CN105106140A - Antidote calcium folinate composition granules as folic acid antagonist - Google Patents
Antidote calcium folinate composition granules as folic acid antagonist Download PDFInfo
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- CN105106140A CN105106140A CN201510639167.7A CN201510639167A CN105106140A CN 105106140 A CN105106140 A CN 105106140A CN 201510639167 A CN201510639167 A CN 201510639167A CN 105106140 A CN105106140 A CN 105106140A
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Abstract
The invention belongs to the technical field of medicines, and relates to antidote calcium folinate composition granules as a folic acid antagonist. The composition is prepared from calcium folinate, mannitol, dioctyl sodium sulfosuccinate, sucralose and 95% ethyl alcohol. The calcium folinate is a new crystal form compound and is different from calcium folinate reported in existing technologies as shown in picture 1 of X-ray powder diffraction diagram obtained by Cu-Ka ray measurement; and as discovered in experiments, the calcium folinate crystal form compound provided by the invention is good in stability, low in impurity and good in stability compared with the existing technology, the solubility and mobility in water are remarkably improved compared with the prior art, and the problem that calcium folinate in the existing technology is poor in water solubility and stability and high in related substances is solved; the calcium folinate crystal form compound provides convenience for preparation of preparations, and the pharmacological efficacy is also greatly improved. The granules prepared from the new crystal form compound are good in stability, high in bioavailability and very suitable for clinical application.
Description
Technical field
The invention belongs to medical art, relate to a kind of antidote calcium folinate composition granule of antifol.
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.
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 granule good stability that this crystal compound is obtained, bioavailability is high, is very suitable for clinical practice.
Summary of the invention
Goal of the invention of the present invention is the antidote calcium folinate composition granule providing a kind of antifol.
In order to complete object of the present invention, the technical scheme of employing is:
The present invention relates to a kind of antidote calcium folinate composition granule of antifol, described compositions is made up of calcium folinate, mannitol, sodium dioctyl sulfosuccinate, sucralose, 95% ethanol; 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: with parts by weight, and described compositions is made up of the calcium folinate of 2.5 weight portions, the mannitol of 20-24 weight portion, the sodium dioctyl sulfosuccinate of 2.5-3.5 weight portion, the sucralose of 0.5-0.7 weight portion, 95% ethanol of 4-5 weight portion.
Second optimal technical scheme of the present invention is: with parts by weight, and described compositions is made up of the calcium folinate of 2.5 weight portions, the mannitol of 22 weight portions, the sodium dioctyl sulfosuccinate of 3 weight portions, the sucralose of 0.6 weight portion, 95% ethanol of 4.5 weight portions.
3rd optimal technical scheme of the present invention is that the preparation method of described composition granule comprises the following steps:
(1) weigh: weigh according to technology preparation;
(2) supplementary material process: calcium folinate was pulverized 100 mesh sieves;
(3) mixing granulation: be added in wet mixing pelletizer by calcium folinate, mannitol, sodium dioctyl sulfosuccinate, sucralose, opens stirring motor and is dry mixed 10 minutes; Add the 95% ethanol wet mixing cutting got ready, with 16 mesh sieve soft materials;
(4) drying and screening: the wet granular of granulation gained is evenly split on the drip pan of baking oven, set temperature 60-65 DEG C, dry total time is 2.5-3.0 hour, and sieve material after drying 16-30 order;
(6) mix: after sieving, granule drops into three-dimensional motion mixer, arranges premixing speed 10 revs/min, incorporation time 5 minutes;
(7) pack: carry out subpackage according to after the theoretical loading amount scope of total mixed gained material cubage.
4th optimal technical scheme of the present invention is that the preparation method of the crystal of described calcium folinate comprises the following steps:
Be dissolved in by calcium folinate in the mixed solvent of water that 35 DEG C of volumes are 6 times of calcium folinate weight, dimethyl sulfoxine, the volume ratio of water and dimethyl sulfoxine is 5:1.5; First add with the speed of 40 ml/min the ethanol of 9 times and the mixed solvent of ether that volume is calcium folinate weight, the volume ratio of ethanol, ether is 2:2, and limit edged stirs, control temperature 35 DEG C, growing the grain 3 hours; And then the isopropyl alcohol of 7 times that volume total amount is calcium folinate weight is added with the speed of 20 ml/min, growing the grain, after 1 hour, is cooled to-5 DEG C with the speed of 10 DEG C/h, then keeps mixing speed 90 revs/min of stirring and crystallizing, growing the grain 3 hours; Filter, washing, drying under reduced pressure obtains calcium folinate crystalline compounds.
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 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 granule good stability that this crystal compound is obtained, bioavailability is high, is 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
Be dissolved in by calcium folinate in the mixed solvent of water that 35 DEG C of volumes are 6 times of calcium folinate weight, dimethyl sulfoxine, the volume ratio of water and dimethyl sulfoxine is 5:1.5; First add with the speed of 40 ml/min the ethanol of 9 times and the mixed solvent of ether that volume is calcium folinate weight, the volume ratio of ethanol, ether is 2:2, and limit edged stirs, control temperature 35 DEG C, growing the grain 3 hours; And then the isopropyl alcohol of 7 times that volume total amount is calcium folinate weight is added with the speed of 20 ml/min, growing the grain, after 1 hour, is cooled to-5 DEG C with the speed of 10 DEG C/h, then keeps mixing speed 90 revs/min of stirring and crystallizing, growing the grain 3 hours; Filter, washing, drying under reduced pressure obtains calcium folinate crystalline compounds.
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 granule
Prescription: with parts by weight
Preparation method:
(1) weigh: weigh according to technology preparation;
(2) supplementary material process: calcium folinate was pulverized 100 mesh sieves;
(3) mixing granulation: be added in wet mixing pelletizer by calcium folinate, mannitol, sodium dioctyl sulfosuccinate, sucralose, opens stirring motor and is dry mixed 10 minutes; Add the 95% ethanol wet mixing cutting got ready, with 16 mesh sieve soft materials;
(4) drying and screening: the wet granular of granulation gained is evenly split on the drip pan of baking oven, set temperature 60-65 DEG C, dry total time is 2.5-3.0 hour, and sieve material after drying 16-30 order;
(6) mix: after sieving, granule drops into three-dimensional motion mixer, arranges premixing speed 10 revs/min, incorporation time 5 minutes;
(7) pack: carry out subpackage according to after the theoretical loading amount scope of total mixed gained material cubage.
embodiment 3:the preparation of calcium folinate granule
Prescription: with parts by weight
Preparation method:
(1) weigh: weigh according to technology preparation;
(2) supplementary material process: calcium folinate was pulverized 100 mesh sieves;
(3) mixing granulation: be added in wet mixing pelletizer by calcium folinate, mannitol, sodium dioctyl sulfosuccinate, sucralose, opens stirring motor and is dry mixed 10 minutes; Add the 95% ethanol wet mixing cutting got ready, with 16 mesh sieve soft materials;
(4) drying and screening: the wet granular of granulation gained is evenly split on the drip pan of baking oven, set temperature 60-65 DEG C, dry total time is 2.5-3.0 hour, and sieve material after drying 16-30 order;
(6) mix: after sieving, granule drops into three-dimensional motion mixer, arranges premixing speed 10 revs/min, incorporation time 5 minutes;
(7) pack: carry out subpackage according to after the theoretical loading amount scope of total mixed gained material cubage.
embodiment 4:the preparation of calcium folinate granule
Prescription: with parts by weight
Preparation method:
(1) weigh: weigh according to technology preparation;
(2) supplementary material process: calcium folinate was pulverized 100 mesh sieves;
(3) mixing granulation: be added in wet mixing pelletizer by calcium folinate, mannitol, sodium dioctyl sulfosuccinate, sucralose, opens stirring motor and is dry mixed 10 minutes; Add the 95% ethanol wet mixing cutting got ready, with 16 mesh sieve soft materials;
(4) drying and screening: the wet granular of granulation gained is evenly split on the drip pan of baking oven, set temperature 60-65 DEG C, dry total time is 2.5-3.0 hour, and sieve material after drying 16-30 order;
(6) mix: after sieving, granule drops into three-dimensional motion mixer, arranges premixing speed 10 revs/min, incorporation time 5 minutes;
(7) pack: carry out subpackage according to after the theoretical loading amount scope of total mixed gained material cubage.
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, embodiment 2-4 contained humidity, total assorted, single assorted amount are low, and without significant change after accelerated test, good stability.
Claims (5)
1. an antidote calcium folinate composition granule for antifol, is characterized in that: described compositions is made up of calcium folinate, mannitol, sodium dioctyl sulfosuccinate, sucralose, 95% ethanol; 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 antidote calcium folinate composition granule of antifol according to claim 1, it is characterized in that: with parts by weight, described compositions is made up of the calcium folinate of 2.5 weight portions, the mannitol of 20-24 weight portion, the sodium dioctyl sulfosuccinate of 2.5-3.5 weight portion, the sucralose of 0.5-0.7 weight portion, 95% ethanol of 4-5 weight portion.
3. the antidote calcium folinate composition granule of antifol according to claim 2, it is characterized in that: with parts by weight, described compositions is made up of the calcium folinate of 2.5 weight portions, the mannitol of 22 weight portions, the sodium dioctyl sulfosuccinate of 3 weight portions, the sucralose of 0.6 weight portion, 95% ethanol of 4.5 weight portions.
4. the antidote calcium folinate composition granule of the antifol according to any one of claim 1-3, it is characterized in that, the preparation method of described composition granule comprises the following steps:
(1) weigh: weigh according to technology preparation;
(2) supplementary material process: calcium folinate was pulverized 100 mesh sieves;
(3) mixing granulation: be added in wet mixing pelletizer by calcium folinate, mannitol, sodium dioctyl sulfosuccinate, sucralose, opens stirring motor and is dry mixed 10 minutes; Add the 95% ethanol wet mixing cutting got ready, with 16 mesh sieve soft materials;
(4) drying and screening: the wet granular of granulation gained is evenly split on the drip pan of baking oven, set temperature 60-65 DEG C, dry total time is 2.5-3.0 hour, and sieve material after drying 16-30 order;
(6) mix: after sieving, granule drops into three-dimensional motion mixer, arranges premixing speed 10 revs/min, incorporation time 5 minutes;
(7) pack: carry out subpackage according to after the theoretical loading amount scope of total mixed gained material cubage.
5. the antidote calcium folinate composition granule of antifol according to claim 1, it is characterized in that, the preparation method of the crystal of described calcium folinate comprises the following steps:
Be dissolved in by calcium folinate in the mixed solvent of water that 35 DEG C of volumes are 6 times of calcium folinate weight, dimethyl sulfoxine, the volume ratio of water and dimethyl sulfoxine is 5:1.5; First add with the speed of 40 ml/min the ethanol of 9 times and the mixed solvent of ether that volume is calcium folinate weight, the volume ratio of ethanol, ether is 2:2, and limit edged stirs, control temperature 35 DEG C, growing the grain 3 hours; And then the isopropyl alcohol of 7 times that volume total amount is calcium folinate weight is added with the speed of 20 ml/min, growing the grain, after 1 hour, is cooled to-5 DEG C with the speed of 10 DEG C/h, then keeps mixing speed 90 revs/min of stirring and crystallizing, growing the grain 3 hours; Filter, washing, drying under reduced pressure obtains calcium folinate crystalline compounds.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510639167.7A CN105106140A (en) | 2015-10-08 | 2015-10-08 | Antidote calcium folinate composition granules as folic acid antagonist |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510639167.7A CN105106140A (en) | 2015-10-08 | 2015-10-08 | Antidote calcium folinate composition granules as folic acid antagonist |
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| CN105106140A true CN105106140A (en) | 2015-12-02 |
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| CN201510639167.7A Withdrawn CN105106140A (en) | 2015-10-08 | 2015-10-08 | Antidote calcium folinate composition granules as folic acid antagonist |
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Application publication date: 20151202 |