CN101869562B - Levamlodipine compound medicinal preparation - Google Patents
Levamlodipine compound medicinal preparation Download PDFInfo
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- CN101869562B CN101869562B CN2010101669452A CN201010166945A CN101869562B CN 101869562 B CN101869562 B CN 101869562B CN 2010101669452 A CN2010101669452 A CN 2010101669452A CN 201010166945 A CN201010166945 A CN 201010166945A CN 101869562 B CN101869562 B CN 101869562B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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Abstract
The invention discloses a levamlodipine compound medicinal composition, which comprises levamlodipine or a pharmaceutically acceptable salt thereof, and a beta-alpha receptor antagonist. The medicament combining the levamlodipine and the beta-alpha receptor antagonist is used for treating high blood pressure, has good synergetic blood pressure reducing function, can reduce the administration dosage of the levamlodipine and the beta-alpha receptor antagonist while achieving the same or better blood pressure reducing effect, and reduces adverse reaction caused by large-dosage single medicament. In addition, the beta-alpha receptor antagonist also can suppress reflex tachycardia caused by the levamlodipine.
Description
Technical field
The invention belongs to pharmaceutical field, refer to a kind of Levamlodipine compound medicinal preparation especially.
Background technology
In recent years, along with improving constantly and the change of diet structure, the increase of life stress, the increase of aging population of China's living standards of the people, hypertensive sickness rate has progressively trend of rising, and it can cause the infringement of organs such as the heart, brain, kidney, and confidential relation is arranged with sugar, lipid metabolic disorder and diabetes, obviously reduce patient's quality of life, when serious in addition entail dangers to patient's life.And a large amount of internal authority hypertension clinical researches show the blood pressure lowering dynamics that strengthens, actively, make hyperpietic's blood pressure reduce to 130/85 millimetres of mercury following (it is following that the best should be reduced to 120/80 millimetres of mercury) enduringly, the target organ damages such as heart and brain kidney that cause of alleviating hypertension effectively, reduce or postpone the generation of complication such as apoplexy, coronary heart disease, angina pectoris, myocardial infarction, renal failure, atherosclerosis, aneurysm, reduce cardiovascular and cerebrovascular vessel incident rate, mortality rate and disability rate, improve patients ' life quality, prolong patient's life-span.
Studies show that much hypertension is by the coefficient result of different pathophysiological mechanisms, a kind of antihypertensive drugs can not act on these pathogenesis simultaneously, and escalated dose can only cause unnecessary side effect, stimulate the compensatory mechanism of body simultaneously, partial offset because of antihypertensive effect that escalated dose obtained.Purpose to hyperpietic's blood pressure lowering treatment is exactly patient's blood pressure to be reduced to normal range or acceptable level as far as possible, reduce the danger of the caused target organ damage of hypertension, the side effect of simultaneously avoiding antihypertensive drugs to greatest extent and being brought, and discover in addition, the hypotensive effect of most antihypertensive drugs is not enhanced with the increase of dosage, but its side effect strengthens with dosage.Therefore adopting two or more medication combined is the hypertensive effective ways of treatment, when the patient uses single medicine routine dose blood pressure can not be up to standard the time, recommends to adopt to comprise that the scheme of combination drug therapy of compound preparation treats.
Levamlodipine is China's the first chiral separation optical voidness medicine, also is the first chiral separation antihypertensive drug in the world, is a kind of long-acting, alkaline dihydropyridine calcium ion antagonist.It works by a kind of site that links to each other with dihydropyridine (N site) on the cell, and the retardance calcium ion is striden film and entered cardiac muscle and vascular smooth muscle cell, makes smooth muscle loosening, and vascular resistance descends, and brings high blood pressure down.At present the clinical experiment evidence Levamlodipine that shows therapeutic dose is atomic or do not have to cardiac contractile force and chamber conduction, is to the medicine of sympathetic activation effect minimum in the calcium ion antagonist.It can also treat the hypertension of heart failure; reverse ventricular hypertrophy; improve the lax function of diastole, renal function protecting, slight diuresis; prevention coronary heart disease, myocardial infarction and apoplexy; can also partly reverse the unusual circadian rhythm of blood pressure rhythm and pace of moving things, slight antiplatelet resists myocardial ischemia; arrhythmia increases insulin sensitivity and certain effects such as atherosclerosis.But Levamlodipine can cause the Secondary cases norepinephrine in the blood pressure lowering process and epinephrine increases, make increased heart rate and headache is arranged, untoward reaction such as blush, and be the reason of quite a few patient's drug withdrawal, be subjected to certain restriction clinically.
At present the hold concurrently medicine of α receptor retardation of β is widely used gradually, and wherein α receptor retardation distends the blood vessels and reduces peripheral vascular resistance, makes blood pressure drops, simultaneously blood fat and insulin resistant is produced useful influence.And the beta receptor retardation reduces cardiac output, and body produces adaptation response, and peripheral vascular resistance reduces; Reduce the nerve conduction of sympathetic fiber, the blocking-up sympathetic nerve suppresses norepinephrine and discharges; Blocking-up kidney beta receptor suppresses feritin and discharges, thereby causes blood pressure drops.The beta receptor retardation also can suppress the α receptor and block caused reflex tachycardia simultaneously.Its mechanism may for, the beta receptor retardation can cause that the activity (particularly skeletal muscle lipoprotein lipase) of weight increase, body endoenzyme reduces, insulin is removed and discharge capacity changes and the peripheral blood flow reduces so that reflexive peripheral vascular resistance raises, above-mentioned effect can alleviate because of simultaneous α receptor retarding effect, so in the collaborative raising of efficacy of antihypertensive treatment, the also corresponding minimizing of metabolism side reaction due to the beta receptor retardation merely.In a word, the α and the beta-blocker of a new generation obviously are better than beta-blocker in blood pressure lowering, do not have tangible glycolipid metabolism disorder, can be used as the first-selected medication of the sympathetic activation of hypertensive patients or angina pectoris, ventricular arrhythmia and patients with heart failure.Also there is the weak point of β and α receptor blocking agent simultaneously in the α receptor blocking agent but β holds concurrently, and can cause patient's bradycardia etc.
Summary of the invention
The present invention is directed to Levamlodipine of the prior art and easily cause the side effect of reflex tachycardia in independent medication blood pressure lowering process, purpose is to provide a kind of Levamlodipine compound medicinal preparation.
Levamlodipine compound drug composition of the present invention comprises Levamlodipine or its pharmaceutically acceptable salt, and the β α receptor blocking agent of holding concurrently.
Wherein, the described β α receptor blocking agent of holding concurrently is carvedilol, labetalol or arotinolol.
The structure of Levamlodipine of the present invention can make by the method for introducing among Chinese patent literature CN00102701.8 and the CN03821593.4 suc as formula shown in the I:
The structure of described carvedilol is suc as formula shown in the II,
The structure of described labetalol shown in formula III,
The structure of described arotinolol is suc as formula shown in the IV,
Preferably, the weight ratio of described Levamlodipine and described carvedilol is 1: 0.25-60, preferred 1: 2-8; The weight ratio of described Levamlodipine and described labetalol is 1: 5-800, preferred 1: 40-320; Perhaps, the weight ratio of described Levamlodipine and described arotinolol is 1: 0.25-60, preferred 1: 2-12.
Preferably, the content of described Levamlodipine is 0.05-10 weight %, preferred 0.125-2.5 weight %; The content of described carvedilol is 0.25-30 weight %, preferred 0.5-10 weight %, and the content of described labetalol is 5-80 weight %, preferred 10-60 weight %, perhaps the content of described arotinolol is 0.25-30 weight %, preferred 0.5-15 weight %.
Described pharmaceutically acceptable salt is selected from one or more in the following salt group: benzene sulfonate, mesylate, acetate, aspat, tartrate, maleate, sulfate, hydrochlorate and hydrobromate, preferred benzene sulfonate.
Levamlodipine compound medicinal preparation of the present invention also can comprise acceptable auxiliary on the pharmacopedics, for example is selected from the following material group one or more: microcrystalline Cellulose, pregelatinized Starch, lactose, Sodium Hydroxymethyl Stalcs magnesium stearate, Pulvis Talci and polyvinylpyrrolidone (being called for short PVP-k30).Adjuvant can add according to conventional amount used well known to those of ordinary skill in the art.
Levamlodipine compound medicinal preparation of the present invention can also comprise: acceptable diluent, binding agent, disintegrating agent, lubricant, coloring agent and/or correctives on the pharmacopedics.
Levamlodipine compound medicinal preparation of the present invention can be preferably oral formulations for any form preparation, and oral formulations can be dosage forms such as solution, suspension, tablet, pill, capsule, powder.These dosage forms can be according to well known to a person skilled in the art the method preparation.
Levamlodipine compound medicinal preparation of the present invention can also be controlled release form such as slow releasing preparation or quick releasing formulation, and this controlled release preparation can be according to well known to a person skilled in the art the method preparation.
Positive progressive effect of the present invention is: the present invention has good collaborative hypotensive effect each other with Levamlodipine and the β α receptor blocking agent drug combination of holding concurrently.When reaching identical even more excellent blood pressure lowering effect, can reduce the hold concurrently dosage of α receptor blocking agent of Levamlodipine and β, reduced the untoward reaction that single medicine heavy dose causes, patient's compliance is good, can also reduce the incidence rate of cardiovascular and cerebrovascular vessel incident, improve patient's quality of life.The β α receptor blocking agent of holding concurrently also can suppress the caused reflex tachycardia of Levamlodipine in addition.
The specific embodiment
The drop test of effect embodiment 1 rat
Experimental technique: get 110 of healthy spontaneously hypertensive SHR rats, male and female half and half, body weight 200-240g, the male and female rat balancedly is divided into 11 groups according to the blood pressure height, and concrete group technology sees Table 1.Adopt gastric infusion, one day twice, adopt rat electronic blood pressure instrument for blood pressure, the clear-headed systolic pressure when quiet of tail volumetric method indirect determination rat, respectively before medication, one week of medication, two weeks, three weeks, the end is carried out the arteria caudalis systolic pressure and is measured all around.
The grouping of table 1SHR rat
Remarks: Levamlodipine besylate is in Levamlodipine in the table
Experimental result: 1 group of single medicine, 2 groups of single medicines, 3 groups of single medicines, 4 groups of single medicines, 1 group of compound recipe, 2 groups of compound recipes, 3 groups of compound recipes, 4 groups of compound recipes, 5 groups of compound recipes, 6 groups of compound recipes and model group relatively have significant hypotensive effect; 1 group of compound recipe, 2 groups of compound recipes and 1 group of single medicine, single medicine relatively have significant hypotensive effect for 2 groups; 3 groups of compound recipes, 4 groups of compound recipes and 1 group of single medicine, single medicine relatively have significant hypotensive effect for 3 groups; 5 groups of compound recipes, 6 groups of compound recipes and 1 group of single medicine, single medicine relatively have significant hypotensive effect for 4 groups.1 group of single medicine, 2 groups of single medicines, 3 groups of single medicines, 4 groups of single medicines, 1 group of compound recipe, 2 groups of compound recipes, 3 groups of compound recipes, 4 groups of compound recipes, 5 groups of compound recipes, 6 groups of blood pressure lowering rates of compound recipe are followed successively by 19.2%, 15.2%, 15.0%, 13.5%, 28.2%, 30.6%, 30.0%, 31.3%, 27.6%, 30.7%.Concrete experimental result sees Table 2.
Table 2 Levamlodipine, β α receptor blocking agent and compound preparation administration thereof the influence of holding concurrently to the SHR rat blood pressure
Remarks:
#Compare p＜0.05 with the blank group of model,
*Compare p＜0.01 with the blank group of model,
﹠amp;Compare p＜0.05 for 1 group with single medicine,
Compare p＜0.01 for 1 group with single medicine,
Compare p＜0.05 for 2 groups with single medicine,
■Compare p＜0.01 for 2 groups with single medicine,
◇Compare p＜0.05 for 3 groups with single medicine,
◆Compare p＜0.01 for 3 groups with single medicine,
△Compare p＜0.05 for 4 groups with single medicine,
▲Compare p＜0.01 for 4 groups with single medicine.
Conclusion: the hold concurrently compound preparation of α receptor blocking agent of Levamlodipine and β has better hypotensive effect than Levamlodipine and the β α receptor blocking agent of holding concurrently, on antihypertensive effect, has significant difference, Levamlodipine and the β α receptor blocking agent drug combination of holding concurrently has shown certain synergism to spontaneous hypertensive rat, is better than two kinds of curative effects that medicine is individually dosed.
The preparation of embodiment 1-12 compound tablet
The prescription of table 3 embodiment 1-12 compound tablet
The prescription of table 3 (continuing) embodiment 1-12 compound tablet
Preparation technology: with Levamlodipine besylate, β hold concurrently α receptor blocking agent, microcrystalline Cellulose, pregelatinized Starch, lactose, that Sodium Hydroxymethyl Stalcs is put into the mortar ground and mixed is even, cross 20 mesh sieves, add an amount of 95% ethanol and make soft material, granulate by 20 mesh sieves, 40 ℃ of aeration-dryings, dry granular adds magnesium stearate with 16 mesh sieve granulate, and tabletting promptly behind the mix homogeneously.
The preparation of embodiment 13-17 compound capsule
The prescription of table 4 embodiment 13-17 compound capsule
Preparation technology: with Levamlodipine besylate, β hold concurrently the α receptor blocking agent, that microcrystalline Cellulose is put into the mortar ground and mixed is even, cross 20 mesh sieves, add an amount of 0.5%PVP-k30 alcoholic solution and make soft material, granulate by 20 mesh sieves, 40 ℃ of aeration-dryings, dry granular adds Pulvis Talci with 16 mesh sieve granulate, divides promptly encapsulated behind the mix homogeneously.
Claims (6)
1. a Levamlodipine compound medicinal preparation is characterized in that comprising Levamlodipine besylate, and the β α receptor blocking agent of holding concurrently, and the described β α receptor blocking agent of holding concurrently is carvedilol, labetalol or arotinolol; The weight ratio of described Levamlodipine besylate and described carvedilol is 1: 0.25-60; The weight ratio of described Levamlodipine besylate and described labetalol is 1: 5-800; Perhaps, the weight ratio of described Levamlodipine besylate and described arotinolol is 1: 0.25-60; In the above proportioning, the Levamlodipine besylate conversion is the weight meter of Levamlodipine.
2. Levamlodipine compound medicinal preparation as claimed in claim 1, the weight ratio that it is characterized in that described Levamlodipine besylate and described carvedilol is 1: 2-8; The weight ratio of described Levamlodipine besylate and described labetalol is 1: 40-320; Perhaps, the weight ratio of described Levamlodipine besylate and described arotinolol is 1: 2-12.
3. Levamlodipine compound medicinal preparation as claimed in claim 2, the content that it is characterized in that described Levamlodipine besylate are 0.05-10 weight %; The content of described carvedilol is 0.25-30 weight %, and the content of described labetalol is 5-80 weight %, and perhaps the content of described arotinolol is 0.25-30 weight %.
4. Levamlodipine compound medicinal preparation as claimed in claim 3, the content that it is characterized in that Levamlodipine besylate are 0.125-2.5 weight %; The content of described carvedilol is 0.5-10 weight %, and the content of described labetalol is 10-60 weight %, and perhaps the content of described arotinolol is 0.5-15 weight %.
5. Levamlodipine compound medicinal preparation as claimed in claim 1 is characterized in that also comprising acceptable auxiliary on the pharmacopedics; Acceptable auxiliary is selected from one or more in the following material group on the described pharmacopedics: microcrystalline Cellulose, pregelatinized Starch, lactose, Sodium Hydroxymethyl Stalcs, magnesium stearate, Pulvis Talci and polyvinylpyrrolidone.
6. Levamlodipine compound medicinal preparation as claimed in claim 5 is characterized in that described pharmaceutical preparation also comprises: acceptable diluent, binding agent, disintegrating agent, lubricant, coloring agent and/or correctives on the pharmacopedics.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101669452A CN101869562B (en) | 2010-05-06 | 2010-05-06 | Levamlodipine compound medicinal preparation |
| PCT/CN2010/074130 WO2011137601A1 (en) | 2010-05-06 | 2010-06-21 | Compound pharmaceutical formulation of levoamlodipine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101669452A CN101869562B (en) | 2010-05-06 | 2010-05-06 | Levamlodipine compound medicinal preparation |
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| Publication Number | Publication Date |
|---|---|
| CN101869562A CN101869562A (en) | 2010-10-27 |
| CN101869562B true CN101869562B (en) | 2011-12-07 |
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| CN2010101669452A Expired - Fee Related CN101869562B (en) | 2010-05-06 | 2010-05-06 | Levamlodipine compound medicinal preparation |
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| WO (1) | WO2011137601A1 (en) |
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| CN103239723B (en) * | 2013-04-26 | 2014-03-19 | 江苏吉贝尔药业有限公司 | Compound antihypertensive agent |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1562369A (en) * | 2004-03-29 | 2005-01-12 | 王德山 | Combination of medication for curing high blood pressure |
| WO2005099699A1 (en) * | 2004-04-07 | 2005-10-27 | Sepracor Inc. | Combination of (s)-amlodipine and a beta-blocker, and methods for reducing hypertension |
| CN101249083A (en) * | 2008-03-21 | 2008-08-27 | 北京润德康医药技术有限公司 | Compound extended release formulation containing amlodipine and metoprolol and preparation |
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2010
- 2010-05-06 CN CN2010101669452A patent/CN101869562B/en not_active Expired - Fee Related
- 2010-06-21 WO PCT/CN2010/074130 patent/WO2011137601A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1562369A (en) * | 2004-03-29 | 2005-01-12 | 王德山 | Combination of medication for curing high blood pressure |
| WO2005099699A1 (en) * | 2004-04-07 | 2005-10-27 | Sepracor Inc. | Combination of (s)-amlodipine and a beta-blocker, and methods for reducing hypertension |
| CN101249083A (en) * | 2008-03-21 | 2008-08-27 | 北京润德康医药技术有限公司 | Compound extended release formulation containing amlodipine and metoprolol and preparation |
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| CN101869562A (en) | 2010-10-27 |
| WO2011137601A1 (en) | 2011-11-10 |
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