CN101816644B - Composition of taxol and phenylalanine and preparation method thereof - Google Patents
Composition of taxol and phenylalanine and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicaments, and in particular relates to a composition of taxol and phenylalanine and a preparation method thereof. The weight ratio of the taxol to the phenylalanine in the composition is 1 to 0.01-0.8. The invention also provides a method for preparing a composition injection and application of the composition in preparing an anti-cancer medicament.
Description
1, technical field
The invention belongs to medical technical field, be specifically related to the composition and method of making the same of a kind of paclitaxel and phenylalanine, and be used for treating the purposes of medicines such as ovarian cancer, breast carcinoma and nonsmall-cell lung cancer in preparation.
2, background technology
Paclitaxel belongs to Ramulus et folium taxi cuspidatae class medicine (Taxoids).Ramulus et folium taxi cuspidatae class medicine is by extracting or semisynthetic effective ingredient in trunk, bark or the needle of Ramulus et folium taxi cuspidatae.Americanized scholar Wani in 1971 etc. isolate taxane diterpene compound--the paclitaxel with active anticancer from know leaf Ramulus et folium taxi cuspidatae Taxus breuifilia bark.Paclitaxel has unique antitumor action, belongs to mitotic inhibitor or Spindle toxin (Spindle poison), and is different with the chemotherapeutic mechanism of action commonly used at present, and it is the assembling of inducing and promote microtubule.Paclitaxel has the effect of polymerization and stabilize microtubules; It can combine with microtubular protein, forms stable microtubule fasolculus, causes quick splitted tumor cell fixing by firmly in the mitosis stage; Cancerous cell is stopped at G2 late period or M phase; Suppress cellular replication, stop cancer cell multiplication, cancerous cell is duplicated blocked and death.This peculiar effect has caused the great attention of NCI (the state-run cancer institute of the U.S.), has promoted the carrying out of clinical trial work.The clinical practice through for many years now proves; Paclitaxel mainly is applicable to a line and the second line treatment of ovarian cancer and breast carcinoma and nonsmall-cell lung cancer; Pulmonary carcinoma, colorectal cancer, melanoma, incidence cancer, lymphoma, cerebroma also all there are certain curative effect, and in numerous clinical trials and process of clinical application, find the possibility that its clinical indication further expands in addition.
According to bibliographical information, the blood plasma Chinese medicine is the two-phase elimination behind the tumour patient instillation paclitaxel, eliminates t
1/2Average out to 5.3-17.4 hour.The medicine of 89-98% combines with plasma protein, plasma C
MaxWith dosage and instillation time correlation.Only there is a small amount of original shape medicine to discharge in the urine.Paclitaxel injection II clinical trial phase by the sea medicine development of Hainan light cavalry shows: 333 examples get into clinical research, and 167 examples have been accepted single medicine chemotherapy of paclitaxel, and 166 examples have been accepted paclitaxel and added cisplatin or amycin or other medicines treatment; The effective percentage of paclitaxel list medicine chemotherapy is following: ovarian cancer 37%, breast carcinoma 39%, nonsmall-cell lung cancer 31%; Small cell lung cancer 40%, nasopharyngeal carcinoma 67%, the effective percentage of paclitaxel combined chemotherapy is following: ovarian cancer 38%; Breast carcinoma 44%; Nonsmall-cell lung cancer 31%, small cell lung cancer 40%, nasopharyngeal carcinoma 44%.This shows that paclitaxel is very effective cancer therapy drug, also is topmost cancer therapy drug.
The dissolubility of paclitaxel in water is very little, water-soluble hardly (＜0.004mg/mL), oral administration biaavailability is poor, can only pass through intravenous administration, and, the requirement of the physical and chemical stability of injection is also improved day by day.Clinical formulation for paclitaxel commonly used is the oil preparation that is mixed and made at 1: 1 with polyoxyethylene castor oil and dehydrated alcohol now; Polyoxyethylene castor oil wherein plays the effect that increases taxol soluble; Meeting degradation in vivo when but the polyoxyethylene castor oil amount is big; Discharge histamine, thereby cause allergic reaction.Though the anticancer effect of paclitaxel is fine, the ability of its target cancer cell is not very strong.These have all limited paclitaxel application clinically.
Figure below is the structural formula of paclitaxel:
In order to overcome the problem of taxol soluble difference and side effect; Prevent oxidation, the hydrolysis of paclitaxel in the solution-type injection simultaneously; The physical and chemical stability of goods is obviously improved; The safety of paclitaxel injection in application process strengthened greatly, press for a kind of medicine clinically and solve these problems.
Phenylalanine is one of eight kinds of essential amino acids of human body; Research shows; With aminoacid is that carrier imports the carcinoma district to the molecule of cancer therapy drug or gene, just can reach both to have suppressed the carcinoma growth, can reduce the toxic and side effects of former tumour medicine again; And the most desirable in these amino acid carriers with phenylalanine, its effect be other amino acid whose 3-5 doubly.Simultaneously, phenylalanine also is one of solubilizing agent commonly used in the injection.
3, summary of the invention
The present invention is through the surprised discovery of a large amount of experiments; After paclitaxel and phenylalanine make up with certain proportion; Solved the problem of its water solublity with stability, side effect also reduces accordingly, makes things convenient for clinical application; And add phenylalanine and can play synergistic function, more can strengthen active anticancer with paclitaxel than single.
The purpose of this invention is to provide the compositions that contains paclitaxel and phenylalanine, said composition strengthens active anticancer and reduces side effect.
Another object of the present invention provides the injection of the compositions that contains paclitaxel and phenylalanine, and the water solublity of this injection and good stability can be stored the long period.
A purpose more of the present invention provides the method for preparing of the injection of the compositions that contains paclitaxel and phenylalanine, and the injection preparation cost of the paclitaxel that this method makes and the compositions of phenylalanine is low, quality controllable.
An also purpose of the present invention provides the application of compositions in the preparation cancer therapy drug that contains paclitaxel and phenylalanine.
The invention provides the composition and method of making the same that contains paclitaxel and phenylalanine, technical scheme is following:
The compositions that contains paclitaxel and phenylalanine provided by the invention is characterized in that, the weight ratio of described paclitaxel and phenylalanine is 1: 0.01～0.8.
The described compositions that contains paclitaxel and phenylalanine is characterized in that, the weight ratio of paclitaxel and phenylalanine is preferably 1: 0.05～and 0.5.
The described compositions that contains paclitaxel and phenylalanine is characterized in that, the weight ratio of paclitaxel and phenylalanine further is preferably 1: 0.1～and 0.3.
The described compositions that contains paclitaxel and phenylalanine is characterized in that, a step is preferably 1: 0.2 to the weight ratio of paclitaxel and phenylalanine again.
The described compositions that contains paclitaxel and phenylalanine is characterized in that, the compositions of paclitaxel and phenylalanine is an injection.
The described injection that contains the compositions of paclitaxel and phenylalanine is characterized in that, the solubilizing agent in the injection is a polyoxyethylene castor oil, and solvent is a dehydrated alcohol.
The described injection that contains the compositions of paclitaxel and phenylalanine is characterized in that, the volume ratio of polyoxyethylene castor oil and dehydrated alcohol is 1: 2.
The described injection that contains the compositions of paclitaxel and phenylalanine is characterized in that, the method for preparing that contains the injection of paclitaxel and phenylalanine compositions is:
(1) join auxilliary liquid: polyoxyethylene castor oil adds exsiccant molecular sieve, fills nitrogen, seal three days subsequent use; Be sealed in the exsiccator subsequent use after the active carbon activation; It is transparent that molecular sieve is washed till ethanol with dehydrated alcohol, flings to ethanol, drying, cool be sealed in the exsiccator subsequent use; Polyoxyethylene castor oil, ethanol and active carbon are mixed (rustless steel container), ultrasonic agitation.
(2) the auxilliary aseptic filter pressing of liquid: with the aseptic filter pressing of microporous filter membrane, weigh, calculating need be added the dehydrated alcohol amount;
(3) dissolve principal agent: principal agent is at the vacuum drying oven inner drying, and precision takes by weighing principal agent, joins in the filtrating of step (2), adds the dehydrated alcohol flushing, fills high pure nitrogen, sealing, and jog ultrasonicly dissolves to sample fully;
(4) the aseptic filter pressing of solution: solution is ultrasonic, with the aseptic filter pressing of microporous filter membrane;
(5) packing and sealing: liquor separator is cleaned, oven dry; Just filtrating is regulated loading amount, and the rim pure nitrogen gas of leaping high is divided on the limit; Seal rapidly after the packing, promptly get.
The described compositions that contains paclitaxel and phenylalanine is characterized in that the application in the preparation cancer therapy drug.
Composition and method of making the same and the immediate existing close compared with techniques that contains paclitaxel and phenylalanine of the present invention,
Have the following advantages:
The present invention has improved the water solublity of paclitaxel through adding phenylalanine, makes things convenient for clinical application;
Greatly reduce side effect such as allergy, simultaneously, also increased its active anticancer;
The present invention improves prepared paclitaxel injection stability through the improvement to paclitaxel prescription and injection technology, and simultaneously, products obtained therefrom is rapid-action;
Dose controlled, good appearance;
Processing technology is simple, and use is reliable, convenient, safe and practical, can reduce production costs, and is applicable to the realization suitability for industrialized production.
Below further set forth the beneficial effect of the compositions of paclitaxel of the present invention and phenylalanine, but should this compositions that is interpreted as paclitaxel of the present invention and phenylalanine only not had following beneficial effect through experimental example.
The proportioning of experimental example 1 etoh solvent and solubilizing agent polyoxyethylene castor oil and stable screening experiment
Whether stable to investigate solution at low temperatures after the ethanol volume ratio mixing different with polyoxyethylene castor oil.
1, experimental technique
Polyoxyethylene castor oil adds the exsiccant molecular sieve of 17.5% (m/v), fill nitrogen, the sealing three days subsequent use.Active carbon is sealed in the exsiccator subsequent use 121 ℃ of activation 2 hours.It is transparent that molecular sieve is washed till ethanol with dehydrated alcohol, flings to ethanol, 150 ℃ of dryings 5 hours, cool be sealed in the exsiccator subsequent use.
The polyoxyethylene castor oil that drying is good and ethanol than mixing, are tested stability of solution at low temperatures by different volumes.
2, experimental result and conclusion
The proportioning of table 1 ethanol and polyoxyethylene castor oil and stable screening experiment
Conclusion: above test shows, ethanol and polyoxyethylene castor oil volume ratio be 2: 1 o'clock the most stable, liquid viscosity is suitable, is easy to filter, and helps producing.
Conditional filtering among experimental example 2 preparation technologies
Prescription and technological basis analysis show that preparation technology mainly contains two key conditions: dry, fill nitrogen.Drying mainly is insoluble in water because of principal agent, and solubilizing agent and water unmixing.Fill nitrogen and mainly prevent the oxidation of principal agent and the corruption of polyoxyethylene castor oil.
1, experimental technique
Prepare three kinds of preparations, relatively polyoxyethylene castor oil is being carried out dried and be untreated the outward appearance of prepared paclitaxel injection and its related substances of filling nitrogen and not filling the preparation for preparing under the nitrogen condition respectively.
Preparation one: according to the preparation preparation of mentioning in " method for preparing ";
Preparation two: in " joining auxilliary liquid " process, polyoxyethylene castor oil is without molecular sieve drying, and other parts are according to the preparation preparation of mentioning in " method for preparing " two;
Preparation three: in " joining auxilliary liquid " process, polyoxyethylene castor oil does not fill nitrogen after adding molecular sieve drying, and other parts are according to the preparation preparation of mentioning in " method for preparing " three;
2, experimental result and conclusion
(1) dried
Polyoxyethylene castor oil is carried out dried investigate with the outward appearance of paclitaxel injection preparation that is untreated prepared one and preparation two, the result is following:
The injection of the table 2 polyoxyethylene castor oil dried and the preparation of being untreated relatively
The selection result shows, polyoxyethylene castor oil is carried out dried after, with the comparison of being untreated, no matter place 5 or 10 days, solution appearance all shows clarification.
(2) fill nitrogen
Carry out related substance investigation (10 days) to filling nitrogen with preparation that does not fill nitrogen one and preparation three, the result is following:
Table 3 fills nitrogen and compares with the preparation that does not fill nitrogen
The selection result shows, preparation fills nitrogen to be placed 10 days, with do not fill nitrogen place 10 days preparation relatively, 1% contrast area, assorted peak area and its related substances all are significantly less than does not fill the preparation that nitrogen is handled.
Conclusion: The selection result shows that the reply polyoxyethylene castor oil prepares process and carries out the intensive drying processing, simultaneously solution is filled nitrogen, to guarantee stability of formulation.
Experimental example 3 formulation and technology screening experiment
1, experimental technique
According to above-mentioned design principle, press the different prescriptions of table 1 preparation.Research paclitaxel related substance, content, medicinal liquid pH and change in color situation.
Table 4 paclitaxel injection prescription screening
2, experimental result and conclusion
Get the solution of aseptic filter pressing, pH and the clarity and the color of the related substance of mensuration paclitaxel, content, medicinal liquid.The result sees table 5.
Table 5 paclitaxel injection prescription screening testing result
Conclusion: through above A, B, C, the D screening of side everywhere; Learn that prescription A stickiness height is difficult for filter pressing and unstable at low temperatures; The solution of prescription B, C and D all has ideal physical stability and chemical stability, can be as the prescription of this preparation, because prescription D design less expensive; Therefore, with prescription D be the first-selection prescription of these article.
Experimental example 4 influence factors experiment
The injection for preparing the present composition according to the method for preparing of mentioning in the patent.Select the injection (lot number 0306011) of one group of present composition to place under the condition of illumination (illumination 4500Lx), high temperature (60 ℃) and low temperature (4 ℃) arbitrarily; The sampling respectively in 5,10 days; Investigate character, clarity, pH value, related substance and content; Measure result and 0 month numeric ratio, investigate prescription and the adaptability of technology and the influence of packaging material, the result sees table 6.
Table 6 influence factor experiment
Conclusion: data can be found out from table, compositions of the present invention place under illumination, high temperature and the cryogenic condition mensuration result and 0 month numeric ratio, its character, pH value and content all do not have obvious change, clarity and related substance are all up to specification.Result of the test shows that this prescription and Technological adaptability are good, stablizes feasiblely, and the packaging material ampoule does not have influence to the stability of principal agent.
The experiment of experimental example 5 compatibilities
The injection of paclitaxel and phenylalanine preparation of compositions and 5% glucose injection and 0.9% sodium chloride injection compatibility are tested its stability and whether are had incompatibility.
The injection of table 7 present composition and the test of 5% glucose injection compatibility
The injection of table 8 present composition and the test of 0.9% sodium chloride injection compatibility
Conclusion: result of the test shows that behind these article and 5% glucose injection or the 0.9% sodium chloride injection compatibility, outward appearance, clarity, pH value and peak area all do not have significant change, and ie in solution is stable in 12 hours, no incompatibility.
Experimental example 6 solubility experiments
This experimental example is to utilize prepared injection of the present composition and commercially available similar drug taxol to carry out dissolubility comparative study.
1, medicine
The injection of the compositions of paclitaxel of the present invention and phenylalanine adopts the proportioning preparation of prescription 6;
Taxol: commercial (30mg/ props up).
2, method
The present composition and taxol are dissolved in respectively in the 5mL water, and sonic oscillation a period of time filters to no longer including the solid dissolving, and the gained solid drying is weighed, and can approximately learn the solubility values of the present composition and taxol.
3, result
The dissolubility of taxol is 1.2mg/mL, and the dissolubility of the present composition is 3.3mg/mL.Experimental result shows that the dissolubility of the present composition is 2.75 times of taxol, has promptly obviously improved water solublity.
Experimental example 7 inside and outside antitumor comparative experimentss
Material and medicine
Medicine: the present composition: with 6 the proportioning self-control of writing out a prescription;
Taxol: commercial.
Animal: ICR strain white mice, 18～22g, male and female half and half.
Tumor strain: tumor-bearing mice S
180, tumor strain oophoroma cell AO
10/17
Instrument: Olympus microscope BHT (Japan makes); PB303 electronic balance (Switzerland's manufacturing); HL-2920P enzyme mark automatic analyzer (Chinese 262 factories make); SHELLAB-2300 CO2 gas incubator (U.S. SHELDON manufacturing).
1,
The extracorporeal anti-tumor comparative experiments-to ovarian cancer cell strain AO 10/17 Cytotoxicity
1.1, method
The employing mtt assay detects.Get tumor strain AO
10/17, regularly go down to posterity in containing the complete RPMI1640 culture fluid of 10% calf serum in the recovery back; Treat that cell grows to increased logarithmic phase, with pancreatin EDTA digestion, Hank ' s liquid is washed twice; Be suspended in the RPMI1640 culture fluid of 10% calf serum adjustment cell concentration 0.3 * 10
6/ mL gets the flat culture plate in 96 holes, and it is for use that every hole adds above-mentioned cell suspension 100 μ L.Solvent control group, taxol group and present composition group are established in experiment.The present composition and taxol divide 6 concentration, all with the initial concentration two-fold dilution of 46.86 μ L/mg.Its concentration is respectively 46.86,23.43,11.72,5.86,2.93,1.47 μ L/mg, and each dosage is established the solvent control under the concentration of the same race.Add for the every hole of culture plate by above-mentioned dosage and tried thing 100 μ L, select 6 holes else and add 100 μ L fresh mediums as background, each dosage is done 3 parallel appearance.Under 37 ℃, 5% carbon dioxide conditions, act on 4h, form the hyacinthine crystallization, abandon supernatant; Wash twice with fresh complete culture solution; Add the lysigenous navy blue granule of 100 μ L/ hole DMSO,, under the 570nm wavelength, read optical density (OD) with HL-2920P enzyme mark automatic analyzer.According to formula, calculate and kill and wound percentage rate.
Kill and wound percentage rate=(1-tests optical density/bias light density) * 100
Parallel testing 3 times.
1.2, result and conclusion
The present composition and taxol are to AO
10/17The cytotoxicity of tumor strain is seen table 9.
Table 9 present composition and taxol are to AO
10/17The cytotoxicity of tumor strain
The ratio of outflow extremely of the present composition and taxol itself is the ratio of outflow that kills that ratio of outflow deducts corresponding solvent respectively that kills of the present composition and taxol, and the result sees table 10.
The ratio of outflow extremely of table 10 present composition and taxol
Conclusion: data are visible from table, and 3 times result of the test all shows, the present composition itself kill ratio of outflow than taxol itself to kill ratio of outflow high about 2 times, promptly the present composition is better active.
2, anti-tumor in vivo comparative test-to the influence of mice S180 solid tumor
2.1, method
Get the S of inoculation 7～10d
1801 of solid tumor mice is got the tumor piece under the sterile working, the tumor body is cut into small pieces, and grinds with glass homogenizer, adds the tumor cell suspension that sterile saline is diluted to 1: 4.Other gets 60 of ICR mices, and axillary fossa Sc inoculation liquid 0.2mL/ only through the right side.The inoculation back is divided into 6 groups next day at random, and 10 every group, male and female half and half.Divide physiology saline negative group, solvent control group, present composition group and taxol group, quiet notes; Once a day, the 0.2mL/10g body weight continuous 4 days, was put to death each treated animal on the 9th day in the inoculation back; Weigh, separation tumor body is also weighed, and calculates the tumor body than (the contained tumor of every 100g body weight is heavily asked tumour inhibiting rate.Following formula is pressed in therapeutic evaluation):
Tumor control rate=(the average tumor of the average tumor weight-administration of matched group group is heavy)/average tumor of matched group weighs * 100 parallel testings 3 times.
2.2, result and conclusion
The present composition and taxol are to S
180The experimental result of the influence of tumor strain is seen table 11.
Table 11 present composition and taxol are to S
180The influence of tumor strain
(mean±s)
Conclusion: the present composition and taxol are to mice S
180The tumor body weight of solid tumor all has inhibitory action, and 3 experiments all show, active obviously active good than taxol of the present composition.
4, the specific embodiment
Below, foregoing of the present invention is done further to specify through the specific embodiment of embodiment and experimental example form.But should this scope that is interpreted as the above-mentioned theme of the present invention only not limited to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The preparation of the composite injection of embodiment paclitaxel of the present invention and phenylalanine
1, prescription
Prescription 1:
Paclitaxel 12g
Phenylalanine 0.6g
Polyoxyethylene castor oil 671g
Dehydrated alcohol 1072g
Full dose 2000mL
Process 1000 altogether
Prescription 2:
Paclitaxel 12g
Phenylalanine 2.4g
Polyoxyethylene castor oil 670g
Dehydrated alcohol 1072g
Full dose 2000mL
Process 1000 altogether
Prescription 3:
Paclitaxel 12g
Phenylalanine 6g
Polyoxyethylene castor oil 666g
Dehydrated alcohol 1072g
Full dose 2000mL
Process 1000 altogether
Prescription 4:
Paclitaxel 30g
Phenylalanine 1.5g
Polyoxyethylene castor oil 1679g
Dehydrated alcohol 2680g
Full dose 5000mL
Process 1000 altogether
Prescription 5:
Paclitaxel 30g
Phenylalanine-3,4-quinone g
Polyoxyethylene castor oil 1677g
Dehydrated alcohol 2680g
Full dose 5000mL
Process 1000 altogether
Prescription 6:
Paclitaxel 30g
Phenylalanine 6g
Polyoxyethylene castor oil 1674g
Dehydrated alcohol 2680g
Full dose 5000mL
Process 1000 altogether
Prescription 7:
Paclitaxel 30g
Phenylalanine 9g
Polyoxyethylene castor oil 1671g
Dehydrated alcohol 2680g
Full dose 5000mL
Process 1000 altogether
Prescription 8:
Paclitaxel 30g
Phenylalanine 15g
Polyoxyethylene castor oil 1665g
Dehydrated alcohol 2680g
Full dose 5000mL
Process 1000 altogether
Prescription 9:
Paclitaxel 60g
Phenylalanine-3,4-quinone g
Polyoxyethylene castor oil 3357g
Dehydrated alcohol 5360g
Full dose 10000mL
Process 1000 altogether
Prescription 10:
Paclitaxel 60g
Phenylalanine 6g
Polyoxyethylene castor oil 3354g
Dehydrated alcohol 5360g
Full dose 10000mL
Process 1000 altogether
Prescription 11:
Paclitaxel 60g
Phenylalanine 12g
Polyoxyethylene castor oil 3348g
Dehydrated alcohol 5360g
Full dose 10000mL
Process 1000 altogether
Prescription 12:
Paclitaxel 60g
Phenylalanine 18g
Polyoxyethylene castor oil 3342g
Dehydrated alcohol 5360g
Full dose 10000mL
Process 1000 altogether
Prescription 13:
Paclitaxel 60g
Phenylalanine-3,4-quinone 0g
Polyoxyethylene castor oil 3330g
Dehydrated alcohol 5360g
Full dose 10000mL
Process 1000 altogether
2, method for preparing
(1) join auxilliary liquid: polyoxyethylene castor oil adds the exsiccant molecular sieve of 17.5% (m/v), fill nitrogen, the sealing three days subsequent use.Active carbon is sealed in the exsiccator subsequent use 121 ℃ of activation 2 hours.It is transparent that molecular sieve is washed till ethanol with dehydrated alcohol, flings to ethanol, 150 ℃ of dryings 5 hours, cool be sealed in the exsiccator subsequent use.
Polyoxyethylene castor oil, ethanol and 0.05% active carbon are mixed (rustless steel container), ultrasonic agitation 30 minutes (the ultrasonic water bath temperature is no more than 45 ℃, promptly takes out stirring like heat, falls cold continuation again).
(2) the auxilliary aseptic filter pressing of liquid: with the aseptic filter pressing of 2 0.22 μ m microporous filter membrane (nitrogen pot pressure between 0.15-0.3mpa, the filtrating receiving vessel is should be transparent visual and bore is little, with the minimizing solvent evaporates), weigh, calculating need be added the dehydrated alcohol amount.
(3) dissolve principal agent: principal agent is at vacuum drying oven inner drying 24 hours (vacuum 0.09, temperature 42-45 ℃), and precision takes by weighing principal agent; Add in the filtrating of step (2), add the dehydrated alcohol flushing, fill high pure nitrogen; Sealing, jog ultrasonicly dissolves (estimating no granule) to sample fully.
(4) the aseptic filter pressing of solution: with ultrasonic 10 minutes of solution, with the aseptic filter pressing of 2 0.22 μ m microporous filter membrane, that receiving vessel is wanted was clean (can not residual alkali liquor, 180 ℃ dry heat sterilization three hours).
(5) packing: the liquor separator wash clean, use earlier the 70-75% soak with ethanol, the flushing of reuse dehydrated alcohol, 100 ℃ of oven dry.Just filtrating is regulated loading amount, and the rim pure nitrogen gas of leaping high is divided on the limit, and pressure is at 0.01-0.05mpa.
(6) seal: seal rapidly,, promptly get in case nitrogen overflows.
Claims (7)
1. a compositions that contains paclitaxel and phenylalanine is characterized in that, the weight ratio of described paclitaxel and phenylalanine is 1: 0.1～0.3.
2. the compositions that contains paclitaxel and phenylalanine as claimed in claim 1 is characterized in that, the weight ratio of described paclitaxel and phenylalanine is 1: 0.2.
3. like each described compositions that contains paclitaxel and phenylalanine of claim 1～2, it is characterized in that the described compositions that contains paclitaxel and phenylalanine is an injection.
4. the injection that contains the compositions of paclitaxel and phenylalanine as claimed in claim 3 is characterized in that, the solubilizing agent in the injection is a polyoxyethylene castor oil, and solvent is a dehydrated alcohol.
5. the injection that contains the compositions of paclitaxel and phenylalanine as claimed in claim 4 is characterized in that, the volume ratio of described polyoxyethylene castor oil and dehydrated alcohol is 1: 2.
6. the injection that contains the compositions of paclitaxel and phenylalanine as claimed in claim 5 is characterized in that, the described method for preparing that contains the injection of paclitaxel and phenylalanine compositions is:
(1) join auxilliary liquid: polyoxyethylene castor oil adds exsiccant molecular sieve, fills nitrogen, seal three days subsequent use; Be sealed in the exsiccator subsequent use after the active carbon activation; It is transparent that molecular sieve is washed till ethanol with dehydrated alcohol, flings to ethanol, drying, cool be sealed in the exsiccator subsequent use; Polyoxyethylene castor oil, ethanol and active carbon are mixed in the rustless steel container ultrasonic agitation;
(2) the auxilliary aseptic filter pressing of liquid: with the aseptic filter pressing of microporous filter membrane, weigh, calculating need be added the dehydrated alcohol amount;
(3) dissolve principal agent: principal agent is at the vacuum drying oven inner drying, and precision takes by weighing principal agent, joins in the filtrating of step (2), adds the dehydrated alcohol flushing, fills high pure nitrogen, sealing, and jog ultrasonicly dissolves to sample fully;
(4) the aseptic filter pressing of solution: solution is ultrasonic, with the aseptic filter pressing of microporous filter membrane;
(5) packing and sealing: liquor separator is cleaned, oven dry; Just filtrating is regulated loading amount, and the rim pure nitrogen gas of leaping high is divided on the limit; Seal rapidly after the packing, promptly get.
7. like each described compositions application in the preparation cancer therapy drug that contains paclitaxel and phenylalanine of claim 1～2.
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| CN110123745B (en) * | 2019-06-27 | 2020-08-28 | 四川汇宇制药股份有限公司 | Preparation method of paclitaxel injection resistant to terminal sterilization |
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