Summary of the invention
The purpose of this invention is to provide the Chinese medicine of ultrafiltration preparation technology's preparation that a kind of impurity is few, loss of effective components is little, cost is low, it has overcome the deficiencies in the prior art, has solved the difficult problem of suitability for industrialized production ultrafiltration technology condition operability.
The present invention realizes by following technical step: with Radix Salviae Miltiorrhizae, Radix Notoginseng and Lignum Dalbergiae Odoriferae oil is crude drug, is prepared according to following steps:
(1) with Radix Salviae Miltiorrhizae, panax mixed or make water extract or alcohol extract respectively separately;
(2) described extracting solution being carried out predefecation handles;
(3) further described extracting solution is carried out hyperfiltration treatment;
(4) ultrafiltrate is concentrated, add Lignum Dalbergiae Odoriferae oil, make preparation according to a conventional method.
The percentage by weight of above-mentioned raw materials medicine is: Radix Salviae Miltiorrhizae 20%~97%, Radix Notoginseng 2%~79%, Lignum Dalbergiae Odoriferae oil 0.2%~3%; Be preferably Radix Salviae Miltiorrhizae 63.0%%~94%, Radix Notoginseng 4.0%~35.0%, Lignum Dalbergiae Odoriferae oil 0.5%~2.0%; More preferably Radix Salviae Miltiorrhizae 75.2%~90%, Radix Notoginseng 9%~23.5%, Lignum Dalbergiae Odoriferae oil 0.5%~1.3%.The percentage by weight sum of Radix Salviae Miltiorrhizae, Radix Notoginseng, Lignum Dalbergiae Odoriferae oil is 100%.
The above-mentioned raw materials Lignum Dalbergiae Odoriferae can be replaced with Styrax, and promptly the above-mentioned raw materials medicine can be Radix Salviae Miltiorrhizae 20%~97%, Radix Notoginseng 2%~79%, Styrax 0.2%~3%; Be preferably Radix Salviae Miltiorrhizae 63.0%%~94%, Radix Notoginseng 4.0%~35.0%, Styrax 0.5%~2.0%; More preferably Radix Salviae Miltiorrhizae 75.2%~90%, Radix Notoginseng 9%~23.5%, Styrax 0.5%~1.3%.The percentage by weight sum of Radix Salviae Miltiorrhizae, Radix Notoginseng, Styrax is 100%.
In the technology of the present invention step (1), alcohol extract can be the extracting solution of the lower alcohol of variable concentrations such as methanol, ethanol, normal propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutanol etc. or the extracting solution of its mixture.Carrying out next step predefecation after alcohol extract can not concentrate or suitably concentrate handles.
In the technology of the present invention step (2), preliminary clarifying treatment can be carried out coarse filtration with general material such as gauze, tiffany etc., the also available material such as the ceramic membrane of specialty carry out microfiltration, also can behind high speed centrifugation, divide and get supernatant, adsorption clarifications such as also available flocculating agent such as flocculate with chitosan clarifier, 101 fruit juice clarifiers, ZTC1+1 natural clarifying agent, Ovum Gallus domesticus album flocculating agent and remove particle bigger in the medicinal liquid, also available alcohol deposition method is removed most impurity.Both can singly use above-mentioned defecation method, but also use in conjunction, coarse filtration-adsorption clarification for example, adsorption clarification-high speed centrifugation, coarse filtration-microfiltration, coarse filtration-precipitate with ethanol etc.After can not concentrating or suitably concentrate, the solution that predefecation is handled carries out next step ultrafiltration; Preferably do not concentrate the ultrafiltration of promptly carrying out next step.
In the technology of the present invention step (3), the used ultrafilter membrane of ultrafiltration can be cellulose diacetate film (CA), three cellulose acetate membrane (CTA), cyanoethyl cellulose film (CN-CA), polysulfone membrane (PS), sulfonated polysulfone membrane (SPS), poly (ether sulfone) film (PES), sulfonated polyether sulfone film (SPES), polysulfonamides film (PSA), phenolphthalein side group polyarylsulfone (PAS) film (PDS), polyvinylidene fluoride film (PVDF), polyacrylonitrile film (PAN), polyimide film (N), cellulose membrane, methyl methacrylate-acrylonitrile copolymer film (MMA-AN), polyacrylonitrile/cellulose diacetate (PAN/CA) blend film, the dynamically ultrafilter membrane that forms, and the Modified Membrane of above-mentioned film.Be preferably cellulose diacetate film (CA), three cellulose acetate membrane (CTA), polysulfone membrane (PS), sulfonated polysulfone membrane (SPS), poly (ether sulfone) film (PES), sulfonated polyether sulfone film (SPES), polysulfonamides film (PSA), polyvinylidene fluoride film (PVDF), polyacrylonitrile film (PAN).
The molecular cut off of above-mentioned ultrafilter membrane is generally 6000~80000, is preferably 10000~70000, and the best is 20000~50000.
Ultrafiltration both can be adopted cross flow filter, also can adopt dead-end filtration, but preferred cross flow filter.
The operating condition of ultrafiltration technology is as follows:
(1) the inlet pressure of ultrafiltration is 0.1~0.5MPa, is preferably 0.1~0.35Mpa, and the best is 0.25~0.35Mpa; The liquid outlet pressure ratio inlet pressure of ultrafiltration hangs down 0.5~0.25kPa.The ultrafiltration initial stage is adopted lower pressure, slowly boosts then; In ultra-filtration process, adopt the periodic pressure fluctuation, the pressure wave moment is 0.1~0.2Mpa.
(2) the feed liquid flow velocity is 1.0~4.0m/s, is preferably 2.0~3.0m/s.In the ultra-filtration process, adopt the fluctuation of periodicity flow so that produce pulsating flow or non-stationary flow in membrane channels, the flow speed wave moment is 1.0~2.0m/s.
(3) feed high-pressure inert gas such as nitrogen in the ultrafiltration system discontinuous, form the gas-liquid stream of pulses, the cycle is that 0.5h~2h ventilates once, each 1 minute.
(3) feed temperature is 15~50 ℃, is preferably 20~40 ℃.
(4) when feed liquid stock solution is concentrated 1/15~1/5, add water or dilute alcohol solution ultrafiltration 1~2 time again; Be preferably when feed liquid stock solution is concentrated 1/12~1/8, add water or dilute alcohol solution ultrafiltration 1~2 time again.
(5) pH value of feed liquid is controlled at 5~9, is preferably 6.0~7.5;
(6) backwash condition: backwashing pressure is 0.15~2.5MPa, backwashing period is that 0.5~1.5h, backwashing time are that 1min~10min. is when replacing the method for recoil with ultrafiltration module use in parallel, wherein a cover or a few cover carry out normal ultrafiltration and distribute the recoil ultrafilter membrane of another set of or several grip assemblies of a part of filtrate, exchange is carried out behind the certain interval of time, generally be work 10~20min, recoil 30sec~3min.
(7) the Chemical cleaning cycle is 0.5 month~February, the Chemical cleaning medicament is generally diluted acid, diluted alkaline, surfactant, be preferably diluted alkaline, 0.5%~4.0% sodium hydroxide for example, the mixed solution of 1.5% sodium hydroxide and 2% sodium hypochlorite etc., pH value is 10~12, and cleaning pressure is 0.05~1.0MPa.After cleaning with chemical, the flushing of reuse water is near neutral.
In ultra-filtration process, both periodic pressure oscillation or the fluctuation of periodicity flow or periodicity fed noble gas separately, also can unite use, be periodic pressure fluctuation and periodically flow fluctuation associating use, perhaps the periodic pressure fluctuation is with periodically feeding noble gas unites use, perhaps periodically the flow fluctuation is with periodically feeding noble gas unites use, and perhaps the three unites use together.
In the technology of the present invention step (4), ultrafiltrate is condensed into extractum after, make preparation more according to a conventional method.For example, can be mixed and made into tablet, capsule, granule, oral liquid, slow releasing preparation, controlled release preparation, gel, ointment, ointment, cream, suppository, injection, injectable powder, patch, drop pill, suspensoid or the like with adjuvant on any or more than one pharmaceuticss such as starch, dextrin, lactose, microcrystalline Cellulose, hydroxypropyl methylcellulose, Polyethylene Glycol, magnesium stearate, micropowder silica gel, xylitol, lactose, glucose, glycine, mannitol, glycine etc.
The clinical observation of experimental example Drug therapy angina pectoris of the present invention
1 data and method
1.1 case is selected
" name of ischemic heart desease and the diagnostic criteria " that the angina pectoris diagnostic criteria of all cases is formulated with reference to WHO, symptom such as that the patient has is uncomfortable in chest, feel suffocated, but through having a rest or sublingual administration nitroglycerin relief of symptoms.Include 120 examples altogether in, be divided into two groups in proper order according to patient's prescription on individual diagnosis by 2: 1.80 examples are organized in treatment, male 51 examples, women 29 examples, year at age (55 ± 9), the course of disease (5.1 ± 1.3) year.Matched group 40 examples, male 29 examples, women 11 examples, year at age (55 ± 6), the course of disease (3.2 ± 1.1) year.Two groups of patients in sex, age, course of disease constituent ratio through x
2Or t check P>0.05, have comparability.
1.2 administrated method
The treatment group is taken medicine of the present invention (tablet), and each 3, every day 3 times.Matched group is given sorbitrate, each 10mg, every day 3 times, sublingual administration nitroglycerin in case of necessity.Be 2 months two groups of courses of treatment.
All do blood, routine urinalysis, liver, renal function, blood fat, blood glucose, Electrocardioscopy before and after the case treatment, write down the angina pectoris attacks number of times weekly, detect electrocardio, blood pressure, and inquiry adverse effect.
2 efficacy assessment standards
Judgement angina pectoris and ECG curative effect are all evaluated by " the medicine for cardiovascular system clinical research guideline " of bureau of drug administration of Ministry of Health of the People's Republic of China promulgation in 1993.The angina pectoris symptom curative effect determinate standard: produce effects, equal tired degree do not cause that angina pectoris or angina pectoris attacks number of times reduce more than 80%, and the nitroglycerin consumption reduces 80%; Effectively: angina pectoris attacks number of times and nitroglycerin consumption all reduce 50%~80%; Invalid: angina pectoris attacks number of times and nitroglycerin consumption all reduce less than 50%; Increase the weight of: angina pectoris attacks number of times, degree and persistent period increase, and the nitroglycerin consumption increases.
ECG curative effect criterion: produce effects: transference cure, electrocardiogram check ST section and T ripple recover normal, and exercise test transfers feminine gender to by the positive; Effectively: sx, electrocardiogram check ST section is low flat, and the T ripple is inverted to some extent and is corrected; Invalid: symptom basic with treatment before identical, the low flat or T ripple of electrocardiogram check ST section is inverted not improvement.
3 observed results
3.1 symptom and ECG curative effect (seeing Table 1)
Table 1 a liang group medicine compares angina pectoris symptom and ECG curative effect
Two groups of symptom curative effects, obvious effective rate is analyzed through Ridit, P<0.05; Two groups of ECG curative effect, obvious effective rate is analyzed through Ridit, P<0.05, the treatment group obviously is better than matched group.
3.2 the comparison (seeing Table 2) of heart rate and blood pressure before and after two groups of Drug therapys
The variation comparison of heart rate blood pressure before and after the table 2 liang group Drug therapy (x ± s)
Treatment front and back self paired t-test, t check between group group of P<0.05, two, P<0.05.
3.3 other
The blood fat of treatment group and matched group, blood glucose, liver function, renal function all change not quite before and after being determined at treatment.
The specific embodiment
The invention will be further elaborated below in conjunction with embodiment.These embodiment only are used to the purpose that exemplifies, rather than limit the present invention by any way.
Embodiment one
Crude drug adopts Radix Salviae Miltiorrhizae 450g, Radix Notoginseng 141g, Lignum Dalbergiae Odoriferae oil 8g.
Obtain the ethanol extract of Radix Salviae Miltiorrhizae with the ethanol extraction Radix Salviae Miltiorrhizae, with gauze with this extracting liquid filtering, collect filtrate. filtrate is that 6000 cellulose diacetate film carries out ultrafiltration with molecular cut off, filter type adopts cross flow filter. and the operating condition of ultrafiltration technology is: the inlet pressure of ultrafiltration is 0.1Mpa, the low 0.5kPa. ultrafiltration initial stage of the liquid outlet pressure ratio inlet pressure of ultrafiltration is adopted lower pressure, slowly boosts then; In ultra-filtration process, the fluctuation of employing periodic pressure, the pressure wave moment is that 0.1Mpa. feed liquid flow velocity is 1.0m/s, in the ultra-filtration process, adopt periodically flow fluctuation so that in membrane channels, produce pulsating flow or non-stationary flow, the flow speed wave moment is 1.0m/s, feed nitrogen in the ultrafiltration system discontinuous, form the gas-liquid stream of pulses, cycle is that 0.5h ventilates once, each 1 minute. feed temperature is 15 ℃, when feed liquid stock solution is concentrated 1/15, add water or dilute alcohol solution ultrafiltration 1 time again, it is 0.15MPa that the pH value of feed liquid is controlled at 5. backwashing pressures, backwashing period is 0.5h, backwashing time is that 1min. is when replacing the method for recoil with ultrafiltration module use in parallel, wherein a cover or a few cover carry out normal ultrafiltration and distribute the recoil ultrafilter membrane of another set of or several grip assemblies of a part of filtrate, exchange is carried out behind the certain interval of time, work 10min, the recoil 30sec. Chemical cleaning cycle is 0.5 month, the Chemical cleaning medicament is 0.5%~4.0% sodium hydroxide, the mixed solution of 1.5% sodium hydroxide and 2% sodium hypochlorite, pH value is 10~12, and cleaning pressure is 0.05MPa. after cleaning with chemical, and the flushing of reuse water is near neutral.
Described ultrafiltrate concentrated obtain the Radix Salviae Miltiorrhizae extractum that relative density is 1.35~1.39 (55 ℃).Radix Notoginseng powder is broken into fine powder, mixes all with Radix Salviae Miltiorrhizae extractum, drying is made granule, sprays into Lignum Dalbergiae Odoriferae oil, is mixed with above-mentioned granule, is pressed into 1000, sugar coating, promptly.
Embodiment two
Crude drug adopts Radix Salviae Miltiorrhizae 558g, Radix Notoginseng 34g, Lignum Dalbergiae Odoriferae oil 8g.
Obtain the ethanol extract of Radix Salviae Miltiorrhizae with the ethanol extraction Radix Salviae Miltiorrhizae, carry out microfiltration, collect filtrate with ceramic membrane.Filtrate is that 80000 polysulfone membrane is carried out ultrafiltration with molecular cut off, and filter type adopts dead-end filtration.The operating condition of ultrafiltration technology is: the inlet pressure of ultrafiltration is 0.5Mpa, and the liquid outlet pressure ratio inlet pressure of ultrafiltration hangs down 0.25kPa.The ultrafiltration initial stage is adopted lower pressure, slowly boosts then; In ultra-filtration process, adopt the periodic pressure fluctuation, the pressure wave moment is 0.2Mpa.The feed liquid flow velocity is 4.0m/s, in the ultra-filtration process, adopts periodically flow fluctuation so that produce pulsating flow or non-stationary flow in membrane channels, the flow speed wave moment is 2.0m/s, feeds nitrogen in the ultrafiltration system discontinuous, forms the gas-liquid stream of pulses, cycle is that 2h ventilates once each 1 minute.Feed temperature is 50 ℃, when feed liquid stock solution is concentrated 1/5, adds water or dilute alcohol solution ultrafiltration 2 times again, and the pH value of feed liquid is controlled at 9.Backwashing pressure is 2.5MPa, and backwashing period is that 1.5h, backwashing time are 10min.When with the in parallel method of using alternately recoil of ultrafiltration module, wherein a cover or a few cover carry out normal ultrafiltration and distribute the recoil ultrafilter membrane of another set of or several grip assemblies of a part of filtrate, and exchange is carried out behind the certain interval of time, work 20min, recoil 3min.The Chemical cleaning cycle is 2 months, and the Chemical cleaning medicament is the mixed solution of 0.5%~4.0% sodium hydroxide, 1.5% sodium hydroxide and 2% sodium hypochlorite, and pH value is 10~12, and cleaning pressure is 1.0MPa.After cleaning with chemical, the flushing of reuse water is near neutral.
Described ultrafiltrate concentrated obtain the Radix Salviae Miltiorrhizae extractum that relative density is 1.35~1.39 (55 ℃).Radix Notoginseng powder is broken into fine powder, mixes all with Radix Salviae Miltiorrhizae extractum, drying is made granule, sprays into Lignum Dalbergiae Odoriferae oil; be mixed with above-mentioned granule, add 3% polyvidone alcoholic solution system soft material, cross 18 mesh sieve system granules, 60 ℃ of dryings 30~45 minutes, granulate; add Pulvis Talci, mixing fills in capsule, promptly.
Embodiment three
Crude drug adopts Radix Salviae Miltiorrhizae 360g, Radix Notoginseng 232g, Lignum Dalbergiae Odoriferae oil 8g.
Obtain the ethanol extract of Radix Salviae Miltiorrhizae with the ethanol extraction Radix Salviae Miltiorrhizae, get supernatant with dividing behind this extracting solution high speed centrifugation. with this liquid molecular cut off is that 50000 polysulfone membrane is carried out ultrafiltration, filter type adopts cross flow filter. and the operating condition of ultrafiltration technology is: the inlet pressure of ultrafiltration is 0.35Mpa, the low 0.20kPa. ultrafiltration initial stage of the liquid outlet pressure ratio inlet pressure of ultrafiltration is adopted lower pressure, slowly boosts then; In ultra-filtration process, the fluctuation of employing periodic pressure, the pressure wave moment is that 0.2Mpa. feed liquid flow velocity is 3.0m/s, in the ultra-filtration process, adopt periodically flow fluctuation so that in membrane channels, produce pulsating flow or non-stationary flow, the flow speed wave moment is 2.0m/s, feed nitrogen in the ultrafiltration system discontinuous, form the gas-liquid stream of pulses, cycle is that 2h ventilates once, each 1 minute. feed temperature is 40 ℃, when feed liquid stock solution is concentrated 1/8, add water or dilute alcohol solution ultrafiltration 2 times again, it is 2.5MPa that the pH value of feed liquid is controlled at the 7.5. backwashing pressure, backwashing period is 1.5h, backwashing time is that 10min. is when replacing the method for recoil with ultrafiltration module use in parallel, wherein a cover or a few cover carry out normal ultrafiltration and distribute the recoil ultrafilter membrane of another set of or several grip assemblies of a part of filtrate, exchange is carried out behind the certain interval of time, work 20min, the recoil 3min. Chemical cleaning cycle is 2 months, the Chemical cleaning medicament is 0.5%~4.0% sodium hydroxide, the mixed solution of 1.5% sodium hydroxide and 2% sodium hypochlorite, pH value is 10~12, and cleaning pressure is 1.0MPa. after cleaning with chemical, and the flushing of reuse water is near neutral.
Described ultrafiltrate concentrated obtain the Radix Salviae Miltiorrhizae extractum that relative density is 1.35~1.39 (55 ℃).Radix Notoginseng powder is broken into fine powder, mixes all with Radix Salviae Miltiorrhizae extractum, drying is made granule, sprays into Lignum Dalbergiae Odoriferae oil, is mixed with above-mentioned granule, is pressed into 1000, or sugar coating, promptly.
Embodiment four:
Crude drug adopts Radix Salviae Miltiorrhizae 500 grams, Radix Notoginseng 94 grams, Lignum Dalbergiae Odoriferae oil 6 grams.
The Radix Salviae Miltiorrhizae of coarse pulverization, pseudo-ginseng to extraction pot, are added 5 times of water gagings, decocted 2 hours, filter, filtering residue carries out second time and extracts, and adds 4 times of water gagings, fried in shallow oil 1 hour, and filtration, filtering residue discards, merging filtrate.Filtrate is that 6000 cellulose diacetate film carries out ultrafiltration with molecular cut off, and filter type adopts cross flow filter.The operating condition of ultrafiltration technology is: the inlet pressure of ultrafiltration is 0.1Mpa, and the liquid outlet pressure ratio inlet pressure of ultrafiltration hangs down 0.5kPa.The ultrafiltration initial stage is adopted lower pressure, slowly boosts then; In ultra-filtration process, adopt the periodic pressure fluctuation, the pressure wave moment is 0.1Mpa.The feed liquid flow velocity is 1.0m/s, in the ultra-filtration process, adopts periodically flow fluctuation so that produce pulsating flow or non-stationary flow in membrane channels, the flow speed wave moment is 1.0m/s, feeds nitrogen in the ultrafiltration system discontinuous, forms the gas-liquid stream of pulses, cycle is that 0.5h ventilates once each 1 minute.Feed temperature is 15 ℃, when feed liquid stock solution is concentrated 1/15, adds water or dilute alcohol solution ultrafiltration 1 time again, and the pH value of feed liquid is controlled at 5.Backwashing pressure is 0.15MPa, and backwashing period is that 0.5h, backwashing time are 1min.When with the in parallel method of using alternately recoil of ultrafiltration module, wherein a cover or a few cover carry out normal ultrafiltration and distribute the recoil ultrafilter membrane of another set of or several grip assemblies of a part of filtrate, and exchange is carried out behind the certain interval of time, work 10min, recoil 30sec.The Chemical cleaning cycle is 0.5 month, and the Chemical cleaning medicament is the mixed solution of 0.5%~4.0% sodium hydroxide, 1.5% sodium hydroxide and 2% sodium hypochlorite, and pH value is 10~12, and cleaning pressure is 0.05MPa.After cleaning with chemical, the flushing of reuse water is near neutral.
Described ultrafiltrate concentrated obtain the extractum that relative density is 1.32~1.40 (55 ℃), spray into Lignum Dalbergiae Odoriferae oil, mix homogeneously, with the lactose fluidisation, drying is made granule, promptly in the batch (-type) fluid bed.
Embodiment five
Crude drug adopts Radix Salviae Miltiorrhizae 290 grams, Radix Notoginseng 306 grams, Lignum Dalbergiae Odoriferae oil 6 grams.
The Radix Salviae Miltiorrhizae of coarse pulverization, pseudo-ginseng to extraction pot, are added 5 times of water gagings, decocted 2 hours, filter, filtering residue carries out second time and extracts, and adds 4 times of water gagings, fried in shallow oil 1 hour, and filtration, filtering residue discards, merging filtrate.Filtrate is that 80000 polysulfone membrane is carried out ultrafiltration with molecular cut off, and filter type adopts dead-end filtration.The operating condition of ultrafiltration technology is: the inlet pressure of ultrafiltration is 0.5Mpa, and the liquid outlet pressure ratio inlet pressure of ultrafiltration hangs down 0.25kPa.The ultrafiltration initial stage is adopted lower pressure, slowly boosts then; In ultra-filtration process, adopt the periodic pressure fluctuation, the pressure wave moment is 0.2Mpa.The feed liquid flow velocity is 4.0m/s, in the ultra-filtration process, adopts periodically flow fluctuation so that produce pulsating flow or non-stationary flow in membrane channels, the flow speed wave moment is 2.0m/s, feeds nitrogen in the ultrafiltration system discontinuous, forms the gas-liquid stream of pulses, cycle is that 2h ventilates once each 1 minute.Feed temperature is 50 ℃, when feed liquid stock solution is concentrated 1/5, adds water or dilute alcohol solution ultrafiltration 2 times again, and the pH value of feed liquid is controlled at 9.Backwashing pressure is 2.5MPa, and backwashing period is that 1.5h, backwashing time are 10min.When with the in parallel method of using alternately recoil of ultrafiltration module, wherein a cover or a few cover carry out normal ultrafiltration and distribute the recoil ultrafilter membrane of another set of or several grip assemblies of a part of filtrate, and exchange is carried out behind the certain interval of time, work 20min, recoil 3min.The Chemical cleaning cycle is 2 months, and the Chemical cleaning medicament is the mixed solution of 0.5%~4.0% sodium hydroxide, 1.5% sodium hydroxide and 2% sodium hypochlorite, and pH value is 10~12, and cleaning pressure is 1.0MPa.After cleaning with chemical, the flushing of reuse water is near neutral.
Described ultrafiltrate concentrated obtain the extractum that relative density is 1.32~1.40 (55 ℃), with this extractum and an amount of magnesium stearate mix homogeneously, spray into Lignum Dalbergiae Odoriferae oil, be mixed with above-mentioned granule, compacting is wrapped film-coat in flakes.
Embodiment six
Crude drug adopts Radix Salviae Miltiorrhizae 210 grams, Radix Notoginseng 380 grams, Lignum Dalbergiae Odoriferae oil 4 grams.
The Radix Salviae Miltiorrhizae of coarse pulverization, pseudo-ginseng to extraction pot, are added 5 times of water gagings, decocted 2 hours, filter, filtering residue carries out second time and extracts, and adds 4 times of water gagings, fried in shallow oil 1 hour, and filtration, filtering residue discards, merging filtrate.Filtrate is that 50000 polysulfone membrane is carried out ultrafiltration with molecular cut off, and filter type adopts cross flow filter.The operating condition of ultrafiltration technology is: the inlet pressure of ultrafiltration is 0.35Mpa, and the liquid outlet pressure ratio inlet pressure of ultrafiltration hangs down 0.20kPa.The ultrafiltration initial stage is adopted lower pressure, slowly boosts then; In ultra-filtration process, adopt the periodic pressure fluctuation, the pressure wave moment is 0.2Mpa.The feed liquid flow velocity is 3.0m/s, in the ultra-filtration process, adopts periodically flow fluctuation so that produce pulsating flow or non-stationary flow in membrane channels, the flow speed wave moment is 2.0m/s, feeds nitrogen in the ultrafiltration system discontinuous, forms the gas-liquid stream of pulses, cycle is that 2h ventilates once each 1 minute.Feed temperature is 40 ℃, when feed liquid stock solution is concentrated 1/8, adds water or dilute alcohol solution ultrafiltration 2 times again, and the pH value of feed liquid is controlled at 7.5.Backwashing pressure is 2.5MPa, and backwashing period is that 1.5h, backwashing time are 10min.When with the in parallel method of using alternately recoil of ultrafiltration module, wherein a cover or a few cover carry out normal ultrafiltration and distribute the recoil ultrafilter membrane of another set of or several grip assemblies of a part of filtrate, and exchange is carried out behind the certain interval of time, work 20min, recoil 3min.The Chemical cleaning cycle is 2 months, and the Chemical cleaning medicament is the mixed solution of 0.5%~4.0% sodium hydroxide, 1.5% sodium hydroxide and 2% sodium hypochlorite, and pH value is 10~12, and cleaning pressure is 1.0MPa.After cleaning with chemical, the flushing of reuse water is near neutral.
Described ultrafiltrate concentrated obtain the extractum that relative density is 1.32~1.40 (55 ℃),, spray into Lignum Dalbergiae Odoriferae oil, be mixed, be pressed into tablet with above-mentioned granule with this extractum and an amount of magnesium stearate mix homogeneously.
Embodiment seven
Crude drug adopts Radix Salviae Miltiorrhizae 450g, Radix Notoginseng 141g, Styrax 8g.
Obtain the ethanol extract of Radix Salviae Miltiorrhizae with the ethanol extraction Radix Salviae Miltiorrhizae, with this extracting liquid filtering, collect filtrate with gauze.Filtrate is that 6000 cellulose diacetate film carries out ultrafiltration with molecular cut off, and filter type adopts cross flow filter.The operating condition of ultrafiltration technology is: the inlet pressure of ultrafiltration is 0.1Mpa, and the liquid outlet pressure ratio inlet pressure of ultrafiltration hangs down 0.5kPa.The ultrafiltration initial stage is adopted lower pressure, slowly boosts then; In ultra-filtration process, adopt the periodic pressure fluctuation, the pressure wave moment is 0.1Mpa.The feed liquid flow velocity is 1.0m/s, in the ultra-filtration process, adopts periodically flow fluctuation so that produce pulsating flow or non-stationary flow in membrane channels, the flow speed wave moment is 1.0m/s, feeds nitrogen in the ultrafiltration system discontinuous, forms the gas-liquid stream of pulses, cycle is that 0.5h ventilates once each 1 minute.Feed temperature is 15 ℃, when feed liquid stock solution is concentrated 1/15, adds water or dilute alcohol solution ultrafiltration 1 time again, and the pH value of feed liquid is controlled at 5.Backwashing pressure is 0.15MPa, and backwashing period is that 0.5h, backwashing time are 1min.When with the in parallel method of using alternately recoil of ultrafiltration module, wherein a cover or a few cover carry out normal ultrafiltration and distribute the recoil ultrafilter membrane of another set of or several grip assemblies of a part of filtrate, and exchange is carried out behind the certain interval of time, work 10min, recoil 30sec.The Chemical cleaning cycle is 0.5 month, and the Chemical cleaning medicament is the mixed solution of 0.5%~4.0% sodium hydroxide, 1.5% sodium hydroxide and 2% sodium hypochlorite, and pH value is 10~12, and cleaning pressure is 0.05MPa.After cleaning with chemical, the flushing of reuse water is near neutral.
Described ultrafiltrate concentrated obtain the Radix Salviae Miltiorrhizae extractum that relative density is 1.35~1.39 (55 ℃).Radix Notoginseng powder is broken into fine powder, mixes all with Radix Salviae Miltiorrhizae extractum, drying is made granule, adds Styrax, is mixed, and is pressed into 1000, sugar coating, promptly.
Embodiment eight
Crude drug adopts Radix Salviae Miltiorrhizae 558g, Radix Notoginseng 34g, Styrax 8g.
Obtain the ethanol extract of Radix Salviae Miltiorrhizae with the ethanol extraction Radix Salviae Miltiorrhizae, carry out microfiltration, collect filtrate with ceramic membrane.Filtrate is that 80000 polysulfone membrane is carried out ultrafiltration with molecular cut off, and filter type adopts dead-end filtration.The operating condition of ultrafiltration technology is: the inlet pressure of ultrafiltration is 0.5Mpa, and the liquid outlet pressure ratio inlet pressure of ultrafiltration hangs down 0.25kPa.The ultrafiltration initial stage is adopted lower pressure, slowly boosts then; In ultra-filtration process, adopt the periodic pressure fluctuation, the pressure wave moment is 0.2Mpa.The feed liquid flow velocity is 4.0m/s, in the ultra-filtration process, adopts periodically flow fluctuation so that produce pulsating flow or non-stationary flow in membrane channels, the flow speed wave moment is 2.0m/s, feeds nitrogen in the ultrafiltration system discontinuous, forms the gas-liquid stream of pulses, cycle is that 2h ventilates once each 1 minute.Feed temperature is 50 ℃, when feed liquid stock solution is concentrated 1/5, adds water or dilute alcohol solution ultrafiltration 2 times again, and the pH value of feed liquid is controlled at 9.Backwashing pressure is 2.5MPa, and backwashing period is that 1.5h, backwashing time are 10min.When with the in parallel method of using alternately recoil of ultrafiltration module, wherein a cover or a few cover carry out normal ultrafiltration and distribute the recoil ultrafilter membrane of another set of or several grip assemblies of a part of filtrate, and exchange is carried out behind the certain interval of time, work 20min, recoil 3min.The Chemical cleaning cycle is 2 months, and the Chemical cleaning medicament is the mixed solution of 0.5%~4.0% sodium hydroxide, 1.5% sodium hydroxide and 2% sodium hypochlorite, and pH value is 10~12, and cleaning pressure is 1.0MPa.After cleaning with chemical, the flushing of reuse water is near neutral.
Described ultrafiltrate concentrated obtain the Radix Salviae Miltiorrhizae extractum that relative density is 1.35~1.39 (55 ℃).Radix Notoginseng powder is broken into fine powder, mixes all,, be mixed, add 3% polyvidone alcoholic solution system soft material, cross 18 mesh sieve system granules with above-mentioned granule with the Styrax porphyrize with Radix Salviae Miltiorrhizae extractum, 60 ℃ of dryings 30~45 minutes, granulate, the adding Pulvis Talci, mixing fills in capsule, promptly.
Embodiment nine
Crude drug adopts Radix Salviae Miltiorrhizae 360g, Radix Notoginseng 232g, Styrax 8g.
Obtain the ethanol extract of Radix Salviae Miltiorrhizae with the ethanol extraction Radix Salviae Miltiorrhizae, get supernatant dividing behind this extracting solution high speed centrifugation.With this liquid molecular cut off is that 50000 polysulfone membrane is carried out ultrafiltration, and filter type adopts cross flow filter.The operating condition of ultrafiltration technology is: the inlet pressure of ultrafiltration is 0.35Mpa, and the liquid outlet pressure ratio inlet pressure of ultrafiltration hangs down 0.20kPa.The ultrafiltration initial stage is adopted lower pressure, slowly boosts then; In ultra-filtration process, adopt the periodic pressure fluctuation, the pressure wave moment is 0.2Mpa.The feed liquid flow velocity is 3.0m/s, in the ultra-filtration process, adopts periodically flow fluctuation so that produce pulsating flow or non-stationary flow in membrane channels, the flow speed wave moment is 2.0m/s, feeds nitrogen in the ultrafiltration system discontinuous, forms the gas-liquid stream of pulses, cycle is that 2h ventilates once each 1 minute.Feed temperature is 40 ℃, when feed liquid stock solution is concentrated 1/8, adds water or dilute alcohol solution ultrafiltration 2 times again, and the pH value of feed liquid is controlled at 7.5.Backwashing pressure is 2.5MPa, and backwashing period is that 1.5h, backwashing time are 10min.When with the in parallel method of using alternately recoil of ultrafiltration module, wherein a cover or a few cover carry out normal ultrafiltration and distribute the recoil ultrafilter membrane of another set of or several grip assemblies of a part of filtrate, and exchange is carried out behind the certain interval of time, work 20min, recoil 3min.The Chemical cleaning cycle is 2 months, and the Chemical cleaning medicament is the mixed solution of 0.5%~4.0% sodium hydroxide, 1.5% sodium hydroxide and 2% sodium hypochlorite, and pH value is 10~12, and cleaning pressure is 1.0MPa.After cleaning with chemical, the flushing of reuse water is near neutral.
Described ultrafiltrate concentrated obtain the Radix Salviae Miltiorrhizae extractum that relative density is 1.35~1.39 (55 ℃).Radix Notoginseng powder is broken into fine powder, mixes all with Radix Salviae Miltiorrhizae extractum, drying is made granule, adds Styrax, is mixed, and is pressed into 1000, or sugar coating, promptly.
Embodiment ten
Crude drug adopts Radix Salviae Miltiorrhizae 500 grams, Radix Notoginseng 94 grams, Styrax 6 grams.
With the Radix Salviae Miltiorrhizae of coarse pulverization, pseudo-ginseng to extraction pot, add 5 times of water gagings, decocted 2 hours, filter, filtering residue carries out the second time and extracts, add 4 times of water gagings, fried in shallow oil 1 hour, filter, filtering residue discards, merging filtrate. and filtrate is that 6000 cellulose diacetate film carries out ultrafiltration with molecular cut off, and filter type adopts cross flow filter. and the operating condition of ultrafiltration technology is: the inlet pressure of ultrafiltration is 0.1Mpa, the low 0.5kPa. ultrafiltration initial stage of the liquid outlet pressure ratio inlet pressure of ultrafiltration is adopted lower pressure, slowly boosts then; In ultra-filtration process, the fluctuation of employing periodic pressure, the pressure wave moment is that 0.1Mpa. feed liquid flow velocity is 1.0m/s, in the ultra-filtration process, adopt periodically flow fluctuation so that in membrane channels, produce pulsating flow or non-stationary flow, the flow speed wave moment is 1.0m/s, feed nitrogen in the ultrafiltration system discontinuous, form the gas-liquid stream of pulses, cycle is that 0.5h ventilates once, each 1 minute. feed temperature is 15 ℃, when feed liquid stock solution is concentrated 1/15, add water or dilute alcohol solution ultrafiltration 1 time again, it is 0.15MPa that the pH value of feed liquid is controlled at 5. backwashing pressures, backwashing period is 0.5h, backwashing time is that 1min. is when replacing the method for recoil with ultrafiltration module use in parallel, wherein a cover or a few cover carry out normal ultrafiltration and distribute the recoil ultrafilter membrane of another set of or several grip assemblies of a part of filtrate, exchange is carried out behind the certain interval of time, work 10min, the recoil 30sec. Chemical cleaning cycle is 0.5 month, the Chemical cleaning medicament is 0.5%~4.0% sodium hydroxide, the mixed solution of 1.5% sodium hydroxide and 2% sodium hypochlorite, pH value is 10~12, and cleaning pressure is 0.05MPa. after cleaning with chemical, and the flushing of reuse water is near neutral.
Described ultrafiltrate concentrated obtain the extractum that relative density is 1.32~1.40 (55 ℃), add Styrax, mix homogeneously, with the lactose fluidisation, drying is made granule, promptly in the batch (-type) fluid bed.
Embodiment 11
Crude drug adopts Radix Salviae Miltiorrhizae 290 grams, Radix Notoginseng 306 grams, Styrax 6 grams.
The Radix Salviae Miltiorrhizae of coarse pulverization, pseudo-ginseng to extraction pot, are added 5 times of water gagings, decocted 2 hours, filter, filtering residue carries out second time and extracts, and adds 4 times of water gagings, fried in shallow oil 1 hour, and filtration, filtering residue discards, merging filtrate.Filtrate is that 80000 polysulfone membrane is carried out ultrafiltration with molecular cut off, and filter type adopts dead-end filtration.The operating condition of ultrafiltration technology is: the inlet pressure of ultrafiltration is 0.5Mpa, and the liquid outlet pressure ratio inlet pressure of ultrafiltration hangs down 0.25kPa.The ultrafiltration initial stage is adopted lower pressure, slowly boosts then; In ultra-filtration process, adopt the periodic pressure fluctuation, the pressure wave moment is 0.2Mpa.The feed liquid flow velocity is 4.0m/s, in the ultra-filtration process, adopts periodically flow fluctuation so that produce pulsating flow or non-stationary flow in membrane channels, the flow speed wave moment is 2.0m/s, feeds nitrogen in the ultrafiltration system discontinuous, forms the gas-liquid stream of pulses, cycle is that 2h ventilates once each 1 minute.Feed temperature is 50 ℃, when feed liquid stock solution is concentrated 1/5, adds water or dilute alcohol solution ultrafiltration 2 times again, and the pH value of feed liquid is controlled at 9.Backwashing pressure is 2.5MPa, and backwashing period is that 1.5h, backwashing time are 10min.When with the in parallel method of using alternately recoil of ultrafiltration module, wherein a cover or a few cover carry out normal ultrafiltration and distribute the recoil ultrafilter membrane of another set of or several grip assemblies of a part of filtrate, and exchange is carried out behind the certain interval of time, work 20min, recoil 3min.The Chemical cleaning cycle is 2 months, and the Chemical cleaning medicament is the mixed solution of 0.5%~4.0% sodium hydroxide, 1.5% sodium hydroxide and 2% sodium hypochlorite, and pH value is 10~12, and cleaning pressure is 1.0MPa.After cleaning with chemical, the flushing of reuse water is near neutral.
Described ultrafiltrate concentrated obtain the extractum that relative density is 1.32~1.40 (55 ℃), add Styrax, again with mannitol 30g, calcium disodium edetate 5g, distilled water 5ml, behind the said components mixing, lyophilization, packing, promptly.
Embodiment 12
Crude drug adopts Radix Salviae Miltiorrhizae 210 grams, Radix Notoginseng 380 grams, Styrax 4 grams.
With the Radix Salviae Miltiorrhizae of coarse pulverization, pseudo-ginseng to extraction pot, add 5 times of water gagings, decocted 2 hours, filter, filtering residue carries out the second time and extracts, add 4 times of water gagings, fried in shallow oil 1 hour, filter, filtering residue discards, merging filtrate. and filtrate is that 50000 polysulfone membrane is carried out ultrafiltration with molecular cut off, and filter type adopts cross flow filter. and the operating condition of ultrafiltration technology is: the inlet pressure of ultrafiltration is 0.35Mpa, the low 0.20kPa. ultrafiltration initial stage of the liquid outlet pressure ratio inlet pressure of ultrafiltration is adopted lower pressure, slowly boosts then; In ultra-filtration process, the fluctuation of employing periodic pressure, the pressure wave moment is that 0.2Mpa. feed liquid flow velocity is 3.0m/s, in the ultra-filtration process, adopt periodically flow fluctuation so that in membrane channels, produce pulsating flow or non-stationary flow, the flow speed wave moment is 2.0m/s, feed nitrogen in the ultrafiltration system discontinuous, form the gas-liquid stream of pulses, cycle is that 2h ventilates once, each 1 minute. feed temperature is 40 ℃, when feed liquid stock solution is concentrated 1/8, add water or dilute alcohol solution ultrafiltration 2 times again, it is 2.5MPa that the pH value of feed liquid is controlled at the 7.5. backwashing pressure, backwashing period is 1.5h, backwashing time is that 10min. is when replacing the method for recoil with ultrafiltration module use in parallel, wherein a cover or a few cover carry out normal ultrafiltration and distribute the recoil ultrafilter membrane of another set of or several grip assemblies of a part of filtrate, exchange is carried out behind the certain interval of time, work 20min, the recoil 3min. Chemical cleaning cycle is 2 months, the Chemical cleaning medicament is 0.5%~4.0% sodium hydroxide, the mixed solution of 1.5% sodium hydroxide and 2% sodium hypochlorite, pH value is 10~12, and cleaning pressure is 1.0MPa. after cleaning with chemical, and the flushing of reuse water is near neutral.
Described ultrafiltrate concentrated obtain the extractum that relative density is 1.32~1.40 (55 ℃), with this extractum and an amount of magnesium stearate mix homogeneously, the adding Styrax is mixed, and is pressed into tablet.