KR20080087845A - Pharmaceutical Formulations of Fenofibrate with 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

PHARMACEUTICAL FORMULATIONS OF FENOFIBRATE HAVING IMPROVED BIOAVAILABILITY}

The present invention provides a pharmaceutical composition comprising fenofibrate, polyethylene glycol, and polyethylene-polypropylene glycol, wherein the sublimation of a sublimable carrier from a solid solution containing a sublimation carrier such as fenofibrate, polyethylene glycol, polyethylene-polypropylene glycol, and menthol It relates to a pharmaceutical composition prepared by.

Fenofibrate, (2- [4- (4-chlorobenzoyl) phenoxy] -2-methyl-propanoic acid, 1-methylethyl ester) is one of the fibrate classes of drugs. It is available in both capsules and tablets. Fenofibrate is clearly a prodrug. Reportedly the active moiety is the metabolite fenofibric acid, which is reported to be produced in vivo by the action of an estase. When fenofibrate is administered, it is clear that complete fenofibrate is not found in plasma (Physician's Desk Reference, 58 ^th ed. 2004 pages 522-525 (PDR)).

Fenofibrate has very low solubility in water. That is, it is a drug that is almost insoluble in water. Despite its low solubility in water, it is reported to be absorbed to a therapeutically effective level when administered in the "fed state" but less absorbed when administered in the "fasted state". The actual "bioavailability" of the metabolite fenofibric acid is not clear since many of it is known to be metabolized to glucuronide in both the presystemic and first pass positions.

Determining the absolute bioavailability of fenofibrate may be impossible because fenofibrate is insoluble in media suitable for intravenous infusion. After oral administration to healthy volunteers, approximately 60% of the radiolabeled fenofibrate single dose appeared in urine, predominantly as fenofibric acid and its glucuronide conjugate, 25% excreted in feces ( PDR). It is known that the absorption of fenofibrate is increased when administered with food. When tablets were taken with food, the absorption from orally administered tablets increased approximately 35% (PDR, Martindale 33 ^rd ed. Page 889).

Many efforts have been made to improve the formulation of fenofibrate, particularly with regard to the bioavailability of fenofibrate. US Pat. Nos. 4,895,726 and 5,880,148 disclose co-finening of fenofibrate with a surfactant. US Pat. Nos. 6,074,670, 6,277,405 disclose micronized fenofibrate coated on a water soluble carrier with optional surfactant. US Pat. No. 6,814,977 discloses fenofibrate dissolved in medium chain glycerol esters of fatty acids. US Pat. No. 6,719,999 discloses fenofibrate dissolved in glycerin, propylene glycol or dimethylisosorbide, and US Pat. No. 5,827,536 discloses fenofibrate dissolved in diethylene glycol monoethyl ether.

Some patents disclose certain formulations of fenofibrate with specific polymer additives or surfactant additives, while others disclose emulsions and suspensions of fenofibrate. For example, US Patent Application Publication No. 20040087656 discloses fenofibrate having a particle size of less than 2000 nm, which is claimed to have improved bioavailability. US Patent Application Publication No. 20030224059 discloses microparticles of active pharmaceutical ingredients, drug delivery vehicles comprising the same, and methods of making the same.

Micronization of fenofibrate and the combination of surfactant and micronized fenofibrate raise the bioavailability of fenofibrate to some extent, while maintaining the same bioavailability in the fed state while maintaining the government-approved amount of the administered drug at 100 per dose. From mg to 67 mg per dose and then to 54 mg per dose. Nanoparticle formulations of the drug can further reduce the dosage up to 48 mg per dose with bioavailability of the “fasted state” reported to be similar to the fed state. There is still much room for improvement since the actual bioavailability of fenofibrate is still considered to be relatively low.

Summary of the Invention

In one aspect, the invention provides non-mechanically micronized fenofibrate microparticles, in particular sublimated micronized fenofibrate microparticles using menthol as a sublimable carrier; Polyethylene glycol, in particular polyethylene glycol 6000; And polyethylene-polypropylene glycol, in particular poloxamer 407. Pharmaceutical compositions include crospovidone, carboxymethyl cellulose, in particular crosslinked carboxymethylcellulose sodium (crosamelose sodium), bicarbonate or carbonate salts; Especially alkali metal bicarbonates or carbonates such as sodium bicarbonate; Organic carboxylic acids, in particular citric acid, tannic acid, ascorbic acid, benzoic acid, citric acid. Fumaric acid, lactic acid, malic acid, sorbic acid, and tartaric acid; And it may further comprise a pharmaceutical disintegrant selected from the group consisting of.

In another aspect, the invention provides about 15% to about 25% by weight of non-mechanically micronized fenofibrate microparticles, in particular sublimated micronized fenofibrate; From about 7 wt% to about 13 wt% poloxamer 407; About 7% to about 13% polyethylene glycol 6000; About 15% by weight microcrystalline cellulose; About 18% crospovidone; About 12% sodium bicarbonate; And a pharmaceutical composition comprising about 12% citric acid or tartaric acid.

In another aspect, the invention provides about 15% to about 25% by weight of non-mechanically micronized fenofibrate microparticles, in particular sublimated micronized fenofibrate; From about 7 wt% to about 13 wt% poloxamer 407; About 7% to about 13% polyethylene glycol 6000; About 15% by weight microcrystalline cellulose; About 18% crospovidone; About 12% sodium bicarbonate; And a pharmaceutical composition comprising about 12% citric acid or tartaric acid, wherein the formulation releases at least about 51% by weight, in particular from about 51% to about 81% of fenofibrate within about 10 minutes, At least about 73 weight percent, in particular from about 73 weight percent to about 93 weight percent of fenofibrate is released in about 15 minutes, and at least about 85 weight percent, in particular from about 85 weight percent to essentially all fenofibrate is released in about 30 minutes It relates to a solid oral dosage form having a time dependent in vitro fenofibrate release profile.

In another aspect, the invention provides a solid oral formulation, in particular a compressed tablet, comprising a pharmaceutical composition comprising about 145 mg of sublimated micronized fenofibrate, in a human in vivo pharmacokinetic study in which the formulation is administered on an empty stomach, for 48 hours. The area under the AUC curve (AUC ₄₈ ) is between about 121367 h * ng / g and about 287539 h * ng / g; The area under the AUC curve extrapolated to infinite time (AUC _∞ ) is between about 134750 h * ng / g and about 345390 h * ng / g; And a solid oral formulation, in particular compressed tablets, having a maximum plasma concentration (C _max ) of about 6357 ng / g to about 14627 ng / g. In general, such solid oral formulations will exhibit an average AUC ₄₈ of about 175335 h * ng / g, an average AUC _∞ of about 213652 h * ng / g, and an average C _max of about 10570 ng / g.

In another aspect, the invention provides a solid oral formulation, in particular a compressed tablet, comprising a pharmaceutical composition having about 145 mg of sublimated micronized fenofibrate, in a human in vivo pharmacokinetic study in which the formulation is administered in a fed state, a 48 hour AUC The area under the curve (AUC ₄₈ ) is from about 91601 h * ng / g to about 217512 h * ng / g; The area under the AUC curve extrapolated to infinite time (AUC _∞ ) is about 97182 h * ng / g to about 308070 h * ng / g, and also the average AUC ₄₈ is about 150511 h * ng / g and the average AUC _∞ is It relates to a solid oral formulation, in particular compressed tablets, of about 185149 h * ng / g. The formulation may comprise a disintegrant.

In another aspect, the present invention provides fenofibrate; Especially about 15% to about 25% by weight of fenofibrate; From about 7 wt% to about 13 wt% polyethylene glycol, in particular polyethylene glycol 6000; And from about 7% to about 13% by weight of a polyethylene-polypropylene glycol, in particular a combination of poloxamer 407, having a plurality of pharmaceutical carrier particles, especially microcrystalline cellulose particles, deposited thereon. A pharmaceutical composition is deposited by sublimation of a sublimable carrier, in particular menthol, from a solid solution comprising fenofibrate, polyethylene glycol, polyethylene-polypropylene glycol, and a sublimable carrier. The compositions also include crospovidone, crosslinked carboxymethylcellulose salts (particularly crosslinked carboxymethylcellulose sodium), bicarbonate or carbonate salts; Especially alkali metal bicarbonates or carbonates such as sodium bicarbonate; Organic carboxylic acids, in particular citric acid, tannic acid, ascorbic acid, benzoic acid, citric acid. Fumaric acid, lactic acid, malic acid, sorbic acid, and tartaric acid; And it may include a pharmaceutical disintegrant selected from the group consisting of.

In another aspect, the invention provides a solid oral formulation comprising a pharmaceutical composition having about 145 mg of fenofibrate deposited on a plurality of microcrystalline cellulose particles by sublimation of a sublimable carrier from a solid solution comprising fenofibrate and a sublimable carrier. In human in vivo pharmacokinetic studies in which the formulation is administered in a fasted state, the area under the 48 hour AUC curve (AUC ₄₈ ) is from about 121367 h * ng / g to about 287539 h * ng / g; The area under the AUC curve extrapolated to infinite time (AUC _∞ ) is between about 134750 h * ng / g and about 345390 h * ng / g; And a maximum oral plasma concentration (C _max ) of about 6357 ng / g to about 14627 ng / g. In certain of the foregoing aspects, such solid oral formulations exhibit an average AUC ₄₈ of about 175335 h * ng / g, an average AUC _∞ of about 213652 h * ng / g, and an average C _max of about 10570 ng / g.

Detailed description of the invention

In one embodiment, the present invention provides a pharmaceutical composition comprising non-mechanically micronized fenofibrate microparticles, polyethylene glycol, and polyethylene-polypropylene glycol.

Non-mechanically micronized microparticles have an average dimension of about 0.1 μm to about 10 μm and are produced by non-mechanical grinding techniques. Non-mechanical grinding techniques are techniques other than milling (ball, impact, high energy), spray drying, and high pressure homogenization. For the purposes of the present application, lyophilization techniques are considered to be mechanical micronization techniques, and therefore, microparticles produced by lyophilization are excluded from non-mechanical micronization microparticles. Particle size measurements are well known to those skilled in the art and can be performed, for example, by well known laser light scattering techniques.

The non-mechanically micronized fenofibrate microparticles of the invention can be obtained, for example, by sublimation micronization techniques. The microparticles thus obtained are called "sublimation micronization" microparticles, and the material composed of these microparticles is called "sublimation micronization". Sublimation micronization techniques are described in published US patent application US 2003/0224059 (Lerner et al.), Which is hereby incorporated by reference in its entirety.

The fenofibrate microparticles of the present invention are obtained through sublimation micronization by removing the sublimable carrier from the solid solution of fenofibrate in the sublimable carrier. Fenofibrate may be present as a separate molecule with a sublimable carrier in solid solution, or as an aggregate of hundreds, thousands, or more molecules. It is required that the drug be dispersed on a small enough scale so that a sufficiently small, separate microparticle can eventually be obtained. Preferably, fenofibrate in solid solution is dissolved in a sublimable carrier.

Sublimable carriers have a measurable vapor pressure below their melting point. Preferred sublimable carriers have a vapor pressure of at least about 10 Pascals, and more preferably at least about 50 Pascals, at temperatures about 10 ° C. or more below their standard melting point. Preferably, the sublimable carrier has a melting point of about −10 ° C. to about 200 ° C., more preferably about 20 ° C. to about 60 ° C., and most preferably about 40 ° C. to about 50 ° C. . Preferably, the sublimable carrier is a substance classified as being generally safe (ie, GRAS) by the US Food and Drug Administration. Examples of suitable sublimable carriers include menthol, thymol, camphor, t-butanol, trichloro-t-butanol, imidazole, coumarin, acetic acid (glacial acetic acid), dimethylsulfone, urea, vanillin, camphor, salicyamide, and 2- Aminopyridine. Menthol is a particularly preferred sublimable carrier.

The microparticles of the present invention are formed by removing a sublimable carrier from a solid solution prepared as described above at a temperature below the melting point of the solid solution. In order to preserve the solid solution during the process of removing the sublimable carrier, the solid solution must be maintained at a temperature below its melting point. The sublimable carrier may be removed from the solid solution, for example by treating a solid solution deposited on the usable pharmaceutical carrier particles as discussed later in a fluid bed dryer, in an air stream, preferably heated air. .

The pharmaceutical composition of the present invention further comprises polyalkylene glycol. Preferably the pharmaceutical composition of the present invention comprises at least one polyethylene glycol (PEG) and at least one polyethylene-polypropylene glycol.

Polyethylene glycols usable in the practice of the present invention have the general formula-(-CH ₂ -CH ₂ -O-) _x- , for example Polyethylene It may be specified by the arithmetic mean value X (<X _N >) or equivalent molecular weight as described in Glycols , 23 National Formulary, 3052 (United States Pharmacopeial Convention, 2005). Polyethylene glycol 6000 is a preferred polyethylene glycol for use in the practice of the present invention.

Polyethylene-polypropylene glycols usable in the practice of the present invention have the general structure-(O-CH ₂ CH _2- ) _a -O-(-CH (CH ₃ ) CH _2- ) _b -(-O-CH ₂ CH ₂ -) has _a -OH and is commonly referred to as "poloxamer". Preferred poloxamers for use in the practice of the present invention are described in US National Formulary. Poloxamers , 23 National Formulary, 3051 (United States Pharmacopeial Convention, 2005). Polyethylene-polypropylene glycol commonly named "poloxamer 407" is a particularly preferred polyethylene-polypropylene glycol for use in the practice of the present invention.

The pharmaceutical composition of the present invention may be deposited on a plurality of pharmaceutical carrier particles, and in a preferred embodiment the pharmaceutical composition is deposited on a plurality of pharmaceutical carrier particles. Pharmaceutical carrier particles useful as a support, substrate, or carrier for the pharmaceutical formulations of the present invention consist of edible materials and are well known in the art. Examples of useful pharmaceutical carrier particles are particles generally of about 0.1 mm to about 2 mm in diameter, for example particles that may be non-pariel pellets made of starch, microcrystalline cellulose particles, lactose particles, or Especially sugar particles. Suitable sugar particles (eg pellets, eg non-pariel 103, Nu-core, Nu-pariel) range in size from 35 x 40 mesh to 18 x 14 mesh. Commercially available. Preferred pharmaceutical carrier particles consist of a water-insoluble material, for example microcrystalline cellulose. Carrier particles (Avicel®) consisting of microcrystalline cellulose are particularly preferred pharmaceutical carrier particles. One skilled in the art knows other pellets or spheres useful as pharmaceutical carrier particles.

The pharmaceutical composition according to the invention can be prepared by mixing fenofibrate, polyethylene glycol, polyethylene-polypropylene glycol, and a sublimable carrier. The components may be mixed purely or may be mixed with a suitable solvent in embodiments where the composition is deposited onto a plurality of pharmaceutical carrier particles. Suitable solvents dissolve fenofibrate, polyethylene glycol, polyethylene-polypropylene glycol, and sublimable carriers, but do not dissolve pharmaceutical carrier particles, are also chemically inert with any of the ingredients, and conveniently with the aid of a vacuum optionally used. Easily removed at temperatures, especially below 100 ° C. Ethanol is an example of a suitable solvent.

The combination of components is combined and warmed to form a homogeneous mixture, preferably a solution, and cooled to obtain a solid solution. Fenofibrate may be present as a separate molecule with a sublimable carrier in solid solution, or as an aggregate of hundreds, thousands, or more molecules. It is required that the drug be dispersed on a small enough scale so that a sufficiently small, separate microparticle can eventually be obtained.

Preferably, the drug in solid solution is dissolved in a sublimable carrier. In embodiments in which sublimation micronized microparticles are deposited on a plurality of pharmaceutical carrier particles, the warm component solution in the sublimable carrier is combined with the pharmaceutical carrier particles, for example by mixing, and the combination is cooled to form pharmaceutical carrier particles. A solid solution is formed on the top. Alternatively, the pharmaceutical carrier particles are mixed with a solution of a sublimable carrier, fenofibrate, polyethylene glycol, and polyethylene-polypropylene glycol in a suitable solvent (eg ethanol). The solvent is optionally removed with the aid of heat and vacuum used to obtain pharmaceutical carrier particles having a solid solution of fenofibrate, polyethylene glycol, and polyethylene-polypropylene glycol in the sublimable carrier (eg menthol) deposited thereon. Lose.

After formation of the solid solution, the pharmaceutical formulation of the invention is formed by removing the sublimable carrier from the solid solution prepared as described above, whether or not deposited on the pharmaceutical carrier particles, at a temperature below the melting point of the solid solution. In order to preserve the solid solution during the process of removing the sublimable carrier, the solid solution must be maintained at a temperature below its melting point. The sublimable carrier may be removed from the solid solution, for example by treating a solid solution deposited on the usable pharmaceutical carrier particles, in a fluid bed dryer, in an air stream, preferably heated air.

In a preferred embodiment, the removal of the sublimable carrier forms non-mechanically micronized fenofibrate microparticles, wherein the microparticles may further contain at least some polyethylene glycol and polyethylene-polypropylene glycol. In addition, at least some of the fenofibrate may be in a dissolved state or may be intimately associate with one or both of polyethylene glycol and polyethylene-polypropylene glycol that are not essential for non-mechanically micronized microparticles. .

Applicant's invention is not limited by specific process theory. However, Applicants believe that after removal of the sublimable carrier, at least some of the fenofibrate may be dissolved in or intimately associated with the polyalkylene glycol. The expression "intimately associated" excludes simple physical mixing, such as can be achieved by dry blending, dry granulation, or wet granulation, for example, in the presence of a liquid that does not at least partially dissolve the components. .

The pharmaceutical compositions of the invention, especially those deposited on a plurality of pharmaceutical carrier particles, are well suited for the preparation of liquid and especially solid oral formulations such as compressed tablets and filled capsules. In another embodiment, the present invention provides oral formulations, particularly solid oral formulations, preferably compressed tablets, comprising the pharmaceutical composition of the present invention.

Compressed tablets are formulated from pharmaceutical compositions containing microparticles of pharmacologically active substances or drugs, or pharmaceutical carrier particles which make such microparticles, and pharmacologically inert (pharmaceutically acceptable) additives or excipients. It is formulated using.

In making tablets, it is usually desirable to include one or more suitable pharmaceutical excipients in the pharmaceutical composition. The pharmaceutical compositions of the present invention may contain one or more diluents which are added to make the tablets larger to make them easier to handle by patients and caregivers. Common diluents include microcrystalline cellulose (e.g., Avicel ^® ), microwave cellulose, lactose, starch, pregelitinized starch, calcium carbonate, calcium sulfate, sugars, dextrates, dextrins, dextrose, calcium phosphate Dihydrate, calcium triphosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate (eg Eudragit ^® ), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

Binders may also be included in the tablet formulation to help maintain the tablet after compression. Some conventional binders include acacia, alginic acid, carbomer (eg carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oils, hydroxyethyl cellulose, hydroxypropyl cellulose (eg , Klucel ^® ), hydroxypropyl methyl cellulose (eg Methocel ^® ), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylate, povidone (eg Kollidon ^® , Plasdone ^® ), Gelatinized starch, sodium alginate and starch.

The tablet may further comprise a disintegrant which promotes disintegration of the tablet in the stomach of the patient. Disintegrants include alginic acid, carboxymethyl cellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, cross-linked carboxymethylcellulose sodium or calcium (crocamellos sodium (e.g. Ac-Di-Sol ^® , Primellose ^® ) or croscarmellose Calcium), crospovidone (e.g., Kollidon ^® , Polyplasdone ^® ), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polyacrylic potassium, powdered cellulose, gelatinized starch, sodium alginate, sodium starch glycolate (Eg, Explotab ^® ) and starch.

Other organic carboxylic acids may be included in the formulation together with or in place of alginic acid. 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 the two embodiments of the present invention and in other embodiments.

The pharmaceutical compositions of the present invention may contain bicarbonates or carbonates, in particular alkali metal bicarbonates or carbonates, which in preferred embodiments contain them. 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 may also be used.

Pharmaceutical compositions for the manufacture of compressed tablets may further comprise glidants, glidants, flavorings, colorants and other commonly used excipients.

Pharmaceutical carrier particles that form microparticles of drugs prepared according to the present invention have good bulk flow properties and can be used directly to make capsule formulations, either alone or in combination with drug-free carrier particles. If necessary, in the preparation of capsules, diluents such as lactose, mannitol, calcium carbonate and magnesium carbonate mentioned several times above may be formulated with pharmaceutical carrier particles which form microparticles.

The liquid oral pharmaceutical compositions of the present invention comprise microparticles or pharmaceutical carrier particles which form microparticles and liquid carriers such as water, vegetable oils, alcohols, polyethylene glycols, propylene glycol or glycerin, most preferably water do.

Liquid oral pharmaceutical compositions may contain excipients, drug delivery vehicles, or emulsifiers to homogeneously disperse the active ingredient throughout the composition in a liquid carrier. Emulsifying agents that can be used in the liquid compositions of the invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanta, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl Contains alcohol.

The liquid oral pharmaceutical compositions of the present invention may also contain viscosity enhancers to improve the mouth feel of the product and / or the coating of the gastrointestinal wall. Such materials include acacia, alginate bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, malto Dextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanta and xanthan gum.

Liquid oral pharmaceutical compositions also include sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar; Preservatives and chelating agents such as alcohols, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisol and ethylenediamine tetraacetic acid; And buffers such as guconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate.

Solid oral formulations formulated and mixed with sublimated micronized fenofibrate microparticles, prepared as described above, together with sublimated micronized fenofibrate microparticles, can be used for both in vitro dissolution (release) and human in vivo pharmacokinetic (plasma concentration) testing. Provides improved bioavailability of fenofibrate as evidenced by both branches. Results in both the in vivo and in vitro tests disclosed herein were obtained with tablets containing about 145 mg of fenofibrate and each having a unit weight of 792 mg.

The time dependent in vitro release (dissolution) profile disclosed herein was obtained at 37 ° C. using a USP Type-II dissolution tester operated at 50 rpm and filled with 0.5 wt% sodium lauryl sulfate in 1000 mL of water. The concentration of fenofibrate in the test liquid was measured by HPLC.

The pharmacokinetic data disclosed herein were obtained in human in vivo experiments by measuring the blood plasma concentrations of the metabolite, fenofibric acid, as a function of time, to obtain a well-known Boltzmann form cumulative plasma concentration (AUC) curve. Individual points are recorded as references to allow selection of actual or extrapolated time points in the AUC curve.

Thus, the area under the 48 hour AUC curve, AUC ₄₈ represents the cumulative blood concentration up to the 48 hour time point (measured end point). AUC _∞ represents the area under the AUC curve extrapolated to infinite time. C _max represents the maximum absolute plasma concentration measured in the 48 hour test (ie, the maximum point on the 48 hour AUC curve). The mean AUC (<AUC>) is the arithmetic mean plasma concentration of fenofibric acid measured over the course of the plasma concentration measurement period (about 48 hours).

In certain embodiments the invention is illustrated by the following non-limiting examples. In the following examples, fasted state means that the patient has not consumed food within 10 hours prior to administration. Eating means that the patient has eaten about 30 minutes before administration.

A. fenofibrate granules

Menthol (1.333 Kg) was melted in a glass reactor with stirring at 50 ° C. Fenofibrate (133.3 gm), Poloxamer 407 (Lutrol F127, 76 gm), and polyethylene glycol 6000 (76 gm) were placed in the reactor. The menthol melt was stirred at 50 ° C. until all components had dissolved. Microcrystalline cellulose (Avicel PH 101, 106.7 gm) was added to the melt and stirred until a homogeneous suspension was obtained.

The menthol melt was divided equally into three portions, poured into three trays (stainless steel, 0.133 m ² each) and cooled to −40 ° C. for rapid solidification of the menthol suspension. The solid material on the tray was removed and coarsely milled through a 2.5 mm screen using an Erweka mill. The obtained powder was divided into three parts again and returned to the tray. Menthol was removed from the material on the tray by sublimation in a high vacuum tray dryer at 0.2 mbar and 36 ° C. for about 53 hours. The resulting powder was removed from the tray and milled through a 1.6 mm screen using an Erweka mill so as not to effect substantial grinding of the already formed particles. The granules thus obtained were weighed (346.4 gm) at a yield of 88%.

B. fenofibrate tablets (145 mg)

The fenofibrate granules from step A were milled through a 0.8 mm screen using an Erweka mill. Milled granules (336 gm) were added to a polyethylene bag (50 × 70 cm). Crospovidone (108 gm), sodium bicarbonate (72 gm) and citric anhydride (72 gm) were added and the blend was mixed for 5 minutes. Magnesium stearate (12 gm) was added to the bag and the blend was further mixed for 30 seconds. The total amount of blend thus obtained was 600 grams.

The blend was compressed into tablets on a Manesty F3 single punch tablet press using an elliptical (8.8 mm × 17.6 mm) standard concave punch. Tablet design weight was 785 mg ± 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 prepared and labeled with MAZ149B, MAZ149Bl and MAZ149B2, respectively.

C. In Vitro Release

Release (dissolution) of fenofibrate from the tablets was performed at 37 ° C. and 50 rpm using a USP Type II dissolution tester filled with 0.5% sodium lauryl sulfate (SLS) (w / v) in 1000 mL of water. Tested. The amount of fenofibrate in each sample was measured by HPLC as above. The results in the three batches are shown in Tables C1 to C3.

Table C1. In vitro release of fenofibrate (% label claim)

Table C2. In vitro release results of fenofibrate (% label claim) MAZ149Bl

Table C3. In vitro release of fenofibrate (% label claim) MAZ149B2

D. In Vivo Pharmacokinetic Attempts

Pharmacokinetic Test of MAZ149B and TriCor® 145 mg

Four mode cross-biological equivalent pharmacokinetic trials were performed in 12 healthy volunteers using MAZ149B (145 mg, above) and Tricor® (145 mg) as two test arms. The other two cancers were other test formulations made according to the present invention. There was a one week washout between each arm tested. Blood samples are taken 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 trial) Fenofibric acid was analyzed by a validated method. Four cancer trials were performed for both fasting and feeding conditions.

result

Fasting state data were obtained for Candidate 1-11 (N = 11) for Test MAZ149B and Candidate 2-11 (N = 1O) for Control TriCor®. The results are shown in Table D1 below. The mean value is that the bioavailability of the test is 97.4% of the control based on AUC ₄₈ (175334 vs 180010 h * ng / g) and 97.7% of the control based on AUC _∞ (213653 vs 218628 h * ng / g) Showed. The corresponding geometric mean was 97.5% of the control based on AUC ₄₈ (169481 vs 173880 h * ng / g) and 97.5% of the control based on AUC _∞ (205217 vs 210558 h * ng / g). . The geometric mean of the individual ratios of the test to control AUC _∞ was 1.006. The mean value for C _max showed that the test was 99% of the control (10570 vs 10624 ng / g) and the geometric mean was 100.7% (10340 vs 10270 ng / g). The geometric mean of the ratio of test articles to the control of individual volunteers was 1.021. The variability of bioavailability for% CV (variation of variables) of AUC ₄₈ values was very similar, 28.95% vs. 27.16%. The mean terminal half-life (terminal half-life in excretion) was 20.0 hours for the test and 19.9 hours for the control, while the average T _max was 2.5 hours for the test and 2.1 hours for the control. It can be concluded that the two agents are biologically equivalent in the fasting state.

Feeding status data for volunteers 1-5, 7-10 and 12 (N = 10) for both Test MAZ149B and Control TriCor® were obtained. The results are shown in Table D2 below. The mean value was that the bioavailability of the test was 107.1% of the control based on AUC ₄₈ (150511 vs 140627 h * ng / g) and 112.0% of the control based on AUC _∞ (185149 vs 165310 h * ng / g). Showed. The corresponding geometric mean was 106.8% of the control based on AUC ₄₈ (145402 vs 136134 h * ng / g) and 111.2% of the control based on AUC _∞ (174021 vs 156459 h * ng / g). . The geometric mean of the individual ratios of the test to control AUC _∞ was 1.112. The average value for C _max showed that the test was 79.0% of the control (7557 vs 9567 ng / g) and the geometric mean was 77.5% (7147 vs 9217 ng / g). The geometric mean of the ratio of test articles to the control of individual volunteers was 0.775. The variability of bioavailability for% CV (variation of variables) of AUC ₄₈ values was very similar, 27.16% vs. 26.41%. The mean terminal half-life was 17.4 hours for the test and 16.1 hours for the control, while the average T _max was 8.0 hours for the test and 3.6 hours for the control. Improved bioavailability coupled with lower C _max and later T _max suggests that the test article improved in the fed state.

Table D1 (fasting state)

Table D2 (Eating States)

Claims (36)

A pharmaceutical composition comprising non-mechanically micronized fenofibrate microparticles, polyethylene glycol, and polyethylene-polypropylene glycol. The pharmaceutical composition of claim 1, wherein the non-mechanically micronized fenofibrate microparticles are prepared by sublimation micronization. The pharmaceutical composition of claim 2, wherein the non-mechanically micronized microparticles are deposited on the plurality of pharmaceutical carrier particles. 4. The pharmaceutical composition of claim 3, wherein the menthol is a sublimable carrier in the sublimation micronization step. The pharmaceutical composition of claim 1, wherein the polyethylene glycol is polyethylene glycol 6000. The pharmaceutical composition of claim 1, wherein the polyethylene-polypropylene glycol is poloxamer 407. The solid of claim 6, wherein the pharmaceutical composition comprises about 15% to about 25% fenofibrate, about 7% to about 13% poloxamer 407, and about 7% to about 13% polyethylene glycol 6000 Pharmaceutical compositions in the form of oral formulations. 8. The solid oral dosage form of claim 7, further comprising a pharmaceutical disintegrant selected from the group consisting of crospovidone, croscarmellose sodium, bicarbonate salts, organic carboxylic acids, and combinations thereof. The pharmaceutical composition of claim 8, wherein the organic carboxylic acid is citric acid or tartaric acid. From about 15% to about 25% by weight of non-mechanically micronized fenofibrate microparticles, from about 7% to about 13% by weight of poloxamer 407, from about 7% to about 13% of polyethylene glycol 6000, by about 15% by weight A solid oral formulation comprising a pharmaceutical composition comprising microcrystalline cellulose, about 18 wt% crospovidone, about 12 wt% sodium bicarbonate, and about 12 wt% citric acid or tartaric acid. The solid oral dosage form of claim 10, comprising about 12 weight percent citric acid. The method of claim 10, wherein at least about 51 wt% of fenofibrate is released in about 10 minutes, at least about 73 wt% of fenofibrate is released in about 15 minutes, and at least about 85 wt% of fenofibrate is released in about 30 minutes. Solid oral formulation with in vitro fenofibrate release profile. The method of claim 10, wherein from about 51 wt% to about 81 wt% fenofibrate is released in about 10 minutes, from about 73 wt% to about 93 wt% fenofibrate is released in about 15 minutes, and from about 85 wt% to A solid oral formulation having a time dependent in vitro release profile in which almost all fenofibrate is released in about 30 minutes. A solid oral formulation comprising a pharmaceutical composition comprising about 145 mg of sublimated micronized fenofibrate in a human in vivo pharmacokinetic study in which the formulation is administered on an empty stomach, the area under the 48 hour AUC curve (AUC ₄₈ ) is about 121367 h * ng / g to about 287539 h * ng / g; The area under the AUC curve extrapolated to infinite time (AUC _∞ ) is between about 134750 h * ng / g and about 345390 h * ng / g; And a solid oral formulation having a maximum plasma concentration (C _max ) of about 6357 ng / g to about 14627 ng / g. The method of claim 14, wherein in a human in vivo pharmacokinetic study in which the formulation is administered on an empty stomach, the average AUC ₄₈ is about 175335 h * ng / g, the average AUC _∞ is about 213652 h * ng / g, and the average C solid oral dosage form with a _max of about 10570 ng / g. The solid oral dosage form of claim 14, wherein the solid oral dosage form is a compressed tablet. A solid oral formulation comprising a pharmaceutical composition comprising about 145 mg of sublimated micronized fenofibrate, wherein in a human in vivo pharmacokinetic study where the formulation is administered in the fed state, the area under the 48 hour AUC curve (AUC ₄₈ ) is about 91601 h * ng / g to about 217512 h * ng / g; And a solid oral formulation having an area under the AUC curve extrapolated to infinite time (AUC _∞ ) from about 97182 h * ng / g to about 308070 h * ng / g. The solid oral dosage form of claim 17, wherein the average AUC ₄₈ is about 150511 h * ng / g and the average AUC _∞ is about 185149 h * ng / g. The solid oral dosage form of claim 18, wherein the solid oral dosage form is a compressed tablet. A pharmaceutical composition comprising a plurality of pharmaceutical carrier particles having a combination of fenofibrate, polyethylene glycol, and polyethylene-polypropylene glycol deposited thereon, the combination comprising fenofibrate, polyethylene glycol, polyethylene-polypropylene glycol, and a sublimable carrier Pharmaceutical composition is deposited by sublimation of a sublimable carrier from a solid solution comprising a. The pharmaceutical composition of claim 20, wherein the sublimable carrier is menthol. The pharmaceutical composition of claim 20, wherein the polyethylene glycol is polyethylene glycol 6000. The pharmaceutical composition of claim 20, wherein the polyethylene-polypropylene glycol is poloxamer 407. The solid of claim 20, wherein the pharmaceutical composition comprises about 15% to about 25% fenofibrate, about 7% to about 13% poloxamer 407, and about 7% to about 13% polyethylene glycol 6000 Pharmaceutical compositions in the form of oral formulations. The solid oral dosage form of claim 24, further comprising a pharmaceutical disintegrant selected from the group consisting of crospovidone, croscarmellose sodium, bicarbonate salt, organic carboxylic acid, and combinations thereof. The pharmaceutical composition of claim 25, wherein the organic carboxylic acid is citric acid or tartaric acid. About 15% to about 25% fenofibrate, about 7% to about 13% poloxamer 407, about 7% to about 13% polyethylene glycol 6000, about 15% by weight microcrystalline cellulose, about 18% A solid oral formulation comprising a pharmaceutical composition comprising% crospovidone, about 12 wt% sodium bicarbonate, and about 12 wt% citric acid or tartaric acid, the solid oral formulation comprising at least fenofibrate, poloxamer 407, and polyethylene A solid oral formulation wherein at least fenofibrate, poloxamer 407, and polyethylene glycol 6000 are deposited on microcrystalline cellulose by sublimation of a sublimable carrier from a solid solution of glycol 6000. The solid oral dosage form of claim 27 comprising about 12 wt% citric acid. The method of claim 27, wherein at least about 51 wt% of fenofibrate is released in about 10 minutes, at least about 73 wt% of fenofibrate is released in about 15 minutes, and at least about 85 wt% of fenofibrate is released in about 30 minutes. Solid oral formulation with in vitro fenofibrate release profile. The method of claim 27, wherein from about 51 wt% to about 81 wt% fenofibrate is released in about 10 minutes, from about 73 wt% to about 93 wt% fenofibrate is released in about 15 minutes, and from about 85 wt% A solid oral formulation having a time dependent in vitro release profile in which almost all fenofibrate is released in about 30 minutes. A solid oral formulation comprising a pharmaceutical composition comprising about 145 mg of fenofibrate deposited on a plurality of microcrystalline cellulose particles by sublimation of a sublimable carrier and a solid solution comprising fenofibrate, wherein the formulation is in an empty state. In human in vivo pharmacokinetic studies, the area under the 48 hour AUC curve (AUC ₄₈ ) is from about 121367 h * ng / g to about 287539 h * ng / g; The area under the AUC curve extrapolated to infinite time (AUC _∞ ) is between about 134750 h * ng / g and about 345390 h * ng / g; And a solid oral formulation having a maximum plasma concentration (C _max ) of about 6357 ng / g to about 14627 ng / g. The method of claim 31, wherein in a human in vivo pharmacokinetic study in which the formulation is administered on an empty stomach, the average AUC ₄₈ is about 175335 h * ng / g, the average AUC _∞ is about 213652 h * ng / g, and the average C solid oral dosage form with a _max of about 10570 ng / g. The solid oral dosage form of claim 31, wherein the solid oral dosage form is a compressed tablet. A solid oral formulation comprising a pharmaceutical composition comprising about 145 mg of fenofibrate deposited on a plurality of microcrystalline cellulose particles by sublimation of a sublimable carrier and a solid solution comprising fenofibrate, in a fed state In human in vivo pharmacokinetic studies in which the formulation is administered, the area under the 48 hour AUC curve (AUC ₄₈ ) is from about 91601 h * ng / g to about 217512 h * ng / g; And a solid oral formulation having an area under the AUC curve extrapolated to infinite time (AUC _∞ ) from about 97182 h * ng / g to about 308070 h * ng / g. The solid oral dosage form of claim 34, wherein the average AUC ₄₈ is about 150511 h * ng / g and the average AUC _∞ is about 185149 h * ng / g. 36. The solid oral dosage form of claim 35 wherein the solid oral dosage form is a compressed tablet.