CN102871970A - Puerarin oral adhesion microballoon spheres and preparation method thereof - Google Patents
Puerarin oral adhesion microballoon spheres and preparation method thereof Download PDFInfo
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Abstract
The invention discloses puerarin oral adhesion microballoon spheres and a preparation method thereof, and the spheres and the preparation method belong to the technical field of medicine. The puerarin oral adhesion microballoon spheres comprise components in the following weight portions: 100 portions of puerarin, 100 portions to 300 portions of mitigating skeleton material, 50 portions to 100 portions of adhesive material, 50 portions to 100 portions of emulsifier, and 100 portions to 300 portions of liquid paraffin. The preparation process of the puerarin oral adhesion microballoon spheres comprises the following steps that soak containing puerarin is prepared into suspension; oil phase is prepared; the suspension is added into the oil phase to be stirred; the temperature rises, and the microballoon spheres are formed; and the microballoon spheres are washed by petroleum ether and dried at room temperature, and finished products are formed. The puerarin oral adhesion microballoon spheres can significantly improve the neurological symptoms of a cerebral ischemia rat, enhance the vitality of superoxide dismutase (SOD) and reduce the content of malondialdehyde (MDA). Compared with injection, the puerarin oral adhesion microballoon spheres have good oral compliance; and compared with ordinary oral preparation puerarin tablets, the puerarin oral adhesion microballoon spheres can improve the characteristic of oral bioavailability, and make up for the defects of current puerarin preparation.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of puerarin oral and stick microsphere and preparation method.
Background technology
Puerarin (Puerarin) is to refine the effective ingredient that obtains from Radix Puerariae (Radix Puerariae), and Radix Puerariae usually is used for the treatment of cardiovascular and cerebrovascular disease with injection clinically, can coronary artery dilator and cerebrovascular.Its chemistry 4 ', 7-dihydroxy by name-8-β-D glucose isoflavone has blood circulation promoting and blood stasis dispelling, improves microcirculation, can coronary artery dilator and cerebrovascular, be usually used in the treatment of various cardiovascular and cerebrovascular diseases.In recent years, along with increasingly extensive in clinical practice of puerarin injection, its Reporting of harms quantity is showed increased also.In February, 2003, on the third phase " adverse drug reaction circular " of national drug untoward reaction inspection center issue, puerarin is appeared on the list of successful candidates as the medicine of suspicious serious adverse reaction.Wherein account at most 21.33% with hemolytic reaction quantity; All the other are followed successively by skin lesion and account for 20.67%; Circulatory involvement accounts for 16%; Respiratory system damage accounts for 12.67%, and digestive system damage accounts for 11.33%; Drug fever account for 7.33% and anaphylactic shock account for 6.00% etc.State Food and Drug Administration gives a warning to 5 kinds of higher medicines of untoward reaction occurrence frequency such as puerarins, particularly " national drug untoward reaction communication " successively twice serious adverse reaction proposition caution with regard to puerarin injection makes people especially pay close attention to the safety of puerarin injection.Because the safety of drug administration by injection has much room for improvement, and independently administration, thereby limited the application of puerarin.In addition, in the cerebrovascular later stage, client need resumes treatment for a long time, but because injection is difficult for realizing autonomous administration, has limited to a certain extent the clinical practice of puerarin.
The oral administration patient dependence is better, be fit to the autonomous administration of the rehabilitation stage of cerebrovascular disease, but the common oral preparation bioavailability is low, needs the development of new oral formulations.For cerebrovascular disease, need long-term prescription, use the drug administration by injection during except emergency rescue, generally adopt oral administration.Oral administration is compared with drug administration by injection, and production cost reduces greatly, is conducive to reduce patient's financial burden.Dosage form take puerarin as main component mostly is oral formulations except injection in the market, but because having many phenyl ring and polyhydroxy in the puerarin structure, polarity is larger, and water solublity is less, and the dissolubility in the water only is 1.1 * 10
-2Mol/L, fat-soluble also little, be difficult to be absorbed by biomembranes such as gastrointestinal tract, the bioavailability of rat oral gavage and clinical oral administration puerarin is all lower, and oral administration biaavailability is less than 15%, and this affects the performance of its curative effect to a certain extent.
Summary of the invention
For problems of the prior art, the object of the invention is providing a kind of puerarin oral to stick microsphere and preparation method.
The present invention is realized by the following technical programs:
Described puerarin oral sticks microsphere, it is characterized in that being comprised of the component of following parts by weight:
100 parts of puerarins
Sustained-release matrix material 100-300 part
Pasting material 50-100 part
Emulsifying agent 50-100 part
Liquid paraffin 100-300 part
Wherein the sustained-release matrix material is water-insoluble sustained-release matrix material ethyl cellulose, and pasting material is carbomer; Emulsifying agent is one or more among Ovum Gallus domesticus Flavus lecithin, soybean lecithin and the span-80.
Described puerarin oral sticks microsphere, it is characterized in that being comprised of the component of following parts by weight:
100 parts of puerarins
Sustained-release matrix material 100-250 part
Pasting material 50-80 part
Emulsifying agent 50-80 part
Liquid paraffin 100-250 part
Wherein the sustained-release matrix material is water-insoluble sustained-release matrix material ethyl cellulose, and pasting material is carbomer; Emulsifying agent is one or more among Ovum Gallus domesticus Flavus lecithin, soybean lecithin and the span-80.
Described puerarin oral sticks the preparation method of microsphere, it is characterized in that by following processing step:
(1) by weight, get 100 parts of puerarins, sustained-release matrix material 100-300 part, place 100-300 part dehydrated alcohol or acetone, stir and make the sustained-release matrix Uniform Dispersion, then add airtight behind 50-100 part pasting material, 10 ℃-25 ℃ lower 12-24h of immersion, get soak;
(2) soak that step (1) is made uses magnetic stirring apparatus at 800 ~ 1200 rmin
-1, 0 ~ 10 ℃ of lower stirring makes suspension;
(3) by weight, get emulsifying agent 50-100 part, join in 100-300 part liquid paraffin and stir 5-10min, mixing speed is 400-1200 rmin
-1, make oil phase;
(4) suspension that makes in the step (2) is joined in the oil phase that step (3) makes and stir, at 0-10 ℃, 800-1200 rmin
-1Behind the lower stirring 30-60min temperature is risen to 20-30 ℃, dehydrated alcohol or acetone volatilize gradually with the rising of temperature, and microsphere forms, cross the 20-40 mesh sieve, collect microsphere, the petroleum ether take parts by weight as 50-150 part 3-6 time places the exsiccator drying at room temperature and get final product.
Described puerarin oral sticks the preparation method of microsphere, it is characterized in that described sustained-release matrix material is ethyl cellulose, and its viscosity is 45cp, and described pasting material is carbomer 934 p.
Described puerarin oral sticks the preparation method of microsphere, and it is characterized in that the soaking temperature in the step (1) is: 15-20 ℃, soak time is: 16-20h.
Described puerarin oral sticks the preparation method of microsphere, it is characterized in that the mixing speed in the step (2) is: 1000 ~ 1200 rmin
-1, temperature is: 5 ~ 10 ℃.
Described puerarin oral sticks the preparation method of microsphere, it is characterized in that the mixing time in the step (3) is 8-10min, and mixing speed is: 600-1000 rmin
-1
Described puerarin oral sticks the preparation method of microsphere, it is characterized in that in the step (4) at 5-10 ℃ 1000-1200 rmin
-1Behind the lower stirring 40-50min temperature is risen to 25-30 ℃.
Compare with existing preparation, the present invention has following having a few:
(1) envelop rate can reach 88.1 ~ 93.5%, and drug loading can reach 56% ~ 63.4%.Prepared microsphere particle is full, and outward appearance is spherical, and particle size distribution is even, meets the galenic pharmacy requirement.This preparation method have technique simple, easy to operate, with low cost, be easy to amplify, can realize the advantage such as suitability for industrialized production, can be used as the treatment that a kind of good puerarin class oral formulations is used for cerebrovascular class Recovery Phase of diseases.
(2) this oral microsphere that sticks can prolong puerarin in the holdup time of gastric mucosa, and adherence rate is 89.7 ~ 95.5%, prolongs the puerarin release in vitro time.
(3) this oral microsphere that sticks can improve the puerarin oral bioavailability, compares with the puerarin sheet, and its relative bioavailability is 919.5% ~ 966.1%, is 9.2 ~ 9.7 times of tablet bioavailability.
(4) this puerarin oral sticks function of nervous system's symptom that microsphere can significantly improve rats with cerebral ischemia, and enhance SOD vigor reduces MDA content (being the degree of injury of cerebral tissue).And compare with injection, oral compliance is good, compares with common oral preparation puerarin sheet, can improve again the characteristics of oral administration biaavailability, has remedied the deficiency of present puerarin class preparation.
The specific embodiment
The invention will be further described by following specific embodiment.
Embodiment 1
Get 100 parts of puerarins, 100 parts of the ethyl celluloses of 45cp place 100 parts of dehydrated alcohol, stirring makes the ethyl cellulose Uniform Dispersion, then adds 50 parts of carbomer 934 p, and is airtight, use magnetic stirrer behind 10 ℃ of lower immersion 24h, mixing speed is 800 rmin
-1, temperature is controlled at 0 ℃, makes suspension.
Get 50 parts of soybean lecithins, 100 parts of liquid paraffin join soybean lecithin and stir 5min in the liquid paraffin, and mixing speed is 1200 rmin
-1, then the suspension that makes is joined in the liquid paraffin oil phase that contains soybean lecithin, at 0 ℃, 1200 rmin
-1Then lower stirring 30min is warming up to 30 ℃, and dehydrated alcohol volatilizees gradually by the rising of temperature, and microsphere forms, and sieves, and collects 20-40 purpose microsphere, and petroleum ether 3-6 time, places the exsiccator drying at room temperature namely to make the oral microsphere that sticks by each 50 parts.
Embodiment 2
Get 100 parts of puerarins, 150 parts of the ethyl celluloses of 45cp place 200 parts of acetone, stir and make the ethyl cellulose Uniform Dispersion, then add 60 parts of carbomer 934 p, and are airtight, use magnetic stirrer behind 15 ℃ of lower immersion 20h, and mixing speed is 1000 rmin
-1, temperature is controlled at 5 ℃, makes suspension.
Get 60 parts of soybean lecithins, 200 parts of liquid paraffin join soybean lecithin in the liquid paraffin, stir 8min, and mixing speed is 1000rmin
-1, then the suspension that makes is joined in the liquid paraffin oil phase that contains soybean lecithin, at 5 ℃ of temperature, 1000rmin
-1Rotating speed under stir 40min, then be warming up to 25 ℃, acetone volatilizees gradually by the rising of temperature, microsphere forms, and sieves, and collects 20-40 purpose microsphere, petroleum ether 3-6 time, places the exsiccator drying at room temperature namely to make the oral microsphere that sticks by each 70 parts.
Embodiment 3
Get 100 parts of puerarins, 200 parts of the ethyl celluloses of 45cp place 250 parts of acetone, stir and make the ethyl cellulose Uniform Dispersion, then add 80 parts of carbomer 934 p, and are airtight, use magnetic stirrer behind 20 ℃ of lower immersion 16h, and mixing speed is 1000 rmin
-1, temperature is controlled at 8 ℃, makes suspension.
Get 75 parts of soybean lecithins, 250 parts of liquid paraffin join soybean lecithin in the liquid paraffin, stir 10min, and mixing speed is 400rmin
-1, then the suspension that makes is joined in the liquid paraffin oil phase that contains soybean lecithin, at 8 ℃ of temperature, 1100rmin
-1Rotating speed under stir 45min, then be warming up to 28 ℃, acetone volatilizees gradually by the rising of temperature, microsphere forms, and sieves, and collects 20-40 purpose microsphere, petroleum ether 3-6 time, places the exsiccator drying at room temperature namely to make the oral microsphere that sticks by each 90 parts.
Embodiment 4
Get 100 parts of puerarins, 300 parts of the ethyl celluloses of 45cp place 300 parts of dehydrated alcohol, stirring makes the ethyl cellulose Uniform Dispersion, then adds 100 parts of carbomer 934 p, and is airtight, use magnetic stirrer behind 25 ℃ of lower immersion 12h, mixing speed is 1200 rmin
-1, temperature is controlled at 10 ℃, makes suspension.
Get 100 parts of soybean lecithins, 300 parts of liquid paraffin join soybean lecithin in the liquid paraffin, stir 10min, and mixing speed is 600rmin
-1, then the suspension that makes is joined in the liquid paraffin oil phase that contains soybean lecithin, at 10 ℃ of temperature, 1200rmin
-1Rotating speed under stir 50min, then be warming up to 20 ℃, dehydrated alcohol volatilizees gradually by the rising of temperature, microsphere forms, and sieves, and collects 20-40 purpose microsphere, petroleum ether 3-6 time, places the exsiccator drying at room temperature namely to make the oral microsphere that sticks by each 110 parts.
Embodiment 5
Get 100 parts of puerarins, 250 parts of the ethyl celluloses of 45cp place 300 parts of dehydrated alcohol, stirring makes the ethyl cellulose Uniform Dispersion, then adds 80 parts of carbomer 934 p, and is airtight, use magnetic stirrer behind 18 ℃ of lower immersion 18h, mixing speed is 1200 rmin
-1, temperature is controlled at 10 ℃, makes suspension.
Get 80 parts of soybean lecithins, 300 parts of liquid paraffin join soybean lecithin in the liquid paraffin, stir 9min, and mixing speed is 800rmin
-1, then the suspension that makes is joined in the liquid paraffin oil phase that contains soybean lecithin, at 5 ℃ of temperature, 1200rmin
-1Rotating speed under stir 60min, then be warming up to 30 ℃, dehydrated alcohol volatilizees gradually by the rising of temperature, microsphere forms, and sieves, and collects 20-40 purpose microsphere, petroleum ether 3-6 time, places the exsiccator drying at room temperature namely to make the oral microsphere that sticks by each 130 parts.
Embodiment 6
Get 100 parts of puerarins, 280 parts of the ethyl celluloses of 45cp place 300 parts of acetone, stir and make the ethyl cellulose Uniform Dispersion, then add 100 parts of carbomer 934 p, and are airtight, use magnetic stirrer behind 18 ℃ of lower immersion 20h, and mixing speed is 1200 rmin
-1, temperature is controlled at 10 ℃, makes suspension.
Get 90 parts of soybean lecithins, 280 parts of liquid paraffin join soybean lecithin in the liquid paraffin, stir 9min, and mixing speed is 1000rmin
-1, then the suspension that makes is joined in the liquid paraffin oil phase that contains soybean lecithin, at 5 ℃ of temperature, 1200rmin
-1Rotating speed under stir 60min, then be warming up to 28 ℃, dehydrated alcohol volatilizees gradually by the rising of temperature, microsphere forms, and sieves, and collects 20-40 purpose microsphere, petroleum ether 3-6 time, places the exsiccator drying at room temperature namely to make the oral microsphere that sticks by each 150 parts.
The mensuration of drug loading and envelop rate
Get microsphere 50mg, add the 50mL distilled water as mobile phase, with preservative film sealing, ultrasonic 30min.Be settled to 50mL with mobile phase behind the jolting 10min, at 5000rmin
-1Centrifugal 50s under the condition.Get supernatant 1mL, again be settled to 50mL with distilled water, with the filtering with microporous membrane of 0.45 μ m, use at last high performance liquid chromatography in 248nm place detected peaks area A.
Chromatographic condition: mobile phase: methanol: 0.5% acetic acid water (28 72).
Shimadzu LC-10AD chromatograph of liquid: manual injector, LC-10ADVP pump, SPD-10AVP detector; Mobile phase: (28 72, v v) for methanol-0.5% acetic acid water;
Immobile phase: phenomenex GEMINI C
18Post, 150mm * 4.6mm, 5 μ m;
Column temperature: 25 ℃;
Flow velocity: 1.0mLmin
-1
Detect wavelength: 248nm.
In measured peak area A value substitution standard curve equation, try to achieve the medicine assay value, calculate the medicament contg in the solution.According to the medicament contg in the certain mass microsphere that records, calculate drug loading according to following formula:
×100%
Orthogonal experiment
On the basis of single factor analysis, choose ethyl cellulose viscosity, dosage, mixing speed and decentralized photo and continuous phase than four factors, on the basis of experiment of single factor, each factor is selected three levels, design orthogonal table such as following table.Design 9 groups of experiments according to four factors, three horizontal quadratures, measure respectively envelop rate and drug loading, weight proportion according to envelop rate and drug loading 7:3 carries out comprehensive grading, then carries out intuitive analysis and variance analysis, the quality of optimization factor affecting primary and secondary order and level.
Table 1 quadrature factor water-glass
Table 2 L
9(3
4) orthogonal experiments
Annotate: comprehensive grading envelop rate weight is 70%, and drug loading is 30%.
Table 3 analysis of variance table
Annotate: F (0.01) (1,2)=99; F (0.05) (1,2)=19.
From quadrature analysis result and analysis of variance table: affecting the factor primary and secondary that Radix Puerariae flavone adheres to microsphere drug loading and envelop rate sequentially is: C〉D〉A〉B, C, D factor are significant factors C
2C
1C
3, D
3D
2D
1, B, A are non-significant factors.A
3A
1A
2, B
3B
1B
2, consider and save cost and resource, so best preparation technology is A
2B
3C
2D
3, namely EC viscosity is 45cp, and puerarin: EC:CP is 2:2:1, and mixing speed is 1200 rmin
-1
Process certification
Verify by the optimised process that result of the test obtains, test by the optimised process combination condition, high performance liquid chromatography scanning, and calculate drug loading and envelop rate, and recording and the results are shown in Table 4, the result shows, can prepare optimum bioadhesive microspheres according to this technique.
Table 4 process certification experimental result
| Number of times | 1 | 2 | 3 | 4 | 5 | 6 |  |
| Drug loading (%) | 59.3 | 58.7 | 59.0 | 54 | 62 | 65 | 59.7 +3.7 |
| Envelop rate (%) | 90.2 | 91.9 | 88.5 | 87 | 94 | 93 | 90.8 +2.7 |
The bioadhesive experimental result
Precision takes by weighing 8 parts of 50mg microspheres, and uniform spreading is on the gastric mucosa of the rat that cuts, and fully aquation is washed, and flushing liquor is dry in 60 ℃ drying baker, and precise weighing calculates the retention rate on the gastric mucosa, the results are shown in Table 5.
Table 5 Radix Puerariae flavone bio-adhesive microsphere adherence rate is measured
The result shows, puerarin bio-adhesive microsphere has preferably bioadhesive.
The extracorporeal releasing experiment result
Choose the finished product microsphere that has prepared and carry out extracorporeal releasing experiment by experimental procedure, adopt the dissolving analyzer to measure, high performance liquid chromatography detects, and testing conditions is constant.Data see Table 6.
Table 6 microsphere release in vitro 9h data
| Sample time (h) | Appearance time (min) | Peak area (A) |
| 0.5 | 6.05 | 147270 |
| 1 | 6.025 | 240954 |
| 2 | 6.008 | 370754 |
| 3 | 6.025 | 560538 |
| 4 | 6.075 | 768555 |
| 5 | 6.2 | 939801 |
| 6 | 6.983 | 1104295 |
| 7 | 6.042 | 1187542 |
| 8 | 5.85 | 1386499 |
| 9 | 5.958 | 1291506 |
Therefore can be found out by above chart, test prepared Radix Puerariae flavone bioadhesive microspheres, release ratio is slower, can improve absorption and the bioavailability of medicine, has the characteristics such as long-acting, slow release, controlled release.
Blood drug level and biological utilisation degrees of data
Blood drug level rheological parameters' change with time after puerarin sheet, puerarin bio-adhesive microsphere, the puerarin injection administration in the rat body sees Table 7, the pharmacokinetic parameters that obtains through the match of 3P97 software sees Table 8, and absolute bioavailability and the relative bioavailability data of puerarin bio-adhesive microsphere see Table 8.
Table 7 different dosage form, different time points puerarin blood drug level (n=8,
+S)
The pharmacokinetic parameters of table 8 different dosage form puerarin and bioavailability (n=8,
+S)
After puerarin was made the bio-adhesive microsphere, absolute bioavailability increased substantially, and was 47.5%-66.7%, was significantly higher than the bioavailability of common puerarin tablet; Compare with the puerarin sheet, its relative bioavailability is 919.5%-966.1%, is the 9.2-9.7 of tablet bioavailability doubly.Can be the oral formulations exploitation with higher bioavailability and slow release controlled-release effect certain experimental basis is provided.
Puerarin bio-adhesive microsphere is on the impact of cerebral ischemia index
40 SD rats are divided into four groups at random, 10 every group.Be that sham operated rats, model group, puerarin sheet group (are amounted to 0.5g puerarin kg
-1), puerarin bio-adhesive microsphere group (amounts to 0.5g puerarin kg
-1).Medicine is suspended in the normal saline, respectively at filled with again 0 o'clock and the 6h gastric infusion once, sham operated rats and model group gavage the equivalent normal saline.
1) on the impact of rats with cerebral ischemia neurologic impairment symptom
Observe the neuroethology variation in pouring into again 24 h after rat is clear-headed.Rat carries out behavioristics with reference to 0 ~ 3 minute stage division of Bederson etc. and scores.See Table 9.
Table 9 on rat cerebral ischemia after neurological deficits score impact (
± s, n=10)
Annotate: compare with sham operated rats, ▲
P＜0.01;
Compare * with model group
P＜0.05.
2) on the impact of rats with cerebral ischemia cerebral tissue SOD
Ischemia 24h, broken end is got brain, according to the operational approach detection absorbance (A) of test kit description, calculates the value of SOD, MDA, sees Table 10.
Table 10 on the impact of rats with cerebral ischemia cerebral tissue SOD, MDA (
± s, n=10)
Annotate: compare with sham operated rats, ▲
P＜0.01;
Compare * with model group
P＜0.05;
Compare △ with puerarin sheet group
P＜0.05.
Claims (10)
1. puerarin oral sticks microsphere, it is characterized in that being comprised of the component of following parts by weight:
100 parts of puerarins
Sustained-release matrix material 100-300 part
Pasting material 50-100 part
Emulsifying agent 50-100 part
Liquid paraffin 100-300 part.
2. puerarin oral according to claim 1 sticks microsphere, it is characterized in that being comprised of the component of following parts by weight:
100 parts of puerarins
Sustained-release matrix material 100-250 part
Pasting material 50-80 part
Emulsifying agent 50-80 part
Liquid paraffin 100-250 part.
3. puerarin oral according to claim 1 sticks microsphere, it is characterized in that described sustained-release matrix material is water-insoluble sustained-release matrix material ethyl cellulose, and described pasting material is carbomer.
4. puerarin oral according to claim 1 sticks microsphere, it is characterized in that described emulsifying agent is one or more among Ovum Gallus domesticus Flavus lecithin, soybean lecithin and the span-80.
5. puerarin oral sticks the preparation method of microsphere, it is characterized in that by following processing step:
(1) by weight, get 100 parts of puerarins, sustained-release matrix material 100-300 part, place 100-300 part dehydrated alcohol or acetone, stir and make the sustained-release matrix Uniform Dispersion, then add airtight behind 50-100 part pasting material, 10 ℃-25 ℃ lower 12-24h of immersion, get soak;
(2) soak that step (1) is made uses magnetic stirring apparatus at 800 ~ 1200 rmin
-1, 0 ~ 10 ℃ of lower stirring makes suspension;
(3) by weight, get emulsifying agent 50-100 part, join in 100-300 part liquid paraffin and stir 5-10min, mixing speed is 400-1200 rmin
-1, make oil phase;
(4) suspension that makes in the step (2) is joined in the oil phase that step (3) makes and stir, at 0-10 ℃, 800-1200 rmin
-1Behind the lower stirring 30-60min temperature is risen to 20-30 ℃, dehydrated alcohol or acetone volatilize gradually with the rising of temperature, and microsphere forms, cross the 20-40 mesh sieve, collect microsphere, the petroleum ether take parts by weight as 50-150 part 3-6 time places the exsiccator drying at room temperature and get final product.
6. puerarin oral according to claim 5 sticks the preparation method of microsphere, it is characterized in that described sustained-release matrix material is ethyl cellulose, and its viscosity is 45cp, and described pasting material is carbomer 934 p.
7. puerarin oral according to claim 5 sticks the preparation method of microsphere, and it is characterized in that the soaking temperature in the step (1) is: 15-20 ℃, soak time is: 16-20h.
8. puerarin oral according to claim 5 sticks the preparation method of microsphere, it is characterized in that the mixing speed in the step (2) is: 1000 ~ 1200 rmin
-1, temperature is: 5 ~ 10 ℃.
9. puerarin oral according to claim 5 sticks the preparation method of microsphere, it is characterized in that the mixing time in the step (3) is 8-10min, and mixing speed is: 600-1000 rmin
-1
10. puerarin oral according to claim 5 sticks the preparation method of microsphere, it is characterized in that in the step (4) at 5-10 ℃ 1000-1200 rmin
-1Behind the lower stirring 40-50min temperature is risen to 25-30 ℃.
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| CN107582527A (en) * | 2017-10-10 | 2018-01-16 | 雷笑天 | A kind of enteral administration bioadhesive microspheres preparation and preparation method thereof |
| CN107982244A (en) * | 2017-12-27 | 2018-05-04 | 石药集团中诺药业（石家庄）有限公司 | A kind of new ceftriaxone sodium for injection |
| CN108014090A (en) * | 2017-12-27 | 2018-05-11 | 石药集团中诺药业（石家庄）有限公司 | A kind of new cefamandole nafate for injection |
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| WO2012079203A1 (en) * | 2010-12-17 | 2012-06-21 | Liu Li | Puerarin hydrates, preparation methods and uses thereof |
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