JP2009522258A - Pharmaceutical formulation of fenofibrate with increased bioavailability - Google Patents

Abstract

  Pharmaceutical compositions of fenofibrate comprising fenofibrate, polyethylene glycol and polyethylene-polypropylene glycol, and dosage forms comprising them are provided; wherein the composition uses a sublimable carrier, such as menthol. And by sublimating a sublimable carrier from fenofibrate, polyethylene glycol, and polyethylene-polypropylene glycol.

Description

  The present invention relates to fenofibrate, polyethylene glycol made by sublimation of a sublimable carrier from a solid solution comprising sublimation carriers such as fenofibrate, polyethylene glycol, polyethylene-polypropylene glycol, and methanol. And a pharmaceutical composition comprising polyethylene-polypropylene glycol.

  Fenofibrate, (2- [4- (4-chlorobenzoyl) phenoxy] -2-methyl-propanoic acid, 1-methylethyl ester) is one of the fibrate class of drugs. It is available as both a capsule and a tablet. Fenofibrate is clearly a prodrug. The active moiety is reported to be the metabolite fenofibric acid, which is reported to be produced in the body by the action of esterases. Obviously unchanged fenofibrate is not found in plasma when fenofibrate is administered (Physician's Desk Reference, 58th edition, 2004, 522-525 (PDR)).

  Fenofibrate is very poorly soluble in water. That is, it is a poorly water-soluble drug. Despite its poor solubility in water, it is absorbed to a therapeutically acceptable extent when administered in a “fed state” and more when administered in a “fasted state”. Less reported. The true “bioavailability” of the metabolite fenofibric acid is unclear as it is understood that much is metabolized to glucuronide at both the presystemic and first pass sites.

  The absolute bioavailability of fenofibrate is probably not measurable because it is insoluble in medium suitable for intravenous injection. When administered orally to healthy volunteers, approximately 60% of a single dose of radiolabeled fenofibrate was found primarily in urine as fenofibric acid and its glucuronide conjugate, and 25% was excreted in feces ( PDR). It is understood that the absorption of fenofibrate increases when administered with food. The degree of absorption from orally administered tablets increases to about 35% when the tablets are taken with food (PDR, Martindale, 33rd edition, page 889).

  Attempts have been made to improve fenofibrate formulations, particularly with respect to fenofibrate bioavailability. U.S. Pat. Nos. 4,895,726 and 5,880,148 disclose co-micronizing fenofibrate with a surfactant. US Pat. Nos. 6,074,670 and 6,277,405 disclose micronized fenofibrate coated with an optional surfactant on a water-soluble carrier. US Pat. No. 6,814,977 discloses fenofibrate dissolved in fatty acid medium chain glycerol esters. US Pat. No. 6,719,999 discloses fenofibrate dissolved in glycerin, propylene glycol, or dimethyl isosorbide, and US Pat. No. 5,827,536 discloses fenofibrate dissolved in diethylene glycol monoethyl ether. Is disclosed.

  Some patents disclose specific formulations of micronized fenofibrate containing specific polymers or surfactant additives, and other patents describe fenofibrate emulsions and suspensions. For example, US Patent Application Publication No. 20040087656 discloses fenofibrate with a particle size of less than 2000 nm alleged to have increased bioavailability. U.S. Patent Application Publication No. 20030224059 discloses microparticles of an active pharmaceutical ingredient, drug delivery excipients containing the same, and methods of making the same.

  Fenofibrate micronization and the combination of micronized fenofibrate with surfactants gently increases the bioavailability of fenofibrate, increasing the agency-approved drug dosage from 100 mg per dose to 67 mg per dose And then reduced to 54 mg per dose while maintaining bioavailability in the fed state. Drug nanoparticulate formulations have further allowed dose reductions up to 48 mg per dose, and the “fasted” bioavailability has been reported to be similar to the fed state. Since true fenofibrate bioavailability is still assumed to be relatively low, there is still much room for improvement.

SUMMARY OF THE INVENTION In one aspect, the present invention provides non-mechanically micronized fenofibrate microparticles, particularly fenofibrate sublimated micronized microparticles using menthol as a sublimable carrier; polyethylene glycol, particularly polyethylene glycol. And a pharmaceutical composition comprising polyethylene-polypropylene glycol, in particular poloxamer 407. The pharmaceutical composition comprises crospovidone, carboxymethylcellulose, especially crosslinked carboxymethylcellulose sodium (croscarmellose sodium), bicarbonate or carbonate; in particular alkali metal bicarbonate or carbonate such as sodium bicarbonate; organic Pharmaceutical disintegration selected from the group consisting of carboxylic acids, especially citric acid, tannic acid, ascorbic acid, benzoic acid, citric acid, fumaric acid, lactic acid, malic acid, sorbic acid, and tartaric acid; and any combination of the above An agent may further be included.

  In another aspect, the present invention provides about 15% to about 25% by weight non-mechanically micronized fenofibrate microparticles, particularly sublimated micronized fenofibrate; about 7% to about 13% poloxamer 407 About 7% to about 13% polyethylene glycol 6000; about 15% microcrystalline cellulose; about 18% crospovidone; about 12% sodium bicarbonate; and about 12% Relates to a solid oral dosage form comprising a pharmaceutical composition comprising any of citric acid or tartaric acid.

  In a further aspect, the present invention provides about 15% to about 25% by weight non-mechanically micronized fenofibrate microparticles, particularly sublimated micronized fenofibrate; about 7% to about 13% by weight poloxamer 407 About 7% to about 13% polyethylene glycol 6000; about 15% microcrystalline cellulose; about 18% crospovidone; about 12% sodium bicarbonate; and about 12% A solid oral dosage form comprising a pharmaceutical composition comprising any of citric acid or tartaric acid, wherein at least about 51 wt.%, In particular from about 51 wt.% To about 81 wt.% Fenofibrate is present in about 10 minutes. Release at least about 73 wt.%, Especially about 73 wt.% To about 93 wt.% Of fenofibrate in about 15 minutes, and at least about 30 minutes. About 85 wt%, substantially all of the fenofibrate is released in particular from about 85 wt%, related to the dosage form with fenofibrate release profile in vitro time-dependent.

In another aspect, the present invention is a solid oral dosage form, particularly a compressed tablet, comprising a pharmaceutical composition comprising about 145 mg of sublimated micronized fenofibrate, wherein the in vivo human being administered in a fasted state. In the pharmacokinetic study, the area under the 48 hour AUC curve (AUC ₄₈ ) is about 121367 h * ng / g to about 287539 h * ng / g; the estimated area under the AUC curve (AUC _∞ ) for infinite time is about 134750 h * ng / g to about 345390 h * ng / g; with respect to said dosage form, wherein the maximum plasma concentration is (C _max ) from about 6357 ng / g to about 14627 ng / g. Typically, such solid oral dosage forms 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 yet another aspect, the present invention relates to a solid oral dosage form comprising a pharmaceutical composition having about 145 mg sublimed micronized fenofibrate, particularly a compressed tablet, wherein the in vivo drug in humans is administered in the fed state In the kinetic study, the area under the 48 hour AUC curve (AUC ₄₈ ) is about 91601 h * ng / g to about 217512 h * ng / g; the estimated area under the AUC curve (AUC _∞ ) for infinite time is about 97182 h. * Ng / g to about 308070 h * ng / g, and further relates to said dosage form wherein the average AUC ₄₈ is about 150511 h * ng / g and the average AUC _∞ is about 185149 h * ng / g. This dosage form may contain a disintegrant.

  In a further aspect, the present invention provides a plurality of pharmaceutical carrier particles, particularly microcrystalline cellulose particles, fenofibrate deposited thereon; especially about 15% to about 25% by weight fenofibrate; about 7% by weight From about 13% by weight polyethylene glycol, in particular polyethylene glycol 6000; and from about 7% to about 13% by weight polyethylene-polypropylene glycol, in particular poloxamer 407, The combination relates to said pharmaceutical composition 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 composition comprises crospovidone, crosslinked carboxymethylcellulose salt (especially crosslinked carboxymethylcellulose sodium), bicarbonate or carbonate thereof; in particular alkali metal bicarbonate or carbonate, such as sodium bicarbonate; organic carboxylic acid, In particular citric acid, tannic acid, ascorbic acid, benzoic acid, citric acid, fumaric acid, lactic acid, malic acid, sorbic acid, and tartaric acid; and also includes a pharmaceutical disintegrant selected from the group consisting of any combination of the above be able to.

In a further aspect, the present invention provides a medicament 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 an in vivo pharmacokinetic study of a solid oral dosage form comprising a composition 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 The estimated area under the AUC curve (AUC _∞ ) for infinite time is about 134750 h * ng / g to about 345390 h * ng / g, and the maximum plasma concentration is (C _max ) about 6357 ng / g To about 14627 ng / g. This solid oral formulation exhibits, in certain details thereof, 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 diameter 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 this application, lyophilization techniques are considered mechanical pulverization techniques, and therefore the microparticles produced by lyophilization are excluded from non-mechanically micronized microparticles. Particle size measurement is well known to those skilled in the art and can be accomplished, for example, by well known techniques of laser light scattering.

  The non-mechanically differentiated fine particles of fenofibrate of the present invention can be obtained by, for example, sublimation fine powder technology. The microparticles thus obtained are referred to as “sublimation micronized” microparticles, and the substances constituting such microparticles are referred to as “sublimation micronization”. Sublimation micronization techniques are described in US Patent Application No. 2003/0224059 (Lerner et al.), Which is incorporated herein by reference in its entirety.

  The fine particles of fenofibrate of the present invention can be obtained by sublimation pulverization by removing the sublimable carrier from the solid solution of fenofibrate in the sublimable carrier. Fenofibrate can be present as a discrete molecule with a sublimable carrier in solid solution, or it can be present in an aggregate of hundreds, thousands, or more molecules. The drug only needs to be dispersed in a sufficiently small size so that discrete particles can ultimately be obtained. Preferably, the 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, more preferably at least about 50 pascals at about 10 ° C., or below their normal 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 by the US Food and Drug Administration that is generally recognized as safe (ie, GRAS). Examples of suitable sublimable carriers include menthol, thymol, camphor, t-butanol, imidazole, coumarin, acetic acid (ice), dimethyl sulfone, urea, vanillin, camphene, salicylamide, and 2-aminopyridine. . Menthol is a particularly preferred sublimable carrier.

  The fine particles of the present invention are formed by removing the sublimable carrier from the solid solution prepared as described above at a temperature lower than the melting point of the solid solution. The solid solution must be kept at a temperature below its melting point in order to retain the solid solution during the sublimable support removal process. Sublimable carriers can be obtained, for example, by treating the solid solution deposited on the pharmaceutical carrier particles where applicable as discussed below in an air stream, preferably hot air, for example in a fluidized bed dryer. It can be removed from the solid solution.

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

Useful polyethylene glycol in the practice of the present invention - le have the general formula _{- (- CH 2 -CH 2 -O-} ) x- have, for example Polyethylene Glycols, 23 National Formulary, 3052 (United States Pharmacopeial Convention, 2005) Can be characterized by the arithmetic average value X (<X _N >) or the corresponding molecular weight. Polyethylene glycol 6000 is a preferred polyethylene glycol for use in the practice of the present invention.

The polyethylene-polypropylene glycol useful in the practice of this invention is of the general formula — (O—CH ₂ CH ₂ —) _a —O — (— CH (CH ₃ ) CH ₂ —) _b — (— O—CH ₂ CH ₂ —) _a —OH, commonly referred to as “poloxamer”. Preferred poloxamers for use in the practice of the present invention are US Pat. S. It is described in a monograph with a similar name in the National Formula. Poloxamers, 23 National Formulary, 3051 (United States Pharmaceutical Cooperative, 2005). Polyethylene-polypropylene glycol, generally designated “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 can be deposited on a plurality of pharmaceutical carrier particles, and in a preferred embodiment is deposited. Pharmaceutical carrier particles useful as a support, substrate, or carrier for the pharmaceutical formulations of the present invention are produced from edible materials and are well known in the art. Examples of useful pharmaceutical carrier particles can be non-pariel pellets, typically from about 0.1 mm to about 2 mm in diameter, such as particles made from starch, microcrystalline cellulose Particles, lactose particles, or specifically sugar particles. Suitable sugar particles (pellets such as non-pariel 103, Nu-core, Nu-pariel) are commercially available and are 35-40 mesh to 18-14 mesh. Preferred pharmaceutical carrier particles are made from water-insoluble materials such as microcrystalline cellulose. Carrier particles comprising microcrystalline cellulose (eg Avicel®) are particularly preferred pharmaceutical carrier particles. Those skilled in the art are aware of other pellets or spheres useful as pharmaceutical carrier particles.

  The pharmaceutical composition of the present invention can be produced by mixing fenofibrate, polyethylene glycol, polyethylene-polypropylene glycol, and a sublimable carrier. The above components can be mixed appropriately or, in embodiments where the composition is deposited on a plurality of pharmaceutical carrier particles, can be mixed with a suitable solvent. Suitably the solvent dissolves fenofibrate, polyethylene glycol, polyethylene-polypropylene glycol, and sublimable carrier, but does not dissolve the pharmaceutical carrier particles and is chemically inert to any ingredients. Yes, it can be easily removed at any convenient temperature, particularly below 100 ° C., optionally by application of a vacuum. Ethanol is an example of a suitable solvent.

  The combination of ingredients are mixed and warmed to form a homogeneous mixture, preferably a solution, and cooled to obtain a solid solution. The fenofibrate can be present as a discrete molecule with a sublimable support in solid solution, or it can be present in an aggregate of hundreds, thousands, or more molecules. The drug only needs to be dispersed on a sufficiently small scale so that sufficiently small discrete microparticles are ultimately obtained.

  Preferably, the drug in solid solution is dissolved in a sublimable carrier. In embodiments in which sublimated micronized microparticles are deposited on a plurality of pharmaceutical carrier particles, a warm solution of the components in the sublimable carrier is mixed with the pharmaceutical carrier particles, for example, by mixing, and the mixture is cooled, A solid solution is formed on the pharmaceutical carrier particles. Alternatively, the pharmaceutical carrier particles are mixed with a solution of sublimable carrier, fenofibrate, polyethylene glycol, and polyethylene-polypropylene glycol in a suitable solvent (eg, ethanol). The solvent is optionally removed by application of heat and vacuum to remove the pharmaceutical carrier particles deposited with a solid solution of fenofibrate, polyethylene glycol, and polyethylene-polypropylene glycol in a sublimable carrier (eg, menthol). obtain.

  Whether or not deposited on the pharmaceutical carrier particles after the formation of the solid solution, the pharmaceutical formulation of the present invention can then be sublimated from the solid solution produced as described above at a temperature below the melting point of the solid solution. It is formed by removing. This solid solution must be kept at a temperature below its melting point in order to retain the solid solution during the process of removing the sublimable support. The sublimable carrier can be removed from the solid solution, for example by treating the solid solution deposited on the pharmaceutical carrier particles where applicable, in an air stream, preferably hot air, for example in a fluidized bed dryer. Can do.

  In a preferred embodiment, removal of the sublimable carrier results in the formation of non-mechanically micronized microparticles of fenofibrate, the microparticles further comprising at least some polyethylene glycol and polyethylene-polypropylene glycol. Can be included. Further, at least some fenofibrate is dense with either or both of polyethylene glycol and polyethylene-polypropylene glycol that are present in solution or not necessarily present with non-mechanically micronized microparticles. Can be bound to.

  Applicant's invention is not limited by any particular theory of operation. However, applicants have noted that after removal of the sublimable carrier, at least some of the fenofibrate is dissolved or tightly bound in the polyalkylene glycol. The expression “tightly coupled” excludes a simple physical mixture that can be obtained, for example, by dry mixing, dry granulation, or wet granulation in the presence of a liquid that does not at least partially dissolve the components. To do.

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

  Compressed tablets are from pharmaceutical compositions containing pharmacologically active substances or drug microparticles, or such microparticles are used with pharmaceutical carrier particles and pharmacologically inactive (pharmaceutically acceptable) additives or excipients. Can be formulated.

  In order to produce tablets, it will typically be desirable to include one or more amphoteric pharmaceutical excipients in the pharmaceutical composition. The pharmaceutical composition of the present invention can include one or more diluents added to make the tablet larger, thus facilitating handling for patients and caregivers. Common diluents are microcrystalline cellulose (eg, Avicel®), ultrafine cellulose, lactose, starch, alpha starch, calcium carbonate, calcium sulfate, sugar, dextrate, dextrin, dextrose, dicalcium phosphate Dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate (eg Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc .

  Binders can also be included in the tablet formulation to help pack the tablets after compression. Some typical binders are acacia, alginic acid, carbomer (eg carbopol), sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethylcellulose, hydroxypropylcellulose (eg Klucel ( (Registered trademark)), hydroxypropyl methylcellulose (for example, Methocel (registered trademark)), liquid glucose, magnesium magnesium silicate, maltodextrin, methylcellulose, polymethacrylate, povidone (for example, Kollidon (registered trademark), Plasdone (registered trademark)) Trademark)), alpha starch, sodium alginate and starch.

  The tablet may further comprise a disintegrant that accelerates the disintegration of the tablet in the patient's stomach. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, cross-linked carboxymethylcellulose sodium or calcium (for example, croscarmellose sodium (eg Ac-Di-Sol (registered trademark), Primeellose (registered trademark) or Croscarmellose calcium), crospovidone (eg, Kollidon®, Polyplastdone®), guar gum, aluminum magnesium silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, alpha starch, alginic acid Examples include sodium, sodium starch glycolate (eg, Explotab®) and starch. It is.

  In addition to or in place of alginic acid, other organic carboxylic acids can be included in the formulation. Examples of the organic acid 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 other embodiments of the present invention.

  The pharmaceutical composition of the present invention may in a preferred embodiment comprise bicarbonate or carbonate, in particular alkali metal bicarbonate or carbonate. Examples of preferred alkali metal bicarbonates or carbonates include sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate. Alkaline earth metal carbonates such as calcium carbonate and magnesium carbonate can also be used.

  Pharmaceutical compositions for making compressed tablets can further comprise glidants, lubricants, flavoring agents, coloring agents and other commonly used excipients.

  The pharmaceutical carrier particles carrying the drug microparticles produced according to the present invention have excellent bulk flow properties and can be used directly or with single particles that do not carry the drug to form a capsule dosage form. Can be manufactured. If necessary, diluents such as lactose, mannitol, calcium carbonate, and magnesium carbonate (only a few are mentioned) can be formulated with the microparticle-supported pharmaceutical carrier particles when the capsule is made.

  The liquid oral pharmaceutical composition of the present invention comprises microparticles or microparticle-supported pharmaceutical carrier particles and a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin, most preferably water.

  Liquid oral pharmaceutical compositions can include emulsifiers to uniformly disperse active ingredients, drug delivery vehicles, or excipients having low solubility in liquid carriers throughout the composition. Emulsifiers that may be useful in the liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methylcellulose, carbomer, cetostearyl alcohol and cetyl alcohol. Can be mentioned.

  The liquid oral pharmaceutical composition of the present invention may also contain a viscosity enhancer for improving the oral sensation of the product and / or coating the intima of the gastrointestinal tract. Such drugs include acacia, bentonite alginate, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, maltodextrin, polyvinyl alcohol, povidone, Examples include propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.

  Liquid oral pharmaceutical compositions include sweeteners such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar; preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole And ethylenediaminetetraacetic 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 dosage forms formulated and mixed with sublimed fine particles of fenofibrate with polyethylene glycol and polyethylene-polypropylene glycol, prepared as described above, are dissolved (released) in vitro. ) Provide increased bioavailability of fenofibrate, as demonstrated by both studies and human in vivo pharmacokinetic (plasma concentration) studies. The in vivo and in vitro test results disclosed herein were obtained with tablets containing about 145 mg fenofibrate and having a nominal weight of 792 mg.

  The time-dependent in vitro release (dissolution) profile disclosed herein is USP type − operating at 50 rpm at 37 ° C. and filled with 0.5% by weight sodium lauryl sulfate in 1000 mL of water— Obtained using a II dissolution test apparatus. The concentration of fenofibrate in the test liquid was measured by HPLC.

  The pharmacokinetic data disclosed herein is obtained by measuring the blood plasma concentration of the metabolite, fenofibrate, as a function of time providing a well-known Boltzmann-type cumulative plasma concentration (AUC) curve. Obtained in an in vivo experiment. Individual points are reported with respect to selected actual or extrapolated time points on 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 (the last point measured). 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). Mean AUC (<AUC>) is the arithmetic mean plasma concentration of fenofibrate measured over a series of plasma concentration measurement periods (approximately 48 hours).

  The invention, in its particular embodiments, is illustrated by the following non-limiting examples. In the following examples, a fed state means that the subject has consumed food within 10 hours prior to administration. A fed state means that the subject has consumed food about 1.5 hours prior to administration.

Experiment A. Fenofibrate granules Menthol (1.333 Kg) was melted by stirring in a glass reactor at 50 ° C. Fenofibrate (133.3 gm), poloxamer 407 (Lutrol F127, 76 gm), and polyethylene glycol 6000 (76 gm) were charged to the reactor. The menthol melt was stirred at 50 ° C. until all the compound was dissolved. Microcrystalline cellulose (Avicel PH 101, 106.7 gm) was added to the melt, which was stirred until a uniform suspension was obtained.

The menthol melt was divided into three equal parts and poured into three trays (stainless steel, 0.133 m ² each) 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 sieve using an Erweka mill. The resulting powder was again divided into three parts and returned to the tray. The material on the menthol tray was removed by sublimation in a high vacuum tray dryer at 0.2 mbar, 36 ° C. for about 53 hours. The resulting powder was removed from the tray and milled through a 1.6 mm sieve using an Erweka mill so as not to affect the substantial grinding of the already formed particles. The granules thus obtained were weighed (346.4 gm), yielding 88%.

B. Fenofibrate tablets (145 mg)-
The fenofibrate granules from stage A were milled through a 0.8 mm sieve 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 anhydrous citric acid (72 gm) were added and the mixture was mixed for 5 minutes. Magnesium stearate (12 gm) was added to the bag and the mixture was mixed for an additional 0.5 minutes. The total amount of the mixture thus obtained was 600 grams.

  The mixture was compressed into tablets using a normal concave punch in the shape of an egg (8.8 mm x 17.6 mm) on a Manesty F3 single shot tablet press. The tablet design mass was 785 mg ± 39.3 mg with a hardness of 5-7 Kp. The resulting tablet had an average mass of 792 mg and a hardness of 6 Kp. Several batches were manufactured and labeled MAZ149B, MAZ149B1 and MAZ149B2, respectively.

C In vitro release Release (dissolution) of fenofibrate from tablets using a USP Type II dissolution test apparatus filled with 0.5% (w / v) sodium lauryl sulfate (SLS) in 1000 ml of water. At 37 ° C. and 50 rpm. The amount of fenofibrate in each sample was measured by HPLC as described above. The results are shown in Tables C1-C3 for the three batches.

  D. In vivo pharmacokinetic studies

  Pharmacokinetic study of MAZ149B and TriCor® 145 mg

  A four-way crossing bioequivalence pharmacokinetic study was performed in 12 volunteers using MAZ149B (145 mg, described above) and TriCor® (145 mg) as two study groups. Carried out. The other two groups were other test formulations prepared according to the present invention. A 1 week washout was performed between each test group. Blood samples were collected 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 test) were collected and analyzed for fenofibric acid by an effective method. A 4-group study was performed in both the fasted and fed states.

Results Fasted state data were obtained from 1-11 volunteers (N = 11) for MAZ149B in the study and 2-11 volunteers (N = 10) for the baseline TriCor®. The results are summarized in Table D1. The mean value is that the test bioavailability is 97.4% (175334 vs 180010h * ng / g) based on AUC ₄₈ and 97.7% (213635 vs 218628h * ng) based on AUC _∞. / G). The corresponding geometric mean value was 97.5% (169481 vs. 173880 h * ng / g) based on AUC ₄₈ and 97.5% (205217 vs. 210558 h * ng / g) based on AUC _∞ . The geometric mean of the ratio of the individual ratios of test to reference AUC _∞ was 1.006. The mean value of C _max was 99% of the test (10570 vs. 10624 ng / g) and the geometric mean of 100.7% (10340 vs. 10270 ng / g). The geometric mean of the ratio of the test to the individual volunteer criteria was 1.021. The variability of bioavailability was very similar, 28.95% vs. 27.16% with respect to CV (%) of AUC ₄₈ value (variable change). The average terminal half-life (terminal half-life for exclusion) is 20.0 hours for the test product and 19.9 hours for the reference, while the average T _max is 2.5 hours for the test and the reference Was 2.1 hours. It can be concluded that the two formulations are bioequivalent in the fasted state.

Eating status data were obtained for 1-5, 7-10 and 12 (N = 10) volunteers for both test MAZ49B and TriCor® reference products. The results are summarized in Table D2. The mean value is that the bioavailability of the test is 107.1% of the baseline based on AUC ₄₈ (150511 vs 140627h * ng / g) and 112.0% of the baseline based on AUC _∞ (185149 vs 165310h * ng) / G). Corresponding geometric mean values, 106.8% based on AUC ₄₈ indicates (145402 vs. 136134h * ng / g), it showed 111.2% based on AUC _∞ (174 021 vs. 156459h * ng / g). The geometric mean of the ratio of the individual ratios of test to reference AUC _∞ was 1.112. The average value of C _max was 79.0% of the standard of the test (7557 vs. 9567 ng / g) and the geometric mean of 77.5% (7147 vs. 9127 ng / g). The geometric mean of the ratio of the test to the individual volunteer criteria was 0.775. The bioavailability variability was very similar, with 27.16% vs. 26.41% for the AUC ₄₈ value CV (%) (variable change). The mean terminal half-life was 17.4 hours for the test product and 16.1 hours for the reference, while the mean T _max was 8.0 hours for the test and 3.6 hours for the reference. It was. Increased bioavailability is linked to a lower C _max , and a later T _max suggests an improved product in the fed state.

Claims (36)

  A pharmaceutical composition comprising non-mechanically micronized microparticles of fenofibrate, polyethylene glycol, and polyethylene-polypropylene glycol.   The pharmaceutical composition according to claim 1, wherein the non-mechanically micronized microparticles of fenofibrate are made by sublimation micronization.   The pharmaceutical composition according to claim 2, wherein the non-mechanically micronized microparticles are deposited on a plurality of pharmaceutical carrier particles.   4. A pharmaceutical composition according to claim 3, wherein menthol is a sublimable carrier in the sublimation micronization stage.   The pharmaceutical composition according to claim 1, wherein the polyethylene glycol is polyethylene glycol 6000.   The pharmaceutical composition according to claim 1, wherein the polyethylene-polypropylene glycol is poloxamer 407.   A solid oral dosage form wherein the pharmaceutical composition comprises about 15% to about 25% by weight fenofibrate, about 7% to about 13% poloxamer 407, and about 7% to about 13% polyethylene glycol 6000. 7. A pharmaceutical composition according to claim 6 present in form.   The solid oral dosage form of claim 7, further comprising a pharmaceutical disintegrant selected from the group consisting of crospovidone, croscarmellose sodium, bicarbonate, organic carboxylic acid, and combinations of any of the foregoing.   The pharmaceutical composition according to claim 8, wherein the organic carboxylic acid is citric acid or tartaric acid.   About 15% to about 25% by weight non-mechanically micronized fenofibrate microparticles, about 7% to about 13% poloxamer 407, about 7% to about 13% polyethylene glycol 6000, about Solid oral dosage form comprising a pharmaceutical composition comprising 15% by weight microcrystalline cellulose, about 18% by weight crospovidone, about 12% by weight sodium bicarbonate, and about 12% by weight of either citric acid or tartaric acid .   The solid oral dosage form of claim 10, comprising about 12% by weight citric acid.   At least about 51% by weight fenofibrate is released in about 10 minutes, at least about 73% by weight fenofibrate is released in about 15 minutes, and at least about 85% by weight fenofibrate is released in about 30 minutes. 11. A solid oral dosage form according to claim 10 having a dependent in vitro fenofibrate release profile.   About 51% to about 81% fenofibrate is released in about 10 minutes, about 73% to about 93% fenofibrate is released in about 15 minutes, and about 85% to almost all fenofibrate 11. The solid oral dosage form of claim 10, having a time-dependent in vitro release profile that releases in about 30 minutes. In in vivo pharmacokinetic studies in humans where the dosage form is administered in the 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 estimated area under the AUC curve (AUC _∞ ) is from about 134750 h * ng / g to about 345390 h * ng / g; the maximum plasma concentration is (C _max ) from about 6357 ng / g to about 14627 ng / g, about Solid oral dosage form comprising a pharmaceutical composition comprising 145 mg sublimed micronized fenofibrate. In an in vivo pharmacokinetic study in humans where the dosage form is administered in a fasted state, the average value of AUC ₄₈ is about 175335 h * ng / g and the average value of AUC _∞ is about 213652 h * ng / g The solid oral dosage form of claim 14, wherein the mean value of C _max is about 10570 ng / g.   15. The solid oral dosage form according to claim 14, wherein the solid oral dosage form is a compressed tablet. In in vivo pharmacokinetic studies in humans where the dosage form is administered in a fed state, the area under the 48 hour AUC curve (AUC ₄₈ ) is from about 91601 h * ng / g to about 217512 h * ng / g; A solid oral dosage form comprising a pharmaceutical composition comprising about 145 mg sublimed micronized fenofibrate, wherein the estimated area under the AUC curve (AUC _∞ ) is from about 97182 h * ng / g to about 308070 h * ng / g. 18. The solid oral dosage form of claim 17, wherein the average value of AUC ₄₈ is about 150511 h * ng / g and the average value of 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 plurality of pharmaceutical carrier particles deposited with a mixture of fenofibrate, polyethylene glycol, and polyethylene-polypropylene glycol, the mixture comprising fenofibrate, polyethylene glycol, polyethylene-polypropylene glycol, and sublimation A pharmaceutical composition deposited by sublimation of a sublimable carrier from a solid solution comprising the carrier.   21. A pharmaceutical composition according to claim 20, wherein the sublimable carrier is menthol.   The pharmaceutical composition according to claim 20, wherein the polyethylene glycol is polyethylene glycol 6000.   21. The pharmaceutical composition according to claim 20, wherein the polyethylene-polypropylene glycol is poloxamer 407.   Present in the form of a solid oral dosage form comprising about 15% to about 25% fenofibrate, about 7% to about 13% poloxamer 407, and about 7% to about 13% polyethylene glycol 6000. 21. A pharmaceutical composition according to claim 20.   25. The solid oral dosage form of claim 24, further comprising a pharmaceutical disintegrant selected from the group consisting of crospovidone, croscarmellose sodium, bicarbonate, organic carboxylic acid, 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.   Sublimation of a sublimable carrier from a solid solution of at least fenofibrate, poloxamer 407, and polyethylene glycol 6000 including at least fenofibrate, poloxamer 407, and polyethylene glycol 6000 includes a sublimable carrier. About 15% to about 25% fenofibrate, about 7% to about 13% poloxamer 407, about 7% to about 13% polyethylene glycol 6000, about 15% deposited on cellulose. A solid oral dosage form comprising a pharmaceutical composition comprising 1% microcrystalline cellulose, about 18% crospovidone, about 12% sodium bicarbonate, and about 12% citric acid or tartaric acid.   28. A solid oral dosage form according to claim 27 comprising about 12% by weight citric acid.   Time dependent that at least about 51% fenofibrate is released in about 10 minutes, at least about 73% by weight fenofibrate is released in about 15 minutes, and at least about 85% by weight fenofibrate is released in about 30 minutes 28. The solid oral dosage form of claim 27, having a sex in vitro fenofibrate release profile.   About 51% to about 81% fenofibrate is released in about 10 minutes, about 73% to about 93% fenofibrate is released in about 15 minutes, and about 85% to almost all fenofibrate 28. The solid oral dosage form of claim 27, having a time-dependent in vitro release profile that releases in about 30 minutes. In in vivo pharmacokinetic studies in humans where the dosage form is administered in the 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 estimated area under the AUC curve (AUC _∞ ) is from about 134750 h * ng / g to about 345390 h * ng / g; the maximum plasma concentration is (C _max ) from about 6357 ng / g to about 14627 ng / g, A solid oral dosage form comprising a pharmaceutical composition comprising about 145 mg of fenofibrate deposited on a plurality of microcrystalline cellulose particles by sublimation of a sublimable carrier from a solid solution comprising fibrate and a sublimable carrier. In an in vivo pharmacokinetic study in humans where the dosage form is administered in a fasted state, the average value of AUC ₄₈ is about 175335 h * ng / g and the average value of AUC _∞ is about 213652 h * ng / g 32. The solid oral dosage form of claim 31, wherein the mean value of C _max is about 10570 ng / g.   32. The solid oral dosage form according to claim 31, wherein the solid oral dosage form is a compressed tablet. In in vivo pharmacokinetic studies in humans where the dosage form is administered in a fed state, the area under the 48 hour AUC curve (AUC ₄₈ ) is from about 91601 h * ng / g to about 217512 h * ng / g; The estimated area under the AUC curve (AUC _∞ ) is about 97182 h * ng / g to about 308070 h * ng / g, due to sublimation of the sublimable carrier from the solid solution comprising fenofibrate and the sublimable carrier, A solid oral dosage form comprising a pharmaceutical composition comprising about 145 mg of fenofibrate deposited on a plurality of microcrystalline cellulose particles. 35. The solid oral dosage form of claim 34, wherein the average value of AUC ₄₈ is about 150511 h * ng / g and the average value of 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.