CN110755390A - Compound antihypertensive drug tablet and application thereof - Google Patents
Compound antihypertensive drug tablet and application thereof Download PDFInfo
- Publication number
- CN110755390A CN110755390A CN201811499328.7A CN201811499328A CN110755390A CN 110755390 A CN110755390 A CN 110755390A CN 201811499328 A CN201811499328 A CN 201811499328A CN 110755390 A CN110755390 A CN 110755390A
- Authority
- CN
- China
- Prior art keywords
- hydrochlorothiazide
- amiloride
- acid
- amlodipine
- layer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
-
- 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
- A61K31/4965—Non-condensed pyrazines
-
- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Hospice & Palliative Care (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a compound antihypertensive drug tablet, which comprises the following components: amlodipine or a pharmaceutically acceptable salt thereof, amiloride or an inorganic acid salt or an organic acid salt of amiloride, and hydrochlorothiazide or an inorganic acid salt or an organic acid salt of hydrochlorothiazide. The compound antihypertensive drug tablet provided by the invention reduces the dosage of a single drug and the number of drugs actually taken by a patient, thereby reducing the side effect of the drug and increasing the compliance of the patient in taking the drug.
Description
Technical Field
The invention relates to the field of medicines, in particular to a compound antihypertensive medicine tablet and application thereof.
Background
Cardiovascular and cerebrovascular diseases have become the leading cause of death of residents in our country. Hypertension is a main factor causing cardiovascular diseases such as cerebral apoplexy, coronary heart disease, congestive heart failure and the like, and a large number of clinical test researches at home and abroad prove that the reduction of the blood pressure level of patients with hypertension can obviously reduce the morbidity, disability rate and mortality of the cardiovascular diseases and the cerebrovascular diseases. Recent epidemiological data show that more than 2.4 million adults in China have hypertension. How to effectively control the blood pressure of hypertension people to prevent stroke and cardiovascular events is a major public health problem faced by China at present
The existing hypertension effective treatment medicines are more, and the first-line antihypertensive medicines recommended by international hypertension guidelines comprise diuretics, amlodipine (CCB), Angiotensin Converting Enzyme Inhibitors (ACEI) and angiotensin receptor Antagonists (ARB), β -blockers, five types of medicines which are all suitable for initial treatment and maintenance treatment of hypertension patients and can achieve good antihypertensive effects.
Evidence of evidence shows that most hypertension (2/3) patients need two or more antihypertensive drugs for combined treatment to reach the blood pressure standard, and the small dose of the antihypertensive drugs combined with different types shows good clinical efficacy. Different types of antihypertensive drugs in combination therapy have different antihypertensive mechanisms, but can complement each other, and enhance the treatment effect. The dosage of the drug for the combination therapy is lower than that of the single drug, thereby obviously reducing the incidence rate of side effects, improving the life quality of patients, increasing the tolerance of the patients and improving the drug compliance.
Amlodipine belongs to CCB, can selectively inhibit calcium ions from entering vascular smooth muscle and cardiac muscle, mainly acts on peripheral arterial vascular smooth muscle to expand peripheral arteries and reduce peripheral vascular resistance, thereby playing a role in reducing blood pressure. The oral preparation is characterized by good oral absorption and no influence of food intake, the blood concentration reaches a peak 6-12 hours after administration, the absolute bioavailability is about 64-80%, the terminal elimination half-life period is about 35-50 hours, but the speed of combination with a receptor and dissociation is slow, so the effect of the medicine is slow and the maintenance time is long. Chemical name: 3-Ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1, 4-dihydro-6-methyl-3, 5-pyridinedicarboxylate benzenesulfonate. The benzene sulfonate, maleate, etc. thereof are commonly used.
The compound amiloride compound preparation consisting of amiloride and hydrochlorothiazide has the synergistic effects of potassium retention, diuresis, hypertension resistance and the like, and has the characteristics of the action of both amiloride and hydrochlorothiazide. The hydrochlorothiazide belongs to a middle-effect natriuretic, and can inhibit the reabsorption of the front section of a distal tubule and a proximal tubule of the renal tubule (with a lighter effect) on sodium chloride, so that the Na + -K + exchange of the distal tubule and the collecting duct is increased, the K + secretion is increased, the excretion of the kidney on the sodium chloride is increased, the diuretic effect is generated, the blood volume is reduced, the cardiac output is reduced, and the blood pressure is reduced. After continuous administration for several weeks, hydrochlorothiazide can reduce the content of sodium ions in cells of arterial wall, reduce the reactivity of vascular smooth muscle to endogenous vasoactive substances, and cause peripheral vasodilation. The Chinese medicinal composition has the characteristics of good absorption, action after being taken for 2 hours, time for reaching a peak of blood concentration of 4 hours, action duration of 6-12 hours, half-life of 15 hours, quick response and short action time. Amiloride is a powerful potassium-protecting diuretic, acts on the far end of renal tubules, blocks a sodium-potassium exchange mechanism, promotes excretion of sodium and chlorine, reduces secretion of potassium and hydrogen ions, has weak natriuretic and antihypertensive activities, and has a synergistic antihypertensive effect when being used with thiazide diuretics. It is characterized by poor oral absorption of only 15-20%. The plasma protein binding rate is very low, the plasma protein is not metabolized in vivo, the half-life period is 6-9 hours, the single oral administration onset time is 2 hours, the blood concentration reaches the peak in 6-10 hours, and the sustained action is 24 hours.
The prior art discloses a technical scheme for treating hypertension by combining amlodipine, hydrochlorothiazide and amiloride, which generally adopts two or three tablets, such as amlodipine tablet + compound amiloride tablet or amlodipine tablet + hydrochlorothiazide tablet + amiloride tablet, but the application in practical clinic finds that at least two tablets must be taken by a patient each time by adopting the above-mentioned medicine taking mode, and the hypertension patient is usually the old, so that the inconvenience of taking medicine for the old is caused, the condition of missing is often caused, and the effective treatment of hypertension is not facilitated. In addition, each tablet contains a plurality of auxiliary materials, different auxiliary materials have different influences on the release of the active pharmaceutical ingredients, and after the three active pharmaceutical ingredients are taken together, the release of the three active pharmaceutical ingredients at an ideal speed is difficult to control, so that the treatment effect is influenced. Therefore, the development of a compound medicinal preparation containing the three active medicaments has great significance.
Currently, the combination of a renin angiotensin aldosterone system blocker and amlodipine is the major antihypertensive combination regimen in clinical applications. Although the prior studies show that the combination of CCB and ARB has a certain synergistic effect, for example, patent document CN200580033928.9 discloses a bilayer tablet comprising telmisartan and amlodipine; CN1765362A discloses a composition comprising amlodipine and an angiotensin II receptor Antagonist (ARB), but whether this combination regimen can better prevent the advanced cardiovascular complications in hypertensive patients is currently short of evidence support. And large-scale clinical tests prove that the amlodipine and the amlodipine compound can reduce the incidence rate of cardiovascular diseases of hypertension patients better than the amlodipine and the telmisartan for the first time. And compared with ARB, the compound amiloride has rapid antihypertensive effect and obviously reduced cost, and researches prove that the small dose of diuretic has low side effect incidence rate and good patient compliance even if the compound amiloride is taken for a long time, and the ARB can have serious adverse reactions such as myalgia, angioedema and the like.
Disclosure of Invention
Therefore, the invention aims to solve the problem that the combined antihypertensive drug has high cost and serious side effect in the prior art, thereby providing a novel compound antihypertensive drug tablet, which not only reduces the dosage of a single drug, but also reduces the number of drugs actually taken by a patient, thereby reducing the side effect of the drug and increasing the compliance of the patient in taking the drug.
In order to solve the technical problems, the invention adopts the following technical scheme:
a compound antihypertensive drug tablet comprises compound antihypertensive drug active components and a pharmaceutically acceptable carrier;
the active components of the compound antihypertensive drug comprise the following three components:
component 1: amlodipine or a pharmaceutically acceptable salt thereof, wherein the amlodipine or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier form an amlodipine layer, and the amlodipine layer is coated with a film coating layer;
and (2) component: the hydrochlorothiazide or hydrochlorothiazide inorganic acid salt or organic acid salt, the hydrochlorothiazide or hydrochlorothiazide inorganic acid salt or organic acid salt and the medicinal carrier form a hydrochlorothiazide layer;
and (3) component: the amiloride or the inorganic acid salt or the organic acid salt of the amiloride forms an amiloride particle layer with a pharmaceutically acceptable carrier;
the tablet comprises an amlodipine layer and a hydrochlorothiazide layer which are arranged in an overlapping mode, and the amiloride particles are arranged on the hydrochlorothiazide layer.
As another embodiment, the amiloride particles are dispersed in an adjuvant to form an amiloride layer;
the hydrochlorothiazide layer and the amiloride layer are respectively arranged on two sides of the amlodipine layer.
In each preparation unit, the amlodipine or the pharmaceutically acceptable salt thereof is 1.0-10.0mg in terms of amlodipine; 2.5-20.0mg of amiloride or inorganic acid salt or organic acid salt of amiloride calculated as amiloride; 6.25-50.0mg of inorganic acid salt or organic acid salt of hydrochlorothiazide or hydrochlorothiazide calculated by hydrochlorothiazide.
Preferably, the amlodipine or the pharmaceutically acceptable salt thereof is 2.5-5.0mg in terms of amlodipine; 5.0-10.0mg of amiloride or inorganic acid salt or organic acid salt of amiloride calculated as amiloride; 12.5-25.0mg of inorganic acid salt or organic acid salt of hydrochlorothiazide or hydrochlorothiazide calculated by hydrochlorothiazide.
The amlodipine comprises levamlodipine or pharmaceutically acceptable salts thereof, wherein the pharmaceutically acceptable salts are benzenesulfonate, fumarate, acetate, benzoate, citrate, gluconate, hydrochloride, lactate, maleate, malate, methanesulfonate, nitrate, phosphate, succinate, phosphate and tartrate.
The inorganic acid salt or organic acid salt includes: hydrochloric acid, hydrobromic acid, iodohydric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, mandelic acid, trifluoroacetic acid, pantothenic acid, methylsulfuric acid and p-toluenesulfonic acid.
The compound antihypertensive drug tablet is applied to preventing cerebral apoplexy.
The compound antihypertensive drug tablet is applied to preventing congestive heart failure.
The compound antihypertensive drug tablet is applied to preventing cardiovascular diseases of diabetic patients.
Compared with the prior art, the technical scheme of the invention has the following advantages:
the compound antihypertensive drug tablet comprises amlodipine or a pharmaceutically acceptable salt thereof, hydrochlorothiazide or an inorganic acid salt or an organic acid salt of hydrochlorothiazide, and amiloride or an inorganic acid salt or an organic acid salt of amiloride, wherein in each preparation unit, the amlodipine or the pharmaceutically acceptable salt thereof is 1.0-10.0mg calculated as amlodipine; 2.5-20.0mg of amiloride or inorganic acid salt or organic acid salt of amiloride calculated as amiloride; 6.25-50mg of inorganic acid salt or organic acid salt of hydrochlorothiazide or hydrochlorothiazide calculated by hydrochlorothiazide, and the balance of pharmaceutically acceptable carrier. Further preferably, the amlodipine or the pharmaceutically acceptable salt thereof is 2.5 to 5.0mg in terms of amlodipine per formulation unit; 12.5-25.0mg of inorganic acid salt or organic acid salt of hydrochlorothiazide or hydrochlorothiazide calculated by hydrochlorothiazide, and 5.0-10.0mg of inorganic acid salt or organic acid salt of amiloride calculated by amiloride; the balance being pharmaceutically acceptable carriers.
The compound accords with the application principle of compound treatment of the antihypertensive drug, the compound formed by amlodipine, amiloride and hydrochlorothiazide has good synergistic effect, and the dosage of amlodipine, amiloride and hydrochlorothiazide can be reduced when the same or even better antihypertensive effect is achieved. The low dose of amlodipine can obviously reduce edema side reaction caused by sodium water retention, and the diuresis and natriuresis effects of amiloride and hydrochlorothiazide can further reduce edema side reaction caused by amlodipine. Low doses of amiloride and hydrochlorothiazide reduce the incidence of side effects caused by diuretics such as hypokalemia, hyperglycemia and hyperuricemia, in addition amiloride is a potassium sparing diuretic and hydrochlorothiazide is a potassium excreting diuretic, which in combination further reduce the incidence of side effects of hypokalemia. In addition, amlodipine can increase the insulin sensitivity of the body and can partially offset hyperglycemia caused by amiloride and hydrochlorothiazide. Not only does this, the compound medicine taken for a long time not only reduces blood pressure obviously, but also can reduce the incidence rate of cardiovascular diseases. The compound uses amlodipine and low-cost diuretic amiloride and hydrochlorothiazide, has higher cost performance compared with the combination of amlodipine and a renin-angiotensin system inhibitor, and is convenient for popularization and use in a large number of people.
The invention combines amlodipine, amiloride and hydrochlorothiazide for use, and provides the compound antihypertensive drug tablet with lower cost, better treatment effect and smaller side effect. The combination provides a drug combination which is superior to the combination of amlodipine and telmisartan in the aspects of target organ protection and reduction of the risk of cardiovascular and cerebrovascular events, and has no increase of side effects. However, large-scale clinical tests prove that the combination of amlodipine and amiloride and hydrochlorothiazide can reduce the incidence rate of cardiovascular diseases of hypertension patients better than the combination of amlodipine and telmisartan, and evidence-based data support is provided for the combination of amlodipine, amiloride and hydrochlorothiazide. Meanwhile, compared with ARBs (arginine-glycine-aspartic acid), the combination of amiloride and hydrochlorothiazide has the advantages of rapid antihypertensive effect and obviously reduced cost, researches also prove that the small dose of diuretic has low side effect incidence rate and good patient compliance even if the combination is taken for a long time, and the ARB in the background technology can have serious adverse reactions such as myalgia, angioedema and the like.
The existing clinical test data show that amlodipine can not only obviously reduce the blood pressure level of a hypertensive patient and reduce the occurrence of cardiovascular events, but also has low side effect incidence rate, particularly low-dose medication, obviously reduces the side effect, has better response to the patient and has wide application in clinical treatment. The calcium antagonist is suitable for treating various types and degrees of hypertension, especially for the elderly and patients with coronary heart disease, angina pectoris and peripheral blood vessel; those with impaired glucose tolerance and renal impairment; combined with secondary prevention of stroke. The calcium antagonist has the advantages of quick effect, large blood pressure reduction amplitude, safety, effectiveness, no influence on blood sugar and lipid metabolism, and obvious target organ protection.
Diuretics have been the basis of antihypertensive therapy for many years, and both developed and developing countries currently have diuretics as the basis of antihypertensive drugs. The antihypertensive effect is clear, and the adverse effect on metabolism is small when the antihypertensive drug is applied in small dosage. The us guideline JNC7 recommends diuretics as the first choice for hypotensive therapy, and a diuretic must be included in combination therapy. The diuretic is low in price, obvious in blood pressure reducing effect and remarkable in social and economic benefits. Hydrochlorothiazide is a potassium-removing diuretic, hypokalemia is easy to occur to patients after long-term application, amiloride is a potassium-retaining diuretic, and the combination of the hydrochlorothiazide and the potassium-removing diuretic is beneficial to keeping the blood potassium balance, improving the antihypertensive curative effect, reducing the respective dosage and reducing the side effect incidence rate caused by long-term use of the diuretic.
The invention combines amlodipine with diuretic amiloride and hydrochlorothiazide, and both the calcium antagonist and the diuretic have the functions of expanding blood vessels, promoting urination and natriuresis and reducing blood volume from the aspect of a blood pressure reducing mechanism. The combination of the two can effectively reduce blood volume and improve elasticity of aorta, thereby being beneficial to people with high blood volume and excessive sodium salt intake in the simple systolic period, especially Asian people and patients with low renin level. Common side effects of amlodipine are lower limb edema caused by sodium water retention, which causes drug withdrawal of some patients and limits the clinical application of amlodipine. Amiloride and hydrochlorothiazide reduce amlodipine-induced edema by inducing diuresis to expel sodium. The medicine composition can effectively reduce the blood pressure of a patient, can reduce the occurrence of cerebral apoplexy and cardiovascular events, relieves the medical burden of the patient, and creates higher social and economic values with lower medicine cost. The three medicines are combined into one medicine, so that the medicine dosage of a single medicine is reduced, and the number of medicines actually taken by a patient is reduced, so that the side effect of the medicine is reduced, and the medicine taking compliance of the patient is improved.
Currently, the combination of renin angiotensin aldosterone system blocker with amlodipine or a diuretic is the clinically most prominent antihypertensive combination regimen. However, large-scale clinical trials prove that the combination of amlodipine and the amiloride and the hydrochlorothiazide can reduce the incidence rate of cardiovascular diseases of hypertension patients better than the combination of amlodipine and the telmisartan.
Drawings
In order to more clearly illustrate the embodiments of the present invention, the drawings which are needed to be used in the embodiments will be briefly described below, and it is apparent that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained from the drawings without inventive labor to those skilled in the art.
Fig. 1 is a schematic structural diagram of a first embodiment of a compound antihypertensive drug tablet provided by the invention;
fig. 2 is a schematic structural diagram of a second embodiment of the compound antihypertensive drug tablet provided by the invention.
Detailed Description
The technical solutions of the present invention will be described clearly and completely below, and it should be apparent that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides a compound antihypertensive drug tablet, which comprises compound antihypertensive drug active components and a pharmaceutically acceptable carrier;
the active components of the compound antihypertensive drug comprise the following three components:
a compound antihypertensive drug tablet comprises compound antihypertensive drug active components and a pharmaceutically acceptable carrier;
the active components of the compound antihypertensive drug comprise the following three components:
component 1: amlodipine or a pharmaceutically acceptable salt thereof, wherein the amlodipine or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier form an amlodipine layer 1, and the amlodipine layer is coated with a film coating layer 4;
and (2) component: the hydrochlorothiazide or hydrochlorothiazide inorganic acid salt or organic acid salt, the hydrochlorothiazide or hydrochlorothiazide inorganic acid salt or organic acid salt and the medicinal carrier form a hydrochlorothiazide layer 2;
and (3) component: amiloride or an inorganic acid salt or an organic acid salt of amiloride, wherein the amiloride or the inorganic acid salt or the organic acid salt of amiloride and a pharmaceutically acceptable carrier form an amiloride particle layer 3;
the tablet comprises an amlodipine layer 1 and a hydrochlorothiazide layer 2 which are arranged in an overlapping mode, and the amiloride particles 3 are arranged in the hydrochlorothiazide layer 2.
As a first embodiment, as shown in fig. 1, the tablet has a three-layer structure, and the component 3 is granular and dispersed in an auxiliary material to form an amiloride layer; the amiloride layer and the hydrochlorothiazide layer are respectively arranged on two sides of the amlodipine layer.
Amiloride has poor oral absorption rate, the absorption rate is low, only 15-20%, and the absorption rate is improved by preparing the amiloride into granules. The amiloride and hydrochlorothiazide are quickly absorbed by oral administration, take effect within 2 hours after oral administration, have a serum concentration peak value of 3-4 hours, an action half-life period of 6-9 hours and an effective action time of 6-10 hours. The embodiment enables amiloride and hydrochlorothiazide to be dissolved and released simultaneously after being taken, and the potassium-retaining effect of the amiloride can avoid the low-potassium effect caused by the hydrochlorothiazide, so that the synergistic pressure-reducing effect of the amiloride and the hydrochlorothiazide can be better exerted.
The amlodipine takes the amlodipine besylate as an example, the amlodipine besylate is good in oral absorption, the blood concentration reaches the peak within 6-12h, the onset time is slower than that of hydrochlorothiazide, but the action time is longer, the amlodipine is finally released by the design, and when the drug effects of the amlodipine and the hydrochlorothiazide are reduced, the amlodipine can timely play a role in reducing blood pressure, so that the blood pressure of a patient is kept relatively stable, and the effect in reducing blood pressure is longer. The design not only avoids the defect of short duration of drug effects of amiloride and hydrochlorothiazide, but also overcomes the defect of slow response of the antihypertensive effect of amlodipine, and better plays the drug combination effect.
As a second embodiment, as shown in fig. 2, the tablet has a three-layer structure, and amiloride granules and hydrochlorothiazide are uniformly mixed and then made into a double-layer tablet with an amlodipine layer. Specifically, the tablet comprises an amlodipine layer 1 and a hydrochlorothiazide layer 2 which are arranged in an overlapping mode, the amiloride particles 3 which are formed are arranged in the hydrochlorothiazide layer 2, and the amlodipine layer 1 and the hydrochlorothiazide layer 2 are both coated with a film coating layer 4.
Amiloride is poorly absorbed by oral administration, slightly soluble in water, long in disintegration time, poor in absorption of only 15-20%, and can be made into granule to improve absorption rate. The amiloride and hydrochlorothiazide are quickly absorbed by oral administration, take effect within 2 hours after oral administration, have a serum concentration peak value of 3-4 hours, an action half-life period of 6-9 hours and an effective action time of 6-10 hours. The design is favorable for simultaneously exerting the pressure reduction effect on the amiloride and the hydrochlorothiazide, the potassium-retaining effect of the amiloride can avoid the low-potassium effect caused by the hydrochlorothiazide, and the synergistic pressure reduction effect of the amiloride and the hydrochlorothiazide can be better exerted.
The amlodipine takes the amlodipine besylate as an example, the amlodipine besylate is good in oral absorption, the blood concentration reaches the peak within 6-12h, the onset time is slower than that of hydrochlorothiazide, but the action time is longer, the design not only avoids the defect of short duration of the drug effects of amiloride and hydrochlorothiazide, but also overcomes the defect of slow onset of the antihypertensive effect of the amlodipine, so that the antihypertensive effect is longer, the blood pressure is kept stable, and the drug combination effect is better exerted.
Preferably, the amlodipine or the pharmaceutically acceptable salt thereof is 1.0 to 10.0mg in terms of amlodipine per formulation unit; 2.5-20.0mg of amiloride or inorganic acid salt or organic acid salt of amiloride calculated as amiloride; 6.25-50mg of inorganic acid salt or organic acid salt of hydrochlorothiazide or hydrochlorothiazide calculated by hydrochlorothiazide, and the balance of pharmaceutically acceptable carrier.
Further preferably, said amlodipine or pharmaceutically acceptable salt thereof is 2.5 to 5.0mg in terms of amlodipine per formulation unit; 5.0-10.0mg of amiloride or inorganic acid salt or organic acid salt of amiloride calculated as amiloride; 12.5-25.0mg of inorganic acid salt or organic acid salt of hydrochlorothiazide or hydrochlorothiazide calculated by hydrochlorothiazide, and the balance of pharmaceutically acceptable carrier.
The pharmaceutically acceptable salts are benzene sulfonate, fumarate, acetate, benzoate, citrate, gluconate, hydrochloride, lactate, maleate, malate, methanesulfonate, nitrate, phosphate, succinate, phosphate and tartrate.
The inorganic acid salt or organic acid salt comprises: hydrochloric acid, hydrobromic acid, iodohydric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, mandelic acid, trifluoroacetic acid, pantothenic acid, methylsulfuric acid and p-toluenesulfonic acid.
The pharmaceutically acceptable carrier includes excipients and adjuvants which are helpful for formulating the active compound into a pharmaceutical preparation, such as one or a combination of more of starch, microcrystalline cellulose, inorganic salts, sucrose, dextrin, lactose, powdered sugar, glucose, sodium chloride, cysteine, citric acid, sodium sulfite, etc.
The compound antihypertensive drug tablet is applied to preventing cerebral apoplexy.
The compound antihypertensive drug tablet is applied to preventing congestive heart failure.
The compound antihypertensive drug tablet is applied to preventing cardiovascular diseases of diabetic patients.
Examples 1 to 5 are structured tablets as shown in fig. 1, and examples 6 to 9 are structured tablets as shown in fig. 2.
Examples 1-9 are tabulated below:
the proportion of the main components is as follows:
the film coating comprises the following components: polymeric coating materials comprising hydroxypropylmethylcellulose (or hydroxypropylcellulose or polyvinyl acetate phthalate), polyethylene glycol, talc, titanium dioxide and pigments are commercially available as OPADRYY-1-7000 from kalekon coating technology, inc. Suitable film coatings are well known and commercially available or may be prepared according to well known methods. The film coating material is typically a polymeric film coating material comprising, for example, hydroxypropylmethyl cellulose, polyethylene glycol, talc and a colorant material. Generally, the film coating material is used in an amount to provide a film coating of about 1% to about 7% by weight of the film coated tablet.
Examples 1-9 film coating ingredients used OPADRYY-1-7000 film coating materials, available from Shanghai Carlekang coating technology, Inc., in an amount of 4% by weight of the tablet;
the medicinal auxiliary materials are selected from microcrystalline cellulose serving as a medicinal filler, crospovidone serving as a disintegrant and magnesium stearate serving as a lubricant, so that the medicinal powder has good fluidity, compressibility and compatibility during tabletting. The pharmaceutical excipients adopted by the invention are safe and reliable, and play a very good auxiliary role in the dissolution rate and the stability of the tablet.
The replaceable medicinal filler can be one or more selected from microcrystalline cellulose, pregelatinized starch, lactose, mannitol, etc.;
the disintegrant can be one or more selected from crospovidone, sodium carboxymethyl starch, and croscarmellose sodium;
the replaceable lubricant can be one or more selected from magnesium stearate, pulvis Talci, sodium fumarate stearate, silica gel micropowder, hydrogenated vegetable oil, etc.;
as other examples, the pharmaceutically acceptable salt of amlodipine of the present invention may be selected from benzenesulfonate, fumarate, acetate, benzoate, citrate, gluconate, hydrochloride, lactate, maleate, malate, methanesulfonate, nitrate, phosphate, succinate, phosphate and tartrate; an inorganic acid salt or an organic acid salt of amiloride, the inorganic acid salt or the organic acid salt comprising: salts formed from hydrochloric acid, hydrobromic acid, iodohydric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, mandelic acid, trifluoroacetic acid, pantothenic acid, methylsulfuric acid and p-toluenesulfonic acid; an inorganic or organic acid salt of hydrochlorothiazide, said inorganic or organic acid salt comprising: hydrochloric acid, hydrobromic acid, iodohydric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, mandelic acid, trifluoroacetic acid, pantothenic acid, methylsulfuric acid and p-toluenesulfonic acid. Any combination of the above compounds, provided that it satisfies the combination of 1.0-10.0mg of amlodipine, 2.5-20.0mg of amiloride and 6.25-50.0mg of hydrochlorothiazide, can satisfy the purpose of lowering blood pressure of the present invention.
The clinical efficacy test of the compound antihypertensive drug tablet for treating hypertension of the invention comprises the following steps:
1. general data:
selecting 450 cases of essential hypertension patients who do not take any antihypertensive drug, wherein the patients are 50-64 years old and 300 cases old; age 65-80 years old, 150 cases.
2. Hypertension diagnosis standard: according to the definition of hypertension in 2010 version of the Chinese guidelines for hypertension prevention and treatment: under the condition of not using antihypertensive drugs, the systolic pressure is more than or equal to 140mmHg and/or the diastolic pressure is more than or equal to 90 mmHg.
3. The treatment method comprises the following steps: the 450 patients in the group are averagely divided into 9 groups by adopting a random grouping method, 50 patients in each group are respectively orally taken 1 time a day by adopting the compound tablets obtained in the embodiments 1-9, and the compound tablets are taken for 2 weeks by 1 tablet or 2 tablets each time according to different dosage of the tablets.
4. And (3) evaluating the curative effect: according to the blood pressure reduction target recommended by the 2010 version of Chinese hypertension control guidelines, the blood pressure of general hypertension patients is reduced to 140/90 mmHg; the systolic blood pressure of the aged 65 years old and older is lower than 150 mmHg.
5. The treatment results are as follows: blood pressure was measured for all patients in the group on days 2, 4, 6, 8, 10, 12 and 14 from the start of administration. The result shows that after 2 weeks of administration, 386 patients in 450 primary hypertension patients in the group of 6 patients with primary hypertension have reached the standard, and the average standard-reaching rate is 85.8%, which shows that the compound antihypertensive tablet provided by the embodiment of the invention has a good effect of treating hypertension.
The curative effect is shown in the following table:
number of cases | Blood pressure reaches the standard number | Blood pressure not reaching the standard | Mean blood pressure achievement rate |
450 | 386 | 64 | 85.8% |
The compound antihypertensive drug combination tablet is suitable for treating hypertension and can obtain higher standard reaching rate of blood pressure.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.
Claims (9)
1. A compound antihypertensive drug tablet is characterized by comprising compound antihypertensive drug active components and a pharmaceutically acceptable carrier;
the active components of the compound antihypertensive drug comprise the following three components:
component 1: amlodipine or a pharmaceutically acceptable salt thereof, wherein the amlodipine or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier form an amlodipine layer (1), and the amlodipine layer is coated with a film coating layer (4);
and (2) component: the hydrochlorothiazide coating comprises inorganic acid salts or organic acid salts of hydrochlorothiazide or hydrochlorothiazide, wherein the inorganic acid salts or organic acid salts of the hydrochlorothiazide or hydrochlorothiazide and a pharmaceutically acceptable carrier form a hydrochlorothiazide layer (2);
and (3) component: amiloride or an inorganic acid salt or an organic acid salt of amiloride, wherein the amiloride or the inorganic acid salt or the organic acid salt of amiloride and a pharmaceutically acceptable carrier form an amiloride particle layer (3);
the tablet comprises an amlodipine layer and a hydrochlorothiazide layer which are arranged in an overlapping mode, and the amiloride particles are arranged in the hydrochlorothiazide layer.
2. The compound antihypertensive drug tablet according to claim 1,
the amiloride particles are dispersed in auxiliary materials to form an amiloride layer;
the hydrochlorothiazide layer and the amiloride layer are respectively arranged on two sides of the amlodipine layer.
3. The compound antihypertensive drug tablet according to claim 1 or 2,
in each preparation unit, the amlodipine or the pharmaceutically acceptable salt thereof is 1.0-10.0mg in terms of amlodipine; 2.5-20.0mg of amiloride or inorganic acid salt or organic acid salt of amiloride calculated as amiloride; 6.25-50mg of inorganic acid salt or organic acid salt of hydrochlorothiazide or hydrochlorothiazide calculated by hydrochlorothiazide.
4. The compound antihypertensive drug tablet according to claim 3, wherein the amlodipine or the pharmaceutically acceptable salt thereof is 2.5-5.0mg in terms of amlodipine; 5.0-10.0mg of amiloride or inorganic acid salt or organic acid salt of amiloride calculated as amiloride; 12.5-25.0mg of inorganic acid salt or organic acid salt of hydrochlorothiazide or hydrochlorothiazide calculated by hydrochlorothiazide.
5. The compound antihypertensive drug tablet according to claim 1 or 2,
the amlodipine comprises levamlodipine or pharmaceutically acceptable salts thereof, wherein the pharmaceutically acceptable salts are benzenesulfonate, fumarate, acetate, benzoate, citrate, gluconate, hydrochloride, lactate, maleate, malate, methanesulfonate, nitrate, phosphate, succinate, phosphate and tartrate.
6. The compound antihypertensive drug tablet according to claim 1 or 2,
the inorganic acid salt or organic acid salt includes: hydrochloric acid, hydrobromic acid, iodohydric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, mandelic acid, trifluoroacetic acid, pantothenic acid, methylsulfuric acid and p-toluenesulfonic acid.
7. The compound antihypertensive drug tablet of claim 1 or 2 is used for preventing cerebral apoplexy.
8. Use of the compound antihypertensive drug tablet according to claim 1 or 2 for preventing congestive heart failure.
9. Use of a compound antihypertensive pharmaceutical tablet according to claim 1 or 2 for preventing cardiovascular disease in diabetic patients.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810836843 | 2018-07-26 | ||
CN2018108368433 | 2018-07-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN110755390A true CN110755390A (en) | 2020-02-07 |
Family
ID=69328469
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201811499329.1A Pending CN110755397A (en) | 2018-07-26 | 2018-12-08 | Compound antihypertensive drug tablet and application thereof |
CN201811499342.7A Pending CN110755429A (en) | 2018-07-26 | 2018-12-08 | Compound antihypertensive medicine composition, preparation and application thereof |
CN201811499328.7A Pending CN110755390A (en) | 2018-07-26 | 2018-12-08 | Compound antihypertensive drug tablet and application thereof |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201811499329.1A Pending CN110755397A (en) | 2018-07-26 | 2018-12-08 | Compound antihypertensive drug tablet and application thereof |
CN201811499342.7A Pending CN110755429A (en) | 2018-07-26 | 2018-12-08 | Compound antihypertensive medicine composition, preparation and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (3) | CN110755397A (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113616651B (en) * | 2020-05-08 | 2023-12-29 | 深圳奥萨制药有限公司 | Compound antihypertensive pharmaceutical composition and application thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20090057538A (en) * | 2007-12-03 | 2009-06-08 | 박사룡 | A composition for treating hypertension comprising angiotensin ii antagonist, calsium andtagonist and diuretics |
WO2009154810A2 (en) * | 2008-02-25 | 2009-12-23 | Dr. Reddy's Laboratories Ltd. | Delivery systems for multiple active agents |
CN101780079A (en) * | 2010-03-03 | 2010-07-21 | 施慧达药业集团(吉林)有限公司 | Levamlodipine compound drug composition |
CN102008711A (en) * | 2009-07-14 | 2011-04-13 | 邬林祥 | Compound preparation containing enalapril for treating hypertension |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101966188A (en) * | 2009-07-14 | 2011-02-09 | 邬林祥 | Amlodipine and candesartan-containing compound preparation for treating hypertension |
CN106310273A (en) * | 2016-03-23 | 2017-01-11 | 深圳奥萨制药有限公司 | Quadruple antihypertensive drug composition |
-
2018
- 2018-12-08 CN CN201811499329.1A patent/CN110755397A/en active Pending
- 2018-12-08 CN CN201811499342.7A patent/CN110755429A/en active Pending
- 2018-12-08 CN CN201811499328.7A patent/CN110755390A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20090057538A (en) * | 2007-12-03 | 2009-06-08 | 박사룡 | A composition for treating hypertension comprising angiotensin ii antagonist, calsium andtagonist and diuretics |
WO2009154810A2 (en) * | 2008-02-25 | 2009-12-23 | Dr. Reddy's Laboratories Ltd. | Delivery systems for multiple active agents |
CN102008711A (en) * | 2009-07-14 | 2011-04-13 | 邬林祥 | Compound preparation containing enalapril for treating hypertension |
CN101780079A (en) * | 2010-03-03 | 2010-07-21 | 施慧达药业集团(吉林)有限公司 | Levamlodipine compound drug composition |
Non-Patent Citations (3)
Title |
---|
周敏,等: "老年高血压采取小剂量氨氯地平联合复方阿米洛利的疗效和安全性", 《临床医学研究与实践》 * |
张兆旺著: "《中药药剂学 供中药类专业用 新世纪 第2版》", 31 July 2017, 中国中医药出版社 * |
李钦俦编著: "《家庭用药与保健》", 28 February 2017, 上海科学普及出版社 * |
Also Published As
Publication number | Publication date |
---|---|
CN110755429A (en) | 2020-02-07 |
CN110755397A (en) | 2020-02-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR100888131B1 (en) | Combination preparation for Cardiovascular disease therapy by Chronotherapy theory. | |
US8247417B2 (en) | Methods of treatment of chronic pain using eszopiclone | |
Bayley et al. | Nifedipine in the treatment of hypertension: report of a double‐blind controlled trial. | |
WO2006119692A1 (en) | A medicament for the treatment of hypertension | |
CN110755390A (en) | Compound antihypertensive drug tablet and application thereof | |
JP2015512919A (en) | Lercanidipine hydrochloride and losartan potassium combination and preparation method thereof | |
CN102370965A (en) | Pharmaceutical composition containing pharmaceutically acceptable salts of levoamlodipine and pharmaceutically acceptable salts of perindopril | |
EP1532979A1 (en) | Drug composition for blood sugar control | |
AU2010276461B2 (en) | Pharmaceutical composition of levamlodipine or pharmaceutically acceptable salt thereof and beta receptor blocking agent, and use thereof | |
CA2257946A1 (en) | A composition of enalapril and losartan | |
WO2006105726A1 (en) | A composition for treating hypertension | |
Daniels et al. | Monotherapy with the calcium channel antagonist nisoldipine for systemic hypertension and comparison with diuretic drugs | |
CN102058591A (en) | Levamlodipine and telmisartan compound preparation | |
US8470363B2 (en) | Antihypertensive pharmaceutical composition | |
CN101756929A (en) | Pharmaceutical preparation containing isosorbide mononitrate | |
US20220079920A1 (en) | Pharmaceutical composition containing amlodipine, chlorthalidone, and amiloride and application thereof | |
EP2543373A1 (en) | Compound pharmaceutical composition of levoamlodipine | |
CN1706385B (en) | New composition for treating seasonal and perennial allergic rhinitis | |
CN102362865B (en) | Compound preparation containing benidipine hydrochloride and valsartan and application thereof | |
CN101721413A (en) | Pharmaceutical composition for preventing and curing metabolic syndrome and application thereof | |
EP1552830A1 (en) | Drug composition for prevention or inhibition of advance of diabetic complication | |
CN102106853A (en) | Chemical medicine composition for treating hypertension | |
CA2727957A1 (en) | Pharmaceutical composition comprising levamlodipine and indapamide | |
CN102379875A (en) | Compound preparation containing benidipine hydrochloride and metoprolol tartrate and application thereof | |
UA146315U (en) | PHARMACEUTICAL COMPOSITION |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |