CN104940936A - Long-acting slow release preparation for treating keratomycosis as well as preparation method and application thereof - Google Patents
Long-acting slow release preparation for treating keratomycosis as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a preparation for treating treating keratomycosis, and particularly relates to a long-acting slow release preparation for treating keratomycosis as well as a preparation method and application thereof. The substrate of the long-acting slow release preparation is formed through electrostatic bonding of a graphene material and a drug-carried chitosan material, drugs are carried on the sheet structure of the graphene material, the structure is stable, and the loading rate is high. The preparation provided by the invention has excellent bacteriostatic activity on fungus and bacterium, and is excellent in cytocompatibility, toughness, and tensile strength. The preparation can be simply and conveniently applied onto cornea, and has no toxic effects on normal tissue while achieving excellent bacteriostatic activity. The long-acting slow release preparation is taken as a dosage form in ophthalmology, can be adhered onto a cornea of a patient for long-acting slow release, so as to achieve effective drug concentration, and the preparation has the advantages that the preparation is simple and convenient, the drug-carried material self is excellent in bacteriostatic activity and mechanical property, stimulation and toxic or side effects on orbital tissue can be avoided, and the use is convenient.
Description
Technical field
The present invention relates to a kind of preparation controlling antifungal drug, be specifically related to a kind of long-acting slow-release preparation for the treatment of fungal keratitis and preparation method thereof and application.
Background technology
Fungal keratitis is a kind of serious blinding oculopathy, and cause the Main Pathogenic Bacteria of fungal keratitis based on S fungus, common have Fusarium spp., aspergillosis etc.Along with the generally abuse of broad-spectrum antibiotic, corticosteroid and antiviral drugs clinically, cause the drug resistance of antibacterial to strengthen, fungal keratitis sickness rate increases gradually in recent years, and the state of an illness is also more serious.
Voriconazole (voriconazole, UK-109,496) is second filial generation triazole type broad-spectrum antifungal medicine, and comparatively conventional antifungal medicine is as amphotericin B, itraconazole, and its anti-fungus spectra is wider, and its curative effect is also more definite.But because its dissolubility difficulty can not be overcome very well, also do not develop collyrium or the eye ointment preparation of voriconazole at present clinically.When voriconazole is used for clinical treatment fungoid ophthalmic, intravitreal can only be adopted, medicine half-life in vitreous chamber short (about 2.5h), need repeatedly inject, and owing to repeatedly having potential endophthalmitis, vitreous hemorrhage and detachment of retina equivalent risk at intravitreal.The injection patent of invention of report voriconazole is had in current open source literature, as CN200510095595, CN200710143810, CN200910019770 etc., all need to add cyclodextrin adjuvant with voriconazole injection prepared by these patent of invention methods, although add the meltage of voriconazole, but the adjuvant cyclodextrin used or tween, at eyes, have stronger physiological-toxicity.Chinese invention patent CN201110380218 reports the micro-composite granule of receiving using the adjuvant such as PEG400, lecithin to make, although adjuvant safety used is high, the drug particles particle diameter obtained is little, dispersion liquid is transparent, but easily prominently during drug release releases, and long-acting slow-release effect is also undesirable.
At present, mostly eye antifungal preparation conventional is clinically eye drop, and make with water or buffer, bioavailability is low, needs frequent drug administration, and patient's compliance is poor.Therefore, be necessary to develop the medicament for the eyes dosage form that makes new advances to make up the deficiency of convenient administration mode, and guarantee the excellent results of antifungic action simultaneously.
Summary of the invention
In order to overcome the deficiencies in the prior art and shortcoming, primary and foremost purpose of the present invention is to provide a kind of long-acting slow-release preparation for the treatment of fungal keratitis, said preparation adopts Chitosan-phospholipid complex/Graphene class material to be carrier, load voriconazole medicament for the eyes, itself has good bacteriostatic activity, can stick on patient's cornea, fixed point long-acting slow-releasing medicine, enhance the fungistatic effect of corneal focal zone fungus, and extend administration time, greatly improve the drug bioavailability of novel formulation.
Another object of the present invention is to the preparation method of the long-acting slow-release preparation that above-mentioned treatment fungal keratitis is provided.
Another object of the present invention is the application of the long-acting slow-release preparation providing above-mentioned treatment fungal keratitis.
Object of the present invention is achieved through the following technical solutions:
Treat a preparation method for the long-acting slow-release preparation of fungal keratitis, comprise following steps:
(1) chitosan class material is dissolved in acetic acid solution, obtains chitosan class material-acetic acid solution;
(2) chitosan class material-acetic acid solution step (1) prepared mixes with Graphene class material dispersion liquid, stirring reaction 1 ~ 5h at 20 ~ 80 DEG C, obtains the composite of chitosan class material electrostatical binding Graphene class material;
(3) antimycotic medicine voriconazole is added in the composite of the chitosan class material electrostatical binding Graphene class material prepared in step (2), then at 30 ~ 80 DEG C, 3 ~ 12h is reacted, dialysis, the long-acting slow-release preparation of the fungal keratitis that obtains medical treatment;
The volume fraction of the acetic acid solution described in step (1) is preferably 1% ~ 2% (v/v);
Chitosan class material described in step (1) is any one or at least two kinds in chitosan and chitosan derivatives;
Described chitosan derivatives is preferably chitosan quaternary ammonium salt;
Fully stir 1 ~ 3d after preferably chitosan class material being added acetic acid solution in step (1), make it fully dissolve; Described mixing time is preferably 1 ~ 3d;
Graphene class material described in step (2) is any one or at least two kinds in Graphene and modified graphene;
Described modified graphene is preferably carboxyl Graphene;
Graphene class material dispersion liquid described in step (2) needs fully dispersion, and described dispersing mode is preferably ultrasonic 30min ~ 3h;
The mass fraction of Graphene class material described in step (2) in the composite of chitosan class material electrostatical binding Graphene class material is 0.1% ~ 1%;
In the composite of the chitosan class material electrostatical binding Graphene class material described in step (2), the mass ratio of chitosan and Graphene class material is (100:1) ~ (200:1);
Voriconazole described in step (3) final concentration is in the composite 5 ~ 10mg/mL;
The time of the dialysis described in step (3) is 12 ~ 24h;
The long-acting slow-release preparation of described treatment fungal keratitis can be processed further and prepare suspensoid, gel type formulations or vacuum drying film forming, obtains medicine carrying membrane preparation;
The matrix of the long-acting slow-release preparation of the treatment fungal keratitis that the present invention prepares is made up of Graphene class material electrostatical binding medicine carrying chitosan class material, and drug loading is in the laminated structure of Graphene class material, and Stability Analysis of Structures, load capacity is large.Described carrying medicine has good biocompatibility, inhibitory action is not had to the normal cell of health, to fungal keratitis, there is good curative effect, corneal can produce obvious inhibitory action at the growth of fungus and bacterium, there is good cell compatibility and pliability and tensile strength.
The present invention has following advantage and effect relative to prior art:
(1) the novel carrying medicine drug loading prepared by the present invention is large, can reach 70%, and preparation stabilization.
(2) carrying medicine prepared by the present invention has good biocompatibility, does not have obvious inhibitory action to Normocellular growth.
(3) preparation prepared by the present invention can stick on patient's cornea, and fixed point long-acting slow-releasing medicine, enhances the fungistatic effect of corneal focal zone fungus, and extend administration time, greatly improve the drug bioavailability of novel formulation.
(4) medicine carrying membrane prepared by the present invention has excellent mechanical performance, and preparation method is easy.
Accompanying drawing explanation
Fig. 1 is the surface topography map of embodiment 1 gained medicine carrying membrane.
Fig. 2 is embodiment 5 medicament slow release interpretation figure.
Detailed description of the invention
Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail, but embodiments of the present invention are not limited thereto.
Embodiment 1
(1) get 2g chitosan to be dissolved in 2% (v/v) acetic acid solution of 200mL, mechanical agitation, is transferred to after 2 days in there-necked flask, prepares chitosan-acetic acid solution; Get the 2mg/mL graphene dispersing solution of 7.6mL, the ultrasonic 30min of 300W, makes it fully disperse;
(2) graphene dispersing solution after ultrasonic for step (1) abundant dispersion is dripped in the chitosan-acetic acid solution prepared in step (1), continue Keep agitation 5h at 60 DEG C, obtain the composite of chitosan electrostatical binding Graphene;
(3) the injection normal saline dilution of voriconazole is got, drip in the composite of the chitosan electrostatical binding Graphene prepared in step (2) under stirring, voriconazole ultimate density is in the composite made to be 5mg/mL, Keep agitation 12h at 30 DEG C; Load in bag filter (retaining size 800Da), be placed in deionized water and remove the medicine do not carried, after dialysis 12h, the long-acting slow-release preparation of the fungal keratitis that obtains medical treatment, is placed in 4 DEG C of preservations.Obtain new type gel preparation after can concentrating further, or curtain coating obtains medicine carrying membrane preparation (Fig. 1) on glass after drying further.
Embodiment 2
(1) get 2g chitosan quaternary ammonium salt to be dissolved in 1% (v/v) acetic acid solution of 200mL, mechanical agitation, is transferred to after 1 day in there-necked flask, prepares chitosan quaternary ammonium salt-acetic acid solution; Get the 2mg/mL graphene dispersing solution of 10mL, the ultrasonic 1h of 300W, makes it fully disperse;
(2) graphene dispersing solution after ultrasonic for step (1) abundant dispersion is dripped in the chitosan quaternary ammonium salt-acetic acid solution prepared in step (1), continue Keep agitation 3h at 20 DEG C, obtain the composite of chitosan quaternary ammonium salt electrostatical binding Graphene;
(3) the injection normal saline dilution of voriconazole is got, drip in the composite of the chitosan quaternary ammonium salt electrostatical binding Graphene prepared in step (2) under stirring, voriconazole ultimate density is in the composite made to be 8mg/mL, Keep agitation 3h at 80 DEG C; Load in bag filter (retaining size 800Da), be placed in deionized water and remove the medicine do not carried, after dialysis 18h, the long-acting slow-release preparation of the fungal keratitis that obtains medical treatment, is placed in 4 DEG C of preservations.Obtain new type gel preparation after can concentrating further, or curtain coating obtains medicine carrying membrane preparation on glass after drying further.
Embodiment 3
(1) get 2g chitosan to be dissolved in 1.5% (v/v) acetic acid solution of 200mL, mechanical agitation, is transferred to after 3 days in there-necked flask, prepares chitosan-acetic acid solution; Get the 2mg/mL carboxyl graphene dispersing solution of 20mL, the ultrasonic 1h of 300W, makes it fully disperse;
(2) the carboxyl graphene dispersing solution after ultrasonic for step (1) abundant dispersion is dripped in the chitosan-acetic acid solution prepared in step (1), continue Keep agitation 1h at 80 DEG C, obtain the composite of chitosan electrostatical binding Graphene;
(3) the injection normal saline dilution of voriconazole is got, drip in the composite of the chitosan electrostatical binding carboxyl Graphene prepared in step (2) under stirring, voriconazole ultimate density is in the composite made to be 10mg/mL, Keep agitation 8h at 50 DEG C; Load in bag filter (retaining size 800Da), be placed in deionized water and remove the medicine do not carried, after dialysis 24h, the long-acting slow-release preparation of the fungal keratitis that obtains medical treatment, is placed in 4 DEG C of preservations.Obtain new type gel preparation after can concentrating further, or curtain coating obtains medicine carrying membrane preparation on glass after drying further.
Embodiment 4
(1) get 2g chitosan quaternary ammonium salt to be dissolved in 2% (v/v) acetic acid solution of 200mL, mechanical agitation, is transferred to after 2 days in there-necked flask, prepares chitosan-acetic acid solution; Get the 2mg/mL carboxyl graphene dispersing solution of 7.6mL, the ultrasonic 30min of 300W, makes it fully disperse;
(2) the carboxyl graphene dispersing solution after ultrasonic for step (1) abundant dispersion is dripped in the chitosan quaternary ammonium salt-acetic acid solution prepared in step (1), continue Keep agitation 5h at 60 DEG C, obtain the composite of chitosan electrostatical binding Graphene;
(3) the injection normal saline dilution of voriconazole is got, drip in the composite of the chitosan electrostatical binding Graphene prepared in step (2) under stirring, voriconazole ultimate density is in the composite made to be 10mg/mL, Keep agitation 12h at 50 DEG C; Load in bag filter (retaining size 800Da), be placed in deionized water and remove the medicine do not carried, after dialysis 12h, the long-acting slow-release preparation of the fungal keratitis that obtains medical treatment, is placed in 4 DEG C of preservations.Obtain new type gel preparation after can concentrating further, or curtain coating obtains medicine carrying membrane preparation on glass after drying further.
Embodiment 5 medicament slow release is tested
(1) according to the long-acting slow-release preparation of the method preparation treatment fungal keratitis of embodiment 1, getting its 20mL loads in bag filter (MWCO=800Da), after the medicine of non-load has been dialysed, survey its absorbance value, calculate the amount of non-load, thus calculate drug loading and be: the drug delivery amount on 1mg composite material film is 0.7977mg.
(2) according to the long-acting slow-release preparation of the method preparation treatment fungal keratitis of embodiment 1, remove the medicine of non-load with bag filter after, another bag filter is proceeded to; Be placed in the PBS solution of pH 7.4, constant-temperature incubation at 37 DEG C, arrange three parallel group.Often 4mL PBS solution is taken out in group timing, then fills into the fresh PBS solution of 4mL to it.Liquid of getting detects absorbance value under 255nm, and with each sample point (time) for abscissa, the total volume of voriconazole accumulative on each sample point is vertical coordinate, and curve plotting figure, result as shown in Figure 2.As can be seen from the figure, slow release slowly increases, and finally tends towards stability, and slow release effect is good.
Embodiment 6 bacteriostatic test
(1) escherichia coli (ATCC8739, Microbiological Lab of resource environment institute of Agricultural University Of South China provides) and staphylococcus aureus (ATCC6538, Microbiological Lab of resource environment institute of Agricultural University Of South China provides) be inoculated in LB culture medium, cultivate at 37 DEG C; Fusarinm solani (CGMCC3.1829, purchased from Chinese medicine fungus preservation administrative center of Institute of Micro-biology of the Chinese Academy of Medical Sciences) and Aspergillus fumigatus (AS3.772, purchased from Chinese medicine fungus preservation administrative center of Institute of Micro-biology of the Chinese Academy of Medical Sciences) be then inoculated in husky Borrow (Sabourand's) agar culture medium, cultivate at 28 DEG C.After more bacterium colony to be formed, normal saline eluting, and be diluted to 10
5/ mL, respectively gets 15 μ L coated plates.The sterilizing filter paper dick of 5 diameter 8mm is added in the 2mg/mL suspension of the long-acting slow-release preparation (embodiment 1) for the treatment of fungal keratitis, after filter paper dick adsorbs suspension completely, be attached at smeared bacterium liquid flat board on, be then placed in constant incubator and cultivate.After inhibition zone to appear, vernier caliper measurement antibacterial circle diameter.Each inhibition zone measurement three times.Be 9mm to the antibacterial circle diameter of Fusarinm solani, be 8mm to the antibacterial circle diameter of Aspergillus fumigatus, being 16mm to colibacillary antibacterial circle diameter, is 15mm to the antibacterial circle diameter of staphylococcus aureus, and preparation is comparatively eager to excel to the fungistatic effect of fungus to the fungistatic effect of antibacterial.
(2), after above-mentioned bacterial strains (escherichia coli, staphylococcus aureus, Fusarinm solani and Aspergillus fumigatus) liquid culture, coubling dilution is adopted to detect minimum inhibitory concentration (MIC).Get sterilizing small test tube 10, in the 1st pipe, add culture fluid 1.9mL, each 1mL in 2 ~ 10 pipes; Add medicine or the medicine carrying material 0.1mL of test in 1st pipe, get 1mL after mixing and join the 2nd pipe, doubling dilution successively, draw 1mL from the 9th pipe and discard, do not add medicine or medicine carrying material in the 10th pipe, in contrast; 10 are added in each pipe
5cFU/mL, bacterium liquid is 50 μ L, and mixing is cultivated.With do not occur lowest concentration of drug that naked eyes visible colonies grows by the MIC of survey material.To survey voriconazole to the MIC of Fusarinm solani be 2.5 μ g/mL, be 2.5 ~ 5 μ g/mL to the MIC of Aspergillus fumigatus, and the MIC of long-acting slow-release preparation to these two kinds of funguses of the treatment fungal keratitis that embodiment 1 prepares is 1.25 μ g/mL.
Embodiment 7 cytotoxicity experiment
(1) toxicity of mtt assay test material corneal epithelial cell is adopted.In 96 porocyte plates, add the corneal epithelial cell (HECEs, purchased from middle mountain Eye Center) being in logarithmic (log) phase, the cell density in each hole is 5000/ hole, adds the culture medium of hyclone.After 24h, suck culture medium, every hole adds fresh culture 200 μ L.Processed group respectively adds the long-acting slow-release preparation 30 μ L of the treatment fungal keratitis that embodiment 1 prepares, and matched group adds culture medium 30 μ L.All establish 6 multiple holes for each group.
(2) after 24h, replace with 200 μ L basal mediums (namely not increase serum) in each hole, in each hole, add 20 μ L 5mg/mL MTT solution (PBS solution of pH7.4 is dissolved) simultaneously.After cultivating 3h at 37 DEG C, suck aerial culture fluid, respectively add 200 μ L dimethyl sulfoxide, make the cell dissolving crystallized of formation.Whether this 96 orifice plate is placed in microplate reader, surveys its light absorption value under 580nm wavelength, detecting medicine carrying material with this numerical value has inhibitory action to Normocellular growth.
According to result, obtaining medicine carrying material cell growth does not have inhibitory action.
Embodiment 8 animal experiment
Select the C57BL/6j mice (being purchased from Nanfang Medical Univ's animal feeding center) of 6 ~ 8 week age, body weight 18 ~ 22 grams.Injection in coneal stroma method is adopted to set up the scorching model of fungoid mouse cornea, concrete grammar is: have the syringe needle on 30 ° of inclined-planes periphery inserting needle in cornea with a 30-gauge, do the corneal tunnel that a degree of depth reaches hypothallus, that then changes a 33-gauge has the syringe needle on 30 ° of inclined-planes along tunnel entering angle membrane matrix, injects 1.5 μ L Aspergillus fumigatus suspensions (1 × 10 subsequently
8/ mL).The medicine carrying membrane that embodiment 1 prepares being cut into suitable size is placed under the left eye of rabbit in conjunctival sac, and right eye in contrast, observes cornea change under slit lamp continuous 7 days.We obtain, and the fungal keratitis of mice is cured gradually, and eyes are got well.
A kind of long-acting slow-release suspensoid, gel preparation or thin film class preparation for the treatment of fungal keratitis prepared by the specific embodiment of the invention, carry out medicament slow release test to it, antibacterial test, toxicity assessment, cornea change test etc., obtain good experimental result.
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (10)
1. treat a preparation method for the long-acting slow-release preparation of fungal keratitis, it is characterized in that comprising following steps:
(1) chitosan class material is dissolved in acetic acid solution, obtains chitosan class material-acetic acid solution;
(2) chitosan class material-acetic acid solution step (1) prepared mixes with Graphene class material dispersion liquid, stirring reaction 1 ~ 5h at 20 ~ 80 DEG C, obtains the composite of chitosan class material electrostatical binding Graphene class material;
(3) antimycotic medicine voriconazole is added in the composite of the chitosan class material electrostatical binding Graphene class material prepared in step (2), then at 30 ~ 80 DEG C, 3 ~ 12h is reacted, dialysis, the long-acting slow-release preparation of the fungal keratitis that obtains medical treatment.
2. the preparation method of the long-acting slow-release preparation for the treatment of fungal keratitis according to claim 1, is characterized in that:
Chitosan class material described in step (1) is any one or at least two kinds in chitosan and chitosan derivatives.
3. the preparation method of the long-acting slow-release preparation for the treatment of fungal keratitis according to claim 1, is characterized in that:
The volume fraction of the acetic acid solution described in step (1) is 1% ~ 2%.
4. the preparation method of the long-acting slow-release preparation for the treatment of fungal keratitis according to claim 1, is characterized in that:
Graphene class material described in step (2) is any one or at least two kinds in Graphene and modified graphene.
5. the preparation method of the long-acting slow-release preparation for the treatment of fungal keratitis according to claim 1, is characterized in that:
The mass fraction of Graphene class material described in step (2) in the composite of chitosan class material electrostatical binding Graphene class material is 0.1% ~ 1%.
6. the preparation method of the long-acting slow-release preparation for the treatment of fungal keratitis according to claim 1, is characterized in that:
In the composite of the chitosan class material electrostatical binding Graphene class material described in step (2), the mass ratio of chitosan and Graphene class material is (100:1) ~ (200:1).
7. the preparation method of the long-acting slow-release preparation for the treatment of fungal keratitis according to claim 1, is characterized in that:
Voriconazole described in step (3) final concentration is in the composite 5 ~ 10mg/mL.
8. the preparation method of the long-acting slow-release preparation for the treatment of fungal keratitis according to claim 1, is characterized in that:
The long-acting slow-release preparation of described treatment fungal keratitis can be processed further and prepare suspensoid, gel type formulations or vacuum drying film forming, obtains medicine carrying membrane preparation.
9. treat a long-acting slow-release preparation for fungal keratitis, it is characterized in that: the preparation method according to any one of claim 1 ~ 8 prepares.
10. the application of long-acting slow-release preparation in preparation treatment fungal keratitis medicine for the treatment of fungal keratitis according to claim 9.
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| CN105726517A (en) * | 2016-02-19 | 2016-07-06 | 浙江大学 | Ocular insert containing voriconazole |
| CN107466686A (en) * | 2017-09-28 | 2017-12-15 | 重庆市林业科学研究院 | A kind of disconnected anvil cleft grafting Cultivating techniques of safflower oil tea |
| CN107580950A (en) * | 2017-09-29 | 2018-01-16 | 重庆市林业科学研究院 | A kind of Nanchuan wood pineapple sand bed method for culturing seedlings |
| CN107670116A (en) * | 2017-08-29 | 2018-02-09 | 广州市朴道联信生物科技有限公司 | A kind of preparation method of antimycotic cornea repair material |
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| CN113278531A (en) * | 2021-04-25 | 2021-08-20 | 中国热带农业科学院热带生物技术研究所 | Inducer for inducing Hainan dragon tree to rapidly generate dragon's blood and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105477647A (en) * | 2015-12-02 | 2016-04-13 | 常州大学 | Graphene quantum dot/chitosan xerogel preparation and application of graphene quantum dot/chitosan xerogel to fluorescent imaging and drug sustained release |
| CN105726517A (en) * | 2016-02-19 | 2016-07-06 | 浙江大学 | Ocular insert containing voriconazole |
| CN105726517B (en) * | 2016-02-19 | 2019-01-29 | 浙江大学 | A kind of ocular inserts containing voriconazole |
| CN107670116A (en) * | 2017-08-29 | 2018-02-09 | 广州市朴道联信生物科技有限公司 | A kind of preparation method of antimycotic cornea repair material |
| CN107670116B (en) * | 2017-08-29 | 2020-12-08 | 广州市朴道联信生物科技有限公司 | Preparation method of antifungal cornea repair material |
| CN107466686A (en) * | 2017-09-28 | 2017-12-15 | 重庆市林业科学研究院 | A kind of disconnected anvil cleft grafting Cultivating techniques of safflower oil tea |
| CN107580950A (en) * | 2017-09-29 | 2018-01-16 | 重庆市林业科学研究院 | A kind of Nanchuan wood pineapple sand bed method for culturing seedlings |
| CN108434093A (en) * | 2018-06-22 | 2018-08-24 | 青岛大学 | A kind of preparation method of the injection aquagel of voriconazole intraocular drug controlled release |
| CN108434093B (en) * | 2018-06-22 | 2020-02-18 | 青岛大学 | Preparation method of voriconazole intraocular drug controlled-release injectable hydrogel |
| CN112773778A (en) * | 2020-10-14 | 2021-05-11 | 中山大学中山眼科中心 | Medical material for treating fungal keratitis and preparation method thereof |
| CN113278531A (en) * | 2021-04-25 | 2021-08-20 | 中国热带农业科学院热带生物技术研究所 | Inducer for inducing Hainan dragon tree to rapidly generate dragon's blood and preparation method and application thereof |
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