CN1486695A - Delayed releasing Acipimox prepn - Google Patents
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- CN1486695A CN1486695A CNA031303625A CN03130362A CN1486695A CN 1486695 A CN1486695 A CN 1486695A CN A031303625 A CNA031303625 A CN A031303625A CN 03130362 A CN03130362 A CN 03130362A CN 1486695 A CN1486695 A CN 1486695A
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Abstract
The delayed releasing Acipimox preparation consists of Acipimox 100(in weight portions, the same below), delayed releasing agent 50.5-150, adhesive 0.5-29.5, pharmaceutically applicable supplementary material 0-150 and lubricant 0-1.5. Taking the delayed releasing Acipimox preparation ince every 24 hr can maintain stable blood medicine density, and the preparation is suitable for light and IV-type hyperlipemia patient. The delayed releasing Acipimox preparation accords with Higuchi model and has very high delayed releasing level.
Description
Technical field
The present invention relates to a kind of slow releasing preparation medicine, the slow-releasing acipimox preparation of the blood lipid regulation pharmaceutical preparation that particularly a kind of energy is efficient, long-acting, safe.
Background technology
Atherosclerosis and coronary heart disease are frequently-occurring disease, are the main causes of myocardial infarction and cerebral infarction.The death that national coronary artery diseases such as present America and Europe cause accounts for the over half of dead sum.The U.S. has nearly million people to die from coronary atherosclerotic heart disease (CHD) every year, and is though the M ﹠ M of China CHD is lower than the America and Europe, on the rise in recent years.The generation and the atherosclerosis of hyperlipemia have substantial connection, and the blood fat of known atherosclerosis and patients with coronary heart disease (cholesterol and triglyceride) content is high than the normal person.Therefore, adjust blood lipid metabolism and can prevent curing hyperlipemia, atherosclerosis and coronary heart disease.Hyperlipidemia generally is divided into five types: I, II, III, IV, V, and acipimox is used for the treatment of II, III, IV, V-type hyperlipemia clinically.
Acipimox is the derivant of nicotinic acid, is a kind of New-type long-acting hypolipidemic, has good accent fat effect, and untoward reaction is few, can effectively reduce the danger of coronary heart disease.Acipimox is the most promising lipid lowering agent in the nicotinic acid class preparation so far, compares with nicotinic acid to have the following advantages:
1, lipotropism is separated the strong this product lipotropism of effect and is separated 20 times that act as nicotinic acid, and the effect that reduces plasma F FA and TG is respectively 3.3 times and 6.5 times of nicotinic acid, and the FFA rebound phenomenon significantly is lower than the latter.
2, the wide acipimox of the scope of application is used for the treatment of II, III, IV, V-type hyperlipemia clinically.This product can significantly be improved patient's glucose dosis tolerata, and does not have interaction with oral antidiabetic drug.This product does not influence blood uric acid metabolism in addition, the clinical hyperuricemia that can be used for.
3, consumption is little, and the taking convenience patient takes this product 500～750mg at every turn, can obtain satisfied effect for reducing blood fat every day for 1 time.The consumption per day of nicotinic acid is 3g, is equivalent to 4～6 times of acipimox.
4, the little acipimox untoward reaction of side effect is similar to nicotinic acid basically, but light many of degree, and general toleration is good, and need to stop medication person less because of untoward reaction, more is applicable to long-term prescription.
The Acipimox in materials medicine is developed by Italian Farmitalia Carlo Erba company, and the patent No. is US4002750 (1977).The acipimox capsule is developed by Italian Farmitalia Carlo Erba company, in 1985 in Italy's listing, specification is the 250mg/ grain, consumption is a 250mg, 2～3 times on the one.CN1395928A discloses a kind of slow-releasing acipimox tablet in addition, acipimox wherein, slow releasing agent and binder wt ratio are 100: 1.5～50: 30～60 (taking 1 time in per 12 hours), the specification of this slow-releasing acipimox tablet is 375mg/ sheet (750mg every day), be only applicable to take (750mg every day) of II, III, V-type hyperlipidemia patient, this be because, each dose slight and IV type hyperlipidemia patient is 250mg (500mg every day), so above-mentioned slow releasing tablet can't adapt to the requirement of taking medicine of slight and IV type hyperlipidemia patient.The hyperlipidemia patient great majority are middle-aged and elderly people, and it is extremely inconvenient repeatedly to take medicine every day.
Summary of the invention
In order to solve the problem that exists in the above-mentioned technology, it is adjustable flexibly to the purpose of this invention is to provide a kind of dosage, and the blood drug level of remaining valid in 24 hours reduces and takes number of times, reduces toxic and side effects; The slow-releasing acipimox preparation of treatment II, the III that in 16 hours, steadily discharges, IV, V-type hyperlipemia.
For achieving the above object, technical solution of the present invention provides a kind of slow-releasing acipimox preparation, and said preparation contains following composition by weight percentage:
100 parts of acipimoxs
50.5～150 parts of slow releasing agents
0.5～29.5 part of binding agent
0～150 part of the adjuvant that pharmacy is suitable for
0～1.5 part of lubricant
Described slow releasing agent is selected from one or more mixture in the solubility/insoluble salt of hydroxypropyl methylcellulose, methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, polyvinylpyrrolidone, cellulose acetate, polycarboxy ethene, sodium carboxymethyl cellulose, polyvinyl alcohol, Rikemal B 200, alginic acid.Hypromellose employing in the described slow releasing agent includes the extensive stock of hydroxypropyl methylcellulose (HPMC) such as U.S. many elegant (Methocel) of all size, and ethyl cellulose adopts the extensive stock that includes ethyl cellulose (EC).
Described binding agent can adopt a kind of in polyvinylpyrrolidone, hypromellose, 50～95% alcoholic solution.
Described lubricant can adopt a kind of in stearic acid, magnesium stearate, Pulvis Talci, starch, the paraffin.
The adjuvant that described pharmacy is suitable for: one or more mixture in porogen, wetting agent, solubilizing agent, emulsifying agent, membrane material, foaming agent, bleach activator, the solvent.Described porogen can adopt sucrose, mannitol, starch, Pulvis Talci, silicon dioxide; Described wetting agent can adopt the ethanol-water solution of water, dehydrated alcohol, various concentration; Described solubilizing agent can be adopted tartaric acid, citric acid etc.; Emulsifying agent can adopt span80, span85 etc.; Membrane material can adopt polyvinyl alcohol, hydroxyl methylcellulose, hyetellose, hymetellose, methylcellulose; Foaming agent can adopt basic magnesium carbonate, sodium bicarbonate; Bleach activator can adopt hexadecanol, octadecanol, Cera Flava etc.; Solvent can adopt dehydrated alcohol, ethanol, water.
This preparation comprises the various preparations of film control, skeleton, gel, porous matrix type, also comprises making the various preparations that micropill or granule or microcapsule or microsphere etc. are made again earlier.Preparation formulation of the present invention is sheet type, coating type.
Effect of the present invention is that this product only needs take every day (24 hours) 1 time, and the disclosed slow-releasing acipimox tablet of CN1395928A every day (24 hours) need be taken 2 times, compare this product slow release effect with it and obviously strengthen, take number of times and reduce, make taking medicine of patient more convenient.The pharmacokinetic of this product shows that blood drug level is more steady in the body, the blood drug level of can remaining valid for a long time.The hyperlipidemia patient great majority are middle-aged and elderly people, and it is extremely inconvenient repeatedly to take medicine every day, if the slow releasing preparation of only taking a kind of every day once is provided, can improve compliance of patients to a great extent.The present invention's design has also prepared this slow-releasing acipimox tablet of only taking once in a day.In order to keep stable blood concentration in the body, the present invention has strengthened the consumption of slow-release material, has exceeded slow-release material amount ranges of the prior art, makes it reach the purpose that steadily discharged in 16 hours.Slow-releasing acipimox tablet discharges and to meet Higuchi model (a kind of release profiles fit equation of slow releasing preparation), has reached very high slow release level, makes this medicine be able to be administered once in one day.
Description of drawings
Fig. 1 is the releasing curve diagram of embodiments of the invention 1 preparation slow-releasing acipimox tablet;
Fig. 2 is the releasing curve diagram of the slow-releasing acipimox tablet of embodiments of the invention 2 preparations;
The drug-time curve figure of Fig. 3 blood drug level.
The specific embodiment
Below in conjunction with drawings and Examples slow-releasing acipimox preparation of the present invention is illustrated.
Embodiment 1:
The slow-releasing acipimox tablet agent of the present invention of adopting the known method of pharmaceuticals industry to make contains following composition (every contains acipimox 250mg) by weight percentage:
100 parts of acipimoxs
60 parts of hydroxypropyl emthylcelluloses (K15M)
1.5 parts of magnesium stearate
1 part of 90% ethanol
HPMCK15M is a hydrophilic polymer, is framework material in said preparation, meets the expansion of water or Digestive system and forms the gel barrier, and the diffusion of control acipimox reaches the slow release purpose.Wherein HPMCK15M can be replaced by the HPMCK100LV of different amounts or HPMCK4M or HPMCK100M, or is used in combination, to adjust release curve, the releasing curve diagram of the slow-releasing acipimox tablet of preparation as shown in Figure 1.
Embodiment 2:
The slow-releasing acipimox tablet agent of the present invention of adopting the known method of pharmaceuticals industry to make contains following composition (every contains acipimox 250mg) by weight percentage:
100 parts of acipimoxs
60 parts of carbopol
1.5 parts of magnesium stearate
1 part of 90% ethanol
Hydrophilic polymer carbopol (carbomer) is a framework material, meets the expansion of water or Digestive system and forms the gel barrier, and the diffusion of control acipimox reaches the slow release purpose.The releasing curve diagram of the slow-releasing acipimox tablet of preparation as shown in Figure 2.
Embodiment 3:
The slow-releasing acipimox tablet agent of the present invention of adopting the known method of pharmaceuticals industry to make contains following composition (every contains acipimox 250mg) by weight percentage:
100 parts of acipimoxs
30 parts of sodium alginates
30 parts of calcium alginates
10 parts of lactose
1.5 parts of magnesium stearate
1 part of 90% ethanol
The insoluble salt of hydrophilic polymer alginic acid and soluble-salt are framework material, meet the gel barrier that the expansion of water or Digestive system forms commissure, and the diffusion of control acipimox reaches the slow release purpose.
Embodiment 4:
The slow-releasing acipimox tablet agent of the present invention of adopting the known method of pharmaceuticals industry to make contains following composition (every contains acipimox 250mg) by weight percentage:
100 parts of acipimoxs
52 parts of ethyl cellulose and stearic acid
1.5 parts of magnesium stearate
1 part of 90% ethanol
Bioerodable material stearic acid in vivo gradually corrosion make principal agent discharge slow releasing function gradually, ethyl cellulose is a not corrosion framework material, treats that drug release excretes after intact.
Embodiment 5:
Adopt the slow-releasing acipimox gastric floating tablet of the present invention of the known method preparation of pharmaceuticals industry to contain following composition (every contains acipimox 250mg) by weight percentage:
100 parts of acipimoxs
20 parts of HPMCK100LV
60 parts of HPMCK4M
7 parts of stearic acid
11 parts of basic magnesium carbonates
5 parts of PVPK30
6 parts of lactose
1.5 parts of magnesium stearate
1 part of 90% ethanol
HPMCK100LV is a hydrophilic polymer, meets gastric juice and expands and form the gel barrier, and the density of keeping skeleton is less than gastric content density, and floats on the gastric juice; Stearic acid is a bleach activator, and can reduce the hydration rate of skeleton; Basic magnesium carbonate is a foaming agent, meets gastric acid and produces CO2, can further alleviate the density of preparation, thereby prolong the acipimox sheet holdup time under one's belt, reaches the slow release purpose.
Embodiment 6:
Slow-releasing acipimox tablet agent of the present invention contains following composition (every contains acipimox 250mg) by weight percentage:
100 parts of acipimoxs
100 parts of ethyl celluloses
1.5 parts of magnesium stearate
Acipimox and ethyl cellulose are dissolved in the ethanol solution jointly, after fully grinding, the ethanol decompression are volatilized, the grinding dispersion body, add the magnesium stearate tabletting, wherein acipimox is scattered in the ethyl cellulose, and ethyl cellulose plays slow releasing function in solid dispersion.
According to bibliographical information, the minimum effective blood drug concentration of acipimox is 0.2 μ g/ml, and taking this product maximum safe dose every day for a long time is 1200mg.Research situation in the body of not mentioned slow releasing tablet in CN1395928A, consider the complexity of performance in slow releasing preparation release in vitro and the body, also in order to further specify slow release effect of the present invention, now blood drug level data in the body of the domesticated dog single oral dose of the embodiment of the invention 1 are seen attached list 1,2, pharmacokinetic parameters 3 (are the reference control formulation with commercially available conventional capsule agent) of seeing attached list, the drug-time curve of blood drug level is seen accompanying drawing 3.By subordinate list as can be known: this preparation can be kept effective blood drug concentration and reach 24 hours.Subordinate list 1,2,3 is as follows:
The commercially available conventional capsule agent of table 1 domesticated dog single oral dose blood drug level data
Blood drug level (μ g/ml)
Time
(h)
Canis familiaris L. A Canis familiaris L. B Canis familiaris L. C Canis familiaris L. D Canis familiaris L. E Canis familiaris L. F Mean ± SD
0 0 0 0 0 0 0 0
0.5 3.847 5.811 0.304 1.328 4.178 4.889 3.393±2.131
1 29.551 45.028 1.052 13.055 10.813 17.543 19.507±15.581
1.5 51.106 46.978 17.267 18.356 20.305 35.653 31.611±15.112
2 56.227 37.616 34.354 29.973 22.386 40.987 36.924±11.453
3 42.591 16.227 46.515 25.556 23.557 34.245 31.448±11.727
4 20.259 7.306 44.481 13.229 33.097 20.846 23.203±13.543
5 8.301 4.646 23.489 7.532 34.505 11.586 15.010±11.593
6 5.134 1.785 12.183 3.347 19.784 8.452 8.448±6.691
7 3.245 1.134 6.887 1.797 10.919 3.884 4.644±3.671
8 1.798 0.624 2.840 1.056 6.051 1.802 2.362±1.959
10 0.805 0.304 1.056 0.556 1.891 0.764 0.896±0.549
12 0.475 ND 0.599 0.522 1.436 0.469 0.583±0.468
16 ND ND ND ND 0.912 ND ND
24 ND ND ND ND 0.488 ND ND
ND: blood drug level is low excessively, is lower than detectability
Table 2 domesticated dog single oral dose self-control slow releasing tablet blood drug level data
Blood drug level (μ g/ml)
Time (h)
Canis familiaris L. A Canis familiaris L. B Canis familiaris L. C Canis familiaris L. D Canis familiaris L. E Canis familiaris L. F Mean ± SD
0 0 0 0 0 0 0 0
0.5 0.791 0.791 0.937 ND 0.385 0.587 0.582±0.344
1 5.957 2.061 3.743 0.424 0.444 2.521 2.525±2.108
1.5 9.891 7.706 7.360 1.922 0.789 5.603 5.350±3.472
2 14.810 11.585 18.690 9.705 2.784 9.341 11.152±5.400
3 21.038 24.220 34.077 20.296 9.798 18.073 21.250±7.944
4 22.573 30.827 34.353 22.688 16.355 26.573 25.472±6.365
5 21.923 23.602 32.559 22.036 20.155 19.935 23.368±4.701
6 18.196 12.722 25.404 17.538 35.438 13.360 20.443±8.634
7 13.776 8.327 14.252 13.071 31.377 10.257 15.177±8.256
8 17.780 5.395 7.129 6.990 21.960 7.198 11.075±6.971
10 12.140 3.126 1.959 1.886 6.701 4.759 5.095±3.907
12 7.167 1.839 0.996 0.716 1.696 2.087 2.417±2.385
16 0.987 0.999 0.549 0.304 0.448 1.031 0.720±0.323
24 0.796 0.458 0.475 ND 0.465 0.475 0.445±0.254
36 0.684 ND ND ND ND ND ND
ND: blood drug level is low excessively, is lower than detectability
Table 3 domesticated dog single oral dose self-control slow releasing tablet and commercially available conventional capsule agent medicine kinetic parameter
The agent of pharmacokinetic parameters slow releasing tablet conventional capsule
AUC(μg·h·ml
-1) 159.92 147.51
Tmax(h) 4.33 2.58
Cmax(μg/ml) 29.32 42.53
t
1/2(h) 2.25 1.63
MRT(h) 6.05 3.89
Fr％ 111.04
AUC: lower area of blood concentration-time curve; Tmax: peak reaching time of blood concentration; Cmax: maximum plasma concentration; t
1/2: plasma half-life;
MRT: mean residence time in the body; Fr%: relative bioavailability
The two one side test result of single dose experiment shows: slow releasing tablet and conventional capsule agent bioequivalence; Slow releasing tablet is compared mean residence time (MRT) prolongation in maximum plasma concentration (Cmax) reduction, peak reaching time of blood concentration (Tmax) prolongation, the body with the conventional capsule agent, relative bioavailability (reflection slow releasing tablet and ordinary tablet Chinese medicine are absorbed by body and enter the ratio of sanguimotor amount) is 111.04%, show that slow releasing tablet of the present invention has the good slow release effect, blood drug level is steady, bioavailability is reasonable, meets the intended purposes of slow releasing preparation design.Adopt the deconvolution point-score to carry out date processing, its result shows: slow-releasing acipimox tablet has good inside and outside dependency, meet A level relevant (being that external stripping is point-to-point relevant with the interior bioavailability of body), can control drug quality by external stripping, to guarantee medicine performance in vivo.Experimental results show that by increasing the consumption of slow releasing agent, prolong the release time of acipimox, strengthened slow release effect, thereby can reduce administration number of times, improve patient's compliance, keep stable blood concentration, reduce side effect.
Claims (5)
1, a kind of slow-releasing acipimox preparation, said preparation contains following composition by weight percentage:
100 parts of acipimoxs
50.5～150 parts of slow releasing agents
0.5～29.5 part of binding agent
0～150 part of the adjuvant that pharmacy is suitable for
0～1.5 part of lubricant
2, slow-releasing acipimox preparation according to claim 1 is characterized in that: described slow releasing agent is selected from one or more mixture in the solubility/insoluble salt of hydroxypropyl methylcellulose, methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, polyvinylpyrrolidone, cellulose acetate, polycarboxy ethene, sodium carboxymethyl cellulose, polyvinyl alcohol, Rikemal B 200, alginic acid.
3, slow-releasing acipimox preparation according to claim 1 is characterized in that: described binding agent can adopt a kind of in polyvinylpyrrolidone, hypromellose, 50～95% alcoholic solution.
4, slow-releasing acipimox preparation according to claim 1 is characterized in that: described lubricant can adopt a kind of in stearic acid, magnesium stearate, Pulvis Talci, starch, the paraffin.
5, slow-releasing acipimox preparation according to claim 1 is characterized in that: the adjuvant that described pharmacy is suitable for: porogen, wetting agent, solubilizing agent, emulsifying agent, membrane material, foaming agent, bleach activator, solvent, and their one or more mixture.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031303625A CN1486695A (en) | 2003-07-04 | 2003-07-04 | Delayed releasing Acipimox prepn |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031303625A CN1486695A (en) | 2003-07-04 | 2003-07-04 | Delayed releasing Acipimox prepn |
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| CN1486695A true CN1486695A (en) | 2004-04-07 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA031303625A Pending CN1486695A (en) | 2003-07-04 | 2003-07-04 | Delayed releasing Acipimox prepn |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1741431A1 (en) * | 2004-04-30 | 2007-01-10 | Lunan Pharmaceutical Group Corporation | The combination for treating hyperlipemia |
| CN103893152A (en) * | 2014-03-28 | 2014-07-02 | 北京联合大学 | Method for preparing acipimox-ethylcellulose sustained release micro-capsule |
| CN104586810A (en) * | 2015-01-22 | 2015-05-06 | 山东新时代药业有限公司 | Acipimox sustained-release tablet and preparation method thereof |
-
2003
- 2003-07-04 CN CNA031303625A patent/CN1486695A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1741431A1 (en) * | 2004-04-30 | 2007-01-10 | Lunan Pharmaceutical Group Corporation | The combination for treating hyperlipemia |
| EP1741431B1 (en) * | 2004-04-30 | 2012-08-15 | Lunan Pharmaceutical Group Corporation | The combination for treating hyperlipemia |
| CN103893152A (en) * | 2014-03-28 | 2014-07-02 | 北京联合大学 | Method for preparing acipimox-ethylcellulose sustained release micro-capsule |
| CN104586810A (en) * | 2015-01-22 | 2015-05-06 | 山东新时代药业有限公司 | Acipimox sustained-release tablet and preparation method thereof |
| CN104586810B (en) * | 2015-01-22 | 2017-06-30 | 山东新时代药业有限公司 | A kind of slow-releasing acipimox tablet and preparation method thereof |
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