WO2004002458A1

WO2004002458A1 - Formulations of fenofibrate and/or fenofibrate derivatives with improved oral bioavailability

Info

Publication number: WO2004002458A1
Application number: PCT/US2002/041093
Authority: WO
Inventors: Amir H. Shojaei; Scott A. Ibrahim; Beth A. Burnside
Original assignee: Shire Laboratories Inc.
Priority date: 2002-06-28
Filing date: 2002-12-20
Publication date: 2004-01-08
Also published as: EP1539117A1; EP1539117A4

Abstract

A fibrate oral formulation with improved bioavailability when compared to commercially available formulations containing a therapeutically effective dose of fenofibrate or a fenofibrate derivative dissolved in N-alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, C8-12 fatty acid ester of polyethylene glycol, fatty acids, or combinations thereof useful for the treatment of hypercholesterolaemia or hypertriglyceridaemia in mammals.

Description

Formulations of Fenofibrate and/or Fenofibrate Derivatives with Improved Oral Bioavailability

FIELD OF THE INVENTION The present invention relates to a non-aqueous pharmaceutical formulation of fenofibrate or fenofibrate derivatives having an improved oral bioavailability when compared to a commercial available formulation.

BACKGROUND OF THE INVENTION

Fenofibrate is a fibrate used in the treatment of endogenous hyperlipidaemias, hypercholesterolaemias and hypertriglyceridaemias in adults. The preparation of fenofibrate is disclosed in US patent. No. 4,058,552. Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides and thglyceride rich lipoprotein (VLDL) in treated patients. Also, treatment with fenofibrate results in increases in high-density lipoprotein (HDL) and apoproteins apoAI and apoAII. Prolonged treatment with fenofibrate at the rate of 300 to 400 mg per day makes it possible to obtain a reduction in total cholesterol of 20 to 25% and a reduction in the levels of triglycerides of 40 to 50%. It thus opposes the development of arteriosclerosis. The customary adult fenofibrate dosage is three gelatin capsules per day, each containing 100 mg of fenofibrate.

Fenofibrate is not soluble in water, which limits its absorption in the gastrointestinal (Gl) tract. To remedy this problem, research groups have tried a multitude of strategies. In U.S. patents 4,800,079 and 4,895,726 micronized fenofibrate formulations of are disclosed. In US patent 6,277,405 the immediate release of micronized fenofibrate in a tablet or in the form of granules inside a capsule is shown. In US patent 6,074,670 the immediate release of micronized fenofibrate in a solid state is shown. In US patent 5,880,148 the combination of fenofibrate and vitamin E is discussed, this formulation is claimed to be useful as an antiatheromatous drug and exhibit a synergistic effect in regards to protecting low-density lipoproteins (LDL) from oxidation. In US patent 5,827,536 the use of diethylene glycol monoethyl ether (DGME) as solubilizer is discussed and an enhancement in bioavailability claimed. In US patent 5,545,628 the combination of fenofibrate with one or more polyglycolyzed glycerides is disclosed.

In order to prepare the solid formulations of Fenofibrate, the compound is normally dissolved in a proper solvent or solubilizers. Fenofibrate is known to be soluble in many different solubilizers, including anionic (e.g. SDS) and non-ionic (e.g. Triton X -100) surfactants, complexing agents (N-methyl pyrrolidone) (Temeljotov et al (1995) Farmacevtski Vestnik (Slovenia), 46/(Special Issue)).

The technology developed to increase the bioavailability of fenofibrate includes elements and process steps that increase the cost of production making them commercially unattractive. If a formulation for the use fenofibrate and its method of preparation of said formulation could be simplified while increasing the bioavailability of fenofibrate, the resulting product would satisfy an existing need in this field. The present invention provides such a product, a liquid or semi-solid formulation with improved bioavailability for oral administration of fenofibrate or fenofibrate derivatives wherein the particle size of the active agent is not critical to the bioavailability of the product. SUMMARY OF THE INVENTION

The object of the present invention includes an oral pharmaceutical formulation with improved bioavailability when compared to a commercial available formulation comprising a therapeutically effective amount of the a fibrate dissolved in N- alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, C_8-12 fatty acid ester of polyethylene glycol or combinations thereof The present invention additionally includes oral pharmaceutical formulations with improved bioavailability comprising a therapeutically effective amount of fenofibrate or a fenofibrate derivative in a N- alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, C_8-i₂fatty acid ester of polyethylene glycol or combinations thereof wherein the bioavailability of the active ingredient is enhanced due to a significant (P<0.05) change in the rate, Cm_ax, and/or

extent, AUCo-oo, of absorption when compared to a commercial available formulation

such as Lipanthyl® (trade mark of Groupe Foumier) or TriCor® (trade mark of Abbott Laboratories) .

In an alternate embodiment of the invention a fibrate pharmaceutical formulation containing a therapeutically effective amount of the fenofibrate or its derivatives dissolved in N- alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, C_8-12 fatty acid ester of polyethylene glycol or combinations thereof and at least one surfactant is disclosed.

According to a further aspect of the invention, there is provided a method for treating a mammal with hypercholesterolaemia or hypertriglyceridaemia comprising the oral administration of a fibrate formulation containing a therapeutically effective dose of fenofibrate or a fenofibrate derivative dissolved in N- alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, fatty acids, fatty acids, C_8-12 fatty acid ester of polyethylene glycol or combinations thereof.

The present invention includes an self-emulsifying oral pharmaceutical formulation with improved bioavailability comprising a therapeutically effective amount of fenofibrate or a fenofibrate derivative, at least one non-ionic hydrophobic surfactant (HLB value lower than or equal to 10), and a water miscible fenofibrate solubilizer selected from N-C_1- alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, or combinations thereof mixed with at least one of fatty acids or C_8-12 fatty acid ester of polyethylene glycol.

The present invention also includes oral self-emulsifying pharmaceutical formulations with improved bioavailability when compared to a commercial available formulation comprising a therapeutically effective amount of fenofibrate or a fenofibrate derivative, one or more non-ionic surfactant with an HLB value higher about 10, one or more non- ionic co-surfactant with a HLB value lower or equal to about 6, provide that the surfactant/co-surfactant combination has a HLB value lower than or equal to about 10 and a water miscible fenofibrate solubilizer selected from N-C-ι_-4 alkyl derivative of 2- pyrrolidone, ethylene glycol monoether, or combinations thereof mixed with at least one of fatty acids or C_8-12 fatty acid ester of polyethylene glycol.

The present invention additionally includes an oral self-emulsifying pharmaceutical formulation with improved bioavailability comprising a therapeutically effective amount of the fenofibrate or a fenofibrate derivative, one or more non-ionic surfactant with an HLB value between 10 and 18, one or more non-ionic co-surfactant with a HLB value between 2 and 6, and a fenofibrate solubilizer selected from water miscible N-C- alkyl derivative of 2-pyrrolidone, water miscible ethylene glycol monoether, fatty acids, Cβ-12 fatty acid ester of polyethylene glycol and combinations thereof wherein the bioavailability of the active ingredient is significantly enhanced when compared to a commercial available formulation due to a significantly (PO.05) enhanced rate (C_maχ, reduction in the time to reach maximum plasma levels, T_max) and/or extent of absorption

(AUCo-oo) of the fibrate.

In an embodiment of the present invention fibrate formulations described above wherein the improvement in C_maχ is at least 1.2 times than that for commercial formulation and/or

the AUCo_-∞ improvement is at least 1.5 times that of commercial formulation are

disclosed.

The scope of the invention includes a pharmaceutical dosage unit for oral administration comprising of a fibrate formulation containing a therapeutically effective dose of fenofibrate or a fenofibrate derivative dissolved in N- alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, fatty acids, C_8-12 fatty acid ester of polyethylene glycol or combinations thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides non-aqueous formulations with enhanced systemic absorption of fenofibrate and/or derivatives of fenofibrate when compared to a commercial available formulation.

Due to the physicochemical properties of fibrates such as fenofibrate, the systemic absorption of the drug is believed to be dissolution rate limited. By providing an oral formulation wherein the fenofibrate or fenofibrate derivative is dissolved in a water miscible organic solvent such as the N-alkyl derivatives of 2-pyrrolidone, ethylene glycol monoether, C₈.ι₂ fatty acid ester of polyethylene glycol or combinations thereof. The water miscible solvent or solubilizer used in the present invention additionally may act as an agent that prevents or minimizes the crystallization of fibrate in the formulation upon contact with an aqueous environment. The fibrate solubilizer may be a complexing agent soluble in water. With the complete dissolution of the fibrate, the fibrate solution allows for an increase in absorption by the patient. The ease with which the fenofibrate or fenofibrate derivative dissolves in a solvent is inversely proportional to the particle size of the fibrate. Therefore, the present invention includes an oral fibrate formulation comprising fenofibrate or a fenofibrate derivative and a water miscible organic solubilizer that allows the complete dissolution of the fenofibrate or a fenofibrate derivative and prevents or minimizes the crystallization of fibrate in the formulation upon contact with an aqueous environment. The present invention includes fibrate formulation wherein the fibrate to fibrate solubilizer weight ratio is between about 1 :1 and about 1 :100.

As used in this application, the term "fatty acid" represents a C₁-₃₀ unbranched or branched, saturated or unsaturated hydrocarbon chain and a terminal carboxyl group.

The solubilizer comprises the combination of solvents, surfactants, optional co- surfactants, and stabilizing agents used in the formulation. In an embodiment of the present invention the fibrate solubilizer may contain an oily component and a non-oily component. The oily component of the solubilizer may consist of alcohols, propylene glycol, polyethylene glycol, propylene glycol esters, medium chain mono-, di-, or triglycerides, long chain fatty acids, naturally occurring oils, and a mixture thereof. The oily component of the solubilizer may contain non-surface active oils, which have no hydrophile lipophile balance value. The non-oily component of the solubilizer may contain molecules with highly polar functionalities such as carbonyl groups as well as primary amines with short chain (C₁-C₃) alkyl groups. The present invention includes self-emulsifying fibrate formulation wherein the fibrate to fibrate solubilizer weight ratio is between about 1:1 and about 1 :100.

In a further embodiment of the present invention an oral fenofibrate formulation comprising fenofibrate or a fenofibrate derivative and a water miscible fibrate solubilizer is N-alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, C_8-12 fatty acid ester of polyethylene glycol or combinations thereof is provided. The formulations described may further contain a gelling agent that alters the texture of the final formulation through formation of a gel.

Gelling agents used in the present invention include but are not limited to carrageenan, cellulose gel, colloidal silicon dioxide, gelatin, propylene carbonate, carbonic acid, alginic acid, agar, carboxyvinyl polymers or carbomers and polyacrylamides, acacia, ester gum, guar gum, gum arabic, ghatti, gum karaya, tragacanth, terra, pectin, tamarind seed, larch arabinogalactan, alginates, locust bean, xanthan gum, starch, veegum, tragacanth, polyvinyl alcohol, gellan gum, hydrocolloid blends, and povidone.

The present invention further includes an oral self-emulsifying fibrate formulation with improved oral bioavailability comprising a therapeutically effective amount of the fenofibrate or fenofibrate derivative dissolved in a water miscible fibrate solubilizer selected from

alkyl derivative of 2-pyrrolidone or ethylene glycol monoether and mixtures thereof, in combination with at least one of fatty acids and/or C₈-₁₂ fatty acid ester of polyethylene glycol and at least one non-ionic surfactant with a high HLB value lower than or equal to 10.

The present invention also provides an oral self-emulsifying formulation wherein the fenofibrate is dissolved in one or more non-ionic surfactant with an HLB value higher or equal to about 10, one or more non-ionic co-surfactant with a HLB value lower or equal to about 6, and a water miscible fenofibrate solubilizer selected from N-C-i_-4 alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, C_8-12 fatty acid ester of polyethylene glycol and combinations thereof, wherein the resulting fenofibrate self- emulsifying formulation allows for an improved systemic absorption of the fenofibrate by the patient.

The term "HLB" value is defined as hydrophilic-lipophilic balance and defines the relative hydrophilicity and hydrophobicity of the surfactant. Surfactants with lower HLB values are more hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. Surfactants having an HLB value less than about 10 are considered to be hydrophobic surfactants. Therefore hydrophilic surfactants have HLB values greater than about 10. Combinations of hydrophilic surfactants and hydrophobic surfactants thereof are within the scope of the present invention.

The surfactants used in the present invention include those having a HLB value of less than or equal to 10. These surfactants may include propylene glycols, glyceryl fatty acids, glyceryl fatty acid esters, polyethylene glycol esters, propylene glycol laureate, glyceryl glycol esters, polyglycolyzed glycerides, propylene glycol esters or partial esters and polyoxyethyl steryl ethers. Mixtures of surfactants are also included in the _^ _ _ _{^ | j,} scope of the invention. These surfactants, mixtures, and other equivalent composition's having an HLB less than or equal to 10 may be used for the self-emulsifying formulation.

The use of surfactants with an HLB greater than 10 are within the scope of the present invention. Surfactants that have a HLB value greater than 10 may be used in combination with other surfactant as co-surfactants. Suitable co-surfactants include glyceryl glycol esters, polyethylene glycol esters, polyglycolyzed glycerides, polyoxyethylene glycerol esters, oleate or laureate ester of a polyalcohol copolymerized with ethylene oxide and a mixture thereof. Examples of commercially available surfactants are Labrasol , Gelucire 44/14 and Tween 80

The term "fenofibrate" is a fibrate and is defined as a compound of formula (I), 2-[4-(4- Chlorobenzoyl ) phenoxy]-2-methylpropanoic acid 1-methylethyl ester:

The term "fenofibrate derivatives" is defined as a compound of formula (II)

wherein Ri represents a phenyl group or a phenyl group substituted by one or more CH₃, CF₃ or by halogens;

R₂ and R₃ independently represent a hydrogen atom or a halogen atom (preferably fluorine, chlorine, or bromine), an C- alkyl or an Cι_-5 alkoxy or one of the following groups: CF₃, SCH₃, SOCH₃, SO₂CH₃, or OH; and

Y represents one of the following groups: OH; C-i_-5 alkoxy, preferably in d-C ; - NR₄R₅ ; --NHCH₂CH₂NR₄R₅ ; or --O- C_1-6 alkylene-NR₄R₅, with the alkylene having, in particular, two to six atoms of carbon, and with R₄ and R₅ being identical or different and each representing a hydrogen atom or one of the following groups: C-ι-₅ alkyl, C₃-C₇ cycloalkyl , preferably C_5-6 cycloalkyl; Cβ-io aryl or aryl substituted on the aromatic residue by one or more halogen, methyl, or -CF₃ groups; or else R₄ and R₅ constitute, together with the nitrogen atom to which they are connected, one of the following groups: either an n-heterocyclic group having 5 to 7 vertices capable of enclosing a second heteroatom selected from N, O, and S, and capable of being substituted; or else an amide residue derived from lysine or cysteine; including the pharmaceutically acceptable salts, esters, amides and prodrugs thereof wherein said derivative has a solubility not less than 0.5 mg/ml in the water miscible solubilizer used in the fibrate formulation object of the present invention.

The scope of the present invention includes formulations summarized in Tables 1A and 1 B: Table 1A.

Quantitative representation of fenofibrate formulations in the form of non- emulsifiable systems, such as binary solutions

*Excipients required for stability enhancement of the final formulation these would include antioxidants, thickening agents, suspending agents, etc.

Table 1B. Quantitative representation of self-emulsifying formulations providing for enhanced systemic absorption of fenofibrate

^*Excipients required for stability enhancement of the final ormulation, these would include antioxidants, thickening agents, suspending agents, etc.

The present invention includes a fenofibrate formulation wherein the water miscible fenofibrate solubilizer includes the use of N-alkyl derivatives 2-pyrrolidones, wherein the alkyl group has 1 to 4 carbons, Cβ-β ethylene glycol monoethers, acid ester of polyethylene glycol, fatty acids or combinations thereof is provided. The present invention includes N-alkyl derivatives 2-pyrrolidone wherein the alkyl group has 1 to 3 carbons.

The amount of fibrates such as fenofibrate, fenofibrate derivatives or mixtures thereof contained in the formulation of this invention is not specifically restricted but may be any amount convenient for pharmaceutical purposes. For filling a gel capsule, a concentrated solution of up to the saturation point of the fibrate solubilizer may be of interest. For example the solubility of fenofibrate in N-methyl-2-pyrrolidone is about 591 mg/ml, so a concentrated fenofibrate solutions of >500 mg/ml would be of interest for use in the oral formulation object of the present invention. The present invention would also include fenofibrate in N-methyl-2-pyrrolidone solutions with concentrations below about 500 mg/ml.

In an alternate embodiment of the present invention, the fenofibrate or fenofibrate derivative solubilizer is selected from N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, N- propyl-2-pyrrolidone, N-isopropyl-2-pyrrolidone, N-butyl-2-pyrrolidone, N-(2- hydroxyethyl)-2-pyrrolidone, diethylene glycol monoethyl ether, polyethylene glycol mono- and diester of C_8-ι₂ fatty acids and combinations thereof. The invention includes the combination of the N-alkyl derivatives of 2-pyrrolidone with ethylene glycol monoether and/or C_8-ι₂ fatty acid ester of polyethylene glycol; or combinations of fatty acids and C_8-ι₂ fatty acid ester of polyethylene glycol. The formulation object of the present invention may use N-methyl-2-pyrrolidone, diethylene glycol monoethyl ether, polyethylene glycol mono- and diester of caproic acid, caprylic acid, capric acid, lauric acid or mixtures of polyethylene glycol mono- and diester of caproic acid, caprylic acid, capric acid, lauric acid with one or more fatty acids selected from caproic acid, caprylic acid, capric acid, lauric acid and mixtures thereof; and combinations thereof as solubilizers of fenofibrate. The mono- and diester of C_8-ι₂ fatty acids and combinations thereof also include use of Captex® 100 , Captex® 200, Captex® 200 E-6, Capmul® MCM, Capmul® PG-8, Capmul® PG-10, (Abitec Corp.) and Gelucire® 44/14, Gelucire® 50/13 (Gattefosse Corp.). Combinations of N-Methyl-2-Pyrrolidone and diethylene glycol monoethyl ether as fibrate solubilizers are within the scope of the present invention. The invention includes combinations of N-methyl-2-pyrrolidone and diethylene glycol monoethyl ether wherein the weight rations of N-methyl-2-pyrrolidone to diethylene glycol monoethyl ether is between about 1 :0.01 and about 0.01 :1. The invention also includes combinations of N-methyl-2-pyrrolidone and diethylene glycol monoethyl ether wherein the weight rations of N-methyl-2-pyrrolidone to diethylene glycol monoethyl ether is between about 1 :0.1 and about 0.1 :1.

In a further embodiment of the present invention, the water miscible fibrate solubilizer is chosen from combinations of N-C- alkyl derivative of 2-pyrrolidone or a ethylene glycol monoether or combinations thereof, with one or more polyethylene glycol mono- or diester of Cs-₁₂ fatty acids or mixtures polyethylene glycol mono- and diester of C_8-12 fatty acids and fatty acids. The weight ratio of the N-C₁ alkyl derivative of 2-pyrrolidone or a ethylene glycol monoether or combinations thereof to one or more polyethylene glycol mono- and diester of C_8-ι₂ fatty acids or mixtures polyethylene glycol mono- and diester of C_8-ι₂ fatty acids and fatty acids is between about 100:1 to about 1 :4. The present invention includes rations between 20:1 to about 1 :4.

The amount of fibrate solubilizer used will depend on the dose of fibrate; enough solubilizer should be used to maintain the fibrate in solution. The weight ratio fibrate to the fibrate solubilizer is chosen so as to obtain a complete dissolution of fenofibrate or fenofibrate derivative. The fibrate: fibrate solubilizer ratio is chosen to obtain a solution whose fibrate concentration is below the saturation point. The weight ratio of fibrate to fibrate solubilizer may be between about 1 :1 to about 1 :100. The weight ratios include about 1 :1 to about 1 :10. The fibrate: fibrate solubilizer weight ratio may also be between about 3: 4 to about 1 :100. The fibrate: fibrate solubilizer weight ratio between about 3: 4 to about 1 :10 is within the scope of the invention.

The present invention includes an oral fibrate formulation comprising fenofibrate or a fenofibrate derivative and a water miscible organic solubilizer that allows the complete dissolution of the fenofibrate or a fenofibrate derivative and prevents or minimizes the crystallization of fibrate in the formulation upon contact with an aqueous environment with an improved bioavailability equal to or greater that about 10%. The invention includes fibrate formulation comprising a therapeutically effective amount of the fenofibrate, a fenofibrate derivative or combinations thereof and a N- alkyl derivative of 2-pyrrolidone, or combinations of N-alkyl derivative of 2-pyrrolidones, ethylene glycol monoether, C_8-ι₂ fatty acid ester of polyethylene glycol or combinations thereof. The bioavailability is enhanced due to a significantly (P<0.05) enhanced rate (Cmax, reduction in the time to reach maximum plasma levels, T_max) and/or extent of absorption

(AUCo-co). The % bioavailability enhancement value is defined as the ratio obtained by

formula (III):

{(AUCo-24 (fibrate formulation) /DθSθfjbrate formulation) (AUCn-24 (Commercial

formulation L'OSΘcommercial formulation)} X 1 UU (III) The present invention includes the use of N-methyl-2-pyrrolidone ^"(NMP in a formulation to solubilize fenofibrate and/or its derivatives with similar solubility profile, and enhance bioavailability after oral administration to a % enhancement value equal to or greater than 50%. N-methyl-2-pyrrolidone is an organic liquid excipient and is also known as 1- methylpyrrolidinone, N-methyl-2-pyrrolidinone, 1-methyl-5-pyrrolidinone, methylpyrrolidinone, N-methyl pyrrolidinone, methylpyrrolidinone, N-methylpyrrolidone, M-pyrol, and NMP.

The present invention additionally includes an oral pharmaceutical formulation with improved oral bioavailability comprising a therapeutically effective amount of fenofibrate, a fenofibrate derivative or mixtures thereof and one or more solubilizers selected from N- alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, C_8-12 fatty acid ester of polyethylene glycol, mixtures of C_8-ι₂ fatty acid ester of polyethylene glycol and fatty acids, or combinations thereof wherein the bioavailability of said formulation is

significantly (P<0.05) enhanced in both the rate (C_maχ) and the extent (AUCo-oo) of absorption as compared to that of a commercial formulation. The present invention includes said formulations wherein the improvement in C_max is at least about 1.2 times that of a commercial formulation such as Lipanthyl ® (trade mark of Groupe Fournier) or

TriCor® (trade mark of Abbott Laboratories) and/or the AUC_0-∞ improvement is at least

about 1.5 times that of a commercial formulation such as Lipanthyl ® (trade mark of Groupe Fournier) or TriCor® (trade mark of Abbott Laboratories).

The present invention further includes oral self-emulsifying fibrate formulation with improved oral bioavailability comprising a therapeutically effective amount of the fenofibrate or fenofibrate derivative dissolved in a water miscible fibrate solubilizer selected from N-C_1- alkyl derivative of 2-pyrrolidone or ethylene glycol monoether and mixtures thereof, in combination with at least one C_8-ι₂ fatty acid ester of polyethylene glycol and at least one non-ionic surfactant with a high HLB value lower than or equal to 10 wherein the oral bioavailability of said formulation is significantly (P<0.05) enhanced

in both the rate (C_maχ) and the extent (AUCo-_∞) of absorption as compared to that of a commercial formulation such as Lipanthyl ® (trade mark of Groupe Fournier) or TriCor® (trade mark of Abbott Laboratories) . The present invention includes said formulations wherein the improvement in C_max is at least 1.2 times that a commercial formulation such as Lipanthyl ® (trade mark of Groupe Fournier) or TriCor® (trade mark of Abbott

Laboratories) and/or the AUCo-_∞ improvement is at least 1.5 times that of a commercial formulation such as Lipanthyl ® (trade mark of Groupe Fournier) or TriCor® (trade mark of Abbott Laboratories) .

The present invention also provides an oral self-emulsifying formulation wherein the fenofibrate is dissolved in one or more non-ionic surfactant with an HLB value higher or equal to about 10, one or more non-ionic co-surfactant with a HLB value lower or equal to about 6, and a water miscible fenofibrate solubilizer selected from N-Ci^ alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, C_8-ι₂ fatty acid ester of polyethylene glycol or mixtures of C_8-12 fatty acid ester of polyethylene glycol and fatty acids, and combinations thereof, wherein the resulting fenofibrate self-emulsifying formulation allows for an improved systemic absorption of the fenofibrate by the patient and the oral bioavailability of said formulation is significantly (P<0.05) enhanced in both

the rate (C_max) and the extent (AUCo-<») of absorption as compared to that of a

commercial formulation such as Lipanthyl ® (trade mark of Groupe Fournier) or TriCor® (trade mark of Abbott Laboratories) . The present invention includes said formulations wherein the improvement in C_maχ is at least 1.2 times that a commercial formulation such as Lipanthyl ® (trade mark of Groupe Fournier) or TriCor® (trade mark of Abbott Laboratories) . and/or the AUCo-_∞ improvement is at least 1.5 times that of a commercial formulation such as Lipanthyl ® (trade mark of Groupe Fournier) or TriCor® (trade mark of Abbott Laboratories) .

The present invention additionally includes an oral self-emulsifying pharmaceutical formulation with improved bioavailability comprising a therapeutically effective amount of the fenofibrate or a fenofibrate derivative, one or more non-ionic surfactant with an HLB value between 10 and 18, one or more non-ionic co-surfactant with a HLB value between 2 and 6, and a fenofibrate solubilizer selected from water miscible N-C_1-4 alkyl derivative of 2-pyrrolidone, water miscible ethylene glycol monoether, C_8-12 fatty acid ester of polyethylene glycol or mixtures of C_8-ι₂ fatty acid ester of polyethylene glycol and fatty acids, and combinations thereof wherein the bioavailability of the active ingredient is significantly enhanced, wherein the fenofibrate may or may not be micronized. The bioavailability when compared to a commercial available formulation is enhanced due to a significantly (P<0.05) enhanced rate (reduction in the time to reach

maximum plasma levels, T_maχ) and/or extent of absorption (AUCo-_∞).

The oral formulation object of the present invention may be provided in the form of a solution, a self-emulsifying system, a straight binary system, semi-solid system or any other pharmaceutically acceptable form. The oral formulation may be encapsulated in a hard or soft gelatin capsule, a starch capsule or any other pharmaceutically acceptable capsule.

The present invention includes a pharmaceutical formulation with improved oral bioavailability when compared to a commercially available formulation comprising a therapeutically effective amount of the fenofibrate, a fenofibrate derivative or mixtures thereof dissolved in a solubilizer selected from N- alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, C_8-ι₂ fatty acid ester of polyethylene glycol or mixtures of C_8-ι₂ fatty acid ester of polyethylene glycol and fatty acids, or mixtures thereof and at least one non-ionic surfactant with an HLB value higher or equal to about 10.

The present invention includes the use of surfactants selected from sucrose esters, polysorbates, polyethylene glycosylated glycerides, PEGylated glycehdes and combinations thereof. These non-ionic surfactant may include mixtures of monoglycerides, diglycerides, and triglycerides and monoesters and diesters of polyethylene glycol, polyethylene glycosylated almond glycerides, polyethylene glycosylated corn glycerides, polyethylene glycosylated caprylic/capric t glyceride, polysorbate 20, polysorbate 60, polysorbate 80, Polyoxyl 20 Cetostearyl Ether, Polyoxyl 10 Oleyl Ether and combinations thereof. Additionally suitable non-ionic surfactants include PEG stearate, PEG hydrogenated castor oil, PEG laurate, PEG apricot kernel oil esters, PEG caprylate, PEG caprate, PEG myristate, PEG palmitate, and PEG oleate and combinations thereof.

The present invention includes an oral self-emulsifying pharmaceutical formulation with improved bioavailability comprising a therapeutically effective amount of the fenofibrate, a fenofibrate derivative or mixtures thereof and dissolved in one or more N- alkyl derivative of 2-pyrrolidone or ethylene glycol monoether or mixtures thereof, combined with at least one C_8-12 fatty acid ester of polyethylene glycol or mixtures of C_8-12 fatty acid ester of polyethylene glycol and fatty acids, and at least one non-ionic hydrophobic surfactants. The formulation includes the use of surfactants with an HLB value lower than or equal to about 10. The present invention also includes the use of non-ionic surfactants with an HLB value lower or equal to about 6. The present invention also includes the use of surfactants selected from mono-acyl glycerides, sorbitan fatty acid esters, sucrose distearate, ethylene glycol monoether and combinations thereof.

Non-ionic surfactants used in the oral self-emulsifying pharmaceutical formulation with improved bioavailability object of the present invention may include sorbitan tristearate, sorbitan sesquioleate, glyceryl monostearate, sorbitan monooleate, sorbitan monostearate, sorbitan distearate, propylene glycol monostearate, glyceryl monooleate, glyceryl stearate mono, propylene glycol monolaurate, glyceryl monolaurate, diethylene glycol monoethyl ether and combinations thereof.

The present invention includes an oral self-emulsifying pharmaceutical formulation with improved bioavailability comprising a therapeutically effective amount of the fenofibrate, a fenofibrate derivative or mixtures thereof and one or more N-alkyl derivative of 2- pyrrolidone, ethylene glycol monoether and mixtures thereof in combination with at least one C_8-ι₂ fatty acid ester of polyethylene glycol or mixtures of Cβ-ι₂ fatty acid ester of polyethylene glycol and fatty acids, at least one non-ionic surfactant with an HLB value higher than about 10 and at least one non-ionic co-surfactants with an HLB value lower than or equal to about 6. The invention includes formulations wherein the combinations of the high HLB and low HLB value surfactants have a final HLB value equal to or lower than 10.

The present invention includes an oral self-emulsifying pharmaceutical formulation comprising a fibrate dissolved in a fibrate solubilizer composed of a non-oily component selected from N- alkyl derivative of 2-pyrrolidone, ethylene glycol monoether and mixtures thereof and an oily component comprising one or more Cβ-12 fatty acid esters of polyethylene glycol; and at least one surfactant with an HLB value lower than or equal to about 10.

The present invention also includes an oral self-emulsifying pharmaceutical formulation with improved bioavailability comprising a therapeutically effective amount of the fenofibrate, a fenofibrate derivative or mixtures thereof and combinations of one or more N- alkyl derivative of 2-pyrrolidone with ethylene glycol monoether , at least one C_8-12 fatty acid ester of polyethylene glycol or mixtures of C_8-12 fatty acid ester of polyethylene glycol and fatty acids, at least one non-ionic surfactant with an HLB value higher than about 10 selected from sucrose esters, polysorbates, polyethylene glycosylated glycerides, PEGylated glycerides and combinations thereof; and at least one non-ionic co-surfactant with an HLB value lower or equal to about 6 selected from mono-acyl glycerides, sorbitan fatty acid esters, sucrose distearate, ethylene glycol monoether and combinations thereof wherein the combination of the high HLB and low HLB value surfactants have a final HLB value equal to or lower than 10. The invention includes those oral self-emulsifying pharmaceutical formulation with improved bioavailability described above wherein the improvement in C_maχ is at least 1.2 times that of a commercial formulation such as Lipanthyl ® (trade mark of Groupe Fournier) or TriCor®

(trade mark of Abbott Laboratories) .and/or the AUCo-oo improvement is at least 1.5 times

that of a commercial formulation such as Lipanthyl ® (trade mark of Groupe Fournier) or TriCor® (trade mark of Abbott Laboratories).

All the formulations object of the present invention may be prepared using both micronized and non-micronized fibrate. Other commonly used pharmaceutical excipients which may also be added to the formulations object of the present invention, these may include antioxidants, preservatives or stabilizing agents, such as butylated hydroxytoluene, butylated hydroxyanisole sodium bisulfide, sodium sulfite, citric acid, ascorbic acid, or EDTA, coloring agents and flavoring agents (to improve patient acceptance, especially for liquid dosage forms), and ingredients used to stabilize gelatin capsules, such as glycerine, or gelatin.

The fibrate formulations disclosed are useful in the treatment of hypercholesterolaemias and hypertriglyceridaemias. According to a further aspect of the invention, there is provided a method for treating a patient with hypercholesterolaemia or hypertriglyceridaemia comprising the oral administration of a fibrate formulation containing a therapeutically effective dose of fenofibrate, a fenofibrate derivative or mixtures thereof dissolved in a water miscible solubilizer selected from N- Cι_-4 alkyl derivative of 2-pyrrolidone, 2- C_6-8 ethylene glycol monoethers, Cs-₁₂ fatty acid ester of polyethylene glycol or combinations thereof. The method of treatment may include the use of fibrate formulation described above. As will be appreciated by those skilled in the art, the formulations object of the present invention can be used prophylaxis as well as the treatment of established symptoms.

In an alternate embodiment of the present invention includes the use of a therapeutically effective dose of fenofibrate, a fenofibrate derivative or mixtures thereof dissolved in a water miscible solubilizer selected from N- Cι- alkyl derivative of 2- pyrrolidone, C_6-8 ethylene glycol monoethers, C_8-12 fatty acid ester of polyethylene glycol, fatty acids or combinations thereof in the preparation of a medicament for the treatment of hypercholesterolaemias and hypertriglyceridaemias. The present invention includes a solubilization process of fenofibrate, fenofibrate derivative or mixtures thereof wherein fenofibrate, fenofibrate derivative or combinations thereof are solubilized in N-alkyl derivative of 2-pyrrolidone or mixtures of N- Cι_-4 alkyl derivative of 2-pyrrolidones or combinations of N- C_1- alkyl derivative of 2-pyrrolidone with Cβ-β ethylene glycol monoethers. The NMP is included in the scope of the invention.

A further aspect of the present invention includes a process for improving the bioavailability of fenofibrate, a fenofibrate derivative or mixtures thereof comprising dissolving the active agent in water miscible solubilizer selected from N-alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, C₈.ι₂ fatty acid ester of polyethylene glycol, fatty acids or combinations thereof. The present invention includes a process for improving the bioavailability of fenofibrate or a fenofibrate derivative comprising dissolving the fenofibrate or a fenofibrate derivative in N-methyl-2-pyrrolidone.

The scope of the invention includes a pharmaceutical dosage unit for oral administration comprising of a fibrate formulation containing a therapeutically effective dose of fenofibrate or a fenofibrate derivative dissolved in N- alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, C_8-12 fatty acid ester of polyethylene glycol, fatty acids, or combinations thereof.

The scope of the invention includes a pharmaceutical dosage unit for oral administration comprising of a fibrate formulation containing a therapeutically effective amount of the fenofibrate, a fenofibrate derivative or mixtures thereof and one or more N- alkyl derivative of 2-pyrrolidone, ethylene glycol monoether and mixtures thereof in combination with at least one of C_8-12 fatty acid ester of polyethylene glycol, fatty acids an mixtures thereof, and at least one non-ionic surfactant with an HLB value lower than about 10.

The scope of the invention includes a pharmaceutical dosage unit for oral administration comprising of a self emulsifying fibrate formulation containing a therapeutically effective amount of the fenofibrate, a fenofibrate derivative or mixtures thereof and one or more N- alkyl derivative of 2-pyrrolidone, ethylene glycol monoether and mixtures thereof in combination with at least one of C₈-ι₂ fatty acid ester of polyethylene glycol or mixtures of Cs-₁₂ fatty acid ester of polyethylene glycol and fatty acids, at least one non-ionic surfactant with an HLB value higher than about 10 and at least one non-ionic co- surfactants with an HLB value lower than or equal to about 6. The invention includes a pharmaceutical dosage unit for oral administration comprising of a self-emulsifying fibrate formulation wherein the combinations of the high HLB and low HLB value surfactants have a final HLB value equal to or lower than 10.

In an alternate embodiment of the present invention a method of preparation for a oral formulation of fenofibrate or fenofibrate derivative with an improved bioavailability comprising: dissolving the fenofibrate, fenofibrate derivative or mixtures thereof in an appropriate volume of water miscible solubilizer selected from N-alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, C_8-ι₂ fatty acid ester of polyethylene glycol or combinations thereof to obtain a fenofibrate solution; and incorporating the fibrate solution into a capsule. The present process may additionally include the banding of the capsule to prevent leakage.

In an alternate embodiment of the present invention a method of preparation for a oral formulation of fenofibrate or fenofibrate derivative with an improved bioavailability comprising: dissolving the fenofibrate, fenofibrate derivative or mixtures thereof in an appropriate volume of water miscible solubilizer selected from N-alkyl derivative of 2-pyrrolidone, C₆.₈ ethylene glycol monoethers, C_8-1₂ fatty acid ester of polyethylene glycol, mixtures of C_8-1₂ fatty acid ester of polyethylene glycol and fatty acids, or combinations thereof; and incorporating the fenofibrate formulation into a capsule.

In an alternate embodiment of the present invention a method of preparation for a oral formulation of fenofibrate or fenofibrate derivative with an improved bioavailability comprising: dissolving the fenofibrate, fenofibrate derivative or mixtures thereof in an appropriate volume of water miscible solubilizer selected from combinations of one or more N- alkyl derivative of 2-pyrrolidone, with ethylene glycol monoether or C_8-12 fatty acid ester of polyethylene glycol or fatty acids or mixtures thereof; and a surfactant/co-surfactant mixture comprising at least one non-ionic surfactants with an HLB value higher or equal to about 10 and least one non- ionic co-surfactants with an HLB value lower or equal to about 6 ; and incorporating the fenofibrate formulation into a capsule. In an alternate embodiment of the present invention a method of preparation for a oral formulation of fenofibrate or fenofibrate derivative with an improved bioavailability comprising: dissolving the fenofibrate, fenofibrate derivative or mixtures thereof in an appropriate volume of a fibrate solubilizers defined above to obtain a fenofibrate solution; mixing the fenofibrate solution with an appropriate amount of a molten gelling agent to obtain a hot fenofibrate gel; and incorporating the fenofibrate gel into a capsule.

In an alternate embodiment of the present invention a method of preparation for a oral formulation of fenofibrate or fenofibrate derivative with an improved bioavailability comprising: dissolving the fenofibrate, fenofibrate derivative or mixtures thereof in an appropriate volume of a fibrate solubilizers defined above to obtain a fenofibrate solution; the liquid solution is mixed with appropriate amounts of an adsorbing powder (suitable adsorbing powder include dibasic calcium phosphate); to obtain a free flowing powder mixture; and incorporation of said free flowing powder mixture into a capsule.

The present invention also includes a commercial package containing a fenofibrate formulation containing a therapeutically effective dose of fenofibrate, a fenofibrate derivative or mixtures thereof dissolved water miscible solubilizer selected from

alkyl derivative of 2-pyrrolidone, Cβ-β ethylene glycol monoethers, C_8-ι₂ fatty acid ester of polyethylene glycol, fatty acids or combinations thereof. The formulation may further contain one or more non-ionic surfactants. The commercial package further includes instructions for the use of the pharmaceutical formulation in the treatment of hypercholesterolaemias and hypertriglyceridaemias in mammals. If required, the pharmaceutical formulation is admixed with a pharmaceutically acceptable carrier, excipient or adjuvant. The pharmaceutical agent may be incorporated into a drug delivery device suitable for oral administration and enclosed in a pharmaceutical acceptable container.

The following examples illustrate the present invention in a manner of which it can be practiced but, as such, should not be construed as limitations upon the overall scope of the processes of this invention.

Example 1

Liquid Formulation

Formulation PD0106-40B was prepared by first dissolving the active (fenofibrate) in appropriate amounts of NMP. Upon complete dissolution of the drug in NMP, the remaining excipients were added and the final solution was encapsulated in size 0 hard gelatin capsules. The filled capsules were then banded using a Quali-Seal lab top banding machine to prevent leakage of the fill contents from the capsules.

Formulation PD0106-50 was prepared similarly in that the drug was first dissolved in NMP and then an appropriate amount of a molten agent such as polyglycolyzed glyceride (e.g. Gelucire 50/13) was added to this solution. The hot melt was encapsulated into size 1 hard gelatin capsules. The solution in the capsules congealed upon reaching room temperature and thus the final state of the fill material was semi-solid, gel-like, matter. This formulation is advantageous in that once processing step, namely leak proof banding, is eliminated from the manufacturing scheme.

Table 2.

Composition of Typical Formulations of Fenofibrate

A = composition in mg per capsule B = composition in % weight

Note:

• Captex 200 is a trade name for Propylene Glycol Dicaprylate/Dicaprate and marketed by Abitec Corp.

• Gelucire 44/14 and 50/13 are trade names for a mixture of mono-,di-and

10 triglycerides and mono-and di-fatty acid esters of polyethylene glycol and marketed by Gattefosse Corp.

• Cremophor RH40 is a trade name for PEG-n-Hydrogenated Castor Oil and marketed by BASF Corp.

• Span 80 is a trade name for sorbitan monooleate and marketed by ICI Chemical. Content uniformity tests were conducted by determining the amount of fenofibrate in each of 10 capsules (Samples A through J) using a high pressure liquid chromatography (HPLC) methodology specific for fenofibrate detection. The relative standard deviation (RSD) of the average of 10 capsules is then taken as an indicator of content uniformity with %RSD < 5.0 as passing. The content uniformity data is given in Table 2 below.

Table 3.

Content Uniformity Data for Fenofibrate Capsule Formulation

X = weight (mg) per capsule

Y = percent label claim per capsule Example 2

Biologic Activity

Formulations tested were administered orally to dogs using 67 mg capsules of fenofibrate. Two formulations containing NMP as a solubilizer were tested in vivo as part of the dog study (n=5). The formulations were prepared similar to that described in

example I. Lipanthyl® (current marketed fenofibrate product) served as the reference

formulation, and the two test formulations were liquid filled (PD0106-40B) and gel filled (PD0106-50) capsules.

Table 4

Plasma Concentrations of Fenofibrate in Fasted Dogs after a 67 mg Dose

* Enhancement values were calculated by (AUCo-24 (test) / AUCo-24 (upanthyi)) x100

The data summarized in Table 3. The mean C_maxfor Lipanthyl ®, PD0106-40B,

and PD0106-50 were 1.88, 6.11 , and 3.60 μg/ml, respectively. The mean AUCo-₂₄ for

Lipanthyl ®, PD0106-40B, and PD0106-50 were 11.08, 29.96, and 18.11 μg.hr/ml, respectively. Both test formulations were effective in significantly increasing the C_max and AUCo-24 compared to Lipanthyl ®.

Note:

Lipanthyl is a registered trademark of Groupe Fournier and is used as a reference formulation.

EXAMPLE 3

Semi-solid Fenofibrate formulation Formulations are prepared following the procedure outlined in Example 1.

Table 5 Examples of formulations of fenofibrate in hard gelatin capsule:

Example 4

Self-Emulsifying Formulations

A) Formulation PD0106-36 and PD0106-72

The formulations were prepared by first dispersing non-micronized fenofibrate in appropriate amounts of DGME. Upon complete wetting and dispersion of the drug in

DGME, the remaining excipients were added and the final formulation was in the form of a solution. This solution was encapsulated in size 0 hard gelatin capsules. The filled capsules were then banded using a Quali-Seal lab top banding machine to prevent leakage of the fill contents from the capsules.

Table 6A Composition of A Self-Emulsifying Formulation of Fenofibrate

A = composition in mg per capsule B = composition in % weight Note:

• Transcutol® P is a trade name for Diethylene Glycol Monoethyl Ether, USP/NF, and is marketed by Gattefosse Corp.

• Captex® 200 is a trade name for Propylene Glycol Dicaprylate/Dicaprate and marketed by Abitec Corp.

• Labrasol® is a trade name for Caprylocaproyl Macrogolglycerides, EP, and is marketed by Gattefosse Corp.

• Span® 80 is a trade name for sorbitan monooleate and marketed by ICI Chemical.

Content uniformity tests were conducted by determining the amount of fenofibrate in each of 10 capsules (Samples A through J) using a high pressure liquid chromatography (HPLC) methodology specific for fenofibrate detection. The relative standard deviation (RSD) of the average of 10 capsules is then taken as an indicator of content uniformity with %RSD < 5.0 as passing. The content uniformity data is given in Table 6C below.

B) Formulation PD0106-40B

Formulation PD0106-40B was prepared by first dissolving the non-micronized fenofibrate in appropriate amounts of NMP. Upon complete dissolution of the drug in NMP, the remaining excipients were added and the final solution was encapsulated in size 0 hard gelatin capsules. The filled capsules were then banded using a Quali-Seal lab top banding machine to prevent leakage of the fill contents from the capsules. Table 6B

Composition of A Self-Emulsifying PD0106-40B Formulation of Non-Micronized

Fenofibrate

A = composition in mg per capsule B = composition in % weight

Note:

• Gelucire ©44/14 and 50/13 are trade names for a mixture of mono-,di-and triglycerides and mono-and di-fatty acid esters of polyethylene glycol and marketed by Gattefosse Corp.

• Cremophor® RH40 is a trade name for PEG-n-Hydrogenated Castor Oil and marketed by BASF Corp.

• Span ® 80 is a trade name for sorbitan monooleate and marketed by ICI Chemical. Table 6C Content Uniformity Data for Fenofibrate Capsule Formulation

Table 6D Self-emulsifying system with NMP/ Captex 200 as the solubilizer

^* Formulation in both LiCaps (CAPSUGEL) and Conisnaps (CAPSUGEL) Note :

Table 6E Self-emulsifying system with NMP/Transcutol/ Captex 200 mixture as the solubilizer

* Formulation in both LiCaps (CAPSUGEL) and Conisnaps (CAPSUGEL) Table 6F Self-emulsifying system with NMP Transcutol/ Captex 200 mixture as the solubilizer

^* Formulation in both LiCaps (CAPSUGEL) and Conisnaps (CAPSUGEL)

Table 6G Self-emulsifying system with NMP/Transcutol/ Miglyol 812 mixture as the solubilizer

Formulation in both LiCaps (CAPSUGEL) and Conisnaps (CAPSUGEL) Note:

Miglyol is a registered trade mark for of Caprylic-/ Capric acid Triglycerides composed of saturated C₈ (50-65%) and C₁₀ (30-45%) triglycerides and owned by Dynamit Nobel Aktiengesellschaft Corporation

Table 6H Self-emulsifying system with NMP/Transcutol/fatty acids/Captex 200 mixture as the solubilizer

Formulation in both LiCaps (CAPSUGEL) and Conisnaps (CAPSUGEL)

Table 61 Self-emulsifying system with NMP/Transcutol/fatty acids/Migylol 812 mixture as the solubilizer

Formulation in both LiCaps (CAPSUGEL) and Conisnaps (CAPSUGEL)

Example 5

In vivo Activity of Self-Emulsifying Formulation

Formulations tested were administered orally to dogs using 67 mg capsules of fenofibrate. The self-emulsifying formulation of Example 1 (Table 1 A) was tested in vivo as part of the dog study (n=5). Lipanthyl® 67 mg (current marketed fenofibrate product) served as the reference formulation, and the test formulation was liquid filled hard gelatin capsule.

The data summarized in Table 7.

Table 7

Plasma Concentrations of Fenofibrate in Fasted Dogs after a 67 mg Dose

The mean C_maχ or Lipanthyl ® and PD0106-36 were 1.88 and 4.17 μg/ml, respectively.

The mean AUC₀-₂₄for Lipanthyl ® and PD0106-36 were 11.08 and 24.17 μg.hr/ml,

respectively. The test formulation was effective in significantly increasing the C_maχ and AUCo-24 compared to Lipanthyl ®. Note:

• Lipanthyl ® is a marketed product of Groupe Fournier and is used as a reference formulation.

Example 6 Self-Emulsifying Properties

To evaluate the behavior of the self-emulsifying formulation as it becomes exposed to aqueous media, five grams of various fenofibrate solution formulations were prepared and known amounts of water were added to the respective formulas. The compositions of the formulations along with the outcome of the water addition are shown in Table 8.

Table 8. Effect of water addition on various liquid fenofibrate formulations

^* All formulations were in complete solution before water addition Note:

The self-emulsifying formulations (PD0106-61 B and PD0106-65C) did not crash in presence of excessive amounts of water, whereas all other formulations containing various solutions of fenofibrate severely crashed out of solution by forming large crystalline particulates upon addition of 1 or 2 ml of water. Our self-emulsifying formulations are superior to solution formulations containing the drug and a solubilizer.

Claims

1- A pharmaceutical formulation of a fibrate with improved oral bioavailability comprising a fibrate selected from fenofibrate , derivative of fenofibrate or mixtures thereof dissolved in a water miscible fibrate solubilizer selected from N-alkyl derivative of 2- pyrrolidone, ethylene glycol monoether, C_8-12 fatty acid ester of polyethylene glycol, fatty acids and combinations thereof; wherein the fibrate to solubilizer weight ratio is between about 1 :1 and about 1 :100.

2 - A formulation according to claim 1 wherein the formulation further includes at least one surfactant.

3 - A formulation according to claim 1 wherein the formulation further includes a gelling agent.

4- A formulation according to claim 2 wherein the formulation is a self-emulsifying formulation wherein the water miscible fibrate solubilizer is selected from N-C_1- alkyl derivative of 2-pyrrolidone or Cβ-β ethylene glycol monoether and mixtures thereof, in combination with at least one C_8-12 fatty acid ester of polyethylene glycol and at least one non-ionic surfactant with a HLB value lower than or equal to 10.

5 - A formulation according to claim 2 wherein the solubilizer comprises a non-oily component selected from N-Cι-₄ alkyl derivative of 2-pyrrolidone, C_δ-s ethylene glycol monoether and combinations thereof; and an oily component selected from C_8-12 fatty acid ester of polyethylene glycol, fatty acids and mixtures thereof. - ormu a ion accor ng to claim 2 wherein the surfactant is nόnϊόnic hydrόphobiό surfactant.

- A formulation aocording to claims 1 or 5 wherein the solubilizer is seleoted from mixtures of N-Cι- alkyl derivative of 2-pyrrolidones, C_6-8 ethylene glycol monoethers or combinations thereof; with one or more polyethylene glyool mono- and diester of C_8-1₂ fatty aόids or oombinations of polyethylene glyool mono- and diester of C_8--|₂ fatty aoids and fatty aoids.

- A formulation aόoording to olaim 7 wherein the weight ratio of the N-C-ι_-4 alkyl derivative of 2-pyrrolidone or a C_6-8 ethylene glycol monoethers or combinations thereof to one or more polyethylene glyool mono- and diester of C_8-12 fatty aoids or oombinations of polyethylene glyool mono- and diester of C_8-ι₂ fatty aoids and fatty acids is between about 100: 1 to about 1 :4.

- A formulation aooording to claim 1 wherein the N-Cι- alkyl derivative of 2-pyrrolidone is seleoted from N-Methyl-2-Pyrrolidone, N-Ethyl-2-pyrrolidone, N-Propyl-2- pyrrolidone, N-lsopropyl-2-pyrrolidone, N-Butyl-2-pyrrolidone, and N-(2- Hydroxyethyl)-2-pyrrolidone or mixtures thereof.

0 - A formulation according to claim 9 wherein the N-C-ι_-4 alkyl derivative of 2- pyrrolidone is N-methyl-2-pyrrolidone.

1 - A formulation according to claim 1 wherein the ethylene glycol monoether is diethylene glycol monoethyl ether. 12 - A formulation according to claim 6 wherein the surfactant has ^'a^'ΗBL value lower ^' than or equal to 10.

13 - A formulation according to claim 2 wherein the formulation further includes at least 5 one co-surfactant.

14 - A formulation according to claim 13 wherein the surfactant/co-surfactant combination has a HLB value lower than or equal to 10.

10 15- A formulation according to claim 14 wherein the formulation further includes a surfactant selected from non-ionic surfactants with HLB values greater than 10 and at least one non-ionic co-surfactant with low HLB values lower than or equal to 6.

16 - A formulation according to claim 15 wherein the co-surfactant is at least one non- 15 ionic surfactants with HLB value between 10 and 18, one or more non-ionic co- surfactant with a HLB value between 2 and 6, provided that the HBL value of the combination is less than or equal to 10.

17 - A self-emulsifying oral pharmaceutical formulation with improved bioavailability 20 comprising: a therapeutically effective amount of the fenofibrate or a fenofibrate derivative; at least one non-ionic hydrophobic surfactant; and a water miscible fibrate solubilizer selected from N-C- alkyl derivative of 2-pyrrolidone, C_3-8 ethylene glycol monoether, or combinations thereof; mixed with at least one of C_8-12 fatty acid ester of polyethylene glycol, fatty acids or mixtures thereof. 25 18 - A method of treating endogenous hyperiipidaemias, hypercholesterolaemias and hypertriglyceridaemias in mammals comprising the administration of a fibrate formulation of any of claims 1 or 5.

5 19 - A process for improving the bioavailability of fenofibrate or a fenofibrate derivative comprising dissolving the fenofibrate or a fenofibrate derivative in N-methyl-2- pyrrolidone.

20 - A pharmaceutical dosage unit for oral administration comprising of a fibrate 10 formulation containing a therapeutically effective dose of fenofibrate or a fenofibrate derivative dissolved in N- alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, C_8-ι₂ fatty acid ester of polyethylene glycol, fatty acids, or combinations thereof.

15 21 - A pharmaceutical dosage unit for oral administration comprising of a fibrate formulation containing a therapeutically effective amount of the fenofibrate, a fenofibrate derivative or mixtures thereof and one or more N- alkyl derivative of 2- pyrrolidone, ethylene glycol monoether and mixtures thereof in combination with at least one of C_8-ι₂ fatty acid ester of polyethylene glycol, fatty acids and mixtures 0 thereof, and at least one non-ionic hydrophobic surfactant or surfactant combinations.