EA025946B1 - Multilayer pharmaceutical composition comprising telmisartan and amlodipine - Google Patents

Abstract

The invention relates to a solid pharmaceutical dosage form comprising at least a first portion comprising telmisartan or a pharmaceutically acceptable salt thereof, and at least a second portion comprising amlodipine or a pharmaceutically acceptable salt thereof, and at least one non-hygroscopic pharmaceutically acceptable excipient having an equilibrium moisture content of 6 wt.% or less as determined by dynamic vapor sorption (DVS) at a relative humidity of 60% and a temperature of 25°C and selected from the group of fillers consisting of glucose, fructose, saccharose, raffinose, trehalose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitol, lactitol, calcium hydrogen phosphate, calcium carbonate, calcium lactate and mixtures thereof, wherein the second portion comprises less than 2 wt.% by weight of the second portion of a disintegrant. The invention also relates to a process for the preparation of said dosage form. The dosage form by the invention exhibits high chemical and physical stability, it can be prepared from inexpensive excipients and can be manufactured using a simple and economical process.

Description

The invention relates to a solid pharmaceutical composition comprising telmisartan or a pharmaceutically acceptable derivative thereof and at least one calcium channel blocker.

More specifically, the invention discloses a pharmaceutical composition comprising a first part containing telmisartan and a second part containing amlodipine. The amlodipine part further comprises at least one non-hygroscopic filler and / or at least one non-hygroscopic binder that does not exhibit a loosening effect, and / or at least one hydrophilic lubricant, where this second part does not exhibit a loosening effect.

State of the art

Telmisartan, whose chemical name is 2- (4 - {[4-methyl-6- (1-methylbenzimidazol-2yl) -2-propylbenzimidazol-1-yl] methyl} phenyl) benzoic acid, is an antagonist of the angiotensin II receptor, useful for the treatment of hypertension, which was first disclosed in EP 0502314A1. Telmisartan is commercially available, in particular in the form of its free acid, which is slightly soluble in neutral or acidic environments. Therefore, a telmisartan preparation is typically prepared together with a basic agent or in the form of a basic salt for improved solubility.

Calcium channel blockers, such as amlodipine, nifedipine, nimodipine, nilvadipine, manidipine, barnidipine, nitrendipine, benidipine, nicardipine, lercanidipine, nizoldipine, efonidipine, cilnidipine, qelidipodipin contractions and therefore result in reduced peripheral vascular resistance and reduced blood pressure.

Amlodipine, whose chemical name is 3-ethyl-5-methyl-2 - [(2-aminoethoxy) methyl] -4 (2-chlorophenyl) -6-methyl-1,4-dihydropyridine-3,5-dicarboxylate, is long-acting calcium channel blocker (dihydropyridine class), used as an antihypertensive and in the treatment of angina pectoris, which was first disclosed in EP 0089167 A1. Amlodipine is commercially available in the form of a salt of maleate, besylate or mesylate. It is known that amlodipine and / or its pharmaceutically acceptable salts are prone to hydrolysis under the influence of an alkaline medium.

Discovery of the study described authors 5> 1apschsg c1 a1., I S1sh Ragshaeo1 2000, 40, 1347-1354, show that telmisartan and amlodipine can be administered concomitantly, as clinically significant variation in the primary pharmacokinetic parameters of amlodipine in the presence of telmisartan is absent, and safety is comparable with one for amlodipine.

In order to solve the problem consisting in the fact that amlodipine is prone to hydrolysis by alkaline agents, which are usually used together with the free acid form of telmisartan, various approaches have been developed. One approach is to include each incompatible substance individually in separate forms in the preparation, which are then included in the preparation together in the same dosage form. The purpose of this approach is to minimize interactions between substances and to improve the stability and release rate of the final combined preparation. According to one aspect, two compositions are provided in physically separated forms selected from the group consisting of powders, granules, pills, beads, mini-tablets and tablets, and the like. Another approach is to coat particles that readily disintegrate with water-soluble polymers. Another other approach is to place each incompatible substance in a specific layer, while the layers can be further separated by an inert intermediate layer.

The document \ νϋ 2006/048208 addresses the stability problem caused by the incompatibility of amlodipine with the main components of the telmisartan preparation by preparing a two-layer pharmaceutical tablet containing the first layer of telmisartan, essentially in an amorphous form in the soluble matrix of the tablet and the second layer of amlodipine in a disintegrating or eroding matrix tablets. As used herein, the term “soluble tablet matrix” refers to a pharmaceutical tablet base composition having quick release (quick dissolving) characteristics that dissolves readily in a physiological aqueous medium, and the term loosening or eroding tablet matrix refers to a pharmaceutical tablet base composition having quick release characteristics, which easily loosens or erodes in a physiological aqueous medium. The soluble matrix of the tablet has been described to have neutral or basic properties, with the basic matrix of the tablet being preferred. It contains a basic agent, a water-soluble diluent, and possibly other excipients and adjuvants. The following disintegrating agents are listed as preferred disintegrants used to prepare a loosening or eroding tablet matrix: croscarmellose sodium salt (cross-linked croscarmellose sodium), starch glycolate sodium, crospovidrosyl-vinyl-vinyl-vinyl-vinyl-vinyl-vinyl-vinylacetamide) cellulose. Starch glycolate sodium and crospovidone are particularly preferred.

νθ 2007/001067 relates to a solid dosage form containing an antagonist of the anti-1 025946 hyotensin II receptor, such as, but not limited to, telmisartan, and a calcium channel blocker, such as, inter alia, amlodipine, where the active ingredients are not closely mixed in this dosage form. This application discloses a two-layer tablet containing olmesartan medoxomil and amlodipine mesylate, both of which are present in a loosening matrix.

In композиция 2008/146178, a pharmaceutical composition is disclosed comprising a telmisartan mixture layer having a loosening matrix and amlodipine tablets having a loosening matrix, where these amlodipine tablets are included in a layer of inert excipients, also representing a loosening matrix.

In prior art pharmaceutical compositions, fixed-dose complex preparations of telmisartan and amlodipine are necessary to solve the incompatibility of these active agents and to stabilize the compositions. These complex preparations require the use of sufficient quantities of expensive special excipients. In addition, complex and expensive processing steps, such as wet granulation, are involved in the preparation of these preparations.

Thus, it is an object of the present invention to provide a pharmaceutical composition containing telmisartan or its pharmaceutically acceptable salts and amlodipine or its pharmaceutically acceptable salts in a fixed dose form, avoiding the disadvantages discussed above, and which not only exhibits high chemical and physical stability, but also an appropriate dissolution profile and bioavailability, but which can, in addition, be obtained from inexpensive excipients, and can be made using simple and economical process.

This goal was unexpectedly achieved by a pharmaceutical composition containing telmisartan or its pharmaceutically acceptable salts and amlodipine or its pharmaceutically acceptable salts, described in this work below. In particular, the pharmaceutical composition contains telmisartan or its pharmaceutically acceptable salts and amlodipine or its pharmaceutically acceptable salts present in various parts of this pharmaceutical composition, and at least one non-hygroscopic excipient and / or at least one non-hygroscopic binder that does not exhibit disintegrating effect, and / or at least one hydrophilic lubricant, wherein the amlodipine moiety does not exhibit a loosening effect. More specifically, telmisartan or its pharmaceutically acceptable salts and amlodipine or its pharmaceutically acceptable salts present in various parts of this pharmaceutical composition are separated by layers, coatings and / or dosage units. Even more specifically, the pharmaceutical composition of the present invention can be prepared in the form of a tablet containing at least two layers, either in the form of telmisartan tablets coated with amlodipine or its pharmaceutically acceptable salts, or in the form of a capsule containing at least one dosage unit containing telmisartan or its pharmaceutically acceptable salts, and at least one dosage unit containing amlodipine or its pharmaceutically acceptable salts. The invention also relates to a method for producing said pharmaceutical composition comprising telmisartan or a pharmaceutically acceptable salt thereof and amlodipine or a pharmaceutically acceptable salt thereof in a fixed dose form.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a solid pharmaceutical composition comprising (a) at least one first portion containing telmisartan or a pharmaceutically acceptable salt thereof; and (b) at least one second part comprising amlodipine or a pharmaceutically acceptable salt thereof and at least one non-hygroscopic excipient and / or at least one hydrophilic lubricant.

Preferably, the non-hygroscopic excipient is selected from non-hygroscopic fillers and / or non-hygroscopic binders. In addition, at least one non-hygroscopic excipient preferably does not exhibit any disintegrating effect, that is, the second part of the composition readily dissolves in a physiological aqueous medium, but does not loosen or erode in such a medium. In particular, the second part contains less than 2 wt.%, In particular less than 1 wt.%, More preferably less than 0.5 wt.%, Most preferably less than 0.1 wt.% Baking powder, as defined in this work below, based on mass of the second part.

Thus, in a first aspect, the present invention relates to a pharmaceutical composition comprising telmisartan or its pharmaceutically acceptable salts, present in one part, and amlodipine or its pharmaceutically acceptable salts and at least one non-hygroscopic excipient and / or at least one non-hygroscopic binder which does not exhibit a loosening effect, and / or at least one hydrophilic lubricant, present in another part of the pharmaceutical composition, wherein lodipinovaya part does not show a disintegrating effect.

The term part according to the present invention means that both active ingredients are not in close contact, and that they are separated from each other, for example, by means of layers, coatings and / or dosage units. Thus, as used in this work, the term part refers to

- 2,025,946 physical parts of a solid pharmaceutical composition, wherein the components of said part are not closely mixed with the components of another part or element of the composition. In particular, the interaction between the components of one part and the components of the other part is reduced, for example, by physically separating the first part of the composition from the second part of the composition, for example, by providing the first part of the composition and the second part of the composition in different tablet layers or dosage units and / or by providing a separation layer.

In contrast to the idea of the prior art, it has now been unexpectedly discovered that when at least one non-hygroscopic excipient and, in particular, at least one non-hygroscopic filler and / or at least one non-hygroscopic binder that does not exhibit a disintegrating effect, and / or at least one hydrophilic lubricant is present in a part containing amlodipine or its pharmaceutically acceptable salts, where said part does not exhibit a disintegrating effect, can be achieved similar to the release of amlodipine or its pharmaceutically acceptable salts compared to known standard preparations containing disintegrant (s) and / or hydrophobic lubricant (s) in the amlodipine part. In particular, it was found that the composition exhibits a dissolution profile comparable to that typically found for tablets containing telmisartan in the dissolving portion and amlodipine in the disintegrating portion.

In addition, it was unexpectedly discovered that due to the specific composition of the second part of the solid pharmaceutical composition, the stability of amlodipine can be increased, and the amount of decomposition products of amlodipine resulting from hydrolysis during storage of the composition is reduced.

Particularly preferably, the solid pharmaceutical composition according to the invention includes (a) at least one first portion containing telmisartan or a pharmaceutically acceptable salt thereof; and (b) at least one second portion comprising amlodipine or a pharmaceutically acceptable salt thereof and at least one non-hygroscopic excipient.

As used in this work, the term non-hygroscopic refers to a substance that has a low ability to absorb and retain water. More specifically, the term non-hygroscopic refers to a substance that has an equilibrium moisture content of about 6% (wt.%) Or less, as determined by dynamic vapor sorption (DSP) at a relative humidity of 60% and a temperature of 25 ° C. In particular, the equilibrium humidity is determined on the basis of the isothermal sorption curve measured by particleboard at a relative humidity of 60% and a temperature of 25 ° C.

It is also particularly preferred that, in addition to at least one non-hygroscopic excipient, the second part of the composition further comprises at least one hydrophilic lubricant.

As noted above, the non-hygroscopic excipient is preferably selected from the group consisting of non-hygroscopic fillers, non-hygroscopic binders and mixtures thereof.

In addition, it is preferable that the combined mass of amlodipine or its pharmaceutically acceptable salt and non-hygroscopic excipient or the combined mass of amlodipine or its pharmaceutically acceptable salt, non-hygroscopic excipient and hydrophilic lubricant, if present, is at least 50 wt.%, Preferably at least at least 85 wt.%, more preferably at least 93 wt.%, such as at least 95 wt.% or at least 97 wt.%, such as at least 98 wt.%, and most pre preferably at least 99 wt.% by weight of the second part. In one embodiment, the second part of the composition essentially consists of amlodipine or a pharmaceutically acceptable salt thereof and at least one non-hygroscopic excipient. In another embodiment, the second part of the composition essentially consists of amlodipine or a pharmaceutically acceptable salt thereof, at least one non-hygroscopic excipient and at least one hydrophilic lubricant.

Preferably, the second part of the composition of the invention contains less than 2 wt.%, Preferably less than 1 wt.%, More preferably less than 0.5 wt.%, Most preferably less than 0.1 wt.% Of disintegrant based on the weight of the second part. According to a particularly preferred embodiment, the second part essentially does not contain a baking powder.

The term baking powder, as used in this work, refers to any substance that has the properties of absorption and / or swelling when it comes into contact with water. In particular, the term disintegrant refers to a group of compounds consisting of croscarmellose sodium, starch glycolate sodium, crospovidone, corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose and microcrystalline cellulose. In particular, the term disintegrant refers to a group of compounds consisting of crospovidone, pregelatinized starch, sodium starch glycolate, hydroxypropyl starch, sodium and calcium salt of carboxymethyl cellulose, sodium salt of crosslinked carboxymethyl cellulose, sodium polyvinyl acetate, sodium acetate , agar, guar gum, chitosan and alginic acid. More specifically, the term “disintegrant” refers to a group of compounds consisting of povidone, crospovidone, starch, pregelatinized starch, sodium starch glycolate, hydroxypropyl starch, microcrystalline cellulose, sodium carboxymethyl cellulose nitroxycellulose cellulose, sodium carboxymethyl cellulose nitrocellulose, sodium and calcium salt of carboxymethyl cellulose cellulose; , sodium alginate and calcium, docusate sodium, methyl cellulose, agar, guar gum, chitosan and alginic acid.

Bilayer tablets according to the prior art tend to be slightly hygroscopic and, therefore, are preferably packaged using moisture-resistant packaging material, such as aluminum foil blister packs or polypropylene tubes and bottles of HDPE (high density polyethylene), which preferably contain a desiccant. It has been found that disintegrants are hygroscopic or even very hygroscopic in nature. Typically, disintegrants may contain 5% by weight of water or more. At the same time, since amlodipine is sensitive to hydrolysis, it was found that it is useful to obtain a pharmaceutical preparation that contains substantial amounts or essentially consists of substances containing as little water as possible. In other words, it was found that it is useful to obtain a pharmaceutical composition containing amlodipine, where this composition is free from baking powder and, in addition, dissolves the active ingredient very quickly. If non-hygroscopic materials are used, there is no possibility that water will enter the preparation and jeopardize the stability of amlodipine.

In one embodiment, the composition of the invention is in the form of a multilayer tablet, wherein at least one first part is at least one first tablet layer and at least one second part is at least one second tablet layer.

As used in this work, the term multilayer tablet refers to a pharmaceutical tablet, which consists of at least two separate layers, such as at least two layers, at least three layers, at least four layers, at least five layers, etc., where the individual layers are located one on top of the other. A multilayer tablet typically has a sandwich-like appearance since the edges of each layer are bare. In a typical case, adjoining tablet layers have a different composition. It is understood that the terms first tablet layer and second tablet layer, as used in this work, refer to tablet layers having a specific composition. However, these terms do not necessarily reflect the order in which these layers are arranged in a tablet.

In another embodiment, the composition of the invention is in the form of a coated tablet, wherein at least one first part is a tablet and at least one second part is at least one coating on said tablet.

A multilayer or coated tablet of the invention may further comprise at least one release coating.

In the case of a multilayer tablet, such as a two-layer tablet, the separating coating is located between at least one first layer of the tablet and at least one second layer of the tablet. In the case of a coated tablet, the separating coating is an insulating or intermediate coating located between the tablet representing the first part and the coating representing at least one second part. The separation layer may contain a pharmaceutically acceptable excipient, such as a polymer excipient, and, in particular, selected from the group consisting of povidone and cellulose derivatives, such as hydroxypropyl methylcellulose.

In another embodiment, the composition of the invention is in the form of a capsule containing at least one first part in the form of a first dosage unit and at least one second part in the form of a second dosage unit. As used in this work, the term dosage unit refers to tablets, microtablets, pills, powder forms, granules and granules. Therefore, the first and second dosage units are independently selected from the group consisting of tablets, microtablets, pills, powder forms, granules and granules.

The above embodiments, which are a multilayer tablet, a coated tablet, and also a capsule, can be characterized by the same features as disclosed in connection with the general embodiment of the composition of the invention, that is, a composition comprising at least one first portion containing telmisartan or a pharmaceutically acceptable salt thereof and at least one second portion comprising amlodipine or a pharmaceutically acceptable salt thereof and at least one non-hygroscopic excipient.

For example, in one aspect, the present invention relates to a pharmaceutical composition in the form of a tablet, comprising

a) at least one layer containing telmisartan or a pharmaceutically acceptable salt thereof,

b) optionally at least one separating layer containing any pharmaceutically acceptable excipient, and

c) at least one layer containing:

- 4,025,946 c1) amlodipine or a pharmaceutically acceptable salt thereof and c2) at least one non-hygroscopic excipient and / or at least one non-hygroscopic binder that does not exhibit a disintegrating effect, and / or at least one non-hydrophobic lubricant, where said layer does not exhibit a loosening effect.

In another aspect, the present invention relates to a pharmaceutical composition in the form of a tablet, comprising

a) at least one layer containing from 1 to 50 wt.% telmisartan or its pharmaceutically acceptable salt by weight of the specified layer

b) optionally at least one separating layer containing any pharmaceutically acceptable excipient, and

c) at least one layer containing:

c1) from 1 to 50% by weight of amlodipine or a pharmaceutically acceptable salt thereof by weight of said layer; and c2) from 1 to 99% by weight of at least one non-hygroxopic excipient and / or from 1 to 99% by weight of at least one non-hygroscopic a binder that does not exhibit a loosening effect, and / or from 1 to 99 wt.% at least one non-hydrophobic lubricant from the mass of the specified layer, where the specified layer does not exhibit a loosening effect.

In another aspect, the present invention relates to a pharmaceutical composition in the form of a coated tablet, comprising:

a) a telmisartan portion containing:

telmisartan or a pharmaceutically acceptable salt thereof, compressed into a tablet, wherein said tablet is coated

b) optionally at least one release coat containing any pharmaceutically acceptable excipient, and

c) an amlodipine moiety containing:

c1) amlodipine or its pharmaceutically acceptable salts and c2) at least one non-hygroscopic filler and / or at least one non-hygroscopic binder that does not exhibit a loosening effect, and / or at least one non-hydrophobic lubricant, where the specified amlodipine part does not show a loosening effect.

In another aspect, the present invention relates to a pharmaceutical composition in the form of a coated tablet, comprising:

a) a telmisartan portion containing:

from 1 to 50 wt.% telmisartan or its pharmaceutically acceptable salts, based on the weight of said portion, compressed into a tablet, wherein said tablet is coated

b) optionally at least one release coat containing any pharmaceutically acceptable excipient, and

c) an amlodipine moiety containing:

c1) from 1 to 90% by weight of amlodipine or a pharmaceutically acceptable salt thereof, by weight of said portion; c2) from 1 to 99% by weight of at least one non-hygroxopic excipient and / or from 1 to 99% by weight of at least one non-hygroscopic binder a substance that does not exhibit a loosening effect, and / or from 1 to 99 wt.% at least one non-hydrophobic lubricant, based on the weight of the specified part, where the specified amlodipine layer does not exhibit a loosening effect.

In another aspect, the present invention relates to a pharmaceutical composition in the form of a capsule, comprising:

a) at least one dosage unit containing telmisartan or its pharmaceutically acceptable salts, and

b) at least one dosage unit containing: b1) amlodipine or its pharmaceutically acceptable salts and

B2) at least one non-hygroscopic filler and / or at least one non-hygroscopic binder that does not exhibit a loosening effect, and / or at least one non-hydrophobic lubricant, where the dosage unit does not exhibit a loosening effect.

In another aspect, the present invention relates to a pharmaceutical composition in the form of a capsule, comprising:

B) at least one dosage unit containing from 1 to 50% by weight of telmisartan or its pharmaceutically acceptable salts by weight of said dosage unit; and

B) at least one dosage unit containing:

B1) from 1 to 90% by weight of amlodipine or its pharmaceutically acceptable salts, based on the weight of said dosage unit; and

B2) from 1 to 99 wt.% At least one non-hygroxopic filler and / or from 1 to 99

- 5,025,946% by weight of at least one non-hygroscopic binder that does not exhibit a loosening effect, and / or from 1 to 99% by weight of at least one hydrophilic lubricant, based on the weight of the indicated dosage unit, where the indicated amlodipine dosage unit does not exhibit loosening effect.

The term dosage unit refers to tablets, microtablets, pills or powder form, which do not include a tablet containing layers, and coated tablets, as defined above.

The following description of preferred embodiments of the composition of the invention is intended to apply to the general embodiment of the composition described above, which is characterized by the presence of at least one first part and at least one second part, as well as to the above described embodiments, which are a multilayer tablet, coated tablet and capsule .

The first part of the composition of the invention, such as the first tablet layer, contains telmisartan or a pharmaceutically acceptable salt thereof. Telmisartan is typically used in the form of its free acid, although pharmaceutically acceptable salts may also be used. The telmisartan-containing part preferably contains from 1 to 50% by weight, in particular from 5 to 35% by weight, more preferably from 10 to 20% by weight of telmisartan or a pharmaceutically acceptable salt thereof, based on the weight of said first part.

According to one embodiment, the first part of the pharmaceutical composition of the present invention contains telmisartan and a basic agent. The term basic agent, as used in this work, refers to a substance that is characterized in that 3 wt.% Of its aqueous solution has a pH value of at least 8.0. Suitable basic agents include ammonia, ΝαΟΗ, KOH, Ca (OH) ₂ , No.-1 ₂ CO ₃ . K ₂ CO _3, YaNSO _3, KHCO _3, Να ₃ ΡΟ. ₁ . K ₃ PO ₄ , Na ₂ NRO ₄ , K ₂ NRO ₄ , choline, tert-butylamine, ethanolamine, meglumine, piperazine, diethylamine, L-arginine, and mixtures thereof.

Alkali metal hydroxides, such as NaOH and KOH, amino sugars, such as meglumine, and mixtures thereof are preferred basic agents. It is particularly preferred that the main agent comprise a mixture of an alkali metal hydroxide such as NaOH or KOH and an amino sugar such as meglumine in a weight ratio of from 1: 1 to 1:10, more specifically from 1: 2 to 1: 5, more preferably from 1: 3 to 1: 4, most preferably about 1: 3.5. The first part containing telmisartan preferably contains from 0.25 to 20 wt.%, In particular from 1 to 15 wt.%, More preferably from 2 to 10 wt.% Of the main agent.

Telmisartan may be amorphous or crystalline. As used in this work, the term amorphous includes amorphous and partially crystallized forms. Amorphous telmisartan can be obtained by methods well known in the art, such as lyophilization of aqueous solutions, coating particles of a carrier in a fluidized bed, and precipitating the solvent on sugar granules or other carriers.

According to another embodiment, the pharmaceutical composition of the present invention contains a pharmaceutically acceptable salt of telmisartan. Suitable pharmaceutically acceptable salts include alkaline salts such as telmisartan sodium. The pharmaceutically acceptable salt of telmisartan may be amorphous or crystalline.

Telmisartan or its pharmaceutically acceptable salts can be obtained by any method known in the art, as, for example, disclosed in documents EP 0502314 A1, EP 1173407 B1, 1. Mei. Oh. 1993, 36, 4051, СЫ 1182122, СЫ 1204124, JSC 2004/087676, СЫ 1548421, JSC 2005/108375, JSC 2006/044648, JSC 2006/044754, JSC 2006/050921, JSC 2006/067215, I8 2006/211866, I8 7692027, AO 2007/010558, I8 2006/0264491, AO 2007/147889, СЫ 101983962, ΙΝ 2008MI02449, AO 101024631, AO 2009/004064, AO 2009/116089, AO 2009/115585, AO 2009/123483, EP 2123648 A AO 2010/004385, AO 2010/018441, AO 2010/146187 or AO 2010/149565.

In addition, telmisartan or its pharmaceutically acceptable salts may be in any known stable polymorphic forms known in the art, such as, for example, disclosed in documents EP 1144386, EP 1442023, AO 2006/050509, I8 2006/111417, ΙΝ 2005MI00164, I8 2006/0276525 or AO 2009/006860.

The first part, such as the first layer of a tablet, of the pharmaceutical composition of the present invention may contain pharmaceutically acceptable excipients. The term pharmaceutically acceptable excipient, as used in this work, refers to additives useful for converting pharmaceutically active compounds into pharmaceutical dosage forms that are suitable for administration to patients. Excipients suitable for use in the first part may include fillers, binders, surfactants, crystallization inhibitors, lubricants, glidants, and colorants. Other pharmaceutically acceptable excipients may also be included.

The first part containing telmisartan, typically contains at least one filler. In general, water soluble excipients are preferred. Suitable excipients for use in the portion containing telmisartan may include monosaccharides, oligosaccharides and sugar alcohols such as glucose, fructose, sucrose, lactose (anhydrous and monohydrate), raffinose, trehalose, dextrans, mannitol, erythritol, sorbitol, maltitol, xylitol and lactitol, pressed sugar, calcium hydrogen phosphate, calcium carbonate, calcium lactate and mixtures thereof. Preferred excipients are monosaccharides and oligosaccharides such as glucose, fructose, sucrose and lactose, sugar alcohols such as mannitol, erythritol, sorbitol, maltitol, xylitol and lactitol, and mixtures thereof. Particularly preferred are lactose, sorbitol, and mixtures thereof. It is particularly preferred that the filler comprises a monosaccharide or oligosaccharide, such as lactose, and a sugar alcohol, such as sorbitol, in a weight ratio of from 1: 1 to 1:10, in particular from 1: 2 to 1: 5, most preferably about 1 : 2.5. The telmisartan-containing part preferably contains from 30 to 95 wt.%, In particular from 60 to 90 wt.%, More preferably from 70 to 80 wt.% Of the filler.

Suitable binders for use in the first part containing telmisartan may include povidone (polyvinylpyrrolidone), co -ovidone (copolymer of vinyl pyrrolidone and vinyl acetate), cellulose powder, crystalline cellulose, microcrystalline cellulose, hydroxycellulose hydroxycellulose, hydroxycellulose, hydroxycellulose, hydroxycellulose, hydroxycellulose, hydroxycellulose, hydroxycellulose, hydroxycellulose, hydroxycellulose, hydroxycellulose, hydroxycellulose, hydroxycellulose, hydroxycellulose, hydroxycellulose, hydroxycellulose, hydroxycellulose, hydroxycellulose, hydroxycellulose, hydroxy cellulose, hydroxycellulose, hydroxy cellulose, hydroxy cellulose, hydroxy cellulose, hydroxy cellulose, hydroxy cellulose, hydroxy cellulose, hydroxy cellulose, hydroxy cellulose, hydroxy cellulose, hydroxy cellulose, hydroxy cellulose, hydroxy cellulose, hydroxy cellulose, hydroxy cellulose, hydroxy cellulose and hydroxypropyl methylcellulose, maltose, starch, pregelatinized starch, polymethacrylates and mixtures thereof . Povidone is particularly preferred. The telmisartan-containing part preferably contains from 1 to 30% by weight, in particular from 2 to 10% by weight, more preferably from 3 to 7% by weight of a binder.

Suitable surfactants for use in the first part of the pharmaceutical composition of the present invention may include anionic, cationic, ampholytic and nonionic surfactants such as sodium lauryl sulfate, cetrimide, N-dodecyl-Y. Ndimethyl betaine, polysorbates (such as Twins® ), poloxamers and mixtures thereof. Non-ionic surfactants such as polysorbates and poloxamers are preferred. The first part preferably contains from 1 to 30 wt.%, In particular from 2 to 10 wt.%, More preferably from 3 to 7 wt.% Surfactant by weight of the specified part. In addition, the pharmaceutical composition preferably contains from 1 to 30 wt.%, In particular from 2 to 10 wt.%, More preferably from 3 to 7 wt.% Surfactant by weight of the specified composition.

Suitable crystallization retardants for use in the first part of the pharmaceutical composition of the present invention may include povidone, co-povidone, crospovidone, carboxymethyl cellulose sodium, hydroxypropyl cellulose and hydroxypropyl methyl cellulose. The first part preferably contains from 0.1 to 20 wt.%, In particular, from 0.25 to 10 wt.%, More preferably from 0.25 to 4 wt.% Of the crystallization retardant by weight of the specified part. In addition, the pharmaceutical composition preferably contains from 0.1 to 20 wt.%, In particular from 0.25 to 10 wt.%, More preferably from 0.25 to 4 wt.% A crystallization retardant by weight of the composition.

Suitable lubricants for use in the first part containing telmisartan may include stearic acid and stearic acid salts such as magnesium stearate, magnesium palmitate and magnesium oleate, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, macrogols and mixtures thereof. Stearic acid, magnesium stearate and hydrogenated vegetable oil are particularly preferred. The first part containing telmisartan preferably contains from 0.1 to 10 wt.%, In particular from 0.25 to 5 wt.%, More preferably from 0.5 to 2 wt.% A lubricant.

Suitable glidants for use in the first part of the pharmaceutical composition of the present invention include colloidal silicon dioxide and magnesium trisilicate. The first part containing telmisartan preferably contains from 0.1 to 10 wt.%, In particular from 0.25 to 5 wt.%, More preferably from 0.5 to 2 wt.% Of a moving substance.

Suitable colorants for use in the first part of the pharmaceutical composition of the present invention include paints and pigments such as iron oxide and titanium oxide. The first part containing telmisartan preferably contains from 0.001 to 1 wt.%, In particular from 0.01 to 0.5 wt.%, More preferably from 0.05 to 0.2 wt.% Of the dye.

According to a specific embodiment, the first part of the composition, such as a first tablet layer, a first tablet or a first dosage unit, comprises:

(aa) from 3 to 50 wt.%, in particular from 5 to 35 wt.%, more preferably from 10 to 20 wt.% of telmisartan or a pharmaceutically acceptable salt thereof;

(B) from 0.25 to 20 wt.%, In particular from 1 to 15 wt.%, More preferably from 2 to 10 wt.% Of the main agent;

(cc) from 30 to 95 wt.%, in particular from 60 to 90 wt.%, more preferably from 70 to 80 wt.% of the filler;

(bb) from 1 to 30 wt.%, in particular from 2 to 10 wt.%, more preferably from 3 to 7 wt.% a binder;

(her) from 0 to 30 wt.%, in particular from 2 to 10 wt.%, more preferably from 3 to 7 wt.% of a surfactant;

(£ E) from 0 to 10 wt.%, In particular from 0.25 to 5 wt.%, More preferably from 0.5 to 2 wt.% Of a lubricant; and (dd) from 0 to 1 wt.%, in particular from 0.01 to 0.5 wt.%, more preferably from 0.05 to 0.2 wt.% of the dye.

According to another preferred embodiment, the first part of the composition, such as a first tablet layer, a first tablet or a first dosage unit, comprises:

(aa) from 3 to 50 wt.%, in particular from 5 to 35 wt.%, more preferably from 10 to 20 wt.% of telmisartan or a pharmaceutically acceptable salt thereof;

(B) from 0.25 to 20 wt.%, In particular from 1 to 15 wt.%, More preferably from 2 to 10 wt.% Of the main agent, where the specified main agent is preferably selected from ΝαΟΗ, KOH, Ca (OH ) _2, Na ₂ CO _3, K ₂ CO _3, YaNSO _3, KHCO _3, Να ₃ ΡΟ. ₁ . K ₃ PO ₄ , Na ₂ NRO ₄ , K ₂ NRO ₄ , choline, tert-butylamine, ethanolamine, meglumine, piperazine, diethylamine, L-arginine and mixtures thereof, and more preferably selected from NaOH, meglumine and mixtures thereof;

(cc) from 30 to 95 wt.%, in particular from 60 to 90 wt.%, more preferably from 70 to 80 wt.% of a filler, wherein said filler is preferably selected from monosaccharides and oligosaccharides, such as glucose, fructose, sucrose and lactose, sugar alcohols such as mannitol, erythritol, sorbitol, maltitol, xylitol and lactitol, and mixtures thereof, and more preferably selected from lactose, sorbitol and mixtures thereof;

(άά) from 1 to 30 wt.%, in particular from 2 to 10 wt.%, more preferably from 3 to 7 wt.% a binder, wherein said binder is preferably selected from povidone, co-vidone, cellulose powder, crystalline cellulose microcrystalline cellulose, siliconized microcrystalline cellulose, cellulose derivatives such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose, starch, pregelatinized starch, polymethacrylates and mixtures thereof, and more edpochtitelno selected from povidone;

(s) from 0 to 10 wt.%, in particular from 0.25 to 5 wt.%, more preferably from 0.5 to 2.5 wt.% a lubricant, wherein said lubricant is preferably selected from stearic acid and salts stearic acid, such as magnesium stearate, magnesium palmitate and magnesium oleate, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium fumarate, macrogols and mixtures thereof, and more preferably selected from magnesium stearate, sodium stearyl fumarate and mixtures thereof; and (K) from 0 to 1 wt.%, in particular from 0.01 to 0.5 wt.%, more preferably from 0.05 to 0.2 wt.% of the dye.

The second part of the composition according to the invention contains a calcium channel blocker and at least one non-hygroscopic excipient. In particular, the second part contains amlodipine or a pharmaceutically acceptable salt thereof and at least one non-hygroscopic excipient.

Amlodipine may be in the form of pharmaceutically acceptable salts, such as, for example, the maleate salt, besylate or mesylate, or in the form of a free base. Preferably, amlodipine is in the form of a salt of besylate or maleate.

The non-hygroscopic excipient of the second part is preferably selected from the group consisting of non-hygroscopic fillers, non-hygroscopic binders and mixtures thereof.

Thus, the second part containing amlodipine preferably contains at least one non-hygroxopic excipient that does not exhibit a loosening effect. Preferably, the filler of the second part is selected from the group of fillers defined above in connection with the first part of the composition, or mixtures thereof. Therefore, the filler of the second part is preferably selected from the group consisting of monosaccharides, oligosaccharides, sugar alcohols, and mixtures thereof. Preferred non-hygroxopic excipients that do not exhibit a disintegrating effect are mannitol and lactose monohydrate. Thus, the filler of the second part is preferably selected from the group consisting of mannitol, lactose monohydrate and mixtures thereof.

The second part containing amlodipine may additionally contain at least one binder and, in particular, at least one non-hygroscopic binder that does not exhibit a disintegrating effect, selected from the group of binders defined above in connection with the first part of the composition. Preferred non-hygroscopic binders that do not exhibit a disintegrating effect are hydroxypropyl cellulose and maltose. Therefore, the binder of the second part is preferably selected from the group consisting of hydroxypropyl cellulose, maltose, and mixtures thereof.

The second part containing amlodipine preferably further comprises at least one non-hydrophobic lubricant selected from the group of lubricants defined above in connection with the first part of the composition. Preferred non-hydrophobic lubricants are sodium stearyl fumarate and macrogols. Thus, the second part of the composition preferably contains at least one hydrophilic lubricant selected from the group consisting of stearic acid, magnesium stearate, magnesium palmitate, magnesium oleate, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, macrogols and their mixtures. More preferably, the second part of the composition is preferably

- 8,025,946 contains at least one hydrophilic lubricant selected from the group consisting of sodium stearyl fumarate, macrogol and mixtures thereof.

The second part of the composition of the invention may typically contain additional pharmaceutically acceptable excipients. Such additional excipients suitable for use in the second part may include glidants, colorants and coating agents.

Suitable glidants for use in the second part of the pharmaceutical composition of the present invention include colloidal silicon dioxide and magnesium trisilicate.

Suitable colorants for use in the second part of the pharmaceutical composition of the present invention include paints and pigments such as iron oxide and titanium oxide.

According to a preferred embodiment, the second part of the composition, such as a second tablet layer, comprises:

(aa) from 1 to 50 wt.%, in particular from 2 to 20 wt.%, more preferably from 3 to 8 wt.%, such as from 4 to 9 wt.% of amlodipine or a pharmaceutically acceptable salt thereof;

(B) from 50 to 99 wt.%, In particular from 80 to 98 wt.%, More preferably from 90 to 96 wt.% Of the filler;

(cc) from 0 to 30 wt.%, in particular from 2 to 10 wt.%, more preferably from 3 to 7 wt.% a binder;

(άά) from 0 to 10 wt.%, in particular from 0.25 to 5 wt.%, more preferably from 0.5 to 2 wt.% a lubricant;

(her) from 0 to 10 wt.%, in particular from 0.25 to 5 wt.%, more preferably from 0.5 to 2 wt.% a moving substance; and (£ T) from 0 to 1 wt.%, in particular from 0.01 to 0.5 wt.%, more preferably from 0.05 to 0.2 wt.% of the dye.

According to another preferred embodiment, the second part of the composition, such as a second tablet layer, comprises:

(aa) from 1 to 50 wt.%, in particular from 2 to 20 wt.%, more preferably from 3 to 8 wt.%, such as, for example, from 4 to 9 wt.% amlodipine or a pharmaceutically acceptable salt thereof;

(B) from 50 to 99 wt.%, In particular from 80 to 98 wt.%, More preferably from 88 to 94 wt.% Of a filler, preferably selected from sugar alcohol, such as isomalt, xylitol or mannitol, lactose monohydrate and their mixtures;

(cc) from 0 to 5 wt.%, in particular from 0.1 to 3 wt.%, more preferably from 0.1 to 1.5 wt.% a binder, preferably selected from hydroxypropyl cellulose, maltose and mixtures thereof, and more preferably hydroxypropyl cellulose; and (άά) from 0 to 10 wt.%, in particular from 0.25 to 5 wt.%, more preferably from 0.5 to 3 wt.% a lubricant, preferably selected from sodium stearyl fumarate, macrogols and mixtures thereof.

If the second part of the composition is in the form of a coating containing amlodipine covering the first part, such as a tablet containing telmisartan, suitable coating agents for use in the second part of the pharmaceutical composition of the present invention include calcium salt of carmellose, shellac, co-vidone, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, polymethacrylate, hydroxypropyl cellulose, chitosan, hypromellose, polyvinyl alcohol, methyl cellulose, polyethylene oxide, povidone, cetyl alcohol or mixtures thereof.

The second part containing amlodipine preferably contains from 0.01 to 20 wt.%, More preferably from 0.1 to 10 wt.%, Of a coating agent based on the total weight of the coated pharmaceutical composition comprising together the tablet core and the coating.

According to another specific embodiment, the second part is a tablet layer that contains granules and an extragranular phase. Preferably, the granules contain amlodipine, at least one non-hygroscopic filler, at least one non-hygroscopic binder, and optionally additional excipients, such as a dye. In addition, it is preferable that the extragranular phase of the second tablet layer according to this embodiment contain at least one non-hygroxopic filler, at least one hydrophilic lubricant and optionally additional excipients, such as at least one dye and at least one lubricant . At least one filler of the extragranular phase may be the same or different from the filler of the granules. Preferably, the filler of the extragranular phase is the same as the filler of the granules. Typically, preferred embodiments with respect to specific components and their amounts are described above. In particular, the filler used in the granules and in the extragranular phase is a sugar alcohol such as mannitol and / or lactose monohydrate.

As indicated above, it is preferable that in any of the above embodiments the combined mass of amlodipine or its pharmaceutically acceptable salt and non-hygroscopic excipient, i.e., non-hygroscopic excipient and non-hygroscopic binder, or the combined mass of amlodipine or its pharmaceutically acceptable salt, non-hygroscopic excipient, i.e. non-hygroscopic excipient and non-hygroscopic binder, and hydrophilic lubricant

- 9,025,946 substances of the second part, such as the second layer of the tablet, amounted to at least 50 wt.%, Preferably at least 85 wt.%, More preferably at least 93 wt.%, Such as at least 95 wt. wt.% or at least 97 wt.%, such as, for example, at least 98 wt.% and most preferably at least 99 wt.% by weight of the second part. In one embodiment, a second part of the composition, such as a second tablet layer, essentially consists of amlodipine or a pharmaceutically acceptable salt thereof and at least one non-hygroscopic excipient. In another embodiment, the second part of the composition essentially consists of amlodipine or a pharmaceutically acceptable salt thereof, at least one non-hygroscopic excipient and at least one hydrophilic lubricant.

In an additional aspect, the present invention is directed to a method for producing a pharmaceutical composition according to the invention. The production method may be direct compression, dry granulation or wet granulation, or any other known method or combination thereof.

A method for preparing a solid pharmaceutical composition of the invention typically comprises (ί) providing a first part of a composition containing telmisartan or a pharmaceutically acceptable salt thereof, (i) providing a second part of a composition containing amlodipine or a pharmaceutically acceptable salt and at least one non-hygroscopic excipient, and (w) combining said parts of the composition, resulting in a solid pharmaceutical composition having separated first and second parts.

If the composition according to the invention is in the form of a multilayer pharmaceutical tablet, such a tablet can in principle be obtained by any method used for the manufacture of tablets. The preparation of a tablet typically involves the preparation of a composition of a first layer of a tablet containing telmisartan and a composition of a second layer of a tablet containing amlodipine and compression of the compositions of the tablet layers to form a multilayer tablet.

The composition of the first layer of a tablet containing telmisartan can be obtained in various ways. Suitable methods include spray drying and fluidized bed granulation. One method for preparing the composition of the first tablet layer comprises preparing a spray solution by dissolving telmisartan together with at least one basic agent in a suitable solvent (for example, water or an organic solvent). Optionally, additional excipients, such as a crystallization retardant and / or surfactant, may be included in the sprayed solution. Then, the spray solution is spray dried to obtain a spray dried granulate. The spray dried granules were mixed with additional excipients to formulate a tablet layer composition ready for tabletting.

Another way to obtain the composition of the first tablet layer involves the preparation of a granulation liquid by dissolving telmisartan together with at least one basic agent in a suitable solvent (for example, water or an organic solvent). Optionally, additional excipients, such as a crystallization retardant and / or surfactant, may be included in the spray solution. At least one excipient selected from fillers, binders and mixtures thereof is placed in a fluidized bed granulator and sprayed with granulation liquid. When the granulation is completed, the granulate is dried and possibly mixed with additional excipients to obtain a tablet layer composition ready for tabletting.

The composition of the second tablet layer containing amlodipine or a pharmaceutically acceptable salt thereof can also be obtained by various methods, such as direct compression, compression of granules obtained by prior art methods, such as wet, dry or thermoplastic granulation or melt extrusion. For example, the composition of the second tablet layer in the first embodiment of the present invention can be obtained using the wet granulation method. A suitable wet granulation method involves preparing the granulation liquid by dissolving at least a portion of the filler and / or binder in a suitable solvent (e.g., water, an organic solvent or a mixture thereof) and granulating amlodipine or its salt, optionally with additional excipients. The obtained wet granules may be dried and / or sieved and mixed with at least one excipient and, optionally, with other pharmaceutical excipients, such as at least one lubricant, to obtain a second tablet layer composition.

According to another embodiment, the composition of the second tablet layer is prepared using a direct compression method, wherein the powdered premix of amlodipine or its salt and at least one additional excipient selected from a filler, a binder, a lubricant, a sliding substance, and mixtures thereof are directly pressed onto the first telmisartan-containing layer.

Preferred embodiments of the composition of the first layer of a tablet containing telmisartan in

- 10 025946 in relation to specific components and their quantities, as well as methods for its preparation, are as described above. Preferred embodiments of the composition of the second tablet layer with respect to specific components and their amounts are as described above.

If the composition of the invention is in the form of a coated tablet, these coated tablets can be prepared first by preparing a tablet containing telmisartan or a pharmaceutically acceptable salt thereof. Then this tablet can be coated by wet and / or dry coating. The wet coating method consists in dissolving a suitable coating agent in solution along with other possible ingredients and spraying on the core tablets. A dry coating consists of spraying a suitable coating agent onto a layer of tablets and / or pills while spraying a suitable plasticizing agent. This can be achieved either by using a fluidized bed, or a hole pan or other suitable equipment.

The invention is illustrated in more detail by the following non-limiting examples.

Examples

Example 1. A two-layer tablet.

Telmisartan layer A [mg] In [mg] Telmisartan 80.0 80.0 Meglumine 24.0 24.0 Sodium hydroxide 6.7 6.7 Povidone 24.0 24.0 Lactose Monohydrate 120.0 120.0 Sorbitol 299.7 299.7 Magnesium stearate 5,6 Sodium Stearyl Fumarate 5,6 Whole telmisartan layer 560.0 560.0

Telmisartan, sodium hydroxide and povidone were dissolved in the required amount of water in order to prepare a granulation liquid. Lactose monohydrate and meglumine were placed in a fluidized bed granulator and sprayed with granulation liquid. When the granulation was completed, the granulate was dried and mixed with sorbitol and magnesium stearate or sodium stearyl fumarate to form the final composition ready for tabletting.

Amlodipine layer BUT [mg] IN [mg] FROM [mg] ϋ [mg] E [mg] R [mg] FROM [mg] N [mg] Amlodipine besilat 13.89 13.89 13.89 13.89 Amlodipine maleate 12.84 12.84 12.84 12.84 Xylitol 182.11 183.16 Lactose Monohydrate 182.11 183.16 Mannitol 182.11 183.16 Isomalt 182.11 183.16 Magnesium stearate 4.00 4.00 4.00 4.00 Sodium Stearyl Fumarate 4.00 4.00 4.00 4.00 Whole amlodipine layer 200.00 200.00 200.00 200.00 200.00 200.00 200.00 200.00

Amlodipine in the form of a besylate or maleate was mixed with any of xylitol, lactose monohydrate, mannitol or isomalt. A lubricant (magnesium stearate or sodium stearyl fumarate) was then added to the mixture to form the final composition, ready for tabletting by direct compression.

Bilayer tablets containing telmisartan and amlodipine were prepared by first introducing into the tablet machine a mixture containing telmisartan ready for tabletting and then a mixture containing amlodipine ready for tabletting. Then these two layers were pressed on a rotary tablet press in a two-layer tabletting mode.

Example 2. A two-layer tablet.

The telmisartan layer was obtained in the same way as in example 1.

Amlodipine layer A [mg] In [mg] C [mg] ϋ [mg] E [mg] E [mg] Amlodipine besylate 13.89 13.89 13.89 Amlodipine maleate 12.84 13.89 12.84 Mannitol 50.00 50.00 50.00 Lactose Monohydrate 100.00 50.00 100.00 Hydroxypropylchlelupose 1,50 1,50 1,50 Maltose 3.75 3.75 3.75

- 11 025946

Mannitol 130.61 81.66 130.61 Lactose Monohydrate 128.36 128.36 79.41 Magnesium stearate 4.00 4.00 4.00 Sodium Stearyl Fumarate 4.00 4.00 4.00 Whole amlodipine layer 200.00 200.00 200.00 200.00 200.00 200.00

Amlodipine in the form of a besylate or maleate and either mannitol or lactose monohydrate was granulated with an aqueous solution of either hydroxypropyl cellulose or maltose. The resulting granulate was dried. Then the granulate was mixed with either mannitol or lactose monohydrate. A lubricant (magnesium stearate or sodium stearyl fumarate) was then added to the mixture to form the final composition, ready for tabletting.

Two-layer tablets containing telmisartan and amlodipine were prepared by first introducing into the tablet machine a mixture containing telmisartan ready for tabletting, and then a mixture containing amlodipine ready for tabletting. Then these two layers were pressed on a rotary tablet press in a two-layer tabletting mode.

Example 3. A multilayer tablet.

The telmisartan layer was obtained in the same way as in example 1. The amlodipine layer was obtained in the same way as in example 1 (example 3 a) or in example 2 (example 3b).

Malta, or maltitol with sodium stearyl fumarate in a drum mixer in order to obtain the final composition, ready for tabletting.

Multilayer tablets containing telmisartan and amlodipine were obtained by first introducing into the tablet machine a mixture containing telmisartan ready for tabletting. Then, a separating layer was introduced, and then a mixture containing amlodipine ready for tabletting. Then these three layers were pressed on a rotary tablet press in a three-layer tabletting mode.

Example 4. Coated Tablet

A [mg] In [mg] C [mg] Telmisartan Tablet Telmisartan 80.0 80.0 80.0 Sodium hydroxide 6.72 6.72 6.72 Povidone 24.0 24.0 24.0 Meglumine 24.0 24.0 24.0 Lactose Monohydrate 120.0 120.0 120.0 Sorbitol 98.08 215.68 294.08 Magnesium stearate 3.6 4.8 5,6 Sodium Stearyl Fumarate 3.6 4.8 5,6 Whole Telmisartan Tablet 360,0 480.0 560.0

Amlodipine part A [mg In [mg C [mg] G ipromellose 10.80 14.40 16.80 Amlodipine besylate 13.89 13.89 Amlodipine maleate 12.84 The entire amlodipine portion 24.69 27.24 30.69

- 12 025946

Telmisartan, sodium hydroxide, and povidone were dissolved in water to prepare a granulation liquid. Lactose monohydrate and meglumine were placed in a fluidized bed granulator and sprayed with granulation liquid. When the granulation was completed, the granulate was dried and mixed with sorbitol and a lubricant (magnesium stearate and sodium stearyl fumarate) to form the final composition, ready for tabletting. Tablets were prepared by compression.

Then hypromellose was dissolved in water. Amlodipine in the form of a besylate or maleate was suspended in the resulting hypromellose solution. Then tablets containing telmisartan were coated with the resulting amlodipine suspension.

Example 5. A coated tablet with a release coating.

A [mg In [mg] C [mg] Telmisartan Tablet Telmisartan 80.0 80.0 80.0 Sodium hydroxide 6.72 6.72 6.72 Povidone 24.0 24.0 24.0 Meglumine 24.0 24.0 24.0 Lactose Monohydrate 120.0 120.0 120.0 Sorbitol 98.08 215.68 294.08 Magnesium stearate 3.6 4.8 5,6 Sodium Stearyl Fumarate 3.6 4.8 5,6 Whole Telmisartan Tablet 360,0 480.0 560.0

Separation coating A [mg In [mg] C [mg] G ipromellose 5.40 7.20 Povidone 8.40 All separation coating 5.40 7.20 8.40 Amlodipine part G ipromellose 10.80 14.40 16.80 Amlodipine besylate 13.89 13.89 Amlodipine maleate 12.84 All amlodipine coating 24.69 27.24 30.69

Telmisartan, sodium hydroxide, and povidone were dissolved in water to prepare a granulation liquid. Lactose monohydrate and meglumine were placed in a fluidized bed granulator and sprayed with granulation liquid. When the granulation was completed, the granulate was dried and mixed with sorbitol and a lubricant (magnesium stearate and sodium stearyl fumarate) to form the final composition, ready for tabletting. Tablets were prepared by compression.

Hypromellose or povidone was dissolved in water, and tablets containing telmisartan were coated with a release coating.

Hypromellose was dissolved in water. Amlodipine in the form of besylate or maleate was suspended in the resulting solution. Then, the preformed coated tablets were coated with the resulting amlodipine suspension.

Example 6. A capsule comprising two or more than two dosage units.

A [mg] In [mg] C [mg] Telmisartan 80.0 80.0 80.0 Sodium hydroxide 6.72 6.72 6.72 Povidone 24.0 24.0 24.0 Meglumine 24.0 24.0 24.0 Lactose Monohydrate 120.0 120.0 120.0 Sorbitol 98.08 215.68 294.08 Magnesium stearate 3.6 4.8 5,6 Sodium Stearyl Fumarate 3.6 4.8 5,6 Whole telmisartan 360,0 480.0 560.0

Telmisartan, sodium hydroxide, and povidone were dissolved in water to prepare a granulation liquid. Lactose monohydrate and meglumine were placed in a fluidized bed granulator and sprayed with granulation liquid. After granulation was completed, the granulate was dried and mixed with sorbitol and a lubricant (magnesium stearate and sodium stearyl fumarate) to form a dosage unit containing telmisartan.

Then, a pharmaceutical composition containing at least one dosage unit of telmisartan was prepared by tabletting this dosage unit into one tablet layer. Alternatively, the composition is obtained in the form of microtablets. Alternatively, the composition is obtained in the form of a powder or pills.

As the dosage unit for amlodipine, the amlodipine moiety was used as described in Example 1 or Example 2.

A pharmaceutical composition comprising at least one amlodipine dosage unit is prepared by tabletting the amlodipine dosage unit into one tablet layer. Alternatively, the composition is obtained in the form of microtablets. Alternatively, the composition is obtained in the form of a powder or pills.

Then, any of the above dosage units of telmisartan (as, for example, in the form of tablets, microtablets, pills or powder) was used together with any of the above dosage units of amlodipine (as, for example, in the form of tablets, microtablets, pills or powder) for filling in any type of hard capsules (gelatin, hypromellose or polysaccharide).

Example 7. Two separate dosage units in a combined blister pack.

Any of the above dosage units of telmisartan from Example 6 (as, for example, in the form of tablets, microtablets, pills or powder) was used together with any of the above dosage units of amlodipine (as, for example, in the form of tablets, microtablets, pills or powder) from example 6 to obtain a combination blister pack containing at least one dosage unit of telmisartan and at least one dosage unit of amlodipine.

Example 8. Obtaining cyanotelmisartan.

360 ml of acetonitrile, 8.32 g (126 mmol) of solid 85% KOH, 36.5 g (113 mmol) of 1,7'-dimethyl-2'-propyl-1H, 3'N-2,5 were added to the reaction vessel '-dibenzo [b] imidazole and 32.4 g (119 mmol) 4' - (bromomethyl) - [1,1'-diphenyl] -2-carbonitrile. The reaction mixture was stirred at room temperature for 4 hours. The mixture was cooled to 0 ° C. and filtered. The resulting product was washed with water and partially dried.

The product was suspended in 430 ml of ethyl acetate and heated to reflux and stirred at this temperature for 1 hour. The suspension was cooled to below 0 ° C, filtered and dried.

Yield: 47.9 g (87%).

HPLC: 98.7%.

Example 9. Obtaining and isolation of telmisartan.

10 g (20 mmol) of cyanotelmisartan and 20 ml (180 mmol) of H ₂ §O ₄ (1: 1) were added to the reaction vessel. The reaction mixture was heated to about 125 ° C and stirred at this temperature for 24 hours. The reaction mixture was cooled and 200 ml of water and 10 ml of dichloromethane were added. Then the pH of the mixture was adjusted to 5.3 by the addition of 6M ΝαΝ. The precipitated product was isolated and washed with water and dried at 65 ° C under reduced pressure.

Yield: 10.5 g (100%)

Peak Area% HPLC: Telmisartan 98.2%.

The product was recrystallized from DMF.

Yield: 90%.

Peak Area% HPLC: Telmisartan 99.29%.

Claims (14)

CLAIM 1. A solid pharmaceutical dosage form comprising: (a) at least one first portion containing telmisartan or a pharmaceutically acceptable salt thereof; and (b) at least one second part containing amlodipine or a pharmaceutically acceptable salt thereof and at least one non-hygroscopic pharmaceutically acceptable excipient having an equilibrium moisture content of 6 wt.% or less, as determined by dynamic vapor sorption (DSP) at a relative humidity 60% and a temperature of 25 ° C, and selected from the group of fillers consisting of glucose, fructose, sucrose, raffinose, trehalose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitol, lactitol, calcium hydrogen phosphate, calcium carbonate, l Ktati calcium and mixtures thereof; while the second part contains less than 2 wt.% baking powder from the mass of the second part. 2. The dosage form according to claim 1, where the second part further comprises at least one hydrophilic lubricant. 3. The dosage form according to claim 1 or 2, where the combined mass of amlodipine or its pharmaceutically acceptable salt and non-hygroscopic pharmaceutically acceptable excipient or combined - 14,025,946 the weight of amlodipine or its pharmaceutically acceptable salt, non-hygroscopic pharmaceutically acceptable excipient and hydrophilic lubricant is at least 50 wt.% By weight of the second part. 4. The dosage form according to any one of claims 1 to 3, where the second part contains less than 2 wt.% By weight of the second part of one or more than one baking powder selected from the group consisting of croscarmellose sodium, starch glycolate sodium, crospovidone, corn starch, pregelatinized starch, low substituted hydroxypropyl cellulose and microcrystalline cellulose. 5. A dosage form according to any one of claims 1 to 4, having the form of a multilayer tablet, where at least one first part is at least one first layer of the tablet, and at least one second part is at least one second layer tablets. 6. The dosage form according to any one of claims 1 to 4, having the form of a coated tablet, where at least one first part is at least one tablet, and at least one second part is at least one coating on the specified a pill. 7. The dosage form according to claim 5 or 6, containing at least one separating coating. 8. A dosage form according to any one of claims 1 to 4, having the form of a capsule containing at least one first part in the form of a first dosage unit and at least one second part in the form of a second dosage unit. 9. The dosage form of claim 8, where the first and second dosage units are independently selected from the group consisting of tablets, microtablets, pills, powder forms and granules. 10. The dosage form according to any one of claims 1 to 9, where the first part contains telmisartan and a basic agent. 11. The dosage form according to any one of claims 1 to 10, where the specified excipient of the second part is selected from mannitol. 12. A dosage form according to any one of claims 2-11, wherein the hydrophilic lubricant of the second part is selected from the group consisting of stearic acid, magnesium stearate, magnesium palmitate, magnesium oleate, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, macrogol and mixtures thereof. 13. The dosage form according to item 12, where the hydrophilic lubricant of the second part is selected from the group consisting of sodium stearyl fumarate, macrogol and mixtures thereof. 14. A method of obtaining a solid pharmaceutical dosage form according to any one of claims 1 to 13, including: (ί) providing a first part containing telmisartan or a pharmaceutically acceptable salt thereof, (ίί) providing a second part containing amlodipine or a pharmaceutically acceptable salt and at least one non-hygroscopic pharmaceutically acceptable excipient, and (ίίί) combining said parts to give the result is a solid pharmaceutical dosage form.