CN105434391A - Atorvastatin calcium enteric-coated tablet as well as preparation method and application thereof - Google Patents
Atorvastatin calcium enteric-coated tablet as well as preparation method and application thereof Download PDFInfo
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- CN105434391A CN105434391A CN201610031061.3A CN201610031061A CN105434391A CN 105434391 A CN105434391 A CN 105434391A CN 201610031061 A CN201610031061 A CN 201610031061A CN 105434391 A CN105434391 A CN 105434391A
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- atorvastatin calcium
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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Abstract
The invention discloses an atorvastatin calcium enteric-coated tablet. The atorvastatin calcium enteric-coated tablet consists of a tablet core and a unidirectional adhesive coating layer, wherein the tablet core is prepared from atorvastatin calcium, sodium caprate, mannitol, PVP-K30, superfine silica powder and magnesium stearate, and the unidirectional adhesive coating layer comprises an isolation layer, a unidirectional adhesive layer and an enteric-coated layer from inside to outside. According to the atorvastatin calcium enteric-coated tablet provided by the invention, a technology of combining a sorbefacient and unidirectional release is adopted for the first time, the sodium caprate is used as the sorbefacient, ethyl cellulose with a bioadhesion function is taken as a unidirectional layer, and L30D55 is used as a enteric-coated coating material, so as to ensure that the atorvastatin calcium enteric-coated tablet cannot be damaged in a gastric acid environment and can be adhered to a specific area of intestinal canal, and the main drug, i.e. atorvastatin calcium and the sorbefacient, i.e. sodium caprate are slowly released unidirectionally through ostioles, so that not only can bioavailability of the drug be improved, but also individual difference is reduced and side effects are reduced.
Description
Technical field
The invention belongs to blood lipid-lowering medicine technical field, be specifically related to a kind of Atorvastatin calcium enteric coatel tablets and its preparation method and application.
Background technology
Cardiovascular diseases is the maximum disease of harm humans health.Cardiovascular and cerebrovascular vessel patient ten thousand people more than more than 1500 are died from the whole world every year on average.Leap to as first place in many national cardiovascular disease.Its M & M is too high closely related with arteriosclerosis with Human Lipid Metabolism imbalance, serum total cholesterol.Clinic, epidemiology and pathological research show, the coronary heart disease of the mankind and atherosclerosis are formed and in evolution process, too much low density lipoprotein, LDL will affect biologically active pdgf and form thrombosis.
Investigation display: China person in middle and old age hyperlipidemia is very general, major part person in middle and old age hyperlipidemia belongs to high-cholesterol disease (TC) and triglyceride (TG) is abnormal, this is the main pathological basis that formation atherosclerosis causes cardiovascular and cerebrovascular disease, and lipid-regulation medicine is then the strategic essential measure of control cardiovascular and cerebrovascular disease.Hydroxyl first glutaryl coenzyme A (HMG-CoA) reductase inhibitor, since the beginning of the eighties comes out, developed into third generation product, and statins has occupied dominant contribution in blood fat reducing medicine.
Atorvastatin calcium (AtorvastatinCalcium) belongs to HMG-CoA reductase inhibitor, by suppressing the biosynthesis of HMG-CoA reductase and cholesterol in liver thus reducing cholesterol and serum lipoprotein concentration in blood plasma, and by the low density lipoprotein receptor in rat liver that increases cell surface to strengthen picked-up and the metabolism of low density lipoprotein, LDL.Atorvastatin calcium effectively can reduce homozygote and heterozygote familial hypercholesterolemia, non-familial hypercholesterolemia and mixed type disorder of lipid metabolism patients blood plasma T-CHOL, low-density lipoprotein cholesterol, apolipoprotein and triglyceride levels, simultaneously high density lipoprotein increasing cholesterol and ApoA l level to some extent.
Atorvastatin calcium has highly lipophilic, poorly water-soluble, all responsive to humidity, light, heat and low pH etc., in low pH situation, (under gastric acid condition) can be degraded to the lactone form of Lipid-lowering activities especially, after the solid preparation oral administration of therefore Atorvastatin calcium, be detained in gastric juice, inevitably can degrade, make stomach dissolution type atorvastatin of the prior art agent all there is the problems such as the large and side effect large (as the myalgia that statins causes) of bioavailability difference, individual difference.
Chinese patent CN103705484A discloses a kind of stable atorvastatin and preparation method thereof, belong to stomach dissolution type, label is by the Atorvastatin calcium of 5%-20%, the complex stabilizer composition of the filler of 15-60%, the disintegrating agent of 5%-20%, lubricant and suitable consumption, film-coat layer contains the stabilizing agents such as calcium carbonate, magnesium oxide, sodium bicarbonate, but the alkaline matters such as the calcium carbonate added can react with gastric acid, cause the bad side reactions such as constipation, flatulence, dyspepsia.
Chinese patent CN104127391A discloses a kind of solid composite medicament containing Atorvastatin calcium, belong to the agent of enteric solubility atorvastatin, there is good stability and controllability, but do not describe bioavailability and the individual difference of this enteric solubility tablet.
Atorvastatin calcium enteric coatel tablets of the prior art are common enteric coated preparation, and medicine discharges at random in intestinal, can not ensure that Atorvastatin calcium is fully absorbed and utilizes.Therefore, prepare a kind of Atorvastatin calcium enteric coatel tablets, can ensure to carry out in the specific region that Atorvastatin calcium and absorption enhancer optionally stick to intestinal unidirectionally to discharge lentamente, thus improve absorbance and the bioavailability of medicine, reduce individual variation and side reaction simultaneously, become market be badly in need of, tool is of great significance.
Summary of the invention
First object of the present invention is to solve Atorvastatin calcium in prior art and is mostly stomach dissolution type, the absorption difference existed, individual difference is large, the problems such as side effect is large, thus a kind of Atorvastatin calcium enteric coatel tablets are provided, discharge slowly in the specific region that optionally can stick to intestinal, improve the bioavailability of Atorvastatin calcium, reduce individual difference and side reaction.
Second object of the present invention is the preparation method providing a kind of Atorvastatin calcium enteric coatel tablets.
3rd object of the present invention is the application providing a kind of Atorvastatin calcium enteric coatel tablets as blood lipid-lowering medicine.
For solving above-mentioned technical problem, Atorvastatin calcium enteric coatel tablets of the present invention, be made up of label and unidirectional adhesive coatings, described label is made up of Atorvastatin calcium, Capric acid sodium salt, mannitol, polyvinylpyrrolidone-k30 (PVP-k30), micropowder silica gel, magnesium stearate, and described unidirectional adhesive coatings comprises sealing coat, unidirectional adhesion layer and enteric layer from inside to outside successively.
Preferably, described label is composed of the following components by weight percentage:
Described sealing coat component is hydroxypropyl emthylcellulose (HPMCE5), and described unidirectional adhesion layer component is ethyl cellulose EC, and described enteric layer component is methacrylic acid-acrylic acid polymerizable methacrylate thing aqueous dispersion (L30D55).
Preferably, described HPMCE5 layer content is 3 ~ 4mg/ sheet, and described EC layer content is less than 2mg/ sheet, and described L30D55 enteric layer content is greater than 30mg/ sheet.
Described unidirectional adhesion layer and described sealing coat has the aperture discharging medicine.
Preferably, the preparation method of described Atorvastatin calcium enteric coatel tablets comprises the following steps:
(1) supplementary material process: by the adjuvant Capric acid sodium salt of formula ratio, mannitol and PVP-k30 mix homogeneously, obtain adjuvant mixture; By the Atorvastatin calcium of the formula ratio abundant suspendible of appropriate dehydrated alcohol, be then added in adjuvant mixture, obtained supplementary material mixture;
(2) granulate: supplementary material mixture is sieved, then granulates, dry after merging granule, collect dried granule, then add micropowder silica gel and magnesium stearate, granulate;
(3) tabletting: carry out tabletting after heavy according to the theoretical sheet of total mixed gained material cubage;
(4) coating:
1) first wrapping HPMCE5, is sealing coat;
2) wrap EC layer again, be unidirectional adhesion layer, after having wrapped, carry out one side laser boring;
3) finally wrapping L30D55, is enteric layer.
(5) pack.
Described Atorvastatin calcium enteric coatel tablets can be used as the application of blood lipid-lowering medicine.
Beneficial effect of the present invention is as follows:
Atorvastatin calcium enteric coatel tablets of the present invention and preparation method thereof, have employed the technology that absorption enhancer combines with unidirectional release first, adopt Capric acid sodium salt as absorption enhancer, the ethyl cellulose with bioadhesion effect is unidirectional adhesion layer, and carry out laser boring at one side, L30D55 is enteric solubility coating material, ensure that Atorvastatin calcium enteric coatel tablets can not be destroyed in gastric acid environment, and can stick in the specific region of intestinal, principal agent Atorvastatin calcium and absorption enhancer Capric acid sodium salt is discharged lentamente by release aperture is unidirectional, not only increase bioavailability, also reduce individual difference, decrease side reaction.
Accompanying drawing illustrates:
Fig. 1 embodiment 1 is at pH6.8 buffer release profiles.
Fig. 2 embodiment 2 is at pH6.8 buffer release profiles.
Fig. 3 embodiment 3 is at pH6.8 buffer release profiles.
Fig. 4 embodiment 4 is at pH6.8 buffer release profiles.
Fig. 5 embodiment 5 is at pH6.8 buffer release profiles.
(n=4) plasma concentration curve after Fig. 6 lipitor administration 20mg.
(n=3) plasma concentration curve after Fig. 7 lipitor administration 60mg.
(n=5) plasma concentration curve after Fig. 8 embodiment 1 administration 10mg.
(n=4) plasma concentration curve after Fig. 9 embodiment 1 administration 30mg.
(n=5) plasma concentration curve after Figure 10 embodiment 2 administration 10mg.
(n=4) plasma concentration curve after Figure 11 embodiment 5 administration 20mg.
Detailed description of the invention
Below by way of specific embodiment, the present invention is described in further details.Should be understood that following examples only for illustration of the present invention but not for limiting scope of the present invention.
The supplementary material used in following examples, unless otherwise indicated, all by commercially available acquisition.
embodiment 1-5
By with the formula shown in following table 1, prepare Atorvastatin calcium enteric coatel tablets.
Table 1 Atorvastatin calcium enteric coatel tablets formula
The preparation method of embodiment 1-5 is as follows:
(1) supplementary material process: by the adjuvant Capric acid sodium salt of formula ratio, mannitol and PVP-k30 mix homogeneously, obtain adjuvant mixture; By the Atorvastatin calcium of the formula ratio abundant suspendible of appropriate dehydrated alcohol, be then added in adjuvant mixture, obtained supplementary material mixture;
(2) granulate: supplementary material mixture is divided and sieves for 2 times, then granulate, dry after merging granule, collect dried granule, then add micropowder silica gel and magnesium stearate, granulate;
(3) tabletting: carry out tabletting after heavy according to the theoretical sheet of total mixed gained material cubage;
(4) coating:
1) first wrapping HPMCE5, is sealing coat;
2) wrap EC layer again, be unidirectional adhesion layer, after having wrapped, carry out one side laser boring;
3) finally wrapping L30D55, is enteric layer.
(5) pack.
The Atorvastatin calcium enteric coatel tablets sample obtained is further used for follow-up embodiment.
embodiment 6,enteric coatel tablets dissolution test
Get each 3 of the sample prepared according to the embodiment of the present invention 1 to 5 formula, with the hydrochloric acid of pH1.0 (900ml) for solvent, control rotating speed 100 revs/min, temperature is 37 ± 0.5 DEG C, operate, 2 hours sampling 1.5ml, detect by high performance liquid chromatography (HPLC) in accordance with the law.Then enteric coatel tablets are carefully taken out, hydrochloric acid solution is toppled over totally, then add the phosphate buffer solution (900ml) of pH6.8, control rotating speed 100 revs/min, temperature is 37 ± 0.5 DEG C, operates in accordance with the law, respectively at 0,10,20,30,40,50,1.5ml is sampled during 60min, supplement the phosphate buffer solution 1.5ml of pH6.8 at every turn after getting liquid simultaneously, adopt HPLC to detect its release, the results are shown in Table shown in 2 and Fig. 1-5.
The release result of table 2 Atorvastatin calcium enteric coatel tablets in pH1.0 hydrochloric acid
| Time (min) | Release rate (%) in pH1.0 hydrochloric acid | |
| Embodiment 1 | 120 | 0 |
| Embodiment 2 | 120 | 0 |
| Embodiment 3 | 120 | 0 |
| Embodiment 4 | 120 | 0 |
| Embodiment 5 | 120 | 0 |
As can be seen from Table 2, the Atorvastatin calcium enteric coatel tablets that prepared by embodiment 1 to 5 all do not discharge in the hydrochloric acid of pH1.0; As can be seen from Fig. 1 to Fig. 5, Atorvastatin calcium enteric coatel tablets releasing trend in pH6.8 buffer solution is consistent, can reach more than 90%, meet " Chinese Pharmacopoeia " regulation to enteric coatel tablets release in 40 ~ 50min burst size.
embodiment 7,the generation test of beasle dog medicine
Beasle dog is adopted to carry out pharmacokinetic trial respectively in the sample (at random) prepared according to embodiment of the present invention formula, adopt the commercially available medicine lipitor of import (specification 20mg simultaneously, pfizer inc's import subpackage) as positive control, 12h fasting before beasle dog administration, duration of test is freely drunk water.Respectively at after administration 0,0.5,1,1.5,2.0,3.0,4.0,5.0, within 6.0 hours, get blood 0.5ml (get blood vessel and add heparin), centrifugal (5000r/min, 10min), gets supernatant blood plasma.Detect the concentration of atorvastatin calcium in blood plasma by LC/MS/MS method, the results are shown in Figure shown in 6-11, statistical analysis mean serum pharmacokinetic parametric results is as shown in table 3.
Table 3 investigational agent and contrast medicine mean serum pharmacokinetic parameter
Mean serum pharmacokinetic parametric statistics result as can be seen from table 3, in the present invention, the beasle dog bioavailability of enteric coatel tablets sample is approximately 2 ~ 3 times of commercially available lipitor.
As can be seen from above-mentioned result of the test, in the present invention, the beasle dog medicine generation test individual variation of sample is all little than lipitor.
In sum, the technology that the absorption enhancer adopted in the present invention and unidirectional release combine, adopt Capric acid sodium salt as absorption enhancer, the ethyl cellulose with bioadhesion effect is unidirectional adhesion layer, both Atorvastatin calcium enteric coatel tablets can have been avoided destroyed in gastric acid environment, in turn ensure that Atorvastatin calcium enteric coatel tablets optionally stick to certain privileged sites in intestinal, unidirectional release principal agent Atorvastatin calcium and absorption enhancer Capric acid sodium salt lentamente, not only increase bioavailability, reduce individual variation and decrease Atorvastatin calcium and degrade under one's belt and the side effect brought to human body.
Be described in detail specific embodiments of the invention above, but it is as example, the present invention is not restricted to specific embodiment described above.To those skilled in the art, any equivalent modifications that this practicality is carried out and substituting also all among category of the present invention.Therefore, equalization conversion done without departing from the spirit and scope of the invention and amendment, all should contain within the scope of the invention.
Claims (7)
1. Atorvastatin calcium enteric coatel tablets, it is characterized in that, described Atorvastatin calcium enteric coatel tablets are made up of label and unidirectional adhesive coatings, described label is made up of Atorvastatin calcium, Capric acid sodium salt, mannitol, PVP-k30, micropowder silica gel, magnesium stearate, and described unidirectional adhesive coatings comprises sealing coat, unidirectional adhesion layer and enteric layer from inside to outside successively.
2. Atorvastatin calcium enteric coatel tablets as claimed in claim 1, it is characterized in that, described label is composed of the following components by weight percentage:
3. Atorvastatin calcium enteric coatel tablets as claimed in claim 1, it is characterized in that, described sealing coat component is HPMCE5, and described unidirectional adhesion layer component is EC, and described enteric layer component is L30D55.
4. Atorvastatin calcium enteric coatel tablets as claimed in claim 3, it is characterized in that, described HPMCE5 layer content is 3 ~ 4mg/ sheet, and described EC layer content is less than 2mg/ sheet, and described L30D55 enteric layer content is greater than 30mg/ sheet.
5. Atorvastatin calcium enteric coatel tablets as claimed in claim 1, is characterized in that, described unidirectional adhesion layer and described sealing coat have the aperture discharging medicine.
6. Atorvastatin calcium enteric coatel tablets as claimed in claim 1, it is characterized in that, the preparation method of described Atorvastatin calcium enteric coatel tablets comprises the following steps:
(1) supplementary material process: by the adjuvant Capric acid sodium salt of formula ratio, mannitol and PVP-k30 mix homogeneously, obtain adjuvant mixture; By the Atorvastatin calcium of the formula ratio abundant suspendible of appropriate dehydrated alcohol, be then added in adjuvant mixture, obtained supplementary material mixture;
(2) granulate: supplementary material mixture is sieved, then granulates, dry after merging granule, collect dried granule, then add micropowder silica gel and magnesium stearate, granulate;
(3) tabletting: carry out tabletting after heavy according to the theoretical sheet of total mixed gained material cubage;
(4) coating:
1) first wrapping HPMCE5, is sealing coat;
2) wrap EC layer again, be unidirectional adhesion layer, after having wrapped, carry out one side laser boring;
3) finally wrapping L30D55, is enteric layer.
(5) pack.
7. the Atorvastatin calcium enteric coatel tablets according to any one of claim 1-6 are as the application of blood lipid-lowering medicine.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3370703A4 (en) * | 2015-11-06 | 2019-06-19 | Gemphire Therapeutics Inc. | Gemcabene combinations for the treatment of cardiovascular disease |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102335431A (en) * | 2010-07-14 | 2012-02-01 | 上海蓝心医药科技有限公司 | Administration composition as well as preparation and use methods thereof |
| CN102552919A (en) * | 2010-12-15 | 2012-07-11 | 上海蓝心医药科技有限公司 | Administration combination and preparation and use methods thereof |
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- 2016-01-18 CN CN201610031061.3A patent/CN105434391A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102335431A (en) * | 2010-07-14 | 2012-02-01 | 上海蓝心医药科技有限公司 | Administration composition as well as preparation and use methods thereof |
| CN102552919A (en) * | 2010-12-15 | 2012-07-11 | 上海蓝心医药科技有限公司 | Administration combination and preparation and use methods thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3370703A4 (en) * | 2015-11-06 | 2019-06-19 | Gemphire Therapeutics Inc. | Gemcabene combinations for the treatment of cardiovascular disease |
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Application publication date: 20160330 |