CN103751196B - Ceftiofur hydroxypropyl-beta-cyclodextrin inclusion and preparation method thereof - Google Patents
Ceftiofur hydroxypropyl-beta-cyclodextrin inclusion and preparation method thereof Download PDFInfo
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- CN103751196B CN103751196B CN201410008732.5A CN201410008732A CN103751196B CN 103751196 B CN103751196 B CN 103751196B CN 201410008732 A CN201410008732 A CN 201410008732A CN 103751196 B CN103751196 B CN 103751196B
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- 229960005229 ceftiofur Drugs 0.000 title claims abstract description 51
- ZBHXIWJRIFEVQY-IHMPYVIRSA-N ceftiofur Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC(=O)C1=CC=CO1 ZBHXIWJRIFEVQY-IHMPYVIRSA-N 0.000 title claims abstract description 50
- 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 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 239000000843 powder Substances 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000003814 drug Substances 0.000 abstract description 13
- 229940079593 drug Drugs 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 5
- 230000003647 oxidation Effects 0.000 abstract description 5
- 238000007254 oxidation reaction Methods 0.000 abstract description 5
- 239000007787 solid Substances 0.000 abstract description 5
- 238000013270 controlled release Methods 0.000 abstract description 3
- 230000007062 hydrolysis Effects 0.000 abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 3
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 238000005286 illumination Methods 0.000 abstract description 2
- 238000002441 X-ray diffraction Methods 0.000 description 10
- 238000002156 mixing Methods 0.000 description 6
- 229920000858 Cyclodextrin Polymers 0.000 description 5
- 239000006069 physical mixture Substances 0.000 description 5
- 238000011160 research Methods 0.000 description 4
- 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 description 4
- WCZBUQIZTSIQFE-UHFFFAOYSA-N furan;thiophene Chemical compound C=1C=COC=1.C=1C=CSC=1 WCZBUQIZTSIQFE-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000031700 light absorption Effects 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 229910016523 CuKa Inorganic materials 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 108090000279 Peptidyltransferases Proteins 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229910052593 corundum Inorganic materials 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 238000004455 differential thermal analysis Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 230000003028 elevating effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000686 essence Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 229910001845 yogo sapphire Inorganic materials 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses the preparation method of a kind of ceftiofur and the solid clathrates of hydroxypropyl beta cyclodextrin, by ceftiofur and hydroxypropyl beta cyclodextrin using the mol ratio of 1:1 ~ 3 as reaction raw materials, at 20 50 DEG C, add the water of reaction raw materials gross weight 5 times amount and grind 2 5h, then 12h it is vacuum dried, filter, obtain white powder,.The formation of clathrate of the present invention can effectively protect compound to avoid the reactions such as oxidation or hydrolysis, also increases the water solublity of medicine, enhanced stability simultaneously, reduces toxic and side effects, and Drug controlled release improves bioavailability.Ceftiofur β CD clathrate prepared by the present invention can improve dissolubility and the bioavailability of ceftiofur crude drug.The clathrate prepared, at illumination, high temperature, can significantly improve the oxidation resistance of crude drug under damp condition, the exploitation that this is ceftiofur novel form provides a kind of very effective means.
Description
Technical field
The present invention relates to the clathrate of a kind of ceftiofur.
Background technology
Ceftiofur be the eighties in 20th century exploitation mainly for third generation cephalosporin for animals.Its mechanism of action is to make
Block the synthesis of cell wall for bacterial transpeptidase, present bactericidal action, be used for treating and control the bacillary intestinal of domestic animal and
Respiratory tract infection.Owing to the water solublity of ceftiofur is very poor, and there is a lot of problem in existing ceftiofur formulation, thus grinds
Fixture has good ceftiofur novel formulation to be always the focus that researcher is paid close attention to.Along with the development of related science technical field,
The research of antibacterials dosage form just develops towards efficient, targeting, intelligentized direction, and it is little, malicious that preferable dosage form should have dosage
Property little, advantage that side effect is little, the good news is that the drug-supplying system with slow-release controlled-release, targeting as representative has shown good sending out
Exhibition prospect.Hydrophobic outer hydrophilic structure in there is uniqueness due to cyclodextrin and the guest molecule suitable with many sizes forms bag
Compound, can form liquid inclusion complex by cyclodextrin to ceftiofur inclusion.Compound can be effectively protected in the formation of clathrate
Avoid the reactions such as oxidation or hydrolysis, also increase the water solublity of medicine, enhanced stability simultaneously, reduce toxic and side effects, control medicine
Release improves bioavailability.Recently, the research in terms of cyclodextrin is used for improving the physical chemistry of medicine and biological property should
With increasingly being paid close attention to by people.Particularly it is used for improving stability and the bioavailability of dewatering medicament, has some solution
The report of middle clathration, and the preparation of cyclodextrin ceftiofur solid clathrates and property Quality Research thereof have no report.Cephalo
Thiophene furan is atomic is dissolved in water, limits its range of application.Utilize the construction features of beta-schardinger dextrin-, both are prepared as ceftiofur-β-
Cyclodextrin clathrate, can improve ceftiofur dissolubility in water, have good clinical value.
Summary of the invention
The technical problem to be solved in the present invention is to overcome existing defect, it is provided that a kind of ceftiofur hydroxy propyl-Beta-ring
Dextrin solid clathrates；
The preparation method of another object of the present invention above-mentioned ceftiofur HP-β-CD solid clathrates.
The purpose of the present invention implements by the following technical programs:
A kind of preparation method of ceftiofur and the clathrate of HP-β-CD (HP-β-CD), by ceftiofur and
HP-β-CD, using the mol ratio of 1:1 ~ 3 as reaction raw materials, adds reaction raw materials gross weight 5 times amount at 20-50 DEG C
Water and grind 2-5h, be then vacuum dried 12h, filter, obtain white powder,.
Preferably, ceftiofur: the mol ratio of HP-β-CD is 1:2.
Preferably, temperature is 40 DEG C.
Preferably, milling time is 4h.
A kind of ceftiofur hydroxypropyl-beta-cyclodextrin inclusion, with HP-β-CD as outer casing framework, cephalo thiophene
Furan molecule is by inclusion wherein.
Preferably, above-mentioned ceftiofur hydroxypropyl-beta-cyclodextrin inclusion, according to above-mentioned method preparation
Become.
Beneficial effect:
The formation of clathrate of the present invention can effectively protect compound to avoid the reactions such as oxidation or hydrolysis, also increases medicine simultaneously
The water solublity of thing, enhanced stability, reduce toxic and side effects, Drug controlled release improves bioavailability.Head prepared by the present invention
Spore thiophene furan-beta-CD inclusion can improve dissolubility and the bioavailability of ceftiofur crude drug.The clathrate prepared exists
Illumination, high temperature, the oxidation resistance of crude drug can be significantly improved under damp condition, this is that the exploitation of ceftiofur novel form carries
For a kind of very effective means.Meanwhile, present invention achieves solid clathrates and formed, can effectively open up ceftiofur
Application.
Accompanying drawing explanation
Accompanying drawing is for providing a further understanding of the present invention, and constitutes a part for description, with the reality of the present invention
Execute example together for explaining the present invention, be not intended that limitation of the present invention.In the accompanying drawings:
Fig. 1 is the standard curve of variable concentrations ceftiofur uv absorption, wherein, A trap, C drug level；
Fig. 2 is means of differential scanning calorimetry figure (DTA curve), wherein, a. ceftiofur; b. HP-β-CD;C. physical mixed
Thing;D. clathrate；
Fig. 3 is ceftiofur (a) x-ray diffraction pattern, horizontal is designated as x-ray diffraction angle/(°)；
Fig. 4 is HP-β-CD (b) x-ray diffraction pattern, horizontal is designated as x-ray diffraction angle/(°)；
Fig. 5 is physical mixture (c) x-ray diffraction pattern, horizontal is designated as x-ray diffraction angle/(°)；
Fig. 6 is clathrate (d) x-ray diffraction pattern, horizontal is designated as x-ray diffraction angle/(°).
Detailed description of the invention
Below in conjunction with accompanying drawing, the preferred embodiments of the present invention are illustrated, it will be appreciated that preferred reality described herein
Execute example be merely to illustrate and explain the present invention, be not intended to limit the present invention.
One, Phase solubility method research
Low concentration system, dilution effect makes the HP-β-CD (HP-β-CD) shadow to ceftiofur uv absorption
Sound can be ignored.Gained standard curve is Y=0.0279X+0.0118 (R2=0.9997) (Fig. 1).
According to standard curve result, when HP-β-CD concentration is 0, ceftiofur intrinsic solubility is equal to 4.70 × 10- 7mol/L。
Two, inclusion condition optimizing
1, the raw material different proportion impact on inclusion
Ceftiofur and HP-β-CD (HP-β-CD), temperature is 40 DEG C, time 4h, with 1:2 mol ratio
During mixing, light absorption value difference maximum, the probability that thus both result promptings carry out inclusion with 1:2 ratio is maximum.It is shown in Table 1.
The different proportion HP-β-cdinclusion ultraviolet absorptivity of table 1 ceftiofur is poor
。
2, the reaction temperature impact on inclusion
When ceftiofur and HP-β-CD are with 1:2 mixed in molar ratio, time 4h, 40 DEG C of light absorption value differences of mixing temperature
Maximum, thus result prompting mixing temperature 40 DEG C carries out the probability maximum of inclusion, is shown in Table 2.
When table 2 ceftiofur is 1:2 than HP-β-CD, mixing temperature inclusion ultraviolet absorptivity is poor
。
3, the response time impact on inclusion
When ceftiofur and HP-β-CD are with 1:2 mixed in molar ratio, mixing temperature 40 DEG C, the response time is 4h extinction
Value difference maximum, thus the result prompting hybrid reaction time is the probability maximum that 4h carries out inclusion, is shown in Table 3.
Table 3 ceftiofur and HP-β-CD are that response time inclusion ultraviolet absorptivity is poor
。
Note: mixing temperature 40 DEG C when ceftiofur is 1:2 than HP-β-CD.
Three, the Discriminating materials of clathrate
1, differential thermal analysis
Take ceftiofur, HP-β-CD, clathrate, four kinds of samples of physical mixture carry out differential scanning calorimeter: with
Al2O3 is reference, weighs about 5.0mg sample, and range is ± 25 V, and temperature elevating range is 40-400 DEG C, and heating rate is 10
DEG C/min, make DTA collection of illustrative plates, see Fig. 2, wherein, a. ceftiofur; b. HP-β-CD;C. ceftiofur and HP-β-CD
Physical mixture;D. spore thiophene furan and the clathrate of HP-β-CD.
As shown in Fig. 2, ceftiofur has a melting peak at about 203.8 DEG C, HP-β-CD at 80.6 DEG C and
It is respectively arranged with a peak at 310.6 DEG C, is the dehydration endotherm peak of HP-β-CD and melted-decomposition peak respectively.Mixture maintains HP-
β-CD and the endothermic peak of ceftiofur, the substantially superposition of single compound collection of illustrative plates, and each peak on the collection of illustrative plates of clathrate
Position and shape all there occurs change, thus it is speculated that clathrate is formed.
2, X-ray diffraction analysis
Test condition is: CuKa target, high pressure 5kV, pipe flow 20mA, 4 ° of min-1 of scanning speed, sweep limits 5-
40°。
X ray diffraction results is shown in that Fig. 3-6, ceftiofur (a) and HP-β-CD (b) have visibly different diffraction maximum,
In physical mixture (c), the diffraction maximum of existing HP-β-CD, has again the diffraction maximum of ceftiofur, be ceftiofur and HP-β-
The diffraction maximum superposition of CD.Clathrate (d) is different from physical mixture, and the Partial Feature diffraction maximum of ceftiofur disappears or position
Move, show really to define clathrate, and d has the crystal formation different from a and b.
Four, brief summary:
The HYDROXYPROPYL BETA-CYCLODEXTRIN (HP-β-CD) of ceftiofur is according to result above i.e.: ceftiofur is raw material, passes through
With HP-β-CD with suitable mol ratio 1:2,400Add a small amount of water under C and grind 4h, be then vacuum dried 12h, filter, obtain white
Color powder, for optimum condition, completes the preparation of inclusion and clathrate.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, although with reference to aforementioned reality
Executing example to be described in detail the present invention, for a person skilled in the art, it still can be to aforementioned each enforcement
Technical scheme described in example is modified, or wherein portion of techniques feature is carried out equivalent.All essences in the present invention
Within god and principle, any modification, equivalent substitution and improvement etc. made, should be included within the scope of the present invention.
Claims (2)
1. the preparation method of a ceftiofur and the clathrate of HP-β-CD, it is characterised in that: by ceftiofur and
HP-β-CD, using the mol ratio of 1:2 as reaction raw materials, adds the water of reaction raw materials gross weight 5 times amount at 40 DEG C
And grind 4h, then it is vacuum dried 12h, filters, obtain white powder,.
2. a ceftiofur hydroxypropyl-beta-cyclodextrin inclusion, it is characterised in that: described clathrate is according to claim 1 institute
The method stated is prepared from.
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|---|---|---|---|
| CN201410008732.5A CN103751196B (en) | 2014-01-08 | 2014-01-08 | Ceftiofur hydroxypropyl-beta-cyclodextrin inclusion and preparation method thereof |
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| CN103751196B true CN103751196B (en) | 2016-08-17 |
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| CN104524585B (en) * | 2014-12-08 | 2018-11-09 | 悦康药业集团有限公司 | Cefathiamidine composition |
| CN104489268A (en) * | 2014-12-09 | 2015-04-08 | 中国农业科学院兰州畜牧与兽药研究所 | Micro-ecological preparation and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102462686A (en) * | 2010-11-05 | 2012-05-23 | 天津瑞普生物技术股份有限公司 | Pharmaceutical composition used for preventing and treating colibacillosis in livestock and poultry |
| CN103230364A (en) * | 2013-05-13 | 2013-08-07 | 青岛农业大学 | Preparation method of ceftiofur acid long-acting injection |
-
2014
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102462686A (en) * | 2010-11-05 | 2012-05-23 | 天津瑞普生物技术股份有限公司 | Pharmaceutical composition used for preventing and treating colibacillosis in livestock and poultry |
| CN103230364A (en) * | 2013-05-13 | 2013-08-07 | 青岛农业大学 | Preparation method of ceftiofur acid long-acting injection |
Non-Patent Citations (1)
| Title |
|---|
| β-环糊精对头孢噻呋盐酸盐的增溶作用;姜静等;《中国兽医杂志》;20071231;第43卷(第12期);第87-88页 * |
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Denomination of invention: Cefotaxifur hydroxypropyl - b - cyclodextrin inclusion complex and its preparation method Granted publication date: 20160817 Pledgee: Bank of China Limited Sheqi Branch Pledgor: HENAN HUA MU BIOLOGICAL TECHNOLOGY Co.,Ltd. Registration number: Y2024980021100 |