CN106310278A - Multi-cascade antihypertensive drug composition containing folic acid - Google Patents
Multi-cascade antihypertensive drug composition containing folic acid Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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Abstract
The invention relates to a drug composition. The drug composition consists of an effective treating amount of calcium antagonist (CCB), an angiotensin II receptor blocker (ARB), a thiazide diuretic, a folic acid compound and a pharmaceutically acceptable carrier, wherein the content of the CCB is 2-240 mg, the content of the ARB is 4-600 mg, the content of the thiazide diuretic is 0.625-25 mg, and the content of the folic acid compound is 0.4-0.4 mg. The drug composition has the advantages that the drug composition can effectively improve the treatment effect of reducing blood pressure of class-2 and class-3 hypertensive patients, strengthen the effect of protecting target organs of the patients and reduce the occurrence risk of cerebral apoplexy complications caused by high blood pressure. In addition, the drug composition can be conveniently taken by patients, the treatment compliance is greatly improved, and the medical costs can be also reduced.
Description
Technical field
The present invention relates to a kind of containing calcium antagonist (CCB), angiotensin ii receptor blocker (ARB), thiazide profit
Urine agent and the pharmaceutical composition of folic acid, in treatment, severe hypertension, prevent and delay the apoplexy caused by hypertension.
The invention belongs to pharmaceutical field.
Background technology
Essential hypertension is the principal element causing coronary heart disease, apoplexy, congestive heart failure and kidney damage.Mesh
It is 27.2% that front hypertension has gone up in China's prevalence, and estimation there are about 300,000,000 patients accordingly.Hypertension people mainly controls
Treating target is to reduce cardiovascular complication and dead overall risk to greatest extent, and medicine reduces blood pressure and can be effectively reduced
The M & M of cardiovascular complication.
The drug main being currently used in blood pressure lowering to have: calcium channel blocker (Calcium Channel Blocker, CCB), blood
ACE inhibitor, Angiotensin Ⅱ receptor antagonist (Angiotensin Receptor Blocker,
ARB), diuretic, receptor,β blocker etc..At present, condition of medicine treatment for hypertension has been enter into seeking optimal antihypertensive drugs
Combination, optimum organization epoch.Most 2,3 grades of hyperpietics need two or more antihypertensive drug to control blood pressure, two
Kind of above medicine can individually prescription or be fixed dosage compound preparation [Chinese hypertension prevention and control guide Drafting Committee. Chinese
Hypertension prevention and control guide. hypertension magazine, 2000:8 (1): 94-102,103-112].International clinical trial proves to close
And medication has it to need and is worth, the dosage of every kind of medicine is little, and the therapeutical effect of medicine has collaborative or at least summation action, its
Ill effect can be cancelled out each other or the most overlapping or addition.
With advancing age, the prolongation etc. of the course of disease, many 1 grade of hyperpietics are developing progressively 2,3 grades (in, severe)
Hypertension, and the state of an illness is obstinate, uses one or two kinds of antihypertensive drug can not control this kind of patient's well
Blood pressure, so needing to use three kinds of antihypertensive drug to control blood pressure.Three kinds of antihypertensive drug are by different effect machines
System, acting on different target spots and work in coordination with blood pressure lowering, single survival dose can reduce in addition, therefore reduce to a certain extent or even cancel out each other
Adverse effect, often receives splendid effect.Drug combination can become the first-line treatment plan of 2-3 level hyperpietic
Slightly, hyperpietic's great majority of companion's cardiovascular high risk factor need using drug combination as treatment means.Although it addition, reducing
It is crucial that blood pressure reaches target blood pressure, but target-organ protection is the final goal of hypertension therapeutic.It is currently used for treating hypertension
Medicine be mainly focused on antihypertensive effect, and the effect of target-organ protection is paid close attention to not enough, and in, severe hypertension patient
Target organ damage has reached to a certain degree, seriously reduces the quality of life of patient, so strengthening centering, severe hypertension
The target-organ protection of patient seems the most urgent and important.
CCB hypotensor, by reducing the free calcium concentration in vascular smooth muscle cell, distends the blood vessels, blood pressure drops,
Platelet aggregation can also be suppressed, lipid metabolism is had no adverse effects.Can effectively treat all kinds of hypertension clinically, especially old
Hypertension or accompany anginal hypertension.Conventional CCB is divided into dihydropyridines: amlodipine (amlodipine), felodipine
(felodipine), isradipine (isradipine), nicardipine (nicardipine), nifedipine (nifedipine),
Nisoldipine (nisoldipine), nitrendipine (nitrendipine), lacidipine (lacidipine) and non-dihydropyridine
Class: diltiazem, verapamil.Owing to the part CCB half-life is shorter, first pass effect is relatively big, and therefore medicining times is more, gives disease
People brings inconvenience.ESC's report in 2003, in 9 experimental studies including 67435 randomized patients, compares
CCB and the curative effect of conventional medicament, evaluation index includes general mortality rate, cardiovascular death rate, all cardiovascular events, cardiac muscle stalk
Plug and heart failure do not find the clear superiority of CCB in interior all prognostic indicators, result, efficacy of antihypertensive treatment when this is alone with CCB
Limited relevant.
ARB hypotensor is mainly by blocking angiotensinⅡ (Ang II) and corresponding receptor AT1Combination and play medicine
Reason effect.Ang II is a kind of biological effect thing of most critical in renin angiotensin aldosterone system (RAAS), it and
Specific receptor AT1Combination can mediate vascular smooth muscle contraction, vassopressin and Aldosterone Secretion release (retention of sodium and water),
Sympathetic nerve catecholamine discharges a series of biological actions such as increasing, causes blood pressure to raise.Therefore, selective exclusion AT1It is subject to
Body is one of effective way of Hypertension.ARB class drug main to have the most clinically: losartan (Losartan), figured silk fabrics
Sha Tan (Valsartan), irbesartan (Irbesartan), telmisartan (Telmisartan), Candesartan
(Candesartan), Olmesartan (Olmesartan Medoxomil), Tasosartan (Tasosartan) and eprosartan
(Eprosartan) etc..Certain deficiency is there is also clinically, when increasing including blood pressure lowering total effective rate and dosage when ARB is alone
Untoward reaction.
It is found that antihypertensive drugs based on low-dose diuretic, aged patients with hypertension cardiovascular can be significantly reduced
Sick prevalence and mortality rate；Low-dose diuretic is compared with heavy dose, and antihypertensive effect is similar and adverse reaction reduction；Diuretic
It is the treatment necessary to hypertension that the effective blood volume caused reduces, it may be possible to the basis of other antihypertensive drug therapies.Above-mentioned ARB
Long-term taking easily causes hyperkalemia, and thiazide diuretic has natriuretic diuretic, row's potassium effect, and prolonged application easily causes hypokalemia.Cause
This, ARB associating thiazide diuretic is also a kind of perfect match, both can largely offset the adverse effect to blood potassium, and can assist again
Same blood pressure lowering.
Folacin compound includes folic acid, 5-methyltetrahydrofolate etc., belongs to water soluble vitamins, via intestinal absorption,
External by urine ejection, in human body, retention time is of short duration, seldom accumulates, thus must often from external picked-up with meet nutrition and
Metabolism needs.The metabolism of homocysteine (Hcy) is affected during folic acid deficiency, it is now recognized that Hcy is a kind of cardiovascular in human body
Risk factor, with relevant [1.Herrmann W.Significance of of possibility such as vascular endothelial injury, inducing thrombosis formation
hyperhomocysteinemia.Clin Lab.2006,52(7-8):367-374.2.Sun Y,et al.Use of serum
homocysteine to predict stroke,coronary heart disease and death in Ethnic
Chinese:a 12-year prospective cohort study.Circ J.2009；73:1423-1430], Supplement of folic acid
Hcy level can be reduced, be likely to be of and reduce the effect that cardiovascular event (including apoplexy) occurs.
This patent breaks through the limitation of conventional drug combination, overcomes antihypertensive drug alone or the deficiency of bigeminy medication,
By three kinds of antihypertensive drug CCB, ARB, thiazide diuretic and folic acid merge together be used for treatment in, severe hypertension, in advance
Anti-apoplexy, experiment also proves that tetrad medication can be preferably for the target organ offer of hypertension animal than bigeminy or three-drug therapy
Protection.
Summary of the invention
When the technical problem to be solved is to overcome alone CCB, ARB and diuretic depressor exist above-mentioned not
Foot, it is provided that a kind of be superior in terms of efficacy of antihypertensive treatment and target-organ protection CCB, ARB, diuretic or they two-by-two drug combination,
And the pharmaceutical composition that toxicity has reduced.
For achieving the above object, the present invention is by the following technical solutions:
A kind of pharmaceutical composition, is made up of following composition
1) CCB of pharmaceutical dosage；
2) ARB of pharmaceutical dosage；
3) thiazide diuretic of pharmaceutical dosage；
4) folacin compound of pharmaceutical dosage；
5) acceptable carrier on pharmaceutics.
In the present invention, CCB is selected from dihydropyridines, including nifedipine, amlodipine, Levamlodipine, non-Lip river
Horizon, lacidipine, nimodipine, nicardipine, nisoldipine, nitrendipine, nilvadipine, isradipine, benidipine,
Cilnidipine, lercanidipine etc., preferably amlodipine, Levamlodipine, felodipine, lacidipine, nicardipine, Buddhist nun group
Horizon, the one of benidipine.As a kind of change that anticipated that, above-mentioned substance can with corresponding active metabolite,
Esters or salt substitute.
The content of CCB is respectively as follows: amlodipine (2.5～20mg), Levamlodipine (2.5～10mg), nifedipine
(10～120mg), nicardipine (30～240mg), lacidipine (2～8mg), nisoldipine (5～60mg), nitrendipine
(10～60mg), felodipine (2.5～30mg), nimodipine (40-240mg), nilvadipine (2-8mg), isradipine
(2.5-10mg)。
Above-mentioned the most more preferably content is respectively as follows: amlodipine (2.5～7.5mg), Levamlodipine (2.5
～5mg), nifedipine (10～40mg), nicardipine (30～120mg), lacidipine (2～6mg), nisoldipine (5～
20mg), nitrendipine (10～30mg), felodipine (2.5～10mg), nimodipine (40-120mg), nilvadipine (2-
4mg), isradipine (2.5-5mg).
In the present invention, ARB selected from losartan, valsartan, irbesartan, telmisartan, Candesartan, Olmesartan,
One in Tasosartan and eprosartan.As a kind of change that anticipated that, above-mentioned substance can be with corresponding activity generation
Thank product, esters or salt to substitute.
ARB content be respectively as follows: losartan (25～200mg), valsartan (40～320mg), irbesartan (75～
600mg), telmisartan (20～160mg), Candesartan (4～64mg), Olmesartan (20～80mg), Tasosartan (25～
300mg), eprosartan (200～800mg), the active metabolite of above-mentioned substance, esters or salt content are above-mentioned with corresponding
Content of material is equal to.
ARB the most more preferably content is respectively as follows: losartan (25～100mg), valsartan (80～160mg), strategic point
Bei Shatan (150～300mg), telmisartan (20～80mg), Candesartan (4～32mg), Olmesartan (20～40mg), he
Suo Shatan (50～200mg), eprosartan (300～600mg), the active metabolite of above-mentioned substance, esters or salt content
It is equal to corresponding above-mentioned substance content.
In the present invention, thiazide diuretic is selected from hydrochlorothiazide, chlortalidone, the one of indopamide, and content is 0.625
～25mg.
In the present invention, folacin compound is selected from folic acid, 5-methyltetrahydrofolate, formyl tetrahydrofolic acid, calcium folinate
Or levoleucovorin calcium, dosage is 0.2～2mg, preferably 0.4～1.6mg.
CCB, ARB of above-mentioned pharmaceutical dosage and diuretic, its specific category see table with dosage, but is not limited to following table model
Enclose.
The CCB of above-mentioned pharmaceutical dosage is amlodipine 2.5～5mg, and the ARB of pharmaceutical dosage is losartan 25～100mg, medicine
Being indapamide 0.625～2.5mg with the diuretic of dosage, folacin compound is folic acid, and dosage is 0.4～1.2mg.
The CCB of above-mentioned pharmaceutical dosage is amlodipine 2.5～5mg；The ARB of pharmaceutical dosage is valsartan 80～160mg；Medicine
It is indapamide 0.625～2.5mg with the diuretic of dosage；Folacin compound is folic acid or 5～methyl tetrahydrofolate, dosage
It is 0.4～1.2mg.
The CCB of above-mentioned pharmaceutical dosage is amlodipine 2.5～5mg；The ARB of pharmaceutical dosage be irbesartan 150～
300mg；The diuretic of pharmaceutical dosage is indapamide 0.625～2.5mg；Folacin compound is folic acid or 5～methyl tetrahydrochysene
Folic acid, dosage is 0.4～1.2mg.
The CCB of above-mentioned pharmaceutical dosage is Levamlodipine 2.5～5mg；The ARB of pharmaceutical dosage be telmisartan 20～
80mg；The diuretic of pharmaceutical dosage is hydrochlorothiazide 10～25mg；Folacin compound is folic acid or 5～methyl tetrahydrofolate,
Dosage is 0.4～1.2mg.
The CCB of above-mentioned pharmaceutical dosage is Levamlodipine 2.5～5mg；The ARB of pharmaceutical dosage be Candesartan 4～
32mg；The diuretic of pharmaceutical dosage is hydrochlorothiazide 10～25mg；Folacin compound is folic acid or 5～methyl tetrahydrofolate,
Dosage is 0.4～1.2mg.
The CCB of above-mentioned pharmaceutical dosage is nifedipine 20～60mg；The ARB of pharmaceutical dosage is Olmesartan 20～40mg；
The diuretic of pharmaceutical dosage is hydrochlorothiazide 10～25mg；Folacin compound is folic acid or 5～methyl tetrahydrofolate, and dosage is
0.4～1.2mg.
The pharmaceutical composition of the present invention emphatically in, severe hypertension patient (usually gerontal patient), purpose except
Outside more effectively controlling blood pressure, making it up to standard, also can strengthen the protection to patient's target organ and to reduce cerebrovascular events dangerous.This
Be because: along with the age increase, the course of disease extend, conditions of patients progressively develops, and can cause GAS, cause the heart, brain,
The infringement of the important organ such as kidney, eye.The target organ damage that hypertension causes, including left ventricular hypertrophy, benign arteriolar nephrosclerosis
Disease, pernicious arteriolar nephrosclerosis, renal failure, retinal arteriosclerosis or Hypertensive Fundus pathological changes.When above-mentioned these
Target organ damage still can not effectively control, then develop into the generation of more serious consequence, i.e. cardiocerebrovasculaevents events, wherein cerebrovascular
Event includes cerebral infarction and cerebral hemorrhage, is referred to as apoplexy.The main target of Hypertension people is to reduce to greatest extent
Cardiovascular and cerebrovascular vessel morbidity and dead overall risk, it is the core of hypertension therapeutic that blood pressure lowering and target-organ protection develop simultaneously.
Research finds, the pharmaceutical composition that the present invention provides not only has the strongest hypotensive effect, moreover it is possible to effectively protect
Target organ.When CCB/ARB/ diuretic and folacin compound share, not only in, severe hypertension there is the strongest fall
Pressure effect, moreover it is possible to work in coordination with intensifier target organ protection, and its protective effect is better than ARB/ diuretic/folic acid three compound blood pressure reducing
Medicine.Therefore, the invention provides the CCB/ARB/ diuretic of above-mentioned pharmaceutical dosage and the folacin compound composition of pharmaceutical dosage
Pharmaceutical composition in preparation in treatment, severe hypertension, and prevent and delay the targets such as the apoplexy that caused by hypertension
The purposes of organ injury.
Further, in test it was found that work as and the folacin compound of CCB/ARB/ diuretic and pharmaceutical dosage is closed
Used time, the danger reducing cerebrovascular events can be worked in coordination with, and effect is better than only multiple with ARB/ diuretic/folacin compound three
Side's depressor, difference has statistical significance.
And then, the present invention also provides for the cerebrovascular events danger that this pharmaceutical composition causes for reducing hypertension in preparation
Purposes in the medicine of property；Wherein reduce cerebrovascular events danger and refer to reduce cerebral infarction or the incidence rate of cerebral hemorrhage, or
Say the incidence rate being to reduce apoplexy.
Described pharmaceutical composition can be made into conventional tablet, conventional capsule, granule, slow releasing tablet, sublingual lozenge, oral cavity speed
Disintegrating tablet, dispersible tablet, enteric coatel tablets, enteric coated capsule, delayed-release tablet, regularly/position releasing piece, slow releasing capsule, controlled release capsule, containing micro-
The dosage form such as ball or the capsule of small pieces, PH dependent form capsule, granule, oral liquid, membrane or patch containing micropill or small pieces.
Possibly together with pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into common oral preparation, including ordinary tablet
Agent, conventional capsule, granule etc., when making tablet, described pharmaceutically acceptable carrier includes contributing to joining reactive compound
Make excipient and accessory drugs such as starch, microcrystalline Cellulose, inorganic salts, sucrose, dextrin, lactose, Icing Sugar, the Fructus Vitis viniferae of pharmaceutical formulation
The compositions of one or more materials of sugar, sodium chloride, cysteine, citric acid and sodium sulfite etc., belongs to common sense in the field.
Possibly together with pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into slow releasing tablet, including excipient and auxiliary
Material etc..Described excipient and accessory drugs included the adjuvant of slow releasing function be hypromellose and/or ethyl cellulose and/or
Polyacrylic resin class and/or polycarboxy ethene and/or the solubility/insoluble salt of alginic acid and/or other play slow releasing function
Adjuvant, hypromellose uses the U.S.A of extensive stock such as all size including hydroxypropyl methylcellulose (HPMC) how elegant
(Methocel), ethyl cellulose uses the extensive stock including ethyl cellulose (EC), and polyacrylic resin class uses and includes
The acrylic resin (Eudragit) of polyacrylic resin Ⅱ, III class or the like such as all size.Above-mentioned adjuvant is pore
Agent, binding agent, lubricant, membrane material, solvent or other adjuvant, porogen can use sucrose, mannitol, starch, Pulvis Talci, two
Silicon oxide etc.；Binding agent can use polyvinylpyrrolidone, hypromellose etc.；Wetting agent can use water, dehydrated alcohol, each
Plant the ethanol-water solution of concentration；Lubricant can use stearic acid, magnesium stearate, Pulvis Talci, starch, paraffin etc.；Solubilizing agent can be adopted
With tartaric acid, citric acid etc.；Emulsifying agent can use span80/span85 etc.；Membrane material can use polyvinyl alcohol, hydroxyl first fiber
Element, hyetellose, hymetellose, methylcellulose etc.；Foaming agent can use basic magnesium carbonate, sodium bicarbonate etc.；Help
Drift agent can use hexadecanol, octadecanol, Cera Flava etc.；Solvent can use dehydrated alcohol, ethanol, water etc..
Possibly together with pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into controlled release tablet, including active medicine and
Play the adjuvant of controlled-release function.The adjuvant of above-mentioned controlled-release function is polyoxyethylene and/or hypromellose and/or ethyl cellulose
Element and/or sodium chloride and/or lactose and/or mannitol and/or fructose and/or glucose and/or sucrose/or low substituted hydroxy-propyl
Cellulose and/or cross-linking sodium carboxymethyl cellulose and/or crospolyvinylpyrrolidone and/or cellulose acetate.Above-mentioned is auxiliary
Material is pharmaceutical carrier, expanding material, permeation-promoter, solubilizing agent, binding agent, wetting agent, lubricant, coloring agent, porogen, film material
Material, antiplastering aid, plasticizer, lucifuge agent, solvent.Pharmaceutical carrier, expanding material can use polyoxyethylene, hypromellose, second
Base cellulose, Glyceryl Behenate class etc.；Permeation-promoter can use sodium chloride, lactose, mannitol, fructose, glucose, sucrose etc.；
Solubilizing agent can use the sodium lauryl sulphate can poloxamer etc.；Binding agent can use polyvinylpyrrolidone, hypromellose
Element etc.；Wetting agent can use water, dehydrated alcohol, the ethanol-water solution of various concentration；Lubricant can use stearic acid, stearic acid
Magnesium, Pulvis Talci, starch, paraffin etc.；Coloring agent can use iron oxide red, iron oxide yellow etc.；Porogen can use sucrose, manna
Alcohol, Polyethylene Glycol, titanium dioxide, Pulvis Talci, silicon dioxide etc.；Membrane material can use cellulose acetate, ethyl cellulose etc.；Molten
Agent can use acetone, dehydrated alcohol, ethanol, water etc..
Possibly together with pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into sublingual lozenge, oral cavity quick disintegrating slice or divide
Discrete piece etc., including excipient and adjuvant etc..Described excipient and adjuvant have low substituted hydroxy-propyl methylcellulose, microcrystalline cellulose
Element, carboxymethyl starch sodium, cross-linked carboxymethyl cellulose sodium, crospolyvinylpyrrolidone, process agar and mannitol, lactose
Deng.
Possibly together with pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into enteric coatel tablets or enteric coated capsule etc., including
Excipient and adjuvant etc., described excipient and adjuvant have starch, microcrystalline Cellulose, inorganic salts, hydroxypropyl methyl cellulose,
Ethyl cellulose, polyacrylic resin class, polycarboxy ethene, the solubility/insoluble salt of alginic acid, octadecanol, stearic acid,
One or more materials of sucrose, dextrin, lactose, Icing Sugar, glucose, sodium chloride, cysteine, citric acid and sodium sulfite etc.
Compositions, enteric-coating material includes: Lac, CAP, crylic acid resin are (such as Eudragit L and S
Type etc.), polyvinyl acetate phthalic acid ester, Hydroxypropyl Methyl Cellulose Phthalate, succinic acid acetic acid hydroxypropyl methylcellulose,
And plasticizer (as diethyl phthalate, Polyethylene Glycol, propylene glycol, glycerol triacetate, dimethyl phthalate,
Dibutyl sebacate, triethyl citrate, tributyl citrate, CitroflexA-2, Oleum Ricini and various percentage ratio
Acetylated monoglycerides etc.) with the various medicaments adjuvant such as porogen (such as PEG6000 etc.).
Possibly together with pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into delayed-release tablet or timing (position) release
Sheet, including excipient and adjuvant, described excipient and adjuvant have starch, microcrystalline Cellulose, inorganic salts, hydroxypropyl methyl fine
Dimension element, ethyl cellulose, polyacrylic resin class, polycarboxy ethene, the solubility/insoluble salt of alginic acid, octadecanol, ten
The one or several of eight acid, sucrose, dextrin, lactose, Icing Sugar, glucose, sodium chloride, cysteine, citric acid and sodium sulfite etc.
Planting the compositions of material, the described coating material postponing to discharge or timing (position) discharges that rises includes: Lac, cellulose acetate phthalein
Acid esters, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, crylic acid resin are (such as Eudragit L and S type
Deng), polyvinyl acetate phthalic acid ester, Hydroxypropyl Methyl Cellulose Phthalate, succinic acid acetic acid hydroxypropyl methylcellulose, vinegar
Acid hydroxypropyl methyl cellulose phthalate, and plasticizer is (such as diethyl phthalate, Polyethylene Glycol, propylene glycol, glycerol three
Acetas, dimethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl citrate three
Acetylated monoglycerides of ethyl ester, Oleum Ricini and various percentage ratio etc.) with the various medicaments such as porogen (such as PEG6000 etc.)
Learn adjuvant.
Possibly together with pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into slow releasing capsule, controlled release capsule, containing micro-
Ball or the capsule of small pieces, the PH dependent form capsule etc. containing micropill or small pieces, including excipient and adjuvant, described excipient and
Adjuvant has starch, microcrystalline Cellulose, inorganic salts, hydroxypropyl methyl cellulose, ethyl cellulose, polyacrylic resin class, gathers
Carboxylic vinyl, the solubility/insoluble salt of alginic acid, octadecanol, stearic acid, sucrose, dextrin, lactose, Icing Sugar, glucose,
The compositions of one or more materials of sodium chloride, cysteine, citric acid and sodium sulfite etc., coating material includes: Lac,
Cellulose acetate, CAP, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, acrylic acid tree
Lipid (such as Eudragit series), polyvinyl acetate phthalic acid ester, Hydroxypropyl Methyl Cellulose Phthalate, succinic acid acetic acid
Hydroxypropyl methylcellulose, hydroxypropylmethylcellulose acetate methylcellulose phthalate ester, mono stearate glyceryl ester and plasticizer are (such as O-phthalic
Diethyl phthalate, Polyethylene Glycol, propylene glycol, glycerol triacetate, dimethyl phthalate, dibutyl sebacate, citric acid three
Ethyl ester, tributyl citrate, CitroflexA-2, Oleum Ricini and the acetylated monoglycerides etc. of various percentage ratio
Deng) with the various medicaments adjuvant such as porogen (such as PEG6000 etc.).
Possibly together with pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into granule, oral liquid, membrane, patch
Etc. dosage form.Making patch, during membrane, described pharmaceutically acceptable carrier includes contributing to being configured to by reactive compound medicinal
The excipient of preparation and accessory drugs, such as polyvinyl alcohol, Triafol T, ethylene-vinyl acetate copolymer, polyvinylpyrrolidine
Ketone, polyacrylamide, polyisobutylene class pressure sensitive adhesive, crylic acid resin pressure sensitive adhesive, silicone pressure sensitive adhesive etc., and poly-fluorine second
Alkene, polyethylene, aluminium foil, polypropylene, polyester etc. by lining material, the one of the protecting film etc. such as polyethylene, polystyrene, polypropylene or
The compositions of several materials.
Invention formulation can use simultaneously or the most sequentially use, optimal to use simultaneously.The while of above-mentioned
Use and include that, with fixed Combination and non-fixed combinations, optimal uses with fixed Combination.
Invention formulation can take once a day or twice, or with slow release or controlled fashion every day or take one every other day
Secondary, the most once.
Described pharmaceutical composition can be flexible use with " Combined drug box " form.Above-mentioned " Combined drug box " is a kind of box-like
Container, the drug regimen of built-in multiple dosage form, and take description." Combined drug box " is more suitable for personalized medicine.
The invention has the beneficial effects as follows: the pharmaceutical composition energy emphasis that the present invention provides spends hyperpietic for middle and high,
Having obvious curative effect and synergism, its synergism is to work in coordination with the cerebrovascular events caused with hypertension that reduces blood pressure
Dangerous.Therefore, the invention provides the CCB/ARB/ thiazide diuretic of above-mentioned pharmaceutical dosage and the folic acid class of pharmaceutical dosage
The pharmaceutical composition of compound composition in preparation, and prevents and delays to be caused by hypertension in treatment, severe hypertension
Purposes in the medicine of apoplexy.This pharmaceutical composition can improve the curative effect of blood pressure lowering combination medicine further, strengthens it to target device
The protective effect of official, reduces the incidence rate of the Stroke Complicated disease caused by hypertension.It can in addition contain make patient take medicine conveniently,
Improve patient compliance, reduce medical expense, there is preferable market prospect.
Below in conjunction with detailed description of the invention, the present invention will be further described, not limitation of the invention, all according to this
The equal replacement of any this area that summary of the invention is carried out, belongs to protection scope of the present invention.
Detailed description of the invention
Embodiment 1: prepare compound amlodipine 5mg/ valsartan 80mg/ indapamide 2.5mg/ folic acid 0.4mg
Prescription:
Preparation technology:
(1) take the amlodipine of recipe quantity, valsartan, indapamide, folic acid, after crossing 100 mesh sieves, press the mixing of equal increments method
The most standby；
(2) after 100 mesh sieves crossed respectively by other adjuvants, 75 DEG C are dried 2 hours；
(3) press the microcrystalline Cellulose of recipe quantity, starch, carboxymethylstach sodium mixing after again with mixed crude drug equal increments
Method mix homogeneously；
(4) with 5% appropriate PVP K-30 soft material, 24 mesh sieves are pelletized, 20 mesh sieve granulate, and 40-45 DEG C is dried；
The most dry granule adds the mixing of appropriate magnesium stearate, tabletting after assay.
Embodiment 2: prepare compound amlodipine 5mg/ irbesartan 150mg/ indapamide 2.5mg/ folic acid 0.4mg
Prescription:
Preparation technology:
(1) take the amlodipine of recipe quantity, irbesartan, indapamide, folic acid, press equal increments method after crossing 100 mesh sieves and mix
Close the most standby；
(2) after 100 mesh sieves crossed respectively by other adjuvants, 75 DEG C are dried 2 hours；
(3) press the microcrystalline Cellulose of recipe quantity, starch, carboxymethylstach sodium mixing after again with mixed crude drug equal increments
Method mix homogeneously；
(4) with 5% appropriate PVP K-30 soft material, 24 mesh sieves are pelletized, 20 mesh sieve granulate, and 40-45 DEG C is dried；
The most dry granule adds the mixing of appropriate magnesium stearate, tabletting after assay.
Embodiment 3: prepare compound recipe nicardipine 65mg/ telmisartan 20mg/ hydrochlorothiazide 10mg/ folic acid 0.8mg
Prescription:
Preparation technology:
(1) take the nicardipine of recipe quantity, telmisartan, hydrochlorothiazide, folic acid, after crossing 100 mesh sieves, press equal increments method
Mix homogeneously is standby；
(2) after 100 mesh sieves crossed respectively by other adjuvants, 75 DEG C are dried 2 hours；
(3) press the microcrystalline Cellulose of recipe quantity, starch, carboxymethylstach sodium mixing after again with mixed crude drug equal increments
Method mix homogeneously；
(4) with 5% appropriate PVP K-30 soft material, 24 mesh sieves are pelletized, 20 mesh sieve granulate, and 40-45 DEG C is dried；
(5) dry granule adds the mixing of appropriate magnesium stearate, tabletting after assay.
Embodiment 4: prepare compound recipe lacidipine 4mg/ Candesartan 8mg/ hydrochlorothiazide 12.5mg/ folic acid 0.8mg
Prescription:
Preparation technology:
(1) take the lacidipine of recipe quantity, Candesartan, hydrochlorothiazide, folic acid, after crossing 100 mesh sieves, press equal increments method
Mix homogeneously is standby；
(2) after 100 mesh sieves crossed respectively by other adjuvants, 75 DEG C are dried 2 hours；
(3) press the microcrystalline Cellulose of recipe quantity, starch, carboxymethylstach sodium mixing after again with mixed crude drug equal increments
Method mix homogeneously；
(4) with 5% appropriate PVP K-30 soft material, 24 mesh sieves are pelletized, 20 mesh sieve granulate, and 40-45 DEG C is dried；
(5) dry granule adds the mixing of appropriate magnesium stearate, tabletting after assay.
Embodiment 5: the Synergistic Hypotensive Effects of amlodipine+valsartan+indapamide+folate composition
Method: 10-12 week old SHRsP is purchased from Shanghai City hypertension institute, Fuwai Hospital's Experimental Animal Center respectively,
Raise in room temperature (23 ± 2) DEG C, relative humidity (50 ± 10) %, each 12h of illumination light and shade, standard feed of each ingesting.Measure big
Mus blood pressure 1 week (the 1st, 6 days), takes the rat of blood pressure stabilization for testing.By spontaneous hypertensive rat random packet, it is respectively
Model group (to solvent), valsartan+indapamide+folic acid group (8+0.25+0.04) mg/kg, amlodipine+valsartan+Yin reach
Handkerchief amine+folic acid group (0.5+1+0.25+0.04) mg/kg, separately sets Normal group.Gastric infusion, continuous two weeks.Measure respectively and give
Before medicine and be administered after different time blood pressure, calculate Amplitude of Hypotensive: SBPBefore administration-SBPAfter administration。
Result: valsartan+indapamide+folic acid group antihypertensive effect is obvious, the highest Amplitude of Hypotensive reaches 21.4 ±
6.7, but amlodipine+valsartan+indapamide+folic acid group further enhancing its antihypertensive effect, and average Amplitude of Hypotensive reaches
29.8±4.7.The results are shown in Table 1.
The table 1 amlodipine+valsartan+indapamide+folic acid hypotensive effect (blood pressure lowering rate) to spontaneous hypertensive rat
(x ± SD, n=15)
Experimental example 6: the blood pressure lowering of amlodipine+irbesartan+indapamide+folic acid and target organ protection function
Method: with 0.2mm silver brain clip narrow Wistar rat left renal artery, after 16-18 week, rat blood pressure increases to over
More than 180mmHg is hypertension animal model.According to rat blood pressure level, hypertension is randomly divided into model group, irbesartan+
Indapamide+folic acid group (15+0.25+0.04) mg/kg, amlodipine group 0.5mg/kg, amlodipine+irbesartan+Yin reach
Handkerchief amine+folic acid group (0.5+15+0.25+0.04) mg/kg, separately sets Normal group, often organizes 15, gastric infusion, once a day,
Weigh weekly once, according to body weight adjust dose, continuous 26 weeks.Observation index:
(1) inner skin cell function 26 weekend, take blood and measure Plasma Nitric Oxide (NO), Endothelin by test kit description
(ET) level.
(2) renal function 26 weekend, collect urine, survey 24h urine creatine, urine protein, 24h Urinary α1-microglobulin；Take blood, measure
Serum creatinine, blood urea nitrogen (BUN), serum calculates creatinine clearance rate (Ccr).
(3) hemodynamics last is administered latter 1 hour, and 20% urethane (1g/kg ip) is anaesthetized, and faces upward position and fixes, and separates the right side
Side common carotid artery, inserts one and is full of heparin-saline conduit to left ventricle, by pressure transducer, connect RM6240BD type many
Leading physiological signal collection processing system, stablize 10min, after record medicine, 3 hours left rooms peak pressure meansigma methods (LVSP), left room maximums become
Change speed (± dp/dtmax).
(4) after left room weight assessment of indices cardiac function, take rat heart, clean with pre-cold saline, separate left ventricle (bag
Include interventricular septum), weigh, calculate left room weight index (left ventricle mg/ body weight g).
(5) at Myocardial hydroxyproline mensuration rat after death, Qu Zuo room cardiac muscular tissue about 50mg, use Bergman method to measure
Hydroxyproline content, and calculate collagen content.Collagen content=8.2 × hydroxyproline content (mg/g).
Statistical analysis: measurement data is usedRepresent, between two groups, compare employing t inspection.
Result: compare with rat normal group, hypertension group rat plasma NO level reduces, and ET level raises.With hypertension
Group compares, and irbesartan+indapamide+folic acid group, amlodipine group rat plasma NO raise, ET reduces；Amlodipine+E Bei
Sha Tan+indapamide+folic acid group rat plasma NO raises further, and ET reduces further, and with irbesartan+indapamide+
Folic acid group, amlodipine group compares significant difference.Show: significant vascular endothelial cell merit occurs in renal hypertensive rat
Can reduce, amlodipine+irbesartan+indapamide+folic acid pharmaceutical composition protective effect effect to vascular endothelial cell
Significantly, there is obvious synergism.It is shown in Table 2.
Table 2 amlodipines/irbesartan/indapamide/folic acid is to renal hypertensive rat blood pressure, serum NO level, ET level
Impact (x ± SD)
Compare with normal group,P<0.01；Compare with hypertension group,▲P < 0.05,▲▲P<0.01；With amlodipine+E Bei
Sha Tan+indapamide+folic acid group compares,#P < 0.05,##P<0.01。
Comparing with normal rats, hypertension group rat urine 24h α 1-microglobulin, urine protein, BUN significantly raise, Ccr
Substantially reduce.Compare with hypertension group, 24h α 1-microglobulin, urine protein in irbesartan+indapamide+folic acid group rat urine
Reducing, Ccr raises, and BUN reduces；Amlodipine group 24h α 1-microglobulin, urine protein reduce.Amlodipine+irbesartan+Yin
Reach handkerchief amine+folic acid group rat urine 24h α 1-microglobulin, urine protein, BUN reduce further, and Ccr raises further, and with strategic point shellfish
Sha Tan+indapamide+folic acid group, amlodipine group compares significant difference.Show that certain journey occurs in renal hypertensive rat
The kidney damage of degree, amlodipine+irbesartan+indapamide+folic acid pharmaceutical composition has significant coordinative role, to kidney
The Renoprotective Effect of property Hypertensive Rats is obviously enhanced.It is shown in Table 3.
Renal hypertensive rat is urinated microsphere egg by table 3 amlodipines/irbesartan/indapamide+folic acid pharmaceutical composition
In vain, the impact (x ± SD) of urine protein, blood inosine clearance rate, blood urea nitrogen
Compare with normal group,P<0.01；Compare with hypertension group,▲P < 0.05,▲▲P<0.01；With amlodipine+E Bei
Sha Tan+indapamide+folic acid group compares,#P < 0.05,##P<0.01。
Irbesartan compares with normal rats, and hypertension group rat left ventricle weight, room weight index, myocardial collagen contain
Amount, LVSP significantly raise, and ± dp/dtmax declines.Comparing with hypertension model group, irbesartan+indapamide+folic acid group is big
Mus left ventricular mass, room weight index, myocardial collagen content, LVSP decrease, and ± dp/dtmax compares with model group and risen
High；Compare with hypertension model group, amlodipine group left ventricular mass, room weight index, myocardial collagen content without significant change,
LVSP reduces, and ± dp/dtmax compares with model group and raised.Amlodipine+irbesartan+indapamide+folic acid group rat
Left ventricular mass, room weight index, myocardial collagen content, LVSP significantly reduce, and ± dp/dtmax significantly raises, with irbesartan+
Indapamide+folic acid group, amlodipine group compares significant difference.Show renal hypertensive rat cardiac preload, bear afterwards
Lotus increases, systolic pressure, diastolic pressure dysfunction amlodipine+irbesartan+indapamide+folic acid medicine 2 compositions tool
Having synergism, the cardiac function protective effect to renal hypertensive rat is obviously enhanced.It is shown in Table 4,5.
Table 4 amlodipines+irbesartan+indapamide+folic acid pharmaceutical composition to renal hypertensive rat left ventricle weight,
Room weight index, the impact (x ± SD) of myocardial collagen protein content
Compare with normal group,P<0.01；Compare with hypertension group,▲P < 0.05,▲▲P<0.01；With amlodipine+E Bei
Sha Tan+indapamide+folic acid group compares,#P < 0.05,##P<0.01。
Table 5 amlodipines+irbesartan+indapamide+folic acid pharmaceutical composition is to renal hypertensive rat hemodynamic
The impact (x ± SD) learned
Compare with normal group,P<0.01；Compare with hypertension group,▲P < 0.05,▲▲P<0.01；With amlodipine+E Bei
Sha Tan+indapamide+folic acid group compares,#P < 0.05,##P<0.01。
Embodiment 7: amlodipine+telmisartan+hydrochlorothiazide+folic acid is to Hypertensive Rats blood pressure lowering and the protection of target organ
Effect
Spontaneous hypertensive rat packet and dosage are shown in Table 6, separately set WKY Normal group, often group 20.Gavage is given
Medicine, every day 1 time, weighs weekly once, according to body weight adjust dose, continuous 26 weeks.Observation index:
(1) measure be administered before and the blood pressure of different time after being administered, after shrinking pressure-administration before calculating Amplitude of Hypotensive=administrations
Shrink pressure.(2) inner skin cell function 26 weekend, take blood and measure Plasma Nitric Oxide (NO), Endothelin by test kit description
(ET) level.(3) renal function 26 weekend, urine is collected, with sulfosalicylic acid method at spectrophotometric determination urinary protein concentrations, meter
Calculate 24h urine albumen amount.Put method of exempting from and measure 24h urine α 4 microglobulin, measure urine creatine according to test kit description；Take blood, measure
Serum creatinine, blood urea nitrogen (BUN), serum calculates creatinine clearance rate (Ccr).(4) left ventricle weight and room weight index take rat heart,
Clean with pre-cold saline, separate left ventricle (including interventricular septum), claim left ventricle weight, calculate left room weight index (left ventricle mg/
Body weight g).(5) at Myocardial hydroxyproline mensuration rat after death, Qu Zuo room cardiac muscular tissue about 50mg, use Bergman method to measure hydroxyl
Proline content, and calculate collagen content.Collagen content=8.2 dried meat hydroxyproline content (mg/g).(6) cardiomyopathy Neo-Confucianism checks
Cardiac muscular tissue's routine section, Picro-Sirius red-picric acid dyeing, measure around myocardial collagen fraction by volume (CVF) and myocardial vascular
Area of collagen (PVCA).CVF is the ratio of area of collagen and the cardiac muscle gross area, and wherein area of collagen does not include perivascular collagen
Area, 5 visuals field of stochastic analysis, take its average.PVCA be each specimen measure 4 in small artery in cross section wall around
Area and official jargon area ratio, take its average.
Result: compare with normal rats, hypertension group rat blood pressure significantly raises；Compare with hypertension group, for meter Sha
Smooth+hydrochlorothiazide+folic acid group rat blood pressure reduces, and amlodipine group rat blood pressure reduces；With telmisartan+hydrochlorothiazide+leaf
Acid group is compared with amlodipine group, and amlodipine+telmisartan+hydrochlorothiazide+folic acid group rat blood pressure reduces, further with training
Diindyl Puli+hydrochlorothiazide+folic acid group, amlodipine group compares significant difference.
Inner skin cell function imbalance receives significant attention as the early sign of Cardiovascular Damage, endothelial cell activity mark
Thing (nitric oxide and metabolite thereof, Endothelin etc.) research can be as a kind of straightforward procedure detecting endothelial function.With rat
Normal group compares, and hypertension group rat plasma NO level significantly reduces, and ET level significantly raises, and compares with hypertension group, ammonia chlorine
Horizon group, telmisartan+hydrochlorothiazide+folic acid group rat plasma NO level raises, and ET level reduces, and amlodipine+for meter Sha
Smooth+hydrochlorothiazide+folic acid group rat plasma NO level raises further, and ET level reduces further, with amlodipine group, for rice
Sha Tan+hydrochlorothiazide+folic acid group compares significant difference.Show: a certain degree of blood vessel occurs in spontaneous hypertensive rat
Inner skin cell function damages, and amlodipine+telmisartan+hydrochlorothiazide+folic acid pharmaceutical composition has synergism, to rat
The protective effect of blood vessel inner skin cell function further enhances.It is shown in Table 6.
Twenty-four-hour urine α 1 microglobulin is the label of reflection proximal convoluted tubule infringement, and albuminuria is except as a kind of kidney infringement
Outside mark, a kind of independent hazard factor promoting nephropathy to be in progress.Compare with normal group, hypertension group rat urine 24h α 1-
Microglobulin, urine protein and BUN significantly raise, and Ccr substantially reduces；Compare with hypertension group, amlodipine group, telmisartan+
Hydrochlorothiazide+folic acid group rat urine 24h α 1-microglobulin, urine protein and BUN reduce, Ccr raises, amlodipine+telmisartan
+ hydrochlorothiazide+folic acid group rat urine 24h α 1-microglobulin, urine protein and BUN reduce further, and Ccr raises further, with ammonia
Flordipine group, telmisartan+hydrochlorothiazide+folic acid group compares significant difference.Show: spontaneous hypertensive rat occurs one
Determining the kidney damage of degree, amlodipine+telmisartan+hydrochlorothiazide+folic acid pharmaceutical composition has synergism, to spontaneous
The Renoprotective Effect of property Hypertensive Rats is obviously enhanced.It is shown in Table 7.
Table 6 amlodipines+telmisartan+hydrochlorothiazide+folic acid pharmaceutical composition is to spontaneous hypertensive rat blood pressure, blood
The impact (x ± SD) of clear NO, ET
Compare with normal group,P<0.01；Compare with hypertension group,▲P < 0.05,▲▲P<0.01；With amlodipine+for rice
Sha Tan+hydrochlorothiazide+folic acid group compares,#P < 0.05,##P<0.01。
Table 7 amlodipines+telmisartan+hydrochlorothiazide+folic acid pharmaceutical composition is micro-to spontaneous hypertensive rat urine 24h
Globulin, urine protein, blood inosine clearance rate, the impact (x ± SD) of blood urea nitrogen
Compare with normal group,P<0.01；Compare with hypertension group,▲P < 0.05,▲▲P<0.01；With amlodipine+for rice
Sha Tan+hydrochlorothiazide+folic acid group compares,#P < 0.05,##P<0.01。
Comparing with normal group, hypertension group rat left heart weight and room weight index substantially increase；Compared with hypertension group rat,
Telmisartan+hydrochlorothiazide+folic acid group rat left heart weight and room weight index reduce, and amlodipine group is without significant change；Ammonia chlorine ground
Flat+telmisartan+hydrochlorothiazide group+folic acid group rat left heart weight and room weight index reduce further with amlodipine group, for rice
Sha Tan+hydrochlorothiazide+folic acid group compares significant difference.Show: a certain degree of myocardium of left ventricle occurs in Hypertensive Rats
Plumpness, amlodipine+telmisartan+hydrochlorothiazide+folic acid group rat long term administration can be treated heart hypertrophy in rats, be had aobvious
The synergism write.It is shown in Table 10.
Remodeling ventricle is the important pathological change of hypertension, mainly shows as cardiomyocyte proliferation, hypertrophy and interstitial fibers
Changing, hydroxyproline is peculiar by collagen fiber, and its content can reflect fibrosis.Compare with normal group, hypertension group rat
Myocardial collagen protein content significantly raises.Comparing with hypertension group, telmisartan+hydrochlorothiazide+folic acid group, amlodipine group are big
Mus myocardial collagen protein content is without notable change, amlodipine+telmisartan+hydrochlorothiazide+folic acid group rat heart muscle collagen egg
Bai Hanliang significantly reduces, and shows that above-mentioned composition has significant synergism.It is shown in Table 8.
Table 8 amlodipines+telmisartan+hydrochlorothiazide+folic acid pharmaceutical composition is to spontaneous hypertensive rat left ventricle
Weight, room weight index, the impact (x ± SD) of myocardial collagen protein content
Compare with normal group,P<0.01；Compare with hypertension group,▲P < 0.05,▲▲P<0.01；With amlodipine+for rice
Sha Tan+hydrochlorothiazide+folic acid group compares,#P < 0.05,##P<0.01。
Compare with normal rats, hypertension group rat heart muscle interstitial fibrosis index CVF, myocardial vascular surrounding annulus
Index PVCA all dramatically increases, CVF with PVCA raises the most synchronize, shows that Myocardial Interstitial Fibrosis take part in SHR cardiac remodeling
Pathological process.Compare with hypertension group, amlodipine group, telmisartan+hydrochlorothiazide+folic acid group rat heart muscle CVF, PVCA
Reducing, amlodipine+telmisartan+hydrochlorothiazide+folic acid group rat heart muscle CVF, PVCA reduces, further with amlodipine
Group, telmisartan+hydrochlorothiazide+folic acid group compares significant difference.Show telmisartan+hydrochlorothiazide+folic acid medicine group
Compound has significant synergism, has the action effect of protection cardiac muscle.It is shown in Table 9.
Table 9 amlodipines+telmisartan+hydrochlorothiazide+folic acid pharmaceutical composition is to spontaneous hypertensive rat cardiac muscle glue
The impact (x ± SD) of former fraction by volume (CVF) and collagen volume fraction (PVCA)
Compare with normal group,P<0.01；Compare with hypertension group,▲P < 0.05,▲▲P<0.01；With amlodipine+for rice
Sha Tan+hydrochlorothiazide+folic acid group compares,#P < 0.05,##P<0.01。
Claims (9)
1. a pharmaceutical composition, by the calcium antagonist of therapeutically effective amount, angiotensin ii receptor blocker, thiazide diuresis
Agent, folacin compound and pharmaceutically acceptable carrier composition.
Pharmaceutical composition the most according to claim 1, it is characterised in that: calcium antagonist is selected from amlodipine, left-handed ammonia chlorine
One in Horizon, nifedipine, nicardipine, lacidipine, nisoldipine, nitrendipine, felodipine, benidipine,
Content is 2～240mg.
Pharmaceutical composition the most according to claim 1, it is characterised in that: angiotensin ii receptor blocker is husky selected from chlorine
One in smooth, valsartan, irbesartan, telmisartan, Candesartan, Olmesartan, Tasosartan and eprosartan, content
It is 4～600mg.
Pharmaceutical composition the most according to claim 1, it is characterised in that: thiazide diuretic is rattled away selected from hydrochlorothiazide, Yin
One in handkerchief amine, chlortalidone, content is 0.625～25mg.
Pharmaceutical composition the most according to claim 1, it is characterised in that: folacin compound is selected from folic acid, 5-methyl four
Hydrogen folic acid, formyl tetrahydrofolic acid, calcium folinate or levoleucovorin calcium, content is 0.4～1.6mg.
Pharmaceutical composition the most according to claim 1, it is characterised in that: described calcium antagonist is amlodipine, and blood vessel is tight
Opening plain II receptor blocking agent is valsartan, and thiazide diuretic is hydrochlorothiazide, and folacin compound is folic acid.Wherein, calcium is short of money
The content of anti-agent is 2.5～5mg, and the content of angiotensin ii receptor blocker is 80～160mg, containing of thiazide diuretic
Amount is 10～25mg, and folate content is 0.4～0.8mg.
Pharmaceutical composition the most according to claim 1, it is characterised in that: described calcium antagonist is felodipine, and blood vessel is tight
Opening plain II receptor blocking agent is telmisartan, and thiazide diuretic is hydrochlorothiazide, and folacin compound is folic acid.Wherein, calcium
The content of antagonist is 2.5～15mg, and the content of angiotensin ii receptor blocker is 20～80mg, thiazide diuretic
Content is 10～25mg, and folate content is 0.4～0.8mg.
Pharmaceutical composition the most according to any one of claim 1 to 7, it is characterised in that: described pharmaceutical composition can be made
Become conventional tablet, conventional capsule, granule, slow releasing tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, enteric coatel tablets, enteric glue
Capsule, delayed-release tablet, regularly/position releasing piece, slow releasing capsule, controlled release capsule, PH dependent form capsule containing micropill or small pieces,
The dosage forms such as granule, oral liquid, membrane, patch.
9. the pharmaceutical composition according to any one of claim 1 to 7 is used for 2～3 grades of hypertension for the treatment of in preparation, prevents and prolong
Purposes in the medicine of the slow apoplexy caused by hypertension.
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| WO2018138578A1 (en) * | 2017-01-25 | 2018-08-02 | The George Institute for Global Health | Compositions for the treatment of hypertension |
| CN108785313A (en) * | 2018-07-06 | 2018-11-13 | 苏州大学附属第医院 | A kind of pharmaceutical composition |
| US10369156B2 (en) | 2016-11-15 | 2019-08-06 | The George Institute for Global Health | Compositions for the treatment of hypertension |
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| CN103599537A (en) * | 2013-11-15 | 2014-02-26 | 深圳奥萨医药有限公司 | Pharmaceutical composition of calcium channel blocker/thiazide diuretic/5-methyltetrahydrofolate |
| CN103721259A (en) * | 2014-01-07 | 2014-04-16 | 深圳奥萨医药有限公司 | Angiotensin II receptor blocker/thiazide diuretics/5-methyltetrahydrofolate pharmaceutical composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103599537A (en) * | 2013-11-15 | 2014-02-26 | 深圳奥萨医药有限公司 | Pharmaceutical composition of calcium channel blocker/thiazide diuretic/5-methyltetrahydrofolate |
| CN103721259A (en) * | 2014-01-07 | 2014-04-16 | 深圳奥萨医药有限公司 | Angiotensin II receptor blocker/thiazide diuretics/5-methyltetrahydrofolate pharmaceutical composition |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10369156B2 (en) | 2016-11-15 | 2019-08-06 | The George Institute for Global Health | Compositions for the treatment of hypertension |
| WO2018138578A1 (en) * | 2017-01-25 | 2018-08-02 | The George Institute for Global Health | Compositions for the treatment of hypertension |
| US10322117B2 (en) | 2017-01-25 | 2019-06-18 | The George Institute for Global Health | Compositions for the treatment of hypertension |
| US10799487B2 (en) | 2017-01-25 | 2020-10-13 | The George Institute for Global Health | Compositions for the treatment of hypertension |
| US11478462B2 (en) | 2017-01-25 | 2022-10-25 | The George Institute for Global Health | Compositions for the treatment of hypertension |
| CN108785313A (en) * | 2018-07-06 | 2018-11-13 | 苏州大学附属第医院 | A kind of pharmaceutical composition |
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