CN101347434B - Medicament composition containing renin inhibitor and acidum folicum compound and uses thereof - Google Patents
Medicament composition containing renin inhibitor and acidum folicum compound and uses thereof Download PDFInfo
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- CN101347434B CN101347434B CN2007101200166A CN200710120016A CN101347434B CN 101347434 B CN101347434 B CN 101347434B CN 2007101200166 A CN2007101200166 A CN 2007101200166A CN 200710120016 A CN200710120016 A CN 200710120016A CN 101347434 B CN101347434 B CN 101347434B
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- pharmaceutical composition
- aliskiren
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- folic acid
- renin inhibitor
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
The invention relates to a pharmaceutical composition containing a rennin inhibitor and a folic acid compound and an application thereof, which belong to the field of pharmacology. The pharmaceutical composition comprises the pharmaceutical dose of the rennin inhibitor, the pharmaceutical dose of the folic acid compound and a pharmaceutically acceptable carrier. The invention provides an application of the pharmaceutical composition containing the rennin inhibitor and the folic acid compound in preparing drugs for preventing, treating or delaying hypertension and target organ impairment resulting from the hypertension, and also provides an application of the pharmaceutical composition in preparing drugs for lowering risks of cardiovascular and cerebrovascular events resulting from the hypertension. By implementing the pharmaceutical composition containing the rennin inhibitor and the folic acid compound and the application thereof, patients are provided with the pharmaceutical composition with specific applications, which can improve compliance of patients, is convenient for patients to take, lower medical expenses and has better market prospect.
Description
Technical field
The present invention relates to a kind of medical composition and its use that contains renin inhibitor and folacin compound, belong to pharmaceutical field.
Background technology
RAS (RAS) is one of most important blood pressure regulating system, and it is made up of a series of hormones and corresponding enzyme, through the control to blood volume and Peripheral resistance, regulates human blood-pressure, fluid and electrolyte balance.RAS does not exist only in blood circulation, has local RAS in many tissues, in many physiology and pathological process, plays an important role.The medicine of anti-RAS comprises renin inhibitor, angiotensin-convertion enzyme inhibitor (ACEI), angiotensin receptor antagonist (ARB), aldosterone receptor antagonist.ACEI is confirmed to have to bring high blood pressure down by large-scale clinical trial, reverses the effect of ventricular hypertrophy, reduces myocardial infarction and congestive heart failure case fatality rate.Last link of ARB blocking-up RAS, clinical trial confirm and can bring high blood pressure down, and alleviate trunk atherosclerosis and the incidence rate and the case fatality rate that reduce the cardiovascular diseases.But because ACEI and ARB all can not block RAS fully, and ACEI is not high to the specificity of RAS; Possibly influence the metabolism of Kallidin I and prostaglandin; Can cause untoward reaction such as cough, therefore, research RAS first link---the feritin blocade has significance.
The beginning rotating ring joint of feritin (Aspartic Acid protease) catalysis RAS, and to the specificity of the original height of angiotensin, promptly hypertensinogen is its unique catalytic substrate, so renin inhibitor is used as the target of a research for a long time.Early stage feritin blocade, like enalkiren (enalkiren), remikiren (remikiren), enalkiren (enalkiren), remikiren (remikiren), ditekiren (ditekiren), terlakiren (terlakiren), zankiren (zankiren).The SPP800 series of the SPP600 series of calendar year 2001 Ho.mann-La Roche development and Speedel development in 2005 belongs to non-peptide class second filial generation renin inhibitor; Owing to made full use of based on the drug design of structure theoretical; Compound activity and pharmaco-kinetic properties are greatly improved, and in zoopery, have high bioavailability.
(Aliskiren also is the oral non-peptide class renin inhibitor of the second filial generation SPP100) to aliskiren, can effectively bring high blood pressure down and treats related cardiovascular disease.Aliskiren and endogenous feritin are combined closely competitively, and mechanism of action is mainly: aliskiren is dose dependent ground and reduces RA, stops the generation of Ang I and Ang II, can not cause increasing of hypertensinogen level; Aldosterone level in reducing blood plasma and urinating; Promote natruresis, and kaliuresis is constant.
The aliskiren structure is open by in detail in EP678503A, has following chemical formula (I):
The renin inhibitor chemical name of formula (I) is 2 (S), 4 (S), 5 (S); (3-amino-2 for 7 (S)-N-; 2-dimethyl-3-oxopropyl)-2,7-two (1-Methylethyl)-4-hydroxyl-5-amino-8-[4-methoxyl group-3-(3-methoxyl group-propoxyl group) phenyl]-caprylamide, preferably its hemifumarate.
About the patent situation that contains the aliskiren renin inhibitor following: publication number is that the patent of CN1655819A discloses a kind of pharmaceutical composition that comprises renin inhibitor, calcium channel blocker and diuretic, and the application people is a Novannis company; Publication number is that the patent of CN1656058A discloses a kind of renin inhibitor and ARB, ACEI, beta-blocker, calcium channel blocker, aldosterone synthetase inhibitors, aldosterone receptor antagonist, the coupling combination of diuretic; Publication number is that the patent of CN1882528A discloses a kind of organic compound, relates to renin inhibitor and antidiabetic drug, lipid lowerers, appetrol, the coupling combination of depressor; Publication number is that the patent of CN1474690A discloses a kind of concertedness drug combinations that contains renin inhibitor that is used to treat cardiovascular disease, relates to the cooperative programs of a kind of renin inhibitor or its officinal salt, comprises renin inhibitor and AT
1-receptor antagonist, HMG-Co-A reductase inhibitor, ACEI, calcium channel blocker, aldosterone synthase inhibitors, aldosterone antagonists, the coupling combination of diuretic.
Also there is weak point in aliskiren in treatment hypertension and relevant disease thereof, the aliskiren list can stimulate a kind of compensatory reflection with treatment, and the partial offset blood pressure reduces, and is reduced to ideal value thereby hinder blood pressure.The modal untoward reaction of aliskiren is weak, gastrointestinal reaction or headache.Aliskiren also has much room for improvement to the curative effect of target-organ protection aspect.Because treatment hypertensive patient's main purpose is to reduce cardiovascular diseases's death and invalid total danger to greatest extent; Suitable aliskiren compound preparation not only can reduce the untoward reaction of aliskiren; Improve efficacy of antihypertensive treatment; Also can improve the target organ protection function of aliskiren, the risk of the cardiovascular and cerebrovascular vessel incident that reduction hypertension causes to the hyperpietic.Therefore, the aliskiren compound preparation of developing suitable prescription has the important clinical meaning.
Summary of the invention
The objective of the invention is to overcome the above-mentioned deficiency that renin inhibitor depressor exists, a kind of compound hypertension medicine that aspect target-organ protection, is superior to renin inhibitor is provided, and the pharmaceutical composition that side effect does not increase.
For realizing above-mentioned purpose, the present invention adopts following technical scheme:
A kind of pharmaceutical composition comprises:
(1) renin inhibitor of pharmaceutical dosage;
(2) folacin compound of pharmaceutical dosage;
(3) acceptable carrier on the pharmaceutics.
Above-mentioned renin inhibitor is aliskiren (Aliskiren), ditekiren (ditekiren), terlakiren (terlakiren), zankiren (zankiren), SPP600, or SPP800.
The preferred aliskiren of above-mentioned renin inhibitor.
The pharmaceutical dosage of above-mentioned renin inhibitor is 100～600mg.
The folacin compound of above-mentioned pharmaceutical dosage is folic acid, calcium folinate or levoleucovorin calcium, and dosage is 0.2-1.6mg, preferred 0.4-1.0mg.
We use in the research process of medicine of the present invention to hypertension therapeutic, emphatically to target-organ protection and the dangerous aspect of reduction cardiovascular and cerebrovascular vessel incident.This be because: if hypertension do not control effectively; Continue several Nian Houke and cause the tiny arteriosclerosis of whole body, become stiff and lack flexibility, tube chamber narrows down; The VPV that is delivered to tissue slows down, and causes important organs such as the heart, brain, kidney, eye to damage and cisco unity malfunction.The target organ damage that hypertension causes comprises left ventricular hypertrophy, optimum arteriolar nephrosclerosis, pernicious arteriolar nephrosclerosis, renal failure, retinal arteriosclerosis or hypertension retinopathy.The cardiovascular and cerebrovascular vessel incident comprises angina pectoris, myocardial infarction, heart failure, cerebral infarction or cerebral hemorrhage, and wherein cerebral infarction and cerebral hemorrhage close the title apoplexy.Controlling of blood pressure is bad, target organ damage can occur, if blood pressure can not get further control, causes the generation of cardiovascular and cerebrovascular vessel incident when serious.Therefore, treatment hypertensive patient's main purpose is to reduce the death of cardiovascular and cerebrovascular disease and invalid total danger to greatest extent, and target-organ protection and blood pressure lowering develop simultaneously, and are the cores of hypertension therapeutic.
Discover that pharmaceutical composition provided by the invention not only has hypotensive effect and also has target organ protection function; When renin inhibitor and folacin compound are share, can work in coordination with the intensifier target organ protection, and its protective effect is better than and singly use renin inhibitor depressor, also be better than singly and use folacin compound, difference all has statistical significance.
Further, in experiment, we find; When renin inhibitor and folacin compound are share, can work in coordination with that to reduce the cardiovascular and cerebrovascular vessel incident dangerous, and its effect is better than single renin inhibitor depressor of using; Also be better than list and use folacin compound, difference all has statistical significance.
Therefore, the invention provides pharmaceutical composition that the folacin compound of renin inhibitor and the pharmaceutical dosage of above-mentioned pharmaceutical dosage forms is used for preventing, treating or delay hypertensive medicine in preparation purposes; The present invention provides this pharmaceutical composition to be used for preventing, treat or delay the purposes of the medicine of the target organ damage that hypertension causes in preparation; The target organ damage that hypertension causes comprises left ventricular hypertrophy, optimum arteriolar nephrosclerosis, pernicious arteriolar nephrosclerosis, renal failure, retinal arteriosclerosis or hypertension retinopathy.The present invention also provides this pharmaceutical composition to be used for reducing the purposes of the dangerous medicine of cardiovascular and cerebrovascular vessel incident that hypertension causes in preparation; Wherein reduce cardiovascular and cerebrovascular vessel incident danger and be meant the incidence rate that reduces angina pectoris, myocardial infarction, heart failure, cerebral infarction or cerebral hemorrhage, reduce the incidence rate that cardiovascular and cerebrovascular vessel incident danger also refers to reduce apoplexy.
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition; Can be made into common oral preparation; Comprise conventional tablet, capsule, granule etc.; Said pharmaceutically acceptable carrier includes excipient and the accessory drugs that helps reactive compound is mixed with pharmaceutical formulation when processing tablet; Compositions like one or more materials of starch, microcrystalline Cellulose, inorganic salts, sucrose, dextrin, lactose, Icing Sugar, glucose, sodium chloride, cysteine, citric acid and sodium sulfite etc. belongs to this area general knowledge.
The dosage form of this pharmaceutical composition include but not limited to conventional tablet, bilayer tablet, multilayer tablet, slow releasing tablet, single chamber controlled release tablet, two chambers controlled release tablet, pore type controlled release tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, enteric coatel tablets, granule, pill, enteric coated capsule, delayed-release tablet, regularly/position releasing piece, conventional capsule, slow releasing capsule, controlled release capsule, contain micropill or small pieces capsule, contain the dosage forms such as pH dependent form capsule, granule, oral liquid, membrane or patch of micropill or small pieces, wherein preferred tablet, capsule or granule.
According to the present invention, pharmaceutical composition also can be meant the medicine box that contains two independent medicines.When " pharmaceutical composition " was meant the medicine box that contains two independent medicines, above-mentioned " Combined drug box " was a kind of case type container, the drug regimen of built-in multiple dosage form, and take description, " Combined drug box " more is applicable to personalized medicine; First medicine is a renin inhibitor, contains folacin compound in second medicine.In this medicine box two independently medicine can concomitant dosing, also can be in a kind of pharmaceutical preparation or in the different drug preparation sequential administration.
The invention has the beneficial effects as follows: pharmaceutical composition provided by the invention has obvious synergism, and its synergism is target organ damage and the collaborative cardiovascular and cerebrovascular vessel incident danger that reduces that ability coordinating protection hypertension causes.Therefore; The invention provides pharmaceutical composition that the folacin compound of renin inhibitor and the pharmaceutical dosage of above-mentioned pharmaceutical dosage forms and be used for preventing, treat or delay the purposes of the medicine of the target organ damage that hypertension, hypertension causes in preparation, the present invention also provides this pharmaceutical composition to be used for reducing the purposes of the dangerous medicine of cardiovascular and cerebrovascular vessel incident that hypertension causes in preparation.Through enforcement of the present invention, the pharmaceutical composition that offers this special-purpose of patient can improve patient's compliance, and the patient is taken medicine conveniently, reduces medical expense, has better market prospect.
Below in conjunction with the specific embodiment the present invention is further specified, the experiment support of pharmacological action sees the following specific embodiment for details.
The specific embodiment
Embodiment 1: aliskiren+folic acid is to the protective effect of spontaneous hypertensive rat (SHR) blood pressure lowering and target organ damage
The SHR rat; Body weight 150～180g; Be equally divided into 6 groups; Every group 20, be respectively model group, aliskiren+folic acid (15+0.04mg/kg) group, aliskiren+folic acid (15+0.08mg/kg) group, aliskiren+folic acid (15+0.16mg/kg) group, aliskiren (15mg/kg) group, folic acid (0.08mg/kg) group, other gets 20 normal rats as the normal control group.Wait capacity 0.5%CMC solution, weigh weekly once, according to body weight adjustment dose, 20 weeks of successive administration.
Detect index:
(1) measure before the administration respectively and different time Mus tail systolic pressure, relatively blood pressure difference between each group after the administration.
(2) collect urine, with the turbidimetry for Determination urine protein, put the method for exempting from and measure 24h and urinate α 1 microglobulin; Get blood, measure serum creatinine, calculate creatinine clearance rate (Ccr).
(3) myocardium hydroxyproline determination is got left ventricular free wall cardiac muscular tissue; Be prepared into cardiac muscular tissue's homogenate of 10%, press hydroxyproline testing cassete description, digestion method is measured myocardium hydroxyproline content; Press collagen content=hydroxyproline content * 7.46, be converted into collagen content.
(4) the conventional section of cardiac muscular tissue, Sirius is red-picric acid dyeing, measures myocardial collagen fraction by volume (CVF) and myocardial vascular area of collagen (PVCA) on every side.CVF is the ratio of the area of collagen and the myocardium gross area, and wherein area of collagen does not comprise PVCA, and its average is got in 5 visuals field of stochastic analysis.PVCA measures 4 ratios that are arteriolar surrounding area and tube chamber area in the cross section wall for each BIAO and BEN, gets its average.
(5) small artery is observed through abdominal aortic cannulation in the kidney, and behind the abundant blood vessel dilating of 0.1mg/ml sodium nitroprusside, the formalin with 10% is poured into fixing under 10～12kPa; Separate left kidney; The place cuts kidney from the hilus renalis, places 4% formaldehyde fixing, conventional dehydration, FFPE, transverse section, HE dyeing.Choosing external diameter under the optical microscope is the interior small artery of kidney of 50～100 μ m, measures small artery internal diameter, wall thickness in the kidney, calculated wall thickness internal diameter ratio.Each BIAO and BEN is measured 4 and is small artery in the cross section wall, gets its meansigma methods.
Measurement data representes that with x ± s data statistics is handled and adopted the SPSS10.0 statistical package, relatively adopts the t check between two groups.
The result:
(1) aliskiren+folic acid compared with normal rats the 20th weekend that influenced of SHR hypertensive rat blood pressure, and model group rat systolic pressure significantly raises; Compare with model group, folic acid group rat systolic pressure makes moderate progress, and (0.04～0.16mg/kg) group rat systolic pressure all significantly reduces aliskiren group and aliskiren (15mg/kg)+various dose folic acid; But compare with aliskiren folk prescription group, the blood pressure lowering amplitude of aliskiren+various dose folic acid group rat systolic pressure does not significantly change.See table 1.
(2) aliskiren+folic acid compares the influence and the normal rats of SHR Hypertensive Rats renal function, and model group rat urine 24h α 1-microglobulin, urine protein significantly raise, and Ccr obviously reduces.Compare with model group, aliskiren group rat urine 24h α 1-microglobulin, urine protein significantly reduce, and Ccr significantly raises.Compare with the aliskiren group, (0.04～0.16mg/kg) group rat Ccr's aliskiren+various dose folic acid further raises, and 24h α 1-microglobulin, urine protein further reduce.Show that aliskiren has protective effect to the early stage renal function injury that the SHR Hypertensive Rats occurs, folic acid and aliskiren share, and the protecting renal function effect of SHR Hypertensive Rats is significantly strengthened, and see table 2.
Table 1 aliskiren+folic acid is to the influence of SHR Hypertensive Rats systolic pressure (mmHg) (X ± SD)
Compare with normal group,
*P<0.05,
*P<0.01; Compare with model group,
▲P<0.05,
▲ ▲P<0.01
Table 2 aliskiren+folic acid is to the influence of SHR Hypertensive Rats renal function (X ± SD)
Compare with normal group,
*P<0.01; Compare with model group,
▲P<0.05,
▲ ▲P<0.01; Compare with the aliskiren group,
★P<0.05
(3) aliskiren+folic acid compares the influence and the normal rats of area of collagen (PVCA) around SHR Hypertensive Rats myocardial collagen protein content and myocardial collagen fraction by volume (CVF) and the myocardial vascular; Model group rat heart muscle collagen content; Fibrosis index PVCA all significantly increases around cardiac muscle interstitial fibrosis index CVF, the myocardial vascular; CVF and PVCA raise almost synchronous, show that myocardium interstitial fibrosis participated in the pathological process of Hypertensive Rats cardiac remodeling.Compare with model group, aliskiren group rat heart muscle collagen content, myocardium CVF, PVCA all significantly reduce.Compare with aliskiren (15mg/kg) group; (0.04～0.16mg/kg) group rat heart muscle collagen content and myocardium CVF, PVCA further reduce aliskiren (15mg/kg)+various dose folic acid, with aliskiren (15mg/kg) folk prescription group significant difference are arranged relatively.Show that folic acid and aliskiren share, the Hypertensive Rats myocardium protecting action is strengthened.See table 3.
Table 3 aliskiren+folic acid is to the influence of area of collagen (PVCA) around SHR Hypertensive Rats myocardial collagen protein content, myocardial collagen fraction by volume (CVF) and the myocardial vascular (X ± SD)
Compare with normal group,
*P<0.01; Compare with model group,
▲P<0.05,
▲ ▲P<0.01; Compare with the aliskiren group,
★P<0.05
(4) aliskiren+folic acid changes the arteriolar blood vessel that influences Hypertensive Rats in the SHR Hypertensive Rats kidney, mainly shows as the fibrosis of blood vessel wall adventitia, and the tube wall middle level thickens (due to being increased by smooth muscle cell proliferation, plumpness and intercellular substance); Inner membrance vitreous degeneration, endotheli ocytosis, above-mentioned variation reduce blood vessel wall thickness/tube chamber ratio.Compare with normal rats, model group kidney of rats small artery wall thickness increases, and internal diameter reduces, and wall thickness/internal diameter is than increasing.Compare with model group, aliskiren group kidney of rats small artery wall thickness reduces, wall thickness/internal diameter ratio increases, and aliskiren+folic acid group kidney of rats small artery wall thickness further reduces, wall thickness/internal diameter increases than further, with the aliskiren group significant difference is arranged relatively.See table 4.
Table 4 aliskiren+folic acid is to (the X ± SD) of arteriolar influence in the SHR Hypertensive Rats kidney
Compare with normal group,
*P<0.01; Compare with model group,
▲ ▲P<0.01; Compare with the aliskiren group,
★P<0.05,
★ ★P<0.01
Embodiment 2: aliskiren+folic acid is to the protective effect of apoplexy susceptible type SH (SHR-SP) rat
Male SHR-SP rat is totally 60 about 8 ages in week, in conjunction with blood pressure values, is divided into model group, aliskiren+folic acid (30+0.08mg/kg) group, aliskiren (30mg/kg) group.Raising condition: 22 ± 2 ℃ of room temperatures; Relative humidity 50%; Solid feed and bedding and padding provide by Chinese Academy of Medical Sciences's laboratory animal breeding field; Drinking water is a pure water.Other establishes the WKY matched group, 20 every group.Gastric infusion is weighed weekly once every day 1 time, according to body weight adjustment dose, continuous 8 weeks.
Observation index:
(1) observe animal diet followed, survival and behavioral activity every day, a situation arises to write down each treated animal apoplexy in 8 weeks.
(2) function of nervous system's classification is with reference to function of nervous system's grade scale (Bederson, J B, the Pi tts of Bederson; L H, Tsuji.M, et al.Ratmiddle cerebral artery occlusion:Evaluation of the model anddevelopment a eurologic examination [J] .Stroke; 1986; 17 (3): 472-476.), be divided into following 5 grades, observe once weekly.
0 grade (normally): impassivity functional impairment symptom.
1 grade (slightly): forelimb is rolled up or flexing, mainly is to receive companion's ancon in persistence wrist flexing or the shoulder to stretch.
2 grades (moderate): the forelimb persistence is rolled up or flexing, receives or inward turning in visible wrist, the whole flexings of elbow, the shoulder.
3 grades (seriously): the persistence limbs are rolled up or flexing, and the anti-persistence of a side limbs thrust body weakens, and does not accompany limbs to draw the circle behavior during autonomic activities.
4 grades (very heavy): bilateral limbs persistence is rolled up or flexing, and the anti-persistence of a side limbs thrust body weakens, and occurs limbs during autonomic activities and draws the circle behavior.
(3) the desirable rat that gets pathological tissue of all surviving animals of pathological observation and dead back is all got cerebral tissue, and cerebral hemorrhage, cerebral infarction or Combination apoplexy are observed in section, HE dyeing, calculate and respectively organize the rat brain stroke incidence.Model group has 2, and the compound recipe group has 1, is eaten by other animals after 1 animal dead is arranged in the folk prescription group, fails to obtain cerebral tissue and carries out pathologic finding.
The result:
In this experimentation, obvious lethargy appears after the model group rat apoplexy, and drowsiness; Hair is fluffy, withered or come off, tarnish, weight loss, active movement obviously reduces; Be slow in action; Limbs are in various degree paralysis, and the morbidity of part rat is simultaneously with symptoms such as tic, diarrhoea, urinary incontinence, eyeball are hemorrhage, and are dead in the person of being in a bad way several hours.Most of animal nerve functional impairment of treatment group is slight than model group, and the mental status obviously is superior to model group, and autonomic activities increases, and initiatively looks for food, drinks water, and weight loss is not obvious, and hair is also glossy along sliding than model group.
There are 14 apoplexy takes place in 20 rats of model group, wherein dead 5, except that 2 animals fail in time to obtain the tissue after death at night; Other 18 animals have all carried out the histopathology observation, and totally 16 have only apoplexy that 5 of its midbrains hemorrhage take place; 6 of cerebral infarctions, 5 of Combination apoplexy.Apoplexy kitchen range and all visible on every side small artery hyaline degeneration or fibrinoid necrosis, tube wall thickens, and all oozings of blood are managed in visible microthrombusis in the luminal stenosis, the tube chamber that has.20 rats of aliskiren matched group have 12 apoplexy takes place, and wherein dead 3,1 animal fails to obtain pathological tissue, and other 19 animals have all carried out the histopathology observation, and totally 14 have only apoplexy to take place, and do not see significant difference with model group.Aliskiren+20 rats of folic acid group have 8 apoplexy takes place; When experiment finishes dead 2, wherein 1 animal fails to obtain pathological tissue, and other 19 animals have all carried out the histopathology observation; Totally 7 have only apoplexy to take place; Its apoplexy incidence rate obviously reduces, and has significance (P < 0.05) with the model control group comparing difference, sees table 5 for details.
In 4 weeks and 8 whens week, observe, and find to give function of nervous system's classification that compound recipe aliskiren folic acid (30+0.08mg/kg) can obviously improve rat (P < 0.05), see table 6 and table 7 for details.
Table 5 aliskiren+8 weeks of folic acid successive administration are to the influence of SHR-SP rat brain apoplexy (X ± SD)
x
2Check is compared with normal group,
*P<0.01; Compare with model group,
▲P<0.05; 2 of model group, 1 of compound recipe group is failed to obtain cerebral tissue behind 1 animal dead of folk prescription group and is carried out pathologic finding, in not calculating in the statistics.
Table 6 aliskiren+4 weeks of folic acid successive administration are to SHR-SP rat brain apoplexy function of nervous system size scale (only)
x
2Check is compared with normal group,
*P<0.01; Compare with model group,
▲P<0.05;
Table 7 aliskiren+8 weeks of folic acid successive administration are to SHR-SP rat brain apoplexy function of nervous system size scale (only)
x
2Check is compared with normal group,
*P<0.01; Compare with model group,
▲P<0.05;
Embodiment 3: aliskiren+calcium folinate is to blood pressure lowering and the target organ protection function of double transgenic rat (dTGR)
6 the week age human renin; 60 of angiotensin double transgenic rats (dTGR); According to blood pressure level and twenty-four-hour urine albumen situation rat is divided into model group, aliskiren+calcium folinate (15+0.10mg/kg) group, aliskiren (15mg/kg) group; Valsartan (1mg/kg) matched group is all fed with 1% saline in the experimentation.Other establishes 15 of normal control groups.Normal control group, model group such as give at capacity 0.5%CMC solution, weigh weekly once, according to body weight adjustment dose, 3 weeks of successive administration.
Detect index:
(1) each treated animal arteria caudalis systolic pressure before and after general state and the administration.
(2) dissect during off-test and core dirty and kidney, calculate organ coefficient.
(3) collect urine, survey urine protein, 24h urine α 1 microglobulin; Get blood, measure serum creatinine, calculate creatinine clearance rate (Ccr).
The result:
(1) the dTGR rat is with the growth at age, and blood pressure constantly raises.Model group animal mortality rate when 9 ages in week is 100%; Thereby add valsartan (1mg/kg) matched group in this test in the design and be used for for the 9th when week and replace model group to compare with other each groups; This dosage only can play to minimum degree blood pressure lowering and target-organ protection, is as a kind of measure that reduces the animal dead rate.During the 9th weekend off-test, in 15 animals of this group dead 4, survive 11.The rat and the normal rat survival rate that give the treatment of aliskiren (15mg/kg) and aliskiren+calcium folinate (15+0.1mg/kg) are 100%.Aliskiren folk prescription and compound recipe group blood pressure all can significantly reduce, and compare with the folk prescription group, and compound recipe group hypotensive effect unknown significance difference is seen table 8.
Table 8 aliskiren+3 weeks of calcium folinate successive administration are to the influence of dTGR rat blood pressure (mmHg) (X ± SD)
Compare with normal group,
*P<0.01; Compare with model group,
▲ ▲P<0.01; Compare for model group with valsartan,
★P<0.05
(2) dTGR Rats Organs and Tissues coefficient influenced the valsartan model group rat heart; Brain; Kidney device coefficient all obviously increases than normal treated animal, gives aliskiren (15mg/kg) and aliskiren+calcium folinate (15+0.1mg/kg), and the heart, brain, the kidney device coefficient of dTGR rat all had tangible attenuating effect; Folk prescription and compound recipe group are not seen notable difference, see table 9.
Table 9 aliskiren+3 weeks of calcium folinate successive administration are to the influence of dTGR Rats Organs and Tissues coefficient (g/100g) (X ± SD)
Compare with normal group,
*P<0.05; Compare for model group with valsartan,
▲P<0.05
(3) influence and the normal rats to dTGR kidney of rats function compares, valsartan model group rat urine 24h α
1-microglobulin, urine protein significantly raise, and Ccr obviously reduces.Compare aliskiren group rat urine 24h α with this group
1-microglobulin, urine protein significantly reduce, and Ccr significantly raises.Ccr further raises with calcium folinate combination group rat, 24h α
1-microglobulin, urine protein further reduce.Show that aliskiren has protective effect to the early stage renal function injury that the dTGR rat occurs, calcium folinate and aliskiren share, and effect significantly strengthens to protecting renal function, sees table 10.
Table 10 aliskiren+3 weeks of calcium folinate successive administration are to the influence of dTGR kidney of rats function (X ± SD)
Compare with normal group,
*P<0.01; Compare with the valsartan model group,
▲ ▲P<0.01; Compare with the aliskiren group,
★P<0.05
Embodiment 4: terlakiren+folic acid is to the protective effect of spontaneous hypertensive rat (SHR) blood pressure lowering and target organ damage
The SHR rat; Body weight 150～180g; Be equally divided into 6 groups; Every group 20, be respectively model group, terlakiren+folic acid (30+0.04mg/kg) group, terlakiren+folic acid (30+0.08mg/kg) group, terlakiren+folic acid (30+0.16mg/kg) group, terlakiren (30mg/kg) group, folic acid (0.08mg/kg) group, other gets 20 normal rats as the normal control group.Wait capacity 0.5%CMC solution, weigh weekly once, according to body weight adjustment dose, 20 weeks of successive administration.
Detect index:
(1) measure before the administration respectively and different time Mus tail systolic pressure, relatively blood pressure difference between each group after the administration.
(2) collect urine, with the turbidimetry for Determination urine protein, put the method for exempting from and measure 24h and urinate α 1 microglobulin; Get blood, measure serum creatinine, calculate creatinine clearance rate (Ccr).
(3) myocardium hydroxyproline determination is got left ventricular free wall cardiac muscular tissue; Be prepared into cardiac muscular tissue's homogenate of 10%, press hydroxyproline testing cassete description, digestion method is measured myocardium hydroxyproline content; Press collagen content=hydroxyproline content * 7.46, be converted into collagen content.
(4) the conventional section of cardiac muscular tissue, Sirius is red-picric acid dyeing, measures myocardial collagen fraction by volume (CVF) and myocardial vascular area of collagen (PVCA) on every side.CVF is the ratio of the area of collagen and the myocardium gross area, and wherein area of collagen does not comprise PVCA, and its average is got in 5 visuals field of stochastic analysis.PVCA measures 4 ratios that are arteriolar surrounding area and tube chamber area in the cross section wall for each BIAO and BEN, gets its average.
(5) small artery is observed through abdominal aortic cannulation in the kidney, and behind the abundant blood vessel dilating of 0.1mg/ml sodium nitroprusside, the formalin with 10% is poured into fixing under 10～12kPa; Separate left kidney; The place cuts kidney from the hilus renalis, places 4% formaldehyde fixing, conventional dehydration, FFPE, transverse section, HE dyeing.Choosing external diameter under the optical microscope is the interior small artery of kidney of 50～100 μ m, measures small artery internal diameter, wall thickness in the kidney, calculated wall thickness internal diameter ratio.Each BIAO and BEN is measured 4 and is small artery in the cross section wall, gets its meansigma methods.
Measurement data representes that with x ± s data statistics is handled and adopted the SPSS10.0 statistical package, relatively adopts the t check between two groups.
The result:
(1) terlakiren+folic acid compared with normal rats the 20th weekend that influenced of SHR hypertensive rat blood pressure, and model group rat systolic pressure significantly raises; Compare with model group, folic acid group rat systolic pressure makes moderate progress, and (0.04～0.16mg/kg) group rat systolic pressure all significantly reduces terlakiren group and terlakiren (30mg/kg)+various dose folic acid; But compare with terlakiren folk prescription group, the blood pressure lowering amplitude of terlakiren+various dose folic acid group rat systolic pressure does not significantly change.See table 11.
(2) terlakiren+folic acid compares the influence and the normal rats of SHR Hypertensive Rats renal function, and model group rat urine 24h α 1-microglobulin, urine protein significantly raise, and Ccr obviously reduces.Compare with model group, terlakiren group rat urine 24h α 1-microglobulin, urine protein significantly reduce, and Ccr significantly raises.Compare with the terlakiren group, (0.04～0.16mg/kg) group rat Ccr's terlakiren+various dose folic acid further raises, and 24h α 1-microglobulin, urine protein further reduce.Show that terlakiren has protective effect to the early stage renal function injury that the SHR Hypertensive Rats occurs, folic acid and terlakiren share, and the protecting renal function effect of SHR Hypertensive Rats is significantly strengthened.See table 12.
(3) terlakiren+folic acid compares the influence and the normal rats of area of collagen (PVCA) around SHR Hypertensive Rats myocardial collagen protein content and myocardial collagen fraction by volume (CVF) and the myocardial vascular; Model group rat heart muscle collagen content; Fibrosis index PVCA all significantly increases around cardiac muscle interstitial fibrosis index CVF, the myocardial vascular; CVF and PVCA raise almost synchronous, show that myocardium interstitial fibrosis participated in the pathological process of Hypertensive Rats cardiac remodeling.Compare with model group, terlakiren group rat heart muscle collagen content, myocardium CVF, PVCA all significantly reduce.Compare with terlakiren (15mg/kg) group; (0.04～0.16mg/kg) group rat heart muscle collagen content and myocardium CVF, PVCA further reduce terlakiren (15mg/kg)+various dose folic acid, with terlakiren (15mg/kg) folk prescription group significant difference are arranged relatively.Show that folic acid and terlakiren share, the Hypertensive Rats myocardium protecting action is strengthened.See table 13.
Table 11 terlakiren+folic acid is to the influence of SHR Hypertensive Rats systolic pressure (mmHg) (X ± SD)
Compare with normal group,
*P<0.05,
*P<0.01; Compare with model group,
▲P<0.05,
▲ ▲P<0.01
Table 12 terlakiren+folic acid is to the influence of SHR Hypertensive Rats renal function (X ± SD)
Compare with normal group,
*P<0.01; Compare with model group,
▲P<0.05,
▲ ▲P<0.01; Compare with the terlakiren group,
★P<0.05
Table 13 terlakiren+folic acid is to the influence of area of collagen (PVCA) around SHR Hypertensive Rats myocardial collagen protein content, myocardial collagen fraction by volume (CVF) and the myocardial vascular (X ± SD)
Compare with normal group,
*P<0.01; Compare with model group,
▲P<0.05,
▲ ▲P<0.01; Compare with the terlakiren group,
★P<0.05
(4) terlakiren+folic acid changes the arteriolar blood vessel that influences Hypertensive Rats in the SHR Hypertensive Rats kidney, mainly shows as the fibrosis of blood vessel wall adventitia, and the tube wall middle level thickens (due to being increased by smooth muscle cell proliferation, plumpness and intercellular substance); Inner membrance vitreous degeneration, endotheli ocytosis, above-mentioned variation reduce blood vessel wall thickness/tube chamber ratio.Compare with normal rats, model group kidney of rats small artery wall thickness increases, and internal diameter reduces, and wall thickness/internal diameter is than increasing.Compare with model group, terlakiren group kidney of rats small artery wall thickness reduces, wall thickness/internal diameter ratio increases, and terlakiren+folic acid group kidney of rats small artery wall thickness further reduces, wall thickness/internal diameter increases than further, with the terlakiren group significant difference is arranged relatively.See table 14.
Table 14 terlakiren+folic acid is to (the X ± SD) of arteriolar influence in the SHR Hypertensive Rats kidney
Compare with normal group,
*P<0.01; Compare with model group,
▲ ▲P<0.01; Compare with the terlakiren group,
★P<0.05,
★ ★P<0.01
Embodiment 5: the capsular preparation of aliskiren 150mg/ folic acid 0.2mg
Prescription
Preparation technology: with aliskiren 150g, folic acid 0.2g, microcrystalline Cellulose 80g, polyvinylpolypyrrolidone 44g, the polyvidon K12g back mix homogeneously of pulverizing, sieve; Process behind the soft material with 5% an amount of polyvidone k-30 aqueous solution granulate, dry, add about 1% magnesium stearate mix homogeneously, promptly get by encapsulated 1000 of conventional method.
Embodiment 6: the capsular preparation of aliskiren 300mg/ folic acid 1.6mg
Prescription
Preparation technology: with embodiment 5.
Embodiment 7: the preparation of aliskiren 150mg/ folic acid 0.4mg sheet
Prescription
Preparation technology: folic acid is crossed 80 mesh sieves, and other adjuvants are crossed behind 100 mesh sieves 75 ℃ of dryings 2 hours respectively, and are subsequent use; Accurate aliskiren, microcrystalline Cellulose, polyvinylpolypyrrolidone and the polyvidon K that claims the to decide recipe quantity mixing that sieves, subsequent use; Get the folic acid and pool Luo Samu F of recipe quantity
68Add low amounts of water, fully equivalent increases progressively good aliskiren, microcrystalline Cellulose, polyvinylpolypyrrolidone and the polyvidon K of adding premix behind the mix homogeneously, adds binding agent system soft material, and 30 mesh sieves are granulated, 60 ℃ of dry 3h; 30 order granulate add an amount of magnesium stearate mixing, tabletting behind the assay, packing.
Embodiment 8: the preparation of aliskiren 150mg/ folic acid 0.8mg sheet
Prescription
Preparation technology: with embodiment 7.
Embodiment 9: the preparation of aliskiren 300mg/ folic acid 0.4mg sheet
Prescription
Preparation technology: folic acid is crossed 80 mesh sieves, and other adjuvants are crossed behind 100 mesh sieves 75 ℃ of dryings 2 hours respectively, and are subsequent use; The mixings that sieve such as the accurate aliskiren of claiming decide recipe quantity, lactose, microcrystalline Cellulose, pregelatinized Starch, polyvinylpolypyrrolidone add binding agent system soft material, the granulation of 30 mesh sieves, 60 ℃ of dry 3h; 30 order granulate add an amount of magnesium stearate mixing, tabletting behind the assay, packing.
Embodiment 10: the preparation of aliskiren 300mg/ folic acid 0.8mg sheet
Prescription
Preparation technology: with embodiment 9.When aliskiren daily requirement consumption is 600mg, can once take like two slices/of the 300mg aliskiren preparation specifications of embodiment 6,9 or 10.
Embodiment 11: the capsular preparation of aliskiren 100mg/ folic acid 0.2mg
Prescription
Preparation technology: with aliskiren, folic acid, microcrystalline Cellulose, polyvinylpolypyrrolidone, the polyvidone back mix homogeneously of pulverizing, sieve; Be mixed and made into behind the soft material with an amount of sodium lauryl sulphate granulate, dry, add about 1% magnesium stearate mix homogeneously, promptly get by encapsulated 1000 of conventional method.
Embodiment 12: the capsular preparation of terlakiren 300mg/ folic acid 0.4mg
Prescription
Preparation technology: with embodiment 5.
Embodiment 13: the capsular preparation of zankiren 250mg/ folic acid 0.4mg
Prescription
Preparation technology: with embodiment 5.
Claims (12)
1. pharmaceutical composition comprises:
(1) renin inhibitor of pharmaceutical dosage;
(2) folacin compound of pharmaceutical dosage;
(3) acceptable carrier on the pharmaceutics, wherein said renin inhibitor are aliskiren, ditekiren, terlakiren, zankiren, SPP 600 or SPP 800.
2. pharmaceutical composition as claimed in claim 1 is characterized in that: said renin inhibitor is an aliskiren.
3. pharmaceutical composition as claimed in claim 1 is characterized in that: the pharmaceutical dosage of said renin inhibitor is 100～600mg.
4. pharmaceutical composition as claimed in claim 1 is characterized in that: the folacin compound of said pharmaceutical dosage is folic acid, calcium folinate or levoleucovorin calcium, and said dosage is 0.2～1.6mg.
5. pharmaceutical composition as claimed in claim 4 is characterized in that: said dosage is 0.4～1.0mg.
6. like arbitrary described pharmaceutical composition in the claim 1～5, it is characterized in that the pharmacy dosage form of said pharmaceutical composition is an oral formulations, comprise tablet, capsule or granule.
7. arbitrary described pharmaceutical composition is used for preventing, treating or delay the purposes of hypertensive medicine in the claim 1～5 in preparation.
8. arbitrary described pharmaceutical composition is used for preventing, treat or delay the purposes of the medicine of the target organ damage that hypertension causes in the claim 1～5 in preparation.
9. purposes as claimed in claim 8 is characterized in that: described target organ comprises left ventricular hypertrophy, optimum arteriolar nephrosclerosis, pernicious arteriolar nephrosclerosis, retinal arteriosclerosis or hypertension retinopathy.
10. arbitrary described pharmaceutical composition is used for reducing the purposes of the dangerous medicine of cardiovascular and cerebrovascular vessel incident that hypertension causes in the claim 1～5 in preparation.
11. purposes as claimed in claim 10 is characterized in that: the cardiovascular and cerebrovascular vessel incident danger that said reduction hypertension causes is meant the incidence rate that reduces angina pectoris, myocardial infarction, cerebral infarction or cerebral hemorrhage.
12. purposes as claimed in claim 10 is characterized in that: the cardiovascular and cerebrovascular vessel incident danger that said reduction hypertension causes is meant the incidence rate that reduces apoplexy.
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| WO2005025673A1 (en) * | 2003-09-08 | 2005-03-24 | Franco Folli | Multi-system therapy for diabetes, the metabolic syndrome and obesity comprising a hypoglycemic agent |
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| Title |
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| 吕玲春等.新型肾素阻滞药--阿利吉仑.医药导报25 3.2006,25(3),255-256. |
| 吕玲春等.新型肾素阻滞药--阿利吉仑.医药导报25 3.2006,25(3),255-256. * |
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