CN105106171A - Pitavastatin calcium composition capsules for treating hyperlipidemia - Google Patents
Pitavastatin calcium composition capsules for treating hyperlipidemia Download PDFInfo
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- CN105106171A CN105106171A CN201510622493.7A CN201510622493A CN105106171A CN 105106171 A CN105106171 A CN 105106171A CN 201510622493 A CN201510622493 A CN 201510622493A CN 105106171 A CN105106171 A CN 105106171A
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Abstract
The invention relates to pitavastatin calcium composition capsules for treating hyperlipidemia and belongs to the technical field of medicine. The pitavastatin calcium composition capsules comprise pitavastatin calcium, pregelatinized starch, white dextrin, gentian ethanolamine, hydroxypropyl methylcellulose, purified water and talcum powder. The pitavastatin calcium is a new crystal compound, the X-ray powder diffraction diagram, obtained by using Cu-K alpha rays for measuring, of the pitavastatin calcium is shown in figure 1, and the pitavastatin calcium is different from pitavastatin calcium reported in the prior art. Experimental researches show that the stability of the capsules prepared by the new crystal compound is increased while pitavastatin calcium's inhibition effect on HMG-CoA reductase activity is increased evidently, and the lipid lowering effect of the capsules is increased evidently.
Description
Technical field
The invention belongs to medical art, relate to a kind of medicine Pitavastatin Calcium composition capsule 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 blood fat reducing 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 capsule that this compound is made has the effect significantly improving Pitavastatin Calcium and suppress HMG-CoA reductase activity while improving stability by experimental study, thus significantly improve its lipid-lowering effect.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of medicine Pitavastatin Calcium composition capsule for the treatment of hyperlipidemia.
In order to complete object of the present invention, the technical scheme of employing is:
A kind of medicine Pitavastatin Calcium composition capsule for the treatment of hyperlipidemia of the present invention, described composition capsule is made up of Pitavastatin Calcium, pregelatinized Starch, white dextrin, gentisic acid ethanolamine, hypromellose, purified water, Pulvis Talci; Described Pitavastatin Calcium 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 composition capsule is made up of the Pitavastatin Calcium of 2 weight portions, the pregelatinized Starch of 38-42 weight portion, the white dextrin of 98-100 weight portion, the gentisic acid ethanolamine of 11-13 weight portion, the hypromellose of 1-3 weight portion, the purified water of 37-39 weight portion, the Pulvis Talci of 4-6 weight portion.
Second optimal technical scheme of the present invention is: with parts by weight, and described composition capsule is made up of the Pitavastatin Calcium of 2 weight portions, the pregelatinized Starch of 40 weight portions, the white dextrin of 99 weight portions, the gentisic acid ethanolamine of 12 weight portions, the hypromellose of 2 weight portions, the purified water of 38 weight portions, the Pulvis Talci of 5 weight portions.
3rd optimal technical scheme of the present invention is: the preparation method of described composition capsule comprises the following steps:
(1) weigh: weigh according to technology preparation;
(2) supplementary material process: the Pitavastatin Calcium of recipe quantity and the pregelatinized Starch of recipe quantity are mixed by equivalent method of progressively increasing, pulverizes 100 mesh sieves after mix homogeneously, obtained supplementary material mixture;
(3) preparation of binding agent: get recipe quantity hypromellose and be dissolved in purified water, stand-by;
(4) mixing granulation: add adjuvant white dextrin by supplementary material mixture complete for premix and residue, gentisic acid ethanolamine is added in wet mixing pelletizer, open stirring motor and be dry mixed 15min; Add the binding agent wet mixing cutting prepared, with 20 mesh sieve soft materials;
(5) dry: the wet granular of granulation gained to be joined in fluid bed dryer, set temperature 55-60 DEG C, dry 90-110min, by material 20 order granulate after drying;
(6) mix: granule after granulate and Pulvis Talci are dropped into three-dimensional motion mixer, premixing speed 10r/min, incorporation time 30min are set;
(7) capsule-filling: carry out fill according to after the theoretical loading amount scope of total mixed gained material cubage;
(8) pack.
4th optimal technical scheme of the present invention is: the preparation method of the crystal of described Pitavastatin Calcium comprises the following steps:
Be dissolved in by Pitavastatin Calcium in the mixed solvent of methanol that 45 DEG C of volumes are 6 times of Pitavastatin Calcium weight, dimethyl sulfoxine, the volume ratio of methanol and dimethyl sulfoxine is 5:1.5; First add with the speed of 40ml/min the ethanol of 9 times and the mixed solvent of ether that volume is Pitavastatin Calcium weight, the volume ratio of ethanol, ether is 2:2, and limit edged stirs, control temperature 45 DEG C, growing the grain 3h; And then the acetonitrile of 7 times that volume total amount is Pitavastatin Calcium weight is added with the speed of 20ml/min, after growing the grain 1h, be cooled to-5 DEG C with the speed of 10 DEG C/h, then keep mixing speed 90r/min stirring and crystallizing, growing the grain 3h; Filter, washing, drying under reduced pressure obtains Pitavastatin Calcium crystalline compounds.
Below technical scheme of the present invention is made further explanation:
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 obtains a kind of Pitavastatin Calcium novel crystal forms structure being different from prior art through a large amount of tests, and by test, show that the capsule that this crystal compound is made has the effect significantly improving Pitavastatin Calcium and suppress HMG-CoA reductase activity while improving stability, thus significantly improve its lipid-lowering effect.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction that the Pitavastatin Calcium 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 Pitavastatin Calcium crystal:
Be dissolved in by Pitavastatin Calcium in the mixed solvent of methanol that 45 DEG C of volumes are 6 times of Pitavastatin Calcium weight, dimethyl sulfoxine, the volume ratio of methanol and dimethyl sulfoxine is 5:1.5; First add with the speed of 40ml/min the ethanol of 9 times and the mixed solvent of ether that volume is Pitavastatin Calcium weight, the volume ratio of ethanol, ether is 2:2, and limit edged stirs, control temperature 45 DEG C, growing the grain 3h; And then the acetonitrile of 7 times that volume total amount is Pitavastatin Calcium weight is added with the speed of 20ml/min, after growing the grain 1h, be cooled to-5 DEG C with the speed of 10 DEG C/h, then keep mixing speed 90r/min stirring and crystallizing, growing the grain 3h; Filter, washing, drying under reduced pressure obtains Pitavastatin Calcium crystalline compounds.
The X-ray powder diffraction pattern that the Pitavastatin Calcium crystal prepared uses the measurement of Cu-K alpha ray to obtain as shown in Figure 1.
embodiment 2:the preparation of Pitavastatin calcium capsule
Prescription: with parts by weight
Preparation method:
(1) weigh: weigh according to technology preparation;
(2) supplementary material process: the Pitavastatin Calcium of recipe quantity and the pregelatinized Starch of recipe quantity are mixed by equivalent method of progressively increasing, pulverizes 100 mesh sieves after mix homogeneously, obtained supplementary material mixture;
(3) preparation of binding agent: get recipe quantity hypromellose and be dissolved in purified water, stand-by;
(4) mixing granulation: add adjuvant white dextrin by supplementary material mixture complete for premix and residue, gentisic acid ethanolamine is added in wet mixing pelletizer, open stirring motor and be dry mixed 15min; Add the binding agent wet mixing cutting prepared, with 20 mesh sieve soft materials;
(5) dry: the wet granular of granulation gained to be joined in fluid bed dryer, set temperature 55-60 DEG C, dry 90-110min, by material 20 order granulate after drying;
(6) mix: granule after granulate and Pulvis Talci are dropped into three-dimensional motion mixer, premixing speed 10r/min, incorporation time 30min are set;
(7) capsule-filling: carry out fill according to after the theoretical loading amount scope of total mixed gained material cubage;
(8) pack.
embodiment 3:the preparation of Pitavastatin calcium capsule
Prescription: with parts by weight
Preparation method:
(1) weigh: weigh according to technology preparation;
(2) supplementary material process: the Pitavastatin Calcium of recipe quantity and the pregelatinized Starch of recipe quantity are mixed by equivalent method of progressively increasing, pulverizes 100 mesh sieves after mix homogeneously, obtained supplementary material mixture;
(3) preparation of binding agent: get recipe quantity hypromellose and be dissolved in purified water, stand-by;
(4) mixing granulation: add adjuvant white dextrin by supplementary material mixture complete for premix and residue, gentisic acid ethanolamine is added in wet mixing pelletizer, open stirring motor and be dry mixed 15min; Add the binding agent wet mixing cutting prepared, with 20 mesh sieve soft materials;
(5) dry: the wet granular of granulation gained to be joined in fluid bed dryer, set temperature 55-60 DEG C, dry 90-110min, by material 20 order granulate after drying;
(6) mix: granule after granulate and Pulvis Talci are dropped into three-dimensional motion mixer, premixing speed 10r/min, incorporation time 30min are set;
(7) capsule-filling: carry out fill according to after the theoretical loading amount scope of total mixed gained material cubage;
(8) pack.
embodiment 4:the preparation of Pitavastatin calcium capsule
Prescription: with parts by weight
Preparation method:
(1) weigh: weigh according to technology preparation;
(2) supplementary material process: the Pitavastatin Calcium of recipe quantity and the pregelatinized Starch of recipe quantity are mixed by equivalent method of progressively increasing, pulverizes 100 mesh sieves after mix homogeneously, obtained supplementary material mixture;
(3) preparation of binding agent: get recipe quantity hypromellose and be dissolved in purified water, stand-by;
(4) mixing granulation: add adjuvant white dextrin by supplementary material mixture complete for premix and residue, gentisic acid ethanolamine is added in wet mixing pelletizer, open stirring motor and be dry mixed 15min; Add the binding agent wet mixing cutting prepared, with 20 mesh sieve soft materials;
(5) dry: the wet granular of granulation gained to be joined in fluid bed dryer, set temperature 55-60 DEG C, dry 90-110min, by material 20 order granulate after drying;
(6) mix: granule after granulate and Pulvis Talci are dropped into three-dimensional motion mixer, premixing speed 10r/min, incorporation time 30min are set;
(7) capsule-filling: carry out fill according to after the theoretical loading amount scope of total mixed gained material cubage;
(8) pack.
test example 1:
Pitavastatin calcium capsule prepared by Example 2-4, detects dissolution (see table 1), related substance (see table 1), vitro inhibition HMG-CoA reductase activity (see table 2) 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 hyperlipemia method.High lipid food formula is as follows: normal feedstuff 86.3%, cholesterol 3%, Adeps Sus domestica 10%, methylthiouracil 0.2%, Fel Sus domestica salt 0.5%, ensures composition mix homogeneously, 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 nicotinamide adenine dinucleotide (NADP).NADPH has absorption maximum 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 capsule prepared by three embodiments to the inhibitory action 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: Pitavastatin calcium capsule of the present invention, what the sheet power of comparatively going on the market was clear has higher dissolution, impurity content well below listing sheet power clear it.
table 2 each group of IC to HMG-CoA reductase
50
As seen from Table 2: Pitavastatin calcium capsule of the present invention, what sheet power of comparatively going on the market was clear has the activity better suppressing HMG-CoA reductase.
test example 2: embodiment accelerated test and long term test
Accelerated test: according to the requirement of " Chinese Pharmacopoeia version in 2010 " stability test guideline, long term test has been carried out to Pitavastatin calcium capsule of the present invention.By embodiment 2-4 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.
Long term test: according to the requirement of " Chinese Pharmacopoeia version in 2010 " stability test guideline, long term test has been carried out to Pitavastatin calcium capsule of the present invention.By embodiment 2-4 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 capsule accelerated test 6 months prepared by embodiment of the present invention 2-4 or long term test are after 24 months, and disintegration, dissolution and related substance are without significant change, and dissolution is high, good stability.
Claims (5)
1. treat a medicine Pitavastatin Calcium composition capsule for hyperlipidemia, it is characterized in that: described composition capsule is made up of Pitavastatin Calcium, pregelatinized Starch, white dextrin, gentisic acid ethanolamine, hypromellose, purified water, Pulvis Talci; Described Pitavastatin Calcium 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 medicine Pitavastatin Calcium composition capsule for the treatment of hyperlipidemia according to claim 1, it is characterized in that: with parts by weight, described composition capsule is made up of the Pitavastatin Calcium of 2 weight portions, the pregelatinized Starch of 38-42 weight portion, the white dextrin of 98-100 weight portion, the gentisic acid ethanolamine of 11-13 weight portion, the hypromellose of 1-3 weight portion, the purified water of 37-39 weight portion, the Pulvis Talci of 4-6 weight portion.
3. the medicine Pitavastatin Calcium composition capsule for the treatment of hyperlipidemia according to claim 2, it is characterized in that: with parts by weight, described composition capsule is made up of the Pitavastatin Calcium of 2 weight portions, the pregelatinized Starch of 40 weight portions, the white dextrin of 99 weight portions, the gentisic acid ethanolamine of 12 weight portions, the hypromellose of 2 weight portions, the purified water of 38 weight portions, the Pulvis Talci of 5 weight portions.
4., according to the medicine Pitavastatin Calcium composition capsule of the arbitrary described treatment hyperlipidemia of claim 1-3, it is characterized in that, the preparation method of described composition capsule comprises the following steps:
(1) weigh: weigh according to technology preparation;
(2) supplementary material process: the Pitavastatin Calcium of recipe quantity and the pregelatinized Starch of recipe quantity are mixed by equivalent method of progressively increasing, pulverizes 100 mesh sieves after mix homogeneously, obtained supplementary material mixture;
(3) preparation of binding agent: get recipe quantity hypromellose and be dissolved in purified water, stand-by;
(4) mixing granulation: add adjuvant white dextrin by supplementary material mixture complete for premix and residue, gentisic acid ethanolamine is added in wet mixing pelletizer, open stirring motor and be dry mixed 15min; Add the binding agent wet mixing cutting prepared, with 20 mesh sieve soft materials;
(5) dry: the wet granular of granulation gained to be joined in fluid bed dryer, set temperature 55-60 DEG C, dry 90-110min, by material 20 order granulate after drying;
(6) mix: granule after granulate and Pulvis Talci are dropped into three-dimensional motion mixer, premixing speed 10r/min, incorporation time 30min are set;
(7) capsule-filling: carry out fill according to after the theoretical loading amount scope of total mixed gained material cubage;
(8) pack.
5. the medicine Pitavastatin calcium composition for the treatment of hyperlipidemia according to claim 1, it is characterized in that, the preparation method of the crystal of described Pitavastatin Calcium comprises the following steps:
Be dissolved in by Pitavastatin Calcium in the mixed solvent of methanol that 45 DEG C of volumes are 6 times of Pitavastatin Calcium weight, dimethyl sulfoxine, the volume ratio of methanol and dimethyl sulfoxine is 5:1.5; First add with the speed of 40ml/min the ethanol of 9 times and the mixed solvent of ether that volume is Pitavastatin Calcium weight, the volume ratio of ethanol, ether is 2:2, and limit edged stirs, control temperature 45 DEG C, growing the grain 3h; And then the acetonitrile of 7 times that volume total amount is Pitavastatin Calcium weight is added with the speed of 20ml/min, after growing the grain 1h, be cooled to-5 DEG C with the speed of 10 DEG C/h, then keep mixing speed 90r/min stirring and crystallizing, growing the grain 3h; Filter, washing, drying under reduced pressure obtains Pitavastatin Calcium crystalline compounds.
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| CN201510622493.7A CN105106171A (en) | 2015-09-28 | 2015-09-28 | Pitavastatin calcium composition capsules for treating hyperlipidemia |
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| CN201510622493.7A CN105106171A (en) | 2015-09-28 | 2015-09-28 | Pitavastatin calcium composition capsules for treating hyperlipidemia |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| JP2013035798A (en) * | 2011-08-10 | 2013-02-21 | Kyowa Yakuhin Kogyo Kk | Stabilized pharmaceutical composition containing pitavastatin |
| CN104844506A (en) * | 2015-05-15 | 2015-08-19 | 苗怡文 | Medicinal pitavastatin calcium compound for treating hyperlipidemia |
| CN104860882A (en) * | 2015-05-15 | 2015-08-26 | 苗怡文 | Drug pitavastatin calcium composition for treating hyperlipidemia |
-
2015
- 2015-09-28 CN CN201510622493.7A patent/CN105106171A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013035798A (en) * | 2011-08-10 | 2013-02-21 | Kyowa Yakuhin Kogyo Kk | Stabilized pharmaceutical composition containing pitavastatin |
| 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 |
| CN104844506A (en) * | 2015-05-15 | 2015-08-19 | 苗怡文 | Medicinal pitavastatin calcium compound for treating hyperlipidemia |
| CN104860882A (en) * | 2015-05-15 | 2015-08-26 | 苗怡文 | Drug pitavastatin calcium composition for treating hyperlipidemia |
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