CN101474163B - Lovastatin and niacin sustained-release preparation and preparation method thereof - Google Patents
Lovastatin and niacin sustained-release preparation and preparation method thereof Download PDFInfo
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- CN101474163B CN101474163B CN200910014116XA CN200910014116A CN101474163B CN 101474163 B CN101474163 B CN 101474163B CN 200910014116X A CN200910014116X A CN 200910014116XA CN 200910014116 A CN200910014116 A CN 200910014116A CN 101474163 B CN101474163 B CN 101474163B
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Abstract
The invention relates to a lovastatin and niacin sustained-release preparation. Each tablet contains 500mg niacin and 20mg lovastatin according to weight proportion; matrix tablets preparation technology is adopted to prepare the niacin as a sustained-release share and the lovastatin as a quick-release share; and the two shares are compressed to be a compound sustained release tablet. The compound preparation is mainly used for treating hypercholesterolemia, and the HDL is increased by 41%, the LDL is decreased by 45%, and the triglyceride is decreased by 42% after one year treatment. The development of the sustained release tablet can effectively control the release of medicament so that the medicament release rate can reach a preset value, the blood concentration is smoother and the fluctuation phenomenon lead by common preparation is decreased. The invention ensures that not only the toxic side effect caused by the common preparation is reduced, and the deficient of frequent medicine taking is overcame but also the situations of missing or forgetting are avoided and the use is convenient for a patient. When the two are jointly used, synergic action is obtained. The invention has simple preparation process and is suitable for industrial production.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, specifically a kind of Lovastatin nicotinic acid slow-release preparation and preparation method thereof.
Background technology
But nicotinic acid claims Buddhist nun's butanoic acid again, belongs to a kind of of vitamin B group, is one of active drug of treatment hyperlipemia, and it can reduce the content of low density lipoprotein, LDL, triglyceride, the content of high density lipoprotein increasing.
Lovastatin is a kind of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, is the choice drug of cholesterol reducing clinically.Clinical research proves, takes these the two kinds alleviation hypercholesterolemia curative effects that medicine had simultaneously and obviously is better than only taking arbitrary single preparations of ephedrine.Both drug combinations can totally improve blood fat fat situation.China Patent No. ZL200510112698.7 discloses " a kind of retard capsule of compound nicotinic acid and its preparation method ", and above-mentioned two kinds of single preparationss of ephedrine are made slow release and release pills respectively, loads in mixture into capsule and makes compound capsule.Though realized the unification of two medicines, can impel each component to bring into play the synergism of drug effect in vivo.But, piller coated preparation production technology more complicated, coating material is had relatively high expectations to storage condition, all is easy to take place rotten under high temperature and cryogenic condition, pellets preparation behind the coating is in depositing process, and its rate of releasing drug is difficult to the stable perfect condition that is controlled at.
Summary of the invention
The present invention proposes a kind of compound preparation, be mainly used in the treatment hypercholesterolemia, release by effective control medicine, make blood drug level more steady, reduce ordinary preparation wave phenomenon and toxic and side effects, to take number of times few, preparation technology is simple, is fit to Lovastatin nicotinic acid slow-release preparation of suitability for industrialized production and preparation method thereof.
The present invention seeks to realize by following technical scheme:
A kind of Lovastatin nicotinic acid slow-release preparation is characterized in that by weight ratio every tablet preparation contains nicotinic acid 500mg, lovastatin 20mg; Adopt the matrix tablet technology of preparing, nicotinic acid is made slow-released part, lovastatin is made immediate release section, again two parts are pressed into compound slow-release tablet, concrete preparation method is as follows:
(1) by following weight proportion, nicotinic acid 500mg, HPMC K100M framework material 120～140mg, PVPK90 binding agent 50mg, magnesium stearate 6.5mg makes niacin sustained release layer granule;
(2) by following weight proportion, lovastatin 20mg, carboxymethyl starch sodium 5mg, microcrystalline Cellulose 25mg, starch 15mg, lactose 15mg, PVPK30 binding agent 5mg, magnesium stearate 1mg make lovastatin release layer granule;
(3) niacin sustained release layer granule and lovastatin release layer granule are adopted double-deck pressed-disc technique, be pressed into Lovastatin nicotinic acid slow-release tablets through twice.
Lovastatin has remarkable result to reducing LDL (low-density lipoprotein, low density lipoprotein, LDL), but to a little less than increase HDL (high-density lipoprotein, the high density lipoprotein) 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.Relevant studies show that, the effect of uniting use nicotinic acid and lovastatin is addition, it is more more obvious than only taking single preparations of ephedrine to alleviate the hypercholesterolemia curative effect.
Nicotinic acid is used for the treatment of hyperlipidemia needed take in one three times, each 1-2g, 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 lovastatin effect is strong, the curative effect height, side effect is slight, be used for the treatment of hypercholesterolemia at present clinically, fall the blood ester, improve blood flow, antithrombotic etc., common dose is 20mg, and the FDA maximum permissible dose is 80mg, effectively reaches therapeutic purposes rapidly for making it, need rapid release, thereby make rapid release.
Two kinds of drug developments of lovastatin and nicotinic acid are become compound tablet, and wherein nicotinic acid adopts the matrix tablet technology of preparing, makes slow-releasing granules, and lovastatin is an immediate-release granules.And utilize pharmaceutical equipment, and adopt double-deck pressed-disc technique, twice compacting of different granules is in blocks, make compound slow-release tablet.Both are shared, and synergism is arranged.Can control the release of medicine effectively, make blood drug level more steady, reduce the wave phenomenon of ordinary preparation, both can reduce ordinary tablet toxic and side effects, overcome the deficiency of taking often, can avoid occurring the situation that misses, forgets to obey again.
Quality index: nicotinic acid content should be labelled amount 95.0～105.0%, and lovastatin should be 90.0～110.0% of labelled amount.Release reaches 3 release control criterions: release was 20～40% in 2 hours; Release was 40～70% in 5 hours; Release was more than 75% in 10 hours.
The niacin sustained release layer granule that Lovastatin nicotinic acid slow-release tablets is every is 677～697mg, and the release layer granule is 86mg.
A kind of preparation method of Lovastatin nicotinic acid slow-release preparation is characterized in that its preparation method is as follows:
(1) preparation of niacin sustained release part:
Every by following weight proportion, nicotinic acid 500mg, HPMC K100M framework material 120～140mg, PVPK90 binding agent 50mg, magnesium stearate 6.5mg, with the nicotinic acid raw material cross behind 100 mesh sieves with the abundant mix homogeneously of framework material HPMCK100M after, add the PVPK90 binding agent soft material that is made by handwork, through 20 mesh sieve system wet granulars, place baking oven to carry out 60 ℃ of dryings 2 hours,, add magnesium stearate after weighing through 20 mesh sieve granulate, mixing is made niacin sustained release layer granule;
(2) preparation of lovastatin immediate release section:
Every by following weight proportion, lovastatin 20mg, carboxymethyl starch sodium 5mg, microcrystalline Cellulose 25mg, starch 15mg, lactose 15mg, PVPK30 binding agent 5mg, magnesium stearate 1mg, after lovastatin crossed 100 mesh sieves, fully mix, add the manual system of PVPK30 alcoholic solution soft material with carboxymethyl starch sodium, microcrystalline Cellulose, starch, lactose, cross 22 mesh sieve granulate, placed 60 ℃ of baking ovens dry 1 hour, dried granule adds magnesium stearate 1mg with 22 mesh sieve granulate, mix homogeneously is made lovastatin release layer granule;
(3) preparation of double-deck tabletting:
According to niacin sustained release layer granule 677～697mg of every, the weight proportion of release layer granule 86mg adopts double-deck pressed-disc technique with niacin sustained release layer granule and lovastatin release layer granule, is pressed into Lovastatin nicotinic acid slow-release tablets through twice.
Lovastatin nicotinic acid slow-release tablets is the niacin sustained release layer granule of elder generation with 677～697mg, and after precompressed on the bi-layer tablet press, the lovastatin release layer granule of inserting 86mg again is in blocks through twice compacting of tablet machine.
The preparation technology of above-mentioned preparation method is simpler, is fit to suitability for industrialized production.
The weight proportion of preferred framework material, binding agent and magnesium stearate is: HPMC K100M framework material 120mg, PVPK90 binding agent 50mg, magnesium stearate 6.5mg.
Advantage of the present invention is: nicotinic acid 500mg/ sheet is adopted the matrix tablet technology of preparing, add lovastatin 20mg/ sheet and make compound slow-release tablet, the former is a slow-released part, and the latter is an immediate release section, and both are shared, and synergism is arranged.This compound preparation is mainly used in the treatment hypercholesterolemia, treats after 1 year, can increase HDL41%, reduces LDL45%, reduces triglyceride 42%.The development of this slow releasing tablet can be controlled the release of medicine effectively, rate of releasing drug reaches the rate of releasing drug of drafting, make blood drug level more steady, reduced the wave phenomenon of ordinary preparation, both can reduce ordinary tablet toxic and side effects, overcome the deficiency of taking often, can avoid occurring the situation that misses, forget to obey again, the patient is easy to use.And preparation technology is simpler, is fit to suitability for industrialized production.
The specific embodiment
Embodiment 1
After the nicotinic acid raw material is crossed 100 mesh sieves, by every weight ratio that contains nicotinic acid 500mg, behind the abundant mix homogeneously of HPMC K100M framework material 120mg, add PVPK90 binding agent 50mg, soft material is made by handwork, through 20 mesh sieve system wet granulars, place baking oven to carry out 60 ℃ of dryings 2 hours,, add magnesium stearate 6.5mg after weighing through 20 mesh sieve granulate, mixing is made niacin sustained release layer granule;
Get lovastatin, cross 100 mesh sieves, by every weight ratio that contains lovastatin 20mg, fully mix with carboxymethyl starch sodium 5mg, microcrystalline Cellulose 25mg, starch 15mg, lactose 15mg, add the manual system of PVPK30 alcoholic solution soft material, cross 22 mesh sieve granulate, placed 60 ℃ of baking ovens dry 1 hour, dried granule adds magnesium stearate 1mg, mix homogeneously with 22 mesh sieve granulate.Make lovastatin release layer granule.
With the niacin sustained release layer granule of 677mg, after precompressed on the special-shaped tablet machine, the lovastatin release layer granule of inserting 86mg again adopts double-deck pressed-disc technique through tablet machine, is pressed into Lovastatin nicotinic acid slow-release tablets through twice earlier.
Embodiment 2
After the nicotinic acid raw material is crossed 100 mesh sieves, by every weight ratio that contains nicotinic acid 500mg, behind the abundant mix homogeneously of HPMC K100M framework material 130mg, add PVPK90 binding agent 50mg, soft material is made by handwork, through 20 mesh sieve system wet granulars, place baking oven to carry out 60 ℃ of dryings 2 hours,, add magnesium stearate 6.5mg after weighing through 20 mesh sieve granulate, mixing is made niacin sustained release layer granule;
Get lovastatin, cross 100 mesh sieves, by every weight ratio that contains lovastatin 20mg, fully mix with carboxymethyl starch sodium 5mg, microcrystalline Cellulose 25mg, starch 15mg, lactose 15mg, add the manual system of PVPK30 alcoholic solution soft material, cross 22 mesh sieve granulate, placed 60 ℃ of baking ovens dry 1 hour, dried granule adds magnesium stearate 1mg, mix homogeneously with 22 mesh sieve granulate.Make lovastatin release layer granule.With the niacin sustained release layer granule of 687mg, after precompressed on the special-shaped tablet machine, the lovastatin release layer granule of inserting 86mg mg again adopts double-deck pressed-disc technique through tablet machine, is pressed into Lovastatin nicotinic acid slow-release tablets through twice earlier.
Embodiment 3
After the nicotinic acid raw material is crossed 100 mesh sieves, by every weight ratio that contains nicotinic acid 500mg, behind the abundant mix homogeneously of HPMC K100M framework material 140mg, add PVPK90 alcoholic solution 50mg, soft material is made by handwork, through 20 mesh sieve system wet granulars, place baking oven to carry out 45 ℃ of dryings 2 hours,, add magnesium stearate 6.5mg after weighing through 20 mesh sieve granulate, mixing is made niacin sustained release layer granule;
Get lovastatin, cross 100 mesh sieves, by every weight ratio that contains lovastatin 20mg, fully mix with carboxymethyl starch sodium 5mg, microcrystalline Cellulose 25mg, starch 15mg, lactose 15mg, add the manual system of PVPK30 alcoholic solution soft material, cross 22 mesh sieve granulate, placed 60 ℃ of baking ovens dry 1 hour, dried granule adds magnesium stearate 1mg with 22 mesh sieve granulate, mix homogeneously is made lovastatin release layer granule.With the niacin sustained release layer granule of 697mg, after precompressed on the special-shaped tablet machine, insert the lovastatin release layer granule of 86mg more earlier, adopt double-deck pressed-disc technique, be pressed into Lovastatin nicotinic acid slow-release tablets through twice.
The analysis of niacin sustained release layer:
The niacin sustained release layer is to be framework material with HPMC K100M, is binding agent with PVP K90 alcoholic solution, reaches the rate of releasing drug of drafting to regulate its rate of releasing drug.(draft release and see attached list 1)
The investigation result of subordinate list 1 1～3 embodiment
As seen from the above table, the average release of embodiment 3 is a preferred plan of the present invention.
The discussion of factor:
1. firmness change is to the influence of niacin sustained release layer release:
At stator heavily down, adopt different pressure to carry out tabletting, make slice, thin piece hardness between 90N ~ 140N, investigate the influence of tabletting pressure to release, the release assay sees attached list 2
Subordinate list 2 release assays
As above shown in the table, several indifferences of the rate of release of the niacin slow-release tablet that hardness is different, influence the formation speed that HPMC matrix tablet release principal element is a gel layer, result of the test shows, within the specific limits, the change of matrix tablet density is to the formation of HPMC gel layer, that is aquation, swelling rate and medicine extend influence not quite, tablet hardness variation does not within the specific limits influence external rate of releasing drug.
2. binder concn changes the influence to niacin sustained release layer release:
According to the preparation method of embodiment 3, the concentration that changes binding agent under the prerequisite of ceteris paribus is granulated, to investigate its influence to niacin sustained release layer release.
Subordinate list 3 concentration change are to the influence of niacin sustained release layer release
As above shown in the table, along with the also increase accordingly of its consumption of increase of binder concn, release reduces thereupon to some extent, but changes little.
3. the consumption of HPMC K100M changes the influence to niacin sustained release layer release:
According to the preparation method of embodiment 3, adopting 15%PVP K90 to granulate and fix its consumption is the 50mg/ sheet, changes the consumption of HPMC K100M under the prerequisite of ceteris paribus, to investigate its influence to niacin sustained release layer release.
HPMC K100M is the most important factor that influences the niacin slow-release tablet release, have only its consumption to reach certain ratio in one embodiment after, could form the needed framing structure of slow release.
Conclusion
From above experimental result, embodiment 3 is optimum prescription.
Claims (5)
1. a Lovastatin nicotinic acid slow-release preparation is characterized in that by weight ratio, and every tablet preparation contains nicotinic acid 500mg, lovastatin 20mg; Adopt the matrix tablet technology of preparing, nicotinic acid is made slow-released part, lovastatin is made immediate release section, the compound slow-release tablet that two parts are pressed into again, and concrete preparation method is as follows:
(1) by following weight proportion, nicotinic acid 500mg, HPMC K100M framework material 120～140mg, PVPK90 binding agent 50mg, magnesium stearate 6.5mg makes niacin sustained release layer granule;
(2) by following weight proportion, lovastatin 20mg, carboxymethyl starch sodium 5mg, microcrystalline Cellulose 25mg, starch 15mg, lactose 15mg, PVPK30 binding agent 5mg, magnesium stearate 1mg make lovastatin release layer granule;
(3) niacin sustained release layer granule and lovastatin release layer granule are adopted double-deck pressed-disc technique, be pressed into Lovastatin nicotinic acid slow-release tablets through twice.
2. a kind of Lovastatin nicotinic acid slow-release preparation according to claim 1 is characterized in that the niacin sustained release layer granule of every of Lovastatin nicotinic acid slow-release tablets is 677～697mg, and the release layer granule is 86mg.
3. the preparation method of a Lovastatin nicotinic acid slow-release preparation is characterized in that its preparation method is as follows:
(1) preparation of niacin sustained release part:
Every by following weight proportion, nicotinic acid 500mg, HPMC K100M framework material 120～140mg, PVPK90 binding agent 50mg, magnesium stearate 6.5mg, with the nicotinic acid raw material cross behind 100 mesh sieves with the abundant mix homogeneously of framework material HPMCK100M after, add the PVPK90 binding agent soft material that is made by handwork, through 20 mesh sieve system wet granulars, place baking oven to carry out 60 ℃ of dryings 2 hours,, add magnesium stearate after weighing through 20 mesh sieve granulate, mixing is made niacin sustained release layer granule;
(2) preparation of lovastatin immediate release section:
Every by following weight proportion, lovastatin 20mg, carboxymethyl starch sodium 5mg, microcrystalline Cellulose 25mg, starch 15mg, lactose 15mg, PVPK30 binding agent 5mg, magnesium stearate 1mg, after lovastatin crossed 100 mesh sieves, fully mix, add the manual system of PVPK30 alcoholic solution soft material with carboxymethyl starch sodium, microcrystalline Cellulose, starch, lactose, cross 22 mesh sieve granulate, placed 60 ℃ of baking ovens dry 1 hour, dried granule adds magnesium stearate 1mg with 22 mesh sieve granulate, mix homogeneously is made lovastatin release layer granule;
(3) preparation of double-deck tabletting:
Niacin sustained release layer granule according to every is 677～697mg, and the release layer granule is the weight proportion of 86mg, and niacin sustained release layer granule and lovastatin release layer granule are adopted double-deck pressed-disc technique, is pressed into Lovastatin nicotinic acid slow-release tablets through twice.
4. the preparation method of a kind of Lovastatin nicotinic acid slow-release preparation according to claim 3, it is characterized in that Lovastatin nicotinic acid slow-release tablets is the niacin sustained release layer granule of elder generation with 677～697mg, after precompressed on the special-shaped tablet machine, the lovastatin release layer granule of inserting 86mg again is in blocks through twice compacting of tablet machine.
5. the preparation method of a kind of Lovastatin nicotinic acid slow-release preparation according to claim 3, the weight proportion that it is characterized in that framework material, binding agent and magnesium stearate is: HPMC K100M framework material 120mg, PVPK90 binding agent 50mg, magnesium stearate 6.5mg.
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| CN101991853A (en) * | 2009-08-19 | 2011-03-30 | 北京利乐生制药科技有限公司 | Statin magnesium-containing blood lipid lowering composition |
| CN102362862B (en) * | 2011-11-25 | 2013-04-24 | 陕西师范大学 | Double-layer sustained-release tablet for reducing blood fat coordinately |
| CN102921009A (en) * | 2012-11-23 | 2013-02-13 | 江苏长泰药业有限公司 | Novel niacin compound sustained release preparation for treating hyperlipidemia |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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