MXPA00004791A - High drug load immediate and modified release oral dosage formulations and processes for their manufacture - Google Patents

Abstract

This invention relates to high drug load granulation of (E)-&agr;- [2-n-butyl-1- [(4-carboxyphenyl) methyl]-1H- imidazol-5-yl]methylene-2- thiophenepropionic acid in the anhydrous form, a process for its production, compositions containing the compound and methods of using the compound to block angiotensin II receptors and to treat hypertension, congestive heart failure and renal failure.

Description

FORMULATIONS OF ORAL DOSE OF IMMEDIATE RELEASE AND MODIFIED WITH HIGH BURDEN OF DRUG AND PROCEDURES FOR ITS MANUFACTURE FIELD OF THE INVENTION This invention relates to formulations with high drug loading, methods for preparing these formulations and methods for using formulations with high drug loading in the treatment of certain disease states in mammals, in particular in man. Specifically, the present invention relates to the use of anhydrous (E) - [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene-2-thiophenepropionic acid in the preparation of tablet formulations of immediate and modified release with high drug loading, wet or dry granulation procedures to prepare granules with high drug loading, oral dosage forms containing these granules with high drug loading and methods for using formulations with high load of (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene-2-thiophenepropionic acid drug to block angiotensin receptors II (All) and to treat hypertension, congestive heart failure and renal impairment.

BACKGROUND OF THE INVENTION The compound, (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene-2-thiophenepropionic acid is known by the name of "eprosartan. and is the subject of United States Patent No. 5,185,351 (the 351 patent), published on February 9, 1993. This patent describes a process for making the anhydrous form of (E) -a- [2-n- butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene-2-thiophenepropionic acid and its methanesulfonate salt. Additionally, the '351 patent describes the conventional techniques for formulating (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene-2-thiophenpropionic acid. . This compound is claimed to be useful for blocking angiotensin II receptors and for being useful in the treatment of hypertension, congestive heart failure and renal impairment. International application number PCT / US97 / 04877, filed March 26, 1997, refers to a novel dihydrated form of (E) - - [2-n-butyl-1 - [(4-carboxyphenyl) methyl) monomethanesulfonate] -1H-imidazol-5-yl] methylene-2-thiophenepropionic acid, in particular in pharmaceutical compositions for the treatment of diseases in which blockade of angiotensin II receptors is indicated, for example, in the treatment of hypertension, congestive heart failure and kidney failure. This form of (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene-2-thiophenepropionic acid monomethanesulfonate is produced during wet granulation of the anhydrous form of (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1 H -imidazol-5-yl] methylene-2-thiophenpropionic acid monomethanesulfonate. Surprisingly, it has been found that (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene-2-thiophenepropionic acid does not form an anhydrous hydrate during wet granulation. This discovery has allowed the preparation of tablets with high drug load of reduced size. This is particularly important in the formulation of eprosartan for commercial use.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides formulations with high drug loading of (E) - [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene-2-thiophenepropionic acid anhydrous and oral solid dosage forms of this compound for the treatment of diseases in which blockade of angiotensin II receptors is indicated, for example, in the treatment of hypertension, congestive heart failure and renal impairment. These formulations with high drug loading are in the form of an oral solid dose of immediate or modified release. The present invention also provides methods for preparing tablet formulations with high loading of (E) -a- [2-n-butyl-1 - [(4-carboxylphenyl) methyl] -1H-imidazole-5-drug drugs. -yl] methylene-2-thiophenepropionic acid by dry or wet granulation of the anhydrous form of (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazole-5- il] methylene-2-thiophenepropionic acid in the presence of pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS Figures 1 (A), 2 (A) and 3 (A) show, respectively, the thermogravimetric analysis (TGA), the differential scanning calorimetric thermogram (DSC) and the powder diffraction pattern by lightning.

X (XRD) of the free base of (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1 H-imidazol-5-yl] methylene-2-thiophenepropionic acid anhydrous. The anhydrous form of (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene-2-thiophenepropionic acid presents a simple thermal event, a melting endotherm at about 269 C associated with a weight loss, which suggests that the melt is followed by decomposition of the drug (Figure 2A). No significant loss in weight prior to melting is observed in its TGA (thermogravimetric analysis) [Figure 1 (A)], which suggests that this compound does not contain significant amounts of water and / or residual solvents adsorbed on the surface. The X-ray powder diffraction pattern [Figure 3 (A)] presents characteristic diffraction lines corresponding to 2T values of 8.15, 9.74, 14.20, 16.09, 17.09, 19.99, 20.71, 21.81, 22.38, 24.49, 26.84 and 31.39 degrees . Figures 1 BD, 2B-D and 3B-D show respectively the thermogravimetric analysis (TGA), the differential scanning calorimetric thermogram (DSC) and the X-ray powder diffraction pattern (XRD) for the granulations of the base free of (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene-2-thiophenepropionic anhydride with different binders and binder combinations- diluent. Figures 1 B, 2B and 3B show, respectively, the thermogravimetric analysis (TGA), the differential scanning calorimetric thermogram (DSC) and the powder diffraction patterns by X-ray (XRD) for the granulations of acid (E) -a - [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1 H -amidazol-5-yl] methylene-2-thiophenepropionic with Starch 1551 (free base of eprosartan 96/4 / Starch 1551 ). Figures 1C, 2C and 3C show, respectively, the thermogravimetric analysis (TGA), the differential scanning calorimetric thermogram (DSC) and the powder diffraction patterns by X-ray (XRD) for the granulations of acid (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-ymdazol-5-yl] methylene-2-thiophenepropionic acid with L-arginine (eprosartan free base 95/5 / L-arginine ). Figures 1 D and 2D show, respectively, the thermogravimetric analysis (TGA) and the differential scanning calorimetric thermogram (DSC) for the granulations of (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl ) methyl] -1H-imidazol-5-yl] methylene-2-thiophenepropionic with Starch 1551, microcrystalline cellulose, hydrated lactose (eprosartan free base 88/4/4/4 / Starch 1551 / microcrystalline cellulose / lactose hydrate). Figure 3D shows X-ray powder diffraction patterns (XRD) for granulations of (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-methyldazole- 5-yl] methylene-2-thiophenepropionic with Povidone (PVP) (free base of eprosartan 96/4 / PVP). These figures illustrate that, unlike the mesylate salt form, the free base of (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazole-5 acid -yl] methylene-2-thiophenepropionic does not form a hydrate during wet granulation.

DETAILED DESCRIPTION OF THE INVENTION It is known that (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene-2-thiophenepropionic acid exists in an anhydrous form . This compound has the following structure: (E) - - [2-n-Butyl-1 - [(4-carboxylphenyl) methyl] -1H-imidazol-5-yl] methylene-2-thiophenepropionic acid, eprosartan, is claimed in the US No. 5,185,351. Reference should be made to said patent for its complete description, including methods for preparing and using this compound. The full description of the patent 351 is incorporated herein by reference. By immediate release formulation it is understood any formulation that at the moment in which eposartan leaves the stomach, be it in solution or in the form of a suspension in fine particles, that is, a form from which eposartan can be easily absorbed. By "modified release" is meant a controlled release or delayed release formulation. By controlled release is meant any formulation that achieves a slow release of the drug over a prolonged period. In the controlled release formulations of the present invention, a portion of eposartan is available in the formulation as an initial dose and the remnant is released in a sustained manner. An example of a controlled release system is a matrix formulation. By "delayed release" is meant any formulation that uses intermittent and repetitive dosages of eposartan from one or more immediate release units incorporated in a single dosage form. Examples of delayed-release systems include tablets and repeated-action capsules and enteric-coated tablets wherein programmed release is achieved by a barrier coating. Examples of controlled release formulations that are suitable for incorporating eprosartan are described in: Sustained Relase Medications, Chemical Technology, Review No. 177, Ed. J.C. Johnson, Noyes Data Corporation (1980); and Controlled Drug Delivery, Fundamentals and Applications 2- Edition, Eds. J.R. Robinson, V.H.L. Lee, Mercel Dekkes Inc., New York (1987). Examples of delayed-release formulations that are suitable for incorporating eprosartan are described in: Remington's Pharmaceutical Sciences, 16th Edition, Ed. A. Osol, Mack Publishing Company (1980). Other examples of controlled release formulations that are suitable for incorporating eprosartan are described in the U.S. patent. No. 4,839,177, published June 13, 1989, and in the patent E.U.A. No. 5,422,123, published June 6, 1995. Matrix controlled release formulations for eprosartan are detailed in the U.S. patent. No. 4,389,393, published June 21, 1983 and in the patent E.U.A. No. 4,968,508, published November 6, 1990. Eprosartan is an amphiphilic molecule containing two acid functional groups (allylic carboxylic acid and phenyl carboxylic acid) and a basic one (imidazole). At a lower pH (less than 2) the imidazole nitrogen will be protonated (form ii). As the pH increases, the allylic carboxylic group will be deprotonated (form iii). The estimated pka of the allylic carboxylic group is 2.9. As the pH continues to increase, the phenyl carboxylic group will be deprotonated (form iv) followed by deprotonation of the protonated imidazole group (form v). The estimated pka of the phenyl carboxyl group is 5.9 and that of the imidazole group is 6.8. According to the pH division absorption theory, only non-ionized species (form ii) or neutral ion species (form iii) will be absorbed by passive diffusion. According to the present invention, eprosartan is preferably in the free base form in anhydrous form. Eprosartan as the free base is a zwitterionic or zwitterionic ion, because an acid group and a basic group are part of the same molecule and in a neutral environment this compound exists as a dipolar ion. Human clinical studies indicate that (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) -methyl] -1H-imidazol-5-yl] -methylene-2-thiophenepropionic acid or its Monometansulfonate salt is safe and with good tolerance, even up to 800 mg a day. The time for maximum concentration is between 1 to 2.5 hours in fasting and 2.5 to 4 hours after having eaten food. The (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) -methyl] -1H-imidazol-5-yl] -methylene-2-thiophenepropionic acid monomethanesulfonate exhibits an average absolute bioavailability of approximately 13%. As a result, doses of up to 800 mg per day may be required to treat hypertension, congestive heart failure and kidney failure. Because (E) -a- [2-n-butyl-1 - [(4-carboxylphenyl) -methyl] -1H-imidazole-5-yl] -methylene-2- is presently present thiophenepropionic acid is formulated from its methanesulfonic acid in anhydrous form, which then forms a dihydrate in the wet granulation process, the tablets are prepared for commercial use in which the loading of active ingredient in the total weight of the tablet is in a ratio of approximately 1: 2 (w / w). For example, a tablet containing 600 mg of active ingredient weighs 1, 200.0 mg. It has been found that the free base of eprosartan anhydrous does not form a hydrate during wet granulation, thus, this form of the compound is useful in the preparation of granules with high drug loading and tablets with high drug loading in which they are produced. drug loads of approximately 70%, preferably drug loads exceeding 85%. For example, a tablet containing 600 mg of active ingredient weighs about 860 mg. Preferably, a tablet containing 600 mg of active ingredient weighs about 660 mg. In accordance with the present invention, it has been found that formulations of stable tablet with high charge of (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) -methyl] -1 acid drug are produced. H-imidazol-5-yl] -methylene-2-thiophenepropionic acid by wet granulation processing of the anhydrous form of said compound with water in the presence of pharmaceutically acceptable excipients, for example, binders, such as corn starch, pregelatinized starch [Starch 1551], polyvinylpyrrolidone (PVP), gelatin, low molecular weight hydroxypropylmethylcellulose (HPMC), or hydroxypropylcellulose (HPC), methylcellulose and L-arginine. Granules by dry granulation processing are produced, for example, by disc compression or disc roller compaction or roller compaction, milling and sieving, of the anhydrous form of (E) -a- [2-n-butyl] -1 - [(4-carboxyphenyl) -methyl] -1 H -imidazol-5-yl] -methylene-2-thiophenepropionic acid in the presence of pharmaceutically acceptable excipients. Granules with a high drug loading of (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) -methyl] -1H-imidazol-5-yl] -methanol- Anhydrous 2-thiophenepropionic formed during the wet granulation process are prepared using a planetary / high shear / fluid bed granulator to prepare solid dosage forms of the anhydrous form of said compound with water in the presence of binder. A disc compression press or a roller compactor can also be used to prepare dry granules to be incorporated into oral solid dosage forms. The drug using either a wet or dry granulation process does not form a hydrate, and it does not form a hydrate during storage of its oral solid dosage forms. Any combination of pharmaceutically acceptable excipients, for example diluents, fillers, binders and disintegrants, may be used in the desired proportions in accordance with the wet or dry granulation process of the present invention. The excipients commonly used in the pharmaceutical industry are described in the literature [refer to the Handbook of Pharmaceutical Excipients, A. Wade and P.J. Weller (Editors), American Pharmaceutical Association (1994)]. The pharmaceutically acceptable fillers and diluents include, but are not limited to the following. Lactose (hydrated as well as anhydrous), starch [unmodified (corn starch) or modified (for example, Starch 1500 available from Colorcon)], mannitol sorbitol, cellulose, sulfates and inorganic phosphates. Disintegrants include but are not limited to the following: sodium starch glycolate, sodium carmellose, and interlaced polyvinylpyrrolidone, and binders include but are not limited to the following: gelatin, corn starch, modified starch (Starch 1551, pregelatinized starch) ), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), carboxymethylcellulose, sodium, alginic acid, acacia and amino acids, such as glycine and L-arginine. Examples of suitable excipients for modified release applications include but are not limited to the following: HPMC, high molecular weight, polymethacrylate polymers known as Eudragits, polyethylene oxide, Poiyox® (Union Carbide Corporation), Surelease® modified ethylcellulose (Colorcon ), interlaced acrylic acid polymers, Carbopol® (BF Goodrich Specialty Chemicals) and waxed materials, such as glyceryl behenate (Compritol®, glyceryl palmitostearate (Precirol®), and Gelucires® [all from Gattefosse SA, France] and wax of carnauba.Preferably, the pharmaceutically acceptable excipients used as binders, diluents and fillers during the wet granulation process of this invention are lactose, mannitol, sorbitol, starch (corn starch, soluble starch, or Starch 1551), gelatin, gum of xantan, sodium alginate, Povidone (PVP) and microcrystalline or powdered cellulose, each of which can be to act as a facilitator in the formation of a stable solid dosage form with high drug loading of eprosartan. Preferably, the excipients are lactose, Starch 1551, microcrystalline cellulose, Povidone (PVP), and arginine. Preferably, the excipients are lactose, cellulose and Starch 1551 or arginine. Preferably, the excipients used in the wet or dry granulation process are present at 0-25% on a weight-by-weight basis. Preferably, the excipients may be present as low as 0-15% on a weight-for-weight basis in order to produce granules with a high drug loading. The process for preparing the solid dosage forms according to the present invention can be carried out using a combination of a planetary mixer, a V-blender, a high shear granulator, a fluid bed granulator, a compression press in discs, a roller compactor, a grinding mill, sieving equipment or a tablet press. Optionally, the granulation of the anhydrous form of (E) -a- [2-n-butyl-1 - [(4-carbonylphenyl) methyl] -1H-imidazol-5-yl] methylene-2-thiophenepropionic acid, produced using conventional dry or wet granulation equipment, it is suitable for the preparation of immediate or modified release dosage forms. Optionally, dry granulation of 1: 1 molar or 1: 1 w / w of (E) -a- [2-n-butyl-1 - [(4-carbonylphenyl) methyl] -1H-imidazole-5- il] methylene-2-thiophenepropionic produced using conventional dry or wet granulation equipment is suitable for the preparation of modified immediate release dosage forms. The immediate release tablet cores may be coated with a membrane of a polymer that provides sustained sustained release properties. Thus, the present invention provides a pharmaceutical composition which consists of (E) -a- [2-n-butyl-1 - [(4-carbonylphenyl) methyl] -1H-imidazol-5-yl] acid] methylene-2-thiophenepropionic acid and a pharmaceutically acceptable carrier. The pharmaceutical composition is adapted for oral administration. The composition is presented as a unit dose pharmaceutical composition containing from about 50 mg to about 1.0 g of (E) -a- [2-n-butyl-1 - [(4-carbonylphenyl) methyl] -1 H acid. -imidazoI-5-yl] methylene-2-thiophenepropionic acid, preferably from 200 to about 400 mg. Said composition is usually taken 1 to 4 times a day, preferably 1 to 2 times a day. Preferred unit dosage forms include tablets or capsules. The compositions of this invention can be formulated by conventional mixing methods such as mixing, filling and compression. Pharmaceutically acceptable vehicles suitable for use in this invention include diluents, fillers, binders and disintegrants. The (E) -a- [2-n-butyl-1 - [(4-carbonylphenyl) methyl] -1H-imidazol-5-yl] methylene-2-thiophenepropionic acid can be co-administered with other pharmaceutically active compounds , for example, in physical combination or by consecutive administration. Conveniently, the compound of this invention and the other active compound are formulated in a pharmaceutical composition. Thus, this invention also relates to pharmaceutical compositions containing (E) -a- [2-n-butyl-1 - [(4-carbonylphenyl) methyl] -1H-imidazol-5-yl] methylene- 2-thiophenepropionic acid, a pharmaceutically acceptable carrier and a second pharmaceutically active compound selected from the group consisting of a diuretic, a calcium channel blocker, a β-adrenoceptor blocker, a renin inhibitor and an angiotensin-converting enzyme inhibitor . Examples of compounds that can be included in pharmaceutical compositions in combination with (E) -a- [2-n-butyl-1 - [(4-carbonylphenyl) methyl] -1H-imidazol-5-yl] methylene-2 acid -thiophenpropionic are diuretics, particularly a thiazide diuretic, such as hydrochlorothiazide or a loop diuretic, such as furosemide, calcium channel blockers, particularly dihydropyridine antagonists, such as nifedipine, β-adrenoceptor blockers, such as propranolol, inhibitors of renin, such as enalkinen and angiotensin-converting enzyme inhibitors, such as captopril or enalapril. Preferably, the pharmaceutical composition contains 200 to 400 mg of (E) -a- [2-n-butyl-1 - [(4-carbonylphenyl) methyl] -1H-imidazol-5-yl] methylene-2-acid. thiophenpropionic in combination with 6.25-25 mg of hydrochlorothiazide. No unacceptable toxicological effects are expected when (E) -a- [2-n-butyl-1 - [(4-carbonylphenyl) methyl] -1H-imidazol-5-yl] methylene-2-thiophenepropionic acid is administered. according to the present invention. (E) -a- [2-n-butyl-1 - [(4-carbonylphenyl) methyl] -1H-imidazol-5-yl] methylene-2-thiophenepropionic acid is useful for treating diseases where it would be beneficial to Blockade of angiotensin II receptor. Preferably, this compound is used alone or in combination with said second pharmaceutically active compounds in the treatment of hypertension, congestive heart deficiency and renal impairment. In addition, (E) -a- [2-n-butyl-1 - [(4-carbonylphenyl) methyl] -1H-imidazol-5-yl] methylene-2-thiophenepropionic acid is of value in the regression treatment of left ventricular hypertrophy, diabetic nephropathy, diabetic retinopathy, muscular degeneration, hemorrhagic cerebral vascular disease, primary and secondary infarction prevention, prevention of atheroma progression and atheroma regression, prevention of restenosis after angioplasty or bypass surgery, improvement of cognitive function, angina, glaucoma and CNS disorders, such as anxiety. The following examples are illustrative of the present invention.

These examples are not intended to limit the scope of this invention as defined above and as claimed below. Next, in Examples 1 to 7, the term "internal granules" means the granulation obtained by mixing and granulating ingredients (drug and excipients) by a wet and dry granulation process.

EXAMPLES EXAMPLE 1 In a planetary mixer 96.0 parts of Eprosartan and 4.0 parts of pregelatinized starch (Starch 1551), a binder, are granulated using purified water as the granulating agent. The wet granules are milled wet and dried using a fluid bed dryer or a suitable drying device. The dry granulation is milled to produce granules that pass through a # 30 mesh or an appropriately sized screen. Compression blends with ingredients as mentioned in formulas 1 and 2 are prepared by mixing and compressed into 300 mg tablets with a tensile strength in the range of 1.5-2.2 MPa (8-13 KP) using a press Tablet. The tablets of formulas 1 and 2 disintegrate in less than 2 minutes when tested in purified water at 37 ° C.

Ingredients (%) Formula 1 Formula 2 Internal granules 95.42 89.29 Microcrystalline cellulose - 5.71 Crospovidone, interlaced PVP 3.82 4.00 Magnesium stearate 0.76 1.00 Total 100.0 100.0 EXAMPLE 2 In a high shear granulator, 95.0 parts of Eprosartan and 5.0 parts of L-Arginine, a binder, are granulated, using purified water as the granulating agent. The wet granules are wet milled using a Fitz mill and dried using a tray dryer or a suitable drying device. The dry granulation is milled to produce granules that pass through a # 30 mesh or sieve of adequate size. Compression blends with ingredients as recited in formulas 3 and 4 are prepared by mixing and compressing into tablets of 300 mg thickness on the 10 KP scale using a tablet press (disintegration time: 10 to 16 minutes).

Ingredients (%) Formula 3 Formula 4 Internal granules 95.41 90.23 Microcrystalline cellulose - 5.00 Crospovidone, interlaced PVP 3.84 4.00 Magnesium stearate 0.75 0.77 Total 100.0 100.0 EXAMPLE 3 In a planetary mixer 86.0 parts of Eprosartan, 4.0 parts microcrystalline cellulose (Avicel PH102), 4.0 parts hydrated lactose, 2.0 parts interlaced plivinilpirrolidone (Crospovidone) and 4.0 parts of pregelatinized starch (Starch 1551), a binder, using purified water are granulated the granulation agent. The wet granules are milled wet and dried using a fluid bed dryer or a suitable drying device. The dry granulation is milled to produce granules that pass through a # 30 mesh or sieve of the appropriate size. Compression blends with ingredients as mentioned in formula 5 are prepared by mixing and compressing into tablets of 300 mg (tablet weight: 400 mg) in thickness on the scale of 5-10 kP using a tablet press: Ingredients (%) Formula 5 Granules 87.2 Microcrystalline cellulose 10.0 Ac-Di-Sol, croscarmellose 2.0 sodium Magnesium stearate 0.8 Total 100.0 EXAMPLE 4 92. 0 parts of Eprosartan and 4.0 parts of L-Arginine or PVP, 20% Crospovidone, and 2% glyceryl behenate (Compritol) are mixed, compacted by roller, milled using a Fitz mill to produce granules that pass through a # 30 mesh or appropriate size sieve. Compression blends with ingredients as mentioned in formulas 6 and 7 are prepared by mixing and compressing into tablets of 200 mg thickness on the 4-10 kP scale using a tablet press: Ingredients (%) Formula 6 Formula 7 (L-Arginine) (PVP) Internal granules 89.34 86.96 Cellulose 6.97 9.24 microcrystalline Crospovidone, PVP 3.01 3.00 interlaced Stearate 0.68 0.80 mg Total 100.0 100.0 Modified release formulations EXAMPLE 5 In a high shear granulator, 70.8 parts of Eprosartan and 29.2 parts of L-arginine are granulated using purified water as the granulating agent. The wet granules are milled wet and dry using a fluid bed dryer or a suitable drying device. The dry granulation is milled to produce granules that pass through a # 30 mesh or sieve of adequate size. In another prototype development, 50 parts of Eprosartan and 50 parts L-arginine are granulated using a fluid bed granulator and the dried granules in the fluid bed are milled to produce granules that pass through a # 30 mesh or suitable screen . Compression blends with ingredients as recited in formulas 8 and 9 are prepared by mixing and compressing into 50 mg tablets (tablet weight: 85 and 120 mg, respectively) of suitable thickness using a tablet press: Ingredients (mq) Formula 8 Formula 9 Granules 70.6 100.0 Cellulose 10.1 14.0 Microcrystalline Crospovidone 3.6 5.0 Stearate 0.7 1.0 Magnesium Total 85.0 120.0 EXAMPLE 6 47 parts of Eprosartan and 47 parts of L-Arginine, 2% Crospovidone, and 3% glyceryl behenate (Compritol) are mixed, roller compacted, ground using a Fitz mill to produce granules that pass through a mesh # 30 or sieve of adequate size. In another variation of the formulation, 67.4 parts of Eprosartan, 27.8 parts of L-Arginine, 1.9% of Crospovidone and 2.9% of glyceryl behenate (Compritol) are mixed, compacted with a roller, ground in a milling of Fitz to produce granules that pass through a # 30 mesh or suitable screen. Compression blends with ingredients as mentioned in formulas 10 and 11 are prepared by mixing and compressing into tablets of 200 mg thickness on the 8-14 kP scale using a rotary tablet press: Ingredients (mq) Formula 10 Formula 11 (1: 1 w / w) (1: 1 mol) Internal granules 425.5 296.7 Cellulose 41.0 32.0 Microcrystalline Crospovidone, PVP 10.0 14.0 Interlaced 3.5 Stearate 2.3 Magnesium Total 480.0 345.0 EXAMPLE 7 In a high-shear granulator, 96.0 parts of Eprosartan and 4.0 parts of Starch 1551 are granulated. The compression mixtures with ingredients as mentioned in formulas 12 and 13 are prepared Mixing and compressing into 200 mg tablets using a tablet press: Ingredients (%) Formula 12 Formula 13 (1: 1 Molar) (1: 2 Molar) Internal granules 208.3 208.3 L-Arginine 82.7 165.0 Cellulose 41.3 42.7 Microcrystalline Crospovidone, PVP 15.0 20.0 Interlaced Stearate 3.0 4.0 Magnesium Total 350.0 440.0 Film coating: The tablets of formulas 1 to 4 may optionally be provided with an aqueous film coating. Generally, these tablets are first coated with a polymer solution to form a transparent film and then coated with a solution / suspension of aqueous polymer to form an opaque, white or colored film. This film coating has no effect on the disintegration of the tablet, and therefore, the dissolution of the drug is not affected. In contrast, the tablets of formulas 5 to 7 are first coated with an aqueous polymer solution to form a clear film (often called a seal coat) and then with an aqueous solution / suspension of an enteric layer polymer such as Eudragit. L30D, hydroxypropylmethylcellulose acetate phthalate (HPMCP) cellulose acetate phthalate (CAP) or polyvinyl acetate phthalate (PVAP). The weight gains that follow the seal coating and the enteric coating are approximately 3-6% and 4-12% (preferably 3-4% and 4-6%) respectively. The modified release tablets produced in this way release < 20% of drug in the stomach that follows oral administration and rapidly releases the drug at higher pHs, depending on the polymer used (eg, at a pH >; 4.0 for PVAP, > 5.0 for HPMCP and 5.5 for Eudragit), even though the solubility of the drug at these initial pHs is negligible. The water absorbed in the tablets dissolves arginine creating a high pH environment where the Eprosartan dissolves. This high pH also dissolves the film coating, releasing the drug into the environment. It is understood that the invention is not limited to the embodiments illustrated herein and reserves the right to the illustrated embodiments and all modifications included within the scope of the following claims. The various references to journals, patents and other publications that are cited herein comprise the state of the art and are incorporated herein by reference.

Claims (42)

NOVELTY OF THE INVENTION CLAIMS

1. - Wet or dry granulation of (E) - - [2-n-butyl-1- [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene-2-thiophenepropionic acid anhydrous with high charge drug.

2. A formulation with high drug loading comprising (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene-2 acid -thiophenpropionic anhydrous in unit form of oral dose.

3. An immediate release formulation with high drug loading comprising (E) - - [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene -2-thiophenepropionic anhydrous in unitary form of oral dose.

4. A modified release formulation with high drug loading comprising (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] anhydrous methylene-2-thiophenepropionic in unit dose of oral dose.

5.- A process for preparing a formulation with high charge of (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene acid drug. -2-thiophenepropionic anhydride in which a wet or dry granulation of (E) - - [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene is prepared -2-thiophenepropionic anhydride with high drug loading in the presence of water and pharmaceutically acceptable excipients.

6.- A process for preparing a formulation with high charge of (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene acid drug. -2-thiophenepropionic anhydride in which a wet granulation of (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene- 2-thiophenepropionic anhydride with high drug loading in the presence of water and pharmaceutically acceptable excipients.

7. A process for the preparation of a granulation of an acid (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene-2 anhydrous propionic phenylpropionate with high drug loading which comprises: (i) mixing the anhydrous form of (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazole- 5-yl] methylene-2-thiophenepropionic and Starch 1551 (pregelatinized starch), optionally with one or more pharmaceutically acceptable excipients; and (ii) granulating the mixture with water.

8.- A process for the preparation of a granulation of an (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene-2 acid. -thiophenpropionic with high drug loading which comprises: (i) mixing the anhydrous form of (E) - - [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazole-5- il] methylene-2-thiophenepropionic acid and L-arginine, optionally with one or more pharmaceutically acceptable excipients; and (ii) granulating the mixture with water.

9. A process for the preparation of a granulation of an acid (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene-2 -thioprophenic with high drug loading which comprises: (i) mixing the anhydrous form of the acid (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazole-5 -yl] methylene-2-thiophenepropionic, Starch 1551 (pregelatinized starch) with one or more pharmaceutically acceptable excipients selected from interlaced polyvinylpyrrolidone (Crospovidone, a disintegrant), and glyceryl behenate (Compritol, a lubricant); (ii) compressing in discs or roller compaction of the mixture; and (iii) milling and sieving the granulation.

10. A process for the preparation of an (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene-2-thiophenepropionic acid anhydrous in oral dosage form which comprises: (i) producing granules with high drug loading containing (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1 acid H-imidazol-5-yl] methylene-2-thiophenepropionic acid and a binder; and (ii) mixing said granules with other pharmaceutically acceptable excipients to be compressed into a tablet.

11. A process for the preparation of an anhydrous (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene-2-thiophenepropionic acid in the form of oral dose of modified release which comprises: (i) producing granules with high drug loading of the anhydrous form of (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] ] -1 H-imidazol-5-yl] methylene-2-thiophenepropionic acid and L-arginine in a 1: 1 molar ratio or 1: 1 w / w by a wet or dry granulation method; and (ii) mixing said granules with other pharmaceutically acceptable excipients to be compressed into a tablet.

12. A process for the preparation of an anhydrous (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene-2-thiophenepropionic acid in the form of oral dose of modified release which comprises: (i) producing granules with high drug loading of the anhydrous form of (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] ] -1 H-imidazol-5-yl] methylene-2-thiophenepropionic and Starch 1551; (ii) mixing said granules and L-arginine in a 1: 1 molar ratio or 1: 1 w / w; and (iii) mixing said mixture optionally with other pharmaceutically acceptable excipients to be compressed into a tablet.

13. A pharmaceutical composition comprising a granulation with high drug loading of (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] anhydrous methylene-2-thiophenepropionic acid, a pharmaceutically acceptable carrier and a second pharmaceutically active compound selected from the group consisting of a diuretic, a calcium channel blocker, a β-adrenoceptor blocker, a renin inhibitor and an enzyme converting enzyme inhibitor. angiotensin.

14. The pharmaceutical composition according to claim 13, further characterized in that the second pharmaceutically active compound is a diuretic.

15. The pharmaceutical composition according to claim 14, further characterized in that the diuretic is hydrochlorothiazide.

16. The pharmaceutical composition according to claim 13, further characterized in that the second pharmaceutically active compound is a loop diuretic.

17. The pharmaceutical composition according to claim 16, further characterized in that the loop diuretic is furosemide.

18. The pharmaceutical composition according to claim 13, further characterized in that the second pharmaceutically active compound is a calcium channel blocker.

19. The pharmaceutical composition according to claim 18, further characterized in that the calcium channel blocker is nifedipine.

20. The pharmaceutical composition according to claim 13, further characterized in that the second pharmaceutically active compound is a β-adrenoceptor blocker.

21. The pharmaceutical composition according to claim 20, further characterized in that the β-adrenoceptor blocker is propanolol.

22. The pharmaceutical composition according to claim 13, further characterized in that the second pharmaceutically active compound is an inhibitor of angiotensin-converting enzyme.

23. The pharmaceutical composition according to claim 22, further characterized in that the inhibitor of angiotensin-converting enzyme is captopril or enalapril.

24. The pharmaceutical composition according to claim 13, further characterized in that the second pharmaceutically active compound is a renin inhibitor.

25. The pharmaceutical composition according to claim 24, further characterized in that the renin inhibitor is enalkinen.

26.- The use of a formulation with high drug loading of (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene- 2-thiophenepropionic anhydride for the manufacture of a medicament for blocking angiotensin II receptors in a subject.

27.- The use of a formulation with high drug loading of (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene- 2-thiophenepropionic anhydride for the manufacture of a medicament for treating hypertension in a subject.

28.- The use of a granulation with a high drug charge of (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene- 2-thiophenepropionic anhydride and a second pharmaceutically active compound selected from the group consisting of a diuretic, a calcium channel blocker, a β-adrenoceptor blocker, a renin inhibitor and an angiotensin-converting enzyme inhibitor for the manufacture of a medicament for treating hypertension in a subject, wherein said granulation with high drug loading and said second pharmaceutically active compound are administered in steps or in physical combination.

29. The use according to claim 28, wherein the second pharmaceutically active compound is a diuretic.

30. - The use according to claim 29, wherein the diuretic is hydrochlorothiazide.

31. The use according to claim 28, wherein the second pharmaceutically active compound is a loop diuretic.

32. The use according to claim 31, wherein the loop diuretic is furosemide.

33. The use according to claim 28, wherein the second pharmaceutically active compound is a calcium channel blocker.

34. The use according to claim 33, wherein the calcium channel blocker is nifedipine.

35. The use according to claim 28, wherein the second pharmaceutically active compound is a β-adrenoceptor blocker.

36. The use according to claim 35, wherein the β-adrenoceptor blocker is propranolol.

37. The use according to claim 28, wherein the second pharmaceutically active compound is an inhibitor of angiotensin-converting enzyme.

38. The use according to claim 37, wherein the inhibitor of angiotensin-converting enzyme is captopril or enalapril.

39. The use according to claim 28, wherein the second pharmaceutically active compound is a renin inhibitor.

40. - The use according to claim 39, wherein the renin inhibitor is enalkinen. 41.- The use of a formulation with high acid (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene- 2-thiophenepropionic anhydride for the manufacture of a medicament for treating congestive heart deficiency in a subject. 42.- The use of a formulation with high acid (E) -a- [2-n-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methylene- 2-thiophenepropionic anhydride for the manufacture of a medicament for treating renal impairment in a subject.