Pharmaceutical compositions containing irbesartan

Abstract: Pharmaceutical compositions containing irbesartan, alone or in combination with a diuretic, providing tablets with a high relative amount of active agent and excellent wetting and disintegration properties.

Description: 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. Irbesartan, 2-n-butyl-4-spirocyclopentane-1-[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one, is a potent, long-acting angiotensin II receptor antagonist which is particularly useful in the treatment of cardiovascular ailments such as hypertension and heart failure. Irbesartan has the following structure: and is described in Bernhart et al., U.S. Patent No. 5,270,317. Irbesartan may be administered in dosages containing a substantial quantity of the active agent (e.g., 75 - 300 mg). Certain physical properties of the drug present a challenge in developing formulations suitable for preparing a tablet having both a substantial quantity of active agent and a small enough tablet mass to allow ease of swallowing. Irbesartan is, for example, a fluffy material, with relatively low bulk and tap densities. These properties make it difficult to formulate a large amount of the drug into a small tablet with uniformity of weight, hardness, and other desirable tablet properties. In addition, irbesartan has certain undesirable flow characteristics, for example, is sticky and can adhere to surfaces such as tablet punch faces and dies, causing problems in tableting, especially on a high speed tablet press. The low aqueous solubility of irbesartan also presents a challenge, since, to keep the tablet mass small, only limited amounts of excipients may be added to facilitate wetting, disintegration, and ultimately, rapid and complete drug release. Thus, there is a need in the art for pharmaceutical compositions containing irbesartan, which have good properties for tablet formation, and yet which contain a low mass of excipients so that small, easily swallowed tablets with a high content of active agent may be prepared. WO-A-91 14679 (of which US 5,270,317 above cited is a continuation-in-part) discloses heterocyclic N-substituted derivatives, namely irbesartan (claim), to be used in particular against hypertension and heart failure. EP-A-0475895 discloses a family of azacyclic compounds having Angiotensin-II antagonist properties and pharmaceutical compositions containing them. At least in its preferred forms, the present invention provides pharmaceutical compositions containing irbesartan which (1) have a minimal mass of added excipients, thereby allowing preparation of small, easily swallowed tablets which enhance patient acceptance and compliance, and yet which (2) have excellent properties for tablet formation, and (3) provide tablets with excellent wetting, disintegration, and ultimately, rapid and complete drug release properties. In particular, the present invention provides pharmaceutical compositions, especially suitable for forming tablets, comprising from 20 to 70% by weight irbesartan or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients, wherein a tablet formed from said composition has a dissolution performance such that 80% or greater, preferably 85% or greater, of the irbesartan or salts thereof contained in said tablet dissolve within 30 minutes. Preferred compositions containing irbesartan comprise, based on a total of 100% by weight: (a) from 20 to 70% (preferably, 50%) irbesartan, (b) from 1 to 70% diluent, (c) from 2 to 20% binder, (d) from 1 to 10% disintegrant, (e) from 0.1 to 5% antiadherent, and (f) from 0.2 to 5% lubricant, and, (g) from 0.2 to 6% surfactant, and/or (h) up to 2% (preferably, from 0.1 to 1%) coloring agent. The present compositions may contain up to 70% w/w irbesartan, and yet can be employed in the reproducible manufacture of tablets on a large scale. The present compositions can, for example, be compressed on high speed tableting equipment (especially, a high speed tablet press) to form tablets which are uniform in both weight and content and which exhibit desirable physical properties, including elegant appearance, low friability, and fast disintegration time. Tablets prepared from the present compositions are capable of releasing the active component(s), by dissolution, in a fast and reproducible manner. Unless otherwise indicated, mention of irbesartan herein also includes pharmaceutically acceptable salts thereof. The present invention is described in further detail as follows. The components employed in the compositions of the present invention should be pharmaceutically acceptable, particularly as described in the National Formulary (NF) or 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 irbesartan contained in the tablet, which dissolves within 30 minutes under the following conditions: using a tablet having a total weight of from 150 to 600 mg and a USP Apparatus 2, placing the tablet in 1000 mL of 0.1 N hydrochloric acid at 37°C, with a paddle speed of 50 rpm, and measuring the amount of irbesartan dissolved (especially, using UV at 244 nm) at 30 minutes. (If desired, the progress of dissolution may also be monitored at various time points.) The "diluent" employed in a composition of the present invention may be one or more compounds which are capable of providing bulk 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 dibasic calcium phosphate; sugars such as lactose hydrous or lactose anhydrous; and cellulose or cellulose derivatives such as microcrystalline cellulose. The "binder" employed in a composition of the present invention may be one or more compounds which are capable of facilitating granulation of the irbesartan and/or diuretic into larger, denser, and/or more free-flowing particles. Preferred binders are alginic acid (most preferably employed in the range of 2 - 5% by weight) or sodium alginate (most preferably employed in the range of 2 - 3% by weight); cellulose or cellulose derivatives such as carboxymethylcellulose sodium (most preferably employed in the range of 2 - 6% by weight), ethylcellulose (most preferably employed in the range of 2 - 3% by weight), hydroxyethyl cellulose (most preferably employed in the range of 2 - 5% by weight), hydroxypropyl cellulose (most preferably employed in the range of 2 - 6% by weight), hydroxypropyl methylcellulose (most preferably employed in the range of 2 - 5% by weight), or methylcellulose (most preferably employed in the range of 2 - 6% by weight); gelatin (most preferably employed in the range of 2 - 10% by weight); povidone (polyvinylpyrrolidone, i.e., 1-ethenyl-2-pyrrolidinone homopolymer) (e.g., povidone K-30) (most preferably employed in the range of 2 - 20% by weight); or starch (most preferably employed in the range of 5 - 20% by weight) or pregelatinized starch (most preferably employed in the range of 2 - 20, such as 5 - 20% by weight). The "disintegrant" employed in a composition of the present invention may be one or more compounds which are capable of facilitating the break up of a tablet prepared from the composition when placed in contact with an aqueous medium. Preferred disintegrants are alginic acid (most preferably employed in the range of 2 - 5% by weight) or sodium alginate (most preferably employed in the range of 2.5 - 10% by weight); cellulose or cellulose derivatives such as carboxymethylcellulose sodium (most preferably employed in the range of 2 - 6% by weight), microcrystalline cellulose (most preferably employed in the range of 5 - 15% by weight), powdered cellulose (most preferably employed in the range of 5 - 15% by weight), or croscarmellose sodium (cross-linked polymer of carboxymethylcellulose sodium) (most preferably employed in the range of 2 - 5% by weight); crospovidone (cross-linked homopolymer of N-vinyl-2-pyrrolidinone, i.e., cross-linked 1-ethenyl-2-pyrrolidinone) (most preferably employed in the range of 2 - 5% by weight); pregelatinized starch (most preferably employed in the range of 5 - 10% by weight), sodium starch glycolate (most preferably employed in the range of 2 - 8% by weight), or starch (most preferably employed in the range of 3 - 15% by weight). The "antiadherent" employed in a composition of the present invention may be one or more compounds which are capable of reducing the stickiness of the formulation, for example, preventing adherence to metal surfaces. Preferred antiadherents are silicon-containing compounds such as silicon dioxide (most preferably employed in the range of 0.25 - 5% (such as 0.5 - 2 or 2.5 to 3.0%) by weight), magnesium trisilicate (most preferably employed in the range of 0.5 - 2% by weight), or talc (most preferably employed in the range of 1 - 5% by weight). The "lubricant" employed in a composition of the present invention may be one or more compounds which are capable of preventing tableting problems, such as those relating to the release of a tablet prepared from the composition from the apparatus on which it is formed, for example, preventing adherence to the face of the upper punch (picking) or lower punch (sticking) of a tableting apparatus. Preferred lubricants are fatty acids or fatty acid derivatives such as calcium stearate (most preferably employed in the range of 0.5 - 2% by weight), glyceryl monostearate (most preferably employed in the range of 0.5 - 2% by weight), glyceryl palmitostearate (most preferably employed in the range of 0.5 - 2% by weight), magnesium stearate (most preferably employed in the range of 0.2 - 2% by weight), sodium lauryl sulfate (most preferably employed in the range of 1 - 2% by weight), sodium stearyl fumarate (most preferably employed in the range of 0.5 - 2% by weight), zinc stearate (most preferably employed in the range of 0.5 - 1.5% by weight) or stearic acid (most preferably employed in the range of 1 - 3% by weight); hydrogenated vegetable oil (most preferably employed in the range of 1 - 5% by weight); polyalkylene glycols such as polyethylene glycol (most preferably employed in the range of 1 - 5% by weight); sodium benzoate (most preferably employed in the range of 2 - 5% by weight); or talc (most preferably employed in the range of 1 - 5% by weight). The "surfactant" employed in a composition of the present invention may be one or more compounds which are capable of improving the wetting of the tablets and/or enhancing dissolution. Preferred surfactants are sodium lauryl sulfate (most preferably employed in the range of 0.2 - 6% by weight), and poly(oxyethylene),poly(oxypropylene) block co-polymers such as poloxamers, especially poloxamer 188 (most preferably employed in the range of 1 - 6% by weight). The "coloring agent" (or "colorant") employed in a composition of the present invention may be one or more compounds which impart a desired color to a tablet prepared from the composition. Addition of a coloring agent may be used, for example, so that tablets of different potencies may be easily distinguished. Preferred coloring agents are ferric oxides, which are universally accepted. As can be seen from the above, a single compound may perform two or more functions. Calculation of weight percent is preferably on the basis of the primary function of a compound in a given composition. The present compositions preferably consist essentially of, most preferably, consist of the above-described components. Preferred Compositions Preferred compositions of the present invention contain one or more of the following components in the indicated concentration range (% by weight): irbesartan, 20 to 60 (e.g., 25 to 60), such as 30 to 60, most preferably, 30 to 50, especially 50%; diluent, 1 to 70, most preferably 1 to 60, especially 1 to 40%; binder, 5 to 20, most preferably 5 to 15%; disintegrant, 4 to 8, most preferably 5%; antiadherent, 0.25 to 5.0% (such as 2.5 to 3.0%, for example); lubricant, 0.5 to 1.5, most preferably 1%; and surfactant, 1 to 3, most preferably, 3%. The following tables recite preferred compositions of the present invention which produce tablets of especially high quality and superior performance. Table A recites preferred compositions containing irbesartan. IRBESARTAN Preferred Ingredient Component Concentration Range (% w/w) irbesartan active drug 20 - 50 lactose hydrous diluent 1 - 70 microcrystalline cellulose (e.g., Avicel® PH 102 ) diluent 5 - 20 pregelatinized starch (e.g., Starch® 1500 ) binder 10 - 20 croscarmellose sodium (e.g., Ac-Di-Sol® ) disintegrant 4 - 8 poloxamer, especially poloxamer 188 (e.g., Pluronic® F68 ) surfactant 1 - 6 silicon dioxide (e.g., Syloid® 244 ) antiadherent 0.25 - 5.0 (0.25 to 1.5 especially, 2 to 3.0) magnesium stearate lubricant 0.5 - 1.5 TOTAL 100 In the above compositions of Table A, the combination of magnesium stearate and silicon dioxide provides a superior lubrication effect while minimizing any decline in tablet dissolution performance; the intragranular:extragranular placement ratio of the disintegrant croscarmellose sodium is superior (e.g., 1:1); and the poloxamer surfactant improves the aqueous granulation of irbesartan (which is hydrophobic), eases the ejection of tablets after compression and accelerates the dissolution of the irbesartan active agent. The composition of Table A preferably also contain 0.08 to 0.12% by weight ferric oxide, red and 0.08 to 0.12% by weight ferric oxide, yellow as a colorant. Methods of Manufacture Tablets may be prepared from the present compositions by any suitable method for forming tablets. Preferably, tablets are prepared from the present compositions by a wet granulation process. An exemplary such method comprises the following steps: (a) preparing an intragranular composition by: (i) mixing the irbesartan, a portion of the diluent (preferably, from 5 to 80% by weight of the total diluent), a portion of the disintegrant (preferably, from 50 to 80% by weight of the total disintegrant), the binder, and, optionally, a portion of the antiadherent (preferably, from 50 to 80% by weight of the total antiadherent), to form a powder blend and, optionally, sizing the blend (e.g., milling the blend to break up aggregates); (ii) re-mixing the blend; (iii) granulating the blend with a granulating fluid, preferably an aqueous solution of the surfactant, to form granules (e.g., using a high shear mixer/granulator) ; (iv) drying the granules (e.g., in an oven or, preferably, in a fluid bed dryer); and (v) sizing the dried granules (e.g., by milling or screening); (b) preparing a mixture of the sized granules of step (a) (v) with an extragranular composition by: (i) mixing the remainder of the diluent, the remainder of the disintegrant, the antiadherent or the remainder of the antiadherent, and, optionally, the coloring agent, where one or more of these may be preblended, sized (e.g., milled to break up aggregates) and re-mixed prior to this step, with the sized granules from step (a) (v) to form a granule blend; and (ii) mixing the lubricant with the granule blend; and (c) compressing the mixture from step (b) (ii) to form tablets (for example, employing a tablet press). The solid starting materials of the present compositions are preferably screened prior to use. The weight ratio of water (preferably, purified water, USP or water for injection, USP) to solids employed in step (a) (iii) is preferably within the range of from 0.25:1 to 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 25 to 300 mg of irbesartan, most preferably from 75 to 300 mg of irbesartan. The total weight of the tablets prepared is preferably from 50 to 600 mg. In addition to tablets, the compositions of the present invention may be used to prepare beads, granules for dispersion or capsules, the latter, for example, filled with powder or the aforementioned beads or granules. Methods such as those well known in the art may be used to prepare these dosage forms. The compositions and tablets of the present invention may be used to treat or prevent disorders such as those described in U.S. Patent No. 5,270,317. Such disorders include cardiovascular disorders, for example, hypertension or heart failure, venous insufficiency, as well as glaucoma, diabetic retinopathy, renal insufficiency and various complaints of the central nervous system. The present compositions or tablets are preferably administered orally, in an effective amount, to a mammalian (especially, human) subject to treat or prevent the aforementioned disorders. For human subjects, preferred dosages of from 75 mg to 300 mg of irbesartan may be administered, for example, 1 to 2 times per day. The following Examples are provided to illustrate 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 were prepared in three potencies from the composition of the present invention described in the following Table 1: (1) 75 mg irbesartan with a total weight of 150 mg per tablet; (2) 150 mg irbesartan with a total weight of 300 mg per tablet; and (3) 300 mg irbesartan with a total weight of 600 mg per tablet. Ingredient Component Concentration (% w/w) INTRAGRANULAR irbesartan active drug 50 lactose hydrous, NF diluent 10.25 pregelatinized starch, NF binder 15.0 croscarmellose sodium, NF disintegrant 2.5 poloxamer 188, NF surfactant 3.0 EXTRAGRANULAR microcrystalline cellulose, NF diluent 15.0 croscarmellose sodium, NF disintegrant 2.5 silicon dioxide, NF antiadherent 0.75 magnesium stearate, USP lubricant 1.0 TOTAL 100.00 100.00 Using the above formulation, the tablets were prepared by a wet granulation process as follows. In this process, the total amount of water employed (by weight) was up to 50% of the total solids weight. The irbesartan, lactose, pregelatinized starch, and a portion (1/2) of the croscarmellose sodium were mixed in a mixer. The powder blend prepared was passed through sizing equipment (cone mill or oscillator), and mixed in a mixer. The poloxamer 188 was dissolved in water (purified, USP or water for injection, USP) (25% of the weight of total solids), and used to wet granulate (with the further addition of water in an amount which was up to 25% of the weight of total solids as needed) the mixed powder. The granules obtained were dried (tray or fluid bed dryer) until the loss-on-drying (LOD) was 2% or less. The dried granules were passed through a screen or milled to obtain the proper size (1 to 3 mm). The sized granules were mixed with the silicon dioxide, the microcrystalline cellulose and the remaining croscarmellose sodium in a mixer. The blend obtained was then mixed with the magnesium stearate. By compressing the mixture using tableting equipment, tablets were prepared for each potency having the compositions indicated in the following Table 2. Ingredient 75 mg Potency (mg) 150 mg Potency (mg) 300 mg Potency (mg) irbesartan 75.00 150.00 300.00 lactose hydrous, 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 Pluronic F68, NF) 4.50 9.00 18.00 silicon dioxide, NF 1.12 2.25 4.50 magnesium stearate, USP 1.50 3.00 6.00 Tablet Weight 150.00 300.00 600.00 EXAMPLE 2 PREPARATION OF TABLETS CONTAINING IRBESARTAN; ALTERNATIVE FORMULATION Tablets were prepared having the composition of the following Table 3 by a method analogous to that of Example 1. Ingredient Amount mg/tablet (% w/w) INTRAGRANULAR irbesartan 300.0 (50) lactose hydrous, NF (diluent) 121.5 (20.25) povidone K-30, USP (binder) 30.0 (5) croscarmellose sodium (disintegrant) 24.0 (4) Pluronic F68, NF (poloxamer, surfactant) 18.0 (3) EXTRAGRANULAR microcrystalline cellulose, NF (diluent) 90.0 (15) croscarmellose sodium (disintegrant) 6.0 (1) silicon dioxide, NF (antiadherent) 4.5 (0.75) magnesium stearate (lubricant) 6 (1) TOTAL WEIGHT 600.00 (100) EXAMPLE 3 PREPARATION OF TABLETS CONTAINING IRBESARTAN Tablets containing irbesartan were prepared in three potencies from the composition of the present invention described in the following Table 4: (1) 75 mg irbesartan with a total weight of 150 mg per tablet; (2) 150 mg irbesartan with a total weight of 300 mg per tablet; and (3) 300 mg irbesartan with a total weight of 600 mg per tablet. Ingredient Component Concentration (% w/w) INTRAGRANULAR irbesartan active drug 50 lactose hydrous, NF diluent 10.25 pregelatinized starch, NF binder 15.0 croscarmellose sodium, NF disintegrant 2.5 poloxamer 188, NF surfactant 3.0 silicon dioxide, NF antiadherent 2.0 EXTRAGRANULAR microcrystalline cellulose NF diluent 13.0 croscarmellose sodium, NF disintegrant 2.5 silicon dioxide, NF antiadherent 0.75 magnesium stearate, USP lubricant 1.0 TOTAL 100.00 100.00 Using the above formulation, the tablets were prepared by a wet granulation process as follows. In this process, the total amount of water employed (by weight) was up to 50% of the total solids weight. The irbesartan, lactose, pregelatinized starch, a portion (1/2) of the croscarmellose sodium, and a portion (about 73%) of the silicon dioxide were mixed in a mixer. The powder blend prepared was passed through sizing equipment (cone mill or oscillator), and mixed in a mixer. The poloxamer 188 was dissolved in water (purified, USP or water for injection, USP) (25% of the weight of total solids), and used to wet granulate (with the further addition of water in an amount which was up to 25% of the weight of total solids as needed) the mixed powder. The granules obtained were dried (tray or fluid bed dryer) until the loss-on-drying (LOD) was 2% or less. The dried granules were passed through a screen or milled to obtain the proper size (1 to 3 mm). The sized granules were mixed with the remaining silicon dioxide, the microcrystalline cellulose and the remaining croscarmellose sodium in a mixer. The blend obtained was then mixed with the magnesium stearate. By compressing the mixture using tableting equipment, tablets were prepared for each potency having the compositions indicated in the following Table 5. Ingredient 75 mg Potency (mg) 150 mg Potency (mg) 300 mg Potency (mg) irbesartan 75.00 150.00 300.00 lactose hydrous, 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 Pluronic F68, NF) 4.50 9.00 18.00 silicon dioxide, NF 4.12 8.25 16.50 magnesium stearate, USP 1.50 3.00 6.00 Tablet Weight 150.00 300.00 600.00 Tablets comprising irbesartan or a pharmaceutically acceptable salt thereof, prepared (such as is described herein) by mixing an extragranular composition with granules comprising an antiadherent (preferably, silicon dioxide), may dissolve more rapidly and/or completely, and thus may exhibit an improved dissolution performance. EXAMPLE 4 PREPARATION OF TABLETS CONTAINING IRBESARTAN; ALTERNATIVE FORMULATION Tablets were prepared having the composition of the following Table 6 by a method analogous to that of Example 3. Ingredient Amount mg/tablet (% w/ INTRAGRANULAR irbesartan 300.0 (50) lactose hydrous, NF (diluent) 121.5 (20.25) povidone K-30, USP (binde 30.0 (5) croscarmellose sodium (disintegrant) 24.0 (4) Pluronic F68, NF (poloxamer, surfactant) 18.0 (3) silicon dioxide, NF (antiadherent) 12.0 (2) EXTRAGRANULAR microcrystalline cellulos NF (diluent) 78.0 (13) croscarmellose sodium (disintegrant) 6.0 (1) silicon dioxide, NF (antiadherent) 4.5 (0.75) magnesium stearate (lubricant) 6 (1) TOTAL WEIGHT 600.00 (100) In the following claims list of ingredients are intended to cover (a) either the ingredients in the actual composition as would be ascertained by analysis or (b) in the ingredients from which the composition is prepared (this allowing for any reaction which might take place between the ingredients).

Claims: A pharmaceutical composition, wherein said composition comprises, based on weight: (a) from 20 to 70% irbesartan or a pharmaceutically acceptable salt thereof, (b) from 1 to 70% diluent, (c) from 2 to 20% binder, (d) from 1 to 10% disintegrant, (e) from 0.1 to 5.0% antiadherent, (f) from 0.2 to 5% lubricant, (g) from 0.2 to 6% surfactant, wherein a tablet formed from said composition has a dissolution performance such that 80% or greater of the irbesartan or salt thereof contained in said tablet dissolves within 30 minutes. The pharmaceutical composition of claim 1, wherein a tablet formed from said composition has a dissolution performance such that about 85% or greater of the irbesartan or salt thereof contained in said tablet dissolves within 30 minutes. A pharmaceutical composition according to claim 1 or 2, further comprising up to 2% coloring agent. A pharmaceutical composition according to any one of claims 1 to 3, wherein the diluent is one or more compounds selected from the group consisting of dibasic calcium phosphate, lactose hydrous, lactose anhydrous, and microcrystalline cellulose; the binder is one or more compounds selected from the group consisting of alginic acid, sodium alginate, carboxymethylcellulose sodium, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, gelatin, povidone, starch and pregelatinized starch; the disintegrant is one or more compounds selected from the group consisting of alginic acid, sodium alginate, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, pregelatinized starch, sodium starch glycolate, and starch; the antiadherent 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 palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, and talc; 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. The pharmaceutical composition according to any one of claims 1 to 4, comprising, based on weight, from 20 to 50% irbesartan; from 1 to 70% diluent; from 10 to 20% binder; from 4 to 8% disintegrant; from 0.25 to 5.0% antiadherent; and from 0.5 to 1.5% lubricant; and from 1 to 6% surfactant. The pharmaceutical composition according to any one of claims 1 to 5, wherein said diluent is lactose hydrous and microcrystalline cellulose; said binder is pregelatinized starch; said disintegrant is croscarmellose sodium; said antiadherent is silicon dioxide; said lubricant is magnesium stearate; and said surfactant is poloxamer 188. The pharmaceutical composition according to any one of claims 1 to 6, comprising, based on weight, 50% irbesartan; 10.25% lactose hydrous; 15.0% pregelatinized starch; 5.0% croscarmellose sodium; 3.0% poloxamer 188; 15% microcrystalline cellulose; 0.75% silicon dioxide; and 1.0% magnesium stearate. The pharmaceutical composition according to any one of claims 1 to 6, comprising, based on weight, 50% irbesartan; 10.25% lactose hydrous; 15.0% pregelatinized starch; 5.0% croscarmellose sodium; 3.0% poloxamer 188; 13% microcrystalline cellulose; 2.75% silicon dioxide; and 1.0% magnesium stearate. The pharmaceutical composition according to any one of claims 1 to 4, comprising, based on weight, 50% irbesartan; 20.25% lactose hydrous; 5.0% povidone K-30; 5.0% croscarmellose sodium; 3.0% poloxamer; 15% microcrystalline cellulose; 0.75% silicon dioxide; and 1.0% magnesium stearate. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that it comprises, based on weight, 50% irbesartan; 20.25% lactose hydrous; 5.0% povidone K-30; 5.0% croscarmellose sodium; 3.0% poloxamer; 13% microcrystalline cellulose; 2.75% silicon dioxide; and 1.0% magnesium stearate. A tablet formed from the composition according to any one of the preceding claims. A tablet of claim 11, wherein the total weight of said tablet is from 50 to 600 mg. A tablet formed from the composition of any one of claims 1 to 10, wherein said tablet is prepared by mixing an extragranular composition with granules comprising an antiadherent. The tablet of claim 13, wherein said antiadherent is silicon dioxide.

Inventors: DESAI DIVYAKANT S, KU CATHY C, RUBITSKI BETH A, SPROCKEL OMAR L, DESAI, DIVYAKANT S., KU, CATHY C., RUBITSKI, BETH A., SPROCKEL, OMAR L.
Applicants: SANOFI SYNTHELABO, SANOFI-SYNTHELABO
Application year: 1996
Main classification: A61K31
IPC codes: A61K31, A61K47, A61P9, A61P7, A61K9, C07D403, A61P43