MXPA96002103A - Pharmaceutical compositions containing irbesar - Google Patents

Abstract

A pharmaceutical composition containing irbesartan, alone or in combination with a diuretic, is described, which provides tablets with a relatively large amount of active ingredient and excellent wetting and disintegrating properties.

Description

REF: 22522 PHARMACEUTICAL COMPOSITIONS CONTAINING IRBESARTAN FIELD OF THE INVENTION The present invention relates to pharmaceutical compositions containing irbesartan, preferably in the form of a tablet. The present invention also relates to tablets prepared from these compositions.

BACKGROUND OF THE INVENTION Irbesartan, 2-n-butyl-4-spirocyclopentan-1 - [(2 '- (tetrazol-5-yl) biphenyl-4-yl) methyl] -2-imidazolin-5-one, is a potent receptor antagonist of angiotensin II, long-acting, which is particularly useful in the treatment of cardiovascular diseases such as hypertension and heart failure. The irbesartan has the following structure: and is described in Bernhart et al., U.S. Patent No. 5,270,317, incorporated by reference herein. Preferred pharmaceutical compositions of this drug contain, as active ingredient (s), irbesartan alone or in combination with a diuretic such as hydrochlorothiazide. Irbesartan can be administered in doses containing a substantial amount of the active agent (eg, 75 to 300 mg). Certain physical properties of the drug present a challenge in the development of formulations suitable for the preparation of a tablet having a substantial amount of the active agent, and a tablet mass sufficiently small to allow ease of swallowing. Irbesartan is, for example, a spongy material, with apparent density and apparent powder density after releasing the content, relatively low. These properties make it difficult to formulate a large amount of the drug in a small tablet with uniform weight, hardness, and other desirable properties of the tablet. In addition, irbesartan has certain undesirable flow characteristics, for example, it is sticky and can adhere to surfaces such as the punch faces of the tableting machine and the dies, causing problems in the formation of the tablets, especially in a high speed tabletting machine. The low solubility in water of irbesartan also presents a challenge, since only small amounts of excipients can be added to keep the tablet mass small to facilitate wetting, disintegration and, at the end, rapid and complete release of the drug. . The addition of a diuretic such as hydrochlorothiazide, which is also a spongy material which shows poor fluidity and low solubility in water, may also contribute to the problems of tablet formation. Thus, there is a need in the art for pharmaceutical compositions containing irbesartan, alone or in combination with a diuretic, which have good tabletting properties, and which contain even a low mass of excipients so that they can small, easily swallowable tablets with a high content of active agent are prepared.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides pharmaceutical compositions containing irbesartan, alone or in combination with a diuretic, which (1) have a minimum mass of added excipients, which allows the preparation of small, easily swallowable tablets, which improve the acceptance and compliance of the patient, and which still (2) have excellent properties for the formation of tablets, and (3) provide tablets with excellent wetting, disintegration, and at the end, properties of rapid and complete release of the drug. In particular, the present invention provides pharmaceutical compositions, especially suitable for tabletting, comprising from about 20 to about 70% by weight irbesartan or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients, wherein a tablet formed at from said composition has a dissolution performance such that about 80% or more, preferably 85% or more, of the irbesartan or the salts thereof contained in said tablet, dissolve within a period of 30 minutes. The present compositions also optionally comprise from about 2 to about 33% of a diuretic, wherein the combined amount of the irbesartan and the diuretic does not exceed about 85%.

Preferred compositions containing irbesartan comprise, based on a total of 100% by weight: (a) from about 20 to about 70% (preferably, about 50%) of irbesartan, (b) from about 1 to about 70% of diluent, (c) from about 2 to about 20% binder, (d) from about 1 to about 10% disintegrant, (e) from about 0.1 to about 5% non-stick, and (f) from about 0.2 to about 5% lubricant, and, optionally (g) from about 0.2 to about 6% surfactant, and / or (h) to about 2% (preferably, from about 0.1 to about 1%) of coloring agent. Preferred compositions containing irbesartan and the diuretic comprise, based on a total of 100% by weight: (a) from about 20 to about 70% (preferably, about 50%) of irbesartan, (b) from about 2 to about 33% diuretic, wherein the combined charge of (a) and (b) does not exceed about 85%, (c) from about 1 to about 70% diluent, (d) from about 2 to about 20% binder, (e) from about 1 to about 10% disintegrant, (f) from about 0.1 to about 5% non-stick, and (g) from about 0.2 to about 5% lubricant, and, optionally, (h) up about 2% (preferably, from about 0.1 to about 1%) of coloring agent. The present compositions may contain up to about 70% w / w of irbesartan, or up to about 85% w / w of irbesartan and diuretic, and can even be employed in the reproducible manufacture of tablets on a large scale. The present compositions can, for example, be compressed in high speed tabletting equipment (especially, a high speed tablet forming press) to form tablets that are uniform in weight and in content, and which exhibit physical properties desirable, including elegant appearance, low friability, and fast disintegration time. The tablets prepared from the present compositions are capable of releasing the active component (s), by dissolution, in a rapid and reproducible manner. Unless otherwise indicated, the mention of irbesartan herein also includes pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION The present invention is described in further detail, as follows. The components employed in the compositions of the present invention must be pharmaceutically acceptable, particularly as described in the National Formulary (NF) or the United States Pharmacopeia (USP). The "dissolution performance" of a tablet, as used herein with respect to irbesartan, refers to the weight% of irbesartan, based on the total weight of the irbesartan contained in the tablet, which dissolves within 30 minutes. minutes under the following conditions: use a tablet that has a total weight of 150 to 600 mg and an Apparatus 2 of the USP, placing the tablet in 1,000 ml of 0.1 N hydrochloric acid at 37 ° C, with a palette speed of 50 rpm, and measuring the amount of dissolved irbesartan (especially, using UV at 244 nm or, when hydrochlorothiazide is also present, using high performance liquid chromatography, wavelength 272 nm) in 30 minutes. (If desired, the progress of the dissolution can also be verified periodically at different time points). The "dissolution performance" of a tablet, as used herein with respect to a diuretic (preferably, hydrochlorothiazide), refers to the weight% of the diuretic, based on the total weight of the diuretic contained in the tablet, which dissolves in a period of 30 minutes under the conditions described above for the dissolution of irbesartan. The solution performance for the diuretic preferably complies with the dissolution specification of the USP for the diuretic (for hydrochlorothiazide, greater than 60% dissolution in 30 minutes). The dissolution performance of a hydrochlorothiazide-containing tablet is more preferably such that about 90% or more of the hydrochlorothiazide dissolves within 30 minutes. The "diuretic" employed in a composition of the present invention may be any suitable diuretic, or a combination of two or more diuretics, such as hydrochlorothiazide, bendroflumethiazide, benzthiazide, chlorothiazide, chlorthalidone, cyclothiazide, hydroflumethiazide, methylclothiazide, metolazone, politia-zida, quinetazone, and trichlormethiazide. Preferably, the diuretic is hydrochlorothiazide. The "diluent" employed in a composition of the present invention can be one or more compounds that are capable of providing volume to obtain a desired tablet mass. It is desirable to employ the diluent in an amount at the lower end of the weight range for the diluent. Preferred diluents are inorganic phosphates such as calcium dibasic phosphate; sugars such as hydrated lactose or anhydrous lactose; and cellulose or cellulose derivatives, such as microcrystalline cellulose. The "binder" employed in a composition of the present invention can be one or more compounds that are capable of facilitating granulation of the irbesartan and / or the diuretic into larger, denser, and / or freer-flow particles. Preferred binders are alginic acid (more preferably used in the range of 2 to 5% by weight) or sodium alginate (more preferably used in the range of 2 to 3% by weight); cellulose or cellulose derivatives such as sodium carboxymethyl cellulose (more preferably used in the range of 2 to 6% by weight), ethyl cellulose (more preferably used in the range of 2 to 3% by weight), hydroxyethyl cellulose (more preferably used in the range of 2 to 5% by weight), hydroxypropyl cellulose (more preferably used in the range of 2 to 6% by weight), hydroxypropylmethylcellulose (more preferably used in the range of 2 to 5% by weight). weight), or methyl cellulose (more preferably used in the range of 2 to 6% by weight); gelatin (more preferably used in the range of 2 to 10% by weight); povidone (polyvinylpyrrolidone, for example, l-ethenyl-2-pyrrolidinone homopolymer) (for example, povidone K-30) (more preferably used in the range of 2 to 20% by weight); or starch (more preferably employed in the range of 5 to 20% by weight) or pregelatinized starch (more preferably employed in the range of 2 to 20%, such as 5 to 20% by weight). The "disintegrator" employed in a composition of the present invention may be one or more compounds that are capable of facilitating the breaking of a tablet prepared from the composition, when placed in contact with an aqueous medium. Preferred disintegrants are alginic acid (more preferably used in the range of 2 to 5% by weight) or sodium alginate (more preferably employed in the range of 2.5 to 10% by weight); cellulose or cellulose derivatives such as sodium carboxymethyl cellulose (more preferably used in the range of 2 to 6% by weight), microcrystalline cellulose (more preferably used in the range of 5 to 15% by weight), powdered cellulose ( more preferably employed in the range of 5 to 15% by weight), or croscarmellose sodium (cross-linked polymer of sodium carboxymethylcellulose) (more preferably employed in the range of 2 to 5% by weight); crospovidone (cross-linked homopolymer of N-vinyl-2-pyrrolidinone, for example, cross-linked l-ethenyl-2-pyridinone) (more preferably used in the range of 2 to 5% by weight); pregelatinized starch (more preferably employed in the range of 5 to 10% by weight), sodium starch glycolate (most preferably employed in the range of 2 to 8% by weight), or starch (most preferably employed in the range from 3 to 15% by weight). The "anti-adherent" employed in a composition of the present invention may be one or more compounds that are capable of reducing the tackiness of the formulation, for example, the prevention of adhesion to metal surfaces. Preferred antiadhesives are silicon-containing compounds, such as silicon dioxide (more preferably employed in the range of 0.25 to 5% (such as 0.5 to 2 or 2.5 to 3.0%) by weight), magnesium trisilicate (most preferably employed in the range of 0.5 to 2% by weight), or talc (more preferably used in the range of 1 to 5% by weight).

The "lubricant" employed in a composition of the present invention may be one or more compounds which are capable of preventing the problems of tablet formation, such as those related to the release of a tablet prepared from the composition from the or on which it is formed, for example, by preventing adhesion to the face of the upper punch (reco gnning) or of the lower punch (adhesion) of a device for the formation of tablets. Preferred lubricants are fatty acids or fatty acid derivatives such as calcium stearate (more preferably used in the range of 0.5 to 2% by weight), glyceryl monostearate (more preferably used in the range of 0.5 to 2% by weight) ), palmitoestearate or glyceryl (more preferably used in the range of 0.5 to 2% by weight), magnesium stearate (more preferably used in the range of 0.2 to 2% by weight), sodium lauryl sulfate (more preferably used in the range of 1 to 2% by weight), sodium stearyl fumarate (more preferably employed in the range of 0.5 to 2% by weight), zinc stearate (more preferably employed in the range of 0.5 to 1.5% by weight ) or stearic acid (more preferably employed in the range of 1 to 3% by weight); hydrogenated vegetable oil (more preferably employed in the range of 1 to 5% by weight); polyalkylene glycols such as polyethylene glycol (more preferably employed in the range of 1 to 5% by weight); sodium benzoate (most preferably employed in the range of 2 to 5% by weight); or talc (more preferably employed in the range of 1 to 5% by weight). The "surfactant" employed in a composition of the present invention can be one or more compounds that are capable of improving tablet wetting and / or improving dissolution. Preferred surfactants are sodium lauryl sulfate (more preferably employed in the range of 0.2 to 6% by weight), and block copolymers of poly (oxyethylene) and poly (oxypropylene), such as poloxamers, especially poloxamer 188 (more preferably employed in the range of 1 to 6% by weight). The "coloring agent" (or "colorant") employed in a composition of the present invention can be one or more compounds that impart a desired color to a tablet prepared from the composition. The addition of a coloring agent can be used, for example, so that tablets of different potencies can be easily distinguished. The preferred coloring agents are ferric oxides, which are universally accepted.

As can be seen from the above, a simple compound can perform two or more functions. The calculation of the percent by weight is preferably based on the primary function of a compound in a given composition. The present compositions preferably consist essentially of, more preferably, consist of the components described above.

Preferred compositions Preferred compositions of the present invention contain one or more of the following components in the indicated concentration range (in% by weight): irbesartan, 20 to 60 (eg, 25 to 60), such as 30 to 60 , more preferably from 30 to 50, especially about 50%; diuretic, from 2 to 20, more preferably from 2 to 17, especially from 4 to 9%; diluent, from 1 to 70, more preferably from 1 to 60, especially from 1 to 40%; binder, from 5 to 20, more preferably from 5 to 15%; disintegrator, from 4 to 8, more preferably about 5%; non-stick, from 0.25 to 5.0% (such as 0.25 to 1.5, more preferably from 0.7 to 0.8%, for example, when a diuretic is present or 2.5 to 3.0%, for example, when a diuretic is not present); lubricant, from 0.5 to 1.5, more preferably approximately 1%; and surfactant, from 1 to 3, more preferably, about 3%. The following tables show the preferred compositions of the present invention, which produce tablets of substantially high quality and superior performance. Table A shows the preferred compositions containing irbesartan; Table B shows the preferred compositions containing irbesartan in combination with a diuretic.

TABLE TO IRBESARTAN Preferred Ingredient Component Concentration Interval (% W / W) Irbesartan active drug 20 - 50 Lactose hydrated diluent 1 - 70 Microcrystalline cellulose diluent 5 - 20 R + (for example, Avicel PH 102) Pregelat starch binder 10 - 20 R + (for example, Starch 1500) - ló - TABLE A (continued) IRBESARTAN Preferred Ingredient Component Concentration Interval (% W / w) Sodium croscarmellose disintegrator 4 - 8 R + (eg Ac-Di-Sol) Poloxamer, * especially poloxamer 188 188 - 6 R + surfactant (eg, Pluronic F68) Non-stick silicon dioxide 0.25 - 5.0 R + (eg , Syloid 244) (0.25 to 1.5 or, especially, 2.5 to 3.0) Magnesium stearate lubricant 0.5 - 1.5 TOTAL 100 * Optional component, but preferred. + These exemplary compounds can be used as desired throughout this specification, as appropriate. For example, Starch 1500 can be used as desired provided that the pregelatized starch appears in this specification In the above compositions of Table A, the combination of magnesium stearate and silicon oxide provides a superior lubricating effect while minimizing any decline in the operation of the tablet solution; the proportion of intragranular: extragranular placement of the croscarmellose sodium disintegrator is higher (eg, 1: 1); and the poloxamer surfactant improves the aqueous granulation of irbesartan (which is hydrophobic), facilitates the ejection of the tablets after compression, and accelerates the dissolution of the active agent irbesartan.

TABLE B IRBESARTAN IN COMBINATION WITH DIURÉTICO Preferred Ingredient Component Interval concentration (% P / P) Ir besartan Active drug 20 - 50 Hydrochlorothiazide diuretic, drug - 2 - 50 * active maco TABLE B (continued) IRBESARTAN IN COMBINATION WITH DIURETHIC Preferred Ingredient Component Concentration Interval (% W / W) Lactose hydrated diluent 1 - 70 Microcrystalline Cellulose Diluent 10 - 20 (for example, Avicel PH 102) Croscarmellose sodium disintegrator 4 - 6 D (for example, Ac-Di-Sol) Pregelatinized agglutinating starch 10 - 20 (for example, Starch 1500) Non-stick silicon dioxide 0.5 - 1.0 (for example, Syloid 244) Lubricating magnesium stearate 0.5 - 1.5 TOTAL 100 * The concentration of hydrochlorothiazide may vary according to the desired potency of hydrochlorothiazide, in the tablet in combination, which is preferably in the range of 6.25 mg to 25 mg per tablet.

The compositions of Tables A and B also preferably contain 0.08 to 0.12% by weight of ferric oxide, red and 0.08 to 0.12% by weight of yellow ferric oxide, as a dye.

Manufacturing Methods Tablets can be prepared from the present compositions by any suitable method for tabletting. Preferably, the tablets are prepared by cutting the present compositions by a wet granulation process. An exemplary method of such methods comprises the following steps: (a) the preparation of an intra-granular composition by: (i) mixing irbesartan, diuretic (for combination tablets), a portion of the diluent (preferably, from about 5 to about 80% by weight of the total diluent), a portion of the disintegrator (preferably, from about 50 to about 80% by weight of the total disintegrator), the binder, and, optionally, a portion of the release (preferably, from about 50 to about 80% by weight of the total non-stick), to form a powder mixture and, optionally, the mixture is sized (for example, grinding the mixture to break up the aggregates); (ii) the re-mixing of the mixture; (iii) granulating the mixture with a granulation fluid, preferably water and / or an aqueous solution of the surfactant, to form granules (for example, using a high shear mixer / granulator); (iv) drying the granules (for example, in an oven or, preferably, in a fluidized bed dryer); and (v) adjusting the size of the dried granules (for example, by grinding or sieving); (b) the preparation of a mixture of the granules adjusted to the size of step (a) (v) with an extragranular composition by: (i) mixing the remaining diluent, the remainder of the disintegrator, the anti-adherent or the remaining non-stick , and, optionally, the coloring agent, where one or more of these can be premixed, adjusted to size (for example, ground to break up the aggregates) and re-mixed before this step, with the size-adjusted granules provided. from step (a) (v) to form a mixture of granules; and (ii) mixing the lubricant with the mixture of granules; and (c) compressing the mixture from step (b) (ii) to form tablets (e.g., using a tablet press). The solid initial materials of the present compositions are preferably screened before use. The weight ratio of the water (preferably, purified water, USP or water for injection, USP) to the solids employed in step (a) (iii) is preferably within the range of about 0.25: 1 to about 0.6: 1. The tablets may, optionally, be finished or coated, such as by methods known in the art. The tablets prepared from the compositions of the present invention preferably contain (per tablet) from about 25 to about 300 mg of irbesartan, more preferably from about 75 to 300 mg of irbesartan and, for the combined tablets, an additional amount of about 1 to about 25 mg of diuretic, more preferably from about 6.25 to about 25 mg of hydrochlorothiazide. The total weight of the tablets prepared is preferably from about 50 to about 600 mg. In addition to the tablets, the compositions of the present invention can be used to prepare spheres, dispersion granules or capsules, the latter being, for example, filled with powder or with the aforementioned spheres or granules. Methods such as those well known in the art can be used to prepare these dosage forms. The compositions and tablets of the present invention can be used to treat or prevent disorders such as those described in U.S. Patent No. 5,270,317, incorporated by reference herein. Such disorders include cardiovascular disorders, for example, hypertension or heart failure, venous insufficiency, as well as glaucoma, diabetic retinopathy, renal failure and various conditions of the central nervous system. The present compositions or tablets are preferably administered orally, in an effective amount, to a mammal (especially, a human) subject to treatment, or to prevent the aforementioned disorders. For human subjects, preferred doses of about 75 mg to about 300 mg of irbesartan (alone or in combination with diuretic) can be administered, for example, 1 to 2 times a day. The following examples are provided to illustrate the preferred embodiments of the invention, and are not intended to limit the scope of the present claims.

EXAMPLE 1 PREPARATION OF TABLETS CONTAINING IRBESARTAN Tablets containing irbesartan in three potencies were prepared from the composition of the present invention, described in Table 1 below: (1) 75 mg of irbesartan with a total weight of 150 mg per tablet; (2) 150 mg of irbesartan with a total weight of 300 mg per tablet; and (3) 300 mg of irbesartan with a total weight of 600 mg per tablet.

TABLE 1 Ingredient Component Concentration (% P / P) INTRAGRANULAR Ir besartan active drug 50 Hydrated lactose, NF diluent 10.25 Pregelatinized starch, NF binder 15.0 Croscarmellose sodium, NF disintegrator 2.5 Poloxamer 188, NF surfactant 3.0 EXTRAGRANULAR Microcrystalline Cellulose, NF Thinner 15.0 Croscarmellose Sodium, NF Disintegrator 2.5 Silicon Dioxide, Non-stick NF 0.75 Magnesium Stearate, USP Lubricant 1.0 TOTAL 100.00 100.00 Using the above formulation, the tablets were prepared by a wet base granulation process as follows. In this process, the total amount of water used (by weight) was up to 50% of the total weight of solids. The irbesartan, the lactose, the pregelatinized starch, and a portion (1/2) of the croscarmellose sodium, were mixed in a mixer. The prepared powder mixture was passed through a size adjustment equipment (conical mill or oscillator), and mixed in a mixer. Poloxamer 188 was dissolved in water (purified, USP or water for injection, USP) (25% of the weight of the total solids), and was used to wet granulate the mixed powder (with the subsequent addition of water in an amount which was up to 25% of the total weight of the solids, as necessary). The obtained granules were dried (tray dryer or fluidized bed dryer) until the loss at drying was 2% or less. The dried granules were passed through a sieve or milled to obtain the appropriate size (1 to 3 mm). The size-adjusted granules were mixed with the silicon dioxide, with the microcrystalline cellulose and with the remaining croscarmellose sodium, in a mixer. The obtained mixture was then mixed with the magnesium stearate. By compressing the mixture using the tabletting equipment, tablets were prepared for each potency, having the compositions indicated in Table 2 below.

TABLE 2 Ingredient 75 mg 150 mg 300 mg Potency Potency Potency (mg) (mg) (mg) Irbesartan 75.00 150.00 300.00 Lactose hydrated, NF 15.38 30.75 61.50 Microcrystalline cellulose, NF 22.50 45.00 90.00 Pregelatinized starch, NF 22.50 45.00 90.00 Croscarmellose sodium, NF 7.50 15.00 30.00 Poloxamer 188, NF (or 4.50 9.00 18.00 Pluronic F68, NF) Silicon dioxide, NF 1.12 2.25 4.50 Magnesium stearate, USP 1.50 3.00 6.00 Weight of Tablet 150.00 300.00 600.00 EXAMPLE 2 PREPARATION OF TABLETS CONTAINING IRBESARTAN; ALTERNATIVE FORMULATION Tablets having the composition of Table 3 below were prepared by a method analogous to that of Example 1.

TABLE 3 Ingredient Amount mg / tablet (% w / w) INTRAGRANULAR Irbesartan 300.0 (50) Hydrated lactose, NF 121.5 (20.25) (diluent) Povidone K-30, USP 30.0 (5) (binder) Croscarmellose sodium 24.0 (4) (disintegrator) Pluronic F68, NF 18.0 (3) (poloxamer, surfactant) EXTRAGRANULAR Microcrystalline cellulose, NF 90.0 (15) (diluent) Croscarmellose sodium 6.0 (1) (disintegrator) Silicon dioxide, NF 4.5 (0.75) (non-stick) Magnesium stearate (1) (lubricant) TOTAL WEIGHT 600.00 (100) EXAMPLE 3 PREPARATION OF TABLETS IN COMBINATION IRBESARTAN AND HYDROCHLOROTIAZIDE Tablets containing a combination of irbesartan and hydrochlorothiazide in two potencies were prepared from the composition of the present invention, described in Table 4 below: (1) 75 mg irbesartan / 12.5 mg hydrochlorothiazide with a total weight of 150 mg per tablet; and (2) 150 mg of irbesar-tan / 12.5 mg of hydrochlorothiazide with a total weight of 300 mg per tablet.

TABLE 4 Ingredient Quantity Quantity (% w / w) in (% w / w) in 75 mg / 12.5 mg 150 mg / 12.5 mg Tablets Tablets INTRAGRANULAR Ir besartán 50.00 50.00 Hydrochlorothiazide, USP 8.33 4.17 Hydrated lactose, NF 4.72 8.88 (diluent) TABLE 4 (continued) Ingredient Quantity Quantity (% w / w) in (% w / w) in 75 mg / 12.5 mg 150 mg / 12.5 mg Tablets Tablets Pregelatinized starch, NF 15.00 15.00 (binder) Croscarmellose sodium, NF 4.00 4.00 (disintegrator) EXTRAGRANULAR Microcrystalline cellulose, NF 15.00 15.00 (diluent) Croscarmellose sodium, NF 1.00 1.00 (disintegrator) Silicon dioxide, NF 0.75 0.75 (non-stick) Ferric oxide, NF, red 0.10 0.10 (colorant) Ferric oxide, NF, yellow 0.10 0.10 (colorant) Magnesium stearate, NF 1.00 1.00 (lubricant) TOTAL 100.00 100.00 Tablets having the above compositions were prepared using a wet granulation process, as follows. The drug substances irbesartan and hydrochlorothiazide, the hydrated lactose, the pregelatinized starch, and a portion (4/5 of the total amount) of the croscarmellose sodium, were weighed and mixed. This powder mixture was then milled to undo the drug or drug aggregates. The milled powder mixture was then mixed again, followed by granulation with water (in an amount that was about 55% of the total weight of the solids), in a mixer / granulator. The wet granules were then dried in an equi. drying unit (tray dryer or fluidized bed dryer) until a drying loss of 2% or less, followed by grinding of dry granules. A color mixture was made by mixing the ferric oxides with one portion (1/3 of the total amount) of the microcrystalline cellulose, grinding the color mixture, and then mixing again. The remaining microcrystalline cellulose, the remaining croscarmellose sodium, the color mixture, and the silicon dioxide were then weighed, sieved, and mixed in a mixer with the ground, dry granules. In a final step, sieved magnesium stearate was weighed and mixed with the above granule mixture. This final mixture was then compressed into tablets using a suitable tabletting press.

Prepared Tablets For the irbesartan / hydrochloro-thiazide tablets of 75 mg / 12.5 mg, the tablet weight was 150 mg and the hardness of the tablet was 10 - 14 SCU (Cobb Force Units). For tablets of 150 mg / 12.5 mg of potency, the weight of the tablet was 300 mg and the hardness of the tablet was 14-18 SCU. For both power tablets, the friability was less than 0.5%, the disintegration time was below 7 minutes, and the coefficient of variation for the weight of the tablet was below 2%. In addition, the dissolution of these tablets meets the specification for the dissolution of irbesartan of 85% or greater in 30 minutes, and easily meets the dissolution specification of USP for 60% hydrochlorothiazide in 30 minutes. It was found that the tablets of this formulation had good stability. Under certain conditions, hydrochlorothiazide can be hydrolyzed to form, as by-products, a free amine and formaldehyde degrader (D.S. Desai et al., International Journal of Pharmaceutics, 107 (2), 141-47 (1994)). The selection of excipients can have an impact on the stability of hydrochlorothiazide. The use of pregelatinized starch as a binder in the present compositions was found to impart greater stability to chlorothiazide than, for example, povidone (which resulted in the formation of amounts of the free amine degrader). It was also found that the poloxamer increases the degradation of hydrochlorothiazide, and therefore, while being employed as a preferred component in the compositions without hydrochlorothiazide, the poloxamer is not a preferred component for the compositions of irbesartan / hydrochlorothiazide. the present invention. The aforementioned preferred compositions of the present invention, containing irbesartan and hydrochlorothiazide are thus further advantageous, since the excipients employed therein minimize or eliminate the degradation of hydrochlorothiazide.

EXAMPLE 4 PREPARATION OF TABLETS IN COMBINATION; IRBESARTAN AND HYDROCHLOROTIAZIDE; ALTERNATIVE FORMULATIONS Tablets were prepared having the compositions 4 (A), 4 (B) 4 (C) or 4 (D) of Table 5 below, by methods analogous to those of Example 3.

TABLE 5 Ingredient 4 (A) 4 (B) 4 (C) 4 (D) mg per mg per mg per mg per tablet tablet tablet tablet (% W / W) (% w / w) (% W / W) (% P / P) INTRAGRANULAR Irbesartan (drug 75.0 75.0 150.0 150.0 active) (50) (50) (50) (50) Hydrochlorothiazide 12.5 12.5 12.5 12.5 (diuretic, active drug) (8.33) (8.33) (4.17) (4.17) Hydrated lactose, NF 2.575 17.575 17.65 47.65 (diluent) (1.72) (11.72) (5.88) (15.88) TABLE 5 (continued) Ingredient 4 (A) 4 (B) 4 (C) 4 (D) mg per mg per mg per mg per tablet tablet tablet tablet (% W / W) (% W / W) (% W / W) (% P / P) Pregelatinized starch, 22.5 45.0 -__ NF (binder) (15) (15) Povidone K-30, USP 7.5 15.0 • (binder) (5) (5) Croscarmellose sodium 6.0 6.0 12.0 12.0 (disintegrator) (4) (4) (4) (4) Pluronic F68, NF 4.5 4.5 9.0 9.0 (poloxamer, surfactant) (3) (3) (3) (3) EXTRAGRANULAR Microcrystalline cellulose, 22.5 22.5 45.0 45.0 NF (diluent) (15) (15) (15) (15) Croscarmellose sodium 1.5 1.5 3.0 3.0 (disintegrator) (1) (1) (1) (1) Ferric oxide, red NF 0.15 0.15 0.3 0.3 (colorant) (0.1) (0.1) (0.1) (0.1) Ferric oxide, yellow NF 0.15 0.15 0.3 0.3 (dye) (0.1) (0.1) (0.1) (0.1) TABLE 5 (continued) Ingredient 4 (A) 4 (B) 4 (C) 4 (D) mg per mg per mg per mg per tablet tablet tablet tablet (% W / W) (% W / W) (% W / W) (% P / P) Silicon dioxide 1.125 1.125 2.25 2.25 (non-stick) (0.75) (0.75) (0.75) (0.75) Magnesium stearate 1.5 1.5 3.0 3.0 (lubricant) (1) (1) (1) (1) TOTAL WEIGHT 150.0 150.0 300.0 300.0 (100) (100) (100) (100) EXAMPLE 5 PREPARATION OF TABLETS WHAT IRBESARTAN CONTAINS Tablets containing irbesartan in three potencies were prepared, from the composition of the present invention described in Table 6 below: (1) 75 mg of irbesartan with a total weight of 150 mg per tablet; (2) 150 mg of irbesartan with a total weight of 300 mg per tablet; and (3) 300 mg of irbesartan with a total weight of 600 mg per tablet.

TABLE 6 I n g r e d i n t Component Concentration (% p / p) INTRAGRANULAR Ir besartan active drug 50 Lactose hydrate, NF diluent 10.25 Pregelatinized starch, 'NF binder 15.0 Croscarmellose sodium, NF disintegrator 2.5 Poloxamer 188, NF surfactant 3.0 Silicon dioxide, NF 2.0 Sticky EXTRAGRANULAR Microcrystalline Cellulose, NF Thinner 13.0 Croscarmellose Sodium, NF Disintegrator 2.5 Silicon Dioxide, Non-stick NF 0.75 Magnesium Stearate, USP Lubricant 1.0 TOTAL 100.00 100.00 Using the above formulation, tablets were prepared by a wet granulation process as follows. In this process, the total amount of water used (by weight) was up to 50% of the total weight of the solids. The irbesartan, the lactose, the pregelatinized starch, a portion (1/2) of the croscarmellose sodium, and a portion (approximately 73%) of the silicon dioxide, were mixed in a mixer. The prepared powder mixture was passed through a size adjustment equipment (conical mill or oscillator), and mixed in a mixer. Poloxamer 188 was dissolved in water (purified, USP or water for injection, USP) (25% by weight of the total solids), and used to wet granulate the mixed powder (with the subsequent addition of water in an amount that was up to 25% of the weight of the total solids, as necessary). The granules obtained were dried (tray dryer or fluid bed dryer) until the loss at drying was 2% or less. The dried granules were passed through a sieve or milled to obtain the appropriate size (1 to 3 mm). The size-adjusted granules were mixed with the remaining silicon dioxide, with the microcrystalline cellulose and with the remaining croscarmellose sodium, in a mixer. The obtained mixture was then mixed with the magnesium stearate. When compressing the mixture using the tabletting equipment, tablets were prepared for each potency, having the compositions indicated in Table 7 below.

TABLE 7 Ingredient 75 mg 150 mg 300 mg Potency Potency Potency (mg) (mg) (mg) Irbesar so 75.00 150.00 300.00 Hydrated lactose, NF 15.38 30.75 61.50 Microcrystalline cellulose, NF 19.50 39.00 78.00 Pregelatinized starch, NF 22.50 45.00 90.00 Croscarmellose sodium, NF 7.50 15.00 30.00 Poloxamer 188, NF (or 4.50 9.00 18.00 Pluronic F68, NF) Silicon dioxide, NF 4.12 8.25 16.50 Magnesium stearate, USP 1.50 3.00 6.00 Weight of Tablet 150.00 300.00 600.00 Tablets comprising irbesartan or a pharmaceutically acceptable salt thereof (as described herein) were prepared by mixing an extragranular composition with granules comprising an anti-adherent (preferably, silicon dioxide), they can be dissolved more rapidly and / or completely, and in this way can show improved dissolution performance.

EXAMPLE 6 PRI .PARATION OF TABLETS THAT CONTAIN IRBESARTAN; ALTERNATIVE FORMULATION Tablets having the composition of Table 8 below were prepared by a method analogous to that of Example 5.

TABLE 8 Ingredient Amount mg / tablet (% w / w) INTRAGRANULAR Irbesartan 300.0 (50) Hydrated lactose, NF 121.5 (20.25) (diluent) Povidone K-30, USP 30.0 (5) (binder) Croscarmellose sodium 24.0 (4) (disintegrator) TABLE 8 (continued) Ingredient Amount mg / tablet (% w / w) Pluronic F68, NF 18.0 (3) (poloxamer, surfactant) Silicon dioxide, NF 12.0 (2) (non-stick) EXTRAGRANULAR Microcrystalline cellulose, NF 78.0 (13) (diluent) Croscarmellose sodium 6.0 (1) (disintegrator) Silicon dioxide , NF 4.5 (0.75) (non-stick) Magnesium stearate 6 (1) (lubricant) TOTAL WEIGHT 600.00 (100) It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (63)

1. A pharmaceutical composition, characterized in that the composition comprises from about 20 to about 70% by weight of irbesartan or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein a tablet formed from said composition has an operation of dissolution such that approximately 80% or more of the irbesartan or the salt thereof contained in the tablet dissolves within a period of 30 minutes.

2. The pharmaceutical composition according to claim 1, characterized in that a tablet formed from said composition has a dissolution performance such that approximately 85% or more of the irbesartan or the same salt contained in the tablet, is dissolved within a 30 minute period.

3. A pharmaceutical composition according to claim 1, characterized in that it comprises, on a weight basis: (a) from about 20 to about 70% by weight irbesartan, (b) from »; about 1 to about 70% by weight of diluent, (c) from about 2 to about 20% by weight of binder, (d) from about 1 to about 10% of disintegrant, (e) from about 0.1 to about 5% of non-stick, and (f) from about 0.2 to about 5% lubricant, and, optionally (g) from about 0.2 to about 6% surfactant, and / or (h) to about 2% coloring agent.

4. A pharmaceutical composition according to claim 3, characterized in that: the diluent is one or more compounds selected from the group consisting of calcium dibasic phosphate, hydrated lactose, anhydrous lactose, and microcrystalline cellulose; the binder is one or more compounds selected from the group consisting of alginic acid, sodium alginate, sodium carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gelatin, povidone, starch and pregelatinized starch; the disintegrator is one or more compounds selected from the group consisting of alginic acid, sodium alginate, sodium carboxymethyl cellulose, microcrystalline cellulose, cellulose powder, croscarmellose sodium, crospovidone, pregelatinized starch, sodium starch glycolate, and starch; the anti-adherent is one or more compounds selected from the group consisting of silicon dioxide, magnesium trisilicate, and talc; the lubricant is one or more compounds selected from the group consisting of calcium stearate, glyceryl monostearate, glyceryl palmito stearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, vegetable oil hydrogenated, polyethylene glycol, sodium benzoate, and talc; when present, the surfactant is one or more compounds selected from the group consisting of sodium lauryl sulfate, and poloxamers; and when present, the coloring agent is one or more ferric oxides.

5. A pharmaceutical composition according to claim 3, characterized in that it comprises, on a weight basis, approximately 20 to 50% irbesartan; about 1 to 70% diluent; about 10 to 20% binder; approximately 4 to 8% disintegrator; approximately 0.25 to 5.0% non-stick; approximately 0.5 to 1.5% lubricant; and about 1 to 6% surfactant.

6. The pharmaceutical composition according to claim 5, characterized in that the diluent is lactose hydrate and microcrystalline cellulose; the binder is pregelatinized starch; the disintegrator is croscarmellose sodium; the anti-adherent is silicon dioxide; the lubricant is magnesium stearate; and the surfactant is poloxamer 188.

7. A pharmaceutical composition according to claim 1, characterized in that it comprises, based on weight, approximately 50% irbesartan; approximately 10.25% hydrated lactose; approximately 15.0% pregelatinized starch; approximately 5.0% croscarmellose sodium; about 3.0% poloxamer 188; about 15% microcrystalline cellulose; about 0.75% silicon dioxide; and about 1.0% magnesium stearate.

8. A pharmaceutical composition according to claim 1, characterized in that it comprises, based on weight, approximately 50% irbesartan; approximately 10.25% hydrated lactose; Approximately 15.0% of pregelatinized starch; approximately 5.0% croscarmellose sodium; about 3.0% poloxamer 188; about 13% microcrystalline cellulose; approximately 2.75% silicon dioxide; and about 1.0% magnesium stearate.

9. A pharmaceutical composition according to claim 1, characterized in that it comprises, based on weight, approximately 50% irbesartan; approximately 20.25% hydrated lactose; about 5.0% povidone K-30; approximately 5.0% croscarmellose sodium; about 3.0% poloxamer; about 15% microcrystalline cellulose; about 0.75% silicon dioxide; and about 1.0% magnesium stearate.

10. A pharmaceutical composition according to claim 1, characterized in that it comprises, based on weight, approximately 50% irbesartan; approximately 20.25% hydrated lactose; about 5.0% povidone K-30; approximately 5.0% croscarmellose sodium; about 3.0% poloxamer; about 13% micro-crystalline cellulose; approximately 2.75% silicon dioxide; and about 1.0% magnesium stearate.

11. A pharmaceutical composition according to claim 1, further characterized in that it comprises from about 2 to about 33% diuretic, wherein the total% by weight of the irbesartan or the salt thereof and the diuretic, does not exceed about 85%.

12. A pharmaceutical composition according to claim 11, characterized in that the diuretic is one or more compounds selected from the group consisting of hydrochlorothiazide, bendroflu-methiazide, benzthiazide, chlorothiazide, chlorthalidone, cyclothiazide, hydroflumethiazide, methyclothiazide, metola-zone, polythiazide, kinetazone , and trichlormetiazide.

13. A pharmaceutical composition according to claim 12, characterized in that the diuretic is hydrochlorothiazide.

14. A pharmaceutical composition according to claim 11, characterized in that it comprises, based on weight: (a) from about 20 to about 70% irbesartan, from about 2 to about 33% diuretic, wherein the combined charge of (a) and (b) does not exceed about 85%, (c) from about 1 to about 70% diluent, (d) from about 2 to about 20% binder, (e) from about 1 to about 10% disintegrant, (f) from about 0.1 to about 5% non-stick, and (g) from about 0.2 to about 5% of lubricant, and, optionally (h) up to about 2% of coloring agent.

15. A pharmaceutical composition according to claim 14, characterized in that: the diuretic is hydrochlorothiazide; the diluent is one or more compounds selected from the group consisting of calcium dibasic phosphate, hydrated lactose, anhydrous lactose, and microcrystalline cellulose; the binder is one or more compounds selected from the group consisting of alginic acid, sodium alginate, sodium carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gelatin, povidone, starch and pregelatinized starch; the disintegrator is one or more compounds selected from the group consisting of alginic acid, sodium alginate, sodium carboxymethylcellulose, microcrystalline cellulose, cellulose powder, croscarmellose sodium, crospovidone, pregelatinized starch, sodium starch glycolate, and starch; the anti-adherent is one or more compounds selected from the group consisting of silicon dioxide, magnesium trisilicate, and talc; the lubricant is one or more compounds selected from the group consisting of calcium stearate, glyceryl monostearate, glyceryl palmito stearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, vegetable oil Hydrogating, polyethylene glycol, sodium benzoate, and talc; and when present, the coloring agent is one or more ferric oxides.

16. A pharmaceutical composition according to claim 14, characterized in that it comprises, on a weight basis, approximately 20 to 50% irbesartan; approximately 2 to 20% diuretic; about 1 to 70% diluent; approximately 10 to 20% binder; about 4 to 6% disintegrator; approximately 0.5 to 1.0% non-stick; and approximately 0.5 to 1.5% lubricant

17. The pharmaceutical composition according to claim 16, characterized in that the diuretic is hydrochlorothiazide; the diluent is hydrated lactose and microcrystalline cellulose; the binder is pregelatinized starch; the disintegrator is croscarmellose sodium; the anti-adherent is silicon dioxide; and the lubricant is magnesium stearate.

18. A pharmaceutical composition according to claim 11, characterized in that it comprises, based on weight, approximately 50% irbesartan; approximately 8.33% hydrochlorothiazide; approximately 4.72% of hydrated lactose; approximately 15.0% pregelatinized starch; approximately 5.0% croscarmellose sodium; about 15% microcrystalline cellulose; about 0.75% silicon dioxide; about 1.0% magnesium stearate; approximately 0.1% ferric oxide, red; and about 0.1% ferric oxide, yellow.

19. A pharmaceutical composition according to claim 11, characterized in that it comprises, based on weight, approximately 50% irbesartan; about 4.17% hydrochlorothiazide; approximately 8.88% hydrated lactose; approximately 15.0% pregelatinized starch; approximately 5.0% croscarmellose sodium; about 15% microcrystalline cellulose :; about 0.75% silicon dioxide; about 1.0% magnesium stearate; approximately 0.1% ferric oxide, red; and about 0.1% ferric oxide, yellow.

20. A pharmaceutical composition according to claim 11, characterized in that it comprises, based on weight, approximately 50% irbesartan; approximately 8.33% hydrochlorothiazide; approximately 1.72% hydrated lactose; Approximately 15.0% of pregelatinized starch; approximately 5.0% croscarmellose sodium; about 3% poloxamer; about 15% microcrystalline cellulose; about 0.75% silicon dioxide; about 1.0% magnesium stearate; approximately 0.1% ferric oxide, red; and about 0.1% ferric oxide, yellow.

21. A pharmaceutical composition according to claim 11, characterized in that it comprises, based on weight, approximately 50% irbesartan; approximately 8.33% hydrochlorothiazide; approximately 11.72% of hydrated lactose; about 5.0% povidone K-30; approximately 5.0% croscarmellose sodium; about 3% poloxamer; about 15% microcrystalline cellulose; about 0.75% silicon dioxide; about 1.0% magnesium stearate; approximately 0.1% ferric oxide, red; and about 0.1% ferric oxide, yellow.

22. A pharmaceutical composition according to claim 11, characterized in that it comprises, based on weight, approximately 50% irbesartan; about 4.17% hydrochlorothiazide; approximately 5.88% hydrated lactose; approximately 15.0% pregelatinized starch; approximately 5.0% croscarmellose sodium; about 3% poloxamer; about 15% microcrystalline cellulose; about 0.75% silicon dioxide; about 1.0% magnesium stearate; approximately 0.1% ferric oxide, red; and about 0.1% ferric oxide, yellow.

23. A pharmaceutical composition according to claim 11, characterized in that it comprises, based on weight, approximately 50% irbesartan; about 4.17% hydrochlorothiazide; about 15.88% hydrated lactose; about 5.0% povidone K-30; approximately 5.0% croscarmellose sodium; about 3% poloxamer; about 15% microcrystalline cellulose; about 0.75% silicon dioxide; about 1.0% magnesium stearate; approximately 0.1% ferric oxide, red; and about 0.1% ferric oxide, yellow.

24. A tablet, characterized in that it is formed from the composition according to claim 1.

25. A tablet, characterized in that it is formed from the composition according to claim 7.

26. A tablet, characterized in that it is formed from the composition according to claim 8.

27. A tablet, characterized in that it is formed from the composition according to claim 9.

28. A tablet, characterized in that it is formed from the composition according to claim 10.

29. A tablet, characterized in that it is formed from the composition according to claim 18.

30. A tablet, characterized in that it is formed from the composition according to claim 19.

^ 31. A tablet, characterized in that it is formed from the composition according to claim 20.

32. A tablet, characterized in that it is formed from the composition according to claim 21.

33. A tablet, characterized in that it is formed from the composition according to claim 22.

34. A tablet, characterized in that it is formed from the composition according to claim 23.

35. A tablet according to claim 24, characterized in that the total weight of the tablet is from about 50 to about 600 mg.

36. A pharmaceutical composition, characterized in that it comprises irbesartan or a pharmaceutically acceptable salt thereof, hydrochlorothiazide, and a binder which is pregelatinized starch and / or starch.

37. A pharmaceutical composition according to claim 36, characterized in that the binder is pregelatinized starch.

38. A tablet, characterized in that it is formed from the composition according to claim 37.

39. A tablet formed from the composition according to claim 1, characterized in that the tablet is prepared by mixing an extragranular composition with granules comprising an anti-adherent.

40. The tablet according to claim 39, characterized in that the anti-adherent is silicon dioxide.

41. A pharmaceutical composition, characterized in that the composition is prepared by mixing the components comprising from about 20 to about 70% by weight of irbesartan or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable excipients, wherein a tablet formed from said composition has a dissolution performance such that about 80% or more of the irbesartan or the salt thereof contained in the tablet dissolves within a period of 30 minutes.

42. The pharmaceutical composition according to claim 41, characterized in that a tablet formed from said composition has a dissolution performance such that approximately 85% or more of the irbesartan or the salt thereof, contained in the tablet, is dissolved within a 30 minute period.

43. A pharmaceutical composition according to claim 41, characterized in that it is prepared by mixing the components comprising, on a weight basis: (a) from about 20 to about 70% irbesartan, (b) from about 1 to about about 70% diluent, (c) from about 2 to about 20% binder, (d) from about 1 to about 10% disintegrant, (e) from about 0.1 to about 5% non-stick, and (f) from about 0.2 to about 5% lubricant, and, optionally (g) from about 0.2 to about 6% surfactant, and / or (h) to about 2% coloring agent.

44. A pharmaceutical composition according to claim 43, characterized in that: the diluent is one or more compounds selected from the group consisting of calcium dibasic phosphate, hydrated lactose, anhydrous lactose, and microcrystalline cellulose; the binder is one or more compounds selected from the group consisting of alginic acid, sodium alginate, sodium carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, gelatin, povidone, starch and pregelatinized starch; the disintegrator is one or more compounds selected from the group consisting of alginic acid, sodium alginate, sodium carboxymethylcellulose, microcrystalline cellulose, cellulose powder, croscarmellose sodium, crospovidone, regelatinized starch, sodium starch glycolate, and starch; the anti-adherent is one or more compounds selected from the group consisting of silicon dioxide, magnesium trisilicate, and talc; the lubricant is one or more compounds selected from the group consisting of calcium stearate, glyceryl monostearate, glyceryl palmito stearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, vegetable oil hydrogenated, polyethylene glycol, sodium benzoate, and talc; when present, the surfactant is one or more compounds selected from the group consisting of sodium lauryl sulfate, and poloxamers; and when present, the coloring agent is one or more ferric oxides.

45. A pharmaceutical composition according to claim 43, characterized in that it is prepared by mixing the components comprising, on a weight basis, approximately 20 to 50% irbesartan; about 1 to 70% diluent; about 10 to 20% binder; approximately 4 to 8% disintegrator; approximately 0.25 to 5.0% non-stick; approximately 0.5 to 1.5% lubricant; and about 1 to 6% surfactant.

46. The pharmaceutical composition according to claim 45, characterized in that the diluent is lactose hydrate and microcrystalline cellulose; the binder is pregelatinized starch; the disintegrator is croscarmellose sodium; the anti-adherent is silicon dioxide; the lubricant is magnesium stearate; and the surfactant is poloxamer 188.

47. A pharmaceutical composition according to claim 41, characterized in that it is prepared by mixing the components comprising, on a weight basis, approximately 50% irbesartan; approximately 10.25% hydrated lactose; approximately 15.0% pregelatinized starch; approximately 5.0% croscarmellose sodium; about 3.0% poloxamer 188; about 15% microcrystalline cellulose; about 0.75% silicon dioxide; and about 1.0% magnesium stearate.

48. A pharmaceutical composition according to claim 41, characterized in that it is prepared by mixing the components comprising, on a weight basis, approximately 50% irbesartan; approximately 10.25% hydrated lactose; approximately 15.0% pregelatinized starch; approximately 5.0% croscarmellose sodium; about 3.0% poloxamer 188; about 13% microcrystalline cellulose; approximately 2.75% silicon dioxide; and about 1.0% magnesium stearate.

49. A pharmaceutical composition according to claim 41"characterized in that it is prepared by mixing the components comprising, on a weight basis, about 50% irbesartan; approximately 20.25% hydrated lactose; about 5.0% povidone K-30; approximately 5.0% croscarmellose sodium; about 3.0% poloxamer; about 15% microcrystalline cellulose; about 0.75% silicon dioxide; and about 1.0% magnesium stearate.

50. A pharmaceutical composition according to claim 41, characterized in that it is prepared by mixing the components comprising, on a weight basis, approximately 50% irbesartan; approximately 20.25% hydrated lactose; about 5.0% povidone K-30; approximately 5.0% croscarmellose sodium; about 3.0% poloxamer; about 13% micro-crystalline cellulose; approximately 2.75% silicon dioxide; and about 1.0% magnesium stearate.

51. A pharmaceutical composition according to claim 4, characterized in that it is prepared by mixing the components comprising, in addition, about 2 to about 33% diuretic, wherein the total% by weight of the irbesartan or the salt thereof and the mixed diuretic, does not exceed approximately 85%.

52. A pharmaceutical composition according to claim 51, characterized in that the diuretic is one or more compounds selected from the group consisting of hydrochlorothiazide, bendroflu-methiazide, benzthiazide, chloro-iazide, chlorthalidone, cyclothiazide, hydroflumethiazide, methyclothiazide, metola-zone, polythiazide , quininezone, and trichlormethiazide.

53. A pharmaceutical composition according to claim 52, characterized in that the diuretic is hydrochlorothiazide.

54. A pharmaceutical composition according to claim 51, characterized in that it is prepared by mixing the components comprising, on a weight basis: (a) from about 20 to about 70% irbesartan, (b) from about 2 to about 33 % diuretic, wherein the combined charge of (a) and (b) does not exceed about 85%, (c) from about 1 to about 70% diluent, (d) from about 2 to about 20% binder, (e) from about 1 to about 10% disintegrant, (f) from about 0.1 to about 5% non-stick, and (g) from about 0.2 to about 5% lubricant, and, optionally (h) to about 2% of coloring agent.

55. A pharmaceutical composition according to claim 54, characterized in that: the diuretic is hydrochlorothiazide; the diluent is one or more compounds selected from the group consisting of calcium dibasic phosphate, hydrated lactose, anhydrous lactose, and microcrystalline cellulose; the binder is one or more compounds selected from the group consisting of alginic acid, sodium alginate, sodium carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gelatin, povidone, starch and pregelatinized starch; the disintegrator is one or more compounds selected from the group consisting of alginic acid, sodium alginate, sodium carboxymethylcellulose, microcrystalline cellulose, cellulose powder, croscarmellose sodium, crospovidone, pregelatinized starch, sodium starch glycolate, and starch; the anti-adherent is one or more compounds selected from the group consisting of silicon dioxide, magnesium trisilicate, and talc; the lubricant is one or more compounds selected from the group consisting of calcium stearate, glyceryl monostearate, glyceryl palmito stearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, vegetable oil hydrogenated, polyethylene glycol, sodium benzoate, and talc; and when present, the coloring agent is one or more ferric oxides.

56. A pharmaceutical composition according to claim 54, characterized in that it is prepared by mixing the components comprising, on a weight basis, approximately 20 to 50% irbesartan; approximately 2 to 20% diuretic; about 1 to 70% diluent; about 10 to 20% binder; about 4 to 6% disintegrator; approximately 0.5 to 1.0% non-stick; v approximately 0.5 to 1.5% lubricant;

57. The pharmaceutical composition according to claim 56, characterized in that the diuretic is hydrochlorothiazide; the diluent is hydrated lactose and microcrist.aliña cellulose; the binder is pregelatinized starch; the disintegrator is croscarmellose sodium; the anti-adherent is silicon dioxide; and the lubricant is magnesium stearate.

58. A pharmaceutical composition according to claim 51, characterized in that it is prepared by mixing the components comprising, on a weight basis, approximately 50% irbesartan; approximately 8.33% hydrochlorothiazide; approximately 4.72% of hydrated lactose; approximately 15.0% pregelatinized starch; approximately 5.0% croscarmellose sodium; about 15% microcrystalline cellulose; about 0.75% silicon dioxide; about 1.0% magnesium stearate; approximately 0.1% ferric oxide, red; and about 0.1% ferric oxide, yellow.

59. A pharmaceutical composition according to claim 51, characterized in that it is prepared by mixing the components comprising, on a weight basis, about 50% irbesartan; about 4.17% hydrochlorothiazide; approximately 8.88% hydrated lactose; approximately 15.0% pregelatinized starch; approximately 5.0% croscarmellose sodium; about 15% microcrystalline cellulose; about 0.75% silicon dioxide; about 1.0% magnesium stearate; approximately 0.1% ferric oxide, red; and about 0.1% ferric oxide, yellow.

60. A pharmaceutical composition according to claim 51, characterized in that it is prepared by mixing the components comprising, on a weight basis, about 50% irbesartan; approximately 8.33% hydrochlorothiazide; approximately 1.72% hydrated lactose; approximately 15.0% pregelatinized starch; approximately 5.0% croscarmellose sodium; about 3% poloxamer; about 15% microcrystalline cellulose; about 0.75% silicon dioxide; about 1.0% magnesium stearate; approximately 0.1% ferric oxide, red; and about 0.1% ferric oxide, yellow.

61. A pharmaceutical composition according to claim 51, characterized in that it is prepared by mixing the components comprising, on a weight basis, about 50% irbesartan; approximately 8.33% hydrochlorothiazide; approximately 11.72% of hydrated lactose; Approximately 5.0% povidone K-30; approximately 5.0% croscarmellose sodium; about 3% poloxamer; about 15% microcrystalline cellulose; about 0.75% silicon dioxide; about 1.0% magnesium stearate; approximately 0.1% ferric oxide, red; and about 0.1% ferric oxide, yellow.

62. A pharmaceutical composition according to claim 51, characterized in that it is prepared by mixing the components comprising, on a weight basis, approximately 50% irbesartan; about 4.17% hydrochlorothiazide; approximately 5.88% hydrated lactose; approximately 15.0% pregelatinized starch; approximately 5.0% croscarmellose sodium; about 3% poloxamer; about 15% microcrystalline cellulose; about 0.75% silicon dioxide; about 1.0% magnesium stearate; approximately 0.1% ferric oxide, red; and about 0.1% ferric oxide, yellow.

63. A pharmaceutical composition according to claim 51, characterized in that it is prepared by mixing the components comprising, on a weight basis, about 50% irbesartan; about 4.17% hydrochlorothiazide; about 15.88% hydrated lactose; about 5.0% povidone K-30; approximately 5.0% croscarmellose sodium; about 3% poloxamer; about 15% microcrystalline cellulose; about 0.75% silicon dioxide; about 1.0% magnesium stearate; approximately 0.1% ferric oxide, red; and about 0.1% ferric oxide, yellow.