CN103980279B - A kind of methotrexate compound and methotrexate for injection - Google Patents
A kind of methotrexate compound and methotrexate for injection Download PDFInfo
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Abstract
The present invention relates to field of medicine preparations, disclose methotrexate compound and compositions thereof shown in a kind of formula (I), described methotrexate compound powder X-ray diffraction algoscopy measures, and demonstrates characteristic diffraction peak with the X-ray powder diffraction pattern that 2 θ ± 0.2 angles of diffraction represent 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 ° of places.Methotrexate compound stability provided by the invention is significantly improved, quality controllable, and long-time placement is not susceptible to change, substantially increases 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 injection.
Background technology
Methotrexate is first treatment effective antimetabolite of tumor, chorionic epithelioma and acute lymphatic leukemia there is good therapeutic effect, the forties in 20th century, scientist found, the effective ingredient suppressing mice transplanted tumor euphorbia egg decoctum and spontaneous mammary carcinoma in lactobacillus casei is pterin three glutamic acid, and the latter has weak anti-folic acid effect；And observe shortage folic acid then bone marrow suppression system；Folic acid can promote the phenomenons such as leukemia development, therefore starts to find anticarcinogen from antifolate.Nineteen forty-seven aminopterin is tried out in clinic, and leukemia of children is effective.Continue after find methotrexate mouse leukemia L1210 is had higher therapeutic index, try out the fifties in clinic, quickly instead of aminopterin for leukemia treating, be extended to later treatment other tumor.It is to study one of the most deep antitumor drug.
Methotrexate, also known as Cytotoxic drugs, in order to alleviate its cytotoxic toxicity, calcium leucovorin can be coordinated to use together, be mainly used in treatment acute leukemia (acute lymphoblastic leukemia), breast carcinoma, chorionic epithelioma and malignant mole, incidence cancer, bone tumor, leukemia meninges spinal cord infiltration, pulmonary carcinoma, genital system tumor, hepatocarcinoma, intractable conventional kraft tinea, dermatomyositis, body myositis, ankylosing spondylitis, Crohn disease, psoriasis and psoriasis arthropathica, behcets disease and autoimmune disease.
Methotrexate is also a kind of immunosuppressant, it is possible to alleviate rheumatism process, and the therapeutic effect of the synovial membrane inflammation of rheumatoid arthritis is especially good, is one of medicine of employing up to of rheumatoid disease Disease.
Currently available technology discloses the multiple preparation containing methotrexate, tablet.Injection etc., as:
China application CN1754538 discloses a kind of methotrexate orally disintegrating tablet, it is made up of components such as methotrexate, dry adhesive, lubricant, disintegrating agent and correctivess, it is characterized in that the composition content of described oral cavity disintegration tablet, it is by weight percentage: the methotrexate of 3.5-7.5wt%, the carboxymethyl starch sodium of 20.0-24.0wt%, the microcrystalline Cellulose of 55.0-65.0wt%, the magnesium stearate of 1.0-2.0wt%, the mannitol of 10.0-20.0wt%.Although this oral cavity disintegration tablet can improve bioavailability to a certain extent, but its clinical application effect is still far away from drug administration by injection.
Lyophilized formulations is a kind of desirably drug administration by injection form, but owing to methotrexate raw material being proposed high requirement by methotrexate lyophilized formulations itself and process of clinical application, and the storage stability of methotrexate itself is not good, therefore, still await finding a kind of desirably methotrexate compound, be significantly better than the methotrexate for injection of prior art obtaining stability, curative effect etc. further.
Summary of the invention
The first object of the present invention is in that to provide a kind of methotrexate compound, to improve the stability of the methotrexate as preparation raw material itself.
For achieving the above object, the present invention adopts the following technical scheme that
A kind of methotrexate compound, described methotrexate compound powder X-ray diffraction algoscopy measures, and demonstrates characteristic diffraction peak with the X-ray powder diffraction pattern that 2 θ ± 0.2 angles of diffraction represent 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 ° of places；
Although methotrexate is a kind of known substance, but inventor finds in actual application, the poor stability of methotrexate itself, shows active constituent content and comparatively significantly decline in long-time preservation process, the drug safety of serious threat patient.
Inventor has been surprisingly found that in the process that methotrexate carries out recrystallization purifying, when selecting different dicyandiamide solutions, beat all can induce a kind of brand-new methotrexate compound by recrystallization method is controlled, with existing disclosed methotrexate powder diagram, the X-ray powder diffraction figure of this compound is compared discovery, and what the present invention obtained is a kind of brand-new methotrexate compound.This novel methotrexate compound itself and preparation thereof all show, at stability test etc., the advantage being significantly better than commercially available known methotrexate compound.
Additionally, in order to obtain a kind of maturation, the recrystallization method of repeatable realization industrial application, this has been done the test of a large amount of specific aim by inventor, optimize each operating procedure further, enable described preparation method stably to realize, it is thus achieved that homogeneous high-quality methotrexate compound.
It should be noted that methotrexate crude product of the present invention and commercially available known methotrexate, the concrete those skilled in the art that are retrieved as are grasped.
Preparation method of the present invention comprises the steps:
At (1) 35 DEG C-45 DEG C, weigh methotrexate crude product, join in the dibutyl phthalate that volume is equivalent to methotrexate crude product weight 20-40 times, stir；
(2) mixed liquor of ethanol and ether is configured by the amount ratio of 2～5:1, the volume of mixed liquor is the 1/5-8/5 of dibutyl phthalate, and in 1-3 hour, this mixed liquor at the uniform velocity stream is added in the dibutyl phthalate containing methotrexate, controlling solution system temperature simultaneously and be down to 20 DEG C-25 DEG C, stream adds the stirring at low speed in process with 5-10rmp；
(3) after stream adds, solution temperature is down to 0～5 DEG C, stands growing the grain 8～12 hours, filter, filter cake washed with diethylether, less than 40 DEG C cold drying 1～3 hour, obtain methotrexate compound.
Wherein, in described step 1, mixing speed is 30-40rmp, it is preferable that mixing speed is 35rmp.
In step 2, configure the mixed liquor of ethanol and ether by the amount ratio of 3:1, the volume of mixed liquor is the 4/5 of dibutyl phthalate, is added in solution A by this mixed liquor at the uniform velocity stream in 2 hours, controlling solution system temperature simultaneously and be down to 22 DEG C, stream adds the stirring at low speed in process with 6rmp.
In step 3, after stream adds, solution temperature is down to 2 DEG C, stands growing the grain 10 hours, filter, filter cake washed with diethylether, less than 40 DEG C cold drying 2 hours, obtain methotrexate compound.
In described step 3, cooling rate is 0.2-0.5 DEG C/min.
Unless otherwise indicated, weight of the present invention is g/ml with the unit of volume ratio.
Adopting technique scheme, the present invention can obtain high-quality methotrexate compound in batches, and above-mentioned preparation method is simple to operate, and equipment and artificial requirement is low, and repeatability is strong, and purity and yield high, be suitable for promoting production.
The second object of the present invention is in that to provide a kind of methotrexate for injection containing above-mentioned methotrexate compound.
Methotrexate for injection of the present invention, by weight, is prepared from by the raw material including following components: methotrexate 5g, sodium chloride 4-5g, mannitol 75-85g, makes 1000.
Or by weight, the raw material including following components be prepared from: methotrexate 100g, sodium chloride 0.5-1.5g, make 1000.
Further, as the best-of-breed technology scheme of the present invention, it is preferable that by weight, the raw material including following components it is prepared from: methotrexate 5g, sodium chloride 4.3g, mannitol 80g, makes 1000；Or methotrexate 100g, sodium chloride 1g, make 1000.
Above-mentioned methotrexate for injection can adopt various preparation methoies disclosed in prior art to prepare, and present invention preferably employs following technical scheme:
(1) methotrexate is weighed by prescription, inject water to the 80% of recipe quantity, regulating pH value with 1% sodium hydroxide solution is 8.5～9.0, add sodium chloride or sodium chloride and mannitol, stirring and dissolving, add to the full amount of water for injection, add 0.03% pin charcoal to adsorb 20 minutes, filtering decarbonization, degerming with 0.22um filtering with microporous membrane, middle product examine is surveyed；
(2) subpackage, partly jumps a queue；
(3) lyophilization:
Goods are put into and has been cooled in the freeze drying box of-40 DEG C, when products temperature is down to-40 DEG C, pre-freeze 3 hours, condenser freezes, and evacuation, after actuator temperature to be condensed and vacustat, shelf heats, and makes goods slowly heat up, and 3 DEG C/h of speed of speed are warming up to-8 DEG C, it is warming up to 10 DEG C with 2 DEG C/h of speed again, then is warming up to 30 DEG C with 4 DEG C/h of speed, keep 4 hours, terminate lyophilizing, tamponade, rolls lid, to obtain final product.
Above-mentioned freeze-drying process can prepare high-quality freeze-dried powder, and its outward appearance is good, and solubility and stability are superior to known formulations, thus ensure that the drug safety of patient.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction figure of methotrexate compound of the present invention；
Fig. 2 is the plasma concentration curve that test example 3 of the present invention obtains.
Detailed description of the invention
Following example are used for illustrating the present invention, but are not limited to the scope of the present invention.
The preparation of embodiment 1 methotrexate compound
The preparation of methotrexate compound:
At (1) 40 DEG C, weighing methotrexate crude product, join in the dibutyl phthalate that volume is equivalent to methotrexate crude product weight 30 times, stir, mixing speed is 35rmp；
(2) mixed liquor of ethanol and ether is configured by the amount ratio of 4:1, the volume of mixed liquor is the 4/5 of dibutyl phthalate, and in 2 hours, this mixed liquor at the uniform velocity stream is added in the dibutyl phthalate containing methotrexate, controlling solution system temperature simultaneously and be down to 22 DEG C, stream adds the stirring at low speed in process with 8rmp；
(3) after stream adds, solution temperature being down to 2 DEG C, cooling rate is 0.4 DEG C/min, stands growing the grain 10 hours, filter, filter cake washed with diethylether, less than 40 DEG C cold drying 2 hours, obtaining methotrexate compound, 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 (demonstrating 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 ° of places).
The preparation of embodiment 2 methotrexate compound
The preparation of methotrexate compound:
At (1) 35 DEG C, weighing methotrexate crude product, join in the dibutyl phthalate that volume is equivalent to methotrexate crude product weight 20 times, stir, mixing speed is 30rmp；
(2) mixed liquor of ethanol and ether is configured by the amount ratio of 2:1, the volume of mixed liquor is the 1/5 of dibutyl phthalate, and in 1 hour, this mixed liquor at the uniform velocity stream is added in the dibutyl phthalate containing methotrexate, controlling solution system temperature simultaneously and be down to 20 DEG C DEG C, stream adds the stirring at low speed in process with 5rmp；
(3) after stream adds, solution temperature being down to 0 DEG C, cooling rate is 0.2 DEG C/min, stands growing the grain 8 hours, filter, filter cake washed with diethylether, less than 40 DEG C cold drying 1 hour, obtaining methotrexate compound, 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 compound
The preparation of methotrexate compound:
At (1) 45 DEG C, weighing methotrexate crude product, join in the dibutyl phthalate that volume is equivalent to methotrexate crude product weight 40 times, stir, mixing speed is 40rmp；
(2) mixed liquor of ethanol and ether is configured by the amount ratio of 5:1, the volume of mixed liquor is the 8/5 of dibutyl phthalate, and in 3 hours, this mixed liquor at the uniform velocity stream is added in the dibutyl phthalate containing methotrexate, controlling solution system temperature simultaneously and be down to 25 DEG C, stream adds the stirring at low speed in process with 10rmp；
(3) after stream adds, solution temperature being down to 5 DEG C, cooling rate is 0.5 DEG C/min, stands growing the grain 12 hours, filter, filter cake washed with diethylether, less than 40 DEG C cold drying 3 hours, obtaining methotrexate compound, 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 compound
The preparation of methotrexate compound:
At (1) 42 DEG C, weighing methotrexate crude product, join in the dibutyl phthalate that volume is equivalent to methotrexate crude product weight 25 times, stir, mixing speed is 32rmp；
(2) mixed liquor of ethanol and ether is configured by the amount ratio of 3:1, the volume of mixed liquor is the 2/5 of dibutyl phthalate, and in 1.5 hours, this mixed liquor at the uniform velocity stream is added in the dibutyl phthalate containing methotrexate, controlling solution system temperature simultaneously and be down to 20 DEG C, stream adds the stirring at low speed in process with 6rmp；
(3) after stream adds, solution temperature being down to 2 DEG C, cooling rate is 0.4 DEG C/min, stands growing the grain 9 hours, filter, filter cake washed with diethylether, less than 40 DEG C cold drying 1 hour, obtaining methotrexate compound, 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 compound
The preparation of methotrexate compound:
At (1) 38 DEG C, weighing methotrexate crude product, join in the dibutyl phthalate that volume is equivalent to methotrexate crude product weight 25 times, stir, mixing speed is 40rmp；
(2) mixed liquor of ethanol and ether is configured by the amount ratio of 4:1, the volume of mixed liquor is the 3/5 of dibutyl phthalate, and in 1 hour, this mixed liquor at the uniform velocity stream is added in the dibutyl phthalate containing methotrexate, controlling solution system temperature simultaneously and be down to 20 DEG C, stream adds the stirring at low speed in process with 5rmp；
(3) after stream adds, solution temperature being down to 0～5 DEG C, cooling rate is 0.2 DEG C/min, stands growing the grain 9 hours, filter, filter cake washed with diethylether, less than 40 DEG C cold drying 2 hours, obtaining methotrexate compound, 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 injection
Prescription: the methotrexate compound methotrexate 5g obtained by embodiment 1, sodium chloride 4.3g, mannitol 80g, makes 1000；
Preparation method:
(1) methotrexate is weighed by prescription, inject water to the 80% of recipe quantity, regulating pH value with 1% sodium hydroxide solution is 8.8, add sodium chloride and mannitol, stirring and dissolving, add to the full amount of water for injection, add 0.03% pin charcoal to adsorb 20 minutes, filtering decarbonization, degerming with 0.22um filtering with microporous membrane, middle product examine is surveyed；
(2) subpackage, partly jumps a queue；
(3) lyophilization:
Goods are put into and has been cooled in the freeze drying box of-40 DEG C, when products temperature is down to-40 DEG C, pre-freeze 3 hours, condenser freezes, and evacuation, after actuator temperature to be condensed and vacustat, shelf heats, and makes goods slowly heat up, and 3 DEG C/h of speed of speed are warming up to-8 DEG C, it is warming up to 10 DEG C with 2 DEG C/h of speed again, then is warming up to 30 DEG C with 4 DEG C/h of speed, keep 4 hours, terminate lyophilizing, tamponade, rolls lid, to obtain final product.
Embodiment 7 methotrexate for injection
Prescription: the methotrexate compound methotrexate 100g obtained by embodiment 2, sodium chloride 1g, makes 1000.
Preparation method:
(1) methotrexate is weighed by prescription, inject water to the 80% of recipe quantity, regulating pH value with 1% sodium hydroxide solution is 8.9, add sodium chloride, stirring and dissolving, add to the full amount of water for injection, add 0.03% pin charcoal to adsorb 20 minutes, filtering decarbonization, degerming with 0.22um filtering with microporous membrane, middle product examine is surveyed；
(2) subpackage, partly jumps a queue；
(3) lyophilization:
Goods are put into and has been cooled in the freeze drying box of-40 DEG C, when products temperature is down to-40 DEG C, pre-freeze 3 hours, condenser freezes, and evacuation, after actuator temperature to be condensed and vacustat, shelf heats, and makes goods slowly heat up, and 3 DEG C/h of speed of speed are warming up to-8 DEG C, it is warming up to 10 DEG C with 2 DEG C/h of speed again, then is warming up to 30 DEG C with 4 DEG C/h of speed, keep 4 hours, terminate lyophilizing, tamponade, rolls lid, to obtain final product.
Embodiment 8 methotrexate for injection
Prescription: the methotrexate compound methotrexate 5g obtained by embodiment 1, sodium chloride 4g, mannitol 75g, makes 1000；
Preparation method:
(1) methotrexate is weighed by prescription, inject water to the 80% of recipe quantity, regulating pH value with 1% sodium hydroxide solution is 9.0, add sodium chloride and mannitol, stirring and dissolving, add to the full amount of water for injection, add 0.03% pin charcoal to adsorb 20 minutes, filtering decarbonization, degerming with 0.22um filtering with microporous membrane, middle product examine is surveyed；
(2) subpackage, partly jumps a queue；
(3) lyophilization:
Goods are put into and has been cooled in the freeze drying box of-40 DEG C, when products temperature is down to-40 DEG C, pre-freeze 3 hours, condenser freezes, and evacuation, after actuator temperature to be condensed and vacustat, shelf heats, and makes goods slowly heat up, and 3 DEG C/h of speed of speed are warming up to-8 DEG C, it is warming up to 10 DEG C with 2 DEG C/h of speed again, then is warming up to 30 DEG C with 4 DEG C/h of speed, keep 4 hours, terminate lyophilizing, tamponade, rolls lid, to obtain final product.
Embodiment 9 methotrexate for injection
Prescription: the methotrexate compound methotrexate 100g obtained by embodiment 2, sodium chloride 0.5g, makes 1000.
Preparation method:
(1) methotrexate is weighed by prescription, inject water to the 80% of recipe quantity, regulating pH value with 1% sodium hydroxide solution is 9.0, add sodium chloride, stirring and dissolving, add to the full amount of water for injection, add 0.03% pin charcoal to adsorb 20 minutes, filtering decarbonization, degerming with 0.22um filtering with microporous membrane, middle product examine is surveyed；
(2) subpackage, partly jumps a queue；
(3) lyophilization:
Goods are put into and has been cooled in the freeze drying box of-40 DEG C, when products temperature is down to-40 DEG C, pre-freeze 3 hours, condenser freezes, and evacuation, after actuator temperature to be condensed and vacustat, shelf heats, and makes goods slowly heat up, and 3 DEG C/h of speed of speed are warming up to-8 DEG C, it is warming up to 10 DEG C with 2 DEG C/h of speed again, then is warming up to 30 DEG C with 4 DEG C/h of speed, keep 4 hours, terminate lyophilizing, tamponade, rolls lid, to obtain final product.
Embodiment 10 methotrexate for injection
Compared with embodiment 7, distinctive points is only that the present embodiment prescription is: the methotrexate 100g obtained by embodiment 3, sodium chloride 1.5g, makes 1000.
Embodiment 11 methotrexate for injection
Compared with embodiment 7, distinctive points is only that the present embodiment prescription is: the methotrexate 5g obtained by embodiment 4, sodium chloride 5g, mannitol 85g, makes 1000.
The present invention furthermore provides following test example, further technical scheme to be illustrated.
Test example 1 methotrexate stability test
This test example have detected the stability (result of the test all calculates) of methotrexate compound provided by the present invention with each test group methotrexate weight.
This test carries out according to 2005 editions second annex XIXC medicine stability test guideline 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% |
| Matched group 1 | 99.90% | 99.52% | 98.41% | 94.51% | 92.02% |
Table 2, long-term test results
Wherein:
Matched group 1 is commercially available methotrexate；
The methotrexate compound of experimental group 1～4 respectively embodiment of the present invention 1～4 preparation；
This description of test, methotrexate compound good stability provided by the invention, accelerate, long term test purity changes of contents little.And prior art other hydrate crystal poor stabilities disclosed.With the optimal stability of embodiment 1 in aforementioned stable test.
Test example 2 methotrexate for injection stability test
Accelerated test
Method: take each experimental group sample, places six months in constant temperature 40 ± 2 DEG C, relative humidity 75 ± 5% drying baker.During testing in the 1st, 2,3 and 6 months respectively sampling once, detect by above-mentioned investigation project, and with 0 month results contrast.Result of the test shows, the character of obtained freeze-drying injectable powder of the present invention, pH value, clarity of solution and color, content and have related substance substantially unchanged.Concrete measurement result is in Table 3.
Table 3 methotrexate for injection accelerated test result
Long term test
Method: take each experimental group sample, in 25 ± 2 DEG C, places when relative humidity 60 ± 10%, during testing in the 3rd, 6,9,12 months respectively sampling once, detect by above-mentioned investigation project, and compared with 0 month.
Long term test to 12 months it is shown that the character of three batch samples, pH value, clarity of solution and color, content and have related substance substantially unchanged.Measurement result is in Table 4 and 5.
Table 4 methotrexate for injection long term test investigates result
Table 5 long term test pyrogen, sterility test result
Wherein sample 1,2 is the methotrexate for injection of the embodiment of the present invention 6,7 preparation；
Sample 3 is replace methotrexate compound of the present invention as raw material using commercially available methotrexate, by the methotrexate for injection that the preparation method identical with embodiment 6 and formula preparation obtain.
Conclusion (of pressure testing):
Trial target is the aseptic freeze-dried product adopting brown cillin bottle packaging, through 6 months accelerated tests and 12 months long term tests, compared with 0 month, every inspection target has no significant change, trial target has good stability, and is significantly better than the preparation prepared with commercially available methotrexate for raw material.
Other embodiments of the invention product has been also carried out identical experiment, and obtains the experimental result of same trend, but length is limit, and the present invention will not enumerate.
Test example 3 pharmacodynamics test
1. case selection suffers from Children with Malignant Tumors 20 example, male 11 examples, female 9 example, age 5-12 year, body weight 15-31kg.Sick 8 examples of acute lymphoblastic, non_hodgkin lymphoma 12 example, before chemotherapy, routine blood test and Liver and kidney function inspection are showed no exception.
Above-mentioned 20 experimenters are randomly divided into matched group and test group two groups.
2. medicine, reagent and first ammonia butterfly cry of certain animals concentration measure
Experimental group: the methotrexate for injection prepared by embodiment 6
Matched group: the sample 3 in test example 2, namely uses commercially available methotrexate crude product as raw material, other methotrexate for injection being prepared from by the technical scheme that embodiment 6 is identical.
Measuring first ammonia butterfly cry of certain animals blood drug level with fluorescence polarization immunoassay (FPIA), TDx instrument and methotrexate test kit Abbott of the U.S. of system (AbbottLaboratories) are produced.Regularly (0,6,12,18,24h) adopt the centrifugal 5min of venous blood 0.5ml, 3000r/min, draw serum, 4 DEG C of preservations are to be measured.Determination step is undertaken by TDx instrument operating guidance.FPIA method measures the minimum of first ammonia butterfly cry of certain animals and is limited to 0.01 μm of ol/L, in a few days difference and difference in the daytime equal < 10%.
3. chemotherapy regimen first ammonia butterfly cry of certain animals dosage is 1-2g/m2.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 be more than or equal to 7.Calcium leucovorin 6h after drug withdrawal gives, each intramuscular injection 15mg, 8-12 time altogether, or until methotrexate blood drug level is less than 0.05 μm of ol/L.
4. data process the plasma drug concentration data adopting the 3P87 program that Chinese Pharmacological Society's quantitative pharmacology can be compiled to process gained on SUN-386 computer.
Result is shown in Fig. 2, and wherein, series 1 is matched group plasma concentration curve, and series 2 is experimental group plasma concentration curve.Abscissa unit is h, and vertical coordinate unit is a μm ol/L.
From figure 2 it can be seen that the product of the present invention has more consistent blood drug level variation tendency, and product plasma concentration curve of the present invention change is more mild, it was shown that its bioavailability is high, and the plasma concentration curve of mitigation makes drug effect be able to better performance.
The methotrexate for injection of other embodiments of the present invention has also under equal conditions been carried out identical test respectively, and it has and upper identical trend.
Although, above use generality explanation, detailed description of the invention and test, the present invention is described in detail, but on basis of the present invention, it is possible to it is made some modifications or improvements, and this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, belong to the scope of protection of present invention.
Claims (10)
1. a methotrexate compound, it is characterized in that, described methotrexate compound powder X-ray diffraction algoscopy measures, described methotrexate compound has the X-ray powder diffraction pattern shown in Fig. 1, demonstrates characteristic diffraction peak with the X-ray powder diffraction pattern that 2 θ ± 0.2 angles of diffraction represent 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 ° of places；
2. the preparation method of methotrexate compound according to claim 1, comprises the following steps:
At (1) 35 DEG C-45 DEG C, weigh methotrexate crude product, join in the dibutyl phthalate that volume is equivalent to methotrexate crude product weight 20-40 times, stir；
(2) mixed liquor of ethanol and ether is configured by the amount ratio of 2～5:1, the volume of mixed liquor is the 1/5-8/5 of dibutyl phthalate, and in 1-3 hour, this mixed liquor at the uniform velocity stream is added in the dibutyl phthalate containing methotrexate, controlling solution system temperature simultaneously and be down to 20 DEG C-25 DEG C, stream adds the stirring at low speed in process with 5-10rmp；
(3) after stream adds, solution temperature is down to 0～5 DEG C, stands growing the grain 8～12 hours, filter, filter cake washed with diethylether, less than 40 DEG C cold drying 1～3 hour, obtain methotrexate compound.
3. preparation method according to claim 2, it is characterised in that in described step 1, mixing speed is 30-40rmp.
4. preparation method according to claim 2, it is characterized in that, in step 2, the mixed liquor of ethanol and ether is configured by the amount ratio of 3:1, the volume of mixed liquor is the 4/5 of dibutyl phthalate, being added in solution A by this mixed liquor at the uniform velocity stream in 2 hours, control solution system temperature simultaneously and be down to 22 DEG C, stream adds the stirring at low speed in process with 6rmp；Described solution A is the dibutyl phthalate containing methotrexate.
5. preparation method according to claim 2, it is characterised in that in step 3, after stream adds, is down to 2 DEG C by solution temperature, stands growing the grain 10 hours, filters, filter cake washed with diethylether, less than 40 DEG C cold drying 2 hours, obtains methotrexate compound.
6. the preparation method according to claim 2 or 5, it is characterised in that in described step 3, cooling rate is 0.2-0.5 DEG C/min.
7. contain the methotrexate for injection of methotrexate compound described in claim 1.
8. methotrexate for injection according to claim 7, it is characterised in that: by weight, the raw material including following components it is prepared from: methotrexate 5g, sodium chloride 4-5g, mannitol 75-85g, makes 1000.
9. methotrexate for injection according to claim 7, it is characterised in that: by weight, the raw material including following components it is prepared from: methotrexate 100g, sodium chloride 0.5-1.5g, makes 1000.
10. methotrexate for injection according to claim 8 or claim 9, it is characterised in that: by weight, the raw material including following components it is prepared from: methotrexate 5g, sodium chloride 4.3g, mannitol 80g, makes 1000；Or methotrexate 100g, sodium chloride 1g, make 1000.
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| 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 |
| CN117064850B (en) * | 2023-08-16 | 2024-05-03 | 海南卓泰制药有限公司 | Methotrexate injection and preparation method thereof |
Citations (2)
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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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Patent Citations (2)
| 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 |
Non-Patent Citations (2)
| Title |
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| Characterization of solvatomorphs of methotrexate using thermoanalytical;Renu Chadha，等;《Acta Pharmaceutica》;20091231;第59卷(第3期);第245-257页 * |
| Crystal and Molecular Structure of Methotrexate;T. W. Hambley，等;《J. Am. Chem. Soc.》;19861231;第108卷(第8期);第2103-2105页 * |
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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. |