WO2016159535A1 - Formulation complexe pharmaceutique comportant de l'amlodipine, du losartan et de la chlorthalidone - Google Patents
Formulation complexe pharmaceutique comportant de l'amlodipine, du losartan et de la chlorthalidone Download PDFInfo
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- 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
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Definitions
- the present invention relates to a pharmaceutical complex formulation comprising amlodipine, losartan and chlorthalidone, and more specifically, to a pharmaceutical complex formulation comprising a first mixture containing amlodipine and chlorthalidone and a second mixture containing losartan, which has an improved dissolution and stability.
- hypertension Approximately 90 ⁇ 95% of patients with hypertension have essential (primary) hypertension, of which the cause is not found. Although the underlying cause of essential hypertension is not clear, increase of cardiac output (the volume of blood being pumped by the heart whenever it contracts) or increased peripheral vascular resistance is known to cause it. Risk factors for hypertension are physiological and environmental factors such as drinking, smoking, old age, lack of exercise, obesity, dietary habits eating salty food, stress, etc. Furthermore, since hypertension has a tendency toward family history, when both parents are hypertensive, 80% of their children may be hypertensive later, and when one of parents is hypertensive, 25 ⁇ 50% of their children may be hypertensive.
- the primary goal in the treatment of hypertension is to prevent damage of internal organs resulting from hypertension by maintaining the blood pressure within a normal range. Accordingly, improvement of lifestyle is as important as taking medicine.
- Patients suffering from hypertension aim to control blood pressure to less than 140/90 mmHg. If the patients have diabetes or renal diseases, the blood pressure goal should be less than 130/80 mmHg.
- Treatment of hypertension may reduce mortality from a stroke or cardiovascular diseases. Controlling blood pressure of the patients with hypertension may reduce the occurrence of a stroke by 35 ⁇ 40%, myocardial infarction by 20 ⁇ 25%, and heart failure by 50% or higher. Reduction of systolic blood pressure by 5 mmHg may decrease the mortality from a stroke by 14%, the mortality from coronary artery diseases by 9%, and total mortality by 7%. Furthermore, since the control of blood pressure relates to dementia, a proper control of blood pressure of hypertensive patients may reduce the occurrence of dementia.
- Antihypertensive agents are required to administer for a long time, and advanced therapy using a combination of two or more drugs having different pharmacological actions may result in improved preventive or therapeutic effects, while lowering side effects arising from the long term administration of a single drug by reducing the dose.
- Vasodilators are widely prescribed antihypertensive drugs, and they are divided into several groups according to their pharmacological action which include ACE (angiotensin converting enzyme) inhibitors, angiotensin II receptor antagonists and calcium channel blockers.
- ACE angiotensin converting enzyme
- Amlodipine is the generic name for 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(2-chlorophenyl)-6-methyl-l,4-dihydro-3,5-pyridine dicarboxylate.
- Amlodipine besylate is currently marketed as Norvasc ® (trade name).
- Camsylate salt of amlodipine which has superior physical properties such as solubility or stability compared with besylate salt, has been disclosed in Korean Patent Registration No. 452491, and is currently marketed as Amodipin ® (trade name).
- Amlodipine is a calcium channel blocker which is useful in treating cardiovascular diseases such as angina, hypertension and congestive heart failure.
- Losartan is the generic name for 2-butyl-4-chloro-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4-yl]methyl]-lH-imidazol-5-methanol, which has been disclosed in U.S. Patent Nos. 5,608,075; 5,138,069; and 5,153,197.
- Losartan potassium is commercially available as Cozaar ® (trade name).
- Losartan blocks the interaction of vasoconstrictor angiotensin II and its receptor, and is mainly used for treating hypertension and heart failure. It is also used for treating ischemic peripheral circulatory disorder, myocardial ischemia (angina pectoris), diabetic neuropathy and glaucoma, and also for preventing the progression of post-myocardial infarction heart failure.
- a combined formulation comprising amlodipine and losartan having different pharmacological activities has an advantage that it is more effective on preventing or treating hypertension and cardiovascular diseases than a single drug, and it reduces side effects resulting from a single drug and improves patient compliance.
- the combined formulation has been disclosed in Korean Patent Registration Nos. 1160151 and 1232296, and is commercially available as Amosartan ® (trade name).
- Chlorthalidone is the generic name for benzenesulfonamide-2-chloro-5-(2,3-dihydro-1-hydroxy-3-oxo-1H-isoindol-1-yl), which is currently marketed as Hygroton ® (trade name). Chlorthalidone, a thiazide diuretic, blocks Na + /Cl - symporter of renal distal tubules, thereby inhibiting the reuptake of Na + and Cl - and increasing the excretion of K + , which results in water retention in urine.
- Chlorthalidone has a half-life of 50 to 60 hours and a reaction time of 48 to 72 hours, and it is more useful for controlling blood pressure at night since it has longer duration of action and reaction time compared with hydrochlorothiazide having a half-life of 9 to 10 hours and a reaction time of 16 to 24 hours.
- An object of the present invention is to provide a pharmaceutical complex formulation comprising amlodipine, losartan and chlorthalidone, which is very effective on treating cardiovascular diseases by actuating different mechanism, and has high dissolution rates of amlodipine, losartan and chlorthalidone and improved storage stability.
- the present invention provides a pharmaceutical complex formulation for preventing or treating cardiovascular diseases, the formulation comprising:
- a first mixture including amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive;
- first mixture and the second mixture are present in a form separated physically from each other.
- the complex formulation according to the present invention comprising amlodipine, losartan and chlorthalidone may achieve improved preventive or therapeutic effects for cardiovascular diseases by actuating different mechanism, and exhibits high dissolution rates of amlodipine, losartan and chlorthalidone and improved storage stability, due to the minimized drug interactions, and therefore, it is useful in the fields of pharmaceuticals and medicine.
- Fig. 1 is a schematic diagram of the bilayer tablet according to an embodiment of the present invention.
- Fig. 2 is a graph showing the amlodipine dissolution rate observed for the tablets prepared in Example 1 and Comparative Example 1.
- Fig. 3 is a graph showing the chlorthalidone dissolution rate observed for the tablets prepared in Example 1 and Comparative Example 1.
- Fig. 4 is a graph showing the losartan dissolution rate observed for the tablets prepared in Example 1 and Comparative Example 1.
- Fig. 5 is a graph showing the amlodipine dissolution rate observed for the tablets prepared in Examples 1 to 3 and Comparative Examples 3 to 6.
- Fig. 6 is a graph showing the chlorthalidone dissolution rate observed for the tablets prepared in Examples 1 to 3 and Comparative Examples 3 to 6.
- Fig. 7 is a graph showing the losartan dissolution rate observed for the tablets prepared in Examples 1 to 3 and Comparative Examples 3 to 6.
- Fig. 8 is a graph showing the amlodipine dissolution rate observed for the tablets prepared in Example 1 and Comparative Examples 7 and 8.
- Fig. 9 is a graph showing the chlorthalidone dissolution rate observed for the tablets prepared in Example 1 and Comparative Examples 7 and 8.
- Fig. 10 is a graph showing the losartan dissolution rate observed for the tablets prepared in Example 1 and Comparative Examples 7 and 8.
- Fig. 11 is a graph showing the amlodipine dissolution rate observed for the tablets prepared in Examples 4 to 6 and Comparative Examples 9 to 12.
- Fig. 12 is a graph showing the chlorthalidone dissolution rate observed for the tablets prepared in Examples 4 to 6 and Comparative Examples 9 to 12.
- Fig. 13 is a graph showing the losartan dissolution rate observed for the tablets prepared in Examples 4 to 6 and Comparative Examples 9 to 12.
- the present invention provides a pharmaceutical complex formulation for preventing or treating cardiovascular diseases, the formulation comprising a first mixture including amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; and a second mixture including losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, wherein the first mixture and the second mixture are present in a form separated physically from each other.
- the first mixture and the second mixture are physically separated from each other. Since the formulation comprises separately amlodipine and losartan, the interaction of amlodipine and losartan may be prevented, which achieves high stability.
- the complex formulation may be a bilayer tablet comprising a first layer including amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; and a second layer including losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive (see Fig. 1).
- the formulation according to the present invention may be prepared in various forms (for example, core-shell structure) in which the first mixture may be physically separated from the second mixture.
- the complex formulation of the present invention includes amlodipine or a pharmaceutically acceptable salt thereof in the first mixture (or the first layer).
- the pharmaceutically acceptable salts of amlodipine are those prepared from an acid which forms non-toxic acid addition salts comprising pharmaceutically acceptable anions, and include, for example, hydrochloride, hydrobromide, sulfate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, besylate and camsylate salts, but are not limited thereto.
- these salts preferred are the amlodipine besylate and camsylate, and more preferred is the amlodipine camsylate.
- amlodipine used in the present invention may include an amlodipine racemate and (S)-amlodipine.
- the dose of amlodipine or its pharmaceutically acceptable salts varies depending on age, sex or body weight of patients, severity of the diseases, route of administration, etc., a typical dose for adults (body weight: 60 kg) may be in the range of about 5 to 10 mg per day.
- the complex formulation of the present invention includes chlorthalidone or a pharmaceutically acceptable salt thereof in the first mixture.
- the dose of chlorthalidone or its pharmaceutically acceptable salts varies depending on age, sex or body weight of patients, severity of the diseases, route of administration, etc.
- a typical dose for adults may be in the range of about 12.5 to 25 mg per day.
- the complex formulation of the present invention includes losartan or a pharmaceutically acceptable salt thereof in the second mixture (or the second layer).
- An example of the pharmaceutically acceptable salt of losartan is losartan potassium, but is not limited thereto.
- a typical dose for adults may be in the range of about 50 to 100 mg per day.
- amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof and losartan or a pharmaceutically acceptable salt thereof may be used in amounts corresponding to a weight ratio in the range of 1:1.25 ⁇ 5:5 ⁇ 20, preferably 1:2.5 ⁇ 5:10 ⁇ 20.
- the pharmaceutically acceptable additives which may be used in the first mixture and the second mixture, may be, for example, pharmaceutically acceptable carriers or excipients.
- the pharmaceutically acceptable carriers or excipients may include, for example, lactose hydrate, microcrystalline cellulose, mannitol, sodium citrate, calcium phosphate, glycine, starch, disintegrants (e.g., crospovidone, copovidone, sodium starch glycolate, croscarmellose sodium and a specific composite silicate) and binders (e.g., polyvinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin and acacia gum).
- disintegrants e.g., crospovidone, copovidone, sodium starch glycolate, croscarmellose sodium and a specific composite silicate
- binders e.g., polyvinylpyrrolidone, hydroxypropylmethyl
- the complex formulation of the present invention may comprise an additive selected from the group consisting of lactose hydrate, microcrystalline cellulose, mannitol, starch and combinations thereof in the first mixture.
- Preferred additive comprises lactose hydrate and/or microcrystalline cellulose.
- the lactose hydrate may be comprised in an amount of 20 to 60% by weight based on the total amount of the first mixture.
- the weight ratio of lactose hydrate and microcrystalline cellulose may be 1:0.5 to 1:2 within the above range of amount.
- lactose hydrate When lactose hydrate is used in an amount of the above range as a water-soluble excipient, it accelerates dissolution of active substances by forming wetting channel in the formulation, thereby resulting in rapid dissolution. While an amount less than the above range could not accomplish the rapid dissolution, an amount exceeding the above range extends the time for lactose hydrate to be dissolved completely, thereby delaying dissolution of active substances.
- microcrystalline cellulose is used in an amount of the above range, it accomplishes smooth formulation molding in tablet pressing. While an amount less than the above range causes difficulties in tablet pressing, an amount exceeding the above range results in excessively large formulation to be produced.
- the dissolution rates of amlodipine, chlorthalidone and losartan may be considerably improved by using lactose hydrate and microcrystalline cellulose in an amount of the above range.
- the first mixture and the second mixture of the complex formulation may be granulated by conventional granulation method, for example, compression granulation method, and then tablet pressed.
- the first mixture and the second mixture may be granule forms prepared by roller compression process.
- the results of the Test Examples of the present invention shows that the bilayer tablets comprising the first mixture and the second mixture prepared by compression granulation exhibit enhanced dissolution rates of amlodipine, chlorthalidone and losartan, and excellent dissolution of amlodipine and chlorthalidone.
- Losartan shows very good dissolution pattern in purified water or at a relatively high pH (e.g., pH 4.0 or pH 6.8), but it is very slowly released at a low pH (e.g., pH 1.2 or pH 2.0) because of its gelation.
- pH 4.0 or pH 6.8 a relatively high pH
- pH 1.2 or pH 2.0 a relatively low pH
- gelation of losartan may have a decisive effect on the dissolution rate of the formulation, and also on the uptake of the drugs.
- the gelation of losartan may be prevented by physically separating the first mixture including amlodipine and chlorthalidone from the second mixture including losartan and reducing the area contacting with losartan, thereby accomplishing improved dissolution and stability of amlodipine, chlorthalidone and losartan.
- the present invention provides a fixed-dose combination formulation for preventing or treating cardiovascular diseases, the formulation comprising a first mixture including amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; and a second mixture including losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, wherein the first mixture and the second mixture are present in a form separated physically from each other.
- amlodipine or a pharmaceutically acceptable salt thereof may be comprised in an amount of 5 to 10 mg in the form of amlodipine free acid
- chlorthalidone or a pharmaceutically acceptable salt thereof may be comprised in an amount of 12.5 to 25 mg in the form of chlorthalidone free acid
- losartan or a pharmaceutically acceptable salt thereof may be comprised in an amount of 50 to 100 mg in the form of losartan free acid.
- the present invention also provides a method of preparing a pharmaceutical complex formulation for preventing or treating cardiovascular diseases, the method comprising the steps of a) mixing amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; and b) mixing losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.
- the present invention provides a method of preparing a bilayer tablet for preventing or treating cardiovascular diseases, the method comprising the steps of a) mixing amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive to obtain a mixture and granulating the mixture; b) mixing losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive to obtain a mixture and then granulating the mixture; and c) tablet pressing the resultant granules prepared in steps a) and b) into a bilayer tablet.
- the cardiovascular diseases may be selected from the group consisting of angina pectoris, hypertension, artery vasospasm, cardiac arrhythmia, cardiac hypertrophy, cerebral infarct, congestive heart failure and myocardial infarction, but not limited thereto.
- amlodipine camsylate, chlorthalidone, lactose hydrate, microcrystalline cellulose and crospovidone were mixed and the mixture was screened through 30 mesh sieve.
- the screened part was compressed by using a roller compactor (Roller compactor WP200, Alexanderwerk) under a minimum pressure of 20 kN and a roller speed of 2 to 10 rpm to form flake-type granule part.
- After the obtained granule part was shear-treated by using a mill (Fitz mill; BAS 06, Fitzpatrick, USA) and passed through 20 mesh sieve, magnesium stearate was added thereto and the mixture was finally mixed by a mixer to obtain an amlodipine and chlorthalidone granule part.
- Losartan potassium, microcrystalline cellulose and crospovidone were mixed and the mixture was screened through 30 mesh sieve.
- the screened part was compressed by using a roller compactor (Roller compactor WP200, Alexanderwerk) under a minimum pressure of 20 kN and a roller speed of 2 to 10 rpm to form flake-type granule part.
- After the obtained granule part was shear-treated by using a mill (Fitz mill; BAS 06, Fitzpatrick, USA) and passed through 20 mesh sieve, magnesium stearate was added thereto and the mixture was finally mixed by a mixer to obtain a losartan granule part.
- a complex bilayer tablet consisting of amlodipine and chlorthalidone granule part (first layer; upper layer) and losartan granule part (second layer; under layer) was manufactured by using a tablet press (Tablet press; Kilian Synthesis 700, Germany).
- Example 1 Example 2
- Example 3 Amlodipine and chlorthalidone layer
- Amlodipine camsylate 7.8(Amlodipine 5 mg) 7.8 7.8 Chlorthalidone 25.0 25.0 25.0 Lactose hydrate 58.0 87.0 116.0
- Comparative Example 1 Preparation of single-layer tablet by dry-type direct compression method
- amlodipine camsylate, chlorthalidone, losartan potassium, lactose hydrate, microcrystalline cellulose and crospovidone were mixed and the mixture was screened through 30 mesh sieve. Magnesium stearate was added to the screened part and the mixture was finally mixed by a mixer. The mixed part was pressed to obtain a single-layer tablet.
- Comparative Example 2 Preparation of bilayer tablet by dry-type direct compression method
- amlodipine camsylate, chlorthalidone, lactose hydrate, microcrystalline cellulose and crospovidone were mixed and the mixture was screened through 30 mesh sieve. Magnesium stearate was added thereto and the mixture was finally mixed by a mixer to obtain an amlodipine and chlorthalidone mixture part.
- Losartan potassium, microcrystalline cellulose and crospovidone were mixed and the mixture was screened through 30 mesh sieve. Magnesium stearate was added thereto and the mixture was finally mixed by a mixer to obtain a losartan mixture part.
- a complex bilayer tablet consisting of amlodipine and chlorthalidone mixture part (first layer; upper layer) and losartan mixture part (second layer; under layer) was manufactured by using a tablet press.
- a complex bilayer tablet having a first layer of amlodipine and losartan granule part and a second layer of chlorthalidone granule part was manufactured according to the same procedures as in Example 1.
- Example 4 Example 5
- Example 6 Amlodipine and chlorthalidone layer
- Amlodipine camsylate 7.8(Amlodipine 5 mg) 7.8 7.8 Chlorthalidone 12.5 12.5 12.5 Lactose hydrate 52.8 79.2 105.5 Microcrystalline cellulose 105.5 79.2 52.8
- Test Example 1 Dissolution test of bilayer tablet and single-layer tablet
- Example 1 The tablet prepared in Example 1 and the tablet prepared in Comparative Example 1 were subjected to a drug dissolution test under the following condition to measure dissolution rates of amlodipine, chlorthalidone and losartan over time.
- Dissolution test system USP paddle method, 50 rpm
- Dissolution time After dissolution rates were measured at 5, 10, 15, 30, 45, 60, 90 and 120 minutes, the paddle speed was changed from 50 rpm to 150 rpm, and then final dissolution rate was measured at 150 minutes.
- Figs. 2 to 4 The measured results of dissolution rates are shown in Figs. 2 to 4.
- the bilayer tablet having amlodipine and chlorthalidone layer separated from losartan layer according to Example 1 exhibited higher dissolution rates compared with the single-layer tablet prepared by dry-type direct compression method in Comparative Example 1.
- the bilayer tablet of Example 1 showed good dissolution characteristics and the dissolution rates of amlodipine and chlorthalidone satisfied the criteria.
- the dissolution rate of losartan was 20% or lower at 60 minutes in the single-layer tablet of Comparative Example 1 while the bilayer tablet of Example 1 exhibited remarkably high dissolution rate of losartan.
- Test Example 2 Uniformity of dosage units in bilayer tablet prepared by compression granulation method and bilayer tablet prepared by dry-type direct compression method
- the bilayer tablet prepared by dry-type direct compression of simple mixture, without using roller compactor, in Comparative Example 2 exhibited relatively degraded mass variation compared with the bilayer tablet prepared in Example 1.
- the bilayer tablet of Comparative Example 2 did not satisfy the criteria of content uniformity (acceptance value of 15 or lower) in amlodipine and chlorthalidone.
- the bilayer tablet prepared in Comparative Example 2 without being processed by compression and screening, showed low productivity by the occurrence of capping in tablet pressing.
- the bilayer tablet prepared by using roller compactor in Example 1 exhibited excellent content uniformity of amlodipine and chlorthalidone, and satisfied the criteria of uniformity of dosage units
- Test Example 3 Change in dissolution depending on ratio of excipients in amlodipine-chlorthalidone layer
- lactose hydrate of 20 to 60% by weight and the weight ratio of lactose hydrate and microcrystalline cellulose of 1:0.5 to 1:2 in amlodipine-chlorthalidone layer result in preferable dissolution rates.
- Test Example 4 Dissolution test of tablet prepared in Comparative Example 7 (consisting of amlodipine - losartan layer and chlorthalidone layer) and tablet prepared in Comparative Example 8 (consisting of amlodipine layer and losartan-chlorthalidone layer)
- the bilayer tablet of Example 1 consisting of amlodipine-chlorthalidone layer and losartan layer exhibited rapid and good dissolution satisfying the criteria of dissolution rates for amlodipine and chlorthalidone.
- the bilayer tablet of Comparative Example 7 consisting of amlodipine-losartan layer and chlorthalidone layer did not satisfy the criteria of dissolution rate for amlodipine
- the bilayer tablet of Comparative Example 8 consisting of amlodipine layer and losartan-chlorthalidone layer did not satisfy the criteria of dissolution rate for chlorthalidone.
- Test Example 5 Change in contents according to stability test under accelerated storage condition
- Storage condition packaged in HDPE (High Density Polyethylene) bottle at 40°C, 75% relative humidity
- Test time 0(initial), 1, 2, 4 and 6 months
- Test Example 6 Storage test under light and heat stress conditions
- Test time beginning of test and after light exposure (after exposure at 1,200,000 lux)
- Test time beginning of test and after 28-day storage
- Comparative Example 7 shows that the bilayer tablet consisting of amlodipine-losartan layer and chlorthalidone layer is difficult to ensure sufficient stability due to changes over time under light or heat stress condition.
- Comparative Example 8 shows that the bilayer tablet consisting of amlodipine layer and losartan-chlorthalidone layer is also difficult to ensure sufficient stability due to changes over time under light or heat stress condition.
- Test Example 7 Change in dissolution depending on ratio of excipients in amlodipine - chlorthalidone layer in bilayer tablet with varied amounts of active components
- the tablets of Examples 4 to 6 exhibited dissolution patterns similar to those of Examples 1 to 3, satisfying the criteria, although the amounts of losartan and chlorthalidone are changed to 50 mg and 12.5 mg, respectively.
Abstract
Priority Applications (5)
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RU2017134562A RU2713883C2 (ru) | 2015-03-31 | 2016-03-11 | Сложный фармацевтический состав, включающий амлодипин, лозартан и хлорталидон |
CN201680020057.5A CN108289850B (zh) | 2015-03-31 | 2016-03-11 | 含有氨氯地平、氯沙坦和氯噻酮的药物复合制剂 |
MX2017012459A MX2017012459A (es) | 2015-03-31 | 2016-03-11 | Formulacion de complejo farmaceutico que comprende amlodipina, losartan y clortalidona. |
MYPI2017703447A MY190016A (en) | 2015-03-31 | 2016-03-11 | Pharmaceutical complex formulation comprising amlodipine, losartan and chlorthalidone |
PH12017501769A PH12017501769B1 (en) | 2015-03-31 | 2017-09-26 | Pharmaceutical complex formulation comprising amlodipine, losartan and chlorthalidone |
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KR1020150045645A KR101914930B1 (ko) | 2015-03-31 | 2015-03-31 | 암로디핀, 로자탄 및 클로르탈리돈을 포함하는 약제학적 복합 제제 |
KR10-2015-0045645 | 2015-03-31 |
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KR (1) | KR101914930B1 (fr) |
CN (1) | CN108289850B (fr) |
AR (1) | AR105758A1 (fr) |
JO (1) | JO3461B1 (fr) |
MX (1) | MX2017012459A (fr) |
MY (1) | MY190016A (fr) |
PH (1) | PH12017501769B1 (fr) |
RU (1) | RU2713883C2 (fr) |
TW (1) | TWI714560B (fr) |
UY (1) | UY36595A (fr) |
WO (1) | WO2016159535A1 (fr) |
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KR101910902B1 (ko) * | 2016-11-03 | 2018-10-24 | 한미약품 주식회사 | 암로디핀, 로자탄 및 클로르탈리돈을 포함하는 약제학적 복합제제 |
KR20180053044A (ko) * | 2016-11-11 | 2018-05-21 | 주식회사유한양행 | 클로르탈리돈 또는 이의 염 및 암로디핀 또는 이의 염을 포함하는 단일 매트릭스 정제 형태의 약학 조성물 및 이의 제조방법 |
KR20200143914A (ko) * | 2019-06-17 | 2020-12-28 | 주식회사유한양행 | 암로디핀 또는 이의 염 및 클로르탈리돈 또는 이의 염을 포함하는 다층 정제 형태의 약학 조성물 |
KR20210074428A (ko) | 2019-12-11 | 2021-06-22 | 한미약품 주식회사 | 암로디핀, 로자탄 및 클로르탈리돈을 포함하는 약제학적 복합제제 |
CN115666564A (zh) * | 2020-06-09 | 2023-01-31 | 韩美药品株式会社 | 在单层片剂中包括氨氯地平、氯沙坦和氯噻酮的预防或治疗心血管系统疾病的药学上组合制剂 |
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US20030152622A1 (en) * | 2001-10-25 | 2003-08-14 | Jenny Louie-Helm | Formulation of an erodible, gastric retentive oral diuretic |
US20070237815A1 (en) * | 2006-04-06 | 2007-10-11 | Lawrence Solomon | Dosage forms and methods comprising amlodipine and chlorthalidone |
WO2009084040A1 (fr) * | 2007-12-28 | 2009-07-09 | Rubicon Research Private Limited | Formule d'antagonistes des récepteurs de l'angiotensine administrée une fois par jour |
US20120115854A1 (en) * | 2002-05-17 | 2012-05-10 | Suraj Shivappa Shetty | Pharmaceutical composition containing antihypertensive agents |
WO2013100630A1 (fr) * | 2011-12-30 | 2013-07-04 | Hanmi Pharm. Co., Ltd. | Formulation de combinaison de doses fixes comprenant du losartan, de l'amlodipine et de l'hydrochlorothiazide |
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US5138069A (en) | 1986-07-11 | 1992-08-11 | E. I. Du Pont De Nemours And Company | Angiotensin II receptor blocking imidazoles |
WO1995017396A1 (fr) | 1993-12-23 | 1995-06-29 | Merck & Co., Inc. | Polymorphes de losartane et procede de preparation de la forme ii du losartane |
KR100452491B1 (ko) | 2001-03-29 | 2004-10-12 | 한미약품 주식회사 | 신규한 결정형 암로디핀 캠실레이트 염 및 그의 제조방법 |
EP1648515B1 (fr) * | 2003-07-16 | 2012-11-21 | Boehringer Ingelheim International GmbH | Combinaisons de chlorthalidone |
KR101247583B1 (ko) * | 2006-12-08 | 2013-03-26 | 한미사이언스 주식회사 | 암로디핀 또는 이의 약제학적 허용가능한 염, 및 로자탄또는 이의 약제학적 허용가능한 염을 함유하는 약제학적조성물 |
KR20090057538A (ko) * | 2007-12-03 | 2009-06-08 | 박사룡 | 안지오텐신 투 안타고니스트, 칼슘 안타고니스트 및이뇨제를 함유하는 고혈압 치료제 조성물 |
ES2580777T3 (es) | 2009-01-23 | 2016-08-26 | Hanmi Holdings Co., Ltd. | Composición farmacéutica sólida que comprende amlodipino y losartán y procedimiento para producir la misma |
KR101392364B1 (ko) * | 2012-04-17 | 2014-05-07 | 한국유나이티드제약 주식회사 | 안정성이 향상된 암로디핀 및 로잘탄을 함유하는 복합제 조성물 |
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2015
- 2015-03-31 KR KR1020150045645A patent/KR101914930B1/ko active IP Right Grant
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- 2016-03-11 CN CN201680020057.5A patent/CN108289850B/zh active Active
- 2016-03-11 MX MX2017012459A patent/MX2017012459A/es unknown
- 2016-03-11 WO PCT/KR2016/002437 patent/WO2016159535A1/fr active Application Filing
- 2016-03-11 MY MYPI2017703447A patent/MY190016A/en unknown
- 2016-03-11 RU RU2017134562A patent/RU2713883C2/ru active
- 2016-03-18 TW TW105108523A patent/TWI714560B/zh not_active IP Right Cessation
- 2016-03-27 JO JOP/2016/0058A patent/JO3461B1/ar active
- 2016-03-29 AR ARP160100825A patent/AR105758A1/es unknown
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030152622A1 (en) * | 2001-10-25 | 2003-08-14 | Jenny Louie-Helm | Formulation of an erodible, gastric retentive oral diuretic |
US20120115854A1 (en) * | 2002-05-17 | 2012-05-10 | Suraj Shivappa Shetty | Pharmaceutical composition containing antihypertensive agents |
US20070237815A1 (en) * | 2006-04-06 | 2007-10-11 | Lawrence Solomon | Dosage forms and methods comprising amlodipine and chlorthalidone |
WO2009084040A1 (fr) * | 2007-12-28 | 2009-07-09 | Rubicon Research Private Limited | Formule d'antagonistes des récepteurs de l'angiotensine administrée une fois par jour |
WO2013100630A1 (fr) * | 2011-12-30 | 2013-07-04 | Hanmi Pharm. Co., Ltd. | Formulation de combinaison de doses fixes comprenant du losartan, de l'amlodipine et de l'hydrochlorothiazide |
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Publication number | Publication date |
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UY36595A (es) | 2016-10-31 |
CN108289850A (zh) | 2018-07-17 |
TW201639563A (zh) | 2016-11-16 |
KR20160117055A (ko) | 2016-10-10 |
CN108289850B (zh) | 2021-04-09 |
MY190016A (en) | 2022-03-22 |
RU2017134562A3 (fr) | 2019-08-15 |
AR105758A1 (es) | 2017-11-08 |
TWI714560B (zh) | 2021-01-01 |
MX2017012459A (es) | 2018-01-30 |
KR101914930B1 (ko) | 2018-11-05 |
RU2713883C2 (ru) | 2020-02-10 |
PH12017501769A1 (en) | 2018-03-19 |
JO3461B1 (ar) | 2020-07-05 |
PH12017501769B1 (en) | 2018-03-19 |
RU2017134562A (ru) | 2019-04-04 |
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