CN104758290A - A compound antihypertensive composition and applications thereof - Google Patents
A compound antihypertensive composition and applications thereof Download PDFInfo
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- CN104758290A CN104758290A CN201510103438.7A CN201510103438A CN104758290A CN 104758290 A CN104758290 A CN 104758290A CN 201510103438 A CN201510103438 A CN 201510103438A CN 104758290 A CN104758290 A CN 104758290A
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- hypertension
- pharmaceutical composition
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A pharmaceutical composition for treating hypertension is provided. The composition includes (1) an alpha receptor blocker, (2) a diuretic metolazone and (3) pharmaceutically acceptable accessories, wherein the weight ratio of a vasodilator to the metolazone is 0.5-30:0.1-20. By composition of the vasodilator and the metolazone, synergistic antihypertensive effects are improved, untoward effects are reduced, patient compliance is improved, the medicine taking population is wide, and the composition can be used for patients with serious renal function injury. The composition is suitable for mild and moderate essential hypertension, particularly secondary hypertension caused by renal damage and hypertension accompanied with senile hyperlipidemia.
Description
Technical field
The present invention relates to drug world, be specifically related to α
1receptor blocking agent and medetofazone are pharmaceutical composition and the application thereof of effective ingredient.
Background technology
Hypertension is a kind of clinical syndrome being feature with body circulation systolic arterial pressure (SBP) and (or) diastolic pressure (DBP) rising, especially the 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.
Along with society and expanding economy our people living standard standard are shown in raising, but crowd's Prevalence of Hypertension is still in growing trend.To the end of the year 2010, just there is 1 people to suffer from hypertension in every 5 adults, estimate national hyperpietic at least 2 hundred million, and annual newly-increased more than 3,000,000.But hypertension awareness, treatment rate and control rate are lower.Simultaneously coronary heart disease and apoplexy are my hypertensive complications, control the growing trend that hypertension can contain cardiovascular and cerebrovascular disease morbidity and death.
Except controlling in life, sodium is taken in, low fat diet controls body weight and adjustment is spiritual and except emotion, treatment hypertension mainly relies on medicine at present.The conventional hypertensive medicine for the treatment of has calcium-channel antagonists (CCBs), beta-blocker, angiotensin-convertion enzyme inhibitor (ACEI), Angiotensin Ⅱ receptor antagonist (ARBs), diuretic five class medicine, in addition also has the antihypertensive drugs such as alpha receptor blocking agent, renin inhibitor, vasodilation.But because 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 direction that compound preparation has become the exploitation of current antihypertensive drugs by the drug development of different mechanism of action.
There is the situation that Peripheral resistance increases in most hyperpietic, alpha receptor blocking agent can block the effect of catecholamine for vascular smooth muscle contraction, makes the small artery diastole of contraction state, produces antihypertensive effect.Nonselective alpha receptor blocking agent can reflexive activation sympathetic nerve and renin-angiotensin system, untoward reaction is more, long-term antihypertensive effect is poor, except for controlling except Patients With Pheochromocytoma and hypertensive crisis, is not suitable as the application of conventional hypertension drug.And optionally α
1receptor blocking agent is because of initial stage reduction Artery resistance and VC, sympathetic activity reflexive is increased, increased heart rate and plasma renin activity is caused to increase, but hypertension is the disease needing long-term treatment, such medicine of prolonged application can produce lasting vasodilative effect, cardiac output, heart rate and plasma renin levels all may recover normal, affect less.α 1 receptor blocking agent can not produce the side effect such as increased heart rate, vascular headache and the flush risen as direct expansion blood vessel guiding drug; Also can not produce the decreased heart rate caused by beta-blocker and cardiac output minimizing, the hypokalemia etc. that more can not cause as diuretic, be specially adapted to the hyperpietic needing long-term Treatment of Hypertension.Do not affect glomerular filtration rate and renal blood flow, thus for have renal insufficiency and impaired renal function hyperpietic also can use safely.Prazosin on the metabolism such as fatty, sugared all without impact, after simultaneously in such antihypertensive drug of application, the level of T-CHOL (TC) and triglyceride (TG) can slightly reduce, the concentration of plasma TC, TG and low-density lipoprotein cholesterol (LDL-C) reduces, and the ratio (HDL-C/TC) of HDL-C (HDL-C), HDL-C and T-CHOL rises.But easily there is showing as dizzy, nauseating, cardiopalmus, perspiration in α 1 receptor blocking agent in use dosage discomfort, " first-dose response " of even fainting, need to start to reduce dosage, slowly increase dosage gradually to avoid, the use of such medicine also can with the untoward reaction of postural hypotension simultaneously
Medetofazone (Matolazone) (former name metolazone) is a kind of Thiazoling type derivant, there is diuretic antihypertensive effect, drug effect is similar with thiazide diuretic, its natriuretic diuretic effect is 10 times of hydrochlorothiazide, but the effect of unrestraint carbonic anhydrase, significant to the acid-base balance in body.Diuretic its be applicable to old and Elder hypertension, separately systolic hypertension or accompany heart failure patient, be also one of basic pharmaceutical of refractory hypertension, its untoward reaction and dosage closely related.Thiazide diuretic 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 medetofazone 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.But the same with thiazide diuretic, prolonged application can cause blood fat to raise because of its diuresis, and this is to elderly patients and itself is more unfavorable with hyperlipidemia patient.
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 α 1 receptor blocking agent, if prazosin, terazosin, doxazosin and medetofazone 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 to provide a kind of hypertensive pharmaceutical composition for the treatment of containing α 1 receptor blocking agent and medetofazone.
The hypertensive pharmaceutical composition for the treatment of of the present invention, containing α 1 receptor blocking agent antagonist, medetofazone and pharmaceutically acceptable adjuvant.
Wherein, count by weight, the ratio of two components is α 1 receptor blocking agent: medetofazone is 0.5 ~ 30:0.1 ~ 20; Preferred α 1 receptor blocking agent: medetofazone is 0.5 ~ 20:0.2 ~ 10.
α 1 receptor blocking agent of the present invention is one or more mixture of prazosin, terazosin, doxazosin, trimazosin, Alfuzosin, its physiologically acceptable salt of urapidil or ester.
Preferably, α 1 receptor blocking agent of the present invention is one or more mixture of prazosin, terazosin, doxazosin and physiologically acceptable salt or ester.
Further preferred, α 1 receptor blocking agent of the present invention is doxazosin and physiologically acceptable salt thereof or ester.
Wherein, described pharmaceutically acceptable adjuvant is selected from one or more mixture of binding agent, filler, disintegrating agent, lubricant, 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, magnesium laurylsulfate, 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.
Concrete, pharmaceutical composition of the present invention, is grouped into by the one-tenth of following percentage by weight:
Pharmaceutical composition of the present invention, its pharmaceutical dosage forms can be any pharmaceutically useful dosage form, and these dosage forms comprise: tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, suck agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, ointment, plaster, cream, spray, drop, patch.Preparation of the present invention, preferably peroral dosage form, as: capsule, tablet, oral liquid, granule, pill, powder, sublimed preparation, unguentum etc.
Another object of the present invention is the preparation method providing pharmaceutical composition.
Preparation method of the present invention can select preparation method conventional on any pharmaceutics.
The preparation method of pharmaceutical composition involved in the present invention, comprises the 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.
Preferably, preparation method of the present invention asks for an interview embodiment.
Another object of the present invention is to provide the application of this pharmaceutical composition in preparation treatment hypertension drug.Wherein, described hypertension is light, moderate essential hypertension, the secondary hypertension particularly caused by kidney damage.
Hypertension of the present invention is the hypertension with old hyperlipidemia.
The diuretic medicine mainly hydrochlorothiazide that current resisting hypertension drug combination uses, such medicine can disturb tubular excretion uric acid, and minority can bring out gout outbreak; To severe renal hypothyroid, can cause drug accumulation during heavy dose of use, toxicity increases, and then damages renal function further, affects curative effect of medication.Kidney damage mainly raises according to serum creatinine, and the glomerular filtration rate (eGFR) of estimation reduces or urinaryalbumin output (UAE) increases.Microalbuminuria has been proved to be the independent predictor of cardiovascular event, thus clinically in the urgent need to a kind of new diuretic to reduce its untoward reaction.Medetofazone can not make renal blood flow and glomerular filtration rate reduce at generation diuresis simultaneously; and α 1 receptor blocking agent can also increase glomerule blood flow and filtration rate; both drug combinations can work in coordination with the effect producing kidney protection; microdose urine protein in effective reduction urine, ensures the continuous and effective of antihypertensive drugs.
Medetofazone is the same with phenothiazine drug can make TG in blood plasma occur ascendant trend significantly because of the draining of its diuresis, and simultaneously HDL-C and HDL-C/TC then obviously reduces, and long its of patient makes the dyslipidemia often causing separately secondary with diuretic.And α 1 receptor blocking agent is the antihypertensive drug uniquely clearly with effect for reducing blood fat, and there is drug dose dependency.Find in comparing with diuretic, two medicines all can reduce the blood pressure of hyperpietic significantly, but the patient of application α 1 receptor blocking agent, favourable Lipid-regulating effect is obvious, and TG obviously reduces, HDL-C and HDL-C/TC obviously raises.By selecting suitable α 1 receptor blocking agent and the combination of diuretic medetofazone, because of the postural hypotension of dosage appearance bigger than normal when the consumption strengthening decreasing while Synergistic Hypotensive Effects respective medicine prevents from being used alone α 1 receptor blocking agent, reduce hyperpietic blood fat simultaneously, effectively prevent prolonged application medetofazone and the secondary hyperlipidemia that produces.
Pharmaceutical composition of the present invention, reduces the consumption of respective single medicine, and the untoward reaction originally of both reductions medicine, improve the compliance of patient, medication crowd is extensive.Pharmaceutical composition of the present invention is applicable to be particularly useful for light, Moderate Essential Hypertension, the secondary hypertension particularly caused by old high kidney damage, the hypertension with hyperlipidemia.
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 doxazosin or its pharmaceutically useful salt or ester is identical, and therefore in the following example, doxazosin can be regarded as doxazosin or its pharmaceutically useful salt or ester.Equally, prazosin, terazosin, should understand like this.
Effect example 1: α 1 receptor blocking agent and medetofazone drug regimen are to the experiment of old hypertension in spontaneous hypertensive rats antagonism effect, Renoprotective Effect and Regulating Blood Lipid Effect
1, laboratory animal and experiment grouping
Male aged spontaneous hypertensive rat 140 (12 monthly age), body weight 330g ± 20g, is divided into 14 groups at random, often organizes 10.
(1) model control group: gavage gives same volume normal saline;
(2) medetofazone group: 0.05mg/kg*d
(3) doxazosin group: 0.4mg/kg*d
(4) terazosin group: 0.5mg/kg*d
(5) prazosin group: 0.2mg/kg*d
(6) medetofazone+doxazosin group: 0.05mg/kg*d+0.4mg/kg*d
(7) medetofazone+terazosin group: 0.05mg/kg*d+0.5mg/kg*d
(8) medetofazone+prazosin group: 0.05mg/kg*d+0.2mg/kg*d
(9) hydrochlorothiazide+doxazosin group: 1.2mg/kg*d+0.4mg/kg*d
(10) hydrochlorothiazide+terazosin group: 1.2mg/kg*d+0.5mg/kg*d
(11) hydrochlorothiazide+prazosin group: 1.2mg/kg*d+0.2mg/kg*d
(12) indapamide+doxazosin group: 0.25mg/kg*d+0.4mg/kg*d
(13) indapamide+terazosin group: 0.25mg/kg*d+0.5mg/kg*d
(14) indapamide+prazosin group: 0.25mg/kg*d+0.2mg/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 is terminated optical fundus one day after and gets blood, centrifuging and taking serum, uses AU5800 series automatic clinical chemistry analyzer (Beckman Ku Erte) triglyceride (TG), the results are shown in Table 2.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 3.
3, experimental result:
Impact (X ± S, n=10) (mmHg) of table 1 different pharmaceutical combination on old 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 | 181±5.8 | 182±6.8 | 182±7.7 | 184±10.5 | 183±9.8 |
| 2 | 180±8.9 | 172±4.3 | 163±7.2 | 162±8.2 | 159±6.6*# |
| 3 | 181±6.8 | 175±6.2 | 170±7.3 | 168±8.2 | 161±5.8*# |
| 4 | 182±7.1 | 176±7.0 | 171±8.2 | 166±6.8 | 160±8.9*# |
| 5 | 180±4.3 | 176±6.8 | 172±7.2 | 163±5.5 | 159±8.4*# |
| 6 | 179±4.5 | 165±7.3 | 151±6.6 | 139±8.4 | 126±9.1*#& |
| 7 | 180±5.1 | 166±7.4 | 152±6.9 | 145±9.2 | 130±8.2*#& |
| 8 | 181±4.6 | 168±6.6 | 150±8.7 | 142±9.4 | 128±7.3*#& |
| 9 | 180±3.3 | 169±5.6 | 162±7.8 | 154±8.8 | 144±7.3*# |
| 10 | 181±4.9 | 170±6.6 | 164±7.7 | 155±6.3 | 147±8.6*# |
| 11 | 180±4.0 | 171±6.1 | 163±6.6 | 156±7.9 | 145±8.9*# |
| 12 | 179±6.6 | 170±5.9 | 164±7.1 | 154±8.2 | 144±6.3*# |
| 13 | 179±6.6 | 170±5.9 | 164±7.1 | 154±8.2 | 144±6.3*# |
| 14 | 180±5.5 | 169±4.2 | 162±5.6 | 155±8.6 | 142±6.9*# |
*: compare p<0.05 with model control group; #: with contrast before self treatment; &: each compound preparation group and hydrochlorothiazide doxazosin group ratio
As can be seen from Table 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 medetofazone of the present invention and α 1 receptor blocking agent compared with hydrochlorothiazide and the compound recipe of α 1 receptor blocking agent or the compound recipe of indapamide associating α 1 receptor blocking agent better on antihypertensive effect.
The impact (X ± S, n=10) (unit: mmol/L) of table 2 different pharmaceutical combination on content of triglyceride in old spontaneous hypertensive rat blood
| Group | Before treatment | After treatment |
| 1 | 1.21±0.09 | 1.20±0.16 |
| 2 | 1.22±0.13 | 1.36±0.19 |
| 3 | 1.30±0.21 | 0.92±0.20*# |
| 4 | 1.26±0.13 | 1.01±0.14*# |
| 5 | 1.19±0.16 | 0.98±0.20*# |
| 6 | 1.27±0.22 | 1.04±0.09*# |
| 7 | 1.23±0.08 | 1.11±0.14*# |
| 8 | 1.22±0.10 | 1.05±0.05*# |
| 9 | 1.24±0.23 | 1.20±0.21 |
| 10 | 1.25±0.18 | 1.22±0.25 |
| 11 | 1.20±0.15 | 1.16±0.33 |
| 12 | 1.19±0.05 | 1.14±0.21 |
| 13 | 1.28±0.11 | 1.17±0.33 |
| 14 | 1.18±0.07 | 1.17±0.13 |
*: compare p<0.05 with model control group; #: with contrast contrast p<0.05 before self treatment
2 groups of triglyceride raise to some extent as can be seen from the above results, 3,4,5,6,7,8 triglyceride reduce obviously, and all the other group changes are not obvious, the blood fat that can significantly to reduce when α 1 receptor blocking agent and medetofazone coupling in blood is described, and antagonist/diuretic agent bring rise blood fat.And medetofazone antihypertensive effect comparatively thiazide diuretic action effect is stronger, hydrochlorothiazide Compound and the larger dosage of indapamide compound recipe bring and larger rise blood fat so not obvious with lipid-lowering effect during α 1 receptor blocking agent coupling.
The impact (X ± S, n=10) (unit μ g/ml) of table 3 different pharmaceutical combination on old spontaneous hypertensive rat Microalbuminuria
| Group | Before treatment | After treatment |
| 1 | 96.5±6.6 | 147.6±9.2 |
| 2 | 89.3±11.2 | 87.6±7.1 |
| 3 | 94.1±10.9 | 92.5±6.2 |
| 4 | 88.6±9.6 | 93.5±12.6 |
| 5 | 9.3±7.3 | 89.2±11.3 |
| 6 | 91.3±7.8 | 44.6±7.7*#& |
| 7 | 96.5±11.6 | 48.9±8.6*#& |
| 8 | 93.2±12.3 | 51.1±9.3*#& |
| 9 | 94.8±6.9 | 86.5±10.2 |
| 10 | 89.6±10.8 | 91.2±11.4 |
| 11 | 89.9±11.9 | 95.4±12.9 |
| 12 | 95.7±9.7 | 89.2±9.5 |
| 13 | 88.9±13.0 | 93.3±11.0 |
| 14 | 94.4±12.5 | 92.7±12.3 |
*: compare p<0.05 with model control group; #: compare p<0.05 with before self treatment; &: contrast with hydrochlorothiazide doxazosin group
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.
In effect example 3: α 1 receptor blocking agent and medetofazone drug regimen, different pharmaceutical ratio is to old hypertension in spontaneous hypertensive rats antagonism effect experimental
1, laboratory animal and experiment grouping
Male aged spontaneous hypertensive rat 250, body weight 330g ± 20g, adapts to raising after one week, is divided into 25 groups at random, often organize 10.
1. model control group: gavage gives same volume normal saline;
2. medetofazone+doxazosin group: 2.1mg/kg*d+0.01mg/kg*d
3. medetofazone+doxazosin group: 0.005mg/kg*d+1.8mg/kg*d
4. medetofazone+doxazosin group: 1.35mg/kg*d+0.034mg/kg*d
5. medetofazone+doxazosin group: 0.005mg/kg*d+1.5mg/kg*d
6. medetofazone+doxazosin group: 1.2mg/kg*d+0.06mg/kg*d
7. medetofazone+doxazosin group: 0.012mg/kg*d+1.2mg/kg*d
8. medetofazone+doxazosin group: 0.9mg/kg*d+0.65mg/kg*d
9. medetofazone+doxazosin group: 0.65mg/kg*d+0.9mg/kg*d
10. medetofazone+terazosin group: 1.9mg/kg*d+0.03mg/kg*d
11. medetofazones+terazosin group: 0.005mg/kg*d+2.2mg/kg*d
12. medetofazones+terazosin group: 1.2mg/kg*d+0.03mg/kg*d
13. medetofazones+terazosin group: 0.007mg/kg*d+2.1mg/kg*d
14. medetofazones+terazosin group: 1.35mg/kg*d+0.068mg/kg*d
15. medetofazones+terazosin group: 0.019mg/kg*d+1.9mg/kg*d
16. medetofazones+terazosin group: 0.95mg/kg*d+0.55mg/kg*d
17. medetofazones+terazosin group: 0.55mg/kg*d+0.95mg/kg*d
18. medetofazones+prazosin group: 1.6mg/kg*d+0.01mg/kg*d
19. medetofazones+prazosin group: 0.005mg/kg*d+2.5mg/kg*d
20. medetofazones+prazosin group: 1.15mg/kg*d+0.029mg/kg*d
21. medetofazones+prazosin group: 0.006mg/kg*d+1.75mg/kg*d
22. medetofazones+prazosin group: 1.26mg/kg*d+0.063mg/kg*d
23. medetofazones+prazosin group: 0.015mg/kg*d+1.5mg/kg*d
24. medetofazones+prazosin group: 0.9mg/kg*d+0.75mg/kg*d
25. medetofazones+prazosin group: 0.75mg/kg*d+0.95mg/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, after administration, 4th week measures blood pressure three times, averages; Each group of rat before administration one day and experiment is terminated optical fundus one day after and gets blood, centrifuging and taking serum, uses AU5800 series automatic clinical chemistry analyzer (Beckman Ku Erte) triglyceride (TG), the results are shown in Table 4.
3. experimental result
Table 4 different pharmaceutical combines the impact to old spontaneous hypertensive rat blood pressure (X ± S, n=10) (mmHg) and triglyceride (X ± S, n=10) (unit: mmol/L).
| Group | Blood pressure before treatment | Blood pressure after treatment | Triglyceride before treatment | Triglyceride after treatment |
| 1 | 176±5.8 | 179±10.6 | 1.25±0.08 | 1.27±0.12 |
| 2 | 178±8.9 | 169±11.5 | 1.22±0.11 | 1.32±0.15 |
| 3 | 180±6.8 | 168±13.0 | 1.19±0.13 | 0.98±0.14## |
| 4 | 179±7.1 | 164±9.8** | 1.26±0.05 | 1.29±0.17 |
| 5 | 177±4.3 | 165±8.5** | 1.23±0.12 | 1.05±0.11## |
| 6 | 179±4.5 | 149±9.7**** | 1.21±0.15 | 1.25±0.09 |
| 7 | 182±5.1 | 152±11.2**** | 1.24±0.09 | 1.06±0.13## |
| 8 | 180±4.6 | 125±10.2**** | 1.18±0.16 | 1.02±0.11## |
| 9 | 177±5.7 | 129±9.8**** | 1.23±0.05 | 1.06±0.06## |
| 10 | 179±3.3 | 170±15.6 | 1.21±0.18 | 1.31±0.05 |
| 11 | 178±4.9 | 169±14.0 | 1.19±0.25 | 0.92±0.13## |
| 12 | 177±9.0 | 165±5.9** | 1.20±0.21 | 1.29±0.15 |
| 13 | 181±6.9 | 165±9.2** | 1.23±0.14 | 0.96±0.12### |
| 14 | 179±6.6 | 156±8.2**** | 1.18±0.19 | 1.21±0.21 |
| 15 | 180±5.5 | 154±11.2**** | 1.21±0.22 | 1.04±0.06# |
| 16 | 181±4.7 | 134±13.1**** | 1.25±0.08 | 1.06±0.13### |
| 17 | 179±5.9 | 131±11.2**** | 1.21±0.15 | 1.03±0.07## |
| 18 | 179±8.8 | 168±9.9* | 1.19±0.13 | 1.30±0.15 |
| 19 | 181±6.4 | 171±7.2 | 1.26±0.17 | 1.01±0.10### |
| 20 | 180±4.2 | 162±9.5** | 1.24±0.14 | 1.27±0.11 |
| 21 | 178±8.6 | 164±10.2** | 1.18±0.12 | 1.05±0.04## |
| 22 | 182±5.1 | 153±9.6**** | 1.20±0.15 | 1.15±0.14 |
| 23 | 181±6.5 | 156±8.8**** | 1.19±0.08 | 1.06±0.12# |
| 24 | 178±9.9 | 129±12.7**** | 1.26±0.11 | 1.09±0.08### |
| 25 | 180±6.5 | 130±11.6**** | 1.20±0.07 | 1.02±0.14## |
*: with blood pressure contrast P<0.05 before self treatment; *: with blood pressure contrast P<0.01 before self treatment; * *: with blood pressure contrast P<0.001 before self treatment; * * *: with blood pressure contrast P<0.0001 before self treatment; #: with content of triglyceride contrast P<0.05 before self treatment; ##: with content of triglyceride contrast P<0.01 before self treatment; ###: with content of triglyceride contrast P<0.001 before self treatment
8,9,16,17,24,25 can obtain the most obvious blood pressure range of decrease and stablize the obvious triglyceride range of decrease as can be seen from the above results, the result shows and can obtain obvious antihypertensive effect when the weight ratio of α 1 receptor blocking agent and medetofazone is within 0.5 ~ 30:0.1 ~ 20, then more significantly can reduce rat blood pressure when reducing this ratio range to 0.5 ~ 20:0.2 ~ 10, meanwhile can stablize and the content of triglyceride in obvious reduction rat blood.And when exceeding this ratio of 0.5 ~ 30:0.1 ~ 20, antihypertensive effect is not obvious.
In effect example 3: α 1 receptor blocking agent and medetofazone 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. medetofazone+doxazosin group: 0.05mg/kg*d+0.4mg/kg*d
3. medetofazone+doxazosin group: 0.04mg/kg*d+0.75mg/kg*d
4. medetofazone+doxazosin group: 0.06mg/kg*d+0.2mg/kg*d
5. medetofazone+terazosin group: 0.05mg/kg*d+0.5mg/kg*d
6. medetofazone+terazosin group: 0.04mg/kg*d+0.9mg/kg*d
7. medetofazone+terazosin group: 0.06mg/kg*d+0.1mg/kg*d
8. medetofazone+prazosin group: 0.05mg/kg*d+0.2mg/kg*d
9. medetofazone+prazosin group: 0.04mg/kg*d+0.5mg/kg*d
10. medetofazone+prazosin group: 0.06mg/kg*d+0.1mg/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 4 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 | 180±4.7 | 181±5.6 | 182±10.5 | 185±11.2 | 183±9.4 |
| 2 | 182±9.4 | 168±4.3 | 152±8.9 | 143±6.8 | 125±5.9*# |
| 3 | 183±7.2 | 167±7.7 | 153±7.2 | 140±9.2 | 123±7.7*# |
| 4 | 179±10.7 | 171±8.8 | 156±6.7 | 139±8.8 | 128±8.2*# |
| 5 | 181±9.7 | 171±12.3 | 155±9.9 | 145±7.6 | 130±9.2*# |
| 6 | 182±6.4 | 169±7.1 | 151±10.5 | 144±10.3 | 131±10.2*# |
| 7 | 180±5.5 | 168±5.1 | 154±4.6 | 146±11.5 | 129±9.7*# |
| 8 | 178±6.3 | 170±6.9 | 153±5.7 | 141±10.1 | 128±11.3*# |
| 9 | 184±4.3 | 169±10.2 | 158±11.2 | 138±7.9 | 132±5.1*# |
| 10 | 182±5.6 | 169±8.9 | 160±4.6 | 142±8.8 | 129±12.4*# |
*: compare p<0.05 with model control group; #: compare p<0.05 with before self treatment
Above result is found out, in appropriateness adjustment pharmaceutical composition, the ratio (part by weight is within 0.5 ~ 20:0.2 ~ 10) of medetofazone and α 1 receptor blocking agent, can play good therapeutic effect to high blood pressure disease.
Embodiment 1: the preparation (in 1000) of compound medicament composition 1 (tablet)
Core formulation:
Coating prescription
Opadry coating powder 4g
Purified water 45g
Preparation method:
(1) take the doxazosin of recipe quantity, medetofazone, pulverized 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) take the microcrystalline Cellulose of recipe quantity, calcium hydrogen phosphate, lactose, pregelatinized Starch, cross-linking sodium carboxymethyl cellulose, micropowder silica gel, magnesium stearate, sodium lauryl sulphate, pulverize 60 mesh sieves, mix homogeneously.
(3) by (1) and (2) mix homogeneously, intermediate is obtained.
(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: the preparation (in 1000) of compound medicament composition 2 (tablet)
Core formulation:
Coating prescription:
Opadry coating powder 4g
Purified water 45g
Preparation method:
(1) take the doxazosin of recipe quantity, medetofazone, pulverized 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) take the microcrystalline Cellulose of recipe quantity, calcium hydrogen phosphate, lactose, pregelatinized Starch, cross-linking sodium carboxymethyl cellulose, micropowder silica gel, magnesium stearate, sodium lauryl sulphate, pulverize 60 mesh sieves, mix homogeneously.
(3) by (1) and (2) mix homogeneously, intermediate is obtained.
(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%.
The preparation (in 1000) of embodiment 3, compound medicament composition 3 (capsule)
Prescription:
Preparation technology:
(1) pregelatinized Starch taking recipe quantity is dissolved in appropriate purified water, makes the aqueous solution of 3%, for subsequent use as binding agent.
(2) principal agent is crossed 80 sieves, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and magnesium stearate cross 60 mesh sieves respectively, for subsequent use.
(3) by principal agent, microcrystalline Cellulose, calcium hydrogen phosphate, lactose, carboxymethylstach sodium, micropowder silica gel, sodium lauryl sulphate 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.
The preparation (in 1000) of embodiment 4 compound medicament composition 4 (tablet)
Prescription:
Preparation method:
(1) take the terazosin of recipe quantity, medetofazone, pulverized 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) take the microcrystalline Cellulose of recipe quantity, calcium hydrogen phosphate, polyvinylpolypyrrolidone, lactose, pregelatinized Starch, cross-linking sodium carboxymethyl cellulose, micropowder silica gel, magnesium stearate, sodium lauryl sulphate, pulverize 60 mesh sieves, mix homogeneously.
(3) by (1) and (2) mix homogeneously, intermediate is obtained.
(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%.
The preparation (in 1000) of embodiment 5 compound medicament composition 5 (tablet)
Prescription:
Preparation technology:
(1) take the terazosin of recipe quantity, medetofazone, pulverized 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) take the microcrystalline Cellulose of recipe quantity, calcium hydrogen phosphate, lactose, polyvinylpolypyrrolidone, pregelatinized Starch, cross-linking sodium carboxymethyl cellulose, micropowder silica gel, magnesium stearate, sodium lauryl sulphate, pulverize 60 mesh sieves, mix homogeneously.
(3) by (1) and (2) mix homogeneously, intermediate is obtained.
(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%.
The preparation (in 1000) of embodiment 6 compound medicament composition 6 (capsule)
Prescription:
Preparation technology:
(1) pregelatinized Starch taking recipe quantity is dissolved in appropriate purified water, makes the aqueous solution of 3%, for subsequent use as binding agent.
(2) principal agent is crossed 80 sieves, microcrystalline Cellulose, calcium hydrogen phosphate, lactose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, micropowder silica gel, magnesium stearate, sodium lauryl sulphate cross 60 mesh sieves respectively, for subsequent use.
(3) by principal agent, dried starch, microcrystalline Cellulose, calcium hydrogen phosphate, lactose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, micropowder silica gel, sodium lauryl sulphate, add (1), make soft material, 20 orders are granulated.
(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: the preparation (in 1000) of compound medicament composition 7 (tablet)
Prescription:
Preparation technology:
(1) take the prazosin of recipe quantity, medetofazone, pulverized 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) take the microcrystalline Cellulose of recipe quantity, calcium hydrogen phosphate, lactose, pregelatinized Starch, carboxymethylstach sodium, micropowder silica gel, magnesium stearate, sodium lauryl sulphate, pulverize 60 mesh sieves, mix homogeneously.
(3) by (1) and (2) mix homogeneously, intermediate is obtained.
(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 8: the preparation (in 1000) of compound medicament composition 8 (tablet)
Prescription:
Preparation technology:
(1) take the prazosin of recipe quantity, medetofazone, pulverized 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) take the microcrystalline Cellulose of recipe quantity, calcium hydrogen phosphate, lactose, pregelatinized Starch, carboxymethylstach sodium, micropowder silica gel, magnesium stearate, sodium lauryl sulphate, pulverize 60 mesh sieves, mix homogeneously.
(3) by (1) and (2) mix homogeneously, intermediate is obtained.
(4) check intermediates content, calculate sheet weight, tabletting, control tablet hardness is 9kg.
(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 9: the preparation (in 1000) of compound medicament composition 9 (capsule)
Prescription:
Preparation technology:
(1) by prazosin, medetofazone, microcrystalline Cellulose, calcium hydrogen phosphate, lactose, pregelatinized Starch, carboxymethylstach sodium, micropowder silica gel, magnesium stearate, sodium lauryl sulphate 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.
Embodiment 10: the preparation (in 1000) of compound medicament composition 10 (tablet)
Core formulation:
Coating prescription
Opadry coating powder 4g
Purified water 45g
Preparation method:
(1) take the doxazosin of recipe quantity, medetofazone, pulverized 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) take the microcrystalline Cellulose of recipe quantity, calcium hydrogen phosphate, lactose, pregelatinized Starch, cross-linking sodium carboxymethyl cellulose, micropowder silica gel, magnesium stearate, sodium lauryl sulphate, pulverize 60 mesh sieves, mix homogeneously.
(3) by (1) and (2) mix homogeneously, intermediate is obtained.
(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%.
The preparation (in 1000) of embodiment 11 compound medicament composition 11 (tablet)
Prescription:
Preparation method:
(1) take the terazosin of recipe quantity, medetofazone, pulverized 80 mesh sieves, adopt equal increments method mix homogeneously.
(2) take the microcrystalline Cellulose of recipe quantity, calcium hydrogen phosphate, polyvinylpolypyrrolidone, lactose, pregelatinized Starch, cross-linking sodium carboxymethyl cellulose, micropowder silica gel, magnesium stearate, sodium lauryl sulphate, pulverize 60 mesh sieves, mix homogeneously.
(3) by (1) and (2) mix homogeneously, intermediate is obtained.
(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 12: the preparation (in 1000) of compound medicament composition 12 (capsule)
Prescription:
Preparation technology:
(1) by prazosin, medetofazone, microcrystalline Cellulose, calcium hydrogen phosphate, lactose, pregelatinized Starch, carboxymethylstach sodium, micropowder silica gel, magnesium stearate, sodium lauryl sulphate 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 (10)
1. treat a hypertensive pharmaceutical composition, it is characterized in that, by α
1receptor blocking agent, medetofazone and pharmaceutically acceptable adjuvant form, and wherein the weight ratio of α 1 receptor blocking agent and medetofazone is 0.5 ~ 30:0.1 ~ 20.
2. pharmaceutical composition as claimed in claim 1, is characterized in that, α 1 receptor blocking agent: medetofazone is 0.5 ~ 20:0.2 ~ 10.
3. pharmaceutical composition as claimed in claim 1, is characterized in that, described α
1receptor blocking agent is one or more mixture of prazosin, terazosin, doxazosin, trimazosin, alfuzosin, urapidil and physiologically acceptable salt or ester.
4. pharmaceutical composition as claimed in claim 1, is characterized in that, described α 1 receptor blocking agent is one or more mixture of prazosin, terazosin, doxazosin and physiologically acceptable salt or ester.
5. pharmaceutical composition as claimed in claim 1, it is characterized in that, described α 1 receptor blocking agent is one or more mixture of doxazosin and physiologically acceptable salt or ester.
6. the pharmaceutical composition as described in any one of claim 1-5, it 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.
7. pharmaceutical composition as claimed in claim 6, it is characterized in that, described binding agent is selected from: distilled water, ethanol, starch slurry, sodium carboxymethyl cellulose, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, hydroxypropyl emthylcellulose, polyvidone, syrup, rubber cement; Described filler is selected from: starch, Icing Sugar, dextrin, lactose, amylum pregelatinisatum, microcrystalline Cellulose, inorganic salts and mannitol; Described disintegrating agent is selected from: dried starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, gas-producing disintegrant; Described lubricant is selected from: magnesium stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycols and magnesium laurylsulfate; Described fluidizer is selected from: micropowder silica gel, Pulvis Talci; Described coating material is selected from: hydroxypropyl emthylcellulose, hydroxypropyl cellulose, No. VI, acrylic resin, polyvinylpyrrolidone, ethyl cellulose, cellulose acetate; Other described adjuvants are selected from: plasticizer, opacifier, and wherein plasticizer is as propylene glycol, Oleum Ricini, Polyethylene Glycol, silicone oil, glycerol, dimethyl phthalate or dibutyl ester, and wherein opacifier is as titanium dioxide.
8. the preparation method of pharmaceutical composition according to claim 1, comprises the 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.
9. the application of pharmaceutical composition as claimed in claim 1 in the hypertensive medicine of preparation treatment.
10. apply as claimed in claim 9, it is characterized in that, described hypertension is slight, Moderate Essential Hypertension, the secondary hypertension particularly caused by kidney damage; Described hypertension is the hypertension with old hyperlipidemia.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11771867B2 (en) | 2017-05-24 | 2023-10-03 | Mivi Neuroscience, Inc. | Suction catheter systems for applying effective aspiration in remote vessels, especially cerebral arteries |
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