CN102038636A - Taxane medicine solution containing chelating agent and preparation method thereof - Google Patents
Taxane medicine solution containing chelating agent and preparation method thereof Download PDFInfo
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- CN102038636A CN102038636A CN2009100709322A CN200910070932A CN102038636A CN 102038636 A CN102038636 A CN 102038636A CN 2009100709322 A CN2009100709322 A CN 2009100709322A CN 200910070932 A CN200910070932 A CN 200910070932A CN 102038636 A CN102038636 A CN 102038636A
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- emulsion
- solution
- taxone
- chelating agen
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention provides a taxane medicine solution containing a chelating agent and a preparation method therefore as well as application of the taxane medicine solution with an emulsion. Before being applied, the medicine solution is dispersed in the emulsion, shaken to be uniform and then can be used for intravenous drip; since a chelating agent is added, stable time of the medicine solution dispersing in the emulsion is prolonged unexpectedly, and the problem of oil spill on dispersion liquid is also solved, thereby further improving the safety and the effectiveness of clinical administration. The invention also provides the preparation method of the taxane medicine solution, a composite containing the taxane medicine solution and the emulsion, and a combined package consisting of the taxane medicine solution and the emulsion, as well as the emulsion containing the chelating agent.
Description
Invention field
The present invention relates to drug preparation technique, be specifically related to a kind of taxone solution and preparation method thereof.
Background technology
Taxane (taxanes) class medicine comprises paclitaxel (paclitaxel, merchant Taxol by name) and Docetaxel (docetaxel, commodity are called Taxotem), is two kinds of taxanes cancer therapy drugs by the FDA approval.Taxone is the cytotoxic agent of a quasi-representative, has the broad-spectrum anti-tumor effect, preinvasive cancers such as breast carcinoma, ovarian cancer, small cell lung cancer, nonsmall-cell lung cancer, incidence squamous cell carcinoma and malignant melanoma and metastatic carcinoma all there is stronger effect, its Anticancer Effect and Mechanism is the polymerization by the stimulating catheter bundle, promote the microtubule dimer to be assembled into microtubule, and cause microtubule overstable and suppress the reorganization of microtubule net kinetics, finally make cancer cell multiplication stop at the stage of mitostatic phase, reach the antineoplastic purpose.
Paclitaxel and Docetaxel water solublity are very little, and water-soluble hardly (about 4 μ g/ml), the oral absorption rate only is 2%～4%, so can only intravenously administrable.In order to improve the water solublity of paclitaxel, the paclitaxel injection of clinical practice is by polyoxyethylene castor oil and dehydrated alcohol (50: 50, V/V) the colourless thick concentrated solution of making, though this double solvent has solved the problems of dissolution of paclitaxel, but contain the polyoxyethylene castor oil that easily causes allergic reaction in this injection, occur anaphylaxiss such as dyspnea, flushing, palpitating speed, erythra after the medication, brought potential safety hazard and misery to the patient.And the Docetaxel clinical preparation is alcoholic solution two parts composition of tween 80 solution and 13%, during medication it is dispersed in normal saline medium-sized vein drop, though solved the problems of dissolution of Docetaxel, but this injection contains the tween 80 with haemolysis, hemolytic reaction easily takes place in clinical application, and safety is relatively poor.In view of there are many deficiencies in clinical existing preparation, old friends are comparatively active to the research and development of taxone injection.Mainly be to serve as the research focus to the research of taxone injection in recent years with liposome, fat milk, nanoparticle, the crosslinked precursor of albumin, cyclodextrin clathrate etc.Present key problem in technology concentrates in the biocompatibility, body of the selection of material on the problem such as toleration and dosage form stability.Although some dosage form research makes a breakthrough, because drug loading is low, do not reach effective medicine concentration, its application still is restricted.
Report from (Am.J.Hosp.Pharm. (1975) 32,582-584)) such as Fortner, poorly water soluble drugs be dissolved in the suitable solvent for injection make drug solution, be scattered in the injectable emulsion during use and instil that this form of administration progressively is that everybody payes attention to.
" the non-intestinal of paclitaxel is stablized toxic formulation " (Chinese patent: 97196934.5) of B.S Anderson, the medicine solvent of drug solution part is made up of with 3: 1 ratio PEG400 and dimethyl acetylamide, though dimethyl acetylamide can improve the dissolution velocity of medicine, also increased the toxic and side effects of pharmaceutical preparation simultaneously.Zhou Lianfang etc. (the poisonous effect progress [J] of dimethyl acetylamide. Chinese occupational medicine, 2009,36 (1): 66-67) report, point out that dimethyl acetylamide can cause that big mice loses weight, neurodeatrophia, brain wave changes, infringements such as lung, stomach, liver, kidney.
(Chinese patent: 200680007345.3), the medicine solvent of drug solution part mainly is made up of PEG400 and oleic acid " medical compositions that contains poorly water soluble drugs " such as Wu Tianguang cities.R.C. sieve etc. (pharmaceutic adjuvant handbook [M]. original work the 4th edition: show that 476) oleic acid can cause breaking of erythrocyte, promptly have hemolytic, only allow to be used for non-injection in Britain.
" a kind of concentration emulsifier and the using method thereof that contains paclitaxel analog compound " of Hu Yufang (Chinese patent: 200410025522.3), contain surfactant in the drug solution part, as Tween 80, polyvidone, lecithin etc.These surfactants all have certain hemolytic and zest.
For make taxone safer, effective, stable, economically be applied to clinical, bring into play its antitumor action better, we have developed a kind of assembly packaging, contain the solution packing and the medicinal Emulsion packing of taxone in the assembly packaging, two kinds of packings are discrete, and combination is put together.Before the medication drug solution is dispersed in the Emulsion, shake up, get final product intravenous drip, the present invention has added chelating agen in this combination medicament, the dispersion stability that makes drug solution be dispersed in the Emulsion significantly improves, overcome the deficiency of dispersion liquid oil spill, improved the safety and the effectiveness of this drug delivery system.
Summary of the invention
The invention provides a kind of taxone compositions, formulated by taxone solution and Emulsion two parts medicament, wherein contain chelating agen in drug solution or the Emulsion, content is the preferred 0.1-1% (grams per milliliter) of 0.05-2% (grams per milliliter).Described formulated be to be 1 by volume: the ratio of 10-100 is mixed drug solution and Emulsion.Preferably 1: the mixed of 20-50 most preferably is 1: 25 ratio.
Compositions of the present invention makes taxone show strong stability after mixing with injectable emulsion because of added chelating agen in taxone solution or Emulsion before preparation.
The invention provides a kind of taxone solution for this reason, wherein contain taxone, chelating agen, solvent.
Preferably the ratio of each component is:
Taxone 1-8% (grams per milliliter)
Chelating agen 0.05-2% (grams per milliliter)
All the other are solvent and the other medicines carrier that adds in case of necessity.
Preferred the ratio of each component is:
Taxone 1-6% (grams per milliliter)
Chelating agen 0.1-1% (grams per milliliter)
All the other are solvent and the other medicines carrier that adds in case of necessity.
Wherein said other medicines carrier is in the process of obtain solution, adds as required, as: cosolvent, isotonic agent, surfactant, pH value regulator etc., these carriers can add, also can not add, according to taxone, the character of intercalating agent and solvent is selected.
Solution of the present invention, described taxone is any taxone, paclitaxel that has preferably gone on the market or Docetaxel.
Solution of the present invention, wherein said chelating agen is added in the solution of medicine, wherein said chelating agen is selected from: the mixture of one or more in ethylenediaminetetraacetic acid, citric acid, lactic acid, malic acid, tartaric acid, disodiumedetate, sodium versenate, the disodium citrate, optimization citric acid, lactic acid, ethylenediaminetetraacetic acid, disodiumedetate, most preferably disodiumedetate.
Solution of the present invention, described solvent are selected from one or more the mixture in Macrogol 200, Liquid Macrogol, PEG400, Macrogol 600, propylene glycol, glycerol, dehydrated alcohol, the water for injection; Preferred PEG400.
The present invention also comprises the preparation method of solution of the present invention, comprises taxone and chelating agen are dissolved in solvent, adds the step of other medicines carrier in case of necessity.
Preferably comprise the steps: to take by weighing paclitaxel or Docetaxel, chelating agen in 50-100 ℃ of following heated and stirred or shearing dissolving, is settled to full dose with solvent then to solvent; Adding the bulking value percentage composition is the needle-use activated carbon of 0.01%-3% grams per milliliter, and absorption is 15-120 minute under 25-100 ℃ heating-up temperature, filtration, packing then, seals, sterilizes, promptly.
The present invention also provides a kind of drug regimen packing, is formed by taxone solution of the present invention and Emulsion assembly packaging, and two kinds of medicaments are loaded in respectively in the container, discrete placement, and assembly packaging is together.Assembly packaging of the present invention, be with taxone solution of the present invention and medicinal Emulsion, be potted in respectively in plastic bottle or the vial that two kinds of medicines are with 1: 10-10: 1 ratio assembly packaging together, preferred 1: 1 ratio is packaged in the same big packing container.Be packaged as suitable with a use amount.
Emulsion of the present invention is the blended emulsification preparation of a kind of profit, is that oils medicine or medicine oil solution are dispersed in formed non-homogeneous dispersion in the disperse medium with the drop state, and the branch of Orally taken emulsion, intravenous injection emulsion is arranged.The present invention uses intravenous Emulsion, preferred infatmul agent, concrete as: in 20%/long-chain fat Emulsion, 20% long-chain fat Emulsion etc.
Emulsion of the present invention is commercially available injectable emulsion product or the Emulsion product of preparing according to prior art.Generally contain oil for injection, emulsifying agent, antioxidant, isoosmotic adjusting agent, pH regulator agent, water for injection etc.
Characteristics of the present invention are, can add chelating agen in the Emulsion of the present invention, content is the preferred 0.1-1% (grams per milliliter) of 0.05-2% (grams per milliliter), described chelating agen is selected from: the mixture of one or more in ethylenediaminetetraacetic acid, citric acid, lactic acid, malic acid, tartaric acid, disodiumedetate, sodium versenate, the disodium citrate, optimization citric acid, lactic acid, ethylenediaminetetraacetic acid, disodiumedetate, most preferably disodiumedetate.
Emulsion of the present invention, wherein said oil for injection is selected from hot tricaprin, sad monoglyceride, Sunfat GDC-S, Trivent OCG, Ganoderma spore oil, the capric acid monoglyceride, the capric acid diglyceride, tricaprin, hot capric acid monoglyceride, Semen Coicis oil, Oleum Fructus Bruceae, Herba Artemisiae Annuae oil, hot capric acid diglyceride, soybean oil, fish oil, Semen Lini oil, Oleum Helianthi, Radix Oenotherae erythrosepalae oil, Oleum Hippophae, Oleum Curcumae, safflower oil, Oleum sesami, Semen Maydis oil, elemene oil, the mixture of one or more in the Bulbus Allii wet goods, its heavy content is the 1-30% grams per milliliter.
Preferred oil for injection is selected from one or more the mixture in hot tricaprin, the soybean oil, and content is the 10-30% grams per milliliter.
Wherein said emulsifying agent is selected from one or more mixture of soybean phospholipid, egg yolk lecithin, dimyristoyl phosphatidyl choline, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, dioleoyl phospholipid phatidylcholine, palmityl oleoyl phosphatidylcholine, DSPE, poloxamer 188, and its content is the 0.5-5% grams per milliliter.Preferred solvent is selected from one or more the mixture in soybean phospholipid, the egg yolk lecithin, and content is the 0.8-3% grams per milliliter.
Wherein said antioxidant is tocopherol, and its content is the 0-0.5% grams per milliliter.Preferred content is the 0-0.3% grams per milliliter.
Wherein said isoosmotic adjusting agent is selected from one or more in glycerol, sorbitol, mannitol, glucose, the sodium chloride, is preferably glycerol.
Wherein said pH regulator agent is selected from one or more in citric acid, malic acid, hydrochloric acid, acetic acid, lactic acid, sodium carbonate, sodium bicarbonate, the sodium hydroxide, is preferably sodium hydroxide, regulates pH to 6.0-9.0.The preferred pH to 6.5-8.5 that regulates.
The preparation method of used for intravenous injection Emulsion as oil for injection, antioxidant are mixed, is heated to 50-90 ℃ for having routine techniques now, adds emulsifying agent, stirs or shear to make emulsifiers dissolve, gets oil phase; Isoosmotic adjusting agent, stabilizing agent are added in an amount of water for injection, be heated to 50-90 ℃ of stirring and dissolving, get water; Oil phase and water are mixed under 50-90 ℃ of temperature, and with emulsification pretreatment device emulsifying or stirring and emulsifying 5-60 minute, rotating speed was 5000-30000 rev/min, colostrum.With the further emulsifying of colostrum, use the water for injection standardize solution then, regulating pH with the pH regulator agent is 6.0-9.0, filters, nitrogen is filled in packing, seals, sterilization, promptly.
Comprise in the preparation process of Emulsion generally speaking emulsifiers dissolve in oil for injection or emulsifiers dissolve in water.Wherein the further emulsifying of colostrum is to adopt high pressure homogenizer emulsifying, and pressure is 5000-25000psi.Sterilization in the preparation process of Emulsion is to adopt sterilizations such as rotating type high-pressure steam sterilization pot, flowing steam or mistake microporous filter membrane, wherein high temperature sterilize temperature 100-121 ℃, time 8-45 minute.Filtration device in the preparation process of Emulsion includes but not limited to microporous filter membrane, sand filtration rod, vertical molten funnel or bag type filter.Emulsion is white or off-white color emulsion liquid, and opalescence is arranged, and mean diameter is 100-500nm, and pH is 6.0-9.0.
The present invention also comprises the using method of taxone solution of the present invention, this method comprises that with taxone solution and medicinal Emulsion be 1 by volume: 10-100, preferred 1: 25 ratio, drug solution is dispersed in the Emulsion, shake up, intravenous drip, the medicine after also can disperseing with Emulsion add normal saline or glucose solution is used for injection.
Following data declaration beneficial effect of the present invention by experiment.
1, contains chelating agen (citric acid) and the stability that does not contain dispersion liquid before the paclitaxel injection compositions administration of chelating agen relatively
In order further to embody substantial characteristics and the beyond thought effect that contains chelating agen among the present invention, we will make comparisons with the stability of the preceding dispersion liquid of the paclitaxel injection compositions administration that does not contain chelating agen to containing chelating agen (citric acid).
Prepare the drug solution that contains chelating agen (citric acid) according to embodiment 1 described embodiment, must supply reagent thing solution; According to embodiment 1 described embodiment, remove the drug solution that the citric acid preparation does not contain chelating agen, get control drug solution; Draw respectively above-mentioned for 4 milliliters of reagent thing solution and control drug solution, be dispersed in respectively embodiment 1 described 100 milliliters in antigalactic, shake up, must specimen.With high performance liquid chromatograph, particle size determination instrument, measure medicament contg, the particle diameter of this dispersion liquid respectively in different time points; When measuring content, extract the microporous filter membrane that an amount of dispersion liquid is crossed 0.45 μ m with syringe earlier, measure the content of filtrate Chinese medicine, calculate the sign percentage composition, estimate medicine with this content and whether separate out crystallization; Particle diameter is then directly measured, and the perusal outward appearance, the results are shown in Table 1, table 2.
Table 1 is the study on the stability (disperseing Emulsion is from antigalactic) of the preceding dispersion liquid of the paclitaxel injection compositions administration that contains chelating agen (citric acid) of representative with embodiment 1
Table 2 is the study on the stability (disperseing Emulsion is from antigalactic) of the preceding dispersion liquid of the paclitaxel injection compositions administration that does not contain chelating agen (citric acid) of representative with embodiment 1
Interpretation of result:
Draw from the comparison of test results of table 1 with table 2, equally by embodiment 1 under the prepared prerequisite that contains chelating agen (citric acid) and the paclitaxel injection compositions that does not contain chelating agen, the dispersion stable that contains chelating agen is for up to more than 6 days, and the dispersion stable time that does not contain chelating agen is about 3 days; From apparent, contain no oil spill phenomenon in the dispersion liquid 6 days of chelating agen, apparent better and it is more not contain the oil spill of chelating agen, and along with the prolongation of time, oil spill increases gradually, and is apparent relatively poor; Particle diameter changes in stabilization time not quite, and particle diameter becomes big when medicine is separated out.
The result shows, the paclitaxel injection compositions that contains chelating (citric acid) has significant effect, its advantage shows that the dispersion stability that makes than the paclitaxel injection compositions that does not contain chelating agen improves greatly, and the beyond thought deficiency that overcomes the dispersion liquid oil spill.To contain chelating agen be the feature that the present invention has substantive excellent results so further embodied.
2, contain chelating agen (disodiumedetate) with do not contain chelating agen the administration of Docetaxel injection composition before the estimation of stability of dispersion liquid
In order further to embody substantial characteristics and the beyond thought effect that contains chelating agen among the present invention, we will make comparisons with the stability of the preceding dispersion liquid of the Docetaxel injection composition administration that does not contain chelating agen to containing chelating agen (disodiumedetate).
Contain the Docetaxel injection composition of chelating agen (disodiumedetate) respectively according to embodiment 2 described embodiment preparations, must supply test agent; According to embodiment 2 described embodiments, remove the Docetaxel injection composition that chelating agen (disodiumedetate) preparation does not contain chelating agen, get control sample; Draw respectively and above-mentionedly be dispersed in respectively in 100 milliliters of Emulsions separately, shake up for 4 milliliters of the examination and the drug solutions of control sample, specimen.With high performance liquid chromatograph, particle size determination instrument, measure medicament contg, the particle diameter of this dispersion liquid respectively in different time points; When measuring content, extract the microporous filter membrane that an amount of dispersion liquid is crossed 0.45 μ m with syringe earlier, measure the content of filtrate Chinese medicine, calculate the sign percentage composition, estimate medicine with this content and whether separate out crystallization; Particle diameter is then directly measured, and the perusal outward appearance, the results are shown in Table 3, table 4.
Table 3 is the study on the stability (disperseing Emulsion is from antigalactic) of the preceding dispersion liquid of the Docetaxel injection composition administration that contains chelating agen (disodiumedetate) of representative with embodiment 2
Table 4 is the study on the stability (disperseing Emulsion is from antigalactic) of the preceding dispersion liquid of the Docetaxel injection composition administration that does not contain chelating agen (disodiumedetate) of representative with embodiment 2
Interpretation of result:
Draw from the comparison of test results of table 3 with table 4, equally by embodiment 2 under the prepared prerequisite that contains chelating agen (disodiumedetate) and the Docetaxel injection composition that does not contain chelating agen, the dispersion stable that contains chelating agen is for up to more than the two weeks, and the dispersion stable time that does not contain chelating agen is about 6 days; From apparent, contain no oil spill phenomenon in the dispersion liquid two weeks of chelating agen, apparent better, and it is more not contain the oil spill of chelating agen, and along with the prolongation of time, oil spill increases gradually, and is apparent relatively poor; Particle diameter changes in stabilization time not quite, and particle diameter becomes big when medicine is separated out.
The result shows, the Docetaxel injection composition that contains chelating agen (disodiumedetate) has significant effect, its advantage shows that the dispersion stabilization that makes than the Docetaxel injection composition that does not contain chelating agen improves greatly, and the beyond thought deficiency that overcomes the dispersion liquid oil spill, to contain chelating agen be the feature that the present invention has substantive excellent results so further embodied.
3, contain the present invention and the contrast test that contains dimethyl acetylamide contrast patent working scheme of chelating agen (disodiumedetate)
(Chinese patent: show 97196934.5) that this patent mainly is to have added dimethyl acetylamide on the basis of PEG400, the ratio of itself and PEG400 is 1: 3, and its drug loading is 25 mg/ml in patent.According to this embodiment compounding pharmaceutical solution, drug solution in contrast; According to embodiment 18 described embodiment compounding pharmaceutical solution, must supply reagent thing solution; Draw 4 milliliters of above-mentioned control drug solution respectively, supply reagent thing solution, be dispersed in respectively in embodiment 18 described 100 milliliters of commercially available Emulsions.Shake up, get specimen.Use high performance liquid chromatograph, measure the medicament contg of this dispersion liquid respectively in different time points; When measuring content, extract the microporous filter membrane that an amount of dispersion liquid is crossed 0.45 μ m with syringe earlier, measure the content of filtrate Chinese medicine, calculate the sign percentage composition, estimate medicine with this content and whether separate out crystallization; And the perusal outward appearance the results are shown in Table 5.
Table 5 contains the preparation dispersion liquid of the present invention and the study on the stability (disperseing Emulsion is commercially available Emulsion) that contains dimethyl acetylamide contrast proprietary preparation dispersion liquid of chelating agen (disodiumedetate)
Interpretation of result:
Drawn by test, in identical commercially available Emulsion disperse medium, the dispersion stable of the present composition that contains chelating agen (disodiumedetate) is for up to more than 24 hours, and contains dimethyl acetylamide control formulation dispersion stable deficiency of time 6 hours; Estimate from the outward appearance angle, preparation dispersion liquid of the present invention does not have the oil spill phenomenon, and it is more serious to contain dimethyl acetylamide control formulation dispersion liquid oil spill, and a large amount of oil stain wall built-ups are arranged, beyond thought this problem that solved of the adding of chelating agen.As seen preparation scheme of the present invention is compared with the contrast patent has significant advantage and beyond thought effect.To contain chelating agen be the feature that the present invention has substantive excellent results so further embodied.
4, contain the present invention and the contrast test that contains oleic acid patent working scheme of chelating agen (ethylenediaminetetraacetic acid)
(Chinese patent: show 200680007345.3) that this patent mainly is to have added oleic acid on the basis of PEG400, its consumption is 0.01-5% in publication.With reference to its embodiment, prepare 0.3%, 1.0%, 5.0% oleic acid PEG400 solution respectively; Be the paclitaxel solution of 25 mg/ml, solution in contrast with its preparation content of taxol respectively then; According to embodiment 19 described embodiment compounding pharmaceutical solution, get test solution; Draw 4 milliliters of above-mentioned contrast solutions, test solution respectively, be dispersed in respectively in embodiment 19 described 100 milliliters of commercially available Emulsions, shake up, get specimen.Use high performance liquid chromatograph, measure the medicament contg of this dispersion liquid respectively in different time points; When measuring content, extract the microporous filter membrane that an amount of dispersion liquid is crossed 0.45 μ m with syringe earlier, measure the content of filtrate Chinese medicine, calculate the sign percentage composition, estimate medicine with this content and whether separate out crystallization; And the perusal outward appearance sees Table 6.
Table 6 contains the preparation dispersion liquid of the present invention and the study on the stability (disperseing Emulsion is commercially available Emulsion) that contains oleic acid contrast proprietary preparation dispersion liquid of chelating agen (ethylenediaminetetraacetic acid)
Interpretation of result:
Draw by test, in identical commercially available Emulsion disperse medium, the dispersion stable of the present composition that contains chelating agen (ethylenediaminetetraacetic acid) is for up to more than 20 hours, and contains oleic acid control formulation dispersion stable deficiency of time 6 hours, and along with oleic increase stability reduces; Estimate from the outward appearance angle, dispersion liquid of the present invention does not have the oil spill phenomenon, and it is more serious to contain serial oleic contrast proprietary preparation dispersion liquid oil spill, and a large amount of oil stain wall built-ups are arranged, beyond thought this problem that solved of the adding of chelating agen.As seen preparation scheme of the present invention is compared with the contrast patent has significant advantage and beyond thought effect.To contain chelating agen be the feature that the present invention has substantive excellent results so further embodied.
5, contain the present invention and the contrast test that contains surfactant patent working scheme of chelating agen (citric acid)
At publication (Chinese patent: show 200410025522.3), this patent mainly is made up of paclitaxel, Tween 80, polyvidone, lecithin, solvent for injection, the embodiment close with the present invention is embodiment 3, i.e. paclitaxel 1.8g, phosphatidase 12 2g, propylene glycol 40g, dehydrated alcohol to 100 milliliter.According to this scheme compounding pharmaceutical solution, solution in contrast; According to embodiment 20 described embodiment compounding pharmaceutical solution, get test solution; Draw 4 milliliters of above-mentioned contrast solutions, test solution respectively, be dispersed in respectively in embodiment 20 described 100 milliliters of commercially available Emulsions, shake up, get specimen.Use high performance liquid chromatograph, measure the medicament contg of this dispersion liquid respectively in different time points; When measuring content, extract the microporous filter membrane that an amount of dispersion liquid is crossed 0.45 μ m with syringe earlier, measure the content of filtrate Chinese medicine, calculate the sign percentage composition, estimate medicine with this content and whether separate out crystallization; And the perusal outward appearance the results are shown in Table 7.
Table 7 contains the preparation dispersion liquid of the present invention and the study on the stability (disperseing Emulsion is commercially available Emulsion) that contains surfactant contrast proprietary preparation dispersion liquid of chelating agen (citric acid)
Interpretation of result:
Drawn by test, in identical commercially available Emulsion disperse medium, the dispersion stable of the present composition that contains chelating agen (citric acid) is for up to more than 20 hours, and contains surfactant contrast proprietary preparation dispersion stable deficiency of time 8 hours; Estimate from the outward appearance angle, present composition dispersion liquid does not have the oil spill phenomenon, and it is more serious to contain the contrast proprietary preparation dispersion liquid oil spill of surfactant, a large amount of oil stain wall built-ups is arranged, beyond thought this problem that solved of the adding of chelating agen.As seen preparation scheme of the present invention is compared with the contrast patent has significant advantage and beyond thought effect.To contain chelating agen be the feature that the present invention has substantive excellent results so further embodied.
Advantage of the present invention is:
1. safety is good: do not contain any solubilizing agent with toxic and side effects, as polyoxyethylene castor oil, tween 80, dimethyl acetylamide, oleic acid, polyvidone etc., wherein polyoxyethylene castor oil, tween 80 have serious haemolysis and anaphylaxis, and safety is relatively poor; The oral LD of dimethyl acetylamide mice
50Be 4.620g/kg, and solvent for injection preferred for this invention is a PEG400, nontoxic, nonirritant, the oral LD of its mice
50Up to 28.9g/kg, LD on year-on-year basis
50Be 6.3 times of dimethyl acetylamide, so PEG400 is a kind of safe solvent for injection; R.C. sieve etc. (pharmaceutic adjuvant handbook [M]. original work the 4th edition: show that 476) oleic acid can cause breaking of erythrocyte, promptly have hemolytic, only allow to be used for non-injection in Britain.So not containing the solubilizing agent with toxic and side effects in the preparation of the present invention also is a spotlight of the present invention;
2. good stability: adopt the dispersion stability of solution of the present invention to obtain improving greatly, prolonged the stabilization time of dispersion liquid significantly, and the beyond thought deficiency that overcomes the dispersion liquid oil spill, further improved dispersion stability.
The specific embodiment
In order further to embody substantive advantage of the present invention and beyond thought effect, we will realize by following embodiment, but be not limited to following embodiment.
Embodiment 1 paclitaxel injection and assembly packaging
The preparation of drug solution:
Take by weighing paclitaxel 2.5 grams, citric acid 0.5 gram, join in an amount of PEG400,85 ℃ add the hot shearing dissolving, are settled to 100 milliliters with PEG400 then; The needle-use activated carbon that adds 0.3 gram, absorption is 30 minutes under 25 ℃ temperature, filters with bag type filter then, and packing is sealed, and with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 15 minutes, promptly gets paclitaxel solution.
The preparation of Emulsion:
Take by weighing injection soybean oil 100 gram, hot tricaprin 100 grams, heating in water bath to 80 ℃ adds injection soybean phospholipid 20 grams, shear and make dissolving, stirring and evenly mixing, oil phase; Measure 740 milliliters of waters for injection, add 10 gram poloxamers 188, glycerol 22.5 grams, stir and make dissolving, be heated to 80 ℃ and get water; Oil phase and water are mixed under 80 ℃ of temperature,, get colostrum with emulsification pretreatment device emulsifying 10 minutes (15000 rev/mins of rotating speeds); With the further emulsifying of high pressure homogenizer (pressure 12000psi), water for injection is quantitatively to 1000 milliliters with colostrum, and regulating its pH with sodium hydroxide solution is 7.86, filter with bag type filter, nitrogen is filled in packing, seal,, obtain Emulsion with 121 ℃ of sterilizations of rotating type high-pressure steam kettle 15 minutes.After measured, its mean diameter is 148nm, and pH is 7.12.
Above paclitaxel solution and medicinal Emulsion are potted in respectively in plastic bottle or the vial, and two kinds of medicines are packaged in the same big packing container with 1: 1 ratio assembly packaging together.
In use, paclitaxel solution and Emulsion are 1: 25 ratio by volume, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip also can add normal saline or glucose solution and be used for injection.
Embodiment 2 Docetaxel injection and assembly packagings
The preparation of drug solution:
Take by weighing Docetaxel 2.5 grams, join in an amount of PEG400,90 ℃ add the hot shearing dissolving, are settled to 100 milliliters with PEG400 then; The needle-use activated carbon that adds 0.3 gram, absorption is 30 minutes under 25 ℃ temperature, uses filtering with microporous membrane then, and packing is sealed, and with 115 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 30 minutes, promptly gets Docetaxel solution.
The preparation of Emulsion:
Take by weighing injection soybean oil 100 gram, hot tricaprin 100 grams, heating in water bath to 80 ℃ adds injection soybean phospholipid 20 grams, shear and make dissolving, stirring and evenly mixing, oil phase; Measure 740 milliliters of waters for injection, adding disodiumedetate 0.5 gram, 10 gram poloxamers 188, glycerol 22.5 grams stir and make dissolving, are heated to 80 ℃ and get water; Oil phase and water are mixed under 80 ℃ of temperature,, get colostrum with emulsification pretreatment device emulsifying 8 minutes (20000 rev/mins of rotating speeds); With the further emulsifying of high pressure homogenizer (pressure 12000psi), water for injection is quantitatively to 1000 milliliters with colostrum, and regulating its pH with sodium hydroxide solution is 7.56, filter with bag type filter, nitrogen is filled in packing, seal,, get Emulsion with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 15 minutes.After measured, its mean diameter is 140nm, and pH is 7.04.
Above Docetaxel solution and Emulsion are potted in respectively in plastic bottle or the vial, and two kinds of medicines are packaged in the same big packing container with 1: 1 ratio assembly packaging together.
During administration, drug solution and Emulsion are 1: 25 ratio by volume, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 3 paclitaxel injections and assembly packaging
The preparation of drug solution:
Take by weighing paclitaxel 2.0 grams, join in the 90 gram PEG400s, 90 ℃ of heated and stirred dissolvings get paclitaxel solution; Take by weighing disodiumedetate 1.2 grams, it is dissolved, get chelating agent solution with 10 gram waters for injection; With chelating agent solution and drug solution mix homogeneously, be settled to 100 milliliters with PEG400; The needle-use activated carbon that adds 0.8 gram, absorption is 120 minutes under 30 ℃ temperature, uses filtering with microporous membrane then, and packing is sealed, and with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 8 minutes, promptly gets paclitaxel solution.
The preparation of Emulsion:
Take by weighing soybean oil 150 gram, hot tricaprin 150 grams, mix, heating in water bath to 60 ℃ adds injection egg yolk lecithin 12 grams, shear and make dissolving, oil phase; Measure 600 milliliters of waters for injection, add glycerol 25 grams, stir and make dissolving, be heated to 60 ℃ and get water; Oil phase and water are mixed under 60 ℃ of temperature,, get colostrum with emulsification pretreatment device emulsifying 30 minutes (6000 rev/mins of rotating speeds); With the further emulsifying of high pressure homogenizer (pressure 22000psi), water for injection is quantitatively to 1000 milliliters with colostrum, and regulating its pH with sodium hydroxide solution is 8.00, filter with bag type filter, nitrogen is filled in packing, seal,, promptly get Emulsion with 115 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 30 minutes.After measured, its mean diameter is 284.2nm, and pH is 7.64.
Above paclitaxel solution and Emulsion are potted in respectively in plastic bottle or the vial, and two kinds of medicines are packaged in the same big packing container with 1: 1 ratio assembly packaging together.
During administration, drug solution and Emulsion are 1: 20 ratio by volume, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 4 Docetaxel injection and assembly packagings
The preparation of drug solution:
Take by weighing Docetaxel 2.5 grams, citric acid 0.3 gram, join in an amount of PEG400,90 ℃ add the hot shearing dissolving, are settled to 100 milliliters with PEG400 then; The needle-use activated carbon that adds 0.3 gram, absorption is 45 minutes under 25 ℃ temperature, filters with bag type filter then, and with 0.22 μ m filtering with microporous membrane degerming, packing is sealed, and promptly gets Docetaxel solution.
The preparation of Emulsion:
Take by weighing injection soybean oil 200 gram, heating in water bath to 80 ℃ adds injection soybean phospholipid 20 grams, stir make dissolve oil phase; Measure 700 milliliters of waters for injection, add 10 gram poloxamers 188, glycerol 22.5 grams, stir and make dissolving, be heated to 80 ℃ and get water; Oil phase and water are mixed under 80 ℃ of temperature,, get colostrum with emulsification pretreatment device emulsifying 15 minutes (10000 rev/mins of rotating speeds); With the further emulsifying of high pressure homogenizer (pressure 15000psi), water for injection is quantitatively to 1000 milliliters with colostrum, and regulating its pH with sodium hydroxide solution is 8.53, use filtering with microporous membrane, nitrogen is filled in packing, seal,, get Emulsion with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 15 minutes.After measured, its mean diameter is 181nm, and pH is 8.01.
Above Docetaxel solution and Emulsion are potted in respectively in plastic bottle or the vial, and two kinds of medicines are packaged in the same big packing container with 1: 1 ratio assembly packaging together.
During administration, drug solution and Emulsion are 1: 25 ratio by volume, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 5 paclitaxel injections and assembly packaging
The preparation of drug solution:
Take by weighing paclitaxel 1.5 grams, ethylenediaminetetraacetic acid 0.05 gram, join in an amount of PEG400,90 ℃ add the hot shearing dissolving, are settled to 100 milliliters with PEG400 then; The needle-use activated carbon that adds 1.0 grams, absorption is 20 minutes under 50 ℃ temperature, filters with husky filter stick then, and packing is sealed, and 100 ℃ of sterilizations of flowing steam 45 minutes promptly get paclitaxel solution.
The preparation of Emulsion:
Take by weighing soybean oil 75 gram, hot tricaprin 75 grams, heating in water bath to 60 ℃, oil phase; Measure 750 milliliters of waters for injection, add egg yolk lecithin 12 grams, glycerol 22.5 grams, stir and make homodisperse, be heated to 60 ℃ and get water.Oil phase and water are mixed under 60 ℃ of temperature, with emulsification pretreatment device emulsifying 20 minutes (5000 rev/mins of rotating speeds), colostrum, with colostrum with the further emulsifying of high pressure homogenizer (pressure 12000psi), water for injection is quantitatively to 1000 milliliters, regulating its pH with sodium hydroxide solution is 7.50, filters packing with bag type filter, fill nitrogen, seal,, promptly get Emulsion with 115 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 30 minutes.After measured, its mean diameter is 214.5nm, and pH is 6.84.
Above paclitaxel solution and Emulsion are potted in respectively in plastic bottle or the vial, and two kinds of medicines are packaged in the same big packing container with 1: 1 ratio assembly packaging together.
During administration, drug solution and Emulsion are 1: 80 ratio by volume, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 6 Docetaxel injection and assembly packagings
The preparation of drug solution:
Take by weighing Docetaxel 6 grams, citric acid 0.7 gram, join in the mixed solution of 80 gram PEG400s, 10 gram dehydrated alcohol, 80 ℃ of heated and stirred dissolvings are settled to 100 milliliters with PEG400 then; The needle-use activated carbon that adds 0.5 gram, absorption is 45 minutes under 25 ℃ temperature, filters with bag type filter then, and packing is sealed, and with 115 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 30 minutes, promptly gets Docetaxel solution.
The preparation of Emulsion:
Take by weighing injection soybean oil 50 gram, Oleum Bulbus Allii 50 grams, heating in water bath to 70 ℃ adds injection egg yolk lecithin 12 grams, shears dissolving, oil phase; Measure 850 milliliters of waters for injection, add glycerol 22.5 grams, stir and make dissolving, be heated to 70 ℃ and get water; Oil phase and water are mixed under 70 ℃ of temperature,, get colostrum with emulsification pretreatment device emulsifying 5 minutes (30000 rev/mins of rotating speeds); With the further emulsifying of high pressure homogenizer (pressure 20000psi), water for injection is quantitatively to 1000 milliliters with colostrum, and regulating its pH with sodium hydroxide solution is 8.25, use filtering with microporous membrane, nitrogen is filled in packing, seal,, get Emulsion with 117 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 20 minutes.After measured, its mean diameter is 175.6nm, and pH is 7.53.
Above Docetaxel solution and Emulsion are potted in respectively in plastic bottle or the vial, and two kinds of medicines are packaged in the same big packing container with 1: 1 ratio assembly packaging together.
During administration, drug solution and Emulsion are 1: 90 ratio by volume, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 7 paclitaxel injections and assembly packaging
The preparation of drug solution:
Take by weighing paclitaxel 7.0 grams, add 80 gram PEG400s, 85 ℃ add the hot shearing dissolving, are settled to 100 milliliters with PEG400 then; The needle-use activated carbon that adds 2 grams, absorption is 70 minutes under 30 ℃ temperature, filters with bag type filter then, and packing is sealed, and 100 ℃ of sterilizations of flowing steam 45 minutes promptly get paclitaxel solution.
The preparation of Emulsion:
Sad monoglyceride 100 grams, fish oil 50 grams, Oleum sesami 50 grams, tocopherol 3.0 grams mix, heating in water bath to 83 ℃, stirring and evenly mixing, oil phase; Measure 700 milliliters of waters for injection, adding disodiumedetate 0.8 gram, glycerol 22.5 restrain, Ovum Gallus domesticus Flavus lecithin 20 restrains, dimyristoyl phosphatidyl choline (DMPC) 15 grams, and shearing disperses, and is heated to 83 ℃, gets water; Oil phase and water are mixed under 83 ℃ of temperature,, get colostrum with emulsification pretreatment device emulsifying 27 minutes (8000 rev/mins of rotating speeds); With the further emulsifying of high pressure homogenizer (pressure 21000psi), water for injection is quantitatively to 1000 milliliters with colostrum, and regulating its pH with sodium hydroxide solution is 7.56, use filtering with microporous membrane, nitrogen is filled in packing, seal,, get Emulsion with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 15 minutes.After measured, its mean diameter is 261nm, and pH is 7.05.
Above paclitaxel solution and Emulsion are potted in respectively in plastic bottle or the vial, and two kinds of medicines are packaged in the same big packing container with 1: 1 ratio assembly packaging together.
During administration, drug solution and Emulsion are 1: 40 ratio by volume, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 8 Docetaxel injection and assembly packagings
The preparation of drug solution:
Take by weighing Docetaxel 2.5 grams, join in the mixed solvent of 60 gram dehydrated alcohol, 20 gram Macrogol 200s, 10 gram propylene glycol, 55 ℃ of heated and stirred dissolvings are settled to 100 milliliters with dehydrated alcohol then; The needle-use activated carbon that adds 0.6 gram, absorption is 50 minutes under 55 ℃ temperature, filters with bag type filter then, and packing is sealed, and with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 15 minutes, promptly gets Docetaxel solution.
The preparation of Emulsion:
Take by weighing Semen Coicis oil 25 gram, Oleum Fructus Bruceae 25 grams, mix, heating in water bath to 80 ℃, stirring and evenly mixing, oil phase; Measure 900 milliliters of waters for injection, adding egg yolk lecithin 10 grams, DSPE (DSPE) 2 restrain, disodiumedetate 0.5 restrains, glycerol 22.5 grams, and shearing disperses, and is heated to 60 ℃ and gets water; Oil phase and water are mixed under 60 ℃ of temperature, with emulsification pretreatment device emulsifying 13 minutes (20000 rev/mins of rotating speeds), colostrum, with colostrum with the further emulsifying of high pressure homogenizer (pressure 20000psi), water for injection is settled to 1000 milliliters, regulating its pH with sodium hydroxide solution is 7.14, filters packing with bag type filter, fill nitrogen, seal,, promptly get Emulsion with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization pot sterilization 15 minutes.After measured, its mean diameter is 134.5nm, and pH is 6.40.
Above Docetaxel solution and Emulsion are potted in respectively in plastic bottle or the vial, and two kinds of medicines are packaged in the same big packing container with 1: 1 ratio assembly packaging together.
During administration, drug solution and Emulsion are 1: 50 ratio by volume, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 9 paclitaxel injections and assembly packaging
The preparation of drug solution:
Take by weighing paclitaxel 8 grams, ethylenediaminetetraacetic acid 0.3 gram, add in the mixed solvent of an amount of PEG400 and dehydrated alcohol, 70 ℃ add the hot shearing dissolving, are settled to 100 milliliters with dehydrated alcohol then; The needle-use activated carbon that adds 1.5 grams, absorption is 90 minutes under 25 ℃ temperature, filters with bag type filter then, and packing is sealed, and 100 ℃ of sterilizations of flowing steam 45 minutes promptly get paclitaxel solution.
The preparation of Emulsion:
Take by weighing Oleum Curcumae 10 gram, Oleum Helianthi 90 grams, capric acid monoglyceride 25 grams, Sunfat GDC-S 25 grams, tocopherol 0.5 gram, mix, heating in water bath to 60 ℃, stirring and evenly mixing, oil phase; Measure 800 milliliters of waters for injection, adding dipalmitoyl phosphatidyl choline (DPPC) 6 restrains, distearoyl phosphatidylcholine (DSPC) 4 restrains, glycerol 25 grams, shears dispersion, is heated to 70 ℃, gets water; Oil phase and water are mixed under 60 ℃ of temperature, with emulsification pretreatment device emulsifying 6 minutes (30000 rev/mins of rotating speeds), colostrum, with colostrum with the further emulsifying of high pressure homogenizer (pressure 10000psi), water for injection is settled to 1000 milliliters, regulating its pH with sodium hydroxide solution is 8.10, uses filtering with microporous membrane, packing, fill nitrogen, seal,, promptly get Emulsion with 115 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 30 minutes.After measured, its mean diameter is 250nm, and pH is 7.46.
Above paclitaxel solution and Emulsion are potted in respectively in plastic bottle or the vial, and two kinds of medicines are packaged in the same big packing container with 1: 1 ratio assembly packaging together.
During administration, drug solution and Emulsion are 1: 90 ratio by volume, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 10 Docetaxel injection and assembly packagings
The preparation of drug solution:
Take by weighing Docetaxel 6 grams, malic acid 2.5 grams, join in the mixed solvent of 50 gram Macrogol 200s, 35 gram Macrogol 600s, 75 ℃ add the hot shearing dissolving, are settled to 100 milliliters with Macrogol 600 then; The needle-use activated carbon that adds 0.05 gram, absorption is 120 minutes under 25 ℃ temperature, filters with bag type filter then, and packing is sealed, and 100 ℃ of sterilizations of flowing steam 45 minutes promptly get Docetaxel solution.
The preparation of Emulsion:
Take by weighing hot capric acid diglyceride 100 grams, elemene oil 30 grams, safflower oil 34 grams, Trivent OCG 36 grams, tocopherol 5.0 grams, heating in water bath to 75 ℃, add injection soybean phospholipid 2.0 grams, dioleoyl phospholipid phatidylcholine (DOPC) 3.0 grams, palmityl oleoyl phosphatidylcholine (POPC) 1.0 grams, stirring makes dissolving, gets oil phase; Measure 730 milliliters of waters for injection, add glycerol 21.0 grams, be heated to 75 ℃, stir and make dissolving, get water; Oil phase and water are mixed under 75 ℃ of temperature, stirring and emulsifying 25 minutes, colostrum, with colostrum with the further emulsifying of high pressure homogenizer (pressure 15000psi), water for injection is settled to 1000 milliliters, regulating its pH with sodium hydroxide solution is 7.04, filters packing with sintered filter funnel, fill nitrogen, seal,, promptly get Emulsion with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 10 minutes.After measured, its mean diameter is 219nm, and pH is 6.58.
Above Docetaxel solution and Emulsion are potted in respectively in plastic bottle or the vial, and two kinds of medicines are packaged in the same big packing container with 1: 1 ratio assembly packaging together.
During administration, drug solution and Emulsion are 1: 80 ratio by volume, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 11 paclitaxel injections and assembly packaging
The preparation of drug solution:
Take by weighing paclitaxel 2.5 grams, citric acid 0.05 gram, join in an amount of PEG400,85 ℃ add the hot shearing dissolving, are settled to 100 milliliters with PEG400 then; The needle-use activated carbon that adds 0.2 gram, absorption is 30 minutes under 25 ℃ temperature, uses filtering with microporous membrane then, and packing is sealed, and with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 30 minutes, promptly gets paclitaxel solution.
The preparation of Emulsion:
Take by weighing Herba Artemisiae Annuae oil 10 gram, Semen Maydis oil 100 grams, heating in water bath to 60 ℃ adds injection soybean phospholipid 20 grams, shear and make dissolving, stirring and evenly mixing, oil phase; Measure 810 milliliters of waters for injection, add glycerol 25.0 grams, stir and make dissolving, be heated to 60 ℃ and get water; Oil phase and water are mixed under 60 ℃ of temperature,, get colostrum with emulsification pretreatment device emulsifying 15 minutes (23000 rev/mins of rotating speeds); With the further emulsifying of high pressure homogenizer (pressure 15000psi), water for injection is quantitatively to 1000 milliliters with colostrum, and regulating its pH with sodium hydroxide solution is 6.88, use filtering with microporous membrane, nitrogen is filled in packing, seal,, get Emulsion with 115 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 45 minutes.After measured, its mean diameter is 232nm, and pH is 6.56.
Above paclitaxel solution and Emulsion are potted in respectively in plastic bottle or the vial, and two kinds of medicines are packaged in the same big packing container with 1: 1 ratio assembly packaging together.
During administration, drug solution and Emulsion are 1: 30 ratio by volume, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 12 Docetaxel injection and assembly packagings
The preparation of drug solution:
Take by weighing Docetaxel 4.0 grams, join in the 80 gram PEG400s, 95 ℃ of heated and stirred dissolvings get Docetaxel solution; Take by weighing disodiumedetate 0.8 gram, it is dissolved, get chelating agent solution with 8 gram waters for injection; With chelating agent solution and Docetaxel solution mix homogeneously, be settled to 100 milliliters with PEG400; The needle-use activated carbon that adds 1.0 grams, absorption is 20 minutes under 60 ℃ temperature, uses filtering with microporous membrane then, and packing is sealed, and with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 12 minutes, promptly gets Docetaxel solution.
The preparation of Emulsion:
Take by weighing hot tricaprin 50 grams of injection, soybean oil 20 grams, Ganoderma spore oil 30 grams, heating in water bath to 70 ℃ adds injection egg yolk lecithin 12 grams, shear and make dissolving, stirring and evenly mixing, oil phase; Measure 850 milliliters of waters for injection, add glycerol 22.5 grams, stir and make dissolving, be heated to 75 ℃ and get water; Oil phase and water are mixed under 75 ℃ of temperature,, get colostrum with emulsification pretreatment device emulsifying 10 minutes (12000 rev/mins of rotating speeds); With the further emulsifying of high pressure homogenizer (pressure 15000psi), water for injection is quantitatively to 1000 milliliters with colostrum, and regulating its pH with sodium hydroxide solution is 7.81, use filtering with microporous membrane, nitrogen is filled in packing, seal,, get Emulsion with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 10 minutes.After measured, its mean diameter is 208nm, and pH is 7.15.
Above Docetaxel solution and Emulsion are potted in respectively in plastic bottle or the vial, and two kinds of medicines are packaged in the same big packing container with 1: 1 ratio assembly packaging together.
During administration, drug solution and Emulsion are 1: 70 ratio by volume, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 13 paclitaxel injections and assembly packaging
The preparation of drug solution:
Take by weighing paclitaxel 2.5 grams, citric acid 0.2 gram, join in an amount of PEG400,88 ℃ add the hot shearing dissolving, are settled to 100 milliliters with PEG400 then; The needle-use activated carbon that adds 0.3 gram, absorption is 15 minutes under 25 ℃ temperature, filters with bag type filter then, and packing is sealed, and with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 15 minutes, promptly gets paclitaxel solution.
The preparation of Emulsion:
Take by weighing injection soybean oil 50 gram, hot tricaprin 50 grams, heating in water bath to 55 ℃ adds injection Ovum Gallus domesticus Flavus lecithin 12 grams, shear and make dissolving, stirring and evenly mixing, oil phase; Measure 800 milliliters of waters for injection, add glycerol 22.5 grams, stir and make dissolving, be heated to 55 ℃ and get water; Oil phase and water are mixed under 55 ℃ of temperature,, get colostrum with emulsification pretreatment device emulsifying 15 minutes (22000 rev/mins of rotating speeds); With the further emulsifying of high pressure homogenizer (pressure 20000psi), water for injection is quantitatively to 1000 milliliters with colostrum, and regulating its pH with sodium hydroxide solution is 6.54, filter with bag type filter, nitrogen is filled in packing, seal,, get Emulsion with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 12 minutes.After measured, its mean diameter is 179nm, and pH is 6.00.
Above paclitaxel solution and Emulsion are potted in respectively in plastic bottle or the vial, and two kinds of medicines are packaged in the same big packing container with 1: 1 ratio assembly packaging together.
During administration, drug solution and Emulsion are 1: 50 ratio by volume, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 14 Docetaxel injection and assembly packagings
The preparation of drug solution:
Take by weighing Docetaxel 4.0 grams, ethylenediaminetetraacetic acid 0.3 gram, join in an amount of PEG400,85 ℃ add the hot shearing dissolving, are settled to 100 milliliters with PEG400 then; The needle-use activated carbon that adds 0.1 gram, absorption is 80 minutes under 25 ℃ temperature, filters with bag type filter then, and packing is sealed, and with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 15 minutes, promptly gets Docetaxel solution.
The preparation of Emulsion:
Take by weighing injection soybean oil 100 gram, hot tricaprin 100 grams, heating in water bath to 70 ℃ adds injection egg yolk lecithin 1.2 grams, shear and make dissolving, stirring and evenly mixing, oil phase; Measure 750 milliliters of waters for injection, add glycerol 22.5 grams, stir and make dissolving, be heated to 70 ℃ and get water; Oil phase and water are mixed under 70 ℃ of temperature,, get colostrum with emulsification pretreatment device emulsifying 10 minutes (18000 rev/mins of rotating speeds); With the further emulsifying of high pressure homogenizer (pressure 17000psi), water for injection is quantitatively to 1000 milliliters with colostrum, and regulating its pH with sodium hydroxide solution is 6.50, use filtering with microporous membrane, nitrogen is filled in packing, seal,, get Emulsion with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization 12 minutes.After measured, its mean diameter is 227nm, and pH is 6.01.
Above Docetaxel solution and Emulsion are potted in respectively in plastic bottle or the vial, and two kinds of medicines are packaged in the same big packing container with 1: 1 ratio assembly packaging together.
During administration, drug solution and Emulsion are 1: 60 ratio by volume, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 15 paclitaxel injections and assembly packaging
The preparation of drug solution:
Take by weighing paclitaxel 6.0 grams, citric acid 1.5 grams, join in an amount of PEG400,84 ℃ add the hot shearing dissolving, are settled to 100 milliliters with PEG400 then; The needle-use activated carbon that adds 2 grams, absorption is 30 minutes under 25 ℃ temperature, uses filtering with microporous membrane then, packing, 100 ℃ of sterilizations of flowing steam 45 minutes promptly get paclitaxel solution.
The preparation of Emulsion:
Take by weighing hot tricaprin 150 grams of injection, soybean oil 150 grams, heating in water bath to 75 ℃ adds injection egg yolk lecithin 20 grams, shear and make dissolving, stirring and evenly mixing, oil phase; Measure 650 milliliters of waters for injection, add 10 gram poloxamers 188, glycerol 22.5 grams, stir and make dissolving, be heated to 75 ℃ and get water; Oil phase and water are mixed under 75 ℃ of temperature,, get colostrum with emulsification pretreatment device emulsifying 16 minutes (11000 rev/mins of rotating speeds); With the further emulsifying of high pressure homogenizer (pressure 20000psi), water for injection is quantitatively to 1000 milliliters with colostrum, and regulating its pH with sodium hydroxide solution is 7.50, filter with bag type filter, nitrogen is filled in packing, seal,, get Emulsion with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 15 minutes.After measured, its mean diameter is 400nm, and pH is 7.03.
Above paclitaxel solution and Emulsion are potted in respectively in plastic bottle or the vial, and two kinds of medicines are packaged in the same big packing container with 1: 1 ratio assembly packaging together.
During administration, drug solution and Emulsion are 1: 60 ratio by volume, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 16 Docetaxel injection and assembly packagings
The preparation of drug solution:
Take by weighing Docetaxel 4.0 grams, ethylenediaminetetraacetic acid 0.05 gram, join in an amount of PEG400,95 ℃ of heated and stirred dissolvings are settled to 100 milliliters with PEG400; The needle-use activated carbon that adds 1.0 grams, absorption is 30 minutes under 25 ℃ temperature, uses filtering with microporous membrane, uses 0.22 μ m membrane filtration degerming then, and packing is sealed, and promptly gets Docetaxel solution.
The preparation of Emulsion:
Take by weighing injection soybean oil 100 gram, heating in water bath to 70 ℃ adds injection egg yolk lecithin 12 grams, shear and make dissolving, stirring and evenly mixing, oil phase; Measure 850 milliliters of waters for injection, add glycerol 22.5 grams, stir and make dissolving, be heated to 75 ℃ and get water; Oil phase and water are mixed under 75 ℃ of temperature,, get colostrum with emulsification pretreatment device emulsifying 10 minutes (12000 rev/mins of rotating speeds); With the further emulsifying of high pressure homogenizer (pressure 17000psi), water for injection is quantitatively to 1000 milliliters with colostrum, and regulating its pH with sodium hydroxide solution is 6.88, filter with bag type filter, nitrogen is filled in packing, seal,, get Emulsion with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 10 minutes.After measured, its mean diameter is 194nm, and pH is 6.58.
Above Docetaxel solution and Emulsion are potted in respectively in plastic bottle or the vial, and two kinds of medicines are packaged in the same big packing container with 1: 1 ratio assembly packaging together.
During administration, drug solution and Emulsion are 1: 40 ratio by volume, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 17 paclitaxel injections
The preparation of drug solution:
Take by weighing paclitaxel 4.0 grams, join in the 90 gram PEG400s, 85 ℃ of heated and stirred dissolvings get paclitaxel solution; Take by weighing disodiumedetate 0.5 gram, it is dissolved, get chelating agent solution with 10 gram waters for injection; With chelating agent solution and drug solution mix homogeneously, be settled to 100 milliliters with PEG400; The needle-use activated carbon that adds 0.5 gram, absorption is 45 minutes under 25 ℃ temperature, uses filtering with microporous membrane then, and packing is sealed, and with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 15 minutes, promptly gets paclitaxel solution.
Commercially available Emulsion: [specification]: 250 milliliters: in 20%/long-chain fat Emulsion, [lot number]: 80BM072, [manufacturer]: Huarui Pharmaceutical Co. Ltd.
During administration, drug solution and commercially available Emulsion volume ratio are 1: 15 ratio, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 18 paclitaxel injections
The preparation of drug solution:
Take by weighing paclitaxel 2.5 grams, join in an amount of PEG400,80 ℃ add the hot shearing dissolving, take by weighing disodiumedetate 0.5 gram, with 10 gram waters for injection it are dissolved, and get chelating agent solution; With chelating agent solution and drug solution mix homogeneously, be settled to 100 milliliters with PEG400; The needle-use activated carbon that adds 0.5 gram, absorption is 45 minutes under 25 ℃ temperature, uses filtering with microporous membrane then, and packing is sealed, and with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 15 minutes, promptly gets paclitaxel solution.
Commercially available Emulsion: [specification]: 100 milliliters: in 20%/long-chain fat Emulsion, [lot number]: GM0809034, [manufacturer]: Guangzhou Baite Jiaoguang Medical Product Co., Ltd
During administration, drug solution and commercially available Emulsion volume ratio are 1: 25 ratio, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 19 paclitaxel injections
The preparation of drug solution:
Take by weighing paclitaxel 2.5 grams, ethylenediaminetetraacetic acid 0.1 gram, join in an amount of PEG400,85 ℃ of heated and stirred dissolvings are settled to 100 milliliters with PEG400; The needle-use activated carbon that adds 0.5 gram, absorption is 45 minutes under 25 ℃ temperature, uses filtering with microporous membrane then, and packing is sealed, and with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 12 minutes, promptly gets paclitaxel solution.
Commercially available Emulsion: [specification]: 100 milliliters: in 20%/long-chain fat Emulsion, [lot number]: GM0809034, [manufacturer]: Guangzhou Baite Jiaoguang Medical Product Co., Ltd
During administration, drug solution and commercially available Emulsion volume ratio are 1: 25 ratio, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 20 paclitaxel injections
The preparation of drug solution:
Take by weighing paclitaxel 2.5 grams, citric acid 0.3 gram, join in an amount of PEG400,85 ℃ add the hot shearing dissolving, are settled to 100 milliliters with PEG400 then; The needle-use activated carbon that adds 0.3 gram, absorption is 30 minutes under 25 ℃ temperature, filters with bag type filter then, and packing is sealed, and with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 15 minutes, promptly gets paclitaxel solution.
Commercially available Emulsion: [specification]: 100 milliliters: in 20%/long-chain fat Emulsion, [lot number]: GM0809034, [manufacturer]: Guangzhou Baite Jiaoguang Medical Product Co., Ltd
During administration, drug solution and commercially available Emulsion volume ratio are 1: 25 ratio, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 21 paclitaxel injections
The preparation of drug solution:
Take by weighing paclitaxel 3.0 grams, ethylenediaminetetraacetic acid 0.8 gram, join in an amount of PEG400,75 ℃ add the hot shearing dissolving, are settled to 100 milliliters with PEG400 then; The needle-use activated carbon that adds 1.0 grams, absorption is 15 minutes under 60 ℃ temperature, filters with bag type filter then, and packing is sealed, and with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 15 minutes, promptly gets paclitaxel solution.
Commercially available Emulsion: [specification]: 250 milliliters: 20% long-chain fat Emulsion, [lot number]: F090203C2, [manufacturer]: Kelun Pharm Ind Co., Ltd., Sichuan
During administration, drug solution and commercially available Emulsion volume ratio are 1: 60 ratio, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 22 paclitaxel injections
The preparation of drug solution:
Take by weighing paclitaxel 2.5 grams, ethylenediaminetetraacetic acid 0.5 gram, join in an amount of PEG400,80 ℃ add the hot shearing dissolving, are settled to 100 milliliters with PEG400 then; The needle-use activated carbon that adds 2.0 grams, absorption is 15 minutes under 25 ℃ temperature, uses filtering with microporous membrane then, and packing is sealed, and with 115 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 30 minutes, promptly gets paclitaxel solution.
Commercially available Emulsion: [specification]: 250 milliliters: in 20%/long-chain fat Emulsion, [lot number]: F090203C2, [manufacturer]: Kelun Pharm Ind Co., Ltd., Sichuan
During administration, drug solution and commercially available Emulsion volume ratio are 1: 25 ratio, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 23 paclitaxel injections
The preparation of drug solution:
Take by weighing paclitaxel 6.0 grams, citric acid 2.0 grams, join in an amount of PEG400,80 ℃ add the hot shearing dissolving, are settled to 100 milliliters with PEG400 then; The needle-use activated carbon that adds 1.2 grams, absorption is 20 minutes under 25 ℃ temperature, uses filtering with microporous membrane then, and packing is sealed, and 100 ℃ of sterilizations of flowing steam 45 minutes promptly get paclitaxel solution.
Commercially available Emulsion: [specification]: 250 milliliters: 20% long-chain fat Emulsion, [lot number]: 0811212-1, [manufacturer]: Zhejiang Kanglaite Pharmaceutical Co., Ltd
During administration, drug solution and commercially available Emulsion volume ratio are 1: 100 ratio, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 24 Docetaxel injections
The preparation of drug solution:
Take by weighing Docetaxel 2.5 grams, citric acid 1.4 grams, join in an amount of PEG400,70 ℃ add the hot shearing dissolving, are settled to 100 milliliters with PEG400 then; The needle-use activated carbon that adds 3 grams, absorption is 15 minutes under 25 ℃ temperature, uses filtering with microporous membrane then, and packing is sealed, and with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 15 minutes, promptly gets Docetaxel solution.
Commercially available Emulsion: [specification]: 100 milliliters: in 20%/long-chain fat Emulsion, [lot number]: GM0809034, [manufacturer]: Guangzhou Baite Jiaoguang Medical Product Co., Ltd
During administration, drug solution and commercially available Emulsion volume ratio are 1: 25 ratio, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 25 paclitaxel injections
The preparation of drug solution:
Take by weighing paclitaxel 2.5 grams, tartaric acid 0.8 gram, join in an amount of PEG400,70 ℃ add the hot shearing dissolving, are settled to 100 milliliters with PEG400 then; The needle-use activated carbon that adds 0.06 gram, absorption is 90 minutes under 25 ℃ temperature, uses filtering with microporous membrane then, and packing is sealed, and 100 ℃ of sterilizations of flowing steam 45 minutes promptly get paclitaxel solution.
Commercially available Emulsion: [specification]: 250 milliliters: in 20%/long-chain fat Emulsion, [lot number]: GM0810022, [manufacturer]: Guangzhou Baite Jiaoguang Medical Product Co., Ltd
During administration, drug solution and commercially available Emulsion volume ratio are 1: 25 ratio, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 26 paclitaxel injections
The preparation of drug solution:
Take by weighing paclitaxel 2.5 grams, join in the 90 gram PEG400s, 90 ℃ of heated and stirred dissolvings get paclitaxel solution; Take by weighing disodiumedetate 1.0 grams, it is dissolved, get chelating agent solution with 5 gram waters for injection; With chelating agent solution and drug solution mix homogeneously, be settled to 100 milliliters with PEG400; The needle-use activated carbon that adds 0.5 gram, absorption is 30 minutes under 25 ℃ temperature, uses filtering with microporous membrane then, and packing is sealed, and with 121 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 12 minutes, promptly gets paclitaxel solution.
Commercially available Emulsion: [specification]: 250 milliliters: 30% long-chain fat Emulsion, [lot number]: GM0810022, [manufacturer]: Huarui Pharmaceutical Co. Ltd.
During administration, drug solution and commercially available Emulsion volume ratio are 1: 25 ratio, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 27 Docetaxel injections
The preparation of drug solution:
Take by weighing Docetaxel 3.0 grams, citric acid 0.1 gram, join in an amount of PEG400,70 ℃ add the hot shearing dissolving, are settled to 100 milliliters with PEG400 then; The needle-use activated carbon that adds 0.7 gram, absorption is 60 minutes under 45 ℃ temperature, uses filtering with microporous membrane then, and packing is sealed, and with 115 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 30 minutes, promptly gets Docetaxel solution.
Commercially available Emulsion: [specification]: 250 milliliters: in 20%/long-chain fat Emulsion, [lot number]: 8192A181, [manufacturer]: the bright medical joint-stock company of German shellfish
During administration, drug solution and commercially available Emulsion volume ratio are 1: 40 ratio, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 28 Docetaxel injections
The preparation of drug solution:
Take by weighing Docetaxel 2.5 grams, ethylenediaminetetraacetic acid 0.25 gram, join in an amount of PEG400,80 ℃ add the hot shearing dissolving, are settled to 100 milliliters with PEG400 then; The needle-use activated carbon that adds 0.3 gram, absorption is 30 minutes under 25 ℃ temperature, uses filtering with microporous membrane then, and packing is sealed, and with 115 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 30 minutes, promptly gets Docetaxel solution.
Commercially available Emulsion: [specification]: 250 milliliters: 30% long-chain fat Emulsion, [lot number]: GM0810022, [manufacturer]: Huarui Pharmaceutical Co. Ltd.
During administration, drug solution and commercially available Emulsion volume ratio are 1: 25 ratio, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Embodiment 29 Docetaxel injections
The preparation of drug solution:
Take by weighing Docetaxel 2.5 grams, lactic acid 0.25 gram, join in an amount of PEG400,80 ℃ add the hot shearing dissolving, are settled to 100 milliliters with PEG400 then; The needle-use activated carbon that adds 0.3 gram, absorption is 30 minutes under 25 ℃ temperature, uses filtering with microporous membrane then, and packing is sealed, and with 115 ℃ of sterilizations of rotating type high-pressure steam sterilization pot 30 minutes, promptly gets Docetaxel solution.
Commercially available Emulsion: [specification]: 250 milliliters: 30% long-chain fat Emulsion, [lot number]: GM0810022, [manufacturer]: Huarui Pharmaceutical Co. Ltd.
During administration, drug solution and commercially available Emulsion volume ratio are 1: 25 ratio, and drug solution is dispersed in the Emulsion, shake up, and intravenous drip gets final product.
Claims (12)
1. a taxone solution is characterized in that, contains taxone, chelating agen, solvent.
2. the described taxone solution of claim 1 is characterized in that the ratio of each component is:
Taxone 1-8% (grams per milliliter)
Chelating agen 0.05-2% (grams per milliliter)
All the other are solvent and the other medicines carrier that adds in case of necessity.
3. the described taxone solution of claim 2 is characterized in that the ratio of each component is:
Taxone 1-6% (grams per milliliter)
Chelating agen 0.1-1% (grams per milliliter)
All the other are solvent and the other medicines carrier that adds in case of necessity.
4. any described taxone solution of claim 1～3, described taxone is paclitaxel or Docetaxel.
5. any described taxone solution of claim 1～3, described chelating agen are selected from one or more the mixture in ethylenediaminetetraacetic acid, citric acid, lactic acid, malic acid, tartaric acid, disodiumedetate, sodium versenate, the disodium citrate; Perhaps, be selected from citric acid, lactic acid, ethylenediaminetetraacetic acid or disodiumedetate.
6. any described taxone solution of claim 1～3, described solvent are selected from one or more the mixture in Macrogol 200, Liquid Macrogol, PEG400, Macrogol 600, propylene glycol, glycerol, dehydrated alcohol, the water for injection; Perhaps, PEG400.
7. the preparation method of any described taxone solution of claim 1-6 is characterized in that taxone and chelating agen are dissolved in solvent, adds the other medicines carrier in case of necessity.
8. the described preparation method of claim 7 is characterized in that comprising the steps: to take by weighing taxone and chelating agen to solvent, 50-100 ℃ of following heated and stirred or shear dissolving, is settled to full dose with solvent then; Adding the bulking value percentage composition is the needle-use activated carbon of 0.01%-3% grams per milliliter, and absorption is 15-120 minute under 25-100 ℃ heating-up temperature, filtration, packing then, seals, sterilizes, promptly.
9. a taxone compositions is formulated by any described taxone solution of claim 1～6 and Emulsion two parts medicament; Described preparation is to be 1 by volume: the ratio of 10-100 is mixed taxone solution and Emulsion.
10. a drug regimen packing is characterized in that formed by any described taxone solution of claim 1～6 and Emulsion assembly packaging, two kinds of medicaments are loaded in respectively in the container, discrete placement, and assembly packaging is together.
11. drug regimen packing, it is characterized in that, form by taxone solution and Emulsion assembly packaging, two kinds of medicaments are loaded in the container respectively, discrete placement, assembly packaging wherein contains chelating agen in taxone solution or the Emulsion together, and content is 0.05-2% (grams per milliliter).
12. Emulsion that contains chelating agen, it is characterized in that, chelating agen content is 0.05-2% (grams per milliliter), and described chelating agen is selected from: the mixture of one or more in ethylenediaminetetraacetic acid, citric acid, lactic acid, malic acid, tartaric acid, disodiumedetate, sodium versenate, the disodium citrate.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910070932.2A CN102038636B (en) | 2009-10-23 | 2009-10-23 | Taxane medicine solution containing chelating agent and preparation method thereof |
| PCT/CN2010/077998 WO2011047639A1 (en) | 2009-10-23 | 2010-10-22 | Pharmaceutical solution of taxanes comprising chelating agent and preparation method thereof |
| ARP100103881A AR078737A1 (en) | 2009-10-23 | 2010-10-22 | A TAXAN DRUG SOLUTION THAT INCLUDES A CHEMICAL AGENT AND ITS PREPARATION METHOD |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910070932.2A CN102038636B (en) | 2009-10-23 | 2009-10-23 | Taxane medicine solution containing chelating agent and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102038636A true CN102038636A (en) | 2011-05-04 |
| CN102038636B CN102038636B (en) | 2014-08-13 |
Family
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| Application Number | Title | Priority Date | Filing Date |
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| CN200910070932.2A Expired - Fee Related CN102038636B (en) | 2009-10-23 | 2009-10-23 | Taxane medicine solution containing chelating agent and preparation method thereof |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN102038636B (en) |
| AR (1) | AR078737A1 (en) |
| WO (1) | WO2011047639A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110496103A (en) * | 2018-05-18 | 2019-11-26 | 上海维洱生物医药科技有限公司 | A kind of docetaxel palmitate lipid body and preparation method thereof |
| CN112933137A (en) * | 2021-02-22 | 2021-06-11 | 青岛康地恩动物药业有限公司 | Nanoemulsion consisting of oregano essential oil and guanidinoacetic acid and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101094646A (en) * | 2004-09-28 | 2007-12-26 | 陈献 | Low oil emulsion compositions for delivering taxoids and other insoluble drugs |
| CN101288642A (en) * | 2007-11-07 | 2008-10-22 | 中国人民解放军第二军医大学 | Taxanes medicine preparation for intravenous injection and preparation method thereof |
| WO2009047794A2 (en) * | 2007-10-01 | 2009-04-16 | Intas Pharmaceuticals Limited | Taxane derivative composition |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5877205A (en) * | 1996-06-28 | 1999-03-02 | Board Of Regents, The University Of Texas System | Parenteral paclitaxel in a stable non-toxic formulation |
| US6136846A (en) * | 1999-10-25 | 2000-10-24 | Supergen, Inc. | Formulation for paclitaxel |
| CN1535679A (en) * | 2003-04-04 | 2004-10-13 | 齐鲁制药厂 | Medicine composition containing taxol substance and its preparation method |
-
2009
- 2009-10-23 CN CN200910070932.2A patent/CN102038636B/en not_active Expired - Fee Related
-
2010
- 2010-10-22 AR ARP100103881A patent/AR078737A1/en unknown
- 2010-10-22 WO PCT/CN2010/077998 patent/WO2011047639A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101094646A (en) * | 2004-09-28 | 2007-12-26 | 陈献 | Low oil emulsion compositions for delivering taxoids and other insoluble drugs |
| WO2009047794A2 (en) * | 2007-10-01 | 2009-04-16 | Intas Pharmaceuticals Limited | Taxane derivative composition |
| CN101288642A (en) * | 2007-11-07 | 2008-10-22 | 中国人民解放军第二军医大学 | Taxanes medicine preparation for intravenous injection and preparation method thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110496103A (en) * | 2018-05-18 | 2019-11-26 | 上海维洱生物医药科技有限公司 | A kind of docetaxel palmitate lipid body and preparation method thereof |
| CN110496103B (en) * | 2018-05-18 | 2022-05-10 | 上海维洱生物医药科技有限公司 | Docetaxel palmitate liposome and preparation method thereof |
| CN112933137A (en) * | 2021-02-22 | 2021-06-11 | 青岛康地恩动物药业有限公司 | Nanoemulsion consisting of oregano essential oil and guanidinoacetic acid and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2011047639A1 (en) | 2011-04-28 |
| AR078737A1 (en) | 2011-11-30 |
| CN102038636B (en) | 2014-08-13 |
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