NO346970B1 - Nanoparticulate fiber formulations - Google Patents

Description

FIELD OF THE INVENTION

The present invention relates to a nanoparticle composition comprising a fibrate, preferably fenofibrate or a salt thereof. The nanoparticulate fibrate particles, preferably the fenofibrate particles, have a particle size of less than about 500 nm.

BACKGROUND OF THE INVENTION

A. Background related to nanoparticulate compositions

Nanoparticulate compositions, first described in U.S. patent No. 5,145,684 (the "'684 patent"), are particles consisting of poorly soluble therapeutic or diagnostic agents which have adsorbed on their surface a non-crosslinked surface stabilizing agent. The '684 patent does not disclose nanoparticulate compositions of a fibrate.

Methods for preparing nanoparticulate compositions are described, for example, in U.S. Pat. Patent Nos. 5,518,187 and 5,862,999, both relating to "Methods of Milling Pharmaceutical Compounds," U.S. Pat. Patent No. 5,718,388, "Continuous Process for Grinding Pharmaceutical Compounds;" and the U.S. patent no. 5,510,118, "Processes for the preparation of therapeutic compositions containing nanoparticles".

Nanoparticulate compositions are also described, for example, in U.S. Pat. patent no.

5,298,262, "Use of Ionic Transient Point Modifiers to Prevent Particle Aggregation During Sterilization;" 5,302,401, "Method of Reducing Particle Size Growth During Lyophilization;" 5,318,767, "X-ray contrast compositions useful in medical imaging;" 5,326,552 , "New Formulations for Nanoparticulate X-ray Blood Collection Contrast Agents Using High Molecular Weight Nonionic Surfactants;" 5,328,404, "Procedure for X-ray Imaging Using Iodinated Aromatic Propanedioates;" 5,336,507 , "Use of Charged Phospholipids to Reduce Nanoparticle Aggregation;" 5,340,564, "Formulations comprising Olin 10-G to prevent particle aggregation and increase stability;" 5,346,702, "Use of Nonionic Transient Point Modifiers to Minimize Nanoparticulate Aggregation During Sterilization;" 5,349,957, "Preparation and Magnetic Properties of Very Small Magnetic Dextran Particles;" 5,352,459, "Use of Purified Surfactant Modifiers to Prevent Particle Aggregation During Sterilization;" 5,399,363 and 5,494,683, both related to "Surfactant Modified Anticancer Nanoparticles;" 5,401,492, "Water-Soluble Non-Magnetic Manganese Particles as Magnetic Resonance Enhancers;" 5,429,824, "Use of Tyloxapol as a Nanoparticle Stabilizer;" 5,447,710 , "Method of Making Nanoparticulate X-ray Blood Collection Contrast Agents Using High Molecular Weight Nonionic Surfactants;" 5,451,393 , "X-ray contrast compositions useful in medical imaging;" 5,466,440 , "Formulations of Oral Gastrointestinal Diagnostic X-ray Contrast Agents in Combination with Pharmaceutically Acceptable Clays;" 5,470,583 , "Methods of preparing nanoparticulate compositions containing charged phospholipids to reduce aggregation;" 5,472,683 , "Nanoparticulate Diagnostic Mixed Carbamine Anhydrides as X-ray Contrast Agents for Blood Collection and Lymphatic System Imaging;" 5,500,204 , "Nanoparticulate Diagnostic Dimers as X-ray Contrast Agents for Blood Collection and Lymphatic System Imaging;" 5,518,738, "Nanoparticulate NSAID Formulations;" 5,521,218 , "Nanoparticulate iododipamide derivatives for use as X-ray contrast agents;" 5,521,328 , "Nanoparticulate Diatrizooxyester Diagnostic X-Ray Contrast Agents for Blood Collection and Lymphatic System Imaging;" 5,543,133 , "Method of Preparation of X-ray Contrast Compositions Containing Nanoparticles;" 5,552,160 , "Surface Modified NSAID Nanoparticles;" 5,560,931, "Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;" 5,565,188, "Polyalkylene Block Copolymers as Surfactant Modifiers for Nanoparticles;" 5,569,448 , "Sulfated Nonionic Block Copolymer Surfactants as Stabilizing Coatings for Nanoparticle Compositions;" 5,571,536, "Formulations of Compounds as Nanoparticle Dispersions in Digestible Oils or Fatty Acids;" 5,573,749 , "Nanoparticulate Diagnostic Mixed Carboxylic Anhydrides as X-ray Contrast Agents for Blood Collection and Lymphatic System Imaging;" 5,573,750 , "Diagnostic X-ray Contrast Imaging Agents;" 5,573,783 , "Redispersible nanoparticulate film matrices with protective overcoats;" 5,580,579 , "Site-specific adhesion within the GI tract using nanoparticles stabilized with high molecular weight linear poly(ethylene oxide) polymers;" 5,585,108 , "Formulations of Oral Gastrointestinal Therapeutic Agents in Combination with Pharmaceutically Acceptable Clays;" 5,587,143, "Butylene oxide ethylene oxide block copolymer surfactants as stabilizing coatings for nanoparticle compositions;" 5,591,456, "Malt Naproxen with Hydroxylpropyl Cellulose as Dispersion Stabilizers;" 5,593,657, "New Barium Salt Formulations Stabilized Through Nonionic and Anionic Stabilizers;" 5,622,938 , "Sugar-Based Surfactants for Nanocrystals;" 5,628,981 , "Improved Formulations of Gastrointestinal Diagnostic X-Ray Contrast Agents and Oral Gastrointestinal Therapeutic Agents;" 5,643,552 , "Nanoparticulate Diagnostic Mixed Carbon Anhydrides as X-ray Contrast Agents for Blood Collection and Lymphatic System Imaging;" 5,718,388 , "Continuous Process for Milling Pharmaceutical Compounds;" 5,718,919 , "Nanoparticles containing the R(-) enantiomer of Ibuprofen;" 5,747,001, "Aerosols Containing Beclomethasone Nanoparticle Dispersions;" 5,834,025 , "Reduction of Intravenously Administered Nanoparticle Formulation Induced Physiological Side Effects;" 6,045,829 "Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surfactant Stabilizers;" 6,068,858 , "Processes for preparing nanocrystalline formulations of human immunodeficiency virus (HIV) protease inhibitors using cellulosic surfactant stabilizers;" 6,153,225 , "Injectable Formulations of Nanoparticulate Naproxen;" 6,165,506, "New Solid Dosage Forms of Nanoparticulate Naproxen;" 6,221,400 , "Methods of Treating Mammals Using Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors;" 6,264,922 , "Fine Aerosols Containing Nanoparticle Dispersions;" 6,267,989 , "Methods of Preventing Crystal Growth and Particle Aggregation in Nanoparticle Preparations;" 6,270,806 , "Use of PEG-derivatized lipids as surfactant stabilizers for nanoparticle compositions;" 6,316,029 , "Rapidly Disintegrating Solid Oral Dosage Forms;" 6,375,986, "Solid dosage form of nanoparticulate compositions comprising a synergistic combination of a polymeric surfactant stabilizer and dioctyl sodium sulfosuccinate;" 6,428,814, "Bioadhesive Nanoparticulate Compositions with Cationic Surfactant Stabilizers;" 6,431,478 , "Small Scale Grinder;" and 6,432,381, "Methods for Targeting Drug Delivery in the Upper and/or Lower Gastrointestinal Tract,". In addition, the U.S. describes patent application no.

20020012675 A1, published Jan. 31, 2002, “Controlled release nanoparticulate compositions” nanoparticulate compositions.

Amorphous small particle compositions are described, for example, in U.S. Pat. patent no.

4,783,484, "Particulate composition and use thereof as an antimicrobial agent;" 4,826,689 , "Processes for preparing particles of uniform size from water-insoluble organic compounds;" 4,997,454, "Process for the Preparation of Uniformly Sized Particles from Insoluble Compounds;" 5,741,522 , "Ultrasmall, Non-Aggregated Porous Particles of Uniform Size for Entrapping Gas Bubbles and Methods;" and 5,776,496, "Ultrasmall porous particles for enhancing ultrasound backscatter."

B. Background related to fenofibrate

The compositions according to the invention comprise a fibrate, preferably fenofibrate. Fenofibrate, also known as 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoic acid, 1-methylethyl ester, is a lipid-regulating agent. The compound is insoluble in water. See The Physicians' Desk Reference, 56th ed., pages 513-516 (2002).

For example, fenofibrate is described in U.S. Pat. Patent No. 3,907,792, "Phenoxyalkylcarboxylic acid derivatives and their preparation;" 4,895,726 for "New Dosage Forms of Fenofibrate;" 6,074,670 and 6,277,405, both relating to "Fenofibrate Pharmaceutical Compositions with High Bioavailability and Methods of Preparation Thereof." U.S. Patent No. 3,907,792 describes a class of phenoxyalkyl carboxyl compounds that include fenofibrate. U.S. patent no. 4,895,726 describes a therapeutic gelatin capsule composition useful in the oral treatment of hyperlipidemia and hypercholesterolemia, containing micronized fenofibrate. U.S. patent No. 6,074,670 refers to fenofibrate immediate release compositions comprising micronized fenofibrate and at least one inert hydrosoluble carrier. U.S. patent no. 4,739,101 describes a process for preparing fenofibrate. U.S. patent No. 6,277,405 is directed to micronized fenofibrate compositions with a specified dissolution profile. In addition, International Publication No. WO 02/24193, "Stabilized Fibrate Microparticles," published March 28, 2002, describes a microparticulate fenofibrate composition comprising a phospholipid. Finally, International Application No. WO 02/067901, "Fibrate Statin Combinations with Reduced Food Intake/Fasting Effects," published September 6, 2002, describes a microparticulate fenofibrate composition comprising a phospholipid and a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor or statin. US Patent No. 6,368,620 B1 discloses a process for preparing a fenofibrate composition comprising the steps of dissolving a fibrate in a supercritical fluid, spraying the solution through a nozzle to form small particles of the fibrate, forming a suspension of the particles of said fibrate in a liquid, and collect fibrate nanocrystal or nanoparticles where the particle size of the fibrate agent is less than 5000 nm. US patent no. 2002/056206 A1 describes a composition comprising small particles containing fenofibrate and phospholipid surface stabilizing substance (Lipoid E80) with an average size in the range of 0.1-2 micrometres.

WO 01/80828, "Improved water-insoluble drug particle process", and International Publication No. WO 02/24193, "Stabilized fibrate microparticles," describe a process for preparing small particle compositions of drugs with poor water solubility. The method requires the preparation of a mixture of a drug and one or more surfactants, followed by heating the drug mixture to at or above the melting point of the drug with poor water solubility. The heated suspension is then homogenized. The use of such a heating process is undesirable, as heating the drug to its melting point destroys the crystal structure of the drug. On cooling, the drug may be amorphous or recrystallized in another isoform, thereby producing a composition that is physically and structurally different from what is desired. Such a "different" composition may have different pharmacological properties. This is important as the U.S. Food and Drug Administration (USFDA) approval of a drug compound requires that the drug compound be stable and manufactured using a repeatable process.

WO 03/013474, "Nanoparticle formulations of fenofibrate", published February 20, 2003, describes fibrate compositions comprising vitamin E-TGPS (polyethylene glycol (PEG)-derivatized vitamin E). The fibrate compositions of this reference comprise particles of fibrate and vitamin E-TPGS having an average diameter of from about 100 nm to about 900 nm (page 8, lines 12-15 of WO 03/013474), a D50 of 350-750 nm and a D99 of 500 to 900 nm (page 9, lines 11-13 of WO 03/013474) (50% of the particles in the composition fall below a "D50" and 99% of the particles in a composition fall below a D99). The reference does not teach that the disclosed compositions show minimal or no variability when administered under fasted or non-fasted conditions.

Several clinical studies have shown that elevated levels of total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apo B), an LDL membrane complex, are associated with human atherosclerosis. Likewise, reduced levels of high-density lipoprotein cholesterol (HDL-C) and its transport complex, apolipoprotein A (apo A2 and apo AII), are associated with the development of atherosclerosis. Epidemiological investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C, LDL-C and triglycerides, and inversely with the level of HDL-C.

Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides, and triglyceride-rich lipoprotein (VLDL) in treated patients. Treatment with fenofibrate also results in increases in high-density lipoprotein (HDL) and apolipoprotein apoAI and apoAII. See The Physicians' Desk Reference, 56th ed., pages 513-516 (2002).

Because fibrates, including fenofibrate, are insoluble in water, significant bioavailability can be problematic. In addition, conventional fibrate formulations, including fibrate formulations, have dramatically different effects depending on the fed or fasted state of the patient. Finally, conventional fibrate formulations, including fenofibrate formulations, require relatively large doses to achieve the desired therapeutic effects. There is a need for nanoparticulate fibrate formulations that overcome these and other problems associated with prior conventional microcrystalline fibrate formulations. The present invention satisfies these needs.

SUMMARY OF THE INVENTION

The present invention relates to nanoparticle compositions as defined in claim 1, which comprise a fibrate, preferably fenofibrate. The compositions comprise a fibrate, preferably fenofibrate, and at least one surface stabilizer (surface stabilizing agent) adsorbed on the surface of the fibrate particles. At least 99% of the fibrate particles by weight, preferably the fenofibrate particles, have a particle size of less than about 500 nm or that at least 50% of the fibrate particles by weight have a particle size of less than 350 nm.

A preferred dosage form according to the invention is a solid dosage form, although any other pharmaceutically acceptable dosage form can be used.

Another aspect of the present invention is directed to pharmaceutical compositions comprising a nanoparticulate fibrate composition, preferably fenofibrate composition according to the invention. The pharmaceutical compositions comprise a fibrate, preferably fenofibrate, at least one surfactant stabilizer and a pharmaceutically acceptable carrier, as well as any desired excipients.

One embodiment of the invention comprises a fibrate composition, preferably a fenofibrate composition, in which the pharmacokinetic profile of the fibrate is not affected by whether the individual ingesting the composition is in a fasting state or is consuming food, particularly as defined through the Cmax and AUC guidelines provided by the U.S. Food and Drug Administration and the corresponding European Regulatory Office (EMEA).

Another aspect of the invention is directed to a nanoparticulate fibrate composition, preferably fenofibrate composition, with improved pharmacokinetic profiles compared to conventional microcrystalline fibrate formulations such as Tmax, Cmax and AUC.

In yet another embodiment, the invention comprises a fibrate composition, preferably the fenofibrate composition, wherein the administration of the composition to a fasting subject is bioequivalent to the administration of the composition to a fed subject, particularly as defined by the Cmax and AUC guidelines provided by the U.S. Food and Drug Administration and the corresponding European Regulatory Office (EMEA).

Another embodiment of the invention is directed to nanoparticulate fibrate compositions, preferably fenofibrate compositions, which additionally comprise one or more compounds that are useful in the treatment of dyslipidemia, hyperlipidemia, hypercholesterolemia, cardiovascular diseases or related conditions.

Another embodiment of the invention includes, but is not limited to, nanoparticulate fibrate compositions, preferably fenofibrate compositions, which compared to conventional non-nanoparticulate formulations of a fibrate, especially a fenofibrate such as TRICOR <® > (160 mg microcrystalline fenofibrate tablets or 200 mg microcrystalline fenofibrate capsule formulations), have one or more of the following characteristics: (1) Smaller tablet or other solid dosage form size; (2) smaller doses of the drug are required to achieve the same pharmacological effect; (3) increased bioavailability; (4) substantially similar pharmacokinetic profiles for the nanoparticulate fibrate composition, preferably the fenofibrate composition, when administered in a fasted state as in a fed state; (5) an increased dissolution rate of the nanoparticulate fibrate composition, preferably the fenofibrate composition; and (6) bioadhesive fibrate composition, preferably fenofibrate composition.

This invention further comprises a method for producing a nanoparticulate fibrate composition, preferably a fenofibrate composition, according to the invention. Such a method comprises bringing a fibrate, preferably fenofibrate, and at least one surface stabilizing agent into contact for a period of time and under conditions sufficient to provide a nanoparticulate fibrate composition, and preferably a fenofibrate composition. One or more of the surface stabilizing agents can be brought into contact with a fibrate, preferably a fenofibrate, either before, during or after the reduction of the fibrate size.

The present invention is also directed to treatment methods using the nanoparticulate fibrate compositions, preferably fenofibrate compositions, according to the invention for conditions such as hypercholesterolemia, hypertriglyceridemia, coronary heart disease and peripheral vascular disease (including symptomatic carotid artery disease). The compositions according to the invention can be used as additional therapy to diet for the reduction of LDL-C, total-C, triglycerides and Apo B in adult patients with primary hypercholesterolemia or mixed dyslipidemia (Fredrickson types IIa and IIb). The compositions can also be used as additional therapy to diet for the treatment of adult patients with hypertriglyceridemia (Fredrickson types IV and V hyperlipidemia). Markedly elevated levels of serum triglycerides (eg >2000 mg/dl) may increase the risk of developing pancreatitis. Such methods comprise administering, to an individual, a therapeutically effective amount of a nanoparticulate fibrate composition, preferably a fenofibrate composition, according to the invention. Other treatment methods using the nanoparticulate compositions according to the invention are known to professionals in the field.

Both the foregoing general description and the subsequent detailed description are exemplary and explanatory and are not intended to provide further explanation of the claimed invention. Other objects, advantages and novel features will be readily apparent to those skilled in the art following the detailed description of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Shows the fenofibric acid concentration (μg/ml) over a period of 120

minutes for a single dose of: (a) A 160 mg nanoparticulate fenofibrate tablet administered to a fasting subject; (b) a 160 mg nanoparticulate fenofibrate tablet administered to a high fat fed subject; and (c) a 200 mg microcrystalline (TRICOR <®>; Abbott Laboratories, Abbott Park, IL) capsule administered to a low-fat fed subject; and

Figure 2: Shows the fenofibric acid concentration (μg/ml) over a 24 hour period for a single dose of: (a) A 160 mg nanoparticulate fenofibrate tablet administered to a fasting subject; (b) a 160 mg nanoparticulate fenofibrate tablet administered to a high-fat fed subject; and (c) a 200 mg microcrystalline (TRICOR<®>; Abbott Laboratories, Abbott Park, IL) capsule administered to a low-fat fed subject.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to nanoparticulate compositions comprising a fibrate, preferably fenofibrate. The compositions comprise a fibrate, preferably a fenofibrate, and preferably at least one surface stabilizing agent adsorbed on the surface of the drug. At least 99% of the nanoparticulate fibrate, preferably fenofibrate particles, based on weight, have a particle size of less than about 500 nm or that at least 50% of the fibrate particles by weight have a particle size of less than 350 nm.

According to the teachings of the '684 patent and as exemplified in the examples below, not every combination of surface stabilizing agents and active agent will result in a stable nanoparticulate composition. It was surprisingly discovered that stable, nanoparticulate fibrate formulations, preferably fenofibrate formulations, can be prepared.

The advantages of the nanoparticulate fibrate formulations, preferably the fenofibrate formulations, of the invention compared to conventional non-nanoparticulate formulations of a fibrate, especially a fenofibrate such as TRICOR <® > (microcrystalline fenofibrate tablet or capsule formulations) include, but are not limited to: (1) Less size of tablet or other solid dosage form; (2) smaller doses of drug are required to achieve the same pharmacological effect; (3) increased bioavailability; (4) substantially similar pharmacokinetic profiles of the nanoparticulate fibrate compositions, preferably the fenofibrate compositions when administered in the fasted state versus the non-fasted state; (5) improved pharmacokinetic profiles; (6) bioequivalence of the nanoparticulate nanofibrate compositions, preferably the fenofibrate compositions, when administered in the fasted state versus the non-fasted state; (7) an increased dissolution rate of the nanoparticulate fibrate compositions, preferably the fenofibrate compositions; (8) bioadhesive fibrate compositions, preferably fenofibrate compositions; and (9) the nanoparticulate fibrate compositions, preferably the fenofibrate compositions, can be used in conjunction with other active agents useful for the treatment of dyslipidemia, hyperlipidemia, hypercholesterolemia, cardiovascular diseases, or related conditions.

The present invention also includes nanoparticulate fibrate compositions, preferably fenofibrate compositions, together with one or more non-toxic physiologically acceptable carriers, adjuvants or vehicles, collectively referred to as carriers. The compositions may be formulated for parenteral injection (eg, intravenous, intramuscular or subcutaneous), oral administration in solid, liquid or aerosol form, vaginal, nasal, rectal, ocular, topical (powders, ointments or drops), buccal, intracisternal, intraperitoneal or topical administration and such.

A preferred dosage form according to the invention is a solid dosage form, although any other pharmaceutically acceptable dosage form can be used. Examples of solid dosage forms include, but are not limited to, tablets, capsules, sachets, lozenges, powders, pills or granules, and the solid dosage form can be, for example, a solidified dosage form, controlled release dosage form, lyophilized dosage form, delayed release dosage form , extended release dosage form, pulsed release dosage form, mixed immediate release and controlled release dosage form or a combination thereof. A fixed tablet dose formulation is preferred.

The present invention is described herein using several definitions as indicated below and throughout the description.

As used herein, "approximately" will be understood by those skilled in the art and will vary to some extent in relation to the context in which it is used. If there are uses of the term that are not clear to professionals in the field in the context in which it is used, "approximately" will mean plus or minus 10% of the specific designation.

As used herein, with reference to stable fibrate particles, preferably fenofibrate particles, "stable" includes, but is not limited to, one or more of the following parameters: (1) That the fibrate particles do not significantly flocculate or agglomerate as a result of interparticle attractive forces or on otherwise significantly increases in particle size over time; (2) that the physical structure of the fibrate particles, preferably the fenofibrate particles, does not change over time such as through transformation from an amorphous phase to a crystalline phase; (3) that the fibrate particles, preferably the fenofibrate particles, are chemically stable; and/or (4) where the fibrate has not been exposed to a heating step at or above the melting point of the fibrate in the preparation of the nanoparticles according to the invention.

A. Preferred characteristics of the fibrate composition according to the invention

1. Increased bioavailability

The fibrate formulations, preferably the fenofibrate formulations, according to the invention have increased bioavailability at the same dose of the same fibrate, and require smaller doses compared to previously known conventional fibrate formulations, preferably fenofibrate formulations.

For example, as shown in Example 6, the administration of a 160 mg nanoparticulate fenofibrate tablet in a fasted state is not bioequivalent to the administration of a 200 mg conventional microcrystalline fenofibrate capsule (TRICOR <®>) in a non-fasted state, in accordance with regulatory guidelines . According to the U.S. According to the FDA's guidelines, two methods or products are bioequivalent if the 90% confidence intervals (CI) for AUC and Cmax are between 0.80 and 1.25 (Tmax measurements are not relevant for bioequivalence for regulatory purposes). To demonstrate bioequivalence between two compounds or conditions of administration in accordance with European EMEA guidelines, the 90% CI for AUC must be between 0.80 and 1.25 and the 90% CI for Cmax must be between 0.70 and 1.43.

The non-bioequivalence is significant as it means that the nanoparticulate fenofibrate dosage form shows significantly greater drug absorption. For the nanoparticulate fenofibrate dosage form to be bioequivalent to the conventional microcrystalline fenofibrate dosage form (eg TRICOR <®>), the nanoparticulate fenofibrate dosage form must contain significantly less drug. Consequently, the nanoparticulate fenofibrate dosage form significantly increases the bioavailability of the drug.

Furthermore, as shown in Example 6 below, the administration of a 160 mg nanoparticulate fenofibrate tablet in the non-fasting state is bioequivalent to the administration of a 200 mg conventional microcrystalline fenofibrate capsule (TRICOR®) in the non-fasting state. Consequently, the nanoparticulate fenofibrate dosage form requires less drug to achieve the same pharmacological action observed with the conventional microcrystalline fenofibrate dosage form (eg TRICOR <®>). The nanoparticulate fenofibrate dosage form therefore has an increased bioavailability compared to the conventional microcrystalline fenofibrate dosage form (for example TRICOR <®>).

Greater bioavailability of the fibrate compositions according to the invention can enable a fixed dosage form with a smaller size. This is particularly significant for patient populations such as the elderly, young people and children. In one embodiment of the invention, a stable solid dosage form of fenofibrate composition comprises: (a) A therapeutically effective dose of 145 mg of particles of fenofibrate or a salt thereof; and (b) at least one surface stabilizing agent associated with the surface thereof. Characteristics of the composition include: (i) the fenofibrate particles have an effective average particle size of less than about 500 nm; (ii) the fixed dose is bioequivalent to TRICOR <® >160 mg tablet, where bioequivalence is established using a 90% confidence interval of between 0.80 and 1.25 for both Cmax and AUC or a 90% confidence interval of between 0 .80 and 1.25 for AUC and a 90% confidence interval of between 0.70 and 1.43 for Cmax; and (iii) the fixed dose is approximately 10% less than the TRICOR <®> tablet. In another embodiment of the invention, a stable solid dosage form of a fenofibrate composition comprises: (a) A therapeutically effective dose of 48 mg of fenofibrate particles or a salt thereof; and (b) at least one surface stabilizing agent associated with the surface thereof. The properties of the composition include: (i) the fenofibrate particles have an effective average particle size of less than about 500 nm; (ii) the fixed dose is bioequivalent to the TRICOR <® >54 mg tablet where bioequivalence is established through a 90% confidence interval of between 0.80 and 1.25 for both Cmax and AUC or a 90% confidence interval of between 0.80 and 1.25 for AUC and a 90% confidence interval of between 0.70 and 1.43 for Cmax; and (iii) the fixed dose is approximately 10% less than the TRICOR <®> tablet.

2. Improved pharmacokinetic profiles

The invention also provides fibrate compositions, preferably fenofibrate compositions, which have a desired pharmacokinetic profile when administered to mammalian subjects. The desired pharmacokinetic profile of the fibrate compositions, preferably the fenofibrate compositions, comprises the parameters: (1) That the Tmax of a fibrate, preferably a fenofibrate, when assayed in the plasma of the mammalian subject, is less than from about 6 to about 8 hours, preferably the Tmax is parameter of the pharmacokinetic profile less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour, or less than about 30 minutes after administration. The desired pharmacokinetic profile as used herein is the pharmacokinetic profile measured after the initial dose of a fibrate, preferably a fenofibrate. The compositions may be formulated in any manner as described below and known to those skilled in the art.

Currently marketed formulations of fenofibrate include tablets, i.e. TRICOR <®> tablets, sold by Abbott Laboratories. According to the description of TRICOR <®>, the pharmacokinetic profile of the tablets contains parameters such that the median Tmax is 6-8 hours (Physicians Desk Reference, 56th edition, 2002). Because the compound is practically insoluble in water, the absolute bioavailability of TRICOR <® >cannot be determined (Physicians Desk Reference, 56th edition, 2002). The compositions according to the invention improve at least the Tmax parameter of the pharmacokinetic profile of a fibrate, preferably fenofibrate.

A preferred fibrate formulation, preferably a fenofibrate formulation, according to the invention has, in pharmacokinetic comparability testing with a commercial formulation of the same fibrate such as TRICOR <®> tablets from Abbott Laboratories for fenofibrate, a Tmax no greater than about 90%, no greater than about 80%, not greater than about 70%, not greater than about 60%, not greater than about 50%, not greater than about 30% or not greater than about 25% of the Tmax of a standard commercial fibrate formulation such as TRICOR <®> Tablets for Fenofibrate.

Any formulation with the desired pharmacokinetic profile is suitable for administration according to the present methods. Examples of formulation types with such profiles are liquid dispersions, gels, aerosols, ointments, creams, solid dosage forms, etc. of a nanoparticulate fibrate, preferably nanoparticulate fenofibrate.

In a preferred embodiment of the invention, a fenofibrate composition according to the invention comprises fenofibrate or a salt thereof which when administered to a human as a dose of about 160 mg gives an AUC of about 139 μg/ml/hour.

In yet another preferred embodiment of the invention, a fenofibrate composition of the invention comprises fenofibrate and has a Cmax under fasting conditions that is greater than the Cmax under high fat feeding (HFF) conditions when administered to a human.

3. The pharmacokinetic profiles of the fibrate compositions according to the invention are not affected by the fasting or non-fasting state of the individual consuming the compositions

The invention comprises a fibrate composition, preferably a fenofibrate composition, in which the pharmacokinetic profile of the fibrate is not significantly affected by whether the individual consuming the composition is fasting or not when it is administered to a human. This means that there is no significant difference in the amount of drug absorbed or the rate of drug absorption when the nanoparticulate fibrate compositions, preferably the fenofibrate compositions, are administered in the fasted versus non-fasted state.

For conventional fenofibrate formulations, i.e. TRICOR <®>, absorption of fenofibrate is increased by approximately 35% when administered with food. This significant difference in observed absorption with conventional fenofibrate formulations is undesirable. The fibrate formulations, preferably the fenofibrate formulations, of the invention overcome this problem as the fibrate formulations reduce or preferably substantially eliminate significantly different levels of absorption when administered under fasting compared to non-fasting conditions when administered to a human.

In a preferred embodiment of the invention, a fenofibrate composition according to the invention comprises about 145 mg of fenofibrate and exerts minimal or no food effects when administered to a human. In another preferred embodiment of the invention, the fenofibrate composition of the invention comprises about 48 mg of fenofibrate and exhibits minimal or no food effect when administered to a human.

As shown in Example 6, the pharmacokinetic parameters of the fenofibrate compositions according to the invention are the same when the composition is administered in the fasted and non-fasted state when administered to a human. Specifically, there was no significant difference in the rate or amount of drug absorption when the fenofibrate formulation was administered in the non-fasted versus fasted state. The fibrate compositions, and preferably the fenofibrate compositions, according to the invention therefore essentially eliminate the effect of food on the pharmacokinetics of the fibrate when administered to a human.

Advantages of a dosage form that substantially eliminates the effect of food include an increase in the individual's convenience and thereby increases the individual's compliance, as the individual does not have to ensure that they are taking a dose either with or without food. This is significant as an increase in the medical condition for which the drug is prescribed can be observed as in poor individual compliance, i.e. cardiovascular problems for poor individual compliance with a fibrate such as fenofibrate.

4. Bioequivalence of the fibrate compositions according to the invention when administered in the fasting versus non-fasting state

The invention also includes a fibrate composition, preferably a fenofibrate composition, where administration of the composition to an individual in a fasting state is bioequivalent to administration of the composition to an individual in a non-fasting state. "Bioequivalence" is established through a 90% confidence interval (CI) of between 0.80 and 1.25 for both Cmax and AUC under the USFDA's regulatory guidelines, or a 90% CI for AUC of between 0.80 and 1.25 and a 90% CI for Cmax of between 0.70 and 1.43 under the European EMEA regulatory guidelines.

The difference in absorption of the fibrate composition, preferably the fenofibrate composition, of the invention when administered in the non-fasted versus fasted state is preferably less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5% or less than about 3%.

As shown in Example 6, the administration of a fenofibrate composition according to the invention in a fasted state was bioequivalent to the administration of a fenofibrate composition according to the invention in a non-fasting state, in accordance with regulatory guidelines. According to USFDA guidelines, two products or methods are bioequivalent if the 90% confidence intervals (CI) for Cmax (peak concentration) and AUC (area under the concentration/time curve) are between 0.80 and 1.25. For Europe, the test for bioequivalence is if two products or procedures have a 90% CI for AUC between 0.80 and 1.25 and a 90% CI for Cmax between 0.70 and 1.43. The fibrate compositions, preferably the fenofibrate compositions, according to the invention satisfy both the American and the European guidelines for bioequivalence for administration in the non-fasting versus fasting state.

5. Dissolution profiles for the fibrate compositions according to the invention The fibrate compositions, preferably the fenofibrate compositions, according to the invention have surprisingly dramatic dissolution profiles. Rapid dissolution of an administered active agent is preferred, as faster dissolution usually results in faster onset of action and greater bioavailability. To improve the dissolution profile and bioavailability of fibrates, and especially fenofibrate, it would be useful to increase the drug's dissolution so that it can reach a level close to 100%.

The fibrate compositions, preferably the fenofibrate compositions, according to the invention preferably have a dissolution profile where at least approximately 20% of the composition is dissolved within approximately 5 minutes. In another embodiment of the invention, at least about 30% or about 40% of the fibrate composition, preferably the fenofibrate composition, is dissolved within about 5 minutes. In yet another embodiment of the invention, preferably at least about 40%, about 50%, about 60%, about 70% or about 80% of the fibrate composition, preferably the fenofibrate composition, is dissolved within about 10 minutes. Finally, in another embodiment of the invention, preferably at least about 70%, about 80%, about 90% or about 100% of the fibrate composition, preferably the fenofibrate composition, is dissolved within about 20 minutes.

The resolution is preferably measured in a medium that is discriminating. Such a dissolution medium will give two very different dissolution curves for two products with very different dissolution profiles in gastric juices; that is, the dissolution medium is predictive of in vivo dissolution of a composition. An example of a dissolution medium is an aqueous medium containing the surfactant sodium lauryl sulfate at 0.025 M. Determination of the amount of solute can be performed by spectrophotometry. The rotating leaf method (European pharmacopoeia) can be used to measure dissolution.

6. Redispersibility profiles of the fibrate compositions according to the invention

A further feature of the fibrate compositions, preferably the fenofibrate compositions, according to the invention is that the compositions redisperse so that the effective average particle size of the redispersed fibrate particles is less than about 500 nm. This is significant, because if the nanoparticle fibrate compositions according to the invention did not redisperse to a substantially nanoparticulate particle size, the dosage form would lose the advantages that result from formulating the fibrate in a nanoparticulate particle size.

This is because the nanoparticulate active preparation composition takes advantage of the tiny particle size of the active agent; if the active agent does not redisperse to the tiny particle size upon administration, then "clumps" or agglomerated particles of active agent will form as a result of the extremely high free surface active energy of the nanoparticulate system and the thermodynamic driving force to achieve an overall reduction in free Energy. With the formation of such agglomerated particles, the bioavailability of the dosage form may fall well below that observed with the liquid dispersion form of the nanoparticulate active agent.

Furthermore, the nanoparticulate fibrate compositions, preferably the fenofibrate compositions, according to the invention show dramatic redispersion of the nanoparticulate fibrate particles upon administration to a mammal such as a human or animal, as demonstrated through reconstitution/redispersion in a biorelevant aqueous medium so that the effective average particle size of the redispersed the fibrate particles are smaller than about 500 nm. Such biorelevant aqueous media can be any aqueous medium having the desired ionic strength and pH value, which form the basis of the biorelevance of the medium. The desired pH value and ionic strength are those representative of physiological conditions found in the human body. Such biorelevant aqueous media can for example be aqueous electrolyte solutions or aqueous solutions of any salt, acid or base, or a combination thereof which has the desired pH value and ionic strength.

Biorelevant pH value is well known to those skilled in the art. For example, the pH value in the stomach is in the range from slightly below 2 (but usually greater than 1) up to 4 or 5. In the small intestine, the pH value is in the range from 4 to 6 and in the large intestine in the range from 6 to 8. Biorelevant ionic strength is also well known to those skilled in the art. Gastric fluid in the fasting state has an ionic strength of approximately 0.1 M, while intestinal fluid in the fasting state has an ionic strength of approximately 0.14. See, for example, Lindahl et al., "Characterization of Fluids from the Stomach and Proximal Jejunum in Men and Women," Pharm. Res., 14 (4): 497-502 (1997).

It is believed that the pH and ionic strength of the test solutions are more critical than the specific chemical content. Accordingly, suitable pH and ionic strength values can be achieved through several combinations of strong acids, strong bases, salts, single or multiple conjugate acid-base pairs (that is, weak acids and corresponding salts of that acid), monoprotic and polyprotic electrolytes, etc.

Representative electrolyte solutions can be, but are not limited to, HCl solutions in the concentration range from about 0.001 to about 0.1 M and NaCl solutions in the concentration range from about 0.001 to about 0.1 M and mixtures thereof. For example, electrolyte solutions can be, but are not limited to, about 0.1 M HCl or less, about 0.01 M HCl or less, about 0.001 M HCl or less, about 0.1 M NaCl or less, about 0.01 M NaCl or less, about 0.001 M NaCl or less, and mixtures thereof. Of these electrolyte solutions, 0.01 M HCl and/or 0.1 M NaCl are most representative of fasting human physiological conditions, due to the pH and ionic strength conditions of the proximal gastrointestinal tract.

Electrolyte concentrations of 0.001 M HCl, 0.01 M HCl and 0.1 M HCl correspond to pH 3, pH 2 and pH 1 respectively. A 0.01 M HCl solution therefore stimulates the typical acid conditions found in the stomach. A solution of 0.1 M NaCl provides a reasonable approximation of the ionic strength conditions found in the body, including the gastrointestinal fluids, although concentrations higher than 0.1 M can be used to simulate non-fasting conditions in the human GI tract.

Examples of solutions are salts, acids, bases or combinations thereof that exhibit the desired pH value and ionic strength including, but not limited to, phosphoric acid/phosphate salts sodium, potassium and calcium salts of chloride, acetic acid/acetate salts sodium, potassium and calcium salts of chloride, carbonic acid/bicarbonate salts sodium, potassium and calcium salts of chloride, and citric acid/citrate salts sodium, potassium and calcium salts of chloride.

In other embodiments of the invention, at least 99% of the redispersed fibrate particles, preferably the fenofibrate particles, based on weight, according to the invention (redispersed in an aqueous, biorelevant or any other suitable medium) have a particle size of less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm or less than about 50 nm by light scattering methods, microscopy or other suitable methods.

Redispersibility can be tested using any suitable means known to those skilled in the art. See, for example, parts of the U.S. Patent No. 6,375,986, "Solid nanoparticulate dosage compositions comprising a synergistic combination of a polymeric surfactant and dioctyl sodium sulfosuccinate."

7. Bioadhesive fibrate compositions

Bioadhesive fibrate compositions, preferably fenofibrate compositions, according to the invention comprise at least one cationic surface stabilizing agent which is described in more detail below. Bioadhesive formulations of fibrate, especially fenofibrate, show exceptional bioadhesion to biological surfaces such as mucus. The term bioadhesion refers to any attractive interaction between two biological surfaces or between a biological and a synthetic surface. In the case of bioadhesive nanoparticulate compositions, the term bioadhesion is used to describe the adhesion between the nanoparticulate fibrate compositions, preferably the fenofibrate compositions, and a biological substrate (ie gastrointestinal mucosa, lung tissue, nasal mucosa, etc.). See, for example, U.S.

Patent No. 6,428,814, "Bioadhesive Nanoparticle Compositions with Cationic Surface Stabilizers".

There are basically two mechanisms that can be responsible for this bioadhesion phenomenon: Mechanical or physical interactions and chemical interactions. The first of these, mechanical or physical mechanisms, involves the physical interlocking or interpenetration between a bioadhesive device and the receptor tissue, which results from a good wetting of the bioadhesive surface, swelling of the bioadhesive polymer, penetration of the bioadhesive device into in a crack in the tissue surface, or interpenetration of bioadhesive composition chains with those adjacent to mucous tissue or other such related tissue. The other possible mechanism of bioadhesion incorporates forces such as ionic attraction, dipolar forces, van der Waals interactions and hydrogen bonds. It is this form of bioadhesion that is primarily responsible for the bioadhesive properties of the nanoparticulate fibrate compositions, preferably the fenofibrate compositions, according to the invention. However, physical and mechanical interactions may also play a secondary role in the bioadhesion of such nanoparticulate compositions.

The bioadhesive fibrate compositions, preferably the fenofibrate compositions, according to the invention are applicable in any situation where it is desirable to apply the compositions to a biological surface. The bioadhesive fibrate compositions, preferably the fenofibrate compositions, coat the target surface as a continuous and uniform film which is invisible to the naked human eye.

A bioadhesive fibrate composition, preferably a fenofibrate composition, lowers the passage of the composition and individual fibrate particles will also most likely attach to tissues other than mucosal cells and therefore provide a prolonged exposure of the fibrate and thereby increase the absorption and bioavailability of the administered dose.

8. Fibrate compositions used together with other active agents

The fibrate compositions, preferably the fenofibrate compositions, according to the invention may additionally comprise one or more compounds that are useful in the treatment of dyslipidemia, hyperlipidemia, hypercholesterolemia, cardiovascular diseases or related conditions, or the fibrate compositions, preferably the fenofibrate compositions, can be administered together with such a compound. Examples of such compounds include, but are not limited to, statins or HMG CoA reductase inhibitors and antihypertensive agents. Examples of antihypertensive agents include, but are not limited to, diuretics ("water pills"), beta blockers, alpha blockers, alpha-beta blockers, sympathetic nerve inhibitors, angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers, angiotensin receptor blockers (formerly medical name angiotensin-2- receptor antagonists known as "sartans").

Examples of statins or HMG CoA reductase inhibitors include, but are not limited to, lovastatin; pravastatin; simvastatin; velostatin; atorvastatin (Lipitor ® ) and other 6-[2-(substituted pyrrol-1-yl)alkyl]pyran-2-ones and derivatives as described in U.S. Pat. Patent No. 4,467,576); fluvastatin (Lescol <®>); fluindostatin (Sandoz XU-62-320); pyrazole analogues of mevalonolactone derivatives as described in PCT application WO 86/03488; rivastatin and other pyridyldihydroxyheptenoic acids as described in European Patent 491226A; Searle=s SC-45355 (a 3-substituted pentanedioic acid derivative); dichloroacetate; imidazole analogues of mevalonolactone as described in PCT application WO 86/07054; 3-carboxy-2-hydroxypropanephosphonic acid derivatives as described in French Patent No. 2,596,393; 2,3-disubstituted pyrrole, furan and thiophene derivatives as described in European Patent Application No. 0221025; naphthyl analogs of mevalonolactone as described in U.S. Pat. Patent No. 4,686,237; octahydronaphthalenes such as those described in U.S. Pat. Patent No. 4,499,289; keto analogs of mevinolin (lovastatin) as described in European Patent Application No. 0,142,146 A2; phosphinic acid compounds; as well as other HMG CoA reductase inhibitors.

B. Compositions

The invention provides compositions comprising fibrate particles, preferably fenofibrate particles, and at least one surface stabilizing agent. The surface stabilizing agents are preferably adsorbed on, or in association with, the fibrate particle surface, preferably the fenofibrate particle surface. The surface stabilizing agents particularly useful herein preferably physically adhere to, or in association with, the surface of the nanoparticulate fibrate particles but do not react chemically with the fibrate particles or themselves. Individually adsorbed molecules of surface stabilizing agents are essentially free of intermolecular cross-links.

The present invention also includes fibrate compositions, preferably fenofibrate compositions, together with one or more non-toxic physiologically acceptable carriers, adjuvants or vehicles, collectively referred to as carriers.

The compositions may be formulated for parenteral injection (eg, intravenous, intramuscular, or subcutaneous), oral administration in solid, liquid, or aerosol form, vaginal, nasal, rectal, ocular, topical (powders, ointments, or drops), buccal, intracisternal, intraperitoneal, or topical administration and the like.

1. Fibrate particles

As used herein, the term "fibrate" means all of the fibric acid derivatives useful in the methods described herein, for example, fenofibrate. Fenofibrate is a fibrate compound, other examples of fibrate are bezafibrate, beclobrate, binifibrate, ciplofibrate, clinofibrate, clofibrate, clofibric acid, etofibrate, gemfibrozil, nikofibrate, pirifibrate, ronifibrate, simfibrate, teofibrate, etc. See U.S. Patent No. 6,384,062.

Commonly, fibrates are used for conditions such as hypercholesterolaemia, mixed lipidaemia, hypertriglyceridemia, coronary heart disease and peripheral vascular disease (including symptomatic carotid artery disease) and prevention of pancreatitis. Fenofibrates may also be useful in preventing the development of pancreatitis (inflammation of the pancreas) caused by high triglyceride levels in the blood. Fibrates are known to be useful in the treatment of renal failure (U.S. Patent No.

4,250,191). Fibrates can also be used for other indications where lipid-regulating agents are typically used.

As used herein, the term "fenofibrate" is used to mean fenofibrate (2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoic acid, 1-methylethyl ester or a salt thereof.

Fenofibrate is well known and easily recognized by those skilled in the art. It is used to lower triglyceride levels (fat-like compounds) in the blood. Specifically, fenofibrate reduces elevated LDL-C, total-C, triglycerides and Apo-B and increases HDL-C. The drug is also approved as adjunctive therapy for the treatment of hypertriglyceridemia, a disorder characterized by elevated levels of very low density lipoprotein (VLDL) in the plasma.

The mechanism of action of fenofibrate has not been fully established in humans.

Fenofibric acid, the active metabolite of fenofibrate, apparently lowers plasma triglycerides by inhibiting triglyceride synthesis and resulting in a reduction of VLDL released into the circulation, and also by stimulating the catabolism of triglyceride-rich lipoprotein (that is, VLDL). Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal subjects by increasing urinary excretion of uric acid.

The absolute bioavailability of conventional microcrystalline fenofibrate cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection. However, fenofibrate is well absorbed from the gastrointestinal tract. After oral administration in healthy volunteers, approximately 60% of a single dose of conventionally radiolabeled fenofibrate (ie, TRICOR <®>) was visible in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. See http://www.rxlist.com/cgi/generic3/fenofibrate_cp.htm.

After oral administration, fenofibrate is rapidly hydrolysed by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate is detected in plasma.

Fenofibric acid is primarily conjugated with glucuronic acid and excreted in the urine. A small amount of fenofibric acid is reduced at the carbonyl unit to a benzhydrol metabolite which is in turn conjugated with glucuronic acid and excreted in urine. Id.

2. Surface stabilizers

The choice of a surface stabilizer for a fibrate is not obvious and requires extensive experimentation to find a desired formulation. The present invention is therefore directed to the surprising discovery that nanoparticulate fibrate compositions, preferably fenofibrate compositions, can be formed.

Combinations of more than one surface stabilizing agent can be used in the invention. Useful surface stabilizing agents which can be used in the invention include, but are not limited to, known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Surface stabilizing agents include nonionic, anionic, cationic, ionic, and zwitterionic surfactants.

Representative examples of surface stabilizers useful in the invention include, but are not limited to, hydroxypropylmethylcellulose (now known as hypromellose), hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctyl sulfosuccinate, gelatin, casein, lecithin (phosphatides), dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying waxes, sorbitan esters, polyoxyethylene alkyl ethers (for example, macrogolethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (for example, the commercially available Tweens <® > such as, for example, Tween 20 <® >and Tween 80 <® >(ICI Specialty Chemicals)); polyethylene glycols (such as Carbowax's 3550 <® >and 934 <® >(Union Carbide)), polyoxyethylene stearates, colloidal silicon dioxide, phosphates, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hyrpomellose phthalate, non-crystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA) , 4-(1,1,3,3-tetramethylbutyl)phenolic polymer with ethylene oxide and formaldehyde (also known as tyloxapol, superion and triton), poloxamers (for example Pluronics F68 <® >and F108 <® >which are block copolymers of ethylene oxide and propylene oxide); poloxamines (for example, Tetronic 908 <®>, also known as Ploxamin 908 <® >which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, N.J.)); Tetronic 1508 <® >(T-1508) (BASF Wyandotte Corporation), Triton's X-200 <® >which is an alkylaryl polyether sulfonate (Rohm and Haas); Crodestas F-110 <® >which is a mixture of sucrose stearate and sucrose distearate (Croda Inc.); p-isononylphenoxypoly-(glycidol), also known as Olin-IOG <® >or Surfactant 10-G <® >(Olin Chemicals, Stamford, CT); Crodesta's SL-40 <® >(Croda, Inc.); and SA9OHCO which is C18H37CH2(CON(CH3)-CH2(CHOH)4(CH20H)2 (Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl-β-D-glucopyranoside; n-decyl-β-D -maltopyranoside; n-dodecyl-β-D-glucopyranoside; n-dodecyl-β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-glucopyranoside; n-heptyl-β-D-thioglucoside; n-hexyl - β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl-β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; octyl-β-D-thioglucopyranoside; PEG-phospholipid , PEG cholesterol, PEG cholesterol derivative, PEG vitamin A, PEG vitamin E, lysozyme, random copolymers of vinyl pyrrolidone and vinyl acetate and the like.

If desired, the nanoparticulate fibrate compositions, preferably the fenofibrate compositions, according to the invention can be formulated as phospholipid-free.

Examples of useful cationic surface stabilizers include, but are not limited to, polymers, biopolymers, polysaccharides, cellulose compounds, alginates, phospholipids and non-polymeric compounds such as zwitterionic stabilizers, poly-n-methylpyridinium, anthrylpyridinium chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polybrene, polymethyl methacrylate trimethylammonium bromide bromide (PMMTMABr), hexyldecyltrimethylammonium bromide (HDMAB) and polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate.

Other useful cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, phosphonium and quaternary ammonium compounds such as stearyltrimethylammonium chloride, benzyl di(2-chloroethyl)ethylammonium bromide, coconut trimethylammonium chloride or bromide, coconut methyldihydroxyethylammonium chloride or bromide, decyltriethylammonium chloride, decyldimethylhydroxyethylammonium chloride. or bromide, C12-15dimethylhydroxyethylammonium chloride or bromide, coconut dimethylhydroxyethylammonium chloride or bromide, myristyltrimethylammonium methyl sulfate, lauryldimethylbenzylammonium chloride or bromide, lauryldimethyl (ethenoxy)4 ammonium chloride or bromide, N-alkyl-(C12-18)dimethylbenzylammonium chloride, N-alkyl-( C14-18)dimethylbenzylammonium chloride, N-tetradecylmethylbenzylammonium chloride monohydrate, dimethyldidecylammonium chloride, N-alkyl- and (C12-14)dimethyl-1-naphthylmethylammonium chloride, trimethylammonium halide, alkyltrimethylammonium salts and dialkyldimethylammonium salts, lauryltrimethylammonium chloride, ethoxylated alkylamidoalkyldialkylammonium salt and/or an ethoxylated trialkylammonium dialkylbenzene chloride, N Didecyldimethylammonium chloride, N-tetradecyldimethylbenzylammonium, chloride monohydrate, N-alkyl(C12-14)dimethyl-1-naphthylmethylammonium chloride and dodecyldimethylbenzylammonium chloride, dialkylbenzenealkylammonium chloride, lauryltrimethylammonium chloride, alkylbenzylmethylammonium chloride, alkylbenzyldimethylammonium bromide, C12-, C15-, C17-trimethylammonium bromide, dodecylbenzyltriethyldimethylammonium chloride (DAMAC), diallyldiammonium chloride ammonium chlorides , alkyldimethylammonium halides, tricetylmethylammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride (ALIQUAT 336<TM>), POLYQUAT 10<TM>, tetrabutylammonium bromide, benzyltrimethylammonium bromide, choline esters (such as cholinesters of fatty acids), benzalkonium chloride, stearyl chloride and steryl diammonium chloride. ), cetylpyridinium bromide or chloride, halide salts of quaternary polyoxyethyl alkylamines, MIRAPOL<TM >and ALKAQUAT<TM >(Alkaril Chemical Company), alkylpyridinium salts; amines such as alkylamines, dialkylamines, alkanolamines, polyethylene polyamines, N,N-dialkylamine alkyl acrylates and vinylpyridine, amine salts such as laurylamine acetate, stearylamine acetate, alkylpyridinium salt and alkylimidazolium salt and amine oxides; imidazolinium salts; protonated quaternary acrylamides; methylated quaternary polymers such as poly[diallyldimethylammonium chloride] and poly-[N-methylvinylpyridinium chloride]; and cationic guar.

Such examples of cationic surfactants and other useful cationic surfactants are described in J. Cross and E. Singer, Cationic Surfactans: Analytical and Biological Evaluation (Marcel Dekker, 1994); P. and D. Rubingh (publisher), Cationic Surfactants: Physical Chemistry (Marcel Dekker, 1991); and J. Richmond, Cationic Surfactants: Organic Chemistry, (Marcel Dekker, 1990).

Non-polymeric surface stabilizers are any non-polymeric compound such as benzalkonium chloride, a carbonium compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quaternary phosphorus compound, a pyridinium compound, an anilinium compound, an ammonium compound, a hydroxylammonium compound, a primary ammonium compound, a secondary ammonium compound, a tertiary ammonium compound and quaternary ammonium compounds of the formula NR1R2R3R3<(+)>. For compounds with the formula NR1R2R3R3<(+)>:

(i) none of R 1 -R 4 is CH 3 ;

(ii) one of R 1 -R 4 is CH 3 ;

(iii) three of R 1 -R 4 are CH 3 ;

(iv) all R 1 -R 4 are CH 3 ;

(v) two of R1-R4 are CH3, one of R1-R4 is C6H5CH2 and one of R1-R4 is an alkyl chain of less than or equal to seven carbon atoms;

(vi) two of R1-R4 are CH3, one of R1-R4 is C6H5CH2 and one of R1-R4 is an alkyl chain of more than or equal to nineteen carbon atoms;

(vii) two of R1-R4 are CH3 and one of R1-R4 is the group C6H5(CH2)n, where n > 1;

(viii) two of R 1 -R 4 are CH 3 , one of R 1 -R 4 is C 6 H 5 CH 2 and one of R 1 -R 4 comprises at least one heteroatom;

(ix) two of R1-R4 are CH3, one of R1-R4 is C6H5CH2 and one of R1-R4 comprises at least one halogen;

(x) two of R1-R4 are CH3, one of R1-R4 is C6H5CH2 and one of R1-R4 comprises at least one cyclic fragment;

(xi) two of R1-R4 are CH3, one of R1-R4 is a phenyl ring; or

(xii) two of R1-R4 are CH3 and two of R1-R4 are simply aliphatic fragments.

Such compounds include, but are not limited to, behenalkonium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cetylamine hydrofluoride, chlorallyl methenamine chloride (Quaternium-15), distearyldimonium chloride (Quaternium-5), dodecyldimethylethylbenzylammonium chloride (Quaternium-14), -22, Quaternium-26, Quaternium-18 hectorite, dimethylaminoethyl chloride hydrochloride, cysteine hydrochloride, diethanolammonium POE (10)-oleyl ether phosphate, diethanolammonium POE (3)oleyl ether phosphate, tallow alkonium chloride, dimethyldioctadecylammonium bentonite, stearalkonium chloride, domiphene bromide, denatonium benzoate, myristalkonium chloride, laurtrimonium chloride, ethylene diamine dihydrochloride, guanixidine hydrochloride, pyrido -HCl, iofematine hydrochloride, meglumine hydrochloride, methylbenzetonium chloride, myrtrimonium bromide, oleyltrimonium chloride, polyquaternium-1, procaine hydrochloride, cocobetaine, stearalkonium bentonite, stearalkonium hectonite, stearyltrihydroxyethylpropylenediamine dihydrofluoride, tallowtrimonium chloride and hexadecyltrimethylammonium bromide.

In one embodiment of the invention, the preferred one or more surface stabilizing agents according to the invention are any suitable surface stabilizing agent as described below, with the exception of PEG-derivatized vitamin E which is a nonionic compound. In another embodiment of the invention, the preferred one or more surface stabilizing agents according to the invention are any suitable surface stabilizing agent as described below with the exception of phospholipids.

Finally, in another embodiment of the invention, the one or more surface stabilizing agents of the invention are any compound categorized by the USFDA as GRAS ("Generally Recognized As Safe").

Preferred surface stabilizers of the invention include, but are not limited to, hypromellose, docusate sodium (DOSS), Plasdone ® S630 (random copolymer of vinyl pyrrolidone and vinyl acetate in a 60:40 ratio), hydroxypropyl cellulose SL (HPC-SL), sodium lauryl sulfate (SLS ) and combinations of these. Particularly preferred combinations of surfactants include, but are not limited to, hypromellose and DOSS; Plasdone ® S630 and DOSS; HPC-SL and DOSS; and hypromellose, DOSS and SLS.

The surface stimulating agents are commercially available and/or can be prepared using known techniques. Most surface stabilizers are known pharmaceutical excipients and are described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain (The Pharmaceutical Press, 2000).

3. Other pharmaceutical excipients

Pharmaceutical compositions according to the invention may also comprise one or more binders, fillers, lubricants, suspending agents, sweeteners, flavourings, preservatives, buffers, wetting agents, disintegrating agents, foaming agents and other excipients. Such excipients are known in the art.

Examples of fillers are lactose monohydrate, anhydrous lactose and various starches; examples of binders are various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose such as Avicel <® >PH101 and Avicel <® >PH102, microcrystalline cellulose and silicon-added microcrystalline cellulose (ProSolv SMCC<TM>).

Suitable lubricants, including agents that affect the flowability of the powder to be compressed, are colloidal silicon dioxide such as Aerocil <® >200, talc, stearic acid, magnesium stearate, calcium stearate and silica gel.

Examples of sweeteners are any natural or artificial sweetener such as sucrose, xylitol, sodium saccharide, cyclamate, aspartame and acsulfame. Examples of flavorings are Magnasweet <® > (trademark from MAFCO), chewing gum flavor and fruit flavors and the like.

Examples of preservatives are potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol or quaternary compounds such as benzalkonium chloride.

Suitable diluents include pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides and/or mixtures of any of the foregoing compounds. Examples of diluents include microcrystalline cellulose such as Avicel <® >PH101 and Avicel <® >PH102; lactose such as lactose monohydrate, anhydrous lactose and Pharmatose <® >DCL21; dibasic calcium phosphate such as Emcompress <®>; mannitol; starch; sorbitol; sucrose; and glucose.

Suitable disintegrating agents include lightly cross-linked polyvinylpyrrolidone, corn starch, potato starch, corn starch and modified starches, croscarmellose sodium, crospovidone, sodium starch glycolate and mixtures thereof.

Examples of foaming agents are foaming couplers such as an organic acid and a carbonate or bicarbonate. Suitable organic acids include, for example, citric, tartaric, malic, fumaric, adipic, succinic and alginic acids and anhydrides and acid salts. Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate and arginine carbonate. Alternatively, only the sodium bicarbonate component of the foaming couple may be present.

4. Nanoparticulate fibrate particle size

The compositions of the invention contain nanoparticulate fibrate particles, preferably nanoparticulate fenofibrate particles, wherein at least 99% of the fibrate particles by weight have an effective average particle size of less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, less than about 50 nm, as measured by light scattering methods, microscopy, or other suitable methods.

In one embodiment of the invention, at least 99% of the fibrate particles ("D99") have a particle size that is less than about 500 nm, less than about 450 nm, less than about 400 nm, less than about 350 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, or less than about 100 nm. In another embodiment of the invention, at least 50% of the fibrate particles ("D50") have a particle size of less than about 350 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm or less than about 75 nm. In yet another embodiment of the invention, the average particle size of the fibrate composition is less than about 100 nm, less than about 75 nm, or less than about 50 nm.

In the present invention, the D50 value of a nanoparticulate fibrate composition, preferably a fenofibrate composition, is the particle size where less than 50% by weight of the fibrate particles are located. Similarly, D90 is the particle size below which 90% by weight of the fibrate particles are located.

5. Concentration of the fibrate and surface stabilizers

The relative amounts of a fibrate, preferably fenofibrate, and one or more surfactants can vary widely. The optimal amount of the individual components may depend on, for example, the specific fibrate chosen, the hydrophilic lipophilic balance (HLB), melting point and surface tension of aqueous solutions of stabilizers, etc.

The concentration of the fibrate, preferably fenofibrate, can vary from about 99.5 wt% to about 0.001 wt%, from about 95 wt% to about 0.1 wt% or from about 90 wt% to about 0.5 wt%, based on the total combined weight of the fibrate and at least one surfactant, not including other excipients.

The concentration of the at least one surface stabilizing agent can range from about 0.5 wt% to about 99.999 wt%, from about 5.0 wt% to about 99.9 wt% or from about 10 wt% to about 99.5 wt% %, based on the total combined dry weight of the fibrate and the at least one surfactant, not including other excipients.

6. Examples of nanoparticulate fenofibrate tablet formulations

Several examples of fenofibrate tablet formulations according to the invention are given below. These examples are not intended to limit the claims in any way, but rather provide examples of tablet formulations of fenofibrate according to the invention which can be utilized in the methods according to the invention. Such examples of tablets may also include a coating agent.

7. Examples of embodiments of the invention

The invention encompasses a stable fibrate composition comprising: (a) Particles of a fibrate or a salt thereof, wherein the fibrate particles have an average effective particle size of less than about 500 nm; and (b) at least one surface stabilizing agent associated with the surface thereon, wherein the surface stabilizing agent is: (i) Non-PEG derivatized vitamin E; or (ii) categorized by the U.S. Food and Drug Administration as GRAS; or (iii) selected from the group consisting of hypromellose, docusate sodium, Plasdon ® S630, HPC-SL, sodium lauryl sulfate and combinations thereof, wherein the composition does not comprise PEG-derivatized vitamin E; or

(iv) not a phospholipid.

The invention also includes a stable fibrate composition comprising:

(a) Particles of a fibrate or a salt thereof, wherein the fibrate particles have a

(i) particle size wherein D99 is less than about 500 nm; or

(ii) particle size wherein D50 is less than about 350 nm; or

(iii) average particle size is less than about 100 nm; and (b) at least one surface stabilizing agent associated with the surface thereof.

In yet another embodiment, the invention comprises a fibrate composition comprising: (a) Particles of a fibrate or a salt thereof, wherein the fibrate particles have an effective average particle size of less than about 500 nm; and (b) wherein dioctyl sodium sulfosuccinate and hypromellose are associated with the surface thereof; in which the composition does not include PEG-derivatized vitamin E. Such a composition may further include sodium lauryl sulfate.

The invention encompasses a fibrate composition comprising: (a) Particles of a fibrate or a salt thereof, wherein the fibrate particles have an average effective particle size of less than about 500 nm; and (b) at least one surface stabilizing agent associated on the surface thereof; wherein the composition is bioadhesive.

In another embodiment of the invention, a fibrate composition comprising: (a) Particles of a fibrate or a salt thereof, wherein the fibrate particles have an effective average particle size of less than about 500 nm; and (b) at least one surface stabilizing agent associated with the surface thereof, wherein the composition redisperses such that the fibrate particles have a particle size, based on weight, selected from the group consisting of less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm and less than about 50 nm upon administration. The invention also includes a fibrate composition comprising (a) particles of a fibrate or a salt thereof, wherein the fibrate particles have an effective average particle size of less than about 500 nm; and (b) at least one surface stabilizing agent associated with the surface thereof, wherein the composition redisperses in a biorelevant medium such that the fibrate particles have an effective average particle size selected from the group consisting of less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm.

The invention comprises a composition comprising a fibrate or a salt thereof, in which the pharmacokinetic profile of the fibrate is not significantly affected by whether the individual is in a fasting or non-fasting state when the composition is ingested, when it is administered to a human. In another embodiment, the invention comprises a composition comprising a fibrate or a salt thereof, wherein the administration of the composition to an individual in a fasting state is bioequivalent to the administration of the composition to an individual in a non-fasting state, when administered to a human. "Bioequivalence" can be established through a 90% confidence interval of between 0.80 and 1.25 for both Cmax and AUC when administered to a human; or through a 90% confidence interval of between 0.80 and 1.25 for AUC and a 90% confidence interval of between 0.70 and 1.43 for Cmax when administered to a human.

The invention includes a stable fibrate composition wherein at least about 20%, at least about 30%, or at least about 40% of the composition is dissolved within about 5 minutes, wherein the dissolution is measured in a medium that is discriminating and wherein the method of rotating blades (European pharmacopoeia) are used to measure the dissolution. In another embodiment, the invention comprises a stable fibrate composition in which at least 40%, at least about 50%, about 60%, about 70%, or about 80% of the composition is dissolved within about 10 minutes, wherein the dissolution is measured in a medium which is discriminating and in which the method of rotating blades (European pharmacopoeia) is used to measure the dissolution. The invention also includes a stable fibrate composition wherein at least about 70%, at least about 80%, about 90%, or about 100% of the composition is dissolved within about 20 minutes, wherein the dissolution is measured in a medium that is discriminating and wherein the rotating blade method (European Pharmacopoeia) is used to measure the dissolution. Upon redispersion, the fibrate particles in these compositions may have an effective average particle size of less than about 500 nm.

For any of the compositions described above, the fibrate may be fenofibrate or a salt thereof.

In yet another embodiment, the invention comprises a fenofibrate composition comprising a dosage of about 145 mg of fenofibrate particles or a salt thereof, wherein: (a) Said dosage is therapeutically effective; and (b) the composition is bioequivalent to a TRICOR <® >160 mg tablet or 200 mg capsule, wherein the bioequivalence is established through a 90% confidence interval of between 0.80 and 1.25 for both Cmax and AUC or a 90% confidence interval of between 0.80 and 1.25 for AUC and a 90% confidence interval of between 0.70 and 1.43 for Cmax when administered to a human. The invention also includes a fenofibrate composition comprising a dosage of 48 mg of fenofibrate particles or a salt thereof, wherein: (a) Said dosage is therapeutically effective; and (b) the composition is bioequivalent to a TRICOR <® >54 mg tablet, wherein the bioequivalence is established through a 90% confidence interval of between 0.80 and 1.25 for both Cmax and AUC or a 90% confidence interval of between 0.80 and 1.25 for AUC and a 90% confidence interval of between 0.70 and 1.43 for Cmax when administered to a human. For each of these compositions, the fenofibrate particles may have at least one surface stabilizing agent associated with the surface thereof. In addition, the fenofibrate particles may have an effective average particle size of less than about 500 nm. Also for these compositions, the dosage form can be approximately 10% smaller than for a TRICOR <® >160 mg tablet or 200 mg capsule.

In yet another embodiment, the invention comprises a composition comprising about 145 mg of fenofibrate or a salt thereof and which exhibits minimal or no effects of food when administered to a human. The invention includes a composition comprising about 48 mg of fenofibrate or a salt thereof and which exhibits minimal or no effect of food when administered to a human.

D. Methods of Making Nanoparticulate Fibrate Compositions

The nanoparticulate fibrate compositions, preferably the fenofibrate compositions, can be prepared using, for example, grinding, homogenization or precipitation techniques. Examples of methods for preparing nanoparticulate compositions are described in the '684 patent. Methods for preparing nanoparticulate compositions are also described in U.S. Pat. Patent No. 5,518,187, "Method of Milling Pharmaceutical Compounds;" U.S. patent no.

5,718,388, "Continuous Processes for Milling Pharmaceutical Compounds;" U.S. Patent No. 5,862,999, "Methods of Milling Pharmaceutical Compounds;" U.S. Patent No. 5,665,331, "Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers;" U.S. Patent No. 5,662,883, "Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers;" U.S. Patent No. 5,560,932, "Microprecipitation of Nanoparticulate Pharmaceutical Agents;" U.S. Patent No. 5,543,133, "Method of Preparation of X-Ray Contrast Compositions Containing Nanoparticles;" U.S. Patent No. 5,534,270, "Method of Preparation of Stable Drug Nanoparticles;" U.S. Patent No. 5,510,118, "Method of Preparation of Therapeutic Compositions Containing Nanoparticles;" and the U.S. Patent No. 5,470,583, "Method of Making Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation,".

The resulting nanoparticulate fibrate compositions, preferably the fenofibrate compositions, or dispersions can be used in solid or liquid dosage formulations such as liquid dispersions, oral suspensions, gels, aerosols, ointments, requires, controlled release formulations, quick melt formulations, lyophilized formulations, tablets, capsules, delayed release formulations, extended release formulations, pulsed release formulations, mixed immediate release and controlled release formulations, etc.

In one embodiment of the invention, the temperature is kept below the melting point of the fibrate, preferably fenofibrate, if heat is used during the process to prepare the nanoparticulate composition.

1. Grinding to obtain nanoparticulate fibrate dispersions

Milling a fibrate, preferably fenofibrate, to achieve a nanoparticulate dispersion comprises dispersing the fibrate particles in a liquid dispersing medium in which the fibrate is poorly soluble, followed by applying mechanical means in the presence of crushing media to reduce the particle size of the fibrate to the desired effective average the particle size. The dispersion medium can be, for example, water, safflower thistle oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG), hexane or glycol. A preferred dispersing medium is water.

The fibrate particles, preferably the fenofibrate particles, can be reduced in size in the presence of at least one surface stabilizing agent. Alternatively, the fibrate particles can be brought into contact with one or more surface stabilizing agents after grinding. Other compounds, such as a diluent, may be added to the fibrate/surfactant composition during the size reduction process. The dispersions can be prepared continuously or in a batch fashion.

In one embodiment of the invention, a mixture of a fibrate and one or more surface stabilizers is heated during the painting process. If a polymeric surface stabilizer is used, the temperature is raised to above the flash point of the polymeric surface stabilizer, but below the actual or suppressed melting point of the fibrate. The application of heat can be important for scaling up the painting process, as it can be an aid in the dissolution of one or more of the active agents.

2. Precipitation to obtain nanoparticulate fibrate compositions

Another method for forming a desired nanoparticulate fibrate composition, preferably fenofibrate composition, is by means of microprecipitation. This is a process for preparing stable dispersions of poorly soluble active agents in the presence of one or more surface stabilizing agents and one or more colloidal stability enhancing surfactants which are free from any trace of toxic solvents or impurities of dissolved heavy metals. Such a method comprises, for example: (1) Dissolving a fibrate in a suitable solvent; (2) adding the formulation from step (1) to a solution comprising at least one surface stabilizing agent; and (3) precipitating the formulation from step (2) using a suitable non-solvent. The process may be followed by removal of any salt formed, if present, by dialysis or diafiltration and concentration of the dispersion by conventional means.

3. Homogenization to obtain nanoparticulate fibrate compositions

Examples of homogenization methods for the preparation of nanoparticulate compositions comprising active agent are described in U.S. Pat. Patent No. 5,510,118, "Method of Preparation of Therapeutic Compositions Comprising Nanoparticles." One such method comprises dispersing particles of a fibrate, preferably fenofibrate, in a liquid dispersing medium followed by subjecting the dispersion to homogenization to reduce the particle size of the fibrate to the desired effective average particle size. The fibrate particles may be reduced in size in the presence of at least one surface stabilizing agent. Alternatively, the fibrate particles can be brought into contact with one or more surface stabilizing agents, either before or after grinding. Other compounds, such as a diluent, may be added to the fenofibrate/surfactant composition either before, during or after the size reduction process. Dispersions can be prepared continuously or in a batch fashion.

4. Examples of embodiments of the invention

The invention comprises a process for preparing a fibrate composition comprising contacting the fibrate particles with at least one surface stabilizing agent for a period of time and under conditions sufficient to provide a fibrate composition having an effective average particle size of less than about 500 nm, wherein the surface stabilizing agent is not PEG-derivatized vitamin E. In another embodiment, the invention comprises a method of preparing a fibrate composition comprising contacting fibrate particles with at least one surface stabilizing agent for a period of time and under conditions sufficient to providing a fibrate composition having an effective average particle size of less than about 500 nm, and wherein the temperature is maintained below the melting point or below the suppressed melting point of the fibrate if heat is used during the process. For such methods, the contacting step may include: (1) Painting, such as wet painting or (2) homogenization; or (3) a process that includes

(a) dissolving the fibrate particles in a solvent; (b) adding the resulting fibrate solution to a solution comprising at least one surface stabilizing agent; and

(c) precipitating the dissolved fibrate with at least one surface stabilizing agent adsorbed on the surface thereof by adding a non-solvent thereto.

For all of the foregoing methods, the fibrate may be fenofibrate.

D. Methods for using the fibrate compositions according to the invention

The invention provides a method for rapidly increasing plasma levels of a fibrate, preferably fenofibrate, in an individual. One such method comprises orally administering to a subject an effective amount of a composition comprising a fibrate, preferably fenofibrate. The fibrate composition, when tested in fasting subjects according to standard pharmacokinetic practice, produces a peak blood plasma concentration profile of less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour or less than about 30 minutes after the initial dose of the composition.

The compositions according to the invention are applicable in the treatment of conditions such as hypercholesterolaemia, hypertriglyceridemia, cardiovascular diseases, coronary heart disease and peripheral vascular disease (including symptomatic carotid artery disease). The compositions according to the invention can be used as additional therapy to diet to reduce LDL-C, total-C, triglycerides and Apo B in adult patients with primary hypercholesterolemia or mixed dyslipidemia (Fredrickson type IIa and IIb). The compositions can also be used as additional therapy to diet for the treatment of adult patients with hypertriglyceridemia (Fredrickson type IV and V hyperlipidemia). Markedly elevated levels of serum triglycerides (eg > 2000 mg/dl) may increase the risk of developing pancreatitis. The compositions according to the invention can also be used for other indications where lipid-regulating agents are usually used.

The fenofibrate compositions of the invention may be administered to an individual via any conventional means including, but not limited to, oral, rectal, ocular, parenteral (e.g., intravenous, intramuscular, or subcutaneous), intracisternal, pulmonary, intravaginal, intraperitoneal, topical (e.g., powders, ointments or drops) or as a buccal or nasal spray. As used herein, the term "individual" refers to an animal, preferably a mammal, including a human or non-human. The terms patient and individual can be used interchangeably.

Compositions suitable for parenteral injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous or non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Suitable fluidity can be maintained for example by using a coating such as lecithin, by maintaining the required particle size in the case of dispersions and the use of surfactants.

The nanoparticulate fibrate composition, preferably the fenofibrate composition, may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the growth of microorganisms can be ensured through various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be achieved by the use of agents that delay absorption such as aluminum monostearate and gelatin.

Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active agent is mixed with at least one of the following: (a) One or more inert excipients (or carriers) such as sodium citrate or dicalcium phosphate; (b) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; (c) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (d) humectants such as glycerol; (e) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (f) dissolution retarding agents such as paraffin; (g) absorption accelerators such as quaternary ammonium compounds; (h) wetting agents such as cetyl alcohol and glycerol monostearate; (i) adsorbents such as kaolin and bentonite; and (j) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. For capsules, tablets and pills, the dosage forms may also include buffering agents.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the fibrate, the liquid dosage forms may comprise inert diluents which are usually used in the known art such as water or other solvents, solvents and emulsifiers. Examples of emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan or mixtures of these compounds and the like.

Alongside inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying agents and suspending agents, sweeteners, flavoring agents and perfumes.

"Therapeutically effective amount" as used herein with respect to a fibrate dose, preferably a fenofibrate dose, shall mean that dose which provides the specific pharmacological response for which the fibrate is administered in a significant number of individuals in need of such treatment. It is emphasized that "therapeutically effective amount", administered to a specific individual in a specific case need not be effective for 100% of the patients treated for a specific disease, and will not always be effective in the treatment of the diseases described herein even if so dosage is believed to be a "therapeutically effective amount" by those skilled in the art. It should also be understood that fibrate dosages, in special cases, are measured as oral dosages or with regard to drug levels measured in the blood.

Those skilled in the art will appreciate that effective amounts of a fibrate, such as fenofibrate, can be determined empirically and can be used in pure form or, if such forms exist, in pharmaceutically acceptable salt, ester or prodrug form. Actual dosage levels of a fibrate, such as a fenofibrate, in the nanoparticle compositions of the invention can be varied to achieve an amount of the fibrate that will effectively achieve a desired therapeutic response for a specific composition and method of administration. The dosage level selected therefore depends on the desired therapeutic effect, the route of administration, the strength of the fibrate administered, the desired duration of treatment and other factors.

Dosage unit compositions may contain such amounts of such factors thereof as may be used to make the daily dose. However, it should be understood that the specific dosage level for a particular patient will depend on several factors: The type and degree of cellular or physiological response to be achieved; the activity of the specific agent or composition used; the specific agents or compositions used; the age, body weight, general health, gender and diet of the patient; the time of administration, the route of administration and the rate of excretion of the agent; duration of treatment; drugs used in combination or simultaneously with the specific agent; and factors well known in the medical field.

1. Examples of embodiments of the invention

The invention includes a method of treating an individual in need thereof comprising administering to the individual an effective amount of a composition comprising: (a) Particles of a fibrate or a salt thereof having an effective average particle size of less than about 500 nm; and (b) at least one surface stabilizing agent associated with the surface of the fibrate particles, wherein the surface stabilizing agent is (i) non-PEG derivatized vitamin E; or (ii) categorized by the U.S. Food and Drug Administration as GRAS.

In another embodiment, the invention comprises a therapeutic method comprising orally administering to an individual in need of such treatment an effective amount of a composition comprising a fibrate or a salt thereof formulated in such a manner as to provide a blood plasma concentration profile, after an initial dose of the composition, with a Tmax for the fibrate of less than about 6 hours.

In another embodiment, the invention comprises a method of treating an individual comprising administering to the individual an effective amount of a composition comprising: (a) Particles of a fibrate or salt thereof having an effective average particle size of less than about 500 nm; and (b) at least one surface stabilizing agent associated with the surface of the fibrate particles wherein, when the composition is administered to a human in a nonfasting state, the composition is bioequivalent to the composition when administered to a human in a fasted state, as established through a 90% confidence interval of between 0.80 and 1.25 for both Cmax and AUC or a 90% confidence interval of between 0.80 and 1.25 for AUC and a 90% confidence interval of between 0.70 and 1.43 for Cmax.

For all of the foregoing methods, a maximum blood plasma concentration of the fibrate can be achieved within a time period selected from the group consisting of less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours , less than about 1 hour and less than about 30 minutes after administration to fasting subjects.

For all of the foregoing methods, the administration of the fibrate composition may not provide significantly different levels of absorption when administered under non-fasting compared to fasting conditions when administered to a human. The difference in absorption of the fibrate composition of the invention when administered in the non-fasted versus fasted state may be selected from the group consisting of less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5% and less than about 3%.

The aforementioned methods can be used to treat a condition selected from the group consisting of hypercholesterolemia, hypertriglyceridemia, coronary heart disease, cardiovascular diseases and peripheral vascular disease. The procedures can also be used as adjunctive therapy to diet to reduce LDL-C, total-C, triglycerides or Apo B in adult patients with primary hypercholesterolemia or mixed dyslipidemia. The methods can be used as adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia to reduce the risk of pancreatitis or to treat indications where lipid-regulating agents are usually used.

For all of the aforementioned methods, the fibrate may be fenofibrate.

* * * * *

Further possible features and combinations of features of what has been described appear in the following numbered aspects, which should not be confused with patent claims.

Aspect 1. Stable fibrate composition, characterized by including:

(a) particles of a fibrate or salt thereof wherein the fibrate particles have an effective average particle size of less than about 2000 nm; and

(b) at least one surface stabilizing agent associated on the surface thereof, wherein the surface stabilizing agent is not PEG-derivatized vitamin E.

Aspect 2. Stable fibrate composition, characterized by including:

(a) particles of a fibrate or salt thereof wherein the fibrate particles have an effective average particle size of less than about 2000 nm; and

(b) associated with the surface thereof, at least one surface stabilizing agent wherein said surface stabilizing agent is categorized by the U.S. Food and Drug Administration as GRAS.

Aspect 3. Stable fibrate composition, characterized by including:

(a) particles of a fibrate or salt thereof wherein the fibrate particles have an effective average particle size of less than about 2000 nm; and

(b) associated with the surface thereof, at least one surface stabilizing agent selected from the group consisting of hypromellose, docusate sodium, Plasdone ® S630, HPC-SL, sodium lauryl sulfate and combinations thereof,

where the composition does not include PEG-derivatized vitamin E.

Aspect 4. Stable fibrate composition, characterized by including:

(a) particles of a fibrate or a salt thereof wherein the fibrate particles have a particle size wherein D99 is less than about 500 nm; and

(b) associated with the surface thereof, at least one surface stabilizing agent.

Aspect 5. Stable fibrate composition, characterized by including:

(a) particles of a fibrate or a salt thereof wherein the fibrate particles have a particle size wherein D50 is less than about 350 nm; and

(b) with at least one surface stabilizing agent associated with the surface thereof.

Aspect 6. Stable fibrate composition, characterized by including:

(a) particles of a fibrate or a salt thereof wherein the fibrate particles have an average particle size of less than about 100 nm; and

(b) at least one surface stabilizing agent associated with the surface thereof.

Aspect 7. Fibrate composition, characterized by including:

(a) particles of a fibrate or salt thereof wherein the fibrate particles have an effective average particle size of less than about 2000 nm; and

(b) associated with the surface thereof, at least one surface stabilizing agent wherein said surface stabilizing agent is not a phospholipid.

Aspect 8. Fibrate composition, characteristics including:

(a) particles of a fibrate or salt thereof wherein the fibrate particles have an effective average particle size of less than about 2000 nm; and

(b) dioctyl sodium sulfosuccinate and hypromellose associated with the surface thereof;

where the composition does not include PEG-derivatized vitamin E.

Aspect 9. Composition according to aspect 8, characterized in that the composition further comprises sodium lauryl sulfate.

Aspect 10. Fibrate composition, characteristics including:

(a) particles of a fibrate or salt thereof wherein the fibrate particles have an effective average particle size of less than about 2000 nm; and

(b) at least one surface stabilizing agent associated on the surface thereto, wherein the surface stabilizing agent is not PEG-derivatized vitamin E;

where the composition is bioadhesive.

Aspect 11. Fibrate composition, characteristics including:

(a) particles of a fibrate or salt thereof wherein the fibrate particles have an effective average particle size of less than about 2000 nm; and

(b) at least one surface stabilizing agent associated on the surface thereof;

wherein the composition is redispersed such that the fibrate particles have an effective average particle size selected from the group consisting of less than about 2000 nm, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm and less than about 50 nm upon administration.

Aspect 12. Fibrate composition, characterized by including:

(a) particles of a fibrate or salt thereof wherein the fibrate particles have an effective average particle size of less than about 2000 nm; and

(b) at least one surface stabilizing agent associated on the surface thereof;

wherein the composition redisperses in a biorelevant medium such that the fibrate particles have an effective average particle size selected from the group consisting of less than about 2 microns, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm and less than about 50 nm upon administration.

Aspect 13. Composition, characterized by comprising a fibrate or salt thereof wherein the pharmacokinetic profile of the fibrate is not significantly affected by whether an individual ingesting the composition is in a non-fasting or fasting state when administered to a human.

Aspect 14. Composition characterized by comprising a fibrate or salt thereof wherein the administration of the composition to an individual in a fasted state is bioequivalent to the administration of the composition to an individual in a non-fasted state when administered to a human.

Aspect 15. Composition, characterized by comprising a fibrate or a salt thereof wherein the administration of the composition to an individual in a fasted state is bioequivalent to the administration of the composition to an individual in a non-fasted state, wherein "bioequivalence" is established through a 90% confidence interval of between 0.80 and 1.25 for both Cmax and AUC when administered to a human.

Aspect 16. Composition, characterized by comprising a fibrate or a salt thereof, wherein the administration of the composition to an individual in a fasted state is bioequivalent to the administration of the composition to an individual in a non-fasted state, wherein "bioequivalence" is established through a 90% confidence interval of between 0.80 and 1.25 for AUC and a 90% confidence interval of between 0.70 and 1.43 for Cmax when administered to a human.

Aspect 17. Composition characterized by comprising a fibrate or a salt thereof wherein the composition has a Tmax selected from the group consisting of less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour and less than about 30 minutes after administration to fasting subjects.

Aspect 18. Stable fibrate composition, wherein at least about 20% of the composition is dissolved within about 5 minutes, wherein the dissolution is measured in a medium that is discriminating and the rotating blade method (European Pharmacopoeia) is used to measure dissolution.

Aspect 19. The composition of aspect 18, wherein at least about 30% or about 40% of the composition is dissolved within about 5 minutes.

Aspect 20. Stable fibrate composition, wherein at least about 40% of the composition is dissolved within about 10 minutes, wherein the dissolution is measured in a medium that is discriminating and the rotating blade method (European Pharmacopoeia) is used to measure dissolution.

Aspect 21. The composition of aspect 20, wherein at least about 50%, about 60%, about 70%, or about 80% of the composition is dissolved within about 10 minutes.

Aspect 22. Stable fibrate composition, wherein at least about 70% of the composition is dissolved within about 20 minutes, wherein the dissolution is measured in a medium that is discriminating and the rotating blade method (European Pharmacopoeia) is used to measure dissolution.

Aspect 23. The composition of aspect 22, wherein at least about 80%, about 90%, or about 100% of the composition is dissolved within about 20 minutes.

Aspect 24. The composition of any one of aspects 18-23, wherein the fibrate particles have an effective average particle size of less than about 2 microns upon redispersion.

Aspect 25. The composition of any one of aspects 1-24, wherein the fibrate is fenofibrate or a salt thereof.

Aspect 26. Fenofibrate composition, characterized by comprising a dose of approximately 145 mg of fenofibrate particles or a salt thereof wherein:

(a) said dose is therapeutically effective; and

(b) the composition is bioequivalent to a TRICOR <® >160 mg tablet or 200 mg capsule, wherein bioequivalence is established through a 90% confidence interval of between 0.80 and 1.25 for both Cmax and AUC and a 90% confidence interval of between 0 .80 and 1.25 for AUC and a 90% confidence interval of between 0.80 and 1.43 for Cmax when administered to a human.

Aspect 27. Fenofibrate composition, characterized by comprising a dosage of 48 mg of fenofibrate particles or a salt thereof in which:

(a) said dose is therapeutically effective; and

(b) the composition is bioequivalent to a TRICOR <® >54 mg tablet, wherein bioequivalence is established through a 90% confidence interval of between 0.80 and 1.25 for both Cmax and AUC and a 90% confidence interval of between 0.80 and 1 .25 for AUC and a 90% confidence interval of between 0.80 and 1.43 for Cmax when administered to a human.

Aspect 28. The composition of aspect 26 or 27, wherein the fenofibrate particles are associated with at least one surface stabilizing agent on the surface thereof.

Aspect 29. The composition of any one of aspects 26-28, wherein the fenofibrate particles have an effective average particle size of less than about 2000 nm.

Aspect 30. The composition of any one of aspects 26-29, wherein the dosage form is about 10% smaller than a TRICOR <® >160 mg tablet or a 200 mg capsule.

Aspect 31. Fenofibrate composition, characterized in that it includes the following:

(a) about 50 to about 500 g/kg fenofibrate or salt thereof;

(b) about 10 to about 70 g/kg hypromellose;

(c) about 1 to about 10 g/kg docusate sodium;

(d) about 100 to about 500 g/kg sucrose;

(e) about 1 to about 40 g/kg sodium lauryl sulfate;

(f) about 50 to about 300 g/kg siliceous microcrystalline cellulose;

(g) about 20 to about 300 g/kg crospovidone; and

(h) about 0.5 to about 5 g/kg magnesium stearate.

Aspect 32. Fenofibrate composition, characterized in that it comprises the following:

(a) about 100 to about 300 g/kg of fenofibrate or salt thereof;

(b) about 30 to about 50 g/kg hypromellose;

(c) about 0.5 to about 10 g/kg docusate sodium;

(d) about 100 to about 300 g/kg sucrose;

(e) about 1 to about 30 g/kg sodium lauryl sulfate;

(f) about 100 to about 300 g/kg of lactose monohydrate;

(g) about 50 to about 200 g/kg siliceous microcrystalline cellulose;

(h) about 50 to about 200 g/kg crospovidone; and

(i) about 0.5 to about 5 g/kg magnesium stearate.

Aspect 33. Fenofibrate composition, characterized in that it includes the following:

(a) about 200 to about 225 g/kg of fenofibrate or salt thereof;

(b) about 42 to about 46 g/kg hypromellose;

(c) about 2 to about 6 g/kg docusate sodium;

(d) about 200 to about 225 g/kg sucrose;

(e) about 12 to about 18 g/kg sodium lauryl sulfate;

(f) about 200 to about 205 g/kg of lactose monohydrate;

(g) about 130 to about 135 g/kg siliceous microcrystalline cellulose;

(h) about 112 to about 118 g/kg crospovidone; and

(i) about 0.5 to about 3 g/kg magnesium stearate.

Aspect 34. Fenofibrate composition, characterized in that it includes the following:

(a) about 119 to about 224 g/kg of fenofibrate or salt thereof;

(b) about 42 to about 46 g/kg hypromellose;

(c) about 2 to about 6 g/kg docusate sodium;

(d) about 119 to about 224 g/kg sucrose;

(e) about 12 to about 18 g/kg sodium lauryl sulfate;

(f) about 119 to about 224 g/kg of lactose monohydrate;

(g) about 129 to about 134 g/kg siliceous microcrystalline cellulose;

(h) about 112 to about 118 g/kg crospovidone; and

(i) about 0.5 to about 3 g/kg magnesium stearate.

Aspect 35. Composition according to any one of aspects 31-34, characterized in that the composition further comprises a coating agent.

Aspect 36. Composition, characterized in that it comprises about 145 mg of fenofibrate or a salt thereof and that shows minimal or no effect of food when administered to a human.

Aspect 37. Composition, characterized in that it comprises about 48 mg of fenofibrate or a salt thereof and that shows minimal or no effect of food when administered to a human.

Aspect 38. Composition, characterized in that it comprises a fenofibrate or a salt thereof and having a Cmax under fattening conditions greater than the Cmax under high fat conditions when administered to a human.

Aspect 39. Composition, characterized in that it comprises fenofibrate or a salt thereof, wherein comparable pharmacokinetic testing with a TRICOR <® >160 mg tablet or 200 mg capsule which are standard commercial formulations of microcrystalline fenofibrate, wherein the fenofibrate composition exhibits a Tmax selected from the group consisting of less than about 90%, less than about 80%, less than about 70%, less than about 50%, less than about 30% and less than about 25% of the Tmax of the standard commercial microcrystalline fenofibrate formulations.

Aspect 40. Fenofibrate composition, characterized in that it comprises fenofibrate or a salt thereof which, when administered to a human as a dose of about 160 mg, exhibits an AUC of about 130 μg/ml.h.

Aspect 41. The composition of any one of aspects 1-40, wherein the fibrate is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase and mixtures thereof.

Aspect 42. The composition of any one of aspects 1-41, wherein the effective average particle size of the fibrate particles is selected from the group consisting of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm and less than about 50 nm.

Aspect 43. The composition of any one of aspects 1-42, wherein the composition is formulated for administration selected from the group consisting of oral, pulmonary, rectal, ophthalmic, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, topical, buccal, nasal and topical administration.

Aspect 44. The composition of any one of aspects 1-43, wherein the composition is formulated into a dosage form selected from the group consisting of liquid dispersions, oral suspensions, gels, aerosols, ointments, creams, controlled release formulations, fast melting formulations, lyophilized formulations, tablets, capsules, delayed release formulations, extended release formulations, pulsed release formulations and mixed immediate and controlled release formulations.

Aspect 45. The composition of any one of aspects 1-44, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers or a combination thereof.

Aspect 46. The composition of any one of aspects 1-45, wherein the fibrate is present in an amount selected from the group consisting of from about 99.5 to about 0.001% by weight, from about 95 to about 0.1% by weight and from about 90 to about 0.5% by weight, based on the total combined weight of the fibrate and at least one surfactant and not including other excipients.

Aspect 47. The composition of any one of aspects 1-12, 28 or 41-46, wherein the at least one surface stabilizing agent is selected from the group consisting of from about 0.5% to about 99.999% by weight, from about 5.0 to about 99.9% by weight and from about 10 to about 99.5% by weight, based on the total combined dry weight of the fibrate and at least one surfactant and not including other excipients.

Aspect 48. Composition according to any one of aspects 1-12, 28 or 41-47, characterized in that it comprises at least one primary surface stabilizing agent and at least one secondary surface stabilizing agent.

Aspect 49. The composition of any one of aspects 1-12, 28 or 41-48, wherein the surface stabilizing agent is selected from the group consisting of an anionic surface stabilizing agent, a cationic surface stabilizing agent, a zwitterionic surface stabilizing agent and an ionic surface stabilizing agent .

Aspect 50. The composition of aspect 49, wherein at least one surface stabilizing agent is selected from the group consisting of cetylpyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene salmon oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyltrimethylammonium bromide, polyoxyethylene stearate, colloidal silicone dioxide, phosphates, sodium dodecyl sulfate, carboxymethylcellulose calcium, hydroxypropylcellulose, hypromellose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hypromellose sulfate, non-crystalline cellulose, non-magnesium triamine silicate. polyvinyl alcohol, polyvinyl pyrrolidone, 4-(1,1,3,3-tetramethylbutyl)phenol polymer with ethylene oxide and formaldehyde, poloxamers; poloxamis, a charged phospholipid, dioctyl sulfosuccinate, dialkyl esters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkylaryl polyether sulfonates, mixtures of sucrose stearate and sucrose distearate, pisononylphenoxypoly(glycidol), decanoyl-N-methylglucamide; n-decyl-β-D-glucopyranoside; n-decyl-β-D-maltopyranoside; n-dodecyl-β-D-glucopyranoside; ndodecyl-β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl-β-D-thioglucoside; n-hexyl-β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl-β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; octyl-β-D-thioglucopyranoside; lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG vitamin A and random copolymers of vinyl acetate and vinyl pyrrolidone.

Aspect 51. The composition of aspect 49, wherein the at least one cationic surface stabilizing agent is selected from the group consisting of a polymer, a biopolymer, a polysaccharide, a cellulose, an alginate, a non-polymeric compound and a phospholipid.

Aspect 52. The composition of aspect 49, wherein the surface stabilizing agent is selected from the group consisting of cationic lipids, polymethyl methacrylate trimethylammonium bromide, sulfonium compounds, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethylammonium bromide, phosphonium compounds, quaternary ammonium compounds, benzyl di(2-chloroethyl)ethylammonium bromide, coconut trimethylammonium chloride, coconut trimethylammonium bromide, coconut methyldihydroxyethylammonium chloride, coconut methyldihydroxyethylammonium bromide, decyltriethylammonium chloride, decyldimethylhydroxyethylammonium chloride, decyldimethylhydroxyethylammonium chloride bromide, C12-

15dimethylhydroxyethylammonium chloride, C12-

15dimethylhydroxyethylammonium chloride bromide, coconut dimethylhydroxyethylammonium chloride, coconut dimethylhydroxyethylammonium bromide, myristyltrimethylammonium methylsulfate, lauryldimethylbenzylammonium chloride, lauryldimethylbenzylammonium bromide, lauryldimethyl(ethenoxy)4 ammonium chloride, lauryldimethyl(ethenoxy)4 ammonium bromide, N-alkyl (C12-18)dimethylbenzylammonium chloride, N-alkyl (C14-

18)dimethylbenzylammonium chloride, N-tetradecylmethylbenzylammonium chloride monohydrate, dimethyldidecylammonium chloride, N-alkyl- and (C12-14) dimethyl-1-naphthylmethylammonium chloride, trimethylammonium halide, alkyltrimethylammonium salts, dialkyldimethylammonium salts, lauryltrimethylammonium chloride, ethoxylated alkylamidoalkyldialkylammonium salt, an ethoxylated trialkyldidecylammonium dialkylammonium chloride, dialkylbenzenediammonium chloride N-tetradecyldimethylbenzylammonium , chloride monohydrate, N-alkyl(C12-14) dimethyl-1-naphthylmethylammonium chloride, dodecyldimethylbenzylammonium chloride, dialkylbenzenealkylammonium chloride, lauryltrimethylammonium chloride, alkylbenzylmethylammonium chloride, alkylbenzyldimethylammonium bromide, C12-trimethylammonium bromides, C15-trimethylammonium bromides, C17-trimethylammonium bromides, dodecylbenzyltriethylammonium chloride (DADMAM), polydimethylammonium chloride are, alkyldimethylammonium halides, tricetylmethylammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride, POLYQUAT 10<TM>, tetrabutylammonium bromide, benzyltrimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetylpyridinium bromide, cetylpyridinium chloride, halide salts of quaternized polyoxyethylalkylpyridine amines, MIRAPOL<TM>, ALKAQUAT; amines, amine salts, amine oxides, imidazolinium salts, protonated quaternary acrylamides, methylated quaternary polymers and cationic guar.

Aspect 53. The composition of any one of aspects 49, 51 or 52, wherein the composition is bioadhesive.

Aspect 54. Composition according to any one of aspects 1-53, characterized in that the composition further comprises one or more active agents selected from the group consisting of HMG CoA reductase inhibitors and antihypertensive agents.

Aspect 55. Composition according to any one of aspects 1-12, 28 or 41-49, characterized in that it comprises hypromellose, dioctyl sodium sulfosuccinate and sodium lauryl sulfate as surface stabilizers.

Aspect 56. The composition of any of aspects 1-16 or 17-55, wherein the composition exhibits a Tmax selected from the group consisting of less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour, and less than about 30 minutes after administration to fasting subjects.

Aspect 57. The composition of any one of aspects 1-56, wherein the composition does not result in significantly different absorption levels when administered under non-fasting compared to fasting conditions.

Aspect 58. The composition of aspect 57, wherein the difference in absorption of the fibrate composition of the invention when administered under nonfasting versus fasting conditions is selected from the group consisting of less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, and less than about 3%.

Aspect 59. The composition of any one of aspects 1-38 or 40-58, characterized by comprising fenofibrate or a salt thereof, wherein the composition has a Tmax selected from the group consisting of less than about 90%, less than about 80%, less than about 70%, less than about 50%, less than about 30%, and less than about 25% of the Tmax of a TRICOR <®> tablet or capsule with comparable pharmacokinetic testing to a TRICOR <® >160 mg tablet or 200 mg capsule, which are standard commercial formulations of microcrystalline fenofibrate.

Aspect 60. Method for preparing a fibrate composition,

characterized in that the method comprises contacting the fibrate particles with at least one surface stabilizing agent for a period of time and under conditions sufficient to provide a fibrate composition having an effective average particle size of less than about 2000 nm, wherein the surface stabilizing agent is not a PEG-derivatized vitamin E.

Aspect 61. Method for preparing a fibrate composition,

characterized in that the method comprises contacting fibrate particles with at least one surface stabilizing agent for a period of time and under conditions sufficient to provide a fibrate composition having an effective average particle size of less than about 2000 nm, wherein the temperature is maintained below the melting point or suppressed melting point to the fibrate if heat is used during the process.

Aspect 62. Method according to aspect 60 or 61, wherein said contact comprises paint.

Aspect 63. Method according to aspect 62, wherein said paint comprises wet paint.

Aspect 64. The method of aspect 60 or 61, wherein contacting comprises homogenization.

Aspect 65. Method according to aspect 60 or 61, wherein said contact comprises:

(a) dissolving the fibrate particles in a solvent;

(b) adding the resulting fibrate solution to a solution comprising at least one surface stabilizing agent; and

(c) precipitating the dissolved fibrate with at least one surface stabilizing agent adsorbed on the surface thereof by the addition thereto of a non-solvent.

Aspect 66. The method of any one of aspects 60-65, wherein the fibrate is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase or a mixture thereof.

Aspect 67. The method of any one of aspects 60-66, wherein the effective average particle size of the fibrate particles is selected from the group consisting of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm , less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm and less than about 50 nm.

Aspect 68. The method of any one of aspects 60-67, wherein the composition is formulated for administration selected from the group consisting of oral, pulmonary, rectal, ophthalmic, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, local, buccal, nasal and topical administration.

Aspect 69. The method of any of aspects 60-68, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers or a combination thereof.

Aspect 70. The method of any one of aspects 60-69, wherein the fibrate is present in an amount selected from the group consisting of from about 99.5 to about 0.001% by weight, from about 95 to about 0.1% by weight and from about 90 to about 0.5% by weight, based on the total combined weight of the fibrate and at least one surfactant and not including other excipients.

Aspect 71. The method of any of aspects 60-70, wherein the at least one surface stabilizing agent is present in an amount selected from the group consisting of from about 0.5% to about 99.999% by weight, from about 5.0 to about 99.9% by weight and from about 10 to about 99.5% by weight, based on the total combined dry weight of the fibrate and at least one surfactant and not including other excipients.

Aspect 72. A method according to any one of aspects 60-71, characterized by comprising at least one primary surface stabilizing agent and at least one secondary surface stabilizing agent.

Aspect 73. The method of any of aspects 60-72, wherein the surface stabilizing agent is selected from the group consisting of an anionic surface stabilizing agent, a cationic surface stabilizing agent, a zwitterionic surface stabilizing agent and an ionic surface stabilizing agent.

Aspect 74. Method according to aspect 73,

wherein at least one surface stabilizer is selected from the group consisting of cetylpyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene salmon oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyltrimethylammonium bromide, polyoxyethylene stearate, colloidal silicone dioxide, phosphates, sodium dodecyl sulfate, carboxymethylcellulose calcium, hydroxypropylcelluloses, hypromellose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, non-crystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinyl-(1)pyrrolidone, 4 ,1,3,3-tetramethylbutyl)phenol polymer with ethylene oxide and formaldehyde, poloxamers; poloxamis, a charged phospholipid, dioctyl sulfosuccinate, dialkyl esters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkylaryl polyether sulfonates, mixtures of sucrose stearate and sucrose distearate, pisononylphenoxypoly(glycidol), decanoyl-N-methylglucamide; n-decyl-β-D-glucopyranoside; n-decyl-β-D-maltopyranoside; n-dodecyl-β-D-glucopyranoside; ndodecyl-β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl-β-D-thioglucoside; n-hexyl-β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl-β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; octyl-β-D-thioglucopyranoside; lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG vitamin A and random copolymers of vinyl acetate and vinyl pyrrolidone.

Aspect 75. Method according to aspect 73,

wherein at least one cationic surface stabilizing agent is selected from the group consisting of a polymer, a biopolymer, a polysaccharide, a cellulose, an alginate, a non-polymeric compound and a phospholipid.

Aspect 76. Method according to aspect 73,

wherein the surface stabilizing agent is selected from the group consisting of cationic lipids, polymethyl methacrylate trimethylammonium bromide, sulfonium compounds, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethylammonium bromide, phosphonium compounds, quaternary ammonium compounds, benzyl di(2-chloroethyl)ethylammonium bromide, coconut trimethylammonium chloride, coconut trimethylammonium bromide, coconut methyldihydroxyethylammonium chloride coconut methyldihydroxyethylammonium bromide, decyltriethylammonium chloride, decyldimethylhydroxyethylammonium chloride, decyldimethylhydroxyethylammonium chloride bromide, C12-

15dimethylhydroxyethylammonium chloride, C12-

15dimethylhydroxyethylammonium chloride bromide, coconut dimethylhydroxyethylammonium chloride, coconut dimethylhydroxyethylammonium bromide, myristyltrimethylammonium methylsulfate, lauryldimethylbenzylammonium chloride, lauryldimethylbenzylammonium bromide, lauryldimethyl(ethenoxy)4 ammonium chloride, lauryldimethyl(ethenoxy)4 ammonium bromide, N-alkyl (C12-18)dimethylbenzylammonium chloride, N-alkyl (C14-

18)dimethylbenzylammonium chloride, N-tetradecylmethylbenzylammonium chloride monohydrate, dimethyldidecylammonium chloride, N-alkyl- and (C12-14) dimethyl-1-naphthylmethylammonium chloride, trimethylammonium halide, alkyltrimethylammonium salts, dialkyldimethylammonium salts, lauryltrimethylammonium chloride, ethoxylated alkylamidoalkyldialkylammonium salt, an ethoxylated trialkyldidecylammonium dialkylammonium chloride, dialkylbenzenediammonium chloride N-tetradecyldimethylbenzylammonium , chloride monohydrate, N-alkyl(C12-14) dimethyl-1-naphthylmethylammonium chloride, dodecyldimethylbenzylammonium chloride, dialkylbenzenealkylammonium chloride, lauryltrimethylammonium chloride, alkylbenzylmethylammonium chloride, alkylbenzyldimethylammonium bromide, C12-trimethylammonium bromides, C15-trimethylammonium bromides, C17-trimethylammonium bromides, dodecylbenzyltriethylammonium chloride (DADMAM), polydimethylammonium chloride are, alkyldimethylammonium halides, tricetylmethylammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride, POLYQUAT 10<TM>, tetrabutylammonium bromide, benzyltrimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetylpyridinium bromide, cetylpyridinium chloride, halide salts of quaternized polyoxyethylalkylpyridine amines, MIRAPOL<TM>, ALKAQUAT; amines, amine salts, amine oxides, imidazolinium salts, protonated quaternary acrylamides, methylated quaternary polymers and cationic guar.

Aspect 77. The method of any one of aspects 73, 75 or 76, wherein the composition is bioadhesive.

Aspect 78. The method of any one of aspects 60-74, wherein the composition comprises hypromellose, dioctyl sodium sulfosuccinate and sodium lauryl sulfate as surface stabilizers.

Aspect 79. The method of any of aspects 60-78, wherein the fibrate is fenofibrate or a salt thereof.

Aspect 80. Method for treating an individual, characterized in that the method comprises administering to an individual an effective amount of a composition comprising:

(a) particles of a fibrate or salt thereof wherein the fibrate particles have an effective average particle size of less than about 2000 nm; and

(b) at least one surface stabilizing agent associated on the surface thereof, wherein the surface stabilizing agent is not PEG-derivatized vitamin E.

Aspect 81. Therapeutic method, characterized in that the method comprises orally administering to a mammalian individual in need of such treatment an effective amount of a composition comprising a fibrate or a salt thereof formulated in such a way as to provide a blood plasma concentration profile, after an initial dose of the composition, where the Tmax of the fibrate is less than about 6 hours.

Aspect 82. Method for treating an individual in need of such treatment, characterized in that the method comprises administering to the individual an effective amount of a composition comprising:

(a) particles of a fibrate or salt thereof wherein the fibrate particles have an effective average particle size of less than about 2000 nm; and

(b) associated with the surface thereof, at least one surface stabilizing agent wherein said surface stabilizing agent is categorized by the U.S. Food and Drug Administration as GRAS.

Aspect 83. Method for treating an individual in need of such treatment, characterized in that the method comprises administering to the individual an effective amount of a composition comprising:

(a) particles of a fibrate or salt thereof wherein the fibrate particles have an effective average particle size of less than about 2000 nm; and

(b) at least one surface stabilizing agent associated with the surface of the fibrate particles;

wherein, when the composition is administered to a human in a non-fasted state, the composition is bioequivalent to the composition when administered to a human in a fasted state, as established through a 90% confidence interval of between 0.80 and 1.25 for both Cmax and AUC or a 90% confidence interval of between 0.80 and 1.25 for AUC and a 90% confidence interval of between 0.70 and 1.43 for Cmax.

Aspect 84. The method of any one of aspects 80-83, wherein a maximum blood plasma concentration of the fibrate is achieved in a time period selected from the group consisting of less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour, and less than about 30 minutes after administration to fasting subjects.

Aspect 85. The method of any one of aspects 80-84, wherein the fibrate is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase and mixtures thereof.

Aspect 86. The method of any one of aspects 80-85, wherein the effective average particle size of the fibrate particles is selected from the group consisting of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm and less than about 50 nm.

Aspect 87. The method of any one of aspects 80-86, wherein the composition is formulated for administration selected from the group consisting of oral, pulmonary, rectal, ophthalmic, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, topical, buccal, nasal, and topical administration.

Aspect 88. The method of any of aspects 80-87, wherein the composition is in a dosage form selected from the group consisting of liquid dispersions, oral suspensions, gels, aerosols, ointments, creams, controlled release formulations, fast melting formulations, lyophilized formulations, tablets, capsules, delayed release formulations, extended release formulations, pulsed release formulations and mixed immediate release and controlled release formulations.

Aspect 89. The method of any of aspects 80-88, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers or a combination thereof.

Aspect 90. The method of any one of aspects 80-89, wherein the fibrate is present in an amount selected from the group consisting of from about 99.5 to about 0.001% by weight, from about 95 to about 0.1% by weight and from about 90 to about 0.5% by weight, based on the total combined weight of the fibrate and at least one surfactant and not including other excipients.

Aspect 91. The method of any one of aspects 80 or 81-90, wherein the at least one surface stabilizing agent is selected from the group consisting of from about 0.5% to about 99.999% by weight, from about 5.0 to about 99.9% by weight and from about 10 to about 99.5% by weight, based on the total combined dry weight of the fibrate and at least one surfactant and not including other excipients.

Aspect 92. A method according to any one of aspects 80 or 81-91, characterized in that it comprises at least one primary surface stabilizing agent and at least one secondary surface stabilizing agent.

Aspect 93. The method of any of aspects 80 or 81-92, wherein the surface stabilizing agent is selected from the group consisting of an anionic surface stabilizing agent, a cationic surface stabilizing agent, a zwitterionic surface stabilizing agent and an ionic surface stabilizing agent.

Aspect 94. The method of aspect 93, wherein at least one surface stabilizing agent is selected from the group consisting of cetylpyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene salmon oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyltrimethylammonium bromide, polyoxyethylene stearate, colloidal silicone dioxide, phosphates, sodium dodecyl sulfate, carboxymethylcellulose calcium, hydroxypropylcellulose, hypromellose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hypromellose sulfate, non-crystalline cellulose, non-magnesium triamine silicate. polyvinyl alcohol, polyvinyl pyrrolidone, 4-(1,1,3,3-tetramethylbutyl)phenol polymer with ethylene oxide and formaldehyde, poloxamers; poloxamis, a charged phospholipid, dioctyl sulfosuccinate, dialkyl esters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkylaryl polyether sulfonates, mixtures of sucrose stearate and sucrose distearate, pisononylphenoxypoly(glycidol), decanoyl-N-methylglucamide; n-decyl-β-D-glucopyranoside; n-decyl-β-D-maltopyranoside; n-dodecyl-β-D-glucopyranoside; ndodecyl-β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl-β-D-thioglucoside; n-hexyl-β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl-β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; octyl-β-D-thioglucopyranoside; lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG vitamin A and random copolymers of vinyl acetate and vinyl pyrrolidone.

Aspect 95. Method according to aspect 93,

wherein at least one cationic surface stabilizing agent is selected from the group consisting of a polymer, a biopolymer, a polysaccharide, a cellulose, an alginate, a non-polymeric compound and a phospholipid.

Aspect 96. Method according to aspect 93,

wherein the surface stabilizing agent is selected from the group consisting of cationic lipids, polymethyl methacrylate trimethylammonium bromide, sulfonium compounds, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethylammonium bromide, phosphonium compounds, quaternary ammonium compounds, benzyl di(2-chloroethyl)ethylammonium bromide, coconut trimethylammonium chloride, coconut trimethylammonium bromide, coconut methyldihydroxyethylammonium chloride coconut methyldihydroxyethylammonium bromide, decyltriethylammonium chloride, decyldimethylhydroxyethylammonium chloride, decyldimethylhydroxyethylammonium chloride bromide, C12-

15dimethylhydroxyethylammonium chloride, C12-

15dimethylhydroxyethylammonium chloride bromide, coconut dimethylhydroxyethylammonium chloride, coconut dimethylhydroxyethylammonium bromide, myristyltrimethylammonium methylsulfate, lauryldimethylbenzylammonium chloride, lauryldimethylbenzylammonium bromide, lauryldimethyl(ethenoxy)4 ammonium chloride, lauryldimethyl(ethenoxy)4 ammonium bromide, N-alkyl (C12-18)dimethylbenzylammonium chloride, N-alkyl (C14-

18)dimethylbenzylammonium chloride, N-tetradecylmethylbenzylammonium chloride monohydrate, dimethyldidecylammonium chloride, N-alkyl- and (C12-14) dimethyl-1-naphthylmethylammonium chloride, trimethylammonium halide, alkyltrimethylammonium salts, dialkyldimethylammonium salts, lauryltrimethylammonium chloride, ethoxylated alkylamidoalkyldialkylammonium salt, an ethoxylated trialkyldidecylammonium dialkylammonium chloride, dialkylbenzenediammonium chloride N-tetradecyldimethylbenzylammonium , chloride monohydrate, N-alkyl(C12-14) dimethyl-1-naphthylmethylammonium chloride, dodecyldimethylbenzylammonium chloride, dialkylbenzenealkylammonium chloride, lauryltrimethylammonium chloride, alkylbenzylmethylammonium chloride, alkylbenzyldimethylammonium bromide, C12-trimethylammonium bromides, C15-trimethylammonium bromides, C17-trimethylammonium bromides, dodecylbenzyltriethylammonium chloride (DADMAM), polydimethylammonium chloride are, alkyldimethylammonium halides, tricetylmethylammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride, POLYQUAT 10<TM>, tetrabutylammonium bromide, benzyltrimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetylpyridinium bromide, cetylpyridinium chloride, halide salts of quaternized polyoxyethylalkylpyridine amines, MIRAPOL<TM>, ALKAQUAT; amines, amine salts, amine oxides, imidazolinium salts, protonated quaternary acrylamides, methylated quaternary polymers and cationic guar.

Aspect 97. The method of any one of aspects 93, 95 or 96, wherein the composition is bioadhesive.

Aspect 98. The method of any of aspects 80 or 81-94, wherein the composition comprises hypromellose, dioctyl sodium sulfosuccinate and sodium lauryl sulfate as surface stabilizers.

Aspect 99. The method of any one of aspects 80-98, wherein the administration of the fibrate composition does not result in significantly different absorption levels when administered under non-fasting compared to fasting conditions, when administered to a human.

Aspect 100. The method of aspect 99, wherein the difference in absorption of the fibrate composition of the invention, when administered in the non-fasted versus fasted state, is selected from the group consisting of less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5% and less than about 3%.

Aspect 101. The method of any one of aspects 80-100, wherein said Tmax of the fibrate is selected from the group consisting of less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour and less than about 30 minutes after administration to fasting subjects.

Aspect 102. Method according to any one of aspects 80-101, characterized in that the method further comprises administering one or more active agents selected from the group consisting of HMG CoA reductase inhibitors and antihypertensive agents.

Aspect 103. The method of any one of aspects 80-102, wherein the subject is a human.

Aspect 104. The method of any one of aspects 80-103, wherein the method is used to treat a condition selected from the group consisting of hypercholesterolemia, hypertriglyceridemia, coronary heart disease, cardiovascular diseases, and peripheral vascular disease.

Aspect 105. The method of any one of aspects 80-104, wherein the method is used as adjunctive therapy to diet to reduce LDL-C, total-C, triglycerides or Apo B in adult patients with primary hypercholesterolemia or mixed dyslipidemia.

Aspect 106. The method of any one of aspects 80-105, wherein the method is used as adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia.

Aspect 107. The method of any one of aspects 80-106, wherein the method is used to reduce the risk of pancreatitis.

Aspect 108. The method of any of aspects 80-107, wherein the method is used to treat indications where lipid-regulating agents are typically used.

Aspect 109. The method of any of aspects 80-108, wherein the fibrate is fenofibrate or a salt thereof.

The following examples are given to illustrate the present invention. However, it should be understood that the invention is not to be limited to the specific conditions or detailed descriptions in these examples. Throughout the description, each and every reference is to a publicly available document, including a U.S. Pat. patent.

Several of the formulations in the examples that follow were examined using a light microscope. Here, "stable" nanoparticulate dispersions (uniform Brownian motion) were easily distinguishable from "aggregated" dispersions (relatively large, non-uniform particles without motion).

Example 1

The purpose of this example was to prepare nanoparticulate dispersions of fenofibrate and to test the prepared compositions with regard to stability in water and in various simulated biological fluids.

Two formulations of fenofibrate were milled, as described in Table 1, by milling the components of the compositions under high energy milling conditions in a DYNO ® -Mill KDL (Will A. Bachofen AG, Maschinenfabrik, Basle, Switzerland) for ninety minutes.

Formulation 1 comprised 5% (w/w) fenofibrate, 1% (w/w) hypromellose and 0.05% (w/w) dioctyl sodium sulfosuccinate (DOSS), and formulation 2 comprised 5% (w/w) fenofibrate, 1% (w/w) Pluronic ® S-630 (a random copolymer of vinyl acetate and vinyl pyrrolidone) and 0.05% (w/w) DOSS. The particle size of the resulting compositions was measured using a Horiba LA-910 laser scattering particle size distribution analyzer (Horiba Instruments, Irvine, CA).

Next, the stability of the two formulations was tested in various simulated biological fluids (Table 2) and in water (Table 3) over a longer period of time. For tests in various simulated biological fluids, the compositions were considered stable if the particles remained in a dispersion format without any visible increase in size or agglomeration after 30 minutes of incubation at 40 ºC. Testing in fluids that represent electrolyte fluids is useful, as such fluids are representative of physiological conditions found in the human body.

The stability results indicate that formulation 1 is preferred over formulation 2, as formulation 2 exhibits some agglomeration in simulated intestinal fluid and unacceptable particle size growth over time.

Example 2

The purpose of this example was to prepare nanoparticulate dispersions of fenofibrate followed by testing the stability of the compositions in various simulated biological fluids.

Four formulations of fenofibrate were prepared as described in Table 4 by grinding the components of the compositions in a DYNO ® -Mill KDL (Willy A. Bachofen AG, Maschinenfabrik, Basle, Switzerland) for ninety minutes.

Formulation 3 comprised 5% (w/w) fenofibrate, 1% (w/w) hydroxypropyl cellulose SL (HPC-SL) and 0.01% (w/w) DOSS; formulation 4 comprised 5% (w/w) fenofibrate, 1% (w/w) hypromellose and 0.01% (w/w) DOSS; formulation 5 comprised 5% (w/w) fenofibrate, 1% (w/w) polyvinylpyrrolidone (PVP K29/32) and 0.01% (w/w) DOSS; and formulation 6 comprised 5% (w/w) fenofibrate, 1% (w/w) Pluronic ® S630 and 0.01% (w/w) DOSS.

The particle size of the resulting compositions was measured using a Horiba LA-910 laser scattering particle size distribution analyzer (Horiba Instruments, Irvine, Ca).

The results indicate that PVP is not a satisfactory surface stabilizer for fenofibrate at the specific concentrations of fenofibrate and PVP shown in combination with DOSS, as the average particle size for formulation 5 was above two microns. However, PVP may be useful as a surface stabilizing agent for fenofibrate when used alone, in combination with another surface stabilizing agent or when different concentrations of PVP and/or fenofibrate are used.

Next, the stability of formulations 4 and 5 in various simulated biological fluids (Table 5).

The results indicate that formulation 4 comprising hypromellose and DOSS as surface stabilizers is preferred as the initial particle size is within the applicable range (ie 90% < 512 nm) and the composition does not show any aggregation in various simulated biological fluids.

The next step of examples concerns the redispersibility of the syringe granulated powders of the nanoparticulate fenofibrate compositions. The purpose of establishing the redispersibility of spray granulated powders is to determine whether the solid, nanoparticulate fenofibrate composition according to the invention will redisperse when introduced in in vitro or in vivo biologically relevant media.

Example 3

The purpose of this example was to evaluate the redispersibility of spray granulated powders of preferred nanoparticulate fenofibrate compositions comprising hypromellose and DOSS with or without SLS, a preferred low anionic surfactant.

The redispersibility of two powder forms of a syringe granulated powder of nanoparticulate fenofibrate was determined and the results are shown in Table 6.

TABLE 6

The results show that powders prepared from a granulation-lined dispersion with hypromellose, DOSS and SLS exhibit excellent redispersibility.

Example 4

The purpose of this example was to test the redispersibility of a syringe granulated powder of nanoparticulate fenofibrate comprising higher levels of DOSS and SLS, compared to example 3. The results are shown in Table 7.

TABLE 7

Excellent redispersibility was observed for all the tested compositions in simulated biological fluids.

Example 5

The purpose of this example was to prepare a nanoparticulate fenofibrate tablet formulation.

A fenofibrate nanoparticulate dispersion was prepared by combining the materials listed in Table 8 followed by grinding the mixture in a Netzsch LMZ2 media mill with a grinding chamber at a flow rate of 1.0 ± 0.2 LPM and an agitation speed of 3000 ± 100 RPM, using Dow PolyMill<TM >500 micron grinding medium. The resulting mean particle size of the nanoparticulate fenofibrate dispersion (NCD) as measured using a Horiba LA-910 laser scattering particle size distribution analyzer (Horiba Instruments, Irvine, CA), 169 nm.

Next, a granular lined dispersion (GFD) was prepared by combining the nanoparticulate fenofibrate dispersion with the additional components listed in Table 9.

The fenofibrate (GFD) was sprayed onto lactose monohydrate (500 g) to form a spray granulated intermediate (SGI) using the Vector Multi-1 powder bed system set to run at the parameters specified in Table 10 below.

The resulting syringe granulated intermediate (SGI) of the nanoparticulate fenofibrate is detailed in Table 11 below.

The nanoparticulate fenofibrate SGI was then tableted using a Kilian tablet press with a 0.700 x 0.300" flat upper and lower tablet shaped punches. Each tablet has 160 mg of fenofibrate. The resulting tablet formulation is shown below in Table 12.

Example 6

The purpose of this example was to assess the effect of food on the bioavailability of a nanoparticulate fenofibrate tablet formulation as prepared in example 5.

Design of the survey

A single dose, three-way crossover design study, with eighteen individuals, was conducted. The three treatments consisted of:

Treatment A: 160 mg nanoparticulate fenofibrate tablet administered under fasting conditions;

Treatment B: 160 mg nanoparticulate fenofibrate tablet administered under high-fat diet conditions; and

Treatment C: 200 mg micronized fenofibrate capsule (TRICOR <®>) administered under conditions of a low-fat diet.

"Low fat diet" conditions are defined as 30% fat - 400 Kcal and "high fat diet" conditions are defined as 50% fat - 1000 Kcal.

The time interval between the doses in the study was 10 days.

Results

Figure 1 shows the plasma fenofibric acid profiles (that is, the fenofibric acid concentration (μg/ml)) over a period of 120 hours for treatment A, treatment B and treatment C. Figure 2 shows the same fenofibric acid profiles, but over a 24 hour period rather than a 120 hour period period.

Surprisingly, all treatments produced approximately the same profile, although the nanoparticulate fenofibrate tablet administered under fasting conditions had a marginally higher maximum fenofibrate concentration. These results are significant for several reasons. First, the nanoparticulate fenofibrate tablet is effective at a lower dose than the conventional microcrystalline fenofibrate capsule: 160 mg versus 200 mg. A lower dose is always beneficial to the patient, as less active agent is administered to the patient.

Second, the results show that the nanoparticulate fenofibrate tablet formulation does not show any significant differences in absorption when administered under non-fasting versus fasting conditions. This is significant as it eliminates a patient's need to ensure they take a dose with or without food. Therefore, the nanoparticulate fenofibrate dosage form will result in increased patient compliance. With poor patient compliance, an increase in cardiovascular problems or other conditions for which fenofibrate is prescribed may result.

The pharmacokinetic parameters of the three tests are shown below in Table 13.

The pharmacokinetic parameters first demonstrated that there is no difference in the amount of drug absorbed when the nanoparticulate fenofibrate tablet is administered under non-fasting versus fasting conditions (see the AUC results; 139.41 μg/ml.h for the dosage form administered under fasting conditions and 138 .55 μg/ml.h for the dosage form administered under non-fasting conditions). Second, the data show that there was no difference in the rate of drug absorption when the nanoparticulate fenofibrate tablet is administered under nonfasting versus fasting conditions (see the Cmax results; 8.30 μg/ml for the dosage form administered under fasting conditions and 7.88 μg/ml for the dosage form administered under non-fasting conditions). The nanoparticulate fenofibrate dosage form therefore eliminates the effect of food on the pharmacokinetics of fenofibrate. Consequently, the invention comprises a fibrate composition in which the pharmacokinetic profile of the fibrate is not affected by the non-fasting or fasting state of an individual consuming the composition.

Bioequivalence of the nanoparticulate fenofibrate dosage form when administered under nonfasting versus fasting conditions

Using the data from Table 13, it was determined whether administration of a nanoparticulate fenofibrate tablet in a fasted state was bioequivalent to administration of a nanoparticulate fenofibrate tablet in a non-fasted state according to regulatory guidelines. The relevant data from Table 13 are shown below in Table 14 together with 90% confidence intervals (CI). According to the U.S. According to the FDA's guidelines, two products or procedures are bioequivalent if the 90% CI for AUC and Cmax is between 0.80 and 1.25. As shown below in Table 14, the 90% CI ratio for the nanoparticulate fenofibrate nonfasting/fasting methods is 0.952:1.043 for AUC and 0.858:1.031 for Cmax.

Accordingly, according to the regulatory guidelines, the administration of a nanoparticulate fenofibrate tablet in a fasted state is bioequivalent to the administration of a nanoparticulate fenofibrate tablet in a non-fasted state. Accordingly, the invention comprises a fibrate composition wherein the administration of the composition to an individual in a fasting state is bioequivalent to the administration of the composition to an individual in a non-fasting state.

Furthermore, as shown by the data in Table 15 below, the administration of a 160 mg nanoparticulate fenofibrate tablet in a non-fasting state is bioequivalent to the administration of a 200 mg conventional microcrystalline fenofibrate capsule (TRICOR®) in a non-fasting state. This is because the CI 90% for the two treatments is within 0.80 to 1.25 for AUC and Cmax.

Finally, as shown in Table 16 below, the administration of a 160 mg nanoparticulate fenofibrate tablet in a fasted state is not bioequivalent to the administration of a 200 mg conventional microcrystalline fenofibrate capsule (TRICOR®) in a non-fasted state. This is because the CI 90% for those treatments is outside 0.80 to 1.25 for AUC and Cmax.

The non-bioequivalence is significant, because it means that the nanoparticulate fenofibrate dosage form has significantly greater drug absorption. For the nanoparticulate fenofibrate dosage form to be bioequivalent to the conventional microcrystalline fenofibrate dosage form (eg TRICOR <®>), the dosage form must contain significantly less drug. The nanoparticulate fenofibrate dosage form therefore significantly increases the bioavailability of the drug.

Example 7

The purpose of this example was to provide nanoparticulate fenofibrate tablet formulations prepared as in example 5 above.

As shown in Table 17 below, the nanoparticulate fenofibrate dispersion is used to prepare the nanoparticles

the fenofibrate tablet formulations.

The two different tablets were prepared using the dispersion: A 145 mg nanoparticulate fenofibrate tablet and a 48 mg nanoparticulate fenofibrate tablet.

A granular lined dispersion (GFD) was prepared by combining the nanoparticulate fenofibrate dispersion with sucrose, docusate sodium and sodium lauryl sulfate.

The fenofibrate GFD was prepared and dried in a powder bed column (Vector Multi-1 Fluid Bed System) together with lactose monohydrate. The resulting syringe granulated intermediate (SGI) was processed through a cone mill followed by (1) processing in a mixer with siliceous microcrystalline cellulose and crospovidone, and (2) processing in a mixer with magnesium stearate. The resulting powder was tableted in a rotary tablet press followed by coating with Opadry ® AMB using a pan coater.

Table 18 provides the 145 mg fenofibrate tablet composition and Table 19 provides the 48 mg fenofibrate tablet composition.

Example 8

The purpose of this example was to compare the dissolution of a nanoparticulate 145 mg fenofibrate dosage form according to the invention with a conventional microcrystalline form of fenofibrate (TRICOR®) in a dissolution medium that was representative of in vivo conditions.

The dissolution of the 145 mg nanoparticulate fenofibrate tablet prepared in Example 7 was tested in a dissolution medium that is discriminating. Such a dissolution medium will give two very different dissolution curves for two products with very different dissolution profiles in gastric juices; that is, the dissolution medium says something about the in vivo dissolution of a composition.

The dissolution medium used was an aqueous medium containing the surfactant sodium lauryl sulfate at 0.025 M. Determination of the dissolved amount was performed by spectrophotometry and the tests were repeated 12 times. The rotary leaf method (European pharmacopoeia) was used under the following conditions:

media volume: 1000 ml;

media temperature: 37 ºC;

blade rotation speed: 75 RPM;

samples taken: every 2.5 minutes.

The results are shown below in Table 20. The table shows the amount (%) of solid dosage form dissolved at 5, 10, 20 and 30 minutes for twelve different samples as well as the mean (%) and standard deviation (%) results.

U.S. Patent No. 6,277,405, "Fenofibrate pharmaceutical composition with high bioavailability and methods of preparation thereof," describes the dissolution of a conventional microcrystalline 160 mg fenofibrate dosage form, for example TRICOR <®>, using the same method as described above for the nanoparticulate fenofibrate dosage form (Example 2, column 8-9). The results show that the conventional fenofibrate dosage form has a dissolution profile of 10% in 5 minutes, 20% in 10 minutes, 50% in 20 minutes and 75% in 30 minutes.

The results show that the nanoparticulate fenofibrate dosage form had dramatically faster dissolution compared to the conventional microcrystalline form of fenofibrate. For example, while 41.7% of the nanoparticulate fenofibrate dosage form was dissolved within 5 minutes, only 10% of the TRICOR<®> dosage form was dissolved. Similarly, while approximately 82.6% of the nanoparticulate fenofibrate dosage form was dissolved after 10 minutes, only approximately 20% of the TRICOR<®> dosage form was dissolved during the same time period. Finally, while virtually 100% of the nanoparticulate dosage form was dissolved after 30 minutes, only about 75% of the conventional fenofibrate dosage form was dissolved after the same time period.

Accordingly, the nanoparticulate fenofibrate dosage form of the invention has dramatically improved dissolution rates.

* * * *

Claims (18)

PATENT CLAIMS 1. Fenofibrate composition for oral administration characterized in that it includes: (a) particles of fenofibrate or a salt thereof, wherein at least 99% of the fibrate particles by weight have a particle size of less than 500 nm or that at least 50% of the fibrate particles by weight have a particle size of less than 350 nm; and (b) associated with the surface thereof, a surface stabilizer composition consisting of hypromellose, docusate sodium, and sodium lauryl sulfate in which the composition does not comprise PEG-derivatized vitamin E, and wherein the composition does not provide significantly different levels of absorption when administered under non-fasting compared to fasting conditions wherein administration of the composition to an individual in a fasted state is bioequivalent to administration of the composition to an individual in a non-fasted state, wherein “bioequivalence” is established through: (a) a 90% confidence interval that is between 0.80 and 1.25 for both Cmax and AUC in accordance with the U.S. Food and Drug Administration regulatory guidelines, or (b) a 90% confidence interval for AUC that is between 0.80 and 1.25 and a 90% confidence interval for Cmax that is between 0.7 and 1.43 in accordance with European EMEA regulatory guidelines. 2. Composition according to claim 1, characterized in that the fenofibrate is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, and mixtures thereof. 3. Composition according to claim 1 or 2, characterized in that at least 50% of the fibrate particles by weight have a particle size selected from the group consisting of less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm. 4. Composition according to any one of claims 1-3, characterized in that the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof. 5. Composition according to any one of claims 1-4, characterized in that the fibrate is present in an amount selected from the group consisting of from 99.5 wt% to 0.001 wt%, from 95 wt% to 0.1 wt%, and from 90 wt% to 0.5 wt%, based on the total combined weight of the fibrate and at least the three surfactants, not including other excipients. 6. Composition according to any one of claims 1-5, characterized in that the at least three surface stabilizing agents are present in an amount selected from the group consisting of from 0.5% by weight to 99.999% by weight, from 5.0% by weight to 99.9% by weight, and from 10% by weight to 99.5% by weight, based on the total combined dry weight of the fibrate and at least one surface stabilizer, not including other excipients. 7. Composition according to any one of claims 1-6, characterized in that the composition exhibits a Tmax selected from the group consisting of less than 6 hours, less than 5 hours, less than 4 hours, less than 3 hours, less than 2 hours, less than 1 hour, and less than 30 minutes after administration to fasting individuals. 8. Composition according to claim 2, characterized in that the difference in absorption of the fibrate composition according to the invention, when administered in the non-fasting versus fasting state, is selected from the group consisting of less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, and less than 3%. 9. Composition according to any one of claims 1-8, characterized in that it comprises fenofibrate or a salt thereof, wherein in comparative pharmacokinetic testing with a TRICOR® 160 mg tablet or 200 mg capsule, which is the standard commercial formulation of microcrystalline fenofibrate, the composition shows a Tmax, selected from the group consisting of less than 90% , less than 80%, less than 70%, less than 50%, less than 30%, and less than 25% of the Tmax shown by the TRICOR® tablet or capsule. 10. Composition according to any one of claims 1-9, characterized in that the fibrate particles have a particle size where D50 is less than 350 nm. 11. A composition according to any one of claims 1-10, for use in the treatment of a condition selected from the group consisting of hypercholesterolemia, hypertriglyceridemia, coronary heart disease, cardio-vascular disease, and peripheral vascular disease. 12. Composition according to claim 1, characterized in that it further comprises an HMG-CoA reductase inhibitor. 13. Composition according to claim 12, characterized in that the HMG-CoA reductase inhibitor is selected from the group consisting of lovastatin; pravastatin; simvastatin; velostatin; atorvastatin; fluvastatin; fluindostatin; rivastatin; Searle's SC-45355; dichloroacetate; octahydronaphthalenes; and phosphinic acid compounds. 14 Fixed dosage form characterized in that it comprises a composition according to each of the preceding claims. 15. Dosage form according to claim 14, characterized in that it is in the form of a tablet. 16. Dosage form according to claim 14 or 15, characterized in that the fenofibrate or a salt thereof is mixed with at least one of the following: (a) one or more inert excipients or carriers; (b) fillers or extenders; (c) binders, (d) humectants, (e) disintegrants, (f) dissolution retarding agents, (g) absorption accelerators, (h) wetting agents, (i) adsorbents, and (j) lubricants. 17. Dosage form according to claim 14, 15 or 16, characterized in that it further comprises an HMG-CoA reductase inhibitor. 18. Composition according to claim 17, characterized in that the HMG-CoA reductase inhibitor is selected from the group consisting of lovastatin; pravastatin; simvastatin; velostatin; atorvastatin; fluvastatin; fluindostatin; rivastatin; Searle's SC-45355; dichloroacetate; octahydronaphthalenes and phosphinic acid compounds.