CN101143129A - Methotrexate intravenous emulsion and its preparation method - Google Patents
Methotrexate intravenous emulsion and its preparation method Download PDFInfo
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- CN101143129A CN101143129A CNA2006101131049A CN200610113104A CN101143129A CN 101143129 A CN101143129 A CN 101143129A CN A2006101131049 A CNA2006101131049 A CN A2006101131049A CN 200610113104 A CN200610113104 A CN 200610113104A CN 101143129 A CN101143129 A CN 101143129A
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- methotrexate
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Abstract
The invention relates to a methotrexate combination, which is used for the vein transfusion and is in a stable oil-in-water emulsion. The invention also relates to the method of mixing the methotrexate into the oil to form the stable oil-in-water emulsion. The combination includes the methotrexate, the oil, the water and a surfactant.
Description
Invention field
The present invention relates to vein emulsion of a kind of methotrexate and preparation method thereof, belong to the medical sci-tech field.
Background technology
(Methotrexate MTX) is a kind of of antineoplastic agent to methotrexate, and it is an antifol, combine with the catalytic site of dihydrofolate reductase, organize this enzyme to be reduced to tetrahydrofolic acid, owing to lack tetrahydrofolate coenzyme in the cell, the one carbon unit transfer process is just received inhibition.At first be that deoxyuridylic acid can not become the necessary deoxythymidylic acid of synthetic DNA, the synthetic commitment of purine nucleotides is also suppressed simultaneously, and DNA and RNA are synthetic all can be obstructed, thereby the cell growth is suppressed.Methotrexate is used for acute leukemia, chorionic epithelioma, malignant mole and psoriasis.Heavy dose of administration is all effective to osteosarcoma, soft tissue sarcoma, pulmonary carcinoma, breast carcinoma and ovarian cancer etc.Some solid tumor such as incidence tumor, hepatocarcinoma, digestive tract cancer etc. are all effective.
Methotrexate; chemistry is by name: N-4-(2; 4-diaminourea-6-pteridyl) methyl] methylamino] benzoyl-L-glutamic acid methotrexate is the orange colour powder, the carbonate solution that is soluble in diluted alkaline, bronsted lowry acids and bases bronsted lowry metal is slightly soluble in that dilute hydrochloric acid is water-soluble hardly, chloroform, alcohol, ether.
A kind of methotrexate orally disintegrating tablet and preparation method thereof is disclosed in the Chinese patent (CN200410035779.7).Existing methotrexate dosage form has injection, tablet etc., and the described oral cavity disintegration tablet of CN200410035779.7 can improve bioavailability really to a certain extent, but far away from drug administration by injection.
Vein emulsion is with two kinds of not miscible liquid, makes by the emulsification of emulsifying agent.He can also obtain polymolecularity and high bioavailability as the carrier of many oiliness or fat-soluble medicine except energetic nourishing is provided, be used for other pathological changes.If it as carrier, is then had the function of directed (liver, lung, kidney, spleen etc.) distribution to a certain degree.If as the anticarcinogen carrier, lymphoid directivity is arranged again with him, the diffusion of may command cancerous cell, transfer to improve curative effect, reduce the postoperative recurrence rate, with cancerous cell stronger affinity are arranged simultaneously, but the anticancer growth.Moderns Yao Chong Shun etc. once proposed Oleum Fructus Bruceae from the Fructus Bruceae mature fruit, make the Oleum Fructus Bruceae vein emulsion, and experiment in vitro finds that this medicine can kill or anticancer, examination all receive good the effect in clinical for digestive tract cancer, cervical cancer etc.This is to have reached directed requirement because distribute in this pharmaceutically active ingredient carrier, thereby has guaranteed anticancer effect.
Summary of the invention
Based on this reason of methotrexate dosage form dullness, we have invented vein emulsion of a kind of methotrexate and preparation method thereof by big quantity research.
The inventor has overcome above-mentioned various shortcoming, has invented a kind of methotrexate vein emulsion of novelty.
The compositions of the stable emulsion that contains methotrexate that a kind of injection for intravenous is used is characterized in that it comprises methotrexate, vegetable oil, emulsifying agent, antioxidant, organic solvent.
Described vegetable oil can be Semen Maydis oil, soybean oil, Oleum sesami, safflower oil or their mixture.
Described emulsifying agent can be Ovum Gallus domesticus Flavus lecithin, soybean phospholipid, cholesterol, ethyoxyl cholesterol, diacetyl glycerol, dialkyl ether glycerol.
Preferred solvent is an Ovum Gallus domesticus Flavus lecithin.
Described antioxidant is: sulphite, vitamin C derivatives, thio-compounds, amino acids, organic acid, phenols, amine, oil-soluble antioxidant or the mixture of two kinds and two or more antioxidant wherein.
Preferred antioxidant is vitamin E.
In addition, the present invention also provides a kind of preparation method of methotrexate vein emulsion, described preparation method step is: at first get a certain amount of methotrexate and be dissolved in the benzyl alcohol, 80 degrees centigrade of water bath with thermostatic control heating, add fabaceous lecithin, fully stirred 3 minutes, make the fabaceous lecithin homodisperse, the Oleum Glycines that is preheated to 80 degrees centigrade is added aforesaid liquid, make colostrum with the emulsify at a high speed device, the water for injection that adds preheating in first Ruzhong is settled to 1000ml to capacity, change the homogenizer homogenizing over to, then after filtration, embedding and sterilization promptly.
The methotrexate vein emulsion that we developed is compared with existing dosage form, and it has certain slow-releasing, has reduced toxic and side effects and its zest to blood vessel of medicine; Medicine has also improved stability because of being wrapped in the oil droplet.
Specific embodiment
Below relevant purposes more of the present invention are done further to understand by infinite embodiment.
Embodiment 1
Methotrexate 1.2g is dissolved in the 8g benzyl alcohol, 80 degrees centigrade of water bath with thermostatic control heating, add fabaceous lecithin 12g, fully stirred 3 minutes, make the fabaceous lecithin homodisperse, the Oleum Glycines 100g that is preheated to 80 degrees centigrade is added aforesaid liquid, make colostrum with the emulsify at a high speed device, the water for injection that adds preheating in first Ruzhong is settled to 1000ml to capacity, change the homogenizer homogenizing over to, then after filtration, embedding and sterilization promptly.
Embodiment 2,
Methotrexate 1.2g is dissolved in the 8g benzyl alcohol, 80 degrees centigrade of water bath with thermostatic control heating, add Ovum Gallus domesticus Flavus lecithin 12g, fully stirred 3 minutes, make the fabaceous lecithin homodisperse, the Oleum Glycines 100g that is preheated to 80 degrees centigrade is added aforesaid liquid, make colostrum with the emulsify at a high speed device, the water for injection that adds preheating in first Ruzhong is settled to 1000ml to capacity, change the homogenizer homogenizing over to, then after filtration, embedding and sterilization promptly.
Embodiment 3
The irritation test of ftorafur vein emulsion
1, tame rabbit ear edge hypodermic injection
Test method: select 6 of healthy earless disease rabbit, body weight 2.0_3.0kg divides two groups immediately.Administration group ear edge subcutaneous injection methotrexate Emulsion 0.05ml, matched group man rabbit ear edge subcutaneous injection 0.9% normal saline solution was observed one hour.
Observation index: during injection, the rabbit peace and quiet do not have because of the action of shaking the head due to stimulating, after the injection, the rabbit ear does not have redness, and irriate phenomenons such as hyperemia after one hour, can be seen, the administration rabbit ear is compared with the matched group rabbit ear, and rabbit ear administration topical remedy absorbs good, does not have knot lump or downright bad phenomenon.
Conclusion: methotrexate Emulsion is organized non-stimulated or damaging action to the rabbit ear after giving tame rabbit ear edge subcutaneous injection.
2, white mice intravenous injection
Test method: select 10 of healthy mices, body weight 20.0_25.0g. divides two groups at random. one group of 5 mice, and tail vein injection 0.2ml methotrexate Emulsion injection, 5 mices of matched group, tail vein injection is with dosage 0.9% normal saline.
Observation index: after the administration in one hour. observe the no abnormal behavior of administration mice, the nonirritant reflection, mice is movable and diet is unaffected, and the methotrexate Emulsion of being injected is to the blood vessel nonirritant.
Conclusion: methotrexate Emulsion is organized non-stimulated damaging action to the mice vascular venous after giving mouse tail vein injection.
The haemolysis of embodiment 6, methotrexate Emulsion and hemagglutination test (HA test)
Test method: get one of rabbit, heart extracting blood 10ml, Glass rod stirs except that Fibrinogen, makes into defibrinated blood, adds the 100ml normal saline and shakes up, centrifugal, remove supernatant, sedimentary erythrocyte reuse normal saline washs 4 times to the apparent redness of supernatant, with gained erythrocyte 3ml, add normal saline 150ml, it is stand-by to be prepared into 2% red blood cell suspension.
Get 7 in test tube, indicate 1_7 number, the according to the form below parallelism, add 2% red blood cell suspension and normal saline successively, put 37 ℃ of calorstats interior 30 minutes, and added not commensurability methotrexate Emulsion then, the negative control tube of the 6th pipe, the positive haemolysis sample of the 7th pipe. after shaking up, put in 37 ℃ of calorstats and observed once every 20 minutes approximately, observe to 6 hours, the 1_5 pipe is compared with 6 pipes, the clarity of supernatant is identical, transparent red normal complexion rufous flocky precipitate all do not occur, 7 pipes are learned the erythrocyte complete hemolysis, and the 1-5 pipe is compared with 7 pipes, phenomenon is opposite fully, and result of the test sees Table 1:
Table 1 methotrexate Emulsion haemolysis agglutination test (ml)
| Numbering | ?1 | ?2 | ?3 | ?4 | ?5 | ?6 | ?7 |
| Be subjected to reagent liquid | ?0.1 | ?0.2 | ?0.3 | ?0.4 | ?0.5 | ?0 | ?0 |
| Normal saline | ?2.4 | ?2.3 | ?2.2 | ?2.1 | ?2.0 | ?2.5 | ?0 |
| Deionized water | ?0 | ?0 | ?0 | ?0 | ?0 | ?0 | ?2.5 |
| 2% red blood cell suspension | ?2.5 | ?2.5 | ?2.5 | ?2.5 | ?2.5 | ?2.5 | ?2.5 |
The result judges: the 1-5 pipe is in 2-6 hour, and its supernatant is compared basic identical with 6 pipes, the brown flocky precipitate of transparent red normal complexion all do not occur.The 1-5 pipe was compared with 7 pipes in 2-6 hour, and then phenomenon is opposite fully, and whole red haemolysises have appearred in 7 pipes.
Conclusion: methotrexate Emulsion does not have blood coagulation, no erythroagglutination.
Claims (7)
1. the compositions of the stable emulsion that contains methotrexate used of an injection for intravenous is characterized in that it comprises ftorafur, vegetable oil, emulsifying agent, antioxidant, organic solvent.
2. as claim 1 described compositions, it is characterized in that described vegetable oil can be Semen Maydis oil, soybean oil, Oleum sesami, safflower oil or their mixture.
3. as claim 1 described compositions, it is characterized in that described emulsifying agent can be Ovum Gallus domesticus Flavus lecithin, soybean phospholipid, cholesterol, ethyoxyl cholesterol, diacetyl glycerol, dialkyl ether glycerol.
4. as claim 1 described compositions, it is characterized in that described antioxidant is: sulphite, vitamin C derivatives, thio-compounds, amino acids, organic acid, phenols, amine, oil-soluble antioxidant or the mixture of two kinds and two or more antioxidant wherein.
5. as claim 1 described compositions, it is characterized in that described emulsifying agent is an Ovum Gallus domesticus Flavus lecithin.
6. as claim 1 described compositions, it is characterized in that described antioxidant is vitamin E.
7. the preparation method of a methotrexate Emulsion, it is characterized in that described preparation method step is: at first get a certain amount of ftorafur and be dissolved in the benzyl alcohol, 80 degrees centigrade of water bath with thermostatic control heating add fabaceous lecithin, fully stirred 3 minutes, make the fabaceous lecithin homodisperse, the Oleum Glycines that is preheated to 80 degrees centigrade is added aforesaid liquid, make colostrum with the emulsify at a high speed device, add the water for injection of preheating to capacity in first Ruzhong, be settled to 1000ml, change the homogenizer homogenizing over to, then after filtration, embedding and sterilization promptly.
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2006101131049A CN101143129A (en) | 2006-09-14 | 2006-09-14 | Methotrexate intravenous emulsion and its preparation method |
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| CNA2006101131049A CN101143129A (en) | 2006-09-14 | 2006-09-14 | Methotrexate intravenous emulsion and its preparation method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101401792B (en) * | 2008-09-01 | 2010-12-01 | 中国人民解放军第二军医大学 | Method for preparing nanocapsule and nanocapsule composite microsphere |
| CN107136098A (en) * | 2017-05-27 | 2017-09-08 | 四川奥恒环保科技有限公司 | A kind of Biocidal algae-killing agent |
-
2006
- 2006-09-14 CN CNA2006101131049A patent/CN101143129A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101401792B (en) * | 2008-09-01 | 2010-12-01 | 中国人民解放军第二军医大学 | Method for preparing nanocapsule and nanocapsule composite microsphere |
| CN107136098A (en) * | 2017-05-27 | 2017-09-08 | 四川奥恒环保科技有限公司 | A kind of Biocidal algae-killing agent |
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Application publication date: 20080319 |