Methods and Compositions for Treating and Preventing Fatty Acid Deficiency - Patent application

Abstract

Described herein are compositions and methods relating to lipid formulations (eg, lipid emulsions) comprising: (a) arachidonic acid (ARA); and (b) docosahexaenoic acid (DHA) and / or eicosapentaenoic acid (EPA). TIFF2024545117000009.tif172129

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 63 / 287,564, filed December 9, 2021, the contents of which are incorporated by reference herein in their entirety.

[0002] Technical Field The technology described herein relates to lipid emulsions, for example, for administration orally or parenterally to a patient. [Background technology]

[0003] background Neonatal patients, especially those in intensive care units (ICUs), may require parenteral nutrition. However, existing lipid emulsions are formulated for adults and therefore have problems with providing sufficient amounts of nutrition to neonates, especially preterm infants, due to total volume, lipid content, toxicological concerns, etc. For example, fluid administration in newborns is extremely challenging due to fluid shifts, physiological changes in renal function, and extensive insensible and sensible losses. Standard emulsions may accelerate or hasten complications of preterm birth, such as retinopathy, bronchopulmonary dysplasia, liver injury, and cholestasis. Summary of the Invention

[0004] overview Described herein is a new emulsion formulation that avoids or reduces the total volume and toxicological side effects when administered to neonates.The emulsion of the present invention thus enables a method to provide the necessary fatty acids / nutrients to neonatal patients, especially premature infants.

[0005] In one aspect of any of these embodiments, a composition is described herein that comprises (a) one or more omega-6 fatty acids, including arachidonic acid (ARA), and (b) one or more omega-3 fatty acids, including docosahexaenoic acid (DHA) and / or eicosapentaenoic acid (EPA).In one aspect of any of these embodiments, a composition is described herein that comprises (a) arachidonic acid (ARA) and (b) docosahexaenoic acid (DHA) and / or eicosapentaenoic acid (EPA).In some embodiments of any of these aspects, the composition comprises DHA.In some embodiments of any of these aspects, the composition comprises EPA.In some embodiments of any of these aspects, the composition comprises EPA and DHA.

[0006] In some embodiments of any of these aspects, the weight ratio of (a) ARA to (b) DHA and / or EPA is 3:2 to 3:5. In some embodiments of any of these aspects, the weight ratio of (a) ARA to (b) DHA and / or EPA is 1:2 to 3:5. In some embodiments of any of these aspects, the weight ratio of (a) ARA to (b) DHA and / or EPA is 1:2 to 1:5. In some embodiments of any of these aspects, the weight ratio of (a) ARA to (b) DHA and / or EPA is 2:1 to 1:4. In some embodiments of any of these aspects, the weight ratio of (a) ARA to (b) DHA and / or EPA is 1:1 to 1:2.

[0007] In some embodiments of any of these aspects, the composition comprises additional ω6 fatty acids and / or ω3 fatty acids. In some embodiments of any of these aspects, ARA and DHA and / or EPA constitute at least 60% of the total amount of ω3 fatty acids and ω6 fatty acids. In some embodiments of any of these aspects, ARA and DHA and / or EPA constitute at least 70% of the total amount of ω3 fatty acids and ω6 fatty acids. In some embodiments of any of these aspects, ARA and DHA and / or EPA constitute at least 80% of the total amount of ω3 fatty acids and ω6 fatty acids. In some embodiments of any of these aspects, ARA and DHA and / or EPA constitute at least 90% of the total amount of ω3 fatty acids and ω6 fatty acids.

[0008] In some embodiments of any of these aspects, ARA comprises at least 20% of the total ω6 fatty acids. In some embodiments of any of these aspects, ARA comprises at least 30% of the total ω6 fatty acids. In some embodiments of any of these aspects, ARA comprises at least 40% of the total ω6 fatty acids. In some embodiments of any of these aspects, DHA and / or EPA comprise at least 20% of the total ω3 fatty acids. In some embodiments of any of these aspects, DHA and / or EPA comprise at least 30% of the total ω3 fatty acids. In some embodiments of any of these aspects, DHA and / or EPA comprise at least 40% of the total ω3 fatty acids. In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids is 2:1 to 1:4. In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids is 1:1 to 1:2.

[0009] In some embodiments of any of these aspects, the composition and its components are not distilled or re-esterified. In some embodiments of any of these aspects, the total combined triglyceride and diglyceride content of the composition comprises 10% or less diglycerides. In some embodiments of any of these aspects, the composition does not comprise diglycerides. In some embodiments of any of these aspects, the DHA and / or EPA are not distilled or re-esterified. In some embodiments of any of these aspects, the total combined triglyceride and diglyceride content of the DHA and / or EPA comprises 10% or less diglycerides. In some embodiments of any of these aspects, the DHA and / or EPA does not comprise diglycerides. In some embodiments of any of these aspects, the ARA is not distilled or re-esterified. In some embodiments of any of these aspects, the total combined triglyceride and diglyceride content of the ARA comprises 10% or less diglycerides. In some embodiments of any of these aspects, the ARA does not comprise diglycerides.

[0010] In some embodiments of any of these aspects, the composition comprises 5% (w / w) or less sterol. In some embodiments of any of these aspects, the composition comprises 2% (w / w) or less sterol. In some embodiments of any of these aspects, the composition comprises 1.5% (w / w) or less sterol. In some embodiments of any of these aspects, the composition comprises 120 mg / L or less phytosterol. In some embodiments of any of these aspects, the composition comprises 70 mg / L or less phytosterol. In some embodiments of any of these aspects, the composition comprises 35 mg / L or less phytosterol. In some embodiments of any of these aspects, the composition comprises 4% (w / w) or less stigmasterol. In some embodiments of any of these aspects, the composition comprises 10 mg / L or less stigmasterol.

[0011] In some embodiments of any of these aspects, the composition comprises a vegetable oil or a fungal oil, or the ARA is provided in the form of a vegetable oil or a fungal oil. In some embodiments of any of these aspects, the vegetable oil or fungal oil is not distilled or re-esterified. In some embodiments of any of these aspects, the total combined triglyceride and diglyceride content of the vegetable oil or fungal oil comprises 10% or less diglycerides. In some embodiments of any of these aspects, the vegetable oil or fungal oil does not comprise diglycerides. In some embodiments of any of these aspects, the vegetable oil or fungal oil comprises 5% (w / w) or less sterols, 70 mg / L or less phytosterols, 4% (w / w) or less stigmasterol, and / or 10 mg / L or less stigmasterol. In some embodiments of any of these aspects, the vegetable oil is soybean oil or olive oil, or the fungal oil is Mortierella alpina oil.

[0012] In some embodiments of any of these aspects, the composition comprises fish oil, and / or the DHA and / or EPA are provided in the form of fish oil. In some embodiments of any of these aspects, the fish oil is not distilled or re-esterified. In some embodiments of any of these aspects, the total combined triglyceride and diglyceride content of the fish oil comprises 10% or less diglycerides. In some embodiments of any of these aspects, the fish oil does not comprise diglycerides. In some embodiments of any of these aspects, the fish oil comprises 5% (w / w) or less sterols, 70 mg / L or less phytosterols, 4% (w / w) or less stigmasterol, and / or 10 mg / L or less stigmasterol.

[0013] In some embodiments of any of these aspects, the composition comprises algal oil, and / or the DHA and / or EPA are provided in the form of algal oil. In some embodiments of any of these aspects, the algal oil is oil from Crypthecodinium cohnii. In some embodiments of any of these aspects, the algal oil is not distilled or re-esterified. In some embodiments of any of these aspects, the total combined triglyceride and diglyceride content of the algal oil comprises 10% or less diglycerides. In some embodiments of any of these aspects, the algal oil is diglyceride-free. In some embodiments of any of these aspects, the algal oil comprises 5% (w / w) or less sterols, 70 mg / L or less phytosterols, 4% (w / w) or less stigmasterol, and / or 10 mg / L or less stigmasterol.

[0014] In some embodiments of any of these aspects, the composition is a lipid emulsion. In some embodiments of any of these aspects, the emulsion is an oil-in-water type with at least 10% oil. In some embodiments of any of these aspects, the emulsion is an oil-in-water type with at least 20% oil. In some embodiments of any of these aspects, the emulsion is an oil-in-water type with at least 30% oil. In some embodiments of any of these aspects, the emulsion is an oil-in-water type with about 10% to about 50% oil. In some embodiments of any of these aspects, the emulsion is an oil-in-water type with about 10% to about 40% oil. In some embodiments of any of these aspects, the emulsion is an oil-in-water type with about 10% to about 30% oil. In some embodiments of any of these aspects, the emulsion is an oil-in-water type with about 20% to about 40% oil.

[0015] In some embodiments of any of these aspects, the composition further comprises one or more of medium chain triglycerides (MCT); egg lecithin; sunflower seed oil; sunflower lecithin; an emulsifier derived from sunflower seeds; and krill oil. In some embodiments of any of these aspects, the composition is formulated to comprise (a) ARA in a dosage of up to 300 mg / kg / day and / or (b) DHA and / or EPA in a dosage of up to 500 mg / kg / day. In some embodiments of any of these aspects, the composition is formulated to comprise (a) ARA in a dosage of up to 200 mg / kg / day and / or (b) DHA and / or EPA in a dosage of up to 400 mg / kg / day. In some embodiments of any of these aspects, the composition is formulated to comprise (a) ARA in a dosage of 20-60 mg / kg / day and / or (b) DHA and / or EPA in a dosage of 40-100 mg / kg / day. In some embodiments of any of these aspects, the composition is formulated to include (a) ARA in a dosage of 20-60 mg / kg / day and / or (b) DHA and / or EPA in a dosage of 10 mg / kg / day to 3 g / kg / day. In some embodiments of any of these aspects, the composition is formulated for parenteral or intravenous administration.

[0016] In one aspect of any of these embodiments, described herein is a method for providing nutrition to a subject and / or promoting neurodevelopment in a subject, comprising administering to a subject the composition described herein.In one aspect of any of these embodiments, described herein is (a) arachidonic acid (ARA) and (b) docosahexaenoic acid (DHA) and / or eicosapentaenoic acid (EPA) for use in the method for providing nutrition to a subject and / or promoting neurodevelopment in a subject.

[0017] In some embodiments of any of these aspects, the composition is administered at a dose of 5 g / kg / day or less. In some embodiments of any of these aspects, the composition is administered to provide (a) ARA at a dosage of 20-60 mg / kg / day and / or (b) DHA and / or EPA at a dosage of 40-100 mg / kg / day. In some embodiments of any of these aspects, the subject is an infant. In some embodiments of any of these aspects, the subject is a newborn and / or a premature infant. In some embodiments of any of these aspects, the neurodevelopment is neurodevelopment in the brain and / or eye. In some embodiments of any of these aspects, the administration treats, prevents, or reduces the risk of one or more conditions selected from the group consisting of retinopathy, bronchopulmonary dysplasia, and perinatal sepsis. In some embodiments of any of these aspects, the administration is parenteral and / or intravenous. In some embodiments of any of these aspects, the nutrition is parenteral nutrition or total parenteral nutrition. In some embodiments of any of these aspects, the administration is parenteral or total parenteral administration. In some embodiments of any of these aspects, the subject is in need of parenteral nutrition or total parenteral nutrition. In some embodiments of any of these aspects, the patient does not receive oral nutrition. In some embodiments of any of these aspects, the patient does not receive other parenteral preparations. In some embodiments of any of these aspects, the patient does not receive oral nutrition that is sufficient to maintain nutritional balance. In some embodiments of any of these aspects, the patient does not receive other parenteral preparations that are sufficient to maintain nutritional balance. In some embodiments of any of these aspects, the patient does not receive other nutritional sources and / or parenteral nutrition sources for fatty acids. In some embodiments of any of these aspects, the patient does not receive other nutritional sources and / or parenteral nutrition sources for essential fatty acids. In some embodiments of any of these aspects, the composition is administered as a monotherapy. In some embodiments of any of these aspects, the composition is administered as a monotherapy for nutritional needs.

[0018] In some embodiments of any of these aspects, the patient is diagnosed with fatty liver, intestinal failure, parenteral nutrition associated liver disease (PNALD), sepsis, cystic fibrosis, sickle cell anemia, pancreatitis, inflammatory bowel disease, Crohn's disease, biliary atresia, primary sclerosing cholangitis, inflammatory infection, inflammatory condition, systemic inflammatory response syndrome (SIRS), hypertriglyceridemia, severe hypertriglyceridemia, severe fatty liver, retinopathy of prematurity, acute tubular necrosis, IgA nephropathy, ischemia-reperfusion injury, traumatic brain injury, multiple organ failure, respiratory distress syndrome, acute myocardial infarction, myocardial infarction, persistent angina, asthma attack. The patient is in need of treatment for a condition selected from the group consisting of status epilepticus, status epilepticus, follicular conditions, inflammatory bowel disease, regional enteritis, ulcerative colitis, severe or debilitating arthritis, arthritis, psoriasis, severe psoriasis, burns, third degree burns, pancreatitis, acute pancreatitis, liver disease associated with intestinal failure (IFALD), cholestasis associated with parenteral nutrition (PNAC), essential fatty acid deficiency (EFAD), parenteral nutrition dependent states complicated by soy allergy, local anesthetic toxicity, conditions for treatment of systemic toxicities, and conditions requiring a vehicle or excipient for parenteral therapeutics. [Brief description of the drawings]

[0019] [Figure 1A] Figures 1A-1H show graphs of fatty acid composition in plasma of 8-week-old C57Bl / 6J mice that received a daily oral gavage of lipid emulsion in addition to ad libitum consumption of a fat-free high-carbohydrate diet (or received a normal rodent chow control and daily oral gavage of normal saline) for 4 weeks. Statistical comparisons were performed using one-way ANOVA, and individual comparisons with chow control were performed using Dunnett's multiple comparison test. *P<0.05 **P<0.01 ***P<0.001 ****P<0.0001. [Figure 1B] See legend to Figure 1A. [Figure 1C] See legend to Figure 1A. [Figure 1D] See legend to Figure 1A. [Figure 1E] See legend to Figure 1A. [Figure 1F] See legend to Figure 1A. [Figure 1G] See legend to Figure 1A. [Figure 1H] See legend to Figure 1A. [Figure 2A] Figures 2A-2H show graphs of fatty acid composition in livers of 8-week-old C57Bl / 6J mice that received daily oral gavage of lipid emulsion in addition to ad libitum consumption of a fat-free high-carbohydrate diet (or received normal rodent chow control and daily oral gavage of normal saline) for 4 weeks. Statistical comparisons were performed using one-way ANOVA, and individual comparisons with chow control were performed using Dunnett's multiple comparison test. *P<0.05 **P<0.01 ***P<0.001 ****P<0.0001. [Figure 2B] See legend to Figure 2A. [Figure 2C] See legend to Figure 2A. [Figure 2D] See legend to Figure 2A. [Figure 2E] See legend to Figure 2A. [Figure 2F] See legend to Figure 2A. [Figure 2G] See legend to Figure 2A. [Figure 2H] See legend to Figure 2A. [Figure 3A] Figures 3A-3H show graphs of fatty acid composition in the frontal cortex of 8-week-old C57Bl / 6J mice that received daily oral gavage of lipid emulsion in addition to ad libitum consumption of a fat-free high-carbohydrate diet (or received normal rodent chow control and daily oral gavage of normal saline) for 4 weeks. Statistical comparisons were performed using one-way ANOVA, and individual comparisons with chow control were performed using Dunnett's multiple comparison test. *P<0.05 **P<0.01 ***P<0.001 ****P<0.0001. [Figure 3B] See legend to Figure 3A. [Figure 3C] See legend to Figure 3A. [Figure 3D]See legend to Figure 3A. [Figure 3E] See legend to Figure 3A. [Figure 3F] See legend to Figure 3A. [Figure 3G] See legend to Figure 3A. [Figure 3H] See legend to Figure 3A. [Figure 4] 4A-4B show graphs demonstrating that 8-week-old C57Bl / 6J mice that received daily oral gavage of NLE A, NLE B, or NLE C in addition to ad libitum intake of a fat-free high-carbohydrate diet for 4 weeks showed no signs of essential fatty acid deficiency, whereas mice that received daily oral gavage of Intralipid showed high triene:tetraene ratios in both plasma and liver tissue, which are associated with essential fatty acid deficiency. Statistical comparisons were performed using one-way ANOVA, and individual comparisons with chow controls were performed using Dunnett's multiple comparison test. *P<0.05 **P<0.01 ***P<0.001 ****P<0.0001. [Diagram 5] Figures 5A-5C demonstrate that mice fed a nonfat high-carbohydrate diet ad libitum and given saline injections via tail vein every other day develop biochemical liver injury characterized by elevated alanine aminotransferase. Giving lipid emulsion (or saline injections in addition to chow diet) via tail vein injection every other day prevents biochemical liver injury. Statistical comparisons were performed using one-way ANOVA test and Dunnett's multiple comparison test against the saline group. Mean ± SEM and individual values ​​were plotted. *P<0.05 **P<0.01 ***P<0.001. [Figure 6]We demonstrate that mice fed a nonfat high carbohydrate diet ad libitum and tail vein injected with saline or Intralipid every other day develop micro- and macrodroplet steatosis. Representative liver tissue stained with hematoxylin and eosin is shown. Mice fed a high carbohydrate diet and NLE B or NLE C have no steatosis, while some mice fed NLE A show mild micro- and macrodroplet steatosis. Mice fed a chow diet (along with tail vein injections of saline) have normal histology without steatosis. [Figure 7] We demonstrate that compared to mice fed a high carbohydrate diet with tail vein injections of saline for 19 days, mice in the NLE B, NLE C, Omegaven, and chow groups had significantly lower lipidosis scores consistent with reduced steatosis. Mice in the Intralipid and NLE A groups did not have significantly lower lipidosis scores than the saline group. Statistical comparisons were performed using the Kruskal-Wallis test and Dunn's multiple comparison test against the saline group. Mean ± SEM and individual values ​​were plotted. *P<0.05 **P<0.01. [Figure 8-1] 8A-8F show graphs of plasma fatty acid profiles and triene / tetraene ratios for mice fed either a chow control or a high carbohydrate diet for 19 days along with tail vein injections of saline or lipid emulsion. Statistical comparisons were performed using one-way ANOVA, and individual comparisons with chow control were performed using Dunnett's multiple comparison test. *P<0.05 **P<0.01 ***P<0.001 ****P<0.0001. [Figure 8-2] See description of Figure 8-1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Detailed Description As described herein, a fat-free and high-carbohydrate diet induces liver damage (e.g., as indicated by alanine aminotransferase activity or steatosis). Supplementation with soybean oil lipid emulsions high in omega-6 fatty acids (e.g., Intralipid) only partially alleviates some characteristics of liver damage; in particular, patients who are given Intralipid as part of a TPN regimen experience liver damage at levels significantly higher than those of normal diets, and often at the same levels as patients who are not given any fat (see, e.g., Figures 5A and 7). Clinically, there is a great deal of evidence showing that the use of Intralipid leads to the development of intestinal failure-associated liver damage. Similar liver damage is also observed when using lipid mixtures, such as sumoflipids, which contain soybean oil, medium-chain triglycerides, olive oil, and fish oil. This liver damage can be avoided if patients are given lipid emulsions high in omega-3 fatty acids (e.g., Omegaven; see, e.g., Figures 5A and 7). However, Omegaven is a 10% oil-in-water emulsion of fish oil, which requires that a relatively large total volume of emulsion be administered, often approaching or exceeding the upper limit of volumes recommended for infants. In addition, the total fat calories of Omegaven require the administration of additional dextrose in a higher dose than is normally used to provide sufficient total calories.

[0021] Surprisingly, the inventors have now found that this liver damage associated with the administration of formulations such as Intralipid can be avoided by adding an appropriate dose of arachidonic acid (ARA). See Figure 5A and Figure 7. As shown in Figure 7, the combination of high DHA / EPA oil and high ARA oil at 80% and 2.5%, respectively (NLE A) actually exacerbated steatosis compared to high DHA / EPA oil alone. See Figure 7. However, when the proportion of high ARA was increased (NLE B and NLE C), no exacerbation of steatosis was observed. Histological examination confirmed this, and it was found that mice fed NLE B or NLE C did not have steatosis, whereas some mice fed NLE A had mild microdroplet and macrodroplet steatosis. See Figure 6.

[0022] These new formulations also provide important advantages over fish oil emulsions such as Omegaven. For example, the compositions described herein can be formulated as emulsions of more than 10%, allowing for administration of a total volume that is safer for infants. In addition, the compositions described herein contain sufficient fat calories to reduce the need for administration of dextrose and / or glucose (e.g., reduce the amount or frequency of dextrose administration) and provide substantially more ARA than Omegaven.

[0023] Thus, compositions, such as emulsions, are described herein for administration, for example, by parenteral nutrition (PN) or total parenteral nutrition (TPN), to promote neurodevelopment in infants or newborns (e.g., premature infants or newborns).These compositions, such as emulsions, also achieve a reduction in the risk of cholestasis, intestinal failure-associated liver disease (IFALD), retinopathy, and bronchopulmonary dysplasia.The compositions, such as emulsions, are particularly formulated for administration to infants, such as newborn infants, and provide an advantageous administration volume for such patients.

[0024] In one aspect of any of these embodiments, a composition comprising (a) arachidonic acid (ARA) and (b) docosahexaenoic acid (DHA) and / or eicosapentaenoic acid (EPA) is described herein. In some embodiments of any of these aspects, the composition is an emulsion. In some embodiments of any of these aspects, the composition comprises an emulsion. In some embodiments of any of these aspects, the composition comprises an emulsion of at least (a) ARA and (b) DHA and / or EPA. In some embodiments of any of these aspects, the composition comprises a mixture of (a) an emulsion of at least ARA and (b) an emulsion of at least DHA and / or EPA.

[0025] In one aspect of any of these embodiments, a composition is described herein that comprises one or more ω6 fatty acids comprising at least arachidonic acid (ARA) and one or more ω3 fatty acids comprising at least docosahexaenoic acid (DHA) and / or EPA. In some embodiments of any of these aspects, the composition is an emulsion. In some embodiments of any of these aspects, the composition comprises an emulsion. In some embodiments of any of these aspects, the composition comprises an emulsion of one or more ω6 fatty acids comprising at least arachidonic acid (ARA) and one or more ω3 fatty acids comprising at least docosahexaenoic acid (DHA). In some embodiments of any of these aspects, the composition comprises an emulsion of one or more ω6 fatty acids comprising at least arachidonic acid (ARA) and one or more ω3 fatty acids comprising at least EPA. In some embodiments of any of these aspects, the composition comprises an emulsion of one or more ω6 fatty acids comprising at least arachidonic acid (ARA) and one or more ω3 fatty acids comprising at least DHA and EPA. In some embodiments of any of these aspects, the composition comprises a mixture of (a) an emulsion of one or more ω6 fatty acids comprising at least arachidonic acid (ARA) and (b) an emulsion of one or more ω3 fatty acids comprising at least docosahexaenoic acid (DHA). In some embodiments of any of these aspects, the composition comprises a mixture of (a) an emulsion of one or more ω6 fatty acids comprising at least arachidonic acid (ARA) and (b) an emulsion of one or more ω3 fatty acids comprising at least EPA. In some embodiments of any of these aspects, the composition comprises a mixture of (a) an emulsion of one or more ω6 fatty acids comprising at least arachidonic acid (ARA) and (b) an emulsion of one or more ω3 fatty acids comprising at least DHA and EPA.

[0026] As used herein, the term "emulsion" refers to a heterogeneous system that includes at least two or more substantially immiscible liquids, with one liquid dispersed in another liquid in the form of droplets.By way of example only, an emulsion can be a biphasic system that includes two immiscible liquid phases that are well mixed and dispersed with each other.Examples of emulsions include, but are not limited to, water-in-oil emulsions, oil-in-water emulsions, water-in-water, water-in-oil-in-water emulsions, and oil-in-water-in-oil emulsions.In some embodiments of any of these aspects, the continuous phase of the emulsion is water.

[0027] In some embodiments of any of these aspects, the emulsion comprises water. In some embodiments, the emulsion has a total fat in water amount of about 20% w / v. In some embodiments, the emulsion has a total fat in water amount of about 10% w / v to about 50% w / v. In some embodiments, the emulsion has a total fat in water amount of about 20% w / v. In some embodiments, the emulsion has a total fat in water amount of about 10% w / v to about 50% w / v.

[0028] Usually, emulsions are unstable mixtures and do not form spontaneously. Therefore, energy input is required to mix the continuous phase and the dispersed phase and form an emulsion. This energy can be added, for example, by shaking, stirring, homogenizing, spraying, high pressure pumping, and ultrasonic emulsification. The emulsion formulations described herein can be made by blending the fat components listed herein with any protein, carbohydrate, and / or other additional additives, and homogenizing the mixture to form a stable emulsion. In some embodiments of any of these aspects, neither (a) ARA nor (b) DHA and / or EPA are emulsified, e.g., not only mixed, nor mixed into the emulsion of the other. However, over time, the emulsion formed may tend to return to a stable state of separate oil and water layers. Thus, in some embodiments, the emulsion formulations described herein can further include any natural or synthetic emulsifier known in the art. The addition of emulsifiers can increase the kinetic stability of the emulsion, so that once formed, the emulsion does not change significantly upon long-term storage.

[0029] The emulsion described herein can be prepared by some conventional techniques known to those skilled in the art.For example, core lipid is first mixed with one or more emulsifiers and any additional components or additives.Then, this oil layer is slowly added to water while constantly stirring to prepare emulsion.If osmolality adjuster is used, it is added to water before mixing with oil layer.If necessary, pH can be adjusted at this stage, and if necessary, final volume can be adjusted with water.

[0030] In some embodiments of any of these aspects, for example, when formulated for parenteral administration, the particle size of the oil droplets in the emulsion is within or below the size range of natural chylomicrons, i.e., within the range of 0.4-1.0 um. If the particle size is larger, the lipid particles may deposit in the liver, spleen, and lungs, resulting in significant fat loading after injection (Rahui CM, et I al., Am. Hosp. Pharm. 1992, 49:2749-2755). Lipids with smaller particle size tend to disperse better in emulsions, resulting in safer and more stable emulsions. The selection of appropriate conditions for preparing emulsions according to the present invention is considered to be within the ordinary skill of researchers in the art.

[0031] In some embodiments of any of these aspects, the emulsion is a stable emulsion.As used herein, the term "stable emulsion" refers to an emulsion in which droplets remain substantially evenly distributed throughout the continuous phase (or liquid carrier) for a long period of time (e.g., at least about 1 month or longer), including a reasonable storage period and usage period.For example, droplets do not aggregate or settle after a long period of time (e.g., at least about 1 month or longer).

[0032] As used herein, the term "substantially immiscible" refers to two or more liquids that do not form a homogeneous mixture when in contact with each other. In some embodiments, when two or more substantially immiscible liquids are in contact with each other, one of these liquids may have incomplete solubility (e.g., only 10% or less) in another substantially immiscible liquid. As used herein, the term "homogeneous mixture" refers to all components and / or liquids in the mixture being readily present in a single phase. For example, one or more of the components and / or liquids do not separate into separate phases even when the mixture is allowed to stand for an extended period of time (e.g., at least about 6 hours or more, including, by way of example, at least about 12 hours, at least about 18 hours, at least about 24 hours, or longer). When referring to the miscibility of a droplet and a liquid carrier, the term "substantially immiscible" refers to the liquid (e.g., a thin liquid layer) and the liquid carrier that form at least the outer surface of the droplet that do not form a homogeneous mixture when in contact with each other.

[0033] As used herein and throughout the present specification, the term "droplet" refers to a finite volume of matter that includes at least one liquid or at least one liquid phase, including at least two or more liquids or liquid phases as examples. A droplet can be of any size, shape, and / or form. In some embodiments of the various aspects described herein, a droplet can have a droplet size that is smaller (e.g., at least 50% smaller) than the inner diameter of the needle used to administer the emulsion that includes the droplet. It will be understood by those skilled in the art that droplets usually exhibit a distribution of droplet sizes around a designated "size". Unless otherwise stated, the term "droplet size" or "size" as used herein refers to the mode of the size distribution of droplets, i.e., the value that occurs most frequently in the size distribution. Methods for measuring droplet size are known to those of skill in the art, for example, by dynamic light scattering (such as photon correlation spectroscopy, laser diffraction, low angle laser light scattering (LALLS), and medium angle laser light scattering (MALLS)), light obscuration methods (such as Coulter analysis), or other techniques (such as rheology, and optical or electron microscopy).

[0034] The compositions described herein are intended to be administered as emulsions, but other forms of formulation are also encompassed by the present invention.For example, the compositions described herein as emulsions can also be made in powder form by increasing the proportion of total solids in the formulation, using procedures well known to those skilled in the art.Concentrates or powders can be reconstituted for nutritional use by adding water (tap water or deionized sterilized water) to form emulsions.

[0035] As used herein, the term "docosahexaenoic acid" or "DHA" is an omega-3 fatty acid, i.e., all cis-docosa-4,7,10,13,16,19-hexaenoic acid or 22:6 (omega-3).

[0036] As used herein, the term "eicosapentaenoic acid" or "EPA" is an omega-3 fatty acid, i.e., (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoic acid or 20:5 (omega-3).

[0037] As used herein, the term "arachidonic acid" or "ARA" refers to an omega-6 fatty acid, i.e., cis-5,8,11,14-eicosatetraenoic acid or 20:4 (omega-6).

[0038] As used herein, the term "fatty acid" includes fatty acids, such as unsaturated (e.g., monounsaturated, polyunsaturated) or saturated fatty acids, as well as pharma- ceutically acceptable esters, free acids, monoglycerides, diglycerides, and triglycerides, derivatives, conjugates, precursors, salts, and mixtures thereof.

[0039] As used herein, the term "ω6 fatty acid" includes natural and synthetic ω6 fatty acids, as well as their pharma- ceutically acceptable esters, free acids, triglycerides, derivatives, conjugates, precursors, salts, and mixtures. ω6 fatty acids may include, but are not limited to, linoleic acid (LA), γ-linolenic acid (GLA), calendic acid, eicosadienoic acid, dihomo γ-linolenic acid (DGLA), arachidonic acid (ARA), docosadienoic acid, adrenic acid, osbondoic acid, tetracosatetraenoic acid, and tetracosapentaenoic acid. ω6 fatty acids may be provided in the form of ω6 oil. ω6 oil for use in the compositions (e.g., emulsions) described herein may have a high content of ARA. ω6 oil and / or ω6 fatty acids may be derived from animals, plants, algae, or synthetic sources. In some embodiments of any of these aspects, the omega-6 oil and / or omega-6 fatty acids may be derived from plants, algae, or synthetic sources. For example, suitable sources of omega-6 oil and / or omega-6 fatty acids include flaxseed oil, canola oil, mustard seed oil, palm oil, olive oil, soybean oil, and Mortierella alpina oil.

[0040] In some embodiments of any of these aspects, the omega-6 fatty acids of the compositions (e.g., emulsions) described herein can comprise, consist of, or consist essentially of ARA.

[0041] Examples of omega-6 fatty acids and mixtures thereof encompassed by this disclosure include CAS 506-32-1; GRAS dossiers GRN 730, GRN 326, GRN 94, GRN 80, GRN 41 (see fda.gov / media / 112256 / download); and omega-6 fatty acids as defined in FSANZ (Food Standards Australia New Zealand) 2003. DHASCO and ARASCO oils as sources of long-chain polyunsaturated fatty acids in infant formula: A safety assessment. Technical report series 22: 1-54 (available on the world wide web at foodstandards.gov.au); which are incorporated herein by reference in their entireties.

[0042] In some embodiments of any of these aspects, the ARA and / or omega-6 fatty acids are provided in the form of ARASCO™ (DSM; Heerlen, Netherlands). In some embodiments of any of these aspects, the compositions described herein include ARASCO™. Suitable algal oils are also available from Cargill, Fementlag (e.g., DHA ORIGINS™), and Corbion (e.g., ALGAPRIME™). Other commercially available examples of omega-6 fatty acids suitable for the present disclosure include various fatty acid mixtures (which can exist, for example, in triglyceride (TG), ethyl ester (EE), free fatty acid (FA) form, and / or as phospholipids) and include, but are not limited to, omega-6 fatty acid preparations available from Linyi Youkang Biology Co, Yukang Biotechnology Co. Ltd., Alfrebro LLC, Archer Daniels Midland Co., BOC Sciences, Best of Chemicals Supplier, Jiangyin Healthway International Trade Co., Ltd., Penta International Corporation, TCI AMERICA, and Qingdao Free Trade Zone United International Co Ltd.

[0043] The ω6 fatty acid used herein can be purified, for example, to meet the quality standard for parenteral administration.In some embodiments of any of these aspects, the ω6 fatty acid can be enriched with additional or further ω6 fatty acid, for example, the ω6 fatty acid can be supplemented with purified or synthetic ω6 fatty acid from another source to increase the ω6 fatty acid content.The method of extracting and refining oils is well known in the art.These oils do not need to be re-esterified in order to purify, extract or refine them.

[0044] In some embodiments of any of these aspects, the composition comprises a vegetable oil or fungal oil (e.g., an omega-6 oil). In some embodiments of any of these aspects, the composition comprises a vegetable oil or fungal oil that includes ARA. In some embodiments of any of these aspects, the ARA of the composition is provided in the form of a vegetable oil or fungal oil. In some embodiments of any of these aspects, the vegetable oil or fungal oil is not distilled or re-esterified. In some embodiments of any of these aspects, the total combined triglyceride and diglyceride content of the vegetable oil or fungal oil comprises 10% or less diglycerides. In some embodiments of any of these aspects, the vegetable oil or fungal oil does not comprise diglycerides. In some embodiments of any of these aspects, the vegetable oil or fungal oil comprises 5% (w / w) or less sterols, 70 mg / L or less phytosterols, 4% (w / w) or less stigmasterol, and / or 10 mg / L or less stigmasterol. In some embodiments of any of these aspects, the vegetable oil is, comprises, consists of, or consists essentially of soybean oil or olive oil. In some embodiments of any of these aspects, the fungal oil is, comprises, consists of, or consists essentially of Mortierella alpina oil.

[0045] As shown in Example 2 herein, formulations such as Intralipid show significant toxicity (e.g., liver damage) compared to compositions described herein. The experiment in Example 2 compares soybean oil, which has a low linoleic acid content, with Intralipid, and shows that linoleic acid and / or phytosterols are significant sources of toxicity of ω6 fatty acids such as soybean oil or Intralipid. Thus, in some embodiments, the compositions described herein (or components thereof, such as (a) DHA and / or EPA or (b) ARA) contain 40% w / v or less of linoleic acid. In some embodiments, the compositions described herein (or components thereof, such as (a) DHA and / or EPA or (b) ARA) contain 30% w / v or less of linoleic acid. In some embodiments, the compositions described herein (or components thereof, such as (a) DHA and / or EPA or (b) ARA) contain 20% w / v or less of linoleic acid. In some embodiments, the compositions described herein (or components thereof, e.g., (a) DHA and / or EPA or (b) ARA) comprise 10% w / v or less linoleic acid. In some embodiments, the compositions described herein (or components thereof, e.g., (a) DHA and / or EPA or (b) ARA) comprise 5% w / v or less linoleic acid. In some embodiments of any of these aspects, the vegetable oil or fungal oil does not comprise linoleic acid. In some embodiments of any of these aspects, the compositions described herein do not comprise linoleic acid.

[0046] In some embodiments, the composition described herein (or its components, e.g., (a) DHA and / or EPA or (b) ARA) comprises linoleic acid at a dose of 621 mg / kg / day or less or is administered at a dose of 621 mg / kg / day or less of linoleic acid. In some embodiments, the composition described herein (or its components, e.g., (a) DHA and / or EPA or (b) ARA) comprises linoleic acid at a dose of 401 mg / kg / day or less or is administered at a dose of 401 mg / kg / day or less of linoleic acid. In some embodiments, the composition described herein (or its components, e.g., (a) DHA and / or EPA or (b) ARA) comprises linoleic acid at a dose of 287 mg / kg / day or less or is administered at a dose of 287 mg / kg / day or less of linoleic acid.

[0047] Intralipid is used at a dose that provides about 2-3 g fat per kg / day, with about 55% of the total fatty acids being linoleic acid. Sumoflipid is used at a dose that provides about 1 g fat per kg / day. These levels have been demonstrated to be liver toxic. Thus, in some embodiments of any of these aspects, formulations or methods are described herein for doses that provide less than 1 g linoleic acid per kg / day. In some embodiments of any of these aspects, formulations or methods are described herein for doses that provide less than 500 mg linoleic acid per kg / day. In some embodiments of any of these aspects, formulations or methods are described herein for doses that provide less than 400 mg linoleic acid per kg / day. In some embodiments of any of these aspects, formulations or methods are described herein for doses that provide less than 300 mg linoleic acid per kg / day.

[0048] As used herein, the term "omega-3 fatty acid" includes natural and synthetic omega-3 fatty acids, as well as their pharma- ceutically acceptable esters, free acids, triglycerides, derivatives, conjugates, precursors, salts, and mixtures. Omega-3 fatty acids may include, but are not limited to, hexadecatrienoic acid (HTA), alpha-linolenic acid (ALA), stearidonic acid (SDA), eicosatrienoic acid (ETE), eicosatetraenoic acid (ETA), eicosapentaenoic acid (EPA), heneicosapentaenoic acid (HPA), docosapentaenoic acid (DPA), clupanodonic acid, docosahexaenoic acid (DHA), tetracosapentaenoic acid, and tetracosahexaenoic acid (nisinic acid). The omega-3 fatty acids for use in the compositions (e.g., emulsions) described herein can have a high content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The omega-3 fatty acids can be provided in the form of omega-3 oil. The omega-3 oil and / or the omega-3 fatty acids can be of animal origin. The omega-3 oil and / or the omega-3 fatty acids can be of marine or synthetic origin. For example, a suitable source of omega-3 oil and / or the omega-3 fatty acids is fish oil or seal oil. Suitable sources of fish oil include deep sea fish, shark, salmon, cod, salmon, bonito, mackerel, Atlantic mackerel, haddock, herring, mahi-mahi, menhaden, mackerel, capelin, tilapia, pacific saury, krill, anchovy, pollack, trout, whitefish, tuna, smelt, shad, and sardines, as well as the cold water fish described elsewhere herein.

[0049] The fatty acids described in this disclosure may be derived from animal oils and / or non-animal oils. In some embodiments of this disclosure, the fatty acids are derived from at least one oil selected from marine oils, algal oils, fungal oils, plant-based oils, and microbial oils. Marine oils include, for example, fish oils, such as tuna fish oil, krill oil, and lipid compositions derived from fish. Plant-based oils include, for example, linseed oil, canola oil, mustard seed oil, olive oil, and soybean oil. Microbial oils include, for example, products by Martek. Fungal and algal oils include, for example, products by DSM.

[0050] In some embodiments of any of these aspects, the omega-3 fatty acids of the compositions (e.g., emulsions) described herein can comprise, consist of, or consist essentially of DHA. In some embodiments of any of these aspects, the omega-3 fatty acids of the compositions (e.g., emulsions) described herein can comprise, consist of, or consist essentially of EPA. In some embodiments of any of these aspects, the omega-3 fatty acids of the compositions (e.g., emulsions) described herein can comprise, consist of, or consist essentially of EPA and DHA.

[0051] Examples of omega-3 fatty acids and mixtures thereof encompassed by the present disclosure include omega-3 fatty acids as defined in the European Pharmacopoeia omega-3 triglycerides, the European Pharmacopoeia omega-3 acid ethyl esters 60, or monographs on fish oils rich in omega-3 acids, which are incorporated herein by reference in their entireties.

[0052] In some embodiments of any of these aspects, the DHA, EPA, and / or omega-3 fatty acids are provided in the form of DHASCO™ (DSM; Heerlen, Netherlands). In some embodiments of any of these aspects, the compositions described herein include DHASCO™.

[0053] Further commercial examples of omega-3 fatty acids suitable for the present disclosure include various fatty acid mixtures (which may exist, for example, in the form of triglycerides (TG), ethyl esters (EE), free fatty acids (FA), and / or as phospholipids), including, but not limited to, the following: Incromega™ omega-3 marine oil concentrates, such as Incromega™ E1070, Incromega™ TG7010 SR, Incromega™ E7010 SR, Incromega™ TG6015, Incromega™ EPA500TG SR, Incromega™ E400200 SR, Incromega™ E4010, Incromega™ DHA700TG SR, Incromega™ DHA700E SR, Incromega™ DHA500TG SR, Incromega™ TG3322 SR, Incromega(TM) E3322 SR, Incromega(TM) TG3322, Incromega(TM) E3322, Incromega(TM) Trio TG / EE(Croda International PLC, Yorkshire, England);EPAX6000FA, EPAX5000TG, EPAX4510TG, EPAX2050TG, EPAX7010EE, EPAX5500EE, EPAX5500TG, EPAX5000EE, EPA X5000TG, EPAX6000EE, EPAX6000TG, EPAX6000FA, EPAX6500EE, EPAX6500TG, EPAX4510TG, EPAX1050TG, EPAX2050TG, EPAX 7010TG, EPAX7010EE, EPAX6015TG / EE, EPAX4020TG, and EPAX4020EE (EPAX is a wholly owned subsidiary of Austevoll Seafood ASA, a Norwegian company); MEG-3® EPA / DHA fish oil concentrate (Ocean Nutrition Canada); DHA FNO "Functional Nutritional Oil" and DHA CL "Clear Liquid" (Lonza); Superba™ krill oil (Aker); omega-3 products containing DHA from Martek;Neptune krill oil (Neptune); cod liver oil products and anti-reflux fish oil concentrate (TG) from Mollers; omega-3 fish oil from Lysi; Seven Seas Triomega® cod liver oil blend (Seven Seas); and Fri Flyt Omega-3 (Vesteralens).

[0054] The ω3 fatty acid used herein can be purified, for example, to meet the quality standard for parenteral administration.In some embodiments of any of these aspects, the ω3 fatty acid can be enriched with additional or further ω3 fatty acid, for example, the ω3 fatty acid can be supplemented with purified or synthetic ω3 fatty acid from another source to increase the ω3 fatty acid content.The method of extracting and refining oils is well known in the art.These oils do not need to be re-esterified in order to purify, extract or refine them.

[0055] In some embodiments of any of these aspects, the composition comprises fish oil and / or DHA is provided in the form of fish oil. As used herein, "fish oil" refers to oil derived from fish or fish tissue. Fish oil is commercially available, for example, 10% (wt / wt) fish oil triglyceride can be obtained from Nisshin Flour Milling Co., Nisshin, Japan. Omegaven (Fresnius Kabi) is suitable for use in the methods and compositions described herein. In some embodiments of any of these aspects, the fish oil can comprise omega-3 fatty acids, DHA, and / or EPA. In some embodiments of any of these aspects, the fish oil can be derived from one or more cold-water fishes known to be high in omega-3 fatty acid content. Non-limiting examples of cold water fish may include deep sea fish, shark, salmon, cod, salmon, bonito, mackerel, Atlantic mackerel, haddock, herring, mahi-mahi, menhaden, mackerel, capelin, tilapia, pacific saury, krill, anchovy, pollack, trout, whitefish, tuna, smelt, shad, and sardine. In some embodiments of any of these aspects, the fish oil may be derived from one or more marine cold water fish. In some embodiments of any of these aspects, the fish oil can be derived from shark, salmon, cod, salmon, bonito, mackerel, Atlantic mackerel, haddock, herring, mahi-mahi, menhaden, mackerel, capelin, tilapia, pacific saury, krill, anchovy, pollack, trout, whitefish, tuna, smelt, shad, sardine, or any combination thereof.In some embodiments of any of these aspects, the fish oil is not distilled or re-esterified.In some embodiments of any of these aspects, the total combined triglyceride and diglyceride content of the fish oil comprises 10% or less diglycerides.In some embodiments of any of these aspects, the fish oil does not comprise diglycerides.In some embodiments of any of these aspects, the fish oil contains no more than 5% (w / w) sterols, no more than 70 mg / L phytosterols, no more than 4% (w / w) stigmasterol, and / or no more than 10 mg / L stigmasterol.

[0056] In some embodiments of any of these aspects, the composition comprises algal oil and / or the DHA and / or EPA is provided in the form of algal oil.

[0057] In some embodiments of any of these aspects, the algal oil is, comprises, consists of, or consists essentially of oil from Crypthecodinium cohnii. In some embodiments of any of these aspects, the algal oil has not been distilled or re-esterified. In some embodiments of any of these aspects, the total combined triglyceride and diglyceride content of the algal oil comprises 10% or less diglycerides. In some embodiments of any of these aspects, the algal oil is diglyceride-free. In some embodiments of any of these aspects, the algal oil comprises 5% (w / w) or less sterols, 70 mg / L or less phytosterols, 4% (w / w) or less stigmasterol, and / or 10 mg / L or less stigmasterol.

[0058] In some embodiments of any of these aspects, the composition comprises (a) a vegetable oil that is, comprises, consists of, or consists essentially of soybean oil, and (b) an algal oil that is, comprises, consists of, or consists essentially of oil from Crypthecodinium cohnii. In some embodiments of any of these aspects, the composition does not comprise a source of ω6 or ω3 fatty acids other than the vegetable oil and the algal oil. In some embodiments of any of these aspects, the composition comprises (a) a vegetable oil that is, comprises, consists of, or consists essentially of soybean oil, and (b) a fish oil. In some embodiments of any of these aspects, the composition does not comprise a source of ω6 or ω3 fatty acids other than the vegetable oil and the fish oil.

[0059] In some embodiments of any of these aspects, the composition comprises (a) a vegetable oil that is, comprises, consists of, or consists essentially of olive oil, and (b) an algal oil that is, comprises, consists of, or consists essentially of oil from Crypthecodinium cohnii. In some embodiments of any of these aspects, the composition does not comprise a source of ω6 or ω3 fatty acids other than the vegetable oil and the algal oil. In some embodiments of any of these aspects, the composition comprises (a) a vegetable oil that is, comprises, consists of, or consists essentially of olive oil, and (b) a fish oil. In some embodiments of any of these aspects, the composition does not comprise a source of ω6 or ω3 fatty acids other than the vegetable oil and the fish oil.

[0060] In some embodiments of any of these aspects, the composition comprises (a) a fungal oil that is, comprises, consists of, or consists essentially of Mortierella alpina oil, and (b) an algal oil that is, comprises, consists of, or consists essentially of an oil from Crypthecodinium cohnii. In some embodiments of any of these aspects, the composition does not comprise a source of ω6 or ω3 fatty acids other than the fungal oil and the algal oil. In some embodiments of any of these aspects, the composition comprises (a) a fungal oil that is, comprises, consists of, or consists essentially of Mortierella alpina oil, and (b) a fish oil. In some embodiments of any of these aspects, the composition does not comprise a source of ω6 or ω3 fatty acids other than the fungal oil and the fish oil.

[0061] In some embodiments of any of these aspects, the composition does not include a source of omega-6 or omega-3 fatty acids other than fungal and algal oils.

[0062] In some embodiments of any of these aspects, the (a) ARA and (b) DHA and / or EPA present in the compositions described herein are present in a particular ratio, e.g., a weight ratio.

[0063] In some embodiments of any of these aspects, the weight ratio of (a) ARA to (b) DHA and / or EPA is about 1:1 to about 1:20. In some embodiments of any of these aspects, the weight ratio of (a) ARA to (b) DHA and / or EPA is about 1:1 to about 1:15. In some embodiments of any of these aspects, the weight ratio of (a) ARA to (b) DHA and / or EPA is about 1:2 to about 1:15. In some embodiments of any of these aspects, the weight ratio of (a) ARA to (b) DHA and / or EPA is about 1:2.8 to about 1:12.5. In some embodiments of any of these aspects, the weight ratio of (a) ARA to (b) DHA and / or EPA is about 3:2 to about 3:5. In some embodiments of any of these aspects, the weight ratio of (a) ARA to (b) DHA and / or EPA is about 1:2 to about 3:5. In some embodiments of any of these aspects, the weight ratio of (a) ARA to (b) DHA and / or EPA is about 1:2 to about 1:5. In some embodiments of any of these aspects, the weight ratio of (a) ARA to (b) DHA and / or EPA is about 2:1 to about 1:4. In some embodiments of any of these aspects, the weight ratio of (a) ARA to (b) DHA and / or EPA is about 1:1 to about 1:2.

[0064] In some embodiments of any of these aspects, the weight ratio of (a) ARA to (b) DHA and / or EPA is 3:2 to 3:5. In some embodiments of any of these aspects, the weight ratio of (a) ARA to (b) DHA and / or EPA is 1:2 to 3:5. In some embodiments of any of these aspects, the weight ratio of (a) ARA to (b) DHA and / or EPA is 1:2 to 1:5. In some embodiments of any of these aspects, the weight ratio of (a) ARA to (b) DHA and / or EPA is 2:1 to 1:4. In some embodiments of any of these aspects, the weight ratio of (a) ARA to (b) DHA and / or EPA is 1:1 to 1:2.

[0065] In some embodiments of any of these aspects, the compositions described herein include additional ω6 fatty acids and / or ω3 fatty acids, such as (a) ARA and (b) ω6 fatty acids and / or ω3 fatty acids in addition to DHA and / or EPA. In some embodiments of any of these aspects, ARA and DHA and / or EPA constitute at least 10% of the total amount of ω3 fatty acids and ω6 fatty acids. In some embodiments of any of these aspects, ARA and DHA and / or EPA constitute at least 20% of the total amount of ω3 fatty acids and ω6 fatty acids. In some embodiments of any of these aspects, ARA and DHA and / or EPA constitute at least 30% of the total amount of ω3 fatty acids and ω6 fatty acids. In some embodiments of any of these aspects, ARA and DHA and / or EPA constitute at least 35% of the total amount of ω3 fatty acids and ω6 fatty acids. In some embodiments of any of these aspects, ARA and DHA and / or EPA constitute at least 60% of the total amount of ω3 fatty acids and ω6 fatty acids. In some embodiments of any of these aspects, ARA and DHA and / or EPA constitute at least 70% of the total amount of ω3 and ω6 fatty acids. In some embodiments of any of these aspects, ARA and DHA and / or EPA constitute at least 80% of the total amount of ω3 and ω6 fatty acids. In some embodiments of any of these aspects, ARA and DHA and / or EPA constitute at least 90% of the total amount of ω3 and ω6 fatty acids.

[0066] In some embodiments of any of these aspects, greater than 20% (by weight) of the total amount of omega-3 fatty acids present in the composition is DHA. In some embodiments of any of these aspects, greater than 25% (by weight) of the total amount of omega-3 fatty acids present in the composition is DHA.

[0067] In some embodiments of any of these aspects, more than 30% (by weight) of the total amount of omega-3 fatty acids present in the composition is DHA. In some embodiments of any of these aspects, more than 35% (by weight) of the total amount of omega-3 fatty acids present in the composition is DHA. In some embodiments of any of these aspects, more than 40% (by weight) of the total amount of omega-3 fatty acids present in the composition is DHA. In some embodiments of any of these aspects, more than 45% (by weight) of the total amount of omega-3 fatty acids present in the composition is DHA.

[0068] In some embodiments of any of these aspects, DHA is the predominant omega-3 fatty acid in the composition. In some embodiments of any of these aspects, DHA is present in the composition by weight greater than any other omega-3 fatty acid. In some embodiments of any of these aspects, more than 50% (by weight) of the total amount of omega-3 fatty acids present in the composition is DHA.

[0069] In some embodiments of any of these aspects, greater than 20% (by weight) of the total amount of omega-3 fatty acids present in the composition is EPA. In some embodiments of any of these aspects, greater than 25% (by weight) of the total amount of omega-3 fatty acids present in the composition is EPA.

[0070] In some embodiments of any of these aspects, greater than 30% (by weight) of the total amount of omega-3 fatty acids present in the composition is EPA. In some embodiments of any of these aspects, greater than 35% (by weight) of the total amount of omega-3 fatty acids present in the composition is EPA. In some embodiments of any of these aspects, greater than 40% (by weight) of the total amount of omega-3 fatty acids present in the composition is EPA. In some embodiments of any of these aspects, greater than 45% (by weight) of the total amount of omega-3 fatty acids present in the composition is EPA.

[0071] In some embodiments of any of these aspects, EPA is the predominant omega-3 fatty acid in the composition. In some embodiments of any of these aspects, EPA is present in the composition by weight greater than any other omega-3 fatty acid. In some embodiments of any of these aspects, greater than 50% (by weight) of the total amount of omega-3 fatty acids present in the composition is EPA.

[0072] In some embodiments of any of these aspects, greater than 20% (by weight) of the total amount of omega-3 fatty acids present in the composition is DHA and EPA. In some embodiments of any of these aspects, greater than 25% (by weight) of the total amount of omega-3 fatty acids present in the composition is DHA and EPA.

[0073] In some embodiments of any of these aspects, more than 30% (by weight) of the total amount of omega-3 fatty acids present in the composition are DHA and EPA. In some embodiments of any of these aspects, more than 35% (by weight) of the total amount of omega-3 fatty acids present in the composition are DHA and EPA. In some embodiments of any of these aspects, more than 40% (by weight) of the total amount of omega-3 fatty acids present in the composition are DHA and EPA. In some embodiments of any of these aspects, more than 45% (by weight) of the total amount of omega-3 fatty acids present in the composition are DHA and EPA.

[0074] In some embodiments of any of these aspects, more than 20% (by weight) of the total amount of ω6 fatty acids present in the composition is ARA. In some embodiments of any of these aspects, more than 25% (by weight) of the total amount of ω6 fatty acids present in the composition is ARA. In some embodiments of any of these aspects, more than 30% (by weight) of the total amount of ω6 fatty acids present in the composition is ARA. In some embodiments of any of these aspects, more than 35% (by weight) of the total amount of ω6 fatty acids present in the composition is ARA. In some embodiments of any of these aspects, more than 40% (by weight) of the total amount of ω6 fatty acids present in the composition is ARA. In some embodiments of any of these aspects, more than 45% (by weight) of the total amount of ω6 fatty acids present in the composition is ARA.

[0075] In some embodiments of any of these aspects, ARA is the predominant omega-6 fatty acid in the composition. In some embodiments of any of these aspects, ARA is present in the composition by weight greater than any other omega-6 fatty acid. In some embodiments of any of these aspects, greater than 50% (by weight) of the total amount of omega-6 fatty acids present in the composition is ARA.

[0076] In some embodiments of any of these aspects, (a) ARA and (b) DHA and / or EPA, taken together, are at least 50% (e.g., by weight) of the total amount of ω3 and ω6 fatty acids present in the composition. In some embodiments of any of these aspects, (a) ARA and (b) DHA and / or EPA, taken together, are at least 60% (e.g., by weight) of the total amount of ω3 and ω6 fatty acids present in the composition. In some embodiments of any of these aspects, (a) ARA and (b) DHA and / or EPA, taken together, are at least 65% (e.g., by weight) of the total amount of ω3 and ω6 fatty acids present in the composition. In some embodiments of any of these aspects, (a) ARA and (b) DHA and / or EPA, taken together, are at least 70% (e.g., by weight) of the total amount of ω3 and ω6 fatty acids present in the composition. In some embodiments of any of these aspects, (a) ARA and (b) DHA and / or EPA, taken together, are at least 75% (e.g., by weight) of the total amount of ω3 and ω6 fatty acids present in the composition. In some embodiments of any of these aspects, (a) ARA and (b) DHA and / or EPA, taken together, are at least 80% (e.g., by weight) of the total amount of ω3 and ω6 fatty acids present in the composition. In some embodiments of any of these aspects, (a) ARA and (b) DHA and / or EPA, taken together, are at least 85% (e.g., by weight) of the total amount of ω3 and ω6 fatty acids present in the composition. In some embodiments of any of these aspects, (a) ARA and (b) DHA and / or EPA, taken together, are at least 90% (e.g., by weight) of the total amount of ω3 and ω6 fatty acids present in the composition. In some embodiments of any of these aspects, (a) ARA and (b) DHA and / or EPA, collectively, are at least 95% (e.g., % by weight) of the total amount of omega-3 and omega-6 fatty acids present in the composition.

[0077] As shown in Example 2 herein, the ω6 to ω3 ratio of the composition correlates with the pro-inflammatory and anti-inflammatory effects of the composition. Thus, in some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids in the composition is about 2:1 to about 1:1. In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids in the composition is about 3:2 to about 3:5. In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids in the composition is about 1:2 to about 3:5. In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids in the composition is about 1:2 to about 1:5. In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids in the composition is about 2:1 to about 1:4. In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids in the composition is about 1:1 to about 1:2. In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids in the composition is about 8.41:1 to about 1:11.1. In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids in the composition is about 8.41:1 to about 1.44:1. In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids in the composition is about 8.41:1 to about 1:1.27. In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids in the composition is about 8.41:1 to about 1:2.17. In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids in the composition is about 2:1 to about 1:11.1. In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids in the composition is about 2:1 to about 1.44:1. In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids in the composition is about 2:1 to about 1:1.27. In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids in the composition is about 2:1 to about 1:2.17. In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids in the composition is about 8.41:1 to about 1:4.In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids in the composition is about 1:1 to about 1:11.1. In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids in the composition is about 1:1 to about 1.44:1. In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids in the composition is about 1:1 to about 1:1.27. In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids in the composition is about 8.41:1 to about 1:2. In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids in the composition is about 1.44:1 to about 1:11.1. In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids in the composition is about 1.44:1 to about 1:1.27. In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids in the composition is from about 1.44:1 to about 1:2.17. In some embodiments of any of these aspects, the weight ratio of ω6 fatty acids to ω3 fatty acids in the composition is from about 1:1.27 to about 1:2.17.

[0078] In some embodiments of any of the aspects described herein, the ω3 fatty acids and / or ω6 fatty acids can be highly purified, e.g., as part of this particular procedure, highly enriched to more than the initial content of ω3 fatty acids and / or ω6 fatty acids and / or their triglycerol compounds.In some embodiments of any of these aspects, these compositions can comprise at least 95% by weight, e.g., 96%, 97%, 98% or more by weight of monomeric triglycerides.In some embodiments of any of these aspects, these compositions can comprise less than 1% by weight of oxidized triglycerides, less than 0.2% by weight of trimer triglycerides and oligomer triglycerides, and less than 0.8% by weight of dimer polyglycerides, and less than 1.5% by weight of non-emulsifiable, specifically carbohydrates and steranes. In some embodiments of any of these aspects, the cholesterol content of the omega-3 fatty acids and / or omega-6 fatty acids and / or compositions described herein (e.g., after purification or enrichment) contains less than 2500 ppm cholesterol, e.g., less than 1500 ppm cholesterol.

[0079] In some embodiments of any of these aspects, the ω3 and / or ω6 fatty acids of the compositions described herein are natural triglycerides, e.g., they have not been distilled or re-esterified. Although distillation and / or re-esterification of triglycerides is utilized in certain compositions known in the art (e.g., to remove myristic acid or palmitoleic acid), it is specifically anticipated herein that such procedures alter the triglycerides to induce toxicity therein and increase the presence of diglycerides, monoglycerides, and free fatty acids.

[0080] In some embodiments of any of these aspects, the ω3 fatty acid and / or ω6 fatty acid of the composition described herein is triglyceride, e.g., they are not diglyceride as described elsewhere.In some embodiments of any of these aspects, the ω3 fatty acid of the composition described herein is triglyceride.In some embodiments of any of these aspects, the ω6 fatty acid of the composition described herein is triglyceride.In some embodiments of any of these aspects, the DHA of the composition described herein is triglyceride.In some embodiments of any of these aspects, the ARA of the composition described herein is triglyceride.

[0081] In some embodiments of any of these aspects, the ω3 fatty acids and / or ω6 fatty acids of the compositions described herein contain 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or less diglycerides, e.g., as a percentage of the total diglyceride and triglyceride content combined. In some embodiments of any of these aspects, the ω3 fatty acids of the compositions described herein contain 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or less diglycerides, e.g., as a percentage of the total diglyceride and triglyceride content combined. In some embodiments of any of these aspects, the omega-6 fatty acids of the compositions described herein, for example as a percentage of the total combined diglyceride and triglyceride content, contain 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or no diglycerides.In some embodiments of any of these aspects, the DHA of the compositions described herein, for example as a percentage of the total combined diglyceride and triglyceride content, contains 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or no diglycerides. In some embodiments of any of these aspects, the EPA of the compositions described herein contains, e.g., as a percentage of the total diglyceride and triglyceride content combined, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or less, or no diglycerides.In some embodiments of any of these aspects, the DHA and EPA of the compositions described herein, collectively, for example, as a percentage of the total combined diglyceride and triglyceride content, comprise 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or no diglyceride.In some embodiments of any of these aspects, the ARA of the compositions described herein, for example, as a percentage of the total combined diglyceride and triglyceride content, comprise 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or no diglyceride. In some embodiments of any of these aspects, the total combined diglyceride and triglyceride content of the compositions described herein contains 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or less, or no diglycerides.

[0082] In some embodiments of any of these aspects, the ω3 fatty acid and / or ω6 fatty acid of the composition described herein comprises 10% or less diglyceride, for example as a percentage of the total combined diglyceride and triglyceride content.In some embodiments of any of these aspects, the ω3 fatty acid of the composition described herein comprises 10% or less diglyceride, for example as a percentage of the total combined diglyceride and triglyceride content.In some embodiments of any of these aspects, the ω6 fatty acid of the composition described herein comprises 10% or less diglyceride, for example as a percentage of the total combined diglyceride and triglyceride content.In some embodiments of any of these aspects, the DHA of the composition described herein comprises 10% or less diglyceride, for example as a percentage of the total combined diglyceride and triglyceride content. In some embodiments of any of these aspects, the EPA of the composition described herein comprises 10% or less diglyceride, for example as a percentage of the total combined diglyceride and triglyceride content.In some embodiments of any of these aspects, the DHA and EPA of the composition described herein collectively comprise 10% or less diglyceride, for example as a percentage of the total combined diglyceride and triglyceride content.In some embodiments of any of these aspects, the ARA of the composition described herein comprises 10% or less diglyceride, for example as a percentage of the total combined diglyceride and triglyceride content.In some embodiments of any of these aspects, the total combined diglyceride and triglyceride content of the composition described herein comprises 10% or less diglyceride.

[0083] In some embodiments of any of these aspects, the omega-3 fatty acid and / or omega-6 fatty acid of the composition described herein does not include diglycerides. In some embodiments of any of these aspects, the omega-3 fatty acid of the composition described herein does not include diglycerides. In some embodiments of any of these aspects, the omega-6 fatty acid of the composition described herein does not include diglycerides. In some embodiments of any of these aspects, the DHA of the composition described herein does not include diglycerides. In some embodiments of any of these aspects, the EPA of the composition described herein does not include diglycerides. In some embodiments of any of these aspects, the DHA and EPA of the composition described herein collectively do not include diglycerides. In some embodiments of any of these aspects, the ARA of the composition described herein does not include diglycerides. In some embodiments of any of these aspects, the composition described herein does not include diglycerides.

[0084] In some embodiments of any of these aspects, the ω3 fatty acids and / or ω6 fatty acids of the compositions described herein comprise, e.g., as a percentage of the total combined content of mono-, di-, and triglycerides, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or less, monoglycerides. In some embodiments of any of these aspects, the ω3 fatty acids of the compositions described herein comprise, e.g., as a percentage of the total combined content of mono-, di-, and triglycerides, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or less, monoglycerides. In some embodiments of any of these aspects, the omega-6 fatty acids of the compositions described herein, for example as a percentage of the total combined content of monoglycerides, diglycerides, and triglycerides, comprise 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or less, monoglycerides. In some embodiments of any of these aspects, the DHA of the compositions described herein, for example as a percentage of the total combined content of monoglycerides, diglycerides, and triglycerides, comprises 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or less, monoglycerides. In some embodiments of any of these aspects, the EPA of the compositions described herein contains, e.g., as a percentage of the total combined mono-, di-, and triglyceride content, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or less, or no monoglycerides.In some embodiments of any of these aspects, the DHA and EPA of the compositions described herein, collectively, for example, as a percentage of the total content of monoglycerides, diglycerides, and triglycerides, comprise 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or no monoglycerides.In some embodiments of any of these aspects, the ARA of the compositions described herein, for example, as a percentage of the total content of monoglycerides, diglycerides, and triglycerides, comprise 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or no monoglycerides. In some embodiments of any of these aspects, the total combined mono-, di-, and triglyceride content of the compositions described herein 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%, or less than monoglycerides, or no monoglycerides.

[0085] In some embodiments of any of these aspects, the ω3 fatty acid and / or ω6 fatty acid of the composition described herein comprises 10% or less monoglyceride, for example as a percentage of the total content of monoglycerides, diglycerides and triglycerides combined.In some embodiments of any of these aspects, the ω3 fatty acid of the composition described herein comprises 10% or less monoglyceride, for example as a percentage of the total content of monoglycerides, diglycerides and triglycerides combined.In some embodiments of any of these aspects, the ω6 fatty acid of the composition described herein comprises 10% or less monoglyceride, for example as a percentage of the total content of monoglycerides, diglycerides and triglycerides combined.In some embodiments of any of these aspects, the DHA of the composition described herein comprises 10% or less monoglyceride, for example as a percentage of the total content of monoglycerides, diglycerides and triglycerides combined. In some embodiments of any of these aspects, the EPA of the composition described herein comprises 10% or less monoglyceride, for example as a percentage of the total content of monoglycerides, diglycerides and triglycerides combined.In some embodiments of any of these aspects, the DHA and EPA of the composition described herein collectively comprise 10% or less monoglyceride, for example as a percentage of the total content of monoglycerides, diglycerides and triglycerides combined.In some embodiments of any of these aspects, the ARA of the composition described herein comprises 10% or less monoglyceride, for example as a percentage of the total content of monoglycerides, diglycerides and triglycerides combined.In some embodiments of any of these aspects, the total content of monoglycerides, diglycerides and triglycerides combined of the composition described herein comprises 10% or less monoglyceride.

[0086] In some embodiments of any of these aspects, the ω3 fatty acids and / or ω6 fatty acids of the compositions described herein include, or do not include, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or less of monoglycerides and diglycerides, e.g., as a percentage of the total combined content of monoglycerides, diglycerides, and triglycerides. In some embodiments of any of these aspects, the ω3 fatty acids of the compositions described herein include, or do not include, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or less of monoglycerides and diglycerides, e.g., as a percentage of the total combined content of monoglycerides, diglycerides, and triglycerides. In some embodiments of any of these aspects, the omega-6 fatty acids of the compositions described herein, for example as a percentage of the total combined content of monoglycerides, diglycerides and triglycerides, comprise 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or less, of monoglycerides and diglycerides, or do not comprise monoglycerides and diglycerides.In some embodiments of any of these aspects, the DHA of the compositions described herein, for example as a percentage of the total combined content of monoglycerides, diglycerides and triglycerides, comprise 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or less, of monoglycerides and diglycerides, or do not comprise monoglycerides and diglycerides.In some embodiments of any of these aspects, the EPA of the composition described herein comprises, for example, as a percentage of the total combined content of monoglycerides, diglycerides and triglycerides, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or less, of monoglycerides and diglycerides, or does not comprise monoglycerides and diglycerides.In some embodiments of any of these aspects, the DHA and EPA of the composition described herein comprise, for example, as a percentage of the total combined content of monoglycerides, diglycerides and triglycerides, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or less, of monoglycerides and diglycerides, or does not comprise monoglycerides and diglycerides. In some embodiments of any of these aspects, the ARA of the compositions described herein, e.g., as a percentage of the total combined mono-, di-, and triglyceride content, contains 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or less, of mono- and diglycerides. In some embodiments of any of these aspects, the total combined mono-, di-, and triglyceride content of the compositions described herein contains 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or less, of mono- and diglycerides.

[0087] In some embodiments of any of these aspects, the ω3 fatty acids and / or ω6 fatty acids of the compositions described herein comprise 10% or less of monoglycerides and diglycerides, e.g., as a percentage of the total combined content of monoglycerides, diglycerides, and triglycerides. In some embodiments of any of these aspects, the ω3 fatty acids of the compositions described herein comprise 10% or less of monoglycerides and diglycerides, e.g., as a percentage of the total combined content of monoglycerides, diglycerides, and triglycerides. In some embodiments of any of these aspects, the ω6 fatty acids of the compositions described herein comprise 10% or less of monoglycerides and diglycerides, e.g., as a percentage of the total combined content of monoglycerides, diglycerides, and triglycerides. In some embodiments of any of these aspects, the DHA of the composition described herein comprises 10% or less of monoglyceride and diglyceride, for example, as a percentage of the total content of monoglyceride, diglyceride and triglyceride combined.In some embodiments of any of these aspects, the EPA of the composition described herein comprises 10% or less of monoglyceride and diglyceride, for example, as a percentage of the total content of monoglyceride, diglyceride and triglyceride combined.In some embodiments of any of these aspects, the DHA and EPA of the composition described herein collectively comprise 10% or less of monoglyceride and diglyceride, for example, as a percentage of the total content of monoglyceride, diglyceride and triglyceride combined. In some embodiments of any of these aspects, the ARA of the compositions described herein comprises 10% or less mono- and diglycerides, e.g., as a percentage of the total combined mono-, di- and triglyceride content. In some embodiments of any of these aspects, the total combined mono-, di- and triglyceride content of the compositions described herein comprises 10% or less mono- and diglycerides.

[0088] In some embodiments of any of these aspects, the omega-3 fatty acid and / or omega-6 fatty acid of the composition described herein does not include diglycerides. In some embodiments of any of these aspects, the omega-3 fatty acid of the composition described herein does not include diglycerides. In some embodiments of any of these aspects, the omega-6 fatty acid of the composition described herein does not include diglycerides. In some embodiments of any of these aspects, the DHA of the composition described herein does not include diglycerides. In some embodiments of any of these aspects, the EPA of the composition described herein does not include diglycerides. In some embodiments of any of these aspects, the DHA and EPA of the composition described herein collectively do not include diglycerides. In some embodiments of any of these aspects, the ARA of the composition described herein does not include diglycerides. In some embodiments of any of these aspects, the composition described herein does not include diglycerides.

[0089] In one aspect of any of these embodiments, the composition and its components are not distilled or re-esterified. In one aspect of any of these embodiments, omega-6 fatty acids are not distilled or re-esterified. In one aspect of any of these embodiments, omega-3 fatty acids are not distilled or re-esterified. In one aspect of any of these embodiments, ARA is not distilled or re-esterified. In one aspect of any of these embodiments, DHA is not distilled or re-esterified. In one aspect of any of these embodiments, EPA is not distilled or re-esterified. In one aspect of any of these embodiments, DHA and EPA, taken together, are not distilled or re-esterified.

[0090] In some embodiments, the fatty acids are obtained by transesterification of oils (e.g., vegetable oils, fish oils, algae oils, or microbial oils) as described herein. In some embodiments, the fatty acids are obtained by transesterification of oils (e.g., vegetable oils, fish oils, algae oils, or microbial oils) as described herein, and a subsequent physiochemical purification process including urea fractionation followed by molecular distillation. In some embodiments, the crude fatty acids may also be subjected to a stripping step to reduce the amount of environmental pollutants and / or cholesterol prior to transesterification. In another embodiment, the fatty acids are obtained by, for example, concentrating specific fatty acids to high concentrations using supercritical CO2 extraction or chromatography techniques.

[0091] In some embodiments of any of these aspects, the compositions described herein or components thereof (e.g., omega-3 fatty acid oils and / or omega-6 fatty acid oils) have low sterol levels. As used herein, the term "sterol" refers to any of the following structures: TIFF2024545117000002.tif47128, and optionally further comprises additional functional groups or ring system modifications. In some embodiments, the sterol can be a steroid. Exemplary sterols include, but are not limited to, cholesterol, ergosterol, hydroxysteroids, phytosterols, steroids, and zoosterols.

[0092] In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 10% (w / w) or less of sterol. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 9% (w / w) or less of sterol. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 8% (w / w) or less of sterol. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 7% (w / w) or less of sterol. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 6% (w / w) or less of sterol. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 5% (w / w) or less of sterol. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 4% (w / w) or less of sterol. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 3% (w / w) or less of sterol. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 2% (w / w) or less of sterol. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 1.5% (w / w) or less of sterol.In some embodiments of any of these aspects, a composition described herein or a component thereof (e.g., an omega-3 fatty acid oil and / or an omega-6 fatty acid oil) comprises 1% (w / w) or less of sterols.

[0093] In some embodiments of any of these aspects, the compositions described herein or components thereof (e.g., omega-3 fatty acid oil and / or omega-6 fatty acid oil) have low phytosterol levels. As used herein, "phytosterol" refers to plant-derived sterols and stanols, such as phytosteroids. Non-limiting examples of phytosterols can include β-sitosterol, campesterol, stigmasterol, sitostanol, and campestanol.

[0094] In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 120 mg / L or less of phytosterols. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 110 mg / L or less of phytosterols. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 100 mg / L or less of phytosterols. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 80 mg / L or less of phytosterols. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 70 mg / L or less of phytosterols. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 60 mg / L or less of phytosterols. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 50 mg / L or less of phytosterols. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 45 mg / L or less of phytosterols. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 40 mg / L or less of phytosterols. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 35 mg / L or less of phytosterols.In some embodiments of any of these aspects, the composition described herein or its components (e.g., omega-3 fatty acid oil and / or omega-6 fatty acid oil) comprises 30 mg / L or less of phytosterols. In some embodiments of any of these aspects, the composition described herein or its components (e.g., omega-3 fatty acid oil and / or omega-6 fatty acid oil) comprises 25 mg / L or less of phytosterols. In some embodiments of any of these aspects, the composition described herein or its components (e.g., omega-3 fatty acid oil and / or omega-6 fatty acid oil) comprises 20 mg / L or less of phytosterols.

[0095] Phytosterol levels can be reduced or maintained within the thresholds described herein by various methods.For example, oils or compositions that are naturally low in phytosterols can be used.In some embodiments, high phytosterol oils can be combined with low phytosterol oils in a ratio that results in the final phytosterol content described herein.In some embodiments, phytosterols can be removed from oils, for example by purification.

[0096] In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 20 mg / L or less of stigmasterol. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 10 mg / L or less of stigmasterol. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 5 mg / L or less of stigmasterol. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 3 mg / L or less of stigmasterol. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 2 mg / L or less of stigmasterol. In some embodiments of any of these aspects, a composition described herein or a component thereof (e.g., an omega-3 fatty acid oil and / or an omega-6 fatty acid oil) contains 1 mg / L or less of stigmasterol.

[0097] In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 5% (w / w) or less of stigmasterol. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 4% (w / w) or less of stigmasterol. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 3% (w / w) or less of stigmasterol. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 2% (w / w) or less of stigmasterol. In some embodiments of any of these aspects, the composition described herein or its components (e.g., ω3 fatty acid oil and / or ω6 fatty acid oil) comprises 1% (w / w) or less of stigmasterol. In some embodiments of any of these aspects, a composition described herein or a component thereof (e.g., an omega-3 fatty acid oil and / or an omega-6 fatty acid oil) comprises 0.5% (w / w) or less of stigmasterol.

[0098] In some embodiments of any of these aspects, the composition is formulated to include ARA in a dosage of 5-150 mg / kg / day. In some embodiments of any of these aspects, the composition is formulated to include DHA and / or EPA in a dosage of 10-200 mg / kg / day. In some embodiments of any of these aspects, the composition is formulated to include DHA and / or EPA in a dosage of 10 mg / kg / day to 3 g / kg / day. In some embodiments of any of these aspects, the composition is formulated to include ARA in a dosage of 5-150 mg / kg / day and DHA and / or EPA in a dosage of 10-200 mg / kg / day. In some embodiments of any of these aspects, the composition is formulated to include ARA in a dosage of 5-150 mg / kg / day and DHA and / or EPA in a dosage of 10 mg / kg / day to 3 g / kg / day.

[0099] In some embodiments of any of these aspects, the composition is formulated to include ARA in a dosage of 10-120 mg / kg / day. In some embodiments of any of these aspects, the composition is formulated to include DHA and / or EPA in a dosage of 20-150 mg / kg / day. In some embodiments of any of these aspects, the composition is formulated to include ARA in a dosage of 10-120 mg / kg / day and / or DHA and / or EPA in a dosage of 20-150 mg / kg / day. In some embodiments of any of these aspects, the composition is formulated to include ARA in a dosage of 10-120 mg / kg / day and DHA and / or EPA in a dosage of 20-150 mg / kg / day.

[0100] In some embodiments of any of these aspects, the composition is formulated to include ARA in a dosage of 20-60 mg / kg / day. In some embodiments of any of these aspects, the composition is formulated to include DHA and / or in a dosage of 40-100 mg / kg / day. In some embodiments of any of these aspects, the composition is formulated to include ARA in a dosage of 20-60 mg / kg / day and / or DHA and / or ePA in a dosage of 40-100 mg / kg / day. In some embodiments of any of these aspects, the composition is formulated to include ARA in a dosage of 20-60 mg / kg / day and DHA and / or EPA in a dosage of 40-100 mg / kg / day.

[0101] In some embodiments of any of these aspects, the composition is formulated to include ARA in a dosage of 20-200 mg / kg / day. In some embodiments of any of these aspects, the composition is formulated to include DHA and / or in a dosage of 40-400 mg / kg / day. In some embodiments of any of these aspects, the composition is formulated to include ARA in a dosage of 20-200 mg / kg / day and / or DHA and / or ePA in a dosage of 40-400 mg / kg / day. In some embodiments of any of these aspects, the composition is formulated to include ARA in a dosage of 20-200 mg / kg / day and DHA and / or EPA in a dosage of 40-400 mg / kg / day.

[0102] In the above dosages, "kg" refers to the mass of the subject to which the composition is administered.

[0103] In some embodiments of any of these aspects, the composition is a lipid emulsion, eg, a lipid-in-water emulsion.

[0104] In some embodiments of any of these aspects, the composition (e.g., emulsion) is at least 5% oil in water. In some embodiments of any of these aspects, the composition (e.g., emulsion) is at least 10% oil in water. In some embodiments of any of these aspects, the composition (e.g., emulsion) is at least 15% oil in water. In some embodiments of any of these aspects, the composition (e.g., emulsion) is at least 20% oil in water. In some embodiments of any of these aspects, the composition (e.g., emulsion) is at least 25% oil in water. In some embodiments of any of these aspects, the composition (e.g., emulsion) is at least 30% oil in water. In some embodiments of any of these aspects, the composition (e.g., emulsion) is at least 35% oil in water. In some embodiments of any of these aspects, the composition (e.g., emulsion) is at least 40% oil in water.

[0105] In some embodiments of any of these aspects, the composition (e.g., emulsion) is about 10% to about 50% oil in water. In some embodiments of any of these aspects, the composition (e.g., emulsion) is about 10% to about 40% oil in water. In some embodiments of any of these aspects, the composition (e.g., emulsion) is about 10% to about 30% oil in water. In some embodiments of any of these aspects, the composition (e.g., emulsion) is about 20% to about 50% oil in water. In some embodiments of any of these aspects, the composition (e.g., emulsion) is about 20% to about 40% oil in water. In some embodiments of any of these aspects, the composition (e.g., emulsion) is about 25% to about 35% oil in water.

[0106] In some embodiments of any of these aspects, the composition (e.g., emulsion) is 10% to 50% oil in water. In some embodiments of any of these aspects, the composition (e.g., emulsion) is 10% to 40% oil in water. In some embodiments of any of these aspects, the composition (e.g., emulsion) is 10% to 30% oil in water. In some embodiments of any of these aspects, the composition (e.g., emulsion) is 20% to 50% oil in water. In some embodiments of any of these aspects, the composition (e.g., emulsion) is 20% to 40% oil in water. In some embodiments of any of these aspects, the composition (e.g., emulsion) is 25% to 35% oil in water.

[0107] In some embodiments of any of these aspects, the ω6 fatty acids (e.g., ARA) and ω3 fatty acids (e.g., DHA and / or EPA) described herein comprise about 5% w / v to about 50% w / v of the total amount of fat in the total volume of the composition. In some embodiments of any of these aspects, the ω6 fatty acids (e.g., ARA) and ω3 fatty acids (e.g., DHA and / or EPA) described herein comprise about 15% w / v to about 25% w / v of the total amount of fat in the total volume of the composition. In some embodiments of any of these aspects, the ω6 fatty acids (e.g., ARA) and ω3 fatty acids (e.g., DHA and / or EPA) described herein comprise about 5% w / v to about 50% w / v of the total amount of fat in the total volume of the composition. In some embodiments of any of these aspects, the ω6 fatty acids (e.g., ARA) and ω3 fatty acids (e.g., DHA and / or EPA) described herein comprise about 20% w / v of the total amount of fat in the total volume of the composition. In some embodiments of any of these aspects, the ω6 fatty acids (e.g., ARA) and ω3 fatty acids (e.g., DHA and / or EPA) described herein comprise 5% w / v to 50% w / v of the total amount of fat in the total volume of the composition. In some embodiments of any of these aspects, the ω6 fatty acids (e.g., ARA) and ω3 fatty acids (e.g., DHA and / or EPA) described herein comprise 15% w / v to 25% w / v of the total amount of fat in the total volume of the composition. In some embodiments of any of these aspects, the ω6 fatty acids (e.g., ARA) and ω3 fatty acids (e.g., DHA and / or EPA) described herein comprise 5% w / v to 50% w / v of the total amount of fat in the total volume of the composition. In some embodiments of any of these aspects, the ω6 fatty acids (e.g., ARA) and ω3 fatty acids (e.g., DHA and / or EPA) described herein comprise 20% w / v of the total amount of fat in the total volume of the composition.

[0108] The compositions described herein, such as emulsions, can be administered, for example, orally, parenterally, or intravenously.In some embodiments of any of these aspects, the compositions described herein, such as emulsions, are formulated for oral administration.In some embodiments of any of these aspects, the compositions described herein, such as emulsions, are formulated for parenteral and / or intravenous administration.

[0109] In some embodiments of any of these aspects, the compositions described herein can be prepared by first emulsifying each component as a separate emulsion and then mixing or combining these emulsions together, for example by emulsifying an omega-3 fatty acid oil source (e.g., fish oil or algal oil) and emulsifying an omega-6 fatty acid oil source (e.g., vegetable oil or fungal oil) and then mixing or combining these two emulsions together to produce the final combined emulsion in combination with the foregoing.

[0110] In some embodiments of any of these aspects, each emulsion can be formulated individually by high pressure homogenization as follows: First, a lipid dispersion is made under high shear mixing conditions with egg phospholipid emulsifier added to heated (75-90°C) USP grade sterile water for injection (SWFI). The temperature is reduced to 40-45°C. Sodium oleate is then added and shear mixing is continued for 40 minutes at 3900-4000 RPM. Heated SWFI is then added in stages to maintain the temperature at 40-45°C. With continued shear mixing, glycerin is added. This results in a dispersion composed of 12% egg phospholipids, 25% glycerin, and 0.3% sodium oleate. The crude dispersion is then transferred to a homogenizer and homogenized at 40-45°C and 9000 psi for 20 cycles, filtered through a 0.45 μm membrane, and the pH is adjusted to 10.4 with 0.5 N sodium hydroxide (NaOH). All steps are performed under a nitrogen atmosphere. To create the emulsion, oil (e.g., omega-3 or omega-6 oil) is added in a thin stream to the dispersion under continuous shear mixing conditions at 3500-4500 RPM for 40-45 minutes while maintaining a temperature of 40-45°C. The resulting crude emulsion is transferred to a homogenizer and the emulsion is homogenized at 40-45°C and 5000 psi for 9 or more cycles. The pH of the emulsion is buffered to above 8.8 with 0.1 N NaOH. All steps of the creation process are performed under a nitrogen atmosphere. The completed emulsions were aliquoted into glass serum vials and sealed after filling the head space with nitrogen gas. All vials were heat sterilized. This allows optimal homogenization of each oil type and improves compliance with the United States Pharmacopeia (USP) Chapter 729 requirement that parenteral fat emulsions have a fat droplet mean size less than 500 nm and a percentage of fat droplets greater than 5 μm (PFAT5) of 0.05% or less.

[0111] In some embodiments of any of these aspects, the emulsions described herein can be a mixture of two or more emulsions. This approach can have the advantage of allowing additional components to be easily added to the mixture after the initial emulsification of the lipids. As a non-limiting example, a 50:50 blend of omega-3 and omega-6 oils can be further supplemented with, for example, additional oil emulsions, triglycerides, DHA, EPA, ARA, or other lipids as needed to address the patient's unique condition at the time of administration rather than at the time of manufacture. This allows the prescriber more flexibility in dosing the oil blend to address the patient's unique condition and reduces the prescriber's need to maintain a large number of emulsion combinations.

[0112] In some embodiments of any of these aspects, the compositions described herein can be prepared by first mixing the components together and then preparing an emulsion of the mixture, for example, by mixing an omega-3 oil and an omega-6 oil and then emulsifying the mixture. In some embodiments of any of these aspects, the emulsions described herein can be emulsions of a mixture of lipid preparations.

[0113] To prepare an emulsion according to the present invention, one or more emulsifying agents can be mixed with, for example, a source of omega-3 oil, omega-6 oil, ARA, EPA, or DHA.Usually, the emulsifying agent for this purpose is a phospholipid of natural, synthetic, or semi-synthetic origin.Various suitable emulsifying agents are known in the art.Examples of suitable emulsifying agents include, but are not limited to, egg phosphatidylcholine, egg lecithin, L-α-dipalmitoylphosphatidylcholine (DPPC), DL-α-dipalmitoylphosphatidylethanolamine (DPPE), and dioleoylphosphatidylcholine (DOPC).According to the present invention, the total concentration of diglycerides and monoglycerides and free fatty acids in the emulsifier should be low to minimize their contribution to the total oil concentration of the emulsion.In one embodiment of the present invention, the total concentration of triglycerides and free fatty acids in the emulsifier is less than about 3.5%. In some embodiments of any of these aspects, lecithin is used as an emulsifying agent in lipid emulsions. Alternatively, egg lecithin can be used as an emulsifying agent. Egg lecithin containing 80-85% phosphatidylcholine and less than about 3.5% fat can also be used as an emulsifying agent. Those skilled in the art will appreciate that other components can be present in egg lecithin without adversely affecting the emulsifying properties. For example, egg lecithin can include one or more of phosphatidylethanolamine, lysophosphatidylcholine, lysophosphatidylethanolamine, sphingomyelin, and other natural components.

[0114] In some embodiments of any of these aspects, the emulsions described herein comprise between about 0.5% and about 5% (w / v) emulsifying agent. In some embodiments of any of these aspects, the emulsions described herein comprise between about 0.6% and about 2% (w / v) emulsifying agent. In some embodiments of any of these aspects, the emulsions described herein comprise between about 0.8% and about 1.8% (w / v) emulsifying agent. In some embodiments of any of these aspects, the emulsions described herein comprise between about 1.0% and about 1.5% (w / v) emulsifying agent. In some embodiments of any of these aspects, the emulsions described herein comprise about 1.2% (w / v) emulsifying agent.

[0115] The ratio of lecithin to oil in an emulsion is important in determining the size of the oil droplets formed within the emulsion. In some embodiments of any of these aspects, the ratio of lecithin to oil is between about 1:4 and about 1:20. In some embodiments of any of these aspects, the ratio is between about 1:4 and about 1:18. In some embodiments of any of these aspects, the ratio is between about 1:4 and about 1:15. In some embodiments of any of these aspects, the ratio is between about 1:4 and about 1:10.

[0116] The compositions, e.g., lipid emulsions, according to the present invention may further comprise additional components that improve the stability, homogeneity, and / or other properties of the composition (e.g., emulsion), such as antioxidants, chelating agents, osmolality adjusting agents, buffering agents, and neutralizing agents. Suitable antioxidants that can be added to lipid emulsions include, but are not limited to, α-tocopherol (vitamin E) and tocotrienol. As is known in the art, tocotrienol is a natural blend of tocotrienol and vitamin E extract concentrated from rice bran oil distillate. Tocotrienol has a similar structure to vitamin E and contains three double bonds in the carbon side chain of the molecule. In some embodiments of any of these aspects, the concentration of antioxidant added to the composition (e.g., emulsion) is typically between about 0.002 and about 1.0% (w / v). In some embodiments of any of these aspects, the concentration of the antioxidant used in the composition (e.g., emulsion) is between about 0.02% and about 0.5% (w / v). In some embodiments of any of these aspects, tocotrienol is added to the composition (e.g., emulsion) as an antioxidant. In some embodiments of any of these aspects, about 0.5% (w / v) tocotrienol is added to the composition (e.g., emulsion). In some embodiments of any of these aspects, vitamin E is added to the composition (e.g., emulsion) as an antioxidant. In some embodiments of any of these aspects, about 0.02% (w / v) vitamin E is added to the composition (e.g., emulsion).

[0117] In some embodiments of any of these aspects, α-tocopherol is present in the emulsion at a level of at least 50 mg / L. In some embodiments of any of these aspects, α-tocopherol is present in the emulsion at a level of at least 75 mg / L. In some embodiments of any of these aspects, α-tocopherol is present in the emulsion at a level of at least 100 mg / L. In some embodiments of any of these aspects, α-tocopherol is present in the emulsion at a level of at least 120 mg / L. In some embodiments of any of these aspects, α-tocopherol is present in the emulsion at a level of at least 150 mg / L. In some embodiments of any of these aspects, α-tocopherol is present in the emulsion at a level of at least 200 mg / L.

[0118] The composition (e.g., emulsion) can further include a chelating agent to improve the stability of the composition (e.g., emulsion) and reduce the formation of oxidized fatty acids. Suitable chelating agents are known in the art and are generally recognized as safe (GRAS) compounds. Examples include, but are not limited to, EDTA. In some embodiments of any of these aspects, the composition (e.g., emulsion) includes EDTA. In some embodiments of any of these aspects, the composition (e.g., emulsion) includes about 1×10 -6 M~5×10 -5 Contains EDTA at a concentration between M.

[0119] Osmolality adjusting agents can also be incorporated into the composition (e.g., emulsion) to adjust the osmolality of the composition (e.g., emulsion) to a value suitable for parenteral administration. The amount and type of osmolality adjusting agents for use in parenteral emulsions are well known in the art. An example of a suitable osmolality adjusting agent is glycerol. Typically, the concentration of the osmolality adjusting agent ranges from about 2% to about 5% (w / v). In some embodiments of any of these aspects, the amount of osmolality adjusting agent added to the composition (e.g., emulsion) is between about 2% to about 4%. In some embodiments of any of these aspects, the amount of osmolality adjusting agent added to the composition (e.g., emulsion) is between about 2% to about 3%. In some embodiments of any of these aspects, about 2.25% (w / v) glycerol is added to the composition (e.g., emulsion) as an osmolality adjusting agent. In some embodiments of any of these aspects, the final product is isotonic to allow for injection of the composition (eg, an emulsion) via either a central or peripheral venous catheter.

[0120] The pH of the composition (e.g., emulsion) can be adjusted using a buffer or neutralizing agent. It has been shown that emulsions with pH values ​​close to or above physiological pH are less prone to fatty acid peroxidation. Those skilled in the art will understand that the pH of the composition (e.g., emulsion) can be adjusted using a suitable base that neutralizes the negative charge of fatty acids, using a suitable buffer, or by a combination thereof. A variety of bases and buffers are suitable for use with the compositions (e.g., emulsions) of the present invention. Those skilled in the art will understand that the addition of a buffer to a composition (e.g., emulsion) affects not only the final pH of the composition (e.g., emulsion) but also the ionic strength. High ionic strength can adversely affect the zeta potential (i.e., the surface charge of the oil droplets) of the composition (e.g., emulsion) and is therefore undesirable. The selection of an appropriate buffer strength to provide an appropriate pH is considered to be within the ordinary skill of a researcher in the art. In some embodiments of any of these aspects, the pH of the composition (e.g., emulsion) is adjusted using sodium hydroxide. In some embodiments of any of these aspects, the pH is adjusted using a buffering agent. In some embodiments of any of these aspects, the buffering agent is a phosphate buffer. In some embodiments of any of these aspects, both sodium hydroxide and a phosphate buffer are added to the composition (e.g., emulsion). In some embodiments of any of these aspects, the final pH of the composition (e.g., emulsion) is between about 6.0 and about 9.0. In some embodiments of any of these aspects, the pH of the composition (e.g., emulsion) is between about 7.0 and about 8.5. In some embodiments of any of these aspects, the pH of the emulsion is between about 7.0 and about 8.0.

[0121] In some embodiments of any of these aspects, the lipid emulsion can further comprise a component for adjusting the stability of the composition (e.g., emulsion), such as amino acids or carbohydrates, such as fructose, glucose, or dextrose.The lipid emulsion can also be formulated to include nutrients, such as glucose or dextrose, amino acids, vitamins, or other parenteral nutritional supplements.It is also considered within the scope of the present invention to formulate the lipid emulsion to incorporate a therapeutic agent.As used herein, "therapeutic agent" refers to a physiologically or pharmacologically active substance that produces one or more local or systemic effects in animals, and generally refers to drugs, nutritional supplements, vitamins, minerals, enzymes, hormones, proteins, polypeptides, antigens, and other compounds useful for treatment or diagnosis.

[0122] In some embodiments of any of these aspects, the composition (e.g., emulsion) can further comprise an additive that is one or more additional fatty acids or a mixture thereof. In some embodiments of any of these aspects, the methods described herein can further comprise administering an additive that is one or more additional fatty acids or a mixture thereof. The additive can comprise one or more fatty acids that are therapeutic for a disease, e.g., a disease for which the subject is in need of treatment. For example, DHA can be therapeutic for cystic fibrosis patients, and an additive for a cystic fibrosis subject can comprise DHA, e.g., in an amount greater than that required for nutritional balance. In some embodiments of any of these aspects, the additive comprises a fatty acid in a ratio or combination that is therapeutic. In some embodiments of any of these aspects, the additive is provided in a dose of nanograms to grams / kg / day. In some embodiments of any of these aspects, the additive is provided in a dose of 1 nanogram to 10 grams / kg / day. In some embodiments of any of these aspects, the additive is provided in a dose of 1 nanogram to 100 grams / kg / day. In some embodiments of any of these aspects, the additive is given in a dosage of 1 nanogram to 1000 grams / kg / day.

[0123] In some embodiments of any of these aspects, the composition further comprises one or more of medium chain triglycerides (MCT), egg lecithin, sunflower seed oil, sunflower lecithin, emulsifier obtained from sunflower seeds, and krill oil / krill lecithin.Sunflower lecithin is an emulsifier known for its higher phosphatidylcholine content, and is commercially available, for example, from Lipoid.Krill oil or krill lecithin is self-emulsifying due to its high phospholipid content.

[0124] As used herein, "medium chain triglyceride" or "MCT" refers to a triglyceride having fatty acids with a chain of 6 to 12 carbon atoms. Triglycerides ("TG") (also known as triacylglycerols or triacylglycerides) are glycerides in which glycerol is esterified with three fatty acids. MCTs can include fatty acids selected from, for example, caprylic acid, capric acid, lauric acid, and caproic acid. MCTs can be derived from plants, such as fruits or vegetables, for example, from multiple plants. A description of MCTs for use in this disclosure can meet, for example, the requirements of EP Monograph 0868, entitled "Triglycerides, Medium Chain" (Triglycerida saturate media), which is incorporated herein by reference in its entirety. In some embodiments of any of these aspects, the MCTs include omega-9 fatty acids and / or saturated fatty acids.

[0125] In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can further include α-tocopherol. As used herein, "α-tocopherol" refers to a form of vitamin E, in any of its stereoisomers, having the structure of Formula I: TIFF2024545117000003.tif27128.

[0126] In some embodiments of any of these aspects, α-tocopherol is present in the composition (e.g., emulsion) at a level of at least 50 mg / L. In some embodiments of any of these aspects, α-tocopherol is present in the composition (e.g., emulsion) at a level of at least 75 mg / L. In some embodiments of any of these aspects, α-tocopherol is present in the composition (e.g., emulsion) at a level of at least 100 mg / L. In some embodiments of any of these aspects, α-tocopherol is present in the composition (e.g., emulsion) at a level of at least 120 mg / L. In some embodiments of any of these aspects, α-tocopherol is present in the composition (e.g., emulsion) at a level of at least 150 mg / L. In some embodiments of any of these aspects, α-tocopherol is present in the composition (e.g., emulsion) at a level of at least 200 mg / L.

[0127] In some embodiments of any of these aspects, the composition (e.g., emulsion) comprises α-tocopherol and other forms of vitamin E (e.g., β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, and / or δ-tocotrienol) in a weight ratio of at least 2:1. In some embodiments of any of these aspects, the composition (e.g., emulsion) comprises α-tocopherol and other forms of vitamin E in a weight ratio of at least 3:1. In some embodiments of any of these aspects, the composition (e.g., emulsion) comprises α-tocopherol and other forms of vitamin E in a weight ratio of at least 5:1. In some embodiments of any of these aspects, the composition (e.g., emulsion) comprises α-tocopherol and other forms of vitamin E in a weight ratio of at least 10:1. In some embodiments of any of these aspects, the composition (e.g., emulsion) does not comprise forms of vitamin E other than α-tocopherol.

[0128] In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can comprise one or more ω6 fatty acids including at least arachidonic acid (ARA) and one or more ω3 fatty acids including at least docosahexaenoic acid (DHA) and / or EPA. In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can consist essentially of one or more ω6 fatty acids including at least arachidonic acid (ARA) and one or more ω3 fatty acids including at least docosahexaenoic acid (DHA) and / or EPA. In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can consist of one or more ω6 fatty acids including at least arachidonic acid (ARA) and one or more ω3 fatty acids including at least docosahexaenoic acid (DHA) and / or EPA.

[0129] In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can comprise one or more ω6 fatty acids, including at least arachidonic acid (ARA), and one or more ω3 fatty acids, including at least docosahexaenoic acid (DHA). In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can consist essentially of one or more ω6 fatty acids, including at least arachidonic acid (ARA), and one or more ω3 fatty acids, including at least docosahexaenoic acid (DHA). In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can consist of one or more ω6 fatty acids, including at least arachidonic acid (ARA), and one or more ω3 fatty acids, including at least docosahexaenoic acid (DHA).

[0130] In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can comprise one or more ω6 fatty acids including at least arachidonic acid (ARA) and one or more ω3 fatty acids including at least EPA. In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can consist essentially of one or more ω6 fatty acids including at least arachidonic acid (ARA) and one or more ω3 fatty acids including at least EPA. In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can consist of one or more ω6 fatty acids including at least arachidonic acid (ARA) and one or more ω3 fatty acids including at least EPA.

[0131] In some embodiments of any of these aspects, the ω6 fatty acids comprise ARA. In some embodiments of any of these aspects, the ω6 fatty acids consist essentially of ARA. In some embodiments of any of these aspects, the ω3 fatty acids comprise DHA and EPA. In some embodiments of any of these aspects, the ω3 fatty acids consist essentially of DHA and EPA. In some embodiments of any of these aspects, the ω3 fatty acids consist of DHA and EPA. In some embodiments of any of these aspects, the ω3 fatty acids comprise DHA. In some embodiments of any of these aspects, the ω3 fatty acids consist essentially of DHA. In some embodiments of any of these aspects, the ω3 fatty acids consist of DHA. In some embodiments of any of these aspects, the ω3 fatty acids comprise EPA. In some embodiments of any of these aspects, the ω3 fatty acids consist essentially of EPA. In some embodiments of any of these aspects, the ω3 fatty acids consist of EPA.

[0132] In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can include (a) one or more omega-6 fatty acids including at least arachidonic acid (ARA), (b) one or more omega-3 fatty acids including at least docosahexaenoic acid (DHA) and / or EPA, and (c) an emulsifier (e.g., phospholipids and / or egg phospholipids). In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can consist essentially of (a) one or more omega-6 fatty acids including at least arachidonic acid (ARA), (b) one or more omega-3 fatty acids including at least docosahexaenoic acid (DHA) and / or EPA, and (c) an emulsifier (e.g., phospholipids and / or egg phospholipids). In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can consist of (a) one or more omega-6 fatty acids including at least arachidonic acid (ARA); (b) one or more omega-3 fatty acids including at least docosahexaenoic acid (DHA) and / or EPA; and (c) an emulsifier (e.g., phospholipids and / or egg phospholipids).

[0133] In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can include (a) one or more ω6 fatty acids including at least arachidonic acid (ARA), (b) one or more ω3 fatty acids including at least docosahexaenoic acid (DHA) and / or EPA, and (c) one or more emulsifiers (e.g., phospholipids and / or egg phospholipids), glycerin, and sodium oleate. In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can consist essentially of (a) one or more ω6 fatty acids including at least arachidonic acid (ARA), (b) one or more ω3 fatty acids including at least docosahexaenoic acid (DHA) and / or EPA, and (c) one or more emulsifiers (e.g., phospholipids and / or egg phospholipids), glycerin, and sodium oleate. In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can consist of (a) one or more omega-6 fatty acids including at least arachidonic acid (ARA); (b) one or more omega-3 fatty acids including at least docosahexaenoic acid (DHA) and / or EPA; and (c) one or more of an emulsifier (e.g., phospholipids and / or egg phospholipids), glycerin, and sodium oleate.

[0134] In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can include (a) one or more ω6 fatty acids including at least arachidonic acid (ARA), (b) one or more ω3 fatty acids including at least docosahexaenoic acid (DHA) and / or EPA, and (c) water. In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can consist essentially of (a) one or more ω6 fatty acids including at least arachidonic acid (ARA), (b) one or more ω3 fatty acids including at least docosahexaenoic acid (DHA) and / or EPA, and (c) water. In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can consist essentially of (a) one or more ω6 fatty acids including at least arachidonic acid (ARA), (b) one or more ω3 fatty acids including at least docosahexaenoic acid (DHA) and / or EPA, and (c) water.

[0135] In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can include (a) one or more ω6 fatty acids including at least arachidonic acid (ARA), (b) one or more ω3 fatty acids including at least docosahexaenoic acid (DHA) and / or EPA, (c) water, and (d) one or more emulsifiers (e.g., phospholipids and / or egg phospholipids), glycerin, and sodium oleate. In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can consist essentially of (a) one or more ω6 fatty acids including at least arachidonic acid (ARA), (b) one or more ω3 fatty acids including at least docosahexaenoic acid (DHA) and / or EPA, (c) water, and (d) one or more emulsifiers (e.g., phospholipids and / or egg phospholipids), glycerin, and sodium oleate. In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can consist of (a) one or more omega-6 fatty acids including at least arachidonic acid (ARA); (b) one or more omega-3 fatty acids including at least docosahexaenoic acid (DHA) and / or EPA; (c) water; and (d) one or more of an emulsifier (e.g., phospholipids and / or egg phospholipids), glycerin, and sodium oleate.

[0136] In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can further include one or more of an emulsifier (e.g., phospholipids and / or egg phospholipids), glycerin, and sodium oleate. In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can include 0.5-2.5% egg phospholipids, 0.5-5.0% glycerin, and 0.005-0.1% sodium oleate.

[0137] In one aspect, a kit is described herein that includes a composition described herein, such as a composition (e.g., an emulsion) described herein. A kit is any article of manufacture (e.g., a package or container) that includes at least one reagent, such as a composition (e.g., an emulsion), that is promoted, distributed, or sold as a unit for carrying out a method described herein. A kit described herein can optionally include additional components useful for carrying out a method described herein, such as needles, tubes, etc., useful for administration by a desired route. By way of example, a kit can include fluids (e.g., buffers) suitable for use with a composition described herein (e.g., an emulsion), and instructional materials, etc., that describe carrying out a method described herein. A kit can also further include an apparatus and / or reagents for delivering a composition described herein. Additionally, a kit can include an instruction leaflet and / or provide information regarding dosage, frequency of administration, etc.

[0138] The kit of the present invention includes one or more packages or containers that contain the composition (e.g., emulsion) together with a set of instructions, usually written instructions, regarding the use and dosage of the composition (e.g., emulsion). The kit may further include additional containers that contain one or more nutrients or therapeutic or diagnostic compounds that can be added to the composition (e.g., emulsion) prior to administration. The package containing the composition (e.g., emulsion) may be in the form of a unit dose or pharmaceutical bulk package. The doses may be packaged in such a manner that each dose is associated, for example, with a day of the week. The kit may be accompanied by a notice in a format prescribed by a governmental agency that regulates the manufacture, use, or sale of biological products, indicating that the product has been approved by that agency for manufacture, use, or sale for human or animal administration.

[0139] The design of the container is also an important factor in producing fat emulsions. For example, if the composition (e.g., emulsion) is packaged in glass, the container can be filled with nitrogen before adding the actual emulsion. After the composition (e.g., emulsion) is added, the glass container can be filled with nitrogen again to eliminate dead space during capping. Such nitrogen filling prevents peroxide formation. If the product is packaged in plastic, a gas-tight, DEHP-free container can be used. The container can also have a suitable overwrap to minimize peroxide formation in the lipid as well as the seepage of plasticizers from the container into the product itself. Additionally, if plastic is used, a desiccant can also be included in the bag along with an indicator to indicate if there is an air leak in the overwrap. In some embodiments of any of these aspects, the container can be latex-free.

[0140] In some embodiments, the kit comprises a bag, bottle, or syringe containing the composition described herein. In some embodiments of any of these aspects, the composition is formulated for parenteral administration and is one or more of sterile, free of visible particulate matter, and free of endotoxins. In some embodiments of any of these aspects, the composition is formulated for oral administration. In some embodiments of any of these aspects, the kit comprises an infant formula in admixture or blend with the composition described herein, for example for use by parents and caregivers. In some embodiments of any of these aspects, the kit comprises an infant formula in admixture or blend with the composition described herein, for example for use in non-therapeutic methods.

[0141] In some embodiments of any of these aspects, the kit includes a container containing a composition described herein and an administration device. The administration device allows a user to measure or dispense a predetermined dose. Exemplary, but non-limiting, administration devices may include measuring cups, syringes, containers containing only single doses, spoons, and the like. In some embodiments of any of these aspects, the administration device is sized to provide a dose of 5 g or less fatty acid / kg / day. In some embodiments of any of these aspects, the administration device is sized to provide a dose of 4 g or less fatty acid / kg / day. In some embodiments of any of these aspects, the administration device is sized to provide a dose of 3 g or less fatty acid / kg / day. In some embodiments of any of these aspects, the administration device is sized to provide a dose of 5 cc / day or less. In some embodiments of any of these aspects, the administration device is sized to provide a dose of 4 cc / day or less. In some embodiments of any of these aspects, the administration device is sized to provide a dose of 3 cc / day or less.

[0142] In one aspect of any of these embodiments, a method is described herein that comprises administering to a subject in need thereof a formulation (e.g., composition or emulsion) as described herein.The subject in need of the formulation described herein can be a subject in need of supplemental nutrition (either orally or parenterally), a subject in need of parenteral nutrition, or a subject in need of total parenteral nutrition.Those skilled in the art can easily identify subjects in need of the formulation described herein, for example, subjects receiving parenteral nutrition, including those who manifest symptoms that are interpreted as indicators that traditional PN or TPN should be reduced or discontinued due to risk of side effects (including liver disease). Such subjects and their symptoms are described in detail, for example, in Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (ASPEN), Taylor et al. (available on the world wide web at journals.lww.com / ccmjournal / Fulltext / 2016 / 02000 / Guidelines_for_the_Provision_and_Assessment_of.20.aspx), which is incorporated herein by reference in its entirety.

[0143] The compositions described herein can be utilized in at least two ways for two different purposes. In the first approach, the compositions provided herein are administered parenterally (e.g., by total parenteral nutrition) as nutrition to provide fatty acids for growth and development. This approach is particularly applicable to premature infants, most particularly infants born at or before 34 weeks of gestation, whose digestive system has not yet fully developed to allow for total enteral nutrition. In the second approach, the compositions provided herein are administered as supplements (e.g., via central or peripheral venous catheters, subcutaneous injection, or enteral administration) to provide the additional fatty acid requirement for growth and development. In this second approach, the compositions can provide more DHA / ARA than is available in or can be digested from other lipid emulsions or enteral human milk or infant formulas.

[0144] In one aspect of any of these embodiments, the present invention provides a method for providing nutrition to a subject and / or promoting the neurodevelopment in a subject, comprising administering to the subject the composition described herein.In some embodiments of any of these aspects, the neurodevelopment is the neurodevelopment in the brain and / or eye.

[0145] In some embodiments of any of these aspects, administering treats, prevents, or reduces the risk of one or more conditions selected from the group consisting of retinopathy, bronchopulmonary dysplasia, and perinatal sepsis.In one aspect of any of these aspects, described herein is a method for treating, prevents, or reduces the risk of one or more conditions selected from the group consisting of retinopathy, bronchopulmonary dysplasia, and perinatal sepsis, comprising administering to subject the composition described herein.In some embodiments of any of these aspects, the subject treated according to the method described herein has, is diagnosed with, or is at risk of having retinopathy, bronchopulmonary dysplasia, or perinatal sepsis.

[0146] In some embodiments of any of these aspects, the patient to whom the composition (e.g., emulsion) described herein is administered is an individual having an inflammatory disease, such as a pulmonary artery disease (PAD), pulmonary edema, ... The subject may be in need of treatment for a condition selected from the group consisting of: a pleural effusion state, an alveolar condition, inflammatory bowel disease, regional enteritis, ulcerative colitis, severe or debilitating arthritis, arthritis, psoriasis, severe psoriasis, burns, third degree burns, pancreatitis, acute pancreatitis, liver disease associated with intestinal failure (IFALD), cholestasis associated with parenteral nutrition (PNAC), essential fatty acid deficiency (EFAD), a parenteral nutrition dependent state complicated by soy allergy, local anesthetic toxicity, a state for the treatment of systemic toxicities, a state requiring a vehicle or excipient for parenteral therapeutics, or an allergy to lipid emulsions comprising ingredients other than MCT and fish oil and / or omega-3 fatty acids.In some embodiments of any of these aspects, the patient to whom the composition (e.g., emulsion) described herein is administered is an individual having an inflammatory disease, such as fatty liver, intestinal failure, parenteral nutrition associated liver disease (PNALD), sepsis, cystic fibrosis, sickle cell anemia, pancreatitis, inflammatory bowel disease, Crohn's disease, biliary atresia, primary sclerosing cholangitis, inflammatory infection, inflammatory condition, systemic inflammatory response syndrome (SIRS), hypertriglyceridemia, severe hypertriglyceridemia, severe fatty liver, retinopathy of prematurity, acute tubular necrosis, IgA nephropathy, ischemia-reperfusion injury, traumatic brain injury, multiple organ failure, respiratory distress syndrome, acute myocardial infarction, myocardial infarction, angina pectoris, The subject may be a subject having or diagnosed as having a condition selected from the group consisting of chronic asthmatic conditions, status asthmaticus, status epilepticus, follicular conditions, inflammatory bowel disease, regional enteritis, ulcerative colitis, severe or debilitating arthritis, arthritis, psoriasis, severe psoriasis, burns, third degree burns, pancreatitis, acute pancreatitis, liver disease associated with intestinal failure (IFALD), cholestasis associated with parenteral nutrition (PNAC), essential fatty acid deficiency (EFAD), parenteral nutrition dependent conditions complicated by soy allergy, local anesthetic poisoning, conditions for treatment of systemic toxicosis, or conditions requiring a parenteral therapeutic vehicle or excipient.

[0147] In some embodiments of any of these aspects, the subject receiving the composition (e.g., emulsion) described herein has or requires treatment for liver disease, such as fatty liver disease. As used herein, "fatty liver disease" refers to a disease in which fat (hepatocytes) accumulates excessively in the liver, which can lead to severe diseases such as chronic hepatitis and cirrhosis. In patients with fatty liver disease, lipids, particularly triglycerides, accumulate in liver cells to an extent that the amount exceeds the physiologically acceptable range. From a biochemical point of view, the criterion for determining fatty liver is that the weight of triglycerides is about 10% (100 mg / g wet weight) or more of the wet weight of liver tissue. Usually, fatty liver disease is detected by observing an increase in serum levels of liver-specific enzymes such as aminotransferases ALT and AST, which are indicative of hepatocyte damage, and based on the presentation of symptoms including fatigue and pain in the liver area, but in many cases, a definitive diagnosis requires a biopsy.

[0148] In some embodiments of any of these aspects, the subject who receives the composition (e.g., emulsion) described herein has or needs treatment for PN-related or PN-induced liver disease. The disease includes both biochemical changes, i.e., elevated serum aminotransferases, bilirubin, and alkaline phosphatase, and histological changes, e.g., steatosis, steatohepatitis, lipidosis, cholestasis, fibrosis, and cirrhosis. The disease may be progressive and worsen with the course of PN administration, and appears to be more prevalent in the pediatric population. Additional risk factors for this condition include premature birth, low birth weight, prolonged use, concurrent lack of oral intake, sepsis, and multiple surgical procedures. Overall, the severity of PN-induced liver lesions is believed to be inversely related to the age of the patient.

[0149] In some embodiments of any of these aspects, the compositions (eg, emulsions) described herein are administered parenterally or intravenously.

[0150] In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein are administered by parenteral administration (PN). In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein are administered by total parenteral administration (TPN). In some embodiments of any of these aspects, the subject who receives the compositions (e.g., emulsions) described herein is in need of parenteral administration (PN). In some embodiments of any of these aspects, the subject who receives the compositions (e.g., emulsions) described herein is in need of total parenteral administration (TPN). Methods of administering lipid emulsions to patients for PN use or therapeutic benefit are known in the art. Typically, the compositions (e.g., emulsions) are administered by infusion for an appropriate period of time. Appropriate dosages and administration; treatment regimes can be easily determined by those skilled in the clinical field.

[0151] In some embodiments of any of these aspects, a subject receiving a composition (e.g., an emulsion) described herein for PN or TPN is not administered and / or permitted to receive any oral nutrition during the treatment period (e.g., the period of several days or weeks during which they are administered the composition (e.g., the emulsion). In some embodiments of any of these aspects, a subject receiving a composition (e.g., an emulsion) described herein for PN or TPN is not administered and / or permitted to receive any oral nutrition that includes fats and / or fatty acids during the treatment period (e.g., the period of several days or weeks during which they are administered the composition (e.g., the emulsion).

[0152] In some embodiments of any of these aspects, subjects receiving a composition (e.g., an emulsion) described herein for PN or TPN do not receive any other parenteral formulation during the treatment period during which they are receiving the composition (e.g., an emulsion) (e.g., the period of days or weeks during which they are receiving the composition (e.g., an emulsion)). In some embodiments of any of these aspects, subjects receiving a composition (e.g., an emulsion) described herein for PN or TPN do not receive any other parenteral formulation that includes fats and / or fatty acids during the treatment period during which they are receiving the composition (e.g., an emulsion) (e.g., the period of days or weeks during which they are receiving the composition (e.g., an emulsion).

[0153] In some embodiments of any of these aspects, subjects administered a composition (e.g., an emulsion) described herein are not administered and / or allowed any other nutritional sources of fat and / or fatty acids during the treatment period during which they are administered the composition (e.g., an emulsion) (e.g., the period of several days or weeks during which they are administered the composition (e.g., an emulsion)).

[0154] In some embodiments of any of these aspects, a subject receiving a composition (e.g., an emulsion) described herein is not administered and / or allowed any other nutritional source of essential fatty acids during the treatment period during which they are administered the composition (e.g., an emulsion) (e.g., a period of several days or weeks during which they are administered the composition (e.g., an emulsion)). In some embodiments of any of these aspects, a subject receiving a composition (e.g., an emulsion) described herein is not administered and / or allowed any other oral nutritional source of essential fatty acids during the treatment period during which they are administered the composition (e.g., an emulsion) (e.g., a period of several days or weeks during which they are administered the composition (e.g., an emulsion). In some embodiments of any of these aspects, a subject receiving a composition (e.g., an emulsion) described herein is not administered and / or allowed any other parenteral nutritional source of essential fatty acids during the treatment period during which they are administered the composition (e.g., an emulsion) (e.g., a period of several days or weeks during which they are administered the composition (e.g., an emulsion).

[0155] In some embodiments of any of these aspects, the composition (e.g., emulsion) described herein is orally administered. In some embodiments of any of these aspects, the subject who is administered the composition (e.g., emulsion) described herein is in need of oral nutrition. Methods for orally administering lipid emulsion to patients are known in the art. Oral administration of the emulsified form of the composition described herein is particularly advantageous, since it can improve absorption in the digestive system.

[0156] In some embodiments of any of these aspects, subjects receiving a composition (e.g., an emulsion) described herein are not administered and / or allowed any other nutritional sources that would be sufficient to maintain nutritional balance during the treatment period (e.g., the period of days or weeks during which they are receiving the composition (e.g., an emulsion)) during which they are receiving the composition (e.g., an emulsion). In some embodiments of any of these aspects, subjects receiving a composition (e.g., an emulsion) described herein are not administered and / or allowed any other oral / enteral nutritional sources that would be sufficient to maintain nutritional balance during the treatment period (e.g., the period of days or weeks during which they are receiving the composition (e.g., an emulsion). In some embodiments of any of these aspects, subjects receiving a composition (e.g., emulsion) described herein are not administered and / or allowed any other parenteral nutritional source that would be sufficient to maintain nutritional balance during the treatment period during which they receive the composition (e.g., emulsion) (e.g., the period of several days or weeks during which they receive the composition (e.g., emulsion)). As used herein, "nutritional balance" refers to the provision of adequate nutrition to maintain growth, development, and the absence of nutritional deficiencies. Nutritional balance meets the requirements of each individual without providing too much of any particular nutrient that may result in adverse outcomes.

[0157] In some embodiments of any of these aspects, the patient does not receive or is not administered dextrose.In some embodiments of any of these aspects, the patient does not receive or is not administered a dextrose solution.

[0158] As described elsewhere herein, the compositions (e.g., emulsions) described herein have been demonstrated to be suitable for monotherapy, e.g., they do not induce retinopathy, bronchopulmonary dysplasia, perinatal sepsis, essential fatty acid deficiency, inflammation, and / or other nutritional deficiencies when administered as monotherapy. This is a feature not shared by all fat / fatty acid compositions that may otherwise be suitable for administration (e.g., parenteral administration). Thus, in some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein are administered as monotherapy for a condition that the subject needs treatment for. In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein are administered as monotherapy for nutritional needs, e.g., anti-inflammatory agents that have no effective nutritional value may be administered simultaneously, but the compositions (e.g., emulsions) are still monotherapy for nutritional needs. In some embodiments of any of these aspects, a composition (e.g., an emulsion) described herein is administered as a monotherapy with respect to fatty acids, e.g., no other source of fatty acids is administered to or ingested by the subject.

[0159] In some embodiments of any of these aspects, the subject is a newborn or a newborn infant.As used herein, the term "newborn" refers to an infant from birth to 28 days after birth.In some embodiments of any of these aspects, the newborn is a human infant.In embodiments where the newborn is a premature infant, 28 days is extended to include the days of premature birth.

[0160] In some embodiments of any of these aspects, the subject is an infant. As used herein, the term "infant" refers to a young child from birth to 1 year of age.

[0161] In some embodiments of any of these aspects, the subject is a premature newborn or infant.As used herein, the term "premature" refers to a human being born after less than 38 weeks of gestation.In some embodiments of any of these aspects, less than 38 weeks of gestation refers to a menstrual age or gestational age less than 38 weeks.

[0162] In some embodiments of any of these aspects, the subject is a premature newborn or infant born between 34-36 weeks of gestation (late premature infant). In some embodiments of any of these aspects, the subject is a premature newborn or infant born between 32-34 weeks of gestation (moderate premature infant). In some embodiments of any of these aspects, the subject is a premature newborn or infant born before 32 weeks of gestation (very premature infant). In some embodiments of any of these aspects, the subject is a premature newborn or infant born at or before 25 weeks of gestation (very premature infant).

[0163] For preterm infants, nutritional considerations and correction for gestational age are continued until the corrected age (not chronological age) is 2 years.

[0164] The final weeks of pregnancy provide the essential supplies and nutrients required for neural, retinal, and bronchopulmonary development. As demonstrated herein, administration of the compositions (e.g., emulsions) described herein can effectively provide nutrition, regulate fatty acid levels and ratios in a desirable manner, and reduce toxic effects. In addition, administration of the compositions described herein can cross the blood-brain barrier to provide these beneficial and therapeutic effects, which is understood to be reflected in the effects seen in the eye through the structurally similar blood-retinal barrier. Thus, described herein are therapeutic methods for treating premature infants, including administering the compositions described herein, for example, according to the methods described herein. In some aspects of any of these embodiments, described herein are therapeutic methods for treating intraventricular hemorrhage, developmental cognitive impairment, developmental delay, speech or language impairment, or visual impairment, including administering the compositions described herein, for example, according to the methods described herein. In some aspects of any of these embodiments, therapeutic methods are described herein for treating intraventricular hemorrhage, developmental cognitive impairment, developmental delay, speech or language impairment, or visual impairment in subjects born prematurely, including, for example, administering a composition described herein according to the methods described herein. In some aspects of any of these embodiments, therapeutic methods are described herein for treating neurological developmental disorders, including, for example, administering a composition described herein according to the methods described herein. In some aspects of any of these embodiments, therapeutic methods are described herein for treating retinal developmental disorders, including, for example, administering a composition described herein according to the methods described herein. In some aspects of any of these embodiments, therapeutic methods are described herein for treating bronchopulmonary developmental disorders, including, for example, administering a composition described herein according to the methods described herein.In some aspects of any of these embodiments, described herein are therapeutic methods for treating bronchopulmonary dysplasia, e.g., comprising administering a composition described herein, according to a method described herein.

[0165] In some aspects of any of these embodiments, compositions (e.g., emulsions) described herein for use as pharmaceuticals are described herein. In some aspects of any of these embodiments, compositions (e.g., emulsions) described herein for use as pharmaceuticals in the treatment of premature infants are described herein. In some aspects of any of these embodiments, compositions (e.g., emulsions) described herein for use as pharmaceuticals in the treatment of neurological developmental disorders are described herein. In some aspects of any of these embodiments, compositions (e.g., emulsions) described herein for use as pharmaceuticals in the treatment of retinal developmental disorders are described herein. In some aspects of any of these embodiments, compositions (e.g., emulsions) described herein for use as pharmaceuticals in the treatment of bronchopulmonary developmental disorders are described herein. In some aspects of any of these embodiments, compositions (e.g., emulsions) described herein for use as pharmaceuticals in the treatment of bronchopulmonary dysplasia are described herein. In some aspects of any of these embodiments, the compositions described herein (e.g., emulsions) are described herein for use as medicines in the treatment of premature infants.In some aspects of any of these embodiments, the compositions described herein (e.g., emulsions) are described herein for use as medicines in the treatment of intraventricular hemorrhage, developmental cognitive impairment, developmental delay, speech or language disorder, or visual disorder.In some aspects of any of these embodiments, the compositions described herein (e.g., emulsions) are described herein for use as medicines in the treatment of intraventricular hemorrhage, developmental cognitive impairment, developmental delay, speech or language disorder, or visual disorder in subjects born prematurely.

[0166] In some aspects of any of these embodiments, compositions (e.g., emulsions) described herein are used as non-therapeutic adjuncts. In some aspects of any of these embodiments, compositions (e.g., emulsions) described herein are used in non-therapeutic methods of improving or speeding up the rate of brain development. In some aspects of any of these embodiments, compositions (e.g., emulsions) described herein are used in non-therapeutic methods of improving or speeding up the rate of retinal development. In some aspects of any of these embodiments, compositions (e.g., emulsions) described herein are used in non-therapeutic methods of improving or speeding up the rate of bronchopulmonary development. In some aspects of any of these embodiments, compositions (e.g., emulsions) described herein are used in non-therapeutic methods of improving or speeding up the rate of growth and / or development of infants.

[0167] Premature infants born before 34 weeks of gestation cannot properly digest orally administered formulations.Therefore, in one embodiment of any of these aspects, a method is described herein that includes parenterally administering a composition described herein to a premature infant born before 34 weeks of gestation.In one embodiment of any of these aspects, a method is described herein that includes parenterally administering a composition described herein to a premature infant born before 34 weeks of gestation from birth to an age equivalent to 38 weeks of gestation.In one embodiment of any of these aspects, a method is described herein that includes parenterally administering a composition described herein to a premature infant born before 34 weeks of gestation and does not include orally administering a composition described herein. In one embodiment of any of these aspects, a method is described herein that includes parenterally administering a composition described herein to a premature infant born before 34 weeks of gestation from birth to an age equivalent to 38 weeks of gestation, and does not include orally administering a composition described herein from birth to an age equivalent to 38 weeks of gestation.

[0168] In one embodiment of any of these aspects, methods are described herein that include administering a composition described herein parenterally to a premature infant born before 34 weeks of gestation from birth to an age equivalent to 38 weeks of gestation, and then administering a composition described herein orally and / or parenterally (e.g., from an age equivalent to 38 weeks of gestation to 2 years of age). In one embodiment of any of these aspects, methods are described herein that include administering a composition described herein parenterally to a premature infant born before 34 weeks of gestation from birth to an age equivalent to 38 weeks of gestation, and not administering a composition described herein orally from birth to an age equivalent to 37 weeks of gestation, and then administering a composition described herein orally and / or parenterally (e.g., from an age equivalent to 38 weeks of gestation to 2 years of age).

[0169] In one embodiment of any of these aspects, a method is described herein that includes parenterally administering a composition described herein to a premature infant born before 34 weeks of gestation from birth to an age equivalent to 38 weeks of gestation, and then orally administering a composition described herein (e.g., from an age equivalent to 38 weeks of gestation to 2 years of age). In one embodiment of any of these aspects, a method is described herein that includes parenterally administering a composition described herein to a premature infant born before 34 weeks of gestation from birth to an age equivalent to 38 weeks of gestation, and not orally administering a composition described herein from birth to an age equivalent to 38 weeks of gestation, and then orally administering a composition described herein (e.g., from an age equivalent to 38 weeks of gestation to 2 years of age).

[0170] Although premature infants born between 34 and 38 weeks of gestation may have the ability to digest orally administered formulations, oral administration alone may not be efficient enough for digestion. Thus, in one embodiment of any of these aspects, methods are described herein that include parenterally and / or orally administering a composition described herein to a premature infant born between 34 and 38 weeks of gestation. In one embodiment of any of these aspects, methods are described herein that include parenterally and / or orally administering a composition described herein to a premature infant born between 34 and 38 weeks of gestation from birth to an age equivalent to 38 weeks of gestation. In one embodiment of any of these aspects, methods are described herein that include parenterally administering a composition described herein to a premature infant born between 34 and 38 weeks of gestation. In one embodiment of any of these aspects, described herein is a method comprising parenterally administering a composition described herein to a preterm infant born between 34-38 weeks of gestation from birth to an age equivalent to 38 weeks of gestation. In one embodiment of any of these aspects, described herein is a method comprising orally administering a composition described herein to a preterm infant born between 34-38 weeks of gestation from birth to an age equivalent to 38 weeks of gestation. In one embodiment of any of these aspects, described herein is a method comprising orally administering a composition described herein to a preterm infant born between 34-38 weeks of gestation from birth to an age equivalent to 38 weeks of gestation. In one embodiment of any of these aspects, described herein is a method comprising parenterally and orally administering a composition described herein to a preterm infant born between 34-38 weeks of gestation. In one embodiment of any of these aspects, described herein is a method comprising parenterally and orally administering a composition described herein to a premature infant born between 34-38 weeks of gestation from birth to an age equivalent to 38 weeks of gestation.

[0171] For all infants, i.e., infants born at or after 38 weeks of gestation, or both premature infants, oral administration may be sufficient past the age equivalent to 38 weeks of gestation. In one embodiment of any of these aspects, methods are described herein that include orally administering a composition described herein to an infant past the age equivalent to 38 weeks of gestation.

[0172] In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) can be administered at a dose of about 0.5 g fatty acid / kg / day to about 5 g fatty acid / kg / day. In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) can be administered at a dose of 0.5 g fatty acid / kg / day to 5 g fatty acid / kg / day. In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) can be administered at a dose of about 1 g fatty acid / kg / day to about 3 g fatty acid / kg / day. In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) can be administered at a dose of 1 g fatty acid / kg / day to 3 g fatty acid / kg / day. In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) can be administered at a dose of about 2 g fatty acid / kg / day.

[0173] In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) can be administered at a dose of 5 g or less fatty acid / kg / day. In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) can be administered at a dose of 4 g or less fatty acid / kg / day. In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) can be administered at a dose of 3 g or less fatty acid / kg / day. In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) can be administered at a dose of 2 g or less fatty acid / kg / day. In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) can be administered at a dose of 1 g or less fatty acid / kg / day.

[0174] In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) are administered at a dose of 5-200 mg / kg / day of ARA and / or 10 mg / kg / day to 3 g / kg / day of DHA and / or EPA. In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) are administered at a dose of 5-200 mg / kg / day of ARA. In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) are administered at a dose of 10 mg / kg / day to 3 g / kg / day of DHA and / or EPA. In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) are administered at a dose of 5-200 mg / kg / day of ARA and 10 mg / kg / day to 3 g / kg / day of DHA and / or EPA.

[0175] In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) are administered at a dose of 20-60 mg / kg / day of ARA and / or 40-100 mg / kg / day of DHA and / or EPA. In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) are administered at a dose of 20-60 mg / kg / day of ARA. In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) are administered at a dose of 40-100 mg / kg / day of DHA and / or EPA. In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) are administered at a dose of 20-60 mg / kg / day of ARA and 40-100 mg / kg / day of DHA and / or EPA.

[0176] In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) are administered at a dose of 10-120 mg / kg / day of ARA and / or 20-200 mg / kg / day of DHA and / or EPA. In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) are administered at a dose of 10-120 mg / kg / day of ARA. In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) are administered at a dose of 20-200 mg / kg / day of DHA and / or EPA. In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) are administered at a dose of 10-120 mg / kg / day of ARA and 20-200 mg / kg / day of DHA and / or EPA.

[0177] In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) are administered at a dose of 5-200 mg / kg / day of ARA and / or 10-300 mg / kg / day of DHA and / or EPA. In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) are administered at a dose of 5-200 mg / kg / day of ARA. In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) are administered at a dose of 10-300 mg / kg / day of DHA and / or EPA. In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) are administered at a dose of 5-200 mg / kg / day of ARA and 10-300 mg / kg / day of DHA and / or EPA. In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein are administered at a dose of 5-200 mg / kg / day of ARA and 10-400 mg / kg / day of DHA and / or EPA. In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein are administered at a dose of up to 200 mg / kg / day of ARA and up to 400 mg / kg / day of DHA and / or EPA.

[0178] In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) are administered at a dose of 5-200 mg / kg / day of ARA and / or 10-750 mg / kg / day of DHA and / or EPA. In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) are administered at a dose of 5-200 mg / kg / day of ARA. In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) are administered at a dose of 10-750 mg / kg / day of DHA and / or EPA. In some embodiments of any of these aspects, the compositions described herein (e.g., emulsions) are administered at a dose of 5-200 mg / kg / day of ARA and 10-750 mg / kg / day of DHA and / or EPA.

[0179] As described elsewhere herein, infants are susceptible to the total dosage volume of the formulation. For example, the current clinical standard for the use of Omegaven typically requires a daily dosage volume of about 10 cc / kg / day, which is more than desired. In some embodiments of any of these aspects, the compositions and methods described herein relate to administering a total daily volume of the compositions described herein that is less than 10 cc / kg / day. In some embodiments of any of these aspects, the compositions and methods described herein relate to administering a total daily volume of the compositions described herein that is less than 9 cc / kg / day. In some embodiments of any of these aspects, the compositions and methods described herein relate to administering a total daily volume of the compositions described herein that is less than 8 cc / kg / day. In some embodiments of any of these aspects, the compositions and methods described herein relate to administering a total daily volume of the compositions described herein that is less than 7 cc / kg / day. In some embodiments of any of these aspects, the compositions and methods described herein relate to administering a total daily volume of the compositions described herein that is less than 6 cc / kg / day. In some embodiments of any of these aspects, the compositions and methods described herein relate to administering a total daily volume of the compositions described herein of less than 5 cc / kg / day. In some embodiments of any of these aspects, the compositions and methods described herein relate to administering a total daily volume of the compositions described herein of less than 4 cc / kg / day. In some embodiments of any of these aspects, the compositions and methods described herein relate to administering a total daily volume of the compositions described herein of less than 3 cc / kg / day. In some embodiments of any of these aspects, the compositions and methods described herein relate to administering a total daily volume of the compositions described herein of less than 2 cc / kg / day.

[0180] In some embodiments of any of these aspects, the compositions (e.g., emulsions) described herein can be administered at a dose of no more than 3 g fatty acid / kg / day and in a total volume of no more than 5 cc / kg / day.

[0181] In some embodiments of any of these aspects, administration of the composition (e.g., emulsion) described herein continues for at least 3 days, e.g., 3 days or more, 4 days or more, 5 days or more, 7 days or more, 2 weeks or more, 3 weeks or more, 4 weeks or more, 6 weeks or more, 2 months or more, or 3 months or more. In some embodiments of any of these aspects, administration of the composition (e.g., emulsion) described herein continues for at least 3 weeks. In some embodiments of any of these aspects, administration of the composition (e.g., emulsion) described herein continues for at least 6 weeks. In some embodiments of any of these aspects, administration of the composition (e.g., emulsion) described herein continues for at least 3 months.

[0182] The compositions and methods described herein can be administered to subjects who have or are diagnosed as having the conditions described herein. In some embodiments, the methods described herein include administering to a subject an effective amount of a composition described herein, such as a composition (e.g., an emulsion), to alleviate the symptoms of the conditions described herein. As used herein, "alleviating symptoms" refers to improving any condition or symptoms associated with the condition. Compared to an equivalent untreated control, the degree of such relief is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, 99%, or more, as measured by any standard technique. Various means for administering the compositions described herein to a subject are known to those skilled in the art. Such methods can include, but are not limited to, oral administration, parenteral administration, or intravenous administration.

[0183] In some embodiments of any of these aspects, preventive treatment methods are described herein.As used herein, "prophylactic" refers to the timing and intent of treatment against a disease or condition, i.e., treatment is administered before the clinical detection or diagnosis of a particular disease or condition to protect the patient from the disease or condition.Prophylactic treatment can include reducing the severity or onset rate of a disease or condition, or can contribute to a more rapid recovery from the disease or condition.Thus, the methods described herein can be preventive against retinopathy, bronchopulmonary dysplasia, or perinatal sepsis.In some embodiments of any of these aspects, prophylactic treatment is not the prevention of all symptoms or signs of a disease.

[0184] The term "effective amount" as used herein means the amount of the composition (e.g., emulsion) described herein that is required to alleviate at least one or more symptoms of a disease or disorder, and relates to the amount of a pharmacological composition that is sufficient to produce a desired effect. Thus, the term "therapeutically effective amount" means the amount of the composition (e.g., emulsion) described herein that is sufficient to produce a particular effect (e.g., nutritional effect, or anti-retinopathy effect, anti-bronchopulmonary dysplasia effect, or anti-perinatal sepsis effect) when administered to a typical subject. Effective amount as used in various contexts herein also includes an amount that is sufficient to delay the onset of disease symptoms, change the course of disease symptoms (e.g., but not limited to, slowing the progression of disease symptoms), or improve disease symptoms. Thus, it is usually not practical to specify an exact "effective amount". However, in any given case, the appropriate "effective amount" can be determined by one of ordinary skill in the art using only routine experimentation.

[0185] Effective doses, toxicity, and therapeutic efficacy can be determined, for example, by standard pharmaceutical procedures in cell cultures or experimental animals to determine the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). Dosages can vary depending on the dosage form used and the route of administration utilized. The dose ratio between toxic effects and therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50 / ED50. Compositions and methods that exhibit larger therapeutic indices are preferred. Therapeutically effective doses can be estimated initially from cell culture assays. Doses can also be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the composition (e.g., emulsion) or its components that achieves half-maximal inhibition of symptoms) as determined in cell culture or a suitable animal model. Plasma levels can be measured, for example, by high performance liquid chromatography. The effect of any particular dosage can be monitored by suitable bioassays, for example, assays for liver function in particular. Dosages can be determined by the physician and adjusted, if necessary, to meet the observed therapeutic effect.

[0186] In some embodiments, the technology described herein relates to a pharmaceutical composition comprising a composition described herein (e.g., an emulsion) as described herein and optionally a pharma- ceutically acceptable carrier. In some embodiments, the active ingredient of the pharmaceutical composition comprises a composition described herein (e.g., an emulsion) as described herein. In some embodiments, the active ingredient of the pharmaceutical composition consists essentially of a composition described herein (e.g., an emulsion) as described herein. In some embodiments, the active ingredient of the pharmaceutical composition consists of a composition described herein (e.g., an emulsion) as described herein. Pharmaceutically acceptable carriers and diluents include saline, aqueous buffer solutions, solvents, and / or dispersion media. The use of such carriers and diluents is well known in the art.Some non-limiting examples of materials which can serve as pharma- ceutically acceptable carriers include: (1) sugars, such as lactose, glucose, dextrose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, e.g., sodium carboxymethylcellulose, methylcellulose, ethylcellulose, microcrystalline cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) lubricants, such as magnesium stearate, sodium lauryl sulfate, and talc; (8) excipients, such as cocoa butter and suppository wax; and (9) propylene glycol. (10) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol (PEG); (11) esters such as ethyl oleate and ethyl laurate; (12) agar; (13) buffers such as magnesium hydroxide and aluminum hydroxide; (14) alginic acid; (15) pyrogen-free water; (16) isotonic saline; (17) Ringer's solution; (18) ethyl alcohol; (19) pH buffer solutions; (20) polyesters, polycarbonates, and / or polyanhydrides; (21) bulking agents such as polypeptides and amino acids; (22) serum components such as serum albumin, HDL, and LDL; (23) C2-C such as ethanol. 12 Alcohol; and (24) other non-toxic and compatible substances used in pharmaceutical formulations. Wetting agents, coloring agents, release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives, and antioxidants can also be present in the formulation. Terms such as "excipients," "carriers," or "pharmaceutical acceptable carriers" are used interchangeably herein. In some embodiments, the carrier inhibits the degradation of the active substances described herein. It should be noted that the composition (e.g., emulsion) itself can contain water. The composition (e.g., emulsion) can be administered with other components used in parenteral nutrition solutions (e.g., dextrose, crystalline amino acids, trace elements, multivitamins, electrolytes, and minerals).

[0187] In some embodiments, pharmaceutical compositions comprising compositions (e.g., emulsions) described herein as described herein can be in parenteral dosage form. Because administration of parenteral dosage forms typically bypasses the patient's natural defense against contaminating bacteria, parenteral dosage forms are preferably sterile or can be sterilized before administration to a patient. Examples of parenteral dosage forms include, but are not limited to, ready-to-inject solutions, dry products that can be dissolved or suspended in a pharma- ceutically acceptable injection vehicle, ready-to-inject suspensions, and emulsions. In addition, controlled release parenteral dosage forms, including but not limited to DUROS® type dosage forms and overdose, can also be prepared for administration to a patient.

[0188] Pharmaceutical compositions including compositions (e.g., emulsions) described herein can also be formulated for oral administration, for example, as individual dosage forms, such as, but not limited to, tablets (including, but not limited to, scored or coated tablets), pills, caplets, capsules, chewable tablets, powders in sachets, cachets, lozenges, wafers, or liquids, such as, but not limited to, syrups, elixirs, solutions or suspensions in aqueous liquids, non-aqueous liquids, oil-in-water emulsions, or water-in-oil emulsions. Such compositions contain a predetermined amount of pharma- ceutically acceptable salts of the disclosed compounds and can be prepared by pharmaceutical methods well known to those skilled in the art. See generally Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams, and Wilkins, Philadelphia PA. (2005).

[0189] The method described herein can further include administering a second agent and / or carrying out a second treatment to the subject, for example, as part of a combination therapy.As a non-limiting example, the subject can also be administered a second agent that is known to be beneficial to subjects suffering from inflammation, and / or carry out a second treatment that is known to be beneficial to subjects suffering from inflammation. Examples of such agents and / or treatments include, but are not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., aspirin, ibuprofen, or naproxen); corticosteroids, including glucocorticoids (e.g., cortisol, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, and beclomethasone); methotrexate; sulfasalazine; leflunomide; anti-TNF agents; cyclophosphamide; inflammation-resolving drugs; mycophenolic acid; or opiates (e.g., endorphins, enkephalins, and dynorphins), steroids, analgesics, barbiturates, oxycodone, morphine, and lidocaine.

[0190] In certain embodiments, an effective dose of a composition comprising the compositions described herein (e.g., emulsions) as described herein can be administered to a patient once. In certain embodiments, an effective dose of a composition comprising the compositions described herein (e.g., emulsions) can be administered to a patient repeatedly, for example, daily or several times a day for a period of at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 2 months, or at least 3 months.

[0191] The dosage of the compositions described herein can be determined by a physician and can be adjusted, if necessary, to suit the observed therapeutic effect. With regard to the duration and frequency of treatment, it is typical for a skilled clinician to monitor the subject to determine when the treatment is providing therapeutic benefit and to determine whether to increase or decrease the dosage, increase or decrease the frequency of administration, discontinue treatment, resume treatment, or make other changes to the treatment plan. The administration schedule can vary from once a week to daily, depending on several clinical factors, such as the sensitivity of the subject to the components of the composition (e.g., emulsion). The dose or amount desired for activation can be administered once or divided into divided doses, e.g., 2-4 divided doses, and administered at appropriate intervals over a period of time, e.g., throughout the day or through other suitable schedules. In some embodiments, administration can be chronic, e.g., daily, one or multiple administrations and / or treatments over a period of weeks or months. Examples of administration and / or treatment schedules are daily, twice daily, three times daily, or four or more times daily for one week, two weeks, three weeks, four weeks, one month, two months, three months, four months, five months, or six months or longer. Compositions, including compositions described herein (e.g., emulsions), can be administered over a period of time, for example, 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 25 minutes.

[0192] The dosage range of the compositions (e.g., emulsions) described herein when administered according to the methods described herein varies depending, for example, on the form of the composition (e.g., emulsion), its potency, and the degree to which the symptoms, markers, or indicators of the conditions described herein are desired to be reduced. The dosage should not be so large as to cause adverse side effects. In general, the dosage varies with the age, condition, and sex of the patient, and can be determined by those skilled in the art. If any complications arise, the dosage can also be adjusted by the individual physician.

[0193] For example, the effectiveness of the compositions (e.g., emulsions) described herein in treating a condition described herein or inducing a response described herein can be determined by a skilled clinician. However, as the term "effective treatment" is used herein, a treatment is deemed "effective treatment" if one or more of the signs or symptoms of a condition described herein are beneficially altered, other clinically recognized symptoms are improved or even better, or a desired response is induced, for example, at least 10% after treatment according to the methods described herein. Efficacy can be assessed, for example, by measuring markers, indicators, symptoms, and / or incidence of a condition treated according to the methods described herein, or any other suitable measurable parameters, such as nutritional balance, inflammation, and / or liver function. Efficacy can also be measured based on an individual not getting worse (i.e., progression of the disease is halted) as assessed based on the need for hospitalization or medical intervention. Methods for measuring these indicators are known to those skilled in the art and / or described herein. Treatment includes any treatment of disease in an individual or animal (some non-limiting examples include humans or animals), including (1) suppressing the disease, e.g., preventing the worsening of symptoms (e.g., pain or inflammation), or (2) relieving the severity of the disease, e.g., causing a reduction in symptoms. An effective amount for treating a disease means an amount that, when administered to a subject in need thereof, is sufficient to bring about an effective treatment for the disease as the term is defined herein. The effectiveness of an agent can be determined by assessing physical indicators of the condition or the desired response. It is well within the capabilities of a person skilled in the art to monitor the effectiveness of administration and / or treatment by measuring any one or any combination of such parameters. Efficacy can be evaluated in animal models of the conditions described herein.When experimental animal models are used, efficacy of treatment is demonstrated when a statistically significant change in a marker is observed.

[0194] Provided herein is an in vitro assay and an animal model assay that allows the evaluation of a given dose of the composition (e.g., emulsion) described herein.As a non-limiting example, the effect of a dose of a composition (e.g., emulsion) can be determined by orally or parenterally administering the composition (e.g., emulsion), and then evaluating serum fatty acid level and the histology of liver, spleen, and / or kidney.

[0195] For convenience, the meanings of some terms and phrases used in the specification, examples, and the appended claims are provided below. Unless otherwise stated or implied by context, the following terms and phrases include the meanings provided below. Since the scope of the present invention is limited only by the claims, these definitions are provided to help explain individual aspects and are not intended to limit the claimed invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. If there is an apparent discrepancy between the usage of a term in the art and its definition provided herein, the definition provided herein shall prevail.

[0196] For convenience, some terms used in this document in the specification, examples, and appended claims are collected here.

[0197] In one respect, the present invention relates to compositions, methods, and each of their components described herein that are essential to the technology, but accepts the inclusion of unspecified elements, whether essential or not, ("comprising"). In some embodiments of any of these aspects, other elements that may be included in the description of the compositions, methods, or each of their components are limited to those that do not substantially affect the basic and novel features of the technology (e.g., the compositions, methods, or each of their components "consist essentially of" the elements described herein). This applies equally to the steps included in the described methods and the compositions and components therein. In other embodiments of any of these aspects, the compositions, methods, and each of their components described herein are intended to exclude any elements that are not considered essential elements to the components, compositions, or methods (e.g., the compositions, methods, or each of their components "consist of" the elements described herein). This applies equally to the steps included in the described methods and the compositions and components therein.

[0198] The terms "reduce", "reduced", "reduction" or "inhibit" are all used herein to mean a statistically significant amount of reduction. In some embodiments, "reduce", "reduction" or "reduce" or "inhibit" typically means a reduction of at least 10% compared to a reference level (e.g., in the absence of a given treatment or agent), and can include, for example, a reduction of at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or more. As used herein, "reduce" or "inhibit" does not include a total inhibition or reduction compared to a reference level. "Total inhibition" is 100% inhibition compared to a reference level. The decrease can preferably be to a level recognized as being within the normal range for individuals without a given disorder.

[0199] The terms "increased", "increase", "improve", or "activate" are all used herein to mean a statistically significant amount of increase. In some embodiments, the terms "increased", "increase", "improve", or "activate" can mean an increase of at least 10% compared to a reference level, such as an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or an increase up to and including 100%, or any increase between 10-100% compared to a reference level, or an increase of at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 10-fold, or any increase between 2-fold and 10-fold or more than 10-fold compared to a reference level. In the context of a marker or symptom, an "increase" is a statistically significant increase in such level.

[0200] As used herein, "subject" refers to a human or animal. Usually, an animal is a vertebrate, such as a primate, a rodent, a domestic animal, or a game animal. Primates include chimpanzees, cynomolgus monkeys, spider monkeys, and macaques, such as rhesus monkeys. Rodents include mice, rats, woodchucks, ferrets, rabbits, and hamsters. Domestic and game animals include cows, horses, pigs, deer, bison, buffalo, feline species, such as domestic cats, canine species, such as dogs, foxes, wolves, avian species, such as chickens, emus, ostriches, and fish, such as trout, catfish, and salmon. In some embodiments, the subject is a mammal, such as a primate, such as a human. The terms "individual," "patient," and "subject" are used interchangeably herein.

[0201] Preferably, the subject is a mammal. The mammal can be, but is not limited to, a human, a non-human primate, a mouse, a rat, a dog, a cat, a horse, or a cow. A non-human mammal can be advantageously used as a subject to become an animal model of the diseases and conditions described herein. The subject can be male or female.

[0202] The subject can be a subject who has been previously diagnosed or identified as suffering from or having a condition that requires treatment or one or more complications related to such condition, and optionally has already been treated for the condition or one or more complications related to such condition.Alternatively, the subject can also be a subject who has not previously been diagnosed as having the condition or one or more complications related to such condition.For example, the subject can be a subject who shows one or more risk factors for the condition or one or more complications related to such condition, or a subject who does not show risk factors.

[0203] A "subject in need" of treatment for a particular condition can be a subject who has the condition, has been diagnosed with the condition, or is at risk for developing the condition.

[0204] As used herein, the terms "treat", "treatment", "treating" or "amelioration" refer to therapeutic treatments whose purpose is to reverse, alleviate, improve, inhibit, slow or stop the progression or severity of a condition associated with a disease or disorder, such as a condition, disease or disorder described herein. The term "treating" includes reducing or alleviating at least one adverse effect or symptom of a condition, disease or disorder. Generally, a treatment is "effective" if one or more symptoms or clinical markers are reduced. Alternatively, a treatment is "effective" if the progression of a disease is slowed or stopped. That is, "treatment" includes not only the improvement of symptoms or markers, but also the stopping or at least slowing the progression or worsening of symptoms compared to what would be expected in the absence of treatment. Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptoms, whether detectable or undetectable, reduction in the extent of disease, stabilized (i.e., not worsening) disease state, delay or slowing of disease progression, improvement or palliation of disease state, remission (whether partial or total), and / or reduced mortality. The term "treatment" of a disease also includes the removal of symptoms or side effects of the disease (including palliative care).

[0205] As used herein, the term "pharmaceutical composition" refers to an active agent combined with a pharmaceutically acceptable carrier, e.g., a carrier commonly used in the pharmaceutical industry. The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, and other problems or complications, and are commensurate with a reasonable benefit / risk ratio. In some embodiments of any of these aspects, the pharmaceutically acceptable carrier can be a carrier other than water. In some embodiments of any of these aspects, the pharmaceutically acceptable carrier can be an emulsion, gel, liposome, nanoparticle, and / or ointment. In some embodiments of any of these aspects, the pharmaceutically acceptable carrier can be an artificial or engineered carrier, e.g., a carrier in which the active ingredient would not naturally occur.

[0206] As used herein, the term "administering" refers to placing a compound disclosed herein into the subject's body by a method or route that results in at least partial delivery of the agent to a desired site. Pharmaceutical compositions containing the compounds disclosed herein can be administered by any suitable route that results in an effective treatment for the subject.

[0207] The terms "statistically significant" or "significantly" refer to statistical significance, usually meaning a difference of two standard deviations (2 SD) or greater.

[0208] Other than in the illustrative examples, or unless otherwise specified, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood to be modified in all instances by the term "about." When used in connection with percentages, the term "about" can mean ±1%.

[0209] As used herein, the term "comprises" means that other elements may also be present in addition to the defined elements set forth. The use of "comprises" indicates inclusion rather than limitation.

[0210] The term "consisting of" means compositions, methods, and each component thereof described herein, excluding any element not recited in the description of that embodiment.

[0211] As used herein, the term "consisting essentially of" means those elements required for a given embodiment. The term permits the presence of additional elements that do not materially affect the basic and novel or functional characteristics of that embodiment of the invention.

[0212] The singular terms "a," "an," and "the" include plural referents unless the context dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context dictates otherwise. Methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present disclosure, and suitable methods and materials are described below. The abbreviation "eg" is derived from the Latin exempli gratia and is used herein to indicate a non-limiting example. Thus, the abbreviation "eg" is synonymous with the term "for example."

[0213] Grouping of alternative elements or aspects of the invention disclosed herein should not be construed as limiting. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group may be included in or deleted from a group for reasons of convenience and / or patentability. When any such inclusion or deletion is made, the specification is deemed herein to include the modified group, and thus fulfills all Markush group descriptions used in the appended claims.

[0214] Unless otherwise specified herein, scientific and technical terms used in connection with this application have the meanings commonly understood by those skilled in the art to which this disclosure belongs. It should be understood that the present invention is not limited to the specific methodology, protocols, and reagents, etc. described herein, and thus may vary. The terminology used herein is only for the purpose of describing specific embodiments, and is not intended to limit the scope of the present invention, which is defined solely by the claims.Definitions of common terms in immunology and molecular biology can be found in The Merck Manual of Diagnosis and Therapy, 19th Edition, published by Merck Sharp & Dohme Corp., 2011 (ISBN 978-0-911910-19-3); Robert S. Porter et al. (eds.), The Encyclopedia of Molecular Cell Biology and Molecular Medicine, published by Blackwell Science Ltd., 1999-2012 (ISBN 9783527600908); and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc., 1995 (ISBN 1-56081-569-8); Immunology by Werner Luttmann, published by Elsevier, 2006; Janeway's Immunobiology, Kenneth Murphy, Allan Mowat, Casey Weaver (eds.), Taylor & Francis Limited, 2014 (ISBN 0815345305, 9780815345305); Lewin's Genes XI, published by Jones & Bartlett Publishers, 2014 (ISBN-1449659055); Michael Richard Green and Joseph Sambrook, Molecular Cloning: A Laboratory Manual, 4. thed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, USA (2012) (ISBN 1936113414); Davis et al., Basic Methods in Molecular Biology, Elsevier Science Publishing, Inc., New York, USA (2012) (ISBN 044460149X); Laboratory Methods in Enzymology: DNA, Jon Lorsch (ed.) Elsevier, 2013 (ISBN 0124199542); Current Protocols in Molecular Biology (CPMB), Frederick M. Ausubel (ed.), John Wiley and Sons, 2014 (ISBN 047150338X, 9780471503385), Current Protocols in Protein Science (CPPS), John E. Coligan (ed.), John Wiley and Sons, Inc., 2005; and Current Protocols in Immunology (CPI) (John E. Coligan, ADA M Kruisbeek, David H Margulies, Ethan M Shevach, Warren Strobe, (eds.) John Wiley and Sons, Inc., 2003 (ISBN 0471142735, 9780471142737), the contents of which are all incorporated herein by reference in their entireties.

[0215] Other terms are defined herein within the scope of the description of various aspects of the invention.

[0216] All patents and other publications, including references, issued patents, published patent applications, and co-pending patent applications, cited throughout this application are expressly incorporated herein by reference to describe and disclose, for example, the methodologies described in such publications that may be used in connection with the technology described herein. These publications are provided solely for their disclosure prior to the filing date of this application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the content of these documents are based on the information available to the applicants and do not constitute any admission as to the accuracy of the dates or contents of these documents.

[0217] The description of the aspects of the present disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. Specific aspects of the present disclosure and examples for the present disclosure are described herein for illustrative purposes, but as one skilled in the relevant art will recognize, various equivalent modifications are possible within the scope of the present disclosure. For example, although steps or functions of a method are presented in a given order, in alternative embodiments, the functions may be performed in a different order or substantially simultaneously. The teachings of the present disclosure provided herein can be applied to other procedures or methods as appropriate. Various embodiments described herein can be combined to provide other embodiments. Aspects of the present disclosure can be modified as necessary to use the compositions, functions, and concepts of the above references and applications to provide further aspects of the present disclosure. These and other changes can be made to the present disclosure in light of the detailed description. All such modifications are intended to be within the scope of the appended claims.

[0218] Particular elements of any of the foregoing embodiments may be combined with or substituted for elements of other embodiments. Additionally, although advantages associated with particular embodiments of the present disclosure have been discussed in connection with those embodiments, other embodiments may exhibit such advantages as well, and not all embodiments necessarily need to exhibit such advantages in order to fall within the scope of the present disclosure.

[0219] In some aspects, the present technology can be defined by any of the following numbered items: 1 (a) arachidonic acid (ARA); and (b) docosahexaenoic acid (DHA) and / or eicosapentaenoic acid (EPA) A composition comprising: 2. The composition of item 1, comprising DHA. 3 The composition of item 1, comprising EPA. 4. The composition of item 1, comprising DHA and EPA. 5. The composition of any one of the preceding items, wherein the weight ratio of (a) ARA to (b) DHA and / or EPA is 3:2 to 3:5. 6. The composition of any one of the preceding items, wherein the weight ratio of (a) ARA to (b) DHA and / or EPA is 1:2 to 3:5. 7. The composition of any one of the preceding items, wherein the weight ratio of (a) ARA to (b) DHA and / or EPA is 1:2 to 1:5. 8. The composition of any one of the preceding items, wherein the weight ratio of (a) ARA to (b) DHA and / or EPA is 2:1 to 1:4. 9. The composition of any one of the preceding items, wherein the weight ratio of (a) ARA to (b) DHA and / or EPA is 1:1 to 1:2. 10. The composition of any one of the preceding items, further comprising an omega-6 fatty acid and / or an omega-3 fatty acid. 11. The composition of item 10, wherein ARA and DHA and / or EPA constitute at least 60% of the total amount of omega-3 and omega-6 fatty acids. 12. The composition of item 10, wherein ARA and DHA and / or EPA constitute at least 70% of the total amount of omega-3 and omega-6 fatty acids. 13 The composition of item 10, wherein ARA and DHA and / or EPA constitute at least 80% of the total amount of omega-3 and omega-6 fatty acids. 14. The composition of item 10, wherein ARA and DHA and / or EPA constitute at least 90% of the total amount of omega-3 and omega-6 fatty acids. The composition of any one of the preceding items, wherein 15 ARA constitutes at least 20% of the total omega-6 fatty acids. The composition of any one of the preceding items, wherein 16 ARA constitutes at least 30% of the total omega-6 fatty acids. The composition of any one of the preceding items, wherein 17 ARA constitutes at least 40% of the total omega-6 fatty acids. 18. The composition of any one of the preceding items, wherein DHA and / or EPA constitute at least 20% of the total omega-3 fatty acids. 19. The composition of any one of the preceding items, wherein DHA and / or EPA constitute at least 30% of the total omega-3 fatty acids. 20. The composition of any one of the preceding items, wherein DHA and / or EPA constitute at least 40% of the total omega-3 fatty acids. 21. The composition of any one of the preceding items, wherein the weight ratio of omega-6 fatty acids to omega-3 fatty acids is 2:1 to 1:4. 22. The composition of any one of the preceding items, wherein the weight ratio of omega-6 fatty acids to omega-3 fatty acids is 1:1 to 1:2. 23. The composition of any one of the preceding items, wherein the composition and its components have not been distilled or re-esterified. 24. The composition of any one of the preceding claims, wherein the total combined triglyceride and diglyceride content of the composition comprises 10% or less diglycerides. 25. The composition of item 23 or 24, which does not contain diglycerides. 26 The composition of any one of the preceding items, wherein the DHA and / or EPA is neither distilled nor re-esterified. 27. The composition of any one of the preceding items, wherein the total combined triglyceride and diglyceride content of DHA and / or EPA comprises 10% or less diglycerides. 28. The composition of any one of the preceding items, wherein the DHA and / or EPA does not comprise a diglyceride. 29. The composition of any one of the preceding items, wherein the ARA is neither distilled nor re-esterified. The composition of any one of the preceding items, wherein the total combined triglyceride and diglyceride content of 30 ARA contains 10% or less diglycerides. 31 The composition of any one of the preceding items, wherein the ARA does not contain diglycerides. 32. The composition of any one of the preceding items, comprising 5% (w / w) or less of a sterol. 33. The composition of any one of the preceding items, comprising 2% (w / w) or less of a sterol. 34. The composition of any one of the preceding items, comprising 1.5% (w / w) or less of a sterol. The composition of any one of the preceding items, comprising 35-70 mg / L or less of phytosterols. The composition of any one of the preceding items, comprising 36-35 mg / L or less of phytosterols. 37. The composition of any one of the preceding items, comprising 4% (w / w) or less of stigmasterol. 38. The composition of any one of the preceding items, comprising 10 mg / L or less of stigmasterol. 39. The composition of any one of the preceding items, wherein the composition comprises a vegetable oil or a fungal oil, or the ARA is provided in the form of a vegetable oil or a fungal oil. 40. The composition of claim 39, wherein the vegetable or fungal oil is neither distilled nor re-esterified. 41. The composition of claim 39 or 40, wherein the total combined triglyceride and diglyceride content of the vegetable or fungal oil contains 10% or less diglycerides. 42. The composition of items 39 or 40, wherein the vegetable or fungal oil does not contain diglycerides. 43. The composition of any one of items 39 to 42, wherein the vegetable or fungal oil contains 5% (w / w) or less of sterols, 70 mg / L or less of phytosterols, 4% (w / w) or less of stigmasterol, and / or 10 mg / L or less of stigmasterol. 44. The composition of any one of items 39 to 43, wherein the vegetable oil is soybean oil or olive oil, or the fungal oil is Mortierella alpina oil. 45. The composition of any one of the preceding items, wherein the composition comprises fish oil and / or the DHA and / or EPA are provided in the form of fish oil. 46. ​​The composition of item 45, wherein the fish oil is neither distilled nor re-esterified. 47. The composition of claim 45 or 46, wherein the total combined triglyceride and diglyceride content of the fish oil contains 10% or less diglycerides. 48. The composition of items 45 or 46, wherein the fish oil does not contain diglycerides. 49. The composition of any one of items 45 to 48, wherein the fish oil contains 5% (w / w) or less of sterols, 70 mg / L or less of phytosterols, 4% (w / w) or less of stigmasterol, and / or 10 mg / L or less of stigmasterol. 50. The composition of any one of the preceding items, wherein the composition comprises algal oil and / or the DHA and / or EPA is provided in the form of algal oil. 51. The composition of item 50, wherein the algal oil is oil derived from Crypthecodinium cohnii. 52. The composition of items 50 or 51, wherein the algal oil has not been distilled or re-esterified. 53. The composition of any one of items 50-52, wherein the total combined triglyceride and diglyceride content of the algal oil comprises 10% or less diglycerides. 54. The composition of any one of items 50 to 52, wherein the algal oil does not contain diglycerides. 55. The composition of any one of items 50-54, wherein the algal oil contains 5% (w / w) or less of sterols, 70 mg / L or less of phytosterols, 4% (w / w) or less of stigmasterol, and / or 10 mg / L or less of stigmasterol. 56. The composition of any one of the preceding items, which is a lipid emulsion. 57. The composition of item 56, wherein the emulsion is an oil-in-water type with at least 10% oil. 58. The composition of item 56, wherein the emulsion is an oil-in-water type with at least 20% oil. 59. The composition of item 56, wherein the emulsion is an oil-in-water type with at least 30% oil. 60. The composition of item 56, wherein the emulsion is an oil-in-water type having from about 10% to about 50% oil. 61. The composition of item 56, wherein the emulsion is an oil-in-water type having from about 10% to about 40% oil. 62. The composition of item 56, wherein the emulsion is an oil-in-water type having from about 10% to about 30% oil. 63. The composition of item 56, wherein the emulsion is an oil-in-water type having from about 20% to about 40% oil. 64 The composition of any one of the preceding items, further comprising one or more of the following: medium chain triglycerides (MCT); egg lecithin; sunflower seed oil; and an emulsifier derived from sunflower seeds. 65. The composition of any one of the preceding items, formulated to contain (a) ARA in a dosage of 20-60 mg / kg / day and / or (b) DHA and / or EPA in a dosage of 40-100 mg / kg / day. 66. The composition of any one of the preceding items, formulated to contain (a) ARA in a dosage of 20-60 mg / kg / day and / or (b) DHA and / or EPA in a dosage of 10 mg / kg / day to 3 g / kg / day. 67. The composition of any one of the preceding items, formulated for parenteral or intravenous administration. 68. A method of providing nutrition to a subject and / or promoting neurodevelopment in a subject, comprising administering to the subject a composition of any of the preceding items. 69. The method of any one of the preceding items, wherein the composition is administered at a dosage of 5 g / kg / day or less. 70. The method of any one of the preceding items, wherein the composition is administered to provide (a) ARA in a dosage of 20-60 mg / kg / day and / or (b) DHA and / or EPA in a dosage of 40-100 mg / kg / day. 71. The method of any one of the preceding items, wherein the subject is an infant. 72. The method of any one of the preceding items, wherein the subject is a newborn and / or a premature infant. 73. The method of any one of the preceding items, wherein the neurodevelopment is neurodevelopment in the brain and / or eye. 74. The method of any one of the preceding items, wherein administration treats, prevents, or reduces the risk of one or more conditions selected from the group consisting of retinopathy, bronchopulmonary dysplasia, and perinatal sepsis. 75. The method of any one of the preceding items, wherein administration is parenteral and / or intravenous. 76. The method of any one of the preceding items, wherein the nutrition is parenteral nutrition or total parenteral nutrition. 77. The method of any one of the preceding items, wherein administration is parenteral or totally parenteral. 78. The method of any one of the preceding items, wherein the subject is in need of parenteral nutrition or total parenteral nutrition. 79. The method of any of the preceding items, wherein the patient does not receive oral nutrition. 80. The method of any of the preceding items, wherein the patient is not receiving other parenteral preparations. 81. The method of any of the preceding items, wherein the patient does not receive oral nutrition sufficient to maintain nutritional balance. 82. Any method of any of the preceding items, wherein the patient receives no other parenteral preparations that are sufficient to maintain nutritional balance. 83. The method of any of the preceding items, wherein the patient receives no other nutritional sources and / or parenteral nutrition sources for fatty acids. 84. The method of any of the preceding items, wherein the patient receives no other nutritional and / or parenteral sources of essential fatty acids. 85. The method of any of the preceding items, wherein the composition of any of items 1 to 67 is administered as a monotherapy. 86. The method of any of the preceding items, wherein the composition of any of items 1 to 67 is administered as a sole therapy for nutritional needs. 87 Patients were diagnosed with fatty liver, intestinal failure, parenteral nutrition-associated liver disease (PNALD), sepsis, cystic fibrosis, sickle cell anemia, pancreatitis, inflammatory bowel disease, Crohn's disease, biliary atresia, primary sclerosing cholangitis, inflammatory infections, inflammatory conditions, systemic inflammatory response syndrome (SIRS), hypertriglyceridemia, severe hypertriglyceridemia, severe fatty liver, retinopathy of prematurity, acute tubular necrosis, IgA nephropathy, ischemia-reperfusion injury, traumatic brain injury, multiple organ failure, respiratory distress syndrome, acute myocardial infarction, persistent angina, and acute myocardial infarction. 4. The method of any of the preceding items, wherein the patient is in need of treatment for a condition selected from the group consisting of: chronic obstructive pulmonary disease, chronic myocardial infarction, chronic obstructive pulmonary disease, chronic myocardial infarction, chronic obstructive pulmonary disease, chronic obstructive pulmonary disease (COPD), ...

[0220] The technology described herein is further illustrated by the following examples, which should not be construed as further limiting in any way. EXAMPLES

[0221] Example 1 Parenteral nutrition (PN) is a life-saving treatment for patients with intestinal failure due to insufficient gastrointestinal length or function. Although life-saving, PN presents significant clinical challenges in the neonatal population.

[0222] First, the standard-of-care lipid emulsions used (the source of fat in PN) are low in docosahexaenoic acid (DHA) and arachidonic acid (ARA); these are fatty acids that are essential for neurodevelopment and accumulate rapidly in the brain during the third trimester and first year of life.

[0223] Second, these emulsions contribute to a continuum of cholestasis and liver failure known as intestinal failure associated liver disease (IFALD).

[0224] Third, administration of PN requires very large fluid volumes, with a typical PN volume in preterm neonates being 130 mL / kg / day. Fluid administration to neonates is inherently extremely challenging due to fluid shifts, physiologic changes in renal function, and high levels of insensible losses.

[0225] Fourth, in addition to IFALD, major complications in preterm infants (retinopathy of prematurity and bronchopulmonary dysplasia) have also been associated with the use of standard lipid emulsions. Despite the fact that most neonatal ICU patients require PN, lipid emulsions have never been designed for or specifically studied in the neonatal population.

[0226] Described herein is the preparation of a novel parenteral lipid emulsion designed to (1) provide docosahexaenoic acid and arachidonic acid necessary for neonatal growth and development, (2) minimize phytosterols and prevent hepatotoxicity, and (3) reduce inflammatory and neurological complications in premature infants, including bronchopulmonary dysplasia, retinopathy of prematurity, and cerebral palsy.

[0227] The lipid emulsion is a unique composition that contains several types of oils, including sources of arachidonic acid (e.g., ARASCO oil), DHA and / or EPA (e.g., fish oil or DHASCO oil, for example), and low phytosterol oils (e.g., soybean oil, olive oil, or other low phytosterol oils with reduced phytosterols). The ARA dose is sufficient to provide 20-60 mg / kg / day based on the total lipid emulsion administered, while the DHA and / or EPA dose ranges from 40-100 mg / kg / day based on estimated fetal absorption rates and requirements for normal development (Robinson and Martin, Seminars in Fetal & Neonatal Medicine, 2017). Additionally, the emulsion is an oil-in-water emulsion with at least 20% oil and can be further concentrated (e.g., 25% or 30%) to minimize the need for fluid administration.

[0228] Example 2 Experiment 1: Creation of a new lipid emulsion for preterm neonates Objective: To develop a fatty acid composition that is anti-inflammatory (i.e., low omega6 / omega3 ratio), hepatoprotective (low phytosterols, high alpha-tocopherol), and contains sufficient arachidonic acid and docosahexaenoic acid to support growth and development, using USP <729> Create a new lipid emulsion that meets specifications.

[0229] Methods: Three oils were obtained: fish oil (Lipoid GmbH, Ludwigshafen, Germany), phytosterol-removed soybean oil (Lipoid GmbH, Ludwigshafen, Germany), and a fungal oil from Mortierella alpine (Cargill, Inc., Minneapolis, MN) rich in arachidonic acid. Each oil was individually prepared as an oil-in-water lipid emulsion at 20% oil using high-pressure homogenization. First, a dispersion was made. Frozen egg phospholipids were dispersed in sterile water for injection under high-shear mixing, followed by sodium oleate and glycerin. This dispersion was then passed through a high-pressure homogenizer (PandaPlus 2000, GEA, Parma, Italy) for 20 cycles at 5000 PSI and then 10 cycles at 9000 PSI. The dispersion was then filtered through a 0.45um membrane and the pH was adjusted to 10.2-10.8. Oil was then added in a thin stream to the dispersion under high shear mixing, followed by high pressure homogenization at 9000 PSI for 10 cycles and 13000 PSI for 5 cycles. α-Tocopherol was added to the fish and fungal oil emulsions during high shear mixing to 150mg / L, which is similar to the content in low phytosterol soybean oil. The pH of the emulsions was then adjusted to 8.8-9.2 and bottled in sterile vials, followed by autoclaving. All steps were performed under a nitrogen atmosphere to prevent lipid peroxidation. The final composition of the lipid emulsions was 200g / L oil, 12g / L egg phospholipids, 0.3g / L sodium oleate, 25g / L glycerin, and sterile water for injection. USP <729> To assess compliance, the lipid emulsions were sent to an independent laboratory (Micro Measurement Labs, Wheeling, IL). Following this, three new lipid emulsions (hereafter NLE A, NLE B, and NLE C) were made by mixing the three single oil lipid emulsions in various ratios, which were rebottled under sterile conditions with a nitrogen headspace and then autoclaved.

[0230] Results: Three oil-in-water lipid emulsions were made with 20% oil: a fish oil lipid emulsion, a low phytosterol soybean oil lipid emulsion, and an arachidonic acid-rich lipid emulsion. All three lipid emulsions were formulated according to USP <729> The results passed methods I and II as defined in (Table 1). Following this, three new lipid emulsions were created by varying the ratio of the three single oil lipid emulsions. Table 2 shows the fatty acid composition of each new lipid emulsion. The three lipid emulsions (NLE A, NLE B, and NLE C) provided at 3 g / kg / day met or exceeded the recommended minimum arachidonic acid intake (35-45 mg / kg / day), 34.3 mg, 102.83 mg, and 137.1 mg, respectively (dx.doi.org / 10.1016 / j.siny.2016.08.009). Similarly, NLE A, NLE B, and NLE C are well above the recommended minimum intake of docosahexaenoic acid (55–60 mg / kg / day), at 230.6 mg, 195.1 mg, and 144.9 mg, respectively.

[0231] Table 1. USP for lipid emulsions of fish oil, low-phytosterol soybean oil, and ARA-rich fungal oil. <729> Injectable lipid emulsion testing. All lipid emulsions passed the specifications for PFAT% (less than 0.05% passes) and DLS mean diameter (less than 500 nm). TIFF2024545117000004.tif44164

[0232] (Table 2) New lipid emulsions were made using various ratios of fish oil, low phytosterol soybean oil, and ARA fungal oil. TIFF2024545117000005.tif22128

[0233] Table 3: Fatty acid composition and tocopherol content of the three constituent oils and the new lipid emulsion. Testing of the fatty acid composition and tocopherols of the oils used in the new lipid emulsion was performed by Eurofins Microbiology Laboratories (North Kingstown, RI). TIFF2024545117000006.tif153162

[0234] Table 4. Fatty acid supply when the new lipid emulsion was administered at 3g / kg / day TIFF2024545117000007.tif67128

[0235] Table 5. Phytosterol and cholesterol content of existing lipid emulsions (Intralipid, Sumoflipid, and Omegaven) compared to the phytosterol content of the constituent oils and new lipid emulsion formulations. The phytosterol content of existing lipid emulsions was taken from Llop-Talaveron, J et al. (2020). Phytosterolemia associated with parenteral nutrition administration in adult patients. British Journal of Nutrition, 123(12), 1365-1372 doi:10.1017 / S0007114520000574. Phytosterol content testing of oils used in new lipid emulsions was performed by Eurofins Microbiology Laboratories (North Kingstown, RI). TIFF2024545117000008.tif90169

[0236] Discussion: Using fish oil, low-phytosterol soybean oil, and arachidonic acid-rich fungal oil, USP <729> Three single-oil lipid emulsions that met the specifications were then used to create three new lipid emulsions for subsequent experiments that exceeded the recommended intakes of docosahexaenoic acid and arachidonic acid for preterm infants.

[0237] Experiment 2: 4-week administration of the novel lipid emulsion as the sole fat source in young C57Bl / 6J mice Objective: To evaluate whether chronic (4 weeks) feeding of a novel lipid emulsion as the sole fat source to young mice affects plasma, liver, and brain fatty acid composition, essentially supporting their use in the neonatal population as a source of docosahexaenoic and arachidonic acids to prevent fatty acid deficiency.

[0238] METHODS: Four-week-old male C57Bl / 6J mice (Jackson Laboratory, Bar Harbor, ME) were obtained and randomized to receive either standard rodent chow (Prolab Isopro RMH 3000, LabDiet, St. Louis, MO) or a liquid, fat-free, high-carbohydrate diet (20% dextrose, 2% amino acids, 30 mEq / L sodium, 20 mEq / L potassium, 15 mEq / L calcium, 10 mEq / L magnesium, 10 mMol / L phosphate, 36.67 mEq / L chloride, 19.4 mEq / L acetate, multivitamins, trace elements) given ad libitum. Chow-fed mice received daily oral gavage of saline (10 ml / kg), whereas liquid-free diet mice received daily oral gavage of one of four lipid emulsions (10 ml / kg, 2 g / kg / day fat) as the sole source of fatty acids. After 4 weeks (8 weeks of age), mice were euthanized with CO2; liver and brain tissues were flash frozen in liquid nitrogen and stored at -80°C for further analysis. Liver and frontal cortex samples (n=5 / group) were sent to an independent CLIA-certified laboratory for fatty acid analysis by gas chromatography with flame ionization detection (Omegaquant, Sioux Falls, SD).

[0239] Results: Total fatty acid content in frontal cortex tissue was similar between groups (chow mean 32.7 ± 1.0 ug / ml vs. Intralipid mean 34.2 ± 0.4 ug / mg) but substantially different in liver tissue (chow mean 27.3 ± 2.2 ug / mg vs. Intralipid mean 70.1 ug / mg ± 22.0). The marked variability in liver tissue fat content may be attributed to a large increase in oleic acid content in non-chow animals, especially in the Intralipid group. Therefore, the fatty acid composition of the frontal cortex was compared as a percentage of total cortical fatty acids and the fatty acid composition of the liver was compared as fatty acid content per unit liver tissue. Figures 1A-1H show the fatty acid composition in plasma, liver, and frontal cortex of the various groups.

[0240] Mice on NLE A, NLE B, and NLE C showed increased ω3 fatty acids, decreased ω6 fatty acids, and a lower ω6 / ω3 ratio, consistent with more ω3 fatty acids being provided to plasma and liver tissue (Figures 2A-2H). In frontal cortex tissue, ω3 fatty acids were similar between chow control and NLE A, NLE B, and NLE C. Intralipid showed a pro-inflammatory fatty acid profile, with decreased ω3 fatty acids and increased ω6 / ω3 ratios in both liver and frontal cortex tissue compared to chow.

[0241] NLE A, NLE B, and NLE C mice all showed increased docosahexaenoic acid in plasma and liver tissue compared to chow and Intralipid, but maintained similar docosahexaenoic acid in frontal cortex tissue compared to chow (Figures 3A-3H). Notably, Intralipid mice had substantially less docosahexaenoic acid in liver and frontal cortex tissue than chow. NLE A, NLE B, and NLE C mice also had increased eicosapentaenoic acid in plasma, liver, and brain compared to chow and Intralipid mice. In plasma, NLE B, NLE C, and Intralipid mice had increased arachidonic acid compared to chow, while NLE A was similar to chow. NLE A and NLE B had some decrease in arachidonic acid in liver and frontal cortex tissue compared to chow.

[0242] Triene / tetraene ratios were evaluated for prevention of biochemical essential fatty acid deficiency (a ratio of 0.2 or greater is diagnostic of essential fatty acid deficiency). Notably, NLE A, NLE B, and NLE C all maintained normal triene / tetraene ratios in plasma and liver, similar to the chow control group. Meanwhile, the Intralipid group showed a significant elevation compared to the chow control, consistent with borderline essential fatty acid deficiency (Figures 4A-4B) (plasma >0.2 in 2 of 4 mice, mean 0.19 ± 0.01, P < 0.001; liver >0.2 in 3 of 5 mice, mean 0.19 ± 0.05, P < 0.001).

[0243] Conclusions: In juvenile mice subjected to chronic (4 weeks) daily lipid emulsion feeding as the sole fat source, NLE A, NLE B, and NLE C prevented essential fatty acid deficiency with triene / tetraene ratios similar to chow controls, whereas Intralipid produced a significantly elevated triene / tetraene ratio consistent with borderline essential fatty acid deficiency. Compared with chow controls and Intralipid, NLE A, NLE B, and NLE C increased omega-3 fatty acid content and decreased omega-6 / omega-3 ratios in plasma, liver, and frontal cortex, consistent with an anti-inflammatory fatty acid profile.

[0244] Experiment 3: Administration of a new lipid emulsion in a mouse model of parenteral nutrition-associated liver disease Objective: To evaluate whether a new lipid emulsion prevents biochemical liver injury and hepatic steatosis in a mouse model of parenteral nutrition-induced liver disease.

[0245] METHODS: Eight-week-old male C57Bl / 6J mice (Jackson Laboratory, Bar Harbor, ME) were obtained and randomized to receive either standard rodent chow (Prolab Isopro RMH 3000, LabDiet, St. Louis, MO) or a liquid nonfat high-carbohydrate diet (20% dextrose, 2% amino acids, 30 mEq / L sodium, 20 mEq / L potassium, 15 mEq / L calcium, 10 mEq / L magnesium, 10 mMol / L phosphate, 36.67 mEq / L chloride, 19.4 mEq / L acetate, multivitamins, trace elements) given ad libitum. Mice fed a liquid nonfat high-carbohydrate diet were administered one of five lipid emulsions or an equal volume of saline intravenously every other day via tail vein injection (4.8 g fat / kg body weight / dose), whereas chow-fed mice received an equal volume of saline via tail vein injection (chow group). After 19 days, mice were euthanized with CO2. Plasma was assessed for biochemical markers of liver injury using a Vetscan VS2 (Zoetis, Parsippany, NJ). Plasma fatty acid profiles were assessed as previously described (Carlson et al., 2019). Hematoxylin and eosin stained liver tissue was assessed by a board-certified independent veterinary pathologist using a semiquantitative scoring system established for fatty liver (Liang et al. Establishment of a General NAFLD Scoring System for Rodent Models and Comparison to Human Liver Pathology. PLoS ONE 9(12): e115922. doi:10. 1371 / journal.pone.0115922). For normally distributed data, comparisons were made using one-way ANOVA test, with multiple comparisons of individual groups (vs. HCD / saline group) made using Dunnett's multiple comparison test. For non-normally distributed data, comparisons were made using Kruskal-Wallis test, with multiple comparisons of individual groups (vs. HCD / saline group) made using Dunn's multiple comparison test.

[0246] Results: Mice in all groups showed similar weight gain (P=0.12). Biochemical markers of liver injury are shown in Figure 5A-5C. Mice in the Omegaven, NLE A, NLE B, and NLE C groups all maintained normal alanine aminotransferase levels (and significantly lower than the saline control group), consistent with prevention of liver injury induced by the high-carbohydrate diet. Histological evaluation of the liver was performed by a board-certified independent veterinary pathologist. Representative liver sections stained with hematoxylin and eosin are shown in Figure 6. Mice fed a high-carbohydrate diet containing NLE B or NLE C have no steatosis, while some mice fed NLE A show mild microdroplet and macrodroplet steatosis. Mice fed a chow diet (along with tail vein injections of saline) have normal histology without steatosis. All mice in the saline group had a lipidosis score of 2, which was significantly higher than the chow, NLE B, NLE C, and Omegaven groups, which did not have steatosis in any liver sections (n=5 / group, P=0.0051 for each comparison). There were no significant differences in lipidosis scores between the saline and Intralipid groups (2 of 5 liver sections had a lipidosis score of 3, P=0.61) or between the saline and NLE A groups (2 of 5 liver sections had a lipidosis score of 2, P=0.27) (Figure 7).

[0247] Compared to chow, mice fed NLE A, NLE B, or NLE C showed similar increases in arachidonic acid, docosahexaenoic acid, increased ω3 fatty acids, decreased ω6 fatty acids, and decreased ω6 / ω3 ratios (Figures 8A-8F). Mice fed NLE A, NLE B, and NLE C also showed similar (normal) triene / tetraene ratios as those fed chow, consistent with prevention of essential fatty acid deficiency. Mice in the saline group showed a significant increase in the triene / tetraene ratio, consistent with essential fatty acid deficiency.

[0248] Conclusions: In a 19-day model of parenteral nutrition-induced liver injury and steatosis, administration of NLE A, NLE B, or NLE C by tail vein injection rescues mice from biochemical liver injury. Administration of NLE B or NLE C by tail vein injection prevented hepatic steatosis and no steatosis was observed in any samples. Administration of NLE A, NLE B, or NLE C prevented essential fatty acid deficiency and resulted in normal triene / tetraene ratios (Figures 8A-8F).

Claims

1. (a) arachidonic acid (ARA); (b) docosahexaenoic acid (DHA) and / or eicosapentaenoic acid (EPA); and (c) additional omega-3 and omega-6 fatty acids A lipid emulsion composition comprising: The lipid emulsion composition, wherein the weight ratio of omega-6 fatty acids to omega-3 fatty acids is 2:1 to 1:

4.

2. 2. The lipid emulsion composition of claim 1, comprising DHA, EPA, or DHA and EPA.

3. 2. The lipid emulsion composition according to claim 1, wherein the weight ratio of (a) ARA to (b) DHA and / or EPA is 1:1 to 1:

20.

4. 2. The lipid emulsion composition according to claim 1, wherein the weight ratio of (a) ARA to (b) DHA and / or EPA is 1:2 to 1:

5.

5. (a) ARA and (b) DHA and / or EPA, taken together, are at least 50% by weight of the total amount of omega-3 and omega-6 fatty acids present in the composition; (a) ARA and (b) DHA and / or EPA, taken together, are at least 60% by weight of the total amount of omega-3 and omega-6 fatty acids present in the composition; (a) ARA and (b) DHA and / or EPA, taken together, are at least 65% by weight of the total amount of omega-3 and omega-6 fatty acids present in the composition; (a) ARA and (b) DHA and / or EPA, taken together, are at least 70% by weight of the total amount of omega-3 and omega-6 fatty acids present in the composition; (a) ARA and (b) DHA and / or EPA, taken together, are at least 75% by weight of the total amount of omega-3 and omega-6 fatty acids present in the composition; (a) ARA and (b) DHA and / or EPA, taken together, are at least 80% by weight of the total amount of omega-3 and omega-6 fatty acids present in the composition; (a) ARA and (b) DHA and / or EPA, taken together, are at least 85% by weight of the total amount of omega-3 and omega-6 fatty acids present in the composition; (a) ARA and (b) DHA and / or EPA, taken together, are at least 90% by weight of the total amount of omega-3 and omega-6 fatty acids present in the composition; or (a) ARA and (b) DHA and / or EPA, taken together, are at least 95% by weight of the total amount of omega-3 and omega-6 fatty acids present in the composition; The lipid emulsion composition of claim 1.

6. greater than 20% by weight of the total omega-6 fatty acids present in the composition is ARA; greater than 25% by weight of the total amount of omega-6 fatty acids present in the composition is ARA; greater than 30% by weight of the total omega-6 fatty acids present in the composition is ARA; greater than 35% by weight of the total omega-6 fatty acids present in the composition is ARA; greater than 40% by weight of the total omega-6 fatty acids present in the composition is ARA; greater than 45% by weight of the total omega-6 fatty acids present in the composition is ARA; greater than 20% by weight of the total amount of omega-3 fatty acids present in the composition are DHA and EPA; greater than 25% by weight of the total amount of omega-3 fatty acids present in the composition are DHA and EPA; greater than 30% by weight of the total amount of omega-3 fatty acids present in the composition are DHA and EPA; greater than 35% by weight of the total amount of omega-3 fatty acids present in the composition are DHA and EPA; greater than 40% by weight of the total omega-3 fatty acids present in the composition are DHA and EPA; or greater than 45% by weight of the total omega-3 fatty acids present in the composition are DHA and EPA; The lipid emulsion composition of claim 1.

7. 2. The lipid emulsion composition of claim 1, wherein the weight ratio of omega-6 fatty acids to omega-3 fatty acids is 2:1 to 1.44:1, 2:1 to 1:1.27, 2:1 to 1:2.17, 1:1 to 1:2, 1:1 to 1.44:1, 1:1 to 1:1.27, 1.44:1 to 1:1.27, or 1.44:1 to 1:2.

17.

8. The composition and its components have not been distilled or re-esterified; the DHA and / or EPA is not distilled or re-esterified; or the ARA is neither distilled nor re-esterified; The lipid emulsion composition of claim 1.

9. (a) the total combined triglyceride and diglyceride content of the composition contains 10% or less diglycerides, or the composition is diglyceride-free; or (b) the total combined monoglyceride, triglyceride, and diglyceride content of said composition contains 10% or less monoglycerides and diglycerides, or said composition contains no monoglycerides or diglycerides; The lipid emulsion composition of claim 1.

10. 10. The lipid emulsion composition of claim 1, comprising no more than 5% (w / w) sterols, no more than 2% (w / w) sterols, or no more than 1.5% (w / w) sterols.

11. 2. The lipid emulsion composition of claim 1, comprising less than 120 mg / L of phytosterols, less than 110 mg / L of phytosterols, less than 70 mg / L of phytosterols, less than 35 mg / L of phytosterols, less than 4% (w / w) of stigmasterol, less than 10 mg / L of stigmasterol, or less than 3 mg / L of stigmasterol.

12. linoleic acid less than or equal to 40% w / v, less than or equal to 30% w / v, less than or equal to 20% w / v, less than or equal to 10% w / v, or less than or equal to 5% w / v; containing less than or equal to 621 mg / kg / day, less than or equal to 401 mg / kg / day, or less than or equal to 287 mg / kg / day of linoleic acid; and / or Contains no linoleic acid; The lipid emulsion composition of claim 1.

13. the composition comprises a vegetable oil or a fungal oil and / or the ARA is provided in the form of a vegetable oil or a fungal oil, optionally wherein the vegetable oil is soybean oil or olive oil, or the fungal oil is Mortierella alpina oil; The lipid emulsion composition of claim 1.

14. the composition comprises fish oil and / or the DHA and / or EPA is provided in the form of fish oil; or the composition comprises algal oil and / or the DHA and / or EPA is provided in the form of algal oil, optionally wherein the algal oil is oil derived from Crypthecodinium cohnii; The lipid emulsion composition of claim 1.

15. 2. The lipid emulsion composition of claim 1, wherein the lipid emulsion is an oil-in-water type having at least 10%, at least 20%, at least 30%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, or about 20% to about 40% oil.

16. 10. The lipid emulsion composition of claim 1, further comprising one or more of medium chain triglycerides (MCT), egg lecithin, sunflower seed oil, sunflower lecithin, an emulsifier derived from sunflower seeds, and krill oil.

17. Formulated to contain (a) ARA in a dose of 20-200 mg / kg / day and / or (b) DHA and / or EPA in a dose of 40-400 mg / kg / day; or Formulated to contain (a) ARA in a dosage of 20-60 mg / kg / day and / or (b) DHA and / or EPA in a dosage of 40-100 mg / kg / day; or Formulated to contain (a) ARA in a dose of 20-60 mg / kg / day and / or (b) DHA and / or EPA in a dose of 10 mg / kg / day to 3 g / kg / day; The lipid emulsion composition of claim 1.

18. 20. A method of providing nutrition to a subject and / or non-therapeutically promoting neurodevelopment in a subject, the method comprising administering to said subject a lipid emulsion composition according to any one of claims 1 to 17.

19. 20. The lipid emulsion composition of any one of claims 1 to 17 for administration to a subject in need thereof for treating preterm birth, neurological developmental disorders, retinal developmental disorders, bronchopulmonary developmental disorders, and / or bronchopulmonary dysplasia.

20. administered at a dose of 5 g / kg / day or less; or administered to provide (a) ARA at a dose of 20-200 mg / kg / day and / or (b) DHA and / or EPA at a dose of 40-400 mg / kg / day; or administered to provide (a) ARA at a dose of 20-60 mg / kg / day and / or (b) DHA and / or EPA at a dose of 40-100 mg / kg / day; 20. The lipid emulsion composition of claim 19.

21. the subject is an infant; or the subject is a newborn and / or premature infant; 20. The lipid emulsion composition of claim 19.

22. the neurodevelopment is neurodevelopment in the brain and / or eye; or said administering treats, prevents, or reduces the risk of one or more conditions selected from the group consisting of retinopathy, bronchopulmonary dysplasia, and perinatal sepsis; 20. The lipid emulsion composition of claim 19.

23. the administration is parenteral and / or intravenous; or the nutrition is parenteral nutrition or total parenteral nutrition; or the administration is parenteral or totally parenteral; or the subject is in need of parenteral nutrition or total parenteral nutrition; or the subject does not receive oral nutrition; or the subject is not receiving other parenteral formulations; or The subject does not receive oral nutrition sufficient to maintain nutritional balance; or the subject is not receiving other parenteral preparations sufficient to maintain nutritional balance; or the subject does not receive other nutritional and / or parenteral nutritional sources of fatty acids; or the subject does not receive other nutritional and / or parenteral sources of essential fatty acids; 20. The lipid emulsion composition of claim 19.

24. The object is Fatty liver, intestinal failure, parenteral nutrition-associated liver disease (PNALD), sepsis, cystic fibrosis, sickle cell anemia, pancreatitis, inflammatory bowel disease, Crohn's disease, biliary atresia, primary sclerosing cholangitis, inflammatory infections, inflammatory conditions, systemic inflammatory response syndrome (SIRS), hypertriglyceridemia, severe hypertriglyceridemia, severe fatty liver, retinopathy of prematurity, acute tubular necrosis, IgA nephropathy, ischemia-reperfusion injury, traumatic brain injury, multiple organ failure, respiratory distress syndrome, acute myocardial infarction, myocardial infarction, persistent angina, asthma Status epilepticus, status epilepticus, pituitary state, inflammatory bowel disease, regional enteritis, ulcerative colitis, severe or debilitating arthritis, arthritis, psoriasis, severe psoriasis, burns, third-degree burns, pancreatitis, acute pancreatitis, liver disease associated with intestinal failure (IFALD), cholestasis associated with parenteral nutrition (PNAC), essential fatty acid deficiency (EFAD), parenteral nutrition-dependent states complicated by soy allergy, local anesthetic poisoning, states for the treatment of systemic toxicosis, and states requiring a vehicle or excipient for parenteral therapeutic agents.

20. The lipid emulsion composition of claim 19, wherein the subject is in need of treatment for a condition selected from the group consisting of:

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