SI22571A - Stable solid pharmaceutical preparation which includes candesartan orits pharmaceutically acceptable forms - Google Patents

Abstract

The invention relates to a stable solid pharmaceutical composition which comprises candesartan or its pharmaceutically acceptable forms, where granules of an active ingredient and at least one pharmaceutically acceptable component is prepared in a high-shear granulator, and where candesartan or its pharmaceutically acceptable forms are not dispersed in a solvent.

Description

A stable solid pharmaceutical composition comprising candesartan or pharmaceutically acceptable forms thereof

FIELD OF THE INVENTION

The present invention is in the field of the pharmaceutical industry, in particular with respect to a solid pharmaceutical composition. The invention particularly relates to a stable solid pharmaceutical composition comprising candesartan or its pharmaceutically acceptable forms, wherein the granules of the active ingredient and at least one pharmaceutically acceptable ingredient are prepared in a high shear granulation and where candesartan or its pharmaceutically acceptable forms are not dispersed in a solvent.

BACKGROUND OF THE INVENTION

Candesartan is a selective ATI subtype of angiotensin I-converting enzyme (ACE) inhibitory enzyme. It belongs to the class of medicines benzimidazole-7-carboxylic acid and its derivatives. These agents have a stronger and more effective hypotensive effect and are less likely to cause coughing as a side effect compared to other classes of ACE inhibitors.

In general, the formulation of candesartan or its pharmaceutically acceptable forms for effective oral administration to a subject has been difficult to date because of the unique physical and chemical properties of the compound. Candesartan or its pharmaceutically acceptable forms are known to be stable against temperature, moisture and light when in solid state and when incorporated into the pharmaceutical composition a decrease in the content of the active ingredient is observed. So far, they have addressed this problem in many different ways, with the main focus on solving stability problems.

EP 546358 A addresses the decomposition problem of candesartan and / or its pharmaceutically acceptable salts by incorporating a low melting point oily substance into the formulation.

WO 2005/070398 describes the dispersion of candesartan cilexetil in a solution comprising co-solvent and water to form a suspension.

A pharmaceutical formulation containing candesartan cilexetil and one or more fatty acids is described in WO 2005/079751.

As described in WO 2005/072709 and WO 2006074218, the formation of nanoparticles or microparticles of the drug can be solved.

WO 2005/084648 describes the use of water-soluble polymers to form a stable pharmaceutical composition of candesartan cilexetil with respect to impurity levels.

WO 2006/079496 discloses a solid pharmaceutical composition comprising from 2 to 20% of a hydrophilic substance having hydrocolloid properties.

US 2007/0014864 A, US 2007/0014853 A and US 2007/0014854 A describe pharmaceutical granules containing a substance with poor water solubility and at least one pharmaceutically acceptable sugar.

Therefore, it is desirable to design a stable solid pharmaceutical composition comprising candesartan or its pharmaceutically acceptable forms.

In particular, there is an ongoing need for an effective solid oral pharmaceutical composition comprising candesartan or pharmaceutically acceptable forms thereof having one or more of the following characteristics:

suitable particle size distribution of the active substance, suitable solubility of the active substance, suitable degradation time of the active substance, suitable dissolution profile of the active substance, suitable processability, commonly used and cost-effective pharmaceutically acceptable excipients, suitable economics of the technological process for the preparation of the finished medicinal product, adequate chemical and physical stability of the finished medicinal product , suitable bioavailability of the finished medicinal product prepared by the wet granulation process to:

increase the uniformity of distribution of the active substance in the formulation, thicken the granulate, such as e.g. a mixture of the active ingredient and at least one pharmaceutically acceptable excipient, increase the flow rates and speed uniformity, i.e. improve physical characteristics, reduce dust, improve appearance of solid dosage form.

Summary of the Invention

The invention relates to a process for stabilizing candesartan or its pharmaceutically acceptable forms by providing a stable solid pharmaceutical composition comprising candesartan or its pharmaceutically acceptable forms, wherein the granules of the active ingredient and at least one pharmaceutically acceptable ingredient are prepared in a high shear granulate and wherein candesartan or its pharmaceutically acceptable forms are not dispersed in the solvent.

Another aspect of the present invention relates to a stable solid pharmaceutical composition comprising candesartan or its pharmaceutically acceptable forms, wherein the granules of non-dispersible candesartan or its pharmaceutically acceptable forms and at least one pharmaceutically acceptable ingredient are prepared in a high shear granulate and where candesartan or its pharmaceutical forms they are not dispersed in the solvent.

In another aspect of the present invention, the present invention relates to a process for the preparation of a stable solid pharmaceutical composition comprising candesartan or pharmaceutically acceptable forms thereof, wherein the active ingredient granules and at least one pharmaceutically acceptable ingredient are prepared in a high shear granulation and wherein candesartan or pharmaceutically acceptable the forms are not dispersed in the solvent.

In another aspect of the present invention, the present invention relates to a method for treating hypertension, heart disease, cerebral apoplexy or renal disease in a patient in need of such treatment by administering a stable solid pharmaceutical composition comprising candesartan or its pharmaceutically acceptable forms, wherein the granules the active ingredients and at least one pharmaceutically acceptable ingredient are prepared in a high shear granulation and where candesartan or its pharmaceutically acceptable forms are not dispersed in the solvent.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a stable solid pharmaceutical composition comprising candesartan or its pharmaceutically acceptable forms, characterized in that the content, uniformity of contents and low impurity level are ensured by the choice of specific predefined pharmaceutically acceptable ingredients and by the technological process used for preparation of a solid stable pharmacist granulate. Furthermore, it has been an object of the present invention to provide a pharmaceutical composition comprising candesartan or pharmaceutically acceptable forms thereof, which is independent of the particle size of candesartan or its pharmaceutically acceptable forms. In addition, the object of the present invention was to achieve a homogeneous distribution of the active ingredient in the pharmaceutical composition.

More specifically, the invention relates to a process for stabilizing candesartan or its pharmaceutically acceptable forms by providing a stable solid pharmaceutical composition comprising candesartan or its pharmaceutically acceptable forms, wherein the granules of the active ingredient and at least one pharmaceutically acceptable ingredient are prepared in a high shear granulation and where candesartan or its pharmaceutically acceptable forms are not dispersed in the solvent.

The aforementioned goals are achieved by mitigating the negative effect of the electrostatic forces of candesartan or its pharmaceutically acceptable forms when incorporated into a pharmaceutical composition. It is known from the prior art that during the preparation of a pharmaceutical composition containing small, poorly soluble particles of the active substance, an electrostatic force plays an important role in a fluidized-bed pellet granulate. All known procedures, such as e.g. the use of candesartan or a pharmaceutically acceptable form thereof, wherein the active ingredient may or may not be dispersed in at least one pharmaceutically acceptable solvent, with the addition of specific excipients, to improve both solubility and stability, e.g. low-melting oily substances, fatty substances, water-soluble polymers, co-solvents, formation of candesartan formulations in nanoparticles, etc., did not give satisfactory results when candesartan or its pharmaceutically acceptable forms are present in the pharmaceutical composition. They found that the negative effect of electrostatic forces is even greater when candesartan or its pharmaceutically acceptable forms are not dispersed in a pharmaceutically acceptable solvent. Namely, due to the low solubility of candesartan or its pharmaceutically acceptable forms, the addition of one or more surfactants or one or more co-solvents is required, or other methods known in the pharmaceutical industry are required to improve solubility in order to improve solubility.

Surprisingly, we found that the negative effect of electrostatic forces is mitigated when a high shear granulator is used in the granulation process. Furthermore, it was surprisingly found that non-dispersible candesartan or its pharmaceutically acceptable forms can be used in the preparation of the granulate in a high shear granulator, which is a significant advantage over a fluid-bed granulator. This advantage is of particular importance in the case of candesartan or its pharmaceutically acceptable forms with content problems and content uniformity.

Furthermore, the processing time required for granulation in a high shear granulator is significantly shorter, which is particularly important in the case of candesartan or its pharmaceutically acceptable forms, when

a) the substance is exposed for a short time to high temperatures (it is known that candesartan or its pharmaceutically acceptable forms can be degraded at temperatures above about 50 ° C)

b) there is less possibility of including the particles of candesartan or its pharmaceutically acceptable forms in at least one pharmaceutically acceptable excipient, which means that the content of the active substance remains unchanged in the process,

c) granules of candesartan or its pharmaceutically acceptable forms and at least one pharmaceutically acceptable excipient are larger, which means that they cannot pass through the pores of filter bags than in the case of a fluid-cushion granulate and at the same time the influence of electrostatic forces is less;

d) the influence of the saturated density of candesartan or its pharmaceutically acceptable forms is reduced.

In addition, defects known in the art when using a high shear granulator in the case of candesartan or its pharmaceutically acceptable forms, represent an important precedent, such as:

a) the variation from batch to batch is less, while the influence of the electrostatic forces of candesartan or its pharmaceutically acceptable forms is minimized,

b) the uncontrolled growth of the granulate can be controlled by previously well-defined process parameters such as e.g. spray rate of granulime fluid, amount of solvent of granulime fluid, mixing of powders before, during and after addition of granulime fluid, kneading time, rotary speed of chopper, etc.

Another aspect of the present invention relates to a stable solid pharmaceutical composition comprising candesartan or its pharmaceutically acceptable forms, wherein the granules of non-dispersible candesartan or its pharmaceutically acceptable forms and at least one pharmaceutically acceptable ingredient are prepared in a high shear granulate and wherein candesartan or its pharmaceutical forms they are not dispersed in the solvent.

The term candesartan or its pharmaceutically acceptable forms, as used herein, refers to a prodrug that is hydrolyzed to candesartan during absorption from the gastrointestinal tract, more specifically to candesartan cilexetil. The concentration of candesartan or its pharmaceutically acceptable forms may be between about 1 to about 99%, especially between about 1 to about 30%, and in particular between about 2 to about 10%, determined by HPLC.

The term candesartan or its pharmaceutically acceptable forms as used herein refers to candesartan or its pharmaceutically acceptable esters, such as e.g. cilexetil, or pharmaceutically acceptable salts thereof, such as e.g. alkali salts or ammonium salts, and the active ingredient is candesartan cilexetil.

The average particle size of candesartan or its pharmaceutically acceptable forms may be between 1 and 50 µm, preferably between 41 µm, more preferably less than 20 µm, determined by laser diffraction on a Small Mastersizer 2000 instrument equipped with a Hydro S dispersion unit that is suitable for changing particle size distributions in the range of 20 nm to 2000 μιη. Usually isopar L. is used as the dispersing agent. Usually, 100-800 mg of the substance is dispersed in 5-10 ml of 2% epicuron (lecithin) solution in isopar L to obtain a homogeneous sample suspension. Measurement is started after adding the sample suspension to the dispersion unit and homogenizing with sonication, a reasonable time to split the agglomerates, and re-circulating at a stirrer / pump speed of about 50-70% of maximum speed.

Candesartan or its pharmaceutically acceptable forms present in the stable solid pharmaceutical composition of the present invention can be prepared by any method known in the art and can be in any known polymorphic form, in particular polymorphic Form I or in an amorphous form, more specifically in polymorphic form I.

As used herein, the term stable refers to candesartan or its pharmaceutically acceptable forms, wherein the content of candesartan or its pharmaceutically acceptable forms is between about 85 to about 115%, especially between about 90 to about 110% and more specifically about 95 to about 105% , determined by HPLC, where the uniformity of the content of at least two samples, such as e.g. granules, compression mixtures, tablets or, optionally, film-coated tablets, between about 75 and about 125%, in particular about 85 to about 115%, and in particular about 90 to 110%, determined by HPLC, where the sum of all impurities is less than 0 , 10% determined by HPLC, and where the sum of all impurities does not exceed 6% w / w, more preferably 2 and most preferably 1% w / w, determined by liquid chromatography, if stored for 7 days at 60 ° C in a closed dishes.

The stable solid pharmaceutical composition of the present invention may optionally contain one or more other active ingredients. Suitable other agents may include, but are not limited to, other angiotensin-II antagonists, diuretics, sympathetic agents, Ca-channel blockers, vasodilatoids, ACE inhibitors, angiotensin receptor antagonists, HMG-CoA reductase inhibitors and any other pharmaceutically acceptable combination, and in particular, other the active substance is selected from the group consisting of, but not limited to, angiotensin-II-antagonist, Ca channel blocker, diuretic, HMG-CoA reductase inhibitor. When two or more other active ingredients are present in the stable pharmaceutical composition of the present invention, they may be present at the same stage (intragranular phase or extragranular phase) as candesartan or its pharmaceutically acceptable forms or at a different stage as candesartan or its pharmaceutically acceptable forms. In addition, candesartan or its pharmaceutically acceptable forms and one or more other active ingredients may be present partially in the intragranules and partly in the extragranules phase. The concentration of candesartan or its pharmaceutically acceptable forms and one or more other active ingredients may be between about 1 and about 99%, especially between about 1 and about 30% and especially about 2 to about 20%, determined by HPLC.

The stable solid pharmaceutical composition of the present invention may further include one or more pharmaceutically acceptable ingredients, i.e. excipients, such as e.g. stabilizers, diluents, binders, decomposers, surfactants and lubricants. Other and further excipients may be included. The term pharmaceutically acceptable excipients denotes additives used to convert pharmacologically active compounds into pharmaceutical dosage forms suitable for administration to patients. The pharmaceutically acceptable excipients may be solid, liquid or semi-solid and, during the process, are converted to a condition which permits the preparation of a stable solid pharmaceutical composition comprising candesartan or pharmaceutically acceptable forms thereof. A pharmaceutically acceptable excipient may be present in the stable solid pharmaceutical composition of the present invention in an amount of from about 1 to about 99%, in particular from about 70 to about 99%, in particular from about 90 to about 98%.

The particle size of the excipients used in the stable solid pharmaceutical composition of the present invention is in the range D90 <750 pm, preferably D90 <500, to ensure homogeneity of the compression mixture and homogeneous granulation and compression. D90 means it has at least 90 vol. % of particles the particle size below the specified value.

A stable solid pharmaceutical composition of the present invention may contain one or more stabilizing agents selected from the group consisting of, but not limited to, polyols, such as e.g. glycerol, propylene glycol and macrogols, oils / glycerides such as e.g. castor oil, acetylated monoglycerides, fractionated coconut oil and lanolin, organic esters such as e.g. triacetin, phthalate esters such as polyvinyl acetate phthalate, cellulose acetate phthalate, dibutyl phthalate, diethyl phthalate, dimethyl phthalate, hypromellose phthalate, and sebacate, such as dibutyl sebacate and diethyl sebacate, aliphatic polyesters such as e.g. polylactide, polyglycolide, polylactide-co-glycolide, polycaprolactone and polylactide-co-caprolactone, copolymers of polymethyl vinyl ether / maleic anhydride such as Gantrez polymers, alginates such as e.g. sodium, potassium, ammonium, calcium and propylene glycol alginate, natural polysaccharides of marine origin, such as e.g. agar and carrageenan, of vegetable origin, such as acacia, ceratonia and tragacanth, or of animal origin, such as gelatin, surfactants such as e.g. sodium lauryl sulfate, benzalkonium chloride, cetrimide, sodium sodium, calcium stearoyl-2lactylate, citrate esters (such as triethyl citrate, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, acetyltri-2-ethylhexyl citrate, polyacrylate, polyacrylate eg Eudragit and Plastoid polymers, ethylene and vinyl and acetate polymers and copolymers such as polyethylene, polyvinyl alcohol, polyvinyl alcohol / poly vinyl acetate copolymer and ethylene vinyl acetate, various sweeteners such as sorbitol and xylitol, various additional softeners such as glycofurol, sodium benzoate, sodium polyphosphate and sodium stearyl fumarate, and other stabilizers such as menthol, amyl alcohol, etc. Preferably, one or more polyols, more preferably macrogols with an average molecular weight of between 900 and 35,000, are used as stabilizing agents. 900 and 20000, especially between 3000 and 9000. One or more stabilizers are present in an amount of from about 0.1 to about 20%, evil about 0.5 to about 15%, especially about 0.5 to about 10%.

The diluents used in the stable solid pharmaceutical composition of the present invention may be selected from, but not limited to, microcrystalline cellulose, powdered cellulose, lactose (anhydrous and monohydrate), compressible sugar, fructose, dextrates, sugar alcohols, such as mannitol, sorbitol, maltitol, xylitol, lactitol, or other sweetening matter, such as sucrose, raffinose, trehalose, fructose or mixtures thereof, siliconized microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate or any mixture thereof, preferably microcrystalline microcrystalline and mannitol or any mixture thereof, more preferably microcrystalline cellulose and lactose.

The binders used in the stable solid pharmaceutical composition of the present invention may be selected from, but not limited to, polyvinylpyrrolidone, microcrystalline cellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose or other cellulose acrylate or other cellulose acrylate or other cellulose acrylate, or other cellulose acrylate, ether any mixture thereof. It is preferable to use a binder with good water solubility. Due to the practical insolubility of starch in cold water, binders with very good cold water solubility are very preferred. They are many binders that have very good water solubility, such as. povidone with different strengths and hydroxypropylcellulose, such as partially substituted poly (hydroxypropyl) cellulose ether and / or low substituted poly (hydroxypropyl) cellulose ether. Preferably at least one binder is selected from polyvinylpyrrolidone and hydroxypropylcellulose.

The disintegrants used in the stable solid pharmaceutical composition of the present invention can be selected from, but not limited to, crospovidone, starch, pre-gelatinized starch, sodium starch glycolate, microcrystalline cellulose, sodium carboxymethylcellulose (CMC-Na) or calcium carboxymethylcellulose (CMC-Ca), cross-linked CMC-Na, polacrylin potassium, low substituted hydroxypropylcellulose, or any mixture thereof. Preferably at least one disintegrant is selected from crosslinked CMC-Na, starch and low substituted hydroxypropylcellulose.

Surfactants used in the stable solid pharmaceutical composition of the present invention can be selected from, but are not limited to, the group:

Anionic surfactants wherein the hydrophilic group bears a negative charge, such as e.g. carbonyl (RCOO), sulfonate (RSO ₃ ) or sulfate (ROSO3), examples are potassium laurate, CH ₃ (CH ₂ ) and ₀ COO'K ⁺ and sodium lauryl sulfate, CH ₃ (CH ₂ ) nSO ₄ 'Na ⁺ .

2. Cationic surfactants in which the hydrophilic group bears a positive charge (eg quartemium ammonium halides, (KtN + Cf), examples being cetrimide, a mixture consisting mainly of tetradecyl (about 68%), dodecyl (about 22%) and hexadecyltrimethylammonium bromides (about 7%), as well as benzalkonium chloride, a mixture of alkylbenzyldimethylammonium chlorides of the general formula [CeHjCH ^ (CH ₃ ) ₂ R] Cr, where R represents a mixture of alkyl of CgHn to C ₈ H ₃ 7.

3. Ampholytic surfactants (also called amphoteric surfactants), wherein the molecule contains or can potentially contain both a negative and a positive charge, (e.g. sulfobetaine, RN ⁺ (CH3) 2CH2CH2SO3), examples being 7V-dodecyl-A, N-dimethylbetaine, Ci ₂ H 25 N ⁺ (CH 3) ₂ CH ₂ COO.

4. Non-ionic surfactants, where the hydrophil is not charged but originates its water solubility from high-polymers such as hydroxyl or polyoxyethylene (OCH ₂ CH ₂ O) groups, such as polyoxyethylated glycol monoethers (eg cetomacrogol), sorbitan esters (Span® ) and polysorbates (Tween ^@ ), polyoxyethylene-polyoxypropylene copolymers.

The lubricants used in the stable solid pharmaceutical composition of the present invention may be selected from, but not limited to, stearic acid or salts of stearic acid, such as e.g. magnesium stearate, magnesium palmitate, magnesium oleate, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, macrogols or mixtures thereof. Preferably the excipients include at least one lubricant selected from stearic acid, magnesium stearate, hydrogenated vegetable oil, hydrogenated castor oil and talc, more preferably magnesium stearate, hydrogenated castor oil and talc.

Optionally, the cores / tablets can be coated with conventional materials used for film coating, i.e. as described in Pharmaceutical Coating Technology (G. Cole (ed.), 1995). Film coating formulations typically contain the following components:

polymer (s), plasticizer (s), dye (s) / misting agent (s), solvent (s).

In the film coating suspension, smaller amounts of flavors, surfactants and waxes can be used. Most of the polymers used in the film coating are either cellulose derivatives, such as cellulose ethers, or acrylic polymers and copolymers. Occasionally, high molecular weight polyethylene glycols such as e.g. macrogols, polyvinylpyrrolidone, polyvinyl alcohol and waxy materials. Their function is usually to prevent bad feeling and / or taste in the mouth and, in some cases, decomposition, e.g. oxidation of the substances and / or excipients used.

Typical cellulose ethers that can be applied as coatings are hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose. Acrylic polymers comprise a group of synthetic polymers with different functionalities. Some of these can be further modified to increase swelling and permeability, by embedding materials such as water-soluble cellulose ethers and starches to ensure complete decomposition / dissolution of the film.

Commonly used plasticizers can be categorized into three groups:

polyols (glycerol, propylene glycol, macrogols), organic esters (phthalate esters, dibutyl sebacetate, citrate esters, triacetin), oils / glycerides (castor oil, acetylated monoglycerides, fractionated coconut oil).

Coloring agents / opacifiers are classified into several groups:

organic dyes and their varnishes, inorganic dyes, natural dyes.

Solvents are materials that perform the necessary function by providing a means of transporting coating materials to the surface of a tablet or particle. The main classes of solvents that can be used are water, alcohols, ketones, esters, chlorinated hydrocarbons.

Different materials from each group can also be combined in defined proportions. Film-coated suspensions can also be used as ready-made, commercially available preparations.

The film coating dispersion can be prepared using various solvents, such as e.g. water, alcohols, ketones, esters and chlorinated hydrocarbons, preferably water.

Coating suspension composition (calculated on dry material) comprising:

1-99 wt. %, preferably 1-95 wt. % of polymer,

1-50 wt. %, preferably 1-40 wt. % plasticizer,

0.1-20 wt. %, preferably 0.1-10 wt. % dye / opacifying agent is particularly preferred.

An ingredient described as a component of a coating layer, e.g. such as colorants can also be embedded in the tablet core or distributed between the tablet core and the film coating layer.

The stable solid pharmaceutical composition of the present invention is preferably in the form of tablets, pills, powders, suction tablets, bags, soft and hard gelatin capsules, suppositories, etc. The dosage form is preferably suitable for oral administration.

The stable solid pharmaceutical composition of the present invention is preferably formulated in a unit dosage form, each dose containing about 1 to 100 mg, more typically about 1 to about 50 mg of candesartan cilexetil, preferably from about 2 to 32 mg. When one or more other active ingredients are present in the stable solid pharmaceutical composition of the present invention, the other active ingredient may be present in an amount of 6.25 to 50 mg, preferably in an amount of 12.5 to 25 mg. The term unit dosage form refers to physically discrete units suitable as unit doses for humans and other mammals, each unit containing a predetermined amount of candesartan cilexitil calculated to produce the desired therapeutic effect, together with a suitable pharmaceutically acceptable excipient. In another aspect of the present invention, the invention relates to a process for the preparation of a stable solid pharmaceutical composition comprising candesartan or pharmaceutically acceptable forms thereof, wherein the active ingredient granules and at least one pharmaceutically acceptable ingredient are prepared in a high shear granulator and where candesartan or its pharmaceutically acceptable forms are not dispersed in the solvent.

The process for preparing a stable solid pharmaceutical composition of the present invention comprises the following steps:

granulation process for the preparation of the intragranulame phase, comprising the following steps:

o granulation of a mixture of individual components, that is, at least one component selected from the group of one or more active ingredients and one or more pharmaceutically acceptable excipients, using a fluid granuloma, o drying the resulting mixture, o optionally sieving to obtain a granulate, preparation of the extragranular phase, comprising the addition of at least one component selected from the group of one or more active ingredients and one or more pharmaceutically acceptable excipients to the granulate to obtain a compression mixture, compression compression mixture, optionally coating.

The granulation process is performed in a high shear granulation. The term high shear granulator, as used herein, defines various ways of performing granulation known in the art, such as e.g. in Handbook of Pharmaceutical Granulation Technology (D. M. Parikh (ed.), 1997):

low shear mixer, high shear mixer, extrusion a / spheres a, continuous mixing granulator (mechanical).

Candesartan or its pharmaceutically acceptable forms are first prepared by a suitable synthetic process and then purified, such as e.g. by crystallization or otherwise. The size of the active ingredient is then determined and if the particles are found to have an average diameter of more than 50 µm, then these active ingredient particles are reduced in any known pharmaceutically acceptable manner, such as e.g. grind or grind to a smaller average particle size of less than 50 pm, preferably less than 40 pm and more preferably less than 20 pm.

Table 1: Incorporation of candesartan or its pharmaceutically acceptable forms into a stable solid pharmaceutical composition of the present invention

Performance Intragranular phase Extragranules phase candesartan or his pharmaceutically acceptable forms candesartan or his pharmaceutically acceptable forms A - + B + - C + +

+ present in the intragranules and / or extragranules phase

- is not present in the intragranules and / or extragranules phase

Table 2: Incorporation of candesartan or its pharmaceutically acceptable forms and other active ingredients into a stable solid pharmaceutical composition of the present invention

Performance Intragranular phase Extragranules phase candesartan or its pharmaceutical acceptable forms the other active substance candesartan or his pharmaceutical acceptable forms the other active substance a ' - + + - a - - + + b ' + + - - b + - - + c ' + + + - c + - + + d ' + + - + d - + + + d ' + + + +

+ present in the intragranules and / or extragranules phase

- is not present in the intragranules and / or extragranules phase

Table 1 contains at least one component selected from the group of candesartan or its pharmaceutically acceptable forms and one or more pharmaceutically acceptable excipients in both the intragranules and the extragranules phase. In embodiment A, the granulate is prepared without including candesartan cilexetil or its pharmaceutically acceptable forms. In embodiment B, a granulate comprising candesartan cilexetil or pharmaceutically acceptable forms thereof is prepared. In embodiment C, candesartan cilexetil or its pharmaceutically acceptable form is partitioned between the intragranular and extragranular phases. Further, the pharmaceutically acceptable excipients and film coating components may be distributed between the intragranular and extragranular phases and optionally per coating layer, either individually or in a mixture of at least two components. Further, at least two components may be homogenized together prior to use in a technological process to ensure homogeneity in a pharmaceutical formulation, e.g. homogenisation of the dye (dyes / opacifying agent (s) with at least one diluent, etc.).

Table 2 contains at least one component selected from the group of candesartan or its pharmaceutically acceptable forms and other active ingredient and one or more pharmaceutically acceptable excipients in both the intragranules and the extragranules phase. In embodiments (a '), (a) and (d), the granulate is prepared without including candesartan cilexetil or its pharmaceutically acceptable forms. In embodiments (a), (b) and (c), the granulate is prepared without the inclusion of another active ingredient. In embodiments (b '), (b) and (d'), a granulate comprising candesartan cilexetil or its pharmaceutically acceptable forms is prepared. In embodiments (a ¹ ), (b ') and (c'), a granulate comprising the second active ingredient is prepared. In embodiments (c ') and (c), candesartan cilexetil or its pharmaceutically acceptable forms are distributed between the intragranular and extragranular phases. In embodiments (d ') and (d), the second active ingredient is distributed between the intragranular and extragranular phases. In embodiment (d '), both candesartan cilexetil or its pharmaceutically acceptable salts and other active ingredient are distributed between the intragranular and extragranular phases.

The process of granulating a mixture of individual components, as defined above, can be performed in conventional high shear granulation equipment by spraying water, alcohol, water / alcohol mixture, or aqueous, alcoholic or aqueous / alcoholic granulating fluid per excipient, or a mixture of excipients by conventional pharmaceutical techniques. for granulation. The granulation process may also be carried out by the direct addition of water, alcohol, a water / alcohol mixture or the aqueous, alcoholic or aqueous / alcohol granulomas of a mixture of excipients during a mixing operation in a mixing device. The preferred solvent is purified water. The term aqueous, alcoholic or aqueous / alcoholic granulima fluid refers to an aqueous, alcoholic or aqueous / alcoholic dispersion containing purified water or demineralized water or lower alcohols, such as e.g. methanol, ethanol and isopropanol and optionally at least one pharmaceutically acceptable excipient which is dispersed, suspended or dissolved in a solvent. In the present invention candesartan or its pharmaceutically acceptable forms are not dispersed in the solvent.

Drying of the mixture obtained as described above can be accomplished in any of the following ways: trays, fluid cushion, vacuum / gas evacuation using microwaves (single pot processing), or any other pharmaceutically acceptable means.

The sieving process can be carried out by conventional known methods.

The preparation of the extragranuloma phase, comprising the addition of at least one component selected from the group of one or more active ingredients and one or more pharmaceutically acceptable excipients, to the granulate to form a compression mixture can be carried out in a conventional apparatus used for mixing powders, such as e.g. passive mixers, diffusion, dual cone diffusion, single cone, double cone, turbulence, cubic, planetary,

Υ-, V-shaped mixers, low-shear or high-shear mixers, or in any other pharmaceutically acceptable manner.

The process of compressing the compression mixture can be performed by conventional known methods performed on conventional equipment, such as e.g. on an automatic rotary press machine.

The coating process can be performed by conventional known methods performed on conventional equipment, such as e.g. on an automatic coating machine.

Another aspect of the present invention is a method of treating hypertension, heart disease, cerebral apoplexy or renal disease in a patient in need of such treatment by administering a stable solid pharmaceutical composition comprising candesartan or its pharmaceutically acceptable forms, wherein the active ingredient granules and at least one the pharmaceutically acceptable constituents are prepared in a high shear granulation and where candesartan or its pharmaceutically acceptable forms are not dispersed in the solvent.

For a more complete understanding of the present invention, reference is made to the following illustrative examples, although it should be clearly understood that the present invention is by no means limited thereto.

Reference case 1

The formulation was prepared according to Example 1 EP 546358 A with the following composition:

The pattern Control A B candesartan cilexetil 1.0 mg 1.0 mg lactose 93,0 mg 99.0 mg corn starch 20,0 mg 20,0 mg

macrogol 6000 6.0 mg / hydroxypropylcellulose (water) 4.0 mg (0.135 mL) 4.0 mg (0.135 mL) calcium carboxymethyl- cellulose 5,6 mg 5,6 mg magnesium stearate 0,40 mg 0.4 mg

Preparation of Reference Example 1 - Sample A

Candesartan cilexetil, lactose, corn starch and macrogol 6000 were homogenized in a fluid-bed dryer chamber and sprayed with an aqueous hydroxypropyl cellulose solution. The mass is granulated and dried to give a granulate. The loss on drying (measurement performed on a Mettler Toledo HR73 halogen humidity analyzer at 85 ° C for 20 minutes) of the granulate is 1.90%. Calcium carboxymethylcellulose and magnesium stearate are added to the granulate to form a compression mixture. The mixture was compressed into tablets of a theoretical weight of 130 mg. The tablet hardness is 67-75 N and the break-up time (purified water 37 ° C) is 7 minutes.

Preparation of Reference Example 1 - Control B

Candesartan cilexetil, lactose and corn starch were homogenized in a fluid-bed dryer and sprayed with an aqueous hydroxypropylcellulose solution. The mass was granulated and dried to give a granulate. The loss on drying (measurement performed on a Mettler Toledo HR73 halogen humidity analyzer at 85 ° C for 20 minutes) of the granulate is 1.16%. Calcium carboxymethylcellulose and magnesium stearate are added to the granulate to form a compression mixture. The mixture was compressed into tablets of a theoretical weight of 130 mg. The tablet hardness is 78-92 N and the breakup time (purified water, 37 ° C) is 7 minutes.

Table 3: Stability test results - amount of impurity of tensile candesartan (or oxocandesartan) and initial candesartan cilexetil content

test time sample control A B start time 0.29% 0.34% after storage at 40 ° C / 75% for 14 days 0.32% 0.35% after storage at 40 ° C 14 days 0.36% 0.52% after storage at 50 ° C 14 days 0.40% 0.64% after storage at 40 ° C / 75% 1 month 0.35% 0.42% after storage at 40 ° C 1 month 0.41% 0.59% after storage at 50 ° C 1 month 0.52% 0.83% candesartan content cilexetil at initial time 116,1% 98.1%

Stability testing is performed under different storage conditions (40 ° C / 75% relative humidity, 40 ° C, 50 ° C) at a defined test time (initial, after 14 days and after 1 month). Table 3 above shows that the granulation of sample A (a formulation comprising macrogol 6000) in the fluid cushion shows an advantage over the control sample over the impurity level, while at the same time the candesartan cilexetil content in sample A is high.

Example 1

Candesartan cilexetil, lactose monohydrate, maize starch and ferrioxide red (except in the case of 3 A) were homogenized in a fluidized bed granulator chamber and sprayed with an aqueous solution of macrogol 8000 (or macrogol 6000) and hydroxypropylcellulose. The mass was granulated and dried to give a granulate. Calcium carboxymethylcellulose and magnesium stearate are added to the granulate to form a compression mixture.

sample sample sample sample sample sample sample A (mg) B (mg) C (mg) D (mg) E (mg) F (mg) G (mg) candesartan Cilexetil 4.0 32,0 32,0 32,0 32,0 32,0 32,0 lactose monohydrate 94.0 336,5 336,5 336,5 328,4 336,5 336,5 corn starch 16.0 56,0 56,0 56,0 56,0 56,0 56,0 ferioxide Red / 4.0 4.0 4.0 2.0 4.0 4.0 macrogol 8000 6,00 12,0 12,0 12,0 macrogol 6000 24,0 12,0 12,0 hydroxy- propyl- cellulose 4.0 16.0 16.0 16.0 16.0 16.0 16.0 calcium carboxy- methylcellulose 5,6 20,0 20,0 20,0 20,0 20,0 20,0

magnesium stearate 0.4 3.5 3.5 3.5 16,00 16.0 16.0 size labor. labor. labor. labor. pilot industr. industr. batches criterion criterion criterion criterion criterion criterion criterion content candesartan Cilexetil at initial time 103,9% 94.7% 97.8% 95.7% 103,0% 93,3% 97.3%

Table 4: Particle size distribution of candesartan cilexetil used in the samples as described above (laser diffraction measurement)

distribution size candesartan particles Cilexetil batch 1 used in samples A, B, C, F, Mr batch 2 used in sample D batch 3, used in sample E average size particles 4 pm 36 pm 41 pm 10% of the particles smaller than 1,1 pm 5,0 pm 2,1 pm 90% of the particles smaller than 6,8 pm 81 pm 40,1 pm

The main difference between sample B and sample C is that in sample B, the ferioxide was ground with corn starch, while in the latter, the ferrioxide was ground with lactose monohydrate. Ferioxide was also ground with corn starch in sample E, while in sample F and G, ferioxide was ground with lactose monohydrate.

In sample G, candesartan cilexetil was added to other excipients at a lower air flow rate (200 m / h) and was exposed to a maximum air flow rate of 350 m / h.

In sample F with the same formulation composition as in sample G, candesartan cilexetil was exposed to an air velocity of 750 m / h.

As can be seen from the results in the table above, in the proportional increase of the pharmaceutical compositions described above, there is a problem with the content of candesartan cilexetil. The above results of testing the candesartan cilexetil content at the initial time, where the granulate is prepared by granulation in a fluid cushion, show great variation from batch to batch. This negative effect is particularly pronounced in the case of candesartan cilexetil with a small average particle size.

Example 2

Candesartan cilexetil, lactose monohydrate, ferrioxide red and calcium carboxymethylcellulose are mixed in a high-shear granulation. Macrogol 8000 and hydroxypropylcellulose were dissolved in purified water to give a granular liquid. The homogenized mixture is granulated with a granular fluid. The mass is granulated and dried to give a granulate. Drying loss reduction (IPS) is performed on a Mettler Toledo HR73 halogen humidity analyzer at 85 ° C for 20 minutes. Corn starch and magnesium stearate are added to the granulate to form a compression mixture. The mixture was compressed into tablets of a theoretical weight of 480 mg. We measure tablet hardness and decay time (purified water, 37 ° C) for all formulations.

sample A sample B candesartan cilexetil 32,0 mg 32,0 mg lactose monohydrate 336,5 mg 324.5 mg calcium carboxymethyl- cellulose 20,0 mg 20,0 mg ferioxide red 4.0 mg 4.0 mg macrogol 8000 12.0 mg 24,0 mg hydroxypropylcellulose 16.0 mg 16.0 mg corn starch 56,0 mg 56,0 mg magnesium stearate 3,50 mg 3,50 mg

batch size labor. criterion industrial scale IPS granules 1.61% 1.43% IPS Compression Compounds 2.30% 2.35% hardness 83-113 N 92-108 N decay time 13.5-14 minutes 12 minutes candesartan content cilexetil at initial time 100.7% 100,5%

The total impurity content of both samples A and B was <0.5% determined by HPLC.

The above table shows that the preparation of pharmaceutical compositions, where the granulation is carried out in a high shear granulation, produces similar results on a laboratory and industrial scale on various scales, i.e. within the specification for candesartan cilexetil content (specification: 95-105%) (result 100.7% and 100.5% for samples A and B) and within the specification for impurities (specification: <0.5%). Drying in a fluid cushion dryer does not depend on the size of the candesartan cilexetil particles, so that the wet mixture cannot flow through the filter bags of the fluid cushion granulate even if a small size of candesartan cilexetil is used.

It can be concluded that the problems of candesartan cilexetil content in the pharmaceutical composition depend largely on the use of granulation in the fluid cushion and, moreover, on the criterion used. The negative effect is particularly pronounced in the case of candesartan cilexetil with a small average particle size. Furthermore, the granulation of pharmaceutical compositions in a fluid cushion, as described in Example 1, may be affected by the pore size of the filter bags in the granulate and process parameters such as e.g. air flow velocity, etc. These effects are controlled by the stabilization process of candesartan or its pharmaceutically acceptable forms by providing a stable solid pharmaceutical composition comprising candesartan or its pharmaceutically acceptable forms, wherein the active ingredient granules and at least one pharmaceutically acceptable ingredient are prepared in a high shear granulator and wherein candesartan or its pharmaceutically acceptable forms are not dispersed in the solvent.

Example 3

The hydroxypropyl cellulose and triethyl citrate were dissolved in water and candesartan cilexetil, lactose monohydrate and starch were granulated in a high shear granulator. After the granulation step is performed, calcium carboxymethylcellulose and magnesium stearate are added to the granules. The resulting composition is then molded into tablets.

ingredient quantity (mg) candesartan cilexetil 4.0 lactose monohydrate 90,0 starch 20,0 triethyl citrate 6.0 hydroxypropyl cellulose 4.0 calcium carboxymethyl cellulose 5,6 magnesium stearate 0.4

Claims (26)

A method for stabilizing candesartan or its pharmaceutically acceptable forms by providing a stable solid pharmaceutical composition comprising candesartan or its pharmaceutically acceptable forms, wherein the active ingredient granules and at least one pharmaceutically acceptable ingredient are prepared in a high shear granulate and wherein candesartan or its the pharmaceutically acceptable forms are not dispersed in the solvent. A method for stabilizing candesartan or its pharmaceutically acceptable forms according to claim 1, wherein the stable solid pharmaceutical composition comprises candesartan or its pharmaceutically acceptable forms and at least one of the pharmaceutically acceptable ingredients selected from the group consisting of one or more stabilizable agents, one or multiple diluents, one or more binders, one or more disintegrating agents, one or more surfactants, one or more lubricants. The process for stabilizing candesartan or its pharmaceutically acceptable forms according to claim 2, wherein the one or more stabilizable agents is selected from the group consisting of polyethylene glycol having an average molecular weight between 900 and 35000. A method for stabilizing candesartan or its pharmaceutically acceptable forms according to claim 2, wherein one or more stabilizable agents is selected from citrate esters. The process for stabilizing candesartan or its pharmaceutically acceptable forms according to claim 2, wherein one or more diluents are selected from the group consisting of microcrystalline cellulose and lactose. The process for stabilizing candesartan or its pharmaceutically acceptable forms according to claim 2, wherein one or more binders are selected from the group consisting of polyvinylpyrrolidone and hydroxypropyl cellulose. The method for stabilizing candesartan or its pharmaceutically acceptable forms according to claim 2, wherein one or more disintegrants are selected from the group consisting of CMC-Na, starch and low substituted hydroxypropyl cellulose. The process for stabilizing candesartan or its pharmaceutically acceptable forms according to claim 2, wherein one or more surfactants are selected from the group consisting of anionic or cationic surfactants, ampholytic surfactants and non-ionic surfactants. The process for stabilizing candesartan or its pharmaceutically acceptable forms according to claim 2, wherein one or more lubricants are selected from the group consisting of stearic acid, magnesium stearate, hydrogenated vegetable oil, hydrogenated castor oil and talc. The process for stabilizing candesartan or its pharmaceutically acceptable forms according to claim 2, wherein the stable solid pharmaceutical composition comprises candesartan cilexetil, lactose, corn starch, polyethylene glycol, hydroxypropylmethyl cellulose, calcium carboxymethyl cellulose and magnesium stearate. The method for stabilizing candesartan or its pharmaceutically acceptable forms according to claim 2, wherein the stable solid pharmaceutical composition comprises candesartan cilexetil, lactose, corn starch, citrate ester, hydroxypropylmethyl cellulose, calcium carboxymethyl cellulose and magnesium stearate. The method for stabilizing candesartan or its pharmaceutically acceptable forms according to claim 2, wherein the stable solid pharmaceutical composition comprises candesartan cilexetil, lactose, microcrystalline cellulose, citrate ester and magnesium stearate. A stable solid pharmaceutical composition comprising candesartan or its pharmaceutically acceptable forms, wherein the granules of non-dispersible candesartan or its pharmaceutically acceptable forms and at least one pharmaceutically acceptable ingredient are prepared in a high shear granulate and where candesartan or its pharmaceutically acceptable forms are not dispersible. A stable solid pharmaceutical composition comprising candesartan or its pharmaceutically acceptable forms according to claim 13, wherein the stable solid pharmaceutical composition comprises candesartan or its pharmaceutically acceptable forms and at least one of the pharmaceutically acceptable ingredients selected from the group consisting of one or more stabilizers agents, one or more diluents, one or more binders, one or more disintegrating agents, one or more surfactants, one or more lubricants. A stable solid pharmaceutical composition comprising candesartan or its pharmaceutically acceptable forms according to claim 14, wherein one or more stabilizing agents is selected from the group consisting of polyethylene glycol with an average molecular weight between 900 and 35000. 16. A stable solid pharmaceutical composition comprising candesartan or pharmaceutically acceptable forms thereof according to claim 14, wherein one or more stabilizing agents is selected from citrate esters. 17. A stable solid pharmaceutical composition comprising candesartan or pharmaceutically acceptable forms thereof according to claim 14, wherein one or more diluents are selected from the group consisting of microcrystalline cellulose and lactose. 18. A stable solid pharmaceutical composition comprising candesartan or pharmaceutically acceptable forms thereof according to claim 14, wherein one or more binders are selected from the group consisting of vinylpyrrolidone and hydroxypropyl cellulose. A stable solid pharmaceutical composition comprising candesartan or its pharmaceutically acceptable forms according to claim 14, wherein one or more disintegrants are selected from the group consisting of CMC-Na, starch and low substituted hydroxypropyl cellulose. 20. A stable solid pharmaceutical composition comprising candesartan or its pharmaceutically acceptable forms according to claim 14, wherein one or more surfactants are selected from the group consisting of anionic or cationic surfactants, ampholytic surfactants and non-ionic surfactants. A stable solid pharmaceutical composition comprising candesartan or its pharmaceutically acceptable forms according to claim 14, wherein one or more lubricants are selected from the group consisting of stearic acid, magnesium stearate, hydrogenated vegetable oil, hydrogenated castor oil and talc. A stable solid pharmaceutical composition comprising candesartan or pharmaceutically acceptable forms thereof according to claim 14, wherein the stable solid pharmaceutical composition comprises candesartan cilexetil, lactose, corn starch, polyethylene glycol, hydroxypropylmethyl cellulose, calcium carboxymethyl cellulose methylcellulose cellulose methylcellulose. 23. A stable solid pharmaceutical composition comprising candesartan or pharmaceutically acceptable forms thereof according to claim 14, wherein the stable solid pharmaceutical composition comprises candesartan cilexetil, lactose, corn starch, citrate ester, hydroxypropylmethyl cellulose, calcium carboxymethyl celluloseearyl celluloseearl. A stable solid pharmaceutical composition comprising candesartan or pharmaceutically acceptable forms thereof according to claim 14, wherein the stable solid pharmaceutical composition comprises candesartan cilexetil, lactose, microcrystalline cellulose, citrate ester and magnesium stearate. 25. A process for the preparation of a stable solid pharmaceutical composition comprising candesartan or its pharmaceutically acceptable forms according to claims 13 to 24, comprising the steps of: granulation process for the preparation of the intragranulame phase, comprising the following steps: o granulation of a mixture of individual components, that is, at least one component selected from the group of one or more active ingredients and one or more pharmaceutically acceptable excipients, using a fluid granuloma, o drying the resulting mixture, o optionally sieving to obtain a granulate, preparation of the extragranular phase, comprising the addition of at least one component selected from the group of one or more active ingredients and one or more pharmaceutically acceptable excipients to the granulate to obtain a compression mixture, compression compression mixture, optionally coating. 26. A method for treating hypertension, cardiac infections, cerebral apoplexy, or kidney disease in a patient in need of such treatment, by administering a stable solid pharmacists ^ gg ^ composition ^ J ^ comprising candesartan or its pharmaceutically acceptable forms ^^ gram gram-active ingredient and at least one pharmaceutical acceptable ingredients are prepared in a high shear gnbnulator and where candesartan or its pharmaceutically acceptable forms are not dispersed in the solvent.