WO2017054787A1

WO2017054787A1 - Pharmaceutical composition comprising the combination of candesartan, amlodipine and hydrochlorothiazide

Info

Publication number: WO2017054787A1
Application number: PCT/CZ2016/000110
Authority: WO
Inventors: Praveen Khullar; Kum PRASAD; Kishor KOTHAWADE; Prashant Gupta; Saravanan DEVARAJAN; Santosh Kumar Deolia; Kalsotra SACHIN
Original assignee: Zentiva KS
Current assignee: Zentiva KS
Priority date: 2015-10-02
Filing date: 2016-09-27
Publication date: 2017-04-06
Anticipated expiration: 2018-04-02
Also published as: CZ2015687A3

Abstract

The present invention relates to a composition for preventing or treating cardiovascular disorders comprising the combination of candesartan of formula (I), chemically 2-ethoxy-1-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1H-1,3-benzodiazole-7-carboxylic acid, or a pharmaceutically acceptable salt thereof, with Hydrochlorothiazide of formula (II), chemically 6-chloro-1,1-dioxo-3,4- dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide, or a pharmaceutically acceptable salt thereof, and Amlodipine of formula (III), chemically 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(2-chlorophenyl)- 6-methyl-1,4-dihydro-3,5-pyridine dicarboxylate, or a pharmaceutically acceptable salt thereof, and a method of preparing the same. The choice of these agents and their dosage in the combination regime are designed to enhance the tolerability by minimizing the risk of dose-dependent adverse effects usually associated with individual agents that can be expressively eliminated by the proposed triple combination product. (Formulae (I), (II), (III))

Description

PHARMACEUTICAL COMPOSITION COMPRISING THE COMBINATION OF CANDESARTAN, AMLODIPINE AND HYDROCHLOROTHIAZIDE

Field of the Invention

The present invention relates to a composition for preventing or treating cardiovascular disorders comprising the combination of candesartan of formula I, chemically 2-ethoxy-l-({4-[2-(2H-l,2,3,4- tetrazol-5-yl)phenyl]phenyl}methyl)-lH-l,3-benzodiazoIe-7-carboxylic acid, or a pharmaceutically acceptable salt thereof, with Hydrochlorothiazide of formula II, chemically 6-chloro-l,l-dioxo-3,4- dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide, or a pharmaceutically acceptable salt thereof, and Amlodipine of formula III, chemically 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(2-chlorophenyl)- 6-methyl-l,4-dihydro-3,5-pyridine dicarboxylate, or a pharmaceutically acceptable salt thereof, and a method of preparing the same. The choice of these agents and their dosage in the combination regime are designed to enhance the tolerability by minimizing the risk of dose-dependent adverse effects usually associated with individual agents which is expressively eliminated by the invention of the proposed triple combination product.

Background Art

Hypertension can be classified into essential or secondary hypertension, and most (approximately 90 - 95%) of the hypertension belongs to the essential hypertension class. While secondary hypertension is generally treatable by correcting the known causes, essential hypertension, the exact cause of which is not yet elucidated, is generally treated by relaxation therapy, dietary therapy and exercise therapy which are optionally combined with medication. Notable antihypertensive drugs include diuretics, sympatholytic agents and vasodilators. Vasodilators are most 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.

Diuretic drugs, due to their mild hypotensive effects, have long been clinically used as antihypertensive agents. However, as undesirable side effects caused by the use for a long time, influences on metabolism, for example, hypokalaemia, hyperuricemia, hyperlipidemia and diabetes mellitus, have been taken up.

While calcium antagonists have been used as therapeutic agents of circulatory diseases such as hypertension, cardiac diseases, cerebral apoplexy, nephritis and arteriosclerosis, it has also been known that they tend to cause such undesirable side effects as tachycardia, hypotension, erythroprosopaigia and encephalagia, which are considered to be due to their abrupt vasodilative action.

On the other hand, it is disclosed in EP0425921, EP0459136 and EP0520423 that benzimidazole derivatives have an angiotensin II antagonistic activities and are useful for the therapy of circulatory diseases including hypertension, cardiac diseases (cardiac insufficiency, myocardial infarction, etc.), cerebral apoplexy, nephritis and arteriosclerosis. The mechanism of the action is considered that the benzimidazole derivatives inhibit the binding of angiotensin II having a strong vasoconstrictive action to an angiotensin II acceptor. And, while, in JPA H3(1991)-27362 and JPA H5(1993)-132467, it is disclosed that an imidazole derivative having angiotensin II antagonistic action is administered together with a diuretic agent or a calcium antagonistic agent.

WO2008044862 relates to a functional combination preparation comprising a dihydropyridine-based calcium channel blocker such as amlodipine and an ARB (angiotensin-2 receptor blocker) such as losartan. In particular, the document relates to chronotherapeutically designed combination formulations for the preparation and treatment of cardiovascular diseases, which are formulated based on xenobiotics and chronotherapy for enabling the two drugs to be chronotherapeutically released, thereby improving the therapeutic activity as compared to the co-administration of each drug in the form of a single tablet, while reducing side effects and maintaining the therapeutic activity as high as possible during the period of time of a day when the risk of a compliance of cardiovascular disease is highest.

WO2005070463 relates to a pharmaceutical composition comprising enantiomerically pure (S)- amlodipine malate, an ARB and optionally other active agents. Moreover, the document is directed to methods for treating, preventing and managing cardiovascular diseases and disorders and symptoms thereof, using the composition.

EP1314425 is directed to medicinal compositions for preventing or treating heart failure and discloses compositions containing a HMG-CoA reductase inhibitor selected from the group consisting of pravastatin, simvastatin, lovastatin, pitavastatin and ZD-4522, an angiotensin II receptor antagonist and optionally a calcium channel blocker.

The Indian patent application 755/MUM/2003 is concerned with a process of making a stable pharmaceutical formulation of tablet comprising an effective amount of (S)-amlodipine besylate salt with pharmaceutically acceptable and compatible (physical and chemical) excipients.

In the treatment of hypertension, it is more important to maintain the blood pressure within a normal range on a consistent basis than to simply lower the blood pressure levels itself, for reducing the risks of complications such as coronary heart diseases and cardiovascular diseases, e.g., stroke, heart failure and myocardial infarction. Accordingly, antihypertensive agents should be effective for long- term treatment of hypertension. Further, advanced therapy using a combination of two or more drugs having different pharmacological actions makes it possible to improve preventive or therapeutic effects, while lowering side effects arising from the long term administration of a single drug. Therefore, a need for further development of methods of treatment, combination, and pharmaceutical compositions clearly exists. It is further much more user friendly for the patients to take just once a fixed-dose combination product comprising ail three active pharmaceutical ingredients: (i) an angiotensin receptor blocker (ARB) or a pharmaceutically acceptable salt thereof, (ii) a calcium channel blocker (CCB) and (iii) a diuretic, preferably comprising candesartan (ARB), amlodipine (CCB) and hydrochlorothiazide (diuretic) in comparison with separate single-dosed products.

It is the object of the present invention to provide a composition for preventing or treating cardiovascular disorders comprising the combination of candesartan or a pharmaceutically acceptable salt thereof with hydrochlorothiazide or a pharmaceutically acceptable salt thereof and amlodipine or a pharmaceutically acceptable salt thereof and the method of preparing the same.

Disclosure of the Invention

The object of the present invention is to provide a pharmaceutical composition comprising: (i) an angiotensin receptor blocker (ARB) or a pharmaceutically acceptable salt thereof, (ii) a calcium channel blocker (CCB) or a pharmaceutically acceptable salt thereof, and (iii) a diuretic or a pharmaceutically acceptable salt thereof.

This invention relates to the pharmaceutical composition, wherein (i) the angiotensin receptor blocker (ARB) is selected from the group consisting of candesartan, losartan, olmesartan, telmisartan, valsartan, irbesartan, azilsartan; (ii) the calcium channel blocker (CCB) is selected from the group consisting of amlodipine, barnidipine, felodipine, nifedipine, lercanidipine, manidipine; and (iii) the diuretic is selected from the group consisting of bumetanide, furosemide, chlorothalidone, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methylchlorothiazide. Specifically this invention relates pharmaceutical composition, wherein (i) the angiotensin receptor blocker (ARB) is candesartan; (ii) the calcium channel blocker (CCB) is amlodipine; and (iii) the diuretic is hydrochlorothiazide. In a preferred embodiment this invention relates to the pharmaceutical composition which is administered orally, preferably in a form of a tablet. More preferably, a pharmaceutical composition which is administered orally in a form of a bi-layer tablet.

Yet in another embodiment this invention relates to a pharmaceutical composition, wherein the first layer comprises candesartan or its pharmaceutically acceptable salt and hydrochlorothiazide and in the second layer comprises amlodipine or its pharmaceutically acceptable salt. In a preferred embodiment this invention relates to pharmaceutical composition, wherein the pharmaceutically acceptable salt of candesartan is candesartan cilexetil and the pharmaceutically acceptable salt of amlodipine is amlodipine besylate.

Thus, this invention relates to a pharmaceutical composition, wherein candesartan is contained in an amount from 5 to 150 mg, amlodipine is contained in an amount from 1 mg to 50 mg, and hydrochlorothiazide is contained in an amount from 0.5 mg to 30 mg.

In a preferred embodiment of this invention relates to a pharmaceutical composition, wherein candesartan is contained in an amount from 10 to 50 mg, amlodipine is contained in an amount from 5 mg to 35 mg, and hydrochlorothiazide is contained in an amount from 1 mg to 20 mg. A further aspect of the present invention is a method of preparation of the pharmaceutical composition, comprising the step of granulating candesartan or a pharmaceutically acceptable salt thereof along with hydrochlorothiazide or a pharmaceutically acceptable salt thereof to obtain a candesartan and hydrochlorothiazide granule part. Preferably the method further comprises the step wherein the candesartan and hydrochlorothiazide granule part with a mixture part comprising amlodipine or a pharmaceutically acceptable salt thereof are mixed together. More preferably the method further comprising the steps: (i) manufacture of layer 1: candesartan or a pharmaceutically acceptable salt thereof and hydrochlorothiazide granules using wet granulation approach; and (II) manufacture of layer 2: amlodipine or a pharmaceutically acceptable salt thereof granules using slugging approach. Preferably the pharmaceutically acceptable salt of candesartan is candesartan cilexetil. Preferably the pharmaceutically acceptable salt of amlodipine is amlodipine besylate.

The invention also relates to a pharmaceutical composition for use in preventing or treating of a condition or disease selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (whether unstable or stable), renal insufficiency (diabetic and non-diabetic), heart failure, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive dysfunction (such as Alzheimer's), glaucoma and stroke.

In another embodiment the present invention relates to a pharmaceutical composition for use in preventing or treating the appropriate cardiovascular disorders. More preferably the cardiovascular disorders are selected from the group consisting of angina pectoris, hypertension, artery vasospasm, deep vein thrombosis, cardiac hypertrophy, cerebral infarct, congestive heart failure and myocardial infarction.

The solved technical issue, when preparing the triple combination product of amlodipine, candesartan and hydrochlorothiazide or their pharmaceutically acceptable salts was the respective impurity related to hydrochlorothiazide, i.e. salamide (4-amino-6-chlorobenzene-l,3-disulphonamide) impurity. This issue is being solved by the by the ratio of hydrochlorothiazide to lactose monohydrate in the final composition. The preferable ratio of hydrochlorothiazide to lactose in a combined tablet should be maintained from 1 : 3 to 1 : 10, even more preferably in a ration of from 1 : 5 to 1 : 7.

Nevertheless, the newly invented triple combination product is surprisingly maintaining the same properties of the original mono or dual combination reference product (Atacand Plus - Candesartan cilexetil and Hydrochlorothiazide tablet) and Esidrix Tablets (Hydrochlorothiazide) - e.g. dissolution rates, stability. The combination formulation prevents an excessive degradation of the mono components and therefore contributes to a better stability of the final triple combination product. Therefore it is not necessary to somehow adjust the storage limits of the triple combination product. Thus there is a need for a dosage form to be developed that can overcome the difficulties of the prior art and the difficulties found during the manufacturing process. More particularly, there is a need to develop a simple and cost-effective means to manufacture a dosage form which allows easy laboratory testing and that limits the potential of interactions of one API with further APIs or with one or more of the excipients used in the formulation.

Brief Description of the Drawings

The above and other objects and features of the present invention will become apparent from the following description of the invention, when taken in conjunction with the accompanying drawings which respectively show:

Fig 1: Dissolution rates of Candesartan cilexetil 32 mg when compared between different reference product combinations and Test Example 1

Fig 2: Dissolution rates of Hydrochlorothiazide 25 mg when compared between different reference product combinations and Test Example 1

Detailed Description of the Invention

The present invention relates to a pharmaceutical composition for the treatment of cardiovascular disorders, which comprises 2-ethoxy-l-({4-[2-(2H-l,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-lH-l,3- benzodiazole-7-carboxylic acid (candesartan) or a pharmaceutically acceptable salt thereof in combination with 6-chloro-l,l-dioxo-3,4-dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide (hydrochlorothiazide, HCTZ) or a pharmaceutically acceptable salt thereof and 3-ethyl 5-methyl 2-[(2- aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-l,4-dihydropyridine-3,5-dicarboxylate

(amiodipine) or a pharmaceutically acceptable salt thereof, in an one tablet.

Amiodipine 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, and EP Patent Publication No. 89167 discloses various forms of pharmaceutically acceptable salts of amiodipine. The pharmaceutically acceptable salts of amiodipine used in the present invention may be formed using acids which form non-toxic, pharmaceutically acceptable acid addition salts, which include but are not limited to hydrochloride, hydrobromide, sulphate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, besylate and camsylate salts and amiodipine is currently available as Norvasc.

Candesartan is the generic name for 2-ethoxy-l-({4-[2-(2H-l,2,3,4-tetrazol-5- yl)phenyl]phenyl}methyl)-lH-l,3-benzodiazole-7-carboxylic acid and it is disclosed in EP0425921, EP0459136 and EP0520423 that benzimidazole derivatives have an angiotensin II antagonistic activities and are useful for the therapy of circulatory diseases including hypertension, cardiac diseases (cardiac insufficiency, myocardial infarction, etc.), cerebral apoplexy, nephritis and arteriosclerosis. Candesartan cilexetil is currently available as Atacand. Accordingly, the preferred pharmaceutically acceptable salt of candesartan that can be used in the present invention is candesartan cilexetil.

Hydrochlorothiazide is the generic name for 6-chloro-l,l-dioxo-3,4-dihydro-2H-l,2,4- benzothiadiazine-7-sulfonamide and Hydrochlorothiazide is currently available as Esidrix and Combination of Candesartan cilexetil along with hydrochlorothiazide is currently available as Atacand Plus. The mechanism of the action is considered that the benzimidazole derivatives inhibit the binding of angiotensin II having a strong vasoconstrictive action to an angiotensin II acceptor. And, while, in JPA H3(1991)-27362 and JPA H5(1993)-132467, it is disclosed that an imidazole derivative having angiotensin II antagonistic action is administered together with a diuretic agent or a calcium antagonistic agent.

The inventive composition of candesartan or a pharmaceutically acceptable salt thereof with hydrochlorothiazide or a pharmaceutically acceptable salt thereof and amlodipine or a pharmaceutically acceptable salt or a pharmaceutically acceptable salt thereof can achieve improved preventive or therapeutic effects for cardiovascular disorders, such as angina pectoris, hypertension, artery vasospasm, deep vein, cardiac hypertrophy, cerebral infarct, congestive heart failure and myocardial infarction, as compared with conventional single formulations, while minimizing adverse effects of the single drugs.

The said composition is prepared as an uncoated bi-layer tablet and manufacturing process comprising the following steps:

a) Manufacture of first layer: Candesartan and Hydrochlorothiazide granules using wet granulation approach, and

b) Manufacture of second layer: Amlodipine granules using slugging approach. Examples

The following composition and manufacturing procedure are intended to further illustrate the present invention without limiting its scope. Manufacturing composition and process for candesartan hydrochlorothiazide and amlodipine tablets containing candesartan (as candesartan cilexetil), hydrochlorothiazide (HCTZ), amlodipine besylate (as amlodipine besylate) are provided for illustration. The pharmaceutical composition of the present invention can be prepared by the prescriptions described as follows.

The abbreviation "qs" refers to "Quantum satis" meaning the amount which is necessarily needed. It refers to a specific amount for an ingredient that is necessarily needed to achieve the desired result, but not more. Table 1

Test Example 1: Preparation of combined tablet I

32/25/10 mg

Candesartan + HCTZ Layer 1 mg/tab % w/w

Candesartan Cilexetil 32.00 11.43

Hydrochlorothiazide 25.00 8.93

Lactose (Pharmatose 200 M) 170.60 60.93

Maize Starch 30.00 10.71

Croscarmellose Sodium 5.00 1.79

Hydroxy Propyl Cellulose (LF) 5.00 1.79

Poly Ethylene Glycol 8000 5.20 1.86

Purified Water qs 0.00

Ferric Oxide Yellow / Red 0.20 0.07 Croscarmellose Sodium 6.00 2.14

Magnesium Stearate 1.00 0.36

Cande + HCTZ Layer weight 280.00 100.00

Amlodipine Layer 2

Amlodipine besylate eq. to Amlodipine 13.89 8.68

MCC (Avicel PH 112) 110.00 68.75

Starch 1500 34.61 21.63

Magnesium Stearate 1.50 0.94

Amlodipine Layer weight 160.00 100.00

Final bi-layer Weight 440.00

The ingredients of the candesartan and hydrochlorothiazide mixture part were wet-granulated using PEG and HPC solution and dried to obtain the granule part having the specified amounts of the ingredient. The candesartan and hydrochlorothiazide mixture part was mixed with the ingredients of the amlodipine granules part according to the corresponding amounts, and the resulting mixture was compressed into tablets using a bi-layered tablet press having 32 mg of candesartan (as candesartan cilexetil) and 25 mg of hydrochlorothiazide as the first layer and 13.89 mg of amlodipine (as amlodipine besylate) as the second layer.

Combined tablet prepared in Example 1 and Reference Products - Atacand (Candesartan cilexetil), Atacand Plus (Candesartan cilexetil and Hydrochlorothiazide Tablet), Esidrix (Hydrochlorothiazide) and Norvasc (Amlodipine besylate) tablets were subjected to drug dissolution testing for comparison purposes. Obtained dissolution rates are shown in Figure 1 and 2.

Table 2

Test Example 2: Preparation of combined tablet I

16/12.5/10

Candesartan + HCTZ Layer 1 mg/tab % w/w

Candesartan Cilexetil 16.00 11.43

Hydrochlorothiazide 12.50 8.93

Lactose (Pharmatose 200 M) 85.30 60.93

Maize Starch 15.00 10.71

Croscarmellose Sodium 2.50 1.79

Hydroxy Propyl Cellulose (LF) 2.50 1.79

Poly Ethylene Glycol 8000 2.60 1.86

Purified Water qs 0.00

Ferric Oxide Yellow / Red 0.10 0.07

Croscarmellose Sodium 3.00 2.14

Magnesium Stearate 0.50 0.36

Cande + HCTZ Layer weight 140.00 100.00

Amlodipine Layer 2

Amlodipine besylate eq. to Amlodipine 13.89 8.68

MCC (Avicel PH 112) 110.00 68.75

Starch 1500 34.61 21.63

Magnesium Stearate 1.50 0.94

Amlodipine Layer weight 160.00 100.00

Final bi-layer Weight 300.00 A combined tablet containing 16 mg of candesartan (as candesartan cilexetii), 12.50 mg of hydrochlorothiazide and 13.89 mg of amiodipine (as amiodipine besylate) was prepared by repeating the procedure of example 1.

Table 3

Test Example 3: Preparation of combined tablet III

A combined tablet containing 16 mg of candesartan (as candesartan cilexetii), 12.50 mg of hydrochlorothiazide and 6.95 mg of amiodipine (as amiodipine besylate) was prepared by repeating the procedure of example 1.

Table 4

Test Example 4: Preparation of combined tablet IV

Cande + HCTZ Layer weight 280.00 100.00

Amlodipine Layer 2

Amlodipine besylate eq. to Amlodipine 13.89 8.68

MCC (Avicel PH 112) 110.00 68.75

Starch 1500 34.61 21.63

Magnesium Stearate 1.50 0.94

Amlodipine Layer weight 160.00 100.00

Final bi-layer Weight 440.00

A combined tablet containing 32 mg of candesartan (as candesartan cilexetil), 12.50 mg of hydrochlorothiazide and 13.89 mg of amlodipine (as amlodipine besylate) was prepared by repeating the procedure of example 1.

Table 5

Test Example 5: Preparation of combined tablet V

A combined tablet containing 32 mg of candesartan (as candesartan cilexetil), 12.50 mg of hydrochlorothiazide and 6.95 mg of amlodipine (as amlodipine besylate) was prepared by repeating the procedure of example 1.

Stability Analysis

Stability test was performed for the combined tablet obtained in the above Example I, II, III, and IV & V under the following condition

Incubation Conditions: PVC / PVDC Blister at 40°C /75% relative humidity

Incubation Time: 0, 3 and 6 months

Subject of Test: Related substance for candesartan, hydrochlorothiazide and amlodipine Stability Results of Example I, II and III are shown in Table 6 and stability Results of Example IV and V are shown in Table 7.

Table 6: Stability Results of Examples I, II and III

Example 1 Example II Example III

Strengths 32/25/10 mg 16/12.5/5 mg 16/12.5/10 mg

Tests Initial 3 M 6M Initial 3 M 6M Initial 3 M 6M

Candesartan

Ethyl Ester 0.053 0.055 0.048 0.056 0.054 0.051 0.054 0.053 0.054

Ketone Cilexetil 0.210 0.213 0.272 0.186 0.175 0.221 0.199 0.211 0.278

/V-Ethyl Candesartan 0.167 0.183 0.226 0.148 0.154 0.187 0.177 0.168 0.243

Maximum Unknown 0.051 0.057 0.032 0.049 0.050 0.028 0.065 0.077 0.075

Total Impurity 0.712 0.715 0.815 0.744 0.644 0.718 0.920 0.857 0.967

Amlodipine

Impurity-D 0.026 0.164 0.303 0.018 0.028 0.259 0.023 0.172 0.093

Impurity-F 0.068 0.064 0.065 0.058 0.057 0.055 0.067 0.059 0.067

Impurity-E 0.029 0.032 0.039 0.034 0.029 0.024 0.035 0.029 0.026

Maximum Unknown 0.020 0.035 0.061 0.015 ND 0.056 0.014 0.045 0.013

Total Impurity 0.186 0.411 0.703 0.152 0.273 0.626 0.146 0.406 0.247

Hydrochlorothiazide

5-Chloro-HCTZ ND ND 0.02 ND ND 0.026 ND ND 0.013

Chlorothiazide 0.012 0.012 0.021 0.012 0.011 0.02 0.011 0.011 0.022

Salamide 0.086 0.398 0.972 0.079 0.347 0.896 0.090 0.356 0.870

Maximum Unknown 0.043 0.094 0.065 0.044 0.094 0.067 0.043 0.061 0.054

Total Impurity 0.204 0.817 1.399 0.187 0.737 1.332 0.196 0.844 1.686

Table 7: Stability Results of Examples IV and V

Example IV Example V

Strengths 32/12.5/10 mg 32/12.5/ 5 mg

Tests Initial 3 M 6M Initial 3 M 6M

Candesartan

Ethyl Ester 0.056 0.055 0.053 0.055 0.05 0.052

Ketone Cilexetil 0.183 0.173 0.206 0.155 0.144 0.198

W-Ethyl Candesartan 0.144 0.144 0.175 0.12 0.114 0.197

Maximum Unknown 0.052 0.049 0.09 0.042 0.038 0.024

Total Impurity 0.659 0.661 0.742 0.563 0.534 0.635

Amlodipine

Impurity-D 0.018 0.149 0.295 0.02 0.12 0.25

Impurity-F 0.063 0.065 0.066 0.073 0.068 0.118

Impurity-E 0.029 0.031 0.031 0.036 0.034 0.023

Maximum Unknown 0.019 0.039 0.056 0.033 0.04 0.069

Total Impurity 0.172 0.375 0.644 0.231 0.375 0.656 Hydrochlorothiazide

5-Chloro-HCTZ ND ND 0.017 ND ND 0.045

Chlorothiazide 0.011 0.011 0.021 0.012 0.01 0.02

Salamide 0.101 0.686 1.731 0.116 0.546 1.345

Maximum Unknown 0.047 0.171 0.141 0.046 0.201 0.179

Total Impurity 0.228 1.356 2.445 0.272 1.279 2.237

As shown in Tables 6 and 7, Impurity related to hydrochlorothiazide - salamide was observed more in Examples IV and V as compared to Examples I, II and III. Main difference between composition of Examples IV and V as compared to Examples I, II and III is ratio of Hydrochlorothiazide to Lactose, i.e. 1 : 6.72 for 32/25 and 16/12.5 mg when compared to 1 : 14.42 for 32/12.5 mg as part of layer I (Candesartan cilexetil and Hydrochlorothiazide).

The following Example and open exposure stability study is intended to further illustrate the impact of Hydrochlorothiazide to lactose ratio on salamide impurity

Table 8

Test Example 6: Preparation of combined tablet VI

A combined tablet containing 32 mg of candesartan (as candesartan cilexetil), 12.50 mg of hydrochlorothiazide and 13.89 mg of amiodipine (as amiodipine besylate) was prepared by repeating the procedure of example 1. Open Exposure stability study for Hydrochlorothiazide

Open exposure stability study was performed for the combined tablet obtained in above Example IV and VI with Innovator samples Atacand plus 32/12.5 mg under the following condition

Incubation Conditions: Open exposure, 40°C /75% relative humidity

Incubation Time: Initial, 2 weeks (2W)

Subject of Test: Substance related to hydrochlorothiazide

Open exposure stability results shown in below table 9.

Table 9: Open Exposure stability Results

Results obtained in 2 Week open exposure stability study have shown that salamide impurity was decreased with reduced quantity of lactose monohydrate and comparable with the invention.

Claims

A pharmaceutical composition comprising: (i) an angiotensin receptor blocker (ARB) or a pharmaceutically acceptable salt thereof, (ii) a calcium channel blocker (CCB) or a pharmaceutically acceptable salt thereof, and (iii) a diuretic or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition according to claim 1, wherein (i) the angiotensin receptor blocker (ARB) is candesartan of formula I or a pharmaceutically acceptable salt thereof; (ii) the calcium channel blocker (CCB) is amlodipine of formula III or a pharmaceutically acceptable salt thereof; and (iii) the diuretic is hydrochlorothiazide of formula II or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition according to claims 1 to 2, wherein the composition is in a form to be administered orally.

4. A pharmaceutical composition according to claims 1 to 3, wherein the composition is a tablet.

5. A pharmaceutical composition according to claim 4, wherein the tablet is in a form of a bi-layer tablet.

6. A pharmaceutical composition according to claim 5, wherein the first layer comprises candesartan or a pharmaceutically acceptable salt thereof and hydrochlorothiazide and the second layer comprises amlodipine or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to any one of the preceding claims, further comprising one or more pharmaceutically acceptable carriers or excipients.

8. The pharmaceutical composition according to any one of the preceding claims, further comprising lactose.

9. The pharmaceutical composition according to any one of the preceding claims, further comprising lactose in one layer with hydrochlorothiazide and optionally further comprising one or more pharmaceutically acceptable carriers or excipients.

10. The pharmaceutical composition according to any one of the preceding claims, further comprising lactose in one layer with hydrochlorothiazide with a ratio of hydrochlorothiazide to lactose from 1 : 3 to 1 : 10, more preferably in a ratio of from 1 : 5 to 1 : 7.

11. The pharmaceutical composition according to any one of the preceding claims, further comprising maize starch, croscarmellose sodium and magnesium stearate.

12. The pharmaceutical composition according to any one of the preceding claims, further comprising hydroxy propyl cellulose and poly ethylene glycol.

13. A pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutically acceptable salt of candesartan is candesartan cilexetil.

14. A pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutically acceptable salt of amlodipine is amlodipine besylate.

15. A pharmaceutical composition according to any one of the claims 1 to 11, wherein candesartan is contained in an amount from 5 to 150 mg, amlodipine is contained in an amount from 1 mg to 50 mg and hydrochlorothiazide is contained in an amount from 0.5 mg to 30 mg.

16. A pharmaceutical composition according to claim 12, wherein candesartan is contained in an amount from 10 to 50 mg, amlodipine is contained in an amount from 5 mg to 35 mg, and hydrochlorothiazide is contained in an amount from 1 mg to 20 mg.

17. A method for preparing the pharmaceutical composition as claimed in any one of the claims 1 to 16, comprising the step of granulating candesartan or a pharmaceutically acceptable salt thereof along with hydrochlorothiazide or a pharmaceutically acceptable salt thereof to obtain a candesartan and hydrochlorothiazide granule part.

18. The method as claimed in claim 17, wherein the candesartan and hydrochlorothiazide granule part with a mixture part comprising amlodipine or a pharmaceutically acceptable salt thereof are mixed together.

19. The method as claimed in claim 18, further comprising the steps: a) manufacture of layer 1: candesartan or a pharmaceutically acceptable salt thereof and hydrochlorothiazide granules using wet granulation approach; and

b) manufacture of layer 2: amlodipine or a pharmaceutically acceptable salt thereof granules using slugging approach.

20. A pharmaceutical composition according to any one of the claims 1 to 16 for use in preventing or treating of a condition or disease selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (whether unstable or stable), renal insufficiency (diabetic and non-diabetic), heart failure, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive dysfunction (such as Alzheimer's disease), glaucoma and stroke.

21. A pharmaceutical composition according to any one of the claims 1 to 16 for use in preventing or treating corresponding cardiovascular disorders.

22. A pharmaceutical composition according to claim 21, wherein the cardiovascular disorders are selected from the group consisting of angina pectoris, hypertension, artery vasospasm, deep vein thrombosis, cardiac hypertrophy, cerebral infarction, congestive heart failure and myocardial infarction.