosan, polyvinylpyrrolidone, poly lactide-glycolide acid and polyvinyl alcohol
One of or it is a variety of, the difference of first solvent and saturated vapor pressure of second solvent at 20 DEG C is 4-35kPa, institute
Stating the first solvent is the organic solvent that can dissolve the pharmaceutical carrier polymer material, and second solvent is ethyl alcohol, second
One of acid, acetonitrile, ethyl acetate, methanol, methyl acetate, n-butanol and propylene glycol are a variety of.
22. preparation method according to claim 21, wherein relative to pharmaceutical carrier polymer material described in 1g, institute
The dosage for stating drug is 0.025-0.2g.
23. the preparation method according to claim 21 or 22, wherein the drug is antineoplastic, anti-inflammatory drug, analgesic
One of medicine, antibiotic, anticoagulant, antiallergic and antifungal are a variety of.
24. preparation method according to claim 21, wherein first solvent and second solvent are full at 20 DEG C
Difference with vapour pressure is 5-30kPa.
25. drug bearing microsphere obtained by the preparation method of the drug bearing microsphere as described in any one of claim 21-24.
26. drug bearing microsphere described in claim 19,20 or 25 is in preparing the drug for treating the relevant disease of mucous membrane
Using.
27. application according to claim 26, wherein the relevant disease of the mucous membrane is and respiratory mucosa, alimentary canal
Lesion or inflammation in mucous membrane, urinary system mucous membrane or the relevant tumour of reproductive system mucous membrane, epithelial tissue.
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| CN102941043A (en) * | 2012-10-12 | 2013-02-27 | 华侨大学 | Method of preparing porous polymer microspheres by high voltage electrostatic anti-solvent process |
| CN103585635A (en) * | 2013-10-31 | 2014-02-19 | 江苏大学 | Slow-release polylactic acid microsphere capable of maintaining protein and polypeptide drug activity and preparation method thereof |
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| CN102941043A (en) * | 2012-10-12 | 2013-02-27 | 华侨大学 | Method of preparing porous polymer microspheres by high voltage electrostatic anti-solvent process |
| CN103585635A (en) * | 2013-10-31 | 2014-02-19 | 江苏大学 | Slow-release polylactic acid microsphere capable of maintaining protein and polypeptide drug activity and preparation method thereof |
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