WO2020109319A1

WO2020109319A1 - Pharmaceutical composition comprising ramipril and indapamide

Info

Publication number: WO2020109319A1
Application number: PCT/EP2019/082610
Authority: WO
Inventors: Julia Hrakovsky; Anna Madanecka; Przerada SZYMON
Original assignee: Zaklady Farmaceutyczne Polpharma S.A
Priority date: 2018-11-27
Filing date: 2019-11-26
Publication date: 2020-06-04
Also published as: EP3886817A1

Abstract

It relates to an oral multilayer tablet comprising (a) a first layer comprising an indapamide compound, and one or more pharmaceutically acceptable excipients, and (b) a second layer comprising a ramipril compound, and a stabilizing agent; and wherein the second layer has an impurity level of (2S,3aS,6aS)-1-[(S)-2-[[(S)-1- carboxy-3-phenylpropyl]amino]propanoyl]octahydrocyclopenta-[b]pyrrole2-carboxylic acid (impurity E) equal to or lower than 1.0% after 6 months at 40°C/75% RH as measured by ultra performance liquid chromatography (UPLC). It also relates to a process for the preparation of the multilayer tablet.

Description

Pharmaceutical composition comprising ramipril and indapamide

This application claims the benefit of European Patent Application 18460069.0 filed November 27, 2018.

Technical Field

The present invention relates to a pharmaceutical composition for oral administration in the form of a multilayer tablet comprising ramipril, or a pharmaceutically acceptable salt or a stereoisomer thereof, and indapamide, or a pharmaceutically acceptable salt thereof. It also relates to a process for the preparation of the pharmaceutical composition and to its medical uses, in particular in the treatment of hypertension.

Background Art

Ramipril is the generic name of compound (2S,3aS,6aS)-1-[(2S)-2-{[(2S)-1-ethoxy-1- oxo-4-phenylbutan-2-yl]amino}propanoyl]octahydrocyclo-penta[b]-pyrrole-2- carboxylic acid, the chemical structure of which is the following:

Ramipril is a prodrug belonging to the angiotensin-converting enzyme (ACE) inhibitor class of medications. It is metabolized to ramiprilat in the liver and, to a lesser extent, kidneys. Ramiprilat is a potent, competitive inhibitor of ACE, the enzyme responsible for the conversion of angiotensin I (ATI) to angiotensin II (ATI I). Ramipril may be used in the treatment of hypertension, congestive heart failure, nephropathy, and to reduce the rate of death, myocardial infarction and stroke in individuals at high risk of cardiovascular events.

The chemical name for ramiprilat (ramipril diacid) is (2S,3aS,6aS)-1-[(S)- 2-[[(S)-1-carboxy-3-phenylpropyl]amino]propanoyl]octahydrocyclopenta-[b]pyrrole2- carboxylic acid, and its chemical structure, the following: Ramipril exhibits a strong sensitivity to heat and moisture and decomposes easily. In addittion, WO2013/121233 discloses that excipients having high specific surface area and acidic character such as colloidal silicon dioxide are incompatible with ramipril and that their use during the formulation should be avoided.

Moreover, ramipril is also susceptible to degradation caused by the mechanical compression used in the manufacturing process for the preparation of prior art tablets. Hence, the hydrolysis of the ester groups of ramipril results in the impurity corresponding to the active metabolite, ramiprilat, which is identified as Impurity E. Another important decomposition product resulting from ramipril is ramipril diketopiperazine (DKP, chemical name ethyl (2S)-2-[(3S,5aS,8aS,9aS)-3-methyl-1 ,4- dioxodecahydro-2/-/-cyclopenta[4,5]pyrrolo-[1 ,2-a]pyrazin-2-yl]-4-phenylbutanoate) which is identified as Impurity D. Impurities D and E are cited in the ramipril monograph of the European Pharmacopoeia (see for example, European

Pharmacopoeia 8).

Pharmaceutical compositions containing ramipril are disclosed for example in W02007/120930 and WO2013/121233.

W02007/120930 discloses that an increase in the stability of the ramipril formulations (by reduction of the DKP impurity) is achieved by relatively decreasing the amount of inactive ingredients and increasing the amount of active ingredient in the formulation. This document specifically discloses capsules of ramipril containing pregelatinized starch, lactose anhydrous and sodium stearyl fumarate as excipients.

WO2013/121233 discloses ramipril formulations, in particular in the form of capsules, which contain a disintegrant directly granulated with a binder. It also discloses a comparative example which is a tablet as disclosed in W02007/120930 with the modification that it is supplemented with sodium hydrogen carbonate. Specifically, the comparative tablet contains as excipients: sodium hydrogen carbonate, lactose, croscarmellose sodium, pregelatinized starch, and sodium stearyl fumarate. The tablet is prepared by mixing lactose, ramipril, sodium hydrogen carbonate, croscarmellose sodium and starch and granulating the mixture with 1 :1 (v/v) mixture of 96% (v/v) ethanol and water. The granules are sieved and dried and then mixed with sodium stearyl fumarate and tabletted. According to this document, this tablet shows a concentration of the impurity E (which corresponds to ramipril diacid) of 3.42% at 25°C/60% r.h., and 6.0 at 40°C/75% r.h after stability of 6 months.

Indapamide is an oral antihypertensive/diuretic. Its chemical name is 4-chloro-N-(2- methyl-2, 3-dihydroindol-1-yl)-3-sulfamoyl-benzamide, and its chemical structure, the following:

One of the impurities of indapamide is impurity B (4-chloro-N-(2-methyl-1 H-indol-1- yl]-3-sulphamoyl-benzamide) and is cited in the indapamide monograph of the European Pharmacopoeia (see for example, European Pharmacopoeia 5.0).

On the other hand, the combination of ramipril and indapamide, its synergistic antihypertensive effect and diminished side effects were described in

W02008/124611. This document specifically discloses a capsule containing an immediate-release composition comprising ramipril in the form of a blend, and a controlled-release composition comprising indapamide in the form of a tablet coated with a HPMC-based coating.

However, it is known that the use of capsules may be unsuitable with regard to patients' compliance, especially for high dose combinations which require the use of large capsule sizes, which may be difficult to swallow.

Therefore, a need exists of having an alternative fixed dose combination comprising ramipril and indapamide that shows suitable drug stability and drug release of both active ingredients and which even in a high dose are of a suitably small size allowing for easy swallowing by the patient. Summary of Invention

The inventors have developed a pharmaceutical composition for oral adminitration in the form of a multilayer tablet which comprises a first layer comprising indapamide, and a second layer comprising ramipril, wherein the second layer has an impurity level of (2S,3aS,6aS)-1 -[(S)-2-[[(S)-1 -carboxy-3- phenylpropyl]amino]propanoyl]octahydrocyclopenta-[b]pyrrole2-carboxylic acid (impurity E) equal to or lower than 1.0% after 6 months at 40 °C / 75% RH as measured by ultra performance liquid chromatography (UPLC). This oral multilayer tablet is stable, showing particularly low levels of impurities. Especially the examples of the multilayer tablet of the invention show very reduced levels of the ramipril impurity E in comparison to the ramipril tablet of the prior art (see comparative example in WO2013/121233).

Moreover, the oral multilayer tablets of the invention have the advantage that they allow the administration of both ramipril and indapamide in a single dosage form. Further, they avoid any chemical incompatibilities between the active ingredients and/or accompanying pharmaceutically excipients by physical separation.

The oral multilayer tablets of the invention also enable the development of different drug release profiles, such as immediate release for ramipril and sustained release for indapamide.

Moreover, the oral multilayer tablet of the invention has the advantage that it shows better patient convenience and compliance compared to the capsules. In particular, the oral multilayer tablet of the invention is easier to swallow and shows less tendency for hang-up (sticking to the mucosa) when swallowed. Moreover, the manufacture of capsules requires more manufacture steps in comparison to the preparation of an oral multilayer tablet. Thus, the multilayer tablet of the invention is more cost/energy effective.

Therefore, an aspect of the invention relates to an oral multilayer tablet according to claim 1 comprising:

a) a first layer comprising an indapamide compound, and one or more

pharmaceutically acceptable excipients; and

b) a second layer comprising a ramipril compound and a stabilizing agent; wherein the ramipril compound is selected from ramipril, a pharmaceutically acceptable salt thereof, and a stereoisomer either of ramipril or of a pharmaceutically acceptable salt thereof; and the indapamide compound is selected from indapamide, a pharmaceutically acceptable salt thereof, and a stereoisomer either of indapamide or of a pharmaceutically acceptable salt thereof; and

wherein the second layer has an impurity level of (2S,3aS,6aS)-1-[(S)-2-[[(S)-1- carboxy-3-phenylpropyl]amino]propanoyl]octahydrocyclopenta-[b]pyrrole2-carboxylic acid (impurity E) equal to or lower than 1.0% after 6 months at 40 °C / 75% RH as measured by ultra performance liquid chromatography (UPLC).

The oral multilayer tablets of the invention have the further advantage that they can be prepared by a process comprising fewer steps in comparison to the process for preparing the prior art capsules.

It is to be understood that in the oral multilayer tablet the first and second layers can be in any order.

Thus, another aspect of the invention relates to a process for the preparation of the multilayer tablet as defined above which comprises the following steps:

a) providing a first layer composition by:

i) blending an indapamide compound with one or more pharmaceutically acceptable excipients,

b) providing a second layer composition by:

i) mixing a ramipril compound with water and a stabilizing agent, wherein water is a granulation liquid, in order to obtain a first mixture;

ii) mixing the mixture of step i) with one or more pharmaceutically acceptable excipients in order to obtain a second mixture;

iii) granulating the mixture of step ii), optionally in the presence of an additional granulation liquid in order to obtain granules;

iv) milling and drying the granules obtained in step iii) in order to obtain a granulate;

c) optionally, providing one or more additional layer compositions either comprising or not a further active ingredient; and

d) compressing the first and second layer compositions from step a) and b) and, optionally, the one or more additional layer compositions of step c), to form a multilayer tablet comprising a first layer comprising an indapamide compound and a second layer comprising a ramipril compound;

wherein steps a), b), and c) can be carried out in any order; and

Surprisingly, by carrying out the process of the invention, wherein ramipril is first blended with water and a stabilizing agent a particularly stable tablet is obtained, which is characterized by having a ramipril layer with a relatively low level of

(2S,3aS,6aS)-1 -[(S)-2-[[(S)-1 -carboxy-3- phenylpropyl]amino]propanoyl]octahydrocyclopenta-[b]pyrrole2-carboxylic acid (impurity E).

A further advantage of the invention is that the ramipril granulates containing a stabilizing agent show good flowability properties.

Another aspect of the invention relates the oral multilayer tablet comprising ramipril and indapamide as defined above, for use as a medicament.

Another aspect of the invention relates to the oral multilayer tablet comprising ramipril and indapamide as defined above, for use in the treatment of hypertension, particularly of hypertension in patients whose blood pressure is not adequately controlled on ramipril alone, in patients whose blood pressure is not adequately controlled on indapamide alone, or in patients whose blood pressure is not adequately controlled with ramipril alone followed by indapamide alone or vice versa. Thus, this aspect relates to the use of ramipril and indapamide for the manufacture of an oral multilayer tablet as defined above for the treatment of hypertension, particularly of hypertension in patients whose blood pressure is not adequately controlled on ramipril alone, in patients whose blood pressure is not adequately controlled on indapamide alone, or in patients whose blood pressure is not adequately controlled with ramipril alone followed by indapamide alone or vice versa; and may also be formulated as a method for the treatment of hypertension, particularly of hypertension in patients whose blood pressure is not adequately controlled on ramipril alone, in patients whose blood pressure is not adequately controlled on indapamide alone, or in patients whose blood pressure is not adequately controlled with ramipril alone followed by indapamide alone or vice versa, which comprises administering a therapeutically effective amount of the oral multilayer tablet comprising ramipril and indapamide as defined above in a subject in need thereof, including a human.

Detailed description of the invention

Unless stated otherwise herein, the percentages given within the scope of the present invention are always percent by weight.

The invention refers to an oral multilayer tablet as defined above comprising a first layer containing an indapamide compound and a second layer containing a ramipril compound, and, optionally, one or more additional layers either comprising or not a further active ingredient.

For the purposes of the invention, the term“multilayer tablet” refers to a tablet containing two or more layers that have been arranged in a stepwise manner and then compressed into a single dosage form. Each of the layers of the multilayer tablet of the invention comprises one active ingredient and pharmaceutically acceptable excipients. Particularly, the multilayer tablet is a bilayer tablet.

The multilayer tablets of the invention can be uncoated or film-coated.

Calculation of impurities D and E refer to the peak area in the chromatogram of standard solution (certified and independent standard).

The term indapamide compound encompasses indapamide, as well as any pharmaceutically acceptable salt thereof, and any stereoisomer or mixtures thereof, either of indapamide or of any of its pharmaceutically acceptable salts. Moreover, any solid forms of the indapamide compound, such as anhydrates, solvates, hydrates, crystalline and amorphous forms, are also encompassed by the present invention.

In an embodiment of the oral multilayer tablet of the invention, wherein the second layer has an impurity level of impurity E equal to or lower than 0.1%, particularly equal to or lower than 0.05%, after 6 months at 40 °C / 75% RH as measured by ultra performance liquid chromatography (UPLC). In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the second layer does not comprise any binder.

In another embodiment of the invention, optionally in combination with one or more features of the various embodiments described above or below, the indapamide compound is present in the first layer in an amount from 0.6 to 40%, more particularly from 0.7 to 10%, by weight with respect to the total weight of the first layer. More particularly, the indapamide compound is indapamide.

As used herein the term ramipril compound encompasses ramipril, as well as any pharmaceutically acceptable salt thereof, and any stereoisomer or mixtures thereof, either of ramipril or of any of its pharmaceutically acceptable salts. Moreover, any solid forms of the ramipril compound, such as anhydrates, solvates, hydrates, crystalline and amorphous forms, are also encompassed by the present invention.

In an embodiment of the invention, optionally in combination with one or more features of the various embodiments described above or below, the ramipril compound is present in the second layer in an amount from 1 to 20%, more particularly from 1 to 10%, and even more particularly, from 2 to 6% by weight with respect to the total weight of the second layer. More particularly, the ramipril compound is ramipril. As used herein, the term“pharmaceutically acceptable salt” refers to any non-toxic salt which can be used for therapeutic purposes. The preparation of pharmaceutically acceptable salts of the compounds of the invention can be carried out by methods known in the art. For instance, they can be prepared from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods.

Generally, such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate pharmaceutically acceptable base or acid in water or in an organic solvent or in a mixture of them. The base compounds and their salts may differ in some physical properties but they are equivalent for the purposes of the present invention.

Some ramipril and/or indapamide compounds of formula of the invention can have chiral centres that can give rise to various stereoisomers. As used herein, the term "stereoisomer" refers to all isomers of individual compounds that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), and isomers that are not mirror images of one another (diastereoisomers). The present invention relates to each of these stereoisomers and also mixtures thereof.

The multilayer tablets of present invention are intended for oral administration and provide for immediate release of the ramipril compound and sustained release of the indapamide compund when administered.

For the purposes of the invention, the term“immediate release” means that ramipril is released substantially immediately upon contact with gastric juices and results in substantially complete dissolution within about 45 minutes. In one embodiment, about equal or higher than 80% by weight of ramipril is completely dissolved after 45 minutes. By contrast, the term“sustained release” means that indapamide is released over a prolonged period of time. In this case dissolved amount of inadapamide, using USP I method, meets acceptance criteria:

In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the first layer comprises a sustained release-matrix former selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), ethyl cellulose (EC), methyl cellulose (MC), carboxymethyl cellulose (CMC), povidone, poly(meth)acrylates (such as Eudragit NE, Eudragit RS) or mixtures thereof. Particularly, the sustained release- matrix former is hydroxypropyl methylcellulose (HPMC). More particularly, the sustained release-matrix former is in an amount from 10 to 60% by weight with respect to the total weight of the first layer, particularly from 20 to 50%, even particularly from 30 to 40%.

In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the first layer, i.e. the indapamide layer, does not comprise a carbomer.

Surprisingly, the oral multilayer tablet of the present disclosure, does not present friability problems. Particularly, no delamination of the layers is produced.

As commented above, the second layer comprises a stabilizing agent. In an embodiment, optionally in combination with one or more features of the various embodiments described above or below, the stabilizing agent is present in the second layer in an amount from 1 to 20 wt%, more particularly from 1 to 10 wt%, such as of 1.25 wt%, 2.5 wt% or 5 wt%, with respect to the total weight of the second layer.

In a more particular embodiment, the stabilizing agent is selected from the group consisting of metal oxides, disodium edetate, tocopherol, cyclodextrins and derivatives, alkali or alkaline earth metal (particularly sodium, magnesium, and calcium) bicarbonates, carbonates, citrates and phosphates, and mixtures thereof. More particularly, the stabilizing agent is selected from the group consisting of alkali or alkaline earth metal (particularly sodium, magnesium, and calcium) bicarbonates, carbonates, and mixtures thereof. Even more particularly, the stabilizing agent is an alkali or alkaline earth metal bicarbonate, such as sodium hydrogen carbonate.

As mentioned above, the first and the second layer contain one or more

pharmaceutically acceptable excipients. Particularly, this one or more

pharmaceutically acceptable excipients may be selected from the group consisting of diluents, disintegrants, glidants, surfactants, colorants, and lubricants.

Examples of diluents include, without limitation, lactose; cellulose derivatives such as crystalline cellulose and powdered cellulose; carbonates and phosphates, such as calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate; sucrose; sugar alcohols such as mannitol, sorbitol, xylitol, and isomalt (Galen IQ (Beneo)); starches such as maize starch, potato starch, rice starch, wheat starch, pregelatinized starch; coprocessed lactose and celullose (Cellatose 80 (Meggle)), coprocessed lactose and microcrystalline cellulose (Microcelac (Meggle)), coprocessed starch and lactose (Starlac (Meggle)), coprocessed starch, lactose and microcrystalline cellulose (Combilac (Meggle)), coprocessed microcrystalline cellulose and silicon dioxide (prosolv (JRS)), and the like. Examples of disintegrants include, without limitation, carmellose calcium,

carboxymethylstarch sodium, croscarmellose sodium (cross-linked sodium

carboxymethylcellulose), crospovidone (crosslinked povidone), and low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium starch glycolate, colloidal silicon dioxide, dried corn starch, and the like.

Examples of glidants include, without limitation, talc, silica derivatives, such as colloidal silicon dioxide, and the like.

Examples of lubricants include, without limitation, magnesium stearate, stearic acid, sodium stearyl fumarate, zinc stearate, and the like.

Examples of surfactants include, without limitation, sodium lauryl sulfate, polysorbate 80, poloxamers, and the like.

Examples of solvents include, without limitation, water, lower alcohols like ethanol, and the like. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the first and/or second layer contain one or more diluents, in particular in an amount from 10 to 95%, more particularly from 30 to 90%, by weight with respect to the total weight of the corresponding layer. More particularly, the diluents are selected from lactose, maize starch, starch pregelatinized, microcrystalline cellulose, and a mixture thereof.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the second layer contains a disintegrant, in particular in an amount from 0.5 to 15%, more particularly from 1 to 8%, by weight with respect to the total weight of the second layer. Particularly, the disintegrant is croscarmellose sodium.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the first layer contains one or more glidants, in particular in an amount from 0.1 to 10%, more particularly from 0.2 to 5%, by weight with respect to the total weight of the first layer. Particularly, the glidants are selected from talc and colloidal silicon dioxide. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the first and/or second layer contain a lubricant, in particular in an amount from 0.1 to 10%, more particularly from 0.2 to 5%, by weight with respect to the total weight of the corresponding layer. Particularly, the lubricant is selected from magnesium stearate and sodium stearyl fumarate.

In an embodiment, optionally in combination with one or more features of the various embodiments described above or below, the second layer, i.e. the ramipril layer, comprises lactose as a diluent, particularly lactose monohydrate. This provides a better flowability of the ramipril granulate. Flowability of the granulate is particularly important to ensure uniform filling of the matrices during compression in the process for the manufacture of a multilayer tablet. More particularly, lactose monohydrate is spray dried lactose monohydrate, which provides a particularly good flowability.

Additionally, it is known that a multilayer tableting process is much more demanding than standard mono tableting. Thus, in a multilayer tableting process, particle size of a granulate can be important to assure good mass uniformity and uniformity of the manufactured dosage form unit.

Accordingly, in another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the ramipril layer is made of a ramipril granulate having a particle size wherein from about 60% to 90% are below 250 micrometers, particularly from about 65% to about 75%, such as about 70% of the particles are below 150 micrometers.

In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the oral multilayer tablet, in particular an uncoated multilayer tablet, comprises or consists of:

a) a first layer which comprises:

i) an indapamide compound, in particular indapamide, in an amount from 0.6 to 40%, particularly from 1 to 10%, by weight with respect to the total weight of the first layer;

ii) a sustained release-matrix former, in particular hydroxypropyl methyl cellulose (HPMC), in an amount from 10 to 60% by weight with respect to the total weight of the first layer;

iii) optionally a diluent, in particular lactose, in an amount from 10 to 95%, particularly from 30 to 90%, by weight with respect to the total weight of the first layer;

iv) optionally one or more glidants, in particular colloidal silicon dioxide, in an amount from 0.1 to 10%, particularly from 0.2 to 5%, by weight with respect to the total weight of the first layer; and

v) optionally a lubricant, in particular magnesium stearate, in an amount from 0.1 to 10%, particularly from 0.2 to 5%, by weight with respect to the total weight of the first layer;

b) a second layer which comprises:

i) a ramipril compound, particularly ramipril, in an amount from 1 to 20%, particularly from 1 to 10%, by weight with respect to the total weight of the second layer;

ii) a stabilizing agent, in particular an alkali or alkaline earth metal

bicarbonate, in an amount from 1 to 20%, particularly from 1 to 10%, by weight with respect to the total weight of the second layer;

iii) optionally one or more diluents, in particular lactose and maize starch, in an amount from 10 to 95%, particularly from 30 to 90%, by weight with respect to the total weight of the second layer;

iv) optionally a disintegrant, in particular croscarmellose sodium, in an amount from 0.5 to 15%, particularly from 1 to 8%, by weight with respect to the total weight of the second layer; and

v) optionally a lubricant, in particular sodium stearyl fumarate, in an amount from 0.1 to 10%, particularly from 0.2 to 5%, by weight with respect to the total weight of the second layer.

In another embodiment, in the second layer of the above embodiment, the glidant is other than colloidal silicon dioxide.

In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the second layer does not comprise any binder.

In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the oral multilayer tablet, in particular an uncoated oral multilayer tablet, consists of:

a) a first layer which consists of:

ii) a sustained release-matrix former, in particular hydroxypropyl

methylcellulose (HPMC), in an amount from 10 to 60% by weight with respect to the total weight of the first layer;

iii) a diluent, in particular lactose, in an amount from 10 to 95%, particularly from 30 to 90%, by weight with respect to the total weight of the first layer; iv) one or more glidants, in particular talc and colloidal silicon dioxide, in an amount from 0.1 to 10%, particularly from 0.2 to 5%, by weight with respect to the total weight of the first layer; and

v) a lubricant, in particular magnesium stearate, in an amount from 0.1 to 10%, particularly from 0.2 to 5%, by weight with respect to the total weight of the first layer;

b) a second layer which consists of:

ii) a stabilizing agent, in particular an alkali or alkaline earth metal

iii) one or more diluents, in particular lactose and maize starch, in an amount from 10 to 95%, particularly from 30 to 90%, by weight with respect to the total weight of the second layer;

iv) a disintegrant, in particular croscarmellose sodium, in an amount from 0.5 to 15%, particularly from 1 to 8%, by weight with respect to the total weight of the second layer; and

v) a lubricant, in particular sodium stearyl fumarate, in an amount from 0.1 to 10%, particularly from 0.2 to 5%, by weight with respect to the total weight of the second layer.

As used herein, the expression "pharmaceutically acceptable excipients" refers to pharmaceutically acceptable materials, compositions or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit/risk ratio.

The expression "therapeutically effective amount" as used herein, refers to the amount of ramipril and indapamide in the oral multilayer tablet as defined above that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease which is addressed. The particular dose of ramipril and indapamide in the oral multilayer tablet as defined above administered according to this invention will of course be determined by the particular circumstances surrounding the case, including the particular condition being treated, and other similar considerations.

It also forms part of the invention a process for the preparation of the oral multilayer tablet as defined above. As mentioned above, the process comprises the following steps:

a) providing a first layer composition by:

b) providing a second layer composition by:

wherein steps a), b), and c) can be carried out in any order; and wherein the second layer has an impurity level of (2S,3aS,6aS)-1-[(S)-2-[[(S)-1- carboxy-3-phenylpropyl]amino]propanoyl]octahydrocyclopenta-[b]pyrrole2-carboxylic acid (impurity E) equal to or lower than 1.0%, 0.1%, or 0.05% after 6 months at 40 °C / 75% RH as measured by ultra performance liquid chromatography (UPLC).

It is to be understood that in step d) the first and second layer compositions from step a) and step b) and, optionally, the one or more additional layer compositions of step c), can be compressed in any order. As an example, in a process for the preparation of a bilayered tablet, it is possible to have the ramipril layer tableted first and then tableting the indapamide layer on a bilayer machine, or to have the indapamide layer tableted first and then tableting the ramipril layer on a bilayer machine.

As an example, the water and the stabilizing agent can be in the form of an aqueous solution.

In a particular embodiment, drying in step iv) is performed untill loss on drying of the granulate is equal to or lower than 1.4%, particularly equal to or lower than 1.0, more particularly of 0.9, 0.8, 0.7, 0.6 or 0.5%.

Loss on drying can be determined by drying the granulate, particularly by heating at 80°C, using a dryer with a precision balance.

In an embodiment, after obtaining the mixture of step i) and before granulating it, one or more pharmaceutically aceptable excipients are added. Examples of

pharmaceutical aceptable excipients diluents, disintegrants, glidants, surfactants, colorants, and lubricants.

In an example, the one or more pharmarceutical aceptable excipients comprised in the second layer are one or more diluents and one or more disintegrants. More particularly, the one or more diluents are lactose and maize starch, particularly in an amount from 10 to 95%, more particularly from 30 to 90%, by weight with respect to the total weight of the second layer; and the one or more disintegrants is

croscarmellose sodium, particularly in an amount from 0.5 to 15%, more particularly from 1 to 8%, by weight with respect to the total weight of the second layer.

In an embodiment of the process of the invention, optionally in combination with one or more features of the various embodiments described above or below, the second layer does not comprise any binder.

In another example, the first layer comprises a lubricant and step a) of the process above comprises the following steps:

i') blending an indapamide compound with one or more pharmaceutically acceptable excipients, except the lubricant in order to obtain a mixture; and ii’) blending the mixture obtained in step i') with the lubricant.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the additional granulation liquid used for preparing the second layer is a (Ci-C4)alcohol, more particularly ethanol, particularly in a water:(Ci-C4)alcohol ratio of 1 :1 v/v or in a water:(Ci-C4)alcohol ratio of 2.1 :1 v/v. In a particular embodiment, the second layer contains a lubricant and step b) of the process above comprises the following steps:

i’) mixing a ramipril compound with water and a stabilizing agent, wherein water is a granulation liquid, in order to obtain a first mixture;

ii') mixing the mixture of step i) with one or more pharmaceutically acceptable excipients in order to obtain a second mixture;

iii’) granulating the second mixture of step ii’) by optionally adding a granulation liquid, preferably a (C1-C4) alcohol, in order to obtain granules; iv’) milling and drying the granules obtained in step iii’) in order to obtain a granulate; and

v’) blending the granules obtained in step iv’) with the lubricant.

Step d) may be carried out in a usual manner, e.g. a high-speed rotary press (i.e. Korsch XL400) in a multilayer tableting mode. With regard to the compression parameters to be used, the skilled expert will know how to determine them, in particular with respect to the suitable compression force to be applied, tableting speed, feeders speed, vaccum and the diameter punch. For instance, the first tablet layer may be compressed at a force of 0.1 to 5.0 kN, precompression of first plus second layer may be performed at a force of 0.1 to 15.0 kN, whereas the main compression of first plus second layer may be performed at a force of 5.0 to 25.0 kN. Generally, the diameter punch may be from 7-1 1 mm, more particularly 9 mm.

Generally, the ramipril-containing layer is placed onto the indapamide-containing layer). In one embodiment, the multilayer tablet thickness is from 4.2 to 6.3 mm. The present invention also relates to an oral multilayer tablet comprising:

a) a first layer comprising an indapamide compound, and one or more

pharmaceutically acceptable excipients; and

b) a second layer comprising a ramipril compound and a stabilizing agent; and wherein the ramipril compound is selected from ramipril, a pharmaceutically acceptable salt thereof, and a stereoisomer either of ramipril or of a pharmaceutically acceptable salt thereof; and the indapamide compound is selected from indapamide, a pharmaceutically acceptable salt thereof, and a stereoisomer either of indapamide or of a pharmaceutically acceptable salt thereof; and wherein the second layer has an impurity level of (2S,3aS,6aS)-1-[(S)-2-[[(S)-1-carboxy-3- phenylpropyl]amino]propanoyl]octahydrocyclopenta-[b]pyrrole2-carboxylic acid (impurity E) equal to or lower than 1.0% after 6 months at 40 °C / 75% RH as measured by ultra performance liquid chromatography (UPLC); and wherein the multilayer tablet is obtainable by the processes as previously described.

The expression "obtainable by” is used herein for defining the oral multilayer tablet of the invention by its preparation process. In particular, it refers to the multilayer tablet that can be obtained through the preparation process which comprises the steps of: a) providing a first layer composition by:

b) providing a second layer composition by:

iii) granulating the second mixture of step ii), optionally in the presence of an additional granulation liquid in order to obtain granules;

wherein steps a), b), and c) can be carried out in any order.

In a particular embodiment, drying in step iv) is performed untill loss on drying is equal to or lower than 1.4%, particularly of 1.0, 0.9, 0.8, 0.7, 0.6 or 0.5%.

As mentioned above, the present disclosure also relates to a the multilayer tablet comprising ramipril and indapamide as defined above for use in the treatment of hypertension, particularly:

- in patients whose blood pressure is not adequately controlled on ramipril alone.

- in patients whose blood pressure is not adequately controlled on indapamide alone

- in patients whose blood pressure is not adequately controlled on ramipril or

indapamide alone

- in patients whose blood pressure is adequately controlled with the individual products, given concurrently, but as separate tablets at the same dose level as in the combination.

- in treatment-naive patients which are expected to benefit from initiation of antihypertensive therapy using combination product.

In the context of the present disclosure, the expresion "is not adequately controlled on" a pharmaceutically active ingredient means that blood pressure remains above 140/90 mmHg despite use of the pharmaceutically active ingredient.

For the purposes of the present disclosure, the expressions“obtainable”,“obtained” and similar equivalent expressions are used interchangeably and, in any case, the expression“obtainable” encompasses the expression“obtained”.

Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word“comprise” encompasses the case of“consisting of”. The following examples are provided by way of illustration, and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.

Examples

Example 1. Preparation of bilaver tablets

Preparation of the first layer (Indapamide) - dry mixing

Indapamide was mixed with all the excipients except magnesium stearate. After that, magnesium stearate was screened and mixed with the rest of components. A blend ready for the tabletting process was obtained.

Preparation of the second layer (ramipril) - wet granulation

Ramipril, sodium hydrogen carbonate, lactose monohydrate, starch pregelatinised, croscarmellose sodium, and iron oxide yellow were weighed. All materials were screened apart from ramipril and sodium hydrogen carbonate.

Purified water and sodium hydrogen carbonate were added to high-shear granulator and mixed. Then, ramipril was added to high-shear granulator and mixed. Lactose monohydrate, starch pregelatinised, croscarmellose sodium, iron oxide yellow were added to the high-shear granulator and mixed. Granulation is performed after adding ethanol anhydrous. Subsequently, wet milling was performed. The milled granulate was dried in a fluid bed dryer until loss on drying was less than 1.4%. The dry granulate was milled. Sodium stearyl fumarate was screened and added to the granulate and the whole mass was mixed. A mixture ready for the tabletting process was obtained.

Preparation of a bilaver tablet - compression

Both layers as previously obtained were tabletted using a bilayer tableting machine (ramipril layer was placed onto the indapamide layer). Tablets were manufactured using a bilayer, rotary tablet press (Korsch XL400 MFP) equipped with 9 mm, biconvex punches to achieve proper friability (below 1 %, prefered below 0.4%) and tablet hardeness of about 80N. Process parameters are described below:

rotation speed - 15RPM, main compression force - 10kN,

tapping force - 1500N

precompression force - 3kN A bilayer tablet was obtained with each one of the following compositions: Example 1a (1.5 mg indapamide / 5 mg ramipril)

Example 1 b (1.5 mg indapamide / 10 mg ramipril)

Examples 1c, 1d and 1e

Comparative Example 1 The indapamide-containing layer was prepared as in example 1.

The ramipril-containg layer was obtained by wet granulation. Ramipril and all excipients (except stearyl fumarate) were placed into a high shear granulator. The mixture was granulated with water and dried in a fluid bed. After dry screening the blend, it was mixed with stearyl fumarate and croscarmellose sodium. A mixture ready for the tabletting process was obtained.

The preparation of the bilayer tablet was carried out as in example 1. Example 2. Stability

Detection of impurities was performed using a Ultra Performance Liquid

Chromatography (UPLC) aparatus with UV-VIS detection. Analysis was performed using gradient elution (acetonitrile-triethylamine in water (1 mL/L)) with Waters Acquity UPLC BEH C18 column. Detection was performed at 206 nm.

Examples 2.1 and 2.4 are bilayer tablets made with compositions of Example 1c Examples 2.2 and 2.3 are bilayer tablets made with compositions of Example 1d Their stability was evaluated on samples placed in stability chambers. Results after 6 or 18 months at 25°C/60%RH and at 40°C/75%RH are summarized in Table 1 to 4 below.

Table 1 - Example 2.1

NT: not tested

BLOQ: below limit of quantification, namely below 0.05 %

Table 2 - Example 2.2

NT : not tested

BLOQ: below limit of quantification, namely below 0.05 % Table 3 - Example 2.3

NT : not tested

BLOQ: below limit of quantification, namely below 0.05 %

Table 4 - Example 2.4

NT : not tested

BLOQ: below limit of quantification, namely below 0.05 % As can be observed from the Examples 2.1 to 2.4 impurity E was below limit of quantification (BLOQ), namely below 0.05 %, even after 18 months. Additionally, after 6 months, or even after 18 months, at 25°C/60% RH, impurity D was maintained considerably low. Thus, the oral multilayer tablets above are stable, showing particularly low levels of impurities. More particularly, they show very reduced levels of the ramipril impurity E in comparison to the ramipril tablet of the prior art (see comparative example in WO2013/121233).

Example 3. Friability

Friability of the tablet of Example 1 c was assessed.

Friability test was performed according to Ph. Eur. method. Friability is the % of weight loss of tablets caused by mechanical action during the test. Tablets are weighed before test and after testing. Friability is expressed as a percentage loss on pre test tablet weight.

Results of core physical results for the tablet of Example 1 b are shown in Table 5 below:

Table 5

Composition of indapamide with hypromellose did not present friability or delamination problems. Low friability was observed in the whole hardness range tested. Example 4. Flowability

Flowability of the granulate is particularly important to ensure uniform filling of the matrices during compression in the process for the manufacture of a bilayer tablet. Two ramipril granulates were prepared using the following two types of lactose monohydrate as diluent:

a) milled lactose monohydrate (Type M200) - used for granulate A;

b) spray dried lactose monohydrate (Flowlac 100) - used for granulate B. The granulates were prepared according to the composition shown in Table 6.

Table 6

The ramipril granulate was manufactured as described in Example 1 d.

In Table 7 below the physical parameters of granulates are shown.

Table 7

Ramipril granules comprising spray dried lactose monohydrate were characterized with a much better flowability than ramipril granules comprising milled lactose monohydrate. Granulate composed of spray dried lactose contained less fine particles (having a particle size wherein about 30% of the particles were below 75 pm). Particularly, granulate comprising spray dried lactose monohydrate flew through a 10 mm nozzle during the test, whereas granulate comprising milled lactose monohydrate did not. Example 5. Particle size of ramipril granulate

A ramipril granulate having a particle size wherein about 70% of the particles were below 150 micrometers was prepared acording to Example 4, granulate A. The details are shown in Table 8 below.

The obtained granulate allowed providing a bilayer tablet with a ramipril layer having a good mass uniformity.

References cited in the application

- WO2013/121233

- Ramipril monograph of the European Pharmacopoeia 8.0

- W02007/120930

- W02007/142546

- W02008/124611

- WO2013050339

Claims

1. An oral multilayer tablet comprising:

a) a first layer comprising an indapamide compound, and one or more

pharmaceutically acceptable excipients; and

b) a second layer comprising a ramipril compound and a stabilizing agent;

wherein the ramipril compound is selected from ramipril, a pharmaceutically acceptable salt thereof, and a stereoisomer either of ramipril or of a pharmaceutically acceptable salt thereof; and the indapamide compound is selected from indapamide, a pharmaceutically acceptable salt thereof, and a stereoisomer either of indapamide or of a pharmaceutically acceptable salt thereof; and

2. The oral multilayer tablet according to claim 1 , wherein the impurity E is equal to or lower than 0.05% after 6 months at 40 °C / 75% RH as measured by ultra

performance liquid chromatography (UPLC).

3. The oral multilayer tablet according to claims 1 or 2, which provides for immediate release of the ramipril compound and sustained release of the indapamide compound when administered.

4. The oral multilayer tablet according to any of the claims 1 to 3, wherein the first layer comprises the indapamide compound in an amount from 0.6 to 40% by weight with respect to the total weight of the first layer, and the second layer comprises the ramipril compound in an amount from 1 to 20% by weight with respect to the total weight of the second layer.

5. The oral multilayer tablet according to any of the claims 1 to 4, wherein the indapamide compound is indapamide and the ramipril compound is ramipril.

6. The oral multilayer tablet according to any of the claims 1 to 5, wherein the first layer comprises a sustained release-matrix former selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, povidone, a poly(meth)acrylate, and mixtures thereof, and wherein the sustained release-matrix former is in an amount from 10 to 60% by weight with respect to the total weight of the first layer.

7. The oral multilayer tablet according to claim 6, wherein the sustained release- matrix former is hydroxypropyl methylcellulose.

8. The oral multilayer tablet according to any of the claims 1 to 7, wherein the second layer comprises the stabilizing agent in an amount from 1 to 20% by weight with respect to the total weight of the second layer.

9. The oral multilayer tablet according to claims 1 or 2, comprising:

a) a first layer which comprises:

i) an indapamide compound in an amount from 0.6 to 40% by weight with respect to the total weight of the first layer;

iii) a sustained release-matrix former in an amount from 10 to 60% by weight with respect to the total weight of the first layer;

iv) optionally a diluent in an amount from 10 to 95% by weight with respect to the total weight of the first layer;

v) optionally one or more glidants, in particular talc and colloidal silicon dioxide, in an amount from 0.1 to 10% by weight with respect to the total weight of the first layer; and

vi) optionally a lubricant, in particular magnesium stearate, in an amount from 0.1 to 10% by weight with respect to the total weight of the first layer;

b) a second layer which comprises:

i) a ramipril compound in an amount from 1 to 20% by weight with respect to the total weight of the second layer;

ii) a stabilizing agent in an amount from 1 to 20% by weight with respect to the total weight of the second layer;

iii) optionally one or more diluents in an amount from 10 to 95% by weight with respect to the total weight of the second layer;

iv) optionally a disintegrant in an amount from 0.5 to 15% by weight with respect to the total weight of the second layer; and

v) optionally a lubricant in an amount from 0.1 to 10% by weight with respect to the total weight of the second layer.

10. Process for the preparation of the oral multilayer tablet as defined in claims 1 or 2, which comprises the following steps:

a) providing a first layer composition by:

b) providing a second layer composition by:

wherein steps a), b), and c) can be carried out in any order; and

1 1. The process according to claim 10, wherein the additional granulation liquid is a (Ci-C4)alcohol.

12. The process according to claims 10 or 11 , wherein drying in step iv) is performed untill loss on drying of the granulate is equal to or lower than 1.4%.

13. The process according to claim 12, wherein loss on drying of the granulate is equal to or lower than 1.0%.

14. An oral multilayer tablet as defined in any of the claims 1 to 9, for use in the treatment of hypertension.

15. The oral multilayer tablet according to claim 14, for use in the treatment of hypertension in patients whose blood pressure is not adequately controlled on ramipril alone, in patients whose blood pressure is not adequately controlled on indapamide alone, or in patients whose blood pressure is not adequately controlled with ramipril alone followed by indapamide alone or vice versa.