CN101433536A - Therapeutic compositions containing amlodipine niacin and losartan medicament - Google Patents
Therapeutic compositions containing amlodipine niacin and losartan medicament Download PDFInfo
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Abstract
The invention relates to a pharmaceutical composition of amlodipine besylate and sartan compounds or pharmaceutically salts thereof and a preparation method thereof, and a medicine box of a drug combination containing the composition of amlodipine besylate compound and the sartan compound. The composition or the medicine box can be used for treating patients suffering from hypertension, angina pectoris, atherosclerosis and/or accompanied hypertension, and patients (including human beings) having heart risky symptoms.
Description
Technical field
The present invention relates to pharmaceutical composition of amlodipine niacin and Sha Tan compounds or its officinal salt and preparation method thereof, the invention still further relates to the medicine box of the drug combination that comprises amlodipine niacin compositions and Sha Tan compounds compositions.Above-mentioned composition or medicine box can be used to treatment and suffer from hypertension, angina pectoris, atherosclerosis, and/or there are patient's (comprising the mankind) of cardiac risk symptom in the patient of complicated hypertension and treatment.
Background technology
Hypertension has become one of main killer of harm humans health.At present, more American-European national hypertension incidence rates are up to 20%, and according to statistics, the U.S. has 4,300 ten thousand people to suffer from hypertension; China's hypertension average attack rate is 11.88%, and China surpasses 1.4 hundred million people and suffers from hypertension, and affluent city (as Beijing, Shanghai, Guangzhou) up to 14%, in recent years, and in the speed increment that surpasses 3,000,000 people with every year.
World Health Organization's suggestion Evaluation of Diagnostic Criteria of Hypertension surpasses 21.3/12.6kPa (160/95mmHg) person for adult's blood pressure.Hypertension is divided into essential hypertension and secondary hypertension by morbidity, and wherein essential hypertension accounts for 90%; Secondary hypertension accounts for 5%～10%.Hypertension is a kind of performance of some disease, as is secondary to renal artery stenosis, excess of the kidney matter pathological changes, pheochromocytoma, gestation or because of drug-induced etc.Essential hypertension is under various factors influence, and due to the blood pressure regulating functional disorder, the cause of disease is not illustrated fully, but its Drug therapy existing remarkable break-throughs in nearly decades.
Because hypertensive influence, annual have a large amount of people to suffer from complication, serious caused deformity even death such as cerebral hemorrhage, apoplexy, coronary heart disease, renal failure again.The rational Application antihypertensive drug really can controlling blood pressure and reduce or prevent complication such as the heart, brain, kidney, as heart failure, sudden death etc., thereby reduces sickness rate and mortality rate, life-saving.Most hyperpietics finally need take medicine with controlling symptoms for a long time, if can cooperate non-drug therapy, as low salt diet, reduce and drink, controlling body weight, change lifestyles etc., can obtain better effect.
Antihypertensive medicine is a lot, according to the mechanism of action and the position of medicine, antihypertensive drug can be divided into following a few class: (one) diuretic mainly influences the antihypertensive of blood volume, as the chlorothiazides diuretic; (2) tonin inhibitor influences the antihypertensive that Angiotensin II forms, as captopril; (3) beta receptor blocking agent is as Propranolol; (4) calcium antagonists is as nifedipine; (5) sympathetic nerve depressant comprises that 1. mainly act on the antihypertensive of central position, as clonidine; 2. ganglion blocker is as mecamylamine; 3. anti-noradrenergic nerve tip medicine, as reserpine, guanethidine etc.; 4. adrenoreceptor blocking agent is as prazosin, labetalol.(6) antihypertensive of vasoactive smooth muscle is as hydralazine.
In recent years, because the development of molecular biology, biochemical research technology, the angiotensin-ii receptor Research development of inhibitors is rapid, and great breakthrough has been arranged.Angiotensin-ii receptor has four kinds of hypotypes, i.e. AT
1, AT
2, AT
3And AT
4In human body cardiovascular, adrenal cortex and kidney, AT
1Receptor has comparative advantage, and the medicine that is used for clinical treatment at present is to have optionally AT
1Acceptor inhibitor.
After Angiotensin II (Ang II) acceptor inhibitor listing in 1994, research worker is on the basis of its parent nucleus, to its compound structure addition, derive, modify, constantly strengthened its blood pressure lowering curative effect, prolonged action time, reduce toxic and side effects, further promoted the development process of this class medicine, thereby formed the serial chemicals that is referred to as " husky smooth class ".Sartans is a class newtype drug of developing in recent years, has brand-new blood pressure lowering mechanism, hypotensive effect steadily, good effect, long action time, patient tolerability be good, become antihypertensive first-line treatment medication at present, carrying out the clinical research of its treatment diabetes and heart failure at present.The angiotensin-ii receptor inhibitor of present clinical use is non-peptide medicament, comprises Losartan Potassium, irbesartan, Candesartan, Tasosartan, eprosartan, telmisartan and valsartan.
Amlodipine and relevant dihydropyridine compound are disclosed in United States Patent (USP) 4,572,909, and this article is hereby incorporated by reference, and they are effective anti-ischemic and antihypertensive.United States Patent (USP) 4,879,303, this article is hereby incorporated by reference, and discloses amlodipine sulfonate (being also referred to as the sulfonic acid amlodipine).Amlodipine sulfonate is sold with " Norvasc " trade name at present.Amlodipine sulfonate and amlodipine and other pharmaceutically acceptable acid addition salts can be used as antihypertensive and anti-ischemic.Chinese patent CN00,124,812 disclose amlodipine niacin, and this article is hereby incorporated by reference.
Because hypertension is a cause of disease and the very complicated syndrome of pathogenesis, existing nerve also has the unusual of body fluid aspect, and often have influence on the 26S Proteasome Structure and Function of each organ of body, system, the patient most simultaneously with other disease after one's own heart, brain, kidney or angiopathy, insulin sensitivity reduction, dyslipidemia etc.Therefore, share the different depressor of mechanism of action and often can strengthen therapeutic effect, look after the different links in the hypertension incidence mechanism simultaneously, make multiple risk factor or and deposit disease and obtain Optimal Control, more help the protection of hypertension target organ 26S Proteasome Structure and Function, further reduce the incidence rate of cardiovascular event; Secondly, because when forming immobilised compound, the dosage of each single medicine all has minimizing, thereby the incidence rate of drug side effect reduces; About medical expense, reduce when using separately owing to used drug dose ratio, not only can not increase, may descend on the contrary, feasible benefit/expense ratio for the treatment of is significantly improved.Therefore patient's treatment compliance increases greatly, and quality of life also just obviously improves.The fixed compound preparation of antihypertensive low dose not only can be used as the two wires medicine, also can be used as a line medicine and is used for hypertensive treatment, and is all the more so when especially the patient has other complication or complication to exist simultaneously.
CN99,809,776 and division CN200,510,072,738 have described the pharmaceutical composition of Amlodipine Besylate Tablet and valsartan, and the method for suffering from the patient of hypertension or heart failure with these combination treatments.CN200,510,098,619 describe and to contain the compositions that comprises Amlodipine Besylate Tablet and angiotensin-ii receptor inhibitor and to hypertension and individual and exist the individuality of cardiac risk symptom to comprise the method that the people treats.
Yet Amlodipine Besylate Tablet does not have enough good dissolubility in water, and is well-known, amlodipine itself promptly has onset weakness more slowly, this will further influence the bioavailability and the onset time of amlodipine, and in addition, Amlodipine Besylate Tablet does not have enough lights resistance.Thereby with its be the compositions of composition will have further space improve its in aqueous solution dissolubility and improve light resistance.Therefore, an object of the present invention is to provide stabilization formulations with good bioavailability.Another object of the present invention provides the stable composition with levels of impurities and/or catabolite, and described impurity and/or degraded may betide preparation of compositions and/or lay up period subsequently.Amlodipine and Sha Tan compounds can be mixed with stable single dose form, and use the bioavailability with equivalence separately with separate dosage forms, and contain very low-level impurity and/or catabolite.
Summary of the invention
Niacin compound serving belongs to vitamin B group, comprises nicotinic acid and derivant thereof.Nicotinic acid has another name called vitamin B3, vitamin PP, nicotinic acid, antipellagra factor etc.The nicotinic acid stable in properties, survivable under acid, alkali, oxygen, light or heating condition.Under high pressure, 120 ℃ were not destroyed in 20 minutes yet.Amlodipine niacin is the same with nicotinic acid to have excellent stability.
Thereby a first aspect of the present invention provides a kind of " compositions " that contains following composition that relate to:
A) a certain amount of amlodipine niacin;
B) a certain amount of one or more husky smooth compounds or its officinal salts; And
C) pharmaceutically suitable carrier or diluent,
Amlodipine niacin in the compositions has dissolubility and the light stability of significantly improving than Amlodipine Besylate Tablet, and then the pharmacologically active of enhancing composition.In addition, salifiable nicotinic acid is not only salifiable auxiliary element, and itself also has useful pharmacological action.
A second aspect of the present invention relates to the medicine box hereinafter referred to as " medicine box A " that obtains therapeutic effect mammal on one's body, and it consists of the following components:
A) contain first kind of unit dosage forms of a certain amount of amlodipine niacin and pharmaceutically suitable carrier or diluent;
B) contain second kind of unit dosage forms of a certain amount of one or more husky smooth compounds or its officinal salt and pharmaceutically suitable carrier or diluent;
C) be used for holding the container of said first and second kinds of unit dosage forms.
A third aspect of the present invention relates to above-mentioned composition or the application of medicine box on the angina pectoris of treatment mammal, atherosclerosis and/or complicated hypertension and hyperlipemia.
Because 4 of dihydropyridine ring are asymmetric, amlodipine is a racemic compound.Its R and S enantiomer can be by people such as Arrowsmith (J Med Chem, 1986,26,1696 described method preparations.The calcium channel blocking-up activity of amlodipine is confined to the S-isomer basically, (sees that International Patent Application PCT/EP94/02697) the R isomer is few of, does not have the calcium channel blocking-up active in other words at all in the racemic mixture of isomer.But R (+) isomer is effective smooth muscle cell migration inhibitor.Therefore, R (+) isomer is used to treatment or prevention of arterial atherosis (seeing International Patent Application PCT 95/00847).Based on above-mentioned viewpoint, the professional and technical personnel can select R (+) isomer, and the racemic mixture of S (-) isomer and R (+) isomer and S (-) isomer is united and is used for the present invention.
Detailed Description Of The Invention
The present invention relates to contain the pharmaceutical composition of amlodipine niacin and/or husky smooth compounds or its officinal salt.
Amlodipine can be at an easy rate according to United States Patent (USP) 4,572,909 described method preparations, and this article is hereby incorporated by reference.Amlodipine niacin can be at an easy rate according to Chinese patent CN00,124,812 described method preparations, and this article is hereby incorporated by reference.Amlodipine and amlodipine niacin all are effective and long-acting calcium channel blockers.
Described " husky smooth class " chemical compound refers to Losartan Potassium, irbesartan, Candesartan, Tasosartan, eprosartan, telmisartan and valsartan or its officinal salt, preferred irbesartan and valsartan or its officinal salt.
Term " officinal salt " had both comprised the pharmaceutically acceptable acid addition salts, also comprised pharmaceutically acceptable cationic salts.Term " pharmaceutically acceptable cationic salts " is to define (but being not limited to) following salt: alkali metal salt (as sodium salt and potassium salt), alkali salt (as calcium salt and magnesium salt), aluminum salt, ammonia salt and the salt that forms with organic amine, organic amine comprises that Benzathini Benzylpenicilinum (is N, N '-dibenzyl-ethylenediamin), choline, diethanolamine, ethylenediamine, meglumine (being the N-methylglucosamine), benzyl ethamine (being N-benzyl ethamine), diethylamine, piperazine, trometamol (being 2-amino-2-methylol-1, ammediol) and procaine.
The pharmaceutically acceptable cationic salts of other husky smooth class can be by the smooth class of sand free acid form and the suitable two normal alkali that are generally in cosolvent, react and make at an easy rate.Typical alkali comprises sodium hydroxide, Feldalat NM, Sodium ethylate, sodium hydride, Feldalat KM, magnesium hydroxide, calcium hydroxide, Benzathini Benzylpenicilinum, choline, diethanolamine, according to calling out and meglumine.By concentrating or separating this salt by adding non-solvent.As a rule, preferably acid solution is mixed in solvent (as ethyl acetate) with different cationic salts (as hexyl Sodium caproate or potassium, magnesium oleate), obtain desired salt by precipitation.Also can and/or add non-solvent and isolate salt by concentrated reaction solution.
But compositions described herein self is applied to the patient, or itself and other active component, or suitable carriers or mixed with excipients become to be used for therapeutic alliance in the pharmaceutical compositions.The preparation of the application's chemical compound and the technology of using are found in " Remington ' spharmaceutical " Mack Publishing Co., Easton, PA, 18
ThEdition, 1990.
That suitable route of administration can comprise is oral, rectum, stride mucosa or enteral is used.Perhaps, can the part rather than the mode administered compound of whole body, for example, with the form of depot or slow releasing preparation.In addition, can drug target delivery system drug administration, for example, with the liposome form of tissue specificity antibody sandwich.Organ will be with liposome as target and carry out selectivity and absorb.
Can produce pharmaceutical compositions of the present invention in known manner, for example, by traditional mixing, dissolving, granulation, one-tenth ingot, grinding, emulsifying, encapsulation or tabletting method.
Therefore, pharmaceutical compositions used according to the invention can be made in a conventional manner, and this mode uses one or more physiology to go up acceptable carrier, and these carriers comprise pharmaceutically acceptable excipient and the adjuvant of being convenient to reactive compound is processed into preparation.Appropriate formulation depends on the route of administration of selection.Can use this area any suitable know technology, carrier and excipient, described in above-mentioned Remington ' s pharmacy.
For Orally administered, can be by reactive compound and pharmaceutically suitable carrier well known in the art combination be easily made compositions.These carriers can be made The compounds of this invention tablet, pill, powder agent, lozenge, capsule, gel, syrup, unguentum, suspension, cachet and suppository etc., are used for the patient and orally use.The pharmaceutical formulations that orally uses can be by mixing acquisitions with one or more solid excipient with pharmaceutical compositions of the present invention, chooses the mixture that adds when needed after the proper supplementary material generation wantonly and grinds, and handle that particulate mixture gets tablet or lozenge is examined.Particularly, suitable excipient, particularly filler such as sugar comprise lactose, sucrose, mannitol or sorbitol; Cellulose preparation for example, corn starch, wheaten starch, rice starch, potato starch, gelatin, tragakanta, methylcellulose, HYDROXY PROPYL METHYLCELLULOSE, sodium carboxy methyl cellulose and/or polyvinylpyrrolidone (PVP).If need, can be with disintegrating agent, as crospolyvinylpyrrolidone, agar or alginic acid or its salt, as sodium alginate.Anion surfactant comprises docusate sodium, sodium lauryl sulfate; Binding agent comprises arabic gum, sodium carboxymethyl cellulose, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, aluminium-magnesium silicate, maltodextrin, methylcellulose, polymethacrylates, polyvidon, starch,pregelatinized, sodium alginate, starch and zein; Cationic surfactant comprises Benzalkonii Chloridum, benzene rope chloramines; Diluent comprises calcium carbonate, calcium sulfate, dextrose, dextrin, Macrose, bibasic calcium phosphate dihydrate, palmityl stearoyl glyceride, hydrogenated vegetable oil, Kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline Cellulose, polymethacrylates, potassium chloride, cellulose powder, starch,pregelatinized, sodium chloride, Sorbitol, starch, Talcum and three alkali valency calcium phosphate; Disintegrating agent comprises carboxymethylcellulose calcium, sodium carboxymethyl cellulose, silica sol, polyvinylpyrrolidone, guar gum, aluminium-magnesium silicate, methylcellulose, microcrystalline Cellulose, cellulose powder, starch,pregelatinized, sodium alginate, glycolic sodium starch and starch; Correctives comprises ethyl maltitol, ethyl vanillin, maltol, menthol and vanillin; Fluidizer comprises silica sol, magnesium trisilicate, cellulose powder, starch, Talcum and dalcium biphosphate; Granulation agent comprises arabic gum, glucose, gelatin, polyvidon, starch and yellow glue; Lubricant comprises that calcium stearate, tristerin, palmityl stearoyl glyceride, castor oil hydrogenated, hydrogenated vegetable oil, stearic silicon magnesium, mineral oil, Polyethylene Glycol, sodium benzoate, sodium lauryl sulfate, stearoyl prolong fumaric acid sodium, stearic acid, Talcum and zinc stearate; Nonionic surfactant comprises olein, polyoxyethylene sorbitan fatty acid esters, polyvinyl alcohol and sorbitan ester; Antiseptic comprises alcohol, Benzalkonii Chloridum, benzethonium chloride, benzylalcohol, bronopol, butyl p-hydroxybenzoate, cetab, chlohexidine, methaform, chlorocresol, cresol, ethylparaben, glycerol, methyl parahydroxybenzoate, phenol, phenyl phenol, phenyl hexyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium sorbate, propylene glycol, propyl p-hydroxybenzoate, sodium benzoate, sodium propionate and thimerosal; Solubilizing agent comprises Benzalkonii Chloridum, benzyl rope chloramines, benzyl benzoate, cyclodextrin, tristerin, lecithin, poloxamer, polyoxyethylene alkyl ether, castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, Myrj 45, sorbitan ester and stearic acid; Suspending agent comprises arabic gum, bentonite, Linesless charcoal, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, silica sol, dextrin, gelatin, guar gum, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, Kaolin, aluminium-magnesium silicate, maltitol solution, methylcellulose, microcrystalline Cellulose, polyvidon, cellulose powder, propylene glycol alginate, sodium alginate, primojel, starch, yellow glue and Xanthan gum.
For lozenge nuclear provides suitable coating.For this purpose, available spissated sugar juice, it can be chosen wantonly and comprise arabic gum, Talcum, polyvinylpyrrolidone, carbopol gel, Polyethylene Glycol and/or titanium dioxide, lacquer solution and appropriate organic solvent or solvent mixture.Dyestuff or pigment can be added in tablet or the lozenge coating combination with identification or qualitative different activities chemical compound dosage.
The pharmaceutical formulations that can orally use comprises plug-in type capsule of being made by gelatin and sealing soft capsule and the plasticizer of being made by gelatin, as glycerol or sorbitol.The plug-in type capsule can comprise active component, this composition and filler, and as lactose, binding agent is as starch and/or lubricant, as Talcum or magnesium stearate and optional stabilizer mixing.In soft capsule, can or be suspended in suitable fluid with the reactive compound dissolving, in fatty oil, liquid paraffin or liquid macrogol.In addition, can add stabilizing agent.All Orally administered preparations should be and are suitable for Orally administered dosage form.
For oral administration, compositions can adopt tablet or the lozenge form of making in a conventional manner.
Chemical compound also can be made into the rectum compositions, as suppository or enema,retention, for example, comprises traditional suppository base, as cupu oil or other glyceride.
Except that previous formulations, chemical compound also can be made into depot formulation.These durative action preparations can pass through to implant, for example, and subcutaneous or intramuscular.Therefore, for example, polymerization that chemical compound can be suitable or hydrophobic material (for example, the Emulsion in the suitable oil) or ion exchange resin, or slightly soluble derivant, for example, the preparation of slightly soluble salt.
In powder agent, carrier is finely divided solid, it be with the mixture of finely divided active component in.
Perhaps, can use other delivery system of hydrophobic pharmaceutical compound.Liposome and Emulsion are to send the medium of dewatering medicament or the well-known example of carrier.Also can use some organic solvent, as dimethyl sulfoxide, although have bigger toxicity usually.In addition, can use lasting delivery systme to send chemical compound, as comprise the polymeric semi permeability substrate of solid hydrophobic of medicine.Set up the material of various lasting releases, and be well known to those skilled in the art.Depend on its chemical property, the capsule that continues to discharge can discharge several weeks of chemical compound, nearly more than 100 day.Depend on the chemical property and the biological stability of treatment reagent, can use other strategy of stabilize proteins.
The chemical compound lot that is used for pharmaceutical compositions of the present invention can be the salt with pharmaceutically acceptable equilibrium ion.Officinal salt can be many acid form, these acid include, but are not limited to hydrochloric acid, sulphuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid etc.The dissolubility of salt in aqueous or other protonic solvent is tending towards greater than corresponding free acid or alkali form.
The pharmaceutical compositions that is suitable for the present invention's use comprises some compositions, wherein comprises effective amount of actives, to realize its intended purposes.More specifically, effectively therapeutic dose refers to that chemical compound effectively prevents, alleviates or improve the amount of disease symptoms or extended treatment patient survival.Effectively the definite of therapeutic dose is positioned within those skilled in the art's the limit of power well, especially according to provided herein disclosing in detail.
Pharmaceutical preparation preferably contains the unit dosage form of the active component of appropriate amount.Unit dosage form can be a packaged preparation, and packing contains the preparation dispersion amount, parcel tablet for example, the powder agent in capsule and bottle or the ampoule.Also have, unit dosage form itself can be a capsule, tablet, and cachet or lozenge, perhaps it can be the packaged form of proper number.
Specifically, the present invention relates to contain " compositions " of following composition:
A) a certain amount of amlodipine niacin;
B) a certain amount of one or more husky smooth compounds or its officinal salts; And
C) pharmaceutically suitable carrier or diluent.
It can improve the dissolubility of amlodipine in the compositions and improve light stability, and then the pharmacologically active of enhancing composition.In addition, salifiable nicotinic acid is not only salifiable auxiliary element, and itself also has useful pharmacological action.Simultaneously, use benzenesulfonic acid to have shortcoming in process of production, promptly benzenesulfonic acid is difficult in industrial processing because of corrosivity and toxicity, its height hygroscopicity requires specific transportation, conveying and use step, in addition, another shortcoming is that the water content of benzenesulfonic acid is too high, approximates 10%.Described " husky smooth class " chemical compound refers to Losartan Potassium, irbesartan, Candesartan, Tasosartan, eprosartan, telmisartan and valsartan or its officinal salt, preferred irbesartan and valsartan or its officinal salt.
One skilled in the art can judge the dosage that obtains the necessary active component of expected effect.This dosage depends on species, age and individual instances and the administering mode of homoiothermic animal.In normal conditions, in case of oral administration, be for the patient of the about 70kg of body weight, the oral roughly daily dose of amlodipine niacin is 0.1-100mg, preferred 1-25mg, more preferably 2.5-10mg.Described " husky smooth class " chemical compound refers to irbesartan, telmisartan, valsartan, losartan, Candesartan or its officinal salt, wherein consumption every day of irbesartan, telmisartan, valsartan, losartan, Candesartan is 1-300mg, more preferably 10-200mg, 20-120mg more preferably from about, for example valsartan 40-80mg most preferably.
The invention still further relates to preparation and obtain the said composition preparation of therapeutic effect on one's body, comprise conventional tablet, pill, powder or granule, lozenge, capsule, gel, syrup, unguentum, suspension, cachet and suppository etc. mammal.
The invention still further relates to the medicine box hereinafter referred to as " medicine box A " that obtains therapeutic effect mammal on one's body, it consists of the following components:
A) contain first kind of unit dosage forms of a certain amount of amlodipine niacin and pharmaceutically suitable carrier or diluent;
B) contain second kind of unit dosage forms of a certain amount of one or more husky smooth compounds or its officinal salt and pharmaceutically suitable carrier or diluent;
C) be used for holding the container of said first and second kinds of unit dosage forms.
The compound preparation of amlodipine of the present invention and sartans meets the Therapeutic Principle of hypertension drug combination.At first, go up from the pharmacology, when this two classes medicine share, sartans acts on the effect of the end eventually link in the feritin one angiotensin booster system, and the direct boosting of blocking-up Angiotensin II (Aug 11) also is reduced in the tension force that has the sympathetic nervous system of important function in the blood pressure regulating process; Amlodipine then acts on the target organ one blood vessel wall tension force of various neuro humor factors in the blood pressure regulating process, and the two can carry out complementation from pharmacotoxicological effect mechanism, strengthens the hypotensive effect of the two.Secondly, can reduce the relative consumption of each medicine after share, reduce the generation of adverse effect, improve patient's compliance, reach the target that improves the hypertension control rate; Once more, the pharmacokinetics feature of two class medicines is similar substantially, all can medication on the one once can keep 24 hours hypotensive effects, and the suitable feature of pharmacokinetics is arranged; In addition, the two, share and may improve total effective rate all between 83%～95% light, moderate hypertension patient's blood pressure lowering total effective rate; At last; this two classes drug combination is better to the hypertension induced effect of chronic kidney hypofunction institute; after share, two class medicines can delay the progress of kidney disease; and this drug effect can be explained with active and effective hypotensive activity; if and kidney damage is obviously changed, more should use two class medicines and share with renal function protecting.Share the back except that light, the moderate hypertension patient who can be used for not having any complication, also be specially adapted to hyperpietic, also be applicable to the patient's of renal hypertension, hypertension companion's renal function injury or companion's diabetes renal function injury treatment simultaneously with Cardiovascular Remodeling.
Thereby, the invention still further relates to the application on the angina pectoris of treatment mammal, atherosclerosis and/or complicated hypertension and hyperlipemia with above-mentioned composition or medicine box.
According to the present invention, be example with the valsartan, be the fixed double treatment dosage combination of using in the preferred pharmaceutical composition below.
The present invention relates to use can be with the combination of the active component as mentioned above of solid dosage form administration that low-level catabolite and/or impurity are arranged in treatment bag or the test kit, to the treatment of for example suffering from angina pectoris, atherosclerosis, hypertension and hyperlipemia complication and/or hypercholesteremic disease of patient and symptom with to patient's that the dangerous sign of heart disease occurs treatment.Test kit comprises solid dosage form and container.Typically, test kit comprises dosage form administration explanation.Container can be any conventional shape known in the art or form, for example, and carton, vial or plastic bottle.
Pharmaceutical composition of the present invention and method all are suitable as mammal, mammal is optional from mice, rat, rabbit, Cavia porcellus, Canis familiaris L., cat, sheep, goat, milch cow, primates, as monkey, orangutan and ape and people, particularly to human therapy, angina pectoris, atherosclerosis hypertension and hyperlipemia complication occur with being characterised in that.
Other dosage that the following dosage of mentioning in description and claims and other place are mentioned is to be the patient of about 65kg-70kg at weight average.The disease historical according to patient's medication and the experimenter exists, diabetes for example, the technical staff can easily determine the dosage of the experimenter needs of body weight outside 65kg-70kg.All dosage of mentioning in description and claims is daily dose.
Description of drawings
Accompanying drawing 1a: the related substance HPLC figure of reference substance in the time of 0 day;
Accompanying drawing 1b: the related substance HPLC figure of research product in the time of 0 day;
Accompanying drawing 2a: the related substance HPLC figure of reference substance during 4 weeks;
Accompanying drawing 2b: the related substance HPLC figure of reference substance during 4 weeks;
Accompanying drawing 3: the structural formula of amlodipine niacin
Following non-limiting example describes preparation in detail and uses the method for pharmaceutical composition of the present invention.
The present invention is example with the valsartan, preparation amlodipine niacin valsartan composition, and investigate the hypotensive effect of said composition to spontaneous hypertensive rat.
Embodiment
The general preparation method of embodiment 1 valsartan/amlodipine niacin tablet
Valsartan, amlodipine niacin are pulverized, and cross 100 mesh sieves, and be standby; Lactose, microcrystalline Cellulose, pregelatinized Starch, carboxymethyl starch sodium, magnesium stearate are crossed 80 mesh sieves respectively, and be standby.
Take by weighing amlodipine niacin and valsartan by recipe quantity, mix homogeneously is more successively by equivalent progressively increase method and carboxymethyl starch sodium, lactose, microcrystalline Cellulose and pregelatinized Starch, mix homogeneously.
It is an amount of to add purified water, makes even soft material, crosses 20 mesh sieves and granulates, and drying is 2 hours under 50 ℃, adds the recipe quantity magnesium stearate, crosses 20 mesh sieve granulate, mix homogeneously.
Measure granule content, heavy according to granule content result adjustment sheet in the sign scope.Tabletting, control strip hardness are 4～9kg.
Table 1. valsartan microcapsule/1000 g of unit of amlodipine niacin ordinary tablet prescription
The experiment of embodiment 2 lights resistance
The pharmaceutical composition of research product Amlodipine Besylate Tablets (5mg) and valsartan (80mg) is as described in the embodiment 1.The pharmaceutical composition of reference substance Amlodipine Besylate Tablet (5mg) and valsartan (80mg) is according to CN99, and 809,776 prepare.Research product and reference substance are exposed to 50 ℃ and place the electric filament lamp at 30cm place above the sample (220V, 100W) following 2 weeks, the result was that the reference substance variable color becomes light yellow, and the product of research do not have color change; In 4 weeks under the similarity condition, the result is a reference substance variable color yellowly, and the research product still do not have color change.The HPLC collection of illustrative plates of reference substance when Fig. 1 a represented for 0 week; The HPLC collection of illustrative plates of research product when Fig. 1 b represented for 0 week; The HPLC collection of illustrative plates of reference substance when Fig. 2 a represented for 4 weeks; The HPLC collection of illustrative plates of reference substance when Fig. 2 b represented for 4 weeks.Find out obviously from The above results, compare that the research product show the light resistance of improvement with reference substance.
The contrast experiment of the blood pressure lowering pharmacology effect of embodiment 3 valsartan/amlodipine niacin tablet
1 experiment purpose
This experiment comparative study amlodipine niacin (5mg)/valsartan (80mg), as described in embodiment 1, with the influence of Amlodipine Besylate Tablet (5mg, lot number 45805012), valsartan (80mg, lot number SC03004) to spontaneous hypertensive rat (SHR) blood pressure.
The self-control of material amlodipine niacin, Amlodipine Besylate Tablet is available from hammer pharmcetical S.P.A (lot number: AB034K00).SHR male and female dual-purpose, body weight 250～280g is provided by Military Medical Science Institute zoopery center.RBP21 type rat blood pressure meter (Chinese-Japanese Friendship Clinic Medical Inst).
2 experimental designs and process
Learn from else's experience 40 of qualified SHR of screening are divided into 4 groups at random, i.e. blank group, amlodipine niacin/valsartan group, Amlodipine Besylate Tablet group and valsartan group, 10 every group.Administration the previous day, take blood pressure with RBP21 type rat blood pressure instrumentation, as numerical value before the medicine.Irritate stomach once with 1.0mg/kg every day, and the blank group is irritated stomach once with the isometric(al) normal saline, continuous irrigation stomach 17d every day.Each treated animal respectively at medicine after 1,3,5,7,9,11,13,15 and 17d, 1h is with the clear-headed rat blood pressure of RBP21 type rat blood pressure instrumentation amount after administration.After drug withdrawal, measure blood pressure and heart rate on the 8th day again, carry out statistical procedures at last.
3 results
Amlodipine niacin/valsartan is to the influence of SHR blood pressure
Behind amlodipine niacin/valsartan gastric infusion, blood pressure descends gradually, and blood pressure obviously reduces behind the 9d, and 13d reaches the peak, and it is stable that later blood pressure keeps.Blood pressure descends gradually behind the Amlodipine Besylate Tablet 1.0mg/kg gastric infusion, and blood pressure obviously reduces behind the 9d, and 14d reaches the peak, and it is stable that later blood pressure keeps.Amlodipine niacin/valsartan group is compared with three contrast groups, the effect of blood pressure lowering best (P＜0.01) after the administration, and after 1 week of drug withdrawal, blood pressure recovers normal during 25d.The results are shown in Table 1.
Amlodipine niacin/valsartan to the comparative study of the influence of SHR blood pressure (x ± s, p/kPa)
Claims (13)
1. " compositions " that contains following composition:
A) a certain amount of amlodipine niacin;
B) a certain amount of one or more husky smooth compounds or its officinal salts; And
C) pharmaceutically suitable carrier or diluent.
2. the described compositions of claim 1, the amount of amlodipine niacin is 0.1-100mg.
3. the described compositions of claim 1-2, the amount of amlodipine niacin is 1-25mg.
4. the described compositions of claim 1-3, the amount of amlodipine niacin is 2.5-10mg.
5. the described compositions of claim 1, described " husky smooth class " chemical compound refers to Losartan Potassium, irbesartan, Candesartan, Tasosartan, eprosartan, telmisartan or valsartan or its officinal salt.
6. claim 1 or 5 described compositionss, described " husky smooth class " chemical compound refers to irbesartan or valsartan or its officinal salt.
7. the described compositions of claim 1 or 5-6, described " husky smooth class " chemical compound refers to valsartan or its officinal salt.
8. claim 1 or 5 described compositionss, the amount of described " husky smooth class " chemical compound is 1-500mg.
9. claim 1,5 or 7 described compositionss, the amount of described " husky smooth class " chemical compound is 10-200mg.
10. claim 1, the described compositions of 6-9, the amount of described valsartan is 20-80mg.
11. obtain the preparation that comprises the described compositions of claim 1 of therapeutic effect on one's body mammal, comprise conventional tablet, pill, powder or granule, lozenge, capsule, gel, syrup, unguentum, suspension, cachet and suppository etc.
12. obtain the medicine box that therapeutic effect comprises the described compositions of claim 1 on one's body mammal, it consists of the following components:
A) contain first kind of unit dosage forms of a certain amount of amlodipine niacin and pharmaceutically suitable carrier or diluent;
B) contain second kind of unit dosage forms of a certain amount of one or more husky smooth compounds or its officinal salt and pharmaceutically suitable carrier or diluent;
C) be used for holding the container of said first and second kinds of unit dosage forms.
13. described compositions of claim 1-12 or the medicine box application on treatment or prevention mammal (comprising the mankind) hypertension, diabetes or heart failure disease.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101771834A CN101433536A (en) | 2007-11-12 | 2007-11-12 | Therapeutic compositions containing amlodipine niacin and losartan medicament |
| PCT/CN2008/001871 WO2009070973A1 (en) | 2007-11-12 | 2008-11-12 | Therapeutic composition containing amlodipine nicotinate and sartans |
| CN200880115206A CN101854934A (en) | 2007-11-12 | 2008-11-12 | Therapeutic composition containing amlodipine nicotinate and sartans |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
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| CNA2007101771834A CN101433536A (en) | 2007-11-12 | 2007-11-12 | Therapeutic compositions containing amlodipine niacin and losartan medicament |
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| CNA2007101771834A Pending CN101433536A (en) | 2007-11-12 | 2007-11-12 | Therapeutic compositions containing amlodipine niacin and losartan medicament |
| CN200880115206A Pending CN101854934A (en) | 2007-11-12 | 2008-11-12 | Therapeutic composition containing amlodipine nicotinate and sartans |
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| WO (1) | WO2009070973A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103006650A (en) * | 2012-12-31 | 2013-04-03 | 广州白云山天心制药股份有限公司 | Compound hypotensive tablet containing sodium chloride medicine carrier |
| CN107033129A (en) * | 2017-02-28 | 2017-08-11 | 吉林修正药业新药开发有限公司 | The synthetic method of Irbesartan impurity |
| CN112979617A (en) * | 2019-12-17 | 2021-06-18 | 中国科学院苏州纳米技术与纳米仿生研究所 | Irbesartan piperazine salt and preparation method and application thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TR200100062T2 (en) * | 1998-07-10 | 2001-06-21 | Novartis Ag | Anti-hypertensive combination of valsartan and calcium channel blocker |
| CN100420673C (en) * | 2002-09-11 | 2008-09-24 | 韩林制药株式会社 | S-(-)-amlodipine nicotinate and process for the preparation thereof |
| CN100364532C (en) * | 2004-09-30 | 2008-01-30 | 江苏恒瑞医药股份有限公司 | Composition containing amlodipine and angiotensin II receptor inhibitor |
-
2007
- 2007-11-12 CN CNA2007101771834A patent/CN101433536A/en active Pending
-
2008
- 2008-11-12 CN CN200880115206A patent/CN101854934A/en active Pending
- 2008-11-12 WO PCT/CN2008/001871 patent/WO2009070973A1/en active Application Filing
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103006650A (en) * | 2012-12-31 | 2013-04-03 | 广州白云山天心制药股份有限公司 | Compound hypotensive tablet containing sodium chloride medicine carrier |
| CN103006650B (en) * | 2012-12-31 | 2014-07-23 | 广州白云山天心制药股份有限公司 | Compound hypotensive tablet containing sodium chloride medicine carrier |
| CN107033129A (en) * | 2017-02-28 | 2017-08-11 | 吉林修正药业新药开发有限公司 | The synthetic method of Irbesartan impurity |
| CN112979617A (en) * | 2019-12-17 | 2021-06-18 | 中国科学院苏州纳米技术与纳米仿生研究所 | Irbesartan piperazine salt and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101854934A (en) | 2010-10-06 |
| WO2009070973A1 (en) | 2009-06-11 |
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