CN105079029A - Detoxifying antagonist and calcium folinate composition injection for tumor medication - Google Patents
Detoxifying antagonist and calcium folinate composition injection for tumor medication Download PDFInfo
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- CN105079029A CN105079029A CN201510619132.7A CN201510619132A CN105079029A CN 105079029 A CN105079029 A CN 105079029A CN 201510619132 A CN201510619132 A CN 201510619132A CN 105079029 A CN105079029 A CN 105079029A
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- calcium folinate
- calcium
- folinate
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Abstract
The invention relates to a detoxifying antagonist and calcium folinate composition injection for tumor medication, and belongs to the technical field of medicine. The composition consists of calcium folinate and calcium chloride, wherein the calcium folinate is crystal, and an X-ray powder diffraction figure measured by a Cu-K alpha ray is shown in the figure 1. The new crystal form of the provided calcium folinate is different from the crystal form structure in the prior art, and experiments prove that compared with the prior art, the provided calcium folinate crystal form compound is good in stability, low in impurity content and better in stability. Compared with the prior art, the solubility and the flowability of the provided calcium folinate crystal form compound in water are obviously improved, the problems that in the prior art, the water solubility of calcium folinate is poor, the stability is poor and the related substance content is high are solved, convenience is provided for agent preparation, the medical effects are also improved, and the injection prepared by utilizing the new crystal form compound is good in stability and very suitable for clinical application.
Description
Technical field
The invention belongs to medical art, relate to the removing toxic substances antagonist calcium folinate compositions aqueous injection in a kind of tumor pharmacother.
Background technology
Calcium folinate has Detoxication to methotrexate (MTX).MTX is antifol, the Antitumor Mechanism of MTX is that its similar is in folic acid, can suppress the activity of dihydrofolate reductase, causes cell tetrahydrofolic acid (FH4) to lack, thus affecting purine and the synthesis of miazines nucleotide, inhibition tumor cell grows.Also make while the growth of MTX inhibition tumor cell normal cell especially grow faster in cell FH4 lack, and produce larger toxic action.Therefore the antitumor action of MTX not only depends on its suppression to tumor cell, and body also affects its final result to the toleration of MTX.CF is the formylated derivant of reduction of folates type, is folic acid activated form in vivo, can be cell and directly provide FH4, and do not need the effect of dihydrofolate reductase, thus CF can the toxic action of obvious antagonism MTX.
Calcium folinate can strengthen the anti-tumor activity of 5-fluorouracil (5-FU).5-FU can change fluorine Deoxydization nucleotide (FdUMP) in vivo into, suppresses thymidylate synthetase (TS), and then suppresses the synthesis of DNA.The combination of FdUMP and TS needs the participation of formyl tetrahydrofolic acid (CH2FH4), in cell, form TS-CH2FH4-FdUMP ternary complex.But the ternary complex that physiological concentration CH2FH4 is formed easily is separated.CH2FH4 in cell can be made to reach high concentration after providing the CF of heavy dose, make TS-CH2FH4-FdUMP ternary complex combine closely, stablize, thus enhance the anti-tumor activity of 5-FU.
The dissolubility of calcium folinate in water is not ideal, calcium folinate is found in water temperature lower than not soluble when 30 DEG C in practice, dissolving bad meeting causes content to reduce, responsive to factors such as temperature, pH value, oxygen, cause related substance to increase, unstable, meet light easily to decompose, shelf life stability is poor, makes its formulation application and clinical practice all be subject to a definite limitation, and adds preparation cost.Although calcium folinate reduces the toxic action of antitumor drug MTX, its toxic action still can not be ignored.Prior art is all by changing the adjuvant of preparation and preparation method solves its problem such as water solublity and stability, must rely on specific prescription and technique to reach its stablizing effect, make the preparation of preparation and the selection of adjuvant bring certain limitation.
Calcium folinate liquid drugs injection commercially available is at present unstable, meets light and easily degrades, storage period poor stability.The present inventor starts with from the research of calcium folinate solid chemical material existence, has prepared a kind of new calcium folinate crystalline compounds through a large amount of tests.Calcium folinate crystal-form compound provided by the present invention comparatively prior art compares good stability, dissolubility in water, mobility comparatively prior art are compared and are significantly improved, solve calcium folinate poorly water-soluble in prior art, stability is bad, its related substances is high problem, preparation for preparation provides conveniently, also drug effect is substantially increased, utilize the aqueous injection that this crystal compound is obtained, good stability, is very suitable for clinical practice.
Summary of the invention
Goal of the invention of the present invention is to provide the aqueous injection of the removing toxic substances antagonist calcium folinate compositions in a kind of tumor pharmacother.
In order to complete object of the present invention, the technical scheme of employing is:
A removing toxic substances antagonist calcium folinate compositions aqueous injection in tumor pharmacother, described compositions is made up of calcium folinate, calcium chloride; Described calcium folinate is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
First optimal technical scheme of the present invention is the weight ratio of calcium folinate and calcium chloride is 1:0.3-0.7.
Second optimal technical scheme of the present invention is the weight ratio of calcium folinate and calcium chloride is 1:0.4-0.6.
3rd optimal technical scheme of the present invention is the weight ratio of calcium folinate and calcium chloride is 1:0.5.
4th optimal technical scheme of the present invention is that the preparation method of described compositions aqueous injection comprises the following steps:
Get the calcium folinate of recipe quantity, calcium chloride, be dissolved in water for injection, add the active carbon stirring at room temperature 30min of 1% of calcium folinate weight, filter carbon removal, filtrate injects water to 2000ml, crosses 0.22 μm of filter membrane, dividing is filled in 2ml ampoule, 121 DEG C of pressure sterilizing 45min, lamp inspection, obtains calcium folinate aqueous injection.
The preparation method of the calcium folinate crystal in the present composition comprises the following steps:
(1) be that in the water of 10 times of calcium folinate weight and the mixed solution of carbon tetrachloride, the volume ratio of described water and carbon tetrachloride is 4:2.5 to 35 DEG C of volumes by calcium folinate dissolving crude product;
(2) add the activated carbon decolorizing that weight is 0.2 times of calcium folinate weight, filter, obtain calcium folinate solution;
(3) by calcium folinate solution warms to 40 DEG C, in calcium folinate solution, drip propyl ether under the condition of stirring, the volume of propyl ether is 8 times of calcium folinate weight, at the uniform velocity dropwises in 0.5h, and described stir speed (S.S.) is 30rmp;
(4) be cooled to-10 DEG C with the speed of 15 DEG C/h after being added dropwise to complete, continue to stir 2h under the stir speed (S.S.) of 15rmp, leave standstill 3h crystallize out, filter, washing, vacuum drying obtains calcium folinate crystal.
The polymorphism of solid chemical is the natural phenomena that a kind of general material exists, this phenomenon refers to that a kind of solid chemical can exist 2 kinds or two or more crystal form state, be also called the polymorphic state of material, the polymorphic state of material is also referred to as " allomorphism " phenomenon.Although its chemical nature of allomorphous solid matter is identical, its physicochemical property may be different.For " allomorphism medicine " that physicochemical property is different, also can show the curative effect of different disease preventing and treating clinically, directly affect application and the clinical effectiveness of medicine.
The present invention is by the precise controlling to crystallization condition, and prepared a kind of calcium folinate novel crystal forms unlike the prior art, the X-ray powder diffraction pattern of this calcium folinate crystal unlike the prior art.Simultaneously due to the ins and outs of this crystal formation, find through test, calcium folinate crystal-form compound provided by the present invention comparatively prior art compares good stability, dissolubility in water, mobility comparatively prior art are compared and are significantly improved, solve calcium folinate poorly water-soluble in prior art, stability is bad, its related substances is high problem, preparation for preparation provides conveniently, also drug effect is substantially increased, utilize the aqueous injection good stability that this crystal compound is obtained, be very suitable for clinical practice.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction that the calcium folinate crystal of the embodiment of the present invention 1 preparation uses the measurement of Cu-K alpha ray to obtain.
Detailed description of the invention
Below by specific embodiment, summary of the invention of the present invention is described in further detail, but does not therefore limit content of the present invention.
embodiment 1:the preparation of calcium folinate crystal
(1) be that in the water of 10 times of calcium folinate weight and the mixed solution of carbon tetrachloride, the volume ratio of described water and carbon tetrachloride is 4:2.5 to 35 DEG C of volumes by calcium folinate dissolving crude product;
(2) add the activated carbon decolorizing that weight is 0.2 times of calcium folinate weight, filter, obtain calcium folinate solution;
(3) by calcium folinate solution warms to 40 DEG C, in calcium folinate solution, drip propyl ether under the condition of stirring, the volume of propyl ether is 8 times of calcium folinate weight, at the uniform velocity dropwises in 0.5h, and described stir speed (S.S.) is 30rmp;
(4) be cooled to-10 DEG C with the speed of 15 DEG C/h after being added dropwise to complete, continue to stir 2h under the stir speed (S.S.) of 15rmp, leave standstill 3h crystallize out, filter, washing, vacuum drying obtains calcium folinate crystal.
The X-ray powder diffraction pattern that the calcium folinate crystal prepared uses the measurement of Cu-K alpha ray to obtain as shown in Figure 1.
embodiment 2:the preparation of calcium folinate compositions
Consist of: calcium folinate crystal 1 weight portion prepared by the present invention, calcium chloride 0.3 weight portion.
Preparation method is:
Get the calcium folinate of recipe quantity, calcium chloride, be dissolved in water for injection, add the active carbon stirring at room temperature 30min of 1% of calcium folinate weight, filter carbon removal, filtrate injects water to 2000ml, crosses 0.22 μm of filter membrane, dividing is filled in 2ml ampoule, 121 DEG C of pressure sterilizing 45min, lamp inspection, obtains calcium folinate aqueous injection.
embodiment 3:the preparation of calcium folinate compositions
Consist of: calcium folinate crystal 1 weight portion prepared by the present invention, calcium chloride 0.4 weight portion.
Preparation method is:
Get the calcium folinate of recipe quantity, calcium chloride, be dissolved in water for injection, add the active carbon stirring at room temperature 30min of 1% of calcium folinate weight, filter carbon removal, filtrate injects water to 2000ml, crosses 0.22 μm of filter membrane, dividing is filled in 2ml ampoule, 121 DEG C of pressure sterilizing 45min, lamp inspection, obtains calcium folinate aqueous injection.
embodiment 4:the preparation of calcium folinate compositions
Consist of: calcium folinate crystal 1 weight portion prepared by the present invention, calcium chloride 0.5 weight portion.
Preparation method is:
Get the calcium folinate of recipe quantity, calcium chloride, be dissolved in water for injection, add the active carbon stirring at room temperature 30min of 1% of calcium folinate weight, filter carbon removal, filtrate injects water to 2000ml, crosses 0.22 μm of filter membrane, dividing is filled in 2ml ampoule, 121 DEG C of pressure sterilizing 45min, lamp inspection, obtains calcium folinate aqueous injection.
embodiment 5:the preparation of calcium folinate compositions
Consist of: calcium folinate crystal 1 weight portion prepared by the present invention, calcium chloride 0.6 weight portion.
Preparation method is:
Get the calcium folinate of recipe quantity, calcium chloride, be dissolved in water for injection, add the active carbon stirring at room temperature 30min of 1% of calcium folinate weight, filter carbon removal, filtrate injects water to 2000ml, crosses 0.22 μm of filter membrane, dividing is filled in 2ml ampoule, 121 DEG C of pressure sterilizing 45min, lamp inspection, obtains calcium folinate aqueous injection.
embodiment 6:the preparation of calcium folinate compositions
Consist of: calcium folinate crystal 1 weight portion prepared by the present invention, calcium chloride 0.7 weight portion.
Preparation method is:
Get the calcium folinate of recipe quantity, calcium chloride, be dissolved in water for injection, add the active carbon stirring at room temperature 30min of 1% of calcium folinate weight, filter carbon removal, filtrate injects water to 2000ml, crosses 0.22 μm of filter membrane, dividing is filled in 2ml ampoule, 121 DEG C of pressure sterilizing 45min, lamp inspection, obtains calcium folinate aqueous injection.
test example 1:dissolubility test
The dissolubility of following calcium folinate is detected:
Comparative example: commercially available calcium folinate (Zhejiang is pharmaceutcal corporation, Ltd greatly).
Be determined at the quality of calcium folinate in 100g water saturation solution under 20 DEG C of conditions, experimental result is as shown in table 1.
Table 1 dissolubility comparative test result
As can be seen from Table 1, the water solublity of calcium folinate of the present invention improves greatly, brings conveniently to preparation preparation.
test example 2:fluidity test
Method: prepare calcium folinate crystal-form compound three batch sample according to the method for the embodiment of the present invention 1, sample respectively, adopt fixed funnel method, funnel is placed in the suitable height on graph paper, calcium folinate is freely flowed down from bell mouth, until the cone top formed contacts with bell mouth, measure hypotenuse and the horizontal angle (θ angle of repose) of calcium folinate accumulation horizon, the results are shown in Table shown in 2.
The fluidity test result of table 2 calcium folinate
test example 3:accelerated test
By embodiment of the present invention 2-4 40 DEG C, accelerated test 6 months under the condition of relative humidity 75%, result of the test is in table 3.
Table 3 accelerated test result
As can be seen from Table 3, contained total assorted, the single assorted content of embodiment 2-4 is low, and without significant change after accelerated test, good stability, has carried out identical test to other embodiments, obtains similar test result.
Claims (6)
1. the removing toxic substances antagonist calcium folinate compositions aqueous injection in tumor pharmacother, is characterized in that: described compositions is made up of calcium folinate, calcium chloride; Described calcium folinate is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
2. the removing toxic substances antagonist calcium folinate compositions aqueous injection in tumor pharmacother according to claim 1, is characterized in that: the weight ratio of described calcium folinate and calcium chloride is 1:0.3-0.7.
3. the removing toxic substances antagonist calcium folinate compositions aqueous injection in tumor pharmacother according to claim 2, is characterized in that: the weight ratio of described calcium folinate and calcium chloride is 1:0.4-0.6.
4. the removing toxic substances antagonist calcium folinate compositions aqueous injection in tumor pharmacother according to claim 3, is characterized in that: the weight ratio of described calcium folinate and calcium chloride is 1:0.5.
5., according to the removing toxic substances antagonist calcium folinate compositions aqueous injection in the arbitrary described tumor pharmacother of claim 1-4, it is characterized in that, the preparation method of described compositions aqueous injection comprises the following steps:
Get the calcium folinate of recipe quantity, calcium chloride, be dissolved in water for injection, add the active carbon stirring at room temperature 30min of 1% of calcium folinate weight, filter carbon removal, filtrate injects water to 2000ml, crosses 0.22 μm of filter membrane, dividing is filled in 2ml ampoule, 121 DEG C of pressure sterilizing 45min, lamp inspection, obtains calcium folinate aqueous injection.
6. the removing toxic substances antagonist calcium folinate compositions aqueous injection in tumor pharmacother according to claim 1, it is characterized in that, the crystal preparation method of described calcium folinate is:
(1) be that in the water of 10 times of calcium folinate weight and the mixed solution of carbon tetrachloride, the volume ratio of described water and carbon tetrachloride is 4:2.5 to 35 DEG C of volumes by calcium folinate dissolving crude product;
(2) add the activated carbon decolorizing that weight is 0.2 times of calcium folinate weight, filter, obtain calcium folinate solution;
(3) by calcium folinate solution warms to 40 DEG C, in calcium folinate solution, drip propyl ether under the condition of stirring, the volume of propyl ether is 8 times of calcium folinate weight, at the uniform velocity dropwises in 0.5h, and described stir speed (S.S.) is 30rmp;
(4) be cooled to-10 DEG C with the speed of 15 DEG C/h after being added dropwise to complete, continue to stir 2h under the stir speed (S.S.) of 15rmp, leave standstill 3h crystallize out, filter, washing, vacuum drying obtains calcium folinate crystal.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510619132.7A CN105079029A (en) | 2015-09-25 | 2015-09-25 | Detoxifying antagonist and calcium folinate composition injection for tumor medication |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510619132.7A CN105079029A (en) | 2015-09-25 | 2015-09-25 | Detoxifying antagonist and calcium folinate composition injection for tumor medication |
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| CN105079029A true CN105079029A (en) | 2015-11-25 |
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| CN201510619132.7A Withdrawn CN105079029A (en) | 2015-09-25 | 2015-09-25 | Detoxifying antagonist and calcium folinate composition injection for tumor medication |
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Application publication date: 20151125 |