CN1660431A - Combination of medication containing reductase inhibitor HMG CoA and Melatonin - Google Patents
Combination of medication containing reductase inhibitor HMG CoA and Melatonin Download PDFInfo
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- CN1660431A CN1660431A CN 200410075802 CN200410075802A CN1660431A CN 1660431 A CN1660431 A CN 1660431A CN 200410075802 CN200410075802 CN 200410075802 CN 200410075802 A CN200410075802 A CN 200410075802A CN 1660431 A CN1660431 A CN 1660431A
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- melatonin
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Abstract
A composite medicine in the form of tablet, capsule, softgel, or dispersing tablet for preventing the atherosclerosis by cutting off the oxidization modification to low-density lipoprotein (LDL) and decreasing the LDL contains HMG-CoA reductase inhibitor (tatin-type medicine and melatonin.
Description
Technical field
The invention belongs to medical technology, it relates to a kind of more efficiently pharmaceutical composition that improves blood fat.
Background technology
Along with the continuous development of medical science, people recognize cholesterol, fatty equal size is too high is the basic cause of disease that cardiovascular disease takes place, and hyperlipidemia is that coronary heart disease and hypertensive main hazard factor take place.Therefore, people begin the exploitation of blood lipid regulation medicine as the emphasis of preventing and treating cardiovascular disease.From late 1980s, blood lipid-lowering medicine is released in a large number, and wherein statins is subjected to people's favorable comment, and its clinical efficacy good is that other all kinds of blood lipid regulation medicines institute is incomparable.During the last ten years, finishing of the extensive coronary heart disease control test in several worlds, confirm that statins can reduce evidence of coronary heart diseases and mortality rate, and the atheromatous plaque development that has formed is slowed down, even go down, thereby broken the irreversible traditional view of coronary heart disease, risen in the whole world by the blood fat revolution that cause in " his spit of fland ".At present, the world of medicine is filled with unbounded confidence in the effect that prevents and treats aspect the cardiovascular disease to fat regulation medicine, transfers the fat therapy to become the main method of angiocardiopathy preventing.3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor is clinical prevention atherosclerosis drug of first choice as the novel blood lipid-lowering medicine of a class.Be used for clinically having 6 kinds at present: lovastatin (lovastatin); Simvastatin (simvastatin); Pravastatin (pravastatin); Fluvastatin (flulatatin); Atorvastatin (atorvastatin); Rosuvastatin (rosuvastatin) and Pitavastatin (pitavastatin) etc.Dyslipidemia, comprising the rising of serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), apolipoprotein B (aPoB) and the reduction of HDL-C (HDL-C), is the main hazard factor of atherosclerosis and coronary heart disease.Thereby statins has obtained using very widely clinically.
Although statins is being obtained huge achievement aspect the control cardiovascular and cerebrovascular disease, therefore the medical expert of countries in the world does not slow down the foot step of research; Because patient's individual variation, his spit of fland is in effective blood fat reducing, and also part causes individual oxidation resistance to descend, and the transaminase raises.Therefore, the medical expert of many countries is attempting improvement even is surmounting his spit of fland.
People have generally acknowledged that hyperlipemia is to cause one of atherosclerotic reason for many years.Usually can see that clinically somebody's blood fat is not high, but carotid artery stenosis is very serious; Someone is then opposite.In zoopery, raise with 6 weeks of high fat diet for Carnis Coturnicis japonicae, rabbit, white mice simultaneously, the former two not only blood fat raises, and arteriosclerosis is serious; Though and the white mice blood fat exceeds normal 4～5 times, atherosclerosis is very slight.This explanation, the mechanism that atherosclerosis forms between the different genera of animal is different.In recent years, the low density lipoprotein, LDL of relevant oxidative modification (OX-LDL) starts atherosclerosis and promotes the research of its progress more and more to come into one's own, and their series of studies has confirmed that also OX-LDL is the significant effects factor in atherosclerotic generation and evolution.
In addition, from the low density lipoprotein, LDL metabolic pathway, ldl receptor plays an important role in the LDL metabolic process.After the oxidized modification of LDL, just can not combine, so the ldl receptor gene expression reduces with ldl receptor.OX-LDL is then formed foam cell by scavenger receptor by the macrophage picked-up.In the carotid artery stenosis patient, its ldl receptor gene down-regulated expression, and scavenger receptor up-regulated.Further confirmed the effect of OX-LDL atherosclerosis forms and makes progress from molecular level.The oxidative modification of LDL is a kind of of its chemical modification, and chemical modification also comprises saccharifying modification, glycosyloxy modification and immune modification etc.Oxidative modification is most important in these four kinds of chemical modifications.Above-mentioned series of studies confirms, prevents and treats in the process atherosclerotic, uses the Statins cholesterol reducing, especially reduce LDL and just transfer one of approach of fat treatment, and the oxidative modification of blocking-up LDL is only more direct approach.
Melatonin all has stronger antioxidant activity in vivo and in vitro, a lot of studies show that, melatonin in vivo or the external oxidative modification that can effectively prevent LDL, statins also has certain inhibitory action to the oxidation of LDL, and this may be that statins delays and treats one of atherosclerotic mechanism.
Statins is when significantly reducing plasma triglyceride, blood plasma LDL, also significantly reduce the intravital OX-LDL level of animal, the melatonin list is used not significantly influence of blood lipid level, the bibliographical information melatonin that clinical research arranged has tangible reduction effect to part patient's serum LDL, but generally to the not consistent influence of the blood lipid level of hyperlipemic patients.
Seek a kind of plasma blood-fat level that not only effectively reduces, prevent that more effectively atherosclerotic medicine from being the target that vast pharmaceutical manufacturer struggles for many years.
Summary of the invention
The inhibitory action that we produce for OX-LDL according to incidence of atherosclerosis mechanism progress of research and antioxidant, creatively propose statins and melatonin are united use, carried out series of studies by clinical experiment, find that statins is with the melatonin use in conjunction time, compare with the lipid-lowering effect that statins is used separately, melatonin is to the not significantly influence of lipid-lowering effect of statins, but melatonin has tangible reduction effect to intravital OX-LDL level, and we find unexpectedly, aspect melatonin and all statins OX-LDL in reducing body are horizontal significant synergism are arranged.Be our disclosed part of test results below, melatonin and lovastatin, simvastatin, rosuvastatin are united the influence of use to OX-LDL level in the body.
Because zoopery has obtained beyond thought result, indicating that statins has good prospects for application clinically in the future, atherosis and the various cardiovascular and cerebrovascular diseases of prevention of arterial there is important effect, thereby we are according to the physicochemical property with statins and melatonin, from numerous adjuvants, selected lactose, carboxymethyl starch sodium, microcrystalline Cellulose, hydroxypropyl cellulose, pregelatinized Starch, Rikemal B 200, magnesium stearate, micropowder silica gel, PVP, tertiary butyl-4-hydroxy methyl phenyl ethers anisole (BHA), carboxymethylcellulose calcium, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, vitamin E, PEG400, the PEG-3 oleate, glycerol, gelatin, adjuvants such as propylene glycol and PEG-60 glyceryl isostearate, with they the exploitation become various can be for the dosage form of clinical use, as tablet, capsule, soft capsule and dispersible tablet etc.
The specific embodiment
Embodiment 1
Lovastatin melatonin compound tablet
Prescription A
Melatonin 3g
Lactose 30g
Carboxymethyl starch sodium 30g
Microcrystalline Cellulose 18g
The ethanol solution 100g of 6%PVP
Magnesium stearate 2g
Preparation technology:
Melatonin is crossed 100 mesh sieves, lactose, carboxymethyl starch sodium, microcrystalline Cellulose are crossed 80 mesh sieves, take by weighing the melatonin of recipe quantity and lactose, carboxymethyl starch sodium, microcrystalline Cellulose mix homogeneously, adding the 6%PVP ethanol solution granulates in right amount, 60 ℃ of dryings, 16 mesh sieves are put in order dried granule, add the magnesium stearate of recipe quantity in the dried granule.Prescription B
Lovastatin 10g
Hydroxypropyl cellulose 15g
Pregelatinized Starch 10g
The ethanol solution 30g of 6%PVP
Rikemal B 200 1g
Preparation technology:
Simvastatin is crossed 100 mesh sieves, 80 mesh sieves are crossed in hydroxypropyl cellulose, pregelatinized Starch, take by weighing the simvastatin of recipe quantity and hydroxypropyl cellulose, pregelatinized Starch mix homogeneously, the ethanol solution that adds 6%PVP is granulated in right amount, 60 ℃ of dryings, 16 mesh sieves are put in order dried granule, add the Rikemal B 200 of recipe quantity in the dried granule.C, with above-mentioned a, two kinds of b prescription adopts the bi-layer tablet press stampings promptly to get double-layer tablet.
Embodiment 2
Atorvastatin melatonin compound tablet
Melatonin 10g
Mannitol 10g
Lactose 40g
Microcrystalline Cellulose 20g
The 95% alcoholic solution 120g of 6%PVP
Magnesium stearate 2g
Preparation technology:
Melatonin is crossed 100 mesh sieves, mannitol, lactose, microcrystalline Cellulose are crossed 80 mesh sieves, take by weighing the melatonin of recipe quantity and mannitol, lactose, microcrystalline Cellulose mix homogeneously, 95% alcoholic solution that adds 6%PVP is granulated in right amount, 60 ℃ of dryings, 16 mesh sieves are put in order dried granule, add the magnesium stearate of recipe quantity in the dried granule.
Atorvastatin 10g
Pregelatinized Starch 50g
Mannitol 50g
Lactose 40g
The 95% alcoholic solution 100g of 6%PVP
Micropowder silica gel 5g
Preparation technology:
Simvastatin is crossed 100 mesh sieves, pregelatinized Starch, mannitol, lactose are crossed 80 mesh sieves, take by weighing the simvastatin of recipe quantity and pregelatinized Starch, mannitol, lactose mix homogeneously, 95% alcoholic solution that adds 6%PVP is granulated in right amount, 60 ℃ of dryings, 16 mesh sieves are put in order dried granule, add the magnesium stearate of recipe quantity in the dried granule.
Adopt the bi-layer tablet press punching press promptly to get double-layer tablet two kinds of components of above-mentioned prescription A, B.
Embodiment 3
Simvastatin melatonin compound capsule
Melatonin 5g
Simvastatin 10g
Lactose 20g
Microcrystalline Cellulose 60g
Tertiary butyl-4-hydroxy methyl phenyl ethers anisole (BHA) 0.05g
Micropowder silica gel 5g
95% alcoholic solution of 6%PVP is an amount of
Preparation technology:
100 mesh sieves are crossed in melatonin, simvastatin, lactose, microcrystalline Cellulose, tertiary butyl-4-hydroxy methyl phenyl ethers anisole and micropowder silica gel in the prescription respectively, mixing, 95% alcoholic solution that adds 6%PVP are granulated in right amount, 60 ℃ of oven dry, 18 mesh sieve granulate, capsule charge gets final product.
Embodiment 4
Pravastatin melatonin compound dispersed tablet
Melatonin 5g
Pravastatin 5g
Hydroxypropyl starch 168g
The 10%PVPk30 alcoholic solution is an amount of
Magnesium stearate 1g
Preparation technology:
The melatonin and the pravastatin of recipe quantity are crossed 100 mesh sieves, and hydroxypropyl starch is crossed 80 mesh sieves, adds an amount of 10%PVPk30 alcoholic solution behind the mixing and granulates, and tabletting gets final product after the adding magnesium stearate.
Embodiment 5
Pitavastatin melatonin compound dispersed tablet
Pitavastatin 8g
Melatonin 5g
Carboxymethylcellulose calcium 15g
Crospolyvinylpyrrolidone 15g
Microcrystalline Cellulose 140g
10% starch slurry is an amount of
Magnesium stearate 6g
Preparation technology:
The melatonin and the Pitavastatin of recipe quantity are crossed 100 mesh sieves, and carboxymethylcellulose calcium, crospolyvinylpyrrolidone, microcrystalline Cellulose are crossed 80 mesh sieves, add an amount of 10% starch slurry behind the mixing and granulate, and tabletting gets final product after the adding magnesium stearate.
Embodiment 6
Fluvastatin melatonin compound dispersed tablet
Fluvastatin 8g
Melatonin 5g
Crosslinked carboxymethyl fecula sodium 120g
Microcrystalline Cellulose 70g
Vitamin E 5g
Magnesium stearate 2g
Preparation technology:
With embodiment 5.
Embodiment 7
Simvastatin melatonin compound capsules
Prescription A
Simvastatin 15g
Melatonin 3g
PEG400 200g
PEG-3 oleate 20g
Vitamin E 2g
Prescription B
Glycerol 80g
Gelatin 30g
Water 90g
Preparation technology:
Simvastatin and melatonin are crossed 100 mesh sieves, take by weighing recipe quantity, add in the PEG400 of recipe quantity, stir and make dissolving, add the PEG-3 oleate of recipe quantity again, stir.
Take by weighing gelatin, the G ﹠ W of recipe quantity, 80 ℃ of preparation gelatin solutions, standby.
Medicinal liquid and gelatin are pressed into soft capsule with rotation rolling capsule machine automatically, and air blast was carried out drying 24 hours under the relative humidity 25%, the 30 ℃ of temperature.Separate defective work with shaking screen after cleaning capsule with dehydrated alcohol, get final product semi-finished product, two aluminum pack finished product.
Embodiment 8
Rosuvastatin melatonin compound capsules
Prescription A
Rosuvastatin 10g
Melatonin 5g
Propylene glycol 60g
PEG-60 glyceryl isostearate 170g
Tertiary butyl-4-hydroxy methyl phenyl ethers anisole (BHA) 0.05g
Prescription B
Glycerol 60g
Gelatin 40g
Water 80g
Preparation technology:
With embodiment 7.
Statins and melatonin are united use to hyperlipemic patients blood lipid level and oxidized low density lipoprotein
The influence of level
Statins is the ideal blood lipid-lowering medicine of clinical now result of use, and the atherosclerotic has the trend of increase now, unite the influence of use to blood lipid level and OX-LDL level in the clinical hyperlipemic patients body in order to observe statins and melatonin, we have carried out serial clinical research to this.
Material and method
The patient who participates in this test has 256 examples, year mean age (58.6 ± 9), wherein male 126 examples, women 130 examples.All patients that participate in test all do not have serious cardiac disorder, get rid of blood, liver, kidney, endocrinopathy and diabetes.Be divided into 7 groups at random according to the blood lipid level of participating in the test patient, i.e. melatonin group, lovastatin group, simvastatin group, rosuvastatin group, melatonin+lovastatin group, melatonin+simvastatin group, melatonin+rosuvastatin group.According to the clinical common dose of melatonin and every kind of statins, determine that consumption every day of melatonin is 3mg, lovastatin is 20mg, and simvastatin is 10mg, and rosuvastatin is 10mg.The preceding decoction being taken at a draught of sleeping every night.The period in a medicine diet does not adjust.All patients are empty stomach ulnar vein blood sampling in the 10th early morning in week 10mL before taking medicine and after taking medicine, and carries out the mensuration of low density lipoprotein, LDL (OX-LDL) blood plasma level of triglyceride (TG), low density lipoprotein, LDL (LDL) and oxidative modification respectively.
Measuring LDL and TG agents useful for same is provided by Shanghai Biological Products Inst., Ministry of Public Health, and automatic clinical chemistry analyzer is Tianjin, island 7300 types.Ox-LDL adopts enzyme linked immunosorbent assay, and reagent is provided by Shanghai Rongsheng Bioisystech Co., Ltd, and microplate reader is Bio Rad Laboratories's 450 types.
The statistical disposition of data, all data represent with x ± s that all the t check of two sample means is relatively adopted between group and treatment front and back.
Experimental result
Lovastatin, simvastatin and rosuvastatin all have significant reduction effect to plasma TG, LDL, the Ox-LDL level of hyperlipemic patients; Melatonin is used the not significantly influence of blood fat to the patient separately, and TG there is slight increase effect, but does not have significant difference, but the Ox-LDL level is had significant reduction effect, and also more more obvious than statins; Under the situation of statins and melatonin use in conjunction, melatonin reduces the not influence of effect of TG and LDL to statins, but the effect that reduces Ox-LDL has been produced beyond thought concertedness effect, and concrete experimental result sees the following form.
Statins and melatonin are united the influence of use to hyperlipemic patients blood lipid level and oxidized low density lipoprotein level
| Group | ??n | ??????????TG(mmol·L -1) | ????LDL(mmol·L -1)???Ox-LDL(mg·L -1) |
| Lovastatin group Simvastatin group rosuvastatin group epiphysin group Lovastatin+epiphysin group Simvastatin+epiphysin group rosuvastatin+epiphysin group | ??36 ??37 ??37 ??36 ??36 ??37 ??37 | After preceding 3.18 ± 0.56 medications of medication 1.96 ± 0.72 **After preceding 3.20 ± 0.54 medications of medication 1.69 ± 0.66 **After preceding 3.19 ± 0.67 medications of medication 1.61 ± 0.51 **After preceding 3.21 ± 0.58 medications of medication after preceding 3.17 ± 0.51 medications of 3.32 ± 0.78 medications 1.99 ± 0.49 **After preceding 3.22 ± 0.46 medications of medication 1.71 ± 0.58 **After preceding 3.19 ± 0.60 medications of medication 1.60 ± 0.63 ** | ????4.80±1.52????????0.77±0.36 ????2.71±1.02 **?????0.55±0.19 *????4.86±1.69????????0.79±0.26 ????2.69±1.23 **?????0.54±0.21 *????4.81±1.50????????0.70±0.20 ????2.60±1.35 **?????0.51±0.22 *????4.89±1.58????????0.72±0.29 ????4.35±1.28????????0.46±0.25 **????4.78±1.36????????0.75±0.25 ????2.68±1.34 **?????0.26±0.15 **#※※???????4.77±1.41????????0.78±0.35 ????2.65±1.07 **?????0.25±0.11 **#☆☆???????4.85±1.67????????0.75±0.30 ????2.61±1.19 **?????0.23±0.12 **##&& |
Annotate:
*With compare P＜0.05 before the corresponding group of medication;
*With compare P＜0.01. before the corresponding group of medication
#With compare P＜0.05 after the medication of melatonin group;
##With compare P＜0.01. after the medication of melatonin group
※ ※With compare P＜0.01. after the medication of lovastatin group
☆ ☆With compare P＜0.01. after the medication of simvastatin group
﹠amp; ﹠amp;With compare P＜0.01. after the medication of rosuvastatin group
Claims (5)
1. a pharmaceutical composition that is used for the atherosis or treatment hyperlipidemia of prevention of arterial is characterized in that it contains statins and two kinds of active component of melatonin.
2. statins as claimed in claim 1, they are lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or Pitavastatin.
3. pharmaceutical composition as claimed in claim 1 is characterized in that it can be prepared into tablet, capsule, soft capsule or dispersible tablet.
4. tablet as claimed in claim 3, capsule or dispersible tablet, it is characterized in that it also contains in the following adjuvant one or more, they are lactose, carboxymethyl starch sodium, microcrystalline Cellulose, hydroxypropyl cellulose, pregelatinized Starch, Rikemal B 200, magnesium stearate, micropowder silica gel, PVP, tertiary butyl-4-hydroxy methyl phenyl ethers anisole, carboxymethylcellulose calcium, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium or vitamin E.
5. soft capsule as claimed in claim 3 is characterized in that it also contains in vitamin E, PEG400, PEG-3 oleate, glycerol, gelatin, propylene glycol and the PEG-60 glyceryl isostearate one or more.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410075802 CN1287860C (en) | 2004-12-23 | 2004-12-23 | Combination of medication containing reductase inhibitor HMG CoA and Melatonin |
| HK06102023A HK1081843A1 (en) | 2004-12-23 | 2006-02-16 | Pharmaceutical composition comprising reductase inhibitor hmg-coa and melatonin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410075802 CN1287860C (en) | 2004-12-23 | 2004-12-23 | Combination of medication containing reductase inhibitor HMG CoA and Melatonin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1660431A true CN1660431A (en) | 2005-08-31 |
| CN1287860C CN1287860C (en) | 2006-12-06 |
Family
ID=35010166
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410075802 Expired - Fee Related CN1287860C (en) | 2004-12-23 | 2004-12-23 | Combination of medication containing reductase inhibitor HMG CoA and Melatonin |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1287860C (en) |
| HK (1) | HK1081843A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101966167A (en) * | 2010-09-16 | 2011-02-09 | 杭州海王生物工程有限公司 | Melatonin soft capsules and preparation method thereof |
| CN103861117A (en) * | 2014-03-18 | 2014-06-18 | 王洪安 | Pravastatin sodium dispersible tablets and preparation method thereof |
| CN104721184A (en) * | 2015-02-16 | 2015-06-24 | 中国农业大学 | Preparation capable of improving cow conception rate as well as preparation method and application of preparation |
| WO2022129002A1 (en) * | 2020-12-15 | 2022-06-23 | Dsm Ip Assets B.V. | Coarse dispersion comprising statin and vitamin e oil |
-
2004
- 2004-12-23 CN CN 200410075802 patent/CN1287860C/en not_active Expired - Fee Related
-
2006
- 2006-02-16 HK HK06102023A patent/HK1081843A1/en not_active IP Right Cessation
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101966167A (en) * | 2010-09-16 | 2011-02-09 | 杭州海王生物工程有限公司 | Melatonin soft capsules and preparation method thereof |
| CN103861117A (en) * | 2014-03-18 | 2014-06-18 | 王洪安 | Pravastatin sodium dispersible tablets and preparation method thereof |
| CN103861117B (en) * | 2014-03-18 | 2016-03-30 | 王洪安 | A kind of pravastatin sodium dispersible tablets and preparation method thereof |
| CN104721184A (en) * | 2015-02-16 | 2015-06-24 | 中国农业大学 | Preparation capable of improving cow conception rate as well as preparation method and application of preparation |
| WO2022129002A1 (en) * | 2020-12-15 | 2022-06-23 | Dsm Ip Assets B.V. | Coarse dispersion comprising statin and vitamin e oil |
Also Published As
| Publication number | Publication date |
|---|---|
| HK1081843A1 (en) | 2006-05-26 |
| CN1287860C (en) | 2006-12-06 |
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