CN112791056A - Florfenicol solid dispersion and preparation method thereof - Google Patents
Florfenicol solid dispersion and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
The invention relates to the technical field of pharmaceutical preparations, and particularly discloses a florfenicol solid dispersion and a preparation method thereof. The preparation method of the florfenicol solid dispersion comprises the following steps: a. dissolving the hydroxypropyl methyl cellulose acetate succinate in a solvent, and adding florfenicol to obtain a mixed solution; b. adding the mixed solution into an anti-solvent, and stirring and filtering to obtain a solid retentate; c. and sequentially freezing, drying and grinding the solid retentate to obtain the florfenicol solid dispersion. The florfenicol solid dispersion prepared by the preparation method of the florfenicol solid dispersion provided by the invention has higher solubility, dissolution speed and in-vitro dissolution rate, and has higher stability and bioavailability.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a florfenicol solid dispersion and a preparation method thereof.
Background
Florfenicol is a fluorinated derivative of thiamphenicol, and is a special broad-spectrum antibiotic for amide alcohol animals. Compared with TAP, florfenicol has wider antibacterial range, has an inhibiting effect on both gram-negative bacteria and gram-positive bacteria, and has the characteristics of quick acting, long acting, quick absorption, wide in-vivo distribution, systemic distribution, long half-life period and high blood concentration.
The florfenicol is mainly applied to dosage forms such as premix, solution, injection, powder and the like in clinic. The premix is administrated by mixed feeding, but under the condition of serious infection of animals, the curative effect of the mixed feeding is difficult to ensure due to the reduction of the food intake of the animals, the requirement of a clinical preparation of 300mg/mL cannot be met, and high-dose administration or frequent administration is often required, so that the pressure is brought to the animals, and the labor cost is increased. The injection needs to add organic solvent to increase solubility, however, the solvent can cause irritation and toxic and side effects to the injection site. The oral solid preparation has small toxic and side effect and stable drug effect, is convenient to use and store, but the application of the oral solid preparation in veterinary clinic is limited to a great extent due to the problem of low solubility of the florfenicol.
The florfenicol solid preparation disclosed at present improves the absorption rate and the solubility of the florfenicol solid preparation to a certain extent through technical improvement, but the existing preparation method of the florfenicol solid preparation is complex and needs high-temperature operation, and the capability of improving the drug solubility and the blood concentration is extremely limited, so that the problem of low solubility of the florfenicol is not well solved.
Disclosure of Invention
Aiming at the problems of the existing florfenicol medicinal preparation, the invention provides a florfenicol solid dispersion and a preparation method thereof.
In order to achieve the purpose of the invention, the embodiment of the invention adopts the following technical scheme:
a preparation method of florfenicol solid dispersion. The preparation method at least comprises the following steps:
a. dissolving hydroxypropyl methyl cellulose acetate succinate in a solvent, and adding florfenicol to obtain a mixed solution, wherein the solvent is at least one of N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane and chloroform;
b. adding the mixed solution into an anti-solvent, and stirring and filtering to obtain a solid retentate;
c. and sequentially freezing, drying and grinding the solid retentate to obtain the florfenicol solid dispersion.
Compared with the prior art, the preparation method of the florfenicol solid dispersion provided by the invention has the advantages that the hydroxypropyl methyl cellulose acetate succinate and the florfenicol are added into a specific solvent to be dissolved, then the obtained solution is added into an anti-solvent to be filtered, so that the florfenicol solid dispersion with higher solubility, dissolution speed and in-vitro dissolution rate can be obtained, the solubility of the florfenicol solid dispersion is higher than that of a florfenicol original drug by more than 6 times, and the solubility stability is good. Meanwhile, the obtained florfenicol solid dispersion has high stability, can keep an amorphous state for a long time in a high-temperature and high-humidity environment, can obviously improve the bioavailability of the florfenicol in an animal body, and increases the absorption efficiency of the florfenicol.
In addition, the preparation method of the florfenicol solid dispersion provided by the invention has the advantages of mild conditions, simple operation, good reproducibility and low production cost, and is suitable for large-scale production of the florfenicol solid dispersion.
Preferably, the molar ratio of the florfenicol to the hydroxypropyl methyl cellulose acetate succinate is 1-5: 5-9.
The molar ratio of florfenicol to hydroxypropyl methylcellulose acetate succinate can further improve the solubility and inclusion rate of florfenicol.
Preferably, in step a, the solvent is at least one of N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane and chloroform.
Preferably, in step a, the concentration of hydroxypropyl methyl cellulose acetate succinate dissolved in the solvent is 0.05-0.1 g/mL.
Preferably, in step b, the anti-solvent is an acidic aqueous solution with a pH value of 1-4.
The acidic aqueous solution with the pH value of 1-4 is used as an anti-solvent, so that the raw material utilization rate and the product yield of the florfenicol solid dispersion can be further improved.
Preferably, in the step b, the volume ratio of the mixed solution to the anti-solvent is 1-10: 10-100.
Preferably, in step b, the rate of adding the mixed solution to the antisolvent is 1-30 mL/min.
The mixed solution is injected into the anti-solvent at the speed of 1-30mL/min, so that the uniformity of the florfenicol solid dispersion can be further improved, and the yield and the activity of the nano-scale florfenicol solid dispersion can be improved.
Preferably, in the step c, the rotation speed of the stirring is 1200-1600r/min, and the time is 10-20 min.
Preferably, in step c, the freeze-drying time is 4-8 h.
The invention also provides the florfenicol solid dispersion prepared by the preparation method of the florfenicol solid dispersion.
The invention also provides a pharmaceutical composition which comprises the florfenicol solid dispersion and a pharmaceutically acceptable carrier.
Drawings
FIG. 1 is a powder X-ray diffraction pattern of a florfenicol solid dispersion obtained in example 4 of the present invention;
FIG. 2 is a powder X-ray diffraction pattern of florfenicol obtained in example 4 of the present invention;
FIG. 3 is a powder X-ray diffraction pattern of hydroxypropylmethylcellulose acetate succinate obtained in example 4 of the present invention;
FIG. 4 is a thermogravimetric analysis (TG) graph of the florfenicol solid dispersion obtained in example 4 of the present invention;
FIG. 5 is a thermogravimetric analysis (TG) plot of florfenicol obtained in example 4 of the present invention;
FIG. 6 is a thermogravimetric analysis (TG) graph of hydroxypropylmethylcellulose acetate succinate obtained in example 4 of the present invention;
FIG. 7 is a Differential Scanning Calorimetry (DSC) plot of the florfenicol amorphous solid dispersion obtained in example 4 of the present invention;
FIG. 8 is a Differential Scanning Calorimetry (DSC) profile of florfenicol obtained in example 4 of the present invention;
FIG. 9 is a Differential Scanning Calorimetry (DSC) chart of hydroxypropyl methylcellulose acetate succinate obtained in example 4 of the present invention;
FIG. 10 is a scanning electron micrograph of a florfenicol solid dispersion obtained in example 4 of the present invention;
FIG. 11 is a scanning electron micrograph of florfenicol obtained in example 4 of the present invention;
FIG. 12 is a powder X-ray diffraction pattern of the florfenicol solid dispersion obtained in the stability test in example 4 of the present invention;
FIG. 13 is a differential scanning calorimetry thermogram of the florfenicol solid dispersion obtained in the stability test in example 4 of the present invention;
FIG. 14 is an in vitro solubility curve of the florfenicol solid dispersion obtained in example 4 of the present invention;
FIG. 15 is a graph showing the change in blood concentration of florfenicol in a solid dispersion obtained from the pharmacokinetic experiment in example 4 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
A florfenicol solid dispersion is prepared by taking hydroxypropyl methyl cellulose acetate succinate as a carrier to include florfenicol. The molar ratio of florfenicol to hydroxypropyl methylcellulose acetate succinate is 1: 9.
The preparation method of the florfenicol solid dispersion comprises the following steps:
dissolving 2.574g of hydroxypropyl methylcellulose acetate succinate in 51.5mL of DMF (N, N-dimethylformamide), stirring overnight until dissolved, and then adding 0.358g of florfenicol to obtain a mixed solution; injecting the mixed solution into 52mL of hydrochloric acid aqueous solution with pH of 1 at a rate of 1mL/min, stirring at 1200r/min for 10min, and performing suction filtration to obtain a solid retentate; freezing the solid retentate at-80 ℃ for 4h, drying for 12h by using a freeze dryer, and finally grinding and sieving by using a 80-mesh sieve to obtain the nano florfenicol solid dispersion.
Example 2
A florfenicol solid dispersion is prepared by taking hydroxypropyl methyl cellulose acetate succinate as a carrier to include florfenicol. The molar ratio of florfenicol to hydroxypropyl methylcellulose acetate succinate is 1: 5.
The preparation method of the florfenicol solid dispersion comprises the following steps:
dissolving 1.43g of hydroxypropyl methyl cellulose acetate succinate in 20mL of DMSO (dimethyl sulfoxide), stirring overnight until the solution is dissolved, and then adding 0.358g of florfenicol to obtain a mixed solution; injecting the mixed solution into 200mL of hydrochloric acid aqueous solution with pH of 2 at the speed of 10mL/min, stirring at 1400r/min for 15min, and performing suction filtration to obtain a solid retentate; freezing the solid retentate at-80 ℃ for 6h, drying for 24h by using a freeze dryer, and finally grinding and sieving by using a 80-mesh sieve to obtain the nano florfenicol solid dispersion.
Example 3
A florfenicol solid dispersion is prepared by taking hydroxypropyl methyl cellulose acetate succinate as a carrier to include florfenicol. The molar ratio of florfenicol to hydroxypropyl methylcellulose acetate succinate is 1: 1.
The preparation method of the florfenicol solid dispersion comprises the following steps:
dissolving 2.86g of hydroxypropyl methyl cellulose acetate succinate in 28.6mL of dichloromethane, stirring overnight for dissolving, and then adding 3.58g of florfenicol to obtain a mixed solution; injecting the mixed solution into 2860mL of hydrochloric acid aqueous solution with pH of 4 at the speed of 30mL/min, stirring for 20min at the speed of 1600r/min, and performing suction filtration to obtain a solid retentate; freezing the solid retentate at-80 ℃ for 8h, drying for 48h by using a freeze dryer, and finally grinding and sieving by using a 80-mesh sieve to obtain the nano florfenicol solid dispersion.
Example 4
1. Sample determination and structural characterization
The florfenicol solid dispersion prepared in example 1 is determined and structurally characterized by the following specific methods:
powder X-ray diffraction (PXRD) the samples were measured using a german bruke D8 Advance diffractometer calibrated with a silicon sample before measurement and after meeting the requirements.
The measurement conditions were as follows: cuka (λ ═ 0.15418nm) radiation, tube voltage 40kV, tube flow 40mA, scan range 5-35 °, scan step pitch 0.02 °, scan speed 1sec per step.
The powder X-ray diffraction of the florfenicol solid dispersion in example 1 is shown in figure 1;
the powder X-ray diffraction of florfenicol tested under the same conditions is shown in fig. 2, which has characteristic peaks at diffraction angles 2 θ of 8.0 ± 0.2, 16.2 ± 0.2, 19.7 ± 0.2, 20.1 ± 0.2, 21.0 ± 0.2, 22.4 ± 0.2, 23.5 ± 0.2, 23.7 ± 0.2, 24.4 ± 0.2, 26.9 ± 0.2, 28.9 ± 0.2, 31.7 ± 0.2, 32.4 ± 0.2, 35.7 ± 0.2, 38.6 ± 0.2 degrees.
The powder X-ray diffraction pattern of hydroxypropyl methylcellulose acetate succinate tested using the same conditions is shown in figure 3.
As can be seen from a comparison of fig. 1-3, the product obtained in example 1 is an amorphous drug, i.e., an amorphous solid dispersion of florfenicol.
2. Thermogravimetric analysis (TG)
Thermogravimetric analysis (TG) was performed on the florfenicol solid dispersion prepared in example 1, as follows:
4mg of florfenicol solid dispersion is placed in a standard thermogravimetric analysis aluminum tray, a thermogravimetric analyzer (SDT Q500 of TA company in America) is protected by nitrogen, the nitrogen flow rate is 20mL/min, the temperature is increased from 25 ℃ to 210 ℃, and the temperature increase rate is 10 ℃/min. The Thermogravimetric (TG) pattern obtained is shown in fig. 4.
The thermogravimetric analysis (TG) profile of florfenicol tested using the same conditions is shown in figure 5.
The thermogravimetric analysis (TG) of hydroxypropyl methylcellulose acetate succinate tested using the same conditions is shown in figure 6.
3. Differential Scanning Calorimetry (DSC)
Differential Scanning Calorimetry (DSC) was performed on florfenicol, hydroxypropyl methylcellulose acetate succinate, and the florfenicol solid dispersion prepared in example 1.
A differential scanning calorimeter (TA, USA, Q2000) equipped with a cooling system was used to measure the sample after calibration with indium metal in advance. After 4mg of samples (florfenicol, hydroxypropyl methyl cellulose acetate succinate and florfenicol solid dispersion) are respectively placed in a sealed aluminum disc, under the protection of nitrogen, the nitrogen flow rate is 50mL/min, the temperature is increased from 25 ℃ to 210 ℃, and the temperature increasing rate is 10 ℃/min.
The Differential Scanning Calorimetry (DSC) chart of the obtained florfenicol solid dispersion is shown in FIG. 7.
A Differential Scanning Calorimetry (DSC) profile of florfenicol is shown in figure 8.
A Differential Scanning Calorimetry (DSC) profile of hydroxypropyl methylcellulose acetate succinate is shown in FIG. 9.
The results in FIG. 8 show that florfenicol has a sharp absorption peak at 154.96 deg.C, indicating a melting point of 154.96 deg.C.
The results in fig. 9 show that hydroxypropyl methylcellulose acetate succinate has no endothermic peak during temperature increase, indicating that it is amorphous.
As can be seen from fig. 7, the crystalline melting point peak of florfenicol in the florfenicol amorphous solid dispersion completely disappeared and a single glass transition temperature existed.
4. Scanning Electron microscope analysis (SEM)
A sample of the florfenicol solid dispersion prepared in example 1 was attached to a conductive tape, tested after gold spraying, and a scanning electron microscope photograph taken is shown in FIG. 10.
A scanning electron micrograph of florfenicol taken under the same conditions is shown in FIG. 11.
Comparing fig. 10 and fig. 11, it can be seen that florfenicol is bulk crystal with different sizes, smooth surface and small specific surface area; the blocky drug structure in the florfenicol solid dispersion disappears, no obvious crystal exists, the solid dispersion is in a loose and porous form, and the obtained nano florfenicol solid dispersion has uniform particle size and good dispersion.
5. Stability test
The florfenicol solid dispersion prepared in example 1 was subjected to a stability test, which was carried out as follows:
precisely weighing a proper amount of sample, spreading the sample in a container with the same specification, placing the container in a constant temperature and humidity box with the temperature of 40 ℃ and the humidity of RH 70%, and measuring powder X-ray diffraction and differential scanning calorimetry in 0d, 7d, 14d, 30d, 60d and 90d, wherein the powder X-ray diffraction diagram is shown in figure 12, and the differential scanning calorimetry diagram is shown in figure 13.
The results in fig. 12 and 13 show that the florfenicol solid dispersion prepared in example 1 has no crystallization peak and no endothermic peak within 3 months, and still maintains amorphous state and has good stability.
6. Supersaturation in vitro dissolution test
The supersaturated in vitro dissolution experiment is carried out on the florfenicol and the florfenicol solid dispersion prepared in the example 1, and the specific method comprises the following steps:
200mg of florfenicol raw material drug and the florfenicol solid dispersion (equivalent to 200mg of florfenicol) prepared in example 1 are precisely weighed to measure the in-vitro dissolution, and a D-800LS intelligent drug dissolution instrument (manufactured by Tianjin university wireless power plant) is used for carrying out a supersaturated in-vitro dissolution experiment. The dissolution medium was phosphate buffer solution of pH6.8, the volume of the dissolution medium was 20mL, the temperature was (37. + -. 0.5) deg.C, samples were taken at different time points and filtered through a 0.45 μm microporous aqueous phase membrane, and absorbance was measured by UV-visible spectrophotometer 6850UV (JENWAY, USA) and repeated three times.
As shown in FIG. 14, the florfenicol and the florfenicol solid dispersion both reach the dissolution equilibrium within 2 hours, and the saturation solubility of the florfenicol solid dispersion is 7.73mg/mL, which is 6.72 times higher than that of original florfenicol drug (1.15 mg/mL). Meanwhile, the florfenicol solid dispersion reaches the maximum solubility of 7.60mg/mL at 30min, which is increased by 5.97 times compared with the FF solubility (1.09 mg/mL).
Therefore, the florfenicol amorphous solid dispersion prepared in the example 1 obviously increases the solubility and the dissolution speed of the florfenicol, and the florfenicol solid dispersion is stable and can keep the solubility unchanged within 120 min.
7. Pharmacokinetic testing
Selection of test animals
15 220-250g male SD rats were randomly selected and divided into 3 groups of 5 rats each. Rats were fasted overnight before the experiment and had free access to water.
Administration and sampling
CMC-Na aqueous solution (0.1 percent) is selected as a suspending agent, 1mL of the suspending agent (the dosage is determined according to the weight of a rat, the dosage of the florfenicol is 20mg/kg, and the dosage of the florfenicol solid dispersion is equal to 20mg/kg of florfenicol bulk drug) is respectively added into the florfenicol and the florfenicol solid dispersion obtained in example 1, and the mixture is evenly dispersed by vortex treatment. Then, administration is carried out intragastrically. After dosing, 0.5mL of blood was collected in centrifuge tubes pre-treated with heparin. And blood was collected at 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 h. Centrifuging at 6000rpm for 10min, separating supernatant of collected blood to obtain plasma, and storing in refrigerator at-20 deg.C for use. (wherein the first and second groups are administered with a solid dispersion of florfenicol and the third group is administered with florfenicol.)
After pretreatment of the plasma sample, HPLC detection was performed, and a standard curve was prepared based on the peak area obtained, as shown in FIG. 15.
As shown by the results of fig. 15, florfenicol is rapidly absorbed in rats, reaching the maximum blood concentration at 1.1h, while the peak reaching time of the florfenicol solid dispersion is 2.8 h; the Cmax of the florfenicol is 3.89 mu g/mL, the Cmax of the florfenicol solid dispersion is 6.58 mu g/mL, and the peak concentration of the florfenicol solid dispersion is 1.69 times of that of the florfenicol; the MRT of florfenicol is 15.03h, while that of the solid dispersion of florfenicol is 7.52 h; the AUC for florfenicol was 29.84. mu.g.h/mL, while that for florfenicol solid dispersions was 40.94. mu.g.h/mL. The results show that the bioavailability of the florfenicol solid dispersion prepared in example 1 is improved by 37.2% compared with florfenicol.
The florfenicol solid dispersions prepared in the embodiments 2 and 3 are respectively subjected to structural characterization, thermogravimetric analysis (TG), Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM) and stability test, supersaturated in vitro dissolution test and pharmacokinetic test, and the analysis and test results are all equivalent to those of the florfenicol solid dispersion prepared in the embodiment 1.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. A preparation method of florfenicol solid dispersion is characterized by comprising the following steps: the method comprises the following steps:
a. dissolving hydroxypropyl methyl cellulose acetate succinate in a solvent, and adding florfenicol to obtain a mixed solution, wherein the solvent is at least one of N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane and chloroform;
b. adding the mixed solution into an anti-solvent, and stirring and filtering to obtain a solid retentate;
c. and sequentially freezing, drying and grinding the solid retentate to obtain the florfenicol solid dispersion.
2. The method for preparing a florfenicol solid dispersion according to claim 1, wherein: the molar ratio of the florfenicol to the hydroxypropyl methyl cellulose acetate succinate is 1-5: 5-9.
3. The method for preparing a florfenicol solid dispersion according to claim 1, wherein: in the step a, the hydroxypropyl methyl cellulose acetate succinate is dissolved in the solvent at the concentration of 0.05-0.1 g/mL.
4. The method for preparing a florfenicol solid dispersion according to claim 1, wherein: in the step b, the anti-solvent is an acidic aqueous solution with the pH value of 1-4.
5. The method for preparing a florfenicol solid dispersion according to claim 1, wherein: in the step b, the volume ratio of the mixed solution to the anti-solvent is 1-10: 10-100.
6. The method for preparing a florfenicol solid dispersion according to claim 1, wherein: in the step b, the rate of adding the mixed solution into the anti-solvent is 1-30 mL/min.
7. The method for preparing a florfenicol solid dispersion according to claim 1, wherein: in the step c, the rotation speed of the stirring is 1200-1600r/min, and the time is 10-20 min.
8. The method for preparing a florfenicol solid dispersion according to claim 1, wherein: in the step c, the freezing time is 4-8 h.
9. The method for preparing a florfenicol solid dispersion according to any one of claims 1-8, wherein the obtained florfenicol solid dispersion is prepared.
10. A pharmaceutical composition comprising the florfenicol solid dispersion of claim 9 and a pharmaceutically acceptable carrier.
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| CN114948879A (en) * | 2022-04-19 | 2022-08-30 | 河北农业大学 | Griseofulvin solid dispersion and preparation method thereof |
| CN114948879B (en) * | 2022-04-19 | 2024-02-02 | 河北农业大学 | Griseofulvin solid dispersion and preparation method thereof |
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Application publication date: 20210514 |