CN101744831B - Preparation method of tylosin tartrate-doxycycline hydrochloride pharmaceutical composition - Google Patents
Preparation method of tylosin tartrate-doxycycline hydrochloride pharmaceutical composition Download PDFInfo
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- CN101744831B CN101744831B CN 200910227729 CN200910227729A CN101744831B CN 101744831 B CN101744831 B CN 101744831B CN 200910227729 CN200910227729 CN 200910227729 CN 200910227729 A CN200910227729 A CN 200910227729A CN 101744831 B CN101744831 B CN 101744831B
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Abstract
The invention discloses a preparation method of tylosin tartrate-doxycycline hydrochloride pharmaceutical composition, which comprises the following steps: dissolving a high molecular material in an organic solvent to prepare a dispersion medium; respectively adding tylosin tartrate powder and doxycycline hydrochloride powder to the dispersion medium slowly, heating, stirring, dissolving and then cooling to respectively obtain a tylosin tartrate microsphere suspension and a doxycycline hydrochloride microsphere suspension; and centrifuging, filtering, washing and drying the dispersion microsphere suspension to obtain microspheres. The weight ratio of the tylosin tartrate microspheres to the doxycycline hydrochloride microspheres is 3-4:1 counted by tylosin to doxycycline, and the microspheres are mixed uniformly and adjuvant is added to prepare soluble powder, particles and oral liquid. The pharmaceutical composition prepared in the invention has good curative effect, covers up the bitterness of the medicine, and is favorable for livestock and fowl to take.
Description
Technical field
The present invention relates to the preparation of tylosin tartrate and doxycycline hydrochloride pharmaceutical composition.
Technical background
Present commercially available tylosin tartrate-doxycycline hydrochloride soluble powder or granule; Be mainly used in the infectious disease that treatment poultry gram positive bacteria, negative bacterium and mycoplasma cause; Like cureless multi-pathogenesis respiratory tract disease; The chicken Bacillus pasteurii disease, the escherichia coli of virosis secondary such as newcastle, bird flu, infectious bronchitis and mycoplasma mixed infection etc.; Swine enzootic pneumonia, contagious pleuropneumonia, Bacillus pasteurii disease, dysentery etc.; The respiratory symptom that poultry cause because of stressors such as change in weather, commentaries on classics crowd, vaccinations.
At present commercially available tylosin tartrate-doxycycline hydrochloride soluble powder and its curative effect of granule are undesirable; Mainly be because commercially available tylosin tartrate soluble powder and granule employing drug powder are raw material; And tylosin tartrate and doxycycline hydrochloride itself all has intensive bitter in the mouth, so that palatability is bad, thereby influences searching for food and drinking water of poultry; Especially bigger to the more sensitive pig feed intake influence of olfactory sensation; Be difficult to reach dose therapeutically effective, thereby influence the curative effect of medicine, and cause a large amount of wastes of medicine.
Summary of the invention
To the weak point that prior art exists, the technical problem that the present invention will solve provides the method for preparing of a kind of tylosin tartrate and doxycycline hydrochloride pharmaceutical composition.This method has been covered its poor taste through medication preparation is become microsphere, is beneficial to the absorption of fowl poultry, and the pharmaceutical composition good effect of preparation.
The inventive method is respectively tylosin tartrate, doxycycline hydrochloride to be prepared into microsphere, and the two mixes the back and adds adjuvant, can be prepared into soluble powder, granule or oral liquid respectively.
Preparation of drug combination method of the present invention, contain following steps:
1) macromolecular material is dissolved in organic solvent prepared composition dispersion media;
2) respectively tylosin tartrate, doxycycline hydrochloride powder are slowly joined in the disperse medium, heated and stirred dissolving postcooling obtains tylosin tartrate microsphere suspension, doxycycline hydrochloride microsphere suspension respectively;
3) the microsphere suspension is centrifugal, filtration, washing, drying obtain tylosin tartrate microsphere and doxycycline hydrochloride microsphere;
4) tylosin tartrate microsphere and doxycycline hydrochloride microsphere add adjuvant and are prepared into soluble powder, granule or oral liquid respectively according to the drug ratios mix homogeneously.
The amount of tylosin tartrate microsphere of the present invention and doxycycline hydrochloride microsphere is generally 3～4 in tylosin and doxycycline: 1, preferred 3.5～3.8: 1.
The macromolecular material that the present invention adopted can be ethyl cellulose, paraffin, Lac, arabic gum, methylcellulose, hydroxypropyl cellulose, cellulose acetate-phthalate, Polyethylene Glycol-4000, polyethylene one or more a mixture wherein.
The organic solvent that macromolecular material is dissolved in the present invention can be a kind of or its mixture in ethanol, cyclohexane extraction, methanol, the acetone.
The weight ratio of macromolecular material of the present invention and tylosin tartrate or doxycycline hydrochloride is 1～3: 1.
When speed of agitator is 1000rpm～3000rpm method for preparing step 2 of the present invention), stirs 10～60min and get final product.
Centrifugal, filter, washing, dryly get final product by conventional method.When centrifugal rotational speed was 3000～5000rpm, centrifugation time was 5～30min; Washer solvent can be selected petroleum ether, ether, cyclohexane extraction for use; Drying mode such as can select vacuum dehydrating at lower temperature, lyophilization or room temperature to place to dry for use at mode.
The tylosin tartrate-doxycycline hydrochloride microsphere is prepared into the method for soluble powder, granule or oral liquid and the adjuvant of use all is conventional.Preparation soluble powder adjuvant commonly used such as sucrose, glucose, lactose etc. all are suitable for the present invention.The adjuvant of preparation drug particles such as dextrin, the two mixture of sucrose, weight ratio is a sucrose: dextrin=3～2: 1 is better.The adjuvant of preparation oral liquid comprises water, suspending agent, chelating agent etc.; Suspending agent such as sodium carboxymethyl cellulose etc., consumption are 0.1%～0.5% of oral liquid; Chelating agent such as disodiumedetate etc., consumption are 0.001%～0.05% of oral liquid.
The inventive method compared with prior art has following beneficial effect:
1. adopt tylosin tartrate that microcapsule technology will all have a bitterness and doxycycline hydrochloride through being prepared into microsphere, covered the bitterness of medicine, be beneficial to the absorption that fowl is raiseeed.
2. the pharmaceutical preparation good effect that the tylosin tartrate-doxycycline hydrochloride pharmaceutical composition for preparing with the inventive method prepares.
The specific embodiment
Below in conjunction with embodiment the present invention is further specified.Drug particles according to embodiment 6 preparations has carried out palatability testing and clinical trial.
The preparation of embodiment 1 tylosin tartrate microsphere
(1) get ethyl cellulose 100g, add cyclohexane extraction 1000ml, heated and stirred makes dissolving process ethyl cellulose solution;
(2) get tylosin tartrate fine powder 60g, be dispersed in the above-mentioned solution, be heated to 80 ℃, stir 30min, be cooled to room temperature and get dispersion microsphere suspension;
(3) with dispersion microsphere suspension with the centrifugal 20min of the rotating speed of 3000rpm, filter, dry tylosin tartrate microsphere.
This tylosin tartrate microsphere is tested, and its roundness is good, good dispersion in aqueous solution, and mean diameter 38.5 μ m, particle size distribution range accounts for 87% of sum at the microsphere of 60～180 μ m, and the microsphere envelop rate is 52.6%, drug loading 28.4%.
The preparation of embodiment 2 tylosin tartrate microspheres
(1) taking polyethylene glycol-4000 140g, with the dissolving of 2400ml ethanol heated and stirred, preparation PEG solution;
(2) get and add tylosin tartrate powder 60g after the paraffin 40g heat fused, stirring is dispersed in the above-mentioned solution while hot rapidly, and temperature is 80 ℃ during stirring, and mixing time 30min is cooled to room temperature and gets suspension;
(3) with dispersion microsphere suspension with the centrifugal 20min of the rotating speed of 3000rpm, filter, with petroleum ether, drying obtains the tylosin tartrate microsphere.
This tylosin tartrate microsphere is tested, and its roundness is good, good dispersion in aqueous solution, and mean diameter 22.4 μ m, particle size distribution range accounts for 76% of sum at the microsphere of 60～180 μ m, and the microsphere envelop rate is 71.2%, drug loading 21.6%.
The preparation of embodiment 3 doxycycline hydrochloride microspheres
(1) taking polyethylene glycol-4000 40g, with the dissolving of 600ml ethanol heated and stirred, preparation PEG solution;
(2) get and add doxycycline hydrochloride powder 35g after the paraffin 10g heat fused, stirring is dispersed in the above-mentioned solution while hot rapidly, and temperature is 80 ℃ during stirring, and mixing time 30min is cooled to room temperature and gets suspension;
(3) with dispersion microsphere suspension with the centrifugal 20min of the rotating speed of 3000rpm, filter, with petroleum ether, drying obtains the doxycycline hydrochloride microsphere.
This doxycycline hydrochloride microsphere is tested, and its roundness is good, good dispersion in aqueous solution, and mean diameter 30.1 μ m, particle size distribution range accounts for 82% of sum at the microsphere of 60～180 μ m, and the microsphere envelop rate is 64.6%, drug loading 33.2%.
The preparation of embodiment 4 doxycycline hydrochloride microspheres
(1) get ethyl cellulose 30g, add cyclohexane extraction 500ml, heated and stirred makes dissolving process ethyl cellulose solution;
(2) get doxycycline hydrochloride fine powder 30g, be dispersed in the above-mentioned solution, 80 ℃ of heating-up temperatures stir 30min, are cooled to room temperature and get suspension;
(3) with dispersion microsphere suspension with the centrifugal 20min of the rotating speed of 3000rpm, filter, drying, the doxycycline hydrochloride microsphere.
This doxycycline hydrochloride microsphere is tested, and its roundness is good, good dispersion in aqueous solution, and mean diameter 35.4 μ m, particle size distribution range accounts for 84% of sum at the microsphere of 60～180 μ m, and the microsphere envelop rate is 61.1%, drug loading 38.2%.
The preparation of embodiment 5 tylosin tartrate-doxycycline hydrochloride soluble powders
Treating excess syndrome is executed the doxycycline hydrochloride microsphere 9.43g (being equivalent to doxycycline 3.33g) of 1 preparation tylosin tartrate microsphere 47.81g (being equivalent to tylosin 11.67g) and embodiment 4 preparations; Add lactose and complement to 100g; Mixing; Cross 80 mesh sieves, promptly get the tylosin tartrate-doxycycline hydrochloride soluble powder.
The particulate preparation of embodiment 6 tylosin tartrate-doxycycline hydrochlorides
Treating excess syndrome is executed the doxycycline hydrochloride microsphere 9.43g (being equivalent to doxycycline 3.33g) of 1 preparation tylosin tartrate microsphere 47.81g (being equivalent to tylosin 11.67g) and embodiment, 4 preparations, and with sucrose: dextrin (2: 1) complements to 100g, and granule is made by handwork.
The particulate preparation of embodiment 7 tylosin tartrate-doxycycline hydrochlorides
Get embodiment 2 preparation tylosin tartrate 64.65 (being equivalent to tylosin 12g) of microspheres and and the doxycycline hydrochloride microsphere 8.50g (being equivalent to doxycycline 3g) of embodiment 4 preparations, with sucrose: dextrin (3: 1) complements to 100g, and granule is made by handwork.
The preparation of embodiment 8 tylosin tartrate-doxycycline hydrochloride oral liquids
Get purified water 900ml and add sodium carboxymethyl cellulose 1.5g, disodiumedetate 0.1g; Stir; Add the tylosin tartrate microsphere 60.60g (being equivalent to tylosin 11.25g) of embodiment 2 preparations and reach the doxycycline hydrochloride microsphere 10.62g (being equivalent to doxycycline 3.75g) that embodiment 4 prepares; Add purified water and supply 1000ml, the speed with 800 rev/mins of rotating speeds under 50 ℃ stirred 6 hours, promptly got the tylosin tartrate-doxycycline hydrochloride oral liquid.
Embodiment 9 tylosin tartrate-doxycycline hydrochloride granule palatability testings relatively
Test specimen 1: according to embodiment 6 preparation tylosin tartrate-doxycycline hydrochloride granule 600g (lot numbers: 20090306)
Test specimen 2: tylosin tartrate-doxycycline hydrochloride granule 600g (lot number 20090301; Method for preparing: get and get tylosin tartrate-doxycycline hydrochloride respectively; Add sucrose: dextrin=2: 1 is prepared into granule, wherein 100g granule: tylosin 12.5g+ doxycycline 2.5g)
Laboratory animal: pig, body weight 30-35kg, physical health, grow normal, mental status is good.
Test is divided into groups: blank group, 1 group of test specimen, 2 groups of test specimens, every group of 5 pigs.
Usage and dosage: mix drink, these article of 1L water 1g, negative control group gives tap water.
Test place: Henan Province's veterinary drug Engineering Technical Research Centre
Test method: preceding 5 days equal drinking public water supplies of administration, give tap water at 9 in morning every day, morning next day 9 records animal inflow.Negative control group, test specimen group gave corresponding medicine according to usage and dosage respectively in the 6th day to the 10th day, and give tap water at 9 in morning every day, morning next day 9 records animal inflow.Calculating is respectively organized preceding 5 days, back 5 days average every pig inflows, and the result sees table 1.
Table 1 pig is to the statistical result of different pharmaceutical drinking-water situation
Result: test 1 group of preceding 5 days test specimen, 2 groups of amounts of drinking water of test specimen and negative control group there was no significant difference; Test 1 group of amount of drinking water of back 5 days test specimens and negative control group there was no significant difference, 5 days amounts of drinking water and negative control group have notable difference behind 2 groups of the test specimens.Therefore, explain that the tylosin tartrate-doxycycline hydrochloride pharmaceutical composition palatability of the inventive method preparation is better.
The colibacillary curative effect contrast test of embodiment 10 artificial challenges
Contaminating mode and dosage: escherichia coli O
78Derive from China Veterinery Drug Inspection Office, each test group chest muscle injection, 0.5ml, 1.0 * 10
9CFU/ml.
Divide into groups and administration:
Select 200 of healthy SPF chickens in 3 ages in week for use, be divided into 4 groups at random, 50 every group.
Test 1 group: the blank group, do not contaminate not administration, isolated rearing.
Test 2 groups: negative control group, after the contamination, not administration, isolated rearing.
1 group of test specimen: (lot number: 20090306), mix drink, every premium on currency contains these article 1g to the tylosin tartrate-doxycycline hydrochloride granule, logotype 5 days.
2 groups of test specimens: tylosin tartrate-doxycycline hydrochloride granule (lot number 20090301; Method for preparing: get and get tylosin tartrate-doxycycline hydrochloride respectively; Add sucrose: dextrin=be prepared into granule, wherein 100g granule at 2: 1: tylosin 12.5g+ doxycycline 2.5g), mix drink; Every premium on currency contains these article 1g, logotype 5 days.
The result: observe and write down the clinical symptoms of respectively organizing chicken, and the chicken that dies of illness is cutd open inspection and antibacterial separation, statistics mortality rate, cure rate, rate of body weight gain and effective percentage, the result sees table 2.
Table 2 clinical treatment result of the test statistics
| Group | Mortality rate/% | Cure rate/% | Rate of body weight gain/% | Effective percentage/% |
| The blank group | 0 | - | 100 | - |
| Negative control group | 84 | - | 61.3 | - |
| 1 group of test specimen | 6 | 90 | 97.5 | 94 |
| 2 groups of test specimens | 18 | 74 | 80.3 | 78 |
The result: find out that from table 2 test specimen 1, test specimen 2 all can control the clinical symptoms of artificial challenge escherichia coli chicken, reduce the mortality rate of chicken, wherein the mortality rate of 1 group of chicken of test specimen is lower; The effective percentage that test specimen is 1 group, cure rate, rate of body weight gain all are higher than 2 groups of test specimens.The curative effect that the tylosin tartrate-doxycycline hydrochloride pharmaceutical composition treatment colibacillosis that the inventive method prepares is described is better.
Claims (1)
1. the method for preparing of a tylosin tartrate-doxycycline hydrochloride pharmaceutical composition, it comprises the steps:
(1) preparation tylosin tartrate microsphere: get ethyl cellulose 100g, add cyclohexane extraction 1000ml, heated and stirred makes dissolving process ethyl cellulose solution; Get tylosin tartrate fine powder 60g, be dispersed in the above-mentioned solution, be heated to 80 ℃, stir 30min, be cooled to room temperature and get dispersion microsphere suspension; Dispersion microsphere suspension with the centrifugal 20min of the rotating speed of 3000rpm, is filtered, dry tylosin tartrate microsphere;
(2) preparation doxycycline hydrochloride microsphere: get ethyl cellulose 30g, add cyclohexane extraction 500ml, heated and stirred makes dissolving process ethyl cellulose solution; Get doxycycline hydrochloride fine powder 30g, be dispersed in the above-mentioned solution, 80 ℃ of heating-up temperatures stir 30min, are cooled to room temperature and get suspension; Dispersion microsphere suspension with the centrifugal 20min of the rotating speed of 3000rpm, is filtered, and drying gets the doxycycline hydrochloride microsphere;
(3) get made tylosin tartrate microsphere 47.81g and doxycycline hydrochloride microsphere 9.43g: add lactose and complement to 100g, mixing is crossed 80 mesh sieves, promptly gets the tylosin tartrate-doxycycline hydrochloride soluble powder.
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| CN 200910227729 CN101744831B (en) | 2009-12-30 | 2009-12-30 | Preparation method of tylosin tartrate-doxycycline hydrochloride pharmaceutical composition |
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| CN101744831B true CN101744831B (en) | 2012-09-05 |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102552152B (en) * | 2011-12-26 | 2014-02-19 | 成都中牧生物药业有限公司 | Veterinary doxycycline hydrochloride-polymer composite particle and preparation method thereof |
| CN105030801B (en) * | 2015-05-27 | 2018-12-04 | 洛阳惠德生物工程有限公司 | A kind of safe ten thousand rhzomorphs formulation preparation method and its ten thousand rhzomorph preparation of Thailand and pharmaceutical composition of preparation |
| CN107837241A (en) * | 2017-11-03 | 2018-03-27 | 河南益华动物药业有限公司 | A kind of retens micro-capsule and preparation method thereof |
| CN108938563A (en) * | 2018-08-16 | 2018-12-07 | 重庆布尔动物药业有限公司 | A method of by the quickly dissolution/swelling of the water soluble polymer suspending agent in drug suspension |
| CN110075068A (en) * | 2019-06-04 | 2019-08-02 | 河南健恒动物药业有限公司 | A kind of doxycycline hydrochloride soluble powder and preparation method thereof |
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| CN1985838A (en) * | 2005-12-21 | 2007-06-27 | 天津市润拓生物技术有限公司 | Lung-targeting tylan microsphere for animal and birds and its preparing method |
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| Raghavendra C. Mundargi et al.Development and evaluation of novel biodegradable microspheres based on poly(D,L-lactide-co-glycolide) and poly(ε-caprolactone) for controlled delivery of doxycycline in the treatment of human periodontal pocket: In vitro and in vivo studies.《Journal of Controlled Release》.2007,第119卷(第1期),59-68. * |
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