CN1736429A - Blood stasis dispelling dripping pills for treating coronary heart disease, angina pectoris and hyperlipemia and preparation process thereof - Google Patents
Blood stasis dispelling dripping pills for treating coronary heart disease, angina pectoris and hyperlipemia and preparation process thereof Download PDFInfo
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Abstract
Disclosed is a blood stasis dispelling dripping pills for treating coronary heart disease, angina pectoris and hyperlipemia and preparation process, wherein the drop pills are prepared from matrix of polyethylene glycol 6000, active constituents of peach kernel, Chinese angelica root, bitter orange, Ligusticum wallichii, Bupleurum root, safflower, achyranthes and cyathula root, radix paeoniae rubrathe, dried rehmannia root, root of ballon flower and licorice root. The weight portion of active constituent and matrix is 1:1.8-2.
Description
Technical field
The invention belongs to the Chinese medicine preparation technical field, particularly relate to a kind of Xuefuzhuyu drop pills for the treatment of coronary heart disease, angina pectoris and hyperlipemia and preparation method thereof.
Background technology
XUEFU ZHUYU JIAONANG is a kind of classical Chinese patent medicine, Ministry of Public Health standard WS
2-B-0928-91 puts down in writing prescription:
Semen Persicae (stir-fry) 200g Radix Angelicae Sinensis 150g Fructus Aurantii (parched with bran) 100g Rhizoma Chuanxiong 75g
Radix Bupleuri 50g Flos Carthami 150g Radix Achyranthis Bidentatae 150g Radix Paeoniae Rubra 100g
Radix Rehmanniae 150g Radix Platycodonis 75g Radix Glycyrrhizae 50g
Function with cure mainly: blood circulation promoting and blood stasis dispelling, promoting the circulation of QI to relieve pain.Be used for blood-stasis internal-depression, chest pain or headache, interior-heat blurring of vision accompanied with oppressive feeling, insomnia and dreamful sleep, severe palpitation, impatience and irascibility.
Preparation technology:
Semen Persicae 100g, Radix Angelicae Sinensis, Radix Paeoniae Rubra, Fructus Aurantii, Rhizoma Chuanxiong, Radix Bupleuri are ground into fine powder, sieve, mixing, the five tastes such as all the other Flos Carthamis and Semen Persicae 100g decoct with water three times, filter merging filtrate, being condensed into relative density is the thick paste of 1.15～1.25 (65～70 ℃), with above-mentioned powder mixing, make granule, oven dry, pulverize, sieve, encapsulated, promptly.
Other has applying date 2001.1.5, the patent record prescription of publication number CN1362075A " nano blood stasis dispersing preparation medicine and preparation method thereof ":
Nanometer Semen Persicae 10-50 part nano Chinese angelica 8-60 part nanometer Fructus Aurantii 10-70 part
Nanometer Rhizoma Chuanxiong 8-60 part nano bupleurum 10-60 part nano safflower 8-60 part
Nanometer Radix Achyranthis Bidentatae 8-50 part nanometer Radix Paeoniae Rubra 8-60 part nanometer Radix Rehmanniae 10-60 part
Nanometer Radix Platycodonis 5-50 part nanometer Radix Glycyrrhizae 5-30 part
Function with cure mainly: can be used for treatment of conditions such as headache, dizzy, brain injury sequela, angina pectoris.
Pharmacology and Clinics of Chinese Materia Medica, 1990,6 (6), the 1-4 page or leaf, Peng Kang, Zheng Youshun work " side's of tearing open research of decoction for removing blood stasis---to microcirculatory pharmacological action " prove can microcirculation improvement, and the hypertension that causes because of the increase of blood capillary resistance is had certain inhibitory action.Shang Weijian has drops.
Summary of the invention
It is little to the purpose of this invention is to provide a kind of taking dose, and dissolution velocity is fast, the blood circulation promoting and blood stasis dispelling that bioavailability is high, the Chinese patent medicine Xuefuzhuyu drop pills of promoting the circulation of QI to relieve pain.
Another object of the present invention provides a kind of easy and simple to handle, quality controllable Xuefuzhuyu drop pills preparation method.
For the purpose that reaches foregoing invention the invention provides a kind of Xuefuzhuyu drop pills for the treatment of coronary heart disease, angina pectoris and hyperlipemia, it is characterized in that it is by as the polyethylene glycol 6000 of substrate with as the following weight parts Chinese crude drug of active component:
Semen Persicae (stir-fry) 10-20 part Radix Angelicae Sinensis 7-15 part Fructus Aurantii (parched with bran) 5-12 part
Rhizoma Chuanxiong 4-10 part Radix Bupleuri 2-8 part Flos Carthami 7-15 part
Radix Achyranthis Bidentatae 7-15 part Radix Paeoniae Rubra 5-12 part Radix Rehmanniae 7-15 part
The extract of Radix Platycodonis 4-10 part Radix Glycyrrhizae 2-8 part is made.
The Xuefuzhuyu drop pills of described treatment coronary heart disease, angina pectoris and hyperlipemia is characterized in that it is by as the polyethylene glycol 6000 of substrate with as following preferred weight part Chinese crude drug of active component:
8 parts of Semen Persicae (stir-fry) 12 parts of Fructus Aurantiis of 16 parts of Radix Angelicae Sinensis (parched with bran)
12 parts on 4 parts of Flos Carthamis of 6 parts of Radix Bupleuri of Rhizoma Chuanxiong
12 parts of 8 portions of Radix Rehmanniae of 12 parts of Radix Paeoniae Rubra of Radix Achyranthis Bidentatae
The extract that 6 portions of Radix Glycyrrhizaes of Radix Platycodonis are 4 parts is made.
The Xuefuzhuyu drop pills of described treatment coronary heart disease, angina pectoris and hyperlipemia is characterized in that described active component and substrate ratio of weight and number are 1: 2.
The Xuefuzhuyu drop pills of described treatment coronary heart disease, angina pectoris and hyperlipemia is characterized in that the described water extract-alcohol precipitation that is extracted as adds alcohol extracting-water precipitating, extraction; Or extract the system drop pill behind the water extract-alcohol precipitation; Or alcohol extraction extraction+water is proposed extraction, the system drop pill; Or extract the system drop pill behind the percolation.
A kind of preparation method for the treatment of the Xuefuzhuyu drop pills of coronary heart disease, angina pectoris and hyperlipemia is characterized in that comprising the steps:
1) medical material is handled: the weighting profit requires 1 or 2 described weight portion Chinese crude drugs as active component, get 11 flavor medical materials and carry oil, the medicinal residues water is carried 2-3 time, amount of water 4-8 doubly, decocting time 1-3h, filter, medicinal residues are 1. standby, merge 3 times filtrate, through being evaporated to the extractum that relative density is 1.10-1.25 (a 60-75 ℃ of mensuration), adding ethanol makes and contains the alcohol amount and be 60-80%, stir evenly, leave standstill (12-24h) and make precipitation, get supernatant and reclaim ethanol, the clear paste that is evaporated to relative density and is 1.25-1.40 (60-70 ℃) 2., and is standby; With 1. reuse ethanol extraction 1-2 time of medicinal residues, alcohol adding amount be 6-8 doubly, backflow 1-2h, merge alcohol extract, reclaim ethanol, being evaporated to relative density is the extractum of 1.15-1.25 (60-70 ℃), add 4-6 times of water gaging, stir evenly, leave standstill (12-24h) and make precipitation, sucking filtration, get precipitate 3., merge 2. and 3., the clear paste that is evaporated to relative density again and is 1.25-1.40 (60-75 ℃ of mensuration) 4., and is standby; Get the ethyl acetate extraction several of 4. doubly measuring with 1-2, combining extraction liquid reclaims ethyl acetate, is evaporated to the clear paste that relative density is 1.35-1.5;
2) medicinal liquid preparation: according to extract clear paste and polyethylene glycol 6000 amount portion rate is 1: 2 ratio adding extract clear paste, is stirred to dissolving, mixing; Add an amount of polyethylene glycol 6000, make fusion in 70-90 ℃, mixing, standby;
3) drip system: the medicinal liquid for preparing is forwarded in the liquid reservoir, and airtight and insulation is at 80 ℃, regulator solution titer valve, and dripping speed is 60 droplets/minute, column length is 140cm, splashes in 10～15 ℃ of liquid paraffin, as condensing agent, carries out drop pill with liquid paraffin in the drop pill machine;
4) drying: the drop pill of above-mentioned formation is drained, and the erasing liquor paraffin body, the drop pill of drying, standby;
5) film coating: the drop pill bag film-coat that drying is made, the bag film-coat, (proportioning of coating solution is hypromellose 2.25g, Tween-80 1.125g, steviosin 0.225g, water 22.5ml, dehydrated alcohol 90ml), make the Xuefuzhuyu drop pills for the treatment of coronary heart disease, angina pectoris and hyperlipemia.
6, a kind of preparation method for the treatment of the Xuefuzhuyu drop pills of coronary heart disease, angina pectoris and hyperlipemia is characterized in that comprising the steps:
1) medical material is handled: the weighting profit requires 1 or 2 described weight portion Chinese crude drugs as active component, with 11 flavor medical materials water extraction 2-3 times, amount of water is 4-8 times, decocting time 1-3h, merging filtrate, being evaporated to relative density is the extractum of 1.15-1.20 (60-75 ℃ of mensuration), add ethanol and make and contain the alcohol amount and be 60-80%, stir evenly, leave standstill (12-24h) and make precipitation, get supernatant and reclaim ethanol, being evaporated to relative density is the clear paste of 1.25-1.40 (60-70 ℃); The ethyl acetate extraction several that reuse 1-2 doubly measures, combining extraction liquid reclaims ethyl acetate, and being evaporated to relative density is the clear paste of 1.40-1.50 (60-70 ℃ of mensuration);
2) medicinal liquid preparation: according to extract clear paste and polyethylene glycol 6000 amount portion rate is 1: 2 ratio adding extract clear paste, is stirred to dissolving, mixing; Add an amount of polyethylene glycol 6000, make fusion in 70-90 ℃, mixing, standby;
3) drip system: the medicinal liquid for preparing is forwarded in the liquid reservoir, and airtight and insulation is at 80 ℃, regulator solution titer valve, and dripping speed is 60 droplets/minute, column length is 140cm, splashes in 10～15 ℃ of liquid paraffin, as condensing agent, carries out drop pill with liquid paraffin in the drop pill machine;
4) drying: the drop pill of above-mentioned formation is drained, and the erasing liquor paraffin body, the drop pill of drying, standby;
5) film coating: with the drop pill bag film-coat that drying is made, the bag film-coat, the proportioning of coating solution is hypromellose 2.1g, Tween-80 1.05g, steviosin 0.21g, water 21ml, dehydrated alcohol 84ml makes the Xuefuzhuyu drop pills for the treatment of coronary heart disease, angina pectoris and hyperlipemia.
A kind of preparation method for the treatment of the Xuefuzhuyu drop pills of coronary heart disease, angina pectoris and hyperlipemia is characterized in that comprising the steps:
1) medical material is handled: the weighting profit requires 1 or 2 described weight portion Chinese crude drugs as active component, with 11 flavor medical materials ethanol extraction 2-3 times, alcohol adding amount is 4-8 times, decocting time 1-3h, merging filtrate, being evaporated to relative density is the extractum of 1.05-1.20 (60-70 ℃ of mensuration), with the ethyl acetate extraction several that 1-2 doubly measures, combining extraction liquid reclaims ethyl acetate, the clear paste that is evaporated to relative density and is 1.10-1.25 (60-70 ℃ of mensuration) 1., and is standby.With the medicinal residues after the alcohol extraction, carry 1-2 time through water, amount of water is 5-9 times, decocting time 1-3h, merging filtrate, being evaporated to relative density is the extractum of 1.05-1.20 (60-75 ℃ of mensuration), the water-saturated n-butanol extracted several times of doubly measuring with 1-2, combining extraction liquid reclaims n-butyl alcohol, and the clear paste that is evaporated to relative density and is 1.10-1.25 (60-70 ℃ of mensuration) 2..With 1. and clear paste 2. merge;
2) medicinal liquid preparation: according to extract clear paste and polyethylene glycol 6000 amount portion rate is 1: 2 ratio adding extract clear paste, is stirred to dissolving, mixing; Add an amount of polyethylene glycol 6000, make fusion in 70-90 ℃, mixing, standby;
3) drip system: the medicinal liquid for preparing is forwarded in the liquid reservoir, and airtight and insulation is at 80 ℃, regulator solution titer valve, and dripping speed is 60 droplets/minute, column length is 140cm, splashes in 10～15 ℃ of liquid paraffin, as condensing agent, carries out drop pill with liquid paraffin in the drop pill machine
4) drying: 4) drying: the drop pill of above-mentioned formation is drained, and the erasing liquor paraffin body, drying is made drop pill.
Drain,
5) film coating: with the drop pill bag film-coat that drying is made, the bag film-coat, the proportioning of coating solution is hypromellose 2g, Tween-80 1g, steviosin 0.2g, water 20ml, dehydrated alcohol 80ml) make the Xuefuzhuyu drop pills of treatment coronary heart disease, angina pectoris and hyperlipemia.
The preparation method of the Xuefuzhuyu drop pills of described treatment coronary heart disease, angina pectoris and hyperlipemia is characterized in that best preparation method comprises the steps:
1) medical material is handled: the weighting profit requires 1 or 2 described weight portion Chinese crude drugs as active component, and 11 flavor medical materials with 80% ethanol extraction 2 times, are added 7 times of amount ethanol for the first time, decocts 2h, collection filtrate; Add for the second time 5 times of amount ethanol, decocting time 1h collects filtrate, merges filtrate twice.Filtrate decompression being concentrated into relative density is the extractum of 1.10-1.15 (60-70 ℃ of mensuration) again, with the ethyl acetate extraction of 1 times of amount 2 times, reclaims ethyl acetate, and the clear paste that is evaporated to relative density and is 1.15-1.20 (60-70 ℃ of mensuration) 1., and is standby.With the medicinal residues after the alcohol extraction, carry 2 times through water, add 8 times of water gagings for the first time, decoct 2h, collect filtrate; Add for the second time 5 times of water gagings, decoct 1h, collect filtrate, merge filtrate twice.Filtrate decompression being concentrated into relative density is the extractum of 1.15-1.20 (60-75 ℃ of mensuration) again, with the water-saturated n-butanol of 1 times of amount extraction 2 times, reclaims n-butyl alcohol, and the clear paste that is evaporated to relative density and is 1.15-1.20 (60-70 ℃ of mensuration) 2..With 1. and clear paste 2. merge, standby;
2) medicinal liquid preparation:: according to extract clear paste and polyethylene glycol 6000 amount portion rate is 1: 2 ratio adding extract clear paste,, make fusion in 80 ℃, be stirred to dissolving, mixing, standby;
3) drip system: the medicinal liquid for preparing is forwarded in the liquid reservoir, and airtight and insulation is at 80 ℃, regulator solution titer valve, and dripping speed is 60 droplets/minute, column length is 140cm, splashes in 10～15 ℃ of liquid paraffin, as condensing agent, carries out drop pill with liquid paraffin in the drop pill machine;
4) drying: the drop pill of above-mentioned formation is drained, and the erasing liquor paraffin body, drying is made drop pill.
5) film coating: with the drop pill bag film-coat that drying is made, the proportioning of coating solution is hypromellose 2g, Tween-80 1g, steviosin 0.2g, water 20ml, dehydrated alcohol 80ml), make 1000 of drop pill (every gram drop pill is equivalent to crude drug 9.98-10.20g).
A kind of preparation method for the treatment of the Xuefuzhuyu drop pills of coronary heart disease, angina pectoris and hyperlipemia is characterized in that comprising the steps:
1) medical material is handled: the weighting profit requires 1 or 2 described weight portion Chinese crude drugs as active component, with the soak with ethanol of 11 flavor medical materials with 60-70%, speed with 10-20ml/ minute behind the 2-4h is carried out percolation, collect percolate 48-72h, get percolate and reclaim ethanol, being evaporated to relative density is the extractum of 1.35-1.45 (60-70 ℃ of mensuration), the ethyl acetate extraction of doubly measuring with 1-2 for several times, combining extraction liquid, reclaim ethyl acetate, being evaporated to relative density is the clear paste of 1.40-1.50 (60-70 ℃ of mensuration);
2) medicinal liquid preparation:: according to extract clear paste and polyethylene glycol 6000 amount portion rate is 1: 2 ratio adding extract clear paste, is stirred to dissolving, mixing; Add an amount of polyethylene glycol 6000, make fusion in 70-90 ℃, mixing, standby;
3) drip system: the medicinal liquid for preparing is forwarded in the liquid reservoir, and airtight and insulation is at 80 ℃, regulator solution titer valve, and dripping speed is 60 droplets/minute, column length is 140cm, splashes in 10～15 ℃ of liquid paraffin, as condensing agent, carries out drop pill with liquid paraffin in the drop pill machine
4) drying: 4) drying: the drop pill of above-mentioned formation is drained, and the erasing liquor paraffin body, drying is made drop pill.
5) film coating: with the drop pill bag film-coat that drying is made, the proportioning of coating solution is hypromellose 3.9g, Tween-80 1.95g, steviosin 0.39g, water 39ml, dehydrated alcohol 156ml makes the Xuefuzhuyu drop pills for the treatment of coronary heart disease, angina pectoris and hyperlipemia.
The present invention has designed 4 preparation technology:
(1) get 11 flavor medical materials and carry oil, the medicinal residues water is carried 2-3 time, and amount of water 4-8 doubly, decocting time 1-3h filters, and medicinal residues are 1. standby, merge 3 times filtrate, through being evaporated to the extractum that relative density is 1.10-1.25 (a 60-75 ℃ of mensuration), add ethanol and make and contain the alcohol amount and be 60-80%, stir evenly, leave standstill (12-24h) and make precipitation, get supernatant and reclaim ethanol, the clear paste that is evaporated to relative density and is 1.25-1.40 (60-70 ℃) 2., and is standby; With 1. reuse ethanol extraction 1-2 time of medicinal residues, alcohol adding amount be 6-8 doubly, backflow 1-2h, merge alcohol extract, reclaim ethanol, being evaporated to relative density is the extractum of 1.15-1.25 (60-70 ℃), add 4-6 times of water gaging, stir evenly, leave standstill (12-24h) and make precipitation, sucking filtration, get precipitate 3., merge 2. and 3., the clear paste that is evaporated to relative density again and is 1.25-1.40 (60-75 ℃ of mensuration) 4., and is standby.Get the ethyl acetate extraction several of 4. doubly measuring with 1-2, combining extraction liquid, reclaim ethyl acetate, be evaporated to the clear paste that relative density is 1.35-1.5, add an amount of polyethylene glycol 6000, make fusion in 70-90 ℃, mixing carries out drop pill, drains, the bag film-coat is made drop pill (every gram drop pill is equivalent to crude drug 9.80-10.20g).
(2) with 11 flavor medical materials water extraction 2-3 times, amount of water is 4-8 times, decocting time 1-3h, merging filtrate, being evaporated to relative density is the extractum of 1.15-1.20 (60-75 ℃ of mensuration), adds ethanol and makes and contain the alcohol amount and be 60-80%, stir evenly, leave standstill (12-24h) and make precipitation, get supernatant and reclaim ethanol, being evaporated to relative density is the clear paste of 1.25-1.40 (60-70 ℃); The ethyl acetate extraction that reuse 1-2 doubly measures for several times, combining extraction liquid, reclaim ethyl acetate, being evaporated to relative density is the clear paste of 1.40-1.50 (60-70 ℃ of mensuration), adds an amount of polyethylene glycol 6000, make fusion in 70-90 ℃, mixing carries out drop pill, drains, the bag film-coat is made drop pill (every gram drop pill is equivalent to crude drug 9.80-10.20g).
(3) with 11 flavor medical materials ethanol extraction 2-3 times, alcohol adding amount is 4-8 times, decocting time 1-3h, merging filtrate, being evaporated to relative density is the extractum of 1.05-1.20 (60-70 ℃ of mensuration), the ethyl acetate extraction of doubly measuring with 1-2 is for several times, combining extraction liquid, reclaim ethyl acetate, the clear paste that is evaporated to relative density and is 1.10-1.25 (60-70 ℃ of mensuration) 1., and is standby.With the medicinal residues after the alcohol extraction, carry 1-2 time through water, amount of water is 5-9 times, decocting time 1-3h, merging filtrate, being evaporated to relative density is the extractum of 1.05-1.20 (60-75 ℃ of mensuration), the water-saturated n-butanol extracted several times of doubly measuring with 1-2, combining extraction liquid reclaims n-butyl alcohol, and the clear paste that is evaporated to relative density and is 1.10-1.25 (60-70 ℃ of mensuration) 2..With 1. and clear paste 2. merge, add an amount of polyethylene glycol 6000, make fusion in 70-90 ℃, mixing carries out drop pill, drains, the bag film-coat is made drop pill (every gram drop pill is equivalent to crude drug 9.98-10.20g).
(4) with the soak with ethanol of 11 flavor medical materials with 60-70%, speed with 10-20ml/ minute behind the 2-4h is carried out percolation, collect percolate 48-72h, get percolate and reclaim ethanol, being evaporated to relative density is the extractum of 1.35-1.45 (60-70 ℃ of mensuration), with the ethyl acetate extraction several that 1-2 doubly measures, combining extraction liquid reclaims ethyl acetate, being evaporated to relative density is the clear paste of 1.40-1.50 (60-70 ℃ of mensuration), add an amount of polyethylene glycol 6000, make fusion, mixing in 70-90 ℃, carry out drop pill, drain, the bag film-coat is made drop pill (every gram drop pill is equivalent to crude drug 9.90-10.50g).
Four preparation technology's pharmacodynamicss compare:
This product is treatment Blood stasis medicine, and the ingredient in the prescription mainly contains liposoluble constituent and water soluble ingredient, this EXPERIMENTAL DESIGN four process routes, take four kinds of different extraction separation methods:
(A) No. 1 technology: water extract-alcohol precipitation+alcohol extracting-water precipitating, extraction, system drop pill.
(B) No. 2 technologies: extract the system drop pill behind the water extract-alcohol precipitation;
(C) No. 3 technologies: alcohol extraction extraction+water is proposed extraction, the system drop pill;
(D) No. 4 technologies: extract the system drop pill behind the percolation.
1. test objective
1. observe 'Xue Fu Zhu Yu ' No. 1, No. 2, No. 3, No. 4 technology samples repeatedly gastric infusion to influence by blood high viscosity syndrome hemorheology of rat due to the high molecular dextran.
2. observe 'Xue Fu Zhu Yu ' No. 1, No. 2, No. 3, No. 4 technology samples repeatedly gastric infusion to the influence of rat carotid artery thrombus formation time.
2. test material
2.1 medicine
No. 1 sample of 'Xue Fu Zhu Yu ': dark-brown, every gram drop pill is equivalent to crude drug 10.10g, lot number 0409.
No. 2 samples of 'Xue Fu Zhu Yu ': dark-brown, every gram drop pill is equivalent to crude drug 10.05g, lot number 0410.
No. 3 samples of 'Xue Fu Zhu Yu ': light brown, every gram drop pill is equivalent to crude drug 10.14g, lot number 0411.
No. 4 samples of 'Xue Fu Zhu Yu ': light brown, every gram drop pill is equivalent to crude drug 10.08g, lot number 0412.
XUEFU ZHUYU JIAONANG: provide by Tianjin Hong Rentang pharmaceutical factory, every capsules dress 0.4g medicated powder,
Every gram powder is equivalent to crude drug 1.69 grams, lot number D03012.
FUFANG DANSHEN PIAN: Shijiazhuang City China imperial Pharmaceutical limited company produces lot number 040504.10% high molecular dextran injection: Chinese Academy of Medical Sciences's Blood Research Institute product, molecular weight 300,000.
Aspirin: white crystals, content 99.5%, synthesis pharmaceutical factory in northwest provides.
2.2 animal
Rat: the Wistar kind, body weight 200 ~ 250g, the male and female dual-purpose, animal housing provides by Tianjin Inst. of Materia Medica.The quality certification number: No. the 001st, Tianjin kinoplaszm word.
2.3 instrument
BR2-500E type cone and plate viscometer: Tokyo gauge Co., Ltd. product.
The experimental thrombus in vivo of BT87-3 type forms analyzer: the development of packet header medical college.
3. test method and result
3.1 No. 1, No. 2, No. 3, No. 4 technology samples of 'Xue Fu Zhu Yu ' are to the influence of hemorheology of rat due to the high molecular dextran
Choose above-mentioned healthy rat, be divided into normal control group, model control group, No. 1 technology group, No. 2 technology groups, No. 3 technology groups, No. 4 technology groups, former dosage form group, positive drug FUFANG DANSHEN PIAN group at random by sex, body weight.No. 1 technology group of 'Xue Fu Zhu Yu ', No. 2 technology groups, No. 3 technology groups, No. 4 technology groups, former dosage form group, positive drug FUFANG DANSHEN PIAN group all by 1.5,3,6g crude drug/kg gastric infusion, the positive drug control group FUFANG DANSHEN PIAN is pressed 2.0g medicated powder/kg gastric infusion, the administration volume is 1ml/100g, model control group, normal control group such as give at capacity 0.5%CMC, once a day, continuous 10 days.Each organized rat (except the normal control group) all after the last administration 1 hour, pentobarbital sodium intraperitoneal anesthesia (40mg/kg), and tail vein injection 10% high molecular dextran injection 1ml/kg causes the blood high viscosity syndrome model.Quiet notes from abdominal aortic blood, with 3.8% sodium citrate anticoagulant (anticoagulant is 1: 9 with the ratio of whole blood), were upward measured 4 whole blood viscosity of cutting under the speed at cone-plate type viscometer (Japanese import) after 10 minutes.In the hematocrit pipe, measure packed cell volume and erythrocyte sedimentation rate.3000 rev/mins centrifugal 10 minutes, get blood plasma and on the blood capillary viscometer, measure plasma viscosity.Result of the test adopts two groups of mean statistical analysiss-t value method to carry out significance test, see Table 1.
No. 1, No. 2, No. 3, No. 4 technology samples of table 1 'Xue Fu Zhu Yu ' are to the influence of hemorheology of rat due to the high molecular dextran (X ± SD)
| Group | Dosage | Number of animals | Whole blood viscosity (mpa.s) | Plasma viscosity | Erythrocyte sedimentation rate | Hematocrit | |||
| (the g crude drug/kg) | (only) | 7.5S 1 | 18.8S -1 | 37.5S 1 | 75S 1 | (cm/h) | (％) | ||
| Normal control | 10 | 7.14±1.95 | 3.38±0.80 | 3.08±0.55 | 2.80±0.40 | 1.06±0.15 | 0.20±0.08 | 42.4±4.19 | |
| The model contrast | 10 | 13.56±2.53 △△ | 7.32±1.66 △△ | 6.12+1.30 △△ | 5.29+1.06 △△ | 1.46±0.11 △△ | 0.21+0.10 | 45.6±4.09 | |
| No. 1 technology | 6 | 10 | 11.50±2.12* | 6.71±1.23* | 5.86±0.88* | 4.24+0.66* | 1.26±0.14* | 0.23±0.09 | 43.7±3.34 |
| 3 | 8 | 11.65±1.46* | 7.21±1.11 | 6.07±0.85 | 4.77±0.71 | 1.34±0.14 | 0.25±0.08 | 43.5±3.16 | |
| 1.5 | 8 | 13.30±2.33 | 7.30±1.57 | 6.10±1.35 | 4.90±1.25 | 1.38±0.06 | 0.24±0.11 | 44.3±3.62 | |
| No. 2 technologies | 6 | 10 | 11.28±2.09* | 6.00±1.44 | 5.74+1.00* | 4.34+0.88* | 1.31±0.18* | 3.27±0.1I | 43.7±3.53 |
| 3 | 8 | 11.18±2.32* | 7.12±2.27 | 5.96±1.78 | 4.63±1.37 | 1.37±0.12 | 0.24±0.05 | 43.8±7.80 | |
| 1.5 | 8 | 13.51+3.54 | 7.29±2.01 | 6.11+1.51 | 4.83±1.15 | 1.40±0.09 | 0.26±0.11 | 45.6±5.63 | |
| No. 3 technologies | 6 | 10 | 10.01+2.03** | 5.11+1.21** | 4.21+1.11** | 3.83±0.88** | 1.16±0.14** | 0.22±0.18 | 43.1±3.43 |
| 3 | 8 | 10.20±2.12* | 5.25±2.04* | 4.54±1.64* | 4.23±1.37* | 1.25±0.11* | 3.24±0.07 | 43.3±7.46 | |
| 1.5 | 8 | 11.51±3.14 | 6.24+2.07 | 5.11±1.31 | 4.64±1.15 | 1.36±0.07 | 0.25±0.04 | 44.2±5.11 | |
| No. 4 technologies | 6 | 10 | 10.07±2.14** | 5.21+1.26** | 4.76±0.85* | 4.32±0.63* | 1.26±0.18* | 0.23±0.08 | 43.2±3.41 |
| 3 | 8 | 10.42±1.37* | 5.49+1.18* | 4.51±0.75* | 4.61±0.74 | 1.30±0.15* | 0.24±0.07 | 43.9±3.06 | |
| 1.5 | 8 | 11.74±2.12 | 6.44+1.47 | 5.20±1.42 | 4.83±1.21 | 1.39±0.03 | 3.25±0.19 | 44.5±3.51 | |
| Former dosage form | 6 | 10 | 10.14±3.07* | 5.50±1.51* | 4.40±1.02* | 3.56±0.79** | 1.24+0.14* | 0.22±0.09 | 42.0±4.76 |
| 3 | 8 | 10.50±2.63* | 5.46±1.45* | 4.84±0.85* | 4.17±0.75* | 1.31+0.11* | 0.24±0.09 | 41.8±7.11 | |
| 1.5 | 8 | 11.88±3.33 | 6.48±1.12 | 5.22±0.93 | 4.43±0.96 | 1.39±0.10 | 0.25±0.12 | 43.5±11.78 | |
| FUFANG DANSHEN PIAN | 2g medicated powder | 8 | 10.80±2.70* | 5.28+2.04* | 4.53±1.59* | 4.02±1.28* | 1.25±0.21* | 0.24±0.07 | 42.5±8.54 |
△ △: P＜0.01 (comparing) with the normal control group
* P＜0.05, * * P＜0.01 (with model control group relatively)
Table 1 is the result show, compares with the normal control group, and whole blood viscosity, the plasma viscosity under the speed respectively cut in the obvious rising of model control group, shows the moulding success.No. 1, No. 2, No. 3, No. 4 technology 6g crude drugs of Xuefuzhuyu drop pills/kg dosage group compare with model control group, and obviously the whole blood viscosity under the speed is respectively cut in reduction, obviously reduces plasma viscosity.The former dosage form of 'Xue Fu Zhu Yu ', positive control FUFANG DANSHEN PIAN also have obvious effect.Each dosage group does not all have obvious influence to erythrocyte erythrocyte sedimentation rate, packed cell volume.Wherein, the most remarkable with No. 3 process acts.
3.2 No. 1, No. 2, No. 3, No. 4 technology samples of 'Xue Fu Zhu Yu ' are to the thrombotic influence of carotid artery
Select above-mentioned healthy WISTAR kind rat for use, be divided into normal control group, No. 1 technology group, No. 2 technology groups, No. 3 technology groups, No. 4 technology groups, former dosage form group, positive drug aspirin matched group at random by sex, body weight.No. 1 technology group of 'Xue Fu Zhu Yu ', No. 2 technology groups, No. 3 technology groups, No. 4 technology groups, former dosage form group all by 6,3,1.5g crude drug/kg gastric infusion, once a day, continuous 10 days, the positive drug control group aspirin is pressed the 150mg/kg gastric infusion, once a day, continuous 5 days, the administration volume was 1ml/100g, and the normal control group waits the 0.5%CMC of capacity.Each dosage group rat all after the last administration 1 hour, pentobarbital sodium intraperitoneal anesthesia (40mg/kg), separate the about 15mm of a bilateral common carotid artery, with BT-87-3 type thrombosis instrument stimulating electrode and temperature sensor hook on carotid artery, electric current with 1.5mA continues to stimulate blood vessel wall 7 minutes, simultaneously by temperature sensor monitors blood vessel surface variation of temperature, work as thrombosis, during plug flow, blood vessel distal end temperature bust, instrument are reported to the police, from stimulation begin to time of fire alarming as thrombus formation time (OT value), result of the test adopts two groups of mean statistical analysis t-value methods to carry out test of significance, sees Table 2.
No. 1, No. 2, No. 3, No. 4 technology samples of table 2 'Xue Fu Zhu Yu ' are to the thrombotic influence of carotid artery (X ± SD)
| Group | Dosage (the g life/kg) | Number of animals (only) | OT value (branch) |
| Normal control | 8 | 16.29± 4.90 | |
| No. 1 technology | 6 | 8 | 27.31±9.45** |
| 3 | 8 | 22.65±9.21* | |
| 1.5 | 8 | 16.89± 4.86 | |
| No. 2 technologies | 6 | 8 | 27.42±8.99** |
| 3 | 8 | 22.50±4.52* | |
| 1.5 | 8 | 16.95± 5.76 | |
| No. 3 technologies | 6 | 8 | 29.33±9.85** |
| 3 | 8 | 23.55±9.30* | |
| 1.5 | 8 | 19.57± 4.64 | |
| No. 4 technologies | 6 | 8 | 28.37±9.57** |
| 3 | 8 | 22.85±9.32* | |
| 1.5 | 8 | 18.54± 4.51 | |
| Former dosage form | 6 | 8 | 28.40±5.87** |
| 3 | 8 | 22.62±6.25* | |
| 1.5 | 8 | 18.64± 4.37 | |
| Aspirin | 150mg/kg | 8 | 28.79±5.47** |
*: P＜0.05 * *:: P＜0.01 (comparing) with the normal control group
Table 2 is the result show, compares No. 1, No. 2, No. 3, No. 4 technology 6 crude drugs of the Xuefuzhuyu drop pills/obvious prolong rats carotid artery of dosage group thrombus formation time with the normal control group.The former dosage form of 'Xue Fu Zhu Yu ', positive control drug aspirin also have obvious effect.Wherein, the most remarkable with No. 3 process acts.
4. conclusion (of pressure testing)
Above result of the test shows, No. 1, No. 2, No. 3, No. 4 technology sample 6g of Xuefuzhuyu drop pills crude drug/kg dosage group can both obviously reduce the blood high viscosity syndrome rat respectively cut speed under whole blood viscosity, plasma viscosity, obviously prolong rats carotid artery thrombus formation time is suitable with the effect of former dosage form group.Wherein, the most remarkable with No. 3 process acts, determine that therefore No. 3 technologies are best preparation technology, (1), (2) number technology are general preparation technology, (4) number technology is effective preparation technology.
The best preparation technology's of Xuefuzhuyu drop pills research data
One. best prescription is formed:
Semen Persicae (stir-fry) 200g Radix Angelicae Sinensis 150g Radix Paeoniae Rubra 100g Rhizoma Chuanxiong 75g Radix Bupleuri 50g
Fructus Aurantii (parched with bran) 100g Flos Carthami 150g Radix Achyranthis Bidentatae 150g Radix Rehmanniae 150g Radix Platycodonis 75g
Radix Glycyrrhizae 50g
Adjuvant:
Ethanol meets " requirement under two 11 pages of items of Chinese pharmacopoeia version in 2000.
Ethyl acetate meets " requirement under two appendix XV of Chinese pharmacopoeia version in 2000 A ethyl acetate item.
Water-saturated n-butanol meets " requirement under two appendix XV of Chinese pharmacopoeia version in 2000 A butanols item.
Polyethylene glycol 6000 meets " requirement under two 992 pages of items of Chinese pharmacopoeia version in 2000.
Hydroxypropyl emthylcellulose meets " requirement under two 775 pages of items of Chinese pharmacopoeia version in 2000.
Liquid paraffin meets " requirement under two 780 pages of items of Chinese pharmacopoeia version in 2000.
Two. best preparation technology
With 11 flavor medical materials with 80% ethanol extraction 2 times, add 7 times of amount ethanol for the first time, decoct 2h, collection filtrate; Add for the second time 5 times of amount ethanol, decocting time 1h collects filtrate, merges filtrate twice.Filtrate decompression being concentrated into relative density is the extractum of 1.10-1.15 (60-70 ℃ of mensuration) again, with the ethyl acetate extraction of 1 times of amount 2 times, reclaims ethyl acetate, and the clear paste that is evaporated to relative density and is 1.15-1.20 (60-70 ℃ of mensuration) 1., and is standby.With the medicinal residues after the alcohol extraction, carry 2 times through water, add 8 times of water gagings for the first time, decoct 2h, collect filtrate; Add for the second time 5 times of water gagings, decoct 1h, collect filtrate, merge filtrate twice.Filtrate decompression being concentrated into relative density is the extractum of 1.15-1.20 (60-75 ℃ of mensuration) again, with the water-saturated n-butanol of 1 times of amount extraction 2 times, reclaims n-butyl alcohol, and the clear paste that is evaporated to relative density and is 1.15-1.20 (60-70 ℃ of mensuration) 2..With 1. and clear paste 2. merge, press 2 times of amount adding polyethylene glycol 6000s of clear paste, make fusion in 80 ℃, with above-mentioned clear paste mixing, as condensing agent, (temperature of charge is 80 ℃ to carry out drop pill in the drop pill machine with liquid paraffin, dripping speed is 60 droplets/minute, and column length is 140cm), drain, (proportioning of coating solution is hypromellose 2g to film coating, Tween-80 1g, steviosin 0.2g, water 20ml, dehydrated alcohol 80ml), make 1000 of drop pill (every gram drop pill is equivalent to crude drug 9.98-10.20g).
Three. preparation technology's research
(1) Study on extraction process
According to above-mentioned pharmacodynamic experiment result, and consider the practical operation of the big production of factory, determine the dropping pill technique route No. 4, promptly use earlier alcohol extraction, pure liquid ethyl acetate extraction; Medicinal residues water are again carried, and use the water saturation n-butanol extraction, merging filtrate.And this process route investigated.
1. the investigation of alcohol extraction ethyl acetate extraction technology
Get recipe quantity 50g medical material, alcohol extraction 2 times concentrates the back and adds a certain amount of ethyl acetate, extracts, and investigates its paste volume.Select L for use
9(3
3) orthogonal design table tests, and the results are shown in Table 3, table 4, table 5
Table 3 factor level table
| Level | Factor | ||
| Alcohol adding amount (doubly) | Extraction time (h) | Ethyl acetate amount (doubly) | |
| 1 | 5 | 1 | 2 |
| 2 | 7 | 2 | 1.5 |
| 3 | 8 | 3 | 1 |
Table 4 alcohol extraction ethyl acetate extraction worker reed is investigated L
9(3
3) test computer chart result
PR：C＞A＞B
Table 5 analysis of variance table
| Soruces of variation | Quadratic sum | Degree of freedom | Mean square | F | Factor affecting |
| Alcohol adding amount | 0.72 | 2 | 0.36 | 0.71 | Not remarkable |
| Extraction time | 0.31 | 2 | 0.155 | 0.30 | Not remarkable |
| The ethyl acetate amount | 16.35 | 2 | 8.175 | 16.03 | Not remarkable |
| Error | 1.02 | 2 | 0.51 | ||
| Summation | 18.4 | 8 |
The results of analysis of variance shows: the orthogonal test factor affecting is not remarkable.
Orthogonal experiments shows: the ethyl acetate amount has certain influence to paste volume, and R value explanation ethyl acetate amount is a principal element, and alcohol adding amount and extraction time are secondary causes.The degree of each factor affecting is followed successively by RC＞RA＞RB, and A factor A
1=A
2＜A
3, B factor B
1=B
2＜B
3, C factor C
3＜C
2＜C
1So determine A
1B
1C
3Condition is promptly: with twice of alcohol extraction (7,5 times), and 2h for the first time, 1h for the second time, the ethyl acetate amount is 1 times of amount.
2. the investigation of the saturated n-butanol extraction technology of water water lift
Get recipe quantity 50g medical material, water extraction 2 times concentrates the back and adds a certain amount of water-saturated n-butanol, extracts, and investigates its paste volume.Select L for use
9(3
3) orthogonal design table tests, and the results are shown in Table 6, table 7, table 8
Table 6 factor level table
| Level | Factor | ||
| Amount of water (doubly) | Extraction time (h) | Ethyl acetate amount (doubly) | |
| 1 | 5 | 1 | 2 |
| 2 | 8 | 2 | 1.5 |
| 3 | 9 | 3 | 1 |
Table 7 water is put forward n-butanol extraction technology and is investigated L
9(3
3) test computer chart result
R：C＞A＞B
Table 8 analysis of variance table
| Soruces of variation | Quadratic sum | Degree of freedom | Mean square | F | Factor affecting |
| Amount of water | 0.96 | 2 | 0.48 | 0.82 | Not remarkable |
| Extraction time | 0.54 | 2 | 0.27 | 0.43 | Not remarkable |
| The n-butyl alcohol amount | 13.4 | 2 | 6.7 | 12.9 | Not remarkable |
| Error | 1.05 | 2 | 0.525 | ||
| Summation | 15.95 | 8 |
The results of analysis of variance shows: the orthogonal test factor affecting is not remarkable.
Orthogonal experiments shows: the n-butyl alcohol amount has certain influence to paste volume, and R value explanation n-butyl alcohol amount is a principal element, and amount of water and extraction time are secondary causes.The degree of each factor affecting is followed successively by RC＞RA＞RB, and A factor A
1=A
2＜A
3, B factor B
1=B
2＜B
3, C factor C
3＜C
2＜C
1So determine A
1B
1C
3Condition is promptly: with twice of water extraction (8,5 times), and 2h for the first time, 1h for the second time, the water-saturated n-butanol amount is 1 times of amount.
It is reliable for this test technology condition is described, again its process conditions have been carried out checking and the component target peoniflorin has been carried out Determination on content (calculating with peoniflorin amount contained in the prescription), simultaneously also the water-saturated n-butanol of 1.5 times and 2 times amounts is got thing and investigate result such as following table 9
Content of paeoniflorin measurement result in table 9 extract
| Water-saturated n-butanol amount (doubly) | 1 | 1.5 | 2 |
| Extractive content (mg/g peoniflorin) | 1.12 | 0.84 | 0.79 |
The result shows: the composition content of paeoniflorin during with 1 times of saturated n-butanol extraction of water gaging is higher than 1.5 and 2 times of amounts, so further 1 times of water-saturated n-butanol extraction of checking selection is feasible, through five batches of verification experimental verifications, this stable process conditions can be operated.
(2) investigation of preparations shaping technology
According to this product treatment Blood stasis, consider easy absorption, quick-acting dosage forms in conjunction with preparation technology, are designed to drop pill.Prepare easyly, preparation process is advanced, and the condition of its preparations shaping is investigated:
1. choice of base selects fusing point low, and the PEG6000 with good dispersion force and big cohesiveness satisfies the requirement of clinical treatment and active ingredient character as substrate.At first select for use PEG4000 to make substrate, the mix homogeneously under blender with fusion substrate and medicine, 80% insulation splash into 70cm long 10 ~ 15 " in the C liquid paraffin cooling column, can be shaped to foundation substantially with drop pill, as a result the drop pill difference of hardness.On this basis, it is better to replace the hardness of PEG4000 drop pill with PEG6000.
2. the proportioning of extract and substrate screening: with drop pill substantially can molding and required dose be foundation, the minimum proportioning of screening of medicaments and substrate.The results are shown in Table 10
The proportioning of table 10 extract and substrate is investigated
| Extract (g) | Substrate (doubly) | Medicine is deployment conditions in substrate | Drop pill molding situation |
| 10 | 1.5 | Can not be uniformly dispersed | Drop pill is slightly flat, the color inequality |
| 10 | 1.8 | Be uniformly dispersed | The equal forming of circular smooth color |
| 10 | 2.0 | Be uniformly dispersed | The equal forming of circular smooth color |
Test shows: the proportioning of extract and substrate 1: 1.8 or 1: 2.0 all can, consider that the needs of dose determine that selecting minimum proportioning is 1: 1.8.
3. being chosen in the above-mentioned experiment of coolant selects for use liquid paraffin as coolant, and the result can.In order to illustrate that liquid paraffin is better selecting for use of coolant in this medicine, under same temperature, tested again with methyl-silicone oil as coolant, drip and make drop pill, the results are shown in Table 11,
The selection of table 11 coolant
| Coolant | Sedimentation velocity (branch) | The molding situation |
| Methyl-silicone oil | Landing in 2～5 fens is slower | The part drop pill is floating shape therein and becomes the rib shape |
| Liquid/paraffin | 1~1.5 | Drop pill sedimentation bottom, forming |
The result shows: determine that liquid paraffin is that coolant is advisable.
4. after the above-mentioned condition of Study on Forming is determined, further investigate (to water dropper bore, droplet distance and chilling temperature) to dripping the system condition effect, experiment changes water dropper bore or a coolant temperature and a distance repeatedly.The result shows that coolant temperature drips apart from 5cm 10 ~ 15 ℃ of scopes preferably, and it is better that the water dropper bore is preferably 2.0mm.
The system of dripping of drop pill, except substrate and the coolant of selecting to suit, medicine adds beyond mode and the ratio, and post height, temperature of charge, a speed also are the factors that influences the drop pill molding.Therefore,, designed three levels, used L these three factors
9(3
3) orthogonal table has been arranged test, serves as to investigate index with drop pill ratio of briquetting in the unit interval, preferably drips the system condition.The factor level table sees 12, and orthogonal test sees Table 13
Table 12 factor level table
| Level | Factor | ||
| Temperature of charge (℃) | Drip speed (droplet/minute) | Column length (cm) | |
| 1 | 70 | 30~40 | 50 |
| 2 | 80 | 40~50 | 70 |
| 3 | 90 | 50~60 | 140 |
Table 13 orthogonal test L
9(3
3) orthogonal table and result
RA＞RB＞RC
Analysis result: from R value A＞B＞C, A (material temperature) is a principal element, and B drips speed and the C column length also has certain influence to drop pill.Successively in proper order: A:A
2＞A
3＞A
1, B:B
3＞B
2＞B
1, C:C
1＞C
3＞C
2Substantially close, from the roundness C of drop pill
3Be the best.So selected A
2, B
3, C
3Be that temperature of charge is 80 ℃, dripping speed is 50 ~ 60 droplets/minute, and column length is that 140cm is that the best of Pollen Typhae drop pill is dripped the system process conditions.Through five batches of lab scale checking conditional stabilitys, can operate.
5. the coating of drop pill is investigated: the dropping pill formulation bitter in the mouth, be not easy to be accepted by extensive patients, and so consider to adopt the film coating method, make it can satisfy crowd's needs widely.Investigate as follows to its coating conditions:
(1). the selection of coating solution has been tested three kinds of coating materials according to the effect of this product, the results are shown in Table 14
The selection of table 14 coating material
| Title | Dissolving | Coating |
| Hypromellose | Water-soluble and 80% following alcoholic solution, the solution clarification | The water white transparency on drop pill surface, evenly, thinner, drop pill does not have acid |
| Ka Lekang coating material (white) | All be suspension at water or water alcohol liquid, place not stratified | Lead white, thicker, evenly, drop pill does not have acid |
| Ka Lekang coating material (salmon pink) | Water insoluble or pure liquid is placed layering | Salmon pink fine particle shape, inhomogeneous, thicker, drop pill does not have acid |
Result of the test shows: from dissolubility, and outward appearance, mouthfeel is observed, and hypromellose more is applicable to the coating of this product.The film property of hypromellose is better, is used for coating merely, the coated drop pill dry tack free, and after placing, skin covering of the surface is the part projection easily, influences the presentation quality of drop pill, so add an amount of ductile material Tween-80 in addition to increase the plasticity and the toughness of film-coat.And add an amount of steviosin and make its mouthfeel better.Through multiple comparison test, determine that its coating solution is a hypromellose, Tween-80, steviosin, water, dehydrated alcohol.
(2). the selection of coating solution proportioning is reference with its outward appearance and mouthfeel, and has considered the ease for operation of experiment, has carried out the selection experiment of coating solution proportioning, the results are shown in Table 15
The selection of table 15 coating solution proportioning
| Numbering | Hypromellose (g) | Steviosin (g) | Polysorbate 80 (g) | Water (ml) | Dehydrated alcohol (ml) | The result |
| 1 | 4 | 0 | 1 | 20 | 80 | Denseness is big, is difficult to ejection |
| 2 | 3 | 0 | 0 | 20 | 80 | Denseness is bigger, easily stops up, and the coating time is long, and coating is even, and acid is lighter |
| 3 | 2 | 0.2 | 1 | 20 | 80 | Easily ejection, coating is even, and medicine acid is lighter, and it is sweet to distinguish the flavor of |
| 4 | 2 | 0.5 | 1 | 20 | 80 | Easily ejection, coating is even, and is very sweet |
| 5 | 2 | 0.1 | 1 | 20 | 80 | Easily ejection, coating is even, and is little sweet |
The result shows: the proportioning of coating solution is hypromellose 2g, Tween-80 1g, and steviosin 0.2g, water 20ml, more satisfactory during dehydrated alcohol 80ml.
(3). suitable coating solution and proportioning thereof have been selected in the research of coating and shaping technology, the flow velocity of coating solution, consumption, the rotating speed of coating pan, temperature has determined the quality of last coating.Test of many times shows:
Make drop pill variable wet when 1) flow velocity of coating solution and coating time flow velocity are big, cause the composition stripping; Flow velocity hour then is easy to cutout, and finally selected flow velocity is 2～3ml/min.In order to be able to correct the acid of drop pill, can bring into play the advantage of drop pill fast Absorption again, so select with less coating solution consumption, experiment shows repeatedly, the coating time is that 15 minutes/50g drop pill can reach above-mentioned requirements.
2) rotation of the rotating speed of coating pan and temperature requirement coating pan can make drop pill flow fast therein, just can reach the coating effect of uniform.Because the fusing point of the substrate PEG of drop pill is lower, thus the temperature of selecting coating pan between 35～42 ℃, rotating speed is preferable at 20 rev/mins.
Xuefuzhuyu drop pills (No. 3 technology) pharmacodynamics test
Summary 'Xue Fu Zhu Yu ' (former dosage form is a capsule) is the compound Chinese medicinal preparation that Tianjin Hong Rentang pharmaceutical factory produces.This medicine has been widely used in clinical, and has obtained effect preferably.Because clinical large usage quantity, my institute modernization of cmm chamber is accepted this factory and is entrusted, XUEFU ZHUYU JIAONANG has been carried out the dosage form improvement, we have carried out the pharmacodynamic study of hemorheology, platelet aggregation, microcirculation and 4 test models of hyperlipemia to the new technology sample that is provided, and and former dosage form compare.The result is as follows:
1. (the 6g crude drug/kg) group all can obviously reduce the whole blood viscosity of blood high viscosity syndrome rat for Xuefuzhuyu drop pills 1.5,3,6g crude drug/kg dosage group and former dosage form, 6g crude drug/kg dosage group also obviously reduces plasma viscosity and packed cell volume, and each dosage group does not all have obvious influence to erythrocyte sedimentation rate.
2. (the 6g crude drug/kg) group all obviously suppresses " blood stasis " rat by ADP, AA (removing 1.5g crude drug/kg dosage group), the inductive platelet aggregation of collagen (removing 1.5g crude drug/kg dosage group) for Xuefuzhuyu drop pills 1.5,3,6g crude drug/kg dosage group and former dosage form.
3. (the 3g crude drug/kg) group all obviously reduces the rank of microcirculation disturbance rabbit conjunctive bulbi blood capillary blood fluidised form, obviously increasing blood flow speed and point of intersect of the capillary network number for Xuefuzhuyu drop pills 1.5,3g crude drug/kg dosage group and former dosage form.
4. (the 4g crude drug/kg) group all can reduce its serum cholesterol (TC), serum triglycerides (TG) and its HDL-C (HDL-C) level that raises in 20 days to some extent to the administration of hyperlipidemia rats oral administration gavage for Xuefuzhuyu drop pills 2,4g crude drug/kg dosage group and former dosage form.
5. (serum TC, the TG of the group of the 4g crude drug/kg) zero difference (p＞0.05) of comparing with the blank group, (0.1g crude drug/kg) is organized all has the decline effect to mice serum TC, TG to fenofibrate for Xuefuzhuyu drop pills 1,2,4g crude drug/kg dosage group and former dosage form.
More than test all increases with dosage, and effect strengthens.The Xuefuzhuyu drop pills of same dose is suitable with former dosage form effect.
1. test objective
Rat blood high viscosity syndrome test model due to the employing intravenous injection high molecular dextran is observed the influence of Xuefuzhuyu drop pills to hemorheology of rat.
Adopt rat " blood stasis " test model, observe the influence of Xuefuzhuyu drop pills platelet aggregation.Adopt the intravenous injection high molecular dextran to cause the rabbit microcirculation disturbance, observe the influence of Xuefuzhuyu drop pills conjunctive bulbi blood capillary blood fluidised form, flow velocity and point of intersect of the capillary network number.Adopt high lipid food to feed rat and cause hyperlipemia model, observe the influence of Xuefuzhuyu drop pills hyperlipidemia rats TC, TG, HDL-C level.
Observe the influence of Xuefuzhuyu drop pills to normal mouse TC, TG, HDL-C level.
2. test material
2.1 medicine and reagent
Xuefuzhuyu drop pills: pale brown color drop pill, every gram drop pill are equivalent to crude drug 1.69 grams, lot number 041026.Provide by Tianjin Hong Rentang pharmaceutical Co. Ltd.
XUEFU ZHUYU JIAONANG: every capsules dress 0.4g medicated powder, every gram powder is equivalent to crude drug 1.69 grams, lot number 040504.Provide by Tianjin Hong Rentang pharmaceutical Co. Ltd.
FUFANG DANSHEN PIAN: Shijiazhuang City China imperial Pharmaceutical limited company produces lot number 20041004.10% high molecular dextran injection: Chinese Academy of Medical Sciences's Blood Research Institute product, molecular weight 300,000.
Aspirin: Qingdao No. 3 Pharmaceutical Factory produces, 25mg/ sheet, lot number 020412.Adrenalin hydrochloride: Tianjin gold credit aminoacid company limited is produced 1mg/ml, lot number 0405171.Fenofibrate: the Xuzhou magnificent pharmaceutical factory that tries to win favour is commercial, lot number 031103.
T-CHOL test kit CHO: Zhongsheng Beikong Biological Science ﹠ Technology Co., Ltd., lot number 180261.
Triglyceride test kit TG: Zhongsheng Beikong Biological Science ﹠ Technology Co., Ltd., lot number 220911.
HDL-C HDL-C: Zhongsheng Beikong Biological Science ﹠ Technology Co., Ltd., lot number 190031.
ADP:Sigma company product, lot number A2754.
AA:Sigma company product.
Collagen: self-control, get rat abdomen skin, unhairing shreds, in ice bath, grind with tissue grinder, 3000 rev/mins centrifugal 10 minutes, get supernatant and be for experiment.
2.2 animal
Rat: the Wistar kind, sex, body weight are determined according to the test needs.
Mice: Kunming kind, male and female dual-purpose, body weight 18 ~ 22g.
Rabbit: big ear white race, male and female dual-purpose, body weight 2 ~ 2.6kg.
Above animal provides by Tianjin Inst. of Materia Medica animal housing.The quality certification number: No. the 001st, Tianjin kinoplaszm word.
2.3 instrument
Blood viscometer: LG-R-80C, diligent generation Supreme Being's scientific instrument company limited product in Beijing.
Platelet aggregation instrument: PAM-3 type, Danyang, Jiangsu radio factory product.
Optical microscope: Olympus, Japanese import.
3. test method and result
3.1 Xuefuzhuyu drop pills is to the influence of blood high viscosity syndrome hemorheology of rat
Choose above-mentioned healthy rat, male and female dual-purpose, body weight 200 ~ 250g.Be divided into normal control group, model control group, Xuefuzhuyu drop pills 1.5,3,6g crude drug/kg dosage group at random by sex, body weight, ((the dosage group of 3g medicated powder/kg), totally 7 groups, every group is 10 to former dosage form for the dosage group of 6g crude drug/kg), positive drug compound Salviae Miltiorrhizae.Gastric infusion, once a day, continuous 10 days, to irritate the stomach volume and be the 1ml/100g body weight, normal control group and model control group are all irritated stomach and are waited capacity 0.5%CMC.After the last administration 1 hour, except that the normal control group, all the other respectively organized the equal tail vein injection 10% high molecular dextran injection 1ml/kg of rat, cause the blood high viscosity syndrome model.Quiet notes from abdominal aortic blood, with 3.8% sodium citrate anticoagulant (anticoagulant is 1: 9 with the ratio of whole blood), were measured 4 whole blood and plasma viscosities of cutting under the speed after 10 minutes on the LG-R-80C viscometer.In the hematocrit pipe, measure packed cell volume and erythrocyte sedimentation rate.Result of the test adopts two groups of mean statistical analysiss-t value method to carry out significance test, see Table 1.
Table 1 Xuefuzhuyu drop pills is to the influence of blood high viscosity syndrome hemorheology of rat (X ± SD)
| Group | Dosage (the g crude drug/kg) | Number of animals (only) | Whole blood viscosity (mpa.s) | Plasma viscosity | Erythrocyte sedimentation rate | Hematocrit | |||
| 1S1 | 5S 1 | 30S 1 | 200S 1 | (cm/h) | (％) | ||||
| Normal control | 10 | 9.77±0.98 | 4.58±0.36 | 2.78±0.18 | 2.16±0.13 | 1.07±0.04 | 1.80±0.42 | 30.0±1.63 | |
| The model contrast | 10 | 19.65±2.30 △△△ | 8.35±0.95 △△△ | 4.63±0.54 △△△ | 3.38±0.41 △△ | 1.21±0.06 △△△ | 1.00±0.00 △△ | 48.2±4.98 △△ | |
| The drop pill group | 6 | 10 | 13.62±1.32*** | 6.32±0.60*** | 3.81±0.37** | 2.93±0.30* | 1.13±0.07* | 1.00±0.00 | 41.0±4.80* |
| 3 | 10 | 15.05±1.47*** | 6.80±0.58*** | 4.0±0.30** | 3.04±0.21* | 1.20±0.06 | 1.00±0.00 | 46.0±5.08 | |
| 1.5 | 10 | 16.77±2.15** | 7.42±0.75* | 4.27±0.33 | 3.21±0.21 | 1.17±0.08 | 1.00±0.00 | 43.8±5.83 | |
| Former dosage form | 6 | 10 | 14.12±0.93*** | 6.47±0.37*** | 3.85±0.21** | 2.94±0.16* | 1.19±0.05 | 1.00±0.00 | 40.2±3.36* |
| Compound Salviae Miltiorrhizae | 3g medicated powder | 10 | 15.28±1.88*** | 6.81±0.65*** | 3.95±0.29** | 2.97±0.18* | 1.21±0.08 | 1.00±0.00 | 44.4±4.81 |
△ △ △: p＜0.001 (comparing) with the normal control group
* p＜0.05 * * p＜0.01 * * * p＜0.001 (with the model control group comparison)
Table 1 is the result show, compares with the normal control group, and whole blood viscosity, the plasma viscosity under the speed respectively cut in the obvious rising of model control group, and packed cell volume obviously reduces erythrocyte sedimentation rate, shows the moulding success.Compare with model control group, Xuefuzhuyu drop pills 1.5,3,6g crude drug/kg dosage group all obviously reduce the whole blood viscosity of blood high viscosity syndrome rat, and 6g crude drug/kg dosage group also obviously reduces plasma viscosity and packed cell volume.Each dosage group is to the equal no significant difference of erythrocyte sedimentation rate.The former dosage form of 'Xue Fu Zhu Yu ', positive control drug FUFANG DANSHEN PIAN also have similar action.
3.2 Xuefuzhuyu drop pills is to the influence of " blood stasis " rat platelet aggregation function
Select healthy male Wistar kind rat for use, body weight 250g～300g is divided into 6 groups at random by body weight, 10 every group.Xuefuzhuyu drop pills administration group irritates respectively that stomach gives 1.5,3,6g crude drug/kg, the former dosage form group of 'Xue Fu Zhu Yu ' irritate that stomach gives 6g crude drug/kg, the positive drug group is irritated stomach and given aspirin 150mg/kg, irritate the stomach volume and be the 1ml/100g body weight, model control group is irritated stomach and is waited capacity 0.5%CMC, once a day, continuous 10 days.Each dosage group rat is all in the adrenalin hydrochloride 0.08ml/100g body weight of preceding 1 day subcutaneous injection 1mg/ml of test, and totally twice, 6 hours at interval, (about 3 hours) put into frozen water swimming 5 minutes with rat therebetween, and fasting then (can't help water) is spent the night.Behind the next day gastric infusion 1 hour, pentobarbital sodium (40mg/kg) intraperitoneal anesthesia, abdominal aortic blood, with 3.8% sodium citrate anticoagulant (anticoagulant is 1: 9 with the ratio of whole blood), centrifugal, preparation platelet rich plasma (PRP) and platelet poor plasma (PPP), (platelet count is about 300,000/mm to transfer PRP with PPP
3).Adopt turbidimetry, as derivant, carry out PAgT,, calculate the maximum percentage rate of assembling of platelet, observe its effect according to tracing curve at PAM-3 type dual pathways platelet aggregation instrument with ADP, AA, collagen.The result adopts two groups of mean statistical analysiss-t value method to carry out significance test, see Table 2.
Table 2 Xuefuzhuyu drop pills is to the influence of " blood stasis " rat platelet aggregation function (X ± SD)
| Group | Dosage (the g crude drug/kg) | Number of animals (only) | The maximum percentage rate (%) of assembling of platelet | ||
| ADP | A A | Collagen | |||
| The model contrast | 10 | 59.0±16.31 | 83.0±15.04 | 48.4±7.35 | |
| The drop pill group | 6 | 10 | 23.0±14.94*** | 43.2±27.50** | 24.17±10.20*** |
| 3 | 10 | 36.0±9.31* | 59.8±26.00* | 37.8±7.04* | |
| 1.5 | 10 | 41.7±12.67* | 75.5±15.23 | 42.8±5.55 | |
| Former dosage form | 6 | 10 | 26.6±11.43*** | 41.7±26.58** | 25.0±11.58*** |
| Aspirin | 150mg/kg | 10 | 24.7±10.64*** | 14.3±16.48*** | 19.5±14.34*** |
*: p＜0.05 * *: p＜0.01 * * *: p＜0.001 (comparing) with model control group
Table 2 is the result show: Xuefuzhuyu drop pills 1.5,3,6g crude drug/kg dosage group and model control group are relatively, obviously suppress platelet aggregation by ADP, AA (removing 1.5g crude drug/kg dosage group), collagen (removing 1.5g crude drug/kg dosage group) inductive " blood stasis " rat, and increase with dosage, effect strengthens, and shows that Xuefuzhuyu drop pills has tangible antiplatelet aggregative activity.The former dosage form of 'Xue Fu Zhu Yu ', positive drug aspirin also have obvious inhibitory action.
3.3 'Xue Fu Zhu Yu ' is to the microcirculatory influence of rabbit conjunctive bulbi
Select healthy big ear white race rabbit for use, the male and female dual-purpose, body weight 2 ~ 2.6kg is divided into 7 groups at random by sex, body weight, and every group is 8.Normal control group, model control group, Xuefuzhuyu drop pills 0.75,1.5,3g crude drug/kg dosage group, the former dosage form 3g crude drug of 'Xue Fu Zhu Yu '/kg dosage group, positive drug FUFANG DANSHEN PIAN 2g medicated powder/kg dosage group are established in experiment.Gastric infusion, once a day, continuous 7 days, to irritate the stomach volume and be the 5ml/kg body weight, normal control group and model control group are all irritated stomach and are waited capacity 0.5%CMC.After the last administration 1 hour, intravenous injection pentobarbital sodium 30mg/kg, after the anesthesia, (20 * 2.5 times) are observed and the microvascular red cell velocity of record rabbit conjunctive bulbi, fluidised form and point of intersect of the capillary network number under anatomic microscope, as numerical value before the moulding.Auricular vein is injected 10% high molecular dextran (except the normal control group) 1ml/kg body weight then, cause the rabbit microcirculation disturbance, back 20 minutes microvascular red cell velocity in same position of record injection, fluidised form, point of intersect of the capillary network number, relatively its effect is observed in the variation before and after the moulding.Fluidised form adopts grade preface value method to carry out significance test, and flow velocity and point of intersect of the capillary network number adopt pairing t-value method to carry out significance test.The results are shown in Table 3, table 4, table 5.
Observation index:
Flow velocity: measuring the hemocyte bore of flowing through with eyepiece mircrometer gauge and stopwatch is 2 ~ 3 erythrocytic required times of blood capillary certain distance, repeats 3 times, gets average.
Fluidised form: 0 grade is straight line (line grain) shape; 1 grade is dotted line (grain line) shape; 2 grades is grain (wadding) shape; 3 grades are the stagnant shape of the stasis of blood.
The point of intersect of the capillary network number: choosing area is 1mm
2Around surround the fixed area on border by blood capillary, count the number of hits of blood capillary and border blood vessel in this zone.
Table 3 Xuefuzhuyu drop pills is to the influence of microcirculation disturbance rabbit conjunctive bulbi blood capillary erythrocyte fluidised form
| Group | Dosage (the g crude drug/kg) | Number of animals (only) | The erythrocyte fluidised form | ||||||||
| Before the moulding | After the moulding | ||||||||||
| 0 | 1 | 2 | 3 | 0 | 1 | 2 | 3 | ||||
| Normal control | 8 | 8 | |||||||||
| The model contrast | 8 | 8 | 4 | 4 | △△ | ||||||
| The drop pill group | 3 | 8 | 8 | 5 | 3 | ** | |||||
| 1.5 | 8 | 8 | 3 | 4 | 1 | * | |||||
| 0.75 | 8 | 8 | 1 | 5 | 2 | ||||||
| Former dosage form | 3 | 8 | 8 | 4 | 4 | ** | |||||
| FUFANG DANSHEN PIAN | 2g medicated powder | 8 | 8 | 4 | 3 | 1 | ** | ||||
△ △: P＜0.01 (comparing) with the normal control group
*: P＜0.05 * *: P＜0.01 (comparing) with model control group
Table 4 Xuefuzhuyu drop pills is to the influence of microcirculation disturbance rabbit conjunctive bulbi blood capillary red cell velocity (X ± SD)
| Group | Dosage (the g crude drug/kg) | Number of animals | Flow velocity (second/mm) | ||
| Before the moulding | After the moulding | Difference | |||
| Normal control | 8 | 6.25±0.47 | 6.46±0.44 | 0.21±0.35 | |
| The model contrast | 8 | 6.43±0.45 | 19.17±0.89 | 12.74±0.55 △△ | |
| The drop pill group | 3 | 8 | 6.58±0.56 | 16.14±1.86 | 9.56±2.01** |
| 1.5 | 8 | 6.56±0.46 | 17.46±1.77 | 10.90±2.03* | |
| 0.75 | 8 | 6.27±0.42 | 19.09±0.97 | 12.82±1.03 | |
| Former dosage form | 3 | 8 | 6.49±0.46 | 16.78±1.92 | 10.30±1.95** |
| FUFANG DANSHEN PIAN | 2g medicated powder | 8 | 6.56±0.57 | 17.14±1.91 | 10.58±1.74** |
△ △: P＜0.01 (comparing) with the normal control group
*: P＜0.05 * *: P＜0.01 (comparing) with model control group
Table 5 Xuefuzhuyu drop pills is to the influence of microcirculation disturbance rabbit conjunctive bulbi blood capillary point of intersect of the capillary network number (X ± SD)
| Group | Dosage (the g crude drug/kg) | Number of animals | Point of intersect of the capillary network number (individual) | ||
| Before the moulding | After the moulding | Difference | |||
| Normal control | 8 | 5.25±1.04 | 5.00±0.75 | 0.13±0.35 | |
| The model contrast | 8 | 5.38±0.86 | 1.88±1.36 | 3.50±0.93 △△ | |
| The drop pill group | 3 | 8 | 5.25±0.71 | 3.38±0.92 | 1.88±0.83** |
| 1.5 | 8 | 5.25±0.71 | 3.25±1.04 | 2.00±0.76** | |
| 0.75 | 8 | 5.38±0.74 | 2.62±1.41 | 2.75±1.04 | |
| Former dosage form | 3 | 8 | 5.38±0.74 | 3.25±1.16 | 2.13±1.13** |
| FUFANG DANSHEN PIAN | 2g medicated powder | 8 | 5.38±0.74 | 3.25±1.04 | 2.13±1.13** |
△ △: P＜0.01 (comparing) with the normal control group
*: P＜0.01 (comparing) with model control group
Result of the test shows: with the normal control group relatively, the model control group rabbit before the moulding of injection high molecular dextran, the microvascular blood fluidised form of conjunctive bulbi, flow velocity, point of intersect of the capillary network number average no significant difference; After the moulding 20 minutes, velocity of blood flow obviously slowed down, the fluidised form rank obviously increases, the point of intersect of the capillary network number obviously reduces, and showed that oneself forms microcirculation disturbance, the model copy success.Compare the microvascular blood fluidised form of each dosage group conjunctive bulbi, flow velocity, point of intersect of the capillary network number average no significant difference before the moulding with model control group; After the moulding 20 minutes, Xuefuzhuyu drop pills 1.5,3g crude drug/kg and former dosage form 3g crude drug/kg dosage group all can obviously increase velocity of blood flow and point of intersect of the capillary network number, obviously reduces blood fluidised form rank.Positive drug FUFANG DANSHEN PIAN 2g medicated powder/kg dosage group also has obvious effect.
3.4 Xuefuzhuyu drop pills is to the effect for reducing fat of experimental hyperlipidemia rat
Get 80 of rats, half and half, 70 of male and female are thrown high lipid food and were fed 7 days, get tail blood and survey TC in the 8th day.Determine the hyperlipemia model of rats establishment according to the TC index, be divided into 5 groups at random, 10 every group.Three dosage groups of Xuefuzhuyu drop pills (1,2,4g crude drug/kg), former dosage form group (4g crude drug/kg), positive known medicine group fenofibrate (0.1g crude drug/kg) and high lipid food model group.The blank group is thrown normal diet.Every day, oral administration gavage was administered once, and successive administration is 20 days altogether, and hyperlipidemia model group and normal diet group wait water gaging (model group and given the test agent group still give high lipid food).Administration fasting 12 hours after 21 days is got blood by the rat eye socket, with enzymatic assays TC, TG and HDL-C.Experimental data is organized a t test statistics with SPSS10.0 statistics software and is handled.The results are shown in Table 6.
The effect for reducing fat of table 6 pair hyperlipidemia rats
| Group | Dosage g/kg | TC(mmol/L) | TG (mmol/L) | HDL-C (mmol/L) | |
| Before the administration | After the administration | ||||
| The normal diet group | 1.57±0.28 | 1.65±0.29 | 1.07±0.18 | 1.27±0.20 | |
| The hyperlipidemia model group | 3.71±0.53 △△ △ | 3.84±0.32 △△△ | 1.34±0.21 △△ | 0.80±0.17 △△△ | |
| The drop pill group | 4.0 | 3.75±0.31 △△△ | 3.24±0.55** | 1.16±0.20* | 1.01±0.22* |
| 2.0 | 3.76±0.55 △△△ | 3.49±0.39* | 1.17±0.21 | 0.97±0.15* | |
| 1.0 | 3.74±0.71 △△△ | 3.52±0.42 | 1.22±0.19 | 0.89±0.14 | |
| Former dosage form group | 4.0 | 3.75±0.40 △△△ | 3.26±0.35** | 1.20±0.12* | 1.03±0.32* |
| The fenofibrate group | 0.1 | 3.74±0.34 △△△ | 2.91±0.42*** | 1.09±0.13** | 1.18±0.19*** |
Annotate: administration group *: p＜0.05 * *: p＜0.01 * * * that compares with the hyperlipidemia model group: p＜0.001
Administration group and normal diet group be △ △ relatively: p＜0.01 △ △ △: p＜0.001
The result shows: TC of each group of hyperlipidemia model difference highly significant (p＜0.001) of comparing with the normal diet group before the administration, and behind the prompting feed high lipid food, rat serum TC raises, and hyperlipemia model of rats is successful.Xuefuzhuyu drop pills (2, the 4g crude drug/kg) the dosage group can reduce serum total cholesterol.(the 4g crude drug/kg) the dosage group can triglyceride reducing for Xuefuzhuyu drop pills.Xuefuzhuyu drop pills (2, the 4g crude drug/kg) the dosage group has the effect of high density lipoprotein increasing.((0.1 crude drug/kg) also has same function to former dosage form group for 4g crude drug/kg) and fenofibrate group.
3.5 Xuefuzhuyu drop pills is to the influence of normal mouse blood fat
Get 50 of 20-22g body weight Kunming mouses, male and female half and half are divided into 5 groups at random, 10 every group.Three dosage groups of Xuefuzhuyu drop pills (1,2,4g/kg), and former dosage form group (the 4g crude drug/kg), positive known medicine fenofibrate group (0.1g/kg) and blank group (waiting water gaging).Every day, oral administration gavage was administered once, continuous 14 days.The eyeball blood sampling is plucked in fasting in the 15th day after 12 hours, the survey serum TC,
TG content.Experimental data is organized a t test statistics with SPSS10.0 statistics software and is handled.The results are shown in Table 7.
The influence of the table 7 pair normal mouse blood fat (N=10 of X ± SD)
| Group | Dosage (g/kg) | TC( mmol/L) | TG(mmol/L) |
| The blank group | 4.32±0.72 | 1.19±0.26 | |
| The drop pill group | 4.0 | 4.12±0.64 | 1.08±0.28 |
| 2.0 | 4.21±0.42 | 1.15±0.23 | |
| 1.0 | 4.20±0.47 | 1.13±0.25 | |
| Former dosage form group | 4.0 | 4.15±0.51 | 1.12±0.22 |
| The fenofibrate group | 0.1 | 3.62±0.50* | 0.96±0.20* |
Annotate: respectively be subjected to examination group *: p＜0.05 of comparing with the blank group
The result shows: Xuefuzhuyu drop pills (1,2, the dosage group of 4g crude drug/kg) and former dosage form group (4g crude drug/serum TC kg), the TG zero difference (p＞0.05) of comparing with the blank group, fenofibrate group (0.1g crude drug/kg) mice serum TC, TG are all had the decline effect.Prompting Xuefuzhuyu drop pills and former dosage form do not have obvious influence to normal mice serum TC, TG.
4, conclusion (of pressure testing)
1. (the 6g crude drug/kg) group all obviously reduces the whole blood viscosity of blood high viscosity syndrome rat, and 6g crude drug/kg dosage group also obviously reduces plasma viscosity and packed cell volume for 'Xue Fu Zhu Yu ' 1.5,3,6g crude drug/kg dosage group and former dosage form.
2. (the 6g crude drug/kg) group all obviously suppresses " blood stasis " rat by ADP, AA (removing 1.5g crude drug/kg dosage group), the inductive platelet aggregation of collagen (removing 1.5g crude drug/kg dosage group) for 'Xue Fu Zhu Yu ' 1.5,3,6g crude drug/kg dosage group and former dosage form.
3. (the 6g crude drug/kg) group all obviously reduces the rank of microcirculation disturbance rabbit conjunctive bulbi blood capillary blood fluidised form, obviously increasing blood flow speed and point of intersect of the capillary network number for 'Xue Fu Zhu Yu ' 1.5,3g crude drug/kg dosage group and former dosage form.
4. (the 4g crude drug/kg) group all can reduce its serum cholesterol (TC), serum triglycerides (TG) and its HDL-C (HDL-C) level that raises in 20 days to some extent to the administration of hyperlipidemia rats oral administration gavage for Xuefuzhuyu drop pills 2,4g crude drug/kg dosage group and former dosage form.
5. (serum TC, the TG of the group of the 4g crude drug/kg) zero difference (p＞0.05) of comparing with the blank group, (0.1g crude drug/kg) is organized all has the decline effect to mice serum TC, TG to fenofibrate for Xuefuzhuyu drop pills 1,2,4g crude drug/kg dosage group and former dosage form.
Above result of the test shows that Xuefuzhuyu drop pills has significantly " blood circulation promoting and blood stasis dispelling " and effect for reducing blood fat.Cure mainly substantially with the function of this medicine and to conform to.Suitable with the former dosage form effect of same dose 'Xue Fu Zhu Yu '.
Advantage of the present invention is: the Xuefuzhuyu drop pills taking dose is little, and every clothes dosage is the 6-8 ball only, is convenient to the patient and accepts and take; Dissolution velocity is fast, is beneficial to absorption; The preparation method of the relatively more existing XUEFU ZHUYU JIAONANG of bioavailability height, the preparation method of Xuefuzhuyu drop pills is more advanced, reasonable.
The specific embodiment
Embodiment 1
Prescription:
Semen Persicae (stir-fry) 0.25kg Radix Angelicae Sinensis 0.15kg Fructus Aurantii (parched with bran) 0.1kg Rhizoma Chuanxiong 0.075kg
Radix Bupleuri 0.05kg Flos Carthami 0.15kg Radix Achyranthis Bidentatae 0.15kg Radix Paeoniae Rubra 0.18kg
Radix Rehmanniae 0.15kg Radix Platycodonis 0.075kg Radix Glycyrrhizae 0.5kg
Measure 11 flavor medicinal material extract volatile oil 2ml by prescription, the medicinal residues water is carried 3 times, and amount of water is respectively 6 times, decocting time was respectively 1 hour, filtered, and medicinal residues are 1. standby, merging filtrate, through being evaporated to the extractum 1.38kg that relative density is 1.16 (75 ℃ of mensuration), add ethanol and make that to contain the alcohol amount be 60%, stir evenly, leave standstill 24h and make precipitation, get supernatant and reclaim ethanol, the clear paste 0.62kg that is evaporated to relative density and is 1.30 (70 ℃ of mensuration) 2., and is standby; With 1. reuse 80% ethanol extraction 2 times of medicinal residues, alcohol adding amount is respectively 7 times, refluxes 1 hour, merge alcohol extract, reclaim ethanol, being evaporated to relative density is the extractum 1.03kg of 1.18 (70 ℃ of mensuration), add 5 times of water gagings, stir evenly, leave standstill 24h and make precipitation, sucking filtration, get precipitate 0.583kg 3., merge 2. and 3., the clear paste 0.675kg that is evaporated to relative density again and is 1.30 (75 ℃ of mensuration) 4., and is standby.Get the ethyl acetate extraction 4 times of 4. using 1 times of amount, combining extraction liquid, reclaim ethyl acetate, be evaporated to relative density and be 1.40 clear paste 0.015kg, add the polyethylene glycol 6000 of 2 times of amounts, make fusion in 80 ℃, mixing, as condensing agent, (temperature of charge is 80 ℃, and dripping speed is 60 droplets/minute to carry out drop pill in the drop pill machine with liquid paraffin, column length is 140cm), drain, (proportioning of coating solution is hypromellose 2.25g to film coating, Tween-80 1.125g, steviosin 0.225g, water 22.5ml, dehydrated alcohol 90ml), make drop pill (every gram drop pill is equivalent to crude drug 10.08g).
Embodiment 2
Prescription:
Semen Persicae (stir-fry) 0.25kg Radix Angelicae Sinensis 0.15kg Fructus Aurantii (parched with bran) 0.1kg Rhizoma Chuanxiong 0.075kg
Radix Bupleuri 0.05kg Flos Carthami 0.15kg Radix Achyranthis Bidentatae 0.15kg Radix Paeoniae Rubra 0.18kg
Radix Rehmanniae 0.15kg Radix Platycodonis 0.075kg Radix Glycyrrhizae 0.5kg
Press recipe quantity with 11 flavor medical materials water extraction 2 times, amount of water is respectively 8 times, decocting time 1 hour filters merging filtrate, being evaporated to relative density is the extractum 1.24kg of 1.18 (75 ℃ of mensuration), add ethanol and make that to contain the alcohol amount be 70%, stir evenly, leave standstill 24h and make precipitation, get supernatant and reclaim ethanol, being evaporated to relative density is the clear paste 0.35kg of 1.30 (70 ℃ of mensuration); The ethyl acetate extraction of 1 times of amount of reuse 4 times, combining extraction liquid, reclaim ethyl acetate, being evaporated to relative density is the clear paste 0.014kg of 1.40 (70 ℃ of mensuration), adds 2 times of amount polyethylene glycol 6000s, makes fusion in 80 ℃, mixing, as condensing agent, (temperature of charge is 80 ℃, and dripping speed is 60 droplets/minute to carry out drop pill in the drop pill machine with liquid paraffin, column length is 140cm), drain, (proportioning of coating solution is hypromellose 2.1g to film coating, Tween-80 1.05g, steviosin 0.21g, water 21ml, dehydrated alcohol 84ml), make drop pill (every gram drop pill is equivalent to crude drug 10.05g).
Embodiment 3
Prescription:
Semen Persicae (stir-fry) 0.25kg Radix Angelicae Sinensis 0.15kg Fructus Aurantii (parched with bran) 0.1kg Rhizoma Chuanxiong 0.075kg
Radix Bupleuri 0.05kg Flos Carthami 0.15kg Radix Achyranthis Bidentatae 0.15kg Radix Paeoniae Rubra 0.18kg
Radix Rehmanniae 0.15kg Radix Platycodonis 0.075kg Radix Glycyrrhizae 0.5kg
Press recipe quantity with 11 flavor medical materials with 80% ethanol extraction 2 times, add 7 times of amount ethanol for the first time, decoct 2h, collection filtrate; Add for the second time 5 times of amount ethanol, decocting time 1h collects filtrate, merges filtrate twice.Filtrate decompression being concentrated into relative density is the extractum 1.02kg of 1.15 (70 ℃ of mensuration) again, with the ethyl acetate extraction of 1 times of amount 2 times, reclaims ethyl acetate, and the clear paste 0.007kg that is evaporated to relative density and is 1.20 (70 ℃ of mensuration) 1., and is standby.With the medicinal residues after the alcohol extraction, carry 2 times through water, add 8 times of water gagings for the first time, decoct 2h, collect filtrate; Add for the second time 5 times of water gagings, decoct 1h, collect filtrate, merge filtrate twice.Filtrate decompression being concentrated into relative density is the extractum 1.21kg of 1.15 (75 ℃ of mensuration) again, with the water-saturated n-butanol of 1 times of amount extraction 2 times, reclaims n-butyl alcohol, and the clear paste 0.0065kg that is evaporated to relative density and is 1.20 (70 ℃ of mensuration) 2..With 1. and clear paste 2. merge, press 2 times of amount adding polyethylene glycol 6000s of clear paste 0.0135kg, make fusion in 80 ℃, mixing, as condensing agent, (temperature of charge is 80 ℃ to carry out drop pill in the drop pill machine with liquid paraffin, dripping speed is 60 droplets/minute, and column length is 140cm), drain, (proportioning of coating solution is hypromellose 2g to film coating, Tween-80 1g, steviosin 0.2g, water 20ml, dehydrated alcohol 80ml), make drop pill (every gram drop pill is equivalent to crude drug 10.14g).
Embodiment 4
Prescription:
Semen Persicae (stir-fry) 0.25kg Radix Angelicae Sinensis 0.15kg Fructus Aurantii (parched with bran) 0.1kg Rhizoma Chuanxiong 0.075kg
Radix Bupleuri 0.05kg Flos Carthami 0.15kg Radix Achyranthis Bidentatae 0.15kg Radix Paeoniae Rubra 0.18kg
Radix Rehmanniae 0.15kg Radix Platycodonis 0.075kg Radix Glycyrrhizae 0.5kg
Press recipe quantity with the 65% soak with ethanol 3h of 11 flavor medical materials with 5L, percolation is carried out with 10ml/ minute speed in the back, with percolation with adding ethanol, percolation stopped after 34 hours, collect percolate, reclaim ethanol, being evaporated to relative density is the extractum 0.55kg of 1.38 (70 ℃ of mensuration), with the ethyl acetate extraction of 1 times of amount 4 times, combining extraction liquid reclaims ethyl acetate, and being evaporated to relative density is the clear paste 0.026kg of 1.40 (70 ℃ of mensuration), the polyethylene glycol 6000 that adds 2 times of amounts, make fusion in 80 ℃, mixing, with liquid paraffin as condensing agent, (temperature of charge is 80 ℃ to carry out drop pill in the drop pill machine, dripping speed is 60 droplets/minute, and column length is 140cm), drain, (proportioning of coating solution is hypromellose 3.9g to film coating, Tween-80 1.95g, steviosin 0.39g, water 39ml, dehydrated alcohol 156ml), make drop pill (every gram drop pill is equivalent to crude drug 10.10g).Every heavy 40mg of drop pill.
Claims (9)
1, a kind of Xuefuzhuyu drop pills for the treatment of coronary heart disease, angina pectoris and hyperlipemia is characterized in that it is by as the polyethylene glycol 6000 of substrate with as the following weight parts Chinese crude drug of active component:
The extract of Semen Persicae (stir-fry) 10-20 part Radix Angelicae Sinensis 7-15 part Fructus Aurantii (parched with bran) 5-12 part Rhizoma Chuanxiong 4-10 part Radix Bupleuri 2-8 part Flos Carthami 7-15 part Radix Achyranthis Bidentatae 7-15 part Radix Paeoniae Rubra 5-12 part Radix Rehmanniae 7-15 part Radix Platycodonis 4-10 part Radix Glycyrrhizae 2-8 part is made.
2, the Xuefuzhuyu drop pills of treatment coronary heart disease, angina pectoris and hyperlipemia according to claim 1 is characterized in that it is by as the polyethylene glycol 6000 of substrate with as following preferred weight part Chinese crude drug of active component:
The extract that 6 portions of Radix Glycyrrhizaes of 12 parts of Radix Platycodoniss of 8 portions of Radix Rehmanniae of 12 parts of Radix Paeoniae Rubra of 12 parts of Radix Achyranthis Bidentataes of 4 parts of Flos Carthamis of 6 parts of Radix Bupleuri of 8 parts of Rhizoma Chuanxiongs of Semen Persicae (stir-fry) 12 parts of Fructus Aurantiis of 16 parts of Radix Angelicae Sinensis (parched with bran) are 4 parts is made.
3,, it is characterized in that described active component and substrate ratio of weight and number are 1: 2 according to the Xuefuzhuyu drop pills of claim 1 and 2 described treatment coronary heart disease, angina pectoris and hyperlipemias.
4,, it is characterized in that the described water extract-alcohol precipitation that is extracted as adds alcohol extracting-water precipitating, extraction according to the Xuefuzhuyu drop pills of claim 1 and 2 described treatment coronary heart disease, angina pectoris and hyperlipemias; Or extract the system drop pill behind the water extract-alcohol precipitation; Or alcohol extraction extraction+water is proposed extraction, the system drop pill; Or extract the system drop pill behind the percolation.
5, a kind of preparation method for the treatment of the Xuefuzhuyu drop pills of coronary heart disease, angina pectoris and hyperlipemia is characterized in that comprising the steps:
1) medical material is handled: the weighting profit requires 1 or 2 described weight portion Chinese crude drugs as active component, get 11 flavor medical materials and carry oil, the medicinal residues water is carried 2-3 time, amount of water 4-8 doubly, decocting time 1-3h filters, and medicinal residues are 1. standby, merge 3 times filtrate, through being evaporated to relative density is 1.10-1.25, and the extractum of 60-75 ℃ of mensuration adds ethanol and makes and contain the alcohol amount and be 60-80%, stir evenly, leave standstill 12-24h and make precipitation, get supernatant and reclaim ethanol, being evaporated to relative density is 1.25-1.40, the clear paste of 60-70 ℃ of mensuration 2., and is standby; With 1. reuse ethanol extraction 1-2 time of medicinal residues, alcohol adding amount be 6-8 doubly, backflow 1-2h, merge alcohol extract, reclaim ethanol, being evaporated to relative density is 1.15-1.25, the extractum of 60-70 ℃ of mensuration adds 4-6 times of water gaging, stirs evenly, leave standstill 12-24h and make precipitation, 3. sucking filtration gets precipitate, merge 2. and 3., being evaporated to relative density again is 1.25-1.40, and the clear paste of 60-75 ℃ of mensuration 4., and is standby; Get the ethyl acetate extraction several of 4. doubly measuring with 1-2, combining extraction liquid reclaims ethyl acetate, is evaporated to the clear paste that relative density is 1.35-1.5;
2) medicinal liquid preparation: according to extract clear paste and polyethylene glycol 6000 amount portion rate is 1: 2 ratio adding extract clear paste, is stirred to dissolving, mixing; Add an amount of polyethylene glycol 6000, make fusion in 70-90 ℃, mixing, standby;
3) drip system: the medicinal liquid for preparing is forwarded in the liquid reservoir, and airtight and insulation is at 80 ℃, regulator solution titer valve, and dripping speed is 60 droplets/minute, column length is 140cm, splashes in 10～15 ℃ of liquid paraffin, as condensing agent, carries out drop pill with liquid paraffin in the drop pill machine.
4) drying: the drop pill of above-mentioned formation is drained, and the erasing liquor paraffin body, the drop pill of drying, standby;
5) film coating: with the drop pill bag film-coat that drying is made, the proportioning of coating solution is hypromellose 2.25g, Tween-80 1.125g, steviosin 0.225g, water 22.5ml, dehydrated alcohol 90ml makes the Xuefuzhuyu drop pills for the treatment of coronary heart disease, angina pectoris and hyperlipemia.
6, a kind of preparation method for the treatment of the Xuefuzhuyu drop pills of coronary heart disease, angina pectoris and hyperlipemia is characterized in that comprising the steps:
1) medical material is handled: the weighting profit requires 1 or 2 described weight portion Chinese crude drugs as active component, and with 11 flavor medical materials water extraction 2-3 times, amount of water is 4-8 times, decocting time 1-3h, merging filtrate, being evaporated to relative density is 1.15-1.20, the extractum of 60-75 ℃ of mensuration, adding ethanol makes and contains the alcohol amount and be 60-80%, stir evenly, leave standstill 12-24h and make precipitation, get supernatant and reclaim ethanol, being evaporated to relative density is 1.25-1.40, the clear paste of 60-70 ℃ of mensuration; The ethyl acetate extraction several that reuse 1-2 doubly measures, combining extraction liquid reclaims ethyl acetate, is evaporated to the clear paste that relative density is a 1.40-1.5060-70 ℃ of mensuration;
2) medicinal liquid preparation: according to extract clear paste and polyethylene glycol 6000 amount portion rate is 1: 2 ratio adding extract clear paste, is stirred to dissolving, mixing; Add an amount of polyethylene glycol 6000, make fusion in 70-90 ℃, mixing, standby;
3) drip system: the medicinal liquid for preparing is forwarded in the liquid reservoir, and airtight and insulation is at 80 ℃, regulator solution titer valve, and dripping speed is 60 droplets/minute, column length is 140cm, splashes in 10～15 ℃ of liquid paraffin, as condensing agent, carries out drop pill with liquid paraffin in the drop pill machine;
4) drying: the drop pill of above-mentioned formation is drained, and the erasing liquor paraffin body, the drop pill of drying, standby;
5) film coating: with the drop pill bag film-coat that drying is made, the proportioning of coating solution is hypromellose 2.1g, Tween-80 1.05g, steviosin 0.21g, water 21ml, dehydrated alcohol 84ml makes the Xuefuzhuyu drop pills for the treatment of coronary heart disease, angina pectoris and hyperlipemia.
7, a kind of preparation method for the treatment of the Xuefuzhuyu drop pills of coronary heart disease, angina pectoris and hyperlipemia is characterized in that comprising the steps:
1) medical material is handled: the weighting profit requires 1 or 2 described weight portion Chinese crude drugs as active component, and with 11 flavor medical materials ethanol extraction 2-3 times, alcohol adding amount is 4-8 times, decocting time 1-3h, merging filtrate, being evaporated to relative density is 1.05-1.20, the extractum of 60-70 ℃ of mensuration, the ethyl acetate extraction of doubly measuring with 1-2 for several times, combining extraction liquid reclaims ethyl acetate, and being evaporated to relative density is 1.10-1.25, the clear paste of 60-70 ℃ of mensuration 1., and is standby; With the medicinal residues after the alcohol extraction,
Carry 1-2 time through water, amount of water is 5-9 times, decocting time 1-3h, merging filtrate, being evaporated to relative density is 1.05-1.20, the extractum of 60-75 ℃ of mensuration, with the water-saturated n-butanol extracted several times that 1-2 doubly measures, combining extraction liquid, reclaim n-butyl alcohol, being evaporated to relative density is 1.10-1.25, and the clear paste of 60-70 ℃ of mensuration 2..With 1. and clear paste 2. merge;
2) medicinal liquid preparation: according to extract clear paste and polyethylene glycol 6000 amount portion rate is 1: 2 ratio adding extract clear paste, is stirred to dissolving, mixing; Add an amount of polyethylene glycol 6000, make fusion in 70-90 ℃, mixing, standby;
3) drip system: the medicinal liquid for preparing is forwarded in the liquid reservoir, and airtight and insulation is at 80 ℃, regulator solution titer valve, and dripping speed is 60 droplets/minute, column length is 140cm, splashes in 10～15 ℃ of liquid paraffin, as condensing agent, carries out drop pill with liquid paraffin in the drop pill machine;
4) drying: the drop pill of above-mentioned formation is drained, and the erasing liquor paraffin body, drying is made drop pill;
5) film coating: with the drop pill bag film-coat that drying is made, the proportioning of coating solution is hypromellose 2g, Tween-80 1g, steviosin 0.2g, water 20ml, dehydrated alcohol 80ml) make the treatment coronary heart disease, angina pectoris and hyperlipemia Xuefuzhuyu drop pills.
8, the preparation method of the Xuefuzhuyu drop pills of treatment coronary heart disease, angina pectoris and hyperlipemia according to claim 7 is characterized in that best preparation method comprises the steps:
1) medical material is handled: the weighting profit requires 1 or 2 described weight portion Chinese crude drugs as active component, and 11 flavor medical materials with 80% ethanol extraction 2 times, are added 7 times of amount ethanol for the first time, decocts 2h, collection filtrate; Add for the second time 5 times of amount ethanol, decocting time 1h collects filtrate, merges filtrate twice; Filtrate decompression being concentrated into relative density is 1.10-1.15 again, and the extractum of 60-70 ℃ of mensuration with the ethyl acetate extraction of 1 times of amount 2 times, reclaims ethyl acetate, and being evaporated to relative density is 1.15-1.20, and the clear paste of 60-70 ℃ of mensuration 1., and is standby; With the medicinal residues after the alcohol extraction, carry 2 times through water, add 8 times of water gagings for the first time, decoct 2h, collect filtrate; Add for the second time 5 times of water gagings, decoct 1h, collect filtrate, merge filtrate twice.Filtrate decompression being concentrated into relative density is 1.15-1.20 again, and the extractum of 60-75 ℃ of mensuration with the water-saturated n-butanol of 1 times of amount extraction 2 times, reclaims n-butyl alcohol, and being evaporated to relative density is 1.15-1.20, and the clear paste of 60-70 ℃ of mensuration 2..With 1. and clear paste 2. merge, standby;
2) medicinal liquid preparation:: according to extract clear paste and polyethylene glycol 6000 amount portion rate is 1: 2 ratio adding extract clear paste, makes fusion in 80 ℃, is stirred to dissolving, mixing, standby;
3) drip system: the medicinal liquid for preparing is forwarded in the liquid reservoir, and airtight and insulation is at 80 ℃, regulator solution titer valve, and dripping speed is 60 droplets/minute, column length is 140cm, splashes in 10～15 ℃ of liquid paraffin, as condensing agent, carries out drop pill with liquid paraffin in the drop pill machine;
4) drying: the drop pill of above-mentioned formation is drained, and the erasing liquor paraffin body, drying is made drop pill;
5) film coating: with the drop pill bag film-coat that drying is made, the proportioning of coating solution is hypromellose 2g, Tween-80 1g, and steviosin 0.2g, water 20ml, dehydrated alcohol 80ml makes the Xuefuzhuyu drop pills for the treatment of coronary heart disease, angina pectoris and hyperlipemia.
9, a kind of preparation method for the treatment of the Xuefuzhuyu drop pills of coronary heart disease, angina pectoris and hyperlipemia is characterized in that comprising the steps:
1) medical material is handled: the weighting profit requires 1 or 2 described weight portion Chinese crude drugs as active component, with the soak with ethanol of 11 flavor medical materials with 60-70%, speed with 10-20ml/ minute behind the 2-4h is carried out percolation, collect percolate 48-72h, get percolate and reclaim ethanol, being evaporated to relative density is 1.35-1.45, the extractum of 60-70 ℃ of mensuration, the ethyl acetate extraction of doubly measuring with 1-2 for several times, combining extraction liquid, reclaim ethyl acetate, being evaporated to relative density is 1.40-1.50, the clear paste of 60-70 ℃ of mensuration;
2) medicinal liquid preparation:: according to extract clear paste and polyethylene glycol 6000 amount portion rate is 1: 2 ratio adding extract clear paste, makes fusion in 70-90 ℃, is stirred to dissolving, mixing, standby;
3) drip system: the medicinal liquid for preparing is forwarded in the liquid reservoir, and airtight and insulation is at 80 ℃, regulator solution titer valve, and dripping speed is 60 droplets/minute, column length is 140cm, splashes in 10～15 ℃ of liquid paraffin, as condensing agent, carries out drop pill with liquid paraffin in the drop pill machine;
4) drying: the drop pill of above-mentioned formation is drained, and the erasing liquor paraffin body, drying is made drop pill;
5) film coating: with the drop pill bag film-coat that drying is made, the proportioning of coating solution is hypromellose 3.9g, Tween-80 1.95g, steviosin 0.39g, water 39ml, dehydrated alcohol 156ml makes the Xuefuzhuyu drop pills for the treatment of coronary heart disease, angina pectoris and hyperlipemia.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100149816A CN1331465C (en) | 2005-09-05 | 2005-09-05 | Blood stasis dispelling dripping pills for treating coronary heart disease, angina pectoris and hyperlipemia and preparation process thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100149816A CN1331465C (en) | 2005-09-05 | 2005-09-05 | Blood stasis dispelling dripping pills for treating coronary heart disease, angina pectoris and hyperlipemia and preparation process thereof |
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| Application Number | Title | Priority Date | Filing Date |
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| CN200610170298A Division CN1981836B (en) | 2005-09-05 | 2005-09-05 | Stasis-expelling drop pills for treating coronary heart disease, angina cordis and high blood fat and thereof making method |
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| CN1736429A true CN1736429A (en) | 2006-02-22 |
| CN1331465C CN1331465C (en) | 2007-08-15 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103862912A (en) * | 2014-03-19 | 2014-06-18 | 嘉兴职业技术学院 | Preparing method of protection film for protecting books |
| CN107308290A (en) * | 2017-06-27 | 2017-11-03 | 郑国玉 | A kind of lowering blood pressure and blood fat, hypoglycemic health care granular tea and preparation method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1552364A (en) * | 2003-05-29 | 2004-12-08 | 毛友昌 | Xuefu ecchymosis eliminating pills and their preparation |
| CN1491706A (en) * | 2003-08-02 | 2004-04-28 | 浙江天一堂集团有限公司 | Soft capsule for removing blood stasis in chest and its preparing method |
| CN1296075C (en) * | 2003-09-12 | 2007-01-24 | 北京国仁堂医药科技发展有限公司 | Xuefu Zhuyu soft capsule and its preparation method |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103862912A (en) * | 2014-03-19 | 2014-06-18 | 嘉兴职业技术学院 | Preparing method of protection film for protecting books |
| CN103862912B (en) * | 2014-03-19 | 2015-09-16 | 嘉兴职业技术学院 | For the protection of the preparation method of the diaphragm of books |
| CN107308290A (en) * | 2017-06-27 | 2017-11-03 | 郑国玉 | A kind of lowering blood pressure and blood fat, hypoglycemic health care granular tea and preparation method thereof |
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