MXPA06008156A - Pharmaceutical formulations comprising metformin and a fibrate, and processes for obtaining them - Google Patents

Abstract

The present invention relates to granulates comprising particles of metformin and particles of a fibrate. The invention further relates to pharmaceutical compsitions containing such granulates. The invention also relates to processes for preparing said granulates and said pharmaceutical compositions.

Description

PHARMACEUTICAL FORMULATIONS THAT COMPRISE METFORMIN AND AN F1BRATQ, AND PROCEDURES TO OBTAIN THEM The present invention relates to a pharmaceutical composition comprising metformin and a fibrate, such as fenofibrate and to processes for preparing said pharmaceutical composition.

BACKGROUND OF THE INVENTION Combination products present several challenges to pharmaceutical scientists beyond those that are inherent in the development of any pharmaceutical product. These additional challenges arise for several reasons, including: a requirement to make sure that the combination is stable, a requirement to make sure that the dosage form produced is acceptable to patients despite potentially large doses of individual components and a requirement to match the pharmacokinetic performance of each active compound in the combination to that resulting from the administration of the drugs as monotherapy. The last requirement is especially important to ensure the safety and efficacy of the combination product. These challenges are greater if the physicochemistry of the active compounds that are combined is significantly different. For example, if it is required to combine a hydrophobic active compound with a hydrophilic active compound or a water soluble active compound with a water insoluble active compound, the challenge for the formulator is expected to be enlarged. In addition to these general considerations, the combination should adopt formulation strategies that address specific pharmaceutical problems associated with each of the active compounds. For example, it can be found that, an active compound is not well understood, thus restricting the choice of binder or compression aid. Alternatively, it can be found that the flow properties of an active compound do not lead to high production manufacture thus determining a choice of slipper, lubricant or other external phase components. Combinations of hydrophobic, water-insoluble active compounds with water-soluble hydrophilic compounds are a particular challenge if the pharmacokinetic properties of either or both of the active compounds are known to be affected by the formulation. Metformin is a biguanide that is known primarily for its antihyperglycemic activity and is widely used in the treatment of non-insulin dependent diabetes; Metformin can also be administered to the patient in combination with insulin. Metformin is freely soluble in water (Martindale, 33rd Ed, pp 332 (2002)). It is also known that it is a little compressible substance. A poorly compressible substance is one that does not clump together to form a tablet when applying the compressive force. Therefore, such substances may require additional processing and special formulation before they can be compressed into tablets. With such substances, the necessary additional processing is usually a step of wet granulation, since the compression would not be effective. These substances can be formulated with binders or other materials that have high agglutination capacity (or that act as an auxiliary for compression) in such a way that the non-binding properties of the non-compressible material are overcome. Other techniques to aid compression include having residual moisture in the mixture before compression or having the non-compressible material in very low amounts in the tablet formulation. High-dose drugs, such as metformin, do not lead to direct compression due to the relatively low proportion of diluent or compression aid in the tablet, insufficient powder flow and poor compressibility. Fibrates are known for their antihyperlipidemic properties. More specifically, fibrates act on hypercholesterolemia by inducing a reaction in the total cholesterol level as well as low density lipoprotein cholesterol (LDL cholesterol) and an even greater reduction in the level of triglycerides and in particular triglycerides linked to very low density lipoproteins (VLDL triglycerides). Usually, fibrates are used for conditions such as hypercholesterolemia, mixed lipidemia, hypertriglyceridemia, coronary heart disease and peripheral vascular disease (including symptomatic carotid artery disease), and prevention of pancreatitis. Fenofibrate can also help prevent the development of pancreatitis (inflammation of the pancreas) caused by high levels of triglycerides in the blood. It is known that fibrates are useful in the treatment of renal failure (U.S. Patent No. 4,250,191). Fibrates can also be used for other locations where lipid regulating agents are typically used. Fenofibrate, also known as 2- [4- (4-chlorobenzoyl) phenoxy] -2-methylpropanoic acid 1-methylethyl ester, is a lipid regulating agent. The compound is insoluble in water. (The Physicians' Desk Reference, 56th Ed., Pp. 513-516 (2002) and Martindale, 33rd Ed, pp889 (2002)). Fenofibrate is described, for example, in the patents of E.U.A. Nos. 3,907,792 for "Phenoxy-Alkyl-Carboxylic Acid Derivatives and the Preparation Thereof"; 4,895,726 for "Novel Dosage Form of Fenofibrate"; 6,074,670 and 6,277,405, both for "Fenofibrate Pharmaceutical Composition Having High Bioavailability and Method for Preparing It". The patent of E.U.A. No. 3,907,892 discloses a class of phenoxy alkylcarboxylic compounds comprising fenobibrate. A variety of clinical studies have shown that elevated levels of total cholesterol (total C), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apo B), an LDL membrane complex, are associated with atherosclerosis human Similarly, reduced levels of high-density lipoprotein cholesterol (HDL-C) and its transport complex, apolipoprotein A (apo A2 and apo All), are associated with the development of atherosclerosis. Epidemiological investigations have established that cardiovascular morbidity and mortality vary directly with the level of total C, LDL-C, and triglycerides, and inversely with the level of HDL-C. Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides and triglyceride-rich lipoprotein (VLDL) in treated patients. In addition, treatment with fenofibrate results in an increase in high density lipoprotein (HDL) and apolipoprotein supports and supports. (The Physicians' Desk Reference, 56th Ed., Pp. 513-516 (2002)). Fenofibrate is used to reduce high levels of triglyceride (substances in the form of fats) in the blood. Specifically, fenofibrate reduces high LDL-C, total C, triglycerides, and Apo-B and increases HDL-C. The drug has also been approved as adjunctive therapy for the treatment of hypertriglyceridemia, a disorder characterized by elevated levels of very low density lipoprotein (VLDL) in the plasma. The mechanism of action of fenofibrate has not been clearly established in man. Fenofibric acid, the active metabolite of fenofibrate, reduces plasma triglycerides apparently by inhibiting triglyceride synthesis, resulting in a reduction of VLDL released into the circulation, and also by stimulating triglyceride-rich lipoprotein catabolism (ie , VLDL). Fenofibrate also reduces uric acid levels in serum in normal and hyperuricemic individuals by increasing the urinary excretion of uric acid. Fenofibrate is a compound that is associated with a low bioavailability after oral administration, a property that has been attributed to its low solubility and hydrophobic character. In addition, the bioavailability of fibrate is substantially lower when administered to fasted patients compared to patients who have had breakfast. Considerable efforts have been made to develop pharmaceutical forms of fenofibrate with improved bioavailability and less variability less between fed and fasted states. For example, the patent of E.U.A. No. 4,895,726 discloses a therapeutic composition of gelatin capsules, useful in the oral treatment of hyperlipidemia and hypercholesterolemia, which contains micronized fenofibrate. The patent of E.U.A. No. 6,074,670 refers to immediate release fenofibrate compositions comprising micronized fenofibrate and at least one water-soluble inert carrier. The patent of E.U.A. No. 6,277,405 is directed to micronized fenofibrate compositions having a specified dissolution profile. In addition, WO 02/24192 for "Stabilized Fibrate Microparticles", describes a composition of fenofibrate in microparticles comprising a phospholipid. WO 02/067901 for "Fibrate-Statin Combinations with Reduced Fed-Fastened Effects", describes a microparticle fenofibrate composition comprising a phospholipid and an inhibitor of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase or statin. WO 03/013474 for "Nanoparticulate Formulations of Fenofibrate", describes fibrate compositions comprising vitamin E TGPS (vitamin E with polyethylene glycol (PEG)). EP 1 054 665 describes a combination of metformin and a fibrate chosen from fonofibrate and benzafibrate for the treatment of non-insulin-dependent diabetes. In this patent application, no specific formulation or specific method is described for producing a pharmaceutical formulation of a fibrate and metformin.

BRIEF DESCRIPTION OF THE INVENTION An objective of the invention is to provide a pharmaceutical composition that addresses the general challenges associated with the development of a pharmaceutical product, the specific challenges associated with the individual active compounds incorporated in the dosage form and also the challenges associated with bringing the active substances to combination. A particular challenge associated with this combination is to ensure the bioequivalence of each active compound to the respective components when administered separately despite the biopharmaceutical problems associated with fenofibrate and the different physicochemical properties of both active compounds. Another object of the invention is to obtain a formulation of a fibrate and metformin with a size suitable for administration and acceptable to patients despite the fact that the composition of the invention contains a high amount of metformin (metformin is generally prescribed at 850 mg once or twice a day or 500 mg, three to four times a day). The considerable mass of metformin must be combined in the same unit of pharmaceutical dosage with a fibrate in smaller amounts than metformin (for example, fenofibrate is prescribed once a day at 200 mg or at 160 mg for Tricor 160®). The prior art teaches that said combination is associated with a large amount of excipient in order to maintain an acceptable bioavailability (as taught in U.S. Patent No. 6,074,670). A further objective of the invention is to obtain a formulation that gives rise to high adherence by the patient, by reducing the number of unit dosage forms that need to be taken, such as tablets. Type II diabetes mellitus often requires treatment with more than one active substance. In addition, among type II diabetes, the predominance of other disorders associated with insulin resistance (dyslipidemia, hypertension), which frequently require additional pharmacological forms of treatment, is high. Compliance by the patient under these circumstances is a problem, because the individual dose units are necessarily very large in view of the high amounts of active substances that need to be administered (as described above), and the practical limits with respect to the mass of the pharmaceutical composition that can be administered to a patient as a single dose unit. A further objective of the invention is to avoid a possible interaction between fibrate and metformin, which could alter the bioavailability of fibrate and / or metformin. Since metformin is a hydrophilic component and fibrate is a hydrophobic component, the bioavailability of both active components can be prevented, in a single combination. The presence of a hydrophobic fibrate can in fact alter the bioavailability of metformin by slowing its dissolution with a consequent effect on bioavailability. Because fibrates, including fenofibrate, are so insoluble in water, significant bioavailability can be problematic. Therefore, an additional objective of this invention is to provide a pharmaceutical composition containing both active components, metformin and a fibrate, while maintaining a bioavailability of each of the two components equivalent to or greater than those obtained with metformin alone or with the fibrate alone. The objective of the present invention is to obtain a formulation wherein both products are bioequivalent or suprabioavailable compared to the bioavailability of monotherapy. Another object of the invention is to provide methods for preparing pharmaceutical compositions that satisfy the above-listed objectives, said methods being capable of being achieved with a limited number of different steps and being of low cost. It has now been unexpectedly found that the aforementioned objects can be achieved with a pharmaceutical composition comprising metformin particles and particles of a fibrate, wherein the metformin acts as a vehicle for fenofibrate, wherein said metformin and fibrate are present in a combined amount of at least 50% by weight, based on the total weight of the composition, and wherein the ratio in Weight of metformin to fibrate is comprised between 500: 90 and 850: 35, and with the proviso that if the composition by weight of metformin to fibrate is between 500: 90 and 500: 65, said composition comprises a dispersion aid as a mandatory excipient. In a preferred embodiment of the invention, the weight ratio of metformin to fibrate is between 500: 54 and 850: 65. In another preferred embodiment of the invention, the weight ratio of metformin to fibrate is between 850: 54 and 850: 35. In these latter two preferred embodiments, the presence of a dispersion aid as excipient is not mandatory, but it is possible. It has surprisingly been found that the addition of a dispersion aid allows the bioavailability of each of the two active products, when combined in the composition of the invention, to be at least equivalent to that of the corresponding product when formulated for monotherapy, and if necessary when the weight ratio of metformin to fibrate is less than or equal to 500: 65 in order to achieve bioequivalence of both active substances. In one embodiment of the invention, the pharmaceutical composition of the invention comprises a fibrate and metformin in a combined amount of about 60% to about 98% by weight, most preferably between about 70% to about 95% by weight, most preferably still of about 74 to about 90% by weight, and most preferably still about 74 to about 79% by weight based on the total weight of the composition. In accordance with the invention, a reduced amount of excipients can therefore be used in the preparation of the pharmaceutical compositions. The composition can therefore show a suitable size for administration while maintaining bioequivalence to monotherapy, ie separate administration of metformin and a fibrate. The amount of excipients of the composition is in the range of from about 1 to about 50% by weight, preferably from about 2 to about 40%, most preferably from about 5 to about 30% by weight, most preferably still about 10% by weight. about 26% by weight, and most preferably still from about 21% to about 26% by weight, based on the total weight of the composition. Preferred pharmaceutical compositions according to the invention will therefore comprise: •• from about 50% to about 99% by weight, most preferably from about 60% to about 98% by weight, preferably from about 70% to about 95% by weight weight, and most preferably from about 74% to about 90% by weight of metformin combined with each other; and •• from about 1% to about 50% by weight, preferably from about 2% to about 40% by weight, preferably from about 5% to about 30% by weight, and most preferably from about 10% to about 26% by weight Weight of pharmaceutically acceptable excipients. The ratio of fibrate to metformin in the composition of the invention will vary depending on whether the present pharmaceutical composition is to be taken more than once a day, or if it is to be taken only once a day. The ratio will also vary depending on the particular fibrate selected. A preferred embodiment of the invention consists of a composition twice a day containing fibrate and metformin in a weight ratio between 500: 54 and 850: 65, the total weight of the composition being between approximately 800 mg and approximately 1600 mg , and preferably between about 800 mg and about 1300 mg. Another preferred embodiment of the invention consists of a composition twice a day containing fibrate and metformin in a weight ratio comprised between 850: 54 and 850: 35, the total weight of the composition being between about 1000 mg and about 1600 mg, and preferably between about 1100 mg and about 1300 mg. Another preferred embodiment of the invention consists of a composition three times a day (three per day) containing fibrate and metformin in a weight ratio of 500: 90 to 500: 65, the total weight of the composition being between approximately 600 mg and about 1200 mg, and preferably between about 700 mg and about 900 mg. Preferably, the composition of the present invention consists of metformin particles, fibrate and a dispersion aid, the latter being present in an amount equal to or less than 20% of the total weight of the composition. The fibrate particles, preferably fenofibrate, and the metformin particles can be linked together in a suitable binder. The average particle size of the fibrate particles will preferably be less than that of the metformin particles. Preferably, the metformin particles and the fibrate particles, preferably fenofibrate, will form granules consisting of metformin particles, to which the (pheno) fibrate particles adhere. The granules of the present invention therefore preferably comprise metformin particles which are either isolated or agglomerated, and particles of a fibrate adhered to the metformin particles. The invention also provides processes for the manufacture of granules which make it possible to obtain the pharmaceutical compositions of the present invention. In addition, the invention provides a process for the manufacture of pharmaceutical compositions containing said granules. The compositions of the invention also allow an improvement in patient convenience with a reduction in the number of tablets that need to be taken, thereby increasing compliance by the patient. This is significant, since a poor compliance of the subject can be observed a deterioration of the medical condition for which the drug is prescribed, that is, cardiovascular problems for deficient compliance by the subject treated with a fibrate or metformin. The pharmaceutical compositions of the present invention can be used for the treatment of non-insulin-dependent diabetes mellitus (or type 2 diabetes), dyslipidemia with impaired glucose tolerance, hyperlipidemia, hypercholesterolemia, for the prevention of cardiovascular events, for the treatment and prevention of metabolic syndrome and for the treatment or prevention of any disease in which treatment with a fibrate and metformin is desirable, such as obesity. The invention will be described in more detail in the following description, with reference to the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the dissolution profile of the test products (ratios of metformin to fibrate 850: 80 (A, B), 850: 54 (C), 500: 80 (EF), 500: 54 (D)) and 80 mg of fenofibrate reference therapy. Figure 2 shows the dissolution profile of the composition in which the ratio of metformin to fenofibrate is 500: 80 with dispersion aid (F) or without dispersion aid (E).

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES The composition according to the present invention comprises particles of metformin and particles of a fibrate, wherein metformin acts as a carrier for fenofibrate, wherein said metformin and fibrate are present in a combined amount of at least 50% by weight, with total basis in weight of the composition, and wherein the ratio of metformin to fibrate is between 500: 90 and 850: 35, and with the proviso that if the weight ratio of metformin to fibrate is between 500: 90 and 500: 65, said composition comprises a dispersion aid as a mandatory excipient. Advantageously, the fibrate is in a crystalline phase, an amorphous phase, a semicrystalline phase, or a semi-amorphous phase. The fibrate can be selected from the group consisting of gemfibrozil, fenofibrate, bezafibrate, clofibrate, ciprofibrate, beclofibrate, binifibrate, ciplofibrate, clinofibrate, etofibrate, nicofibrate, pirifibrate, ronifibrate, simfibrate, theofibrate a fibric acid derivative (eg , fenofibric acid or clofibric acid) or a pharmaceutically acceptable salt or ester of said fibric acid derivative. Preferably, the fibrate is fenofibrate, fenofibric acid or a pharmaceutically acceptable salt or ester of fenofibric acid.

In a preferred embodiment of the invention, the fibrate is fenofibrate. As used herein, the term "fenofibrate" is used to mean 1-methyl ethyl ester of 2- (4- (4-chlorobenzoyl) phenoxy] -2-methylpropanoic acid) or a salt thereof. The fibrate can be of a reduced particle size. The fibrate for example can be micronized or co-micronized with a surfactant. Any surfactant is suitable, whether amphoteric, non-ionic, cationic or anionic. Examples of such surfactants are: sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or another polyoxyethylene sorbitan ester, dioctiisulfosuccinato sodium (DOSS; also known as sodium docusate), lecithin, stearyl alcohol, cetostearyl alcohol, cholesterol, oil polyoxyethylene castor, polyoxyethylene fatty acid glycerides, a poloxamer and mixtures thereof also suitable. The preferred surfactant is sodium laurylsulfate, which can be (co-) fenofibrate as described in EP 0 330 532. In a preferred embodiment of the invention, the fibrate particles have an average particle size less than about 20 μm, preferably less than about 10 μm. The fibrate can also be in the form of nanoparticles that can be obtained using, for example, milling, homogenization or precipitation techniques. Methods for making nanoparticle compositions are also described in the U.S.A. No. 5,518,187 for "Method of Grinding Pharmaceutical Substances"; patent of E.U.A. No. 5,718,388 for "Continuous Method of Grinding Pharmaceutical Substances"; patent of E.U.A. No. 5,862,999 for "Method of Grinding Pharmaceutical Substances"; patent of E.U.A. No. 5,665,331 for "Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers"; patent of E.U.A. No. 5,662,883 for "Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers"; patent of E.U.A. No. 5,560,932 for "Microprecipitation of Nanoparticulate Pharmaceutical Agents"; patent of E.U.A. No. 5,543,133 for "Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles"; patent of E.U.A. No. 5,534,270 for "Method of Preparing Stable Drug Nanoparticles"; patent of E.U.A. No. 5,510,118 for "Process of Preparing Therapeutic Compositions Containing Nanoparticles"; patent of E.U.A. No. 5,470,583 for "Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation"; and patent application of E.U.A. 2003/0 224 058 for "Nanoparticulate fibrate formulations", all of which are specifically incorporated by reference. Dispersions of fibrate in nanoparticles can be obtained by grinding: for example, a fibrate, preferably fenofibrate, to obtain a nanoparticle dispersion comprising dispersing the fibrate particles in a liquid dispersion medium in which the fibrate is poorly soluble, followed by the application of mechanical means in the presence of grinding media to reduce the particle size of the fibrate to the desired effective average particle size. The dispersion medium can be, for example, water, sunflower oil, methanol, t-butanol, glycerin, polyethylene glycol (PEG), hexane or glycol. A preferred dispersion medium is water. The fibrate particles, preferably fenofibrate, can be reduced in size in the presence of at least one surface stabilizer. Alternatively, the fibrate particles may be contacted with one or more surface stabilizers after rubbing. Other compounds, such as a diluent, can be added to the fibrate / surface stabilizer composition during the size reduction process. The dispersions can be manufactured continuously or intermittently. Combinations of more than one surface stabilizer can be used. Useful surface stabilizers that can be used include but are not limited to organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Surface stabilizers include nonionic, anionic, cationic, ionic and zwitterionic surfactants. Suitable surface stabilizers are those mentioned in the patent application of E.U.A. 2003/0224058, the content of which is incorporated herein by reference and is described below. Another method of forming desired nanoparticle fibrate, preferably fenofibrate, is by microprecipitation. This is a method for preparing stable dispersions of poorly soluble active agents in the presence of one or more surface stabilizers and one or more surface active agents free colloid stability enhancers free of any traces of toxic solvents or solubilized heavy metal impurities. Said method comprises, for example: (1) dissolving the fibrate in a suitable solvent; (2) adding the formulation of step (1) to a solution comprising at least one surface stabilizer; and (3) precipitating the formulation of step (2) using an appropriate non-solvent compound. The method can be followed by removal of any salt formed, if present, by dialysis or diafiltration and concentration of the dispersion by conventional means. Fibrate in nanoparticles can also be obtained by homogenization: illustrative homogenization methods for preparing active agent nanoparticle compositions are described in US Pat. No. 5,510,118, for "Process of Preparing Therapeutic Compositions Containing Nanoparticles". Said method comprises dispersing particles of a fibrate, preferably fenofibrate, in a liquid dispersion medium, followed by subjecting the dispersion to homogenization to reduce the particle size of the fibrate to the desired particle size. The fibrate particles can be reduced in size in the presence of at least one surface stabilizer. Alternatively, the fibrate particles may be contacted with one or more surface stabilizers either before or after rubbing. Other compounds such as a diluent, they can be added to the fenofibrate / surface stabilizer composition either before, during or after the size reduction process. The dispersions can be manufactured continuously or in an intermittent mode. According to the invention, the nanoparticle fibrate has an average particle size of less than about 2000 nm, e.g., less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm; preferably less than about 1500 nm, e.g., less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm; preferably less than about 1000 nm, e.g., less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm; preferably less than about 500 nm, e.g., less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm; preferably less than about 100 nm, e.g., less than about 75 nm, or less than about 50 nm. When the granules of the invention are prepared, metformin can be used either as the free base or in the form of a pharmaceutically acceptable acid addition salt thereof such as hydrochloride, acetate, benzoate, citrate, fumarate, embonate, chlorophenoxyacetate, glycolate, palmoate, aspartate, methanesulfonate, maleate, parachlorophenoxyisobutyrate, formate, lactate, succinate, sulfate, tartrate, cyclohexanecarboxylate, hexanoate, octonoate, decanoate, hexadecanoate, octodecanoate, benzenesulfonate, trimethoxybenzoate, paratoluenesulfonate, adamantancarboxylate, glycoxylate, glutamate, pyrrolidonecarboxylate, naphthalenesulfonate, 1- glucose phosphate, nitrate, sulfite, dithionate or phosphate. Among these salts, hydrochloride, fumarate, embonate and chlorophenoxyacetate are particularly preferred, the hydrochloride being especially preferred. Advantageously, the metformin particles have an average size in the range between 50 μm and 500 μm. The invention provides a pharmaceutical composition comprising metformin particles and particles of a fibrate, wherein the metformin and the fibrate are present in a total amount greater than at least 50% by weight, based on the total weight of the composition, and wherein the ratio of metformin to fibrate is very particularly equal to the following ratios: 500: 80, 500: 54, 850: 80, or 850: 54, or where the weight ratio is insufficiently different from these exact ratios for have a material effect of the operation of the invention. The compositions are most preferably such that at least about 70% of the fibrate dissolves within about 15 minutes, at least about 80% of the fibrate dissolves within about 30 minutes, to at least about 85% of the fibrate. dissolves within about 45 minutes, as measured using the rotary knife method at 75 rpm in accordance with the European Pharmacopoeia, in a dissolution medium containing 0.025 M sodium lauryl sulfate. As shown in examples 9 and 10, for a ratio of metformin to fibrate below 500: 65 (ie 500: 80), the dissolution profile, in the absence of a dispersion aid, does not conform to the aforementioned requirement. The addition of a dispersion aid is necessary to improve this dissolution. According to a preferred embodiment of the invention, the dispersion aid is present in an amount less than or equal to 20% by weight, preferably from 5% to 15% by weight, and most preferably from 5% to 10% by weight . The pharmaceutical composition according to the invention may comprise one or more excipients known in the art. Such excipients include (a) surface stabilizers, (b) dispersion aids, (c) binders, (d) fillers, (e) lubricants, (f) slippers, (g) suspending agents, (h) sweeteners (i) flavoring agents, (j) preservatives, (k) pH regulators, (I) wetting agents, (m) disintegrants, (n) effervescent or wetting agents, (p) controlled release agents, (q) accelerators of absorption, (r) absorbers, (s) plasticizers. (a) Surface Stabilizers Examples of surface stabilizers that can be used within the scope of the invention are polymers, low molecular weight oligomers, natural products and surfactants including nonionic, anionic, cationic, ionic and zwitterionic surfactants, as well as as mixtures thereof. Representative examples of surface stabilizers include hydroxypropylmethylcellulose (now known as hypromellose), hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctylisulfosuccinate, gelatin, casein, lecithin (phosphatides), dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, stearate of calcium, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters (e.g., Spans® such as Span® 80 and Span® 20), polyoxyethylene alkyl ethers (e.g. macrogol such as cetomacrogol 1000), polyoxyethylene castor oil derivatives (e.g., Tweens® such as e.g., Tween 20® and Tween 80® (ICI Specialty Chemicals)); polyethylene glycols (e.g., Carbowaxs 3550® and 934® (Union Carbide)), polyoxyethylene stearates, colloidal silicon dioxide, phosphates, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, non-crystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), 4- (1,1,3,3-tetramethylbutyl) phenol polymer with ethylene oxide and formaldehyde (also known as Tyloxapol®, Superione®, and Triton®, poloxamers (e.g., Pluronics F68® and F108®, which are block copolymers of ethylene oxide and propylene oxide); poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, NJ); Tetronic 1508 (T-1508) (BASF Wyandotte Corporation); Triton X-200 (R), which is a polyether sulfonat or alquilicil (Rohm and Haas); Crodestas F-110®, which is a mixture of sucrose stearate and sucrose distearate (Croda Inc.); p-isononylphenoxypoli- (glycidol), also known as Olin-10® or 10-G® surfactant (Olin Chemicals, Stamford, Conn.); Crodestas SL-40® (Croda, Inc.); and SA9OHCO® (Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside; n-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl ß-D-glucopyranoside; nonanoyl-N-methylglucamide; p-nonyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; octyl β-D-thioglucopyranoside; PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme, random copolymers of vinylpyrrolidone and vinyl acetate, and the like. If desired, the fibrate compositions preferably fenofibrate, in nanoparticles, of the invention can be formulated to be free of phospholipids. Examples of cationic surface stabilizers include but are not limited to polymers, biopolymers, polysaccharides, cellulosics, alginates, phospholipids and non-polymeric compounds, such as zwitterionic stabilizers, poly-n-methylpyridinium, antriolpyridinium chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polybrene, polymethyl methacrylate-trimethylammonium bromide (PMMTMABr), hexyldesyltrimethylammonium bromide (HDMAB) and polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate-dimethyl sulfate. Other useful cationic stabilizers include but are not limited to cationic lipids, sulfonium, phosphonium and quaternary ammonium compounds, such as stearyltrimethylammonium chloride, benzyl-di (2-chloroethyl) ethylammonium bromide, coconut or trimethylammonium chloride or bromide, or coconut-methyldihydroxyethylammonium bromide, decyltriethylammonium chloride, decyl dimethylhydroxyethylammonium chloride or bromide, alkyl-dimethylhydroxyethylammonium chloride or bromide, coconut-dimethylhydroxyethylammonium chloride or bromide, myristyltrimethylammoniomethyl sulfate, lauryldimethylbenzylammonium chloride or bromide, lauryl dimethyl (ethenoxy) ammonium chloride or bromide, N-chloride -alkyl (C-? 2 -? 8) dimethylbenzylammonium chloride, N-alkyl (C-? 4 -? 8) dimethylbenzylammonium chloride, N-tetradecyldimethylbenzylammonium chloride monohydrate, dimethyldidecylammonium chloride, N-alkyl ( C? 2-1) dimethyl-1-naptylmethylammonium, trimethylammonium halide, alkyl trimethyl ammonium salts and dialkyl dimethylammonium salts, lauryltrimethylammonium chloride, ethoxylated alkylaminoalkyldialkylammonium salt and / or an ethoxylated trialkylammonium salt, dialkylbenzenedialkyl ammonium chloride, N-didecyldimethylammonium, N-tetradecyldimethylbenzylammonium chloride, monohydrate chloride, N-alkyl (C12-14) dimethyl 1-naphthylmethylammonium chloride and dodecyldimethylbenzyl ammonium chloride, dialkylbenzealkylammonium chloride, lauryltrimethylammonium chloride, alkylbenzylmethylammonium chloride, alkylbenzyldimethylammonium bromide, trimethyl ammonium bromides of C12, C15, C17, dodecylbenzyltriethylammonium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethylammonium chlorides, alkyldimethylammonium halides , tricetylmethylammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride (ALIQUAT® 336), POLIQUAT® 10, tetrabutylammonium bromide, benzyltrimethylammonium bromide, choline esters (such as choline esters of fatty acids ), benzalkonium chloride, stearalkonium chloride comds (such as stearyltrimonium chloride and di-stearyldimonium chloride), cetylpyridinium bromide or chloride quaternized polyoxyethylalkylamino halide salts, MIRAPOL® and ALKAQUAT® (Alkaril Chemical Company), salts of to l-alkyl pyridinium; amines, such as alkylamines, dialkylamines, alkanolamines, polyethylenepolyamines, N, N-dialkylaminoalkylacrylates, and vinylpyridine, amine salts, such as lauryl amine acetate, stearylamine acetate, alkylpyridinium salt, and alkylimidazolium salt, and amine oxides; imidaazolinium salts; protonated quaternary acrylamides; methylated quaternary polymers, such as poly [diallyldimethylammonium chloride] poly- [N-methylvinylpyridinium chloride]; and cationic guar.

Illustrative cationic surface stabilizers and other useful cationic surface stabilizers are described in J. Cross and E. Singer, Cationic Surfactants: Analytical and Biological Evaluation (Marcel Dekker, 1994); P. and D. Rubingh (Editor), Cationic Surfactants: Physical Chemistry (Marcel Dekker, 1991); and J. Richmond, Cationic Surfactants: Organic Chemistry, (Marcel Dekker, 1990). Particularly preferred surface stabilizers for use within the scope of the present invention are sodium lauryl sulfate, sodium sulfosuccinate (sodium docusate, DOSS) and polyoxyethylene sorbitan fatty acid esters. (b) Dispersion aid Examples of dispersion aids for use within the scope of the present invention include lactose and lactose monohydrate, dextrose, dextrates, sucrose, starch, mannitol, sorbitol, crospovidone, polyplasdone, croscarmellose sodium, methylcellulose, carboxymethylcellulose calcium, sodium starch glycolate, alginic acid, sodium carboxymethylcellulose, guar gum, magnesium aluminum silicate, polacrilin sodium, potassium polacrilin, cellulose powder, pregelatinized starch, starch. It will be noted that certain excipients are known in the galenics art that are capable of playing different roles according to the exact circumstances in which they are used, and in particular the amount in which they are used. In particular, some of the dispersion aids of the present invention are known as fillers, they are used in an amount of more than 20% by weight in relation to the total weight of the composition and some of the dispersion aids of the present invention. They are known as disintegrating agents, in which case they are used in an amount of less than 5% by weight relative to the total weight of the composition. The species used as dispersion aids within the framework of the present invention are used in an amount that is equal to or greater than 5% and less than or equal to 20% by weight relative to the total weight of the composition. (c) Binders Examples of binders for use within the scope of the present invention include acacia gum, alginic acid, carboxymethylcellulose, sodium carboxymethylcellulose, carboxyethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose , liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone, pregelatinized starch, sodium alginate, starch, xanthan gum, tragacanth gum, zein and mixtures thereof. Any binder that allows an improvement in the compressibility of metformin can be used, such as for example pregelatinized starch, glucose or sucrose. In a particularly preferred embodiment of the invention, the binder is selected from povidone and / or hydroxypropyl (methyl) cellulose. (d) Fillers Examples of fillers that can be used within the scope of the present invention include calcium carbonate, calcium sulfate, sucrose, dextrates, dextrin, calcium phosphate, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactose , magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinized starch, sodium chloride, sorbitol, starch, talc and calcium phosphate and mixtures thereof same. (e) Lubricating agents Examples of lubricating agents (lubricants) that may be used within the scope of the present invention include calcium stearate, glyceryl monostearate, glyceryl palmito stearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, stearate of magnesium, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, stearic acid, talc and zinc stearate and mixtures thereof. (f) Slippers Examples of slippers that can be used within the scope of the present invention include colloidal silicon dioxide, magnesium trisilicate, cellulose powder, starch, talc and calcium phosphate and mixtures thereof. (g) Suspending agents Examples of suspending agents that can be used within the framework of the present invention include acacia, agar, caragenan, guar gum, sodium alginate, starch, tragacanth, xanthan gum, sodium carmellose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, microcrystalline cellulose, dispersible cellulose, propylene glycol alginate, aluminum magnesium silicate, bentonite, carbomers, colloidal anhydrous silica, polyvinyl alcohol, povidone and gelatin. (h) Sweeteners Examples of sweeteners that may be used within the scope of the present invention include any natural or artificial sweetener, such as sucrose, dextrose, glycerin, lactose, liquid glucose, mannitol, sorbitol, xylitol, acesulfame potassium, aspartame, saccharin, sodium saccharin, sodium cyclamate and mixtures thereof. (i) Flavoring agents Examples of flavoring agents that can be used within the framework of the present invention include ethylmaltol, ethyl vanillin, fumaric acid, malic acid, maltol, menthol, vanillin, Magnasweet® (trade name of MAFCO), rubber flavor of chewing and fruit flavors and the like.

(!) Preservatives Examples of preservatives that may be used within the scope of the present invention include alcohol, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, bronopol, butyl-paraben, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben, glycerin, imidurea, methylparaben, phenol, phenoxyethanol, phenylethyl alcohol, phenyl mercuric acetate, phenyl meryluric borate, phenylmercuric nitrate, potassium sorbate, propylene glycol, propyl paraben, sodium benzoate, sodium propionate, sorbic acid and thiomersal. (k) pH Regulators Examples of pH regulators that can be used within the framework of the present invention include phosphate, bicarbonate, tris-hydroxymethylethylamine, glycine, borate, citrate.

(I) Wetting agents Examples of wetting agents that can be used within the framework of the present invention include cetyl alcohol, sodium lauryl sulfate, poloxamers, polyoxyethylene sorbitan fatty acid derivatives, polysorbate, glycerol monostearate. (m) Disintegrants Examples of disintegrants that may be used within the scope of the present invention include alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, sodium polacriline, cellulose powder, pregelatinized starch, sodium alginate, sodium starch glycolate, starch and mixtures thereof. (n) Effervescent agents Examples of effervescent agents that can be used within the framework of the present invention include effervescent couples such as an organic acid and a carbonate or bicarbonate. Suitable organic acids include, for example, citric, tartaric, malic, fumaric, atypical, succinic and alginic acid and anhydrides and acid salts. Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium carbonate-glycine, L-lysine carbonate, and arginine carbonate. Alternatively, only the sodium bicarbonate component of the effervescent couple can be present. (o) Moisturizers As an example of a humectant that can be used within the scope of the present invention, glycerol can be mentioned. (p) Controlled release agents Controlled release examples that can be used to sustain, retard, modify or otherwise control release within the scope of the present invention include, but are not limited to: alginic acid, aliphatic polyesters, bentonite , carbomers, carrageenan, cellulose acetate, cellulose acetate phthalate, ceratonin, carnuba wax, chitosan, ethylcellulose, guar gum, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, microcrystalline wax, paraffin, polymethacrylates, povidone, xanthan gum, yellow wax. (q) Absorption Accelerators As examples of absorption accelerators that can be used within the framework of the present invention, quaternary ammonium compounds can be mentioned. (r) Adsorbents As examples of adsorbents that can be used within the framework of the present invention, caolin and bentonite can be mentioned. (s) Plasticizers Examples of plasticizers that may be used within the scope of the present invention include, but are not limited to: acetyl tributyl citrate, acetyltriethyl citrate, benzyl benzoate, chlorbutanol, dextrin, dibutyl phthalate, dibutyl sebacate, diethyl phthalate, glycerin, glycerin monostearate, mannitol, palmitic acid, polyethylene glycol, polyvinyl phthalate-acetate, propylene glycol, sorbitol, stearic acid, triacetin, tributyl citrate, triethanolamine, triethyl citrate. In one embodiment of the invention, the excipients of the invention can be selected from the group consisting of hydroxypropylmethylcellulose, lactose, lactose monohydrate, croscarmellose sodium, povidone, crospovidone, guar and xanthan gums, polyethylene glycol, cellulose, microcrystalline cellulose, hydroxypropylcellulose, hydroxyethylcellulose , carboxymethylcellulose, carboxyethylcellose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, methylcellulose, acacia gum, tragacanth gum, polyethylene oxide, magnesium stearate, colloidal silicon dioxide, sodium lauryl sulfate, sodium docusate and mixtures thereof. The compositions of the invention can be administered to a subject by any conventional means including, but not limited to, oral, rectal, ocular, parenteral (e.g., intravenous, intramuscular or subcutaneous), intracisternal, pulmonary, intravaginal, intraperitoneal administration , local (eg, powders, ointments or drops), or as a buccal or nasal spray. As used herein, the term "subject" is used to mean an animal, preferably a mammal, including a human or non-human. The terms patient and subject can be used interchangeably. A preferred dosage form of the invention is a solid dosage form, although any pharmaceutically acceptable dosage form can be used. Illustrative solid dosage forms include, but are not limited to, tablets, capsules, pouches, pills, powders, pills or granules, and the dosage form can be, for example, a fast-acting dosage form, a chewable form, a controlled release dosage form, a lyophilized dose form, a delayed release dosage form, a sustained release dosage form, a pulsatile release dosage form, an immediate release dosage form and mixed controlled release or a combination of them. A solid dosage form, such as a tablet or capsule, is preferred. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. The liquid dosage forms may comprise inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers. Illustrative emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils such as cottonseed oil, ground walnut oil, corn germ, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, sorbitan fatty acid esters or mixtures of these substances and the like. In addition to these inert diluents, the composition may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavors and perfume agents. The effective amount of fibrate and metformin in the compositions of the invention will be an effective amount for treatment or prevention of glycemic or lipidaemic disease disorder. How it is used here"effective amount" means the dose or effective amount to be administered to a patient and the frequency of administration to the subject can be easily determined by one skilled in the art by the use of known techniques and by observing the results obtained under analogous circumstances . The dose or effective amount to be administered to a patient and the frequency of administration to the subject can easily be determined by one skilled in the art by the use of known techniques and by observing the results obtained under analogous circumstances. To determine the effective amount or dose, a number of factors are considered or the doctor making the diagnosis, including but not limited to the potency and duration of action of the compounds used.; the nature and severity of the disease to be treated as well as the sex, age, weight, general health and individual response of the patient to be treated, and other relevant circumstances. In one embodiment, when the fibrate is fenofibrate, the amount of fenofibrate is preferably chosen to be from about 10 to 300 mg, most preferably from 40 to 160 mg, and most preferably from 40 to 90 mg. In a further embodiment, when the fibrate is fenofibrate, the composition of the invention contains a daily dose of fenofibrate, such as 160 mg of dose of fenofibrate as used in Tricor® 160, or a dose bioequivalent to said formulation Tricor® 160. The amount of metformin or a pharmaceutically acceptable salt thereof can be chosen in an amount ranging from about 100 mg to 200 mg, preferably from 200 mg to 1500 mg, and most preferably still from about 500 mg to 1000 mg. The pharmaceutical compositions according to the invention can comprise, for example, 850 mg of metformin and 80 mg of fenofibrate; 850 mg of metformin and 54 mg of fenofibrate; 500 mg of metformin and 80 mg of fenofibrate; 500 mg of metformin and 54 mg of fenofibrate; 500 mg of metformin and 40 mg of fenofibrate; or 2000 mg of metformin and 160 mg of fenofibrate, 500 mg of metformin and 45 mg of fenofibrate, 500 mg of metformin and 71 mg of fenofibrate, 850 mg of metformin and 71 mg of fenofibrate, 850 mg of metformin and 145 mg of fenofibrate , 1,600 mg of metformin and 145 mg of fenofibrate, depending on whether the composition is taken once a day or more than once a day. To reduce the size of the metformin-fibrate combination in order to give the pharmaceutical composition a suitable size for oral administration, the total drug content of the composition can be reduced while maintaining bioequivalence to the active compounds administered individually. For example, the composition of the invention may contain 150 mg or 70 mg of fenofibrate with 1400 or 700 mg of metformin respectively and remain bioequivalent for a composition containing 160 mg or 80 mg of fenofibrate and 1500 mg or 850 mg of metformin. In another embodiment of the invention, the composition may be a slow release formulation with, for example, a reduced amount of active substance. Various sustained release formulations of metformin are described in several patents such as the U.S. patent. No. 6,475,521, patent of E.U.A. No. 5,972,389, EP No. 1, 335,708. In a preferred embodiment of the invention, when the composition is in the form of a tablet for administration once a day, the amount of fenofibrate is between 160 and 130 mg and the weight of the tablet may vary from 1200 mg to 2000 mg , most preferably from 1200 mg to 1700 mg and most preferably still from 1400 mg to 1500 mg. In another preferred embodiment of the invention, when the composition is in the form of a tablet for administration twice daily, the amount of fenofibrate is between 65 and 80 mg and the weight of the tablet may vary from 80 mg to 1600 mg , most preferably from 800 mg to 1300 mg and most preferably still from 1100 mg to 1300 mg. In another preferred embodiment of the invention, when the composition is in the form of a tablet for administration three times a day, the amount of fenofibrate is between 50 and 54 mg and the weight of the tablet may vary from 500 mg to 1200 mg, most preferably from 700 mg to 900 mg and most preferably still from 700 mg to 800 mg. In another preferred embodiment of the invention, when the composition is in the form of a tablet for administration four times a day, the weight of the tablet may vary from 500 mg to 1000 mg, most preferably from 600 mg to 900 mg and most preferably still of 650 mg a 750 mg. The invention provides compositions when the pharmacokinetic profiles of fibrate and metformin are not substantially affected when administered to a human, in the sense that there is no substantial difference in the amount of drug absorbed or the rate of drug absorption when the composition of The invention is administered in comparison with the separate co-administration of each component. The invention also encompasses a composition as defined above in which the administration of the composition is bioequivalent to the co-prescription of a composition containing either fibrate or metformin. "Bioequivalence" is established by a confidence interval (Cl) to 90% of between 0.80 and 1.25 for Cmax and AUC under the regulatory guidelines of the USFDA or a Cl at 90% for AUC between 0.80 to 1.25 and a Cl at 90% for Cmax between 0.70 to 1.43 for the regulatory guidelines of the European EMEA. It has surprisingly been found that for a metformin to fibrate ratio of less than 500: 65 (i.e., 500: 80) and to meet dissolution and bioequivalence requirements, said composition with a reduced amount of excipient must contain a small amount. of dispersion aid. In one embodiment of the invention, the compositions of the invention have a specific dissolution profile. Rapid dissolution of an administered active agent is preferable, since the faster dissolution generally leads to a rapid onset of action and greater bioavailability. To improve the dissolution profile and bioavailability of fibrates and in particular fenofibrate, it would be useful to increase the dissolution of the drug so that it could achieve a level close to 100%. The compositions of the invention preferably have a dissolution profile in which within about 15 minutes at least about 70% of the fibrate, preferably fenofibrate, is dissolved. In yet another embodiment of the invention, preferably at least about 80% of the fibrate, preferably fenofibrate, is dissolved within about 30 minutes. In another embodiment of the invention, at least about 85% of the fibrate, preferably fenofibrate, dissolves within about 45 minutes.

The dissolution is usually measured in a medium that is discriminatory. Said dissolution medium will produce two different dissolution curves for two products having very different dissolution profiles in gastric juices; that is, the dissolution medium is predictive of in vivo dissolution of a composition. An illustrative dissolution medium is an aqueous medium containing the surfactant sodium lauryl sulfate at 0.025 M. The determination of the dissolved amount can be carried out by spectrophotometry. The rotary knife method (75 rpm) according to the European pharmacopoeia can be used when measuring the solution. The pharmaceutical compositions of the present invention can be used for the treatment of non-insulin dependent diabetes mellitus (or type 2 diabetes), dyslipidemia (optionally associated with impaired glucose tolerance), hyperlipidemia, hypercholesterolemia or related conditions, for the prevention of cardiovascular events, coronary heart disease and peripheral vascular disease (including symptomatic carotid artery disease), for the treatment and prevention of metabolic syndrome and for the treatment or prevention of any disease in which treatment with a fibrate and metformin is desirable, such as obesity. The pharmaceutical compositions of the invention can be used as adjunctive therapy to the diet for the reduction of LDL-C, total C, triglycerides and Apo B in adult patients with primary hypercholesterolemia or mixed dyslipidemia (types Ia and llb of Fredrickson). These compositions can also be used as adjunctive therapy to the diet for the treatment of adult patients with hypertriglyceridemia (type IV hyperlipidemia and Fredrickson V). Significantly elevated triglyceride levels in serum (eg, >2000 mg / dl) may actually increase the risk of developing pancreatitis. Accordingly, the invention also provides treatment or prevention of the aforementioned diseases, disorders or events, which comprises administering to a subject in need thereof the pharmaceutical composition as defined above. The composition of the invention may further comprise, or may be administered in combination with, one or more active substances selected from the group consisting of PPAR activators, HMG CoA inhibitors and antihypertensive agents. Examples of PPAR activators? include but are not limited to thiazolidinedione compounds, such as rosiglitazone, pioglitazone, ciglitazone, englitazone, darglitazone, and analogs and derivatives and pharmaceutically acceptable salts thereof. Examples of HMG CoA reductase inhibitors (or statins) include, but are not limited to, lovastatin; pravastatin; simavastatin (Zocor®); velostatin; atorvastatin (Lipitor®) and other 6- [2- (substituted pyrrol-1-yl) alkyl] pyran-2-ones and derivatives, as described in the patent of E.U.A. No. 4,647,576); fluvastatin (Lescol®); Fluindostatin (Sandoz XU-62-320); pyrazole analogs of mevalonolactone derivatives, as described in WO 86/03488; rivastatin and other pyridyldihydroxyheptenoic acids, as described in European Patent 491226A; dichloroacetate; imidazole analogs of mevalonolactone, as described in PCT application WO 86/07054; 3-carboxy-2-hydroxy-propan-phosphonic acid derivatives, as described in French Patent No. 2,596,393; 2,3-di-substituted pyrrole, furan and thiophene derivatives, as described in European Patent Application No. 0221025; mevalonolactone naphthyl analogs, as described in the US patent. No. 4,686,237; Octahydronaphthalenes, such as those described in the U.S.A. No. 4,499,289; mevinolin keto analogs (lovastatin), as described in European Patent Application No. 0,142,146 A2; phosphinic acid compounds; as well as other HMG CoA reductase inhibitors. Examples of antihypertensives include, but are not limited to, diuretics ("water pills"), beta blockers, alpha blockers, alpha-beta blockers, sympathetic nerve inhibitors, angiotensin converting enzyme (ACE) inhibitors, channel blockers of calcium, angiotensin receptor blockers. A preferred embodiment of the present invention comprises a pharmaceutical composition, comprising metformin particles and particles of a fibrate, in association with at least one vehicle, adjuvant or other pharmaceutically acceptable excipient, it being understood that the vehicle, adjuvant or other excipient does not have a direct pharmacological effect as an active substance in the framework of the invention. Although the presence of a third or subsequent active substance, beyond metformin and fibrate, is not excluded in the present invention, the compositions according to the present invention preferably will contain only metformin and fibrate as the two unique active substances. Preferred compositions in accordance with the present invention will therefore essentially consist of a metformin combined with an individual fibrate, the other elements present in the composition being excipients that have no intrinsic pharmacological activity and therefore do not materially modify the nature of the actions of the combination of metformin + fibrate in the operation of the present invention. The present invention also relates to processes for preparing a pharmaceutical composition as defined above which consists of granules comprising particles of metformin and particles of a fibrate, wherein metformin acts as a vehicle for the fibrate. Preferably, the granules of the present invention consist of metformin particles, to which fenofibrate particles adhere. The granules of the present invention therefore preferably comprise metformin particles that are either isolated or agglomerated, and particles of a fibrate, which adhere to said metformin particles. Preferred methods according to the present invention allow the production of granules, comprising metformin particles and particles of a fibrate, these processes include fluid bed granulation process in which an aqueous dispersion of fibrate is sprayed on a fluidized bed of metformin , high shear granulation process and granulation process in "one container". In a preferred embodiment according to the present invention, the process for preparing granules is a fluid bed granulation process comprising the steps of: a) preparing an aqueous dispersion of the fibrate, preferably in the presence of at least one dispersion aid , at least one binder and / or surface stabilizer; b) spraying the resulting dispersion on a fluidized bed of metformin, thereby obtaining the granules; c) drying the resulting granules According to one embodiment of this process, the dispersion prepared in step a) may further comprise one or more additives eg, a controlled release barrier, a surfactant (or emulsifier) and / or a plasticizer. According to another embodiment of this process, the dispersion in step a) is prepared from a dispersion of fibrate nanoparticles, preferably fenofibrate, which can be obtained as described for example in the patent application of E.U.A. 2003/0224058. In another preferred embodiment, the process for preparing granules is a high shear granulation process comprising the steps of: a) subjecting a mixture of metformin, the fibrate and optionally a dispersion aid, at high shear stress, preferably in the presence of at least agglutinating and / or surface stabilizer; b) adding water to the high shear mixing mixture thus obtaining the granules; c) drying the resulting granules in a fluid bed dryer. According to one embodiment of this method, a controlled release barrier is added in step a) to the mixture of metformin and fibrate, and a surfactant (emulsifier) and / or a plasticizer are added in step b). In another preferred embodiment, the process for preparing granules is a "container" granulation process comprising the steps of: a) subjecting a mixture of metformin, the fibrate and optionally at least one dispersion aid to a high shear stress, preferably in the presence of at least one binder and / or surface stabilizer; b) add water to the high shear mix thus obtaining the granules. c) drying the resulting granules in a container system. The drying step in the "one vessel" system is carried out by passing dry gas through the granule bed, and applying heat to it eg by an external jacket, by microwave radiation or a combination of these methods. Surprisingly, it has been found that both the high shear granulation method and the "one pot" granulation method allow compositions analogous to those produced by the fluid bed granulation method to be produced. The use of high shear granulation allows a procedure with relatively short processing times. The use of granulation in a container gives a process with relatively short processing times and a reduction in the number of processing steps required to produce the product In yet another embodiment of the invention, a pharmaceutical composition can be prepared by a process which comprises a) adding suitable containers and optionally one or more active substances selected from the group consisting of activators of PPAR ?, inhibitors of HMG CoA reductase and antihypertensives, to the granules as defined above and b) formulating the resulting mixture or combination in the desired composition Several exemplary tablet formulations of the invention are given below These examples are not intended to limit the claims in any way, but rather to provide illustrative tablet formulations of the invention, said illustrative tablets may also comprise a coating agent. The tablets of these examples are suitable for oral administration, that is, they can be easily swallowed. The weight of the 850 mg / 80 dose form or 850 mg / 71 controlled release dosage form of the examples is between about 1080 and 1440 9- In these examples, the total drug content is about 60 to 90% by weight, based on the total weight of the tablets. Both the foregoing description and the following examples are illustrative and explanatory and are intended to provide a further explanation of the invention as claimed. Other objects such as advantages and novel features will be readily apparent to those skilled in the art from the description and examples of the invention.

EXAMPLE 1 Manufacture of pharmaceutical composition by fluid bed granulation (procedure A) A pharmaceutical composition comprising fenofibrate and metformin was prepared as follows: 1. Water, povidone and fenofibrate (co-micronized with sodium lauryl sulfate and having an average particle size of about 8 μm are shaken together to form dispersion A. Metformin (which has an average particle size between 125 μm and 250 μm) is placed in a container in a fluid bed granulator and is fluidized with air at 60 ° C - 70 ° C. 3. Dispersion A is sprayed on the fluidized bed of metformin to effect the granulation 4. The granules are dried 5. The granules are sieved through a 1 mm sieve 6. Microcrystalline cellulose, crospovidone, colloidal silicon dioxide and magnesium stearate are added to the granules and mixed. 7. Optionally, the mixture can be compressed into tablets. The tablets can be coated. The mixture can also be put into capsules.

EXAMPLE 2 Manufacture of pharmaceutical composition by high shear granulation (procedure B) A pharmaceutical composition comprising fenofibrate and metformin was prepared as follows: 1. Povidone, fenofibrate (co-micronized with sodium lauryl sulfate and having an average particle size of about 8 μm) and metformin (having an average particle size of between 125 μm and 250 μm) are stirred together and subjected to high shear stress. 2. Water is added to this mixture to effect granulation. 3. The resulting granules are transferred to a fluid bed dryer and dried. 4. Dry granules are sieved through a 1 mm sieve. 5. Microcrystalline cellulose, crospovidone, colloidal silicon dioxide and magnesium stearate are added to the granules and mixed. 6. Optionally, the mixture can be compressed into tablets. These tablets can be coated.

EXAMPLE 3 Manufacture of combination by means of granulation in "one vessel" (procedure C) A pharmaceutical composition comprising fenofibrate and metformin was prepared as follows: 1.- Povidone, fenofibrate (co-micronized with sodium lauryl sulfate and having an average particle size of about 8 μm) and metformin (having an average particle size) between 125 μm and 250 μm) are shaken together and subjected to high shear stress. 2.- Water is added to this mixture to carry out the granulation. 3. The resulting granules are dried within the "one vessel" system by passing dry gas through the granule bed, applying heat by an external jacket, by microwave radiation or by a combination of two or more of these methods. 4.- The granules are sieved through a 1 mm sieve. Microcrystalline cellulose, crospovidone, colloidal silicon dioxide and magnesium stearate are added to the granules and mixed. 6. Optionally, the mixture can be compressed into tablets. These tablets can be coated.

EXAMPLE 4 Composition A A tablet having the following composition was prepared according to procedure A: EXAMPLE 5 Composition B A tablet having the following composition was prepared according to procedure B: EXAMPLE 6 Composition C A tablet having the following composition was prepared according to procedure B: EXAMPLE 7 Composition D A tablet having the following composition was prepared according to procedure B: EXAMPLE 8 Composition E A tablet having the following composition was prepared according to procedure B: The release profiles of these compositions (Composition A, B, C, D and E) versus fenofibrate monotherapy and versus metformin monotherapy were measured. The bioequivalence of fenofibrate and metformin were also analyzed. The results are reported in the following tables, where the following abbreviations are used: AUC: area under the concentration time curve. C max: maximum concentration (μg / ml) Cl: Confidence interval EXAMPLE 9 Bioequivalence analysis of denofibrate and metformin EXAMPLE 10 Dissolution profile The purpose of this example was to evaluate the dissolution of a composition in accordance with the invention.

The dissolution of metformin and fenofibrate tablets with formulations as detailed in Examples 4-8 and as prepared in detail in Examples 1 and 2 was tested in a dissolution medium. The dissolution medium used was an aqueous medium containing sodium lauryl sulfate at 0.025 M. The determination of the dissolved amount was carried out by means of HPLC, and the tests were repeated 12 times. The rotary knife method (European Pharmacopoeia) was used under the following conditions: Volume of medium: 1000 ml; Temperature of the medium: 37 ° C; Blade rotation speed: 75 rpm; Samples taken: 5, 15, 30, 45 and 60 minutes. The dissolution data for all batches manufactured for compositions A, B, C and D are listed in the following table: The dissolution profiles of metformin have not been reported here. For all lots, 100% dissolution of metformin is achieved by the point in time of 15 minutes. At 5 minutes, the metformin solution varies from 56.9% to 100%.

As can be seen, composition E does not dissolve as quickly as the other composition, and as a consequence, composition E does not meet the requirement for bioequivalence (example 10: Cmax 0.845- 1.064). To improve the dissolution of this composition (ratio of metformin to fenofibrate: 500: 80), another formulation was designed, as shown in further examples below. The nt of E.U.A. No. 6,277,405, for "Fenofibrate Pharmaceutical Composition Having High Bioavailability and Method for Preparing It ", provides a composition of micronized fenofibrate that has a dissolution profile of at least 10% in 5 minutes, 20% in 10 minutes, 50% in 20 minutes and 75% in 30 minutes. The above results (compositions A, B, C, D) show that the compositions of the invention have a rapid dissolution profile, at least as fast as that of the composition of US 6,277,405. As shown in example 9, the pharmacokinetic parameters of the fibrate and metformin of the compositions of the invention (A, B, C, D) are the same as those obtained when the metformin or fibrate is administered as a single composition, to a human. Specifically, there was no substantial difference in the rate or amount of drug absorption when the composition was administered versus co-administration. Therefore, the compositions of the invention, preferably compositions of metformin and fenofibrate, allow to present the same pharmacokinetics of fibrate and metformin when administered as a single product.

EXAMPLE 11 Composition F A tablet having the following composition was prepared according to procedure B: EXAMPLE 12 Dissolution profile of compound F By adding a dispersion aid (here lactose in an amount of 6.4%), the dissolution profile of composition F (ratio of metformin to fenofibrate: 500: 80) was significantly improved. This dispersion aid is absolutely required to obtain a composition that meets the requirements of bioequivalence and dissolution.

EXAMPLE 13 Composition G A tablet having the following composition was prepared according to the procedure detailed below: The tablets were manufactured according to procedure A delineated in Example 1 with the exception that the dispersion A is prepared by mixing together water, sucrose and a dispersion of fenofibrate nanoparticles obtainable for example as described in the application US nt 2003/0224058, whose content is incorporated by reference.

EXAMPLE 14 Controlled release H composition A tablet having the following composition was prepared according to the procedure detailed below: The tablets were manufactured according to procedure A delineated in example 1 with the exception that dispersion A is prepared by mixing together water, povidone, fenofibrate, polymethacrylate, mono / di-glycerides and polysorbate 80. In this example, the polymethacrylate It works as a controlled release barrier. The polysorbate 80 serves to emulsify the mono / di-glycerides which, in turn, serve to plasticize the polymethacrylate.

Claims (23)

NOVELTY OF THE INVENTION CLAIMS

1. - A pharmaceutical composition comprises metformin particles and fibrate particles, wherein the metformin acts as a vehicle for fibrate, wherein the metformin and fibrate are present in a combined amount of at least 50% by weight, based on the weight total of the composition, wherein the weight ratio of metformin to fibrate is comprised between 500: 90 and 850: 35, and wherein the fibrate is selected from the group consisting of: fenofibrate, fenofibric acid or a pharmaceutically acceptable salt or ester of fenofibric acid; and with the proviso that if the weight ratio of metformin to fibrate is between 500: 90 and 500: 65, said composition comprises a dispersion aid as a mandatory excipient.

2. The pharmaceutical composition according to claim 1, further characterized in that the weight ratio of metformin to fibrate is between 500: 54 and 850: 65.

3. The pharmaceutical composition according to claim 1, further characterized in that the weight ratio of metformin to fibrate is between 850: 54 and 850: 35.

4. The pharmaceutical composition according to any of claims 1 to 3, further characterized in that at least 70% of the fibrate is dissolved within about 15 minutes, at least about 80% of the fibrate dissolves within about 30 minutes , at least about 85% of the fibrate dissolves within about 45 minutes, as measured using the rotary knife method at 75 rpm in accordance with the European Pharmacopoeia, in a dissolution medium containing 0.025 M sodium lauryl sulfate.

5. The pharmaceutical composition according to any of claims 1 to 4, further characterized in that it comprises: from about 60% to about 98% by weight, preferably from about 70% to about 95% by weight, and most preferably from about 74% to about 90% by weight of fibrate and metformin combined together; and from about 2% to about 40% by weight, preferably from about 5% to about 30% by weight, and most preferably from about 10% to about 26% by weight of pharmaceutically acceptable excipients.

6. The pharmaceutical composition according to any of claims 1 to 5, further characterized in that the fibrate is in a crystalline phase, an amorphous phase, a semicrystalline phase or a semi-amorphous phase.

7 - The pharmaceutical composition according to any of claims 1 to 6, further characterized in that the fibrate is fenofibrate.

8. - The pharmaceutical composition according to any of claims 1 to 7, further characterized in that the fibrate is micronized or co-micronized.

9. The pharmaceutical composition according to any of claims 1 to 8, further characterized in that the fibrate is co-micronized with a surfactant.

10. The pharmaceutical composition according to any of claims 1 to 9, further characterized in that the fibrate particles have an average size of less than about 20 μm, preferably less than about 10 μm.

11. The pharmaceutical composition according to any of claims 1 to 10, further characterized in that the fibrate is in the form of nanoparticles having an average size of less than about 2000 nm, preferably less than about 1500 nm, preferably less than of about 1000 nm, preferably less than about 500 nm, and preferably less than about 100 nm.

12. The pharmaceutical composition according to any of claims 1 to 11, further characterized in that metformin is in the form of the free base or a pharmaceutically acceptable salt thereof.

13. The pharmaceutical composition according to any of claims 1 to 12, further characterized in that it comprises 2000 mg of metformin and 160 mg of fenofibrate.; 850 mg of metformin and 80 mg of fenofibrate; 850 mg of metformin and 54 mg of fenofibrate; 500 mg of metformin and 80 mg of fenofibrate; 500 mg of metformin and 54 mg of fenofibrate; or 500 mg of metformin and 40 mg of fenofibrate; 500 mg of metformin and 45 mg of fenofibrate, 500 mg of metformin and 71 mg of fenofibrate, 850 mg of metformin and 71 mg of fenofibrate, 850 mg of metformin and 145 mg of fenofibrate, 1600 mg of metformin and 145 mg of fenofibrate.

14. The pharmaceutical composition according to any of claims 1 to 13, further characterized in that the composition is formulated for oral, pulmonary, rectal, ophthalmic, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, local, buccal, nasal or Topical

15. The pharmaceutical composition according to any of claims 1 to 14, further characterized in that it is a tablet.

16. The pharmaceutical composition according to any of claims 1 to 14, further characterized in that it is a capsule.

17. The pharmaceutical composition according to claim 15, further characterized in that it is in the form of a tablet weighing from about 500 mg to about 1500 mg.

18. The pharmaceutical composition according to any of claims 1 to 17, further characterized in that it comprises one or more substances selected from the group consisting of activators of PPAR ?, inhibitors of HMG CoA reduc and antihypertensive agents.

19. - The use of metformin in a pharmaceutical composition comprising metformin and fenofibrate, wherein metformin acts as a vehicle for the fibrate.

20. The use of metformin according to claim 19, wherein the metformin and fibrate are present in a combined amount greater than or equal to 50% by weight with respect to the overall weight of the composition.

21. A process for preparing a pharmaceutical composition according to one of claims 1 to 18, wherein said pharmaceutical composition comprises granules obtained by the process comprising the steps of: a) preparing an aqueous dispersion of the fibrate, preferably in the presence of of at least one binder and / or surface stabilizer; b) spraying the resulting dispersion on a fluidized bed of metformin, thereby obtaining the granules; c) drying the resulting granules.

22. A process for preparing a pharmaceutical composition according to one of claims 1 to 18, wherein said pharmaceutical composition comprises granules obtained by the process comprising the steps of: a) high shear stress a mixture of metformin and the fibrate, preferably in the presence of at least one binder and / or surface stabilizer; b) adding water to the mixture subjected to high shear stress thus obtaining the granules; c) drying the resulting granules in a fluidized bed dryer.

23. - A method for preparing a pharmaceutical composition according to one of claims 1 to 18, wherein said pharmaceutical composition comprises granules obtained by the process comprising the steps of: a) subjecting a mixture of metformin and fibrate to high shear stress , preferably in the presence of at least one binder and / or surface stabilizer; b) adding water to the mixture subjected to high shear stress thus obtaining the granules; c) drying the resulting granules in a container system.