Liposomal composition and methods for the production and use thereof

Abstract

The present group of inventions relates to the field of applied biotechnology and can be used in cosmetology and in the pharmaceutical and food industries, and in particular for producing specialized, functional and enriched food products. A liposomal composition is described which contains a composition of powdered biologically active substances, a phospholipid component, and a protective component. The thickness of the coating produced on the particles of the composition of powdered biologically active substances by the phospholipid component is equal to 5-20% of the linear dimensions of the particles of the composition of powdered biologically active substances, and the relative moisture content of the liposomal composition is not more than 10%.

Description

LIPOSOMAL COMPOSITION, METHOD OF ITS PRODUCTION AND APPLICATION Field of technology

[0001] The present group of inventions relates to the field of applied biotechnology and can be used in cosmetology, pharmaceutical and food industries, in particular, in the production of specialized, functional and enriched food products. State of the art

[0002] Currently, forms of biologically active additives are being improved, increasing their bioavailability, while reducing the frequency and degree of side effects. One of the methods for improving the forms of biologically active additives is the creation of liposomal compositions, which, upon hydration or contact with biological fluids in the body of a person or animal, spontaneously form liposomal vesicles (liposomes). The following technical solutions are known from the state of the art concerning the creation of liposomes or liposomal compositions.

[0003] Patent RU2621145C2 (published 31.05.2017; MIC: A61K 9 / 127, A61K 31 / 685, B28B 3 / 00) describes an invention related to the field of biotechnology, which makes it possible to obtain nanocontainers for various types of substances used in cosmetology, pharmacology, and medicine. The technical result of the analogue consists in obtaining a monodisperse homogeneous system with a particle size from 59.9 nm to 106.2 nm. The analogue describes a method for producing liposomes, which is characterized in that a 1% solution of lecithin in ethyl alcohol is evaporated in a PSA RV10 control rotary evaporator at a water bath temperature of 60°C, as a result of which a lipid film is obtained on the wall of the evaporation flask; then add centimolecular sodium phosphate buffer pH 7.4 in a volume equal to the volume of lecithin solution in ethyl alcohol; stir for 1 minute; then the resulting solution is exposed to ultrasound for 15 minutes, due to which a monodisperse homogeneous system with a particle size of 59.9 nm to 106.2 nm is obtained at the output. The first disadvantage of the analogue is the need to use an organic solvent when obtaining liposomal particles, ethanol is used as an organic solvent. The organic solvent is toxic, respectively, its presence in the composition of liposomal particles that enter the animal's body. or a person, is dangerous and puts the health of a living organism at risk. Also, the presence of an organic solvent in the composition of liposomal particles worsens the physical, chemical and biological characteristics of liposomes. At the same time, the removal of the organic solvent is a complex technological process, which leads to an increase in the labor intensity of the technological process for obtaining liposomal particles of the analogue. Another disadvantage of the analogue is the use of additional stages of suspension processing, consisting of ultrasound irradiation and extrusion through membrane filters of liposomal particles, which ensures their micronization. This complicates the technological process of obtaining liposomal particles in the analogue. In addition, ultrasound treatment of liposomal particles leads to their excessive heating, which worsens the physical, chemical and biological characteristics of liposomes.The next disadvantage of the analogue is the low reproducibility of obtaining liposomal particles, which makes it impossible to scale up the process of their production.

[0004] Patent RU2216315C2 (published 20.11.2003; IPC: A61K 9 / 127) describes an invention related to the field of medicine and concerns a method for producing liposomes. The technical result of the analogue consists in reducing the number of stages of the composition manufacturing process and in obtaining stable liposomes with highly effective encapsulating capacity. The analogue describes a method for producing a composition containing a reagent, which includes the stages of (i) forming empty liposomes from a lipid; (iii) mixing the liposomes obtained in stage (i) with a solution of sugar and a reagent and (iii) drying the mixture obtained in stage (j), characterized in that the ratio of the mass of sugar in stage (j) and the mass of lipid in stage (i) is from 1: 1 to 6: 1 (w / w). The first disadvantage of the analogue consists in the need to use an organic solvent in obtaining the composition.The organic solvent is toxic, therefore, its presence in the composition that enters the body of an animal or a person is dangerous and puts the health of a living organism at risk. Also, the presence of an organic solvent in the composition worsens the physical, chemical and biological characteristics of liposomes. At the same time, the removal of the organic solvent is a complex technological process, which leads to an increase in the labor intensity of the technological process for manufacturing the analog composition. Another disadvantage of the analog is the multi-stage method for obtaining the composition, which also complicates the technological process of its manufacture. The next disadvantage of the analog is the low reproducibility of obtaining the composition, which leads to the impossibility of scaling the process of its production. Another disadvantage of the analogue is that lyophilic (sublimation) drying is used to obtain the composition, which also complicates the technological process of obtaining the composition, since the specified technological process requires vacuum and cryogenic conditions.

[0005] A widely used method for obtaining liposomes was proposed by Mozafari [Reza Mozafari M., Johnson C., Hatziantoniou S., & Demetzos C. (2008). Nanoliposomes and their applications in food nanotechnology. Journal of liposome research, 18(4), pp. 309–327.]. In Mozafari’s work, a method for obtaining liposomes by a thermal method is described, according to which a 1% aqueous solution of lecithin containing 3 vol.% glycerol is heated to a temperature of 60–120°C, and the said aqueous solution of lecithin is stirred with a mechanical stirrer at a speed of 1000 rpm for 30 minutes. This makes it possible to obtain monodisperse liposomes with an average diameter of 20–25 μm. The main disadvantage of the method for producing liposomes described by Mozafari is the production of large single-layer liposomes, the size of which is 20-25 μm. This leads to low encapsulating activity of the liposomes of the analogue.

[0006] In the work [Gala R. P., Khan I., Elhissi A. M., & Alhnan M. A. (2015). A comprehensive production method of self-cryoprotected nano-liposome powders. International Journal of Pharmaceutics, 486(1 - 2), pp. 153 - 158] a method for producing liposomes is described, according to which sucrose carrier particles are selected in such a way that their size is 400 - 800 μm; then the phospholipid component is mixed with an organic solvent, which is ethanol, using a magnetic stirrer at a temperature of 60 ° C for 1 hour; then the mixture of the organic solvent and the phospholipid component is sprayed onto the sucrose carrier particles in a fluidized bed at a rate of 2.1 ml / min and a spray pressure of 0.3 bar for 2 hours; Next, the resulting liposomal composition is subjected to hydration; then the resulting liposomes are dispersed; after that, the dispersed liposomes are subjected to lyophilic (sublimation) drying.The main disadvantage of the method for obtaining liposomes in the work is its multi-stage nature, which complicates the technological process of manufacturing liposomes, which leads to the impossibility of scaling the process of their production. Another disadvantage of the analogue is that lyophilic (sublimation) drying is used, which also complicates the technological process of obtaining liposomes, since vacuum and cryogenic conditions are necessary in this technological process. The next disadvantage of the work devoted to the method for obtaining liposomes is the need to use an organic solvent during production. proliposomes, which form liposomes when hydrated. The organic solvent is toxic, therefore, its presence in the liposomes that enter the body of an animal or a person is dangerous and puts the health of the living organism at risk. Also, the presence of an organic solvent in the liposomal composition worsens the physical, chemical and biological characteristics of the liposomes formed from it during hydration. At the same time, the removal of the organic solvent is a complex technological process, which leads to an increase in the labor intensity of the technological process of obtaining liposomes in work.

[0007] However, the use of liposomes in the production of biologically active additives is limited by the complexity of the technology for obtaining liposomal forms, which leads to their high cost. Also, the limitations of using liposomes in the production of biologically active additives include: their lack of resistance to negative temperatures, for example, during transportation and storage of the product in the winter; low stability of their physical, chemical and biological properties, due to the high water content in liposomes, etc.

[0008] Dry liposomal compositions, which are proliposomes (liposome precursors), are the most promising for commercial use. Their prospects for commercial use are due to the fact that proliposomes have stable physical, chemical and biological properties, ensuring a long shelf life, and allow achieving high efficiency of loading with the active substance due to increased bioavailability.

[0009] Thus, in the work [Chen S. M., & Alli D. (1987). Use of fluidized bed in proliposome manufacturing. Journal of pharmaceutical sciences, 76(5)] they describe a method for producing proliposomes, according to which a 2.8% (vol / vol) aqueous dispersion of a plasticizer, which is dibutyl sebacate, is applied to the surface of sugar beads with a diameter of 700-800 μm in a fluidized bed with a temperature of 65-68°C to impart smoothness to the surface of the sugar beads; then a 10% solution of lecithin in an organic solvent is applied to the prepared surface of the sugar beads. The described method makes it possible to obtain liposomes by adding water to the proliposomes prepared according to the method described above, where the average size of the liposomes is about 10 μm. The main disadvantage of the analogue is the need to use an organic solvent in obtaining the composition.An organic solvent is toxic, therefore, its presence in the composition of a composition that enters the body of an animal or a person is dangerous and puts the health of a living organism at risk. Also, the presence of an organic solvent in the composition. composition worsens the physical, chemical and biological characteristics of liposomes. At the same time, the removal of the organic solvent is a complex technological process, which leads to an increase in the labor intensity of the technological process for obtaining proliposomes. In addition, the presence of an organic solvent in proliposomes containing biologically active substances leads to their inactivation.

[0010] Patent RU2311449C2 (published 27.11.2007; IPC: SPV 1 / 00, A61K 9 / 50, A61K 9 / 127) describes an invention related to the food industry, veterinary science, pharmacology, biology, medicine and cosmetics industry. The technical result of the analogue consists in obtaining a composition with a high degree of stability and incorporating capacity. The analogue describes a method for obtaining a liposomal composition, which includes forming a mixture of lipids with lipophilic and hydrophilic additives, finely dispersed powder and dispersion, characterized in that, at the stage of preparing the fatty phase, the lipids are preliminarily treated with amino-containing compounds to redistribute the charge, as well as partially hydrated the lipids, then additives are introduced in the required quantities, wherein liposomes are formed at the interface of the two-phase system water / water-insoluble particles.The first disadvantage of the analogue is the use of an organic amino-containing liposome stabilizer, since the said stabilizer is toxic and causes an allergic reaction. The next disadvantage of the analogue is the formation of liposomes only on the liquid / solid phase interface, which complicates the use of the method for obtaining the liposomal composition of the analogue on an industrial scale.

[0011] Patent RU2437649C2 (published 27.12.2011; IPC: A61K 9 / 127) describes an invention related to the field of applied biotechnology, namely to methods for producing highly dispersed liposomal preparations for the prevention and treatment of human and animal diseases, which can be used in medicine, cosmetology, the food and chemical industries, and in agriculture. The technical result of the analogue consists in increasing the efficiency and safety of the industrial technology for producing highly dispersed active liposomal preparations, applicable for the inclusion of virtually any biologically active substances in liposomes. The analogue describes a method for producing dry liposomal preparations, including mixing phospholipids, a powder carrier and a biologically active substance and further processing the resulting mixture, characterized in that a composition is poured into the loading hopper of a jet mill, consisting of a biologically active substance, a phospholipid from the group including vitol and lecithin PRO, and a water-soluble powder carrier, and subjecting said mixture to milling in a jet mill at a pressure of at least 2.5 atm and a gas flow rate of at least 100 l / min with subsequent separation of a fraction with a particle size smaller than 50 μm. As an option in the analog, it is proposed to subject a mixture of phospholipids and a powder carrier to milling, and then add a solution of the biologically active substance in a polar solvent to the resulting product, and subject the suspension to lyophilic drying, treating it, if necessary, before drying with ultrasound at a frequency of 40 kHz.The first disadvantage of the analogue is the processing of the liposomal mixture in a jet mill to obtain a highly dispersed powder, since jet mills have a high energy consumption and, as a result, high energy intensity of the processes; in addition, when using jet mills, it is necessary to evenly feed it with material and maintain a constant aerodynamic operating mode. Another disadvantage of the analogue is the complexity of regulating the process of manufacturing the liposomal composition, which negatively affects the reproducibility and quality of the manufactured dry liposomal composition. The next disadvantage of the analogue is that the components of the dry liposomal composition are additionally ground before mixing to obtain microparticles (less than 10 μm). The listed disadvantages of the analogue complicate the technological process of manufacturing the dry liposomal composition.The next disadvantage of the analogue is that lyophilic (sublimation) drying is used to obtain a dry liposomal composition, which also complicates the technological process of obtaining a dry liposomal composition, since vacuum and cryogenic conditions are required in the said technological process. In addition, the lyophilized material must be additionally subjected to a granulation stage in order to then encapsulate and / or tablet the manufactured analogue composition. Another disadvantage of the analogue is that the dry liposomal composition is subjected to ultrasound treatment at a frequency of 40 kHz. The use of ultrasound treatment of the composition complicates the use of the analogue method on an industrial scale due to low productivity. Also, ultrasound treatment of the liposomal composition leads to its excessive heating, which worsens the physical, chemical and biological characteristics of the liposomes.The next disadvantage of the analogue is the use of polar solvents in the manufacture of dry liposomal. compositions, since polar solvents are toxic, and therefore their entry into the human or animal body has a negative effect on it. The essence of the invention

[0012] The objective of the present invention is to develop a composition of a liposomal composition, a method for its production and use, ensuring an increase in the bioavailability and stability of the physical, chemical and biological properties of biologically active substances.

[0013] The stated objective is achieved due to such a technical result as ensuring an increase in bioavailability and stability of physical, chemical and biological properties of biologically active substances. The stated objective is achieved including, but not limited to:

[0014] the presence in the liposomal composition of a phospholipid component, a composition of powdered biologically active substances, and a protective component;

[0015] the thickness of the coating of the particles of the composition of powdered biologically active substances with a phospholipid component, which is 5 - 20% of the linear dimensions of the particles of the composition of powdered biologically active substances;

[0016] relative humidity of the liposomal composition, which is no more than 10%;

[0017] by applying a 2-15% aqueous emulsion of the phospholipid component to the fluidized particles of the powder component by spraying;

[0018] drying the said particles coated with a phospholipid component.

[0019] The essence of the claimed liposomal composition is that a thin dry phospholipid film is formed on the surface of the particles of the composition of powdered biologically active substances, this ensures an increase in the bioavailability and stability of the physical, chemical and biological properties of biologically active substances, which reduces the need for high concentrations of biologically active substances when taken orally. To protect the phospholipid film that covers the particles of the composition of powdered biologically active substances from environmental influences and mechanical damage, a layer of a protective component is applied.

[0020] More specifically, the liposomal composition comprises a composition of powdered biologically active substances, a phospholipid component, a protective component with the following ratio of components to the total weight of the composition, wt.%: composition of powdered biologically active substances 80 - 95; phospholipid component 2 - 15; protective component 3 - 10. In this case, the coating thickness of the particles of the composition of powdered biologically active substances with the phospholipid component is 5 - 20% of the linear dimensions of the particles of the composition of powdered biologically active substances, and the relative humidity of the liposomal composition is no more than 10%.

[0021] The composition of powdered biologically active substances such as vitamins, minerals, amino acids and other macronutrients is an important component of the liposomal composition, the said composition is necessary for the body to receive the necessary set of nutrients to maintain its vital functions. The use of the phospholipid component in the liposomal composition is due to the fact that, firstly, it is non-toxic; secondly, the phospholipid component is biodegradable, does not cause allergic reactions when entering a living organism; thirdly, the phospholipid component, due to its structure and composition, has a high affinity for cell membranes, which allows the substances contained inside the phospholipid component to be delivered directly into the cell.The presence of a protective component is necessary for the formation of a protective layer of particles of the composition of powdered biologically active substances coated with a phospholipid component, thereby protecting the phospholipid coating of the particles of the composition of powdered biologically active substances from environmental influences, including air oxidation, and from mechanical damage, for example, during transportation.

[0022] The combination of a composition of powdered biologically active substances, a phospholipid component, and a protective component in a liposomal composition with the following ratio of components to the total mass of the composition, wt.%: composition of powdered biologically active substances 80-95; phospholipid component 2-15; protective component 3-10, provides increased bioavailability and stability of the physical, chemical, and biological properties of biologically active substances.

[0023] In this case, the coating thickness of the particles of the composition of powdered biologically active substances with a phospholipid component is 5 - 20% of the linear dimensions of the particles of the composition of powdered biologically active substances. Coating the particles of the composition of powdered biologically active substances with a phospholipid component improves absorption and passing through biological membranes of biologically active substances, protects them from metabolism, improves the tissue distribution profile of biologically active substances, and also enhances their permeability into the cell. Changing the thickness of the coating with a phospholipid component in the specified range allows you to regulate the rate of release of biologically active substances. The thickness of the coating of the particles of the composition of powdered biologically active substances with a phospholipid component, which is 5 - 20% of the linear dimensions of the particles of the composition of powdered biologically active substances, ensures an increase in the stability of the physical, chemical, biological properties and bioavailability of biologically active substances.This is achieved due to the fact that the coating of the particles of the composition of powdered biologically active substances with a phospholipid component at the specified range of thickness performs a protective function of the particles of the composition of powdered biologically active substances until the particles of the specified composition, coated with a phospholipid component, reach the less aggressive environment of the small intestine, in which liposomes are formed from the liposomal composition with a minimal risk of destruction under the influence of the environment of a living organism, allowing the biologically active substances contained in them to be delivered directly into the cell.

[0024] Moreover, the relative humidity of the liposomal composition is no more than 10%. This allows increasing the stability of the physical, chemical and biological characteristics of the biologically active substances contained in the liposomal composition.

[0025] Thus, the claimed liposomal composition is a dry powder or dry granules, which upon hydration or contact with biological fluids in the body of a human or animal spontaneously forms liposomes (liposomal vesicles). In this regard, the present liposomal composition is the most promising for commercial use.

[0026] The particle size of the composition of powdered biologically active substances can be 50 - 500 μm, which helps to increase the solubility of the composition of powdered biologically active substances during hydration or upon contact with biological fluids in the body of an animal or human, which, accordingly, additionally increases the bioavailability of biologically active substances.

[0027] Hydrophilic biologically active substances or lipophilic biologically active substances, or their mixture. This allows to improve the bioavailability and stability of physical, chemical and biological properties of not only hydrophilic biologically active substances, but also lipophilic biologically active substances.

[0028] The phospholipid component is an obligatory and necessary component for the formation of liposomes, which in this case are formed during hydration or contact with biological fluids of the present liposomal composition. In addition, the phospholipid component is an emulsifier that stabilizes the emulsion obtained during hydration or contact with biological fluids of the present liposomal composition. In this regard, soy lecithin and / or egg lecithin and / or sunflower lecithin and / or phosphatidylcholine can be used as a phospholipid component in the liposomal composition.

[0029] A plant resin or monosaccharide, or disaccharide, or polysaccharide can be used as a protective component. This allows protecting the phospholipid layer that coats the particles of the composition of powdered biologically active substances from mechanical damage during transportation, as well as preventing the impact of the environment on the phospholipid layer during storage of the liposomal composition, eliminating clumping and sticking of particles coated with a phospholipid component, which allows maintaining increased bioavailability and stability of the physical, chemical and biological properties of biologically active substances.

[0030] Additionally, a powdered anti-caking component can be used in the liposomal composition in an amount of 1 - 5 wt.% of the total weight of the composition. Silicon dioxide and / or calcium orthophosphate and / or calcium stearate can be used as an anti-caking component. This allows maintaining the flowability of the liposomal composition, preventing lumping and adhesion of the liposomal composition particles during storage.

[0031] The essence of the claimed method for producing a liposomal composition consists in applying a phospholipid coating to the surface of dry particles of the composition of powdered biologically active substances in a fluidized bed by spraying an aqueous emulsion of the phospholipid component. Coating the particles of the composition of powdered biologically active substances with a phospholipid component increases the bioavailability and stability of the physical, chemical and biological properties of the biologically active substances. Next, the particles of the composition of powdered biologically active substances coated with a phospholipid component are dried. active substances. Then, a protective coating is applied to the surfaces of dry particles of the composition of powdered biologically active substances coated with a phospholipid component in a fluidized bed by spraying a solution of the protective component to protect the phospholipid film from environmental influences and mechanical damage. Afterwards, the particles of the composition of powdered biologically active substances coated with the protective component and the phospholipid component are dried.

[0032] More specifically, the method for producing a liposomal composition containing a powder component, a phospholipid component, a protective component, wherein a composition of powdered biologically active substances is used as the powder component, consists in producing a 2-15% aqueous emulsion of the phospholipid component; preparing the powder component in such a way that its relative humidity is no more than 10%; applying a 2-15% aqueous emulsion of the phospholipid component to the fluidized particles of the powder component by spraying; drying said particles coated with the phospholipid component; producing a 20-40% solution of the protective component; applying a 20-40% solution of the protective component to the fluidized particles of the powder component coated with the phospholipid component by spraying; drying said particles coated with the phospholipid component and the protective component.Moreover, the thickness of the coating of the particles of the composition of powdered biologically active substances with the phospholipid component is 5 - 20% of the linear dimensions of the particles of the composition of powdered biologically active substances.

[0033] The combination of a composition of powdered biologically active substances, a phospholipid component, and a protective component in the liposomal composition ensures increased bioavailability and stability of the physical, chemical, and biological properties of biologically active substances.

[0034] First, according to the method for obtaining a liposomal composition, a 2-15% aqueous emulsion of the phospholipid component is prepared for its application to the fluidized particles of the powder component. The preparation of a 2-15% aqueous emulsion of the phospholipid component allows the use of phospholipid components with a high melting point for the preparation of a liposomal composition, which helps to increase the bioavailability and stability of the physical, chemical and biological properties of biologically active substances.

[0035] The powder component is then prepared in such a way that its relative humidity is no more than 10%. This preparation helps to improve the uniformity of distribution of the phospholipid component over the surfaces of the particles of the powder active component.

[0036] Next, a 2-15% aqueous emulsion of the phospholipid component is applied to the fluidized particles of the powder component by spraying. This ensures the formation of a thin, uniform phospholipid coating on the surfaces of the said particles.

[0037] Afterwards, the said particles coated with the phospholipid component are dried. This allows for an increase in the stability of the physical, chemical and biological characteristics of the biologically active substances coated with the phospholipid component, due to the removal of excess moisture from the liposomal composition, provided by applying an aqueous emulsion of the phospholipid component to the particles of the powder component.

[0038] Then a 20-40% solution of the protective component is prepared, which allows the said solution to be sprayed onto particles coated with the phospholipid component for its uniform distribution over the surfaces of said particles.

[0039] Then, a 20-40% solution of the protective component is applied to the fluidized particles of the powder component coated with the phospholipid component by spraying. This promotes the formation of a thin, uniform coating of the protective component on the surfaces of the said particles.

[0040] Next, the said particles coated with a phospholipid component and a protective component are dried, which makes it possible to increase the stability of the physical, chemical and biological characteristics of the biologically active substances coated with a phospholipid component and a protective component during storage due to the removal of excess moisture from the liposomal composition, provided by applying a solution of the protective component to the particles coated with a phospholipid component.

[0041] Moreover, the coating thickness of the particles of the composition of powdered biologically active substances with a phospholipid component is 5 - 20% of the linear dimensions of the particles of the composition of powdered biologically active substances. Coating the particles of the composition of powdered biologically active substances with a phospholipid component improves the absorption and passage of biologically active substances through biological membranes, protects them from metabolism, improves the tissue distribution profile of biologically active substances, and also enhances their permeability into the cell. Changing the coating thickness of the phospholipid component of the said particles in the specified range allows one to regulate the rate of release of biologically active substances of the liposomal composition. The coating thickness of the particles of the composition of powdered biologically active substances with a phospholipid component, which is 5 - 20% of the linear dimensions of the particles of the composition of powdered biologically active substances, ensures an increase in the stability of the physical, chemical, biological properties and bioavailability of biologically active substances.This occurs as a result of the fact that the coating of the particles of the composition of powdered biologically active substances with a phospholipid component at the specified range of thickness performs a protective function of the biologically active substances until the particles coated with the phospholipid component reach the less aggressive environment of the small intestine, in which liposomal vesicles are formed from the liposomal composition with a minimal risk of destruction under the influence of the environment of a living organism, allowing the biologically active substances contained in them to be delivered directly into the cell.

[0042] Thus, the claimed method for obtaining a liposomal composition is characterized by high reproducibility of the process of manufacturing the composition without strict fractional selection of particles by size. According to the claimed method for obtaining a liposomal composition, dry powder or dry granules of a liposomal composition are manufactured, which spontaneously forms liposomes (liposomal vesicles) upon hydration or contact with biological fluids in the body of a human or animal. In this regard, the present liposomal composition is the most promising for commercial use.

[0043] A 2-15% aqueous emulsion of the phospholipid component can be produced by mixing the phospholipid component with purified water at a temperature of 40-80°C. The use of purified water to produce an aqueous emulsion of the phospholipid component eliminates the possibility of various bacteria and viruses entering the liposomal composition, ensuring the safety of the liposomal composition. Mixing the phospholipid component with purified water at a temperature of 40-80°C allows for the production of a fluid heterogeneous emulsion with a homogeneously distributed phospholipid component in it, which ensures uniform distribution of the aqueous emulsion of the phospholipid component when sprayed onto the surfaces of particles. powder component. The uniform distribution of the phospholipid component over the surfaces of the particles of the powder component further enhances the bioavailability and stability of the physical, chemical and biological characteristics of biologically active substances.

[0044] Before applying the powder component to the fluidized particles by spraying 2-15% of the aqueous emulsion of the phospholipid component, the powder component particles can be selected by passing them through a sieve with a hole diameter of no more than 500 μm. Selecting the powder component particles, the size of which is no more than 500 μm, allows increasing the solubility of the composition of powdered biologically active substances during hydration or upon contact with biological fluids in the body of an animal or a person, which, accordingly, additionally increases the bioavailability of biologically active substances.

[0045] A 2-15% aqueous emulsion of the phospholipid component is applied to the fluidized particles of the powder component, the temperature of which can be 30-45°C, by spraying; the specified temperature range is due to the thermal lability of the applied composition of powdered biologically active substances.

[0046] When spraying, the temperature of the 2-15% aqueous emulsion of the phospholipid component can be 35-60°C. In the specified temperature range, the aqueous emulsion of the phospholipid component is plastic and has fluidity, which allows it to be applied by spraying onto fluidized particles of the powder component.

[0047] The spray rate can be changed from 300 ml / min to 1000 ml / min in such a way that with an increase in the mass of the powder component by 1 - 3 wt.%, the spray rate can be increased by 10 - 20%. This ensures uniform distribution of the phospholipid component and the protective component over the surfaces of the particles of the powder component, which helps to increase the stability of the physical, chemical and biological properties and increase the bioavailability of the biologically active substances of the liposomal composition.

[0048] Spraying can be carried out in a direct flow. Direct flow spraying improves the uniformity of distribution of the phospholipid component and the protective component over the surfaces of the particles of the powder component, which additionally contributes to increasing the stability of the physical, chemical and biological properties and increasing the bioavailability of the biologically active substances of the liposomal composition.

[0049] Spraying can be carried out through the nozzles of spray injectors. This allows to regulate the spraying rate of the aqueous emulsion of the phospholipid component and the solution of the protective component and the thickness of the phospholipid coating and the protective coating of the particles of the powder component, and also ensures the constancy of the spray angle and the droplet size of the aqueous emulsion of the phospholipid component and the solution of the protective component. The constancy of the spray angle and the droplet size of the aqueous emulsion of the phospholipid component and the solution of the protective component ensures the reproducibility of the manufacture of the liposomal composition. In this case, the nozzle diameter can be 0.2 - 1 mm, and the distance from the nozzle to the surface layer of the fluidized particles of the powder component can vary from 80 cm to 200 cm.

[0050] Drying is carried out in such a way that the relative humidity of the liposomal composition may not exceed 10%. This allows for an increase in the stability of the physical, chemical and biological characteristics of the biologically active substances contained in the liposomal composition.

[0051] Drying is carried out by feeding compressed gas, the temperature of which can be 50 - 80 °C, while compressed air can be used as the compressed gas. At the specified temperature range, the water contained in the phospholipid coating and protective coating evaporates, and the specified coatings of the particles of the powder component harden and are fixed on the specified particles.

[0052] A 20-40% solution of the protective component can be prepared by mixing the protective component with purified water, ensuring the component dissolves in water. Using purified water to prepare a solution of the protective component eliminates the possibility of various bacteria and viruses entering the liposomal composition, ensuring the safety of using the liposomal composition. Mixing the protective component with purified water allows you to prepare a homogeneous solution, this additionally ensures the uniformity of the distribution of the solution of the protective component when spraying it on particles of the powder component coated with a phospholipid component. This is necessary to form a protective layer from mechanical damage and from environmental impacts of particles of the powder component coated with a phospholipid component.This, in turn, ensures the preservation of increased stability of the physical, chemical and biological properties and bioavailability of biologically active substances contained in the liposomal composition.

[0053] Additionally, a powdered anti-caking component can be used in the liposomal composition. This allows maintaining the flowability of the liposomal composition, preventing its clumping and sticking together.

[0054] The technical result is also achieved by the method of using the liposomal composition, according to which the liposomal composition is manufactured according to the method described above; the liposomal composition is encapsulated and / or tabletted, and / or powder is manufactured from the liposomal composition to obtain a suspension from the said composition for oral use. This ensures the convenience of using the liposomal composition, which spontaneously forms liposomes (liposomal vesicles) upon hydration or contact with biological fluids. Detailed description

[0055] In the following detailed description of the embodiment of the invention, numerous implementation details are provided in order to provide a clear understanding of the present invention. However, it will be obvious to one skilled in the art how the present invention can be used with or without these implementation details. In other instances, well-known methods, procedures, and components have not been described in detail in order not to unnecessarily obscure the features of the present invention.

[0056] In addition, it is clear from the above presentation that the invention is not limited to the given implementation. Numerous possible modifications, changes, variations and replacements, preserving the essence and form of the present invention, are obvious to specialists skilled in the subject area.

[0057] The most promising forms of biologically active additives for commercial use are those that are dry liposomal compositions that spontaneously form liposomal vesicles (liposomes) upon hydration or contact with biological fluids in the human or animal body. Their prospects for commercial use are due to the fact that proliposomes have stable physical, chemical and biological properties with a long shelf life, and also allow for high efficiency of active substance loading due to increased bioavailability of the biologically active substances contained in them.

[0058] The claimed liposomal composition contains a composition of powdered biologically active substances, a phospholipid component, protective component with the following ratio of components to the total weight of the composition, wt.%: composition of powdered biologically active substances 80 - 95; phospholipid component 2 - 15; protective component 3 - 10.

[0059] The composition of powdered biologically active substances is an important component of the liposomal composition, the said composition is necessary for the body to receive the necessary set of nutrients to maintain its vital functions. Biologically active substances preferably have pharmaceutical, nutraceutical, dietary and / or therapeutic and prophylactic activity. Vitamins, minerals and other substances with nutritional and / or physiological activity, including essential amino acids, branched amino acids, peptides, plant extracts (e.g. flavonoids, waxes, polyphenols) can be used as biologically active substances with pharmaceutical, nutraceutical, dietary and / or therapeutic and prophylactic activity.

[0060] The use of a phospholipid component in a liposomal composition is due to a number of reasons: it is non-toxic, therefore, it does not have a negative effect on a living organism; the phospholipid component is biodegradable, does not cause allergic reactions when entering a living organism. The main advantage of using a phospholipid component in a liposomal composition is its ability to emulsify and disperse during hydration or upon contact with biological fluids in the body of a human or animal with the formation of liposomes. This feature of the phospholipid component, which has a high affinity for cell membranes due to its structure and composition, allows the delivery of substances contained inside the phospholipid component directly into the cell.Soy lecithin and / or egg lecithin and / or sunflower lecithin and / or phosphatidylcholine and / or phosphatidic acid and / or phosphatidylglycerol and / or phosphatidylethanolamine and / or phosphatidylinosine and / or phosphatidylserine and / or plasmalogens and / or sphingomyelin can be used as a phospholipid component in the liposomal composition. Soy lecithin is the most economical, safe and stable phospholipid component from a production point of view.

[0061] The presence of a protective component is necessary for the formation of a protective layer of particles of the composition of powdered biologically active substances coated with a phospholipid component, thereby protecting the phospholipid coating. the said particles from environmental influences, including air oxidation, and from mechanical damage, for example, during transportation. A plant resin or monosaccharide, or disaccharide, or polysaccharide can be used as a protective component. Gum arabic, locust bean gum, carrageenan are preferably used as a plant resin. Ribose, glucose, mannose, galactose are preferably used as a monosaccharide. Palatinose, lactose are preferably used as a disaccharide. Maltodextrin, inulin, methylcellulose are preferably used as a polysaccharide.

[0062] The combination of a composition of powdered biologically active substances, a phospholipid component, and a protective component in a liposomal composition with the following ratio of components to the total mass of the composition, wt.%: composition of powdered biologically active substances 80-95; phospholipid component 2-15; protective component 3-10, provides increased bioavailability and stability of the physical, chemical, and biological properties of biologically active substances.

[0063] In this case, the coating thickness of the particles of the composition of powdered biologically active substances with the phospholipid component is 5 - 20% of the linear dimensions of the particles of the composition of powdered biologically active substances. If the coating thickness of the particles of the composition of powdered biologically active substances with the phospholipid component is less than 5%, the encapsulating capacity of the liposomes formed from the liposomal composition decreases, and the bioavailability of the biologically active substances worsens. If the coating thickness of the particles of the composition of powdered biologically active substances with the phospholipid component is more than 20%, the resulting thick phospholipid shell prevents the hydration of the particles of the liposomal composition. This significantly complicates the self-assembly of liposomes during hydration or contact with biological fluids of the liposomal composition.The coating thickness of the particles of the composition of powdered biologically active substances with a phospholipid component, which is 5 - 20% of the linear dimensions of the particles of the composition of powdered biologically active substances, improves the absorption and passage of biologically active substances through biological membranes, protects them from metabolism, improves the tissue distribution profile of biologically active substances, and also enhances their permeability into the cell. Changing the coating thickness with a phospholipid component in the specified range allows you to regulate the rate of release of biologically active substances. Thickness of the coating of particles. compositions of powdered biologically active substances with a phospholipid component, comprising 5-20% of the linear dimensions of the particles of the composition of powdered biologically active substances, provides for an increase in the stability of the physical, chemical, biological properties and bioavailability of biologically active substances. This is achieved due to the fact that the coating of the particles of the composition of powdered biologically active substances with a phospholipid component at the specified thickness range performs a protective function of the said particles until the particles of the said composition, coated with a phospholipid component, reach the less aggressive environment of the small intestine, in which liposomes are formed from the liposomal composition with a minimal risk of destruction under the influence of the environment of a living organism, allowing the biologically active substances contained therein to be delivered directly into the cell.The thickness of the coating of the protective component of the particles of the composition of powdered biologically active substances coated with the phospholipid component is preferably 5 - 20% of the linear dimensions of the particles of the composition of powdered biologically active substances. This allows maintaining improved bioavailability and stability of the physical, chemical and biological properties of biologically active substances.

[0064] Moreover, the relative humidity of the liposomal composition is no more than 10%. If the relative humidity of the liposomal composition is more than 10%, then the excess humidity of the composition leads to its accelerated deterioration, i.e. the stability of the physical, chemical and biological characteristics of the biologically active substances contained in the liposomal composition decreases, and the excess humidity of the composition leads to adhesion and clumping of its particles, which makes it impossible to accurately dose the liposomal composition when placing it, for example, in capsules or sachets. The relative humidity of the liposomal composition, which is no more than 10%, makes it possible to increase the stability of the physical, chemical and biological characteristics of the biologically active substances contained in the liposomal composition, and also ensures accurate dosing of the liposomal composition when placing it, for example, in capsules or sachets.

[0065] The particle size of the composition of powdered biologically active substances may be less than 50 μm, 50 - 500 μm or more than 500 μm. If the particle size of the composition of powdered biologically active substances is less than 50 μm, the risk of adverse reactions in the body increases. of a person or an animal to orally administered biologically active substances. If the particle size of the composition of powdered biologically active substances is greater than 500 μm, then the area of ​​the active surface of the particles of the composition of said substances decreases, which leads to a decrease in the bioavailability of the biologically active substances of the liposomal composition. The particle size of the composition of powdered biologically active substances is preferably 50 - 500 μm, this helps to increase the solubility of the composition of powdered biologically active substances during hydration or upon contact with biological fluids in the body of an animal or a person, which, accordingly, additionally increases the bioavailability of biologically active substances without the risk of adverse reactions to them.

[0066] Hydrophilic biologically active substances or lipophilic biologically active substances, or a mixture thereof, can be used as biologically active substances in the liposomal composition. This allows improving the bioavailability and stability of the physical, chemical and biological properties of not only hydrophilic biologically active substances, but also lipophilic biologically active substances. For example, the percentage ratio of the masses of hydrophilic and lipophilic biologically active substances from the total mass of lipophilic and hydrophilic biologically active substances can be 90: 10 - 70: 30.

[0067] Additionally, a powdered anti-caking component may be used in the liposomal composition. Preferably, the powdered anti-caking component is used in the liposomal composition in an amount of 1 - 5 wt.% of the total weight of the composition. Silicon dioxide and / or calcium orthophosphate and / or calcium stearate may be used as the anti-caking component. This allows maintaining the flowability of the liposomal composition, preventing its clumping and sticking. The particle size of the powdered anti-caking component may be 50 - 500 μm.

[0068] For a better understanding of the present invention in relation to the liposomal composition, the following Examples 1-4 and Table 1 describe the components used, their ratio in the composition of the liposomal composition, which illustrate, but do not limit the proposed invention.

[0069] Example 1. A composition of powdered biologically active substances, phospholipid and protective components are used to produce a liposomal composition. The composition of powdered biologically active substances contains mixture A, including powdered choline bitartrate, uridine 5- monophosphate and policosanol, wherein the percentage ratio of the masses of powdered choline bitartrate, uridine 5-monophosphate, policosanol from the total mass of the composition of powdered biologically active substances is 53: 30: 17. Soy lecithin is used as a phospholipid component. A plant resin, more specifically, gum arabic, is used as a protective component. The ratio of the components of the liposomal composition to the total mass of the composition is given in Table 1.

[0070] Example 2. The liposomal composition is prepared using components similar to those in Example 1, with the exception of the mixture contained in the composition of powdered biologically active substances. The composition of powdered biologically active substances contains mixture B, including powdered ascorbic acid, calcium ascorbate, ascorbyl palmitate, wherein the percentage ratio of the masses of powdered ascorbic acid, calcium ascorbate, ascorbyl palmitate from the total mass of the composition of powdered biologically active substances is 38: 32: 30. The ratio of the components of the liposomal composition to the total mass of the composition is given in Table 1.

[0071] Example 3. The liposomal composition is prepared using components similar to those in Example 1, with the exception of the mixture contained in the composition of powdered biologically active substances. The composition of powdered biologically active substances contains mixture C, including powdered amino acids L-tryptophan, 5-hydroxytryptophan and saffron extract, wherein the percentage ratio of the masses of the powdered amino acids L-tryptophan, 5-hydroxytryptophan and saffron extract from the total mass of the composition of powdered biologically active substances is 61: 30: 9. The ratio of the components of the liposomal composition to the total mass of the composition is given in Table 1.

[0072] Example 4. The liposomal composition is prepared using components similar to those in Example 1, with the exception of the mixture contained in the composition of powdered biologically active substances. The composition of powdered biologically active substances contains mixture D, including powdered amino acids y-aminobutyric acid, L-theanine and a complex of B vitamins (B3, B2, B6), lavender extract, wherein the percentage ratio of the masses of powdered y-aminobutyric acid, L-theanine, a complex of B vitamins (B3, B2, B6), lavender extract from the total mass of the composition of powdered biologically active substances is 56: 29: 1: 14. The ratio of the components of the liposomal composition to the total mass of the composition is given in Table 1. Table 1 Composition and quantity of components of the liposomal composition Note*: BAS – biologically active substances.

[0073] In examples 1-4, the coating thickness of the particles of the composition of powdered biologically active substances with the phospholipid component is 5-20% of the linear dimensions of the particles of the composition of powdered biologically active substances, and the relative humidity of the liposomal composition is no more than 10%.

[0074] Thus, the claimed liposomal composition is a dry powder or dry granules, which upon hydration or contact with biological fluids in the body of a human or animal spontaneously forms liposomes (liposomal vesicles). In this regard, the present liposomal composition is the most promising for commercial use.

[0075] The formation of liposomes during hydration of the present liposomal composition is assessed, for example, by light microscopy in dark or phase-contrast modes. A sample of 20-50 mg of the present liposomal composition is dissolved in distilled water, the volume of which is 1-2 ml, during dissolution, slight shaking of the resulting suspension is allowed. In the presence of poorly or poorly soluble substances, centrifugation of the suspension is carried out at revolutions that do not exceed 2000 rpm. The size of liposomes formed from liposomal compositions, the composition of which is described in examples 1-4, is 0.2-25 μm.

[0076] A method is described for producing a liposomal composition containing a powdered component, a phospholipid component, and a protective component, where a composition of powdered biologically active substances is used as the powdered component.

[0077] The combination of a composition of powdered biologically active substances, a phospholipid component, and a protective component in a liposomal composition provides increased bioavailability and stability of the physical, chemical, and biological properties of biologically active substances. The liposomal composition preferably contains a composition of powdered biologically active substances, a phospholipid component, and a protective component in the following ratio of components to the total weight of the composition, wt.%: composition of powdered biologically active substances 80-95; phospholipid component 2 - 15; protective component 3 - 10.

[0078] First, 2 are prepared using the method for obtaining a liposomal composition. - a 15% aqueous emulsion of a phospholipid component for applying it to the fluidized particles of the powder component. The said concentration of the aqueous emulsion of the phospholipid component allows regulating the coating thickness of the particles of the powder component with the phospholipid component in the range of 5 - 20% of the linear dimensions of the particles of the powder component, where a composition of powdered biologically active substances is used as the powder component. In addition, the production of a 2 - 15% aqueous emulsion of the phospholipid component allows using phospholipid components with a high melting point for the production of a liposomal composition, this contributes to an increase in the bioavailability and stability of the physical, chemical and biological properties of biologically active substances.

[0079] Then, according to the method for obtaining the liposomal composition, the powder component is prepared in such a way that its relative humidity is no more than 10%. This is necessary so that the excess moisture contained in the powder active component does not interfere with the subsequent described technological stages of obtaining the liposomal composition. For example, excess moisture contained in the powder component prevents the uniform application of the phospholipid component to the particles of the powder component, which, accordingly, leads to a deterioration in the bioavailability and stability of the physical, chemical and biological properties of biologically active substances. The said preparation of the powder component, in which its relative humidity is no more than 10%, helps to improve the uniformity of distribution of the phospholipid component over the surfaces of the particles of the powder component.

[0080] Next, a 2-15% aqueous emulsion of the phospholipid component is applied to the fluidized particles of the powder component by spraying. The spraying pressure is preferably 0.1-0.5 MPa. The said aqueous emulsion is applied to the fluidized particles of the powder component in a sealed vessel, for example, in a container. In this case, the loading volume of the powder component in the sealed vessel is from 15% to 90% of the nominal capacity of the vessel. Application of a 2-15% aqueous emulsion of the phospholipid component to the fluidized particles of the powder component by spraying ensures the formation of a thin, uniform phospholipid coating on the surfaces of the said particles. The coating of the phospholipid component on the surfaces of the particles of the composition of powdered biologically active substances can be carried out by spraying from below or by spraying from above in a fluidized bed.Application of a phospholipid coating by spraying from above reduces the efficiency of coating the particles of the composition of powdered biologically active substances, since when spraying from above, the particles interact with each other, which initiates agglomeration of the particles and their granulation, and when spraying from below, encapsulation (coating) of individual particles occurs, eliminating their adhesion. In this regard, it is preferable to apply the phospholipid coating by spraying from below.

[0081] Afterwards, the said particles coated with the phospholipid component are dried. This allows for an increase in the stability of the physical, chemical and biological characteristics of the biologically active substances coated with the phospholipid component, for example, during storage, due to the removal of excess moisture from them, provided by applying an aqueous emulsion of the phospholipid component to the particles of the powder component.

[0082] Then, a 20-40% solution of the protective component is prepared, which allows the said solution to be sprayed onto particles coated with the phospholipid component for its uniform distribution over the surfaces of said particles. The said concentration of the aqueous emulsion of the phospholipid component allows the coating thickness of said particles with the protective component to be adjusted in a range that preferably amounts to 5-20% of the linear dimensions of the particles of the powder component.

[0083] Afterwards, according to the method for producing the liposomal composition, a 20-40% solution of the protective component is applied to the fluidized particles of the powder component coated with the phospholipid component by spraying. This promotes the formation of a thin, uniform coating of the protective component on the surfaces of said particles. The coating of the protective component on the surfaces of the particles of the composition of powdered biologically active substances coated with the phospholipid component can be applied by spraying from below or by spraying from above in a fluidized bed. Applying the protective coating by spraying from above reduces the efficiency of coating said particles, since when spraying from above, the particles interact with each other, which initiates agglomeration of the particles and their granulation, and when spraying from below, encapsulation (coating) of individual particles occurs, eliminating their adhesion. In this regard, it is preferable to apply the protective coating by spraying from below.

[0084] Next, the said particles coated with the phospholipid component and the protective component are dried, which makes it possible to increase the stability of the physical, chemical and biological characteristics of the biologically active substances coated with the phospholipid component and the protective component, for example, during storage, due to the removal of excess moisture from the liposomal composition, provided by applying a solution of the protective component to the particles coated with the phospholipid component.

[0085] Moreover, the coating thickness of the particles of the composition of powdered biologically active substances with the phospholipid component is 5 - 20% of the linear dimensions of the particles of the composition of powdered biologically active substances. If the coating thickness of the particles of the composition of powdered biologically active substances with the phospholipid component is less than 5%, then the encapsulating capacity of the liposomes formed from the liposomal composition decreases, and the bioavailability of the biologically active substances worsens. If the coating thickness of the particles of the composition of powdered biologically active substances with the phospholipid component is more than 20%, then the resulting thick phospholipid shell prevents the hydration of the particles of the liposomal composition. This significantly complicates the self-assembly of liposomes during hydration or contact with biological fluids of the liposomal composition.The thickness of the coating of the particles of the composition of powdered biologically active substances with a phospholipid component, which is 5 - 20% of the linear dimensions of the particles of the composition of powdered biologically active substances, ensures improved absorption. and passage of biologically active substances through biological membranes, protects them from metabolism, improves the tissue distribution profile of biologically active substances, and also enhances their permeability into the cell. Changing the thickness of the coating with a phospholipid component in the specified range allows you to regulate the rate of release of biologically active substances. The thickness of the coating of the particles of the composition of powdered biologically active substances with a phospholipid component, which is 5 - 20% of the linear dimensions of the particles of the composition of powdered biologically active substances, ensures an increase in the stability of the physical, chemical, biological properties and bioavailability of biologically active substances.This is achieved due to the fact that the coating of the particles of the composition of powdered biologically active substances with a phospholipid component at the specified range of thickness performs a protective function of the said particles until the particles of the said composition, coated with a phospholipid component, reach the less aggressive environment of the small intestine, in which liposomes are formed from the liposomal composition with a minimal risk of destruction under the influence of the environment of a living organism, allowing the biologically active substances contained in them to be delivered directly into the cell.

[0086] Thus, the claimed method for obtaining a liposomal composition is characterized by high reproducibility of the process of manufacturing the composition without strict fractional selection of particles by size. According to the claimed method for obtaining a liposomal composition, dry powder or dry granules of a liposomal composition are manufactured, which spontaneously forms liposomes upon hydration or contact with biological fluids in the body of a human or animal. In this regard, the present liposomal composition is the most promising for commercial use.

[0087] A 2-15% aqueous emulsion of the phospholipid component can be produced by mixing the phospholipid component with water at a temperature of 20-35°C, 40-80°C or more than 80°C. If the phospholipid component is mixed with water at a temperature of less than 40°C, the phospholipid component does not form a homogeneous emulsion, which leads to an uneven distribution of the aqueous emulsion of the phospholipid component over the surfaces of the particles of the powder component. If the phospholipid component is mixed with water at a temperature of more than 80°C, the physicochemical properties of the phospholipid component change, the phospholipid emulsion darkens and oxidizes, which leads to the loss of the ability of the phospholipid component to form liposomes. Preferably, a 2-15% aqueous emulsion of the phospholipid component is prepared by mixing the phospholipid component with purified water at a temperature of 40-80°C, with only short-term heating to a temperature of 80°C possible. In this case, the mixing speed of the purified water and the phospholipid component is preferably 60-80 rpm, where mixing can be carried out using paddle mixers. The use of purified water for the preparation of an aqueous emulsion of the phospholipid component eliminates the entry of various bacteria and viruses into the liposomal composition, ensuring the safety of using the liposomal composition.Mixing the phospholipid component with purified water at a temperature of 40 - 80°C allows for the production of a fluid heterogeneous emulsion with the phospholipid component homogeneously distributed in it, which ensures uniform distribution of the aqueous emulsion of the phospholipid component when it is applied to the surfaces of the particles of the powder component.

[0088] Before applying the powder component to the fluidized particles by spraying 2-15% of the aqueous emulsion of the phospholipid component, the powder component particles can be selected by passing them through a sieve. It is preferable to use a sieve with a hole diameter of no more than 500 μm. If the size of the powder component particles is more than 500 μm, the active surface area of ​​the powder component particles decreases, which leads to a decrease in the bioavailability of the powder components of the liposomal composition, namely, the composition of powdered biologically active substances. Selecting the powder component particles whose size is no more than 500 μm allows increasing the solubility of biologically active substances during hydration or upon contact with biological fluids in the body of an animal or a person, which, accordingly, additionally increases the bioavailability of biologically active substances.

[0089] A 2-15% aqueous emulsion of the phospholipid component is applied to the fluidized particles of the powder component, the temperature of which can be 30-45°C, by spraying; the specified temperature range is due to the thermal lability of the applied composition of powdered biologically active substances; this additionally contributes to increasing the stability of the physical, chemical and biological properties and increasing the bioavailability of biologically active substances of the liposomal composition.

[0090] When spraying, the temperature of the 2-15% aqueous emulsion of the phospholipid component is preferably 35-60°C. The specified temperature range of the aqueous emulsion of the phospholipid component is due to the fact that in this temperature range the emulsion is plastic and has fluidity, which allows it to be applied by spraying onto fluidized particles of the powder component.

[0091] The spray rate can be changed from 300 ml / min to 1000 ml / min in such a way that with an increase in the mass of the powder component by 1 - 3 wt.%, the spray rate can be increased by 10 - 20%. This ensures uniform distribution of the phospholipid component and the protective component over the surfaces of the particles of the powder component, which helps to increase the stability of the physical, chemical and biological properties and increase the bioavailability of the biologically active substances of the liposomal composition.

[0092] Spraying can be carried out in a straight line or tangentially. However, tangential spraying has low efficiency, leading to uneven distribution of the emulsion and solution over the surfaces of the particles of the powder component, in addition, tangential spraying leads to the loss of part of the sprayed substance, which increases production costs. Spraying is preferably carried out in a straight line. Straight line spraying means spraying substances in an ascending flow of particles of the powder component, i.e., drops of the sprayed substance and particles of the powder component move in parallel. Straight line spraying improves the uniformity of distribution of the phospholipid component and the protective component over the surfaces of the particles of the powder component, namely, the composition of powdered biologically active substances.

[0093] Preferably, spraying is carried out through nozzles of spray injectors, wherein the number of nozzles can be 1 - 5. This allows to regulate the spraying rate of the aqueous emulsion of the phospholipid component and the solution of the protective component and the thickness of the phospholipid coating and the protective coating of the particles of the powder component, and also ensures the constancy of the spray angle and the droplet size of the aqueous emulsion of the phospholipid component and the solution of the protective component. The constancy of the spray angle and the droplet size of the aqueous emulsion of the phospholipid component and the solution of the protective component ensures the reproducibility of the manufacture of the liposomal composition. In this case, the nozzle diameter can be 0.2 - 1 mm, and the distance from the nozzle to the surface layer of fluidized particles of the powder component can vary from 80 cm to 200 cm.

[0094] Drying is carried out in such a way that the relative humidity of the liposomal composition is preferably no more than 10%. If the relative humidity of the liposomal composition is more than 10%, then the excess humidity of the composition leads to its accelerated deterioration, i.e. the stability of the physical, chemical and biological characteristics of the biologically active substances contained in the liposomal composition decreases, and the excess humidity of the composition leads to adhesion and clumping of its particles, which makes it impossible to accurately dose the liposomal composition when placing it, for example, in capsules or sachets. The relative humidity of the liposomal composition, which is no more than 10%, makes it possible to increase the stability of the physical, chemical and biological characteristics of the biologically active substances contained in the liposomal composition, and also ensures accurate dosing of the liposomal composition when placing it, for example, in capsules or sachets.

[0095] Drying is carried out by feeding compressed gas, the temperature of which is preferably 50 - 80 °C. The volumetric flow rate of the compressed gas supply can be 2000 - 4000 m 3 / h. Compressed air can be used as the compressed gas. At the specified temperature range, the water contained in the phospholipid coating and protective coating evaporates, and the specified coatings of the powder component particles harden and are fixed on the specified particles.

[0096] A 20-40% solution of the protective component can be prepared by mixing the protective component with water, ensuring the component dissolves in water. Preferably, a 20-40% solution of the protective component is prepared by mixing the protective component with purified water. The use of purified water to prepare the solution of the protective component eliminates the possibility of various bacteria and viruses entering the liposomal composition, ensuring the safety of using the liposomal composition. Mixing the protective component with purified water allows you to prepare a homogeneous solution containing the protective component and water, this additionally ensures uniform distribution of the solution of the protective component when it is sprayed on the surfaces of the particles of the powder component coated with the phospholipid component. This contributes to the formation of a protective layer from environmental influences and mechanical damage to the particles of the powder component coated with phospholipid component. This, in turn, ensures the preservation of increased stability of the physical, chemical and biological properties and bioavailability of the biologically active substances contained in the liposomal composition.

[0097] Additionally, a powdered anti-caking component may be used in the liposomal composition. Preferably, the powdered anti-caking component is used in an amount of 1 - 5 wt.% of the total weight of the liposomal composition. In one embodiment, when preparing the powdered component, a powdered anti-caking component is additionally added to it to impart flowability to the composition of powdered biologically active substances. In another embodiment, a powdered anti-caking component is added to particles of the powdered component coated with phospholipid and protective components. This makes it possible to impart flowability to the particles of the liposomal composition and prevent their sticking together on the process equipment.

[0098] The method for using the liposomal composition consists in producing the liposomal composition according to the method described above; encapsulating and / or tabletting the liposomal composition, and / or producing a powder from the liposomal composition to obtain a suspension from the said composition for oral use. Moreover, the liposomal composition is preferably encapsulated in gelatin and / or cellulose capsules. This ensures the convenience of using the liposomal composition, which spontaneously forms liposomes (liposomal vesicles) upon hydration or contact with biological fluids.

[0099] Thus, the developed composition of the liposomal composition, the method of its production and use ensure increased bioavailability and stability of the physical, chemical and biological properties of biologically active substances. [000100] The present application materials present a preferred disclosure of the implementation of the claimed technical solution, which should not be used as limiting other, particular embodiments of its implementation that do not go beyond the requested scope of legal protection and are obvious to specialists in the relevant field of technology.

Claims

Invention formula 1. A liposomal composition containing a composition of powdered biologically active substances, a phospholipid component, a protective component, with the following ratio of components to the total weight of the composition, wt.%: • composition of powdered biologically active substances 80 - 95; • phospholipid component 2 - 15; • protective component 3 - 10, wherein the coating thickness of the particles of the composition of powdered biologically active substances with the phospholipid component is 5 - 20% of the linear dimensions of the particles of the composition of powdered biologically active substances, and the relative humidity of the liposomal composition is no more than 10%.

2. A liposomal composition according to claim 1, characterized in that the particle size of the composition of powdered biologically active substances is 50 - 500 μm.

3. A liposomal composition according to claim 1, characterized in that hydrophilic biologically active substances or lipophilic biologically active substances, or a mixture thereof, are used as biologically active substances.

4. A liposomal composition according to claim 1, characterized in that soy lecithin and / or egg lecithin and / or sunflower lecithin and / or phosphatidylcholine is used as the phospholipid component.

5. A liposomal composition according to claim 1, characterized in that a plant resin or a monosaccharide, or a disaccharide, or a polysaccharide is used as the protective component.

6. The liposomal composition according to claim 1, characterized in that a powdered anti-caking component is additionally used in an amount of 1 - 5 wt.% of the total weight of the liposomal composition.

7. A liposomal composition according to item 6, characterized in that silicon dioxide and / or calcium orthophosphate and / or calcium stearate are used as the anti-caking component.

8. A method for producing a liposomal composition containing a powdered component, a phospholipid component, a protective component, wherein a composition of powdered biologically active substances is used as the powdered component, according to which: • prepare a 2–15% aqueous emulsion of the phospholipid component; • prepare the powder component in such a way that its relative humidity is no more than 10%; • a 2–15% aqueous emulsion of the phospholipid component is applied to the fluidized particles of the powder component by spraying; • dry the said particles coated with a phospholipid component; • prepare a 20-40% solution of the protective component; • a 20-40% solution of the protective component is applied to the fluidized particles of the powder component coated with the phospholipid component by spraying; • the said particles coated with a phospholipid component and a protective component are dried, wherein the coating thickness of the particles of the composition of powdered biologically active substances with a phospholipid component is 5 - 20% of the linear dimensions of the particles of the composition of powdered biologically active substances.

9. A method for producing a liposomal composition according to claim 8, characterized in that a 2-15% aqueous emulsion of the phospholipid component is prepared by mixing the phospholipid component with purified water at a temperature of 40-80°C.

10. A method for producing a liposomal composition according to claim 8, characterized in that, before applying a powder component to the fluidized particles by spraying a 2-15% aqueous emulsion of the phospholipid component, particles of the powder component are selected by passing them through a sieve with a hole diameter of no more than 500 μm.

11. A method for producing a liposomal composition according to claim 8, characterized in that a 2-15% aqueous emulsion of a phospholipid component is applied to fluidized particles of a powder component, the temperature of which is 30-45°C, by spraying.

12. A method for producing a liposomal composition according to claim 8, characterized in that during spraying the temperature of the 2-15% aqueous emulsion of the phospholipid component is 35-60° C.

13. A method for producing a liposomal composition according to claim 8, characterized in that the spray rate is changed from 300 ml / min to 1000 ml / min in such a way that when the mass of the powder component increases by 1 - 3 wt.%, the spray rate is increased by 10 - 20%.

14. A method for producing a liposomal composition according to claim 8, characterized in that the spraying is carried out in a straight line.

15. A method for producing a liposomal composition according to claim 8, characterized in that spraying is carried out through spray nozzles.

16. A method for producing a liposomal composition according to I.15, characterized in that the nozzle diameter is 0.2 - 1 mm.

17. A method for producing a liposomal composition according to item 15, characterized in that the distance from the nozzle to the surface layer of fluidized particles of the powder component is 80–200 cm.

18. A method for obtaining a liposomal composition according to item 8, characterized in that drying is carried out in such a way that the relative humidity of the liposomal composition is no more than 10%.

19. A method for producing a liposomal composition according to item 8, characterized in that drying is carried out by supplying compressed gas, the temperature of which is 50 - 80°C.

20. A method for producing a liposomal composition according to Article 19, characterized in that compressed air is used as the compressed gas.

21. A method for producing a liposomal composition according to item 8, characterized in that a 20-40% solution of the protective component is prepared by mixing the protective component with purified water.

22. A method for producing a liposomal composition according to claim 8, characterized in that a powdered anti-caking component is additionally used in the liposomal composition.

23. A method of using a liposomal composition, according to which: • prepare a liposomal composition according to I. 8; • encapsulate and / or tablet the liposomal composition, and / or prepare a powder from the liposomal composition to obtain a suspension from the said composition.

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