CN102631357B - Composite tablet of valsartan and hydrochlorothiazide and preparation method thereof - Google Patents
Composite tablet of valsartan and hydrochlorothiazide and preparation method thereof Download PDFInfo
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Abstract
The invention provides a composite tablet of valsartan and hydrochlorothiazide, and the composite tablet is prepared from valsartan, hydrochlorothiazide, phosphatidylcholine, magnesium carbonate, magnesium carbonate, starch, hydroxy propyl cellulose, powered sugar and silica, wherein the valsartan, the hydrochlorothiazide and the phosphatidylcholine are active ingredients. According to the composite tablet provided by the invention, the absorption capability of the active ingredients is stronger, and the therapeutic effect to the primary hypertension is better; and moreover, the composite tablet can be used for protecting the liver, and meanwhile has therapeutic effects to the left ventricular hypertrophy caused by hypertension.
Description
Technical field
The present invention relates to a kind of pharmaceutical preparation, relate in particular a kind of valsartan and hydrochlorothiazide pharmaceutical composition tablet and preparation method thereof.
Technical background
About hypertension (Hypertension) guideline of prevention and treatment, uncomplicated patients with hypertension target blood pressure need be controlled in ﹤ 140/90mmHg according to ESH/ESC; Complication with diabetes, nephropathy or other high risk factors (such as cerebrovascular accident or myocardial infarction) patient's target blood pressure need be controlled in ﹤ 130/80mmHg.For reaching above-mentioned therapeutic goal value, present most of hypertension guide all advises uniting two kinds of depressor of use in initial therapy.Yet, many studies show that under two depressor therapeutic schemes, 1/3 patients with hypertension of only having an appointment can reach target.
Chinese patent application publication number CN101780090A discloses the tablet of the lucky smooth and hydrochlorothiazide of a kind of figured silk fabrics, a kind of bilayer tablet that contains valsartan and hydrochlorothiazide 80mg/12.5mg with Synergistic Hypotensive Effects is provided, and valsartan provided by the invention/hydrochlorothiazide 80mg/12.5mg compares curative effect with the compound recipe monolayer Tablet and Capsula of valsartan/hydrochlorothiazide 80mg/12.5mg and increases.It is characterized in that it is bilayer tablet configuration, one deck is the valsartan layer, is comprised of 80mg valsartan, 312mg microcrystalline Cellulose, 60mg polyvinylpolypyrrolidone, 6mg silica sol and 18mg magnesium stearate; Another layer is the hydrochlorothiazide layer, is comprised of 12.5mg hydrochlorothiazide, 400.4mg microcrystalline Cellulose, 28mg primojel, 0.2mg iron oxide red and 2.9mg magnesium stearate.China Patent Publication No. be CN101972263A patent disclosure valsartan hydrochlorothiazide pharmaceutical composition liposome solid preparation, its method for making and can not fully control application in the medicine of light, Moderate Essential Hypertension of blood pressure at preparation treatment single medicine.Described valsartan and Hydrochlorothiade medicine compound liposome mainly comprises valsartan, hydrochlorothiazide, S-PC acyl serine, natrii tauroglycocholas, tween 80.Above-mentioned patent provides the drug regimen of the lucky smooth and hydrochlorothiazide of figured silk fabrics, and the adjustment by dosage form improves the drug absorption of the lucky smooth and hydrochlorothiazide of figured silk fabrics, improves curative effect.Although publication number is to mention S-PC acyl serine and phosphatidylcholine in the patent of CN101972263A, do not have activity but disclose S-PC acyl serine in the application documents, S-PC acyl serine and phosphatidylcholine are a kind of adjuvant in preparation.
Summary of the invention
Research is found, valsartan is potent specificity AT1 receptor antagonist, energy selective exclusion AT1 receptor, but can reduce the again effect of antagonism Ang II stimulating growth of pressure load, thiazide diuretic and valsartan have good synergism, diuretic has activated the RAS system on the one hand, and valsartan then suppresses the RAS system; Slight guarantor's potassium effect of valsartan has reduced again the possible low potassium side effect of thiazide diuretic on the other hand, so both share and have both strengthened hypotensive effect.The effect that phosphatidylcholine has emulsifying, cuts grease, can promote blood circulation, improve serum lipids, remove peroxide, make Blood Cholesterol and neutral fat content, reduce fat in the holdup time of blood vessel, promote the dissipation of atherosis speckle, prevent the tunica intima damage that is caused by cholesterol.Take phosphatidylcholine hyperlipidemia and hypercholesterolemia are had significant effect, thereby can prevent and treat the arteriosclerosiss such as hypertension, myocardial infarction, cerebral hemorrhage.In addition, phosphatidylcholine not only can prevent fatty liver, can also promote liver cell regeneration, and simultaneously, phosphatidylcholine can reduce serum cholesterol content, prevents liver cirrhosis and helps liver and the recovery of renal function.This drug regimen is lowering blood pressure, in the time of the diseases such as treatment diabetic hypertension, essential hypertension, can also repair the hepar damnification that causes because of diseases such as diabetic hypertension and essential hypertensions.In order to address the above problem, the invention provides the tablet that a kind of active component is valsartan, hydrochlorothiazide and phosphatidylcholine; Concrete summary of the invention is:
A kind of valsartan and hydrochlorothiazide pharmaceutical composition tablet, the prescription of described medicinal tablet are valsartan, hydrochlorothiazide, phosphatidylcholine, magnesium carbonate, starch, hydroxypropyl cellulose, Icing Sugar and silicon dioxide; Wherein, valsartan, hydrochlorothiazide and phosphatidylcholine are active component.
Described valsartan: hydrochlorothiazide: phosphatidylcholine: magnesium carbonate: starch: hydroxypropyl cellulose: Icing Sugar: the weight ratio of silicon dioxide is 20～60:3～25:80～150:80～150:30～60:30～60:30～60:2～7.
Described valsartan: hydrochlorothiazide: phosphatidylcholine: magnesium carbonate: starch: hydroxypropyl cellulose: Icing Sugar: the weight ratio of silicon dioxide is 32:6:100:1O0:40:40:40:3.5.
The preparation method of above-mentioned valsartan and hydrochlorothiazide pharmaceutical composition tablet, for valsartan, hydrochlorothiazide, magnesium carbonate, starch, hydroxypropyl cellulose, Icing Sugar are dry mixed 2O minute, then the phosphatidylcholine that adds dissolve with ethanol, wet mixing 15 minutes is granulated with 16 order nylon mesh, aeration-drying below 65 ℃ 4～6 hours. with 14 order ferrum sieve granulate, add silicon dioxide, be mixed, through using after the assay was approved dark strong stamping, coating and get final product.
The application of above-mentioned tablet in the left ventricular hypertrophy disease that the preparation treatment causes because of hypertension.
Useful technique effect of the present invention is: medicinal composition tablets provided by the invention, the effective ingredient absorbability is stronger, and is better for the therapeutic effect of essential hypertension, for having protected liver, has therapeutical effect for the left ventricular hypertrophy disease that causes that causes because of hypertension simultaneously.
The specific embodiment
Embodiment 1
The preparation method of a kind of valsartan and hydrochlorothiazide pharmaceutical composition tablet is investigated
Studies have shown that valsartan is white powder; Odorless, tasteless.Easily molten in methanol, in chloroform, dissolve, almost insoluble in water; Hydrochlorothiazide is white crystalline powder; Odorless, mildly bitter flavor.This product is dissolved in acetone, and slightly soluble in ethanol is insoluble in water, chloroform or ether; In sodium hydroxide solution, dissolve; The phosphatidylcholine odorless or slightly nut gas hide.Meet air and photo-labile, it is water insoluble, is insoluble in acetone, acetate, is partially soluble in ethanol, ether, chloroform.Meet oxidant, stronger acid, the reactions such as alkali generation oxidation, decomposition also can be by esterase hydrolyzed.Containing according to phosphatidylcholine itself has this situation of a certain amount of oils and fats, makes absorbent with magnesium carbonate, and the magnesium carbonate oil absorption is strong, stable chemical nature.Substantially water insoluble and other solvent of magnesium carbonate salt according to making water show alkalescence, can be dissolved in diluted acid and produce bubble, and is stable under dry air and illumination.Make diluent and filler, usually consumption≤45%.The magnesium carbonate consumption is about 10% in this preparation.
Take by weighing valsartan 32g, hydrochlorothiazide 6g, phosphatidylcholine lOOg, magnesium carbonate 1O0g, starch 40g, DEXTRIN g, Icing Sugar 40g, 95% ethanol 20g, magnesium stearate 3.5g are dry mixed 2O minute with adjuvant magnesium carbonate, starch, dextrin, Icing Sugar, then add phosphatidylcholine ethanol liquid, wet mixing 15 minutes was granulated with 16 order nylon mesh, at aeration-drying 4-6 below 65 ℃ hour. with 14 order ferrum sieve granulate, add magnesium stearate, be mixed, through using after the assay was approved dark strong stamping, coating and get final product.Manufacture experimently altogether 1000.Obtain experimental group 1.
Research finds that the granule of experimental group 1 is through after the assay was approved, with the trial-production of one-shot tablet machine.It is poor mobility of particle to occur in the tabletting process, moisture absorption sticking phenomenon.Slice, thin piece is loose, the sled lid, and difficult forming, the substrate of compacting is cooked slaking test, and disintegration is 35 minutes.Not meeting substrate all should disintegrate in l5 minute.
According to the problem that above trial-production occurs, we have changed partial supplementary material, have used medicinal new material, hydroxypropyl cellulose, silicon dioxide (silica gel).Hydroxy propyl cellulose have strong hydrophilic, and swelling degree is slightly soluble in cold water very much in cold water.This specific character makes tablet have adhesive property in pressing process.Can be used as binding agent and disintegrating agent.Its consumption is 2-10%, in add, all can add.Silicon dioxide is that the trickle amorphous powder of white odorless hygroscopicity is water insoluble, ethanol and other organic solvent, also is insoluble to acid, is dissolved in hot hydroxide alkali liquor.In pharmacy, mainly make disintegrating agent, antiplastering aid, fluidizer.Internal desiccant etc.
Claim valsartan 32g, hydrochlorothiazide 6g, phosphatidylcholine 100g, magnesium carbonate 1O0g, starch 40g, hydroxypropyl cellulose 40g, Icing Sugar 40g, 95% ethanol 20g, silicon dioxide 3.5g, as stated above film-making is manufactured experimently 1000 altogether.Obtain medicine group I.
Through changing adjuvant, granule is through after the assay was approved, tabletting, and mobility of particle is good, the slice, thin piece easy-formation, hardness is qualified, and outward appearance is better, without sticking, sliver phenomenon.Measuring the substrate disintegration is 1O minute, meets the requirement of substrate disintegrate in 15 minutes.The use of new material has greatly improved mobility of particle and has improved bulk density. and the tablet hardness that makes is increased, shortened disintegration, very high drug-eluting speed.A series of difficult problems such as molding, hardness, loose sheet, the sled that has solved tablet covers, disintegrate is transfinited.
The preparation of embodiment 2 valsartan and hydrochlorothiazide pharmaceutical composition tablet
Take by weighing respectively valsartan 20g, hydrochlorothiazide 25g, phosphatidylcholine 150g, magnesium carbonate 1O0g, starch 40g, hydroxypropyl cellulose 40g, Icing Sugar 40g, 95% ethanol 20g, silicon dioxide 3.5g, as stated above film-making is manufactured experimently 1000 altogether.Take the preparation method of embodiment 1 described medicine group I to obtain medicine group II.
Take by weighing respectively valsartan 60g, hydrochlorothiazide 3g, phosphatidylcholine 80g, magnesium carbonate 1O0g, starch 40g, hydroxypropyl cellulose 40g, Icing Sugar 40g, 95% ethanol 20g, silicon dioxide 3.5g, as stated above film-making is manufactured experimently 1000 altogether.Take the preparation method of embodiment 1 described medicine group I to obtain medicine group III.
3 pairs of Renoprotective Effects of embodiment are investigated
12 week spontaneous hypertensive rat in age (SHR) 40,10 of Wistar.Kyoto of the same age (WKY) rats, be male, SHR is divided into 3 groups at random, SHR matched group (10) SHR drug treatment group (10) and SHR valsartan matched group (10 and SHR valsartan and hydrochlorothiazide matched group (10), elder generation's adaptability is fed 3d, then the valsartan matched group gives valsartan 30 mg/ (kgd) gavage, the contrast of SHR valsartan and hydrochlorothiazide gives the gavage of the mixture of valsartan 22 mg and hydrochlorothiazide 8mg/(kgd), the SHR medication therapy groups adopts embodiment 1 described medicine group I according to valsartan content 15mg/ (kgd), SHR matched group and WKY organize and give equivalent distilled water gavage every day, 2 kinds of rats all breed the center available from Chinese Academy of Medical Sciences's laboratory animal, all feed with normal diet, feed for 12 weeks+put to death simultaneously behind the 3d, detect.
Respectively at gathering blood before the experiment behind the rat eye socket, the heart blood sampling added anticoagulant tube when experiment finished, and the centrifugal 5min censorship of 3000r/min detects blood urea nitrogen (BUN), creatinine (Scr), collected rat 24h urine with metabolic cage simultaneously, urine β
2-microglobulin (β 2-MG) adopts urine β 2-MG radioimmunological kit (Chinese Research Institute of Atomic Energy Sciences) to detect.
The nephridial tissue specimen is fixed through 10% neutral formalin, paraffin embedding, be cut into 3 μ m slabs, respectively after dimethylbenzene dewaxing, classification ethanol aquation, press the operation of sP method test kit, primary antibodie is respectively goat-anti rat CTGF polyclonal antibody, and two anti-are the anti-sheep monoclonal antibody of rabbit, haematoxylin redye, dewater mounting, observation after the DAB colour developing.The Microscopic observation cell, with cell cytosol and between pipe week matter the brown color positive signal that dyes appears.
The SABC semi-quantitative analysis of nephridial tissue CTGF adopts image analysis software, amplifies the kidney cortical area of 400 times of images in each specimen and chooses successively 5 visuals field, and the depth and the scope at stained positive position represent with average optical.
Adopt the SPSS statistical software, data relatively adopts the t check between 5 groups.The expression of CTGF is adopted the analysis of spearman rank correlation with the dependency of urine trace albumin in the nephridial tissue.Concrete outcome is as shown in table 1.
The comparison of 5 groups of rat different phases of table 1 blood pressure (
± s mmHg)
Compare with other groups
*P ﹤ 0.01 is relatively front with experiment
△P ﹤ 0.05
After 12 weeks, compare the blood pressure of SHR matched group obviously raise (P＜0.01) with the SHR medication therapy groups with WKY group.Each organizes rat urine β 2-MG, change in renal function is as shown in table 2.
Urinate β before and after 5 groups of rat experiments of table 2 and after 12 weeks
2-MG, change in renal function (
± s)
Relatively front with the experiment of WKY group
*P ﹤ 0.05 and rear WKY of 12 weeks organize and the SHR group compares
△P ﹤ 0.01 is relatively front with the experiment of SHR medication therapy groups
△ △P ﹤ 0.05
5 groups of rat CTGF expression and β 2-MG and rat tail artery pass between pressing in kidney ties up to the SHR matched group, prolongation along with the hypertension persistent period, the expression of kidney CTGF obviously increases, simultaneously, urine β 2-MG also increases, and comparing difference with the WKY group with the SHR medication therapy groups has significance (P＜0.01).The expression of urine β 2-MG and kidney CTGF is proportionate (r=0.783, P＜0.05), with the tail arterial blood pressure of the rat (r=0 that also is proportionate.723，P<0.05)。Concrete outcome is as shown in table 3.
The expression of table 3 CTGF in each group rat kidney and urine β
2Relation between-MG and rat tail artery are pressed (
± s)
Relatively front with the experiment of WKY group
*P ﹤ 0.01 compares with the SHR medication therapy groups
△ △P ﹤ 0.01
Normal rat glomerule, renal tubules only have micro-CTGF to express, and at the SHR matched group, CTGF expresses obviously to be increased, be distributed widely in the epithelial cell endochylema from proximal tubule to MCD, also can see the expression of CTGF in some downright bad exfoliative cyte, SHR medication therapy groups CTGF positive expression then obviously reduces.
Chronic to advance property row nephropathy be an important behaviour of primary hypertension patient target organ damage, also is clinical one of the most important disease of renal failure in latter stage that causes.Spontaneous hypertensive rat is similar to human essential hypertension, is the good animal model of research hypertension and target organ damage thereof.
Trace albumin is drained the early signal that increase is the target organs of patients with essential hypertension infringement in the urine, and blood BUN and Scr generally just reflect the index of middle and advanced stage change in renal function, in addition, albuminuria is the initial signal that renal damage occurs, and also is the principal element that promotes that renal function further worsens.Because albuminuria can aggravate the infringement of glomerule conversely, both mutually promote, and As time goes on, will cause at last the change of middle and advanced stage renal function.Studies confirm that, during hypertension in the nephridial tissue Ang II level obviously increase, and the Ang II plays an important role in the process of albuminuretic generation and renal fibrosis.The confirmations such as Wolf also can stimulate TGF-β in kidney cell Ang II
1Synthetic, find that again the Ang II can make TGF-β
1The expression of mRNA raises.Oemar etc. and Igarashi etc. find TGF-β in fibroblast and vascular smooth muscle cell
1But specificity is induced the expression of CTGF mRNA, and it can stimulate cellular proliferation and extracellular matrix synthetic, is TGF-β
1The downstream effect medium.It has only mediated TGF-β
1Negative effect, assemble such as ECM etc.So CTGF is with regard to TGF-β capable of blocking in blocking-up
1Negative effect, and do not affect TGF-β
1Positive effect, thereby explanation will be than for TGF-β for the treatment of CTGF
1Treatment have more prospect.Valsartan is to act at present the strongest Ang II receptor antagonist (ARB), and AT is mainly passed through in its physiology and pharmacological action
1Receptor plays a role.The effect of ARB mainly is blocking-up AT
1Receptor-mediated reaction, thereby the TGF-β that blocking-up Ang II is induced
1Expression raise and the increase of urine trace albumin the performance Renoprotective Effect.
Originally studies show that SHR contrast association urinates the obvious increased perosn's kidney of β 2-MG CTGF expression and also obviously increases, and CTGF expresses and urine β 2-MG is remarkable positive correlation.And SHR medication therapy groups and WKY group are not accompanied urine β 2-MG increased perosn, and kidney CTGF expresses and do not increase, and expression and the SHR matched group kidney target organ damages of prompting kidney CTGF are closely related.This explanation valsartan may be the TGF-β that induces by blocking-up Ang II
1Expression raise, thereby indirect TGF-β
1Induce the expression of CTGF to increase and the performance Renoprotective Effect.
In a word, along with hypertensive continuous action, the expression of SHR matched group compared with normal group and treatment group kidney CTGF all significantly increases, and with urine β
2-MG increases closely related, and urine β
2The increase of-MG is again the early signal of target organs of patients with essential hypertension infringement.Therefore, further study the mechanism that CTGF participates in early nephropathy, will have important clinical meaning for generation and the development of the renal damage of prevention and control caused by hypertension.
The comparison of embodiment 4 blood pressure lowerings and reversing left ventricular hypertrophy effect
30 SHR are divided into 5 groups at random, and 6 every group, 1 group is matched group, and all the other 4 groups is the medication group.The medication group be respectively give valsartan 8mg/ (kgd) as the mixture mg/ (kgd) of SHR valsartan matched group, valsartan 8mg and hydrochlorothiazide 2mg as SHR valsartan and hydrochlorothiazide matched group and with embodiment 1 described medicine group I according to valsartan content 8mg/ (kgd) as the SHR medication therapy groups.Rat plain particles forage feed.Add respectively medicine with gavage behind a certain amount of normal saline morning 9 o'clock every day.Matched group and WKY group are all used 4 weeks of equivalent normal saline gavage.
Before experiment with after 4 weeks of medication, survey respectively arteria caudalis systolic pressure and the body weight (body weight, BW) of rat.In drug withdrawal time daily 2% penthiobarbital 40mgkg
-1The intraperitoneal injection anesthetized rat, sacrificed by decapitation, take out immediately heart, with giving cold normal saline row aorta retroperfusion flushing, remove the trunk undesirable root, take by weighing wet heart weight (heart weight, HW) behind the filter paper suck dry moisture, calculate the ratio (HW/BW) of wet heart weight and body weight.Get again 0.5cm * 0 5cm cardiac muscle piece from cross section, left ventricle stage casing, place fixedly 24-48h of 10% formalin.Then, make the thick tissue slice of 4 μ m, HE dyeing.Select nuclear myocardial cell placed in the middle to measure cell transverse diameter (transverse diame-ter of myocyte, TDM) with the micrometering instrument under light microscopic, 20 cells are surveyed in every section at random, get its average.
Adopt the SPSS statistical software, data are used
± S represents that the significance of mean difference adopts non-matching f check between group, the relatively employing paired t-test of data before and after the medication.The blood pressure of each group of SHR all is significantly higher than WKY group (P＜0.01) before the variation medication of SHR and WKY blood pressure, the difference not statistically significant of blood pressure between each group of SHR (P〉0.05).
After 4 weeks of medication, the blood pressure of SHR matched group raises but there was no significant difference before to some extent, and still highly significant is higher than WKY group (P＜0.01).The blood pressure of medication group is respectively than the reduction that highly significant is arranged before the medication (P＜0.01), wherein SHR valsartan matched group is similar with the amplitude of hydrochlorothiazide matched group blood pressure lowering with the SHR valsartan, and the Amplitude of Hypotensive of medicine SHR medication therapy groups more obvious (with front two groups than P＜0.01), concrete outcome is as shown in table 4.
Before and after table 4 medication each group and WKY group blood pressure relatively (
± s)
The WKY group compares with each group before the medication
*Compare before and after P＜0.01 medication
*Compare with other two groups before and after P＜0.01 medicine group medication
△P＜0.01
With HW, HW/BW and TDM reaction left ventricular hypertrophy, there are no significant the difference (P＜0.05) of the BW between each group of SHR and WKY and SHR; The HW of matched group SHR is significantly higher than w KY (P＜0.05), and Hw/BW and TDM all are higher than wKY (P＜0.01) significantly.
SHR valsartan and hydrochlorothiazide matched group, HW in SHR valsartan matched group and the SHR medication therapy groups, HW/BW and TDM all are lower than matched group to some extent, wherein HW/the BW of the TDM of SHR valsartan and hydrochlorothiazide matched group and SHR valsartan matched group has statistical significance (one-side t check P＜0.05) with matched group than difference, the TDM of SHR valsartan matched group has significant (P＜0.05) with matched group than difference, yet each index of SHR valsartan matched group and SHR valsartan and hydrochlorothiazide matched group is asked difference there are no significant meaning (P〉0.05); Valsartan group (24 mgkg
-1) HW/BW and TDM and matched group between all have highly significant difference (P＜0.01), and with SHR valsartan matched group significant difference (P＜0.05) is arranged, concrete outcome is as shown in table 5.
Table 5 WKY group and administration respectively organize the LVH index relatively (
± s n=6)
Compare with matched group
*P ﹤ 0.05 P ﹤ 0.01
This result of study shows that the pressure reduction effect of SHR valsartan matched group is similar with the hydrochlorothiazide matched group with the SHR valsartan, and the effect that alleviates LVH is then slightly inferior; The SHR medication therapy groups shows obvious blood pressure lowering and reverses the LVH effect, and significantly is better than SHR valsartan matched group.These results suggest: HR valsartan matched group and SHR valsartan and hydrochlorothiazide matched group all have the effect that reverses LVH in blood pressure lowering.
Embodiment 5 Renoprotective Effects investigate 2
Adopt embodiment 3 described methods, embodiment 2 protection of medicine group II to kidney that provide is provided, concrete outcome is as shown in table 6.
The comparison of 5 groups of rat different phases of table 6 blood pressure (
± s mmHg)
Compare with other groups
*P ﹤ 0.01 is relatively front with experiment
△P ﹤ 0.05
After 12 weeks, compare the blood pressure of SHR matched group obviously raise (P＜0.01) with the SHR medication therapy groups with WKY group.Each organizes rat urine β 2-MG, change in renal function is as shown in table 7.
Urinate before and after 5 groups of rat experiments of table 7 and after 12 weeks β 2-MG, change in renal function (
± s)
Relatively front with the experiment of WKY group
*P ﹤ 0.05 and rear WKY of 12 weeks organize and the SHR group compares
△P ﹤ 0.01 is relatively front with the experiment of SHR medication therapy groups
△ △P ﹤ 0.05
5 groups of rat CTGF expression and β 2-MG and rat tail artery pass between pressing in kidney ties up to the SHR matched group, and along with the prolongation of hypertension persistent period, the expression of kidney CTGF obviously increases, simultaneously, and urine β
2-MG also increases, and comparing difference with the WKY group with the SHR medication therapy groups has significance (P＜0.01).Urine β
2The expression of-MG and kidney CTGF is proportionate (r=0.783, P＜0.05), with the tail arterial blood pressure of the rat (r=0 that also is proportionate.723，P<0.05)。Concrete outcome is as shown in table 8.
The expression of table 8 CTGF in each group rat kidney and urine β
2Relation between-MG and rat tail artery are pressed (
± s)
Relatively front with the experiment of WKY group
*P ﹤ 0.01 compares with the SHR medication therapy groups
△ △P ﹤ 0.01
The cumulated volume experimental studies results shows: the experiment conclusion of medicine group II is close with embodiment 3 described experiment conclusion.
The investigation 2 of embodiment 6 blood pressure lowerings and reversing left ventricular hypertrophy effect
Adopt the hypotensive effect of the method investigation embodiment 2 described medicine group II identical with embodiment 4 and to the reverse effect of left ventricular hypertrophy effect.
After 4 weeks of medication, the blood pressure of SHR matched group raises but there was no significant difference before to some extent, and still highly significant is higher than WKY group (P＜0.01).The blood pressure of medication group is respectively than the reduction that highly significant is arranged before the medication (P＜0.01), wherein SHR valsartan matched group is similar with the amplitude of hydrochlorothiazide matched group blood pressure lowering with the SHR valsartan, and the Amplitude of Hypotensive of medicine SHR medication therapy groups more obvious (with front two groups than P＜0.01), concrete outcome is as shown in table 9.
Before and after table 9 medication each group and WKY group blood pressure relatively (
± s)
The WKY group compares with each group before the medication
*Compare before and after P＜0.01 medication
*Compare with other two groups before and after P＜0.01 medicine group medication
△P＜0.01
With HW, HW/BW and TDM reaction left ventricular hypertrophy, there are no significant the difference (P＜0.05) of the BW between each group of SHR and WKY and SHR; The HW of matched group SHR is significantly higher than w KY (P＜0.05), and Hw/BW and TDM all are higher than wKY (P＜0.01) significantly.
SHR valsartan and hydrochlorothiazide matched group, HW in SHR valsartan matched group and the SHR medication therapy groups, HW/BW and TDM all are lower than matched group to some extent, wherein HW/the BW of the TDM of SHR valsartan and hydrochlorothiazide matched group and SHR valsartan matched group has statistical significance (one-side t check P＜0.05) with matched group than difference, the TI of SHR valsartan matched group) M has significant (P＜0.05) with matched group than difference, yet each index of SHR valsartan matched group and SHR valsartan and hydrochlorothiazide matched group is asked difference there are no significant meaning (P〉0.05); Valsartan group (24 mgkg
-1) HW/BW and TDM and matched group between all have highly significant difference (P＜0.01), and with SHR valsartan matched group significant difference (P＜0.05) is arranged, concrete outcome is as shown in table 10.
Table 10 WKY group and administration respectively organize the LVH index relatively (
± s n=6)
Compare with matched group
*P ﹤ 0.05 P ﹤ 0.01
The cumulated volume experimental studies results shows: the experiment conclusion of medicine group II is close with embodiment 3 described experiment conclusion.
Embodiment 7 Renoprotective Effects investigate 3
Adopt embodiment 3 described methods, embodiment 2 protection of medicine group III to kidney that provide is provided, concrete outcome is as shown in table 11.
The comparison of 5 groups of rat different phases of table 11 blood pressure (
± s mmHg)
Compare with other groups
*P ﹤ 0.01 is relatively front with experiment
△P ﹤ 0.05
After 12 weeks, compare the blood pressure of SHR matched group obviously raise (P＜0.01) with the SHR medication therapy groups with WKY group.Each organizes rat urine β
2-MG, change in renal function are as shown in table 12.
Urinate β before and after 5 groups of rat experiments of table 12 and after 12 weeks
2-MG, change in renal function (
± s)
Relatively front with the experiment of WKY group
*P ﹤ 0.05 and rear WKY of 12 weeks organize and the SHR group compares
△P ﹤ 0.01 is relatively front with the experiment of SHR medication therapy groups
△ △P ﹤ 0.05
5 groups of rat CTGF expression and β in kidney
2Pass between-MG and rat tail artery are pressed ties up to the SHR matched group, and along with the prolongation of hypertension persistent period, the expression of kidney CTGF obviously increases, simultaneously, and urine β
2-MG also increases, and comparing difference with the WKY group with the SHR medication therapy groups has significance (P＜0.01).Urine β
2The expression of-MG and kidney CTGF is proportionate (r=0.783, P＜0.05), with the tail arterial blood pressure of the rat (r=0 that also is proportionate.723，P<0.05)。Concrete outcome is as shown in table 13.
The expression of table 13 CTGF in each group rat kidney and urine β
2Relation between-MG and rat tail artery are pressed (
± s)
Relatively front with the experiment of WKY group
*P ﹤ 0.01 compares with the SHR medication therapy groups
△ △P ﹤ 0.01
The cumulated volume experimental studies results shows: the experiment conclusion of medicine group III is close with embodiment 3 described experiment conclusion.
The investigation 3 of embodiment 6 blood pressure lowerings and reversing left ventricular hypertrophy effect
Adopt the hypotensive effect of the method investigation embodiment 2 described medicine group III identical with embodiment 4 and right
The reverse effect of left ventricular hypertrophy effect.
After 4 weeks of medication, the blood pressure of SHR matched group raises but there was no significant difference before to some extent, and still highly significant is higher than WKY group (P＜0.01).The blood pressure of medication group is respectively than the reduction that highly significant is arranged before the medication (P＜0.01), wherein SHR valsartan matched group is similar with the amplitude of hydrochlorothiazide matched group blood pressure lowering with the SHR valsartan, and the Amplitude of Hypotensive of medicine SHR medication therapy groups more obvious (with front two groups than P＜0.01), concrete outcome is as shown in table 14.
Before and after table 14 medication each group and WKY group blood pressure relatively (
± s)
The WKY group compares with each group before the medication
*Compare before and after P＜0.01 medication
*Compare with other two groups before and after P＜0.01 medicine group medication
△P＜0.01
With HW, HW/BW and TDM reaction left ventricular hypertrophy, there are no significant the difference (P＜0.05) of the BW between each group of SHR and WKY and SHR; The HW of matched group SHR is significantly higher than w KY (P＜0.05), and Hw/BW and TDM all are higher than wKY (P＜0.01) significantly.
SHR valsartan and hydrochlorothiazide matched group, HW in SHR valsartan matched group and the SHR medication therapy groups, HW/BW and TDM all are lower than matched group to some extent, wherein HW/the BW of the TDM of SHR valsartan and hydrochlorothiazide matched group and SHR valsartan matched group has statistical significance (one-side t check P＜0.05) with matched group than difference, the TDM of SHR valsartan matched group has significant (P＜0.05) with matched group than difference, yet each index of SHR valsartan matched group and SHR valsartan and hydrochlorothiazide matched group is asked difference there are no significant meaning (P〉0.05); Valsartan group (24 mgkg
-1) HW/BW and TDM and matched group between all have highly significant difference (P＜0.01), and with SHR valsartan matched group significant difference (P＜0.05) is arranged, concrete outcome is as shown in Table 15.
Table 15 WKY group and administration respectively organize the LVH index relatively (
± s n=6)
Compare with matched group
*P ﹤ 0.05 P ﹤ 0.01
The cumulated volume experimental studies results shows: the experiment conclusion of medicine group III is close with embodiment 3 described experiment conclusion.
Claims (4)
1. a valsartan and hydrochlorothiazide pharmaceutical composition tablet, it is characterized in that: the prescription of medicinal tablet is valsartan, hydrochlorothiazide, phosphatidylcholine, magnesium carbonate, starch, hydroxypropyl cellulose, Icing Sugar and silicon dioxide; Wherein, valsartan, hydrochlorothiazide and phosphatidylcholine are active component;
Described valsartan: hydrochlorothiazide: phosphatidylcholine: magnesium carbonate: starch: hydroxypropyl cellulose: Icing Sugar: the weight ratio of silicon dioxide is 20～60:3～25:80～150:80～150:30～60:30～60:30～60:2～7.
2. valsartan according to claim 1 and hydrochlorothiazide pharmaceutical composition tablet, it is characterized in that: described valsartan: hydrochlorothiazide: phosphatidylcholine: magnesium carbonate: starch: hydroxypropyl cellulose: Icing Sugar: the weight ratio of silicon dioxide is 32:6:100:100:40:40:40:3.5.
3. the preparation method of the arbitrary described valsartan of claim 1-2 and hydrochlorothiazide pharmaceutical composition tablet, it is characterized in that: preparation method is for to be dry mixed 20 minutes with valsartan, hydrochlorothiazide, magnesium carbonate, starch, hydroxypropyl cellulose, Icing Sugar, then the phosphatidylcholine that adds dissolve with ethanol, wet mixing 15 minutes is granulated with 16 order nylon mesh, at aeration-drying 4-6 below 65 ℃ hour, with 14 order ferrum sieve granulate, add silicon dioxide, be mixed, use the deep-draw tabletting through after the assay was approved, coating and get final product.
4. the arbitrary described valsartan of claim 1-2 and the hydrochlorothiazide pharmaceutical composition tablet application in the left ventricular hypertrophy disease medicine that the preparation treatment causes because of hypertension.
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| CN1732952A (en) * | 2005-09-02 | 2006-02-15 | 姚俊华 | Compound dispersible tablet for treating hypertension |
| CN101396366A (en) * | 2007-09-25 | 2009-04-01 | 浙江华海药业股份有限公司 | Solid oral preparation containing valsartan and preparation method thereof |
| CN101780090A (en) * | 2010-02-09 | 2010-07-21 | 鲁南贝特制药有限公司 | tablet containing valsartan and hydrochlorothiazide |
| CN101972263A (en) * | 2010-09-13 | 2011-02-16 | 海南美兰史克制药有限公司 | Valsartan hydrochlorothiazide pharmaceutical composition liposome solid preparation |
| CN102247376A (en) * | 2011-08-15 | 2011-11-23 | 北京赛科药业有限责任公司 | Compound solid preparation of valsartan and hydrochlorothiazide, and preparation method thereof |
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|---|---|---|---|---|
| CN1732952A (en) * | 2005-09-02 | 2006-02-15 | 姚俊华 | Compound dispersible tablet for treating hypertension |
| CN101396366A (en) * | 2007-09-25 | 2009-04-01 | 浙江华海药业股份有限公司 | Solid oral preparation containing valsartan and preparation method thereof |
| CN101780090A (en) * | 2010-02-09 | 2010-07-21 | 鲁南贝特制药有限公司 | tablet containing valsartan and hydrochlorothiazide |
| CN101972263A (en) * | 2010-09-13 | 2011-02-16 | 海南美兰史克制药有限公司 | Valsartan hydrochlorothiazide pharmaceutical composition liposome solid preparation |
| CN102247376A (en) * | 2011-08-15 | 2011-11-23 | 北京赛科药业有限责任公司 | Compound solid preparation of valsartan and hydrochlorothiazide, and preparation method thereof |
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