CN104825398A - Preparation method and use of surface mesoporous silk fibroin microsphere drug slow-release carrier - Google Patents
Preparation method and use of surface mesoporous silk fibroin microsphere drug slow-release carrier Download PDFInfo
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- CN104825398A CN104825398A CN201510197114.4A CN201510197114A CN104825398A CN 104825398 A CN104825398 A CN 104825398A CN 201510197114 A CN201510197114 A CN 201510197114A CN 104825398 A CN104825398 A CN 104825398A
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- silk fibroin
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Abstract
The invention discloses a preparation method and use of a surface mesoporous silk fibroin microsphere drug slow-release carrier. The preparation method comprises the following steps of carrying out degumming, dissolution and dialysis treatment on silkworm cocoons to obtain a silk fibroin solution, putting the silk fibroin solution into a dialysis bag, putting the dialysis bag in a water bath at a temperature of 16-20 DEG C, carrying out standing for 1-5 days, washing the solution, carrying out refrigeration centrifugation to obtain the surface mesoporous silk fibroin microsphere drug slow-release carriers, carrying out ultrasonic dispersion on surface mesoporous silk fibroin microspheres in a surface mesoporous silk fibroin microsphere solution with a concentration of 5g/L, adding a desired drug into the solution, carrying out dispersion treatment on the mixed solution at a room temperature for 10min, and carrying out high rate refrigeration and centrifugation at a temperature of 4 DEG C to obtain drug-loaded surface mesoporous silk fibroin microspheres. The surface mesoporous silk fibroin microsphere drug slow-release carrier does not damage activity and is suitable for various desired slow release drugs. The drug-loaded surface mesoporous silk fibroin microsphere has a smooth and slow release rate, good stability and substantial slow release effects.
Description
Technical field
The invention belongs to slow releasing carrier of medication field, particularly a kind of method not preparing surface mesoporous fibroin albumen microsphere drug slow-released carrier containing organic solvent.
Background technology
To esophagus and gastric mucosa powder excitatory or granule medicament; because mouthfeel is bad, is easy to volatilization, easily sucks trachea, easily the reason such as is decomposed by saliva in the oral cavity; often be loaded into capsule; avoid the impact of moisture, air, light; the medicine smelling taste or poor stability to tool has covering and protective effect to a certain extent; both stop the medicine property of medicine not to be destroyed, also protect digestive organs and respiratory tract.In addition, capsule can delay release and the positioning release medicine of medicine, reaches the effect of slow release prolongation of effect and positioning intelligent administration.Capsule as enteral solution absorption medicine can protect medicine not by stomach acids destroy.Meanwhile, the bioavailability of capsule is higher.The impact of the factors such as the medicine in capsule is not stressed, can disperse rapidly, stripping and absorption in the gastrointestinal tract.But for the gene repair medicine of costliness, need high-precision site-specific delivery of drugs, high drug load and slow release prolongation of effect.The disintegration time of conventional capsule is within 30 minutes, and tablet, pill, within 1 hour, can not meet the needs of gene class medicine.In drug controlled release system, pharmaceutical carrier plays critical effect.
At present, the carrier material that Loaded Microspheres Drug Delivery System is conventional has sodium alginate, Poly(D,L-lactide-co-glycolide (PLGA), chitosan (CS) and the biodegradation material such as derivant and fibroin thereof.The fibroin albumen wherein deriving from silkworm silk is because of its good biocompatibility, biodegradable, physics and chemistry and biological stability, extremely low toxicity, and the advantage such as higher medicine carrying, has been widely used as the carrier of medicine, enzyme and vaccine.But the fibroin microsphere preparation method of current reported nanometer and submicron-scale is complicated, technique is harsh, and also may add other harmful substance, and microsphere surface is smooth, drug loading is low, and rate of release is too fast.Therefore, develop more high-specific surface area, drug loading, the fibroin albumen microsphere of prolong drug release time be very urgent.
Chinese invention patent (CN102977381A) discloses a kind of Wild antheraea pernyi silk fibroin microsphere and preparation method thereof, tussah silk carried out come unstuck, dissolve, obtain tussah silk fibroin solution after dialysis treatment, adjustment solution concentration is 10 ~ 100mg/mL, at 10 ~ 60 DEG C, adding citric acid or hac buffer regulates pH value to be 3 ~ 6, through ultrasonic wave concussion and stir process, obtain Wild antheraea pernyi silk fibroin microsphere suspension; Through centrifugalize, lyophilization, obtaining diameter is 0.1 ~ 10 μm, biodegradable Wild antheraea pernyi silk fibroin microsphere.Document (Biomaterials 31 (2010) 4583-4591) is pointed out in preparation process, use the preparation-obtained microsphere of organic reagent to be unsuitable for being used as slow releasing carrier of medication.In preparation process, adopt citric acid or acetic acid because Chinese invention patent (CN102977381A) adopts, the microsphere therefore obtained is unsuitable for being used as slow releasing carrier of medication.
Document (Biomaterials 31 (2010) 4583-4591) there was reported and utilizes salting out method to prepare the controlled fibroin microsphere of particle diameter (0.5 ~ 2 μm), secondary structure and zeta current potential, this slow-released carrier is regulated and controled by the concentration of salt, but medicine-releasing performance affects greatly by interactional between secondary structure and electric charge, is difficult to use in medicament slow release.Document (Soft Matter, 3 (2007) 910 – 915) report and utilize the method for self assembly to prepare particle diameter the pure fibroin microsphere of 0.2 ~ 1.5 μm, particle diameter and the distribution of fibroin microsphere can be regulated and controled by controlling ethanol addition, freeze temperature and silk fibroin protein solution concentration.But the practicality of the organic solvents such as ethanol limits its application in medicament slow release field.
Document (Biomaterials 31 (2010) 1025 – 1035) report utilize SF/ polyvinyl alcohol (PVA) blended-dissolve the fibroin albumen microsphere that PVA-lyophilized prepares embedding medicinal again, microspherulite diameter is at 0.3 ~ 20 μm, but its drug release rate and burst size affect larger by the molecular weight of medicine and water solublity, and PVA may be there is remain, limit its application on medicament slow release.
Summary of the invention
Technical problem to be solved by this invention is for problems of the prior art, provides a kind of method not preparing surface mesoporous fibroin albumen microsphere drug slow-released carrier containing organic solvent.This preparation method is easy to operate, does not use any organic reagent, and technique is simple, mild condition; The surface mesoporous fibroin albumen microsphere of preparation has that drug loading is high, unharmful substance adds, and microsphere release is mild, and good stability, slow release effect is remarkable.
For solving the problems of the technologies described above, the present invention by the following technical solutions:
Principle of the present invention is: the main component of fibroin albumen is aminoacid, is divided into polar amino acid and nonpolar amino acid by its hydrophilic difference.Non-polar amino acids sequence and Polar Amides acid sequence is comprised according in the typical aminoacid sequence of document (Applied Surface Science 258 (2012) 3948 – 3955) report fibroin albumen, wherein non-polar amino acids sequence is easy to regular arrangement, forms crystalline texture.And remaining strand contains more polar group (-COOH ,-NH
2), there is good hydrophilic, be easy to and water molecules.In fibroin albumen weak solution, macromolecular chain can produce relative movement, and at a certain temperature in the long-time process left standstill, non-polar amino acids sequence can progressively be assembled, and regular arrangement crystallization, form nucleus, and polarity segment is distributed in around.The formation of surface mesoporous structure may be that self-assembly microspheres surface does not form hydrogen bond-COOH and-NH
2associate micro-hydrone.After centrifugal drying, caused by moisture evaporation.
Beneficial effect of the present invention: (1) the present invention utilizes regenerated silk fibroin solution self-assembling method, do not use organic reagent, at room temperature prepare surface mesoporous fibroin albumen microsphere, surface mesoporous fibroin albumen microspherulite diameter size is 500nm ~ 6 μm, surface has the uniform loose structure of regular shape, and need not process there is good resistance to water, drug target is loaded in microsphere, be prepared into carried medicine sustained-release microsphere, drug target stablizes slow releasing, effectively can discharge 90% at 120h, be a kind of avirulence, the significant slow releasing carrier of medication of slow release prolongation of effect; (2) the present invention does not use organic reagent, easy to operate, and technique is simple, mild condition, and operability is good; (3) prepared surface mesoporous microsphere has good resistance to water, without the need to insoluble process (organic solvent process, induction generation crystalline texture, improve its resistance to water) and crosslinking Treatment (generally use organic crosslinking agent, as glutaraldehyde, improve its resistance to water), add without poisonous and harmful substance; (4) compared with general microsphere, the microsphere features smooth surface that the present invention prepares, obtained fibroin microsphere surface distributed has many apertures, there is loose structure, and the shape in hole is evenly regular, between Kong Yukong mutually through (as shown in Figure 1), these apertures are conducive to exchange between material or transmission; (5) the surface mesoporous fibroin albumen microsphere drug slow-released carrier prepared of the present invention, to its active not damaged, is applicable to various targeted sustained release medicine, and microsphere release is mild, good stability, and slow release effect is remarkable, has a good application prospect.
Accompanying drawing explanation
Fig. 1 is the FESEM figure of the surface mesoporous toothed oak fibroin albumen microsphere drug slow-released carrier that the embodiment of the present invention 4 prepares.
Fig. 2 is the release in vitro collection of illustrative plates without fluorouracil (5-Fu) load Wild antheraea pernyi silk fibroin microsphere in the embodiment of the present invention 4.
Detailed description of the invention
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.In addition should be understood that those skilled in the art can make various changes or modifications the present invention, and these equivalent form of values fall within the application's appended claims limited range equally after the content of having read the present invention's instruction.
Embodiment 1
The preparation method of the surface mesoporous fibroin albumen microsphere drug slow-released carrier of the present embodiment is as follows:
(1) Bombyxmori Linnaeus Bombyx bombycis (removing pupa) is in 0.5%(w/w) Na
2cO
3aqueous solution boils 30min and repeats 3 times, removes sericin, and the fibroin that will come unstuck uses CaCl under 75 ± 2 DEG C of conditions
2/ H
2o/C
2h
5oH 1:8:2 ternary solution dissolves 2h, and bath raio is 1:10, solution through filtered through gauze be placed in molecular cut off be the bag filter of 12-14kD dialyse 3d, filter and obtain the Bombyx mori silk fibroin solution that concentration is 0.4 ~ 0.6wt%;
(2) the Bombyx mori silk fibroin solution of 100mL0.4 ~ 0.6wt % is placed in bag filter (molecular cut off is 12-14kD), 2 days are left standstill in 16 DEG C of water-baths, by gained solution ultra-pure water cyclic washing, and cold under the condition of 4 DEG C frozen centrifugation 30min, obtain surface mesoporous Bombyx mori silk fibroin microsphere drug slow-released carrier, be 1.06 ± 0.85 μm through adding up its particle diameter, surface apertures is 60.78 ± 0.5 μm.
Using 5-Fluorouracil (5-FU) as model drug, evaluate the slow-release capability of surface mesoporous Bombyx mori silk fibroin microsphere, the application of the surface mesoporous Bombyx mori silk fibroin microsphere drug slow-released carrier that the present embodiment prepares is as follows:
(1) take the surface mesoporous Bombyx mori silk fibroin microsphere of 5 g 4 DEG C, frequency of oscillation be the condition of 150 ~ 200 revs/min under ultrasonic disperse in ultra-pure water, configure the fibroin protein microspheres solution of 5g/L, add 0.5g without fluorouracil (5-Fu), by mixed solution at room temperature dispersion treatment 10min, then high speed freezing (4 DEG C) is centrifugal, obtains the surface mesoporous Bombyx mori silk fibroin sustained-release micro-spheres of medicine carrying;
(2) take and measure 3g medicine carrying microballoons and be placed in bag filter, add the phosphate buffer solution 5mL of pH=7.4, concussion makes it be uniformly dispersed, and then bag filter is placed in the flask of the phosphate buffer solution of 1000mLpH=7.4, in 37 DEG C of isothermal vibrations, carry out drug release.Ultraviolet spectrophotometer is utilized to carry out the absorbance (get 10mL impregnation liquid, supplement 10mL phosphate buffer) of periodic detection impregnation liquid at 264nm place, according to the release property of drug target in langbobier law gauging surface mesoporous Mulberry fibroin albumen microsphere.Result shows: in front 2h, and release amount of medicine is about 24%(and is less than 40%, does not belong to prominent and releases).5-FU stablizes slow releasing subsequently, effectively can discharge 92% at 120h.Illustrate that bag carries the surface mesoporous Bombyx mori Silk Fibroin microsphere release of 5-FU gently, slow release effect is remarkable.
Embodiment 2
The preparation method of the surface mesoporous fibroin albumen microsphere drug slow-released carrier of the present embodiment is as follows:
In Example 1,100mL Bombyx mori silk fibroin solution is placed in bag filter (molecular cut off is 12-14kD) by step (1) gained Bombyx mori silk fibroin weak solution, 5 days are left standstill in 20 DEG C of water-baths, by gained solution ultra-pure water cyclic washing, and cold under the condition of 0 DEG C frozen centrifugation 10min, obtain surface mesoporous Bombyx mori silk fibroin microsphere drug slow-released carrier.
Embodiment 3
The preparation method of the surface mesoporous fibroin albumen microsphere drug slow-released carrier of the present embodiment is as follows:
In Example 1, the Bombyx mori silk fibroin solution of 100mL is placed in bag filter (molecular cut off is 12-14kD) by step (1) gained Bombyx mori silk fibroin weak solution, 1 day is left standstill in 18 DEG C of water-baths, by gained solution ultra-pure water cyclic washing, and cold under the condition of 5 DEG C frozen centrifugation 15min, obtain surface mesoporous Bombyx mori silk fibroin microsphere drug slow-released carrier.
Embodiment 4
The preparation method of the surface mesoporous fibroin albumen microsphere drug slow-released carrier of the present embodiment is as follows:
(1) Antherea pernyi Guerin-Meneville Bombyx bombycis (removing pupa) is in 0.5%(w/w) Na
2cO
3aqueous solution boils 30min and repeats 3 times, removes sericin.The certain solvent of fibroin will be come unstuck in 75 ± 2 DEG C with saturated lithium rhodanate solubilize 2h; bath raio is 1:30, solution through filtered through gauze be placed in molecular cut off be the bag filter of 12-14kD dialyse 3d, filter and obtain the tussah silk fibroin solution that concentration is 0.4 ~ 0.6wt%;
(2) 100mL tussah silk fibroin solution is placed in bag filter (molecular cut off is 12-14kD), 1 day is left standstill in room-temperature water bath, by gained solution ultra-pure water cyclic washing, and cold under the condition of 4 DEG C frozen centrifugation 10min, obtain surface mesoporous Wild antheraea pernyi silk fibroin microsphere slow releasing carrier of medication.Wherein microspherulite diameter size is 500nm ~ 6 μm, surface apertures be 30nm ~ 210nm(as shown in Figure 1).
Using 5-Fluorouracil (5-FU) as model drug, evaluate the slow-release capability of surface mesoporous Wild antheraea pernyi silk fibroin microsphere, the application of the surface mesoporous Wild antheraea pernyi silk fibroin microsphere slow releasing carrier of medication that the present embodiment prepares is as follows:
(1) take the surface mesoporous Wild antheraea pernyi silk fibroin microsphere of 5g 4 DEG C, frequency of oscillation adopts constant temperature oscillator to carry out dispersion treatment under being the condition of 150 ~ 200 revs/min in ultra-pure water, configuration obtains the fibroin protein microspheres solution of 5g/L, by concentration be 1 mg/mL add in surface mesoporous fibroin albumen microsphere suspension liquid without fluorouracil (5-Fu) 500mL, by mixed solution at room temperature dispersion treatment 10min, then high speed freezing (4 DEG C) is centrifugal, obtains the surface mesoporous tussah silk fibroin sustained-release micro-spheres of medicine carrying;
(2) take and measure 3g medicine carrying microballoons and be placed in bag filter, add the phosphate buffer solution 5mL of pH=7.4, concussion makes it be uniformly dispersed, and then bag filter is placed in the flask of the phosphate buffer solution of 1000mLpH=7.4, in 37 DEG C of isothermal vibrations, carry out drug release.Utilize ultraviolet spectrophotometer to carry out the absorbance (get 10mL impregnation liquid, supplement 10mL phosphate buffer) of periodic detection impregnation liquid at 264nm place, in the mesoporous fibroin albumen microsphere of foundation langbobier law gauging surface, the release profiles of drug target as shown in Figure 2.
Result shows: in front 2h, and release amount of medicine is about 20%(and is less than 40%, does not belong to prominent and releases).5-FU stablizes slow releasing subsequently, effectively can discharge 90% at 120h.Illustrate that bag carries the surface mesoporous tussah silk peptide microsphere release of 5-FU gently, good stability, slow release effect is remarkable.
Claims (8)
1. the preparation method of a surface mesoporous fibroin albumen microsphere drug slow-released carrier, Bombyx bombycis carried out come unstuck, dissolve, obtain silk fibroin protein solution after dialysis treatment, it is characterized in that: silk fibroin protein solution is placed in bag filter, then bag filter is placed in the water-bath of 16 ~ 20 DEG C, leave standstill 1 ~ 5 day, by gained solution washing, and frozen centrifugation obtains surface mesoporous fibroin albumen microsphere drug slow-released carrier.
2. the preparation method of surface mesoporous fibroin albumen microsphere drug slow-released carrier according to claim 1, is characterized in that: described Bombyx bombycis is mulberry cocoon or tussah cocoon.
3. the preparation method of surface mesoporous fibroin albumen microsphere drug slow-released carrier according to claim 1, is characterized in that: described bag filter molecular cut off is 12-14kD.
4. the preparation method of surface mesoporous fibroin albumen microsphere drug slow-released carrier according to claim 1, is characterized in that: the concentration of described silk fibroin protein solution is 0.4 ~ 0.6wt%.
5. the preparation method of surface mesoporous fibroin albumen microsphere drug slow-released carrier according to claim 1, is characterized in that: the solvent that described washing adopts is ultra-pure water, and the temperature of frozen centrifugation is 0 ~ 5 DEG C, and the time is 10 ~ 30min.
6. the application of surface mesoporous fibroin albumen microsphere drug slow-released carrier according to claim 1, it is characterized in that: surface mesoporous fibroin albumen microsphere ultrasonic disperse is configured to the surface mesoporous fibroin albumen microspheres solution that concentration is 5g/L in ultra-pure water, add drug target, by mixed solution at room temperature dispersion treatment 10min, then under the condition of 4 DEG C, high speed is freezing, centrifugal, obtains the surface mesoporous fibroin albumen microsphere of medicine carrying.
7. the application of surface mesoporous fibroin albumen microsphere drug slow-released carrier according to claim 6, is characterized in that: described ultrasonic disperse be 4 DEG C, frequency of oscillation adopts constant temperature oscillator to carry out dispersion treatment under being the condition of 150 ~ 200 revs/min.
8. the application of surface mesoporous fibroin albumen microsphere drug slow-released carrier according to claim 6, is characterized in that: described drug target is slow releasing pharmaceutical or gene repair class medicine.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105832682A (en) * | 2016-05-27 | 2016-08-10 | 浙江大学 | Method for preparing honeycomb silk fibroin porous microsphere sustained drug release vector |
| CN107043412A (en) * | 2017-04-19 | 2017-08-15 | 东华大学 | The green fast standard production method of the controllable silkworm regenerated silk fibroin of molecular weight |
| CN109316462A (en) * | 2018-09-06 | 2019-02-12 | 温州医科大学附属第医院 | A kind of pillow Chinese materia medica preparation pharmaceutical carrier and preparation method thereof |
| CN109602952A (en) * | 2018-12-27 | 2019-04-12 | 上海北陆医药科技有限公司 | A kind of long-acting slow-release cytoskeleton and preparation method thereof, application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102977381A (en) * | 2012-12-10 | 2013-03-20 | 苏州大学 | Wild antheraea pernyi silk fibroin microsphere and preparation method thereof |
| CN103965310A (en) * | 2014-04-21 | 2014-08-06 | 浙江大学 | Self-assembling method for preparing fibroin microspheres |
| CN104434812A (en) * | 2014-11-12 | 2015-03-25 | 苏州大学 | Tussah silk protein adriamycin sustained release microsphere and preparation method thereof |
-
2015
- 2015-04-24 CN CN201510197114.4A patent/CN104825398B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102977381A (en) * | 2012-12-10 | 2013-03-20 | 苏州大学 | Wild antheraea pernyi silk fibroin microsphere and preparation method thereof |
| CN103965310A (en) * | 2014-04-21 | 2014-08-06 | 浙江大学 | Self-assembling method for preparing fibroin microspheres |
| CN104434812A (en) * | 2014-11-12 | 2015-03-25 | 苏州大学 | Tussah silk protein adriamycin sustained release microsphere and preparation method thereof |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105832682A (en) * | 2016-05-27 | 2016-08-10 | 浙江大学 | Method for preparing honeycomb silk fibroin porous microsphere sustained drug release vector |
| CN105832682B (en) * | 2016-05-27 | 2018-11-13 | 浙江大学 | A kind of preparation method of cellular silk fibroin porous microsphere drug slow-released carrier |
| CN107043412A (en) * | 2017-04-19 | 2017-08-15 | 东华大学 | The green fast standard production method of the controllable silkworm regenerated silk fibroin of molecular weight |
| CN109316462A (en) * | 2018-09-06 | 2019-02-12 | 温州医科大学附属第医院 | A kind of pillow Chinese materia medica preparation pharmaceutical carrier and preparation method thereof |
| CN109602952A (en) * | 2018-12-27 | 2019-04-12 | 上海北陆医药科技有限公司 | A kind of long-acting slow-release cytoskeleton and preparation method thereof, application |
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