CN101411689B - Danofloxacin mesylate microsphere formulation for livestock and poultry and preparation method thereof - Google Patents
Danofloxacin mesylate microsphere formulation for livestock and poultry and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a danofloxacin mesylate microsphere preparation, which is prepared by the following steps: adding gelatin, or gelatin and polyglycol, or gelatin and polyglycol as well as xanthan gum into water, and adding danofloxacin mesylate for dissolution to obtain a water phase; adding an emulsifying agent into liquid petrolatum to mix evenly to obtain an oil phase; and adding the water phase into the oil phase, emulsifying, cross linking and solidifying the mixed phases and removing supernatant to obtain the danofloxacin mesylate microsphere preparation for livestock and birds. The preparation adopts an emulsifying and condensing method to wrap the danofloxacin mesylate in microspheres, can release slowly after using the microspheres for intramuscular injection, and prolong elimination half-life of medicament in vivo. The preparation technology has the advantages of simple operation, low requirements on preparation equipment and conditions, round shape of the obtained microspheres, and good dispersing property in water solution; and can prolong effective acting time of the medicament in vivo after intramuscular injection for pigs.
Description
Technical field
The invention belongs to the animal drug field, be specifically related to a kind of microball preparation and preparation method thereof of fluoroquinolone antibacterial agent Danofloxacin mesylate of animal specific.
Background technology
Danofloxacin mesylate is the mesylate of danofloxacin, and danofloxacin is the third generation fluoroquinolone antibacterial agent of animal specific, has broad-spectrum bactericidal action, and gram positive bacteria, negative bacterium, mycoplasma, chlamydia are all had killing action.Be mainly used in the responsive microbial various infection of various animals clinically.
The danofloxacin preparation of Chu Shouing only has for the oral soluble powder and the normal injection agent of intramuscular injection in the market.Yet because the danofloxacin elimination half-life in animal body is shorter, so brought inconvenience to clinical practice.Therefore, the present invention can prolong the danofloxacin microball preparation of elimination half-life in animal body for veterinary clinic provides a kind of, and can be the veterinary clinic medication and provide convenient.
Summary of the invention
The purpose of this invention is to provide a kind of Danofloxacin mesylate microsphere formulation and preparation method thereof, Danofloxacin mesylate is wrapped in the microsphere, can slowly discharge after utilizing the microsphere intramuscular injection, to reach the prolong drug effect of elimination half-life in vivo.
Technical scheme of the present invention is: Danofloxacin mesylate microsphere formulation, comprise Danofloxacin mesylate and biodegradable carrier material (preferably also containing pharmaceutic adjuvant), and adopt the emulsifying condensation method to prepare Danofloxacin mesylate is wrapped in interior microsphere.
Described biodegradable carrier material is a gelatin, and pharmaceutic adjuvant is Polyethylene Glycol or Polyethylene Glycol and xanthan gum.
The preparation method of Danofloxacin mesylate microsphere formulation of the present invention may further comprise the steps:
(1) preparation water: gelatin or gelatin are added in the entry with Polyethylene Glycol and xanthan gum with Polyethylene Glycol or gelatin, and adding Danofloxacin mesylate again, to dissolve the aqueous solution obtain promptly be water;
(2) preparation oil phase: emulsifying agent is added in the liquid paraffin, evenly mixed, obtain oil phase;
(3) emulsifying: under 40～65 ℃ of stirring conditions, water is added in the oil phase, obtain emulsification system to emulsifying below 5 ℃ then;
(4) dehydration and curing: stir down, in emulsification system, add isopropyl alcohol and dewater, drip chemical cross-linking agent again, continue the stirring crosslinking curing;
(5) washing, filtration and dry: abandoning supernatant, washing, filtration and dry that faint yellow poultry are used the Danofloxacin mesylate microsphere powder.
Described emulsifying agent is a sorbester p17, and consumption is 1～4% of an oil phase cumulative volume.
Step (3), the described stirring condition of step (4) are 500～1100r/min.
The volume ratio of described water and oil phase is 1:5～15.
Described chemical cross-linking agent consumption is 4～10% of an emulsification system volume.
Described chemical cross-linking agent is formaldehyde, dextran or glutaraldehyde.
Step (3), the described stirring condition of step (4) are 500～1100r/min.
Described Danofloxacin mesylate microsphere mean diameter is 10-11 μ m, and medicament contg is 2.0～6.3%.
The present invention adopts the emulsifying condensation method, and Danofloxacin mesylate is wrapped in the microsphere, can slowly discharge the effect of prolong drug elimination half-life in vivo after utilizing the microsphere intramuscular injection.
The present invention has improved medicament contg and envelop rate by adding the affinity between Polyethylene Glycol enhancing medicine and the carrier; The present invention share xanthan gum and Polyethylene Glycol and can further improve medicament contg in addition.Preparation technology of the present invention is simple to operate, and is low to preparation equipment, conditional request, the microsphere form rounding that obtains, good dispersion in aqueous solution; But to prolong drug effective acting time in vivo behind the pig intramuscular injection said preparation.
Description of drawings
100 times of light microscopic figure of the Danofloxacin mesylate microsphere that Fig. 1 makes for embodiment 4;
3500 times of Electronic Speculum figure of the Danofloxacin mesylate microsphere that Fig. 2 makes for embodiment 4;
Fig. 3 be Danofloxacin mesylate injection and Danofloxacin mesylate microsphere formulation to the pig intramuscular injection after the concentration-time graph of danofloxacin in the blood plasma.
The specific embodiment
The preparation method of the Danofloxacin mesylate microsphere formulation that the present invention proposes, concrete steps are as follows: get gelatin or gelatin and Polyethylene Glycol or gelatin and Polyethylene Glycol and xanthan gum and add in the entry, in water bath with thermostatic control, treat the gelatin complete swelling, add the dissolving of Danofloxacin mesylate mixing again, add dropwise then that (0.5-2ml/min) contains in the liquid paraffin of sorbester p17, electromagnetic agitation in the water-bath of uniform temp, to milky, ice bath is reduced to below 5 ℃ rapidly and is continued and stirs, add isopropanol dehydration again, solidify with the chemical cross-linking agent commissure.Wash repeatedly with isopropyl alcohol at last, wash most cross-linking agent, the liquid paraffin of ether, petroleum ether flush away microsphere surface, sucking filtration, drying makes little yellow microsphere powder.
Further describe the present invention below in conjunction with specific embodiment.
Embodiment 1
(1) takes by weighing the 1.2g gelatin in 8ml water, put in 60 ℃ of waters bath with thermostatic control,,, make it be dissolved in the aqueous gelatin solution fully to wherein adding the 0.15g Danofloxacin mesylate to the gelatin complete swelling;
(2) in the 250ml round-bottomed flask, add 60ml liquid paraffin and 1.8ml sorbester p17, stir, make it mix homogeneously;
(3) under 60 ℃ of water bath with thermostatic control conditions, the Danofloxacin mesylate aqueous gelatin solution is slowly dripped (0.8ml/ minute) in the liquid paraffin that contains emulsifying agent, magnetic agitation, mixing speed is 800r/min, emulsifying 15min, form emulsion, emulsion is transferred to rapidly in the ice-water bath, temperature is reduced to below 5 ℃;
(4) continue to stir,, continue to stir and continue to stir 1h to wherein dripping isopropyl alcohol 60ml.To wherein dripping chemical cross-linking agent formaldehyde 4ml, the about per minute 1.5ml of rate of addition continues to stir 3h, stops to stir, and leaves standstill 30min in the ice-water bath again;
(5) abandoning supernatant, repeatedly with isopropyl alcohol, ether and petroleum ether flushing, sucking filtration, drying promptly gets faint yellow Danofloxacin mesylate gelatine microsphere dry powder.
The microsphere physicochemical property is stable, good reproducibility, and mean diameter is 11.63 μ m, average drug loading and envelop rate are respectively 1.01% and 8.1%.
Embodiment 2
(1) precision takes by weighing the 0.8g gelatin in 8ml water, puts in 60 ℃ of waters bath with thermostatic control, to the gelatin complete swelling, to wherein adding the 0.4g Danofloxacin mesylate, makes it be dissolved in the aqueous gelatin solution fully;
(2) in the 250ml round-bottomed flask, add 60ml liquid paraffin and 1.8ml sorbester p17, stir, make it mix homogeneously;
(3) under 60 ℃ of water bath with thermostatic control conditions, the Danofloxacin mesylate aqueous gelatin solution is slowly dripped (2ml/ minute) in the liquid paraffin that contains emulsifying agent, magnetic agitation, mixing speed is 900r/min, emulsifying 15min, form emulsion, emulsion is transferred to rapidly in the ice-water bath, temperature is reduced to below 5 ℃;
(4) continue to stir,, continue to stir and continue to stir 1h to wherein dripping isopropyl alcohol 60ml.To wherein dripping chemical cross-linking agent dextran (dextran) 5ml, the about per minute 0.5ml of rate of addition continues to stir 3h, stops to stir, and leaves standstill 30min in the ice-water bath again;
(5) abandoning supernatant, repeatedly with isopropyl alcohol, ether and petroleum ether flushing, sucking filtration, drying promptly gets faint yellow Danofloxacin mesylate gelatine microsphere dry powder.
The microsphere physicochemical property is stable, good reproducibility, and mean diameter is 12.58 μ m, average drug loading and envelop rate are respectively 1.62% and 8.16%.
Embodiment 3
(1) precision takes by weighing 1.2g gelatin and 0.24g Polyethylene Glycol in 8ml water, puts in 60 ℃ of waters bath with thermostatic control, to the gelatin complete swelling, to wherein adding the 0.30g Danofloxacin mesylate, it is dissolved fully;
(2) in the 250ml round-bottomed flask, add 60ml liquid paraffin and 1.5ml sorbester p17, stir, make it mix homogeneously;
(3) under 60 ℃ of water bath with thermostatic control conditions, the Danofloxacin mesylate aqueous gelatin solution is slowly dripped (1.5ml/ minute) in the liquid paraffin that contains surfactant, magnetic agitation, mixing speed is 1000r/min, emulsifying 15min, form emulsion, emulsion is transferred to rapidly in the ice-water bath, temperature is reduced to below 5 ℃;
(4) continue to stir,, continue to stir and continue to stir 1h to wherein dripping isopropyl alcohol 60ml.To wherein dripping chemical cross-linking agent glutaraldehyde 5ml, the about per minute 2ml of rate of addition continues to stir 3h, stops to stir, and leaves standstill 30min in the ice-water bath again;
(5) abandoning supernatant, repeatedly with isopropyl alcohol, ether and petroleum ether flushing, sucking filtration, drying promptly gets faint yellow Danofloxacin mesylate gelatine microsphere dry powder.
The microsphere physicochemical property is stable, good reproducibility, and mean diameter is 10.75 μ m, average drug loading and envelop rate are respectively 3.33% and 16.5%.
Embodiment 4
(1) precision takes by weighing 1.2g gelatin, 0.24g Polyethylene Glycol and 0.02g xanthan gum in 8ml water, puts in 60 ℃ of waters bath with thermostatic control, to the gelatin complete swelling, to wherein adding the 0.30g Danofloxacin mesylate, it is dissolved fully;
(2) in the 250ml round-bottomed flask, add 60ml liquid paraffin and 1.5ml sorbester p17, stir, make it mix homogeneously;
(3) under 60 ℃ of water bath with thermostatic control conditions, the Danofloxacin mesylate aqueous gelatin solution is slowly dripped (1.5ml/ minute) in the liquid paraffin that contains surfactant, magnetic agitation, mixing speed is 1000r/min, emulsifying 15min, form emulsion, emulsion is transferred to rapidly in the ice-water bath, temperature is reduced to below 5 ℃;
(4) continue to stir,, continue to stir and continue to stir 1h to wherein dripping isopropyl alcohol 60ml.To wherein dripping chemical cross-linking agent glutaraldehyde 5ml, the about per minute 1.5ml of rate of addition continues to stir 3h, stops to stir, and leaves standstill 30min in the ice-water bath again;
(5) abandoning supernatant, repeatedly with isopropyl alcohol, ether and petroleum ether flushing, sucking filtration, drying promptly gets faint yellow Danofloxacin mesylate gelatine microsphere dry powder.
The microsphere physicochemical property that the present invention makes is stable, good reproducibility, and mean diameter is 10.75 μ m, average drug loading and envelop rate are respectively 6.26% and 36.5%.100 times of light microscopics of the Danofloxacin mesylate microsphere that makes are observed as shown in Figure 1 down, and it is even, smooth to observe the microsphere size; As shown in Figure 2, can observe microsphere surface has micropore under 3500 times of scanning electron microscopies, is the passage of drug release.
Danofloxacin mesylate microsphere formulation carries the test of pig interior medicine dynamics
One, experiment material:
1. main agents and medicine
Danofloxacin mesylate injection (Kang Erle of Anhui Province pharmaceutcal corporation, Ltd, lot number 070814); Danofloxacin mesylate microsphere (face with preceding and be mixed with suspension) with the distilled water mixing; The equal Pass Test requirement of other reagent.
2. the preparation of mobile phase
Get 85% phosphatase 11 ml and dilute with an amount of distilled water, to wherein adding the 1ml triethylamine, be settled to 250ml with distilled water, be made into mobile phase with acetonitrile according to the mixed of 82:18 (v:v) then, with 0.22 μ m membrane filtration, the degassing is handled standby.
3. key instrument equipment
Agilent1100 type high performance liquid chromatograph U.S. Agilent company
YKH type liquid flash mixer Jiangxi medical apparatus and instruments factory
Tianjin, island AUY120 type analysis balance Daojin International Trade (Shanghai) Co., Ltd.
HHS type rustless steel electric-heated thermostatic water bath Wuhan City Qin Tai medical apparatus and instruments factory
KQ-100B type ultrasonic washing unit Kunshan Ultrasonic Instruments Co., Ltd.
Eppendorf superspeed refrigerated centrifuge Germany Eppendorf company
Hai'an booth science and technology instrument plant on the TGL-16G type desk centrifuge
The automatic dual pure water distillator of SZ-93 type Shanghai Yarong Biochemical Instrument Plant
4. laboratory animal
Healthy piglet, body weight is 25 ± 1kg, totally 12, and it is divided into crude drug group (6) and microsphere group (6) at random.Free choice feeding drinking-water, feeding does not add the perfect compound feed of antibacterials, supports a week temporarily before the test, to conform.
Two, experimental technique
1. administration
The crude drug group is injected the Danofloxacin mesylate injection with 2.5mg/kg b.w. in auricularis posterior, the microsphere group is injected the Danofloxacin mesylate microsphere suspension in 2.5mg/kg b.w. (with Danofloxacin mesylate) in auricularis posterior.
2. sample collecting
Take a blood sample by following time point vena cava anterior after the administration: 0min, 15min, 30min, 45min, 1h, 1.5h, 2h, 4h, 6h, 8h, 12h, 24h, 48h, 72h, the blood sample of gathering places the plastic centrifuge tube of handling through heparin sodium, the centrifugal 10min of 3000r/min, separated plasma is preserved in-20 ℃ of refrigerators, and is to be measured.
3. plasma sample is handled
From refrigerator, take out plasma sample, thaw naturally under the room temperature.Accurately draw 1000 μ l blood plasma in centrifuge tube, after the vibration of adding 5ml dichloromethane, with the centrifugal 10min of 10000r/min, collect supernatant in another centrifuge tube, nitrogen dries up in 50 ℃ of water-baths.Mobile phase is settled to 200 μ l, gets 20 μ l sample introduction HPLC and measures.
4. the drafting of standard curve
Accurately take by weighing Danofloxacin mesylate 0.0200g,, be made into the standard reserving solution of 200 μ g/ml with being settled to 100ml after an amount of distilled water dissolving.Get standard reserving solution, be diluted to the serial working solution that concentration is respectively 0.4,1.0,2.0,5.0,10,20 μ g/ml with distilled water.In 6 centrifuge tubes, add 1000 μ l blank plasmas, add working solution 100 μ l then successively, just obtain the plasma sample that drug level is followed successively by 0.04,0.1,0.2,0.5,1,2 μ g/ml.According to sample introduction analysis after the plasma sample disposal methods.Peak area (A) with Danofloxacin mesylate is an abscissa, and the concentration (C) of Danofloxacin mesylate in sample is vertical coordinate, sets up standard curve, draws regression equation: C=0.0008A+0.0043 (r=0.9993).
5. the response rate and precision test
Get blank plasma, add an amount of Danofloxacin mesylate standard operation liquid, be mixed with and contain the plasma sample that Danofloxacin mesylate concentration is respectively 1,0.5,0.1 μ g/ml, according to the disposal methods of plasma sample and carry out HPLC and detect, the response rate of Danofloxacin mesylate in plasma sample is greater than 75%, the coefficient of variation is little, illustrates that this method can be used for sample determination.The day within variance coefficient of high, medium and low 3 concentration (1,0.5,0.1 μ g/ml) is respectively 4.4,3.1,4.1%, and the coefficient of variation is respectively 3.9,3.0,5.6% in the daytime.The result shows that this method can be used for pharmacokinetics test.
6. chromatographic condition
Chromatographic column: Agilent TC-C
18Post (250mm * 4.6mm, 5 μ m)
Mobile phase: acetonitrile: water (phosphoric acid 0.4%, triethylamine 0.4%)=18:82 (v/v)
Ultraviolet detection wavelength: 280nm
Flow velocity: 1.0ml/min
Column temperature: 30 ℃
Sample size: 50 μ l
7. date processing
Pharmacokinetics model adopts 3P97 pharmacokinetics software to carry out match; Curve chart adopts Excel software to draw during medicine.
Three, experimental result
1. blood plasma Chinese medicine-time data
After Danofloxacin mesylate injection and the administration of Danofloxacin mesylate microsphere suspension in the blood plasma concentration-time graph of danofloxacin see accompanying drawing 3, microsphere of the present invention is as we know from the figure compared with general preparation to have the long half-life.
2. pharmacokinetic data analysis
Behind pig difference intramuscular injection Danofloxacin mesylate and Danofloxacin mesylate microsphere, pharmacokinetic parameter sees Table 1.Through the compartment model analysis, two kinds of preparations, its blood drug level-time data all meets one-level and absorbs two Room open models.
The pharmacokinetic parameters of table 1 pig intramuscular injection Danofloxacin mesylate and Danofloxacin mesylate microsphere
As can be seen from the results, after the Danofloxacin mesylate microsphere intramuscular injection, the T of danofloxacin
1/2 β3 times have been prolonged than the agent of intramuscular injection Danofloxacin mesylate normal injection, because microsphere at the slow releasing function of medicine-feeding part to medicine, makes T
P0.64h by ordinary preparation has postponed till 2.62h.Therefore the slow release effect of Danofloxacin mesylate microsphere formulation is better.
Claims (7)
1. the preparation method of Danofloxacin mesylate microsphere formulation for livestock and poultry may further comprise the steps:
(1) preparation water: gelatin or gelatin are added in the entry with Polyethylene Glycol and xanthan gum with Polyethylene Glycol or gelatin, and adding Danofloxacin mesylate again, to dissolve the aqueous solution obtain promptly be water; Gelatin is that the concentration of 10～30wt%, Polyethylene Glycol is that 2～5wt%, concentration of xanthan gum are that the mass ratio of 0.1～0.5wt%, Danofloxacin mesylate and gelatin is in the concentration of aqueous phase: 1: 1～8;
(2) preparation oil phase: emulsifying agent is added in the liquid paraffin, evenly mixed, obtain oil phase;
(3) emulsifying: under 40～65 ℃ of stirring conditions, water is added in the oil phase, obtain emulsification system to emulsifying below 5 ℃ then; The volume ratio of described water and oil phase is 1: 5～15;
(4) dehydration and curing: stir down, in emulsification system, add isopropyl alcohol and dewater, add chemical cross-linking agent again, continue the stirring crosslinking curing;
(5) abandoning supernatant, washing, filtration and dry that poultry are used Danofloxacin mesylate microsphere.
2. preparation method according to claim 1 is characterized in that: described emulsifying agent is a sorbester p17, and consumption is 1～4% of an oil phase cumulative volume.
3. preparation method according to claim 1 and 2 is characterized in that: described chemical cross-linking agent consumption is 4～10% of an emulsification system volume.
4. preparation method according to claim 1 and 2 is characterized in that: described chemical cross-linking agent is formaldehyde, dextran or glutaraldehyde.
5. preparation method according to claim 1 and 2 is characterized in that: step (3), the described stirring condition of step (4) are 500～1100r/min.
6. the Danofloxacin mesylate microsphere formulation for livestock and poultry that makes of claim 1 or 2 described methods.
7. Danofloxacin mesylate microsphere formulation for livestock and poultry according to claim 6 is characterized in that: the Danofloxacin mesylate microsphere mean diameter is 10-11 μ m, and medicament contg is 2.0～6.3wt%.
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101703469B (en) * | 2009-11-24 | 2011-10-19 | 东北农业大学 | Preparation method and products of danofloxacin mesylate liposome |
| CN102552160B (en) * | 2010-12-24 | 2013-07-17 | 华中农业大学 | Veterinary danofloxacin mesylate slow-release microsphere preparation as well as preparation method and application of veterinary danofloxacin mesylate slow-release microsphere preparation |
| CN102600075A (en) * | 2012-04-19 | 2012-07-25 | 烟台海研制药有限公司 | Danofloxacin mesylate suspension and preparation method thereof |
| CN110237075A (en) * | 2019-06-25 | 2019-09-17 | 华中农业大学 | A kind of purposes of Danofloxacin in treatment haemophilus parasuis drug |
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