EP1539117A1 - Formulations a base de fenofibrate et/ou de derives de fenofibrate ayant une biodisponibilite orale amelioree - Google Patents

Formulations a base de fenofibrate et/ou de derives de fenofibrate ayant une biodisponibilite orale amelioree

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Publication number
EP1539117A1
EP1539117A1 EP02801215A EP02801215A EP1539117A1 EP 1539117 A1 EP1539117 A1 EP 1539117A1 EP 02801215 A EP02801215 A EP 02801215A EP 02801215 A EP02801215 A EP 02801215A EP 1539117 A1 EP1539117 A1 EP 1539117A1
Authority
EP
European Patent Office
Prior art keywords
fenofibrate
formulation
pyrrolidone
derivative
surfactant
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02801215A
Other languages
German (de)
English (en)
Other versions
EP1539117A4 (fr
Inventor
Amir H. Shojaei
Scott A. Ibrahim
Beth A. Burnside
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shire Laboratories Inc
Original Assignee
Shire Laboratories Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shire Laboratories Inc filed Critical Shire Laboratories Inc
Publication of EP1539117A1 publication Critical patent/EP1539117A1/fr
Publication of EP1539117A4 publication Critical patent/EP1539117A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • 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.
  • 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.
  • VLDL thglyceride rich lipoprotein
  • 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.
  • Gl gastrointestinal
  • US patents 4,800,079 and 4,895,726 micronized fenofibrate formulations of are disclosed.
  • 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.
  • US patent 6,074,670 the immediate release of micronized fenofibrate in a solid state is shown.
  • Fenofibrate 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)).
  • anionic e.g. SDS
  • non-ionic e.g. Triton X -100
  • complexing agents N-methyl pyrrolidone
  • 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.
  • 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- i 2 fatty 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
  • 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.
  • 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.
  • HLB value lower than or equal to 10 non-ionic hydrophobic surfactant
  • 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- ⁇ -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, C ⁇ -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 ma ⁇ , reduction in the time to reach maximum plasma levels, T max ) and/or extent of absorption
  • 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.
  • 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.
  • fibrates such as fenofibrate
  • the systemic absorption of the drug is believed to be dissolution rate limited.
  • a water miscible organic solvent such as the N-alkyl derivatives of 2-pyrrolidone, ethylene glycol monoether, C 8 . ⁇ 2 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.
  • 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.
  • fatty acid represents a C 1 - 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.
  • 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 (C 1 -C 3 ) 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.
  • 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 C 8 - 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.
  • 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 C 8 - 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.
  • 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 ⁇ _ _ ⁇
  • 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.
  • 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
  • fibrate is a fibrate and is defined as a compound of formula (I), 2-[4-(4- Chlorobenzoyl ) phenoxy]-2-methylpropanoic acid 1-methylethyl ester:
  • Ri represents a phenyl group or a phenyl group substituted by one or more CH 3 , CF 3 or by halogens;
  • R 2 and R 3 independently represent a hydrogen atom or a halogen atom (preferably fluorine, chlorine, or bromine), an C- alkyl or an C ⁇ -5 alkoxy or one of the following groups: CF 3 , SCH 3 , SOCH 3 , SO 2 CH 3 , or OH; and
  • Y represents one of the following groups: OH; C-i -5 alkoxy, preferably in d-C ; - NR 4 R 5 ; --NHCH 2 CH 2 NR 4 R 5 ; or --O- C 1-6 alkylene-NR 4 R 5 , with the alkylene having, in particular, two to six atoms of carbon, and with R 4 and R 5 being identical or different and each representing a hydrogen atom or one of the following groups: C- ⁇ - 5 alkyl, C 3 -C 7 cycloalkyl , preferably C 5-6 cycloalkyl; C ⁇ -io aryl or aryl substituted on the aromatic residue by one or more halogen, methyl, or -CF 3 groups; or else R 4 and R 5 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
  • the scope of the present invention includes formulations summarized in Tables 1A and 1 B: Table 1A.
  • antioxidants required for stability enhancement of the final formulation these would include antioxidants, thickening agents, suspending agents, etc.
  • antioxidants 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, C ⁇ - ⁇ 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.
  • a concentrated solution of up to the saturation point of the fibrate solubilizer may be of interest.
  • 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.
  • 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- ⁇ 2 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- ⁇ 2 fatty acid ester of polyethylene glycol; or combinations of fatty acids and C 8- ⁇ 2 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- ⁇ 2 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.
  • 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-C 1 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- ⁇ 2 fatty acids or mixtures polyethylene glycol mono- and diester of C 8- ⁇ 2 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- ⁇ 2 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
  • the % bioavailability enhancement value is defined as the ratio obtained by
  • 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, 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- ⁇ 2 fatty acid ester of polyethylene glycol and fatty acids, or combinations thereof wherein the bioavailability of said formulation is
  • 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
  • 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- ⁇ 2 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
  • 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) .
  • 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- ⁇ 2 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 present invention includes said formulations wherein the improvement in C ma ⁇ 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- ⁇ 2 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
  • T ma ⁇ maximum plasma levels
  • AUCo- ⁇ extent of absorption
  • 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- ⁇ 2 fatty acid ester of polyethylene glycol or mixtures of C 8- ⁇ 2 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.
  • a solubilizer selected from N- alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, C 8- ⁇ 2 fatty acid ester of polyethylene glycol or mixtures of C 8- ⁇ 2 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.
  • 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- ⁇ 2 fatty acid ester of polyethylene glycol or mixtures of C ⁇ - ⁇ 2 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 C ⁇ -12 fatty acid esters of polyethylene glycol; and at least one surfactant with an HLB value lower than or equal to about 10.
  • 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 C ⁇ -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 surfact
  • the invention includes those oral self-emulsifying pharmaceutical formulation with improved bioavailability described above wherein the improvement in C ma ⁇ is at least 1.2 times that of a commercial formulation such as Lipanthyl ® (trade mark of Groupe Fournier) or TriCor®
  • 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.
  • antioxidants 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
  • ingredients used to stabilize gelatin capsules such as glycerine, or gelatin.
  • the fibrate formulations disclosed are useful in the treatment of hypercholesterolaemias and hypertriglyceridaemias.
  • 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- C ⁇ -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.
  • the formulations object of the present invention can be used prophylaxis as well as the treatment of established symptoms.
  • a water miscible solubilizer selected from N- C ⁇ - 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- C ⁇ -4 alkyl derivative of 2-pyrrolidones or combinations of N- C 1- alkyl derivative of 2-pyrrolidone with C ⁇ - ⁇ 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, C 8 . ⁇ 2 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 C 8 - ⁇ 2 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.
  • 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- ⁇ 2 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.
  • 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, C 6 . 8 ethylene glycol monoethers, C 8- 1 2 fatty acid ester of polyethylene glycol, mixtures of C 8- 1 2 fatty acid ester of polyethylene glycol and fatty acids, or combinations thereof; and incorporating the fenofibrate formulation into a capsule.
  • 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.
  • 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.
  • 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.
  • an adsorbing powder include dibasic calcium phosphate
  • 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, C ⁇ - ⁇ ethylene glycol monoethers, C 8- ⁇ 2 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.
  • 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.
  • 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.
  • composition in mg per capsule B composition in % weight
  • 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
  • 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.
  • HPLC high pressure liquid chromatography
  • 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.
  • test formulation and the two test formulations were liquid filled (PD0106-40B) and gel filled (PD0106-50) capsules.
  • Lipanthyl ®, PD0106-40B, and PD0106-50 were 11.08, 29.96, and 18.11 ⁇ g.hr/ml, respectively. Both test formulations were effective in significantly increasing the C max and AUCo-24 compared to Lipanthyl ®.
  • Lipanthyl is a registered trademark of Groupe Fournier and is used as a reference formulation.
  • 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.
  • 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.
  • 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 in mg per capsule B composition in % weight
  • 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 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
  • Transcutol® P is a trade name for Diethylene Glycol Monoethyl Ether, USP/NF, and is marketed by Gattefosse Corp.
  • Miglyol is a registered trade mark for of Caprylic-/ Capric acid Triglycerides composed of saturated C 8 (50-65%) and C 10 (30-45%) triglycerides and owned by Dynamit Nobel Aktiengesellschaft Corporation
  • Formulations tested were administered orally to dogs using 67 mg capsules of fenofibrate.
  • Lipanthyl® 67 mg (current marketed fenofibrate product) served as the reference formulation, and the test formulation was liquid filled hard gelatin capsule.
  • the mean C ma ⁇ or Lipanthyl ® and PD0106-36 were 1.88 and 4.17 ⁇ g/ml, respectively.
  • AUC 0 - 24 for Lipanthyl ® and PD0106-36 were 11.08 and 24.17 ⁇ g.hr/ml
  • test formulation was effective in significantly increasing the C ma ⁇ and AUCo-24 compared to Lipanthyl ®. Note:
  • Lipanthyl ® is a marketed product of Groupe Fournier and is used as a reference formulation.
  • 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.
  • the self-emulsifying formulations 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.

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Abstract

Une formulation orale à base de fibrates a une biodisponibilité plus élevée en comparaison aux formulations disponibles dans le commerce; elle contient une dose de fénofibrate ou de dérivés de fénofibrate, efficace du point de vue thérapeutique et dissoute dans un dérivé N-alkyle de 2-pyrrolidone, un monoéther d'éthylèneglycol, un ester d'acide gras C8-12 de polyéthylèneglycol, des acides gras ou leurs combinaisons. Elle peut s'utiliser dans traitement d'hypercholestérolémie ou d'hypertriglyceridémie chez les mammaliens.
EP02801215A 2002-06-28 2002-12-20 Formulations a base de fenofibrate et/ou de derives de fenofibrate ayant une biodisponibilite orale amelioree Withdrawn EP1539117A4 (fr)

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WO2007130713A1 (fr) * 2006-02-01 2007-11-15 Transform Pharmaceuticals, Inc. Nouvelles formules de fénofibrate et méthodes de traitement correspondantes
MX2008001597A (es) * 2005-08-04 2008-04-04 Transform Pharmaceuticals Inc Formulaciones novedosas que comprenden fenofibrato y una estatina y metodos relacionados de tratamiento.
KR20110027778A (ko) * 2008-07-03 2011-03-16 파나세아 바이오테크 리미티드 향상된 경구 생체 이용성을 갖는 페노피브레이트 제제
EP2775831A4 (fr) 2011-10-21 2015-08-12 Seachaid Pharmaceuticals Inc Compositions pharmaceutiques et leurs utilisations
CA2924827C (fr) 2013-09-18 2023-01-03 Georgetown University Traitement d'une maladie neurodegenerative au moyen de fenofibrate et de ses analogues

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AU1809499A (en) * 1997-12-10 1999-06-28 Awadhesh K. Mishra Self-emulsifying fenofibrate formulations
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SHEU ET AL: "Characterization and dissolution of fenofibrate solid dispersion systems" INTERNATIONAL JOURNAL OF PHARMACEUTICS, AMSTERDAM, NL, vol. 103, no. 2, 1994, pages 137-146, XP002091325 ISSN: 0378-5173 *
TEMELJOTOV ET AL: "Solubilization and dissolution enhancement for sparingly soluble fenofibrate" ACTA PHARMACEUTICA, ZAGREB, HR, vol. 46, no. 2, 1996, pages 131-136, XP002104609 ISSN: 1330-0075 *

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