CN111643456A - Preparation method and application of florfenicol solid dispersion with high dissolution rate - Google Patents
Preparation method and application of florfenicol solid dispersion with high dissolution rate Download PDFInfo
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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
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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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
- 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 discloses a preparation method and application of a florfenicol solid dispersion with high dissolution rate, which are carried out according to the following steps: 1) weighing florfenicol and auxiliary materials according to the proportion of 1:5.5-1:7.5, and mixing for 25-35 minutes; 2) setting the extrusion temperature of a hot-melt extruder to be 100-120 ℃, and the rotating speed of a screw to be 90-100 rpm; 3) slowly adding the uniformly mixed powder into a hot-melt extruder, extruding, collecting an extruded sample by a machine head, cutting the extruded sample into small sections, crushing the small sections, and sieving the small sections with a 120-mesh sieve to obtain the florfenicol/auxiliary material hot-melt extruded solid dispersion. The invention uses the hot-melt extrusion technology to deeply modify the original florfenicol, changes the crystal structure of the florfenicol into an amorphous structure through melting, and fully mixes and dissolves the florfenicol with auxiliary materials.
Description
Technical Field
The invention belongs to the technical field of chemical pharmaceutical preparations, and particularly relates to a preparation method and application of a florfenicol solid dispersion with high dissolution rate.
Background
Florfenicol belongs to amidol broad-spectrum antibacterial drugs and has strong antibacterial activity on various gram-positive bacteria, gram-negative bacteria, mycoplasma and the like. Florfenicol is mainly a bacteriostatic agent which inhibits the synthesis of bacterial proteins by binding with ribosome 50S subunit. Florfenicol has similar or stronger antibacterial activity to a plurality of microorganisms in vitro with chloramphenicol and thiamphenicol, and some bacteria which are resistant to chloramphenicol due to acetylation, such as escherichia coli, klebsiella pneumoniae and the like, can still be sensitive to the florfenicol. Pasteurella haemolytica, pasteurella multocida and actinobacillus pleuropneumoniae are highly sensitive to florfenicol. The molecular formula is as follows: c12H14Cl2FNO4S, molecular weight of 358.2, melting point of 157 ℃, Chinese alias [ R- - ((R1. T) -2, 2-dichloro-N- { fluoromethyl) -2-hydroxy-2- [4- (methylsulfonyl) phenyl group]Ethyl } acetamide. Florfenicol is white or white-like powder, has no odor and slightly bitter taste, is easily dissolved in dimethylformamide, is dissolved in methanol, is slightly dissolved in glacial acetic acid and is slightly dissolved in water, and belongs to insoluble medicines.
Florfenicol has an antibacterial spectrum similar to that of chloramphenicol, has the characteristic of being superior to that of chloramphenicol, has extremely small side effect, does not cause serious side effects such as renal failure and the like, and is widely applied to clinically treating respiratory diseases, pleurisy and the like. However, the florfenicol has poor solubility and dispersibility, greatly limits the application range of the florfenicol, and also increases difficulty for modifying the florfenicol into other dosage forms. In addition, the florfenicol has low solubility, slow dissolution and low dissociation degree at an absorption part, thereby causing low bioavailability of the florfenicol in a living body. At present, common dosage forms for improving the solubility of florfenicol comprise suspension, injection, aqueous solvent and the like. But the effect is not ideal, for example, the florfenicol preparation prepared by adding solvents, cosolvents and other methods has poor stability and large irritation, thereby causing secondary damage to animal organisms.
The Hot-melt extrusion (HME) technology was first applied to the plastic and polymer processing industries, and since the 90 s of the 20 th century, the technology was introduced into the pharmaceutical industry and rapidly developed and applied. The HME technique is a technique in which a drug and a polymer excipient are simultaneously added to an extruder to mix, melt, and mold the drug and the excipient in a single extruder, and the multiphase state is converted into a single-phase state, and is widely used for preparing Solid Dispersions (SD), and the drug can be more uniformly dispersed in a carrier due to the strong mixing and shearing effects of the SD. The HME technology is mainly used for improving the water solubility, slow release, taste masking and the like of insoluble drugs and shows unique advantages. However, the technology is still rarely used in China, and no system research and application exist in the pharmaceutical industry.
Disclosure of Invention
The invention aims to solve the defects and shortcomings in the prior art, and provides a preparation method and application of a high-dissolution florfenicol solid dispersion, wherein the original florfenicol is deeply modified by using a hot-melt extrusion technology, the crystal structure of the florfenicol is changed into an amorphous structure through melting, the florfenicol is fully mixed and dissolved with PEG, and part of the florfenicol exists in a molecular form and is wrapped in a carrier, so that the dissolution rate of the florfenicol is increased, and the bioavailability of the florfenicol is improved.
The technical scheme of the invention is as follows: a preparation method of a florfenicol solid dispersion with high dissolution rate comprises the following steps:
1) weighing florfenicol and auxiliary materials according to the proportion of 1:5.5-1:7.5, and mixing for 25-35 minutes;
2) setting the extrusion temperature of a hot-melt extruder to be 100-120 ℃, and the rotating speed of a screw to be 90-100 rpm;
3) slowly adding the uniformly mixed powder into a hot-melt extruder, extruding, collecting an extruded sample by a machine head, cutting the extruded sample into small sections, crushing the small sections, and sieving the small sections with a 120-mesh sieve to obtain the florfenicol/auxiliary material hot-melt extruded solid dispersion.
Preferably, the florfenicol and the PEG are weighed according to the ratio of 1:6.5 in the step 1) and mixed for 30 minutes, and the extrusion temperature of the hot-melt extruder is set to be 110 ℃ and the screw rotation speed is set to be 92rpm in the step 2).
Preferably, the types of the auxiliary materials, the drug loading ratio, the temperature of the hot-melt extruder and the screw rotation speed in the step 1) are determined by the following steps;
(1) weighing florfenicol and auxiliary materials according to a certain proportion, mixing for 30 minutes, setting the extrusion temperature of an extruder at 160 ℃, the rotation speed of a screw at 100rpm, slowly adding the uniformly mixed powder into a hot-melt extruder, extruding, collecting an extruded sample at a machine head, cutting the extruded sample into small sections, crushing, and sieving by a 120-mesh sieve to obtain the florfenicol/auxiliary material hot-melt extruded solid dispersion;
(2) on the basis of the early-stage melting method research, a HME technology is further adopted to prepare the florfenicol solid dispersion, the influence of a carrier on the solubility and the dissolution rate is investigated, wherein the drug-loading rate is fixed to be 30%, the carrier amount is fixed to be 70%, and the selected carrier is PVP K30, VA64, PEG and an auxiliary material B;
(3) after the carrier is determined, the rotation speed of the screw determines the retention time of the material in the machine barrel, so that insufficient mixing can be caused when the rotation speed of the screw is too fast, and the material can be degraded when the rotation speed of the screw is too slow, and the rotation speeds are respectively 30r/min, 60r/min, 90r/min and 120 r/min;
(4) the HME technology is adopted to prepare the solid dispersion, the temperature has great influence on the dissolution of the solid dispersion, and the temperature is too low, so that the drug and the carrier cannot be melted, and the effect cannot be achieved only by simple physical mixing; if the temperature is too high, the medicament and the carrier are likely to be gelatinized and decomposed, so that the selection of the proper operating temperature is particularly important; selecting 80 deg.C, 100 deg.C, 120 deg.C, 150 deg.C and 160 deg.C;
(5) along with the larger using amount of PEG, the solid dispersion is dissolved out more quickly, and considering that the carrier is prepared into powder, the using amount of the carrier is too large, the content of the main drug is reduced, the volume of the carrier is increased, and the exertion of the drug effect is influenced, so the solid dispersion is prepared by selecting the main drug and the PEG according to the mass ratio of 1:3, 1:5, 1:7 and 1: 9;
(6) according to the center combination design principle of Box and Hunter, 3 factors which have obvious influence on FF-SD, namely the drug loading ratio, the screw rotating speed and the extrusion temperature of the hot melt extruder are selected for optimization research; the saturated solubility is used as a response value, the center combination design of three factors and three levels is designed, and a regression model is
Y＝Ao+ΣAiXi+ΣAiiXi2+ Σ AijXiXj, Ao, Ai, Aii and Aij are intercept and regression constants respectively, Xi, Xj are arguments after change, and data are counted and response surfaces are described by DESIGN-EXPERT.V10 software; carrying out 17 times of tests, 14 times of factorial tests and three zero tests for testing errors, repeating each test for 3 times, and taking the average value of the 3 times of tests; the result is subjected to multiple regression to obtain a quadratic regression equation:
Y＝3.23189-0.0538187*A-0.0088875*B+0.00345625*C+0.0286375*A*A+0.116525*A*B-0.0069125*A*C-0.133708*B*B-0.099145*B*C-0.102107*C*C；
7) according to the regression equation, a response surface graph can be made by using DESIGN-EXPERT.V10 software;
8) it can also be seen visually from the corresponding response surface diagram that the inflection point of the response surface can be obtained by the standard analysis and judged whether the inflection point is the maximum point, the minimum point or the saddle point, the test result is analyzed by the standard analysis, the obtained inflection point is the maximum point, the predicted drug loading ratio is 1:6.46, the screw rotation speed is 91.88r/min, the extrusion temperature of the hot melting machine is 109.4 ℃, and the predicted stability coefficient is 3.046. And (4) carrying out experimental verification under the optimal prediction condition, and obtaining a stability coefficient after reaction.
Preferably, the florfenicol in the step 3) is fully miscible with the water-soluble PEG in a molten state, and a part of original drug is wrapped in the carrier and exists in a molecular form, so that the dissolving effect is achieved.
The florfenicol solid dispersion prepared by the preparation method of the florfenicol solid dispersion with high dissolution rate is applied, 20 healthy yellow feather broilers with age of 40 days are selected, the weight of each half of a male and a female is about 1.50kg, the yellow feather broilers are randomly divided into 2 groups, 1 group is orally administrated, 1 group adopts a 1mL sterile syringe to accurately extract medicines and then is infused into the esophagus of a chicken through a lengthened rat gavage needle for administration, and the administration dosage is 15 mg/kg.
Preferably, 2mL of the infrapterygeal venous blood is taken at 0.083, 0.167, 0.25, 0.5, 0.75, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72, 96 and 120h after administration, and is respectively placed in a centrifuge tube coated with 1% heparin sodium in advance, centrifuged at 4000r/min for 15min, plasma is separated, and is placed at-20 ℃ for cryopreservation, and the blood concentration is measured.
Preferably, the plasma pretreatment step is as follows: taking 15mL of 500-mu plasma, adding 10 mu L of chloramphenicol internal standard with the concentration of 50 mu g/mL into a centrifuge tube, shaking for 1min, adding 2mL of ethyl acetate, shaking at high speed for 10min, then centrifuging at 6000r/min for 12min, taking supernate, repeatedly extracting once, combining extracting solutions into a 10mL glass tube, drying the extracting solutions with nitrogen in a water bath at 40 ℃, redissolving residues with 500 mu L of mobile phase, then adding 500 mu L of n-hexane, centrifuging at 2min and 13000r/min for 12min, discarding the upper organic phase, filtering the lower layer with a microfiltration membrane with the aperture of 0.22 mu m, and injecting the lower layer into a liquid phase sampling bottle to be tested.
Preferably, experimental liquid chromatography conditions: mobile phase: acetonitrile-water (25: 75; v/v); flow rate: 1.0 mL/min; a chromatographic column: atlantis C18 column (4.6X 250mm, particle size 5 μm); column temperature: 30 ℃; ultraviolet detection wavelength: 223 nm; sample introduction volume: 50 μ L.
The invention uses the hot-melt extrusion technology to deeply modify the original florfenicol, changes the crystal structure of the florfenicol into an amorphous structure through melting, and fully mixes and dissolves with PEG.
Drawings
FIG. 1 is a schematic diagram showing the effect of different excipients on the in vitro dissolution rate of FF-SD;
FIG. 2 is a schematic diagram showing the effect of different screw speeds on the in vitro dissolution rate of FF-SD;
FIG. 3 is a schematic diagram showing the effect of different hot melt extruder temperatures on the dissolution rate of FF-SD in vitro;
FIG. 4 is a schematic diagram showing the effect of different drug loading ratios on the in vitro dissolution rate of FF-SD;
in FIG. 5, Y is ═ f1A response surface map of (A, B);
in FIG. 6, Y is ═ f2A response surface map of (B, C);
in FIG. 7, Y is ═ f3And (A, C) response surface diagrams.
Detailed Description
The present invention will be described in further detail with reference to the attached drawings, but the present invention is not limited thereto.
A preparation method of a florfenicol solid dispersion with high dissolution rate comprises the following specific steps: (1) weighing florfenicol and auxiliary materials according to a certain proportion, mixing for 30 minutes, setting the extrusion temperature of an extruder at 160 ℃, the rotation speed of a screw at 100rpm, slowly adding the uniformly mixed powder into a hot-melt extruder, extruding, collecting an extruded sample at a machine head, cutting the extruded sample into small sections, crushing, and sieving by a 120-mesh sieve to obtain the florfenicol/auxiliary material hot-melt extruded solid dispersion;
(2) on the basis of the early-stage melting method research, the solid florfenicol dispersion is further prepared by adopting an HME technology, and the influence of the carrier on the solubility and the dissolution rate is examined. Wherein the drug-loading rate is fixed at 30%, the carrier amount is fixed at 70%, the selected carriers are PVP K30, VA64, PEG and adjuvant B, and the dissolution rate is detailed in figure 1;
(3) after the carrier is determined, the rotation speed of the screw determines the retention time of the material in the cylinder, so that insufficient mixing can be caused when the rotation speed of the screw is too fast, the material can be degraded when the rotation speed is too slow, the rotation speeds are respectively 30r/min, 60r/min, 90r/min and 120r/min, and the dissolution rate is detailed in figure 2;
(4) the HME technology is adopted to prepare the solid dispersion, and the dissolution of the solid dispersion is greatly influenced by the temperature. The temperature is too low, so that the medicine and the carrier cannot be melted, and the effect cannot be achieved only by simple physical mixing; if the temperature is too high, the medicament and the carrier may be gelatinized and decomposed, so that the selection of an appropriate operating temperature is particularly important. Selecting 80 deg.C, 100 deg.C, 120 deg.C, 150 deg.C and 160 deg.C, and showing the dissolution rate in figure 3;
(5) the solid dispersion dissolves faster with higher PEG usage. Considering that the carrier is excessively used when the carrier is prepared into powder, the content of the main medicine is reduced and the volume is increased, so that the exertion of the medicine effect is influenced. Therefore, the solid dispersion is prepared by selecting the main drug and PEG with the mass ratio of 1:3, 1:5, 1:7 and 1:9, and the dissolution rate is shown in figure 4 in detail;
(6) according to the center combined design principle of Box and Hunter, on the basis of a reference, earlier experience and a single-factor experiment, 3 factors which have obvious influence on FF-SD, namely the proportion (A) of the medicament and the auxiliary material, the rotating speed (B) and the extrusion temperature (C), are selected for optimization research. The saturated solubility (Y, close to 1 is excellent) is taken as a response value, the three-factor three-level central combination design is designed, and the regression model is as follows:
Y＝Ao+ΣAiXi+ΣAiiXi2+ Σ AijXiXj, Ao, Ai, Aii and Aij are the intercept and regression constants, respectively, Xi, Xj are the arguments after the change,
data were counted and response profiles were described using DESIGN-EXPERT. V10 software, and factors and test levels were selected as in Table 1. The results were averaged over 3 determinations according to the design of table 1, 17 trials, 14 factorial trials and three zero point trials of test error, each trial being repeated 3 times, and the results are given in table 2. The result is subjected to multiple regression to obtain a quadratic regression equation:
Y＝3.23189-0.0538187*A-0.0088875*B+0.00345625*C+0.0286375*A*A+0.116525*A*B-0.0069125*A*C-0.133708*B*B-0.099145*B*C-0.102107*C*C；
(7) according to the regression equation, a response surface map can be made by using DESIGN-EXPERT.V10 software, and the response surface map is shown in detail in FIGS. 5, 6 and 7;
(8) it can also be seen from the corresponding response surface map that the effect of a is most significant, and the effects of B and C are close and not significant. The inflection point of the response surface can be found by normative Analysis (Canonical Analysis) and judged whether it is the maximum point, the minimum point or the saddle point, the found inflection point is the maximum point by the normative Analysis test result, the predicted drug loading ratio (A) is 1:6.46, the rotation speed (B)91.88r/min and the stable extrusion temperature (C) is 109.4, and the predicted stability coefficient is 3.046. The stability coefficients are shown in table 3 after reaction through experimental verification under the predicted optimal conditions;
(9) after oral administration at a dose of 15mg/kg, the average drug concentrations of florfenicol technical product and FF-SD in the plasma of yellow-feathered broilers at different time points are detailed in Table 4.
In step 9, the plasma pretreatment step 500. mu.L of plasma was placed in a 15mL centrifuge tube and 10. mu.L of chloramphenicol internal standard at a concentration of 50. mu.g/mL was added. Shaking for 1min, adding 2mL ethyl acetate, shaking at high speed for 10min, centrifuging at 6000r/min for 12min, taking supernatant, extracting once again, combining extract in a 10mL glass tube, drying with nitrogen in water bath at 40 ℃, redissolving residues with 500 μ L mobile phase, adding 500 μ L n-hexane, swirling for 2min, centrifuging at 13000r/min for 12min, discarding the upper organic phase, filtering the lower layer with a microfiltration membrane with the aperture of 0.22 μm, and injecting into a liquid phase sampling bottle for testing.
Experimental liquid chromatography conditions: mobile phase: acetonitrile-water (25: 75; v/v); flow rate: 1.0 mL/min; a chromatographic column: atlantis C18 column (4.6X 250mm, particle size 5 μm); column temperature: 30 ℃; ultraviolet detection wavelength: 223 nm; sample introduction volume: 50 μ L.
TABLE 1
TABLE 2
TABLE 3
TABLE 4
The invention has the technical advantages that: by adopting a hot-melt extrusion technology, according to the result of single-factor investigation of a pre-experiment, orthogonal test factors and levels are determined, 10min accumulated dissolution is used as an evaluation index, response surface analysis is carried out, and under the optimal conditions that the drug-loading ratio is 1:6.5, the rotating speed (B) is 92r/min and the stable extrusion temperature (C) is 110 ℃, the florfenicol solid dispersion is synthesized, the dissolution is increased, and the blood concentration is improved.
Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (8)
1. A preparation method of a florfenicol solid dispersion with high dissolution rate is characterized by comprising the following steps: the method comprises the following steps:
1) weighing florfenicol and auxiliary materials according to the proportion of 1:5.5-1:7.5, and mixing for 25-35 minutes;
2) setting the extrusion temperature of a hot-melt extruder to be 100-120 ℃, and the rotating speed of a screw to be 90-100 rpm;
3) slowly adding the uniformly mixed powder into a hot-melt extruder, extruding, collecting an extruded sample by a machine head, cutting the extruded sample into small sections, crushing the small sections, and sieving the small sections with a 120-mesh sieve to obtain the florfenicol/auxiliary material hot-melt extruded solid dispersion.
2. The preparation method of the florfenicol solid dispersion with high dissolution rate as claimed in claim 1, characterized in that: weighing florfenicol and PEG according to the ratio of 1:6.5 in the step 1), mixing for 30 minutes, and setting the extrusion temperature of the hot-melt extruder to be 110 ℃ and the screw rotation speed to be 92rpm in the step 2).
3. The preparation method of the florfenicol solid dispersion with high dissolution rate as claimed in claim 2, characterized in that: in the step 1), the types of the auxiliary materials, the medicine carrying ratio, the temperature of the hot-melt extruder and the rotating speed of the screw are determined through the following steps;
(1) weighing florfenicol and auxiliary materials according to a certain proportion, mixing for 30 minutes, setting the extrusion temperature of an extruder at 160 ℃, the rotation speed of a screw at 100rpm, slowly adding the uniformly mixed powder into a hot-melt extruder, extruding, collecting an extruded sample at a machine head, cutting the extruded sample into small sections, crushing, and sieving by a 120-mesh sieve to obtain the florfenicol/auxiliary material hot-melt extruded solid dispersion;
(2) on the basis of the early-stage melting method research, a HME technology is further adopted to prepare the florfenicol solid dispersion, the influence of a carrier on the solubility and the dissolution rate is investigated, wherein the drug-loading rate is fixed to be 30%, the carrier amount is fixed to be 70%, and the selected carrier is PVP K30, VA64, PEG and an auxiliary material B;
(3) after the carrier is determined, the rotation speed of the screw determines the retention time of the material in the machine barrel, so that insufficient mixing can be caused when the rotation speed of the screw is too fast, and the material can be degraded when the rotation speed of the screw is too slow, and the rotation speeds are respectively 30r/min, 60r/min, 90r/min and 120 r/min;
(4) the HME technology is adopted to prepare the solid dispersion, the temperature has great influence on the dissolution of the solid dispersion, and the temperature is too low, so that the drug and the carrier cannot be melted, and the effect cannot be achieved only by simple physical mixing; if the temperature is too high, the medicament and the carrier are likely to be gelatinized and decomposed, so that the selection of the proper operating temperature is particularly important; selecting 80 deg.C, 100 deg.C, 120 deg.C, 150 deg.C and 160 deg.C;
(5) along with the larger using amount of PEG, the solid dispersion is dissolved out more quickly, and considering that the carrier is prepared into powder, the using amount of the carrier is too large, the content of the main drug is reduced, the volume of the carrier is increased, and the exertion of the drug effect is influenced, so the solid dispersion is prepared by selecting the main drug and the PEG according to the mass ratio of 1:3, 1:5, 1:7 and 1: 9;
(6) according to the center combination design principle of Box and Hunter, 3 factors which have obvious influence on FF-SD, namely the drug loading ratio, the screw rotating speed and the extrusion temperature of the hot melt extruder are selected for optimization research; a three-factor three-level central combination design is designed by taking the saturation solubility as a response value, and a regression model is Y ═ Ao + Sigma Aixi + Sigma Aiixi2+ Σ AijXiXj, Ao, Ai, Aii and Aij are intercept and regression constants respectively, Xi, Xj are arguments after change, and data are counted and response surfaces are described by DESIGN-EXPERT.V10 software; carrying out 17 times of tests, 14 times of factorial tests and three zero tests for testing errors, repeating each test for 3 times, and taking the average value of the 3 times of tests; the result is subjected to multiple regression to obtain a quadratic regression equation:
Y＝3.23189-0.0538187*A-0.0088875*B+0.00345625*C+0.0286375*A*A+0.116525*A*B-0.0069125*A*C-0.133708*B*B-0.099145*B*C-0.102107*C*C；
7) according to the regression equation, a response surface graph can be made by using DESIGN-EXPERT.V10 software;
8) it can also be seen visually from the corresponding response surface diagram that the inflection point of the response surface can be obtained by the standard analysis and judged whether the inflection point is the maximum point, the minimum point or the saddle point, the test result is analyzed by the standard analysis, the obtained inflection point is the maximum point, the predicted drug loading ratio is 1:6.46, the screw rotation speed is 91.88r/min, the extrusion temperature of the hot melting machine is 109.4 ℃, and the predicted stability coefficient is 3.046. And (4) carrying out experimental verification under the optimal prediction condition, and obtaining a stability coefficient after reaction.
4. The preparation method of the florfenicol solid dispersion with high dissolution rate as claimed in claim 1, characterized in that: the florfenicol in the step 3) is fully mixed and dissolved with the water-soluble PEG in a molten state, and part of original drug is wrapped in the carrier and exists in a molecular form, so that the dissolving effect is achieved.
5. Use of a high dissolution florfenicol solid dispersion prepared by the process of claim 1, wherein: 20 healthy yellow-feathered broilers of 40 days old are selected, the weight of each broilers is about 1.50kg, the broilers are divided into 2 groups randomly, 1 group is orally administrated, 1 group adopts a 1mL sterile syringe to accurately extract medicines and then is infused into the esophagus of a chicken through a lengthened rat gastric lavage needle for administration, and the administration dose is 15 mg/kg.
6. The use of the high dissolution florfenicol solid dispersion according to claim 4, characterized in that: after administration, 2mL of infrapterygeal venous blood is taken at 0.083, 0.167, 0.25, 0.5, 0.75, 1, 2, 4, 8, 12, 16, 24, 36, 48, 72, 96 and 120h and is respectively placed in a centrifuge tube coated with 1% heparin sodium in advance, centrifuged at 4000r/min for 15min, plasma is separated and is placed at-20 ℃ for freezing storage, and the blood concentration is measured.
7. The use of the high dissolution florfenicol solid dispersion according to claim 6, characterized in that: the plasma pretreatment steps are as follows: taking 15mL of 500-mu plasma, adding 10 mu L of chloramphenicol internal standard with the concentration of 50 mu g/mL into a centrifuge tube, shaking for 1min, adding 2mL of ethyl acetate, shaking at high speed for 10min, then centrifuging at 6000r/min for 12min, taking supernate, repeatedly extracting once, combining extracting solutions into a 10mL glass tube, drying the extracting solutions with nitrogen in a water bath at 40 ℃, redissolving residues with 500 mu L of mobile phase, then adding 500 mu L of n-hexane, centrifuging at 2min and 13000r/min for 12min, discarding the upper organic phase, filtering the lower layer with a microfiltration membrane with the aperture of 0.22 mu m, and injecting the lower layer into a liquid phase sampling bottle to be tested.
8. The use of a high dissolution florfenicol solid dispersion according to claim 7, characterized in that: experimental liquid chromatography conditions: mobile phase: acetonitrile-water (25: 75; v/v); flow rate: 1.0 mL/min; a chromatographic column: atlantis C18 chromatographic column, 4.6X 250mm, particle size 5 μm; column temperature: 30 ℃; ultraviolet detection wavelength: 223 nm; sample introduction volume: 50 μ L.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112370424A (en) * | 2020-11-25 | 2021-02-19 | 佛山市正典生物技术有限公司 | Florfenicol solution and preparation method and application thereof |
| CN113384535A (en) * | 2021-07-12 | 2021-09-14 | 河南金大众生物工程有限公司 | Florfenicol solid dispersion and preparation method thereof |
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| CN112370424A (en) * | 2020-11-25 | 2021-02-19 | 佛山市正典生物技术有限公司 | Florfenicol solution and preparation method and application thereof |
| CN113384535A (en) * | 2021-07-12 | 2021-09-14 | 河南金大众生物工程有限公司 | Florfenicol solid dispersion and preparation method thereof |
| CN113750050A (en) * | 2021-10-13 | 2021-12-07 | 杭州艾贝德生命科技研究院有限公司 | Method for preparing florfenicol solid dispersion through hot-melt extrusion |
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Application publication date: 20200911 |