RU2367415C2 - Perfluorinated gas-transferring emulsion for medical and biological purposes, composition, method of obtaining and pharmaceutical thereof (versions) - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention refers to the chemical pharmaceutical industry and relates to the composition, method of obtaining and application of the means based on the perfluorinated emulsions intended for usage as blood substitutes and other medicinal preparations. The essence of the method lies in the development of the method and composition consisting of two promptly excreting (C₈-C₁₀) and/or slowly excreting (C₁₁-C₁₂) perfluorcarbons in the ratio from 1/1 to 10/10, or mixture of three perfluorocarbons: two promptly excreting (C₈-C₁₀) and one slowly excreting (C₁₁-C₁₂), or one promptly excreting (C₈-C₁₀) and two slowly excreting (C₁₁-C₁₂) in the ratio 1/1/1 to 10/10/10, or mixture of four perfluorocarbons: two promptly excreting (C₈-C₁₀) and two slowly excreting (C₁₁-C₁₂) in the ratio 1/1/1/1 to 10/10/10/10. The perfluorocarbon mixture has the concentration in the range from 1% (0.5% vol.) to 100% (50% vol.) with average particle size in the range 30-80 nm, it is emulgated with proxanol-268 taken in amount from 0.2% to 20% with molecular mass 6000-12000.

EFFECT: compound contains acceptable electrolyte solution or other acceptable media.

17 cl, 12 ex, 1 tbl, 1 dwg

Description

The invention relates to the life sciences industry and relates to a composition, a method for producing and using perfluorocarbon gas-transferring emulsions, intended for use as synthetic perfluorocarbon blood-replacing agents and agents for treating various diseases, as well as perfusion, radiopaque and cosmetic agents.

State of the art

The compositions of perfluorocarbon emulsions.

Perfluorocarbon emulsions are a dispersion of a liquid phase (perfluorocarbons) distributed in another liquid (water) - a dispersion medium. Such a disperse system in the state of aggregation has the designation F / F. In a perfluorocarbon emulsion, the dispersed medium is a polar liquid - water. Perfluorocarbon emulsions are direct emulsions. Most dispersed systems with a liquid dispersed medium are aggregatively unstable, i.e. lyophobic, they include perfluorocarbon emulsions - thermodynamically nonequilibrium colloidal systems.

The properties of dispersed systems depend on the number of particles of the dispersed phase. When there are few particles and the contact between them is insignificant and the particles are able to move relative to each other, such dispersed systems are free-dispersed. Perfluorocarbon emulsions belong to free-dispersed systems, and the number of particles in 1 liter of a 20% emulsion of perfluorocarbons is 1.53 × 10 ¹⁸ .

In most cases, the creation of highly dispersed systems requires the cost of work in the form of mechanical energy. The dispersion method, the most suitable for producing nanoemulsions, is based on a mechanical method of overcoming intermolecular forces. Dispersion using high pressure homogenizers causes the grinding of perfluorocarbons to submicron sizes. In this case, the dispersion increases very strongly and a dispersed system is formed with a developed specific surface, i.e. when an emulsion is formed during the dispersion of two liquids, the interface is not reduced, but increased. The fragmentation of the dispersed phase gives the dispersed systems special qualities associated with the size of the interface between the dispersed phase and the dispersed medium. The homogenization efficiency, as a rule, is determined by the average particle diameter of the resulting dispersed phase. Medium, the particle diameter of the emulsion depends on the number of dispersion cycles Dav. = f (N).

According to their dispersion, perfluorocarbon emulsions can be conditionally divided into two types in general terms - these are monodisperse and polydisperse emulsions. The size of the polydispersed emulsions is in the range from 0.1 μm (100 nm) to 10 μm and higher, which corresponds to the size of the medium and coarse systems. The size of monodisperse emulsions is in the range from 1 nm (10 ^-9 m) to 100 nm, which corresponds to the size of finely dispersed systems. It is necessary to formulate a colloid-chemical definition of medical-biological perfluorocarbon emulsions - these are direct, concentrated, highly and freely dispersed, heterogeneous thermodynamically unstable colloidal systems with significant free energy and a huge gas exchange surface (interface), in which the dispersed phase is insoluble monodispersed perfluorocarbon nanoparticles are coated with a surface-active emulsifier layer and are located in a dispersed aqueous structure suspended medium. In this state, the substance - perfluoroemulsion nanoparticles (10 ^-8 m) will have special properties, since this state is a special intermediate between molecular compounds and the ultrafine (colloidal) state of the substance. According to structural features, the range of particle sizes in the range from 10 to 30 nm (10 ^-8 m) is already transitional.

In compositions for biomedical purposes based on perfluorocarbon emulsions, as a rule, several types of perfluorocarbons are used simultaneously. One of them is selected from the group (C ₈ -C ₁₀ ), containing, for example, perfluorodecalin (PFD) C ₁₀ F ₁₈ or perfluorotripropylamine (PFPA) C ₉ F ₂₁ N, or perfluorooctyl bromide (PFOB) C ₈ F ₁₇ Br, the second from the group (C ₁₁ -C ₁₂ ) containing, for example, perfluoromethylcyclohexylpiperidine (GTFMTSP) C ₂ F ₂₃ N or perfluorotributylamine (PFBA) C ₂ F ₂₇ N. These perfluorocarbons dissolve about 40 vol.% oxygen (at рО ₂ = 760 mm . Hg) and 150-190% by volume of carbon dioxide (pCO ₂ = at 760 torr), whereupon they began to be used as a main component - carrier gas - while creating synthetic cr vezameschayuschih funds. However, perfluorocarbons are insoluble in water and other liquids, therefore, they can be used only in the form of emulsions with a certain size of perfluorocarbon particles coated with a layer of emulsifier (proxanol or phospholipid). The smaller the particle size of the emulsion, the better, because the emulsion is administered intravenously, and with large particle sizes, emulsion formulations can cause embolism (blockage) of blood vessels, as well as severe adverse reactions to the presence of coarse particles of the emulsion. Compounds of the first type are rapidly eliminated from the body (within a month), but do not provide sufficient stability for their emulsions, while compounds of the second type, on the contrary, give the emulsion high stability, allowing them to be stored without freezing, but they are not excreted for several years.

A known composition of emulsions containing, for example, perfluorodecalin (PFD) and perfluorotripropylamine (PFPA), emulsifying agents, for example, a polyoxyethylene-propylene copolymer (Pluronic F-68, domestic analogue - proxanol-268), egg yolk phospholipids or soybean phospholipids and water ( USSR copyright certificate No. 797546, published in the publication "Discoveries, Inventions ...", 1981, No. 2). In accordance with this composition, the concentration of perfluorocarbons is 24% in a physiologically acceptable aqueous medium. The disadvantages of this composition in the specified invention include the fact that the composition of the emulsion has a sufficiently coarse particle size and cannot be stored in thawed form, as well as the presence of severe adverse reactions and the inability to sterilize.

In another 20% emulsion prepared for medical purposes based on PFD and PFPA - Fluosol-DA 20%, a Japanese company, proxanol and egg yolk phospholipids were used as an emulsifier. However, the average particle diameter in the composition of this emulsion was also large, due to the fact that at high temperatures in the process of emulsification and pasteurization coarsening of the particles of the emulsion. In addition, particles of perfluorocarbons used in the emulsion are coarsened quite quickly even at room temperature (Mitsuno T. et al., 1981). This composition of the emulsion is stored only in frozen form, because after 8-12 hours of storage at room temperature, enlargement of the particles of the emulsion takes place and, therefore, its clinical use becomes impossible. In addition, the disadvantages of this composition in the specified invention should also include the presence of severe adverse reactions.

The known composition of perfluorocarbon emulsions for medical purposes (RF patent No. 2070033, published in the bulletin "Discoveries, inventions ..." in 1996, No. 34), in which there are perfluorodecalin or perfluorooctyl bromide and perfluoromethylcyclohexylpiperidine in a ratio of 2/1 and a concentration of 20/1 up to 40%. The disadvantages of this composition are adverse reactions, the low concentration of perfluorocarbons in the emulsion is not higher than 40%.

The composition of perfluorocarbon emulsion for biomedical purposes is close to the claimed composition (RF patent No. 2122404, publ. In “Discovery, Invention ...” 1998, No. 33), which contains perfluorodecalin, perfluoromethylcyclohexylpiperidine, perfluorooctyl bromide, perfluoromethromate -268. The disadvantages of this composition are adverse reactions, comprising about 20% and a low concentration of perfluorocarbons in the emulsion - not higher than 40%.

The closest to the claimed composition is an emulsion based on organofluorine compounds for biomedical purposes (RF patent No. 2162692, publ. In the bulletin "Discoveries, inventions ..." 02/10/2002, No. 4), which contains perfluorodecalin, perfluoromethylcyclohexylpiperidine, perfluorooctyl bromide , perfluorotributylamine concentration of 1-20%, emulsifiable with 0.4-4.8% proxanol-268. The disadvantages of this composition include the low concentration of perfluorocarbons in the emulsion - not higher than 20%, which significantly narrows the scope.

The closest to the claimed composition is an emulsion based on PFD and PFMTSP (RF patent No. 2199311, published in the bulletin "Discoveries, inventions ..." 02/27/2003, No. 6) concentration of 1-30%, emulsifiable 0.2-6% proxanol for 9 cycles to an average particle size of 50-100 nm. The disadvantage of this emulsion is the low concentration of perfluorocarbons in the emulsion composition - not higher than 30%, which significantly narrows the scope and long emulsification time (for example, 10 liters of 10 vol.% Emulsion is produced in 3-4 conventional hours on one extrusion device).

Methods for producing perfluorocarbon emulsions.

Common methods for producing perfluorocarbon emulsions are based on methods using ultrasound or homogenization on high pressure disintegrants. To obtain emulsions on an industrial scale, a homogenization method is preferable, because it makes it possible to obtain emulsions in large quantities and with better physicochemical characteristics, for example, improved particle size distribution (J. Riess, 1991).

A known method of producing perfluorocarbon emulsions containing, for example, perfluorodecalin and perfluorotripropylamine, emulsifying agents, for example, a polyoxyethylene-propylene copolymer (pluronic F-68, domestic analogue - proxanol-268), egg yolk phospholipids or soybean phospholipids and water, USSR Patent No. 79, No. 79, USSR Patent No. 79 published in the bulletin "Discoveries, inventions ..." 1981, No. 2). In accordance with this method, the initial perfluorocarbon emulsion is prepared by mixing the components in a physiologically acceptable aqueous medium using a homogeneous mixer or propeller stirrer, then the initial emulsion is emulsified by injection in a high pressure homogenizer at a pressure of from 100 to 500 atm and a temperature of up to +55 degrees C °. The perfluorocarbon mixture is emulsified through one homogenizer extrusion device up to 12 times (emulsification cycles). The disadvantages of this invention include the fact that a perfluorocarbon emulsion is obtained with this method for a sufficiently long time (12 cycles of emulsification), low concentration (not higher than 24%), cannot be stored in thawed form and the inability to sterilize the emulsion.

A known method of producing perfluorocarbon emulsions for medical purposes (RF patent No. 2070033, published in the bulletin "Discoveries, inventions ..." 1996, No. 34) is close to the claimed method, in which 12-fold (12 cycles) emulsification of perfluorodecalin or perfluorooctyl bromide with perfluoromethylcyclohexylpiperidine, takes place in 3 containers. The disadvantage of the above-described method for producing perfluorocarbon emulsions is a long time to obtain 12-fold (cycles) emulsification, the inability to prepare highly concentrated emulsions of more than 30-40% and the inability to sterilize emulsions.

A known method of producing perfluorocarbon compositions for medical purposes (RF patent No. 2122404, publ. In the bulletin "Discoveries, inventions ..." 11/27/1998, No. 33), close to the claimed method, in which due to 9-fold (9 cycles ) emulsification and jet-drop transmission of a multicomponent mixture of several perfluorocarbons receive a 40% emulsion. The disadvantage of the above method for producing perfluorocarbon emulsions is the long-term emulsification of perfluorocarbons - 9 cycles, the inability to obtain a highly concentrated emulsion (over 40%) and the inability to sterilize emulsions.

Closest to the claimed method for producing emulsions is a method for producing perfluorocarbon emulsions for medical purposes (RF patent No. 2200544, publ. In the bulletin "Discoveries, inventions ..." March 20, 2003, No. 8), in which due to 9-fold (9 cycles) of emulsification and jet-drop transmission of a multicomponent mixture of perfluorocarbons, consisting of a mixture of several perfluorocarbons, through a solution of proxanol-268 and through one extrusion device of a homogenizer, a 40% emulsion is obtained. The disadvantage of the above method of creating perfluorocarbon emulsions is the inability to obtain highly concentrated emulsions (over 40%) due to the presence of one extrusion device of the homogenizer, long emulsification time (for example, 10 liters of 10 vol.% Emulsion is produced in 3-4 conditional hours), which is due to with the presence of only one working extrusion device of the homogenizer in which the formation of the emulsion. This leads to a prolonged presence of the operator in a sterile box and the possible sterilization (insemination) of the emulsion.

Disclosure of the invention.

The first objective of the invention is to create a composition of multicomponent, highly concentrated, highly stable perfluorocarbon emulsions, with various physicochemical properties, with a reduced number of adverse reactions, with the inclusion of physiologically acceptable and simple electrolyte solutions.

The second objective of the invention is to provide a method for producing multicomponent, highly concentrated, highly stable, sterilizable perfluorocarbon emulsions with a nanoscale average particle diameter, as well as accelerating the entire process for producing perfluorocarbon emulsions, which is necessary for the production of perfluoroemulsions on a pilot scale.

The third objective of the invention is the use of the developed means based on perfluorocarbon gas-transferring emulsions in various biomedical fields.

The first task is solved by the fact that the known composition based on perfluorocarbon gas-transferring emulsion for biomedical purposes, including: perfluorocarbons, emulsifying agent and electrolyte solution, according to the invention contains: a mixture of two perfluorocarbons: quickly derived (C ₈ -C ₁₀ ) and / or slowly excreted (C ₁₁ -C ₁₂ ), such as perfluorodecalin (PFD) / perfluoromethylcyclohexylpiperidine (PFMTSP), or PFD / perfluorotributylamine (PFTA), or perfluorooctyl bromide (PFOB) / PFMP / PFB or PFPT or PFPT, PFB or PFPT, PFB / PFBA according Values from 1/1 to 10/10, respectively; or a mixture of three perfluorocarbons: two rapidly output (C ₈ -C ₁₀ ) and one slowly output (C ₁₁ -C ₁₂ ), or one quickly output (C ₈ -C ₁₀ ) and two slowly output (C ₁₁ -C ₁₂ ) as PFOB / PFD / PFMTSP, or PFOB / PFD / PFTBA, or PFOB / PFMTSP / PFTBA, or PFOB / PFMTSP / PFTBA in the ratio from 1/1/1 to 10/10/10, respectively; or a mixture of four perfluorocarbons: two rapidly eliminating (C ₈ -C ₁₀ ) and two slowly eliminating (C ₁₁ -C ₁₂ ) PFOB / PFD / PFMTSP / PFTA in the ratio from 1/1/1/1 to 10/10/10 / 10 respectively; a mixture of perfluorocarbons in an emulsion from 1% (0.5 vol.%) to 100% (50 vol.%). As quickly eliminated perfluorocarbons (C ₈ -C ₁₀ ) are used: perfluorodecalin (PFD) and perfluorooctyl bromide (PFOB). The perfluorocarbons that are slowly derived (C ₁₁ -C ₁₂ ) are perfluoromethylcyclohexylpiperidine (PFMCP) and perfluorotributylamine (PFBA). As an emulsifying agent, a nonionic block copolymer of ethylene oxide and propylene is used - proxanol-268 from 0.2% to 20% with a molecular weight of 6-12 thousand Yes.

The composition of perfluorocarbon gas-transporting emulsions contains: a dispersion of particles from 1 to 100 nanometers in an amount of 88%, from 100 to 200 nanometers - 12%, of which particles in 200 nm are not more than 0.1%, with an average particle size of the emulsion is 30-80 nanometers (before ultrafiltration).

The composition of the perfluorocarbon gas-transferring emulsion includes a physiologically acceptable electrolyte solution: NaCl, KCl, MgCl ₂ , NaHCO ₃ , NaH ₂ PO ₄ , D-glucose.

The composition of the perfluorocarbon emulsion, characterized in that the electrolyte solution contains: sodium chloride - 5.0-9.5 g / l; sodium phosphate - 0.20-0.60 g / l; sodium bicarbonate - 0.35-0.70 g / l; potassium chloride - 0.35-0.45 g / l; magnesium chloride - 0.18-0.25 g / l; glucose - 1.8-2.5 g / l.

The composition of the perfluorocarbon emulsion, characterized in that in the preferred first embodiment, the 1% emulsion contains: rapidly derived perfluorocarbon - PFD - 6.5-7.0 g / l, slowly derived perfluorocarbon - PFMTSP - 3.25-3.5 g / l , proxanol - 2.0-2.2 g / l, electrolyte solution: sodium chloride - 5.0-9.5 g / l; sodium phosphate - 0.20-0.60 g / l; sodium bicarbonate - 0.35-0.70 g / l; potassium chloride - 0.35-0.45 g / l.

The composition of the perfluorocarbon emulsion, characterized in that in the preferred second embodiment, the 5% emulsion contains: rapidly derived perfluorocarbon - PFD - 32.5-35 g / l, slowly derived perfluorocarbon - PFMTSP - 16.5-17 g / l, proxanol - 10 -11 g / l, electrolyte solution: sodium chloride - 5.0-9.5 g / l; sodium phosphate - 0.20-0.60 g / l; sodium bicarbonate - 0.35-0.70 g / l; potassium chloride - 0.35-0.45 g / l.

The composition of the perfluorocarbon emulsion, characterized in that in the preferred third embodiment, the 10% emulsion contains: rapidly derived perfluorocarbon - PFD - 65-70 g / l; slowly eliminated perfluorocarbon - PFMTSP - 32.5-35 g / l; proxanol - 20-22 g / l; electrolyte solution: sodium chloride -5.0-9.5 g / l; sodium phosphate - 0.20-0.60 g / l; sodium bicarbonate - 0.35-0.70 g / l; potassium chloride - 0.35-0.45 g / l.

The composition of the perfluorocarbon emulsion, characterized in that in the preferred fourth embodiment, the 10% emulsion contains: rapidly derived perfluorocarbon - PFD - 65-70 g / l; slowly eliminated perfluorocarbon - PFMTSP - 32.5-35 g / l; proxanol - 20-22 g / l; electrolyte solution: sodium chloride - 5.0-9.5 g / l; sodium phosphate - 0.20-0.60 g / l; sodium bicarbonate - 0.35-0.70 g / l; potassium chloride - 0.35-0.45 g / l; magnesium chloride - 0.18-0.25 g / l; glucose - 1.8-2.5 g / l.

The composition of the perfluorocarbon emulsion, characterized in that in the preferred fourth embodiment, the 20% emulsion contains: rapidly derived perfluorocarbon - PFD - 130-140 g / l; slowly eliminated perfluorocarbon - PFMTSP - 65-70 g / l; proxanol - 40-42 g / l; electrolyte solution: sodium chloride - 5.0-9.5 g / l; sodium phosphate - 0.20-0.60 g / l; sodium bicarbonate - 0.35-0.70 g / l; potassium chloride - 0.35-0.45 g / l.

The proposed composition based on perfluorocarbon gas-transferring emulsion includes up to four different perfluorocarbons with physicochemical properties ranging from extremely lipophilic (PFOB) to pronounced lipophobic (PFBA).

The proposed composition based on perfluorocarbon gas-transferring emulsion has a wide range of different physicochemical and biomedical properties due to lipophilic-lipophobic properties that are part of perfluorocarbons: rapidly excreted (PFOB, PFD) and slowly excreted (PFMTSP, PFTBA): increases the efficiency and emulsion quality; reduces intramolecular diffusion; improves emulsion stability; improves emulsification; reduces the toxicity of the emulsion; reduces the number of adverse reactions of the emulsion; extends the shelf life of the emulsion; expands the scope.

The proposed composition based on perfluorocarbon gas-transferring emulsions can be used as synthetic perfluorocarbon blood substituting agents or agents for treating various diseases.

The proposed composition based on perfluorocarbon gas-transferring emulsion can be used as synthetic perfusion agents.

The proposed composition based on perfluorocarbon gas-transferring emulsion can be used as synthetic radiopaque agents.

The proposed composition based on a perfluorocarbon gas-transferring emulsion can be used for external use as the basis of water-soluble therapeutic ointments or creams for applying, irrigation, wetting, non-healing wounds, ulcers, and other external diseases.

The proposed composition based on perfluorocarbon gas-transferring emulsion can be used for external use as the basis of cosmetic water-soluble ointments or creams for skin care.

The proposed composition based on perfluorocarbon gas-transferring emulsion has a concentration of perfluorocarbons 2.5 times higher than that of analog compositions, which significantly increases the oxygen capacity of the resulting emulsions.

Thus, all the positive factors presented contribute to a more efficient and safe use of the proposed perfluorocarbon gas-transferring emulsion compositions in medicine and biology, and expand their field of application.

The second task is solved by the fact that in the known method for producing perfluorocarbon gas-transferring emulsions, including obtaining an emulsion by mixing the total amount of perfluorocarbons with an emulsifying agent, repeatedly homogenizing the resulting mixture on a high-pressure homogenizer, according to the invention, obtaining an emulsion is carried out by mixing the output amount of perf c ₈ -C ₁₀₎ FPD, PFOB and are excreted slowly (c ₁₁ -C _12): PFMCP, PFTBA with emulsifying agent - Proxanol m, and multiple homogenization of the mixture in two extrusion devices of a high pressure homogenizer, passing the emulsion through the main and additional extrusion devices of the homogenizer up to 5-6 times, passing the emulsion through a buffer tank located between the two extrusion devices of the homogenizer and designed to equalize the pressure between the devices By passing the emulsion through the main extrusion device, they increase the homogenization pressure by 2–3 times compared to the pressure using an additional extrusion device, passing the emulsion through the buffer and the main tank, carbon dioxide is supplied.

A method of obtaining a composition of a perfluorocarbon emulsion, characterized in that it contains:

- a mixture of two perfluorocarbons: quickly derived (C ₈ -C ₁₀ ) and slowly removed (C ₁₁ -C ₁₂ ), as PFD / PFMTSP in a ratio of 1/1 to 10/10, respectively;

- a mixture of two perfluorocarbons: quickly derived (C ₈ -C ₁₀ ) and slowly removed (C ₁₁ -C ₁₂ ), as PFD / PFBA in a ratio of 1/1 to 10/10, respectively;

- a mixture of two perfluorocarbons: quickly derived (C ₈ -C ₁₀ ) and slowly derived (C ₁₁ -C ₁₂ ), as PFOB / PFMTSP in a ratio of 1/1 to 10/10, respectively;

- a mixture of two perfluorocarbons: quickly derived (C ₈ -C ₁₀ ) and slowly removed (C ₁₁ -C ₁₂ ), as PFOB / PFTA in a ratio of 1/1 to 10/10, respectively;

- a mixture of two perfluorocarbons: rapidly eliminated (C ₈ -C _10), as PFOB / PFD in the ratio from 1/1 to 10/10, respectively;

- a mixture of two perfluorocarbons: slowly derived (C ₁₁ -C ₁₂ ), as PFMTSP / PFTA in a ratio of 1/1 to 10/10, respectively;

- a mixture of three perfluorocarbons: two quickly eliminated (C ₈ -C ₁₀ ) and one slowly removed (C11-C12), as PFD / PFOB / PFMTSP in a ratio of 1/1/1 to 10/10/10, respectively;

- a mixture of three perfluorocarbons: two quickly eliminated (C ₈ -C ₁₀ ) and one slowly removed (C ₁₁ -C ₁₂ ), as PFD / PFOB / PFTA in a ratio of 1/1/1 to 10/10/10, respectively;

- a mixture of three perfluorocarbons: one quickly output (C ₈ -C ₁₀ ) and two slowly output (C ₁₁ -C ₁₂ ), as PFD / PFMTSP / PFTA in a ratio of 1/1/1 to 10/10/10, respectively;

- a mixture of three perfluorocarbons: one quickly derived (C ₈ -C ₁₀ ) and two slowly removed (C ₁₁ -C ₁₂ ), as PFOB / PFMTSP / PFTA in a ratio of 1/1/1 to 10/10/10, respectively;

- a mixture of four perfluorocarbons: two quickly eliminated (C ₈ -C ₁₀ ) and two slowly removed (C ₁₁ -C ₁₂ ), as PFD / PFOB / PFMTSP / PFTA in a ratio of 1/1/1/1 to 10/10 / 10/10, respectively.

A method of producing a perfluorocarbon emulsion composition, characterized in that the emulsion is obtained by spraying a mixture of perfluorocarbons through an aqueous solution of an emulsifying agent to obtain the desired ratio of components.

A method of producing a perfluorocarbon emulsion composition, characterized in that the emulsion is prepared under pressure in all two extrusion devices from 120 to 1500 kg / cm ² .

A method of producing a perfluorocarbon emulsion composition, characterized in that the emulsion is passed sequentially through the first and second extrusion device of a high pressure homogenizer.

A method of obtaining the composition of a perfluorocarbon emulsion, characterized in that the required amount of an electrolyte solution is added to the resulting emulsion including: sodium chloride, sodium phosphate, sodium bicarbonate, potassium chloride.

A method of obtaining the composition of a perfluorocarbon emulsion, characterized in that the dosage form of the emulsion is sterilized by dynamic ultrafiltration.

A method of obtaining a composition of perfluorocarbon emulsion, characterized in that the dosage form of the emulsion after sterilization of dynamic ultrafiltration has a maximum particle size of not more than 200 nm with an average particle size of 30-80 nm.

A tool based on the composition of perfluorocarbon emulsion intended for use as synthetic perfluorocarbon blood substituting agents and agents for treating various diseases, as well as perfusion, radiopaque and cosmetic products, characterized in that the composition can be used for intravenous, intraarterial, oral, intracavitary use and before use can be diluted with any emulsion compatible solution or composition, can also be used in As an external agent for cosmetic and therapeutic ointments or creams for wounds, ulcers, and other external diseases, it can be diluted with any antiviral, antibacterial, antifungal, or colloidal silver or other medium before use.

Brief Description of the Drawing

The invention is illustrated by a process diagram for implementing a method for producing a perfluorocarbon gas-transferring emulsion, which depicts a homogenization system consisting of: an upper (perfluorocarbon) tank 1 for a mixture of perfluorocarbons; pipeline 2 connecting the tank 1 with the lower (main) tank 3; a pipeline 4 connecting the tanks 1 and 3 with the main extrusion device of the homogenizer 5; pipelines 6 and 8 connecting the main extrusion device 5 and the buffer tank 7 and the additional extrusion device 9; a pipeline 10 connecting the main tank 3 and the device 9; a pipe 11 connecting the filtration system 12 and sterilization 13; the pipeline 14 connecting the packaging container 15.

A method for producing a perfluorocarbon gas-transferring emulsion is carried out as follows: to obtain a pre-emulsion (micron size), the mixture of perfluorocarbons is jetted from the upper (perfluorocarbon) tank 1 through line 2 to the lower (main) tank 3 with an emulsifying agent - proxanol-268 and through the pipe 4 pre-emulsion into the main extrusion device 5 of the high pressure homogenizer, where a high "shock" pressure is set from 120 to 1500 kg / cm ² . Then the pre-emulsion from the main extrusion device 5, enters through the pipe 6 into the buffer tank 7, equalizing the pressure between the extrusion devices, from the tank 7 through the pipe 8 the emulsion enters the additional extrusion device 9 of the high-pressure homogenizer, in which the homogenization pressure is set to 2-3 times lower than in the main extrusion device. From the additional extrusion device, the pre-emulsion enters through the pipeline 10 into the main tank 3. The first cycle of the pre-emulsion production is closed: instead of one homogenization treatment (“crushing” to nanoscale), the pre-emulsion received an additional (second) equivalent treatment (“crushing”) in the additional extrusion device, which reduces the preparation time of a nanoscale emulsion. After the second emulsification cycle, which is completely analogous to the first cycle, the third emulsification cycle begins, etc. up to 5 cycles. During the entire process of obtaining nanoemulsions, carbon dioxide is blown in the tank and the temperature is maintained from + 15 ° C to + 60 ° C in both extrusion devices. After obtaining a nanosized perfluorocarbon emulsion, it is mixed in the main tank 3 with electrolytes to obtain the finished dosage form. Then the emulsion lexform enters the filtration 12 and sterilization chambers 13, for filtration and sterilization, with the subsequent receipt of the finished dosage form of the emulsion in the container 15 for bottling.

The proposed method for producing perfluorocarbon emulsions with an increase in the exposure power due to two extrusion devices of a high-pressure homogenizer allows the creation of multicomponent emulsions, which improves the physicochemical and biomedical properties, increases the efficiency of the emulsion.

The proposed method for producing perfluorocarbon emulsions with an increase in the exposure power due to two extrusion devices of a high pressure homogenizer makes it possible to create highly concentrated emulsions, which increases the field of application and the number of manufactured dosage forms.

The proposed method for producing perfluorocarbon emulsions with an increase in the exposure power due to two extrusion devices of a high pressure homogenizer allows the creation of highly stable emulsions, which increases the quality and level of safe use.

The proposed method for producing perfluorocarbon emulsions with an increase in the exposure power due to two extrusion devices of a high pressure homogenizer allows the creation of emulsions sterilized by ultrafiltration, which increases the quality and level of safe use.

The proposed method for producing perfluorocarbon emulsions with an increase in the exposure power due to two extrusion devices of a high pressure homogenizer makes it possible to create nanoscale emulsions with an average particle size of 30-80 nanometers, which increases the quality and efficiency of use, reduces the number of side reactions.

The proposed method for creating perfluorocarbon emulsions with an increase in the exposure rate due to two extrusion devices of a high-pressure homogenizer makes it possible to reduce the emulsion production time by ~ 2 or more times by reducing emulsification cycles in comparison with analogous methods, which increases the number of emulsion dosage forms produced and increases the level quality and safety of the emulsion.

In the proposed method for producing perfluorocarbon emulsions, in addition to the above factors, there is another important advantage: in the inventive method, the operator preparing the emulsion is half as much in the sterile box as in the analogue method. A prolonged stay in the box may adversely affect the operator’s actions and cause his subsequent errors during technological operations (see table 1). In addition, there is a saving of both human and energy resources.

The developed method can be confidently applied not only in laboratory conditions, but also in the industrial production of perfluorocarbon emulsions to obtain industrial batches of synthetic perfluorocarbon blood-replacing nanopreparations and other therapeutic agents.

DETAILED DESCRIPTION OF THE INVENTION

Getting the composition.

Example 1. Obtaining a composition of 1% (0.5 vol.%) Emulsion perfluorocarbons PFD / PFMTSP.

A composition based on a perfluorocarbon mixture consisting of slowly excreted PFD and rapidly excreted PFMTSP (PFD / PFMTSP ratio 2: 1) in an amount of 20 ml, containing weighed (liquid) 26 g PFD and 13 g PFMTSP, mixed with 80 ml of an aqueous solution of proxanol, containing 8 grams of emulsifier. The specific gravity of perfluorocarbons is ~ 2. The resulting mixture of perfluorocarbons and proxanol was passed through two extrusion devices of a high pressure homogenizer. After that, an electrolyte solution was added to the resulting perfluorocarbon emulsion to the desired concentration.

The final formulation (dosage form) of the perfluorocarbon emulsion had the following composition: PFD / PFMTSP (ratio 2/1) - 1% (0.5 vol.%); PFD - 6.5 g / l; PFMTSP - 3.25 g / l; proxanol - 2.0 g / l; sodium chloride - 6.0 g / l; sodium phosphate - 0.20 g / l; sodium bicarbonate - 0.35 g / l; potassium chloride - 0.40 g / l.

The resulting perfluorocarbon composition can be used as a blood substitute for intravenous and intraarterial administration, for oral, intracavitary, internal and external use.

Example 2. Obtaining a composition of 20% (10 vol.%) Emulsion perfluorocarbon PFD / PFMTSP.

A composition based on a perfluorocarbon mixture consisting of slowly excreted PFD and rapidly excreted PFMTSP (PFD / PFMTSP ratio 2: 1) in an amount of 200 ml containing weighed portions (liquid) of 260 g of PFD and 130 g of PFMTSP was mixed with 800 ml of an aqueous solution of proxanol, containing 80 grams of emulsifier. The resulting mixture of perfluorocarbons and proxanol was passed through two extrusion devices of a high pressure homogenizer. After that, an electrolyte solution was added to the resulting perfluorocarbon emulsion to the desired concentration.

The final formulation (dosage form) of the perfluorocarbon emulsion had the following composition: PFD / PFMTSP (ratio 2/1) - 20% (10 vol.%); PFD - 130 g / l; PFMTSP - 65 g / l; proxanol - 40 g / l; sodium chloride - 6.0 g / l; sodium phosphate - 0.20 g / l; sodium bicarbonate - 0.35 g / l; potassium chloride - 0.40 g / l.

The resulting perfluorocarbon composition can be used as a blood substitute for intravenous and intraarterial administration, for oral, intracavitary, internal and external use.

Example 3. Obtaining a composition of 30% (15 vol.%) Emulsion perfluorocarbons PFD / PFMTSP.

A composition based on a perfluorocarbon mixture consisting of slowly excreted PFD and rapidly excreted PFMTSP (PFD / PFMTSP ratio 2: 1) in an amount of 300 ml containing weighed portions (liquid) 400 g PFD and 200 g PFMTSP was mixed with 700 ml of an aqueous solution of proxanol containing 120 grams of emulsifier. The resulting mixture of perfluorocarbons and proxanol was passed through two extrusion devices of a high pressure homogenizer. After that, a simplified electrolyte solution was added to the resulting perfluorocarbon emulsion to the desired concentration.

The final formulation (dosage form) of the perfluorocarbon emulsion had the following composition: PFD / PFMTSP (ratio 2/1) - 30% (15 vol.%); PFD - 200 g / l; PFMTSP - 100 g / l; proxanol - 60 g / l; sodium chloride - 6.0 g / l; sodium phosphate - 0.20 g / l; sodium bicarbonate - 0.35 g / l; potassium chloride - 0.40 g / l; magnesium chloride - 0.19 g / l; glucose - 2.0 g / l.

The resulting perfluorocarbon composition can be used as a blood substitute for intravenous and intraarterial administration, for oral, intracavitary, internal and external use.

Example 4. Obtaining a composition of 80% (40 vol.%) Emulsion of perfluorocarbons PFOB / PFD / PFMTSP / PFBA

Perfluorocarbon mixture, consisting of a pair of rapidly releasing perfluorocarbons PFOB / PFD and slowly releasing perfluorocarbons PFMTSP / PFTBA (ratio 10/1/1/1) in an amount of 400 ml, containing weighed (liquid) PFOB / PFD / PFMTSP / PFTBA, which amounted to respectively 617/61/61/61 grams. A mixture of perfluorocarbons was mixed with 600 ml of an aqueous solution of proxanol containing 160 grams of emulsifier. The resulting mixture of perfluorocarbons and proxanol was passed through two extrusion devices of a high pressure homogenizer. After that, electrolytes were added to the resulting perfluorocarbon emulsion to the desired concentration.

The final formulation (dosage form) of the perfluorocarbon emulsion had the following composition: PFOB / PFD / PFMTSP / PFTA (ratio 10/1/1/1) - 80% (40 vol.%); PFOB - 617 g / l; PFD - 61 g / l; PFMTSP - 61 g / l; PFBA - 61 g / l; proxanol - 160 g / l; sodium chloride - 6.0 g / l; sodium phosphate - 0.20 g / l; sodium bicarbonate - 0.35 g / l; potassium chloride - 0.40 g / l.

The resulting perfluorocarbon composition can be used as a radiopaque agent for intravenous and intraarterial administration, for oral, intracavitary, internal use.

Example 5. Obtaining a composition of 100% (50 vol.%) Emulsion perfluorocarbons PFD / PFMTSP.

A composition based on a perfluorocarbon mixture consisting of slowly excreted PFD and rapidly excreted PFMTSP (PFD / PFMTSP ratio 2: 1) in an amount of 500 ml, containing weighed (liquid) 666 g PFD and 333 g PFMTSP, mixed with 500 ml of an aqueous solution of proxanol, containing 200 grams of emulsifier. The specific gravity of perfluorocarbons is ~ 2. The resulting mixture of perfluorocarbons and proxanol was passed through two extrusion devices of a high pressure homogenizer. After that, electrolytes were added to the resulting perfluorocarbon emulsion to the desired concentration.

The final formulation (dosage form) of the perfluorocarbon emulsion had the following composition: PFD / PFMTSP (ratio 2/1) - 100% (50 vol.%); PFD - 666 g / l; PFMTSP - 333 g / l; proxanol - 200 g / l; sodium chloride - 6.0 g / l; sodium phosphate - 0.20 g / l; sodium bicarbonate - 0.35 g / l; potassium chloride - 0.40 g / l.

The resulting perfluorocarbon composition can be used for external use, as an ointment or cream for medical and cosmetic purposes.

Example 6. A method of obtaining 80% (40 vol.%) Perfluorocarbon emulsion PFOB / PFD / PFMTSP / PFBA.

A perfluorocarbon mixture consisting of a pair of rapidly releasing perfluorocarbons PFOB / PFD and slowly releasing perfluorocarbons PFMTSP / PFTBA in a total ratio of 10/1/1/1 in an amount of 400 ml containing weighed (liquid) PFOB / PFD / PFMTSP / PFTBA, which were respectively 617/61/61/61 grams. A mixture of perfluorocarbons was mixed with 600 ml of an aqueous solution of proxanol containing 160 grams of emulsifier. The specific gravity of perfluorocarbons is ~ 2.

The resulting mixture of perfluorocarbons and proxanol was passed through two extrusion devices of a high pressure homogenizer. After that, electrolytes were added to the resulting perfluorocarbon emulsion to the desired concentration.

The final formulation (dosage form) of the perfluorocarbon emulsion had the following composition: PFOB / PFD / PFMTSP / PFTA (ratio 10/1 / 1/1) - 80% (40 vol.%); PFOB - 617 g / l; PFD - 61 g / l; PFMTSP - 61 g / l; PFBA - 61 g / l; proxanol - 160 g / l; sodium chloride - 6.0 g / l; sodium phosphate - 0.20 g / l; sodium bicarbonate - 0.35 g / l; potassium chloride - 0.40 g / l.

The resulting perfluorocarbon composition can be used for external use, as an ointment or cream for medical and cosmetic purposes.

DETAILED DESCRIPTION OF THE INVENTION

The method of obtaining.

Example 7. A method of obtaining 1% (0.5 vol.%) Perfluorocarbon emulsion PFD / PFMTSP.

A composition based on a perfluorocarbon mixture consisting of slowly excreted PFD and rapidly excreted PFMCP in an amount of 200 ml, in a ratio of PFD / PFMCP 2/1, containing weighed portions (liquid) of 260 g PFD and 130 g PFMCP, mixed with 800 ml of a proxanol solution containing 80 grams of emulsifier. The specific gravity of perfluorocarbons is ~ 2.

To obtain a pre-emulsion (micron size), the mixture of perfluorocarbons flows jet from the upper (perfluorocarbon) container 1 through the pipe 2 to the lower (main) container 3 with an emulsifying agent - proxanol-268 and through the pipe 4 the pre-emulsion enters the main extrusion device 5 of the high pressure homogenizer, where a high "shock" pressure is set from 120 to 1500 kg / cm. Then the pre-emulsion from the main extrusion device 5 enters through the pipe 6 into the buffer tank 7, equalizing the pressure between the extrusion devices, from the tank 7 through the pipe 8 the emulsion enters the additional extrusion device 9 of the high-pressure homogenizer, in which the homogenization pressure is 2-3 times lower than in the main extrusion device. From the additional extrusion device, the pre-emulsion enters through the pipeline 10 into the main tank 3. The first cycle of the pre-emulsion production is closed: instead of one homogenization treatment (“crushing” to nanoscale), the pre-emulsion received an additional (second) equivalent treatment (“crushing”) in the additional extrusion device, which reduces the preparation time of a nanoscale emulsion by 2 times. After the second emulsification cycle, which is completely analogous to the first cycle, with the exception of the homogenization pressure, the third emulsification cycle begins, etc. up to 5-6 cycles. During the entire process of obtaining nanoemulsions, carbon dioxide is blown and the temperature is maintained from +15 ° C to +60 ° C in containers and in both extrusion devices. After obtaining a nanosized perfluorocarbon emulsion, it is mixed in the main tank 3 with electrolytes to obtain the finished dosage form. Then the emulsion lexform enters the filtration 12 and sterilization chambers 13, for filtration and / or sterilization, with the subsequent delivery of the finished dosage form of the emulsion into the container 15 for filling into bottles.

The final formulation (dosage form) of the perfluorocarbon emulsion had the following composition: PFD / PFMTSP (ratio 2/1) - 1% (0.5 vol.%); PFD - 6.5 g / l; PFMTSP - 3.25 g / l; proxanol - 2.0 g / l; sodium chloride - 6.0 g / l; sodium phosphate - 0.20 g / l; sodium bicarbonate - 0.35 g / l; potassium chloride - 0.40 g / l.

The number of emulsification cycles is 6 with an average particle size of 60 nanometers. After 3 times freezing / thawing, the emulsion is stable, the average particle size was 80 nm. Reactogenicity of the emulsion did not exceed 5%.

Example 8. The method of obtaining 20% (10 vol.%) Perfluorocarbon emulsion PFD / PFMTSP.

A composition based on a perfluorocarbon mixture consisting of slowly excreted PFD and rapidly excreted PFMCP in an amount of 200 ml in a ratio of PFD / PFMCP 2/1, containing weighed portions (liquid) of 260 g of PFD and 130 g of PFMCP, mixed with 800 ml of a proxanol solution, containing 80 grams of emulsifier. The specific gravity of perfluorocarbons is ~ 2. After that, the resulting mixture of perfluorocarbons and proxanol was treated as described in Example 1. Electrolytes were added to the resulting emulsion to the desired concentration.

The final formulation (dosage form) of the perfluorocarbon emulsion had the following composition: PFD / PFMTSP (ratio 2/1) - 20% (10 vol.%); PFD - 130 g / l; PFMTSP - 65 g / l; proxanol - 40 g / l; sodium chloride - 6.0 g / l; sodium phosphate - 0.20 g / l; sodium bicarbonate - 0.35 g / l; potassium chloride - 0.40 g / l.

The number of cycles of emulsification 6 with an average particle size of 60 nm. After 3 times freezing / thawing, the emulsion is stable, the average particle size was 80 nm. Reactogenicity of the emulsion did not exceed 6%.

Example 9. The method of obtaining 30% (15 vol.%) Perfluorocarbon emulsion PFD / PFMTSP.

A composition based on a perfluorocarbon mixture consisting of slowly excreted PFD and rapidly excreted PFMTSP (PFD / PFMTSP ratio 2: 1) in an amount of 300 ml containing weighed (liquid) 400 g PFD and 200 g PFMTSP was mixed with 700 ml of an aqueous solution of proxanol, containing 120 grams of emulsifier. The specific gravity of perfluorocarbons is ~ 2. After that, the resulting mixture of perfluorocarbons and proxanol was treated as described in Example 1. Electrolytes were added to the resulting emulsion to the desired concentration.

The final formulation (dosage form) of the perfluorocarbon emulsion had the following composition: PFD / PFMTSP (ratio 2/1) - 30% (15 vol.%); PFD - 200 g / l; PFMTSP - 100 g / l; proxanol - 60 g / l; sodium chloride - 6.0 g / l; sodium phosphate - 0.20 g / l; sodium bicarbonate - 0.35 g / l; potassium chloride - 0.40 g / l; magnesium chloride - 0.19 g / l; glucose - 2.0 g / l.

The number of cycles of emulsification 6 with an average particle size of 70 nm. After 3 times freezing / thawing, the emulsion is stable, the average particle size was 80 nm. Reactogenicity of the emulsion did not exceed 6%.

Example 10. A method of obtaining 100% (50 vol.%) Perfluorocarbon emulsion PFD / PFMTSP.

A perfluorocarbon mixture consisting of one rapidly excreting PFD and slowly excreting PFMTSP (PFD / PFMTSP ratio 2: 1) in the amount of 500 ml containing weighed (liquid) 666 g PFD and 333 g PFMTSP was mixed with 500 ml of an aqueous solution of proxanol containing 200 gram of emulsifier. The specific gravity of perfluorocarbons is ~ 2. After this, the resulting mixture of perfluorocarbons and proxanol was treated in the same manner as described in Example 1. Electrolytes were added to the resulting emulsion to the required concentration.

The final formulation (dosage form) of the perfluorocarbon emulsion had the following composition: PFD / PFMTSP (ratio 2/1) - 100% (50 vol.%); PFD - 666 g / l; PFMTSP - 333 g / l; proxanol - 200 g / l; sodium chloride - 6.0 g / l; sodium phosphate - 0.20 g / l; sodium bicarbonate - 0.35 g / l; potassium chloride - 0.40 g / l.

The number of cycles of emulsification 6 with an average particle size of 70 nm. After 3 times freezing / thawing, the emulsion is stable, the average particle size was 80 nm.

Example 11. The method of obtaining 80% (40 vol.%) Perfluorocarbon emulsion PFD / PFMTSP / PFTBA.

A perfluorocarbon mixture consisting of one rapidly releasing perfluorocarbon PFD and two slowly releasing perfluorocarbons PFMTSP / PFTBA in a total ratio of 10/1/1 in an amount of 400 ml containing weighed (liquid) PFD / PFMTSP / PFTBA, which were respectively 663/66, 3 / 66.3 grams. A mixture of perfluorocarbons was mixed with 600 ml of an aqueous solution of proxanol containing 160 grams of emulsifier. The specific gravity of perfluorocarbons is ~ 2. After that, the resulting mixture of perfluorocarbons and proxanol was treated as described in Example 1. Electrolytes were added to the resulting emulsion to the desired concentration.

The final formulation (dosage form) of the perfluorocarbon emulsion had the following composition: PFD / PFMTSP / PFTBA (ratio 10/1/1) - 80% (40 vol.%); PFD - 663 g / l; PFMTSP - 66.3 g / l; PFBA - 66.3 g / l; proxanol - 160 g / l; sodium chloride - 6.0 g / l; sodium phosphate - 0.20 g / l; sodium bicarbonate - 0.35 g / l; potassium chloride - 0.40 g / l.

The number of cycles of emulsification 6 with an average particle size of 70 nm. After 3 times freezing / thawing, the emulsion is stable, the average particle size was 80 nm.

Example 12. A method of obtaining 80% (40 vol.%) Perfluorocarbon emulsion PFOB / PFD / PFMTSP / PFTA.

A perfluorocarbon mixture consisting of a pair of rapidly releasing perfluorocarbons PFOB / PFD and a pair of slowly releasing perfluorocarbons PFMTSP / PFTA in a total ratio of 10/1/1/1 in an amount of 400 ml containing a portion (liquid) of PFOB / PFD / PFMTSP / PFTA, which were respectively 617/61/61/61 grams. A mixture of perfluorocarbons was mixed with 600 ml of an aqueous solution of proxanol containing 160 grams of emulsifier. The specific gravity of perfluorocarbons is ~ 2. After this, the resulting mixture of perfluorocarbons and proxanol was treated in the same manner as described in Example 1. Electrolytes were added to the resulting emulsion to the required concentration.

The final formulation (dosage form) of the perfluorocarbon emulsion had the following composition: PFOB / PFD / PFMTSP / PFTA (ratio 10/1 / 1/1) - 80% (40 vol.%); PFOB - 617 g / l; PFD - 61 g / l; PFMTSP - 61 g / l; PFBA - 61 g / l; proxanol - 160 g / l; sodium chloride - 6.0 g / l; sodium phosphate - 0.20 g / l; sodium bicarbonate - 0.35 g / l; potassium chloride - 0.40 g / l.

The number of cycles of emulsification 6 with an average particle size of 70 nm. After 3 times freezing / thawing, the emulsion is stable, the average particle size was 80 nm.

Table 1. Some physico-chemical and biomedical characteristics of perfluorocarbon emulsions Indicators Composition analogue 1 Fluosol-DA (Japan) Composition-analogue 2 patent No. 2199311 The inventive composition: Particle Distribution (%) less than 100 nm 39.2 87.1 88.0 100-200 nm 53.0 12.9 12.0 200-300 nm 5.9 no no 300-400 nm 1,5 no no 400-500 nm 0.4 no no average particle size (nm) 120-150 50-100 30-80 Other indicators Sterilization no sterilizes. sterilizes. Adverse Reactions (%) not known 6-7 5 The number of cycles of homogenization not known 10 times 5-6 times PFOS content twenty% up to 30% up to 100% Cooking time 10 lit. emulsions not known 3-4 hours. 1.5 hours Number of extrusion devices (pcs.) one one 2

Claims (17)

1. The composition of the perfluorocarbon emulsion for biomedical purposes, intended for use as synthetic perfluorocarbon blood substituting agents and agents for treating various diseases, as well as perfusion, radiopaque and cosmetic products, including: perfluorocarbons, emulsifying agent and electrolyte solution, characterized in that contains a mixture of perfluorocarbons selected from the group:
a mixture of two perfluorocarbons: quickly excreted (C ₈ -C ₁₀ ) and slowly excreted (C ₁₁ -C ₁₂ ), like PFD / perfluorotributylamine (PFBA) in a ratio of 1/1 to 10/10, respectively;
a mixture of two perfluorocarbons: rapidly excreted (C ₈ -C ₁₀ ) and slowly excreted (C ₁₁ -C ₁₂ ), such as perfluorooctyl bromide (PFOB) / PFMTSP in a ratio of 1/1 to 10/10, respectively;
a mixture of two perfluorocarbons: rapidly eliminating (C ₈ -C ₁₀ ) and slowly eliminating (C ₁₁ -C ₁₂ ), as PFOB / PFTA in a ratio of 1/1 to 10/10, respectively;
a mixture of two perfluorocarbons: quickly derived (C ₈ -C ₁₀ ), as PFOB / PFD in a ratio of 1/1 to 10/10, respectively;
a mixture of two perfluorocarbons: slowly derived (C ₁₁ -C ₁₂ ), as PFMTSP / PFTA in a ratio of 1/1 to 10/10, respectively;
a mixture of three perfluorocarbons: two rapidly releasing (C ₈ -C ₁₀ ) and one slowly releasing (C ₁₁ -C ₁₂ ), as PFD / PFOB / PFMTSP in a ratio of 1/1/1 to 10/10/10, respectively;
a mixture of three perfluorocarbons: two rapidly releasing (C ₈ -C ₁₀ ) and one slowly releasing (C ₁₁ -C ₁₂ ), as PFD / PFOB / PFTA in a ratio of 1/1/1 to 10/10/10, respectively;
a mixture of three perfluorocarbons: one rapidly releasing (C ₈ -C ₁₀ ) and two slowly removing (C ₁₁ -C ₁₂ ), as PFD / PFMTSP / PFTA in a ratio of 1/1/1 to 10/10/10, respectively;
a mixture of three perfluorocarbons: one rapidly releasing (C ₈ -C ₁₀ ) and two slowly releasing (C ₁₁ -C ₁₂ ), as PFOB / PFMTSP / PFTA in a ratio of 1/1/1 to 10/10/10, respectively;
a mixture of four perfluorocarbons: two rapidly releasing (C ₈ -C ₁₀ ) and two slowly releasing (C ₁₁ -C ₁₂ ), as PFD / PFOB / PFMTSP / PFTA in the ratio from 1/1/1/1 to 10/10 / 10/10 respectively. 2. The composition of the perfluorocarbon emulsion according to claim 1, characterized in that PFD and PFOB are used as the quickly derived perfluorocarbons (C ₈ -C ₁₀ ). 3. The composition of perfluorocarbon emulsion according to claim 1, characterized in that the output of this slow (C ₁₁ -C ₁₂₎ perfluorocarbons are used PFMCP and PFTBA. 4. The composition of the perfluorocarbon emulsion according to claim 1, characterized in that the content of perfluorocarbons in the emulsion is from 0.5% (0.25 vol.%) To 100% (50 vol.%). 5. The composition of the perfluorocarbon emulsion according to claim 1, characterized in that the dispersion of particles up to 100 nm is 88%, from 100 to 200 nm - 12%, of which particles in 200 nm are not more than 0.1%, with an average particle size of the emulsion - 30-80 nm. 6. The composition of the perfluorocarbon emulsion according to claim 1, characterized in that proxanol from 0.1 to 20% with a molecular weight of 5-15 thousand Da is used as an emulsifying agent. 7. The composition of the perfluorocarbon emulsion according to claim 1, characterized in that the physiologically acceptable electrolyte solution includes: sodium chloride, sodium phosphate, sodium bicarbonate, potassium chloride. 8. The composition of the perfluorocarbon emulsion according to claim 1, characterized in that the electrolyte solution contains, g / l: sodium chloride, 5.0-9.5; sodium phosphate 0.20-0.60; sodium bicarbonate 0.35-0.70; potassium chloride 0.35-0.45; magnesium chloride 0.18-0.25; glucose 1.8-2.5. 9. The method of obtaining the composition of perfluorocarbon emulsions for biomedical purposes, intended for use as synthetic perfluorocarbon blood substitutes and agents for treating various diseases, as well as perfusion, radiopaque and cosmetic products, characterized in that the emulsion is produced by mixing the total amount how rapidly eliminated perfluorocarbons (C ₈ -C ₁₀₎ FPD, PFOB and are excreted slowly (C ₁₁ -C _12): PFMCP, PFTBA with emulsifying agent - proxy ol, and repeated homogenization of the mixture in two extrusion devices of the high-pressure homogenizer, passing the emulsion sequentially through the primary and secondary extrusion devices of the homogenizer up to 5-6 times, passing the emulsion through a buffer tank located between the two extrusion devices of the homogenizer and designed to equalize the pressure between the devices by passing the emulsion through the main extrusion device, increase the homogenization pressure by 2-3 times compared to by pouring in an additional extrusion device, passing the emulsion through the buffer and the main tank, carbon dioxide is supplied. 10. The method of obtaining the composition of perfluorocarbon emulsion according to claim 9, characterized in that it contains:
a mixture of two perfluorocarbons: quickly derived (C ₈ -C ₁₀ ) and slowly removed (C ₁₁ -C ₁₂ ), as PFD / PFMTSP in a ratio of 1/1 to 10/10, respectively;
a mixture of two perfluorocarbons: rapidly eliminating (C ₈ -C ₁₀ ) and slowly eliminating (C ₁₁ -C ₁₂ ), as PFD / PFTA in a ratio of 1/1 to 10/10, respectively;
a mixture of two perfluorocarbons: quickly derived (C ₈ -C ₁₀ ) and slowly derived (C ₁₁ -C ₁₂ ), as PFOB / PFMTSP in a ratio of 1/1 to 10/10, respectively;
a mixture of two perfluorocarbons: quickly derived (C ₈ -C ₁₀ ) and slowly removed (C ₁₁ -C ₁₂ ), as PFOB / PFBA in a ratio of 1/1 to 10/10, respectively;
a mixture of two perfluorocarbons: quickly eliminated (C ₈ -C ₁₀ ) as PFOB / PFD in a ratio of 1/1 to 10/10, respectively;
a mixture of two perfluorocarbons: slowly derived (C ₁₁ -C ₁₂ ), as PFMTSP / PFTA in a ratio of 1/1 to 10/10, respectively;
a mixture of three perfluorocarbons: two rapidly releasing (C ₈ -C ₁₀ ) and one slowly releasing (C ₁₁ -C ₁₂ ), as PFD / PFOB / PFMTSP in a ratio of 1/1/1 to 10/10/10, respectively;
a mixture of three perfluorocarbons: two rapidly eliminating (C ₈ -C ₁₀ ) and one slowly eliminating (C ₁₁ -C ₁₂ ), as PFD / PFOB / PFTA in a ratio of 1/1/1 to 10/10/10, respectively;
a mixture of three perfluorocarbons: one rapidly releasing (C ₈ -C ₁₀ ) and two slowly releasing (C ₁₁ -C ₁₂ ), as PFD / PFMTSP / PFTA in a ratio of 1/1/1 to 10/10/10, respectively;
a mixture of three perfluorocarbons: one rapidly releasing (C ₈ -C ₁₀ ) and two slowly releasing (C ₁₁ -C ₁₂ ), as PFOB / PFMTSP / PFTA in a ratio of 1/1/1 to 10/10/10, respectively;
a mixture of four perfluorocarbons: two rapidly releasing (C ₈ -C ₁₀ ) and two slowly releasing (C ₁₁ -C ₁₂ ), as PFD / PFOB / PFMTSP / PFTA in the ratio from 1/1/1/1 to 10/10 / 10/10 respectively. 11. The method of obtaining the composition of the perfluorocarbon emulsion according to claim 9, characterized in that the emulsion is obtained by spraying a mixture of perfluorocarbons through an aqueous solution of an emulsifying agent to obtain the desired ratio of components. 12. A process for preparing the composition of perfluorocarbon emulsion according to claim 9, characterized in that the emulsion is prepared under pressure in all the two extrusion devices from 120 to 1500 kg / cm ^2. 13. The method of obtaining the composition of the perfluorocarbon emulsion according to claim 9, characterized in that the emulsion is passed sequentially through the first and second extrusion devices of the high pressure homogenizer. 14. The method of obtaining the composition of the perfluorocarbon emulsion according to claim 9, characterized in that the required amount of electrolyte solution is added to the resulting emulsion, including: sodium chloride, sodium phosphate, sodium bicarbonate, potassium chloride. 15. The method of obtaining the composition of the perfluorocarbon emulsion according to claim 9, characterized in that the dosage form of the emulsion is sterilized by dynamic ultrafiltration. 16. The method of obtaining the composition of the perfluorocarbon emulsion according to claim 9, characterized in that the dosage form of the emulsion after sterilization of dynamic ultrafiltration has a maximum particle size of not more than 200 nm with an average particle size of 30-80 nm. 17. A tool based on the composition of perfluorocarbon emulsion, intended for use as synthetic perfluorocarbon blood substituting agents and means for treating various diseases, as well as perfusion, radiopaque and cosmetic products, characterized in that the composition according to claim 1 can be used for intravenous, intraarterial, oral, intracavitary use and before use can be diluted with any solution compatible with the emulsion or composition, can also be used atsya as an external agent for cosmetic and curative ointment or cream for wounds, ulcers and other external diseases, before the use can divorce any compatible with the emulsion antiviral, antibacterial, antifungal compound or colloidal silver, or a compatible medium.

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