RU2200544C1 - Method of sterile perfluorocarbon emulsions preparing for artificial perfluorocarbon blood substitutes - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: invention relates to method of preparing perfluorocarbon emulsions able to transfer oxygen and other gases. Invention describes preparing submicron perfluorocarbon particles of emulsions by homogenization of perfluorocarbons and their mixtures under high pressure from 50 to 1100 atm. The application of sterilization filtration system for prepared perfluorocarbon emulsions allows to obtain the sterilized, more monodispersed, areactogenic (safety), submicron particles of emulsion for medicinal aims. Their maximal diameter does not exceed 0.2 mcm that ensures to enhance safety of clinical application of perfluorocarbon blood substitutes and other media. Invention provides preparing sterile, monodispersed, submicron, areactogenic perfluorocarbon emulsions. Emulsions are designated for artificial perfluorocarbon media and solutions and can be used in medicine as artificial blood, X-ray contrast agents, media for organ preserving and media for development of ointments, gels and cosmetic agents. EFFECT: improved method of preparing, valuable medicinal properties of emulsions. 2 cl, 2 tbl, 1 dwg, 16 ex

Description

 The invention relates to methods for producing perfluorocarbon emulsions capable of transporting oxygen and other gases and intended for artificial perfluorocarbon media and solutions, and can be used in medicine as artificial blood, radiopaque agents, media for preserving organs, and also environments for creating ointments, gels and cosmetics.

 It is known that the quality of perfluorocarbon emulsions is more dependent and determined by the size and distribution of the particles of the emulsion. Thus, the presence of large particles larger than 0.2-0.3 μm, as shown in (Mitsuno Toka, Kokuritsu Kobe, Medical Institute, Japan, "The Practical Use of Artificial Blood," Shizen, 1981, 36 (9), p. 62-69), is the cause of the toxicity of emulsions. An important indicator is also the stability, which depends mainly on the properties of the used perfluorocarbons and emulsifying agents.

To obtain perfluorocarbon emulsions, as a rule, two types of perfluororganic compounds are used simultaneously, as a rule. One of them is selected from the group (C ₈ -C ₁₀ ) containing, for example, perfluorodecalin (PFD) or perfluorooctyl bromide (PFOB), the second from the group (C ₁₁ -C ₁₂ ) containing, for example, perfluorotripropylamine (PFPA), perfluoromethylcyclohexylpiperidine (PFMTSP) or perfluorotributilimine (PFTBA). These perfluorocarbons dissolve about 40 vol.% Oxygen (at pO ₂ = 760 mm Hg) and 150-190 vol.% Carbon dioxide (at pCO ₂ = 760 mm Hg), so they began to be used as the main component is the carrier gas when creating artificial blood. 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) and the smaller the particle size of the emulsion, the better, because emulsions are administered intravenously and with large particle sizes can cause embolism (blockage) of blood vessels. 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.

 The most common emulsion technology of this kind is based on methods using ultrasound or high pressure homogenization. To obtain emulsions on an industrial scale, a homogenization method is preferable, because it allows the production of emulsions in large quantities and with better physicochemical characteristics, for example, improved particle size distribution (Jean G. Riess and Maurice Le Blanc. Preparation of perfluoro-chemical emulsions for biochemical use: principles, materials and methods. Ellis Horwood Series in Biomedicinne, VCH, Blood Substituts, Preparation, Physiology and Medical Applications. 1991. Ch. 5, pp 113-115).

A known method for producing perfluorocarbon 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 USSR patent N-797546, publ. in the bulletin "Discoveries, inventions ...." N 2, 1981). 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 a propeller mixer, 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 ^o . The perfluorocarbon mixture is passed through the homogenizer slit up to 12 times.

 The disadvantages of this invention include the fact that the perfluorocarbon emulsion obtained with this method is sufficiently coarse in size and cannot be stored in thawed form.

 The average particle size of another perfluorocarbon emulsion, intended for medical purposes, by Fluosol-DA 20%, of the same company, prepared in a similar way based on PFD and PFPA, is significantly smaller than the previous emulsion and was 0.118 μm, the proportion of particles ranging in size from 0.2 to 0.5 μm was 7.8%. As an emulsifier, proxanol and egg yolk phospholipids were used.

 However, the average particle diameter of this emulsion was also large due to the fact that at high temperatures in the process of emulsification and sterilization coarsening of the particles of the emulsion occurs. In addition, due to the use of mixers such as a propeller mixer does not provide sufficient sterility of the process. All this leads to the need to filter the fraction of large particles and sterilize the emulsion, which complicates the process (Mitsuno T. et al., "Intake and retension of perfluorochemical substance of Fluosol-DA in res human", Proceedings of the 5. Int. Sympos. On Oxygen-Carring Colloidal Blood Substituts, Meinz, March, 1981. P.220). The emulsion obtained by this method is stored only in frozen form, because after 8-12 hours of storage at room temperature, coarsening of the particles of the emulsion takes place and in this connection its clinical use becomes impossible.

 A known method of producing perfluorocarbon emulsions for medical purposes (RF patent N 2070033, publ. 1996, N 34) is close to the claimed method, in which 12-fold emulsification of perfluorodecalin or perfluorooctyl bromide and perfluoromethylcyclohexylpiperidine in a ratio of 2/1 takes place in 3 containers at alternating pressure by increasing the pressure in the homogenizer 1.1-1.2 times when passing the emulsion in an additional container compared to the pressure when passing the emulsion in the main circuits, which allowed us to obtain an emulsion with an average size rum particles of 0.06 microns.

 The disadvantage of this method, consisting of 3 containers (circulation circuit), is that the perfluorocarbon mixture is fed into the homogenizer from the first tank, which is no longer used (after digging the mixture of perfluorocarbons) and the latter needs to be disconnected from the entire homogenization system, except of this, the slow instillation of perfluorocarbons does not contribute to a sufficiently complete contact of the mixture of perfluorocarbons and emulsifier and sharply slows down the process of emulsification, which negatively affects the average size and size definiteness emulsion particles and also leads to an increase in the homogenization time. Another disadvantage of this method is the alternate change in the process of emulsification of pressure in the homogenizer itself. The alternation of pressure from 500 atm (during the first cycle) to 550 atm (during the second cycle), again at 500 atm (during the third cycle) and vice versa during the fourth and all this for 12 cycles is technically quite difficult, in addition, each pressure change is accompanied by direct rasterization of the system through the pressure gauge sensor, which can ultimately lead to the introduction of microflora into the emulsion. In addition, in the emulsion prepared by this method, there are coarse particles with a diameter of more than 0.2 μm to 0.4%, which can increase the number of reactogenic (allergic) reactions. Another disadvantage of this method is the narrow temperature range in which the emulsion is prepared from +20 to +22 degrees C. At this temperature, it is difficult to prepare highly concentrated emulsions of 30-40%, because at low temperature conditions of emulsification, the viscosity of the preemulsion sharply increases, which leads to stagnation in the homogenization system.

A known method of producing perfluorocarbon emulsions for medical purposes (RF patent 2122404, publ. 11/27/1998, 33), the closest to the claimed method, in which due to 9-fold emulsification and jet transmission of a multicomponent mixture of two perfluorocarbons: PFD / PFTA , PFD / PFMTSP, PFOB / PFTBA, PFOB / PFMTSP in the ratio from 1/1 to 10/1, respectively; or of three: PFOB / PFD / PFMTSP, PFOB / PFD / PFBA in the ratio from 1/1/1 to 10/1/1, respectively; or from four: PFOB / PFD / PFMTSP / PFTBA in a ratio of 1/1/1/1 to 10/1/1/1, respectively, with a solution of proxanol through a homogenizer under a pressure of 700-1000 atm and cooling at a temperature of +24 to +34 degrees C ^o , then the resulting emulsion is subjected to further cyclic homogenization (8-9 cycles) under a constant pressure of 400-490 atm and with constant cooling to obtain an emulsion with an average particle size of 0.03-0.05 microns, followed by addition to the emulsion physiologically acceptable electrolyte solution to the desired concentration.

 The disadvantage of the above method for producing perfluorocarbon emulsions is the presence of particles after emulsification with an average size of up to 0.05 μm and the absence of an important process in the production cycle of perfluorocarbon emulsions - filtration sterilization.

 The objective of the invention is the creation of sterile, pyrogen-free, submicron, monodispersed, multicomponent, perfluorocarbon emulsions by reducing the average particle size of the emulsion and the reduction of coarse fractions of the particles of the emulsion by homogenization and filtration sterilization of perfluorocarbon emulsions.

 The problem is solved in that in the inventive method for producing perfluorocarbon emulsions for medical purposes, including the preparation of a pre-emulsion by mixing the total amount of perfluorocarbons with an emulsifying agent and multiple homogenization of the mixture in a closed pressure circuit, according to the invention, the pre-emulsion is obtained by jet-droplet per-droplet concentration of multi-droplet per-droplet peronotropic multi-droplet transmission from 1 to 40%, consisting of two perfluorocarbons: perfluorodecalin (PFD) / perfluoromethyl clo-geksilpiperidina (PFMCP), or PFD / perfluorotributylamine (PFTBA), or perfluorooctyl bromide (PFOB) / perftortripromilamina (PFTPA), or PFOB / PFMCP, or PFOB / PFTBA in ratio from 1/1 to 10/10, respectively; or from a mixture of three perfluorocarbons: PFOB / PFD / PFMTSP, or PFOB / PFD / PFTPBA, or PFOB / PFD / PFTPA in a ratio of 1/1/1 to 10/10/10, respectively; or from a mixture of four perfluorocarbons: PFOB / PFD / PFMTSP / PFTBA or PFOB / PFD / PFMTSP / PFTPA in a ratio of 1/1/1/1 to 10/10/10/10, respectively, or from a mixture of five perfluorocarbons: PFOB / PFD / PFMTSP / PFTA / PFTPA in a ratio of 1/1/1/1/1 to 10/10/10/10/10, with a solution of proxanol (with a final concentration of 0.2 to 8% in the finished perfluorocarbon emulsion) (or with a solution of phospholipids) through a homogenizer under pressure from 50 to 1100 atm until a submicron perfluorocarbon emulsion with an average particle size of 0.025 μm is obtained with further addition to the perfluorocarbon emulsion iju electrolytes: sodium chloride 5,0-9,5 g / l; potassium chloride 0.30-0.45 g / l; magnesium chloride 0.15-0.25 g / l; sodium bicarbonate 0.40-0.70 g / l; sodium hydrogen phosphate 0.15-0.25 g / l; glucose 1.5-2.5 g / l, then the resulting perfluorocarbon emulsion is subjected to sterilization filtration through a pore diameter of 0.2 μm in the filter and is subsequently used as an artificial blood substitute or other media.

 The invention is illustrated by the diagram (see drawing) of the process intended for implementing the method of producing perfluorocarbon emulsion, which shows a homogenization system consisting of an upper tank 1 for a mixture of perfluorocarbons, pipe 2 connecting the tank 1 with the lower tank 3, the pipe 4 connecting the tank 1 and 3 with a high pressure homogenizer 5, pipelines 6 and 7, used to transfer the emulsion from the homogenizer 5 to the tank 1 and 3, as well as the main element for obtaining a sterile submicron emulsion x, calibrated dimensions - sterilizing filter system 8 and the tank 9 with the electrolyte solution.

The method is as follows: to obtain a pre-emulsion (micron size), the mixture of perfluorocarbons is supplied dropwise from the upper container 1 through a pipe 2 to a lower container 3 with an emulsifier - proxanol (or phospholipids) and fed through a pipe 4 to a homogenizer 5 with a high “shock” pressure in the homogenizer 650-1100 atm. The pre-emulsion from the homogenizer 5 under a high "shock" pressure of 650-1100 atm enters through the pipe 6 back to the tank 3. The first cycle of the pre-emulsion is closed: tank 3, pipe 4, homogenizer 5, pipe 6 and again the tank 3. Obtaining an emulsion with smaller particles are carried out in a new cycle: from the homogenizer 5, the emulsion enters through the pipe 7 into the upper tank 1 at an oscillating pressure in the homogenizer from 50 to 600 atm. Then, from the container 1, the emulsion enters through the pipe 2 into the lower container 3 and the pipe 4 into the homogenizer 5 at an oscillating pressure in the homogenizer from 50 to 600 atm. The second cycle of emulsion production is closed: tank 1, pipe 2, tank 3, pipe 4, homogenizer 5, pipe 7 and again tank 1. In the first and second cycles, as well as in the subsequent, both tanks are completely freed from the emulsion, thereby eliminating the so-called "stagnant zones" where the largest particles of the emulsion accumulate. After the third emulsification cycle, which is completely similar to the first cycle, with the exception of the homogenization pressure, which, starting from the second cycle, does not change further and ranges from 50 to 600 atm in the oscillating mode, the fourth emulsification cycle begins, which is completely similar to the third, etc. up to 8-9 cycles. During the entire process of obtaining the emulsion, cooling is carried out at t from +20 to +50 degrees C ^o in tanks 1 and 3 and in the homogenizer 5 itself, due to the fact that an increase in the temperature of the emulsion during homogenization leads to enlargement of the particles of the emulsion, which is unacceptable. After receiving a submicron perfluorocarbon emulsion with an average particle size of 0.025 μm, the emulsion enters the filtration sterilization system 8 with a filter pore diameter of 0.2 μm by means of a pump for filtering and sterilization and cutting off coarse particles, followed by filling into a container 9 with an electrolyte solution.

 The proposed method for producing perfluorocarbon emulsions allows the creation of submicron, multicomponent, perfluorocarbon emulsions with a low degree of reactogenicity compared to the similar method, since the presence of an average particle size (0.03-0.05 μm) in the analogue, capable of causing reactogenicity (side, negative action) of the emulsion, reduced by 20-50% in the present method, and the new emulsion has a more monodisperse distribution of particles (tables 1, 2). In addition, there is another very important difference: in the claimed method, the emulsion is subjected to filtration sterilization, and in the similar method in the technological cycle there is no sterilization and filtration of the emulsion, which affects the safety of the use of perfluorocarbon emulsions in medical practice.

 Thus, the proposed method for creating perfluorocarbon emulsions allows to obtain sterile, monodispersed, submicron, areactogenic, perfluorocarbon emulsions and to "cut off" coarse emulsion particles (reactogenic) using a sterilization filtration system. The developed method is much preferable in comparison with the analogue method and the method of obtaining the Japanese drug Fluozol - DA 20%.

 Obtaining a 20% perfluorocarbon emulsion.

Example 1. A perfluorocarbon mixture PFD / PFBA in a ratio of 1/1 in an amount of 200 ml, containing 200 g PFD specific gravity 1.938 and 200 g PFBA specific gravity 1.899, was passed in a droplet droplet from tank 1 through line 2 to tank 3, where the solution was proxanol in an amount of 800 ml. After that, the resulting mixture of perfluorocarbons and proxanol was passed through line 4 to homogenizer 5, in which the high "shock" pressure was 650-1100 atm. The pre-emulsion obtained from the homogenizer 5 under a high "shock" pressure of 650-1100 atm was fed through the pipe 6 again to the tank 3. From the tank 3, the pre-emulsion was fed through the pipe 4 to the homogenizer 5, the oscillating pressure of which ranged from 50 to 600 atm and then did not change during the whole operating time. The resulting emulsion through the pipe 7 was fed into the tank 1 through the pipe 2 to the tank 3 and through the pipe 4 to the homogenizer 5, the oscillating pressure in which was 50-600 atm. From homogenizer 5, the emulsion was fed through conduit 7 to container 1. To obtain a submicron emulsion, 8–9 cycles of a mixture of perfluorocarbons and proxanol passed through homogenizer 5 and containers 1 and 3. The cooling temperature of the emulsion in containers 1 and 3 and homogenizer 5 throughout the process receiving ranged from +20 to +50 degrees C ^o . After receiving a submicron perfluorocarbon emulsion with an average particle size of 0.025 μm, the emulsion was pumped to the filtration sterilization system 8 with a pore diameter of 0.2 microns for filtration and sterilization and cutting off coarse particles, followed by filling and mixing in a container 9 with concentrated electrolyte solution to the required concentration of electrolytes.

 The final formulation of the perfluorocarbon emulsion had the following composition: PFD / PFTA (1/1 ratio) - 20% (or 10 vol.%), Proxanol 4-4.8% and electrolyte composition.

 Example 2. An emulsion was prepared as described in Example 1.

 The ratio of PFD / PFMTSP was 2/1, the weighed portion of PFD / PFMTSP was 266 g and 133 g. The specific gravity of PFMCP was -1.920.

 The final formulation of the perfluorocarbon emulsion had the following composition: PFD / PFMTSP (ratio 2/1) - 20% (or 10 vol.%), Proxanol 4-4.8% and electrolyte composition.

 Example 3. An emulsion was prepared as described in Example 1.

 The ratio of PFOB / PFTPA was 3/1, the weight of PFOB / PFBA was 300 g and 100 g. The specific gravity of PFOB was 1.920.

 The final formulation of the perfluorocarbon emulsion had the following composition: PFOB / PFBA (ratio 3/1) - 20% (or 10 vol.%), Proxanol - 4-4.8% and electrolyte composition.

 Example 4. An emulsion was prepared as described in Example 1.

 The ratio of PFOB / PFMTSP was 7/1, the weights of PFOB / PFMTSP were 350 g and 50 g.

 The final perfluorocarbon emulsion formulation had the following composition: PFOB / PFMTSP (ratio 7/1) - 20% (or 10 vol.%), Proxanol - 4-4.8% and electrolyte composition.

 Example 5. An emulsion was prepared as described in Example 1.

 The ratio of PFOB / PFMTSP was 10/1, the weights of PFOB / PFMTSP were 363 g and 37 g.

 The final formulation of the perfluorocarbon emulsion had the following composition: PFOB / PFMTSP (ratio 10/1) - 20% (or 10 vol.%), Proxanol 4-4.8% and electrolyte composition.

 Example 6. An emulsion was prepared as described in Example 1.

 The ratio of PFOB / PFD / PFMTSP was 1/1/1, the weights of PFOB / PFD / PFMTSP were 133/133/133, respectively.

 The final formulation of the perfluorocarbon emulsion consisted of the following: PFOB / PFD / PFMTSP (1/1/1 ratio) - 20% (or 10 vol.%), Proxanol 4-4.8% and electrolyte composition.

 Example 7. An emulsion was prepared as described in Example 1.

 The ratio of PFOB / PFD / PFBA was 10/1/1, the weights of PFOB / PFD / PFTA were 333/33/33 g respectively.

 The final formulation of the perfluorocarbon emulsion had the following composition: PFOB / PFD / PFTBA (ratio 10/1/1) - 20% (or 10 vol.%), Proxanol 4-4.8% and electrolyte composition.

 Example 8. An emulsion was prepared as described in Example 1.

 The ratio of PFOB / PFD / PFMTSP / PFTBA was 1/1/1/1, the weights of PFOB / PFD / PFMTSP / PFTA were respectively 100/100/100/100 g.

 The final formulation of the perfluorocarbon emulsion had the following composition: PFOB / PFD / PFMTSP / PFTBA (ratio 1/1/1/1) - 20% (or 10 vol.%), Proxanol 4-4.8% and electrolyte composition.

 Example 9. An emulsion was prepared as described in Example 1.

 The ratio of PFOB / PFD / PFMTSP / PFTBA was 10/1/1/1, the weights of PFOB / PFD / PFMTSP / PFTA were 307/31/31/31, respectively.

 The final formulation of the perfluorocarbon emulsion had the following composition: PFOB / PFD / PFMTSP / PFTBA (ratio 10/1/1/1) - 20% or (10 vol.%), Proxanol 4-4.8% and electrolyte composition.

 Getting 40% perfluorocarbon emulsion.

 Example 10. A perfluorocarbon mixture of PFD / PFBA in a ratio of 1/1 in an amount of 400 ml, containing 400 g of PFD specific gravity 1.938 and 400 g PFTA specific gravity 1.899, was mixed with a solution of proxanol in a volume of 800 ml. After that, the resulting mixture of perfluorocarbons and proxanol was prepared in the same manner as described in example 1.

 The final perfluorocarbon emulsion formulation had the following composition: PFD / PFBA (1/1 ratio) - 40% (or 20 vol.%), Proxanol 5.6-8% and electrolyte composition.

 Example 11. Prepared emulsion in the same manner as described in example 1.

 The ratio of PFD / PFMC was 10/1, the weighed portion of PFD / PFMTSP was 725 g and 75 g.

 The final perfluorocarbon emulsion formulation had the following composition: PFD / PFMTSP (ratio 10/1) - 40% (or 20 vol.%), Proxanol 5.6-8% and electrolyte composition.

 Example 12. Prepared emulsion in the same manner as described in example 1.

 The ratio of PFOB / PFD / PFMTSP was 1/1/10, the weights of PFOB / PFD / PFMTSP were 67/67/666, respectively.

 The final formulation of the perfluorocarbon emulsion had the following composition: PFOB / PFD / PFMTSP (1/1/10 ratio) - 40% (or 20 vol.%), Proxanol 5.6-8% and electrolyte composition.

 Example 13. Prepared emulsion in the same manner as described in example 1.

 The ratio of PFOB / PFD / PFMTSP / PFTBA was 10/1/1/1, the weights of PFOB / PFD / PFMTSP / PFTA were 614/62/62/62, respectively.

 The final formulation of the perfluorocarbon emulsion had the following composition: PFOB / PFD / PFMTSP / PFTBA (ratio 10/1/1/1) - 40% (or 20 vol.%), Proxanol 5.6-8% and electrolyte composition.

 Example 14. Prepared emulsion in the same manner as described in example 1.

 The ratio of PFOB / PFD / PFMTSP / PFTBA / PFTPA was 10/1/1/1/1, the weights of PFOB / PFD / PFMTSP / PFTA / PFTPA were 572/57/57/57/57/57, respectively.

 The final formulation of the perfluorocarbon emulsion had the following composition: PFOB / PFD / PFMTSP / PFTA / PFPA (ratio 10/1/1/1/1) - 40% (or 20 vol.%), Proxanol 5.6-8% and electrolyte composition .

 Obtaining 1% perfluorocarbon emulsion.

 Example 15. A perfluorocarbon mixture PFD / PFMCP in a ratio of 1/2 in an amount of 200 ml, containing 266 g PFD specific gravity 1.938 and 133 g PFMCP specific gravity 1.920, was mixed with a solution of proxanol in a volume of 800 ml. After that, the resulting mixture of perfluorocarbons and proxanol was prepared in the same manner as described in example 1.

 The final perfluorocarbon emulsion formulation had the following composition: PFD / PFMTSP (ratio 2/1) - 1% (or 0.5 vol.%), Proxanol 0.2-0.25% and electrolyte composition.

 Example 16. An emulsion was prepared in the same manner as described in example 1.

 The ratio of PFOB / PFD / PFMTSP / PFTBA was 1/1/1/10, the weights of PFOB / PFD / PFMTSP / PFTA were 62/62/62/614, respectively.

 The final formulation of the perfluorocarbon emulsion had the following composition: PFOB / PFD / PFMTSP / PFTBA (ratio 1/1/1/10) - 1% (or 0.5 vol.%), Proxanol 0.2-0.25% and electrolyte composition .

Claims (2)

 1. A method of producing emulsions based on perfluorocarbons for artificial perfluorocarbon blood substitutes, including the preparation of a pre-emulsion by mixing the total amount of perfluorocarbons with an emulsifying agent - proxanol and repeated homogenization of the mixture in a closed circulation circuit under pressure, followed by physiologically acceptable addition of the resulting emulsion to the emulsion with an electrolyte that the pre-emulsion is obtained by jet-drop transmission of a multicomponent perfluorocarbon mixture birth concentration from 1 to 40%, consisting of two perfluorocarbons: PFD / PFMTSP, or PFD / PFTBA, or PFOB / PFMTSP, or PFOB / PFTBA or PFOB / perfluorotripropylamine (PFTPA) in a ratio of 1/1 to 10/10, respectively or from a mixture of three perfluorocarbons - PFOB / PFD / PFMTSP, or PFOB / PFD / PFTPBA, or PFOB / PFD / PFTPA in a ratio of 1/1/1 to 10/10/10, respectively, or from a mixture of four perfluorocarbons - PFOB / PFD / PFMTSP / PFTA or PFOB / PFD / PFMTSP / PFTPA in the ratio from 1/1/1/1 to 10/10/10/10, respectively, or from a mixture of five perfluorocarbons: - PFOB / PFD / PFMTSP / PFTBA / PFTPA in the ratio from 1/1/1/1/1 to 10/10/10/10/10, respectively, with a solution of proxanol with a final concentration of 0.2 to 8% in the finished perfluorocarbon emulsion or with a solution of phospholipids through a homogenizer under a pressure of 50 up to 1100 atm, until submicron perfluorocarbon emulsions with an average particle size of 0.025 μm are obtained, with further addition of sodium chloride electrolytes of 5.0-9.5 g / l, potassium chloride 0.30-0.45 g / l, magnesium to the perfluorocarbon emulsion chloride 0.15-0.25 g / l, sodium bicarbonate 0.40-0.70 g / l, sodium hydrogen phosphate 0.15-0.25 g / l, glucose 1.5-2.5 g / l, then the resulting perfto a carbon emulsion is subjected to sterilization filtration through a pore diameter of 0.2 μm in the filter.  2. The method according to p. 1, characterized in that in the resulting perfluorocarbon emulsion with a concentration of perfluorocarbons from 1 to 40% and proxanol from 0.2 to 8% (or phospholipids), injection water is added to the desired concentration and perfluorocarbon emulsion is used as a therapeutic funds for oral, intracavitary and external use.

Images