CN104324377B - A kind of composite antihypertensive preparation and its application - Google Patents

Abstract

The present invention provides a kind of pharmaceutical composition for treating hypertension, it is characterised in that component includes：（1）Angiotensin Ⅱ receptor antagonist；（2）Diuretics metolazone；（3）Pharmaceutically acceptable auxiliary material.Wherein the part by weight of Angiotensin Ⅱ receptor antagonist and metolazone is 20~200：0.5~10.The two is combined, and strengthens Synergistic Hypotensive Effects, is reduced adverse reaction, is improved the compliance of patient；Medication crowd is wide, and the patient of the serious infringement of renal function can be used.Suitable for the secondary hypertension caused by light, Moderate Essential Hypertension, particularly kidney damage.

Description

A kind of composite antihypertensive preparation and its application

Technical field

The present invention relates to drug field, and in particular to Angiotensin Ⅱ receptor antagonist and metolazone for effectively into The pharmaceutical composition divided and its application.

Background technology

With the rapid growth of China's economy, the drastic change of people life style, cardiovascular disease turns into threatens human health Maximum killer.Hypertension is one of current most common angiocardiopathy, it has also become the great public health in global range Problem.Shown according to national hygiene department's statistics, to the end of the year 2010, China patients with hypertension crowd is up to 200,000,000 people, and often Year newly-increased more than 3,000,000.Hypertension is one kind with body circulation arterial systolic blood pressure（SBP）With（Or）Diastolic pressure（DBP）Raise as spy The infringement of the target organs such as the heart, brain, kidney that the clinical syndrome levied, especially hypertension are excited, has a strong impact on life-span and the life of patient Bioplasm amount.

The medicine for the treatment of hypertension has many kinds at present, and the more commonly used has calcium-channel antagonists（CCBs）, β-acceptor resistance Stagnant dose, angiotensin converting enzyme inhibitors（ACEI）, Angiotensin Ⅱ receptor antagonist（ARBs）, the class medicine of diuretics five Thing, but single medicine treatment hypertension is more difficult in a short time up to standard, and Most patients need to take two or more antihypertensives Object space can reach that decompression target, especially blood pressure exceed desired value 20/10mmHg patient.Drug combination is hypertension therapeutic Preferred option, is depressured by different mechanism, complements one another, prevent the cancellation mechanism after single medicine dosage；Different peak Effect times It is medication combined can extend the antihypertensive effect time, reduce adverse reaction, so as to strengthen the protective effect to target organ.But it is several Medicine is taken simultaneously, and patient compliance is poor, and the dosage of several drugses is the problem of arrange in pairs or groups due to formulation dosage and doctor recognizes Know degree, be frequently not the proportioning of optimization.With raising drug compliance the need in order to meet hyperpietic, make different It is that compound preparation has turned into the Main way that domestic and international medicine is looked forward to competitively chasing with the drug development of mechanism.

Angiotensin Ⅱ receptor antagonist（ARB）It is a class novel antihypertensive medicament, was described as 20th century 90 years For a milestone of cardiovascular drugs.From side effect angle, it has higher than conventional drug for hypertension Security.Renin-angiotensin system during hypertension（RAS）Excessive activation, the angiotensinⅡ excessively generated（AngⅡ） Just start to play illeffects after combining with angiotensin-ii-receptor.Research have shown that angiotensin-ii-receptor be divided into AT1, Two kinds of AT2, Ang II mainly acts on AT1 acceptors, causes blood pressure rise, damage target organ.For this link, scientist opens Sent out Angiotensin Ⅱ receptor antagonist, ARB be exactly with the competitive contention AT1 of Ang II, by block angiotensinⅡ and AT1 combination, so as to play a part of decompression protection target organ.And ARB can also indirect activation AT2, cause vasodilation, subtract Negligent dirty burden.Angiotensin Ⅱ receptor antagonist medicine can be used while albuminuria, protection can be played The effect of kidney, reduces the high filtration state of glomerulus inner high voltage, and its mechanism of action increases urine volume, row's sodium row's chlorine increase, and Improve the blood perfusion of kidney, improve protein, lipid and carbohydrate metabolism disturbance in kidney trouble, it is a certain degree of to reduce urine egg In vain.Such as：Valsartan, Telmisartan, Irbesartan etc..

Japanese Hypertension Guideline in 2009,《Chinese hypertension prevention and control guide 2010》Recommend, angiotensin-ii-receptor Antagonist and diuretics are widely used in hyperpietic as the preferred option of drug combination.Diuretics had been depressured Unfavorable aspect in journey is activation renin-angiotensin-aldosterone system, and this can strengthen ARB to renin-angiotensin on the contrary The blocking effect of element-RAAS, so that more strong antihypertensive effect is produced, and also ARB has the work of slight rise blood potassium There is row's potassium effect with, diuretics, the two influence to blood potassium can cancel each other.The ARB listed at present combines answering for diuretics Square preparation has Valsartan/Hydrochioro, Telmisartan/Hydrochioro, Losartan Potassium/Hydrochioro, Irbesartan/esodrix Piperazine, olmesartan medoxomil/Hydrochioro etc., wherein diuretics is entirely Hydrochioro.And Hydrochioro can disturb tubular excretion Uric acid, minority can induce gout breaking-out；To severe renal hypothyroid, drug accumulation can be caused when heavy dose is used, toxicity increases, It should use with caution, so clinically in the urgent need to a kind of new diuretics to reduce its adverse reaction.

Metolazone (Metolazone) is a kind of Thiazoling type derivative, with diuretic antihypertensive effect, the same thiazine of drug effect Class diuretics is similar, and the effect of its natriuretic diuretic is 10 times of Hydrochioro, but unrestraint carbonic anhydrase is acted on, to internal soda acid Balance is significant.This product oral absorption is rapid, but not exclusively (about 64%), some cardiac's absorptivities are 40%.Extensively General and plasma protein and erythrocyte binding, plasma half-life about 8h.There is diuresis in 1h after medication, continues 12~24h.Mei Tuo Draw the adverse reaction of ancestor similar to Hydrochioro, occur palpitaition, pectoralgia, room individually and quiver, but be different from Hydrochioro, will not make Renal blood flow and glomerular filtration rate(GFR reduction, serious kidney function damage person still apply.

One entitled《Nanoparticulate candesartan formulations》Chinese invention patent（Publication number：CN101132770A）It is open A kind of pharmaceutical composition of Candesartan, said composition is used to treat hypertension or related cardiovascular disorders comprising one or more The compound of trouble, is directed to metolazone（Zaroxolyn®）.The composition being previously mentioned in the document, is mainly used The feature of Candesartan nanoparticle, improves the dissolution rate and bioavilability of Candesartan, and then improves its effect.In patent Do not mentioned medication crowd, it is known that Candesartan to the patient of hepatosis there is a possibility that deterioration of liver function, clinic makes With should be very careful, the patient of serious kidney function damage should also be used with caution.Rational prescription should improve the curative effect of medicine, again Toxic side effect is reduced, therefore seeks suitable Angiotensin Ⅱ receptor antagonist species, is combined with metolazone and compound is made Preparation, be clinical application in the urgent need to.So present invention exploitation one kind is using metolazone as diuretics, with angiotensinⅡ The compound preparation of receptor antagonist composition, it is secondary caused by light, moderate essential hypertension, particularly kidney damage for treating Property hypertension.

The content of the invention

The technical problem to be solved in the present invention is to provide reasonable recipe, the composite antihypertensive preparation of ratio optimization, to increase it Synergy, reduces adverse reaction and toxic action.

The present invention is by substantial amounts of experiment discovery, Angiotensin Ⅱ receptor antagonist, such as Valsartan, Telmisartan and strategic point Bei Shatan and metolazone are in the ratio range of doses, with good synergy and blood pressure lowering effect.It is applied to Gently, the secondary hypertension caused by moderate essential hypertension, particularly kidney damage.

Therefore, the technical scheme is that a kind for the treatment of containing Angiotensin Ⅱ receptor antagonist and metolazone The pharmaceutical composition of hypertension.

The pharmaceutical composition of the treatment hypertension, it is characterised in that contain Angiotensin Ⅱ receptor antagonist, Mei Tuo Draw ancestor and pharmaceutically acceptable auxiliary material.

Wherein, count by weight, the ratio of two components is Angiotensin Ⅱ receptor antagonist：Metolazone be 1~ 500：0.1~50；It is preferred that Angiotensin Ⅱ receptor antagonist：Metolazone is 20~200：0.5~10.

Described Angiotensin Ⅱ receptor antagonist is Losartan, Valsartan, Telmisartan, Irbesartan, Aomei sand One or more kinds of mixtures of smooth, eprosartan and its physiologically acceptable salt or ester.

Described Angiotensin Ⅱ receptor antagonist is preferably Valsartan, Telmisartan, Irbesartan and its physiologically One or more kinds of mixtures of acceptable salt or ester.

Wherein, the pharmaceutically acceptable auxiliary material is selected from adhesive, filler, disintegrant, lubricant, glidant, bag One or more kinds of mixtures of clothing material and other auxiliary materials etc..

Described adhesive can be distilled water, ethanol, starch slurry, sodium carboxymethylcellulose, hydroxypropyl cellulose, methyl Cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, PVP, syrup, rubber cement etc..

Described filler can be starch, Icing Sugar, dextrin, lactose, amylum pregelatinisatum, microcrystalline cellulose, inorganic salts And mannitol etc..

Described disintegrant can be dried starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crosslinked polyethylene pyrrole Pyrrolidone, Ac-Di-Sol, gas-producing disintegrant etc..

Described lubricant can be magnesium stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycols and magnesium laurylsulfate Deng.

Described glidant can be superfine silica gel powder, talcum powder etc..

Described coating material can be hydroxypropyl methyl cellulose, hydroxypropyl cellulose, acrylic resin VI, poly- second Alkene pyrrolidone, ethyl cellulose, cellulose acetate etc..

Other described auxiliary materials can be plasticizer, opacifier etc., plasticizer such as propane diols, castor oil, polyethylene glycol, silicon Oil, glycerine, repefral or dibutyl ester etc., opacifier such as titanium dioxide etc..

In addition, the present invention, which also provides a kind of described pharmaceutical composition, is preparing the purposes in being used to treat hypertension drug. Wherein, described hypertension is the secondary hypertension caused by light, moderate essential hypertension, particularly kidney damage.

The preparation method of involved pharmaceutical composition in the present invention, its preparation should be selected from, but not limited to, following steps： Crush, sieve, weighing, adding the processes such as adhesive, granulation, drying, total mixed, tabletting or filling.Wherein adhesive can be outer Plus, Nei Jia or interior it is additional；Granulation can be dry granulation or wet granulation；Drying can be vacuum drying, spray drying, freezing Dry, pneumatic conveying drying or fluidized drying；Tabletting can be direct tablet compressing or pelletizing press sheet.

The pharmaceutical composition of the present invention, by the group for selecting suitable Angiotensin Ⅱ receptor antagonist and diuretics Close, strengthen Synergistic Hypotensive Effects, reduce adverse reaction, improve the compliance of patient, medication crowd is wide, serious to renal function to damage Harmful patient can be used.The present invention pharmaceutical composition be particularly suitable for use in gently, Moderate Essential Hypertension, particularly kidney damage Secondary hypertension caused by evil.

Brief description of the drawings Fig. 1 is influence of the different pharmaceutical combination to spontaneous hypertensive rat blood pressure.

Embodiment

The present invention is further illustrated below by embodiment.It should be understood that product and the preparation of the embodiment of the present invention Method is only used for the explanation present invention, rather than limitation of the present invention, to present invention production under the concept thereof of the present invention The simple modifications of product and preparation method belong to the scope of protection of present invention.Unless otherwise indicated, in the present invention " % " is equal It is quality criteria.

Because the active constituents of medicine that Valsartan or its pharmaceutically useful salt or ester play therapeutic action is identical, therefore following implementation Valsartan can be regarded as Valsartan or its pharmaceutically useful salt or ester in example.Equally, Telmisartan, Candesartan also should be managed so Solution.

Effect example 1：Angiotensin Ⅱ receptor antagonist and metolazone drug regimen are big to spontaneous hypertension Mouse hypertension resists effect and Renoprotective Effect experiment

1st, experimental animal and experiment packet

Male spontaneously hypertensive rat 140, body weight 250g ± 20g adapt to after raising one week, are randomly divided into 14 groups, Every group 10.

（1）Model control group：Gavage gives same volume physiological saline；

（2）Metolazone group：0.05mg/kg*d

（3）Valsartan group：7.5mg/kg*d

（4）Irbesartan group：14mg/kg*d

（5）Telmisartan group：3.7mg/kg*d

（6）Metolazone+Valsartan group：0.05mg/kg*d+7.5mg/kg*d

（7）Metolazone+Irbesartan group：0.05mg/kg*d+14mg/kg*d

（8）Metolazone+Telmisartan group：0.05mg/kg*d+3.7mg/kg*d

（9）Hydrochioro+Valsartan group：1.2mg/kg*d+7.5mg/kg*d

（10）Hydrochioro+Irbesartan group：1.2mg/kg*d+14mg/kg*d

（11）Hydrochioro+Telmisartan group：1.2mg/kg*d+3.7mg/kg*d

（12）Indapamide+Valsartan group：0.25 mg/kg*d+7.5mg/kg*d

（13）Indapamide+Irbesartan group：0.25mg/kg*d+14mg/kg*d

（14）Indapamide+Telmisartan group：0.25mg/kg*d+3.7mg/kg*d

2nd, test method：Once, totally 4 weeks, receptacle temperature control was wet at 25 DEG C or so for the daily gastric infusion of each group every Degree 45% ~ 65%.BP-2006A intelligence non-invasive blood pressure measurings（Beijing is soft grand）Tail arterial blood pressure under rat waking state is measured, it is every after administration Determine blood pressure three times in week, average.It the results are shown in Table 1.Each group rat before administration one day and experiment terminate last natural gift It is not placed in metabolic cage and raises, collects 12h urines overnight and detect microdose urine protein with immunoturbidimetry（MA）To be used as kidney Dirty damage mark, the results are shown in Table 2.

3rd, experimental result：

The different pharmaceutical of table 1 combines the influence to spontaneous hypertensive rat blood pressure（X ± S, n=10）(mmHg)

Group	Before treatment	Treat one week after	Treat two weeks after	Three weeks after treatment	Surrounding after treatment
						1	170±6.9	172±8.8	173±10.6	176±7.4	175±11.2
2	171±12.6	164±8.3	162±9.4	154±6.9	152±10.2
						3	173±11.8	170±12.4	166±6.8	157±9.7	155±7.9
4	169±8.5	165±9.4	163±7.0	160±8.1	156±5.9
						5	172±6.2	166±9.4	164±11.1	159±9.9	155±7.9
6	173±8.4	160±5.6	147±9.5	136±7.2	130±6.3*#
						7	170±7.3	161±3.5	144±8.9	133±6.2	128±7.7*#
8	169±11.5	158±7.9	148±10.2	135±10.6	131±5.5*#
						9	166±12.4	160±5.9	153±10.8	148±8.6	144±4.8*#
10	171±8.6	164±7.9	158±8.9	150±6.8	147±8.9*#
						11	170±7.2	162±11.8	155±9.1	152±9.8	148±4.3*#
12	172±6.2	164±5.8	154±6.6	150±4.5	145±8.1*#
						13	169±7.2	161±3.9	156±7.7	151±5.9	149±7.3*#
14	171±5.3	164±5.7	154±9.4	150±4.8	147±6.9*#

*：P is compared with model control group<0.05; #：Compare p with before itself treatment<0.05；

By 6-14 groups drug regimen it can be seen from table 1 and Fig. 1 relative to there is obvious antihypertensive effect before treatment, relative to Model control group blood pressure measurement is also respectively provided with significant difference, meanwhile, 6,7,8 groups of drug regimens be substantially better than 9-14 group medicines again Thing is combined, it is seen then that drug regimen metolazone of the present invention and the compound of Sha Tan classes are than Hydrochioro and the compound and hydrogen of Sha Tan classes The compound that chlorothiazide or indapamide combine husky smooth class is more preferable on antihypertensive effect.

The different pharmaceutical of table 2 combines the influence to spontaneous hypertensive rat Microalbuminuria（X ± S, n=10）

（Unit：ug/ml）

Group	Before treatment	After treatment
			1	82.3±7.3	135.2±13.9
2	92.4±14.3	99.5±8.4
			3	89.5±14.9	92.5±8.0
4	88.6±9.6	87.7±10.3
			5	94.3±7.3	87.6±12.5
6	89.5±10.2	48.2±5.9*#
			7	93.7±7.6	52.3±6.8*#
8	97.4±10.1	49.2±7.3*#
			9	98.6±7.3	94.2±7.6
10	84.6±12.9	87.5±15.6
			11	91.2±10.6	84.3±9.4
12	89.3±9.5	90±11.2
			13	92.7±8.8	89.4±10.8
14	96.7±7.6	91.5±8.3

*：P is compared with model control group<0.05; #：Compare p with before itself treatment<0.05

Result above finds out, drug regimen 6 of the present invention, 7,8 groups relative to other groups to significantly reduce rat urine micro white Protein level, points out its protective effect over the course for the treatment of to kidney injury best.

Effect example 2：Different pharmaceutical ratio pair in Angiotensin Ⅱ receptor antagonist and metolazone drug regimen Hypertension in spontaneous hypertensive rats resists effect experiment

1st, experimental animal and experiment packet

Male spontaneously hypertensive rat 100, body weight 250g ± 20g adapt to after raising one week, are randomly divided into 10 groups, Every group 10.

1. model control group：Gavage gives same volume physiological saline；

2. metolazone+Valsartan group：0.05mg/kg*d+7.5mg/kg*d

3. metolazone+Valsartan group：0.04mg/kg*d+9mg/kg*d

4. metolazone+Valsartan group：0.06mg/kg*d+6mg/kg*d

5. metolazone+Irbesartan group：0.05mg/kg*d+14mg/kg*d

6. metolazone+Irbesartan group：0.04mg/kg*d+17mg/kg*d

7. metolazone+Irbesartan group：0.06mg/kg*d+11mg/kg*d

8. metolazone+Telmisartan group：0.05mg/kg*d+3.7mg/kg*d

9. metolazone+Telmisartan group：0.04mg/kg*d+4.2mg/kg*d

10. metolazone+Telmisartan group：0.06mg/kg*d+3.0mg/kg*d

2nd, test method：Once, totally 4 weeks, receptacle temperature control was wet at 25 DEG C or so for the daily gastric infusion of each group every Degree 45% ~ 65%.BP-2006A intelligence non-invasive blood pressure measurings（Beijing is soft grand）Tail arterial blood pressure under rat waking state is measured, it is every after administration Determine blood pressure three times in week, average.

3rd, experimental result

Influence of the different proportion drug regimen of table 3 to spontaneous hypertensive rat blood pressure（X ± S, n=10）(mmHg)

Group	Before treatment	Treat one week after	Treat two weeks after	Three weeks after treatment	Surrounding after treatment
						1	171±5.2	171±4.6	174±11.3	175±8.6	175±8.1
2	171±4.3	160±5.8	146±7.5	132±4.2	129±8.1*#
						3	175±10.9	162±7.8	150±7.5	136±9.3	130±5.0*#
4	168±4.3	161±6.5	146±5.9	137±3.7	126±5.6*#
						5	172±6.8	164±8.4	142±6.7	135±5.9	129±7.5*#
6	173±7.2	157±10.2	144±5.5	135±3.8	131±4.6*#
						7	175±4.7	163±6.8	147±5.9	130±9.7	125±7.1*#
8	169±10.9	162±5.2	152±6.7	140±6.9	133±6.7*#
						9	172±4.8	161±6.5	148±5.9	138±6.7	129±4.6*#
10	170±3.7	162±5.3	148±9.8	136±7.1	125±10.4*#

*：P is compared with model control group<0.05; #：Compare p with before itself treatment<0.05

Result above finds out that appropriateness adjustment metolazone does not interfere with its prescription with the composition of proportions in ARB drug regimens To the therapeutic effect of hypertension.

Embodiment 1：Compound medicament composition 1（Tablet）Preparation（In terms of 1000）

Core formulation：

Valsartan 80

Metolazone 0.5

Microcrystalline cellulose 60

Starch 20

PVPP 10

Ac-Di-Sol 4.5

Superfine silica gel powder 3

Magnesium stearate 2.5

It is coated prescription

Opadry coating powder 4g

Purified water 45g

Preparation method：

（1）Valsartan, the metolazone of recipe quantity are weighed, 80 mesh sieves were crushed, it is well mixed using equal increments method.

（2）Weigh microcrystalline cellulose, starch, PVPP, Ac-Di-Sol, the micro mist silicon of recipe quantity Glue, 60 mesh sieves were crushed, be well mixed.

（3）Will（1）With（2）It is well mixed, magnesium stearate is added, is well mixed, obtains intermediate.

（4）Intermediates content is examined, piece weight is calculated, tabletting controls tablet hardness for 8kg.

（5）Purified water is weighed in prescription ratio, under agitation, the Opadry coating powder of recipe quantity is slowly added into, fills Divide stirring 45 minutes.

（6）High-efficiency coating machine, regulation air intake and leaving air temp are placed a tablet into, is started when tablet temperature is 40-45 DEG C It is coated, is increased weight to tablet untill 2.0% or so.

Embodiment 2：Compound medicament composition 2（Tablet）Preparation（In terms of 1000）

Core formulation：

Valsartan 160g

Metolazone 0.25

Microcrystalline cellulose 80g

Starch 26.5g

PVPP 15g

Ac-Di-Sol 10g

Superfine silica gel powder 6g

Magnesium stearate 2.5g

It is coated prescription：

Opadry coating powder 4g

Purified water 45g

Preparation method：

（1）Valsartan, the metolazone of recipe quantity are weighed, 80 mesh sieves were crushed, it is well mixed using equal increments method.

（2）Weigh microcrystalline cellulose, starch, PVPP, Ac-Di-Sol, the micro mist silicon of recipe quantity Glue, 60 mesh sieves were crushed, be well mixed.

（3）Will（1）With（2）It is well mixed, magnesium stearate is added, is well mixed, obtains intermediate.

（4）Intermediates content is examined, piece weight is calculated, tabletting controls tablet hardness for 7kg.

（5）Purified water is weighed in prescription ratio, under agitation, the Opadry coating powder of recipe quantity is slowly added into, fills Divide stirring 45 minutes.

（6）High-efficiency coating machine, regulation air intake and leaving air temp are placed a tablet into, is started when tablet temperature is 40-45 DEG C It is coated, is increased weight to tablet untill 2.0% or so.

Embodiment 3, compound medicament composition 3（Capsule）Preparation（In terms of 1000）

Prescription：

Valsartan 40g

Metolazone 1g

The g of microcrystalline cellulose 50

PVPP 15g

PVP K30 12g

Lauryl sodium sulfate 0.8g

Magnesium stearate 1.2g

Preparation method：

（1）Former, auxiliary material crosses 80 mesh sieves respectively, standby.

（2）PVP K30, lauryl sodium sulfate are taken, warm water is dissolved to 50ml, is used as adhesive；

（3）Valsartan, metolazone, microcrystalline cellulose, PVPP are weighed, it is well mixed with equal increments method, plus Softwood is made in adhesive, and the granulation of 18 mesh sieves is dried at 80 DEG C.

（4）After particle drying, 20 mesh sieve whole grains add magnesium stearate, are well mixed.

（5）Intermediates content is calculated, loading amount is calculated.

（6）Filled with No. 3 capsules.

The compound medicament composition 4 of embodiment 4（Tablet）Preparation（In terms of 1000）

Prescription：

Irbesartan 150g

Metolazone 0.5g

Lactose 50g

Microcrystalline cellulose 50g

Pregelatinized starch 70g

Ac-Di-Sol 40g

Superfine silica gel powder 2g

Magnesium stearate 3.5g

Preparation method：

（1）Irbesartan, the metolazone of recipe quantity are taken, 80 mesh sieves are crossed；Lactose, microcrystalline cellulose, pregelatinized starch, are handed over Connection sodium carboxymethylcellulose crosses 60 mesh sieves, well mixed with equal increments method.

（2）Softwood, the granulation of 18 eye mesh screens is made in the ethanol for adding 50%.

（3）Wet granular is in 45 DEG C of drying, 18 eye mesh screen whole grains.

（4）Add superfine silica gel powder and magnesium stearate is well mixed.

（5）Intermediates content is detected, piece weight is calculated, tabletting controls tablet hardness for 8kg.

The compound medicament composition 5 of embodiment 5（Tablet）Preparation（In terms of 1000）

Prescription：

Irbesartan 300g

Metolazone 0.25g

Lactose 30g

Microcrystalline cellulose 30g

Pregelatinized starch 70g

Ac-Di-Sol 60.75g

Superfine silica gel powder 4g

Magnesium stearate 5g

Preparation technology：

（1）Irbesartan, the metolazone of recipe quantity are taken, 80 mesh sieves are crossed；Lactose, microcrystalline cellulose, pregelatinized starch, are handed over Connection sodium carboxymethylcellulose crosses 60 mesh sieves, well mixed with equal increments method.

（2）Softwood, the granulation of 20 eye mesh screens is made in the ethanol for adding 50%.

（3）Wet granular is in 45 DEG C of drying, 20 eye mesh screen whole grains.

（4）Add superfine silica gel powder and magnesium stearate is well mixed.

（5）Intermediates content is detected, piece weight is calculated, tabletting controls tablet hardness for 9kg.

The compound medicament composition 6 of embodiment 6（Capsule）Preparation（In terms of 1000）

Prescription：

Irbesartan 75g

Metolazone 1g

Pregelatinized starch 55g

Microcrystalline cellulose 55g

Ac-Di-Sol 5g

Hydroxypropyl methyl cellulose 6g

Lauryl sodium sulfate 1g

Magnesium stearate 2g

Preparation technology：

（1）Weigh the hydroxypropyl methyl cellulose of recipe quantity, be dissolved in appropriate purified water, 3% aqueous solution is made, as Adhesive is standby.

（2）Main ingredient is crossed into 80 sieves, pregelatinized starch, microcrystalline cellulose, Ac-Di-Sol and magnesium stearate point 60 mesh sieves are not crossed, it is standby.

（3）Main ingredient, pregelatinized starch, microcrystalline cellulose, Ac-Di-Sol are mixed according to equal increments method Uniformly, add（1）, softwood, the granulation of 20 mesh is made.

（4）Above-mentioned particle adds magnesium stearate and is well mixed, obtain dry particl in 60 DEG C of drying, 24 eye mesh screen whole grains.

（5）Intermediates content is detected, loading amount is calculated.

（6）Filled with No. 2 capsules.

Embodiment 7：Compound medicament composition 7（Tablet）Preparation（In terms of 1000）

Prescription：

Telmisartan 80g

Metolazone 0.25g

Sodium hydroxide 10g

Meglumine 30g

PVP 24g

Microcrystalline cellulose 59.75g

Pregelatinized starch 98g

Lactose 30g

Sodium carboxymethyl starch 15g

Magnesium stearate 3g

95% ethanol 10ml

Preparation technology：

（1）By Telmisartan, metolazone, sodium hydroxide, meglumine, PVP, microcrystalline cellulose, pregelatinized starch, Lactose, sodium carboxymethyl starch are well mixed.

（2）Add appropriate 95% ethanol and softwood is made, pelletized by 20 mesh sieves, in 40 DEG C of aeration-dryings, 16 mesh of dry granular Whole grain is sieved, magnesium stearate is added, is well mixed

（3）Intermediates content is examined, piece weight is calculated, tabletting controls tablet hardness for 8kg.

Embodiment 8：Compound medicament composition 8（Tablet）Preparation（In terms of 1000）

Prescription：

Telmisartan 40g

Metolazone 0.5g

Sodium hydroxide 5g

Meglumine 15g

PVP 6g

Microcrystalline cellulose 75g

Sorbierite 200g

Sodium carboxymethyl starch 15g

Magnesium stearate 3g

95% ethanol 10ml

Preparation technology：

（1）Telmisartan is dissolved in 95% ethanol, sodium hydroxide is then added, in 30 ~ 50 revs/min stir Mix down and be slowly added to meglumine, stop stirring until completely dissolved, the sodium salt of telmisartan can be obtained after 60 DEG C of dryings.

（2）Metolazone, PVP, microcrystalline cellulose, sorbierite, sodium carboxymethyl starch mixing are added by equal increments method Uniformly, magnesium stearate is then added to be well mixed.

（3）Intermediates content is examined, piece weight is calculated, tabletting controls tablet hardness for 7kg.

Embodiment 9：Compound medicament composition 9（Capsule）Preparation（In terms of 1000）

Prescription：

Telmisartan 20g

Metolazone 1g

Sodium hydroxide 2.5g

Meglumine 7.5g

PVP 6g

Microcrystalline cellulose 75g

Pregelatinized starch 100g

Sodium carboxymethyl starch 15g

Magnesium stearate 3g

95% ethanol 10ml

Preparation technology：

（1）By Telmisartan, metolazone, sodium hydroxide, meglumine, PVP, microcrystalline cellulose, pregelatinized starch, Sodium carboxymethyl starch is well mixed.

（2）Add appropriate 95% ethanol and softwood is made, pelletized by 20 mesh sieves, in 40 DEG C of aeration-dryings, 16 mesh of dry granular Whole grain is sieved, magnesium stearate is added and is well mixed.

（3）Intermediates content is calculated, loading amount is calculated.

（4）Filled with No. 2 capsules.

Claims (2)

1. the pharmaceutical composition of metolazone, Angiotensin Ⅱ receptor antagonist and pharmaceutically acceptable auxiliary material composition is in system Be ready for use on treatment kidney injury caused by secondary hypertension medicine in purposes, it is characterised in that described angiotensins II receptor antagonist be Valsartan, Telmisartan, Irbesartan and its physiologically acceptable salt or ester one kind or it is a kind of with On mixture, described pharmaceutical composition, it is characterised in that count by weight, the ratio of two components is Xie Sha Tan ﹕ U.S.s support Drawing ancestor is 6 ~ 9 ﹕ 0.04 ~ 0.06；E Beishatan ﹕ metolazones are 11 ~ 17 ﹕ 0.04 ~ 0.06；Ti meters of Sha Tan ﹕ metolazones are 3 ~ 4.2 ﹕ 0.04 ~ 0.06.

2. purposes as claimed in claim 1, it is characterised in that the pharmaceutically acceptable auxiliary material is selected from adhesive, filling One or more kinds of mixtures in agent, disintegrant, lubricant, glidant and coating material.