CN105106160A - Antianemic calcium folinate combination tablet - Google Patents
Antianemic calcium folinate combination tablet Download PDFInfo
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- CN105106160A CN105106160A CN201510645294.8A CN201510645294A CN105106160A CN 105106160 A CN105106160 A CN 105106160A CN 201510645294 A CN201510645294 A CN 201510645294A CN 105106160 A CN105106160 A CN 105106160A
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- calcium folinate
- calcium
- folinate
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Abstract
The invention relates to an antianemic calcium folinate combination tablet, belonging to the technical field of drugs. A combination is prepared from calcium folinate, pregelatinized starch, calcium hydrophosphate, croscarmellose sodium, carbopol and glyceryl behenate. The calcium folinate is a new crystal form compound different from those reported in the prior art, an X-ray powder diffraction pattern obtained by Cu-Kalpha ray measurement is shown as picture 1, as discovered from tests, the calcium folinate crystal form compound provided by the invention is good in stability, low in impurity content and obviously improved in solubility and liquidity in water in comparison to the prior art, solves the problems in the prior art that calcium folinate is poor in water solubility, poor in stability and high in related substance content, provides convenience for preparation of a preparation, and also greatly improves the medicine effect; the tablet prepared by using the new crystal form compound is high in dissolution rate, 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 anti-anemic drug calcium folinate composition tablet.
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 substantially increases drug effect, utilizes the tablet that this crystal compound is obtained, dissolution is high, good stability, bioavailability is high, is very suitable for clinical practice.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of anti-anemic drug calcium folinate composition tablet.
In order to complete object of the present invention, the technical scheme of employing is:
A kind of anti-anemic drug calcium folinate of the present invention composition tablet, described compositions is made up of calcium folinate, pregelatinized Starch, calcium hydrogen phosphate, cross-linking sodium carboxymethyl cellulose, carbopol, Glyceryl Behenate; 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 pregelatinized Starch of 6-8 weight portion, the calcium hydrogen phosphate of 6-8 weight portion, the cross-linking sodium carboxymethyl cellulose of 2.0-2.4 weight portion, the carbopol of 0.8-1.2 weight portion, the Glyceryl Behenate of 0.8-1.2 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 pregelatinized Starch of 7 weight portions, the calcium hydrogen phosphate of 7 weight portions, the cross-linking sodium carboxymethyl cellulose of 2.2 weight portions, the carbopol of 1 weight portion, the Glyceryl Behenate of 1 weight portion.
3rd optimal technical scheme of the present invention is that the preparation method of described composition tablet comprises the following steps:
(1) supplementary material process: calcium folinate was pulverized 100 mesh sieves;
(2) weigh: weigh according to technology preparation;
(3) mix: calcium folinate, pregelatinized Starch, calcium hydrogen phosphate, cross-linking sodium carboxymethyl cellulose, carbopol, Glyceryl Behenate are dropped into three-dimensional motion mixer, premixing speed 15 revs/min, incorporation time 60 minutes are set;
(4) tabletting: carry out tabletting according to after the heavy scope of the theoretical sheet of total mixed gained material cubage;
(5) pack.
4th optimal technical scheme of the present invention is that the preparation method of the crystal of described calcium folinate comprises the following steps:
Prepare 40 DEG C of saturated alcoholic solution of calcium folinate crude product, then the isobutanol of 8 times and the mixed solvent of petroleum ether that volume is saturated volumes of aqueous ethanol is added, described isobutanol, the volume ratio of petroleum ether are 3:1, after stirring, cooling limit, limit is stirred, cooling rate is 10 DEG C/h, mixing speed is 105 revs/min, add the ether that volume is the mixed solvent volume 3 times of isobutanol and petroleum ether simultaneously, stop after being cooled to 0 DEG C stirring, leave standstill growing the grain 3 hours, filter, after drying under reduced pressure, obtain 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 substantially increases drug effect, utilizes the tablet that this crystal compound is obtained, dissolution is high, good stability, 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
Prepare 40 DEG C of saturated alcoholic solution of calcium folinate crude product, then the isobutanol of 8 times and the mixed solvent of petroleum ether that volume is saturated volumes of aqueous ethanol is added, described isobutanol, the volume ratio of petroleum ether are 3:1, after stirring, cooling limit, limit is stirred, cooling rate is 10 DEG C/h, mixing speed is 105 revs/min, add the ether that volume is the mixed solvent volume 3 times of isobutanol and petroleum ether simultaneously, stop after being cooled to 0 DEG C stirring, leave standstill growing the grain 3 hours, filter, after drying under reduced pressure, obtain 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 tablets
Prescription: with parts by weight
Preparation method:
(1) supplementary material process: calcium folinate was pulverized 100 mesh sieves;
(2) weigh: weigh according to technology preparation;
(3) mix: calcium folinate, pregelatinized Starch, calcium hydrogen phosphate, cross-linking sodium carboxymethyl cellulose, carbopol, Glyceryl Behenate are dropped into three-dimensional motion mixer, premixing speed 15 revs/min, incorporation time 60 minutes are set;
(4) tabletting: carry out tabletting according to after the heavy scope of the theoretical sheet of total mixed gained material cubage;
(5) pack.
embodiment 3:the preparation of calcium folinate tablets
Prescription: with parts by weight
Preparation method:
(1) supplementary material process: calcium folinate was pulverized 100 mesh sieves;
(2) weigh: weigh according to technology preparation;
(3) mix: calcium folinate, pregelatinized Starch, calcium hydrogen phosphate, cross-linking sodium carboxymethyl cellulose, carbopol, Glyceryl Behenate are dropped into three-dimensional motion mixer, premixing speed 15 revs/min, incorporation time 60 minutes are set;
(4) tabletting: carry out tabletting according to after the heavy scope of the theoretical sheet of total mixed gained material cubage;
(5) pack.
embodiment 4:the preparation of calcium folinate tablets
Prescription: with parts by weight
Preparation method:
(1) supplementary material process: calcium folinate was pulverized 100 mesh sieves;
(2) weigh: weigh according to technology preparation;
(3) mix: calcium folinate, pregelatinized Starch, calcium hydrogen phosphate, cross-linking sodium carboxymethyl cellulose, carbopol, Glyceryl Behenate are dropped into three-dimensional motion mixer, premixing speed 15 revs/min, incorporation time 60 minutes are set;
(4) tabletting: carry out tabletting according to after the heavy scope of the theoretical sheet of total mixed gained material cubage;
(5) pack.
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 dissolution is high, and without significant change after accelerated test, good stability.
Claims (5)
1. an anti-anemic drug calcium folinate composition tablet, is characterized in that: described compositions is made up of calcium folinate, pregelatinized Starch, calcium hydrogen phosphate, cross-linking sodium carboxymethyl cellulose, carbopol, Glyceryl Behenate; 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. anti-anemic drug calcium folinate composition tablet 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 pregelatinized Starch of 6-8 weight portion, the calcium hydrogen phosphate of 6-8 weight portion, the cross-linking sodium carboxymethyl cellulose of 2.0-2.4 weight portion, the carbopol of 0.8-1.2 weight portion, the Glyceryl Behenate of 0.8-1.2 weight portion.
3. anti-anemic drug calcium folinate composition tablet 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 pregelatinized Starch of 7 weight portions, the calcium hydrogen phosphate of 7 weight portions, the cross-linking sodium carboxymethyl cellulose of 2.2 weight portions, the carbopol of 1 weight portion, the Glyceryl Behenate of 1 weight portion.
4. the anti-anemic drug calcium folinate composition tablet according to any one of claim 1-3, it is characterized in that, the preparation method of described composition tablet comprises the following steps:
(1) supplementary material process: calcium folinate was pulverized 100 mesh sieves;
(2) weigh: weigh according to technology preparation;
(3) mix: calcium folinate, pregelatinized Starch, calcium hydrogen phosphate, cross-linking sodium carboxymethyl cellulose, carbopol, Glyceryl Behenate are dropped into three-dimensional motion mixer, premixing speed 15 revs/min, incorporation time 60 minutes are set;
(4) tabletting: carry out tabletting according to after the heavy scope of the theoretical sheet of total mixed gained material cubage;
(5) pack.
5. anti-anemic drug calcium folinate composition tablet according to claim 1, it is characterized in that, the preparation method of the crystal of described calcium folinate comprises the following steps:
Prepare 40 DEG C of saturated alcoholic solution of calcium folinate crude product, then the isobutanol of 8 times and the mixed solvent of petroleum ether that volume is saturated volumes of aqueous ethanol is added, described isobutanol, the volume ratio of petroleum ether are 3:1, after stirring, cooling limit, limit is stirred, cooling rate is 10 DEG C/h, mixing speed is 105 revs/min, add the ether that volume is the mixed solvent volume 3 times of isobutanol and petroleum ether simultaneously, stop after being cooled to 0 DEG C stirring, leave standstill growing the grain 3 hours, filter, after drying under reduced pressure, obtain calcium folinate crystalline compounds.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510645294.8A CN105106160A (en) | 2015-10-09 | 2015-10-09 | Antianemic calcium folinate combination tablet |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510645294.8A CN105106160A (en) | 2015-10-09 | 2015-10-09 | Antianemic calcium folinate combination tablet |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105106160A true CN105106160A (en) | 2015-12-02 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510645294.8A Withdrawn CN105106160A (en) | 2015-10-09 | 2015-10-09 | Antianemic calcium folinate combination tablet |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105106160A (en) |
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2015
- 2015-10-09 CN CN201510645294.8A patent/CN105106160A/en not_active Withdrawn
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| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20151202 |
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| WW01 | Invention patent application withdrawn after publication |