CN117959462A - Preparation method and application of water-soluble carrier composition - Google Patents
Preparation method and application of water-soluble carrier composition Download PDFInfo
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- CN117959462A CN117959462A CN202410138862.4A CN202410138862A CN117959462A CN 117959462 A CN117959462 A CN 117959462A CN 202410138862 A CN202410138862 A CN 202410138862A CN 117959462 A CN117959462 A CN 117959462A
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- florfenicol
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- 239000000203 mixture Substances 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 46
- 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 claims abstract description 34
- 229960003760 florfenicol Drugs 0.000 claims abstract description 34
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class 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 29
- 239000008367 deionised water Substances 0.000 claims abstract description 28
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 28
- 239000000661 sodium alginate Substances 0.000 claims abstract description 28
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 28
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 28
- 238000003756 stirring Methods 0.000 claims abstract description 28
- -1 aldehyde sodium alginate Chemical class 0.000 claims abstract description 14
- 239000000843 powder Substances 0.000 claims abstract description 13
- 239000003381 stabilizer Substances 0.000 claims abstract description 13
- 239000002131 composite material Substances 0.000 claims abstract description 12
- 239000002270 dispersing agent Substances 0.000 claims abstract description 7
- 238000004321 preservation Methods 0.000 claims abstract description 5
- 229920000858 Cyclodextrin Polymers 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 19
- 239000001116 FEMA 4028 Substances 0.000 claims description 18
- 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 description 18
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 18
- 229960004853 betadex Drugs 0.000 claims description 18
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 15
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 238000004108 freeze drying Methods 0.000 claims description 11
- 239000007795 chemical reaction product Substances 0.000 claims description 10
- 239000013067 intermediate product Substances 0.000 claims description 10
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 7
- 239000012312 sodium hydride Substances 0.000 claims description 7
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 238000007873 sieving Methods 0.000 claims description 6
- 238000001694 spray drying Methods 0.000 claims description 6
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 claims description 5
- GJOWSEBTWQNKPC-UHFFFAOYSA-N 3-methyloxiran-2-ol Chemical compound CC1OC1O GJOWSEBTWQNKPC-UHFFFAOYSA-N 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- RZJRJXONCZWCBN-UHFFFAOYSA-N octadecane Chemical compound CCCCCCCCCCCCCCCCCC RZJRJXONCZWCBN-UHFFFAOYSA-N 0.000 claims description 4
- 239000004721 Polyphenylene oxide Substances 0.000 claims description 3
- 229920000570 polyether Polymers 0.000 claims description 3
- 229940113115 polyethylene glycol 200 Drugs 0.000 claims description 3
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 3
- 229940057847 polyethylene glycol 600 Drugs 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 229940038384 octadecane Drugs 0.000 claims description 2
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 claims 1
- 238000009372 pisciculture Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 10
- 239000002994 raw material Substances 0.000 abstract description 6
- 241000251468 Actinopterygii Species 0.000 abstract description 4
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 239000003651 drinking water Substances 0.000 abstract description 2
- 235000020188 drinking water Nutrition 0.000 abstract description 2
- 244000144972 livestock Species 0.000 abstract description 2
- 244000144977 poultry Species 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 18
- 239000011259 mixed solution Substances 0.000 description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
- 238000000502 dialysis Methods 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 7
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 4
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical group CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 4
- 229930003779 Vitamin B12 Natural products 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 4
- 229940055726 pantothenic acid Drugs 0.000 description 4
- 235000019161 pantothenic acid Nutrition 0.000 description 4
- 239000011713 pantothenic acid Substances 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 235000019163 vitamin B12 Nutrition 0.000 description 4
- 239000011715 vitamin B12 Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000012738 dissolution medium Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 210000004051 gastric juice Anatomy 0.000 description 2
- 238000007037 hydroformylation reaction Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 238000000691 measurement method Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- OTVAEFIXJLOWRX-NXEZZACHSA-N thiamphenicol Chemical class 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 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 101000623895 Bos taurus Mucin-15 Proteins 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000012653 anionic ring-opening polymerization Methods 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
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229920000587 hyperbranched polymer Polymers 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
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- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960003053 thiamphenicol Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
Abstract
The invention discloses a preparation method and application of a water-soluble carrier composition, belonging to the technical field of veterinary medicine preparations, and comprising the following steps: florfenicol and hyperbranched modified cyclodextrin are placed in a mixer for 5-10min to obtain composite powder, and the composite powder is added into deionized water at 75-90 ℃ and stirred for 2-4h to obtain a component I; adding a water-soluble carrier, a stabilizer and a dispersing agent into the first component, carrying out heat preservation and stirring for 2-3 hours, then adding aldehyde sodium alginate, and stirring for 10-20 minutes to obtain a second component; the water-soluble carrier composition is prepared by reasonably controlling the content of raw material components and technological parameters, has good water solubility and enteric solubility, improves the bioavailability of florfenicol, reduces the administration dosage, reduces the administration volume, and is suitable for drinking water administration and disease treatment of livestock and poultry farmers and fish farmers.
Description
Technical Field
The invention belongs to the technical field of veterinary drug preparations, and particularly relates to a preparation method and application of a water-soluble carrier composition.
Background
In drug delivery systems, water-soluble carrier compositions play an important role. They can increase the solubility of the drug in water, improve the bioavailability of the drug, reduce the toxicity of the drug, and thus improve the therapeutic effect of the drug.
Florfenicol (Florfenicol, FF) is a fluorinated derivative of thiamphenicol (Thiamphenicol, TAP), is an amide alcohol type broad-spectrum antibiotic special for animals, has a molecular formula of C 12H14Cl2FNO4 S, and crystalline powder of the florfenicol is odorless, bitter in taste and white or white-like, and is mainly applied to bacterial diseases of animals such as fishes, pigs, cattle and the like at present. The florfenicol has poor water solubility, and the solubility in water at normal temperature is only 1.05-1.35mg/mL, which affects the in vivo absorption and biological utilization.
The current florfenicol preparation technology and form mainly comprise: the method of adding cosolvent (water-soluble carrier), micronizing, cyclodextrin saturation, superfine pulverizing, etc. has the problems of unsatisfactory effect and low water solubility, and the existing florfenicol preparation has high solubility in animal stomach, is easily damaged by gastric acid, can cause irritation to gastric mucosa, has low bioavailability and causes adverse reaction.
Disclosure of Invention
The invention aims to provide a preparation method and application of a water-soluble carrier composition, and solves the problems of poor water solubility and low enteric solubility of the existing florfenicol preparation.
The aim of the invention can be achieved by the following technical scheme:
a method of preparing a water-soluble carrier composition comprising the steps of:
(1) Florfenicol and hyperbranched modified cyclodextrin are placed in a mixer for 5-10min to obtain composite powder, and the composite powder is added into deionized water at 75-90 ℃ and stirred for 2-4h to obtain a component I;
(2) Adding a water-soluble carrier, a stabilizer and a dispersing agent into the first component, carrying out heat preservation and stirring for 2-3 hours, then adding aldehyde sodium alginate, and stirring for 10-20 minutes to obtain a second component;
(3) And (3) spray drying, sieving and mixing the mixture II to obtain the water-soluble carrier composition.
Wherein, the mass ratio of florfenicol, hyperbranched modified cyclodextrin, deionized water, a water-soluble carrier, a stabilizer, a dispersing agent and aldehyde sodium alginate is 25-35:30-60:100-150:3-8:1-2:5-10:8-20.
The hyperbranched modified cyclodextrin is aniline-terminated hyperbranched polyether grafted beta cyclodextrin.
Further, the preparation method of the hyperbranched modified cyclodextrin comprises the following steps:
S1, adding beta cyclodextrin, hexaoxacyclooctadecane and sodium hydride into anhydrous DMF, stirring for 2-3 hours, heating to 80 ℃, dropwise adding epoxypropanol, stirring at 80 ℃ for 24 hours after the dropwise adding is finished, cooling to room temperature, adding deionized water, dialyzing a reaction product in the deionized water for 48 hours by using a dialysis bag, dialyzing in the anhydrous ethanol for 12 hours, and freeze-drying to obtain an intermediate product;
S2, adding the intermediate product, pyridine, paraaminobenzoyl chloride and DMF into a flask, reacting for 3-5h at 60 ℃, dialyzing the reaction product in deionized water for 48h by using a dialysis bag, dialyzing in absolute ethyl alcohol for 12h, and freeze-drying to obtain the hyperbranched modified cyclodextrin.
Beta cyclodextrin is a product produced by acidolysis cyclization of starch, the periphery of the beta cyclodextrin contains a large number of hydrophilic hydroxyl groups, the inner cavity has hydrophobicity, the inner cavity can be combined with a hydrophobic drug to improve the water solubility of the drug, but the beta cyclodextrin has relatively strong structural rigidity to ensure that the solubility of the beta cyclodextrin in water is very limited, so that the beta cyclodextrin is modified, firstly, hyperbranched polyether-shaped shells are formed on the surface of the beta cyclodextrin by utilizing anionic ring-opening polymerization reaction and then, aniline structures are introduced by utilizing esterification reaction to obtain hyperbranched modified cyclodextrin with high water solubility and strong embedding capacity.
Further, in the step S1, the dosage ratio of the beta cyclodextrin, the hexaoxolane octadecane, the sodium hydride, the anhydrous DMF, the glycidoxy and the deionized water is 0.6-0.8g:0.99-0.12g:0.4-0.6g:25-40mL:10.86mL:5-8mL.
Further, the ratio of the amounts of intermediate product, pyridine, paraaminobenzoyl chloride and DMF in step S2 was 10g:15-20mL:0.5-2g:150-200mL.
The aldehyde sodium alginate is obtained by the light-shielding reaction of sodium alginate and sodium periodate in an ethanol solution.
Further, the preparation steps of the aldehyde sodium alginate are as follows:
Adding sodium alginate into absolute ethyl alcohol, magnetically stirring to obtain a mixed solution a, adding sodium periodate into deionized water, uniformly stirring to obtain a mixed solution b, adding the mixed solution b into the mixed solution a, carrying out light-shielding reaction at 25 ℃ for 6 hours, adding ethylene glycol, stirring for 0.5 hour, pouring a reaction product into absolute ethyl alcohol, precipitating, removing a supernatant, pouring a precipitate at the lower layer into a dialysis bag, dialyzing with deionized water for 3d, and freeze-drying to obtain the hydroformylation sodium alginate.
Further, the mass ratio of the sodium alginate to the sodium periodate to the ethylene glycol is 10:9.89:2.8, the dosage ratio of sodium alginate to absolute ethyl alcohol in the mixed solution a is 1g:10mL, the dosage ratio of sodium periodate to deionized water in the mixed solution b is 1g:10mL.
Further, the water-soluble carrier is one or more of polyethylene glycol 200, polyethylene glycol 400 and polyethylene glycol 600.
Further, the stabilizer consists of pantothenic acid and vitamin B12 according to the mass ratio of 2-5: 1.
Further, the dispersant is hydroxypropyl methylcellulose.
Further, the air inlet temperature of spray drying is 180-220 ℃, the air outlet temperature is 75-95 ℃, and the sieving particle size is 100-180 mu m.
The application of the water-soluble carrier composition obtained by the preparation method in veterinary and fish culture.
The invention has the beneficial effects that:
the invention provides a preparation method of a water-soluble carrier composition, which is suitable for drinking water administration and disease treatment of livestock and poultry farmers and fish farmers by reasonably controlling the contents of florfenicol, hyperbranched modified cyclodextrin, deionized water, a water-soluble carrier, a stabilizer, a dispersing agent and an aldehyde sodium alginate component and the technological parameters of the preparation process, wherein the prepared water-soluble carrier composition has good water solubility and enteric solubility, improves the bioavailability of florfenicol, reduces the administration dosage and the administration volume.
Compared with the existing beta cyclodextrin, the branched polyether is introduced to effectively improve the hydrophilicity of the cyclodextrin, greatly improve the solubility of the cyclodextrin in water, indirectly extend the branched structure and enlarge the size of a beta cyclodextrin molecular cavity, provide more space for loading florfenicol, and provide additional interaction sites with the florfenicol by the structures such as benzene ring, amino and the like in the hyperbranched polymer, so that the interaction strength of the hyperbranched modified cyclodextrin and the florfenicol is improved, the inclusion rate of the florfenicol in the composition is improved, the florfenicol content is improved, the administration volume is reduced, and the stability of the medicine is improved.
Based on the characteristics of low cost, high biocompatibility, pH sensitivity (easy dissolution at high pH) and the like of sodium alginate, the invention ensures that sodium alginate and sodium periodate react in ethanol solution in a dark place to obtain aldehyde sodium alginate, improves the reactivity of the sodium alginate, utilizes the active aldehyde groups of the sodium alginate to combine with hyperbranched modified cyclodextrin and other components in the raw materials of the composition through condensation reaction to form a network structure to embed more florfenicol, further improves the drug loading capacity of the composition, and in addition, ensures good enteric solubility of the composition, reduces the dissolution of the composition in gastric juice and improves the bioavailability of the florfenicol.
Detailed Description
The technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In the following examples and comparative examples:
Sodium alginate: analytically pure, viscosity (200.+ -.20) mPa.S, aladdin company.
Example 1
The preparation method of the hyperbranched modified cyclodextrin comprises the following steps:
S1, adding 0.6g of beta cyclodextrin, 0.99g of hexaoxacyclooctadecane and 0.4g of sodium hydride into 25mL of anhydrous DMF, heating to 80 ℃ after stirring for 2 hours, dropwise adding 10.86mL of epoxypropanol, stirring for 24 hours at 80 ℃ after the dropwise adding is finished, cooling to room temperature, adding 5mL of deionized water, dialyzing a reaction product in deionized water for 48 hours by using a dialysis bag (the molecular weight cut-off is 3500), dialyzing in the anhydrous ethanol for 12 hours, and freeze-drying to obtain an intermediate product;
S2, adding 10g of intermediate product, 15mL of pyridine, 0.5g of paraaminobenzoyl chloride and 150mL of DMF into a flask, reacting for 3h at 60 ℃, dialyzing the reaction product in deionized water for 48h by using a dialysis bag (molecular weight cut-off is 3500), dialyzing in absolute ethyl alcohol for 12h, and freeze-drying to obtain the hyperbranched modified cyclodextrin.
Example 2
The preparation method of the hyperbranched modified cyclodextrin comprises the following steps:
S1, adding 0.8g of beta cyclodextrin, 0.12g of hexaoxacyclooctadecane and 0.6g of sodium hydride into 40mL of anhydrous DMF, heating to 80 ℃ after stirring for 3 hours, dropwise adding 10.86mL of epoxypropanol, stirring for 24 hours at 80 ℃ after the dropwise adding is finished, cooling to room temperature, adding 8mL of deionized water, dialyzing the reaction product in deionized water for 12 hours by using a dialysis bag (the molecular weight cut-off is 3500), dialyzing in absolute ethanol, and freeze-drying to obtain an intermediate product;
S2, adding 10g of intermediate product, 20mL of pyridine, 2g of paraaminobenzoyl chloride and 200mL of DMF into a flask, reacting for 5h at 60 ℃, dialyzing the reaction product in deionized water for 48h by using a dialysis bag (molecular weight cut-off is 3500), dialyzing in absolute ethyl alcohol for 12h, and freeze-drying to obtain the hyperbranched modified cyclodextrin.
Comparative example 1
The preparation method of the hyperbranched modified cyclodextrin comprises the following steps:
S1, adding 0.6g of beta cyclodextrin, 0.99g of hexaoxacyclooctadecane and 0.4g of sodium hydride into 25mL of anhydrous DMF, heating to 80 ℃ after stirring for 2 hours, dropwise adding 10.86mL of epoxypropanol, stirring for 24 hours at 80 ℃ after the dropwise adding is finished, cooling to room temperature, adding 5mL of deionized water, dialyzing a reaction product in deionized water for 48 hours by using a dialysis bag (with the molecular weight cut-off of 3500), dialyzing in the anhydrous ethanol for 12 hours, and freeze-drying to obtain the hyperbranched modified cyclodextrin.
Comparative example 2
The comparative example is beta cyclodextrin.
Example 3
The preparation method of the aldehyde sodium alginate comprises the following steps:
adding 10g of sodium alginate into 100mL of absolute ethyl alcohol, magnetically stirring to obtain a mixed solution a, adding 9.89g of sodium periodate into 98.9mL of deionized water, uniformly stirring to obtain a mixed solution b, adding the mixed solution b into the mixed solution a, carrying out light-shielding reaction for 6 hours at 25 ℃, adding 2.8g of ethylene glycol, stirring for 0.5 hour, pouring the reaction product into the absolute ethyl alcohol, precipitating, removing supernatant, pouring the precipitate at the lower layer into a dialysis bag (with the molecular weight cut-off of 3500), dialyzing for 3d with deionized water, and freeze-drying to obtain the hydroformylation sodium alginate.
Example 5
A method of preparing a water-soluble carrier composition comprising the steps of:
(1) 25g of florfenicol and 30g of hyperbranched modified cyclodextrin of example 1 are placed in a mixer for 5min to obtain composite powder, and 100g of deionized water at 75 ℃ is added into the composite powder to be stirred for 2-4h to obtain a component I;
(2) Adding 3g of water-soluble carrier, 1g of stabilizer and 5g of hydroxypropyl methyl cellulose into the first component, stirring for 2 hours at a constant temperature, adding 8g of the sodium alginate of the example 3, and stirring for 10 minutes to obtain a second component;
(3) Spray drying the mixture II, air temperature is 180deg.C, air outlet temperature is 75deg.C, sieving (particle diameter is 100-180 μm), and mixing to obtain water-soluble carrier composition.
Wherein the water-soluble carrier is polyethylene glycol 200, and the stabilizer consists of pantothenic acid and vitamin B12 according to the mass ratio of 2: 1.
Example 6
A method of preparing a water-soluble carrier composition comprising the steps of:
(1) 30g of florfenicol and 45g of hyperbranched modified cyclodextrin of example 1 are placed in a mixer for 8min to obtain composite powder, and 120g of deionized water at 80 ℃ is added into the composite powder to be stirred for 3h to obtain a component I;
(2) Adding 5g of water-soluble carrier, 1.5g of stabilizer and 8g of hydroxypropyl methylcellulose into the component I, stirring for 2.5h under heat preservation, adding 15g of the sodium alginate of the example 3, and stirring for 15min to obtain a component II;
(3) Spray drying the mixture two at 200deg.C with air temperature of 85deg.C, sieving (particle diameter of 100-180 μm), and mixing to obtain water-soluble carrier composition.
Wherein the water-soluble carrier is polyethylene glycol 400, and the stabilizer consists of pantothenic acid and vitamin B12 according to the mass ratio of 4: 1.
Example 7
A method of preparing a water-soluble carrier composition comprising the steps of:
(1) 35g of florfenicol and 60g of hyperbranched modified cyclodextrin of example 2 are placed in a mixer for 10min to obtain composite powder, and 150g of deionized water at 90 ℃ is added into the composite powder to be stirred for 4h to obtain a component I;
(2) Adding 8g of water-soluble carrier, 2g of stabilizer and 10g of hydroxypropyl methylcellulose into the first component, stirring for 3h under heat preservation, adding 20g of aldehyde sodium alginate of example 3, and stirring for 20min to obtain a second component;
(3) Spray drying the mixture II, wherein the air temperature is 220 ℃, the air outlet temperature is 95 ℃, sieving (the particle size is 100-180 μm), and mixing to obtain the water-soluble carrier composition.
Wherein the water-soluble carrier is polyethylene glycol 600, and the stabilizer consists of pantothenic acid and vitamin B12 according to the mass ratio of 5: 1.
Comparative example 3
A method for preparing a water-soluble carrier composition, compared with example 5, the hyperbranched modified cyclodextrin in example 5 is replaced by the product prepared in comparative example 1, and the rest raw materials and the preparation process are the same as in example 5.
Comparative example 4
In comparison with example 5, the hyperbranched modified cyclodextrin in example 5 was replaced with the material in comparative example 2, and the remaining raw materials and the preparation process were the same as in example 5.
Comparative example 5
A preparation method of a water-soluble carrier composition is compared with example 5, aldehyde sodium alginate in example 5 is removed, and other raw materials and preparation processes are the same as in example 5.
Dissolution experiments were performed on the water-soluble carrier compositions obtained in example 5-example 7 and comparative example 3-comparative example 5, as follows: (1) 6 200mL beakers were prepared, numbered example 5, example 6, example 7, comparative example 3, comparative example 4, comparative example 5, each containing 100mL of purified water (25 ℃ C.) for use; (2) 1.5g of the composition corresponding to each test group is added into a beaker, stirred by a glass rod until the composition is completely clear, and the dissolution effect is observed; then, each test group is continuously added and stirred into a beaker until the test group cannot be completely dissolved, the weight of the added composition of each test group is recorded, the percentage content of florfenicol in the composition of each group is calculated according to the mass percentage, the content of florfenicol which can be maximally dissolved is calculated, and the test results are shown in table 1:
TABLE 1
From the data in Table 1, it can be seen that the compositions prepared in examples 5-7 of the present invention have a higher maximum solubility of florfenicol in water, and that example 7 works best.
(II) performing inclusion rate detection on the water-soluble carrier compositions obtained in example 5-example 7 and comparative example 3-comparative example 5, and referring to an inclusion rate test method disclosed in Chinese patent CN112641954B, wherein inclusion rate (%) = (mass of florfenicol in composition/mass of florfenicol raw material) ×100%, a mass measurement method of florfenicol in composition is the same as a florfenicol content measurement method in inclusion compound in the patent, and test results are shown in Table 2:
TABLE 2
| Project | Example 5 | Example 6 | Example 7 | Comparative example 1 | Comparative example 2 | Comparative example 3 |
| Inclusion rate (%) | 98.1 | 98.7 | 98.9 | 96.5 | 90.2 | 92.4 |
From the examination data in Table 2, it can be seen that the compositions prepared in examples 5 to 7 of the present invention have a higher inclusion rate of florfenicol.
(III) gastrointestinal sustained release test was performed on the water-soluble carrier compositions obtained in example 5-example 7 and comparative example 3-comparative example 5:
firstly, preparing two dissolution media; preparing artificial gastric juice: taking 16.4mL of dilute hydrochloric acid, adding 800mL of water and 10g of pepsin, shaking uniformly, and then adding water to dilute to 100mL to obtain the aqueous solution; preparing artificial intestinal juice: taking 6.8g of monopotassium phosphate, adding 500mL of water to dissolve, adjusting the pH value to 6.8 by using 0.1mol/L sodium hydroxide solution, taking 10g of pancreatin, adding a proper amount of water to dissolve, mixing the two solutions, and adding water to dilute to 1000mL to obtain the potassium dihydrogen phosphate;
According to the first method of the second edition of the appendix XC of the second edition of the pharmacopoeia of the people's republic of China, 900mL of corresponding dissolution media are respectively taken and placed in each dissolution cup, the temperature is raised to (37+/-0.5), 6 parts (0.3 g each part) of test sample is respectively placed in a dissolution basket of a dissolution instrument after constant temperature, the rotation speed is regulated to 100r/min, sampling is respectively carried out when the rotation basket is started for 10, 30, 60min and 2, 4, 6, 8 and 12 hours (simultaneously, the equivalent dissolution media are respectively added, 0.1mol/L of hydrochloric acid solution mL is taken as a release medium in the first 2 hours, and then 0.2mol/L of sodium phosphate solution is added for 250mL after 2 hours, so that the pH value of the release medium is 6.8), filtering is carried out, and the peak area A is measured at 224nm of the subsequent filtrate. The concentration of the released solution was calculated according to the standard curve equation, and the cumulative drug release percentage was calculated, and the test results are shown in table 3:
TABLE 3 Table 3
From the examination data in Table 3, it can be seen that florfenicol in the compositions prepared in examples 5 to 7 of the present invention has a good enteric effect.
It is noted that relational terms such as first and second, and the like are used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Moreover, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (8)
1. A method of preparing a water-soluble carrier composition comprising the steps of:
(1) Florfenicol and hyperbranched modified cyclodextrin are placed in a mixer for 5-10min to obtain composite powder, and the composite powder is added into deionized water at 75-90 ℃ and stirred for 2-4h to obtain a component I;
(2) Adding a water-soluble carrier, a stabilizer and a dispersing agent into the first component, carrying out heat preservation and stirring for 2-3 hours, then adding aldehyde sodium alginate, and stirring for 10-20 minutes to obtain a second component;
(3) Spray drying, sieving, and mixing to obtain water-soluble carrier composition;
Wherein, the mass ratio of florfenicol, hyperbranched modified cyclodextrin, deionized water, a water-soluble carrier, a stabilizer, a dispersing agent and aldehyde sodium alginate is 25-35:30-60:100-150:3-8:1-2:5-10:8-20.
2. The method of preparing a water-soluble carrier composition according to claim 1, wherein the hyperbranched modified cyclodextrin is aniline-terminated hyperbranched polyether grafted beta cyclodextrin.
3. The method of preparing a water-soluble carrier composition according to claim 1, wherein the hyperbranched modified cyclodextrin is prepared by the steps of:
S1, adding beta cyclodextrin, hexaoxacyclooctadecane and sodium hydride into anhydrous DMF, stirring for 2-3 hours, heating to 80 ℃, dropwise adding epoxypropanol, stirring for 24 hours at 80 ℃ after the dropwise adding is finished, cooling to room temperature, adding deionized water, dialyzing, and freeze-drying to obtain an intermediate product;
s2, adding the intermediate product, pyridine, paraaminobenzoyl chloride and DMF into a flask, reacting for 3-5h at 60 ℃, dialyzing the reaction product, and freeze-drying to obtain the hyperbranched modified cyclodextrin.
4. A method of preparing a water-soluble carrier composition according to claim 3, wherein the dosage ratio of β -cyclodextrin, hexaoxolane octadecane, sodium hydride, anhydrous DMF, glycidol and deionized water in step S1 is 0.6-0.8g:0.99-0.12g:0.4-0.6g:25-40mL:10.86mL:5-8mL.
5. A process for the preparation of a water-soluble carrier composition as claimed in claim 3, wherein the ratio of the amounts of intermediate product, pyridine, paraaminobenzoyl chloride and DMF used in step S2 is 10g:15-20mL:0.5-2g:150-200mL.
6. A method for preparing a water-soluble carrier composition according to claim 3, wherein the aldehyde sodium alginate is obtained by reacting sodium alginate and sodium periodate in ethanol solution in the absence of light.
7. The method of claim 1, wherein the water-soluble carrier is one or more of polyethylene glycol 200, polyethylene glycol 400, and polyethylene glycol 600.
8. Use of a water-soluble carrier composition prepared by the method of any one of claims 1-7 in veterinary and fish farming.
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