CN103393687B - A kind of pharmaceutical composition containing calcium levofolinate and fluorouracil - Google Patents
A kind of pharmaceutical composition containing calcium levofolinate and fluorouracil Download PDFInfo
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- CN103393687B CN103393687B CN201310332724.1A CN201310332724A CN103393687B CN 103393687 B CN103393687 B CN 103393687B CN 201310332724 A CN201310332724 A CN 201310332724A CN 103393687 B CN103393687 B CN 103393687B
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Abstract
The present invention relates to the pharmaceutical composition of a kind of calcium levofolinate and fluorouracil, especially Combination application packaging, comprise l-leucovorin calcium injection and the injection containing fluorouracil.By the intravenous injection of l-leucovorin calcium injection during use, then use Adrucil intravenous injection.
Description
Technical field
The present invention relates to the pharmaceutical composition of a kind of calcium levofolinate and fluorouracil, be specifically related to the Combination application packaging of a kind of l-leucovorin calcium injection and the injection containing fluorouracil, belong to medical art.
Background technology
Folinic acid is the non-enantiomer mixture of the 5-formyl derivative of tetrahydrofolic acid (THF), and its bioactive substance is that levo form is called l-leucovorin.Folinic acid does not need the reduction through dihydrofolate reductase and participates in the biological respinse using folic acid as transfer " carbon-based group " carrier in body directly.L-folinic acid (L-5 formyl tetrahydrofolic acid) tachymetabolism (being followed successively by 5,10-methyl tetrahydrofolate, 5,10-folinic acid tetrahydrofolic acid) is L-5-methyl tetrahydrofolate.L-5-methyl tetrahydrofolate can be 5,10-CH2-THFA by other approach metabolism, and 5,10-CH2-THFA, by the catalytic reduction of PDAH2 and NADPH coenzyme, is irreversibly converted into 5-methyltetrahydrofolate.
Use folinic acid can offset therapeutic effect and the toxicity of the salt acid antagonist (such as methotrexate) suppressing dihydrofolate reductase.
Folinic acid can strengthen the curative effect of 5-FU (as 5-fluorouracil) in oncotherapy and toxic action.Use folinic acid to seem not change the pharmacokinetics process of 5-fluorouracil in blood plasma simultaneously.5-fluorouracil in vivo metabolism is deoxyfluoruridine nucleotide, in conjunction with and suppress thymidylate synthetase (this enzyme DNA repair and very important in copying).Folinic acid is easy to change into 5,10-CH2-THFA in vivo, and this conversion product can the acid of stabilized deoxy fluorouracil nucleoside and the combination of thymidylate synthetase, and then strengthens the inhibitory action to this enzyme.
Fluorouracil is the fluoride of miazines, belongs to antimetabolic antineoplastic agent, can suppress thymidylate synthase, blocks deoxyribonucleotides nucleotide and converts thymidine core to, and interference DNA synthesis, also has certain inhibitory action to the synthesis of RNA.
Fluorouracil is 5-fluorouracil deoxynucleoside through enzymic transformation in vivo, forms covalent bond, the activity of this enzyme is suppressed with the active center of thymidine synzyme, thymidine is generated and reduces, cause the biosynthesis of DNA to be obstructed; In addition, it also can change triphosphoric acid fluorouracil nucleoside into, mixes in RNA with pseudo-metabolite form, thus the normal physiological function of RNA interfering, affect the biosynthesis of protein.Recent study finds, the active metabolite 5-fluorouracil deoxynucleoside of fluorouracil and tetrahydrofolic acid can form three complex with thymidine synzyme, stops the activation plays of thymidine synzyme, thus suppresses the synthesis of DNA.
Fluorouracil antitumor spectra is comparatively wide, is mainly used in treating digestive tract tumor, or larger dose fluorouracil in treatment chorionic epithelioma.Also treatment breast carcinoma, ovarian cancer, pulmonary carcinoma, cervical cancer, bladder cancer and skin carcinoma etc. are usually used in.
From oncobiology angle, continuous infusion 5-Fu and l-leucovorin simultaneously, to utilizing thymine synthetase, 5-Fu metabolite completely in whole infusion process, and l-leucovorin derivant forms the effect that stable tetrahedron complex produces, this is also suppress and destroy the key mechanism of fast breeding tumor cell.
But normally used l-leucovorin is calcium salt clinically, and calcium levofolinate active component is l-leucovorin, and calcium ion does not have pharmacological action, and does not help activity.Use calcium levofolinate and 5-Fu simultaneously, transfusion can be made to produce precipitation, cause the blocking of transfusion catheter.Clinically, calcium levofolinate must to be staggered the time administration with 5-Fu.But, the hypercalcemia of calcium levofolinate, vascular stimulation, heart damage and drip the side effect such as speed is limited.
Be badly in need of the preparation that l-leucovorin calcium injection and Adrucil can be provided with assembly packaging clinically, not only meet the mutual promoting action of calcium levofolinate and fluorouracil, more importantly be to reduce both potential side effect well, improve drug safety.
Summary of the invention
In order to overcome the series of problems existed in prior art, the present inventor has creatively found to adopt the l-leucovorin calcium injection of particular excipient and the use in conjunction of Adrucil, not only completely solve water solublity and the stability problem of calcium levofolinate, facilitate clinical application, and owing to adding stevioside in l-leucovorin calcium injection, more can strengthen the anti-tumor activity of 5-fluorouracil than alone calcium folinate and reduce methotrexate toxic and side effects.
The stevioside that the present invention adds has good hydrotropy effect to calcium levofolinate, solves the problem of its poorly water-soluble, avoids introducing too much impurity, and the membership that adds of some inorganic salt cosolvent makes freeze-dried powder occur volume-diminished, duricrust and the crisp phenomenon such as loose; Stevioside also has good bulk skeleton function simultaneously, makes prepared calcium levofolinate freeze-dried powder substantially keep original volume, uniform color by adding stevioside, is easy to dissolve form clear and bright solution.
In fact, inventor is surprisingly found out that, the transfusion of the calcium levofolinate after adding stevioside produces precipitation, causes the problem of the blocking of transfusion catheter not only to obtain unexpected solution, in addition calcium levofolinate also mitigate hypercalcemia, vascular stimulation, heart damage side effect.
An object of the present invention, provides the pharmaceutical composition of a kind of calcium levofolinate and fluorouracil, and wherein, calcium levofolinate is the injection adding stevioside; Fluorouracil is sterile freeze-drying preparation containing fluorouracil or aseptic parenteral solution.
An object of the present invention, provide the pharmaceutical composition of a kind of l-leucovorin calcium injection and Adrucil, wherein, l-leucovorin calcium injection is the sterile freeze-drying preparation or the aseptic parenteral solution that add stevioside, and fluorouracil is sterile freeze-drying preparation containing fluorouracil or aseptic parenteral solution.
An object of the present invention, provide the Combination application packaging of a kind of l-leucovorin calcium injection and fluorouracil, wherein, l-leucovorin calcium injection is the sterile freeze-drying preparation or the aseptic parenteral solution that add stevioside, and fluorouracil is sterile freeze-drying preparation containing fluorouracil or aseptic parenteral solution.
Combination application packaging provided by the invention, usage is: calcium levofolinate 100mg/m
2(in l-leucovorin) adds normal saline 100ml iv drip 1 hour, gives 5-fluorouracil 375 ~ 425mg/m afterwards
2intravenous drip 4 ~ 6 hours.
Combination application packing specification provided by the invention is contain calcium levofolinate in l-leucovorin calcium injection per unit preparation in l-leucovorin 3mg-0.5g, and in Adrucil per unit preparation, containing fluorouracil is 40mg-0.5g.
As one of specific embodiment, concrete set of specifications is divided and is comprised:
(1) 3mg; (2) 5mg; (3) 25mg; (4) 30mg; (5) 50mg; (6) 100mg; (7) 200mg; (8) 300mg; (9) 350mg; (10) 150mg; (11) 3ml:30mg; (12) 5ml:50mg; (13) 10ml:100mg; (14) 50ml: l-leucovorin 50mg and sodium chloride 0.45g; (15) 100ml: l-leucovorin 100mg and sodium chloride 0.9g; (16) 100ml: l-leucovorin 200mg and sodium chloride 0.9g; (17) 250ml: l-leucovorin 300mg and sodium chloride 2.25g.
Present invention also offers a kind of preparation method of l-leucovorin calcium injection, concrete steps are:
(1) in material-compound tank, first add the water for injection of recipe quantity 80%;
(2) add calcium levofolinate and the stevioside of recipe quantity, stirring and dissolving is complete, regulates pH to be 7.0-8.0 with 1mol/L sodium hydroxide solution or 1mol/L hydrochloric acid solution;
(3) add total amount 0.03%(g/ml) injection-use activated carbon, add residue water for injection, standardize solution, stirring and adsorbing 30 minutes;
(4) solution coarse filtration takes off charcoal, through 0.45 μm of cartridge filter coarse filtration, then uses 0.22 μm of microporous filter membrane aseptic filtration qualified to visible foreign matters;
(5) fill, sealing, sterilizing, obtains calcium levofolinate injection; Or fill, lyophilization, obtains injection calcium levofolinate.
As the present invention one preferred embodiment, wherein in preparation method, lyophilized injectable powder freeze drying process is:
1. the pre-freeze phase, shelf temperature is cooled to-40 DEG C ± 2 DEG C, when products temperature reaches-35 DEG C ± 2 DEG C, (approximately needs 3 hours), be incubated about 2 hours, make product freeze reality completely;
2. distil the phase, when in case, force value reaches below 10Pa, arranging flaggy temperature is-4 DEG C ± 2 DEG C, and arranging dry case vacuum is 30Pa, slowly heat up to flaggy, product starts to distil (plate temperature rises to-4 DEG C ± 2 DEG C by-40 DEG C ± 2 DEG C) under vacuum.Shelf temperature rises to-4 DEG C ± 2 DEG C, after ice crystal disappears, be incubated about 2 hours;
3. dry period, arranging flaggy temperature is 30 DEG C, and flaggy continues slowly to heat up, and product carries out drying (plate temperature rises to 30 DEG C ± 1 DEG C by-4 DEG C ± 2 DEG C and about needs 2 hours) under vacuum; Shelf temperature reaches 30 DEG C ± 1 DEG C, and products temperature is warming up to about 20 DEG C ± 2 DEG C, is incubated about 2 ~ 3 hours, terminates lyophilizing, carries out pressing full plug.
Adrucil of the present invention is sterile freeze-drying preparation containing fluorouracil or aseptic parenteral solution.
As one of specific embodiment, under concrete set of specifications is divided and is comprised:
(1) 0.125g:(2) 0.25g; (3) 0.5g; (4) 10ml:0.25g; (5) 10ml:40mg:(6) 250ml: fluorouracil 0.25g and sodium chloride 2.25g; (7) 250ml: fluorouracil 0.5g and sodium chloride 2.25g; (8) 100ml: fluorouracil 0.25g and sodium chloride 0.9g; (9) 100ml: fluorouracil 0.5g and sodium chloride 0.9g; (10) 200ml: fluorouracil 0.5g and sodium chloride 1.8g; (11) 500ml: fluorouracil 0.5g and glucose 25g.
Present invention also offers a kind of preparation method of Adrucil, concrete steps are:
(1) in material-compound tank, first add the water for injection of recipe quantity 80%;
(2) add fluorouracil and other adjuvants of recipe quantity, stirring and dissolving is complete, regulates pH to be 8.4-9.2 with 1mol/L sodium hydroxide solution or 1mol/L hydrochloric acid solution;
(3) add total amount 0.05%(g/ml) injection-use activated carbon, add residue water for injection, standardize solution, stirring and adsorbing 30 minutes;
(4) solution coarse filtration takes off charcoal, through 0.45 μm of cartridge filter coarse filtration, then uses 0.22 μm of microporous filter membrane aseptic filtration qualified to visible foreign matters;
(5) fill, sealing, sterilizing, obtains Fluorouracil Injection; Or fill, lyophilization, obtains injection fluorouracil.
The Combination application that present invention also offers a kind of l-leucovorin calcium injection and Adrucil is packaged in the application in auxiliary treatment of colon-rectum etc.Calcium levofolinate associating fluorouracil uses, and can extend survival period.
The present invention, by adding stevioside, reduces methotrexate toxic and side effects, meanwhile, also add the anti-tumor activity of fluorouracil; Improve the water solublity of calcium folinate freeze-dried powder, more easily make the preparation of high concentration, facilitate clinical application; Supplementary product consumption is few, can maximum possible avoid interaction between adjuvant or adjuvant to the negative effect of medicine, human body; The present invention, by the improvement to calcium folinate prescription and freeze-dry process, makes the quality of obtained calcium folinate lyophilized powder loosen, and can dissolve rapidly and recover the primary characteristic of medicinal liquid, and the stability of calcium folinate improves after adding water.Meanwhile, make products obtained therefrom rapid-action, bioavailability is high; Dosage is controlled, good appearance; Processing technology is simple, and it is reliable, convenient, safe and practical to use, and can reduce production cost, be applicable to realize suitability for industrialized production.
Detailed description of the invention
embodiment 1the preparation of injection calcium levofolinate freeze-dried powder
Prescription:
Preparation process:
(1) first 7200ml water for injection is added in a reservoir;
(2) add calcium levofolinate in l-leucovorin 225g and stevioside 720g, stirring and dissolving is complete, regulates pH to be 7.7 with 1mol/L sodium hydroxide solution or 1mol/L hydrochloric acid solution;
(3) add 2.7g injection-use activated carbon, add residue water for injection, standardize solution 9000ml, stirring and adsorbing 30 minutes;
(4) solution coarse filtration takes off charcoal, through 0.45 μm of cartridge filter coarse filtration, then uses 0.22 μm of microporous filter membrane aseptic filtration qualified to visible foreign matters;
(5) fill, 1ml/ bottle or 2ml/ bottle or 6ml/ bottle;
(6) lyophilization
1. the pre-freeze phase, shelf temperature is cooled to-40 DEG C ± 2 DEG C, when products temperature reaches-35 DEG C ± 2 DEG C, (approximately needs 3 hours), be incubated about 2 hours, make product freeze reality completely;
2. distil the phase, when in case, force value reaches below 10Pa, arranging flaggy temperature is-4 DEG C ± 2 DEG C, and arranging dry case vacuum is 30Pa, slowly heat up to flaggy, product starts to distil (plate temperature rises to-4 DEG C ± 2 DEG C by-40 DEG C ± 2 DEG C) under vacuum.Shelf temperature rises to-4 DEG C ± 2 DEG C, after ice crystal disappears, be incubated about 2 hours;
3. dry period, arranging flaggy temperature is 30 DEG C, and flaggy continues slowly to heat up, and product carries out drying (plate temperature rises to 30 DEG C ± 1 DEG C by-4 DEG C ± 2 DEG C and about needs 2 hours) under vacuum; Shelf temperature reaches 30 DEG C ± 1 DEG C, and products temperature is warming up to about 20 DEG C ± 2 DEG C, is incubated about 2 ~ 3 hours, terminates lyophilizing, carries out pressing full plug.
embodiment 2the preparation of calcium levofolinate injection
Prescription:
Preparation process:
(1) first in Agitation Tank, 14400ml water for injection is added;
(2) add calcium levofolinate in l-leucovorin 180g and stevioside 90g, stirring and dissolving is complete, regulates pH to be 7.6 with 1mol/L sodium hydroxide solution or 1mol/L hydrochloric acid solution;
(4) add 5.4g injection-use activated carbon, add residue water for injection, standardize solution 18000ml, stirring and adsorbing 30 minutes;
(5) solution coarse filtration takes off charcoal, through 0.45 μm of cartridge filter coarse filtration, then uses 0.22 μm of microporous filter membrane aseptic filtration qualified to visible foreign matters;
(6) fill, 3ml/ props up or 50ml/ props up or 10ml/ props up, and sealing, sterilizing, obtains calcium levofolinate injection.
embodiment 3the preparation of Fluorouracil Injection
Prescription:
Preparation process:
(1) water for injection of 8000ml is first added in a reservoir;
(2) add 250g fluorouracil, stirring and dissolving is complete, regulates pH to be 8.8 with 1mol/L sodium hydroxide solution;
(3) add the injection-use activated carbon of 5g, add residue water for injection, standardize solution, stirring and adsorbing 30 minutes;
(4) solution coarse filtration takes off charcoal, through 0.45 μm of cartridge filter coarse filtration, then uses 0.22 μm of microporous filter membrane aseptic filtration qualified to visible foreign matters;
(5) fill, 10ml/ props up, and sealing, sterilizing, obtains Fluorouracil Injection.
embodiment 4the preparation of injection fluorouracil freeze-dried powder
Prescription:
Preparation process:
(1) water for injection of 4000ml is first added in a reservoir;
(2) add 250g fluorouracil, stirring and dissolving is complete, regulates pH to be 8.9 with 1mol/L sodium hydroxide solution;
(3) add the injection-use activated carbon of 2.5g, add residue water for injection, standardize solution, stirring and adsorbing 30 minutes;
(4) solution coarse filtration takes off charcoal, through 0.45 μm of cartridge filter coarse filtration, then uses 0.22 μm of microporous filter membrane aseptic filtration qualified to visible foreign matters;
(5) fill, 5ml/ bottle, lyophilization, obtains injection fluorouracil.
embodiment 5the preparation of assembly packaging medicine
Combination 1: injection calcium levofolinate freeze-dried powder 25mg and Fluorouracil Injection 10ml:0.25g.
Combination 2: injection calcium levofolinate freeze-dried powder 25mg and injection fluorouracil freeze-dried powder 0.25g.
Combination 3: injection calcium levofolinate freeze-dried powder 50mg and Fluorouracil Injection 10ml:0.25g.
Combination 4: injection calcium levofolinate freeze-dried powder 50mg and injection fluorouracil freeze-dried powder 0.25g.
Combination 5: injection calcium levofolinate freeze-dried powder 150mg and Fluorouracil Injection 10ml:0.25g.
Combination 6: injection calcium levofolinate freeze-dried powder 150mg and injection fluorouracil 0.25g.
Combination 7: calcium levofolinate injection 3ml:30mg and Fluorouracil Injection 10ml:0.25g.
Combination 8: calcium levofolinate injection 3ml:30mg and injection fluorouracil freeze-dried powder 0.25g.
Combination 9: calcium levofolinate injection 5ml:50mg and Fluorouracil Injection 10ml:0.25g.
Combination 10: calcium levofolinate injection 5ml:50mg and injection fluorouracil freeze-dried powder 0.25g.
Combination 11: calcium levofolinate injection 10ml:100mg and Fluorouracil Injection 10ml:0.25g.
Combination 12: calcium levofolinate injection 10ml:100mg and injection fluorouracil freeze-dried powder 0.25g.
Test example 1 pharmacology irritant test
Get the New Zealand Journal of Health Physical Education doe 24 of body weight 2.0-2.5kg, be divided into six groups at random.New zealand rabbit is placed in holder, first group of abdominal part hypodermic embodiment of the present invention 5 combines the medicine of 3, second group of abdominal part hypodermic embodiment of the present invention 5 combines the medicine of 4, 3rd group of abdominal part hypodermic embodiment of the present invention 5 combines the medicine of 9, 4th group of abdominal part hypodermic embodiment of the present invention 5 combines the medicine of 10, the injection calcium levofolinate of the 5th group of same specification of the abdominal part hypodermic embodiment of the present invention 1, the calcium levofolinate injection of the 6th group of same specification of the abdominal part hypodermic embodiment of the present invention 2, every new zealand rabbit injection 5ml, during injection and after injection, note observing injection site with or without redness, congested, the stimulation such as hemorrhage and downright bad.In last administration after 24 hours, by sacrifice of animal, drawn materials in injection site, carry out histopathologic examination.
Result of the test:
Perusal: six groups all do not occur the irritant reaction such as obvious redness, hyperemia, necrosis.
Pathological examination: six groups of skin texture are normal, and epidermis is without thickening, and subcutaneous tissue has no the morphological changes such as hyperemia, edema, has no the changes such as inflammatory cell infiltration.
Conclusion: assembly packaging product of the present invention relative to the effect of one-component application of stimulus without obvious increase.
Test example 2 clinical effect trial
Choose patient 140 example of certain hospital's colon-rectum treatment, be divided into seven groups at random, often organize 20 examples,
First group of intravenous injection injection calcium levofolinate freeze-dried powder 50mg, once a day,
Second group of intravenous injection calcium levofolinate injection 5ml:50mg, once a day,
3rd group of intravenous injection injection calcium levofolinate 50mg+ Fluorouracil Injection 10ml:0.25g, once a day,
4th group of intravenous injection calcium levofolinate injection 5ml:50mg+ Fluorouracil Injection 10ml:0.25g, once a day,
5th group of intravenous injection injection calcium levofolinate freeze-dried powder 50mg+ injection fluorouracil 0.25g, once a day,
6th group of intravenous injection calcium levofolinate injection 5ml:50mg+ injection fluorouracil freeze-dried powder 0.25g, once a day.Above product is all products of the embodiment of the present invention.
(Shanxi Powerdone Pharmaceutical Co., Ltd. produces 7th group of venoclysis commercially available injection calcium levofolinate freeze-dried powder, lot number 120301)+commercially available Fluorouracil Injection 10ml:0.25g(Changchun Tian Cheng pharmaceutcal corporation, Ltd production, lot number 20111203), once a day.
Continuous use 6 days.Efficacy result is as following table:
The clinical effectiveness of table 1 seven groups of patients
| Group | Number of cases | Effective | Effectively | Invalid | Total effective rate |
| First group | 20 | 11 | 3 | 6 | 70% |
| Second group | 20 | 9 | 5 | 6 | 70% |
| 3rd group | 20 | 14 | 4 | 2 | 90% |
| 4th group | 20 | 12 | 6 | 2 | 90% |
| 5th group | 20 | 10 | 7 | 3 | 85% |
| 6th group | 20 | 13 | 6 | 1 | 95% |
| 7th group | 20 | 10 | 6 | 4 | 80% |
The untoward reaction of table 2 seven groups of patients
| Group | Number of cases | Hypercalcemia | Vascular stimulation | Heart damage | Amount to |
| First group | 20 | 4 | 2 | 5 | 11 |
| Second group | 20 | 3 | 4 | 3 | 10 |
| 3rd group | 20 | 1 | 0 | 2 | 3 |
| 4th group | 20 | 2 | 1 | 1 | 4 |
| 5th group | 20 | 0 | 2 | 1 | 3 |
| 6th group | 20 | 1 | 2 | 0 | 3 |
| 7th group | 20 | 2 | 3 | 2 | 7 |
Can be found out by above result, the total effective rate the 3rd group to the 6th group of seven groups of patients is apparently higher than first, second and the 7th group, and untoward reaction the 3rd group to the 6th group is starkly lower than first, second and the 7th group; Illustrate employing of the present invention add particular excipient as the l-leucovorin calcium injection after stevioside and fluorouracil share after better efficacy, and significantly reduce two kinds of existing side effect of active component, thus demonstrate innovative point place of the present invention.
Claims (1)
1. containing calcium levofolinate and fluorouracil a pharmaceutical composition, it is characterized in that calcium levofolinate is injection, l-leucovorin calcium injection is selected from the sterile freeze-drying preparation of injection calcium levofolinate; Fluorouracil is injection, is selected from the sterile freeze-drying preparation containing fluorouracil or aseptic parenteral solution;
Wherein, the sterile freeze-drying preparation of injection calcium levofolinate is made up of following composition:
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| CN102125558A (en) * | 2011-01-10 | 2011-07-20 | 齐建新 | Compound sodium levofolinate fluorouracil antineoplastic medicament |
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| CN102125558A (en) * | 2011-01-10 | 2011-07-20 | 齐建新 | Compound sodium levofolinate fluorouracil antineoplastic medicament |
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| Title |
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| 亚叶酸钙与生化调节;李克俭;《中国癌症杂志》;19990331;第9卷(第1期);参见第54页左栏第2段-第55页右栏第4段 * |
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