Summary of the invention
For the deficiencies in the prior art, the object of the present invention is to provide a kind of preparation method of animal specific phosphoric acid tilmicosin microspheres, after adopting specific coating coated the fallow phosphoric acid tilmicosin crude drug to light red brown particle shape, obtain the white phosphoric acid tilmicosin microspheres that drug loading is moderate, envelop rate is high, solved the poor problem of this medicine palatability, to meet better need of production.
To achieve these goals, the preparation method of a kind of animal specific phosphoric acid of technical scheme of the present invention tilmicosin microspheres, its step is as follows:
1. acrylic resin is dissolved in dehydrated alcohol, is mixed with the ethanol solution that concentration is the acrylic resin of 5-15wt%, be called solution A;
Described acrylic resin is German rom (Rohm) acrylic resin (especially strange) RSPO;
2. phosphoric acid tilmicosin crude drug and soybean oil are mixed according to weight ratio 1:1.25-1:6.5, stir and make both mix homogeneously, obtain mixture B;
3. solution A is joined in mixture B, ultrasonic 1min fully mixes it, obtains mixture C;
Wherein the weight ratio of the phosphoric acid tilmicosin crude drug in mixture B and the acrylic resin in solution A is 1:2.12-1:3.52;
4. Arlacel-80 (SP-80), powder silicon dioxide and liquid paraffin are mixed and be placed in 40 ℃ of water-baths, under the speed of 800-1000r/min stirs, drip mixture C, drip and finish rear continuation at 40 ℃ of stirred in water bath 1-3h, make absolute ethanol volatilizes complete, obtain mixture D;
Wherein in Arlacel-80, powder silicon dioxide, liquid paraffin and mixture C, the ratio of institute's phosphoric acid tilmicosin crude drug is: (0.45-0.75g): (0.3-0.5g): (30-50mL): (0.25-0.5g);
5. mixture D petroleum ether 3 times, to wash away liquid paraffin, then carry out vacuum filtration, and gained solid is dried at 40 ℃, obtains phosphoric acid tilmicosin microspheres of the present invention.
It is raw material that the fallow phosphoric acid tilmicosin crude drug to light red brown particle shape is take in the present invention, acrylic resin is coating, water soluble drug powder packets is entrained in the Semen sojae atricolor oil phase of sealing coat, by interface molecular force, wrap up and the encapsulation for the second time of hydrophobic polymer solution subsequently.Prepared microsphere is greatly improved the palatability of medicine, and the envelop rate of medicine reaches 74.57%~99.82%.
Advantage of the present invention and beneficial effect are as follows:
1, the present invention adopts the coating acrylic resin that people's medicine is conventional to be coated with the poor phosphoric acid tilmicosin crude drug of palatability, and the envelop rate of medicine is significantly improved compared with additive method;
2, in the present invention, selected preparation technology is simple, and good stability, has good commercial application prospect;
3, the prepared phosphoric acid tilmicosin microspheres of the inventive method has solved the poor problem of the caused palatability of crude drug Direct-fed well, for good basis has been established in the clinical practice of medicine.
The specific embodiment
Below in conjunction with specific embodiment, the inventive method is further elaborated.
Embodiment 1
A preparation method for animal specific phosphoric acid tilmicosin microspheres, its step is as follows:
(1) take acrylic resin RSPO1.11g, be dissolved in the dehydrated alcohol of 10mL, obtain solution A;
(2) take 0.5g phosphoric acid tilmicosin crude drug, join in 1.25g soybean oil, stir, obtain mixture B;
(3) solution A is joined in mixture B, ultrasonic 1min fully mixes it, obtains mixture C;
(4) 0.75g SP-80,0.5g silicon dioxide and 50mL liquid paraffin are mixed and be placed in 40 ℃ of water-baths, under the speed of 900r/min stirs, drip mixture C, drip and finish rear continuation at 40 ℃ of stirred in water bath 1.0h, make absolute ethanol volatilizes complete, obtain mixture D;
(5) petroleum ether 3 times for mixture D is used petroleum ether 20mL at every turn, vibrates after centrifugal and discards solution, to wash away liquid paraffin, then carries out vacuum filtration, and gained solid is dried at 40 ℃, obtains phosphoric acid tilmicosin microspheres of the present invention.
The physicochemical property of the phosphoric acid tilmicosin microspheres of gained is stable, and the result that records drug loading and envelop rate by high performance liquid chromatography is respectively 24.56% and 74.57%.The microsphere sample that this example is made is distributed into three batches, deposit respectively to 4 ℃ of refrigerators, room temperature and 40 ℃ of baking ovens and investigate, before mode of appearance, particle diameter and the distribution thereof of discovery microsphere, drug loading, tablets in vitro percentage rate and investigation, all without significant change, polymeric microspheres stabilize is good.
Embodiment 2
A preparation method for animal specific phosphoric acid tilmicosin microspheres, its step is as follows:
(1) take acrylic resin RSPO0.53g, be dissolved in the dehydrated alcohol of 10mL, obtain solution A;
(2) take 0.25g phosphoric acid tilmicosin crude drug, join in 0.625g soybean oil, stir, obtain mixture B;
(3) solution A is joined in mixture B, ultrasonic 1min fully mixes it, obtains mixture C;
(4) 0.45g SP-80,0.5g silicon dioxide and 50mL liquid paraffin are mixed and be placed in 40 ℃ of water-baths, under the speed of 900r/min stirs, drip mixture C, drip and finish rear continuation at 40 ℃ of stirred in water bath 1.5h, make absolute ethanol volatilizes complete, obtain mixture D;
(5) petroleum ether 3 times for mixture D is used petroleum ether 20mL at every turn, vibrates after centrifugal and discards solution, to wash away liquid paraffin, then carries out vacuum filtration, and gained solid is dried at 40 ℃, obtains phosphoric acid tilmicosin microspheres of the present invention.
The physicochemical property of the phosphoric acid tilmicosin microspheres of gained is stable, and the result that records drug loading and envelop rate by high performance liquid chromatography is respectively 26.45% and 99.82%.The microsphere sample that this example is made is distributed into three batches, deposit respectively to 4 ℃ of refrigerators, room temperature and 40 ℃ of baking ovens and investigate, before mode of appearance, particle diameter and the distribution thereof of discovery microsphere, drug loading, tablets in vitro percentage rate and investigation, all without significant change, polymeric microspheres stabilize is good.
Embodiment 3
A preparation method for animal specific phosphoric acid tilmicosin microspheres, its step is as follows:
(1) take acrylic resin RSPO1.11g, be dissolved in the dehydrated alcohol of 10mL, obtain solution A;
(2) take 0.375g phosphoric acid tilmicosin crude drug, join in 0.625g soybean oil, stir, obtain mixture B;
(3) solution A is joined in mixture B, ultrasonic 1min fully mixes it, obtains mixture C;
(4) 0.6g SP-80,0.4g silicon dioxide and the mixing of 40mL liquid paraffin are placed in 40 ℃ of water-baths, under the speed of 900r/min stirs, drip mixture C, drip and finish rear continuation at 40 ℃ of stirred in water bath 2.0h, make absolute ethanol volatilizes complete, obtain mixture D;
(5) petroleum ether 3 times for mixture D is used petroleum ether 20mL at every turn, vibrates after centrifugal and discards solution, to wash away liquid paraffin, then carries out vacuum filtration, and gained solid is dried at 40 ℃, obtains phosphoric acid tilmicosin microspheres of the present invention.
The physicochemical property of the phosphoric acid tilmicosin microspheres of gained is stable, and the result that records drug loading and envelop rate by high performance liquid chromatography is respectively 25.39% and 97.83%.The microsphere sample that this example is made is distributed into three batches, deposit respectively to 4 ℃ of refrigerators, room temperature and 40 ℃ of baking ovens and investigate, before mode of appearance, particle diameter and the distribution thereof of discovery microsphere, drug loading, tablets in vitro percentage rate and investigation, all without significant change, polymeric microspheres stabilize is good.
Embodiment 4
A preparation method for animal specific phosphoric acid tilmicosin microspheres, its step is as follows:
(1) take acrylic resin RSPO1.76g, be dissolved in the dehydrated alcohol of 10mL, obtain solution A;
(2) take 0.5g phosphoric acid tilmicosin crude drug, join in 1.625g soybean oil, stir, obtain mixture B;
(3) solution A is joined in mixture B, ultrasonic 1min fully mixes it, obtains mixture C;
(4) 0.75g SP-80,0.5g silicon dioxide and 50mL liquid paraffin are mixed and be placed in 40 ℃ of water-baths, under the speed of 1000r/min stirs, drip mixture C, drip and finish rear continuation at 40 ℃ of stirred in water bath 1.5h, make absolute ethanol volatilizes complete, obtain mixture D;
(5) petroleum ether 3 times for mixture D is used petroleum ether 20mL at every turn, vibrates after centrifugal and discards solution, to wash away liquid paraffin, then carries out vacuum filtration, and gained solid is dried at 40 ℃, obtains phosphoric acid tilmicosin microspheres of the present invention.
The physicochemical property of the phosphoric acid tilmicosin microspheres of gained is stable, and the result that records drug loading and envelop rate by high performance liquid chromatography is respectively 26.88% and 96.72%.The microsphere sample that this example is made is distributed into three batches, deposit respectively to 4 ℃ of refrigerators, room temperature and 40 ℃ of baking ovens and investigate, before mode of appearance, particle diameter and the distribution thereof of discovery microsphere, drug loading, tablets in vitro percentage rate and investigation, all without significant change, polymeric microspheres stabilize is good.
Phosphoric acid tilmicosin microspheres Dissolution Rate Testing
One, experiment material
1. main agents and medicine
Phosphoric acid tilmicosin microspheres (the prepared product of embodiments of the invention); The equal Pass Test requirement of other reagent.
2. key instrument equipment
RC-6D type drug dissolution tester, Tianjin Guoming Medicine Equipment Co., Ltd..
Two, experimental technique
Take phosphoric acid tilmicosin microspheres 0.1g, with reference to Chinese < < Chinese veterinary pharmacopoeia > > (version in 2010) First dissolution method first method, take 900mL0.02%Tween-20(g/mL) aqueous solution is release medium, rotating speed is 75rpm, temperature is 37 ± 0.5 ℃, respectively at 5min, 10min, 15min, 30min, 45min, 1h, 1.5h, 2h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, when 11h and 12h, sample 5mL(and supplement the synthermal fresh dissolution medium of equal-volume simultaneously), measure in accordance with the law, calculate its dissolution.
Three, experimental result
Carry out as stated above dissolution determination, the medicine microspheres release curve chart of embodiment 1-4 is shown in that Fig. 1 is to Fig. 4.As we know from the figure, the rate of release of the microsphere Chinese medicine of embodiment 1 is fast compared with other 3 embodiment's, and short compared with other embodiment of the interval that discharges of sustained drug.The release profiles of embodiment 2,3,4 microsphere Chinese medicines is close.In microsphere, phosphoric acid tilmicosin is the trend that continues slow release, and the release initial stage of phosphoric acid tilmicosin microspheres is quick release, and in this stage, the medicine that is present in microsphere surface discharges quickly; Later stage is slow release, and the medicine being present in acrylic resin microsphere hole discharges gradually.
Phosphoric acid tilmicosin microspheres palatability testing
One, experiment material
1. main agents and medicine
Phosphoric acid tilmicosin microspheres (the prepared product of embodiments of the invention), Zhi Lejing (Wuhan Hvsen Biotechnology Co., Ltd.'s product).
2. laboratory animal
Landrace, body weight 25-30kg, totally 36, to raise in cages, free choice feeding drinking-water, feeds not containing the adequate diet of antibacterials, raises 5d before test.
Two, experimental technique
1. animal grouping
36 pigs are divided into 6 groups at random, every group of 6 repetitions.
I group is fed and is not contained the complete feedstuff (matched group) of antibacterials;
II group is fed and is added the complete feedstuff of Zhi Lejing;
III group is fed and is added the complete feedstuff of the prepared phosphoric acid tilmicosin microspheres of embodiment 1;
IV group is fed and is added the complete feedstuff of the prepared phosphoric acid tilmicosin microspheres of embodiment 2;
V group is fed and is added the complete feedstuff of the prepared phosphoric acid tilmicosin microspheres of embodiment 3;
VI group is fed and is added the complete feedstuff of the prepared phosphoric acid tilmicosin microspheres of embodiment 4.
2. administration
Control animals is pressed the administration of Zhi Lejing operation instructions, in other test group, first the medicine in microsphere and crude drug is carried out to content conversion, guarantees that the phosphoric acid tilmicosin content that each test group feeds with II group is identical.15d continuously feeds.
3. evaluation index
With daily ingestion amount, daily gain and three indexs of feedstuff-meat ratio, evaluate the palatability problem of coated rear medicine (phosphoric acid tilmicosin microspheres).
Three, experimental result
Daily ingestion amount, daily gain and the feedstuff-meat ratio of feeding after the product of each embodiment the results are shown in Table 1-4.
Daily ingestion amount, daily gain and the feedstuff-meat ratio of 1 three groups of table 1 embodiment
The relative deviation that adds the experimental group of phosphoric acid tilmicosin microspheres and daily ingestion amount, daily gain and the feedstuff-meat ratio of matched group is respectively-34.27% ,-43.81% and 17.20%; The relative deviation that adds the experimental group of phosphoric acid tilmicosin and daily ingestion amount, daily gain and the feedstuff-meat ratio of matched group is respectively-44.87% ,-53.47% and 19.0%; The experimental group that adds phosphoric acid tilmicosin is respectively-24.26% ,-24.46% and 0.31% with the relative deviation of daily ingestion amount, daily gain and the feedstuff-meat ratio of the experimental group of interpolation phosphoric acid tilmicosin microspheres.
Daily ingestion amount, daily gain and the feedstuff-meat ratio of 2 three groups of table 2 embodiment
The relative deviation that adds the experimental group of phosphoric acid tilmicosin microspheres and daily ingestion amount, daily gain and the feedstuff-meat ratio of matched group is respectively-5.35% ,-5.44% and 0.36%; The relative deviation that adds the experimental group of phosphoric acid tilmicosin and daily ingestion amount, daily gain and the feedstuff-meat ratio of matched group is respectively-44.87% ,-53.47% and 19.0%; The experimental group that adds phosphoric acid tilmicosin is respectively-41.76% ,-50.79% and 18.57% with the relative deviation of daily ingestion amount, daily gain and the feedstuff-meat ratio of the experimental group of interpolation phosphoric acid tilmicosin microspheres.
Daily ingestion amount, daily gain and the feedstuff-meat ratio of 3 three groups of table 3 embodiment
The relative deviation that adds the experimental group of phosphoric acid tilmicosin microspheres and daily ingestion amount, daily gain and the feedstuff-meat ratio of matched group is respectively-7.73% ,-4.22% and 1.0%; The relative deviation that adds the experimental group of phosphoric acid tilmicosin and daily ingestion amount, daily gain and the feedstuff-meat ratio of matched group is respectively-50.22% ,-57.55% and 17.56%; The experimental group that adds phosphoric acid tilmicosin is respectively-49.68% ,-55.68% and 13.49% with the relative deviation of daily ingestion amount, daily gain and the feedstuff-meat ratio of the experimental group of interpolation phosphoric acid tilmicosin microspheres.
Daily ingestion amount, daily gain and the feedstuff-meat ratio of 4 three groups of table 4 embodiment
The relative deviation that adds the experimental group of phosphoric acid tilmicosin microspheres and daily ingestion amount, daily gain and the feedstuff-meat ratio of matched group is respectively-7.73% ,-8.03% and 0.72%; The relative deviation that adds the experimental group of phosphoric acid tilmicosin and daily ingestion amount, daily gain and the feedstuff-meat ratio of matched group is respectively-50.22% ,-57.55% and 17.56%; The experimental group that adds phosphoric acid tilmicosin is respectively-46.05% ,-53.85% and 16.73% with the relative deviation of daily ingestion amount, daily gain and the feedstuff-meat ratio of the experimental group of interpolation phosphoric acid tilmicosin microspheres.
Result shows: the phosphoric acid tilmicosin microspheres after coated in embodiment 1-4, has had good improvement compared with Direct-fed phosphoric acid tilmicosin crude drug to the palatability of animal.