CN104324377A - Compound antihypertensive preparation and application of compound antihypertensive preparation - Google Patents
Compound antihypertensive preparation and application of compound antihypertensive preparation Download PDFInfo
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- CN104324377A CN104324377A CN201410274529.2A CN201410274529A CN104324377A CN 104324377 A CN104324377 A CN 104324377A CN 201410274529 A CN201410274529 A CN 201410274529A CN 104324377 A CN104324377 A CN 104324377A
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Abstract
The invention provides a medicine composition for treating hypertension. The medicine composition is characterized in that the medicine composition comprises (1) angiotensin II receptor antagonists, (2) diuretic metolazone and (3) acceptable auxiliary materials on pharmaceutical science. The weight proportion of the angiotensin II receptor antagonists to the metolazone is 20-200:0.5-10; the angiotensin II receptor antagonists and the metolazone are combined to strengthen the collaboration antihypertensive effect; untoward effects are reduced; the compliance of patients is improved; the medication crowds are wide; and the medicine composition can be used by the patients with the seriously-damaged renal function. The medicine composition is suitable for treating mild and moderate primary hypertension, and is particularly suitable for treating secondary hypertension caused by kidney damage.
Description
Technical field
The present invention relates to drug world, be specifically related to pharmaceutical composition and application thereof that Angiotensin Ⅱ receptor antagonist and metolazone are effective ingredient.
Background technology
Along with the quick growth of China's economy, the drastic change of people life style, cardiovascular diseases has become the maximum killer threatening human health.Hypertension is one of current modal cardiovascular disease, has become the great public health problem in global range.According to the statistics display of national hygiene department, to the end of the year 2010, China patients with hypertension crowd will have reached 200,000,000 people, and annual newly-increased more than 3,000,000.Hypertension a kind of raises clinical syndrome for feature with body circulation systolic arterial pressure (SBP) and (or) diastolic pressure (DBP), and the especially infringement of the target organ such as the heart, brain, kidney that excites of hypertension, has a strong impact on life-span and the quality of life of patient.
The hypertensive medicine of current treatment has a variety of, relatively more conventional has calcium-channel antagonists (CCBs), β-receptor blocking agent, angiotensin-convertion enzyme inhibitor (ACEI), Angiotensin Ⅱ receptor antagonist (ARBs), diuretic five class medicine, but single medicine treatment hypertension is more difficult up to standard in a short time, Most patients needs to take two or more antihypertensive drug can reach blood pressure lowering target, and especially blood pressure exceedes the patient of desired value 20/10mmHg.Drug combination is the preferred option of hypertension therapeutic, by different machine-processed blood pressure lowerings, complements one another, and prevents the cancellation mechanism after single medicine dosage; The medication combined of different peaks Effect time can extend the hypotensive effect time, reduces untoward reaction, thus strengthens the protective effect to target organ.But several drugs is taken simultaneously, patient compliance is poor, and the collocation of the dosage of several drugs is due to the problem of formulation dosage and the degree of awareness of doctor, is not often optimized proportioning.In order to meet the needs of hyperpietic and improve drug compliance, be the Main way that compound preparation has become domestic and international medicine and looks forward to competitively chasing by the drug development of different mechanism of action.
Angiotensin Ⅱ receptor antagonist (ARB) is a class novel antihypertensive medicament, is described as a milestone of 20th century the nineties cardiovascular drugs.Side effect angle, it has higher safety than antihypertensive drug in the past.Renin-angiotensin system (RAS) excessive activation during hypertension, just starts to play illeffects after the angiotensinⅡ (Ang II) too much generated and angiotensin-ii-receptor combine.Research proves that angiotensin-ii-receptor is divided into AT1, AT2 two kinds, and Ang II mainly acts on AT1 receptor, causes blood pressure to raise, damages target organ.For this link, scientist develops Angiotensin Ⅱ receptor antagonist, and ARB fights for AT1 with Ang II competitiveness, by blocking the combination of angiotensinⅡ and AT1, thus plays the effect of blood pressure lowering protection target organ.And ARB also can indirect activation AT2, causes vasodilation, alleviates heart burden.Angiotensin Ⅱ receptor antagonist medicine can be used in early days while injury of kidney; the effect of protection kidney can be played; decrease glomerule inner high voltage height filtration state; its mechanism of action makes urine volume increase; row's sodium row chlorine increases; and improve the blood perfusion of kidney, improve protein in nephropathy, lipid and carbohydrate metabolism disturbance, to a certain degree decrease urine protein.Such as: valsartan, telmisartan, irbesartan etc.
Within 2009, Japanese Hypertension Guideline, " Chinese hypertension prevention and control guide 2010 " are all recommended, and Angiotensin Ⅱ receptor antagonist and diuretic, as the preferred option of drug combination, are widely used in hyperpietic.Activate renin angiotensin aldosterone system in unfavorable in pressure reduction of diuretic, this can strengthen the blocking effect of ARB to renin angiotensin aldosterone system on the contrary, thus produce more strong hypotensive effect, and ARB has the effect slightly rising hyperkalemia, diuretic has the effect of row's potassium, and the two can cancel each other on the impact of blood potassium.The compound preparation of the ARB associating diuretic of current listing has valsartan/hydrochlorothiazide, telmisartan/hydrochlorothiazide, Losartan Potassium/hydrochlorothiazide, irbesartan/hydrochlorothiazide, olmesartan medoxomil/hydrochlorothiazide etc., and wherein diuretic is all hydrochlorothiazide.And hydrochlorothiazide can disturb tubular excretion uric acid, minority can bring out gout outbreak; To severe renal hypothyroid, heavy dose of can cause drug accumulation when using, toxicity increases, should careful use, thus clinically in the urgent need to a kind of new diuretic to reduce its untoward reaction.
Metolazone (Metolazone) is a kind of Thiazoling type derivant, have diuretic antihypertensive effect, drug effect is similar with thiazide diuretic, and its natriuretic diuretic effect is 10 times of hydrochlorothiazide, but the effect of unrestraint carbonic anhydrase, significant to the acid-base balance in body.This product oral absorption is rapid, but not exclusively (about 64%), some cardiac's absorbance is 40%.Extensively and plasma protein and erythrocyte binding, plasma half-life is about 8h.After taking medicine there is diuresis in 1h, continues 12 ~ 24h.The untoward reaction of metolazone is similar to hydrochlorothiazide, occurs individually cardiopalmus, chest pain, room quivers, but be different from hydrochlorothiazide, and renal blood flow and glomerular filtration rate can not be made to reduce, and severe renal functional lesion person still can apply.
One section of Chinese invention patent (publication number: CN101132770A) being entitled as " Nanoparticulate candesartan formulations " discloses a kind of pharmaceutical composition of Candesartan, said composition comprises one or more compounds being used for the treatment of hypertension or related cardiovascular sufferer, wherein relates to metolazone (Zaroxolyn).The compositions mentioned in the document, mainly utilizes the feature of Candesartan nanoparticle, improves dissolution and the bioavailability of Candesartan, and then improves its effect.Do not mentioned medication crowd in patent, we know, the patient of Candesartan to hepatic insufficiency likely makes deterioration of liver function, and Clinical practice should be very careful, also should be cautious use of the patient of severe renal functional lesion.Rational prescription should improve the curative effect of medicine, reduces toxic and side effects again, therefore seeks suitable Angiotensin Ⅱ receptor antagonist kind, combines make compound preparation with metolazone, be clinical application in the urgent need to.So it is diuretic with metolazone that the present invention develops a kind of, the compound preparation formed with Angiotensin Ⅱ receptor antagonist, is used for the treatment of light, moderate essential hypertension, the secondary hypertension particularly caused by kidney damage.
Summary 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 its synergism, reduces untoward reaction and toxic action.
The present invention finds through a large amount of tests, and Angiotensin Ⅱ receptor antagonist, if valsartan, telmisartan and irbesartan and metolazone are in the ratio range of doses, has good synergism and blood pressure lowering effect.Be applicable to light, moderate essential hypertension, the secondary hypertension particularly caused by kidney damage.
Therefore, technical scheme of the present invention is a kind of hypertensive pharmaceutical composition for the treatment of containing Angiotensin Ⅱ receptor antagonist and metolazone.
The hypertensive pharmaceutical composition of described treatment, is characterized in that containing Angiotensin Ⅱ receptor antagonist, metolazone and pharmaceutically acceptable adjuvant.
Wherein, count by weight, the ratio of two components is Angiotensin Ⅱ receptor antagonist: metolazone is 1 ~ 500:0.1 ~ 50; Preferred Angiotensin Ⅱ receptor antagonist: metolazone is 20 ~ 200:0.5 ~ 10.
Described Angiotensin Ⅱ receptor antagonist is one or more mixture of losartan, valsartan, telmisartan, irbesartan, Olmesartan, eprosartan and physiologically acceptable salt or ester.
Described Angiotensin Ⅱ receptor antagonist is preferably one or more mixture of valsartan, telmisartan, irbesartan and physiologically acceptable salt or ester.
Wherein, described pharmaceutically acceptable adjuvant is selected from one or more mixture of binding agent, filler, disintegrating agent, lubricant, fluidizer, coating material and other adjuvants etc.
Described binding agent can be distilled water, ethanol, starch slurry, sodium carboxymethyl cellulose, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, hydroxypropyl emthylcellulose, polyvidone, syrup, rubber cement etc.
Described filler can be starch, Icing Sugar, dextrin, lactose, amylum pregelatinisatum, microcrystalline Cellulose, inorganic salts and mannitol etc.
Described disintegrating agent can be dried starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, gas-producing disintegrant etc.
Described lubricant can be magnesium stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycols and magnesium laurylsulfate etc.
Described fluidizer can be micropowder silica gel, Pulvis Talci etc.
Described coating material can be hydroxypropyl emthylcellulose, hydroxypropyl cellulose, No. VI, acrylic resin, polyvinylpyrrolidone, ethyl cellulose, cellulose acetate etc.
Other described adjuvants can be plasticizer, opacifier etc., and plasticizer is as propylene glycol, Oleum Ricini, Polyethylene Glycol, silicone oil, glycerol, dimethyl phthalate or dibutyl ester etc., and opacifier is as titanium dioxide etc.
In addition, the present invention also provide a kind of described pharmaceutical composition for the preparation for the treatment of hypertension drug in purposes.Wherein, described hypertension is light, moderate essential hypertension, the secondary hypertension particularly caused by kidney damage.
The preparation method of pharmaceutical composition involved in the present invention, its preparation should be selected from but be not limited to following steps: pulverize, sieve, weigh, add the processes such as binding agent, granulation, drying, total mixed, tabletting or filling.Wherein binding agent can be additional, Nei Jia or interior additional; Granulation can be dry granulation or wet granulation; Drying can be vacuum drying, spraying dry, lyophilization, pneumatic conveying drying or airpillow-dry; Tabletting can be direct compression or pelletizing press sheet.
Pharmaceutical composition of the present invention, by selecting suitable Angiotensin Ⅱ receptor antagonist and the combination of diuretic, strengthens Synergistic Hypotensive Effects, reduce untoward reaction, improve the compliance of patient, medication crowd is wide, all can use the patient of renal function grievous injury.Pharmaceutical composition of the present invention is particularly useful for gently, Moderate Essential Hypertension, the secondary hypertension particularly caused by kidney damage.
accompanying drawing explanationfig. 1 is the impact of different pharmaceutical combination on spontaneous hypertensive rat blood pressure.
Detailed description of the invention
The present invention is further illustrated below by embodiment.It should be understood that; the product of the embodiment of the present invention and preparation method are only used for the present invention is described; instead of limitation of the present invention, under concept thereof of the present invention, all the scope of protection of present invention is belonged to the simple modifications of product of the present invention and preparation method.Except as otherwise noted, " % " in the present invention is all quality criterias.
The active constituents of medicine playing therapeutical effect due to valsartan or its pharmaceutically useful salt or ester is identical, and therefore in the following example, valsartan can be regarded as valsartan or its pharmaceutically useful salt or ester.Equally, telmisartan, Candesartan also should be understood like this.
effect example 1: Angiotensin Ⅱ receptor antagonist and metolazone drug regimen are to hypertension in spontaneous hypertensive rats antagonism effect and Renoprotective Effect experiment
1, laboratory animal and experiment grouping
Male spontaneously hypertensive rat 140, body weight 250g ± 20g, adapts to raising after one week, is divided into 14 groups at random, often organize 10.
(1) model control group: gavage gives same volume normal 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) hydrochlorothiazide+valsartan group: 1.2mg/kg*d+7.5mg/kg*d
(10) hydrochlorothiazide+irbesartan group: 1.2mg/kg*d+14mg/kg*d
(11) hydrochlorothiazide+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
2, test method: once, totally 4 weeks, receptacle temperature controlled at about 25 DEG C each group every gastric infusion every day, humidity 45% ~ 65%.Tail arterial blood pressure under BP-2006A intelligence non-invasive blood pressure measuring (Beijing is soft grand) measurement rat waking state, measures weekly blood pressure three times, averages after administration.The results are shown in Table 1.Each group of rat before administration one day and experiment terminates last day and is placed in metabolic cage respectively to raise, and collects 12h urine overnight and detects microdose urine protein (MA) using as kidney injury mark with immunoturbidimetry, the results are shown in Table 2.
3, experimental result:
Impact (X ± S, n=10) (mmHg) of table 1 different pharmaceutical combination on spontaneous hypertensive rat blood pressure
| Group | Before treatment | Latter one week for the treatment of | Latter two weeks for the treatment of | Latter three weeks for the treatment of | 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*# |
*: compare p<0.05 with model control group; #: compare p<0.05 with before self treatment;
As can be seen from table 1 and Fig. 1,6-14 group drug regimen has obvious antihypertensive effect relative to before treatment, also all there is significant difference relative to model control group blood pressure measurement, simultaneously, 6,7,8 groups of drug regimens are obviously better than again 9-14 group drug regimen, visible, the compound recipe of drug regimen metolazone of the present invention and Sha Tan class than hydrochlorothiazide and the compound recipe of Sha Tan class and the compound recipe of hydrochlorothiazide or the husky smooth class of indapamide associating better on antihypertensive effect.
The impact (X ± S, n=10) of table 2 different pharmaceutical combination on spontaneous hypertensive rat Microalbuminuria
(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 |
*: compare p<0.05 with model control group; #: compare p<0.05 with before self treatment
Above result is found out, drug regimen of the present invention 6,7,8 groups can significantly reduce rat Microalbuminuria relative to other groups, points out it best to the protective effect of kidney injury over the course for the treatment of.
effect example 2: in Angiotensin Ⅱ receptor antagonist and metolazone drug regimen, different pharmaceutical ratio resists effect experimental to hypertension in spontaneous hypertensive rats
1, laboratory animal and experiment grouping
Male spontaneously hypertensive rat 100, body weight 250g ± 20g, adapts to raising after one week, is divided into 10 groups at random, often organize 10.
1. model control group: gavage gives same volume normal 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
2, test method: once, totally 4 weeks, receptacle temperature controlled at about 25 DEG C each group every gastric infusion every day, humidity 45% ~ 65%.Tail arterial blood pressure under BP-2006A intelligence non-invasive blood pressure measuring (Beijing is soft grand) measurement rat waking state, measures weekly blood pressure three times, averages after administration.
3, experimental result
Table 3 different proportion drug regimen is on impact (X ± S, n=10) (mmHg) of spontaneous hypertensive rat blood pressure
| Group | Before treatment | Latter one week for the treatment of | Latter two weeks for the treatment of | Latter three weeks for the treatment of | 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*# |
*: compare p<0.05 with model control group; #: compare p<0.05 with before self treatment
Above result is found out, the composition of proportions that appropriateness adjusts in metolazone and ARB drug regimen can not affect its prescription to hypertensive therapeutic effect.
embodiment 1: compound medicament composition 1(tablet) preparation (in 1000)
core formulation:
Valsartan 80
Metolazone 0.5
Microcrystalline Cellulose 60
Starch 20
Polyvinylpolypyrrolidone 10
Cross-linking sodium carboxymethyl cellulose 4.5
Micropowder silica gel 3
Magnesium stearate 2.5
coating prescription
Opadry coating powder 4g
Purified water 45g
preparation method:
(1) take the valsartan of recipe quantity, metolazone, pulverized 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) take the microcrystalline Cellulose of recipe quantity, starch, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, micropowder silica gel, pulverize 60 mesh sieves, mix homogeneously.
(3) by (1) and (2) mix homogeneously, then add magnesium stearate, mix homogeneously, obtain intermediate.
(4) check intermediates content, calculate sheet weight, tabletting, control tablet hardness is 8kg.
(5) take purified water in prescription ratio, under agitation, slowly add the Opadry coating powder of recipe quantity, fully stir 45 minutes.
(6) tablet is placed in high-efficiency coating machine, regulates air intake and leaving air temp, when tablet temperature is 40-45 DEG C, start coating, to tablet weightening finish to about 2.0%.
embodiment 2: compound medicament composition 2(tablet) preparation (in 1000)
core formulation:
Valsartan 160g
Metolazone 0.25
Microcrystalline Cellulose 80g
Starch 26.5g
Polyvinylpolypyrrolidone 15g
Cross-linking sodium carboxymethyl cellulose 10g
Micropowder silica gel 6g
Magnesium stearate 2.5g
coating prescription:
Opadry coating powder 4g
Purified water 45g
preparation method:
(1) take the valsartan of recipe quantity, metolazone, pulverized 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) take the microcrystalline Cellulose of recipe quantity, starch, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, micropowder silica gel, pulverize 60 mesh sieves, mix homogeneously.
(3) by (1) and (2) mix homogeneously, then add magnesium stearate, mix homogeneously, obtain intermediate.
(4) check intermediates content, calculate sheet weight, tabletting, control tablet hardness is 7kg.
(5) take purified water in prescription ratio, under agitation, slowly add the Opadry coating powder of recipe quantity, fully stir 45 minutes.
(6) tablet is placed in high-efficiency coating machine, regulates air intake and leaving air temp, when tablet temperature is 40-45 DEG C, start coating, to tablet weightening finish to about 2.0%.
embodiment 3, compound medicament composition 3(capsule) preparation (in 1000)
prescription:
Valsartan 40g
Metolazone 1g
Microcrystalline Cellulose 50 g
Polyvinylpolypyrrolidone 15g
PVP K30 12g
Sodium lauryl sulphate 0.8g
Magnesium stearate 1.2g
preparation method:
(1) former, adjuvant crosses 80 mesh sieves respectively, for subsequent use.
(2) get PVP K30, sodium lauryl sulphate, warm water is dissolved to 50ml, as binding agent;
(3) take valsartan, metolazone, microcrystalline Cellulose, polyvinylpolypyrrolidone, with equal increments method mix homogeneously, add binding agent and make soft material, 18 mesh sieves are granulated, dry at 80 DEG C.
(4) after granule is dried, 20 mesh sieve granulate, then add magnesium stearate, mix homogeneously.
(5) calculate intermediates content, calculate loading amount.
(6) with No. 3 capsule-fillings.
embodiment 4 compound medicament composition 4(tablet) preparation (in 1000)
prescription:
Irbesartan 150g
Metolazone 0.5g
Lactose 50g
Microcrystalline Cellulose 50g
Pregelatinized Starch 70g
Cross-linking sodium carboxymethyl cellulose 40g
Micropowder silica gel 2g
Magnesium stearate 3.5g
preparation method:
(1) get the irbesartan of recipe quantity, metolazone, cross 80 mesh sieves; Lactose, microcrystalline Cellulose, pregelatinized Starch, cross-linking sodium carboxymethyl cellulose crosses 60 mesh sieves, with equal increments method mix homogeneously.
(2) soft material made by the ethanol adding 50%, and 18 eye mesh screens are granulated.
(3) wet granular is in 45 DEG C of oven dry, 18 eye mesh screen granulate.
(4) micropowder silica gel and magnesium stearate mix homogeneously is added.
(5) detect intermediates content, calculate sheet weight, tabletting, control tablet hardness is 8kg.
embodiment 5 compound medicament composition 5(tablet) preparation (in 1000)
prescription:
Irbesartan 300g
Metolazone 0.25g
Lactose 30g
Microcrystalline Cellulose 30g
Pregelatinized Starch 70g
Cross-linking sodium carboxymethyl cellulose 60.75g
Micropowder silica gel 4g
Magnesium stearate 5g
preparation technology:
(1) get the irbesartan of recipe quantity, metolazone, cross 80 mesh sieves; Lactose, microcrystalline Cellulose, pregelatinized Starch, cross-linking sodium carboxymethyl cellulose crosses 60 mesh sieves, with equal increments method mix homogeneously.
(2) soft material made by the ethanol adding 50%, and 20 eye mesh screens are granulated.
(3) wet granular is in 45 DEG C of oven dry, 20 eye mesh screen granulate.
(4) micropowder silica gel and magnesium stearate mix homogeneously is added.
(5) detect intermediates content, calculate sheet weight, tabletting, control tablet hardness is 9kg.
embodiment 6 compound medicament composition 6(capsule) preparation (in 1000)
prescription:
Irbesartan 75g
Metolazone 1g
Pregelatinized Starch 55g
Microcrystalline Cellulose 55g
Cross-linking sodium carboxymethyl cellulose 5g
Hydroxypropyl emthylcellulose 6g
Sodium lauryl sulphate 1g
Magnesium stearate 2g
preparation technology:
(1) take the hydroxypropyl emthylcellulose of recipe quantity, be dissolved in appropriate purified water, make the aqueous solution of 3%, for subsequent use as binding agent.
(2) principal agent is crossed 80 sieves, pregelatinized Starch, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and magnesium stearate cross 60 mesh sieves respectively, for subsequent use.
(3) by principal agent, pregelatinized Starch, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose according to equal increments method mix homogeneously, add (1), make soft material, 20 orders granulate.
(4) above-mentioned granule is 60 DEG C of oven dry, and 24 eye mesh screen granulate, add magnesium stearate mix homogeneously, obtain dry granule.
(5) detect intermediates content, calculate loading amount.
(6) with No. 2 capsule-fillings.
embodiment 7: compound medicament composition 7(tablet) preparation (in 1000)
prescription:
Telmisartan 80g
Metolazone 0.25g
Sodium hydroxide 10g
Meglumine 30g
Polyvidone 24g
Microcrystalline Cellulose 59.75g
Pregelatinized Starch 98g
Lactose 30g
Carboxymethyl starch sodium 15g
Magnesium stearate 3g
95% ethanol 10ml
preparation technology:
(1) by telmisartan, metolazone, sodium hydroxide, meglumine, polyvidone, microcrystalline Cellulose, pregelatinized Starch, lactose, carboxymethyl starch sodium mix homogeneously.
(2) add appropriate 95% ethanol and make soft material, granulated by 20 mesh sieves, 40 DEG C of aeration-dryings, dry granular 16 mesh sieve granulate, add magnesium stearate, mix homogeneously
(3) check intermediates content, calculate sheet weight, tabletting, control tablet hardness is 8kg.
embodiment 8: compound medicament composition 8(tablet) preparation (in 1000)
prescription:
Telmisartan 40g
Metolazone 0.5g
Sodium hydroxide 5g
Meglumine 15g
Polyvidone 6g
Microcrystalline Cellulose 75g
Sorbitol 200g
Carboxymethyl starch sodium 15g
Magnesium stearate 3g
95% ethanol 10ml
preparation technology:
(1) telmisartan is dissolved in the ethanol of 95%, and then adds sodium hydroxide, under the stirring of 30 ~ 50 revs/min, slowly add meglumine, stop until completely dissolved stirring, after 60 DEG C of dryings, can the sodium salt of telmisartan be obtained.
(2) add metolazone, polyvidone, microcrystalline Cellulose, sorbitol, carboxymethyl starch sodium mix homogeneously by equal increments method, and then add magnesium stearate mix homogeneously.
(3) check intermediates content, calculate sheet weight, tabletting, control tablet hardness is 7kg.
embodiment 9: compound medicament composition 9(capsule) preparation (in 1000)
prescription:
Telmisartan 20g
Metolazone 1g
Sodium hydroxide 2.5g
Meglumine 7.5g
Polyvidone 6g
Microcrystalline Cellulose 75g
Pregelatinized Starch 100g
Carboxymethyl starch sodium 15g
Magnesium stearate 3g
95% ethanol 10ml
preparation technology:
(1) by telmisartan, metolazone, sodium hydroxide, meglumine, polyvidone, microcrystalline Cellulose, pregelatinized Starch, carboxymethyl starch sodium mix homogeneously.
(2) add appropriate 95% ethanol and make soft material, granulated by 20 mesh sieves, 40 DEG C of aeration-dryings, dry granular 16 mesh sieve granulate, add magnesium stearate mix homogeneously.
(3) calculate intermediates content, calculate loading amount.
(4) with No. 2 capsule-fillings.
Claims (7)
1. treat a hypertensive pharmaceutical composition, it is characterized in that containing Angiotensin Ⅱ receptor antagonist, metolazone and pharmaceutically acceptable adjuvant.
2. pharmaceutical composition as claimed in claim 1, is characterized in that described Angiotensin Ⅱ receptor antagonist is one or more mixture of losartan, valsartan, telmisartan, irbesartan, Olmesartan, eprosartan and physiologically acceptable salt or ester.
3. pharmaceutical composition as claimed in claim 1, is characterized in that described Angiotensin Ⅱ receptor antagonist is one or more mixture of valsartan, telmisartan, irbesartan and physiologically acceptable salt or ester.
4. pharmaceutical composition as claimed in claim 1, it is characterized in that counting by weight, the ratio of two components is Angiotensin Ⅱ receptor antagonist: metolazone is 1 ~ 500:0.1 ~ 50; Be preferably Angiotensin Ⅱ receptor antagonist: metolazone is 20 ~ 200:0.5 ~ 10.
5. chemicals compositions as claimed in claim 1, is characterized in that described pharmaceutically acceptable adjuvant is selected from one or more mixture of binding agent, filler, disintegrating agent, lubricant, fluidizer, coating material and other adjuvants etc.
6. pharmaceutical composition as claimed in claim 1 is for the preparation of the purposes in treatment hypertension drug.
7. purposes as claimed in claim 6, wherein said hypertension is light, moderate essential hypertension, the secondary hypertension particularly caused by kidney damage.
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| CN201410274529.2A CN104324377B (en) | 2014-06-19 | 2014-06-19 | A kind of composite antihypertensive preparation and its application |
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| CN201410274529.2A CN104324377B (en) | 2014-06-19 | 2014-06-19 | A kind of composite antihypertensive preparation and its application |
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| CN104324377A true CN104324377A (en) | 2015-02-04 |
| CN104324377B CN104324377B (en) | 2017-08-04 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104758289A (en) * | 2015-03-09 | 2015-07-08 | 西安力邦制药有限公司 | A compound antihypertensive composition containing metolazone and applications thereof |
| CN105106962A (en) * | 2015-08-29 | 2015-12-02 | 西安力邦肇新生物科技有限公司 | Compound antihypertensive preparation and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1652777A (en) * | 2002-05-17 | 2005-08-10 | 诺瓦提斯公司 | Combination of organic compounds |
| CN101472557A (en) * | 2006-06-16 | 2009-07-01 | Lts罗曼治疗方法有限公司 | Combination antihypertensive wafer |
-
2014
- 2014-06-19 CN CN201410274529.2A patent/CN104324377B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1652777A (en) * | 2002-05-17 | 2005-08-10 | 诺瓦提斯公司 | Combination of organic compounds |
| CN101472557A (en) * | 2006-06-16 | 2009-07-01 | Lts罗曼治疗方法有限公司 | Combination antihypertensive wafer |
Non-Patent Citations (3)
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| 倪鑫，沈颖: "《儿科诊疗常规》", 30 September 2013 * |
| 王海燕 等: "《实用药物学应用指南》", 30 September 2009 * |
| 陈登登: "《内科用药手册》", 31 October 2003 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104758289A (en) * | 2015-03-09 | 2015-07-08 | 西安力邦制药有限公司 | A compound antihypertensive composition containing metolazone and applications thereof |
| CN104758289B (en) * | 2015-03-09 | 2019-05-03 | 西安力邦制药有限公司 | A kind of compound antihypertensive drug combination and its application containing medetofazone |
| CN105106962A (en) * | 2015-08-29 | 2015-12-02 | 西安力邦肇新生物科技有限公司 | Compound antihypertensive preparation and application thereof |
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| Publication number | Publication date |
|---|---|
| CN104324377B (en) | 2017-08-04 |
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