Omega-3 fatty acid ester compositions

Abstract

Compositions including at least one Omega-3 fatty acid ester and at least one surface active agent are provided; wherein the compositions form micelles when in contact with an aqueous medium. Also provided is a method of administering to a subject such a composition, wherein the at least one Omega-3 fatty acid ester forms micelles when in contact with an aqueous medium, and the bioavailability of the at least one Omega-3 fatty acid ester is substantially independent of a food effect. The compositions are useful for treating cardiovascular conditions or disorders in a subject and for reducing side effects associated with the ingestion of Omega-3 fatty acid esters. Further provided are also various dosage forms for administering the compositions and use of the compositions in functional foods. Provided herein are also kits with instructions on how to administer the compositions.

1 . A pharmaceutical composition comprising EPA ethyl ester, DHA ethyl ester and at least one surface active agent, wherein said composition when administered to a patient in need of treatment for hypertriglyceridemia, provides for a reduction of circulating triglyceride blood plasma levels of at least 25% greater than the reduction of circulating triglyceride blood plasma levels provided by the administration of an Omega-3 fatty acid ethyl ester having an EPA:DHA ratio of about 1.3:1 at equivalent dosage strengths of EPA ethyl ester and DHA ethyl ester in said composition. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein said reduction of circulating triglyceride blood plasma levels is observed as early as 7 days after the initial administration. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein said reduction said reduction of circulating triglyceride blood plasma levels is observed 28 days after the initial administration. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein said patient in need of treatment has a mildly elevated base-line level of circulating triglycerides (271-368 mg/dL). 
     
     
         5 . A pharmaceutical composition comprising a mixture of EPA ethyl ester and DHA ethyl ester and at least one surface active agent; wherein said at least one surface active agent comprises from about 0.5% (wt/wt) to about 5% (wt/wt) of a block copolymer of polyethylene glycol and polypropylene glycol poloxamer having a chemical formula HO(C 2 H 4 O) 64 (C 3 H 6 O) 37 (C 2 H 6 O) 37 (C 2 H 4 O) 64 H (Poloxamer 237); wherein the surfactant HLB value is about 15 to about 17, wherein the composition is formulated in the form of a capsule, and wherein said composition is free of omega-3 free fatty acids; and wherein said composition when administered to a patient in need of treatment for hypertriglyceridemia, provides for a reduction of circulating triglyceride blood plasma levels of at least 25% greater than the reduction of circulating triglyceride blood plasma levels provided by the administration of an Omega-3 fatty acid ethyl ester having an EPA:DHA ratio of about 1.3:1 at equivalent dosage strengths of EPA ethyl ester and DHA ethyl ester in said composition. 
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein said reduction of circulating triglyceride blood plasma levels is observed as early as 7 days after the initial administration. 
     
     
         7 . The pharmaceutical composition of  claim 5 , wherein said reduction said reduction of circulating triglyceride blood plasma levels is observed 28 days after the initial administration. 
     
     
         8 . The pharmaceutical composition of  claim 5 , wherein said patient in need of treatment has a mildly elevated base-line level of circulating triglycerides (271-368 mg/dL). 
     
     
         9 . The pharmaceutical composition of  claim 5 , wherein the composition self-micellizes in an aqueous medium. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein the micelles have an average diameter of from about 1 μm to about 10 μm. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the micelles are stable for at least 12 months at ambient temperature. 
     
     
         12 . A micelle dosage form composition comprising pre-formed micelles in an aqueous medium, wherein said dosage form composition is prepared by adding the composition of  claim 9  to an aqueous medium. 
     
     
         13 . The composition of  claim 12 , wherein said adding is without any agitation. 
     
     
         14 . The pharmaceutical composition of  claim 5 , further comprising polysorbate 80 present between about 20% (wt/wt) to about 31% (wt/wt) of said composition. 
     
     
         15 . The pharmaceutical composition of  claim 5 , further comprising the ingredient pure d-limonene. 
     
     
         16 . A pharmaceutical composition comprising EPA ethyl ester and DHA ethyl ester and at least one surface active agent, wherein when administered to a patient in need of treatment for hypertriglyceridemia, provides an increase of at least 1.5 fold of the circulating blood plasma levels of EPA and DHA total lipids compared to the respective circulating blood plasma levels of EPA and DHA total lipids provided by the administration of an Omega-3 fatty acid ethyl ester having an EPA:DHA ratio of about 1.3:1® or a combination of EPA and DHA in free acid form at equivalent dosage strengths of EPA ethyl ester and DHA ethyl ester in said composition under a fed state. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein said increase of circulating EPA and DHA total lipid levels in the blood plasma levels is observed as early as 7 days after the initial administration. 
     
     
         18 . The pharmaceutical composition of  claim 16 , wherein said increase of circulating EPA and DHA total lipid levels in the blood plasma levels is observed 28 days after the initial administration. 
     
     
         19 . The pharmaceutical composition of  claim 16 , wherein said patient in need of treatment has a mildly elevated base-line level of circulating triglycerides (271-368 mg/d L). 
     
     
         20 . A pharmaceutical composition comprising a mixture of EPA ethyl ester and DHA ethyl ester and at least one surface active agent; wherein said at least one surface active agent comprises from about 0.5% (wt/wt) to about 5% (wt/wt) of a block copolymer of polyethylene glycol and polypropylene glycol poloxamer having a chemical formula HO(C 2 H 4 O) 64 (C 3 H 6 O) 37 (C 2 H 6 O) 37 (C 2 H 4 O) 64 H (Poloxamer 237); wherein the surfactant HLB value is about 15 to about 17, wherein the composition is formulated in the form of a capsule, and wherein said composition is free of omega-3 free fatty acids; and wherein said composition when administered to a patient in need of treatment for hypertriglyceridemia, provides an increase of at least 1.5 fold of the circulating blood plasma levels of EPA and DHA total lipids compared to the respective circulating blood plasma levels of EPA and DHA total lipids provided by the administration of an Omega-3 fatty acid ethyl ester having an EPA:DHA ratio of about 1.3:1 or a combination of EPA and DHA in free acid form at equivalent dosage strengths of EPA ethyl ester and DHA ethyl ester in said composition under a fed state. 
     
     
         21 . The pharmaceutical composition of  claim 20 , wherein said increase in circulating EPA and DHA total lipids in blood plasma levels is observed as early as 7 days after the initial administration. 
     
     
         22 . The pharmaceutical composition of  claim 20 , wherein said increase in circulating EPA and DHA total lipids in blood plasma levels is observed 28 days after the initial administration. 
     
     
         23 . The pharmaceutical composition of  claim 20 , wherein said patient in need of treatment has a mildly elevated base-line level of circulating triglycerides (271-368 mg/d L). 
     
     
         24 . The pharmaceutical composition of  claim 20 , wherein the composition self-micellizes in an aqueous medium. 
     
     
         25 . The pharmaceutical composition of  claim 24 , wherein the micelles have an average diameter of from about 1 μm to about 10 μm. 
     
     
         26 . The pharmaceutical composition of  claim 25 , wherein the micelles are stable for at least 12 months at ambient temperature. 
     
     
         27 . A micelle dosage form composition comprising pre-formed micelles in an aqueous medium, wherein said dosage form composition is prepared by adding the composition of  claim 24  to an aqueous medium. 
     
     
         28 . The composition of  claim 27 , wherein said adding is without any agitation. 
     
     
         29 . The pharmaceutical composition of  claim 20 , further comprising polysorbate 80 present between about 20% (wt/wt) to about 31% (wt/wt) of said composition. 
     
     
         30 . The pharmaceutical composition of  claim 20 , further comprising the ingredient pure d-limonene. 
     
     
         31 . A pharmaceutical composition comprising EPA ethyl ester and DHA ethyl ester and at least one surface active agent, wherein when administered to a patient in need of treatment for hypertriglyceridemia, provides an increase of at least 10-fold of the circulating blood plasma levels of EPA and DHA total lipids compared to the respective circulating blood plasma levels of EPA and DHA total lipids provided by the administration of an Omega-3 fatty acid ethyl ester having an EPA:DHA ratio of about 1.3:1 at equivalent dosage strengths of EPA ethyl ester and DHA ethyl ester under a fasted state. 
     
     
         32 . The pharmaceutical composition of  claim 31 , wherein said increase in circulating EPA and DHA total lipids in blood plasma levels is observed as early as 7 days after the initial administration. 
     
     
         33 . The pharmaceutical composition of  claim 31 , wherein said increase in circulating EPA and DHA total lipids in blood plasma levels is observed 28 days after the initial administration. 
     
     
         34 . The pharmaceutical composition of  claim 31 , wherein said patient in need of treatment has a mildly elevated base-line level of circulating triglycerides (271-368 mg/d L). 
     
     
         35 . A pharmaceutical composition comprising a mixture of EPA ethyl ester and DHA ethyl ester and at least one surface active agent; wherein said at least one surface active agent comprises from about 0.5% (wt/wt) to about 5% (wt/wt) of a block copolymer of polyethylene glycol and polypropylene glycol poloxamer having a chemical formula HO(C 2 H 4 O) 64 (C 3 H 6 O) 37 (C 2 H 6 O) 37 (C 2 H 4 O) 64 H (Poloxamer 237); wherein the surfactant HLB value is about 15 to about 17, wherein the composition is formulated in the form of a capsule, and wherein said composition is free of omega-3 free fatty acids; and wherein said composition when administered to a patient in need of treatment for hypertriglyceridemia, provides an increase of at least 10-fold of the circulating blood plasma levels of EPA and DHA total lipids compared to the respective circulating blood plasma levels of EPA and DHA total lipids provided by the administration of an Omega-3 fatty acid ethyl ester having an EPA:DHA ratio of about 1.3:1 at equivalent dosage strengths of EPA ethyl ester and DHA ethyl ester under a fasted state. 
     
     
         36 . The pharmaceutical composition of  claim 35 , wherein said increase in circulating EPA and DHA total lipids in blood plasma levels is observed as early as 7 days after the initial administration. 
     
     
         37 . The pharmaceutical composition of  claim 35 , wherein said increase in circulating EPA and DHA total lipids in blood plasma levels is observed 28 days after the initial administration. 
     
     
         38 . The pharmaceutical composition of  claim 35 , wherein said patient in need of treatment has a mildly elevated base-line level of circulating triglycerides (271-368 mg/d L). 
     
     
         39 . The pharmaceutical composition of  claim 35 , wherein the composition self-micellizes in an aqueous medium. 
     
     
         40 . The pharmaceutical composition of  claim 39 , wherein the micelles have an average diameter of from about 1 μm to about 10 μm. 
     
     
         41 . The pharmaceutical composition of  claim 40 , wherein the micelles are stable for at least 12 months at ambient temperature. 
     
     
         42 . A micelle dosage form composition comprising pre-formed micelles in an aqueous medium, wherein said dosage form composition is prepared by adding the composition of  claim 39  to an aqueous medium. 
     
     
         43 . The composition of  claim 42 , wherein said adding is without any agitation. 
     
     
         44 . The pharmaceutical composition of  claim 35 , further comprising polysorbate 80 present between about 20% (wt/wt) to about 31% (wt/wt) of said composition. 
     
     
         45 . The pharmaceutical composition of  claim 35 , further comprising the ingredient pure d-limonene. 
     
     
         46 . A pharmaceutical composition of  claim 1  wherein said composition does not contain at least one selected from the group consisting of palmitic acid, linoleic acid, oleic acid either individually or in combination. 
     
     
         47 . A pharmaceutical composition comprising EPA ethyl ester, DHA ethyl ester and at least one surface active agent, when administered to a patient in need of treatment for hypertriglyceridemia, wherein the C max  of total EPA and DHA total lipid plasma concentration provided by said composition is at least about 1.5 times greater than the C max  of total EPA and DHA total lipid plasma concentration provided by an equal dosage of an Omega-3 fatty acid ethyl ester having an EPA:DHA ratio of about 1.3:1 or a combination of EPA and DHA in free acid form when administered under fed conditions. 
     
     
         48 . The pharmaceutical composition of  claim 47 , wherein said reduction of circulating triglyceride blood plasma levels is observed as early as 7 days after the initial administration. 
     
     
         49 . The pharmaceutical composition of  claim 47 , wherein said reduction said reduction of circulating triglyceride blood plasma levels is observed 28 days after the initial administration. 
     
     
         50 . The pharmaceutical composition of  claim 47 , wherein said patient in need of treatment has a mildly elevated base-line level of circulating triglycerides (271-368 mg/d L). 
     
     
         51 . A pharmaceutical composition comprising EPA ethyl ester, DHA ethyl ester and at least one surface active agent, when administered to a patient in need of treatment for hypertriglyceridemia, wherein the C max  of total EPA and DHA total lipid plasma concentration provided by said composition is at least about 1.5 times greater than the C max  of total EPA and DHA total lipid plasma concentration provided by an equivalent dosage of an Omega-3 fatty acid ethyl ester having an EPA:DHA ratio of about 1.3:1 or a combination of EPA and DHA in free acid form when administered under fed conditions. 
     
     
         52 . A pharmaceutical composition comprising EPA ethyl ester, DHA ethyl ester and at least one surface active agent, when administered to a patient in need of treatment for hypertriglyceridemia, provide for a C max  of total EPA and DHA total lipid plasma concentration that is at least about 10-fold greater than the C max  of total EPA and DHA total lipid plasma concentration provided by an equivalent dosage of an Omega-3 fatty acid ethyl ester having an EPA:DHA ratio of about 1.3:1 when administered under fasted conditions. 
     
     
         53 . A pharmaceutical composition comprising a mixture of EPA ethyl ester and DHA ethyl ester and at least one surface active agent; wherein said at least one surface active agent comprises from about 0.5% (wt/wt) to about 5% (wt/wt) of a block copolymer of polyethylene glycol and polypropylene glycol poloxamer having a chemical formula HO(C 2 H 4 O) 64 (C 3 H 6 O) 37 (C 2 H 6 O) 37 (C 2 H 4 O) 64 H (Poloxamer 237); wherein the surfactant HLB value is about 15 to about 17, wherein the composition is formulated in the form of a capsule, and wherein said composition is free of omega-3 free fatty acids; and wherein said composition when administered to a patient in need of treatment for hypertriglyceridemia, provide for a C max  of total EPA and DHA total lipid plasma concentration that is at least about 10-fold greater than the C max  of total EPA and DHA total lipid plasma concentration provided by an equivalent dosage of an Omega-3 fatty acid ethyl ester having an EPA:DHA ratio of about 1.3:1 when administered under fasted conditions. 
     
     
         54 . A pharmaceutical composition comprising a mixture of EPA ethyl ester and DHA ethyl ester and at least one surface active agent; wherein said at least one surface active agent comprises from about 0.5% (wt/wt) to about 5% (wt/wt) of a block copolymer of polyethylene glycol and polypropylene glycol poloxamer having a chemical formula HO(C 2 H 4 O) 64 (C 3 H 6 O) 37 (C 2 H 6 O) 37 (C 2 H 4 O) 64 H (Poloxamer 237); wherein the surfactant HLB value is about 15 to about 17, wherein the composition is formulated in the form of a capsule, and wherein said composition is free of omega-3 free fatty acids; and wherein said composition when administered to a patient in need of treatment for hypertriglyceridemia, provide for a C max  of total EPA and DHA total lipid plasma concentration that is at least about 1.5-fold greater than the C max  of total EPA and DHA total lipid plasma concentration provided by an equivalent dosage of an Omega-3 fatty acid ethyl ester having an EPA:DHA ratio of about 1.3:1 or a combination of EPA and DHA in free acid form when administered under fed conditions.