Parenteral nutrition formulation

Abstract

To provide a parenteral nutrition formulation for pediatric patients.SOLUTION: The nutritional formulation comprises a lipid formulation comprising an aqueous phase and an oil phase, wherein the lipid formulation is in the form of an oil-in-water emulsion. Also provided is a multi-chamber container for parenteral nutrition administration comprising a carbohydrate formulation present in a first chamber, an amino acid formulation present in a second chamber, and a lipid formulation present in a third chamber.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001]

[0001] The present disclosure is directed to parenteral nutrition formulations, including ready-to-use triple parenteral nutrition formulations. More particularly, the present disclosure is directed to lipid formulations and multi-chamber containers containing lipid, carbohydrate, and amino acid formulations, particularly for use in pediatric patients. [Background technology]

[0002]

[0002] Pharmaceutical solutions for pediatric nutrition must be formulated with the needs of preterm infants, newborns, infants, children, and adolescents in mind. Preterm infants lack substantial energy and fat stores, making it important to provide adequate lipid intake, for example, via parenteral nutrition. Lipids, particularly long-chain polyunsaturated fatty acids, have been found to be involved in growth, visual development, neurodevelopment, and long-term health, among other functions.

[0003] Docosahexaenoic acid (DHA) (C22:6 n-3) is a long-chain polyunsaturated fatty acid synthesized from alpha-linolenic acid (ALA). DHA is the major structural lipid for cell membranes of the brain and retina of the eye, and is an important component of the heart. While the use of parenteral nutrition is associated with liver disease (e.g., liver failure, fatty liver, and cirrhosis), DHA has been found to have a beneficial effect on fatty liver.

[0004]

[0004] Arachidonic acid (ARA) (C20:4 n-6) is a long-chain polyunsaturated fatty acid formed by biosynthesis from linoleic acid (LA). ARA is the most abundant fatty acid in the brain and plays important roles in cell division, signal transduction, and many fundamental cellular functions.

[0005]

[0005] Therefore, there is a need for improved parenteral nutrition products for pediatric patients, including preterm infants, neonates, infants, children and adolescents, who require parenteral nutrition when oral and enteral nutrition is not possible, inadequate or contraindicated. Summary of the Invention [Means for solving the problem]

[0006]

[0006] In light of this disclosure and without limiting the scope of the present invention in any way, a first aspect of the present disclosure, which may be combined with any other aspect recited herein unless otherwise specified, provides a multi-chamber container for parenteral administration, comprising a carbohydrate preparation present in a first chamber, an amino acid preparation present in a second chamber, and a lipid preparation present in a third chamber. The lipid preparation has an aqueous phase and an oil phase, and comprises about 5% to about 35% by weight of the oil phase based on the total weight of the lipid preparation, and is present in the form of an oil-in-water emulsion. Further, the oil phase contains docosahexaenoic acid (DHA) obtained from a single-cell source, the single-cell source being an extract of microalgae. In the oil phase, DHA is present at a concentration of 0.1 g to 5.0 g per 100 g of oil phase. The lipid preparation contains about 70 mg or less of phytosterols per 100 g of oil phase, and is essentially free of water-soluble forms of choline and / or arachidonic acid (ARA).

[0007]

[0007] In a second aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, DHA is present in a concentration of 0.25 g to 3.0 g per 100 g of oil phase.

[0008]

[0008] In a third aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, DHA is present in a concentration of 1.5 g to 2.5 g per 100 g of oil phase.

[0009]

[0009] In a fourth aspect of the present disclosure, which may be combined with any other aspect listed in this specification unless otherwise specified, the DHA is present in triglyceride form or ethyl ester form, preferably in triglyceride form.

[0010]

[0010] In a fifth aspect of the present disclosure, which may be combined with any other aspect enumerated in this specification unless otherwise specified, the lipid formulation comprises eicosapentaenoic acid (EPA), and the ratio of DHA to EPA in the lipid formulation is 10:1 to 1000:1 (w / w).

[0011]

[0011] In a sixth aspect of the present disclosure, which may be combined with any other aspect enumerated in this specification unless otherwise specified, the lipid formulation comprises EPA, and the ratio of DHA to EPA in the lipid formulation is 10:1 to 200:1.

[0012]

[0012] In a seventh aspect of the present disclosure, which may be combined with any other aspect enumerated in this specification unless otherwise specified, the lipid formulation comprises EPA, and the ratio of DHA to EPA in the lipid formulation is 20:1 to 150:1.

[0013]

[0013] In an eighth aspect of the present disclosure, which may be combined with any other aspect listed in this specification unless otherwise specified, DHA and / or EPA are present in triglyceride form or ethyl ester form, preferably in triglyceride form.

[0014]

[0014] In a ninth aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, the lipid formulation is essentially free of EPA.

[0015]

[0015] In a tenth aspect of the present disclosure, which may be combined with any other aspect enumerated in this specification unless otherwise specified, the microalgae is Crypthecodinium cohnii or Schizochytrium sp., preferably Schizochytrium sp.

[0016]

[0016] In an eleventh aspect of the present disclosure, which may be combined with any other aspect enumerated in this specification unless otherwise specified, the lipid formulation comprises from about 15 mg to about 35 mg of phytosterol per 100 g of oil phase, and in one preferred embodiment, not more than about 25 mg of phytosterol per 100 g of oil phase.

[0017]

[0017] In a twelfth aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, the lipid formulation comprises one or more pharmaceutically acceptable surfactants selected from the group consisting of phospholipids, oleates, and combinations thereof.

[0018]

[0018] In a thirteenth aspect of the present disclosure, which may be combined with any other aspect enumerated in this specification unless otherwise specified, the phospholipid is selected from the group consisting of egg phosphatides and soybean lecithin.

[0019]

[0019] In a fourteenth aspect of the present disclosure, which may be combined with any other aspect listed in this specification unless otherwise specified, the lipid formulation comprises one or more pharmaceutically acceptable isotonic agents.

[0020]

[0020] In a fifteenth aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, the pharmaceutically acceptable isotonic agent is glycerol.

[0021]

[0021] In a sixteenth aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, the lipid formulation comprises one or more pharmaceutically acceptable antioxidants selected from the group consisting of tocopherol, ascorbyl palmitate, and combinations thereof.

[0022]

[0022] In a seventeenth aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, the lipid formulation has a pH in the range of about 6 to about 9, and in one preferred embodiment, a pH of about 7 to about 8.

[0023]

[0023] In an eighteenth aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, the carbohydrate preparation and / or amino acid preparation comprises at least one water-soluble form of choline, preferably glycerophosphocholine, selected from the group consisting of choline chloride, choline bitartrate, choline citrate, choline gluconate, choline malate, choline cytidine diphosphate choline (CDP) salt and glycerophosphocholine.

[0024]

[0024] In a nineteenth aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, at least one choline is present at a concentration of 20 mg to 2000 mg of choline equivalents per liter of reconstituted multi-chamber container, for example, at a concentration of 30 mg to 1000 mg of choline equivalents per liter of reconstituted multi-chamber container.

[0025]

[0025] In a twentieth aspect of the present disclosure, which may be combined with any other aspect recited herein unless otherwise specified, a method for treating a patient in need of parenteral nutrition when oral and enteral nutrition are impossible, insufficient, or contraindicated comprises parenterally administering the contents of a multi-chamber container containing a lipid formulation. The lipid formulation has an aqueous phase and an oil phase, and comprises about 5% to about 35% by weight of the oil phase, based on the total weight of the lipid formulation, and is present in the form of an oil-in-water emulsion. Further, the oil phase contains docosahexaenoic acid (DHA) obtained from a single-cell source, the single-cell source being an extract of microalgae. In the oil phase, DHA is present at a concentration of 0.1 g to 5.0 g per 100 g of oil phase. The lipid formulation contains about 70 mg or less of phytosterols per 100 g of oil phase and is essentially free of water-soluble forms of choline and / or arachidonic acid (ARA).

[0026]

[0026] In a twenty-first aspect of the present disclosure, which may be combined with any other aspect recited herein unless otherwise specified, the patient is a pediatric patient.

[0027]

[0027] In a twenty-second aspect of the present disclosure, which can be combined with any other aspect recited herein unless otherwise specified, a lipid formulation for parenteral administration comprises an aqueous phase and an oil phase. The lipid formulation comprises about 5% to about 35% by weight of the oil phase, based on the total weight of the lipid formulation, and is present in the form of an oil-in-water emulsion. Further, the aqueous phase contains at least one pharmaceutically acceptable water-soluble form of choline. The oil phase contains docosahexaenoic acid (DHA). The lipid formulation contains about 70 mg or less of phytosterols per 100 g of oil phase and is essentially free of arachidonic acid (ARA).

[0028]

[0028] In a 23rd aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, the DHA is obtained from a single-cell source, and the single-cell source is an extract of microalgae.

[0029]

[0029] In a 24th aspect of the present disclosure, which may be combined with any other aspect enumerated in this specification unless otherwise specified, the microalgae is Crypthecodinium cohnii or Schizochytrium species, preferably Schizochytrium species.

[0030]

[0030] In a 25th aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, DHA is present at a concentration of 0.25 g to 3.0 g per 100 g of oil phase.

[0031]

[0031] In a 26th aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, DHA is present at a concentration of 1.5 g to 2.5 g per 100 g of oil phase.

[0032]

[0032] In a 27th aspect of the present disclosure, which may be combined with any other aspect listed in this specification unless otherwise specified, DHA is present in triglyceride form or ethyl ester form, preferably in triglyceride form.

[0033]

[0033] In a 28th aspect of the present disclosure, which may be combined with any other aspect enumerated in this specification unless otherwise specified, the lipid formulation comprises eicosapentaenoic acid (EPA), and the ratio of DHA to EPA in the lipid formulation is 10:1 to 1000:1 (w / w).

[0034]

[0034] In a 29th aspect of the present disclosure, which may be combined with any other aspect enumerated in this specification unless otherwise specified, the lipid formulation comprises EPA, and the ratio of DHA to EPA in the lipid formulation is 10:1 to 200:1 (w / w).

[0035]

[0035] In a 30th aspect of the present disclosure, which may be combined with any other aspect enumerated in this specification unless otherwise specified, the lipid formulation comprises EPA, and the ratio of DHA to EPA in the lipid formulation is 20:1 to 150:1 (w / w).

[0036]

[0036] In a thirty-first aspect of the present disclosure, which may be combined with any other aspect listed in this specification unless otherwise specified, DHA and / or EPA are present in triglyceride form or ethyl ester form, preferably in triglyceride form.

[0037]

[0037] In a thirty-second aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, the lipid formulation is essentially free of EPA.

[0038]

[0038] In a thirty-third aspect of the present disclosure, which may be combined with any other aspect enumerated in this specification unless otherwise specified, the lipid formulation comprises 15 mg to 35 mg of phytosterol per 100 g of oil phase, and in one preferred embodiment, about 25 mg or less of phytosterol per 100 g of oil phase.

[0039]

[0039] In a 34th aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, the lipid formulation comprises one or more pharmaceutically acceptable surfactants selected from the group consisting of phospholipids, oleates, and combinations thereof.

[0040]

[0040] In a thirty-fifth aspect of the present disclosure, which may be combined with any other aspect enumerated in this specification unless otherwise specified, the phospholipid is selected from the group consisting of egg phosphatides and soy lecithin.

[0041]

[0041] In a 36th aspect of the present disclosure, which may be combined with any other aspect listed in this specification unless otherwise specified, the lipid formulation comprises one or more pharmaceutically acceptable isotonic agents.

[0042]

[0042] In a thirty-seventh aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, the pharmaceutically acceptable isotonic agent is glycerol.

[0043]

[0043] In a 38th aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, the lipid formulation comprises one or more pharmaceutically acceptable antioxidants selected from the group consisting of tocopherol, ascorbyl palmitate, and combinations thereof.

[0044]

[0044] In a 39th aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, the lipid formulation has a pH in the range of about 6 to about 9, and in one preferred embodiment, a pH of about 7 to about 8.

[0045]

[0045] In a fortieth aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, at least one choline is selected from the group consisting of choline chloride, choline bitartrate, choline citrate, choline gluconate, choline malate, choline cytidine diphosphate choline (CDP) salt and glycerophosphocholine, preferably glycerophosphocholine.

[0046] In a forty-first aspect of the present disclosure, which may be combined with any other aspect recited herein unless otherwise specified, the at least one choline is selected from the group consisting of 0.1 g to 12 g choline equivalents per liter of lipid emulsion, e.g., 0.2 g to 10 g choline equivalents per liter of lipid emulsion, 3 g to 6 g choline equivalents per liter of lipid emulsion, 0.5 to 4 g choline equivalents per liter of lipid emulsion, 0.1 g to 0.5 g choline equivalents per liter of lipid emulsion, 0.5 g to 1 g choline equivalents per liter of lipid emulsion, 1 g to 2 g choline equivalents per liter of lipid emulsion, The choline may be present at a concentration of 2g to 3g choline equivalents per liter of lipid emulsion, 3g to 4g choline equivalents per liter of lipid emulsion, 4g to 5g choline equivalents per liter of lipid emulsion, 5g to 6g choline equivalents per liter of lipid emulsion, 6g to 7g choline equivalents per liter of lipid emulsion, 7g to 8g choline equivalents per liter of lipid emulsion, 8g to 9g choline equivalents per liter of lipid emulsion, 9g to 10g choline equivalents per liter of lipid emulsion, 10g to 11g choline equivalents per liter of lipid emulsion, and / or 11g to 12g choline equivalents per liter of lipid emulsion.

[0047]

[0047] In a forty-second aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, at least one choline is present at a concentration of 0.2 g to 10 g of choline equivalents per liter of lipid emulsion.

[0048]

[0048] In a forty-third aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, at least one choline is present at a concentration of 3 g to 6 g of choline equivalents per liter of lipid emulsion.

[0049]

[0049] In a forty-fourth aspect of the present disclosure, which may be combined with any other aspect recited herein unless otherwise specified, a method for treating a patient in need of parenteral nutrition when oral and enteral nutrition are impossible, insufficient, or contraindicated comprises parenterally administering a lipid formulation. The lipid formulation comprises an aqueous phase and an oil phase, and the oil phase comprises about 5% to about 35% by weight, based on the total weight of the lipid formulation, and is present in the form of an oil-in-water emulsion. Further, the aqueous phase contains at least one pharmaceutically acceptable water-soluble form of choline. The oil phase contains docosahexaenoic acid (DHA). The lipid formulation contains about 70 mg or less of phytosterols per 100 g of oil phase and is essentially free of arachidonic acid (ARA).

[0050]

[0050] In a forty-fifth aspect of the present disclosure, which may be combined with any other aspect recited herein unless otherwise specified, the patient is a pediatric patient.

[0051]

[0051] In a forty-sixth aspect of the present disclosure, which may be combined with any other aspect recited herein unless otherwise specified, a multi-chamber container for parenteral administration comprises a carbohydrate preparation present in a first chamber, an amino acid preparation present in a second chamber, and a lipid preparation present in a third chamber. The lipid preparation comprises an aqueous phase and an oil phase, and the oil phase comprises about 5% to about 35% by weight of the oil phase based on the total weight of the lipid preparation, and is present in the form of an oil-in-water emulsion. Further, the aqueous phase contains at least one pharmaceutically acceptable water-soluble form of choline. The oil phase contains docosahexaenoic acid (DHA). The lipid preparation contains about 70 mg or less of phytosterols per 100 g of oil phase and is essentially free of arachidonic acid (ARA).

[0052]

[0052] In a forty-seventh aspect of the present disclosure, which may be combined with any other aspect recited herein unless otherwise specified, a lipid formulation for parenteral administration comprises an aqueous phase and an oil phase. The lipid formulation comprises about 5% to about 35% by weight of the oil phase, based on the total weight of the lipid formulation, and is present in the form of an oil-in-water emulsion. Further, the aqueous phase contains at least one pharmaceutically acceptable water-soluble form of choline. The oil phase comprises docosahexaenoic acid (DHA) and arachidonic acid (ARA), and the ratio of DHA to ARA in the lipid formulation is 10:1 to 1:5 (w / w). The lipid formulation comprises about 70 mg or less of phytosterols per 100 g of oil phase.

[0053]

[0053] In a forty-eighth aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, the ratio of DHA to ARA in the lipid formulation is 1:1 to 1:3 (w / w).

[0054]

[0054] In a forty-ninth aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, the DHA is obtained from a single cell source, and the single source is an extract of microalgae.

[0055]

[0055] In a 50th aspect of the present disclosure, which may be combined with any other aspect enumerated in this specification unless otherwise specified, the microalgae is Crypthecodinium cohnii or Schizochytrium species, preferably Schizochytrium species.

[0056]

[0056] In a fifty-first aspect of the present disclosure, which may be combined with any other aspect enumerated in this specification unless otherwise specified, the ARA is obtained from a single-cell source, and the cell source is a fungus.

[0057]

[0057] In a fifty-second aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, the fungus is Mortierella alpina.

[0058]

[0058] In a fifty-third aspect of the present disclosure, which may be combined with any other aspect listed in this specification unless otherwise specified, DHA and / or ARA are present in triglyceride form or ethyl ester form, preferably in triglyceride form.

[0059]

[0059] In a fifty-fourth aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, ARA is present at a concentration ranging from 0.1 g to 15 g per 100 g of oil phase.

[0060]

[0060] In a fifty-fifth aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, ARA is present at a concentration ranging from 1.5 g to 7.5 g per 100 g of oil phase.

[0061]

[0061] In a fifty-sixth aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, DHA is present at a concentration of 0.25 g to 3.0 g per 100 g of oil phase.

[0062]

[0062] In a fifty-seventh aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, DHA is present at a concentration of 1.5 g to 2.5 g per 100 g of oil phase.

[0063]

[0063] In a 58th aspect of the present disclosure, which may be combined with any other aspect enumerated in this specification unless otherwise specified, the lipid formulation comprises EPA, and the ratio of DHA to EPA in the lipid formulation is 10:1 to 1000:1 (w / w).

[0064]

[0064] In a fifty-ninth aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, the lipid formulation comprises EPA, and the ratio of DHA to EPA in the lipid formulation is 10:1 to 200:1 (w / w).

[0065]

[0065] In a 60th aspect of the present disclosure, which may be combined with any other aspect enumerated in this specification unless otherwise specified, the lipid formulation comprises EPA, and the ratio of DHA to EPA in the lipid formulation is 20:1 to 150:1 (w / w).

[0066]

[0066] In a 61st aspect of the present disclosure, which may be combined with any other aspect listed in this specification unless otherwise specified, DHA and / or EPA are present in triglyceride form or ethyl ester form, preferably in triglyceride form.

[0067]

[0067] In a sixty-second aspect of the present disclosure, which may be combined with any other aspect listed herein unless otherwise specified, the lipid formulation is essentially free of EPA.

[0068]

[0068] In a 63rd aspect of the present disclosure, which may be combined with any other aspect enumerated in this specification unless otherwise specified, the lipid formulation comprises 15 mg to 35 mg of phytosterol per 100 g of oil phase, and in one preferred embodiment, about 25 mg or less of phytosterol per 100 g of oil phase.

[0069]

[0069] In a 64th aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, the lipid formulation comprises one or more pharmaceutically acceptable surfactants selected from the group consisting of phospholipids, oleates, and combinations thereof.

[0070]

[0070] In a 65th aspect of the present disclosure, which may be combined with any other aspect enumerated in this specification unless otherwise specified, the phospholipid is selected from the group consisting of egg phosphatides and soybean lecithin.

[0071]

[0071] In a 66th aspect of the present disclosure, which may be combined with any other aspect listed in this specification unless otherwise specified, the lipid formulation comprises one or more pharmaceutically acceptable isotonic agents.

[0072]

[0072] In a 67th aspect of the present disclosure, which may be combined with any other aspect listed in this specification unless otherwise specified, the pharmaceutically acceptable isotonic agent is glycerol.

[0073]

[0073] In a 68th aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, the lipid formulation comprises one or more pharmaceutically acceptable antioxidants selected from the group consisting of tocopherol, ascorbyl palmitate, and combinations thereof.

[0074]

[0074] In a 69th aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, the lipid formulation has a pH in the range of about 6 to about 9, and in one preferred embodiment, a pH of about 7 to about 8.

[0075]

[0075] In a 70th aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, at least one water-soluble form of choline is selected from the group consisting of choline chloride, choline bitartrate, choline citrate, choline gluconate, choline malate, choline cytidine diphosphate choline (CDP) salt and glycerophosphocholine.

[0076] In a seventy-first aspect of the present disclosure, which may be combined with any other aspect recited herein unless otherwise specified, the at least one choline is selected from the group consisting of 0.1 g to 12 g choline equivalents per liter of lipid emulsion, e.g., 0.2 g to 10 g choline equivalents per liter of lipid emulsion, 3 g to 6 g choline equivalents per liter of lipid emulsion, 0.5 to 4 g choline equivalents per liter of lipid emulsion, 0.1 g to 0.5 g choline equivalents per liter of lipid emulsion, 0.5 g to 1 g choline equivalents per liter of lipid emulsion, 1 g to 2 g choline equivalents per liter of lipid emulsion, The choline may be present at a concentration of 2g to 3g choline equivalents per liter of lipid emulsion, 3g to 4g choline equivalents per liter of lipid emulsion, 4g to 5g choline equivalents per liter of lipid emulsion, 5g to 6g choline equivalents per liter of lipid emulsion, 6g to 7g choline equivalents per liter of lipid emulsion, 7g to 8g choline equivalents per liter of lipid emulsion, 8g to 9g choline equivalents per liter of lipid emulsion, 9g to 10g choline equivalents per liter of lipid emulsion, 10g to 11g choline equivalents per liter of lipid emulsion, and / or 11g to 12g choline equivalents per liter of lipid emulsion.

[0077]

[0077] In a 72nd aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, at least one choline is present at a concentration of 0.2 g to 10 g of choline equivalents per liter of lipid emulsion.

[0078]

[0078] In a 73rd aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, at least one choline is present at a concentration of 3 g to 6 g of choline equivalents per liter of lipid emulsion.

[0079]

[0079] In a 74th aspect of the present disclosure, which may be combined with any other aspect enumerated herein unless otherwise specified, the choline is present at a concentration of 0.5 to 4 g of choline equivalents per liter of lipid emulsion.

[0080]

[0080] In a seventy-fifth aspect of the present disclosure, which may be combined with any other aspect recited herein unless otherwise specified, a method for treating a pediatric patient in need of parenteral nutrition when oral and enteral nutrition are impossible, insufficient, or contraindicated comprises parenterally administering a lipid formulation. The lipid formulation comprises an aqueous phase and an oil phase, and the oil phase comprises about 5% to about 35% by weight, based on the total weight of the lipid formulation, and is present in the form of an oil-in-water emulsion. Further, the aqueous phase contains at least one pharmaceutically acceptable water-soluble form of choline. The oil phase comprises docosahexaenoic acid (DHA) and arachidonic acid (ARA), and the ratio of DHA to ARA in the lipid formulation is 10:1 to 1:5 (w / w). The lipid formulation comprises about 70 mg or less of phytosterols per 100 g of oil phase.

[0081]

[0081] In a seventy-sixth aspect of the present disclosure, which may be combined with any other aspect recited herein unless otherwise specified, a multi-chamber container for parenteral administration comprises a carbohydrate preparation present in a first chamber, an amino acid preparation present in a second chamber, and a lipid preparation present in a third chamber. The lipid preparation comprises an aqueous phase and an oil phase, and the oil phase comprises about 5% to about 35% by weight of the oil phase based on the total weight of the lipid preparation, and is present in the form of an oil-in-water emulsion. Further, the aqueous phase contains at least one pharmaceutically acceptable water-soluble form of choline. The oil phase comprises docosahexaenoic acid (DHA) and arachidonic acid (ARA), and the ratio of DHA to ARA in the lipid preparation is 10:1 to 1:5 (w / w). The lipid preparation comprises about 70 mg or less of phytosterols per 100 g of oil phase.

[0082]

[0082] In view of the disclosure and embodiments described herein, it is therefore an advantage of the present disclosure to provide parenteral nutrition formulations that are better suited to the needs of pediatric patients.

[0083]

[0083] Another advantage of the present disclosure is that it provides beneficial effects on visual, physical, and / or neurological development.

[0084]

[0084] Reducing parenteral nutrition-associated liver disease (PNALD), which is associated with liver failure, fatty liver, and cirrhosis, is a further advantage of the present disclosure.

[0085]

[0085] Reducing non-alcoholic fatty liver disease (NAFLD) is yet another advantage of the present disclosure.

[0086]

[0086] Reducing chronic liver disease is yet a further advantage of the present disclosure.

[0087]

[0087] Phytosterol depletion is yet another advantage of the present disclosure.

[0088]

[0088] Additional features and advantages of the disclosed formulations are described in and will be apparent from the following detailed description and drawings. The features and advantages described herein are not exhaustive, and many additional features and advantages will become apparent to those skilled in the art, particularly in light of the drawings and description. Also, any particular embodiment need not necessarily possess all of the advantages enumerated herein. Furthermore, it should be noted that the language used herein has been chosen primarily for readability and instructional purposes and is not intended to limit the scope of the inventive subject matter.

[0089]

[0089] The present disclosure will be described and explained with more specificity and detail through the use of the accompanying drawings, with the understanding that the drawings illustrate only typical embodiments of the invention and should not be considered as limiting the scope of the disclosure. [Brief explanation of the drawings]

[0090] [Figure 1] FIG. 1 is a plan view of one embodiment of a 300 ml container of the present invention. [Figure 2] 1 is a graph showing the development of alanine aminotransferase (ALT) function in the animal study described in Example 1. Control groups received saline (NaCl) or LE 10% lipid emulsion alone, while additional groups received the same LE 10% lipid emulsion but with three different choline sources: choline chloride, CDP-choline, and GPC. The term "high" indicates the concentration of choline derivatives in the LE 10% lipid emulsion, which was 31 mmol / L. The graph shows that the decrease in ALT activity from days 5 to 17 demonstrates an improvement in liver condition and is most pronounced when GPC is present in the lipid emulsion. [Figure 3]Figure 3 shows the development of alanine aminotransferase activity in percent of normal plasma values ​​in an animal study as described in Example 1 (Step No. 3). The animals tested were administered either saline or LE 10% lipid emulsion ("LE 10%) alone, which contained a normal amount of phytosterols ("Phyto") but no GPC. Another lipid emulsion containing LE 10% and the same amount of phytosterols also contained GPC at a concentration of 40 mmol / L ("LE 10% + GPC Step No. 2"). A third composition again consisted of lipid emulsion (LE 13%) to which GPC was added at a concentration of 40 mmol / L, with a reduced phytosterol content (phytosterol dosage shown in Figure 3). [Figure 4A] 4A and 4B are graphs showing the results of the animal study described in Example 1 and histopathological evaluation of the livers of animals subjected to parenteral nutrition using saline, LE 10% lipid emulsion, and LE 10% lipid emulsion supplemented with choline chloride, CDP-choline, and GPC, respectively (FIG. 4A). Figure 4A shows that administration of lipid emulsion containing GPC has the most significant effect on the development of vacuolation compared to all choline derivatives tested. [Figure 4B] Figure 4B provides the results of administering saline alone, lipid emulsion supplemented with DHA and ARA (LE 13%) (triangles), and lipid emulsion supplemented with DHA, ARA, and GPC (LE 13%) (squares). Figure 4B shows that the presence of DHA and ARA already has a significant positive effect on liver vacuolation. The term "low" represents a concentration of each choline derivative of 15 mmol / L. The term "high" represents a concentration of each choline derivative of 31 mmol / L. The grades are defined as given in Example 3.3. [Figure 5]This represents the results of an animal study as described in Example 1, in which the effect of parenteral administration of various lipid emulsions was determined based on the ratio of liver weight to body weight in percentage units. Test animals were treated with either saline, an LE 10% lipid emulsion without any choline derivatives ("lipid emulsion 10%"), or the same LE 10% lipid emulsion additionally containing 31 mmol / L of the choline derivative as indicated. The term "high" refers to the concentration of each choline derivative in the lipid emulsion, which is 31 mmol / L. [Figure 6A] Figure 6A shows exemplary photographs of grades 1 to 5 of vacuolation, as determined by histopathological analysis of the livers of test animals (see Examples 1 and 3). The histological slides shown were stained with hematoxylin-eosin. Grades were assigned according to the following scheme: Figure 6A: Grade 1 = minimal / very few / very small scattered vacuoles. [Figure 6B] Figure 6B: Grade 2 = slight / few / small vacuoles, centrilobular to midzone. [Figure 6C] Figure 6C: Grade 3 = moderate / moderate number / moderate size vacuoles, centrilobular to midzone. [Figure 6D] Figure 6D: Grade 4 = obvious / numerous / giant vacuoles, centrilobular to periportal. [Figure 6E] Figure 6E: Grade 5 = severe / numerous / giant vacuoles, diffuse, affecting all liver regions. DETAILED DESCRIPTION OF THE INVENTION

[0091]

[0096] Some embodiments described herein generally relate to the field of parenteral nutrition.More specifically, some embodiments described herein relate to a lipid formulation for parenteral administration, wherein the lipid formulation comprises an aqueous phase and an oil phase, and the lipid formulation is present in the form of an oil-in-water emulsion.Related embodiments described herein relate to a multi-chamber container for parenteral administration, wherein the container comprises a carbohydrate formulation in a first chamber, an amino acid formulation in a second chamber, and a lipid formulation in a third chamber.

[0092]

[0097] As used herein, the term "child" may refer to newborns, including preterm, full-term, and postterm newborns up to the age of one month; infants between one month and one year of age; children between one and twelve years of age, and adolescents between 13 and 21 years of age.

[0093]

[0098] As used herein, the term "long-chain polyunsaturated fatty acid" can refer to a polyunsaturated fatty acid having at least 18 carbon atoms in the fatty acid portion of the molecule (i.e., the portion of the molecule excluding any carbon atoms forming the ester moiety), e.g., at least 20 carbon atoms, at least 22 carbon atoms, or at least 24 carbon atoms in the fatty acid portion of the molecule.

[0094]

[0099] As used herein, the term "essentially free" can refer to a composition that contains less than 5% of a particular component, e.g., less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.05%, less than 0.02%, less than 0.01%, less than 0.005%, less than 0.002%, and / or less than 0.001% of a particular component. For example, a composition that is "essentially free of EPA" can refer to a composition that contains less than 5% EPA, e.g., less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.05%, less than 0.02%, less than 0.01%, less than 0.005%, less than 0.002%, and / or less than 0.001% EPA.

[0095]

[0100] The terms "liver disease", "liver injury" and "liver damage" are used interchangeably herein.The terms refer to the liver condition defined by increased alanine aminotransferase (ALT) activity, histologically determined vacuolation, and increased liver weight / body weight ratio.In particular, the terms refer to fatty liver, which can be diagnosed by the above markers.More particularly, the terms refer to NAFLD.Even more particularly, the terms refer to NAFLD caused by choline deficiency, especially choline deficiency caused by long-term total parenteral nutrition.

[0096] Lipid preparations

[0101] The present disclosure provides lipid formulations for parenteral administration. The lipid formulations disclosed herein comprise an aqueous phase and an oil phase and exist in the form of an oil-in-water emulsion. Typically, the lipid formulation comprises an aqueous phase and about 5% to about 35% by weight of the oil phase, based on the total weight of the lipid formulation. For example, the oil phase of the lipid formulation may be present in an amount of about 10% to about 20% by weight, about 10% to about 15% by weight, about 15% to about 20% by weight, about 12% to about 17% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, and / or about 19% by weight, based on the total weight of the lipid formulation.

[0097]

[0102] The aqueous phase of lipid formulation comprises water. In some cases, the aqueous phase of lipid formulation comprises at least one water-soluble form of choline. As used herein, "water-soluble form of choline" refers to (1) a water-soluble salt containing N,N,N-trimethylethanolammonium cation, and (2) a water-soluble compound containing a choline moiety, such as cytidine diphosphate choline or glycerophosphocholine. The water-soluble form of choline may be selected from the group consisting of choline chloride, choline bitartrate, choline citrate, choline gluconate, choline malate, choline cytidine diphosphate choline (CDP) salt (for example, sodium salt, potassium salt, or inner salt) and glycerophosphocholine. In a preferred embodiment, the water soluble form of choline is from 0.1 g to 12 g choline equivalents per liter of lipid emulsion, for example from 0.2 g to 10 g choline equivalents per liter of lipid emulsion, from 3 g to 6 g choline equivalents per liter of lipid emulsion, from 0.5 to 4 g choline equivalents per liter of lipid emulsion, from 0.1 g to 0.5 g choline equivalents per liter of lipid emulsion, from 0.5 g to 1 g choline equivalents per liter of lipid emulsion, from 1 g to 2 g choline equivalents per liter of lipid emulsion, from 2 g to 3 g choline equivalents per liter of lipid emulsion, The choline-containing lipid emulsion may be present at a concentration of 3g to 4g choline equivalents per liter of lipid emulsion, 4g to 5g choline equivalents per liter of lipid emulsion, 5g to 6g choline equivalents per liter of lipid emulsion, 6g to 7g choline equivalents per liter of lipid emulsion, 7g to 8g choline equivalents per liter of lipid emulsion, 8g to 9g choline equivalents per liter of lipid emulsion, 9g to 10g choline equivalents per liter of lipid emulsion, 10g to 11g choline equivalents per liter of lipid emulsion, and / or 11g to 12g choline equivalents per liter of lipid emulsion.In a further preferred embodiment, the water soluble form of choline is present in an amount of from 0.1 g to 15.0 g per liter of lipid emulsion, for example from 0.1 g to 6.0 g per liter of lipid emulsion, from 0.1 g to 2.0 g per liter of lipid emulsion, from 0.2 g to 0.9 g per liter of lipid emulsion, from 0.5 g to 6.0 g per liter of lipid emulsion, from 0.5 g to 5.0 g per liter of lipid emulsion, from 0.5 g to 4.0 g per liter of lipid emulsion, from 0.5 g to 3 ... The glycerophosphocholine may be at a concentration of 1.0 g to 12.0 g per liter of lipid emulsion, 1.0 g to 10.0 g per liter of lipid emulsion, 1.0 g to 5.0 g per liter of lipid emulsion, 2.0 g to 12.0 g per liter of lipid emulsion, 2.0 g to 9.0 g per liter of lipid emulsion, 2.0 g to 4.0 g per liter of lipid emulsion, 4.0 g to 11.0 g per liter of lipid emulsion, 4.0 g to 10.0 g per liter of lipid emulsion, or 5.0 g to 12.0 g per liter of lipid emulsion.

[0098]

[0103] The oil phase of lipid formulation comprises polyunsaturated fatty acid, for example, long-chain polyunsaturated fatty acid, and polyunsaturated fatty acid can be present as free acid, as ionic form or salt form of free acid, and / or in ester form.Suitable esters of polyunsaturated fatty acid / long-chain polyunsaturated fatty acid include, but are not limited to, alkyl ester (for example, methyl ester, ethyl ester, propyl ester, or combinations thereof) and triglyceride ester.In some cases, long-chain polyunsaturated fatty acid has the structure R(C=O)OR', where R is an alkenyl group having at least 17 carbon atoms, at least 19 carbon atoms, at least 21 carbon atoms, or at least 23 carbon atoms, and R' is absent, H, counterion, alkyl group (for example, methyl, ethyl, or propyl), or glyceryl group (for example, R(C=O)OR' is monoglyceride, diglyceride, or triglyceride). The polyunsaturated fatty acids for use in the lipid formulations disclosed herein include, but are not limited to, linoleic acid (LA), arachidonic acid (ARA), α-linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), stearidonic acid (SDA), γ-linoleic acid (GLA), dihomo-γ-linoleic acid (DPA) and docosapentaenoic acid (DPA), particularly DHA, ARA and EPA, each of which can exist in free acid form, ionic form or salt form, alkyl ester form and / or triglyceride form.In some cases, polyunsaturated fatty acids and / or long-chain fatty acids exist in triglyceride form.

[0099]

[0104] In some cases, the polyunsaturated fatty acids (e.g., long-chain polyunsaturated fatty acids) of the lipid formulation are obtained from a single source. In some cases, the single source is an extract of microalgae. Suitable microalgae sources include, but are not limited to, Crypthecodinium cohnii and Schizochytrium spp. In some cases, Crypthecodinium cohnii or Schizochytrium spp. are the sole source of the long-chain polyunsaturated fatty acid, DHA. In some cases, the amount of DHA in oil isolated from Schizochytrium spp. is about 250 to about 700 mg / g of oil, e.g., about 300 to about 600 mg / g, about 350 to about 550 mg / g, and / or about 400 to about 500 mg / g of oil.

[0100]

[0105] When the lipid formulation includes Schizochytrium spp. as the sole source of polyunsaturated fatty acids, the lipid formulation includes DHA in a relatively higher amount than EPA or ARA. For example, when Schizochytrium spp. is the sole source of polyunsaturated fatty acids in a lipid formulation, the ratio of DHA to EPA in the lipid formulation is typically at least 10:1 (w / w), e.g., from about 10:1 to about 1000:1 (w / w), from about 20:1 to about 1000:1 (w / w), from about 50:1 to about 1000:1 (w / w), from about 100:1 to about 1000:1 (w / w), from about 10:1 to about 200:1 (w / w), from about 20:1 to about 150:1 (w / w), at least about 50:1 (w / w), at least about 100:1 (w / w), at least about 500:1 (w / w), and / or at least about 1000:1 (w / w). Furthermore, when Schizochytrium spp. is the sole source of polyunsaturated fatty acids in the lipid formulation, the ratio of DHA to ARA in the lipid formulation is typically at least 20:1 (w / w), e.g., from about 20:1 to about 1000:1 (w / w), from about 50:1 to about 1000:1 (w / w), from about 100:1 to about 1000:1 (w / w), at least about 50:1 (w / w), at least about 100:1 (w / w), at least about 500:1 (w / w), and / or at least about 1000:1 (w / w).

[0101]

[0106] In some cases, the oil phase comprises DHA obtained from a single-cell source, the single-cell source being a microalgae extract. In some cases, the DHA is present at a concentration of 0.1 g to 5.0 g per 100 g of oil phase, for example, 0.25 g to 3.0 g per 100 g of oil phase, and / or 1.5 g to 2.5 g per 100 g of oil phase. In some cases, the lipid formulation comprises eicosapentaenoic acid (EPA), and the ratio of DHA to EPA in the lipid formulation is 10:1 to 1000:1 (w / w), for example, 10:1 to 200:1 (w / w) and / or 20:1 to 150:1 (w / w).

[0102]

[0107] In some cases, the lipid formulation is essentially free of EPA.

[0103]

[0108] In some cases, the lipid formulation is essentially free of water-soluble forms of choline, such as water-soluble salts containing N,N,N-trimethylethanolammonium cations, and / or water-soluble compounds containing a choline moiety.

[0104]

[0109] In some cases, the lipid formulation is essentially free of ARA.

[0105]

[0110] In some cases, the oil phase comprises a blend of oils derived from the microalga Schizochytrium sp. and the fungus Mortierella alpina. Such blends of oils include, but are not limited to, myristic acid (C14:0), palmitic acid (C16:0), palmitoleic acid (C16:1), stearic acid (C18:0), oleic acid (C18:1), linoleic acid (C18:2 n-6), gamma-linoleic acid (C18:3, n-6), alpha-linoleic acid (C18:3, n-3), arachidic acid (C20:0), ARA (C20:4, n-6), EPA (C20:5, n-3), behenic acid (C22:0), DPA (C22:5, n-3), DHA (C22:6, n-3), and lignoceric acid (C24:0). In some cases, the blends include ARA, DHA, and EPA.

[0106]

[0111] In some cases, ARA is included in lipid formulation.When ARA is added to lipid formulation, the formulation typically contains more ARA than when Schizochytrium species is the sole source of polyunsaturated fatty acids in lipid formulation.In some cases, the ratio of DHA and ARA in lipid formulation is about 10:1 to about 1:5 (w / w), for example, about 5:1 to about 1:5 (w / w), about 3:1 to 1:3 (w / w), about 1:1 to about 1:3 (w / w), about 1:1.5 to about 1:2.5 (w / w), for example, about 1:2 (w / w). Furthermore, when ARA is added to the lipid formulation, the ratio of DHA to EPA in the lipid formulation can be at least 10:1 (w / w), e.g., about 10:1 to about 1000:1 (w / w), about 20:1 to about 1000:1 (w / w), about 50:1 to about 1000:1 (w / w), about 100:1 to about 1000:1 (w / w), about 10:1 to about 200:1 (w / w), about 20:1 to about 150:1 (w / w), at least about 50:1 (w / w), at least about 100:1 (w / w), at least about 500:1 (w / w), and / or at least about 1000:1 (w / w).

[0107]

[0112] In some cases, the oil phase comprises ARA obtained from a single-cell source, where the single-cell source is a fungus, e.g., a fungal extract. In a preferred embodiment, the fungus is Mortierella alpina. In some cases, the ARA is present at a concentration of 0.1 g to 15 g per 100 g of oil phase, e.g., 1.5 g to 7.5 g per 100 g of oil phase.

[0108]

[0113] The lipid formulations disclosed herein typically contain reduced levels of phytosterols. In particular, the oils used in the lipid formulations are typically depleted of phytosterols by at least 25% of the total amount of phytosterols originally present in the oil, for example, by at least 40%, at least 50%, at least 60%, and / or at least 75%. In some cases, the lipid formulations contain 70 mg or less of phytosterols per 100 g of oil phase, for example, about 15 mg to about 35 mg of phytosterols per 100 g of oil phase, and / or about 25 mg or less of phytosterols per 100 g of oil phase. Removal or depletion of phytosterols can be carried out, for example, by short-path distillation, activated carbon treatment followed by filtration, supercritical CO2 chromatography, or chromatographic purification.

[0109]

[0114] The lipid formulations disclosed herein may further comprise saturated, monounsaturated, and polyunsaturated fatty acids. In some cases, saturated, monounsaturated, and polyunsaturated fatty acids are present at a concentration of 95g to 99.1g per 100g of oil phase, for example, 97g to 99.75g per 100g of oil phase, and / or 97.5g to 98.5g per 100g of oil phase. In some cases, saturated, monounsaturated, and polyunsaturated fatty acids may be obtained from animal and / or plant sources. In some cases, saturated, monounsaturated, and polyunsaturated fatty acids may be present mainly as triglycerides.

[0110]

[0115] The lipid formulation disclosed herein may further comprise additional components, such as surfactant (also referred to as emulsifier), co-surfactant, isotonicity agent, pH adjuster and antioxidant.Generally, surfactant is added to stabilize emulsion by reducing the interfacial tension between oil phase and water phase.Surfactant typically comprises hydrophobic part and hydrophilic part, and the amount of surfactant / emulsifier contained in formulation is determined based on the amount required to achieve the desired level of emulsion stabilization. Typically, the amount of surfactant in the lipid formulation is about 0.01% to about 3% by weight, e.g., about 0.01% to about 2.5% by weight, about 0.01% to about 2.3% by weight, about 0.02% to about 2.2% by weight, about 0.02% to about 2.1% by weight, about 0.02% to about 2% by weight, about 0.05% to about 1.8% by weight, about 0.1% to about 1.6% by weight, about 0.5% to about 1.5% by weight, about 0.8% to about 1.4% by weight, about 0.9% to about 1.3% by weight, about 1% to about 1.2% by weight, and / or about 1.2% by weight, based on the total weight of the lipid formulation. Suitable surfactants and co-surfactants include surfactants approved for parenteral use, including, but not limited to, phospholipids (e.g., egg phosphatides and soy lecithin), oleates, and combinations thereof. Exemplary surfactant is lecithin, including both natural and synthetic lecithin, such as egg, corn or soybean lecithin or their mixture.In some cases, lecithin is comprised in an amount of about 1.2% based on the total weight of lipid formulation.In some cases, lipid emulsion formulation comprises co-surfactant. Typically, the amount of co-surfactant in the lipid formulation is less than the amount of surfactant, and typically the amount of co-surfactant in the formulation is about 0.001% to about 0.6% by weight, e.g., about 0.001% to about 0.55% by weight, about 0.001% to about 0.525% by weight, about 0.001% to about 0.5% by weight, about 0.005% to about 0.5% by weight, about 0.01% to about 0.4% by weight, about 0.02% to about 0.3% by weight, about 0.03% to about 0.2% by weight, about 0.04% to about 0.1% by weight, and / or about 0.05% to about 0.08% by weight, based on the total weight of the lipid formulation.An exemplary co-surfactant is oleate, for example, sodium oleate.In some cases, lipid formulation comprises lecithin and oleate as surfactant and co-surfactant, for example, in the amount of 1.2% lecithin and 0.03% oleate.In some cases, sodium oleate is comprised in the amount of about 0.03 wt% based on the total weight of lipid formulation.

[0111]

[0116] An isotonicity agent can be added to a lipid formulation to adjust the osmolality of the lipid emulsion formulation to a desired level, e.g., a physiologically acceptable level. Suitable isotonicity agents include, but are not limited to, glycerol. Typically, the lipid emulsion formulation has an osmolality of about 180 to about 300 mOsmol / L, e.g., about 190 to about 280 mOsmol / L, and / or about 200 to about 250 mOsmol / L. In some cases, the lipid emulsion formulation contains the isotonicity agent in an amount of about 1% to about 10% by weight, e.g., about 1% to about 5% by weight, about 1% to about 4% by weight, and / or about 2% to about 3% by weight, based on the total weight of the lipid formulation. In some cases, the lipid emulsion formulation contains about 2% to about 3% by weight of glycerol.

[0112]

[0117] A pH adjuster can be added to the lipid formulation to adjust the pH to a desired level, e.g., a physiologically acceptable pH for parenteral use. Suitable pH adjusters include, but are not limited to, sodium hydroxide and hydrochloric acid. Typically, the lipid emulsion formulation has a pH of about 6 to about 9, e.g., about 6.1 to about 8.9, about 6.2 to about 8.8, about 6.3 to about 8.7, about 6.4 to about 8.6, about 6.5 to about 8.5, about 6.6 to about 8.4, about 6.7 to about 8.3, about 6.8 to about 8.2, about 6.9 to about 8.1, about 7 to about 8, about 7.1 to about 7.9, about 7.2 to about 7.8, about 7.3 to about 7.7, about 7.4 to about 7.6, about 7, about 7.5, and / or about 8.

[0113]

[0118] The lipid formulation may further comprise an antioxidant. Suitable antioxidants may be pharmaceutically acceptable antioxidants, including, but not limited to, tocopherols (e.g., gamma tocopherol, delta tocopherol, alpha tocopherol), ascorbyl palmitate, or combinations thereof. In some cases, the lipid emulsion formulation comprises the antioxidant in an amount of about 0 to about 200 mg / L, e.g., about 10 to about 200 mg / L, about 40 to about 150 mg / L, about 50 to about 120 mg / L, or about 75 to about 100 mg / L of the antioxidant, e.g., vitamin E.

[0114]

[0119] The aqueous (or water) phase of all intravenous lipid emulsions must comply with pharmacopoeial requirements to make the intravenous lipid emulsion suitable for injection, i.e., the water must be sterile water for injection.

[0115]

[0120] The present disclosure also includes a lipid emulsion in which, if present, a choline source (e.g., GPC) is added to the ready-to-use lipid emulsion or reconstituted solution before administration to a patient, for example, through a medical port.The choline source (e.g., GPC) can be prepared in the form of a suitable solution, for example, in a vial or a suitable flexible or rigid container, or can be prepared in a lyophilized form, for example, in a glass vial, and the lyophilized choline source (e.g., GPC) is dissolved in a suitable solvent before adding the choline source to the lipid emulsion or reconstituted solution.The choline source (e.g., GPC) can be present as the sole active ingredient of such a solution or lyophilized product for addition to the lipid emulsion or reconstituted solution, or can be present in combination with at least one additional active ingredient, for example, vitamins, trace elements, DHA, EPA and / or ARA. Thus, according to another embodiment of the present invention, there is provided a method of providing a choline source (e.g., GPC) to a patient, wherein the choline source (e.g., GPC) is added prior to administration to a ready-to-use lipid emulsion or reconstituted solution from an MCB providing a formulation for parenteral nutrition.

[0116]

[0121] The first lipid formulation according to the present disclosure comprises an oil phase containing docosahexaenoic acid (DHA) obtained from a single-cell source, the single-cell source being an extract of microalgae, and the DHA is present at a concentration of 0.1 g to 5.0 g per 100 g of oil phase. Furthermore, the oil provided in the first lipid formulation is depleted of phytosterols, such that the lipid formulation contains no more than about 70 mg of phytosterols per 100 g of oil phase. Additionally, the first lipid formulation is essentially free of water-soluble forms of choline and / or arachidonic acid (ARA). As discussed in further detail herein, the first lipid formulation comprises about 5% to about 35% by weight of the oil phase, based on the total weight of the aqueous phase and lipid formulation, and the lipid formulation is in the form of an oil-in-water emulsion.

[0117]

[0122] The second lipid formulation according to the present disclosure comprises an oil phase containing at least one pharmaceutically acceptable water-soluble form of choline and docosahexaenoic acid (DHA). Furthermore, the oil provided in the second lipid formulation is depleted of phytosterols, such that the lipid formulation contains no more than about 70 mg of phytosterol per 100 g of oil phase. Additionally, the lipid formulation is essentially free of arachidonic acid (ARA). As discussed in further detail herein, the second lipid formulation comprises about 5% to about 35% by weight of the oil phase, based on the total weight of the aqueous phase and lipid formulation, and the lipid formulation is in the form of an oil-in-water emulsion.

[0118]

[0123] A third lipid formulation according to the present disclosure comprises at least one pharmaceutically acceptable water-soluble form of choline and an oil phase comprising docosahexaenoic acid (DHA) and arachidonic acid (ARA). The third lipid formulation has a DHA to ARA ratio in the lipid formulation of 10:1 to 1:5 (w / w). Furthermore, the oil provided in the third lipid formulation is depleted of phytosterols such that the lipid formulation contains no more than about 70 mg of phytosterol per 100 g of oil phase. As discussed in further detail herein, the third lipid formulation comprises about 5% to about 35% by weight of the oil phase, based on the total weight of the aqueous phase and lipid formulation, and the lipid formulation is in the form of an oil-in-water emulsion.

[0119]

[0124] In some cases, the oil phase according to the present disclosure includes omega-3 fatty acids consisting of DHA and small amounts of EPA, and omega-6 fatty acids, such as ARA.

[0120]

[0125] The lipid emulsions disclosed herein can generally be prepared by well-known processes (see, for example, Hippalgaonkar et al., AAPS PharmSciTech 2010, Vol. 11 (No. 4), pp. 1526-1540). Generally, water-soluble and oil-soluble ingredients are dissolved in the aqueous and oil phases, respectively. Thus, the choline source, if present, is dissolved in the aqueous phase. An emulsifier, such as a phosphatide, can be dispersed in either the oil or aqueous phase. Both phases are heated and stirred sufficiently to disperse or dissolve the ingredients. The lipid phase is then generally added to the aqueous phase under controlled temperature and stirring (using a high-shear mixer) to form a homogeneously dispersed coarse or pre-emulsion. A pre-emulsion with a droplet size of less than 20 μm generally results in a unimodal and physiologically stable fine emulsion. The pre-emulsion is then homogenized (using a microfluidizer or high-pressure homogenizer) at optimized pressure, temperature, and number of cycles to further reduce the droplet size and form a fine emulsion. Factors such as the type and concentration of the oil phase and surfactant, operating temperature, pressure, number of cycles, etc., can affect the average droplet size during high-pressure homogenization and microfluidization. Throughout the emulsion's shelf life, the average droplet size and PFAT5 (volume-weighted percentage of fat globules ≥ 5 μm) of the pourable fine emulsion should be ≤ 500 nm and ≤ 0.05%, respectively. The pH of the resulting fine emulsion is then adjusted to the desired value, and the emulsion is filtered through a 1-5 μm filter. The fine emulsion is then transferred to a suitable container. Plastic containers that are oxygen-permeable and / or contain oil-soluble plasticizers are generally avoided. The whole process (filtration / preparation of coarse and fine emulsions) is usually carried out under nitrogen atmosphere whenever possible, especially when the excipients and certain components of the lipid emulsion are oxygen-sensitive. Sterilization of lipid formulations can be achieved by terminal heat sterilization or by sterile filtration. Terminal sterilization generally provides a more reliable sterility of the final product. However, if the components of the emulsion are heat-labile, sterile filtration can be used.Sterilization by filtration requires that the emulsion droplet size be below 200 nm. Alternatively, aseptic processing may be employed. However, this process is relatively equipment and labor intensive and requires additional process validation data and justification in the regulatory submission.

[0121]

[0126] Thus, the lipid emulsion according to the present invention can be prepared by the steps of: a. heating the oil phase and the water phase separately under stirring to a temperature of about 70°C to about 80°C; b. adding a choline source, e.g., glycerophosphocholine, to the aqueous phase; c. Preparing a pre-emulsion by transferring the oil phase into the water phase under stirring; d. homogenizing the pre-emulsion under pressure at a temperature of about 40°C to 60°C; e. Optionally, adding water to adjust the required volume and concentration; f. optionally, adjusting the pH to a range of about 7.8 to 8.8; and g. Optionally, sterilizing the lipid emulsion It can be prepared by

[0122]

[0127] Sterilization can be carried out by methods well known in the art, for example, by heating. Typically, steps (a) to (d) are carried out in the presence of an inert gas, such as N2, to avoid any oxidation reactions. The pressure used for homogenization of the pre-emulsion can vary over a wide range. Typically, the pressure will be in the range of 100 to 1300 bar, 200 to 1000 bar, 300 to 800 bar, or 400 to 1100 bar.

[0123] Amino acid preparations

[0128] Amino acid preparations contain a sterile aqueous solution of one or more amino acids and one or more electrolytes. Typically, amino acid preparations contain about 2 grams to about 10 grams of amino acids per 100 mL of amino acid preparation, for example, about 3 grams to about 9 grams, about 4 grams to about 8 grams, and / or about 5 grams to about 7 grams per 100 mL of amino acid preparation. Amino acid preparations generally contain isoleucine, leucine, valine, lysine, methionine, phenylalanine, threonine, tryptophan, arginine, histidine, alanine, aspartic acid, cysteine, glutamic acid, glycine, proline, serine, tyrosine, ornithine, and taurine. Furthermore, the tyrosine content can be increased by adding, for example, glycyl-tyrosine dipeptide or acetyl-tyrosine (Ac-Tyr). However, glycyl-tyrosine dipeptide typically has improved pharmacokinetics compared to Ac-Tyr and is excreted more rapidly by the kidney, resulting in reduced release of tyrosine into the blood.

[0124]

[0129] The amino acid formulation further comprises electrolytes, such as sodium, potassium, calcium, magnesium, and / or phosphate ions. For example, the amino acid preparation may contain, per 100 mL of the amino acid preparation, about 0.1 mmol to about 10 mmol of sodium (e.g., about 3.75 mmol to about 10 mmol of sodium), about 0.1 mmol to about 10 mmol of potassium (e.g., about 3.75 mmol to about 6.90 mmol of potassium), about 0.05 mmol to about 1.0 mmol of magnesium (e.g., about 0.05 mmol to about 0.11 mmol and / or about 0.38 mmol to about 0.65 mmol of magnesium), about 0.1 mmol to about 10 mmol of calcium (e.g., about 1.13 mmol to about 5.10 mmol of calcium), about 0.1 mmol to about 10 mmol of phosphate (e.g., about 0.94 mmol to about 5.10 mmol of phosphate), and 10 mmol or less of chloride (e.g., 5.6 mmol or less of chloride). When calcium and phosphate are present together in the same heat sterilization solution, insoluble calcium phosphate precipitation may occur. The use of organic salts of phosphate, such as sodium glycerophosphate pentahydrate or calcium glycerophosphate, allows for increased amounts of calcium and phosphate without solubility problems and without excess sodium or chloride. In amino acid formulations, sodium can be provided in the form of sodium chloride, calcium can be provided in the form of calcium chloride dihydrate or calcium gluconate, magnesium can be provided in the form of magnesium acetate tetrahydrate or magnesium chloride, and potassium can be provided in the form of potassium acetate.

[0125]

[0130] The amino acid formulation may further comprise a water-soluble form of choline selected from the group consisting of choline chloride, choline bitartrate, choline citrate, choline gluconate, choline malate, choline cytidine diphosphate choline (CDP) salt, and glycerophosphocholine. In a preferred embodiment, the water-soluble form of choline is present at a concentration of 20 mg to 2000 mg of choline equivalents per liter of reconstituted multi-chamber container, e.g., 30 mg to 1000 mg of choline equivalents per liter of reconstituted multi-chamber container.

[0126] Carbohydrate preparations

[0131] Carbohydrate preparations provide a supply of calories, typically in the form of glucose. In particular, carbohydrate preparations provide a sufficient amount of carbohydrate to avoid adverse effects, such as hyperglycemia, observed in patients receiving parenteral nutrition. Typically, carbohydrate preparations contain approximately 20 to 50 grams of glucose per 100 mL of carbohydrate preparation.

[0127]

[0132] The carbohydrate formulation may further comprise a water soluble form of choline selected from the group consisting of choline chloride, choline bitartrate, choline citrate, choline gluconate, choline malate, choline cytidine diphosphate choline (CDP) salt, and glycerophosphocholine. In a preferred embodiment, the water soluble form of choline is present at a concentration of 20 mg to 2000 mg of choline equivalents per liter of reconstituted multi-chamber container, for example, 30 mg to 1000 mg of choline equivalents per liter of reconstituted multi-chamber container.

[0128] Multi-chamber container

[0133] The present disclosure provides a multi-chamber container for parenteral administration of nutritional formulations. For example, the container may be in the form of a bag having multiple compartments or chambers. The container, e.g., bag, contains at least two chambers, e.g., three, four, or five chambers, and in a preferred embodiment, contains three chambers. Suitable containers, including bags, are typically sterile, non-pyrogenic, single-use, and / or ready-to-use. Multi-chamber containers are particularly useful for holding pediatric and / or neonatal parenteral nutrition products, and generally provide a carbohydrate formulation as disclosed herein in a first chamber of the container, an amino acid formulation as disclosed herein in a second chamber, and a lipid formulation as disclosed herein in a third chamber.

[0129]

[0134] A multi-chamber container, such as a three-chamber bag, may include vertical chambers. A suitable multi-chamber container is disclosed in U.S. Patent Application Publication No. 2007 / 0092579, the entire contents of which are incorporated by reference. For example, the multi-chamber container may be configured as a bag containing three adjacent chambers or compartments. If desired, a frangible barrier or openable seal (e.g., a peel seal or a frangible seal) is used to separate the chambers of the multi-chamber container. The openable seal allows formulations to be stored separately and mixed immediately before administration, thereby allowing formulations that should not be stored as a mixture for long periods to be stored in a single container. Opening the seal allows communication between the chambers and mixing of the contents of each chamber. The outer seal of the multi-chamber container is a strong seal that will not open under fluid pressure that would result from opening a weaker peel seal or frangible seal between the chambers.

[0130]

[0135] The multi-chamber container may be provided with instructions describing the desired order in which to open the peel seals so that the constituent liquids are mixed in the desired order. The tear strength of two or more peel seals may be varied to facilitate opening the seals in the desired order. For example, the tear strength of the peel seal to be opened first may be 1 / 3 to 1 / 2 of the tear strength required to open the peel seal to be opened second.

[0131]

[0136] FIG. 1 illustrates one embodiment of a multi-chamber container of the present invention. Preferably, container 10, configured as a bag, includes three adjacent chambers or chambers 12, 14, and 16. Chamber 12 is located at a lateral or side end 18, and chamber 16 is located at an opposite lateral or side end 20. The three chambers 12, 14, and 16 are preferably designed to hold aqueous solutions and / or lipid emulsions. Preferably, frangible borders or openable seals 22 and 24 are used to separate the chambers. Container 10 also preferably includes ports 26, 28, and 30 for providing communication with chambers 12, 14, and 16, respectively. Container 10 also preferably includes a hanging portion 36, which, in the embodiment shown in FIG. 1, is a flap with a centrally located hole 38 for hanging the container. Flap 36 defines an upper boundary 40 of all chambers 12, 14, and 16.

[0132] How to use

[0137] The present disclosure provides a method for treating a patient in need of parenteral nutrition when oral and enteral nutrition are impossible, insufficient, or contraindicated. The method involves using a multi-chamber container and a lipid formulation disclosed herein. In particular, the method involves parenterally administering the contents of the multi-chamber container and / or the lipid formulation disclosed herein to the patient. In a preferred embodiment, the patient is a pediatric patient.

[0133]

[0138] In some cases, the lipid emulsions disclosed herein and compositions containing the same are used to prevent and / or treat fatty liver. Fatty liver is defined as intrahepatic fat that accounts for at least 5% of the liver's weight. While simple accumulation of triacylglycerol in the liver can be hepatoprotective, long-term storage of hepatic lipids can lead to liver metabolic dysfunction, inflammation, and advanced forms of nonalcoholic fatty liver disease (NAFLD). NAFLD includes diseases ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma. Histologically, NASH is defined by the presence of macrovesicular steatosis, lobular inflammation, and ballooning of hepatocytes (Kneeman, Secondary Causes of Nonalcoholic Fatty Liver Disease, Therap Adv. Gastroenterol. 2012;5:199-207). Long-term total parenteral nutrition (TPN) may be one of the many causes of NAFLD. TPN can lead to the depletion of carnitine, a compound necessary for the transfer of free fatty acids from the liver cytosol to mitochondria for beta-oxidation. As previously mentioned, TPN also reduces the cytosolic concentration of choline, promoting hepatocyte lipid storage. Such lipid storage leads to the fact that the main histological findings are steatosis, intrahepatic cholestasis, and cystic duct duplication. Therefore, the effect of choline supplementation in TPN can also be determined by examining the histological characteristics of the liver. Such histological analysis allows for the evaluation of the degree of steatosis by analyzing the degree of vacuolation. Example 3 provides the results of such histopathological investigations performed in animal studies. Example 3 shows that liver damage caused by parenteral nutrition followed by a methionine- and choline-deficient diet can be effectively addressed by the presence of glycerophosphocholine in the PN solution. Example 3 also provides evidence that GPC has significantly better effects than other choline derivatives, specifically choline chloride and CDP-choline. The additional presence of DHA and ARA also appears to have additional synergistic benefits.

[0134]

[0139] The serum alanine aminotransferase (ALT) assay is the most common clinical test for detecting liver disease. Because enzyme concentrations in a population form a continuous distribution, the cutoff concentration that distinguishes between healthy and diseased livers has not been clearly defined. However, the upper normal limit for serum alanine aminotransferase has been established at a mean of 40 IU / L, ranging from 30 to 50 IU / L (Kim et al., BMJ 2004, 328:983). This upper limit is used in the context of the present invention as the normal serum alanine aminotransferase (also referred to herein as "aminotransferase" or "ALT") concentration. Kim et al. also documented a significant association between aminotransferase concentration and mortality from liver disease. Therefore, serum aminotransferase concentration was used in the context of the present invention to determine the effectiveness of glycerophosphocholine for the treatment of liver injury caused by, for example, parenteral nutrition, compared with lipid emulsions that do not contain any choline, but also with other choline sources, including choline chloride and CDP-choline. Figures 1 and 2 demonstrate the significantly better effect of GPC on lowering ALT levels.

[0135]

[0140] ALT activity was determined by a modified method recommended by the International Federation of Clinical Chemistry (IFCC) (see Example 2). ALT catalyzes the reaction of alpha-ketoglutarate with L-alanine to form L-glutamate and pyruvate. Under the action of LDH, pyruvate is converted to lactate, and NADH is converted to NAD. The decrease in NADH absorbance measured at 340 nm (the second wavelength is 700 nm) is directly proportional to the serum activity of ALT. This is a kinetic reaction. Generally, serum is used for analysis. Serum is separated from cells within 2 hours of collection and stored at -70°C until assayed. Monitoring ALT activity over time in animal models is used herein as a simple and definitive means to determine the effectiveness of GPC in treating liver disease, specifically liver damage caused by a choline-deficient diet (Examples 1 and 2, Figures 2 and 3).

[0136]

[0141] Plasma free choline concentrations can be determined by high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry according to protocols well known in the art (Pomfret et al.: Measurement of choline and choline metabolite concentrations using high-pressure liquid chromatography and gas chromatography-mass spectrometry. Anal Biochem. 1989;180:85-90).

[0137]

[0142] Methods for depleting phytosterols from oils, particularly plant-derived oils such as olive or soybean oil, are well known. For example, phytosterols can be removed as described in Ostlund et al., Am J Clin Nutr 2002, 75, 1000-1004, or as described in U.S. Pat. No. 6,303,803 B1. [Example]

[0138] Example 1: Animal Model

[0143] Animal studies were conducted to identify and confirm the most effective choline derivatives for use in parenteral nutrition solutions, particularly lipid emulsions, to prevent and / or treat and ameliorate liver damage, particularly fatty liver. The studies further served to identify any potential metabolic interactions between the choline derivatives found to be most effective and polyunsaturated fatty acids, particularly DHA and ARA.

[0139]

[0144] The effects of GPC and the combination of DHA, ARA, and GPC were investigated in a diseased animal model. Male Sprague-Dawley rats with induced adiposity induced by a choline- and methionine-deficient (MCD) diet (SSNIFF MCD pelleted choline / methionine-deficient diet (SSNIFF Spezialdiaten GmbH, Soest, Germany, product number E15653-94)) were maintained on parenteral nutrition. Adiposity was confirmed in each group by histopathology (Example 3).

[0140]

[0145] After 14 days on the MCD diet, parenteral nutrition was initiated. The first measurement was taken after 5 days of parenteral nutrition, followed by measurements at 9 and 17 days later. Daily lipid intake was 2.31 g / kg / d. The rats were divided into groups as described in Table 1 below.

[0141]

[0146] Two groups served as controls. The first group was treated with saline (0.90% w / v NaCl in water for injection). The second group received a lipid emulsion ("LE 10%") for injection containing refined olive oil (80.0 g / L) and refined soybean oil (20.0 g / L) in water, pH 6-8. LE 10% also contained egg lecithin (6.0 g / L), glycerol (11.25 g / L), and sodium oleate (0.15 g / L). LE 10% contained 100 g / L of lipid. In certain experiments, the lipid emulsion "LE" was used at different concentrations, e.g., "LE 13%" or "LE 20%," with "LE 13%" or "LE 20%" indicating the higher concentrations.

[0142]

[0147] Various choline derivatives selected from the group consisting of choline chloride, glycerophosphocholine (GPC), and cytidine diphosphate-choline (CDP-choline) were added to LE 10% at two concentrations (low / high), respectively (see Table I (step 2)). "Low" represents a lipid emulsion concentration of 15 mmol / L, and "high" represents a lipid emulsion concentration of 31 mmol / L. Choline chloride (2-hydroxyethyl)trimethylammonium chloride, a pharmaceutical secondary standard, was purchased from Sigma-Aldrich (Merck KGaA, Germany). CDP-choline (prepared by fermentation) was from TCI Europe NV (Antwerp, Belgium). Glycerophosphocholine prepared by saponification from egg phosphatides was supplied by Lipoid GmbH, Germany. DHA (from the algae Schizochytrium sp.) and ARA (from the fungus Mortierella alpina) were purchased from BASF AG, Germany. Vitamin E was purchased from ADM (IL, USA).

[0143]

[0148] The "LE" lipid emulsion supplemented with choline derivatives was prepared as follows: In the first step, the raw phase was heated. In the case of the oil phase, soybean and olive oils and egg phosphatides, and in the case of the step number 3 experiment, DHA and ARA oils and vitamin E were heated to 75°C in an inox beaker under N2 protection with continuous stirring using an Ultra Turrax. The aqueous phase was prepared by mixing glycerol, sodium oleate, and Milli-Q water, and was continuously heated to about 75°C in an inox beaker under N2 protection. If required, the choline derivative was added under constant stirring. In the second step, a pre-emulsion was prepared by adding the oil phase to the aqueous phase under continuous stirring using a peristaltic pump, and then transferred to a high-shear in-line disperser (e.g., Dispax Reactor® DR). The container was closed and flushed with nitrogen. In a third step, the pre-emulsion is homogenized by passing it several times through a high-pressure homogenizer at 600 bar, at a temperature of about 50° C., under a N 2 atmosphere.

[0144]

[0149] The emulsion is then adjusted to the required volume (2 L) with Milli-Q water and cooled to a temperature of approximately 18-28°C, preferably 20-25°C. The pH is adjusted to a range of 7.8-8.8, preferably about 8.3-8.8, with 0.1 N NaOH. The emulsion is filtered using a 4.5 μm filter and transferred to a 100 mL bag, which is then overpouched with an oxygen absorber / indicator for later use. The lipid emulsion is then autoclaved at 121°C to achieve an F0 of at least 15 minutes.

[0145] [Table 1]

[0146] [Table 2]

[0147] Example 2: Aminotransferase (ALT) Expression

[0150] To evaluate the effect of GPC on the liver status of the animals tested as described in Example 1, the plasma aminotransferase (ALT) activity of the animals tested was measured after 5 and 17 days of parenteral nutrition in both step 2 and step 3 settings. As previously described, liver damage (cholestasis) can be determined by increased aminotransferase levels. ALT activity was determined using an ADVIA 1800 blood biochemistry analyzer / IFCC modified (Siemens) according to the standard protocol as previously described.

[0148]

[0151] To summarize the results of the experiment, Figure 2 shows the development of ALT activity in the tested rats. As can be seen in Figure 2, there is an expected increase in ALT activity during 17 days of parenteral nutrition with LE 10%. In comparison, ALT activity does not increase in the test group in which a choline source is present in the lipid emulsion. However, the effect is most pronounced in the presence of GPC, and a clear decline in ALT activity can be determined. In contrast, choline chloride and CDP-choline rather result in a stable situation in which ALT activity does not significantly increase or decrease. Notably, the phosphatidylcholine contained in the LE lipid emulsion(s) does not appear to have any effect, confirming that choline cannot utilize the choline provided in the lipid emulsion in the form of phosphatidylcholine.

[0149]

[0152] After identifying GPC as a highly effective choline derivative for reducing ALT activity and thus liver damage, another experiment focused on the synergistic effect of GPC with PUFAs DHA and ARA. The lipid emulsion described in Example 1 was used, as further shown in Table III.

[0150]

[0153] Figure 3 summarizes the results for ALT activity in terms of changes in normal activity. This study includes one experiment using a composition in which the phytosterol content of the lipid emulsion was reduced as shown in Figure 3 using step number 3 settings. The results also demonstrate that both saline and lipid emulsion without a choline source and normal phytosterol content ("LE") resulted in increased ALT activity, evidence of progressive liver deterioration. In contrast, both lipid emulsions with GPC (40 mmol / L), regardless of phytosterol content, resulted in significant reductions in ALT activity. Phytosterol doses are shown in Figure 3. Phytosterols were included in the LE 13% lipid emulsion at concentrations ranging from 40 μg / mL to 120 μg / L. Notably, the phosphatidylcholine contained in the lipid emulsion(s) used herein does not appear to have any effect, confirming that the body is unable to utilize the choline provided in the lipid emulsion in the form of phosphatidylcholine.

[0151] Example 3: Determination of histopathological grade Example 3.1: Preparation of histological slides

[0154] Portions of liver were preserved in buffered formalin, and injection sites and sampled gross lesions were trimmed according to RITA guidelines, if applicable (Ruehl-Fehlert et al., Exp Toxic Pathol 2003; 55, 91-106), embedded in paraffin wax, sectioned at approximately 4 microns, and stained with hematoxylin-eosin. Frozen liver samples were cryosectioned onto approximately 5 micron slides and stained with Oil Red O. Tissue processing was performed at Citoxlab, France.

[0152] Example 3.2: Microscopy

[0155] Microscopic examination was performed on both liver slides (hematoxylin and eosin and oil red O), injection site, and gross lesions from all animals in the study. Peer review was performed on at least 30% of animals from the high-dose group and on a sufficient number of slides from identified target organs to ensure that findings recorded by the study pathologist were consistent and accurate. After pathological peer review was completed, all tissue slides were returned to Citoxlab France for completion. During microscopic examination, representative photographs were prepared at the pathologist's discretion.

[0153] Example 3.3: Average histological vacuolation

[0156] Liver samples taken after 8 and 15 days were examined as described above and assigned to one of five grades of hepatocyte vacuolation. For grade 5, vacuolation was generally diffuse and occurred in all areas. For lower grades, vacuolation was less likely to occur in periportal areas and vacuoles were smaller in size. Grades were assigned according to the following definitions: Grade 1 = minimal / very few / scattered very small vacuoles. Grade 2 = slight / few / small vacuoles, centrilobular to midzone. Grade 3 = moderate / moderate number / moderate size vacuoles, centrilobular to midzone. Grade 4 = obvious / numerous / giant vacuoles, centrilobular to periportal. Grade 5 = severe / numerous / giant vacuoles, diffuse, affecting all liver regions.

[0154]

[0157] Exemplary photographs for each grade are shown in Figure 6. The histological slides shown are stained with hematoxylin-eosin (HE).

[0155]

[0158] After 8 days, as a result of saline administration, 4 out of 4 animals showed signs of liver damage in terms of vacuolation at grade 5 (see Table IV). Parenteral nutrition with LE 13% in the presence of DHA and ARA already produced a favorable effect on liver histopathology. Of the 5 animals, 2 still showed grade 5 vacuolation. However, the livers of 3 out of 5 animals could be assigned to grade 4. In the presence of GPC in addition to DHA and ARA, liver vacuolation was even more improved. Only 1 out of 5 animals showed signs of grade 5 liver damage, while another 2 rats showed grade 4 symptoms and 2 showed grade 3 symptoms. Finally, when only GPC was added to the lipid emulsion, none of the 5 rats showed grade 5 liver damage. 3 showed grade 4, 1 showed grade 3, and 1 also showed grade 2 vacuolation.

[0156] [Table 3]

[0157]

[0159] 15 days after starting parenteral nutrition, the above-mentioned effect is even more pronounced.While the liver condition of animals receiving saline is still severe as expected, the presence of GPC in lipid emulsion, as well as the presence of DHA, ARA and GPC, all bring about a clear and significant improvement in the liver condition of animals.After 15 days, it is also clear that the presence of DHA and ARA in a certain concentration range in addition to GPC further brings about synergistically improved results.Figure 4B summarizes the effect of DHA, ARA and GPC on the development of liver vacuolation in terms of the above-defined grade.The graph shows that in the presence of all DHA, ARA and GPC, liver condition is significantly improved, and GPC seems to have an additional surprising effect in the presence of already beneficial DHA and ARA in lipid emulsion.

[0158]

[0160] The same histopathological examination was performed to compare the effects of choline derivatives alone, i.e., in the absence of DHA and ARA. Figure 4A summarizes the results of histopathological examination of the livers of the animal test groups. The effect of GPC was significantly better at both high (31 mmol / L) and low (15 mmol / L) GPC concentrations. CDP-choline (low concentration, 15 mmol / L) also had an effect. No grade could be assigned to the high concentration (31 mmol / L) CDP-choline group. The groups receiving choline chloride as part of the lipid emulsion (high and low concentrations) were superior to those receiving saline alone or lipid emulsion without any choline derivatives. However, the lipid emulsion supplemented with choline chloride was unable to adequately address liver damage.

[0159] [Table 4]

[0160] Example 4: Liver development relative to body weight

[0161] The test groups as described in Example 1 were further evaluated for the development of liver weight relative to body weight. A disproportionate increase in liver weight with body weight is typical of liver damage, specifically the development of steatosis as previously described. Figure 5 further shows the results for the liver-to-body weight ratio in percent for groups of animals administered saline alone, LE 10%, and the same lipid emulsion supplemented with a choline derivative at the previously described concentration ("high": 31 mmol / L). As can be seen, administration of lipid emulsion alone results in an increase in the ratio, indicating an increase in liver weight due to liver damage (steatosis). Addition of choline chloride or CDP-choline both results in a decrease in the ratio, thus improving the liver condition. However, the most significant decrease in the ratio is again achieved with GPC. Furthermore, the phosphatidylcholine contained in the lipid emulsion(s) does not appear to have any effect.

[0161] Example 5: Stability of lipid emulsions in the presence of choline derivatives

[0162] In addition to investigating the effectiveness of choline derivatives in treating liver damage, the lipid emulsions prepared as described in Example 1 were further evaluated for the stability of each lipid emulsion after sterilization (see Table VI).It was found that the stability of lipid emulsions is improved in the presence of GPC compared to choline chloride or CDP-choline.In fact, it was found that choline chloride and CDP-choline destabilize lipid emulsions during sterilization (heating).The lipid emulsions containing either choline chloride or CDP-choline caused the phase separation of lipid emulsions during sterilization.In the presence of GPC, lipid emulsions remained stable.

[0162] [Table 5]

Claims

1. (i) a carbohydrate preparation present in the first chamber; (ii) an amino acid formulation present in the second chamber; and (iii) a lipid formulation present in the third chamber. A multi-chamber container for parenteral administration comprising: the lipid formulation comprises an aqueous phase and about 5% to about 35% by weight of an oil phase, based on the total weight of the lipid formulation; the lipid formulation is in the form of an oil-in-water emulsion, the oil phase comprises docosahexaenoic acid (DHA) obtained from a single-cell source, the single-cell source being an extract of microalgae, and the DHA is present at a concentration of 0.1 g to 5.0 g per 100 g of oil phase; the lipid formulation comprises about 70 mg or less of phytosterols per 100 g of oil phase; A multi-chamber container, wherein the lipid formulation is essentially free of water-soluble forms of choline and / or arachidonic acid (ARA).

2. 2. The multi-chamber container of claim 1, wherein the DHA is present in a concentration of 0.25 g to 3.0 g per 100 g of oil phase.

3. 3. A multi-chamber container according to claim 1 or 2, wherein the DHA is present in a concentration of from 1.5 g to 2.5 g per 100 g of oil phase.

4. 4. A multi-chamber container according to claim 1, 2 or 3, wherein the DHA is present in triglyceride form or in ethyl ester form, preferably in triglyceride form.

5. 5. The multi-chamber container of claim 1, 2, 3 or 4, wherein the lipid formulation comprises eicosapentaenoic acid (EPA) and the ratio of DHA to EPA in the lipid formulation is 10:1 to 1000:1 (w / w).

6. 6. The multi-chamber container of claim 1, 2, 3, 4 or 5, wherein the lipid formulation comprises EPA, and the ratio of DHA to EPA in the lipid formulation is from 10:1 to 200:

1.

7. 7. The multi-chamber container of claim 1, 2, 3, 4, 5 or 6, wherein the lipid formulation comprises EPA, and the ratio of DHA to EPA in the lipid formulation is from 20:1 to 150:

1.

8. 8. Multi-chamber container according to claim 5, 6 or 7, wherein the DHA and / or EPA are present in triglyceride form or in ethyl ester form, preferably in triglyceride form.

9. 5. The multi-chamber container of claim 1, 2, 3 or 4, wherein the lipid formulation is essentially free of EPA.

10. 10. The multi-chamber container according to claim 1, 2, 3, 4, 5, 6, 7, 8 or 9, wherein the microalgae is Crypthecodinium cohnii or Schizochytrium spp., preferably Schizochytrium spp.

11. 11. The multi-chamber container of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, wherein the lipid formulation comprises from about 15 mg to about 35 mg of phytosterols per 100 g of oil phase, preferably up to about 25 mg of phytosterols per 100 g of oil phase.

12. 12. The multi-chamber container of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein the lipid formulation comprises one or more pharmaceutically acceptable surfactants selected from the group consisting of phospholipids, oleates, and combinations thereof.

13. 13. The multi-chamber container of claim 12, wherein the phospholipid is selected from the group consisting of egg phosphatides and soy lecithin.

14. 14. The multi-chamber container of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein the lipid formulation comprises one or more pharmaceutically acceptable isotonicity agents.

15. 15. The multi-chamber container of claim 14, wherein the pharmaceutically acceptable isotonic agent is glycerol.

16. 16. The multi-chamber container of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the lipid formulation comprises one or more pharmaceutically acceptable antioxidants selected from the group consisting of tocopherol, ascorbyl palmitate, and combinations thereof.

17. 17. The multi-chamber container of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, wherein the lipid formulation has a pH in the range of about 6 to about 9, preferably about 7 to about 8.

18. 18. The multi-chamber container of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17, wherein the carbohydrate preparation and / or the amino acid preparation comprises at least one water-soluble form of choline, preferably glycerophosphocholine, selected from the group consisting of choline chloride, choline bitartrate, choline citrate, choline gluconate, choline malate, choline cytidine diphosphate choline (CDP) salt, and glycerophosphocholine.

19. 19. The multi-chamber container of claim 18, wherein the at least one water-soluble form of choline is present at a concentration of 20 mg to 2000 mg of choline equivalents per liter of reconstituted multi-chamber container, such as at a concentration of 30 mg to 1000 mg of choline equivalents per liter of reconstituted multi-chamber container.

20. 20. A method of treating a patient in need of parenteral nutrition when oral and enteral nutrition is impossible, insufficient or contraindicated using the multi-chamber container of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19.

21. 21. The method of claim 20, wherein the patient is a pediatric patient.

22. 1. A lipid formulation for parenteral administration, comprising: an aqueous phase, and comprising about 5% to about 35% by weight of an oil phase based on the total weight of the lipid formulation; the lipid formulation is in the form of an oil-in-water emulsion, the aqueous phase comprising at least one pharmaceutically acceptable water-soluble form of choline; the oil phase comprises docosahexaenoic acid (DHA); the lipid formulation comprises about 70 mg or less of phytosterols per 100 g of oil phase; A lipid formulation, wherein the lipid formulation is essentially free of arachidonic acid (ARA).

23. 23. The lipid formulation of claim 22, wherein the DHA is obtained from a single-cell source, the single-cell source being an extract of microalgae.

24. 24. The lipid formulation of claim 23, wherein the microalgae is Crypthecodinium cohnii or Schizochytrium spp., preferably Schizochytrium spp.

25. 25. The lipid formulation of claim 22, 23, or 24, wherein the DHA is present in a concentration of 0.25 g to 3.0 g per 100 g of oil phase.

26. 26. The lipid formulation of claim 22, 23, 24, or 25, wherein DHA is present in a concentration of 1.5 g to 2.5 g per 100 g of oil phase.

27. 27. The lipid formulation of claim 22, 23, 24, 25 or 26, wherein the DHA is present in triglyceride form or ethyl ester form, preferably in triglyceride form.

28. 28. The lipid formulation of claim 22, 23, 24, 25, 26, or 27, comprising eicosapentaenoic acid (EPA), wherein the ratio of DHA to EPA in the lipid formulation is from 10:1 to 1000:1 (w / w).

29. 29. The lipid formulation of claim 22, 23, 24, 25, 26, 27, or 28, comprising EPA, wherein the ratio of DHA to EPA in the lipid formulation is from 10:1 to 200:1 (w / w).

30. 30. The lipid formulation of claim 22, 23, 24, 25, 26, 27, 28, or 29, comprising EPA, wherein the ratio of DHA to EPA in the lipid formulation is from 20:1 to 150:1 (w / w).

31. 31. The lipid formulation according to claim 28, 29 or 30, wherein the DHA and / or EPA are present in triglyceride form or ethyl ester form, preferably in triglyceride form.

32. 28. The lipid formulation of claim 22, 23, 24, 25, 26, or 27, which is essentially free of EPA.

33. 33. The lipid formulation of claim 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32, comprising 15 mg to 35 mg of phytosterols per 100 g of oil phase, preferably up to about 25 mg of phytosterols per 100 g of oil phase.

34. 34. The lipid formulation of claim 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, or 33, comprising one or more pharmaceutically acceptable surfactants selected from the group consisting of phospholipids, oleates, and combinations thereof.

35. 35. The lipid formulation of claim 34, wherein the phospholipid is selected from the group consisting of egg phosphatides and soy lecithin.

36. 36. The lipid formulation of claim 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35, comprising one or more pharmaceutically acceptable isotonicity agents.

37. 37. The lipid formulation of claim 36, wherein the pharmaceutically acceptable isotonic agent is glycerol.

38. 38. The lipid formulation of claim 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 37, comprising one or more pharmaceutically acceptable antioxidants selected from the group consisting of tocopherol, ascorbyl palmitate, and combinations thereof.

39. 39. The lipid formulation of claim 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, or 38, having a pH in the range of about 6 to about 9, preferably about 7 to about 8.

40. 40. The lipid formulation of claim 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, or 39, wherein the at least one choline is selected from the group consisting of choline chloride, choline bitartrate, choline citrate, choline gluconate, choline malate, choline cytidine diphosphate choline (CDP) salt, and glycerophosphocholine, preferably glycerophosphocholine.

41. At least one of the choline is selected from the group consisting of 0.1 g to 12 g choline equivalents per liter of lipid emulsion, e.g., 0.2 g to 10 g choline equivalents per liter of lipid emulsion, 3 g to 6 g choline equivalents per liter of lipid emulsion, 0.5 to 4 g choline equivalents per liter of lipid emulsion, 0.1 g to 0.5 g choline equivalents per liter of lipid emulsion, 0.5 g to 1 g choline equivalents per liter of lipid emulsion, 1 g to 2 g choline equivalents per liter of lipid emulsion, 2 g to 3 g choline equivalents per liter of lipid emulsion, 3 g to 4 g choline equivalents per liter of lipid emulsion, 41. The lipid formulation of claim 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, wherein the lipid formulation is present at a concentration of 4g to 5g choline equivalents per liter of lipid emulsion, 5g to 6g choline equivalents per liter of lipid emulsion, 6g to 7g choline equivalents per liter of lipid emulsion, 7g to 8g choline equivalents per liter of lipid emulsion, 8g to 9g choline equivalents per liter of lipid emulsion, 9g to 10g choline equivalents per liter of lipid emulsion, 10g to 11g choline equivalents per liter of lipid emulsion, and / or 11g to 12g choline equivalents per liter of lipid emulsion.

42. 42. The lipid formulation of claim 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or 41, wherein the at least one choline is present in a concentration of 0.2 g to 10 g choline equivalents per liter of lipid emulsion.

43. 43. The lipid formulation of claim 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42, wherein the at least one choline is present in a concentration of 3 g to 6 g choline equivalents per liter of lipid emulsion.

44. 44. A method of treating a patient in need of parenteral nutrition when oral and enteral nutrition is impossible, insufficient or contraindicated using the lipid formulation of claim 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42 or 43.

45. 45. The method of claim 44, wherein the patient is a pediatric patient.

46. (i) a carbohydrate preparation present in the first chamber; (ii) an amino acid formulation present in the second chamber; and (iii) the lipid formulation of claim 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43, which is present in a third chamber.

1. A multi-chamber container for parenteral administration comprising:

47. 1. A lipid formulation for parenteral administration, comprising: an aqueous phase, and comprising about 5% to about 35% by weight of an oil phase based on the total weight of the lipid formulation; the lipid formulation is in the form of an oil-in-water emulsion, the aqueous phase comprising at least one pharmaceutically acceptable water-soluble form of choline; the oil phase comprises docosahexaenoic acid (DHA) and arachidonic acid (ARA); the ratio of DHA to ARA in the lipid formulation is 10:1 to 1:5 (w / w); A lipid formulation comprising no more than about 70 mg of phytosterols per 100 g of oil phase.

48. 48. The lipid formulation of claim 47, wherein the ratio of DHA to ARA in the lipid formulation is 1:1 to 1:3 (w / w).

49. 49. The lipid formulation of claim 47 or 48, wherein the DHA is obtained from a single-cell source, the single-cell source being an extract of microalgae.

50. 50. The lipid formulation of claim 49, wherein the microalgae is Crypthecodinium cohnii or Schizochytrium spp., preferably Schizochytrium spp.

51. 51. The lipid formulation of claim 47, 48, 49, or 50, wherein the ARA is obtained from a single-cell source, and the single-cell source is a fungus.

52. 52. The lipid formulation of claim 51, wherein the fungus is Mortierella alpina.

53. 53. The lipid formulation of claim 47, 48, 49, 50, 51 or 52, wherein DHA and / or ARA are present in triglyceride form or ethyl ester form, preferably in triglyceride form.

54. 54. The lipid formulation of claim 47, 48, 49, 50, 51, 52, or 53, wherein ARA is present at a concentration ranging from 0.1 g to 15 g per 100 g of oil phase.

55. 55. The lipid formulation of claim 47, 48, 49, 50, 51, 52, 53, or 54, wherein ARA is present at a concentration in the range of 1.5 g to 7.5 g per 100 g of oil phase.

56. 56. The lipid formulation of claim 47, 48, 49, 50, 51, 52, 53, 54, or 55, wherein the DHA is present in a concentration of 0.25 g to 3.0 g per 100 g of oil phase.

57. 57. The lipid formulation of claim 47, 48, 49, 50, 51, 52, 53, 54, 55, or 56, wherein the DHA is present in a concentration of 1.5 g to 2.5 g per 100 g of oil phase.

58. 58. The lipid formulation of claim 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, or 57, comprising EPA, wherein the ratio of DHA to EPA in the lipid formulation is from 10:1 to 1000:1 (w / w).

59. 59. The lipid formulation of claim 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, or 58, comprising EPA, wherein the ratio of DHA to EPA in the lipid formulation is from 10:1 to 200:1 (w / w).

60. 60. The lipid formulation of claim 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59, comprising EPA, wherein the ratio of DHA to EPA in the lipid formulation is from 20:1 to 150:1 (w / w).

61. 61. The lipid formulation of claim 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60, wherein the DHA and / or EPA are present in triglyceride form or ethyl ester form, preferably in triglyceride form.

62. 58. The lipid formulation of claim 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, or 57, which is essentially free of EPA.

63. 63. The lipid formulation of claim 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, or 62, comprising 15 mg to 35 mg of phytosterols per 100 g of oil phase, preferably about 25 mg or less of phytosterols per 100 g of oil phase.

64. 64. The lipid formulation of claim 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, or 63, comprising one or more pharmaceutically acceptable surfactants selected from the group consisting of phospholipids, oleates, and combinations thereof.

65. 65. The lipid formulation of claim 64, wherein the phospholipid is selected from the group consisting of egg phosphatides and soy lecithin.

66. 66. The lipid formulation of claim 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65, comprising one or more pharmaceutically acceptable isotonicity agents.

67. 67. The lipid formulation of claim 66, wherein the pharmaceutically acceptable isotonic agent is glycerol.

68. 68. The lipid formulation of claim 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, or 67, comprising one or more pharmaceutically acceptable antioxidants selected from the group consisting of tocopherol, ascorbyl palmitate, and combinations thereof.

69. 69. The lipid formulation of claim 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, or 68, having a pH in the range of about 6 to about 9, preferably about 7 to about 8.

70. 68. The lipid formulation of claims 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, wherein at least one of the cholines is selected from the group consisting of choline chloride, choline bitartrate, choline citrate, choline gluconate, choline malate, choline cytidine diphosphate choline (CDP) salt and glycerophosphocholine, preferably glycerophosphocholine.

71. At least one of the choline is selected from the group consisting of 0.1 g to 12 g choline equivalents per liter of lipid emulsion, e.g., 0.2 g to 10 g choline equivalents per liter of lipid emulsion, 3 g to 6 g choline equivalents per liter of lipid emulsion, 0.5 to 4 g choline equivalents per liter of lipid emulsion, 0.1 g to 0.5 g choline equivalents per liter of lipid emulsion, 0.5 g to 1 g choline equivalents per liter of lipid emulsion, 1 g to 2 g choline equivalents per liter of lipid emulsion, 2 g to 3 g choline equivalents per liter of lipid emulsion, 3 g to 4 g choline equivalents per liter of lipid emulsion, 4 g to 5 g choline equivalents per liter of lipid emulsion, 71. The lipid formulation of claim 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70, wherein the lipid formulation is present at a concentration of 5g to 6g choline equivalents per liter of lipid emulsion, 6g to 7g choline equivalents per liter of lipid emulsion, 7g to 8g choline equivalents per liter of lipid emulsion, 8g to 9g choline equivalents per liter of lipid emulsion, 9g to 10g choline equivalents per liter of lipid emulsion, 10g to 11g choline equivalents per liter of lipid emulsion, and / or 11g to 12g choline equivalents per liter of lipid emulsion.

72. 72. The lipid formulation of claim 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, or 71, wherein the at least one choline is present in a concentration of 0.2 g to 10 g choline equivalents per liter of lipid emulsion.

73. 73. The lipid formulation of claim 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, or 72, wherein the at least one choline is present in a concentration of 3 g to 6 g choline equivalents per liter of lipid emulsion.

74. 74. The lipid formulation of claim 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, or 73, wherein the choline is present at a concentration of 0.5 g to 4 g choline equivalents per liter of lipid emulsion.

75. 75. A method of treating a pediatric patient in need of parenteral nutrition when oral and enteral nutrition is impossible, insufficient or contraindicated using the lipid formulation of claim 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73 or 74.

76. (i) a carbohydrate preparation present in the first chamber; (ii) an amino acid formulation present in the second chamber; and (iii) the lipid formulation of claim 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, or 74, wherein the lipid formulation is present in a third chamber.

1. A multi-chamber container for parenteral administration comprising:

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