CN113456595A - Florfenicol oral solid preparation with high bioavailability - Google Patents
Florfenicol oral solid preparation with high bioavailability Download PDFInfo
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- CN113456595A CN113456595A CN202110766846.6A CN202110766846A CN113456595A CN 113456595 A CN113456595 A CN 113456595A CN 202110766846 A CN202110766846 A CN 202110766846A CN 113456595 A CN113456595 A CN 113456595A
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- cyclodextrin
- florfenicol
- oral solid
- inclusion compound
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- AYIRNRDRBQJXIF-NXEZZACHSA-N (-)-Florfenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)C=C1 AYIRNRDRBQJXIF-NXEZZACHSA-N 0.000 title claims abstract description 69
- 229960003760 florfenicol Drugs 0.000 title claims abstract description 68
- 239000007787 solid Substances 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 40
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 34
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 29
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical class OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 18
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000001116 FEMA 4028 Substances 0.000 claims abstract description 6
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims abstract description 6
- 229960004853 betadex Drugs 0.000 claims abstract description 6
- 239000000126 substance Substances 0.000 claims abstract description 6
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims abstract description 6
- YZOUYRAONFXZSI-SBHWVFSVSA-N (1S,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31S,33R,35R,36R,37S,38R,39S,40R,41S,42R,43S,44R,45S,46R,47S,48R,49S)-5,10,15,20,25,30,35-heptakis(hydroxymethyl)-37,39,40,41,42,43,44,45,46,47,48,49-dodecamethoxy-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane-36,38-diol Chemical compound O([C@@H]([C@H]([C@@H]1OC)OC)O[C@H]2[C@@H](O)[C@@H]([C@@H](O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3O)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O3)O[C@@H]2CO)OC)[C@H](CO)[C@H]1O[C@@H]1[C@@H](OC)[C@H](OC)[C@H]3[C@@H](CO)O1 YZOUYRAONFXZSI-SBHWVFSVSA-N 0.000 claims abstract description 5
- -1 ethyl beta-cyclodextrin Chemical compound 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 56
- 238000002156 mixing Methods 0.000 claims description 54
- 238000003756 stirring Methods 0.000 claims description 34
- 238000001035 drying Methods 0.000 claims description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 239000008367 deionised water Substances 0.000 claims description 23
- 229910021641 deionized water Inorganic materials 0.000 claims description 23
- 238000009472 formulation Methods 0.000 claims description 18
- 239000011259 mixed solution Substances 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 11
- 229960000502 poloxamer Drugs 0.000 claims description 11
- 229920001983 poloxamer Polymers 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 239000007921 spray Substances 0.000 claims description 9
- 239000000843 powder Substances 0.000 claims description 8
- 235000011837 pasties Nutrition 0.000 claims description 2
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 244000144972 livestock Species 0.000 abstract description 3
- 238000010521 absorption reaction Methods 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 7
- 238000000227 grinding Methods 0.000 description 6
- 239000002245 particle Substances 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 241000282887 Suidae Species 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
Images
Classifications
-
- 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
-
- 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
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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, in particular to a florfenicol oral solid preparation with high bioavailability. The feed comprises the following raw materials: in the florfenicol oral solid preparation with high bioavailability, the modified beta-cyclodextrin prepared by a chemical method through methyl beta-cyclodextrin, ethyl beta-cyclodextrin and hydroxypropyl beta-cyclodextrin improves the water solubility of the cyclodextrin, increases the solubility of a cyclodextrin inclusion compound in water, performs gelatinization after the florfenicol is included by the cyclodextrin, and is easier to hydrolyze after the gelatinization, thereby being beneficial to the absorption of livestock and increasing the bioavailability.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a florfenicol oral solid preparation with high bioavailability.
Background
Florfenicol is an excellent broad-spectrum antibiotic special for animals, has the advantages of wide antibacterial spectrum, strong bactericidal action, difficult generation of drug resistance and the like, is widely applied to prevention and treatment of infectious diseases of livestock and fishes clinically, has obvious effect, and still has wide application prospect at present.
At present, the existing florfenicol part has poor water solubility, so that the bioavailability is low, in order to increase the water solubility of the florfenicol and improve the bioavailability of the florfenicol oral solid preparation, one type is a chemical method, wherein the florfenicol is prepared into a phosphate-esterified prodrug, a succinic acid mono-esterified prodrug or a sulfonate-esterified prodrug; one is a physical method, the bioavailability of the florfenicol oral solid preparation is improved by an addition method, a method for preparing inclusion, a method for preparing fixed dispersion and the like, the solubility and the bioavailability of the florfenicol are further improved, and the drug effect is reduced by adding matrix for solubilization, although the solubility of the florfenicol is increased, so that a novel florfenicol oral solid preparation is needed to improve the defects in the prior art.
Disclosure of Invention
The present invention aims to provide a florfenicol oral solid preparation with high bioavailability, so as to solve the problems proposed in the background technology.
In order to achieve the above objects, in one aspect, the present invention provides a florfenicol oral solid preparation with high bioavailability, which comprises the following raw materials: 5-10% of florfenicol, 10-20% of modified beta-cyclodextrin, 0.1-0.5% of poloxamer, 15-19% of solvent and the balance of deionized water.
As a further improvement of the technical scheme, the modified beta-cyclodextrin at least comprises methyl beta-cyclodextrin, ethyl beta-cyclodextrin and hydroxypropyl beta-cyclodextrin, and is prepared by a chemical method.
As a further improvement of the present technical solution, the solvent is at least one selected from methanol, ethanol and N, N-dimethylformamide.
In another aspect, the present invention provides a method for preparing a highly bioavailable florfenicol oral solid preparation, comprising the following steps:
s1, mixing and dissolving the modified beta-cyclodextrin and deionized water in proportion to prepare a solution A;
s2, adding florfenicol into the solvent, mixing and dissolving to obtain a solution B;
s3, mixing the solution A and the solution B, and adding poloxamer and hydrochloric acid to prepare a mixed solution;
s4, drying the mixed solution, removing the solvent, and preparing the cyclodextrin inclusion compound;
s5, mixing the prepared cyclodextrin inclusion compound in deionized water, adding sodium hydroxide for heating, stirring until the inclusion compound is dispersed and gelatinized, wherein the pH value is 2-4, and finally drying the pasty matter and crushing to prepare the florfenicol solid preparation.
Preferably, in the S1, the mixing ratio of the modified beta-cyclodextrin to the deionized water is 1: 20-25.
Preferably, in the S3, the mixing temperature of the solution A and the solution B is 40-50 ℃, the stirring time is 0.5-1h, and the stirring speed is 50-60 r/min.
Preferably, in S4, the drying step is performed by a spray dryer under the following conditions: the inlet temperature is 140 ℃ minus 160 ℃, the outlet temperature is 80-110 ℃, and the flow rate is 900 ℃ minus 1100 ml/h.
Preferably, in S5, the mixing ratio of the cyclodextrin inclusion compound to the deionized water is 1: 15-20.
Preferably, in S5, the heating temperature of the clathrate compound during gelatinization is 50-80 ℃, the stirring speed is 15-20r/min, after the clathrate compound is gelatinized, the clathrate compound is kept stand for 2-4h under a sealed condition, and is dried at normal temperature.
Preferably, in S5, after the clathrate compound is gelatinized, the clathrate compound is pulverized by a pulverizer, and then the pulverized clathrate compound is put into a grinder to be ground into powder.
Compared with the prior art, the invention has the beneficial effects that:
1. in the florfenicol oral solid preparation with high bioavailability, the modified beta-cyclodextrin prepared by a chemical method through methyl beta-cyclodextrin, ethyl beta-cyclodextrin and hydroxypropyl beta-cyclodextrin improves the water solubility of the cyclodextrin, and increases the solubility of the cyclodextrin inclusion compound in water.
2. In the florfenicol oral solid preparation with high bioavailability, the florfenicol is included by cyclodextrin and then gelatinized, and the gelatinized florfenicol preparation is easier to hydrolyze, is beneficial to absorption of livestock and increases the bioavailability.
Drawings
FIG. 1 is an overall flow diagram of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1 a highly bioavailable florfenicol oral solid formulation comprising:
first, preparation of inclusion compound
Mixing and dissolving 10% of modified beta-cyclodextrin and deionized water according to the proportion of 1:20-25 to prepare a solution A; adding 5% of florfenicol into 15% of solvent, mixing and dissolving to prepare solution B; mixing the solution A and the solution B, and adding 0.1% of poloxamer and hydrochloric acid to prepare a mixed solution, wherein the mixing temperature of the solution A and the solution B is 40-50 ℃, the stirring time is 0.5-1h, and the stirring speed is 50-60 r/min; drying the mixed solution by a spray dryer under the following drying conditions: the inlet temperature is 140-.
II, gelatinization
Mixing the prepared cyclodextrin inclusion compound in deionized water according to the mixing ratio of 1:15-20, adding sodium hydroxide, heating at the temperature of 50-80 ℃, stirring at the speed of 15-20r/min, stirring until the inclusion compound is dispersed and gelatinized, adjusting the pH value of the inclusion compound to 2-4, gelatinizing the inclusion compound, standing for 2-4h under a sealed condition, drying at normal temperature, gelatinizing the inclusion compound, crushing by a crusher, then grinding into powder in a grinder, and finally preparing the florfenicol solid preparation.
Example 2 a highly bioavailable florfenicol oral solid formulation comprising:
first, preparation of inclusion compound
Mixing and dissolving 12.5 percent of modified beta-cyclodextrin with deionized water according to the proportion of 1:20-25 to prepare a solution A; adding 6% of florfenicol into 16% of solvent, mixing and dissolving to prepare solution B; mixing the solution A and the solution B, and adding 0.2% of poloxamer and hydrochloric acid to prepare a mixed solution, wherein the mixing temperature of the solution A and the solution B is 40-50 ℃, the stirring time is 0.5-1h, and the stirring speed is 50-60 r/min; drying the mixed solution by a spray dryer under the following drying conditions: the inlet temperature is 140-.
II, gelatinization
Mixing the prepared cyclodextrin inclusion compound in deionized water according to the mixing ratio of 1:15-20, adding sodium hydroxide, heating at the temperature of 50-80 ℃, stirring at the speed of 15-20r/min, stirring until the inclusion compound is dispersed and gelatinized, adjusting the pH value of the inclusion compound to 2-4, gelatinizing the inclusion compound, standing for 2-4h under a sealed condition, drying at normal temperature, gelatinizing the inclusion compound, crushing by a crusher, then grinding into powder in a grinder, and finally preparing the florfenicol solid preparation.
Example 3 a highly bioavailable florfenicol oral solid formulation comprising:
first, preparation of inclusion compound
Adding 15% of modified beta-cyclodextrin into deionized water according to the proportion of 1:20-25, mixing and dissolving to prepare a solution A; adding 8% of florfenicol into 17% of solvent, mixing and dissolving to prepare solution B; mixing the solution A and the solution B, and adding 0.3% of poloxamer and hydrochloric acid to prepare a mixed solution, wherein the mixing temperature of the solution A and the solution B is 40-50 ℃, the stirring time is 0.5-1h, and the stirring speed is 50-60 r/min; drying the mixed solution by a spray dryer under the following drying conditions: the inlet temperature is 140-.
II, gelatinization
Mixing the prepared cyclodextrin inclusion compound in deionized water according to the mixing ratio of 1:15-20, adding sodium hydroxide, heating at the temperature of 50-80 ℃, stirring at the speed of 15-20r/min, stirring until the inclusion compound is dispersed and gelatinized, adjusting the pH value of the inclusion compound to 2-4, gelatinizing the inclusion compound, standing for 2-4h under a sealed condition, drying at normal temperature, gelatinizing the inclusion compound, crushing by a crusher, then grinding into powder in a grinder, and finally preparing the florfenicol solid preparation.
Example 4 a highly bioavailable florfenicol oral solid formulation comprising:
first, preparation of inclusion compound
Adding 17.5 percent of modified beta-cyclodextrin into deionized water according to the proportion of 1:20-25, mixing and dissolving to prepare a solution A; adding 9% of florfenicol into 18% of solvent, mixing and dissolving to prepare solution B; mixing the solution A and the solution B, and adding 0.4% of poloxamer and hydrochloric acid to obtain a mixed solution, wherein the mixing temperature of the solution A and the solution B is 40-50 ℃, the stirring time is 0.5-1h, and the stirring speed is 50-60 r/min; drying the mixed solution by a spray dryer under the following drying conditions: the inlet temperature is 140-.
II, gelatinization
Mixing the prepared cyclodextrin inclusion compound in deionized water according to the mixing ratio of 1:15-20, adding sodium hydroxide, heating at the temperature of 50-80 ℃, stirring at the speed of 15-20r/min, stirring until the inclusion compound is dispersed and gelatinized, adjusting the pH value of the inclusion compound to 2-4, gelatinizing the inclusion compound, standing for 2-4h under a sealed condition, drying at normal temperature, gelatinizing the inclusion compound, crushing by a crusher, then grinding into powder in a grinder, and finally preparing the florfenicol solid preparation.
Example 5 a highly bioavailable florfenicol oral solid formulation comprising:
first, preparation of inclusion compound
Adding deionized water into 20% of the modified beta-cyclodextrin according to the proportion of 1:20-25, mixing and dissolving to prepare a solution A; adding 10% of florfenicol into 19% of a solvent, mixing and dissolving to prepare a solution B; mixing the solution A and the solution B, and adding 0.5% of poloxamer and hydrochloric acid to obtain a mixed solution, wherein the mixing temperature of the solution A and the solution B is 40-50 ℃, the stirring time is 0.5-1h, and the stirring speed is 50-60 r/min; drying the mixed solution by a spray dryer under the following drying conditions: the inlet temperature is 140-.
II, gelatinization
Mixing the prepared cyclodextrin inclusion compound in deionized water according to the mixing ratio of 1:15-20, adding sodium hydroxide, heating at the temperature of 50-80 ℃, stirring at the speed of 15-20r/min, stirring until the inclusion compound is dispersed and gelatinized, adjusting the pH value of the inclusion compound to 2-4, gelatinizing the inclusion compound, standing for 2-4h under a sealed condition, drying at normal temperature, gelatinizing the inclusion compound, crushing by a crusher, then grinding into powder in a grinder, and finally preparing the florfenicol solid preparation.
In the above examples 1 to 5, the modified β -cyclodextrin includes at least methyl β -cyclodextrin, ethyl β -cyclodextrin, and hydroxypropyl β -cyclodextrin, which are prepared by a chemical method;
the solvent is at least one selected from methanol, ethanol and N, N-dimethylformamide.
The related indexes of the florfenicol oral solid preparation with high bioavailability prepared by the invention are shown in table 1:
TABLE 1
As shown in Table 1, the florfenicol oral solid preparation with high bioavailability prepared in examples 1-5 of the invention has no solid particles in water when the addition amount is 5-30g in 100ml of water, so that the florfenicol oral solid preparation has better water solubility.
Comparative example 1 a florfenicol oral solid formulation comprising:
1. adding 15% of modified beta-cyclodextrin into deionized water according to the proportion of 1:20-25, mixing and dissolving to prepare a solution A;
2. adding 8% of florfenicol into 17% of solvent, mixing and dissolving to prepare solution B; mixing the solution A and the solution B, and adding 0.3% of poloxamer to prepare a mixed solution, wherein the mixing temperature of the solution A and the solution B is 40-50 ℃, the stirring time is 0.5-1h, and the stirring speed is 50-60 r/min;
3. drying the mixed solution by a spray dryer under the following drying conditions: the inlet temperature is 140-.
Comparative example 2 a florfenicol oral solid formulation comprising:
first, preparation of inclusion compound
Adding 15% of hydroxypropyl beta-cyclodextrin into deionized water according to the proportion of 1:20-25, mixing and dissolving to prepare a solution A; adding 8% of florfenicol into 17% of solvent, mixing and dissolving to prepare solution B; mixing the solution A and the solution B, and adding 0.3% of poloxamer and hydrochloric acid to prepare a mixed solution, wherein the mixing temperature of the solution A and the solution B is 40-50 ℃, the stirring time is 0.5-1h, and the stirring speed is 50-60 r/min; drying the mixed solution by a spray dryer under the following drying conditions: the inlet temperature is 140-.
II, gelatinization
Mixing the prepared cyclodextrin inclusion compound in deionized water according to the mixing ratio of 1:15-20, adding sodium hydroxide, heating at the temperature of 50-80 ℃, stirring at the speed of 15-20r/min, stirring until the inclusion compound is dispersed and gelatinized, adjusting the pH value of the inclusion compound to 2-4, gelatinizing the inclusion compound, standing for 2-4h under a sealed condition, drying at normal temperature, gelatinizing the inclusion compound, crushing by a crusher, then grinding into powder in a grinder, and finally preparing the florfenicol solid preparation.
The florfenicol oral solid preparation with high bioavailability prepared by the invention has better water solubility and bioavailability, has a larger relationship with the modified beta-cyclodextrin and the gelatinization step used by the preparation, and in order to verify the related technical scheme, the applicant carries out the following tests:
comparative examples 1 to 2: by adopting the method of the embodiment 3, the steps of modifying beta-cyclodextrin and pasting are removed, and the related indexes of the prepared florfenicol oral solid preparation are detected, which are specifically shown in the table 2:
TABLE 2
As shown in table 2, when the modified β -cyclodextrin was removed, the formulation showed no solid particles at low levels, when the levels were increased, there were distinct solid particles, and when the gelatinization step was removed, there were distinct solid particles at low to high levels, so it can be seen that the preparation method of the present invention is an important factor in improving the water solubility of florfenicol.
The florfenicol oral solid preparations in comparative examples 1-2 and examples 1-5 are used for carrying out bioavailability comparative tests, 70 breeding pigs are selected and divided into 7 groups, 10 pigs are fed by the florfenicol oral solid preparations in comparative examples 1-2 and examples 1-5 respectively, and the blood concentration 10 hours after feeding is detected, and the corresponding detection indexes are shown in table 3:
TABLE 3
As shown in Table 3, in examples 1 to 5, the blood concentration of the florfenicol oral solid preparation was higher within 2 hours when entering the pig body than in comparative examples 1 to 2, and it can be shown that the bioavailability of the florfenicol oral solid preparation prepared by the present invention was better.
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and the preferred embodiments of the present invention are described in the above embodiments and the description, and are not intended to limit the present invention. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (10)
1. The florfenicol oral solid preparation with high bioavailability is characterized by comprising the following raw materials: 5-10% of florfenicol, 10-20% of modified beta-cyclodextrin, 0.1-0.5% of poloxamer, 15-19% of solvent and the balance of deionized water.
2. The highly bioavailable florfenicol oral solid formulation of claim 1, wherein: the modified beta-cyclodextrin at least comprises methyl beta-cyclodextrin, ethyl beta-cyclodextrin and hydroxypropyl beta-cyclodextrin, and is prepared by a chemical method.
3. The highly bioavailable florfenicol oral solid formulation of claim 1, wherein: the solvent is selected from at least one of methanol, ethanol and N, N-dimethylformamide.
4. A method for preparing a highly bioavailable florfenicol oral solid formulation, comprising the highly bioavailable florfenicol oral solid formulation of any of claims 1-3 above, and operating the steps of:
s1, mixing and dissolving the modified beta-cyclodextrin and deionized water in proportion to prepare a solution A;
s2, adding florfenicol into the solvent, mixing and dissolving to obtain a solution B;
s3, mixing the solution A and the solution B, and adding poloxamer and hydrochloric acid to prepare a mixed solution;
s4, drying the mixed solution, removing the solvent, and preparing the cyclodextrin inclusion compound;
s5, mixing the prepared cyclodextrin inclusion compound in deionized water, adding sodium hydroxide for heating, stirring until the inclusion compound is dispersed and gelatinized, wherein the pH value is 2-4, and finally drying the pasty matter and crushing to prepare the florfenicol solid preparation.
5. The method for preparing a highly bioavailable florfenicol oral solid formulation of claim 4, wherein: in the S1, the mixing ratio of the modified beta-cyclodextrin to the deionized water is 1: 20-25.
6. The method for preparing a highly bioavailable florfenicol oral solid formulation of claim 4, wherein: in the S3, the mixing temperature of the solution A and the solution B is 40-50 ℃, the stirring time is 0.5-1h, and the stirring speed is 50-60 r/min.
7. The method for preparing a highly bioavailable florfenicol oral solid formulation of claim 4, wherein: in S4, the drying step is performed by a spray dryer under the following conditions: the inlet temperature is 140 ℃ minus 160 ℃, the outlet temperature is 80-110 ℃, and the flow rate is 900 ℃ minus 1100 ml/h.
8. The method for preparing a highly bioavailable florfenicol oral solid formulation of claim 4, wherein: in the S5, the mixing ratio of the cyclodextrin inclusion compound to the deionized water is 1: 15-20.
9. The method for preparing a highly bioavailable florfenicol oral solid formulation of claim 4, wherein: in the step S5, the heating temperature of the inclusion compound during gelatinization is 50-80 ℃, the stirring speed is 15-20r/min, after the inclusion compound is gelatinized, the inclusion compound is kept stand for 2-4h under a sealed condition, and the inclusion compound is dried at normal temperature.
10. The method for preparing a highly bioavailable florfenicol oral solid formulation of claim 4, wherein: in the step S5, after the inclusion compound is gelatinized, the inclusion compound is crushed by a crusher and then enters a grinder to be ground into powder.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104667291A (en) * | 2013-12-03 | 2015-06-03 | 中牧实业股份有限公司黄冈动物药品厂 | Improved preparation method of florfenicol clathrate compound |
| CN109602916A (en) * | 2018-12-13 | 2019-04-12 | 广东温氏大华农生物科技有限公司 | A kind of Florfenicol inclusion compound and preparation method thereof |
| CN112190551A (en) * | 2020-11-20 | 2021-01-08 | 湖北龙翔药业科技股份有限公司 | Florfenicol soluble powder and preparation method thereof |
| CN112641954A (en) * | 2020-12-30 | 2021-04-13 | 广东三水正大康畜牧发展有限公司 | Water-soluble florfenicol clathrate compound, simple molecular coating method thereof and prepared solid preparation |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104667291A (en) * | 2013-12-03 | 2015-06-03 | 中牧实业股份有限公司黄冈动物药品厂 | Improved preparation method of florfenicol clathrate compound |
| CN109602916A (en) * | 2018-12-13 | 2019-04-12 | 广东温氏大华农生物科技有限公司 | A kind of Florfenicol inclusion compound and preparation method thereof |
| CN112190551A (en) * | 2020-11-20 | 2021-01-08 | 湖北龙翔药业科技股份有限公司 | Florfenicol soluble powder and preparation method thereof |
| CN112641954A (en) * | 2020-12-30 | 2021-04-13 | 广东三水正大康畜牧发展有限公司 | Water-soluble florfenicol clathrate compound, simple molecular coating method thereof and prepared solid preparation |
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