A combination for the treatment of hypertension

Abstract

The invention relates to a pharmaceutical composition, a pharmaceutical dosage form, preferably a fixed dose single pill combination (SPC), processes for the preparation thereof, and their use in treating hy- pertension or / and reducing the risk of development of a condition associated with hypertension in a hypertensive subject. The pharmaceutical composition comprises (i) perindopril or a physiologically acceptable salt thereof, (ii) lercanidipine or a physiologically acceptable salt thereof, and (iii) preferably, indapamide or a physiologically acceptable salt thereof.

Description

A combination for the treatment of hypertension

[0001] Priority is claimed of European patent application no. 25 163 891.2 that was filed on 14 March 2025.

[0002] The invention relates to a pharmaceutical composition, a pharmaceutical dosage form, preferably a fixed dose single pill combination (SPC), processes for the preparation thereof, and their use in treating hypertension or / and reducing the risk of development of a condition associated with hypertension in a hypertensive subject. The pharmaceutical composition comprises (i) perindopril or a physiologically acceptable salt thereof, (ii) lercanidipine or a physiologically acceptable salt thereof, and (iii) preferably, indapamide or a physiologically acceptable salt thereof.

[0003] Hypertension, also commonly known as high blood pressure, is a medical condition in which the arterial blood pressure is persistently elevated and which represents a major cause of premature death worldwide. According to an estimation provided on the website of the World Health Organization (WHO) in early 2023, about 1.28 billion adults aged 30-79 years worldwide suffer from hypertension, with two-thirds of them living in low- and middle-income countries and only about 46% being aware of their medical condition.

[0004] Risk factors for the development of hypertension include both modifiable risk factors such as physical inactivity, unhealthy diets, consumption of tobacco and alcohol, and non-modifiable risk factors such as a family history of hypertension and co-existing diseases such as diabetes or kidney disease. Despite the existence of effective and affordable techniques, hypertension is not always well detected, especially since it is usually not accompanied by any symptoms. Only in case of very high blood pressures can symptoms such as severe headaches, chest pain, dizziness, nausea, blurred vision, anxiety and abnormal heart rhythm be experienced.

[0005] Although the manipulation of modifiable risk factors can help to lower the blood pressure, most subjects suffering from hypertension require antihypertensive drug treatment alongside lifestyle modifications. In the 2024 hypertension guidelines of the European Society of Hypertension (ESH), five major drug classes are recommended as first-line agents for antihypertensive drug treatment, namely angiotensin-converting-enzyme inhibitors, angiotensin receptor blockers, dihydropyridine calcium channel blockers, thiazide / thiazide-like diuretics and beta blockers. These drugs can be used alone or in combination.

[0006] Typically, therapy is initiated with monotherapy or with a two-drug combination. Preferred two-drug combinations comprise a renin-angiotensin system (RAS) blocker combined with a calcium channel blocker (CCB) or a thiazide / thiazide-like diuretic, even though other combinations of the five major drug classes can also be used (McEvoy et al., "2024 ESC Guidelines for the management of elevatedblood pressure and hypertension", Eur. Heart J. 45 (2024), 3912-4018). Combining anti-hypertensive agents from two different classes has been shown to result in an approximately five-fold greater blood pressure reduction with respect to doubling the dose of a single agent (Wald et al., "Combination therapy versus monotherapy in reducing blood pressure; meta-analysis on 11,000 participants from 42 trials", Am. J. Med. 122(3) (2009), 290-300).

[0007] If, upon administration of the maximum recommended and tolerated dose of both drugs, the blood pressure of the hypertensive subject cannot be adequately controlled with the initial two-drug combination, adopting a triple combination strategy in these subjects is the most reasonable approach. When the use of a three-drug combination becomes necessary, it is recommended that the combination comprises each of a RAS blocker, a calcium channel blocker and a thiazide / thiazide-like diuretic, wherein the RAS blocker may be either an angiotensin-converting-enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB). The rationale behind this is that such three-drug combinations typically result in an antihypertensive effect that is considerably higher than that of the individual components (Volpe et al., "Rationale for triple fixed-dose combination therapy with an angiotensin II receptor blocker, a calcium channel blocker, and a thiazide diuretic", Vase. Health Risk Manag. 8 (2012), 371-380), resulting in adequate control of the blood pressure in up to 90% of the patients (Mancia et al., "2023 ESH Guidelines for the management of arterial hypertension" , J. Hypertension 41(12) (2023), 1874-2071).

[0008] Specific examples of suitable angiotensin receptor blockers comprise azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan and valsartan.

[0009] Common ACE inhibitors include benazepril, captopril, cilazapril, enalapril, fosinopril, im-idapril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril.

[0010] As specific examples of calcium channel blockers, benzothiazepines such as diltiazem, dihydropyridines such as amlodipine, azelnidipine, benidipine, cilnidipine, efonidipine, felodipine, is-radipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine and nitrendipine, and phenylalkylamines such as verapamil are adopted. Thiazide / thiazide-like diuretics suitable for use in a three-drug combination comprise, among others, chlortalidone, hydrochlorothiazide, indapamide and xipamide.

[0011] Considering the plurality of possible combinations conferred by the aforementioned lists of compounds, the provision of an efficient and simultaneously safe antihypertensive therapy employing each of an angiotensin-converting-enzyme (ACE) inhibitor, a calcium channel blocker and a thiazide / thiazide-like diuretic is still a demanding task. In addition, it has turned out that adherence of hypertensive patients to a specific antihypertensive therapy generally decreases if the antihypertensive therapy requires a treatment with two or more drugs which are to be taken separately as combination therapy. By this means, adequate control of blood pressure cannot always be achieved.

[0012] Single-pill combination (SPC) therapy, by reducing the number of pills to be taken by a hypertensive patient, is known to lead to improved adherence and persistence compared with free-equivalent combination (FEC) therapy, and thereby achieves better blood pressure control (Parati et al., "Adherence to single-pill versus free-equivalent combination therapy in hypertension". Hypertension 77 (2021), 692-705). In order to overcome the deficiencies encountered with the separate administration of drugs, manufacturers of pharmaceutical products have tried to provide single dosage forms having more than one antihypertensive agent contained therein.

[0013] Approved double (i.e. binary) fixed dose combinations, selected from a group of ACE inhibitors, calcium channel blockers and diuretics (thiazide or thiazide-like) are:- ACE inhibitor + CCB: {benazepril / amlodipine}, {ramipril / felodipine}, {enalapril / lercanidipine}; - ACE inhibitor + diuretic (thiazide or thiazide-like): {perindopril / indapamide}, {quinapril / HCTZ}, {benazepril / HCTZ}, {enalapril / HCTZ}, {fosinopril / HCTZ}, {cilazapril / HCTZ}, {ramipril / HCTZ}, {moexipril / HCTZ}, {captopril / HCTZ};- CCB + diuretic (thiazide or thiazide-like): {amlodipine / HCTZ}, {amlodipine / indapamide} .

[0014] For treating hypertension, following triple -component (i.e. ternary) single-pill combination (SPC) ({perindopril / amlodipine / indapamide}, {ramipril / amlodipine / HCTZ}, {olmesartan / amlodipine / HCTZ}, {valsartan / amlodipine / HCTZ}, {telmisartan / amlodipine / HCTZ}, {irbesartan / amlodipine / HCTZ}, and {candesartan / amlodipine / HCTZ}) are available in Europe, which mostly include an angiotensin receptor blocker (ARB).

[0015] ACE inhibitors are favored over ARB in patients with certain comorbidities, such as acute or chronic coronary syndromes, diabetes mellitus or heart failure with reduced ejection fraction (McEvoy et al., "2024 ESC Guidelines for the management of elevated blood pressure and hypertension" , Eur. Heart J. 45 (2024), 3912-4018), and thiazide-like diuretics (such as indapamide and chlorthalidone) are preferred over HCTZ (Bumier et al., "Redefining diuretics use in hypertension: why select a thiazide-like diuretic?", J. Hypertens. 37(8) (2019), 1574-1586). {Perindopril / amlodipine / indapamide} is currently the only triple-component (i.e. ternary) single-pill combination (SPC) that includes an ACE inhibitor, calcium channel blocker and a thiazide-like diuretic.

[0016] Each class group selected from ACE inhibitors, calcium channel blockers and thiazide or thia-zide-like diuretics are prescribed for decades. Of the many agents in the drug class, each has significant differences in the precise mechanisms. Despite the availability of several pharmacological classes of antihypertensive drugs, there is a lack of studies assessing the efficacy of specific combinations, and treatment is still not based on a personalized approach. Comorbidities often complicate management and there is an unmet need for new drugs and / or new as well as alternative combinations. From a technical standpoint, formulation complexity correlates with the number of active ingredients incorporated into a fixed-dose combination (FDC) product due to the chemical properties and inherent physical attributes of each individual drug. There is a need for providing a single dosage form comprising acombination of perindopril or a physiologically acceptable salt, preferably perindopril erbumine and perindopril arginine, lercanidipine or a physiologically acceptable salt thereof, preferably lercanidipine hydrochloride, and indapamide or a physiologically acceptable salt thereof, in which all active pharmaceutical substances remain stable and wherein the active substances are provided in a formulation providing maximum bioavailability and / or maximum therapeutic or pharmacological response.

[0017] WO 1999 / 025374 Al relates to the use of a combination of the hypertensin converting enzyme inhibitor (IEC) with a diuretic to obtain pharmaceutical compositions for treating arteriolo-capillary microcirculation disorders.

[0018] WO 2004 / 066910 A2 relates to a controlled release modifying complex for solid suitable comprises modifying excipients.

[0019] WO 2005 / 094793 Al relates to a process for preparing a solid pharmaceutical composition of perindopril or a salt thereof which avoids a wet granulation step and results in very stable pharmaceutical compositions, like tablets.

[0020] US 2005 0101640 Al discloses compositions and methods for treating hypertension comprising lisinopril and lercanidipine and optionally including a diuretic in amounts effective in combination to reduce blood pressure to a patent in need of treatment.

[0021] WO 2008 / 065485 A2 relates to a stable pharmaceutical composition of a combination of a calcium channel blocker and an ACE inhibitor; wherein the two active ingredients are not physically separated and the composition has a pH of more than 6.0.

[0022] WO 2011 / 161223 A2 relates to unitary pharmaceutical oral dosage forms of the active substances lercanidipine and enalapril, as well the pharmacologically acceptable salts thereof, characterized in that the pharmaceutical oral dosage form comprise separate entities of lercanidipine or a physiologically acceptable salt thereof and enalapril or a physiologically acceptable salt thereof.

[0023] US 2011 0159093 Al relates to multiparticulate modified release pharmaceutical compositions comprising: (a) a first portion comprising an active ingredient, at least one surfactant and at least one release modifying agent and (b) a second portion comprising an active ingredient and optionally a release modifying agent.

[0024] WO 2014 / 027334 A2 relates to a composition in the form of microparticles primarily made up of: a) an inert core; b) a layer of active principle formed by spraying onto the inert core, and c) optionally, a second coating comprising one or more layers of physiologically acceptable excipient(s) and / or drug(s).

[0025] WO 2014 / 076632 Al relates to a pharmaceutical composition in the form of a blend consisting of a) a powder containing an ACE inhibitor, and b) a granulate containing a calcium channel blocker, wherein the powder a) and the granulate b) contain one or more excipients.

[0026] WO2021 / 130226 Al relates to granules comprising perindopril arginine, as well as to a process for the preparation of granules comprising perindopril arginine.

[0027] There is a demand for an antihypertensive product that is formulated for oral delivery and that provides an improvement over the antihypertensive products of the prior art. In particular, it would be desirable to provide an orally administrable antihypertensive product that allows to effectively and safely lower the blood pressure of a hypertensive patient while simultaneously providing excellent patient compliance, that can be easily and cost-effectively manufactured and that ensures excellent stability and quick release of the active pharmaceutical ingredients upon administration to the hypertensive patient.

[0028] Further, there is a demand for pharmaceutical compositions and dosage forms comprising new combinations of antihypertensive drugs, which may be advantageously prepared, especially which are obtainable from mixtures having an advantageous flowability, an advantageous compressibility, and an advantageous low sticking tendency, especially during preparation procedures involving compression procedures.

[0029] Furthermore, there remains a demand to develop pharmaceutical compositions and dosage forms that avoid or reduce the amount of excipient(s) which might impair pharmaceutical product stability, induce its degradation and / or act as a source of nitrosamine impurities, or facilitating their formation.

[0030] Moreover, there is a demand for pharmaceutical compositions and dosage forms comprising perindopril, lercanidipine and indapamide and excipients, which are particularly adapted to a preparation process comprising direct tableting.

[0031] It is an object according to the invention to provide stable and bioequivalent pharmaceutical compositions and dosage forms having advantages compared to the prior art.

[0032] The pharmaceutical compositions and dosage forms should be solid and suitable for oral administration.

[0033] The pharmaceutical compositions and dosage forms should have high content uniformity for all pharmacologically active ingredients contained therein, should be producible in an effective manner with regard to time and costs, should be substantially free of or only marginally comprise impurities and / or degradation products, should avoid or reduce sticking and capping during the production process, should avoid or reduce fdming during the production process, should have an acceptable size and patient compliance, should have a short disintegration time as well as good dissolution properties, and / or should enable a high bioavailability of all pharmacologically active ingredients for a patient. Further, the pharmaceutical dosage form should have a reasonable dosage form size, with good properties (e.g. stability, hardness, friability, disintegration, dissolution profde, content uniformity and the like). Furthermore, thepharmaceutical compositions and dosage form should be useful for treating hypertension or for reducing the risk of development of a condition associated with hypertension in a hypertensive subject.

[0034] The aforementioned object has been achieved by the subject-matter of the patent claims.

[0035] In order to solve the aforementioned object, the inventors carried out intense studies and recognized that an orally administrable antihypertensive product allowing to effectively and safely lower the blood pressure of a hypertensive patient while simultaneously providing excellent patient compliance can be reliably obtained by combining perindopril with at least one other antihypertensive agent selected from lercanidipine and indapamide, and formulating the antihypertensive product as a single-pill combination. Moreover, by formulating the antihypertensive product as a single pill combination (SPC), production of the product can be simplified and carried out at low cost.SUMMARY OF THE INVENTION

[0036] The invention broadly relates to pharmaceutical compositions and dosage forms, preferably fixed dose single pill combinations, processes for the preparation thereof, and their use in treating hypertension or / and reducing the risk of development of a condition associated with hypertension in a hypertensive subject.

[0037] The pharmaceutical compositions and dosage form comprises a total of at least two active pharmaceutical ingredients (APIs) representing different drug classes of antihypertensive agents, namely an angiotensin-converting enzyme, a calcium channel blocker and a thiazide / thiazide-like diuretic.

[0038] The invention relates to a pharmaceutical composition comprising(i) perindopril or a physiologically acceptable salt thereof;(ii) lercanidipine or a physiologically acceptable salt thereof; and(iii) preferably, indapamide or a physiologically acceptable salt thereof.

[0039] The invention further relates to a pharmaceutical dosage form comprising or essentially consisting of the pharmaceutical composition according to the invention.

[0040] The pharmaceutical compositions and dosage forms according to the invention combine (i) perindopril or a physiologically acceptable salt thereof with at least one other antihypertensive agent selected from (ii) lercanidipine or a physiologically acceptable salt thereof and (iii) indapamide or a physiologically acceptable salt thereof.

[0041] Most preferred physiologically acceptable salts are perindopril tert-butylamine (i.e., perindopril erbumine), perindopril arginine, and lercanidipine monohydrochloride.

[0042] The pharmaceutical compositions and dosage forms according to the invention are useful for treating hypertension, preferably essential hypertension or / and reducing the risk of development of a condition associated with hypertension, preferably essential hypertension.

[0043] It has been found that suitable dosage forms for the single pill combination (SPC) according to the invention are fdm-coated tablets, mono-layer tablets, bi-layer tablets, tri-layer tablets and press-coated tablets (e.g. tablet-in-tablet or bull's eye tablet), which dosage forms are good measures to achieve the goal under consideration of desired pharmaceutical profdes and characteristics of all pharmacologically active ingredients (i), (ii) and preferably (iii). Said dosage forms have been found to be applicable to the single pill combination (SPC) either keeping the original dissolution profdes of each mono tablet or adjusting the profdes to desired levels, and a reasonable tablet size.

[0044] Furthermore, the ternary combination of (i) perindopril or a physiologically acceptable salt thereof, (ii) lercanidipine or a physiologically acceptable salt thereof, and (iii) indapamide or a physiologically acceptable salt thereof fixed combination medicinal product (i.e., pharmaceutical composition or dosage form) can provide advantageous safety profile with reduced frequency or severeness of some adverse events, e.g. better safety profile when compared to the perindopril / lercanidipine, perindopril / in-dapamide and lercanidipine / indapamide dual therapies.

[0045] Finally, it has been recognized that, by providing a ternary combination of (i) perindopril or a physiologically acceptable salt thereof, (ii) lercanidipine or a physiologically acceptable salt thereof and (iii) indapamide or a physiologically acceptable salt thereof in the form of a single -pill combination having the three antihypertensive agents combined in a single unit, it is additionally possible to reduce treatment complexity, and to thereby reliably increase patient compliance and blood pressure control. Therefore, the ternary combination according to the invention is highly suitable for antihypertensive therapy, and in particular for substitution therapy.DETAILED DESCRIPTION OF THE INVENTION

[0046] Unless expressly stated otherwise, percentages are by weight relative to the total weight of the pharmaceutical composition and the total weight of the pharmaceutical dosage form, respectively.

[0047] Unless expressly stated otherwise, percentages relative to the total weight of the pharmaceutical dosage form exclude any optionally present coating, i.e., do not take into account any potential weight contribution of a coating, e.g. a film coating. Thus, when the pharmaceutical dosage form is e.g. a coated tablet composed of a tablet core and a coating, percentages relative to the total weight of the pharmaceutical dosage form are relative to the total weight of the tablet core, but not relative to the total weight of the sum of the tablet core and the coating.

[0048] Unless expressly stated otherwise, all references to Ph. Eur. refer to the version that is officially valid on January 1, 2025.

[0049] For the purpose of the specification, "essentially consisting of' means that to a large extent only that is comprised which is specified. The presence of amounts of other components in addition to the mandatory components is allowed, provided that the essential characteristics of the claimed pharmaceutical composition or dosage form are not materially affected by their presence. Preferably, to an extentof at least 99.0 wt.-%, more preferably at least 99.5 wt.-%, still more preferably at least 99.9 wt.-%, only that is comprised which is specified.

[0050] For the purpose of the specification, "fixed combination" denotes two or more pharmacologically active substances within a single pharmaceutical composition or dosage form.

[0051] A first aspect of to the invention relates to a pharmaceutical composition comprising(i) perindopril or a physiologically acceptable salt thereof;(ii) lercanidipine or a physiologically acceptable salt thereof; and(iii) preferably, indapamide or a physiologically acceptable salt thereof.

[0052] The invention makes use of a fixed combination comprising (i) perindopril, (ii) lercanidipine and (iii) optionally indapamide, wherein each of the (i) perindopril, (ii) lercanidipine and (iii) optionally indapamide independently of one another may be present as the pharmacologically active ingredient in the non-salt form, in the form of a physiologically acceptable salt, in the form of a physiologically acceptable solvate (especially a hydrate), or in the form of a physiologically acceptable salt solvate (especially a salt hydrate).

[0053] In preferred embodiments, the pharmaceutical composition according to the invention comprises a binary combination of pharmacologically active ingredients, namely (i) perindopril or a physiologically acceptable salt thereof; and (ii) lercanidipine or a physiologically acceptable salt thereof; but is free of (iii) indapamide and physiologically acceptable salts thereof.

[0054] In other preferred embodiments, the pharmaceutical composition according to the invention comprises a ternary combination of pharmacologically active ingredients, namely (i) perindopril or a physiologically acceptable salt thereof; (ii) lercanidipine or a physiologically acceptable salt thereof; and (iii) indapamide or a physiologically acceptable salt thereof.

[0055] Preferred binary combinations of pharmacologically active ingredients (i) and (ii) according to the invention are either (i) perindopril erbumine or perindopril arginine, in combination with (ii) lercanidipine monohydrochloride.

[0056] Each of the (i) perindopril, (ii) lercanidipine and (iii) optionally indapamide independently of one another may be either crystalline or amorphous, the term "crystalline" being intended to encompass all possible polymorphs. In this regard "non-salt form" means that the pharmacologically active ingredient is free, i.e. neither protonated nor deprotonated.

[0057] For the purpose of the specification, the terms "physiologically acceptable salt", "physiologically acceptable solvate" and "physiologically acceptable salt solvate" designate a salt, a solvate or a salt solvate that has been approved or is approvable by a regulatory authority such as the European Medicines Agency (EMA) or the U.S. Food and Drug Administration (FDA), or / and that is listed in a generally recognized pharmacopoeia such as the European Pharmacopoeia or the U.S. Pharmacopoeia and has been found to be acceptable for medical use in humans or animals.

[0058] Specific examples of physiologically acceptable salts are mentioned in "Remington: The Science and Practice of Pharmacy" (20th Edition, edited by A.R. Gennaro, Lippincott Williams & Wilkins, Baltimore and Philadelphia, 2000) and comprise, among others, acetate, besylate, bromide, chloride, citrate, fumarate, glucuronate, hydrobromide, hydrochloride, maleate, mesylate, nitrate, phosphate, potassium, sodium, succinate, sulfate, tartrate and tosylate. Specific examples of physiologically acceptable solvates and physiologically acceptable salt solvates are known to a person skilled in the art and particularly include hydrates, which hydrates may contain either stoichiometric or non -stoichiometric amounts of water.

[0059] Unless expressly stated otherwise, the term "perindopril" refers to a compound selected from the non-salt form of perindopril, a physiologically acceptable salt of perindopril, a physiologically acceptable solvate of perindopril, and a physiologically acceptable salt solvate of perindopril.

[0060] Free perindopril (IUPAC name: (2S,3aS,7aS)- l-[(2S)-2-{[(2S)- 1 -ethoxy- 1 -oxopentan- 2-yl]amino}propanoyl]octahydro-lH-indole-2-carboxylic acid) is a long-acting lipophilic drug with a high-tissue affinity for the ACE. ACE inhibition by perindopril has two main effects: it inhibits the angiotensin II formation and potentiates bradykinin.

[0061] Perindopril exists in different salt forms, wherein salts of perindopril exhibit polymorphism.

[0062] Perindopril (ATC C09AA04, CAS 82834-16-0, Mr 368.47 g / mol)is preferably present as perindopril erbumine (CAS 107133-36-8, Mr 441.61 g / mol) or perindopril arginine (CAS 612548-45-5, Mr 542.67 g / mol).

[0063] Perindopril erbumine (t-butylamine salt) may be amorphous or crystalline, whereas crystalline perindopril erbumine is preferred. Polymorphic forms of perindopril erbumine are described e.g. in EP 1 296947 (form alpha), EP 1 294 689 (form beta), EP 1 296948 (form gamma).

[0064] Perindopril arginine is known from e.g. EP 1 354 873. Perindopril arginine may be amorphous or crystalline, whereas crystalline perindopril arginine is preferred. Crystaline forms of perindopril arginine are known e.g. from EP 1 989 182 (form alpha), EP 2 016 051 (form beta), EP 2 318 365 (form gamma), EP 2 612 850 (form delta). An amorphous perindopril arginine is also known e.g. from EP 2 161 257 and EP 2682388.

[0065] Unless expressly stated otherwise, the term "lercanidipine" refers to a compound selected from the non-salt form of lercanidipine, a physiologically acceptable salt of lercanidipine, a physiologically acceptable solvate of lercanidipine, and a physiologically acceptable salt solvate of lercanidipine.

[0066] Free lercanidipine (IUPAC name: (RS)-2[(3,3-Diphenylpropyl)(methyl)amino]-l,l-dimethyl-ethyl methyl 2,6-dimethyl-4- (3-nitrophenyl)-l,4-dihydropyridine-3,5-dicarboxylate) inhibits the transmembrane influx of calcium into cardiac and smooth muscle. The mechanism of its antihypertensive action is due to a direct relaxant effect on vascular smooth muscle thus lowering total peripheral resistance. As for other asymmetric 1,4-dihydropyridines, the antihypertensive activity of lercanidipine is mainly due to its (S)-enantiomer. Lercanidipine is a racemate with both enantiomers equally effective in slowing the progression of atherosclerosis in vivo and in vitro. The (S)-enantiomer has calcium blocking activity, while the (R) -enantiomer appears to slow atherosclerosis progression without reducing blood pressure.

[0067] Lercanidipine (ATC C08CA13, CAS 100427-26-7, Mr 611.73 g / mol)is preferably present as lercanidipine monohydrochloride (CAS 132866-11-6, Mr 648.19 g / mol).

[0068] Lercanidipine monohydrochloride may be amorphous or crystalline, whereas crystalline lercanidipine monohydrochloride is preferred. Polymorphic crystalline form I of lercanidipine is most preferred, which is known from e.g. EP 1 600441.

[0069] In preferred embodiments, the lercanidipine or physiologically acceptable salt thereof is provided in micronized form, preferably having a particle size distribution, determined by laser diffraction in accordance with Ph. Eur. 2.9.31, with a dv 0 value of at most 150 pm, preferably at most 125 pm, more preferably at most 100 pm, still more preferably at most 75 pm, yet more preferably at most 50 pm, even more preferably at most 25 pm, most preferably at most 10 pm, and in particular at most 5 pm.

[0070] Unless expressly stated otherwise, the term "indapamide" refers to a compound selected from the non-salt form of indapamide, a physiologically acceptable salt of indapamide, a physiologically acceptable solvate of indapamide, and a physiologically acceptable salt solvate of indapamide.

[0071] Free indapamide (IUPAC name: 4-chloro-N-(2-methyl-2,3-dihydroindol-l-yl)-3-sulfamoyl-benzamide) inhibits the sodium-chloride symporter at the proximal segment of the distal convoluted tubule and prevents the kidney from reabsorbing sodium and chloride ions, and finally lowers the blood pressure by increasing urinary excretion.

[0072] Indapamide (ATC C03BA11, CAS 26807-65-8, Mr 365.84 g / mol)ls preferably present in its racemic non-salt form. However, the (R) -enantiomer of indapamide (CAS 77083-52-4) or the (S)-enantiomer of indapamide (CAS 77083-53-5) are also contemplated.

[0073] Indapamide in its non-salt form may be amorphous or crystalline, whereas crystalline indapamide in its non-salt form is preferred.

[0074] In preferred embodiments, the indapamide or physiologically acceptable salt thereof is provided in micronized form, preferably having a particle size distribution, determined by laser diffraction in accordance with Ph. Eur. 2.9.31, with a dv50 value of at most 150 pm, preferably at most 125 pm, more preferably at most 100 pm, still more preferably at most 75 pm, yet more preferably at most 60 pm, even more preferably at most 50 pm, most preferably at most 40 pm, and in particular at most 30 pm. Preferred dv50 values are within the range of from 10 to 20 pm, of from 20 to 30 pm.

[0075] Preferably, the total weight content of (i) perindopril, (ii) lercanidipine and optionally (iii) indapamide in the pharmaceutical composition according to the invention is within the range of 17.0±16.0 wt.-%, preferably 17.0±14.0 wt.-%, more preferably 17.0±12.0 wt.-%, still more preferably 17.0±10.0 wt.-%, yet more preferably 17.0±8.0 wt.-%, even more preferably 17.0±6.0 wt.-%, most preferably 17.0±4.0 wt.-%, and in particular 17.0±2.0 wt.-%, relative to the total weight of the pharmaceutical dosage composition, wherein weight contents refer to the weight of the form of (i) perindopril, (ii) lercanidipine and optionally (iii) indapamide that are actually present (e.g., non-salt form, physiologically acceptable salt, physiologically acceptable solvate, or physiologically acceptable salt solvate).

[0076] Preferably, the weight content of (i) perindopril in the pharmaceutical composition according to the invention is within the range of 4.5±4.0 wt.-%, preferably 4.5±3.5 wt.-%, more preferably 4.5±3.0 wt.-%, still more preferably 4.5±2.5 wt.-%, yet more preferably 4.5±2.0 wt.-%, even more preferably 4.5±1.5 wt.-%, most preferably 4.5±1.0 wt.-%, and in particular 4.5±0.5 wt.-%, relative to the total weight of the pharmaceutical composition, wherein weight content refers to the weight of the form of (i) perindopril that is actually present (e.g., non-salt form, physiologically acceptable salt, physiologically acceptable solvate, or physiologically acceptable salt solvate).

[0077] Preferably, the weight content of (ii) lercanidipine in the pharmaceutical composition according to the invention is within the range of 14.0±13.0 wt.-%, preferably 14.0±12.0 wt.-%, more preferably 14.0±11.5 wt.-%, still more preferably 14.0±11.0 wt.-%, yet more preferably 14.0±10.5 wt.-%, even more preferably 14.0±10.0 wt.-%, most preferably 14.0±9.5 wt.-%, and in particular 14.0±9.0 wt.-%, relative to the total weight of the pharmaceutical composition, wherein weight content refers to the weight of the form of (ii) lercanidipine that is actually present (e.g., non-salt form, physiologically acceptable salt, physiologically acceptable solvate, or physiologically acceptable salt solvate).

[0078] In preferred embodiments, the weight content of (ii) lercanidipine in the pharmaceutical composition according to the invention is within the range of 5 ,5±4.0 wt.-%, preferably 5 ,5±3.5 wt.-%, more preferably 5.5±3.0 wt.-%, still more preferably 5.5±2.5 wt.-%, yet more preferably 5.5±2.0 wt.-%, even more preferably 5.5±1.5 wt.-%, most preferably 5.5±1.0 wt.-%, and in particular 5.5±0.5 wt.-%, relative to the total weight of the pharmaceutical composition, wherein weight content refers to the weight of the form of (ii) lercanidipine that is actually present (e.g., non-salt form, physiologically acceptable salt, physiologically acceptable solvate, or physiologically acceptable salt solvate).

[0079] In further preferred embodiments, the weight content of (ii) lercanidipine in the pharmaceutical composition according to the invention is within the range of 11.0±8.0 wt.-%, preferably 11.0±7.0 wt.-%, more preferably 11 ,0±6.0 wt.-%, still more preferably 11 ,0±5.0 wt.-%, yet more preferably 11 ,0±4.0 wt.-%, even more preferably 11.0±3.0 wt.-%, most preferably 11.0±2.0 wt.-%, and in particular 11.0±1.0 wt.-%, relative to the total weight of the pharmaceutical composition, wherein weight content refers to the weight of the form of (ii) lercanidipine that is actually present (e.g., non-salt form, physiologically acceptable salt, physiologically acceptable solvate, or physiologically acceptable salt solvate).

[0080] In still further preferred embodiments, the weight content of (ii) lercanidipine in the pharmaceutical composition according to the invention is within the range of 22.0±16.0 wt.-%, preferably 22.0±14.0 wt.-%, more preferably 22.0±12.0 wt.-%, still more preferably 22.0±10.0 wt.-%, yet more preferably 22.0±8.0 wt.-%, even more preferably 22.0±6.0 wt.-%, most preferably 22.0±4.0 wt.-%, and in particular 22.0±2.0 wt.-%, relative to the total weight of the pharmaceutical composition, wherein weight content refers to the weight of the form of (ii) lercanidipine that is actually present (e.g., non-salt form, physiologically acceptable salt, physiologically acceptable solvate, or physiologically acceptable salt solvate).

[0081] Preferably, the weight content of (iii) indapamide in the pharmaceutical composition according to the invention is within the range of I.5±1.4 wt.-%, preferably I.5±1.2 wt.-%, more preferably I.5±1.0 wt.-%, still more preferably 1.5±0.8 wt.-%, yet more preferably 1.5±0.6 wt.-%, even more preferably 1.5±0.5 wt.-%, most preferably 1.5±0.4 wt.-%, and in particular 1.5±0.3 wt.-%, relative to the total weight of the pharmaceutical composition, wherein weight content refers to the weight of the form of (iii) indapamide that is actually present (e.g., non-salt form, physiologically acceptable salt, physiologically acceptable solvate, or physiologically acceptable salt solvate).

[0082] Preferably, the pharmaceutical composition according to the invention according to the invention is substantially free of or only marginally comprises impurities and / or degradation products. Preferably, the pharmaceutical composition according to the invention contains about < 5.0 wt.-%, or about < 4.0 wt.-%, or about < 3.0 wt.-%, or about < 2.0 wt.-%, preferably about < 1.0 wt.-%, more preferably about < 0.5 wt.-%, even more preferably about < 0.2 wt.-% of any individual or total impurity or degradation product(s) by total weight.

[0083] The pharmaceutical composition according to the invention typically comprises at least one physiologically acceptable excipient, preferably selected from fdlers / diluents, binders, disintegrants, lubricants, glidants, extended release agents, preservatives, antioxidants, pH modifiers (preferably bases), solubility enhancers, buffering agents, colorants, surfactants, emulsifiers, humectants, taste and odor improving agents, and the like, or mixtures thereof.

[0084] Suitable fillers / diluents include but are not limited to- monosaccharides (e.g. glucose, fructose);- disaccharides (e.g. sucrose, lactose, isomaltose, trehalose); preferably lactose (e.g. anhydrous lactose, lactose monohydrate, partially amorphous lactose, completely amorphous lactose, a-lactose, [3-lac- tose);- oligosaccharides (e.g. raffinose, dextrates);- polysaccharides, (e.g. starches or celluloses); preferably starch selected from partially or wholly pregelatinized starch, com starch, wheat starch, rice starch, tapioca starch, potato starch and any mixture thereof; preferably cellulose selected from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, microcrystalline cellulose co-processed with other excipients such as lactose, starch, silicon dioxide, mannitol, etc.;- compressible sugars;- sugar alcohols (e.g. mannitol, erythritol, sorbitol, maltitol, xylitol, lactitol);- inorganic salts (e.g. inorganic salts of phosphoric acid);and any mixture thereof.

[0085] A particularly preferred filler / diluent is lactose, preferably lactose monohydrate, microcrystalline cellulose or a mixture thereof.

[0086] Preferably, the total weight content of filler / diluent, preferably lactose, preferably lactose monohydrate, microcrystalline cellulose or a mixture thereof, is within the range of 65±27.5 wt.-%, preferably 65±25 wt.-%, more preferably 65±22.5 wt.-%, still more preferably 65±20 wt.-%, yet more preferably 65±17.5 wt.-%, even more preferably 65±15 wt.-%, most preferably 65±12.5 wt.-%, and in particular 65±10 wt.-%, relative to the total weight of the pharmaceutical composition according to the invention.

[0087] Suitable binders include but are not limited to- cellulose ethers (e.g., hydroxypropyl cellulose, hydroxypropyl methyl cellulose);- polyvinyl pyrrolidone (povidone), polyvinylpyrrolidone -vinyl acetate copolymer (copovidone); - polyethylene glycol;- lactose, glucose, sorbitol, mannitol;- polydextrose;- maltodextrin;- starch (e.g., com starch, potato starch, a-starch);- dextrin, dextran;- cellulose (e.g., crystalline cellulose, microcrystalline cellulose);- gum arabic;- silicic anhydride, aluminum silicate, calcium silicate, magnesium metasilicate-aluminate;- calcium hydrogen phosphate, calcium carbonate, calcium sulphate;and mixtures thereof.

[0088] A particularly preferred binder is maltodextrin.

[0089] Preferably, the total weight content of binder, preferably maltodextrin, is within the range of 10.0±9.0 wt.-%, preferably 10.0±8.0 wt.-%, more preferably 10.0±7.0 wt.-%, still more preferably 10.0±6.0 wt.-%, yet more preferably 10.0±5.0 wt.-%, even more preferably 10.0±4.0 wt.-%, most preferably 10.0±3.0 wt.-%, and in particular 10.0±2.0 wt.-%, relative to the total weight of the pharmaceutical composition according to the invention.

[0090] Suitable disintegrants include but are not limited to- crospovidone; starch, maize starch, pregelatinized starch, sodium starch glycollate, modified starch, hydroxypropyl starch, carboxymethyl starch;- sodium and / or calcium salts of carboxymethyl cellulose, cross-linked carboxymethylcellulose (e.g. sodium croscarmellose and / or calcium croscarmellose);- polacrilin potassium; alginic acid or alginates, sodium and / or calcium alginate;- polyacrylates; docusate sodium; methylcellulose; and agar, gums, guar gum, chitosan.

[0091] A particularly preferred disintegrant is sodium starch glycolate.

[0092] Preferably, the total weight content of disintegrant, preferably sodium starch glycolate, is within the range of 3.0±2.7 wt.-%, preferably 3.0±2.4 wt.-%, more preferably 3.0±2.1 wt.-%, still more preferably 3.0± 1.8 wt.-%, yet more preferably 3.0±1.5 wt.-%, even more preferably 3.0± 1.2 wt.-%, most preferably 3.0±0.9 wt.-%, and in particular 3.0±0.6 wt.-%, relative to the total weight of the pharmaceutical composition according to the invention.

[0093] Suitable lubricants include but are not limited to- stearic acid, calcium stearate, magnesium stearate;- talc;- colloidal silica;- waxes (e.g. bees wax or spermaceti);- boric acid;- adipic acid;- sulphates such as sodium sulphate;- glycol;- fumaric acid, sodium stearyl fumarate;- sucrose aliphatic acid ester;- sodium benzoate;- D,L-leucine;- silicic anhydride, silicic acid hydrate;- starch or a starch derivative (e.g. com starch, potato starch, a -starch);- dextrin;and mixtures thereof.

[0094] A particularly preferred lubricant is magnesium stearate.

[0095] Preferably, the total weight content of lubricant, preferably magnesium stearate, is within the range of from 0.01 to 2.5 wt.-%, preferably 0.1 to 1.0 wt.-%, relative to the total weight of the pharmaceutical composition according to the invention.

[0096] Suitable glidants / dispersants include but are not limited to talc, colloidal silica, and silicates.

[0097] A particularly preferred glidant / dispersant is silicon dioxide, preferably colloidal silicon dioxide, more preferably anhydrous colloidal silicon dioxide.

[0098] Preferably, the total weight content of glidant / dispersant, preferably silicon dioxide, is within the range of from 0.01 to 2.5 wt.-%, preferably 0.1 to 1.0 wt.-%, relative to the total weight of the pharmaceutical composition according to the invention.

[0099] Suitable surfactants include but are not limited to a lauryl sulphate such as sodium lauryl sulphate or magnesium lauryl sulphate.

[0100] The skilled person knows that one and the same excipient may serve more than a single purpose. For example, starch may function as binder, lubricant and fdler / diluent.

[0101] Another aspect of to the invention relates to a pharmaceutical dosage form comprising or essentially consisting of the pharmaceutical composition according to the invention as described above.

[0102] For the purpose of the specification, a "pharmaceutical dosage form" is a dose unit for administration that contains an intended therapeutical dose of the pharmacologically active ingredients (i), (ii) and optionally (iii).

[0103] The pharmaceutical dosage form according to the invention is preferably suitable and intended for oral administration, preferably for peroral administration (i.e., excluding buccal or sublingual administration).

[0104] Preferably, the dosage form according to the invention exhibits advantageous physical and / or pharmacological properties. Such properties include, but are not limited to fast disintegration, low friability, ease of assay, content uniformity, flow properties for manufacture, dissolution, bioavailability, and / or storage stability.

[0105] Also contemplated are kits comprising pharmaceutical dosage forms according to the invention.

[0106] Also contemplated are primary packaging comprising pharmaceutical dosage forms according to the invention, preferably Alu / Alu packaging.

[0107] It is contemplated that the pharmaceutical dosage form according to the invention may be administered by various routes and may thus be provided as a tablet, a powder, a capsule, a suppository, a suspension, a liposome, a spray, and the like.

[0108] Preferably, the pharmaceutical dosage form according to the invention is a solid, preferably a monolith.

[0109] Preferably, the pharmaceutical dosage form according to the invention is selected from tablets, capsules, orally disintegrating tablets (orodispersible tablets), effervescent dosage forms, hard or soft gelatin capsules, coated bead systems, granulates, powders, sachets, suspensions, microspheres, and the like.

[0110] Preferably, the pharmaceutical dosage form according to the invention is or comprises a compressed mixture, e.g. tablet or granule(s). The pharmaceutical dosage form comprising a compressed mixture, preferably tablet, can further comprise a coating, preferably a film coating, applied on the compressed mixture, preferably tablet.

[0111] In preferred embodiments, the pharmaceutical dosage form according to the invention is a directly compressed tablet, preferably a directly compressed mono-layer tablet, that is preferably coated, more preferably film-coated. Film-coated tablets are preferred, while non-coated tablets are also contemplated.

[0112] In other preferred embodiments, the pharmaceutical dosage form according to the invention is a dry granulated tablet, preferably a dry granulated mono-layer tablet, that is preferably coated, more preferably film -coated.

[0113] In further preferred embodiments, the pharmaceutical dosage form according to the invention is a wet granulated tablet, preferably a wet granulated mono-layer tablet, that is preferably coated, more preferably film -coated.

[0114] In still further preferred embodiments, the pharmaceutical dosage form according to the invention is a melt granulated tablet, preferably a melt granulated mono-layer tablet, that is preferably coated, more preferably film -coated.

[0115] In preferred embodiments, the pharmaceutical dosage form according to the invention is a tablet, preferably a mono-layer tablet, more preferably a coated mono-layer tablet, still more preferably a film-coated mono-layer tablet.

[0116] In preferred embodiments, the pharmaceutical dosage form according to the invention is a tablet, which essentially consists of a tablet core and optionally a coating, wherein the (i) perindopril or a physiologically acceptable salt thereof, the (ii) lercanidipine or a physiologically acceptable salt thereof, and preferably the (iii) indapamide or a physiologically acceptable salt thereof, if present, are homogeneously mixed with one another within the tablet core.

[0117] In other preferred embodiments, the pharmaceutical dosage form according to the invention is a tablet having more than a single layer, e .g . a bi-layer tablet, a tri -layer tablet, a press-coated tablet (e .g . a tablet-in-tablet or a bull's eye tablet).

[0118] In preferred embodiments, all layers of the pharmaceutical dosage form according to the invention independently of one another provide immediate release of the pharmacologically active ingredi-ent(s) contained therein.

[0119] In other preferred embodiments, one or more layers of the pharmaceutical dosage form according to the invention independently of one another provide immediate release of the pharmacologically active ingredient(s) contained therein, whereas one or more other layers of the pharmaceutical dosage form according to the invention independently of one another provide controlled release of the pharmacologically active ingredient(s) contained therein.

[0120] When the pharmaceutical dosage form according to the invention consists of a tablet core and optionally a coating, and when the tablet core contains a first segment and a second segment having different composition and thus being distinguishable from one another (e.g., or first layer and a second layer, or a first tablet in a second tablet), at least two of the pharmacologically active ingredients (i), (ii) and optionally (iii) are preferably separated from one another by means of said first segment and said second segment.

[0121] In preferred embodiments, (i) perindopril or a physiologically acceptable salt thereof is contained in the first segment but not in the second segment; whereas (ii) lercanidipine or a physiologically acceptable salt thereof is contained in the second segment but not in the first segment; whereas (iii) indapamide or a physiologically acceptable salt thereof, if present, is contained in the first segment but not in the second segment.

[0122] In other preferred embodiments, (i) perindopril or a physiologically acceptable salt thereof is contained in the first segment but not in the second segment; whereas (ii) lercanidipine or a physiologically acceptable salt thereof is contained in the second segment but not in the first segment; whereas (iii) indapamide or a physiologically acceptable salt thereof, if present, is contained in the second segment but not in the first segment.

[0123] In preferred bi-layer tablets, essentially the total amount of (ii) lercanidipine or a physiologically acceptable salt thereof is contained in first layer, whereas essentially the total amount of (i) perindopril or a physiologically acceptable salt thereof and essentially the total amount of (ii) indapamide are contained in the second layer.

[0124] In other preferred bi-layer tablets, essentially the total amount of (i) perindopril or a physiologically acceptable salt thereof and essentially the total amount of (ii) lercanidipine or a physiologically acceptable salt thereof are contained in the first layer, whereas essentially the total amount of (iii) indapamide or a physiologically acceptable salt thereof is contained in the second layer.

[0125] It is also contemplated that in bi-layer tablets, essentially the total amount of (i) perindopril or a physiologically acceptable salt thereof is contained in the first layer, whereas essentially the total amount of (ii) lercanidipine or a physiologically acceptable salt thereof and essentially the total amount of (iii) indapamide or a physiologically acceptable salt thereof are contained in the second layer.

[0126] When the pharmaceutical dosage form according to the invention consists of a tablet core and optionally a coating, and when the tablet core contains a first segment, a second segment, and a third segment having different composition and thus being distinguishable from one another (e.g., or first layer, a second layer, and a third layer), the pharmacologically active ingredients (i), (ii) and optionally (iii) are preferably separated from one another by means of said first segment, said second segment, and said third segment. In preferred embodiments, (i) perindopril or a physiologically acceptable salt thereof is contained in the first segment but neither in the second segment nor in the third segment; whereas (ii) lercanidipine or a physiologically acceptable salt thereof is contained in the second segment but neither in the first segment nor in the third segment; whereas (iii) indapamide or a physiologically acceptable salt thereof, if present, is contained in the third segment but neither in the first segment nor the second segment.

[0127] In preferred embodiments, the pharmaceutical dosage form according to the invention is a tablet, which essentially consists of a tablet core and optionally a coating, wherein the tablet core essentially consists of an intragranular phase and an extragranular phase, wherein essentially the total amount of the (ii) lercanidipine or a physiologically acceptable salt thereof is contained in the intragranular phase, and wherein essentially the total amount of the (i) perindopril or a physiologically acceptable salt thereof, as well as preferably essentially the total amount of the (iii) indapamide or a physiologically acceptable salt thereof, if present, are contained in the extragranular phase.

[0128] In other preferred embodiments, the pharmaceutical dosage form according to the invention is a tablet, which essentially consists of a tablet core and optionally a coating, wherein the tablet core essentially consists of an intragranular phase and an extragranular phase, wherein essentially the total amount of the (i) perindopril or a physiologically acceptable salt thereof, as well as preferably essentially the total amount of the (ii) lercanidipine or a physiologically acceptable salt thereof are contained in theintragranular phase, and wherein essentially the total amount of the (iii) indapamide or a physiologically acceptable salt thereof, if present, is contained in the extragranular phase.

[0129] Other preferred methods of separating at least two of the pharmacologically active ingredients (i), (ii) and optionally (iii) from one another can be achieved by an intragranular phase containing one or two of the pharmacologically active ingredients (i), (ii) and optionally (iii), and an extragranular phase containing the other one or two of the pharmacologically active ingredients (i), (ii) and optionally (iii).

[0130] In preferred embodiments, (ii) lercanidipine or a physiologically acceptable salt thereof is contained in the intragranular phase, which is preferably prepared by high-shear granulation, and (i) perin-dopril or a physiologically acceptable salt thereof and optionally (iii) indapamide or a physiologically acceptable salt thereof, if present, are contained in the extragranular phase. A thus prepared blend is preferably compressed into a mono-layer tablet which may optionally be coated, preferably film -coated.

[0131] Thus, in preferred embodiments, the pharmaceutical dosage form according to the invention, preferably being provided as a tablet, more preferably a mono-layer tablet, comprises- an intragranular phase comprising (ii) lercanidipine or a physiologically acceptable salt thereof, optionally together with one or more intragranular excipients; and- an extragranular phase comprising (i) perindopril or a physiologically acceptable salt thereof, optionally (iii) indapamide or a physiologically acceptable salt thereof, if present, optionally together with one or more extragranular excipients.

[0132] In preferred embodiments, the pharmaceutical dosage form according to the invention comprises one or more binders and essentially the total amount of binder is contained in the intragranular phase.

[0133] In other preferred embodiments, the pharmaceutical dosage form according to the invention comprises one or more binders and a first portion of the total amount of binder is contained in the intragranular phase, whereas the remainder of the total amount of binder is contained in the extragranular phase.

[0134] In preferred embodiments, the pharmaceutical dosage form according to the invention comprises one or more disintegrants and essentially the total amount of disintegrant is contained in the intragranular phase.

[0135] In other preferred embodiments, the pharmaceutical dosage form according to the invention comprises one or more disintegrants and a first portion of the total amount of disintegrant is contained in the intragranular phase, whereas the remainder of the total amount of disintegrant is contained in the extragranular phase.

[0136] In further preferred embodiments, the pharmaceutical dosage form according to the invention comprises one or more disintegrants and essentially the total amount of disintegrant is contained in the extragranular phase.

[0137] In a particularly preferred embodiment, it has been surprisingly found that a stable and effective immediate-release mono-layer tablet can be achieved by combining several specific formulation strategies. This embodiment comprises a tablet core consisting of an intragranular phase and an extragranular phase, wherein the intragranular phase contains lercanidipine or a physiologically acceptable salt thereof, and the extragranular phase contains perindopril or a physiologically acceptable salt thereof and indapamide or a physiologically acceptable salt thereof. Advantageously, the lercanidipine in the intragranular phase and the indapamide in the extragranular phase are both provided in micronized form, with the lercanidipine having a particle size distribution (dv50) of at most 10 pm and the indapamide having a particle size distribution (dv50) of at most 30 pm. This specific combination of phase separation and particle size control has been found to be crucial for ensuring content uniformity, stability, and the desired immediate -release profile for all three active ingredients from a single compressed dosage form.

[0138] Such a tablet is preferably obtainable by a process comprising: (a) preparing the intragranular phase by granulating the micronized lercanidipine with one or more excipients; (b) blending the resulting granules with an extragranular phase comprising perindopril, micronized indapamide, and further excipients; and (c) compressing the final blend into a mono-layer tablet. A particularly suitable set of excipients for this embodiment comprises lactose monohydrate and microcrystalline cellulose as fill-ers / diluents, maltodextrin as a binder, sodium starch glycolate as a disintegrant, and magnesium stearate as a lubricant.

[0139] Preferably the pharmaceutical dosage form according to the invention has a total weight of at most 550 mg, preferably at most 500 mg, more preferably at most 450 mg, still more preferably at most 400 mg, yet more preferably at most 350 mg, even more preferably at most 300 mg, most preferably at most 250 mg, and in particular at most 200 mg.

[0140] Preferably the pharmaceutical dosage form according to the invention is a film coated tablet essentially consisting of tablet core and a film coating, whereas the tablet core has a total weight of at most 550 mg, preferably at most 500 mg, more preferably at most 450 mg, still more preferably at most 400 mg, yet more preferably at most 350 mg, even more preferably at most 300 mg, most preferably at most 250 mg, and in particular at most 200 mg.

[0141] Preferably, the pharmaceutical dosage form according to the invention is a tablet having a crushing strength, determined according to Ph. Eur. 2.9.8., of at least 30 N, preferably at least 40 N, more preferably at least 50 N, still more preferably at least 60 N, yet more preferably at least 70 N, even more preferably at least 80 N, most preferably at least 90 N, and in particular at least 100 N.

[0142] Preferably, the pharmaceutical dosage form according to the invention is a tablet having a tablet friability, determined according to Ph. Eur. 2.9.7., expressed as the loss of mass and calculated as the percentage of the initial mass, of at most 2.00 wt.-%, preferably at most 1.80 wt.-%, more preferably at most 1.60 wt.-%, still more preferably at most 1.40 wt.-%, yet more preferably at most 1.10 wt.-%, evenmore preferably at most 1.00 wt.-%, most preferably at most 0.80 wt.-%, and in particular at most 0.60 wt.-%.

[0143] Preferably, the pharmaceutical dosage form according to the invention is a tablet having a tablet disintegration time, determined according to Ph. Eur. 2.9.1., of at most 9.0 minutes, preferably at most 8.0 minutes, more preferably at most 7.0 minutes, still more preferably at most 6.0 minutes, yet more preferably at most 5.0 minutes, even more preferably at most 4.0 minutes, most preferably at most 3.0 minutes, and in particular at most 2.0 minutes.

[0144] The pharmaceutical dosage form according to the invention may provide immediate release (conventional release) or controlled release of the pharmacologically active ingredients. Controlled release may be delayed release, modified release, sustained release, or any other type of release of any pharmacologically active ingredient (i), (ii) and preferably (iii) (i.e., (i) perindopril and (ii) lercanidipine and (iii) indapamide; or (i) perindopril and (ii) lercanidipine).

[0145] For the purpose of the specification, "immediate release" refers to an in vitro release profile, measured in accordance with Ph. Eur., preferably by means of the paddle method at 75 rpm and 37°C in 900 mb aqueous HC1 at a pH of 1.2, wherein at least 80% have been released after 30 minutes, preferably after 15 minutes.

[0146] For the purpose of the specification, "controlled release" refers to an in vitro release profile, measured in accordance with Ph. Eur., preferably by means of the paddle method at 75 rpm and 37°C in 900 mb aqueous HC1 at a pH of 1.2, wherein less than 80% have been released after 30 minutes.

[0147] Preferably, the pharmaceutical dosage form according to the invention provides immediate release of (i) perindopril or a physiologically acceptable salt thereof.

[0148] Preferably, the pharmaceutical dosage form according to the invention provides immediate release of (ii) lercanidipine or a physiologically acceptable salt thereof.

[0149] In preferred embodiments, the pharmaceutical dosage form according to the invention provides immediate release of (iii) indapamide or a physiologically acceptable salt thereof.

[0150] In other preferred embodiments, the pharmaceutical dosage form according to the invention provides controlled release of (iii) indapamide or a physiologically acceptable salt thereof.

[0151] The pharmaceutical dosage form according to the invention is preferably a tablet, more preferably a coated tablet, still more preferably a film-coated tablet.

[0152] A coating can be prepared by conventional procedures, e.g. using a film coating apparatus. The coating, especially film coating, can be e.g. a sugar coating, a water-soluble film coating, an intestinally soluble film coating (enteric film coating).

[0153] Pharmaceutical dosage forms according to the invention can be coated with conventional materials used for coating, in particular film coating, e.g. as described in Pharmaceutical Coating Technology(G. Cole (ed.), 1995). Coating a compressed mixture can for example comprise contacting the compressed mixture with a fdm coating dispersion to obtain a coated compressed mixture, and optionally drying the coated compressed mixture (e.g. coated tablet or granule). Film coating dispersions can be prepared by combining one or more solvents, such as water or organic solvent(s) such as alcohol(s) (e.g. methanol, ethanol, isopropanol), ketones (e.g. acetone), and mixtures thereof, with fdm-coating excipients).

[0154] A coating can comprise a polymer e.g. selected from cellulose ethers such as hyprolose (hydroxypropyl cellulose) or hypromellose (hydroxypropyl methyl cellulose), block copolymer of polyvinyl alcohol and polyethylene glycol (such as Kollicoat® IR or Kollicoat® protect), polyvinyl alcohol, aminoalkyl methacrylate copolymers (such as Eudragit® E PO), methacrylic acid copolymers, salts of carboxymethylcellulose, and mixtures thereof.

[0155] Advantageous examples of polymers for the coating include, but are not limited to, hydroxypropyl methylcellulose, polyvinyl alcohol (PVA), ethyl cellulose, methacrylic polymers, hydroxypropyl cellulose, starch, and mixtures thereof. The coating layer polymer can be preferably PVA. Presence of PVA in the coating allows for enhanced fdm adhesion, and facilitates faster coating of the drug.

[0156] A coating can further comprise coating additive(s) selected from plasticizers, glidants, pigments, colorants, opacifying agents, preservatives, anti-tacking agents and mixtures thereof.

[0157] Suitable plasticizers include but are not limited to triacetin, diethyl phthalate, tributyl sebacate, polyethylene glycol (PEG), glycerin, triacetin, propylene glycol, polypropylene glycol, glycerol, sorbitol, acetyl triethyl citrate, and mixtures thereof. The plasticizer can be advantageously polyethylene glycol.

[0158] Suitable glidants include but are not limited to talc, fumed silica, magnesium stearate, or a combination thereof.

[0159] Suitable opacifying agents include but are not limited to titanium dioxide.

[0160] Suitable colorants include but are not limited to iron oxide based colorant(s).

[0161] Examples of commercially available coating material include Opadry® HP, Opadry® II HP white.

[0162] The thickness of the coating (in particular fdm coating) applied on the tablet can be in the range of from 10 to 100 pm, preferably from 15 to 50 pm.

[0163] The coating of the tablet (especially fdm coating), where present, can include from 10 to 95 wt.-% of polymer, based on the weight of the coating. The coating (especially fdm coating) of the tablet, where present, can comprise from 20 to 90 wt.-% of polymer, optionally from 2 to 30 wt.-% of plasticizer, each based on the weight of the coating, optionally glidant, optionally opacifying agent and optionally colorant.

[0164] In a preferred embodiment, the film coating of the tablet, where present, can comprise from 20 to 90 wt.-% of polyvinyl alcohol (PVA), from 2 to 30 wt.-% of plasticizer, each based on the weight of the coating, preferably the plasticizer being or including polyethylene glycol; the film coating can further comprise optionally glidant, optionally opacifying agent and optionally colorant.

[0165] The fixed combination pharmaceutical dosage according to the invention can contain different dosages of the pharmacologically active ingredients (i), (ii) and optionally (iii).

[0166] Preferably, the weight equivalent dose of perindopril or a physiologically acceptable salt thereof that is contained in the pharmaceutical dosage form according to the invention is within the range of from 1 to 10 mg, relative to the weight of its non-salt form (Mr 368.47 g / mol).

[0167] In preferred embodiments, perindopril is present as perindopril erbumine (Mr 441.61 g / mol), preferably at a dose of from 2 to 8 mg; more preferably at a dose of 2 mg, 4 mg or 8 mg.

[0168] In other preferred embodiments, perindopril is present as perindopril arginine (Mr 542.67 g / mol); preferably at a dose of from 2 to 10 mg; more preferably at a dose of 2.5 mg, 5 mg or 10 mg.

[0169] The following weights of the non-salt form of perindopril are equivalent to perindopril erbumine and perindopril arginine, respectively:

[0170] Preferably, the weight equivalent dose of lercanidipine or a physiologically acceptable salt thereof that is contained in the pharmaceutical dosage form according to the invention is within the range of from 8 to 20 mg, relative to the weight of its non-salt form (Mr 611.73 g / mol).

[0171] In preferred embodiments, lercanidipine is present as lercanidipine monohydrochloride; preferably at a dose of from 10 to 20 mg; more preferably at a dose of 10 mg or 20 mg.

[0172] The following weights of the non-salt form of lercanidipine are equivalent to lercanidipine monohydrochloride:

[0173] Preferably, the weight equivalent dose of indapamide or a physiologically acceptable salt thereof that is contained in the pharmaceutical dosage form according to the invention is within the range of from 0.625 to 2.5 mg, relative to the weight of its non -salt form (Mr 365.84 g / mol).

[0174] In preferred embodiments, indapamide is present in its non-salt form; preferably at a dose of from 0.625 to 2.5 mg; more preferably at a dose of 0.625 mg, 1.25 mg, 1.5 mg or 2.5 mg.

[0175] In preferred embodiments, the pharmaceutical dosage according to the invention, preferably being provided as a tablet, more preferably mono-layer tablet, comprises(a) (i) perindopril erbumine at a dose of 4 mg or perindopril arginine at a dose of 5 mg and (ii) lercan- idipine monohydrochloride at a dose of 10 mg;(P) (i) perindopril erbumine at a dose of 4 mg or perindopril arginine at a dose of 5 mg and (ii) lercan- idipine monohydrochloride at a dose of 20 mg;(y) (i) perindopril erbumine at a dose of 8 mg or perindopril arginine at a dose of 10 mg and (ii) ler- canidipine monohydrochloride at a dose of 10 mg; or(5) (i) perindopril erbumine at a dose of 8 mg or perindopril arginine at a dose of 10 mg and (ii) ler- canidipine monohydrochloride at a dose of 20 mg.

[0176] In preferred embodiments, the pharmaceutical dosage according to the invention comprises: (a) (i) perindopril erbumine at a dose of 4 mg for immediate release or perindopril arginine at a dose of 5 mg for immediate release, and (ii) lercanidipine monohydrochloride at a dose of 10 mg for immediate release; or(b) (i) perindopril erbumine at a dose of 4 mg for immediate release or perindopril arginine at a dose of 5 mg for immediate release, and (ii) lercanidipine monohydrochloride at a dose of 20 mg for immediate release; or(c) (i) perindopril erbumine at a dose of 8 mg for immediate release or perindopril arginine at a dose of 10 mg for immediate release, and (ii) lercanidipine monohydrochloride at a dose of 10 mg for immediate release; or(d) (i) perindopril erbumine at a dose of 8 mg for immediate release or perindopril arginine at a dose of 10 mg for immediate release, and (ii) lercanidipine monohydrochloride at a dose of 20 mg for immediate release.

[0177] In preferred embodiments, the pharmaceutical dosage form according to the invention comprises (i) 4 mg perindopril erbumine and (ii) 10 mg lercanidipine monohydrochloride, but is free of (iii) indapamide and physiologically acceptable salts thereof.

[0178] In preferred embodiments, the pharmaceutical dosage form according to the invention comprises (i) 5 mg perindopril arginine and (ii) 10 mg lercanidipine monohydrochloride, but is free of (iii) indapamide and physiologically acceptable salts thereof.

[0179] In preferred embodiments, the pharmaceutical dosage form according to the invention comprises (i) 4 mg perindopril erbumine and (ii) 20 mg lercanidipine monohydrochloride, but is free of (iii) indapamide and physiologically acceptable salts thereof.

[0180] In preferred embodiments, the pharmaceutical dosage form according to the invention comprises (i) 5 mg perindopril arginine and (ii) 20 mg lercanidipine monohydrochloride, but is free of (iii) indapamide and physiologically acceptable salts thereof.

[0181] In preferred embodiments, the pharmaceutical dosage form according to the invention comprises (i) 8 mg perindopril erbumine and (ii) 10 mg lercanidipine monohydrochloride, but is free of (iii) indapamide and physiologically acceptable salts thereof.

[0182] In preferred embodiments, the pharmaceutical dosage form according to the invention comprises (i) 10 mg perindopril arginine and (ii) 10 mg lercanidipine monohydrochloride, but is free of (iii) indapamide and physiologically acceptable salts thereof.

[0183] In preferred embodiments, the pharmaceutical dosage form according to the invention comprises (i) 8 mg perindopril erbumine and (ii) 20 mg lercanidipine monohydrochloride, but is free of (iii) indapamide and physiologically acceptable salts thereof.

[0184] In preferred embodiments, the pharmaceutical dosage form according to the invention comprises (i) 10 mg perindopril arginine and (ii) 20 mg lercanidipine monohydrochloride, but is free of (iii) indapamide and physiologically acceptable salts thereof.

[0185] In preferred embodiments, the pharmaceutical dosage according to the invention, preferably being provided as a tablet, more preferably mono-layer tablet, comprises(a) (i) perindopril erbumine at a dose of 4 mg or perindopril arginine at a dose of 5 mg, and (iii) indapamide non -salt form at a dose of 1.25 mg; or(Q (i) perindopril erbumine at a dose of 8 mg or perindopril arginine at a dose of 10 mg, and (iii) indapamide non-salt form at a dose of 2.5 mg.

[0186] These dosages of (i) perindopril and (iii) indapamide are also preferred when the pharmaceutical dosage according to the invention additionally comprises (ii) lercanidipine, preferably at a dose of 10 mg or 20 mg lercanidipine monohydrochloride.

[0187] Preferred ternary combinations of pharmacologically active ingredients (i), (ii) and (iii) according to the invention are either (i) perindopril erbumine or perindopril arginine, in combination with (ii) lercanidipine monohydrochloride and in combination with (iii) indapamide in its non-salt form.

[0188] In preferred embodiments, the pharmaceutical dosage according to the invention, preferably being provided as a tablet, more preferably mono-layer tablet, comprises(r|) (i) perindopril erbumine at a dose of 4 mg or perindopril arginine at a dose of 5 mg, (ii) lercanidipine monohydrochloride at a dose of 10 mg, and (iii) indapamide in its non-salt form at a dose of 1.25 mg;(0) (i) perindopril erbumine at a dose of 4 mg or perindopril arginine at a dose of 5 mg, (ii) lercanidipine monohydrochloride at a dose of 20 mg, and (iii) indapamide in its non-salt form at a dose of 1.25 mg;(r) (i) perindopril erbumine at a dose of 8 mg or perindopril arginine at a dose of 10 mg, (ii) lercanidipine monohydrochloride at a dose of 10 mg, and (iii) indapamide in its non-salt form at a dose of 2.5 mg; or(K) (i) perindopril erbumine at a dose of 8 mg or perindopril arginine at a dose of 10 mg, (ii) lercanidipine monohydrochloride at a dose of 20 mg, and (iii) indapamide in its non-salt form at a dose of 2.5 mg.

[0189] In preferred embodiments, the pharmaceutical dosage according to the invention comprises: (a) (i) perindopril erbumine at a dose of 4 mg for immediate release or perindopril arginine at a dose of 5 mg for immediate release, (ii) lercanidipine monohydrochloride at a dose of 10 mg for immediate release, and (iii) indapamide in its non-salt form at a dose of 1.25 mg for immediate release; or(b) (i) perindopril erbumine at a dose of 4 mg for immediate release or perindopril arginine at a dose of 5 mg for immediate release, (ii) lercanidipine monohydrochloride at a dose of 20 mg for immediate release, and (iii) indapamide in its non-salt form at a dose of 1.25 mg for immediate release; or(c) (i) perindopril erbumine at a dose of 8 mg for immediate release or perindopril arginine at a dose of 10 mg for immediate release, (ii) lercanidipine monohydrochloride at a dose of 10 mg for immediate release, and (iii) indapamide in its non-salt form at a dose of 2.5 mg for immediate release; (d) (i) perindopril erbumine at a dose of 8 mg for immediate release or perindopril arginine at a dose of 10 mg for immediate release, (ii) lercanidipine monohydrochloride at a dose of 20 mg for immediate release, and (iii) indapamide in its non-salt form at a dose of 2.5 mg for immediate release.

[0190] In preferred embodiments, the pharmaceutical dosage form according to the invention comprises (i) 4 mg perindopril erbumine, (ii) 10 mg lercanidipine monohydrochloride, and (iii) 1.25 mg indapamide in its non-salt form.

[0191] In preferred embodiments, the pharmaceutical dosage form according to the invention comprises (i) 5 mg perindopril arginine, (ii) 10 mg lercanidipine monohydrochloride, and (iii) 1.25 mg indapamide in its non-salt form.

[0192] In preferred embodiments, the pharmaceutical dosage form according to the invention comprises (i) 4 mg perindopril erbumine, (ii) 20 mg lercanidipine monohydrochloride, and (iii) 1.25 mg indapamide in its non-salt form.

[0193] In preferred embodiments, the pharmaceutical dosage form according to the invention comprises (i) 5 mg perindopril arginine, (ii) 20 mg lercanidipine monohydrochloride, and (iii) 1.25 mg indapamide in its non-salt form.

[0194] In preferred embodiments, the pharmaceutical dosage form according to the invention comprises (i) 8 mg perindopril erbumine, (ii) 10 mg lercanidipine monohydrochloride, and (iii) 2.5 mg in-dapamide in its non-salt form.

[0195] In preferred embodiments, the pharmaceutical dosage form according to the invention comprises (i) 10 mg perindopril arginine, (ii) 10 mg lercanidipine monohydrochloride, and (iii) 2.5 mg in-dapamide in its non-salt form.

[0196] In preferred embodiments, the pharmaceutical dosage form according to the invention comprises (i) 8 mg perindopril erbumine, (ii) 20 mg lercanidipine monohydrochloride, and (iii) 2.5 mg in-dapamide in its non-salt form.

[0197] In preferred embodiments, the pharmaceutical dosage form according to the invention comprises (i) 10 mg perindopril arginine, (ii) 20 mg lercanidipine monohydrochloride, and (iii) 2.5 mg in-dapamide in its non-salt form.

[0198] Another aspect of the invention relates to the pharmaceutical dosage form according to the invention as described above for use in the treatment, management, and / or prevention of a disease or condition associated with hypertension, preferably essential hypertension (ICD-11 BA00), preferably for use in antihypertensive therapy.

[0199] Preferably, the essential hypertension is selected from combined diastolic and systolic hypertension (ICD-11 BA00.0), isolated diastolic hypertension (ICD-11 BA00.1), isolated systolic hypertension (ICD-11 BA00.2), other specified essential hypertension (ICD-11 BA00.Y), and unspecified essential hypertension (ICD-11 BA00.Z).

[0200] For the purpose of the specification, the terms "essential hypertension", "idiopathic hypertension", and "primary hypertension" are used interchangeably.

[0201] Another aspect of the invention relates to the use of a combination of (i) perindopril or a physiologically acceptable salt thereof; (ii) lercanidipine or a physiologically acceptable salt thereof; and (iii) preferably, indapamide or a physiologically acceptable salt thereof, for the manufacture of a pharmaceutical dosage form according to the invention as described above for treating, managing, and / or preventing a disease or condition associated with hypertension, preferably essential hypertension, preferably for antihypertensive therapy.

[0202] Another aspect of the invention relates to a method for treating, managing, and / or preventing a disease or condition associated with hypertension, preferably essential hypertension, preferably for antihypertensive therapy, comprising administering a pharmaceutical dosage form according to the invention as described above to a subject in need thereof.

[0203] Preferably, antihypertensive therapy according to the invention involves reducing the risk of development of a condition associated with hypertension, preferably essential hypertension.

[0204] Preferably, antihypertensive therapy according to the invention involves(a) a first-line antihypertensive therapy for a hypertensive patient; or(P) a second-line antihypertensive therapy for a hypertensive patient who is a non-responder to a previous antihypertensive therapy; or(y) a substitution antihypertensive therapy for a hypertensive patient whose blood pressure is adequately controlled by a previous antihypertensive therapy.

[0205] Preferably, the pharmaceutical dosage form according to the invention is for administration once daily or twice daily, preferably once daily, preferably orally, more preferably perorally.

[0206] The pharmaceutical compositions and dosage forms (especially in the form of a tablet or gran-ule(s)) according to the invention can be prepared by any of the methods known in the art. For example, the dosage forms can be prepared by uniformly admixing the pharmacologically active ingredients (i), (ii) and optionally (iii) with excipients, and then, if necessary, shaping the product into the desired presentation (e.g., compaction such as roller-compaction). If desired, tablets can be coated by standard aqueous or non-aqueous techniques.

[0207] Thus, another aspect of the invention relates to a method for manufacturing the pharmaceutical composition according to the invention as described above, and for manufacturing the pharmaceutical dosage form according to the invention as described above.

[0208] These methods may involve techniques known to those skilled in the art or as detailed by examples according to the invention. For instance, the pharmaceutical compositions and dosage forms can be produced by processes that comprise mixing, combining, blending, or composing the pharmacologically active and auxiliary ingredients or their pre-mixtures, mentioned hereinbefore and hereinafter. Additionally, the invention encompasses pharmaceutical compositions and dosage forms that are obtainable by these methods or from the components, ingredients, pre-mixtures, and mixtures described herein.

[0209] The mode of preparation can be direct blending, direct compression, high-shear granulation, fluid-bed granulation, dry granulation, wet granulation, melt granulation, extrusion, or any other known method or combination thereof.

[0210] In particular, the pharmaceutical dosage form according to the invention can be prepared by a preparation method, preferably a solvent free preparation method, which can be a direct compression method or a (preferably solvent free) granulation method (dry granulation) such as roller compaction, or slugging; the direct compression method being preferred.

[0211] Preferably, in direct compression a mixture comprising a combination of the pharmacologically active ingredients (i.e., (i) perindopril or a physiologically acceptable salt thereof, (ii) lercanidipine or a physiologically acceptable salt thereof, and (iii) indapamide or a physiologically acceptable salt thereof; or (i) perindopril or a physiologically acceptable salt thereof and (ii) lercanidipine or a physiologicallyacceptable salt thereof) and excipients is subjected to direct compression molding, in particular without any pre -agglomeration processes.

[0212] Preferably, in dry granulation a mixture comprising a combination of the pharmacologically active ingredients (i.e., (i) perindopril or a physiologically acceptable salt thereof, (ii) lercanidipine or a physiologically acceptable salt thereof, and (iii) indapamide or a physiologically acceptable salt thereof; or (i) perindopril or a physiologically acceptable salt thereof and (ii) lercanidipine or a physiologically acceptable salt thereof) and excipients is subjected to compression molding into comprimate or sheet, wherein granules are produced by crushing and division of comprimates and / or sheets by a suitable method.

[0213] Such methods are described in The Theory and Practice of Industrial Pharmacy (Third Edition) (Leon Lachman et al., LEA & LEBIGER 1986) or Pharmaceutical Dosage Porms: Tablets Volume 1 (Second Edition) (Herbert A. Lieberman et al.: MARCEL DEKKER Inc. 1989).

[0214] Granules can be fdled into a capsule to prepare an encapsulated product or, after an optional addition of pharmaceutical additives selected from disintegrating agents and / or lubricants and / or other additives, formulated into tablets by means of compression molding, e.g. in a tableting machine.

[0215] Preferably, a method of manufacturing a tablet according to the invention comprises tabletting (e.g. compression) of one or more final blends in form of granules. Granules of the final blend(s) according to the invention may be prepared by methods well-known to one skilled in the art (e.g. high shear wet granulation or fluid bed granulation).

[0216] In a particularly preferred embodiment, the pharmaceutical dosage form according to the invention is a mono-layer tablet, preferably for immediate release. A method of manufacturing such a mono-layer tablet preferably comprises the steps: (a) mixing the ingredients, (b) compressing the mixture into tablets, and optionally, (c) film coating the tablets. Preferably, the method comprises the steps of: (a) high-shear granulating (ii) lercanidipine or a physiologically acceptable salt thereof with one or more excipients; (b) blending the thus obtained lercanidipine-containing granules with at least one antihypertensive agent selected from (i) perindopril or a physiologically acceptable salt thereof and (iii) indapamide or a physiologically acceptable salt thereof; (c) compressing the thus obtained blend so as to obtain an immediate release mono-layer tablet; and optionally (d) coating the immediate release mono-layer tablet.EXAMPLES

[0217] The following examples further illustrate the invention but are not to be construed as limiting its scope:

[0218] Example 1 (perindopril erbumine):

[0219] Pharmaceutical dosage forms are prepared as film -coated tablets having the following compositions:

[0220] Tablets are prepared by blending, direct compressing the thus obtained blend, and film coating the thus obtained tablet cores.

[0221] Example 2 (perindopril arginine):

[0222] Pharmaceutical dosage forms are prepared as film-coated tablets having the following compositions:

[0223] Tablets are prepared by blending, direct compressing the thus obtained blend, and film coating the thus obtained tablet cores.

Claims

Patent claims:

1.

1. A pharmaceutical composition comprising(i) perindopril or a physiologically acceptable salt thereof;(ii) lercanidipine or a physiologically acceptable salt thereof; and(iii) preferably, indapamide or a physiologically acceptable salt thereof.

2. The composition according to claim 1 , which is free of indapamide and physiologically acceptable salts thereof.

3. The composition according to claim 1 or 2, which comprises at least one physiologically acceptable excipient; preferably selected from fillers / diluents, binders, disintegrants, lubricants, glidants, extended release agents, preservatives, antioxidants, pH modifiers (preferably bases), solubility enhancers, buffering agents, colorants, surfactants, emulsifiers, humectants, taste and odor improving agents, and the like, or mixtures thereof.

4. The composition according to claim 3, wherein the filler / diluent is selected from the group consisting of lactose monohydrate, microcrystalline cellulose, and mixtures thereof.

5. The composition according to any of the preceding claims, which contains a binder, preferably maltodextrin, wherein the total weight content of binder is within the range of 10.0±9.0 wt.-%, preferably 10.0±8.0 wt.-%, more preferably 10.0±7.0 wt.-%, still more preferably 10.0±6.0 wt.- %, yet more preferably 10.0±5.0 wt.-%, even more preferably 10.0±4.0 wt.-%, most preferably 10.0±3.0 wt.-%, and in particular 10.0±2.0 wt.-%, relative to the total weight of the composition.

6. The composition according to any of the preceding claims, which contains a disintegrant, preferably sodium starch glycolate, wherein the total weight content of disintegrant is within the range of 3.0±2.7 wt.-%, preferably 3.0±2.4 wt.-%, more preferably 3.0±2.1 wt.-%, still more preferably 3.0±1.8 wt.-%, yet more preferably 3.0±1.5 wt.-%, even more preferably 3.0±1.2 wt.-%, most preferably 3.0±0.9 wt.-%, and in particular 3.0±0.6 wt.-%, relative to the total weight of the composition.

7. The composition according to any of claims 3 to 6, wherein the at least one physiologically acceptable excipient comprises lactose monohydrate, microcrystalline cellulose, maltodextrin, sodium starch glycolate, and magnesium stearate.

8. A pharmaceutical dosage form comprising or essentially consisting of the pharmaceutical composition according to any of the preceding claims.

9. The dosage form according to claim 8, wherein (i) perindopril or a physiologically acceptable salt thereof, (ii) lercanidipine or a physiologically acceptable salt thereof, and (iii) indapamide or a physiologically acceptable salt thereof, if present, are each in a crystalline form.

10. The dosage form according to any of claims 8 to 9, wherein perindopril is present as:- perindopril erbumine; preferably at a dose of from 2 to 8 mg; more preferably at a dose of 2 mg, 4 mg or 8 mg; or- perindopril arginine; preferably at a dose of from 2 to 10 mg; more preferably at a dose of 2.5 mg, 5 mg or 10 mg.

11. The dosage form according to any of claims 8 to 10, wherein lercanidipine is present as lercanidipine monohydrochloride; preferably at a dose of from 10 to 20 mg; more preferably at a dose of 10 mg or 20 mg.

12. The dosage form according to any of claims 8 to 11 , wherein the lercanidipine or a physiologically acceptable salt thereof has a particle size distribution with a dv50 value of at most 50 pm, as determined by laser diffraction.

13. The dosage form according to any of claims 8 to 12, wherein the lercanidipine or a physiologically acceptable salt thereof has a particle size distribution with a dv50 value of at most 10 pm.

14. The dosage form according to any of claims 8 to 13, wherein indapamide is present in its non -salt form; preferably at a dose of from 0.625 to 2.5 mg; more preferably at a dose of 0.625 mg, 1.25 mg, 1.5 mg or 2.5 mg.

15. The dosage form according to any of claims 8 to 14, wherein the indapamide or a physiologically acceptable salt thereof has a particle size distribution with a dv50 value of at most 30 pm, as determined by laser diffraction.

16. The dosage form according to any of claims 8 to 15, which is a tablet, preferably a coated tablet, more preferably a fdm -coated tablet.

17. The dosage form according to claim 16, wherein the dosage form is a bi-layer tablet, a tri-layer tablet, or a press-coated tablet.

18. The dosage form according to claim 16, wherein the tablet is a mono-layer tablet.

19. The dosage form according to claim 18, wherein the tablet essentially consists of a tablet core and optionally a coating, wherein the (i) perindopril or a physiologically acceptable salt thereof, the (ii) lercanidipine or a physiologically acceptable salt thereof, and preferably the (iii) indapamide or a physiologically acceptable salt thereof, if present, are homogeneously mixed with one another within the tablet core.

20. The dosage form according to claim 18, wherein the tablet essentially consists of a tablet core and optionally a coating, wherein the tablet core essentially consists of an intragranular phase and an extragranular phase, wherein essentially the total amount of the (ii) lercanidipine or a physiologically acceptable salt thereof is contained in the intragranular phase, and wherein essentially the total amount of the (i) perindopril or a physiologically acceptable salt thereof, as well as preferably essentially the total amount of the (iii) indapamide or a physiologically acceptable salt thereof, if present, are contained in the extragranular phase.

21. The dosage form according to any of claims 8 to 20, wherein the (ii) lercanidipine or a physiologically acceptable salt thereof has a particle size distribution with a dv50 value of at most 10 pm, as determined by laser diffraction, and the (iii) indapamide or a physiologically acceptable salt thereof, if present, has a particle size distribution with a dv50 value of at most 30 pm, as determined by laser diffraction.

22. The dosage form according to any of claims 8 to 21, obtainable by a process comprising the steps of: (a) preparing an intragranular phase by granulating (ii) lercanidipine or a physiologically acceptable salt thereof with one or more excipients; (b) blending the intragranular phase with an extragranular phase comprising (i) perindopril or a physiologically acceptable salt thereof and optionally (iii) indapamide or a physiologically acceptable salt thereof; and (c) compressing the blend into a tablet.

23. The dosage form according to any of claims 16 to 22, wherein the film -coating comprises polyvinyl alcohol and a plasticizer.

24. The dosage form according to any of claims 16 to 23, wherein the tablet has a crushing strength of at least 50 N, determined according to Ph. Eur. 2.9.8.

25. The dosage form according to any of claims 16 to 24, wherein the tablet has a friability of at most 1.00 wt.-%, determined according to Ph. Eur. 2.9.7.

26. The dosage form according to any of claims 16 to 25, wherein the tablet has a disintegration time of at most 5.0 minutes, determined according to Ph. Eur. 2.9.1.

27. The dosage form according to any of claims 8 to 26, which provides immediate release of (i) perindopril or a physiologically acceptable salt thereof; immediate release of (ii) lercanidipine or a physiologically acceptable salt thereof; and preferably immediate release of (iii) indapamide or a physiologically acceptable salt thereof, if present.

28. The dosage form according to claim 27, wherein immediate release is characterized by an in vitro release profde wherein at least 80% of the active ingredient is released after 15 minutes, measured by the paddle method at 75 rpm in 900 mb aqueous HC1 at a pH of 1.2.

29. The dosage form according to any of claims 8 to 28, which is for administration once daily or twice daily, preferably once daily.

30. The composition according to any of claims 1 to 7 or the dosage form according to any of claims 8 to 29 for use in the treatment, management, and / or prevention of a disease or condition associated with hypertension, preferably essential hypertension, preferably for use in antihypertensive therapy.

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