MXPA96003038A - Oil emulsions in a - Google Patents

Abstract

The present invention relates to an oil-in-water emulsion comprising in an amount of about 0.01% -50% by weight of the total preparation, an oily material emulsified in a polar solvent in an amount of about 0.1-70% by weight of the total preparation and polar lipids in the amount remaining in the total preparation, wherein the emulsifier is a galactolipid material consisting of at least 50% of digalactosyldiacyl glycerols and wherein the ratio of the emulsifier and the oily material is about 1:10 to 1:40 in pe

Description

OIL EMULSIONS IN WATER Technical Field This invention relates to oil-in-water type emulsions comprising a polar lipid material as an emulsifier. These emulsions are suitable for use as vehicles for an active substance in a pharmaceutical composition, but also in nutritional, cosmetic, food and agricultural products. Background of the Invention Oil-in-water type emulsions for pharmaceutical applications, such as clinical nutrition and for the administration of lipophilic drugs, are generally based on natural lipids. Normally, the oil is typically a vegetable oil such as soybean oil, safflower oil and medium chain triacyl glycerol (MCT) oil. The emulsifier is usually a phospholipid such as egg yolk phospholipids (egg lecithin) or soy phospholipids (soy lecithin). These emulsifiers consist of mixtures of phospholipid classes, such as phosphatidylcholine and phosphatidylethanolamine, which are zwitterionic ionics, and phosphatidylinositol, which is anionic. It is widely known that these lecithin emulsifiers are the most widely used natural lipids for preparing emulsions on an industrial scale of the kind mentioned above. It is also well known that said emulsions suffer from disadvantages and problems that relate to the emulsifier, being phospholipids. Such disadvantages and problems, for example, are distributions of large particles and particle fusions that result in the so-called creaminess. The most commercial fat emulsions are based on egg phospholipids, which are produced from animal sources, in most cases, egg yolk powder. Animal sources, in some cases, are related to problems related to virus contamination, and, in the specific case, egg yolk powder, bacteria such as Salmonella. Another important aspect of egg phospholipids is the containment of polyunsaturated fatty esters, such as arachidonate and docosahexanoate, which are extremely susceptible to oxidation in the presence of even smaller amounts of oxygen. Therefore, the odor and taste of egg phospholipids are often not pleasant, which can be ported through fat emulsions. Pollution and oxidation can often cause problems that relate to industrial safety and management issues. Prior Art Patent E P-A2-0 402 090 describes an edible oil-in-water emulsion suitable for creams and dressings comprising 1 0-99% of all the oil and fat content of a diglyceride mixture. In order to improve the stability, the emulsion may also include 0. 1 - 10% phospholipids, based on the oil phase.

Patent EP-A2-0 391 369 describes a pharmaceutical composition of an oil-in-water type of emulsion, which comprises an effective amount of a lipophilic drug. The emulsion is composed of 3-50% of an oily vehicle, mainly MCT oil, 0.05-20% of a phospholipid, 0.03-10% of a nonionic surfactant, and 0.05% -50% of an agent ionic surfactant. The improved stability is such that it is caused by a synergism between the established ingredients. Glycosyl glycerides are a type of glycolipids that are well-known constituents of plant cell membranes. Two types based on galactose, glycerol monogalactosyldiacil, MGDG, and glycerol digalactosildiacil, DGDG, representing up to 40% of the dry weight of the thylakoid membranes are very common. The glycolipids of plants, dye units of carbohydrates, mainly galactose, attached to glycerol. In MGDG, position 1 of the galactose ring has a ß binding with glycerol, and in DGDG, there is a bond of α, 1-6 between the sugars. A minor constituent is the sulpholipid of the plant, more correctly named glycero sulfoquinovosildiacílico, SQDG, which contains a sulfonate instead of a hydroxyl group attached to carbon 6 of the terminal residue of deoxyglucose. The majority of plant glycolipids can be described by the general formula R, - O - CH; R2 - O - CH H2C [O-carbohydrate-CH2] n -R3 wherein Ri and R2 independent of each other, are saturated or unsaturated fatty acid residues of 2-24 carbon atoms and 0-6 double bonds, furthermore esterified hydroxy acids, which are stolid , or hydrogen; the carbohydrate is a unit of monosaccharide; n = 1 -5; and R3 is a hydroxyl or sulfonate group. To investigate the interaction of glycosyl glycerides with water and other polar solvents, we have surprisingly found that the glycolipid materials of cereals have a behavior that makes such lipid materials suitable, and easy to use as a carrier material especially for compositions. pharmaceuticals, and also for other formulations, such as cosmetic, agricultural, nutritive and food applications. The application of SE 9400368-8 describes an industrially applicable process for preparing a plant glycolipid material, preferably cereals, by means of extraction and chromatographic separations. The glycolipid material thus prepared can be used as an amphiphilic material in pharmaceutical, cosmetic and food products. Description of the invention This invention relates to an oil-in-water emulsion comprising 0.01% -50% by weight of the total preparation, preferably 0.1 to 10%, of an emulsifier and 0.1-70% by weight of the total preparation of an oily material emulsified in a polar solvent, characterized in that the emulsifier is a galactolipid material consisting of at least 50% digalactosyldiacyl glycerol, the remainder being other polar lipids.

In a preferred preparation, the galactolipid material consists of about 70-80% of digalactosyldiacyl glycerols and of 20-30% of other polar lipids. In another preferred preparation, the galactolipid material consists of up to 100% of digalactosyldiacyl glycerols. The digalactosyldiacyl glycerols can be described by the general formula I R2 -O-CH I H2C [O-galactose-CH2] n -R3 unit wherein Ri and R2 independently of each other, are residues of saturated or unsaturated fatty acids of 1 0-22 carbon atoms and 0-4 double bonds, or hydrogen; and R3 is a hydroxyl or sulfonate group. As preferred examples of fatty acid residues Ri and R2, there can be mentioned the fatty acyl groups that exist in nature, such as residues of the saturated palmic acid (C? SH3iCO 16: 0) and stearic acid (C? 7H35CO: 1 8: 0); of the monounsaturated acid, oleic acid (C? 7H35CO; 18: 1); and of polyunsaturated acid, the linoleic (C1 7H3, CO; 1 8: 2) and linolenic acid (C1 7H29CO; 18: 3). The fatty acid residues may also contain hydroxy acids attached to the glycerol portion with its hydroxyl groups esterified by additional fatty acids, the so-called stolides. The other polar lipids being part of the galactolipid material, are a mixture of different glyco- and phospholipids, such as MG DG and phosphatidylcholines. The composition depends on the starting material and process used for the manufacture of galactolipids. The specific proportions of the galactolipid material components are not critical to the present invention, since the DG DG content is at least 50%. However, for many applications, the maximum benefits are realized by a maximum DG DG content, the most important component is that which forms two layers.

The galactolipid material can be extracted from almost any kind of plant material. The preferred plant materials are seeds and centers of grains and cereals, for example, wheat, rye, oats, corn, rice, millet and sesame. Oat semolina, as well as wheat gluten have a high concentration of lipids and, therefore, it is advantageous to use them in the preparation process. The digalactocyldiacyl glycerols from the galatolipid material, if applicable, they can also be of synthetic origin. The oily material is a lipophilic material that has a liquid or semi-solid consistency at room temperature. No particular limitation is imposed on the oily material. By way of example, there may be mentioned plant oils, animal oils, synthetic oils, fatty oils, natural synthetic glycerides and lipophilic drugs, etc. Preferred oils are plant oils containing β-linoleic acid (GLA), such as donkey grass oils, and erasing oil, and fish oils containing eicosapentaenoic acid (ERA) and docosahexaenoic acid (DHA). The ratio between emulsifier and oily material could preferably be within the range of 1: 40-1: 1 by weight, especially 1: 25 to 1: 1 by weight. A beneficial and intrinsic aspect of the galactol lipids is the galactose units that comprise the main polar group in each molecule of lipids, which can sterically establish the emulsion droplets, and thus provide a prolonged life span when injected into the bloodstream. Synthetic diglycosyl diacid glycerols, based on galactose or any other unit of monosaccharides, such as glucose, and natural glycosylglycerides, isolated from any source, based on other carbohydrate units other than galactose, such as glucose, can be used in accordance with invention.

The oil-in-water emulsions of the invention are prepared using the galactolipid material as the emulsifier, but may contain other lower molecular compounds in an effective isotonic amount. The oil-in-water emulsion may also comprise optional additives known in the art to improve different aspects of the composition, such as flavoring agents, colorants, thickeners, co-surfactants, preservatives, antioxidants, etc. The emulsions are prepared by conventional methods. For example, a 30% (W / W) emulsion of medium chain triacyl glycerol oil in water is prepared by dispersing the emulsifier, i.e. the galactolipid material, in the oil. The glycerol and water are mixed. The oil phase, as well as the aqueous phase, are preheated and then the oil phase is added to the aqueous phase under high shear mixing. Then it is subjected to homogenization at high pressures.

The invention also relates to a pharmaceutical composition comprising a therapeutically active substance in combination with the oil in water emulsion. The therapeutically active substance can be a lipophilic drug such as anti-cancer agents, anti-microbial agents and, particularly, anti-fungal agents, immunosuppressive drugs such as cyclosporine dermatological drugs, psychotropic drugs, anesthetic drugs and other drugs, which are lipoph and which may present formulation problems, which could be solved by the use of galactolipids. A preferred oily material for the emulsion is the addition to the above-mentioned preferred oils, also an MCT oil. There are also many lipids such as free fatty acids, glycerols of mono-, di- and triacyl, phospholipids, cholesterol esters and lipids of many other types which have therapeutic actions on themselves and which can be advantageously formulated in the form of an emulsion , based on galactolipids. In this case, the therapeutically active substance, which may also have other bioactive properties. A pharmaceutical composition can be the following: a therapeutically active substance in a therapeutically effective amount; • a galactolipid emulsifier, of 0. 1 -50. % by weight of the total composition; • an oily material, 1-50% by weight of the total composition; • optionally, an isotonic agent in an isotonicly effective amount. The isotonic agent is, for example, glycerol but could also be any isotonic agent in an isotonicly effective amount. The polar solvent may be water or aqueous solutions, such as buffer solutions and saline solutions, or any other conventional solvent, such as ethanol, glycerol, propylene glycol, polyethylene glycol, polypropylene glycol, glycofuran, methyl pyrrolidone, transcutol. However, water is the most preferred solvent. A pharmaceutical composition for parenteral administration may be as follows: • 0.2-3% of 2,6-di-isopropylphenol, • 0.3-5% of galactolipid material, • 5-30% of triacyl glycerol oil, • an amount isotonicly effective of an isotonic agent, • add water up to 100%. The pharmaceutical composition can be formulated for oral, enteral, parenteral, rectal, vaginal, topical, ocular, nasal or otic administration to animals, especially mammals, including humans.

Emulsions based on galactolipids are surprisingly stable preparations compared to phospholipid emulsions made from egg lecithin or soy lecithin. Agitation tests, which destroy the phospholipid emulsions, have no effect on galatolipid emulsions. The galactolipid emulsions also exhibit a narrow and consistent particle size distribution, which It is usually a problem with phospholipid emulsions. Commercially available fat emulsions based on egg lecithin, often have a problem of containing particles that are very large, which results in problems such as the creamy phenomenon the appearance of oil droplets on the surface. The galactolipid emulsions are also surprisingly stable for sterilization by autoclaving in a normal autoclave. Commercially available fat emulsions often need to be sterilized in an autoclave in special rotating autoclaves, which have a technical problem. The use of normal autoclave processes is a pronounced industrial improvement provided by the invention. Galactolipid Material The galactolipid materials have been prepared from different grains as set forth below, and are used to make vehicle preparations and pharmaceutical compositions of the invention as set forth in the examples. In the specification% refers to% by weight if not stated otherwise. The proportion of the solvents in solvent mixtures is given in parts by volume. Galactolipid material of oats 200 kg of oat seeds (Kungsórnen AB, Sweden) were cultured and extracted with 1000 I of 95% ethanol at 70 ° C for 3 hours in an extraction tank under agitation. The slurry was centrifuged while still hot and separated from the solid particles. The liquid fraction was evaporated at 60 ° C which gave approximately 10 kg of a light brown oil. The oil was applied to a stainless steel column containing 6.25 kg of silica gel ("Matrex Slica Si, particle size 20-45 mm, pore diameter 60A, from" Amicon Corp. USA). The temperature of the column was then washed with 30 I of a mixture of hexane: isopropane, 90: 10, in order to remove all the non-polar lipids. The galactolipid material was then eluted from the column with 20 I of a mixture of hexane-isopropane, 60:40, giving a glycerol fraction of galactosyldiacil. The evaporation of this fraction gave approximately 700 g of DGDG, the main class of lipids. The galactolipid material was then dispersed in water and subjected to freeze drying, which resulted in a free flowing powder. Enrichment of DGDG from galactolipids 50 g of oat galactolipids, as obtained above, having a content of about 70%, were dissolved in 250 ml of hexane: isopropanol, 70: 30, giving a total amount of 300 ml. The obtained solution was loaded onto a column of silica gel (1 10 g) and the less polar constituents were eluted with 1 l of the mixture of hexane: isopropane, 70:30. The enriched DGDG fraction was eluted with 21 acetone. The acetone was evaporated and dried by freezing. The total yield was 17 g of an almost pure DGDG product. Hydrogenation of galactolipids 200 g of a mixture of galactolipids obtained from oats, as established above, was dissolved in 2 l of hot isopropanol. 15 g of a palladium carbon catalyst (Pd 15%, moisture 53%, "Engelhard Rome sry" Italy) were placed in the lower part of a pressure reactor (Model No. 4552M; Parr Instrument Co., USA) equipped with two propellers on an arrow of the agitator. The solution was then transferred into the reactor under a nitrogen seal to reduce the fire hazard. The reactor vessel was sealed and pressurized first three times with nitrogen in order to remove air and then three times with hydrogen gas (Plus 4.5, from Gas AB, AGA, Sweden). The hydrogen pressure was then maintained at 6 bars, the agitator was set at 600 rpm and the mixture was heated to 70 ° C. It took 14 minutes for the reaction mixture to reach its fixed temperature point. The hydrogenation process was carried out for 6 hours after which the reaction product was filtered through a 0.45 μm filter in order to remove carbon and palladium particles. The solvent was evaporated in a rotary evaporator, the residual solid material was dispersed in 1600 ml of deionized water and dried by freezing. The yield of hydrogenated galactolipids after filtration and freeze drying was 155 g. The hydrogenation performance was evaluated by gas matography, only saturated fatty acids could be detected in the hydrogenated product. Wheat gluten galactolipids 1 kg of wheat gluten powder ("AB Skánebránnerier, Sweden) was extracted with 4 i of 95% ethanol at 70 ° C for 3 hours in a beaker. 400-500 Kpa and the filter cake obtained was washed with 1 liter of hot 95% ethanol.The combined solutions of ethanol were evaporated at 60 ° C maximum and gave approximately 60 g of a yellow oil. a stainless steel column containing 45 g of silica gel ("Matrex Silica Si", particle size 20-45 μm, pore size 60?, from "Amicon Corp." USA) .The column was then washed with 700 ml. of a mixture of haxane isopropanol, 90: 10, in order to remove neutral lipids In order to remove MGDG and some other polar lipids, the column was subsequently washed with 1000 ml of a mixture of hexane isopropanol, 70.30 Elution DG DG was carried out - with 1000 ml of pure acetone. evaporation, approximately 4 g of an almost pure DGDG product were obtained. Rye galactolipids 100 g of flakes ("Kungsórnen AB", Sweden) were stirred for 60 min. in a mixture of industrial hexane and isopropanol, 90:10. The slurry was filtered and evaporated which yielded 0.5 g of polar lipids. The residue, dissolved in 10 ml of a mixture of hexane and isopropanol, 70:30, was loaded in three columns of "Sep-Pak Silica plus" (Millipore Corp., USA) connected in series, washed with 20 ml of it. mixture of solvents and eluted with 15 ml of acetone. The eluate was evaporated and dried by freezing, and the yield was 47 mg of galactolipids. Chemical and physical characterization of different galactolipid materials Analysis of lipid classes Lipid class analysis was carried out by high performance liquid matography, HPLC, using a column packed with silica modified by diols ("Lisfere 100 DIOL, 5 μm, 250 mm x 4 mm id; E. MerckP Germany) The column was enclosed in a water bath maintained at 75 ° C. The analytical system consisted of a CLAR CM 4000 pump ("LDC / Milton Roy, USA), and an injector, model 7125, with a 20 μl injection loop ("Rheodyne Inc." USA). The evaporator light sweep detector, used as a "Sedex 45" (SEDE R. E, France) equipped with a "Sedex 55" nebulizer chamber with a bypass tube temperature and air inlet pressure of 07 ° C and 2.0 bar, respectively. The flow of the mobile phase was 1 ml / min during the analysis. A gradient of binary solvent, linear for 25 min, was used starting with 100% A and ending with 100% B, where A = hexane: i sopropanol: n-butanol: tetrahydrofuran; isooctane: water, 64: 20: 6: 4.5: 1, and B = isopropanol: n-butanol: tetrahydrofuran: iso-oxetane: water, 75: 6: 4.5: 4.5: 10. All solvents contained ammonium acetate, 180 mg / l. - * The data collection and processing was done with the "GynkoSoft Data" system version 4.22 ("Softron GmgHP Germany).

The normal amount injected for analysis was 100 μg. The identification was based on the comparison of the retention time with authentic normals ("Karlshamn s LipiTeknik ABP Sweden)." The 5 volatile compounds were not detected in this system. , - quantification was based on peak area calculations. The zeta potentials were determined in aqueous dispersions of galactol lipids with a "Zetasizer 4" instrument ("Malvern Instruments Ltd.", United Kingdom) 0 Table 1 Characterization of different galactolipid materials In Table 1, as well as in Table 2 below, the following abbreviations are used: o-GL = oat galactolipids oh-GL = oat hydrogenated galactolipids o-DGDG = enriched oat galactolipids w-GL = wheat galactolipids w -DGDG = wheat enriched galactolipids r-GL = rye galactolipids Analysis of Fatty Acids The analysis of the fatty acid profile was performed by gas chromatography after transesterification of lipids to methyl esters of fatty acids. These were separated and quantified by capillary column gas chromatography in a Capilar Gas Chromatograph "Varían 3500" equipped with a capillary column of 30 m x 0.25 mm i.d. ("DB-WAX; J &W ScientificP EUA), an injector on the column and a flame ionization detector.Helium was used as the vehicle gas.The integration with the system" GynkoSoft Data "version 4.22 was carried out. ("Softron GmbH", Germany) Transesterification was performed by adding 1 ml of a lipid sample to 2 ml of dimethyl carbonate: iso-octane, 1: 1, 1 ml of a solution containing 2.3 g of dissolved sodium was added. in 200 ml of methanol, and the test tube was shaken vigorously for 30 seconds and left at room temperature for 15 minutes to ensure the complete reaction, 3 ml of water was added and the test tube was stirred and then centrifuged. 2 x g 0.5 μl of the organic layer was injected into the Chromatograph with the following separation conditions: The furnace temperature was programmed, starting at 130 ° C (2 min), increasing to 150 ° C (30 ° / min) and 220 ° CX (3.2 ° C / min) with a 10 minute break. Atura of the injector was 130 ° C and the temperature of the detector was 250 ° C. Initially the gas flow was 2.7 ml / min. The results are expressed as normalized weight percentages using the normal external method. No correction factors were used for minor constituents for which there are no normals available or acceptably pure. Table 2 Characterization of fatty acid composition Composition o-CJL o-h-OI. o-DODO w-OL w-DCDG r-OL and guasos acids% weight C 1 10 C 16 ?? 20 21 21 16 15 13 12 C 18? O 74 C lBtl n-9 17 17 19 C 18: 1 n-7 C 18? 2 n-6 53 52 58 71 68 69 C 1BI3 n-3 Mlenores-cu and nó identified Nuclear Magnetic Resonance Spectroscopy of Digalactosyldiacil Glycerols A 13C Nuclear Magnetic Resonance spectrum of natural abundance decoupled by one-dimensional protons was recorded in a "Bruker AM-400" spectrometer ("Bruker Analitische Messtchnik GmbH", Germany) at a frequency of 13C of 100.614 Mhz. The pulse angle was 36 °, the repetition time of pulses of 1.0 second and the resolution of 1526 Hz per data point. During the process, a line extension of 3Hz was applied. The samples (10-40 mg) were diluted in a mixture of 730 μl DMSo-dβ ("Aldrich Chemical Comp., Inc.", E. U.A.) and 20 μl of D2O ("Aldrich Chemical Comp. Inc. ", USA) and transferred to a tube for NMR (5 mm id). Table 3 Chemical changes of 13 C (ppm) of wheat digalactosyl diacyl glycerols and oats EXAMPLES In the following examples, commercially available chemicals were used, without further purification if not stated otherwise. In all the preparations membrane filtered, deionized water was used. As model oils, soybean oil and medium chain triacyl glycerol oil (MCT) were used, fish oils and oils with a high content of α - linoleic acid (GLA), obtained from grass seeds of the ass. However, the type of oily matter is not crucial to obtain the specific benefits of the present invention. Soybean oil, corn oil, and MCT oil were manufactured by Karishamns AB, Sweden, and purified chromatographically.The herb grass oils with different contents of GLA, free GLA and fish oils, were manufactured by "Calinas" Ltd ", Scotland, and were used as received, except fish oils, which were chromatographically purified.Ascorbyl palmitate antioxidants and" E 442"(ammonium phosphatides) were obtained from" Roche Products Ltd. ", Kingdom United, and "Palsgasrd AS", Denmark, respectively.The emulsions were prepared by homogenization at high pressure, using different equipment as set out in the examples.The particle size distributions (drop) and the zeta potential of the resulting emulsions. , was determined by dynamic light sweep ("Zetasizer 4"; "Malvern Instruments Ltd.", United Kingdom) at room temperature. The particle size measurements were carried out at a 90 ° angle, using a cell AZ104 and multimodal analysis. The data were reported as averages of Z. The zeta potentials were measured with the same cell with the following instrumental parameters: cross beam mode, F (xa) = 1.50 and cell voltage 134 V. Example 1. Preparation of a 10% fat emulsion (MCT oil) An oil in water emulsion (batch size of 200 g) was prepared, containing the following ingredients: Ingredient%. Emulsifier 0.5 MCT oil 10.0 Glycerol, 99% 2.3 Water up to 100.0 The emulsifier, which is the galactolipid, was dispersed in the oil. The glycerol and water were mixed. The oil phase and the aqueous phase were preheated to 70 ° C and 85 ° C, respectively. The aqueous phase was added to the oil phase under high shear mixing at 18,000 rpm for 6 min. The pre-emulsion was homogenized at 80 MPa and 50 ° C for 6 cycles ("Mini-Lab 8.30 H; APV Rannie AS", Denmark). The emulsion formed had an average droplet size of 243 nm. Example 2. Preparation of a 20% fat emulsion (MCT oil) An oil in water emulsion (batch size of 200 g) was prepared, containing the following ingredients: Ingredient% _ Emulsifier 1.0 MCT 20.1 Oil Glycerol, 99% 2.3 Water up to 100.0 The emulsifier, which is the galactolipid, was dispersed in the oil. The glycerol and water were mixed. The oil phase was reheated to 90 ° C and the aqueous phase to 50 ° C. The oil phase was added to the aqueous phase under mixing with high shear at 14,000 rpm for 4 min. The pre-emulsion was homogenized at 80 Mpa and 45 ° C for 5 cycles ("Mini-Lab 8.30 H; APV Rannie AS", Denmark). The emulsion formed had an average droplet size of 213 nm. This average size was not significantly altered by autoclaving (121 ° C, 20 min) and shaking (120 hours 150 cycles / min). Example 3. Preparation of a 30% fat emulsion (MCT oil) An oil in water emulsion was prepared (batch size of 200 g), containing the following ingredients: Ingredient% _ E mulsificante 1 .5 Oil MCT 30.1 Glycerol, 99% 2.3 Water until 1 00.0 The emulsifier, which is the galactolípido, was dispersed in the oil. The glycerol and water were mixed. The oil phase was reheated to 67 ° C and the aqueous phase to 55 ° C. The oil phase was added to the aqueous phase during high shear mixing at 13,000 rpm for 6 min. The pre-emulsion was homogenized at 80 MPa and 40 ° C for six cycles ("Mini-Lab 8.30 H; APV Rannie AS", Denmark). The emulsion formed had an average droplet size of 21 3 nm. A part of the resulting emulsion was sterilized by heat in a normal seat autoclave at 1 21 ° C for 20 minutes. After the heat treatment, a droplet size of 209 nm was determined, indicating that the emulsion droplets were not significantly affected during the process.

Another part of the emulsion was exposed to a stirring test at 150 cycles / min for 5 days. No binding of emulsion drops and subsequent creaminess can be observed after the agitation test. The average droplet size, 206 nm, indicated that the emulsion was very stable against high frequency agitation for a long period of time. Also the heat sterilized emulsion was exposed to the same agitation test, without any noticeable change in the execution of the test. An emulsion based on 1.2% of egg phospholipids and 20% of soybean oil, did not support the agitation test at the same frequency; creaminess was observed in the upper part of the egg phospholipid emulsion after 1-2 hours. Example 4. Preparation of a 39% fat emulsion (MCT oil) An oil in water emulsion was prepared (batch size) 200 g), using the following ingredients: Ingredient% _ Emulsifier 2.0 MCT oil 39.4 Water up to 100.0 The emulsifier, which is the galactolipid, was dispersed in the oil. The water and the oil phase were previously heated to 70 ° C and the oil was added to the aqueous phase under high shear mixing at 16,000 rpm for 7 min. The pre-emulsion was homogenized at 85 MPa and 50 ° C for 6 cycles ("Mini- Lab 8.30 H; APV Rannie AS ", Denmark) This formulation gave an emulsion with a slightly creamy consistency and a narrow size distribution with an average droplet size of 206 nm Example 5. Preparation of a 30% fat emulsion (MCT oil) ) An oil-in-water emulsion (batch size of 200 g) was prepared, containing the following ingredients: Ingredient% _ Emulsifier 2.5 MCT oil 50.3 Glycerol, 99% 2.3 Water up to 100.0 The emulsifier, which is the galactolipid, is It was dispersed in the oil, the glycerol and the water were mixed in. The oil phase was reheated to 60 ° C and the aqueous phase to 75 ° C. The oil phase was added to the aqueous phase during mixing with high shear at 20,000 rpm for 4.5 min The pre-emulsion was homogenized at 80 MPa and 55 ° C for 5 cycles ("Mini-Lab 8.30 H; APV Rannie AS", Denmark) .The emulsion formed had very high viscosity ("similar to yoghurt") with an average droplet size of 235 nm, Example 6. P repair of a 20% fat emulsion (MCT / sova oil) An oil-in-water emulsion (batch size of 200 g) was prepared, containing the following ingredients: I ngredient% _ Galactolipid material 1 .0 Phosphatidylcholine from soybean 1.0 Soybean oil 10.0 MCT oil 10.0 Glycerol, 99% 2.3 Water up to 100.0 The soy galactolipid and phosphatidylcholine material were dispersed in the oil mixture. The glycerol and water were mixed. The oil phase was reheated to 65 ° C and the aqueous phase to 55 ° C. The aqueous phase was added to the oil phase under mixing with high shear at 1 1,000 rpm for 9 minutes. The pre-emulsion was then homogenized at 80 MPa and 46 ° C for 5 cycles ("Mini-Lab 8.30 H; APV Rannie AS", Denmark). The emulsion formed had an average droplet size of 262 nm, which did not change significantly after sterilization in an autoclave. Example 7. Preparation of a 20% fat emulsion (soybean oil) An oil-in-water emulsion (batch size of 200 g) was prepared, containing the following ingredients: Ingredient% Emulsifier 1 .5 Soybean oil 20.0 Glycerol , 99% 2.3 Water to 100.0 The emulsifier, which is the galactolipid, was dispersed and hydrated in a portion of water. Then the glycerol and the rest of the water were added and mixed. The aqueous dispersion was subjected to high pressure homogenization for 2 cycles at 60 MPa and 40 ° C. The soybean oil, preheated to 40 ° C, was added to the aqueous dispersion under high shear mixing at 13,000 rpm for 10 minutes. The pre-emulsion was then homogenized at 80 MPa and 40 ° C for 6 cycles ("Mini-Lab 8.30 H; APV Rannie AS ", Denmark) After cooling to room temperature, the emulsion was adjusted to pH 7.2 using a 2M NaOH solution Table 4 summarizes the average drop size in nm of the emulsions described in Example 1 -7 In addition, the zeta potential values in MV are listed in Table 4, indicating that the emulsion droplets carry a significant negative charge, which implies a good shelf life of the emulsions.

An oil in water emulsion was prepared (batch size) 200 g), with the following ingredients: Ingredient% _ Emulsifier, hydrogenated 1 .02 Tan herb oil 20.46 10 Water up to 00.00 The emulsifier, that is the hydrogenated galactol, was dispersed in the oil. The oil phase and water were preheated to 62 ° C and 73 ° C, respectively, and the oil phase was added to the water under mixing with high shear at 1 4,000 rpm for 2.5 min. The pre-emulsion was homogenized at 80 MPa and 56 ° C for 7 cycles ("Mini-Lab 8.3 OH; APV Ranie AS", Denmark). This formulation gave an emulsion with an average droplet size of 240 nm. The zeta potential was -57 mV. Example 9. Preparation of a 20% fat emulsion (donut grass oil containing 9% GLA) An oil in water emulsion (batch size 200 g) was prepared with the following ingredients: Ingredients%. Emulsifier, enriched 1 .01 Ass herb oil 20.16 Water up to 100.00 The emulsifier, ie the enriched galactolipid, was dispersed in the oil. The oil phase and water were preheated to 64 ° C and 63 ° C, respectively, and the oil phase was added to the water under mixing with high shear at 13,500 rpm for 2.5 min. The pre-emulsion was then homogenized at 80 MPa and 50 ° C for 7 cycles ("Mini-Lab 8.30H; APV Ranni AS", Denmark). This formulation gave an emulsion with an average droplet size of 260 nm and a zeta potential of -50 mV. Example 10. The preparation of a 40% fat emulsion (donut grass oil containing 9% GLA) An oil in water emulsion (batch size of 300 g) was prepared, with the following ingredients: Ingredient% _ Emulsifier 1.99 Ass herb oil 39.5 Vitamin E acetate 1.08 Ammonium phosphatides, E 442 0.10 Ascorbyl palmitate 0.02 Sucrose 14.08 Lemon flavor 2.00 Potassium sorbate 0.10 Citric acid 0.01 Water to 100.0 The emulsifier and antioxidants were dispersed in the oil. Sucrose, preservative taste and water were mixed. The oil phase and the aqueous phase were preheated to 60 ° C and 68 ° C, respectively, and the oil phase was added to the aqueous phase under mixing with high shear at 17,000 rpm for 4 minutes.

The pre-emulsion was then homogenized at 80 Mpa and 60 ° C for 5 cycles ("Mini-Lab 8.30 H; APV Rannie AS", Denmark).

This formulation gave an emulsion with an average droplet size of 230 nm and a zeta potential of -72 mV. the pH was 5.8. Example 1 1. Preparation of a 36% fat emulsion (donut grass oil containing 9% GLA) An oil in water emulsion was prepared (batch size) 2300 g), with the following ingredients: Ingredient% _ Emulsifier 1 80 Ass herb oil 35.97 Vitamin E acetate 1 .09 Ammonium phosphatides, E 442 0.10 Ascorbyl palmitate 0.02 Sucrose 15.00 Banana flavor 2.00 Potassium sorbate 0.10 Water up to 100.0 The emulsifier and antioxidants were dispersed in the oil. Sucrose, preservative, flavor and water were mixed. The oil phase and the aqueous phase were preheated to 58 ° C and 63 ° C, respectively, and the oil phase was added to the aqueous phase under mixing with high shear at 16,000 rpm for 7.5 minutes. The pre-emulsion was then homogenized (Model LAB, type 12.51 H, "APV Rannie AS", Denmark) at a total pressure of 50 MPa and a pressure of 10 Pa during the second stage. The flow was 0.82 l / min, the total time of 12 minutes and the temperature of 48 ° C. This formulation gave an emulsion with an average droplet size of 230 nm and a zeta potential of -72 mV. Example 12. The preparation of an emulsion of fat at 40% (herb oil of the enriched ass, containing 20% of G LA) An oil-in-water emulsion was prepared (batch size of 300 g), with the following ingredients: Ingredient% _ Emulsifier 2.49 Ass herb oil enriq. , 20% GLA 39.85 Vitamin E acetate 0.39 Ammonium phosphatides, E 442 0.10 Ascorbyl Palmitate 0.02 Sucrose 15.04 Lemon flavor 2.00 Potassium sorbate 0.10 Water up to 100.0 The emulsifier and antioxidants were dispersed in the oil. Sucrose, preservative, flavor and water were mixed. Both phases were preheated to 65-70 ° C and the oil was added to the aqueous phase under mixing with high shear at 15,000 rpm for 3.5 minutes. The pre-emulsion was then homogenized at 80 Mpa and 60 ° C for 5 cycles ("Mini-Lab 8.30 H; APV Rannie AS ", Denmark) This formulation gave an emulsion with a thick consistency similar to yoghurt Example 13. Preparation of a 1 1% fat emulsion (enrichment herb oil containing 80% GIA) 100 were prepared g of oil in water emulsion containing the following ingredients: Ingredient% _ Emulsifier, enriched 1 .0 Enriched grass herb oil, 80% GLA 1 1 .0 Glycerol, 2.3% in water up to 100.0 The emulsifier, ie the enriched galactolipid material was dissolved in the oil at about 50 ° C under nitrogen.The glycerol and the water were mixed in. The aqueous phase was added to the oil phase under high shear mixing at 12,000 rmp for 30 seconds. The pre-emulsion was heated to 35 ° C and homogenized at 83 MPa for 5 minutes ("EmulsiFlex-C30, Abestin Inc.", Canada) The resulting emulsion had an average droplet size of 224 nm, a zeta potential of - 40 mV and was easily filtered through a membrane filter with a pore size of 0.22 μm. Example 14. Preparation of a 20% fat emulsion (free fatty acid containing 70% GLA) 50 g of an oil in water emulsion was prepared, containing the following ingredients: Ingredient% _ Emulsifier, enriched 2.5 Free fatty oil, 70% GLA 20.0 Glycerol, 2.3% in water up to 100.0 The emulsifier, i.e., the enriched galactolipid material, was dissolved in the fatty acid at about 50 ° C under nitrogen. The glycerol and water were mixed. The aqueous phase was added to the oil phase under high shear mixing at 12,000 rmp for 30 seconds. The pre-emulsion was heated to 35 ° C and homogenized at 86 MPa for 6.5 minutes ("EmulsiFlex-C30, Abestin Inc.", Canada). The resulting emulsion had an average drop size of 21 1 nm, a zeta potential of -40 mV and was easily filtered through a membrane filter with a pore size of 0.22 μm. Example 15. Preparation of a 39% fat emulsion (sardine oil rich in eicosapentanoic acid (ERA) An oil in water emulsion was prepared (batch size 250 g), with the following ingredients: Ingredient% Emulsifier 3.88 Oil of sardines 38.93 Vitamin E acetate 1 .08 Ammonium phosphatides, E 442 1.00 Ascorbyl palmitate 0.02 Sucrose 14.98 Mint flavor 1.00 Potassium sorbate 0.20 Water up to 100.0 The emulsifier and antioxidants were dispersed in the oil Sucrose, preservative was mixed The oil phase and the aqueous phase were preheated to 57 ° C and 51 ° C, respectively, and the oil phase was added to the aqueous phase under mixing with high shear at 16,000 rpm for 3.5 minutes. pre-emulsion was then homogenized (Model LAB, type 12.51 H; "APV Rannie AS", Denmark) at 80 Mpa and at 55 ° C 5 for 7 cycles ("mini-LAb 8.30 H; A PV Rannie AS", Denmark).

This formulation gave an emulsion with an average droplet size of 190 nm and a zeta potential of -72 mV. Example 16. Preparation of a 39% fat emulsion Tuna oil rich in docosahexaenoic acid (DHA) An oil-in-water emulsion was prepared (batch size) 250 g), with the following ingredients: Ingredient% _ Emulsifier 3.91 Tuna oil 39.08 Vitamin E acetate 1.10 Ammonium phosphatides, E 442 1 .00 Ascorbyl palmitate 0.02 Sucrose 14.94 Mint flavor 1.00 Potassium sorbate 0.20 Water up to 100.0 emulsifier and antioxidants were dispersed in the oil. Sucrose, preservative, flavor and water were mixed. The oil phase and the aqueous phase were preheated to 59 ° C and 64 ° C, respectively, and the oil phase was added to the aqueous phase under mixing with high shear at 16,000 rpm for 5 minutes. The pre-emulsion was then homogenized at 80 Mpa 60 ° C for 7 cycles ("Mini-Lab 8.30 H; APV Rannie AS", Denmark). This formulation gave an emulsion with an average droplet size of 190 nm and a zeta potential of -75 mV.

Example 17. Preparation of a 40% fat emulsion (corn oil) An oil in water emulsion (batch size 200 g) was prepared, with the following ingredients: Ingredient%. Emulsifier 2.00 Corn oil 40.08 Ammonium phosphatides, E 442 1 .00 Ascorbyl palmitate 0.02 Sucrose 14.98 Potassium sorbate 0.10 Water up to 100.0 The emulsifier and antioxidants were dispersed in the oil. Sucrose, preservative, and water were mixed. Both phases were preheated to 65 ° C and the oil was added to the aqueous phase under mixing with high shear at 15,000 rpm for 4 min. The pre-emulsion was then homogenized at 80 MPa and 55 ° C for 7 cycles ("Mini-LAb 8.30 H; APV Rannie AS", Denmark). This formulation gave an emulsion with a narrow size distribution and an average drop size of 210 nm and a zeta potential of -74 mV. Example 18. Preparation of a 1% parenteral fat emulsion (soybean oil) containing 2,6-diisopropylphenol.

An oil in water emulsion (batch size 150 g) was prepared, containing a pharmacologically active compound, using the following ingredients: Ingredient%. Emulsifier 1 .27 Soybean oil 10.57 2,6-di-isopropylphenol 1 .05 Glycerol, 99% 2.24 Water up to 100.0 The emulsifier, which is galactolipid, and the active ingredient, an anesthetic drug, were dissolved in the soybean oil. The glycerol and water were mixed. The aqueous dispersion and the oil phase containing drug were preheated to 72 ° C and 68 ° C, respectively. The oil phase was added to the aqueous dispersion under high shear mixing at 13,000 rpm for 1.5 minutes. The pre-emulsion was then homogenized at 80 MPa and 55 ° C for 7 cycles ("Mini-LAb 8.30 H; APV Rannie AS", Denmark). The emulsion formed had an average droplet size of 179 nm and a zeta potential of -63 mV. The osmolality determined with a micro-osmometer (Type 13, "Herman Roebling Messtechnik", Germany) was 257 milliosmoi / kg H2O. Conclusions Our findings in relation to the invention are that it is possible to produce remarkably stable oil-in-water emulsions based on the galactolipid material, which meets the important and necessary requirements to be sterilized in an autoclave and be resistant to severe mechanical treatments. Emulsions have particle size distributions, which are suitable for parenteral and intravenous use. The emulsions do not exhibit any unpleasant odor or taste, and are remarkably stable to oxidation. This invention provides an alternative for phospholipid emulsions which offers concrete advantages compared to said emulsions.

Claims (7)

1. CLAIMS 1. An oil-in-water emulsion comprising 0.01% -50% by weight of the total preparation, preferably 0.1-10%, of an emulsifier and 0.1-70% by weight of the total preparation of an oily material emulsified in a polar solvent, characterized in that the emulsifier is a glactolipid material consisting of at least 50% of digalactosyldiacyl glycerols, the rest of which I feel other polar lipids. An emulsion according to claim 1, wherein the galactolipid material consists of about 70-80% of digalactosyldiacyl glycerols and 20-30% of other polar lipids. 3. An emulsion according to claim 1 or 2, wherein the galactolipid material consists of up to 100% digalactosyldiacyl glycerol. 4. An emulsion according to claims 1-3, wherein the oily material comprises α-linolenic acid in the form of a free acid, its salts or esters. 5. An emulsion according to any of claims 1-4, wherein the oily material is based on donut grass oil or erasing oil. 6. The use of an emulsion according to any of claims 1-5, as a vehicle for an active substance in a pharmaceutical, nutritive or cosmetic composition. 7. A pharmaceutical composition according to claim 7, wherein the oily material comprises α-linolenic acid in the form of a free acid, its salts or esters. 9. A pharmaceutical composition according to claim 7 or 8, wherein the oily material is based on donut grass oil or erasure oil. 10. A pharmaceutical composition according to claim 7, wherein the oily material is a triacyl glycerol oil, preferably a medium chain triacyl glycerol (MCT), or a bioactive substance. 1 1. A pharmaceutical composition according to any of claims 7-10, comprising • a therapeutically active substance in a therapeutically effective amount; • a galactolipid emulsifier, 0.1-50% by weight of the total composition; • an oily material, 1-50% by weight of the total composition; • optionally, an isotonic agent in an isotonicly effective amount; and • a polar solvent. 12. A pharmaceutical composition for parenteral administration according to claim 10 or 1, consisting of, by weight of the total composition, • 0.2-3% of 2,6-di-isopropylphenol, • 0.3-5% of material of galactolipid, • 5-30% triacyl glycerol oil, • an isotonicly effective amount of an isotonic agent, • add water up to 100%. 13. A pharmaceutical composition according to any of claims 7-11, for oral, enteral, parenteral, rectal, vaginal, topical, ocular, nasal or otic administration.