Lipid emulsions with anti-inflammatory effects for total parenteral and enteral nutrition

Abstract

The present invention relates to lipid emulsions for total parenteral nutrition and enteral nutrition (oral or via gastric or duodenal tube). The lipid emulsions have beneficial immunomodulatory, anti-inflammatory, and antidiabetic effects. The lipid emulsions may also contain medicinal agents and can be used as antidotes or to reverse the negative effects of ischemia-reperfusion injury.

Description

[Technical Field]

[0001] This application claims priority to European Patent Application (EP) No. 22193442.5, filed September 1, 2022, which is incorporated herein by reference.

[0002] The present invention relates to lipid emulsions for total parenteral and enteral nutrition (oral or via gastric or duodenal tube) and for administering pharmaceuticals. The lipid emulsions according to the present invention have immunomodulatory, anti-inflammatory, and antidiabetic effects. The lipid emulsions may also contain pharmaceuticals and can be used as antidotes or to reverse the negative effects resulting from ischemia-reperfusion injury. [Background technology]

[0003] Parenteral lipid emulsions (LEs) are heterogeneous systems consisting of an oily phase uniformly dispersed in an aqueous phase in the presence of an emulsifier. A droplet size of typically 200–350 nm characterizes these lipid emulsions suitable for parenteral administration. To prevent instability, they have a physiological pH of around 7, isotonicity, and a high zeta potential. Currently available commercially, lipid emulsions consist of triglycerides from vegetable or fish oils, such as soybean oil, olive oil, coconut oil, or fish oil, or blends thereof (Table 1), egg yolk lecithin (an emulsifier), glycerol (to provide isotonicity), and water. Summary of the Invention [Problem to be solved by the invention]

[0004] Based on the above-mentioned state of the art, the object of the present invention is to provide an immunomodulatory, anti-inflammatory and antidiabetic lipid emulsion for total parenteral and enteral nutrition and administration. This object is achieved by the subject matter of the independent claims herein, with further advantageous embodiments described in the dependent claims herein, the examples, the figures and the general description. [Means for solving the problem]

[0005] Summary of the Invention A first aspect of the present invention relates to a lipid emulsion for parenteral administration, the lipid emulsion comprising an oily phase and an aqueous phase, the oily phase of the lipid emulsion comprising: - Omega-3 fatty acid components, - Omega-6 fatty acid components, - monounsaturated fatty acid components, and - Saturated fatty acid components (Percentages given throughout this specification are to be interpreted as weight / weight unless otherwise specified) in the proportions and relationships set forth in the claims, description, and examples.

[0006] A second aspect of the invention relates to a lipid emulsion according to the first aspect and its embodiments for use in parenteral or enteral nutrition.

[0007] A third aspect of the present invention relates to a lipid emulsion according to the first aspect and its embodiments for use as a counteractant / antidote ("lipid sink") in the treatment of poisoning by lipophilic drugs.

[0008] A fourth aspect of the present invention relates to a lipid emulsion according to the first aspect and embodiments thereof for use in protecting a vital organ against ischemia-reperfusion injury, in certain embodiments the vital organ is selected from the heart, brain, liver, kidney and lung.

[0009] A fifth aspect of the present invention relates to a lipid emulsion according to the first aspect for use in the prevention or treatment of type I and type II diabetes.

[0010] Terms and Definitions For the purposes of interpreting this specification, the following definitions shall apply, and where appropriate, terms used in the singular shall also include the plural and vice versa. In the event that a definition set forth below conflicts with any document incorporated herein by reference, the definition set forth herein shall control.

[0011] As used herein, the terms "comprising," "having," "containing," "including," and other similar forms, and their grammatical equivalents, are intended to be equivalent in meaning and to be open-ended in that the listing of one or more items following any one of these words does not imply an exhaustive listing of such one or more items, or that it is limited to only the listed item or items. For example, an item "comprising" components A, B, and C can consist of components A, B, and C (i.e., contain only components A, B, and C), or it can include not only components A, B, and C, but also one or more other ingredients. Thus, "comprising" and its similar forms, and its grammatical equivalents, are intended and understood to include disclosure of "consisting essentially of" or "consisting of" embodiments.

[0012] Where a range of values ​​is provided, unless the context clearly dictates otherwise, it is understood that each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limit of that range, and any other stated or intervening value within that stated range, is encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where one or both of the limits are included in the stated range, ranges excluding either or both of those included limits are also included in the disclosure.

[0013] As used herein, reference to "about" a value or parameter includes (and describes) a variation on the value or parameter itself. For example, a statement referring to "about X" also includes the statement "X."

[0014] As used in this specification, including the appended claims, the singular forms "a," "or," and "the" include plural references unless the context clearly dictates otherwise.

[0015] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art (e.g., cell culture, molecular genetics, nucleic acid chemistry, hybridization techniques, and biochemistry). Standard procedures are used for molecular, genetic, and biochemical procedures (see generally, Sambrook et al., Molecular Cloning: A Laboratory Manual, 4th ed. (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, and Ausubel et al., Short Protocols in Molecular Biology (2002) 5th ed., John Wiley & Sons, Inc.) and chemical procedures.

[0016] The term "TPN" as used herein relates to total parenteral nutrition.

[0017] The term "SDA" as used herein relates to stearidonic acid.

[0018] The term "ALA" as used herein relates to alpha-linolenic acid.

[0019] The term F3 (see especially the attached figures) stands for Formula #3 and is used for a newly created lipid emulsion with unique physicochemical and biological effects as disclosed herein. TPN-F3, F3, VV-TPN, and VV are used synonymously herein.

[0020] As used herein, the term "pharmaceutical" refers to a chemical substance that produces a biological effect when administered to a living organism. A pharmaceutical is a chemical substance used to treat, cure, prevent, or diagnose disease or to promote health.

[0021] As used herein, the term "toxic compound" refers to a chemical substance that can harm the health or even threaten the life of a patient.

[0022] As used herein, the term "lipophilic" refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents.

[0023] As used herein, the term "antidote" refers to the ability of a chemical substance or mixture to reduce the damage of a drug or compound to a patient's body.

[0024] As used herein, the term "ischemia-reperfusion injury" refers to tissue damage that occurs when blood supply is restored to tissue after a period of ischemia or oxygen deprivation (anoxia or hypoxia).

[0025] As used herein, the term "pharmaceutical composition" refers to an emulsion of the present invention or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition according to the present invention is provided in a form suitable for parenteral administration or injection administration.

[0026] As used herein, the term "pharmaceutically acceptable carrier" includes any solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof, as known to those of skill in the art (see, e.g., Remington: the Science and Practice of Pharmacy, ISBN 0857110624).

[0027] As used herein, the term "treating" or "treatment" of any disease or disorder (e.g., diabetes) refers, in one embodiment, to alleviating the disease or disorder (e.g., delaying, preventing, or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to alleviating or improving at least one physical parameter, including those that may not be discernible to the patient. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. Methods for assessing the treatment and / or prevention of disease are generally known in the art, unless otherwise described herein below. DETAILED DESCRIPTION OF THE INVENTION

[0028] Detailed Description of the Invention A first aspect of the present invention relates to a lipid emulsion for parenteral administration, the lipid emulsion comprising an oily phase and an aqueous phase, the oily phase of the lipid emulsion comprising (all % values ​​as weight / weight): - Omega-3 fatty acid components, - Omega-6 fatty acid components, - monounsaturated fatty acid components, and - Saturated fatty acid content.

[0029] The mass of the omega-3 fatty acid component is 20-50% of the oily layer, the mass of the omega-6 fatty acid component is 3-35%, the mass of the monounsaturated fatty acid component is 5-40%, and the mass of the saturated fatty acid component is 5-45%.

[0030] In a particular embodiment, the omega-3 fatty acid component is 20-40% by weight of the oily phase, the omega-6 fatty acid component is 5-25% by weight, the monounsaturated fatty acid component is 10-35% by weight, and the saturated fatty acid component is 10-40% by weight.

[0031] In a particular embodiment, the omega-3 fatty acid component is 25-35% by weight of the oily phase, the omega-6 fatty acid component is 10-15% by weight, the monounsaturated fatty acid component is 18-30% by weight, and the saturated fatty acid component is 20-35% by weight.

[0032] In a particular embodiment, the mass of the omega-3 fatty acid component is about 32% of the oily phase, the mass of the omega-6 fatty acid component is about 12%, the mass of the monounsaturated fatty acid component is about 27%, and the mass of the saturated fatty acid component is about 29%.

[0033] The omega-3 fatty acid component is one or more omega-3 (C 10 ~C 24 alkyl-oligo-enecarboxylic acid) fatty acids, where one carbon-carbon cis double bond is three atoms away from the terminal methyl group (example structure of alpha-linolenic acid (C18:3 omega-3), an omega-3 fatty acid); [ka]

[0034] In certain embodiments, the omega-3 fatty acid component consists of one or more members of the group consisting of alpha-linolenic acid and stearidonic acid.

[0035] The oily phase of the lipid emulsion contains at least 5% stearidonic acid (C18:4 omega-3) as part of the omega-3 fatty acid component. [ka]

[0036] In certain embodiments, the oily phase of the lipid emulsion comprises about 10% stearidonic acid as part of the omega-3 fatty acid component.

[0037] The oily phase of the lipid emulsion contains at least 15% alpha-linolenic acid (ALA) (C18:3 omega-3) as part of the omega-3 fatty acid component.

[0038] In certain embodiments, the oily phase of the lipid emulsion comprises about 20% alpha-linolenic acid as part of the omega-3 fatty acid component.

[0039] Omega-6 fatty acid components are characterized by the presence of one or more (C 10 ~C 24 alkyl-oligo-enecarboxylic acid) omega-6 fatty acids, where one carbon-carbon cis double bond is six atoms away from the terminal methyl group (exemplary structure of linoleic acid (C18:2 omega-6), an omega-6 fatty acid); [ka]

[0040] In certain embodiments, the omega-6 fatty acid component consists of one or more members of the group consisting of linoleic acid and gamma-linolenic acid.

[0041] The monounsaturated fatty acid component consists of one or more fatty acids characterized by the presence of one carbon-carbon double bond. In certain embodiments, the monounsaturated fatty acid component comprises or consists of oleic acid (CAS number 112-80-1).

[0042] The saturated fatty acid component consists of one or more fatty acids characterized by having no carbon-carbon double bonds and only carbon-carbon single bonds. In certain embodiments, the saturated fatty acid component comprises one or more members of the group consisting of caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, and palmitic acid.

[0043] In certain embodiments, the ratio (m / m) of omega-6 fatty acid components to omega-3 fatty acid components is 1:5 to 2:1. In certain embodiments, the ratio (m / m) of omega-6 fatty acid components to omega-3 fatty acid components is 1:4 to 1:1. In certain embodiments, the ratio (m / m) of omega-6 fatty acid components to omega-3 fatty acid components is 1:3 to 1:2. In certain embodiments, the ratio (m / m) of omega-6 fatty acid components to omega-3 fatty acid components is about 1:2.6.

[0044] In certain embodiments, the oily phase of the lipid emulsion comprises: - 30-60% PUFA (polyunsaturated fatty acids); - 5-45% MUFA (monounsaturated fatty acids); and - 5-50% SFA (saturated fatty acids).

[0045] In certain embodiments, the oily phase of the lipid emulsion comprises: - 35-55% PUFA; - 10-40% MUFA; and - 10-45% SFA.

[0046] In certain embodiments, the oily phase of the lipid emulsion comprises: - 40-50% PUFA; - 20-30% MUFA; and - 20-35% SFA.

[0047] In certain embodiments, the oily phase of the lipid emulsion comprises: - Approximately 44% PUFA; - Approximately 27% MUFA; and - SFA of approximately 29%.

[0048] In certain embodiments, the oily phase of the lipid emulsion comprises: - 5-35% stearidonic acid (C18:4 omega-3); - 5-50% oleic acid (C18:1); - 2-30% linoleic acid (C18:2 omega-6); - 5-50% alpha-linolenic acid (C18:3 omega-3); and - 0.5-15% gamma-linolenic acid (C18:3 omega-6).

[0049] In certain embodiments, the oily phase of the lipid emulsion comprises: - 5-25% stearidonic acid; - 10-40% oleic acid; - 4-20% linoleic acid; - 10-40% alpha-linolenic acid; and - 1-10% gamma-linolenic acid.

[0050] In certain embodiments, the oily phase of the lipid emulsion comprises: - 5-15% stearidonic acid; - 20-30% oleic acid; - 5-15% linoleic acid; - 20-30% alpha-linolenic acid; and - 2-5% gamma-linolenic acid.

[0051] In certain embodiments, the oily phase of the lipid emulsion comprises: - Approximately 10% stearidonic acid; - Approximately 24% oleic acid; - Approximately 9% linoleic acid; - approximately 22% alpha-linolenic acid; and - Approximately 3% gamma-linolenic acid.

[0052] In certain embodiments, the oily phase of the lipid emulsion comprises: - 0.5 to 15% of short-chain fatty acid components selected from caproic acid, caprylic acid, and capric acid (C6:0, C8:0, C10:0); - 3-35% lauric acid (C12:0); - 1-15% myristic acid (C14:0); and - 1-20% palmitic acid (C16:0).

[0053] In certain embodiments, the oily phase of the lipid emulsion comprises: - 1-10% of a short-chain fatty acid component selected from caproic acid, caprylic acid, and capric acid; - 5-25% lauric acid; - 2 to 12% myristic acid; and - 3-15% palmitic acid.

[0054] In certain embodiments, the oily phase of the lipid emulsion comprises: - 2-5% of short-chain fatty acid components selected from caproic acid, caprylic acid, and capric acid; - 10-15% lauric acid; - 3 to 8% myristic acid; and - 5-12% palmitic acid.

[0055] In certain embodiments, the oily phase of the lipid emulsion comprises: - approximately 3.5% of short-chain fatty acid components selected from caproic acid, caprylic acid, and capric acid; - Approximately 12% lauric acid; - about 4.5% myristic acid; and - Approximately 7.9% palmitic acid.

[0056] In certain embodiments, the oily phase of the lipid emulsion comprises: - 8-50% olive oil; - 8 to 50% coconut oil; and - 20-90% Buglossoides arvensis (ahiflower) oil (Ahiflower®).

[0057] In certain embodiments, the oily phase of the lipid emulsion comprises: - 12-40% olive oil; - 12-40% coconut oil; and - 30-70% Buglossoides arvensis oil (Ahiflower®).

[0058] In certain embodiments, the oily phase of the lipid emulsion comprises: - 20-30% olive oil; - 20-30% coconut oil; and - 40-60% Buglossoides arvensis oil (Ahiflower®).

[0059] In certain embodiments, the oily phase of the lipid emulsion comprises: - Approximately 25% olive oil; - Approximately 25% coconut oil; and - Approximately 50% Buglossoides arvensis oil (Ahiflower®).

[0060] In certain embodiments, the lipid emulsion further comprises a stabilizer and / or antioxidant. In certain embodiments, the lipid emulsion further comprises a stabilizer and / or antioxidant selected from: - EDTA; and / or - Alpha tocopherol.

[0061] In certain embodiments, the lipid emulsion further comprises a stabilizer and / or antioxidant selected from: - approximately 2.5 μmol / L EDTA; and / or - Approximately 200 mg / L of alpha-tocopherol.

[0062] In certain embodiments, the lipid emulsion comprises: - Egg yolk lecithin; - glycerol; and -Water.

[0063] In certain embodiments, the ratio of oily phase to aqueous phase (V / V) ranges from 0.1 to 0.9, and in certain embodiments, the ratio of oily phase to aqueous phase (V / V) ranges from 0.2 to 0.8.

[0064] A second aspect of the invention relates to a lipid emulsion according to the first aspect and its embodiments for use in parenteral nutrition.

[0065] In certain embodiments, parenteral nutrition is administered to patients requiring short-term or long-term total parenteral nutrition (TPN). In certain embodiments, parenteral nutrition is administered to TPN patients with metabolic disorders, particularly insulin resistance. In certain embodiments, parenteral nutrition is administered to TPN patients with liver disease. In certain embodiments, parenteral nutrition is administered to TPN patients with systemic acute and / or chronic inflammation. In certain embodiments, parenteral nutrition is administered to TPN patients with a depressed immune system and reduced host defenses. In certain embodiments, parenteral nutrition is administered to patients with sepsis. In certain embodiments, parenteral nutrition is administered to TPN patients undergoing chemotherapy.

[0066] A second alternative aspect of the present invention relates to a lipid emulsion according to the first aspect and embodiments thereof for use in enteral nutrition.

[0067] In certain embodiments, enteral nutrition is administered to patients requiring short-term or long-term enteral nutrition. In certain embodiments, enteral nutrition is administered to patients with metabolic disorders, particularly insulin resistance. In certain embodiments, enteral nutrition is administered to patients with liver disease. In certain embodiments, enteral nutrition is administered to patients with systemic acute and / or chronic inflammation. In certain embodiments, enteral nutrition is administered to patients with a depressed immune system and impaired host defenses. In certain embodiments, enteral nutrition is administered to patients with sepsis. In certain embodiments, enteral nutrition is administered to patients undergoing chemotherapy.

[0068] In certain embodiments, the lipid emulsion further comprises a pharmaceutical agent, which in certain embodiments has a molecular weight of less than 1000 g / mol, particularly less than 500 g / mol, and falls within Lipinski's rule of five.

[0069] In certain embodiments, the pharmaceutical agent is selected from the following: lipophilic drugs, in particular those selected from diazepam, propofol, etomidate, alprostadil, dexamethasone, flurbiprofen, vitamins A, D, E, K, paclitaxel, cyclosporine, clarithromycin, phenobarbital, physostigmine, cinnarizine, chlorambucil and docetaxel; - RNA-based drugs using lipid emulsions as vehicles; - an RNA or DNA vaccine, and optionally an adjuvant.

[0070] A third aspect of the present invention relates to a lipid emulsion according to the first aspect and its embodiments for use as a counteractant / antidote ("lipid sink") in the treatment of poisoning caused by lipophilic pharmaceuticals or lipophilic toxic compounds.

[0071] A fourth aspect of the present invention relates to a lipid emulsion according to the first aspect and embodiments thereof for use in protecting a vital organ against ischemia-reperfusion injury, in certain embodiments the vital organ is selected from the heart, brain, liver, kidney and lung.

[0072] A fifth aspect of the present invention relates to a lipid emulsion according to the first aspect for use in the prevention or treatment of type II diabetes.

[0073] In certain embodiments, the lipid emulsion is formulated for parenteral administration.

[0074] In certain embodiments, the lipid emulsion is formulated for enteral or oral administration.

[0075] Medical Treatments, Dosage Forms, and Salts Also included within the scope of the present invention is a method or procedure for treating a condition associated with an inability to eat in a patient in need thereof, comprising administering to the patient a lipid emulsion as described above.

[0076] Similarly, there is provided a dosage form for the treatment of a condition associated with an inability to eat, comprising a non-agonist ligand or an antisense molecule according to any of the above aspects or embodiments of the invention.

[0077] As used herein, a "condition associated with inability to eat" can refer to any condition in which a patient is temporarily or permanently unable to obtain nutrients through natural intake (i.e., oral intake). Such conditions include unconsciousness, including coma, inability to swallow due to neurological disorders, or other conditions in which the esophageal passage is obstructed or impaired, such as as a result of trauma, neoplastic disease, or other conditions in which the esophageal passage is restricted or impaired.

[0078] Indications for complete or partial parenteral nutrition encompass a wide range of clinical conditions, including critically ill patients (trauma, surgery, sepsis, shock), patients receiving home parenteral nutrition for chronic intestinal failure, cachectic cancer patients, patients with inflammatory bowel disease (Crohn's disease, ulcerative colitis), patients with gastrointestinal obstruction, enterocutaneous fistulas with high output, or short bowel syndrome, (primarily) elderly patients with acute or chronic debilitating illnesses unable to meet nutritional requirements, and patients with intractable nausea and vomiting (hyperemesis gravidarum). Furthermore, malnutrition (calorie- and / or protein-related) is a common medical problem with a high prevalence (20–50%) among hospitalized patients and is clearly associated with increased medical costs due to increased comorbidities, prolonged hospital stays, and increased use of home health care services. Supplemental parenteral nutrition to enteral nutrition, aimed at meeting increased caloric needs under stress, is also believed to reduce comorbidity and associated medical costs in critically ill patients.

[0079] Those skilled in the art will recognize that the drug compounds specifically mentioned herein may exist as pharmaceutically acceptable salts of the drug, which contain an ionized drug and an oppositely charged counterion. Non-limiting examples of pharmaceutically acceptable anionic salt forms include acetate, benzoate, besylate, bitatrate, bromide, carbonate, chloride, citrate, edetate, edisylate, ebonate, estolate, fumarate, gluceptate, gluconate, hydrobromide, hydrochloride, iodide, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl sulfate, mucate, napsylate, nitrate, pamoate, phosphate, diphosphate, salicylate, disalicylate, stearate, succinate, sulfate, tartrate, tosylate, triethiodide, and valerate salts. Non-limiting examples of pharmaceutically acceptable cationic salt forms include aluminum, benzathine, calcium, ethylenediamine, lysine, magnesium, meglumine, potassium, procaine, sodium, tromethamine, and zinc.

[0080] The dosage form may be for parenteral administration. Optionally, pharmaceutically acceptable carriers and / or excipients may be present.

[0081] Pharmaceutical Compositions and Administration Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers as described herein.

[0082] In certain embodiments of the present invention, the compounds of the present invention are typically formulated into pharmaceutical dosage forms to provide easily controllable dosing of the drug and to provide the patient with a clear, easy-to-use product.

[0083] The dosing regimen for the compounds of the invention will vary depending on known factors such as the pharmacodynamic properties of the particular agent and its mode and route of administration: the recipient's species, age, sex, health, condition, and weight; the nature and extent of symptoms; type of concurrent treatment; frequency of treatment; route of administration, the patient's renal and hepatic function, and the desired effect. In certain embodiments, the compounds of the invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses two, three, or four times daily.

[0084] In certain embodiments, the pharmaceutical compositions or combinations of the present invention may be administered in a unit dose of about 1 to 1000 mg of active ingredient(s) for a subject weighing about 50 to 70 kg. The therapeutically effective dosage of the compounds, pharmaceutical compositions, or combinations thereof depends on the species, weight, age, and individual condition of the subject, and the disorder or disease being treated or its severity. A physician, clinician, or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the progression of the disorder or disease.

[0085] The pharmaceutical compositions of the present invention can be subjected to conventional pharmaceutical procedures such as sterilization, and / or can contain conventional inert diluents, lubricants, or buffers, as well as adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers. They can be produced by standard processes, such as conventional mixing, granulation, dissolution, or lyophilization processes. Many such procedures and methods for preparing pharmaceutical compositions are known in the art, see, for example, L. Lachman et al., The Theory and Practice of Industrial Pharmacy, 4th ed., 2013 (ISBN 8123922892).

[0086] Manufacturing and treatment methods according to the present invention The present invention further encompasses, as a further aspect, the use of a lipid emulsion as identified herein for use in a method for the manufacture of a medicament for the treatment or prevention of a condition associated with an inability to eat.

[0087] Similarly, the present invention encompasses a method for treating a patient diagnosed with a disorder associated with an inability to eat, comprising administering to the patient an effective amount of a lipid emulsion as identified herein.

[0088] Where alternatives of a single separable feature, such as lipid concentration or medical indication, are described herein as "embodiments," it is understood that such alternatives can be freely combined to form separate embodiments of the invention disclosed herein. Thus, any of the alternative embodiments relating to lipid concentration can be combined with any of the alternative embodiments of medical indications referred to herein.

[0089] The present invention further includes the following items.

[0090] item Item 1. A lipid emulsion for administration to a patient, in particular for parenteral administration, comprising an oily phase and an aqueous phase, the oily phase of the lipid emulsion comprising: - Omega-3 fatty acid components, where the mass of the omega-3 fatty acid component is 20-50% of the oily phase; the omega-3 fatty acid component is comprised of one or more omega-3 fatty acids characterized by the presence of two or more carbon-carbon double bonds, where one carbon-carbon double bond is three atoms away from the terminal methyl group; and The oily phase of the lipid emulsion contains 5% or more stearidonic acid; and The oily phase of the lipid emulsion must contain at least 15% alpha-linolenic acid (ALA); - Omega-6 fatty acid components, wherein the mass of the omega-6 fatty acid component is 3-35% of the oily phase; the omega-6 fatty acid component is comprised of one or more omega-6 fatty acids characterized by the presence of two or more carbon-carbon double bonds, where one carbon-carbon double bond is six atoms away from the terminal methyl group; - monounsaturated fatty acid components, wherein the mass of the monounsaturated fatty acid component is 5-40% of the oily phase; the monounsaturated fatty acid component is composed of one or more fatty acids characterized by the presence of one carbon-carbon double bond; - Saturated fatty acid components, wherein the mass of the saturated fatty acid component is 5-45% of the oily phase; The saturated fatty acid component is composed of one or more fatty acids that are characterized by having no carbon-carbon double bonds and only carbon-carbon single bonds.

[0091] Item 2: The lipid emulsion according to Item 1, wherein the omega-3 fatty acid component consists of one or more members of the group consisting of alpha-linolenic acid and stearidonic acid.

[0092] Item 3 - the oily phase of the lipid emulsion contains about 10% stearidonic acid; and - The oily phase of the lipid emulsion contains approximately 20% alpha-linolenic acid (ALA) Item 3. The lipid emulsion according to item 1 or 2.

[0093] Item 4: The lipid emulsion according to any one of Items 1 to 3, wherein the omega-6 fatty acid component consists of one or more members selected from the group consisting of linoleic acid and γ-linolenic acid.

[0094] Item 5: The lipid emulsion according to any one of Items 1 to 4, wherein the monounsaturated fatty acid component comprises oleic acid or consists of oleic acid.

[0095] Item 6: The lipid emulsion according to any one of Items 1 to 5, wherein the saturated fatty acid component comprises or consists of one or more members of the group consisting of caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, and palmitic acid.

[0096] Item 7 - the mass of the omega-3 fatty acid component is 20-40% of the oily phase; - the mass of the omega-6 fatty acid component is between 5 and 25% of the oily phase; the mass of the monounsaturated fatty acid component is between 10 and 35% of the oily phase; - the mass of the saturated fatty acid component is 10-40% of the oily phase; 7. The lipid emulsion according to any one of items 1 to 6.

[0097] Item 8 - the mass of the omega-3 fatty acid component is 25-35% of the oily phase; - the mass of the omega-6 fatty acid component is 10-15% of the oily phase; - the mass of the monounsaturated fatty acid component is 18-30% of the oily phase; - the mass of the saturated fatty acid component is 20-35% of the oily phase; 8. The lipid emulsion according to any one of items 1 to 7.

[0098] Item 9 - the mass of the omega-3 fatty acid component is approximately 32% of the oily phase; - the mass of the omega-6 fatty acid component is approximately 12% of the oily phase; the mass of the monounsaturated fatty acid component is approximately 27% of the oily phase; - the mass of the saturated fatty acid component is approximately 29% of the oily phase; 9. The lipid emulsion according to any one of items 1 to 8.

[0099] Item 10: The lipid emulsion according to any one of Items 1 to 9, wherein the ratio (m / m) of the omega-6 fatty acid component to the omega-3 fatty acid component is 1:5 to 2:1.

[0100] Item 11 The lipid emulsion according to any one of Items 1 to 10, wherein the ratio (m / m) of the omega-6 fatty acid component to the omega-3 fatty acid component is 1:4 to 1:1.

[0101] Item 12: The lipid emulsion according to any one of Items 1 to 11, wherein the ratio (m / m) of the omega-6 fatty acid component to the omega-3 fatty acid component is 1:3 to 1:2.

[0102] Item 13: The lipid emulsion according to any one of Items 1 to 12, wherein the ratio (m / m) of the omega-6 fatty acid component to the omega-3 fatty acid component is about 1:2.6.

[0103] Item 14 The oily phase of a lipid emulsion is: - 30-60% PUFA; - 5-45% MUFA; and - 5-50% SFA 14. The lipid emulsion according to any one of items 1 to 13, comprising:

[0104] Item 15 The oily phase of a lipid emulsion is: - 35-55% PUFA; - 10-40% MUFA; and - 10-45% SFA 15. The lipid emulsion according to any one of items 1 to 14, comprising:

[0105] Item 16 The oily phase of a lipid emulsion is: - 40-50% PUFA; - 20-30% MUFA; and - 20-35% SFA 16. The lipid emulsion according to any one of items 1 to 15, comprising:

[0106] Item 17 The oily phase of a lipid emulsion is: - Approximately 44% PUFA; - Approximately 27% MUFA; and - Approximately 29% SFA 17. The lipid emulsion according to any one of items 1 to 16, comprising:

[0107] Item 18 The oily phase of a lipid emulsion is: - 5-35% stearidonic acid; - 5-50% oleic acid; - 2-30% linoleic acid; - 5 to 50% alpha-linolenic acid; and - 0.5-15% gamma-linolenic acid 18. The lipid emulsion according to any one of items 1 to 17, comprising:

[0108] Item 19 The oily phase of a lipid emulsion is: - 5-25% stearidonic acid; - 10-40% oleic acid; - 4-20% linoleic acid; - 10-40% alpha-linolenic acid; and - 1-10% gamma-linolenic acid 19. The lipid emulsion according to any one of items 1 to 18, comprising:

[0109] Item 20 The oily phase of a lipid emulsion is: - 5-15% stearidonic acid; - 20-30% oleic acid; - 5-15% linoleic acid; - 20-30% alpha-linolenic acid; and - 2-5% gamma-linolenic acid 20. The lipid emulsion according to any one of items 1 to 19, comprising:

[0110] Item 21 The oily phase of a lipid emulsion is: - Approximately 10% stearidonic acid; - Approximately 24% oleic acid; - Approximately 9% linoleic acid; - approximately 22% alpha-linolenic acid; and - Approximately 3% gamma-linolenic acid 21. The lipid emulsion according to any one of items 1 to 20, comprising:

[0111] Item 22 The oily phase of a lipid emulsion is: - 0.5 to 15% of a short-chain fatty acid component selected from caproic acid, caprylic acid, and capric acid; - 3-35% lauric acid; - 1 to 15% myristic acid; and - 1-20% palmitic acid 22. The lipid emulsion according to any one of items 1 to 21, comprising:

[0112] Item 23 The oily phase of a lipid emulsion is: - 1-10% of a short-chain fatty acid component selected from caproic acid, caprylic acid, and capric acid; - 5-25% lauric acid; - 2 to 12% myristic acid; and - 3-15% palmitic acid 23. The lipid emulsion according to any one of items 1 to 22, comprising:

[0113] Item 24 The oily phase of a lipid emulsion is: - 2-5% of short-chain fatty acid components selected from caproic acid, caprylic acid, and capric acid; - 10-15% lauric acid; - 3 to 8% myristic acid; and - 5-12% palmitic acid 24. The lipid emulsion according to any one of items 1 to 23, comprising:

[0114] Item 25 The oily phase of a lipid emulsion is: - approximately 3.5% of short-chain fatty acid components selected from caproic acid, caprylic acid, and capric acid; - Approximately 12% lauric acid; - about 4.5% myristic acid; and - Approximately 7.9% palmitic acid 25. The lipid emulsion according to any one of items 1 to 24, comprising:

[0115] Item 26 The oily phase of a lipid emulsion is: - 8-50% olive oil; - 8 to 50% coconut oil; and - 20-90% Buglossoides arvensis oil 26. The lipid emulsion according to any one of items 1 to 25, comprising:

[0116] Item 27 The oily phase of a lipid emulsion is: - 12-40% olive oil; - 12-40% coconut oil; and - 30-70% Buglossoides arvensis oil 27. The lipid emulsion according to any one of items 1 to 26, comprising:

[0117] Item 28 The oily phase of a lipid emulsion is: - 20-30% olive oil; - 20-30% coconut oil; and - 40-60% Buglossoides arvensis oil 28. The lipid emulsion according to any one of items 1 to 27, comprising:

[0118] Item 29 The oily phase of a lipid emulsion is: - About 25% olive oil; - Approximately 25% coconut oil; and - Approximately 50% Buglossoides arvensis oil 29. The lipid emulsion according to any one of items 1 to 28, comprising:

[0119] Item 30: The lipid emulsion according to any one of Items 1 to 29, further comprising a stabilizer and / or an antioxidant.

[0120] Item 31 Lipid emulsions are: - EDTA; and / or - alpha tocopherol 31. The lipid emulsion according to any one of items 1 to 30, further comprising a stabilizer and / or antioxidant selected from:

[0121] Item 32 Lipid emulsions are: - approximately 2.5 μmol / L EDTA; and / or - Approximately 200 mg / L alpha tocopherol 32. The lipid emulsion according to any one of items 1 to 31, further comprising a stabilizer and / or antioxidant selected from:

[0122] Item 33 Lipid emulsions are: - Egg yolk lecithin; - glycerol; and - water 33. The lipid emulsion according to any one of items 1 to 32, comprising:

[0123] Item 34: The lipid emulsion according to any one of Items 1 to 33, wherein the ratio of the oily phase to the aqueous phase (V / V) is in the range of 0.1 to 0.9.

[0124] Item 35: The lipid emulsion according to any one of Items 1 to 34, wherein the ratio of the oily phase to the aqueous phase (V / V) is in the range of 0.2 to 0.8.

[0125] Item 36: The lipid emulsion for use in parenteral nutrition according to any one of Items 1 to 35.

[0126] Item 37 Parenteral nutrition is used in patients with one or more of the following indications: - Patients requiring short-term and long-term total parenteral nutrition (TPN), and / or TPN patients with metabolic disorders, especially insulin resistance, and / or - TPN patients with liver disease, and / or - TPN patients with systemic acute and / or chronic inflammation, and / or - TPN patients with weakened host defenses 37. The lipid emulsion for use in parenteral nutrition according to item 36, wherein the lipid emulsion is administered to the patient.

[0127] Item 38 The lipid emulsion according to any one of Items 1 to 35, further comprising a pharmaceutical agent.

[0128] Item 39. The lipid emulsion according to Item 38, wherein the pharmaceutical agent satisfies Lipinski's Rule of Five and has a molecular weight of less than 500 g / mol.

[0129] Item 40: Medicines lipophilic drugs, in particular those selected from diazepam, propofol, etomidate, alprostadil, dexamethasone, flurbiprofen, vitamins A, D, E, K, paclitaxel, cyclosporine, clarithromycin, phenobarbital, physostigmine, cinnarizine, chlorambucil and docetaxel; - RNA-based drugs using lipid emulsions as vehicles; - an RNA or DNA vaccine, and optionally an adjuvant 40. The lipid emulsion according to item 38 or 39, selected from:

[0130] Item 41. A lipid emulsion according to any one of items 1 to 35 for use as a counteractant / antidote in the treatment of poisoning caused by lipophilic drugs.

[0131] Item 42: The lipid emulsion according to any one of Items 1 to 35, for use in protecting a vital organ, particularly a vital organ selected from the heart, brain, liver, kidney, and lung, against ischemia-reperfusion injury.

[0132] Item 43: The lipid emulsion according to any one of Items 1 to 35 for use in the prevention or treatment of type II diabetes.

[0133] Item 44. The lipid emulsion for use according to any one of claims 1 to 43, wherein the lipid emulsion is formulated for parenteral administration.

[0134] Item 45. The lipid emulsion for use according to any one of claims 1 to 35 or 41 to 43, wherein the lipid emulsion is formulated for enteral administration or oral administration.

[0135] Item 46: The lipid emulsion according to any one of Items 1 to 35, for use in enteral nutrition.

[0136] Item 47 Enteral nutrition is used in patients with one or more of the following indications: - Patients requiring short-term and long-term enteral nutrition, and / or - patients with metabolic disorders, in particular insulin resistance, and / or - patients with liver disease, and / or - patients with systemic acute and / or chronic inflammation, and / or - Patients with weakened host defenses 47. The lipid emulsion for use in enteral nutrition according to item 46, wherein the lipid emulsion is administered to the infant.

[0137] The present invention is further explained by the following examples and figures, from which further embodiments and advantages can be derived, which are intended to illustrate the invention without limiting its scope. [Brief explanation of the drawings]

[0138] [Figure 1] FIG. 1 shows the fatty acid composition of F3 (novel lipid emulsion; TPN-F3, F3, VV-TPN, and VV are used synonymously throughout this specification) as determined by gas chromatography. [Figure 2]Figure 2 shows lipopolysaccharide-binding protein (LBP) (Panel A), the correlation of LBP with the IL-10 to IL-6 ratio (Panel B), suppressor of cytokine signaling (SOCS3) (Panel C), and the correlation of SOCS3 with the IL-10 to IL-6 ratio (Panel D) in whole liver tissue from mice treated with different types of total parenteral nutrition (TPN) for 7 days. A lower IL-10 to IL-6 ratio indicates a lower degree of inflammation in liver tissue. Protein abundance was determined by immunoblotting and normalized to vinculin. The y-axis shows arbitrary relative units. TPN-IL = mice treated with Intralipid-based TPN. TPN-OV = mice treated with Omegaven-based TPN. TPN-F3 = mice treated with F3-based TPN. * indicates a significant increase compared to TPN-IL, and # indicates a significant increase compared to TPN-OV. Box plots show the median, 25th percentile, and 75th percentile. Bars represent the mean ± SD. N = 7 for TPN-IL, N = 7 for TPN-OV, and N = 6 for TPN-F3. [Figure 3] Figure 3 shows the transcription factors PPARα (Panel A), PPARγ1 (Panel B), and PPARγ2 (Panel C) in the nuclear fraction of whole liver tissue from mice treated with different types of total parenteral nutrition (TPN) for 7 days. Protein abundance was measured by immunoblotting and normalized to the nuclear marker TATA-binding protein (TBP). The Y-axis shows arbitrary relative units. TPN-IL = mice treated with Intralipid-based TPN. TPN-OV = mice treated with Omegaven-based TPN. TPN-F3 = mice treated with F3-based TPN. * indicates a significant difference from TPN-IL, and # indicates a significant decrease from TPN-OV. Bars represent the mean ± SD. Box plots show the median plus the 25th and 75th percentiles. N = 6 for each group. [Figure 4]Figure 4 shows the homeostatic model assessment of insulin resistance (HOMA-IR) (Panel A), blood glucose levels (Panel B), plasma insulin concentrations (Panel C), and liver glycogen content (Panel D) in mice treated with different types of total parenteral nutrition (TPN) for 7 days. Outcomes were measured using standard methods (see reference 2 for details). A higher HOMA-IR indicates decreased insulin sensitivity. HOMA-IR was calculated from plasma insulin and total blood glucose using a normalization factor of 14.1, which is the adjustment factor for C57BL / 6J mice. Liver glycogen is a reliable indicator of hepatic insulin signaling and insulin sensitivity: the higher the glycogen content, the more efficient the insulin signaling. TPN-IL = mice treated with Intralipid-based TPN. TPN-OV = mice treated with Omegaven-based TPN. TPN-F3 = mice treated with F3-based TPN. # indicates a significant increase compared to TPN-OV, and * indicates a significant increase compared to TPN-IL. Bars represent the mean ± SD. Box plots show the median plus the 25th and 75th percentiles. N = 12 for each group. [Figure 5]Figure 5 shows the abundance of insulin receptor β subunit (IRβ, panel A), insulin receptor substrate 1 (IRS1, panel B), and insulin receptor substrate 2 (IRS2, panel C) in whole liver tissue homogenates from mice treated with different types of total parenteral nutrition (TPN) for 7 days. IRβ abundance was measured by enzyme-linked immunosorbent assay. IRS protein abundance was determined by immunoblotting and normalized to vinculin. The Y-axis shows arbitrary relative units. TPN-IL = mice treated with Intralipid-based TPN. TPN-OV = mice treated with Omegaven-based TPN. TPN-F3 = mice treated with F3-based TPN. * indicates a significant increase relative to TPN-IL, and # indicates a significant increase relative to TPN-OV. Bars represent mean ± SD. Box plots show the median plus the 25th and 75th percentiles. N = 12 for each group. [Figure 6] Figure 6 shows glycogen synthase (GS, Panel A), glycogen synthase phosphorylation at serine 641 (Panel B), and glucokinase (GCK, Panel C) in liver tissue from mice treated with different types of total parenteral nutrition (TPN) for 7 days, as well as their nuclear (inactive) and cytoplasmic (active) fractions (Panel D). Protein abundance was measured by immunoblotting and normalized to vinculin or TBP, respectively, in the nuclear fraction. chow = tissue samples from mice fed a normal chow diet as a control. TPN-IL = mice treated with Intralipid-based TPN. TPN-OV = mice treated with Omegaven-based TPN. TPN-F3 = mice treated with F3-based TPN. § indicates a significant decrease compared to all other groups. * indicates a significant increase compared to TPN-OV. Box plots show median plus 25th and 75th percentiles. N=6 for each group. [Figure 7]Figure 7 shows the results of the Ferrous Oxidation-Xylenol Orange (FOX) assay: content of primary oxidation products over time in Intralipid, Omegaven, and three different batches of F3 lipid emulsion. [Figure 8] Figure 8 shows the sterol content of Intralipid (IL), Omegaven (OV), and Formulation No. 3 (F3) (Panel A). Plant sterols and plant stanols (phytosterols, Panel C) are plant-derived compounds structurally related to cholesterol (Panel B), an animal-derived sterol. The higher cholesterol content in Intralipid (compared to F3) may be due to the purification process used for the egg lecithin in Intralipid (compared to Lipoid 80 used in F3). Stigmasterol (Panel D) is an unsaturated phytosterol typically present in soy. Other phytosterols include campesterol (Panel E) and β-sitosterol (Panel F). [Figure 9]Figure 9 shows the anti-inflammatory effects of TPN-F3 in key insulin-sensitive tissues. Interleukin-6 (IL6; panels A, D, G, J), interleukin-10 (IL10; panels B, E, H, K), and the IL6 / IL10 ratio (panels C, F, I, L) were measured in whole-tissue homogenates from the liver (panels A, B, C), skeletal muscle (panels D, E, F), epididymal white adipose tissue (WAT) (panels G, H, I), and pancreas (panels J, K, L) of mice treated with different types of total parenteral nutrition (TPN) for 7 days. Cytokine concentrations were measured by enzyme-linked immunosorbent assay. IV-chow: Mice fed a normal (solid) chow diet and continuously infused saline; IL-TPN: Mice treated with Intralipid-based TPN; OV-TPN: Mice treated with Omegaven-based TPN; VV-TPN: Mice treated with TPN-F3-based TPN. #: Significantly increased compared to all other groups; @: Significantly different compared to VV-TPN; **: Significantly different compared to IL-TPN; §: Significantly decreased compared to IV-chow. Bars indicate mean ± SD. N = 6 per group. [Figure 10]Figure 10 shows the regulation of gluconeogenesis under different TPN regimens. Panel A: Glycogen synthase (GS), GS phosphorylation at serine 641, and representative immunoblots in liver tissue from mice treated with different types of total parenteral nutrition (TPN) for 7 days. Panels B–D: Glucokinase (GCK) abundance and representative immunoblots in total tissue lysates (Panel B), cytoplasmic (active) fractions (Panel C), and nuclear (inactive) fractions (Panel D). Protein expression was normalized to vinculin for total tissue lysates or cytoplasmic fractions, respectively, and to TATA-binding protein (TBP) for nuclear fractions. Chow: Mice fed a normal diet (control sample); IL-TPN: Mice treated with Intralipid-based TPN; OV-TPN: Mice treated with Omegaven-based TPN; VV-TPN: Mice treated with TPN-F3-based TPN. # indicates a significant decrease compared to all other groups, * indicates a significant increase compared to normal diet, and ** indicates a significant increase compared to TPN-OV. Bars indicate mean ± SD. N=6 per group. [Figure 11]Figure 11 shows interleukin-10-mediated insulin signaling in TPN-F3-based TPN. The effects of neutralizing anti-IL10 treatment on IL6 and IL10 and their respective ratios (Panel A), liver glycogen content (Panel B), IRS2 protein expression and its tyrosine phosphorylation (Panels C and D), glucokinase (GCK) in total tissue lysates (Panels E and G), and inactive (nuclear) GCK (Panel F) were measured by immunoblotting. The nuclear fraction was normalized to vinculin and TATA-binding protein (TBP), respectively. VV-TPN: Mice treated with TPN-F3-based TPN; VV-TPN(IgG): Mice treated with VV-based TPN and an isotype control antibody; VV-TPN(anti-IL10): Mice treated with VV-based TPN and a neutralizing anti-IL10 antibody. * indicates a significant difference from VV-TPN. # indicates a significant difference from VV-TPN (IgG). Bars indicate mean ± SD. N = 5–6 per group. Note: Isotype control antibody IgG has previously been shown to exert some anti-IL10 effect through Fc receptor binding to immune cells. [Figure 12]Figure 12 shows microbiome analysis of colonic mucosal samples from mice treated with IL-TPN, OV-TPN, and VV-TPN for 7 days compared with control mice. Panel A: TPN altered the relative bacterial abundance at the animal phylum level, resulting in a significant expansion of Bacteroidetes at the expense of Firmicutes. Panel B: Animal phylum-level alpha diversity was significantly affected by TPN containing Intralipid (IL-TPN) and Omegaven (OV-TPN), but to a lesser extent by TPN-F3 (VV-TPN). Panel C: Verrucomicrobiota, i.e., Akkermansia muciniphila, was significantly increased in mice receiving IL-TPN and OV-TPN compared with mice receiving VV-TPN. Normal diet (C): control mice on normal diet; IV-chow (S): mice on normal diet and continuous infusion of saline; IL-TPN (IL): mice treated with Intralipid-based TPN; OV-TPN (OV): mice treated with Omegaven-based TPN; VV-TPN (VV): mice treated with TPN-F3-based TPN. * indicates significant difference from normal diet and IV-normal diet; @ indicates significant difference from VV-TPN. N = 6 per group. Figure generated using MicrobiomeAnalyst. [Figure 13]Figure 13 shows the characteristics of CD4+ T cells in liver tissue from VV-TPN mice. Panel A: Percentage of naive T cells (CD44low / CD62Lhigh) and "antigen-experienced" T cells, i.e., cells expressing low amounts of CD62L / L-selectin, including effector memory T cells (CD44high / CD62Llow). Note the very low abundance of central memory (CD44high / CD62Lhigh) CD4+ T cells in the liver. Panels B–D: Intracellular staining of cytokine production in hepatic CD4+ T cells in response to activation with phorbol myristate acetate (PMA) and ionomycin. Intracellular staining was performed to measure the expression of interferon-γ (IFNγ; panels B and C) and interleukin-17A (IL17A; panels D and E) produced by CD4+ T cells. Data are shown as mean fluorescence intensity ratio (MFI ratio; panels B and D) and percentage of positively stained CD4+ T cells (%CD4+ T cells; panels C and E), respectively. Chow are control mice fed a normal diet; IL-TPN are mice treated with Intralipid-based TPN; and VV-TPN are mice treated with TPN-F3-based TPN. Bars indicate mean ± SE. Dots represent individual experiments. N = 3–4 per group. [Figure 14]Figure 14 shows lipid mediators in liver tissue from mice treated with different TPN regimens. Panel A: Heatmap of measured lipid mediators. Columns correspond to study groups, and rows correspond to lipid mediators derived from polyunsaturated fatty acid (PUFA) precursors, as annotated on the left side of the heatmap. Data are color-coded according to z-scores, which represent the relative abundance of each lipid mediator. Precursors of n-3 PUFAs are α-linolenic acid (ALA), docosapentaenoic acid (DPA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Precursors of n-6 PUFAs are dihomo-γ-linolenic acid (DGLA), linoleic acid (LA), and arachidonic acid (AA). The 15-lipoxygenase metabolite of ALA, 9S-hydroxy-9Z,11E,15Z-octadecatrienoic acid (9(S)-HOTrE), is highlighted. [Figure 15] Figure 15 shows that supplementing Intralipid-based TPN with 9(S) / 13S-hydroxy-9Z,11E,15Z-octadecatrienoic acid (9(S) / 13(S)-HOTrE) mimics the phenotype induced by TPN-F3-based TPN. Mice receiving IL-TPN were treated with 9 / 13-hydroxyoctadecatrienoic acid (5 ng / mL) added to the TPN mixture. Plasma concentrations of interleukin-10 (IL10) in whole liver tissue homogenates (Panel A), tissue interleukin-6 (IL6) levels (Panel B), interleukin-10 levels (Panel C), and the IL6 / IL10 ratio (Panel D). Liver glycogen content (Panel E), insulin receptor substrate 2 protein (IRS2) abundance (Panel F), tyrosine-phosphorylated IRS2 abundance (Panel G), and their respective ratios (Panel H). IL-TPN: Mice treated with Intralipid-based TPN; VV-TPN: Mice treated with TPN-F3-based TPN; IL-TPN+HOTrE: Mice treated with Intralipid-based TPN supplemented with 9(S) / 13(S)-HOTrE. Bars indicate mean ± SD. N = 4–6 per group.

[0139] Table 1 shows the oil phase composition of lipid emulsions commonly used in total parenteral nutrition (amounts are given per 100 mL). The emulsions are 20% with the exception of Omegaven, which is only available as a 10% emulsion. Amounts are given per 100 mL. Intralipid, SMOFlipid, and Omegaven are manufactured by Fresenius Kabi (Bad Homburg, Germany), Lipofundin by B. Braun (Melsungen, Germany), and ClinOleic by Baxter Healthcare Corporation (Deerfield, Illinois, USA). All emulsions use egg yolk lecithin as an emulsifier and glycerol to adjust osmolality. SFAs are saturated fatty acids, MUFAs are monounsaturated fatty acids, and PUFAs are polyunsaturated fatty acids.

[0140] Table 2 shows the composition of F3, listing the main fatty acids present in the lipid emulsion. [Example]

[0141] In the following, TPN-F3, F3, VV-TPN, and VV will be used as synonyms.

[0142] Example 1: Composition of the oily phase in commonly used lipid emulsions [Table 1]

[0143] SMOFlipid was developed taking into account recommendations for optimal dietary intake of polyunsaturated fatty acids, which call for an n-6:n-3 ratio of 1:1 to 4:1. The newly developed oil phase of F3 also meets this dietary requirement, with an n-6:n-3 ratio of 1:2.6. However, it is composed exclusively of non-GMO (non-genetically modified) vegetable oils, one of which is ahiflower oil. Ahiflower oil is a rich single plant source of the n-3 fatty acids alpha-linolenic acid (ALA) and stearidonic acid (SDA), as well as the n-6 fatty acids gamma-linolenic acid (GLA) and linoleic acid (LA). Ahiflower oil contains 17-20% SDA, the highest naturally occurring SDA content of any commercially available edible vegetable oil. SDA-rich oils are increasingly recognized as an excellent source of n-3 fatty acids, which have anti-inflammatory and metabolic effects. Additionally, SDA is less unsaturated than the eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found in fish oil, making it more stable when present in lipid emulsions. The F3 blend oil contains 50% ahiflower, resulting in approximately 10% SDA and 20% ALA. See Table 2 below for details.

[0144] [Table 2]

[0145] F3 also contains EDTA (2.5 μM) and tocopherol (160-200 mg / L) to stabilize unsaturated fatty acids and protect them from oxidation.

[0146] Example 2: Problems commonly associated with TPN Infusion of lipid emulsions that provide fatty acids generally promotes lipid accumulation, which causes insulin resistance and enhances tissue inflammation (especially interleukin-6 release). Furthermore, the use of lipid emulsions in TPN has been associated with impaired immune responses and a higher incidence of infections. For a detailed review, see: Lucchinetti et al. Novel Strategies to Prevent Total Parenteral Nutrition-Induced Gut and Liver Inflammation and Adverse Metabolic Outcomes. Mol Nutr Food Res. 2021;65(5):e1901270. doi:10.1002 / mnfr.201901270. PMID:32359213. F3 is a newly developed lipid emulsion that has unique beneficial effects on inflammation, insulin signaling, and immune responses, and reduces side effects, especially when used in TPN.

[0147] Example 3: TPN-F3 induces potent anti-inflammatory effects in key metabolic insulin-sensitive tissues during TPN compared to standard lipid emulsion After 7 days of TPN, body weight was similar between the TPN groups, consistent with previous reports using the same TPN mouse model. VV-TPN increased plasma IL10 levels compared with IL-TPN and OV-TPN. VV-TPN further reduced the concentration of the pro-inflammatory cytokine IL6 in liver tissue, while simultaneously increasing the production of the anti-inflammatory cytokine IL10, significantly decreasing the IL6 / IL10 ratio (Figure 9). The IL6 / IL10 ratio was higher in liver tissue from IL-TPN and OV-TPN mice. A similar pattern of IL6 / IL10 ratio was observed in skeletal muscle, epididymal white adipose (eWAT), and pancreatic tissue (Figure 9). VV-TPN also reduced TNFα levels in liver tissue compared with IL-TPN. VV-TPN, unlike IL-TPN and OV-TPN, increased the production of lipopolysaccharide-binding protein (LBP) in the liver. LBP is a protein that detoxifies endotoxin (LPS) via high-density lipoprotein (HDL) and chylomicrons. Higher LBP levels correlated with lower inflammation, as evidenced by lower IL6 / IL10 ratios, suggesting that LBP removes endotoxins released from leaky gut, thereby reducing IL6 production in the liver (Figure 2A and B). Similarly, suppressor of cytokine signaling 3 (SOCS3), a protein that inhibits IL6 signaling, was increased in the liver of VV-TPN mice and inversely correlated with the IL6 / IL10 ratio (Figure 2C and D). Similar to OV-TPN, VV-TPN elevated hepatic nuclear PPARα (PPARα is a transcription factor known to increase hepatic fatty acid oxidation and reduce fat-induced hepatitis), but nuclear PPARγ1 did not differ between the different TPN groups (Figure 3A and B). Only VV-TPN reduced nuclear PPARγ2, a transcription factor known to promote hepatic lipid accumulation and pro-inflammatory cytokine production, leading to steatohepatitis (Fig. 3C). VV-TPN and OV-TPN also reduced the LPS content in epididymal white adipose tissue (eWAT) compared with IL-TPN, but only VV-TPN reduced the pro-inflammatory NF-κB expression in eWAT, consistent with a reduced IL6 / IL10 ratio.k VV-TPN significantly reduced the protein expression of B. Finally, VV-TPN also increased anti-inflammatory IL4 in liver and pancreatic tissues. In summary, VV-TPN exerted the strongest anti-inflammatory effects in multiple major metabolic insulin-sensitive tissues when compared with IL-TPN and OV-TPN.

[0148] Example 4: F3 specifically promotes insulin signaling in the liver and further improves whole-body glucose tolerance during TPN TPN impairs insulin signaling, resulting in systemic insulin resistance. TPN-F3 and TPN-OV improved whole-body insulin response, as assessed by HOMA-IR (homeostatic model assessment of insulin resistance), compared with TPN-IL (Figures 4A-C). However, only TPN-F3 maintained insulin signaling in the liver, as evidenced by normalization of glycogen content, a reliable indicator of hepatic insulin sensitivity (Figure 4D). TPN-F3 and TPN-OV increased the abundance of insulin receptors in liver tissue compared with TPN-IL (Figure 5A). However, only TPN-F3 increased the abundance of insulin receptor substrate 2 (IRS2), whereas IRS1 remained unchanged (Figures 5B, 5C and Table 4). TPN-IL significantly reduced the abundance of glycogen synthase in liver tissue, whereas TPN-F3 and TPN-OV did not (Figure 10A). No differences were observed in the phosphorylation status of hepatic glycogen synthase at Ser461 (the phosphorylation site responsible for inhibition) among the three TPNs (Fig. 10A). However, TPN-F3 showed a higher abundance of glucokinase, the rate-limiting step in hepatic glycogen formation (Fig. 10B). Compared with TPN-OV, TPN-F3 had a higher fraction of active cytosolic glucokinase (Fig. 10C), explaining the higher glycogen stores in liver tissue of F3-treated mice. Taken together, these findings demonstrated that TPN-F3 enhanced hepatic insulin sensitivity compared with TPN-IL or TPN-OV. Application of a neutralizing IL-10 antibody to TPN-F3 increased the IL-6 / IL-10 ratio to that observed with TPN-IL (Fig. 11A), and hepatic glycogen accumulation was reduced (Fig. 11F) due to an increased nuclear fraction of glucokinase (Fig. 11B). Taken together, these findings highlight the important role of elevated IL-10 production in hepatic tissue in maintaining insulin signaling in TPN-F3-treated mice and further provide a mechanistic link between the metabolic benefits of TPN-F3 and its anti-inflammatory cytokine profile.

[0149] [Table 4]

[0150] Example 5: Unlike IL and OV, F3 promotes strong host defense against invading bacteria such as Akkermansia muciniphila during TPN TPN causes immune cell depletion and dysfunction of cytokine responses. However, in contrast to TPN-IL, F3-TPN induces an "activated" phenotype of liver resident macrophages (Kupffer cells) with M1-like polarization, resulting in INFγ- and IL-17-producing CD4 + Increases the proportion of insulin-resistant macrophages and CD4 T cells (Figure 13). + Consistent with previously reported enhanced immune responses in insulin-sensitive, as opposed to T-cell, mice treated with TPN-F3 also had elevated liver tissue concentrations of INFγ, a cytokine important for efficient host defense, when compared with mice treated with TPN-IL or TPN-OV.

[0151] Detailed gut microbiome analysis based on 16S RNA sequencing was performed. For this purpose, colonic mucosal samples were collected at the end of the 7-day experimental period. DNA was extracted according to the protocol of the ZymoBIOMICS DNA Miniprep Kit (D4300, Zymo Research Corp; Irvine, CA, USA). Amplification of the V3-V4 hypervariable region was performed using standard primers 341F and 805R. Libraries were prepared at the Fasteris facility (Genesupport / Fasteris SA, Plan-les-Ouates, Switzerland) using the Metafast protocol. 16S rRNA gene sequences were clustered into Operational Taxonomic Units (OTUs) and mapped to the SILVA database. All data analysis was performed using the web-based tool MicrobiomeAnalyst.ca (https: / / www.microbiomeanalyst.ca / ). The following results were obtained: As previously shown, TPN decreased the abundance of Firmicutes and increased the abundance of Bacteroidetes (Figure 12). This analysis further revealed significant changes in the Verrucomicrobium phylum. This phylum encompasses and is defined by the genus Akkermansia, of which the mucin-degrading bacterium Akkermansia muciniphila is the sole and most prominent member. Akkermansia muciniphila is a commensal organism that becomes pathogenic upon gut microbiota disruption and IL-10 deficiency. Importantly, in contrast to mice treated with TPN-IL or TPN-OV, invasion of the intestinal wall was inhibited in mice treated with TPN-F3, providing evidence of enhanced host defenses upon treatment with TPN-F3 (Figure 12).

[0152] To better understand the effects of TPN using different lipid emulsions on host defense, we determined the abundance and phenotype of immune cells in tissues. IL-TPN was chosen for direct comparison with VV-TPN because it exhibits a distinctly different immunometabolic phenotype, in contrast to OV-TPN, which displayed an intermediate phenotype. TPN generally induces a reduction in leukocytes (CD45+) in various organs, including the intestine, which generally exhibits significant intestinal atrophy. Immune cell profiling of the spleen, mesenteric lymph nodes, and liver demonstrated impaired TNFα responses in PMA / ionomycin-stimulated CD4+ T cells compared with normal-fed mice (except for VV-TPN in the liver). However, in contrast to IL-TPN, VV-TPN significantly increased antigen-experienced, i.e., primed, effector, and effector memory CD4+ T cells (CD44 low / CD62L low , CD44 high / CD62L low ) (Fig. 13A), and IFNγ-producing CD4+ T cells (Figs. 13B and 13C) and IL17-producing CD4+ T cells (Figs. 13D and 13E), increased the proportion of activated B cells (CD80+ / CD86+), and simultaneously increased the proportion of M1-like resident macrophages (CD11b low / CD11c+) and non-resident macrophages (CD11b high / CD11c+), while increasing the proportion of M2-like macrophages (CD11b low / CD206+, CD11b high / CD206+). B cell activation was associated with higher levels of IgG against endotoxin (LPS) in VV-TPN compared with OV-TPN and IL-TPN. Similar to the cellular findings, VV-TPN-treated mice had higher liver tissue concentrations of IFNγ, a cytokine important in host defense, compared with IL-TPN and OV-TPN. Although we were unable to reliably measure IL10 intracellular expression in immune cells using flow cytometry, likely due to low intracellular expression, both T cells and macrophages collected 7 days after VV-TPN showed IL10 expression as measured by immunoblotting. Expression of IL6, IFNγ, and TNFα in macrophages was similar in chow-fed, IL-TPN, and VV-TPN mice, as measured by flow cytometry.

[0153] Example 6: TPN-F3 induces a distinctive profile of lipid mediators in liver tissue, and 9-hydroxyoctadecatrienoic acid, an 18-carbon ALA lipid mediator, contributes to the TPN-F3-induced immunometabolic phenotype Oxylipins are oxygenated fatty acid metabolites produced in the liver, including eicosanoids (prostaglandins and leukotrienes) and specialized pro-catabolic mediators known as potent regulators of metabolism and immune responses. To test whether a high supply of 18-carbon n-3 fatty acids, i.e., ALA and SDA, released during VV-TPN, induces a distinct hepatic oxylipin profile, we determined lipid mediators using a targeted lipidomics approach (UHPLC-MS / MS). OV-TPN increased many oxylipins derived (mainly) from long-chain n-3 fatty acids, i.e., EPA and DHA, which are known to have anti-inflammatory properties, whereas VV-TPN not only did not increase these oxylipins, but also failed to increase many common pro-inflammatory oxylipins derived from arachidonic acid, as observed with IL-TPN. 9S-Hydroxy-10E,12Z,15Z-octadecatrienoic acid (9-HOTrE), a monohydroxypolyunsaturated fatty acid generated from ALA by 12 / 15-lipoxygenase, was increased only in VV-TPN mice (Fig. 14). To test whether hydroxyoctadecatrienoic acid contributes to the immunometabolic phenotype induced by VV-TPN, 9 / 13-HOTrE was added to IL-TPN. Provision of these lipid mediators increased plasma and liver tissue concentrations of IL10 after TPN, resulting in a low IL6 / IL10 ratio similar to that observed in liver tissue of VV-TPN mice (Fig. 15D). The decreased IL6 / IL10 ratio was further accompanied by increased expression and tyrosine phosphorylation of IRS2 protein and increased liver glycogen content (Fig. 15F). When added to IL-TPN, HOTrE also increased IFNγ levels in liver tissue, whereas TNFα levels remained elevated similarly to those in IL-TPN. These observations provide evidence that HOTrE indeed contributes to the immunometabolic phenotype induced by VV-TPN.

[0154] Example 7: Advantages of F3 compared to commercial lipid emulsions Sustainability F3 does not contain fish oil, which is a concern due to overfishing in the oceans, nor does it contain toxins that accumulate in the food chain (such as radioactive materials from the 2011 Fukushima nuclear disaster).

[0155] Resistant to oxidation / decomposition F3 has fatty acids with only four double bonds, as opposed to the five or six double bonds present in fish oil, making it more resistant to oxidation / degradation (longer shelf life). Notably, F3 produces 2.5 times fewer primary oxidation products over time than Omegaven (see Figure 7). After 300 days of production, secondary oxidation products (TBARS) for F3 were 18 μmol / kg oil. -1 and Intralipid (4 μmol (kg oil) -1 ), but OV (25 μmol (kg oil) -1 ) is clearly lower than

[0156] Reduced total sterol load F3 has the lowest amount of total sterols, including phytosterols and cholesterol, as measured by mass spectrometry (see Figure 8, which includes four independent measurements of the indicated sterols in Intralipid, Omegaven, and F3). Notably, F3 also contains less stigmasterol than Intralipid, a phytosterol associated with liver inflammation.

[0157] Example 8: Clinical applications of novel lipid emulsion F3 with anti-inflammatory, hepatoprotective, antidiabetic, and host defense enhancing effects Patients requiring short-term and long-term total parenteral nutrition (TPN) Total parenteral nutrition (TPN) is a lifesaving nutritional therapy in situations where enteral nutrition is contraindicated or inadequate. TPN is provided to millions of patients who are unable to orally ingest or assimilate the daily required amount of nutrients (partial parenteral nutrition or TPN). While parenteral nutrition is often temporary, lasting a few days to a few weeks, thousands of patients require long-term (>3 months) home-based parenteral nutrition each year in the United States alone. Additionally, 500,000 infants in the United States, including premature and low-birth-weight infants, rely on TPN. Indications for complete or partial parenteral nutrition encompass a wide range of clinical conditions, such as critically ill patients (trauma, surgery, sepsis, shock), patients receiving home parenteral nutrition for chronic intestinal failure, cachectic cancer patients, patients with inflammatory bowel disease (Crohn's disease, ulcerative colitis), patients with gastrointestinal obstruction, enterocutaneous fistulas with high output, or short bowel syndrome, (mainly) elderly patients with acute or chronic debilitating illnesses that prevent them from meeting their nutritional requirements, and patients with intractable nausea and vomiting (hyperemesis gravidarum). Furthermore, malnutrition (calorie and / or protein related) is a common medical problem with a high prevalence (20-50%) among hospitalized patients.

[0158] Patients who require short-term and long-term enteral nutrition Enteral and parenteral formulations are designed for subjects / patients whose specific conditions prevent them from meeting their nutritional needs through normal food intake. The specifics of the patient's condition determine the route of administration for nutritional support. Parenteral lipid emulsions can also be administered enterally (as part of a complete enteral formulation) because this route of administration has much less stringent requirements regarding sterility, osmolality, and pH. The use of lipid emulsions in enteral formulations offers the distinct advantage of minimizing the side effects of parenteral administration (such as liver disease, metabolic disorders, immunosuppression, and intestinal atrophy; see Lucchinetti et al. Mol Nutr Food Res. 2021 Mar;65(5):e1901270 for a detailed review). Enteral administration of lipid emulsions results in complete systemic absorption, uptake, and distribution of the lipid emulsion and its compounds, which is expected to produce the same biological effects observed with parenteral administration, particularly with regard to inflammation, metabolism, and the immune system.

[0159] Patients with metabolic disorders, especially insulin resistance The most prevalent metabolic disease worldwide is impaired glucose tolerance (also known as prediabetes), with an estimated prevalence of 25-30% in Western populations, including patients with type I and type II diabetes (up to 10%), all metabolic conditions in which insulin resistance is a concern.

[0160] Patients with weakened host defenses Many patients suffer from immune system dysregulation due to metabolic disorders, autoimmune diseases, and infections.

[0161] Patients with liver disease Non-alcoholic steatohepatitis and cirrhosis (NASH) has a prevalence of 30-50% in Western societies. Other liver diseases that may benefit from novel lipid emulsions include Alagille syndrome, alcohol- and drug-related liver disease, alpha-1 antitrypsin deficiency, autoimmune hepatitis, benign liver tumors, biliary atresia, cholestasis, Crigler-Najjar syndrome, galactosemia, Gilbert syndrome, hemochromatosis, hepatic encephalopathy, hepatitis A, B, and C, hepatorenal syndrome, intrahepatic cholestasis of pregnancy, lysosomal acid lipase deficiency, liver cysts, liver cancer, neonatal jaundice, primary biliary cholangitis, primary sclerosing cholangitis, progressive familial intrahepatic cholestasis, Reye's syndrome, glycogen storage disease type I, and Wilson's disease.

[0162] Patients with systemic acute and / or chronic inflammation This includes not only conditions involving infection, but also autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, as well as conditions involving sterile inflammation such as multiple sclerosis, psoriasis, and ankylosing spondylitis.

[0163] Example 9: Further fields of application of the novel lipid emulsion F3 Lipid emulsions can be used as drug delivery systems (vehicles) for parenteral (injectable) or enteral administration of (lipophilic) drugs, including biological drugs, and more recently for nucleic acid-based therapies (i.e., the use of nucleic acids and related compounds to alter gene expression for therapeutic purposes) and vaccines. Further applications of lipid emulsions in medicine include the treatment of (lipophilic) drug overdose / poisoning (emulsions as detoxification) and the prevention of ischemia-reperfusion injury (protection of vital organs).

[0164] Example 10: Drug administered in a lipid emulsion that serves as a vehicle The application of lipid emulsions in parenteral or enteral drug delivery has distinct advantages: 1) reduced pain, irritation, and thrombophlebitis; 2) reduced toxicity; 3) improved stability and solubility due to reduced degradation; and 4) targeted drug delivery, primarily to the liver. Currently available examples of drugs formulated as injectable emulsions include diazepam, propofol, etomidate, alprostadil, dexamethasone, flurbiprofen, vitamins A, D, E, and K, paclitaxel, and cyclosporine. Many other drugs are considered more stable in lipid emulsions, but specific formulations have not yet been developed for the healthcare market. These include clarithromycin, phenobarbital, physostigmine, cinnarizine, chlorambucil, and docetaxel.

[0165] In principle, any highly lipophilic drug can be administered intravenously using lipid emulsions as a safe vehicle.

[0166] Example 11: RNA Therapy Using Lipid Emulsion as a Vehicle This is an emerging field in which lipid-carrying systems are used as vehicles for gene therapy. RNA lipid delivery systems have been used in clinical trials and are currently being used. For example, siRNA-EphA2-DOPC targeting EPHA2 is used for advanced cancers (NCT 01591356), ALN-VSP02 targeting KSP and VEGF is used for solid tumor therapy (NCT 00882180), and TKM-ApoB targeting ApoB is used for the treatment of hypercholesterolemia (NCT 00927459).

[0167] Example 12: Vaccine therapy using lipid emulsion as vehicle and adjuvant Liposomes are ideal carriers for combination vaccines targeting multiple antigens, enhancing the induction of antibodies and cell-mediated immunity, such as the production of a pentavalent vaccine against hepatitis A, hepatitis B, diphtheria, tetanus, and influenza A / B, which has good immunogenicity and excellent tolerance.

[0168] Example 13: Further applications of lipid emulsions as "rescue therapy" in medicine Lipid emulsions can act as a "lipid sink" for patients addicted to lipophilic drugs such as local anesthetics, beta-blockers, neuroleptics, calcium channel blockers, etc. Furthermore, they can be used to protect against ischemia-reperfusion injury in vital organs such as the heart, brain, liver, kidneys, and lungs.

[0169] Discussion The development of a novel lipid emulsion for TPN was motivated by poor clinical outcomes, including hepatotoxicity, diabetes-like metabolic conditions, and immunosuppression-related infection risks, in patients dependent on lifesaving TPN using currently available lipid emulsions. Our newly designed and engineered lipid emulsion is enriched with two short-chain, 18-carbon n-3 fatty acids, α-linolenic acid (ALA) and stearidonic acid (SDA), and optimized for the recommended n-6 / n-3 ratio of 1:2.5. It is more resistant to oxidation and hydrolysis than lipid emulsions based on 20 / 22 carbon n-3 fatty acids, thereby promoting a longer shelf life. Furthermore, it contains less stigmasterol, a toxic phytosterol, than other vegetable oil-based lipid emulsions. This emulsion (herein named TPN-F3(VV)) uses only vegetable oils instead of algae, krill, or fish oil, making it more sustainable in relation to overfishing and reducing the risk of exposure to bioaccumulating marine toxins such as dioxins, mercury, and radionuclides. After detailed comparison with two commonly used lipid emulsions, soybean oil-based Intralipid and fish oil-based Omegaven, we found that TPN-F3 possesses a unique combination of anti-inflammatory, insulin-sensitizing, and immune-enhancing properties unmatched by currently available lipid emulsions. Specifically, we demonstrated that VV-TPN, which releases 18-carbon n-3 fatty acids, mediates its beneficial effects by enhancing IL10-dependent insulin signaling and enhancing immunity.

[0170] During TPN, the immune system is constantly exposed to high amounts of bacterial toxins, namely endotoxins (LPS), which leak from the intestine into the portal venous system. Although the lack of oral nutrition reduces the total bacterial load in the intestine, Gram-negative and invasive bacteria dominate the intestinal microbiome during TPN. At the same time, the immune system suffers from a catabolic state due to insulin resistance. Recent studies in mice suggest that insulin resistance plays a key role in the development of immune cell dysfunction, as both insulin and T cell receptor signaling converge on the same downstream kinase, Akt. Using activated CD4+ T cells lacking the insulin receptor, mice showed reduced proliferation and cytokine production, namely IFNγ, as well as impaired differentiation affecting Th1 and Th17 T cells. Intact insulin signaling appears to benefit T cell metabolism, enabling a more effective immune response to pathogens. Another study in rats showed that CD4+ T cells produced insufficient IL-10 in the absence of insulin receptors. Insulin resistance also promotes "lazy" M2-like macrophages with impaired activation. Thus, VV-TPN induces primed effector CD4+ T cells (CD44) that can acquire a cytotoxic phenotype or induce and modulate the activity of many innate immune cells. low / CD62L lowThis may have improved insulin signaling and strengthened immune cells, as evidenced by increased numbers of IL-TPN-associated proteins (IL-TPN). This enhanced immunity may ultimately help to eliminate the microinvasive bacterium Akkermansia muciniphila from the intestinal mucosa. Notably, we observed a relative deficiency of IL10 in IL-TPN, particularly in liver tissue where IL6 concentrations were increased, but this was not the case in VV-TPN. IL10 deficiency is known to increase Akkermansia muciniphila colonization, accompanied by increased bacterial translocation and production of pro-inflammatory cytokines, including IL6. This also increases the risk of colonization by other pathogens, such as Clostridium difficile, in the absence of immunosuppression. We previously reported the importance of Akkermansia muciniphila development during TPN using the same mouse model. This bacterium has an advantage in growing under conditions of nutritional deprivation, such as prolonged fasting or TPN, because it can utilize mucin as its sole source of carbon and nitrogen. Similar to our mouse model, increased abundance of Akkermansia muciniphila was also demonstrated in the gut microbiome of TPN-fed infants. Importantly, despite immune cell priming in VV-TPN mice, endotoxin content in white adipose tissue was reduced, and inflammation was significantly suppressed, as evidenced by a lower IL6 / IL10 ratio and reduced NFκB protein expression. Therefore, our results suggest that VV-TPN acts as an immune adjuvant, priming the immune system during TPN and enabling the body to eliminate potentially dangerous pathogens.

[0171] In liver macrophages isolated from VV-TPN mice, increased production of IL6, IFNγ, and TNFα was not observed compared with IL-TPN mice. Therefore, the increased expression of IL6 and TNFα in liver tissue from IL-TPN mice, as opposed to VV-TPN mice, is likely due to hepatocyte activation. Furthermore, macrophages (important for both innate nonspecific host defense and adaptive specific immune responses) appear to be activated by IFNγ released from T cells. IFNγ metabolically reprograms macrophages to maintain viability and maintains pro-inflammatory activity, including ROS production, by switching energy metabolism from OXPHOS to glycolysis, whereas IL10 reverts energy metabolism to OXPHOS and suppresses NLRP3 inflammasome activation. This unique cytokine microenvironment may indeed underlie the unique anti-inflammatory yet pro-immune phenotype observed in VV-TPN mice. In a clinical trial of cancer patients, supplemental parenteral nutrition with a lipid emulsion based on olive oil (n-9 fatty acids) was compared with that based on fish oil (long-chain n-3 fatty acids). Innate and adaptive immune system function was found to be higher in patients treated with olive oil, which is thought to be neurological in relation to inflammation and immune stimulation. Patients treated with fish oil showed signs of immunosuppression, evidenced by a decrease in the number of PMA-stimulated IFNγ-producing CD4+ T cells and a relatively increased number of regulatory T cells. Interestingly, in our own study, anti-endotoxin (LPS) IgG1 production was elevated in mice treated with VV-TPN, consistent with helper T cell-mediated B cell activation. These observations are consistent with previous nutritional studies using 18-carbon ALA- and SDA-enriched vegetable oils. Patel et al. compared the pups of pregnant Sprague-Dawley rats fed an SDA-enriched maternal diet with those of pregnant rats fed a control diet. The SDA-enriched diet resulted in higher B cell function as measured by IgG1 production, higher numbers of activated helper T cells, and endotoxin-stimulated spleen cells showed reduced production of IL6 and TNFα but increased production of IL10.Finally, a nutritional study in human volunteers who orally ingested 10 mL of Buglossoides Arvensis oil, rich in ALA and SDA, daily for 4 weeks showed increased IL10 production in endotoxin-stimulated whole blood.

[0172] Hepatotoxicity is a major problem with TPN, and cases of severe steatohepatitis and portal vein fibrosis have been reported in patients receiving fish oil-based TPN. Although immune cell priming in liver tissue was observed, the actual number of leukocytes in liver tissue was reduced during TPN compared with mice fed a normal diet. Indeed, VV-TPN demonstrated many hepatoprotective functions compared with standard lipid emulsion, including a reduction in pro-inflammatory IL6 combined with an increase in anti-inflammatory IL10. IL10 is a protective factor against high-fat diet-induced insulin resistance in the liver. Mice fed a high-fat diet and treated with a neutralizing anti-IL10 antibody showed increased expression of pro-inflammatory cytokines, impaired insulin signaling with downregulation of mitochondrial-dependent apoptotic signaling and IRS2, and reduced liver glycogen content. LBP, a protein specifically produced by hepatocytes that detoxifies endotoxins, was upregulated only with VV-TPN. Similarly, SOCS3, a potent inhibitor of IL6 signaling, was upregulated only by VV-TPN. Increased abundance of LBP and SOCS3 was inversely correlated with the IL6 / IL10 ratio, suggesting a mechanistic contribution to reduced liver inflammation. Furthermore, VV-TPN, like OV-TPN, upregulated anti-inflammatory PPARα in liver tissue, but downregulated only pro-inflammatory and lipogenic PPARγ2. Finally, VV-TPN increased the concentration of the anti-inflammatory T helper cell cytokine IL4 in liver tissue, particularly in pancreatic tissue. IL4 is known to have beneficial effects on β-cell function and lipid and glucose metabolism.

[0173] The immune-metabolic interactions during TPN are ultimately the result of specific fatty acid species released from the administered lipid emulsion. While most TPN formulations have been shown to reduce total T cell counts in patients, TPN that primarily releases long-chain n-6 fatty acids further inhibits T cell function. Supplying specific fatty acids alters the composition of the phospholipid bilayer of T cell membranes, a process known as "lipid remodeling," resulting in altered function of key membrane-associated receptor proteins, including the T cell receptor. In our study, supplying shorter-chain, 18-carbon n-3 fatty acids primed CD4+ effector T cell subpopulations, B cells, and macrophages to express IFNγ and IL-17. Detection of IL-10 expression in these primed immune cells suggests other cell types, such as T cells, macrophages, and potentially hepatocytes, as possible sources of elevated plasma and tissue IL-10 concentrations. Indeed, the occurrence of anti-IL10 activity in the presence of an isotype IgG control antibody, likely mediated by Fc receptor binding, indicates that immune cells are the primary source of elevated IL10. Different lipid emulsions used in TPN also result in different profiles of biologically active lipid mediators. Lipid mediators, also known as oxylipins, are the primary source of fatty acid-induced biological effects in many tissues and cells, including T cells and macrophages. In our study, heat maps of lipid mediators measured in liver tissue showed striking differences among the three TPNs examined. Liver tissue from VV-TPN mice lacked typical n-6 arachidonic acid-derived pro-inflammatory mediators but also many long-chain n-3-derived anti-inflammatory mediators, with the exception of a few EPA-derived mediators. Clearly, VV-TPN induced a unique and distinctive oxylipin profile that cannot be simply attributed to the bioconversion of shorter-chain n-3 fatty acids, i.e., ALA and SDA, to longer-chain n-3 fatty acids (EPA, DHA), because no increased formation of DHA-derived lipid mediators was observed.Indeed, similar observations have been reported in 5-ALA-treated macrophages, where the 18-carbon lipid mediator, i.e., 9 / 13-HOTrE, but not EPA- or DHA-derived lipid mediators, was associated with decreased IL-6 production in M1-polarized macrophages and increased IL-10 production in M2-polarized macrophages combined with enhanced phagocytic activity. Importantly, in our TPN mouse model, supplementing IL-TPN with 9 / 13-HOTrE mimicked many of the immunometabolic phenotypes induced by VV-TPN. 9 / 13-HOTrE has previously been shown to increase IL-10 in mouse peritoneal macrophages, inhibit the NLRP3 inflammasome, and increase survival in mouse endotoxin- and cecal ligation sepsis models. Recent studies have also suggested that activated lymphocytes and potentially other immune cells may increase their own synthesis of lipid mediators, which can directly stimulate activation and proliferation in an autocrine manner.

[0174] Although we have reported the beneficial biological effects of a novel TPN based on short-chain n-3 fatty acids, further studies are needed to gain more mechanistic insight into the lipid mediators derived from 18-carbon n-3 fatty acids in TPN and their specific immunometabolic effects. It will also be essential to demonstrate the transferability of the observed beneficial immunometabolic effects from mouse models to patients.

[0175] In summary, our findings demonstrate that a novel lipid emulsion based on 18-carbon n-3 fatty acids possesses significant anti-inflammatory, antidiabetic, and immune-enhancing properties that act as an "immunonutrition" in TPN. This unique profile is unmatched by currently available lipid emulsions and may be particularly beneficial for vulnerable patients at risk of infection, septic patients with "immunoparalysis," and cancer patients.

[0176] Materials and Methods This study complied with the National Institutes of Health's Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, revised 1996) and adhered to the ARRIVE guidelines (https: / / www.nc3rs.org.uk / arrive-guidelines). The experimental protocol used in this study (AUP000002007) was approved by the University of Alberta Animal Policy and Welfare Committee.

[0177] Preparation of a novel lipid emulsion TPN-F3 (F3 or VV) 1.2% lecithin (LIPOID E80, egg-derived phospholipid containing 80% phosphatidylcholine, suitable for parenteral administration, Lipoid GmbH, Ludwigshafen, Germany) was immersed in purified water (<20% of the final volume; NANOpure Diamond Barnstead, Thermo Scientific, Waltham, MA, USA, or Endotoxin-free Ultra Pure Water, EMD Millipore Corp., Billerica, MA, USA) in a 45°C water bath for 2 hours. Dispersion was facilitated using a Polytron high-shear mixer (Polytron PT6000 drive unit, PT-DA 3012 / 2 TS dispersion aggregate, Kinematica AG, Malters, Switzerland) at 20,000 rpm for 60 seconds. EDTA (EDTA disodium salt dihydrate, Carl Roth GmbH + Co. KG, Karlsruhe, Germany, ≥99%) was added to the lecithin / aqueous phase to a final concentration of 2.5 μM, and 2.2% glycerol (Acros Organics, New Jersey, USA, 99+%) for isotonicity was added to the lecithin / aqueous phase. A 20% premixed lipid phase (Table 4) consisting of 50% ahiflower oil (Natures Crops International, Kensington, Prince Edward Island, Canada), 25% olive oil (LIPOID refined olive oil, Ph.Eur., Lipoid AG, Steinhausen, Switzerland), and 25% coconut oil (Bioriginal, Saskatoon, Saskatchewan, Canada) was added to the lecithin / aqueous phase. 0.016% α-tocopherol (Sigma-Aldrich, St. Louis, MO, USA, Type V, approximately 1000 IU / g) was added, and purified water was added to the final volume. Subsequently, the coarse emulsion was homogenized using a PL300 or HL60, a high-pressure homogenizer (Dyhydromatics, Maynard, MA, USA) equipped with a 75.1 T reaction chamber and a 200.2 L backpressure module (PL300 only), respectively, to obtain a preferred droplet size of 260–300 nm (six cycles at pressures of 18 kpsi (PL300)–22 kpsi (HL60)).The pH was adjusted to >8.5 with 1 M NaOH until the zeta potential exceeded |30| mV. Aliquots were filled into 50 mL glass vials (Müller and Krempel AG, Bülach, Switzerland), the headspace was filled with inert argon gas (PanGas AG, Dagmarselenium, Switzerland, Argon 5.0), and the vials were crimped. The emulsions were autoclaved at 121 °C and 2 bar for 15 min (Systec DE-23, Systec GmbH, Linden, Germany). The absence of microbial growth (membrane filtration method according to Ph Eur 2.6.1) and endotoxin (<0.1 IU / mL, gel clot LAL gel clot assay according to Ph Eur 2.6.14) was confirmed (Bioexam AG, Lucerne, Switzerland). Sterile emulsions were further quantified by dynamic light scattering (Malvern Zetasizer 3000HS A, Malvern Instruments, Malvern, UK), primary oxidation products (mFOX assay) and secondary oxidation products (TBARS assay), as well as non-esterified fatty acids, by fluorescent dye labeling and separation by high-pressure liquid chromatography (FL-RP-HPLCREF). Cholesterol and phytosterols were measured using UPLC-MRM / MS, and the composition of each lipid emulsion was finally confirmed by gas chromatography (Agilent 6890 GC system). Lack of in vitro toxicity to T cells was tested before each in vivo application.

[0178] Metabolic data were compared between mice receiving total parenteral nutrition for 7 days (IL-TPN, OV-TPN, VV-TPN) and conventional chow-fed mice with or without saline infusion (IV-chow).

[0179] Data are shown as mean (SD) or median (25th percentile, 75th percentile). N=6.

[0180] GLP-1: glucagon-like peptide-1, HOMA-IR: homeostatic model assessment of insulin resistance, IRβ: insulin receptor beta subunit, IRS2: insulin receptor substrate 2, pY-IRS2: pan-tyrosine phosphorylated IRS2, OD: optical density, chow: unattached C57BL / 6J mice group-housed in static cages, IV-chow: chow-fed mice administered heparinized saline, IL-TPN: Intralipid-based total parenteral nutrition, OV-TPN: Omegaven-based total parenteral nutrition, VV-TPN: TPN-F3-based total parenteral nutrition.

[0181] Analysis of variance (ANOVA) was performed for the lipid-injected group only, and significant differences (bold type) were indicated when overall P<0.05. Multiple comparison procedures were then performed as appropriate. * * indicates a significant decrease compared to OV-TPN and VV-TPN; * indicates a significant increase compared to IL-TPN and OV-TPN; * indicates a significant increase compared to OV-TPN; * indicates a significant increase compared to IL-TPN.

[0182] TPN mouse model, treatment groups, TPN formulations and doses The TPN mouse model used in this study has been previously described (Lou et al. Molecular nutrition & food research 2021;65:e2000412). Briefly, male C57BL / 6 mice (22–25 g) were fitted with a tunneled jugular vein catheter (JVC) and a magnetic vascular access button. Freedom of movement was ensured by a magnetic tether (VABM1T / 25, Instech Laboratories Inc., Plymouth Meeting, PA, USA) attached to a swivel, and TPN was administered using a programmable syringe pump (SAI Infusion Technologies, Lake Villa, IL, USA). Mice were housed in conventional single-open shoebox cages and maintained under controlled light conditions (12-hour light-dark cycle), at a constant temperature of 21°C, and at 60% relative humidity. They had free access to autoclaved water and regular chow (5L0D PicoLabLaboratory Rodent Diet, Canadian Lab Diets, Inc., Leduc County, Alberta, Canada). Mice were allowed to acclimate for 4 days before the experiment and were then randomly assigned to receive Intralipid-supplemented TPN (IL-TPN), Omegaven-supplemented TPN (OV-TPN), or TPN-F3-supplemented TPN (VV-TPN). Intralipid and Omegaven were purchased from Fresenius Kabi (Switzerland) AG (Kriens, Switzerland). Infusions began on day 5. Mice assigned to TPN received 0.25 mL of TPN solution per hour. -1 (6 mL per day on day 1 of infusion) and then infused continuously up to 0.32 mL hr -1 The dose was increased to 7.7 mL per day on the 4th to 7th days of infusion. Heparin (10 UmL -1Mice were infused with 0.9% saline containing IV-TPN (6 mL / day) and allowed free access to water and normal chow as controls (IV-chow). Age-matched, non-inserted C57BL / 6 mice were housed in conventional cages for 7 days (3 mice per cage, with free access to water and normal chow) and served as additional normal chow-fed controls (chow). Some VV-TPN mice were treated with 100 mg / 24 h of anti-mouse interleukin-10 (IL10) antibody (BioXCell #Be0049) or its IgG1 isotype control antibody (BioXCell #BE0290) added to the TPN mixture. Some IL-TPN mice were treated with 9 / 13-hydroxy-octadecatrienoic acid (5 ng / mL) added to the TPN mixture. Protein requirements were met with an amino acid solution (4 kcal g -1 ) and carbohydrate was glucose (3.4 kcal g -1 ) and lipids were prepared as lipid emulsions (10kcal g -1 Mice receiving TPN received an isocaloric (150 kcal per 100 mL), isonitrogenous TPN solution containing either Intralipid, Omegaven, or TPN-F3. TPN provided 13% of total calories from amino acids, 71% from glucose, and 16% from lipids, resulting in a non-protein energy / nitrogen ratio of 170. This value was calculated to meet the nutritional and energy requirements of a 24 g mouse. See Table 3 for details on TPN composition and dosage. On day 8, tail blood glucose concentrations were measured using a OneTouch VerioIQ (LifeScan Canada Ltd., Burnaby, British Columbia, Canada). Mice were disconnected from the infusion line, weighed, anesthetized with isoflurane, and euthanized by cervical dislocation before blood and tissue collection. Blood samples were collected by cardiac puncture and processed immediately. Meanwhile, tissues were immediately frozen in liquid nitrogen and stored at −80°C until analysis or further processing for immune cell isolation.

[0183] [Table 3]

[0184] The final formulation also contained sodium phosphate (13.4 mmol / L), electrolytes, and heparin (100 U / 10 mL).All TPN formulations provided similar amounts of energy (150 kcal / 100 mL), with 13% coming from amino acids, 16% from lipids, and 71% from carbohydrates (glucose).

[0185] IL-TPN: Intralipid-based total parenteral nutrition, OV-TPN: Omegaven-based total parenteral nutrition, VV-TPN: TPN-F3-based total parenteral nutrition.

[0186] Hormone measurements, glycogen content, insulin receptor and (pY) insulin receptor substrate 2 (IRS2), and phosphoenolpyruvate carboxykinase (PEPCK) activity Plasma insulin, glucagon, and glucagon-like peptide 1 (GLP-1) were measured from heparinized or EDTA-treated blood collected via cardiac puncture using the following ELISA kits: Mercordia #10-1247-01 (insulin), Mercordia #10-1281-01 (glucagon), and Crystal Chem #81508 (GLP-1). Liver glycogen content was measured from tissue powder using Sigma Glycogen Assay Kit #MAK016. Total liver insulin receptor protein β subunit was measured using Insulin Receptor ELISA Kit #KHR9111 (Thermo Fisher Scientific). Total IRS2 and IRS2 tyrosine phosphorylation were measured in liver lysates using an in-house ELISA assay. Liver tissue PEPCK activity was measured using a PEPCK activity kit (Abcam #ab239714) according to the manufacturer's recommendations.

[0187] Cytokine profiling Interferon-γ (IFNγ) #DY485, interleukin-6 (IL6) #DY406, IL10 #DY417, tumor necrosis factor-α (TNFα) #DY410, and interleukin-4 (IL4) #DY405 were measured from the tissue powder using the R&D DuoSet ELISA kit according to the manufacturer's instructions. Using a Qiagen TissueLyser II (Qiagen) setup, 10 mg of powder was washed twice in ice-cold PBS to remove residual blood before homogenization in 100 mL of ice-cold Lysis Buffer #6 (R&D Systems). The homogenate was left on ice for 15 minutes and then centrifuged at 2,000 x g for 5 minutes. The supernatant was collected and stored at -80°C for DC protein assay (Bio-Rad Laboratories) and DuoSet ELISA assay (R&D Systems). All cytokine measurements were normalized to the protein concentration of the sample. Sample dilutions were made as needed to maintain a final urea concentration of 1 M in all samples before addition to the plate. Plasma IL10 was measured using the R&D Quanbtikine ELISA kit #M1000B.

[0188] Immunoblotting Whole tissue homogenates and nuclear / cytoplasmic fractions were prepared as previously described (Lou et al. Molecular nutrition & food research 2021;65:e2000412). Protein concentrations were measured by Bradford or DC protein assay (Bio-Rad Laboratories). Equal amounts of protein were separated by SDS-PAGE, transferred to nitrocellulose membranes, and probed with the desired antibodies. Immunoreactivity was visualized using ECL reagent (PerkinElmer) and quantified using ImageJ software. All immunoreactivity was normalized to vinculin or actin in whole liver lysates and to TATA-binding protein (TBP) in nuclear fractions, respectively. Glucokinase was detected by immunoblotting in both cytoplasmic and nuclear fractions, and bands of interest were normalized to vinculin, actin, or TBP, respectively, for their respective band intensities.

[0189] Immune cell isolation Immune cells from the liver, spleen, mesenteric lymph nodes, large intestine, and small intestine were isolated as previously described (Tsai et al. Cell metabolism 2018;28:922-34 e4). Non-T cells were removed using the EasySep™ Mouse T Cell Isolation Kit (STEMCELL Technologies, Vancouver, BC, Canada) with a biotinylated antibody directed against non-T cells and streptavidin-coated magnetic particles, followed by negative selection of T cells. Macrophages were isolated using the EasySep™ Mouse F4 / 80 Positive Selection Kit (STEMCELL Technologies).

[0190] Flow cytometry Cells obtained from each tissue (1–2 x 10 6 / sample) were stained with fluorochrome-conjugated antibodies for innate immune cells and lymphocytes, run on an LSR Fortessa-SORP flow cytometer, and analyzed using FlowJo V10 software (BD, Ashland, OR, USA).

[0191] Measurement of lipopolysaccharide (LPS) and plasma anti-LPS IgG antibody concentration Endotoxin levels in (epididymal) white adipose tissue were measured using the PyroGene™ Recombinant Factor C Endotoxin Detection Fluorescence Kit (Lonza #50-658U) with a detection limit of 0.005 endotoxin (LPS) units (EU) / mL. Mouse plasma anti-LPS IgG antibody concentrations against E. coli O111:B4 lipopolysaccharide were measured using a commercially available ELISA kit (Chondrex #6106).

[0192] Microbiome analysis using 16S rRNA sequencing Mucosal samples were collected from the colon wall at the end of the 7-day experimental period. DNA was extracted according to the protocol of the ZymoBIOMICS DNA Miniprep Kit (D4300, Zymo Research Corp; Irvine, CA, USA). Amplification of the V3-V4 hypervariable region was performed using standard primers 341F (CCTACGGGNGGCWGCAG, SEQ ID NO: 1) and 805R (GACTACHVGGGTATCTAATCC, SEQ ID NO: 2). Libraries were prepared at the Fasteris facility (Genesupport / Fasteris SA, Plan-les-Ouates, Switzerland) using the Metafast protocol. 16S rRNA gene sequences were clustered into Operational Taxonomic Units (OTUs) and mapped to the SILVA database. All data analysis was performed using the web-based tool MicrobiomeAnalyst.ca (https: / / www.microbiomeanalyst.ca / , Lucchinetti et al. Clin Nutrition ESPEN 2022).

[0193] Quantitative profiling of lipid mediators using UHPLC-MS / MS Lipid mediators were quantified using internal standards, calibrators, and quality controls as previously detailed (Hartling et al. Clinical chemistry and laboratory medicine 2021;59:1811-23). ​​Lipid mediators were extracted from liver tissue powder using methanol and solid-phase extraction. Samples were evaporated under nitrogen and reconstituted for UHPLC-MS / MS injection.

[0194] Statistics Data are summarized as mean (SD) or median (25th and 75th percentiles) for the indicated number of independent observations (N), depending on the underlying data distribution (normal or skewed). Because the study design aimed for direct comparisons between individual TPN groups, comparisons focused on the TPN group. The significance of differences between groups was determined by ANOVA followed by Tukey's test for post-hoc analysis or nonparametric methods (Kruskal-Wallis test followed by Dunn's test for post-hoc analysis), depending on the underlying data distribution. For lipid mediator statistics, all concentrations were log-transformed and converted to z-scores for principal component analysis (PCA). Samples with concentrations below the detection limit were set to half the detection limit if the respective lipid mediator was detected in other samples of the same matrix. Where appropriate, two groups were compared using unpaired t-tests or Mann-Whitney U tests, depending on the data distribution. Differences were considered statistically significant when overall p<0.05 (two-tailed). SigmaPlot (version 14.0; Systat Software Inc, San Jose, CA) was used for analysis.

Claims

1. 1. A lipid emulsion for administration to a patient, the lipid emulsion comprising an oily phase and an aqueous phase, the oily phase of the lipid emulsion comprising: - Omega-3 fatty acid components, wherein the mass of the omega-3 fatty acid component is 25-35% of the oily phase; the omega-3 fatty acid component is comprised of one or more omega-3 fatty acids characterized by the presence of two or more carbon-carbon double bonds, where one carbon-carbon double bond is three atoms away from the terminal methyl group; and the oily phase of the lipid emulsion contains 5% or more stearidonic acid; and the oily phase of the lipid emulsion contains at least 15% alpha-linolenic acid (ALA); - Omega 6 fatty acid components, wherein the mass of the omega-6 fatty acid component is 10-15% of the oily phase; the omega-6 fatty acid component is comprised of one or more omega-6 fatty acids characterized by the presence of two or more carbon-carbon double bonds, where one carbon-carbon double bond is six atoms away from the terminal methyl group; - monounsaturated fatty acid components, wherein the weight of the monounsaturated fatty acid component is between 18 and 30% of the oily phase; the monounsaturated fatty acid component is comprised of one or more fatty acids characterized by the presence of one carbon-carbon double bond; - Saturated fatty acid components, wherein the mass of the saturated fatty acid component is between 20 and 35% of the oily phase; the saturated fatty acid component is comprised of one or more fatty acids characterized by having no carbon-carbon double bonds and only carbon-carbon single bonds; The lipid emulsion comprising:

2. 2. The lipid emulsion according to claim 1, wherein the ratio (m / m) of omega-6 fatty acid components to omega-3 fatty acid components is in the range of 1:3 to 1:

2.

3. The oily phase of the lipid emulsion is: - 40-50% PUFA (polyunsaturated fatty acids); - 20-30% MUFA (monounsaturated fatty acids); and - 20-35% SFA (saturated fatty acids) 3. The lipid emulsion according to claim 1 or 2, comprising:

4. The oily phase of the lipid emulsion is: - 5-15% stearidonic acid; - 20-30% oleic acid; - 5-15% linoleic acid; 20-30% alpha-linolenic acid; and - 2-5% gamma-linolenic acid The lipid emulsion according to any one of claims 1 to 3, comprising:

5. The oily phase of the lipid emulsion is: - 2-5% of short chain fatty acid components selected from caproic acid, caprylic acid and capric acid; - 10-15% lauric acid; - 3-8% myristic acid; and - 5-12% palmitic acid The lipid emulsion according to any one of claims 1 to 4, comprising:

6. The oily phase of the lipid emulsion is: - 20-30% olive oil; - 20-30% coconut oil; and - 40-60% Buglossoides arvensis oil The lipid emulsion according to any one of claims 1 to 5, comprising:

7. Lipid emulsions are: EDTA; and / or - alpha tocopherol The lipid emulsion according to any one of claims 1 to 6, further comprising a stabilizer and / or antioxidant selected from:

8. The lipid emulsion according to any one of claims 1 to 7, further comprising a pharmaceutical agent.

9. A lipid emulsion according to any one of claims 1 to 7 for use as a counter-agent / antidote in the treatment of poisoning caused by lipophilic pharmaceuticals or lipophilic toxic compounds.

10. A lipid emulsion according to any one of claims 1 to 8 for use in protecting vital organs against ischemia-reperfusion injury.

11. A lipid emulsion according to any one of claims 1 to 8 for use in the prevention or treatment of type I or type II diabetes.

12. Parenteral nutrition is indicated for patients with one or more of the following indications: - Patients requiring short-term and long-term total parenteral nutrition (TPN), and / or TPN patients with metabolic disorders, and / or - TPN patients with insulin resistance, and / or TPN patients with liver disease, and / or TPN patients with systemic acute and / or chronic inflammation, and / or TPN patients with reduced host defenses, and / or - patients with sepsis, and / or - TPN patients undergoing chemotherapy, 9. The lipid emulsion for use in parenteral nutrition according to any one of claims 1 to 8, wherein the lipid emulsion is administered to the patient.

13. Enteral nutrition is indicated for patients with one or more of the following indications: - Patients requiring short-term or long-term enteral nutrition, and / or - patients with metabolic disorders, and / or - patients with insulin resistance, and / or - patients with liver disease, and / or - patients with systemic acute and / or chronic inflammation, and / or - patients with compromised host defenses, and / or - patients with sepsis, and / or - Patients undergoing chemotherapy 9. A lipid emulsion according to any one of claims 1 to 8 for use in enteral nutrition, administered to the

14. A lipid emulsion according to any one of claims 1 to 8 or a lipid emulsion for use according to claims 9 to 12, wherein the lipid emulsion is formulated for parenteral administration.

15. 14. The lipid emulsion according to any one of claims 1 to 9 or the lipid emulsion for use according to claims 9 to 11 or 13, wherein the lipid emulsion is formulated for enteral or oral administration.

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