CN104844506A - Medicinal pitavastatin calcium compound for treating hyperlipidemia - Google Patents
Medicinal pitavastatin calcium compound for treating hyperlipidemia Download PDFInfo
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- CN104844506A CN104844506A CN201510247846.XA CN201510247846A CN104844506A CN 104844506 A CN104844506 A CN 104844506A CN 201510247846 A CN201510247846 A CN 201510247846A CN 104844506 A CN104844506 A CN 104844506A
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- pitavastatin calcium
- hyperlipidemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D215/14—Radicals substituted by oxygen atoms
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Abstract
The invention discloses a medicinal pitavastatin calcium compound for treating hyperlipidemia and belongs to the technical field of medicines. The pitavastatin calcium compound is measured by using Cu-K alpha-rays to obtain an X-ray powder diffraction pattern as shown in picture 1. The pitavastatin calcium provided by the invention is a compound in a novel crystal form and is different from the pitavastatin calcium reported in the prior art. As found through tests and researches, tablets prepared by using the compound have a remarkable efficacy of improving the capacity of pitavastatin in inhibiting the activity of HMG-CoA reductase while improving the tablet stability, so that the lipid decreasing effect is obviously improved.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of medicine pitavastatin calcium cpd for the treatment of hyperlipidemia.
Background technology
Pitavastatin Calcium is first complete synthesis HMG-CoA reductase inhibitor of Nissan Chemical company and Kowa company Ltd's exploitation, be the another potent stanin fat-reducing medicament after atorvastatin and Rosuvastatin, be mainly used in treating hypercholesterolemia, familial hypercholesterolemia.In November, 1999 at Japan registration, and on July 17th, 2003 first in Japan's approval listing, follow-up in succession in Korea S, Thailand, China and U.S.A listing.Abroad be described as " superstatin " with the powerful lipopenicillinase effect shown in its clinical trial.In the face of the raising day by day of hyperlipidemia sickness rate, we need to find medicine more efficiently.
The invention provides a kind of Pitavastatin Calcium crystal compound, it is a kind of Pitavastatin Calcium being different from prior art report, find that the tablet that this compound is made has the effect significantly improving Pitavastatin Calcium and suppress HMG-CoA reductase activity while improving tablet stability by experimental study, thus significantly improve its lipid-lowering effect.
Summary of the invention
The first object of the present invention is just to provide a kind of medicine pitavastatin calcium cpd for the treatment of hyperlipidemia, this compound comparatively prior art, it is a kind of Pitavastatin Calcium being different from prior art report, find that the tablet that this compound is made has the effect significantly improving Pitavastatin Calcium and suppress HMG-CoA reductase activity while improving tablet stability by experimental study, thus significantly improve its lipid-lowering effect.
The second object of the present invention is the preparation method providing a kind of above-mentioned Pitavastatin Calcium crystalline compounds, and the method technique is simple, and yield is high, products obtained therefrom high purity 99.9%.
For realizing object of the present invention, the present invention adopts following technical scheme:
Treat a medicine pitavastatin calcium cpd for hyperlipidemia, it is characterized in that, described compound has X-ray powder diffraction pattern as shown in Figure 1.
A preparation method for above-claimed cpd, comprises the following steps:
(1) by Pitavastatin Calcium dissolving crude product in the mixing solutions of methyl alcohol and tetracol phenixin;
(2) add activated carbon decolorizing, filter, obtain pitavastatin calcium solution;
(3) by Pitavastatin Calcium solution warms to 35-40 DEG C, in pitavastatin calcium solution, drip the sodium chloride saturated solution of-15 DEG C-5 DEG C under the condition of stirring, at the uniform velocity dropwise in 0.5h;
(4) be cooled to-15 DEG C-5 DEG C after being added dropwise to complete, stir 0.5-2h, leave standstill 3-5h crystallize out, filter;
(5) wash final vacuum drying successively with distilled water, ethanol and obtain Pitavastatin Calcium crystal.
In preparation method of the present invention, the volume of the mixing solutions of methyl alcohol and tetracol phenixin described in step (1) is 15-20 times of Pitavastatin Calcium weight, and the volume ratio of methyl alcohol and tetracol phenixin is 4:3.5.
In preparation method of the present invention, described in step (1), the temperature of mixing solutions is 15-30 DEG C.
In preparation method of the present invention, the weight of gac described in step (2) is 0.2-0.5 times of Pitavastatin Calcium weight.
In preparation method of the present invention, the volume of sodium chloride saturated solution described in step (3) is 5-8 times of Pitavastatin Calcium weight.
In preparation method of the present invention, described in step (3), stir speed (S.S.) is 25-30rmp, and described in step (4), stir speed (S.S.) is 10-15 rmp.
The polymorphism of solid chemical is the spontaneous phenomenon 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 " paramorphism " phenomenon.Although its chemical nature of allomorphous solid matter is identical, its physico-chemical property may be different.For " paramorphism medicine " that physico-chemical 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 obtains a kind of Pitavastatin Calcium new crystal structure being different from prior art through a large amount of tests, and by test, show that the tablet that this crystal compound is made has the effect significantly improving Pitavastatin Calcium and suppress HMG-CoA reductase activity while improving tablet stability, thus significantly improve its lipid-lowering effect.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction of the Pitavastatin Calcium crystalline compounds that the embodiment of the present invention 1 obtains.
Embodiment
Be below the specific embodiment of the present invention, described embodiment is to further describe the present invention, instead of restriction the present invention.
embodiment 1:the preparation of Pitavastatin Calcium crystalline compounds
(1) be that in the methyl alcohol of 15 times of Pitavastatin Calcium weight and the mixing solutions of tetracol phenixin, the volume ratio of described methyl alcohol and tetracol phenixin is 4:3.5 to 15 DEG C of volumes by Pitavastatin Calcium dissolving crude product;
(2) add the activated carbon decolorizing that weight is 0.2 times of Pitavastatin Calcium weight, filter, obtain pitavastatin calcium solution;
(3) by Pitavastatin Calcium solution warms to 35 DEG C, in pitavastatin calcium solution, the sodium chloride saturated solution of-15 DEG C is dripped under the condition stirred, the volume of sodium chloride saturated solution is 5 times of Pitavastatin Calcium weight, at the uniform velocity dropwises in 0.5h, and described stir speed (S.S.) is 25rmp;
(4) be cooled to-15 DEG C after being added dropwise to complete, continue to stir 0.5h under the stir speed (S.S.) of 10rmp, leave standstill 3h crystallize out, filter;
(5) wash final vacuum drying successively with distilled water, ethanol and obtain Pitavastatin Calcium crystal.
The Pitavastatin Calcium crystalline compounds of gained uses powder X-ray diffraction assay method to measure, and obtains X-ray powder diffraction pattern as shown in Figure 1.
embodiment 2:the preparation of Pitavastatin Calcium crystalline compounds
(1) be that in the methyl alcohol of 17.5 times of Pitavastatin Calcium weight and the mixing solutions of tetracol phenixin, the volume ratio of described methyl alcohol and tetracol phenixin is 4:3.5 to 22.5 DEG C of volumes by Pitavastatin Calcium dissolving crude product;
(2) add the activated carbon decolorizing that weight is 0.35 times of Pitavastatin Calcium weight, filter, obtain pitavastatin calcium solution;
(3) by Pitavastatin Calcium solution warms to 37.5 DEG C, in pitavastatin calcium solution, the sodium chloride saturated solution of-5 DEG C is dripped under the condition stirred, the volume of sodium chloride saturated solution is 6.5 times of Pitavastatin Calcium weight, at the uniform velocity dropwises in 0.5h, and described stir speed (S.S.) is 27.5rmp;
(4) be cooled to-5 DEG C after being added dropwise to complete, under the stir speed (S.S.) of 12.5 rmp, continue stirring 1.25 h, leave standstill 4h crystallize out, filter;
(5) wash final vacuum drying successively with distilled water, ethanol and obtain Pitavastatin Calcium crystal.
The Pitavastatin Calcium crystalline compounds of gained uses powder X-ray diffraction assay method to measure, and the X-ray powder diffraction pattern obtained is similar to embodiment 1.
embodiment 3:the preparation of Pitavastatin Calcium crystalline compounds
(1) be that in the methyl alcohol of 20 times of Pitavastatin Calcium weight and the mixing solutions of tetracol phenixin, the volume ratio of described methyl alcohol and tetracol phenixin is 4:3.5 to 30 DEG C of volumes by Pitavastatin Calcium dissolving crude product;
(2) add the activated carbon decolorizing that weight is 0.5 times of Pitavastatin Calcium weight, filter, obtain pitavastatin calcium solution;
(3) by Pitavastatin Calcium solution warms to 40 DEG C, in pitavastatin calcium solution, the sodium chloride saturated solution of 5 DEG C is dripped under the condition stirred, the volume of sodium chloride saturated solution is 8 times of Pitavastatin Calcium weight, at the uniform velocity dropwises in 0.5h, and described stir speed (S.S.) is 30rmp;
(4) be cooled to 5 DEG C after being added dropwise to complete, continue to stir 2h under the stir speed (S.S.) of 15 rmp, leave standstill 5h crystallize out, filter;
(5) wash final vacuum drying successively with distilled water, ethanol and obtain Pitavastatin Calcium crystal.
The Pitavastatin Calcium crystalline compounds of gained uses powder X-ray diffraction assay method to measure, and the X-ray powder diffraction pattern obtained is similar to embodiment 1.
test example 1:
The each 2mg of Pitavastatin Calcium prepared by Example 1-3, obtained pitavastatin calcium tablet, detects dissolution rate (see table 1), related substance (see table 1), vitro inhibition HMG-CoA reductase activity (see table 2) respectively respectively.
1, animal strains, body weight and sex
Sprague-Dawley rat, 180-220g, male
2, hyperlipemia model of rats preparation
Hyperlipemia model of rats adopts high lipid food to cause hyperlipidaemia method.High lipid food formula is as follows: basal feed 86.3%, cholesterol 3%, lard 10%, Thyreostat I 0.2%, pig cholate 0.5%, ensures that l composition mixes, continuous 2 weeks.High lipid food is given every other day during administration.
3, vitro inhibition HMG-CoA reductase activity test
With sheet power of going on the market clear for positive control, not adding any inhibitor is negative control, simultaneously with without HMG-CoA and unrestraint agent for blank.
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) is under HMG-CoA reductase catalysis, consume two molecule reduced form NADPs (NADPH) and generate 3-methyl-3,5-dihydroxy valeric acid and Reduced nicotinamide-adenine dinucleotide (NADP).NADPH has maximum absorption at ultraviolet 340nm, and NADP at this wavelength without absorption, measure this system and can obtain in the speed that 340nm ultraviolet absorption value declines the speed that this reduction reaction carries out, after adding inhibitor, the rejection ability of inhibitor to enzyme can be calculated by the change of ultraviolet absorption value.The present composition is measured to the inhibit activities of HMG-CoA reductase by the method.
Measure pitavastatin calcium tablet prepared by three embodiments to the restraining effect of HMG-CoA reductase, matching suppresses curve, and obtain half-inhibition concentration (IC50), the positive control drug measured, the IC50 of the embodiment of the present invention the results are shown in Table 2.
Table 1 related substance and dissolution test result
As seen from Table 1: the tablet that gained Pitavastatin Calcium of the present invention is obtained, what sheet power of comparatively going on the market was clear has higher dissolution rate, foreign matter content well below listing sheet power clear it.
Table 2 each group of IC to HMG-CoA reductase
50
Table 2 can be found out: the tablet that gained Pitavastatin Calcium of the present invention is obtained, and what sheet power of comparatively going on the market was clear has the activity better suppressing HMG-CoA reductase enzyme.
Test example 2: embodiment accelerated test and test of long duration
Accelerated test: according to the requirement of " Chinese Pharmacopoeia version in 2010 " stability test governing principle, test of long duration has been carried out to Pitavastatin Calcium of the present invention.By embodiment sample commercially available back, be placed in climatic chamber, 40 DEG C ± 2 DEG C, place 6 months under relative humidity 75% ± 5% condition, detect by stability high spot reviews project.
Test of long duration: according to the requirement of " Chinese Pharmacopoeia version in 2010 " stability test governing principle, test of long duration has been carried out to Pitavastatin Calcium of the present invention.By embodiment sample commercially available back, be placed in climatic chamber, 25 DEG C ± 2 DEG C, place 24 months under relative humidity 60% ± 10% condition, detect by stability high spot reviews project.
Result shows: the Pitavastatin Calcium accelerated test 6 months prepared by embodiment of the present invention 1-3 or test of long duration are after 24 months, and disintegration, dissolution rate and related substance are without considerable change, and dissolution rate is high, good stability.
Claims (7)
1. treat a medicine pitavastatin calcium cpd for hyperlipidemia, it is characterized in that, described compound has X-ray powder diffraction pattern as shown in Figure 1.
2. the medicine pitavastatin calcium cpd for the treatment of hyperlipidemia as claimed in claim 1, it is characterized in that, the preparation method of described compound comprises the following steps:
(1) by Pitavastatin Calcium dissolving crude product in the mixing solutions of methyl alcohol and tetracol phenixin;
(2) add activated carbon decolorizing, filter, obtain pitavastatin calcium solution;
(3) by Pitavastatin Calcium solution warms to 35-40 DEG C, in pitavastatin calcium solution, drip the sodium chloride saturated solution of-15 DEG C-5 DEG C under the condition of stirring, at the uniform velocity dropwise in 0.5h;
(4) be cooled to-15 DEG C-5 DEG C after being added dropwise to complete, stir 0.5-2h, leave standstill 3-5h crystallize out, filter;
(5) wash final vacuum drying successively with distilled water, ethanol and obtain Pitavastatin Calcium crystal.
3. the medicine pitavastatin calcium cpd for the treatment of hyperlipidemia as claimed in claim 2, it is characterized in that, in described step (1), the volume of the mixing solutions of methyl alcohol and tetracol phenixin is 15-20 times of Pitavastatin Calcium weight, and the volume ratio of methyl alcohol and tetracol phenixin is 4:3.5.
4. the medicine pitavastatin calcium cpd for the treatment of hyperlipidemia as claimed in claim 2, it is characterized in that, in described step (1), the temperature of mixing solutions is 15-30 DEG C.
5. the medicine pitavastatin calcium cpd for the treatment of hyperlipidemia as claimed in claim 2, is characterized in that, in described step (2), the weight of gac is 0.2-0.5 times of Pitavastatin Calcium weight.
6. the medicine pitavastatin calcium cpd for the treatment of hyperlipidemia as claimed in claim 2, is characterized in that, in described step (3), the volume of sodium chloride saturated solution is 5-8 times of Pitavastatin Calcium weight.
7. the medicine pitavastatin calcium cpd for the treatment of hyperlipidemia as claimed in claim 2, it is characterized in that, in described step (3), stir speed (S.S.) is 25-30rmp, and in step (4), stir speed (S.S.) is 10-15 rmp.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105106171A (en) * | 2015-09-28 | 2015-12-02 | 青岛华之草医药科技有限公司 | Pitavastatin calcium composition capsules for treating hyperlipidemia |
| CN105213319A (en) * | 2015-09-17 | 2016-01-06 | 青岛华之草医药科技有限公司 | A kind of blood lipid-lowering medicine Pitavastatin calcium composition dry suspension |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1747934A (en) * | 2003-02-12 | 2006-03-15 | 西巴特殊化学品控股有限公司 | Crystalline forms of pitavastatin calcium |
| CN102285917A (en) * | 2011-09-20 | 2011-12-21 | 海南美大制药有限公司 | Pitavastatin calcium compound and preparation method thereof |
| WO2012025939A1 (en) * | 2010-08-25 | 2012-03-01 | Cadila Healthcare Limited | Pitavastatin calcium and process for its preparation |
| CN102653523A (en) * | 2011-12-17 | 2012-09-05 | 东莞达信生物技术有限公司 | Preparation method of pitavastatin calcium by recrystallization |
| WO2013098773A1 (en) * | 2011-12-28 | 2013-07-04 | Dr. Reddy's Laboratories Limited | Crystalline forms of pitavastatin calcium |
| KR20130078086A (en) * | 2011-12-30 | 2013-07-10 | 주식회사 에스텍파마 | Process for preparing pitavastatin hemicalcium |
| CN103508946A (en) * | 2012-06-20 | 2014-01-15 | 徐州万邦金桥制药有限公司 | Preparation method of pitavastatin calcium |
-
2015
- 2015-05-15 CN CN201510247846.XA patent/CN104844506A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1747934A (en) * | 2003-02-12 | 2006-03-15 | 西巴特殊化学品控股有限公司 | Crystalline forms of pitavastatin calcium |
| WO2012025939A1 (en) * | 2010-08-25 | 2012-03-01 | Cadila Healthcare Limited | Pitavastatin calcium and process for its preparation |
| CN102285917A (en) * | 2011-09-20 | 2011-12-21 | 海南美大制药有限公司 | Pitavastatin calcium compound and preparation method thereof |
| CN102653523A (en) * | 2011-12-17 | 2012-09-05 | 东莞达信生物技术有限公司 | Preparation method of pitavastatin calcium by recrystallization |
| WO2013098773A1 (en) * | 2011-12-28 | 2013-07-04 | Dr. Reddy's Laboratories Limited | Crystalline forms of pitavastatin calcium |
| KR20130078086A (en) * | 2011-12-30 | 2013-07-10 | 주식회사 에스텍파마 | Process for preparing pitavastatin hemicalcium |
| CN103508946A (en) * | 2012-06-20 | 2014-01-15 | 徐州万邦金桥制药有限公司 | Preparation method of pitavastatin calcium |
Non-Patent Citations (1)
| Title |
|---|
| 蔡正艳，等: "匹伐他汀钙的合成", 《中国医药工业杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105213319A (en) * | 2015-09-17 | 2016-01-06 | 青岛华之草医药科技有限公司 | A kind of blood lipid-lowering medicine Pitavastatin calcium composition dry suspension |
| CN105106171A (en) * | 2015-09-28 | 2015-12-02 | 青岛华之草医药科技有限公司 | Pitavastatin calcium composition capsules for treating hyperlipidemia |
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Inventor after: Ding Xiuming Inventor after: Xu Liyan Inventor before: Lu Yan |
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Application publication date: 20150819 |