Lymphatic release compositions of fatty acids and their use for lymphatic incorporation and treatment of systemic diseases - Patents.com

Abstract

Provided are compositions comprising one or more polyunsaturated fatty acids or derivatives thereof, a phospholipid source, and optionally one or more additional emulsifiers, and methods of using same to treat various diseases. In some embodiments, provided are lymphatic-releasing compositions of eicosapentaenoic acid ethyl ester (LR-EtEPA) and methods of using same to increase EPA uptake in tissues and treat various diseases, including cardiopulmonary diseases, renal diseases, neurological diseases, and cancer.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 63 / 303,365, filed January 26, 2022, U.S. Provisional Patent Application No. 63 / 303,383, filed January 26, 2022, U.S. Provisional Patent Application No. 63 / 304,042, filed January 28, 2022, U.S. Provisional Patent Application No. 63 / 334,065, filed April 2 ... and U.S. Provisional Patent Application No. 63 / 334,065, filed April 22, 2022. This application claims the benefit of U.S. Provisional Patent Application No. 63 / 334,071, U.S. Provisional Patent Application No. 63 / 340,292, filed May 10, 2022, U.S. Provisional Patent Application No. 63 / 340,304, filed May 10, 2022, U.S. Provisional Patent Application No. 63 / 342,509, filed May 16, 2022, and U.S. Provisional Patent Application No. 63 / 348,908, filed June 3, 2022. The contents of each of these provisional applications are incorporated by reference in their entirety. Summary of the Invention

[0002] Provided are compositions comprising one or more polyunsaturated fatty acids or derivatives thereof, a phospholipid source, and optionally one or more additional emulsifiers, and methods of using same to treat various diseases. For example, in some embodiments, provided are lymphatic-releasing compositions of eicosapentaenoic acid ethyl ester (LR-EtEPA) and methods of using same to increase EPA uptake in tissues and treat various diseases, including cardiopulmonary diseases, renal diseases, neurological diseases, and cancer.

[0003] In one aspect, provided is a composition comprising: (a) at least 15% by weight of one or more polyunsaturated fatty acids (PUFAs) or derivatives thereof; and (b) from 1% to 85% by weight of a phospholipid source. In some embodiments, the composition further comprises (c) from 1% to 20% by weight of one or more emulsifiers.

[0004] In some embodiments, the one or more PUFAs or derivatives thereof are selected from the group consisting of linoleic acid (LA), gamma-linoleic acid (GLA), dihomo-gamma-linoleic acid (DGLA), arachidonic acid (AA), adrenic acid (AdA), omega-6 docosapentaenoic acid (DPA6), alpha-lineoleic acid (ALA), stearidonic acid (SDA), omega-3 eicosatetraenoic acid (ETA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), LA derivatives, GLA derivatives, DGLA derivatives, AA derivatives, AdA derivatives, DPA6 derivatives, ALA derivatives, SDA derivatives, ETA derivatives, EPA derivatives, DPA derivatives, and DHA derivatives.

[0005] In some embodiments, the one or more PUFAs or derivatives thereof are selected from the group consisting of tetracosatetraenoic acid (TTE), tetracosapentaenoic acid (TPA), tetracosahexaenoic acid (THA), TTE derivatives, TPA derivatives, and THA derivatives.

[0006] In some embodiments, the PUFA derivative comprises an oxylipin.

[0007] The one or more PUFAs or derivatives thereof include EPA in its free acid form, or a pharma- ceutically acceptable ester, conjugate, or salt thereof. In some embodiments, the EPA is eicosapentaenoic acid ethyl ester (EtEPA).

[0008] In some embodiments, EPA or EtEPA constitutes at least 66%, 75%, 80%, 90%, 95%, or 96% by weight of all PUFAs present in the composition.

[0009] In some embodiments, the composition comprises 20% by weight or less of all PUFAs present in the composition, including one or more of the following: (a) one or more omega-6 PUFAs or derivatives thereof selected from the group consisting of LA, GLA, DGLA, AdA, DPA6, LA derivatives, GLA derivatives, DGLA derivatives, AdA derivatives, and DPA6 derivatives; (b) one or more omega-3 PUFAs or derivatives thereof selected from the group consisting of ALA, SDA, ETA, DPA, ALA derivatives, SDA derivatives, ETA derivatives, and DPA derivatives; and (c) one or more oxylipins.

[0010] In some embodiments, the composition comprises about 500 mg to about 1 g of EPA or EtEPA.

[0011] In some embodiments, the phospholipid source comprises a glycerophospholipid, a lysophospholipid, or a mixture thereof.

[0012] In some embodiments, the phospholipid source is lecithin, which in some embodiments comprises up to 40%, up to 60%, up to 80%, up to 90%, up to 95%, or up to 97% phosphatidylethanolamine by weight of the lecithin, and up to 10%, up to 5%, up to 4%, up to 3%, up to 2%, or up to 1% phosphatidylinositol by weight of the lecithin.

[0013] In some embodiments, the lecithin comprises (a) 19% to 27% by weight phosphatidylcholine, (b) 4% or less lysophosphatidylcholine, (c) 16% to 22% by weight phosphatidylethanolamine, (d) 11% to 18% by weight phosphatidylinositol, and (e) 1% to 9% by weight phosphatidic acid.

[0014] In some embodiments, the weight ratio of one or more PUFAs or derivatives thereof to the phospholipid source ranges from about 5:1 to about 1:5, from about 3.75:1 to about 1:5, or from about 1:1 to about 1:5, or the weight ratio of EPA or EtEPA to the phospholipid source ranges from about 1:1 to about 1:5.

[0015] In some embodiments, the one or more emulsifiers include polysorbate 80, polyoxyl-35, or both. In some embodiments, the one or more emulsifiers include one or more glycerol derivatives selected from the group consisting of triacylglycerol, diacylglycerol, and monoacylglycerol. In some embodiments, the glycerol derivative is castor oil. In some embodiments, the glycerol derivative is a PUFA-enriched, re-esterified triglyceride (rTG).

[0016] In another aspect, provided is a kit comprising: (a) a first composition comprising one or more polyunsaturated fatty acids (PUFAs) or derivatives thereof; and (b) a second composition comprising a phospholipid source. In some embodiments, the first and / or second composition further comprises one or more emulsifiers.

[0017] In another aspect, provided is a lymph-releasing eicosapentaenoic acid ethyl ester (LR-EtEPA) composition comprising: (a) at least 15% by weight EtEPA; and (b) from 1% to 85% by weight of a phospholipid source. In some embodiments, the LR-EtEPA composition further comprises (c) from 1% to 20% by weight of one or more emulsifiers.

[0018] In another aspect, provided is a method of treating or preventing a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition, kit, or LR-EtEPA composition according to various embodiments of the technology.

[0019] In another aspect, provided is a composition, kit, or LR-EtEPA composition according to various embodiments of the present technology for use in a method of treating or preventing a disease in a subject in need thereof, wherein a therapeutically effective amount of the composition, kit, or LR-EtEPA composition is administered to the subject.

[0020] In some embodiments, the disease is a cardiovascular disease. In some embodiments, the cardiovascular disease is selected from the group consisting of hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, coronary heart disease, stroke, atherosclerosis, arrhythmia, hypertension, myocardial infarction, vasculitis, cardiomyopathy (e.g., viral cardiomyopathy, including that associated with COVID-19), pericarditis, congestive heart failure, myocardial necrosis, vascular ischemia, vascular disease beyond the cardiopulmonary system, thrombotic disease, post-myocardial infarction myocardial remodeling, giant cell arteritis, polyarteritis nodosa, cryoglobulinemia, paroxysmal venular ischemia (Raynaud's disease), deep vein thrombosis, disseminated intravascular coagulation, and erectile dysfunction.

[0021] In some embodiments, the subject has a fasting baseline triglyceride level of about 135 mg / dL to about 500 mg / dL.

[0022] In some embodiments, the subject has one or more of a baseline non-high density lipoprotein cholesterol (HDL-C) value of about 200 mg / dL to about 300 mg / dL, a baseline total cholesterol (TC) value of about 250 mg / dL to about 300 mg / dL, a baseline very low density lipoprotein cholesterol (VLDL-C) value of about 140 mg / dL to about 200 mg / dL, a baseline HDL-C value of about 10 mg / dL to about 30 mg / dL, a baseline low density lipoprotein cholesterol (LDL-C) value of about 40 mg / dL to about 100 mg / dL, and a baseline high sensitivity C-reactive protein (hsCRP) level of about 2 mg / dL or less.

[0023] In some embodiments, the subject is on stable statin therapy. In some embodiments, the stable statin therapy comprises a statin and, optionally, ezetimibe. In some embodiments, the statin is selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0024] In some embodiments, the disease is a pulmonary disease. In some embodiments, the pulmonary disease is selected from the group consisting of community-acquired pneumonia, COVID-19 pneumonia, systemic inflammatory response syndrome (SIRS), sepsis, SIRS, acute respiratory distress syndrome (ARDS), pulmonary embolism, diffuse interstitial pneumonia, radiation pneumonitis, pleuritis, acute eosinophilic pneumonia, chronic eosinophilic pneumonia, Löffler's syndrome, sarcoidosis, interstitial lung disease, chronic obstructive pulmonary disease (COPD), reactive airway disease, asthma, bronchiectasis, bronchitis, cystic fibrosis, bronchial carcinoid, pulmonary arterial hypertension, pulmonary vasculitis, microscopic polyangiitis, granulomatosis with polyangiitis (Wegener's disease), eosinophilic granulomatosis with polyangiitis (Churg-Strauss), nasopharyngitis, Goodpasture's syndrome, cryoglobulinemia, systemic lupus erythematosus (SLE), systemic sclerosis, and antiphospholipid syndrome.

[0025] In some embodiments, the disease is a neurological disease. In some embodiments, the neurological disease is selected from the group consisting of Huntington's disease, sleep disorders, dementia, psychosis, anxiety, treatment-resistant depression, neuropathic pain, schizophrenia, bipolar disorder, dyslexia, dyspraxia, attention deficit hyperactivity disorder (ADHD), epilepsy, autism, Alzheimer's disease, Parkinson's disease, senile dementia, multiple sclerosis, diabetes-induced neuropathy, macular degeneration, retinopathy of prematurity, amyotrophic lateral sclerosis (ALS), retinitis pigmentosa, cerebral palsy, muscular dystrophy, neurological cancer, cystic fibrosis, and neural tube defects.

[0026] In some embodiments, the disease is cancer. In some embodiments, the cancer is a hematological malignancy selected from the group consisting of monoclonal B-cell lymphocytosis, multiple myeloma, myeloid neoplasms, myelodysplastic syndromes (MDS), myeloproliferative / myelodysplastic syndromes, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute phase chronic myeloid leukemia (bcCML), B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoma, and B-cell lymphoma. In some embodiments, the cancer is a solid tumor selected from the group consisting of lung cancer, breast cancer, liver cancer, stomach cancer, colon cancer, rectal cancer, colorectal cancer, kidney cancer, gastric cancer, gallbladder cancer, small intestine cancer, esophageal cancer, melanoma, bone cancer, pancreatic cancer, skin cancer, uterine cancer, ovarian cancer, testicular cancer, thyroid cancer, adrenal cancer, bladder cancer, and glioma.

[0027] In some embodiments, the disease is post-infectious glomerulonephritis, IgA nephropathy (Buerger's disease), Henoch-Schonlein purpura, systemic IgA vasculitis, microscopic polyangiitis, granulomatosis with polyangiitis (Wegener's disease), eosinophilic granulomatosis with polyangiitis (Churg-Strauss), polyarteritis, idiopathic crescentic glomerulonephritis, anti-GBM glomerulonephritis, Goodpasture's syndrome, cryoglobulin-associated glomerulonephritis, idiopathic membranoproliferative glomerulonephritis (MPG) N), hepatitis C-associated glomerulonephritis, systemic lupus erythematosus (SLE)-associated glomerulonephritis, minimal change disease (nill disease, lipoid nephropathy), membranous nephropathy, focal segmental glomerulosclerosis, amyloidosis, diabetic nephropathy, HIV-associated nephropathy, membranoproliferative glomerulonephropathy, edema relief, chronic renal failure relief, and / or mortality / morbidity relief in severe chronic kidney disease (CKD) / end stage renal disease (ESRD).

[0028] In some embodiments, the disease is a disease associated with the pancreas selected from the group consisting of hyperglycemia, prediabetes, diabetes (type 1 and / or type 2), and pancreatitis.

[0029] In some embodiments, the disease is a liver-associated disease selected from the group consisting of chronic viral hepatitis, autoimmune hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease, hemochromatosis, Wilson's disease, primary biliary cholangitis, primary sclerosing cholangitis, and cholelithiasis.

[0030] In some embodiments, the disease is a gut-associated disease selected from the group consisting of gastroesophageal reflux disease (GERD), gastritis, peptic ulcer disease, obesity, cachexia, intestinal angina, Crohn's disease, ulcerative colitis, antibiotic-associated colitis, irritable bowel syndrome, colon cancer, colonic polyposis, and carcinoid.

[0031] In some embodiments, the disease is a disease associated with blood cells selected from the group consisting of iron deficiency anemia, anemia of chronic disease, hemolytic anemia, thalassemia, polycythemia vera, sickle cell anemia, sickle cell pain, immune thrombocytopenia, leukemia, non-Hodgkin's lymphoma, and Hodgkin's lymphoma.

[0032] In some embodiments, the disease is a disease associated with oxidative stress, glutathione (GSH) depletion, Nrf2 activation, and / or heme-oxygenase activation. In some embodiments, the disease is anemia, sickle cell disease, and / or glomerulonephritis. In some embodiments, the method further comprises administering to the subject an N-acetylcysteine ​​(NAC)-related agent. In some embodiments, the NAC-related agent is selected from the group consisting of cystine, methionine, N-acetylcysteine, and L-2-oxothiazolidine-4-carboxylate.

[0033] In some embodiments, the disease is oxidative stress, endothelial dysfunction, narrowing and / or thickening of arteries, and / or inflammation induced by inhalation of particulate matter, hi some embodiments, the disease is oxidative stress, endothelial dysfunction, narrowing and / or thickening of arteries, and / or inflammation induced by long-term and / or short-term exposure to air pollution.

[0034] In some embodiments, the composition, kit, or LR-EtEPA composition is administered to a subject to provide a daily dose of about 1 g to about 20 g of EtEPA, for example, about 4 g of EtEPA.

[0035] In some embodiments, the composition, kit, or LR-EtEPA composition is administered to a subject once or twice daily, with or without food. [Brief description of the drawings]

[0036] [Figure 1A] FIG. 1 shows a comparison of equal doses of lymph-released eicosapentaenoic acid ethyl ester (LR-EtEPA) versus regular EtEPA for tissue EPA enrichment in lymph, heart, lung, brain, and pulmonary alveolar macrophages (AVM). For each tissue, the fold equivalence of LR-EtEPA compared to regular EtEPA is shown for EPA levels and EPA:AA ratios. [Figure 1B] Co-administration of lymphatic releasing compounds (e.g., lecithin (LC) and / or emulsifiers) with EtEPA demonstrates the preferred routing of EPA beyond the portal vein and through the lymphatic system, thereby avoiding visceral EPA losses (e.g., visceral adipose EPA sequestration and hepatic first-pass EPA losses) and increasing tissue EPA levels, for example, in the whole body and in the kidney, jejunum, and pancreas. Percentage increases in EPA levels and EPA:AA ratios with LR-EtEPA over regular EtEPA are shown for each of the exemplary tissues.

[0037] [Diagram 2] LR-EtEPA is superior to plain EtEPA in enriching lymph with EPA after a single dose, and such enrichment is further improved when the relative ratio of lymph-releasing compound to EtEPA (LC:EtEPA) is increased from 1:4 to 1:1.IPE, icosapent ethyl, also referred to as EtEPA;FAME, fatty acid methyl ester, which is an index of the total amount of fatty acid measured (in this case, EPA). [Diagram 3]LR-EtEPA is shown to be superior to EtEPA in increasing tissue EPA levels in the lung and heart after only 7 days (FIG. 3). [Figure 4] LR-EtEPA is shown to be superior to EtEPA in improving the EPA:AA ratio in lung immune cells after only 7 days (FIG. 4). [Diagram 5] LR-EtEPA vs. EtEPA for various phospholipid-EPA (PL-EPA) fraction amounts (FrAmt, 100th) in tissues at day 7. [Figure 6] The ratio of LR-EtEPA:EtEPA versus pool size is shown, comparing various cellular PL-EPA. [Figure 7] A vector plot of the LR-EtEPA:EtEPA ratio comparing various PL-EPA in the lungs at day 7 (FIG. 7) is shown. [Figure 8] A vector plot of LR-EtEPA:EtEPA ratios comparing various PL-EPA in AVMs at day 7 (FIG. 8) is shown. [Figure 9] A vector plot of the LR-EtEPA:EtEPA ratio comparing various PL-EPA in the heart at day 7 (FIG. 9) is shown. [Figure 10] A vector plot of the LR-EtEPA:EtEPA ratio comparing various PL-EPA in blood matrices at day 7 (FIG. 10) is shown. [Figure 11] A vector plot of the LR-EtEPA:EtEPA ratios comparing various PL-EPA in blood cells at day 7 (FIG. 11) is shown. [Figure 12] A vector plot of the LR-EtEPA:EtEPA ratio comparing various PL-EPA in the liver at day 7 (FIG. 12) is shown. [Figure 13] LR-EtEPA vs. EtEPA at various PL-EPA / ARA ratio fraction amounts (FrAmt, 100th) in tissues at day 7 are shown. [Figure 14]Shown is the LR-EtEPA:EtEPA ratio versus pool size comparing different cellular PL-EPA / ARA ratios at day 7. [Figure 15] A vector plot of the LR-EtEPA:EtEPA ratio comparing various PL-EPA / ARA ratios in the lungs at day 7 (FIG. 15) is shown. [Figure 16] A vector plot of LR-EtEPA:EtEPA ratios comparing various PL-EPA / ARA ratios in alveolar macrophages on day 7 (FIG. 16) is shown. [Figure 17] A vector plot of LR-EtEPA:EtEPA ratios comparing various PL-EPA / ARA ratios in the heart at day 7 (FIG. 17) is shown. [Figure 18] A vector plot of LR-EtEPA:EtEPA ratios comparing various PL-EPA / ARA ratios in blood matrices on day 7 (FIG. 18) is shown. [Figure 19] A vector plot of LR-EtEPA:EtEPA ratios comparing various PL-EPA / ARA ratios in blood cells on day 7 (FIG. 19) is shown. [Figure 20] A vector plot of the LR-EtEPA:EtEPA ratios comparing various PL-EPA / ARA ratios in the liver at day 7 (FIG. 20) is shown. [Figure 21] We show that LR-EtEPA (1×(IPE+LC4:1)) is superior to plain EtEPA (IPE) in improving the EPA:ARA ratio in lung immune cells after 7 and 21 days.OA, oleic acid; IPE, icosapent ethyl, also known as EtEPA. [Figure 22] Summary plots showing that equal doses of LR-EtEPA are superior to plain EtEPA in increasing EPA in lymph, lung, pulmonary AVM, heart, and brain in Long-Evans rats after multiple dosing for 7 and / or 21 days.

[0038] [Figure 23A]We present potential mechanisms of different cell types implicated in disease states including atherosclerosis, pulmonary disease, renal disease, and injury, and how EPA (and the oxylipins from which it is derived) may alleviate these disease states. [Figure 23B] We present potential mechanisms of different cell types implicated in disease states including atherosclerosis, pulmonary disease, renal disease, and injury, and how EPA (and the oxylipins from which it is derived) may alleviate these disease states.

[0039] [Figure 24A] Dose-response plots of EPA / AA (FIGS. 24A-B), oxygenation promoter (OXP, containing EPA, GLA, and DHA) / AA (FIGS. 24C-D), and medicinal oxylipin precursor (MOP, containing DGLA, EPA, DPA, and DHA) / AA (FIG. 24E) ratios in lung tissue from rats treated with five treatment arms, presented from left to right: (1) oleic acid (OA), (2) EPA+GLA+DHA, regular EtEPA (EtEPA or IPE), (3) LR-EtEPA (EtEPA+lecithin (LC)) with equimolar EtEPA to regular EtEPA (1×LR-EtEPA), and (5) LR-EtEPA at 1.5 times the molar dose of regular EtEPA (1.5×LR-EtEPA). Figures 24A and 24C are "violin" plots, while Figures 24B, 24D, and 24E show stacked dose-response curves in untransformed (upper panels) and semi-log (lower panels) plots. ME, methyl ester; FAME, fatty acid methyl ester measuring the total amount of fatty acid of interest; intercept, interception; Rel. potency, relative potency; sigma represents the standard error of the residuals. [Figure 24B]Dose-response plots of EPA / AA (FIGS. 24A-B), oxygenation promoter (OXP, containing EPA, GLA, and DHA) / AA (FIGS. 24C-D), and medicinal oxylipin precursor (MOP, containing DGLA, EPA, DPA, and DHA) / AA (FIG. 24E) ratios in lung tissue from rats treated with five treatment arms, presented from left to right: (1) oleic acid (OA), (2) EPA+GLA+DHA, regular EtEPA (EtEPA or IPE), (3) LR-EtEPA (EtEPA+lecithin (LC)) with equimolar EtEPA to regular EtEPA (1×LR-EtEPA), and (5) LR-EtEPA at 1.5 times the molar dose of regular EtEPA (1.5×LR-EtEPA). Figures 24A and 24C are "violin" plots, while Figures 24B, 24D, and 24E show stacked dose-response curves in untransformed (upper panels) and semi-log (lower panels) plots. ME, methyl ester; FAME, fatty acid methyl ester measuring the total amount of fatty acid of interest; intercept, interception; Rel. potency, relative potency; sigma represents the standard error of the residuals. [Figure 24C]Dose-response plots of EPA / AA (FIGS. 24A-B), oxygenation promoter (OXP, containing EPA, GLA, and DHA) / AA (FIGS. 24C-D), and medicinal oxylipin precursor (MOP, containing DGLA, EPA, DPA, and DHA) / AA (FIG. 24E) ratios in lung tissue from rats treated with five treatment arms, presented from left to right: (1) oleic acid (OA), (2) EPA+GLA+DHA, regular EtEPA (EtEPA or IPE), (3) LR-EtEPA (EtEPA+lecithin (LC)) with equimolar EtEPA to regular EtEPA (1×LR-EtEPA), and (5) LR-EtEPA at 1.5 times the molar dose of regular EtEPA (1.5×LR-EtEPA). Figures 24A and 24C are "violin" plots, while Figures 24B, 24D, and 24E show stacked dose-response curves in untransformed (upper panels) and semi-log (lower panels) plots. ME, methyl ester; FAME, fatty acid methyl ester measuring the total amount of fatty acid of interest; intercept, interception; Rel. potency, relative potency; sigma represents the standard error of the residuals. [Figure 24D]Dose-response plots of EPA / AA (FIGS. 24A-B), oxygenation promoter (OXP, containing EPA, GLA, and DHA) / AA (FIGS. 24C-D), and medicinal oxylipin precursor (MOP, containing DGLA, EPA, DPA, and DHA) / AA (FIG. 24E) ratios in lung tissue from rats treated with five treatment arms, presented from left to right: (1) oleic acid (OA), (2) EPA+GLA+DHA, regular EtEPA (EtEPA or IPE), (3) LR-EtEPA (EtEPA+lecithin (LC)) with equimolar EtEPA to regular EtEPA (1×LR-EtEPA), and (5) LR-EtEPA at 1.5 times the molar dose of regular EtEPA (1.5×LR-EtEPA). Figures 24A and 24C are "violin" plots, while Figures 24B, 24D, and 24E show stacked dose-response curves in untransformed (upper panels) and semi-log (lower panels) plots. ME, methyl ester; FAME, fatty acid methyl ester measuring the total amount of fatty acid of interest; intercept, interception; Rel. potency, relative potency; sigma represents the standard error of the residuals. [Figure 24E]Dose-response plots of EPA / AA (FIGS. 24A-B), oxygenation promoter (OXP, containing EPA, GLA, and DHA) / AA (FIGS. 24C-D), and medicinal oxylipin precursor (MOP, containing DGLA, EPA, DPA, and DHA) / AA (FIG. 24E) ratios in lung tissue from rats treated with five treatment arms, presented from left to right: (1) oleic acid (OA), (2) EPA+GLA+DHA, regular EtEPA (EtEPA or IPE), (3) LR-EtEPA (EtEPA+lecithin (LC)) with equimolar EtEPA to regular EtEPA (1×LR-EtEPA), and (5) LR-EtEPA at 1.5 times the molar dose of regular EtEPA (1.5×LR-EtEPA). Figures 24A and 24C are "violin" plots, while Figures 24B, 24D, and 24E show stacked dose-response curves in untransformed (upper panels) and semi-log (lower panels) plots. ME, methyl ester; FAME, fatty acid methyl ester measuring the total amount of fatty acid of interest; intercept, interception; Rel. potency, relative potency; sigma represents the standard error of the residuals.

[0040] [Figure 25A] Similar to Figures 24A-E, Figures 25A-D show dose-response plots of EPA / AA (Figures 25A-B), OXP / AA (Figure 25C), and MOP / AA (Figure 25D) ratios in AVMs of treated rats, presented in order from left to right for the five treatment arms: (1) OA, (2) EPA+GLA+DHA, (3) EtEPA, (4) 1xLR-EtEPA, and (5) 1.5xLR-EtEPA. [Figure 25B] Similar to Figures 24A-E, Figures 25A-D show dose-response plots of EPA / AA (Figures 25A-B), OXP / AA (Figure 25C), and MOP / AA (Figure 25D) ratios in AVMs of treated rats, presented in order from left to right for the five treatment arms: (1) OA, (2) EPA+GLA+DHA, (3) EtEPA, (4) 1xLR-EtEPA, and (5) 1.5xLR-EtEPA. [Figure 25C]Similar to Figures 24A-E, Figures 25A-D show dose-response plots of EPA / AA (Figures 25A-B), OXP / AA (Figure 25C), and MOP / AA (Figure 25D) ratios in AVMs of treated rats, presented in order from left to right for the five treatment arms: (1) OA, (2) EPA+GLA+DHA, (3) EtEPA, (4) 1xLR-EtEPA, and (5) 1.5xLR-EtEPA. [Figure 25D] Similar to Figures 24A-E, Figures 25A-D show dose-response plots of EPA / AA (Figures 25A-B), OXP / AA (Figure 25C), and MOP / AA (Figure 25D) ratios in AVMs of treated rats, presented in order from left to right for the five treatment arms: (1) OA, (2) EPA+GLA+DHA, (3) EtEPA, (4) 1xLR-EtEPA, and (5) 1.5xLR-EtEPA.

[0041] [Figure 26A] Dose-response plots of EPA / AA (FIG. 26A-B), OXP / AA (FIG. 26C), and MOP / AA (FIG. 26D) ratios in cardiac tissue from treated rats are shown, with the five treatment arms presented in order from left to right: (1) OA, (2) EPA+GLA+DHA, (3) EtEPA, (4) 1×LR-EtEPA, and (5) 1.5×LR-EtEPA. [Figure 26B] Dose-response plots of EPA / AA (FIG. 26A-B), OXP / AA (FIG. 26C), and MOP / AA (FIG. 26D) ratios in cardiac tissue from treated rats are shown, with the five treatment arms presented in order from left to right: (1) OA, (2) EPA+GLA+DHA, (3) EtEPA, (4) 1×LR-EtEPA, and (5) 1.5×LR-EtEPA. [Figure 26C] Dose-response plots of EPA / AA (FIG. 26A-B), OXP / AA (FIG. 26C), and MOP / AA (FIG. 26D) ratios in cardiac tissue from treated rats are shown, with the five treatment arms presented in order from left to right: (1) OA, (2) EPA+GLA+DHA, (3) EtEPA, (4) 1×LR-EtEPA, and (5) 1.5×LR-EtEPA. [Figure 26D] Dose-response plots of EPA / AA (FIG. 26A-B), OXP / AA (FIG. 26C), and MOP / AA (FIG. 26D) ratios in cardiac tissue from treated rats are shown, with the five treatment arms presented in order from left to right: (1) OA, (2) EPA+GLA+DHA, (3) EtEPA, (4) 1×LR-EtEPA, and (5) 1.5×LR-EtEPA.

[0042] [Figure 27A] Dose-response plots of EPA / AA (FIG. 27A-B), OXP / AA (FIG. 27C), and MOP / AA (FIG. 27D) ratios in kidney tissue from treated rats are shown, with the five treatment arms presented in order from left to right: (1) OA, (2) EPA+GLA+DHA, (3) EtEPA, (4) 1×LR-EtEPA, and (5) 1.5×LR-EtEPA. [Figure 27B] Dose-response plots of EPA / AA (FIG. 27A-B), OXP / AA (FIG. 27C), and MOP / AA (FIG. 27D) ratios in kidney tissue from treated rats are shown, with the five treatment arms presented in order from left to right: (1) OA, (2) EPA+GLA+DHA, (3) EtEPA, (4) 1×LR-EtEPA, and (5) 1.5×LR-EtEPA. [Figure 27C] Dose-response plots of EPA / AA (FIG. 27A-B), OXP / AA (FIG. 27C), and MOP / AA (FIG. 27D) ratios in kidney tissue from treated rats are shown, with the five treatment arms presented in order from left to right: (1) OA, (2) EPA+GLA+DHA, (3) EtEPA, (4) 1×LR-EtEPA, and (5) 1.5×LR-EtEPA. [Figure 27D] Dose-response plots of EPA / AA (FIG. 27A-B), OXP / AA (FIG. 27C), and MOP / AA (FIG. 27D) ratios in kidney tissue from treated rats are shown, with the five treatment arms presented in order from left to right: (1) OA, (2) EPA+GLA+DHA, (3) EtEPA, (4) 1×LR-EtEPA, and (5) 1.5×LR-EtEPA.

[0043] [Figure 28A] Dose-response plots of EPA / AA ratio in brain tissue from treated rats are shown, with the five treatment arms presented from left to right: (1) OA, (2) EPA+GLA+DHA, (3) EtEPA, (4) 1×LR-EtEPA, and (5) 1.5×LR-EtEPA. [Figure 28B] Dose-response plots of EPA / AA ratio in brain tissue from treated rats are shown, with the five treatment arms presented from left to right: (1) OA, (2) EPA+GLA+DHA, (3) EtEPA, (4) 1×LR-EtEPA, and (5) 1.5×LR-EtEPA.

[0044] [Figure 29A] Dose-response plots of EPA / AA (FIG. 29A-B), OXP / AA (FIG. 29C), and MOP / AA (FIG. 29D) ratios in pancreatic tissue from treated rats are shown, with the five treatment arms presented in order from left to right: (1) OA, (2) EPA+GLA+DHA, (3) EtEPA, (4) 1×LR-EtEPA, and (5) 1.5×LR-EtEPA. [Figure 29B] Dose-response plots of EPA / AA (FIG. 29A-B), OXP / AA (FIG. 29C), and MOP / AA (FIG. 29D) ratios in pancreatic tissue from treated rats are shown, with the five treatment arms presented in order from left to right: (1) OA, (2) EPA+GLA+DHA, (3) EtEPA, (4) 1×LR-EtEPA, and (5) 1.5×LR-EtEPA. [Figure 29C] Dose-response plots of EPA / AA (FIG. 29A-B), OXP / AA (FIG. 29C), and MOP / AA (FIG. 29D) ratios in pancreatic tissue from treated rats are shown, with the five treatment arms presented in order from left to right: (1) OA, (2) EPA+GLA+DHA, (3) EtEPA, (4) 1×LR-EtEPA, and (5) 1.5×LR-EtEPA. [Figure 29D]Dose-response plots of EPA / AA (FIG. 29A-B), OXP / AA (FIG. 29C), and MOP / AA (FIG. 29D) ratios in pancreatic tissue from treated rats are shown, with the five treatment arms presented in order from left to right: (1) OA, (2) EPA+GLA+DHA, (3) EtEPA, (4) 1×LR-EtEPA, and (5) 1.5×LR-EtEPA.

[0045] [Figure 30A] Dose-response plots of EPA / AA (FIG. 30A-B), OXP / AA (FIG. 30C), and MOP / AA (FIG. 30D) ratios in jejunal tissue from treated rats are shown, with the five treatment arms presented in order from left to right: (1) OA, (2) EPA+GLA+DHA, (3) EtEPA, (4) 1×LR-EtEPA, and (5) 1.5×LR-EtEPA. [Figure 30B] Dose-response plots of EPA / AA (FIG. 30A-B), OXP / AA (FIG. 30C), and MOP / AA (FIG. 30D) ratios in jejunal tissue from treated rats are shown, with the five treatment arms presented in order from left to right: (1) OA, (2) EPA+GLA+DHA, (3) EtEPA, (4) 1×LR-EtEPA, and (5) 1.5×LR-EtEPA. [Figure 30C] Dose-response plots of EPA / AA (FIG. 30A-B), OXP / AA (FIG. 30C), and MOP / AA (FIG. 30D) ratios in jejunal tissue from treated rats are shown, with the five treatment arms presented in order from left to right: (1) OA, (2) EPA+GLA+DHA, (3) EtEPA, (4) 1×LR-EtEPA, and (5) 1.5×LR-EtEPA. [Figure 30D] Dose-response plots of EPA / AA (FIG. 30A-B), OXP / AA (FIG. 30C), and MOP / AA (FIG. 30D) ratios in jejunal tissue from treated rats are shown, with the five treatment arms presented in order from left to right: (1) OA, (2) EPA+GLA+DHA, (3) EtEPA, (4) 1×LR-EtEPA, and (5) 1.5×LR-EtEPA.

[0046] [Figure 31A] Figure 31A shows how EtEPA affects the functional index of key enzymes that convert LC-PUFAs to other LC-PUFAs, a process that is rate-limited by desaturase enzymes but also facilitated by elongase enzymes. Figure 31B shows the functional impact of various treatments on the Δ5-desaturation of the ω-6 LC-PUFA DGLA (20:3ω-6), which results in ARA (20:4ω-6). The product / precursor ratio ARA:DGLA is called the Δ5-desaturation index at ω-6 (Δ5D-Iω-6). The x-axis is the dose proportional to EtEPA dose, ranging from 0 to 4.7 mmol EPA / kg / d. With the exception of 3.1 mmol EPA / kg / d, where regular EtEPA was slightly offset to the left, and LR-EtEPA was slightly offset to the right to avoid overprinting. As shown, EtEPA substantially suppresses Δ5D-Iω-6 compared to EPA+GLA+DHA and oleic acid (OA) controls. [Figure 31B] Figure 31B shows how EtEPA affects the functional index of key enzymes that convert LC-PUFAs to other LC-PUFAs, a process that is rate-limited by desaturase enzymes but also facilitated by elongase enzymes. Figure 31B shows the contrasting progression of functional effects of various treatments on the Δ8-desaturation of ω-6 LC-PUFA eicosadienoic acid (EDA 20:2ω-6), which results in DGLA (20:3ω-6). The product / precursor ratio DGLA:EDA is referred to as the Δ8-desaturation index at ω-6 (Δ8D-Iω-6). As shown, EtEPA induces Δ8D-Iω-6 substantially compared to EPA+GLA+DHA and oleic acid (OA) controls. [Figure 31C]Figure 31C shows how EtEPA affects the function index of key enzymes that convert LC-PUFAs to other LC-PUFAs, a process that is rate-limited by desaturase enzymes but also promoted by elongase enzymes. Figure 31C is a schematic diagram summarizing data on the mechanism by which EtEPA (IPE) changes DGLA kinetics and thus increases DGLA pools in contrast to the important long-chain PUFA composition Oxepa®, i.e., GLA, which Oxepa® contains as DGLA precursor.Specifically, Oxepa® is composed of three LC-PUFAs: (1) EPA, (2) GLA, and (3) DHA, and in experiments, the combination of these three LC-PUFAs is referred to as EPA+GLA+DHA. After administration of EtEPA to Long-Evans rats at equimolar doses as total LC-PUFA in [EPA+GLA+DHA], EtEPA altered DGLA kinetics in a "back and forth" manner, meaning that (1) EtEPA promoted DGLA production by improving the conversion of eicosadienoic acid (EDA) to DGLA, as assessed by the Δ8-desaturase index ω-6 (product / precursor ratio = DGLA / EDA), and (2) EtEPA inhibited the catabolism of DGLA by suppressing the conversion of DGLA to arachidonic acid (ARA), as assessed by the Δ5-desaturase index ω-6 (product / precursor ratio = ARA / DGLA). In contrast, the data suggest that the GLA in the EPA+GLA+DHA characteristic of Oxepa® is reduced to provide a substrate for the production of DGLA from GLA, rather than substantially altering the Δ8 desaturase or Δ5-desaturase enzymes, limiting the potential for altering DGLA kinetics. IPE, icosapent ethyl, also known as EtEPA. [Figure 31D]Figure 31D shows how EtEPA affects the functional index of key enzymes that convert LC-PUFAs to other LC-PUFAs, a process that is rate-limited by desaturase enzymes but also facilitated by elongase enzymes. Figure 31D shows the downward progression of the functional effects of various treatments on the Δ5 elongation of the ω-6 LC-PUFA eicosapentaenoic acid (EPA, 20:5ω-6), resulting in the longer omega-3 LC-PUFA DPA (22:5ω-3). The product / precursor ratio DPA:EPA is referred to as the Δ5 elongation index at ω-3 (Δ5D-Iω-3). As shown, EtEPA substantially suppresses Δ5D-Iω-3 compared to EPA+GLA+DHA and oleic acid (OA) controls.

[0047] [Figure 32A]The effect of various formulations on oxylipins present in lung tissue is shown. The oxylipins are listed in the graph title, and the arrow (←) indicates the parent LC-PUFA that was oxygenated to obtain the oxylipin. Notably, EtEPA not only elevated several EPA-derived oxylipins deemed to have therapeutic potential, but also elevated DGLA-derived oxylipins and linoleic acid-derived oxylipins (LA, 18:2ω-6). Lung oxylipins from rats were assayed with or without hydrolysis, thus obtaining total oxylipins (i.e., free / non-esterified plus bound / esterified oxylipins) and free / non-esterified oxylipins. Bound / esterified oxylipins were determined by subtracting free / non-esterified oxylipins from total oxylipins. In many cases, esterified oxylipins were the predominant form, sometimes exceeding free / non-esterified oxylipins by 10-fold. The oxylipin studies confirm that the large increases in tissue EPA achieved from LR-EtEPA vs. regular EtEPA vs. EPA+GLA+DHA are synonymous with substantial increases in EPA-derived oxylipins of therapeutic potential. This reaffirms that pharmacokinetic effects are synonymous with pharmacodynamic effects. Moreover, EPA also exerts functional effects on oxylipins derived from other LC-PUFAs such as DGLA and LA as shown herein. [Figure 32B]The effect of various formulations on oxylipins present in lung tissue is shown. The oxylipins are listed in the graph title, and the arrow (←) indicates the parent LC-PUFA that was oxygenated to obtain the oxylipin. Notably, EtEPA not only elevated several EPA-derived oxylipins deemed to have therapeutic potential, but also elevated DGLA-derived oxylipins and linoleic acid-derived oxylipins (LA, 18:2ω-6). Lung oxylipins from rats were assayed with or without hydrolysis, thus obtaining total oxylipins (i.e., free / non-esterified plus bound / esterified oxylipins) and free / non-esterified oxylipins. Bound / esterified oxylipins were determined by subtracting free / non-esterified oxylipins from total oxylipins. In many cases, esterified oxylipins were the predominant form, sometimes exceeding free / non-esterified oxylipins by 10-fold. The oxylipin studies confirm that the large increases in tissue EPA achieved from LR-EtEPA vs. regular EtEPA vs. EPA+GLA+DHA are synonymous with substantial increases in EPA-derived oxylipins of therapeutic potential. This reaffirms that pharmacokinetic effects are synonymous with pharmacodynamic effects. Moreover, EPA also exerts functional effects on oxylipins derived from other LC-PUFAs such as DGLA and LA as shown herein. [Figure 32C]The effect of various formulations on oxylipins present in lung tissue is shown. The oxylipins are listed in the graph title, and the arrow (←) indicates the parent LC-PUFA that was oxygenated to obtain the oxylipin. Notably, EtEPA not only elevated several EPA-derived oxylipins deemed to have therapeutic potential, but also elevated DGLA-derived oxylipins and linoleic acid-derived oxylipins (LA, 18:2ω-6). Lung oxylipins from rats were assayed with or without hydrolysis, thus obtaining total oxylipins (i.e., free / non-esterified plus bound / esterified oxylipins) and free / non-esterified oxylipins. Bound / esterified oxylipins were determined by subtracting free / non-esterified oxylipins from total oxylipins. In many cases, esterified oxylipins were the predominant form, sometimes exceeding free / non-esterified oxylipins by 10-fold. The oxylipin studies confirm that the large increases in tissue EPA achieved from LR-EtEPA vs. regular EtEPA vs. EPA+GLA+DHA are synonymous with substantial increases in EPA-derived oxylipins of therapeutic potential. This reaffirms that pharmacokinetic effects are synonymous with pharmacodynamic effects. Moreover, EPA also exerts functional effects on oxylipins derived from other LC-PUFAs such as DGLA and LA as shown herein. [Fig. 32D]The effect of various formulations on oxylipins present in lung tissue is shown. The oxylipins are listed in the graph title, and the arrow (←) indicates the parent LC-PUFA that was oxygenated to obtain the oxylipin. Notably, EtEPA not only elevated several EPA-derived oxylipins deemed to have therapeutic potential, but also elevated DGLA-derived oxylipins and linoleic acid-derived oxylipins (LA, 18:2ω-6). Lung oxylipins from rats were assayed with or without hydrolysis, thus obtaining total oxylipins (i.e., free / non-esterified plus bound / esterified oxylipins) and free / non-esterified oxylipins. Bound / esterified oxylipins were determined by subtracting free / non-esterified oxylipins from total oxylipins. In many cases, esterified oxylipins were the predominant form, sometimes exceeding free / non-esterified oxylipins by 10-fold. The oxylipin studies confirm that the large increases in tissue EPA achieved from LR-EtEPA vs. regular EtEPA vs. EPA+GLA+DHA are synonymous with substantial increases in EPA-derived oxylipins of therapeutic potential. This reaffirms that pharmacokinetic effects are synonymous with pharmacodynamic effects. Moreover, EPA also exerts functional effects on oxylipins derived from other LC-PUFAs such as DGLA and LA as shown herein. [Figure 32E]The effect of various formulations on oxylipins present in lung tissue is shown. The oxylipins are listed in the graph title, and the arrow (←) indicates the parent LC-PUFA that was oxygenated to obtain the oxylipin. Notably, EtEPA not only elevated several EPA-derived oxylipins deemed to have therapeutic potential, but also elevated DGLA-derived oxylipins and linoleic acid-derived oxylipins (LA, 18:2ω-6). Lung oxylipins from rats were assayed with or without hydrolysis, thus obtaining total oxylipins (i.e., free / non-esterified plus bound / esterified oxylipins) and free / non-esterified oxylipins. Bound / esterified oxylipins were determined by subtracting free / non-esterified oxylipins from total oxylipins. In many cases, esterified oxylipins were the predominant form, sometimes exceeding free / non-esterified oxylipins by 10-fold. The oxylipin studies confirm that the large increases in tissue EPA achieved from LR-EtEPA vs. regular EtEPA vs. EPA+GLA+DHA are synonymous with substantial increases in EPA-derived oxylipins of therapeutic potential. This reaffirms that pharmacokinetic effects are synonymous with pharmacodynamic effects. Moreover, EPA also exerts functional effects on oxylipins derived from other LC-PUFAs such as DGLA and LA as shown herein. [Fig. 32F]The effect of various formulations on oxylipins present in lung tissue is shown. The oxylipins are listed in the graph title, and the arrow (←) indicates the parent LC-PUFA that was oxygenated to obtain the oxylipin. Notably, EtEPA not only elevated several EPA-derived oxylipins deemed to have therapeutic potential, but also elevated DGLA-derived oxylipins and linoleic acid-derived oxylipins (LA, 18:2ω-6). Lung oxylipins from rats were assayed with or without hydrolysis, thus obtaining total oxylipins (i.e., free / non-esterified plus bound / esterified oxylipins) and free / non-esterified oxylipins. Bound / esterified oxylipins were determined by subtracting free / non-esterified oxylipins from total oxylipins. In many cases, esterified oxylipins were the predominant form, sometimes exceeding free / non-esterified oxylipins by 10-fold. The oxylipin studies confirm that the large increases in tissue EPA achieved from LR-EtEPA vs. regular EtEPA vs. EPA+GLA+DHA are synonymous with substantial increases in EPA-derived oxylipins of therapeutic potential. This reaffirms that pharmacokinetic effects are synonymous with pharmacodynamic effects. Moreover, EPA also exerts functional effects on oxylipins derived from other LC-PUFAs such as DGLA and LA as shown herein. [Fig. 32G]The effect of various formulations on oxylipins present in lung tissue is shown. The oxylipins are listed in the graph title, and the arrow (←) indicates the parent LC-PUFA that was oxygenated to obtain the oxylipin. Notably, EtEPA not only elevated several EPA-derived oxylipins deemed to have therapeutic potential, but also elevated DGLA-derived oxylipins and linoleic acid-derived oxylipins (LA, 18:2ω-6). Lung oxylipins from rats were assayed with or without hydrolysis, thus obtaining total oxylipins (i.e., free / non-esterified plus bound / esterified oxylipins) and free / non-esterified oxylipins. Bound / esterified oxylipins were determined by subtracting free / non-esterified oxylipins from total oxylipins. In many cases, esterified oxylipins were the predominant form, sometimes exceeding free / non-esterified oxylipins by 10-fold. The oxylipin studies confirm that the large increases in tissue EPA achieved from LR-EtEPA vs. regular EtEPA vs. EPA+GLA+DHA are synonymous with substantial increases in EPA-derived oxylipins of therapeutic potential. This reaffirms that pharmacokinetic effects are synonymous with pharmacodynamic effects. Moreover, EPA also exerts functional effects on oxylipins derived from other LC-PUFAs such as DGLA and LA as shown herein. [Fig. 32H]The effect of various formulations on oxylipins present in lung tissue is shown. The oxylipins are listed in the graph title, and the arrow (←) indicates the parent LC-PUFA that was oxygenated to obtain the oxylipin. Notably, EtEPA not only elevated several EPA-derived oxylipins deemed to have therapeutic potential, but also elevated DGLA-derived oxylipins and linoleic acid-derived oxylipins (LA, 18:2ω-6). Lung oxylipins from rats were assayed with or without hydrolysis, thus obtaining total oxylipins (i.e., free / non-esterified plus bound / esterified oxylipins) and free / non-esterified oxylipins. Bound / esterified oxylipins were determined by subtracting free / non-esterified oxylipins from total oxylipins. In many cases, esterified oxylipins were the predominant form, sometimes exceeding free / non-esterified oxylipins by 10-fold. The oxylipin studies confirm that the large increases in tissue EPA achieved from LR-EtEPA vs. regular EtEPA vs. EPA+GLA+DHA are synonymous with substantial increases in EPA-derived oxylipins of therapeutic potential. This reaffirms that pharmacokinetic effects are synonymous with pharmacodynamic effects. Moreover, EPA also exerts functional effects on oxylipins derived from other LC-PUFAs such as DGLA and LA as shown herein. [Fig. 32I]The effect of various formulations on oxylipins present in lung tissue is shown. The oxylipins are listed in the graph title, and the arrow (←) indicates the parent LC-PUFA that was oxygenated to obtain the oxylipin. Notably, EtEPA not only elevated several EPA-derived oxylipins deemed to have therapeutic potential, but also elevated DGLA-derived oxylipins and linoleic acid-derived oxylipins (LA, 18:2ω-6). Lung oxylipins from rats were assayed with or without hydrolysis, thus obtaining total oxylipins (i.e., free / non-esterified plus bound / esterified oxylipins) and free / non-esterified oxylipins. Bound / esterified oxylipins were determined by subtracting free / non-esterified oxylipins from total oxylipins. In many cases, esterified oxylipins were the predominant form, sometimes exceeding free / non-esterified oxylipins by 10-fold. The oxylipin studies confirm that the large increases in tissue EPA achieved from LR-EtEPA vs. regular EtEPA vs. EPA+GLA+DHA are synonymous with substantial increases in EPA-derived oxylipins of therapeutic potential. This reaffirms that pharmacokinetic effects are synonymous with pharmacodynamic effects. Moreover, EPA also exerts functional effects on oxylipins derived from other LC-PUFAs such as DGLA and LA as shown herein. [Fig. 32J]The effect of various formulations on oxylipins present in lung tissue is shown. The oxylipins are listed in the graph title, and the arrow (←) indicates the parent LC-PUFA that was oxygenated to obtain the oxylipin. Notably, EtEPA not only elevated several EPA-derived oxylipins deemed to have therapeutic potential, but also elevated DGLA-derived oxylipins and linoleic acid-derived oxylipins (LA, 18:2ω-6). Lung oxylipins from rats were assayed with or without hydrolysis, thus obtaining total oxylipins (i.e., free / non-esterified plus bound / esterified oxylipins) and free / non-esterified oxylipins. Bound / esterified oxylipins were determined by subtracting free / non-esterified oxylipins from total oxylipins. In many cases, esterified oxylipins were the predominant form, sometimes exceeding free / non-esterified oxylipins by 10-fold. The oxylipin studies confirm that the large increases in tissue EPA achieved from LR-EtEPA vs. regular EtEPA vs. EPA+GLA+DHA are synonymous with substantial increases in EPA-derived oxylipins of therapeutic potential. This reaffirms that pharmacokinetic effects are synonymous with pharmacodynamic effects. Moreover, EPA also exerts functional effects on oxylipins derived from other LC-PUFAs such as DGLA and LA as shown herein.

[0048] [Diagram 33]A model is shown to determine whether the high relative potency (θ) seen across the spectrum of tissue perfusion rates extends to tissues that typically have the lowest perfusion rates (e.g., inactive muscle and fat). To model this, the left panel shows linear regression results for five tissues in the lower half of a typical tissue perfusion spectrum in healthy human adults on the x-axis. The y-axis is the relative potency θ determined by dose-response modeling as detailed elsewhere. The best-fit line had a good fit per R2 (p=0.0153). The slope and y-intercept of this line are given at the top of the graph. This line was used to model lower levels of tissue perfusion shown in the right panel, where the x-axis includes lower perfused tissues. The 90% confidence interval excludes 1 and θ remains close to 3×, reassuring that even the lower perfused tissues are likely to exhibit roughly a 3-fold benefit for LR-EtEPA compared to plain EtEPA at 21 days. If the confidence interval included 1, it would indicate that more than 21 days may be required for the therapeutic effect to appear in less perfused tissues.

[0049] [Figure 34A] A schematic diagram of how EtEPA induces the HMOX-1 gene, which promotes the heme-oxygenase 1 protein (HO-1), is presented. What is not shown is that the upregulation of HMOX-1 is induced through the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. LC-PUFAs and their oxylipins, particularly EPA and its oxylipins, stimulate Nrf2, an essential transcription factor that regulates oxidative stress by inducing the antioxidant response factor (ARE). The ARE in turn induces the production of HMOX1, which leads to HO-1, NQ01, which leads to NAD(P)H dehydrogenase [quinone]1, and GST, which leads to glutathione S-transferase. All of these have beneficial effects exemplified by the vasodilatory, anti-inflammatory, anti-apoptotic, anti-thrombotic, and angiogenic effects of HO-1, mediated by effects on carbon monoxide, the antioxidant biliverdin / bilirubin, and via the antioxidant effects of ferritin. [Figure 34B]We present results from an induced inflammation cell culture study with proteomic results, in which endothelial cells from various tissues were exposed to the inflammatory cytokine IL-6 in the absence or presence of EPA. Notably, heme-oxygenase-1 was significantly increased in endothelial cells from lung, blood vessel, and brain endothelial cells in the presence of EPA. Also interestingly, it is associated with an increase in proteins involved in the related antioxidant ferritin in vascular endothelial cells. Finally, fatty acid desaturase 1 (FADS1) encodes a Δ5-desaturase enzyme, and fatty acid desaturase 2 (FADS2) encodes a Δ6-desaturase enzyme. FADS2 was significantly suppressed in vascular and brain endothelial cells, and FADS1 was significantly suppressed in brain endothelial cells, whose protein suppression is consistent with functional results from Long-Evans rats discussed elsewhere, and in particular showed functional suppression of the Δ5-desaturase. [Figure 34C] 1 illustrates that endothelial nitric oxide bioavailability depends on eNOS coupling efficiency. [Fig. 34D] 1 illustrates that endothelial nitric oxide bioavailability depends on eNOS coupling efficiency.

[0050] [Diagram 35] Volcano plot of regulated proteins: IL-6 vs. EPA+IL-6 (all points above the horizontal line considered significant (p<0.05)). [Diagram 36] Volcano plot of modulated proteins: IL-6 vs. DHA+IL-6 (all points above the horizontal line considered significant (p<0.05)). [Figure 37] Figure 2 shows the effect of EPA and DHA on the relative expression levels (log2 intensity) of eNOS challenged with IL-6. The graph shows the normalized intensity values ​​for each replicate in the treatment group (n=3). [Figure 38]Air pollution particulate matter (PM) induces multi-organ injury and systemic vascular inflammation associated with both innate and adaptive immune responses. These vascular changes lead to increased cardiovascular risk and ischemic injury, including myocardial infarction and stroke.

[0051] [Figure 39A] The particle size distribution of urban particulate matter (Figure 39A) is shown. [Figure 39B] The particle size distribution in fine particulate matter (Figure 39B) is shown.

[0052] [Diagram 40] Schematic diagram of the proteomic analysis protocol.

[0053] [Figure 41A] Volcano plot of all proteins detected in fine PM versus EPA+fine PM. [Figure 41B] Volcano plot of all proteins detected in urban PM versus EPA + urban PM.

[0054] [Figure 42A] The effect of EPA on the relative expression levels (log2 intensity) of the inflammatory protein CXCL6 (FIG. 42A) following challenge with urban PM and fine PM is shown. [Figure 42B] The effect of EPA on the relative expression levels (log2 intensity) of HSP90B1 (FIG. 42B) following challenge with urban PM and fine PM is shown. [Figure 42C] The effect of EPA on the relative expression levels (log2 intensity) of GSTP1 (Figure 42C) following challenge with urban PM and fine PM is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0055] The present invention can be embodied in various forms, and the following description of some embodiments is made with the understanding that the present disclosure is to be considered as an example of the present invention, and is not intended to limit the present invention to the specific embodiments illustrated. Headings are provided for convenience only and should not be construed as limiting the present invention in any manner. An embodiment illustrated under any heading can be combined with an embodiment illustrated under any other heading.

[0056] The use of numerical values ​​in the various quantitative values ​​specified in this application is described as approximations, unless expressly indicated otherwise, such that the minimum and maximum values ​​in the stated ranges are both preceded by the word "about". In this manner, slight variations from the stated values ​​can be used to achieve substantially the same results as the stated values. Also, the disclosure of ranges is intended as a continuous range, including all values ​​between the minimum and maximum values ​​recited, and any ranges that may be formed by such values. Also disclosed herein are any and all ratios (and any such ratio ranges) that may be formed by dividing a disclosed numerical value by any other disclosed numerical value. Thus, one of ordinary skill in the art will understand that many such ratios, ranges, and ratio ranges can be clearly derived from the numerical values ​​presented herein, and in all cases, such ratios, ranges, and ratio ranges represent various embodiments of the present invention.

[0057] composition In some embodiments, provided is a composition comprising one or more polyunsaturated fatty acids (PUFAs) or their derivatives and a phospholipid source. In some embodiments, the composition may further comprise one or more additional emulsifiers. In certain of these embodiments, the PUFAs or their derivatives may function as active ingredients, and the phospholipids and / or additional emulsifiers may be referred to as additives or excipients.

[0058] In some embodiments, provided is a kit comprising a first composition comprising one or more PUFAs or derivatives thereof and a second composition comprising a phospholipid source. In some embodiments, the first and / or second composition may further comprise one or more additional emulsifiers.

[0059] Polyunsaturated fatty acids or their derivatives In some embodiments, the PUFAs or derivatives thereof include long chain PUFAs (LC-PUFAs), which are typically fatty acids having at least 18 carbon atoms, or derivatives thereof. In some embodiments, the PUFAs or derivatives thereof include very long chain PUFAs (VLC-PUFAs), which are typically fatty acids having at least 24 carbon atoms, or derivatives thereof.

[0060] The one or more PUFAs or derivatives thereof of the composition may be selected from the group consisting of omega-6 fatty acids, including linoleic acid (FA18:2ω-6 or LA), gamma-linoleic acid (FA18:3ω-6 or GLA), dihomo-gamma-linoleic acid (FA20:3ω-6 or DGLA), arachidonic acid (FA20:4ω-6, AA, or ARA), adrenergic acid (FA22:4ω-6, or AdA, also known as docosatetraenoic acid or DTA), and omega-6 docosapentaenoic acid (FA22:5ω-6 or DPA6), as well as alpha-linoleic acid (FA18:3ω3 or ALA), stearidonic acid (FA18:3ω4 or DPA). :4ω-3 or SDA), omega-3-eicosatetraenoic acid (FA20:4ω-3 or ETA), eicosapentaenoic acid (FA20:5ω-3 or EPA), docosapentaenoic acid (FA22:5ω-3 or DPA), and docosahexaenoic acid (FA22:6ω-3 or DHA), and derivatives thereof, including LA derivatives, GLA derivatives, DGLA derivatives, AA or ARA derivatives, AdA or DTA derivatives, DPA6 derivatives, ALA derivatives, SDA derivatives, ETA derivatives, EPA derivatives, DPA derivatives, and DHA derivatives. The terms "AA" and "ARA" are used interchangeably in this disclosure to refer to arachidonic acid.

[0061] As used herein, "PUFA", especially written in abbreviated form (e.g., EPA), refers to PUFA in free acid form and / or its pharmaceutically acceptable ester, or conjugate, or salt, or any mixture of the above, so long as the acyl group or carbon chain portion of the molecule remains intact. The term "pharmaceutically acceptable" in this context means that the substance in question does not cause unacceptable toxicity to the subject or interact with other components of the composition. For example, the term "EPA" encompasses eicosapentaenoic acid and its pharmaceutically acceptable ester, conjugate, or salt, or any mixture of the above. A "derivative" of a PUFA includes a molecule in which the acyl group or carbon chain portion of the molecule has one or more modifications.

[0062] In some embodiments, the PUFA derivative is an oxylipin. Oxylipins are bioactive lipids generated from the oxygenation of PUFAs by enzymes such as cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 epoxygenase (CYP), or by non-enzymatic processes. Oxylipins, especially those derived from EPA, may have vasoprotective activity, including protection from septic and hypertensive vascular disease. See Newman et al., PLOS ONE (2014) 9:11. For example, the main oxylipin classes include prostacyclins (potent vasodilators), thromboxanes (potent procoagulants and vasoconstrictors), prostaglandins (vasodilators), leukotrienes (inflammatory mediators), epoxides (potent vasodilators), and resolvins (potent inflammation-resolving agents). Oxylipins derived from PUFAs are believed to mediate the effects of PUFAs in many biological conditions. In certain of these embodiments, the PUFA derivatives have at least one hydroxyl group, epoxide group, non-vicinity di-hydroxyl group, vicinity di-hydroxyl group, tri-hydroxyl group, and / or ketone group. For a description of oxylipin metabolites and potential therapeutic uses, see Gabbs et al., Adv. Nutr. (2015) 6:513-40, which is incorporated by reference in its entirety.

[0063] In some embodiments, the LA derivative is 9-hydroperoxy-octadecadienoic acid (9-HpODE), 13-hydroperoxy-octadecadienoic acid (13-HpODE), 9-hydroxy-octadecadienoic acid (9-HODE), 13-hydroxy-octadecadienoic acid (13-HODE), 9,10,13 trihydroxy-octadecenoic acid (9,10,13TriHOME), 9,12,13 trihydroxy-octadecenoic acid (9,12,13TriHOME). ), 9-oxo-octadecadienoic acid (9-oxo-ODE), 13-oxo-octadecadienoic acid (13-oxo-ODE), 9,10-epoxy-octadecenoic acid (9,10-EpOME), 12,13-epoxy-octadecenoic acid (12,13-EpOME), 9,10-dihydroxy-octadecenoic acid (9,10-DiHOME), and 12,13-dihydroxy-octadecenoic acid (12,13-DiHOME). As examples of potential benefits, selected LA derivatives may be used as therapeutic agents to promote vasodilation / arterial relaxation (e.g., one or more HpODEs, EpOMEs), inhibit platelet aggregation (e.g., one or more HODEs), induce peroxisome proliferator-activated receptors (PPARs) (e.g., one or more HODEs, oxo-ODEs), inhibit leukotriene production (e.g., one or more HODEs), suppress triglyceride-rich lipoprotein (TRL) assembly and secretion (e.g., one or more HODEs), and / or inhibit tumor cell adhesion or proliferation (e.g., one or more HODEs, EpOMEs).

[0064] In some embodiments, the GLA derivative is at least one selected from the group consisting of 6-hydroxy-octatrienoic acid (6-HOTrE or 6-hydroxy-GLA), 7-hydroxy-octatrienoic acid (7-HOTrE or 7-hydroxy-GLA), 9-hydroxy-octatrienoic acid (9-HOTrE or 9-hydroxy-GLA), 10-hydroxy-octatrienoic acid (10-HOTrE or 10-hydroxy-GLA), 12-hydroxy-octatrienoic acid (12-HOTrE or 12-hydroxy-GLA), 13-hydroxy-octatrienoic acid (13-HOTrE or 13-hydroxy-GLA), 6,13-dihydroxy-octadienoic acid (6,13-DiHODE or 6,13-dihydroxy-GLA), and a trihydroxyGLA derivative (trihydroxy-GLA). As examples of potential benefits, selected GLA derivatives may be used as therapeutics to promote vasodilation (e.g., one or more of HOTrE, DiHODE, trihydroxy-GLA), inhibit reactive oxygen species production (e.g., one or more of HOTrE, DiHODE, trihydroxy-GLA), alleviate neurodegenerative conditions (e.g., one or more of HOTrE, DiHODE, trihydroxy-GLA), and / or as anti-inflammatory therapeutics to, for example, reduce production of tumor necrosis factor-α (TNF-α), reduce migration of neutrophils and macrophages to sites of inflammation, reduce interleukin-1β (IL-1β) production in an individual, and / or reduce macrophage migration protein-1 (MCP-1) (e.g., one or more of HOTrE, DiHODE, trihydroxy-GLA). See U.S. Patent Application Publication No. 2007 / 0248586A1, which is incorporated herein by reference in its entirety.

[0065] In some embodiments, the DGLA derivative is selected from the group consisting of prostaglandin D1 (PGD1), prostaglandin E1 (PGE1), 15-hydroxy-PGE1, 19-hydroxy-PGE1, 13,14-dihydroxy-PGE1, 13,14-dihydroxy-15-keto-PGE1, prostaglandin F1α (PGF1α), 6-keto-PGF1α, 15-keto-PGF1α, 13,14-dihydroxy-PGF1α, 15,19-dihydroxy-PGF 1α,13,14-dihydroxy-15-keto PGF1α, prostacyclin I1 (prostaglandin I1 or PGI1), thromboxane A1 (TXA1), thromboxane B1 (TXB1), leukotriene B3 (LTB3), leukotriene C3 (LTC3), leukotriene D3 (LTD3), leukotriene E3 (LTE3), 5-hydroperoxy-eicosatrienoic acid (5-HpETrE), 8-hydroperoxy-eicosatrienoic acid (8-HpETrE), 12-hydroperoxy-eicosatrienoic acid (12-HpETrE), 15-hydroperoxy-eicosatrienoic acid (15-HpETrE), 5-hydroxy-eicosatrienoic acid (5-HETrE), 8-hydroxy-eicosatrienoic acid (8-HETrE), 12-hydroxy-eicosatrienoic acid (12-HETrE), 15-hydroxy-eicosatrienoic acid (15-HETrE), 8,9-epoxy-eicosadienoic acid (8,9-EpEDE), 11,12-epoxy-eicosadienoic acid (11,12-EpEDE), 14,15-epoxy-eicosadienoic acid (14,15-EpEDE), 8,9-dihydroxy-eicosadienoic acid (8,9-DiHEDE), 11,12-dihydroxy-eicosadienoic acid (11,12-DiHEDE), and 14,15-dihydroxy-eicosadienoic acid (14,15-DiHEDE).As examples of potential benefits, selected DGLA derivatives may be used as therapeutic agents to promote vasodilation, including alleviating pulmonary hypertension or improving peripheral blood flow (e.g., one or more PGs or derivatives), inhibiting platelet aggregation (e.g., one or more PGs or derivatives, HETrE), reducing neuropathy (e.g., one or more PGs or derivatives), wound healing (e.g., one or more PGs or derivatives), promoting leukotriene production (e.g., one or more HETrE), and / or inhibiting cellular hyperproliferation (e.g., one or more HETrE). See U.S. Patent Application Publication No. 2007 / 0248586A1, the entire contents of which are incorporated herein by reference.

[0066] In some embodiments, the AA or ARA derivative is 6-keto-prostaglandin F1 alpha (6k-PGF1a), thromboxane B2 (TXB2), 11-dehydro-thromboxane B2 (11-dTXB2), prostaglandin F2 alpha (PGF2a), prostaglandin E2 (PGE2), prostaglandin A2 (PGA2), prostaglandin D2 (PGD2), 2,3-dinol 11 beta-prostaglandin F2 alpha (2,3-dinol 11bPGF2a), prostaglandin J2 (PGJ2), 15-deoxy-delta-12,14-Prostaglandin J2 (15d-PGJ2), leukotriene B4 (LTB4), 20-hydroxy-leukotriene B4 (20-OH-LTB4), leukotriene C4 (LTC4), leukotriene D4 (LTD4), leukotriene E4 (LTE4), 5-hydroperoxy-eicosatetraenoic acid (5-HpETE), 8-hydroperoxy-eicosatetraenoic acid (8-HpETE), 9-hydroperoxy-eicosatetraenoic acid (9-HpETE), 11-hydroperoxy-eicosatetraenoic acid (11-HpETE), 1 2-Hydroperoxy-eicosatetraenoic acid (12-HpETE), 15-Hydroperoxy-eicosatetraenoic acid (15-HpETE), 5-Hydroxy-eicosatetraenoic acid (5-HETE), 8-Hydroxy-eicosatetraenoic acid (8-HETE), 9-Hydroxy-eicosatetraenoic acid (9-HETE), 11-Hydroxy-eicosatetraenoic acid (11-HETE), 12-Hydroxy-eicosatetraenoic acid (12-HETE), 15-Hydroxy-eicosatetraenoic acid (15-HETE), 18-Hydroxy-eicosatetraenoic acid (18-Hydroxy-eicosatetraenoic acid) eicosatetraenoic acid (18-HETE), 19-hydroxy-eicosatetraenoic acid (19-HETE), 20-hydroxy-eicosatetraenoic acid (20-HETE), 5-oxo-eicosatetraenoic acid (5-oxo-ETE), 8-oxo-eicosatetraenoic acid (8-oxo-ETE), 11-oxo-eicosatetraenoic acid (11-oxo-ETE), 12-oxo-eicosatetraenoic acid (12-oxo-ETE), 15-oxo-eicosatetraenoic acid (15-oxo-ETE), lipoxin A4 (LXA4), lipoxin A5 (LXA5), helicose Hepoxilin A3 (HxA3), hepoxilin B3 (HxB3), trioxylin A3 (TrxA3), trioxylin B3 (TrxB3), eoxin A4 (ExA4), eoxin C4 (ExC4), eoxin D4 (ExD4), eoxin E4 (ExE4), 5,6-epoxy-eicosatrienoic acid (5,6-EpETrE or 5,6-EET), 8,9-epoxy-eicosatrienoic acid (8,9-EpETrE or 8,9-EET), 11,12-epoxy-eicosatrienoic acid (11,12-EpETrE or 11,12-EET), 14,At least one selected from the group consisting of 15-epoxy-eicosatrienoic acid (14,15-EpETrE or 14,15-EET), 5,12-dihydroxy-eicosatetraenoic acid (5,12-DiHETE), 5,6-dihydroxy-eicosatrienoic acid (5,6-DiHETrE or 5,6-DiHET), 8,9-dihydroxy-eicosatrienoic acid (8,9-DiHETrE or 8,9-DiHET), 11,12-dihydroxy-eicosatrienoic acid (11,12-DiHETrE or 11,12-DiHET), 14,15-dihydroxy-eicosatrienoic acid (14,15-DiHETrE or 14,15-DiHET), and 12-hydroxyheptadecatrenoic acid (12-HHTrE). As examples of potential benefits, selected AA derivatives may promote vasodilation / arterial relaxation (e.g., one or more PGs or derivatives, HpETE, HETE, EpETrE, DiHETrE), promote angiogenesis (e.g., one or more HETEs, EpETrE, DiHETrE), reduce intracranial or intrarenal pressure (e.g., one or more HETEs), attenuate myocyte apoptosis after reperfusion (e.g., one or more EpETrEs), inhibit platelet aggregation (e.g., one or more PGs and derivatives, HpETEs), attenuate inflammation ( For example, they may be used as therapeutic agents to inhibit reactive oxygen species generation / oxidative damage (e.g., one or more lipoxins), induce PPARs (e.g., one or more PG derivatives, HETEs, DiHETrEs), promote adipocyte differentiation (e.g., one or more hepoxilins), attenuate cancer (e.g., one or more oxo-ETEs), promote wound healing (e.g., one or more HETEs), and / or attenuate LOX activity (e.g., one or more oxo-ETEs). See Gabbs et al., Adv. Nutr. (2015) 6:513-40, which is incorporated by reference in its entirety.

[0067] In some embodiments, the AdA or DTA derivative is selected from the group consisting of dihomo-prostaglandin E2 (dihomo-PGE2), dihomo-prostaglandin D2 (dihomo-PGD2), dihomo-prostaglandin F2α (dihomo-PGF2α), dihomo-prostacycyclin I2 (dihomo-prostaglandin I2 or dihomo-PGI2), dihomo-thromboxane A2 (dihomo-TXA2), dihomo-thromboxane B2 (dihomo-TXB2), 7-hydroperoxy-docosatetraenoic acid (dihomo-7-HpETE), 10-hydroperoxy-docosatetraenoic acid (dihomo-7-HpETE), 12-hydroperoxy-docosatetraenoic acid (dihomo-7-HpETE), 16-hydroperoxy-docosatetraenoic acid (dihomo-7-HpETE), 18-hydroperoxy-docosatetraenoic acid (dihomo-7-HpETE), 19-hydroperoxy-docosatetraenoic acid (dihomo-7-HpETE), 20-hydroperoxy-docosatetraenoic acid (dihomo-7-HpETE), 21-hydroperoxy-docosatetraenoic acid (dihomo-7-HpETE), 22-hydroperoxy-docosatetraenoic acid (dihomo-7-HpETE), 23-hydroperoxy-docosatetraenoic acid (dihomo-7-HpETE), 24-hydroperoxy-docosatetraenoic acid (dihomo-7-HpETE), 25-hydroperoxy-docosatetraenoic acid (dihomo-7-HpETE), 26-hydroperoxy-docosatetraenoic acid (dihomo-7-HpETE), 27-hydroperoxy-docosatetraenoic acid (dihomo-7-HpE 11-Hydroperoxy-docosatetraenoic acid (dihomo-10-HpETE), 11-Hydroperoxy-docosatetraenoic acid (dihomo-11-HpETE), 13-Hydroperoxy-docosatetraenoic acid (dihomo-13-HpETE), 14-Hydroperoxy-docosatetraenoic acid (dihomo-14-HpETE), 17-Hydroperoxy-docosatetraenoic acid (dihomo-17-HpETE), 7-Hydroxy-docosatetraenoic acid (dihomo-7-HETE), 10-Hydroxy-docosatetraenoic acid (dihomo-10-HETE), 11-Hydroxy-docosatetraenoic acid (dihomo-11- HETE), 13-hydroxy-docosatetraenoic acid (dihomo-13-HETE), 14-hydroxy-docosatetraenoic acid (dihomo-14-HETE), 17-hydroxy-docosatetraenoic acid (dihomo-17-HETE), 7,11-dihydroxy-docosatetraenoic acid (dihomo-7,11-DiHETE), 7,14-dihydroxy-docosatetraenoic acid (dihomo-7,14-DiHETE), 7,17-dihydroxy-docosatetraenoic acid (dihomo-7,17-DiHETE), 10,17-dihydroxy-docosatetraenoic acid (dihomo-10, 17-DiHETE), 11,17-dihydroxy-docosatetraenoic acid (dihomo-11,17-DiHETE), 13,15-dihydroxy-docosatetraenoic acid (dihomo-13,15-DiHETE), 13,17-dihydroxy-docosatetraenoic acid (dihomo-13,17-DiHETE), 16,17-dihydroxy-docosatetraenoic acid (dihomo-16,17-DiHETE), 7,8-epoxy-docosatrienoic acid (dihomo-7,8-EpETrE), 10,11-epoxy-docosatrienoic acid (dihomo-10,11-EpETrE), 13,14-epoxy-docosatrienoic acid (dihomo-13,14-EpETrE), 16,17-epoxy-docosatrienoic acid (dihomo-16,17-EpETrE), 7,8-dihydroxy-docosatrienoic acid (dihomo-7,8-DiHETrE), 10,11-dihydroxy-docosatrienoic acid (dihomo-10,11-DiHETrE), 13,14-dihydroxy-docosatrienoic acid ( At least one selected from the group consisting of dihomo-13,14-DiHETrE), 16,17-dihydroxy-docosatrienoic acid (dihomo-16,17-DiHETrE), 7,16,17-trihydroxy-docosatetraenoic acid (dihomo-7,16,17-trihydroxy-ETrE), and 14-hydroxy-7,10,12-nonadecatrienoic acid (14-HNTrE). As one example of potential benefits, selected AdA derivatives may be used as therapeutics to promote vasodilation and / or counter the net vasoconstrictor properties from similar oxylipins, particularly in the kidney (e.g., one or more dihomo-PG or derivatives, dihomo-thromboxane, dihomo-HETE, dihomo-DiHETE dihomo-EpETrE), inhibit reactive oxygen species generation (e.g., one or more dihomo-HETE, dihomo-DiHETE), alleviate neurodegenerative conditions (e.g., one or more dihomo-HETE, dihomo-DiHETE), and as anti-inflammatory therapeutics, for example, to reduce production of tumor necrosis factor-α (TNF-α), reduce migration of neutrophils and macrophages to sites of inflammation, reduce interleukin-1β (IL-1β) production in an individual, and / or reduce macrophage migration protein-1 (MCP-1) (e.g., one or more dihomo-HETE, dihomo-DiHETE). See U.S. Patent Application No. 2006 / 0241088A1, which is incorporated herein by reference in its entirety.

[0068] In some embodiments, the DPA6 derivatives are 7-hydroperoxy-DPA6, 8-hydroperoxy-DPA6, 10-hydroperoxy-DPA6, 11-hydroperoxy-DPA6, 13-hydroperoxy-DPA6, 14-hydroperoxy-DPA6, 17-hydroperoxy-DPA6, 7-hydroxy-DPA6, 8-hydroxy-DPA6, 10-hydroxy-DPA6, 11-hydroxy-DPA6, 13-hydroxy-DPA6, 14-hydroxy-DPA6, 1 At least one selected from the group consisting of 7-hydroxy-DPA6, 4,5-dihydroxy-DPA6, 7,14-dihydroxy-DPA6, 7,17-dihydroxy-DPA6, 8,14-dihydroxy-DPA6, 10,17-dihydroxy-DPA6, 13,17-dihydroxy-DPA6, 16,17-dihydroxy-DPA6, 4,5,17-trihydroxy-DPA6, 7,16,17-trihydroxy-DPA6, and 10,13,17-trihydroxy-DPA6. As examples of potential benefits, selected DPA6 derivatives may be used as therapeutics to promote vasodilation (e.g., one or more hydroxy-DPA6, dihydroxy-DPA6), inhibit reactive oxygen species production (e.g., one or more hydroxy-DPA6, dihydroxy-DPA6), alleviate neurodegenerative conditions (e.g., hydroxy-DPA6, dihydroxy-DPA6), and as anti-inflammatory therapeutics to, for example, reduce production of tumor necrosis factor-α (TNF-α), reduce migration of neutrophils and macrophages to sites of inflammation, reduce interleukin-1β (IL-1β) production in an individual, and / or reduce macrophage migration protein-1 (MCP-1) (e.g., one or more hydroxy-DPA6, dihydroxy-DPA6). See U.S. Patent Application Publication No. 2006 / 0241088A1, the entire contents of which are incorporated herein by reference.

[0069] In some embodiments, the ALA derivative is 9-hydroperoxy-octatrienoic acid (9-HpOTrE), 13-hydroperoxy-octatrienoic acid (13-HpOTrE), 9-hydroxy-octatrienoic acid (9-HOTrE), 13-hydroxy-octatrienoic acid (13-HOTrE), 9,16-dihydroxy-octatrienoic acid (9,16-DiHOTrE), 9-oxo-octatrienoic acid (9-oxo-OTrE), 13-oxo-octatrienoic acid (13-oxo-OtrE). E), 9,10-epoxy-octadienoic acid (9,10-EpODE), 12,13-epoxy-octadienoic acid (12,13-EpODE), 15,16-epoxy-octadienoic acid (15,16-EpODE), 9,10-dihydroxy-octadienoic acid (9,10-DiHODE), 12,13-dihydroxy-octadienoic acid (12,13-DiHODE), and 15,16-dihydroxy-octadienoic acid (15,16-DiHODE). As examples of potential benefits, selected ALA derivatives may be used as therapeutic agents to inhibit platelet aggregation (e.g., one or more DiHOTrEs), attenuate inflammation (e.g., one or more HOTrEs), promote adipocyte differentiation (e.g., one or more oxo-OtrEs), attenuate COX activity (e.g., one or more DiHOTrEs), reduce action potentials in muscle cells (e.g., one or more HpOTrEs), and / or increase glucose uptake (e.g., one or more oxo-OtrEs).

[0070] In some embodiments, the SDA derivative is 6-hydroperoxy-octatetraenoic acid (6-HpOTE or 6-hydroperoxy-SDA), 7-hydroperoxy-octatetraenoic acid (7-HpOTE or 7-hydroperoxy-SDA), 9-hydroperoxy-octatetraenoic acid (9-HpOTE or 9-hydroperoxy-SDA), 10-hydroperoxy-octatetraenoic acid (10-HpOTE or 10-hydroperoxy-SDA), 12-hydroperoxy-octatetraenoic acid (12-HpOTE or 12-hydroperoxy-SDA), 13-hydroperoxy-octatetraenoic acid (13-HpOTE or 13-hydroperoxy-SDA), 14-hydroperoxy-octatetraenoic acid (13-HpOTE or 13-hydroperoxy-SDA), 15-hydroperoxy-octatetraenoic acid (13-HpOTE or 13-hydroperoxy-SDA), 16-hydroperoxy-octatetraenoic acid (13-HpOTE or 13-hydroperoxy-SDA), 17-hydroperoxy-octatetraenoic acid (13-HpOTE or 13-hydroperoxy-SDA), 18-hydroperoxy-octatetraenoic acid (13-HpOTE or 13-hydroperoxy-SDA), 19-hydroperoxy-octatetraenoic acid (13-HpOTE or 13-hydroperoxy-SDA), 20-hydroperoxy-octatetraenoic acid (13-HpOTE or 13-hydroperoxy-SDA), 21-hydroperoxy-octatetraenoic acid (13-HpOTE or 13-hydroperoxy-SDA), 22-hydroperoxy-octatetraenoic acid (13-HpOTE or 13-hydroperoxy-SDA), 13-Hydroperoxy-octatetraenoic acid (13-HpOTE or 13-Hydroperoxy-SDA), 15-Hydroperoxy-octatetraenoic acid (15-HpOTE or 15-Hydroperoxy-SDA), 16-Hydroperoxy-octatetraenoic acid (16-HpOTE or 16-Hydroperoxy-SDA), 6-Hydroxy-octatetraenoic acid (6-HOTE or 6-Hydroxy-SDA), 7-Hydroxy-octatetraenoic acid (7-HOTE or 7-Hydroxy-SDA), 9-Hydroxy-octatetraenoic acid (9-HOTE or 9-hydroxy-SDA), 10-hydroxy-octatetraenoic acid (10-HOTE or 10-hydroxy-SDA), 12-hydroxy-octatetraenoic acid (12-HOTE or 12-hydroxy-SDA), 13-hydroxy-octatetraenoic acid (13-HOTE or 13-hydroxy-SDA), 15-hydroxy-octatetraenoic acid (15-HOTE or 15-hydroxy-SDA), 16-hydroxy-octatetraenoic acid (16-HOTE or 16-hydroxy-SDA), 6,13-dihydroxy-octadecatetraenoic acid (6,13-dihydroxy-SDA), 16-hydroxy-octa ... Trienoic acid (6,13-DiHOTrE or 6,13-dihydroxy-SDA), 6,16-dihydroxy-octadecatrienoic acid (6,16-DiHOTrE or 6,16-dihydroxy-SDA), 6,7-dihydroxy-octadecadienoic acid (6,7-DiHODE or 6,7-dihydroxy-SDA), 9,10-dihydroxy-octadecadienoic acid (9,10-DiHODE or 9,10-dihydroxy-SDA), 12,13-dihydroxy-octadecadienoic acid (12,13-DiHODE or 12,13-dihydroxy-SDA), 15,At least one selected from the group consisting of 16-dihydroxy-octadecadienoic acid (15,16-DiHODE or 15,16-dihydroxy-SDA) and trihydroxy-SDA carrying hydroxyl groups at any three positions between carbons C6, C7, C9, C10, C12, C13, C15 or C16 of SDA (trihydroxy-SDA). As examples of potential benefits, selected SDA derivatives may be used as therapeutics to promote vasodilation (e.g., one or more of HOTE, DiHOTrE, DiHODE, trihydroxy-SDA), inhibit reactive oxygen species generation (e.g., one or more of HOTE, DiHOTrE, DiHODE, trihydroxy-SDA), alleviate neurodegenerative conditions (e.g., one or more of HOTE, DiHOTrE, DiHODE, trihydroxy-SDA), and as anti-inflammatory therapeutics to, for example, reduce production of tumor necrosis factor-α (TNF-α), reduce migration of neutrophils and macrophages to sites of inflammation, reduce interleukin-1β (IL-1β) production in an individual, and / or reduce macrophage migration protein-1 (MCP-1) (e.g., one or more of HOTE, DiHOTrE, DiHODE, trihydroxy-SDA). See U.S. Patent Application Publication No. 2007 / 0248586A1, which is incorporated herein by reference in its entirety.

[0071] In some embodiments, the ETA derivatives are Δ17,18 prostaglandin D1 (Δ17,18 PGD1 or ω-3PGD1), Δ17,18 prostaglandin E1 (Δ17,18PGE1 or ω-3PGE1), and Δ17,18 prostaglandin F1α (Δ17,18PGF1α or ω-3PGF1α), Δ17,18 prostacyclin I1 (Δ17,18PGI1 or ω-3PGE1), Δ17,18 12-hydroperoxy-eicosatetraenoic acid (Δ17,1812-HpETE or ω-3 12-HpETE), Δ17,18 15-hydroperoxy-eicosatetraenoic acid (Δ17,18 15-HpETE or ω-3 15-HpETE), Δ16,17 18-Hydroperoxy-eicosatetraenoic acid (Δ16,17 18-HpETE), Δ17,18 12-Hydroxy-eicosatetraenoic acid (Δ17,18 12-HETE or ω-3 12-HETE), Δ17,18 15-Hydroxy-eicosatetraenoic acid (Δ17,18 15-HETE or ω-3 15-HETE), Δ16,17 18-Hydroxy-eicosatetraenoic acid (Δ16,17 18-HETE), Δ17,18 19-Hydroxy-eicosatetraenoic acid (Δ17,18 19-HETE or ω-3 19-HETE), Δ17,18 20-Hydroxy-eicosatetraenoic acid (Δ17,18 20-HETE or ω-3 20-HETE), Δ17,18 11,12 epoxy-eicosatrienoic acid (Δ17,18 11,12-EpETrE or ω-3 11,12-EpETrE), Δ17,18 14,15 epoxy-eicosatrienoic acid (Δ17,18 14,15-EpETrE or ω-3 14,15-EpETrE), and 17,18 epoxy-eicosatrienoic acid (17,18-EpETrE), Δ17,18 11,12 dihydroxy-eicosatrienoic acid (Δ17,18 11,12-DiHETrE or ω-3 11,12-DiHETrE), Δ17,18 14,15 dihydroxy-eicosatrienoic acid (Δ17,18 14,15-DiHETrE or ω-3 14,15-DiHETrE), and 17,18 dihydroxy-eicosatrienoic acid (17,18-DiHETrE).As examples of potential benefits, selected ETA derivatives may be used as therapeutic agents to inhibit COX, inhibit the conversion of AA to PGs and thromboxanes (e.g., one or more of ω-3 HETE, ω-3 DiHETrE), and / or promote vasodilation or alleviate congestive heart failure (e.g., one or more of ω-3 HETE, ω-3 EpETrE, ω-3 DiHETrE).

[0072] In some embodiments, the EPA derivative is 6-keto-prostaglandin F2 alpha (6k-PGF2a), thromboxane B3 (TXB3), 11-dehydro-thromboxane B3 (11-dTXB3), prostaglandin F3 alpha (PGF3a), prostaglandin E3 (PGE3), prostaglandin A3 (PGA3), prostaglandin D3 (PGD3), 2,3-dinol 11 beta-prostaglandin F3 alpha (2,3-dinol 11bPGF3a), prostaglandin J3 (PGJ3), 15-deoxy-del 15d-PGJ3, leukotriene B5 (LTB5), 20-hydroxy-leukotriene B5 (20-OH-LTB5), leukotriene C5 (LTC5), leukotriene D5 (LTD5), leukotriene E5 (LTE5), 5-hydroperoxy-eicosapentaenoic acid (5-HpEPE), 8-hydroperoxy-eicosapentaenoic acid (8-HpEPE), 9-hydroperoxy-eicosapentaenoic acid (9-HpEPE), 11-hydroperoxy-eicosapentaenoic acid (11-HpEPE) ), 12-hydroperoxy-eicosapentaenoic acid (12-HpEPE), 15-hydroperoxy-eicosapentaenoic acid (15-HpEPE), 18-hydroperoxy-eicosapentaenoic acid (18-HpEPE), 5-hydroxy-eicosapentaenoic acid (5-HEPE), 8-hydroxy-eicosapentaenoic acid (8-HEPE), 9-hydroxy-eicosapentaenoic acid (9-HEPE), 11-hydroxy-eicosapentaenoic acid (11-HEPE), 12-hydroxy-eicosapentaenoic acid (12-HEPE), 15-hydroxy -Eicosapentaenoic acid (15-HEPE), 18-hydroxy-eicosapentaenoic acid (18-HEPE), 19-hydroxy-eicosapentaenoic acid (19-HEPE), 20-hydroxy-eicosapentaenoic acid (20-HEPE), 5-oxo-eicosapentaenoic acid (5-oxo-EPE), 12-oxo-eicosapentaenoic acid (12-oxo-EPE), 15-oxo-eicosapentaenoic acid (15-oxo-EPE), 5,6-epoxy-eicosatetraenoic acid (5,6-EpETE), 8,9-epoxy-eicosatetraenoic acid (8,9-EpETE), 11,12-epoxy-eicosatetraenoic acid (11,12-EpETE), 14,15-epoxy-eicosatetraenoic acid (14,15-EpETE), 5,6-dihydroxy-eicosatetraenoic acid (5,6-diHETE), 8,9-dihydroxy-eicosatetraenoic acid (8,9-diHETE), 11,12-dihydroxy-eicosatetraenoic acid (11,12-diHETE), 14,15-dihydroxy-eicosatetraenoic acid ( and at least one selected from the group consisting of 14,15-diHETE), 17,18-dihydroxy-eicosatetraenoic acid (17,18-diHETE), 17,18-epoxy-eicosatetraenoic acid (17,18-EpETE), lipoxin A5 (LxA5), lipoxin B5 (LxB5), 15-epi-lipoxin A4, resolvin E1 (RvE1), resolvin E2 (RvE2), resolvin E3 (RvE3), and resolvin E4 (RvE4). As examples of potential benefits, selected EPA derivatives may be used as therapeutic agents to promote vasodilation / arterial relaxation (e.g., one or more PGs or derivatives, lipoxins, HEPE, EpETE), inhibit platelet aggregation (e.g., one or more PGs and derivatives, HpEPE, HEPE, EpETE, DiHETE), attenuate inflammation (e.g., one or more PGs and derivatives, LT, HEPE, oxo-EPE, EpETE, RvE), promote adipocyte differentiation / elevate adiponectin (e.g., one or more PGs and derivatives, HEPE), attenuate cancer (e.g., one or more PGs or derivatives), attenuate COX activity (e.g., one or more LTs, HpEPE), attenuate LOX activity (e.g., one or more LTs, HpEPE, HEPE), and / or improve glucose-dependent insulin secretion (e.g., one or more HEPE), either in absolute terms or compared to AA-derived oxylipins.

[0073] In some embodiments, the DPA derivative is 7-hydroperoxy-docosapentaeonic acid (7-hydroperoxy-DPA), 10-hydroperoxy-docosapentaeonic acid (10-hydroperoxy-DPA), 11-hydroperoxy-docosapentaeonic acid (11-hydroperoxy-DPA), 13-hydroperoxy-docosapentaeonic acid (13-hydroperoxy-DPA), 14-hydroperoxy-docosapentaeonic acid (14-hydroperoxy-DPA), 16-hydroperoxy-docosapentaeonic acid (16-hydroperoxy-DPA), 17-hydroperoxy-docosapentaeonic acid (17-hydroperoxy-DPA), 18-hydroperoxy-docosapentaeonic acid (18-hydroperoxy-DPA), 19-hydroperoxy-docosapentaeonic acid (19-hydroperoxy-DPA), 20-hydroperoxy-docosapentaeonic acid (20-hydroperoxy-DPA), 21-hydroperoxy-docosapentaeonic acid (21-hydroperoxy-DPA), 22-hydroperoxy-docosapentaeonic acid (22-hydroperoxy-DPA), 23-hydroperoxy-docosapentaeonic acid (23-hydroperoxy-DPA), 24-hydroperoxy-docosapentaeonic acid (24-hydroperoxy-DPA), 25-hydroperoxy-docosapentaeonic acid (25-hydroperoxy-DPA), 26-hydroperoxy-docosapentaeonic acid (26-hydroperoxy-DPA), 27-hydroperoxy-docosapentaeonic acid (27-hydroperoxy-DPA), 28-hydroperoxy-docosapentaeonic acid (28-hydroperoxy-DPA), 29-hydroperoxy-docosapentaeonic acid (29-hydroperoxy-DPA), 30-hydroperoxy-docosa docosapentaeonic acid (16-hydroperoxy-DPA), 17-hydroperoxy-docosapentaeonic acid (17-hydroperoxy-DPA), 7-hydroxy-docosapentaeonic acid (7-hydroxy-DPA), 10-hydroxy-docosapentaeonic acid (10-hydroxy-DPA), 11-hydroxy-docosapentaeonic acid (11-hydroxy-DPA), 13-hydroxy-docosapentaeonic acid (13-hydroxy-DPA), 1 4-hydroxy-docosapentaeonate (14-hydroxy-DPA), 16-hydroxy-docosapentaeonate (16-hydroxy-DPA), 17-hydroxy-docosapentaeonate (17-hydroxy-DPA), 7,17-dihydroxy-docosapentaeonate (7,17-dihydroxy-DPA), 8,14-dihydroxy-docosapentaeonate (8,14-dihydroxy-DPA), 10,17-dihydroxy-docosapentaeonate 10,17-dihydroxy-DPA, 10,20-dihydroxy-docosapentaeonic acid (10,20-dihydroxy-DPA), 13,20-dihydroxy-docosapentaeonic acid (13,20-dihydroxy-DPA), 16,17-dihydroxy-docosapentaeonic acid (16,17-dihydroxy-DPA), 13-oxo-docosapentaeonic acid (13-oxo-DPA or 13-EFOX-D5), MaR1n-3 DPA, MaR2n-3 DPA, MaR3n-3 DPA, PD1n-3 DPA, PD2n-3 DPA, 7,13,20-trihydroxy-n-3-docosapentaenoic acid (Resolvin T1 or RvT1), 7,12,13-trihydroxy-n-3-docosapentaenoic acid (Resolvin T2 or RvT2), 7,8,At least one selected from the group consisting of 13-trihydroxy-n-3-docosapentaenoic acid (Resolvin T3 or RvT3), 7,16,17-trihydroxy-n-3-docosapentaenoic acid (7,16,17-trihydroxy-DPA), RvD1n-3 DPA, RvD2n-3 DPA, and RvD2n-3 DPA. As examples of potential benefits, selected DPA derivatives may be used as therapeutics to promote vasodilation (e.g., one or more hydroxy-DPAs, dihydroxy-DPAs), inhibit reactive oxygen species generation (e.g., one or more hydroxy-DPAs, dihydroxy-DPAs), alleviate neurodegenerative conditions (e.g., hydroxy-DPAs, dihydroxy-DPAs), and as anti-inflammatory therapeutics to, for example, reduce production of tumor necrosis factor-α (TNF-α), reduce migration of neutrophils and macrophages to sites of inflammation, reduce interleukin-1β (IL-1β) production in an individual, and / or reduce macrophage migration protein-1 (MCP-1) (e.g., one or more hydroxy-DPAs, dihydroxy-DPAs). See Duan et al., Front Physiol. (2021) 12:646491, U.S. Patent Application Publication No. 2006 / 0241088A1, each of which is incorporated herein by reference in its entirety.

[0074] In some embodiments, the DHA derivatives are 4-hydroperoxy-docosahexaenoic acid (4-HpDoHE), 7-hydroperoxy-docosahexaenoic acid (7-HpDoHE), 8-hydroperoxy-docosahexaenoic acid (8-HpDoHE), 10-hydroperoxy-docosahexaenoic acid (10-HpDoHE), 11-hydroperoxy-docosahexaenoic acid (11-HpDoHE), 13-hydroperoxy-docosahexaenoic acid (13-HpDoHE), 14-hydroperoxy-docosahexaenoic acid (14-HpDoHE), 16- Hydroperoxy-docosahexaenoic acid (16-HpDoHE), 17-hydroperoxy-docosahexaenoic acid (17-HpDoHE), 4-hydroxy-docosahexaenoic acid (4-HDoHE), 7-hydroxy-docosahexaenoic acid (7-HDoHE), 8-hydroxy-docosahexaenoic acid (8-HDoHE), 10-hydroxy-docosahexaenoic acid (10-HDoHE), 11-hydroxy-docosahexaenoic acid (11-HDoHE), 13-hydroxy-docosahexaenoic acid (13-HDoHE), 14-hydroxy-docosahexaenoic acid 14-HDoHE), 16-hydroxy-docosahexaenoic acid (16-HDoHE), 17-hydroxy-docosahexaenoic acid (17-HDoHE), 20-hydroxy-docosahexaenoic acid (20-HDoHE), 21-hydroxy-docosahexaenoic acid (21-HDoHE), 22-hydroxy-docosahexaenoic acid (22-HDoHE), 7,14-dihydroxy-docosahexaenoic acid (7,14-DiHDoHE), 7,17-dihydroxy-docosahexaenoic acid (7,17-DiHDoHE), 8,14-dihydroxy-docosahexaenoic acid (8,14-DiHDoHE), docosahexaenoic acid (8,14-DiHDoHE), 10,17-dihydroxy-docosahexaenoic acid (10,17-DiHDoHE), 10,20-dihydroxy-docosahexaenoic acid (10,20-DiHDoHE), 14,20-dihydroxy-docosahexaenoic acid (14,20-DiHDoHE), 14,21-dihydroxy-docosahexaenoic acid (14,21-DiHDoHE), 7-oxo-docosahexaenoic acid (7-oxo-DoHE), 4,5-epoxy-docosapentaenoic acid (4,5-EpDPE), 7,8-epoxy-docosapentaenoic acid (7,8-EpDPE), 10,11-epoxy-docosapentaenoic acid (10,11-EpDPE), 13,14-epoxy-docosapentaenoic acid (13,14-EpDPE), 16,17-epoxy-docosapentaenoic acid (16,17-EpDPE), 19,20-epoxy-docosapentaenoic acid (19,20-EpDPE), 4,5-dihydroxy-docosapentaenoic acid (4,5-DiHDPE), 7,8-dihydroxy-docosapentaenoic acid (7,8-DiHDPE), 10,11- Dihydroxy-docosapentaenoic acid (10,11-DiHDPE), 13,14-dihydroxy-docosapentaenoic acid (13,14-DiHDPE), 16,17-dihydroxy-docosapentaenoic acid (16,17-DiHDPE), 19,20-dihydroxy-docosapentaenoic acid (19,20-DiHDPE), 4,5-epoxy-17-OH-docosahexaenoic acid (4,5-epoxy-17-hydroxy-DHA), 7,8-epoxy-17-OH-docosahexaenoic acid (7,8-epoxy-17-hydroxy-DHA), maresin 1 (MaR1), maresin 2 (MaR2), protectin 1 (PD1), protectin X (PDX), aspirin-induced PD1 (AT-PD1), resolvin D1 (RvD1), resolvin D2 (RvD2), resolvin D3 (RvD3), resolvin D4 (RvD4), resolvin D5 (RvD5), resolvin D6 (RvD 6), aspirin-induced resolvin D1 (AT-RvD1), aspirin-induced resolvin D2 (AT-RvD2), aspirin-induced resolvin D3 (AT-RvD3), aspirin-induced resolvin D4 (AT-RvD4), aspirin-induced resolvin D5 (AT-RvD5), and aspirin-induced resolvin D6 (AT-RvD6). As examples of potential benefits, selected DHA derivatives may be used as therapeutic agents to promote vasodilation / arterial relaxation (e.g., one or more of HDoHE, EpDPE, DiHDPE), inhibit platelet aggregation (e.g., one or more of HDoHE, EpEPE, DiHDPE, PD), attenuate inflammation / inflammatory pain (e.g., one or more of HDoHE, DiHDoHE, DiHDPE, PD, MaR, RvD, AT-RvD), inhibit reactive oxygen species generation / oxidative damage (e.g., one or more of HDoHE, PD), induce PPAR (e.g., one or more of HDoHE), attenuate COX activity (e.g., one or more of HDoHE), attenuate LOX activity (e.g., one or more of PD), improve insulin sensitivity (e.g., one or more of PD), and / or promote wound healing (e.g., one or more of DiHDoHE, PD).

[0075] In some embodiments, the PUFAs or derivatives thereof of the composition may include tetracosatetraenoic acid (TTE, a 24 carbon omega-6 VLC-PUFA with four double bonds), tetracosapentaenoic acid (TPA, a 24 carbon omega-3 VLC-PUFA with five double bonds), tetracosahexaenoic acid (THA, a 24 carbon omega-3 VLC PUFA with six double bonds), or another VLC-PUFA or derivative thereof.

[0076] In some embodiments, the composition of the present technology comprises EPA as an active ingredient. The term "EPA" as used herein refers to eicosapentaenoic acid in free acid form (e.g., all-cis eicosa-5,8,11,14,17-pentaenoic acid), and / or its pharma- ceutically acceptable ester, conjugate, or salt, or any mixture of the foregoing. For example, in some embodiments, EPA comprises eicosapentaenoic acid. In other embodiments, EPA is in the form of eicosapentaenoic acid ester, e.g., C1-C5 alkyl ester of eicosapentaenoic acid. In one embodiment, EPA comprises eicosapentaenoic acid ethyl ester (also referred to herein as ethyl eicosapentaenoic acid, ethyl eicosapentaenoic acid, eicosapentaethyl, ethyl-EPA, EtEPA, IPE, E-EPA, or EPA-E). In another embodiment, EPA comprises eicosapentaenoic acid methyl ester, eicosapentaenoic acid propyl ester, or eicosapentaenoic acid butyl ester. In another embodiment, the EPA comprises lithium eicosapentaenoic acid, mono-, di-, or triglyceride of eicosapentaenoic acid, or any other ester or salt of eicosapentaenoic acid.

[0077] In some embodiments, the EPA comprises an EPA fatty acid conjugate in which the EPA is conjugated to another molecule of EPA or to another fatty acid (or a derivative thereof). In some embodiments, the EPA-fatty acid conjugate comprises a diester formed between EPA and EPA or between EPA and a second fatty acid (or a derivative thereof), as shown in structure (I): [ka] During the ceremony, R1 is an acyl group derived from EPA, R2 is optionally an acyl group derived from a 10-30 carbon fatty acid having one or more cis or trans double bonds, or a derivative thereof, and R2 may be the same as or different from R1; R3 is an alkylene group in which one or more hydrogens are optionally replaced with an alkyl group, a hydroxyl group, an epoxy group, an aryl group, a phosphate group, or a phosphate group modified with a small organic compound.

[0078] In certain of these embodiments, both R1 and R2 can be acyl groups derived from EPA (i.e., an EPA-EPA conjugate). Alternatively, R1 can be derived from EPA and R2 can be derived from a different fatty acid or derivative thereof (i.e., an EPA-fatty acid conjugate), such as an omega-6 fatty acid, such as LA, GLA, DGLA, AA, AdA, and DPA6, or an omega-3 fatty acid, such as ALA, SDA, ETA, DPA, and DHA, or a derivative thereof.

[0079] Synthesis of diester conjugates can be accomplished according to methods well known in the art, including, for example, using metals, metal chlorides, or organic acids as catalysts, using fatty acid chlorides such as EPA-chloride, LA-chloride, conjugated linoleic acid chloride (cLA-chloride), GLA-chloride, DGLA-chloride, AA-chloride, AdA-chloride, DPA6 ALA-chloride, SDA-chloride, ETA-chloride, DPA-chloride, and DHA-chloride, and using immobilized enzymes as catalysts.

[0080] In some embodiments, the EPA-fatty acid conjugate (e.g., EPA-fatty acid diester) comprises a phospholipid-EPA (PL-EPA) conjugate in which the fatty acid at the sn-1 and / or sn-2 positions of the phospholipid molecule is replaced with EPA. In some embodiments, an acyl group derived from EPA and a second acyl group derived from EPA, or a second fatty acid (or derivative thereof) are attached to the sn-1 and sn-2 carbons of the phospholipid molecule, as shown in structure (II): [ka] During the ceremony, Each of R1 and R2 is optionally an acyl group derived from a 10-30 carbon fatty acid having one or more cis or trans double bonds, or a derivative thereof, and at least one of R1 and R2 is derived from EPA; X is selected from the group consisting of an anion, choline, ethanolamine, glycerol, inositol, and serine.

[0081] In certain of these embodiments, the EPA-fatty acid conjugate (e.g., PL-EPA) can also serve as a phospholipid source for the composition. Phospholipids (e.g., glycerophospholipids) having a particular fatty acid composition (e.g., enriched with EPA) can be synthesized according to the methods described in WO2005 / 038037, Int.J.Mol.Sci.(2014)15:15244-15258, and J.Oleo Sci.(2017)66(11):1207-1215, each of which is incorporated herein by reference in its entirety.

[0082] It should be noted that the EPA in the embodiments discussed above is illustrative, and that the EPA in those embodiments can be replaced with another PUFA or derivative thereof disclosed herein, for example, an omega-6 fatty acid such as LA, GLA, DGLA, AA, AdA, and DPA6, or an omega-3 fatty acid such as ALA, SDA, ETA, DPA, and DHA, or a derivative thereof.

[0083] In some embodiments, the composition contains at least 5% by weight of the composition of one or more PUFAs disclosed herein (e.g., EPA, as the term "EPA" is defined and exemplified herein) or derivatives thereof, e.g., at least 5% by weight, at least 10% by weight, at least 15% by weight, at least 20% by weight, at least 30% by weight, at least 40% by weight, at least 50% by weight, at least 60% by weight, at least 70% by weight, at least 80% by weight, at least 90% by weight, at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, or at least 99% by weight of the composition of a PUFA or derivative thereof.

[0084] In some embodiments, the composition contains a mixture of two or more PUFAs or derivatives thereof disclosed herein. In certain of these embodiments, each PUFA or derivative thereof comprises at least 5% by weight of the composition, e.g., at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, or about 50% by weight of the composition.

[0085] In some embodiments, the composition contains at least 5% by weight of the composition of EPA (as the term "EPA" is defined and exemplified herein) or a derivative thereof, e.g., at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% by weight of the composition.

[0086] In some embodiments, the composition contains at least 5% by weight of the EPA-fatty acid conjugate of the composition, for example, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% by weight of the EPA-fatty acid conjugate of the composition. In some embodiments, the composition contains no more than 10%, no more than 9%, no more than 8%, no more than 7%, no more than 6%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1%, no more than 0.6%, no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% by weight of any EPA-fatty acid conjugate other than EPA-EPA diester.

[0087] In some embodiments, the composition contains a mixture of EPA-fatty acid conjugates, such as EPA-fatty acid diesters. In some embodiments, the composition contains less than 20%, less than 15%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, or less than 0.1% by weight of the composition of EPA-DHA conjugates (e.g., EPA-DHA diesters).

[0088] In some embodiments, EPA (as the term "EPA" is defined and exemplified herein) is present in an amount of about 50 mg to about 5000 mg, about 75 mg to about 2500 mg, or about 100 mg to about 1000 mg, e.g., about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, g, approx. 625 mg, approx. 650 mg, approx. 675 mg, approx. 700 mg, approx. 725 mg, approx. 750 mg, approx. 775 mg, approx. 800 mg, approx. 825 mg, approx. 1050mg, 1075mg, 1100mg, 1025mg, 1050mg, 1075mg, 1200mg, 1225mg, 1250mg, 1275mg, 1300mg, 1325mg, 1350mg, 1375mg, 1400mg, 1425m g, approx. 1450 mg, approx. 1475 mg, approx. 1500 mg, approx. 1525 mg, approx. 1550 mg, approx. 1575 mg, approx. 1600 mg, approx. 1625 mg, approx. 825mg, 1850mg, 1875mg, 1900mg, 1925mg, 1950mg, 1975mg, 2000mg, 2025mg, 2050mg, 2075mg, 2100mg, 2125mg, 2150mg, 2175mg, 2200mg , approx. 2225 mg, approx. 2250 mg, approx. 2275 mg, approx. 2300 mg, approx. 2325 mg, approx. 2350 mg, approx. 2375 mg, approx. 2400 mg, approx. 2425 mg, approx. 00mg, about 2625mg, about 2650mg, about 2675mg, about 2700mg, about 2725mg, about 2750mg, about 2775mg, about 2800mg, about 2825mg, about 2850mg, about 2875mg, about 2900mg, about 2925mg, about 2950mg, about 2975mg,About 3000mg, about 3025mg, about 3050mg, about 3075mg, about 3100mg, about 3125mg, about 3150mg, about 3175mg, about 3200mg, about 3225mg, about 3 250mg, about 3275mg, about 3300mg, about 3325mg, about 3350mg, about 3375mg, about 3400mg, about 3425mg, about 3450mg, about 3475mg, about 3500 mg, about 3525mg, about 3550mg, about 3575mg, about 3600mg, about 3625mg, about 3650mg, about 3675mg, about 3700mg, about 3725mg, about 3750mg, About 3775mg, about 3800mg, about 3825mg, about 3850mg, about 3875mg, about 3900mg, about 3925mg, about 3950mg, about 3975mg, about 4000mg, about 40 25mg, about 4050mg, about 4075mg, about 4100mg, about 4125mg, about 4150mg, about 4175mg, about 4200mg, about 4225mg, about 4250mg, about 4275mg, about 4300mg, about 4325mg, about 4350mg, about 4375mg, about 4400mg, about 4425mg, about 4450mg, about 4475mg, about 4500mg, about 4525mg, The compound is present in the composition in an amount of about 4550 mg, about 4575 mg, about 4600 mg, about 4625 mg, about 4650 mg, about 4675 mg, about 4700 mg, about 4725 mg, about 4750 mg, about 4775 mg, about 4800 mg, about 4825 mg, about 4850 mg, about 4875 mg, about 4900 mg, about 4925 mg, about 4950 mg, about 4975 mg, or about 5000 mg.

[0089] In some embodiments, the composition may be administered in an amount of about 1 mg to about 20,000 mg, about 25 mg to about 10,000 mg, about 50 mg to about 5000 mg, about 75 mg to about 2500 mg, or about 100 mg to about 1000 mg, for example, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575mg, about 600mg, about 625mg, about 650mg, about 675mg, about 700mg, about 725mg, about 750mg, about 775mg, about 800mg, about 825mg, about 850mg, about 875mg, about 900mg, about 925mg, about 950mg, about 975mg, about 1000mg , approx. 1025 mg, approx. 1050 mg, approx. 1075 mg, approx. 1100 mg, approx. 1025 mg, approx. 1050 mg, approx. 1075 mg, approx. 1200 mg, approx. 1225 mg, approx. 1250 mg, approx. 0mg, approx. 1425mg, approx. 1450mg, approx. 1475mg, approx. 1500mg, approx. 1525mg, approx. 1550mg, approx. 1575mg, approx. 1600mg, approx. 1800mg, approx. 1825mg, approx. 1850mg, approx. 1875mg, approx. 1900mg, approx. 1925mg, approx. 1950mg, approx. 1975mg, approx. 2000mg, approx. g, approx. 2200 mg, approx. 2225 mg, approx. 2250 mg, approx. 2275 mg, approx. 2300 mg, approx. 2325 mg, approx. 2350 mg, approx. 2375 mg, approx. 75mg, about 2600mg, about 2625mg, about 2650mg, about 2675mg, about 2700mg, about 2725mg, about 2750mg, about 2775mg, about 2800mg, about 2825mg, about 2850mg, about 2875mg, about 2900mg, about 2925mg, about 2950mg,About 2975 mg, about 3000 mg, about 3025 mg, about 3050 mg, about 3075 mg, about 3100 mg, about 3125 mg, about 3150 mg, about 3175 mg, about 3200 mg, about 3225 mg, about 3250 mg, about 3275 mg, about 3300 mg, about 3325 mg, about 3350 mg, about 3375 mg, about 3400 mg, about 3425 mg, about 3450 mg, about 3475 mg, about 3500 mg, about 3525 mg, about 3550 mg, about 3575 mg, about 3600 mg, about 3625 mg, about 3650 mg, about 3675 mg, about 3700 mg, about 3725 mg, about 3750 mg, about 3775 mg, about 3800 mg, about 3825 mg, about 3850 mg, about 3875 mg, about 3900 mg, about 3925 mg, about 3950 mg, about 3975 mg, about 4000 mg, about 4025 mg, about 4050 mg, about 4075 mg, about 4100 mg, about 4125 mg, about 4150 mg, about 4175 mg, about 4200 mg, about 4225 mg, about 4250 mg, about 4275 mg, about 4300 mg, about 4325 mg, about 4350 mg, about 4375 mg, about 4400 mg, about 4425 mg, about 4450 mg, about 4475 mg, about 4500 mg, about 4525 mg, about 4550 mg, about 4575 mg, about 4600 mg, about 4625 mg, about 4650 mg, about 4675 mg, about 4700 mg, about 4725 mg, about 4750 mg, about 4775 mg, about 4800 mg, about 4825 mg, about 4850 mg, about 4875 mg, about 4900 mg, about 4925 mg, about 4950 mg, about 4975 mg, about 5000 mg, about 5025 mg, about 5050 mg, about 5075 mg, about 5100 mg, about 5125 mg, about 5150 mg, about 5175 mg, about 5200 mg, about 5225 mg, about 5250 mg, about 5275 mg, about 5300 mg, about 5325 mg, about 5350 mg, about 5375 mg, about 5400 mg, about 5425 mg, about 5450 mg, about 5475 mg, about 5500 mg, about 5525 mg, about 5550 mg, about 5575 mg, about 5600 mg, about 5625 mg, about 5650 mg, about 5675 mg, about 5700 mg, about 5725 mg, about 5750 mg, about 5775 mg, about 5800 mg, about 5825 mg, about 5850 mg, about 5875 mg, about 5900 mg, about 5925 mg, about 5950 mg, about 5975 mg, about 6000 mg, about 6025 mg, about 6050 mg, about 6075 mgApproximately 6100 mg, approximately 6125 mg, approximately 6150 mg, approximately 6175 mg, approximately 6200 mg, approximately 6225 mg, approximately 6250 mg, approximately 6275 mg, approximately 6300 mg, approximately 6325 mg, approximately 6350 mg, approximately 6375 mg, approximately 6400 mg, approximately 6425 mg, approximately 6450 mg, approximately 6475 mg, approximately 6500 mg, approximately 6525 mg, approximately 6550 mg, approximately 6575 mg, approximately 6600 mg, approximately 6625 mg, approximately 6650 mg, approximately 6675 mg, approximately 6700 mg, approximately 6725 mg, approximately 6750 mg, approximately 6775 mg, approximately 6800 mg, approximately 6825 mg, approximately 6850 mg, approximately 6875 mg, approximately 6900 mg, approximately 6925 mg, approximately 6950 mg, approximately 6975 mg, approximately 7000 mg, approximately 7025 mg, approximately 7050 mg, approximately 7075 mg, approximately 7100 mg, approximately 7125 mg, approximately 7150 mg, approximately 7175 mg, approximately 7200 mg, approximately 7225 mg, approximately 7250 mg, approximately 7275 mg, approximately 7300 mg, approximately 7325 mg, approximately 7350 mg, approximately 7375 mg, approximately 7400 mg, approximately 7425 mg, approximately 7450 mg, approximately 7475 mg, approximately 7500 mg, approximately 7525 mg, approximately 7550 mg, approximately 7575 mg, approximately 7600 mg, approximately 7625 mg, approximately 7650 mg, approximately 7675 mg, approximately 7700 mg, approximately 7725 mg, approximately 7750 mg, approximately 7775 mg, approximately 7800 mg, approximately 7825 mg, approximately 7850 mg, approximately 7875 mg, approximately 7900 mg, approximately 7925 mg, approximately 7950 mg, approximately 7975 mg, approximately 8000 mg, approximately 8025 mg, approximately 8050 mg, approximately 8075 mg, approximately 8100 mg, approximately 8125 mg, approximately 8150 mg, approximately 8175 mg, approximately 8200 mg, approximately 8225 mg, approximately 8250 mg, approximately 8275 mg, approximately 8300 mg, approximately 8325 mg, approximately 8350 mg, approximately 8375 mg, approximately 8400 mg, approximately 8425 mg, approximately 8450 mg, approximately 8475 mg, approximately 8500 mg, approximately 8525 mg, approximately 8550 mg, approximately 8575 mg, approximately 8600 mg, approximately 8625 mg, approximately 8650 mg, approximately 8675 mg, approximately 8700 mg, approximately 8725 mg, approximately 8750 mg, approximately 8775 mg, approximately 8800 mg, approximately 8825 mg, approximately 8850 mg, approximately 8875 mg, approximately 8900 mg, approximately 8925 mg, approximately 8950 mg, approximately 8975 mg, approximately 9000 mg, approximately 9025 mg, approximately 9050 mg, approximately 9075 mg, approximately 9100 mg, approximately 9125 mg, approximately 9150 mg, approximately 9175 mg, approximately 9200 mgAbout 9225mg, about 9250mg, about 9275mg, about 9300mg, about 9325mg, about 9350mg, about 9375mg, about 9400mg, about 9425mg, about 9450mg, about 9475mg, about 9500mg, about 9525mg, about 95 50mg, about 9575mg, about 9600mg, about 9625mg, about 9650mg, about 9675mg, about 9700mg, about 9725mg, about 9750mg, about 9775mg, about 9800mg, about 9825mg, about 9850mg, about 9875m The composition is formulated for administration to a subject in an amount sufficient to provide a daily dose of EPA (as the term "EPA" is defined and exemplified herein) of about 10,000 mg, about 11,000 mg, about 12,000 mg, about 13,000 mg, about 14,000 mg, about 15,000 mg, about 16,000 mg, about 17,000 mg, about 18,000 mg, about 19,000 mg, or about 20,000 mg.

[0090] In some embodiments, EPA (as the term "EPA" is defined and exemplified herein) represents at least 50% by weight of all fatty acids or PUFAs present in the composition, e.g., at least 50% by weight, at least 60% by weight, at least 66% by weight, at least 70% by weight, at least 75% by weight, at least 80% by weight, at least 85% by weight, at least 90% by weight, at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, or 100% by weight of all fatty acids or PUFAs present in the composition.

[0091] In some embodiments, the composition comprises ultra-pure EPA. The term "ultra-pure" as used herein with respect to EPA refers to a composition that comprises at least 96% EPA (as the term "EPA" is defined and exemplified herein) by weight of the composition. Ultra-pure EPA can comprise EPA of even higher purity, for example, at least 97% EPA, at least 98% or at least 99% EPA by weight of the composition, where EPA is in any form as described herein.

[0092] In some embodiments, the composition contains no more than 20% by weight, no more than 15% by weight, no more than 10% by weight, no more than 9% by weight, no more than 8% by weight, no more than 7% by weight, no more than 6% by weight, no more than 5% by weight, no more than 4% by weight, no more than 3% by weight, no more than 2% by weight, no more than 1% by weight, no more than 0.6% by weight, no more than 0.5% by weight, no more than 0.4% by weight, no more than 0.3% by weight, no more than 0.2% by weight, or no more than 0.1% by weight of the total fatty acids or PUFAs present in the composition of any PUFAs other than EPA or derivatives thereof. In some embodiments, the composition contains 20% or less by weight, 15% or less by weight, 10% or less by weight, 9% or less by weight, 8% or less by weight, 7% or less by weight, 6% or less by weight, 5% or less by weight, 4% or less by weight, 3% or less by weight, 2% or less by weight, 1% or less by weight, 0.6% or less by weight, 0.5% or less by weight, 0.4% or less by weight, 0.3% or less by weight, 0.2% or less by weight, or 0.1% or less by weight of DHA (e.g., ethyl-DHA or EDHA) or its derivatives (if present). In some embodiments, the composition is substantially free of DHA (e.g., EDHA) or its derivatives. In some embodiments, the composition is free of DHA (e.g., EDHA) or its derivatives.

[0093] In some embodiments, the composition contains less than 30%, less than 20%, less than 15%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, or less than 0.25% by weight of any PUFA or derivative thereof other than EPA of the composition or of the total fatty acids or PUFAs present in the composition. Illustrative examples of "PUFA other than EPA or derivatives thereof" include LA (e.g., ethyl-LA) or a derivative thereof, GLA (e.g., ethyl-GLA) or a derivative thereof, DGLA (e.g., ethyl-DGLA) or a derivative thereof, AA (e.g., ethyl-AA) or a derivative thereof, AdA (e.g., ethyl-AdA) or a derivative thereof, DPA6 (e.g., ethyl-DPA6) or a derivative thereof, ALA (e.g., ethyl-ALA) or a derivative thereof, SDA (e.g., ethyl-SDA) or a derivative thereof, ETA (e.g., ethyl-ETA) or a derivative thereof, DPA (ethyl-DPA) or a derivative thereof, and DHA (e.g., ethyl-DHA or EDHA) or a derivative thereof.

[0094] Phospholipids In some embodiments, the phospholipid source of the composition may include a glycerophospholipid, a lysophospholipid, or a mixture thereof.

[0095] In some embodiments, the phospholipid source comprises glycerophospholipids. Glycerol-based phospholipids are glycerol-based phospholipids characterized by a glycerol backbone with a polar phosphodiester group attached to the sn-3 carbon and two fatty acid-derived acyl groups attached to the sn-1 and sn-2 carbons. Glycerolphospholipids are major components of biological membranes. Non-limiting examples of glycerophospholipids include phosphatidic acid or phosphatidate (PA), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylinositol (PI), and phosphatidylserine (PS). Glycerolphospholipids can be obtained from krill oil, purified, and optionally enriched for specific fatty acids such as EPA.

[0096] In some embodiments, the phospholipid source comprises lysophospholipid (LPL). LPL is a glycerophospholipid that lacks one acyl chain and only one hydroxyl group of the glycerol backbone is acylated. 1-lysophospholipid (1-LPL) maintains the acyl chain at the sn-2 position, while 2-lysophospholipid (2-LPL) is only acylated at the sn-1 position. Thus, LPL is a small bioactive lipid molecule characterized by a single carbon chain and a polar head group. LPL is a bioactive signaling lipid generated from phospholipase-mediated hydrolysis of membrane phospholipids and sphingolipids. Non-limiting examples of LPLs include sn-1-acyl-glycerol-3-phosphate, sn-2-acyl-glycero-3-phosphate, lysophosphatidic acid (LPA or lyso-PA), lysophosphatidylcholine (LPC or lyso-PE), lysophosphatidylethanolamine (LPE or lyso-PE), lysophosphatidylglycerol (LPG or lyso-PG), lysophosphatidylinositol (IPI or lyso-PI), and lysophosphatidylserine (LPS or lyso-PS).

[0097] In certain of these embodiments, the acyl chains of the glycerophospholipids or LPLs can be derived from any fatty acid, for example, 10-30 long chain hydrocarbon (C10-C30) fatty acids. These fatty acids can be straight or branched, saturated or unsaturated (e.g., containing one or more cis or trans double bonds). In some embodiments, the acyl chains can be derived from a PUFA or derivatives thereof described herein, including, for example, LA, GLA, DGLA, AA, AdA, DPA6, ALA, SDA, ETA, EPA, DPA, DHA, or derivatives thereof.

[0098] In some embodiments, the phospholipid source is lecithin. Lecithin is a mixture of glycerophospholipids, usually including PA, PC, PE, PG, PI, PS, and LPL. It has low water solubility, but can function as a good emulsifier in aqueous solution. Lecithin can be obtained from different sources, such as soybean, milk, egg yolk, marine food, rapeseed, cottonseed, and sunflower oil, with soybean lecithin (refined and / or chemically modified) being the most common commercial form. In some embodiments, the lecithin is soybean lecithin, such as Metarin™ P (Cargill, MN).

[0099] In some embodiments, the content of each glycerophospholipid and / or LPL in the mixture may vary, such as when the phospholipid source comprises a mixture of glycerophospholipids and / or LPLs (e.g., lecithin). Without wishing to be bound by theory, the ratio of PE:PI in lecithin may be particularly important, as certain PUFAs are dominated by certain phospholipids (e.g., EPA is dominated by PE, and AA is dominated by PI), and thus the relative content of PE:PI in lecithin may affect the bioavailability of PUFA components in vivo. In some embodiments, the weight ratio of PE and PI in the phospholipid source (e.g., lecithin) ranges from about 5:1 (PE is predominant) to 1:5 (PI is predominant), for example, about 2:1 (PE is predominant) to 1:2 (PI is predominant).

[0100] In some embodiments, the phospholipid source (e.g., lecithin) is enriched with PE and / or limited in PI. In some embodiments, the phospholipid source comprises up to 40%, up to 60%, up to 80%, up to 90%, up to 95%, or up to 97% by weight of the phospholipid source of PE, and 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less by weight of the phospholipid source of PI. In some embodiments, the phospholipid source (e.g., lecithin) comprises up to 40%, up to 60%, up to 80%, or up to 85% by weight of the phospholipid source of PE, and 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less by weight of the phospholipid source of PI. The PE-enriched and / or PI-limited phospholipid source may be derived from a natural source or may be obtained by chemical processes known to those skilled in the art, including, for example, separation by density and chemical precipitation.

[0101] In some embodiments, the composition contains between 1% and 85% by weight of the composition of a phospholipid source (e.g., lecithin), for example, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, or 85% by weight of the composition of a phospholipid source. In some embodiments, the composition contains 85% or less, 80% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5%, or 1% or less of a phospholipid source by weight of the composition.

[0102] emulsifier In some embodiments, the composition optionally further comprises one or more additional emulsifiers.Non-limiting examples of emulsifiers include polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, polyethylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, and lecithin.In one embodiment, the emulsifier is polysorbate 80, polyoxyl-35, or both.

[0103] In some embodiments, the emulsifier comprises one or more glycerol derivatives selected from the group consisting of triacylglycerol, diacylglycerol, and monoacylglycerol. In one embodiment, the glycerol derivative is castor oil. The glycerol derivative may also be a re-esterified triglyceride (rTG) enriched with the PUFAs (e.g., EPA) of the composition. As used herein, a "re-esterified triglyceride" is a chemically synthesized triglyceride. The re-esterified triglyceride enriched with EPA may be synthesized, for example, according to the method disclosed in J.Agric.Food Chem.(2018)66(1):218-227. In triglycerides extracted from natural fish oil, omega-3 PUFAs are found primarily at the sn-2 position of the glycerol molecule. In the re-esterification process, which adds on average one extra n-3 fatty acid to each triglyceride molecule, the position of EPA and / or DHA in the glyceride molecule is random, and therefore the sn-1 / 3 and sn-2 positions are equally esterified by EPA and DHA in the glycerol molecule.

[0104] In some embodiments, the composition contains between 1% and 20% by weight of the composition of one or more emulsifiers, for example, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or 20% by weight of the composition of one or more emulsifiers. In some embodiments, the composition contains up to 20%, up to 15%, up to 10%, up to 9%, up to 8%, up to 7%, up to 6%, up to 5%, up to 4%, up to 3%, up to 2%, or up to 1% by weight of the composition of one or more emulsifiers.

[0105] In some embodiments, the composition contains from 1% to 85% additive (e.g., phospholipid and / or emulsifier) ​​by weight of the composition, e.g., at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, or 85% additive by weight of the composition. In some embodiments, the composition contains up to 85% by weight, up to 80% by weight, up to 75% by weight, up to 70% by weight, up to 65% by weight, up to 60% by weight, up to 55% by weight, up to 50% by weight, up to 45% by weight, up to 40% by weight, up to 35% by weight, up to 30% by weight, up to 25% by weight, up to 20% by weight, up to 15% by weight, up to 10% by weight, 5% by weight, or up to 1% by weight of the composition of the additive.

[0106] In some embodiments, the composition contains a fixed dose of PUFA (e.g., EPA) or a derivative thereof, as well as varying doses of a phospholipid source and varying doses of an emulsifier relative to the PUFA or derivative thereof. In some embodiments, the weight ratio between the PUFA or derivative thereof and the phospholipid source in the composition ranges from about 20:1 (PUFA or derivative thereof predominates) to about 1:5 (phospholipid source predominates), such as about 5:1 (PUFA or derivative thereof predominates) to about 1:5 (phospholipid source predominates), about 3.75:1 (PUFA or derivative thereof predominates) to about 1:5 (phospholipid source predominates), or about 1:1 to about 1:5 (phospholipid source predominates). In some embodiments, the weight ratio between the PUFA or derivative thereof and the emulsifier in the composition ranges from 10:1 (PUFA or derivative thereof predominates) to 1:1.

[0107] In a preferred embodiment, provided is a lymphatic-released (LR) EPA formulation (herein referred to as "LR-EtEPA") by co-formulating the phospholipids described herein with eicosapentaenoic acid ethyl ester (also referred to as EtEPA, ethyl-EPA, E-EPA, EPA-E, or IPE). The composition may optionally further comprise one or more emulsifiers, such as polysorbate 80, polyoxyl-35, or both. As illustrated herein and demonstrated in the working examples, co-formulation of EtEPA with phospholipids and / or emulsifiers (together referred to as additives or excipients) promotes the in vivo formation of esterified EPA substrates upon administration, thus causing EPA to bind to and be absorbed by phospholipids, and redirect EPA to the lymphatic system for delivery to target tissues. Thus, the phospholipids and / or emulsifiers in the LR-EtEPA formulation may also be referred to as LR compounds. In one example, the phospholipid source is lecithin, such as soy lecithin (e.g., Metarin™ P). Exemplary compositions according to the above embodiments are disclosed in European Patent Application No. 3023098A1 and in Example 1 of the present disclosure, the entire contents of which are incorporated herein by reference.

[0108] It should be noted that the LR-EtEPA compositions in the embodiments discussed above are illustrative and similar lymphatic releasing compositions may be formulated with another PUFA or derivative thereof disclosed herein, for example, an omega-6 fatty acid such as LA, GLA, DGLA, AA, AdA, and DPA6, or an omega-3 fatty acid such as ALA, SDA, ETA, DPA, and DHA, or a derivative thereof.

[0109] In some embodiments, compositions comprising one or more PUFAs or derivatives thereof, a phospholipid source, and optionally one or more additional emulsifiers according to various embodiments disclosed herein may be formulated as one or more dosage units. The term "dosage unit" refers to a portion of a pharmaceutical composition containing an amount of a therapeutic agent suitable for a single administration to provide a therapeutic effect. The terms "composition" and "pharmaceutical composition" are used interchangeably. Such dosage units may be administered one to multiple times (i.e., 2, 3, 4, 5 or more times) per day, or as many times as necessary to elicit a therapeutic response.

[0110] In some embodiments, the composition is orally deliverable or in a form suitable for oral administration. The term "orally deliverable" or "oral administration" includes any form of delivery of a pharmaceutical composition to a subject in which the composition is placed in the subject's mouth, regardless of whether the composition is swallowed. In some embodiments, the dosage unit is a capsule, i.e., the composition is formulated in one or more capsules, such as soft gelatin capsules. One or more capsules can be packaged in a blister pack or container (e.g., a bottle).

[0111] In some embodiments, the PUFA (e.g., EtEPA) or a derivative thereof and the phospholipid source (e.g., lecithin) (and optionally one or more additional emulsifiers) may be co-formulated in the same dosage unit or individually formulated in separate dosage units. In a non-limiting example, EtEPA and the phospholipid source (e.g., lecithin) may be co-formulated in the same capsule or individually formulated in separate capsules. For the latter, the capsule containing EtEPA and the capsule containing the phospholipid source (e.g., lecithin) may be packaged in separate bottles or blister packs, or alternatively, may be packaged in the same bottle or blister pack.

[0112] In some embodiments, the compositions are formulated for administration alone or with food.

[0113] In another embodiment, the composition has an injectable formulation, a lyophilized formulation, or a liquid formulation, depending on the route of administration.In some embodiments, the composition may have various formulations for injection and / or infusion, such as intravenous injection, intraperitoneal injection, intertumoral injection, bone marrow injection, lymph node injection, subcutaneous injection, and cerebrospinal fluid injection.In some embodiments, the composition may be provided in a ready-to-hang formulation for enteric use in intensive care unit (ICU) settings, for example, to treat SIRS, sepsis, and / or ARDS.

[0114] Treatment method In some embodiments, provided is a method for improving the level of PUFAs in lymph or enriching lymph with PUFAs in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising one or more PUFAs or their derivatives according to various embodiments disclosed herein and a phospholipid source.As used herein, "lymph" should be understood to include both non-cellular and cellular components of lymph.Since the cellular compartment of lymph is primarily lymphocytes, these embodiments also include conditions that may involve enriching immune cells with PUFAs or their derivatives, thereby affecting lymphocytes.

[0115] The term "therapeutically effective amount" refers to an amount that is sufficient to effect treatment as defined herein when administered to a mammal in need of such treatment. The therapeutically effective amount varies depending on the subject and disease state being treated, the severity of the affliction and the mode of administration, and can be routinely determined by one of skill in the art.

[0116] Long-chain fatty acids such as EPA can enter the circulation by two routes: the portal vein route and the lymphatic route. As shown in FIG. 1A, once EPA is absorbed in the intestine, the EPA circulation is bifurcated into two, i.e., it can either pass through the lymphatics and completely bypass the liver and visceral fat, or it can pass through the portal vein, where (1) the visceral fat can sequester the EPA and (2) the liver can take up the EPA and oxidize, modify, or pass the fatty acid. EPA traveling through the portal vein undergoes significant fat sequestration and hepatic first-pass loss, resulting in reduced circulation of EPA. EPA traveling through the lymphatics avoids the visceral and hepatic first-pass losses, resulting in improved delivery of EPA to the first tissue bed it encounters, the lungs. Delivery of lipid-soluble drugs to the lungs benefits from high perfusion rates, since the lungs receive 100% of the cardiac output. After the lungs, EPA circulates through the aorta, which supplies blood and nutrients to the coronary and carotid arteries and other parts of the body. EPA that bypasses visceral fat and the liver (and any associated first pass losses) improves cardiopulmonary and cerebrovascular EPA uptake, including the coronary, carotid, and vertebral arteries.

[0117] It is believed that the inclusion of phospholipids (e.g., lecithin) and / or emulsifiers together with fatty acids (e.g., EtEPA) in the composition has different advantages in the method of the present invention, including favorable routing through the lymphatic system and improved bioavailability of the active ingredient at the tissue and cellular levels. For example, without wishing to be bound by theory, it is believed that the co-administration of EtEPA and phospholipids results in the in vivo formation of esterified EPA substrates, thus resulting in the delivery of EPA as phospholipids. It is believed that when the composition of the present technology enters the small intestine, a cross-esterification process occurs between EPA and the fatty acid components of the phospholipid molecule, resulting in PL-EPA. The EPA-phospholipid compound is optimized for uptake by cells, such as enterocytes, since it is in a phospholipid matrix. Thus, EPA is secreted from enterocytes bound to phospholipids and / or triglycerides. It is expected that the presence of excess phospholipid substrates from the administered phospholipids will improve incorporation into enterocyte secreted lipoproteins as phospholipid-EPA in LR-EtEPA compared to plain EtEPA. Thus, provision of phospholipids not only improves absorption and uptake by enterocytes, but also promotes the reassembly of esterified EPA into phospholipids, optimizing cellular uptake and incorporation into cell membranes. Not only that, but phospholipids also promote the assembly and secretion of chylomicrons and / or intestinal very low density lipoproteins (I-VLDL) by enterocytes. Since chylomicrons and I-VLDL are primarily secreted into lymph, the composition of the present technology promotes rerouting of EPA to chylomicrons / I-VLDL, thereby to lymph, thereby avoiding hepatic and adipose first-pass visceral losses associated with the portal vein route. This routing is located in the heart and lungs as first-pass organs, thus increasing EPA concentration and EPA / AA ratio in various tissues (e.g., lungs, heart, brain, kidneys, intestines, and pancreas) (Figure 1B).

[0118] Typically, visceral fat captures about 50% of the fatty acids presented to the portal vein. Long-chain polyunsaturated fatty acids (LC-PUFAs), including EPA, are generally known to be taken up by adipose tissue from studies of subcutaneous fat. Visceral fat is expected to incorporate EPA even more readily than subcutaneous fat, since it is exposed to a greater amount of nutritional forms of EPA. Thus, visceral fat may bypass about half of the EPA present in the portal vein, either by storing it for an indeterminate amount of time or by being catabolized by beta-oxidation in situ. 50% of the fatty acids that bypass the visceral fat capture are present in the liver. The liver typically receives about 75% of its blood through the portal vein and only 25% from the hepatic artery. Nutritional EPA present in the liver via the portal vein is subjected to first-pass metabolism, which may include elongation and desaturation to form other LC-PUFAs, oxygenation to form oxylipins, or beta-oxidation for use as metabolic fuel. Between visceral fat trapping and hepatic first-pass loss, a significant portion of nutritional EPA is expected to be lost or bypassed when shunting through the portal vein. To the extent that lecithin and excipients generally shunt nutritional EPA through lymphatic veins, visceral loss and bypass are avoided, and more EPA remains available to systemic tissues after passing through the cardiopulmonary system.

[0119] As shown in the working examples, the lymphatic-released EtEPA composition of the present technology (LR-EtEPA) has more than two-fold (2.4-fold) lymphatic EPA levels compared to regular EtEPA composition given at equimolar doses of EtEPA (FIG. 1A). LR-EtEPA also significantly increases EPA levels in the first-pass organs lung (1.7-fold) and heart (2.0-fold), as well as in the brain (1.7-fold) compared to EtEPA. An increase was also observed in pulmonary alveolar macrophages (AVMs), the primary immune cells in the lung safeguard against airborne pathogens and tissue damage, which play a key role in the active inflammatory cascade in conditions such as sepsis and ARDS (2.1-fold). Thus, EPA uptake following LR-EtEPA was found to be superior to EtEPA alone when administered at equimolar doses of EtEPA, suggesting that LR-EtEPA is more potent than EtEPA at equimolar doses in increasing EPA levels and / or outcomes in certain tissues and that smaller doses of LR-EtEPA are required to achieve the same amount of tissue EPA as regular EtEPA. EPA / AA ratios were also increased in the same tissues / organs by LR-EtEPA, e.g., 2.6-fold higher in the lungs than levels from regular EtEPA, 2.0-fold higher in the heart, 1.8-fold higher in the brain, and 2.9-fold higher in AVMs.

[0120] The preclinical studies described herein support that LR-EtEPA is superior to EtEPA in achieving cellular EPA uptake in three circulating blood cell types and two broad immune cell types. Co-administration of EtEPA with glycerophospholipids resulted in increased uptake of EPA in lymphoid cells, primarily composed of T lymphocytes, B lymphocytes, and natural killer (NK) cells. The rate of EPA uptake was enhanced in alveolar macrophages, and increased EPA uptake was also observed in resident macrophages of the alveoli. One skilled in the art would expect similar acceleration of EPA uptake in coronary or carotid macrophages.

[0121] Enhanced cellular uptake of EPA with LR-EtEPA compared to plain EtEPA was also observed in several dense tissues, including lung, heart, brain, kidney, pancreas, jejunum, and liver cells. Notably, the superior cellular uptake was not accompanied by consistent differences in acellular blood such as plasma, suggesting that LR-EtEPA is superior at delivering EPA to tissues and increasing tissue / cellular level EPA bioavailability, even when producing comparable acellular blood / plasma EPA levels as plain EtEPA.

[0122] In summary, compared to administering EtEPA alone, co-administration of phospholipids and / or emulsifiers with EtEPA in lymphatic release EPA formulation (LR-EtEPA) shunts EPA to the lymphatic system instead of the portal vein. In so doing, visceral / liver first-pass loss is reduced, resulting in more efficient drug delivery. Due to its high perfusion and reduced first-pass loss, delivering drugs via lymphatic route improves incorporation, particularly in the lungs, heart, and brain. The lungs and heart essentially become first-pass organs, which means that the composition is particularly advantageous for treating cardiopulmonary diseases. The composition also improves EPA delivery and uptake by coronary, carotid, and vertebral arteries, and thus to the heart and brain, as well as other organs / tissues of the body.

[0123] Furthermore, increasing the amount of additives (e.g., phospholipids and / or emulsifiers) appears to result in significantly more EPA delivered to the lymph (Figure 2). By changing the ratio of EtEPA to additive from 4:1 (EtEPA dominating) to 1:1 (i.e., equal parts EtEPA and additive), the cumulative lymphatic delivery of EPA is significantly higher and the increase in EPA uptake is prolonged compared to the less additive formulation, showing a robust dose-dependent effect between the amount of phospholipid and the amount of EPA delivered to the lymph. The lymphatic release effect of the composition and its additives, and the corresponding improved bioavailability in the lymph and enhanced drug delivery to tissues, are expected to be applicable to other PUFAs and their derivatives. Thus, the present technology provides an excellent formulation for delivering PUFAs and their derivatives to various tissues and cells of the body, which presents great therapeutic potential for a variety of diseases.

[0124] It should be noted that the phospholipid of the composition does not need to be administered at the same rate as the fatty acid component, because the intestinal absorption of fatty acid and its subsequent delivery to lymph may be discontinuous.Therefore, in certain medical situations, it may be advantageous to provide phospholipid over a longer period than fatty acid.This will also help to better distribute the volume load of the composition.

[0125] Cardiopulmonary, cardiovascular, and cerebrovascular diseases In some embodiments, provided is a method for treating and / or preventing cardiopulmonary, cardiovascular, and / or cerebrovascular diseases in a subject in need thereof by administering a composition of the present technology to the subject. As described above, the composition of the present technology, for example, lymphatic release EPA formulation (LR-EtEPA), is excellent at rerouting EPA to the lymphatic system and delivering EPA to tissues and cells, including the heart, lungs, and brain. Notably, LR-EtEPA is superior to EtEPA alone in enhancing coronary arteries with EPA, generally suggesting its therapeutic potential in diseases such as atherosclerosis and vasculitis that affect the coronary, carotid, vertebral, and cerebral vasculature. Due to the therapeutic effects of EPA, the composition of the present technology is believed to be particularly useful for delivering EPA to target tissues and cells and treating diseases, including those associated with the heart, lungs, and brain.

[0126] The term "treatment" or "treating" in relation to a given disease or disorder includes, but is not limited to, inhibiting the disease or disorder, e.g., halting the progression of the disease or disorder; relieving the disease or disorder, e.g., causing regression of the disease or disorder; or relieving a condition caused by or resulting from the disease or disorder, e.g., relieving, preventing, or treating the symptoms of the disease or disorder. The term "prevention" or "preventing" in relation to a given disease or disorder includes preventing the onset of disease development if none has occurred, preventing the disease or disorder from occurring in a subject who may be predisposed to the disorder or disorder but has not yet been diagnosed with the disorder or disorder, and / or preventing further development of the disease / disorder if already present.

[0127] In some embodiments, provided is a method of treating and / or preventing cardiovascular and / or cerebrovascular disease or reducing the risk of cardiovascular and / or cerebrovascular disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising one or more PUFAs or derivatives thereof according to various embodiments disclosed herein and a phospholipid source.

[0128] The term "cardiovascular disease" refers to any disease or disorder of the heart (cardiac disease or disorder) or blood vessels (vascular disease or disorder), or any symptoms thereof. Non-limiting examples of cardiovascular disease include hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, coronary heart disease, stroke, atherosclerosis, arrhythmias, hypertension, myocardial infarction, vasculitis, cardiomyopathy (e.g., viral cardiomyopathy, including that associated with COVID-19), pericarditis, congestive heart failure, myocardial necrosis, vascular ischemia, vascular disease beyond the cardiopulmonary system, thrombotic disease, post-myocardial infarction myocardial remodeling, giant cell arteritis, polyarteritis nodosa, cryoglobulinemia, paroxysmal venular ischemia (Raynaud's disease), deep vein thrombosis, disseminated intravascular coagulation, erectile dysfunction, and other cardiovascular or related diseases.

[0129] As used herein, "vascular disease beyond the cardiopulmonary system" includes vasculitis outside the cardiopulmonary system, including the carotid and vertebral arteries and their branches, as well as vasculitis affecting peripheral arteries (e.g., aortitis, renal vasculitis), and atherosclerosis outside the cardiopulmonary system, including the carotid and vertebral arteries and their peripheral arteries and branches. "Thrombotic disease" includes disseminated intravascular coagulation, other diseases involving excessive platelet activation, venous thrombosis, and thrombotic events associated with major adverse cardiovascular events.

[0130] In some embodiments, provided is a method of delaying the onset of cardiovascular and / or cerebrovascular events in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising PUFA or derivatives thereof and a phospholipid source according to various embodiments disclosed herein. "Onset of cardiopulmonary and / or cerebrovascular events" refers to the first appearance of cardiovascular and / or cerebrovascular signs and / or symptoms. In some embodiments, delaying the onset of cardiovascular and / or cerebrovascular events prevents the subject from experiencing a cardiovascular and / or cerebrovascular event and / or from developing any further symptoms of a cardiovascular and / or cerebrovascular event. Non-limiting examples of cardiovascular and / or cerebrovascular events include non-fatal myocardial infarction, stroke, cardiovascular death, unstable angina, coronary revascularization, carotid revascularization, peripheral revascularization, cerebrovascular accident, transient ischemic attachment, and hospitalization due to unstable angina.

[0131] In some embodiments, a subject being treated for cardiopulmonary, cardiovascular, and / or cerebrovascular disease has a fasting baseline triglyceride level (or median fasting baseline triglyceride level, for a subject group) of about 135 mg / dL to about 500 mg / dL, e.g., about 135 mg / dL to less than 500 mg / dL, about 150 mg / dL to less than 500 mg / dL, about 200 mg / dL to less than 500 mg / dL, or about 200 mg / dL to about 499 mg / dL.In some embodiments, the subject has a blood glucose level of about 135 mg / dL, about 140 mg / dL, about 145 mg / dL, about 150 mg / dL, about 155 mg / dL, about 160 mg / dL, about 165 mg / dL, about 170 mg / dL, about 175 mg / dL, about 180 mg / dL, about 185 mg / dL, about 190 mg / dL, about 195 mg / dL, about 200 mg / dL, about 205 mg / dL, about 210 mg / dL, about 215 mg / dL, about 220 mg / dL, about 225 mg / dL, about 230 mg / dL, about 235 mg / dL, about 240 mg / dL, about 245 mg / dL, about 250 mg / dL, about 255 mg / dL, about 260 mg / dL, about 265 mg / dL, about 270 mg / dL, about 275 mg / dL, about 280 mg / dL, about 285 mg / dL, about 290 mg / dL, about 295 mg / dL, about 300 mg / dL, about 305 mg / dL, about 310 mg / dL, about 315 mg / dL, about 320 mg / dL, about 325 mg / dL, about 330 mg / dL, about 340 mg / dL, about 345 mg / dL, about 350 mg / dL, about 355 mg / dL, about 360 mg / dL, about 365 mg / dL, about 370 mg / dL, about 375 mg / dL, about 380 mg / dL, about 385 mg / dL dL, approximately 230 mg / dL, approximately 235 mg / dL, approximately 240 mg / dL, approximately 245 mg / dL, approximately 250 mg / dL, approximately 255 mg / dL, approximately 260 mg / dL, approximately 265 mg / dL, approximately 270 mg / dL, approximately 275 mg / dL , about 280 mg / dL, about 285 mg / dL, about 290 mg / dL, about 295 mg / dL, about 300 mg / dL, about 305 mg / dL, about 310 mg / dL, about 315 mg / dL, about 320 mg / dL, about 325 mg / dL, about 330mg / dL, about 335mg / dL, about 340mg / dL, about 345mg / dL, about 350mg / dL, about 355mg / dL, about 360mg / dL, about 365mg / dL, about 370mg / dL, about 375mg / dL, about 3 80mg / dL, approximately 385mg / dL, approximately 390mg / dL, approximately 395mg / dL, approximately 400mg / dL, approximately 405mg / dL, approximately 410mg / dL, approximately 415mg / dL, approximately 420mg / dL, approximately 425mg / dL, approximately 430 In some embodiments, the subject has a fasting baseline triglyceride level (or median fasting baseline triglyceride level for a group of subjects) of about 435 mg / dL, about 440 mg / dL, about 445 mg / dL, about 450 mg / dL, about 455 mg / dL, about 460 mg / dL, about 465 mg / dL, about 470 mg / dL, about 475 mg / dL, about 480 mg / dL, about 485 mg / dL, about 490 mg / dL, about 495 mg / dL, or about 500 mg / dL. In some embodiments, the subject has a fasting baseline triglyceride level (or median fasting baseline triglyceride level for a group of subjects) of about 135 mg / dL or greater, about 150 mg / dL or greater, or about 200 mg / dL or greater.

[0132] In some embodiments, the subject has a fasting baseline triglyceride level (or median fasting baseline triglyceride level, for a group of subjects) of about 500 mg / dL or greater.

[0133] In some embodiments, the subject has one or more of a baseline non-high density lipoprotein cholesterol (HDL-C) value of about 200 mg / dL to about 300 mg / dL, a baseline total cholesterol (TC) value of about 250 mg / dL to about 300 mg / dL, a baseline low density lipoprotein cholesterol (VLDL-C) value of about 140 mg / dL to about 200 mg / dL, a baseline HDL-C value of about 10 mg / dL to about 30 mg / dL, a baseline low density lipoprotein cholesterol (LDL-C) value of about 40 mg / dL to about 100 mg / dL, and / or a baseline high sensitivity C-reactive protein (hsCRP) level of about 2 mg / dL or less.

[0134] In some embodiments, the subject is administered stable statin therapy, e.g., a statin (with or without ezetimibe). In some embodiments, the statin therapy can include one or more of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. In some embodiments, the statin therapy includes administration of a statin and ezetimibe. In some embodiments, the statin therapy includes administration of a statin without ezetimibe.

[0135] In some embodiments, upon administration of the composition, the subject exhibits one or more of the following: (a) reduction in triglyceride levels compared to baseline or control; (b) a reduction in blood pressure levels compared to baseline or a control; (c) reduction in insulin resistance compared to baseline or control; (d) a reduction in the level of an inflammatory biomarker selected from the group consisting of vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin-1 beta (IL-1β), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), high sensitivity reactive protein (hsCRP), lipoprotein-associated phospholipase A2 (Lp-PLA2), and circulating monocyte levels compared to baseline or a control; (e) a reduction in the level of a metabolic biomarker selected from the group consisting of total cholesterol, VLDL-C, residual lipoprotein cholesterol, LDL-C, small / dense LDL-C, HDL-C, non-HDL-C, HDL-C functionality, apolipoprotein B (ApoB), interleukin-6 (IL-6), apolipoprotein A-1 (ApoA-1), and improvement in homeostasis model assessment of insulin resistance (HOMA-IR including HOMA2-IR), quantitative insulin sensitivity check index (QUICKI), revised quantitative insulin sensitivity check index (rQUICKI), fasting insulin resistance index (FIRI), Bennett's index, fasting insulin, insulin to glucose ratio, insulin sensitivity (Si), and homeostasis model assessment of beta-cell function (HOMA-B including HOMA2-B), compared to baseline or a control; (f) a reduction in the level of an oxidative biomarker selected from the group consisting of lipid oxidation, lipid peroxidation, lipid hydroperoxidation, malondialdehyde, prostaglandin-2 alpha (PGF-2α), platelet-derived growth factor (PDGF), and antioxidant capacity compared to baseline or a control; and (g) A reduction in the risk of one or more of the following, compared to baseline or control: cardiovascular death; nonfatal myocardial infarction; transient ischemic attack; nonfatal stroke; fatal stroke; coronary revascularization; carotid revascularization; peripheral revascularization; unstable angina (e.g., unstable angina determined by invasive or noninvasive testing to be caused by myocardial ischemia and requiring hospitalization); cardiac arrest; peripheral cardiovascular disease requiring intervention, angioplasty, bypass surgery, or aneurysm repair; death; sudden cardiac death; and new-onset congestive heart failure.

[0136] The parameters described herein may be measured according to clinically accepted methodologies. For example, triglycerides, total cholesterol, HDL-C, fasting blood glucose may be sampled from serum and analyzed using standard photometric techniques. VLDL-TG, LDL-C, and VLDL-C may be calculated or determined using serum lipoprotein fractionation by preparative ultracentrifugation and subsequent quantitative analysis by refractometry or analytical ultracentrifugation. ApoA-1, ApoB, and hsCRP may be determined from serum using standard turbidimetric techniques. Small / high density LDL-C and residual cholesterol may be determined by fast protein electrophoresis, ultracentrifugation, or immunolabeling. These techniques are detailed in standard textbooks, such as Tietz Fundamentals of Clinical Chemistry, 6th Ed. (Burtis, Ashwood and Borter Eds.), WB Saunders Company.

[0137] Pulmonary disease, including sepsis, SIRS, and / or ARDS In some embodiments, provided is a method of treating and / or preventing a pulmonary disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising a PUFA or a derivative thereof and a phospholipid source according to various embodiments disclosed herein.

[0138] "Pulmonary disease" includes, but is not limited to, the following types of diseases: pulmonary parenchymal diseases, including acute inflammatory or thrombotic diseases (e.g., community-acquired pneumonia, COVID-19 pneumonia, sepsis, SIRS, ARDS, pulmonary embolism, diffuse interstitial pneumonia, radiation pneumonitis, pleurisy, acute eosinophilic pneumonia, chronic eosinophilic pneumonia, Löffler's syndrome); chronic lung diseases (e.g., sarcoidosis, interstitial lung disease, chronic obstructive pulmonary disease (COPD), reactive airway disease, asthma, bronchiectasis, bronchitis, cystic fibrosis, bronchitis, bronchitis, pulmonary edema, pulmonary pulmonary syndrome ... pulmonary vascular diseases (e.g., pulmonary arterial hypertension, pulmonary vasculitis, microscopic polyangiitis, granulomatosis with polyangiitis (Wegener's disease), eosinophilic granulomatosis with polyangiitis (Churg-Strauss)); upper respiratory tract conditions (e.g., rhinitis); and pulmonary-renal vasculitis (e.g., Goodpasture's syndrome, cryoglobulinemia, systemic lupus erythematosus (SLE), systemic sclerosis, tracheal symptomatic syndrome, lupus erythematosus syndrome, antiphospholipid syndrome).

[0139] As explained above, the lymphatic releasing composition of the present technology is excellent for delivering lipid-soluble drugs such as fatty acids to the lungs since delivery is dependent on perfusion rate and the lungs have the highest perfusion rate in the body, suggesting that the lymphatic releasing composition may be particularly useful in treating pulmonary diseases.

[0140] Furthermore, long-chain PUFAs (LC-PUFAs) are intimately involved in tissue injury responses, as LC-PUFAs are released from cell membrane phospholipids as one of the earliest steps in the inflammatory cascade. As used herein, LC-PUFAs are fatty acids with at least 18 carbon atoms. Once released from membrane phospholipids, LC-PUFAs, especially those that are 18 or 20 carbons long, are oxidized by several enzymes to produce a variety of bioactive metabolites known as oxylipins. Enzymes that promote 18, 20, and 22 carbon LC-PUFA oxygenation include cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 epoxygenase (CYP). The best-known example of this process is arachidonic acid (AA or ARA, also known as omega-6 eicosatetraenoic acid), a 20-carbon LC-PUFA that carries four double bonds, with the last double bond at the omega-6 position. In the case of AA, oxidative enzymes result in a number of bioactive compounds that affect subsequent inflammatory, thrombotic, vasoconstrictive, and bronchoconstrictive responses, including the proliferation of a series of prostanoids (e.g., prostaglandins and prostacyclins), thromboxanes, leukotrienes, and mono-, di-, and tri-alcohols, epoxides, ketones, and related compounds. The seemingly dominant role of AA points to its strong association with 20-carbon LC-PUFAs, contributing to this oxygenation cascade, also called the "eicosanoid" cascade, even though oxygenated metabolites of 18-carbon PUFAs (octadecosanoids) typically constitute the majority of oxylipins under comprehensive oxylipinomics screening. In fact, other LC-PUFAs are also oxidized to a similar or lesser extent by these same enzymes, including oxygenated metabolites of 22-carbon PUFAs (docosanoids). However, in the absence of exogenous administration of parent fatty acids, few are present at levels comparable to AA. Importantly, the oxidative metabolites of other LC-PUFAs may not have the same or any biological effects compared to those from AA, and their levels cannot be easily predicted from those of the parent fatty acid due to differences in oxygenase action.Considering the proinflammatory, prothrombotic, vasoconstrictive, and bronchoconstrictive roles of AA-derived oxylipins, to the extent that these other octadecosanoids, eicosanoids, and docosanoids replace AA, those skilled in the art will understand that this can provide therapeutic benefits in suppressing inflammatory, thrombotic, vasoconstrictive, and bronchoconstrictive responses. This can occur in conditions mediated by excessive activation of the eicosanoid / oxylipin cascade, such as occurs in conditions of excessive inflammation, such as SIRS, sepsis, or ARDS. It can also occur in conditions of excessive platelet activation from thromboxane overproduction, such as disseminated intravascular coagulation with vasoconstriction (DIC), or major atherosclerotic vascular events (MACE), or cerebrovascular events. Excessive leukotriene activation adversely affects bronchospasm and other pathological processes, suggesting that a variety of diseases are influenced by the eicosanoid cascade.

[0141] Among potential candidates to replace AA, EPA is a particularly strong candidate due to its clear therapeutic advantages. Not just an LC-PUFA, EPA is a 20-carbon PUFA like AA, and differs from the latter only in that it has one or more double bonds toward the end of the molecule (i.e., at the omega-3 position versus the omega-6 position in AA). Thus, EPA interacts with the same set of enzymes that oxidize AA, and its metabolic by-products (e.g., oxylipins) resemble those of AA. At the same time, the shape of the metabolites derived from EPA differs from those of AA by the presence of an "extra" double bond at the end. As a result, oxylipins formed from EPA vary in bioactivity compared to those formed from AA. For example, thromboxanes derived from EPA are less thrombotic and therefore less likely to propagate recalcitrant thrombosis. Similarly, prostanoids derived from EPA are less prone to stimulate inflammatory and vasoconstrictive cascades and the associated ischemia. Of particular importance to acute inflammatory lung diseases such as SIRS, sepsis, and / or ARDS, leukotrienes derived from EPA are less likely to stimulate inflammatory and bronchospastic / bronchoconstrictive cascades. Therefore, if the levels of EPA in tissues mediating these conditions can be increased to compete with AA, the deleterious consequences of overactive stimulation of the eicosanoid cascade from AA are expected to be attenuated. This would alleviate the downstream cytokine storm underlying SIRS, sepsis, and / or ARDS, the prothrombotic conditions of DIC and MACE, and intractable inflammatory conditions such as bronchospasm / bronchoconstriction.

[0142] Other potential candidates to replace AA include DPA (22 carbon LC-PUFA with 5 double bonds), DHA (22 carbon LC-PUFA with 6 double bonds), and DGLA (20 carbon LC-PUFA with 3 double bonds). Importantly, fatty acids can vary considerably in terms of affinity for oxygenases. Thus, DPA and DHA not only have more double bonds than AA, but also have two additional carbons in the PUFA chain. In this respect, DHA is further away than EPA due to the "extra" carbon and two "extra" double bonds compared to AA. Thus, the entire set of oxygenated metabolites from DPA and DHA is expected to be less likely to mitigate the proinflammatory effects of AA activation. Like AA and EPA, DGLA features 20 carbons and one less double bond than AA. Its precursor, GLA (18 carbon LC-PUFA with 3 double bonds), can be administered orally and is abundant in certain foods (e.g., borage oil). Conversely, DGLA itself is converted to AA in vivo. This raises the possibility that the GLA / DGLA approach will undermine its own effectiveness by increasing AA levels in vivo. Conversely, EPA does not share this problem, since it is not converted to AA as part of metabolism. Rather, EPA is likely to be oxidized in parallel with AA, and can also be elongated to DPA and DHA.

[0143] Considering that DPA and DHA are more divergent from AA chemistry and metabolism, and that DGLA itself is an AA, EPA occupies a unique position where it avoids conversion to a compound whose effects are avoided, but remains similar enough to be able to compete with the enzymes that oxidize AA. EPA itself may inhibit AA oxygenation beyond simple competitive inhibition. These chemical considerations are consistent with the limited experience from clinical outcome studies. For example, combinations of EPA and DHA are also found in foods, i.e., fish oil. Combinations featuring marine EPA and DHA have been administered with the goal of preventing MACE events in patients at high risk for atherosclerotic MACE events. Interestingly, two large outcome studies featuring EPA purified as an ethyl ester did indeed show that patients randomly assigned to EPA had fewer MACE events compared to a control group that did not receive an EPA-based intervention. On the other hand, a large outcome study featuring EPA mixed with DHA had no such benefit. This is generally consistent with the view that DHA is too far removed from AA to provide meaningful protection against adverse effects. Similarly, studies of borage oil in combination with marine oils suggest an overall benefit in inflammatory conditions, despite mixed results in human studies. Again, this option may undermine its own effectiveness, considering that GLA from borage oil is converted to DGLA, and thereby to AA.

[0144] Considering (1) the specific concern that GLA may elevate AA, (2) the relative differences of DPA and DHA to AA, and (3) the relative identity of EPA to AA in terms of similar metabolism and enzymatic competition, a composition with high purity EPA is expected to alleviate the adverse effects of overactive AA oxygenation and activation seen in conditions such as SIRS, sepsis, and ARDS in a manner superior to other pharmaceutical compositions that use mixtures of fatty acids. Oxepa® is one such pharmaceutical composition used to treat sepsis and ARDS that contains a mixture of various excipients and fatty acids (e.g., EPA, GLA, and DHA), some of which may be converted to AA in vivo and thus elevate AA levels and contribute to the body's inflammatory cascade (Figure 31C). Oxepa® also contains a number of other fatty acids that may "dilute" the effect of the product in alleviating the adverse effects of AA oxylipins. That is, other fatty acids in Oxepa® will naturally compete with GLA, EPA, and DHA for transport, especially retention in cell membranes and tissue delivery.In contrast, LR-EtEPA is administered against dietary fat loading to avoid diluting its effectiveness by providing competing fatty acids.A composition of high-purity EPA that is substantially free of contamination from other fatty acids will not increase AA levels in vivo, but instead likely competes with AA to alleviate its inflammatory effects.

[0145] This prompted us to include an arm of the multi-day dose Long-Evans rat experiment described herein that contained a combination of EtEPA, ethyl-GLA (EtGLA), and ethyl-DHA (EtDHA) (hereafter the "EPA+GLA+DHA" or "E+G+D" arm). These three fatty acids are present in the mixture of fatty acids in Oxepa®. The total sum of these three fatty acids was equimolar to the dose of EtEPA in the regular EtEPA and LR-EtEPA arms of the experiment. Thus, the difference between the pure EtEPA arm and this E+G+D arm is attributable to the "substitution" of the GLA+DHA portion of E+G+D with EtEPA. The E+G+D combination is medically important because it has been shown to improve oxygenation and ventilation in critically ill patients suffering from ARDS. Thus, the relative portions of these three fatty acids were used in the experiment, and the overall dose of LC-PUFA was similar to that used to treat ARDS. Given the medical significance of these oxygenation promoters, this arm is also referred to as "OXP" in the figures and the following discussion. A consistent finding was that plain EtEPA and LR-EtEPA are typically more potent in offsetting / suppressing AA compared to E+G+D. Beyond ARDS, we also assembled a slightly larger set of LC-PUFAs that have been proposed for medical use for a variety of diseases. These are considered to be beneficial to the extent that they or their fatty acid metabolites are oxylipin precursors whose metabolites compete with AA (hereafter they are referred to as therapeutic oxylipin precursors (MOPs) and consist of DGLA, EPA, DPA, and DHA). This results in three ways to compare the set of fatty acids against AA as ratios: (1) EPA / AA, (2) OXP / AA=[DGLA+EPA+DHA] / AA, and (3) MOP / AA=[DGLA+EPA+DPA+DHA] / AA. Of these, the latter two, OXP / AA and MOP / AA, are the most appropriate study arms to compare with E+G+D, as the molecules contain three fatty acids intended to exert a therapeutic effect.In general, LR-EtEPA was superior in increasing all three ratios compared to equimolar doses of plain EtEPA, and typically both EtEPA formulations were superior to equimolar doses of E+G+D. Importantly, as expected, E+G+D itself was superior to equimolar amounts of oleic acid (OA), which is often the reference therapy, and thus E+G+D demonstrated efficacy in replacing AA by elevating fatty acids, including OXP. Thus, the experiment confirmed the mechanism that originally motivated the development of EPA+GLA+DHA as a therapeutic agent, i.e., increasing OXP-derived oxylipins (i.e., oxylipins from EPA, DGLA, and DHA), thereby improving ARDS, i.e., by reducing tissue AA levels in favor of less inflammatory, thrombotic, vasoconstrictive, and most specifically bronchoconstrictive fatty acids. Thus, the superiority of EtEPA in general, and especially LR-EtEPA, implies that these are improved by several-fold improvements in AA replacement by the pharmacologically active oxime precursors, in the case of EPA+GLA+DHA and, in the case of LR-EtEPA.

[0146] Without wishing to be bound by theory, EPA can further reduce AA levels by altering the Δ8-desaturase (D8D) and Δ5-desaturase (D5D) enzymes, which promote DGLA synthesis and suppress the subsequent catabolism leading to AA in the omega-6 PUFA pathway, respectively ( FIG. 2 ). EPA, through its dual function of promoting D8D (and DGLA) and inhibiting 5D5 (and AA), can effectively reduce AA levels and increase metabolites that compete with AA. In addition, fatty acids other than EPA (as found in Oxepa®) can not only "dilute" the anti-inflammatory effect of EPA, but also compete with EPA in the cross-esterification process with the phospholipids of the composition, thereby reducing the absorption and bioavailability of EPA at the lymphatic and tissue levels. Thus, it is contemplated that the lymphatic-released EPA compositions of the present technology (LR-EtEPA) will be particularly valuable and useful for treating diseases involving inflammation, vasoconstriction, and bronchoconstriction from AA-derived oxylipins via the pulmonary route, and will have advantages over plain EtEPA, and both will have advantages over compositions of mixtures of fatty acids such as Oxepa®.

[0147] Thus, in some embodiments, provided is a method of treating and / or preventing SIRS, sepsis, and / or ARDS in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising a PUFA or derivative thereof according to various embodiments disclosed herein and a phospholipid source.

[0148] Neurological disorders Co-administration of PUFA (e.g., EtEPA) with additives including phospholipids and / or additional emulsifiers promotes in vivo absorption of fatty acids in the form of phospholipid conjugates. Since phospholipids are the main components of cell membranes, such compounds are not only optimal for cellular uptake, but are also expected to have higher efficiency as they cross the blood-brain barrier (BBB), thereby delivering the fatty acids, which are the active components of the composition, to the brain. The BBB can be an obstacle for pharmaceutical agents to access therapeutic targets in the brain or reach sufficient levels in the brain. Thus, the lymphatic release formulations of the present technology can provide a novel strategy and platform for delivering fatty acids across the BBB so that they exert anti-inflammatory, cognitive-inducing, and / or other neuroprotective effects useful for the treatment of various neurological diseases and disorders.

[0149] Without wishing to be bound by theory, PUFAs, including EPA, are important in regulating phospholipase A2 (PLA2), an enzyme that catalyzes the cleavage of fatty acids from the sn-2 position of phospholipids and is involved in the PUFA and oxylipin pathways. PLA2 is present in the central nervous system (CNS) and is associated with neurodegenerative diseases due to its role in the inflammatory response. EPA can inhibit PLA2 and prevent the production of proinflammatory eicosanoids. In addition, the inhibitory effects of EPA on Δ5-desaturase and Δ5-elongase discussed above may also contribute to its anti-inflammatory function in various pathological conditions of the CNS.

[0150] Thus, in some embodiments, provided is a method of treating and / or preventing a neurological disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising a PUFA or a derivative thereof and a phospholipid source according to various embodiments disclosed herein.

[0151] In some embodiments, neurological diseases include chorea / Huntington's disease, sleep disorders, dementia, psychosis, anxiety, treatment-resistant depression, neuropathic pain, schizophrenia (especially in patients with tardive dyskinesia), bipolar disorder, dyslexia, dyspraxia, attention deficit hyperactivity disorder (ADHD), epilepsy, autism, Alzheimer's disease, Parkinson's disease, senile dementia, multiple sclerosis, diabetes-induced neuropathy, macular degeneration, retinopathy of prematurity, amyotrophic lateral sclerosis (ALS), retinitis pigmentosa, cerebral palsy, muscular dystrophy, neurological cancers, cystic fibrosis, and / or neural tube defects.

[0152] cancer EPA is currently in clinical trials for the treatment of cancer, including colorectal cancer (see NCT01070355). The compositions of the present technology, such as LR-EtEPA formulations, result in greater EPA uptake in various tissues and therefore may represent a favorable option for cancer treatment.

[0153] Thus, in some embodiments, provided is a method of treating and / or preventing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising a PUFA or a derivative thereof and a phospholipid source according to various embodiments disclosed herein.

[0154] In some embodiments, the cancer is a hematological malignancy. Non-limiting exemplary hematological malignancies include monoclonal B-cell lymphocytosis, multiple myeloma, myeloid neoplasms, myelodysplastic syndromes (MDS), myeloproliferative / myelodysplastic syndromes, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute phase chronic myeloid leukemia (bcCML), B-cell acute lymphocytic leukemia (B-ALL), T-cell acute lymphocytic leukemia (T-ALL), T-cell lymphoma, and B-cell lymphoma.

[0155] In some embodiments, the cancer is a solid tumor. Non-limiting exemplary solid tumors include lung cancer, breast cancer, liver cancer, stomach cancer, colon cancer, rectal cancer, colorectal cancer, kidney cancer, gastric cancer, gallbladder cancer, small intestine cancer, esophageal cancer, melanoma, bone cancer, pancreatic cancer, skin cancer, uterine cancer, ovarian cancer, testicular cancer, thyroid cancer, adrenal cancer, bladder cancer, and glioma.

[0156] Disorders associated with the kidneys, pancreas, liver, intestines, blood cells, lymphatic, and musculoskeletal systems In some embodiments, provided is a method of treating and / or preventing a disease associated with a tissue or organ in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising a PUFA or derivatives thereof according to various embodiments disclosed herein and a phospholipid source, wherein the tissue or organ is selected from the group consisting of the kidney, the endocrine system, the pancreas, the liver, the intestine, blood cells, and the musculoskeletal system.

[0157] As demonstrated in the working examples, the lymphatic release composition of the present technology is excellent at delivering fatty acids (e.g., EPA) to various tissues of the body, including the kidney, pancreas, and intestine, where fatty acids (e.g., EPA) can potentially alleviate damage from inflammation, vasoconstriction, bronchospasm, and / or thrombosis by replacing, competing with, or reducing harmful oxylipins. In addition, EPA and its oxylipins are highly complementary to steroids, and both function by limiting the production of oxylipins. Alternatively, EPA can be used as a steroid-sparing agent. Steroids themselves have many adverse events, but EPA has few known adverse events.

[0158] In some embodiments, the disease associated with the kidney is selected from the group consisting of post-infectious glomerulonephritis, IgA nephropathy (Buerger's disease), Henoch-Schonlein purpura, systemic IgA vasculitis, microscopic polyangiitis, granulomatosis with polyangiitis (Wegener's disease), eosinophilic granulomatosis with polyangiitis (Churg-Strauss), polyarteritis, idiopathic crescentic glomerulonephritis, anti-GBM glomerulonephritis, Goodpasture's syndrome, cryoglobulin-associated glomerulonephritis, including idiopathic membranoproliferative glomerulonephritis (MPGN), hepatitis C associated glomerulonephritis, systemic lupus erythematosus (SLE) associated glomerulonephritis, minimal change disease (nill disease, lipoid nephropathy), membranous nephropathy, focal segmental glomerulosclerosis, amyloidosis, diabetic nephropathy, HIV associated nephropathy, membranoproliferative glomerulonephropathy, edema relief, chronic renal failure relief, and / or mortality / morbidity relief in severe chronic kidney disease (CKD) / end stage renal disease (ESRD).

[0159] In some embodiments, diseases associated with the endocrine system include hypopituitarism, thyroiditis, and / or Paget's disease.

[0160] In some embodiments, diseases associated with the pancreas include hyperglycemia, prediabetes, diabetes (type 1 and / or type 2), and / or pancreatitis.

[0161] In some embodiments, diseases associated with the liver include chronic viral hepatitis, autoimmune hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease, hemochromatosis, Wilson's disease, primary biliary cholangitis, primary sclerosing cholangitis, and / or cholelithiasis.

[0162] In some embodiments, diseases associated with the gut include digestive diseases, including gastroesophageal reflux disease (GERD) (by alleviating esophageal reflux via oxylipin action), gastritis, peptic ulcer disease, obesity (by alleviating obesity by inducing satiety), and cachexia (by limiting inflammation), and bowel disease conditions include intestinal angina, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), antibiotic-associated colitis, irritable bowel syndrome, colon cancer, colonic polyposis, and / or carcinoid.

[0163] In some embodiments, blood cell associated diseases include iron deficiency anemia, hemolytic anemia, thalassemia, polycythemia vera, sickle cell disease anemia, and sickle cell pain / crisis, platelet disorders include immune thrombocytopenia and prothrombotic conditions, and white blood cell disorders include leukemia, non-Hodgkin's lymphoma, and / or Hodgkin's lymphoma.

[0164] In some embodiments, the lymph-associated disease comprises lymphedema.

[0165] In some embodiments, diseases associated with the musculoskeletal system include muscle conditions, including statin myopathy, rhabdomyolysis, polymyalgia rheumatica, polychondritis, and Behcet's syndrome; bone conditions, including gouty arthritis, calcium pyrophosphate deposition, rheumatoid arthritis, Still's disease, ankylosing spondylitis, psoriatic arthritis, and reactive arthritis; and systemic diseases, including systemic lupus erythematosus (SLE), antiphospholipid syndrome, systemic sclerosis (scleroderma), polymyositis, dermatomyositis, Sjogren's syndrome, and IgG4-related disease.

[0166] Diseases associated with oxidative stress and / or glutathione (GSH) depletion In some embodiments, provided is a method of treating and / or preventing a disease or disorder associated with oxidative stress, glutathione (GSH) depletion, Nrf2 activation, and / or heme-oxygenase activation (including conditions involving exposure to free heme during cell lysis, hemolysis, other blood cell lysis, or tissue damage) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising a PUFA or derivative thereof according to various embodiments disclosed herein and a phospholipid source.

[0167] Endothelial nitric oxide (NO) is produced by NO synthase (eNOS) dimers that couple the oxidation of L-arginine with the reduction of molecular oxygen (Figure 34C-D). See Forstermann and Sessa, Euro Heart J. (2011) 33:829-837, incorporated herein by reference in its entirety. Under disease-like conditions and increased oxidative stress (i.e., high glucose, smoking, hypertension), there is eNOS "uncoupling" that favors the production of superoxide (O2-), which reacts with NO to form the cytotoxic radical peroxynitrite (ONOO-). The ratio of [NO] / [ONOO-] is an important index of eNOS coupling efficiency, while loss of NO bioavailability is associated with atherothrombosis risk. EPA is known to have a favorable effect on eNOS coupling in vascular endothelial cells (ECs) compared to DHA. The benefit of EPA was associated with an improved EPA / AA ratio. See Sherratt et al., Prostaglandins Leukot Essent Fatty Acids. (2021) 173, which is incorporated herein by reference in its entirety. The effect of EPA on NO release was improved in combination with high-intensity statins. See Mason et al., Biomed Pharmacother. (2018) 103:1231-1237, which is incorporated herein by reference in its entirety. The mechanism of improvement of eNOS function by EPA is not fully understood but may be related to increased eNOS expression and reduced production of reactive oxygen species (ROS) compared to DHA.

[0168] EPA, administered as icosapent ethyl (IPE), is the first FDA- and EMA-approved drug to reduce cardiovascular risk among patients with elevated triglyceride levels as an add-on to maximally tolerated statin therapy. The REDUCE-IT trial showed that treatment with high-dose IPE (4 g / day) reduced composite cardiovascular events by 25% in statin-treated patients with elevated baseline triglyceride levels. See Bhatt et al., N Engl J Med. (2019) 380:11-22, incorporated herein by reference in its entirety. The benefit of IPE was independent of baseline triglyceride levels but positively correlated with plasma levels of EPA. Imaging studies showed significant regression of plaque volume and composition with IPE compared with statins alone in patients with atherothrombotic disease. See Budoff et al., Euro Heat J. (2020) 41:3925-3932; Watanabe et al., J Cardiol. (2017) 70:537-544, each of which is incorporated herein by reference in its entirety. In contrast to IPE treatment, the results of trials using mixed omega-3 fatty acids failed to reduce cardiovascular events. This may be due to differences in formulations and potential pleiotropic benefits and membrane interactions unique to EPA. See Sherratt et al., Prostaglandins Leukot Essent Fatty Acids. (2021) 173; Mason et al., Metab Clin. (2022) 130:155-161; Sherratt et al., J Lipid Res. (2021) 62; Mason et al., Arterioscler Thromb Vasc Biol. (2020) 40:1135-1147, each of which is incorporated by reference in its entirety.

[0169] To elucidate the mechanism of improved eNOS coupling and NO bioavailability of n-3 fatty acids, the effects of EPA and DHA on the expression of proteins regulating eNOS and reactive oxygen species (ROS) in human ECs during inflammation are compared (see Example 5).

[0170] GSH is an antioxidant that can prevent damage to important cellular components caused by sources such as ROS, free radicals, peroxides, and heavy metals. As shown in Example 5, the protein of glutathione reductase (GSR) was significantly increased by EPA. In addition to heme oxygenase-1 (HO-1), antioxidant response element (ARE) can induce glutathione S-transferase (GST). GSR activity can be evaluated using the mRNA expression of GST. The induction of both GSR and GST can support the antioxidant effect of GSH. Thus, GSH can be influenced by two separate proteins that are independently regulated.

[0171] Due to the effect of EPA on GSR, the compositions of the present technology containing EPA may exhibit a particularly robust effect on overall antioxidant effects by improving GSH metabolism. The compositions may exhibit a wide range of effects on the treatment or prevention of tissue damage caused by diseases including, but not limited to, pulmonary inflammation, anemia, sickle cell disease, and glomerulonephritis. The compositions may also treat diseases / conditions associated with GSH deficiency, such as kwashiorkor, stroke, Alzheimer's disease, Parkinson's disease, liver disease, cystic fibrosis, anemia, sickle cell disease, human immunodeficiency virus (HIV) infection / acquired immune deficiency syndrome (AIDS), cancer, heart attack, stroke, and diabetes.

[0172] Thus, in some embodiments, provided is a method of treating and / or preventing pulmonary inflammation, anemia, sickle cell disease, and / or glomerulonephritis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising a PUFA or derivatives thereof according to various embodiments disclosed herein and a phospholipid source.

[0173] In some embodiments, provided is a method of treating and / or preventing a disease or disorder associated with GSH depletion in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising a PUFA or derivative thereof and a phospholipid source according to various embodiments disclosed herein.

[0174] In some embodiments, the disease or disorder associated with GSH depletion is at least one selected from the group consisting of a neurodegenerative disorder, a pulmonary disease, an immune disease, a cardiovascular disease, a renal disease, a liver disease, an endocrine disease, a red blood cell disease, a gastrointestinal disease, a rheumatic and / or musculoskeletal disease, a skin disease, an obstetric and / or gynecological disease, and an age-related disorder.

[0175] In some embodiments, the neurodegenerative disorder comprises Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and / or Friedreich's ataxia.

[0176] In some embodiments, the pulmonary disease comprises community-acquired pneumonia, sepsis, SIRS, ARDS, chronic obstructive pulmonary disease (COPD), asthma, interstitial lung disease, cystic fibrosis, pulmonary vasculitis (e.g., granulomatosis with polyangiitis (GP), eosinophilic granulomatosis with polyangiitis (EGPA), microscopic polyangiitis (MPA)), pulmonary-renal vasculitis (e.g., Goodpasture's syndrome, cryoglobulinemia, systemic lupus erythematosus (SLE), systemic sclerosis, antiphospholipid syndrome), pulmonary inflammation, non-small cell lung cancer (especially COX-2 overexpressing cancers), and / or chronic / idiopathic hemolytic anemia (e.g., hereditary spherocytosis, thalassemia, hemolysis secondary to other diseases, and transfusion reactions).

[0177] In some embodiments, the immune disease is an autoimmune disease and / or HIV infection / AIDS. Non-limiting exemplary autoimmune diseases include type 1 diabetes, lupus, systemic lupus erythematosus, rheumatoid arthritis, psoriasis, psoriatic arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, Addison's disease, Graves' disease, Sjogren's syndrome, Hashimoto's thyroiditis, myasthenia gravis, autoimmune vasculitis, pernicious anemia, and celiac disease.

[0178] In some embodiments, the cardiovascular disease comprises hypertension, myocardial infarction, and / or cholesterol oxidation.

[0179] In some embodiments, the renal disease comprises renal vasculitis (e.g., Buerger's disease), proteinuria, chronic kidney disease (CKD), and / or end stage renal disease (ESRD).

[0180] In some embodiments, the liver disease comprises non-alcoholic fatty liver disease.

[0181] In some embodiments, the endocrine disorder comprises hyperglycemia, prediabetes, and / or Paget's disease.

[0182] In some embodiments, the red blood cell disorder comprises anemia and / or sickle cell disease.

[0183] In some embodiments, the gastrointestinal disorder comprises pancreatitis, inflammatory bowel disease, irritable bowel syndrome, obesity, cachexia, esophageal reflux disease, and / or biliary cirrhosis.

[0184] In some embodiments, the rheumatic and / or musculoskeletal disorder comprises statin myopathy.

[0185] In some embodiments, the skin condition comprises allergic dermatitis, generalized dermatitis, menopausal hot flashes, and / or medicinal hot flashes.

[0186] In some embodiments, the obstetric and / or gynecological disorder comprises menorrhagia, pre-eclampsia, and / or dysmenorrhea.

[0187] In some embodiments, the age-related disorder comprises cataracts, macular degeneration, hearing loss, and / or glaucoma.

[0188] In some embodiments, the method further comprises administering to the subject an N-acetylcysteine ​​(NAC)-related agent that can elevate GSH.Non-limiting examples of NAC-related agents include cystine, methionine, N-acetylcysteine, and L-2-oxothiazolidine-4-carboxylate.By using one of these NAC-related agents together with the composition of the present disclosure that includes EPA, GSH elevation can be further enhanced.

[0189] In some embodiments, upon administration of the composition, the subject exhibits increased GSR activity.

[0190] In some embodiments, upon administration of the composition, the subject exhibits increased GST activity.

[0191] Air Pollution-Induced Inflammation and Disease Long-term and / or short-term exposure to air pollution contributes to the body's inflammatory response and the pathogenesis of cardiovascular disease and disorders.Air pollution is estimated to cause 7 million deaths per year worldwide, and more than half of these deaths are due to the progression or development of cardiovascular disease or disorders.Given the known anti-inflammatory effects of EPA and the excellent tissue delivery ability of the lymphatic release formulation of the present technology, especially to the cardiopulmonary system, it is contemplated that the composition of the present technology is useful for treating diseases associated with air pollution.

[0192] Thus, in some embodiments, provided is a method of treating and / or preventing oxidative stress, endothelial dysfunction, arterial narrowing and / or thickening, and / or inflammation induced by inhalation of particulate matter in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising PUFAs or derivatives thereof according to various embodiments disclosed herein and a phospholipid source. The term "particulate matter" refers to a mixture of species produced from multiple sources. Particulate matter can be emitted directly into the atmosphere in the form of soot, smoke, and / or dust. Particulate matter can be formed in the atmosphere from the reaction of gases including, but not limited to, nitric oxide (NOx), sulfur oxides (SOx), reactive organic gases (ROG), and / or ammonia.

[0193] As used herein, the term "oxidative stress" refers to an increase in the formation of reactive oxygen species (ROS) and / or a decrease in antioxidant capacity (i.e., the ability to reduce or impair the production of ROS) in an affected individual. The term "endothelial dysfunction" refers to damage or deterioration of the endothelial intima caused by a number of factors, including, but not limited to, high blood pressure, high blood glucose levels, and / or increased blood lipid levels. Endothelial dysfunction can then lead to reduced function in endothelium-dependent vasodilation, procoagulation, and proinflammatory responses. The term "stenosis" of an artery refers to a condition characterized by a decrease or complete decrease in blood flow and oxygen transport to target tissues and organs in an affected individual, for example, resulting from the formation of plaques in the arterial wall and / or as a result of inflammation causing swelling of the arterial wall. Occlusion (i.e., blockage) of a blood vessel prevents sufficient blood flow and thereby oxygen transport to target tissues and organs, which can lead to a wide range of diseases, including, but not limited to, hypoxia, myocardial infarction, stroke, and / or pulmonary embolism. The term "thickening" of an artery in this specification refers to the actual thickening of the arterial wall (i.e., an increase in the ratio of the wall thickness to the radius of the artery) and / or the actual widening (i.e., expansion) of the arterial wall. The thickening of the arterial wall can lead to the weakening and narrowing of the arterial wall, which over time can cause irregular blood flow and oxygen transport. In some cases, the thickening of the arterial wall can result in the actual rupture of the wall, impeding blood flow and oxygen transport. Both partial and complete blockage of blood flow and oxygen transport to target tissues can result in subsequent organ and tissue damage and / or death. The narrowing and thickening of the arterial wall can occur independently or dependently of each other.

[0194] The term "inflammation" refers to inflammation of individual tissues (e.g., lungs) and / or systemically. For example, pulmonary inflammation is characterized by inflammation of the pulmonary system, resulting in restricted oxygen flow due to narrowing of the affected person's airways. The term "pulmonary system" refers to organs and / or structures responsible for bringing oxygen into the body and / or expelling carbon dioxide from the body, including but not limited to those associated with the nasal, pharyngeal, and laryngeal passages, trachea, bronchi, bronchioles, and / or alveoli. In one embodiment, the alveoli in the lungs become inflamed, which can reduce the tracking of oxygen through the alveoli into the bloodstream. This narrowing of the airways can cause sudden dyspnea, coughing, and / or wheezing, all of which are associated with asthma and, in severe cases, death. Systemic inflammation is characterized by inflammation that spreads throughout the affected person's body. Systemic inflammation causes deterioration of both structure and function of vital organs such as muscles, heart and liver, compromises the immune system and can lead to multiple organ failure and death.

[0195] In some embodiments, provided is a method for treating and / or preventing oxidative stress, endothelial dysfunction, arterial narrowing and / or thickening, and / or inflammation induced by long-term and / or short-term exposure to air pollution in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising PUFAs or their derivatives according to various embodiments disclosed herein and a phospholipid source. The term "long-term" in this context refers to exposure to air pollution for a period of one year or more. The term "short-term" refers to exposure to air pollution for a period of less than one year.

[0196] In some embodiments, provided is a method of treating and / or preventing atherosclerotic cardiovascular disease or reducing the risk of atherosclerotic cardiovascular disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising a PUFA or a derivative thereof and a phospholipid source according to various embodiments disclosed herein. The term "atherosclerotic cardiovascular disease" refers to any condition characterized by the accumulation of plaque in blood vessel walls and vascular inflammation.

[0197] Polluted air contains particulate matter, which may be a mixture of particles of varying sizes. The various sizes of particulate matter are classified as coarse, fine, and ultrafine. In some embodiments, coarse particulate matter refers to particles having an average or median diameter of less than about 10 μm and greater than about 2.5 μm on a volumetric basis (PM2.5-10). In some embodiments, fine particulate matter refers to particles having an average or median diameter of about 2.5 μm on a volumetric basis (PM2.5). In some embodiments, ultrafine particulate matter refers to particles having an average or median diameter of less than about 0.1 μm on a volumetric basis (PM0.1). The particulate matter described in any of the embodiments herein may be less than about 10 μm in diameter and greater than about 2.5 μm in diameter, less than or equal to about 2.5 μm in diameter, or less than about 0.1 μm in diameter.

[0198] In some embodiments, upon administration of a composition of the compositions described herein in any of the embodiments herein, a subject may experience a beneficial effect in heart rate and / or cardiac rhythm following administration. In some embodiments, the beneficial effect includes a reduction in arrhythmia suppression levels, ventricular arrhythmia rates, or heart rate, or an increase in heart rate variability.

[0199] In another embodiment, the present disclosure provides a method of suppressing an inflammatory response in the lungs caused by inhalation of particulate matter, in some embodiments, the inflammatory response is observed not only in the lungs but also in other organs, including but not limited to the brain, heart, coronary arteries, liver, kidneys, spleen, pancreas, and intestines.

[0200] In any of the above embodiments disclosed herein, the therapeutically effective dose of the composition of the present technology is 1 mg to 20 g of EPA (as the term "EPA" is defined and exemplified herein) per day, e.g., about 50 mg, about 100 mg, about 500 mg, about 750 mg, about 1 g, about 2 g, about 3 g, about 4 g, about 5 g, about 6 g, about 7 g, about 8 g, about 9 g, about 10 g, about 11 g, about 12 g, about 13 g, about 14 g, about 15 g, about 16 g, about 17 g, about 18 g, about 19 g, or about 20 g of EPA per day. In some embodiments, the therapeutically effective dose is 2 g to 12 g of EPA per day. In some embodiments, the therapeutically effective dose is 4 g to 6 g of EPA per day. In another embodiment, the therapeutically effective dose is 4 g of EPA per day.

[0201] In some embodiments, the amount is about 1 mg to about 20,000 mg, about 25 mg to about 10,000 mg, about 50 mg to about 5000 mg, about 75 mg to about 2500 mg, or about 100 mg to about 1000 mg, for example, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, g, approx. 600 mg, approx. 625 mg, approx. 650 mg, approx. 675 mg, approx. 700 mg, approx. 725 mg, approx. 750 mg, approx. 775 mg, approx. 800 mg, approx. 825 mg, approx. 025mg, approx. 1050mg, approx. 1075mg, approx. 1100mg, approx. 1025mg, approx. 1050mg, approx. 1075mg, approx. 1200mg, approx. 1225mg, approx. 1250mg, approx. 1275mg, approx. , approx. 1425 mg, approx. 1450 mg, approx. 1475 mg, approx. 1500 mg, approx. 1525 mg, approx. 1550 mg, approx. 1575 mg, approx. 1600 mg, approx. 1625 mg, approx. 00mg, approx. 1825mg, approx. 1850mg, approx. 1875mg, approx. 1900mg, approx. 1925mg, approx. 1950mg, approx. 1975mg, approx. 2000mg, approx. , approx. 2200 mg, approx. 2225 mg, approx. 2250 mg, approx. 2275 mg, approx. 2300 mg, approx. 2325 mg, approx. 2350 mg, approx. 2375 mg, approx. 2400 mg, approx. 2425 mg, approx. 75mg, about 2600mg, about 2625mg, about 2650mg, about 2675mg, about 2700mg, about 2725mg, about 2750mg, about 2775mg, about 2800mg, about 2825mg, about 2850mg, about 2875mg, about 2900mg, about 2925mg, about 2950mg,About 2975 mg, about 3000 mg, about 3025 mg, about 3050 mg, about 3075 mg, about 3100 mg, about 3125 mg, about 3150 mg, about 3175 mg, about 3200 mg, about 3225 mg, about 3250 mg, about 3275 mg, about 3300 mg, about 3325 mg, about 3350 mg, about 3375 mg, about 3400 mg, about 3425 mg, about 3450 mg, about 3475 mg, about 3500 mg, about 3525 mg, about 3550 mg, about 3575 mg, about 3600 mg, about 3625 mg, about 3650 mg, about 3675 mg, about 3700 mg, about 3725 mg, about 3750 mg, about 3775 mg, about 3800 mg, about 3825 mg, about 3850 mg, about 3875 mg, about 3900 mg, about 3925 mg, about 3950 mg, about 3975 mg, about 4000 mg, about 4025 mg, about 4050 mg, about 4075 mg, about 4100 mg, about 4125 mg, about 4150 mg, about 4175 mg, about 4200 mg, about 4225 mg, about 4250 mg, about 4275 mg, about 4300 mg, about 4325 mg, about 4350 mg, about 4375 mg, about 4400 mg, about 4425 mg, about 4450 mg, about 4475 mg, about 4500 mg, about 4525 mg, about 4550 mg, about 4575 mg, about 4600 mg, about 4625 mg, about 4650 mg, about 4675 mg, about 4700 mg, about 4725 mg, about 4750 mg, about 4775 mg, about 4800 mg, about 4825 mg, about 4850 mg, about 4875 mg, about 4900 mg, about 4925 mg, about 4950 mg, about 4975 mg, about 5000 mg, about 5025 mg, about 5050 mg, about 5075 mg, about 5100 mg, about 5125 mg, about 5150 mg, about 5175 mg, about 5200 mg, about 5225 mg, about 5250 mg, about 5275 mg, about 5300 mg, about 5325 mg, about 5350 mg, about 5375 mg, about 5400 mg, about 5425 mg, about 5450 mg, about 5475 mg, about 5500 mg, about 5525 mg, about 5550 mg, about 5575 mg, about 5600 mg, about 5625 mg, about 5650 mg, about 5675 mg, about 5700 mg, about 5725 mg, about 5750 mg, about 5775 mg, about 5800 mg, about 5825 mg, about 5850 mg, about 5875 mg, about 5900 mg, about 5925 mg, about 5950 mg, about 5975 mg, about 6000 mg, about 6025 mg, about 6050 mg, about 6075 mgabout 6100 mg, about 6125 mg, about 6150 mg, about 6175 mg, about 6200 mg, about 6225 mg, about 6250 mg, about 6275 mg, about 6300 mg, about 6325 mg, about 6350 mg, about 6375 mg, about 6400 mg, about 6425 mg, about 6450 mg, about 6475 mg, about 6500 mg, about 6525 mg, about 6550 mg, about 6575 mg, about 6600 mg, about 6625 mg, about 6650 mg, about 6675 mg, about 6700 mg, about 6725 mg, about 6750 mg, about 6775 mg, about 6800 mg, about 6825 mg, about 6850 mg, about 6875 mg, about 6900 mg, about 6925 mg, about 6950 mg, about 6975 mg, about 7000 mg, about 7025 mg, about 7050 mg, about 7075 mg, about 7100 mg, about 7125 mg, about 7150 mg, about 7175 mg, about 7200 mg, about 7225 mg, about 7250 mg, about 7275 mg, about 7300 mg, about 7325 mg, about 7350 mg, about 7375 mg, about 7400 mg, about 7425 mg, about 7450 mg, about 7475 mg, about 7500 mg, about 7525 mg, about 7550 mg, about 7575 mg, about 7600 mg, about 7625 mg, about 7650 mg, about 7675 mg, about 7700 mg, about 7725 mg, about 7750 mg, about 7775 mg, about 7800 mg, about 7825 mg, about 7850 mg, about 7875 mg, about 7900 mg, about 7925 mg, about 7950 mg, about 7975 mg, about 8000 mg, about 8025 mg, about 8050 mg, about 8075 mg, about 8100 mg, about 8125 mg, about 8150 mg, about 8175 mg, about 8200 mg, about 8225 mg, about 8250 mg, about 8275 mg, about 8300 mg, about 8325 mg, about 8350 mg, about 8375 mg, about 8400 mg, about 8425 mg, about 8450 mg, about 8475 mg, about 8500 mg, about 8525 mg, about 8550 mg, about 8575 mg, about 8600 mg, about 8625 mg, about 8650 mg, about 8675 mg, about 8700 mg, about 8725 mg, about 8750 mg, about 8775 mg, about 8800 mg, about 8825 mg, about 8850 mg, about 8875 mg, about 8900 mg, about 8925 mg, about 8950 mg, about 8975 mg, about 9000 mg, about 9025 mg, about 9050 mg, about 9075 mg, about 9100 mg, about 9125 mg, about 9150 mg, about 9175 mg, about 9200 mgAbout 9225mg, about 9250mg, about 9275mg, about 9300mg, about 9325mg, about 9350mg, about 9375mg, about 9400mg, about 9425mg, about 9450mg, about 9475mg, about 9500mg, about 9525mg, about 9 550mg, about 9575mg, about 9600mg, about 9625mg, about 9650mg, about 9675mg, about 9700mg, about 9725mg, about 9750mg, about 9775mg, about 9800mg, about 9825mg, about 9850mg, about 987 The composition is administered to a subject in an amount sufficient to provide a daily dose of EPA (as the term "EPA" is defined and exemplified herein) of about 5 mg, about 9900 mg, about 9925 mg, about 9950 mg, about 9975 mg, about 10,000 mg, about 11,000 mg, about 12,000 mg, about 13,000 mg, about 14,000 mg, about 15,000 mg, about 16,000 mg, about 17,000 mg, about 18,000 mg, about 19,000 mg, or about 20,000 mg.

[0202] In some embodiments, the composition is administered to the subject for a period of from about 3 days to about 1 year, e.g., about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 1.5 weeks, about 2 weeks, about 2.5 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 1 year.

[0203] In some embodiments, the composition is administered to the subject once a day, twice a day, three times a day, or four times a day, for a period of about 3 days, about 5 days, about 7 days, about 10 days, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 1.25 years, about 1.5 years, about 1.75 years, about 2 years, about 2.25 years, about 2.5 years, about 2.75 years, about 3 years, about 3.25 years, about 3.5 years, about 3.75 years, about 4 years, about 4.25 years, about 4.5 years, about 4.75 years, about 5 years, or more than about 5 years.

[0204] In some embodiments, the composition is administered to the subject one or more times (e.g., two, three, four or more times) per day. In some embodiments, the composition is administered to the subject daily, every other day, every third day, weekly, biweekly (i.e., every other week), every three weeks, monthly, bimonthly, or every three months. In some embodiments, the composition may be administered continuously or intermittently, for example, in one or more cycles. In those embodiments, within each cycle, the composition may be administered at various lengths and / or frequencies as described above.

[0205] In some embodiments, the composition can be administered for a predetermined period of time. Alternatively, the composition can be administered until a certain therapeutic benchmark is reached. In some embodiments, the method provided herein comprises evaluating one or more therapeutic benchmarks in biological samples, such as, but not limited to, lipid biomarkers, metabolic biomarkers, inflammatory biomarkers, cancer biomarkers, to determine whether to continue administering the composition.

[0206] In some embodiments, the compositions may be administered by a variety of routes as determined by one of skill in the art to be suitable for the indication of interest, hi some embodiments, the compositions are administered orally or enterally, by intravenous injection, intraperitoneal injection, intratumoral injection, bone marrow injection, lymph node injection, subcutaneous injection, and / or cerebrospinal fluid injection.

[0207] In some embodiments, the composition is administered with or without food.In some embodiments, the composition is administered to the subject in a fasting state, for example, without any food intake 12 hours, 8 hours, 4 hours, or 2 hours before.In some embodiments, the composition is administered to the subject in a state of intake, for example, within 2 hours, 1 hour, 45 minutes, or 30 minutes of intake of a meal. EXAMPLES

[0208] Example 1: Exemplary Lymphatic-Released (LR) EtEPA (LR-EtEPA) Compositions This example provides an exemplary LR-EtEPA composition formulated as a 1 g soft gelatin capsule in which EtEPA is the active ingredient and soy lecithin is the phospholipid source. Emulsifiers include polysorbate 80 and polyoxyl-35 (refined from castor oil). The content of each component is listed in Table 1. [Table 1]

[0209] Soy lecithin (Metarin® P) is a mixture of phospholipids, the minimum / maximum content of each of which is specified in Table 2. [Table 2]

[0210] The relative weight ratios of EtEPA and lecithin may be further adjusted from the above formulation according to Table 3 below. [Table 3]

[0211] This model indicates that further increases in the lecithin to EtEPA ratio will likely continue to increase the amount of EPA delivered to the lymph, consistent with the very large volumes of chylomicrons and intestinal VLDL corresponding to a large bolus of fat. Thus, the 1:1 ratio of EtEPA:vehicle given in the single dose experiment (i.e., 1:3.75 LC:EtEPA) likely represents the low end of the potential for LR-EtEPA to enrich EPA in the lymph and thereby in lung, heart, and brain tissues, as well as systemic tissues.

[0212] Example 2: Comparison of single doses of equimolar EtEPA and LR-EPA This was a single-dose study in which equimolar doses of eicosapentaenoic acid ethyl ester (EtEPA) and lymphatic-released EtEPA formulations (LR-EtEPA) were administered to Sprague-Dawley rats to compare their bioavailability in various tissues following administration. Catheters were placed in the mesenteric lymphatics and portal vein of the rats for sampling during the day of administration. The rats were allowed to recover and were gavaged with an equimolar dose of EtEPA at 1.55 mg / kg body weight on the day of administration. They were randomly assigned to three EtEPA administration groups: (1) pure EtEPA (n=12), (2) a 4:1 weight ratio of EtEPA and low-dose lymphatic-released (LR) compound (i.e., 4 parts EtEPA per 1 part LR compound) (n=12), and (3) a 1:1 weight ratio of EtEPA and high-dose LR compound (i.e., 1 part EtEPA per 1 part LR compound) (n=12). The LR compounds (i.e., phospholipids and / or emulsifiers) used in this experiment are shown in Example 1. Lymph and portal blood were collected before administration and then every hour for 6 hours, at which time the animals were sacrificed and other tissues were collected. Results were analyzed by non-parametric pharmacokinetic (PK) parameters, and the primary comparison between groups was the incremental (i.e., net) area under the curve (incAUC). Levels of EPA and other fatty acids of interest were determined by mass spectrometry protocols optimized for the type of lipid studied. Phospholipid esters were assayed by UPLC-Qoadrupole / Orbitrap Q Exactive MS. Cholesteryl esters were assayed by tandem MS (LC-MS / MS). Triacylglycerol esters were assayed by GC-high resolution MS. Fatty acid methyl esters were assayed by GC-MS.

[0213] As shown in Figure 1A, over a 6 hour period following administration, there is a favorable 140% increase in total EPA free acid levels in lymph for LR-EtEPA over EtEPA, a result that is highly statistically significant.

[0214] When EtEPA doses were kept equimolar between treatment groups and only the amount of additive (e.g., phospholipid and / or emulsifier) ​​was varied, the difference between the 1:1 and 4:1 weight mixtures of EPA and additive was also statistically significant at a p-value of 0.002 (Figure 2). Increasing the amount of additive compared to EtEPA improves uptake through lymphatic fluid.

[0215] Assuming equal EPA release by enterocytes, every mole of increase in lymphatic EPA from LR-EtEPA vs. EtEPA represents a mole diverted from the venous system by the additive. Not only was this the case, but it also occurred in a dose-response manner, such that holding the EtEPA dose constant and increasing the dose of additive alone resulted in higher lymphatic EPA levels. Thus, diversion to the lymphatic system is further supported by the dose-response effect of phospholipids (e.g., lecithin) and / or emulsifiers.

[0216] Example 3: Comparison of multiple doses of equimolar EtEPA and LR-EPA The study consisted of multiday dosing of Long-Evans rats by gavage in two cohorts with varying lengths of exposure: (1) a 7-day exposure, and (2) a 21-day exposure. Rats were randomized into the following treatment groups and received equimolar amounts of the following interventional fatty acids (3.1265 mmol FA / kg / day): 1. Ethyl oleate (OA): 3.1265 mmol OA / kg / day; 2. Ethyl-GLA, Ethyl-EPA, and Ethyl-DHA (GLA+EPA+DHA or G+E+D): 3.1265 mmol FA / kg / day; 3. Ethyl-EPA (EtEPA, E-EPA, or IPE): 3.1265 mmol EPA / kg / day; Ethyl-EPA + lecithin (LC) in a 4.4:1 weight ratio (EPA + LC 4:1, LR-EtEPA, or 1 × LR-EtEPA): 3.1265 mmol EPA / kg / day, and 5. 1.5 × (Ethyl-EPA + LC in a 4:1 weight ratio) (1.5 × (EPA + LC 4:1) or 1.5 × LR-EtEPA): 4.68975 mmol EPA / kg / day.

[0217] For reference, a dose of 1.033 g IPE / kg / day in Long-Evans rats is comparable to a dose of 10 g / day in humans. Vascepa® (>96% IPE) is clinically administered at 4 g / day, which is 2.5 times the typical dose. This dose was selected as a reasonable dose to be considered for treatment of diseases including SIRS, sepsis, and ARDS. Several tissues were collected at the time of sacrifice at the end of the administration period. EPA and other fatty acid levels were determined by the same method described above in experiment 2. The LR compounds (i.e., phospholipids and / or emulsifiers) used in this experiment are shown in Example 1.

[0218] As shown in Figures 3-4, LR-EtEPA was superior to plain EtEPA in enriching lung and heart tissues with EPA at equimolar doses of IPE. In the lung, after 7 days of daily administration by gavage, there was a 76% increase in total EPA in favor of LR-EtEPA that was statistically significant (Figure 3) and a 41% increase in the EPA to arachidonic acid (AA) ratio (data not shown). The heart had a statistically significant 19% increase in EPA uptake (Figure 3) and a 30% increase in the EPA to AA ratio (data not shown). LR-EtEPA also elevated the EPA / AA ratio in lung alveolar macrophages (AVMs) compared to plain EtEPA at equimolar doses (Figure 4). Thus, improved uptake through lymph would in turn improve cardiac and pulmonary uptake of EPA.

[0219] Macrophages are key immune cells in the lungs and play a key role in inflammatory diseases, including but not limited to SIRS, sepsis, ARDS, interstitial lung disease, and pneumonia. LR-EtEPA robustly increased the EPA to AA ratio in immune cells after 7 days (Figure 4). EPA levels were slightly decreased, but there was a much greater decrease in AA. Without wishing to be bound by theory, it appears that EPA displaces AA from immune cells, resulting in a higher EPA to AA ratio. Those skilled in the art would expect this result to be highly favorable for the treatment of pulmonary inflammatory diseases, such as SIRS, sepsis, ARDS, and pneumonia.

[0220] The phospholipid-EPA (PL-EPA) composition can be subdivided into phospholipid levels according to six classical types, including phosphatidylcholine and phosphatidylethanolamine, the two most abundant phospholipids in mammalian cell membranes. Most of the uptake is as phospholipids in the membrane. The data is presented in a "heat map" (Figure 5). The heat map uses color intensity to depict the greater difference between LR-EtEPA versus EtEPA. Figure 5 depicts the percent increase or decrease in LR-EtEPA, and the second column of the heat map looks at the p-values. The most robust findings have the darkest colors in both columns. In the lung, a robust numerical increase in LR-EtEPA is shown as a percent difference and a very robust p-value. Notably, phosphatidylcholine (PC) appears to lag behind the others over the 7 days. This may be a case of PC "catching up" at day 21. For comparison, PC is the largest "pool" of phospholipid types, and one skilled in the art would expect PC to lag behind. A larger pool of PC means a slower turnover rate of the pool. Similarly, a heat map of the PL-EPA to AA (or ARA) ratio is presented in FIG.

[0221] PL-EPA levels in alveolar macrophages in the lungs were analyzed. Several of the phospholipid types were increased, both in number and p-values. Similar results were observed in cardiac tissue. PC was delayed at day 7, but robust increases were seen for other phospholipids. There is also a notable increase for several of the phospholipid types in the lungs. The cellular component of blood had a very robust increase in EPA phospholipids according to the heatmap, as evidenced by the percent change and p-values. In comparison, notable changes occurring in the non-cellular portion of the blood (i.e., plasma) were sparse, consistent with a more robust effect on cells versus non-cellular tissues. As a notable exception, phosphatidylethanolamine (PE) was robustly increased in the acellular blood matrix. The increase in PE has biological significance, particularly since when blood PE is delivered to cells and cell membranes, EPA-enriched PE is more likely to be effective than EPA-enriched PC in counteracting the deleterious effects of AA-derived oxylipins, since the PE moieties are more likely to be found at the inner cell membrane and therefore more likely to have their component fatty acids liberated by phospholipases.

[0222] In Figure 6, the five types of cell PL-EPA are represented in a vector plot. Specifically, the five cell PL-EPA types are lung-PL, AVM-PL, heart-PL, blood cell-PL, and liver-PL. The ratio of LR-EtEPA to EtEPA is plotted on the y-axis. A ratio of >1.25 is considered evidence of biological superiority of LR-EtEPA. A ratio of 0.8-1.25 is considered non-inferiority of LR-EtEPA. Most phospholipids are within the range of analytical superiority. At day 7, phosphatidylcholine lags behind. In contrast, phosphatidylethanolamine was superior to LR-EtEPA in all five tissue / cell-PL types. See also Figures 7-12.

[0223] FIG. 14 is a vector plot illustrating the ratio of EPA to AA (or ARA). The plot demonstrates the very robust advantage of LR-EtEPA in biological superiority on a variety of cells. At day 7, PC lags behind, but due to the strong relationship between phospholipid pool sizes, it can be expected that PC will eventually "catch up" after 7 days. See also FIGS. 15-20.

[0224] As shown in FIG. 21, the EPA:ARA ratio in lung AVMs at day 21 is several fold higher with LR-EtEPA compared to IPE alone and even higher compared to day 7, supporting the superior therapeutic efficacy of the claimed compositions / methods. Importantly, tripling the exposure period shows increased EPA:ARA in AVMs in the LR-EtEPA groups (1× and 1.5×). At the 1× dose (equimolar EPA vs. IPE group), the EPA:ARA in AVMs went from 0.3 at day 7 to 0.64 at day 21. Similarly, at the 1.5× dose (1.5×EPA vs. IPE group), the EPA:ARA in AVMs went from 0.53 at day 7 to 1.0 / = at day 21. This demonstrates the ability of LR-EtEPA to translocate EPA to cells, particularly cells of the lung / cardiac system. The results further indicate that longer exposure provides more time for EPA to integrate into AVMs at normal turnover rates.

[0225] Figure 22 summarizes the results of a study comparing LR-EtEPA to EtEPA in rats, (i) understanding the pathway of delivery to plasma and tissues for both drugs, and (ii) supporting the superior cellular / tissue uptake of LR-EtEPA compared to regular EtEPA. Despite administering EPA at equimolar doses, LR-EtEPA generally shows double the uptake of EPA by lung, alveolar macrophages, heart, and brain.

[0226] In summary, the data provided herein demonstrate that LR-EtPA is biologically superior to EtEPA as a pharmaceutical composition for achieving EPA uptake. Biological superiority is evaluated herein by FDA analytical criteria. When comparing the two formulations, analytical non-inferiority is defined as a ratio of 0.8 at the low end to 1.25 at the high end. If the 90% confidence interval is outside of the range, the results support either analytical superiority or inferiority. If the 90% confidence interval is within the range, the results support only analytical non-inferiority. By these analytical criteria, LR-EtEPA is superior to EtEPA in targeting EPA-enriched tissues and cells. As a result, one skilled in the art would expect LR-EtEPA to be superior to EtEPA in treating diseases that would benefit from improved EPA renewal, including the mechanisms shown in Figures 23A-B.

[0227] The relative efficacy of the LR-EtEPA formulations compared to regular EtEPA was also examined in dose-response plots, as shown in Figures 24A-30D. These and all five treatment arms: (1) OA, (2) EPA+GLA+DHA, (3) EtEPA, (4) LR-EtEPA with equimolar EtEPA to regular EtEPA (1xLR-EtEPA), and (5) LR-EtEPA at 1.5 times the molar dose of regular EtEPA (1.5xLR-EtEPA). Subsequent figures present the formulations in the same order from left to right. Importantly, the molar amount of LC-PUFA is equimolar for treatments (1)-(4), with only treatment (5) having a different dose (1.5x). The latter was done to measure the dose / response of LR-EtEPA, e.g., after 21 days of treatment, to understand whether further dose response may be available at higher doses, and further dose response was typically identified.

[0228] In each "violin" plot (e.g., FIG. 24A for lung tissue), the rectangle inside each violin represents a box plot of the interquartile range (IQR, 25th and 75th percentiles), with the median as an uncolored dot within the IQR. The whiskers of the box plot represent the 10th and 90th percentiles, and the dots on the right side of the box plot are the responses of individual subjects. The curved area outside the box plot represents the density of the distribution (kernel density plot). The x-axis is proportional to the EtEPA dose given, so OA is zero, 1.5×LR-EtEPA1 is 4.7 mmol EPA / kg / day, and the other treatments fall in between at appropriate distances. Note that regular EtEPA and LR-EtEPA are slightly offset from 3.1 mmol EPA / kg / day so as not to overprint. Importantly, these treatments involved the same amount of administered EtEPA, so the null hypothesis is that if LR-EtEPA is not different from plain EtEPA, they should be overprinted.

[0229] Thus, the primary finding from these violin plots is whether LR-EtEPA and regular EtEPA are distinguishable. The x-axis also represents dose as a continuous variable, so the violin plots are also dose-response plots. The secondary finding of interest is whether the results change from left to right, and if so, this is evidence of a dose-response. The tertiary finding of interest is whether there is a discontinuity versus whether the dose-response is continuous. The y-axis is the EPA:ARA ratio in Long-Evans rat lung tissue after 21 days of daily treatment by gavage. The findings are interpreted as follows: (1) LR-EtEPA and regular EtEPA are completely distinct, meaning that their actual distributions do not overlap (i.e., the minimum in the LR-EtEPA group is higher than the maximum in the regular EtEPA group); (2) there is strong evidence of a positive dose-response, with increasing EPA:ARA in lung tissue with increasing doses of EtEPA; and (3) the overall dose-response relationship is characterized by a large discontinuity at the 3.1 mmol EPA / kg / day dose, which reflects the nonoverlapping distributions of LR-EtEPA and regular EtEPA.

[0230] These three features were typical enough of the data from the experiment to motivate a formal modeling of this "disconnected" dose-response relationship, including discontinuities. Three statistical models were evaluated: (1) linear, (2) exponential, and (3) E-Max (sigmoidal curve or Hill function). A linear model for all tissues examined proved to be the best. This implies that the results were in the linear region of the underlying dose-response curve (i.e., there was no evidence of a plateau up to 4.7 mmol EPA / kg / day). Therefore, all dose-response curves were modeled as linear. Typically, a linear function is modeled as y=mx+b, where y is the outcome, m is the slope, x is the EtEPA dose, and b is the y-intercept. Modeling discontinuities simply involves including a multiplier for the slope that only acts on the lymphatic release formulation (λ). For OA, EPA+GLA+DHA, and regular EtEPA, λ=0, while for 1×LR-EtEPA and 1.5×LR-EtEPA, λ=1. The slope factor by which the slopes are multiplied is called theta (θ, or relative potency). Thus, the modeled equation is: y=mxθ λ +b.

[0231] The coefficient θ represents the relative efficacy of the lymphatic-release formulation as a multiple or fold change over that of the other three formulations. Thus, the null hypothesis is θ=1, meaning that LR-EtEPA is "1x" as effective as OA, EPA+GLA+DHA, and plain EtEPA (i.e., LR-EtEPA is neither better nor worse, nor non-inferior). If θ is significantly <1, it means that the outcome is significantly decreased by LR-EtEPA. Finally, θ is significantly >1, it means that LR-EtEPA increases the outcome over the plain / pure formulation of EtEPA.

[0232] After estimating θ with the linear model, the dose-response curves are reassigned to the corresponding dose-response curves for each tissue examined (e.g., FIG. 24B from lung tissue) to present the IPE equivalent EPA dose (mmol / kg / day) instead of the actual dose. For the three formulations with normal fatty acids (i.e., OA, EPA+GLA+DHA, and EtEPA), the actual doses are given; however, for the LR-EtEPA formulation, the dose is the equivalent dose of normal EtEPA. Since the actual doses of EtEPA are identical, a 1×LR-EtEPA dose would overlap with the normal EtEPA dose if there was no advantage (i.e., θ=1). If θ>1, LR-EtEPA is separated from normal EtEPA, and the distance between the two reflects the factor θ by which it exceeds normal EtEPA in terms of multiples.

[0233] Thus, FIG. 24B is interpreted as follows for lung tissue EPA / ARA after 21 days of treatment: (1) there is a strong linear dose response, / y=mxθ λ +b=0.037·[Dose]·3.264 λwhere λ=0 for the regular EtEPA formulation and λ=1 for the lymphatic-release formulation. Importantly, θ is significantly >1, as shown by the 95% confidence interval (CI) that excludes 1 by a wide margin (95% CI 2.777-3.867). A θ of 3.264 means that for a given dose of regular EtEPA, LR-EtEPA achieves about 3.3 times the effect of EtEPA on the resulting EPA / ARA (EPA / AA in the figure). In simple terms, to achieve the same increase in EPA / ARA of the LR-EtEPA 1× group, one would need to administer about 3 1 / 3 the dose of regular EtEPA. Purely for illustrative purposes, this is demonstrated by the Vascepa® capsules on the graph. The usual human dose of Vascepa® is 4 capsules per day. Again, just for illustration, if one takes 4 capsules of LR-EtEPA 1x to raise EPA / ARA, one would need to take approximately 3.3 times that amount of regular EtEPA capsules to raise EPA / ARA by the same amount. Thus, 4 x 3.264 ≈ 13 capsules is shown so the reader can compare with the new formulation of 4 capsules. The human equivalent doses received by rats would result in more capsules being plotted, so the typical human dose is shown here (e.g., the dose of LC-PUFA that would be optimal to treat ARDS would be 33 capsules of regular EtEPA vs. 10 capsules of LR-EtEPA). Stated another way, taking 4 capsules of LR-EtEPA is equivalent to taking 33 capsules of regular EtEPA to raise EPA / ARA by the same amount.

[0234] Having such a tremendous difference between the actual dose and the equivalent dose could be medically beneficial in two ways: (1) perhaps conditions that benefit from a moderate increase in EPA / ARA would not require as high a dose, or (2) a greater increase in EPA / ARA could be achieved by taking a more potent formulation of the "normal" dose. Of course, this would vary depending on the condition and the extent to which the outcome benefits the condition. Importantly, while the ability to improve the efficacy of plain EtEPA for a given outcome by multiplying is remarkable in itself, there is a lot of room to extend these effects by increasing the amount of the selected excipient. For example, as shown in Example 2, a 1:1 mixture was used, thereby using equal amounts of EtEPA and excipient. According to Figure 2, by changing the mixture of EtEPA from 4:1 to 1:1, the amount of EPA in lymphatic fluid was significantly increased. Extending to other tissues, increasing the amount of excipient would also improve efficacy, particularly by increasing and / or improving the phospholipid composition.

[0235] Table 4 below shows the relative potency (θ) in several tissues as assessed by EPA / ARA, OXP / ARA (i.e., [EPA+DGLA+DHA] / ARA), and MOP / ARA (i.e., [EPA+DPA+DGLA+DHA] / ARA). Each of these provides an index of the ratio of LC-PUFAs that result in oxylipins that are less likely to exacerbate inflammation, thrombosis, vasoconstriction, and / or bronchoconstriction compared to ARA. Thus, a higher ratio indicates a greater likelihood of offsetting the deleterious effects of oxylipins derived from ARA. [Table 4]

[0236] Surprisingly, the relative potency was always well above 1 for all tissues examined, including lung, AVM, heart, kidney, brain, pancreas, and jejunum, and was often several-fold slope for regular EtEPA formulations and for some configurations of LC-PUFA compared to ARA. The relative potency of EPA / ARA in the brain was nearly three-fold, indicating that three times the dose of regular EtEPA as LR-EtEPA would be required to increase brain EPA / ARA as much as LR-EtEPA. Note that lines cannot always be fitted to dose-response, as is the case for brain OXP / ARA and MOP / ARA (data not shown).

[0237] The six tissues shown here were chosen because they represent a spectrum of tissue perfusion. Fatty acids are distributed according to tissue perfusion rates in various organs, so by sampling across a range of perfusion rates it becomes possible to understand and model how LR-EtEPA works in different tissues. Surprisingly, across the range of tissue perfusion rates, the relative potency remained significantly higher than 1. In fact, the lowest was 1.8, which is still nearly twice the relative potency of plain EtEPA. In this list, the brain, typically receiving 0.5 mL / min per mL of tissue in a 70 kg adult male, is towards the low end of the perfusion spectrum. See Derendorf and Schmidt, eds., Rowland and Tozer's Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications (5th Ed. 2020 Wolters Kluwer, Philadelphia). The lung, receiving 10 mL / min per mL of tissue, represents the other end of the perfusion spectrum. Indeed, the lungs are the most perfused organ in the body, receiving 100% of the cardiac output in parenchyma, and as discussed above, had a high relative potency for EPA / ARA, θ=3.264. Also, at the upper end of the spectrum, the kidneys are very well perfused at 4 mL / min per mL of tissue, and had the highest relative potency for EPA / ARA, θ=4.406 (95% CI 3.594-5.423). This means that in renal diseases that would benefit from a more favorable mixture of oxylipins, including inflammatory renal diseases, or renal diseases sensitive to vasoactive stimuli, the LR-EtEPA formulation can elevate EPA / ARA by more than four times over the same amount of EtEPA taken as plain EtEPA. Given the wide range of tissue perfusion rates that result in fold-changing relative potencies over plain EtEPA, the LR-EtEPA formulation is suitable for tissues with perfusion rates ranging from 0.01 mL / min per mL of tissue to >10 mL / min per mL of tissue in healthy adult males.Thus, LR-EtEPA is suitable for elevating EPA / ARA across this range of tissues, if not OXP / ARA and MOP / ARA, among conditions that could benefit from reduced inflammation, thrombosis, vasoconstriction, and tissue-specific benefits mentioned in the section above detailing oxylipins. Insofar as the lymphatic release properties of the composition apply to several LC-PUFAs and oxygenated LC-PUFAs, the technology would be suitable beyond EPA therapy per se.

[0238] To ensure that the lowest perfused tissues also had relative potencies (θ) greater than 1, regression modeling was used to model the relationship between measured tissue perfusion and θ for tissues that were already in the lower half of the perfusion range (i.e., kidney, pancreas, heart, brain, and jejunum), regressing EPA / ARA, OXP / ARA, and MOP / ARA simultaneously and assigning the appropriate equation to each outcome, with separate slopes for each outcome. The EPA / ARA results are shown in Figure 33 (left panel). The best fit line was y=0.386x+2.908, R 2= 0.82 and p = 0.0153, indicating a very strong goodness of fit. We next modeled a lower perfusion rate that would be more suitable for skin, fat, and inactive muscle (Figure 33, right panel). This implies that even these poorly perfused tissues would achieve a relative efficacy of about 3 after 21 days of therapy. Importantly, the 90% CI excludes 1, and the wide margins reassure us that variations in tissue perfusion (e.g., during disease or in poorly perfused organs) are unlikely to "erase" the relative efficacy advantage of LR-EtEPA compared to plain EtEPA. This was important for modeling, since less strongly perfused tissues generally require longer time to reach steady state, in which case more than 21 days of therapy would be needed to achieve maximum effect in the absence of a loading dose. This model reassures us that 21 days is likely sufficient for LR-EtEPA to reach a relative efficacy that is multiple of plain EtEPA. In summary, the perfusion-relative efficacy relationship is strong, indicating that it is possible to model less perfused tissues, which are also more likely to reveal a efficacy benefit of LR-EtEPA within 21 days.

[0239] Another aspect of this study focused on the effects of different treatment arms on fatty acid metabolism, including fatty acid-derived intermediates and oxylipins, as they may be important in a variety of biological processes, including inflammation, vasoconstriction, bronchospasm, and / or thrombosis. DGLA was one of the fatty acids evaluated. Surprisingly, in alveolar macrophages and cardiac tissue, formulations containing equimolar amounts of EtEPA did not differ from E+G+D in their effects on DGLA (data not shown). This was unexpected, since E+G+D contained the DGLA precursor GLA, and thus it was expected that E+G+D would prove superior to EtEPA in elevating DGLA. This implies that pure EtEPA itself is at least consistent with E+G+D compared to DGLA. Even more surprising, in lung tissue, equimolar EtEPA formulations were actually superior to E+G+D, meaning that EtEPA formulations, despite lacking GLA, significantly elevate DGLA more than E+G+D. This suggests that EPA is altering the kinetics of DGLA. To test this, the product / precursor ratio is an index of the success of DGLA conversion to AA (i.e., the inverse of the ratio presented above). High AA / DGLA indicates efficient conversion of DGLA to its daughter molecule AA. The conversion of DGLA to AA is facilitated by Δ5-desaturase enzymes (e.g., FADS1, fatty acid desaturase 1 gene). When LC-PUFAs are converted to other PUFAs, this occurs by both elongation (addition of carbon units) and desaturation (i.e., addition of new double bonds). Of these processes, desaturation represents the rate-limiting step versus elongation. Thus, the conversion of fatty acids is largely a matter of the activity of a series of desaturase enzymes. The AA / DGLA ratio is therefore the functional Δ5-desaturase index (Δ5D-I-ω6) of these ω-6 fatty acids. Viewed as a functional index of Δ5-desaturase, when EPA inhibits Δ5-desaturase, the result is less efficient synthesis of AA from DGLA, resulting in a significant decrease in the Δ5-desaturase index.Indeed, viewed in this manner, the AA / DGLA ratio provides a more intuitive way to view the effect of EPA on DGLA dynamics (Figure 31A). In a separate experiment with an induced inflammatory challenge (by IL-6 administration), EPA strongly inhibited the protein production of Δ5-desaturase, i.e., fatty acid desaturase 1 (FADS1), in endothelial cells, according to the functional assay represented by Δ5D-I-ω6 (Figure 34B). Similarly, EPA strongly inhibited the protein production of Δ6-desaturase, i.e., fatty acid desaturase 2 (FADS2), in endothelial cells (Figure 34B). These results confirm that the functional test of the desaturase enzyme is accompanied by a decrease in the protein levels of the desaturase, and in the case of Δ5-desaturase, confirms the ability of EPA to inhibit this enzyme, as assayed by Δ5D-I-ω6 (Figure 31A). The substantial suppression of Δ5D-I-ω6 by isolated EtEPA preparations indicates that EPA alters DGLA kinetics by inhibiting the catabolism of DGLA. This in turn increases the DGLA pool size. In particular, since lung tissue is the therapeutic target for DGLA administration as Oxepa® (i.e., to treat ARDS), it is novel and surprising that EtEPA can actually surpass the clinical approach of administering GLA to increase the DGLA pool. To exclude altered DGLA synthesis, Δ8-desaturase enzymes (e.g., FADS2, fatty acid desaturase 2 gene) are important. Δ8-desaturase enzymes catalyze the synthesis of DGLA from the precursor eicosadienoic acid (EDA, a 20-carbon omega-6 LC-PUFA with two double bonds). Like Δ5D-I-ω6, the Δ8-desaturase index (Δ8D-I-ω6) of these omega-6 fatty acids is a functional index of enzyme activity. And surprisingly, isolated EPA preparations actually elevate Δ8D-I-ω6, coinciding with sufficient induction to elevate DGLA synthesis (Figure 31B). Thus, EPA can "go back and forth" elevating the DGLA pool, implying that it promotes DGLA synthesis and inhibits its catabolism by conversion to AA.This would be a boon for treating conditions with pathological levels of harmful AA oxylipins, because not only would the supply of AA be reduced as an oxylipin precursor, but the larger DGLA pool would provide less harmful competing oxylipins. Beyond disfavoring AA through substrate competition with DGLA for oxygenases, certain DGLA oxylipins inhibit the COX and LOX enzymes that oxygenate AA to oxylipins (e.g., PGE1 and 15-HETrE). The apparent effect of IPE and Oxepa® on DGLA kinetics is shown in Figure 31C. The significance of EtEPA's ability to increase DGLA pools and kinetics via Δ5D-I-ω6 and Δ8D-I-ω6 is that this implies that EtEPA is not at all disadvantageous compared to the current practice of administering GLA. In contrast, these results confirm that EtEPA is superior in increasing DGLA in the lung.

[0240] Again, raising DGLA in the lung is expected to be beneficial insofar as (1) it raises less harmful (i.e., less inflammatory, less thrombotic, less bronchoconstrictive) oxylipins derived from DGLA, and (2) the DGLA-derived oxylipins, like the EPA-derived oxylipins, can counterbalance the ARA-derived oxylipins by competing for oxygenating enzymes (synthesis) and receptors (function). The idea that EPA would raise DGLA was surprising, but even more unexpected was the observation that the DGLA-derived oxylipins were in a dose-response relationship to EPA, even in uninduced lung tissue (Figures 32F-H). In uninduced lung tissue, DGLA-oxylipin 15-HETrE was assessed as total oxylipins, non-esterified oxylipins, and esterified oxylipins. Total 15-HETrE was substantially increased by LR-EtEPA compared to E+G+D (p=0.0289) and plain EtEPA (p=0.0619). Because this analysis included only half of the subjects in the main study, the loss of statistical power from half the samples likely explains the borderline p-value compared to plain EtEPA. Furthermore, esterified 15-HETrE was also substantially higher in LR-EtEPA compared to E+G+D (p=0.0007) and plain EtEPA (p=0.0094). Similarly, total and esterified 12-HETrE derived from DGLA were significantly higher in total and esterified 12-HETrE than in E+G+D compared to plain EtEPA. These results reassure us that the unexpected elevated DGLA from LR-EtEPA is also converted to elevated oxylipins derived from DGLA, implying that in general these involve functional differences related to the favorable properties of these oxylipins and those from DGLA.

[0241] This means that both plain EtEPA and LR-EtEPA are distinct from and outperform current practice approaches for ARDS. As these results are more broadly relevant to the mechanism of action of, for example, E+G+D to treat ARDS, to understand how LR-EtEPA outperforms plain EtEPA, one must look to more compelling results such as OXP / AA and MOP / AA. Indeed, plain EtEPA versus E+G+D is superior in elevating OXP / AA (i.e., [EPA+DGLA+DHA] / AA) in the lung. Importantly, and by extension, LR-EtEPA versus plain EtEPA was approximately twice as effective in elevating OXP / AA at equimolar doses (Figures 24C-D). The relative efficacy of the LR formulation was estimated to be 2.6-fold (95% CI 2.2-3.1) that of plain EtEPA. This implies that 2.6 times the dose of regular EtEPA must be administered just to compete with the same molar dose of LR-EtEPA. The disparity is even greater with E+G+D, which again conferred an advantage in this experiment by reserving a number of competing fatty acids to be co-administered with the conventional approach. Similar results were seen in the lung's primary immune cell AVM (Figure 25C). Thus, in treating ARDS, the OXP / AA index indicates that LR-EtEPA is superior to both regular EtEPA and E+G+D in elevating the LC-PUFAs that drive the mechanism of action of Oxepa®. Moving beyond ARDS therapy, the MOP / AA index is broadly applicable to several other diseases, including those outside the pulmonary system. Here, MOP incorporates several LC-PUFAs that have been proposed to be medically beneficial as medicinal oxylipin precursors: EPA+DGLA+DPA+DHA. Thus, the MOP / AA ratio indicates the ability of E+G+D, regular EtEPA, and especially LR-EtEPA to exert a therapeutic effect by limiting the "damage" from AA and its deleterious oxylipins in conditions exacerbated by the inability to regulate said oxylipins.In the lung, the MOP / AA ratio was higher for plain EtEPA versus E+G+D, and more importantly, LR-EtEPA was superior to plain EtEPA (Figure 24E). The relative efficacy of the LR formulation was 2.3-fold (95% CI 2.1-2.6) that of plain EtEPA in lung tissue (Figure 24E) and 2.4-fold (95% CI 2.0-2.8) in alveolar macrophages (Figure 25D). These data indicate several advantages over Oxepa® for treating ARDS. These include: (1) the ability to limit fatty acids to medicinal oxylipin precursors by timing administration opposite a meal featuring other "competing" fatty acids, so that the benefits of MOP are not diluted by said fatty acids; (2) the ability to limit the deleterious conversion of DGLA to AA by reserving GLA; (3) the ability to increase the lecithin portion, particularly for critical care applications, such as the 1:1 ratio of excipient to EtEPA shown in FIG. 3, which elevates EPA significantly and very rapidly (i.e., within a few hours of the first / only dose); and (4) the ability to rely on robust inhibition of the rate-limiting Δ5-desaturase enzyme, and robust induction of the rate-limiting Δ8-desaturase enzyme, thereby elevating DGLA at the expense of AA by robustly altering its kinetics rather than relying on pre-meal administration of the DGLA precursor substrate. In particular, the observation that in the context of Oxepa® and ARDS, LR-EtEPA is significantly superior to plain EtEPA in increasing OXP / AA (and for that matter MOP / AA) and E+G+D implies a higher efficacy of LR-EtEPA.

[0242] Furthermore, administration of LC-PUFAs often results in the inhibition of certain enzymes that facilitate the conversion of one LC-PUFA to its canonical metabolite LC-PUFA. These conversions are facilitated by two broad categories of enzymes: (1) desaturase enzymes, which add double bonds (making LC-PUFAs less saturated / more desaturated), and (2) elongase enzymes, which make LC-PUFAs longer, usually by two carbon units. Of these enzyme families, desaturases are believed to catalyze the rate-limiting step. As an example, EPA is synthesized from omega-3 eicosatetraenoic acid (ETA, a 20-carbon omega-3 LC-PUFA with four double bonds), the conversion of which is catalyzed by Δ5-desaturase. In turn, EPA is converted to omega-3 docosapentaenoic acid (DPA, a 22-carbon omega-3 LC-PUFA with five double bonds), the conversion of which is catalyzed by Δ5-elongase (regulated by factors of the ELOVL gene family). A functional index of the efficiency of the conversion of EPA to DPA is the product / precursor ratio, the Δ5-elongase index of omega-3 (Δ5EI-ω3). A more efficient reaction may increase production and / or decrease precursors, resulting in a higher ratio. Conversely, a less efficient reaction may decrease product and / or increase precursors, either absolutely or relative to each other. Surprisingly, there appears to be a strong dose-response relationship between EPA and Δ5EI-ω3 inhibition. This was evident as a substantial inhibition of the product / precursor ratio, i.e., a sharp decrease in the DPA / EPA ratio (Figure 31D). This effect was highly consistent among several tissues examined. Specifically, LR-EtEPA is consistently inhibited compared to regular EtEPA and E+G+D, and more broadly there is an unmistakable, if unexpected, dose-response trend across the increasing doses of EtEPA represented by the five groups from left to right in the figure. As with many other results, the differences between LR-EtEPA and regular EtEPA occur despite both involving the same molar dose of EtEPA given, and therefore the differences in Δ5EI-ω3 must be due to the different composition of LR-EtEPA.The importance of Δ5-elongase inhibition is that it tends to increase the amount of EPA in the LC-PUFA reservoirs of tissues, e.g., cell membranes. This likely promotes EPA retention in cell membranes, since a larger reservoir is at hand in a given tissue when cell damage occurs. In the event of cell damage, more EPA is available as a substrate for oxylipin production, resulting in more EPA-derived oxylipins compared to the deleterious oxylipins resulting from ARA. In summary, the apparent Δ5-elongase inhibition by LR-EtEPA is an unexpected added benefit of the formulation.

[0243] Example 4: Induced inflammation model to elucidate the effect of icosapent ethyl on tissue heme oxygenase expression Icosapent ethyl (IPE, also referred to as ethyl-EPA, EtEPA, E-EPA, or EPA-E) is an ethyl ester of eicosapentaenoic acid, and a daily gram dose improves dyslipidemia and prevents major atherosclerotic vascular disease events. Currently, a highly purified form of IPE, Vascepa®, is used to treat hypertriglyceridemia and prevent major atherosclerotic vascular events (MACE). Previous examples have shown that co-administration of IPE with a small mixture of excipients featuring soy lecithin, polysorbate 80, and polyoxyl 35 promotes the appearance of EPA in the circulation. Preliminary results suggest that the excipients can achieve this by altering the precirculatory pathway to the circulation and increasing EPA tissue distribution to select tissues accordingly. Notably, in rats, the excipients improved EPA delivery to the lymphatic system upon acute administration, thereby significantly increasing EPA levels in lung and heart tissue upon daily administration.

[0244] Separately, the heme oxygenase 1 gene (HMOX1) is an Nrf2-regulated gene and encodes the enzyme heme oxygenase 1 (HO-1). HO-1 has important antioxidant, anti-inflammatory, anti-apoptotic, and immunomodulatory effects in vascular cells and tissues, whereby HO-1 can mitigate adverse tissue damage responses. These effects, unlike the beneficial effects from oxylipins, are not directly mediated by fatty acid products derived from LC-PUFAs, but rather by protein products induced by gene expression Nrf2. Thus, the antioxidant, anti-inflammatory, anti-apoptotic, and immunomodulatory effects in vascular cells and other tissues from HO-1 and / or other Nrf2-induced antioxidants constitute distinct mechanisms of action, distinct from the beneficial effects from oxylipins. Thus, the antioxidant effects of HO-1 and co-regulated antioxidant gene products involve distinct mechanisms from EtEPA and its derivatives, which mitigate cellular damage and thereby ameliorate disease. Importantly, improving the delivery of LC-PUFAs and their oxylipins, including but not limited to EPA and its oxylipins, will improve the ability to utilize HO-1 and co-regulated antioxidant gene products to alleviate cell damage. This is particularly important in cell lysis conditions, especially hemolysis and other tissue damage that releases free heme into damaged tissues, since HO-1 is well known to limit toxicity from free heme. Thus, cell damage from hemolysis, tumor lysis, or ischemia, as well as SIRS, sepsis, and ARDS, is expected to be repaired by the ability of LC-PUFAs to protect against free heme toxicity, as well as the antioxidant effects from HO-1 itself and other antioxidants that are optionally co-regulated by Nrf2. Indeed, some LC-PUFAs and their oxylipins are likely to promote this injury response by activating Nrf2, including other omega-3 LC-PUFAs other than EPA, such as DHA. All such LC-PUFAs would benefit from a multi-fold improvement in delivery of the LC-PUFA to sites of cellular damage, such as occurs in lymphatic-release formulations, aided by the rapid incorporation of PL-EPA into cell membranes.Without being limited to EPA for this purpose among the different choices among various LC-PUFAs, if multiple LC-PUFAs activate Nrf-2 and induce a robust response from HO-1 and related antioxidants, the optimal choice may be an LC-PUFA that produces a set of oxylipins that best compete with the adverse effects of ARA-derived oxylipins, since cellular damage, including damage from free heme, is accompanied by inflammatory and prothrombotic cascades. Thus, EPA may be well positioned to take advantage of HO-1 due to its ability to (1) strongly suppress ARA synthesis by inhibiting Δ5-desaturase, (2) improve DGLA pools and its associated oxylipins by inhibiting Δ5-desaturase and inducing DGLA production by Δ8-desaturase, and (3) limit EPA loss / conversion to DPA by inhibiting Δ5-elongase, and (4) promote the production of oxylipins from other LC-PUFAs such as HODE from LA, all of which would limit the adverse effects of ARA-derived oxylipins by (1) suppressing ARA synthesis, (2) introducing substrates that compete with ARA for oxygenation of the enzyme, and (3) producing oxylipins that inhibit oxygenases. As previously described, EPA and DGLA are particularly well suited to compete with ARA due to their 20-carbon structures, while longer LC-PUFAs may be more distant and produce a more limited variety of oxylipins. That is, compared to the 22-carbon DHA, EPA has a greater complement of antithrombotic oxylipins, since it produces prostanoids, especially thromboxanes, which have a lower tendency to cause thrombosis, in abundance, versus thromboxanes from ARA, prostacyclin, and prostaglandins.Furthermore, EPA produces leukotrienes that can counteract the adverse effects of leukotrienes from ARA.This set of "medicinal" oxylipins is lacking in DHA.Thus, all things being equal, EPA may have the advantage of counteracting the adverse effects of ARA, while preserving its ability to promote HO-1 and related antioxidants.However, the benefits of LR-EtEPA in delivering LC-PUFAs to sites of cellular damage need not be limited to EPA, even though EPA is a preferred embodiment.

[0245] Classically, HMOX1 is an inducible gene encoding HO-1, induced by a variety of cell injuries and other stimuli. Other experiments suggest that EPA free acid can upregulate HMOX1 and HO-1 (Figure 34A). To the extent that IPE also induces HMOX1, this may itself mediate some of the benefits of IPE, particularly for preventing MACE. Furthermore, to the extent that lymphatic-released IPE formulations improve EPA levels in the lungs, heart, brain, kidneys, pancreas, and jejunum, LR-EtEPA may be particularly useful in diseases that affect these organs, including MACE and lung diseases, as well as any disease involving cell lysis, including hemolysis or lysis of other blood cells, or lysis associated with organ infarction or cancer.

[0246] In contrast to HMOX1, the heme oxygenase 2 gene (HMOX2) is a separate gene with distinct regulators and encodes the protein heme oxygenase-2 (HO-2). Importantly, HMOX2 is thought to be constitutively produced and few molecules have been found that alter its expression. A notable exception to this is that HMOX2 is induced by corticosteroids. Steroid induction can be mediated by inhibiting COX and LOX, thereby strongly inhibiting arachidonic acid (AA) oxidation and thus limiting exposure to bioactive AA-derived oxylipins, a canonical steroid effect. Similarly, LR-EtEPA mimics the effects of steroids insofar as the net effect is to inhibit AA, elevate EPA and EPA / AA, and decrease AA oxidation. This is accomplished by EPA competing with arachidonic acid to be metabolized to different, similar oxylipins, many of which have anti-inflammatory properties. In other words, large doses of IPE are expected to have anti-inflammatory effects via oxylipin metabolites that mimic the severe aspects of corticosteroid effects. Thus, IPE may provide an alternative to steroids for inducing HMOX2 or act as a steroid sparing agent.

[0247] Other genes are tightly co-regulated with HO-1 by the same antioxidant response elements (AREs): NQ01 and GST. COX2 is an enzyme involved in converting EPA to bioactive oxylipins, which may be less inflammatory compared to the analogous oxylipins derived from AA. Angiotensin-converting enzyme (ACE) is produced in the lung and regulates angiotensin I to vasoconstrictor angiotensin II, thereby affecting blood pressure. In an unpublished proteomic study, ACE was inhibited by EPA (Figure 34B).

[0248] In a series of tissue culture experiments, cells were induced with IL-6 to induce an inflammatory and cell damage response, and EPA was added to determine whether it moderated proteins involved in the damage response. Notably, EPA significantly reduced the expression of IL-6 in pulmonary endothelial cells (1.9-fold for EPA + IL-6 vs. IL-6 alone, p = 2.8 × 10 -32 ), vascular endothelial cells (EPA + IL-6 increased the IL-6-induced 2.2-fold increase compared to IL-6 alone, p = 7.9 × 10 -50 ), and brain endothelial cells (1.5-fold increase in EPA+IL-6 versus IL-6 alone, p = 4.70 × 10 -16 ) increased HO-1 upon induction of inflammation in endothelial cells (see Figures 35-36). Notably, in vascular and brain endothelial cells, addition of EPA significantly decreased fatty acid desaturase 2 (FADS2), a gene encoding a Δ6-desaturase, and fatty acid desaturase 1 (FADS1), a gene encoding a Δ5-desaturase. Thus, the proteomic results not only confirm the ability of EPA to promote HO-1, but also the ability of EPA to inhibit Δ5- and Δ6-desaturases, corroborating the aforementioned ability of, for example, EtEPA to suppress the Δ5-desaturase index.

[0249] SIRS, sepsis, and ARDS are considered as examples of conditions that would particularly benefit from the enhancement of HO-1 and related antioxidants. For reference, a dose of 1.033 g IPE / kg / day in Long-Evans rats is equivalent to a dose of 10 g / day in humans. Vascepa® is clinically administered at 4 g / day, so this is 2.5 times the typical dose. This dose was selected as a reasonable dose to be considered for the treatment of SIRS, sepsis, and ARDS. The data from this experiment support the concept that EtEPA, and particularly LR-EtEPA, improves ARDS by altering the cell injury response in several ways: (1) by increasing EPA / AA, OXP / AA, or MOP / AA as a measure of enhanced levels of oxylipin precursors, including oxylipins that are less harmful to AA-derived oxylipins; (2) by inhibiting the synthesis of AA from DGLA by suppressing FADS2 and Δ5-desaturase; (3) by promoting the synthesis of DGLA by inducing FADS1 and Δ8-desaturase; (4) by decreasing AA-derived oxylipins from both (2) and (3) above and / or enhancing DGLA-derived oxylipins; (5) by decreasing AA-derived oxylipins and enhancing EPA-derived oxylipins by providing abundant amounts of EPA, particularly HO-1, an example of which in this section; and (6) by inducing antioxidant response factors and other pathways that induce HMOX1 and / or HMOX2, NQ01, GST, and GHS.

[0250] Example 5: EPA Increased Endothelial Nitric Oxide Synthase (eNOS) Levels and Proteins Associated with the Cellular Response to Oxidative Stress during Inflammation The aim of this study was to measure and compare the effects of EPA and DHA on eNOS levels and the expression of proteins regulating ROS in human vascular ECs under inflammatory conditions.

[0251] Human umbilical vein endothelial cells (HUVECs) were isolated in primary culture from female donors by Clonetics (San Diego, California) and purchased as expanded cells. All cell culture donors were healthy and had no pregnancy or prenatal complications. Cultured cells were incubated at 37°C in 95% air / 5% CO2 and passaged by an enzymatic (trypsin) procedure. Confluent cells (4–5 × 10 5 Cells / 35 mm dish) were plated with minimal essential medium containing 3 mM L-arginine and 0.1 mM BH4 [(6R)-5,6,7,8-tetrahydrobiopterin]. Prior to experimental use, cells (from the second or third passage) were rinsed twice with Tyrode-HEPES buffer containing 1.8 mM CaCl2.

[0252] EPA and DHA were purchased from Sigma-Aldrich (St. Louis, MO) and initially prepared in double distilled ethanol. Primary and secondary stock solutions were prepared and stored under nitrogen at -20°C.

[0253] HUVECs were treated with vehicle, EPA, or DHA (10 μM) for 2 h and then challenged with IL-6 (12 ng / mL) for 24 h. After incubation, cells were pelleted and frozen at -80°C until proteomic analysis was performed.

[0254] The relative protein expression levels between the various treatments were measured using LC / MS proteomics techniques. Following protein digestion, peptides were separated on a reversed-phase column and then identified based on their mass.

[0255] Cell pellets were lysed using methanol / chloroform extraction. Proteins were denatured, reduced, alkylated, and trypsin digested. Samples were then prepared for tandem mass tag (TMT) 10plex labeling. A bicinchoninic acid (BCA) assay was performed on each sample to quantify the total protein in each sample, which is important to ensure that equal amounts of each peptide are added to the multiplex samples. Each peptide in the sample was given a unique low molecular weight (typically 126-130 Da) and the samples were then combined.

[0256] Each multiplexed sample was then fractionated to increase overall protein coverage using high pH reversed-phase fractionation and analyzed by LC / MS using a Dionex UltiMate 3000 RSLC in tandem with a Q-Exactive / Lumos Orbitrap Mass Spectrometer. Chromatography was performed using a 2-h gradient on a Thermo Pepmap C18 column (100 Å pore size, 3.0 μm particle size, 100 μM × 150 mm) set at 50 °C. Mobile phase A was water with 0.1% formic acid and mobile phase B was acetonitrile with 0.1% formic acid.

[0257] Proteins that showed a fold change >1.0 and p<0.05 for relevant comparisons were considered significant and analyzed further. A bioinformatics package was applied to all mass spectrometry intensity data known as Differential Enrichment Analysis of Proteomic Data (DEP) to process the proteomic data (Figures 35-37). [Table 5]

[0258] In summary, EPA and DHA significantly stimulated or inhibited the expression of 544 / 472 and 864 / 767 proteins, respectively, compared to IL-6 alone. Specifically, EPA increased eNOS expression by 1.1-fold (p=0.014) compared to DHA. EPA, but not DHA, increased dimethylarginine dimethylaminohydrolase (DDAH-1) and DDAH-2 levels, enzymes that hydrolyze endogenous eNOS inhibitors. In addition, EPA and DHA increased proteins that limit oxidative stress, including glutathione reductase (GSR), thioredoxin (TXN), and peroxiredoxin (PRDX) species.

[0259] Thus, the present inventors have demonstrated that under inflammatory conditions, EPA significantly increased the expression of eNOS and ROS-reducing proteins in vascular endothelial cells compared with DHA. These changes in protein expression during inflammation may contribute to the preservation of arterial function and reduced cardiovascular risk.

[0260] Example 6: EPA regulates the expression of inflammatory proteins in pulmonary endothelial cells following exposure to air pollution particulate matter As illustrated in Figure 38, air pollution is a major cause of global mortality and various chronic diseases, including cardiovascular disease. See Rajagopalan et al., J. Am. Coll. Cardiol. (2018) 72:2054-2070, which is incorporated herein by reference in its entirety. Exposure to fine particulate matter (PM) (≦2.5 μm in mean diameter) in air pollution causes both acute and chronic tissue damage as a result of penetrating and toxic chemical components. See Franklin et al., Curr. Probl. Cardiol. (2015) 40:207-2382, which is incorporated herein by reference in its entirety. In pulmonary endothelial cells, PM causes nitric oxide (NO) synthase (eNOS) uncoupling, resulting in loss of function, apoptosis, and abnormal immune responses. Cherng et al., Environ. Health Perspect. (2011) 119:98-103, Hansen et al., Toxicol. Appl. Pharmacol. (2007) 219:24-32, Pope et al., Circ. Res. (2016) 119:1204-1214, and Courtois et al., Environ. Health Perspect. (2008) 116:1294-1299, each of which is incorporated by reference in its entirety. Systemic inflammatory damage is also associated with PM exposure, as evidenced by increased neutrophil degranulation. See Lacy, Allergy Asthma Clin. Immunol. (2006) 2:98, Hoenderdos et al., Thorax. (2016) 71:1030-1038, each of which is incorporated by reference in its entirety. When challenged with proinflammatory stimuli, endothelial cells produce signals (IL-8) that induce such neutrophil degranulation. See Gill et al., FASEB J. (1998) 12:673-684, which is incorporated by reference in its entirety. Finally, loss of NO-dependent vasomotor control has been reported in humans and animal models of PM exposure.See Courtois et al., Environ. Health Perspect. (2008) 116:1294-1299; Nurkiewicz et al., Environ. Health Perspect. (2004) 112:1299-1306; Brook et al., Circulation (2002) 105:1534-1536, each of which is incorporated by reference in its entirety.

[0261] EPA, administered as icosapent ethyl (IPE), is the first FDA-approved drug to reduce cardiovascular risk in patients with elevated triglyceride levels as an add-on to maximally tolerated statin therapy. The REDUCE-IT trial showed that treatment with high-dose IPE (4 g / day) reduced composite cardiovascular events by 25% in statin-treated patients with elevated baseline triglyceride levels. See Bhatt et al., N. Engl. J. Med. (2019) 380:11-22, incorporated herein by reference in its entirety. The benefit of IPE was independent of baseline triglyceride levels but positively correlated with plasma levels of EPA. Imaging studies showed significant regression of plaque volume and composition with IPE compared with statins alone in patients with atherothrombotic disease. See Budoff et al., Euro. Heart J. (2020) 41:3925-3932; Watanabe et al., J. Cardiol. (2017) 70:537-544, each of which is incorporated herein by reference in its entirety. In contrast to IPE treatment, the results of trials using mixed omega-3 fatty acids failed to reduce cardiovascular events. This may be due to differences in formulations and potential pleiotropic benefits and membrane interactions unique to EPA. See Mason et al., Metab. Clin. (2022) 130:155-161; Sherratt et al., Prostaglandin Leukot. Essent. Fatty Acid (2021) 173; Sherratt et al., J. Lipid Res. (2021) 62; Mason et al., Arterioscler. Thromb. Vasc. Biol. (2020) 40:1135-1147, each of which is incorporated by reference in its entirety.

[0262] This example evaluated the ability of EPA to modulate inflammatory protein expression and associated pathways, including neutrophil degranulation, in pulmonary endothelial cells following exposure to air pollution PM of different sizes.

[0263] Primary human pulmonary microvascular endothelial cells (HMVEC-L, PEC) were purchased from Lonza (Manassas, VA). Cells were cultured in complete endothelial cell growth medium and maintained in a 95% air / 5% CO2 humidified incubator at 37 °C. Cells were fed with fresh medium every other day and expanded by an enzymatic (trypsin) procedure. Cell culture medium also contained 2% FBS to facilitate fatty acid processing.

[0264] EPA was purchased from Sigma-Aldrich (Saint Louis, Mo.), dissolved in double-distilled ethanol under a nitrogen atmosphere, and stored at −20° C.

[0265] Urban airborne particulate matter and fine particulate matter were purchased from Sigma-Aldrich (SRM1648a), catalog numbers: NIST1648a3110 and NIST27863110. The mean particle diameters were 5.85 and 2.8 μm, respectively.

[0266] 39A-B show particle size distributions for SRM1648a and SRM2786 after 10 minutes and 1 hour of sonication in water, respectively. The solid line represents % by volume (see NIST Certificate of Analysis, SRM1648a and NIST Certificate of Analysis, SRM2786).

[0267] PECs were pretreated with EPA (40 μM) for 2 h in 2% FBS-containing medium and then challenged with urban particulate matter (50 μg / mL) for 2 h. After 2 h, the medium was washed out and HBSS buffer was added. After incubation, cells were pelleted and frozen at -80°C until proteomic analysis was performed. Relative protein expression levels between the various treatments were measured using LC / MS proteomic techniques (Figure 40).

[0268] Cell pellets were lysed using methanol / chloroform extraction. Proteins were then denatured, reduced, alkylated, and trypsin digested. Samples were labeled by tandem mass tag (TMT) 10plex labeling to multiplex samples and ensure that injection, LC, and MS conditions were identical for each sample. A bicinchoninic acid (BCA) assay was performed to quantify total protein in each sample. Each peptide in the sample was given a unique low molecular weight (typically 126-130 Da) and the samples were then combined.

[0269] Each multiplexed sample was then fractionated to increase overall protein coverage using high pH reversed-phase fractionation and analyzed by LC / MS using a Dionex UltiMate 3000 RSLC in tandem with a Q-Exactive / Lumos Orbitrap Mass Spectrometer.

[0270] Proteins that showed a fold change >1.0 and p<0.05 for relevant comparisons were considered significant and analyzed further. The ComBat function was applied to all mass spectrometry intensity data to correct for batch effects. The bioinformatics package Differential Enrichment Analysis of Proteomic Data (DEP) was used to process the proteomic data and generate figures.

[0271] In this study, the inventors discovered the following results:

[0272] First, as shown in Figures 41A-B, EPA significantly regulated the expression of 205 and 347 proteins for fine PM and urban PM, respectively.

[0273] Figures 42A-C show normalized intensity values ​​for each replicate in the treatment group (N=3). CXCL6, -XC motif chemokine 6; HSP90B1, heat shock protein 90-β, GSTP1, glutathione S-transferase P. §p=0.015 vs. fine PM; fp=0.011 vs. urban PM; †p=0.030 vs. fine PM; *p=8.88x10-9 vs. control; **p=3.79x10-7 vs. control; ‡p=0.0008 vs. urban PM; p=0.036 vs. urban PM.

[0274] Second, among the pathways regulated by both PMs was neutrophil degranulation (Gene Ontology ID: 0043312), with fine and urban PMs regulating 36 and 13 proteins, respectively, as summarized in Table 6 below. Eight proteins were common to fine and urban PMs, including a 1.5- and 1.3-fold increase in the C-X-C motif chemokine 6, respectively. [Table 6]

[0275] Third, EPA treatment modulated 22 and 35 proteins associated with neutrophil degranulation for fine and urban PM, respectively.

[0276] Fourth, in fine PM, EPA increased the expression of heat shock protein 90-β and decreased the expression of interleukin enhancer binding factor 2.

[0277] Fifth, compared with urban PM, EPA decreased the expression of C-X-C motif chemokine 6 and increased the expression of glutathione S-transferase P.

[0278] In summary, EPA favorably regulated the expression of various cytoprotective and proinflammatory proteins in lung ECs during exposure to multiple air pollution PM. These findings support the potential cardiovascular benefits of EPA under inflammatory conditions induced by air pollution PM.

[0279] The present technology includes, but is not limited to, the following specific embodiments.

[0280] 1. A composition comprising: (a) at least 15% by weight of one or more polyunsaturated fatty acids (PUFAs) or derivatives thereof; and (b) 1% to 85% by weight of a phospholipid source.

[0281] 2. The composition of embodiment 1, further comprising:(c) 1% to 20% by weight of one or more emulsifiers.

[0282] 3. The composition according to embodiment 1 or 2, wherein the one or more PUFAs or derivatives thereof are selected from the group consisting of linoleic acid (LA), gamma-linoleic acid (GLA), dihomo-gamma-linoleic acid (DGLA), arachidonic acid (AA), adrenic acid (AdA), omega-6 docosapentaenoic acid (DPA6), alpha-lineoleic acid (ALA), stearidonic acid (SDA), omega-3 eicosatetraenoic acid (ETA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), LA derivatives, GLA derivatives, DGLA derivatives, AA derivatives, AdA derivatives, DPA6 derivatives, ALA derivatives, SDA derivatives, ETA derivatives, EPA derivatives, DPA derivatives, and DHA derivatives.

[0283] 4. The composition of any one of embodiments 1-3, wherein the PUFA derivative comprises an oxylipin.

[0284] 5. LA derivatives are 9-hydroperoxy-octadecadienoic acid (9-HpODE), 13-hydroperoxy-octadecadienoic acid (13-HpODE), 9-hydroxy-octadecadienoic acid (9-HODE), 13-hydroxy-octadecadienoic acid (13-HODE), 9,10,13 trihydroxy-octadecenoic acid (9,10,13TriHOME), 9,12,13 trihydroxy-octadecenoic acid (9,12,13TriHOME), 9-oxo 12,13-epoxy-octadecenoic acid (12,13-EpOME), 9,10-dihydroxy-octadecenoic acid (9,10-DiHOME), and 12,13-dihydroxy-octadecenoic acid (12,13-DiHOME).

[0285] 6. The composition according to embodiment 3, wherein the GLA derivative is selected from the group consisting of 6-hydroxy-octatrienoic acid (6-HOTrE or 6-hydroxy-GLA), 7-hydroxy-octatrienoic acid (7-HOTrE or 7-hydroxy-GLA), 9-hydroxy-octatrienoic acid (9-HOTrE or 9-hydroxy-GLA), 10-hydroxy-octatrienoic acid (10-HOTrE or 10-hydroxy-GLA), 12-hydroxy-octatrienoic acid (12-HOTrE or 12-hydroxy-GLA), 13-hydroxy-octatrienoic acid (13-HOTrE or 13-hydroxy-GLA), 6,13-dihydroxy-octadienoic acid (6,13-DiHODE or 6,13-dihydroxy-GLA), and trihydroxy GLA derivatives (trihydroxy-GLA).

[0286] 7. DGLA derivatives include prostaglandin D1 (PGD1), prostaglandin E1 (PGE1), 15-hydroxy-PGE1, 19-hydroxy-PGE1, 13,14-dihydroxy-PGE1, 13,14-dihydroxy-15-keto-PGE1, prostaglandin F1α (PGF1α), 6-keto-PGF1α, 15-keto-PGF1α, 13,14-dihydroxy-PGF1α, 15,19-dihydroxy-PGF1α, 13,14- Dihydroxy-15-keto PGF1α, prostacyclin I1 (prostaglandin I1 or PGI1), thromboxane A1 (TXA1), thromboxane B1 (TXB1), leukotriene B3 (LTB3), leukotriene C3 (LTC3), leukotriene D3 (LTD3), leukotriene E3 (LTE3), 5-hydroperoxy-eicosatrienoic acid (5-HpETrE), 8-hydroperoxy-eicosatrienoic acid (8-HpET rE), 12-hydroperoxy-eicosatrienoic acid (12-HpETrE), 15-hydroperoxy-eicosatrienoic acid (15-HpETrE), 5-hydroxy-eicosatrienoic acid (5-HETrE), 8-hydroxy-eicosatrienoic acid (8-HETrE), 12-hydroxy-eicosatrienoic acid (12-HETrE), 15-hydroxy-eicosatrienoic acid (15-HETrE), 8,9-epoxy-eicosadienoic acid (8,9- 11,12-Epoxy-eicosadienoic acid (11,12-EpEDE), 14,15-Epoxy-eicosadienoic acid (14,15-EpEDE), 8,9-dihydroxy-eicosadienoic acid (8,9-DiHEDE), 11,12-dihydroxy-eicosadienoic acid (11,12-DiHEDE), and 14,15-dihydroxy-eicosadienoic acid (14,15-DiHEDE).

[0287] 8.AA derivatives include 6-keto-prostaglandin F1 alpha (6k-PGF1a), thromboxane B2 (TXB2), 11-dehydro-thromboxane B2 (11-dTXB2), prostaglandin F2 alpha (PGF2a), prostaglandin E2 (PGE2), prostaglandin A2 (PGA2), prostaglandin D2 (PGD2), 2,3-dinol 11 beta-prostaglandin F2 alpha (2,3-dinol 11bPGF2a), prostaglandin J2 (PGJ2), 15-deoxy-delta-12,14-Prostaglandin J2 (15d-PGJ2), leukotriene B4 (LTB4), 20-hydroxy-leukotriene B4 (20-OH-LTB4), leukotriene C4 (LTC4), leukotriene D4 (LTD4), leukotriene E4 (LTE4), 5-hydroperoxy-eicosatetraenoic acid (5-HpETE), 8-hydroperoxy-eicosatetraenoic acid (8-HpETE), 9-hydroperoxy-eicosatetraenoic acid (9-HpETE), 11-hydroperoxy-eicosatetraenoic acid (11-HpETE), 1 2-Hydroperoxy-eicosatetraenoic acid (12-HpETE), 15-Hydroperoxy-eicosatetraenoic acid (15-HpETE), 5-Hydroxy-eicosatetraenoic acid (5-HETE), 8-Hydroxy-eicosatetraenoic acid (8-HETE), 9-Hydroxy-eicosatetraenoic acid (9-HETE), 11-Hydroxy-eicosatetraenoic acid (11-HETE), 12-Hydroxy-eicosatetraenoic acid (12-HETE), 15-Hydroxy-eicosatetraenoic acid (15-HETE), 18-Hydroxy-eicosatetraenoic acid (18-Hydroxy-eicosatetraenoic acid) eicosatetraenoic acid (18-HETE), 19-hydroxy-eicosatetraenoic acid (19-HETE), 20-hydroxy-eicosatetraenoic acid (20-HETE), 5-oxo-eicosatetraenoic acid (5-oxo-ETE), 8-oxo-eicosatetraenoic acid (8-oxo-ETE), 11-oxo-eicosatetraenoic acid (11-oxo-ETE), 12-oxo-eicosatetraenoic acid (12-oxo-ETE), 15-oxo-eicosatetraenoic acid (15-oxo-ETE), lipoxin A4 (LXA4), lipoxin A5 (LXA5), helicose Hepoxilin A3 (HxA3), hepoxilin B3 (HxB3), trioxylin A3 (TrxA3), trioxylin B3 (TrxB3), eoxin A4 (ExA4), eoxin C4 (ExC4), eoxin D4 (ExD4), eoxin E4 (ExE4), 5,6-epoxy-eicosatrienoic acid (5,6-EpETrE or 5,6-EET), 8,9-epoxy-eicosatrienoic acid (8,9-EpETrE or 8,9-EET), 11,12-epoxy-eicosatrienoic acid (11,12-EpETrE or 11,12-EET), 14,The composition according to embodiment 3, wherein the hydroxyl group is selected from the group consisting of 15-epoxy-eicosatrienoic acid (14,15-EpETrE or 14,15-EET), 5,12-dihydroxy-eicosatetraenoic acid (5,12-DiHETE), 5,6-dihydroxy-eicosatrienoic acid (5,6-DiHETrE or 5,6-DiHET), 8,9-dihydroxy-eicosatrienoic acid (8,9-DiHETrE or 8,9-DiHET), 11,12-dihydroxy-eicosatrienoic acid (11,12-DiHETrE or 11,12-DiHET), 14,15-dihydroxy-eicosatrienoic acid (14,15-DiHETrE or 14,15-DiHET), and 12-hydroxyheptadecatrenoic acid (12-HHTrE).

[0288] 9. The AdA derivative is dihomo-prostaglandin E2 (dihomo-PGE2), dihomo-prostaglandin D2 (dihomo-PGD2), dihomo-prostaglandin F2α (dihomo-PGF2α), dihomo-prostacycycline I2 (dihomo-prostaglandin I2 or dihomo-PGI2), dihomo-thromboxane A2 (dihomo-TXA2), dihomo-thromboxane B2 (dihomo-TXB2), 7-hydroperoxy-docosatetraenoic acid (dihomo-7-HpETE), 10-hydroperoxy-docosatetraenoic acid (dihomo-10- HpETE), 11-hydroperoxy-docosatetraenoic acid (dihomo-11-HpETE), 13-hydroperoxy-docosatetraenoic acid (dihomo-13-HpETE), 14-hydroperoxy-docosatetraenoic acid (dihomo-14-HpETE), 17-hydroperoxy-docosatetraenoic acid (dihomo-17-HpETE), 7-hydroxy-docosatetraenoic acid (dihomo-7-HETE), 10-hydroxy-docosatetraenoic acid (dihomo-10-HETE), 11-hydroxy-docosatetraenoic acid (dihomo-11-HETE), 1 3-hydroxy-docosatetraenoic acid (dihomo-13-HETE), 14-hydroxy-docosatetraenoic acid (dihomo-14-HETE), 17-hydroxy-docosatetraenoic acid (dihomo-17-HETE), 7,11-dihydroxy-docosatetraenoic acid (dihomo-7,11-DiHETE), 7,14-dihydroxy-docosatetraenoic acid (dihomo-7,14-DiHETE), 7,17-dihydroxy-docosatetraenoic acid (dihomo-7,17-DiHETE), 10,17-dihydroxy-docosatetraenoic acid (dihomo-10,17-D iHETE), 11,17-dihydroxy-docosatetraenoic acid (dihomo-11,17-DiHETE), 13,15-dihydroxy-docosatetraenoic acid (dihomo-13,15-DiHETE), 13,17-dihydroxy-docosatetraenoic acid (dihomo-13,17-DiHETE), 16,17-dihydroxy-docosatetraenoic acid (dihomo-16,17-DiHETE), 7,8-epoxy-docosatrienoic acid (dihomo-7,8-EpETrE), 10,11-epoxy-docosatrienoic acid (dihomo-10,11-EpETrE), 13,14-epoxy-docosatrienoic acid (dihomo-13,14-EpETrE), 16,17-epoxy-docosatrienoic acid (dihomo-16,17-EpETrE), 7,8-dihydroxy-docosatrienoic acid (dihomo-7,8-DiHETrE), 10,11-dihydroxy-docosatrienoic acid (dihomo-10,11-DiHETrE), 13,14-dihydroxy-docosatrienoic acid (di The composition of embodiment 3, wherein the hydroxyl group is selected from the group consisting of 16,17-dihydroxy-docosatrienoic acid (dihomo-13,14-DiHETrE), 16,17-dihydroxy-docosatrienoic acid (dihomo-16,17-DiHETrE), 7,16,17-trihydroxy-docosatetraenoic acid (dihomo-7,16,17-trihydroxy-ETrE), and 14-hydroxy-7,10,12-nonadecatrienoic acid (14-HNTrE).

[0289] 10. DPA6 derivatives include 7-hydroperoxy-DPA6, 8-hydroperoxy-DPA6, 10-hydroperoxy-DPA6, 11-hydroperoxy-DPA6, 13-hydroperoxy-DPA6, 14-hydroperoxy-DPA6, 17-hydroperoxy-DPA6, 7-hydroxy-DPA6, 8-hydroxy-DPA6, 10-hydroxy-DPA6, 11-hydroxy-DPA6, 13-hydroxy-DPA6, 14-hydroxy-DPA6, 17-hydroxy 4. The composition of embodiment 3, wherein the hydroxyl group is selected from the group consisting of C-DPA6, 4,5-dihydroxy-DPA6, 7,14-dihydroxy-DPA6, 7,17-dihydroxy-DPA6, 8,14-dihydroxy-DPA6, 10,17-dihydroxy-DPA6, 13,17-dihydroxy-DPA6, 16,17-dihydroxy-DPA6, 4,5,17-trihydroxy-DPA6, 7,16,17-trihydroxy-DPA6, and 10,13,17-trihydroxy-DPA6.

[0290] 11. ALA derivatives are 9-hydroperoxy-octatrienoic acid (9-HpOTrE), 13-hydroperoxy-octatrienoic acid (13-HpOTrE), 9-hydroxy-octatrienoic acid (9-HOTrE), 13-hydroxy-octatrienoic acid (13-HOTrE), 9,16-dihydroxy-octatrienoic acid (9,16-DiHOTrE), 9-oxo-octatrienoic acid (9-oxo-OTrE), 13-oxo-octatrienoic acid (13-oxo-OtrE), 9,1 4. The composition of embodiment 3, wherein the hydroxypropyl ester is selected from the group consisting of 0-epoxy-octadienoic acid (9,10-EpODE), 12,13-epoxy-octadienoic acid (12,13-EpODE), 15,16-epoxy-octadienoic acid (15,16-EpODE), 9,10-dihydroxy-octadienoic acid (9,10-DiHODE), 12,13-dihydroxy-octadienoic acid (12,13-DiHODE), and 15,16-dihydroxy-octadienoic acid (15,16-DiHODE).

[0291] 12. SDA derivatives include 6-hydroperoxy-octatetraenoic acid (6-HpOTE or 6-hydroperoxy-SDA), 7-hydroperoxy-octatetraenoic acid (7-HpOTE or 7-hydroperoxy-SDA), 9-hydroperoxy-octatetraenoic acid (9-HpOTE or 9-hydroperoxy-SDA), 10-hydroperoxy-octatetraenoic acid (10-HpOTE or 10-hydroperoxy-SDA), 12-hydroperoxy-octatetraenoic acid (12-HpOTE or 12-hydroperoxy-SDA), 13-Hydroperoxy-octatetraenoic acid (13-HpOTE or 13-hydroperoxy-SDA), 15-Hydroperoxy-octatetraenoic acid (15-HpOTE or 15-hydroperoxy-SDA), 16-Hydroperoxy-octatetraenoic acid (16-HpOTE or 16-hydroperoxy-SDA), 6-Hydroxy-octatetraenoic acid (6-HOTE or 6-hydroxy-SDA), 7-Hydroxy-octatetraenoic acid (7-HOTE or 7-hydroxy-SDA), 9-Hydroxy-octatetraenoic acid (9-HO TE or 9-hydroxy-SDA), 10-hydroxy-octatetraenoic acid (10-HOTE or 10-hydroxy-SDA), 12-hydroxy-octatetraenoic acid (12-HOTE or 12-hydroxy-SDA), 13-hydroxy-octatetraenoic acid (13-HOTE or 13-hydroxy-SDA), 15-hydroxy-octatetraenoic acid (15-HOTE or 15-hydroxy-SDA), 16-hydroxy-octatetraenoic acid (16-HOTE or 16-hydroxy-SDA), 6,13-dihydroxy-octadecatriet 6,13-DiHOTrE or 6,13-dihydroxy-SDA), 6,16-Dihydroxy-octadecatrienoic acid (6,16-DiHOTrE or 6,16-dihydroxy-SDA), 6,7-Dihydroxy-octadecadienoic acid (6,7-DiHODE or 6,7-dihydroxy-SDA), 9,10-Dihydroxy-octadecadienoic acid (9,10-DiHODE or 9,10-dihydroxy-SDA), 12,13-Dihydroxy-octadecadienoic acid (12,13-DiHODE or 12,13-dihydroxy-SDA), 15,The composition according to embodiment 3, wherein the hydroxyl group is selected from the group consisting of 16-dihydroxy-octadecadienoic acid (15,16-DiHODE or 15,16-dihydroxy-SDA) and trihydroxy-SDA (trihydroxy-SDA) carrying hydroxyl groups at any three positions between carbons C6, C7, C9, C10, C12, C13, C15 or C16 of SDA.

[0292] 13. The ETA derivative is Δ17,18 prostaglandin D1 (Δ17,18 PGD1 or ω-3PGD1), Δ17,18 prostaglandin E1 (Δ17,18PGE1 or ω-3PGE1), and Δ17,18 prostaglandin F1α (Δ17,18PGF1α or ω-3PGF1α), Δ17,18 prostacyclin I1 (Δ17,18PGI1 or ω-3PGE1), Δ17,18 12-hydroperoxy-eicosatetraenoic acid (Δ17,1812-HpETE or ω-3 12-HpETE), Δ17,18 15-hydroperoxy-eicosatetraenoic acid (Δ17,18 15-HpETE or ω-3 15-HpETE), Δ16,17 18-Hydroperoxy-eicosatetraenoic acid (Δ16,17 18-HpETE), Δ17,18 12-Hydroxy-eicosatetraenoic acid (Δ17,18 12-HETE or ω-3 12-HETE), Δ17,18 15-Hydroxy-eicosatetraenoic acid (Δ17,18 15-HETE or ω-3 15-HETE), Δ16,17 18-Hydroxy-eicosatetraenoic acid (Δ16,17 18-HETE), Δ17,18 19-Hydroxy-eicosatetraenoic acid (Δ17,18 19-HETE or ω-3 19-HETE), Δ17,18 20-Hydroxy-eicosatetraenoic acid (Δ17,18 20-HETE or ω-3 20-HETE), Δ17,18 11,12 epoxy-eicosatrienoic acid (Δ17,18 11,12-EpETrE or ω-3 11,12-EpETrE), Δ17,18 14,15 epoxy-eicosatrienoic acid (Δ17,18 14,15-EpETrE or ω-3 14,15-EpETrE), and 17,18 epoxy-eicosatrienoic acid (17,18-EpETrE), Δ17,18 11,12 dihydroxy-eicosatrienoic acid (Δ17,18 11,12-DiHETrE or ω-3 11,12-DiHETrE), Δ17,18 14,15 dihydroxy-eicosatrienoic acid (Δ17,18 14,15-DiHETrE or ω-3 14,15-DiHETrE), and 17,18 dihydroxy-eicosatrienoic acid (17,18-DiHETrE).

[0293] 14. EPA derivatives include 6-keto-prostaglandin F2 alpha (6k-PGF2a), thromboxane B3 (TXB3), 11-dehydro-thromboxane B3 (11-dTXB3), prostaglandin F3 alpha (PGF3a), prostaglandin E3 (PGE3), prostaglandin A3 (PGA3), prostaglandin D3 (PGD3), 2,3-dinol 11 beta-prostaglandin F3 alpha (2,3-dinol 11bPGF3a), prostaglandin J3 (PGJ3), 15-deoxy-delta-12,14-prostaglandin B (PGB ... Staglandin J3 (15d-PGJ3), leukotriene B5 (LTB5), 20-hydroxy-leukotriene B5 (20-OH-LTB5), leukotriene C5 (LTC5), leukotriene D5 (LTD5), leukotriene E5 (LTE5), 5-hydroperoxy-eicosapentaenoic acid (5-HpEPE), 8-hydroperoxy-eicosapentaenoic acid (8-HpEPE), 9-hydroperoxy-eicosapentaenoic acid (9-HpEPE), 11-hydroperoxy-eicosapentaenoic acid (11-HpEPE), 12-hydroperoxy-eicosapentaenoic acid (12-HpEPE), Oxy-eicosapentaenoic acid (12-HpEPE), 15-hydroperoxy-eicosapentaenoic acid (15-HpEPE), 18-hydroperoxy-eicosapentaenoic acid (18-HpEPE), 5-hydroxy-eicosapentaenoic acid (5-HEPE), 8-hydroxy-eicosapentaenoic acid (8-HEPE), 9-hydroxy-eicosapentaenoic acid (9-HEPE), 11-hydroxy-eicosapentaenoic acid (11-HEPE), 12-hydroxy-eicosapentaenoic acid (12-HEPE), 15-hydroxy-eicosapentaenoic acid (15-HEPE), 18-hydroxy-eicosapentaenoic acid (18-HEPE), 19-hydroxy-eicosapentaenoic acid (19-HEPE), 20-hydroxy-eicosapentaenoic acid (20-HEPE), 5-oxo-eicosapentaenoic acid (5-oxo-EPE), 12-oxo-eicosapentaenoic acid (12-oxo-EPE), 15-oxo-eicosapentaenoic acid (15-oxo-EPE), 5,6-epoxy-eicosatetraenoic acid (5,6-EpETE), 8,9-epoxy-eicosatetraenoic acid (8,9-EpETE), 11,12-epoxy-eicosatetraenoic acid (11,12-EpETE), 14,15-epoxy-eicosatetraenoic acid (14,15-EpETE), 5,6-dihydroxy-eicosatetraenoic acid (5,6-diHETE), 8,9-dihydroxy-eicosatetraenoic acid (8,9-diHETE), 11,12-dihydroxy-eicosatetraenoic acid (11,12-diHETE), 14,15-dihydroxy-eicosatetraenoic acid (14,15-d The composition of embodiment 3, wherein the 17,18-dihydroxy-eicosatetraenoic acid (17,18-iHETE), 17,18-epoxy-eicosatetraenoic acid (17,18-EpETE), lipoxin A5 (LxA5), lipoxin B5 (LxB5), 15-epi-lipoxin A4, resolvin E1 (RvE1), resolvin E2 (RvE2), resolvin E3 (RvE3), and resolvin E4 (RvE4).

[0294] 15. DPA derivatives include 7-hydroperoxy-docosapentaeonate (7-hydroperoxy-DPA), 10-hydroperoxy-docosapentaeonate (10-hydroperoxy-DPA), 11-hydroperoxy-docosapentaeonate (11-hydroperoxy-DPA), 13-hydroperoxy-docosapentaeonate (13-hydroperoxy-DPA), 14-hydroperoxy-docosapentaeonate (14-hydroperoxy-DPA), and PA), 16-hydroperoxy-docosapentaeonic acid (16-hydroperoxy-DPA), 17-hydroperoxy-docosapentaeonic acid (17-hydroperoxy-DPA), 7-hydroxy-docosapentaeonic acid (7-hydroxy-DPA), 10-hydroxy-docosapentaeonic acid (10-hydroxy-DPA), 11-hydroxy-docosapentaeonic acid (11-hydroxy-DPA), 13-hydroxy-docosapentaeonic acid (13 -hydroxy-DPA), 14-hydroxy-docosapentaeonic acid (14-hydroxy-DPA), 16-hydroxy-docosapentaeonic acid (16-hydroxy-DPA), 17-hydroxy-docosapentaeonic acid (17-hydroxy-DPA), 7,17-dihydroxy-docosapentaeonic acid (7,17-dihydroxy-DPA), 8,14-dihydroxy-docosapentaeonic acid (8,14-dihydroxy-DPA), 10,17-dihydroxy- C-docosapentaeonate (10,17-dihydroxy-DPA), 10,20-dihydroxy-docosapentaeonate (10,20-dihydroxy-DPA), 13,20-dihydroxy-docosapentaeonate (13,20-dihydroxy-DPA), 16,17-dihydroxy-docosapentaeonate (16,17-dihydroxy-DPA), 13-oxo-docosapentaeonate (13-oxo-DPA or 13-EFOX-D5), MaR1n-3 DPA, MaR2n-3 DPA, MaR3n-3 DPA, PD1n-3 DPA, PD2n-3 DPA, 7,13,20-trihydroxy-n-3-docosapentaenoic acid (Resolvin T1 or RvT1), 7,12,13-trihydroxy-n-3-docosapentaenoic acid (Resolvin T2 or RvT2), 7,8,The composition of embodiment 3, wherein the hydroxyl group is selected from the group consisting of 13-trihydroxy-n-3-docosapentaenoic acid (Resolvin T3 or RvT3), 7,16,17-trihydroxy-n-3-docosapentaenoic acid (7,16,17-trihydroxy-DPA), RvD1n-3 DPA, RvD2n-3 DPA, and RvD2n-3 DPA.

[0295] 16. DHA derivatives include 4-hydroperoxy-docosahexaenoic acid (4-HpDoHE), 7-hydroperoxy-docosahexaenoic acid (7-HpDoHE), 8-hydroperoxy-docosahexaenoic acid (8-HpDoHE), 10-hydroperoxy-docosahexaenoic acid (10-HpDoHE), 11-hydroperoxy-docosahexaenoic acid (11-HpDoHE), 13-hydroperoxy-docosahexaenoic acid (13-HpDoHE), 14-hydroperoxy-docosahexaenoic acid (14-HpDoHE), 16-hydroperoxy- Docosahexaenoic acid (16-HpDoHE), 17-hydroperoxy-docosahexaenoic acid (17-HpDoHE), 4-hydroxy-docosahexaenoic acid (4-HDoHE), 7-hydroxy-docosahexaenoic acid (7-HDoHE), 8-hydroxy-docosahexaenoic acid (8-HDoHE), 10-hydroxy-docosahexaenoic acid (10-HDoHE), 11-hydroxy-docosahexaenoic acid (11-HDoHE), 13-hydroxy-docosahexaenoic acid (13-HDoHE), 14-hydroxy-docosahexaenoic acid (14-HDoHE) ), 16-hydroxy-docosahexaenoic acid (16-HDoHE), 17-hydroxy-docosahexaenoic acid (17-HDoHE), 20-hydroxy-docosahexaenoic acid (20-HDoHE), 21-hydroxy-docosahexaenoic acid (21-HDoHE), 22-hydroxy-docosahexaenoic acid (22-HDoHE), 7,14-dihydroxy-docosahexaenoic acid (7,14-DiHDoHE), 7,17-dihydroxy-docosahexaenoic acid (7,17-DiHDoHE), 8,14-dihydroxy-docosahexaenoic acid (8,14-DiH DoHE), 10,17-dihydroxy-docosahexaenoic acid (10,17-DiHDoHE), 10,20-dihydroxy-docosahexaenoic acid (10,20-DiHDoHE), 14,20-dihydroxy-docosahexaenoic acid (14,20-DiHDoHE), 14,21-dihydroxy-docosahexaenoic acid (14,21-DiHDoHE), 7-oxo-docosahexaenoic acid (7-oxo-DoHE), 4,5-epoxy-docosapentaenoic acid (4,5-EpDPE), 7,8-epoxy-docosapentaenoic acid (7,8-EpDPE), 10,11-epoxy-docosapentaenoic acid (10,11-EpDPE), 13,14-epoxy-docosapentaenoic acid (13,14-EpDPE), 16,17-epoxy-docosapentaenoic acid (16,17-EpDPE), 19,20-epoxy-docosapentaenoic acid (19,20-EpDPE), 4,5-dihydroxy-docosapentaenoic acid (4,5-DiHDPE), 7,8-dihydroxy-docosapentaenoic acid (7,8-Di HDPE), 10,11-dihydroxy-docosapentaenoic acid (10,11-DiHDPE), 13,14-dihydroxy-docosapentaenoic acid (13,14-DiHDPE), 16,17-dihydroxy-docosapentaenoic acid (16,17-DiHDPE), 19,20-dihydroxy-docosapentaenoic acid (19,20-DiHDPE), 4,5-epoxy-17-OH-docosahexaenoic acid, (4,5-epoxy-17-hydroxy 7,8-epoxy-17-hydroxy-DHA), 7,8-epoxy-17-OH-docosahexaenoic acid (7,8-epoxy-17-hydroxy-DHA), maresin 1 (MaR1), maresin 2 (MaR2), protectin 1 (PD1), protectin X (PDX), aspirin-induced PD1 (AT-PD1), resolvin D1 (RvD1), resolvin D2 (RvD2), resolvin D3 (RvD3), resolvin D4 (RvD4), resolvin D5 (RvD 5), resolvin D6 (RvD6), aspirin-induced resolvin D1 (AT-RvD1), aspirin-induced resolvin D2 (AT-RvD2), aspirin-induced resolvin D3 (AT-RvD3), aspirin-induced resolvin D4 (AT-RvD4), aspirin-induced resolvin D5 (AT-RvD5), and aspirin-induced resolvin D6 (AT-RvD6).

[0296] 17. The composition of embodiment 1 or 2, wherein the one or more PUFAs or derivatives thereof are selected from the group consisting of tetracosatetraenoic acid (TTE), tetracosapentaenoic acid (TPA), tetracosahexaenoic acid (THA), TTE derivatives, TPA derivatives, and THA derivatives.

[0297] 18. The composition of embodiment 1 or 2, wherein the one or more PUFAs or derivatives thereof comprise EPA in the free acid form, or a pharma- ceutically acceptable ester, conjugate, or salt thereof.

[0298] 19. The composition of embodiment 18, wherein EPA is eicosapentaenoic acid ethyl ester (EtEPA).

[0299] 20. The composition of embodiment 18 or 19, wherein EPA or EtEPA constitutes at least 66%, 75%, 80%, 90%, 95%, or 96% by weight of all PUFAs present in the composition.

[0300] 21. The composition of embodiment 18 or 19, wherein the composition comprises 20% by weight or less of all PUFAs present in the composition of one or more of the following: (a) one or more omega-6 PUFAs or derivatives thereof selected from the group consisting of LA, GLA, DGLA, AdA, DPA6, LA derivatives, GLA derivatives, DGLA derivatives, AdA derivatives, and DPA6 derivatives; (b) one or more omega-3 PUFAs or derivatives thereof selected from the group consisting of ALA, SDA, ETA, DPA, ALA derivatives, SDA derivatives, ETA derivatives, and DPA derivatives; and (c) one or more oxylipins.

[0301] 22. The composition of any one of embodiments 18 to 21, wherein the composition comprises from about 500 mg to about 1 g of EPA or EtEPA.

[0302] 23. The composition of any one of embodiments 1-22, wherein the phospholipid source comprises a glycerophospholipid, a lysophospholipid, or a mixture thereof.

[0303] 24. The composition of embodiment 23, wherein the phospholipid source is lecithin.

[0304] 25. The composition of embodiment 24, wherein the lecithin comprises up to 40%, up to 60%, up to 80%, up to 90%, up to 95%, or up to 97% phosphatidylethanolamine by weight of the lecithin, and no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1% phosphatidylinositol by weight of the lecithin.

[0305] 26. The composition of embodiment 24, wherein the lecithin comprises (a) 19% to 27% by weight of phosphatidylcholine, (b) 4% or less by weight of lysophosphatidylcholine, (c) 16% to 22% by weight of phosphatidylethanolamine, (d) 11% to 18% by weight of phosphatidylinositol, and (e) 1% to 9% by weight of phosphatidic acid.

[0306] 27. The composition of any one of embodiments 1 to 26, wherein the weight ratio of the one or more PUFAs or derivatives thereof to the phospholipid source is in the range of about 5:1 to about 1:5, about 3.75:1 to about 1:5, or about 1:1 to about 1:5.

[0307] 28. The composition of embodiment 20, wherein the weight ratio of EPA or EtEPA to the phospholipid source ranges from about 1:1 to about 1:5.

[0308] 29. The composition of any one of embodiments 2-28, wherein the one or more emulsifying agents comprises polysorbate 80, polyoxyl-35, or both.

[0309] 30. The composition of any one of embodiments 2-28, wherein the one or more emulsifiers comprise one or more glycerol derivatives selected from the group consisting of triacylglycerol, diacylglycerol, and monoacylglycerol.

[0310] 31. The composition of embodiment 30, wherein the glycerol derivative is castor oil.

[0311] 32. The composition of embodiment 30, wherein the glycerol derivative is a PUFA-enriched, re-esterified triglyceride (rTG).

[0312] 33. A kit comprising: (a) a first composition comprising one or more polyunsaturated fatty acids (PUFAs) or derivatives thereof; and (b) a second composition comprising a phospholipid source.

[0313] 34. The kit of embodiment 33, wherein the first and / or second composition further comprises one or more emulsifiers.

[0314] 35. The kit according to embodiment 33 or 34, wherein the one or more PUFAs or derivatives thereof are selected from the group consisting of linoleic acid (LA), gamma-linoleic acid (GLA), dihomo-gamma-linoleic acid (DGLA), arachidonic acid (AA), adrenic acid (AdA), omega-6 docosapentaenoic acid (DPA6), alpha-lineoleic acid (ALA), stearidonic acid (SDA), omega-3 eicosatetraenoic acid (ETA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), LA derivatives, GLA derivatives, DGLA derivatives, AA derivatives, AdA derivatives, DPA6 derivatives, ALA derivatives, SDA derivatives, ETA derivatives, EPA derivatives, DPA derivatives, and DHA derivatives.

[0315] 36. The kit of embodiment 33 or 34, wherein the one or more PUFAs or derivatives thereof are selected from the group consisting of tetracosatetraenoic acid (TTE), tetracosapentaenoic acid (TPA), tetracosahexaenoic acid (THA), TTE derivatives, TPA derivatives, and THA derivatives.

[0316] 37. The kit of any one of embodiments 33-36, wherein the PUFA derivative comprises an oxylipin.

[0317] 38. The kit of embodiment 33 or 34, wherein the one or more PUFAs or derivatives thereof comprises EPA in the free acid form, or a pharma- ceutically acceptable ester, conjugate, or salt thereof.

[0318] 39. The kit according to embodiment 38, wherein EPA is eicosapentaenoic acid ethyl ester (EtEPA).

[0319] 40. The kit of embodiment 38 or 39, wherein EPA or EtEPA constitutes at least 66%, 75%, 80%, 90%, 95%, or 96% by weight of all PUFAs present in the first composition.

[0320] 41. The composition of embodiment 38 or 39, wherein the first composition comprises 20% by weight or less of all PUFAs present in the first composition of the following: (a) one or more omega-6 PUFAs or derivatives thereof selected from the group consisting of LA, GLA, DGLA, AdA, DPA6, LA derivatives, GLA derivatives, DGLA derivatives, AdA derivatives, and DPA6 derivatives; (b) one or more omega-3 PUFAs or derivatives thereof selected from the group consisting of ALA, SDA, ETA, DPA, ALA derivatives, SDA derivatives, ETA derivatives, and DPA derivatives; and (c) one or more oxylipins.

[0321] 42. A kit according to any one of embodiments 38 to 41, wherein the first composition comprises from about 500 mg to about 1 g of EPA or EtEPA.

[0322] 43. The kit of any one of embodiments 33-42, wherein the phospholipid source comprises a glycerophospholipid, a lysophospholipid, or a mixture thereof.

[0323] 44. The kit of embodiment 43, wherein the phospholipid source is lecithin.

[0324] 45. The kit of embodiment 44, wherein the lecithin comprises up to 40%, up to 60%, up to 80%, up to 90%, up to 95%, or up to 97% phosphatidylethanolamine by weight of the lecithin, and no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1% phosphatidylinositol by weight of the lecithin.

[0325] 46. ​​The kit of embodiment 44, wherein the lecithin comprises (a) 19% to 27% by weight of phosphatidylcholine, (b) 4% or less by weight of lysophosphatidylcholine, (c) 16% to 22% by weight of phosphatidylethanolamine, (d) 11% to 18% by weight of phosphatidylinositol, and (e) 1% to 9% by weight of phosphatidic acid.

[0326] 47. The kit of any one of embodiments 33 to 46, wherein the weight ratio of the one or more PUFAs or derivatives thereof to the phospholipid source is in the range of about 5:1 to about 1:5, about 3.75:1 to about 1:5, or about 1:1 to about 1:5.

[0327] 48. The kit described in embodiment 40, wherein the weight ratio of EPA or EtEPA to the phospholipid source ranges from about 1:1 to about 1:5.

[0328] 49. The kit of any one of embodiments 34-48, wherein the one or more emulsifying agents comprises polysorbate 80, polyoxyl-35, or both.

[0329] 50. The kit of any one of embodiments 34-48, wherein the one or more emulsifiers comprise one or more glycerol derivatives selected from the group consisting of triacylglycerol, diacylglycerol, and monoacylglycerol.

[0330] 51. The kit according to embodiment 50, wherein the glycerol derivative is castor oil.

[0331] 52. The kit of embodiment 50, wherein the glycerol derivative is a PUFA-enriched, re-esterified triglyceride (rTG).

[0332] 53. A lymph-releasing eicosapentaenoic acid ethyl ester (LR-EtEPA) composition comprising: (a) at least 15% by weight of EtEPA; and (b) 1% to 85% by weight of a phospholipid source.

[0333] 54. (c) The LR-EtEPA composition of embodiment 53, further comprising 1% to 20% by weight of one or more emulsifiers.

[0334] 55. The LR-EtEPA composition of embodiment 53 or 54, wherein EtEPA constitutes at least 66%, 75%, 80%, 90%, 95%, or 96% by weight of all fatty acids present in the composition.

[0335] 56. The LR-EtEPA composition of any one of embodiments 53 to 55, wherein the composition comprises from about 500 mg to about 1 g of EtEPA.

[0336] 57. The LR-EtEPA composition of any one of embodiments 53-56, wherein the phospholipid source comprises a glycerophospholipid, a lysophospholipid, or a mixture thereof.

[0337] 58. The LR-EtEPA composition of embodiment 57, wherein the phospholipid source is lecithin.

[0338] 59. The LR-EtEPA composition of embodiment 58, wherein the lecithin comprises up to 40%, up to 60%, up to 80%, up to 90%, up to 95%, or up to 97% phosphatidylethanolamine by weight of the lecithin, and no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1% phosphatidylinositol by weight of the lecithin.

[0339] 60. The LR-EtEPA composition of embodiment 58, wherein the lecithin comprises (a) 19% to 27% by weight of phosphatidylcholine, (b) 4% or less by weight of lysophosphatidylcholine, (c) 16% to 22% by weight of phosphatidylethanolamine, (d) 11% to 18% by weight of phosphatidylinositol, and (e) 1% to 9% by weight of phosphatidic acid.

[0340] 61. The LR-EtEPA composition of any one of embodiments 53 to 60, wherein the weight ratio of EtEPA to the phospholipid source is in the range of about 5:1 to about 1:5, about 3.75:1 to about 1:5, or about 1:1 to about 1:5.

[0341] 62. The LR-EtEPA composition of any one of embodiments 54-61, wherein the one or more emulsifiers include polysorbate 80, polyoxyl-35, or both.

[0342] 63. The LR-EtEPA composition of any one of embodiments 54-61, wherein the one or more emulsifiers comprise one or more glycerol derivatives selected from the group consisting of triacylglycerol, diacylglycerol, and monoacylglycerol.

[0343] 64. The LR-EtEPA composition of embodiment 63, wherein the glycerol derivative is castor oil.

[0344] 65. The LR-EtEPA composition of embodiment 63, wherein the glycerol derivative is a PUFA-enriched, re-esterified triglyceride (rTG).

[0345] 66. The LR-EtEPA composition according to any one of embodiments 53 to 65, wherein the EtEPA and the phospholipid source are co-formulated in the same dosage unit or individually formulated in separate dosage units.

[0346] 67. The LR-EtEPA composition of embodiment 66, wherein the dosage unit is a capsule.

[0347] 68. A method for treating or preventing a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition according to any one of embodiments 1 to 32, a kit according to any one of embodiments 33 to 52, or a LR-EtEPA composition according to any one of embodiments 53 to 67.

[0348] 69. The method of embodiment 68, wherein the disease is a cardiovascular disease.

[0349] 70. The method of embodiment 69, wherein the cardiovascular disease is selected from the group consisting of hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, coronary heart disease, stroke, atherosclerosis, arrhythmias, hypertension, myocardial infarction, vasculitis, cardiomyopathies (e.g., viral cardiomyopathies, including those associated with COVID-19), pericarditis, congestive heart failure, myocardial necrosis, vascular ischemia, vascular disease beyond the cardiopulmonary system, thrombotic disease, post-myocardial infarction myocardial remodeling, giant cell arteritis, polyarteritis nodosa, cryoglobulinemia, paroxysmal venular ischemia (Raynaud's disease), deep vein thrombosis, disseminated intravascular coagulation, and erectile dysfunction.

[0350] 71. The method of embodiment 69 or 70, wherein the subject has a fasting baseline triglyceride level of about 135 mg / dL to about 500 mg / dL.

[0351] 72. The method of any one of embodiments 69-71, wherein the subject has one or more of a baseline non-high density lipoprotein cholesterol (HDL-C) value of about 200 mg / dL to about 300 mg / dL, a baseline total cholesterol (TC) value of about 250 mg / dL to about 300 mg / dL, a baseline very low density lipoprotein cholesterol (VLDL-C) value of about 140 mg / dL to about 200 mg / dL, a baseline HDL-C value of about 10 mg / dL to about 30 mg / dL, a baseline low density lipoprotein cholesterol (LDL-C) value of about 40 mg / dL to about 100 mg / dL, and a baseline high sensitivity C-reactive protein (hsCRP) level of about 2 mg / dL or less.

[0352] 73. The method of any one of embodiments 69-72, wherein the subject is on stable statin therapy.

[0353] 74. The method of embodiment 73, wherein the stable statin therapy comprises a statin, and optionally ezetimibe.

[0354] 75. The method of embodiment 74, wherein the statin is selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0355] 76. The method of embodiment 68, wherein the disease is a pulmonary disease.

[0356] 77. Pulmonary diseases include community-acquired pneumonia, COVID-19 pneumonia, systemic inflammatory response syndrome (SIRS), sepsis, SIRS, acute respiratory distress syndrome (ARDS), pulmonary embolism, diffuse interstitial pneumonia, radiation pneumonitis, pleurisy, acute eosinophilic pneumonia, chronic eosinophilic pneumonia, Löffler syndrome, sarcoidosis, interstitial lung disease, chronic obstructive pulmonary disease (COPD), reactive airway disease, asthma, bronchiectasis, bronchitis, cystic fibrosis 77. The method of embodiment 76, wherein the patient is selected from the group consisting of pulmonary arterial hypertension, pulmonary vasculitis, microscopic polyangiitis, granulomatosis with polyangiitis (Wegener's disease), eosinophilic granulomatosis with polyangiitis (Churg-Strauss), nasopharyngitis, Goodpasture's syndrome, cryoglobulinemia, systemic lupus erythematosus (SLE), systemic scleroderma, and antiphospholipid syndrome.

[0357] 78. The method of embodiment 68, wherein the disease is a neurological disease.

[0358] 79. The method of embodiment 78, wherein the neurological disease is selected from the group consisting of Huntington's disease, sleep disorders, dementia, psychosis, anxiety, treatment-resistant depression, neuropathic pain, schizophrenia, bipolar disorder, dyslexia, dyspraxia, attention deficit hyperactivity disorder (ADHD), epilepsy, autism, Alzheimer's disease, Parkinson's disease, senile dementia, multiple sclerosis, diabetes-induced neuropathy, macular degeneration, retinopathy of prematurity, amyotrophic lateral sclerosis (ALS), retinitis pigmentosa, cerebral palsy, muscular dystrophy, neurological cancer, cystic fibrosis, and neural tube defects.

[0359] 80. The method of embodiment 68, wherein the disease is cancer.

[0360] 81. The method of embodiment 80, wherein the cancer is a hematological malignancy selected from the group consisting of monoclonal B-cell lymphocytosis, multiple myeloma, myeloid neoplasms, myelodysplastic syndromes (MDS), myeloproliferative / myelodysplastic syndromes, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute phase chronic myeloid leukemia (bcCML), B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoma, and B-cell lymphoma.

[0361] 82. The method of embodiment 80, wherein the cancer is a solid tumor selected from the group consisting of lung cancer, breast cancer, liver cancer, stomach cancer, colon cancer, rectal cancer, colorectal cancer, kidney cancer, gastric cancer, gallbladder cancer, small intestine cancer, esophageal cancer, melanoma, bone cancer, pancreatic cancer, skin cancer, uterine cancer, ovarian cancer, testicular cancer, thyroid cancer, adrenal cancer, bladder cancer, and glioma.

[0362] 83. Diseases include post-infectious glomerulonephritis, IgA nephropathy (Buerger's disease), Henoch-Schonlein purpura, systemic IgA vasculitis, microscopic polyangiitis, granulomatosis with polyangiitis (Wegener's disease), eosinophilic granulomatosis with polyangiitis (Churg-Strauss), polyarteritis, idiopathic crescentic glomerulonephritis, anti-GBM glomerulonephritis, Goodpasture's syndrome, cryoglobulin-associated glomerulonephritis, idiopathic membranoproliferative glomerulonephritis (MPGN), and hepatitis C-associated glomerulonephritis. 69. The method of embodiment 68, wherein the disease associated with the kidney is selected from the group consisting of: glomerulonephritis, systemic lupus erythematosus (SLE)-associated glomerulonephritis, minimal change disease (nill disease, lipoid nephropathy), membranous nephropathy, focal segmental glomerulosclerosis, amyloidosis, diabetic nephropathy, HIV-associated nephropathy, membranoproliferative glomerulonephropathy, edema relief, chronic renal failure relief, and / or mortality / morbidity relief in severe chronic kidney disease (CKD) / end stage renal disease (ESRD).

[0363] 84. The method of embodiment 68, wherein the disease is a disease associated with the pancreas selected from the group consisting of hyperglycemia, prediabetes, diabetes (type 1 and / or type 2), and pancreatitis.

[0364] 85. The method of embodiment 68, wherein the disease is a liver-associated disease selected from the group consisting of chronic viral hepatitis, autoimmune hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease, hemochromatosis, Wilson's disease, primary biliary cholangitis, primary sclerosing cholangitis, and cholelithiasis.

[0365] 86. The method of embodiment 68, wherein the disease is a gut-associated disease selected from the group consisting of gastroesophageal reflux disease (GERD), gastritis, peptic ulcer disease, obesity, cachexia, intestinal angina, Crohn's disease, ulcerative colitis, antibiotic-associated colitis, irritable bowel syndrome, colon cancer, colonic polyposis, and carcinoid.

[0366] 87. The method of embodiment 68, wherein the disease is a disease associated with blood cells selected from the group consisting of iron deficiency anemia, anemia of chronic disease, hemolytic anemia, thalassemia, polycythemia vera, sickle cell anemia, sickle cell anemia, immune thrombocytopenia, leukemia, non-Hodgkin's lymphoma, and Hodgkin's lymphoma.

[0367] 88. The method of embodiment 68, wherein the disease is a disease associated with oxidative stress, glutathione (GSH) depletion, Nrf2 activation, and / or heme-oxygenase activation.

[0368] 89. The method of embodiment 88, wherein the disease is anemia, sickle cell disease, and / or glomerulonephritis.

[0369] 90. The method of embodiment 88 or 89, wherein the method further comprises administering an N-acetylcysteine ​​(NAC) related agent to the subject.

[0370] 91. The method of embodiment 90, wherein the NAC-related agent is selected from the group consisting of cystine, methionine, N-acetylcysteine, and L-2-oxothiazolidine-4-carboxylate.

[0371] 92. The method according to embodiment 68, wherein the disease is oxidative stress, endothelial dysfunction, arterial narrowing and / or thickening, and / or inflammation induced by inhalation of particulate matter.

[0372] 93. The method according to embodiment 68, wherein the disease is oxidative stress, endothelial dysfunction, arterial narrowing and / or thickening, and / or inflammation induced by long-term and / or short-term exposure to air pollution.

[0373] 94. The method of any one of embodiments 68-93, wherein the composition, kit, or LR-EtEPA composition is administered to a subject to provide a daily dose of about 1 g to about 20 g of EtEPA.

[0374] 95. The method of embodiment 94, wherein the composition, kit, or LR-EtEPA composition is administered to the subject to provide a daily dose of about 4 g of EtEPA.

[0375] 96. The method of any one of embodiments 68-95, wherein the composition, kit, or LR-EtEPA composition is administered to the subject once or twice per day.

[0376] 97. The method of any one of embodiments 68-96, wherein the composition, kit, or LR-EtEPA composition is administered to the subject with or without food.

[0377] 98. A composition according to any one of embodiments 1 to 32, a kit according to any one of embodiments 33 to 52, or a LR-EtEPA composition according to any one of embodiments 53 to 67, for use in a method for treating or preventing a disease in a subject in need thereof, wherein a therapeutically effective amount of the composition, kit, or LR-EtEPA composition is administered to the subject.

[0378] 99. The composition, kit, or LR-EtEPA composition described in embodiment 98, wherein the disease is a cardiovascular disease.

[0379] 100. The composition, kit, or LR-EtEPA composition of embodiment 99, wherein the cardiovascular disease is selected from the group consisting of hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, coronary heart disease, stroke, atherosclerosis, arrhythmias, hypertension, myocardial infarction, vasculitis, cardiomyopathies (e.g., viral cardiomyopathies, including tho...

Claims

1. (a) at least 15% by weight of one or more polyunsaturated fatty acids (PUFAs) or derivatives thereof; (b) 1% to 85% by weight of a phospholipid source.

2. The composition of claim 1 further comprising: (c) 1% to 20% by weight of one or more emulsifiers.

3. 3. The composition of claim 1 or 2, wherein the one or more PUFAs or derivatives thereof are selected from the group consisting of linoleic acid (LA), gamma-linoleic acid (GLA), dihomo-gamma-linoleic acid (DGLA), arachidonic acid (AA), adrenic acid (AdA), omega-6 docosapentaenoic acid (DPA6), alpha-linolenic acid (ALA), stearidonic acid (SDA), omega-3 eicosatetraenoic acid (ETA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), LA derivatives, GLA derivatives, DGLA derivatives, AA derivatives, AdA derivatives, DPA6 derivatives, ALA derivatives, SDA derivatives, ETA derivatives, EPA derivatives, DPA derivatives, and DHA derivatives.

4. The composition of claim 1 or 2, wherein the PUFA derivative comprises an oxylipin.

5. The LA derivatives include 9-hydroperoxy-octadecadienoic acid (9-HpODE), 13-hydroperoxy-octadecadienoic acid (13-HpODE), 9-hydroxy-octadecadienoic acid (9-HODE), 13-hydroxy-octadecadienoic acid (13-HODE), 9,10,13 trihydroxy-octadecenoic acid (9,10,13TriHOME), and 9,12,13 trihydroxy-octadecenoic acid (9,12,13TriHOME). ), 9-oxo-octadecadienoic acid (9-oxo-ODE), 13-oxo-octadecadienoic acid (13-oxo-ODE), 9,10-epoxy-octadecenoic acid (9,10-EpOME), 12,13-epoxy-octadecenoic acid (12,13-EpOME), 9,10-dihydroxy-octadecenoic acid (9,10-DiHOMEE), and 12,13-dihydroxy-octadecenoic acid (12,13-DiHOMEE); the GLA derivative is selected from the group consisting of 6-hydroxy-octatrienoic acid (6-HOTrE or 6-hydroxy-GLA), 7-hydroxy-octatrienoic acid (7-HOTrE or 7-hydroxy-GLA), 9-hydroxy-octatrienoic acid (9-HOTrE or 9-hydroxy-GLA), 10-hydroxy-octatrienoic acid (10-HOTrE or 10-hydroxy-GLA), 12-hydroxy-octatrienoic acid (12-HOTrE or 12-hydroxy-GLA), 13-hydroxy-octatrienoic acid (13-HOTrE or 13-hydroxy-GLA), 6,13-dihydroxy-octadienoic acid (6,13-DiHODE or 6,13-dihydroxy-GLA), and trihydroxy GLA derivatives (trihydroxy-GLA); The DGLA derivatives include prostaglandin D1 (PGD1), prostaglandin E1 (PGE1), 15-hydroxy-PGE1, 19-hydroxy-PGE1, 13,14-dihydroxy-PGE1, 13,14-dihydroxy-15-keto-PGE1, prostaglandin F1α (PGF1α), 6-keto-PGF1α, 15-keto-PGF1α, 13,14-dihydroxy-PGF1α, 15,19-dihydroxy-PGF1α, 13 , 14-dihydroxy-15-keto PGF1α, prostacyclin I1 (prostaglandin I1 or PGI1), thromboxane A1 (TXA1), thromboxane B1 (TXB1), leukotriene B3 (LTB3), leukotriene C3 (LTC3), leukotriene D3 (LTD3), leukotriene E3 (LTE3), 5-hydroperoxy-eicosatrienoic acid (5-HpETrE), 8-hydroperoxy-eicosatrienoic acid (8-HpETrE), 12-hydroperoxy-eicosatrienoic acid (12-HpETrE), 15-hydroperoxy-eicosatrienoic acid (15-HpETrE), 5-hydroxy-eicosatrienoic acid (5-HETrE), 8-hydroxy-eicosatrienoic acid (8-HETrE), 12-hydroxy-eicosatrienoic acid (12-HETrE), 15-hydroxy-eicosatrienoic acid (15-HETrE), 8,9-epoxy-eicosatrienoic acid selected from the group consisting of cosadienoic acid (8,9-EpEDE), 11,12-epoxy-eicosadienoic acid (11,12-EpEDE), 14,15-epoxy-eicosadienoic acid (14,15-EpEDE), 8,9-dihydroxy-eicosadienoic acid (8,9-DiHEDE), 11,12-dihydroxy-eicosadienoic acid (11,12-DiHEDE), and 14,15-dihydroxy-eicosadienoic acid (14,15-DiHEDE); The AA derivatives include 6-keto-prostaglandin F1 alpha (6k-PGF1a), thromboxane B2 (TXB2), 11-dehydro-thromboxane B2 (11-dTXB2), prostaglandin F2 alpha (PGF2a), prostaglandin E2 (PGE2), prostaglandin A2 (PGA2), prostaglandin D2 (PGD2), 2,3-dinol 11 beta-prostaglandin F2 alpha (2,3-dinol 11bPGF2a), prostaglandin J2 (PGJ2), 15-deoxy-delta-12,14-Prostaglandin J2 (15d-PGJ2), leukotriene B4 (LTB4), 20-hydroxy-leukotriene B4 (20-OH-LTB4), leukotriene C4 (LTC4), leukotriene D4 (LTD4), leukotriene E4 (LTE4), 5-hydroperoxy-eicosatetraenoic acid (5-HpETE), 8-hydroperoxy-eicosatetraenoic acid (8-HpETE), 9-hydroperoxy-eicosatetraenoic acid (9-HpETE), 11-hydroperoxy-eicosatetraenoic acid (11-HpETE), 1 2-Hydroperoxy-eicosatetraenoic acid (12-HpETE), 15-Hydroperoxy-eicosatetraenoic acid (15-HpETE), 5-Hydroxy-eicosatetraenoic acid (5-HETE), 8-Hydroxy-eicosatetraenoic acid (8-HETE), 9-Hydroxy-eicosatetraenoic acid (9-HETE), 11-Hydroxy-eicosatetraenoic acid (11-HETE), 12-Hydroxy-eicosatetraenoic acid (12-HETE), 15-Hydroxy-eicosatetraenoic acid (15-HETE), 18-Hydroxy-eicosatetraenoic acid Eicosatetraenoic acid (18-HETE), 19-hydroxy-eicosatetraenoic acid (19-HETE), 20-hydroxy-eicosatetraenoic acid (20-HETE), 5-oxo-eicosatetraenoic acid (5-oxo-ETE), 8-oxo-eicosatetraenoic acid (8-oxo-ETE), 11-oxo-eicosatetraenoic acid (11-oxo-ETE), 12-oxo-eicosatetraenoic acid (12-oxo-ETE), 15-oxo-eicosatetraenoic acid (15-oxo-ETE), lipoxin A4 (LXA4), lipoxin A5 (LXA5), helic ... Hepoxilin A3 (HxA3), hepoxilin B3 (HxB3), trioxilin A3 (TrxA3), trioxilin B3 (TrxB3), eoxin A4 (ExA4), eoxin C4 (ExC4), eoxin D4 (ExD4), eoxin E4 (ExE4), 5,6-epoxy-eicosatrienoic acid (5,6-EpETrE or 5,6-EET), 8,9-epoxy-eicosatrienoic acid (8,9-EpETrE or 8,9-EET), 11,12-epoxy-eicosatrienoic acid (11,12-EpETrE or 11,12-EET), 14,15-epoxy-eicosatrienoic acid (14,15-EpETrE or 14,15-EET), 5,12-dihydroxy-eicosatetraenoic acid (5,12-DiHETE), 5,6-dihydroxy-eicosatrienoic acid (5,6-DiHETrE, or 5,6-DiHET), 8,9-dihydroxy-eicosatrienoic acid (8,9-DiHETrE, or is selected from the group consisting of 8,9-DiHET), 11,12-dihydroxy-eicosatrienoic acid (11,12-DiHETrE, or 11,12-DiHET), 14,15-dihydroxy-eicosatrienoic acid (14,15-DiHETrE, or 14,15-DiHET), and 12-hydroxyheptadecatrienoic acid (12-HHTrE), The AdA derivatives include dihomo-prostaglandin E2 (dihomo-PGE2), dihomo-prostaglandin D2 (dihomo-PGD2), dihomo-prostaglandin F2α (dihomo-PGF2α), dihomo-prostacycycline I2 (dihomo-prostaglandin I2 or dihomo-PGI2), dihomo-thromboxane A2 (dihomo-TXA2), dihomo-thromboxane B2 (dihomo-TXB2), 7-hydroperoxy-docosatetraenoic acid (dihomo-7-HpETE), 10-hydroperoxy-docosatetraenoic acid (dihomo-10- HpETE), 11-hydroperoxy-docosatetraenoic acid (dihomo-11-HpETE), 13-hydroperoxy-docosatetraenoic acid (dihomo-13-HpETE), 14-hydroperoxy-docosatetraenoic acid (dihomo-14-HpETE), 17-hydroperoxy-docosatetraenoic acid (dihomo-17-HpETE), 7-hydroxy-docosatetraenoic acid (dihomo-7-HETE), 10-hydroxy-docosatetraenoic acid (dihomo-10-HETE), 11-hydroxy-docosatetraenoic acid (dihomo-11-HETE), 1 3-hydroxy-docosatetraenoic acid (dihomo-13-HETE), 14-hydroxy-docosatetraenoic acid (dihomo-14-HETE), 17-hydroxy-docosatetraenoic acid (dihomo-17-HETE), 7,11-dihydroxy-docosatetraenoic acid (dihomo-7,11-DiHETE), 7,14-dihydroxy-docosatetraenoic acid (dihomo-7,14-DiHETE), 7,17-dihydroxy-docosatetraenoic acid (dihomo-7,17-DiHETE), 10,17-dihydroxy-docosatetraenoic acid (dihomo-10,17-D iHETE), 11,17-dihydroxy-docosatetraenoic acid (dihomo-11,17-DiHETE), 13,15-dihydroxy-docosatetraenoic acid (dihomo-13,15-DiHETE), 13,17-dihydroxy-docosatetraenoic acid (dihomo-13,17-DiHETE), 16,17-dihydroxy-docosatetraenoic acid (dihomo-16,17-DiHETE), 7,8-epoxy-docosatrienoic acid (dihomo-7,8-EpETrE), 10,11-epoxy-docosatrienoic acid (dihomo-10,11-EpETrE), 13,14-epoxy-docosatrienoic acid (dihomo-13,14-EpETrE), 16,17-epoxy-docosatrienoic acid (dihomo-16,17-EpETrE), 7,8-dihydroxy-docosatrienoic acid (dihomo-7,8-DiHETrE), 10,11-dihydroxy-docosatrienoic acid (dihomo-10,11-DiHETrE), 13,14-dihydroxy-docosatrienoic acid 16,17-dihydroxy-docosatrienoic acid (dihomo-13,14-DiHETrE), 16,17-dihydroxy-docosatrienoic acid (dihomo-16,17-DiHETrE), 7,16,17-trihydroxy-docosatetraenoic acid (dihomo-7,16,17-trihydroxy-ETrE), and 14-hydroxy-7,10,12-nonadecatrienoic acid (14-HNTrE), The DPA6 derivatives include 7-hydroperoxy-DPA6, 8-hydroperoxy-DPA6, 10-hydroperoxy-DPA6, 11-hydroperoxy-DPA6, 13-hydroperoxy-DPA6, 14-hydroperoxy-DPA6, 17-hydroperoxy-DPA6, 7-hydroxy-DPA6, 8-hydroxy-DPA6, 10-hydroxy-DPA6, 11-hydroxy-DPA6, 13-hydroxy-DPA6, and 14-hydroxy-DPA6. selected from the group consisting of 17-hydroxy-DPA6, 4,5-dihydroxy-DPA6, 7,14-dihydroxy-DPA6, 7,17-dihydroxy-DPA6, 8,14-dihydroxy-DPA6, 10,17-dihydroxy-DPA6, 13,17-dihydroxy-DPA6, 16,17-dihydroxy-DPA6, 4,5,17-trihydroxy-DPA6, 7,16,17-trihydroxy-DPA6, and 10,13,17-trihydroxy-DPA6; The ALA derivatives include 9-hydroperoxy-octatrienoic acid (9-HpOTrE), 13-hydroperoxy-octatrienoic acid (13-HpOTrE), 9-hydroxy-octatrienoic acid (9-HOTrE), 13-hydroxy-octatrienoic acid (13-HOTrE), 9,16-dihydroxy-octatrienoic acid (9,16-DiHOTrE), 9-oxo-octatrienoic acid (9-oxo-OTrE), 13-oxo-octatrienoic acid (13-oxo-Ot 12,13-epoxy-octadienoic acid (12,13-EpODE), 15,16-epoxy-octadienoic acid (15,16-EpODE), 9,10-dihydroxy-octadienoic acid (9,10-DiHODE), 12,13-dihydroxy-octadienoic acid (12,13-DiHODE), and 15,16-dihydroxy-octadienoic acid (15,16-DiHODE); The SDA derivatives include 6-hydroperoxy-octatetraenoic acid (6-HpOTE or 6-hydroperoxy-SDA), 7-hydroperoxy-octatetraenoic acid (7-HpOTE or 7-hydroperoxy-SDA), 9-hydroperoxy-octatetraenoic acid (9-HpOTE or 9-hydroperoxy-SDA), 10-hydroperoxy-octatetraenoic acid (10-HpOTE or 10-hydroperoxy-SDA), 12-hydroperoxy-octatetraenoic acid (12-HpOTE or 12-hydroperoxy-SDA), 13-hydroperoxy-octatetraenoic acid (13-HpOTE or 13-hydroperoxy-SDA), 15-hydroperoxy-octatetraenoic acid (15-HpOTE or 15-hydroperoxy-SDA), 16-hydroperoxy-octatetraenoic acid (16-HpOTE or 16-hydroperoxy-SDA), 6-hydroxy-octatetraenoic acid (6-HOTE or 6-hydroxy-SDA), 7-hydroxy-octatetraenoic acid (7-HOTE or 7-hydroxy-SDA), 9-hydroxy-octatetraenoic acid (9-HO TE or 9-hydroxy-SDA), 10-hydroxy-octatetraenoic acid (10-HOTE or 10-hydroxy-SDA), 12-hydroxy-octatetraenoic acid (12-HOTE or 12-hydroxy-SDA), 13-hydroxy-octatetraenoic acid (13-HOTE or 13-hydroxy-SDA), 15-hydroxy-octatetraenoic acid (15-HOTE or 15-hydroxy-SDA), 16-hydroxy-octatetraenoic acid (16-HOTE or 16-hydroxy-SDA), 6,13-dihydroxy-octadecatrie dihydroxy-octadecadienoic acid (6,13-DiHOTrE or 6,13-dihydroxy-SDA), 6,16-dihydroxy-octadecatrienoic acid (6,16-DiHOTrE or 6,16-dihydroxy-SDA), 6,7-dihydroxy-octadecadienoic acid (6,7-DiHODE or 6,7-dihydroxy-SDA), 9,10-dihydroxy-octadecadienoic acid (9,10-DiHODE or 9,10-dihydroxy-SDA), 12,13-dihydroxy-octadecadienoic acid (12,13-DiHODE or 12,13-dihydroxy-SDA), 15,selected from the group consisting of 16-dihydroxy-octadecadienoic acid (15,16-DiHODE or 15,16-dihydroxy-SDA) and trihydroxy-SDA (trihydroxy-SDA) bearing hydroxyl groups at any three positions between carbons C6, C7, C9, C10, C12, C13, C15 or C16 of SDA, The ETA derivatives include Δ17,18 prostaglandin D1 (Δ17,18 PGD1 or ω-3PGD1), Δ17,18 prostaglandin E1 (Δ17,18PGE1 or ω-3PGE1), and Δ17,18 prostaglandin F1α (Δ17,18PGF1α or ω-3PGF1α), Δ17,18 prostacyclin I1 (Δ17,18PGI1 or ω-3PGE1), Δ17,18 12-hydroperoxy-eicosatetraenoic acid (Δ17,1812-HpETE or ω-3 12-HpETE), Δ17,18 15-hydroperoxy-eicosatetraenoic acid (Δ17,18 15-HpETE or ω-3 15-HpETE), Δ16,17 18-Hydroperoxy-eicosatetraenoic acid (Δ16,17 18-HpETE), Δ17,18 12-Hydroxy-eicosatetraenoic acid (Δ17,18 12-HETE or ω-3 12-HETE), Δ17,18 15-Hydroxy-eicosatetraenoic acid (Δ17,18 15-HETE or ω-3 15-HETE), Δ16,17 18-Hydroxy-eicosatetraenoic acid (Δ16,17 18-HETE), Δ17,18 19-Hydroxy-eicosatetraenoic acid (Δ17,18 19-HETE or ω-3 19-HETE), Δ17,18 20-Hydroxy-eicosatetraenoic acid (Δ17,18 20-HETE or ω-3 20-HETE), Δ17,18 11,12 epoxy-eicosatrienoic acid (Δ17,18 11,12-EpETrE or ω-3 11,12-EpETrE), Δ17,18 14,15 epoxy-eicosatrienoic acid (Δ17,18 14,15-EpETrE or ω-3 14,15-EpETrE), and 17,18 epoxy-eicosatrienoic acid (17,18-EpETrE), Δ17,18 11,12 dihydroxy-eicosatrienoic acid (Δ17,18 11,12-DiHETrE or ω-3 11,12-DiHETrE), Δ17,18 14,15 dihydroxy-eicosatrienoic acid (Δ17,18 14,15-DiHETrE or ω-3 14,15-DiHETrE), and 17,18 dihydroxy-eicosatrienoic acid (17,18-DiHETrE); The EPA derivatives include 6-keto-prostaglandin F2 alpha (6k-PGF2a), thromboxane B3 (TXB3), 11-dehydro-thromboxane B3 (11-dTXB3), prostaglandin F3 alpha (PGF3a), prostaglandin E3 (PGE3), prostaglandin A3 (PGA3), prostaglandin D3 (PGD3), 2,3-dinol 11 beta-prostaglandin F3 alpha (2,3-dinol 11bPGF3a), prostaglandin J3 (PGJ3), 15-deoxy-delta-12,14-prostaglandin F3 alpha (2,3-dinol 11bPGF3a), prostaglandin J3 (PGJ3), and 15-deoxy-delta-12,14-prostaglandin F3 alpha (2,3-dinol 11bPGF3a). Taglandin J3 (15d-PGJ3), leukotriene B5 (LTB5), 20-hydroxy-leukotriene B5 (20-OH-LTB5), leukotriene C5 (LTC5), leukotriene D5 (LTD5), leukotriene E5 (LTE5), 5-hydroperoxy-eicosapentaenoic acid (5-HpEPE), 8-hydroperoxy-eicosapentaenoic acid (8-HpEPE), 9-hydroperoxy-eicosapentaenoic acid (9-HpEPE), 11-hydroperoxy-eicosapentaenoic acid (11-HpEPE), 12-hydroperoxy 12-HpEPE, 15-Hydroperoxy-eicosapentaenoic acid (15-HpEPE), 18-Hydroperoxy-eicosapentaenoic acid (18-HpEPE), 5-Hydroxy-eicosapentaenoic acid (5-HEPE), 8-Hydroxy-eicosapentaenoic acid (8-HEPE), 9-Hydroxy-eicosapentaenoic acid (9-HEPE), 11-Hydroxy-eicosapentaenoic acid (11-HEPE), 12-Hydroxy-eicosapentaenoic acid (12-HEPE), 15-Hydroxy-eicosapentaenoic acid ( 15-HEPE), 18-hydroxy-eicosapentaenoic acid (18-HEPE), 19-hydroxy-eicosapentaenoic acid (19-HEPE), 20-hydroxy-eicosapentaenoic acid (20-HEPE), 5-oxo-eicosapentaenoic acid (5-oxo-EPE), 12-oxo-eicosapentaenoic acid (12-oxo-EPE), 15-oxo-eicosapentaenoic acid (15-oxo-EPE), 5,6-epoxy-eicosatetraenoic acid (5,6-EpETE), 8,9-epoxy-eicosatetraenoic acid (8,9-EpETE), 11,12-epoxy-eicosatetraenoic acid (11,12-EpETE), 14,15-epoxy-eicosatetraenoic acid (14,15-EpETE), 5,6-dihydroxy-eicosatetraenoic acid (5,6-diHETE), 8,9-dihydroxy-eicosatetraenoic acid (8,9-diHETE), 11,12-dihydroxy-eicosatetraenoic acid (11,12-diHETE), 14,15-dihydroxy-eicosatetraenoic acid (1 17,18-dihydroxy-eicosatetraenoic acid (17,18-diHETE), 17,18-epoxy-eicosatetraenoic acid (17,18-EpETE), lipoxin A5 (LxA5), lipoxin B5 (LxB5), 15-epi-lipoxin A4, resolvin E1 (RvE1), resolvin E2 (RvE2), resolvin E3 (RvE3), and resolvin E4 (RvE4), The DPA derivatives include 7-hydroperoxy-docosapentaeonic acid (7-hydroperoxy-DPA), 10-hydroperoxy-docosapentaeonic acid (10-hydroperoxy-DPA), 11-hydroperoxy-docosapentaeonic acid (11-hydroperoxy-DPA), 13-hydroperoxy-docosapentaeonic acid (13-hydroperoxy-DPA), 14-hydroperoxy-docosapentaeonic acid (14-hydroperoxy-DPA), 16-hydroperoxy-docosapentaeonic acid (16-hydroperoxy-DPA), 17-hydroperoxy-docosapentaeonic acid (17-hydroperoxy-DPA), 18-hydroperoxy-docosapentaeonic acid (18-hydroperoxy-DPA), 19-hydroperoxy-docosapentaeonic acid (19-hydroperoxy-DPA), 20-hydroperoxy-docosapentaeonic acid (20-hydroperoxy-DPA), 21-hydroperoxy-docosapentaeonic acid (21-hydroperoxy-DPA), 22-hydroperoxy-docosapentaeonic acid (22-hydroperoxy-DPA), 23-hydroperoxy-docosapentaeonic acid (23-hydroperoxy-DPA), 24-hydroperoxy-docosapentaeonic acid (24-hydroperoxy-DPA), 25-hydroperoxy-docosapentaeonic acid (25-hydroperoxy-DPA), 26-hydroperoxy-docosapentaeonic acid (26-hydroperoxy-DPA), 27-hydroperoxy-docosapentaeonic acid (27-hydroperoxy-DPA), 28-hydroperoxy-docosapentaeonic acid (28-hydroperoxy-DPA), 29-hydroperoxy-docosapentaeonic acid (29-hydroperoxy-DPA), 30-hydroperoxy-docosapentaeon docosapentaeoic acid (16-hydroperoxy-DPA), 17-hydroperoxy-docosapentaeoic acid (17-hydroperoxy-DPA), 7-hydroxy-docosapentaeoic acid (7-hydroxy-DPA), 10-hydroxy-docosapentaeoic acid (10-hydroxy-DPA), 11-hydroxy-docosapentaeoic acid (11-hydroxy-DPA), 13-hydroxy-docosapentaeoic acid (13-hydroxy-DPA), 1 4-hydroxy-docosapentaeonic acid (14-hydroxy-DPA), 16-hydroxy-docosapentaeonic acid (16-hydroxy-DPA), 17-hydroxy-docosapentaeonic acid (17-hydroxy-DPA), 7,17-dihydroxy-docosapentaeonic acid (7,17-dihydroxy-DPA), 8,14-dihydroxy-docosapentaeonic acid (8,14-dihydroxy-DPA), 10,17-dihydroxy-docosapentaeonic acid 10,17-dihydroxy-DPA, 10,20-dihydroxy-docosapentaeonic acid (10,20-dihydroxy-DPA), 13,20-dihydroxy-docosapentaeonic acid (13,20-dihydroxy-DPA), 16,17-dihydroxy-docosapentaeonic acid (16,17-dihydroxy-DPA), 13-oxo-docosapentaeonic acid (13-oxo-DPA or 13-EFOX-D5), MaR1n-3 DPA, MaR2n-3 DPA, MaR3n-3 DPA, PD1n-3 DPA, PD2n-3 DPA, 7,13,20-trihydroxy-n-3-docosapentaenoic acid (resolvin T1 or RvT1), 7,12,13-trihydroxy-n-3-docosapentaenoic acid (resolvin T2 or RvT2), 7,8,selected from the group consisting of 13-trihydroxy-n-3-docosapentaenoic acid (Resolvin T3 or RvT3), 7,16,17-trihydroxy-n-3-docosapentaenoic acid (7,16,17-trihydroxy-DPA), RvD1n-3 DPA, RvD2n-3 DPA, and RvD2n-3 DPA, The DHA derivatives include 4-hydroperoxy-docosahexaenoic acid (4-HpDoHE), 7-hydroperoxy-docosahexaenoic acid (7-HpDoHE), 8-hydroperoxy-docosahexaenoic acid (8-HpDoHE), 10-hydroperoxy-docosahexaenoic acid (10-HpDoHE), 11-hydroperoxy-docosahexaenoic acid (11-HpDoHE), 13-hydroperoxy-docosahexaenoic acid (13-HpDoHE), 14-hydroperoxy-docosahexaenoic acid (14-HpDoHE), 16-hydroperoxy-docosahexaenoic acid (16-HpDoHE), 17-hydroperoxy-docosahexaenoic acid (17-HpDoHE), 18-hydroperoxy-docosahexaenoic acid (18-HpDoHE), 19-hydroperoxy-docosahexaenoic acid (19-HpDoHE), 20-hydroperoxy-docosahexaenoic acid (20-HpDoHE), 21-hydroperoxy-docosahexaenoic acid (21-HpDoHE), 22-hydroperoxy-docosahexaenoic acid (22-HpDoHE), 23-hydroperoxy-docosahexaenoic acid (23-HpDoHE), 24-hydroperoxy-docosahexaenoic acid (24-HpDoHE), 25-hydroperoxy-docosahexaenoic acid (25-HpDoHE), 26-hydroperoxy-docosahexaenoic acid (26-HpDoHE), 27-hydroperoxy-docosahexaenoic acid (27-HpDoHE), 28-hydroperoxy-docosahexaenoic acid (28-HpDoHE), 29-hydroperoxy-docosahexaenoic acid (29-HpDoHE), 30-hydroperoxy Cosahexaenoic acid (16-HpDoHE), 17-hydroperoxy-docosahexaenoic acid (17-HpDoHE), 4-hydroxy-docosahexaenoic acid (4-HDoHE), 7-hydroxy-docosahexaenoic acid (7-HDoHE), 8-hydroxy-docosahexaenoic acid (8-HDoHE), 10-hydroxy-docosahexaenoic acid (10-HDoHE), 11-hydroxy-docosahexaenoic acid (11-HDoHE), 13-hydroxy-docosahexaenoic acid (13-HDoHE), 14-hydroxy-docosahexaenoic acid (14-HDoHE) , 16-hydroxy-docosahexaenoic acid (16-HDoHE), 17-hydroxy-docosahexaenoic acid (17-HDoHE), 20-hydroxy-docosahexaenoic acid (20-HDoHE), 21-hydroxy-docosahexaenoic acid (21-HDoHE), 22-hydroxy-docosahexaenoic acid (22-HDoHE), 7,14-dihydroxy-docosahexaenoic acid (7,14-DiHDoHE), 7,17-dihydroxy-docosahexaenoic acid (7,17-DiHDoHE), 8,14-dihydroxy-docosahexaenoic acid (8,14-DiHDoHE), DoHE), 10,17-dihydroxy-docosahexaenoic acid (10,17-DiHDoHE), 10,20-dihydroxy-docosahexaenoic acid (10,20-DiHDoHE), 14,20-dihydroxy-docosahexaenoic acid (14,20-DiHDoHE), 14,21-dihydroxy-docosahexaenoic acid (14,21-DiHDoHE), 7-oxo-docosahexaenoic acid (7-oxo-DoHE), 4,5-epoxy-docosapentaenoic acid (4,5-EpDPE), 7,8-epoxy-docosapentaenoic acid (7,8-EpDPE), 10,11-epoxy-docosapentaenoic acid (10,11-EpDPE), 13,14-epoxy-docosapentaenoic acid (13,14-EpDPE), 16,17-epoxy-docosapentaenoic acid (16,17-EpDPE), 19,20-epoxy-docosapentaenoic acid (19,20-EpDPE), 4,5-dihydroxy-docosapentaenoic acid (4,5-DiHDPE), 7,8-dihydroxy-docosapentaenoic acid (7,8-Di HDPE), 10,11-dihydroxy-docosapentaenoic acid (10,11-DiHDPE), 13,14-dihydroxy-docosapentaenoic acid (13,14-DiHDPE), 16,17-dihydroxy-docosapentaenoic acid (16,17-DiHDPE), 19,20-dihydroxy-docosapentaenoic acid (19,20-DiHDPE), 4,5-epoxy-17-OH-docosahexaenoic acid, (4,5-epoxy-17-hydroxy hydroxy-DHA), 7,8-epoxy-17-OH-docosahexaenoic acid (7,8-epoxy-17-hydroxy-DHA), maresin 1 (MaR1), maresin 2 (MaR2), protectin 1 (PD1), protectin X (PDX), aspirin-induced PD1 (AT-PD1), resolvin D1 (RvD1), resolvin D2 (RvD2), resolvin D3 (RvD3), resolvin D4 (RvD4), and resolvin D5 (Rv The composition of claim 3, wherein the aspirin-induced resolvin D5 (AT-RvD5), resolvin D6 (RvD6), aspirin-induced resolvin D1 (AT-RvD1), aspirin-induced resolvin D2 (AT-RvD2), aspirin-induced resolvin D3 (AT-RvD3), aspirin-induced resolvin D4 (AT-RvD4), aspirin-induced resolvin D5 (AT-RvD5), and aspirin-induced resolvin D6 (AT-RvD6).

6. the one or more PUFAs or derivatives thereof comprise EPA in free acid form, or a pharmaceutically acceptable ester, conjugate, or salt thereof; the pharmaceutically acceptable ester is eicosapentaenoic acid ethyl ester (EtEPA); 2. The composition of claim 1, wherein the EPA or EtEPA constitutes at least 66%, 75%, 80%, 90%, 95%, or 96% by weight of all PUFAs present in the composition.

7. 7. The composition of claim 6, wherein the composition comprises from about 500 mg to about 1 g of the EPA or EtEPA.

8. The phospholipid source comprises a glycerophospholipid, a lysophospholipid, or a mixture thereof; or the phospholipid source is lecithin; (a) the lecithin comprises up to 40%, up to 60%, up to 80%, up to 90%, up to 95%, or up to 97% phosphatidylethanolamine by weight of the lecithin and no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1% phosphatidylinositol by weight of the lecithin; or (b) the lecithin is (i) 19% to 27% by weight of phosphatidylcholine; (ii) 4% by weight or less of lysophosphatidylcholine; (iii) 16% to 22% by weight of phosphatidylethanolamine; (iv) 11% to 18% by weight of phosphatidylinositol; (v) 1% to 9% by weight of phosphatidic acid; The composition of claim 1.

9. 2. The composition of claim 1, wherein the weight ratio of the one or more PUFAs or derivatives thereof to the phospholipid source ranges from about 5:1 to about 1:5, from about 3.75:1 to about 1:5, or from about 1:1 to about 1:

5.

10. the one or more emulsifiers (a) polysorbate 80, polyoxyl-35, or both; or (b) one or more glycerol derivatives selected from the group consisting of triacylglycerol, diacylglycerol, and monoacylglycerol; The composition of claim 2 comprising:

11. The glycerol derivative is castor oil; or The PUFA-enriched re-esterified triglyceride (rTG), The composition of claim 10.

12. (a) at least 15% by weight of EtEPA; (b) 1% to 85% by weight of a phospholipid source; Lymph-releasing eicosapentaenoic acid ethyl ester (LR-EtEPA) composition.

13. 13. The LR-EtEPA composition of claim 12, further comprising: (c) 1% to 20% by weight of one or more emulsifiers.

14. the EtEPA constitutes at least 66%, 75%, 80%, 90%, 95%, or 96% by weight of all fatty acids present in the composition; and / or the LR-EtEPA composition comprises about 500 mg to about 1 g of the EtEPA; The LR-EtEPA composition according to claim 12 or 13.

15. the phospholipid source comprises a glycerophospholipid, a lysophospholipid, or a mixture thereof; or the phospholipid source is lecithin; (a) the lecithin comprises up to 40%, up to 60%, up to 80%, up to 90%, up to 95%, or up to 97% phosphatidylethanolamine by weight of the lecithin and no more than 10%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1% phosphatidylinositol by weight of the lecithin; or (b) the lecithin is (i) 19% to 27% by weight of phosphatidylcholine; (ii) 4% by weight or less of lysophosphatidylcholine; (iii) 16% to 22% by weight of phosphatidylethanolamine; (iv) 11% to 18% by weight of phosphatidylinositol; (v) 1% to 9% by weight of phosphatidic acid; The LR-EtEPA composition according to claim 12 or 13.

16. 14. The LR-EtEPA composition of claim 12 or 13, wherein the weight ratio of the EtEPA to the phospholipid source ranges from about 5:1 to about 1:5, from about 3.75:1 to about 1:5, or from about 1:1 to about 1:

5.

17. the one or more emulsifiers (a) polysorbate 80, polyoxyl-35, or both; or (b) one or more glycerol derivatives selected from the group consisting of triacylglycerol, diacylglycerol, and monoacylglycerol; 14. The LR-EtEPA composition of claim 13, comprising:

18. The glycerol derivative is castor oil; or The PUFA-enriched re-esterified triglyceride (rTG), 18. The LR-EtEPA composition of claim 17.

19. The composition of claim 1 for use in treating or preventing a disease in a subject, comprising: The disease is (a) a cardiovascular disease selected from the group consisting of hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, coronary heart disease, stroke, atherosclerosis, arrhythmias, hypertension, myocardial infarction, vasculitis, cardiomyopathy (e.g., viral cardiomyopathy, including that associated with COVID-19), pericarditis, congestive heart failure, myocardial necrosis, vascular ischemia, vascular disease beyond the cardiopulmonary system, thrombotic disease, post-myocardial infarction myocardial remodeling, giant cell arteritis, polyarteritis nodosa, cryoglobulinemia, paroxysmal venous ischemia (Raynaud's disease), deep vein thrombosis, disseminated intravascular coagulation, and erectile dysfunction; (b) Community-acquired pneumonia, COVID-19 pneumonia, systemic inflammatory response syndrome (SIRS), sepsis, SIRS, acute respiratory distress syndrome (ARDS), pulmonary embolism, diffuse interstitial pneumonia, radiation pneumonitis, pleuritis, acute eosinophilic pneumonia, chronic eosinophilic pneumonia, Löffler's syndrome, sarcoidosis, interstitial lung disease, chronic obstructive pulmonary disease (COPD), reactive airway disease, asthma, bronchiectasis, bronchitis, cystic pulmonary disease a pulmonary disease selected from the group consisting of fibrosis, bronchial carcinoid, pulmonary arterial hypertension, pulmonary vasculitis, microscopic polyangiitis, granulomatosis with polyangiitis (Wegener's disease), eosinophilic granulomatosis with polyangiitis (Churg-Strauss), nasopharyngitis, Goodpasture's syndrome, cryoglobulinemia, systemic lupus erythematosus (SLE), systemic sclerosis, and antiphospholipid syndrome; (c) a neurological disease selected from the group consisting of Huntington's disease, sleep disorders, dementia, psychosis, anxiety, treatment-resistant depression, neuropathic pain, schizophrenia, bipolar disorder, dyslexia, dyspraxia, attention deficit hyperactivity disorder (ADHD), epilepsy, autism, Alzheimer's disease, Parkinson's disease, senile dementia, multiple sclerosis, diabetes-induced neuropathy, macular degeneration, retinopathy of prematurity, amyotrophic lateral sclerosis (ALS), retinitis pigmentosa, cerebral palsy, muscular dystrophy, neurological cancer, cystic fibrosis, and neural tube defects; (d)(i) a hematological malignancy selected from the group consisting of monoclonal B-cell lymphocytosis, multiple myeloma, myeloid neoplasms, myelodysplastic syndromes (MDS), myeloproliferative / myelodysplastic syndromes, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute phase chronic myeloid leukemia (bcCML), B-cell acute lymphocytic leukemia (B-ALL), T-cell acute lymphocytic leukemia (T-ALL), T-cell lymphoma, and B-cell lymphoma; or (ii) a solid tumor selected from the group consisting of lung cancer, breast cancer, liver cancer, stomach cancer, colon cancer, rectal cancer, colorectal cancer, kidney cancer, gastric cancer, gallbladder cancer, small intestine cancer, esophageal cancer, melanoma, bone cancer, pancreatic cancer, skin cancer, uterine cancer, ovarian cancer, testicular cancer, thyroid cancer, adrenal cancer, bladder cancer, and glioma. Cancer; (e) Postinfectious glomerulonephritis, IgA nephropathy (Buerger's disease), Henoch-Schönlein purpura, systemic IgA vasculitis, microscopic polyangiitis, granulomatosis with polyangiitis (Wegener's disease), eosinophilic granulomatosis with polyangiitis (Churg-Strauss), polyarteritis, idiopathic crescentic glomerulonephritis, anti-GBM glomerulonephritis, Goodpasture's syndrome, cryoglobulin-associated glomerulonephritis, idiopathic membranoproliferative glomerulonephritis (MPGN), type C kidney-related diseases selected from the group consisting of hepatitis-associated glomerulonephritis, systemic lupus erythematosus (SLE)-associated glomerulonephritis, minimal change disease (nill disease, lipoid nephropathy), membranous nephropathy, focal segmental glomerulosclerosis, amyloidosis, diabetic nephropathy, HIV-associated nephropathy, membranoproliferative glomerulonephropathy, edema relief, chronic renal failure relief, and / or mortality / morbidity relief in severe chronic kidney disease (CKD) / end-stage renal disease (ESRD); (f) a pancreas-associated disease selected from the group consisting of hyperglycemia, prediabetes, diabetes (type 1 and / or type 2), and pancreatitis; (g) a liver-associated disease selected from the group consisting of chronic viral hepatitis, autoimmune hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, hemochromatosis, Wilson's disease, primary biliary cholangitis, primary sclerosing cholangitis, and cholelithiasis; (h) a bowel-associated disease selected from the group consisting of gastroesophageal reflux disease (GERD), gastritis, peptic ulcer disease, obesity, cachexia, intestinal angina, Crohn's disease, ulcerative colitis, antibiotic-associated colitis, irritable bowel syndrome, colon cancer, colonic polyposis, and carcinoid; (i) a disease associated with blood cells selected from the group consisting of iron deficiency anemia, anemia of chronic disease, hemolytic anemia, thalassemia, polycythemia vera, sickle cell anemia, sickle cell pain, immune thrombocytopenia, leukemia, non-Hodgkin's lymphoma, and Hodgkin's lymphoma; (j) diseases associated with oxidative stress, glutathione (GSH) depletion, Nrf2 activation, and / or heme-oxygenase activation; (k) anemia, sickle cell disease, and / or glomerulonephritis; or (l) oxidative stress, endothelial dysfunction, arterial narrowing and / or thickening, and / or inflammation induced by inhalation of particulate matter or long-term and / or short-term exposure to air pollution The composition.

20. The object is (a) having a fasting baseline triglyceride level of about 135 mg / dL to about 500 mg / dL; (b) have one or more of a baseline non-high density lipoprotein cholesterol (HDL-C) level of about 200 mg / dL to about 300 mg / dL, a baseline total cholesterol (TC) level of about 250 mg / dL to about 300 mg / dL, a baseline very low density lipoprotein cholesterol (VLDL-C) level of about 140 mg / dL to about 200 mg / dL, a baseline HDL-C level of about 10 mg / dL to about 30 mg / dL, a baseline low density lipoprotein cholesterol (LDL-C) level of about 40 mg / dL to about 100 mg / dL, and a baseline high sensitivity C-reactive protein (hsCRP) level of about 2 mg / dL or less; and / or (c) receiving stable statin therapy; 20. The composition of claim 19.

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