CN117298082A - Preparation method of florfenicol dry suspension - Google Patents
Preparation method of florfenicol dry suspension Download PDFInfo
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- CN117298082A CN117298082A CN202311216281.XA CN202311216281A CN117298082A CN 117298082 A CN117298082 A CN 117298082A CN 202311216281 A CN202311216281 A CN 202311216281A CN 117298082 A CN117298082 A CN 117298082A
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- florfenicol
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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 90
- 229960003760 florfenicol Drugs 0.000 title claims abstract description 90
- 239000000725 suspension Substances 0.000 title claims abstract description 72
- 238000002360 preparation method Methods 0.000 title claims abstract description 53
- 238000003756 stirring Methods 0.000 claims abstract description 44
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 31
- 239000001116 FEMA 4028 Substances 0.000 claims abstract description 31
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound 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 31
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims abstract description 31
- 229960004853 betadex Drugs 0.000 claims abstract description 31
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 239000000843 powder Substances 0.000 claims abstract description 30
- 239000000203 mixture Substances 0.000 claims abstract description 29
- 239000000243 solution Substances 0.000 claims abstract description 28
- 239000008399 tap water Substances 0.000 claims abstract description 28
- 235000020679 tap water Nutrition 0.000 claims abstract description 28
- 238000002156 mixing Methods 0.000 claims abstract description 24
- 239000004721 Polyphenylene oxide Substances 0.000 claims abstract description 20
- 229920000570 polyether Polymers 0.000 claims abstract description 20
- 239000004359 castor oil Substances 0.000 claims abstract description 18
- 235000019438 castor oil Nutrition 0.000 claims abstract description 18
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims abstract description 18
- 239000000230 xanthan gum Substances 0.000 claims abstract description 13
- 229920001285 xanthan gum Polymers 0.000 claims abstract description 13
- 229940082509 xanthan gum Drugs 0.000 claims abstract description 13
- 235000010493 xanthan gum Nutrition 0.000 claims abstract description 13
- 229960001031 glucose Drugs 0.000 claims abstract description 12
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims abstract description 11
- 239000011259 mixed solution Substances 0.000 claims abstract description 11
- 238000001694 spray drying Methods 0.000 claims abstract description 11
- 239000000463 material Substances 0.000 claims abstract description 10
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 claims abstract description 10
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims abstract description 8
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- 238000007873 sieving Methods 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 9
- 229920001223 polyethylene glycol Polymers 0.000 claims description 8
- 239000007921 spray Substances 0.000 claims description 6
- 239000012488 sample solution Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 11
- 238000010790 dilution Methods 0.000 abstract description 2
- 239000012895 dilution Substances 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 17
- 238000002347 injection Methods 0.000 description 14
- 239000007924 injection Substances 0.000 description 14
- 239000000523 sample Substances 0.000 description 14
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 11
- 239000008103 glucose Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 238000001556 precipitation Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 230000001804 emulsifying effect Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 208000032467 Aplastic anaemia Diseases 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229960005091 chloramphenicol Drugs 0.000 description 2
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000031295 Animal disease Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 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
- 230000008859 change Effects 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 229960003053 thiamphenicol Drugs 0.000 description 1
- OTVAEFIXJLOWRX-NXEZZACHSA-N thiamphenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CO)NC(=O)C(Cl)Cl)C=C1 OTVAEFIXJLOWRX-NXEZZACHSA-N 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
-
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
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- A61P31/04—Antibacterial agents
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Abstract
The preparation method of the florfenicol dry suspension comprises the following steps: uniformly mixing florfenicol raw powder and beta-cyclodextrin, adding the mixture into a reaction kettle containing tap water, and heating the mixture while stirring until the materials are uniformly dispersed to obtain a mixed solution A; adding tap water, xanthan gum, castor oil polyether, PEG400 and EDTA into another reaction kettle, stirring to dissolve the components to obtain a solution B; putting the solution B into a reaction kettle of the mixed solution A, maintaining the temperature, and uniformly stirring and mixing; spray drying the obtained mixed solution to obtain a florfenicol dry suspension intermediate; sieving the intermediate of the florfenicol dry suspension preparation, and uniformly mixing the intermediate with beta-cyclodextrin and anhydrous glucose in different proportions in a mixer to obtain the florfenicol dry suspension preparation with the required content. In the preparation process, PEG400 and castor oil polyether are adopted to mix, so that the prepared florfenicol dry suspension has stable performance, good suspension effect, high solubility after dilution, low cost and simple and convenient preparation process.
Description
Technical Field
The invention relates to a preparation method of florfenicol dry suspension, and belongs to the technical field of veterinary drug preparations.
Background
Florfenicol is a novel broad-spectrum antibiotic special for chemically synthesized chloramphenicol animals. The medicine is favored by domestic and foreign veterinary medicine fields by the characteristics of broad antibacterial spectrum, safety, high efficiency, good absorption, wide in-vivo distribution, no potential aplastic anemia and the like. The antibacterial activity of florfenicol on sensitive bacteria is similar to that of chloramphenicol and thiamphenicol, but the florfenicol does not produce adverse reaction of aplastic anemia after being taken. Therefore, the florfenicol has wide application prospect in preventing and treating diseases of animals. Florfenicol is a widely used excellent drug, and the research and development of new dosage forms thereof also becomes a research hotspot of students.
At present, breeding group users mostly adopt a drinking water administration mode of an administration device when treating animal diseases, and the existing main dosage forms of florfenicol are limited by a certain application in the treatment mode, and particularly, uneven concentration distribution is easy to occur after the medicine is dissolved, so that the medicine intake of animals is unstable. Precipitation can occur when the medicine is placed in a concentrated way, so that the phenomenon of blockage of a drinking line of a medicine feeder occurs in the medicine feeding process, and a plurality of inconveniences are brought to clinical medicine.
In order to solve the problems, a stable florfenicol dry suspension preparation is developed, high-concentration preparation can be realized during drinking water administration, the phenomenon of pipe blockage can not occur after long-time placement without precipitation, and meanwhile, the medicine dispersion uniformity can be ensured. Therefore, the development of the florfenicol preparation has important clinical application significance.
Disclosure of Invention
The invention provides a preparation method of a florfenicol dry suspension, which aims to overcome the defects of the prior art, and the preparation process adopts PEG400 and castor oil polyether for mixing, so that the prepared florfenicol dry suspension has stable performance, good suspension effect, high solubility after dilution, low cost and simple and convenient preparation process.
The technical scheme adopted for solving the technical problems is as follows:
the preparation method of the florfenicol dry suspension comprises the following steps:
a. uniformly mixing florfenicol raw powder and beta-cyclodextrin, adding the mixture into a reaction kettle containing tap water, heating the mixture to 80-90 ℃ while stirring, and continuously stirring until the materials are uniformly dispersed to obtain a mixed solution A;
b. adding tap water, xanthan gum, castor oil polyether, PEG400 and EDTA into another reaction kettle, stirring to dissolve the components to obtain a solution B;
c. putting the solution B into a reaction kettle of the mixed solution A, maintaining the temperature, and fully stirring to uniformly mix the solution B;
d. c, carrying out spray drying on the mixed solution obtained in the step c to obtain a florfenicol dry suspension intermediate;
e. sieving the intermediate of the florfenicol dry suspension preparation, and uniformly mixing the intermediate with beta-cyclodextrin and anhydrous glucose in different proportions in a mixer to obtain the florfenicol dry suspension preparation with the required content.
In the step a, in every 1000mL tap water, the adding ratio of the florfenicol to the beta-cyclodextrin is (200-500 g): (300-600 g).
In the above preparation method of florfenicol dry suspension preparation, in the step b, the adding amount of each component in each 500mL tap water is as follows: 1-20 g of xanthan gum, 1-10 g of castor oil polyether, 1-20 g of PEG and 1-10 g of EDTA.
In the above preparation method of florfenicol dry suspension preparation, in the step c, the ratio of tap water added in the solution A to tap water added in the solution B is 2:1.
in the step d, the sample solution is sprayed out in 2-6 hours at the inlet temperature of 180-230 ℃ and the outlet temperature of 85-95 ℃ of the spray dryer.
The beneficial effects of the invention are as follows:
the preparation method disclosed by the invention has the advantages that the process is simple, the raw materials are cheap and easy to obtain, the use of an organic solvent is not needed, the prepared florfenicol dry suspension preparation has stable performance, the suspension effect is good, the high-concentration mixing state is stable, the precipitation is not easy to occur after long-time placement, the solution is diluted into the clinical dosage concentration, and the solution is rapidly clarified.
Detailed Description
PEG400 and castor oil polyether are both oil-in-water type emulsifying agents which are easily soluble in water and have excellent emulsifying and diffusing effects. The PEG400 and castor oil polyether are used together, so that the wettability of the product can be improved, the rapid dispersion and emulsification effects of the florfenicol preparation in stirring and water dissolution are promoted, the florfenicol preparation is easier to disperse in the stirring process, and the phenomenon of agglomeration and balling does not occur. Meanwhile, the PEG400 can also play a role in assisting dissolution, improves the water solubility of the florfenicol raw material, and is more convenient for clinical application. The xanthan gum mainly has the functions of thickening and suspending, so that the drug components which ensure the incompatibility after the product is redissolved in water with high concentration can be uniformly suspended in the aqueous solution, and layering, uneven content and sinking phenomena do not occur after the product is placed for a long time. EDTA is an important complexing agent and stabilizer, and can form water-soluble complex with metal ions in water to prevent the metal ions from reacting with other components in the preparation to generate flocculent precipitate to influence the stability of the solution, so that the EDTA plays a role in stabilizing the protective agent. Beta-cyclodextrin has physical inclusion dissolution promoting effect in the stirring process. Under the multiple actions, the florfenicol can maintain a stable high-concentration suspension state in water, and meanwhile, the high solubility of the product after being diluted according to a certain proportion is ensured.
The preparation method can be used for preparing the florfenicol dry suspension intermediate, and the florfenicol dry suspension powder with different contents of 2% -30% can be prepared by adding different beta-cyclodextrin, anhydrous glucose and the florfenicol dry suspension intermediate in the later period.
The invention is further illustrated below with reference to examples.
Example 1
Uniformly mixing 200g of florfenicol raw powder with 400g of beta-cyclodextrin, adding the mixture into a reaction kettle containing 1000mL of tap water, heating the mixture to the temperature of 80 ℃ while stirring, and continuously stirring until the materials are uniformly dispersed to obtain a mixed solution A; adding 500mL of pure tap water into another reaction kettle, adding 1g of xanthan gum, 2g of castor oil polyether, 400g of PEG and 1g of EDTA into the reaction kettle, and stirring to dissolve to obtain a mixed solution B; maintaining the temperature, mixing the two solutions, stirring thoroughly to mix them uniformly, spray drying, and spray drying at inlet temperature of 180deg.C and outlet temperature of 85deg.C. And (3) adjusting the sample injection speed, and controlling the sample injection within 2 hours to obtain the florfenicol dry suspension intermediate dry powder. Mixing with beta-cyclodextrin according to a certain proportion, and obtaining the florfenicol dry suspension preparation. The preparation method is characterized by preparing 30% florfenicol dry suspension powder, and the specific proportion is as follows:
florfenicol dry suspension intermediate 91g
Beta-cyclodextrin 9g
Example 2
After 250g of florfenicol raw powder and 370g of beta-cyclodextrin are uniformly mixed, adding the mixture into a reaction kettle containing 1000mL of tap water, heating the mixture to the temperature of 82 ℃ while stirring, and continuing stirring until the materials are uniformly dispersed; 500mL of pure tap water is put into another reaction kettle, 4g of xanthan gum, 4g of castor oil polyether, 400g of PEG and 1g of EDTA are added into the reaction kettle, and stirring is carried out to dissolve; maintaining the temperature, mixing the two solutions, and fully stirring to uniformly mix the two solutions; spray drying was carried out at an inlet temperature of 190℃and an outlet temperature of 85 ℃. And (3) adjusting the sample injection speed, and controlling the sample injection within 2.5 hours to obtain the florfenicol dry suspension intermediate dry powder. Mixing with beta-cyclodextrin according to a certain proportion, and obtaining the florfenicol dry suspension preparation. The preparation method is characterized by preparing 30% florfenicol dry suspension powder, and the specific proportion is as follows:
florfenicol dry suspension intermediate 75.9g
Beta-cyclodextrin 24.1g
Example 3
After 300g of florfenicol raw powder and 300g of beta-cyclodextrin are uniformly mixed, adding the mixture into a reaction kettle containing 1000mL of tap water, heating the mixture to the temperature of 82 ℃ while stirring, and continuously stirring until the materials are uniformly dispersed; 500mL of pure tap water was put into another reaction vessel, 6.5g of xanthan gum, 6g of castor oil polyether, 400g of PEG, and 1.5g of EDTA1 were added into the reaction vessel, and the mixture was stirred and dissolved. Maintaining the temperature, mixing the two solutions, and fully stirring to uniformly mix the two solutions; spray drying was carried out at an inlet temperature of 200℃and an outlet temperature of 90 ℃. And (3) adjusting the sample injection speed, and controlling the sample injection within 3 hours to obtain the florfenicol dry suspension intermediate dry powder. Mixing with beta-cyclodextrin according to a certain proportion, and obtaining the florfenicol dry suspension preparation. The preparation method is characterized by preparing 30% florfenicol dry suspension powder, and the specific proportion is as follows:
62.4g florfenicol dry suspension intermediate
Beta-cyclodextrin 37.6g
Example 4
After 350g of florfenicol raw powder and 200g of beta-cyclodextrin are uniformly mixed, adding the mixture into a reaction kettle containing 1000mL of tap water, heating the mixture to the temperature of 82 ℃ while stirring, and continuing stirring until the materials are uniformly dispersed; 500mL of pure tap water is put into another reaction kettle, 10.5g of xanthan gum, 8g of castor oil polyether, 400g of PEG and 1.5g of EDTA1 are added into the reaction kettle, and stirring is carried out to dissolve; maintaining the temperature, mixing the two solutions, and fully stirring to uniformly mix the two solutions; spray drying was performed. The spray dryer inlet temperature was 210℃and the outlet temperature was 90 ℃. And (3) adjusting the sample injection speed, and controlling the sample injection within 3.5 hours to obtain the florfenicol dry suspension intermediate dry powder. Mixing with beta-cyclodextrin and glucose according to a certain proportion uniformly to obtain the florfenicol dry suspension preparation. The preparation method is characterized by preparing 30% florfenicol dry suspension powder, and the specific proportion is as follows:
50g of florfenicol dry suspension intermediate
Beta-cyclodextrin 30g
Glucose up to 100g
Comparative example 1
After 350g of florfenicol raw powder and 200g of betacyclodextrin were mixed uniformly according to example 4, the mixture was added into a reaction kettle containing 1000mL of tap water, heated to a temperature of 82 ℃ while stirring, and stirring was continued until the materials were dispersed uniformly. 500mL of pure tap water was put into another reaction vessel, 10.5g of xanthan gum, 400g of PEG, and 1.5g of EDTA were added to the reaction vessel, and the mixture was stirred and dissolved. Maintaining the temperature, mixing the two solutions, and stirring thoroughly to mix them uniformly. Spray drying was performed. The spray dryer inlet temperature was 210℃and the outlet temperature was 90 ℃. And (3) adjusting the sample injection speed, and controlling the sample injection within 3.5 hours to obtain the florfenicol dry suspension intermediate dry powder. Mixing with beta-cyclodextrin and glucose according to a certain proportion uniformly to obtain the florfenicol dry suspension preparation. The preparation method is characterized by preparing 30% florfenicol dry suspension powder, and the specific proportion is as follows:
florfenicol dry suspension intermediate 42g
Beta-cyclodextrin 38g
Glucose up to 100g
Comparative example 2
After 350g of florfenicol raw powder and 200g of betacyclodextrin were mixed uniformly according to example 4, the mixture was added into a reaction kettle containing 1000mL of tap water, heated to a temperature of 82 ℃ while stirring, and stirring was continued until the materials were dispersed uniformly. 500mL of pure tap water was put into another reaction vessel, and 10.5g of xanthan gum, 8g of castor oil polyether and 1.5g of EDTA1 were added to the reaction vessel and dissolved by stirring. Maintaining the temperature, mixing the two solutions, and stirring thoroughly to mix them uniformly. Spray drying was performed. The spray dryer inlet temperature was 210℃and the outlet temperature was 90 ℃. And (3) adjusting the sample injection speed, and controlling the sample injection within 3.5 hours to obtain the florfenicol dry suspension intermediate dry powder. Mixing with beta-cyclodextrin and glucose according to a certain proportion uniformly to obtain the florfenicol dry suspension preparation. The preparation method is characterized by preparing 30% florfenicol dry suspension powder, and the specific proportion is as follows:
florfenicol dry suspension intermediate 38g
Beta-cyclodextrin 42g
Glucose up to 100g
Comparative example 3
After 350g of florfenicol raw powder and 200g of beta-cyclodextrin are uniformly mixed, the mixture is added into a reaction kettle containing 1000mL of tap water, and the mixture is heated to 82 ℃ while being stirred, and is continuously stirred until the materials are uniformly dispersed. 500mL of pure tap water was put into another reaction vessel, 10.5g of xanthan gum, 8g of propylene glycol block polyether, 400g of PEG and 1.5g of EDTA were added into the reaction vessel, and the mixture was stirred and dissolved. Maintaining the temperature, mixing the two solutions, and stirring thoroughly to mix them uniformly. Spray drying was performed. The spray dryer inlet temperature was 210℃and the outlet temperature was 90 ℃. And (3) adjusting the sample injection speed, and controlling the sample injection within 3.5 hours to obtain the florfenicol dry suspension intermediate dry powder. Mixing with beta-cyclodextrin and glucose according to a certain proportion uniformly to obtain the florfenicol dry suspension preparation. The preparation method is characterized by preparing 30% florfenicol dry suspension powder, and the specific proportion is as follows:
50g of florfenicol dry suspension intermediate
Beta-cyclodextrin 30g
Glucose up to 100g
The samples of the examples and comparative examples and the commercially available 30% common florfenicol powder were each weighed 40g and dissolved in a beaker containing 1L tap water for suspension effect and solubility comparison, and the comparative data are shown in Table 1. Samples of the suspensions of examples 1-4 and comparative examples 1-3 after dissolution in water were left for 6 hours for observation, and the contents of the upper, middle and lower layers of florfenicol were detected by sampling at 0, 3 and 6 hours, respectively, and the content measurement results are shown in Table 2.
Table 1 comparative examples and commercial powder suspension effects and solubilities
The stirring time of examples 1-4 was increased compared to the commercially available samples, possibly related to the addition of suspending agent, etc. to the product, but the increase in stirring time had substantially no effect on the use of the product. After 3 hours of standing after stirring uniformly in examples 1 and 2, a small amount of deposition occurred, but no significant delamination occurred. No precipitation occurred in examples 3-4 after 6 hours of standing and the appearance of the solution distribution was uniform. The solubility of the diluted solution is obviously improved in the examples 1-4 compared with the solubility of common products sold in the market, wherein the increase of the example 3 is most obvious and is 15 times of the solubility of common powder, so that the convenience of clinical application is greatly improved. The stirring time of comparative examples 1 and 2 was increased compared to example 4 and the standing steady state time was shortened compared to example 4, the analytical reasons may be related to the joint addition of castor oil polyether and PEG 400. The castor oil polyether and the PEG400 are both oil-in-water type emulsifying agents which are easily dissolved in water, and have excellent emulsifying and diffusing effects, so that the preparation is easier to disperse in the stirring process by the cooperation of the castor oil polyether and the PEG400, and the emulsifying effect is good, thereby shortening the stirring time and increasing the suspension stability of the solution. Comparative example 3 is based on the formulation of example 4, the castor oil polyether is replaced by an equivalent amount of propylene glycol block polyether, the stirring time and the stable state of the suspension are both obviously reduced, and the effect is poor.
TABLE 2 results of 0-6 hour content determination of the upper, middle and lower layers of florfenicol in examples 1-4 and comparative examples 1-3
In examples 1-2, the difference in florfenicol content of the upper, middle and lower layers was small when examined three hours before the florfenicol suspension. Three hours later, deposition occurred at the bottom of the suspension, and the suspension was again tested and left for six hours, with a large change in the lower layer content, but all within acceptable limits, which may be related to the amount of suspending agent and stabilizer added. The florfenicol suspensions of examples 3 and 4 have smaller difference in the contents of the upper layer, the middle layer and the lower layer in three-time detection, no drug precipitation layering occurs, and the contents of the upper layer, the middle layer and the lower layer in 6 hours of placement are relatively balanced and stable, so that the effect of combined application of the suspending agent, the stabilizing agent and the wetting agent added in the invention is fully proved, a uniform dispersion system can be formed after the drug preparation is dissolved in water, the drug is uniformly dispersed in water, and the phenomenon of uneven drug application in clinical application is avoided. The comparative examples 1-3 showed significant changes in the florfenicol content of the upper, middle and lower layers in three hours of detection, and the florfenicol distribution difference was relatively significant, which was closely related to the prescription and prescription ratio in the formulation, and further demonstrated the rationality of the formulation compatibility of the present invention.
The florfenicol dry suspension powder is detected according to the content specified in the national standard assembly of veterinary medicine of the pharmacopoeia of the people's republic of China, and comprises the following components: the properties, identification, loss on drying, uniformity of appearance, solubility, and content are shown in Table 3.
TABLE 3 monitoring results
As can be seen from table 3: the florfenicol dry suspension preparation provided by the invention is white powder, and all quality inspection indexes accord with the national standard of veterinary medicines.
Claims (5)
1. The preparation method of the florfenicol dry suspension is characterized by comprising the following steps of: the preparation method comprises the following steps:
a. uniformly mixing florfenicol raw powder and beta-cyclodextrin, adding the mixture into a reaction kettle containing tap water, heating the mixture to 80-90 ℃ while stirring, and continuously stirring until the materials are uniformly dispersed to obtain a mixed solution A;
b. adding tap water, xanthan gum, castor oil polyether, PEG400 and EDTA into another reaction kettle, stirring to dissolve the components to obtain a solution B;
c. putting the solution B into a reaction kettle of the mixed solution A, maintaining the temperature, and fully stirring to uniformly mix the solution B;
d. c, carrying out spray drying on the mixed solution obtained in the step c to obtain a florfenicol dry suspension intermediate;
e. sieving the intermediate of the florfenicol dry suspension preparation, and uniformly mixing the intermediate with beta-cyclodextrin and anhydrous glucose in different proportions in a mixer to obtain the florfenicol dry suspension preparation with the required content.
2. The method for preparing the florfenicol dry suspension preparation according to claim 1, which is characterized in that: in the step a, the adding ratio of florfenicol to beta-cyclodextrin in 1000mL of tap water is (200-500 g): (300-600 g).
3. The method for preparing the florfenicol dry suspension preparation according to claim 1, which is characterized in that: in the step b, the addition amount of each component in 500mL of tap water is as follows: 1-20 g of xanthan gum, 1-10 g of castor oil polyether, 1-20 g of PEG and 1-10 g of EDTA.
4. The method for preparing the florfenicol dry suspension preparation according to claim 1, which is characterized in that: in the step c, the tap water added in the solution A and the solution B is in a dosage ratio of 2:1.
5. the method for preparing the florfenicol dry suspension preparation according to claim 1, which is characterized in that: in the step d, the inlet temperature of the spray dryer is 180-230 ℃, the outlet temperature is 85-95 ℃, and the sample solution is sprayed out for 2-6 hours.
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