CN100496606C - Composite preparation containing nitrate esters medicine and HMG-CoA reductase inhibitor - Google Patents
Composite preparation containing nitrate esters medicine and HMG-CoA reductase inhibitor Download PDFInfo
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- CN100496606C CN100496606C CNB200510008615XA CN200510008615A CN100496606C CN 100496606 C CN100496606 C CN 100496606C CN B200510008615X A CNB200510008615X A CN B200510008615XA CN 200510008615 A CN200510008615 A CN 200510008615A CN 100496606 C CN100496606 C CN 100496606C
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Abstract
This invention supplies a drug composition used to prevent angina of coronary arteryosclerosis patients and cure chronic stable anginapectoris. It contains nitrate medicament and HMG-CoA reductase inhibitor two active components. Its clinical test results indicate: the two active components procure unexpected effect and notable synergism, and this ihas crucial meaning to prevent and betimes cure cardiac muscular ischemic disease, to great degree it improves coronary disease patient prognosis.
Description
Technical field
The invention belongs to new Western medicine pharmaceutical composition, in particular for atherosclerotic's the angina pectoris prevention and the treatment of chronic stable angina pectoris.
Background technology
Nitrate esters medicine is the rapidest and definite class medicine of treatment myocardial ischemia curative effect, in to anginal treatment, irreplaceable effect is arranged, nitroglycerin has been century-old old medicine, and still be used for anginal treatment so far clinically, now this type of medicine has had bigger development, and isosorbide mononitrate is its outstanding representative.If myocardial ischemia disease is treated untimely, prognosis is very poor, directly threatens patient's life.Along with the enhancing with extensive patients prophylactic treatment consciousness of improving constantly of medical level, the myocardial ischemia disease early prevention has been become the common practice of extensive patients, also be the effective way of improving the myocardial ischemia disease prognosis.Nitrate esters medicine is easy to generate drug resistance behind life-time service, and this class medicine has cross resistance, and this becomes the disadvantage that this type of medicine is used for the myocardial ischemia disease prophylactic treatment for a long time.In addition, use nitrate esters medicine can not effectively control coronary atherosclerosis separately, do not have good effect for prevention and the pathogenic factor of eliminating myocardial ischemia.Though nitrate esters medicine is improving determined curative effect aspect the myocardial ischemia symptom, the independent application of this type of medicine can not fundamentally reverse and cure myocardial ischemia.In order effectively to improve myocardial ischemia patient's prognosis, early stage, the effective medicine of life-time service is crucial.
Statins is a kind of methyl glutaryl coenzyme A (HMGCoA) reductase inhibitor, can reduce low-density lipoprotein cholesterol and potentiality ground high density lipoprotein increasing cholesterol, be the active drug of present cholesterol reducing and the atherosis generation of prevention of arterial.Large-scale clinical trial subgroup the analysis showed that the matched group that the treatment group is suitable with blood cholesterol levels is compared, and the incidence rate of its cardiovascular event is low significantly; At this moment, though the minimizing of luminal stenosis degree is small, clinical manifestation improves very remarkable, and there is the non-lipid effect in prompting.Bibliographical information, statins have following except that effect for reducing fat, and the pharmacological action very useful to the patient be as having certain hypotensive effect to the normal hyperpietic of serum cholesterol level; Reverse myocardial hypertrophy; Reverse atherosclerotic progress even stop; Reduce the speckle inner lipid, recover vascular endothelial function, antiinflammatory and antithrombotic form, thereby can prevent and the alleviate myocardial ischemia symptom; The control acute coronary syndrome.
Therefore, statins is not only the good fat-reducing medicament of a kind of curative effect, and occupies critical role in the whole control of coronary heart disease.The needs of patients that cholesterol increases is taken statins, and the normal cardiovascular patient of blood fat is also advocated and taken.But, can't reach the definite curative effect that nitrate esters medicine can improve ischemia symptom at once for the patient that myocardial ischemia takes place.
Along with the improvement with medical condition of improving constantly of people's living standard, a lot of myocardial ischemia disease patients just can obtain clear and definite diagnosis in early days at ischemia.Thereby effectively Drug therapy just becomes the key of problem.Though statins the primary prevention that is used for coronary heart disease and secondary prevention treatment obtained other medicines incomparable effect, but this and ideal curative effect also have sizable gap, developing the even more ideal medicaments for resisting myocardial ischemia of a kind of curative effect has the market demand widely, meets the interests of vast cardiovascular patient.Hyperlipidemia, hypertension, oxidative damage and bring out coronary spasm multiple factor fellowship the generation of myocardial ischemia disease, the single medicine mechanism of action is single, be difficult to reach ideal curative effect, choose two or more medication combined use, to obtain better effect, may be a kind of valid approach.But the antagonism between the medicine also may take place in this; for example; aspirin and angiotensin-convertion enzyme inhibitor are singly used all has good protective action to ischemic myocardium; use the back clinical efficacy imprecise but unite; the experimental result that external cardiac muscle is cultivated shows that both exist significant antagonism.
Summary of the invention
The invention provides a kind of pharmaceutical composition that is used for the treatment of angina pectoris prevention and stable angina pectoris, it is characterized in that it contains nitrate esters medicine and two kinds of active component of statins (HMGCoA reductase inhibitor).In a single day myocardial ischemia diseases such as angina pectoris develop into unstable angina pectoris or myocardial infarction, prognosis is very poor, the pharmaceutical composition that we invented has great importance for vast hyperlipemic patients and the patients with stable angina prophylactic treatment of being in, and this prophylactic treatment to myocardial ischemia disease has revolutionary meaning.
Our Lunan Pharmacy Co. Ltd is in domestic top standard in the research and development and the production of the glad health of southern Shandong (isosorbide mononitrate) always, domestic blank has been filled up in the production of crude drug, closely follow the forward position of nitrate esters medicine antianginal study on mechanism in recent years, progress in conjunction with the myocardial ischemia pathological research, proposition is with nitrate esters medicine batch (-type)s such as isosorbide mononitrate single administration in low dose of early morning every day, the prophylactic treatment that is used for hyperlipidemia companion's coronary atherosclerosis and stable angina pectoris, obtained comparatively ideal effect, and further creatively propose nitrate esters medicine and statins are united use, be used for clinical definite myocardial ischemia patient's prevention and treatment.With the associating of how tame hospital, carried out clinical trial for many years, obtained very good effect, the part clinical indices has obtained significant concertedness effect.We show by the clinical test results of large sample, nitrate esters medicine and statins are united use and the coronary atherosclerosis patient prevented myocardial ischemia diseases such as angina pectoris and chronic stable angina pectoris beyond thought effect is arranged, and be all very desirable to the curative effect of various myocardial ischemia diseases.Early stage and adhere to using have the very wholesome effect of two class medicines to myocardial ischemia disease patient prophylaxis of acute cardiovascular event.Specifically be expressed as follows:
Compare with the placebo group, pravastatin uses separately the incidence rate that the acute cardiac incident taken place in 4 years the hyperlipidemia companion coronary artery patient that I～the II level is atherosis not have significant advantage, and the effect that the low dose of batch (-type) of isosorbide mononitrate is taken neither be very good.And drug combination has been obtained the obvious synergistic effect, and the number that gradation administration group patient develops into unstable angina pectoris (UAP) or acute myocardial infarction (AMI) in 4 years significantly reduces than single-dose group.
Nitrose medicine batch (-type) single administration in low dose of early morning every day has played significant effect to preventing anginal outbreak, and this administering mode can not produce toleration in long time.It is particularly remarkable that nitrate esters medicine and Statins are united the minimizing of the single-dose group of use and active reduction of blood plasma cTnT of gradation administration group and anginal attack times, and the number that gradation administration group patient develops into unstable angina pectoris (UAP) or acute myocardial infarction (AMI) in 3 years significantly reduces than single-dose group.But detected total plasma cholesterol (TC) is level result show, the TC level of single-dose group is starkly lower than the TC level of gradation administration group before sleeping, and this time with statins performance effect for reducing blood fat is mainly relevant at night.This beyond thought result who seems contradiction has illustrated that just there be the significance of stable blood drug level of long period for the prevention angina pectoris attacks in statins in blood.The present invention has confirmed statins when being used for preventative curing myocardial ischemia, and the necessity that continues to take daytime has changed a traditional administrated method at a decoction being taken at a draught in night.In a word, our result of the test is indicating in the drug combination preparation that contains nitrate esters medicine and statins, nitrate esters medicine can be used as the rapid release composition, and statins can be used as the slow release composition, and such compound preparation may produce best therapeutic effect to the patient.Nitrate drug and statins drug combination are being obtained beyond thought curative effect aspect improvement of functions in patients with unstable angina ischemic electrocardiogram and angina.The result of the test of following up a case by regular visits in 6 months shows, the early stage of unstable angina pectoris taking place, and in time unites and uses two class medicines can effectively reduce the incidence rate that cardiovascular event takes place at a specified future date.
We are according to the result of clinical trial, and with the proper dosage proportioning, it is manufactured becomes the compound preparation that makes things convenient for the patient to take with nitrate esters medicine and statins.We grope by experiment, find that several dosage forms such as conventional tablet, slow releasing tablet, dispersible tablet, capsule, slow releasing capsule, soft capsule or drop pill are suitable for pharmaceutical composition of the present invention.In conventional tablet, dispersible tablet, capsular developmental research, preferably to one or more in the following adjuvant, they are starch, L-HPC, magnesium stearate, microcrystalline Cellulose, PVP, micropowder silica gel, carboxymethyl starch sodium, tertiary butyl-4-hydroxy methyl phenyl ethers anisole, Pulvis Talci, vitamin E, Henan gelling starch, carboxymethyl starch sodium, lactose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium; Preferred one or more in following slow-release auxiliary material hexadecanol, octadecanol, HPMC-4M, HPMC-15M, glyceryl monostearate, ethyl cellulose, acrylic resin RS100, acrylic resin RL100, polyvinyl alcohol or the ethylene-vinyl acetate copolymer in slow releasing tablet and the capsular development of slow release; Preferred one or more in following adjuvant vitamin E, PEG400, PEG-3 oleate, glycerol, gelatin, propylene glycol or the PEG-60 glyceryl isostearate in the development of soft capsule; Preferred one or more among following adjuvant PEG-1500, PEG-2000, PEG-4000 or the PEG-6000 in the development of drop pill.
The specific embodiment
Embodiment 1-4 is the content of clinical trial.
Embodiment 1
Pravastatin and isosorbide mononitrate are united I～II level coronary atherosclerosis patient is accompanied in use to hyperlipidemia primary prevention effect
One, case is selected
Angina pectoris does not take place for hyperlipidemia companion I～II level coronary atherosclerosis in selected patient as yet, and the routine of controlling oneself of being in is taken medicine and carried out the primary prevention treatment, needn't be in hospital.There is serious hepatic and renal function injure person can not participate in this test.
Two, therapeutic regimen
The patient who participates in this test has 252 examples, and all patients are divided into placebo group, isosorbide mononitrate group, pravastatin group, isosorbide mononitrate+pravastatin single-dose group and isosorbide mononitrate+pravastatin gradation administration group at random according to the degree of blood pressure, blood lipid level and coronary stricture.The patient of isosorbide mononitrate group takes isosorbide mononitrate 10mg early morning every day.Before sleeping every night, pravastatin group patient takes pravastatin 40mg.The patient of isosorbide mononitrate+pravastatin single-dose group takes isosorbide mononitrate 10mg early morning every day, takes pravastatin 40mg before sleeping every night.The patient of isosorbide mononitrate+pravastatin gradation administration group takes isosorbide mononitrate 10mg early morning every day, and takes pravastatin 40mg every day, divides and takes for two to three times.
All patients are carried out secular tracking follow up a case by regular visits to, provide free the medicine that all are taken, to guarantee the compliance of medication.The patient who does not take medicine according to therapeutic regimen is rejected this test.Have 246 routine patients to adhere to taking medicine according to therapeutic regimen, 6 routine patients are because to change clothes other medicines or adverse effect etc. former thereby withdraw from this test.
Three, observation index
Develop into unstable angina pectoris (UAP) or acute myocardial infarction incident such as (AMI) acute cardiac in 4 years and the number of need hospitalization and generation percentage rate.
Four, result of the test
Result of the test shows, compare with the placebo group, pravastatin uses separately the incidence rate that the acute cardiac incident taken place in 4 years the hyperlipidemia companion coronary artery patient that I～the II level is atherosis not have significant advantage, and the effect that the low dose of batch (-type) of isosorbide mononitrate is taken neither be very good.And drug combination has been obtained the obvious synergistic effect, and the number that gradation administration group patient develops into unstable angina pectoris (UAP) or acute myocardial infarction (AMI) in 3 years significantly reduces than single-dose group.Our result of the test is indicating in the drug combination preparation that contains sorbide nitrate and lovastatin, sorbide nitrate can be used as the rapid release composition, and lovastatin can be used as the slow release composition, and such compound preparation may produce best therapeutic effect to the patient.Concrete result of the test sees Table 1.
The coupling of table 1. pravastatin isosorbide mononitrate is to I～II level coronary atherosclerosis patient's primary prevention effect
##Compare P＜0.01. with the isosorbide mononitrate group
※Compare P＜0.05. with the pravastatin group
※ ※Compare P＜0.01 with the pravastatin group
☆ ☆Compare P＜0.01. with the single-dose group
Embodiment 2.
Lovastatin and sorbide nitrate are united the prophylactic treatment effect of use to patients with stable angina
One, case is selected
According to " name of ischemic heart desease and the diagnostic criteria " of World Health Organization (WHO), the patients with stable angina of making a definite diagnosis.Selected patient is the lighter patients with stable angina of angina pectoris degree, and the own routine of can being in is taken medicine, needn't hospitalization.There is serious hepatic and renal function injure person can not participate in this test.
Two, therapeutic regimen
The patient who participates in this test has 232 examples, and all patients are divided into sorbide nitrate group, lovastatin group, sorbide nitrate+lovastatin single-dose group and sorbide nitrate+lovastatin gradation administration group at random according to the number of times (time uncomfortable in chest is longer than 30min person and also counts once) of angina pectoris attacks in an age and the week.The patient of sorbide nitrate group takes sorbide nitrate 5mg early morning every day.Before sleeping every night, lovastatin group patient takes lovastatin 30mg.The patient of sorbide nitrate+lovastatin single-dose group takes sorbide nitrate 5mg early morning every day, takes lovastatin 30mg before sleeping every night.The patient of sorbide nitrate+lovastatin gradation administration group takes sorbide nitrate 5mg early morning every day, and divides every day and take lovastatin 30mg three times.All patients withdraw other drug in participation in preceding 2 weeks of this test.
Because sorbide nitrate is an antianginal drug the most commonly used, lovastatin is the good medicine of lipid-lowering effect, can be used for the prophylactic treatment of myocardial ischemia disease, and their clinical efficacies are definite, consider patients'benefit, do not establish the placebo group.All patients are carried out secular tracking follow up a case by regular visits to, provide free the medicine that all are taken, to guarantee the compliance of medication.The patient who does not take medicine according to therapeutic regimen is rejected this test.Have 198 routine patients to adhere to taking medicine according to therapeutic regimen, 34 routine patients are because to change clothes other medicines or adverse effect etc. former thereby withdraw from this test.To participating in 20 weeks of this test later on owing to develop into the patient of unstable angina pectoris or generation acute myocardial infarction, the while in hospital can be used other therapeutic regimen instead or take other non-drug therapy measure according to patient's practical situation, thereby finishes this test.The patient of stable disease can adhere to 156 weeks of medication to the always.
Three, observation index
(1) get hematometry total plasma cholesterol ester (TC) level and blood plasma cTnT (actin ATP enzyme suppresses subunit) activity the Wednesday in the 2nd week, the 20th week before the medication and after the medication; (2) medication preceding 1 the week in and medication after the 2nd week, the 20th the week in anginal attack times; Develop into unstable angina pectoris (UAP) or acute myocardial infarction acute cardiovascular event such as (AMI) in (3) 3 years and the number of need hospitalization and generation percentage rate.
Four, result of the test
With compare before the medication, after each treatment group medication in 20 weeks the variation of each index show and all obtained significant curative effect; The sorbide nitrate batch (-type) is low dose of once to give the administering mode of 5mg early morning every day under the situation that does not influence the hyperlipidemia level, played significant effect to preventing anginal outbreak, our result of the test shows, this administering mode of sorbide nitrate can not produce toleration (we observed for 20 weeks) in long time, and more rapider than the onset of lovastatin group.It is particularly remarkable that sorbide nitrate and lovastatin are united the minimizing of the single-dose group of use and active reduction of blood plasma cTnT of gradation administration group and anginal attack times, and the number that gradation administration group patient develops into unstable angina pectoris (UAP) or acute myocardial infarction (AMI) in 3 years significantly reduces than single-dose group.But detected total plasma cholesterol (TC) is level result show, the TC level of single-dose group is starkly lower than the TC level of gradation administration group before sleeping, and this time with lovastatin performance effect for reducing blood fat is mainly relevant at night.This beyond thought result who seems contradiction has illustrated that just there be the significance of stable blood drug level of long period for the prevention angina pectoris attacks in lovastatin in blood.In a word, our result of the test is indicating in the drug combination preparation that contains sorbide nitrate and lovastatin, sorbide nitrate can be used as the rapid release composition, and lovastatin can be used as the slow release composition, and such compound preparation may produce best therapeutic effect to the patient.Concrete result of the test sees Table 2.
Table 2. lovastatin and sorbide nitrate are united the prophylactic treatment effect of use to patients with stable angina
*With compare P＜0.05. before the medication
*With compare P＜0.01. before the medication
#Compare P＜0.05. with the sorbide nitrate group
##Compare P＜0.01 with the sorbide nitrate group
※Compare P＜0.05. with the lovastatin group
※ ※Compare P＜0.01. with the lovastatin group
☆Compare P＜0.05. with the single-dose group
☆ ☆Compare P＜0.01. with the single-dose group
Embodiment 3.
Simvastatin and isosorbide mononitrate are united the prophylactic treatment effect of use to patients with stable angina
One, case is selected
With clinical trial 2.
Two, therapeutic regimen
The patient who participates in this test has 253 examples, and all patients are divided into isosorbide mononitrate group, simvastatin group, isosorbide mononitrate+simvastatin single-dose group and isosorbide mononitrate+simvastatin multiple dosing group at random according to the number of times (time uncomfortable in chest is longer than 30min person and also counts once) of angina pectoris attacks in an age and the week.The patient of isosorbide mononitrate group takes isosorbide mononitrate 10mg early morning every day.Before sleeping every night, simvastatin group patient takes simvastatin 15mg.The patient of isosorbide mononitrate+simvastatin single-dose group takes isosorbide mononitrate 10mg early morning every day, takes simvastatin 15mg before sleeping every night.The patient of isosorbide mononitrate+simvastatin multiple dosing group takes isosorbide mononitrate 10mg early morning every day, divides every day and takes simvastatin 15mg three times.All patients withdraw other drug in participation in preceding 2 weeks of this test.
Because isosorbide mononitrate is an antianginal drug the most commonly used, simvastatin is the good medicine of lipid-lowering effect, can be used for the prophylactic treatment of myocardial ischemia disease, and their clinical efficacies are definite, consider patients'benefit, do not establish the placebo group.All patients are carried out secular tracking follow up a case by regular visits to, provide free the medicine that all are taken, to guarantee the compliance of medication.The patient who does not take medicine according to therapeutic regimen is rejected this test.Have 215 routine patients to adhere to taking medicine according to therapeutic regimen, 38 routine patients are because to change clothes other medicines or adverse effect etc. former thereby withdraw from this test.To participating in 20 weeks of this test later on owing to develop into the patient of unstable angina pectoris or generation acute myocardial infarction, the while in hospital can be used other therapeutic regimen instead or take other non-drug therapy measure according to patient's practical situation, thereby finishes this test.The patient of stable disease can adhere to 156 weeks of medication to the always.
Three, observation index
With clinical trial 2.
Four, result of the test
With compare before the medication, after each treatment group medication in 20 weeks the variation of each index show and all obtained significant curative effect; The isosorbide mononitrate batch (-type) is low dose of once to give the administering mode of 10mg early morning every day under the situation that does not influence the hyperlipidemia level, played significant effect to preventing anginal outbreak, our result of the test shows, this administering mode of isosorbide mononitrate can not produce toleration (we observed for 20 weeks) in long time, and more rapider than the onset of simvastatin group.It is particularly remarkable that isosorbide mononitrate and simvastatin are united the minimizing of the single-dose group of use and active reduction of blood plasma cTnT of gradation administration group and anginal attack times, and the number that gradation administration group patient develops into unstable angina pectoris (UAP) or acute myocardial infarction (AMI) in 3 years significantly reduces than single-dose group.But detected total plasma cholesterol (TC) is level result show, the TC level of single-dose group is starkly lower than the TC level of gradation administration group before sleeping, and this time with simvastatin performance effect for reducing blood fat is mainly relevant at night.This beyond thought result who seems contradiction has illustrated that just there be the significance of stable blood drug level of long period for the prevention angina pectoris attacks in simvastatin in blood.In a word, our result of the test is indicating in the drug combination preparation that contains isosorbide mononitrate and simvastatin, isosorbide mononitrate can be used as the rapid release composition, and simvastatin can be used as the slow release composition, and such compound preparation may produce best therapeutic effect to the patient.Concrete result of the test sees Table 3.
Table 3. simvastatin and isosorbide mononitrate are united the prophylactic treatment effect of use to patients with stable angina
*With compare P＜0.05. before the medication
*With compare P＜0.01. before the medication
#Compare P＜0.05. with the isosorbide mononitrate group
##Compare P＜0.01. with the isosorbide mononitrate group
※Compare P＜0.05. with the simvastatin group
※ ※Compare P＜0.01. with the simvastatin group
☆Compare P＜0.05. with the single-dose group
☆ ☆Compare P＜0.01. with the single-dose group
Embodiment 4
Rosuvastatin and nitroglycerin coupling are to the therapeutic effect of functions in patients with unstable angina
Nitrate esters medicine and statins are united use the prophylactic treatment of chronic stable angina pectoris have been obtained beyond thought ideal effect, according to the result of the test of clinical trial 1 and 2, we continue to have investigated the medication combined use of two classes to the functions in patients with unstable angina curative effect.
One, case is selected
According to " name of ischemic heart desease and the diagnostic criteria " of World Health Organization (WHO), the functions in patients with unstable angina of making a definite diagnosis.And eliminating has patient or acute myocardial infarction, advanced heart failure, cardiogenic shock, severe or out of contior hyperpietic of serious hepatic and renal function injure.
Two, therapeutic regimen
The functions in patients with unstable angina that 165 examples are in hospital is divided into nitroglycerin group, rosuvastatin group and nitroglycerin+rosuvastatin group at random according to myocardial ischemia area and the isostatic principle of angina pectoris attacks number of times.The intravenous drip in per 12 hours of nitroglycerin group gives nitroglycerin 2.5mg, the rosuvastatin group gave rosuvastatin 5mg in per 12 hours, the intravenous drip in per 12 hours of nitroglycerin+rosuvastatin group gives nitroglycerin 2.5mg, orally give rosuvastatin 5mg.All patients all do not use lipid-regulation medicine in preceding 4 weeks of being admitted to hospital.All patients are after using full 1 week of this dosage regimen medication, can adjust therapeutic regimen according to patient's the concrete state of an illness (as blood pressure, heart rate, cardiac function, angina pectoris attacks number of times and degree of myocardial ischemia etc.) and clinical examination index, suitably adjust the nitroglycerin consumption or add and use other drug, as beta-blocker etc., the patient of nitroglycerin group can add and uses rosuvastatin, and the patient of rosuvastatin group also can add and uses nitroglycerin.The patient that acute cardiovascular event such as acute myocardial infarction or acute coronary syndrome took place in 2 weeks can take various treatment measures according to the concrete state of an illness.
Three, observation index
Each organizes before patient's medication and the 1st all angina pectoris attacks number of times, persistent period, the Electrocardiographic variation of ischemic after the medication; Measure and respectively to organize before patient's medication and the 6th day serum cTnT concentration after the medication; All patients are followed up a case by regular visits to, and observing (comprising the while in hospital) in 6 months acute cardiovascular event takes place or the number of heart failure, pulmonary edema takes place and percentage rate takes place because of myocardial infarction.
Four, efficacy determination
(1) to reduce 80% be produce effects to angina pectoris symptom disappearance or attack times, persistent period substantially, and it be effective reducing 50%～80%, and minimizing is invalid less than 50%; (2) the original ischemic ST of resting electrocardiogram recovers normal or gos up〉0.1mv is produce effects, go up 0.05～0.1mv or the negative T wave that mainly leads of ST section shoals〉50% for effectively, do not reach These parameters person for invalid.
Five, result of the test
With compare before the medication, the serum cTnT concentration of nitroglycerin group and nitroglycerin and rosuvastatin drug combination group has had significant reduction, the rosuvastatin group has a declining tendency, but does not have statistical significance; The serum cTnT lowering of concentration of drug combination group is the most obvious, compares with level after nitroglycerin group, the medication of rosuvastatin group, and significant difference is all arranged.In addition, the drug combination group all has significant difference comparing with nitroglycerin group, rosuvastatin group aspect improvement of ischemic electrocardiogram and the angina, has obtained beyond thought curative effect.The result of the test of following up a case by regular visits in 6 months shows, in that the early stage of unstable angina pectoris takes place, in time unites and uses nitroglycerin and rosuvastatin, can effectively reduce the incidence rate that cardiovascular event takes place at a specified future date.Concrete outcome sees Table 4.
Table 4. rosuvastatin and nitroglycerin are united the therapeutic effect of use to functions in patients with unstable angina
*With compare P＜0.05. before the medication
*With compare P＜0.01. before the medication
##Compare P＜0.01. with the nitroglycerin group
※ ※Compare P＜0.01. with the rosuvastatin group
Following examples are the compound preparations that contain nitrate esters medicine and statins.Below be 1000 recipe quantity.
Embodiment 5
The isosorbide mononitrate Lovastatin sustained-release tablets
Prescription A
Isosorbide mononitrate 15g
Starch 55g
L-HPC 25g
10% starch slurry is an amount of
Magnesium stearate 1g
Prescription B
Lovastatin 35g
HPMC-4M 30g
HPMC-15M 40g
Microcrystalline Cellulose 20g
PVP 8g
Micropowder silica gel 35g
The 8%PVPk30 ethanol solution is an amount of
Magnesium stearate 2g
Preparation technology:
Isosorbide mononitrate and starch, L-HPC among the A crosses 100 mesh sieves respectively with prescription, and mixing, add 10% starch slurry and granulate in right amount, oven dry below 50 ℃, 18 mesh sieve granulate add the magnesium stearate mixing; 100 mesh sieves are crossed in lovastatin among the prescription B, HPMC--4M, HPMC--1SM, microcrystalline Cellulose, PVP, micropowder silica gel respectively, mixing, add the 8%PVPk30 ethanol solution and granulate in right amount, oven dry, granulate, add the magnesium stearate mixing, the compacting double-layer tablet promptly.
Embodiment 6
Isosorbide mononitrate atorvastatin sheet
Isosorbide mononitrate 10g
Atorvastatin 20g
Starch 60g
Microcrystalline Cellulose 100g
L-HPC 30g
PVP 5g
10% starch slurry is an amount of
Magnesium stearate 2g
Preparation technology:
Isosorbide mononitrate, atorvastatin, starch, microcrystalline Cellulose, L-HPC and PVP in the prescription are crossed 100 mesh sieves respectively, mixing, add 10% starch slurry and granulate in right amount, oven dry below 50 ℃, 18 mesh sieve granulate, add the magnesium stearate mixing of recipe quantity, tabletting promptly.
Embodiment 7
Sorbide nitrate pravastatin slow releasing tablet
Prescription A
Sorbide nitrate 5g
Starch 100g
Carboxymethyl starch sodium 10g
10% starch slurry is an amount of
Magnesium stearate 1g
Prescription B
Pravastatin 15g
Hexadecanol 10g
Glyceryl monostearate 20g
Microcrystalline Cellulose 40g
Tertiary butyl-4-hydroxy methyl phenyl ethers anisole (BHA) 0.05g
The 8%PVPk30 ethanol solution is an amount of
Magnesium stearate 2g
Preparation technology:
Sorbide nitrate and starch, the carboxymethyl starch sodium of prescription among the A crossed 100 mesh sieves respectively, mixing, add 10% starch slurry and granulate in right amount, oven dry below 50 ℃, 18 mesh sieve granulate add the magnesium stearate mixing; Pravastatin, hexadecanol, glyceryl monostearate, microcrystalline Cellulose and tertiary butyl-4-hydroxy methyl phenyl ethers anisole among the prescription B are crossed 100 mesh sieves respectively, mixing, add the 8%PVPk30 ethanol solution and granulate in right amount, oven dry, granulate, add the magnesium stearate mixing, the compacting double-layer tablet promptly.
Embodiment 8
Isosorbide mononitrate rosuvastatin slow releasing tablet
Prescription A
Isosorbide mononitrate 20g
Microcrystalline Cellulose 100g
Henan gelling starch 10g
10% starch slurry is an amount of
Pulvis Talci 1g
Prescription B
Rosuvastatin 5g
Ethyl cellulose 15g
Glyceryl monostearate 20g
Microcrystalline Cellulose 40g
PVP 8g
The 8%PVPk30 ethanol solution is an amount of
Magnesium stearate 2g
Preparation technology:
Isosorbide mononitrate and microcrystalline Cellulose, the Henan gelling starch of prescription among the A crossed 100 mesh sieves respectively, mixing, add 10% starch slurry and granulate in right amount, oven dry below 50 ℃, 18 mesh sieve granulate add the magnesium stearate mixing; Rosuvastatin among the prescription B, ethyl cellulose, glyceryl monostearate, microcrystalline Cellulose, PVP are crossed 100 mesh sieves respectively, mixing, add the 8%PVPk30 ethanol solution and granulate in right amount, oven dry, granulate, add the magnesium stearate mixing, the compacting double-layer tablet promptly.
Embodiment 9
Sorbide nitrate fluvastatin capsule
Sorbide nitrate 8g
Fluvastatin 20g
Lactose 15g
Microcrystalline Cellulose 35g
Carboxymethyl starch sodium 10g
10% starch slurry is an amount of
Preparation technology:
Sorbide nitrate, fluvastatin, lactose, microcrystalline Cellulose and carboxymethyl starch sodium in the prescription are crossed 100 mesh sieves respectively, mixing, add 10% starch slurry and granulate in right amount, 60 (capsule charge gets final product for oven dry below ℃, 18 mesh sieve granulate.
Embodiment 10
Isosorbide mononitrate, pravastatin slow releasing capsule
Prescription A
Isosorbide mononitrate 15g
Celphere 200g
Sodium carboxymethyl cellulose 10g
Carboxymethyl starch sodium 40g
The 7%PVP alcoholic solution is an amount of
Preparation technology:
Isosorbide mononitrate, lisinopril are crossed 160 mesh sieves, and sodium carboxymethyl cellulose, carboxymethyl starch sodium are crossed 100 mesh sieves, and recipe quantity takes by weighing, and be miscible in the 7%PVP alcoholic solution (solvent is a 60-70% ethanol).Drive the granulating and coating machine, go into wind pressure 0.5bar, CYL (inlet air air door pressure) 3bar, CAP1 (atomizing pressure) 0.8bar pours celphere into, pelletize.Blanking velocity 5rpm, the pump 14% of wriggling, rotary speed 130rpm, 50 ℃ of oven dry.
Prescription B
(1) contains the preparation of pill core
Pravastatin 80g
Celphere 200g
7%PVP solution (solvent is 90% ethanol) is an amount of
Preparation technology:
Pravastatin is crossed 160 mesh sieves, and recipe quantity takes by weighing, and pours in the hopper.Drive the granulating and coating machine, go into wind pressure 0.5bar, CYL 2bar, CAP1 0.6bar pours celphere into, pelletize.Blanking velocity 4rpm, the pump 13% of wriggling, rotary speed 145rpm, spray 7%PVP solution (solvent is 90% ethanol), 50 ℃ of oven dry.Pelletize finishes.
Contain pill core 500g
Acrylic resin RS100 15g
Acrylic resin RL100 10g
Polyethylene Glycol-6000 1.5g
Pulvis Talci 3g
95% ethanol is an amount of
Preparation technology:
Recipe quantity takes by weighing and contains pill core, pours in the hopper.Drive the granulating and coating machine, go into wind pressure 0.5bar, CYL 3bar, CAP1 0.9bar, 30 ℃ of inlet air temperature, rotary speed 180rpm, the pump 8% of wriggling sprays into the alcoholic solution of acrylic resin RS 100 and acrylic resin RL 100.Coating finishes.
Is to carry out capsule at 1: 1 to fill and get final product with the pastille piller of prescription A and prescription B gained according to weight ratio.Acrylic resin in the present embodiment can replace with the polyvinyl alcohol or the ethylene-vinyl acetate copolymer of equal number.
Embodiment 11
Pitavastatin sorbide nitrate compound dispersed tablet
Pitavastatin 30g
Sorbide nitrate 3g
Carboxymethylcellulose calcium 15g
Crospolyvinylpyrrolidone 15g
Microcrystalline Cellulose 140g
10% starch slurry is an amount of
Magnesium stearate 6g
Preparation technology:
The sorbide nitrate 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 12
Lovastatin nitroglycerin compound dispersed tablet
Simvastatin 10g
Nitroglycerin 0.5g
Crosslinked carboxymethyl fecula sodium 120g
Microcrystalline Cellulose 70g
Vitamin E 5g
Magnesium stearate 2g
Preparation technology:
With embodiment 11.
Embodiment 13
Simvastatin nitroglycerin compound capsules
Prescription A
Rosuvastatin 15g
Nitroglycerin 0.2g
PEG400 200g
PEG-3 oleate 20g
Vitamin E 2g
Prescription B
Glycerol 80g
Gelatin 30g
Water 90g
Preparation technology:
Rosuvastatin is crossed 100 mesh sieves, take by weighing the rosuvastatin and the nitroglycerin of 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 14
Simvastatin isosorbide mononitrate compound capsules
Prescription A
Simvastatin 30g
Isosorbide mononitrate 5g
Propylene glycol 90g
PEG-60 glyceryl isostearate 130g
Tertiary butyl-4-hydroxy methyl phenyl ethers anisole (BHA) 0.05g
Prescription B
Glycerol 60g
Gelatin 40g
Water 80g
Preparation technology:
With embodiment 13.
Embodiment 15
Isosorbide mononitrate Atrovatadin dropping balls (being the consumption of 5000 drop pill)
Isosorbide mononitrate 30g
Atorvastatin 20g
PEG-2000 50g
PEG-4000 50g
Preparation technology:
Take by weighing recipe quantity and cross the isosorbide mononitrate and the atorvastatin of 100 mesh sieves, add in water-bath in the mixed liquor of the Macrogol 4000 that contains recipe quantity (PEG-2000) of heating and melting, Macrogol 2000 (PEG-4000), fully stir, make it mixing, pack in the drop bottle, in following system of 95 ± 2 ℃ conditions; Splash in the glass condensation column of the methyl-silicone oil that fills 4-6 ℃, take out after the molding, inhale with absorbent paper and remove adherent methyl-silicone oil, promptly.
Embodiment 16
Isosorbide mononitrate lovastatin drop pill (being the consumption of 5000 drop pill)
Isosorbide mononitrate 20g
Lovastatin 40g
PEG-1500 50g
PEG-6000 50g
Tween 80 5g
Preparation technology:
With embodiment 15.
Claims (2)
1. a slow releasing capsule or bilayer tablet of containing isosorbide mononitrate and HMG-CoA reductase inhibitor that is used for the treatment of angina pectoris prevention and stable angina pectoris, it is characterized in that this slow releasing capsule or bilayer tablet are the controlled release preparations that contains immediate release component and slow release component, wherein the active component of immediate release component is an isosorbide mononitrate, and the active component of slow release component is the HMG-CoA reductase inhibitor.
2. a kind of slow releasing capsule or bilayer tablet of containing isosorbide mononitrate and HMG-CoA reductase inhibitor that is used for the treatment of angina pectoris prevention and stable angina pectoris as claimed in claim 1, it is characterized in that HMG-CoA reductase inhibitor contained in this slow releasing capsule or the bilayer tablet be in lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or the Pitavastatin any one or more than one.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200510008615XA CN100496606C (en) | 2005-02-28 | 2005-02-28 | Composite preparation containing nitrate esters medicine and HMG-CoA reductase inhibitor |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200510008615XA CN100496606C (en) | 2005-02-28 | 2005-02-28 | Composite preparation containing nitrate esters medicine and HMG-CoA reductase inhibitor |
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| Publication Number | Publication Date |
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| CN100496606C true CN100496606C (en) | 2009-06-10 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108524939A (en) * | 2018-07-01 | 2018-09-14 | 中国药科大学 | Mitochondrial complex I reversible inhibitors combine the purposes for preparing ischemical reperfusion injury protection drug with active oxygen scavenger |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101889975A (en) * | 2010-07-27 | 2010-11-24 | 北京虹湾医药技术有限公司 | Rosuvastatin calcium sustained-release preparation and preparation method thereof |
| CN108114282B (en) * | 2016-11-28 | 2021-03-02 | 北京大学第三医院 | Use of statins for treating ischemic diseases |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108524939A (en) * | 2018-07-01 | 2018-09-14 | 中国药科大学 | Mitochondrial complex I reversible inhibitors combine the purposes for preparing ischemical reperfusion injury protection drug with active oxygen scavenger |
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