CN102579443A - Atorvastatin and nicotinic acid sustained release preparation and method for preparing same - Google Patents
Atorvastatin and nicotinic acid sustained release preparation and method for preparing same Download PDFInfo
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- CN102579443A CN102579443A CN2011104454993A CN201110445499A CN102579443A CN 102579443 A CN102579443 A CN 102579443A CN 2011104454993 A CN2011104454993 A CN 2011104454993A CN 201110445499 A CN201110445499 A CN 201110445499A CN 102579443 A CN102579443 A CN 102579443A
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- atorvastatin
- nicotinic acid
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Abstract
The invention provides a bilayer tablet which contains nicotinic acid and atorvastatin and a method for preparing the same, in the bilayer tablet, according to parts by weight, a nicotinic acid sustained-release layer comprises 500-1000mg of nicotinic acid and 20-80mg of atorvastatin, a matrix tablet technology is adopted, the nicotinic acid is produced into a sustained-release part, the atorvastatin is produced into a quick release part, and then the two parts are pressed into a compound sustained-release tablet. Through adjusting the variety and dose of each component in each layer, the release rates of drugs in each layer are mutually matched, and a better curative effect can be reached. The preparation of the sustained-release tablet can effectively control the drug release, the drug release rate can reach the selected drug release rate, so the plasma concentration is more stable, the fluctuation phenomenon of common preparation is reduced, the toxic and side effects of the common tablet are reduced, and the defect of a plurality of times of medicine taking is overcome. The sustained-release tablet which is prepared by the invention not only has a good appearance, but also has an upper layer and a lower layer which are closely combined with each other, under the influence of the outside humiture, the swelling speeds and swelling degrees of the two layers are consistent, so the good appearance and drug release speed can be kept all the time. The method for preparing the bilayer tablet is simple, uses easily-obtained raw materials, is suitable to industrial production, and has a good application aspect, and the related equipment is common equipment.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, specifically a kind of atorvastatin niacin sustained-release preparation and preparation method thereof.
Background technology
Atorvastatin is a kind of HMG-CoA reductase selective depressant, and molecular formula is C
33H
35FN
2O
5, molecular weight is 558.65.U.S. FDA was ratified his spit of fland preparation of atorvastatin of Pfizer company on the 17th in December in 1996, and commodity are called
Reduce plasma cholesterol and lipoprotein levels through suppressing HMG-CoA reductase and cholesterol at the biosynthesis of liver, and can increase picked-up and the catabolism of LDL through increasing surface of hepatocytes low density lipoprotein, LDL (LDL) receptor number.Can reduce the generation and its granule number of LDL.Can also reduce low-density lipoprotein cholesterol (LDL-C) level of some subtype familial hypercholesterolemia (FH) that isozygoty, and the crowd of a type replys seldom to the fat-reducing medicament treatment of other types.Can reduce total plasma cholesterol (TC), LDL-C and the apolipoprotein B (ApoB) of homozygote and heterozygote familial hypercholesterolemia, non-familial hypercholesterolemia and Combination lipid metabolism impaired patients; The level of C-VLDL (VLDL-C) and triacylglycerol (TG) can also be reduced, and the level of plasma hdl cholesterol (HDL-C) and ApoA 1 (ApoA1) can be improved to some extent.
But nicotinic acid is claimed Buddhist nun's butanoic acid again, belongs to a kind of of vitamin B group, is the active drug of treatment hyperlipemia, and it can reduce the content of low density lipoprotein, LDL, triglyceride, the content of high density lipoprotein increasing.The nicotinic acid molecular formula is C
6H
5NO
2, molecular weight is 123.11.
Atorvastatin has remarkable result to reducing low density lipoprotein, LDL (LDL), but to a little less than increase high density lipoprotein (HDL) effect.The effect of nicotinic acid has very strong increase HDL effect antithesis, but reduces a little less than the LDL effect.Both can both reduce serum triglyceride level.
Nicotinic acid is used to treat hyperlipidemia needed take in one three times, and each 1-2g is because its half-life is extremely short; Have only 45 minutes, and heavy dose of nicotinic acid that uses, two kinds of side effect of flushing and liver toxicity often appear; For giving full play to its curative effect; Reduce toxic and side effects, reduce patient's medicining times, can be made into slow releasing preparation.And the atorvastatin effect is strong, and curative effect is high, and side effect is slight; Be used to treat hypercholesterolemia at present clinically, blood fat reducing, improve blood flow, antithrombotic etc., common dose is 20mg; For making it effectively reach therapeutic purposes rapidly, need rapid release, thereby process rapid release.
Nicotinic acid and atorvastatin are processed compound slow release preparation, meet clinical application custom and therapeutics demand, have tangible characteristics and advantage:
1. effect for reducing blood fat is had complementary advantages: atorvastatin has remarkable result for reducing LDL and T-CHOL, can reduce TG simultaneously; Nicotinic acid then can effectively increase the level of HDL level, triglyceride reducing and lipoprotein a; Thereby both share the effect that can reach mutual supplement with each other's advantages; Low density lipoprotein, LDL (LDL) and triglyceride (TG) level can be reduced effectively, high density lipoprotein (HDL) level can be increased again.
2. reduce a day dosage: because the two coupling action compensating estimates that consumption per day all reduces separately, the atorvastatin consumption can be reduced to 20mg/ day, and the nicotinic acid consumption can be reduced to maximum 1g/ day; The medication number of times is reduced to every day 1 time, makes things convenient for medication.
3. reduce the side effect incidence rate: owing to reduced the consumption per day of atorvastatin and nicotinic acid; So reduce the risk that side effect takes place greatly; After nicotinic acid is processed slow releasing preparation simultaneously; Reduce the peak valley fluctuation of this medicine, reduced the nicotinic acid incidence rate of adverse reaction, all be superior to existing lipid lowerers aspect safety and the ease of use.
Advantage of the present invention is: nicotinic acid is adopted the matrix tablet technology of preparing, add atorvastatin and process compound slow-release tablet, the former is a slow-released part; The latter utilizes pharmaceutical equipment for immediate release section; Adopt double-deck pressed-disc technique, twice compacting of different granules is in blocks, process compound slow-release tablet.Not only outward appearance is good, and two-layer up and down combination is tight, and under the influence of extraneous humiture, two-layer expansion rate is consistent with degrees of expansion, can remain good surface appearance and rate of releasing drug.
The development of this slow releasing tablet can be controlled the release of medicine effectively, both can reduce ordinary tablet toxic and side effects, overcome the deficiency of taking often, the patient is easy to use, and preparation technology is simpler, is fit to suitability for industrialized production.
Summary of the invention
The present invention proposes a kind of compound preparation; Be mainly used in the treatment hypercholesterolemia; Through the release of effective control medicine, make blood drug level more steady, reduce ordinary preparation wave phenomenon and toxic and side effects, take number of times; Preparation technology is simple, is fit to atorvastatin niacin sustained-release preparation of suitability for industrialized production and preparation method thereof.
The present invention seeks to realize by following technical scheme:
(1) comprises the bilayer tablet of atorvastatin and nicotinic acid
Said bilayer tablet comprises gentle lamella and the pharmaceutically acceptable excipient released of rapid release lamella; Wherein, The slow release lamella comprises the nicotinic acid of pharmacologically effective dose; The rapid release lamella comprises the atorvastatin of physiology effective dose, saidly wants pharmaceutically acceptable excipient, comprises filler, binding agent, lubricant, shows a kind of of activating agent or several kinds.
(2) comprise the release layer of atorvastatin
Said rapid release lamella comprises 20,40, the atorvastatin of 80mg, also comprises one or more mixture of filler, disintegrating agent, binding agent, lubricant and fluidizer.
Said filler can be selected from one or more the combination of following material: starch, amylum pregelatinisatum, dextrin, sucrose, lactose, fructose, glucose, xylitol, mannitol, microcrystalline Cellulose, calcium carbonate, magnesium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, magnesium oxide, aluminium hydroxide, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, preferred sugar alcohols, amylum pregelatinisatum, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline Cellulose.
Disintegrating agent is selected from starch, cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, low substituted hydroxy-propyl methylcellulose.
Binding agent can be selected from one or more the combination of following material: water, ethanol, hypromellose.
Lubricant can be selected from one or more the combination of following material: stearic acid, calcium stearate, magnesium stearate, zinc stearate, Pulvis Talci, glyceryl monostearate, glyceryl palmitostearate, Stepanol MG, Polyethylene Glycol, stearyl fumarate.
Fluidizer can be selected from one or more the combination of following material: silica sol, Pulvis Talci, Powderd cellulose, magnesium trisilicate.
The consumption of above-mentioned excipient can be the conventional amount used of preparation ordinary preparation.Said carrier is not limited to mentioned kind, as long as be fit to the object of the invention, normally used additive all can be included in the prescription of the present invention when the preparation tablet.
(3) comprise the slow release layer of nicotinic acid
Said slow release lamella comprises 500,750,1000mg nicotinic acid, and slow-released carrier, binding agent, lubricant and necessary other excipient that pharmaceutically uses.
The mass percent of nicotinic acid in preparation of the present invention is about 70%-90%w/w, preferably about 80%-85%w/w.Preparation of the present invention comprises 500,750, the nicotinic acid of 1000mg.Slow-released carrier is selected from the cellulose or derivatives thereof of good dilatancy and gelling property, like hydroxypropyl cellulose (HPC), hypromellose (HPMC), methylcellulose (MC), hydroxyethyl-cellulose (HEC) and composition thereof.The hypromellose of preferred moderate tack is as slow-released carrier.The about 10.0%-30 of the mass percent of slow-released carrier in preparation.0%, preferably about 15.0%-20.0%w/w.
Binding agent can be for example PVP, HPC, EC etc. of the known pharmaceutically acceptable binding agent of any routine.Also can use the mixture of above-mentioned binding agent.In embodiments of the invention, the mass percent of binding agent in preparation is about 0.2%-3.25%w/w, is more preferably 2.5-3.0%w/w.
Lubricant can be hydrophobicity or hydrophilic, comprises the common known lubricant of those skilled in the art, such as but not limited to Pulvis Talci, magnesium stearate etc.Tablet of the present invention comprises about 0.5%-2.0%, preferably is about 0.8%-1.5%.
The specific embodiment
Below in conjunction with the specific embodiment the present invention is further described in detail, the embodiment that provides has been merely and has illustrated the present invention, rather than in order to limit scope of the present invention.
Embodiment 1
Prescription:
Release layer
Slow release layer
Method for preparing: get atorvastatin, cross 80 mesh sieves, fully mix,, cross 24 mesh sieves and granulate, after 1.5 hours,, add magnesium stearate and fully mix with 24 mesh sieve granulate 60 ℃ of dryings with the manual system of PVPK30 alcoholic solution soft material with other adjuvant.Get recipe quantity nicotinic acid and pulverized 80 mesh sieves, fully mix with other adjuvant of slow release layer, add water system soft material, cross 24 mesh sieve system wet granulars, 60 ℃ of dryings with 24 mesh sieve granulate, added magnesium stearate and fully mix after 2 hours.
Behind precompressed niacin sustained release layer on the special-shaped tablet machine, insert atorvastatin release layer granule more in flakes through the compacting of tablet machine secondary.
Embodiment 2
Prescription:
Release layer
Slow release layer
Method for preparing: get atorvastatin, cross 80 mesh sieves, fully mix,, cross 24 mesh sieves and granulate, after 2 hours,, add magnesium stearate and fully mix with 24 mesh sieve granulate 60 ℃ of dryings with the manual system of PVPK30 alcoholic solution soft material with other adjuvant.
Get recipe quantity nicotinic acid and pulverized 80 mesh sieves, fully mix with other adjuvant of slow release layer, add water system soft material, cross 24 mesh sieve system wet granulars, 60 ℃ of dryings with 24 mesh sieve granulate, added magnesium stearate and fully mix after 3 hours.
Behind precompressed niacin sustained release layer on the special-shaped tablet machine, insert atorvastatin release layer granule more in flakes through the compacting of tablet machine secondary.
Embodiment 3
Prescription:
Release layer
Slow release layer
Method for preparing: get atorvastatin, cross 80 mesh sieves, fully mix,, cross 24 mesh sieves and granulate, after 2 hours,, add magnesium stearate and fully mix with 24 mesh sieve granulate 60 ℃ of dryings with the manual system of PVPK30 alcoholic solution soft material with other adjuvant.Get recipe quantity nicotinic acid and pulverized 80 mesh sieves, fully mix with other adjuvant of slow release layer, add water system soft material, cross 24 mesh sieve system wet granulars, 60 ℃ of dryings with 24 mesh sieve granulate, added magnesium stearate and fully mix after 3 hours.
Behind precompressed niacin sustained release layer on the special-shaped tablet machine, insert atorvastatin release layer granule more in flakes through the compacting of tablet machine secondary.
Embodiment 4
Prescription:
Release layer
Slow release layer
Method for preparing: get atorvastatin, cross 80 mesh sieves, fully mix,, cross 24 mesh sieves and granulate, after 2 hours,, add magnesium stearate and fully mix with 24 mesh sieve granulate 60 ℃ of dryings with the manual system of PVPK30 alcoholic solution soft material with other adjuvant.Get recipe quantity nicotinic acid and pulverized 80 mesh sieves, fully mix with other adjuvant of slow release layer, add water system soft material, cross 24 mesh sieve system wet granulars, 60 ℃ of dryings with 24 mesh sieve granulate, added magnesium stearate and fully mix after 3 hours.
Behind precompressed niacin sustained release layer on the special-shaped tablet machine, insert atorvastatin release layer granule more in flakes through the compacting of tablet machine secondary.
Embodiment 5
Prescription:
Release layer
Slow release layer
Method for preparing: get atorvastatin, cross 80 mesh sieves, fully mix,, cross 24 mesh sieves and granulate, after 60 ℃ of dry 2-3 hours,, add magnesium stearate and fully mix with 24 mesh sieve granulate with the manual system of PVPK30 alcoholic solution soft material with other adjuvant.Get recipe quantity nicotinic acid and pulverized 80 mesh sieves, fully mix with other adjuvant of slow release layer, add water system soft material, cross 24 mesh sieve system wet granulars, 60 ℃ of dryings with 24 mesh sieve granulate, added magnesium stearate and fully mix after 3 hours.
Behind precompressed niacin sustained release layer on the special-shaped tablet machine, insert atorvastatin release layer granule more in flakes through the compacting of tablet machine secondary.
Claims (6)
1. a pharmaceutical composition that comprises nicotinic acid and atorvastatin exists with the double-layer tablet form.
2. the drug regimen of claim 1, double-layer tablet wherein are the double-layer tablet of processing through substep.
3. the drug regimen of claim 1, one deck is the slow release layer of being processed by nicotinic acid, one deck is the release layer of being processed by atorvastatin.
4. the drug regimen of claim 1 is characterized in that weight proportion, and every tablet preparation contains nicotinic acid 500-1000mg, atorvastatin 20-80mg.
5. the double-layer tablet nicotinic acid layer in the claim 1 is processed slow release layer, adopts the matrix tablet technology of preparing, nicotinic acid is processed slow-released part, wherein; The nicotinic acid consumption is 500-1000mg, and the sustained-release matrix material is hypromellose, sodium carboxymethyl cellulose, wherein preferred hypromellose K100M; Consumption is 10-80%, preferred 30-60%, and binding agent is 30 POVIDONE K 30 BP/USP 30, ethyl cellulose; Preferred 30 POVIDONE K 30 BP/USP 30, binder concn is 2-20%, preferred 5-10%; Lubricant is magnesium stearate, Pulvis Talci, preferred magnesium stearate, and consumption is 0.1-2%.
Atorvastatin is processed release layer, and wherein the atorvastatin consumption is 20-80mg, and diluent is starch, lactose, microcrystalline Cellulose, mannitol; Preferred lactose, microcrystalline Cellulose are diluent, and consumption is 5-90%, and disintegrating agent is carboxymethyl starch sodium, crosslinked carboxymethyl fecula sodium, polyvinylpolypyrrolidone, low-substituted hydroxypropyl methylcellulose; Preferred carboxymethyl starch sodium, consumption is 1-10%, binding agent is a 30 POVIDONE K 30 BP/USP 30; Ethyl cellulose, preferred 30 POVIDONE K 30 BP/USP 30, concentration is 5-10%; Lubricant is magnesium stearate, Pulvis Talci, preferred magnesium stearate, and consumption is 0.1-1%.
6. the method for preparing of the slow releasing tablet of claim 1, its technology is:
Get nicotinic acid, atorvastatin is crossed 80 mesh sieves, lactose, microcrystalline Cellulose, carboxymethyl starch sodium, hypromellose K100M, crosses 100 mesh sieves, and is subsequent use;
The abundant mix homogeneously of nicotinic acid and microcrystalline Cellulose adds 30 POVIDONE K 30 BP/USP 30 alcoholic solution, wet granulation; Granule is dry under 60 ℃, takes out back 24 order granulate, adds the magnesium stearate mixing, crosses 24 mesh sieve granulate, makes niacin sustained release layer granule;
Other gets lactose, microcrystalline Cellulose, carboxymethyl starch sodium and fully mixes; Atorvastatin is dissolved in 30 POVIDONE K 30 BP/USP 30 alcoholic solution, and with binding agent, lactose, microcrystalline Cellulose, the carboxymethyl starch sodium wet granulation of drug, granule is dry down at 60 ℃; Take out back 24 order granulate; Add magnesium stearate and mix, cross 24 mesh sieve granulate, make atorvastatin release layer granule; Behind precompressed niacin sustained release layer on the special-shaped tablet machine, insert atorvastatin release layer granule more in flakes through the compacting of tablet machine secondary.
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| CN2011104454993A CN102579443A (en) | 2011-12-28 | 2011-12-28 | Atorvastatin and nicotinic acid sustained release preparation and method for preparing same |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1485037A (en) * | 2002-09-29 | 2004-03-31 | 中国人民解放军军事医学科学院附属医 | Medication comprising nicotinic acid and tatin-like medicine |
| CN101559057A (en) * | 2009-04-28 | 2009-10-21 | 广西方略药业集团有限公司 | Drug compound for curing hyperlipoidemia and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1485037A (en) * | 2002-09-29 | 2004-03-31 | 中国人民解放军军事医学科学院附属医 | Medication comprising nicotinic acid and tatin-like medicine |
| CN101559057A (en) * | 2009-04-28 | 2009-10-21 | 广西方略药业集团有限公司 | Drug compound for curing hyperlipoidemia and preparation method thereof |
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Application publication date: 20120718 |