KR20080100292A - A method for the preparation of substantially amorphous telmisartan - Google Patents

Abstract

A bilayer pharmaceutical tablet comprises a first layer formulated for immediate release of the angiotensin II receptor antagonist telmisartan from a dissolving tablet matrix which contains telmisartan in substantially amorphous form, and a second layer formulated for immediate release of a diuretic like hydrochlorothiazide from a fast disintegrating tablet matrix. A method of producing the bilayer tablet is also disclosed.

Description

A method for the preparation of substantially amorphous telmisartan}

The present invention relates to a bilayer pharmaceutical tablet formulation comprising angiotensin II receptor antagonist telmisartan in combination with a diuretic such as hydrochlorothiazide (HCTZ). The present invention also provides a method for producing the bilayer tablet described above.

INN telmisartan is an angiotensin II receptor antagonist developed to treat hypertension and other medical conditions (European Publication No. 502314).

Its chemical name is 4 '-[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-ylmethyl] -biphenyl-2-carboxylic acid, It has a structure of Formula (1).

Telmisartan is generally produced and supplied in free acid form. It is characterized by very poor solubility in aqueous systems in the physiological pH range (pH 1-7) of the gastrointestinal tract. As described in WO 00/43370, crystalline telmisartan exists in two polymorphic forms with different melting points. Under the influence of heat and water, polymorph B having a low melting point is irreversibly converted to polymorph A having a high melting point.

Hydrochlorothiazide (HCTZ) is a thiazide diuretic administered orally for the treatment of edema and hypertension.

The chemical name of HCTZ is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide, and has the structure of formula (2).

Purpose of the Invention

Combination therapy with telmisartan and diuretics (eg HCTZ) is thought to show synergistic therapeutic efficacy in the treatment of hypertension.

Accordingly, it is an object of the present invention to provide a dose-fixed combination drug comprising telmisartan and a diuretic (eg HCTZ), which provides the required fast dissolving power and adequate stability. Having drug immediate release profile.

In general, dosage-fixed combinations of drugs intended for immediate release, usually containing the necessary excipients, are carried out by simply adding a second drug component while maintaining the base formulation of the corresponding mono-drug formulation. By the preparation of a powder mixture consisting of the two active ingredients or by simultaneous granulation of the two active ingredients with the necessary excipients.

In the combination of telmisartan and HCTZ, this approach was not suitable because HCTZ is, for example, meglumine (N-methyl-D-glucamine), which is a component of a conventional telmisartan formulation. This is because it is immiscible with the same basic compound and the rate at which HCTZ dissolves from the dissolution matrix is reduced compared to the rate at which HCTZ dissolves from disintegrating tablets.

A number of galenical approaches to herbal formulations to solve the immiscibility problem have been studied. Traditional trials have covered HCTZ particles with a polymer solution containing a water-soluble polymer such as hydroxypropylcellulose, hydroxypropylmethylcellulose or polyvinylpyrrolidone in a fluidized bed granulator, thus mixing the HCTZ particles with telmisar during mixing and compression. It is to reduce the contact area of the burn formulation. However, this method did not reduce the contact area of the HCTZ particles with the telmisartan formulation in the compressed tablets sufficiently to achieve the desired extension of shelf life.

In addition, the rate at which HCTZ dissolves from tablets containing coated HCTZ in telmisartan formulations was further reduced by the gel-forming properties of the polymer.

Another attempt was to make telmisartan and tablets for HCTZ, respectively, having a size and shape that could be filled into capsules. The dose may be divided into two to four small tablets for telmisartan and one to two small tablets for HCTZ and filled into capsules 1 to 0 in length. However, in these trials, due to the time delay effect of the large capsule shell, the drug dissolution rate of telmisartan decreased compared to administration alone. Moreover, with respect to patient compliance, zero length capsules are not reliable.

Summary of the Invention

According to the present invention, the above-mentioned problems associated with conventional attempts to prepare a dose-fixed combination drug containing telmisartan and a diuretic include telmisartan, which is a highly amorphous form in the dissolution tablet matrix. This can be solved by a bilayer pharmaceutical tablet comprising a first layer and a second layer comprising a diuretic in the disintegrating tablet matrix.

The bilayer tablet according to the present invention provides a fairly pH dependent solubility of poorly soluble telmisartan, which facilitates the dissolution of the drug in the physiological pH range, which also allows the immediate release of diuretics from the fast disintegrating matrix. To provide. At the same time, the bilayer tablet structure solves the stability problem due to incompatibility with the basic components of the telmisartan formulation of a diuretic such as HCTZ.

In a further aspect, the present invention is directed to improvements in bilayer tableting techniques,

(i) preparing an aqueous solution comprising (a) telmisartan, at least one basic formulation and optionally a solubilizer and / or crystallization retardant, (b) spray drying the resulting aqueous solution to obtain spray dried granules (C) mixing the spray dried granules with a water-soluble diluent to obtain a premix, (d) mixing the premix with a lubricant to obtain a final blend for the first tablet layer, (e) step (a Providing a first tablet layer composition by optionally adding other excipients and / or adjuvants in any of steps) to (d),

(ii) (f) mixing and / or granulating the diuretic with the tablet matrix and any additional excipient and / or adjuvant components, (g) mixing the lubricant to obtain a final blend for the second tablet layer. Thereby providing a second tablet layer composition,

(iii) introducing a first tablet layer or a second tablet layer composition into a tablet press,

(iv) compressing the introduced one tablet layer composition to form a tablet layer,

(v) introducing the remaining tablet layer composition into a tablet press, and

(vi) compressing the two tablet layer compositions to form a bilayer tablet.

Justice

As used herein, "significantly amorphous" is a product in which an amorphous component is included in a proportion of at least 90%, preferably at least 95% (as measured by X-ray powder diffraction).

A “dissolving tablet matrix” is a rapid release (rapid dissolution) pharmaceutical tablet base formulation that readily dissolves in physiological aqueous media.

"Diuretics" are thiazide and thiazide-homologous diuretics (eg hydrochlorothiazide (HCTZ), clopamid, xipamid or chlorotalidone), any suitable for the treatment of high blood pressure. Other diuretics (eg, furosemide and pyretanide) and combinations of amylolide and triamteren.

A "disintegrating tablet matrix" is an immediate release pharmaceutical tablet based formulation that readily swells and disintegrates in a physiological aqueous medium.

Preferred Embodiments of the Invention

Bilayer tablets according to the present invention include a first layer comprising telmisartan in a highly amorphous form in the dissolution tablet matrix and a second layer comprising a diuretic in the disintegrating tablet matrix.

The active ingredient telmisartan may also be used in the form of a pharmaceutically acceptable salt, but is generally supplied in the form of a free acid. Since telmisartan is typically dissolved and transformed into a highly amorphous form during subsequent processing, its initial crystalline form and particle size are of little importance for the physical and physiological properties of the resulting bilayer tablet formulation. However, it is desirable to remove agglomerates from the starting material, for example by sieving, to facilitate wetting and dissolution in further processing.

The highly amorphous telmisartan can be prepared by any suitable method known to those skilled in the art, for example, by freeze drying an aqueous solution, coating the carrier particles in a fluidized bed, and depositing a solvent on a sugar pellet or other carrier. Can be prepared. Preferably, however, highly amorphous telmisartan is prepared by the specific spray drying method described below.

The remaining active ingredient (ie diuretic) is generally provided as a micro-crystalline powder, optionally in fine-milled form, peg-milled form or in micronized form. For example, the particle size distribution of hydrochlorothiazide measured by laser light scattering in anhydrous dispersion system (Sympatec Helos / Rodos, focal length: 100 mm) is preferably as follows.

d ₁₀ : 20 µm or less, 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

Bilayer tablets according to the invention generally contain 10 to 160 mg, preferably 20 to 80 mg, of telmisartan, and 6.25 to 50 mg, preferably 12.5 to 25 mg of diuretics. Preferred forms to date are bilayer tablets containing 40 / 12.5 mg, 80 / 12.5 mg and 80/25 mg of telmisartan and HCTZ, respectively.

The first purification layer includes telmisartan in a fairly amorphous form dispersed in a dissolution tablet matrix that is rapid release (rapid dissolution). Dissolved tablet matrices may have acidic, neutral or basic properties, but basic purified matrices are preferred.

In this preferred embodiment, the dissolution matrix comprises a basic agent, a water soluble diluent and any other excipients and auxiliaries.

Specific examples of suitable basic agents include alkali metal hydroxides (e.g. NaOH and KOH), basic amino acids (e.g. arginine and lysine) and meglumine (N-methyl-D-glucamine), NaOH and meglumine are preferred.

Specific examples of suitable water-soluble diluents include monosaccharides such as glucose, oligosaccharides such as sucrose, anhydrous lactose and lactose monohydrate, and sugar alcohols such as sorbitol, mannitol, dulitol, ribitol and xylitol. There are carbohydrates such as Sorbitol is preferred as a diluent.

 Other excipients and / or auxiliaries are selected from, for example, binders, carriers, fillers, lubricants, flow control agents, crystallization retardants, solubilizers, colorants, pH adjusters, surfactants and emulsifiers, specific examples of which are second tablets. In connection with the layer composition is presented below. Excipients and / or adjuvants for the first tablet layer composition are preferably selected to obtain a rapidly dissolving tablet matrix that is not acidic.

The first tablet layer composition generally comprises from 3 to 50% by weight, preferably from 5 to 35% by weight of active ingredient; From 0.25 to 20%, preferably from 0.40 to 15% by weight of basic agent; Water-soluble diluent is included in the range of 30 to 95% by weight, preferably 60 to 80% by weight.

Other (optional) components may be selected from, for example, one or more excipients and / or adjuvants in the following designated doses.

Binder, carrier and filler (thus replacing water soluble diluent) 10-30% by weight, preferably 15-25% by weight,

0.1-5% by weight of lubricant, preferably 0.5-3% by weight,

0.1-5% by weight of flow regulator, preferably 0.3-2% by weight,

1 to 10% by weight of crystallization retardant, preferably 2 to 8% by weight,

Solubilizer 1 to 10% by weight, preferably 2 to 8% by weight,

0.05 to 1.5% by weight of colorant, preferably 0.1 to 0.8% by weight,

0.5-10% by weight of pH adjuster, preferably 2-8% by weight,

0.01 to 5% by weight of surfactant and emulsifier, preferably 0.05 to 1% by weight.

The second tablet layer composition includes a diuretic agent in the fast disintegrating tablet matrix. In a preferred embodiment, the disintegrating tablet matrix comprises fillers, binders, disintegrants and any other excipients and auxiliaries.

The filler is preferably selected from anhydrous lactose, spray dried lactose and lactose monohydrate.

The binder is selected from a dry binder group and / or a wet granular binder group, depending on the manufacturing process chosen for the preparation of the second tablet layer. Suitable dry binders are, for example, cellulose powder and microcrystalline cellulose. Specific examples of wet granular binders include corn starch, polyvinyl pyrrolidone [Povidon], vinylpyrrolidone-vinylacetate copolymer [CoPovidone] and cellulose derivatives such as hydroxymethylcellulose, hydroxy Hydroxyethylcellulose, hydroxypropyl-cellulose and hydroxypropylmethylcellulose).

Suitable disintegrants are, for example, sodium starch glycolate, crospovidone, croscarmellose, sodium carboxymethylcellulose and anhydrous corn starch, sodium starch glycolate.

When other excipients and auxiliaries are used, preferably cellulose powder, microcrystalline cellulose, cellulose derivatives (e.g. hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxy-propylmethylcellulose), dibasic phosphoric acid Diluents and carriers such as calcium, corn starch, pregelatinized starch, polyvinyl pyrrolidone (povidone), and the like; Lubricants such as stearic acid, magnesium stearate, sodium stearyl fumarate, glycerol tribehenate and the like; Flow regulators such as colloidal silica, talc and the like; Crystallization retardants such as povidone and the like; Solubilizers such as Pluronic, povidone and the like; Colorants including dyes and pigments such as iron oxide red or yellow, titanium dioxide, talc and the like; PH adjusting agents such as citric acid, tartaric acid, fumaric acid, sodium citrate, calcium phosphate dibasic, sodium phosphate dibasic and the like; Surfactants and emulsifiers such as pluronic, polyethylene glycol, sodium carboxymethyl cellulose, polyethoxylated castor oil, hydrogenated castor oil, and the like; And mixtures of two or more of these excipients and / or auxiliaries.

The second tablet layer composition generally comprises 1.5 to 35% by weight, preferably 2 to 15% by weight of the active ingredient; Filler is comprised between 25 and 75% by weight, preferably between 35 and 65% by weight; Dry binder comprises 10-40 wt%, preferably 15-35 wt%; 0.5 to 5% by weight, preferably 1 to 4% by weight, of the wet granular binder; Disintegrant is included 1 to 10% by weight, preferably 2 to 8% by weight. Other excipients and auxiliaries are generally used in amounts equal to those used in the first tablet layer composition.

The first tablet layer composition and the second tablet layer composition are compressed in a conventional manner in a bilayer tablet press (eg, a high speed rotary press in a bilayer tabletting method), so that a bilayer tablet according to the present invention can be prepared. However, care must be taken not to apply excessive compressive force to the first tablet layer. Preferably, the ratio of the compressive force applied to the compression of the first tablet layer to the compressive force applied to the compression of both the first tablet layer and the second tablet layer is 1:10 to 1: 2. For example, the first tablet layer may be compressed with an intermediate compressive force of 4 to 8 kN, where the first tablet layer and the second tablet layer are mainly compressed to a compressive force of 10 to 20 kN.

In the bilayer tablet compression process, a sufficient binding form between the two layers is achieved by distance attraction force (molecular force) and mechanical interlocking between the particles.

The bilayer tablet obtained quickly releases the active ingredient in a fairly pH-independent manner, completes the release within 60 minutes and the main fraction is released within 15 minutes. Dissolution / disintegration rates of bilayer tablets are controlled in different ways. For example, the two layers may dissolve and disintegrate at the same time. Preferably, however, the second tablet layer containing diuretic is first disintegrated, and the first tablet layer containing telmisartan is dissolved simultaneously or subsequently dissolved.

According to the invention, the rate of dissolution of the active ingredient, in particular telmisartan, is increased significantly. Typically, at least 70%, typically at least 90% of the drug load dissolves after 30 minutes.

Since the bilayer tablets of the present invention are rather hygroscopic, they are preferably moisture-proof, such as aluminum foil blister packs, or preferably polypropylene tubes with desiccant and high density polyethylene (HDPE) bottles. It is packaged using packaging materials.

To optimize dissolution / disintegration properties and drug release properties,

(i) preparing an aqueous solution comprising (a) telmisartan, at least one basic formulation and optionally a solubilizer and / or crystallization retardant, (b) spray drying the resulting aqueous solution to obtain spray dried granules (C) mixing the spray dried granules with a water-soluble diluent to obtain a premix, (d) mixing the premix with a lubricant to obtain a final blend for the first tablet layer, (e) step (a Providing a first tablet layer composition by optionally adding another excipient and / or adjuvant in any of steps) to (d),

(ii) (f) mixing and / or granulating the diuretic with the tablet matrix and any additional excipient and / or adjuvant components, (g) mixing the lubricant to obtain a final blend for the second tablet layer. Thereby providing a second tablet layer composition,

(iii) introducing a first tablet layer or a second tablet layer composition into a tablet press,

(iv) compressing the introduced one tablet layer composition to form a tablet layer,

(v) introducing the remaining tablet layer composition into a tablet press, and

(vi) A specific method of preparing a bilayer tablet according to the present invention has been developed, comprising compressing two tablet layer compositions to form a bilayer tablet.

In a preferred embodiment of the method, an alkaline aqueous solution of telmisartan is prepared by dissolving the active ingredient in purified water with the aid of one or more basic agents such as sodium hydroxide and meglumine. Optionally, solubilizers and / or recrystallization retardants may be added. The content of dry matter in the starting aqueous solution is generally 10 to 40% by weight, preferably 20 to 30% by weight.

The aqueous solution is then spray dried in a cocurrent or countercurrent spray dryer at room temperature or preferably at increased temperature (eg 50-100 ° C.) and spray pressure (eg 1-4 bar). In general, the spray drying conditions are preferably selected in such a way that spray dried granules having a residual moisture of 5% by weight or less, preferably 3.5% by weight or less are obtained in the separation cyclone. Finally, the exhaust air temperature of the spray dryer is preferably maintained between 80 and 90 ° C. and the remaining process parameters such as spray pressure, spray rate, inlet air temperature and the like are adjusted accordingly.

The spray dried granules obtained are preferably fine powders having the following particle size distribution.

d ₁₀ : 20 µm or less, preferably 10 µm or less

d ₅₀ : 80 µm or less, preferably 20 to 55 µm

d ₉₀ : 350 µm or less, preferably 50 to 150 µm

After spray drying, the active ingredient (telmisartan) and excipients contained in the spray dried granules are in a fairly amorphous phase and no crystalline is detected. From a physical point of view, the spray dried granule is a solidified solution or a glass with a glass transition temperature (Tg) of preferably above 50 ° C. and more preferably above 80 ° C.

Based on 100 parts by weight of the active ingredient (telmisartan), the spray dried granules preferably contain 5 to 200 parts by weight of the basic preparation, and optionally contain solubilizers and / or crystallization retardants.

Water-soluble diluents are generally used in the range of 30 to 95% by weight, preferably 60 to 80% by weight, 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% by weight, preferably 0.3 to 2% by weight, based on the weight of the first tablet layer composition.

The mixing comprises a first mixing step in which the spray dried granules and the diluent are mixed, for example using a high shear mixer or a free fall blender, and a second mixing step in which the lubricant is blended with the premix preferably under high shear conditions. Is carried out in a two-stage mixing. However, the method of the present invention is not limited to these mixing methods, and in general, another mixing method, for example, container mixing with an intermediate screen, is carried out in steps (c) and (d). Can also be used in subsequent steps (f) and (g).

For direct compression, the second tablet layer composition can be prepared by dry mixing the constituents, for example with a high strength mixer or a free fall blender. In addition to this, preferably, the second tablet layer composition is prepared using wet granulation technology, in which an aqueous solution of the wet granular binder is added to the premix, and the obtained wet particles are then, for example, fluid bed dryers or dried. It is dried in the chamber. After the dried mixture is screened, the lubricant is mixed using, for example, a tumbling mixer or a free fall blender, which composition can be compressed.

The first tablet layer and the second tablet layer composition are compressed in a bilayer tablet press, for example in a rotary press, in a bilayer tablet mode as described above to produce a bilayer tablet according to the present invention. In order to prevent any cross-contamination between the first and second purification layers (which can lead to decomposition of HTCZ), a die table in the tableting chamber is strongly sucked up during the tableting process. Any particle residues in must be carefully removed

To further illustrate the invention, the following non-limiting examples are presented.

Example  One

Configuration mg / 1.684mg SD granulation Volatile components kg / batch (01) Telmisartan 1.000 45.000 (02) Sodium hydroxide 0.084 3.780 (03) Povidone K 25 0.300 13.500 (04) Meglumine 0.300 13.500 (05) Purified water 5.000 (225.000) 1.684 5.000 75.780

Manufacturing method

1. Spray Solution

Weigh 225.000 kg of purified water in a suitable stainless steel container at 20-40 ° C. Then, 3.780 kg of sodium hydroxide, 45.000 kg of telmisartan (a mixture of polymorph A and polymorph B), 13.500 kg of povidone K 25 and 13.500 kg of meglumine were dissolved in purified water with vigorous stirring until almost clear. A light yellow alkaline solution is obtained.

2. Spray drying

Spray the solution in a suitable spray dryer, eg, "Niro P 6.3" equipped with a 1.0 mm diameter Schlick atomizing nozzle with a flow through heating coil connected to the top of the dryer. And dry to obtain white to off-white fine particles. The spray mode is countercurrent with a spray pressure of about 3 bar, an inlet air temperature of about 125 ° C., a spray rate of about 11 kg / h, and thus a resulting exhaust air temperature of about 85 ° C. The temperature of the continuous heating coil water batch is set to about 80 ° C.

3. Protective screening

The anhydrous particle powder is screened through a screen with a mesh size of 0.5 mm, for example using a Vibra Sieve machine.

The resulting amorphous telmisartan spray dried granules can be further processed into telmisartan monocomponent-tablet or the first layer of the bilayer tablet composition described above.

Example  2

Configuration mg / tablet first layer mg / SD granulation mg / tablet second layer (01) Telmisartan SD Granulation 67.360 Consists of components (02) to (06) (02) Telmisartan 40.000 (03) Sodium hydroxide 3.360 (04) Polyvidone (Kollidon 25) 12.000 (05) Meglumine 12.000 (06) Purified water 264.000 ^* (07) Sorbitol P / 6 168.640 (08) Screened Magnesium Stearate 4.000 1.000 (09) Hydrochlorothiazide 12.500 10 Microcrystalline Cellulose (Avicel PH 101) 64.000 (11) Iron oxide red 0.330 (12) Sodium starch glycolate 4.000 (13) Finely Screened Lactose Monohydrate 112.170 (14) Corn starch dried at 45 ℃ 6.000 240.000  67.360 200.000

^* 200mg at SD granulation + 64mg at granulation liquid of HCTZ granules

Manufacturing method

1. Final Blend A

168.640 kg of sorbitol is mixed with 67.360 kg of telmisartan spray dried granules for 4 minutes in a suitable high shear mixer using an impeller and chopper (eg Diosna P 600). 4.0 kg magnesium stearate is then added to the resulting premix and further mixed for 30 seconds in a high shear mixer.

2. Final Blend B

9.000 kg of purified water at about 70 ° C. is placed in a suitable mixing vessel and the corn starch dried at 45 ° C. is suspended in purified water. The suspension is stirred in 55.000 kg of purified water at about 90 ° C., for example using an Ekato stirrer.

Subsequently, 112.170 kg of lactose monohydrate, 12.500 kg of hydrochlorothiazide, 64.000 kg of microcrystalline cellulose (Avicel PH 101), 0.330 kg of iron oxide red, and 4.000 kg of sodium starch glycolate were added to a suitable high shear granulator (e.g. Diosna P 600). ) Until homogeneous, and moisten with 70.000 kg of the aqueous granulation liquid prepared above.

『Process Parameters of Wet Granulation』

Process steps Duration (minutes) Impeller (setting) Chopper (On) Premix 3 One One Wetting 2 One One Wet mix 4 2 2 exhaust About 0.5 One 0

The resulting wet particles are then dried in a suitable fluidized bed dryer (e.g. Glatt WSG 120) at an inlet air temperature of 100 ° C. and an inlet air flow rate of 2000 to 3000 m ³ / h until the product temperature reaches about 55 ° C. . The particle size is reduced by screening the anhydrous particles using a suitable screen machine (eg Comil screen machine) equipped with a rasp screen with a mesh size of 2 mm. Finally, 1.000 kg of pre-screened magnesium stearate is mixed into the screened granular material and mixed by rotating 100 times at a speed of 8 to 10 rpm in a suitable tumbling mixer (eg Lermer rotating spike mixer).

3. Bilayer Tablet Compression

Using a suitable rotary tablet press, 240 kg final blend A and 200 kg final blend B are extruded into bilayer tablets. The target weight of the first layer is 240 mg and the target weight of the second layer is 200 mg.

『Process Parameter of Purification』

Tablet press Fette 3090 Tableting rate 100.000 (80.000 to 120.000) tablets / hour Stirrer blade speed 1st layer: about 30rpm Second layer: about 75rpm Compressive force 5 (4 to 6) kN 12 (10-14) kN

In general, the hardness of the tablet is controlled by the variation of the main compressive force of the second layer.

『Characteristics of the produced bilayer tablets』

Shape / diameter Oval, double-sided convex / 14 × 6.8mm color First layer: white to off-white second layer: red weight 440 mg (total weight) 240 mg (first layer: containing telmisartan) 200 mg (second layer: containing hydrochlorothiazide) thickness 5.2 mm Hardness About 120N Disintegration time NMT 15 minutes (Total Time)

Example  3

Configuration mg / tablet first layer mg / SD granulation mg / tablet second layer (01) Telmisartan SD Granulation 67.360 Consists of components (02) to (06) (02) Telmisartan 40.000 (03) Sodium hydroxide 3.360 (04) Polyvidone (Kollidon 25) 12.000 (05) Meglumine 12.000 (06) Purified water (200.000) (07) Sorbitol P / 6 168.640 (08) Screened Magnesium Stearate 4.000 1.000 (09) Hydrochlorothiazide 25.000 10 Microcrystalline Cellulose (Avicel PH 101) 64.000 (11) Iron oxide yellow 0.330 (12) Sodium starch glycolate 4.000 (13) Finely Screened Lactose Monohydrate 105.67 240.000 67.360 200.000

Manufacturing method

Prepared in the same manner as in Example 2. Instead of the wet granulation process described in Example 2, the second layer composition was dried by rotating components (09) through component (13) at 200 rpm at a speed of 10 rpm in a suitable free-fall blender (e.g., 1 m ³ container mixer). To prepare. Subsequently, the main mixture is mixed by rotating component (08) an additional 50 times in a container mixer. Further premixing of the manually screened portion of microcrystalline cellulose with iron oxide yellow (eg 2.000 kg) through a 0.8 mm mesh screen is carried out prior to transfer to the main mixture to homogeneously distribute the pigment. The resulting bilayer tablets exhibit substantially the same physical properties as in Example 2 except for the color.

Example  4

`` Composition of telmisartan / hydrochlorothiazide bilayer tablet (mg / tablet) ''

ingredient 40 / 12.5 mg 80 / 12.5 mg Telmisartan  layer Telmisartan 40.000 80.000 Sodium hydroxide 3.360 6.720 Povidone 12.000 24.000 Meglumine 12.000 24.000 Purified water ^* (200.000) (400.000) Sorbitol 168.640 337.280 Magnesium stearate 4.000 8.000 `` The entire Telmisartan floor '' 240.000 480.000 Hydrochlorothiazide  layer Hydrochlorothiazide 12.500 12.500 Lactose Monohydrate 112.170 112.170 Microcrystalline cellulose 64.000 64.000 Corn starch 6.000 6.000 Iron oxide red 0.330 0.330 Sodium starch glycolate 4.000 4.000 Purified water <sup>*</sup> (64.000) (64.000) Magnesium stearate 1.000 1.000 `` HCTZ Floor Entire '' 200.000 200.000 Total weight of tablet 440.000 680.000

^* Not present in final product

Claims (11)

a) dissolving telmisartan in water with at least one basic agent selected from the group consisting of sodium hydroxide and meglumine to prepare an aqueous solution, and b) A process for preparing telmisartan or a pharmaceutically acceptable salt thereof, wherein at least 90% is in amorphous form, comprising spray drying the resulting aqueous solution to obtain spray dried granules. The method of claim 1, wherein the spray dried granules comprise 5 to 200 parts by weight of the basic preparation, based on 100 parts by weight of telmisartan. The method of claim 1 wherein the aqueous solution of telmisartan further comprises a solubilizer and / or a crystallization retardant. 4. A process according to claim 3, wherein the content of dry matter in the starting aqueous solution is generally from 10 to 40% by weight. The method of claim 1, wherein the aqueous solution is spray dried in a cocurrent or countercurrent spray dryer at room temperature or at an increased temperature of from 50 to 100 ° C. The method of claim 1 wherein the aqueous solution is spray dried at a spray pressure of 1-4 bar. The method of claim 1 wherein spray dried granules having a residual moisture of 5% by weight or less are obtained in a separate cyclone. 8. The method of claim 7, wherein the exhaust air temperature of the spray dryer is maintained at 80 to 90 ° C. The method of claim 1 wherein spray dried fine powder granules are obtained having the following particle size distribution. d ₁₀ : 20 µm or less d ₅₀ : 80 μm or less d ₃₀ : 350 µm or less The method of claim 1, wherein the spray dried granules are a solidified solution or a glass with a glass transition temperature (Tg) of greater than 50 ° C. 3. The method of claim 1 wherein the telmisartan and excipients contained in the spray dried granules are in an amorphous state in which no crystalline is detected.