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WO2008115529A1 - Compositions comprenant des acides gras omega-3 et des inhibiteurs de la cetp - Google Patents

Compositions comprenant des acides gras omega-3 et des inhibiteurs de la cetp Download PDF

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Publication number
WO2008115529A1
WO2008115529A1 PCT/US2008/003628 US2008003628W WO2008115529A1 WO 2008115529 A1 WO2008115529 A1 WO 2008115529A1 US 2008003628 W US2008003628 W US 2008003628W WO 2008115529 A1 WO2008115529 A1 WO 2008115529A1
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WIPO (PCT)
Prior art keywords
omega
fatty acids
pharmaceutical composition
cetp inhibitors
acid
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Application number
PCT/US2008/003628
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English (en)
Inventor
George Bobotas
Douglas Kling
Abdel Fawzy
Roelof M.L. Rongen
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Reliant Pharmaceuticals, Inc.
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Publication date
Application filed by Reliant Pharmaceuticals, Inc. filed Critical Reliant Pharmaceuticals, Inc.
Publication of WO2008115529A1 publication Critical patent/WO2008115529A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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, generally, to compositions comprising omega-3 fatty acids and cholesteryl ester transfer protein (CETP) inhibitors, where the compositions are useful, e.g., for treating dyslipidemia and/or increasing levels of high- density lipoprotein (HDL) cholesterol.
  • the present invention also includes pharmaceutical formulations made from the compositions, methods of making such formulations, methods of using the formulations to treat dyslipidemia and increase levels of HDL cholesterol.
  • cholesterol and triglycerides are part of lipoprotein complexes in the bloodstream, and can be separated via ultracentrifugation into high-density lipoprotein (HDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and very- low-density lipoprotein (VLDL) fractions.
  • HDL high-density lipoprotein
  • IDL intermediate-density lipoprotein
  • LDL low-density lipoprotein
  • VLDL very- low-density lipoprotein
  • Cholesterol and triglycerides are synthesized in the liver, incorporated into VLDL, and released into the plasma.
  • High levels of total cholesterol (total-C), LDL cholesterol (LDL-C), and apolipoprotein B (ApoB, which is a membrane complex for LDL-C) promote human atherosclerosis.
  • Non-HDL cholesterol is the sum of all of the LDL fractions (including LDL, lipoprotein (a) or Lp(a), and IDL) and the VLDL fractions, and it includes all lipoproteins that contain ApoB. Elevated levels of ApoB, a component of LDL cholesterol, are a predictor of cardiovascular disease risk.
  • HDL-C HDL cholesterol
  • ApoA apolipoprotein A
  • cardiovascular morbidity and mortality in humans can vary directly with the level of total cholesterol and LDL-C and inversely with the level of HDL-C.
  • Increased levels of HDL-C have been associated with a reduction in the risk of heart disease. Accordingly to the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), levels of HDL-C are considered to be low when ⁇ 40 mg/dL.
  • NCEP National Cholesterol Education Program
  • HDL-C levels should be above 60 mg/dL. It has been suggested that for every 1 mg/DL increase in HDL, the risk of heart disease drops by 2 - 3%. HDL-C may also be involved in removing cholesterol from the arterial walls, where it can lead to atherosclerosis, and transporting it to the liver where it can be metabolized. HDL-C also has anti-inflammatory effects that are beneficial to the arteries. Although measures such as increasing aerobic exercise, losing excess weight, consuming lower levels of trans-fatty acids, consuming higher levels of soluble fiber, and ceasing smoking are known to increase HDL-C levels, it is often difficult for patients to implement these lifestyle changes.
  • Omega-3 fatty acids are known to reduce serum triglycerides by inhibiting diacylglycerol acyltransferase (DGAT) and by stimulating peroxisomal and mitochondrial beta oxidation.
  • Marine oils also commonly referred to as fish oils, are a good source of two omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which have been found to regulate lipid metabolism.
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • Omega-3 fatty acids have been found to have beneficial effects on the risk factors for cardiovascular diseases, especially mild hypertension, hypertriglyceridemia and on the coagulation factor VII phospholipid complex activity.
  • Omega-3 fatty acids lower serum triglycerides, increase serum HDL-cholesterol, lower systolic and diastolic blood pressure and the pulse rate, and lower the activity of the blood coagulation factor Vll-phospholipid complex. Further, omega-3 fatty acids seem to be well tolerated, without giving rise to any severe side effects.
  • omega-3 fatty acid is a concentrate of omega-3, long chain, polyunsaturated fatty acids from fish oil containing DHA and EPA that is sold under the trademark LOVAZATM, formerly known as OMACOR ® Such a form of omega-3 fatty acid is described, for example, in U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594, each of which is incorporated herein by reference.
  • Cholesteryl ester transfer protein is a plasma glycoprotein which facilitates the transfer of cholesteryl esters from HDL-C to apolipoprotein B-containing lipoproteins, such as LDL.
  • CETP also promotes reverse cholesterol transport, by which peripheral cell cholesterol can be returned to the liver for catabolism, and influences the process of atherogenesis, or the formation of plaques in arteries.
  • the gene that codes for CETP is found in chromosome band 16q21. A number of mutations are known in the CETP gene. Some of these mutations result in a CETP deficiency, leading to increased levels of HDL and unusually large cholesterol particles.
  • CETP deficiency appears to be a beneficial genetic mutation that can be anti-atherogenic, and may also confer unusual longevity to the person affected. Inhibiting the action of CETP is therefore one possible approach to increasing HDL-C levels and decreasing LDL-C levels, treating dyslipidemia, and preventing or treating atherosclerosis.
  • Evidence of the effect of CETP inhibition is described in McCarthy, Medicinal Res. Revs., 13, 139-59 (1993) and in Sitori, Pharmac. Then, 67, 443-47 (1995)). This phenomenon was first demonstrated by Swenson et al., (J. Biol. Chem., 264, 14318 (1989)) with the use of a monoclonal antibody that specifically inhibits CETP.
  • Substituted 2-mercaptoaniline amide compounds can be used as CETP inhibitors and such therapeutic compounds are described by H. Shinkai et al. in PCT Patent Application No. WO 98/35937.
  • Some substituted heteroalkylamine compounds are known as CETP inhibitors.
  • European Patent Application No. 796846 Schmidt et al. describe 2-aryl-substituted pyridines as CETP inhibitors useful as cardiovascular agents.
  • One substituent at C 3 of the pyridine ring can be an hydroxyalkyl group.
  • European Patent Application No. 801060 Dow and Wright describe heterocyclic derivatives substituted with an aldehyde addition product of an alkylamine to afford 1-hydroxy-1 -amines. These are reported to be ⁇ 3 -adrenergic receptor agonists useful for treating diabetes and other disorders.
  • Great Britain Patent Application No. 2305665 Fisher et al.
  • Polycyclic compounds that are useful as CETP inhibitors are also disclosed by A. Oomura et al. in Japanese Patent No. 10287662.
  • therapeutic compounds having the structures C-1 and C-8 were prepared by culturing Penicillium spp.
  • Substituted tetrahydronaphthalene compounds useful as CETP inhibitors are described in PCT Patent Application No. WO 99/14174. Specifically described in that disclosure as a useful CETP inhibitor is (8S)-3-cyclopentyl-1-(4-fluorophenyl)-2-[(S)- fluoro(4-trifluoromethylpheny l)methyl]-B-hydroxy-6-spirocclobutyl-5,6,7,8- tetrahydronaphthalene.
  • compositions and methods for increasing HDL levels and treating conditions such as dyslipidemia and atherosclerosis.
  • the invention provides for methods of increasing HDL levels, methods of treating conditions such as dyslipidemia and atherosclerosis, and methods of treating, preventing, or reducing cardiac events, cardiovascular events, and vascular events and symptoms, using omega-3 fatty acids that preferably include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), preferably LOVAZATM omega-3 fatty acids, in combination with one or more CETP inhibitors.
  • omega-3 fatty acids preferably include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), preferably LOVAZATM omega-3 fatty acids, in combination with one or more CETP inhibitors.
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • LOVAZATM omega-3 fatty acids preferably include LOVAZATM omega-3 fatty acids
  • the pharmaceutical composition can optionally have one or more barrier coatings between the unit dosage form and the one or more outer coatings, and/or optionally a seal coating on the unit dosage form.
  • the present invention provides for a pharmaceutical composition in unit dosage form, comprising a heterogeneous suspension or an essentially homogeneous solution of one or more CETP inhibitors in a solvent system comprising omega-3 fatty acids.
  • the present invention also provides for a method of treating a subject having one or more conditions selected from the group consisting of hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, dyslipidemia and related conditions, atherosclerotic disease and related conditions, the treatment and/or prevention and/or reduction of cardiac events and/or cardiovascular events and/or vascular events and/or symptoms, comprising administering to the subject an effective amount of one or more CETP inhibitors, and omega-3 fatty acids.
  • the one or more CETP inhibitors and omega-3 fatty acids may be administered together in a single dosage form or in two or more dosage forms.
  • CETP inhibitor refers to any of the various substances capable of modifying the activity of CETP, as would be understood by those of ordinary skill in the art.
  • Examples of CETP inhibitors include, but are not limited to, those described in the Background of the Invention.
  • anacetrapib, torcetrapib, and JTT-705 also known as dalcetrapib are used.
  • anacetrapib examples include, but are not limited to MK-0859 and (4S,5R)-5-[3,5- bis(trifluoromethyl)phenyl]-3-[[2-(4-fluoro-2-methoxy-5-propan-2-ylphenyl)-5- (thfluoromethyl)phenyl]methyl]-4-methyl-1 ,3-oxazolidin-2-one.
  • torcetrapib examples include, but are not limited to (2R,4S)-4-((3,5-Bis- trifluoromethylbenzyOmethoxycarbonylaminoJ ⁇ -ethyl- ⁇ -trifluoromethyl-S ⁇ -dihydro ⁇ H- quinoline-1-carboxylic acid ethyl ester.
  • JTT-750 examples include, but are not limited to dalcetrapib and FM 658.
  • Dyslipidemia refers to a disorder of lipoprotein metabolism, including lipoprotein overproduction or deficiency. Dyslipidemias may be manifested by elevation of the total cholesterol, LDL, other non-HDL cholesterol, apolipoprotein B (ApoB) and triglyceride concentrations, and a decrease in HDL or apolipoprotein A (ApoA, including ApoA-l and ApoA-ll) concentration in the blood.
  • ApoA apolipoprotein B
  • the total cholesterol level of a subject is generally considered to be normal if less than 200 mg/dL, borderline to high if 200-239 mg/dL, and high if greater than 240 mg/dL.
  • the present invention may be used to reduce a "high" level of total cholesterol . to "borderline to high,” or preferably, to reduce total cholesterol to "normal” levels of less than 200 mg/dL.
  • the LDL cholesterol level of a subject is generally considered to be normal if less than about 130 mg/dL, borderline to high if within about 130-159 mg/dL, and high if greater than about 160 mg/dL.
  • the present invention may be used to reduce a "high" level of LDL cholesterol to "borderline to high,” or preferably, to reduce LDL cholesterol to "normal” levels of less than about 130 mg/dL, including less than 100 mg/dL.
  • the present invention may be used to reduce LDL cholesterol to levels below 100 mg/dL.
  • the non-HDL cholesterol level of a subject is generally considered to be normal if less than about 160 mg/dL, borderline to high if within about 160-189 mg/dL, and high if greater than about 190 mg/dL.
  • the present invention may be used to reduce a "high" level of non-HDL cholesterol to "borderline to high,” or preferably, to reduce non-HDL cholesterol to "normal” levels of less than about 160 mg/dL, including less than 130 mg/dL.
  • the present invention may be used to reduce non-HDL cholesterol to levels below 130 mg/dL.
  • the normal range of ApoB in a subject is from about 40 to 150 mg/dL.
  • An optimal level of ApoB in subjects with risk factors for coronary heart disease is below 90 mg/dL.
  • the present invention may be used to reduce ApoB levels to a normal range, more preferably to a range of about 40 to 150 mg/dL, or most preferably, to levels below about 90 mg/dL.
  • the HDL cholesterol level of a subject is generally considered to be high and desirable when greater than about 60 mg/dL and low if below about 40 mg/dL.
  • the present invention may be used to increase HDL cholesterol to levels greater than 40 mg/dL, or preferably, to greater than 60 mg/dL.
  • the normal range of ApoA-1 in a subject is from about 100 to 200 mg/dL.
  • the normal range of ApoA-ll in a subject is from about 30 to 50 mg/dL.
  • High levels of ApoA- I and ApoA-ll are desired, especially in those subjects with risk factors for coronary disease.
  • the present invention may be used to increase ApoA-1 levels to a normal range, more preferably to about 100 to 200 mg/dL, and most preferably about 200 mg/dL.
  • the present invention may also be used to increase ApoA-ll levels to a normal range, more preferably to a range of 30 to 50 mg/dL, and most preferably above 50 mg/dL.
  • the triglyceride level of a subject is generally considered to be normal if less than about 150 mg/dL, borderline to high if within about 150-199 mg/dL, high if within about 200-499 mg/dL and very high if greater than 500 mg/dL.
  • the present invention may be used to reduce triglyceride levels from "very high” to "high” levels, or preferably to "borderline to high” levels, or more preferably, to "normal” levels.
  • the present invention may be used to reduce triglyceride levels from "high” levels to "borderline to high” levels, or preferably "normal” levels.
  • the present invention may be used to reduce triglyceride levels from "borderline to high" levels to "normal” levels.
  • the compositions of the present invention are useful for treating dyslipidemia (including decreasing triglycerides) and the underlying cause(s) thereof and/or increasing the levels of serum HDL cholesterol.
  • Suitable omega-3 fatty acids include those described in U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594, including, but not limited to omega-3 fatty acids marketed under the name LOVAZATM.
  • the compositions comprise omega-3 fatty acids present in a concentration of at least 40% by weight as compared to the total fatty acid content of the composition.
  • the omega-3 fatty acids comprise at least 50% by weight of EPA and DHA as compared to the total fatty acid content of the composition, and the EPA and DHA are in a weight ratio of EPA:DHA of from 99:1 to 1 :99, preferably from 1 :4 to 4:1 , more preferably from 1 :3 to 3:1 , and most preferably from 1 :2 to 2:1.
  • the omega-3 fatty acids may comprise pure EPA or pure DHA.
  • omega-3 fatty acids includes natural or synthetic omega-3 fatty acids, or pharmaceutically acceptable esters, derivatives, conjugates (see, e.g., Zaloga et al., U.S. Patent Application Publication No. 2004/0254357, and Horrobin et al., U.S. Patent No. 6,245,811 , each hereby incorporated by reference), precursors or salts thereof and mixtures thereof.
  • omega-3 fatty acid oils include but are not limited to omega-3 polyunsaturated, long-chain fatty acids such as a eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), ⁇ -linolenic acid, stearidonic acid, eicosatetraenoic acid, and docosapentaenoic acid; esters of omega-3 fatty acids with glycerol such as mono-, di- and triglycerides; and esters of the omega-3 fatty acids and a primary, secondary or tertiary alcohol such as fatty acid methyl esters and fatty acid ethyl esters.
  • omega-3 polyunsaturated, long-chain fatty acids such as a eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), ⁇ -linolenic acid, stearidonic acid, eicosatetraenoic acid, and do
  • omega-3 fatty acid oils are long-chain fatty acids such as EPA or DHA, triglycerides thereof, ethyl esters thereof and mixtures thereof.
  • the omega-3 fatty acids or their esters, derivatives, conjugates, precursors, salts and mixtures thereof can be used either in their pure form or as a component of an oil such as fish oil, preferably purified fish oil concentrates.
  • omega-3 fatty acids suitable for use in the invention include lncromega F2250, F2628, E2251 , F2573, TG2162, TG2779, TG2928, TG3525 and E5015 (Croda International PLC, Oxford, England), and EPAX6000FA, EPAX5000TG, EPAX4510TG, EPAX2050TG, EPAX6015TG/EE, EPAX4510TG, EPAX4020TG/EE, EPAX6000TG/EE, EPAX5500EE, EPAX1050TG, K85TG, K85EE, K80EE and EPAX7010EE (EPAX AS, NO-6028 Aalesund, Norway).
  • omega-3 fatty acids present in a concentration of at least 40% by weight, preferably at least 50% by weight, more preferably at least 60% by weight, still more preferably at least 70% by weight, most preferably at least 80% by weight, or even at least 90% by weight.
  • the omega-3 fatty acids comprise at least 50% by weight of EPA and DHA, more preferably at least 60% by weight, still more preferably at least 70% by weight, most preferably at least 80%, such as about 84% by weight.
  • the omega-3 fatty acids comprise about 5 to about 100% by weight, more preferably about 25 to about 75% by weight, still more preferably about 40 to about 55% by weight, and most preferably about 46% by weight of EPA.
  • the omega-3 fatty acids comprise about 5 to about 100% by weight, more preferably about 25 to about 75% by weight, still more preferably about 30 to about 60% by weight, and most preferably about 38% by weight of DHA. All percentages above are by weight as compared to the total fatty acid content in the composition, unless otherwise indicated. The percentage by weight may be based on the free acid or ester forms, although it is preferably based on the ethyl ester form of the omega-3 fatty acids, even if other forms are utilized in accordance with the present invention.
  • the omega-3 fatty acids can be present in an amount from about 350 mg to about 10 grams, more preferably about 500 mg to about 6 grams, and most preferably from about 750 mg to about 4 grams. This amount may be in one or more unit dosage forms, preferably one dosage form.
  • the omega-3 fatty acid composition optionally includes chemical antioxidants, such as alpha tocopherol, oils, such as soybean oil and partially hydrogenated vegetable oil, and lubricants such as fractionated coconut oil, lecithin and a mixture of the same.
  • omega-3 fatty acids LOVAZATM omega-3 fatty acids (K85EE, Pronova Biocare A.S., Lysaker, Norway) and preferably comprises the following characteristics (per unit dosage form):
  • the combination product of one or more CETP inhibitors and omega-3 fatty acids may comprise 30 to 99.9% of omega-3 fatty acids, and 0.1 to 70% of one or more CETP inhibitors, by weight of the composition.
  • the combination product of one or more CETP inhibitors and omega-3 fatty acids may be administered by any means known in the art. Such modes include oral, rectal, nasal, topical (including dermal, buccal and sublingual) or parenteral (including subcutaneous, intramuscular, intravenous, intraarticular and intradermal) administration. These compositions are preferably orally administered.
  • the dosage of active ingredients in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredients be such that a suitable dosage form is obtained.
  • the selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment.
  • the combination product of one or more CETP inhibitors and omega-3 fatty acids may be administered in a capsule, a tablet, a powder that can be dispersed in a beverage, a liquid, a soft gel capsule or other convenient dosage form such as oral liquid in a capsule, as known in the art.
  • the capsule is comprised of hard gelatin.
  • the combination product may also be contained in a liquid suitable for injection or infusion.
  • the active ingredients of the present invention may be administered with a combination of one or more non- active pharmaceutical ingredients (also known generally herein as "excipients").
  • the excipients may be essentially inert, which means that they have little or no pharmacologic or therapeutic action, as understood in the art.
  • Non-active ingredients / for example, serve to solubilize, suspend, thicken, dilute, emulsify, stabilize, preserve, protect, color, flavor, and/or fashion the active ingredients into an applicable and efficacious preparation that is safe, convenient, and otherwise acceptable for use.
  • the non-active ingredients may include colloidal silicon dioxide, crospovidone, lactose monohydrate, lecithin, microcrystalline cellulose, polyvinyl alcohol, povidone, sodium lauryl sulfate, sodium stearyl fumarate, talc, titanium dioxide and xanthum gum.
  • Excipients include surfactants, such as propylene glycol monocaprylate, mixtures of glycerol and polyethylene glycol esters of long fatty acids, polyethoxylated castor oils, glycerol esters, oleoyl macrogol glycerides, propylene glycol monolaurate, propylene glycol dicaprylate/dicaprate, polyethylene-polypropylene glycol copolymer, and polyoxyethylene sorbitan monooleate, cosolvents such ethanol, glycerol, polyethylene glycol, and propylene glycol, and oils such as coconut, olive or safflower oils.
  • surfactants, cosolvents, oils or combinations thereof is generally known in the pharmaceutical arts, and as would be understood to one skilled in the art, any suitable surfactant may be used in conjunction with the present invention and embodiments thereof.
  • a soft gelatin capsule is used.
  • the manufacture of soft gelatin capsules is generally known by those of ordinary skill in the art. See, for example, Ebert (1978), “Soft Elastic Gelatin Capsules: A Unique Dosage Form," Pharmaceutical Technology 1 (5), hereby incorporated by reference.
  • one or more CETP inhibitors and/or omega-3 fatty acids are contained in the soft gelatin capsule.
  • the active ingredients in the soft gelatin capsule are combined with a solubilizer.
  • Solubilizers include surfactants, hydrophilic or hydrophobic solvents, oils or combinations thereof.
  • One type of solubilizer that may be used is a vitamin E substance.
  • This group of solubilizers includes a substance belonging to the group of ⁇ -, ⁇ -, v-, ⁇ -, ⁇ 1-, ⁇ 2- and ⁇ - tocopherols, their dl, d and I forms and their structural analogues, such as tocotrienols; the corresponding derivatives, e.g., esters, produced with organic acids; and mixtures thereof.
  • Preferred vitamin E substance solubilizers include tocopherols, tocotrienols and tocopherol derivatives with organic acids such as acetic acid, propionic acid, bile acid, lactic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, polyethylene glycol succinate and salicylic acid.
  • Particularly preferred vitamin E substance solubilizers include alpha-tocopherol, alpha-tocopheryl acetate, alpha- tocopheryl acid succinate, alpha-tocopheryl polyethylene glycol 1000 succinate and mixtures thereof.
  • solubilizers are monohydric alcohol esters of organic acids.
  • the monohydric alcohol can be, for example, ethanol, isopropanol, t-butanol, a fatty alcohol, phenol, cresol, benzyl alcohol or a cycloalkyl alcohol.
  • the organic acid can be, for example, acetic acid, propionic acid, butyric acid, a fatty acid of 6-22 carbon atoms, bile acid, lactic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid and salicylic acid.
  • Preferred solubilizers in this group include trialkyl citrates, lower alcohol fatty acid esters and lactones.
  • Preferred trialkyl citrates include triethyl citrate, acetyltriethyl citrate, tributyl citrate, acetyltributyl citrate and mixtures thereof with triethyl citrate being particularly preferred.
  • Particularly preferred lower alcohol fatty acid esters include ethyl oleate, ethyl linoleate, ethyl caprylate, ethyl caprate, isopropyl myristate, isopropyl palmitate and mixtures thereof.
  • Lactones may also serve as a solubilizer. Examples include ⁇ -caprolactone, ⁇ -valerolactone, ⁇ -butyrolactone, isomers thereof and mixtures thereof.
  • the solubilizer may be a nitrogen-containing solvent.
  • Preferred nitrogen- containing solvents include dimethylformamide, dimethylacetamide, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam and mixtures thereof wherein alkyl is a C 1 - 12 branched or straight chain alkyl.
  • Particularly preferred nitrogen- containing solvents include N-methyl 2-pyrrolidone, N-ethyl 2-pyrrolidone or a mixture thereof.
  • the nitrogen-containing solvent may be in the form of a polymer such as polyvinylpyrrolidone.
  • solubilizers includes phospholipids.
  • Preferred phospholipids include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, lecithins, lysolecithins, lysophosphatidylcholine, polyethylene glycolated phospholipids/lysophospholipids, lecithins/lysolecithins and mixtures thereof.
  • Another group of preferred solubilizers are glycerol acetates and acetylated glycerol fatty acid esters.
  • Preferred glycerol acetates include acetin, diacetin, thacetin and mixtures thereof, with triacetin being particularly preferred.
  • Preferred acetylated glycerol fatty acid esters include acetylated monoglycerides, acetylated diglycerides and mixtures thereof.
  • the solubilizer may be a glycerol fatty acid ester.
  • the fatty acid component is about 6-22 carbon atoms.
  • the glycerol fatty acid ester can be a monoglyceride, diglyceride, triglyceride or mixtures thereof.
  • Preferred glycerol fatty acid esters include monoglycerides, diglycerides, medium chain triglycerides with fatty acids having about 6-12 carbons and mixtures thereof.
  • Particularly preferred glycerol fatty acid esters include medium chain monoglycerides with fatty acids having about 6-12 carbons, medium chain diglycerides with fatty acids having about 6-12 carbons and mixtures thereof.
  • the solubilizer may be a propylene glycol ester.
  • Preferred propylene glycol esters include propylene carbonate, propylene glycol monoacetate, propylene glycol diacetate, propylene glycol fatty acid esters, acetylated propylene glycol fatty acid esters and mixtures thereof.
  • the propylene glycol fatty acid ester may be a propylene glycol fatty acid monoester, propylene glycol fatty acid diester or mixture thereof.
  • the fatty acid has about 6-22 carbon atoms. It is particularly preferred that the propylene glycol ester is propylene glycol monocaprylate (CAPRYOL ® ).
  • Other preferred propylene glycol esters include propylene glycol dicaprylate, propylene glycol dicaprate, propylene glycol dicaprylate/dicaprate and mixtures thereof.
  • Ethylene glycol esters include monoethylene glycol monoacetates, diethylene glycol esters, polyethylene glycol esters and mixtures thereof. Additional examples include ethylene glycol monoacetates, ethylene glycol diacetates, ethylene glycol fatty acid monoesters, ethylene glycol fatty acid diesters, and mixtures thereof.
  • the ethylene glycol ester may be a polyethylene glycol fatty acid monoesters, polyethylene glycol fatty acid diesters or mixtures thereof.
  • the fatty acid component will contain about 6-22 carbon atoms.
  • Particularly preferred ethylene glycol esters are those marketed under the LABRAFIL ® and LABRASOL ® names.
  • Polyoxyethylene-sorbitan-fatty acid esters also called polysorbates
  • e.g. of from 4 to 25 alkylene moieties for example mono- and tri-lauryl, palmityl, stearyl and oleyl esters of the type known and commercially available under the trade name TWEEN ® are also suitable as surfactants.
  • Hydrophilic solvents which may be used include an alcohol, e.g. a water miscible alcohol, e.g. absolute ethanol, or glycerol.
  • Other alcohols include glycols, e.g. any glycol obtainable from an oxide such as ethylene oxide, e.g. 1 ,2-propylene glycol.
  • Other examples are polyols, e.g. a polyalkylene glycol, e.g. poly(C 2-3 )alkylene glycol.
  • a typical example is a polyethylene glycol.
  • the hydrophilic component may preferably comprise an N-alkylpyrolidone, e.g. N-(Cri 4 alkyl)pyrolidone, e.g.
  • the hydrophilic solvent may comprise a main or sole component, e.g. an alcohol, e.g. Ci -4 -alcohol, e.g. ethanol, or alternatively a co-component, e.g. which may be selected from partial lower ethers or lower alkanols.
  • Preferred partial ethers are, for example, TRANSCUTOL ® (which has the formula C 2 H 5 -[O-(CH 2 ) 2 ] 2 -OH), GLYCOFUROL ® (also known as tetrahydrofurfuryl alcohol polyethylene glycol ether), or lower alkanols such as ethanol.
  • TRANSCUTOL ® which has the formula C 2 H 5 -[O-(CH 2 ) 2 ] 2 -OH
  • GLYCOFUROL ® also known as tetrahydrofurfuryl alcohol polyethylene glycol ether
  • lower alkanols such as ethanol.
  • Another embodiment of the present invention is directed to a soft gelatin capsule coated with one or more CETP inhibitors.
  • at least one coating applied to the outside of the soft gelatin capsule comprises the one or more CETP inhibitors and a coating material, such as a film forming material and/or binder, and optionally other conventional additives such as lubricants, fillers and antiadherents.
  • a coating material such as a film forming material and/or binder
  • Preferred coating materials include antioxidants, solubilizers, chelating agents and/or absorption enhancers.
  • Surfactants may act as both solubilizers and absorption enhancers.
  • the coating(s) may be applied by any conventional technique such as pan coating, fluid bed coating or spray coating.
  • the coating(s) may be applied as a suspension, spray, dust or powder.
  • the coating(s) may be formulated for immediate release, delayed/enteric release or sustained release of the one or more CETP inhibitors in accordance with methods well known in the art.
  • the terms "delayed release” and "enteric release” are interchangeable. Conventional coating techniques are described, e.g., in Remington's Pharmaceutical Sciences, 18th Ed. (1990), hereby incorporated by reference.
  • An immediate release coating is commonly used to improve product elegance as well as for a moisture barrier, and taste and odor masking.
  • EUDRAGIT RD100 (Rohm) is an example of such a coating. It is a combination of a water insoluble cationic methacrylate copolymer with a water soluble cellulose ether. In powder form, it is readily dispensable into an easily sprayable suspension that dries to leave a smooth film. Of course, other suitable immediate release coatings may be employed in accordance with the present invention. Such films rapidly disintegrate in aqueous media at a rate that is independent of pH and film thickness.
  • a protective coating layer (i.e., seal coat) may be applied, if desired, by conventional coating techniques such as pan coating or fluid bed coating using solutions of polymers in water or suitable organic solvents or by using aqueous polymer dispersions.
  • Suitable materials for the protective layer include cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, ethyl cellulose aqueous dispersions and the like.
  • the protective coating (seal coating) layer may include antioxidants, chelating agents, colors or dyes.
  • the protective coating (seal coating) layer may be placed on any layer of the dosage form and preferably on a layer outside the layer of the CETP inhibitor, and most preferably on the outermost layer.
  • the enteric coating layer may be applied onto the cores with or without seal coating by conventional coating techniques, such as pan coating or fluid bed coating using solutions of polymers in water or suitable organic solvents or by using aqueous polymer dispersions. All commercially available pH-sensitive polymers are included.
  • the pharmaceutical active is not released in the acidic stomach environment of approximately below pH 4.5, but not limited to this value. The pharmaceutical active should become available when the pH- sensitive layer dissolves at the greater gastrointestinal tract pH; after a certain delayed time; or after the unit passes through the stomach.
  • the preferred delay time is in the range of one to six hours.
  • Enteric polymers include cellulose acetate phthalate, Cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters such as, for instance, materials known under the trade name EUDRAGIT L12.5, L100, or EUDRAGIT S12.5, S100 or similar compounds used to obtain enteric coatings.
  • Aqueous colloidal polymer dispersions or re-dispersions can be also applied, e.g.
  • a sustained release film coat may include a water insoluble material such as a wax or a wax-like substance, fatty alcohols, shellac, zein, hydrogenated vegetable oils, water insoluble celluloses, polymers of acrylic and/or methacrylic acid, and any other slowly digestible or dispersible solids known in the art.
  • the solvent for the hydrophobic coating material may be organic or aqueous.
  • the hydrophobic polymer is selected from (i) a water insoluble cellulosic polymer, such as an alkylcellulose, preferably ethylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof.
  • the hydrophobic material comprising the controlled release coating is an acrylic polymer. Any acrylic polymer which is pharmaceutically acceptable can be used for the purposes of the present invention.
  • the acrylic polymers may be cationic, anionic or non-ionic polymers and may be acrylates, methacrylates, formed of methacrylic acid or methacrylic acid esters.
  • acrylic polymers include but are not limited to acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, methyl methacrylate, copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, methyl methacrylate copolymers, methyl methacrylate copolymers, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, methacrylic acid copolymers, methyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid, methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, methyl methacrylate copolymer, poly(methyl methacrylate), poly(methyl methacryl
  • a barrier coat may be included between an outer coat and the soft gelatin shell.
  • the barrier coat may be comprised of an enteric/delayed release coat (as above), or a barrier (non-functional) layer, which serves as a protective coat to prevent leaching from the shell to the outer pharmaceutical active component, or vice versa.
  • one or more CETP inhibitors are split into first and second portions, with one portion disposed on a coating, and the second portion disposed in the soft gelatin capsule.
  • the dosage form is provided with a lag time between the administration of the first portion and the administration of the second portion, e.g., by an enteric coating provided as a barrier layer.
  • the outer coating is immediate release and the dosage form further includes an enteric/delayed release or sustained release barrier coating.
  • Soft gelatin capsules generally contain a medicament dissolved or dispersed in oils or hydrophilic liquids (fill liquid).
  • fill liquid oils or hydrophilic liquids
  • the inherent flexibility of the soft gelatin capsule is due to the presence of plasticizers and residual moisture in the capsule shell.
  • the soft gelatin capsule is a more dynamic system than conventional tablets or hard gelatin capsules. Atmospheric moisture may permeate into the capsule shell or into the fill liquid. The drug or fill liquid may migrate into the capsule shell, while the plasticizer or residual water gelatin can potentially migrate into the fill liquid. Volatile components in soft gelatin capsules may escape into the atmosphere.
  • polymeric coatings are generally applied as aqueous-based solutions, organic-based solutions or dispersions, in which polymer-containing droplets are atomized with air and sprayed onto the substrate. Heat may be added to the coating equipment to facilitate evaporation of the solvent and film formation.
  • the processing parameters of spray rate and bed temperature must be controlled. Because gelatin is soluble in water, spraying an aqueous-based polymeric material at a high rate could lead to solubilization of the gelatin and capsule agglomeration. A high bed temperature may result in the evaporation of residual water from the capsule shell, causing the capsule to become brittle. Therefore, the present invention comprises a method of coating soft gelatin capsules in which these consequences are avoided.
  • the deposition of a low dose of one or more CETP inhibitors onto the surface of the soft gelatin capsules with high degree of accuracy could be affected by several factors. Coating uniformity, including mass variance of the coated capsules and the variance of the content of the coated one or more CETP inhibitors may be evaluated using methods known in the art
  • the present invention provides for a method of coating a soft gelatin capsule comprising omega-3 fatty acids, with a coating comprising a coating material and one or more CETP inhibitors, the method comprising controlling the rate of coating deposition on the soft gelatin capsule and controlling the temperature during the coating process to produce a physically and chemically stable coated soft gelatin capsule.
  • the coating of the present invention may also be applied onto a hard gelatin capsule or a tablet.
  • the hard gelatin capsule may contain, instead of liquid, powder, beads or microtablets (e.g., similar system to U.S. Patent No. 5,681 ,588, incorporated herein by reference).
  • a pharmaceutical composition in unit dosage form comprises an essentially homogeneous solution comprising one or more CETP inhibitors substantially dissolved (i.e., less than 10%, preferably less than 5% remains undissolved) in a solvent system comprising omega-3 fatty acids.
  • the one or more CETP inhibitors are substantially dissolved in the omega-3 fatty acid oil to provide a substantially homogeneous composition.
  • the one or more CETP inhibitors are completely dissolved.
  • the one or more CETP inhibitors are contained in the pharmaceutical composition without the use of large amounts of solubilizers (other than the omega-3 fatty acids).
  • solubilizers other than the omega-3 fatty acids are present in amounts of 50% or less w/w based on the total weight of the solvent system in the dosage form, preferably 40% or less, more preferably 30% or less, even more preferably 20% or less, still more preferably 10% or less and most preferably 5% or less.
  • the solvent system contains no solubilizers other than the omega-3 fatty acids.
  • solvent system includes the omega-3 fatty acids, generally in the form of an oil.
  • the weight ratio of omega-3 fatty acids to other solubilizer(s) is at least 0.5 to 1 , more preferably at least 1 to 1 , even more preferably at least 5 to 1 , and most preferably at least 10 to 1.
  • omega-3 fatty acids are present in amounts of at least 30% w/w based on the total weight of the solvent system in the dosage form, more preferably at least 40%, even more preferably at least 50%, and most preferably at least 60%. In certain embodiments, the amount can be at least 70%, at least 80% or at least 90%.
  • Dosage forms including the substantially homogenous solution should be stable at room temperature (about 23°C to 27°C, preferably about 25 0 C) and 60% relative humidity for a period of at least one month, preferably at least six months, more preferably at least one year, and most preferably at least two years.
  • stable applicants mean that the solubilized one or more CETP inhibitors should not precipitate out of solution and not become chemically modified to any appreciable degree, for example, in amounts of less than 10%, preferably less than 5%.
  • dosage forms including the essentially homogenous solution should preserve the one or more CETP inhibitors from degradation.
  • Some embodiments include unit dosage forms of one or more CETP inhibitors and omega-3 fatty acids in which at least 90% of the initial amount of one or more CETP inhibitors in the dosage form at an initial measurement time (t 0 ) should be maintained for a period of at least one month, preferably at least six months, more preferably at least one year, and most preferably at least two years, upon storage at room temperature and 60% relative humidity.
  • compositions comprising suspensions of one or more CETP inhibitors in omega-3 fatty acids where a portion of the one or more CETP inhibitors is solubilized in solvent system.
  • the present invention provides a pharmaceutical composition comprising omega-3 fatty acids and one or more CETP inhibitors, wherein about 1-15% of the one or more CETP inhibitors by weight are in solution while the remaining amount of the one or more CETP inhibitors are present in suspension.
  • the present invention provides a pharmaceutical composition comprising omega-3 fatty acids and one or more CETP inhibitors, wherein at least about 80%, preferably about 85%, more preferably about 90%, even more preferably about 95%, and most preferably about 99%, of the one or more CETP inhibitors by weight are present as solid particles in suspension.
  • the CETP inhibitor may be administered in an amount more than, equal to or less than the conventional full-strength dose as a single-administered product.
  • the CETP inhibitor may be administered in an amount of from 10-100%, preferably about 25-100%, most preferably about 50-80%, of the conventional full- strength dose as a single-administered product.
  • Daily dosage ranges for anacetrapib can be 1 to 2,000 mg, more preferably 10 mg to 1 ,000 mg, and most preferably 50 mg to 750 mg.
  • Daily dosage ranges for torcetrapib can be 1 mg to 2,000 mg, more preferably 25 mg to 1 ,000 mg, and most preferably 100 mg to 750 mg.
  • Daily dosage ranges for JTT-750 can be 1 to 5,000 mg, more preferably 25 mg to 2,500 mg, and most preferably 50 to 1 ,500 mg.
  • the daily dosages of CETP inhibitor and concentrated omega-3 fatty acids can be administered together in from 1 to 10 dosages, with the preferred number of dosages from 1 to 4 times a day, most preferred 1 to 2 times a day.
  • the administration is preferably oral administration, although other forms of administration that provides a unit dosage of CETP inhibitor and concentrated omega-3 fatty acids may be used.
  • the present combination of a CETP inhibitor and concentrated omega-3 fatty acids may allow for a greater effect than any expected combined or additive effect of the two drugs alone.
  • Any undesirable side effects may also be reduced as a result of a lower dosage amount and/or a reduction in excipients (e.g., surfactants).
  • excipients e.g., surfactants
  • Formulation 2 Soft gel capsule with the following:
  • Formulation 3 Soft gel capsule with the following:
  • Formulation 4 Soft gel capsule with the following:
  • Formulation 5 Soft gel capsule with the following:

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Abstract

L'invention concerne au moins un inhibiteur de la CETP mélangé à des acides gras oméga 3, des procédés d'administration desdites combinaisons et des dosages unitaires desdites combinaisons.
PCT/US2008/003628 2007-03-20 2008-03-20 Compositions comprenant des acides gras omega-3 et des inhibiteurs de la cetp WO2008115529A1 (fr)

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