MX2008008589A - Pharmaceutical formulations of fenofibrate having improved bioavailability. - Google Patents

Abstract

Provided are pharmaceutical compositions of fenofibrate, and dosage forms containing them, that include fenofibrate, a polyethylene glycol, and a polethylene-polypropylene glycol; wherein the compositions are made by subliming a sublimable carrier from a combination of fenofibrate, the polyethylene glycol, and the polethylene - polypropylene glycol with the sublimable carrier, for example menthol.

Description

PHENOFIBRATE PHARMACEUTICAL FORMULATIONS THAT HAVE IMPROVED BIOAVAILABILITY FIELD OF THE INVENTION The present invention relates to pharmaceutical compositions including fenofibrate, a polyethylene glycol, and a polyethylene glycol-polypropylene glycol, wherein the composition is manufactured by sublimation of a sublimable carrier from a solid solution containing fenofibrate, a polyethylene glycol, a polyethylene glycol-polypropylene glycol, and a sublimation carrier such as menthol.

BACKGROUND OF THE INVENTION Fenofibrate, (1-methylethyl ester of 2- [4- (4-chlorobenzoyl) phenoxy] -2-methylpropanoic acid), is one of the classes of drug fibrates. It is available as capsules and tablets. Fenofibrate is evidently a prodrug. It is reported that the active group is the fenofibric acid metabolite that is reported to be produced in the body by the action of esterases. When fenofibrate is administered, obviously no intact fenofibrate is found in plasma (Physician's Desk Reference, 58th ed., 2004, pages 522-525, (PDR 2004)). Fenofibrate has very little solubility in water. That is, it is a drug poorly soluble in water. Despite its poor solubility in water, it is reported that it is absorbed at a therapeutically acceptable level when dosed in the "fed state" and even less when dosed in the "fasted state". The true "bioavailability" of the fenofibric acid metabolite is uncertain because it is understood that a large part of it must be metabolized to the glucuronide at the presystemic and first-pass sites.

The absolute bioavailability of fenofibrate supposedly can not be determined since it is insoluble in the means suitable for intravenous injection. After oral adminition in healthy volunteers, approximately 60% of a single dose of radiolabeled fenofibrate appeared in the urine, mainly as fenofibric acid and its glucuronide conjugate, and 25% was excreted in fecal matter (PDR). It is understood that the absorption of fenofibrate administered increases when it is administered with food. The extent of absorption from orally administered tablets increases by approximately 35% when tablets are taken with food (PDR, Martindale 33rd ed., Page 889).

Attempts have been made to improve the formulation of fenofibrate, especially with respect to the bioavailability of fenofibrate. U.S. Patent Nos. 4,895,726 and 5,880,148 disclose the joint micronization of fenofibrate with surface active agents. U.S. Patent Nos. 6,074,670 and 6,277,405 disclose the micronized fenofibrate coating water-soluble carriers with optional surface active agents. U.S. Patent No. 6,814,977 discloses fenofibrate dissolved in a medium chain glycerol fatty acid ester, US Patent No. 6,719,999 discloses fenofibrate dissolved in glycerin, propylene glycol or dimethyl isosorbide and US Patent No. 5,827. 536 discloses fenofibrate dissolved in diethylene glycol monoethyl ether.

Several patents disclose specific formulations of micronized fenofibrate with specific surface active agent or polymeric additives and other patents describe emulsions and suspensions of fenofibrate. For example, U.S. Patent Application Publication No. 20040087656 discloses fenofibrate of a particle size less than 2000 nm which is claimed to have improved bioavailability. U.S. Patent Application Publication No. 20030224059 discloses microparticles of active pharmaceutical ingredients, vehicles for adminition of the drug comprising them, and methods for making them.

The micronization of fenofibrate and the combinations of micronized fenofibrate with surface active agents have moderately increased the bioavailability of fenofibrate which allows the amount of the drug approved by the dosages to be reduced from 100 mg per dose to 67 mg per dose and subsequently to 54 mg per dose, while all maintain bioavailability in the state with food. The formulations of nanoparticles of the drug have allowed the reduction of the dose to 48 mg per dose with the bioavailability of the "fasting state" that is reported to be similar to the state with food. There is still room for a great improvement since the true bioavailability of fenofibrate is still relatively low.

EXAMPLE OF THE INVENTION In one aspect, the present invention relates to a pharmaceutical composition comprising non-mechanically micronized microparticles of fenofibrate, especially micronized microparticles by sublimation of fenofibrate using menthol as a sublimable carrier, polyethylene glycol, especially polyethylene glycol 6000; and a polyethylene glycol-polypropylene glycol, especially poloxamer 407. The pharmaceutical composition may also include a disintegrant which is selected from the group consisting of crospovidone, a carboxymethyl cellulose, especially cross-linked carboxymethyl cellulose sodium (croscarmellose sodium), the bicarbonate salts or carbonate, especially bicarbonates or carbonates of metals such as sodium bicarbonate; organic carboxylic acids, especially citric acid, tannic acid, ascorbic acid, benzoic acid, fumaric acid, lactic acid, malic acid, sorbic acid, and tartaric acid; and combinations of any of the preceding.

In another aspect, the present invention relates to a solid oral dosage form that includes a pharmaceutical composition that includes 15% to 25% by weight of non-mechanically micronized microparticles of fenofibrate, especially micronized fenofibrate by sublimation; from 7% to 13% by weight of poloxamer 407; from 7% to 13% polyethylene glycol 6000; 15% by weight of microcrystalline cellulose; 10% by weight of crospovidone; 12% by weight of sodium bicarbonate; and 12% by weight of citric acid or tartaric acid.

In yet another aspect, the present invention relates to a solid oral dosage form that includes a pharmaceutical composition that includes 15% to 25% by weight of non-mechanically micronized microparticles of fenofibrate, especially micronized fenofibrate by sublimation; from 7% to 13% by weight of poloxamer 407; from 7% to 13% by weight of polyethylene glycol 6000; 15% by weight of microcrystalline cellulose; 18% by weight of crospovidone; 12% by weight of sodium bicarbonate; and 12% by weight of citric acid or tartaric acid; wherein the dosage form has a fenofibrate release profile in vitro that depends on time so that at least 15%, especially at least 51% to 81% of the fenofibrate is released in 10 minutes, which at least 73%, especially from 73% to 93% by weight of the fenofibrate is released in 15 minutes and that at least 85% by weight, especially from 85% by weight until essentially all of the fenofibrate is released in 30 minutes In another aspect, the present invention relates to a solid oral dosage form, especially a compressed tablet, comprising a pharmaceutical composition that includes 145 mg of micronized fenofibrate by sublimation where in the in vivo pharmacokinetic studies of humans wherein the form of dosage is administered in the fasted state, the area under the curve AUC of 48 hours (AUC48) is 121367 h * ng / ga 287539 h * ng / g; the area under the curve AUC extrapolated to infinite time (AUC8) is 134750 h * ng / g at 345390 h * ng / g; and the maximum plasma concentration (Cm ^ x) is from 6357 ng / g to 14627 ng / g. Normally, said dosage form solid presents an average AUC48 of 175335 h * ng / g, an AUC »average of 213652 h * ng / g, and an average Cmax of 10570 ng / g.

In yet another aspect, the present invention relates to a solid oral dosage form, especially a compressed tablet, which includes a pharmaceutical composition having 145 mg of micronized fenofibrate by sublimation where, in in vivo pharmacokinetic studies of humans where the dosage form is administered in the food state, the area under the AUC curve of 48 hours (AUC48) at 91601 h * ng / g at 217512 h * ng / g; the area under the curve AUC extrapolated to infinite time (AUC ~) is 97182 h * ng / g at 308070 h * ng / g and also where the average AUC48 is 150511 h * ng / g and the average AUC is 185149 h * ng / g The dosage form can include a disintegrator.

In still another aspect, the present invention relates to a pharmaceutical composition having a plurality of particles of pharmaceutical carrier, especially microcrystalline cellulose particles, having deposited thereon a combination of fenofibrate, especially 15% to 25% by weight of fenofibrate, a polyethylene glycol, especially a polyethylene glycol 6000 7% up to 13% by weight; and a polyethylene glycol-polypropylene glycol, especially poloxamer 407 7% up to 13% by weight; wherein the combination is deposited by sublimation of a sublimable carrier, especially menthol, from a solid solution comprising fenofibrate, polyethylene glycol, polyethylene glycol-polypropylene glycol, and the sublimable carrier. The composition may also include a pharmaceutical disintegrant which is selected from the group consisting of crospovidone, a cross-linked carboxymethyl cellulose salt (especially cross-linked carboxymethyl cellulose sodium), the bicarbonate or carbonate salts; especially bicarbonates or alkali metal carbonates such as sodium bicarbonate; organic carboxylic acids, especially citric acid, tannic acid, ascorbic acid, benzoic acid, fumaric acid, lactic acid, malic acid, sorbic acid, and tartaric acid; and combinations of any of the preceding.

In yet another aspect, the present invention relates to a solid oral dosage form that includes a pharmaceutical composition having 145 mg of fenofibrate that has been deposited on a plurality of microcrystalline cellulose by sublimation of a sublimable carrier from a solid solution that comprises fenofibrate and the sublimable carrier; wherein in in vivo pharmacokinetic studies of humans in which the dosage form is administered in the fasted state, the area under the AUC curve of 49 hours (AUC48) is 121367 h * ng / g at 287539 h * ng / g; the area under the curve AUC extrapolated to infinite time (AUC8) is 134750 h * ng / g at 345390 h * ng / g; and the concentration in the maximum plasma (Crax) is from 6357 ng / g to 14627 ng / g. This solid oral dosage, in certain detailed aspects, presents an average AUC48 of 175335 h * ng / g, an average AUC8 of 213652 h * ng / g, and an average Cmax of 10570 ng / g.

Detailed Description of the Invention In one embodiment, the present invention provides a pharmaceutical composition that includes non-mechanically micronized microparticles of fenofibrate, a polyethylene glycol and a polyethylene glycol-polypropylene glycol.

Micronized microparticles in non-mechanical form have average dimensions of 0.1 μ ?? and they are produced by non-mechanical crushing techniques. Non-mechanical crushing techniques are techniques other than grinding (sphere, impact, high energy), spray drying, and / or high pressure homogenization. For the purposes of the present patent application, the lyophilization technique is considered a mechanical micronization technique, therefore, the microparticles produced by lyophilization are excluded from the Micronized microparticles in non-mechanical form. The measurement of the size of the particles is known to those skilled in the art and can be accompanied, for example, by the known technique of laser light diffusion.

The non-mechanically micronized microparticles of fenofibrate of the present invention can be obtained, for example, by the sublimation micronization technique. The microparticles thus obtained are called microparticles "micronized by sublimation" and the material comprising said microparticles is called "micronized by sublimation". The micronization technique by sublimation is described in published U.S. Patent Application US 2003/0224059 (Lerner et al), which is incorporated herein by reference.

The fenofibrate microparticles of the present invention are obtained by micronization by sublimation eliminating a sublimable carrier of a solid solution of fenofibrate in the sublimable carrier. Fenofibrate can be present with the sublimable carrier in the solid solution as discrete molecules, or it can be present in aggregates of a few hundred, a few thousand or more molecules. The drug needs only to be dispersed on a sufficiently small scale, finally they are obtained discrete microparticles. Preferably, the fenofibrate in the solid solution is dissolved in the sublimable carrier.

Sublimable carriers have a measurable vapor pressure below their melting point. Preferred sublimable carriers have a vapor pressure of at least 10 Pases, more preferably at least 50 Pascals at 10 ° C or more below their normal melting points. Preferably, the sublimable carrier has a melting point of between -10 ° C and 200 ° C, more preferably between 20 ° C and 60 ° C, more preferably between 40 ° and 50 ° C. Preferably, the sublimable carrier is a substance that the Food and Drug Administration of the United States classifies as generally recognized as safe (ie, GRAS). Examples of suitable sublimable carriers include menthol, thymol, camphor, t-butanol, trichloro-butanol, imidazole, curaarin, acetic acid (glacial), dimethylsulfone, urea, vanilla, camphene, salicylamide, and 2-aminopyridine. Menthol is a particularly preferred sublimable carrier.

The microparticles of the present invention are formed by removing the sublimable carrier from a solid solution, processed as described above, at a temperature below the melting point of the solid solution. The solution The solid should be maintained at a temperature below the melting point to preserve the solid solution during the process of removing the sublimable carrier. The sublimable carrier can be removed from the solid solution by, for example, treating the solid solution, deposited on the pharmaceutical carrier particle where applicable as discussed below, in a stream of air, preferably hot air, in for example a dryer. fluidized bed.

The pharmaceutical compositions of the present invention also include polyethylene glycols. Preferably, the pharmaceutical compositions of the present invention include at least one polyethylene glycol (PEG) and at least one polyethylene glycol-polypropylene glycol.

The polyethylene glycols useful in the practice of the present invention have the general formula - (-CH2-CH2-0-) x- and can be characterized by the arithmetic average value of X (<XN>) or the corresponding molecular weight it as described, for example, in Polyethylene Glycols, 23 National Formulary, 3052 (United States Pharmacopoeia Convention, 2005). Polyethylene glycol 6000 is a preferred polyethylene glycol for use in the practice of the present invention.

The polyethylene glycols-polypropylene glycols useful in the practice of the present invention have the general structure - (0-CH2CH2-) x-0- (-CH (CH3) CH2-)? - ?? and they are commonly called "poloxamers". Preferred poloxamers for use in the practice of the present invention are described in the like name monograph in the United States National Formula List. Poloxamers, 23 National Formulary, 3051 (United States Pharmacopoeia Convention, 2005). Polyethylene glycol-polypropylene glycol commonly referred to as "poloxamer 407" is a polyethylene glycol-polypropylene glycol particularly preferred for use in the practice of the present invention.

The pharmaceutical compositions of the present invention can be deposited and deposited in preferred embodiments on a plurality of pharmaceutical carrier particles. The pharmaceutical carrier particles useful as a support, substrate, or carrier for the pharmaceutical formulation of the present invention are made with edible substances and are known in the art. Examples of useful pharmaceutical carrier particles include particles, which may be non-pariel pellets, usually between 0.1 mm and 2 mm in diameter, and made of, for example, starch, microcrystalline cellulose particles, lactose particles or, particularly, sugar particles. The sugar particles suitable (pellets, for example non-pariel 103, nucleus of Nu, pariel of Nu) are commercially available in a size from 35 mesh to 40 mesh up to 18 to 14 mesh. The pharmaceutical carrier particles are made of non-water-soluble material, for example, microcrystalline cellulose. Carrier particles composed of microcrystalline cellulose (e.g., Avicell®) are particularly preferred pharmaceutical carrier particles. The skilled artisan knows other useful pellets or spheres such as pharmaceutical carrier particles.The pharmaceutical compositions according to the present invention can be made by combining fenofibrate, polyethylene glycol, polyethylene glycol-polypropylene glycol and a sublimable carrier. The preceding components can be combined pure, or in embodiments in which the composition is deposited on a plurality of pharmaceutical carrier particles, together with a suitable solvent. Suitable solvents dissolve fenofibrate, polyethylene glycol, polyethylene glycol-polypropylene glycol and the sublimable carrier, but do not dissolve pharmaceutical carrier particles and are also chemically inert to any of the components, and can be removed at a convenient temperature, especially at a temperature of < 100 ° C, optionally with the help of an applied vacuum. Ethanol is an example of a suitable solvent.

The combination of components is combined and heated to form a homogeneous mixture, preferably a solution, and cooled to obtain a solid solution. Fenofibrate can be present with the sublimable carrier in the solid solution as discrete molecules, or it can be present in aggregates of a few hundred, a few thousand or more molecules. It is necessary that the drug only be dispersed on a sufficiently small scale so that finally small discrete microparticles are obtained.

Preferably, the drug in the solid solution is dissolved in the sublimable carrier. In embodiments in which micronized sublimated microparticles are deposited on a plurality of pharmaceutical carrier particles, the hot solution of components in the sublimable carrier is combined with pharmaceutical carrier particles, for example by mixing, and the combination is allowed to cool to form the solid solution on the pharmaceutical carrier particles. Alternatively, the pharmaceutical carrier particles are combined with a solution of sublimable carrier, fenofibrate, polyethylene glycol, and polyethylene glycol-polypropylene glycol in a suitable solvent (for example, ethanol). The solvent is removed, optionally with the aid of heat and vacuum applied, to obtain particles of pharmaceutical carrier which have deposited on them a solid solution of fenofibrate, polyethylene glycol, polyethylene glycol-polypropylene glycol in the sublimable carrier (eg, menthol).

After the formation of the solid solution, whether deposited on pharmaceutical carrier particles or not, the pharmaceutical formulations of the present invention are subsequently formed by removing the sublimable carrier from the solid solution, processed as described above, to a temperature below the melting point of the solid solution. The solid solution must be maintained at a temperature below the melting point to preserve the solid solution during the process of removing the sublimable carrier. The sublimable carrier can be removed from the solid solution, for example, by treating the solid solution, deposited on a particle of pharmaceutical carrier where applicable, in a stream of air, preferably hot air, in, for example, a fluidized bed dryer. . In preferred embodiments, the elimination of the sublimable carrier results in the formation of micronized non-mechanical microparticles of fenofibrate, whose microparticles they may also contain at least a portion of the polyethylene glycol and polyethylene glycol-polypropylene glycol. Moreover, at least a part of the fenofibrate may be in solution or intimately associated with either or both of the polyethylene glycol and the polyethylene glycol-polypropylene glycol which are not necessarily with the micronized microparticles in non-mechanical form.

The invention of the applicants is not limited to the particular theory of operation. But applicants believe that, after removal of the sublimable carrier, at least a portion of the fenofibrate dissolves or is intimately associated with the polyethylene glycols. The term "intimately associated" excludes a simple physical mixture such as can be achieved, for example, by dry blending, dry granulation, or wet granulation in the presence of a liquid that does not at least partially dissolve the components.

The pharmaceutical compositions of the present invention, particularly when deposited on a plurality of pharmaceutical carrier particles, are well suited for the manufacture of liquid and especially solid oral dosage forms such as tablets and filled capsules. In another embodiment, the present invention provides oral dosage forms, especially oral dosage forms, preferably compressed tablets, which include the pharmaceutical compositions of the present invention.

Compressed tablets are formulated from pharmaceutical compositions containing the microparticles of the pharmacologically active substance or drug, or by using particles of pharmaceutical carrier carrying said mi- roparticles, and pharmacologically inert (pharmaceutically acceptable) additives or excipients.

To manufacture a tablet, it is usually desirable to include one or more benign pharmaceutical excipients in the pharmaceutical composition. The pharmaceutical composition of the present invention may contain one or more added diluents to make the tablet larger in size and, therefore, easier to handle for the patient and the caregiver. Common diluents are microcrystalline cellulose (eg, Avicell®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, calcium phosphate dibasic dihydrate, calcium phosphate , kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate (for example, Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

The binders can also be included in tablet formulations to help keep the tablet attached after compression. Some typical binders include acacia, alginic acid, carbomer (eg, carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (eg, Klucel®), hydroxypropyl methyl cellulose (for example, Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (for example, Kollidon®, Plasdone®), pregelatinized starch, sodium alginate and starch.

The tablet may also include a disintegrator to accelerate the disintegration of the tablet in the patient's stomach. Disintegrants include alginic acid, carboxymethylcellulose calcium, sodium carboxymethylcellulose, colloidal silicon dioxide, sodium or calcium carboxymethylcellulose, (croscarmellose sodium (eg, Ac-Di-Sol®, Primellose® or croscarmellose calcium), crospovidone ( for example, Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (for example, Explotab®) and starch.

In addition or in replacement of the alginic acid, other organic carboxylic acids may be included in the formulation. Organic acids include tannic acid, citric acid, fumaric acid, tartaric acid, lactic acid, malic acid, ascorbic acid, benzoic acid, sorbic acid, and the like. Tannic acid and citric acid are particularly preferred organic carboxylic acids for use in these and other embodiments of the present invention.

The pharmaceutical compositions of the present invention may contain and in preferred embodiments contain a bicarbonate or carbonate, especially an alkali metal bicarbonate or carbonate. Examples of preferred alkali metal carbonates and bicarbonates include sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate. Alkaline earth metal carbonates such as calcium carbonate and magnesium carbonate can also be used.

A pharmaceutical composition for making compressed tablets may also include glidants, lubricants, flavors, colorants and other commonly used excipients.

The pharmaceutical carrier particles that carry microparticles of the drug made in accordance with the present invention have excellent overall flow properties and can be used directly, alone or in combination with carrier particles that do not transport a drug, to make capsule dosage forms . If necessary, diluents such as lactose, mannitol, calcium carbonate, and magnesium carbonate, to name but a few, can be formulated with the pharmaceutical carrier particles that carry microparticles when making capsules.

The liquid oral pharmaceutical compositions of the present invention comprise microparticles or particles of pharmaceutical carrier carrying microparticles and a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin, more preferably water.

The liquid oral pharmaceutical compositions may contain emulsifying agents to uniformly disperse throughout the composition the active ingredient, vehicle for administration of drug or excipient that has low solubility in the liquid carrier. Emulsifying agents that may be useful in the liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetoestaryl alcohol, and cetyl alcohol.

The liquid oral pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouthfeel of the product and / or coat the gastrointestinal tract lining. These agents include acacia, alginic acid bentonite, carbomer, calcium or sodium of carboxymethylcellulose, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, tragacanth starch, and xanthan gum.

The liquid oral pharmaceutical composition may also contain sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar; preservatives and chelating agents such as alcohol, benzoate sodium, butylated hydroxy toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid; and buffers such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate.

The selection of the excipients and the amounts used can be easily determined by the scientist formulator based on experience and on the analysis of normal procedures and reference works in the field.

Solid oral dosage forms formulated and compounded with the micronized microparticles by sublimation of fenofibrate together with a polyethylene glycol or a polyethylene glycol-polypropylene glycol, prepared as described above, provide the improved bioavailability of fenofibrate as demonstrated by both the in vitro dissolution (release) as the pharmacokinetic assay (plasma concentration) in vitro of humans. The results of both in vivo and in vitro assays which are disclosed herein were obtained with tablets containing 145 mg of fenofibrate and having a nominal weight of 792 mg each.

The in vitro release (dissolution) profiles that depend on the time revealed herein were obtained at 37 ° C using a USP Type II dissolution test apparatus operating at 50 rpm and filled with 1000 mL of 0, 5% by weight of sodium lauryl sulfate in water. The concentration of fenofibrate in the test liquid was determined by HPLC.

The pharmacokinetic data disclosed herein were obtained in in vivo human experiments by determining the concentration in the blood plasma of the metabolite, fenofibric acid, as a function of time to obtain a concentration curve (AUC) in accumulated plasma in the form of a known Boltzman. The individual points are reported with reference to real or extrapolated time points selected on the AUC curve.

Therefore, the area under the AUC curve of 48 hours, AUC48 / refers to the accumulated blood concentration up to the time point of 48 hours (the last point measured). The AUC- refers to the area under the AUC curve extrapolated to the infinite time. C max refers to the concentration in the absolute maximum plasma measured in the 48-hour test (ie, the peak on the AUC curve of 48 hours) The average AUC (< AUC >) in the average plasma concentration arithmetic of phenophilic acid measured during the course of the plasma concentration measurement period (48 hours).

The present invention, in certain embodiments thereof, is illustrated by the following non-exhaustive examples. In the following examples, status with food means that the subject has not eaten food within the ten hours preceding the dosing. The state with food means that the subject has ingested food an hour and a half before dosing.

EXPERIMENTAL A. Granulated fenofibrate Menthol (1.333 Kg) was melted in a glass reactor at 50 ° C with stirring. Fenofibrate (133.3 g), poloxamer 407 (Lutrol F127, 76 g) and polyethylene glycol 6000 (76 g) were charged to the reactor. The molten menthol was stirred at 50 ° C until all the components had dissolved. Microcrystalline cellulose (Avicel PH 101, 106.7 g) was added to the melt, which was stirred until a uniform suspension was obtained. The molten menthol was divided into three equal portions and poured into three saucers (stainless steel, 0.133 m2 each) which were cooled to -40 ° C for the solidification of the menthol suspension. The solid material on the saucers was removed and coarsely milled through a 2.5 mm sieve using an Erweka mill. The powder obtained again was divided into three portions and returned to the saucers. Menthol was removed from the material on the saucers by sublimation in a high vacuum saucers at 0.2 mbar and at 36 ° C for 53 hours. The resulting powder was removed from the saucers and milled through a 1.6 mm sieve using an Erweka mill in such a manner that no substantial crushing of the already formed particles is effected. The granulate thus obtained was weighed (346.4 g) for a yield of 88%.

B. Fenofibrate Tablets (145 mg) The granulated fenofibrate from step A was milled through a 0.8 mm sieve using an Erweka mill. The ground granulate (336 g) was added to a polyethylene bag (50 x 70 cm). Crospovidone (108 g), sodium bicarbonate (72 g) and anhydrous citric acid (72 g) were added and the mixture was mixed for 5 minutes. Magnesium stearate (12 g) was added to the bag and the mixture was mixed for another 1/2 minute. The total amount of the mixture thus obtained was 600 grams.

The mixture was compressed into tablets on a Manesty F3 single punch tablet machine using normal concave punches with an oval shape (8.8 mm x 17.6 mm). The design weight of the tablets was 785 rng ± 39.3 mg at a hardness of 5-7 Kp. The tablets obtained had an average weight of 792 mg and a hardness of 6 Kp. Several batches were made and MAZ149B, MAZ149B1 and MAZ149B2 were marked, respectively.

C. In Vitro Release The release (dissolution) of the fenofibrate from the tablets was tested using a USP Type II dissolution tester which was filled with 1000 ml of 0.5% sodium lauryl sulfate (SLS) (w / v) in water 37 ° C and at 50 revolutions per minute (rpm). The amount of fenofibrate in each sample was determined by HPLC as above. The results are given in Tables Cl-C3 for three batches.

Table Cl. Results of the in vitro release of fenofibrate (% brand claim) MAZ149B Table C2. Results of the in vitro release of fenofibrate (% brand claim) MAZ149B1 Recip Time. Recip. Recip. Recip. Recip. Recip. Average% RSD (min) 1 2 3 4 5 6 10 58, 6 55, 8 51, 4 55.2 51, 5 61, 5 55, 7 7.11 15 79, 5 77, 3 73, 6 77, 5 74.4 79.2 76, 9 3, 16 30 90, 7 88, 9 86, 5 88, 5 89, 1 89, 5 88, 9 1, 56 Table C3. Results of the in vitro release of fenofibrate (% brand claim) AZ149B2 D. Pharmacokinetic In Vivo Assay Pharmacokinetic Assay of MAZ149B and TriCor® 145 mg A pharmacokinetic assay of four-way crossover bioequivalence was performed in 12 healthy volunteers using MAZ149B (145 mg, described above) and TriCor® (145 mg) as two of the trial arms. The other two arms were other test formulations prepared according to the present invention. A one week wash was taken between each arm of the trial. Blood samples were drawn at 0, 1, 2, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 8, 9, 10, 12, 16, 24 and 48 hours (19 samples per assay) and analyzed by fenofibric acid by a validated method. The 4-arm trials were carried out in the fasting states and with food.

Results The fasting state data were obtained for volunteers 1-11 for the trial MAZ149B (N = ll) and for volunteers 2- 11 for the reference TriCor® (N-10). The results are shown in table DI. The average values showed the bioavailability of the assay was 97.4% of the reference based on AUC48 (175334 against 180010 h * ng / g) and 97.7% of the reference based on AUC »(213653 against 218628 h * ng / g). The corresponding geometric mean values showed 97.5% based on AUC48 (169481 versus 173880 h * ng / g) and 97.5% based on AUCco (205217 against 210558 h * ng / g). The geometric mean of the ratio of the individual test relationships to the AUC ~ reference was 1.006. The average values for the CmaX showed that the test was 99% of the reference (10570 vs. 10624 ng / g) and that the geometric average was 100.7% (10340 vs. 10270 ng / g). The geometric average of the test relationships to the reference of the individual volunteers was 1,021. The variability of the bioavailability was similar 28.95% against 27.16% for the% CV (variation in the variable) of the values of AUC48 - The average terminal half-life (terminal half-life for elimination) was 20.0 hours for the test product and 19.9 hours for the reference while the average Tmax was 2.5 hours for the test and 2.1 hours for the reference. It can be concluded that the two formulations are bioequivalent in the fasting state.

The state data with food was obtained for volunteers 1-5, 7-10 and 12 (N = 10) for the MAZ149B of the trial and the reference product TriCor®. The results are shown in Table D2. The average values showed the bioavailability of the test was 107.1% of the reference based on the AUC48 (150511 against 140627 h * ng / g) and 112.0% of the reference based on the AUC (185149 against 165310 h * ng / g). The corresponding geometric average values showed 106.8% based on the AUC48 (145402 against 136134 h * ng / g) and 111.2% based on the AUC (174021 VS 156459 h * ng / g). The geometric mean of the ratio of the individual AUC ~ ratios to reference was 1,112. The average values for Cm¾x showed that the test was 79.0% of the reference (7557 against 9567 ng / g) and that the geometric average was 77.5% (7147 versus 9217 ng / g). The geometric mean of the test relationships to the reference of the individual volunteers was 0.775. The variability of bioavailability was very similar 27.16% versus 26.41% CV (variation in value) of the values of AUC48. The average terminal half-life was 17.4 hours for the test product and 16.1 hours for the reference, while the average Tmax was 8.0 hours for the test and 3.6 hours for the reference. The improved bioavailability coupled to a Cmax and the subsequent Tmax indicate an improved product in the food state.

Table DI (Fasting State) RESULTS Fasting state of acid Dose 145 OF Fenofibric test 10536004-MAZ149B against (mg) = TriCor® Rate ref 145 (mg) = Voluntary AUC48 AUCinf tl / 2 Tmá * (h) Cmax Cmaxassay / ( h * ng / g) (h * ng / g) (ng / g) Cmaxref (test) 133053, 0 149267, 0 15.5 3.0 9010, 0 (test) 166526, 0 189578, 0 17,1 2 , 0 12699, 0 1, 04 (test) 142995, 0 193559, 0 25.8 2.0 6357, 0 0, 91 (test) 121367, 0 134750, 0 15, 4 2.0 9360, 0 0, 95 (test) 156850, 0 176988, 0 16, 8 2.0 10489, 0 0, 87 (test) 142581, 0 167086, 0 18, 1 1.5 8397, 0 1, 39 (test) 142733, 0 201134, 0 28, 6 4.5 10952, 0 1, 15 (test) 209259, 0 251532, 0 19.7 1.5 11138, 0.74 (test) 191656, 0 227307, 0 18.3 3.0 11300 , 0.113 (test) 287539, 0 345390, 0 19.2 5.0 14627, 0 1, 09 (test) 234120, 0 313588, 0 25.1 1.5 11944, 0 1, 08 (test) (reference) (reference) 199790, 0 239900, 0 19.2 3, 0 12242, 0 (reference) 150941, 0 206776, 0 25, 8 1.5 6966, 0 (reference) 113223, 0 121099, 0 13, 1 2,0 9894, 0 5 (reference) 166239, 0 193362, 0 17, 3 4.0 12085, 0 6 (reference) 117039, 0 153347, 0 23, 7 2.0 6020.0 7 (reference) 151310, 0 179099, 0 18, 7 1.0 9537, 0 8 (reference) 218602, 0 267224, 0 21.4 1.5 15025, 0 9 (reference) 188187, 0 217502, 0 16, 7 2.5 10026, 0 10 (reference) 257562 , 0 298831, 0 18.4 1.5 13396, 0 11 (reference) 237204, 0 309136, 0 24.1 2.0 11052, 0 12 (reference) AVERAGE (test) 175334, 5 213652, 6 20, 0 2.5 10570, 3 1, 03 AVERAGE (ref.) 180009, 7 218627, 6 19, 9 2.1 10624, 3 Geomn (test) 169481, 3 205216, 6 19, 5 2.3 10339, 7 1, 02 Geomn (test) 173879, 9 210558, 3 19, 5 2.0 10270, 3 Stddev (test) 50758 66323 4.48 1.21 2241, 80 0.1 Stdde (ref) 48896 61060 3, 88 0, 88 2761, 61 % CV (test) 28, 95% 31, 04% 0.22 0, 48 0.21% CV (reference) 27, 16% 27, 93% 0.20 0.42 0.26 1_/? Table D2 (Status with food) RESULTS State with Dose food 145 Fenofibric acid assay 10536004-MAZ149B against (mg) = TriCor® Ref dose 145 (mg) = Voluntary AUC48 AUCinf tl / 2 Tmax (h) Cmax maxassay / AUCinfessay / (h * ng / g) (h * ng / g) (ng / g) máKref AUCinfref 1 (test) 151598, 0 201715, 0 23, 6 5, 5 6517, 0 1, 01 1, 15 2 (test) 119863, 0 126328, 0 11, 8 2.0 10583, 0 0, 87 1, 10 3 (test) 91601.0 97182, 0 10.5 9.0 5224, 0.76 1, 05 4 (test) 159339, 0 202949, 0 20.2 5.0 6725, 0. 0.86 1.14 5 (test) 183511, 0 217445, 0 18.6 3, 5 14538, 0 1.06 1, 10 6 (test) 7 (test) 106779, 0 115154, 0 11.9 4.5 5250, 0 0, 62 1, 06 8 (test) 195150, 0 251495, 0 19, 9 12, 0 7083, 0 0, 65 0, 95 9 (test) 119423, 0 129598, 0 12, 8 4.5 6285, 0 0, 60 1.11 10 (test) 217512.0 308070, 0 24.1 10, 0 8236, 0 0, 66 1, 32 11 (test) 12 (test) 160332, 0 201554, 0 20, 6 24.0 5126, 0 0, 81 1, 18 1 (reference) 144704.0 175441, 0 17.4 5, 5 6441, 0 2 (reference) 110211, 0 115275, 0 11.4 2.0 12129, 0 3 (reference) 87114, 0 92310, 0 12, 0 2.0 6898, 0 4 (reference) 147743, 0 178775, 0 18, 7 3.0 7775, 0 O < -? O < -? 5 (reference) 170745, 0 197209, 0 16.8 4.5 13670, 0 6 (reference) 7 (reference) 103810, 0 108394, 0 10.7 3, 0 8532, 0 8 (reference) 200926, 0 264258 , 0 22, 8 3, 0 10912, 0 9 (reference) 111382, 0 116530, 0 11.2 2.0 10440, 0 10 182589, 0 233712, 0 23, 1 2.0 12522, 0 (reference) 11 (reference) 12 147041, 0 171197, 0 16, 9 9.0 6350, 0 (reference) AVERAGE (test 150510, 0 185149, 0 17,4 8,0 7556, 7 0, 790 1,116 o) AVERAGE (ref. ) 140626, 0 165310, 1 16, 1 3, 6 9566, 0 Geomn (test) 145402, 2 174020, 6 16.7 6, 3 7146, 7 0, 775 1,112 Geomn (test) 136133, 6 156458, 7 15, 5 3.2 9217, 4 Stddev (test) 40872 67163 5, 16 6.44 2956, 04 0, 16 0, 09 Stddev (ref) 37136 57016 4, 66 2.23 2712, 70 % CV (trial) 27, 16% 36, 28% 0, 30 0, 80 0, 39% CV 26.41% 34, 49% 0, 29 0, 62 0, 28 (reference)

Claims (36)

1. A pharmaceutical composition comprising non-mechanically micronized microparticles of fenofibrate, polyethylene glycol, and polyethylene glycol-polypropylene glycol.

2. The pharmaceutical composition according to the claim 1, wherein the micronized non-mechanical microparticles of fenofibrate are manufactured by micronization by sublimation.

3. The pharmaceutical composition according to the claim 2, wherein the non-mechanically micronized microparticles are deposited on a plurality of pharmaceutical carrier particles.

4. The pharmaceutical composition according to the claim 3, where menthol is the sublimable carrier in the micronization step by sublimation.

5. The pharmaceutical composition according to claim 1, wherein the polyethylene glycol is polyethylene glycol 6000.

6. The pharmaceutical composition according to claim 1, wherein the polyethylene glycol-polypropylene glycol is poloxamer 407.

7. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is in the form of a solid oral dosage form comprising from 15% to 25% by weight of fenofibrate, from 7% to 23% of poloxamer 407, and from 7% to 13% polyethylene glycol 6000.

8. The solid oral dosage form according to claim 7, which also comprises a pharmaceutical disintegrant which is selected from the group consisting of crospovidone, croscarmellose sodium, the bicarbonate salts, the organic carboxylic acids, and combinations of any of the foregoing.

9. The pharmaceutical composition according to claim 8, wherein the organic carboxylic acid is citric acid or tartaric acid.

10. A solid oral dosage form comprising a pharmaceutical composition comprising 15% to 25% by weight of non-mechanically micronized microparticles of fenofibrate, from 7% to 13% by weight of poloxamer 407, from 7% to 13% of polyethylene glycol 6000, 15% by weight of microcrystalline cellulose, 18% by weight of crospovidone, 12% by weight of sodium bicarbonate, and 12% by weight of citric acid or tartaric acid.

11. The solid oral dosage form according to claim 10 comprising 12% by weight of citric acid.

12. The solid oral dosage form according to claim 10, which has a fenofibrate release profile in vitro that depends on time such that at least 51% by weight of the fenofibrate is released in 10 minutes, which less 73% by weight of fenofibrate is released in 15 minutes and at least 85% by weight of fenofibrate is released in 30 minutes.

13. The solid oral dosage form according to claim 10, which has an in vitro release profile that depends on time such that 51% to 81% by weight of the fenofibrate is released in 10 minutes, from 73% to 93%. % by weight of fenofibrate is released in 15 minutes, and that 85% by weight until the entire fenofibrate is released in 30 minutes.

14. A solid oral dosage form comprising a pharmaceutical composition comprising 145 mg of micronized fenofibrate by sublimation wherein in in vivo pharmacokinetic studies of humans in which the dosage form is administered in the fasted state, the area under the curve of AUC 48 hours (AUC48) is 121367 h * ng / g at 287539 h * ng / g; the area under the curve of AUC extrapolated to infinite time (AUC) is 134750 h * ng / g at 345390 h * ng / g, and the concentration in the maximum plasma (Cmax) is from 6357 to 14627 ng / g.

15. The solid oral dosage form according to claim 14, wherein, in in vivo pharmacokinetic studies of humans in which the dosage form is administered in the fasted state, the average AUC4e is 175335 h * ng / g , the average AUC8 is 213652 h * ng / g, and the average Cm ^ x is 10570 ng / g.

16. The solid oral dosage form according to claim 14, wherein the solid oral dosage form is a compressed tablet.

17. A solid oral dosage form comprising a pharmaceutical composition comprising 145 mg of micronized fenofibrate by sublimation where in pharmacokinetic studies In vivo of humans in which the dosage form is administered in the food state, the area under the AUC curve of 48 hours (AUC48) is from 91601 h * ng / g to 217512 h * ng / g and the area below of the curve extrapolated to infinite time (AUC8) is 97182 h * ng / ga 308070 h * ng / g.

18. The solid oral dosage form according to claim 17, wherein the average AUC4s is 150511 h * ng / g and the average AUC ~ is 185149 h * ng / g.

19. The solid oral dosage form according to claim 18, wherein the solid oral dosage form is a compressed tablet.

20. A pharmaceutical composition comprising a plurality of pharmaceutical carrier particles having deposited thereon a combination of fenofibrate, a polyethylene glycol, and a polyethylene glycol-polypropylene glycol, wherein the combination is deposited by sublimation of a sublimable carrier from a solid solution comprising fenofibrate, polyethylene glycol, polyethylene glycol-polypropylene glycol and the sublimable carrier.

21. The pharmaceutical composition according to claim 20, wherein the sublimable carrier is menthol.

22. The pharmaceutical composition according to claim 20, wherein the polyethylene glycol is polyethylene glycol 6000.

23. The pharmaceutical composition according to claim 20, wherein the polyethylene glycol-polypropylene glycol is poloxamer 407.

2 . The pharmaceutical composition according to claim 20, wherein the pharmaceutical composition is in the form of a solid oral dosage form comprising from 15% to 25% by weight of fenofibrate, from 7% to 13% of poloxamer 407, and from 7% to 13% polyethylene glycol 6000.

25. The solid oral dosage form according to claim 24, which also comprises a disintegrator which is selected from the group consisting of crospovidone, croscarmellose sodium, the bicarbonate salts, the organic carboxylic acids, and combinations of any of the foregoing.

26. The pharmaceutical composition according to claim 25, wherein the organic carboxylic acid is citric acid or tartaric acid.

27. A solid oral dosage form comprising a pharmaceutical composition comprising from 15% to 25% by weight of fenofibrate, from 7% to 13% by weight of poloxamer 407, from 7% to 13% of polyethylene glycol 6000, 15% by weight weight of microcrystalline cellulose, 18% by weight of crospovidone, 12% by weight of sodium bicarbonate, and 12% by weight of citric acid or tartaric acid, wherein at least fenofibrate, poloxamer 407, and polyethylene glycol 6000 are deposited on the microcrystalline cellulose by sublimation of a sublimable carrier from a solid solution of at least fenofibrate, poloxamer 407, and polyethylene glycol 6000 with the sublimable carrier.

28. The solid oral dosage form according to claim 27, which comprises 12% by weight of the citric acid.

29. The solid oral dosage form according to claim 27, which has an in vitro fenofibrate release profile that depends on time so that by at least 51% by weight of the fenofibrate is released in 10 minutes, at least 73% by weight of the fenofibrate is released in 15 minutes and at least 85% by weight of the fenofibrate is released in 30 minutes.

30. The solid oral dosage form according to claim 27, which has a time-dependent in vitro release profile such that 51% to 81% by weight of fenofibrate is released in 10 minutes, from 73% to 93%. % by weight of fenofibrate is released in 15 minutes and from 85% by weight to the entire fenofibrate is released in 30 minutes.

31. a solid oral dosage form comprising a pharmaceutical composition comprising 145 mg of fenofibrate which has been deposited on a plurality of microcrystalline cellulose particles by sublimation of a sublimable carrier from a solid solution comprising fenofibrate and the sublimable carrier, wherein In in vivo pharmacokinetic studies of humans in which the dosage form is administered in the fasted state, the area under the AUC curve of 48 hours (AUC48) is 121367 h * ng / g at 287539 h * ng / g area under the curve of AUC extrapolated to infinite time (AUC-) at 134750 h * ng / ga 345390 h * ng / g; and the concentration in the maximum plasma (Cmax) is from 6357 ng / g to 14627 ng / g. 0 i *

32. The solid oral dosage form according to claim 31, wherein, in in vivo pharmacokinetic studies of humans in which the dosage form is administered in the fasted state, the average AUC 8 is 175335 h * ng / g, the average 5 AUC is 213652 h * ng / g and the average Cmax is 10570 ng / g.

33. The solid oral dosage form according to claim 31, wherein the solid oral dosage form 10 is a compressed tablet.

3 . A solid oral dosage form comprising a pharmaceutical composition comprising 145 mg of fenofibrate that has been deposited on a plurality of cellulose particles 15 microcrystalline by sublimation of a sublimable carrier from a solid solution comprising fenofibrate and the sublimable carrier; wherein in in vivo pharmacokinetic studies of humans in which the dosage form is administered in the state with food, the area under the AUC curve of 48 20 hours (AUC48) is from 91601 h * ng / g to 217512 h * ng / g; and the area under the curve of AUC extrapolated to infinite time (AUC ~) is 97182 h * ng / g at 308070 h * ng / g.

35. The solid oral dosage form according to claim 34, wherein the average AUC48 is 150511 h * ng / g and the average AUC »is 185149 h * ng / g.

36. The solid oral dosage form according to claim 35, wherein the solid oral dosage form is a compressed tablet.