CN103980279A - Methotrexate compound and methotrexate for injection - Google Patents
Methotrexate compound and methotrexate for injection Download PDFInfo
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- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
- C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
Abstract
The present invention relates to the field of pharmaceutical preparations, and discloses a methotrexate compound represented by a formula (I) and a composition thereof, wherein the methotrexate compound is determined by using a powder X-ray determination method, and the 2[theta]+/-0.2 diffraction angle is adopted to represent that the characteristic diffraction peaks are showed at the positions of 5.81 DEG, 8.65 DEG, 11.08 DEG, 12.70 DEG, 15.14 DEG, 18.65 DEG, 20.27 DEG, 21.89 DEG, 24.32 DEG, 28.38 DEG, 30.27 DEG and 32.43 DEG on the X-ray powder diffraction spectrum. The methotrexate compound has characteristics of significantly-increase stability, controllable quality, change resistance after long time placing, and substantially improved patient medication safety.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of methotrexate compound and methotrexate for inj.
Background technology
Methotrexate is the effective metabolic antagonist of first treatment tumour; chorioepithelioma and kemia are had to good therapeutic effect; the forties in 20th century, scientist found; the effective constituent that suppresses mice transplanted tumor sarcoma S180 and spontaneous mammary carcinoma in lactobacterium casei is pterin three L-glutamic acid, and the latter has weak anti-folic acid effect; And observe and lack bone marrow suppression system of folic acid; Folic acid can promote the phenomenons such as leukemia development, therefore start to find anticarcinogen from antifolate.Nineteen forty-seven, aminopterin tried out in clinical, effective to leukemia of children.Continue after find that methotrexate has higher therapeutic index to mouse leukemia L1210, try out the fifties in clinical, replaced very soon aminopterin for leukemia treating, be extended to later treatment other tumour.It is to study one of the most deep antitumor drug.
Methotrexate, claim again Cytotoxic drugs, in order to alleviate its cytotoxic toxicity, can coordinate calcium leucovorin to use together, be mainly used in treating acute leukemia (acute lymphoblastic leukemia), mammary cancer, chorioepithelioma and malignant mole, incidence cancer, bone tumor, the infiltration of leukemia meninx spinal cord, lung cancer, genital system tumor, liver cancer, the common psoriasis of intractable, dermatomyositis, body myositis, ankylosing spondylitis, Crohn's disease, psoriasis and psoriasis arthropathica, behcets disease and autoimmune disease.
Methotrexate is also a kind of immunosuppressor, can alleviate rheumatism process, good especially to the result for the treatment of of the synovial membrane inflammation of rheumatoid arthritis, is that rheumatism Disease is used one of maximum medicine.
Currently available technology discloses the multiple preparation containing methotrexate, tablet.Injection liquid etc., as:
China application CN1754538 discloses a kind of methotrexate orally disintegrating tablet, by components such as methotrexate, dry adhesive, lubricant, disintegrating agent and correctivess, formed, the composition content that it is characterized in that said orally disintegrating tablet, be by weight percentage: the methotrexate of 3.5-7.5wt%, the sodium starch glycolate of 20.0-24.0wt%, the Microcrystalline Cellulose of 55.0-65.0wt%, the Magnesium Stearate of 1.0-2.0wt%, the N.F,USP MANNITOL of 10.0-20.0wt%.Although this orally disintegrating tablet can improve bioavailability to a certain extent, its clinical application effect is still far away from drug administration by injection.
Freeze-dried preparation is a kind of desirable drug administration by injection form, but owing in methotrexate freeze-dried preparation itself and process of clinical application, methotrexate raw material all having been proposed to high requirement, and the storage stability of methotrexate itself is not good, therefore, still await finding a kind of desirable methotrexate compound, further to obtain stability, curative effect etc., be significantly better than the methotrexate for inj of prior art.
Summary of the invention
The first object of the present invention is to provide a kind of methotrexate compound, usings and improves the stability as the methotrexate of preparation raw material itself.
For achieving the above object, the present invention adopts following technical scheme:
A kind of methotrexate compound, described methotrexate compound is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 diffraction angle locates to demonstrate characteristic diffraction peak at 5.81 °, 8.65 °, 11.08 °, 12.70 °, 15.14 °, 18.65 °, 20.27 °, 21.89 °, 24.32 °, 28.38 °, 30.27 ° and 32.43 °;
Although methotrexate is a kind of known substance, contriver finds in actual application, and the poor stability of methotrexate itself shows active constituent content and comparatively significantly declines, serious threat patient's drug safety in long-time preservation process.
Contriver is carrying out the favorite outer discovery of process of recrystallization purifying to methotrexate, when selecting different solvent systems, by being controlled, recrystallization method beat allly can induce a kind of brand-new methotrexate compound, the X-ray powder diffraction figure of this compound and existing disclosed methotrexate powder diagram are relatively found, what the present invention obtained is a kind of brand-new methotrexate compound.This novel methotrexate compound itself and preparation thereof all show in stability test etc. the advantage that is significantly better than commercially available known methotrexate compound.
In addition,, in order to obtain a kind of maturation, can repeat to realize and the recrystallization method of industrial application, contriver has done a large amount of specific aim tests to this, further optimize each operation steps, described preparation method can stably be realized, obtained the high quality methotrexate compound of homogeneous.
It should be noted that methotrexate crude product of the present invention is commercially available known methotrexate, the concrete those skilled in the art that are retrieved as grasp.
Preparation method of the present invention comprises the steps:
At (1) 35 ℃-45 ℃, take methotrexate crude product, join volume and be equivalent to, in methotrexate crude product weight 20-40 dibutyl phthalate doubly, stir;
(2) by the amount ratio configuration ethanol of 2～5:1 and the mixed solution of ether, the volume of mixed solution is the 1/5-8/5 of dibutyl phthalate, and in 1-3 hour by this mixed solution at the uniform velocity stream be added in the dibutyl phthalate that contains methotrexate, control solution system temperature simultaneously and be down to 20 ℃-25 ℃, stream adds in process the stirring at low speed with 5-10rmp;
(3) after stream adds, solution temperature is down to 0～5 ℃, standing growing the grain 8～12 hours, filters, and filter cake washs with ether, and below 40 ℃, cryodrying is 1～3 hour, obtains methotrexate compound.
Wherein, in described step 1, stirring velocity is 30-40rmp, and preferably stirring velocity is 35rmp.
In step 2, press the amount ratio configuration ethanol of 3:1 and the mixed solution of ether, the volume of mixed solution is dibutyl phthalate 4/5, in 2 hours by this mixed solution at the uniform velocity stream be added in solution A, control solution system temperature simultaneously and be down to 22 ℃, stream adds in process the stirring at low speed with 6rmp.
In step 3, after stream adds, solution temperature is down to 2 ℃, standing growing the grain 10 hours, filters, and filter cake washs with ether, and below 40 ℃, cryodrying is 2 hours, obtains methotrexate compound.
In described step 3, cooling rate is 0.2-0.5 ℃/min.
Except special instruction, the unit of weight of the present invention and volume ratio is g/ml.
Adopt technique scheme, the present invention can obtain high-quality methotrexate compound in batches, and above-mentioned preparation method is simple to operate, and to equipment with artificial require lowly, reproducibility is strong, and purity and yield high, suitable popularization is produced.
The second object of the present invention is to provide a kind of methotrexate for inj that contains above-mentioned methotrexate compound.
Methotrexate for inj of the present invention, by weight, is prepared from by the raw material that comprises following component: methotrexate 5g, sodium-chlor 4-5g, N.F,USP MANNITOL 75-85g, make 1000.
Or by weight, by the raw material that comprises following component, be prepared from: methotrexate 100g, sodium-chlor 0.5-1.5g, make 1000.
Further, as best-of-breed technology scheme of the present invention, preferably by weight, by the raw material that comprises following component, be prepared from: methotrexate 5g, sodium-chlor 4.3g, N.F,USP MANNITOL 80g, make 1000; Or methotrexate 100g, sodium-chlor 1g, make 1000.
Above-mentioned methotrexate for inj can adopt the disclosed various preparation method's preparations of prior art, and the present invention preferably adopts following technical scheme:
(1) by prescription, take methotrexate, inject water to 80% of recipe quantity, with 1% sodium hydroxide solution, regulating pH value is 8.5～9.0, add sodium-chlor or sodium-chlor and N.F,USP MANNITOL, stirring and dissolving, adds to the full amount of water for injection, add charcoal absorption 20 minutes for 0.03% pin, filtering decarbonization, with the degerming of 0.22um filtering with microporous membrane, middle product detect;
(2) packing, partly jumps a queue;
(3) lyophilize:
Goods are put into the freeze drying box that is cooled to-40 ℃, when products temperature is down to-40 ℃, pre-freeze 3 hours, condenser refrigeration, vacuumizes, after condenser temperature and vacustat, shelf heating, slowly heats up goods, and 3 ℃/h of speed of speed are warming up to-8 ℃, with 2 ℃/h of speed, be warming up to 10 ℃ again, then be warming up to 30 ℃ with 4 ℃/h of speed, keep 4 hours, finish freeze-drying, tamponade, rolls lid, obtains.
Above-mentioned freeze-drying process can make high-quality freeze-dried powder, and its outward appearance is good, and solubility and stability is all better than known formulations, thereby has guaranteed patient's drug safety.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction figure of methotrexate compound of the present invention.
Embodiment
Following examples are used for illustrating the present invention, but are not used for limiting the scope of the invention.
The preparation of embodiment 1 methotrexate compound
The preparation of methotrexate compound:
At (1) 40 ℃, take methotrexate crude product, join in the dibutyl phthalate that volume is equivalent to 30 times of methotrexate crude product weight, stir, stirring velocity is 35rmp;
(2) press the amount ratio configuration ethanol of 4:1 and the mixed solution of ether, the volume of mixed solution is 4/5 of dibutyl phthalate, and in 2 hours by this mixed solution at the uniform velocity stream be added in the dibutyl phthalate that contains methotrexate, control solution system temperature simultaneously and be down to 22 ℃, stream adds in process the stirring at low speed with 8rmp;
(3) after stream adds, solution temperature is down to 2 ℃, cooling rate is 0.4 ℃/min, and standing growing the grain 10 hours filters, and filter cake washs with ether, and below 40 ℃, cryodrying is 2 hours, obtains methotrexate compound, and total recovery is 95.43%, and purity is 99.5%.
The X-ray powder diffraction figure of gained methotrexate compound is shown in Fig. 1 (locating to demonstrate characteristic diffraction peak at 5.81 °, 8.65 °, 11.08 °, 12.70 °, 15.14 °, 18.65 °, 20.27 °, 21.89 °, 24.32 °, 28.38 °, 30.27 ° and 32.43 °).
The preparation of embodiment 2 methotrexate compounds
The preparation of methotrexate compound:
At (1) 35 ℃, take methotrexate crude product, join in the dibutyl phthalate that volume is equivalent to 20 times of methotrexate crude product weight, stir, stirring velocity is 30rmp;
(2) press the amount ratio configuration ethanol of 2:1 and the mixed solution of ether, the volume of mixed solution is 1/5 of dibutyl phthalate, and in 1 hour by this mixed solution at the uniform velocity stream be added in the dibutyl phthalate that contains methotrexate, control solution system temperature simultaneously and be down to 20 ℃ ℃, stream adds in process the stirring at low speed with 5rmp;
(3) after stream adds, solution temperature is down to 0 ℃, cooling rate is 0.2 ℃/min, and standing growing the grain 8 hours filters, and filter cake washs with ether, and below 40 ℃, cryodrying is 1 hour, obtains methotrexate compound, and total recovery is 93.40%, and purity is 99.2%.
The X-ray powder diffraction figure of gained methotrexate compound is shown in Fig. 1.
The preparation of embodiment 3 methotrexate compounds
The preparation of methotrexate compound:
At (1) 45 ℃, take methotrexate crude product, join in the dibutyl phthalate that volume is equivalent to 40 times of methotrexate crude product weight, stir, stirring velocity is 40rmp;
(2) press the amount ratio configuration ethanol of 5:1 and the mixed solution of ether, the volume of mixed solution is 8/5 of dibutyl phthalate, and in 3 hours by this mixed solution at the uniform velocity stream be added in the dibutyl phthalate that contains methotrexate, control solution system temperature simultaneously and be down to 25 ℃, stream adds in process the stirring at low speed with 10rmp;
(3) after stream adds, solution temperature is down to 5 ℃, cooling rate is 0.5 ℃/min, and standing growing the grain 12 hours filters, and filter cake washs with ether, and below 40 ℃, cryodrying is 3 hours, obtains methotrexate compound, and total recovery is 93.21%, and purity is 99.0%.
The X-ray powder diffraction figure of gained methotrexate compound is shown in Fig. 1.
The preparation of embodiment 4 methotrexate compounds
The preparation of methotrexate compound:
At (1) 42 ℃, take methotrexate crude product, join in the dibutyl phthalate that volume is equivalent to 25 times of methotrexate crude product weight, stir, stirring velocity is 32rmp;
(2) press the amount ratio configuration ethanol of 3:1 and the mixed solution of ether, the volume of mixed solution is 2/5 of dibutyl phthalate, and in 1.5 hours by this mixed solution at the uniform velocity stream be added in the dibutyl phthalate that contains methotrexate, control solution system temperature simultaneously and be down to 20 ℃, stream adds in process the stirring at low speed with 6rmp;
(3) after stream adds, solution temperature is down to 2 ℃, cooling rate is 0.4 ℃/min, and standing growing the grain 9 hours filters, and filter cake washs with ether, and below 40 ℃, cryodrying is 1 hour, obtains methotrexate compound, and total recovery is 92.30%, and purity is 98.8%.
The X-ray powder diffraction figure of gained methotrexate compound is shown in Fig. 1.
The preparation of embodiment 5 methotrexate compounds
The preparation of methotrexate compound:
At (1) 38 ℃, take methotrexate crude product, join in the dibutyl phthalate that volume is equivalent to 25 times of methotrexate crude product weight, stir, stirring velocity is 40rmp;
(2) press the amount ratio configuration ethanol of 4:1 and the mixed solution of ether, the volume of mixed solution is 3/5 of dibutyl phthalate, and in 1 hour by this mixed solution at the uniform velocity stream be added in the dibutyl phthalate that contains methotrexate, control solution system temperature simultaneously and be down to 20 ℃, stream adds in process the stirring at low speed with 5rmp;
(3) after stream adds, solution temperature is down to 0～5 ℃, cooling rate is 0.2 ℃/min, and standing growing the grain 9 hours filters, and filter cake washs with ether, and below 40 ℃, cryodrying is 2 hours, obtains methotrexate compound, and total recovery is 92.43%, and purity is 99.1%.
The X-ray powder diffraction figure of gained methotrexate compound is shown in Fig. 1.
Embodiment 6 methotrexate for inj
Prescription: the prepared methotrexate compound methotrexate of embodiment 1 5g, sodium-chlor 4.3g, N.F,USP MANNITOL 80g, make 1000;
Preparation method:
(1) by prescription, take methotrexate, inject water to 80% of recipe quantity, with 1% sodium hydroxide solution, regulating pH value is 8.8, add sodium-chlor and N.F,USP MANNITOL, stirring and dissolving, adds to the full amount of water for injection, add charcoal absorption 20 minutes for 0.03% pin, filtering decarbonization, with the degerming of 0.22um filtering with microporous membrane, middle product detect;
(2) packing, partly jumps a queue;
(3) lyophilize:
Goods are put into the freeze drying box that is cooled to-40 ℃, when products temperature is down to-40 ℃, pre-freeze 3 hours, condenser refrigeration, vacuumizes, after condenser temperature and vacustat, shelf heating, slowly heats up goods, and 3 ℃/h of speed of speed are warming up to-8 ℃, with 2 ℃/h of speed, be warming up to 10 ℃ again, then be warming up to 30 ℃ with 4 ℃/h of speed, keep 4 hours, finish freeze-drying, tamponade, rolls lid, obtains.
Embodiment 7 methotrexate for inj
Prescription: the prepared methotrexate compound methotrexate of embodiment 2 100g, sodium-chlor 1g, make 1000.
Preparation method:
(1) by prescription, take methotrexate, inject water to 80% of recipe quantity, with 1% sodium hydroxide solution, regulating pH value is 8.9, add sodium-chlor, stirring and dissolving, adds to the full amount of water for injection, add charcoal absorption 20 minutes for 0.03% pin, filtering decarbonization, with the degerming of 0.22um filtering with microporous membrane, middle product detect;
(2) packing, partly jumps a queue;
(3) lyophilize:
Goods are put into the freeze drying box that is cooled to-40 ℃, when products temperature is down to-40 ℃, pre-freeze 3 hours, condenser refrigeration, vacuumizes, after condenser temperature and vacustat, shelf heating, slowly heats up goods, and 3 ℃/h of speed of speed are warming up to-8 ℃, with 2 ℃/h of speed, be warming up to 10 ℃ again, then be warming up to 30 ℃ with 4 ℃/h of speed, keep 4 hours, finish freeze-drying, tamponade, rolls lid, obtains.
Embodiment 8 methotrexate for inj
Prescription: the prepared methotrexate compound methotrexate of embodiment 1 5g, sodium-chlor 4g, N.F,USP MANNITOL 75g, make 1000;
Preparation method:
(1) by prescription, take methotrexate, inject water to 80% of recipe quantity, with 1% sodium hydroxide solution, regulating pH value is 9.0, add sodium-chlor and N.F,USP MANNITOL, stirring and dissolving, adds to the full amount of water for injection, add charcoal absorption 20 minutes for 0.03% pin, filtering decarbonization, with the degerming of 0.22um filtering with microporous membrane, middle product detect;
(2) packing, partly jumps a queue;
(3) lyophilize:
Goods are put into the freeze drying box that is cooled to-40 ℃, when products temperature is down to-40 ℃, pre-freeze 3 hours, condenser refrigeration, vacuumizes, after condenser temperature and vacustat, shelf heating, slowly heats up goods, and 3 ℃/h of speed of speed are warming up to-8 ℃, with 2 ℃/h of speed, be warming up to 10 ℃ again, then be warming up to 30 ℃ with 4 ℃/h of speed, keep 4 hours, finish freeze-drying, tamponade, rolls lid, obtains.
Embodiment 9 methotrexate for inj
Prescription: the prepared methotrexate compound methotrexate of embodiment 2 100g, sodium-chlor 0.5g, make 1000.
Preparation method:
(1) by prescription, take methotrexate, inject water to 80% of recipe quantity, with 1% sodium hydroxide solution, regulating pH value is 9.0, add sodium-chlor, stirring and dissolving, adds to the full amount of water for injection, add charcoal absorption 20 minutes for 0.03% pin, filtering decarbonization, with the degerming of 0.22um filtering with microporous membrane, middle product detect;
(2) packing, partly jumps a queue;
(3) lyophilize:
Goods are put into the freeze drying box that is cooled to-40 ℃, when products temperature is down to-40 ℃, pre-freeze 3 hours, condenser refrigeration, vacuumizes, after condenser temperature and vacustat, shelf heating, slowly heats up goods, and 3 ℃/h of speed of speed are warming up to-8 ℃, with 2 ℃/h of speed, be warming up to 10 ℃ again, then be warming up to 30 ℃ with 4 ℃/h of speed, keep 4 hours, finish freeze-drying, tamponade, rolls lid, obtains.
Embodiment 10 methotrexate for inj
Compare with embodiment 7, distinctive points is only that the present embodiment prescription is: the prepared methotrexate 100g of embodiment 3, sodium-chlor 1.5g, make 1000.
Embodiment 11 methotrexate for inj
Compare with embodiment 7, distinctive points is only that the present embodiment prescription is: the prepared methotrexate 5g of embodiment 4, sodium-chlor 5g, N.F,USP MANNITOL 85g, make 1000.
The present invention also further provides following test example, further technical scheme of the present invention is described.
Test example 1 methotrexate stability test
This test example has detected the stability (test-results is all calculated with each test group methotrexate weight) of methotrexate compound provided by the present invention.
This test is carried out according to 2005 editions second appendix XIX C medicine stability test governing principle of Chinese Pharmacopoeia, and result is as follows:
Table 1, accelerated test result
| Group | 1 month | 2 months | 3 months | 6 months | 12 months |
| Embodiment 1 | 100.1％ | 99.96％ | 99.94％ | 99.72％ | 99.52％ |
| Embodiment 2 | 99.99％ | 99.93％ | 99.90％ | 99.69％ | 99.46％ |
| Embodiment 3 | 99.96％ | 99.92％ | 99.85％ | 99.66％ | 99.41％ |
| Embodiment 4 | 100.0％ | 99.93％ | 99.83％ | 99.70％ | 99.40％ |
| Control group 1 | 99.90％ | 99.52％ | 98.41％ | 94.51％ | 92.02％ |
Table 2, long-term test results
| Group | 3 months | 6 months | 9 months | 12 months | 18 months |
| Embodiment 1 | 99.99％ | 99.84％ | 99.81％ | 99.73％ | 99.69％ |
| Embodiment 2 | 99.96％ | 99.79％ | 99.76％ | 99.65％ | 99.59％ |
| Embodiment 3 | 99.93％ | 99.81％ | 99.72％ | 99.64％ | 99.60％ |
| Embodiment 4 | 99.95％ | 99.92％ | 99.75％ | 99.66％ | 99.61％ |
| Control group 1 | 99.66％ | 98.73％ | 97.56％ | 96.21％ | 95.02％ |
Wherein:
Control group 1 is commercially available methotrexate;
Experimental group 1～4 is respectively the methotrexate compound of the embodiment of the present invention 1～4 preparation;
This description of test, methotrexate compound good stability provided by the invention, accelerates, test of long duration purity content is little.And disclosed other hydrate crystal poor stabilities of prior art.In aforementioned stable test with the optimal stability of embodiment 1.
Test example 2 methotrexate for inj stability tests
Accelerated test
Method: get each experimental group sample, in 40 ± 2 ℃ of constant temperature, place six months in relative humidity 75 ± 5% loft drier.Duration of test in the 1st, 2,3 and 6 months each sampling once, by above-mentioned investigation project, detect, and with result comparison in 0 month.Test-results shows, the proterties of obtained freeze-drying powder injection of the present invention, pH value, clarity of solution and color, content and related substance are substantially unchanged.Concrete measurement result is in Table 3.
Table 3 methotrexate for inj accelerated test result
Test of long duration
Method: get each experimental group sample, in 25 ± 2 ℃, under the condition of relative humidity 60 ± 10%, place, at duration of test in each sampling in the 3rd, 6,9,12 months once, by above-mentioned investigation project, detect, and with 0 month relatively.
The result of test of long duration to 12 month shows, the proterties of three batch samples, pH value, clarity of solution and color, content and related substance are substantially unchanged.Measurement result is in Table 4 and 5.
Table 4 methotrexate for inj test of long duration is investigated result
Table 5 test of long duration pyrogen, sterility test result
Wherein sample 1,2 is the methotrexate for inj of the embodiment of the present invention 6,7 preparations;
Sample 3 replaces methotrexate compound of the present invention as raw material, the methotrexate for inj obtaining by the preparation method identical with embodiment 6 and formula preparation for usining commercially available methotrexate.
Conclusion (of pressure testing):
Trial target is for adopting the aseptic freeze-dried product of brown cillin bottle packing, through 6 months accelerated tests and 12 months test of long duration, to compare with 0 month, every investigation index has no significant change, trial target has good stability, and is significantly better than take the preparation that commercially available methotrexate is prepared as raw material.
Other embodiments of the invention product has also carried out identical experiment, and obtains the experimental result of same trend, but length limits, and the present invention will not enumerate.
Test example 3 pharmacodynamics tests
1. case selection is suffered from Children with Malignant Tumors 20 examples, male 11 examples, female's 9 examples, age 5-12 year, body weight 15-31kg.Sick 8 examples of acute lymphoblastic, non_hodgkin lymphoma 12 examples, before chemotherapy, routine blood test and liver, kidney function test are showed no extremely.
Above-mentioned 20 experimenters are divided into two groups of control group and test group at random.
2. medicine, reagent and first ammonia butterfly cry of certain animals concentration determination
The methotrexate for inj that experimental group: embodiment 6 is prepared
Control group: the sample 3 in test example 2, is used commercially available methotrexate crude product as raw material, the methotrexate for inj that other are prepared from by the identical technical scheme of embodiment 6.
With fluorescence polarization immunoassay (FPIA), measure first ammonia butterfly cry of certain animals Plasma Concentration, TDx instrument and methotrexate test kit are that U.S. Abbott (Abbott Laboratories) produces.Regularly (0,6,12,18,24h) adopt venous blood 0.5ml, and the centrifugal 5min of 3000r/min draws serum, and 4 ℃ of preservations are to be measured.Determination step is undertaken by TDx instrument operational guidance.FPIA method is measured the minimum 0.01 μ mol/L that is limited to of first ammonia butterfly cry of certain animals, in a few days difference and the in the daytime equal <10% of difference.
3. chemotherapy regimen first ammonia butterfly cry of certain animals dosage is 1-2g/m
2.First intravenous injection 1/3 dosage, the first ammonia butterfly cry of certain animals of another 2/3 dosage is assigned in 500ml5% glucose injection, and 24h is quiet to be dripped off.Quiet 250ml5% soda solution of 24h before chemotherapy, keeps urine pH to be more than or equal to 7.Calcium leucovorin 6h after drug withdrawal gives, each intramuscular injection 15mg, and 8-12 time altogether, or until methotrexate Plasma Concentration is less than 0.05 μ mol/L.
4. the 3P87 program that data processing adopts Chinese Pharmacological Society's quantitative pharmacology to compile is processed the Plasma Concentration data of gained on SUN-386 computer.
The results are shown in Figure 2, wherein, series 1 is control group plasma concentration curve, and series 2 is experimental group plasma concentration curve.X-coordinate unit is h, and ordinate zou unit is μ mol/L.
As can be seen from Figure 2, product of the present invention has more consistent Plasma Concentration variation tendency, and product plasma concentration curve of the present invention variation is more mild, shows that its bioavailability is high, and the plasma concentration curve of mitigation makes drug effect be able to better performance.
The methotrexate for inj of other embodiment of the present invention has also under equal conditions been carried out respectively to identical test, and it has and upper identical trend.
Although, above used general explanation, embodiment and test, the present invention is described in detail, on basis of the present invention, can make some modifications or improvements it, and this will be apparent to those skilled in the art.Therefore, these modifications or improvements, all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (10)
1. a methotrexate compound, it is characterized in that, described methotrexate compound is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 diffraction angle locates to demonstrate characteristic diffraction peak at 5.81 °, 8.65 °, 11.08 °, 12.70 °, 15.14 °, 18.65 °, 20.27 °, 21.89 °, 24.32 °, 28.38 °, 30.27 ° and 32.43 °;
2. methotrexate compound according to claim 1, is characterized in that, described methotrexate compound is adopted with the following method and is prepared from:
At (1) 35 ℃-45 ℃, take methotrexate crude product, join volume and be equivalent to, in methotrexate crude product weight 20-40 dibutyl phthalate doubly, stir;
(2) by the amount ratio configuration ethanol of 2～5:1 and the mixed solution of ether, the volume of mixed solution is the 1/5-8/5 of dibutyl phthalate, and in 1-3 hour by this mixed solution at the uniform velocity stream be added in the dibutyl phthalate that contains methotrexate, control solution system temperature simultaneously and be down to 20 ℃-25 ℃, stream adds in process the stirring at low speed with 5-10rmp;
(3) after stream adds, solution temperature is down to 0～5 ℃, standing growing the grain 8～12 hours, filters, and filter cake washs with ether, and below 40 ℃, cryodrying is 1～3 hour, obtains methotrexate compound.
3. methotrexate compound according to claim 2, is characterized in that, in described step 1, stirring velocity is 30-40rmp.
4. methotrexate compound according to claim 2, it is characterized in that, in step 2, press the amount ratio configuration ethanol of 3:1 and the mixed solution of ether, the volume of mixed solution is 4/5 of dibutyl phthalate, in 2 hours by this mixed solution at the uniform velocity stream be added in solution A, control solution system temperature simultaneously and be down to 22 ℃, stream adds in process the stirring at low speed with 6rmp.
5. methotrexate compound according to claim 2, is characterized in that, in step 3, after stream adds, solution temperature is down to 2 ℃, and standing growing the grain 10 hours filters, and filter cake washs with ether, and below 40 ℃, cryodrying is 2 hours, obtains methotrexate compound.
6. according to the methotrexate compound described in claim 2 or 5, it is characterized in that, in described step 3, cooling rate is 0.2-0.5 ℃/min.
7. the methotrexate for inj that contains methotrexate compound described in claim 1-6 any one.
8. methotrexate for inj according to claim 7, is characterized in that: by weight, by the raw material that comprises following component, be prepared from: methotrexate 5g, sodium-chlor 4-5g, N.F,USP MANNITOL 75-85g, make 1000.
9. methotrexate for inj according to claim 7, is characterized in that: by weight, by the raw material that comprises following component, be prepared from: methotrexate 100g, sodium-chlor 0.5-1.5g, make 1000.
10. methotrexate for inj according to claim 8 or claim 9, is characterized in that: by weight, by the raw material that comprises following component, be prepared from: methotrexate 5g, sodium-chlor 4.3g, N.F,USP MANNITOL 80g, make 1000; Or methotrexate 100g, sodium-chlor 1g, make 1000.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114516874A (en) * | 2022-03-11 | 2022-05-20 | 国药一心制药有限公司 | Methotrexate new crystal form and preparation method thereof |
| CN115197223A (en) * | 2022-05-25 | 2022-10-18 | 浙江致新医药科技有限公司 | Methotrexate crystal form A compound and preparation method thereof |
| CN117064850A (en) * | 2023-08-16 | 2023-11-17 | 海南卓泰制药有限公司 | Methotrexate injection and preparation method thereof |
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| US5760229A (en) * | 1995-02-07 | 1998-06-02 | Heinric Mack Nachf | Crystal modification of 2,4-diamino-6-hydroxymethylpteridine hydrobromide |
| CN1277197A (en) * | 1999-04-15 | 2000-12-20 | 阿泼洛发公司 | Stable crystal salt of 5-methyl tetrahydrofolic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5760229A (en) * | 1995-02-07 | 1998-06-02 | Heinric Mack Nachf | Crystal modification of 2,4-diamino-6-hydroxymethylpteridine hydrobromide |
| CN1277197A (en) * | 1999-04-15 | 2000-12-20 | 阿泼洛发公司 | Stable crystal salt of 5-methyl tetrahydrofolic acid |
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| RENU CHADHA，等: "Characterization of solvatomorphs of methotrexate using thermoanalytical", 《ACTA PHARMACEUTICA》, vol. 59, no. 3, 31 December 2009 (2009-12-31), pages 245 - 257 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114516874A (en) * | 2022-03-11 | 2022-05-20 | 国药一心制药有限公司 | Methotrexate new crystal form and preparation method thereof |
| CN115197223A (en) * | 2022-05-25 | 2022-10-18 | 浙江致新医药科技有限公司 | Methotrexate crystal form A compound and preparation method thereof |
| CN117064850A (en) * | 2023-08-16 | 2023-11-17 | 海南卓泰制药有限公司 | Methotrexate injection and preparation method thereof |
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Address after: 100176 No. 6, Hongda Middle Road, Yizhuang economic and Technological Development Zone, Beijing, Daxing District Patentee after: Yuekang Pharmaceutical Group Co., Ltd. Address before: 100176 No. 6, Hongda Middle Road, Yizhuang economic and Technological Development Zone, Beijing, Daxing District Patentee before: YOUCARE PHARMACEUTICAL GROUP CO., LTD. |