Sunflower phospholipid composition containing phosphatidylcholine

Abstract

The present invention relates to a sunflower phospholipid composition containing phosphatidylcholine and less than 0.1 wt. %, particularly less than 0.08 wt. % or less than 0.05 wt. %, and especially less than 0.02 wt. % chlorogenic acid, based on the total weight of the sunflower phospholipid composition, and its combination with at least one anionic stabilizer compound, including at least one anionic phospholipid compound. These combinations are particularly useful as emulsifiers in aqueous oil-in-water emulsions. The present invention also relates to an aqueous oil-in-water emulsion containing such a combination of a sunflower phospholipid composition and at least one anionic stabilizer compound, including at least one anionic phospholipid compound. The present invention also relates to a method for producing such an emulsion. The present invention particularly relates to a sunflower phospholipid composition comprising phosphatidylcholine in an amount of 45% by weight or more and having a low content of chlorogenic acid of less than 0.1% by weight and at least one anionic phospholipid compound.

Description

Technical Field

[0001] The present invention relates to sunflower phospholipid compositions, namely phospholipids obtained from sunflower, and their use as emulsifiers in water-in-oil-in-water emulsions. The present invention also relates to water-in-oil-in-water emulsions containing such sunflower phospholipid compositions and methods for producing the same.

Background Art

[0002] Water-in-oil emulsions for parenteral application or administration, also called parenteral lipid emulsions, are sterile water-in-oil emulsions of physiologically acceptable oils formulated in a manner suitable for parenteral administration. For the requirements of parenteral lipid emulsions, see, for example, Driscoll, D., Lipid Injectable Emulsions: Pharmacopeial and Safety Issues, Pharmaceutical research 2006, 23, 1959 - 69. 10.1007 / s11095-006-9092-4; Driscoll, D., Journal of Parenteral and Enteral Nutrition 2017, 41, 125 - 134, Driscoll, D., Commercial Lipid Emulsions and All-in-One-Mixtures for Intravenous Infusion - Composition and Physicochemical Properties, in ”Intravenous Lipid Emulsions“ (Calder, P.C. et al. eds.), Karger Medical and Scientific Publishers 2014, pp.48 - 56 and the references cited therein; Calder P.C. et al., Intensive Care Medicine, 2010, 36(5), 735 - 749.

[0003] Physiologically acceptable oil-in-water emulsions are primarily used for parenteral nutrition. For parenteral nutrition, patients receive all necessary nutrients, such as carbohydrates, fats, vitamins, electrolytes, trace elements, and water, in injectable liquid formulations, which are administered intravenously, i.e., into the veins of patients requiring parenteral nutrition. Fats are an essential part of complete parenteral nutrition because they deliver essential fatty acids, which the body cannot synthesize on its own, to the patient's body. Parenteral nutrition without fat leads to essential fatty acid deficiency within a few days. Fats can only be administered parenterally in the form of aqueous emulsions because they do not mix with blood, likely because direct injection of fat would occlude blood vessels. For a comprehensive overview of parenteral nutrition, see, for example, M. Stawny et al., Pharmaceutical Point of View on Parenteral Nutrition, The Scientific World Journal 2013: https: / / doi.org / 10.1155 / 2013 / 415310, and the reference cited therein; Driscoll, D. loc.cit.

[0004] Apart from parenteral nutritional intake, parenteral lipid emulsions can be used for parenteral drug delivery of lipophilic drugs. For this purpose, lipophilic drugs are dissolved in the oil phase of the parenteral lipid emulsion. The formulation of drugs in parenteral lipid emulsions offers numerous advantages compared to other formulations, including reduced injection site pain and irritation, reduced thrombophlebitis, reduced drug toxicity, enhanced drug stability, and the possibility of targeted drug delivery. See, for example, Hippalgoankar K, Majumdar S, Kansara V, Injectable Lipid Emulsions - Advancements, Opportunities and Challenges, AAPS PharmSciTech 2010, 11:4, 1526-1540. Typical examples of drugs formulated in parenteral lipid emulsions include propofol, aprepitant, diazepam, etomidate, and clebidipine butyrate.

[0005] Recently, parenteral lipid emulsions have been proposed for the treatment of drug overdose or poisoning caused by lipid-soluble drugs. By intravenously injecting parenteral lipid emulsions into patients suffering from drug overdose or poisoning, lipophilic drugs are extracted into the emulsion phase of the injected lipid emulsion. See, for example, Mirtallo et al., The Annals Pharmacotherapy, 2010, 44; Rothschild et al., Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine 2010, 18, 51-58.

[0006] Oil-in-water emulsions are heterogeneous systems consisting of an oily phase uniformly dispersed or emulsified in an aqueous phase. Because they are thermodynamically unstable, emulsifiers are required to prevent the aggregation of oil droplets and thereby stabilize the emulsion. Synthetic emulsifiers such as poloxamer, macrogol-hydroxystearate, or polysorbate can be used to stabilize parenteral lipid emulsions, but phospholipids are preferred emulsifiers for this type of application due to their excellent toxicity profile. Toxicity is a very important factor in the selection of emulsifiers for parenteral lipid emulsions, as large amounts of emulsifier are administered during parenteral nutrition. For example, a person weighing 70 kg may be administered up to 21 g of phospholipids per day. Since phospholipids are natural components of human cell membranes and are metabolized like other nutritional fats, they can be administered at very high doses without reports of negative side effects. In contrast, undesirable side effects and toxicity, such as fat overload syndrome, hypersensitivity, and injection site side effects, have been reported with parenteral emulsions and other injectable drugs containing synthetic emulsifiers. Therefore, it is desirable to formulate parenteral fat emulsions that do not use synthetic emulsifiers.

[0007] Phospholipids are naturally occurring products with amphiphilic properties. The structure of a phospholipid molecule generally consists of a fatty acid diglyceride moiety, which is esterified with a phosphate group. The phosphate group can be further modified with simple organic molecules such as choline, glycerol, ethanolamine, inositol, or serine, resulting in different phospholipid compounds. Common sources of phospholipids include soybeans, rapeseed, sunflower, chicken eggs, milk, and fish roe. Each source has a unique profile of individual phospholipid compounds in terms of phospholipids, their fatty acid patterns, and consequently, different applications in food, nutrition, pharmaceuticals, cosmetics, and drug delivery.

[0008] For parenteral lipid emulsions, egg phospholipids, specifically those derived from chicken eggs, are the most common emulsifiers. In most cases, egg phospholipids with a phosphatidylcholine content of at least 70-80% are used. Phosphatidylcholine is an amphoteric compound in the pH range of 6-8, which is typically required in parenteral lipid emulsions.

[0009] Although egg phospholipids are very effective emulsifiers for lipid emulsions, they have several drawbacks, including the following: - Potential allergenicity. This is due to residual egg protein in the phospholipids. - Egg phospholipids are animal-derived products, which can raise consumer concerns, cause environmental impacts, and potentially increase the risk of infectious avian diseases.

[0010] Several attempts have been made to replace egg phospholipids in commercially available fat emulsions with plant-based phospholipids such as soybean phospholipids or rapeseed phospholipids, either alone or in combination with poloxamer-type synthetic emulsifiers. However, these products had other drawbacks and were withdrawn from the market in the meantime. [Prior art documents] [Non-patent literature]

[0011] [Non-Patent Document 1] Driscoll, D., Lipid Injectable Emulsions: Pharmacopeial and Safety Issues, Pharmaceutical research 2006,23,1959-69. 10.1007 / s11095-006-9092-4 [Non-Patent Document 2] Driscoll, D., Journal of Parenteral and Enteral Nutrition 2017,41,125-134 [Non-Patent Document 3] Driscoll, D., Commercial Lipid Emulsions and All-in-One-Mixtures for Intravenous Infusion - Composition and Physicochemical Properties, in “Intravenous Lipid Emulsions” (edited by Calder, PC et al.), Karger Medical and Scientific Publishers 2014, pp. 48-56 [Non-Patent Document 4] Calder PC et al., Intensive Care Medicine, 2010, 36(5), 735-749 [Non-Patent Document 5] M. Stawny et al., Pharmaceutical Point of View on Parenteral Nutrition, The Scientific World Journal 2013: https: / / doi.org / 10.1155 / 2013 / 415310 [Non-Patent Document 6] Driscoll, D. loc.cit [Non-Patent Document 7] Hippalgoankar K, Majumdar S, Kansara V, Injectable Lipid Emulsions - Advancements, Opportunities and Challenges, AAPS PharmSciTech 2010,11:4,1526-1540 [Non-Patent Document 8] Mirtallo et al., The Annals Pharmacotherapy,2010,44 [Non-Patent Document 9] Rothschild et al., Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine 2010,18,51-58 [Overview of the project] [Problems that the invention aims to solve]

[0012] Therefore, there is still a need for emulsifiers for parenteral lipid emulsions that are low in toxicity and provide good emulsion stability. Furthermore, these emulsifiers should be compatible with alkaline pH values ​​of pH 7 or higher, which are commonly encountered in the manufacture of parenteral lipid emulsions, especially those for parenteral nutrition, and should not cause discoloration of the emulsion. [Means for solving the problem]

[0013] It has now been found that phospholipid compositions obtained from sunflower seeds, hereinafter referred to as sunflower phospholipids containing phosphatidylcholine and sunflower phospholipid compositions, contain less than 0.1% by weight of chlorogenic acid and, when combined with one or more anionic phospholipid compounds, efficiently stabilize parenteral lipid emulsions and minimize discoloration. Thus, these combinations can be used as emulsifiers in parenteral lipid emulsions. Furthermore, they do not pose any risk of causing allergies or toxicity issues.

[0014] Accordingly, a first aspect of the present invention relates to the use of a sunflower phospholipid composition as an emulsifier in an aqueous oil-in-water emulsion for parenteral administration, abbreviated as a parenteral lipid emulsion, which contains phosphatidylcholine in combination with at least one anionic stabilizer compound including at least one anionic phospholipid compound, and contains chlorogenic acid in an amount of 0.1% by weight or less, particularly 0.08% by weight or less, or 0.05% by weight or less, and especially 0.02% by weight or less, based on the total weight of the sunflower phospholipid composition.

[0015] A combination of a sunflower composition and at least one anionic stabilizer compound containing at least one anionic phospholipid compound is useful as an emulsifier and provides particular benefits to parenteral lipid emulsions. In particular, a sunflower phospholipid composition containing a sufficient amount of phosphatidylcholine, for example 45% or more by weight, for example 45-99% by weight, particularly 50-98.5% by weight, especially 60-98% or 70-98% by weight, relative to the total weight of the sunflower phospholipid composition, and having a low chlorogenic acid content of less than 0.1% by weight, particularly 0.08% or less by weight or less, or 0.05% or less by weight or less, especially 0.02% or less by weight or less, provides a parenteral lipid emulsion in which discoloration is reduced or even not observed at all during manufacturing or storage. Because of the low chlorogenic acid content, the presence of chlorogenic acid can cause severe discoloration during manufacturing or storage if these compounds are present in parenteral lipid emulsions; therefore, the sunflower phospholipid compositions also exhibit better compatibility with compounds having amino groups, such as amino acids. These sunflower phospholipid compositions containing a sufficient amount of phosphatidylcholine are combined with one or more anionic stabilizer compounds containing at least one anionic phospholipid, and this combination imparts improved stability to aqueous oil-in-water emulsions against the aggregation of oil droplets and minimizes discoloration of the emulsion; therefore, this combination provides improved long-term storage stability for months and even years.

[0016] Therefore, a second aspect of the present invention relates to a combination of a sunflower phospholipid composition containing phosphatidylcholine in an amount of at least 45% by weight, for example 45 to 99% by weight, particularly 50 to 98.5% by weight, especially 60 to 98% by weight or 70 to 98% by weight, based on the total weight of the sunflower phospholipid composition, and having a chlorogenic acid content of less than 0.1% by weight, particularly less than or equal to 0.08% by weight or less than 0.05% by weight or less than, especially less than or equal to 0.02% by weight, based on the total weight of the sunflower phospholipid composition, and one or more anionic stabilizer compounds containing at least one anionic phospholipid.

[0017] Furthermore, the inventors have found that the above combination can be formulated as a single composition. Therefore, a third aspect of the present invention relates to a sunflower phospholipid composition containing phosphatidylcholine in an amount of at least 45% by weight, for example 45 to 98.8% by weight, particularly 50 to 98.5% by weight, especially 60 to 98% by weight or 70 to 98% by weight, based on the total weight of the sunflower phospholipid composition, and one or more anionic stabilizer compounds containing at least one anionic phospholipid, and having a chlorogenic acid content of less than 0.1% by weight, particularly less than or equal to 0.08% by weight or less than 0.05% by weight or less than, especially less than or equal to 0.02% by weight, based on the total weight of the sunflower phospholipid composition. The phospholipid composition according to the third aspect of the present invention is also hereinafter referred to as "mixture".

[0018] In a fourth aspect, the present invention relates to a method for producing the sunflower phospholipid composition according to the third aspect of the present invention.

[0019] A fifth aspect of the present invention is an oil-in-water emulsion for parenteral administration, particularly parenteral nutrition, a) an oil phase containing a triglyceride composition suitable for parenteral administration, particularly parenteral nutrition, b) A combination of a sunflower phospholipid composition containing less than 0.1% by weight, particularly less than or equal to 0.08% by weight or less, or less than or equal to 0.05% by weight or less, especially less than or equal to 0.02% by weight or less of chlorogenic acid based on the total weight of the sunflower phospholipid composition, with at least one anionic stabilizer compound containing at least one anionic phospholipid compound as defined herein or a mixture according to the third aspect of the invention as defined herein, and c) water relates to an oil-in-water emulsion in aqueous water containing the same.

[0020] The sixth aspect of the invention relates to a method for producing such an emulsion.

Embodiments for Carrying Out the Invention

[0021] Throughout this specification and the present application, technical terms have their ordinary technical meanings unless otherwise specifically stated.

[0022] The terms "sunflower phospholipid composition" and "sunflower lecithin" refer to a phospholipid composition and lecithin obtained from sunflower oil, respectively. Usually, the sunflower phospholipid composition is obtained by fractionation from sunflower lecithin, and sunflower lecithin is obtained from the dried sludge obtained in the degumming process of sunflower oil.

[0023] The term "phospholipid composition" refers to a composition of phospholipid molecules where the total amount of phospholipid molecules in the composition is generally at least 80% by weight, frequently at least 90% by weight, and the remaining portion is essentially triglyceride and / or fatty acid.

[0024] Sunflower phospholipid compositions differ from other naturally occurring phospholipid compositions due to their characteristic fatty acid composition. For information on its lecithin, see, for example, Hoogevest, P. and Wendel, A., "The use of natural and synthetic phospholipids as pharmaceutical excipients," European Journal of Lipid Science and Technology 116.9(2014):1088-1107, particularly Table 2 on page 1090, and Guiotto, E., Tomas, M., and Diehl, B. (2015) Sunflower Lecithin.10.1016 / B978-1-63067-044-3.50007-8, Chapter 3, page 59, Table 3B. In particular, sunflower phospholipid compositions differ from other naturally occurring phospholipid compositions by their high linoleic acid content (typically at least 60%, e.g., in the range of 60–75%) and low stearic acid content (typically at most 8%, e.g., in the range of 1–8%). Typically, palmitic acid content is at most 12%, e.g., in the range of 6–12%, and oleic acid content is typically in the range of 12–25%. The percentage values ​​shown here refer to the relative peak area of ​​each fatty acid in the sunflower phospholipid composition as determined by analytical HPLC. As a result, phospholipid compounds contained in such sunflower phospholipid compositions, such as phosphatidylcholine, phosphatidylethanolamine, N-acylphosphatidylethanolamine, and lysophosphatidylcholine, as well as any further phospholipid compounds and fatty acid esters contained therein, such as fatty acid triglycerides, will have a similar fatty acid composition. Separately, sunflower phospholipid compositions differ from phospholipid compositions from other sources due to the presence of characteristic residual sunflower protein, which, in contrast to residual egg protein, does not pose a risk of causing allergies.

[0025] According to the present invention, the sunflower phospholipid composition contains phosphatidylcholine, which is mainly useful for stabilizing oil-in-water emulsions, and more precisely, for stabilizing oil droplets of oil-in-water emulsions. Typically, phosphatidylcholine is the main component of the sunflower phospholipid composition. Preferably, the phosphatidylcholine content in the sunflower phospholipid composition is at least 45.0% by weight, particularly at least 50.0% by weight, especially at least 60.0% by weight or at least 70% by weight, based on the total weight of the sunflower phospholipid composition. Often, the phosphatidylcholine content does not exceed 99.0% by weight, particularly 98.5% by weight, especially 98.0% by weight, based on the total weight of the sunflower phospholipid composition.

[0026] Depending on the amount of phosphatidylcholine, the sunflower phospholipid composition may contain one or more additional phospholipid compounds different from phosphatidylcholine, particularly one or more of the following phospholipid compounds: phosphatidylethanolamine, N-acylphosphatidylethanolamine, and lysophosphatidylcholine. The total amount of phospholipid compounds different from phosphatidylcholine is typically in the range of 1.0 to 50.0% by weight, particularly 1.5 to 45.0% by weight, especially 2.0 to 40.0% by weight or 2 to 30% by weight, based on the total weight of the sunflower phospholipid composition. For example, the amount of lysophosphatidylcholine may be trace amounts to a maximum of 25.0% by weight, based on the total weight of the sunflower phospholipid composition. Similarly, the amount of phosphatidylethanolamine may be trace amounts to 25.0% by weight, often in the range of 1.0 to 20.0% by weight, based on the total weight of the sunflower phospholipid composition. Typically, the amount of N-acylphosphatidylethanolamine does not exceed 10.0% by weight based on the total weight of the sunflower phospholipid composition, and may be present in trace amounts to a maximum of 10.0% by weight. In certain embodiments of the group, the sunflower phospholipid composition contains an anionic phospholipid compound, such as phosphatidylglycerol, in an amount ranging from 0.1% to 2% by weight based on the total weight of the sunflower phospholipid composition.

[0027] Sunflower phospholipid compositions may contain lysophosphatidylcholine. For pharmacological reasons, the amount of lysophosphatidylcholine is preferably not more than 10% by weight, and particularly less than or equal to 5% by weight, for example, in the range of 0.1 to 5.0% by weight, based on the total weight of the sunflower phospholipid composition.

[0028] For the purposes of the present invention, it has been found that it is beneficial for the sunflower phospholipid composition to contain phosphatidylethanolamine in an amount particularly in the range of 1.0 to 25.0% by weight, and often in the range of 2.0 to 20.0% by weight, based on the total weight of the sunflower phospholipid composition.

[0029] Furthermore, sunflower phospholipid compositions may contain one or more fatty acid triglycerides and / or free fatty acids, which are residues from their manufacturing process. Typically, the total amount of triglycerides and free fatty acids does not exceed 10.0% by weight, based on the total weight of the sunflower phospholipid composition.

[0030] Due to the presence of free fatty acids, the sunflower phospholipid composition of the present invention may have an acid value different from 0. Hereinafter, the acid value refers to the acid value expressed in mg KOH / g. Typically, the acid value does not exceed 50, especially 40, and is often in the range of 0.01 to 35.

[0031] According to a specific embodiment of Group 1, the sunflower phospholipid composition has a phosphatidylcholine content of at least 85.0% by weight, particularly at least 90.0% by weight, for example, 85.0–99.0% by weight, particularly 90.0–98.5% by weight, based on the total weight of the sunflower phospholipid composition. In these sunflower phospholipid compositions, the total amount of phospholipid compounds other than phosphatidylcholine is generally in the range of 1.0–12.0% by weight, particularly in the range of 1.5–10.0% by weight, based on the total weight of the sunflower phospholipid composition. For example, the amount of lysophosphatidylcholine may be up to a trace amount of ~5.0% by weight, based on the total weight of the sunflower phospholipid composition. Similarly, the amount of phosphatidylethanolamine may be up to a trace amount of ~1.0% by weight, based on the total weight of the sunflower phospholipid composition. Typically, the amount of N-acylphosphatidylethanolamine does not exceed 1.0% by weight, based on the total weight of the sunflower phospholipid composition. The amounts of free fatty acids and fatty acid triglycerides are frequently less than 5% by weight, based on the total weight of the sunflower phospholipid composition. The acid value of these sunflower phospholipid compositions is typically less than 5.

[0032] According to another specific embodiment of Group 2, the sunflower phospholipid composition has a phosphatidylcholine content in the range of 45 to 85.0% by weight, particularly 50 to 85.0% by weight, based on the total weight of the sunflower phospholipid composition. In these sunflower phospholipid compositions, the total amount of phospholipid compounds other than phosphatidylcholine is typically in the range of 1.0 to 50.0% by weight, particularly 1.5 to 45.0% by weight, based on the total weight of the sunflower phospholipid composition. For example, the amount of lysophosphatidylcholine may be in the range of 1.0 to 25.0% by weight, and often in the range of 2.0 to 20.0% by weight, based on the total weight of the sunflower phospholipid composition. Similarly, the amount of phosphatidylethanolamine may be in the range of 1.0 to 25.0% by weight, and often in the range of 2.0 to 20.0% by weight, based on the total weight of the sunflower phospholipid composition. Typically, the amount of N-acylphosphatidylethanolamine does not exceed 10.0% by weight based on the total weight of the sunflower phospholipid composition, and may be present in trace amounts to a maximum of 10.0% by weight. The amounts of free fatty acids and fatty acid triglycerides are often less than 10% by weight based on the total weight of the sunflower phospholipid composition. The acid value of these sunflower phospholipid compositions is typically at most 50, and for example, in the range of 2 to 50.

[0033] Due to the presence of unsaturated fatty acids in the phospholipid compounds of sunflower phospholipid compositions, sunflower phospholipid compositions typically exhibit an iodine value of at least 80, and particularly at least 85. Often, the iodine number of sunflower phospholipid compositions does not exceed 130, and is particularly in the range of 85 to 120.

[0034] For the purposes of the present invention, the sunflower phospholipid composition is generally used such that the concentration of phosphatidylcholine in the oil-in-water emulsion is in the range of 0.1 to 20% by weight, particularly 0.2 to 5% by weight, and especially 0.3 to 3% by weight, based on the total weight of the water-in-oil emulsion. In particular, the amount of the sunflower phospholipid composition is selected such that the weight ratio of phosphatidylcholine to the oil phase in the oil-in-water emulsion is in the range of 0.5:95 to 1:3, particularly 1:99 to 1:5, and especially 2:98 to 1:8.

[0035] The sunflower phospholipid compositions according to the present invention, particularly those according to embodiments of groups 1 and 2, can be prepared in a manner similar to that used to produce phospholipids from other vegetable oils, such as soybeans or rapeseed. A summary of these methods is given in van Hoogevest, P. and Wendel, A., "The use of natural and synthetic phospholipids as pharmaceutical excipients," European journal of lipid science and technology 116.9(2014):1088-1107. Further details can be obtained from the references cited therein. For example, in order to produce a sunflower phospholipid composition having a phosphatidylcholine content of at least 70% by weight or at least 80% by weight, the sunflower lecithin fraction obtained from the degumming step of sunflower oil is de-oiled to obtain a solid lecithin product, and then this is separated into fractions having a higher phosphatidylcholine content by, for example, single-step or multi-step ethanol extraction, chromatographic purification, and a combination of ethanol extraction and chromatographic purification.

[0036] As previously noted, the inventors of the present invention have found that the significant presence of chlorogenic acid in sunflower phospholipid compositions used in parenteral lipid emulsions causes undesirable discoloration of the parenteral lipid emulsions, likely because chlorogenic acid tends to form a green pigment at pH > 6, particularly above pH 7, which is typically encountered in the production of parenteral lipid emulsions. Furthermore, parenteral lipid emulsions tend to be more unstable when the sunflower phospholipid composition used for their production contains a significant amount of chlorogenic acid. Therefore, sunflower phospholipid compositions, particularly those according to embodiments of groups 1 and 2, contain less than 0.1% by weight of chlorogenic acid based on the weight of each sunflower phospholipid composition. In particular, sunflower phospholipid compositions contain a maximum of 0.08% by weight, and especially a maximum of 0.05% by weight, of chlorogenic acid based on the total weight of the sunflower phospholipid composition.

[0037] As used herein, the term "chlorogenic acid" refers to the compound chlorogenic acid, namely (1S,3R,4R,5R)-3-[(E)-3-(3,4-dihydroxyphenyl)prop-2-enoyl]oxy-1,4,5-trihydroxycyclohexane-1-carboxylic acid, and related esters of polyphenol compounds with quinic acid (1,4,5-trihydroxycyclohexane-1-carboxylic acid), namely esters of hydroxycinnamic acid compounds such as caffeic acid, ferulic acid, and p-coumaric acid.

[0038] Therefore, the amount of chlorogenic acid given herein refers to the total amount of such chlorogenic acid compounds in the sunflower phospholipid composition.

[0039] A sunflower phospholipid composition containing less than 0.1% by weight, particularly 0.08% by weight or less, or 0.05% by weight or less, and especially 0.02% by weight or less, of chlorogenic acid, based on the total weight of the sunflower phospholipid composition, in particular, the sunflower phospholipid compositions according to embodiments of Groups 1 and 2, can be prepared by a method comprising the following steps. i) Extracting sunflower lecithin, particularly defatted sunflower lecithin, with a solvent selected from acetone and a mixture thereof with water to obtain an extract and a residue, then, ii) A step of repeatedly extracting the residue with ethanol or a mixture thereof with water to obtain an ethanol extract, iii) A step of combining the ethanol extracts, removing ethanol and any water, to obtain a sunflower phospholipid composition containing phosphatidylcholine having a chlorogenic acid content of less than 0.1% by weight, particularly up to 0.08% by weight, and especially up to 0.05% by weight, based on the total weight of the sunflower phospholipid composition.

[0040] In step i, most of the chlorogenic acid is removed from the sunflower lecithin. While de-oil-removed sunflower lecithin is preferred, unde-oil-removed sunflower lecithin may also be used in step i. In step i, the solvent is preferably an acetone / water mixture, particularly one with a weight ratio of acetone / water of 1:9 to 4:1.

[0041] The amount of phosphatidylcholine in the extract increases depending on the amount of water in the ethanol solvent used in step ii. The solvent in step ii is preferably ethanol having a water content of up to 20% by weight, and especially up to 10% by weight.

[0042] In step iii, a sunflower phospholipid composition is obtained that contains phosphatidylcholine in an amount of at least 45% by weight, particularly at least 50% by weight, for example 45-99% by weight, particularly 50-98.5% by weight, based on the total weight of the sunflower phospholipid composition.

[0043] Following step iii, further chromatographic purification may be carried out, thereby increasing the phosphatidylcholine content to, for example, at least 85% by weight or at least 90% by weight, depending on the desired grade of the sunflower phospholipid composition.

[0044] For the stability of parenteral lipid emulsions, it is preferable that the sunflower phospholipid composition be used in combination with at least one anionic stabilizer compound, which includes at least one anionic phospholipid compound. Anionic stabilizer compounds, also called "anionic stabilizers," are anionic compounds having at least one fatty acid group and negatively charged in water at a pH of 6 at a concentration of 1% by weight. The use of anionic stabilizer compounds imparts a negative charge to the oil droplets of the parenteral lipid emulsion, thereby facilitating emulsification and stabilizing the emulsion through repulsive electrostatic forces. The use of these anionic stabilizer compounds generates a negative zeta potential on the oil droplets. In this respect, anionic phospholipids have been found to be particularly beneficial. Anionic phospholipids may be the sole anionic stabilizer compound; however, they can be combined with one or more additional anionic stabilizers or anionic stabilizer compounds, each distinct from the anionic phospholipid.

[0045] Examples of anionic stabilizer compounds other than anionic phospholipids include fatty acids.

[0046] Anionic stabilizer compounds may be used in their acidic forms or in the form of their pharmaceutically acceptable salts, for example, in the form of their ammonium salts or sodium salts.

[0047] Suitable fatty acids as further anionic stabilizer compounds are saturated and unsaturated aliphatic monocarboxylic acids having 6 to 22 carbon atoms, such as caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidonic acid, behenic acid, lignoceric acid, cerotic acid, myristoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, alpha-linolenic acid, eicosapentaenoic acid, and erucic acid, as well as mixtures thereof. Aliphatic monocarboxylic acids can be used in their acidic forms or in the form of their pharmaceutically acceptable salts, particularly in the form of sodium salts.

[0048] According to the present invention, the anionic stabilizer compound comprises at least one anionic phospholipid compound. These anionic phospholipid compounds may be the sole anionic stabilizer compound, or they may be used in combination with fatty acids. Examples of anionic phospholipid compounds include phosphatidylglycerol, phosphatidylinositol, PEGylated phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, 1,3-bis(sn-3'-phosphatidyl)-sn-glycerol, also known as cardiolipin, or combinations thereof. As previously stated, the anionic phospholipid compound may be used in its acidic form or in the form of its pharmaceutically acceptable salt, particularly in the form of its sodium or ammonium salt.

[0049] PEGylated phosphatidylethanolamines are compounds based on phosphatidylethanolamine and have a polyethylene oxide (PEG) group in which the amino group of a 2-aminoethoxy group is bonded to a nitrogen atom via a carbonyl group. Such PEG groups generally have a number-average molecular weight in the range of 200 to 10,000. These compounds typically have the following formula:

[0050] [ka] In the formula, C(O)-R 1 and C(O)-R 2 R is a fatty acid residue that typically has 10 to 20 carbon atoms and is saturated or unsaturated, such as stearoyl, palmitrail, myristoyl, or oleoyl and combinations thereof. 3 is hydrogen or an alkyl group such as methyl, X is a physiologically acceptable cation such as sodium or ammonium, and n is the number of oxyethylene repeating units, for example, in the range of 4 to 250, corresponding to PEG groups with a number average molecular weight in the range of 200 to 10000.

[0051] Anionic phospholipid compounds are usually obtained from natural sources, particularly sunflower oil. However, synthetic analogs of these anionic phospholipid compounds are equally suitable. Synthetic phospholipid analogs may contain one or two of the above fatty acids in the form of a diacylglyceryl group.

[0052] Anionic phospholipid compounds may be the sole anionic stabilizer. However, it is also possible to use an anionic stabilizer that is a combination of an anionic phospholipid compound and at least one further anionic stabilizer compound that is not an anionic phospholipid compound, particularly a fatty acid or fatty acid salt. In such combinations, the weight ratio of the anionic phospholipid compound(s) to the further anionic stabilizer compound is in the range of 10:1 to 1:10, particularly 8:1 to 1:3.

[0053] In combinations of sunflower phospholipid compositions and one or more anionic stabilizer compounds, the weight ratio of the sunflower phospholipid composition to the total amount of anionic stabilizer is generally in the range of 99.8:0.2 to 80.0:20.0, often in the range of 99.8:0.2 to 90.0:10.0, particularly in the range of 99.5:0.5 to 91.0:9.0, preferably in the range of 99.0:1.0 to 92.0:8.0, and particularly in the range of 98.5:1.5 to 93.0:7.0. In the combination of the present invention, the weight ratio of the sunflower phospholipid composition to the anionic phospholipid is generally in the range of 99.8:0.2 to 80.0:20.0, often in the range of 99.8:0.2 to 90.0:10.0, particularly in the range of 99.5:0.5 to 91.0:9.0, preferably in the range of 99.0:1.0 to 92.0:8.0, and particularly in the range of 98.5:1.5 to 93.0:7.0. In the combination of the present invention, the weight ratio of phosphatidylcholine to anionic phospholipid is generally in the range of 99.8:0.2 to 70.0:30.0, often in the range of 99.8:0.2 to 85.0:15.0, particularly in the range of 99.5:0.5 to 90.0:10.0, especially in the range of 99.0:1.0 to 90.0:10.0, and particularly in the range of 98.5:1.5 to 91.0:9.0.

[0054] A particularly preferred anionic stabilizer compound is phosphatidylglycerol. Suitable phosphatidylglycerols can be obtained from animal sources or, preferably, plant sources, such as phosphatidylglycerols from eggs, sunflower oil, soybean oil, rapeseed oil, canola oil, palm oil, or oat oil. Similarly, suitable or even more preferred are synthetic or semi-synthetic phosphatidylglycerols such as 1,2-dipalmitoyl-sn-glycero-3-phosphorylglycerol (DPPG), 1,2-dimyristoyl-sn-glycero-3-phosphorylglycerol (DMPG), 1,2-distearoyl-sn-glycero-3-phosphorylglycerol (DSPG), 1,2-distearoyl-sn-glycero-3-phosphorylglycerol (DOPG), and 1,2-palmitoyl / oleyl-sn-glycero-3-phosphorylglycerol (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphorylglycerol, 1-oleoyl-2-palmitoyl-sn-glycero-3-phosphorylglycerol and mixtures thereof, POPG). Phosphatidylglycerol is particularly phosphatidylglycerol obtained from sunflower, especially 1,2-dimiristoyl-sn-glycero-3-phosphorylglycerol (also known as DMPG), or its pharmaceutically acceptable salts, particularly its sodium salts. DMPG or DMPG prepared from glycerylphosphorylcholine obtained from sunflower phospholipids is particularly preferred. Similarly, phosphatidylglycerol obtained from sunflower phosphatidylcholine by conversion using phospholipase D, or its pharmaceutically acceptable salts, are also suitable. When a sunflower phospholipid composition is used in combination with phosphatidylglycerol, particularly 1,2-dimiristoyl-sn-glycero-3-phosphorylglycerol, or a pharmaceutically acceptable salt thereof, the weight ratio of the sunflower phospholipid composition to phosphatidylglycerol, calculated as its acid form, is generally in the range of 99.8:0.2 to 80.0:20.0, often in the range of 99.8:0.2 to 90.0:10.0, particularly in the range of 99.5:0.5 to 91.0:9.0, preferably in the range of 99.0:1.0 to 92.0:8.0, and particularly in the range of 98.5:1.5 to 93.0:7.0.

[0055] For the stability of parenteral lipid emulsions and the reproducibility of emulsification and homogenization methods, it is preferable to use a combination of sunflower phospholipid composition and anionic stabilizer compound as a pre-formed mixture of sunflower phospholipid composition and anionic stabilizer compound. Without being bound by theory, the improved reproducibility of the emulsification / homogenization method is thought to be based on the following phenomenon: Since phosphatidylcholine and anionic stabilizers, especially anionic phospholipid compounds, spontaneously form liposomes when dispersed in water, the separate addition of phosphatidylcholine and anionic stabilizers to the aqueous phase will likely form stable liposomes of different compositions with respect to the relative amounts of phosphatidylcholine and anionic stabilizer molecules contained therein. Because the exchange of phospholipid molecules between these liposomes is slow, the distribution of different phospholipid molecules at the water / oil interface is heterogeneous, which can lead to emulsion instability and worsen the reproducibility of the emulsification / homogenization process. By using a pre-formed mixture of phosphatidylcholine and anionic stabilizer compounds, the formation of liposomes with different compositions can be significantly reduced or almost completely avoided. As a result, a more uniform distribution of different phospholipid molecules at the water / oil interface is obtained, improving the reproducibility of the emulsification / homogenization process.

[0056] These mixtures contain phosphatidylcholine in addition to at least one anionic stabilizer compound. In these mixtures, the anionic stabilizer compound comprises at least one anionic phospholipid compound, particularly selected from the group consisting of phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidic acid, 1,3-bis(sn-3'-phosphatidyl)-sn-glycerol and combinations thereof. In these mixtures, the anionic stabilizer compound may exist in its free acid form or in the form of its pharmaceutically acceptable salt. In these mixtures, the anionic stabilizer compound is more preferably phosphatidylglycerol, particularly phosphatidylglycerol obtained from sunflower, especially DMPG, or a pharmaceutically acceptable salt thereof, particularly its sodium salt. In these mixtures, the weight ratio of phosphatidylcholine to the total amount of anionic stabilizer is generally in the range of 99.8:0.2 to 70.0:30.0, often in the range of 99.8:0.2 to 85.0:15.0, particularly in the range of 99.5:0.5 to 90.0:10.0, preferably in the range of 99.0:1.0 to 90.0:10.0, and particularly in the range of 98.5:1.5 to 91.0:9.0.

[0057] The aforementioned mixture of a sunflower phospholipid composition and at least one anionic stabilizing compound containing at least one anionic phospholipid compound corresponds to a sunflower phospholipid composition of the third aspect of the present invention if the amount of phosphatidylcholine contained therein is at least 45% by weight, particularly at least 50.0% by weight, and especially at least 55.0% by weight, based on the total weight of the mixture, for example, 45 to 98.8% by weight, particularly 50 to 98.0% by weight, and especially 55 to 97.0% by weight, based on the total weight of the sunflower phospholipid composition. Depending on the amount of phosphatidylcholine, the sunflower phospholipid composition of the third aspect of the present invention may contain one or more further phospholipid compounds different from phosphatidylcholine and the anionic phospholipid compound, in particular one or more of the following phospholipid compounds, namely phosphatidylethanolamine, N-acylphosphatidylethanolamine, and lysophosphatidylcholine. The total amount of phospholipid compounds other than phosphatidylcholine and anionic phospholipid compounds is typically in the range of 1.0 to 50.0% by weight, particularly 1.5 to 45.0% by weight, and especially 2.0 to 40.0% by weight, based on the total weight of the sunflower phospholipid composition. For example, the amount of lysophosphatidylcholine may be trace amounts to a maximum of 25.0% by weight, based on the total weight of the sunflower phospholipid composition. Similarly, the amount of phosphatidylethanolamine may be trace amounts to a maximum of 25.0% by weight, and often in the range of 1.0 to 20.0% by weight, based on the total weight of the sunflower phospholipid composition. Typically, the amount of N-acylphosphatidylethanolamine does not exceed 10.0% by weight, and may be present in trace amounts to a maximum of 10.0% by weight, based on the total weight of the sunflower phospholipid composition.

[0058] These mixtures, particularly sunflower phospholipid compositions and mixtures containing at least one anionic stabilizer compound including at least one anionic phospholipid compound, and especially sunflower phospholipid compositions of the third aspect of the present invention, can be obtained by concentrating sunflower lecithin from a sunflower lecithin source with respect to phosphatidylcholine, in particular to a phosphatidylcholine level of 80% by weight or less, particularly in the range of 45-75% by weight, based on the weight of the sunflower phospholipid composition. They can also be prepared by supplementing conventional sunflower phospholipid compositions containing phosphatidylcholine by conventional mixing techniques. In particular, these mixtures, particularly sunflower phospholipid compositions of the third aspect of the present invention, can be prepared by a method comprising dissolving a sunflower phospholipid composition containing phosphatidylcholine and at least one anionic stabilizer, particularly an anionic phospholipid compound, in an organic solvent and evaporating the solvent. Typical solvents are organic solvents and mixtures thereof, and the sunflower phospholipid composition containing the components, namely phosphatidylcholine and anionic phospholipid compounds, is completely soluble in the required amount. Suitable solvents include methanol or ethanol. C1 Examples include C4 alkanols and mixtures thereof with water. Halogenated hydrocarbons such as dichloromethane and trichloromethane, as well as mixtures thereof with the aforementioned solvents, can also be used, but are less preferred for toxicological and environmental reasons.

[0059] The sunflower phospholipid compositions described herein, particularly the sunflower phospholipid compositions according to embodiments of groups 1 and 2, and the preferred sunflower phospholipid compositions of the present invention and the sunflower phospholipid compositions of the second and third embodiments may contain pharmaceutically acceptable antioxidants, particularly lipophilic antioxidants, such as tocopherols, such as alpha-tocopherol, alpha-tocopherol acetate, delta-tocopherol, gamma-tocopherol, vitamin E, and ascorbyl palmitate, which may be synthetic or from natural sources, such as animal sources or preferably plant sources.

[0060] The sunflower phospholipid compositions described herein, particularly the sunflower phospholipid compositions according to embodiments of groups 1 and 2, as well as preferred sunflower phospholipid compositions and sunflower phospholipid compositions according to the second and third embodiments of the present invention, meet pharmacopoeial standards, particularly with respect to endotoxin and microbial content.

[0061] The sunflower phospholipid compositions described herein, particularly the sunflower phospholipid compositions according to embodiments of groups 1 and 2, as well as preferred sunflower phospholipid compositions and sunflower phospholipid compositions of the second and third embodiments of the present invention, are particularly suitable as emulsifiers in parenteral lipid emulsions. The pre-formed mixture of the third embodiment of the present invention can be used on its own or in combination with one or more further anionic stabilizer compounds.

[0062] These are particularly suitable as emulsifiers for aqueous oil-in-water emulsions for parenteral nutrition. However, they can also be used as emulsifiers in parenteral fatty emulsions of lipophilic drugs.

[0063] These aqueous oil-in-water emulsions for parenteral administration, particularly parenteral nutrition, include the following: a) An oil phase containing a triglyceride composition suitable for parenteral administration, particularly parenteral nutrition. b) Sunflower phospholipid compositions containing chlorogenic acid in combination with at least one anionic stabilizer comprising at least one anionic phospholipid compound and optionally further anionic stabilizers, particularly in combination with a sunflower phospholipid composition according to one embodiment of group 1 or 2 or a sunflower phospholipid composition according to aspect 3 of the present invention, based on the total weight of the sunflower phospholipid composition as defined herein, in an amount of less than 0.1% by weight, particularly 0.08% by weight or less or 0.05% by weight or less, and especially 0.02% by weight or less, and c) water

[0064] The type of oil phase depends, in known terms, on the intended purpose of the aqueous oil-in-water emulsion. In the case of an oil-in-water emulsion for parenteral nutrition, the oil phase consists of a triglyceride composition that is essentially suitable for parenteral administration. In relation to a triglyceride composition suitable for parenteral administration, the term "consists of" is understood to mean that the oil phase contains at least 95% of its weight, and in particular at least 99% of its weight, of the triglyceride composition.

[0065] Suitable triglyceride compositions for parenteral administration, particularly for parenteral nutrition, include oils and fats, especially those of plant origin and marine organisms, including, but not limited to, soybean oil, safflower oil, sunflower oil, coconut oil, olive oil, medium-chain triglycerides (MCTs), long-chain triglycerides (LCTs), fish oil, krill oil, algal oils, and mixtures of these oils, such as soybean oil / olive oil mixtures, soybean oil / safflower oil mixtures, soybean oil / MCT mixtures, interester mixtures of LCTs and MCTs, and soybean oil / MCT / olive oil / fish oil mixtures. The aforementioned oils consist mainly of triglycerides, but may of course contain small amounts of fatty acids. Typically, oils and fats consist of at least 99% by weight of fatty acid triglycerides and optionally free fatty acids.

[0066] The term "fish oil" refers to both "refined fish oil" and "refined fish oil rich in omega-3 fatty acids," the latter of which, according to European Pharmacopoeia 6.0, contains at least 9% (w / w) of omega-3 fatty acid docosahexaenoic acid (DHA) and at least 13% (w / w) of omega-3 fatty acid isosapentaenoic acid (EPA), expressed as triglycerides.

[0067] For parenteral nutrition, it is preferable that triglycerides and free fatty acids contain a large amount of polyunsaturated fatty acids, including omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (both of which are commonly found in marine fish oils) and alpha-linolenic acid (ALA), which is commonly found in vegetable oils.

[0068] When an oil-in-water emulsion is intended for parenteral administration of a drug, the oil phase typically contains the drug, which is dissolved or dispersed in the oil phase. In particular, the drug is lipophilic. Drugs suitable for parenteral administration may be from the group of anesthetics, analgesics, vasodilators, immunosuppressants, anxiolytics, antiemetics, and antibiotics / antifungals and cell proliferation inhibitors. These include, but are not limited to, propofol, aprepitant, clebidipine butyrate, alprostadil, dexamethasone palmitate, diazepam, amphotericin B, etomidate, flurbiprofen axetil, prostaglandin E1 and cyclosporine, progesterone, lomustine, physostigmine salicylate and perilaketone (1-(3-furanyl)-4-methyl-1-pentanone).

[0069] In an oil-in-water emulsion for parenteral administration, the amount of the oil phase is typically in the range of 5 to 35% by weight, particularly 8 to 30% by weight, more specifically 8 to 25% by weight, particularly 8 to 17% by weight, or 8 to 12% by weight, or 15 to 22% by weight, or 18 to 22% by weight, relative to the total weight of the aqueous oil-in-water emulsion.

[0070] Oil-in-water emulsions for parental administration also contain sunflower phospholipid compositions as defined herein, particularly sunflower phospholipid compositions according to one embodiment of group 1 or 2, and especially sunflower phospholipid compositions according to one embodiment of the present invention of 2 or 3.

[0071] The amount of sunflower phospholipid composition is generally selected such that the concentration of phosphatidylcholine in the oil-in-oil emulsion is in the range of 0.1 to 10% by weight, particularly 0.2 to 5% by weight, and especially 0.3 to 3% by weight, based on the total weight of the water-in-oil emulsion. In particular, the amount of sunflower phospholipid composition is selected such that the weight ratio of phosphatidylcholine to the oil phase in the oil-in-water emulsion is in the range of 0.5:95 to 1:3, particularly 1:99 to 1:5, and especially 2:98 to 1:8.

[0072] As noted above, the inclusion of at least one anionic stabilizer compound in addition to phosphatidylcholine in the sunflower phospholipid composition is beneficial for the stability of the oil-in-water emulsion. According to the present invention, the anionic stabilizer compound comprises or is at least one anionic phospholipid compound selected from the group consisting of at least one anionic phospholipid compound, particularly phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidic acid, 1,3-bis(sn-3'-phosphatidyl)-sn-glycerol and combinations thereof. In the emulsion, the anionic stabilizer compound may exist in the form of its free acid or in the form of its pharmaceutically acceptable salt. In these emulsions, the anionic stabilizer compound is phosphatidylglycerol, particularly phosphatidylglycerol obtained from sunflower, particularly DMPG, or a pharmaceutically acceptable salt thereof, particularly its sodium salt, or more preferably contains the same. In these emulsions, the weight ratio of phosphatidylcholine to the total amount of anionic stabilizers is generally in the range of 99.8:0.2 to 70:30, often in the range of 99.8:0.2 to 85.0:15.0, particularly in the range of 99.5:0.5 to 90.0:10.0, especially in the range of 99.0:1.0 to 90.0:10.0, and particularly in the range of 98.5:1.5 to 91.0:9.0. The concentration of anionic phospholipids in the emulsion is typically in the range of 0.005 to 0.2% by weight, particularly in the range of 0.01 to 0.15% by weight, based on the total weight of the emulsion. The total concentration of anionic stabilizer compounds in the emulsion is typically in the range of 0.005 to 0.25% by weight, particularly in the range of 0.01 to 0.2% by weight, based on the total weight of the emulsion.

[0073] As noted above, for the visual appearance of the oil-in-water emulsion of the present invention, particularly for the reduction or avoidance of discoloration, and for stability, it is beneficial if the oil-in-water emulsion contains little to no chlorogenic acid. Therefore, the sunflower phospholipid composition contained in the emulsion has a chlorogenic acid content of less than 0.1% by weight, particularly at a maximum of 0.08% by weight, and especially at a maximum of 0.05% by weight, based on the total weight of the sunflower phospholipid composition. Typically, the total amount of chlorogenic acid in the emulsion does not exceed 0.001% by weight, particularly at a maximum of 0.0005% by weight, and especially at a maximum of 0.0002% by weight, based on the total weight of the emulsion.

[0074] Apart from the compounds described above, the oil-in-water emulsion of the present invention may contain at least one pharmaceutically acceptable antioxidant. The antioxidant useful in the emulsion of this disclosure may be any pharmaceutically acceptable compound having antioxidant activity, for example, sodium metasulfite, sodium bisulfite, sodium sulfite, sodium thiosulfate, thioglycerol, thiosorbitol, thioglycolic acid, cysteine ​​hydrochloride, n-acetylcysteine, citric acid, alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol, tocotrienol, soluble vitamin E, butylated hydroxyanisole (BHA), butyric acid, etc. The following may be selected from the group consisting of hydroxytoluene (BHT), t-butylhydroquinone (TBHQ), monothioglycerol, propyl gallate, histidine, enzymes such as superoxide dismutase, catalase, selenium glutathione peroxidase, phospholipid hydroperoxides and glutathione peroxidase, coenzyme Q10, carotenoids, quinones, bioflavonoids, polyphenols, bilirubin, ascorbic acid, isoascorbic acid, uric acid, metal-binding proteins, ascorbic acid palmitate, and mixtures thereof.

[0075] At least one antioxidant is selected from the group consisting of alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol, tocotrienol, ascorbic acid, and mixtures of two or more thereof. Preferably, the antioxidant is alpha-tocopherol.

[0076] If present, the total amount of the antioxidant-active agent is preferably in the range of 1 to 200 mg / L, preferably 10 to 200 mg / L, more preferably 40 to 150 mg / L, and even more preferably 50 to 120 mg / L or 75 to 100 mg / L.

[0077] The emulsion may contain one or more pharmaceutically acceptable isotonic agents. The isotonic agent is used to impart isotonicity to the emulsion. Suitable isotonic agents may be selected from the group consisting of sodium chloride, mannitol, lactose, dextrose, sorbitol, and glycerol. Preferably, the isotonic agent is glycerol.

[0078] The amount of isotonic agent depends in a known way on the desired osmotic pressure and the molecular weight of the isotonic agent. Typically, the total amount of isotonic agent is in the range of 0.1 to 10% by weight, more preferably 1 to 5% by weight, more preferably 1 to 4% by weight, more preferably 1 to 3.5% by weight, and particularly 1.5 to 3.0% by weight, based on the total weight of the emulsion. When the isotonic agent is glycerol, the most preferred amount is 2.0 to 3.0% by weight, based on the total weight of the emulsion.

[0079] Preferably, the emulsion has an osmotic pressure in the range of 180-300 mOsmol / L, particularly 190-280 mOsmol / L, and especially 200-250 mOsmol / L.

[0080] The aqueous oil-in-water emulsion of the present invention can have a pH value in the range of pH 4 to pH 10 when measured at 20°C and 1 bar. Preferably, the pH of the emulsion is in the range of pH 6 to pH 9, for example, pH 6.1 to pH 8.9, or pH 6.2 to 8.8, or pH 6.3 to pH 8.7, or pH 6.4 to pH 8.6, or pH 6.5 to pH 8.5, or pH 6.6 to pH 8.4, or pH 6.7 to pH 8.3, or pH 6.8 to pH 8.2, or pH 6.9 to pH 8.1, or pH 7 to pH 8, or pH 7.1 to pH 7.9, or pH 7.2 to pH 7.8, or pH 7.3 to pH 7.7, or pH 7.4 to pH 7.6, for example, pH 7, about pH 7.5, and / or about pH 8.

[0081] The pH of the lipid emulsion can be adjusted by adding a conventionally known acid or base solution such as HCl and NaOH, or, less preferably, by using a buffer such as phosphate buffer. Preferably, the pH of the emulsion according to this disclosure is adjusted using a NaOH solution.

[0082] In the parenteral lipid emulsion of the present invention, the continuous phase is aqueous, and the dispersed phase is formed by droplets of the oil phase (hereinafter also referred to as oil droplets). These oil droplets are stabilized in the aqueous phase by the sunflower phospholipid compositions described herein, particularly by the phosphatidylcholine contained therein, and optionally by further anionic stabilizers. The size of the oil droplets depends on the qualitative and quantitative composition of the emulsion and its preparation. The oil droplets of the emulsions herein preferably have an average diameter of less than 500 nm, for example, in the range of 130 to 450 nm, preferably in the range of 150 to 400 nm, and particularly in the range of 180 to 350 nm. The average diameter given herein refers to the volume or mass moment average, also called the De Broucker mean, determined by dynamic light scattering of a diluted aqueous emulsion at 20°C according to ISO 13320:2009. The aqueous oil-in-water emulsion of the present invention typically contains 0.05% or less USP <729> It has a PFAT5 value, which means that the volume-weighted percentage of oil droplets / fat globules with a diameter greater than 5 μm does not exceed 0.05% by weight.

[0083] Depending on the desired purpose, the parenteral lipid emulsion according to the present invention may include one or more further additives present in the aqueous phase. For example, a parenteral lipid emulsion for parenteral nutrition may include amino acids, including essential amino acids such as histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine, and mineral salts, or one additive selected from pharmaceutically acceptable ammonium compounds such as carnitine or choline and their pharmaceutically acceptable salts or derivatives.

[0084] For example, a parenteral fat emulsion for parenteral nutrition may further contain L-carnitine or a salt or derivative thereof, and / or choline or a salt or derivative thereof. Preferably, L-carnitine is provided in a free form. Preferably, the parenteral fat emulsion according to this disclosure contains L-carnitine at a concentration of 500 to 1500 mg / L, preferably 600 to 1000 mg / L, based on the total volume of the emulsion.

[0085] For example, parenteral fat emulsions for parenteral nutrition may further contain choline. Preferably, choline is provided in the form of cytidine 5'-diphosphocholine sodium, choline chloride, or alpha-glycerylphosphorylcholine (GPC). GPC may be of any origin, but is preferably derived from sunflower. Preferably, parenteral fat emulsions may contain choline at a concentration of 1 to 2 g / L, preferably 1.1 to 1.7 g / L, based on the total volume of the emulsion.

[0086] For example, parenteral fat emulsions for parenteral nutrition may contain both lucarnitine or its salts or derivatives, and choline or its salts or derivatives.

[0087] The parenteral lipid emulsion of the present invention can be prepared in a manner similar to generally known methods, as described in the references cited in the above background, for example, Hippalgaonkar et al., AAPS Pharm Sci Tech 2010, 11(4), 1526-1540) and the references cited therein.

[0088] Generally, the oil phase is emulsified in the aqueous phase in the presence of a phospholipid composition and an optional anionic stabilizer compound. Emulsification is typically carried out in two steps, including a first pre-emulsification step, which yields a coarse emulsion, which is then subjected to a homogenization step to reduce the droplet size of the oil droplets in the coarse emulsion to a droplet size suitable for parenteral administration. Therefore, the preparation method includes the following steps: i. Steps to provide an aqueous phase and an oil phase, ii. A step of emulsifying the oil phase in the aqueous phase, - A sunflower phospholipid composition containing chlorogenic acid in an amount of less than 0.1% by weight, particularly 0.08% by weight or less, or 0.05% by weight or less, especially 0.02% by weight or less, based on the total weight of the sunflower phospholipid composition as defined herein, and in the presence of at least one anionic stabilizer comprising at least one anionic phospholipid compound as defined herein, and optionally further anionic stabilizer compounds, or - A step of emulsifying in the presence of a sunflower phospholipid composition according to a third aspect of the present invention, iii. A step to homogenize the emulsion obtained in step ii into droplets of a size suitable for parenteral administration.

[0089] Of course, the sunflower phospholipid composition used in step ii. has a chlorogenic acid content of less than 0.1% by weight, particularly 0.08% by weight or less, or 0.05% by weight or less, and especially 0.02% by weight or less, based on the total weight of the sunflower phospholipid composition.

[0090] Typically, water-soluble components are dissolved in the aqueous phase, and oil-soluble components, including formulation raw materials, are dissolved in the triglyceride composition of the oil phase. For example, choline sources, amino acids, or carnitine sources, if present, are dissolved in the aqueous phase. The sunflower phospholipid composition can be dissolved in the oil phase or dispersed in the aqueous phase. Similarly, anionic stabilizers can be dispersed in the oil phase or the aqueous phase. In the preferred group of embodiments, the sunflower phospholipid composition and any anionic stabilizers are dispersed in the aqueous phase before the emulsification step.

[0091] For the stability of the resulting emulsion and for the reproducibility of the method, it is beneficial if the combination is used as a pre-formed mixture as described above. Next, the pre-formed mixture is dispersed in the aqueous phase or dissolved in the oil phase. However, it is possible to disperse / dissolve the sunflower phospholipid composition and the anionic stabilizer separately in either the oil phase or the aqueous phase.

[0092] Before carrying out step ii, both phases may be appropriately heated and optionally stirred to disperse or dissolve the components. The heating temperature is typically in the range of 30 to 80°C.

[0093] In step ii, the oil phase is generally introduced into the aqueous phase and stirred, for example, by using a high-shear mixer, to form a homogeneously dispersed coarse or pre-emulsification. Pre-emulsifications with droplet sizes of less than 20 μm generally produce a unimodal and physically stable fine emulsion. Preferably, step ii is carried out at a high temperature, for example, in the range of 40 to 80°C. Preferably, the oil phase and aqueous phase are preheated to a desired temperature, preferably in the range of 40 to 80°C, and the heated oil phase and heated aqueous phase are then mixed for emulsification.

[0094] Next, the pre-emulsion is homogenized, for example, using a microfluidizer or high-pressure homogenizer, to further reduce the droplet size and form a fine emulsion with a particle size suitable for parenteral administration.

[0095] The pressure, operating temperature, and number of homogenization cycles required to carry out step iii of the method can be determined by routines based on the examples disclosed herein. Similarly, other parameters such as the type, composition, and concentration of the oil and aqueous phases may affect the average droplet size during homogenization, and therefore these parameters are adjusted appropriately by known methods. When pressure homogenization is used in step iii, the pressure can vary over a wide range. Generally, the pressure is in the range of 100 to 1300 bar, particularly 200 to 1200 bar, especially 300 to 110 bar, or 400 to 1000 bar.

[0096] Preferably, step iii is carried out at a high temperature, for example, in the range of 30 to 80°C.

[0097] If necessary, the pH of the homogenized parenteral lipid emulsion obtained in step iii can be adjusted to the desired value above. However, it is also possible to adjust the pH before performing step ii or between steps ii and iii. It is also possible to adjust the pH between steps ii and iii and after step iii. It has been found to be beneficial to adjust the pH to at least pH 6, especially at least pH 7, for example, pH 7-9, before step ii and / or before step iii, respectively, in order to facilitate emulsification and homogenization. It should also be noted that the pH of the emulsion may decrease during emulsification, homogenization, or sterilization, so it is also possible to adjust the pH to be slightly higher than the desired pH of the final emulsion.

[0098] Whenever possible, especially when the excipients and specific components of the lipid emulsion are sensitive to oxidation, the entire process (filtration / preparation of coarse and fine emulsions) should be carried out under a nitrogen atmosphere.

[0099] The homogenized parenteral lipid emulsion obtained in step iii is usually subjected to a sterilization step. Sterilization can be carried out by methods known in the art, such as heating or sterile filtration.

[0100] Sterilization of parenteral lipid emulsions is preferably performed by final heat sterilization, also known as autoclaving. Heat sterilization generally provides better assurance of the sterility of the final product. Surprisingly, autoclaving has also been found to provide improved stability of parenteral lipid emulsions against phase separation or droplet growth. However, if the emulsion components are heat-unstable, sterile filtration can be used. Sterilization by filtration requires that the emulsion droplet size be less than 200 nm.

[0101] Alternatively, aseptic processing may be employed. However, this method is relatively equipment- and labor-intensive and requires additional data validation and justification for the method when submitting to regulatory authorities.

[0102] In a very preferred group of embodiments, the method for preparing a parenteral lipid emulsion according to the present invention includes the following steps: a. A step of separately heating the oil phase and the aqueous phase to a temperature of approximately 40 to approximately 80°C while stirring. b. A step of dispersing the sunflower phospholipid composition in the aqueous phase with or without the use of a stabilizer. c. A step of preparing a preemulsion by transferring the oil phase to the aqueous phase while stirring. d. A process of homogenizing the preemulsion under pressure at a temperature of approximately 40°C to 80°C. e. The step of adding water as needed to adjust the required volume and concentration. f. A step of adjusting the pH to a range of approximately 4 to 10, particularly to a range of 6 to 9 or 7 to 9, and g. A step of optionally sterilizing the lipid emulsion by autoclaving and sterile filtration.

[0103] Typically, to avoid oxidation reactions, at least steps a to d, and optionally steps e, f, and g, are carried out in the presence of an inert gas such as N2. Those skilled in the art will readily recognize that steps b, c, d, and g are carried out in this order, and that step f can be carried out at any stage of the method, but can be carried out after step a and before step g. Step a can be carried out before step b, or in parallel with step b, but in any case it can be carried out before step c. Step f can be carried out between steps c and d and / or after steps d or e, or between steps b and c and / or after steps d or e.

[0104] Next, the parenteral lipid emulsion of the present invention obtained in steps iii., d., e., f., or g. is packaged in a suitable container. Plastic containers that allow oxygen to pass through or contain oil-soluble plasticizers are generally avoided.

[0105] For example, the parenteral lipid emulsion of the present invention is packaged in a glass bottle having a suitable rubber stopper and an aluminum closure or piggyback, and satisfies pharmaceutical requirements.

[0106] The parenteral fat emulsion of the present invention may also be packaged in one of the chambers of 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. A container such as a bag may contain not only at least two chambers, but also three, four, or five chambers, and in one preferred embodiment, it may contain two or three chambers. Suitable containers, including soft bags, are typically sterile, non-pyrogenic, single-use, and / or ready-to-use. Multi-chamber containers are particularly useful for holding parenteral nutritional products for children and / or neonates, and generally provide a parenteral fat emulsion as disclosed herein in a first chamber of the container, an amino acid formulation in a second chamber, and a carbohydrate formulation in a third chamber.

[0107] 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 Publication 2007 / 0092579. For example, a multi-chamber container may be configured as a bag containing two or three adjacent chambers or compartments. If desired, the chambers of the multi-chamber container are separated using a fragile barrier or an openable seal (e.g., a peel seal or a fragile seal). A multi-chamber container may also include three chambers for containing parenteral fatty emulsions, carbohydrate formulations and amino acid formulations, and further include at least one, in certain embodiments, two or three smaller chambers for containing, for example, vitamin formulations and / or trace element formulations. In one specific embodiment, the multi-chamber container of the present invention has a first chamber for containing parenteral fatty emulsions according to the present invention, a second chamber for containing amino acid formulations, a third chamber for containing carbohydrate formulations, a fourth chamber for containing vitamin formulations, and a fifth chamber for containing trace element formulations.

[0108] The openable seal of the multi-chamber container allows for the separate storage of formulations and mixing / dissolution immediately before administration, thereby enabling the storage of formulations in a single container that should not be stored for extended periods as a mixture. Opening the seal allows for communication between chambers and mixing of the contents of each chamber. The outer seal of the multi-chamber container is a robust seal that will not open under the fluid pressure supplied to open weaker peeling seals or fragile seals between chambers. In some embodiments, the openable seal of the multi-chamber container can be designed to allow mixing or recombination of only selected chambers of the multi-chamber container, for example, if mixing of a parenteral lipid emulsion with the vitamin chamber and amino acid chamber is desired.

[0109] The multi-chamber container may be provided with instructions for use that describe the desired order for opening the release seals, thereby ensuring that the component fluids are mixed in the desired sequence. The opening strength of two or more release seals may be varied to facilitate opening the seals in the desired order. For example, the opening strength of the first release seal to be opened may be 1 / 3 to 1 / 2 of the opening strength required to open the second release seal. [Examples]

[0110] <abbreviation> %bw weight% DMPG-Na Dimyristoylphosphatidylglycerol, sodium salt DOPS-Na Dioleoyl-glycero-3-phosphoserine, sodium salt LPC (Lysophosphatidylcholine) m month nd undetermined nlt or more nmt or less PC phosphatidylcholine PdI polydispersity index PE phosphatidylethanolamine PG (Phosphatidylglycerol) RT Room temperature, i.e., 22°C w week

[0111] <Analysis and evaluation of quality / stability> The pH value was determined using a calibrated portable pH meter equipped with a glass pH electrode (Portamess(R)911pH, Knick GmbH, Berlin, Germany).

[0112] The average particle size of the emulsion was determined by dynamic light scattering on a ZetasizerNano-ZS90 (Malvern Instruments, UK). The emulsion was diluted with injection water to a concentration suitable for measurement. Measurements were performed at 20°C. The intensity-weighted average droplet diameter is reported.

[0113] Acid values ​​were determined according to the European Pharmacopoeia. All reported values ​​are expressed as mg KOH / g.

[0114] The composition of the sunflower phospholipid composition was evaluated using a standard HPLC protocol, for example, as described in van Hoogevest, P. and Wendel, A., "The use of natural and synthetic phospholipids as pharmaceutical excipients," European Journal of Lipid Science and Technology 116(9)(2014):1088-1107.

[0115] For visual inspection, the emulsion was transferred to a 50 mL glass vial and visually inspected for the presence of free fat droplets under an appropriate light source.

[0116] For stability testing, vials were stored in the dark at approximately 20-25°C and analyzed at specified time points. In accelerated storage testing, vials were stored in a heated oven (Memmert, Schwabach, Germany) at 45°C under light shielding and analyzed after 6 weeks and 3 months.

[0117] <Properties / Quality of the chemicals used> Phospholipid composition P1: Purified fraction of sunflower lecithin. The purified fraction contained nlt96% bwPC, nmt2% bwLPC, <0.1% bwPE, <0.1% bwN-acylphosphatidylethanolamine, <0.05% bw free fatty acids, and nmt1.7% bw triglycerides. The acid value was 0.1-0.3 and the iodine value was 96-108, showing a typical fatty acid spectrum for sunflower phospholipids (approximately 9% palmitic acid, approximately 3% bw stearic acid, approximately 16% bw oleic acid, and approximately 70% bw linoleic acid). The chlorogenic acid content was less than 0.03% bw.

[0118] Phospholipid composition P2: Purified fraction of sunflower lecithin. The purified fraction contained 64% bwPC, 1.9% bwLPC, 6.9% bwPE, and 0.3% bw triglycerides. The acid value was 18, and it showed a typical fatty acid spectrum for sunflower phospholipids (approximately 9% bw palmitic acid, approximately 3% bw stearic acid, approximately 16% bw oleic acid, and approximately 70% bw linoleic acid). The chlorogenic acid content was 1.3% bw.

[0119] Phospholipid composition P3: Purified fraction of sunflower lecithin. The purified fraction contained 71% bwPC, 2.0% bwLPC, 0.9% bwPG, and 7.7% bwPE. The acid value was 11, and it showed a typical fatty acid spectrum for sunflower phospholipids (approximately 9% bw palmitic acid, approximately 3% bw stearic acid, approximately 16% bw oleic acid, and approximately 70% bw linoleic acid). The chlorogenic acid content was 0.06% bw.

[0120] Phospholipid composition P3 was prepared as follows: De-oiled sunflower lecithin with a chlorogenic acid content of 0.64% bw was extracted five times with acetone containing approximately 20% bw of water. The residue was dried under vacuum. Subsequently, the dried residue was extracted with ethanol (96%) and filtered. The extraction process was repeated twice. The filtrates were combined and evaporated to dryness under vacuum to obtain phospholipid composition P3 at a concentration of 13% (relative to the de-oiled lecithin).

[0121] Phospholipid composition P4: A purified fraction of sunflower lecithin having the same overall composition as phospholipid composition P1, but with a chlorogenic acid content of 1.1% bw.

[0122] A mixture of phospholipid composition P5, phospholipid composition P1, and DMPG-Na in a weight ratio of 20:1 (PC:DMPG-Na ratio = 19.6:1).

[0123] Phospholipid composition P5 was prepared by dissolving phospholipid composition P1 (50 g) and DMPG-Na (2.5 g) in a chloroform / methanol / water mixture at 50°C. The solvent was evaporated under vacuum, and the resulting waxy solid was further dried under vacuum at 30°C.

[0124] A mixture of phospholipid composition P6, phospholipid composition P1, and DMPG-Na in a weight ratio of 15.4:1 (PC:DMPG-Na ratio = 15.1:1).

[0125] Phospholipid composition P6 was prepared by dissolving phospholipid composition P1 (20 g) and DMPG-Na (1.3 g) in a chloroform / methanol / water mixture at 50°C. The solvent was evaporated under vacuum, and the resulting waxy solid was further dried under vacuum at 25°C.

[0126] A mixture of phospholipid composition P7, phospholipid composition P1, and DMPG-Na in a weight ratio of 60.6:1 (PC:DMPG-Na ratio = 59.4:1).

[0127] Phospholipid composition P7 was prepared by dissolving phospholipid composition P1 (20 g) and DMPG-Na (0.33 g) in a chloroform / methanol / water mixture at 50°C. The solvent was evaporated under vacuum, and the resulting waxy solid was further dried under vacuum at 25°C.

[0128] A mixture of phospholipid composition P8, phospholipid composition P1, and DMPG-Na in a weight ratio of 20:1 (PC:DOPS-Na ratio = 19.6:1).

[0129] Phospholipid composition P8 was prepared by dissolving phospholipid composition P1 (20 g) and DOPS-Na (1.0 g) in a chloroform / methanol / water mixture at 50°C. The solvent was evaporated under vacuum, and the resulting waxy solid was further dried under vacuum at 25°C.

[0130] DMPG-Na (dimiristoylphosphatidylglycerol, sodium salt) was used as a commercially available product (LIPOID GmbH, Ludwigshafen, Germany). Its chromatographic purity was over 98%. The amount of myristic acid was over 98.0%bw based on the total amount of fatty acids in DMPG-Na.

[0131] DOPS-Na (dioleoyl-glycero-3-phosphoserine, sodium salt), a commercially available product (LIPOID GmbH, Ludwigshafen, Germany), was used. Its chromatographic purity was over 90%. The purity of oleic acid was over 98.0% based on the total amount of fatty acids in DOPS-Na.

[0132] The quality of the glycerol, sodium hydroxide, soybean oil, and MCT oil (medium-chain triglycerides) used met the requirements of the European Pharmacopoeia. Lysine dihydrochloride (over 98%) and glycine (over 99%) were obtained from Sigma-Aldrich.

[0133] <Experimental conditions / equipment> In all experiments, injection water (European Pharmacopoeia) with a maximum conductivity of 5.0 μS / cm was used.

[0134] In the following experiments, Ultra-Turrax T50 (IKA Labortechnik, Staufen, Germany) was used for high-shear mixing.

[0135] High-pressure homogenization was performed using Microfluizider 110T (Microfluidics®, USA).

[0136] Parenteral lipid emulsions were prepared in glass vials according to the following examples and autoclaved. Hydrolysis class 1 glass vials (20 mL) were filled under nitrogen. The glass vials were closed and secured with bromobutyl rubber stoppers and autoclaved in a steam autoclave with a rapid cooling function (Systec GmbH, Linden, Germany). The holding time was 15 minutes at 121°C.

[0137] <Example of preparation> In the following preparation examples, glycerol was used as an isotonic agent at a concentration of 2.25% by weight. In each example, the amount of water was selected to result in a batch size of 500 g.

[0138] [Example 1 (Not in accordance with the present invention)] Glycerol and sterile water for injection were mixed. Phospholipid composition P1 (6.0 g) was added, and the mixture was stirred at 50°C until the phospholipids were completely dispersed. Purified soybean oil (100 g) was separately heated to 60°C. The aqueous phase was mixed using a high-shear mixer at 10,000 rpm. Mixing was continued while gradually adding the heated oil phase. Sodium hydroxide aqueous solution (0.5 M) was added to adjust the pH to 8.5. Next, the obtained pre-emulsion was homogenized using a high-pressure homogenizer in five passes at a pressure of 800 bar. The temperature was maintained at 50-70°C during homogenization. Before the fifth pass, the pH was adjusted again to 8.5. After homogenization, the emulsion was cooled to below 30°C, filled into glass vials, and autoclaved.

[0139] Analysis data: Homogeneous white liquid pH value: 7.4 Average particle size (PdI): 229nm (0.046) Stability: Free fat is visible after 3 months of storage using RT.

[0140] [Example 2] Glycerol and sterile water for injection were mixed. Phospholipid composition P1 (6.0 g) and DMPG-Na (0.30 g) were added, and the mixture was stirred at 50°C until the phospholipids were completely dispersed. Purified soybean oil (100 g) was separately heated to 60°C. The aqueous phase was mixed using a high-shear mixer at 10,000 rpm. Mixing was continued while gradually adding the heated oil phase. Sodium hydroxide aqueous solution (0.5 M) was added to adjust the pH to 7.5. Next, the obtained pre-emulsion was homogenized using a high-pressure homogenizer in five passes at a pressure of 800 bar. The temperature was maintained at 50-70°C during homogenization. Before the fifth pass, the pH was adjusted again to 7.5. After homogenization, the emulsion was cooled to below 30°C, filled into glass vials, and autoclaved.

[0141] Analysis data: Homogeneous white liquid pH value: 6.8 Average particle size (PdI): 220nm (0.099)

[0142] Stability: 3m at 45℃ Homogeneous white liquid pH value: 6.5 Average particle size: 234nm

[0143] 6m at room temperature: Homogeneous white liquid pH value: 7.7 Average particle size: 234nm

[0144] 18m at room temperature: Homogeneous white liquid pH value: 7.6 Average particle size: 238nm

[0145] [Example 3] Glycerol and sterile water for injection were mixed. Phospholipid composition P5 (6.0 g) was added, and the mixture was stirred at 50°C until the phospholipids were completely dispersed. Purified soybean oil (100 g) was separately heated to 60°C. The aqueous phase was mixed using a high-shear mixer at 10,000 rpm. Mixing was continued while gradually adding the heated oil phase. Sodium hydroxide aqueous solution (0.5 M) was added to adjust the pH to 8.3. Next, the obtained pre-emulsion was homogenized using a high-pressure homogenizer in five passes at a pressure of 800 bar. The temperature was maintained at 50-70°C during homogenization. Before the fifth pass, the pH was adjusted again to 8.5. After homogenization, the emulsion was cooled to below 30°C, filled into glass vials, and autoclaved.

[0146] Analysis data: Homogeneous white liquid pH value: 7.7 Average particle size (PdI): 245nm (0.070)

[0147] Stability: 6W at 45℃ Homogeneous white liquid pH value: 7.9 Average particle size: 239nm

[0148] 3m at 45℃: Homogeneous white liquid pH value: 7.9 Average particle size: 241nm

[0149] 12m at room temperature: Homogeneous white liquid pH value: 7.9 Average particle size: 241nm

[0150] [Example 4] Example 4 was carried out according to the protocol of Example 1, using phospholipid composition P3 (6.0 g) instead of phospholipid composition P1 (6.0 g).

[0151] Analysis data: Homogeneous white liquid pH value: 7.7 Average particle size (PdI): 242nm (0.095)

[0152] Stability: 3m at 45℃ Homogeneous white liquid pH value: 7.6 Average particle size: 250nm

[0153] 12m at room temperature: Homogeneous white liquid pH value: 7.6 Average particle size: 260nm

[0154] [Example 5 (Not in accordance with the present invention)] Example 5 was carried out according to the protocol of Example 1, using phospholipid composition P2 (6.0 g) instead of phospholipid composition P1 (6.0 g). After the initial pH adjustment, the pre-emulsion turned green. After autoclaving, the green color faded, and the emulsion was off-white.

[0155] Analysis data: Homogeneous, off-white liquid pH value: 7.6 Average particle size (PdI): 253nm (0.094)

[0156] Stability: 6W at 45℃ An off-white liquid with small oil droplets on its surface. pH value: 7.0 Average particle size: 239nm

[0157] 3m at 45℃: Off-white liquid containing free fat on the surface pH value: 6.9 Average particle size:nd

[0158] 12m at room temperature: An off-white liquid with small oil droplets on its surface. pH value: 7.2 Average particle size: 237nm

[0159] [Example 6 (Not in accordance with the present invention)] Example 6 was carried out according to the protocol of Example 1, using a mixture of refined soybean oil (50g) and refined medium-chain triglycerides (50g) instead of refined soybean oil (100g).

[0160] Analysis data: Homogeneous white liquid pH value: 7.5 Average particle size (PdI): 270nm (0.023)

[0161] Stability: 3m at 45℃ A white liquid with small oil droplets on its surface. pH value: 6.9 Average particle size: 259nm

[0162] 12m at room temperature: A white liquid with small oil droplets on its surface. pH value: 7.9 Average particle size: 276nm

[0163] [Example 7] Glycerol and sterile water for injection were mixed. Phospholipid composition P1 (6.0 g) and DMPG-Na (0.30 g) were added, and the mixture was stirred at 50°C until the phospholipids were completely dispersed. A mixture of purified soybean oil (50 g) and purified medium-chain triglycerides (50 g) was separately heated to 60°C. The aqueous phase was mixed using a high-shear mixer at 10,000 rpm. Mixing was continued while gradually adding the heated oil phase. The pH was adjusted to 8.5 by adding an aqueous sodium hydroxide solution (0.5 M). Next, the obtained pre-emulsion was homogenized using a high-pressure homogenizer in five passes at a pressure of 800 bar. The temperature was maintained at 50-70°C during homogenization. Before the fifth pass, the pH was adjusted again to 8.5. After homogenization, the emulsion was cooled to below 30°C, packed into glass vials, and autoclaved.

[0164] Analysis data: Homogeneous white liquid pH value: 7.8 Average particle size (PdI): 227nm (0.065)

[0165] [Example 8] Example 8 was carried out according to the protocol of Example 3, using a mixture of refined soybean oil (50g) and refined medium-chain triglycerides (50g) instead of refined soybean oil (100g). As in Example 3, a homogeneous mixture of phospholipid composition P1 and DMPG-Na in a weight ratio of 20:1 was used (6g of P5 instead of P1).

[0166] Analysis data: Homogeneous white liquid pH value: 7.5 Average particle size (PdI): 232nm (0.026)

[0167] Stability: 3m at 45℃ Homogeneous white liquid pH value: 7.2 Average particle size: 212nm

[0168] [Example 9] Example 9 was carried out according to the protocol of Example 1, using a mixture of refined soybean oil (50g) and refined medium-chain triglycerides (50g) instead of refined soybean oil (100g), and using phospholipid composition P3 instead of phospholipid composition P1.

[0169] Analysis data: Homogeneous white liquid pH value: 7.8 Average particle size (PdI): 240nm (0.002)

[0170] Stability: 3m at 45℃ Homogeneous white liquid pH value: 7.1 Average particle size: 224nm

[0171] [Example 10 (Not in accordance with the present invention)] Glycerol and sterile water for injection were mixed. Phospholipid composition P2 (6.0 g) was added, and the mixture was stirred at 50°C until the phospholipids were completely dispersed. A mixture of purified soybean oil (50 g) and purified medium-chain triglycerides (50 g) was separately heated to 60°C. The aqueous phase was mixed using a high-shear mixer at 10,000 rpm. Mixing was continued while gradually adding the heated oil phase. A sodium hydroxide aqueous solution (0.5 M) was added to adjust the pH to 8.5. After pH adjustment, the pre-emulsion turned green. Next, the pre-emulsion was homogenized using a high-pressure homogenizer in five passes at a pressure of 800 bar. The temperature was maintained at 50-70°C during homogenization. Before the fifth pass, the pH was adjusted again to 8.5. After homogenization, the emulsion was cooled to below 30°C, filled into glass vials, and autoclaved. After autoclaving, the green color faded, and the emulsion turned off-white to gray.

[0172] Analysis data: Homogeneous, off-white liquid pH value: 7.6 Average particle size (PdI): 243nm (0.005)

[0173] Stability: 3m at 45℃ Homogeneous grayish liquid pH value: 7.0 Average particle size: 230nm

[0174] 12m at room temperature: A grayish liquid with small oil droplets on its surface. pH value: 7.7 Average particle size: 265nm

[0175] [Example 11] Glycerol and sterile water for injection were mixed. Phospholipid composition P1 (6.0 g) and DMPG-Na (0.30 g) were added, and the mixture was stirred at 50°C until the phospholipids were completely dispersed. Purified soybean oil (100 g) was separately heated to 60°C. Glycine (0.05 g) and lysine dihydrochloride (0.05 g) were added to the aqueous phase, and stirring was continued until these amino acids dissolved (approximately 2 minutes). The aqueous phase was mixed using a high-shear mixer at 10,000 rpm. Mixing was continued while gradually adding the heated oil phase. Sodium hydroxide aqueous solution (0.5 M) was added to adjust the pH to 7.5. Next, the obtained pre-emulsion was homogenized using a high-pressure homogenizer in 5 passes at a pressure of 800 bar. The temperature was maintained at 50-70°C during homogenization. Before the 5th pass, the pH was adjusted to 8.5. After homogenization, the emulsion was cooled to below 30°C, filled into glass vials, and autoclaved.

[0176] Analysis data: Homogeneous white liquid pH value: 8.6 Average particle size (PdI): 245nm (0.100)

[0177] Stability: 3m at 45℃ Homogeneous white liquid pH value: 7.9 Average particle size: 240nm

[0178] 12m at room temperature: Homogeneous white liquid pH value: 8.4 Average particle size: 262nm

[0179] [Example 12 (Not in accordance with the present invention)] Glycerol and sterile water for injection were mixed. Phospholipid composition P4 (6.0 g) and DMPG-Na (0.30 g) were added, and the mixture was stirred at 50°C until the phospholipids were completely dispersed. Purified soybean oil (100 g) was separately heated to 60°C. Glycine (0.05 g) and lysine dihydrochloride (0.05 g) were added to the aqueous phase, and stirring was continued until these amino acids dissolved (approximately 2 minutes). The aqueous phase was mixed using a high-shear mixer at 10,000 rpm. Mixing was continued while gradually adding the heated oil phase. Sodium hydroxide aqueous solution (0.5 M) was added to adjust the pH to 7.7. After pH adjustment, the pre-emulsion turned green. Next, the obtained pre-emulsion was homogenized using a high-pressure homogenizer in five passes at a pressure of 800 bar. The temperature was maintained at 50-70°C during homogenization. Before the fifth pass, the pH was adjusted to 8.5. After homogenization, the emulsion was cooled to below 30°C, filled into glass vials, and autoclaved. After autoclaving, the green color faded, and the emulsion became grayish.

[0180] Analysis data: Homogeneous, grayish liquid pH value: 8.6 Average particle size (PdI): 240nm (0.033)

[0181] Stability: 3m at 45℃ Homogeneous grayish liquid pH value: 7.7 Average particle size: 234nm

[0182] 12m at room temperature: A grayish liquid with small oil droplets on its surface. pH value 8.2 Average particle size: 260nm

[0183] [Example 13] Example 13 was carried out according to the protocol of Example 11, using a mixture of refined soybean oil (50g) and refined medium-chain triglycerides (50g) instead of refined soybean oil (100g).

[0184] Analysis data: Homogeneous white liquid pH value: 8.3 Average particle size (PdI): 226nm (0.102)

[0185] Stability: 3m at 45℃ Homogeneous white liquid pH value: 8.1 Average particle size: 224nm

[0186] [Example 14 (Not in accordance with the present invention)] Example 14 was carried out according to the protocol of Example 12, using a mixture of refined soybean oil (50g) and refined medium-chain triglycerides (50g) instead of refined soybean oil (100g). The initial pH adjustment was pH 7.8 instead of pH 7.7. After the initial pH adjustment, the pre-emulsion turned green. After autoclaving, the green color faded, and the emulsion took on a grayish appearance.

[0187] Analysis data: Homogeneous grayish liquid pH value: 8.3 Average particle size (PdI): 237nm (0.014)

[0188] Stability: 3m at 45℃ Homogeneous grayish liquid pH value: 7.4 Average particle size: 227nm

[0189] 12m at room temperature: A grayish liquid with small oil droplets on its surface. pH value 8.1 Average particle size: 224nm

[0190] [Example 15] Example 15 was carried out according to the protocol of Example 2, using 0.4 g (0.08% bw based on emulsion) of DMPG-Na instead of 0.3 g of DMPG-Na.

[0191] Analysis data: Homogeneous white liquid pH value: 7.2 Average particle size (PdI): 229nm (0.105)

[0192] Stability: 3m at 45℃ Homogeneous white liquid pH value: 6.8 Average particle size: 244nm

[0193] 18m at room temperature: Homogeneous white liquid pH value: 7.8 Average particle size: 246nm

[0194] [Example 16] Example 16 was carried out according to the protocol of Example 2, using 0.1 g (0.02% bw based on emulsion) of DMPG-Na instead of 0.3 g of DMPG-Na.

[0195] Analysis data: Homogeneous white liquid pH value: 6.9 Average particle size (PdI): 221nm (0.043)

[0196] Stability: 3m at 45℃ Homogeneous white liquid pH value: 6.8 Average particle size: 239nm

[0197] 18m at room temperature: Homogeneous white liquid pH value: 7.3 Average particle size: 244nm

[0198] [Example 17] Example 17 was carried out according to the protocol of Example 7, using 0.4 g (0.08% bw based on emulsion) of DMPG-Na instead of 0.3 g of DMPG-Na.

[0199] Analysis data: Homogeneous white liquid pH value: 7.7 Average particle size (PdI): 200nm (0.032)

[0200] Stability: 3m at 45℃ Homogeneous white liquid pH value: 7.6 Average particle size: 218nm

[0201] 3m at room temperature: Homogeneous white liquid pH value: 7.9 Average particle size: 209nm

[0202] [Example 18] Example 18 was carried out according to the protocol of Example 7, using 0.1 g of DMPG-Na (0.02% bw based on emulsion) instead of 0.3 g of DMPG-Na.

[0203] Analysis data: Homogeneous white liquid pH value: 7.7 Average particle size (PdI): 209nm (0.035)

[0204] Stability: 3m at 45℃ Homogeneous white liquid pH value: 7.2 Average particle size: 218nm

[0205] 3m at room temperature: Homogeneous white liquid pH value: 7.2 Average particle size: 225nm

[0206] [Example 19] Example 19 was carried out according to the protocol of Example 3, using 6.0 g of phospholipid composition P6 instead of phospholipid composition P5.

[0207] Analysis data: Homogeneous white liquid pH value: 7.8 Average particle size (PdI): 232nm (0.042)

[0208] Stability: 3 m at 45 °C: Homogeneous white liquid pH value: 7.7 Average particle size: 246 nm

[0209] 3 m at room temperature: Homogeneous white liquid pH value: 8.2 Average particle size: 247 nm

[0210] [Example 20] Example 20 was carried out according to the protocol of Example 3 using 6.0 g of phospholipid composition P7 instead of phospholipid composition P5.

[0211] Analysis data: Homogeneous white liquid pH value: 7.7 Average particle size (PdI): 222 nm (0.096)

[0212] Stability: 3 m at room temperature: Homogeneous white liquid pH value: 8.0 Average particle size: 245 nm

[0213] [Example 21] Example 21 was carried out according to the protocol of Example 8 using 6.0 g of phospholipid composition P6 instead of phospholipid composition P5.

[0214] Analysis data: Homogeneous white liquid pH value: 7.6 Average particle size (PdI): 210 nm (0.013)

[0215] Stability: 3 m at room temperature: Homogeneous white liquid pH value: 8.1 Average particle size: 221 nm

[0216] [Example 22] Example 22 was carried out according to the protocol of Example 8 using 6.0 g of phospholipid composition P7 instead of phospholipid composition P5.

[0217] Analysis data: Homogeneous white liquid pH value: 7.8 Average particle size (PdI): 206 nm (0.033)

[0218] Stability: 3 m at room temperature: Homogeneous white liquid pH value: 8.2 Average particle size: 219 nm

[0219] [Example 24] Example 24 was carried out according to the protocol of Example 3 using 6.0 g of phospholipid composition P8 instead of phospholipid composition P5.

[0220] Analysis data: Homogeneous white liquid pH value: 8.2 Average particle size (PdI): 212 nm (0.061)

[0221] Stability: 3 m at 45 °C: Homogeneous white liquid pH value: 7.7 Average particle size: 245 nm

[0222] 6 m at room temperature: Homogeneous white liquid pH value: 8.0 Average particle size: 245 nm

[0223] [Example 25] Example 25 was carried out according to the protocol of Example 7 using 0.3 g of DOPS-NA instead of 6.0 g of phospholipid composition P1 and DMPG-Na.

[0224] Analysis data: Homogeneous white liquid pH value: 8.2 Average particle size (PdI): 216nm (0.071)

[0225] Stability: 3m at 45℃ Homogeneous white liquid pH value: 7.3 Average particle size: 221nm

[0226] [Example 26] Example 26 was carried out according to the protocol of Example 8, using 6.0 g of phospholipid composition P8 instead of phospholipid composition P5.

[0227] Analysis data: Homogeneous white liquid pH value: 8.0 Average particle size (PdI): 203nm (0.013)

[0228] Stability: 3m at 45℃ Homogeneous white liquid pH value: 7.3 Average particle size: 226nm

[0229] 3m at room temperature: Homogeneous white liquid pH value: 7.8 Average particle size: 228nm

[0230] [Example 27] Example 27 was carried out according to the protocol of Example 2, with the addition of 0.15 g (0.03% bw based on the emulsion) of sodium oleate. Sodium oleate was added to the water / glycerin mixture together with phospholipid composition P1 (6.0 g) and DMPG-Na (0.3 g).

[0231] Analysis data: Homogeneous white liquid pH value: 8.6 Average particle size (PdI): 229nm (0.102)

[0232] Stability: 6W at 45℃ Homogeneous white liquid pH value: 8.0 Average particle size: 240nm

[0233] [Example 28] Example 28 was carried out according to the protocol of Example 7, with the addition of 0.15 g (0.03% bw based on the emulsion) of sodium oleate. Sodium oleate was added to the water / glycerin mixture together with phospholipid composition P1 (6.0 g) and DMPG-Na (0.3 g).

[0234] Analysis data: Homogeneous white liquid pH value: 8.5 Average particle size (PdI): 202nm (0.064)

[0235] Stability: 6W at 45℃ Homogeneous white liquid pH value: 7.7 Average particle size: 208nm

[0236] [Example 29] Example 29 was carried out according to the protocol of Example 4, with the addition of 0.15 g (0.03% bw based on the emulsion) of sodium oleate. Sodium oleate was added to the water / glycerin mixture together with phospholipid composition P3 (6.0 g).

[0237] Analysis data: Homogeneous white liquid pH value: 8.3 Average particle size (PdI): 236nm (0.081)

[0238] Stability: 3m at 45℃ Homogeneous white liquid pH value: 7.7 Average particle size: 230nm

[0239] 12m at room temperature: Homogeneous white liquid pH value: 7.9 Average particle size: 235nm

[0240] Example 30 was carried out according to the protocol of Example 9, with the addition of 0.15 g (0.03% bw based on the emulsion) of sodium oleate. Sodium oleate was added to the water / glycerin mixture together with phospholipid composition P3 (6.0 g).

[0241] Analysis data: Homogeneous white liquid pH value: 8.3 Average particle size (PdI): 215nm (0.056)

[0242] Stability: 6W at 45℃ Homogeneous white liquid pH value: 7.6 Average particle size: 234nm

Claims

1. The use of a sunflower phospholipid composition in combination with at least one anionic stabilizer compound for the preparation of emulsifiers in aqueous oil-in-water emulsions for parenteral administration, The sunflower phospholipid composition contains at least 45% by weight of phosphatidylcholine based on the total weight of the phospholipid composition, and contains less than 0.1% by weight of chlorogenic acid based on the total weight of the sunflower phospholipid composition. The use wherein the anionic stabilizer compound comprises at least one anionic phospholipid compound.

2. The use according to claim 1, wherein the sunflower phospholipid composition comprises at least one anionic phospholipid compound in addition to the phosphatidylcholine.

3. The use according to claim 1 or 2, wherein the anionic phospholipid compound is selected from the group consisting of phosphatidylglycerol, phosphatidylinositol, PEG-modified phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, 1,3-bis(sn-3'-phosphatidyl)-sn-glycerol, and combinations thereof.

4. The use according to claim 3, wherein the anionic phospholipid compound is phosphatidylglycerol.

5. The use according to any one of claims 1 to 4, wherein the weight ratio of the anionic phospholipid compound to the sunflower phospholipid composition is in the range of 0.2:99.8 to 20:

80.

6. The use according to any one of claims 1 to 5, wherein the sunflower phospholipid composition comprises phosphatidylethanolamine.

7. The use according to any one of claims 1 to 6, wherein the sunflower phospholipid composition is used in an amount such that the concentration of phosphatidylcholine in the oil-in-water emulsion is in the range of 0.1 to 20% by weight based on the total weight of the oil-in-water emulsion.

8. The use according to any one of claims 1 to 7, wherein the oil-in-water emulsion for parenteral administration is an oil-in-water emulsion for parenteral nutrition.

9. A sunflower phospholipid composition containing at least 45% by weight of phosphatidylcholine based on the total weight of the sunflower phospholipid composition, and having a chlorogenic acid content of less than 0.1% by weight based on the total weight of the sunflower phospholipid composition, an anionic stabilizer compound comprising at least one anionic phospholipid compound A combination of these.

10. A phosphatidylcholine in an amount of at least 45% by weight relative to the total weight of the sunflower phospholipid composition, An anionic stabilizer compound comprising at least one anionic phospholipid compound and having a chlorogenic acid content of less than 0.1% by weight relative to the total weight of the sunflower phospholipid composition. A sunflower phospholipid composition containing the following.

11. The combination according to claim 9 or the composition according to claim 10, wherein the anionic phospholipid compound is selected from the group consisting of phosphatidylglycerol, phosphatidylinositol, PEG-modified phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, 1,3-bis(sn-3'-phosphatidyl)-sn-glycerol and combinations thereof.

12. The combination or composition according to claim 11, wherein the anionic phospholipid compound is phosphatidylglycerol.

13. The combination or composition according to any one of claims 9 to 12, wherein the weight ratio of the anionic phospholipid compound to phosphatidylcholine is in the range of 0.2:99.8 to 30:

70.

14. A water-based oil-in-water emulsion for parenteral administration, a) An oil phase containing a triglyceride composition suitable for parenteral administration, b) A combination of a sunflower phospholipid composition containing less than 0.1% by weight of chlorogenic acid based on the total weight of the sunflower phospholipid composition and at least one anionic stabilizer compound comprising at least one phospholipid compound described in any one of claims 1 to 9, or a sunflower phospholipid composition described in any one of claims 10 to 13, and c) water A water-based oil-in-water emulsion containing [the specified component].

15. The aqueous oil-in-water emulsion according to claim 14, wherein the oil phase comprises a triglyceride composition suitable for parenteral administration.

16. The aqueous oil-in-water emulsion according to claim 14 or 15, wherein the anionic phospholipid compound is selected from the group consisting of phosphatidylglycerol, phosphatidylinositol, PEG-modified phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, 1,3-bis(sn-3'-phosphatidyl)-sn-glycerol, and combinations thereof.

17. The aqueous oil-in-water emulsion according to any one of claims 14 to 16, wherein the weight ratio of the anionic phospholipid compound to the phosphatidylcholine is in the range of 0.2:99.8 to 15:

85.

18. a) Based on the total weight of the aqueous oil-in-water emulsion of the oil phase, 5 to 35% by weight of the oil phase, b) A combination of the sunflower phospholipid composition containing less than 0.1% by weight of chlorogenic acid based on the total weight of the sunflower phospholipid composition, and at least one anionic phospholipid compound according to any one of claims 1 to 9. Or a sunflower phospholipid composition according to any one of claims 10 to 13, The amount of the sunflower composition is such that the concentration of phosphatidylcholine in the oil-in-water emulsion is in the range of 0.1 to 20% by weight, based on the total weight of the oil-in-water emulsion, and the combination or sunflower phospholipid composition, c) water An aqueous oil-in-water emulsion according to any one of claims 14 to 17, comprising:

19. An aqueous oil-in-water emulsion according to any one of claims 14 to 18, comprising less than 100 ppm of chlorogenic acid.

20. An aqueous oil-in-water emulsion according to any one of claims 14 to 19, having a pH value in the range of pH 4 to pH 10 when measured at 20°C and 1 bar.

21. A method for preparing an aqueous oil-in-water emulsion for parenteral administration according to any one of claims 14 to 20, i. Steps to provide an aqueous phase and an oil phase, ii. A step of emulsifying the oil phase in the aqueous phase, - In the presence of a combination of a sunflower phospholipid composition containing less than 0.1% by weight of chlorogenic acid based on the total weight of the sunflower phospholipid composition and at least one anionic stabilizer compound containing an anionic phospholipid compound as defined in any one of claims 1 to 9, or - In the presence of the sunflower phospholipid composition according to any one of claims 10 to 13 Emulsification process, iii. A process to homogenize the emulsion obtained in the process into droplets of a size suitable for parenteral administration. Methods that include...

22. The method according to claim 21, further comprising the step of mixing a sunflower phospholipid composition containing phosphatidylcholine with one or more anionic phospholipids before dispersing the mixture in water.

23. The method according to claim 21 or 22, further comprising the step of sterilizing the homogenized emulsion of step iii by autoclaving.

24. A method for producing the sunflower phospholipid composition according to any one of claims 10 to 13, comprising the following steps: i) Extracting sunflower lecithin with a solvent selected from a mixture of acetone and water to obtain an extract and a residue, then, ii) A step of repeatedly extracting the residue with ethanol or a mixture thereof with water to obtain an ethanol extract, iii) A step of combining the ethanol extracts, removing ethanol and any water, to obtain a sunflower phospholipid composition having at least 45% by weight of phosphatidylcholine based on the total weight of the sunflower phospholipid composition, and having a chlorogenic acid content of less than 0.1% by weight based on the total weight of the sunflower phospholipid composition. iv) Dissolve the sunflower phospholipid composition obtained in step iii) and at least one further anionic phospholipid compound in an organic solvent and evaporate the solvent. Methods that include...

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