The specific embodiment
The present invention is described in more detail below in conjunction with embodiment, but the invention is not restricted to these embodiment.
Embodiment 1
With production Nimodipine lipid microsphere injection product of the present invention is example for 1000 bottles, and used crude drug and adjuvant and quality proportioning thereof are:
Nimodipine 4g
Injection lecithin 60g
Injection soybean oil 250g
Injection medium-chain fatty acid 250g
Glycerol 125g
Tween 80 5g
Enuatrol 1.5g
Add the injection water to 5000ml
In the raw materials used proportioning of present embodiment, the mass percent of effective medicinal components and adjuvant is:
Nimodipine 0.08%
Injection lecithin 1.2%
Injection soybean oil 5%
Injection medium-chain fatty acid 5%
Glycerol 2.5%
Tween 80 0.1%
Enuatrol 0.03%
Water for injection adds to 100%.
Its preparation method is as follows:
1, preparation oil phase
Injection lecithin, injection soybean oil, injection medium-chain fatty acid are heated to 70 ℃, are stirred to injection lecithin and all dissolve, add nimodipine again and mix, be stirred to for 80 rev/mins with blender and be uniformly dispersed, be prepared into oil phase.
2, preparation water
Glycerol in the quality proportioning, enuatrol, tween 80 and 1/3 water for injection are mixed down at 70 ℃, be prepared into water until being uniformly dispersed with 80 rev/mins of stirrings of blender.
3, preparation colostrum
Slowly the oil phase of step 1 preparation is joined the aqueous phase of step 2 preparation, stirred 10 minutes with 80 rev/mins, be transferred in the homogenizer 8000 rev/mins of high-speed stirred 3 times, making colostrum is lipid microsphere.
4, homogenize
Getting above-mentioned colostrum and add the water for injection that is preheated to 50 ℃ and make and reach full dose, is the NaOH aqueous solution adjusting pH to 8.0 of 0.1mol/L with concentration, be transferred in the high pressure dispersing emulsification machine, and 70Mpa homogenize 10 times, 40 ℃ of homogenize temperature are made lipide microsphere injection.
5, canned
In the 5ml ampoule, inflated with nitrogen was sterilized 15 minutes down for 121 ℃, took out natural cooling, was prepared into Nimodipine lipid microsphere injection with the lipide microsphere injection embedding.Every bottle of 5ml contains nimodipine 4mg.
Embodiment 2
With production Nimodipine lipid microsphere injection product of the present invention is example for 1000 bottles, and used crude drug and adjuvant and quality proportioning thereof are:
Nimodipine 4g
Injection lecithin 25g
Injection soybean oil 100g
Injection medium-chain fatty acid 100g
Glycerol 50g
Tween 80 7.5g
Enuatrol 2g
Add the injection water to 5000ml
In the raw materials used proportioning of present embodiment, the mass percent of effective medicinal components and adjuvant is:
Nimodipine 0.08%
Injection lecithin 0.5%
Injection soybean oil 2%
Injection medium-chain fatty acid 2%
Glycerol 1%
Tween 80 0.15%
Enuatrol 0.04%
Water for injection adds to 100%.
Its preparation method is identical with embodiment 1.
Embodiment 3
With production Nimodipine lipid microsphere injection product of the present invention is example for 1000 bottles, and used crude drug and adjuvant and quality proportioning thereof are:
Nimodipine 4g
Injection lecithin 115g
Injection soybean oil 400g
Injection medium-chain fatty acid 400g
Glycerol 150g
Tween 80 10g
Enuatrol 2.5g
Add the injection water to 5000ml
In the raw materials used proportioning of present embodiment, the mass percent of effective medicinal components and adjuvant is:
Nimodipine 0.08%
Injection lecithin 2.3%
Injection soybean oil 8%
Injection medium-chain fatty acid 8%
Glycerol 3%
Tween 80 0.2%
Enuatrol 0.05%
Water for injection adds to 100%.
Its preparation method is identical with embodiment 1.
Embodiment 4
With production Nimodipine lipid microsphere injection product of the present invention is example for 1000 bottles, and used crude drug and adjuvant and quality proportioning thereof are:
In the proportioning raw materials of above embodiment 1~3, used effective medicinal components is identical with respective embodiments with adjuvant and consumption thereof.
In the homogenize step 4 of its preparation method, be the NaOH aqueous solution adjusting pH to 8.5 of 0.1mol/L, be transferred in the high pressure dispersing emulsification machine with concentration, 60Mpa homogenize 15 times, 30 ℃ of homogenize temperature are made lipide microsphere injection, and other step of this processing step is identical with embodiment 1.Other step is identical with embodiment 1.
Embodiment 5
With production Nimodipine lipid microsphere injection product of the present invention is example for 1000 bottles, and used crude drug and adjuvant and quality proportioning thereof are:
In the proportioning raw materials of above embodiment 1~3, used effective medicinal components is identical with respective embodiments with adjuvant and consumption thereof.
In the homogenize step 4 of its preparation method, be the NaOH aqueous solution adjusting pH to 9.05 of 0.1mol/L, be transferred in the high pressure dispersing emulsification machine with concentration, 100Mpa homogenize 8 times, 20 ℃ of homogenize temperature are made lipide microsphere injection, and other step of this processing step is identical with embodiment 1.Other step is identical with embodiment 1.
In order to determine best proportioning of the present invention and optimised process step, the inventor has carried out a large amount of laboratory research tests, and various test situation are as follows:
1, proportioning raw materials of the present invention determines and preparation technology's screening
Table 1 Nimodipine lipid microsphere injection proportioning raw materials
In the drug ratio of the present invention, drug loading and the distribution important influence of medicine in preparation to lipid microsphere, therefore in prescription screening mainly from the composition of inner phase, aspects such as the composition of emulsifying agent and pH value are investigated, with the particle size distribution of lipid microsphere and stability as performance assessment criteria.
(1) injection medium-chain fatty acid and the influence of injecting soybean oil different quality comparison lipid microsphere stability
According to basic proportioning of the present invention, constant in other amounts of components, injection medium-chain fatty acid (MCT) and injection soybean oil (LCT) consumption are fed intake by 2g:8g, 5g:5g, 8g:2g, make Nimodipine lipid microsphere injection respectively by preparation method of the present invention, measure Zeta-potential, particle size distribution with NicompTM380 dynamic light scattering particle size mensuration and Z-potential measurement instrument.Investigate the influence of the relative lipid microsphere stability of miscella of different proportion.Experimental result sees Table 2.
Table 2 injection medium-chain fatty acid and the influence of injecting soybean oil different quality comparison lipid microsphere stability
Oil phase ratio MCT:LCT |
The lipid microsphere outward appearance |
Zeta-potential (mv) |
Particle size distribution (nm) |
2:8 |
Even emulsion liquid |
-16.7 |
205.7±57.5 |
5:5 |
Even emulsion liquid |
-24.8 |
189.6±30.3 |
8:2 |
Place the visible oil droplet of back naked eyes |
-12.4 |
165.4±51.6 |
By table 2 as seen, take all factors into consideration the stability, particle size distribution of dissolubility, the lipid microsphere of medicine etc., selecting injection medium-chain fatty acid (MCT) and injection soybean oil (LCT) ratio is that 5:5 is as oil phase.
(2) adding of enuatrol is to the influence of lipid microsphere
This The effects the enuatrol of different amounts to the influence of Zeta-potential before and after the lipide microsphere injection sterilization.According to the gross proportioning, other amounts of components is constant, enuatrol is respectively 0g, 0.03g, 0.05g feeds intake, make Nimodipine lipid microsphere injection respectively by preparation method of the present invention, measure and Z-potential measurement instrument mensuration sterilization front and back Zeta-potential with the NicompTM380 dynamic light scattering particle size.Test result sees Table 3.
Table 3 enuatrol is to the influence of Nimodipine lipid microsphere injection Zeta-potential
By table 3 as seen, the adding of enuatrol is bigger to stability of drug influence of the present invention.Do not containing the complete breakdown of emulsion of proportioning sterilization back Nimodipine lipid microsphere injection of enuatrol, profit layering.When the enuatrol consumption was 0.03g, lipid microsphere all had bigger improvement from the outward appearance to the Zeta-potential, the sterilization back | Zeta-potential | 20mv.Along with the increase of enuatrol consumption, the absolute value of the Zeta-potential of lipid microsphere increases gradually.Take all factors into consideration the toxicity that itself produces, the consumption of enuatrol is decided to be 0.03%~0.05% of gross weight in drug ratio of the present invention, and wherein the best is 0.03%.
(2) adding of tween 80 is to the influence of lipid microsphere
Not commensurability tween 80 is joined oil phase be prepared into lipid microsphere, investigate the influence of tween 80 emulsion stability.According to gross proportioning of the present invention, other composition consumption is constant, and tween 80 feeds intake by 0g, 0.1g, 0.2g respectively, measures with NicompTM380 dynamic light scattering particle size analyzer and Z-potential measurement instrument.Test result sees Table 4.
The not commensurability tween of table 4 is to the influence of lipid microsphere stability
Tween consumption (g) |
The lipid microsphere outward appearance |
Zeta-potential (mv) |
Particle size distribution (nm) |
0 |
Place the visible oil droplet of back naked eyes |
-12.4 |
208.1±48.7 |
0.1 |
Even emulsion liquid |
-23.6 |
183.5±32.9 |
0.2 |
Even emulsion liquid |
-19.8 |
172.3±45.6 |
By table 4 as seen, after adding tween 80, the stability of Emulsion obviously improves, and particle diameter reduces, along with the increase of tween 80 amount, particle diameter descends, because tween 80 has haemolysis, consumption should be as far as possible little, and the addition of tween 80 is 0.1% of gross mass~0.2% o'clock, lipid microsphere is even emulsion liquid, and dynamics distributes less.The present invention select the addition of tween 80 be gross mass 0.1%~0.2% as coemulsifier, wherein the optimal addn of tween 80 is 0.1% of a gross mass.
Take all factors into consideration, selecting injection lecithin for use is main emulsifying agent (quality be gross mass 1.2%), tween 80 is coemulsifier (quality be gross mass 0.1%), enuatrol is stabilizing agent (quality be gross mass 0.03%), and glycerol (quality be gross mass 2.5%) not only plays Stabilization but also play the effect of regulating osmotic pressure.
(3) pH value is to the influence of the stability of lipid microsphere
According to gross proportioning of the present invention, and preparation method prepares Nimodipine lipid microsphere injection, and in homogenize step 4, the pH value before the homogenize is respectively 5.24,7.08,8.00,9.05.Measure Zeta-potential with Z-potential measurement instrument.Result of the test sees Table 5.
Table 5 pH value is to the influence of lipid microsphere stability
By table 5 as seen, regulating pH value before the high pressure homogenize is 5.24 o'clock, the visible little oil droplet of naked eyes; Regulate pH value before the high pressure homogenize 7.08~9.05, the pH value of lipid microsphere reduces less in sterilization process, Zeta-potential (mv) absolute value is bigger, it is still more stable after room temperature is placed 6 months, the variation of pH value and Zeta-potential (mv) is all less, show that prepared lipide microsphere injection has good stability.Investigate the result according to pH value, in conjunction with the requirement of injection preparation toleration, will be defined as 8.00~9.05 in the pH value range of accommodation before the high pressure homogenize in the preparation method of the present invention, wherein pH value the best is 8.0.
(4) homogenize temperature is to the influence of lipid microsphere
Injection lecithin consumption is 1.2% to be simulation prescription, the homogenize parameter is 70MPa, 10 times, the homogenize temperature is respectively 10 ℃, 20 ℃, 40 ℃, 60 ℃, the range estimation outward appearance, with NicompTM380 dynamic light scattering particle size analyzer test size, distribution, be evaluation index, investigated the influence that temperature controlling prepares lipid microsphere in the homogenize process.Result of the test sees Table 6.
Table 6 homogenize temperature is to the influence of lipid microsphere
By table 6 as seen, no profit lamination after prepared lipide microsphere injection is sterilized when selecting for use 20~40 ℃ to be the high pressure homogenize temperature, and the lipid microsphere particle diameter is less, narrower particle size distribution, explanation injection lecithin under this temperature can be brought into play emulsification preferably, is beneficial to the formation of lipid microsphere.It is 20~40 ℃ that the present invention selects the homogenize temperature, and wherein the best is 40 ℃.
(6) homogenize pressure and number of times are to the influence of lipid microsphere
The colostrum that is prepared into homogenizer can be become granularity less by the homogenize of high speed shear power by the slit of homogenize valve at a high speed through the high-pressure pump of high pressure homogenizer by force, the system that is evenly distributed, the pressure of high-pressure pump is respectively 20,40,60,70,100Mpa homogenize 10 times, 40 ℃ of homogenize temperature are prepared into lipide microsphere injection.Adopt NicompTM380 dynamic light scattering particle size analyzer to measure particle diameter, the method for expressing of particle diameter is directly represented with Gauss (Gaussian) distribution intensity-weight.Result of the test sees Table 7.
Table 7 homogenize is to the influence (40 ℃, 10 times) of particle diameter
By table 7 as seen, along with homogenization pressure increases, particle diameter descends, but homogenization pressure can cause even particle size distribution decline when excessive, and the granularity deviation increases, and takes all factors into consideration each factor, and homogenizing effect was better when homogenize pressure was 60~100Mpa.It is 60~100Mpa that the present invention selects homogenize pressure, and wherein the best is 70Mpa.
In the homogenize pressure test, the pressure of high-pressure pump is 70Mpa, 40 ℃ of homogenize temperature, and the homogenize number of times is respectively 2,4,6,8,10,12,15 times, is prepared into lipide microsphere injection.Adopt NicompTM380 dynamic light scattering particle size analyzer to measure particle diameter, the method for expressing of particle diameter is directly represented with Gauss (Gaussian) distribution intensity-weight.Result of the test sees Table 8.
By table 8 as seen, the homogenize temperature is that 40 ℃, pressure are 70MP, the lipid microsphere particle diameter significantly descends behind the high pressure homogenize 2 times, along with the homogenizing number of times increases, particle diameter descends, and reaches unanimity in 10 particle size distribution of homogenizing, change of size is not remarkable after the homogenize 10 times, but uniformity reduces, and the granularity deviation increases, and homogenize can obtain the dispersion of the less and distribution uniform of granularity for 10 times.Consider commercial production practical operation possibility, the present invention selects the homogenize number of times 8~15 times, and wherein best is homogenize 10 times.
Table 8 homogenize number of times to size influence (40 ℃, 70MPa)
In order to verify the therapeutic effect of medicine of the present invention, the applicant adopts the Nimodipine lipid microsphere injection consignment test unit of the embodiment of the invention 1 quality proportioning preparation to carry out the distributed power test of Nimodipine lipid microsphere injection rat tissue, and test situation is as follows:
Trial drug: Nimodipine lipid microsphere injection, 5mL, 4mg, lot number: 20050526; Provide by the applicant.
Contrast test medicine: nimotop vial, 1mg, 5mL, self-control.
Nimodipine is produced by Shandong XinHua Pharmacy stock Co., Ltd.
Interior mark: nitrendipine is provided by Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
Methanol, normal hexane, chloroform, isopropyl alcohol, chromatographically pure or analytical pure are produced by Concord, Tianjin reagent company.
Experimental water, commercially available WAHAHA pure water.
Experimental apparatus: high performance liquid chromatograph, model are Hitachi, are produced by HIT; Turbine mixer, model are YKH-II, by Jiangxi medical apparatus and instruments factory; Centrifugal precipitation mechanism, model are 80-2, Shanghai Surgical Operation Equipment Factory; AR1140 type electronic analytical balance is resided abroad exact science Instr Ltd. by the Shanghai people and is produced; High pure nitrogen, Shenyang City's metal institute provides.
1, laboratory animal: Wister kind rat, body weight 200 ± 20g, male and female half and half are provided by Shenyang Pharmaceutical University experimental animal center, the quality certification number: SYXK (the Liao Dynasty) 2005-008.
2, the foundation of assay method
Liquid phase chromatogram condition: mobile phase is methanol-water (3: 1), 0.45 μ m filtering with microporous membrane; Flow velocity is 1mL/ minute; Diamonsil (diamond) C18 (4.6mm * 200mm, 5 μ m), Di Ma company; Column temperature: room temperature; Sample size: 20 μ L.
Preparation contrast test solution: precision takes by weighing nimodipine 50mg and places the 50mL measuring bottle, is mixed with the storing solution that mass concentration is 1mg/mL with methanol.Get an amount of above-mentioned storing solution and be diluted to the nimodipine methanol solution that mass concentration is 0.1,0.3,0.5,1,2,3,5,6,10,20 μ g/mL with methanol, stored refrigerated is standby.
The preparation inner mark solution: precision takes by weighing nitrendipine 25mg and places the 50mL measuring bottle, is mixed with the interior mark liquid that mass concentration is 5 μ g/mL with methanol, and stored refrigerated is standby.
3, tissue sample is handled and is measured
Get tissue sample liquid 200 μ L, add 5 μ g/mL inner mark solutions, 5 μ L, vortex concussion 3 minutes, add to extract solvent (normal hexane: chloroform: isopropyl alcohol is 57:38:5) vortex concussion 5 minutes, 4000 rev/mins centrifugal 10 minutes, take out supernatant and under 40 ℃ of water-bath nitrogen current, dry up, add 100 μ L dissolve with methanol, vortex concussion 3 minutes, 4000 rev/mins centrifugal 10 minutes, get the 20 μ L sample introduction analyses of upper strata liquid.
4, the standard curve and the range of linearity are investigated
Core each 6 parts in dirty, liver, spleen, lung, kidney, brain empty tissue fluid 200 μ L, add nimodipine reference substance solution 10 μ L respectively, being configured to mass concentration is the nimodipine tissue sample of 5~1000ng/mL, by " processing of a tissue sample and mensuration " operation down, with concentration C (ng/mL) is abscissa, nimodipine and interior mark peak area ratio (A) are vertical coordinate, adopt weighting (1/C
2) method of least square returns.
5, result and conclusion
The gained regression equation sees Table 9.
The standard curve equation of table 9 nimodipine in each tissue
Result proof nimodipine concentration A and C in 5~1000ng/mL concentration range in heart, liver, spleen, lung, kidney, cerebral tissue are good linear relationship.
6, the response rate and precision are investigated
Experimental technique: by " linear relationship investigations " down method prepare respectively that mass concentration is 5,15,25, the tissue sample of 100ng/ml handle after sample introduction, each concentration is carried out 3 sample analyses, calculate recovery rate.Same sample was measured 5 times in one day, calculated withinday precision, measured every day 1 time, continuous 5 days, calculated day to day precision.Determination of recovery rates and result of calculation see Table 10.Precision is measured and result of calculation sees Table 11.
The nimodipine response rate in table 10 rat tissue
Nimodipine withinday precision and day to day precision in table 11 rat tissue
7, nimodipine rat in-vivo tissue distributed power test
Get 30 rats and be divided into two groups at random, 15 every group, one night of fasting before the experiment.The first group is a matched group, in right back vena femoralis injection nimotop vial (0.2mg/mL) 1.2mL, the second group is organized for being subjected to examination, in right back vena femoralis injection Nimodipine lipid microsphere injection (0.8mg/mL) 0.3mL, respectively at 0.5,2,6,12,24 hours (6 rats of every time point, first, each 3 of second groups) sacrificed by decapitation animal, after draining blood, take out the heart, liver, spleen, lung, kidney, brain, clean with normal saline flushing, blot with filter paper, take by weighing 0.5g, add the homogenate of 1mL normal saline, less than the direct homogenate of the tissue of 0.5g, after handling down by " tissue sample handle with measure ", get 20 μ L sample introductions, calculate the concentration of nimodipine in each time point sample with standard curve.
The determination of drug concentration of each time point the results are shown in Table 12~17 behind laboratory animal intravenous injection Nimodipine lipid microsphere and the nimotop vial, and the drug distribution of respectively organizing of each time point of laboratory animal is seen Fig. 1~6.
Table 12 Nimodipine lipid microsphere injection and nimotop vial be concentration result over time in rat heart
By table 12 as seen, nimodipine is prepared into the lipide microsphere injection intravenously administrable after, do not change holdup time and the drug distribution amount of medicine in rat heart.
Table 13 Nimodipine lipid microsphere injection and nimotop vial be concentration result over time in rat liver
By table 13 as seen, nimodipine is prepared into the lipide microsphere injection intravenously administrable after, do not change the holdup time of medicine in rat liver, the distribution in hepatic tissue slightly increases.
Table 14 Nimodipine lipid microsphere injection and nimotop vial be concentration result over time in Rats Spleen
By table 14 as seen, nimodipine is prepared into the lipide microsphere injection intravenously administrable after, do not change holdup time and the drug distribution amount of medicine in Rats Spleen.
Table 15 Nimodipine lipid microsphere injection and nimotop vial be concentration result over time in induced lung
By table 15 as seen, nimodipine is prepared into the lipide microsphere injection intravenously administrable after, do not change holdup time and the drug distribution amount of medicine in induced lung.
Table 16 Nimodipine lipid microsphere injection and nimotop vial be concentration result over time in rat kidney
By table 16 as seen, nimodipine is prepared into the lipide microsphere injection intravenously administrable after, do not change holdup time and the drug distribution amount of medicine in rat kidney.
Table 17 Nimodipine lipid microsphere injection and nimotop vial be concentration result over time in rat brain
By table 17 as seen, nimodipine is prepared into the lipide microsphere injection intravenously administrable after, do not change holdup time and the drug distribution amount of medicine in rat brain.
8, irritant experiment
(1) the rabbit auricular vein blood vessel irritation of medicine of the present invention test
Get 3 of rabbit, female, 2.0~2.4kg, every left ear is given Nimodipine lipid microsphere injection 3ml/kg (6mg/kg), and auris dextra is given and is waited capacity 0.9% sodium chloride injection.Each ear before injection with after the medical alcohol sterilization, auricular vein apart from the tip about 1cm place inserting needle, the slow injection tried thing (2~3ml/min), is administered once every day, for three days on end.Observe the injection site vein (blood vessel) and the irritant reaction of subcutaneous tissue gill epidermis on every side after each administration and before the administration next time, make itemized record.Mark by " vascular stimulation test standards of grading-macroscopy classification " table 18.Put to death animal in 24 hours after the last administration, auricular concha about 5cm in clip injection site is long, after 10% formalin fixed, and censorship pathology.Last comprehensive naked eyes and histological score value are estimated.
Result of the test sees Table 18.
By table 18 as seen, observe the injection site vein (blood vessel) and the irritant reaction of subcutaneous tissue gill epidermis on every side after each administration and before the administration next time, there is no significant change.Pathological examination results does not also see that blood vessel and surrounding tissue have significant change, presses vascular stimulation standards of grading cumulative score<0.5, and Nimodipine lipid microsphere injection does not have the blood vessel zest.
Scoring of table 18 blood vessel irritation and criterion
(2) rat licks full testing
Get 20 of rat, male and female half and half weigh 70~120g.By sex, the body weight equilibrium is divided into two groups at random with rat, and 10 every group, the first group is in right back foot injection Nimodipine lipid microsphere injection (2mg/mL), and the second group is injected nimodipine solution (2mg/mL), and dosage is 0.1mL.Writing time after the administration, and record lick the sufficient number of times of licking in the foot time and 15 minutes first.Result of the test sees Table 19.
Table 19 rat licks the full result of testing
By table 19 as seen, injection lipid microsphere rat group is on average licked the foot time first has delay slightly than matched group, reduces by more than 50 than matched group but lick sufficient number of times, and two groups have significant difference.Nimodipine lipid microsphere injection and reference preparation are licked foot first rat and the time be there is no significant difference, though most of pharmaceutical pack is wrapped in oil phase and the film, the small amount of drug that is present in aqueous phase still can cause pain when injection; But medicine of the present invention is licked sufficient number of times than the reference preparation rat and is reduced more than 50%.When showing injection medicine of the present invention, the pain degree that causes significantly reduces than reference preparation.
9, conclusion
With the nimodipine solution is reference preparation, measure the intravital tissue distribution dynamic characteristic of rat, the result shows: after nimodipine is prepared into the lipide microsphere injection intravenously administrable, do not change medicine rat spleen, lung, kidney, brain, and blood plasma in holdup time and drug distribution amount, the distribution in hepatic tissue slightly increases.After making lipide microsphere injection, zest obviously reduces, and also obviously reduction of side effect, has demonstrated fully the superiority of this dosage form.
Specification: every bottle of 5ml contains nimodipine 4mg.
Indication: the ischemic nerve injury that prevention and treatment aneurismal subarachnoid hemorrhage cerebral vasospasm cause, treatment acute ischemic cerebrovascular disease disease.The treatment elderly cerebral dysfunction, as hypomnesis, orientation force and attention disorders and anxious state of mind etc.
Usage and dosage: get Nimodipine lipid microsphere injection 5mL, add behind 5% glucose or the 0.9% sodium chloride injection 250mL quiet immediately; Through the central vein intubate with the continuous venoclysis of infusion pump, and through three-way valve can with 5% glucose or 0.9% sodium chloride injection, with the ratio while infusion of 1:16 (this medicine: unite transfusion) roughly.
Treatment beginning 2 hours can be according to 1mg/h medicine (dosage is about 15ug/kg/ hour).If toleration is not when well especially blood pressure has obvious decline, post dose can increase to 2mg/h (dosage is about 30ug/kg/ hour) in 2 hours.Body weight is estimated to be lower than 70 kilograms or the fixed patient of unstable blood pressure, and dosage should be from 0.5mg/h.Every day, consumption was at 24~48mg.