a fixed dose combination according to the present invention represents a pharmaceutical multilayer tablet comprising a first layer of telmisartan in substantially amorphous form , a second layer of ramipril alone or ramipril together with a diuretic in a disintegrating tablet matrix , or optionally a third layer of a diuretic in a disintegrating tablet matrix . the active ingredient telmisartan is generally supplied in its free acid form , although pharmaceutically acceptable salts such as the sodium salt may also be used . since during subsequent processing telmisartan is normally dissolved and transformed into a substantially amorphous form , its initial crystal morphology and particle size are of little importance for the physical and biopharmaceutical properties of the multilayer tablet formulation obtained . it is , however , preferred to remove agglomerates from the starting material , e . g . by sieving , in order to facilitate wetting and dissolution during further processing . substantially amorphous telmisartan may be produced by any suitable method known to those skilled in the art , for instance , by freeze drying of aqueous solutions , coating of carrier particles in a fluidized bed , and solvent deposition on sugar pellets or other carriers . preferably , however , the substantially amorphous telmisartan is prepared by the specific spray - drying method described in wo03 / 059327 . ramipril is supplied as a free ester or stabilized with a polymeric coating as described in ep - a - 317878 . examples of polymers suitable for the protective coating are cellulose derivatives such as hydroxyproplycellulose , hydroxypropylmethyl - cellulose , hydroxypropylmethylcellulose phthalate , hydroxyethylcellulose , ethylcellulose , cellulose acetate phthalate , cellulose acetate , polyvinyl acetate phthalate , polyvinylpyrrolidone , cationic and anionic polymers , copolymer with neutral character based on poly ( meth ) acrylic esters ( eudragit ®( r ) e , eudragit ®( r ) e 30 d ), anionic polymer of methacrylic acid and methyl methacrylate ( eudragit ®( r ) l or s , eudragit ®( r ) l 30 d ) and gelatin . the diuretic is usually employed as a fine - crystalline powder , optionally in fine - milled , peg - milled or micronized form . for instance , the particle size distribution of hydrochlorothiazide , as determined by the method of laser light scattering in a dry dispersion system ( sympatec helos / rodos , focal length 100 mm ) is preferably as follows : d 10 : ≦ 20 μm , preferably 2 to 10 μm d 50 : 5 to 50 μm , preferably 10 to 30 μm d 90 : 20 to 100 μm , preferably 40 to 80 μm a multilayer tablet according to the present invention generally contains 10 to 160 mg , preferably 20 to 80 mg or 40 to 80 mg , of telmisartan ; 1 to 20 mg , preferably 5 to 10 mg , of ramipril ; and 6 . 25 to 50 mg , preferably 12 . 5 to 25 mg , of a diuretic such as hctz . presently preferred forms are multilayer tablets comprising 20 / 10 mg , 40 / 10 mg , 80 / 10 mg , 20 / 5 mg , 40 / 5 mg , 80 / 5 mg , 20 / 2 . 5 mg , 40 / 2 . 5 mg and 80 / 2 . 5 mg of telmisartan and ramipril , respectively . the preferred amounts of diuretic are 12 . 5 mg or 25 mg . the first tablet layer contains telmisartan in substantially amorphous form dispersed in a dissolving tablet matrix having instant release ( fast dissolution ) characteristics . the dissolving tablet matrix may have neutral or basic properties , although a basic tablet matrix is preferred . in such a preferred embodiment , the dissolving matrix of the telmisartan layer comprises a basic agent , a water - soluble diluent and , optionally , other excipients and adjuvants . specific examples of suitable basic agents are alkali metal hydroxides such as naoh and koh ; basic amino acids such as arginine and lysine ; and meglumine ( n - methyl - d - glucamine ), naoh and meglumine being preferred . specific examples of suitable water - soluble diluents are carbohydrates such as monosaccharides like glucose ; oligosaccharides like sucrose , anhydrous lactose and lactose monohydrate ; and sugar alcohols like sorbitol , mannitol , erythrol and xylitol . sorbitol is a preferred diluent . the other excipients and / or adjuvants are , for instance , selected from binders , carriers , fillers , lubricants , flow control agents , crystallization retarders , solubilizers , coloring agents , ph control agents , surfactants and emulsifiers , specific examples of which are given below in connection with the second tablet layer composition . the excipients and / or adjuvants for the first tablet layer composition are preferably chosen such that a non - acidic , fast dissolving tablet matrix is obtained . the first tablet layer composition generally comprises 3 to 50 wt . %, preferably 5 to 35 wt . %, of active ingredient ; 0 . 25 to 20 wt . %, preferably 0 . 40 to 15 wt . %, of basic agent ; and 30 to 95 wt . %, preferably 60 to 80 wt . % of water - soluble diluent ( filler ). other ( optional ) constituents may , for instance , be chosen from one or more of the following excipients and / or adjuvants in the amounts indicated : 10 to 30 wt . %, preferably 15 to 25 wt . %, of binders , carriers and fillers , thereby replacing the water - soluble diluent ; 0 . 1 to 5 wt . %, preferably 0 . 5 to 3 wt . %, of lubricants ; 0 . 1 to 5 wt . %, preferably 0 . 3 to 2 wt . %, of flow control agents ; 1 to 10 wt . %, preferably 2 to 8 wt . %, of crystallization retarders ; 1 to 10 wt . %, preferably 2 to 8 wt . %, of solubilizers ; 0 . 05 to 1 . 5 wt . %, preferably 0 . 1 to 0 . 8 wt . %, of coloring agents ; 0 . 5 to 10 wt . %, preferably 2 to 8 wt . %, of ph control agents ; 0 . 01 to 5 wt . %, preferably 0 . 05 to 1 wt . %, of surfactants and emulsifiers . the second tablet layer composition comprises ramipril dispersed in a disintegrating tablet matrix having instant release ( fast dissolution ) characteristics . alternatively , the second tablet layer composition comprises ramipril together with a diuretic dispersed in a disintegrating tablet matrix having instant release ( fast dissolution ) characteristics . the disintegrating tablet matrix may have weakly acidic , neutral or weakly basic properties , a neutral tablet matrix being preferred . in a preferred embodiment , the disintegrating matrix comprises one or more fillers , a binder or polymer , a disintegrant , a lubricant and , optionally , other excipients and adjuvants . preferred fillers are selected from the group consisting of pregelatinized starch , microcristalline cellulose , low - substituted hydroxypropylcellulose , cellulose , mannitol , erythritol , lactose , saccharose , claciumhydrogenphosphate , sorbitol , and xylitol . particularly preferred are pregelatinized starch , microcrystalline cellulose , mannitol and lactose monohydrate . preferred disintegrants are selected from the group consisting of croscarmellose sodium salt ( cellulose carboxymethylether sodium salt , crosslinked ), sodium starch glycolate , crosslinked polyvinyl pyrrolidone ( crospovidone ), corn starch and low - substituted hydroxypropylcellulose . particularly preferred are sodium starch glycolate and croscarmellose sodium salt . preferred binders are selected from the group consisting of polyvinyl pyrrolidone ( povidone ), copolymers of vinylpyrrolidone with other vinyderivatives ( copovidone ), hydroxypropylmethylcellulose , methylcellulose , hydroxypropyl - cellulose and low - substituted hydroxypropyl - cellulose . particularly preferred are hydroxypropyl - methylcellulose and copovidone . the second tablet layer composition generally comprises 0 . 5 to 25 wt . %, preferably 1 to 15 wt . % of ramipril and 50 to 95wt . %, preferably 75 to 90 wt . % of fillers . the optional content of diuretic amounts to 2 to 15 wt . %. the other excipients and / or adjuvants are , for instance , selected from binders , carriers , fillers , lubricants , flow control agents , crystallization retarders , solubilizers , coloring agents , ph control agents , surfactants and emulsifiers , specific examples of which are given below in connection with the third tablet layer composition . the excipients and / or adjuvants for the second tablet layer composition are preferably chosen such that a neutral , disintegrating tablet matrix is obtained . examples for such fillers are mannitol , pregelatinized starch , lactose monohydrate and cellulose derivatives like low substituted hydroxypropylcellulose . the optional third tablet layer composition contains a diuretic in a fast disintegrating tablet matrix . in a preferred embodiment , the disintegrating tablet matrix comprises a filler , a binder , a disintegrant and , optionally , other excipients and adjuvants . the filler is preferably selected from anhydrous lactose , spray - dried lactose and lactose monohydrate . the binder is selected from the group of dry binders and / or the group of wet granulation binders , depending on the manufacturing process chosen for the second tablet layer . suitable dry binders are , e . g ., cellulose powder and microcrystalline cellulose . specific examples of wet granulation binders are corn starch , polyvinyl pyrrolidone ( povidone ), vinylpyrrolidone - vinylacetate copolymer ( copovidone ) and cellulose derivatives like hydroxymethylcellulose , hydroxyethylcellulose , hydroxypropyl - cellulose and hydroxypropylmethylcellulose . suitable disintegrants are , e . g ., sodium starch glycolate , crospovidon , croscarmellose , sodium carboxymethylcellulose and dried corn starch , sodium starch glycolate being preferred . the other excipients and adjuvants , if used , are preferably selected from diluents and carriers such as cellulose powder , microcrystalline cellulose , cellulose derivatives like hydroxymethylcellulose , hydroxyethylcellulose , hydroxypropylcellulose and hydroxy - propylmethylcellulose , dibasic calcium phosphate , corn starch , pregelatinized starch , polyvinyl pyrrolidone ( povidone ) etc . ; lubricants such as stearic acid , magnesium stearate , sodium stearylfumarate , glycerol tribehenate , etc . ; flow control agents such as colloidal silica , talc , etc . ; crystallization retarders such as povidone , etc . ; solubilizers such as pluronic , povidone , etc . ; coloring agents , including dyes and pigments such as iron oxide red or yellow , titanium dioxide , talc , etc . ; ph control agents such as citric acid , tartaric acid , fumaric acid , sodium citrate , dibasic calcium phosphate , dibasic sodium phosphate , etc . ; surfactants and emulsifiers such as pluronic , polyethylene glycols , sodium carboxymethyl cellulose , polyethoxylated and hydrogenated castor oil , etc . ; and mixtures of two or more of these excipients and / or adjuvants . in a particularly preferred embodiment the third layer is positioned between the first and second layer to avoid contact of telmisartan and ramipril with each other . the layers can be differentiated by using different colors . such a third tablet layer composition generally comprises 1 . 5 to 35 wt . %, preferably 2 to 15 wt . %, of active ingredient ; 25 to 75 wt . %, preferably 35 to 65 wt . %, of filler ; 10 to 40 wt . %, preferably 15 to 35 wt . %, of dry binder ; 0 . 5 to 5 wt . %, preferably 1 to 4 wt . %, of wet granulation binder ; and 1 to 10 wt . %, preferably 2 to 8 wt . %, of disintegrant . the other excipients and adjuvants are generally employed in the same amount as in the first tablet layer composition . for preparing a bilayer tablet according to the present invention , the first and second tablet layer compositions may be compressed in the usual manner in a bilayer tablet press , e . g . a high - speed rotary press in a bilayer tableting mode . however , care should be taken not to employ an excessive compression force for the first tablet layer . preferably , the ratio of the compression force applied during compression of the first tablet layer to the compression force applied during compression of both the first and second tablet layers is in the range of from 1 : 10 to 1 : 2 . for instance , the first tablet layer may be compressed at moderate force of 4 to 8 kn , whereas the main compression of first plus second layer is performed at a force of 10 to 20 kn . during bilayer tablet compression adequate bond formation between the two layers is achieved by virtue of distance attraction forces ( intermolecular forces ) and mechanical interlocking between the particles . the multilayer tablets obtained release the active ingredients rapidly and in a largely ph - independent fashion , with complete release occurring within less than 60 min and release of the major fraction occurring within less than 15 min . the dissolution /- disintegration kinetics of the multilayer tablet may be controlled in different ways . for instance , the layers may dissolve / disintegrate simultaneously . preferably , however , the second layer containing ramipril and the third tablet layer containing a diuretic disintegrate first whereas the first layer containing telmisartan dissolves subsequently . in accordance with the present invention , a substantially increased dissolution rate of the active ingredients and , in particular , of telmisartan is achieved . normally , at least 70 % and typically at least 90 % of the drug load are dissolved after 30 min . the multilayer tablets of the present invention tend to be slightly hygroscopic and are therefore preferably packaged using a moisture - proof packaging material such as aluminium foil blister packs , or polypropylene tubes and high density polyethylene ( hdpe ) bottles which preferably contain a desiccant . a preferred method of producing the bilayer tablet according to the present invention comprises : a ) preparing an aqueous solution of telmisartan , at least one basic agent and , optionally , a solubilizer and / or a crystallization retarder ; b ) spray - drying said aqueous solution to obtain a spray - dried granulate ; c ) mixing said spray - dried granulate with a water - soluble diluent to obtain a premix ; d ) mixing said premix with a lubricant to obtain a final blend for the first layer ; and e ) optionally , adding other excipients and / or adjuvants in any of steps a ) to d ); ( ii ) providing a second tablet layer composition comprising ramipril alone or together with a diuretic ; ( iii ) optionally providing a third tablet layer composition comprising a diuretic ; ( iv ) compressing each of the first , second and third tablet layer composition to form a tablet layer ; and ( v ) compressing the separate tablet layers to form a multilayer tablet . to provide a first tablet layer composition , an aqueous alkaline solution of telmisartan is prepared by dissolving the active ingredient in purified water with the help of one or more basic agents like sodium hydroxide and meglumine . optionally , a solubilizer and / or a recrystallization retarder may be added . the dry matter content of the starting aqueous solution is generally 10 to 40 wt . %, preferably 20 to 30 wt . %. the aqueous solution is then spray - dried at room temperature or preferably at increased temperatures of , for instance , between 50 ° c . and 100 ° c . in a co - current or countercurrent spray - drier at a spray pressure of , for instance , 1 to 4 bar . generally speaking , the spray - drying conditions are preferably chosen in such a manner that a spray - dried granulate having a residual humidity of ≦ 5 wt . %, preferably ≦ 3 . 5 wt . %, is obtained in the separation cyclone . to that end , the outlet air temperature of the spray - drier is preferably kept at a value of between about 80 ° c . and 90 ° c . while the other process parameters such as spray pressure , spraying rate , inlet air temperature , etc . are adjusted accordingly . the spray - dried granulate obtained is preferably a fine powder having the following particle size distribution : d 10 : ≦ 20 μm , preferably ≦ 10 μm d 50 : ≦ 80 μm , preferably 20 to 55 μm d 90 : ≦ 350 μm , preferably 50 to 150 μm after spray - drying , the active ingredient telmisartan as well as the excipients contained in the spray - dried granulate are in a substantially amorphous state with no crystallinity being detectable . from a physical point of view , the spray - dried granulate is a solidified solution or glass having a glass transition temperature tg of preferably & gt ; 50 ° c ., more preferably & gt ; 80 ° c . based on 100 parts by weight of active ingredient telmisartan , the spray - dried granulate preferably contains 5 to 200 parts by weight of basic agent and , optionally , solubilizer and / or crystallization retarder . the water - soluble diluent is generally employed in an amount of 30 to 95 wt . %, preferably 60 to 80 wt . %, based on the weight of the first tablet layer composition . the lubricant is generally added to the premix in an amount of 0 . 1 to 5 wt . %, preferably 0 . 3 to 2 wt . %, based on the weight of the first tablet layer composition . mixing is carried out in two stages , i . e . in a first mixing step the spray - dried granulate and the diluent are admixed using , e . g ., a high - shear mixer or a free - fall blender , and in a second mixing step the lubricant is blended with the premix , preferably also under conditions of high shear . the method of the invention is however not limited to these mixing procedures and , generally , alternative mixing procedures may be employed in steps c ), d ), and also in the subsequent steps f ) and g ), such as , e . g ., container mixing with intermediate screening . to provide a second tablet layer composition comprising ramipril alone , ramipril is premixed and granulated with a binder solution using a fluid bed granulator . part of the excipients can be premixed and granulated together with ramipril in the fluid bed granulator . optionally ramipril can be dissolved or suspended in the binder solution in order to improve content uniformity of ramipril in the final product . the dried granules are sieved through an appropriate sieve . after addition of the other excipients the mixture is blended in a free fall blender . alternative methods for granulation of ramipril and excipients with the binder solution are high shear granulation or one pot granulation , followed by wet sieving , drying and dry sieving of the granules . first and second tablet layer compositions as described above can be compressed into bilayer tablets of the target tablet weight with appropriate size and crushing strength , using an appropriate tablet press . optionally , an appropriate external lubricant spray system for the dies and punches can be used during manufacturing of tablets in order to improve lubrication . to provide an alternative second tablet layer composition comprising ramipril together with a diuretic such as hydrochlorothiazide ( hctz ), ramipril and hydrochlorothiazide are premixed and granulated together with part of the excipients with a binder solution in a fluid bed granulator as described above . optionally , the active ingredients can be dissolved or suspended in the binder solution in order to improve content uniformity in the final product . after addition of the other excipients the mixture is blended in a free fall blender . first and alternative second layer compositions as described above can be compressed into bilayer tablets with appropriate size and crushing strength , using an appropriate tablet press . optionally , an appropriate external lubricant spray system for the dies and punches can be used during manufacturing of tablets in order to improve lubrication . in a further embodiment , a third tablet layer composition comprising a diuretic may be prepared by dry - mixing the constituent components , e . g . by means of a high - intensity mixer or a free - fall blender . alternatively and preferably , the third tablet layer composition is prepared using a wet granulation technique wherein an aqueous solution of a wet granulation binder is added to a premix and subsequently the wet granulate obtained is dried , e . g . in a fluidized - bed dryer or drying chamber . the dried mixture is screened and then a lubricant is admixed , e . g . using a tumbling mixer or free - fall blender . first , second and third layer compositions as described above can be compressed into 3 - layer tablets with appropriate size and crushing strength using an appropriate tablet press . for the production of bilayer tablets according to the present invention , the separate tablet layer compositions can be compressed in a bilayer tablet press , e . g . a rotary press in the bilayer tableting mode , in the manner described above . in order to avoid any cross - contamination between the tablet layers ( which could lead to decomposition of ramipril or hctz ), any granulate residues have to be carefully removed during tableting by intense suction of the die table within the tableting chamber . in order to further illustrate the present invention , the following non - limiting examples are given .
a multilayer tablet comprises a first layer formulated for instant release of the angiotensin ii receptor antagonist telmisartan from a dissolving tablet matrix , a second layer formulated for instant release of the angiotensin converting enzyme inhibitor ramipril and optionally a diuretic from a disintegrating tablet matrix , and , optionally , a third layer formulated for instant release of a diuretic like hydrochlorothiazide from a fast disintegrating tablet matrix .