CN100367991C - Daphne freeze-drying powder injection and its preparation method - Google Patents
Daphne freeze-drying powder injection and its preparation method Download PDFInfo
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- CN100367991C CN100367991C CNB2005100564467A CN200510056446A CN100367991C CN 100367991 C CN100367991 C CN 100367991C CN B2005100564467 A CNB2005100564467 A CN B2005100564467A CN 200510056446 A CN200510056446 A CN 200510056446A CN 100367991 C CN100367991 C CN 100367991C
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Abstract
The present invention relates to a lyophilized powder injection which is prepared from the extract of the velamen and the bark of girald daphne bark, and a preparation method of the injection. The preparation is used for treating diseases of limb edema pain, limb stabbing pain, limb crymodynia, etc., and is obtained by a single percolation method. The preparation is prepared by a method that the extracting solution of the velamen and the bark of girald daphne bark is filtered and distilled by reducing pressure to reclaim ethanol, which makes each milliliter of the solution is equal to 0.5 to 1.5g of the medicinal material of the velamen and the bark of girald daphne bark; the solution is filtered, and the pH value of the solution is adjusted to be 6.5 to 7.5, which makes the mannitol in the solution reach a concentration of 50 mg to 200 mg/ml; the solution is filtered and lyophilized, and then the lyophilized powder injection is obtained. The present invention has high therapeutic effect and obvious effect. The lyophilized powder injection is prepared by drying under the condition of low temperature and vacuum, so the decomposition or oxidation of the active medicinal components is avoided, and the medicine has high stability.
Description
Technical field
The present invention relates to utilize the made pharmaceutical preparation and the method for making thereof of extract of vegetable material, more specifically say so with made lyophilized injectable powder of the extract of the root bark of Daphne giraldii Nitsche, peel of stem and preparation method thereof.
Background technology
The chemical name 7 of daphnetin (Daphnetin), 8-dihydroxycoumarin (7,8-dihydoxyCoumarin) be the root bark of Daphne giraldii Nitsche and the effective ingredient in the peel of stem, has expelling wind and removing dampness, the effect of promoting blood circulation and stopping pain, have the expansion coronary vasodilator again, coronary blood flow increasing reduces heart arteries and veins oxygen consumption, improve myocardial metabolism, promote effects such as cardiac function recovery.
Chinese patent literature application number 93104946.0, open day 1994.11.9 day, publication number is that CN1094627A has reported Giraldi daphne tablet and preparation method thereof, the Giraldi daphne tablet component prescription is Daphne giraldii Nitsche extractum (being equivalent to the methanol extractum) 34.5% (weight), starch 62.1% (weight), calcium carbonate 3.4% (weight) adds an amount of magnesium stearate.Its preparation method is at first to get the Daphne giraldii Nitsche root bark, Daphne giraldii Nitsche peel of stem, chopping, decoct with water three times, 2 hours for the first time, 1.5 hours for the second time, 1.5 hours for the third time, filter, merging filtrate, and be condensed into 1: 1 thick paste, add ethanol to 75%, leave standstill, filter, regain ethanol, be condensed into thick paste, dry below 80 ℃, crushing screening is measured leaching thing content, and is standby; Get Daphne giraldii Nitsche and invade cream powder adding adjuvant, stir, with 50% alcohol granulation, dry tabletting, this medicine sheet has wind dehumidifying, promoting blood circulation to remove blood stasis, antiinflammatory, analgesic effect, and the heart, liver, kidney and leukocyte are had no side effect, and its medicine source is wide.But owing to be tablet, child, old man, bed patient and dysphagia person take very inconvenient, have influenced the performance of daphnetin therapeutical effect.
Chinese patent literature 01100357.X, in open day on August 7th, 2002, publication number CN1362199A has reported a kind of nano girald daphne preparation medicine and preparation method thereof, selects the formula Chinese drug material to concoct the addition worker and becomes the prepared slices of Chinese crude drugs.Chinese crude drug places extraction pot, and solubilizer also imports microwave extracting, makes it do the change in polarity motion with hundred million times/second speed of 20-30, and the temperature of its microwave extracting is 30-60 ℃, time 1-10 hour; Above-mentioned extract is carried out concentrating under reduced pressure, and temperature is 30-60 ℃, and the time is 3-72 hour, collects the Chinese medicine volatile material simultaneously in addition; Decompressed concentrate and volatile material merging are placed spray drying tower, use the supersonic jet technology, 30-60 ℃ of temperature, under 0 to the 0.05Mpa pressure, with the instantaneous drying of supersonic velocity, wherein supersonic jet speed is the 330-990 meter per second, makes the prepared slices of Chinese crude drugs.According to the report of this patent documentation, can make various dosage forms such as pill, tablet, drop pill, injection, but not report the concrete prescription of these preparations and the method for preparation thereof.
Chinese patent literature application number 03159195.7, in open day on May 5th, 2004, publication number CN1493280A has reported the preparation method of winter daphne drop pill.The winter daphne fine powder through superfine powder of 1 weight portion is added in the 1-10 weight portion molten matrix, abundant mixing, dropping preparation method is cooled to ball in coolant, remove coolant, drying.Described substrate is polyethylene glycol 6000, Macrogol 4000, polyethylene glycol 1500, cetomacrogol 1000, sodium stearate, glycerin gelatine, poloxamer, stearic acid, glycerol monostearate acid, insect wax etc.Used coolant is dimethicone, liquid paraffin, vegetable oil, water, alcoholic solution etc.This drop pill is than tablet the taking of patient of being more convenient for.
Contain materials such as starch and/or stearic acid in the tablet drop pill, these materials are easy to mouldy in the high environment of high humidity, temperature, be difficult for preserving, and tablet, drop pill all be by oral administration, absorbed by the intestines and stomach, and it is slower to take effect, injection is by the injection system administration, instant effect, but its poor stability also are difficult for storing.
Summary of the invention
Purpose of the present invention just is that with Daphne giraldii Nitsche root bark and peel of stem be the lyophilized injectable powder that raw material is developed a kind of injection Daphne giraldii Nitsche extract.
Another object of the present invention is the preparation method that works out injection Daphne giraldii Nitsche extract lyophilized injectable powder.
A kind of daphne freeze-drying powder injection of the present invention, root bark and its peel of stem with the Daphne giraldii Nitsche of constant weight unit are raw material, Daphne giraldii Nitsche root bark and peel of stem extracting solution through single percolation gained, after filtration, ethanol is reclaimed in distilling under reduced pressure, adds sterilized water for injection and is diluted to or is evaporated to every ml soln and be equivalent to Daphne giraldii Nitsche root bark and peel of stem medical material 0.5-1.5 gram, cold preservation, filter and regulate PH to 3.0-4.0, cold preservation is filtered, and transfers PH to 1.2-1.7 again, reflux, transfer PH to 6.5-7.5, add the injection activated carbon, add mannitol and make the mannitol that contains 50mg-200mg/ml in the solution, filter, again the daphne freeze-drying powder that forms through lyophilization.
Said unit of weight is gram (g), jin, kilogram (kg), ton etc.
Water content 2.0-6.0% percetage by weight in the daphne freeze-drying powder.
Said percolation is that medicinal material coarse powder is placed in the percolation filter, and solvent adds from the top of percolation filter continuously, and percolate constantly flows out from the bottom, thereby leaches a kind of method of effective ingredient in the medical material.(see pharmacy of Chinese materia medica, chief editor Fan Biting, Shanghai science tech publishing house publishes, in December, 1997, front page P101-104).Percolation can be single percolation, heavy percolation, pressurization percolation, the adverse current percolation according to the difference of operational approach.The operation of single percolation generally is followed successively by six steps such as pulverizing medicinal materials, moistening, fitted tube, aerofluxus, dipping, diafiltration.What the present invention was used is single percolation.
The preparation method of a kind of daphne freeze-drying powder injection of the present invention may further comprise the steps:
(1) gets the pretreated Daphne giraldii Nitsche raw material root bark and the peel of stem of process of constant weight unit, pack in the diafiltration tube, aerofluxus, soak (dipping), the ethanol liquation of the 1-2 50-75% percetage by weight doubly that the dried raw material of reuse Daphne giraldii Nitsche root bark and peel of stem is heavy carries out diafiltration under 30-50 ℃ temperature, diafiltration is 2-6 time so repeatedly, merge percolate, filter, get filtrate.
(2) ethanol is reclaimed in filtrate distilling under reduced pressure under 50-60 ℃ temperature, to in reclaiming alcoholic acid solution, add sterilized water for injection, solution dilution to every ml soln is equivalent to crude drug Daphne giraldii Nitsche root bark and peel of stem 0.5-1.5 gram, or will through reclaimed alcoholic acid solution in be evaporated under 50-60 ℃ the temperature every milliliter be equivalent to crude drug Daphne giraldii Nitsche root bark and peel of stem 0.5-1.5 gram after, under 0-5 ℃ temperature cold preservation 1-2 hour, filter, filtrate is regulated PH to 3.0-4.0 with the hydrochloric acid of 2-3 mol, again under 0-5 ℃ temperature, cold preservation 0.5-1.5 hour, filter, filtrate is regulated PH to 1.2-1.7 with the hydrochloric acid solution of 5-6 mol, in 70 ℃ to 100 ℃, and backflow 30-60 minute.
(3) liquid after will refluxing, sodium hydrate aqueous solution with the 35-40% percetage by weight, regulate PH to 6.5-7.5, add Daphne giraldii Nitsche root bark and peel of stem raw material, the injection activated carbon of mannitol gross weight 4-8 ‰, add mannitol again, make in the solution mannitol concentration be 50 milligrams to 200 mg/ml, stir, filter, insulation is 25-30 minute under 40-60 ℃ temperature, filter, under 5-15 ℃ temperature, cold preservation 30-50 minute, use 0.3-0.5 μ m and 0.11-0.22 μ m microporous filter membrane (membrane filter) to filter successively, divide to be filled to (packing is measured accordingly according to production specification) in the container, the false add plug is put into the drying baker of freezer dryer.
(4) compressor of startup freezer dryer, the temperature through the filtrate after the ultrafiltration of the drying baker of putting into freezer dryer is reduced to-30--50 ℃, form frozen block, starting vacuum pump makes its pressure be evacuated to 5-10Pa, under the condition of 5-10Pa, the temperature of frozen block is risen to-25--32 ℃, with programming rate intensification slowly, be exactly with per 1.5 hours intensification 0.5-1.5 ℃ programming rates, be warming up to-22--15 ℃ after, then programming rate heats up routinely, promptly be warming up to 25-40 ℃ with 3-5 ℃ the programming rate of per hour heating up, insulation is 5-15 hour under 25-40 ℃ temperature, and tamponade goes out the drying baker of freezer dryer, rolls lid and forms product.
Said branch is filled to the container in the container, can be glass container, for example vial.Said false add plug is filled in not exclusively exactly and is covered, and leaves the space, makes lyophilized injectable powder and external environment condition in the bottle not exclusively isolated.Said tamponade is exactly that gag is complete, makes lyophilized injectable powder and portion's environment in the bottle isolated.
Get the Daphne giraldii Nitsche root bark and the peel of stem Chinese crude drug of constant weight unit, carry out pretreatment.Said pretreatment is exactly that (a said unit of weight can be 500 unit of weights, 1000 unit of weights, 1500 unit of weights to the Daphne giraldii Nitsche root bark of constant weight unit and peel of stem raw material, unit of weight can be gram, kilogram, ton etc.), pulverize, moistening.Be crushed to said medium powder in the Chinese Pharmacopoeia when pulverizing.Said moistening 1-1.5 distilled water or the sterilized water for injection doubly that adds Daphne giraldii Nitsche root bark and peel of stem grain weight exactly in Daphne giraldii Nitsche root bark and peel of stem powder stirs, and places 30-60 minute, makes Daphne giraldii Nitsche root bark and full and uniform moistening of peel of stem powder and expansion.After Daphne giraldii Nitsche root bark and the moistening of peel of stem powder, in the diafiltration tube of packing into, soak (claiming dipping again).Used percolating device is referring to pharmacy of Chinese materia medica (Fan Biting chief editor, Shanghai science tech publishing house publishes, the percolating device shown in Fig. 6-7 that in December, 1997 front page is 102 pages).After in the diafiltration tube in the Daphne giraldii Nitsche root bark of moistening and peel of stem powder are packed percolating device into, carry out aerofluxus, again under the temperature of room temperature (being 20-30 ℃), fractional ethanol water to the submergence Daphne giraldii Nitsche root bark and peel of stem medicated powder surface that adds 50-75% weight exceeds 2-5 centimetre again, soaked 20-36 hour, ethanol water with the percent of the heavy 1-2 50-75% weight doubly of the dried raw material of Daphne giraldii Nitsche root bark and peel of stem, under 30-50 ℃ temperature, carry out diafiltration, be 1000 gram Daphne giraldii Nitsche root bark and peel of stem medical materials when carrying out diafiltration, it is good that per minute flows out 1-4 milliliter percolate.
Daphne freeze-drying powder injection of the present invention is a pure Chinese medicinal preparation, effect with expelling wind and removing dampness, promoting blood circulation and stopping pain, be used for the treatment of that limbs joint swells and ache, cold type of pain or twinge, movable joint stuffiness, overcast and rainy increasing the weight of, tongue has ecchymosis, deep and stringy pulse person, diseases such as rheumatic arthritis, rheumatoid arthritis.
Daphne freeze-drying powder of the present invention can carry out intramuscular injection, intravenous injection, intravenous drip.
Intramuscular injection, 1-2 time on the one, ampoule is to be equivalent to 1 gram of crude drug material Daphne giraldii Nitsche root bark and peel of stem to 2 grams, adds sterilized water for injection dissolving back injection.
Intravenous injection: 1 time on the one, ampoule is to be equivalent to 4 grams of crude drug material Daphne giraldii Nitsche root bark and peel of stem to 6 grams, adds 20 milliliters of 5% glucose injections, the slowly injection of dissolving back.
Intravenous drip: 1 time on the one, ampoule is for being equivalent to crude drug material Daphne giraldii Nitsche 2 grams to 4 grams, and with 50 milliliters to 100 milliliters of 5% glucose injections, slowly instil in the dissolving back.
To lyophilized injectable powder of the present invention and its aqueous injection, carried out comparative study with regard to its main quality index, the result of qualitative evaluation and quantitative analysis shows, the two ingredient unanimity, content is no significant difference also, and the stability of lyophilized injectable powder especially clarity obviously be better than aqueous injection, improved the safety and the stability of Chinese medicine.The lyophilized injectable powder of Chinese medicine is one of Chinese medicine development in future direction.At present, the application of Freeze Drying Technique in Chinese medicine production is in the trial production stage mostly, is used for the of less types of suitability for industrialized production, and is used for the processing of valuable Chinese crude drug more.
The advantage and the effect of a kind of daphne freeze-drying powder injection of the present invention just are:
1. daphne freeze-drying powder injection of the present invention is to use percolation under lower temperature, extracts active ingredient, and the destroyed of active ingredient avoided in the lyophilization molding, improved curative effect.Because Daphne giraldii Nitsche tablet and drop pill are oral administration, and lyophilized injectable powder drug administration by injection of the present invention takes effect rapidly than Daphne giraldii Nitsche tablet and drop pill.Lyophilized injectable powder product water content of the present invention is low, can dissolve rapidly, is uniformly dispersed, and is convenient to clinical use, be more convenient for transportation and storage.
It is fast that the blood drug level lyophilized injectable powder of the present invention as can be seen of the Giraldi daphne tablet by lyophilized injectable powder more of the present invention and application number 93104946.0 reaches the time ratio Giraldi daphne tablet of the highest blood drug level.
Lyophilized injectable powder of the present invention is compared with the Daphne giraldii Nitsche tablet and application number 03159195.7 (the winter daphne fine powder of micronizing is 1: 1 with the weight ratio of the substrate) therapeutic effect of application number 93104946.6, effect will get well obviously that (the used dosage of three is identical, the present invention is an injection, and the latter two are peroral dosage form)
2. lyophilized injectable powder of the present invention can be used as injection and uses, and can be used as drip liquid again and uses, and is easy to use, and transportation management is also convenient, is easy to storage.
3. the product of lyophilized injectable powder of the present invention, dosage is accurate, and this is because lyophilization when preparing injectable powder, is the form perfusion with solution, and is more much higher than the precision that nebulization or granule powder are loaded.
The advantage and the effect of the preparation method of a kind of daphne freeze-drying powder injection of the present invention just are:
1. the injectable powder goods that method of the present invention is made, it is the effective ingredient that under lower temperature, extracts Daphne giraldii Nitsche with percolation, sublimation drying is made under low temperature and vacuum condition, the decomposition or the oxidation deterioration of active drug composition have been avoided, medicine stability increases, and preserves its biological activity, helps producing in enormous quantities and long term storage, guarantee the quality and the curative effect of finished product, be particularly advantageous in the stability that guarantees the preparation clarity.
The stability of table 1 daphne freeze-drying powder of the present invention, Daphne giraldii Nitsche water preparation and the comparison of clarity
| Standing time | 0 month | 3 months | 6 months | 12 months | 24 months | 36 months | |
| Daphne freeze-drying powder of the present invention (with the sample of embodiment 1) | Stability * (%) | 99.8 | 99.2 | 99.5 | 98.3 | 96.1 | 94.5 |
| Clarity | Clear and bright | Clear and bright | Clear and bright | Clear and bright | Clear and bright | Clear and bright | |
| Daphne giraldii Nitsche aqueous injection (with the sample of embodiment 1) | Stability * (%) | 99.6 | 98.7 | 97.9 | 95.4 | 90.8 | 83.4 |
| Clarity | Clear and bright | Clear and bright | Clear and bright | Clear and bright | Clear and bright | Slight precipitation is arranged | |
* the content that said stability is meant their common representative compositions over time, the representative composition that they have jointly is: Daphnetin.
The clarity of lyophilized injectable powder of the present invention is meant the clarity of depositing aqueous solution water-soluble behind the certain hour.
2. method of the present invention, make extraction effective ingredient purity height, impurity is few, degree of accuracy is high, the industrialization degree height, easy to operate; Because the present invention adopted Freeze Drying Technique to make the Chinese medicine powder injection, contaminant particles is sneaked into and the chance of polluting medicine significantly reduces.
Aqueous injection quality stability is poor, especially promptly produces particulate deposits soon after the sterilization, has brought very big difficulty for industrial production in enormous quantities.Because method of the present invention has adopted freeze drying technology, and aqueous injection is made injectable powder, has avoided the unstable factor of aqueous injection, be caffolding agent with an amount of adjuvant (mannitol) again, the PH of lyophilized preparation stock solution is controlled between the 6.5-7.5, gained formulation products color and luster, formability and clarity are good.
3. because common Chinese medicine injection as having adopted the degerming of aseptic filtration method, because it is a solution, can not be kept the long especially time under the aseptic condition, if the employing high pressure steam sterilization, solution is subjected to temperatures involved, and is perishable, affect the treatment, increase impurity, toxicity increases.After method of the present invention had adopted the microporous filter membrane degerming, vacuum drying was made product and is in the vacuum solid state, made its stability that maximum the assurance be arranged.
The specific embodiment
Below the present invention is further illustrated with embodiment, will help the present invention and effect thereof, advantage are had a better understanding, but embodiment do not limit protection scope of the present invention, and protection scope of the present invention is decided by claim.
Embodiment 1.
A kind of daphne freeze-drying powder injection of present embodiment, root bark and its peel of stem with 1000 gram Daphne giraldii Nitsche are raw material, extracting solution with single percolation gained, after filtration, ethanol is reclaimed in distilling under reduced pressure, adds the sterilized water for injection dilution or be evaporated to every ml soln to be equivalent to Daphne giraldii Nitsche root bark and peel of stem medical material 1 gram, cold preservation, filter, regulate PH to 3.5, cold preservation, filter, transfer PH to 1.5 again, reflux, transfer PH to 7 again, add the injection activated carbon, add mannitol, make and contain mannitol 50mg/ml in the solution, filter, again the daphne freeze-drying powder that forms through lyophilization.
The preparation method of a kind of daphne freeze-drying powder injection of present embodiment may further comprise the steps:
(1) get 1000 the gram Daphne giraldii Nitsche root bark and the dried raw material of peel of stem, carry out pretreatment, said pretreatment is exactly to raw material Daphne giraldii Nitsche root bark and peel of stem is pulverized and moistening, when pulverizing, be crushed to said medium powder in the Chinese Pharmacopoeia, in Daphne giraldii Nitsche root bark and peel of stem, add 1.25 times sterilized water for injection or distilled water of Daphne giraldii Nitsche root bark and peel of stem grain weight, stir, placed 45 minutes, and carried out moistening, make Daphne giraldii Nitsche root bark and abundant moistening of peel of stem powder and expansion.After Daphne giraldii Nitsche root bark and the moistening of peel of stem powder, in the diafiltration tube of packing into, aerofluxus exceeds 3 centimetres in the ethanol water that adds 65% percetage by weight under 25 ℃ the room temperature more again to submergence medicated powder.Soaked 28 hours, the ethanol water that weighs 1.5 times 65% percetage by weight with Daphne giraldii Nitsche root bark and the dried raw material of peel of stem carries out diafiltration under 40 ℃ temperature, when carrying out diafiltration 1000 gram Daphne giraldii Nitsche raw materials, per minute flows out 2.5 milliliters, carry out so repeatedly 4 times, merge percolate, filter, get filtrate.
(2) ethanol is reclaimed in filtrate distilling under reduced pressure under 55 ℃ temperature, to in reclaiming alcoholic acid solution, add sterilized water for injection or distilled water, to be equivalent to 1 gram of crude drug Daphne giraldii Nitsche root bark and peel of stem or will be evaporated to every ml soln in 55 ℃ and be equivalent to crude drug Daphne giraldii Nitsche root bark and peel of stem 1 gram through reclaiming alcoholic acid solution dilution to every ml soln through reclaiming alcoholic acid solution, cold preservation is 1.5 hours under 2.5 ℃ temperature, filter, filtrate is regulated PH to 3.5 with the hydrochloric acid solution of 2.5 mol, cold preservation 1 hour under 2.5 ℃ temperature again, filter, filtrate is regulated PH to 1.5 with the hydrochloric acid solution of 5.5 mol, refluxes 45 minutes in 70 ℃.
(3) liquid after will refluxing, sodium hydrate aqueous solution with 37% percetage by weight, regulate PH to 7.0,6 ‰ the injection activated carbon that adds Daphne giraldii Nitsche root bark and peel of stem raw material, mannitol gross weight, add mannitol again, the concentration that makes mannitol in the solution is 50mg/ml, and agitation and filtration is under 50 ℃ of heat-retaining conditions, stirred 27 minutes, filter, under 10 ℃ temperature, cold preservation 40 minutes, microporous filter membrane with 0.4 μ m and 0.22 μ m respectively filters once successively, can divide to be filled in the control antibiotic bottle, false add plug, goods are put into freezer dryer and are carried out lyophilizing.
(4) lyophilization: the intermediate after the packing can be closed gate after entering freezer dryer, opens refrigeration system, the temperature of intermediate is reduced to-30 ℃, make goods form frozen block, open vacuum system then, making its negative pressure is 5Pa, goods are heated up, the speed controlling that heats up is at 0.5 ℃/hour, and products temperature rises to-22 ℃, and the speed controlling of intensification is at 3 ℃/hour, products temperature rises to 25 ℃ of i.e. insulations, under 25 ℃ temperature, be incubated 15 hours, can go out machine and roll lid.
Embodiment 2
The operational approach of present embodiment and used equipment are substantially with embodiment 1, uniquely different be, root bark and peel of stem with 500 gram Daphne giraldii Nitsche are raw material, get extracting solution through single percolation, filter, after ethanol is reclaimed in distilling under reduced pressure, add the sterilized water for injection dilution or be evaporated to the solution that every ml soln is equivalent to Daphne giraldii Nitsche root bark and peel of stem medical material 0.5 gram, cold preservation, filter, regulate PH to 3.0, cold preservation, filter, transfer PH to 1.2 again, reflux, regulate PH to 6.5, add the injection activated carbon, add mannitol, make and contain mannitol 100mg/ml in the solution, filter, form daphne freeze-drying powder through lyophilization.
Its preparation method is:
(1) gets 500 gram Daphne giraldii Nitsche root bark and the dried raw materials of peel of stem, Daphne giraldii Nitsche root bark and peel of stem are done raw material pulverizing said medium powder to the Chinese Pharmacopoeia, adding Daphne giraldii Nitsche root bark and peel of stem weigh 1 times sterilized water for injection in Daphne giraldii Nitsche root bark and peel of stem medium powder, stir, placed 30 minutes, again under the temperature of 20 ℃ of room temperatures, ethanol water to submergence medicated powder with 50% percetage by weight exceeds 2 centimetres again, soaked 20 hours, alcoholic solution with 50% percetage by weight of 1 times of Daphne giraldii Nitsche root bark and peel of stem dry weight carries out diafiltration under 30 ℃ temperature, be 500 gram Daphne giraldii Nitsche medical materials when carrying out diafiltration, per minute flows out 0.5 milliliter of percolate and (is equivalent to 1000 gram Daphne giraldii Nitsche medical materials, 1 milliliter of percolate of per minute stream), carries out so repeatedly 6 times, merge percolate, filter, get filtrate.
(2) with filtrate under 50 ℃ temperature, ethanol is reclaimed in distilling under reduced pressure, to in reclaiming alcoholic acid solution, add sterilized water for injection, to be equivalent to raw medicinal material Daphne giraldii Nitsche root bark and peel of stem raw material 0.5 gram to every milliliter through reclaiming alcoholic acid solution dilution, maybe will be through reclaiming alcoholic acid solution under 50 ℃ temperature, be evaporated to every milliliter and be equivalent to raw medicinal material Daphne giraldii Nitsche root bark and peel of stem 0.5 gram, cold preservation is 1 hour under 0 ℃ temperature, filter, filtrate is regulated PH to 3.0 with the aqueous hydrochloric acid solution of 2 mol, under 0 ℃ temperature, cold preservation 0.5 hour is filtered again, filtrate is regulated PH to 1.2 with the aqueous hydrochloric acid solution of 5 mol, refluxes 30 minutes under 90 ℃ temperature.
(3) liquid after will refluxing, sodium hydrate aqueous solution with 35% percetage by weight, regulate PH to 6.5, the injection activated carbon that adds Daphne giraldii Nitsche root bark and peel of stem raw material, mannitol gross weight 8 ‰, add mannitol again, the concentration that makes mannitol in the solution is 100 mg/ml, under 40 ℃ of heat-retaining conditions, stirred 25 minutes, filter, under 5 ℃ temperature, cold preservation 30 minutes, the microporous filter membrane with 0.4 μ m and 0.22 μ m respectively filters once successively, can divide to be filled in the control antibiotic bottle, false add plug, goods are put into freezer dryer and are carried out lyophilizing.
(4) lyophilization: the intermediate after the packing can be closed gate after entering freezer dryer, opens refrigeration system, the temperature of intermediate is reduced to-30 ℃, make goods form frozen block, open vacuum system then, making its negative pressure is 5Pa, goods are heated up, the speed controlling that heats up is at 0.5 ℃/hour, and products temperature rises to-22 ℃, and the speed controlling of intensification is at 2 ℃/hour, products temperature rises to 25 ℃ of i.e. insulations, under 25 ℃ temperature, be incubated 5 hours, can go out machine and roll lid.
Embodiment 3
The operational approach of present embodiment and used equipment are substantially with embodiment 1, only different is with root bark and its peel of stem of 1500 gram Daphne giraldii Nitsche is raw material, extracting solution through single percolation gained, after filtration, after ethanol is reclaimed in distilling under reduced pressure, add the sterilized water for injection dilution or be evaporated to the solution that every ml soln is equivalent to Daphne giraldii Nitsche root bark and peel of stem medical material 1.5 grams, cold preservation, filter, regulate PH to 4.0, cold preservation, filter, transfer PH to 1.7 again, reflux, regulate PH to 7.5, add the injection activated carbon, add mannitol, make and contain mannitol 200mg/ml in the solution, filter, form daphne freeze-drying powder through lyophilization.
Its preparation method is:
(1) get 1500 the gram Daphne giraldii Nitsche root bark and the dried raw material of peel of stem, Daphne giraldii Nitsche root bark and peel of stem are done raw material pulverizing said medium powder to the Chinese Pharmacopoeia, in Daphne giraldii Nitsche root bark and peel of stem medium powder, add Daphne giraldii Nitsche root bark and 1.5 times heavy sterilized water for injection of peel of stem, stir, placed 60 minutes, the ethanol water submergence medicated powder that adds 75% percetage by weight again under the room temperature of 30 ℃ of room temperatures exceeds 5 centimetres again, soaked 36 hours, weigh the ethanol water of 2 times 75% percetage by weight with Daphne giraldii Nitsche root bark and peel of stem, under 50 ℃ temperature, carry out diafiltration, be 1500 gram Daphne giraldii Nitsche medical materials when carrying out diafiltration, per minute flows out 4.5 milliliters of percolates (be equivalent to 1000 gram founder (of a school of learning) anaesthetics, per minute flows out 3 milliliters of percolates), carry out so repeatedly 2 times, merge percolate, filter, get filtrate.
(2) with filtrate under 60 ℃ temperature, ethanol is reclaimed in distilling under reduced pressure, to in reclaiming alcoholic acid solution, add sterilized water for injection, will be through reclaiming alcoholic acid solution dilution to every milliliter of 1.5 grams that are equivalent to crude drug Daphne giraldii Nitsche root bark and peel of stem, maybe will through recovery alcoholic acid solution in be evaporated under 60 ℃ of temperature every milliliter be equivalent to crude drug Daphne giraldii Nitsche root bark and peel of stem 1.5 grams after, cold preservation is 2 hours under 5 ℃ temperature, filter, it is 4.0 that filtrate is adjusted to PH with the aqueous hydrochloric acid solution of 3 mol, cold preservation 1.5 hours under 5 ℃ temperature again, filter, aqueous hydrochloric acid solution with 6 mol is regulated PH to 1.7, under 100 ℃ temperature, refluxes 60 minutes.
(3) liquid after will refluxing, sodium hydrate aqueous solution with 40% percetage by weight, regulate PH to 7.5,10 ‰ the injection activated carbon that adds Daphne giraldii Nitsche raw material root bark and peel of stem, mannitol gross weight, add mannitol, the concentration that makes mannitol is 200mg/ml, and agitation and filtration is under 60 ℃ of heat-retaining conditions, stirred 30 minutes, filter, under 15 ℃ temperature, cold preservation 50 minutes, microporous filter membrane with 0.4 μ m and 0.22 μ m respectively filters once successively, can divide to be filled in the control antibiotic bottle, false add plug, goods are put into freezer dryer and are carried out lyophilizing.
(4) lyophilization: the intermediate after the packing can be closed gate after entering freezer dryer, opens refrigeration system, the temperature of intermediate is reduced to-55 ℃, make goods form frozen block, open vacuum system then, making its negative pressure is 10Pa, goods are heated up, the speed controlling that heats up is at 1.5 ℃/hour, and products temperature rises to-15 ℃, and the speed controlling of intensification is at 5 ℃/hour, products temperature rises to 40 ℃ of i.e. insulations, under 40 ℃ temperature, be incubated 15 hours, can go out machine and roll lid.
Claims (7)
1. daphne freeze-drying powder injection, it is characterized in that, root bark and peel of stem with the Daphne giraldii Nitsche of constant weight unit are raw material, Daphne giraldii Nitsche root bark and peel of stem extracting solution through single percolation gained, after filtration, ethanol is reclaimed in distilling under reduced pressure, adding sterilized water for injection is diluted to or is evaporated to every ml soln and be equivalent to Daphne giraldii Nitsche root bark and peel of stem medical material 0.5-1.5 gram, cold preservation, filter regulator solution PH to 3.0-4.0, cold preservation, filter, transfer PH to 1.2-1.7 again, reflux, regulate PH to 6.5-7.5, add the injection activated carbon, add mannitol, make the mannitol that contains 50mg-200mg/ml in the solution, filter, again the daphne freeze-drying powder that forms through lyophilization.
2. a kind of daphne freeze-drying powder injection according to claim 1 is characterized in that, contains moisture content 2.0-6.0% percetage by weight.
3. the preparation method of a daphne freeze-drying powder injection is characterized in that, may further comprise the steps:
(1) gets the pretreated Daphne giraldii Nitsche root bark of process and the peel of stem raw material of constant weight unit, pack in the diafiltration tube, aerofluxus is soaked, the ethanol water of the 1-2 50-75% percetage by weight doubly that the dried raw material of reuse Daphne giraldii Nitsche root bark and peel of stem is heavy, under 30-50 ℃ temperature, carry out diafiltration, so return multiple diafiltration 2-6 time, merge percolate, filter, get filtrate
(2) ethanol is reclaimed in filtrate distilling under reduced pressure under 50-60 ℃ temperature, to in reclaiming alcoholic acid solution, add sterilized water for injection solution dilution to every ml soln is equivalent to crude drug Daphne giraldii Nitsche root bark and peel of stem medical material 0.5-1.5 gram or will be through reclaiming alcoholic acid solution in being evaporated under 50-60 ℃ the temperature after every ml soln is equivalent to crude drug Daphne giraldii Nitsche root bark and peel of stem 0.5-1.5 gram, under 0-5 ℃ temperature, cold preservation 1-2 hour, filter, filtrate is regulated PH to 3.0-4.0 with the hydrochloric acid of 2-3 mol, again under 0-5 ℃ temperature, cold preservation 0.5-1.5 hour, filter, filtrate is regulated PH to 1.2-1.7 with the hydrochloric acid of 5-6 mol, in 70-100 ℃, backflow 30-60 minute
(3) liquid after will refluxing, sodium hydrate aqueous solution with the percent of 35-40% weight is regulated PH to 6.5-7.5, the pin activated carbon that adds material total amount 5-10 ‰, add mannitol again, the concentration that makes mannitol in the solution is 50mg-200mg/ml, under 40-60 ℃ of heat-retaining condition, stirred 25-30 minute, filter, under 5-15 ℃ temperature, cold preservation 30-50 minute, microporous filter membrane with 0.4 μ m and 0.22 μ m respectively filters once successively, can divide to be filled in the control antibiotic bottle, false add plug, goods are put into freezer dryer and are carried out lyophilizing.
(4) lyophilization: the intermediate after the packing can be closed gate after entering freezer dryer, open refrigeration system, the temperature of intermediate is reduced to-30--55 ℃, make goods form frozen block, open vacuum system then, making its negative pressure is 5-10Pa, goods are heated up, the speed controlling that heats up is at 0.5-1.5 ℃/hour, and products temperature rises to-22--15 ℃, the speed controlling of intensification is at 2-5 ℃/hour, products temperature rises to 25-40 ℃ of i.e. insulation, under 25-40 ℃ temperature, be incubated 5-15 hour, can go out machine and roll lid.
4. the preparation method of a kind of daphne freeze-drying powder injection according to claim 3 is characterized in that, said pretreatment is that Daphne giraldii Nitsche root bark, the peel of stem raw material to constant weight unit pulverized, moistening.
5. according to the preparation method of a kind of daphne freeze-drying powder injection of claim 4, it is characterized in that, said moistening is to add Daphne giraldii Nitsche root bark and peel of stem grain weight 1.0-1.5 distilled water or sterilized water for injection doubly in Daphne giraldii Nitsche root bark and peel of stem powder, stirs, and places 30-60 minute.
6. the preparation method of a kind of daphne freeze-drying powder injection according to claim 3 is characterized in that, is 1000 gram Daphne giraldii Nitsche root bark and peel of stem medical materials when carrying out diafiltration, and per minute flows out 1-4 milliliter percolate.
7. the preparation method of a kind of injection Daphne giraldii Nitsche agar injection according to claim 3, it is characterized in that, said immersion is in room temperature 20-30 ℃, the ethanol water that adds the 50-75% percetage by weight, exceed 2-5 centimetre again to submergence Daphne giraldii Nitsche root bark and peel of stem medicated powder surface, soaked 20-36 hour.
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