WO2013024174A1 - Emulsions de triglycérides de dha, d'acides gras libres dha et d'esters éthyliques de dha et procédés de traitement d'une lésion à la moëlle épinière - Google Patents

Emulsions de triglycérides de dha, d'acides gras libres dha et d'esters éthyliques de dha et procédés de traitement d'une lésion à la moëlle épinière Download PDF

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Publication number
WO2013024174A1
WO2013024174A1 PCT/EP2012/066146 EP2012066146W WO2013024174A1 WO 2013024174 A1 WO2013024174 A1 WO 2013024174A1 EP 2012066146 W EP2012066146 W EP 2012066146W WO 2013024174 A1 WO2013024174 A1 WO 2013024174A1
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WO
WIPO (PCT)
Prior art keywords
emulsion
dha
oil
weight
equal
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PCT/EP2012/066146
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English (en)
Inventor
Adina Michael-Titus
Jung Lee
Bernard A. Mikrut
Xuejun Tang
Original Assignee
Dsm Ip Assets B.V.
Queen Mary Universitiy Of London
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Publication of WO2013024174A1 publication Critical patent/WO2013024174A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • an emulsion comprising an emulsifier, an isotonic agent and about 30% by weight of an oil comprising docosahexaenoic acid triglyceride (DHA-TG) wherein the emulsion is provided substantially free of eicosapentaenoic acid (EPA) and is suitable for parenteral administration.
  • DHA-TG docosahexaenoic acid triglyceride
  • EPA eicosapentaenoic acid
  • emulsions comprising docosahexaenoic acid triglyceride
  • parenteral emulsions comprising docosahexaenoic acid free fatty acid (DHA-FFA). Also provided here are methods for the treatment of spinal cord injury.
  • DHA-FFA docosahexaenoic acid free fatty acid
  • emulsions comprising docosahexaenoic acid ethyl ester
  • DHA-EE for parenteral administration. Also provided herein are methods for the treatment of spinal cord injury.
  • An emulsion comprising an emulsifier, an isotonic agent and about 100 milligrams/milliliter (mg/ml) to about 300 mg/ml docosahexaenoic acid triglyceride
  • DHA-TG eicosapentaenoic acid
  • EPA eicosapentaenoic acid
  • An emulsion comprising an emulsifier, an isotonic agent and a docosahexaenoic acid free fatty acid (DHA-FFA) wherein the emulsion is substantially free of eicosapentaenoic acid (EPA) and is suitable for parenteral administration.
  • DHA-FFA docosahexaenoic acid free fatty acid
  • EPA eicosapentaenoic acid
  • the emulsion comprises a secondary emulsifier.
  • An emulsion comprising an emulsifier, an isotonic agent and docosahexaenoic acid ethyl ester (DHA-EE) wherein the emulsion is substantially free of eicosapentaenoic acid (EPA) and is suitable for parenteral administration.
  • the emulsion comprises a secondary emulsifier.
  • methods of treating a subject suffering from spinal cord injury comprising administering to the subject an emulsion comprising an effective amount of a DHA-TG to the subject in need thereof wherein the emulsion is provided in the substantial absence of EPA.
  • Also provided here are methods of treating a subject suffering from spinal cord injury comprising administering to the subject an emulsion comprising an effective amount of a DHA-FFA to the subject in need thereof wherein the emulsion is provided in the substantial absence of EPA.
  • Also provided here are methods of treating a subject suffering from spinal cord injury comprising administering to the subject an emulsion comprising an effective amount of a DHA-EE to the subject in need thereof wherein the emulsion is provided in the substantial absence of EPA.
  • Also provided herein is a method of making an emulsion comprising dispersing an emulsifier and an isotonic agent in water to form a coarse dispersion; homogenizing the coarse dispersion to form a fine dispersion; mixing oil containing DHA-TG to the dispersion, more particularly to the fine dispersions, to form a coarse emulsion; and homogenizing the coarse emulsion to form the emulsion.
  • Also provided herein is a method of making an emulsion comprising dispersing an emulsifier and an isotonic agent in water to form a coarse dispersion; homogenizing the coarse dispersion to form a fine dispersion; mixing oil containing DHA-FFA to the dispersion, more particularly to the fine dispersions, to form a coarse emulsion. Homogenizing the coarse emulsion to form the emulsion.
  • Also provided herein is a method of making an emulsion comprising dispersing an emulsifier and an isotonic agent in water to form a coarse dispersion; homogenizing the coarse dispersion to form a fine dispersion; mixing oil containing DHA-EE to the dispersion, more particularly to the fine dispersions, to form a course emulsion. Homogenizing the coarse emulsion to form the emulsion.
  • the pH is adjusted to about 6 to about 9.
  • the final emulsion can be autoclaved.
  • a secondary emulsifier is mixed with the emulsion, more particularly to the coarse emulsion.
  • FIGs. 1 and 2 provide BMI and body weight results.
  • FIG 3 provides haematoxylin and eosin staining results.
  • FIG 4 provides NeuN staining results.
  • FIG 5 provide GFAP staining results.
  • FIG 6 provides results of administering 0.6 mg/ml DHA-FFA emulsion following spinal cord injury.
  • FIG 7 provides results of effect on the development of hyperalgesia in response to mechanical stimuli following spinal cord injury.
  • FIG 8 provides results of effect on the development of hyperalgesia in response to thermal stimuli following injury.
  • FIG 9 provides results for neurons labeled with NeuN after treatement with DHA
  • an emulsion comprising an emulsifier, an isotonic agent and about 100 mg/ml to about 300 mg/ml docosahexaenoic acid triglyceride (DHA-TG) wherein the emulsion is substantially free of eicosapentaenoic acid (EPA) and is suitable for parenteral administration.
  • DHA-TG docosahexaenoic acid triglyceride
  • EPA eicosapentaenoic acid
  • the emulsion further comprises a secondary emulsifier.
  • an emulsion comprising an emulsifier, an isotonic agent and a docosahexaenoic acid free fatty acid (DHA-FFA) wherein the emulsion is substantially free of eicosapentaenoic acid (EPA) and is suitable for parenteral administration.
  • DHA-FFA docosahexaenoic acid free fatty acid
  • EPA eicosapentaenoic acid
  • the emulsion further comprises a secondary emulsifier.
  • an emulsion comprising an emulsifier, an isotonic agent and docosahexaenoic acid ethyl ester (DHA-EE) wherein the emulsion is substantially free of eicosapentaenoic acid (EPA) and is suitable for parenteral administration.
  • DHA-EE docosahexaenoic acid ethyl ester
  • the concentration of the DHA-TG is greater than about 0.04 milligram per milliliter (mg/ml), more particularly greater than 0.04 mg/ml up to about 0.15 mg/1, more particularly greater than 0.04 mg/ml up to about 0.6 mg/ml, more particularly from about 0.04 mg/ml up to about 30 mg/ml, more particularly form about 0.04 up to about 270 mg/ml.
  • the concentration of the DHA-TG is greater than or equal to about 0.15 milligram per milliliter (mg/ml), more particularly from about greater than or equal to 0.15 mg/ml up to about 0.6 mg/ml, more particularly from about greater than or equal to 0.15 mg/ml up to about 30 mg/ml.
  • the concentration of the DHA-TG in the emulsion is about 100 milligrams per milliliter (mg/ml) to about 300 mg/ml of the emulsion.
  • the concentration of the DHA-TG is about 114 mg/ml to about 300 mg/ml of the emulsion.
  • the concentration of the DHA-TG is about 1 14 mg/ml to about 180 mg/ml of the emulsion. In some embodiments, the concentration of the DHA-TG is about 1 14 mg/ml to about 126 mg/ml of the emulsion. In some embodiments, the concentration of the DHA-TG is about 165 to about 180 mg/ml of the emulsion. In some embodiments, the concentration of the DHA-TG is about 1 65 to about 171 mg/ml. In some embodiments, the concentration of the DHA-TG is about 180 mg/ml of the emulsion. The above concentrations are directed to the DHA content in the triglycerides.
  • the concentration of the DHA-FFA is greater than about 0.04 milligram per milliliter (mg/ml). In some embodiments provided herein the concentration of the DHA-FFA is greater than or equal to about 0.15 mg/ml. In some embodiments provided herein the concentration of the DHA-FFA is greater than or equal to about 0.60 mg/ml. In some embodiments provided herein the concentration of the DHA-FFA is about 0.04 mg/ml to about 300 mg/ml of the emulsion, more particularly from about 0.15 to about 300 mg/ml, further particularly from about 0.6 to about 300 mg/ml.
  • the concentration of the DHA-FFA is about 0.2 milligram per milliliter (mg/ml) to about 300 mg/ml of the emulsion. In some embodiments the concentration of the DHA-FFA is about 0.3 mg/ml to about 300 mg/ml of the emulsion. In some embodiments the concentration of the DHA-FFA is about 20 milligram per milliliter (mg/ml) to about 300 mg/ml of the emulsion. In some embodiments the concentration of the DHA-FFA is about 30 mg/ml to about 300 mg/ml. In some embodiments, the concentration of the DHA-FFA is about 0.2 mg/ml to about 30 mg/ml of the emulsion.
  • the concentration of DHA-FFA is about 140 to about 300 mg/ml of the emulsion. In some embodiments, the concentration of DHA-FFA is about 140 to about 150 mg/ml of the emulsion. In some particular embodiments, the concentration of the DHA-FFA is about 140 mg/ml to about 143 mg/ml of the emulsion. In some embodiments, the concentration of the DHA-FFA is about 270 mg/ml to about 300 mg/ml of the emulsion. In some embodiments, the concentration of the DHA-FFA is about 280 mg/ml to about 300 mg/ml of the emulsion. In some particular embodiments, the concentration of DHA-FFA is about 280 to about 290 mg/ml of the emulsion.
  • the concentration of the DHA-EE is greater than about 0.04 milligram per milliliter (mg/ml), more particularly greater than 0.04 mg/ml up to about 0.15 mg/1, more particularly greater than 0.04 mg/ml up to about 0.6 mg/ml, more particularly from about 0.04 mg/ml up to about 150 mg/ml, more particularly form about 0.04 up to about 270 mg/ml.
  • the concentration of the DHA-EE is greater than or equal to about 0.15 milligram per milliliter (mg/ml), more particularly from about greater than or equal to 0.15 mg/ml up to about 0.6 mg/ml, more particularly from about greater than or equal to 0.15 mg/ml up to about 150 mg/ml, more particularly from about greater than or equal to 0.04 up to about 270 mg/ml. In some embodiments provided herein the concentration of the DHA- EE is greater than or equal to about 0.6 milligram per milliliter (mg/ml), more particularly from about greater than or equal to 0.15 mg/ml up to about 150 mg/ml, more particularly form about greater than or equal to 0.04 up to about 270 mg/ml.
  • the concentration of the DHA-EE in the emulsion is about 150 milligrams per milliliter (mg/ml) to about 300 mg/ml of the emulsion. In some embodiments, the concentration of the DHA-EE is about 250 to about 290 milligrams per milliliter (mg/ml) of the emulsion. In particular embodiments, the concentration of the DHA is about 270 mg/ml of the emulsion. The above concentrations are directed to either the concentration of the DHA-EE or the concentration of the DHA moiety of the DHA- EE.
  • the mean particle size of the emulsion is about 500 nanometers. In some embodiments, the emulsions provided herein have a mean diameter size of less than 500 nanometers (or 0.5 ⁇ ). In some embodiments, the emulsions provided herein have a mean diameter size of less than about 500 nanometers (or 0.5 ⁇ ). In some embodiments, the emulsions provided herein have a mean diameter size of less than 500 nanometers (or 0.5 ⁇ ). In some embodiments, the emulsions provided herein have a percentage of fat residing in globules larger than 500 nm (PFAT5) of 0.05% or less.
  • PFAT5 percentage of fat residing in globules larger than 500 nm
  • the emulsions provided herein have a percentage of fat residing in globules larger than 5 ⁇ (PFAT5) is about 0.05%> or less.
  • PFAT5 percentage of fat residing in globules larger than 5 ⁇
  • Examples of globule size distribution limits and their determination (e.g., mean diameter and large- diameter tail) of an injectable emulsion useful for total parenteral nutrition can be found for example in Chapter 729 of the United States Pharmacopeia (USP).
  • the mean particle size is about 100 to about 200 nanometers.
  • the change in uniformity measurement of the emulsion is less than or equal to about 10%, more particularly 5%, after two months at room temperature.
  • the change in mean diameter of the emulsion is less than or equal to about 10%, more particularly 5% after two months at room temperature.
  • the PFAT5 of the emulsion is about 0.05%> or less after two months at room temperature.
  • the emulsion, or alternatively a diluted emulsion comprises greater than about 0.001%, particularly greater than or equal to 0.002%), and more particularly greater than 0.006%), by weight, of the emulsifier.
  • the emulsifier in the emulsion, or alternatively in the diluted emulsion is provided in an amount, by weight, of greater than about 0.001%, particularly of greater than or equal to 0.002%, and more particularly of greater than 0.006% of the emulsion).
  • the emulsion, or alternatively a diluted emulsion comprises greater than about 0.001%> to about 10%>, by weight, of the emulsifier (e.g., the emulsifier in the emulsion, or alternatively in a diluted emulsion, is provided in an amount, by weight, of greater than about 0.001% to about 10% of the emulsion).
  • the emulsifier e.g., the emulsifier in the emulsion, or alternatively in a diluted emulsion, is provided in an amount, by weight, of greater than about 0.001% to about 10% of the emulsion.
  • the emulsion, or alternatively a diluted emulsion comprises greater than about 0.002% to about 10%>, by weight, of the emulsifier (e.g., the emulsifier in the emulsion, or alternatively in a diluted emulsion, is provided in an amount, by weight, of greater than about 0.002% to about 10% of the emulsion).
  • the emulsifier e.g., the emulsifier in the emulsion, or alternatively in a diluted emulsion, is provided in an amount, by weight, of greater than about 0.002% to about 10% of the emulsion.
  • the emulsion, or alternatively a diluted emulsion comprises greater than about 0.006%) to about 10%>, by weight, of the emulsifier (e.g., the emulsifier in the emulsion, or alternatively in a diluted emulsion, is provided in an amount, by weight, of greater than about 0.006% to about 10% of the emulsion).
  • the emulsifier e.g., the emulsifier in the emulsion, or alternatively in a diluted emulsion, is provided in an amount, by weight, of greater than about 0.006% to about 10% of the emulsion.
  • the emulsion, or alternatively a diluted emulsion comprises about 0.6%> to about 10%>, by weight, of the emulsifier (e.g., the emulsifier in the emulsion, or alternatively in a diluted emulsion, is provided in an amount, by weight, of about 0.6% to about 10% of the emulsion).
  • the emulsion comprises about 1 to about 4%, by weight, of the emulsifier (e.g., the emulsifier in the emulsion, or alternatively in a diluted emulsion, is provided in an amount, by weight, of about 1 to about 4% of the emulsion).
  • the emulsion comprises about 1.8% or about 3.6%, by weight, of the emulsifier (e.g., the emulsifier in the emulsion, or alternatively in a diluted emulsion, is provided in an amount, by weight, of about 1.8 or about 3.6% of the emulsion).
  • Emulsifiers that are suitable for parenteral use (e.g., physiologically safe) can be used in embodiments provided herein.
  • Non- limiting examples of emulsifiers include phospholipids of animal or vegetable origin.
  • Other non-limiting examples include a lecithin including, but not limited to, synthetic and semi- synthetic lecithins.
  • Egg phospholipid mixtures such as Lipoid E-80 SN (Lipoid GmbH, Ludwigshafen, Germany) and Lipoid E PC S, are particular non limiting examples of an emulsifier provided herein.
  • phospholipids have greater than 70%, more particularly greater than 80%, more particularly greater than 90% and more particularly greater than 95% phosphatidylcholine.
  • the oil in the emulsion or, alternatively, in a diluted emulsion is provided an amount, by weight, of greater than about 0.01% up to less than about 10%, more particularly of greater than about 0.02% up to less than about 10%, more particularly of greater than about 0.03% up to less than about 10%, more particularly of greater than about 0.06% up to less than about 10%, of the emulsion, more particularly of greater than about 0.1% up to less than about 10%, of the emulsion (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of greater than or equal to about 0.01% up to less than about 10%>, more particularly of greater than or equal to about 0.02% up to less than about 10%, more particularly of greater than or equal to about 0.03% up to less than about 10% of the emulsion, more particularly of greater than or equal to about 0.06% up to less than about 10% of the emulsion, more particularly of greater than than or equal to about
  • the oil in the emulsion or, alternatively, in a diluted emulsion is provided an amount, by weight, of greater than about 0.01% up to about 10%, more particularly of greater than about 0.02% up to about 10%, more particularly of greater than about 0.03% up to about 10%, more particularly of greater than about 0.06% up to about 10%, of the emulsion, more particularly of greater than about 0.1% up to about 10%, of the emulsion (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of greater than or equal to about 0.01% up to about 10%, more particularly of greater than or equal to about 0.02% up to about 10%, more particularly of greater than or equal to about 0.03% up to about 10% of the emulsion, more particularly of greater than or equal to about 0.06% up to about 10% of the emulsion, more particularly of greater than or equal to about 0.1% up to about 10% of the emulsion
  • An isotonic agent can be added to adjust the osmolarity of the emulsion to a desired physiologically acceptable level.
  • the emulsion has an osmolarity of about 280 to about 300 milliosmols/liter, particularly about 300 milliosmol/liter.
  • the emulsion has an osmolarity of about 270 to about 300, or about 280 to about 300 milliosmols/liter, particularly about 300 milliosmol/liter.
  • the emulsion comprises about 1% to about 5%, by weight, of the isotonic agent (e.g., the isotonic agent in the emulsion, or alternatively in a diluted emulsion, is provided in an amount, by weight, of about 1% to about 5% of the emulsion). In some embodiments, the emulsion comprises about 1% to about 2.5%, by weight, of the isotonic agent (e.g., the isotonic agent in the emulsion, or alternatively in a diluted emulsion, is provided in an amount, by weight, of about 1% to about 2.5% of the emulsion).
  • the isotonic agent e.g., the isotonic agent in the emulsion, or alternatively in a diluted emulsion
  • the emulsion comprises about 2.25 to about 2.5%), by weight, of the isotonic agent (e.g., the isotonic agent in the emulsion, or alternatively in a diluted emulsion, is provided in an amount, by weight, of about 2.25% to about 2.5% of the emulsion).
  • the isotonic agent include, but are not limited to, glycerin, glucose, xylose, and sorbitol.
  • the particular isotonic agent comprises glycerin.
  • the emulsion is diluted into an aqueous solution having a concentration of the isotonic agent and osmolarity as described above.
  • the emulsion comprises about 0.03% to about 0.4%, by weight, more particularly about 0.03%> to about 0.3%>, by weight, a secondary emulsifier
  • suitable secondary emulsifiers that can be used for example are linoleic acid, linolenic acid, oleic acid, palmitic acid or their pharmaceutically acceptable salts (e.g., but not limited to potassium and sodium).
  • the secondary emulsifier is sodium oleate.
  • the sodium oleate is provided in an amount of about 0.3% (equivalent to about 3 mg/ml).
  • an oil comprising a triglyceride is added to the emulsion in an amount sufficient to provide a PFAT5 value for the emulsion of 0.05% or less.
  • the oil containing a triglyceride is provided in an amount greater than about 0.5%) by weight, more particularly from about 0.5%> to 3.3%, by weight and more particularly about 3.3% by weight of the emulsion.
  • the triglyceride content of the oil is greater than 90%.
  • the triglyceride and DHA can be present in the same oil.
  • an oil comprising triglycerides is added to the emulsion in an amount sufficient to provide a PFAT5 value for the emulsion of about 0.05% or less.
  • the oil containing triglycerides is provided in an amount greater than about 0.5%, more particularly from about 0.5% to 3.3%, and more particularly about 3.3% by weight of the emulsion.
  • the triglycerides content of the oil is greater than 90% by weight.
  • specific concentrations of the DHA-TG can be achieved by dilution of an emulsion prepared according to the processes described herein to create a dilute DHA-TG emulsion.
  • This emulsion can also be suitable as a parenteral DHA-TG formulation.
  • a non-limiting example would be to take an emulsion described herein with a high concentration of DHA-TG, for example, but not limited to, 270 mg/ml and dilute it into an aqueous solution and mix or disperse it.
  • the osmolarity of the emulsion is maintained at the same osmolarity of the emulsion having the high concentration of the DHA-TG.
  • specific concentrations of the DHA-FFA can be achieved by dilution of an emulsion prepared according to the processes described herein to create a dilute DHA-FFA emulsion.
  • This emulsion can also be suitable as a parenteral DHA- FFA formulation.
  • a non-limiting example would be to take an emulsion described herein with a high concentration of DHA-FFA, for example, but not limited to, 270 mg/ml, and dilute it into an aqueous solution and mix or disperse it.
  • the osmolarity of the emulsion is maintained at the same osmolarity of the emulsion having the high concentration of the DHA-FFA.
  • specific concentrations of the DHA-EE can be achieved by dilution of an emulsion prepared according to the processes described herein to create a dilute DHA-EE emulsion.
  • This emulsion can also be suitable as a parenteral DHA-EE formulation.
  • a non-limiting example would be to take an emulsion described herein with a high concentration of DHA-EE, for example, but not limited to, 270 mg/ ml and dilute it into an aqueous solution and mix or disperse it.
  • the osmolarity of the emulsion is maintained at the same osmolarity of the emulsion having the high concentration of the DHA-EE.
  • the emulsion or, alternatively, a diluted emulsion comprises greater than about 0.01%, more particularly greater than or equal to about 0.02%, more particularly greater than or equal to about 0.03%, more particularly greater than or equal to about 0.06%, and more particularly greater than or equal to about 0.1%, by weight, oil containing the DHA-EE (e.g., the oil is present in the emulsion or, alternatively, in the diluted emulsion, in an amount, by weight, of greater than about 0.01% more particularly of greater than or equal to about 0.02%, more particularly of greater than or equal to about 0.03%, more particularly of greater than or equal to about 0.06%, and more particularly of greater than or equal to about 0.1% of the emulsion).
  • oil containing the DHA-EE e.g., the oil is present in the emulsion or, alternatively, in the diluted emulsion, in an amount, by weight, of greater than about 0.01% more particularly of greater than or equal to about 0.02%,
  • the emulsion or, alternatively, a diluted emulsion comprises greater than about 0.01% up to about 0.02%, more particularly greater than about 0.01% up to about 0.03%, more particularly greater than about 0.01% up to about 0.06%, more particularly greater than about 0.01% up to about 0.1%, more particularly greater than 0.01% up to less than 10%, by weight of the oil containing the DHA-TG (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided an amount, by weight, of greater than about 0.01% up to about 0.02%, more particularly of greater than about 0.01%) up to about 0.03%>, more particularly of greater than about 0.01% up to about 0.06%, more particularly of greater than about 0.01% up to about 0.1%, more particularly of greater than 0.01% up to less than 10% of the emulsion).
  • the oil containing the DHA-TG e.g., the oil in the emulsion or, alternatively, in the diluted
  • the emulsion or, alternatively, a diluted emulsion comprises greater than or equal to about 0.02%) up to about 0.03%>, more particularly greater than or equal to about 0.02%> up to about 0.06%), more particularly greater than or equal to about 0.02%> up to about 0.1 %, more particularly a greater than or equal to about 0.02% up to less than 10%, by weight of the oil containing the DHA-TG (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of greater than or equal to about 0.02%) up to about 0.03%>, more particularly of greater than or equal to about 0.02%> up to about 0.06%, more particularly of greater than or equal to about 0.02% up to about 0.1%, more particularly of greater than or equal to about 0.02% up to less than 10% of the emulsion).
  • the oil containing the DHA-TG e.g., the oil in the emulsion or, alternatively
  • the emulsion or, alternatively, a diluted emulsion comprises greater than or equal to about 0.03%> up to about 0.06%>, more particularly greater than or equal to about 0.03% up to about 0.1%, more particularly a greater than or equal to about 0.03% up to less than 10%, by weight of the oil containing the DHA-TG (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of greater than or equal to about 0.03%> up to about 0.06%>, more particularly of greater than or equal to about 0.03% up to about 0.1%, more particularly of greater than or equal to about 0.03% up to less than 10% of the emulsion).
  • the oil containing the DHA-TG e.g., the oil in the emulsion or, alternatively, in the diluted emulsion
  • the emulsion or, alternatively, a diluted emulsion comprises greater than or equal to about 0.06% up to about 0.1%, more particularly a greater than or equal to about 0.06%) up to less than 10%>, by weight of the oil containing the DHA-TG (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of greater than or equal to about 0.06%> up to less than 10%>, more particularly of greater than or equal to about 0.06% up to less than 10% of the emulsion).
  • the oil containing the DHA-TG e.g., the oil in the emulsion or, alternatively, in the diluted emulsion
  • the emulsion or, alternatively, a diluted emulsion comprises greater than or equal to about 0.1% up to less than 10%, by weight of the oil containing the DHA-TG (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of greater than or equal to about 0.1 % up to less than 10%>, of the emulsion).
  • the emulsion or, alternatively, a diluted emulsion comprises about 0.01% to about 30%>, by weight, oil containing the DHA-TG (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 0.01% to about 30%> of the emulsion).
  • oil containing the DHA-TG e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 0.01% to about 30%> of the emulsion.
  • the emulsion or, alternatively, a diluted emulsion comprises about 0.02%> to about 30%>, by weight, oil containing the DHA-TG (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 0.02%> to about 30%> of the emulsion).
  • oil containing the DHA-TG e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 0.02%> to about 30%> of the emulsion.
  • the emulsion or, alternatively, a diluted emulsion comprises about 0.03%> to about 30%>, by weight, oil containing the DHA-TG (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight of about 0.03%> to about 30%> of the emulsion).
  • the emulsion or, alternatively, a diluted emulsion comprises about 0.06%> to about 30%>, by weight, oil containing the DHA-TG.
  • the emulsion or, alternatively, a diluted emulsion comprises about 0.1%> to about 30%>, by weight, oil containing the DHA-TG (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of 0.1%) to about 30%> of the emulsion).
  • the emulsion or, alternatively, a diluted emulsion comprises about 0.01% to less than about 30%>, by weight, oil containing the DHA-TG (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 0.01% to less than about 30% of the emulsion).
  • oil containing the DHA-TG e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 0.01% to less than about 30% of the emulsion.
  • the emulsion or, alternatively, a diluted emulsion comprises about 0.02%> to less than about 30%>, by weight, oil containing the DHA-TG (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 0.02%> to less than about 30%> of the emulsion).
  • oil containing the DHA-TG e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 0.02%> to less than about 30%> of the emulsion.
  • the emulsion or, alternatively, a diluted emulsion comprises about 0.03%> to less than about 30%>, by weight, oil containing the DHA-TG (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight of about 0.03%> to less than about 30%> of the emulsion).
  • the emulsion or, alternatively, a diluted emulsion comprises about 0.06%> to less than about 30%, by weight, oil containing the DHA-TG.
  • the emulsion or, alternatively, a diluted emulsion comprises about 0.1 % to less than about 30%), by weight, oil containing the DHA-TG (e.g. , the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of 0.1% to less than about 30% of the emulsion).
  • the emulsion or, alternatively, a diluted emulsion comprises about 3% oil to about 30%>, by weight, oil containing the DHA-TG (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 3% oil to about 30%> of the emulsion).
  • the emulsion or, alternatively, a diluted emulsion comprises about 3% by weight oil containing the DHA-TG (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 3% of the emulsion).
  • the emulsion comprises, about 2% to about 30% oil containing the DHA-TG, by total weight of the emulsion (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 2% to about 30% of the emulsion).
  • the emulsion or, alternatively, a diluted emulsion comprises greater than 10%, up to about 30%, by weight, oil containing the DHA-TG (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of greater than 10% up to about 30% of the emulsion).
  • the emulsion comprises about 15% to about 30% of the oil containing the DHA-TG (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 15% to about 30% of the emulsion.
  • the emulsion or, alternatively, a diluted emulsion comprises about 10%, by weight, oil containing the DHA-TG (e.g. , the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 10% of the emulsion).
  • the emulsion or, alternatively, a diluted emulsion comprises about 30%, by weight, oil containing the DHA-TG (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 30% of the emulsion).
  • oil containing the DHA-TG e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 30% of the emulsion.
  • the emulsion or, alternatively, a diluted emulsion comprises greater than about 0.01%, more particularly greater than or equal to about 0.02%, more particularly greater than or equal to about 0.03%, more particularly greater than or equal to about 0.06%, and more particularly greater than or equal to about 0.1%, by weight, oil containing the DHA-FFA (e.g., the oil is provided in the emulsion or, alternatively, in the diluted emulsion, in an amount, by weight, of greater than about 0.01%, more particularly of greater than or equal to about 0.02%, more particularly of greater than or equal to about 0.03%, more particularly of greater than or equal to about 0.06%, and more particularly of greater than or equal to about 0.1%, of the emulsion).
  • oil containing the DHA-FFA e.g., the oil is provided in the emulsion or, alternatively, in the diluted emulsion, in an amount, by weight, of greater than about 0.01%, more particularly of greater than or equal to
  • the oil in the emulsion or, alternatively, in a diluted emulsion is provided in an amount, by weight, of greater than about 0.01% up to about 30%>, more particularly of greater than about 0.02% up to about 30%, more particularly of greater than about 0.03% up to about 30%, more particularly of greater than about 0.06% up to about 30%, of the emulsion, more particularly of greater than about 0.1% up to about 30%), of the emulsion, (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided an amount, by weight, of greater than about 0.01% up to about 30%, more particularly of greater than about 0.02% up to about 30%, more particularly of greater than about 0.03% up to about 30%, more particularly of greater than about 0.06% up to about 30%, more particularly of greater than 0.
  • the emulsion or, alternatively, a diluted emulsion comprises greater than about 0.01% up to about 0.02%, more particularly greater than about 0.01% up to about 0.03%, more particularly greater than about 0.01% up to about 0.06%, more particularly greater than about 0.01% up to about 0.1%, more particularly greater than 0.01% up to less than 30%, by weight of the oil containing the DHA-FFA (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of greater than about 0.01% up to about 0.02%>, more particularly of greater than about 0.01% up to about 0.03%, more particularly of greater than about 0.01%) up to about 0.06%>, more particularly of greater than about 0.01 % up to about 0.1%, more particularly of greater than 0.01% up to less than about 30% of the emulsion).
  • the oil containing the DHA-FFA e.g., the oil in the emulsion or, alternative
  • the emulsion or, alternatively, a diluted emulsion comprises greater than or equal to about 0.02% up to about 0.03%, more particularly greater than or equal to about 0.02% up to about 0.06%, more particularly greater than or equal to about 0.02% up to about 0.1%, more particularly a greater than or equal to about 0.02% up to less than 30%, by weight of the oil containing the DHA-FFA (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of greater than or equal to about 0.02% up to about 0.03%, more particularly of greater than or equal to about 0.02% up to about 0.06%, more particularly of greater than or equal to about 0.02% up to about 0.1%, more particularly of greater than or equal to about 0.02% up to less than 30%> of the emulsion).
  • the oil containing the DHA-FFA e.g., the oil in the emulsion or, alternatively, in the diluted
  • the emulsion or, alternatively, a diluted emulsion comprises greater than or equal to about 0.03%> up to about 0.06%), more particularly greater than or equal to about 0.03%> up to about 0.1 %, more particularly a greater than or equal to about 0.03% up to less than 30%>, by weight of the oil containing the DHA-FFA (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of greater than or equal to about 0.03%) up to about 0.06%>, more particularly of greater than or equal to about 0.03%> up to about 0.1%, more particularly of greater than or equal to about 0.03% up to less than 30%) of the emulsion).
  • the oil containing the DHA-FFA e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of greater than or equal to about 0.03%
  • the emulsion or, alternatively, a diluted emulsion comprises greater than or equal to about 0.06%> up to about 0.1%>, more particularly a greater than or equal to about 0.06%> up to less than 30%>, by weight of the oil containing the DHA-FFA (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of greater than or equal to about 0.06%> up to about 0.1%), more particularly of greater than or equal to about 0.06%> up to less than 30% of the emulsion).
  • the oil containing the DHA-FFA e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of greater than or equal to about 0.06%> up to about 0.1%), more particularly of greater than or equal to about 0.06%> up to less than 30% of the emulsion.
  • the emulsion or, alternatively, a diluted emulsion comprises greater than or equal to about 0.1%> up to less than 30%>, by weight of the oil containing the DHA-FFA (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of greater than or equal to about 0.1%) up to less than 30%> of the emulsion).
  • the oil containing the DHA-FFA e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of greater than or equal to about 0.1%) up to less than 30%> of the emulsion.
  • the emulsion comprises about 2% to about 30%>, by weight, oil containing the DHA-FFA (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 2% to about 30%> of the emulsion).
  • the emulsion or, alternatively, a diluted emulsion comprises about 3% oil to about 30%>, by weight, oil containing the DHA-FFA (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 3% oil to about 30% of the emulsion).
  • the emulsion or, alternatively, a diluted emulsion comprises about 3% by weight oil containing the DHA-FFA (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 3% of the emulsion). In some embodiments the emulsion or, alternatively, a diluted emulsion, comprises about 10% to about 30% by weight of the oil containing the DHA- FFA (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 10% to about 30% of the emulsion).
  • the emulsion or, alternatively, a diluted emulsion comprises about 15% to about 30% by weight of the oil containing the DHA-FFA (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 15% to about 30% of the emulsion).
  • the oil in the emulsion comprises, by weight, about 84% to about 99% DHA-FFA.
  • the emulsion comprises about >95% DHA-FFA of the total weight of the oil.
  • the emulsion or, alternatively, a diluted emulsion comprises greater than about 0.01%, more particularly greater than or equal to about 0.02%, more particularly greater than or equal to about 0.03%, more particularly greater than or equal to about 0.06%, and more particularly greater than or equal to about 0.1%, by weight, oil containing the DHA-EE (e.g., the oil is present in the emulsion or, alternatively, in the diluted emulsion, in an amount, by weight, of greater than about 0.01% more particularly of greater than or equal to about 0.02%, more particularly of greater than or equal to about 0.03%, more particularly of greater than or equal to about 0.06%, and more particularly of greater than or equal to about 0.1% of the emulsion).
  • oil containing the DHA-EE e.g., the oil is present in the emulsion or, alternatively, in the diluted emulsion, in an amount, by weight, of greater than about 0.01% more particularly of greater than or equal to about 0.02%,
  • the emulsion or, alternatively, a diluted emulsion comprises greater than about 0.01% up to about 0.02%, more particularly greater than about 0.01% up to about 0.03%), more particularly greater than about 0.01 % up to about 0.06%>, more particularly greater than about 0.01% up to about 0.1%, more particularly greater than 0.01% up to less than 10%, by weight of the oil containing the DHA-EE (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided an amount, by weight, of greater than about 0.01% up to about 0.02%, more particularly of greater than about 0.01%) up to about 0.03%>, more particularly of greater than about 0.01% up to about 0.06%, more particularly of greater than about 0.01% up to about 0.1%, more particularly of greater than 0.01% up to less than 10% of the emulsion).
  • the oil containing the DHA-EE e.g., the oil in the emulsion or, alternatively, in the
  • the emulsion or, alternatively, a diluted emulsion comprises greater than or equal to about 0.02%) up to about 0.03%>, more particularly greater than or equal to about 0.02%> up to about 0.06%), more particularly greater than or equal to about 0.02%> up to about 0.1 %, more particularly a greater than or equal to about 0.02% up to less than 10%, by weight of the oil containing the DHA-EE (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of greater than or equal to about 0.02%) up to about 0.03%>, more particularly of greater than or equal to about 0.02%> up to about 0.06%, more particularly of greater than or equal to about 0.02% up to about 0.1%, more particularly of greater than or equal to about 0.02% up to less than 10% of the emulsion).
  • the oil containing the DHA-EE e.g., the oil in the emulsion or, alternatively
  • the emulsion or, alternatively, a diluted emulsion comprises greater than or equal to about 0.03%> up to about 0.06%>, more particularly greater than or equal to about 0.03% up to about 0.1%, more particularly a greater than or equal to about 0.03% up to less than 10%, by weight of the oil containing the DHA-EE (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of greater than or equal to about 0.03%> up to about 0.06%>, more particularly of greater than or equal to about 0.03% up to about 0.1%, more particularly of greater than or equal to about 0.03% up to less than 10% of the emulsion).
  • the oil containing the DHA-EE e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of greater than or equal to about 0.03%> up to about 0.06%>, more particularly of greater
  • the emulsion or, alternatively, a diluted emulsion comprises greater than or equal to about 0.06% up to about 0.1%, more particularly a greater than or equal to about 0.06%) up to less than 10%>, by weight of the oil containing the DHA-EE (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of greater than or equal to about 0.06%> up to about 0.01%, more particularly of greater than or equal to about 0.06% up to less than 10% of the emulsion).
  • the oil containing the DHA-EE e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of greater than or equal to about 0.06%> up to about 0.01%, more particularly of greater than or equal to about 0.06% up to less than 10% of the emulsion.
  • the emulsion or, alternatively, a diluted emulsion comprises greater than or equal to about 0.1% up to less than 10%, by weight of the oil containing the DHA-EE (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of greater than or equal to about 0.1 % up to less than 10%>, of the emulsion).
  • the emulsion or, alternatively, a diluted emulsion comprises about 0.01% to about 30%>, by weight, oil containing the DHA-EE (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 0.01 % to about 30%> of the emulsion).
  • oil containing the DHA-EE e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 0.01 % to about 30%> of the emulsion.
  • the emulsion or, alternatively, a diluted emulsion comprises about 0.02%> to about 30%>, by weight, oil containing the DHA-EE (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 0.02%> to about 30%> of the emulsion).
  • oil containing the DHA-EE e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 0.02%> to about 30%> of the emulsion.
  • the emulsion or, alternatively, a diluted emulsion comprises about 0.03%> to about 30%>, by weight, oil containing the DHA-EE (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight of about 0.03%> to about 30%> of the emulsion).
  • the emulsion or, alternatively, a diluted emulsion comprises about 0.06%> to about 30%>, by weight, oil containing the DHA-EE.
  • the emulsion or, alternatively, a diluted emulsion comprises about 0.1%> to about 30%>, by weight, oil containing the DHA-EE (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of 0.1%) to about 30%> of the emulsion).
  • the emulsion comprises about 0.3% to about 30%>, by weight, oil containing the DHA-EE (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 0.3%> to about 30%> of the emulsion.
  • the emulsion or, alternatively, a diluted emulsion comprises about 0.01% to less than about 30%>, by weight, oil containing the DHA-EE (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 0.01% to less than about 30%) of the emulsion).
  • the emulsion or, alternatively, a diluted emulsion comprises about 0.02%> to less than about 30%>, by weight, oil containing the DHA-EE (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 0.02%> to less than about 30%> of the emulsion).
  • oil containing the DHA-EE e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 0.02%> to less than about 30%> of the emulsion.
  • the emulsion or, alternatively, a diluted emulsion comprises about 0.03%> to less than about 30%>, by weight, oil containing the DHA-EE (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight of about 0.03% to less than about 30% of the emulsion).
  • the emulsion or, alternatively, a diluted emulsion comprises about 0.06%> to less than about 30%, by weight, oil containing the DHA-EE.
  • the emulsion or, alternatively, a diluted emulsion comprises about 0.1 % to less than about 30%, by weight, oil containing the DHA-EE (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of 0.1 % to less than about 30%) of the emulsion).
  • the emulsion comprises about 0.3%> to less than about 30%, by weight, oil containing the DHA-EE (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 0.3%> to less than about 30% of the emulsion.
  • the emulsion or, alternatively, a diluted emulsion comprises about 3% oil to about 30%>, by weight, oil containing the DHA-EE (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 3% oil to about 30% of the emulsion).
  • the emulsion or, alternatively, a diluted emulsion comprises about 3% by weight oil containing the DHA-EE (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 3%) of the emulsion).
  • the emulsion comprises, about 2% to about 30% oil containing the DHA-EE, by total weight of the emulsion (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 2% to about 30% of the emulsion).
  • the emulsion or, alternatively, a diluted emulsion comprises about 10%>, by weight, oil containing the DHA-EE (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 10%> of the emulsion).
  • the emulsion or, alternatively, a diluted emulsion comprises greater than 10%>, up to about 30%), by weight, oil containing the DHA-EE (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of greater than 10%) up to about 30%> of the emulsion).
  • the emulsion comprises about 15% to about 30% of the oil containing the DHA-EE (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 15% to about 30% of the emulsion.
  • the emulsion or, alternatively, a diluted emulsion comprises about 30%>, by weight, oil containing the DHA-EE (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 30% of the emulsion).
  • the oil in the emulsion comprises about 84% to about 95%, by weight, DHA-EE, more particularly about about 90% DHA-EE.
  • the emulsion or, alternatively, a diluted emulsion comprises about 10%, by weight, oil containing the DHA-FFA (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 10%> of the emulsion).
  • oil containing the DHA-FFA e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 10%> of the emulsion.
  • the emulsion or, alternatively, a diluted emulsion comprises about 30%, by weight, oil containing the DHA-FFA (e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 30%> of the emulsion).
  • oil containing the DHA-FFA e.g., the oil in the emulsion or, alternatively, in the diluted emulsion, is provided in an amount, by weight, of about 30%> of the emulsion.
  • the concentration of the DHA-FFA is about 0.3 mg/ml of the emulsion.
  • the concentration of the DHA-TG is about 3.0 mg/ml of the emulsion.
  • the concentration of the DHA-FFA is about 3.0 mg/ml of the emulsion.
  • the concentration of the DHA-EE is about 3.0 mg/ml of the emulsion.
  • the concentration of the DHA-TG is about 30 mg/ml of the emulsion.
  • the concentration of the DHA-FFA is about 30 mg/ml of the emulsion.
  • the concentration of the DHA-EE is about 30 mg/ml of the emulsion.
  • the above oil and/or DHA-TG concentrations can be obtained by starting with a low concentration of oil (e.g., but not limited to 3% by weight) or higher (e.g., but not limited to 30% weight) and then diluted for example into water, more particularly an aqueous solution comprising and isotonic agent the dilution factor including, for example but not limited to, a thousand fold, a hundred fold, and more particularly tenfold.
  • the concentrations of the DHA-TG and other ingredients are calculated based on the dilution factor.
  • the above oil and/or DHA-FFA concentrations can be obtained by starting with a low concentration of oil (e.g., but not limited to 3% by weight) or higher (e.g., but not limited to 30% weight) and then diluted, for example, into water, more particularly an aqueous solution comprising and isotonic agent the dilution factor including, for example but not limited to, a thousand fold, a hundred fold, and more particularly tenfold.
  • the concentrations of the DHA-FFA and other ingredients are calculated based on the dilution factor.
  • the above oil and/or DHA-EE concentrations can be obtained by starting with a low concentration of oil (e.g., but not limited to 3% by weight) or higher (e.g., but not limited to 30%> weight) and then diluted for example into water, more particularly an aqueous solution comprising and isotonic agent the dilution factor including, for example but not limited to, a thousand fold, a hundred fold, and more particularly tenfold.
  • the concentrations of the DHA-EE and other ingredients are calculated based on the dilution factor.
  • the emulsion comprises about 120 milligrams of docosahexaenoic acid triglyceride (DHA-TG) per milliliter of the emulsion; about 18 milligrams of a lecithin per milliliter of the emulsion; and about 25 milligrams of glycerin per milliliter of the emulsion wherein the emulsion has a mean particle size of up to about 500 nanometers, more particularly about 100 to about 200 nanometers, wherein the emulsion is provided substantially free of EPA and is suitable for parenteral administration.
  • DHA-TG docosahexaenoic acid triglyceride
  • the emulsion comprises about 150 milligrams of DHA-
  • FFA per milliliter of the emulsion about 18 milligrams of a lecithin per milliliter of the emulsion; and about 25 milligrams of glycerin per milliliter of the emulsion wherein the emulsion has a mean particle size up to and including about 500 nanometers, more particularly about 100 to about 200 nanometers, wherein the emulsion is substantially free of EPA and is suitable for parenteral administration.
  • the emulsion comprises about 180 milligrams DHA-TG per milliliter of the emulsion wherein the DHA is provided in the form of a triglyceride; about 18 milligrams lecithin per milliliter of the emulsion; and about 25 milligrams of glycerin per milliliter of the emulsion wherein the emulsion has a mean particle size of about 100 to about 200 nanometers and wherein the emulsion is provided substantially free of EPA and is suitable for parenteral administration.
  • the emulsion comprises about 300 milligrams of DHA-
  • FFA per milliliter of the emulsion about 36 milligrams of a lecithin per milliliter of the emulsion; and about 50 milligrams of glycerin per milliliter of the emulsion wherein the emulsion has a mean particle size up to and including about 500 nanometers, more particularly about 100 to about 200 nanometers, wherein the emulsion is substantially free of EPA and is suitable for parenteral administration.
  • the emulsion comprises about 250 to about 290 milligrams of DHA-EE per milliliter of the emulsion wherein the DHA is provided as an ethyl ester; about 18 milligrams of a lecithin per milliliter of the emulsion; and about 25 milligrams of glycerin per milliliter of the emulsion wherein the emulsion has a mean particle size of to about 500 nanometers, more particularly, about 100 to about 200 nanometers, wherein the emulsion is provided substantially free of EPA and is suitable for parenteral administration.
  • the emulsion can also include antioxidants and other agents, including but not limited to Vitamin E, Vitamin C, carotenoids, flavonoids, Lipoic acid, tocotrienols, and tocopherols.
  • Other physiologically safe additives can also be used in some embodiments including, but not limited to, common intravenous salts such as sodium chloride and nonelectrolytes such as glucose, pH modifiers (such as acetic acid and sodium acetate) and buffers (such as acetate, lactate, and phosphate buffer systems composed of the acid and a salt of the acid), emulsion stabilizers like gelatin, polysaccharides, such as agar, and/or detergents like tweens and spans, as well as selenium compounds.
  • the emulsion is provided substantially free of detergents, for example, non- ionic detergents, e.g., tweens.
  • the emulsion is made by mixing an oil containing a DHA-
  • the emulsion is made by mixing an oil containing a DHA free fatty acid, an isotonic agent, an emulsifier and water and further homogenizing the mixture to a desired particle size.
  • the emulsion is made by mixing an oil containing DHA-EE, an isotonic agent, an emulsifier and water and further homogenizing the mixture to a desired particle size.
  • the pH of the emulsion can be adjusted for example to a desired pH.
  • the emulsion has a pH of about 5 to about 9, particularly about 7 to about 9.
  • the emulsion has a pH of 6.5 to about 8.5, more particularly about 7 to about 8.
  • the pH is adjusted with a pH adjuster that is suitable for parenteral use, for example, but not limited to sodium hydroxide.
  • an emulsion is provided substantially free of a therapeutic amount of an active agent other than DHA-TG. In some embodiments, an emulsion is provided in the absence of a therapeutic amount of an anti-cancer agent.
  • an emulsion is provided substantially free of a therapeutic amount of an active agent other than DHA-FFA. In some embodiments, an emulsion is provided in the absence of a therapeutic amount of an anti-cancer agent.
  • an emulsion is provided substantially free of a therapeutic amount of an active agent other than DHA-EE. In some embodiments, an emulsion is provided in the absence of a therapeutic amount of an anti-cancer agent.
  • an emulsion is provided substantially free of a medium chain fatty acid, in particular a medium chain triglyceride
  • the medium chain fatty acid is present in an amount less than about 30% (w/w), less than about 10%) (w/w), less than about 5% (w/w), less than about 2% (w/w), or less than about 1% (w/w) of the total fatty acid content of the emulsion.
  • the medium chain fatty acid is present in an amount less than about 10% (w/w), less than about 5% (w/wt), less than about 2% (w/w), or less than about 1% (w/w) of the total fatty acid content of the emulsion, or the medium chain fatty acid is not detectable in the emulsion. In some embodiments there is no detectable medium chain fatty acid, in particular no detectable medium chain triglyceride.
  • chelating agents such as ethylenediaminetetraacetic acid
  • EDTA diethylenetriaminepentaacetic acid
  • DTP A diethylenetriaminepentaacetic acid
  • preservatives such as benzyl alcohol or sodium benzoate are present in the emulsion.
  • the emulsions provided herein can be provided in an effective amount to treat a subject suffering from traumatic brain injury, including but limited to a closed head injury, such as a concussion or a contusion; or a penetrating head injury.
  • traumatic head injury can be mild, moderate or severe, and involve diffuse axonal injury or hematoma.
  • Some embodiments of the emulsion provided herein are useful to treat subjects suffering from spinal cord injury (SCI). With injury to the spinal cord of a mammal, connections between nerves in the spinal cord are damaged or broken. Such injuries block the flow of nerve impulses for the nerve tracts affected by the injury, with a resulting impairment to both sensory and motor function.
  • SCI spinal cord injury
  • Injuries to the spinal cord can arise from compression or other contusion of the spinal cord, or a crushing or severing of the spinal cord.
  • a severing of the spinal cord also referred to as a "transection,” can be a complete severing or, can be an incomplete severing of the spinal cord.
  • Treatment of subjects with SCI with the emulsions, or alternatively diluted emulsions, provided herein provide functional improvement (e.g., locomotor) and can provide neuroprotective effects.
  • DHA-TG emulsions or alternatively diluted emulsions, provided herein leads to a reduction in oxidative stress and to a modulation of the inflammatory response after injury.
  • DHA-FFA emulsions or alternatively diluted emulsions, provided herein leads to a reduction in oxidative stress and to a modulation of the inflammatory response after injury.
  • DHA-EE emulsions or alternatively diluted emulsions, provided herein leads to a reduction in oxidative stress and to a modulation of the inflammatory response after injury.
  • a method of treating a subject suffering from SCI comprising administering to the subject an emulsion comprising an effective amount of a DHA-TG to the subject in need thereof wherein the emulsion is provided in the substantial absence of EPA and ARA.
  • the DHA-TG is administered to a subject suffering from SCI at a dose greater than about 0.16 mg/kg.
  • the DHA TG emulsion is administered to a subject suffering from SCI as a bolus injection.
  • the DHA-TG emulsion is administered within four hours, more particularly within three hours, more particularly within two hours, more particularly within one hour and more particularly within thirty minutes of the SCI.
  • a method of treating a subject suffering from SCI comprising administering to the subject an emulsion comprising an effective amount of a DHA-FFA to the subject in need thereof wherein the emulsion is provided in the substantial absence of EPA and ARA.
  • the DHA-FFA is administered to a subject suffering from SCI at a dose greater than about 0.16 mg/kg.
  • the DHA FFA emulsion is administered to a subject suffering from SCI as a bolus injection.
  • the DHA-FFA emulsion is administered within four hours, more particularly within three hours, more particularly within two hours, more particularly with one hour and more particularly within thirty minutes of the SCI.
  • a method of treating a subject suffering from SCI comprising administering to the subject an emulsion comprising an effective amount of a DHA-EE to the subject in need thereof wherein the emulsion is provided in the substantial absence of EPA and ARA.
  • the DHA-EE is administered to a subject suffering from SCI at a dose greater than about 0.16 mg/kg.
  • the DHA EE emulsion is administered to a subject suffering from SCI as a bolus injection.
  • the DHA-EE emulsion is administered within four hours, more particularly within three hours, more particularly within two hours, more particularly within one hour and more particularly within thirty minutes of the SCI.
  • Some embodiments provided herein can be used to treat a subject suffering from ischemic brain injury including but not limited to stroke. Some embodiments can be used to treat a subject suffering from a hemorrhagic stroke or other types of brain trauma associated with bleeding.
  • the emulsions provided herein can be used to treat inflammatory conditions including, but not limited to arthritis.
  • Arthritis is defined herein as inflammatory diseases of the joints, including, but not limited to osteoarthritis, gouty arthritis, ankylosing spondylitis, psoriatic arthritis, reactive arthritis, rheumatoid arthritis, juvenile onset rheumatoid arthritis, infectious arthritis, inflammatory arthritis, septic arthritis, degenerative arthritis, arthritis mutilans, and lyme arthritis.
  • the emulsions provided herein can be used to treat a subject suffering from liver disorders such as fatty liver (hepatosteatosis).
  • the liver disorder includes, but is not limited to, nonalcoholic fatty liver disease (NAFLD).
  • NAFLD refers liver diseases including, but not limited to, simple fatty liver (hepatosteatosis), nonalcoholic steatohepatitis (NASH), and cirrhosis (irreversible, advanced scarring of the liver), that result from accumulation of fat in liver cells, that is not due to excessive alcohol intake.
  • Hepatosteatosis is the accumulation of fat in the liver.
  • Steatohepatitis is characterized by fat accumulation in the liver concurrent with hepatic inflammation.
  • the emulsions provided herein can be used to treat a subject suffering from steatohepatitis, resulting from excessive alcohol intake. In some embodiments, an emulsion provided here can be used to treat a subject suffering from primary sclerosing cholangitis.
  • the subject has e.g., hepatosteatosis, hepatic inflammation, cirrhosis, biliary obstruction, and/or hepatic fibrosis.
  • it is desirable to treat e.g., to reduce hepatosteatosis, hepatic inflammation, cirrhosis, biliary obstruction, and/or hepatic fibrosis; prevent hepatosteatosis, hepatic inflammation, cirrhosis, biliary obstruction, and/or hepatic fibrosis; or retard the onset of hepatosteatosis, hepatic inflammation, cirrhosis, biliary obstruction, and/or hepatic fibrosis.
  • the emulsions provided herein can be used to treat hepatic fibrosis. In some embodiments, the emulsions provided herein can be used to prevent formation of new fibroids. In some embodiments, the emulsions provided herein can be used to can be used to reduce the number of fibroids. In some embodiments, the emulsions provided herein can be used to retard the onset of fibroid formation.
  • the emulsions provided herein can be used to treat a subject suffering from congestive heart failure, including both chronic and acute congestive heart failure. In some embodiments, the emulsions provided herein can be used to treat heart arrhythmia originating in either the atrium or the ventricle.
  • the emulsions provided herein can be used to prevent or reduce the risk of post-operative cognitive dysfunction in a subject.
  • emulsions for parenteral use refers to compositions, e.g., emulsions, that are, within the scope of sound medical judgment, suitable for parenteral administration into human beings and/or animals without excessive toxicity or other complications commensurate with a reasonable benefit/risk ratio.
  • suitable for parenteral administration refers to an emulsion which is deemed physiologically safe, or safe for human administration, by a governmental entity, e.g., the United States Food and Drug Administration.
  • An example of a definition of parenteral can be found for example in Stedman's Medical Dictionary, 26 th Edition.
  • parenteral administration of an emulsion provided herein refers particularly to the introduction of the emulsion into a subject by intravenous, subcutaneous, intramuscular, or intramedullary injection.
  • an emulsions provided herein can be administered to a subject as a bolus injection.
  • the intravenous injection is a bolus injection.
  • an emulsion is administered to a subject to provide a dose of DHA-TG of greater than about 0.16 mg/kg, more particularly greater than 0.16 mg/kg up to about 0.66 mg/kg, more particularly greater than 0.16 mg/kg up to about 2.6 mg/kg, more particularly greater than 0.16 mg/kg up to about 9.5 mg/kg, more particularly greater than 0.16 mg/kg up to about 25 mg/kg, more particularly greater than 0.16 mg/kg up to about 38 mg/kg, more particularly greater than 0.16 mg/kg up to about 150 mg/kg and more particularly greater than 0.16 mg/kg up to about 250 mg/kg.
  • an emulsion, or alternatively a diluted emulsion is administered to a subject to provide a dose of DHA-TG of greater than 100 mg/kg up to about 150 mg/kg. In some embodiments, an emulsion, or alternatively a diluted emulsion, is administered to a subject to provide a dose of DHA-TG of greater than 10 mg/kg up to about 15 mg/kg.
  • an emulsion, or alternatively a diluted emulsion is administered to a subject to provide a dose of DHA-FFA of greater than about 0.16 mg/kg, more particularly greater than 0.16 mg/kg up to about 0.66 mg/kg, more particularly greater than 0.16 mg/kg up to about 2.6 mg/kg, more particularly greater than 0.16 mg/kg up to about 9.5 mg/kg, more particularly greater than 0.16 mg/kg up to about 25 mg/kg, more particularly greater than 0.16 mg/kg up to about 38 mg/kg, more particularly greater than 0.16 mg/kg up to about 150 mg/kg and more particularly greater than 0.16 mg/kg up to about 250 mg/kg.
  • an emulsion is administered to a subject to provide a dose of DHA-EE of greater than about 0.16 mg/kg, more particularly greater than 0.16 mg/kg up to about 0.66 mg/kg, more particularly greater than 0.16 mg/kg up to about 2.6 mg/kg, more particularly greater than 0.16 mg/kg up to about 9.5 mg/kg, more particularly greater than 0.16 mg/kg up to about 25 mg/kg, more particularly greater than 0.16 mg/kg up to about 38 mg/kg, more particularly greater than 0.16 mg/kg up to about 150 mg/kg and more particularly greater than 0.16 mg/kg up to about 250 mg/kg.
  • an emulsion is administered to a subject to provide a dose of DHA-TG of greater than about 0.66 mg/kg, more particularly greater than or equal to 0.66 mg/kg up to about 2.6 mg/kg, more particularly greater than or equal to 0.66 mg/kg up to about 9.5 mg/kg, more particularly greater than or equal to 0.66 mg/kg up to about 25 mg/kg, more particularly greater than or equal to 0.66 mg/kg up to about 38 mg/kg, more particularly greater than or equal to 0.66 mg/kg up to about 150 mg/kg and more particularly greater than or equal to 0.66 mg/kg up to about 250 mg/kg.
  • an emulsion is administered to a subject to provide a dose of DHA-FFA of greater than about 0.66 mg/kg, more particularly greater than or equal to 0.66 mg/kg up to about 2.6 mg/kg, more particularly greater than or equal 0.66 mg/kg up to about 9.5 mg/kg, more particularly greater than or equal 0.66 mg/kg up to about 25 mg/kg, more particularly greater than or equal 0.66 mg/kg up to about 38 mg/kg, more particularly greater than or equal 0.66 mg/kg up to about 150 mg/kg and more particularly greater than or equal 0.66 mg/kg up to about 250 mg/kg.
  • an emulsion is administered to a subject to provide a dose of DHA-EE of greater than about 0.66 mg/kg, more particularly greater than or equal to 0.66 mg/kg up to about 2.6 mg/kg, more particularly greater than or equal to 0.66 mg/kg up to about 9.5 mg/kg, more particularly greater than or equal to 0.66 mg/kg up to about 25 mg/kg, more particularly greater than or equal to 0.66 mg/kg up to about 38 mg/kg, more particularly greater than or equal to 0.66 mg/kg up to about 150 mg/kg and more particularly greater than or equal to 0.66 mg/kg up to about 250 mg/kg.
  • an emulsion is administered to a subject to provide a dose of DHA-TG of greater than or equal about 2.6 mg/kg, more particularly greater than or equal 2.6 mg/kg up to about 9.5 mg/kg, more particularly greater than or equal to 2.6 mg/kg up to about 25 mg/kg, more particularly greater than or equal to 2.6 mg/kg up to about 38 mg/kg, more particularly greater than or equal to 2.6 mg/kg up to about 150 mg/kg and more particularly greater than or equal to 2.6 mg/kg up to about 250 mg/kg.
  • an emulsion is administered to a subject to provide a dose of DHA-FFA of greater than or equal about 2.6 mg/kg, more particularly greater than or equal 2.6 mg/kg up to about 9.5 mg/kg, more particularly greater than or equal 2.6 mg/kg up to about 25 mg/kg, more particularly greater than or equal 2.6 mg/kg up to about 38 mg/kg, more particularly greater than or equal 2.6 mg/kg up to about 150 mg/kg and more particularly greater than or equal 2.6 mg/kg up to about 250 mg/kg.
  • a dose of DHA-FFA of greater than or equal about 2.6 mg/kg, more particularly greater than or equal 2.6 mg/kg up to about 9.5 mg/kg, more particularly greater than or equal 2.6 mg/kg up to about 25 mg/kg, more particularly greater than or equal 2.6 mg/kg up to about 38 mg/kg, more particularly greater than or equal 2.6 mg/kg up to about 150 mg/kg and more particularly greater than or equal 2.6 mg/kg up to about 250 mg/kg.
  • an emulsion is administered to a subject to provide a dose of DHA-EE of greater than or equal to about 2.6 mg/kg, more particularly greater than or equal to 2.6 mg/kg up to about 9.5 mg/kg, more particularly greater than or equal to 2.6 mg/kg up to about 25 mg/kg, more particularly greater than or equal to 2.6 mg/kg up to about 38 mg/kg, more particularly greater than or equal to 2.6 mg/kg up to about 150 mg/kg and more particularly greater than or equal 2.6 mg/kg up to about 250 mg/kg.
  • an emulsion is administered to a subject to provide a dose of DHA-TG of greater than or equal to about 9.5 mg/kg, more particularly greater than or equal to 9.5 mg/kg up to about 25 mg/kg, more particularly greater than or equal to 9.5 mg/kg up to about 38 mg/kg, more particularly greater than or equal to 9.5 mg/kg up to about 150 mg/kg and more particularly greater than or equal to 9.5 mg/kg up to about 250 mg/kg.
  • an emulsion is administered to a subject to provide a dose of DHA-FFA of greater than or equal about 9.5 mg/kg, more particularly greater than or equal 9.5 mg/kg up to about 25 mg/kg, more particularly greater than or equal 9.5 mg/kg up to about 38 mg/kg, more particularly greater than or equal 9.5 mg/kg up to about 150 mg/kg and more particularly greater than or equal 9.5 mg/kg up to about 250 mg/kg.
  • an emulsion is administered to a subject to provide a dose of DHA-EE of greater than or equal about 9.5 mg/kg, more particularly greater than or equal to 9.5 mg/kg up to about 25 mg/kg, more particularly greater than or equal to 9.5mg/kg up to about 38 mg/kg, more particularly greater than or equal to 9.5 mg/kg up to about 150 mg/kg and more particularly greater than or equal to 9.5 mg/kg up to about 250 mg/kg.
  • an emulsion or alternatively a diluted emulsion, is administered to a subject to provide a dose of DHA-TG of greater than or equal about 25 mg/kg, more particularly greater than or equal to 25 mg/kg up to about 38 mg/kg, more particularly greater than or equal to 9.5 mg/kg up to about 150 mg/kg and more particularly greater than or equal to 9.5 mg/kg up to about 250 mg/kg.
  • an emulsion or alternatively a diluted emulsion, is administered to a subject to provide a dose of DHA-FFA of greater than or equal about 25 mg/kg, more particularly greater than or equal 25 mg/kg up to about 38 mg/kg, more particularly greater than or equal 9.5 mg/kg up to about 150 mg/kg and more particularly greater than or equal 9.5 mg/kg up to about 250 mg/kg.
  • an emulsion or alternatively a diluted emulsion, is administered to a subject to provide a dose of DHA-EE of greater than or equal to about 25 mg/kg, more particularly greater than or equal to 25 mg/kg up to about 38 mg/kg, more particularly greater than or equal to 9.5 mg/kg up to about 150 mg/kg and more particularly greater than or equal to 9.5 mg/kg up to about 250 mg/kg.
  • an emulsion or alternatively a diluted emulsion, is administered to a subject to provide a dose of DHA-TG of greater than or equal to about 37.8 mg/kg, more particularly greater than or equal to 37.5 mg/kg up to about 150 mg/kg and more particularly greater than or equal to 37.5 mg/kg up to about 250 mg/kg.
  • an emulsion or alternatively a diluted emulsion, is administered to a subject to provide a dose of DHA-FFA of greater than or equal about 37.8 mg/kg, more particularly greater than or equal 37.5 mg/kg up to about 150 mg/kg and more particularly greater than or equal 37.5 mg/kg up to about 250 mg/kg.
  • an emulsion or alternatively a diluted emulsion, is administered to a subject to provide a dose of DHA-EE of greater than or equal to about 37.8 mg/kg, more particularly greater than or equal to 37.5 mg/kg up to about 150 mg/kg and more particularly greater than or equal to 37.5 mg/kg up to about 250 mg/kg.
  • an emulsion or alternatively a diluted emulsion, is administered to a subject to provide a dose of DHA-TG of greater than or equal to about 150 mg/kg, more particularly greater than or equal to 150 mg/kg up to about 250 mg/kg.
  • an emulsion or alternatively a diluted emulsion, is administered to a subject to provide a dose of DHA-FFA of greater than or equal about 150 mg/kg, more particularly greater than or equal 150 mg/kg up to about 250 mg/kg.
  • an emulsion or alternatively a diluted emulsion, is administered to a subject to provide a dose of DHA-EE of greater than or equal to about 150 mg/kg, more particularly greater than or equal to 150 mg/kg up to about 250 mg/kg.
  • an emulsion or alternatively a diluted emulsion, is administered to a subject to provide a dose of DHA-TG of greater than or equal to about 250 mg/kg.
  • an emulsion or alternatively a diluted emulsion, is administered to a subject to provide a dose of DHA-FFA of greater than or equal about 250 mg/kg.
  • an emulsion or alternatively a diluted emulsion, is administered to a subject to provide a dose of DHA-EE of greater than or equal to about 250 mg/kg.
  • the above described doses reflect either the amount of DHA-ethyl ester or the amount of the DHA moiety of the DHA-EE administered.
  • the bolus injections comprise about 1 ⁇ to about 50 ml of an emulsion provided herein.
  • an emulsion provided herein can be administered to a subject as a bolus injection.
  • the bolus injections comprise about 1 ml to about 50 ml of an emulsion provided herein.
  • an emulsion is administered to a subject by at least one 5 ml bolus dose.
  • the bolus injection can comprise about 5 ml of an emulsion provided herein.
  • an emulsion can be administered intravenously (IV) to a subject.
  • the IV administration can be infused continuously.
  • a particular amount of DHA in an emulsion herein that can be administered parenterally to a subject can range about 0.1 g to about 20 g.
  • a particular amount of DHA-FFA in an emulsion herein that can be administered parenterally to a subject can range about 0.1 gram to about 20 grams.
  • administration of the emulsion can be prescribed by a medical professional.
  • subject refers to mammals such as humans or primates, such as apes, monkeys, orangutans, baboons, gibbons, and chimpanzees.
  • subject can also refer to companion animals, e.g., dogs and cats; zoo animals; equids, e.g., horses; food animals, e.g., cows, pigs, and sheep; and disease model animals, e.g., rabbits, mice, and rats.
  • the subject can be a human or non-human.
  • the subject can be of any age.
  • the subject is a human infant, i.e., post natal to about 1 year old; a human child, i.e., a human between about 1 year old and 12 years old; a pubertal human, i.e., a human between about 12 years old and 18 years old; or an adult human, i.e., a human older than about 18 years old.
  • the subject is an adult, either male or female.
  • treat and “treatment” refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological condition or disease, or obtain beneficial or desired clinical results.
  • treatment also refers to the alleviation of symptoms associated with the above conditions or diseases.
  • the DHA-TG is administered continuously.
  • the DHA-FFA is administered continuously.
  • the DHA-EE is administered continuously.
  • continuous or “consecutive,” as used herein in reference to “administration,” means that the frequency of administration is at least once daily. Note, however, that the frequency of administration can be greater than once daily and still be “continuous” or “consecutive,” e.g., twice or even three or four times daily, as long as the dosage levels as specified herein are achieved.
  • DHA docosahexaenoic acid, also known by its chemical name (all-Z)-
  • DHA encompasses the DHA triglyceride (DHA-TG) as well as DHA free fatty acids, phospholipids, esters, monoglycerides, and diglycerides containing DHA.
  • DHA encompasses the free acid DHA (DHA-FFA) as well as DHA phospholipids, esters, monoglycerides, diglycerides, and triglycerides.
  • DHA encompasses DHA ethyl ester (DHA-EE) as well as DHA free fatty acids, phospholipids, other esters, monoglycerides, diglycerides, and triglycerides containing DHA.
  • DHA is an co-3 polyunsaturated fatty acid.
  • a "triglyceride” is a glyceride in which the glycerol is esterified with three fatty acid groups. Typical triglycerides are known to those in the art.
  • the DHA can be in a mono, di, or triglyceride form. For example, one, two or three DHA molecules can be in the mono, di or triglyceride molecule.
  • DHA is the only fatty acid group on a triglyceride or diglyceride molecule. In some embodiments, one or more fatty acid groups of a triglyceride have been hydrolyzed, or cleaved.
  • esters refers to the replacement of the hydrogen in the carboxylic acid group of the DHA molecule with another substituent.
  • Typical esters are known to those in the art. Examples of the most common esters include methyl, ethyl, propyl, butyl, pentyl, t-butyl, benzyl, nitrobenzyl, methoxybenzyl, benzhydryl, and trichloroethyl.
  • the ester is a carboxylic acid protective ester group, esters with aralkyl (e.g., benzyl, phenethyl), esters with lower alkenyl (e.g., allyl, 2-butenyl), esters with lower-alkoxy-lower-alkyl (e.g., methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl), esters with lower-alkanoyloxy-lower-alkyl (e.g., acetoxymethyl, pivaloyloxymethyl, 1- p i v a l o y l o xy e thy l ) , e s t e r s wit h 1 o w e r-alkoxycarbonyl-lower-alkyl (e.g., methoxycarbonylmethyl, isopropoxycarbonylmethyl), esters with carboxy-lower
  • the added substituent is a linear or cyclic hydrocarbon group, e.g., a Cl- C6 alkyl, C1-C6 cycloalkyl, C1-C6 alkenyl, or C1-C6 aryl ester.
  • the ester is an alkyl ester, e.g., a methyl ester, ethyl ester or propyl ester. More particularly, the ester is an ethyl ester.
  • the ester substituent can be added to the DHA free acid molecule when the DHA is in a purified or semi-purified state. Alternatively, the DHA ester is formed upon conversion of a triglyceride to a ester.
  • non-esterified DHA molecules can be present in the present invention, e.g., DHA molecules that have not been esterified, or DHA linkages that have been cleaved, e.g., hydrolyzed.
  • the DHA is an ethyl ester (DHA-EE).
  • DHA-EE ethyl ester
  • ester refers to the replacement of the hydrogen in the carboxylic acid group of the DHA molecule with an ethyl.
  • the ester substituent can be added to the DHA free acid molecule when the DHA is in a purified or semi-purified state.
  • the DHA ester is formed upon conversion of a triglyceride to an ester.
  • non-esterified DHA molecules can be present in the present invention, e.g., DHA molecules that have not been esterified, or DHA linkages that have been cleaved, e.g., hydrolyzed.
  • the non- esterified DHA molecules constitute less than 3% (mol/mol), about 2% to about 0.01% (mol/mol), about 1% to about 0.05%> (mol/mol), or about 5% to about 0.1%> (mol/mol) of the total DHA molecules.
  • the oil containing DHA, or emulsion containing DHA-TG is substantially free of eicosapentaenoic acid (EPA).
  • the oil containing DHA, or emulsion containing DHA-FFA is substantially free of eicosapentaenoic acid (EPA).
  • the oil containing DHA, or emulsion containing DHA-EE is substantially free of eicosapentaenoic acid (EPA).
  • EPA refers to eicosapentaenoic acid, known by its chemical name (all-Z)-5,8,ll,14,17- eicosapentaenoic acid, as well as any salts or derivatives thereof.
  • EPA encompasses the free acid EPA as well as EPA alkyl esters and triglycerides containing EPA.
  • EPA is an ⁇ -3 polyunsaturated fatty acid.
  • an oil “substantially free of EPA” can refer to an oil in which EPA is less than about 3%, by weight, of the total fatty acid content of the oil.
  • the oil comprises, less than about 2% EPA, by weight, of the total fatty acid content of the oil, less than about 1% EPA, by weight, of the total fatty acid content of the oil, less than about 0.5% EPA, by weight, of the total fatty acid content of the oil, less than about 0.2% EPA, by weight, of the total fatty acid content of the oil, or less than about 0.01% EPA by weight, of the total fatty acid content of the oil.
  • the oil has no detectable amount of EPA.
  • an emulsion "substantially free of EPA" can refer to an emulsion in which EPA is less than about 3%, by weight, of the total fatty acid content of the emulsion.
  • the emulsion comprises, less than about 2% EPA, by weight, of the total fatty acid content of the emulsion, less than about 1% EPA, by weight, of the total fatty acid content of the emulsion, less than about 0.5% EPA, by weight, of the total fatty acid content of the emulsion, less than about 0.2% EPA, by weight, of the total fatty acid content of the emulsion, or less than about 0.01% EPA by weight, of the total fatty acid content of the emulsion.
  • the emulsion has no detectable amount of EPA.
  • weight % can be determined by calculating the area under the curve (AUC) using standard means, e.g., dividing the DHA AUC by the total fatty acid AUC.
  • the oil containing DHA, or emulsion containing DHA-TG is substantially free of docosapentaenoic acid 22:5n-6, (DPAn6).
  • the oil containing DHA, or emulsion containing DHA-FFA is substantially free of docosapentaenoic acid 22:5n-6 (DPAn6).
  • the oil containing DHA, or emulsion containing DHA-EE is substantially free of docosapentaenoic acid 22:5n-6, (DPAn6).
  • DPAn6 refers to docosapentaenoic acid, omega 6, known by its chemical name (all-Z)-4,7,10,13,16-docosapentaenoic acid, as well as any salts or esters thereof.
  • DPAn6 encompasses the free acid DPAn6, as well as DPAn6 ethyl esters and triglycerides containing DPAn6.
  • DPAn6 can be removed during purification of DHA, or alternatively, the DHA can be obtained from an organism that does not produce DPAn6, or produces very little DPAn6.
  • an oil “substantially free of DPAn6” refers to an oil containing less than about 2%, by weight, docosapentaenoic acid 22:5n-6, (DPAn6) of the total fatty acid content of the oil. In some embodiments, the oil contains less than about 1% DPAn6, by weight, of the total fatty acid content of the oil. In some embodiments, the oil contains less than about 0.5% DPAn6, by weight, of the total fatty acid content of the oil. In some embodiments, the oil does not contain any detectable amount of DPAn6.
  • an emulsion "substantially free of DPAn6” refers to an emulsion containing less than about 2%, by weight, docosapentaenoic acid 22:5n-6, (DPAn6) of the total fatty acid content of the emulsion. In some embodiments, the emulsion contains less than about 1% DPAn6, by weight, of the total fatty acid content of the emulsion. In some embodiments, the oil contains less than about 0.5% DPAn6, by weight, of the total fatty acid content of the emulsion. In some embodiments, the emulsion does not contain any detectable amount of DPAn6.
  • the oil containing DHA, or emulsion containing DHA-TG can also b e substantially free of arachidonic acid (ARA).
  • the oil containing DHA, or emulsion containing DHA-FFA can also be substantially free of arachidonic acid (ARA).
  • the oil containing DHA, or emulsion containing DHA-EE can also be substantially free of arachidonic acid (ARA).
  • ARA refers to the compound (all-Z)-5,8,l 1,14-eicosatetraenoic acid (also referred to as (5Z,8Z,1 lZ,14Z)-icosa-5,8,l 1,14-tetraenoic acid), as well as any salts or derivatives thereof.
  • ARA encompasses the free acid ARA as well as ARA alkyl esters and triglycerides containing ARA.
  • ARA is an ⁇ -6 polyunsaturated fatty acid.
  • an oil “substantially free of ARA” refers to an oil in which ARA is less than about 3%, by weight of the total fatty acid content of the oil.
  • the oil comprises, less than about 2% ARA, by weight, of the total fatty acid content of the oil, less than about 1% ARA, by weight, of the total fatty acid content of the oil, less than about 0.5% ARA, by weight, of the total fatty acid content of the oil, less than about 0.2% ARA, by weight, of the total fatty acid content of the oil, or less than about 0.01% ARA, by weight, of the total fatty acid content of the oil.
  • the oil has no detectable amount of ARA.
  • an emulsion "substantially free of ARA” refers to an emulsion in which ARA is less than about 3%, by weight of the total fatty acid content of the emulsion.
  • the emulsion comprises, less than about 2% ARA, by weight, of the total fatty acid content of the emulsion, less than about 1% ARA, by weight, of the total fatty acid content of the emulsion, less than about 0.5% ARA, by weight, of the total fatty acid content of the emulsion, less than about 0.2% ARA, by weight, of the total fatty acid content of the emulsion, or less than about 0.01% ARA, by weight, of the total fatty acid content of the emulsion.
  • the emulsion has no detectable amount of ARA.
  • DHA-FFA can be obtained by hydro lyzing the ester bond of a DHA ester or triglyceride containing DHA, resulting in formation of the free fatty acid form of DHA.
  • the DHA of the present invention can be derived from various sources, e.g., from oleaginous microorganisms.
  • oleaginous microorganisms are defined as microorganisms capable of accumulating greater than 20% of the dry weight of their cells in the form of lipids.
  • the DHA is derived from a phototrophic or heterotrophic single cell organism or multicellular organism, e.g., an algae.
  • the DHA can be derived from or initially derived from a diatom, e.g., a marine dino flagellates (algae), such as Crypthecodinium sp., Thraustochytrium sp., Schizochytrium sp., or combinations thereof.
  • the source of the DHA can include a microbial source, including the microbial groups Stramenopiles, Thraustochytrids, and Labrinthulids.
  • Stramenopiles includes microalgae and algae-like microorganisms, including the following groups of microorganisms: Hamatores, Proteromonads, Opalines, Develpayella, Diplophrys, Labrinthulids, Thraustochytrids, Biosecids, Oomycetes, Hypochytridiomycetes, Commation, Reticulosphaera, Pelagomonas, Pelagococcus, Ollicola, Aureococcus, Parmales, Diatoms, Xanthophytes, Phaeophytes (brown algae), Eustigmatophytes, Raphidophytes, Synurids, Axodines (including Rhizochromulinaales, Pedinellales, Dictyochales), Chrysomeridales, Sarcinochrysidales, Hydrurales, Hibberdiales, and Chromulinales.
  • Axodines including Rhizochromul
  • the Thraustochytrids include the genera Schizochytrium (species include aggregatum, limnaceum, mangrovei, minutum, octosporum), Thraustochytrium (species include arudimentale, aureum, benthicola, globosum, kinnei, motivum, multirudimentale, pachydermum, proliferum, roseum, striatum), Ulkenia (species include amoeboidea, kerguelensis, minuta, profunda, radiate, sailens, sarkariana, schizochytrops, visurgensis, yorkensis), Aplanochytrium (species include haliotidis, kerguelensis, profunda, stocchinoi), Japonochytrium (species include marinum), Althornia (species include crouchii), and Elina (species include marisalba, sinorifica).
  • the algal source is, e.g., Crypthecodinium cohnii.
  • Samples of C. cohnii have been deposited with the American Type Culture Collection at Rockville, Md., and assigned accession nos. 40750, 30021, 30334-30348, 30541-30543, 30555-30557, 30571, 30572, 30772-30775, 30812, 40750, 50050-50060, and 50297- 50300.
  • microorganism or any specific type of organism, includes wild strains, mutants or recombinant types. Organisms which can produce an enhanced level of oil containing DHA are considered to be within the scope of this invention. Also included are microorganisms designed to efficiently use more cost- effective substrates while producing the same amount of DHA as the comparable wild- type strains. Cultivation of dino flagellates such as C. cohnii has been described previously. See, U.S. Pat. No. 5,492,938 and Henderson et ah, Phytochemistry 27: 1679- 1683 (1988).
  • Organisms useful in the production of DHA can also include any manner of transgenic or other genetically modified organisms, e.g., plants, grown either in culture fermentation or in crop plants, e.g., cereals such as maize, barley, wheat, rice, sorghum, pearl millet, corn, rye and oats; or beans, soybeans, peppers, lettuce, peas, Brassica species (e.g., cabbage, broccoli, cauliflower, brussel sprouts, rapeseed, and radish), carrot, beets, eggplant, spinach, cucumber, squash, melons, cantaloupe, sunflowers, safflower, canola, flax, peanut, mustard, rapeseed, chickpea, lentil, white clover, olive, palm, borage, evening primrose, linseed, and tobacco.
  • cereals such as maize, barley, wheat, rice, sorghum, pearl millet, corn, rye and oats
  • beans soybeans,
  • Another source of oils containing DHA suitable for the compositions and methods of the present invention includes an animal source.
  • animal sources include aquatic animals (e.g., fish, marine mammals, and crustaceans such as krill and other euphausids) and animal tissues (e.g., brain, liver, eyes, etc.) and animal products such as eggs or milk.
  • the method of the present invention comprises administering daily to the subject an emulsion comprising DHA-TG substantially free of eicosapentaenoic acid (EPA), wherein the DHA-TG is derived from a non-algal source, e.g., fish.
  • EPA eicosapentaenoic acid
  • the method of the present invention comprises administering daily to the subject an emulsion comprising DHA-FFA substantially free of eicosapentaenoic acid (EPA), wherein the DHA-FFA is obtained from DHA, and the DHA is derived from a non-algal source, e.g., fish.
  • the method of the present invention comprises administering daily to the subject an emulsion comprising DHA-EE substantially free of eicosapentaenoic acid (EPA), wherein the DHA is derived from a non-algal source, e.g., fish.
  • DHA can be purified to various levels.
  • DHA purification can be achieved by any means known to those of skill in the art, and can include the extraction of total oil from an organism which produces DHA. In some embodiments, EPA, ARA, DPAn6 and/or flavonoids are then removed from the total oil, for example, via chromatographic methods. Alternatively, DHA purification can be achieved by extraction of total oil from an organism which produces DHA, but produces little, if any, amount of EPA, ARA, DPAn6 and/or flavonoids.
  • DHA-TG can be purified to various levels. For example, various purity levels of DHA-TG can be obtained by using various purities of DHA as described herein.
  • DHA-FFA can be purified to various levels.
  • various purity levels of DHA-FFA can be obtained by using various purities of DHA as described herein.
  • DHA-EE can be purified to various levels.
  • various purity levels of DHA-EE can be obtained by using various purities of DHA as described herein.
  • the oil can be diluted with sunflower oil to achieve the desired concentration of fatty acids.
  • Microbial oils useful in the present invention can be recovered from microbial sources by any suitable means known to those in the art.
  • the oils can be recovered by extraction with solvents such as chloroform, hexane, methylene chloride, methanol and the like, or by supercritical fluid extraction.
  • the oils can be extracted using extraction techniques, such as are described in U.S. Pat. No. 6,750,048 and International Pub. No. WO/2001/053512, both filed Jan. 19, 2001 , and entitled "Solventless extraction process,” both of which are incorporated herein by reference in their entirety.
  • DHA can be prepared as esters using a method comprising: a) reacting a composition comprising polyunsaturated fatty acids in the presence of an alcohol and a base to produce an ester of a polyunsaturated fatty acid from the triglycerides; and b) distilling the composition to recover a fraction comprising the ester of the polyunsaturated fatty acid, optionally wherein the method further comprises: c) combining the fraction comprising the ester of the polyunsaturated fatty acid with urea in a medium; d) cooling or concentrating the medium to form a urea-containing precipitate and a liquid fraction; and e) separating the precipitate from the liquid fraction.
  • the purification process includes starting with refined, bleached, and deodorized oil (RBD oil), then performing low temperature fractionation using acetone to provide a concentrate.
  • the concentrate can be obtained by base- catalyzed transesterification, distillation, and silica refining to produce the final DHA product.
  • DHA free fatty acids can be prepared using a method as described in U.S. Appl. No. 61/444,696 (Attorney Docket No. 2715.2570000), entitled "Method of preparing free polyunsaturated fatty acids" filed February 18, 201 1 , incorporated herein in its entirety.
  • Methods of determining purity levels of fatty acids are known in the art, and can include, e.g., chromatographic methods such as, e.g., HPLC silver ion chromatographic columns (ChromSpher 5 Lipids HPLC Column, Chrompack, Raritan NJ).
  • the purity level can be determined by gas chromatography, with or without converting DHA to the corresponding methyl ester.
  • DHA esters can be derived from undiluted oil from a single cell microorganism described above, and in some embodiments, from undiluted DHASCO ® -T (Martek Biosciences Corporation, Columbia, MD).
  • the oil from which DHA of the invention are derived include single cell microorganism oils that are manufactured by a controlled fermentation process followed by oil extraction and purification using methods common to the vegetable oil industry.
  • the oil extraction and purification steps include refining, bleaching, and deodorizing.
  • the undiluted DHA oil comprises about 40% to about 50% DHA by weight (about 400-500 mg DHA/g oil).
  • the undiluted DHA oil is enriched by cold fractionation (resulting in oil containing about 60% w/w of DHA triglyceride), which DHA fraction optionally can be transesterified, and subjected to further downstream processing to produce the active DHA of the invention.
  • downstream processing of the oil comprises distillation and/or silica refinement.
  • the following steps are used: fermentation of a DHA producing microorganism; harvesting the biomass; spray drying the biomass; extracting oil from the biomass; refining the oil; bleaching the oil; chill filtering the oil; deodorizing the oil; and adding an antioxidant to the oil.
  • the microorganism culture is progressively transferred from smaller scale fermenters to a production size fermenter.
  • the culture is harvested by centrifugation then pasteurized and spray dried.
  • the dried biomass is flushed with nitrogen and packaged before being stored frozen at -20°C.
  • the DHA oil is extracted from the dried biomass by mixing the biomass with n-hexane or isohexane in a batch process which disrupts the cells and allows the oil and cellular debris to be separated. In certain embodiments, the solvent is then removed.
  • the crude DHA oil then undergoes a refining process to remove free fatty acids and phospholipids.
  • the refined DHA oil is transferred to a vacuum bleaching vessel to assist in removing any remaining polar compounds and pro- oxidant metals, and to break down lipid oxidation products.
  • the refined and bleached DHA oil undergoes a final clarification step by chilling and filtering the oil to facilitate the removal of any remaining insoluble fats, waxes, and solids.
  • the DHA is deodorized under vacuum in a packed column, counter current steam stripping deodorizer.
  • Antioxidants such as ascorbyl palmitate and alpha- tocopherol can optionally be added to the deodorized oil to help stabilize the oil.
  • the final, undiluted DHA oil is maintained frozen at -20°C until further processing.
  • the DHA oil is converted to DHA ester by methods known in the art.
  • DHA esters of the invention are produced from DHA oil by the following steps: cold fractionation and filtration of the DHA oil (to yield for example about 60% triglyceride oil); direct transesterification (to yield about 60% DHA ethyl ester); molecular distillation (to yield about 88% DHA ethyl ester); silica refinement (to yield about 90% DHA ethyl ester); and addition of an antioxidant.
  • the cold fractionation step is carried out as follows: undiluted DHA oil (triglyceride) at about 500 mg/g DHA is mixed with acetone and cooled at a controlled rate in a tank with -80°C chilling capabilities. Saturated triglycerides crystallize out of solution, while polyunsaturated triglycerides at about 600 mg/g DHA remain in the liquid state. The solids containing about 300 mg/g are filtered out with a 20 micron stainless steel screen from the liquid stream containing about 600 mg/g DHA. The solids stream is then heated (melted) and collected. The 600 mg/g DHA liquid stream is desolventized with heat and vacuum and then transferred to the transesterification reactor.
  • the cold fractionation step is carried out as follows: undiluted DHA oil (triglyceride) at about 500 mg DHA/g oil is mixed with acetone and cooled at a controlled rate in a tank with -80°C chilling capabilities. Saturated triglycerides crystallize out of solution, while polyunsaturated triglycerides at about 600 mg DHA/g oil remain in the liquid state. The solids containing about 300 mg DHA/g oil are filtered out with a 20 micron stainless steel screen from the liquid stream containing about 600 mg DHA/g oil. The solids stream is then heated (melted) and collected. The 600 mg DHA/g oil liquid stream is desolventized with heat and vacuum and then transferred to the transesterification reactor.
  • undiluted DHA oil triglyceride
  • Saturated triglycerides crystallize out of solution, while polyunsaturated triglycerides at about 600 mg DHA/g oil remain in the liquid state.
  • the transesterification step is carried out on the 600 mg/g
  • DHA oil wherein the transesterification is done via direct transesterification using ethanol and sodium ethoxide.
  • the transesterified material DHA ethyl ester (“DHA-EE”) is then subject to molecular distillation and thus, further distilled (3 passes, heavies, lights, heavies) to remove most of the other saturated fatty acids and some sterols and non-saponifiable material.
  • the DHA-EE is further refined by passing it through a silica column.
  • DHA free fatty acids can be made using, for example, the DHA containing oils described above.
  • the DHA-FFA can be obtained from DHA esters.
  • DHA triglycerides for example, can be saponified followed by a urea adduction step to make free fatty acids.
  • a non-limiting example for making a DHA free fatty acid oil is provided below in the Example section.
  • Additional fatty acids can be present in the oil and/or the emulsion. These fatty acids can include fatty acids that are not removed during the purification process, i.e., fatty acids that are co-isolated with DHA from an organism. These fatty acids can be present in various concentrations.
  • the oil comprises 0.1% to 60% of one or more of the following fatty acids, or esters thereof: (a) capric acid; (b) lauric acid; (c) myristic acid; (d) palmitic acid, (e) palmitoleic acid; (f) stearic acid; (g) oleic acid; (h) linoleic acid; (i) a-linolenic acid; (j) docosapentaenoic acid 22:5n-3, 22:5w3 (DPAn3); and (k) 4,7,10,13,16,19,22,25 octacosaoctaenoic acid (C28:8).
  • fatty acids or esters thereof: (a) capric acid; (b) lauric acid; (c) myristic acid; (d) palmitic acid, (e) palmitoleic acid; (f) stearic acid; (g) oleic acid; (h) linole
  • the oil comprises 20% to 40% of one or more of the following fatty acids, or esters thereof: (a) capric acid; (b) lauric acid; (c) myristic acid; (d) palmitic acid; (e) palmitoleic acid; (f) stearic acid; (g) oleic acid; (h) linoleic acid; (i) a-linolenic acid; U) docosapentaenoic acid 22:5n-3 , 22 :5w3 (DPAn3); and (k) 4,7, 10, 13 , 16, 19,22,25 octacosaoctaenoic acid (C28:8).
  • fatty acids or esters thereof: (a) capric acid; (b) lauric acid; (c) myristic acid; (d) palmitic acid; (e) palmitoleic acid; (f) stearic acid; (g) oleic acid; (h) linoleic acid
  • the oil comprises less than about 1%) each of the following fatty acids, or esters thereof: (a) capric acid; (b) lauric acid; (c) myristic acid; (d) palmitic acid, (e) palmitoleic acid; (f) stearic acid; (g) oleic acid; (h) linoleic acid; (i) ⁇ -linolenic acid; (j) docosapentaenoic acid 22:5n-3, 22:5w3 (DPAn3); and (k) 4,7,10,13,16,19,22,25 octacosaoctaenoic acid (C28:8).
  • fatty acids or esters thereof: (a) capric acid; (b) lauric acid; (c) myristic acid; (d) palmitic acid, (e) palmitoleic acid; (f) stearic acid; (g) oleic acid; (h) linoleic acid
  • an oil is characterized by a fatty acid content of about 0.1% to about 20% (w/w) of one or more of the following fatty acids or esters thereof: (a) capric acid; (b) lauric acid; (c) myristic acid; (d) palmitic acid; (e) palmitoleic acid; (f) stearic acid; (g) oleic acid; (h) linoleic acid; (i) ⁇ -linolenic acid; (j) docosapentaenoic acid 22:5n-3, 22:5w3 (DPAn3); and (k) 4,7,10,13,16,19,22,25 octacosaoctaenoic acid (C28:8).
  • fatty acids or esters thereof (a) capric acid; (b) lauric acid; (c) myristic acid; (d) palmitic acid; (e) palmitoleic acid; (f) stearic acid; (g
  • the terms “or less” or “less than about” refers to percentages that include 0%, or amounts not detectable by current means.
  • “max” refers to percentages that include 0%, or amounts not detectable by current means.
  • an oil is characterized by a fatty acid content of about 1.0% to about 5% (w/w) of one or more of the following fatty acids or esters thereof: (a) capric acid; (b) lauric acid; (c) myristic acid; (d) palmitic acid; (e) palmitoleic acid; (f) stearic acid; (g) oleic acid; (h) linoleic acid; (i) ⁇ -linolenic acid; (j) docosapentaenoic acid 22:5n- 3, 22:5w3 (DPAn3); and (k) 4,7,10,13,16,19,22,25 octacosaoctaenoic acid (C28:8).
  • a fatty acid content of about 1.0% to about 5% (w/w) of one or more of the following fatty acids or esters thereof: (a) capric acid; (b) lauric acid; (c) myristic acid; (
  • an oil is characterized by a fatty acid content of less than about 1%) (w/w) each of the following fatty acids or esters thereof: (a) capric acid; (b) lauric acid; (c) myristic acid; (d) palmitic acid; (e) palmitoleic acid; (f) stearic acid; (g) oleic acid; (h) linoleic acid; (i) ⁇ -linolenic acid; (j) docosapentaenoic acid 22:5n-3, 22:5w3 (DPAn3); (k) docosapentaenoic acid 22:5n-6, 22:5w6 (DPAn6); and ( 1) 4,7,10,13,16,19,22,25 octacosaoctaenoic acid (C28:8).
  • the oil of the present invention does not contain a detectable amount of docosapentaenoic acid 22:5n-3, 22:5w3 (DPAn3); docosapentaenoic acid 22:5n-6, 22:5w6 (DPAn6); and/or 4,7,10,13,16,19,22,25 octacosaoctaenoic acid (C28:8); of the total fatty acid content of the oil or unit dose.
  • DPAn3 docosapentaenoic acid 22:5n-3, 22:5w3
  • DPAn6 docosapentaenoic acid 22:5n-6, 22:5w6
  • C28:8 4,7,10,13,16,19,22,25 octacosaoctaenoic acid
  • an oil is characterized by one or more the following fatty acids (or esters thereof), expressed as wt% of the total fatty acid content.
  • the embodiments provided herein can further comprise about 2% or less (w/w) of capric acid (C10:0).
  • the embodiments herein can further comprise about 6% or less (w/w) of lauric acid (C12:0).
  • the embodiments herein can further comprise about 20% or less, or about 5 to about 20% (w/w) of myristic acid (C14:0).
  • the embodiments herein can further comprise about 20%> or less, or about 5% to about 20%> (w/w) of palmitic acid (CI 6:0).
  • the embodiments herein can further comprise about 3% or less (w/w) of palmitoleic acid (C16: ln-7).
  • the embodiments herein can further comprise about 2% or less (w/w) of stearic acid (CI 8:0).
  • the embodiments herein can further comprise about 40% or less, or about 10% to about 40% (w/w) of oleic acid (C18: ln-9).
  • the embodiments herein can further comprise about 5% or less (w/w) of linoleic acid (CI 8:2).
  • the embodiments herein can further comprise about 2% or less (w/w) of nervonic acid (C24: l).
  • the embodiments herein can further comprise about 3% or less (w/w) of other fatty acids or esters thereof.
  • An oil with the preceding characteristics can include DHASCO® (Martek Biosciences, Columbia, MD), an oil derived from Crypthecodinium cohnii containing docosahexaenoic acid (DHA).
  • An oil with the preceding characteristics can comprise DHASCO® (Martek Biosciences, Columbia, MD), an oil derived from Crypthecodinium cohnii containing docosahexaenoic acid (DHA).
  • An exemplary DHA (triglyceride) containing oil derived from Crypthecodinium cohnii is characterized by the specified amount of components listed in Table 1, where "Max" refers to the amount of the component that can be present up to the specified amount.
  • Crypthecodinium cohnii is characterized by amount of DHA described herein, and one or more, or all of the features listed below in Table 2, where "Max” refers to the amount of the component that can be present up to the specified amount.
  • an oil is characterized by one or more the following fatty acids (or esters thereof), expressed as wt%> of the total fatty acid content.
  • the embodiments provided herein can further comprise about 2%> or less (w/w) of capric acid (CI 0:0).
  • the embodiments provided herein can further comprise about 6%> or less (w/w) of lauric acid (C12:0).
  • the embodiments provided herein can further comprise about 20%) or less, or about 10 to about 20%> (w/w) of myristic acid (C14:0).
  • the embodiments provided herein can further comprise about 15%> or less, or about 5 to about 15%> (w/w) of palmitic acid (C16:0).
  • the embodiments provided herein can further comprise about 5% or less (w/w) of palmitoleic acid (C 16: ln-7).
  • the embodiments provided herein can further comprise about 2%> or less (w/w) of stearic acid (C I 8 :0).
  • the embodiments provided herein can further comprise about 20%> or less, or about 5%> to about 20%> (w/w) of oleic acid (C18: ln-9).
  • the embodiments provided herein can further comprise about 2%> or less (w/w) of linoleic acid (CI 8:2).
  • the embodiments provided herein can further comprise about 2%> or less (w/w) of nervonic acid (C24: l).
  • the embodiments provided herein can further comprise about 3% or less (w/w) of other fatty acids.
  • An oil with the preceding characteristics can be an oil derived from Crypthecodinium cohnii containing docosahexaenoic acid (DHA).
  • An exemplary DHA containing oil derived from Crypthecodinium cohnii is characterized by the specified amount of components listed in Table 3, where "Max" refers to the amount of the component that can be present up to the specified amount.
  • fatty acids or esters thereof, expressed as wt% of the total fatty acid content:
  • the embodiments provided herein can further comprise about 0.1% or less (w/w) of myristic acid (CI 4:0) or is not detectable.
  • the embodiments provided herein can further comprise about 0.5%) or less (w/w) of palmitic acid (C16:0).
  • the embodiments provided herein can further comprise about 0.5%> or less (w/w) of palmitoleic acid (C 16 : ln-7) .
  • the embodiments provided herein can further comprise about 0.5%> or less (w/w) of stearic acid (CI 8:0), or is not detectable.
  • the embodiments provided herein can further comprise about 4% or less (w/w) of oleic acid (C 18: ln-9).
  • the embodiments provided herein can further comprise less than 0.1 % (w/w) of linoleic acid (C I 8 :2) or is not detectable.
  • the embodiments provided herein can further comprise less than 0.1% (w/w) of eicosapentaenoic acid (C20:5) or is not detectable.
  • the embodiments provided herein can further comprise about 2% or less (w/w) of decosapentaenoic acid (22:5n-3).
  • the embodiments provided herein can further comprise about 1% or less (w/w) of octacosaoctaenoic acid (28 :8 n-3).
  • the embodiments provided herein can further comprise about 0.5% or less (w/w) of tetracosaenoic acid (24: ln9).
  • the embodiments provided herein can further comprise about 1% or less (w/w) of other fatty acids.
  • the DHA in oil with the preceding characteristics can be in the form of a DHA ester, preferably an alkyl ester, such as a methyl ester, ethyl ester, propyl ester, or combinations thereof, prepared from an algal oil prepared from the Crypthecodinium, cohnii sp.
  • a DHA ester preferably an alkyl ester, such as a methyl ester, ethyl ester, propyl ester, or combinations thereof, prepared from an algal oil prepared from the Crypthecodinium, cohnii sp.
  • Cohnii wherein the DHA comprises an ethyl ester
  • DHA comprises an ethyl ester
  • the oil is characterized by one or more the following fatty acids (or esters thereof), expressed as wt% of the total fatty acid content.
  • the embodiments provided herein can further comprise about 12% or less, or about 6% to about 12% (w/w) of myristic acid (C14:0).
  • the embodiments provided herein can further comprise about 28% or less, or about 18 to about 28% (w/w) of palmitic acid (C16:0).
  • the embodiments provided herein can further comprise about 2% or less (w/w) of stearic acid (CI 8:0).
  • the embodiments provided herein can further comprise about 8% or less of (w/w) oleic acid (C 18: ln-9).
  • the embodiments provided herein can further comprise about 2%> or less (w/w) of linoleic acid (CI 8:2).
  • the embodiments provided herein can further comprise about 2% or less (w/w) of arachidonic acid (C20:4).
  • the embodiments provided herein can further comprise about 3% or less (w/w) of eicosapentaenoic acid (C20:5).
  • the embodiments provided herein can further comprise about 18% or less, or about 12% to about 18% (w/w) of decosapentaenoic acid (22:5n-6).
  • the embodiments provided herein can further comprise about 10%> or less (w/w) of other fatty acids.
  • the ratio of wt% of DHA to wt% of DPAn6 is about 2.5 to about 2.7.
  • An oil with the preceding characteristics can comprise Life's DHATM (also formerly referenced as DHA-STM and DHASCO®), Martek Biosciences, Columbia, MD), an oil derived from the Thraustochytrid, Schizochytrium sp., that contains a high amount of DHA and also contains docosapentaenoic acid (n-6) (DPAn-6).
  • An exemplary DHA (triglyceride) containing oil derived from Schizochytrium sp. is characterized by the specified amount of components listed in Table 5, where "Max" refers to the amount of the component that can be present up to the specified amount.
  • the DHA in an oil can be in the form of a DHA ester, preferably an alkyl ester, such as a methyl ester, ethyl ester, propyl ester, or combinations thereof, prepared from an algal oil prepared from derived from the Thraustochytrid, Schizochytrium sp.
  • An exemplary DHA (ethyl esters) containing oil derived from Schizochytrium sp. is characterized by the specified amount of components listed in Table 4 of WO 2009/006317, incorporated by reference herein.
  • an oil comprises DHA ⁇ than about 57% (w/w), particularly >about 70%> (w/w) of the total fatty acid content of the oil or unit dose.
  • the ratio of wt% of DHA to wt% of DPAn6 is about 2.5 to about 2.7.
  • An exemplary DHA (free fatty acid) containing oil is characterized by the specified amount of components listed in Table 6:
  • the diluted Lipoid E 80 SN/glycerin dispersion was then passed through a homogenizer (APV Systems APV1000) at -5,000 psi for a time equivalent of 10 discrete passes.
  • the dispersion in the reservoir was continuously stirred with an overhead stirrer during the homogenization and maintained at temperatures between 55 - 75°C under a blanket of nitrogen.
  • the dispersion was transferred to a separate container and pH was adjusted to 10.2 with a solution of 0.5N sodium hydroxide.
  • the emulsion concentrate was then passed through a homogenizer (APV Systems APV 1000) at -10,000 psi for a time equivalent to 15 discrete passes at temperatures between 50 - 70°C.
  • the dispersion in the reservoir was continuously stirred with an overhead stirrer under a blanket of nitrogen. After adding the distilled water to a total volume of 1 ,000 ml under a blanket of nitrogen, a light yellow lipid emulsion resulted.
  • the mean particle size of the lipid dispersion was measured using a Malvern Mastersizer 2000. See Table 7.
  • Lipoid E 80 SN was dispersed while still frozen in 648 ml of distilled water (nitrogen protected) with the temperature of water for injection used being between 65 - 90°C under nitrogen. The dispersion was continued under a blanket of nitrogen until Lipoid E 80 SN is finely divided and a viscous fluid is formed. 300 g of glycerin was added while continuing the dispersion under a blanket of nitrogen. The distilled water (nitrogen protected, between 65 - 90°C) was added to bring the total volume to 1,296 ml.
  • the diluted Lipoid E 80 SN/glycerin dispersion was then passed through a homogenizer (Niro Soavi NS1001L2K) at -5 ,000 psi for a time equivalent to 10 continuous discrete passes.
  • the dispersion in the reservoir was continuously stirred with an overhead stirrer under a blanket of nitrogen.
  • pH of the dispersion was adjusted to 9.0 with a solution of 0.5N sodium hydroxide, to obtain 1,754 g of almost transparent light tan Lipoid E80 SN/glycerin dispersion.
  • Lipoid E80 SN/glycerin dispersion (146 g, one twelfth of the dispersion from Example 2) at 40 - 75°C was added to a thin stream of 300 g of an algal DHA triglyceride oil from Crypthecodinium cohnii (Table 3; contains about 60% DHA triglycerides) that has been previously heated to 70°C, while dispersing using a Silverson high shear mixer under a blanket of nitrogen.
  • the distilled water nitrogen protected, between 65 - 90°C was added to bring the total volume to -1 ,000 ml.
  • the coarse (i.e., "large” particle) emulsion was then passed through a homogenizer (Niro Soavi NS1001L2K) at -5,000 psi for a time equivalent to 5 discrete passes and at -10,000 psi for a time equivalent to 10 discrete passes at temperatures between 50 - 70°C.
  • the dispersion in the reservoir was continuously stirred with an overhead stirrer under a blanket of nitrogen. A pale yellow lipid emulsion resulted, and the mean particle size of lipid emulsion was measured using a Malvern Mastersizer 2000. See Table 8.
  • Example 2 The sample of Example 2 was analyzed at about 2 months (See Table 9).
  • the mixture was continuously passed through the homogenizer at 5,000 psi (ca 350 bars) for a time equivalent to 10 discrete passes while maintaining the temperature at around 70°C and stirring the retained mixture with an overhead stirrer under a nitrogen atmosphere.
  • the dispersion was filtered over 0.45 micron membrane filters.
  • the pH of the filtered dispersion was adjusted to ca. 10.0 with a solution of 0.5 N sodium hydroxide. At this point, the dispersion (2208 g) thus prepared was intended for 12 liters of final lipid emulsions.
  • the coarse emulsion formed was then transferred to a homogenizer (Niro Soavi NS1001L2K).
  • the containers were rinsed with distilled water to allow the combined coarse emulsion to reach a total volume of 2 liters.
  • the emulsion was continuously passed through the homogenizer at 10,000 psi ⁇ ca 690 bars) for a time equivalent to 9 discrete passes while maintaining the temperature at around 70°C and stirring the retained emulsion with an overhead stirrer under a nitrogen atmosphere.
  • the pH and particle size distributions (mean diameter size (D[4,3]), and uniformity) of the emulsion were monitored with a pH meter and Malvern MasterSizer 2000.
  • a 60% algae-based DHA-EE (e.g., as prepared for example according to Example 1)
  • the containers are rinsed with distilled water to allow the combined coarse emulsion to reach a total volume of 1.5 liter having 30% oil, 2.7% emulsifier and 2,5% isotonic agent
  • the emulsion is continuously passed through the homogenizer at 10,000 psi (ca 690 bars) for a time equivalent to 9 discrete passes while maintaining the temperature at around 70°C and stirring the retained emulsion with an overhead stirrer under a nitrogen atmosphere.
  • the pH and particle size distributions (mean diameter size D[4,3] and uniformity) of the emulsion are monitored with a pH meter and Malvern MasterSizer 2000.
  • a white lipid emulsion (1,500 ml) is obtained and weighed. A portion (300 ml) of the lipid emulsion is aliquoted. The pH of the aliquoted emulsion is adjusted to 8.03 with 0.5 N NaOH solution (approximately 137.5 ml) with the final volume at about 450 ml. A sample of the emulsion (15 ml) from the pH adjusted aliquoted portion is lyophilized to provide an oil- like sample and the oil/solid percentage (g/100 ml) is determined. The oil sample is further analyzed by a GC-FAME analysis to give a DHA potency.
  • a 2.5% (g/100 ml) glycerol solution is prepared by mixing 25 g of glycerol with 950 ml of distilled water, adjusting pH of the solution to 8.0 with 0.1 N sodium hydroxide, normalizing the final total volume to 1,000 ml with distilled water, and filtering the final solution with a 0.2- micron Nalgene sterile filtration setup.
  • the pH-adjusted lipid emulsion (50 ml) is serially diluted, with the filtered glycerol solution, to give a 0.60 mg/ml DHA-EE diluted emulsion, a 0.15 mg/ml DHA EE diluted emulsion and a 0.4 mg/ml DHA EE diluted emulsion.
  • the 0.60 (having 0.01% oil, 0.001% emulsifier and about 2.5% isotonic agent), 0.15 (having 0.02% oil, 0.002% emulsifier and about 2.5% isotonic agent), and 0.04 (having 0.06% oil, 0.006% emulsifier and about 2.5% isotonic agent) mg/ml DHA FFA emulsions are aliquoted into 20 ml Type 1 /glass vials (15 ml/vial). The filled vials are flushed with nitrogen and sealed with chlorobutyl rubber stoppers and aluminum seals. The sealed samples are autoclaved at 122°C for 15 min. The pH, D[4,3], PFAT5, and uniformity of the final emulsions are measured (Tables 2, 3, and 4 for the 0.60, 0.15, and 0.04 mg/ml emulsions, respectively).
  • DHA formulations described herein can be tested in rat and mouse models of Spinal Cord Injury for example those described in Huang et al., "A combination of intravenous and dietary docosahexaenoic acid significantly improves outcome after spinal cord injury", Brain (2007) 130: 3004-3019 and King et al, "Omega-3 Fatty Acids Improve Recovery, whereas omega-6 Fatty Acids Worsen Outcome, after Spinal Cord Injury in the Adult Rat," J. Neurosci., (2006) 26(17): 4672-4680.
  • DHA formulations described herein are tested in hemisection and/or compression SCI.
  • adult Sprague-Dawley-rats or mice receive a hemisection or compression injury substantially as described in the above references and then receive 30 min after injury an intravenous bolus of the formulations described herein.
  • the following doses of DHA-TG are tested: 500, 2000 and 8000 nmol/kg (for example in mice using about 100 ⁇ of emulsion having a concentration of about 0.04 mg/ml, 0.15 mg/ml and 0.6 mg/ml respectively).
  • the efficacy of the DHA formulation is assessed by following the recovery of the animals over 8 weeks, using functional behavioral motor outcome, and also histological evaluation, to assess neuronal and glial protection using specific cytochemical markers (Neu Nand APC, respectively).
  • the therapeutic time-window can be re-assessed by injecting the DHA formulations at 30 min, 1 h and 2 h after SCI.
  • long chain fatty acid, "Lights,” removal; the processing conditions are as follows (temperature, 150 - 180°C; pressure, ⁇ 0.1 torr; feed pump setting and feed rate, 10 - 60 and 2 - 9 liter/hr; molecular still wiper rotation, 175 - 200 rpm) 3.
  • the "heavies" removal, i.e., longer chain fatty acids >C22 was performed as follows (temperature, 175 - 209°C; pressure, ⁇ 0.1 torr, feed pump setting and feed rate, 20 - 60 and 3 - 9 liters/hr; molecular still wiper rotation, 175 - 200rpm).
  • the lights removal i.e., shorter chain fatty acids ⁇ C22, was usually performed three times before going into the Heavies removal. After the final Heavies removal, 9.51 kg of the DHA free fatty acid oil, with a >95% purity, was obtained as a light pale yellow oil.
  • the diluted Lipoid E 80 SN/glycerin dispersion was then passed through a homogenizer (Niro Soavi NS1001L2K) at -5,000 psi for a time equivalent to 10 continuous discrete passes.
  • the dispersion in the reservoir was continuously stirred with an overhead stirrer under a blanket of nitrogen.
  • pH of the dispersion was adjusted to 9.0 with a solution of 0.5N sodium hydroxide, to obtain 1,754 gm of almost transparent light tan Lipoid E80 SN/glycerin dispersion.
  • the dispersion in the reservoir was continuously stirred with an overhead stirrer under a blanket of nitrogen.
  • the estimated final was about 2L.
  • the pH was adjusted to about 8.02 with a solution of 0.5N sodium hydroxide
  • Example 9 [0168] Using a Silverson high shear mixer, 72 gm of Lipoid E 80 SN was dispersed while still frozen in 216 ml of the distilled water (nitrogen protected) with the temperature of water for injection used being between 65 - 90°C under nitrogen. The dispersion was continued under a blanket of nitrogen until Lipoid E 80 SN is finely divided and a viscous fluid is formed. 102 gm of glycerin was added while continuing the dispersion under a blanket of nitrogen. The distilled water (nitrogen protected, between 65 - 90°C) was added to bring the total volume to 430 ml.
  • the diluted Lipoid E 80 SN/glycerin dispersion was then passed through a homogenizer (Niro Soavi NS 1001L2K) at -5,000 psi for a time equivalent to 10 continuous discrete passes.
  • the dispersion in the reservoir was continuously stirred with an overhead stirrer under a blanket of nitrogen.
  • pH of the dispersion was adjusted to 10.0 with a solution of 0.5N sodium hydroxide, to obtain almost transparent light tan Lipoid E80 SN/glycerin dispersion.
  • the coarse emulsion was then passed through a homogenizer (Niro Soavi NS1001L2K) at -10,000 psi for a time equivalent to 10 continuous discrete passes at temperatures between 50 - 70°C .
  • the dispersion in the reservoir was continuously stirred with an overhead stirrer under a blanket of nitrogen.
  • a white lipid emulsion resulted, and the mean particle size of lipid emulsion was measured using a Malvern Mastersizer 2000.
  • the pH of the emulsion (350 ml) was adjusted to ca. 8.0 with a solution of 0.5N sodium hydroxide about two days after the preparation outline above. The final volume of pH-adjusted emulsion reached 0.5 liter. Then the pH-adjusted emulsion was aliquoted into 20 ml Type 1 /glass vials (15 ml/vial). The aliquot samples were flushed with nitrogen and sealed with rubber septums and aluminum seals. The sealed samples were autoclaved at 122°C for 15 min. Finally the pH, particle size (volume moment mean of the particle; D[4,3]), and uniformity of the final emulsion were measured again. A sample emulsion was lyophilized to provide an oil-like sample. The oil sample was further analyzed for the DHA potency. See Table 15.
  • Example 10 Frozen Lipoid E 80 SN (324 g) was added to 200 ml distilled water while stirring with a Silverson high shear mixer at temperatures between 65 - 90°C under a nitrogen. The mixing was continued until Lipoid E 80 SN was finely divided and a viscous fluid was formed. Then to the mixture was added 300 g of glycerin portion wise. Additional distilled water was added to bring the total volume to 1300 ml. The diluted mixture was then transferred to a homogenizer (Niro Soavi NS 1001 L2K). The mixture was continuously passed through the homogenizer at 5,000 psi (ca.
  • the dispersion was filtered over 0.45 micron membrane filters. The pH of the filtered dispersion was adjusted to ca. 10.0 with a solution of 0.5N sodium hydroxide. At this point, the dispersion (2400 g) thus prepared was intended for 12 liters of final lipid emulsions.
  • Oil containing DHA (Table 6; > 95% free fatty acid) was preheated at 70°C.
  • the emulsion was continuously passed through the homogenizer at 10,000 psi (ca 690 bars) for a time equivalent to 10 discrete passes while maintaining the temperature at around 70°C and stirring the retained emulsion with an overhead stirrer under a nitrogen atmosphere.
  • the pH and particle size distributions (mean diameter size (D[4,3]), and uniformity) of the emulsion were monitored with a pH meter and Malvern MasterSizer 2000.
  • a white lipid emulsion was obtained and weighed.
  • the pH of the emulsion (240 ml) was adjusted to ca. 8.0 with a solution of 1.0 N sodium hydroxide.
  • a 90% algae-based DHA free fatty acid oil (as prepared for example according to
  • Example 7 was preheated at 70 °C.
  • Four hundred and fifty (450) g of the DHA FFA was added as a thin stream to 300 g of a prepared pH adjusted fine dispersion (e.g., as prepared in Example 10) under a nitrogen atmospherewhile stirring with a Silverson high shear mixer at temperatures between 40 -75°C. Distilled water was used to rinse the containers. At this point, the combined volume of the dispersion was at 90% of the final intended volume. The mixture was allowed to stir at a high shear for 20 min. The coarse emulsion formed was then transferred to a homogenizer (Niro Soavi NS1001L2K).
  • a homogenizer Niro Soavi NS1001L2K
  • the containers were rinsed with distilled water to allow the combined coarse emulsion to reach a total volume of 1.5 liter having about 30% oil, about 2.7% emulsifier and about 2.5%) isotonic agent
  • the emulsion was continuously passed through the homogenizer at 10,000 psi (ca 690 bars) for a time equivalent to 9 discrete passes while maintaining the temperature at around 70°C and stirring the retained emulsion with an overhead stirrer under a nitrogen atmosphere.
  • the pH and particle size distributions (mean diameter size D[4,3] and uniformity) of the emulsion were monitored with a pH meter and Malvern MasterSizer 2000.
  • a white lipid emulsion (1 ,500 ml) was obtained and weighed. A portion (300 ml) of the lipid emulsion was aliquoted. The pH of the aliquoted emulsion was adjusted to 8.03 with 0.5 N NaOH solution (approximately 137.5 ml) with the final volume at about 450 ml. A sample of the emulsion (15 ml) from the pH adjusted aliquoted portion was lyophilized to provide an oil-like sample and the oil/solid percentage (g/100 ml) was determined.
  • the oil sample was further analyzed by a GC- FAME analysis to give a DHA potency of 181.8 mg per milliliter of emulsion (Table 17).
  • a 2.5% (g/100 ml) glycerol solution was prepared by mixing 25 g of glycerol with 950 ml of distilled water, adjusting pH of the solution to 8.0 with 0.1 N sodium hydroxide, normalizing the final total volume to 1 ,000 ml with distilled water, and filtering the final solution with a 0.2-micron Nalgene sterile filtration setup.
  • the pH-adjusted lipid emulsion (50 ml) was serially diluted, with the filtered glycerol solution, to give a 0.60 mg/ml DHA FFA diluted emulsion.
  • a portion (125 ml) of the 0.60 mg/ml DHA FFA emulsion was further diluted to 0.15 mg/ml DHA FFA emulsion.
  • a portion (62.5 ml) of the 0.15 mg/ml DHA FFA emulsion was further diluted to give 0.038 mg/ml DHA FFA diluted emulsion.
  • the 0.60 (having about 0.01% oil, about 0.001%> emulsifier and about 2.5% isotonic agent), 0.15 (having about 0.02%> oil, about 0.002%> emulsifier and about 2.5%) isotonic agent), and 0.04 (having about 0.06%> oil, about 0.006%) emulsifier and about 2.5% isotonic agent) mg/ml DHA FFA emulsions were aliquoted into 20 ml Type 1/glass vials (15 ml/vial). The filled vials were flushed with nitrogen and sealed with chlorobutyl rubber stoppers and aluminum seals. The sealed samples were autoclaved at 122°C for 15 min. The pH, D[4,3], PFAT5, and uniformity of the final emulsions were measured. (See Tables 18, 19, and 20 for the 0.60, 0.15, and 0.04 mg/ml emulsions, respectively).
  • DHA formulations described herein can be tested in rat and mouse models of Spinal Cord Injury for example those described in Huang et al., "A combination of intravenous and dietary docosahexaenoic acid significantly improves outcome after spinal cord injury", Brain (2007) 130: 3004-3019 and King et al., “Omega-3 Fatty Acids Improve Recovery, whereas omega-6 Fatty Acids Worsen Outcome, after Spinal Cord Injury in the Adult Rat," J. Neurosci., (2006) 26(17): 4672-4680.
  • DHA formulations described herein are tested in hemisection and/or compression SCI.
  • DHA-FFA formulations (low, medium and high diluted emulsions described in Example 11 with a calculated concentration of about 0.04 mg/ml, about 0.15 mg/ml, and about 0.60 mg/ml, respectively, and with a target dose of 500 nmol/kg (actual 578 nmol/kg (0.19mg/kg)), 2000 nmol/kg (actual 2312 nmol/kg (0.75 mg/kg)) and 8000 nmol/kg (actual 9248 nmol/kg (3.0mg/kg)) respectively, were tested in compression SCI using a mouse model according to the procedures outlined in Example 12.
  • the target injection volume was about 94 ⁇ (based on the molecular weight of DHA-FFA as 328.49 g/mol and a body weight of a mouse about 20 g) to achieve an injection volume of about 5.0 ml/kg.
  • Sections of spinal cord stained with haematoxylin and eosin showed that the area of gliosis and neuronal loss was smallest in the 2000 nmol/kg treatment group.
  • Figure 3 show that DHA injected as an emulsion in mice following spinal cord compression, retained its neuroprotective properties.
  • the neurological improvement was correlated with tissue protection.
  • Figures 4 and 5 show the tissue with Neun staining (neurons) and GFAP staining (astroglia), respectively.
  • the formulations at the low and high concentrations did not show efficacy in basso mouse scale (BMS) for locomotion or in body weight.
  • the formulation with the medium concentration appears to provide a neuroprotective benefit as determined by BMS and improved body weight; the results are displayed in Figures 1 and 2, respectively.
  • INTRALIPID® 20% (20% i.v. fat emulsion), also referred to as soy bean oil (SBO), was diluted according to the procedure of Example 11 (same dilution factors as the DHA-FFA emulsion) and used as a control for all three experiments. Saline was also used as a control. Body weight loss and BMS scores were measured days post operations (DPO). No toxicity was observed.
  • Two DHA-FFA formulations (diluted emulsions as described in Example 10) with a calculated concentration of about 0.15 mg/ml and about 0.60 mg/ml with a target dose of 2000 nmol/kg (actual 2312 nmol/kg (0.75 mg/kg)) and 8000 nmol/kg (actual 9248 nmol/kg (3.0mg/kg)) respectively, were tested in a rat a hemisection SCI model using adult Sprague-Dawley rats according to the procedures outlined in Example 12.
  • the target injection volume was about 94 ⁇ (based on the molecular weight of DHA- FFA as 328.49 g/mol and a body weight of a mouse about 20 g) to achieve an injection volume of about 5.0 ml/kg.
  • the above emulsions were tested in Sprague-Hawley rats with hemiscetion SCI at vertebral thoracic level T12. Motor outcome was evaluated using the Basso, Beattie and Bresnahan (BBB) score for the recovery of hind limb function. Changes in mechanical and thermal sensitivity were also monitored in order to assess the development of allodynia as an indicator of neuropathic pain.
  • the motor baseline score was recorded in the open field and the sensory baseline response was measured for mechanical (von Frey hair) and thermal sensitivity.
  • the animals received intravenously (i.v.) either a DHA emulsion as described above, or a comparable soybean emulsion as a control.
  • locomotor function recovery was evaluated with BBB.
  • Mechanical and thermal sensitivity threshold began after the animals reached plantar weight support and some hind limb motor control. Animals were monitored for 3 months post-injury.
  • the diluted Lipoid E 80 SN/glycerin dispersion was then passed through a homogenizer (Niro Soavi NS1001L2K) at -5 ,000 psi for a time equivalent to 10 continuous discrete passes.
  • the dispersion in the reservoir was continuously stirred with an overhead stirrer under a blanket of nitrogen.
  • pH of the dispersion was adjusted to 9.0 with a solution of 0.5N sodium hydroxide, to obtain 1,754 g of almost transparent light tan Lipoid E80 SN/glycerin dispersion.
  • the coarse emulsion was then passed through a homogenizer (Niro Soavi NS1001L2K) at -10,000 psi for a time equivalent to 10 discrete passes at temperatures between 50 - 70°C.
  • the dispersion in the reservoir was continuously stirred with an overhead stirrer under a blanket of nitrogen.
  • a white lipid emulsion resulted, and the mean particle size of lipid emulsion was measured using a Malvern Mastersizer 2000. See Table 21.
  • Table 21 Table 21
  • the mixture was continuously passed through the homogenizer at 5,000 psi (ca 350 bars) for a time equivalent to 10 discrete passes while maintaining the temperature at around 70°C and stirring the retained mixture with an overhead stirrer under a nitrogen atmosphere.
  • the dispersion was filtered over 0.45 micron membrane filters.
  • the pH of the filtered dispersion was adjusted to ca. 10.0 with a solution of 0.5 N sodium hydroxide.
  • the dispersion (2400 g) thus prepared was intended for 12 liters of final lipid emulsions.
  • Oil containing DHA (Table 4; containing about 90% DHA ethyl ester) was preheated at 70 °C.
  • a Silverson high shear mixer was used to rinse the containers.
  • the combined volume of the dispersion was at 90% of the final intended volume. The mixture was stirred at a high shear for 20 min.
  • the coarse emulsion formed was then transferred to a homogenizer (Niro Soavi NS1001L2K).
  • the containers were rinsed with distilled water to allow the combined coarse emulsion to reach a total volume of 1.5 liters.
  • the emulsion was continuously passed through the homogenizer at 5,000 psi (ca 350 bars) for a time equivalent to 6 discrete passes while maintaining the temperature at around 70°C and stirring the retained emulsion with an overhead stirrer under a nitrogen atmosphere.
  • the pH and particle size distributions (mean diameter size (D[4,3]) and uniformity) of the emulsion were monitored with a pH meter and Malvern MasterSizer 2000.
  • a white lipid emulsion was obtained and weighed.
  • the emulsion was aliquoted into 20-ml Type 1 glass vials (15 ml/vial). The aliquot samples were flushed with nitrogen and sealed with chlorobutyl rubber stoppers and aluminum seals. The sealed samples were autoclaved at 122°C for 15 min. Finally the pH, D[4,3], and uniformity of the final emulsion were measured again.
  • a sample emulsion was lyophilized to provide an oil-solid mixture. The oil-solid mixture was further analyzed for DHA potency (Table 22).
  • Oil containing DHA (containing about a 9: 1 (w:w) mixture of about 90% DHA ethyl ester oil (Table 4) and about 60% DHA and triglyceride oil (Table 3)) was mixed and preheated at 70 °C.
  • Lipoid sodium oleate (0.45g) was added to 300 g of the dispersion prepared above while stirring with a Silverson high shear mixer at temperatures between 40 - 75°C under a nitrogen atmosphere; this was followed by the addition of a thin stream of 500 g of the preheated DHA ethyl ester/triglyceride oil.
  • the distilled water was used to rinse the containers.
  • the combined volume of the dispersion was at 90% of the final intended volume.
  • the mixture was allowed to stir at a high shear for 20 min.
  • the coarse emulsion formed was then transferred to a homogenizer (Niro Soavi NS1001L2K).
  • the containers were rinsed with distilled water to allow the combined coarse emulsion to reach a total volume of 1.5 liters.
  • the emulsion was continuously passed through the homogenizer at 5,000 psi (ca 350 bars) for a time equivalent to 9 discrete passes while maintaining the temperature at around 70°C and stirring the retained emulsion with an overhead stirrer under a nitrogen atmosphere.
  • a 90% algae-based DHA-EE (e.g., as prepared for example according to Example 1)
  • the containers are rinsed with distilled water to allow the combined coarse emulsion to reach a total volume of 1.5 liter having 30%> oil, 2.7% emulsifier and 2,5% isotonic agent
  • the emulsion is continuously passed through the homogenizer at 10,000 psi (ca 690 bars) for a time equivalent to 9 discrete passes while maintaining the temperature at around 70°C and stirring the retained emulsion with an overhead stirrer under a nitrogen atmosphere.
  • the pH and particle size distributions (mean diameter size D[4,3] and uniformity) of the emulsion are monitored with a pH meter and Malvern MasterSizer 2000.
  • a white lipid emulsion (1,500 ml) is obtained and weighed. A portion (300 ml) of the lipid emulsion is aliquoted. The pH of the aliquoted emulsion is adjusted to 8.03 with 0.5 N NaOH solution (approximately 137.5 ml) with the final volume at about 450 ml. A sample of the emulsion (15 ml) from the pH adjusted aliquoted portion is lyophilized to provide an oil- like sample and the oil/solid percentage (g/100 ml) is determined. The oil sample is further analyzed by a GC-FAME analysis to give a DHA potency.
  • a 2.5% (g/100 ml) glycerol solution is prepared by mixing 25 g of glycerol with 950 ml of distilled water, adjusting pH of the solution to 8.0 with 0.1 N sodium hydroxide, normalizing the final total volume to 1,000 ml with distilled water, and filtering the final solution with a 0.2- micron Nalgene sterile filtration setup.
  • the pH-adjusted lipid emulsion (50 ml) is serially diluted, with the filtered glycerol solution, to give a 0.60 mg/ml DHA-EE diluted emulsion, a 0.15 mg/ml DHA EE diluted emulsion and a 0.4 mg/ml DHA EE diluted emulsion.
  • the 0.60 (having 0.01% oil, 0.001% emulsifier and about 2.5% isotonic agent), 0.15 (having 0.02% oil, 0.002% emulsifier and about 2.5% isotonic agent), and 0.04 (having 0.06% oil, 0.006% emulsifier and about 2.5% isotonic agent) mg/ml DHA FFA emulsions are aliquoted into 20 ml Type 1 /glass vials (15 ml/vial). The filled vials are flushed with nitrogen and sealed with chlorobutyl rubber stoppers and aluminum seals. The sealed samples are autoclaved at 122°C for 15 min. The pH, D[4,3], PFAT5, and uniformity of the final emulsions are measured (Tables 2, 3, and 4 for the 0.60, 0.15, and 0.04 mg/ml emulsions, respectively).
  • DHA formulations described herein can be tested in rat and mouse models of Spinal Cord Injury for example those described in Huang et ah, "A combination of intravenous and dietary docosahexaenoic acid significantly improves outcome after spinal cord injury", Brain (2007) 130: 3004-3019 and King et al, "Omega- 3 Fatty Acids Improve Recovery, whereas omega-6 Fatty Acids Worsen Outcome, after Spinal Cord Injury in the Adult Rat," J. Neurosci., (2006) 26(17): 4672-4680.
  • DHA formulations described herein are tested in hemisection and/or compression SCI.

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Abstract

La présente invention concerne une émulsion comprenant un émulsifiant, un agent isotonique et un triglycéride d'acide docosahexaénoïque (DHA-TG), l'émulsion étant sensiblement exempte d'acide eicosapentaénoïque (EPA) et étant appropriée pour une administration parentérale. La présente invention concerne également une émulsion comprenant un acide gras libre docosahexaénoïque (DHA-FFA) appropriée pour une administration parentérale. La présente invention concerne également un procédé de traitement d'un sujet soufrant d'une lésion à la moëlle épinière, comprenant l'administration au sujet d'une émulsion comprenant une quantité efficace d'un DHA-FFA au sujet en ayant besoin. La présente invention concerne également une émulsion comprenant un émulsifiant, un agent isotonique et un ester éthylique d'acide docosahexaénoïque (DHA-EE), l'émulsion étant sensiblement exempte d'acide eicosapentaénoïque (EPA) et étant appropriée pour une administration parentérale.
PCT/EP2012/066146 2011-08-18 2012-08-17 Emulsions de triglycérides de dha, d'acides gras libres dha et d'esters éthyliques de dha et procédés de traitement d'une lésion à la moëlle épinière WO2013024174A1 (fr)

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