CN101829063B - Lung targeting microsphere of veterinary ceftiofur hydrochloride and preparation method - Google Patents
Lung targeting microsphere of veterinary ceftiofur hydrochloride and preparation method Download PDFInfo
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- CN101829063B CN101829063B CN2010101263951A CN201010126395A CN101829063B CN 101829063 B CN101829063 B CN 101829063B CN 2010101263951 A CN2010101263951 A CN 2010101263951A CN 201010126395 A CN201010126395 A CN 201010126395A CN 101829063 B CN101829063 B CN 101829063B
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Abstract
The invention provides a lung targeting microsphere of veterinary ceftiofur hydrochloride and a preparation method and can solve the problems of harmful toxic and side effects on a tissue due to the increased concentrations of other tissues caused by the low tissue selectivity of medicaments and poor therapeutic effect of the medicaments in the prior art. The lung targeting microsphere adopts the technical scheme of taking ceftiofur hydrochloride as a raw material and glutin as a carrier, wherein the weight ratio of the ceftiofur hydrochloride to the glutin is 1:3 to 30. The invention further provides the preparation method of the lung targeting microsphere. The lung targeting microsphere has the advantages of higher medicament loading rate and encapsulation rate of over 60 percent; after separation, the grain diameter of over 92 percent of the microsphere is between 7 and 30 mu m, so that the lung targeting microsphere meets the grain diameter requirement, improves the tissue selectivity, targets to the lung, reduces the concentrations of the medicaments in other tissues and toxic and side effects, and efficiently treats the pulmonary infection of animals.
Description
Technical field
The invention belongs to antibiotic formulations technical field for animals, specifically, relate to a kind of lung-targeted microspheres and method for preparing of ceftiofur hydrochloride.
Background technology
Ceftiofur has another name called Sai Defu (ceftiofur); It is a kind of cephalosporins; Has a broad antifungal spectrum, antibacterial activity are strong, are the ceftiofur class antibiotic of first animal specific of U.S. Pharmacia S.P.A. initiative, since being used to treat the respiratory system infection of cattle by the FDA approval in 1988; Because of its good antibacterial activity and body internal dynamics process, the application on the now domestic and international veterinary clinic is extensive day by day.
Ceftiofur is the soda acid amphoteric compound, can generate acid soluble-salt and alkali soluble property salt with sodium hydroxide and hydrochloric acid reaction, and the dried powder of its sodium salt and hydrochlorate is very stable.Because the above-mentioned advantage that ceftiofur has has bigger antibacterial activity to clinical and reference culture; Have stable beta-lactam nucleus, be difficult for producing drug resistance and cross resistance, especially can be used for being prone to produce chemical sproof infection of staphylococcus aureus,, be recommended as antimicrobial choice drug by many experts in extensive use all over the world.This medicine is pass on peptidase and is blocked the synthetic of mucopeptide through acting on, and mucopeptide is the important composition composition of bacteria cell wall, and the death so can make the bacteria cell wall disappearance can reach the effect of quick sterilization.
But owing to use widely for a long time, many pathogen have produced certain drug resistance to ceftiofur, thereby cause the reduction of medication effect.As during pulmonary disease, making medicine reach valid density in lung tissue in treatment, certainly will to increase the dosage of medicine, cause medicine residual raising and produce some in its hetero-organization thus easily to the deleterious toxic and side effects of body.
The administration of lung targeting preparation can concentrate on lung tissue to greatest extent with medicine, and medicine is concentrated in pulmonary, exceeds several times and even hundreds of times of conventional formulation, and therapeutic effect can obviously improve; Reduce amount of drug simultaneously, can be convenient to control the speed and the mode of administration, also can reduce the untoward reaction of medicine, reach the therapeutic effect of high-efficiency low-toxicity.In addition, because targeting preparation has improved antimicrobial efficiency, therefore might reduce the possibility that antibacterial develops immunity to drugs to medicine, thereby prolong the time that veterinary clinic more effectively uses antimicrobial drug.
Therefore how to solve the veterinary ceftiofur ordinary preparation because the drug dose increase causes medicine residual raising and producing to the deleterious toxic and side effects of body and because secular use in its hetero-organization; Many antibacterials develop immunity to drugs to medicine; The problem that causes medication effect to reduce; And a kind of ceftiofur lung targeting preparation is provided, then be problem of the present invention.
Summary of the invention
The invention provides a kind of lung-targeted microspheres and method for preparing of veterinary ceftiofur hydrochloride, thereby can solve the low bad problem of therapeutic effect that body is produced deleterious toxic and side effects and medicine in the concentration raising of its hetero-organization that causes of the tissue selectivity owing to medicine that prior art exists.
For solving the problems of the technologies described above, the present invention adopts following technical proposals to be achieved,
A kind of lung-targeted microspheres of veterinary ceftiofur hydrochloride, said microsphere is a raw material with the ceftiofur hydrochloride, is carrier with the gelatin, the weight ratio of ceftiofur hydrochloride and gelatin is 1 ︰ 3 ~ 30.Gelatin is a kind of natural biological macromolecular material, has biodegradability preferably in vivo, and the gelatin wide material sources, and price is lower, and therefore the industrial potentiality of realization are arranged.
For the particle size range of the microsphere that makes preparation realizes the requirement of lung targeting, the particle size range of said microsphere is 7～30 μ m, reaches the requirement of lung-targeted microspheres to particle diameter.According to 419 pages on textbook " pharmaceutics ", held back with the mechanical filter mode by the thin vascular bed of fine, soft fur of pulmonary usually greater than the microsphere of 7 ~ 10 μ m, thereby reach the lung targeting.
A kind of method for preparing of lung-targeted microspheres of veterinary ceftiofur is characterized in that Bao draws together Bu Zhou ︰ under the Ru
1) be that the ratio of 1 ︰ 3 ~ 30 takes by weighing ceftiofur hydrochloride and gelatin respectively according to weight ratio, gelatin swelling in 40 ~ 50 ℃ of water is complete, ceftiofur hydrochloride is dissolved in the gelatin solution, ultrasonic it is disperseed fully;
2) measure certain quantity of fluid paraffin in conical flask, add emulsifying agent, place 40 ~ 50 ℃ of water-baths to disperse fully, the volume ratio of above-mentioned ceftiofur hydrochloride and gelatin mixed solution and liquid paraffin is 1:5 ~ 1:40;
The gelatin solution that 3) will be dissolved with ceftiofur hydrochloride dropwise joins in the conical flask, under 700 ~ 1900rpm rotating speed, 40 ~ 50 ℃ of stirring and emulsifying 10 ~ 20min, after change emulsifying 25 ~ 45min in the ice bath over to;
4) add volumetric concentration 1 ~ 7% glutaraldehyde solution and solidify 0.5 ~ 2h; The glycine solution reaction 20 ~ 40min that adds respective concentration, unreacted aldehyde radical in the shielding glutaraldehyde;
5) in above-mentioned solution, add isopropyl alcohol, dehydration 20 ~ 50min, the volume ratio 1:5 of gelatin solution and isopropyl alcohol ~ 1:20; Add acetone behind the sucking filtration, acetone and liquid paraffin volume ratio 2:10 ~ 6:10, sucking filtration repeats for several times, up to removing liquid paraffin fully;
6) disperse the back to screen microsphere with sub-sieve with acetone, the liquid sucking filtration that lower screen is selected is removed drying at room temperature behind the acetone, promptly gets lung-targeted microspheres.
Further, above-mentioned steps 2) in the volume ratio of ceftiofur hydrochloride and gelatin mixed solution (water) and liquid paraffin (oil phase) be preferred 1:10 ~ 1:30.
Further, above-mentioned steps 2) in emulsifying agent adopt Span80, Tween80.
Further, said gelatin concentration scope is 5% ~ 20%.The concentration here is meant the quality of gelatin and the ratio of the volume of water, i.e. 1g/100ml;
Further, the aperture of said sub-sieve is 400 orders.Because the particle size range of lung-targeted microspheres is 7～30 μ m, for the microsphere that makes preparation reaches this particle size range, realize the requirement of lung targeting, the use aperture is that the sub-sieve of 400 orders (being that the aperture is 37.5 μ m) carries out sorting to microsphere.
Microspherulite diameter narrow distribution after the sorting, more than 92% all in the zone of 7～30 μ m.The method that the present invention adopts is an emulsion process, and the microsphere form of this method preparation is regular, globulate, and envelop rate is more than 60%, and drug loading is between 1.94 ~ 17%, and medicine can slowly discharge and reach 48h.
Compared with prior art, the present invention has the following advantages and Ji utmost point Xiao Guo ︰
The present invention is a carrier through adopting gelatin, and the embedding ceftiofur hydrochloride is processed the lung-targeted microspheres of ceftiofur hydrochloride, and microsphere drug loading and envelop rate are all higher, and envelop rate can reach more than 60%, and drug loading is between 1.94 ~ 17%; The particle diameter of microsphere all between 7 ~ 30 μ m, therefore reaches the requirement of lung-targeted microspheres to particle diameter more than 92% after the sorting, has improved the tissue selectivity of medicine; Reduce the concentration of medicine at its hetero-organization; Targeting delays drug release in pulmonary, heightens the effect of a treatment; Reduce toxic and side effects, thus the pulmonary infection of treating animal efficiently.
The specific embodiment
Below in conjunction with examples of implementation the present invention is made further detailed description.
Embodiment 1
A kind of method for preparing step of lung-targeted microspheres of veterinary ceftiofur hydrochloride is following:
1) preparation of microsphere
Accurately weighing 1g gelatin swelling in 50 ℃ of water of 5ml is complete, takes by weighing the 0.33g ceftiofur hydrochloride and joins in the gelatin solution, and it is dissolved fully; Simultaneously, measure the 150ml liquid paraffin in conical flask, add 2ml emulsifying agent Span80, place 50 ℃ of water-baths to disperse fully; The gelatin solution that is dissolved with ceftiofur hydrochloride is dropwise joined in the conical flask, 1900rpm, 50 ℃ of stirring and emulsifying 20min, after change emulsifying 45min in the ice bath over to; The glutaraldehyde solution that adds 4.5ml7% (volume ratio) solidifies 0.5h; The glycine solution reaction 40min that adds respective concentration, unreacted aldehyde radical in the shielding glutaraldehyde; Add 100ml isopropanol dehydration 20min; Add acetone 30ml behind the sucking filtration and remove liquid paraffin; Disperse the back with 400 order sub-sieve sorting microspheres once more with acetone behind the sucking filtration, drying at room temperature gets microsphere behind the sucking filtration.
2) the microsphere outward appearance is observed
The microsphere of method for preparing, scanning electron microscope show that its mode of appearance is better, and the microsphere dispersibility is better, and be less sticking.
3) mensuration of microspherulite diameter
The mean diameter of dynamic light scattering determination microsphere is 25.44 μ m, and particle size distribution is narrower, and 92% all in 7～30 mu m ranges.
4) research of medicine carrying performance
With the drug loading of high performance liquid chromatogram mensuration microsphere, the sample treatment step accurately takes by weighing 5mg microsphere sample Wei ︰, in centrifuge tube, adds 3ml 0.02M Na
2HPO
4Solution, the ultrasonic 30min of water-bath places shaking table to shake 2h, and the centrifugal 15min of 5000rpm gets supernatant water membrane filtration sample detection.Calculate drug loading LE% and envelop rate EE% according to formula (1) formula (2).
formula (1)
Calculate the microsphere drug loading and reach 16.06%, envelop rate reaches 64.25%.
The medicine dissolution rate is measured
Measure the external medicine dissolution rate of microsphere with dialysis; Step is following: accurately take by weighing the 10.0mg medicine carrying microballoons respectively; As buffer medium, using 37 ℃ of constant temperature shaking tables is the research of carrying out the medicine dissolution rate under 50 rotating speeds (rpm) at rotating speed with the PBS 60ml of pH7.4.Using molecular cut off is the stripping of dialysing of the bag filter of 8000 ~ 14000Da.Regularly each sampling 5ml in the pro-12h, and add isopyknic blank buffer solution immediately, every 12h afterwards changes the outer dialysis solution of bag filter, measures absorbance value, tries to achieve the medicine stripping quantity according to standard curve, can get dissolution rate.The medicine ceftiofur hydrochloride that records in the microsphere that embodiment 1 makes can slowly discharge 48h external, and dissolution rate is comparatively steady.
Embodiment 2
Accurately weighing 0.25g gelatin swelling in 40 ℃ of water of 5ml is complete, takes by weighing the 0.0083g ceftiofur hydrochloride and joins in the gelatin solution, and is complete to dissolving; Simultaneously, measure the 50ml liquid paraffin in conical flask, add 1ml emulsifying agent Span80, place 40 ℃ of water-baths to disperse fully; The gelatin solution that is dissolved with medicine is dropwise joined in the conical flask, 700rpm, 40 ℃ of stirring and emulsifying 10min, after change emulsifying 25min in the ice bath over to; The glutaraldehyde solution that adds 4.5ml 1% (volume ratio) solidifies 2h; The glycine solution reaction 20min that adds respective concentration, unreacted aldehyde radical in the shielding glutaraldehyde; Add 25ml isopropanol dehydration 50min; Add acetone 30ml behind the sucking filtration and remove liquid paraffin; Disperse the back with sub-sieve sorting microsphere, drying at room temperature behind the sucking filtration once more with acetone behind the sucking filtration.
The microsphere of method for preparing, according to the performance of the detection of method described in the embodiment 1 microsphere, scanning electron microscope shows that its mode of appearance is better; The mean diameter of microsphere is 23.93 μ m; And particle size distribution is narrower, and 93% all in 7～30 mu m ranges, and drug loading reaches 1.94%; Envelop rate reaches 60.17%, and external medicine stripping can reach 48h.
Embodiment 3
Accurately weighing 0.5g gelatin swelling in 50 ℃ of water of 2.5ml is complete, takes by weighing the 0.1g ceftiofur hydrochloride and joins in the gelatin solution, and is complete to dissolving; Simultaneously, measure the 50ml liquid paraffin in conical flask, add 1ml emulsifying agent Span80, place 50 ℃ of water-baths to disperse fully; The gelatin solution that is dissolved with medicine is dropwise joined in the conical flask, 1700rpm, 50 ℃ of stirring and emulsifying 15min, after change emulsifying 30min in the ice bath over to; The glutaraldehyde solution that adds 4.5ml 2% (volume ratio) solidifies 1h; The glycine solution reaction 30min that adds respective concentration, unreacted aldehyde radical in the shielding glutaraldehyde; Add 20ml isopropanol dehydration 30min; Add acetone 20ml behind the sucking filtration and remove liquid paraffin; Disperse the back with sub-sieve sorting microsphere, drying at room temperature behind the sucking filtration once more with acetone behind the sucking filtration.
The microsphere of method for preparing, according to the performance of the detection of method described in the embodiment 1 microsphere, scanning electron microscope shows that its mode of appearance is better; The mean diameter of microsphere is 22.85 μ m; And particle size distribution is narrower, and 95% all in 7～30 mu m ranges, and drug loading reaches 11.53%; Envelop rate reaches 69.17%, and external medicine stripping can reach 48h.
It is thus clear that lung-targeted microspheres drug loading of the present invention and envelop rate are all higher, envelop rate can reach more than 60%; The particle diameter of microsphere all between 7 ~ 30 μ m, therefore reaches the requirement of lung-targeted microspheres to particle diameter more than 92% after the sorting, and targeting is in pulmonary, thus the pulmonary infection of treating animal efficiently.
The above only is preferred embodiment of the present invention, is not to be the restriction of the present invention being made other form, and any professional and technical personnel of being familiar with possibly utilize the technology contents of above-mentioned announcement to change or be modified as the equivalent embodiment of equivalent variations.But everyly do not break away from technical scheme content of the present invention, to any simple modification, equivalent variations and remodeling that above embodiment did, still belong to the protection domain of technical scheme of the present invention according to technical spirit of the present invention.
Claims (5)
1. the method for preparing of the lung-targeted microspheres of a veterinary ceftiofur hydrochloride is characterized in that said microsphere is a raw material with the ceftiofur hydrochloride, is carrier with the gelatin, and the weight ratio of ceftiofur hydrochloride and gelatin is l:3～30;
The particle size range of said microsphere is 7～30 μ m;
The method for preparing of said microsphere comprises the steps:
1) be that the ratio of l:3 ~ 30 takes by weighing ceftiofur hydrochloride and gelatin respectively according to weight ratio, gelatin swelling in 40～50 ℃ of water is complete, ceftiofur hydrochloride is dissolved in the gelatin solution dissolving fully;
2) measure certain quantity of fluid paraffin in conical flask, add emulsifying agent, place 40～50 ℃ of water-baths to disperse fully, the volume ratio of above-mentioned ceftiofur hydrochloride and gelatin mixed solution and liquid paraffin is l
:5～l
:40;
The gelatin solution that 3) will be dissolved with ceftiofur hydrochloride dropwise joins in the conical flask, under 700～1900rpm rotating speed, 40～50 ℃ of stirring and emulsifying 10～20min, after change emulsifying 25～45min in the ice bath over to;
4) add volumetric concentration 1～7% glutaraldehyde solution and solidify 0
.5 ~ 2h; The glycine solution reaction 20～40min that adds respective concentration, unreacted aldehyde radical in the shielding glutaraldehyde;
5) in above-mentioned solution, add isopropyl alcohol, dehydration 20～50min, the volume ratio l of gelatin solution and isopropyl alcohol
:5～l
:20; Add acetone behind the sucking filtration, acetone and liquid paraffin volume ratio 2
:10～6
:10, sucking filtration repeats for several times, up to removing liquid paraffin fully;
6) disperse the back to screen microsphere with sub-sieve with acetone, the liquid sucking filtration that lower screen is selected is removed drying at room temperature behind the acetone, promptly gets lung-targeted microspheres.
2. method for preparing according to claim 1 is characterized in that: the volume ratio of ceftiofur hydrochloride and gelatin mixed solution and liquid paraffin is preferably l above-mentioned steps 2)
:10～l
:30.
3. method for preparing according to claim 1 is characterized in that: emulsifying agent adopts span80 or Tween80 above-mentioned steps 2).
4. method for preparing according to claim 1 is characterized in that: said gelatin concentration scope is 5%～20%.
5. method for preparing according to claim 1 is characterized in that: the aperture of said sub-sieve is 400 orders.
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| CN100534433C (en) * | 2005-12-12 | 2009-09-02 | 浙江升华拜克生物股份有限公司 | Ceftiofur-containing powder injection for beast |
| CN1985831A (en) * | 2005-12-21 | 2007-06-27 | 天津市润拓生物技术有限公司 | Lung-targeting cefradine microsphere for animal and birds and its preparing method |
| CN101245078B (en) * | 2007-03-19 | 2010-05-26 | 齐鲁动物保健品有限公司 | Benzathine salt of ceftiofur, preparation method and application thereof |
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Address after: 266061 Shandong city of Qingdao province high tech park of Laoshan district by the No. 29 Shandong Road, building 605 high speed Co-patentee after: Qingdao Conlinent Animal Pharmaceutical Co., Ltd. Patentee after: Qingdao KDN Pharmaceutical Co., Ltd. Address before: 266061 Shandong city of Qingdao province high tech park of Laoshan district by the No. 29 Shandong Road, building 605 high speed Co-patentee before: Qingdao Liuhe Medicine Co., Ltd. Patentee before: Qingdao Continent Biotech Co., Ltd. |
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Address after: 266061 Shandong city of Qingdao province Chengyang Qingda Industrial Park, the first northbound dual Patentee after: QINGDAO VLAND BIOLOGICAL CO., LTD. Patentee after: Qingdao Conlinent Animal Pharmaceutical Co., Ltd. Address before: 266061 Shandong city of Qingdao province high tech park of Laoshan district by the No. 29 Shandong Road, building 605 high speed Patentee before: Qingdao KDN Pharmaceutical Co., Ltd. Patentee before: Qingdao Conlinent Animal Pharmaceutical Co., Ltd. |
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Effective date of registration: 20211028 Address after: 330513 No. 47, Fenghuang East Road, Anyi Industrial Park, Nanchang City, Jiangxi Province Patentee after: JIANGXI PIONEER B-PHARMACEUTICAL CO.,LTD. Address before: 266061 north head of Shuangyuan Road, Qingda Industrial Park, Chengyang District, Qingdao City, Shandong Province Patentee before: QINGDAO VLAND BIOTECH Inc. Patentee before: QINGDAO KDN BIOTECH Co.,Ltd. |