Sunflower lecithin composition containing phosphatidylcholine

Abstract

The present invention relates to a sunflower lecithin composition containing phosphatidylcholine and containing less than 0.1% by weight, in particular less than 0.08% by weight or less than 0.05% by weight, especially less than 0.02% by weight of chlorogenic acid, based on the total weight of the sunflower lecithin composition, and a combination thereof with at least one anionic stabilizer compound comprising 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 lecithin composition and at least one anionic stabilizer compound comprising 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 lecithin composition containing phosphatidylcholine in an amount of 45% by weight or more and having a low chlorogenic acid content of less than 0.1% by weight and at least one anionic phospholipid compound.

Description

[0001] The present invention relates to sunflower lecithin compositions, i.e. lecithin obtained from sunflower, and to their use as emulsifiers in aqueous oil-in-water emulsions. The present invention also relates to aqueous oil-in-water emulsions containing such sunflower lecithin compositions and to methods for their production.

[0002] Oil-in-water emulsions for parenteral application or administration, also known as parenteral fat emulsions, are sterile oil-in-water emulsions of physiologically tolerated oils formulated in a manner suitable for parenteral administration - for requirements for parenteral fat emulsions, see, e.g., 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, PC et al., Eds), Karger Medical and Scientific Publishers 2014, pp. 48–56 and references cited therein; Calder PC et al., Intensive Care Medicine, 2010, 36(5), 735-749.

[0003] Physiologically tolerant oil-in-water emulsions are mainly used for parenteral nutrition. For parenteral nutrition, all necessary nutrients, such as carbohydrates, fats, vitamins, electrolytes, trace elements and water, are provided to the patient by intravenous administration, that is, an injectable liquid preparation that enters the vein of a patient who needs parenteral nutrition. Fat is a basic component of total parenteral nutrition because it delivers essential fatty acids that the human body cannot synthesize on its own to the patient's body. Fat-free parenteral nutrition can lead to essential fatty acid deficiency within a few days. Because fat is immiscible with blood, it can only be administered parenterally in the form of an aqueous emulsion because direct injection of fat can cause vascular obstruction. For a review 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 references cited therein; Driscoll, D.loc.cit.

[0004] In addition to parenteral nutrition, parenteral fat emulsions can also be used for the parenteral administration of lipophilic drugs. For this reason, lipophilic drugs are dissolved in the oil phase of parenteral fat emulsions. Compared with other preparations, the drug preparations in parenteral fat emulsions have many advantages, such as reducing pain and irritation at the injection site, reducing thrombophlebitis, reducing drug toxicity, enhancing drug stability and the possibility of targeted administration-see, for example, Hippalgoankar K, Majumdar S, Kansara V, Injectable Lipid Emulsions-Advancements, Opportunities and Challenges, AAPSPharmSciTech 2010, 11: 4, 1526-1540. Typical examples of drugs formulated in parenteral fat emulsions are propofol, aprepitant, diazepam, etomidate and clevidipine butyrate.

[0005] Recently, parenteral fat emulsions have been suggested for the treatment of drug overdose or poisoning of lipophilic drugs. By intravenous injection of parenteral fat emulsions to patients with drug overdose or poisoning, the lipophilic drug is extracted into the milk phase of the injected fat 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 multiphase systems composed of an oil phase uniformly dispersed or emulsified in an aqueous phase. Since they are thermodynamically unstable systems, emulsifiers are required to prevent the coalescence of oil droplets, thereby stabilizing the emulsion. Although synthetic emulsifiers such as poloxamer, macrogol-hydroxystearates or polysorbates can be used to stabilize parenteral fat emulsions, phospholipids have become preferred emulsifiers for such applications due to their excellent toxicity profile. Due to the large amount of emulsifiers used during parenteral nutrition, toxicity is a very important aspect of selecting the emulsifier used for parenteral fat emulsions. For example, for a person weighing 70 kg, up to 21 grams of phospholipids are administered daily. Since phospholipids are natural components of human cell membranes and metabolized in the same manner as other nutritional fats, they can be administered at very high doses without reporting any negative side effects. On the contrary, for parenteral emulsions and other injections containing synthetic emulsifiers, unwanted side effects and toxicity, such as fat overload syndrome, hypersensitivity reactions and adverse reactions at the infusion site, have been reported. For this reason, it is desirable to formulate parenteral fat emulsions without the use of synthetic emulsifiers.

[0007] Phospholipids are natural products with amphipathic properties. The structure of phospholipid molecules usually consists of a diglyceride portion of fatty acids esterified by a phosphate group. The phosphate group can be further modified with simple organic molecules such as choline, glycerol, ethanolamine, inositol or serine to produce different phospholipid compounds. Common sources of phospholipids are soybeans, rapeseed, sunflower, eggs, milk, fish eggs, etc. Each source has a unique distribution of each phospholipid compound in the phospholipid and a unique fatty acid pattern, and therefore has different applications in food, nutrition, medicine, cosmetics and drug delivery.

[0008] For parenteral fat emulsions, egg lecithin, i.e. lecithin obtained from eggs, is usually the state of the art emulsifier. In most cases, egg lecithin with a phosphatidylcholine content of about at least 70 to 80% is used. Phosphatidylcholine is a zwitterionic compound in the pH range of 6 to 8 that is usually required in parenteral fat emulsions.

[0009] Although egg lecithin is a very effective emulsifier for fat emulsions, it has some disadvantages:

[0010] - Potential allergenicity, caused by residual egg protein in the phospholipids.

[0011] - Egg lecithin is an animal-derived product, which may cause concern to consumers, environmental impacts and increase the risk of possible transmission of avian diseases.

[0012] Although attempts have been made to replace egg lecithin in commercial fat emulsions with plant-based lecithin, such as soy lecithin or rapeseed lecithin (used alone or in combination with synthetic emulsifiers of the poloxamer type), these products have other disadvantages and have been withdrawn from the market.

[0013] Therefore, there is still a need for emulsifiers for parenteral fat emulsions that have low toxicity and do provide good emulsion stability. In addition, the emulsifier should be compatible with the alkaline pH values ​​of pH 7 or higher typically encountered in the production of parenteral fat emulsions, especially those used for parenteral nutrition, and should not cause discoloration of the emulsion.

[0014] It has now been found that phospholipid compositions obtained from sunflower seeds containing phosphatidylcholine, hereinafter also referred to as sunflower lecithin and sunflower lecithin compositions, if they contain less than 0.1% by weight of chlorogenic acid and are combined with one or more anionic phospholipid compounds, are effective in stabilizing parenteral fat emulsions and minimizing discoloration. These combinations can therefore be used as emulsifiers in parenteral fat emulsions. In addition, they do not present allergic risks or toxicity problems.

[0015] Therefore, a first aspect of the present invention relates to the use of a sunflower lecithin composition containing phosphatidylcholine and containing not more than 0.1 wt.-%, in particular not more than 0.08 wt.-% or not more than 0.05 wt.-%, especially not more than 0.02 wt.-% of chlorogenic acid, based on the total weight of the sunflower lecithin composition, in combination with at least one anionic stabilizer compound comprising at least one anionic phospholipid compound as an emulsifier in an aqueous oil-in-water emulsion for parenteral administration (abbreviated herein as parenteral fat emulsion).

[0016] The combination of a sunflower composition and at least one anionic stabilizer compound comprising at least one anionic phospholipid compound can be used as an emulsifier and provides specific benefits for parenteral fat emulsions. In particular, sunflower phospholipid compositions containing a sufficient amount of phosphatidylcholine, for example 45% by weight or more, for example 45 to 99% by weight, in particular 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 low chlorogenic acid content of less than 0.1% by weight, in particular at most or less than 0.08% by weight or at most or less than 0.05% by weight, in particular at most or less than 0.02% by weight, provide parenteral fat emulsions that show reduced discoloration or even no discoloration during production or storage. Due to the low content of chlorogenic acid, they also show better compatibility with compounds having amino groups, such as amino acids, because when these compounds are present in parenteral fat emulsions, the presence of chlorogenic acid may lead to severe discoloration during production or storage. These sunflower lecithin compositions containing sufficient amounts of phosphatidylcholine are combined with one or more anionic stabilizer compounds comprising at least one anionic phospholipid, which combination imparts to aqueous oil-in-water emulsions improved stability against coalescence of oil droplets and also minimizes discoloration of the emulsions, thus providing improved long-term storage stability for months and up to years.

[0017] Therefore, a second aspect of the present invention relates to a sunflower lecithin composition containing an amount of at least 45 wt.-%, for example 45 to 99 wt.-%, in particular 50 to 98.5 wt.-%, especially 60 to 98 wt.-% or 70 to 98 wt.-%, based on the total weight of the sunflower lecithin composition, and having a chlorogenic acid content of less than 0.1 wt.-%, in particular at most or less than 0.08 wt.-% or at most or less than 0.05 wt.-%, especially at most or less than 0.02 wt.-%, based on the total weight of the sunflower lecithin composition, in combination with one or more anionic stabilizer compounds comprising at least one anionic lecithin.

[0018] The inventors have also found that the combination can be formulated as a single composition. Therefore, a third aspect of the invention relates to a sunflower lecithin composition containing phosphatidylcholine in an amount of at least 45 wt%, such as 45 to 98.8 wt%, in particular 50 to 98.5 wt%, especially 60 to 98 wt% or 70 to 98 wt%, based on the total weight of the sunflower lecithin composition, and at least one anionic stabilizer compound comprising at least one anionic phospholipid compound, and having a chlorogenic acid content of less than 0.1 wt%, in particular at most or less than 0.08 wt% or at most or less than 0.05 wt%, especially at most or less than 0.02 wt%, based on the total weight of the sunflower lecithin composition. The phospholipid composition according to the third aspect of the invention is also referred to hereinafter as a "mixture".

[0019] In a fourth aspect, the present invention relates to a method for producing a sunflower lecithin composition according to the third aspect of the invention.

[0020] A fifth aspect of the present invention relates to an aqueous oil-in-water emulsion for parenteral administration, in particular for parenteral nutrition, comprising

[0021] a) an oily phase comprising a triglyceride composition suitable for parenteral administration, in particular for parenteral nutrition,

[0022] b) a sunflower lecithin composition as defined herein having a chlorogenic acid content of less than 0.1 wt.-%, in particular at most or less than 0.08 wt.-% or at most or less than 0.05 wt.-%, especially at most or less than 0.02 wt.-%, based on the total weight of the sunflower lecithin composition, in combination with at least one anionic stabilizer compound comprising at least one anionic phospholipid compound, or a mixture according to the third aspect of the invention as defined herein, and

[0023] c) Water.

[0024] A sixth aspect of the invention relates to a method for producing such an emulsion.

[0025] Here and throughout the application, technical terms have their common technical meanings unless otherwise specified.

[0026] The terms "sunflower lecithin composition" and "sunflower lecithin" refer to a lecithin composition and lecithin obtained from sunflower oil, respectively. Typically, the sunflower lecithin composition is obtained from sunflower lecithin by fractionation, while the sunflower lecithin is obtained from the dried sludge obtained in the degumming step of sunflower oil.

[0027] The term "phospholipid composition" refers to a composition of phospholipid molecules wherein the total amount of phospholipid molecules in the composition is generally at least 80% by weight, typically at least 90% by weight, the remainder being essentially triglycerides and / or fatty acids.

[0028] Sunflower lecithin compositions are distinguished from lecithin compositions of other natural origin by their characteristic fatty acid composition - for 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, in particular Table 2 on page 1090, and Guiotto, E., Tomás, M., Diehl, B. (2015). Sunflower Lecithin. 10.1016 / B978-1-63067-044-3.50007-8. Chapter 3, page 59, Table 3.B. In particular, the sunflower lecithin composition is distinguished from other lecithin compositions of natural origin by its high linoleic acid content, typically at least 60%, for example in the range of 60 to 75%, and low stearic acid content, typically up to 8%, for example 1 to 8%. Typically, the palmitic acid content is up to 12%, for example in the range of 6 to 12%, and the oleic acid content is typically in the range of 12 to 25%. The % values ​​given here relate to the relative peak areas of the corresponding fatty acids in the sunflower lecithin composition as determined by analytical HPLC. Thus, the phospholipid compounds contained in such a sunflower lecithin composition, such as phosphatidylcholine, phosphatidylethanolamine, N-acylphosphatidylethanolamine and lysophosphatidylcholine, as well as any other phospholipid compounds and fatty acid esters contained therein, such as fatty acid triglycerides, have a similar fatty acid composition. In addition, the sunflower lecithin composition is distinguished from lecithin compositions of other origins by the presence of characteristic residual sunflower protein, which does not cause allergic risks compared to residual egg protein.

[0029] According to the invention, the sunflower lecithin composition contains phosphatidylcholine, which is mainly used to stabilize the oil-in-water emulsion, more precisely, to stabilize the oil droplets of the oil-in-water emulsion. Typically, phosphatidylcholine is the main component of the sunflower lecithin composition. Preferably, the content of phosphatidylcholine in the sunflower lecithin composition is at least 45.0% by weight, in particular at least 50.0% by weight, in particular at least 60.0% by weight or at least 70% by weight, based on the total weight of the sunflower lecithin composition. Typically, the content of phosphatidylcholine does not exceed 99.0% by weight, in particular 98.5% by weight, in particular 98.0% by weight, based on the total weight of the sunflower lecithin composition.

[0030] Depending on the amount of phosphatidylcholine, the sunflower phospholipid composition may contain one or more other phospholipid compounds different from phosphatidylcholine, in particular one or more of the following phospholipid compounds: phosphatidylethanolamine, N-acylphosphatidylethanolamine and lysophosphatidylcholine. The total amount of phospholipid compounds different from phosphatidylcholine is usually in the range of 1.0 to 50.0 weight %, in particular in the range of 1.5 to 45.0 weight %, in particular in the range of 2.0 to 40.0 weight % or in the range of 2 to 30 weight % based on the total weight of the sunflower phospholipid composition. For example, the amount of lysophosphatidylcholine can be trace amounts to 25.0 weight % based on the total weight of the sunflower phospholipid composition. Similarly, the amount of phosphatidylethanolamine can be trace amounts to 25.0 weight % based on the total weight of the sunflower phospholipid composition, and is usually in the range of 1.0 to 20.0 weight %. Typically, the amount of N-acylphosphatidylethanolamine does not exceed 10.0 wt % based on the total weight of the sunflower lecithin composition, and may be present in trace amounts up to 10.0 wt %. In a particular set of embodiments, the sunflower lecithin composition contains anionic phospholipid compounds, such as phosphatidylglycerol, for example in an amount of 0.1 to 2 wt % based on the total weight of the sunflower lecithin composition.

[0031] The sunflower lecithin composition may contain lysophosphatidylcholine. For pharmacological reasons, the amount of lysophosphatidylcholine is preferably not more than 10 wt%, in particular not more than 5 wt%, for example in the range of 0.1 to 5.0 wt%, based on the total weight of the sunflower lecithin composition.

[0032] For the purposes of the present invention, it has been found to be advantageous if the sunflower lecithin composition contains phosphatidylethanolamine, in particular in an amount in the range of 1.0 to 25.0 wt.-%, typically in the range of 2.0 to 20.0 wt.-%, based on the total weight of the sunflower lecithin composition.

[0033] In addition, the sunflower lecithin composition may contain one or more fatty acid triglycerides and / or free fatty acids, which are residues from its production 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 lecithin composition.

[0034] Due to the presence of free fatty acids, the sunflower lecithin composition of the invention may have an acid value different from 0. Here and hereinafter, the acid value refers to the acid value in mg KOH / g. Typically, the acid value does not exceed a value of 50, in particular 40, and is typically in the range of 0.01 to 35.

[0035] According to a specific first group of embodiments, the sunflower lecithin composition has a phosphatidylcholine content of at least 85.0% by weight, in particular at least 90.0% by weight, such as 85.0 to 99.0% by weight, in particular 90.0 to 98.5% by weight, based on the total weight of the sunflower lecithin composition. In these sunflower lecithin compositions, the total amount of phospholipid compounds other than phosphatidylcholine is generally in the range of 1.0 to 12.0% by weight, in particular in the range of 1.5 to 10.0% by weight, based on the total weight of the sunflower lecithin composition. For example, the amount of lysophosphatidylcholine may be trace amounts to 5.0% by weight based on the total weight of the sunflower lecithin composition. Similarly, the amount of phosphatidylethanolamine may be trace amounts to 1.0% by weight based on the total weight of the sunflower lecithin composition. Typically, the amount of N-acylphosphatidylethanolamine does not exceed 1.0% by weight based on the total weight of the sunflower lecithin composition. The amount of free fatty acids and fatty acid triglycerides is generally less than 5% by weight, based on the total weight of the sunflower lecithin composition. The acid number of these sunflower lecithin compositions is usually below 5.

[0036] According to another specific second group of embodiments, the sunflower lecithin composition has a phosphatidylcholine content in the range of 45 to 85.0 wt.-%, particularly in the range of 50 to 85.0 wt.-%, based on the total weight of the sunflower lecithin composition. In these sunflower lecithin compositions, the total amount of phospholipid compounds other than phosphatidylcholine is typically in the range of 1.0 to 50.0 wt.-%, particularly in the range of 1.5 to 45.0 wt.-%, based on the total weight of the sunflower lecithin composition. For example, the amount of lysophosphatidylcholine may be in the range of 1.0 to 25.0 wt.-%, particularly in the range of 2.0 to 20.0 wt.-%, based on the total weight of the sunflower lecithin composition. Similarly, the amount of phosphatidylethanolamine may be in the range of 1.0 to 25.0 wt.-%, and typically in the range of 2.0 to 20.0 wt.-%, based on the total weight of the sunflower lecithin composition. Typically, the amount of N-acylphosphatidylethanolamine does not exceed 10.0 wt % and may be present in trace amounts up to 10.0 wt % based on the total weight of the sunflower lecithin composition. The amount of free fatty acids and fatty acid triglycerides is typically less than 10 wt % based on the total weight of the sunflower lecithin composition. The acid number of these sunflower lecithin compositions is typically up to 50, for example in the range of 2 to 50.

[0037] Due to the presence of unsaturated fatty acids in the phospholipid compounds of the sunflower lecithin composition, the sunflower lecithin composition generally exhibits an iodine value of at least 80, in particular at least 85. Typically, the iodine value of the sunflower lecithin composition does not exceed 130, in particular in the range of 85 to 120.

[0038] For the purposes of the present invention, the amount of sunflower lecithin composition used is generally such that the concentration of phosphatidylcholine in the oil-in-water emulsion is in the range of 0.1 to 20% by weight, in particular in the range of 0.2 to 5% by weight, and in particular in the range of 0.3 to 3% by weight, based on the total weight of the water-in-oil emulsion. In particular, the amount of sunflower lecithin composition is selected so that the weight ratio of phosphatidylcholine to oil phase in the oil-in-water emulsion is in the range of 0.5:95 to 1:3, in particular in the range of 1:99 to 1:5, and in particular in the range of 2:98 to 1:8.

[0039] The sunflower lecithin composition according to the present invention, in particular the sunflower lecithin composition according to the first and second group of embodiments, can be prepared similarly to the method for producing other vegetable oil-derived lecithin compositions, such as lecithin from soybean or rapeseed. 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 give a review of these methods. Further details can be obtained from the references cited therein. For example, the sunflower lecithin fraction obtained from the sunflower oil degumming step is deoiled to obtain a solid lecithin product, which is then fractionated into fractions with a higher phosphatidylcholine content, for example, by single-step or multi-step ethanol extraction, by chromatographic purification and / or a combination of ethanol extraction and chromatographic purification, especially for the production of a sunflower lecithin composition with a phosphatidylcholine content of at least 70% by weight or at least 80% by weight.

[0040] As indicated above, the inventors of the present invention have found that the presence of significant chlorogenic acid in a sunflower lecithin composition for parenteral fat emulsions can cause undesirable discoloration of the parenteral fat emulsion, which may be because chlorogenic acid readily forms a green pigment at pH>6, especially pH 7 or higher, which is typically encountered in the production of parenteral fat emulsions. In addition, if the sunflower lecithin composition used to produce them contains a significant amount of chlorogenic acid, the parenteral fat emulsions tend to be less stable. Therefore, the sunflower lecithin composition, in particular the sunflower lecithin composition according to the first and second group of embodiments, contains less than 0.1% by weight, based on the weight of the respective sunflower lecithin composition. In particular, the sunflower lecithin composition contains up to 0.08% by weight, especially up to 0.05% by weight, of chlorogenic acid, based on the total weight of the sunflower lecithin composition.

[0041] The term "chlorogenic acid" as used herein refers to the compound chlorogenic acid, i.e., (1S,3R,4R,5R)-3-[(E)-3-(3,4-dihydroxyphenyl)prop-2-enoyl]oxy-1,4,5-trihydroxycyclohexane-1-carboxylic acid, as well as related esters of polyphenolic compounds with quinic acid (1,4,5-trihydroxycyclohexane-1-carboxylic acid), i.e., esters of hydroxycinnamic acid compounds such as caffeic acid, ferulic acid and p-coumaric acid.

[0042] The amounts of chlorogenic acid given herein therefore relate to the total amount of such chlorogenic acid compounds in the sunflower lecithin composition.

[0043] A sunflower lecithin composition containing less than 0.1% by weight, in particular not more than 0.08% by weight or not more than 0.05% by weight, and especially not more than 0.02% by weight of chlorogenic acid, based on the total weight of the sunflower lecithin composition, in particular a sunflower lecithin composition according to the first and second groups of embodiments, can be prepared by a method comprising the following steps:

[0044] i) extracting sunflower lecithin, in particular de-oiled sunflower lecithin, with a solvent selected from acetone and a mixture of acetone and water to obtain an extract and a residue, and then

[0045] ii) repeatedly extracting the residue with ethanol or a mixture of ethanol and water to obtain an ethanol extract,

[0046] iii) combining the ethanol extracts and removing the ethanol and optionally the water to obtain a sunflower phospholipid composition containing phosphatidylcholine having a chlorogenic acid content of less than 0.1 wt.-%, particularly of at most 0.08 wt.-%, especially of at most 0.05 wt.-%, based on the total weight of the sunflower phospholipid composition.

[0047] In step i., most of the chlorogenic acid is removed from the sunflower lecithin. The sunflower lecithin is in particular de-oiled sunflower lecithin, but in step i., sunflower lecithin that has not been de-oiled can be used instead. In step i., the solvent is preferably a mixture of acetone and water, in particular a mixture of acetone and water in which the weight ratio of acetone to water is from 1:9 to 4:1.

[0048] Depending on the amount of water in the ethanol solvent used in step ii., the extract is enriched in phosphatidylcholine. The solvent in step ii. is preferably ethanol with a water content of at most 20% by weight, in particular at most 10% by weight.

[0049] In step iii., a sunflower phospholipid composition is obtained which contains phosphatidylcholine in an amount of typically at least 45 wt.-%, in particular at least 50 wt.-%, for example 45 to 99 wt.-%, in particular 50 to 98.5 wt.-%, based on the total weight of the sunflower phospholipid composition.

[0050] After step iii., a further chromatographic purification may follow, thereby further increasing the phosphatidylcholine content to a value of, for example, at least 85% by weight or at least 90% by weight, depending on the desired grade of the sunflower phospholipid composition.

[0051] For the stability of the parenteral fat emulsion, it is advantageous that the sunflower lecithin composition is used in combination with at least one anionic stabilizer compound comprising at least one anionic phospholipid compound. Anionic stabilizer compounds, which are also referred to as "anionic stabilizers", are anionic compounds that carry at least one fatty acid group and are negatively charged in water at a concentration of 1% by weight and a pH value of pH 6. By using anionic stabilizer compounds, a negative charge is provided to the oil droplets of the parenteral fat emulsion, thereby promoting the emulsification process and stabilizing the emulsion by electrostatic repulsion. The use of these anionic stabilizer compounds results in a negative zeta potential on the oil droplets. In this regard, it has been found that anionic phospholipids are particularly beneficial. Anionic phospholipids can be the only anionic stabilizer compound. However, they can be combined with one or more other anionic stabilizers or anionic stabilizer compounds that are different from anionic phospholipids.

[0052] Examples of anionic stabilizer compounds other than anionic phospholipids are fatty acids.

[0053] Anionic stabilizer compounds can be used in their acidic form or in the form of their pharmaceutically acceptable salts, for example in the form of their ammonium or sodium salts.

[0054] Fatty acids suitable 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, arachidic acid, behenic acid, lignoceric acid, hexacosanoic acid, myristoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, α-linolenic acid, eicosapentaenoic acid and erucic acid and mixtures thereof. The aliphatic monocarboxylic acids can be used in their acidic form or in the form of their pharmaceutically acceptable salts, in particular in the form of their sodium salts.

[0055] According to the invention, the anionic stabilizer compound comprises at least one anionic phospholipid compound. These anionic phospholipid compounds can be the only anionic stabilizer compound, however, they can also be used in combination with fatty acids. Examples of anionic phospholipid compounds are phosphatidylglycerol, phosphatidylinositol, pegylated phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, 1,3-bis(sn-3'-phosphatidyl)-sn-glycerol (also known as cardiolipin) and combinations thereof. As mentioned above, the anionic phospholipid compounds can be used in their acidic form or in the form of their pharmaceutically acceptable salts, in particular in the form of their ammonium or sodium salts.

[0056] PEGylated phosphatidylethanolamine is a compound based on phosphatidylethanolamine in which the amino group of the 2-aminoethoxy group carries a polyethylene oxide (PEG) group attached to the nitrogen atom via a carbonyl group. Such PEG groups typically have a number average molecular weight in the range of 200 to 10,000. These compounds typically have the following formula:

[0057]

[0058] Where C(O)-R 1 and C(O)-R 2 is a fatty acid residue usually having 10 to 20 carbon atoms and being saturated or unsaturated, such as stearoyl, palmitoleoyl, myristoyl or oleoyl and combinations thereof, R 3 X 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 a number in the range of 4 to 250, corresponding to a PEG group with a number average molecular weight in the range of 200 to 10,000.

[0059] Anionic phospholipid compounds are usually obtained from natural sources, in particular from sunflower oil. However, synthetic analogs of these anionic phospholipid compounds are also suitable. Synthetic phospholipid analogs may contain one or two of the above-mentioned fatty acids in the form of diacylglycerol groups.

[0060] The anionic phospholipid compound may be the only anionic stabilizer. However, it is also possible to use a combination of at least one anionic phospholipid compound and at least one other anionic stabilizer compound that is not anionic phospholipid compound, in particular a fatty acid or a fatty acid salt, as anionic stabilizer. In such a combination, the weight ratio of the anionic phospholipid compound to the other anionic stabilizer compound is in the range of 10:1 to 1:10, in particular in the range of 8:1 to 1:3.

[0061] In the combination of a sunflower lecithin composition and one or more anionic stabilizer compounds, the weight ratio of the sunflower lecithin composition to the total amount of anionic stabilizer is typically in the range of 99.8:0.2 to 80.0:20.0, typically in the range of 99.8:0.2 to 90.0:10.0, especially 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, especially 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 lecithin composition to the anionic lecithin is generally in the range of 99.8:0.2 to 80.0:20.0, typically in the range of 99.8:0.2 to 90.0:10.0, in particular 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, in particular 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 phospholipids is generally in the range of 99.8:0.2 to 70.0:30.0, typically 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, especially in the range of 98.5:1.5 to 91.0:9.0.

[0062] A particularly preferred anionic stabilizer compound is phosphatidylglycerol. Suitable phosphatidylglycerols may be obtained from animal sources or preferably from plant sources, such as phosphatidylglycerols from eggs, sunflower oil, soybean oil, rapeseed oil, canola oil, palm oil or oat oil. Likewise suitable or even preferred are synthetic or semisynthetic phosphatidylglycerols, such as 1,2-dipalmitoyl-sn-glycero-3-phosphatidylglycerol (DPPG), 1,2-dimyristoyl-sn-glycero-3-phosphatidylglycerol (DMPG), 1,2-distearoyl-sn-glycero-3-phosphatidylglycerol (DSPG), 1,2-distearoyl-sn-glycero-3-phosphatidylglycerol (DOPG) and 1,2-palmitoyl / oleoyl-sn-glycero-3-phosphatidylglycerol (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylglycerol, 1-oleoyl-2-palmitoyl-sn-glycero-3-phosphatidylglycerol and mixtures thereof; POPG). The phosphatidylglycerol is in particular a phosphatidylglycerol obtained from sunflower, in particular 1,2-dimyristoyl-sn-glycero-3-phosphatidylglycerol, also known as DMPG, or a pharmaceutically acceptable salt thereof, in particular a sodium salt thereof. DMPG or DMPG prepared from glycerophosphorylcholine obtained from sunflower phospholipids is particularly preferred. Phosphatidylglycerol obtained from sunflower phosphatidylcholine by conversion using phospholipase D or a pharmaceutically acceptable salt thereof is also suitable. If the sunflower lecithin composition is used in combination with phosphatidylglycerol, in particular 1,2-dimyristoyl-sn-glycero-3-phosphatidylglycerol or a pharmaceutically acceptable salt thereof, the weight ratio of the sunflower lecithin composition to the phosphatidylglycerol (calculated in its acid form) is typically in the range of 99.8:0.2 to 80.0:20.0, typically in the range of 99.8:0.2 to 90.0:10.0, in particular 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, in particular in the range of 98.5:1.5 to 93.0:7.0.

[0063] For the stability of the parenteral fat emulsion and for the reproducibility of the emulsification process and the homogenization process, it is advantageous that the combination of the sunflower phospholipid composition and the anionic stabilizer compound is used as a prefabricated mixture of the sunflower phospholipid composition and the anionic stabilizer compound. Without being bound by theory, it is believed that the improved reproducibility of the emulsification / homogenization process is based on the following phenomenon. Since phosphatidylcholine and anionic stabilizers, particularly anionic phospholipid compounds, spontaneously form liposomes when dispersed in water, it is possible to form stable liposomes with different compositions in terms of the relative amounts of phosphatidylcholine and anionic stabilizer molecules contained therein by separate addition of phosphatidylcholine and anionic stabilizers to the aqueous phase. Due to the slow exchange of phospholipid molecules between these liposomes, the distribution of different phospholipid molecules in the water / oil interface is uneven, which may lead to the instability of the emulsion and the poor reproducibility of the emulsification / homogenization step. The use of a preformed mixture of phosphatidylcholine and anionic stabilizer compounds will significantly reduce or even largely avoid the formation of liposomes with different compositions and will provide a more homogeneous distribution of the different phospholipid molecules in the water / oil interface and improve the reproducibility of the emulsification / homogenization step.

[0064] These mixtures contain at least one anionic stabilizer compound in addition to phosphatidylcholine. In these mixtures, the anionic stabilizer compound comprises at least one anionic phospholipid compound, in particular at least one anionic phospholipid compound selected from phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidic acid, 1,3-bis(sn-3'-phosphatidyl)-sn-glycerol and combinations thereof. In these mixtures, the anionic stabilizer compound may be present in the form of its free acid or in the form of its pharmaceutically acceptable salt. In these mixtures, the anionic stabilizer compound is even more preferably phosphatidylglycerol, in particular phosphatidylglycerol obtained from sunflower, in particular DMPG, or a pharmaceutically acceptable salt thereof, in particular 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, typically in the range of 99.8:0.2 to 85.0:15.0, in particular 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, in particular in the range of 98.5:1.5 to 91.0:9.0.

[0065] The above mixture of the sunflower lecithin composition and at least one anionic stabilizer compound comprising at least one anionic phospholipid compound corresponds to the sunflower lecithin composition of the third aspect of the invention if the amount of phosphatidylcholine contained therein is at least 45% by weight or more, in particular at least 50.0% by weight, in particular at least 55.0% by weight, based on the total weight of the mixture, for example 45 to 98.8% by weight, in particular 50 to 98.0% by weight, in particular 55 to 97.0% by weight, based on the total weight of the sunflower lecithin composition. Depending on the amount of phosphatidylcholine, the sunflower lecithin composition of the third aspect of the invention may contain one or more other phospholipid compounds different from phosphatidylcholine and anionic phospholipid compounds, in particular one or more of the following phospholipid compounds: phosphatidylethanolamine, N-acylphosphatidylethanolamine and lysophosphatidylcholine. The total amount of phospholipid compounds different from phosphatidylcholine and anionic phospholipid compounds is generally in the range of 1.0 to 50.0% by weight, particularly in the range of 1.5 to 45.0% by weight, particularly in the range of 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 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 based on the total weight of the sunflower phospholipid composition, and is generally in the range of 1.0 to 20.0% by weight. Generally, the amount of N-acylphosphatidylethanolamine does not exceed 10.0% by weight, and may be present in trace amounts to 10.0% by weight, based on the total weight of the sunflower phospholipid composition.

[0066] These mixtures of sunflower lecithin compositions and at least one anionic stabilizer compound comprising at least one anionic phospholipid compound, especially the sunflower lecithin composition of the third aspect of the present invention, can be obtained from a sunflower lecithin source by enriching sunflower lecithin with respect to phosphatidylcholine, especially by enriching to a phosphatidylcholine content of not more than 80% by weight, especially 45 to 75% by weight, based on the weight of the sunflower lecithin composition. They can also be prepared by supplementing a conventional sunflower lecithin composition containing phosphatidylcholine with the aid of conventional mixing techniques. In particular, these mixtures, especially the sunflower lecithin composition of the third aspect of the present invention, can be prepared by a method comprising dissolving a sunflower lecithin composition containing phosphatidylcholine and at least one anionic stabilizer, especially anionic phospholipid compounds, in an organic solvent and evaporating the solvent. Typical solvents are organic solvents and organic solvent mixtures, wherein the components, i.e., the sunflower lecithin composition containing phosphatidylcholine and the anionic phospholipid compounds, are completely soluble in the desired amount. Suitable solvents include C1-C4 alkanols, such as methanol or ethanol, and mixtures thereof with water. Halogenated hydrocarbons such as methylene chloride and chloroform and mixtures thereof with the above solvents may also be used but are less preferred for toxicological and environmental reasons.

[0067] The sunflower lecithin compositions as described herein, in particular the sunflower lecithin compositions according to the first and second groups of embodiments and the preferred sunflower lecithin compositions and the sunflower lecithin compositions of the second and third aspects of the invention may contain pharmaceutically acceptable antioxidants, in particular lipophilic antioxidants, for example tocopherols, such as alpha tocopherol, alpha tocopherol acetate, delta tocopherol, gamma tocopherol, vitamin E, ascorbyl palmitate, which may be synthetic or may be of natural origin, such as animal or preferably plant origin.

[0068] The sunflower lecithin compositions as described herein, in particular the sunflower lecithin compositions according to Group 1 and Group 2 embodiments and the preferred sunflower lecithin compositions and the sunflower lecithin compositions of the second and third aspects of the invention comply with pharmacopoeia standards, in particular with regard to endotoxin and microbial content.

[0069] The sunflower lecithin compositions as described herein, in particular the sunflower lecithin compositions according to the first and second groups of embodiments and the preferred sunflower lecithin compositions and the sunflower lecithin compositions of the second and third aspects of the invention are particularly suitable as emulsifiers in parenteral fat emulsions. The preformed mixture of the third aspect of the invention can be used as such or in combination with one or more other anionic stabilizer compounds.

[0070] They are particularly suitable as emulsifiers for aqueous oil-in-water emulsions for parenteral nutrition. However, they can also be used as emulsifiers in parenteral fat emulsions of lipophilic drugs.

[0071] These aqueous oil-in-water emulsions for parenteral administration, particularly for parenteral nutrition, contain

[0072] a) an oily phase comprising a triglyceride composition suitable for parenteral administration, in particular for parenteral nutrition,

[0073] b) a combination of a sunflower lecithin composition as defined herein containing less than 0.1 wt.-%, in particular not more than 0.08 wt.-% or not more than 0.05 wt.-%, especially not more than 0.02 wt.-% of chlorogenic acid, based on the total weight of the sunflower lecithin composition, and at least one anionic stabilizer comprising at least one anionic phospholipid compound and optionally a further anionic stabilizer, in particular a combination of a sunflower lecithin composition according to one of the first or second group of embodiments, or a sunflower lecithin composition according to the third aspect of the invention, and

[0074] c) Water.

[0075] The kind of the oil phase depends in a known manner on the intended use of the aqueous oil-in-water emulsion. In the case of an oil-in-water emulsion for parenteral nutrition, the oil phase consists essentially of a triglyceride composition suitable for parenteral administration. In the context of a triglyceride composition suitable for parenteral administration, the term "consisting of" is understood to mean that the oil phase contains at least 95% by weight, in particular at least 99% by weight, of a triglyceride composition.

[0076] Suitable triglyceride compositions for parenteral administration, particularly for parenteral nutrition, include oils and fats, particularly oils and fats from plant sources, and marine oils, including but not limited to soybean oil, safflower oil, sunflower oil, coconut oil, olive oil, medium chain triglycerides (MCT), long chain triglycerides (LCT), fish oil, krill oil, algae oil and mixtures of these oils, such as soybean oil / olive oil mixtures, soybean oil / safflower oil mixtures, soybean oil / MCT mixtures, LCT and MCT transesterified mixtures (inter-esterified mixtures) and soybean oil / MCT / olive oil / fish oil mixtures. The above-mentioned oils are mainly composed of triglycerides, but may certainly contain a small amount of fatty acids. Typically, oils and fats are composed of at least 99% by weight of fatty acid triglycerides and optional free fatty acids.

[0077] The term "fish oil" refers to "purified fish oil" and "purified fish oil enriched in omega-3 fatty acids", the latter comprising at least 9% (w / w) of the omega-3 fatty acid docosahexaenoic acid (DHA) and at least 13% (w / w) of the omega-3 fatty acid eicosapentaenoic acid (EPA), expressed as triglycerides, according to the European Pharmacopoeia 6.0.

[0078] For parenteral nutrition, it is preferred that the triglycerides and free fatty acids contain high amounts of polyunsaturated fatty acids, including omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both commonly found in marine fish oils, and alpha-linolenic acid (ALA), commonly found in vegetable oils.

[0079] If the oil-in-water emulsion is to be used for parenteral administration of the drug, the oil phase usually contains a drug dissolved or dispersed in the oil phase. In particular, the drug is a lipophilic drug. Suitable drugs for parenteral administration may be selected from anesthetics, analgesics, vasodilators, immunosuppressants, antianxiety agents, antiemetics and antibiotics / antifungals and cytostatics. They include but are not limited to propofol, aprepitant, clevidipine butyrate, alprostadil, dexamethasone palmitate, diazepam, amphotericin B, etomidate, flurbiprofen axetil, prostaglandin E1 and cyclosporin, progesterone, lomustine, physostigmine salicylate and perilla ketone (1-(3-furanyl)-4-methyl-1-pentanone).

[0080] In oil-in-water emulsions for parenteral administration, the amount of the oil phase is generally in the range of 5 to 35 wt.-%, particularly in the range of 8 to 30 wt.-%, more particularly in the range of 8 to 25 wt.-%, especially in the range of 8 to 17 wt.-% or in the range of 8 to 12 wt.-% or in the range of 15 to 22 wt.-% or in the range of 18 to 22 wt.-%, based on the total weight of the aqueous oil-in-water emulsion.

[0081] The oil-in-water emulsion for parenteral administration also contains a sunflower lecithin composition as defined herein, in particular a sunflower lecithin composition according to one of Group 1 or Group 2 embodiments, especially a sunflower lecithin composition according to one of aspects 2 or 3 of the invention.

[0082] The amount of the sunflower lecithin composition is generally selected so that the concentration of phosphatidylcholine in the oil-in-water emulsion is in the range of 0.1 to 10 wt.-%, particularly 0.2 to 5 wt.-%, especially 0.3 to 3 wt.-%, based on the total weight of the water-in-oil emulsion. In particular, the amount of the sunflower lecithin composition is selected so that the weight ratio of phosphatidylcholine to 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, especially 2:98 to 1:8.

[0083] As indicated above, it is beneficial for the stability of the oil-in-water emulsion that it contains, in addition to the phosphatidylcholine of the sunflower phospholipid composition, at least one anionic stabilizer compound. According to the invention, the anionic stabilizer compound comprises or is at least one anionic phospholipid compound, in particular at least one anionic phospholipid compound selected from phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidic acid, 1,3-bis(sn-3'-phosphatidyl)-sn-glycerol and combinations thereof. In the emulsion, the anionic stabilizer compound may be present in the form of its free acid or in the form of its pharmaceutically acceptable salt. In these emulsions, the anionic stabilizer compound is even more preferably or comprises phosphatidylglycerol, in particular phosphatidylglycerol obtained from sunflower, in particular DMPG, or a pharmaceutically acceptable salt thereof, in particular its sodium salt. In these emulsions, the weight ratio of the total amount of phosphatidylcholine to the anionic stabilizer is generally in the range of 99.8:0.2 to 70:30, generally in the range of 99.8:0.2 to 85.0:15.0, in particular in the range of 99.5:0.5 to 90.0:10.0, in particular in the range of 99.0:1.0 to 90.0:10.0, in particular in the range of 98.5:1.5 to 91.0:9.0. The concentration of anionic phospholipids in the emulsion is generally in the range of 0.005 to 0.2% by weight, in particular 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 generally in the range of 0.005 to 0.25% by weight, in particular in the range of 0.01 to 0.2% by weight, based on the total weight of the emulsion.

[0084] As indicated above, it is beneficial for the visual appearance, in particular for reducing or avoiding discoloration and for the stability of the oil-in-water emulsion of the present invention that it contains only a small amount of chlorogenic acid or no chlorogenic acid. Therefore, the sunflower lecithin composition contained in the emulsion has a chlorogenic acid content of less than 0.1% by weight, in particular at most 0.08% by weight, especially at most 0.05% by weight, based on the total weight of the sunflower lecithin composition. Typically, the total amount of chlorogenic acid in the emulsion does not exceed 0.001% by weight, in particular 0.0005% by weight, and in particular 0.0002% by weight, based on the total weight of the emulsion.

[0085] In addition to the above-mentioned compounds, the oil-in-water emulsion of the present invention may further comprise at least one pharmaceutically acceptable antioxidant. The antioxidant that can be used in the emulsion of the present disclosure can be any pharmaceutically acceptable compound having antioxidant activity, for example, the antioxidant can be selected from sodium metabisulfite, sodium bisulfite, sodium sulfite, sodium thiosulfate, thioglycerol, thiosorbitol, thioglycolic acid, cysteine ​​hydrochloride, n-acetylcysteine, citric acid, α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, tocotrienols, soluble forms of vitamin E, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-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, ascorbyl palmitate and mixtures thereof.

[0086] The at least one antioxidant is in particular selected from alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol, tocotrienols, ascorbic acid and mixtures of two or more thereof. Preferably, the antioxidant is alpha-tocopherol.

[0087] If present, the total amount of the agent having antioxidant activity is preferably in the range of 1 to 200 mg / L, preferably 10 to 200 mg / L, more preferably 40 to 150 mg / L, even more preferably 50 to 120 mg / L or 75 to 100 mg / L.

[0088] The emulsion may contain one or more pharmaceutically acceptable tonicity agents. Tonicity agents are used to impart tonicity to the emulsion. Suitable tonicity agents may be selected from sodium chloride, mannitol, lactose, dextrose, sorbitol and glycerol. Preferably, the tonicity agent is glycerol.

[0089] The amount of tonicity agent depends in a known manner on the desired osmolality and the molecular weight of the tonicity agent. Typically, the total amount of tonicity agent is in the range of 0.1 to 10 wt.-%, more preferably 1 to 5 wt.-%, more preferably 1 to 4 wt.-%, more preferably 1 to 3.5 wt.-%, especially 1.5 to 3.0 wt.-%, based on the total weight of the emulsion. In the case where the tonicity agent is glycerol, the most preferred amount is 2.0 to 3.0 wt.-%, based on the total weight of the emulsion.

[0090] Preferably, the emulsion has an osmotic pressure in the range of 180 to 300 mOsmol / L, in particular 190 to 280 mOsmol / L, especially 200 to 250 mOsmol / L.

[0091] The aqueous oil-in-water emulsion of the present invention may have a pH value in the range of pH 4 to pH 10 as measured at 20°C and 1 bar. Preferably, the pH of the emulsion is in the range of pH 6 to pH 9, such as pH 6.1 to about pH 8.9, or pH 6.2 to pH 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 about pH 7, about pH 7.5 and / or about pH 8.

[0092] The pH of the lipid emulsion can be adjusted by adding conventionally known acids or bases, such as solutions of HCl and NaOH, or less preferably, by using a buffer, such as a phosphate buffer. Preferably, the pH of the emulsion according to the present disclosure is adjusted using a NaOH solution.

[0093] In the parenteral fat emulsions according to the invention, the continuous phase is an aqueous phase and the dispersed phase is formed by droplets of an oil phase, also referred to below as oil droplets. These oil droplets are stabilized in the aqueous phase by the sunflower phospholipid composition as described herein, in particular by the phosphatidylcholine and optionally other anionic stabilizers contained therein. The size of the oil droplets depends on the qualitative and quantitative composition of the emulsion and its preparation. The oil droplets of the emulsion 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, in particular in the range of 180 to 350 nm. The average diameter given here refers to the volume or mass moment average, also referred to as the De Broucker average, as determined by dynamic light scattering of a diluted aqueous emulsion at 20°C according to ISO 13320:2009. The aqueous oil-in-water emulsions according to the invention generally have not more than 0.05% of the mass fraction according to USP. <729> PFAT5 value of 0.05%, which means that the volume-weighted percentage of oil droplets / fat globules with a diameter greater than 5 μm does not exceed 0.05 wt%.

[0094] Depending on the desired use, the parenteral fat emulsion according to the invention may contain one or more additional additives present in the aqueous phase. For example, the parenteral fat emulsion for parenteral nutrition may contain one or more additives selected from amino acids, including essential amino acids such as histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine and inorganic salts or pharmaceutically acceptable ammonium compounds, such as carnitine or choline and pharmaceutically acceptable salts or derivatives thereof.

[0095] For example, the parenteral fat emulsion for parenteral nutrition may further comprise L-carnitine or its salt or derivative and / or choline or its salt or derivative. Preferably, L-carnitine is provided in free form. Preferably, the parenteral fat emulsion according to the present disclosure comprises L-carnitine in a concentration of 500 to 1500 mg / L, preferably 600 to 1000 mg / L based on the total volume of the emulsion.

[0096] For example, the parenteral fat emulsion for parenteral nutrition may further comprise choline. Preferably, choline is provided in the form of sodium cytidine 5'-diphosphocholine, choline chloride or α-glycerophosphorylcholine (GPC). GPC may be of any origin, but is preferably obtained from sunflower sources. Preferably, the parenteral fat emulsion may comprise choline in a concentration of 1 to 2 g / L, preferably 1.1 to 1.7 g / L, based on the total volume of the emulsion.

[0097] For example, a parenteral fat emulsion for parenteral nutrition may contain L-carnitine or a salt or derivative thereof and choline or a salt or derivative thereof.

[0098] The parenteral fat emulsions of the present invention can be prepared analogously to known methods as described in the references cited in the above background, for example in Hippalgaonkar et al., AAPS Pharm Sci Tech 2010, 11(4), 1526-1540 and references cited therein.

[0099] Typically, the oil phase is emulsified in the aqueous phase in the presence of a phospholipid composition and optionally an anionic stabilizer compound. The emulsification is typically performed in two steps, including a first pre-emulsification step, in which a coarse emulsion is obtained, which is then subjected to a homogenization step to reduce the droplet size of the oil droplets of the coarse emulsion to a droplet size suitable for parenteral administration. Thus, the preparation method comprises the following steps:

[0100] i. Providing an aqueous phase and an oil phase;

[0101] ii. Emulsify the oil phase in the water phase

[0102] - in the presence of a sunflower lecithin composition as defined herein containing less than 0.1 wt.-%, in particular not more than 0.08 wt.-% or not more than 0.05 wt.-%, especially not more than 0.02 wt.-% of chlorogenic acid, based on the total weight of the sunflower lecithin composition, and at least one anionic stabilizer comprising at least one anionic phospholipid compound as defined herein and optionally further anionic stabilizer compounds, or

[0103] - in the presence of the sunflower lecithin composition of the third aspect of the invention;

[0104] iii. Homogenizing the emulsion obtained in step ii. to a droplet size suitable for parenteral administration.

[0105] Of course, the sunflower lecithin composition used in step ii. has a chlorogenic acid content of less than 0.1 wt.-%, in particular not more than 0.08 wt.-%, or not more than 0.05 wt.-%, especially not more than 0.02 wt.-%, based on the total weight of the sunflower lecithin composition.

[0106] Typically, water-soluble ingredients are dissolved in the aqueous phase and oil-soluble ingredients, including drug substances, are dissolved in the triglyceride composition of the oil phase, respectively. For example, a choline source, an amino acid or a carnitine source, if present, will be dissolved in the aqueous phase. The sunflower lecithin 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 a preferred set of embodiments, the sunflower lecithin composition and the optional anionic stabilizer are dispersed in the aqueous phase before the emulsification step.

[0107] It is beneficial for the stability of the resulting emulsion and for the reproducibility of the method that the combination is used as a pre-mixture as described above. The pre-mixture is then dispersed in the aqueous phase or dissolved in the oil phase. However, it is possible to disperse / dissolve the sunflower lecithin composition and the anionic stabilizer separately in the oil phase or in the aqueous phase.

[0108] Both phases may be heated sufficiently and optionally stirred to disperse or dissolve the ingredients before carrying out step ii. The heating temperature is generally in the range of 30 to 80°C.

[0109] In step ii., the oil phase is then typically introduced into the aqueous phase and stirred, for example by using a high shear mixer, to form a uniformly dispersed macroemulsion or preemulsion. Preemulsions with a droplet size of less than 20 μm typically produce unimodal and physically stable fine emulsions. Preferably, step ii. is carried out at elevated temperature, for example in the range of 40 to 80° C. Preferably, the oil phase and the aqueous phase are preheated to the desired temperature, preferably in the range of 40 to 80° C., and the heated oil phase and the heated aqueous phase are then mixed for emulsification.

[0110] The pre-emulsion is then homogenized, for example by using a microfluidizer or a high pressure homogenizer, to further reduce the droplet size and form a fine emulsion having a particle size suitable for parenteral administration.

[0111] The pressure, operating temperature, and number of homogenization cycles required for performing step iii. of the method can be routinely found based on the embodiments disclosed herein. Similarly, other parameters, such as the type, composition, and concentration of the oil phase and the aqueous phase, may affect the average droplet size during high-homogenization, and the above parameters are adjusted accordingly in a known manner. If pressure homogenization is used in step iii., the pressure can vary over a wide range. Typically, it is in the range of 100 to 1300 bar, particularly in the range of 200 to 1200 bar, particularly in the range of 300 to 110 bar or 400 to 1000 bar.

[0112] Preferably, step iii. is performed at elevated temperature, for example in the range of 30 to 80°C.

[0113] If necessary, the pH of the homogenized parenteral fat emulsion obtained in step iii. can be adjusted to the above-mentioned desired value. However, it is also possible to adjust the pH before carrying out 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 is found to be beneficial to adjust the pH to at least pH 6, in particular to a value of at least pH 7, for example to pH 7 to 9 to promote emulsification and homogenization, respectively, before step ii. and / or before step iii. It should also be noted that the pH can be adjusted to a pH slightly higher than the desired pH of the final emulsion, because the pH of the emulsion may decrease during emulsification, homogenization or sterilization.

[0114] The entire process (filtration / coarse and miniemulsion preparation) is usually performed under nitrogen atmosphere whenever possible, especially if excipients and specific components of the lipid emulsion are sensitive to oxidation.

[0115] The homogenized parenteral fat emulsion obtained in step iii. is generally subjected to a sterilization step. Sterilization can be carried out by methods known in the art, for example by heat or by sterile filtration.

[0116] The sterilization of parenteral fat emulsions is preferably carried out by terminal heat sterilization, also known as high pressure steam sterilization. Heat sterilization generally provides greater assurance for the sterility of the final product. In addition, it has been surprisingly found that high pressure steam sterilization provides improved stability against phase separation or droplet growth for parenteral fat emulsions. However, if the components of the emulsion are not heat resistant, sterile filtration can be used. Sterilization by filtration requires that the droplet size of the emulsion is less than 200nm.

[0117] Alternatively, aseptic processing can be used. However, this process is relatively equipment-intensive and labor-intensive, and requires additional process validation data and justification during regulatory submissions.

[0118] In a very preferred group of embodiments, the method for preparing a parenteral fat emulsion according to the present invention comprises the following steps:

[0119] a. The oil phase and the aqueous phase are heated to a temperature of about 40 ℃ to about 80 ℃ respectively under stirring;

[0120] b. dispersing the sunflower lecithin composition containing or not containing a stabilizer in an aqueous phase;

[0121] c. preparing a pre-emulsion by transferring the oil phase to the water phase under stirring;

[0122] d. homogenizing the pre-emulsion at a temperature of about 40°C to 80°C under pressure;

[0123] e. optionally adding water to adjust the desired volume and concentration;

[0124] f. adjusting the pH to a range of about 4 to 10, in particular 6 to 9 or 7 to 9; and

[0125] g. The lipid emulsion is optionally sterilized by autoclaving and / or sterile filtration.

[0126] Typically, 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, to avoid any oxidation reactions. The skilled person will readily recognize that steps b., c., d., e. and g. are carried out in this order, and step f. may be carried out at any stage of the process, but after step a. and before step g. Step a. may be carried out before or in parallel with step b., but in any case before step c. Step f. may be carried out between steps c. and d. and / or after step d. or e. or between steps b. and c. and / or after step d. or e.

[0127] The parenteral fat emulsion of the present invention obtained in step iii., d., e., f. or g. is then packaged into suitable containers. Plastic containers that are oxygen permeable and / or contain oil-soluble plasticizers are generally avoided.

[0128] For example, the parenteral fat emulsion of the present invention is packaged in a glass bottle with a suitable rubber stopper and aluminum cap or piggyback to meet pharmaceutical requirements.

[0129] The parenteral fat emulsion of the present invention can also be packaged in a chamber of a multi-chamber container for parenteral administration of a nutritional formula. For example, the container can be in the form of a bag with multiple compartments or chambers. The container, such as a bag, includes at least two chambers, but may also contain three, four or five chambers, and in a preferred embodiment, two or three chambers. Suitable containers, including soft bags, are typically sterile, pyrogen-free, disposable and / or ready-to-use. The multi-chamber container is particularly useful for accommodating children and / or neonatal parenteral nutrition products, and a parenteral fat emulsion as disclosed herein is typically provided in the first chamber, an amino acid preparation is provided in the second chamber, and a carbohydrate preparation is provided in the third chamber of the container.

[0130] Multi-chamber container, such as three-chamber bag, may include vertical chamber. Suitable multi-chamber container is disclosed in U.S. Patent Publication No.2007 / 0092579. For example, multi-chamber container can be configured to include a bag of two or three adjacent chambers or compartments. If necessary, use a frangible barrier (frangible barrier) or an openable seal (openable seals) (such as peel seals (peel seals) or frangible seals (frangible seals)) to separate the chambers of the multi-chamber container. Multi-chamber container can also include three chambers to accommodate parenteral fat emulsion, carbohydrate preparation and amino acid preparation, and further include at least one, two or three smaller chambers in certain embodiments to accommodate, for example, vitamin preparation and / or trace element preparation. In a specific embodiment, the multi-chamber container of the present invention has a first chamber for accommodating parenteral fat emulsion according to the present invention, a second chamber for accommodating amino acid preparation, a third chamber for accommodating carbohydrate preparation, a fourth chamber for accommodating vitamin preparation and a fifth chamber for accommodating trace element preparation.

[0131] The openable seals of the multi-chamber container allow preparations to be stored separately and mixed / reconstructed before administration, thereby allowing preparations that should not be stored for a long time as a mixture to be stored in a single container. The opening of the seal realizes the mixing of the contents of the communication between the chambers and each chamber. The outside seals of the multi-chamber container are strong seals so that they will not open under the fluid pressure of the weaker peel seals or frangible seals for opening the chambers. In some embodiments, the openable seals of the multi-chamber container can be designed to only allow the mixing or reconstruction of the selected chamber of the multi-chamber container, for example, if desired, the mixing of parenteral fat emulsions with vitamin chambers and amino acid chambers.

[0132] The multi-chamber container may be provided with instructions explaining the desired order in which the peel seals are opened to allow the constituent fluids to mix in the desired order. The tear strength of two or more peel seals may be varied to facilitate opening the seals in the desired order. For example, the tear strength of the peel seal to be opened first may be 1 / 3 to 1 / 2 of the tear strength required to open the peel seal to be opened second.

[0133] abbreviation:

[0134] % bw weight %

[0135] DMPG-Na Dimyristoylphosphatidylglycerol, sodium salt

[0136] DOPS-Na dioleoyl-glycerol-3-phosphoserine, sodium salt

[0137] LPC Lysophosphatidylcholine

[0138] m month

[0139] nd Not determined

[0140] nlt is not less than

[0141] nmt is not greater than

[0142] PC Phosphatidylcholine

[0143] PdI Polydispersity Index

[0144] PE Phosphatidylethanolamine

[0145] PG Phosphatidylglycerol

[0146] RT room temperature, 22°C

[0147] w week

[0148] Quality / stability analysis and evaluation:

[0149] Use a glass pH electrode ( The pH value was determined with a calibrated portable pH meter from 911 pH, Knick GmbH, Berlin, Germany.

[0150] The average particle size of the emulsions was determined by dynamic light scattering technique on a Zetasizer Nano-ZS90 (Malvern Instruments, Malvern, UK). The emulsions were diluted with water for injection to a concentration suitable for measurement. The measurements were performed at 20°C. The intensity-weighted mean droplet diameter was reported.

[0151] The acid number was determined according to the Ph. Eur. method. All values ​​reported are given as mg KOH / g.

[0152] The composition of the sunflower phospholipid composition was evaluated by standard HPLC procedures as described, for example, 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.

[0153] For visual inspection, the emulsion was transferred to a 50 ml glass vial and visually inspected for free fat droplets under a suitable light source.

[0154] For stability testing, vials were stored in the dark at approximately 20-25°C and analyzed at designated time points. For accelerated storage condition testing, vials were stored in a heating oven (Memmert, Schwabach, Germany) at 45°C protected from light and analyzed after six weeks and three months.

[0155] Nature / quality of chemicals used

[0156] Phospholipid composition P1: Purified fraction of sunflower lecithin. This purified fraction contains nlt96% bw PC, nmt2% bw LPC, <0.1% bw PE, <0.1% bw N-acyl-phosphatidylethanolamine, <0.05% bw free fatty acids and nmt1.7% bw triglycerides. The acid value is 0.1–0.3, the iodine value is 96–108, and it exhibits a fatty acid profile typical of sunflower lecithin (ca.9% palmitic acid, ca.3% bw stearic acid, ca.16% bw oleic acid and ca.70% bw linoleic acid). The chlorogenic acid content is less than 0.03% bw.

[0157] Phospholipid composition P2: Purified fraction of sunflower lecithin. This purified fraction contains 64% bw PC, 1.9% bw LPC, 6.9% bw PE and 0.3% bw triglycerides. The acid value is 18, and it shows a typical fatty acid profile of sunflower lecithin (ca.9% bw palmitic acid, ca.3% bw stearic acid, ca.16% bw oleic acid and ca.70% bw linoleic acid). The chlorogenic acid content is 1.3% bw.

[0158] Phospholipid composition P3: Purified fraction of sunflower lecithin. This purified fraction contains 71% bw PC, 2.0% bw LPC, 0.9% bw PG and 7.7% bw PE. The acid value is 11, and it shows a typical fatty acid profile of sunflower lecithin (ca.9% bw palmitic acid, ca.3% bw stearic acid, ca.16% bw oleic acid and ca.70% bw linoleic acid). The chlorogenic acid content is 0.06% bw.

[0159] The 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 with a water content of about 20% bw. The residue was dried under vacuum. The dried residue was then extracted with ethanol (96%) and filtered. This extraction was repeated twice. The filtrates were combined and evaporated to dryness under vacuum, yielding (relative to the de-oiled lecithin) 13% of the phospholipid composition P3.

[0160] Phospholipid composition P4: Purified fraction of sunflower lecithin having a similar overall composition to phospholipid composition P1 but with a chlorogenic acid content of 1.1% bw

[0161] Phospholipid composition P5: a mixture of phospholipid composition P1 and DMPG-Na at a weight ratio of 20:1 (ratio of PC:DMPG-Na = 19.6:1)

[0162] Phospholipid composition P5 was prepared by dissolving phospholipid composition P1 (50 g) and DMPG-Na (2.5 g) in a mixture of chloroform / methanol / water at 50° C. The solvent was evaporated under vacuum and the resulting waxy solid was further dried under vacuum at 30° C.

[0163] Phospholipid composition P6: a mixture of phospholipid composition P1 and DMPG-Na in a weight ratio of 15.4:1 (ratio of PC:DMPG-Na = 15.1:1)

[0164] Phospholipid composition P6 was prepared by dissolving phospholipid composition P1 (20 g) and DMPG-Na (1.3 g) in a mixture of chloroform / methanol / water at 50° C. The solvent was evaporated under vacuum and the resulting waxy solid was further dried under vacuum at 25° C.

[0165] Phospholipid composition P7: a mixture of phospholipid composition P1 and DMPG-Na at a weight ratio of 60.6:1 (ratio of PC:DMPG-Na = 59.4:1)

[0166] Phospholipid composition P7 was prepared by dissolving phospholipid composition P1 (20 g) and DMPG-Na (0.33 g) in a mixture of chloroform / methanol / water at 50° C. The solvent was evaporated under vacuum and the resulting waxy solid was further dried under vacuum at 25° C.

[0167] Phospholipid composition P8: a mixture of phospholipid composition P1 and DMPG-Na in a weight ratio of 20:1 (ratio of PC:DOPS-Na = 19.6:1)

[0168] Phospholipid composition P8 was prepared by dissolving phospholipid composition P1 (20 g) and DOPS-Na (1.0 g) in a mixture of chloroform / methanol / water at 50° C. The solvent was evaporated under vacuum and the resulting waxy solid was further dried under vacuum at 25° C.

[0169] DMPG-Na (dimyristoylphosphatidylglycerol, sodium salt) was used as a commercial product (LIPOID GmbH, Ludwigshafen, Germany). It had a chromatographic purity of ≥98%. The amount of myristic acid was ≥98.0% bw, based on the total amount of fatty acids in DMPG-Na.

[0170] DOPS-Na (dioleoyl-glycero-3-phosphoserine, sodium salt) was used as a commercial product (LIPOID GmbH, Ludwigshafen, Germany). It had a chromatographic purity of ≥90%. The oleic acid purity was ≥98.0% bw based on the total amount of fatty acids in DOPS-Na.

[0171] The quality of glycerol, sodium hydroxide, soybean oil and MCT oil (medium chain triglycerides) used met the requirements of Ph. Eur. Lysine dihydrochloride (≥98%) and glycin (≥99%) were from Sigma-Aldrich.

[0172] Experimental conditions / equipment

[0173] For all experiments, water for injection (Ph. Eur.) with a maximum conductivity of 5.0 μS / cm was used.

[0174] In the following experiments, an Ultra-Turrax T 50 (IKA Labortechnik, Staufen, Germany) was used for high shear mixing.

[0175] Use Microfluizider 110T (Microfluidics TM , USA) for high pressure homogenization.

[0176] Parenteral fat emulsions were prepared in glass vials and autoclaved in the following examples. Filling was performed under nitrogen in glass vials (20 ml) of hydrolytic class 1. The vials were closed with brominated butyl rubber stoppers, crimped and autoclaved in a steam autoclave (Systec GmbH, Linden, Germany) equipped with a rapid cooling function. The holding time was 15 minutes at 121°C.

[0177] Preparation Example:

[0178] In the following preparation examples, glycerol was used as a tonicity agent in an amount of 2.25 wt%. In each example, the amount of water was chosen so that the batch size was 500 grams.

[0179] Example 1 (not according to the invention)

[0180] Glycerol and water for injection were mixed. Lecithin composition P1 (6.0 g) was added and the mixture was stirred at 50°C until the lecithin was completely dispersed. Purified soybean oil (100 g) was heated to 60°C separately. The aqueous phase was mixed with a high shear mixer at 10.000 rpm. Mixing continued while slowly adding the heated oil phase. The pH was adjusted to 8.5 by adding aqueous sodium hydroxide solution (0.5 M). The resulting pre-emulsion was then homogenized five times using a high pressure homogenizer at a pressure of 800 bar. The temperature was maintained at 50°C to 70°C during the homogenization process. Before the fifth pass, the pH was adjusted to 8.5 again. After homogenization, the emulsion was cooled to below 30°C, filled in glass vials and sterilized by high pressure steam.

[0181] Analyze the data:

[0182] Homogeneous white liquid

[0183] pH: 7.4

[0184] Average particle size (PdI): 229nm (0.046)

[0185] Stability: Free fat visible after 3 months storage at RT

[0186] Example 2

[0187] Glycerol and water for injection were mixed. Lecithin composition P1 (6.0 g) and DMPG-Na (0.30 g) were added and the mixture was stirred at 50°C until the lecithin was completely dispersed. Purified soybean oil (100 g) was heated to 60°C alone. The aqueous phase was mixed with a high shear mixer at 10.000 rpm. Mixing was continued while slowly adding the heated oil phase. The pH was adjusted to 7.5 by adding aqueous sodium hydroxide solution (0.5 M). The resulting pre-emulsion was then homogenized five times using a high pressure homogenizer at a pressure of 800 bar. The temperature was maintained at 50°C to 70°C during the homogenization process. Before the fifth pass, the pH was adjusted to 7.5 again. After homogenization, the emulsion was cooled to below 30°C, filled in glass vials and sterilized by high pressure steam.

[0188] Analyze the data:

[0189] Homogeneous white liquid

[0190] pH: 6.8

[0191] Average particle size (PdI): 220nm (0.099)

[0192] Stability: 3m at 45℃:

[0193] Homogeneous white liquid

[0194] pH: 6.5

[0195] Average particle size: 234nm

[0196] At room temperature 6m:

[0197] Homogeneous white liquid

[0198] pH: 7.7

[0199] Average particle size: 234nm

[0200] At room temperature 18m:

[0201] Homogeneous white liquid

[0202] pH: 7.6

[0203] Average particle size: 238nm

[0204] Example 3

[0205] Glycerol and water for injection were mixed. Lecithin composition P5 (6.0 g) was added and the mixture was stirred at 50°C until the lecithin was completely dispersed. Purified soybean oil (100 g) was heated to 60°C separately. The aqueous phase was mixed with a high shear mixer at 10.000 rpm. Mixing continued while slowly adding the heated oil phase. The pH was adjusted to 8.3 by adding aqueous sodium hydroxide solution (0.5 M). The resulting pre-emulsion was then homogenized five times using a high pressure homogenizer at a pressure of 800 bar. The temperature was maintained at 50°C to 70°C during the homogenization process. Before the fifth pass, the pH was adjusted to 8.5 again. After homogenization, the emulsion was cooled to below 30°C, filled in glass vials and sterilized by high pressure steam.

[0206] Analyze the data:

[0207] Homogeneous white liquid

[0208] pH: 7.7

[0209] Average particle size (PdI): 245nm (0.070)

[0210] Stability: 6w at 45℃:

[0211] Homogeneous white liquid

[0212] pH: 7.9

[0213] Average particle size: 239nm

[0214] At 45℃ for 3m:

[0215] Homogeneous white liquid

[0216] pH: 7.9

[0217] Average particle size: 241nm

[0218] At room temperature 12m:

[0219] Homogeneous white liquid

[0220] pH: 7.9

[0221] Average particle size: 241nm

[0222] Example 4

[0223] Example 4 The procedure of Example 1 was followed using phospholipid composition P3 (6.0 g) instead of phospholipid composition P1 (6.0 g).

[0224] Analyze the data:

[0225] Homogeneous white liquid

[0226] pH: 7.7

[0227] Average particle size (PdI): 242nm (0.095)

[0228] Stability: 3m at 45℃:

[0229] Homogeneous white liquid

[0230] pH: 7.6

[0231] Average particle size: 250nm

[0232] At room temperature 12m:

[0233] Homogeneous white liquid

[0234] pH: 7.6

[0235] Average particle size: 260nm

[0236] Example 5 (not according to the invention)

[0237] Example 5 The procedure of Example 1 was carried out using phospholipid composition P2 (6.0 g) instead of phospholipid composition P1 (6.0 g). After the first pH adjustment, the pre-emulsion turned green. After autoclaving, the green color faded and the emulsion had an off-white color.

[0238] Analyze the data:

[0239] Homogeneous gray liquid

[0240] pH: 7.6

[0241] Average particle size (PdI): 253nm (0.094)

[0242] Stability: 6w at 45℃:

[0243] Off-white liquid with small oil droplets on the surface

[0244] pH: 7.0

[0245] Average particle size: 239nm

[0246] At 45℃ for 3m:

[0247] Off-white liquid with free fat on the surface

[0248] pH: 6.9

[0249] Average particle size: nd

[0250] At room temperature 12m:

[0251] Off-white liquid with small oil droplets on the surface

[0252] pH: 7.2

[0253] Average particle size: 237nm

[0254] Example 6 (not according to the invention)

[0255] Example 6 The procedure of Example 1 was carried out using a mixture of purified soybean oil (50 g) and purified medium chain triglycerides (50 g) instead of purified soybean oil (100 g).

[0256] Analyze the data:

[0257] Homogeneous white liquid

[0258] pH: 7.5

[0259] Average particle size (PdI): 270nm (0.023)

[0260] Stability: 3m at 45℃:

[0261] White liquid with small oil droplets on the surface

[0262] pH: 6.9

[0263] Average particle size: 259nm

[0264] At room temperature 12m:

[0265] White liquid with small oil droplets on the surface

[0266] pH: 7.9

[0267] Average particle size: 276nm

[0268] Example 7

[0269] Glycerol and 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 heated to 60°C separately. The aqueous phase was mixed with a high shear mixer at 10.000 rpm. Mixing continued while slowly adding the heated oil phase. The pH was adjusted to 8.5 by adding aqueous sodium hydroxide solution (0.5 M). The resulting pre-emulsion was then homogenized five times using a high-pressure homogenizer at a pressure of 800 bar. The temperature was maintained at 50°C to 70°C during the homogenization process. Before the fifth pass, the pH was adjusted to 8.5 again. After homogenization, the emulsion was cooled to below 30°C, filled in glass vials and sterilized by high-pressure steam.

[0270] Analyze the data:

[0271] Homogeneous white liquid

[0272] pH: 7.8

[0273] Average particle size (PdI): 227nm (0.065)

[0274] Example 8

[0275] Example 8 The procedure of Example 3 was followed using a mixture of purified soybean oil (50 g) and purified medium chain triglycerides (50 g) instead of purified soybean oil (100 g). As in Example 3, a homogeneous mixture of phospholipid composition P1 and DMPG-Na in a weight ratio of 20:1 was used (6 g of P5 instead of P1).

[0276] Analyze the data:

[0277] Homogeneous white liquid

[0278] pH: 7.5

[0279] Average particle size (PdI): 232nm (0.026)

[0280] Stability: 3m at 45℃:

[0281] Homogeneous white liquid

[0282] pH: 7.2

[0283] Average particle size: 212nm

[0284] Example 9

[0285] Example 9 The procedure of Example 1 was carried out using a mixture of purified soybean oil (50 g) and purified medium chain triglycerides (50 g) instead of purified soybean oil (100 g) and using phospholipid composition P3 instead of phospholipid composition P1.

[0286] Analyze the data:

[0287] Homogeneous white liquid

[0288] pH: 7.8

[0289] Average particle size (PdI): 240nm (0.002)

[0290] Stability: 3m at 45℃:

[0291] Homogeneous white liquid

[0292] pH: 7.1

[0293] Average particle size: 224nm

[0294] Example 10 (not according to the invention)

[0295] Glycerol and 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 heated to 60°C separately. The aqueous phase was mixed with a high shear mixer at 10.000 rpm. Mixing continued while slowly adding the heated oil phase. The pH was adjusted to 8.5 by adding an aqueous sodium hydroxide solution (0.5 M). After pH adjustment, the pre-emulsion turned green. The pre-emulsion was then homogenized five times using a high pressure homogenizer at a pressure of 800 bar. The temperature was maintained at 50°C to 70°C during the homogenization process. Before the 5th pass, the pH was adjusted to 8.5 again. After homogenization, the emulsion was cooled to below 30°C, filled in glass vials and autoclaved. After autoclaving, the green color faded and the emulsion had a grayish white to gray color.

[0296] Analyze the data:

[0297] Homogeneous gray liquid

[0298] pH: 7.6

[0299] Average particle size (PdI): 243nm (0.005)

[0300] Stability: 3m at 45℃:

[0301] Homogeneous gray liquid

[0302] pH: 7.0

[0303] Average particle size: 230nm

[0304] At room temperature 12m:

[0305] Gray liquid with small oil droplets on the surface

[0306] pH: 7.7

[0307] Average particle size: 265nm

[0308] Embodiment 11

[0309] Glycerol and 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 heated to 60°C separately. Glycine (0.05 g) and lysine dihydrochloride (0.05 g) were added to the aqueous phase and stirring was continued until the amino acids were dissolved (approximately 2 min). The aqueous phase was mixed with a high shear mixer at 10.000 rpm. Mixing was continued while slowly adding the heated oil phase. The pH was adjusted to 7.5 by adding aqueous sodium hydroxide solution (0.5 M). The resulting pre-emulsion was then homogenized five times using a high pressure homogenizer at a pressure of 800 bar. The temperature was maintained at 50°C to 70°C during the homogenization process. Before the fifth pass, the pH was adjusted to 8.5. After homogenization, the emulsion was cooled to below 30°C, filled in glass vials and sterilized by high pressure steam.

[0310] Analyze the data:

[0311] Homogeneous white liquid

[0312] pH: 8.6

[0313] Average particle size (PdI): 245nm (0.100)

[0314] Stability: 3m at 45℃:

[0315] Homogeneous white liquid

[0316] pH: 7.9

[0317] Average particle size: 240nm

[0318] At room temperature 12m:

[0319] Homogeneous white liquid

[0320] pH: 8.4

[0321] Average particle size: 262nm

[0322] Example 12 (not according to the invention)

[0323] Mix glycerol and water for injection. Add phospholipid composition P4 (6.0 grams) and DMPG-Na (0.30 grams) and stir the mixture at 50°C until the phospholipids are fully dispersed. Purified soybean oil (100 grams) is heated to 60°C alone. Glycine (0.05 grams) and lysine dihydrochloride (0.05 grams) are added to the aqueous phase and stirring is continued until the amino acids are dissolved (about 2 minutes). The aqueous phase is mixed at 10.000rpm with a high shear mixer. Continue mixing while slowly adding the heated oil phase. By adding sodium hydroxide aqueous solution (0.5M), the pH is adjusted to 7.7. After pH adjustment, the pre-emulsion becomes green. The resulting pre-emulsion is then homogenized five times using a high pressure homogenizer at a pressure of 800 bars. The temperature is maintained at 50°C to 70°C during the homogenization process. Before the 5th time, the pH is adjusted to 8.5. After homogenization, the emulsion was cooled to below 30°C, filled in glass vials and autoclaved. After autoclaving, the green color faded and the emulsion had a grey color.

[0324] Analyze the data:

[0325] Homogeneous gray liquid

[0326] pH: 8.6

[0327] Average particle size (PdI): 240nm (0.033)

[0328] Stability: 3m at 45℃:

[0329] Homogeneous gray liquid

[0330] pH: 7.7

[0331] Average particle size: 234nm

[0332] At room temperature 12m:

[0333] Gray liquid with small oil droplets on the surface

[0334] pH: 8.2

[0335] Average particle size: 260nm

[0336] Embodiment 13

[0337] Example 13 The procedure of Example 11 was carried out using a mixture of purified soybean oil (50 g) and purified medium chain triglycerides (50 g) instead of purified soybean oil (100 g).

[0338] Analyze the data:

[0339] Homogeneous white liquid

[0340] pH: 8.3

[0341] Average particle size (PdI): 226nm (0.102)

[0342] Stability: 3m at 45℃:

[0343] Homogeneous white liquid

[0344] pH: 8.1

[0345] Average particle size: 224nm

[0346] Example 14 (not according to the invention)

[0347] Example 14 The procedure of Example 12 was carried out using a mixture of purified soybean oil (50 g) and purified medium chain triglycerides (50 g) instead of purified soybean oil (100 g). The first pH adjustment was pH 7.8 instead of pH 7.7. After the first pH adjustment, the pre-emulsion turned green. After autoclaving, the green color faded and the emulsion had a gray appearance.

[0348] Analyze the data:

[0349] Homogeneous gray liquid

[0350] pH: 8.3

[0351] Average particle size (PdI): 237nm (0.014)

[0352] Stability: 3m at 45℃:

[0353] Homogeneous gray liquid

[0354] pH: 7.4

[0355] Average particle size: 227nm

[0356] At room temperature 12m:

[0357] Gray liquid with small oil droplets on the surface

[0358] pH: 8.1

[0359] Average particle size: 224nm

[0360] Embodiment 15

[0361] Example 15 The procedure of Example 2 was carried out using 0.4 g DMPG-Na (0.08% bw based on the emulsion) instead of 0.3 g DMPG-Na.

[0362] Analyze the data:

[0363] Homogeneous white liquid

[0364] pH: 7.2

[0365] Average particle size (PdI): 229nm (0.105)

[0366] Stability: 3m at 45℃:

[0367] Homogeneous white liquid

[0368] pH: 6.8

[0369] Average particle size: 244nm

[0370] At room temperature 18m:

[0371] Homogeneous white liquid

[0372] pH: 7.8

[0373] Average particle size: 246nm

[0374] Example 16

[0375] Example 16 The procedure of Example 2 was carried out using 0.1 g DMPG-Na (0.02% bw based on the emulsion) instead of 0.3 g DMPG-Na.

[0376] Analyze the data:

[0377] Homogeneous white liquid

[0378] pH: 6.9

[0379] Average particle size (PdI): 221nm (0.043)

[0380] Stability: 3m at 45℃:

[0381] Homogeneous white liquid

[0382] pH: 6.8

[0383] Average particle size: 239nm

[0384] At room temperature 18m:

[0385] Homogeneous white liquid

[0386] pH: 7.3

[0387] Average particle size: 244nm

[0388] Embodiment 17

[0389] Example 17 The procedure of Example 7 was carried out using 0.4 g DMPG-Na (0.08% bw based on the emulsion) instead of 0.3 g DMPG-Na.

[0390] Analyze the data:

[0391] Homogeneous white liquid

[0392] pH: 7.7

[0393] Average particle size (PdI): 200nm (0.032)

[0394] Stability: 3m at 45℃:

[0395] Homogeneous white liquid

[0396] pH: 7.6

[0397] Average particle size: 218nm

[0398] At room temperature 3m:

[0399] Homogeneous white liquid

[0400] pH: 7.9

[0401] Average particle size: 209nm

[0402] Embodiment 18

[0403] Example 18 The procedure of Example 7 was carried out using 0.1 g DMPG-Na (0.02% bw based on the emulsion) instead of 0.3 g DMPG-Na.

[0404] Analyze the data:

[0405] Homogeneous white liquid

[0406] pH: 7.7

[0407] Average particle size (PdI): 209nm (0.035)

[0408] Stability: 3m at 45℃:

[0409] Homogeneous white liquid

[0410] pH: 7.2

[0411] Average particle size: 218nm

[0412] At room temperature 3m:

[0413] Homogeneous white liquid

[0414] pH: 7.2

[0415] Average particle size: 225nm

[0416] Embodiment 19

[0417] Example 19 was carried out according to the procedure of Example 3 using 6.0 g of phospholipid composition P6 instead of phospholipid composition P5.

[0418] Analyze the data:

[0419] Homogeneous white liquid

[0420] pH: 7.8

[0421] Average particle size (PdI): 232nm (0.042)

[0422] Stability: 3m at 45℃:

[0423] Homogeneous white liquid

[0424] pH: 7.7

[0425] Average particle size: 246nm

[0426] At room temperature 3m:

[0427] Homogeneous white liquid

[0428] pH: 8.2

[0429] Average particle size: 247nm

[0430] Embodiment 20

[0431] Example 20 was carried out according to the procedure of Example 3 using 6.0 g of phospholipid composition P7 instead of phospholipid composition P5.

[0432] Analyze the data:

[0433] Homogeneous white liquid

[0434] pH: 7.7

[0435] Average particle size (PdI): 222nm (0.096)

[0436] Stability: at room temperature for 3m:

[0437] Homogeneous white liquid

[0438] pH: 8.0

[0439] Average particle size: 245nm

[0440] Embodiment 21

[0441] Example 21 was carried out according to the procedure of Example 8 using 6.0 g of phospholipid composition P6 instead of phospholipid composition P5.

[0442] Analyze the data:

[0443] Homogeneous white liquid

[0444] pH: 7.6

[0445] Average particle size (PdI): 210nm (0.013)

[0446] Stability: at room temperature for 3m:

[0447] Homogeneous white liquid

[0448] pH: 8.1

[0449] Average particle size: 221nm

[0450] Embodiment 22

[0451] Example 22 was carried out according to the procedure of Example 8 using 6.0 g of phospholipid composition P7 instead of phospholipid composition P5.

[0452] Analyze the data:

[0453] Homogeneous white liquid

[0454] pH: 7.8

[0455] Average particle size (PdI): 206nm (0.033)

[0456] Stability: at room temperature for 3m:

[0457] Homogeneous white liquid

[0458] pH: 8.2

[0459] Average particle size: 219nm

[0460] Embodiment 24

[0461] Example 24 was carried out according to the procedure of Example 3 using 6.0 g of phospholipid composition P8 instead of phospholipid composition P5.

[0462] Analyze the data:

[0463] Homogeneous white liquid

[0464] pH: 8.2

[0465] Average particle size (PdI): 212nm (0.061)

[0466] Stability: 3m at 45℃:

[0467] Homogeneous white liquid

[0468] pH: 7.7

[0469] Average particle size: 245nm

[0470] At room temperature 6m:

[0471] Homogeneous white liquid

[0472] pH: 8.0

[0473] Average particle size: 245nm

[0474] Embodiment 25

[0475] Example 25 was carried out according to the procedure of Example 7 using 6.0 g of phospholipid composition P1 and 0.3 g of DOPS-NA instead of DMPG-Na.

[0476] Analyze the data:

[0477] Homogeneous white liquid

[0478] pH: 8.2

[0479] Average particle size (PdI): 216nm (0.071)

[0480] Stability: 3m at 45℃:

[0481] Homogeneous white liquid

[0482] pH: 7.3

[0483] Average particle size: 221nm

[0484] Embodiment 26

[0485] Example 26 was carried out according to the procedure of Example 8 using 6.0 g of phospholipid composition P8 instead of phospholipid composition P5.

[0486] Analyze the data:

[0487] Homogeneous white liquid

[0488] pH: 8.0

[0489] Average particle size (PdI): 203nm (0.013)

[0490] Stability: 3m at 45℃:

[0491] Homogeneous white liquid

[0492] pH: 7.3

[0493] Average particle size: 226nm

[0494] At room temperature 3m:

[0495] Homogeneous white liquid

[0496] pH: 7.8

[0497] Average particle size: 228nm

[0498] Embodiment 27

[0499] Example 27 The procedure of Example 2 was followed using an additional 0.15 g of sodium oleate (0.03% bw based on the emulsion). Sodium oleate was added to the water / glycerol mixture together with the phospholipid composition P1 (6.0 g) and DMPG-Na (0.3 g).

[0500] Analyze the data:

[0501] Homogeneous white liquid

[0502] pH: 8.6

[0503] Average particle size (PdI): 229nm (0.102)

[0504] Stability: 6w at 45℃:

[0505] Homogeneous white liquid

[0506] pH: 8.0

[0507] Average particle size: 240nm

[0508] Embodiment 28

[0509] Example 28 The procedure of Example 7 was followed using an additional 0.15 g of sodium oleate (0.03% bw based on the emulsion). Sodium oleate was added to the water / glycerol mixture together with the phospholipid composition P1 (6.0 g) and DMPG-Na (0.3 g).

[0510] Analyze the data:

[0511] Homogeneous white liquid

[0512] pH: 8.5

[0513] Average particle size (PdI): 202nm (0.064)

[0514] Stability: 6m at 45℃:

[0515] Homogeneous white liquid

[0516] pH: 7.7

[0517] Average particle size: 208nm

[0518] Embodiment 29

[0519] Example 29 The procedure of Example 4 was followed using an additional 0.15 g of sodium oleate (0.03% bw based on the emulsion). Sodium oleate was added to the water / glycerol mixture together with the phospholipid composition P3 (6.0 g).

[0520] Analyze the data:

[0521] Homogeneous white liquid

[0522] pH: 8.3

[0523] Average particle size (PdI): 236nm (0.081)

[0524] Stability: 3m at 45℃:

[0525] Homogeneous white liquid

[0526] pH: 7.7

[0527] Average particle size: 230nm

[0528] At room temperature 12m:

[0529] Homogeneous white liquid

[0530] pH: 7.9

[0531] Average particle size: 235nm

[0532] Example 30 The procedure of Example 9 was followed using an additional 0.15 g of sodium oleate (0.03% bw based on the emulsion). Sodium oleate was added to the water / glycerol mixture together with the phospholipid composition P3 (6.0 g).

[0533] Analyze the data:

[0534] Homogeneous white liquid

[0535] pH: 8.3

[0536] Average particle size (PdI): 215nm (0.056)

[0537] Stability: 6m at 45℃:

[0538] Homogeneous white liquid

[0539] pH: 7.6

[0540] Average particle size: 234nm

Claims

1. Use of a sunflower lecithin composition containing phosphatidylcholine in an amount of at least 45% by weight, based on the total weight of the lecithin composition, and containing less than 0.1% by weight of chlorogenic acid, based on the total weight of the sunflower lecithin composition, in combination with at least one anionic stabilizer compound comprising at least one anionic phospholipid compound as an emulsifier in an aqueous oil-in-water emulsion for parenteral administration, The anionic phospholipid compound is selected from phosphatidylglycerol, phosphatidylinositol, pegylated phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, 1,3-bis(sn-3'-phosphatidyl)-sn-glycerol and combinations thereof.

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

3. The use according to claim 1, wherein the anionic phospholipid compound is phosphatidylglycerol.

4. The use according to claim 1, wherein the anionic phospholipid compound is 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol.

5. 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. Use according to any one of the preceding claims, wherein the sunflower phospholipid composition contains phosphatidylethanolamine.

7. Use according to any of the preceding claims, wherein the sunflower lecithin composition is used in an amount such that the phosphatidylcholine concentration in the oil-in-water emulsion is in the range of 0.1 to 20 wt.-%, based on the total weight of the water-in-oil emulsion.

8. Use according to any of the preceding claims, wherein the oil-in-water emulsion for parenteral administration is an oil-in-water emulsion for parenteral nutrition.

9. A sunflower lecithin composition containing phosphatidylcholine in an amount of at least 45% by weight, based on the total weight of the sunflower lecithin composition, and having a chlorogenic acid content of less than 0.1% by weight, based on the total weight of the sunflower lecithin composition, in combination with at least one anionic stabilizer compound comprising at least one anionic phospholipid compound, wherein the anionic phospholipid compound is selected from phosphatidylglycerol, phosphatidylinositol, pegylated phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, 1,3-bis(sn-3'-phosphatidyl)-sn-glycerol, and combinations thereof.

10. A sunflower lecithin composition comprising phosphatidylcholine in an amount of at least 45 wt % based on the total weight of the sunflower lecithin composition and at least one anionic stabilizer compound comprising at least one anionic phospholipid compound, and having a chlorogenic acid content of less than 0.1 wt % based on the total weight of the sunflower lecithin composition, wherein the composition is a mixture of a sunflower lecithin composition and an anionic stabilizer, wherein the anionic phospholipid compound is selected from the group consisting of phosphatidylglycerol, phosphatidylinositol, pegylated phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, 1,3-bis(sn-3'-phosphatidyl)-sn-glycerol and combinations thereof.

11. A combination according to claim 9 or a composition according to claim 10, wherein the anionic phospholipid compound is phosphatidylglycerol.

12. A combination according to claim 9 or a composition according to claim 10, wherein the anionic phospholipid compound is 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol.

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

70.

14. An aqueous oil-in-water emulsion for parenteral administration, comprising a) an oily phase comprising a triglyceride composition suitable for parenteral administration, b) a combination of a sunflower lecithin composition as claimed in any one of claims 1 to 9 containing less than 0.1% by weight of chlorogenic acid, based on the total weight of the sunflower lecithin composition, and at least one anionic stabilizer compound comprising at least one phospholipid compound, or the sunflower lecithin composition according to any one of claims 10 to 13, and c) water; The anionic phospholipid compound is selected from phosphatidylglycerol, phosphatidylinositol, pegylated phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, 1,3-bis(sn-3'-phosphatidyl)-sn-glycerol and combinations thereof.

15. An aqueous oil-in-water emulsion according to claim 14, wherein the oil phase consists essentially of a triglyceride composition suitable for parenteral administration.

16. The aqueous oil-in-water emulsion according to claim 14, wherein the aqueous oil-in-water emulsion is an aqueous oil-in-water emulsion for parenteral nutrition.

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 phosphatidylcholine is in the range of 0.2:99.8 to 15:

85.

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

19. An aqueous oil-in-water emulsion according to any one of claims 14 to 18, containing 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 as measured at 20°C and 1 bar.

21. An aqueous oil-in-water emulsion according to claim 14, wherein the oil phase comprises a triglyceride composition for parenteral nutrition.

22. A method for preparing an aqueous oil-in-water emulsion for parenteral administration as claimed in any one of claims 14 to 21, comprising i. Providing an aqueous phase and an oil phase; ii. Emulsify the oil phase in the water phase - in the presence of a sunflower lecithin composition containing less than 0.1% by weight of chlorogenic acid, based on the total weight of the sunflower lecithin composition, as claimed in any one of claims 1 to 9, in combination with at least one anionic stabilizer compound comprising an anionic phospholipid compound or - in the presence of a sunflower lecithin composition according to any one of claims 10 to 13; iii. Homogenizing the emulsion obtained in step 1 to a droplet size suitable for parenteral administration.

23. The method according to claim 22, further comprising mixing the sunflower phospholipid composition containing phosphatidylcholine with one or more anionic phospholipids before dispersing the sunflower phospholipid composition containing phosphatidylcholine and one or more anionic phospholipids in water.

24. The method according to any one of claims 22 or 23, further comprising sterilizing the homogenized emulsion of step iii. by high pressure steam sterilization.

25. An oil-in-water emulsion for parenteral administration obtainable by the method according to any one of claims 22 to 24.

26. A method for producing the sunflower lecithin composition according to any one of claims 10 to 13, comprising the following steps: i) extracting the sunflower lecithin with a solvent selected from acetone and a mixture of acetone and water to obtain an extract and a residue, and then ii) repeatedly extracting the residue with ethanol or a mixture of ethanol and water to obtain an ethanol extract, iii) combining the ethanol extracts and removing the ethanol and optionally the water to obtain a sunflower lecithin composition containing phosphatidylcholine in an amount of at least 45 wt.-%, based on the total weight of the sunflower lecithin composition, and having a chlorogenic acid content of less than 0.1 wt.-%, based on the total weight of the sunflower lecithin composition, iv) dissolving the sunflower lecithin composition obtained in step iii) and at least one other anionic phospholipid compound in an organic solvent and evaporating the solvent.

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