CN102258478B - Animal pefloxacin mesylate pellets, and preparation method thereof - Google Patents
Animal pefloxacin mesylate pellets, and preparation method thereof Download PDFInfo
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Abstract
The invention relates to animal pefloxacin mesylate pellets, and a preparation method thereof. The preparation method of the animal pefloxacin mesylate pellets comprises steps that: pefloxacin mesylate powder, a wall material which is a high-molecular material, and cyclohexane are placed in an organic solvent reaction vessel, and reflux is carried out for 1 to 2 hours under a temperature of 80 to 85 DEG C; the temperature of the materials is reduced to 25 to 35 DEG C at a speed of 1 to 3 DEG C per 5 minutes, such that pefloxacin mesylate is coated with the wall, and pellets with sizes of 40 to 200 meshes are formed; the pellets are vacuum-dried, such that the animal pefloxacin mesylate pellets are obtained. According to the animal pefloxacin mesylate pellets provided by the invention, a high-molecular material or polymer is coated on the surface of the medicine, such that tiny sealed capsules are obtained, and the capsules serve as covers or protective films. Therefore, the bitter taste of the medicine can be covered; medicine stability can be improved; and volatilization of volatile medicines can be controlled. The animal pefloxacin mesylate pellets provided by the invention has advantages of convenient use, simple production technology, low cost, high medicine bioavailability, low irritation to intestines and stomach, and good medicine stability.
Description
Technical field
The present invention relates to a kind of animal pefloxacin mesylate pellets and preparation method thereof.
Background technology
Pefloxacin is a kind of new fluoro-carbostyril class antibacterials, to G-and G+ bacterium, comprise that escherichia coli, Salmonella, klebsiella, Bacillus proteus, haemophilus, pasteurellosis bacillus, knee bacterium, pseudomonas and bacillus rhusiopathiae suis, staphylococcus aureus, meningococcus, mycoplasma infection all have effect.Treat respiratory tract, digestive tract and urinary tract infection effect with pefloxacin and be better than cefalexin and norfloxacin; Chicken colibacillosis, staphylococcus aureus, mycoplasma, Pullorum Disease Salmonella, piglet pujos blancos there is extremely strong antibacterial action.This product is similar with other fluoroquinolones, is antibacterial.Its Antibacterial Mechanism is to act in specific manner the A subunit of DNA topoisomerase II, and dna replication dna is obstructed, and affects unwinding, cut and the process such as sealing again of DNA, causes dna degradation and antibacterial dead, also can suppress RNA and protein synthesis under high concentration.
No matter be drug administration by injection or oral administration, pefloxacin all absorbs rapidly, tissue distribution is extensive, bioavailability is high, and concentration is high and lasting in blood and tissue, long half time.Widely distributed in the body, all can reach valid density in cerebrospinal fluid, tonsil, bronchus, muscle, skeleton, prostate, the peritoneum.
But the injection dosage form belongs to individual administration, be not suitable for the use of intensive large-scale farming, and pre-mixing agent is the main dosage form of poultry oral administration, compare with injection, convenient drug administration, that can avoid animal stress, reduce manpower and materials, save aquaculture cost, very common in animal diseases control.Hygroscopicity, powder zest are strong, oral deficiencies such as stimulation to gastric mucosa but the pefloxacin mesilate raw material has.
Summary of the invention
The present invention is directed to existing injection dosage form and pre-mixing agent pefloxacin above shortcomings, a kind of animal pefloxacin mesylate pellets and preparation method thereof is provided.
The technical scheme that the present invention solves the problems of the technologies described above is as follows: a kind of preparation method of animal pefloxacin mesylate pellets comprises the pefloxacin mesilate powder, places the organic solvent reactor as macromolecular material and the cyclohexane extraction of wall material, at 80～85 ℃ of lower 1～2h that reflux, then fall 1～3 ℃ speed with every 5min and cool the temperature to 25～35 ℃, pefloxacin mesilate is enclosed in the wall, form 40～200 purpose micropills, behind vacuum drying, obtain again animal pefloxacin mesylate pellets.
On the basis of technique scheme, the present invention can also do following improvement.
Further, described pefloxacin mesilate powder is mixed by pure pefloxacin mesilate raw material and anhydrous glucose, and wherein, the content of pure pefloxacin mesilate raw material is 25.2%.
Further, described pefloxacin mesilate powder, be respectively every 100L as macromolecular material and the cyclohexane extraction consumption of wall material cyclohexane extraction in add the pefloxacin mesilate powder of 35～40kg and the macromolecular material as the wall material of 5～10kg.
Further, described macromolecular material as the wall material is one or several the mixture in ethyl cellulose, carboxymethyl cellulose and the polypropylene.
Further, described macromolecular material as the wall material is ethyl cellulose, carboxymethyl cellulose and polyacrylic mixture, and described ethyl cellulose, carboxymethyl cellulose and polyacrylic mass ratio are 1: 1: 0.5.
Further, described macromolecular material as the wall material is the mixture of ethyl cellulose and carboxymethyl cellulose, and the mass ratio of described ethyl cellulose and carboxymethyl cellulose is 1: 1.
Further, described macromolecular material as the wall material is ethyl cellulose and polyacrylic mixture, and described ethyl cellulose and polyacrylic mass ratio are 4: 1.
The present invention also provides a kind of technical scheme that solves the problems of the technologies described above as follows: a kind of animal pefloxacin mesylate pellets that is prepared by the preparation method of above-mentioned animal pefloxacin mesylate pellets.
The invention has the beneficial effects as follows: animal pefloxacin mesylate pellets of the present invention utilizes polymer substance or polymer wrapped in medical surfaces; make it become extremely small sealed bladder, play a part to hide or protecting film, can cover the bitterness of medicine; increase the stability of medicine; waving of control volatile medicine is loose, has easy to usely, and processing technology is simple; the characteristics such as cost is low; drug bioavailability is high, and little to the intestines and stomach stimulation, medicine stability is good.
Description of drawings
Fig. 1 is the dissolution curve chart of pefloxacin mesilate micropill of the present invention;
Fig. 2 is the correction graph of pefloxacin mesilate in the serum of the present invention;
Fig. 3 is the sample determination chromatogram of the blank serum of rabbit of the present invention;
Fig. 4 is the sample determination chromatogram figure that the blank serum of the present invention adds medicine;
Fig. 5 is that the blood serum sample behind the pefloxacin mesilate micropill gastric infusion of the present invention is measured chromatogram;
Fig. 6 is the drug-time curve figure after pefloxacin mesilate micropill of the present invention and pefloxacin mesilate powder gavage to rabbit;
Fig. 7 is the average drug-time curve figure of the quiet notes of pefloxacin mesilate.
The specific embodiment
Below in conjunction with accompanying drawing principle of the present invention and feature are described, institute gives an actual example and only is used for explaining the present invention, is not be used to limiting scope of the present invention.
Pefloxacin mesilate powder 40kg, ethyl cellulose 5kg and cyclohexane extraction 100L are placed the organic solution reactor, at 80 ℃ of lower backflow 1.5h, then every 5min falls 2 ℃ speed and cools the temperature to 25 ℃, the pefloxacin mesilate pruinescence wraps in the wall, form 40～200 purpose micropills, behind vacuum drying, obtain required pefloxacin mesilate micropill.
Pefloxacin mesilate powder 35kg, ethyl cellulose 3kg, carboxymethyl cellulose 3kg and cyclohexane extraction 100L are placed the organic solution reactor, at 85 ℃ of lower backflow 2h, then every 5min falls 1 ℃ speed and cools the temperature to 30 ℃, the pefloxacin mesilate pruinescence wraps in the wall, form 40～200 purpose micropills, behind vacuum drying, obtain required pefloxacin mesilate micropill.
Embodiment 3
Pefloxacin mesilate powder 38kg, ethyl cellulose 3kg, carboxymethyl cellulose 3kg, polypropylene 1.5kg and cyclohexane extraction 100L are placed the organic solution reactor, at 80 ℃ of lower backflow 1h, then every 5min falls 3 ℃ speed and cools the temperature to 35 ℃, the pefloxacin mesilate pruinescence wraps in the wall, form 40～200 purpose micropills, behind vacuum drying, obtain required pefloxacin mesilate micropill.
Pefloxacin mesilate powder 38kg, carboxymethyl cellulose 3kg, polypropylene 4kg cyclohexane extraction 100L are placed the organic solution reactor, at 80 ℃ of lower backflow 1.5h, then every 5min falls 2 ℃ speed and cools the temperature to 35 ℃, the pefloxacin mesilate pruinescence wraps in the wall, form 40～200 purpose micropills, behind vacuum drying, obtain required pefloxacin mesilate micropill.
Pefloxacin mesilate micropill content, envelop rate and vitro release are measured
Extraction and the assay of the outer free drug of micropill: take by weighing 100mg pefloxacin mesilate micropill in the 100mL volumetric flask, add 20mL water, concussion 1min, make the outer medicine of micropill fully dissolve (water insoluble at low temperatures in the micropill material short time), shake up behind the standardize solution, filter immediately, get filtrate, measure the trap value at 277nm wavelength place.
Extraction and the assay of the inside and outside total medicine of microsphere: after getting a certain amount of micropill and pulverizing, get 35mg in the 100ml volumetric flask, add 0.1mo l/L hydrochloric acid 20ml, sonic oscillation 10min, medicine is fully dissolved, with 0.1mol/L hydrochloric acid standardize solution, shake up rear filtration, get filtrate, measure the trap value at 277nm wavelength place.
Drug loading=(micropill Chinese medicine content/micropill quality) * 100%
Envelop rate=(total medicament contg in the medicament contg/micropill that dissociates in the micropill) * 100%
Below be the result of sample embodiment:
Table 1 drug loading and entrapment efficiency determination result
Pefloxacin mesilate micropill Dissolution Rate Testing:
Measure by Chinese Pharmacopoeia (version in 2000) dissolution method the second method (slurry method).Accurately take by weighing pefloxacin mesilate micropill 400mg, take hydrochloric acid (0.1mo l/L) 900ml as dissolution medium, temperature is at (37 ℃), rotating speed 100r/min (estimation) in 20,40,60,90,120,180,240,300, the 360min spot sampling, gets in 5ml to the 100ml volumetric flask at every turn, in time replenish dissolution medium, with filtering behind the 0.1mol/L hydrochloric acid solution standardize solution, get filtrate and survey trap at 277nm wavelength place, such as table 2 and shown in Figure 1.
The Dissolution Rate Testing result of table 2 pefloxacin mesilate micropill
Above data show: the capsule material of the product of each embodiment is swelling when 20min all, sustained release, and during to 2h, medicine discharges fully.
Pharmacokinetics and the bioavailability study thereof of pefloxacin mesilate micropill in the rabbit body
Pefloxacin is a kind of new fluoro-carbostyril class antibacterials, to G-and G+ bacterium, comprise that escherichia coli, Salmonella, klebsiella, Bacillus proteus, haemophilus, pasteurellosis bacillus, knee bacterium, pseudomonas and bacillus rhusiopathiae suis, staphylococcus aureus, meningococcus, mycoplasma infection all have effect.Treat respiratory tract, digestive tract and urinary tract infection effect with pefloxacin and be better than cefalexin and norfloxacin; Chicken colibacillosis, staphylococcus aureus, mycoplasma, Pullorum Disease Salmonella, piglet pujos blancos there is extremely strong antibacterial action.
No matter be drug administration by injection or oral administration, pefloxacin all absorbs rapidly, tissue distribution is extensive, bioavailability is high, and concentration is high and lasting in blood and tissue, long half time (about 10～12h).Widely distributed in the body, all can reach valid density in cerebrospinal fluid, tonsil, bronchus, muscle, skeleton, prostate, the peritoneum.
But the injection dosage form belongs to individual administration, be not suitable for the use of intensive large-scale farming, and pre-mixing agent is the main dosage form of poultry oral administration, compare with injection, convenient drug administration, that can avoid animal stress, reduce manpower and materials, save aquaculture cost, very common in animal diseases control.Hygroscopicity, powder zest are strong, oral deficiencies such as stimulation to gastric mucosa but the pefloxacin mesilate raw material has.During as veterinary drug, that pefloxacin mesilate is added in the animal feed, developed the pefloxacin mesilate pellet preparations for solving the oral series of problems of this medicine, this paper is by gavaging administration relatively micropill and the characteristics of pharmacokinetics of former powder in the rabbit body, for clinical application provides foundation.
1 materials and methods
1.1 material
1.1.1 medicine and reagent embodiment 1 pefloxacin mesilate micropill, content 22.68%; Embodiment 2 pefloxacin mesilate micropills, content 21.05%; Embodiment 3 pefloxacin mesilate micropills, content 20.93%; Embodiment 4 pefloxacin mesilate micropills, content 20.78%; The pefloxacin mesilate powder, content 25.2%.The pefloxacin mesilate reference substance, content 100.1%.Acetonitrile, methanol are chromatographically pure, and ammonium acetate, citric acid etc. is analytical reagent; Water meets the secondary water of GB/T6682 regulation.
1.1.2 the test animal New Zealand white rabbit, body weight 1.5～2kg.Breeding observing 5d before the test, free choice feeding drinking-water, feeding does not contain antibiotic complete feed.Fasting 12h before the administration, 4h free choice feeding after the administration stops material and does not cut off the water.
1.2 method
1.2.1 administration and sampling
After every rabbit weighed, be divided at random PFM crude drug group and PFM micropill group and PFM injection group, 3 every group.Fasting 12h before the administration, before the sample collecting, every treated animal is in dosage (with PFM) the quiet notes pefloxacin mesilate solution of difference and the former medicine of gavage pefloxacin mesilate and each the embodiment micropill of 10mg/kg bw, medicine mixing in water for oral taking after the gavage, with an amount of normal saline flushing stomach tube, guarantee that dosage is accurate again.Before the administration and after the administration 5,10,15,30,45mi n and 1,1.5,2,3,4,6,8,12 auricular veins get blood 1.5ml in centrifuge tube, separation of serum is in-20 ℃ of Refrigerator stores, and is to be measured.
1.2.2 chromatographic condition
Mobile phase is methanol-0.25mol/L ammonium acetate buffer solution (Fructus Citri Limoniae acid for adjusting pH to 4.8), and proportion of mobile phase is 60: 40 (V/V).
Chromatographic column: welchrom-C18,5 μ m, 4.6mm*250mm.
1.2.3 blood sample is processed
Blood places the 5mL centrifuge tube, puts into the inclined-plane, in 37 ℃ of effect 30min, afterwards in 4 ℃ of effect 30min, the centrifugal 15min of 4000r/min, separation of serum.-20 ℃ of preservations are drawn 0.2mL serum to the 2mL centrifuge tube after serum thaws, add acetonitrile 0.6mL, and centrifugal (4000r/min) 20mi n gets supernatant behind 0.45 μ m filtering with microporous membrane, gets 20 μ L sample introduction analyses.
1.2.4 standard curve preparation
Take by weighing pefloxacin mesilate standard substance 2mg in the 10mL volumetric flask, dissolving shakes up, and is mixed with the mother solution that concentration is 200 μ g/mL.Become 100,50,25,12.5,6.25,3.125 μ g/mL series concentration with this mother solution doubling dilution again.After preparing, save backup in 4 ℃.
Get 7 2mL centrifuge tubes and respectively add the blank serum of 0.2mL rabbit, add successively respectively again 10 μ L pefloxacin mesilate titers (3.125,6.25,12.5,25,50,100,200 μ g/mL), the whirlpool mixing is made into following blood drug level: 0.156,0.312,0.625,1.250,2.500,5.000,10.000 μ g/mL.After pressing the processing of 1.2.3 method, get 20 μ L sample introduction analyses.The record chromatographic peak area, calculated standard curve equation.
1.2.5 precision and determination of recovery rates
Precision refers to the someway degree closer to each other of the same equal quality sample gained measured value of replication, and the repeatability of expression analysis result comprises withinday precision and day to day precision.Select high, medium and low three in standard curve range, each concentration is different time replication in a few days and in the daytime 3～5 times, and get final product.Withinday precision should be less than 5%, and day to day precision should be less than 10%.
Get 3 parts of blank serum, add an amount of pefloxacin mesilate titer, be made into three concentration of 5.000,1.250 and 0.312 μ g/mL and in 1d, repeat respectively sample introduction 3 times and in 5d, distinguish 1 repetition every day sample introduction, measure and in a few days reach in the daytime RSD.
The response rate refers to the degree of closeness of measured value and actual value, the expression precision of analysis.Response rate scope should be between 70%～110%, and average recovery rate should be more than 80%.
Get 3 parts of blank serum (each 0.2mL), add 10 μ L pefloxacin mesilate titers (100,25,6.25 μ g/mL), be made into 5.000,1.250 three kinds of concentration of 0.312 μ g/mL are after the sample treatment, replication content 4 times calculates relative recovery with the tret method.
1.2.6 pharmacokinetic parameter calculates
Medicine-time data DAS2.0.1 software processes, pefloxacin mesilate micropill and former powder data when gavaging after the administration at rabbit body giving drugs into nose all meet the one-compartment model that absorption is arranged, quiet notes meet without the two-compartment model that absorbs.
2 results and analysis
2.1 standard curve
Standard curve equation: Y=36636X-2145.5, R2=0.9991, standard curve is seen Fig. 2.
2.2 precision
The precision measurement result of pefloxacin mesilate in table 3 serum
2.3 the response rate
The determination of recovery rates result of pefloxacin mesilate in table 4 serum
The actual measurement scope of precision and the response rate is all within requiring.
2.4 the chromatogram that blood serum sample detects
The blank serum of rabbit, blank serum add the mensuration chromatogram of pefloxacin mesilate standard substance shown in Fig. 3,4.The retention time that shows pefloxacin mesilate is 8.21, and is good with other separating substances of coexistence.
2.5 pefloxacin mesilate micropill embodiment 1-4 and the drug-time curve of former powder in the rabbit body, as shown in Figure 5, the average drug-time curve of the quiet notes of pefloxacin mesilate, as shown in Figure 6.Fig. 5 and Fig. 6 reaction be characteristics of pharmacokinetics behind the former powder of the oral pefloxacin mesilate of rabbit, oral micropill and the quiet notes injection, in the 3rd part discussion, detailed explanation is arranged.
2.6 pharmacokinetic parameter
Curve meets the one-compartment model that absorption is arranged during oral medicine, and quiet notes meet without the two-compartment model that absorbs, major impetus mathematic(al) parameter such as table 5:
Kinetic parameter behind table 5 rabbits after intravenous notes and oral pefloxacin mesilate, the oral pefloxacin mesilate micropill
Annotate: oral micropill group is compared with oral former powder group, and * P＜0.05 (n=3, means ± SD); Absolute biological degree is that oral former powder group and oral micropill group compare with the intravenous injection group respectively; Relative bioavailability is oral micropill group/oral former powder group.
3 discuss
3.1 rabbits after intravenous is annotated the characteristics of pharmacokinetics behind the pefloxacin mesilate
After rabbits after intravenous was annotated pefloxacin mesilate, curve met without absorbing two-compartment model during medicine, was quick distribution and eliminated fast feature.Distribution half-life and eliminate the half-life and be respectively 0.11 ± 0.07 and 1.41 ± 0.15h, short than its distribution half-life (0.1678 ± 0.1298) h in the goat body and elimination half-life (1.6322 ± 0.3189) h, bibliographical information is arranged, the elimination half-life of pefloxacin mesilate on dog is 9h, the people is upper to be reached more than the 10h, and the species variation of the characteristics of pharmacokinetics of visible pefloxacin mesilate is larger.
3.2 the characteristics of pharmacokinetics of the oral pefloxacin mesilate different dosage form of rabbit
Behind the former powder of the oral pefloxacin mesilate of rabbit and the pellet, curve all meets during medicine the absorption one-compartment model, compare with former powder, t1/2 β and Tmax significant prolongation, the Cmax of micropill slightly reduces, the infiltration rate that micropill is described is obviously slow than former powder, but peak time is longer, can keep the longer time.Need the regular hour because the adjuvant that adds in the micropill leaches in the intestines and stomach, drug-eluting and diffusion velocity are restricted, delay drug absorption.
The more former powder of its relative bioavailability is high behind the oral micropill, and the blood drug level in the micropill unit interval is higher than former powder, shows that it not only has higher AUC and eliminates slower characteristics, and absorbs more complete.
The above only is preferred embodiment of the present invention, and is in order to limit the present invention, within the spirit and principles in the present invention not all, any modification of doing, is equal to replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (5)
1. the preparation method of an animal pefloxacin mesylate pellets, it is characterized in that, described preparation method comprises the pefloxacin mesilate powder, places the organic solvent reactor as macromolecular material and the cyclohexane extraction of wall material, at 80～85 ℃ of lower 1～2h that reflux, then fall 1～3 ℃ speed with every 5min and cool the temperature to 25～35 ℃, pefloxacin mesilate is enclosed in the wall, forms 40～200 purpose micropills, behind vacuum drying, obtain again animal pefloxacin mesylate pellets; Described pefloxacin mesilate powder, be respectively every 100L as macromolecular material and the cyclohexane extraction consumption of wall material cyclohexane extraction in add the pefloxacin mesilate powder of 35～40kg and the macromolecular material as the wall material of 5～10kg; Described pefloxacin mesilate powder is mixed by pure pefloxacin mesilate raw material and anhydrous glucose, and wherein, the content of pure pefloxacin mesilate raw material is 25.2%; Described macromolecular material as the wall material is one or several the mixture in ethyl cellulose, carboxymethyl cellulose and the polypropylene.
2. the preparation method of animal pefloxacin mesylate pellets according to claim 1, it is characterized in that, described macromolecular material as the wall material is ethyl cellulose, carboxymethyl cellulose and polyacrylic mixture, and described ethyl cellulose, carboxymethyl cellulose and polyacrylic mass ratio are 1:1:0.5.
3. the preparation method of animal pefloxacin mesylate pellets according to claim 1, it is characterized in that, described macromolecular material as the wall material is the mixture of ethyl cellulose and carboxymethyl cellulose, and the mass ratio of described ethyl cellulose and carboxymethyl cellulose is 1:1.
4. the preparation method of animal pefloxacin mesylate pellets according to claim 1 is characterized in that, described macromolecular material as the wall material is ethyl cellulose and polyacrylic mixture, and described ethyl cellulose and polyacrylic mass ratio are 4:1.
5. animal pefloxacin mesylate pellets by the preparation of the preparation method of the arbitrary described animal pefloxacin mesylate pellets of claim 1 to 4.
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| DE102007009243A1 (en) * | 2007-02-22 | 2008-09-18 | Evonik Röhm Gmbh | Pellets with a drug matrix and a polymer coating, and a method for producing the pellets |
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