RU2811867C1 - Pharmaceutical composition of sterile emulsion of organoperfluorine compounds and polyelectrolytes and method of its obtaining - Google Patents

Abstract

FIELD: pharmaceuticals; medicine.

SUBSTANCE: invention relates to medicinal products, namely to blood substitutes in the form of an emulsion based on perfluoroorganic compounds and polyelectrolytes, as well as methods of their preparation. The following is proposed: a method of production of a sterile perfluorocarbon emulsion for infusion for medical purposes, which consists in carrying out preliminary sterilizing filtration of a mixture of liquids of perfluoroorganic compounds, with a ratio of C₈-C₁₀ perfluoroorganic compounds to C₁₁-C₁₂ perfluoroorganic compounds from 1:1 to 1:4, with mixture densities from 1.872 to 1.945 g/ml in aqueous solution and one or more emulsifiers in total — not more than 270 mg/ml, adding one or more polyelectrolytes in total — not more than 3 mg/ml, dispersed at speeds up to 3,000 rpm; homogenizing the resulting dispersion by passing through a high-pressure homogenizer at a pressure of up to 120 MPa, diluting the resulting emulsion with water for injection.

EFFECT: method allows to reduce the number of homogenization cycles and quickly obtain a PFOS emulsion.

23 cl, 5 dwg, 3 tbl, 23 ex

Description

Field of technology to which the invention relates

The invention relates to the field of pharmaceuticals and medicine, in particular to medicinal products, namely to blood substitutes in the form of an emulsion based on perfluoroorganic compounds and polyelectrolytes, as well as methods for their preparation.

State of the art

Blood substitutes, or otherwise plasma substitutes, are solutions of substances of organic or inorganic origin used to compensate for blood loss or correct human blood pathologies. One type of blood substitutes are blood substitutes with the function of oxygen transfer. Traditionally, chemically inert perfluoroorganic compounds (PFOS) and their perfluorocarbon emulsions (PFOS emulsions) are used as the main component of sterile gas transport blood substitutes, or they are based on modified hemoglobins produced from highly purified human (or cattle) hemoglobin, chemically or genetically modified recombinant modified hemoglobin. Hemoglobin molecules can be encapsulated in liposomes along with other molecules. The difficulty of using modified hemoglobins is associated with the production and purification of hemoglobin from donor blood, as well as with individual intolerance, rejection and other adverse immune reactions; therefore, perfluorocarbon emulsions are considered more promising gas transport blood substitutes.

The most common technologies for producing perfluoride carbon emulsions - the main components of sterile gas transport blood substitutes - are based on methods using ultrasonic cavitation or high-pressure homogenization. For the production of PFOS on an industrial scale, high-pressure homogenization is preferred because it allows the production of emulsions in larger quantities and with better physicochemical characteristics, for example, improved particle size distribution.

When preparing perfluoroorganic emulsions, several types of liquid PFOS - perfluorocarbons (specific density of about 1.872-1.945 g/ml) and their nanoemulsions are used simultaneously. To create stable PFOS emulsions, perfluorocarbons from the C ₈ -C ₁₀ group are used, containing, for example, perfluorodecalin (PFD, CAS No. 306-94-5) C ₁₀ F ₁₈ or perfluorotripropylamine (PFTPA, CAS No. 338-83-0) C ₉ F ₂₁ N, or perfluorooctyl bromide (PFOB, CAS No. 423-55-2) C ₈ F ₁₇ Br, and - from the C ₁₁ -C ₁₂ group containing, for example, perfluoro-N-(4-methylcyclohexyl) piperidine (PFMCP, CAS No. 86630-50-4) C ₁₂ F ₂₃ N or perfluorotributylamine (PFTBA, CAS No. 311-89-7) C ₁₂ F ₂₇ N. These perfluorocarbons dissolve about 40-45 vol. % oxygen (at pO ₂ =760 mm Hg) and 150-190 vol. % carbon dioxide (at pCO ₂ =760 mm Hg), as a result of which they began to be used as the main gas carrier component in the creation of gas transport blood substitutes.

However, perfluorocarbons are insoluble in water and other liquids, so they can only be used in the form of emulsions with a certain size of perfluorocarbon particles, coated with a layer of emulsifiers, one or more, selected from the following list, but without thereby limiting your choice: phospholipids of natural raw materials (egg yolk lecithin, soy lecithin, phosphatidylcholine, etc.), poloxamers, sucrose esters with fatty acids, glycerol esters with fatty acids, purified soybean oil, medium chain triglycerides, purified olive oil, purified fish oil, glycerol (anhydrous), omega 3 fatty acids, omega 6 fatty acids, omega 9 fatty acids, alpha-tocopherol, ascorbyl palmitate, potassium and sodium salts of fatty acids (palmitate, oleate, etc.). The smaller the emulsion particle, the better, since the emulsion penetrates very well through hydrophobic biological barriers, for example, through the skin (transdermal) or cell membranes and delivers oxygen and other nutrients (biologically active compounds) dissolved or adsorbed on the hydrophobic surface or in the bulk of nanoparticles of the emulsion per fluorinated carbons.

Perfluorocompounds of the first type (C ₈ -C ₁₀ ) are quickly eliminated from the body (within a month), but do not provide sufficient stability of emulsions, while compounds of the second type (C ₁₁ -C ₁₂ ), on the contrary, give the emulsion high stability, allowing it to be stored without freezing, but they are not excreted from the body for several years, so the choice of the ratio between rapidly excreted and slowly excreted perfluorocarbons, which affect stability, the distribution of the average particle size in their emulsions, which affects the number of adverse reactions and sedimentation and aggregation stability, remain the most important factors when creating perfluorinated carbon emulsions for gas transport blood substitutes for biomedical purposes.

Some PFOS compositions and methods for preparing their emulsions are known from the prior art.

From the USSR author's certificate SU 797546 (priority date: 02.02.1977) a method is known for producing perfluorocarbon emulsions using, for example, perfluorodecalin (PFD) and perfluorotripropylamine (PFTPA), emulsifying agents, for example, a block copolymer of ethylene oxide and propylene (Pluronic F-68, Russian analogue - proxanol-268), egg yolk phospholipids or soy phospholipids and water. In accordance with this method, the concentration of perfluorocarbons is 24 wt. % in a physiologically acceptable aqueous environment. The disadvantages of this invention include the fact that a per-fluorine carbon emulsion is obtained using this method for quite a long time (12 emulsification cycles), is low concentrated (not higher than 24 wt.%), cannot be stored defrosted and the emulsion cannot be sterilized.

In the method of producing perfluorocarbon 20 wt. % of an emulsion prepared for medical purposes based on PPD and PFTPA - Fluosol-DA 20%, Japanese company Green Cross.

(https://pubchem.ncbi.nlm.nih.gov/compound/Fluosol-DA#section=Chemical-Co-Qccurrences-in-Literature date of access: 12/05/2022), Pluronic F-68 was used as an emulsifier and egg yolk phospholipids. However, the method did not allow creating emulsions with a finely dispersed composition; the average particle diameter in the composition of this emulsion was also large (200 nm), due to the fact that at high temperatures during the process of emulsification and pasteurization, the emulsion particles become larger. In addition, the particles used in the composition of the perfluorocarbon emulsion (average size 0.118 µm, the proportion of particles with sizes from 0.2 to 0.5 µm was 7.8%) quickly enlarge even at room temperature (Mitsuno T. et al., 1981 ). This emulsion is stored only frozen, because after 8-12 hours of storage at room temperature, the emulsion particles become larger and, therefore, its clinical use becomes impossible. In addition, the disadvantages of this invention include the presence of severe side reactions due to large particles and the instability of the emulsion.

Thus, improving the method for producing perfluorocarbon gas transport emulsion is an objective necessity.

There is also a known method for producing a perfluorocarbon emulsion - a gas transport hemocorrector (RF patent RU2122404, priority date: 12/16/1997) based on highly purified perfluorodecalin, perfluoro-N-(4-methylcyclohexyl) piperidine, perfluorooctyl bromide, perfluorotributylamine, emulsified with proxanol-268, with an average particle size 30-50 nm. However, there are some disadvantages, namely the duration of production of perfluorocarbon emulsion.

There is a known method for producing a perfluorocarbon emulsion of a gas transport blood substitute based on a binary mixture of highly purified perfluorodecalin and perfluoro-N-(4-methylcyclohexyl) piperidine (RF patent RU2200582, priority date: 04/02/2001) with a PFOS concentration of 1-40 wt. %, emulsified with 0.2-8 wt % proxanol-268 to an average particle size of 25 nm. However, there are some disadvantages in terms of the stability of the emulsion and the duration of its production.

There is a known method for producing a perfluorocarbon emulsion of a gas transport blood substitute (RF patent RU 2206319, priority date: 07.20.2000) based on a binary mixture of perfluorocarbons with impurities of quickly and slowly released PFOS: perfluorodecalin and perfluoro-]\G-(4-methylcyclohexyl) piperidine. The total concentration of perfluorocarbons with impurities in the emulsion in the preferred embodiment is about 19.21 wt. %, for example, in comparison with the known perfluorane emulsion, where the concentration of perfluorocarbons is 19.5 wt. %. The main rapidly excreted perfluorocarbon in the form of a mixture of cis- and trans-isomers of perfluorodecalin in an amount of 6 vol. %; impurities of rapidly excreting perfluorocarbons, which are a mixture of perfluoromethylindane, perfluoro-1-methyl-3-propylcyclohexane, trans-perfluoroindane, perfluoro-4-oxodecalin, perfluorobutylcyclohexane, perfluoropropylcyclohexane, perfluoroethylcyclohexane, perfluorobutylcyclopentane, cis-perfluoro-1-methyl-2 -ethylcyclohesane in an amount of 0.7 vol.. As a result, the total amount of PPD (specific density 1.917 g/cm3) is 12.84 grams with impurities, which is less, for example, in comparison with the known perfluoran emulsion, where PPD is 13 grams. Another perfluorocarbon, it can be assumed that PFMCP, consisting of a slowly released perfluoro-tertiary amine in the form of a mixture of perfluoro-N-4-(methylcyclohexyl)-piperidine isomers in an amount of 2.3 vol. %; impurities of perfluoro-tertiary amines, which are a mixture of perfluoro-N-(4-methylcyclohexyl)-2-methylpyrrolidine, perfluoromethyl-(4-methylcyclohexyl)-amine, cis- and trans isomers of perfluoromethylpropyl-(4-methylcyclohexyl)-amine, a mixture of perfluoromethylpropyl-( methylcyclopentyl)-amine and perfluoro-N-(4-methylcyclohexyl)-1-methylpiperidine in a total amount of 1.0 vol. %; N-perfluoroalkanes in an amount of 0.02 vol. %. As a result, the total amount of PFMCP (specific density 1.92 g/cm3) is 6.37 grams with impurities, which is less, for example, in comparison with the known perftoran emulsion, where PFMCP is 6.5 grams. A binary mixture of perfluorocarbons is emulsified with Proxanol-168 copolymer of polyoxyethylene-polyoxypropylene with a mol. May. 8 thousand Yes, up to an average emulsion particle level of 50 nm. The disadvantages of this invention are that the specified composition uses proxanol-168, instead of the best emulsifier proxanol-268, as well as impurities, which is unacceptable from the point of view of biomedical use, since impurities significantly affect the toxicity of the emulsion and, as a result, cannot be used in clinical practice . Impurities of rapidly and slowly excreted PFOS, such as perfluorodecalin and perfluoromethylcyclohexylpiperidine. It should be noted that all other patents discussed above use a binary mixture of highly purified PPD and PFMCP. Disadvantages also include the length of time it takes to obtain a perfluorocarbon emulsion.

There is a known method for producing a perfluorocarbon emulsion - a gas transport blood substitute (RF patent RU 2557933, priority date: 03/27/2014), which uses mixtures of perfluorodecalin (PFD), perfluorooctyl bromide (PFOB), perfluorotripropylamine (PFTPA), perfluoromethylcyclohexyl-piperidine (PFMCP), perfluoro tributylamine (PFTBA). Mixtures of these perfluorocarbons are emulsified with 10-30 wt. % surfactants, including proxanol-268 to an average particle size of no more than 150 nm, electrolytes are added to the finished emulsion. The disadvantages of this technical solution also include the time-consuming and labor-intensive technology for producing PFOS emulsion.

There is a known method for producing a perfluorocarbon emulsion of a gas transport blood substitute based on a binary mixture of highly purified perfluorodecalin and perfluoromethylcyclohexylpiperidine (RF patent RU2307647, priority date: December 16, 2004) with a PFOS concentration of 0.5-50 vol. %, emulsified with proxanol-268 to an average particle size of 50-100 nm. However, there are some disadvantages, namely the long and low-tech process of preparing the emulsion, and also with the described method of obtaining perfluorocarbon emulsions, the emulsification temperature increases to +60 ° C in containers and in the homogenizer circuits themselves (extrusion devices); due to the increase in temperature, enlargement of emulsion particles to 150-200 nm, which is not acceptable for medical and biological purposes.

The RF patent RU 2329788 (priority date: 09.29.2006) discloses a method for producing a perfluorocarbon emulsion - a gas transport hemocorrector with a PFOS concentration of 20 wt. %, perfluorocarbons emulsified with proxanol-268. The entire process of preparing the emulsion is carried out in at least two high-pressure extrusion devices, passing the emulsion sequentially through the main and additional extrusion devices. However, there are some disadvantages in emulsification time, emulsion stability and average particle size.

From the RF patent RU 2200544 (priority date: 06.29.2001) a method is known for producing perfluorocarbon emulsion - a gas transport blood substitute with a concentration of PFOS of 1-40 wt. %, emulsifiable 0.2-8 wt. % proxanol-268 to an average particle size of 25 nm. A method in which 40 wt. % PFOS emulsion. Disadvantages include the length of time it takes to obtain a perfluorocarbon emulsion. The duration of production of PFOS emulsion leads to a long stay of the operator in a sterile box and possible contamination (insemination of colonies by forming microorganisms) of the emulsion.

There is a known method for producing a perfluorocarbon emulsion of a gas transport hemocorrector, RF patent RU2308939 (priority date: 05.11.2004). PFOS concentrations 1-40 wt. %), perfluorocarbons emulsified with proxanol-268 at a concentration of 0.2-8 wt. % to an average particle size of 25-30 nm. A method in which, due to repeated emulsification and jet-droplet transmission of a multicomponent mixture of perfluorocarbons, consisting of a mixture of several perfluorocarbons, 40 wt. % emulsion using two extrusion devices on one homogenizer. Disadvantages include the length of time it takes to obtain a perfluorocarbon emulsion.

There is a known method for producing a perfluorocarbon emulsion of a gas transport hemocorrector, RF patent RU2415664 (priority date: 02/11/2009). In the preferred embodiment, with a PFOS concentration of 19.5-20 wt. %, emulsifiable 44.2 wt. %) proxanol-268 to an average particle size of 30-120 nm. A method in which, through repeated emulsification and jet-droplet transmission of a multicomponent mixture of perfluorocarbons, consisting of a mixture of several perfluorocarbons, through a solution of proxanol-268, the emulsion is formed using two high-pressure homogenizers with four extrusion devices with two buffer tanks to equalize the pressure between the extrusion devices. Disadvantages include the length of time it takes to obtain a perfluorocarbon emulsion.

The RF patent RU 2775474 (priority date: 04/30/2021) describes the technology for producing PFOS emulsion with 4-5 homogenization cycles, which also leads to a lengthening of the technological process and a deterioration in the quality of the resulting emulsion.

RF patent RU 2745290 (priority date: 04/12/2019) discloses a method for producing PFOS emulsion at high pressure and temperature, which is undesirable due to the enlargement of the particle size of the emulsion.

The prototype of the proposed technical solution is a binary emulsion of PFOS, disclosed in patent RU 2070033, priority date: November 28, 1994. This emulsion contains perfluorocarbon in the form of cis- and trans isomers of perfluorodecalin and perfluorinated tertiary amine perfluoro-N-(4-methylcyclohexyl)piperidine in concentrations of both components: 7 vol. % and 3.5 vol. %, respectively, and is stabilized by a polyoxyethylene-polyoxypropylene copolymer with a molecular weight of 6-8 thousand daltons (Da). A method for producing perfluorocarbon emulsions, which contain highly purified perfluorodecalin and perfluoro-N-(4-methylcyclohexyl) piperidine with a PFOS concentration of 20-40 wt. %, with an average particle size of 100-150 nm. However, the method has a number of disadvantages, namely the long and low-tech process of preparing the emulsion, because emulsification takes place in 3 containers, at alternating pressure, due to an increase in pressure in the homogenizer by 1.1-1.2 times when the emulsion passes through an additional container compared to the pressure when the emulsion passes through the main circuits. The emulsion prepared using this method contains coarse particles with a diameter greater than 0.2 to 0.4 microns, which can increase the number of adverse reactions, as well as its instability during storage.

Thus, the development of a more technologically advanced, economical process for producing a stable perfluorocarbon emulsion is an objective necessity.

The technical problem, the solution of which is provided by the implementation or use of the proposed technical solution, and which could not be solved by the implementation or use of analogues, is the need to expand the arsenal of stable pharmaceutical compositions of blood substitutes based on PFOS in the dosage form of an emulsion and to develop a method for their preparation that excludes disadvantages of analogues.

Disclosure of the Invention

The development of drugs in the form of emulsions and methods for their preparation is a rather complex technological task, since emulsions are thermodynamically unstable systems.

The technical problem was solved by the development of a stable emulsion of perfluoroorganic compounds and polyelectrolytes and a method for its preparation.

The proposed pharmaceutical emulsion of PFOS is obtained under aseptic conditions, by high-speed dispersion followed by homogenization of two phases that have previously undergone sterilizing filtration - the phase of a liquid mixture of perfluoroorganic compounds (PFOS) with a density of 1.872 to 1.945 g/ml, with a ratio of rapidly excreted PFOS (C ₈ - C ₁₀ ) to slowly released PFOS (C ₁₁ -C ₁₂ ) from 1:1 to 1:4, and the aqueous phase - a solution of one or more emulsifiers in total - no more than 270 g/l, with the addition of one or more polyelectrolytes in total - not more than 3 g/l. Homogenization of the resulting dispersion is carried out by passing through a high-pressure homogenizer with one homogenization chamber at a pressure of up to 120 MPa, passing the perfluorocarbon emulsion sequentially through the homogenizer into a buffer storage tank, then returning the emulsion to the original reactor with a high-speed dispersant and repeating the original sequence of operations from 4 to 15 times , monitoring after each cycle the particle size distribution by laser diffraction to obtain perfluorocarbon emulsion particles of nanosized diameter in the range of 30-150 nm. The resulting emulsion is diluted with an aqueous solution with or without the addition of an anti-macroion, as well as with or without the addition of electrolytes and/or osmolality regulators and/or amino acids and taurine and, if necessary, pH regulators to values from 5.0 to 8.0.

In this case, one or more quickly excreted PFOS (C ₈ -C ₁₀ ) is selected from the following list, but does not thereby limit your choice: perfluorodecalin (PFD, CAS No. 306-94-5) C ₁₀ F ₁₈ or perfluorotripropylamine (PFTPA , CAS No. 338-83-0) C ₉ F ₂₁ N, or perfluorooctyl bromide (PFOB, CAS No. 423-55-2) C ₈ F ₁₇ Br, and one or more slowly excreted PPS (C ₁₁ -C ₁₂ ), choose from the following list, but do not limit your choice thereby: perfluoro-N-(4-methylcyclohexyl) piperidine (PFMCP, CAS No. 86630-50-4) C ₁₂ F ₂₃ N or perfluorotributylamine (PFTBA, CAS No. 311-89- 7) C ₁₂ F ₂₇ N.

An emulsifier, one or more, is selected from the following list, but does not limit your choice: phospholipids of natural raw materials (egg yolk, soy lecithin, phosphatidylcholine, etc.), poloxamers, sucrose esters with fatty acids, glycerol esters with fatty acids, soybean purified bean oil, medium chain triglycerides, purified olive oil, purified fish oil, glycerol (anhydrous), omega 3 fatty acids, omega 6 fatty acids, omega 9 fatty acids, alpha tocopherol, ascorbyl palmitate, potassium salts and sodium fatty acids (palmitate, oleayuta, etc.).

The polyelectrolyte and anti-macroion, one or more, are selected from the following list, but do not thereby limit their choice: polyanions (hyaluronic acid and its salts, sodium hyaluronate, chondroitin sulfate and its salts, sodium chondroitin sulfate, alginic acid and its salts, sodium alginate , α-poly-L-glutamic acid and its salts, α-poly-L-monosodium glutamate, α-poly-L-aspartic acid and its salts, α-poly-L-aspartate sodium and so on) or polycations (chitosan and its salts, chitosan hydrochloride, α-poly-L-lysine and its salts, α-poly-L-lysine hydrobromide, α-poly-L-lysine hydrochloride, α-poly-L-ornithine and its salts, α-poly -L-ornithine hydrobromide, α-poly-L-ornithine hydrochloride, α-poly-L-histidine and its salts, α-poly-L-histidine hydrochloride, α-poly-L-arginine and its salts, α-poly- L-arginine hydrochloride, etc.).

The proposed method for producing PFOS emulsion differs from previously described analogues in that the nanoemulsion can be obtained much easier using a simpler technological scheme without the use of complex and expensive engineering equipment (additional homogenizers or additional homogenization chambers), one homogenizer with one homogenization chamber is sufficient, and faster by reducing the number of homogenization cycles required.

The authors of the proposed technical solution hypothesized that an adsorption layer of dissociated polyelectrolyte is formed on the surface of the emulsion particles of perfluoroorganic compounds, which induces a diffuse layer of counterions in the solvent environment. The appearance of these layers facilitates the emulsification process, since it eliminates the reverse aggregation of the resulting fine particles due to electrostatic repulsion.

As can be seen from the data in Table 3, the technical result (reduction of homogenization cycles) from the introduction of a polyelectrolyte is manifested the more strongly, the lower the dissociation index of ionic groups (pKa) of the selected polyelectrolyte, that is, the easier the ionic group dissociates and the lower the average molar mass of the ionized monomer unit (Mm, g/mol) of polyelectrolyte, which indicates a direct proportional dependence of the severity of the observed effect on the charge density formed on the surface of the emulsion particles.

Also, the authors of this technical solution obtained an unexpected result, namely, it was established that the technical result (reduction of homogenization cycles) can be achieved by introducing lower total concentrations of polymer compounds, if they are used not independently, but in polyelectrolyte-anti-macroion pairs. To do this, before the final homogenization cycle, the emulsion is diluted with a solution containing an anti-macroion. As can be seen from the data in Table 2, the technical result is achieved by introducing polymer concentrations into the composition that are 2.5 times lower than when using one of the polyelectrolytes.

Also, the authors of this technical solution found that the technical result (reduction of homogenization cycles) is observed only when polyelectrolytes or polyelectrolyte-anti-macroion pairs are introduced into the emulsion in concentrations from 0.01 to 1.0 g/l, which is associated with the final adsorption capacity of the emulsion particles .

In addition, the composition of a perfluorocarbon emulsion for infusion for medical purposes is proposed, including the perfluoroorganic compounds perfluorodecalin and perfluoro-N-(4-methylcyclohexyl) piperidine, an emulsifier, amino acids, polyelectrolytes, electrolytes and pH regulators in the following ratio of components, mg per 1 ml of solution:

Perfluorodecalin 104-156 (5.6-8.4 vol.%);

Perfluoro-N-(4-methylcyclohexyl) piperidine 52-78 (2.8-4.2 vol.%);

One or more emulsifiers in total - 32-270;

One or more polyelectrolytes in total - 0.01-3.0;

One or more amino acids, in total in terms of dry matter - 0-2.5;

One or more electrolytes, in total in terms of dry matter - 0.01-9.0;

one or more pH regulators - q.s. up to pH 5.0-8.0;

Water for injection - q.s. up to 1 ml.

The claimed set of components is optimal, found experimentally and ensures the stability of the drug for at least 3 years. Thanks to the stated ratio of components, the pharmaceutical composition maintains the physicochemical stability and microbiological stability of the drug.

To confirm the stability of the emulsion for infusion based on perfluoroorganic compounds, pilot industrial series were studied according to physicochemical and microbiological indicators that characterize the quality of liquid dosage forms for parenteral use under long-term storage conditions for 36 months, namely according to the indicators:

• Description

• Authenticity

• pH

• Oxygen capacity

• Particle size

• Related impurities

• Extractable volume

• Sterility

• Abnormal toxicity

• Bacterial endotoxins

• Quantitative determination of active substances

As can be seen from FIG. 2-5 and Table 1, all quality indicators are within the specification standards established for the prototype, and low variability in the results of the analysis of the three series is also observed. It can be concluded that the developed emulsion for infusion based on perfluoroorganic compounds is stable when stored for at least 36 months.

Brief description of drawings and other graphic materials

In FIG. Figure 1 shows a schematic representation of the hardware circuit for producing an emulsion.

The diagram shows: reactor (R1), reactor (R2), mixing tank (R3) with a high-speed dispersant and high-pressure homogenizer (HPH), storage tank (R4).

In FIG. Figure 2 shows the time dependence of the quantitative content of perfluorodecalin in the emulsion for infusion.

In FIG. Figure 3 shows the time dependence of the quantitative content of perfluoro-N-(4-methylcyclohexyl)piperidine in the emulsion for infusion.

In FIG. Figure 4 shows the dependence of the content of related impurities over time in the emulsion for infusion.

In FIG. Figure 5 shows the dependence of the emulsion particle size on storage time.

Carrying out the invention

The following are examples of the implementation of the proposed technical solution, which illustrate it, but do not cover all possible options for its implementation. It is clear to a person skilled in the art that other particular embodiments of the invention are possible, including other emulsions for infusion of perfluoroorganic compounds in accordance with the proposed technical solution, not described in these examples.

Perfluorodecalin (CAS No. 306-94-5, colorless transparent liquid with a density of about 1.945 g/ml, which is a mixture of a cis isomer (CAS No. 60433-11-6) and a trans isomer (CAS No. 60433-12-7)) . Perfluorodecalin is a colorless liquid, insoluble in water, alcohol, non-polar and polar solvents, dissolves gases well, is chemically inert, stable up to 400°C.

Perfluoro-N-(4-methylcyclohexyl)piperidine (perfluoromethylcyclohexylpiperidine, CAS No. 86630-50-4, colorless transparent liquid with a density of about 1.872 g/ml).

As C ₈ -C ₁₀ - perfluoroorganic compounds, in addition to perfluorodecalin (PFD, CAS No. 306-94-5) C ₁₀ F ₁₈ , perfluorotripropylamine (PTPA, CAS No. 338-83-0) C ₉ F ₂₁ N, perfluorooctyl bromide (PFOB , CAS No. 423-55-2) C ₈ F ₁₇ Br.

In addition to perfluoro->C4-methylcyclohexyl) piperidine (PFMCP, CAS No. 86630-50-4) C2F23N, perfluorotributylamine (PFTBA, CAS No. 311-89-7) C, ₂ F ₂ is used as C ₁₁ -C ₁₂ - perfluoroorganic compounds 7N.

Polyelectrolytes are polymers whose monomer units are capable of electrolytic dissociation. In this case, macroions (polyanions or polycations) and low molecular weight counterions (cations or anions) are formed in the solution. The following agents can be used as polyelectrolytes.

1. Hyaluronic acid and its salts (Polyanion, CAS No. 9067-32-7 is included in the monograph of the European Pharmacopoeia under the name “Sodium Hyaluronate” and is not in the American Pharmacopoeia and is described as a natural non-sulfated glycosaminoglycan, which is obtained from the combs of cockerels or by fermentation from Streptococci, Lancefield groups A and C, is a linear polysaccharide consisting of alternating disaccharides, which include D-N-acetylglucosamine and D-glucuronic acid, connected by β-1,4- and β-1,3-glycosidic bonds, in appearance it is white or almost white, very hygroscopic powder or fibrous aggregate, slightly soluble or soluble in water, practically insoluble in acetone and anhydrous ethanol, losing on drying no more than 20% of its mass and containing no less than 95.0% and no more than 105.0% anhydrous substance), structural formula of the ionic form of the monomer unit:

In the human body, hyaluronic acid is part of connective, epithelial and nervous tissues. It is one of the main components of the extracellular matrix and is found in many biological fluids (saliva, synovial fluid, etc.). Plays an important role in cell proliferation and migration.

2. Chondroitin sulfate and its salts (Polyanion, CAS No. 9082-07-9 included in the monographs of the European and American Pharmacopoeias under the name “Chondroitin Sulfate Sodium”, is described as a natural sulfated linear glycosaminoglycan, which is obtained from cartilage of both terrestrial and marine origin , is a biopolymer consisting of dimers of L-iduronic acid and sulfated N-acetylgalactosamine, externally it is a white or almost white hygroscopic powder, easily soluble in water, practically insoluble in acetone and ethanol (96%), losing no more than 12% of its mass and containing no less than 90.0% and no more than 105.0% anhydrous substance), structural formula of the ionic form of the monomer unit:

In the human body, chondroitin sulfate provides elasticity to cartilage tissue, as well as its shock-absorbing properties due to fluid retention. A deficiency of this component can cause the development of osteoarthritis.

3. Alginic acid and its salts (Polyanion, CAS No. 9005-38-3 included in the monographs of the European and American Pharmacopoeias under the name "Sodium Alginate", described as a natural polysaccharide, which is obtained mainly from algae belonging to the family Phaeophyceae, is block copolymer consisting of fragments of β-D-mannuronic acid homopolysaccharide and α-L-guluronic acid homopolysaccharide, externally it is a white or pale yellowish-brown powder, slowly soluble in water, forming a viscous colloidal solution, practically insoluble in ethanol (96% ), losing no more than 15% of its mass upon drying and containing no less than 90.8% and no more than 106.0% anhydrous substance), structural formula of the ionic form of the monomer unit:

Alginic acid removes heavy metal ions from the human body and improves the functioning of the cardiovascular system.

4. α-Poly-L-glutamic acid and its salts (The polyanion is not described in pharmacopoeias, it is available for purchase in the forms “Poly-L-glutamic acid sodium salt, CAS No. 26247-79-0” and “Poly(L-glutamic acid), CAS No. 25513-46-6" from Sigma-Aldrich and Alamanda Polymers, is described as a synthetic homopolymer of the amino acid L-glutamic acid, a white to almost white or light yellow powder, which at a concentration of 50 mg/ml forms transparent in water solution), structural formula of the ionic form of the monomer unit:

In the human body, poly-L-glutamic acid is metabolized to glutamic acid, which is a neurotransmitter amino acid, present in the proteins of the gray and white matter of the brain, and in free form making up 1/3 of all amino acids in the blood serum.

5. α-Poly-L-aspartic acid and its salts (The polyanion is not described in pharmacopoeias, it is available for purchase in the forms “Poly(l-aspartic acid sodium salt), CAS No. 34345-47-6” and “Poly(1- aspartic acid), CAS No. 25608-40-6" by Alamanda Polymers is described as a synthetic homopolymer of the amino acid L-aspartic acid, a white to pale yellow solid, soluble in water, at a concentration of 50 mg/ml forms a clear solution in water ), structural formula of the ionic form of the monomer unit:

In the human body, poly-L-aspartic acid is metabolized to aspartic acid, which is responsible for transmitting nerve impulses through neurons and stimulating the production of hormones.

6. Chitosan and its salts (Polycation, CAS No. 9012-76-4 included in the monograph of the European Pharmacopoeia entitled "Chitosan Hydrochloride)) in the monograph of the American Pharmacopoeia entitled "Chitosan" is described as a natural unbranched binary polysaccharide or its chloride, which is obtained from shrimp and crab shells, consists of randomly distributed β-(1→4)-linked D-glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit), externally it is a white or almost white fine powder, moderately soluble in water, practically insoluble in anhydrous ethanol, losing no more than 10% of its mass when dried and containing at least 90.0% anhydrous substance), structural formula of the ionic form of the monomer unit:

In the human body, chitosan is able to bind to fat molecules to a certain extent. Fat associated with chitosan is not digested and is excreted from the body. Chitosan is used as a means of promoting weight loss and also to improve cholesterol metabolism.

7. α-Poly-L-lysine and its salts (The polycation is not described in pharmacopoeias, it is available for purchase in the forms: “α-Poly-L-lysine hydrobromide, CAS No. 25988-63-0”, “α-Poly-L -lysine hydrochloride, CAS No. 26124-78-7" by Sigma-Aldrich is described as a synthetic homopolymer of the amino acid L-lysine, a white to light yellow powder, soluble in water, a solution of which in water (50 mg/ml) has the form from colorless, transparent to pale yellow, slightly cloudy), structural formula of the ionic form of the monomer unit:

In the human body, α-Poly-L-lysine is metabolized to L-lysine, an essential (essential) amino acid that is part of almost all proteins, is necessary for the formation of bones and the growth of children, promotes the absorption of calcium, supports nitrogen metabolism, and is involved in the synthesis of antibodies. hormones and enzymes involved in the formation of collagen and tissue repair, increases muscle strength and endurance, helps increase muscle volume (anabolic), improves short-term memory, prevents the development of atherosclerosis, thickens the hair structure, prevents the development of osteoporosis.

8. α-Poly-L-ornithine and its salts (Polycation, not described in pharmacopoeias, available for purchase in the forms “Poly-L-ornithine hydrobromide, CAS No. 27378-49-0” and “Poly-L-ornithine hydrochloride, CAS No. 26982-21-8", described by Sigma-Aldrich as a synthetic homopolymer of the amino acid L-ornithine, a white to almost white powder, soluble in water, a solution of which in water (50 mg/ml) has a transparent appearance), structural formula of the ionic form of the monomer unit:

In the human body, α-Poly-L-ornithine is metabolized to L-ornithine - a non-proteinogenic amino acid, non-essential, not part of proteins, plays an important role in the biosynthesis of urea (ornithine is an important intermediate product in the synthesis of arginine). When taken orally, it stimulates the reaction of urea formation from ammonia in the ornithine urea cycle.

9. α-Poly-L-histidine and its salts (The polycation is not described in pharmacopoeias, it is available for purchase in the forms “Poly-L-histidine, CAS No. 26062-48-6” and “Poly-L-histidine hydrochloride, CAS No. 61857-39-4" by Sigma-Aldrich is described as a synthetic homopolymer of the amino acid L-histidine, a white to light yellow powder or solid, soluble in water (45.6 mg/ml)), structural formula of the ionic form of the monomer links:

In the human body, α-Poly-L-histidine is metabolized to L-histidine, a conditionally essential amino acid; a lack of conditionally essential amino acids causes metabolic disorders, growth arrest, weight loss, and decreased immunity. In the human body, histidine is part of the active centers of many enzymes, promotes tissue growth and repair, is important for joint health, is found in hemoglobin; a lack of histidine can cause hearing loss.

10. α-Poly-L-arginine and its salts (Polycation is not described in pharmacopoeias, is available for purchase in the form of “Poly-L-arginine hydrochloride, CAS No. 26982-20-7” from Sigma-Aldrich and Alamanda Polymers described as synthetic L-arginine amino acid homopolymer, white to almost white powder or solid, soluble in water, forming a clear solution in water at a concentration of 50 mg/ml), structural formula of the ionic form of the monomer unit:

In the human body, α-Poly-L-arginine is metabolized to L-arginine, a conditionally essential amino acid; a lack of conditionally essential amino acids causes metabolic disorders, growth arrest, weight loss, and decreased immunity. In the human body, arginine slows down the growth of tumors, including cancer, by stimulating the body's immune system; promotes liver detoxification; Contained in seminal fluid, helps increase potency; found in connective tissue and skin; participates in metabolism in muscle tissue; dilates blood vessels and increases their blood supply, lowers blood pressure, helps lower cholesterol levels in the blood, and prevents the formation of blood clots; stimulates the synthesis of growth hormone and accelerates growth in children and adolescents; increases the mass of muscle tissue and reduces the mass of adipose tissue, helps to normalize the condition of connective tissue.

Example 1. Method for obtaining 8.4-12.6 vol. % PPS emulsion. The technological process is carried out under aseptic conditions, using equipment schematically shown in Fig. 1

Two phases are pre-prepared and subjected to sterilizing filtration.

Phase 1 - Perfluorocarbon mixture, consisting of a slowly released PFMCP and a quickly released PPD in an amount of 156-234 g/l (or 81-122 ml of PFOS in 1 l, since the density of the PFC mixture is 1.90-1.94 g/l ml), containing samples of (liquid) 104-156 g/l PPD and 52-78 g/l PFMCP, are subjected to preliminary sterilizing filtration under a pressure of about three bar in a three-stage installation consisting of three filters: a coarse filter (1.5- 2.5 microns), fine filter (0.45-0.6 microns) and sterilizing filter (0.22 microns).

Phase 2 - 400 ml of an aqueous solution of the emulsifier - containing 32-270 grams of poloxamer 188, is subjected to preliminary sterilizing filtration under a pressure of about three bar in a three-stage installation consisting of three filters: a coarse filter (1.5-2.5 microns), a filter fine cleaning (0.45-0.6 microns) and sterilizing filter (0.22 microns).

To obtain a pre-emulsion (micron-sized), phase 2 from the reactor (R2) through a three-stage sterilizing filtration unit is fed into the mixing tank (R3), a high-speed dispersant and a high-pressure homogenizer (HPH) are turned on, immediately after that it is jetted from the reactor (R1) through a three-stage sterilizing unit filtration is fed into the mixing tank (R3) phase 1.

From the mixing tank (R3) through a high pressure homogenizer (HPH), the emulsion of phase 1 in phase 2 is pumped into a storage tank (R4) from which a sample is taken to determine the particle size distribution using laser diffraction, if the particle distribution is not in the range of 450 to 2200 nm, the emulsion is recycled to the mixing tank (R3) for the next homogenization cycle. Recirculation and homogenization of the phase 1 emulsion in phase 2 is repeated until the particle distribution, determined by laser diffraction from a sample taken from the storage tank (R4), is in the range of 450 to 2200 nm.

The finished perfluorocarbon nanoemulsion is recycled one last time to the mixing tank (R3) for dilution with phase 3.

Phase 3 is pre-prepared and subjected to sterilizing filtration.

Phase 3 - 519-478 ml of an aqueous solution of electrolytes and/or osmolality regulators and/or amino acids and taurine and, if necessary, pH regulators, is prepared in a reactor (R2), previously emptied and washed from the previously prepared phase 2; after preparation, phase 3 is subjected to sterilizing filtration under a pressure of about three bar on a three-stage installation consisting of three filters: a coarse filter (1.5-2.5 microns), a fine filter (0.45-0.6 microns) and a sterilizing filter (0.22 microns) .

To dilute the nanoemulsion, phase 3 from the reactor (R2) is fed through a three-stage sterilizing filtration unit into the mixing tank (R3), a high-speed dispersant and a high-pressure homogenizer (HPH) are turned on, and immediately after this the finished nanoemulsion is recycled from the storage tank (R4) mixing tank (R3 ).

From the mixing tank (R3) through a high-pressure homogenizer (HPH), the diluted nanoemulsion is pumped into a storage tank (R4), from which a sample is taken to determine the particle size distribution using laser diffraction, if the particle distribution is not in the range from 30 to 150 nm , the emulsion is recycled to the mixing tank (R3) for the next homogenization cycle. Recirculation and homogenization of the phase 1 emulsion in phase 2 is repeated until the particle distribution, determined by laser diffraction from a sample taken from the storage tank (R4), is in the range of 30 to 150 nm.

The finished prototype is fed from the storage tank (R4) through a sterilizing filter (0.22 microns) to the filling line into primary packaging.

The final prototype recipe obtained by the proposed method had the following composition: perfluorocarbons 8.4-12.6 vol. %, of which: rapidly excreted PPD - 104-156 g/l, slowly excreted PFMCP - 52-78 g/l, emulsifier - poloxamer 188 - 32-270 g/l, amino acids (leucine, isoleucine, tryptophan, phenylalanine, valine , threonine, histidine), total in terms of dry matter 0.01 - 2.5 g/l, electrolytes (sodium chloride, potassium chloride, magnesium chloride, sodium dihydrogen phosphate), total in terms of dry matter 0.01-9, 0 g/l, pH regulator - sodium bicarbonate q.s. to pH 5.0-8.0, water for injection q.s. up to 1 l. The emulsion obtained by the proposed method can be used as a gas transport blood substitute to compensate for blood loss. To obtain an emulsion with a particle size in the range from 30 to 150 nm using the proposed method, 15 cycles of recirculation and homogenization were required.

Example 2. Method for obtaining 8.4-12.6 vol. % emulsion of PPS with polyelectrolyte.

The method for preparing the PFOS emulsion is carried out similarly to example 1, but phase 2 additionally contains a polyelectrolyte (sodium hyaluronate or α-poly-L-histidine or α-poly-L-histidine hydrochloride or α-poly-L-arginine hydrochloride) in a concentration of 0. 01 to 3.0 g/l.

The final prototype recipe obtained by the proposed method had the following composition: perfluorocarbons 8.4-12.6 vol. %, of which: rapidly excreted PPD - 104-156 g/l, slowly excreted PFMCP - 52-78 g/l, emulsifier - poloxamer 188 - 32-270 g/l, polyelectrolyte (sodium hyaluronate or α-poly-L- histidine or α-poly-L-histidine hydrochloride or α-poly-L-arginine hydrochloride) in a concentration of 0.01 to 3.0 g/l, amino acids (leucine, isoleucine, tryptophan, phenialanine, valine, threonine, histidine) , total in terms of dry matter 0.01-2.5 g/l, electrolytes (sodium chloride, potassium chloride, magnesium chloride, sodium dihydrogen phosphate), total in terms of dry matter 0.01 - 9.0 g/l, pH regulator - sodium bicarbonate q.s. to pH 5.0-8.0, water for injection q.s. up to 1 l.

To obtain an emulsion using the proposed method, the particle size of which is in the range from 30 to 150 nm at a polyelectrolyte concentration of 0.01 g/l, 15 cycles of recycling and homogenization were required, at a polyelectrolyte concentration of 0.40 g/l, 13 cycles of recycling and homogenization were required, at a polyelectrolyte concentration of 1.00 g/L, 10 cycles of recirculation and homogenization were required; at a polyelectrolyte concentration of 3.00 g/L, 10 cycles of recirculation and homogenization were required. Consequently, the optimal polyelectrolyte concentration has been established to be 1.00 g/l to obtain an emulsion using the proposed method. The established optimal concentrations of polyelectrolytes and their effect on reducing the number of homogenization cycles are summarized in Table 1.

Example 3. Method for obtaining 8.4-12.6 vol. % PFOS emulsion with polyelectrolyte.

The method according to example 1, characterized in that phase 2 additionally contains an electrolyte (α-poly-L-lysine hydrobromide or α-poly-L-lysine hydrochloride or α-poly-L-ornithine hydrobromide or α-poly-L-ornithine hydrochloride ) in concentrations from 0.01 to 3.0 g/l.

The final prototype recipe obtained by the proposed method had the following composition: perfluorocarbons 8.4-12.6 vol. %, of which: rapidly excreted PPD - 104-156 g/l, slowly excreted PFMCP - 52-78 g/l, emulsifier - poloxamer 188 - 32-270 g/l, polyelectrolyte - (α-poly-L-lysine hydrobromide or α-poly-L-lysine hydrochloride or α-poly-L-ornithine hydrobromide or α-poly-L-ornithine hydrochloride) in a concentration of 0.01 to 3.0 g/l, amino acids (leucine, isoleucine, tryptophan, phenialanine, valine, threonine, histidine), total in terms of dry matter 0.01-2.5 g/l, electrolytes (sodium chloride, potassium chloride, magnesium chloride, sodium dihydrogen phosphate), total in terms of dry matter 0.01 -9.0 g/l, pH regulator - sodium bicarbonate q.s. to pH 5.0-.0, water for injection q.s. up to 1 l.

To obtain an emulsion by the proposed method, the particle size of which is in the range from 30 to 150 nm at a polyelectrolyte concentration of 0.01 g/l, 14 cycles of recirculation and homogenization were required, at a polyelectrolyte concentration of 0.40 g/l, 12 cycles of recirculation and homogenization were required, at a polyelectrolyte concentration of 1.00 g/L, 8 cycles of recirculation and homogenization were required; at a polyelectrolyte concentration of 3.00 g/L, 8 cycles of recirculation and homogenization were required. Consequently, the optimal polyelectrolyte concentration has been established to be 1.00 g/l to obtain an emulsion using the proposed method. The established optimal concentrations of polyelectrolytes and their effect on reducing the number of homogenization cycles are summarized in Table 1.

Example 4. Method for obtaining 8.4-12.6 vol. % PFOS emulsion with polyelectrolyte.

The method is carried out as in example 1, characterized in that phase 2 additionally contains a polyelectrolyte (sodium chondroitin sulfate or chitosan or chitosan hydrochloride) in a concentration of 0.01 to 3.0 g/l.

The final prototype recipe obtained by the proposed method had the following composition: perfluorocarbons 8.4-12.6 vol. %, of which: rapidly excreted PPD - 104-156 g/l, slowly excreted PFMCP - 52-78 g/l, emulsifier - poloxamer 188 - 32-270 g/l, polyelectrolyte - (chondroitin sulfate sodium or chitosan or chitosan hydrochloride ) in a concentration of 0.01 to 3.0 g/l, amino acids (leucine, isoleucine, tryptophan, phenyalanine, valine, threonine, histidine), total in terms of dry matter 0.01-2.5 g/l, electrolytes (sodium chloride, potassium chloride, magnesium chloride, sodium dihydrogen phosphate), total in terms of dry matter 0.01-9.0 g/l, pH regulator - sodium bicarbonate q.s. to pH 5.0-8.0, water for injection q.s. up to 1 l.

To obtain an emulsion by the proposed method, the particle size of which is in the range from 30 to 150 nm at a polyelectrolyte concentration of 0.01 g/l, 14 cycles of recirculation and homogenization were required, at a polyelectrolyte concentration of 0.40 g/l, 12 cycles of recirculation and homogenization were required, at a polyelectrolyte concentration of 1.00 g/L, 7 cycles of recirculation and homogenization were required; at a polyelectrolyte concentration of 3.00 g/L, 7 cycles of recirculation and homogenization were required. Consequently, the optimal polyelectrolyte concentration has been established to be 1.00 g/l to obtain an emulsion using the proposed method. The established optimal concentrations of polyelectrolytes and their effect on reducing the number of homogenization cycles are summarized in Table 1.

Example 5. Method for obtaining 8.4-12.6 vol. % PFOS emulsion with polyelectrolyte.

The method is carried out as in example 1, characterized in that phase 2 additionally contains a polyelectrolyte - sodium alginate, in a concentration of 0.01 to 3.0 g/l.

The final prototype recipe obtained by the proposed method had the following composition: perfluorocarbons 8.4-12.6 vol. %, of which: rapidly excreted PPD - 104-156 g/l, slowly excreted PFMCP - 52-78 g/l, emulsifier - poloxamer 188 - 32-270 g/l, polyelectrolyte - sodium alginate, in a concentration of 0.01 up to 3.0 g/l, amino acids (leucine, isoleucine, tryptophan, phenialanine, valine, threonine, histidine), total in terms of dry matter 0.01-2.5 g/l, electrolytes (sodium chloride, potassium chloride, magnesium chloride, sodium dihydrogen phosphate), total in terms of dry matter 0.01-9.0 g/l, pH regulator - sodium bicarbonate q.s. to pH 5.0 - 8.0, water for injection q.s. up to 1 l.

To obtain an emulsion using the proposed method, the particle size of which is in the range from 30 to 150 nm at a polyelectrolyte concentration of 0.01 g/l, 14 cycles of recirculation and homogenization were required, at a polyelectrolyte concentration of 0.40 g/l, 11 cycles of recirculation and homogenization were required, at a polyelectrolyte concentration of 1.00 g/L, 6 cycles of recirculation and homogenization were required; at a polyelectrolyte concentration of 3.00 g/L, 6 cycles of recirculation and homogenization were required. Consequently, the optimal polyelectrolyte concentration has been established to be 1.00 g/l to obtain an emulsion using the proposed method. The established optimal concentrations of polyelectrolytes and their effect on reducing the number of homogenization cycles are summarized in Table 1.

Example 6. Method for obtaining 8.4-12.6 vol. % PFOS emulsion with polyelectrolyte.

The method according to example 1, characterized in that phase 2 additionally contains a polyelectrolyte (α-poly-L-glutamic acid or α-poly-L-sodium glutamate), in a concentration of 0.01 to 3.0 g/l.

The final prototype recipe obtained by the proposed method had the following composition: perfluorocarbons 8.4-12.6 vol. %, of which: rapidly excreted PPD - 104-156 g/l, slowly excreted PFMCP - 52-78 g/l, emulsifier - poloxamer 188 - 32-270 g/l, polyelectrolyte - (α-poly-L-glutamic acid or α-poly-L-sodium glutamate), at a concentration of 0.01 to 3.0 g/l, amino acids (leucine, isoleucine, tryptophan, phenialanine, valine, threonine, histidine), total calculated on dry matter 0, 01-2.5 g/l, electrolytes (sodium chloride, potassium chloride, magnesium chloride, sodium dihydrogen phosphate), total in terms of dry matter 0.01-9.0 g/l, pH regulator - sodium bicarbonate q.s. to pH 5.0-8.0, water for injection q.s. up to 1 l.

To obtain an emulsion using the proposed method, the particle size of which is in the range from 30 to 150 nm at a polyelectrolyte concentration of 0.01 g/l, 14 cycles of recirculation and homogenization were required, at a polyelectrolyte concentration of 0.40 g/l, 11 cycles of recirculation and homogenization were required, at a polyelectrolyte concentration of 1.00 g/L, 5 cycles of recirculation and homogenization were required; at a polyelectrolyte concentration of 3.00 g/L, 5 cycles of recirculation and homogenization were required. Consequently, the optimal polyelectrolyte concentration has been established to be 1.00 g/l to obtain an emulsion using the proposed method. The established optimal concentrations of polyelectrolytes and their effect on reducing the number of homogenization cycles are summarized in Table 2.

Example 7. Method for obtaining 8.4-12.6 vol. % PFOS emulsion with polyelectrolyte.

The method according to example 1, characterized in that phase 2 additionally contains a polyelectrolyte (α-poly-L-aspartic acid or α-poly-L-aspartate sodium), in a concentration of 0.01 to 3.0 g/l.

The final prototype recipe obtained by the proposed method had the following composition: perfluorocarbons 8.4-12.6 vol. %, of which: rapidly excreted PPD - 104-156 g/l, slowly excreted PFMCP - 52-78 g/l, emulsifier - poloxamer 188 - 32-270 g/l, polyelectrolyte - (α-poly-L-aspartic acid or sodium α-poly-L-aspartate), at a concentration of 0.01 to 3.0 g/l, amino acids (leucine, isoleucine, tryptophan, phenialanine, valine, threonine, histidine), total calculated on dry matter 0, 01-2.5 g/l, electrolytes (sodium chloride, potassium chloride, magnesium chloride, sodium dihydrogen phosphate), total in terms of dry matter 0.01-9.0 g/l, pH regulator - sodium bicarbonate q.s. to pH 5.0-8.0, water for injection q.s. up to 1 l.

To obtain an emulsion using the proposed method, the particle size of which is in the range from 30 to 150 nm at a polyelectrolyte concentration of 0.01 g/l, 14 cycles of recirculation and homogenization were required, at a polyelectrolyte concentration of 0.40 g/l, 11 cycles of recirculation and homogenization were required, at a polyelectrolyte concentration of 1.00 g/L, 4 cycles of recirculation and homogenization were required; at a polyelectrolyte concentration of 3.00 g/L, 4 cycles of recirculation and homogenization were required. Consequently, the optimal polyelectrolyte concentration has been established to be 1.00 g/l to obtain an emulsion using the proposed method. The established optimal concentrations of polyelectrolytes and their effect on reducing the number of homogenization cycles are summarized in Table 2.

Example 8. Method for obtaining 8.4-12.6 vol. % PFOS emulsion with a polyelectrolyte - anti-macroion pair.

The method according to example 1, characterized in that phase 3 does not contain amino acids, and in phase 3 the pH regulator (sodium bicarbonate) is replaced by a pair of pH regulators (malic acid or sodium hydroxide), in phase 3 an osmolality regulator (glucose) is additionally introduced in concentration 0.01-50 g/l and an antimacroion (chitosan or chitosan hydrochloride), and also a polyelectrolyte (sodium hyaluronate) was additionally introduced into phase 2, while the total concentration of the polyelectrolyte-antimacroion pair is in the range from 0.01 to 3.0 g /l.

The final prototype recipe obtained by the proposed method had the following composition: perfluorocarbons 8.4-12.6 vol. %, of which: rapidly excreted PPD - 104-156 g/l, slowly excreted PFMCP - 52-78 g/l, emulsifier - poloxamer 188 - 32-270 g/l, pair polyelectrolyte (sodium hyaluronate) - anti-macroion (chitosan or chitosan hydrochloride), total in terms of dry matter 0.01-3.0 g/l, osmolality regulators - glucose - 0.01-50 g/l, electrolytes (sodium chloride, potassium chloride, magnesium chloride, sodium dihydrogen phosphate), total in terms of dry matter 0.01-9.0 g/l, pH regulator - (malic acid or sodium hydroxide) q.s. to pH 5.0-8.0, water for injection q.s. up to 1 l.

To obtain an emulsion using the proposed method, the particle size of which is in the range from 30 to 150 nm with a total concentration of the polyelectrolyte-anti-matroion pair equal to 0.01 g/l, 13 cycles of recirculation and homogenization were required, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 0.40 g/l l required 8 cycles of recirculation and homogenization, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 1.00 g/l, 8 cycles of recirculation and homogenization were required, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 3.00 g/l, 8 cycles of recirculation and homogenization were required. Consequently, the optimal total concentration of the polyelectrolyte-anti-matroion pair has been established to be -0.40 g/l for producing an emulsion using the proposed method. The established optimal total concentrations of polyelectrolyte-counter-ion pairs and their effect on reducing the number of homogenization cycles are summarized in Table 3.

Example 9. Method for obtaining 8.4-12.6 vol. % PFOS emulsion with a polyelectrolyte - anti-macroion pair.

The method according to example 8, characterized in that in phase 2 the polyelectrolyte (sodium hyaluronate) is replaced with a polyelectrolyte (chitosan or chitosan hydrochloride), and in phase 3 the anti-matroion (chitosan or chitosan hydrochloride) is replaced with the anti-matroion (sodium hyaluronate), while the total concentration of the pair polyelectrolyte-anti-matroion is in the range from 0.01 to 3.0 g/L.

The final prototype recipe obtained by the proposed method had the following composition: perfluorocarbons 8.4-12.6 vol. %, of which: rapidly excreted PPD - 104-156 g/l, slowly excreted PFMCP - 52-78 g/l, emulsifier - poloxamer 188 - 32-270 g/l, polyelectrolyte pair (chitosan or chitosan hydrochloride) - anti-macroion ( sodium hyaluronate), total in terms of dry matter 0.01-3.0 g/l, osmolality regulators - glucose - 0.01-50 g/l, electrolytes (sodium chloride, potassium chloride, magnesium chloride, sodium dihydrogen phosphate), total in terms of dry matter 0.01-9.0 g/l, pH regulator - (malic acid or sodium hydroxide) q.s. to pH 5.0-.0, water for injection q.s. up to 1 l.

To obtain an emulsion using the proposed method, the particle size of which is in the range from 30 to 150 nm with a total concentration of the polyelectrolyte-anti-matroion pair equal to 0.01 g/l, 13 cycles of recirculation and homogenization were required, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 0.40 g/l l required 8 cycles of recirculation and homogenization, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 1.00 g/l, 8 cycles of recirculation and homogenization were required, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 3.00 g/l, 8 cycles of recirculation and homogenization were required. Consequently, the optimal total concentration of the polyelectrolyte-anti-matroion pair has been established to be 0.40 g/l for producing an emulsion using the proposed method. The established optimal total concentrations of polyelectrolyte-counter-ion pairs and their effect on reducing the number of homogenization cycles are summarized in Table 3.

Example 10. Method for obtaining 8.4-12.6 vol. % PFOS emulsion with a polyelectrolyte - anti-macroion pair.

The method according to example 8, characterized in that in phase 2 the polyelectrolyte (sodium hyaluronate) is replaced by a polyelectrolyte (sodium chondroitin sulfate or sodium alginate) and the total concentration of the polyelectrolyte-antivomatroion pair is in the range from 0.01 to 3.0 g/l .

The final prototype recipe obtained by the proposed method had the following composition: perfluorocarbons 8.4-12.6 vol. %, of which: rapidly excreted PPD - 104-156 g/l, slowly excreted PFMCP - 52-78 g/l, emulsifier - poloxamer 188 - 32-270 g/l, para polyelectrolyte (chondroitin sulfate sodium or sodium alginate) - anti-macroion (chitosan or chitosan hydrochloride), total in terms of dry matter 0.01-3.0 g/l, osmolality regulators - glucose - 0.01-50 g/l, electrolytes (sodium chloride, potassium chloride, magnesium chloride, sodium dihydrogen phosphate), total in terms of dry matter 0.01-9.0 g/l, pH regulator - (malic acid or sodium hydroxide) q.s. to pH 5.0-8.0, water for injection q.s. up to 1 l.

To obtain an emulsion by the proposed method, the particle size of which is in the range from 30 to 150 nm with a total concentration of the polyelectrolyte-anti-matroion pair equal to 0.01 g/l, 13 cycles of recirculation and homogenization were required, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 0.40 g /l required 7 cycles of recirculation and homogenization, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 1.00 g/l, 7 cycles of recirculation and homogenization were required, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 3.00 g/l, 7 cycles of recirculation and homogenization were required . Consequently, the optimal total concentration of the polyelectrolyte-anti-matroion pair has been established to be 0.40 g/l for producing an emulsion using the proposed method. The established optimal total concentrations of polyelectrolyte-counter-ion pairs and their effect on reducing the number of homogenization cycles are summarized in Table 3.

Example 11. Method for obtaining 8.4-12.6 vol. % PFOS emulsion with a polyelectrolyte - anti-macroion pair.

The method according to example 8, characterized in that in phase 2 the polyelectrolyte (sodium hyaluronate) is replaced by a polyelectrolyte (chitosan or chitosan hydrochloride), and in phase 3 the antimacroion (chitosan or chitosan hydrochloride) is replaced by the antimatroion (chondroitin sulfate sodium or sodium alginate) at In this case, the total concentration of the polyelectrolyte-anti-matroion pair is in the range from 0.01 to 3.0 g/l.

The final prototype recipe obtained by the proposed method had the following composition: perfluorocarbons 8.4-12.6 vol. %, of which: rapidly excreted PPD - 104-156 g/l, slowly excreted PFMCP - 52-78 g/l, emulsifier - poloxamer 188 - 32-270 g/l, polyelectrolyte pair (chitosan or chitosan hydrochloride) - anti-macroion ( chondroitin sodium sulfate or sodium alginate), total in terms of dry matter 0.01-3.0 g/l, osmolality regulators - glucose - 0.01-50 g/l, electrolytes (sodium chloride, potassium chloride, magnesium chloride, sodium dihydrogen phosphate), total in terms of dry matter 0.01-9.0 g/l, pH regulator - (malic acid or sodium hydroxide) q.s. to pH 5.0-8.0, water for injection q.s. up to 1 l.

To obtain an emulsion using the proposed method, the particle size of which is in the range from 30 to 150 nm with a total concentration of the polyelectrolyte-anti-matroion pair equal to 0.01 g/l, 13 cycles of recirculation and homogenization were required, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 0.40 g/l l required 7 cycles of recirculation and homogenization, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 1.00 g/l, 7 cycles of recirculation and homogenization were required, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 3.00 g/l, 7 cycles of recirculation and homogenization were required. Consequently, the optimal total concentration of the polyelectrolyte-anti-matroion pair has been established to be -0.40 g/l for producing an emulsion using the proposed method. The established optimal total concentrations of polyelectrolyte-counter-ion pairs and their effect on reducing the number of homogenization cycles are summarized in Table 3.

Example 12. Method for obtaining 8.4-12.6 vol. % PPS emulsion with a polyelectrolyte - anti-macroion pair.

The method according to example 1, characterized in that phase 3 contains more amino acids and taurine (tyrosine, leucine, asparagine, aspartic acid, glutamic acid, glutamine, isoleucine, tryptophan, phenylalanine, valine, methionine, threonine, histidine, lysine acetate, arginine , alanine, cysteine hydrochloride monohydrate, acetylcysteine, glycine, series, N-acetyl L-tyrosine, proline, taurine), total in terms of dry matter 0.01-170.0 g/l, in phase 3 pH regulator (sodium bicarbonate ) was replaced by a pair of pH regulators (succinic acid or sodium hydroxide), an antimatroion (α-poly-L-histidine or α-poly-L-histidine hydrochloride or α-poly-L-arginine hydrochloride) was additionally introduced into phase 3, and phase 2 contains more emulsifiers (poloxamer 188, a mixture of phospholipids with phosphatidylcholine, alpha-tocopherol), a total of 32-270 g/l, and phase 2 additionally introduced a polyelectrolyte - (α-poly-L-glutamic acid or α-poly-L -monosodium glutamate), while the total concentration of the polyelectrolyte-anti-matroion pair is in the range from 0.01 to 3.0 g/l.

The final prototype recipe obtained by the proposed method had the following composition: perfluorocarbons 8.4-12.6 vol. %, of which: rapidly excreted PPD - 104-156 g/l, slowly excreted PFMCP - 52-78 g/l, emulsifier (poloxamer 188, mixture of phospholipids with phosphatidylcholine, alpha-tocopherol), total - 32-270 g/l , amino acids and taurine (tyrosine, leucine, asparagine, aspartic acid, glutamic acid, glutamine, isoleucine, tryptophan, phenylalanine, valine, methionine, threonine, histidine, lysine acetate, arginine, alanine, cysteine hydrochloride monohydrate, acetylcysteine, glycine, series, N-acetyl L-tyrosine, proline, taurine), total in terms of dry matter - 0.01-170.0 g/l, para polyelectrolyte (α-poly-L-glutamic acid or α-poly-L-sodium glutamate )-anti-macroion (α-poly-L-histidine or α-poly-L-histidine hydrochloride or α-poly-L-arginine hydrochloride), total in terms of dry matter 0.01-3.0 g/l, electrolytes ( sodium chloride, potassium chloride, magnesium chloride, sodium dihydrogen phosphate), total in terms of dry matter 0.01-9.0 g/l, pH regulator - (succinic acid or sodium hydroxide) q.s. to pH 5.0-8.0, water for injection q.s. up to 1 l.

To obtain an emulsion using the proposed method, the particle size of which is in the range from 30 to 150 nm with a total concentration of the polyelectrolyte-anti-matroion pair equal to 0.01 g/l, 13 cycles of recirculation and homogenization were required, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 0.40 g/l l required 8 cycles of recirculation and homogenization, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 1.00 g/l, 8 cycles of recirculation and homogenization were required, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 3.00 g/l, 8 cycles of recirculation and homogenization were required. Consequently, the optimal total concentration of the polyelectrolyte-anti-matroion pair has been established to be -0.40 g/l for producing an emulsion using the proposed method. The established optimal total concentrations of polyelectrolyte-counter-ion pairs and their effect on reducing the number of homogenization cycles are summarized in Table 3.

Example 13. Method for obtaining 8.4-12.6 vol. % PPS emulsion with a polyelectrolyte - anti-macroion pair.

The method according to example 12, characterized in that in phase 2 the polyelectrolyte (α-poly-L-glutamic acid or α-poly-L-sodium glutamate) is replaced by a polyelectrolyte (α-poly-L-histidine or α-poly-L- histidine hydrochloride or α-poly-L-arginine hydrochloride), and in phase 3 the anti-matroion (α-poly-L-histidine or α-poly-L-histidine hydrochloride or α-poly-L-arginine hydrochloride) is replaced by the antimatroion (α -poly-L-glutamic acid or α-poly-L-sodium glutamate), while the total concentration of the polyelectrolyte-anti-matroion pair is in the range from 0.01 to 3.0 g/l.

The final prototype recipe obtained by the proposed method had the following composition: perfluorocarbons 8.4-12.6 vol. %, of which: rapidly excreted PPD - 104-156 g/l, slowly excreted PFMCP - 52-78 g/l, emulsifier (poloxamer 188, mixture of phospholipids with phosphatidylcholine, alpha-tocopherol), total - 32-270 g/l , amino acids and taurine (tyrosine, leucine, asparagine, aspartic acid, glutamic acid, glutamine, isoleucine, tryptophan, phenylalanine, valine, methionine, threonine, histidine, lysine acetate, arginine, alanine, cysteine hydrochloride monohydrate, acetylcysteine, glycine, series, N-acetyl L-tyrosine, proline, taurine), total in terms of dry matter - 0.01-170.0 g/l, para polyelectrolyte (α-poly-L-histidine or α-poly-L-histidine hydrochloride or α-poly-L-arginine hydrochloride)-anti-macroion (α-poly-L-glutamic acid or α-poly-L-sodium glutamate), total in terms of dry matter 0.01-3.0 g/l, electrolytes ( sodium chloride, potassium chloride, magnesium chloride, sodium dihydrogen phosphate), total in terms of dry matter 0.01-9.0 g/l, pH regulator - (succinic acid or sodium hydroxide) q.s. to pH 5.0-8.0, water for injection q.s. up to 1 l.

To obtain an emulsion using the proposed method, the particle size of which is in the range from 30 to 150 nm with a total concentration of the polyelectrolyte-anti-matroion pair equal to 0.01 g/l, 13 cycles of recirculation and homogenization were required, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 0.40 g/l l required 8 cycles of recirculation and homogenization, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 1.00 g/l, 8 cycles of recirculation and homogenization were required, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 3.00 g/l, 8 cycles of recirculation and homogenization were required. Consequently, the optimal total concentration of the polyelectrolyte-anti-matroion pair has been established to be -0.40 g/l for producing an emulsion using the proposed method. The established optimal total concentrations of polyelectrolyte-counter-ion pairs and their effect on reducing the number of homogenization cycles are summarized in Table 3.

Example 14. Method for obtaining 8.4-12.6 vol. % PFOS emulsion with a polyelectrolyte - anti-macroion pair.

Method according to example 12, characterized in that phase 2 may contain more types of polyelectrolytes (α-poly-L-glutamic acid or α-poly-L-monosodium glutamate or α-poly-L-aspartic acid or α-poly-L -sodium aspartate), and phase 3 contains more types of anti-macroions (α-poly-L-histidine or α-poly-L-histidine hydrochloride or α-poly-L-arginine hydrochloride or α-poly-L-lysine hydrobromide or α -poly-L-lysine hydrochloride or α-poly-L-ornithine hydrobromide or α-poly-L-ornithine hydrochloride), while the total concentration of the polyelectrolyte-anti-matroion pair is in the range from 0.01 to 3.0 g/l.

The final prototype recipe obtained by the proposed method had the following composition: perfluorocarbons 8.4-12.6 vol. %, of which: rapidly excreted PPD - 104-156 g/l, slowly excreted PFMCP - 52-78 g/l, emulsifier (poloxamer 188, mixture of phospholipids with phosphatidylcholine, alpha-tocopherol), total - 32-270 g/l , amino acids and taurine (tyrosine, leucine, asparagine, aspartic acid, glutamic acid, glutamine, isoleucine, tryptophan, phenylalanine, valine, methionine, threonine, histidine, lysine acetate, arginine, alanine, cysteine hydrochloride monohydrate, acetylcysteine, glycine, series, N-acetyl L-tyrosine, proline, taurine), total in terms of dry matter - 0.01-170.0 g/l, para polyelectrolyte (α-poly-L-glutamic acid or α-poly-L-sodium glutamate or α-poly-L-aspartic acid or α-poly-L-sodium aspartate)-anti-macroion (α-poly-L-histidine or α-poly-L-histidine hydrochloride or α-poly-L-arginine hydrochloride or α- poly-L-lysine hydrobromide or α-poly-L-lysine hydrochloride or α-poly-L-ornithine hydrobromide or α-poly-L-ornithine hydrochloride), total calculated on dry matter 0.01-3.0 g/ l, electrolytes (sodium chloride, potassium chloride, magnesium chloride, sodium dihydrogen phosphate), total in terms of dry matter 0.01-9.0 g/l, pH regulator - (succinic acid or sodium hydroxide) q.s. to pH 5.0-8.0, water for injection q.s. up to 1 l.

To obtain an emulsion using the proposed method, the particle size of which is in the range from 30 to 150 nm with a total concentration of the polyelectrolyte-anti-matroion pair equal to 0.01 g/l, 13 cycles of recirculation and homogenization were required, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 0.40 g/l l required 7 cycles of recirculation and homogenization, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 1.00 g/l, 7 cycles of recirculation and homogenization were required, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 3.00 g/l, 7 cycles of recirculation and homogenization were required. Consequently, the optimal total concentration of the polyelectrolyte-anti-matroion pair has been established to be -0.40 g/l for producing an emulsion using the proposed method. The established optimal total concentrations of polyelectrolyte-counter-ion pairs and their effect on reducing the number of homogenization cycles are summarized in Table 3.

Example 15. Method for obtaining 8.4-12.6 vol. % PFOS emulsion with a polyelectrolyte - anti-macroion pair.

The method according to example 12, characterized in that in phase 2 the polyelectrolyte (α-poly-L-glutamic acid or α-poly-L-sodium glutamate) is replaced by a polyelectrolyte (α-poly-L-histidine or α-poly-L- histidine hydrochloride or α-poly-L-arginine hydrochloride or α-poly-L-lysine hydrobromide or α-poly-L-lysine hydrochloride or α-poly-L-ornithine hydrobromide or α-poly-L-ornithine hydrochloride), and in phase 3, the antimatroion (α-poly-L-histidine or α-poly-L-histidine hydrochloride or α-poly-L-arginine hydrochloride) is replaced by the antimatroion (α-poly-L-glutamic acid or α-poly-L- monosodium glutamate or α-poly-L-aspartic acid or α-poly-L-sodium aspartate) while the total concentration of the polyelectrolyte-anti-matroion pair is in the range from 0.01 to 3.0 g/l.

The final prototype recipe obtained by the proposed method had the following composition: perfluorocarbons 8.4-12.6 vol. %, of which: rapidly excreted PPD - 104-156 g/l, slowly excreted PFMCP - 52-78 g/l, emulsifier (poloxamer 188, mixture of phospholipids with phosphatidylcholine, alpha-tocopherol), total - 32-270 g/l , amino acids and taurine (tyrosine, leucine, asparagine, aspartic acid, glutamic acid, glutamine, isoleucine, tryptophan, phenylalanine, valine, methionine, threonine, histidine, lysine acetate, arginine, alanine, cysteine hydrochloride monohydrate, acetylcysteine, glycine, series, N-acetyl L-tyrosine, proline, taurine), total in terms of dry matter - 0.01 - 170.0 g/l, para polyelectrolyte (α-poly-L-histidine or α-poly-L-histidine hydrochloride or α-poly-L-arginine hydrochloride or α-poly-L-lysine hydrobromide or α-poly-L-lysine hydrochloride or α-poly-L-ornithine hydrobromide or α-poly-L-ornithine hydrochloride)-anti-macroion (α- poly-L-glutamic acid or α-poly-L-sodium glutamate or α-poly-L-aspartic acid or α-poly-L-sodium aspartate), total calculated on dry matter 0.01-3.0 g/ l, electrolytes (sodium chloride, potassium chloride, magnesium chloride, sodium dihydrogen phosphate), total in terms of dry matter 0.01-9.0 g/l, pH regulator - (succinic acid or sodium hydroxide) q.s. to pH 5.0-8.0, water for injection q.s. up to 1 l.

To obtain an emulsion using the proposed method, the particle size of which is in the range from 30 to 150 nm with a total concentration of the polyelectrolyte-anti-matroion pair equal to 0.01 g/l, 13 cycles of recirculation and homogenization were required, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 0.40 g/l l required 7 cycles of recirculation and homogenization, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 1.00 g/l, 7 cycles of recirculation and homogenization were required, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 3.00 g/l, 7 cycles of recirculation and homogenization were required. Consequently, the optimal total concentration of the polyelectrolyte-anti-matroion pair has been established to be -0.40 g/l for producing an emulsion using the proposed method. The established optimal total concentrations of polyelectrolyte-counter-ion pairs and their effect on reducing the number of homogenization cycles are summarized in Table 3.

Example 16. Method for obtaining 8.4-12.6 vol. % PFOS emulsion with a polyelectrolyte - anti-macroion pair.

The method according to example 12, characterized in that in phase 2 the polyelectrolyte (α-poly-L-glutamic acid or α-poly-L-monosodium glutamate) is replaced by a polyelectrolyte (α-poly-L-aspartic acid or α-poly-L -sodium aspartate), and in phase 3 the anti-macroion (α-poly-L-histidine or α-poly-L-histidine hydrochloride or α-poly-L-arginine hydrochloride) is replaced by the antimacroion (α-poly-L-lysine hydrobromide or α-poly-L-lysine hydrochloride or α-poly-L-ornithine hydrobromide or α-poly-L-ornithine hydrochloride), while the total concentration of the polyelectrolyte-anti-matroion pair is in the range from 0.01 to 3.0 g/l.

The final prototype recipe obtained by the proposed method had the following composition: perfluorocarbons 8.4-12.6 vol. %, of which: rapidly excreted PPD - 104-156 g/l, slowly excreted PFMCP - 52-78 g/l, emulsifier (poloxamer 188, mixture of phospholipids with phosphatidylcholine, alpha-tocopherol), total - 32-270 g/l , amino acids and taurine (tyrosine, leucine, asparagine, aspartic acid, glutamic acid, glutamine, isoleucine, tryptophan, phenylalanine, valine, methionine, threonine, histidine, lysine acetate, arginine, alanine, cysteine hydrochloride monohydrate, acetylcysteine, glycine, series, N-acetyl L-tyrosine, proline, taurine), total in terms of dry matter - 0.01-170.0 g/l, para polyelectrolyte (α-poly-L-aspartic acid or α-poly-L-sodium aspartate )-anti-macroion (α-poly-L-lysine hydrobromide or α-poly-L-lysine hydrochloride or α-poly-L-ornithine hydrobromide or α-poly-L-ornithine hydrochloride), total calculated on dry matter 0.01 -3.0 g/l, electrolytes (sodium chloride, potassium chloride, magnesium chloride, sodium dihydrogen phosphate), total in terms of dry matter 0.01-9.0 g/l, pH regulator - (succinic acid or sodium hydroxide) q.s. to pH 5.0-8.0, water for injection q.s. up to 1 l.

To obtain an emulsion using the proposed method, the particle size of which is in the range from 30 to 150 nm with a total concentration of the polyelectrolyte-anti-macroion pair equal to 0.01 g/l, 13 cycles of recirculation and homogenization were required, with a total concentration of the polyelectrolyte-anti-macroion pair equal to 0.40 g/l l required 6 cycles of recirculation and homogenization, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 1.00 g/l, 6 cycles of recirculation and homogenization were required, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 3.00 g/l, 6 cycles of recirculation and homogenization were required. Consequently, the optimal total concentration of the polyelectrolyte-anti-matroion pair has been established to be -0.40 g/l for producing an emulsion using the proposed method. The established optimal total concentrations of polyelectrolyte-counter-ion pairs and their effect on reducing the number of homogenization cycles are summarized in Table 3.

Example 17. Method for obtaining 8.4-12.6 vol. % PPS emulsion with a polyelectrolyte - anti-macroion pair.

The method according to example 12, characterized in that in phase 2 the polyelectrolyte (α-poly-L-glutamic acid or α-poly-L-sodium glutamate) is replaced by a polyelectrolyte (α-poly-L-lysine hydrobromide or α-poly-L -lysine hydrochloride or α-poly-L-ornithine hydrobromide or α-poly-L-ornithine hydrochloride), and in phase 3 anti-matroion (α-poly-L-histidine or α-poly-L-histidine hydrochloride or α-poly- L-arginine hydrochloride) is replaced by an anti-matroion (α-poly-L-aspartic acid or sodium α-poly-L-aspartate) with the total concentration of the polyelectrolyte-anti-matroion pair ranging from 0.01 to 3.0 g/l.

The final prototype recipe obtained by the proposed method had the following composition: perfluorocarbons 8.4-12.6 vol. %, of which: rapidly excreted PPD - 104-156 g/l, slowly excreted PFMCP - 52-78 g/l, emulsifier (poloxamer 188, mixture of phospholipids with phosphatidylcholine, alpha-tocopherol), total - 32-270 g/l , amino acids and taurine (tyrosine, leucine, asparagine, aspartic acid, glutamic acid, glutamine, isoleucine, tryptophan, phenylalanine, valine, methionine, threonine, histidine, lysine acetate, arginine, alanine, cysteine hydrochloride monohydrate, acetylcysteine, glycine, series, N-acetyl L-tyrosine, proline, taurine), total in terms of dry matter - 0.01-170.0 g/l, para polyelectrolyte (α-poly-L-lysine hydrobromide or α-poly-L-lysine hydrochloride or α-poly-L-ornithine hydrobromide or α-poly-L-ornithine hydrochloride)-anti-macroion (α-poly-L-aspartic acid or α-poly-L-aspartate sodium), total in terms of dry matter 0.01 -3.0 g/l, electrolytes (sodium chloride, potassium chloride, magnesium chloride, sodium dihydrogen phosphate), total in terms of dry matter 0.01-9.0 g/l, pH regulator - (succinic acid or sodium hydroxide) q.s. to pH 5.0-8.0, water for injection q.s. up to 1 l.

To obtain an emulsion using the proposed method, the particle size of which is in the range from 30 to 150 nm with a total concentration of the polyelectrolyte-anti-matroion pair equal to 0.01 g/l, 13 cycles of recirculation and homogenization were required, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 0.40 g/l l required 6 cycles of recirculation and homogenization, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 1.00 g/l, 6 cycles of recirculation and homogenization were required, with a total concentration of the polyelectrolyte-anti-matroion pair equal to 3.00 g/l, 6 cycles of recirculation and homogenization were required. Consequently, the optimal total concentration of the polyelectrolyte-anti-matroion pair has been established to be -0.40 g/l for producing an emulsion using the proposed method. The established optimal total concentrations of polyelectrolyte-counter-ion pairs and their effect on reducing the number of homogenization cycles are summarized in Table 3.

Example 18

The proposed composition is intended for medical purposes, namely for infusion therapy, i.e. a treatment method based on infusions - the introduction of solutions into the circulatory system to correct pathologies of the body or prevent them. Infusion therapy with perfluoroorganic emulsions restores the volume and composition of blood through parenteral administration of medicinal solutions.

Example 19

Before using the proposed emulsion composition, a biological test is carried out: after slowly introducing the first 5 drops of the drug, stop the transfusion for 3 minutes, then add another 30 drops and stop the transfusion again for 3 minutes. If there is no reaction, the administration of the drug continues. The test results must be recorded in the medical history.

Example 20

For the treatment of acute blood loss and shock, the perfluoroorganic emulsion of the proposed composition is administered intravenously by drip or stream in a dose of 5 to 30 ml/kg body weight. The effect of the emulsion is maximum if during and after its infusions the patient breathes a mixture enriched with oxygen for 24 hours.

Example 21

For the treatment of microcirculation disorders of various origins, the perfluoroorganic emulsion of the proposed composition is administered at a dose of 5-8 ml/kg body weight. The emulsion can be re-administered in the same dose three times with an interval of 2-4 days. To increase the oxygenation effect during therapy, it is advisable to supply an air mixture enriched with oxygen through a mask or nasal catheter.

Example 22

For anti-ischemic protection of donor organs, a perfluoroorganic emulsion of the proposed composition is administered dropwise or in a stream at a dose of 20 ml/kg body weight to the donor and recipient 2 hours before surgery.

Example 23

Regional application of a perfluoroorganic emulsion of the proposed composition is used for perfusion of the extremities when filling a standard oxygenator at the rate of 40 ml/kg body weight. Perfusion is a method of supplying and passing blood, blood-substituting solutions and biologically active substances through the vascular system of organs and tissues of the body.

Thus, a new drug in liquid form, successfully combining active substances with excipients, provides the creation of a stable composition of PFOS in the form of an emulsion intended for use as a blood substitute, and the optimal method for its preparation.

Claims (23)

1. A method for producing a sterile perfluorocarbon emulsion for infusion for medical purposes, which consists in carrying out preliminary sterilizing filtration of a mixture of liquids of perfluoroorganic compounds, with a ratio of C ₈ -C ₁₀ perfluoroorganic compounds to C ₁₁ -C ₁₂ perfluoroorganic compounds from 1:1 up to 1:4, with mixture densities from 1.872 to 1.945 g/ml in an aqueous solution and poloxamer 188 emulsifier - 32-270 mg/ml, add one or more polyelectrolytes in total - 0.01-1.0 mg/ml, disperse on speeds 2500-3000 rpm; homogenize the resulting dispersion by passing through a high-pressure homogenizer at a pressure of 70-120 MPa, dilute the resulting emulsion with water for injection. 2. The method according to claim 1, characterized in that perfluorodecalin, perfluorotripropylamine, perfluorooctyl bromide are used as C ₈ -C ₁₀ perfluoroorganic compounds. 3. The method according to claim 1, characterized in that perfluoro-N-(4-methylcyclohexyl) piperidine and perfluorotributylamine are used as C ₁₁ -C ₁₂ perfluoroorganic compounds. 4. The method according to claim 1, characterized in that polyanions are used as polyelectrolytes, namely hyaluronic acid and its salts, sodium hyaluronate, chondroitin sulfate and its salts, sodium chondroitin sulfate, alginic acid and its salts, sodium alginate, α- poly-L-glutamic acid and its salts, α-poly-L-monosodium glutamate, α-poly-L-aspartic acid and its salts, α-poly-L-aspartate sodium or polycations, namely chitosan and its salts, chitosan hydrochloride, α-poly-L-lysine and its salts, α-poly-L-lysine hydrobromide, α-poly-L-lysine hydrochloride, α-poly-L-ornithine and its salts, α-poly-L-ornithine hydrobromide , α-poly-L-ornithine hydrochloride, α-poly-L-histidine and its salts, α-poly-L-histidine hydrochloride, α-poly-L-arginine and its salts, α-poly-L-arginine hydrochloride. 5. The method according to claim 1, characterized in that they additionally carry out high-speed dispersion and high-pressure homogenization in an aqueous solution of one or more emulsifiers with a total of 32-270 mg/ml, with the addition of one or more polyelectrolytes with a total of no more than 1.0 mg/ml . 6. The method according to claim 1, in which the installation for producing the emulsion includes a reactor for diluting the emulsion with water for injection, a homogenizer and pipelines connecting the container and the homogenizer. 7. The method according to claim 1, which is carried out under aseptic conditions. 8. The method according to claim 1, in which, before starting the process, the emulsion production line is checked by washing it with a sterile aqueous solution of one or more emulsifiers with a total of 32-270 mg/ml, with the addition of one or more polyelectrolytes with a total of no more than 1 .0 mg/ml in a volume 2-4 times greater than the working volume of the pipelines and the working chamber of the homogenizer at a pressure in the working chamber of the homogenizer of 70-120 MPa, followed by draining the aqueous solution. 9. The method according to claim 1, in which the emulsion production line contains one or more additional homogenizers connected in parallel to the main homogenizer. 10. The method according to claim 1, characterized in that the emulsion production line contains one or more additional homogenizers connected in parallel to the main homogenizer. 11. The method according to claim 1, characterized in that the homogenizer contains more than one working chamber, where the chambers are connected in parallel. 12. The method according to claim 1, characterized in that the emulsion is diluted with a solution of one or more amino acids and/or taurine with a total concentration of no more than 170 mg/ml. 13. The method according to claim 12, characterized in that the amino acid used is tyrosine, leucine, asparagine, aspartic acid, glutamic acid, glutamine, isoleucine, tryptophan, phenylalanine, valine, methionine, threonine, histidine, lysine acetate, lysine hydrochloride, arginine, arginine hydrochloride, histidine hydrochloride monohydrate, alanine, cysteine hydrochloride monohydrate, acetylcysteine, glycine, serine, N-acetyl L-tyrosine, arginine aspartate, proline, taurine. 14. The method according to claim 12, characterized in that the solution for diluting the emulsion additionally contains one or more electrolytes with a total concentration of no more than 11 mg/ml. 15. The method according to claim 14, characterized in that sodium chloride, potassium chloride, magnesium chloride and its crystal hydrates, mono-, di-, trisubstituted sodium phosphate and its crystal hydrates, calcium chloride and its crystal hydrates are used as electrolytes. 16. The method according to claim 1, characterized in that the emulsion is diluted with a solution of one or more osmolality regulators with a total concentration of no more than 150 mg/ml. 17. The method according to claim 16, characterized in that monosaccharides, disaccharides, and polyalcohols are used as osmolality regulators. 18. The method according to claim 16, characterized in that the solution for diluting the emulsion additionally contains one or more electrolytes with a total concentration of no more than 11 mg/ml. 19. The method according to claim 18, characterized in that sodium chloride, potassium chloride, magnesium chloride and its crystal hydrates, mono-, di-, trisubstituted sodium phosphate and its crystal hydrates, calcium chloride and its crystal hydrates are used as electrolytes. 20. The method according to claim 1, characterized in that the solution for diluting the emulsion additionally contains one or more anti-macroions with a charge opposite to the polyelectrolyte in a total concentration of 0.01-1.0 mg/ml. 21. The method according to claim 20, characterized in that polyanions are used as an anti-macroion, namely hyaluronic acid and its salts, sodium hyaluronate, chondroitin sulfate and its salts, sodium chondroitin sulfate, alginic acid and its salts, sodium alginate, α- poly-L-glutamic acid and its salts, α-poly-L-monosodium glutamate, α-poly-L-aspartic acid and its salts, α-poly-L-aspartate sodium or polycations, namely chitosan and its salts, chitosan hydrochloride, α-poly-L-lysine and its salts, α-poly-L-lysine hydrobromide, α-poly-L-lysine hydrochloride, α-poly-L-ornithine and its salts, α-poly-L-ornithine hydrobromide , α-poly-L-ornithine hydrochloride, α-poly-L-histidine and its salts, α-poly-L-histidine hydrochloride, α-poly-L-arginine and its salts, α-poly-L-arginine hydrochloride. 22. The method according to claim 1, characterized in that the pH of the diluted emulsion is adjusted using pH regulators to values from 5.0 to 8.0. 23. The method according to claim 22, characterized in that inorganic acids, their salts and their solutions, namely carbonic, hydrochloric, phosphoric, sulfuric, are used as pH regulators; organic acids, their salts and their solutions, namely succinic, malic, acetic, fumaric, citric acid; alkali metal hydroxides and their solutions, namely sodium, potassium, lithium hydroxides.