RU2127124C1 - Lipophilic carrier preparations - Google Patents

Abstract

FIELD: pharmaceutics. SUBSTANCE: in a lipophilic carrier containing polar lipid material and non-polar lipid, the former is galactolipid containing at least 50% (advantageously 100%) of digalcatosyl(diacyl)glycerols along with other polar lipids. Carrier may contain polar solvent, for instance, an aqueous solution. It may as well be in the form of reverse vesicles or reverse micelles, or water-in-oil emulsion. Carrier can be used as auxiliary component in pharmaceutical, cosmetic, or food products. Pharmaceutical compositions contain such carriers in combination with bioactive compounds. EFFECT: improved biological compatibility of carrier-containing products. 12 cl, 3 tbl, 8 ex

Description

 The invention relates to preparations of lipophilic carriers with a continuous lipid phase, which include a polar lipid material in combination with a non-polar lipid and, optionally, a polar solvent. The specified carrier drug is suitable for use as a carrier for active materials in pharmaceutical compositions, as well as in cosmetic, food and agricultural products.

BACKGROUND OF THE INVENTION
A common problem for the pharmaceutical industry is the inclusion of drugs in lipophilic carriers that are biocompatible with and well tolerated by humans. The reason for this is, firstly, a wide range of chemical structures and, accordingly, the properties of the active components that need to be introduced into the carriers, and, secondly, it is necessary to find a suitable carrier based on ingredients capable of giving this carrier sufficient flexibility to so that active components with the aforementioned wide range of structural variations can be included in it.

 In order to create flexible lipophilic carriers, polar lipids, preferably natural membrane lipids, must be used, for reasons of biocompatibility and safety, in combination with non-polar lipids, such as vegetable oils and sterol esters. Currently, the only available membrane lipids are phospholipid materials, obtained mainly from soy or egg lecithin or obtained synthetically. Phospholipids are zwitterions such as phosphatidylcholine and phosphatidylethanolamine, or they are negatively charged, such as phosphatidylinositol or phosphatidylglycerol.

 Lipophilic carriers can be organized solutions such as microemulsions or reverse micellar solutions, reverse vesicles, or water-in-oil emulsions.

 Margarines and pastes are water-in-oil emulsions that can contain up to 75% of the aqueous phase by weight. The aqueous phase is dispersed in triglyceride oil, usually in vegetable oil, such as rapeseed. This aqueous phase typically contains a thickening agent, for example, gelatin, to stabilize a homogeneous oil emulsion with a high water content. Phospholipids, such as soybean phospholipids (soya lecithins), are typically used as emulsifiers. These emulsifiers consist of mixtures of phospholipid classes, such as zwitterions such as phosphatidylcholine and phosphatidylethanolamine, and ionic phosphatidylinositol. It is known that these lecithin emulsifiers are the most used natural lipids for the production of stable food emulsions on an industrial scale. It is also well known that such emulsions have disadvantages and problems that are associated with a lecithin emulsifier.

Prior art
There is little information about lipophilic drugs with a continuous lipid phase. WO 92/05771 discloses a matrix forming lipid particles, consisting of at least two lipid components; one is non-polar, and the other is amphiphatic and polar. A particle-forming matrix, which may contain bioactive materials, spontaneously forms discrete lipid particles when interacting with aqueous systems. It is believed that these amphiphatic and polar lipid components form a double layer and are selected from phospholipids, such as phosphatidylcholine; non-polar lipids are mono-, di-, or triglycerides.

 Microemulsion gels containing lecithin, i.e. phosphatidylcholine, described and characterized by P.L. Luisi, see e.g. D. Capitani et al., Langimuir, 1993, V. 9, p. 685-689. In addition to phospholipids, these gels consist of a small amount of water and an organic solvent, such as alkanes, fatty acid esters and amines. They are also called organogels. These gels can be used as a matrix for transdermal drug administration.

 The presence of reverse vesicles, structures opposite to normal vesicles, in oil was first reported by H. Kuneda, see H. Kunieda et al., Advanced Materials, 1992, V. 4, p. 291-293. Reverse vesicles are a dispersion of a lamellar liquid crystal that absorbs a significant amount of oil, i.e., vesicles are composed of inverse bilayer structures. Reverse bilayers usually consist of a mixture of hydrophilic and lipophilic amphiphiles.

 Glycosyl glycerides belong to the type of glycolipids, which are well known constituents of plant cell membranes. Two types, based on galactose, are very common, these are monogalactosyldiacylglycerol, MGDG, and digalactosyldiacylglycerol, DGDG, representing up to 40% of the dry weight of thylakoid membranes.

где R₁ и R₂ независимо друг от друга являются насыщенными или ненасыщенными остатками жирных кислот, содержащими 2-24 углеродных атома и 0-6 двойных связей, дополнительно этерифицированные гидроксикислоты, т.е. эстолиды, или водород; углевод представляет моносахаридный фрагмент n=1-5;
R₃ представляет гидроксильную или сульфонатную группу.Plant glycolipids have carbohydrate fragments, mainly from galactose, combined with glycerol. In the MGDG, the 1-position galactose ring has a beta bond with glycerol, and in the DGDG there is an α1 __ → 6 bond between sugars. A minor component is the plant sulfolipid, a more precise name is sulfoquinovosyldiacylglycerol, SQDG, which contains a sulfonate rather than a hydroxyl group bound to carbon 6 of the terminal deoxyglucose residue. Most plant glycolipids can be represented by the general formula:

where R ₁ and R _{2 are} independently saturated or unsaturated fatty acid residues containing 2-24 carbon atoms and 0-6 double bonds, additionally esterified hydroxy acids, i.e. estolides, or hydrogen; the carbohydrate is a monosaccharide fragment n = 1-5;
R ₃ represents a hydroxyl or sulfonate group.

 SE 9400368-8 discloses an industrial process for the production of glycosyl glycerides from plants, preferably cereals, by extraction and chromatographic separation.

 When studying the interaction of glycosyl glycerides with non-polar lipids, for example, mono-, di-, and triglycerides, fatty alcohols and acids, sterols and sterol esters, optionally combined with other polar lipids, such as phospholipids and sphingolipids, without water, or only with with a small amount of water, we were surprised to find that their behavior allows the use of such drugs as lipophilic carriers for drugs, as well as for the preparation of compositions for skin care, nutritional mixtures and food out products.

Description of the invention
The present invention provides galactolipid-based lipid carriers that are polar lipid material in combination with non-polar lipids. The polar head groups of galactolipids are galactose fragments that have physico-chemical properties that are completely different from phospholipids. So, inclusion mechanisms are based on interactions of the hydroxyl groups of the polar head group, i.e. a galactose fragment and lipophilic chains of galctosylacylglycerols and a non-polar component with the compound to be included in the composition.

 The invention relates to preparations of lipophilic carriers with a continuous lipid phase containing a non-polar lipid in combination with a polar lipid material, and, optionally, a polar solvent, characterized in that the polar lipid material is a galactolipid material consisting of at least 50% digalactosyl diacyl glycerols, the rest is made up of other polar lipids.

 A preferred preparation of galactolipid material consists of 70-80% of dihalactosyldiacylglycerols and 20-30% of other polar lipids.

 Another preferred preparation of galactolipid material consists of up to 100% digalactosyldiacylglycerols.

где R₁ и R₂ независимо друг от друга являются насыщенными или ненасыщенными остатками жирных кислот, содержащими 10-22 атомов углерода и 0-4 двойных связи, или водорода;
R₃ представляет гидроксильную или сульфонатную группу.Digalactosyldiacylglycerols can be represented by the general formula:

where R ₁ and R ₂ independently from each other are saturated or unsaturated fatty acid residues containing 10-22 carbon atoms and 0-4 double bonds, or hydrogen;
R ₃ represents a hydroxyl or sulfonate group.

As preferred examples of fatty acid residues R ₁ and R ₂ , fatty acyl groups can be mentioned, for example, saturated acid, palmitic (C ₁₅ H ₃₁ CO; 16: 0) and stearic acid (C ₁₇ H ₃₅ CO; 18: 0); monounsaturated acid - oleic acid (C ₁₇ H ₃₃ CO; 18: 1); and polyunsaturated acids - linoleic (C ₁₇ H ₃₁ CO; 18: 2) and linolenic acids (C ₁₇ H ₂₉ CO; 18: 3). Fatty acid residues may also contain hydroxy acids bound to the glycerol moiety due to their hydroxyl groups esterified with additional fatty acids, the so-called estolides.

 Other polar lipids, being part of the galactolipid material, are a mixture of various glyco- and phospholipids, for example, MGDG and phosphatidylcholines. This composition depends on the starting material and the method used for the production of galactolipids.

 The specific proportions of the components of the galactolipid material are not critical to the present invention as long as the DGDG content is at least 50%. For many applications, however, the maximum benefits are associated with a high DGDG content, the most important double layer component.

 Galactolipid material can be extracted from almost any kind of plant material. Preferred plant materials are seeds and grains of cereals and cereals, for example, wheat, rye, oats, corn, rice, millet and sesame. Oatmeal, like wheat glutin, have a high lipid content, and therefore it is best to use them to obtain the drug.

 Synthetic diglycosyl diacylglycerols based on galactose or any other monosaccharide moieties such as glucose, and natural glycosyl glycerides isolated from any raw material based on non-galactose but other carbohydrate moieties, such as glucose, can also be used in accordance with the invention.

 There are no particular restrictions in connection with the use of non-polar lipid material. Vegetable oils, animal fats, synthetic oils, fatty acids, natural and synthetic glycerides, sterol esters, fatty alcohols, etc., may be mentioned here by way of example.

 Unexpectedly, it turned out that all types of lipophilic organized solutions can be obtained using galactolipids. The included active substances may themselves enter into organized solutions or may be stabilized by them in the form of, for example, suspensions.

 For example, a lipophilic carrier preparation can be prepared by mixing galactolipids with a non-polar lipid, for example triacylglycerol. This triacylglycerol may be palm oil or natural oils with a similar, relatively high solid fat content or melting point range. It is preferable and more convenient to use triacylglycerols, which are palm oil fractions obtained by fractionating commercial palm oil into certain mixtures of triacylglycerols, based on a combination of mainly palmitic, oleic and stearic glycerol esters.

 A lipophilic carrier preparation can also be prepared by mixing glycosyl glycerides with liquid triglyceride oils, for example medium chain triacyl glycerol (MCT) and soybean oil.

 In addition, a mixture of non-polar lipid and galactolipid may contain increasing amounts of water or an aqueous solution, which can lead to the formation of reverse vesicles, reverse micelles and emulsions such as water in oil.

 Reverse vesicles are prepared by adding a mixture of galactolipids and more polar amphiphile, for example, lysophosphatidylcholine, in a 4: 1 weight ratio, to triglyceride oil, preferably to oil (MCT). The total amphiphyll content is less than 3% (w / w). Then add a small amount of water or an aqueous solution, less than 1% of the total preparation. After sonication, a fine dispersion of the treated vesicles is obtained.

 At higher glycolipid concentrations, but still low in water, 0.5-2% (w / w) of the entire preparation, reverse micelles can be obtained. Reverse micelles, also called microemulsions, consist of aggregates of water in oil. Reverse micelles are thermodynamically stable. The shape and structure of aggregates can lead to the formation of viscous systems, "microemulsion gels."

 At a higher water content,> 5% (w / w) of the entire preparation, emulsions of the type water in oil are formed. These are two-phase systems consisting of finely dispersed droplets of water in oil. Emulsions such as water in oil are thermodynamically unstable, but kinetically they can be stable.

 This aqueous solution may consist of pure water, a buffer solution, saline, glucose, galactose, propylene glycol, polyethylene glycols, glycerol, etc. solutions. In addition, you can use thickeners, for example gelatin, agarose, carrageenan, methyl cellulose and ethyl hydroxyethyl cellulose.

 This invention also relates to the use of a lipophilic carrier preparation, as described, as a carrier for the active substance in a pharmaceutical, cosmetic, food or agricultural product.

 The invention also relates to pharmaceutical compositions comprising a preparation of a lipophilic carrier, as described, in combination with any biologically active substance.

 The invention also relates to pharmaceutical compositions comprising a preparation of a lipophilic carrier, as described, wherein the non-polar lipid is SCT oil, evening primrose oil, palm oil fraction, or a biologically active substance.

 The biologically active substance can be a lipophilic drug substance, for example, with an anti-cancer effect, with an anti-microbial effect and, especially, with an anti-fungal effect, immunosuppressants, for example, cyclosporine, skin preparations, for example, with analgesic and antiflogistic effects, against itching, disinfectants, astringents, emollients, and hormones, psychotropic drugs, anesthetics, and other drugs that are lipophilic and that can cause a problem in the preparation of a drug that can be solved in a use of galactolipids. There are also many lipids such as free fatty acids, mono-, di-, and triacylglycerols, phospholipids, cholesterol esters, as well as other types of lipids that have a therapeutic effect on their own, which could advantageously be given in the form of a lipophilic carrier, based on galactolipids. In this case, the biologically active substance is a non-polar lipid.

Pharmaceutical and cosmetic preparations can be obtained by melting a fraction of palm oil in an open water bath at a temperature of 40 ^o -70 ^o C. The active ingredients and glycosyl glycerides are weighed in an ampoule. The fraction of molten palm oil is placed in this ampoule and the mixture is dispersed in a high shear mixer at a speed of about 1000 rpm at a temperature of 40-70 ^o C for 2-4 minutes. Add as much water or an aqueous solution as is necessary to obtain a composition for surface application, and the resulting composition is thoroughly mixed with a stick.

 The pharmaceutical composition can be prepared for oral, enteral, parenteral, rectal, vaginal, superficial, ocular, nasal or ear administration to animals, in particular mammals, including humans.

 Preparations for superficial skin application can be roughly divided into medical local skin preparations and cosmetic preparations in accordance with their method of use.

 Examples of medical skin preparations are various ointments, which include one or more of the active ingredients. Ointments can be oil-based, or based on emulsions such as oil in water or water in oil.

 When it comes to a cosmetic product, it is possible to mix the usual cosmetic ingredients with the main ingredients, for example, oily substances, UV absorbents, alcohol, chelating agents, pH regulators, antiseptics, thickeners, pigments, perfumes, etc. in the right combinations.

 Cosmetic skin preparations can be formulated in any form, for example, as emulsified cosmetics such as water in oil or oil in water, creams, cosmetic emulsions, eau de toilette, cosmetic oils, lipsticks, bases, skin cleansers, hair strengthening products, preparations hair styling, hair care, hair growth stimulants, etc.

 Emulsions such as water in oil, for example margarines and pastes, are prepared by conventional methods.

Galactolipid material
Galactolipid materials are obtained from various cereal crops, as described below, and are used to obtain carrier preparations and pharmaceutical compositions of the present invention, as evidenced by the examples. In these descriptions,% means weight%, as a rule, unless otherwise indicated. The ratio of solvents to solvent mixture is given in parts by volume.

Galactolipid material from oats
200 g of oat grains (Kungsornen AB, Sweden) are ground and extracted with 1000 L of 95% ethanol at 70 ^° C. for 3 hours in an extraction vat with stirring. The still warm suspension is centrifuged and the solids are separated. The liquid fraction was evaporated at 60 ^° C, whereby 10 kg of a light brown oil were obtained.

от Amicon Corp. USA. Температура колонки 50^oC. Колонку потом промывают 30 л смеси гексан: изопропанол, в пропорции 90:10, для удаления остатков всех неполярных липидов.The oil is then introduced into a stainless steel column containing 6.25 kg of silica gel (Matrex Silica Si, particle size 20-45 mm, pore diameter 60

from Amicon Corp. USA The temperature of the column is 50 ^o C. The column is then washed with 30 l of a mixture of hexane: isopropanol, in a proportion of 90:10, to remove residues of all non-polar lipids.

 The galactolipid material is then eluted from a 20 L column of hexane: isopropanol 60:40 to obtain a galactosyl diacylglycerol fraction. Evaporation of this fraction gives about 700 g of DGDG, which belongs to the main class of lipids.

 Then the galactolipid material is dispersed in water and freeze dried, resulting in a free-crossing powder.

Enrichment of DGTG from galactolipids
50 g of galactolipids obtained from oats, as described above, with a DGTG content of about 70%, are dissolved in 250 ml of a mixture of hexane: isopropanol, 70:30, obtaining a total amount of 300 ml. The resulting solution was introduced into a column of silica gel (110 g), and less polar components were eluted with 1 L of a mixture of hexane: isopropanol 70: 30. The enriched DGTG fraction was eluted with 2 L of acetone. The acetone fraction is then evaporated and freeze dried. The total yield is 17 g of almost pure DGTG.

Hydrogenation of galactolipids
200 g of a mixture of galactolipids obtained from oats by the method described above are dissolved in 2 l of warm isopropanol. 15 g of the catalyst - palladium on carbon (Pd 15%, humidity 53%, Engelhard, Rome sri, Italy) are placed on the bottom of the reactor under pressure (Model 4552M; Parr Instrument Co., USA) equipped with two impellers on the axis of the mixer. The solution is then transferred to this reactor under a nitrogen atmosphere to avoid fire. The reactor is sealed and, first, pressurized with nitrogen three times to remove air, and then three times with hydrogen gas (Plus 4.5 from AGA Gas AB Sweden). The hydrogen pressure is maintained at 6 bar, the mixer rotates at a speed of 600 rpm, and the mixture is heated to 70 ^o C. In 14 minutes the reaction mixture reaches the set temperature. Hydrogenation is carried out for 6 hours, after which the reaction product is filtered through a 0.45 μm filter to remove particles of coal and palladium. The solvent is evaporated on a rotary evaporator. The remaining solid material is dispersed in 1600 ml of deionized water and freeze dried.

 As a result, after filtration and freeze-drying, the yield of hydrogenated galactolipids is 155 g. The hydrogenation results are evaluated by gas chromatography; only saturated fatty acids could be detected in the hydrogenated product.

Wheat Gluten Galactolipids
1 kg of wheat gluten powder (AB Skanebrannerier, Sweden) was extracted with 4 L of 95% ethanol at 70 ^° C. for 4 hours in a beaker. Then the suspension is filtered off at a pressure of 400-500 kPa, and the resulting filter cake is washed with 1 L of warm 95% ethanol. The combined ethanol solutions are evaporated at a temperature not exceeding 60 ^o C, which gives a yield of about 60 g of a yellow oil.

от Amicon Corp. USA. Колонку затем промывают 700 мл смеси гексан:изопропанол, 90-10 для того, чтобы удалить нейтральные липиды.This oil is introduced into a stainless steel column containing 45 g of silica gel (Matrex Silica Si, particle size 20-45 μm with a pore diameter of 60

from Amicon Corp. USA The column is then washed with 700 ml of a mixture of hexane: isopropanol, 90-10 in order to remove neutral lipids.

 To remove MGDG and some other polar lipids, the column was washed successively with 1000 ml of a 70:30 hexane-isopropanol mixture. DGDG was eluted with 1000 ml of pure acetone. After evaporation, about 4 g of almost pure DGDG are obtained.

Galactolipids from rye
100 g of rye flakes (Kungsornen AB, Sweden) was stirred for 60 minutes in a mixture of industrial hexane and isopropanol, 90:10. Then the suspension is passed through a filter and evaporated, resulting in 0.5 g of polar lipids. The residue dissolved in 10 ml of a mixture of hexane and isopropanol, 70:30, is introduced into three Sep-pak Silica plus columns (Millipore Corporation, USA) connected in series, then washed with 20 ml of the same solvent mixture and 15 ml of acetone elute. The eluate is evaporated and freeze-dried to give 47 mg of galactolipids.

Chemical and physical characteristics of various galactolipid materials
Lipid Class Analysis
The lipid class analysis was performed using high performance liquid chromatography, HPLC using a column packed with diol-modified silica (LiChrosphere 100 DIOL, 5 mm, 250 mm x 4 mm inner diameter E. Merck, Germany). The column was placed in a water bath in which the temperature was maintained at 75 ^° C. An analytical system consisting of a CM 4000 HPLC pump (LDC / Milton Roy, USA), an injector, model 7125, with a 20 μm injector loop (Rheodyne Inc. USA). A Sedex 45 scattered light vapor detector (SEDERE, France) was used, equipped with a Sedex 55 atomization chamber at a deflection tube temperature and inlet air pressure of 97 ^° C and 2.0 bar, respectively.

 In the analysis, the flow rate of the mobile phase was 1 ml / min. Use a gradient of a binary solvent linear over 25 min, starting from 100% A and ending with 100% B, where A = hexane: isopropanol: n-butanol: tetrahydrofuran: isooctane: water, 64: 20: 6: 4,5: 4, 5: 1, and B = isopropanol: n-butanol: tetrahydrofuran: isooctane: water, 75: 6: 4.5: 4.5: 10. All solvents contained ammonium acetate, 180 mg / L.

 Data collection and processing was performed using the GynkoSoft data system, version 4.22 (Softtron, Germany). For analysis, usually 100 micrograms was injected. The determination was based on comparing retention times with authentic standards (Karlshamns Lipid Teknik AB, Sweden). Volatile compounds were not detected in this system. Quantitative assessment was carried out based on the determination of peak areas.

 Zeta potentials are determined by dilute aqueous galactolipid dispersions using a Zeta Sizer 4 instrument (Malvern Instruments Ltd. United Kingdom).

In table 1, as in table 2, the following abbreviations are used:
O-GL = Galactolipids from Oats
Oh-GL = hydrogenated oat galactolipids
O-DGDG = Oat Enriched Galactolipids
W-GL = galactolipids from wheat
W-DGDG = enriched galactolipids from wheat
r-GL = galactolipids from rye
Fatty Acid Analysis
The analysis of the characteristics of fatty acids was performed using gas chromatography after transesterification of lipids into methyl esters of fatty acids. They were isolated and quantified by gas chromatography on a capillary column on a Varian 3500 capillary gas chromatograph equipped with a 30 mx 0.25 mm in. Capillary column. (DB-WAX; J&W Scientific, USA), an integrated injector and a flame ionization detector. Helium was used as a carrier gas. Integration was performed using the GyncoSoft data system, version 4.22 (Softtron, Germany). Transesterification is carried out by adding 1 mg of a lipid sample to 2 ml of a mixture of dimethyl carbonate: isooctane 1: 1. 1 ml of a solution containing 2.3 g of sodium dissolved in 200 ml of methanol was added, and the test vial was shaken vigorously for 30 seconds and left at room temperature for 15 minutes to complete the reaction. 3 ml of water are added, the test ampoule is shaken and centrifuged at 2 x g, 0.5 μl of the organic layer is introduced into the chromatograph under the following separation conditions. Thermostat temperature program: starting at 130 ^o C (2 min), increasing to 150 ^o C (30 / min) and 220 ^o C (3.2 ^o C / min) with a 10-minute delay. The temperature of the injector was 130 ^° C and the temperature of the detector was 250 ^° C. Initially, the gas flow rate was 2.7 ml / min. Results are expressed in terms of normalized weight percent using an external standard method. Correction factors were not used for minor components for which standards were not available, or were considered conditionally pure.

NMR spectroscopy of digalactosyldiacylglycerols
One-dimensional proton decoupling NMR spectra were obtained for the natural ¹³ C content on a Bruker AM-400 spectrometer (Bruker Analytische Messtechnik, Germany) at a frequency of ¹³ C 100.614 MHz. The angle of the pulse was 36 ^o , the pulse repetition time of 1.0 seconds and a resolution of 1.526 Hz per data point. 3 Hz line broadening was introduced during data processing. Samples (10-40 mg) were diluted in a mixture of 730 microliters of DMSO-d ₆ (Aldrich Chemical Comp., Inc., USA) and 20 microliters of D ₂ O (Aldrich Chemical Comp., Inc., USA) and placed in NMR vial ampoule (5 mm inner diameter).

 Example 1. Obtaining a lipophilic carrier (enriched with evening primrose oil containing 20% gamma-linolenic acid (GLA).

A lipophilic carrier is prepared from the following ingredients:
Ingredient%
Galactolipid material - 50.0
Enriched evening primrose oil, 20% GLA - 50.0
The galactolipid material is dispersed in oil, mixed with high shear, at 22,000 rpm for 3 minutes. The oil phase is then maintained at 50 ^° C. for 40 minutes. The result is a transparent, high viscosity lipophilic carrier that retains transparency after cooling to room temperature.

 Example 2. Obtaining a lipophilic carrier (enriched with evening primrose oil containing 20% GLA) containing 5% β-cyclosporin A.

A lipophilic carrier containing a pharmacologically active compound is prepared using the following ingredients:
Ingredient%
Galactolipid material - 19.0
Enriched evening primrose oil, 20% GLA - 75.9
Cyclosporin A - 5.1
The galactolipid material is dispersed in oil, mixing with high shear at 22,000 rpm for 2 minutes. The lipophilic carrier is heated to 50 ^° C. and it becomes transparent. Cyclosporin A is added to the clear oil phase. The cyclosporin / oil mixture is kept at a temperature of 50 ^° C., sometimes shaking, until the liquid becomes clear.

Example 3. Obtaining a lipophilic carrier containing ascorbyl-6-GLA)
The gel is obtained from the following ingredients:
Ingredient%
Ascorbyl-6-GLA - 6.25
Galactolipid material - 40.72
MCT Oil - 53.03
Ascorbyl-6-GLA, an ester of gamma-linolenic acid ascorbic acid (from Callanish Ltd., Scotland), is dispersed in oil. Galactolipid material was added to this dispersion, and the mixture was then heated to about 50 ^° C and mixed with high shear. After cooling to room temperature, a viscous and slightly cloudy stable dispersion is obtained.

 Example 4. Obtaining anhydrous compositions of disulfiram.

Composition for parenteral administration with disulfiram, an alcohol preservative is obtained from the following ingredients:
Ingredient%
Galactolipids from oats - 20.0
Disulfiram - 32.0
MCT Oil - 48.0
The ingredients are mixed using an ultra-fast homogenizer at a speed of 2000 rpm for 15 minutes and at a speed of 3000 rpm for 5 minutes.

 Get a suspension containing a large number of finely dispersed particles of disulfiram, homogeneous and homogeneous consistency. The suspension showed exceptional physical stability, and no precipitation was observed during storage at room temperature. The viscosity of the suspension was relatively low, and the composition could be injected using a syringe with a thin (1.0 mm in.diam.) Needle.

 Such a composition can be administered to the patient in the duodenum, where it can act as a storage for disulfiram, thus providing a prolonged alcohol-preserving effect.

Example 5. Obtaining reverse vesicles
Reverse vesicles are obtained from the following ingredients:
Composition A
Ingredient%
Galactolipids from oats - 1.65
Soybean Lysophosphatidylcholine 0.40
Soybean phosphatidylinositol - -
Water - 0.56
MCT Oil - 97.39
Composition B
Ingredient%
Galactolipids from oats - 1.56
Soybean Lysophosphatidylcholine - -
Soybean Phosphatidylinositol - 0.38
Water - 0.64
MCT Oil - 97.42
After weighing the ingredients, the mixtures were sonicated in an ultrasonic bath for 1 hour at a temperature of 30 ^o -40 ^o C. The resulting fine dispersions were stable for more than a week. The presence of large reverse vesicles was evaluated using a differential interference phase contrast microscope (X2F-NTF-21; Nicon, Japan) with a video magnification system (Argus 10; Hamamatsu Photonics Co., Japan).

 The reverse vesicles in this example are based on lipid ingredients that are conveniently used for pharmaceutical and cosmetic purposes. Previously, reverse vesicles were obtained using phospholipids or synthetic surfactants in hydrocarbon oil, the last two ingredients being usually too toxic for humans. Moreover, the reverse vesicles of the present invention demonstrate much greater stability than the previous ones based on synthetic surfactants and hydrocarbon oil.

 Dispersion of reverse vesicles is an example of an organized solution in which active materials, for example, protein drugs like interferons, and peptide hormones, such as calcitonin or insulin, can be included. The incorporation of water-soluble protein drugs or hormones into triglyceride oils through reverse vesicles can facilitate drug delivery through lipophilic cell membranes. Drug molecules are located inside a double layer of reverse vesicles, which has a stabilizing effect on drugs. In particular, in this way, when administered orally, the drug can be protected from degradation in the intestine.

Example 6. Obtaining reverse micelles
High viscosity reversible micellar gel is prepared as follows:
Ingredient%
Galactolipids from oats - 17.9
MCT Oil - 81.9
Water - 0.8
The galactolipid material and MCT oil are mixed together to form a homogeneous dispersion. Water is added dropwise to the dispersion with continuous stirring with a magnetic stirrer. Almost immediately, a clear gel was obtained that retained high viscosity for more than a month.

Example 7. Obtaining microemulsions
The microemulsion is obtained from the following ingredients:
Ingredient%
Ascorbyl-6-GLA - 7.49
Galactolipid material - 17.66
MCT Oil - 63.53
Water - 11.32
Ascorbyl-6-GLA is dispersed in oil. Galactolipid material is added to the dispersion. Warm water passed through a membrane filter is added to the oil phase, mixing with high shear. A clear, slightly yellowish, low viscosity liquid is obtained.

Example 8. Obtaining an emulsion of the type water in oil
An oil-in-water emulsion is prepared from the following ingredients:
Ingredient%
Galactolipids from oats - 20.0
MCT Oil - 49.9
1% aqueous carrageenan gel - 30.1
The galactolipid material and MCT oil are mixed until a homogeneous dispersion is formed. Carrageenan gel, molten at 60 ^° C., is slowly added to the oil phase with high shear mixing. After cooling to room temperature, a highly viscous, milky-oil homogeneous emulsion is obtained.

Claims (9)

 1. The preparation of a lipophilic carrier with a continuous lipid phase containing a polar lipid material in combination with a non-polar lipid and, optionally, a polar solvent, characterized in that this polar lipid material is a galactolipid material consisting of at least 50 wt.% Dihalactosyl diacylglycerols, the rest are other polar lipids.  2. The drug lipophilic carrier according to claim 1, characterized in that the galactolipid material consists of 70 to 80 wt.% Dihalactosyldiacylglycerols and 20 to 30 wt.% Of other polar lipids.  3. The preparation of a lipophilic carrier according to claims 1 and 2, characterized in that the galactolipid material is 100% composed of digalactosyldiacylglycerols.  4. The preparation of a lipophilic carrier according to claims 1 and 3, characterized in that it consists of a galactolipid material - 1 to 50 wt.% And non-polar lipid - up to 100% by weight of the total preparation. 5. The drug is a lipophilic carrier according to claims 1 and 3, characterized in that it has the form of reverse vesicles containing, based on the weight of the whole drug,%:
Galactolipid material and, optionally, other amphiphiles - 0.5 - 3.0
Aqueous solution - 0.1 - 1.0
Nonpolar Lipid - Up to 100
6. The preparation of a lipophilic carrier according to claim 5, characterized in that it further comprises phospholipids or other amphiphiles. 7. The preparation of a lipophilic carrier according to claims 1 to 3, characterized in that it has the form of reverse micelles, including, based on the weight of the whole preparation,%:
Galactolipid material - 1 - 50
Aqueous solution - 0.1 - 5.0
Nonpolar Lipid - Up to 100
8. The preparation of a lipophilic carrier according to any one of claims 1 to 3, characterized in that it has the form of water-in-oil emulsions containing, based on the weight of the whole preparation,%:
Galactolipid material - 1 - 30
Aqueous solution - 1 - 80
Nonpolar Lipid - Up to 100
9. The preparation of a lipophilic carrier according to any one of claims 1 to 8, characterized in that it is a carrier for the active substance in pharmaceutical, cosmetic or food products.  10. A pharmaceutical composition, characterized in that it contains the preparation of a lipophilic carrier according to any one of claims 1 to 8 in combination with a biologically active substance.  11. The pharmaceutical composition of claim 10, wherein the non-polar lipid is triacylglycerol oil, preferably medium chain triacylglycerol oil (MCT), evening primrose oil, palm oil fraction or biologically active substance.  12. The pharmaceutical composition according to claim 10 or 11, characterized in that it is intended for oral, energetic, parenteral, rectal, vaginal, superficial, ocular, nasal or ear administration.

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