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WO2007130713A1 - Nouvelles formules de fénofibrate et méthodes de traitement correspondantes - Google Patents

Nouvelles formules de fénofibrate et méthodes de traitement correspondantes Download PDF

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Publication number
WO2007130713A1
WO2007130713A1 PCT/US2007/061356 US2007061356W WO2007130713A1 WO 2007130713 A1 WO2007130713 A1 WO 2007130713A1 US 2007061356 W US2007061356 W US 2007061356W WO 2007130713 A1 WO2007130713 A1 WO 2007130713A1
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WIPO (PCT)
Prior art keywords
fenofibrate
omega
liquid formulation
weight
percent
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.)
Ceased
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PCT/US2007/061356
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English (en)
Inventor
Orn Almarsson
Pasut Ratanabanangkoon
Julius Remenar
Hector Guzman
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Transform Pharmaceuticals Inc
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Transform Pharmaceuticals Inc
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Publication date
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Publication of WO2007130713A1 publication Critical patent/WO2007130713A1/fr
Priority to US12/184,864 priority Critical patent/US20090030077A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/315—Zinc compounds

Definitions

  • the invention provides novel omega-3 oil liquid formulations comprising fenofibrate. These formulations can be substantially free of food effect, effective in small volumes, and readily bioavailable.
  • the invention also provides novel fenofibrate formulations in which fenofibrate is dissolved in a vehicle comprising an omega-3 oil, an alcohol, and a surfactant.
  • Fenofibrate (2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid 1-methylethyl ester) is an approved substance for the treatment of hypercholesterolemia and hypertriglyceridemia. Fenofibrate is practically insoluble in water. It is normally poorly and variably absorbed in the fasted state and currently is prescribed to be taken with food.
  • fenofibrate dosage forms include Tricor® micronized tablets in which fenofibrate powder is co-micronized with a solid wetting agent such as sodium lauryl sulfate.
  • omega-3 oils from fish oils are well established. Amounts both above and below about 1 gram per day of omega-3 oils from fish oil have been shown to decrease serum triglyceride concentrations by about 25 % to about 40 %, decrease VLDL blood plasma levels, and to increase both LDL and HDL plasma levels (See e.g., Harris, William S, Clin. Cardiol. 22, (Suppl. II), II-40-II- 43 (1999)).
  • a pharmaceutical formulation comprising the beneficial effects of fenofibrate and omega-3 oil could enable both ease of administration and could improve patient compliance where both fenofibrate and omega-3 oil are suitable.
  • the omega-3 oil may lead to even further therapeutic effect than with fenofibrate alone.
  • the invention provides novel omega-3 oil liquid formulations and medicaments of fenofibrate. These formulations are effective in small volumes. Notably, because the formulations and medicaments of the invention contain an omega- 3 oil as the major ingredient, they not only provide antihypertriglyceridemic and antihypercholesterolemic effects due to the fenofibrate active ingredient, they also provide recommended daily dosages of omega-3 oils (i.e., one gram of omega-3 oil per day, as per AHA guidelines), or a portion thereof.
  • the invention also provides novel liquid fenofibrate formulations in which fenofibrate is dissolved in a vehicle comprising an omega-3 oil, a C 1 to C 4 alcohol, and, optionally, a surfactant.
  • formulations of the invention can be administered in a dosage form consisting of one or two capsules as defined hereinafter and at least about 400, 450, 500, 600, 700, 800, 900, or 1000 mg per capsule or per dose of an omega-3 oil.
  • formulations of the invention comprise an omega-3 oil, wherein the omega-3 oil is an omega-3 alkyl ester, such as an omega-3 ethyl ester.
  • formulations of the invention further comprise an omega-3 mono-, di-, or triglyceride oil.
  • the invention provides a liquid formulation comprising about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, or 85.00 % by weight of an omega-3 ester or omega-3 alkyl ester, about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight of a C 1 to C 4 alcohol, and about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight of fenofibrate.
  • the formulation comprises about 75.00, 76.00, 77.00, 78.00, 79.00, or 80.00 % by weight of an omega-3 ester or omega-3 alkyl ester, about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight of a C 1 to C 4 alcohol, and about 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, or 12.00 % by weight of fenofibrate.
  • the invention provides a liquid formulation comprising about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, or 85.00 % by weight of an omega-3 ester or omega-3 alkyl ester, about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight of a C 1 to C 4 alcohol, about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, 20.00, 21.00, 22.00, 23.00, 24.00, or 25.00 % by weight of a surfactant, and about 5.00
  • a liquid formulation of the invention comprises a mixture of fenofibrate dissolved in a vehicle comprising an omega-3 ester or omega-3 alkyl ester and a Ci to C 4 alcohol, wherein:
  • the formulation comprises (i) about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight of fenofibrate (H) about 55.00, 56.00, 57.00, 58.00, 59.00, 60.00, 61.00, 62.00, 63.00, 64.00, 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, or 80.00 % by weight of an omega-3 ester or omega-3 alkyl ester (iii) about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight of a Ci to C 4 alcohol, and (iv) about
  • the solubility of the fenofibrate in the vehicle is about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 milligrams per milliliter at 25 degrees C.
  • the present invention provides a novel polymorph of fenofibrate.
  • the present invention provides a method of making a polymorph of fenofibrate, comprising:
  • the invention provides novel surfactant-containing and surfactant-free, omega-3 oil liquid medicaments of fenofibrate.
  • the present invention provides a novel polymorph of fenofibrate.
  • the present invention provides a method of making a polymorph of fenofibrate, comprising:
  • FIGURE 1 shows a PXRD diffractogram of a fenofibrate polymorph (Form II).
  • FIGURE 2 shows a semi-log plot of the mean plasma concentration of fenofibric acid in humans following oral administration.
  • FIGURE 3 shows fenofibrate solubility as a function of ethanol concentration.
  • FIGURE 4 shows fenofibrate solubility as a function of temperature.
  • FIGURE 5 shows the temperature dependence of fenofibrate solubility in 85:15 E681010:Ethanol.
  • the invention provides novel omega-3 oil formulations of fenofibrate. These formulations are effective in small volumes. Notably, because the formulations of the invention contain an omega-3 oil as the major ingredient, they not only provide an antihypercholesterolemic effect and an antihypertriglyceridemic effect due to the fenofibrate active ingredient, they also provide recommended daily dosages of omega-3 oils (i.e., one gram of omega-3 oil per day, as per AHA guidelines), or a portion thereof.
  • the invention also provides novel fenofibrate formulations in which fenofibrate is dissolved in a vehicle comprising an omega-3 oil, a C 1 to C 4 alcohol, and, optionally, a surfactant.
  • C 1 to C 4 alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, isopropanol, isobutanol, tert-butanol, glycerol, and propylene glycol.
  • An "omega-3 oil” is any oil comprising omega-3 fatty acids, omega-3 mono-, di-, or triglycerides, or omega-3 esters including, but not limited to, omega-3 alkyl esters. Omega-3 oils can be characterized using two unique descriptors, species and component. The species of an omega-3 oil is determined by the structure of the polyunsaturated carbon chain bound to the carboxyl group.
  • omega-3 oil is determined by the chemical nature of the carboxyl group.
  • omega-3 fatty acids employ a -COOH structure bound to the polyunsaturated carbon chain
  • omega-3 esters employ a -COOR structure bound to the polyunsaturated carbon chain
  • omega-3 mono- di- or tri-glycerides employ a -COOR' structure bound to the polyunsaturated carbon chain, where R' comprises a glycerol backbone.
  • Oil composition can be described as both the species and the component(s) of an oil.
  • E681010 comprises about 68 % EPA and about 10 % DHA (mass percent) as ethyl esters.
  • omega-3 oils other than EPA and DHA and other non-omega-3 oils.
  • omega-3 oils can be found in, for example, fish oil, marine mammal fat, cod liver oil, walnuts and walnut oil, wheat germ oil, rapeseed oil, soybean lecithin derived oils, soybean derived oils, tofu derived oils, common bean derived oils, butternut derived oils, seaweed derived oils, flax-borage oil, and flax seed oil.
  • omega-3 oils such as Omegabrite® (Omega Natural Science), EpanovaTM (Tillotts Pharma AG), OMEGA- 3/90 (K D Pharma), Epax® (Pronova Biocare AS), and Incromega (Croda/Bioriginal).
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • Specific omega-3 alkyl esters include the ethyl esters of EPA and DHA.
  • the E681010, OMEGA- 3/90 (K D Pharma), and Incromega (Croda/Bioriginal) omega-3 ethyl esters are potential omega-3 alkyl esters.
  • Liquid formulations and medicaments may be described as mixtures of two or more components "by volume,” which is herein defined as the volume due to one component divided by the volume of all components of the formulation. This ratio may be converted to or reported as a percentage of the total formulation volume. Such a quantity may also be indicated by “v/v” or “percent v/v.” Similarly, the phrases “by weight” and “by mass” describe the weight or mass due to one component divided by the weight or mass of all components of the formulation. This ratio may be converted to or reported as a percentage of the total formulation weight or mass. Such a quantity may also be indicated by “w/w”, “mass percent,” or “percent w/w.”
  • E 107104 is used to describe an omega-3 oil which has a composition comprising 9.7 % EPA, 71.4 % DHA, and about 3.9 % other omega-3 oils (mass percent) where the EPA, DHA, and other omega-3 oils are ethyl esters.
  • E970002 is used to describe an omega-3 oil which has a composition comprising 97 % EPA and about 2 % other omega-3 oils (mass percent) where the EPA and other omega-3 oils are ethyl esters.
  • TG361724" is used to describe an omega-3 oil which has a composition comprising 36 % EPA (expressed as mass percent of free fatty acids), 17 % DHA (expressed as mass percent of free fatty acids), and about 24 % other omega-3 oils (mass percent) where the EPA, DHA, and other omega-3 oils are triglycerides.
  • E351923 is used to describe an omega-3 oil which has a composition comprising 35 % EPA (expressed as mass percent of free fatty acids), 19 % DHA (expressed as mass percent of free fatty acids), and about 23 % other omega-3 oils (mass percent) where the EPA, DHA, and other omega-3 oils are ethyl esters.
  • E681010 is used to describe an omega-3 oil which has a composition comprising 67.8 percent EPA (mg/g), 9.9 percent DHA (mg/g), and about 9.6 percent other omega-3 oils (mg/g), where the EPA, DHA, and other omega-3 oils are ethyl esters.
  • a "liquid formulation” refers to a mixture wherein the majority of the API (active pharmaceutical ingredient) is in solution at equilibrium. For example, at least about 55.00, 60.00, 65.00, 70.00, 75.00, 80.00, 85.00, 90.00, 95.00, 96.00, 97.00, 98.00, 99.00, 99.50, or 99.99 percent of the fenofibrate in the liquid formulation is present in solution at equilibrium.
  • Liquid formulations include, but are not limited to, semi-solid formulations.
  • chemically stable or “chemical stability” refer to a liquid formulation where there is a ⁇ 3.0 percent loss of fenofibrate potency (recovered fenofibrate content) after 2 years at 25 degrees C.
  • surfactants refer to a surface active compound which can alter the surface tension of a liquid in which it is dissolved and includes, but is not limited to, polyoxyl 35 castor oil and sorbitan monolaurate.
  • Liquid formulations and methods of the present invention can also be used with f ⁇ brates other than fenofibrate, such as clofibrate, bezafibrate, ciprofibrate, beclofibrate, etofibrate, and gemfibrozil.
  • Liquid formulations of the present invention can, optionally, include non-omega-3 oils.
  • one or more non-omega-3 oils can be used in combination with or in place of one or more omega-3 oils in the vehicle for fenofibrate solubilization.
  • a liquid formulation of the present invention may be substantially homogeneous. In some embodiments, a liquid formulation may be homogeneous. In some embodiments, a liquid formulation may be a homogeneous liquid solution.
  • an omega-3 oil contains a low percentage of non-omega-3 oil.
  • an omega-3 oil has a low percentage of non-omega-3 oil when it comprises less than about 25.00, 24.00, 23.00, 22.00, 21.00, 20.00, 19.00, 18.00, 17.00, 16.00, 15.00, 14.00, 13.00, 12.00, 11.00, 10.00, 9.00, 8.00, 7.00, 6.00, 5.00, 4.00, 3.00, 2.00, or 1.00 percent w/w non-omega-3 oil.
  • an omega-3 ethyl ester can comprise about 90 percent omega-3 ethyl esters and about 10 percent non-omega-3 ethyl esters.
  • the purity of omega-3 oil is an important aspect of the present invention.
  • Oil purity is defined as a percentage (e.g., by volume or by weight) of one component of the oil with respect to the entire oil composition.
  • an ester oil with a purity of 95 percent by weight comprises at least 95 percent w/w esters.
  • the remaining percentage may comprise free acids, mono- di- and/or triglycerides, or other components.
  • an omega-3 ester oil with a purity of 90 percent by weight comprises at least 90 percent omega-3 esters and the remaining percentage can comprise any one or more of other oil components.
  • a mixture of species of one component e.g., C 8 and C 10 esters
  • a distinction of specific species within a component e.g., C 8 and C 1 O esters
  • Omega-3 oils specifically with a high purity of omega-3 esters, can be used. According to the present invention, omega-3 oils with a high purity comprise greater than about 85.00 percent, 90.00 percent, 91.00 percent, 92.00 percent, 93.00 percent, 94.00 percent, 95.00 percent, 96.00 percent, 97.00 percent, 98.00 percent, 99.00 percent or more of one component by weight or by volume.
  • Omega-3 esters include, but are not limited to, esters of EPA and DHA. Omega-3 esters also include omega-3 ethyl esters.
  • omega-3 alkyl esters with other components of omega-3 oil (e.g., fatty acids, triglycerides) are not preferred according to the present invention. Fenofibrate solubility is shown, herein, to be maximized in omega-3 alkyl esters. Oils containing pure and substantially pure alkyl esters are described in the present invention.
  • omega-3 oil e.g., fatty acids, triglycerides
  • the purity of omega-3 esters or omega-3 alkyl esters is at least about 50.00 percent by weight, at least about 60.00 percent by weight, at least about 70.00 percent by weight, at least about 75.00 percent by weight, at least about 80.00 percent by weight, or at least about 85.00 percent by weight. In another embodiment, the purity of omega-3 esters or omega-3 alkyl esters is about 25.00, 30.00, 35.00, 40.00, 45.00, 50.00, 55.00, 60.00, 65.00, 70.00, 75.00, 80.00, 85.00, 90.00, 95.00, 99.00 percent or more by weight.
  • the purity of omega-3 esters or omega-3 alkyl esters is between about 25.00 and about 100.00 percent by weight, between about 40.00 and about 100.00 percent by weight, between about 50.00 and about 100.00 percent by weight, between about 60.00 and about 100.00 percent by weight, between about 70.00 and about 100.00 percent by weight, between about 75.00 and about 100.00 percent by weight, between about 75.00 and about 95.00 percent by weight, between about 75.00 and about 90.00 percent by weight, or between about 80.00 and about 85.00 percent by weight.
  • the purity of omega- 3 esters or omega-3 alkyl esters is about 100.00 percent by weight, about 99.00 percent by weight, about 96.00 percent by weight, about 92.00 percent by weight, about 90.00 percent by weight, about 85.00 percent by weight, about 80.00 percent by weight, about 75.00 percent by weight, about 70.00 percent by weight, about 65.00 percent by weight, about 60.00 percent by weight, about 55.00 percent by weight, or about 50.00 percent by weight.
  • an omega-3 oil composition comprising EPA and DHA is at least about 50.00 percent by weight, at least about 60.00 percent by weight, at least about 70.00 percent by weight, at least about 75.00 percent by weight, at least about 80.00 percent by weight, or at least about 84.00 percent by weight.
  • an omega-3 oil composition comprising EPA and DHA is about 25.00, 30.00, 35.00, 40.00, 45.00, 50.00, 55.00, 60.00, 65.00, 70.00, 75.00, 80.00, 85.00, 90.00, or 95.00 percent by weight.
  • an omega-3 oil composition comprising EPA and DHA is between about 25.00 and about 95.00 percent by weight, between about 40.00 and about 95.00 percent by weight, between about 50.00 and about 95.00 percent by weight, between about 60.00 and about 95.00 percent by weight, between about 70.00 and about 95.00 percent by weight, between about 75.00 and about 95.00 percent by weight, between about 75.00 and about 90.00 percent by weight, between about 75.00 and about 85.00 percent by weight, or between about 80.00 and about 85.00 percent by weight.
  • an omega-3 oil composition comprising EPA and DHA is about 99.00 percent by weight, about 96.00 percent by weight, about 92.00 percent by weight, about 90.00 percent by weight, about 84.00 percent by weight, about 80.00 percent by weight, about 75.00 percent by weight, about 70.00 percent by weight, about 65.00 percent by weight, about 60.00 percent by weight, about 55.00 percent by weight, or about 50.00 percent by weight.
  • an omega-3 ester or omega-3 alkyl ester has about a 23 : 19 ratio of EPA :DHA, about a 75 : 11 ratio of EPA:DHA, about a 95 : 1 ratio of EPA:DHA, about a 9:2 ratio of EPA:DHA, about a 10:1 ratio of EPA:DHA, about a 5:1 ratio of EPA:DHA, about a 3:1 ratio of EPA:DHA, about a 2:1 ratio of EPA:DHA, about a 1:1 ratio of EPA:DHA, about a 1:2 ratio of EPA:DHA, about a 1:3 ratio of EPA:DHA, or about a 1:5 ratio of EPA:DHA.
  • an omega-3 ester or omega-3 alkyl ester has about a 95:1 ratio of EPA:DHA, about a 75:1 ratio of EPA:DHA, about a 50: 1 ratio of EPA:DHA, about a 25:1 ratio of EPA:DHA, about a 20:1 ratio of EPA:DHA, about a 15:1 ratio of EPA:DHA, about a 10:1 ratio of EPA:DHA, about a 7.5:1 ratio of EPA:DHA, about a 5: 1 ratio of EPA:DHA, about a 4:1 ratio of EPA:DHA, about a 3:1 ratio of EPA:DHA, about a 2: 1 ratio of EPA:DHA, about a 1.5: 1 ratio of EPA:DHA, about a 1: 1 ratio of EPA:DHA, about a 1: 1.5 ratio of EPA:DHA, about a 1:2 ratio of EPA:DHA, about a 1:3 ratio of EPA:DHA, or about a
  • an omega-3 ester or omega-3 alkyl ester has from about a 95 : 1 ratio to about a 1 :5 ratio of EPA:DHA, from about a 50: 1 ratio to about a 1:1 ratio of EPA:DHA, from about a 25:1 ratio to about a 1: 1 ratio of EPA:DHA, from about a 10:1 ratio to about a 1:1 ratio of EPA:DHA, from about a 5:1 ratio to about a 1:1 ratio of EPA:DHA, from about a 3:1 ratio to about a 1:1 ratio of EPA:DHA, from about a 2:1 ratio to about a 1:1 ratio of EPA.DHA, or from about a 1.5:1 ratio to about a 1:1 ratio of EPA:DHA.
  • an omega-3 ester or omega-3 alkyl ester has at least about a 1:5 ratio of EPA:DHA, at least about a 1:1 ratio of EPA:DHA, at least about a 1.5:1 ratio of EPA:DHA, at least about a 2:1 ratio of EPA:DHA, at least about a 3:1 ratio of EPA:DHA, at least about a 5:1 ratio of EPA:DHA, or at least about a 10:1 ratio of EPA:DHA.
  • Alcohols may have one, two, or three or more -OH groups per molecule.
  • the present invention provides a method for increasing the solubility of fenofibrate in an omega-3 oil, comprising adding an alcohol to said omega-3 oil.
  • the fenofibrate solubility in a liquid formulation comprising an omega-3 oil and fenofibrate is increased by at least 10.00 percent by incorporating at least about 5.00, 10.00, 15.00, 20.00, 25.00, 30.00, 35.00, or 40.00 percent by volume of a Ci to C 4 alcohol.
  • the fenofibrate solubility in a liquid formulation comprising an omega-3 oil and fenofibrate is increased by at least 20.00 percent by incorporating at least about 5.00, 10.00, 15.00, 20.00, 25.00, 30.00, 35.00, or 40.00 percent by volume of a Ci to C 4 alcohol.
  • the fenofibrate solubility in a liquid formulation comprising an omega-3 oil and fenofibrate is increased by at least 30.00 percent by incorporating at least about 5.00, 10.00, 15.00, 20.00, 25.00, 30.00, 35.00, or 40.00 percent by volume of a Ci to C 4 alcohol.
  • the fenofibrate solubility in a liquid formulation comprising an omega-3 oil and fenofibrate is increased by at least 40.00 percent by incorporating at least about 5.00, 10.00, 15.00, 20.00, 25.00, 30.00, 35.00, or 40.00 percent by volume of a Ci to C 4 alcohol.
  • the fenofibrate solubility in a liquid formulation comprising an omega-3 oil and fenofibrate is increased by at least 50.00 percent by incorporating at least about 5.00, 10.00, 15.00, 20.00, 25.00, 30.00, 35.00, or 40.00 percent by volume of a C 1 to C 4 alcohol.
  • the fenofibrate solubility in a liquid formulation comprising an omega-3 oil and fenofibrate is increased by at least 60.00 percent by incorporating at least about 5.00, 10.00, 15.00, 20.00, 25.00, 30.00, 35.00, or 40.00 percent by volume of a d to C 4 alcohol.
  • a liquid formulation of the present invention comprises at least about 5 percent by weight of a C 1 to C 4 alcohol.
  • a liquid formulation of the present invention comprises at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 percent by weight of a C 1 to C 4 alcohol.
  • a liquid formulation comprises an omega-3 oil, fenofibrate, and an an amount of a Ci to C 4 alcohol sufficient to increase the solubility of said fenofibrate by at least about 2.50 percent, 5.00 percent, 10.00 percent, 15.00 percent, 20.00 percent, 25.00 percent, 30.00 percent, 35.00 percent, 40.00 percent, 45.00 percent, 50.00 percent, 55.00 percent, or 60.00 percent over that of the same formulation without alcohol.
  • omega- 3 oil is superior in solubilizing fenofibrate.
  • Esters of omega-3 oil have shown greater solubilization power than other forms of omega-3, such as triglycerides.
  • omega-3 alkyl esters have shown higher solubility of fenofibrate.
  • the employment of both omega-3 alkyl esters and an alcohol in a liquid formulation of the present invention have shown greatly unexpected improvements in fenofibrate solubility.
  • the total amount of EPA and DHA is a factor influencing the solubility of fenofibrate.
  • An increase in the amount of EPA and DHA in a liquid formulation results in an increase in fenofibrate solubility.
  • a liquid formulation of the present invention comprises at least about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, 85.00, 86.00, 87.00, 88.00, 89.00, or 90.00 % by weight of an omega-3 ester oil and a fenofibrate solubility of about 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, or 110 mg/mL at 25 degrees C.
  • a liquid formulation of the present invention comprises at least about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00,
  • a liquid formulation of the present invention comprises at least about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, 85.00, 86.00, 87.00, 88.00, 89.00, or 90.00 % by weight of an omega-3 ester oil and a fenofibrate solubility of about 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, or 120 mg/mL at 25 degrees C.
  • a liquid formulation of the present invention comprises at least about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, or 85.00 % by weight of an omega-3 ester oil, about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight C 1 to C 4 alcohol, and a fenofibrate solubility of about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, or 170 mg/mL at 25 degrees C.
  • a liquid formulation of the present invention comprises at least about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, 85.00, 86.00, 87.00, 88.00, 89.00, or 90.00 % by weight of an omega-3 ester oil and a fenofibrate solubility of about from 100 to 110 mg/mL at 25 degrees C.
  • a liquid formulation of the present invention comprises at least about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, 85.00, 86.00, 87.00, 88.00, 89.00, or 90.00 % by weight of an omega-3 ester oil and a fenofibrate solubility of about from 100 to 120 mg/mL at 25 degrees C.
  • a liquid formulation of the present invention comprises at least about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, 85.00, 86.00, 87.00, 88.00, 89.00, or 90.00 % by weight of an omega-3 ester oil and a fenofibrate solubility of about from 110 to 120 mg/mL at 25 degrees C.
  • a liquid formulation of the present invention comprises at least about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00,
  • a liquid formulation of the present invention comprises at least about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, or 85.00 % by weight of an omega-3 ester oil, about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight Ci to C 4 alcohol, and a fenofibrate solubility of about from 120 to 170 mg/mL at 25 degrees C.
  • a liquid formulation of the present invention comprises at least about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, or 85.00 % by weight of an omega-3 ester oil, about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight Ci to C 4 alcohol, and a fenofibrate solubility of about from 130 to 170 mg/mL at 25 degrees C.
  • a liquid formulation of the present invention comprises at least about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, or 85.00 % by weight of an omega-3 ester oil, about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight C 1 to C 4 alcohol, and a fenofibrate solubility of at least about 100 mg/mL at 25 degrees C.
  • a liquid formulation of the present invention comprises at least about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, or 85.00 % by weight of an omega-3 ester oil, about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight Ci to C 4 alcohol, and a fenofibrate solubility of at least about 110 mg/mL at 25 degrees C.
  • a liquid formulation of the present invention comprises at least about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, or 85.00 % by weight of an omega-3 ester oil, about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight Ci to C 4 alcohol, and a fenofibrate solubility of at least about 120 mg/mL at 25 degrees C.
  • a liquid formulation of the present invention comprises at least about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, or 85.00 % by weight of an omega-3 ester oil, about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight C 1 to C 4 alcohol, and a fenofibrate solubility of at least about 130 mg/mL at 25 degrees C.
  • a liquid formulation of the present invention comprises at least about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, or 85.00 % by weight of an omega-3 ester oil, about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight C 1 to C 4 alcohol, and a fenofibrate solubility of at least about 140 mg/mL at 25 degrees C.
  • a liquid formulation of the present invention comprises at least about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, or 85.00 % by weight of an omega-3 ester oil, about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight C 1 to C 4 alcohol, and a fenofibrate solubility of at least about 150 mg/mL at 25 degrees C.
  • a liquid formulation of the present invention comprises at least about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, or 85.00 % by weight of an omega-3 ester oil, about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight Ci to C 4 alcohol, and a fenofibrate solubility of at least about 160 mg/mL at 25 degrees C.
  • a liquid formulation of the present invention comprises at least about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, or 85.00 % by weight of an omega-3 ester oil, about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight C 1 to C 4 alcohol, and a fenofibrate solubility of at least about 170 mg/mL at 25 degrees C.
  • a liquid formulation of the present invention comprises at least about 15.00, 16.00, 17.00, 18.00, 19.00, 20.00, 21.00, 22.00, 23.00, 24.00, 25.00, 26.00, 27.00, 28.00, 29.00, 30.00, 31.00, 32.00, 33.00, 34.00, 35.00,
  • a liquid formulation of the present invention comprises at least about 15.00, 16.00, 17.00, 18.00, 19.00, 20.00, 21.00, 22.00, 23.00, 24.00, 25.00, 26.00, 27.00, 28.00, 29.00, 30.00, 31.00, 32.00, 33.00, 34.00, 35.00, 36.00, 37.00, 38.00, 39.00, 40.00, 41.00, 42.00, 43.00, 44.00, 45.00, 46.00, 47.00, 48.00, 49.00, 50.00, 51.00, 52.00, 53.00, 54.00, 55.00, 56.00, 57.00, 58.00, 59.00, 60.00, 61.00, 62.00, 63.00, 64.00, 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, 85.00, 86.00,
  • a medium-chain triglyceride such as a caprylic/capric triglyceride (e.g., Neobee® M5 Stepan Company) or a medium chain mono-diglyceride such as caprylic/capric mono-diglyceride (e.g., Capmul® MCM, Abitec Corporation) may be included in a formulation of the invention to facilitate digestion of the formulation or reduce the food effect.
  • a surfactant may be included in a formulation of the invention to enhance digestion of the formulation or reduce the food effect.
  • a surfactant-containing liquid formulation or medicament of the invention comprises a mixture of fenofibrate dissolved in a vehicle comprising an omega-3 ester or omega-3 alkyl ester and, optionally, a C 1 to C 4 alcohol, wherein: (a) the formulation comprises (i) about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight of fenofibrate (ii) about 55.00, 56.00, 57.00, 58.00, 59.00, 60.00, 61.00, 62.00, 63.00, 64.00, 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, or 80.00 % by weight of an omega-3 ester or omega-3 alkyl ester (ii)
  • the solubility of the fenofibrate in the vehicle is about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 milligrams per milliliter at 25 degrees C.
  • the surfactant-containing liquid formulation or medicament of the invention comprises a C 1 to C 4 alcohol, such as ethanol.
  • the surfactant increases the bioavailability of the non-aqueous formulation in the fasted state when compared with the nonaqueous formulation without surfactant.
  • a surfactant-containing liquid formulation or medicament of the invention comprises a mixture of fenofibrate dissolved in a vehicle comprising an omega-3 ester or omega-3 alkyl ester and, optionally, a C 1 to C 4 alcohol, wherein: (a) the formulation comprises (i) about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight of fenofibrate (ii) about 55.00, 56.00, 57.00, 58.00, 59.00, 60.00, 61.00, 62.00, 63.00, 64.00, 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, or 80.00 % by weight of an omega-3 ester or omega-3 alkyl ester (i) the formulation comprises
  • the surfactant increases the solubility of the fenofibrate in the non-diluted liquid formulation.
  • the surfactant is contained within the solid material of the capsule (i.e., within the gelatin casing or shell of a gelcap). In such an embodiment, the surfactant is prohibited from interacting with the omega-3 oil, the fenofibrate, and any other contents until after the solid capsule structure begins to dissolve (i.e., in vivo or in an aqueous environment).
  • a liquid formulation according to the present invention comprises a surfactant with a weight percent less than about 50.00 percent of the total formulation. In another embodiment, a liquid formulation according to the present invention comprises a surfactant with a weight percent less than about 40.00 percent of the total formulation. In another embodiment, a liquid formulation according to the present invention comprises a surfactant with a weight percent less than about 30.00 percent of the total formulation. In another embodiment, a liquid formulation according to the present invention comprises a surfactant with a weight percent less than about 25.00 percent of the total formulation. In another embodiment, a liquid formulation according to the present invention comprises a surfactant with a weight percent less than about 20.00 percent of the total formulation.
  • a liquid formulation according to the present invention comprises a surfactant with a weight percent less than about 15.00 percent of the total formulation. In another embodiment, a liquid formulation according to the present invention comprises a surfactant with a weight percent less than about 10.00 percent of the total formulation. In another embodiment, a liquid formulation according to the present invention comprises a surfactant with a weight percent less than about 5.00 percent of the total formulation.
  • a formulation containing a high concentration of surfactant is one which has at least 30.00, 35.00, 40.00, 45.00, or 50.00 percent by weight of one or more surfactants.
  • a liquid formulation according to the present invention comprising a surfactant with a weight percent of about 25.00 or less, has a solubility of fenofibrate equal to or greater than that of formulations containing high concentrations of surfactant.
  • a liquid formulation according to the present invention comprising a surfactant with a weight percent of about 20.00 or less has a solubility of fenofibrate equal to or greater than that of formulations containing high concentrations of surfactant.
  • a liquid formulation according to the present invention comprising a surfactant with a weight percent of about 15.00 or less, has a solubility of fenofibrate equal to or greater than that of formulations containing high concentrations of surfactant.
  • a liquid formulation according to the present invention comprising a surfactant with a weight percent of about 10.00 or less, has a solubility of fenofibrate equal to or greater than that of formulations containing high concentrations of surfactant.
  • a liquid formulation according to the present invention comprising a surfactant with a weight percent of about 5.00 or less, has a solubility of fenofibrate equal to or greater than that of formulations containing high concentrations of surfactant.
  • the bioavailability of a liquid formulation of the invention is at least as high as that of the 160 mg dose of Tricor®.
  • a liquid formulation of the present invention which has about a 160 mg dose of fenofibrate per capsule has a bioavailability approximately equal to or higher than that of the 160 mg dose of Tricor®.
  • a liquid formulation of the present invention which has about a 150 mg dose of fenofibrate per capsule has a bioavailability approximately equal to that of the 160 mg dose of Tricor®.
  • a liquid formulation of the present invention which has about a 145 mg dose of fenofibrate per capsule has a bioavailability approximately equal to that of the 160 mg dose of Tricor®.
  • a liquid formulation of the present invention which has about a 140 mg dose of fenofibrate per capsule has a bioavailability approximately equal to that of the 160 mg dose of Tricor®.
  • a liquid formulation of the present invention which has about a 130 mg dose of fenofibrate per capsule has a bioavailability approximately equal to that of the 160 mg dose of Tricor®.
  • a liquid formulation of the present invention which has about a 120 mg dose of fenofibrate per capsule has a bioavailability approximately equal to that of the 160 mg dose of Tricor®.
  • a particular formulation of the invention comprises fenofibrate dissolved in a vehicle at a concentration of about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 milligrams of fenofibrate per milliliter of formulation, wherein the vehicle consists of EPA and/or DHA ethyl esters, about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, or 15.00 % by volume of ethanol, and a medium-chain triglyceride, and wherein the formulation composition on a weight percentage basis is as follows: about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00,
  • 83.00, 84.00, or 85.00 % by weight of EPA and/or DHA ethyl esters about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, or 15.00 % by weight of ethanol, about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, or 15.00 % by weight of the medium chain triglyceride, and about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight of fenofibrate.
  • Another formulation of the invention comprises fenofibrate dissolved in a vehicle at a concentration of about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 milligrams of fenofibrate per milliliter of formulation, wherein the vehicle comprises about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, or 85.00 % by volume of omega-3 ethyl esters, and about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by volume of ethanol, and wherein: (1) the formulation composition on a weight percentage basis is as follows:
  • a particular capsule dosage form of the invention comprises fenofibrate relatively uniformly dispersed in a vehicle at a concentration of about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 milligrams fenofibrate per milliliter of formulation, wherein the vehicle comprises about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, or 85.00 % by volume an omega-3 ethyl ester, and about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by volume of ethanol, and wherein: (1) the formulation composition on a weight
  • the molar ratio of unsaturated moieties contained with the omega-3 ethyl ester to the total moles of omega-3 ethyl ester is about 5 to about 6.
  • Another capsule dosage form of the invention comprises fenof ⁇ brate relatively uniformly dispersed in a vehicle at a concentration of about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 milligrams fenofibrate per milliliter of formulation, wherein the vehicle comprises about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, or 85.00 % by volume EPA and/or DHA ethyl ester, and about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by volume of ethanol, and wherein the formulation composition on a vehicle at
  • a liquid formulation or medicament of the present invention comprising about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, or 85.00 % by weight of omega-3 ethyl ester, about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight of ethanol, and about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight of fenofibrate completely solubilizes the fenofibrate at 25 degrees C.
  • a liquid formulation or medicament of the present invention comprising about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, or 85.00 % by weight of omega-3 ethyl ester, about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight of ethanol, and about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight of fenofibrate has a fenofibrate solubility greater than or equal to about 70 mg/mL
  • a liquid formulation of the present invention comprising about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, or 85.00 % by weight of omega-3 ethyl ester, about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight of ethanol, and about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight of fenof ⁇ brate has a fenofibrate solubility greater than or equal to about 150 mg/mL at about 22 degrees C.
  • a liquid formulation of the present invention comprising about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, or 85.00 % by weight of omega-3 ethyl ester, about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight of ethanol, and about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight of fenofibrate has a fenofibrate solubility greater than or equal to about 160 mg/mL at about 25 degrees C.
  • a liquid formulation of the present invention comprising about 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74.00, 75.00, 76.00, 77.00, 78.00, 79.00, 80.00, 81.00, 82.00, 83.00, 84.00, or 85.00 % by weight of omega-3 ethyl ester, about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight of ethanol, and about 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight of fenofibrate has a fenofibrate solubility greater than or equal to about 220 mg/mL at about 33 degrees C
  • a liquid formulation or medicament of the present invention comprising about 80.00, 81.00, 82.00, 83.00, 84.00, 85.00, 86.00, 87.00, 88.00, 89.00, 90.00, 91.00, 92.00, 93.00, 94.00, or 95.00 % by weight of omega- 3 ethyl ester and about 5.00, 6.00, 7.00, 8.00, 9.00,10.00, 11.00, 12.00, 13.00, 14.00,
  • a liquid formulation of the present invention comprising about 80.00, 81.00, 82.00, 83.00, 84.00, 85.00, 86.00, 87.00, 88.00, 89.00, 90.00, 91.00, 92.00, 93.00, 94.00, or 95.00 % by weight of omega-3 ethyl ester and about 5.00, 6.00, 7.00, 8.00, 9.00,10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight of fenofibrate has a fenof ⁇ brate solubility greater than or equal to about 100 mg/mL at about 22 degrees C.
  • a liquid formulation of the present invention comprising about 80.00, 81.00, 82.00, 83.00, 84.00, 85.00, 86.00, 87.00, 88.00, 89.00, 90.00, 91.00, 92.00, 93.00, 94.00, or 95.00 % by weight of omega- 3 ethyl ester and about 5.00, 6.00, 7.00, 8.00, 9.00,10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 17.00, 18.00, 19.00, or 20.00 % by weight of fenofibrate has a fenofibrate solubility greater than or equal to about 150 mg/mL at about 33 degrees C.
  • a method of increasing the solubility of fenofibrate in a liquid formulation or a medicament containing an omega-3 oil is provided by adding from about 1 to about 25 percent by volume of an omega-3 ester- based oil.
  • the omega-3 oil exists as triglycerides.
  • the omega-3 oil exists as mono-diglycerides.
  • the omega-3 oil exists as free acids.
  • the omega-3 oil exists as phospholipids.
  • the omega-3 oil exists as a mixture of triglycerides, mono-diglycerides, and free acids.
  • the omega-3 oil exists as a mixture of triglycerides and mono-diglycerides.
  • the omega-3 oil exists as a mixture of triglycerides and free acids.
  • the omega-3 oil exists as a mixture of mono-diglycerides and free acids.
  • the omega-3 oil exists as a mixture of mono-diglycerides and free acids.
  • a liquid formulation or medicament of the present invention can be stored for up to 8 weeks at about 25 degrees C with no detectable degradation of fenofibrate. In another embodiment, a liquid formulation of the present invention can be stored for up to 12 weeks at about 25 degrees C with no detectable degradation of fenofibrate. In another embodiment, a liquid formulation of the present invention can be stored for up to 16 weeks at about 25 degrees C with no detectable degradation of fenofibrate.
  • a liquid formulation of the present invention further comprises pharmaceutically acceptable precipitation nuclei to promote the crystallization of multiple, small crystals.
  • a liquid formulation of the present invention is administered in slow-dissolving gelatin capsules, so as to increase the duration of time such capsules remain intact in the patient's stomach.
  • a slow-dissolving gelatin capsule can take 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 minutes or more to open in vivo.
  • a liquid formulation comprises pharmaceutically acceptable precipitation nuclei and is administered in slow-dissolving gelatin capsules. In another embodiment, a liquid formulation comprises pharmaceutically acceptable precipitation nuclei and is administered in slow-dissolving gelatin capsules so as to effectively provide completely solubilized fenof ⁇ brate upon capsule dissolution in vivo. In another embodiment, a liquid formulation of the present invention maintains fenof ⁇ brate in solution at a temperature of about 22 degrees C. In another embodiment, a liquid formulation of the present invention maintains fenof ⁇ brate in solution at a temperature of about 18 degrees C. In another embodiment, a liquid formulation of the present invention maintains fenof ⁇ brate in solution at a temperature of about 15 degrees C.
  • a liquid formulation of the present invention maintains fenof ⁇ brate in solution at a temperature of about 12 degrees C. In another embodiment, a liquid formulation of the present invention maintains fenof ⁇ brate in solution at a temperature of about 15 degrees C and a fenofibrate concentration of at least 100 mg/mL. In another embodiment, a liquid formulation of the present invention maintains fenof ⁇ brate in solution at a temperature of about 15 degrees C and a fenofibrate concentration of at least 110 mg/mL. In another embodiment, a liquid formulation of the present invention maintains fenofibrate in solution at a temperature of about 15 degrees C and a fenofibrate concentration of at least 120 mg/mL.
  • a liquid formulation of the present invention maintains fenofibrate in solution at a temperature of about 15 degrees C and a fenofibrate concentration of at least 130 mg/mL. In another embodiment, a liquid formulation of the present invention maintains fenofibrate in solution at a temperature of about 15 degrees C and a fenofibrate concentration of at least 140 mg/mL. In another embodiment, a liquid formulation of the present invention maintains fenofibrate in solution at a temperature of about 15 degrees C and a fenofibrate concentration of at least 150 mg/mL. In another embodiment, a liquid formulation of the present invention maintains fenofibrate in solution from its initial manufacture, through storage and handling, to administration.
  • a method of preventing, reducing, and/or treating hypercholesterolemia, atherosclerosis, hypertriglyceridemia, cardiovascular events and disease including coronary events and cerebrovascular events, and coronary artery disease and/or cerebrovascular disease comprises administering an effective amount of a liquid formulation of the present invention to a mammal in need of such prevention, reduction, and/or treatment.
  • the mammal is a human.
  • liquid formulations of the present invention can be prepared according to any one or more methods available in the art.
  • appropriate amounts of said formulation components can be mixed together at room temperature or at a slightly elevated temperature.
  • one or more formulation components contain a solid which has precipitated from solution (e.g., a surfactant), such a component can be heated and mixed so as to induce resolubilization prior to combining with the remaining formulation components.
  • a therapeutically acceptable daily dosage of omega-3 oil has been recommended or considered via several national and international groups including, but not limited to, the American Heart Association (AHA) and the International Society for the Study of Fatty Acids and Lipids (ISSFAL).
  • Table 1 includes daily dosage amounts of omega-3 as considered/recommended via several organizations.
  • the present invention provides a novel polymorph of fenofibrate.
  • the present invention provides a method of making a polymorph of fenofibrate, comprising: (a) combining fenof ⁇ brate with one or more components so as to form a solution of fenofibrate;
  • Liquid formulations of the invention may comprise any one polymorph of fenofibrate or a mixture of two or more polymorphs of fenofibrate.
  • a liquid formulation of the present invention may be prepared from fenofibrate (Form I), fenofibrate (Form II), or a mixture of Forms I and II.
  • Typical dosage forms of the invention comprise from about 10 mg to about 1000 mg, or an amount of from about 25 mg to about 500 mg, or an amount of from 40 mg to 400 mg, or an amount of from about 50 mg to about 200 mg of fenofibrate.
  • dosage forms comprising 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 145, 150, 160, 170, 180, 190, or 200 mg fenofibrate are included. More specifically, doses include 50, 100, 145, 150, and 160 mg of fenofibrate.
  • Liquid formulations of the present invention can be administered in soft gelatin capsules.
  • Such soft gelatin capsules can be in any shape, for example, oval or oblongs.
  • the volume of such capsules can be between about 0.5 mL and about 1.5 mL.
  • one dose consists of a single capsule.
  • one dose consists of two capsules.
  • one dose consists of three or more capsules.
  • each dose can be packaged individually in a blister-pack.
  • the soft gelatin material is both chemically and physically stable while in contact with a liquid formulation of the invention.
  • the soft gelatin material prevents the alcohol in the liquid formulation from escaping the capsule.
  • the soft gelatin material prevents a significant amount of the alcohol in the liquid formulation from escaping the capsule.
  • All X-ray powder diffraction patters were obtained using a D/Max Rapid X-ray Diffiractometer (Rigaku/MSC, The Woodlands, TX, U.S.A.) equipped with a copper source (Cu/K ⁇ l.5406A), manual x-y stage, and 0.3 mm collimator.
  • a sample was loaded into a 0.3 mm quartz capillary tube (Charles Supper Company, Natick, MA, U.S.A.) by sectioning off the closed end of the tube and tapping the small, open end of the capillary tube into a bed of the powdered sample or into the sediment of a slurried sample.
  • the precipitate can be amorphous or crystalline.
  • the loaded capillary tube was mounted in a holder that was placed and fitted into the x-y stage.
  • a diffractogram was acquired using control software (RINT Rapid Control Software, Rigaku Rapid/XRD, version 1.0.0 ( ⁇ 1999 Rigaku Co.)) under ambient conditions at a power setting of 46 kV at 40 mA in transmission mode, while oscillating about the omega-axis from 0-5 degrees at 1 degree/second, and spinning about the phi-axis over 360 degrees at 2 degrees/second.
  • the exposure time was 15 minutes unless otherwise specified.
  • the diffractogram obtained was integrated of 2-theta from 2-60 degrees and chi (1 segment) from 0-36 degrees at a step size of 0.02 degrees using the cyllnt utility in the RINT Rapid display software (RTNT Rapid display software, version 1.18 (Rigaku/MSC)) provided by Rigaku with the instrument.
  • the dark counts value was set to 8 as per the system calibration by Rigaku. No normalization or omega, chi or phi offsets were used for the integration.
  • the relative intensity of peaks in a diffractogram is not necessarily a limitation of the PXRD pattern because peak intensity can vary from sample to sample, e.g., due to crystalline impurities. Further, the angles of each peak can vary by about +/- 0.1 degrees, or by about +/- 0.05. The entire pattern or most of the pattern peaks may also shift by about +/- 0.1 degrees to about +/- 0.2 degrees due to differences in calibration, settings, and other variations from instrument to instrument and from operator to operator. All reported PXRD peaks in the Figures, Examples, and elsewhere herein are reported with an error of about ⁇ 0.1 degrees 2-theta. Unless otherwise noted, all diffractograms are obtained at about room temperature (about 24 degrees C to about 25 degrees C).
  • fenofibrate refers to fenofibrate Form I (the currently marketed form) in the Exemplification.
  • Table 2 summarizes the solubility of Fenofibrate in various liquid vehicles.
  • E9501EE comprises 95 percent EPA, 1 percent DHA, as ethyl esters (mass percent)
  • E9501EE comprises 95 percent EPA, 1 percent DHA (mass percent) as ethyl esters
  • omega-3 oils may also be proportional to the number of double-bonds present in the vehicle.
  • a saturated solution of fenofibrate (125.80 mg) in TG361724 fish oil was prepared by adding the fish oil to the fenofibrate up to a volume of 1 mL.
  • the fish oil was comprised of triglycerides.
  • a stir bar was added and the container was crimp sealed.
  • the container was placed in a water bath at 25 degrees C and stirred overnight.
  • the sample was then filtered through a 0.2 micrometer PVDF syringe filter, the liquid was collected and diluted in ethanol by a factor of 2000.
  • a UV spectrophotometer (285 nm) was used to measure the fenofibrate concentration.
  • the solubility of fenofibrate in pure TG361724 is reported below in Table 5.
  • a saturated solution of fenofibrate (145.47 mg) in a 90:10 solution by volume of TG361724:ethanol was prepared by adding the fish oil:ethanol mixture to the fenofibrate up to a volume of 1 mL.
  • the fish oil was comprised of triglycerides.
  • a stir bar was added and the container was crimp sealed. The container was placed in a water bath at 25 degrees C and stirred overnight.
  • the sample was then filtered through a 0.2 micrometer PVDF syringe filter, the liquid was collected and diluted in ethanol by a factor of 2000.
  • a UV spectrophotometer (285 nm) was used to measure the fenofibrate concentration.
  • the solubility of fenofibrate in a mixture of 90:10 TG361724:ethanol is reported below in Table 5.
  • a saturated solution of fenofibrate (125.46 mg) in E351923 was prepared by adding the fish oil to the fenofibrate up to a volume of 1 mL.
  • the fish oil was comprised of ethyl esters.
  • a stir bar was added and the container was crimp sealed.
  • the container was placed in a water bath at 25 degrees C and stirred overnight.
  • the sample was then filtered through a 0.2 micrometer PVDF syringe filter, the liquid was collected and diluted in ethanol by a factor of 2000.
  • a UV spectrophotometer (285 nm) was used to measure the fenofibrate concentration.
  • the solubility of fenofibrate in pure E351923 is reported below in Table 5.
  • a saturated solution of fenofibrate (201.74 mg) in a 90:10 solution by volume of E351923:ethanol was prepared by adding the fish oil:ethanol mixture to the fenofibrate up to a volume of 1 mL.
  • the fish oil was comprised of ethyl esters.
  • a stir bar was added and the container was crimp sealed. The container was placed in a water bath at 25 degrees C and stirred overnight.
  • the sample was then filtered through a 0.2 micrometer PVDF syringe filter, the liquid was collected and diluted in ethanol by a factor of 2000.
  • a UV spectrophotometer (285 nm) was used to measure the fenofibrate concentration.
  • the solubility of fenofibrate in a mixture of 90:10 E351923:ethanol is reported below in Table 5.
  • a saturated solution of fenofibrate (130.9 mg) in E107104 was prepared by adding the fish oil to the fenofibrate up to a volume of 1 mL.
  • the fish oil was rich in DHA.
  • a stir bar was added and the container was crimp sealed.
  • the container was placed in a water bath at 25 degrees C and stirred overnight.
  • the sample was then filtered through a 0.2 micrometer PVDF syringe filter, the liquid was collected and diluted in ethanol by a factor of 2000.
  • a UV spectrophotometer (285 nm) was used to measure the fenofibrate concentration.
  • the solubility of fenofibrate in pure E107104 is reported below in Table 6.
  • a saturated solution of fenofibrate (151.3 mg) in a 95:5 solution by volume of E107104:ethanol was prepared by adding the fish oilxthanol mixture to the fenofibrate up to a volume of 1 mL.
  • the fish oil was rich in DHA.
  • a stir bar was added and the container was crimp sealed.
  • the container was placed in a water bath at 25 degrees C and stirred overnight.
  • the sample was then filtered through a 0.2 micrometer PVDF syringe filter, the liquid was collected and diluted in ethanol by a factor of 2000.
  • a UV spectrophotometer (285 nm) was used to measure the fenofibrate concentration.
  • the solubility of fenofibrate in a mixture of 95:5 E 107104: ethanol is reported below in Table 6.
  • a saturated solution of fenofibrate (161.6 mg) in a 90: 10 solution by volume of E107104:ethanol was prepared by adding the fish oikethanol mixture to the fenofibrate up to a volume of 1 mL.
  • the fish oil was rich in DHA.
  • a stir bar was added and the container was crimp sealed.
  • the container was placed in a water bath at 25 degrees C and stirred overnight.
  • the sample was then filtered through a 0.2 micrometer PVDF syringe filter, the liquid was collected and diluted in ethanol by a factor of 2000.
  • a UV spectrophotometer (285 nm) was used to measure the fenofibrate concentration.
  • the solubility of fenofibrate in a mixture of 90:10 E107104:ethanol is reported below in Table 6.
  • a saturated solution of fenofibrate (154.2 mg) in E970002 was prepared by adding the fish oil to the fenofibrate up to a volume of 1 mL.
  • the fish oil was rich in EPA.
  • a stir bar was added and the container was crimp sealed.
  • the container was placed in a water bath at 25 degrees C and stirred overnight.
  • the sample was then filtered through a 0.2 micrometer PVDF syringe filter, the liquid was collected and diluted in ethanol by a factor of 2000.
  • a UV spectrophotometer (285 nm) was used to measure the fenofibrate concentration.
  • the solubility of fenofibrate in pure E970002 is reported below in Table 6.
  • a saturated solution of fenofibrate (204.8 mg) in a 90: 10 solution by volume of E970002:ethanol was prepared by adding the fish oil:ethanol mixture to the fenofibrate up to a volume of 1 mL.
  • the fish oil was rich in EPA.
  • a stir bar was added and the container was crimp sealed.
  • the container was placed in a water bath at 25 degrees C and stirred overnight.
  • the sample was then filtered through a 0.2 micrometer PVDF syringe filter, the liquid was collected and diluted in ethanol by a factor of 2000.
  • a UV spectrophotometer (285 nm) was used to measure the fenofibrate concentration.
  • the solubility of fenofibrate in a mixture of 90:10 E970002:ethanol is reported below in Table 6.
  • Table 5 shows an increased solubility of fenofibrate in omega-3 oils when ethanol is added to the formulation. Although this increase is seen in omega-3 triglyceride-based oils as well as omega-3 ethyl ester-based oils, it is only the ethyl ester-based omega-3 oils that provide the fenofibrate solubility at and above 100 mg/mL which is necessary for liquid formulations of the present invention.
  • Table 6 shows a similar increase in fenofibrate solubility with the addition of ethanol.
  • omega-3 oils with a high content of DHA and omega-3 oils with a high content of EPA both provide similar solubilization power. Based on the above data, the ratio of EPA:DHA does not appear to be a critical variable for the increased solubilization power of fenofibrate in omega-3 oil.
  • the fenofibrate polymorph (Form II) was also prepared in pure Gelucire® 44/14 and in pure poloxamer 407.
  • the pharmacokinetics of fenofibric acid were evaluated in humans. 18 healthy subjects (male and female) were selected for this study. The study design was a single-dose, 3 treatment, and 3 -sequence, 3-period crossover with a washout interval of at least one-week between each period. An equal number of subjects (i.e. six) was randomly assigned to each of the three sequences. Following an overnight fast of at least 10 hours, subjects were given a single dose of the following test or reference treatment with 240 mL of water:
  • Tricor ® 160 mg tablet after a standard breakfast
  • fenofibrate/omega-3 administered formulation comprised the components and amounts shown in Table 7.
  • Venous blood samples were collected pre-dose (0 hours) and 1, 2, 3, 4, 6, 8, 10, 14, 24, 34, 48 and 72 hours post-dose. Plasma from the collected blood samples were promptly separated and frozen until assayed using a validated assay for fenofibric acid in human plasma with a lower limit of quantitation of 20.1 ng/mL.
  • the pharmacokinetic measures including AUCo-t, AUCo-inf, C ma ⁇ , T max and X 1 A were calculated from the individual concentration-time data for fenof ⁇ bric acid using PhAST software (Phoenix international).
  • Figure 2 shows a semi-log plot of mean plasma concentration of fenof ⁇ bric acid in humans following oral administration of two formulations of fenofibrate.
  • Table 9 shows the solubility of fenofibrate measured at 15 degrees C in several oils and in several oil/ethanol mixtures.
  • Captex® 200 is also known as propylene glycol dicaprylate/dicaprate
  • Myvacet® 9-45K is also known as acetylated monoglycerides
  • Crodamol EO is also known as ethyl oleate
  • Capmul® MCM is also known as capric/caprylic glycerides
  • Peceol is also known as glycerol oleate
  • Epax® 45 IOTG is a concentrate containing 45 percent EPA and 10 percent DHA (triglycerides)
  • Epax® 1050TG is a concentrate containing 10 percent EPA and 50 percent DHA (triglycerides)
  • Eumulgin® 05 is also known as ethocylated oleyl cetyl alcohol.
  • Formulation two contained E681010:ethanol:TPGS, wherein the weight percent of TPGS was maintained at 20 percent.
  • the samples contained component weight ratios of 70:10:20, 65:15:20, 60:20:20, 55:25:20, and 50:30:20.
  • TPGS is also known as d-alpha-tocopheryl polyethylene glycol 1000 succinate.
  • Figure 3 shows the data from zero percent to 30 percent ethanol by weight.
  • Formulation components were weighed and mixed to form homogeneous solutions. Excess fenofibrate was added to 1 mL of the premixed formulation into 10 mL vials. A stir bar was added and the vials were crimped. The formulations were incubated at fixed temperatures (e.g., 15, 25, 32 0 C) using a circulating water bath for 24 to 72 hours under constant mixing. Post incubation, 1 mL of each mixture was filtered via syringe with a 0.45 micrometer pore size, 13 mm, PTFE filter. 50 to 100 microliters of the filtered solution was collected and diluted 1000-fold in volumetric flask with 30/70 v/v acetonitrile- water. Diluted samples were analyzed for fenofibrate content using HPLC with UV detection.
  • Figure 4 shows the temperature dependence of fenofibrate solubility for three different formulations.
  • the first formulation comprises E681010:ethanol:Cremophor EL:Span 20 in a ratio of 65: 15: 10:10.
  • the second formulation comprises E681010:ethanol:TPGS:Labrafil M2125 in a ratio of 65: 15: 15:5.
  • the third formulation comprises E681010:ethanol:TPGS in a ratio of 65:15:20.
  • Labrafil M2125 is also known as linoleoyl polyoxylglycerides.
  • Table 10 shows several surfactant-containing formulations of fenofibrate in E681010 and ethanol with variable ratios of oil, ethanol, and surfactant.
  • the solubility measurement described in Table 10 were taken at 27 degrees C.
  • the emulsification classification was completed at 37 degrees C. Note: All reports of weight percent in Table 10 are rounded to the nearest whole number, and therefore may include approximations of up to +/- 0.5 percent by weight.
  • Formulation A contained 145 mg fenofibrate in an 800 microliter capsule (91 mg/mL fenofibrate).
  • Formulation B contained 145 mg fenofibrate in an 650 microliter capsule (111 mg/mL fenofibrate).
  • Formulation C contained 130 mg fenofibrate in an 800 microliter capsule (81 mg/mL fenofibrate).
  • Formulation D contained 130 mg fenofibrate in an 650 microliter capsule (100 mg/mL fenofibrate).
  • Fenofibrate solutions were prepared at a concentration of 65 mg/mL in pure oil and mixtures of oil and ethanol at room temperature. The solutions were incubated at 15 degrees C and periodically observed for precipitation of fenofibrate.
  • Table 15 shows results of visual observation of oil samples with 13 percent w/w ethanol after 18 days at 15 degrees C.
  • Table 16 shows results of visual observation of pure oil samples after 18 days at 15 degrees C.
  • the following formulations comprise fenofibrate in about 145 mg doses, where two capsules are administered per dose.
  • Table 17 describes several embodiments of non-surfactant-containing fenofibrate formulations.
  • Table 18 describes several embodiments of surfactant-containing fenofibrate formulations.
  • Table 19 describes a fenofibrate formulation where the solubility of fenofibrate is 106 mg/mL at 15 degrees C. The actual fenofibrate concentration in the formulation is 90.6 mg/mL. A single dose of this formulation (two capsules) includes 0.83 grams of omega-3 oil. This formulation provides similar emulsification to that observed in a similar formulation with a greater percentage of ethanol (13.6 weight percent).
  • Table 20 includes fenofibrate solubility data of four liquid formulations at 4 and 15 degrees C.
  • Table 21 includes precipitation and resolubilization times for two fenofibrate formulations.
  • both formulations were incubated at 4 degrees C and observed for precipitation of fenofibrate.
  • Both formulations J and K precipitated fenofibrate after 2 days. Following such precipitation, the formulations were brought to room temperature and the duration for resolubilization was observed.
  • Formulation J took 2 days to resolubilize at room temperature while formulation K took at least 7 days to resolubilize.
  • Formulations J and K were also incubated at 15 degrees C and did not precipitate after 14 days.

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Abstract

La présente invention concerne de nouvelles formules liquides de fénofibrate dans une huile oméga-3. Ces formules sont susceptibles de ne contenir sensiblement aucun artefact alimentaire, sont efficaces dès les faibles volumes et peuvent être facilement biodisponibles. Spécifiquement, le fait que les formules selon l'invention contiennent une huile oméga-3 au titre d'ingrédient principal entraîne non seulement des effets antihypercholestérolémiques et antihypertriglycéridémiques du fait du principe actif fénofibrate, mais également l'apport des doses journalières recommandées en huiles oméga-3 (c'est-à-dire approximativement 1 gramme d'huile oméga-3 par jour), ou d'une partie desdites doses.
PCT/US2007/061356 2004-08-06 2007-01-31 Nouvelles formules de fénofibrate et méthodes de traitement correspondantes Ceased WO2007130713A1 (fr)

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US11690820B2 (en) 2009-04-29 2023-07-04 Amarin Pharmaceuticals Ireland Limited Methods of treating mixed dyslipidemia
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