WO2015147705A2 - Method for preparing a sterile nano emulsion of perfluoro-organic compounds - Google Patents

Method for preparing a sterile nano emulsion of perfluoro-organic compounds Download PDF

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WO2015147705A2
WO2015147705A2 PCT/RU2015/000318 RU2015000318W WO2015147705A2 WO 2015147705 A2 WO2015147705 A2 WO 2015147705A2 RU 2015000318 W RU2015000318 W RU 2015000318W WO 2015147705 A2 WO2015147705 A2 WO 2015147705A2
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pfos
method according
nanoemulsion
pp
aqueous solution
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PCT/RU2015/000318
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French (fr)
Russian (ru)
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WO2015147705A3 (en
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Сергей Юрьевич ПУШКИН
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Сергей Юрьевич ПУШКИН
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Priority to RU2014106582/15A priority patent/RU2557933C1/en
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Publication of WO2015147705A2 publication Critical patent/WO2015147705A2/en
Publication of WO2015147705A3 publication Critical patent/WO2015147705A3/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/04X-ray contrast preparations
    • A61K49/0433X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A61K49/0447Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
    • A61K49/0461Dispersions, colloids, emulsions or suspensions
    • A61K49/0471Perflubron, i.e. perfluoroctylbromide, C8F17Br emulsions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0026Blood substitute; Oxygen transporting formulations; Plasma extender

Abstract

The present invention relates to the chemical and pharmaceutical industry and presents a method for producing a stable, sterile nano emulsion of perfluoro-organic compounds (PFOC) with an average particle size of a maximum of 150 nm, preferably 30-100 nm, most preferably from 30 to 80 nm, for use in medicine and veterinary medicine, which method comprises filling a circulation circuit in an installation for producing nano emulsions of PFOC with an aqueous solution of stabilizing additive, preferably poloxamer, adding a mixture of PFOC to the aqueous solution of stabilizing additive, with subsequent homogenization of the resulting mixture of PFOC in the aqueous solution of stabilizing additive in order to produce a preliminary emulsion of PFOC having a required particle size, under thermostatic control of the operation of the working chamber of the homogenizer and pipes, adding the resulting preliminary emulsion of PFOC to an aqueous salt solution so as to produce nano emulsions of PFOC with a required concentration of PFOC, stabilizing additive and salts, keeping the nano emulsions of PFOC at a temperature of 2-10̊C, with optional preliminary packaging of the finished product into a sterile consumer pack, and freezing the finished product.

Description

 METHOD FOR PREPARING STERILE NANOEMULSION OF PERFLUORORGANIC COMPOUNDS

 The present invention relates to the pharmaceutical industry and is a method for producing a stable sterile nano-emulsion of perfluororganic compounds (PFOS) for use in medicine and veterinary medicine as gas transport substitutes for donated blood and multifunctional perfluorocarbon preparations to partially maintain gas transport, circulating blood volume and some other physiological parameters, as well as in the composition of drugs for the treatment of systemic and local disorders blood flow, ischemic and hypoxic conditions, improved mass transfer of gases and metabolites between blood and tissues, preservation of function of isolated organs and tissues, reduce inflammation phenomena of infuzionno- transfusion therapy for shock and blood loss.

 State of the art

 Perfluorocarbon emulsions are gas-transferring emulsions based on organofluorine compounds used in the biomedical field as multifunctional preparations. From the point of view of colloid chemistry, perfluorocarbon gas-transporting emulsions are direct, concentrated, highly and freely dispersed, heterogeneous, thermodynamically unstable lyophobic colloidal systems with excess free surface energy and a huge gas exchange area (sorption active phase interface) in which the dispersed phase insoluble ultrafine chemically inert perfluorocarbon particles is coated with an adsorption-solvate layer of a surfactant and retains certain time at low temperatures, aggregative stability and uniform distribution of particles of the dispersed phase over the volume of the dispersed structured medium.

The high energy saturation of perfluorocarbon particles and their ultradispersity leads to special properties and puts them in a special transition region (1 (Г 8 m) next to the colloidal (1 (Г 9 m) and molecular (10 " ° ° m) state of the substance. This is a special state perfluorocarbon dispersed nanosystems is manifested in their high biological activity, in reactivity, in physical interaction with any substances and gases.

 The main parameters of PFOS emulsions, which determine their quality and prospects of use, are:

 1) the average particle diameter of the emulsion PFOS;

 2) the distribution of particles of the emulsion in diameter;

 3) the half-life of PFOS from the body;

4) the toxicity of the emulsion or LD 50 ;

 5) the oxygen capacity of the emulsion;

 6) the vapor pressure of PFOS;

 7) sterility of the emulsion;

 8) the possibility of long-term storage of the emulsion;

 9) the toxicity of a stabilizing additive;

 10) the reactogenicity of the emulsion.

 A comparison of these indicators allows us to evaluate the obtained PFOS emulsion and to determine the advantage of one PFOS emulsion over another.

 The average particle diameter of emulsions depends on both the properties of PFOS and the ability of a stabilizing additive (emulsifier) to reduce surface tension at the PFOS-water interface. The smaller the surface tension, the easier the process of emulsification and the smaller the average particle diameter in the resulting emulsion.

 PFOS emulsions with one or another stabilizing additive should have a long shelf life, and storage conditions should be simple. An indicator of storage of PFOS emulsion is a change (increase) in the average particle diameter of the emulsion during storage.

 The main tasks in obtaining gas transport emulsions PFOS are:

 1) a decrease in the average particle diameter of the PFOS emulsions and a narrowing of the particle diameter distribution of the emulsion;

 2) reliable sterilization of PFOS emulsions;

3) lack of toxicity of PFOS emulsions; 4) increasing the time and simplifying the storage conditions of PFOS emulsions without significantly changing the average particle diameter and broadening the particle diameter distribution.

 It is known that the quality of perfluorocarbon emulsions is determined by the physicochemical properties of the selected PFOS, physicochemical properties and the nature of the stabilizing additive and the technology for producing the emulsion.

 PFOS is insoluble in water and are themselves poor solvents for various water-soluble biologically active substances; therefore, for use as oxygen-transporting media, they are dispersed in an aqueous solution of a stabilizing additive until fine emulsions are formed.

 The task of the stabilizing additive is to form an adsorption layer around perfluorocarbon particles, while the physicochemical properties and nature of the stabilizing additive determine the stability of the dispersed system and its reactogenicity. The key parameters here are the bond strength of the surfactant with the "core" of the emulsion particle, the nature and density of the surfactant molecules on the surface of the particle.

Various methods are known for preparing PFOS emulsions. One of the technologies is based on the method of grinding the oil phase using ultrasound. However, the energy and power of ultrasonic exposure are so great that, along with dispersion, lead to a break in the CF bond. As a result, highly toxic concentrations of F ~ ions appear in the aqueous phase of the emulsion, and the emulsion must be purified from their excessive content by passing through an ion exchange resin. In addition, such an emulsion has an extremely wide dispersion value.

Mechanical dispersion by shaking or mixing allows to obtain only coarse-dispersed emulsions of PFOS with a size unacceptable for medical use - more than 1 mm. To obtain finely dispersed emulsions, the method of extruding the dispersed phase substance through thin holes into the dispersion medium under high pressure (extrusion method) is used, which leads to the breaking of the moving liquid stream into droplets. Dispersion is caused by a pressure gradient and forces hydraulic friction. Typically, the production of PFOS emulsions is carried out on high pressure homogenizers, which makes it possible to obtain a sufficiently thin calibrated emulsion.

Homogenization is achieved by passing a mixture of emulsifier and perfluorocarbon through small holes with a cross section of 10 ~ 6 - 10 -8 m 2 under a pressure of 10.1 to 101.3 MPa. To obtain emulsions, a single-circuit method was previously used, where perfluorocarbon from a separate container was drip fed into a container with an emulsifier (poloxamer), then the entire mixture was supplied to and from the disintegrator into a container with PFOS and an emulsifier. This cycle was repeated many times (from 5 to 15 cycles). However, the emulsion obtained by this method does not fully satisfy the requirements for particle size, since particles with a size of 400-450 nm remain in the composition, which increases the toxicity of the emulsion obtained.

 A known method of producing emulsions of PFOS for medical purposes, in which to reduce reactogenicity it is proposed to reduce the average size and increase the monodispersion of the particles of the emulsion. This is achieved by the drip introduction of a mixture of two types of liquid PFOS into an aqueous solution of a stabilizing agent, which prevents the appearance of a macroscopic phase boundary, increases the time and contact surfaces of PFOS and a stabilizing agent at the stage of preparation of the emulsion. A submicron emulsion is obtained in a dual-circuit homogenization system during 12-fold recirculation in the homogenizer circuits under alternating pressure. However, the first and second circuits of the homogenizer are used interchangeably, which slows down the homogenization process, since returning from the second circuit to the first leads to the penetration of coarse pre-emulsion particles and even drops of PFOS into the finely divided emulsion, which inevitably form and linger on the walls of the chamber and tubes in the first circuit.

RF patent 2122404 describes a method for producing an emulsion by spraying a multicomponent mixture of PFOS and a proxanol solution through a homogenizer under a pressure of 700-1000 atm and cooling at a temperature of 24 to 34 ° C with further cyclic homogenization under a constant pressure of 400-490 atm and with constant cooling . In the proposed method the preparation of an emulsion due to the jet transmission of the PFOS mixture reduces the time of the first homogenization cycle by half, and the regulation and monitoring of the pressure regime in the homogenizer prevents the process of secondary particle enlargement and provides a soft “refinement” of the emulsion to a predetermined particle size of 0.03-0.05 microns.

 RF patent 2206319 describes a method for producing an emulsion, according to which, before mixing the components, the mixture of liquid PFOS and an aqueous solution of a stabilizing agent are saturated with carbon dioxide, and then the aqueous solution of a stabilizing agent is heated at a temperature of no higher than 75 ° C. Then, a mixture of liquid PFOS is introduced in several jets into a cooled aqueous solution of a stabilizing agent with vigorous stirring and blowing carbon dioxide, while passing the coarse pre-emulsion obtained several times through the first homogenizer circuit, after which the crushed pre-emulsion is homogenized in the second homogenizer circuit until the required dispersion is obtained under the required dispersion gas, and water-salt composition is added.

 Saturation of the components to be mixed with carbon dioxide and heating of an aqueous solution of a stabilizing agent (proxanol) allows depyrogenization of the solution without passing through sorbents that impair the quality of the stabilizing agent and change its molecular weight distribution, as well as surface-active properties. Deviations from the indicated temperature values worsen the surface-active properties of the stabilizing agent. The jet introduction of liquid PFOS into an aqueous solution of a stabilizing agent with vigorous stirring and at the same time passing the resulting mixture through a high-pressure homogenizer accelerates the process of preparing a preemulsion. The feed rate of PFOS, mixing and the flow of the mixture through the homogenizer are controlled so as to prevent the formation of a macroscopic PFOS / water phase boundary, which is a necessary condition for obtaining a monodisperse emulsion.

In the patent of the Russian Federation 2070033 describes a method for producing perfluorocarbon emulsions for medical purposes, in which a mixture of PFOS receive by mixing the liquid components, and the pre-emulsion is obtained by passing the PFOS mixture through an aqueous solution of a stabilizing agent (proxanol), while passing the resulting pre-emulsion through the working chamber of the homogenizer, after complete mixing, they are passed through the working chamber of the homogenizer with temperature control at a pressure of 300-660 atm, followed by adding to the resulting emulsion of a sterile physiologically acceptable aqueous saline solution. The resulting PFOS nanoemulsion is frozen.

 The disadvantages of the above method for producing PFOS nanoemulsions are the complexity of obtaining a mixture of PFOS, due to the fact that the liquid components of different densities are weighed to obtain the required volume of the PFOS mixture; thermostating is carried out only by the working chamber of the homogenizer, which does not provide the necessary temperature for obtaining a preemulsion with an average particle size of 30-80 nm; the pressure in the working chamber of the homogenizer above 60 MPa is excessive, and leads to gelation of the aqueous poloxamer solution; the freezing of PFOS nanoemulsions immediately after manufacture leads to a sharp coarsening of the particles of PFOS nanoemulsions, which reduces its stability, shortening its shelf life.

 RF patent 2393849 describes a method for producing a PFOS emulsion in which, before mixing, a mixture of PFOS and an aqueous solution of poloxamer are saturated with carbon dioxide, the preparation of a pre-emulsion and subsequent homogenization is carried out in an atmosphere of carbon dioxide, and a physiologically acceptable water-salt solution is added to the pre-emulsion.

The disadvantages of this method of producing PFOS nanoemulsions are the saturation of a mixture of PFOS and an aqueous solution of poloxamer with carbon dioxide and the implementation of a process of homogenization in an atmosphere of carbon dioxide, which is technologically difficult and makes the manufacturing process of PFOS nanoemulsions more expensive. The volume of production of nanoemulsions is limited by the performance of the homogenizer. The water-salt solution is added to the pre-emulsion with a higher density, which impairs mixing and increases the time of this process. No stabilization of nanoemulsions PFOS before freezing.

 The aim of the present invention was to provide a simple, technologically advanced and economical method for producing PFOS nanoemulsions, which allows obtaining a product with improved stability and simplifying storage conditions of PFOS nanoemulsions without significantly changing the average particle diameter and broadening the particle diameter distribution.

 The inventors of the present invention unexpectedly found that pre-filling the circulation loop of a plant for producing PFOS nanoemulsions, which includes a tank for producing a PFOS preemulsion, a homogenizer and pipelines connecting the tank and the homogenizer, with a solution of a stabilizing additive before adding a PFOS mixture, reduces the average particle diameter of the emulsion and reduces particle diameter distribution, which, in turn, significantly increases the stability of the PFOS emulsion and, as a result, increased ivaet shelf life of the product.

 In addition, the inventors of the present invention unexpectedly found that keeping the PFOS emulsion at a temperature of from 2 to 10 ° C for more than 18 hours before freezing the finished product also significantly improves the stability of the PFOS emulsion.

 SUMMARY OF THE INVENTION

 The present invention relates to a method for producing a sterile nano-emulsion of perfluororganic compounds (PFOS), which includes:

 - adding a mixture of PFOS to an aqueous solution of a stabilizing additive;

- homogenization of a mixture of PFOS with an aqueous solution of a stabilizing additive to obtain a pre-emulsion of PFOS;

 - mixing the PFOS preemulsion with a water-salt solution to obtain PFOS nanoemulsions;

 - keeping PFOS nanoemulsions at a temperature of from 2 to 10 ° C for at least 18 hours;

 - optional freezing of PFOS nanoemulsions.

In a preferred embodiment of the method of the present invention, the circulating circuit of the installation is pre-filled to obtain PFOS nanoemulsion with an aqueous solution of a stabilizing additive.

 The present invention also relates to a method for producing a sterile nano-emulsion of perfluororganic compounds (PFOS), which includes:

 - pre-filling the circulation circuit with an aqueous solution of a stabilizing additive;

 - adding a mixture of PFOS to an aqueous solution of a stabilizing additive;

- homogenization of a mixture of PFOS with an aqueous solution of a stabilizing additive to obtain a pre-emulsion of PFOS;

 - mixing the PFOS preemulsion with a water-salt solution to obtain a PFOS nanoemulsion;

 - optional freezing of PFOS nanoemulsion.

 The circulation loop in the method of the present invention includes a vessel for producing a PFOS preemulsion, a homogenizer, and pipelines connecting the vessel and the homogenizer.

 In a preferred embodiment of the method of the present invention, before starting the process, the tightness of the circulation circuit is checked by washing it with a sterile concentrated aqueous solution of a stabilizing additive in a volume 2-4 times the working volume of the pipelines and the working chamber of the homogenizer at a pressure in the working chamber of the homogenizer 10-45, 5 MPa, followed by draining the solution.

 In a preferred embodiment of the method of the present invention, homogenization of the PFOS preemulsion is carried out at a pressure in the working chamber of the homogenizer in the range from 10 to 60.8 MPa, preferably in the range from 43, 1 to 45, 1 MPa, the working chamber of the homogenizer is thermostated to provide a process temperature of the range from 19 to 30 ° C, preferably from 20 to 26 ° C and carry out thermostating of the pipelines of the circulation circuit to ensure the process temperature of the pipelines in the range from 5 to 20 ° C preferably from 7 to 15 ° C.

In a preferred embodiment of the method of the present invention, the circulation circuit comprises one or more additional homogenizers connected in parallel to the main homogenizer of the circulation circuit.

 In a preferred embodiment of the invention, the homogenizer has more than one working chamber connected in parallel.

 In a preferred embodiment of the method of the present invention, the PFOS nanoemulsion is poured into a consumer packaging before aging.

 In the most preferred embodiment of the method of the present invention, the consumer packaging with PFOS nano-emulsion is gently shaken before freezing until the contents are uniform.

 The consumer packaging used in the method of the present invention is glass bottles, vials, ampoules, syringe tubes, polymer containers, metal cylinders, tubes.

 In a preferred embodiment of the method of the present invention, the method is carried out under aseptic conditions.

In a preferred embodiment of the method of the present invention, the aqueous solution of a stabilizing additive is 10-30 mass. % aqueous solution, preferably 10-20 wt.% aqueous solution and poloxamers, such as copolymers of polyoxyethylene and polyoxypropylene, preferably poloxamers with the trade names Emuxol 268 of the brand “A” and Killiphor PI 88 (Collifor PI 88), C are used as stabilizing additives 10 -C 22 fatty acids and / or their salts or triglycerides or phospholipids of egg yolk or soy.

In the method of the present invention, as a mixture of PFOS, a mixture of at least one rapidly withdrawn PFOS selected from C 8 -C 10 PFOS, for example perfluorodecalin (PFD) or perfluorooctyl bromide (PFOB) and at least one slowly removed PFOS, is used, selected from C 1 C 12 PFOS, for example perfluorotripropylamine (PFTPA), perfluoromethylcyclohexylpiperidine (PFMCP) or perfluorotributylamine (PFTA).

In a preferred embodiment of the method of the present invention, a PFOS mixture for preparing a pre-emulsion is prepared by mixing one or more liquid PFOS.

In the method of the present invention, the water-salt solution comprises NaCl and water, and optionally KCl, MgCl 2 , NaHCO 3 , NaH 2 PO 4 , Na 2 HPO 4 , glucose.

 In a preferred embodiment of the method of the present invention, the PFOS nano-emulsion contains 4.8-7.2 g / l sodium chloride; 0.31-0.47 g / l potassium chloride; 0, 15-0.23 g / l magnesium chloride (in terms of dry matter); 0.55-0.83 g / l sodium bicarbonate; 0, 16-0.24 g of sodium phosphate monosubstituted (in terms of dry matter); 1, 6-2.4 g / l glucose.

 In a preferred embodiment of the method of the present invention, the pH of the PFOS nanoemulsion is from 5 to 8, preferably in the range from 7.2 to 7.8, and to adjust the pH, the quantitative content of sodium bicarbonate and sodium phosphate monosubstituted is changed.

 In a preferred embodiment of the method of the present invention, the PFOS nanoemulsion is frozen at a temperature of from -4 to -18 ° C, preferably at a temperature of from -10 to -18 ° C.

 In a preferred embodiment of the method of the present invention, the PFOS nanoemulsion is maintained at a temperature of from 2 to 10 ° C., preferably at a temperature of from 3 to 6 ° C., most preferably at a temperature of 4 ° C.

 In a preferred embodiment of the invention, the emulsion is kept before freezing for at least 18 hours, preferably for 18-30 hours, most preferably 24 hours.

 DETAILED DESCRIPTION OF THE INVENTION

 Figure 1 presents a preferred setup for producing a PFOS nanemulsion for implementing the method of the present invention.

In the presented diagram, tank 1 is a tank for a mixture of PFOS or a solution of a stabilizing additive, pipeline 2 connects a tank 1 with a tank 3 of a circulation loop to obtain a mixture of PFOS in a solution of a stabilizing additive, pipelines 4 and 6 of a circulation loop connect a tank 3 with a high-pressure circulation homogenizer 5 circuit, pipeline 7 connects the circulation circuit with a tank 8 for water-salt solution to obtain a finished nanoemulsion PFOS, pipeline 9 is designed to remove the finished product and / or packaging the finished PFOS nano-emulsion in consumer packaging.

 The method is as follows.

 To obtain the PFOS preemulsion, the PFOS mixture is supplied dropwise and / or by jet from tank 1 through line 2 to tank 3 with a solution of a stabilizing additive. In a preferred embodiment of the invention, before the start of the process, an aqueous solution of a stabilizing additive is supplied from the tank 1 to the main circulation circuit, including the tank 3, pipelines 4 and 6 and the homogenizer 5 until the circuit is completely filled.

 A mixture of PFOS in an aqueous solution of a stabilizing additive is pumped in the main circulation circuit through pipelines 4 and 6 through a homogenizer 5 at a working pressure in the homogenizer chamber of 10-60.8 MPa, when the homogenizer working chamber is cooled to 19-30 ° С and thermostats of pipelines 4 and 6 circulation loop at a temperature of 5-20 ° C. Carry out 9-15 cycles of homogenization to obtain PFOS preemulsion. Then the PFOS preemulsion is pumped through a pipe 7 into a container 8 with an aqueous-salt solution, where the pre-emulsion, gradually passing through an aqueous-salt solution, the specific gravity of which is less than the specific gravity of the pre-emulsion, is uniformly mixed with an aqueous-salt solution to obtain a finished PFOS nanoemulsion. Next, the finished product is pumped through pipeline 9 to an additional container or to a consumer container, where it is optionally kept at a temperature of 2-10 ° С for at least 18 hours to stabilize the product, after which the product is optionally frozen at a temperature of -4 to -18 ° С .

 In a preferred embodiment of the invention, before the process is started, the tightness of the circulation circuit is checked by filling it with an aqueous solution of a stabilizing additive in an amount 2-4 times greater than the working volume of the pipelines and the working chamber of the homogenizer with the homogenizer turned on at a pressure of 10-45.5 MPa, followed by draining the solution.

The PFOS nanoemulsion of the present invention includes at least one rapidly releasing PFOS and at least one slowly excreted PFOS in an amount of up to 50 vol.%, preferably from 5 to 30 vol.%, even more preferably from 10 to 20 vol.%, a stabilizing additive in an amount of up to 10 wt.%, preferably from 0.5 to 10 wt.% , more preferably from 3.5 to 4.5 wt.%, salts such as NaCl, KCl, MgCl 2 , NaHCO 3 , NaH 2 PO 4 , Na 2 HPO 4 and water.

 The ratio of rapidly excreted and slowly excreted perfluorinated compounds can be from 10: 1 to 1: 10.

The water-salt portion of the finished PFOS emulsion may contain 82-123 mM NaCl, and optionally 4.2-6.3 mM KCl, 1.6-2.4 mM MgCl 2 , 6.6-9.9 mM NaHCO 3 , 3-2 mM NaH 2 PO 4 . Preferably, the ratio of Na to K ions is maintained at 10: 1-30: 1.

 The composition of the finished emulsion PFOS may also include glucose in the amount of 8.9-13.3 mm (or 1, 6-2.4 g / l).

 The pH of the finished emulsion PFOS is from 5 to 8.0, preferably from 7.2 to 7.8.

 The PFOS emulsion has an average particle size of not more than 150 nm, preferably 30-100 nm, most preferably 30-80 nm.

To obtain the PFOS emulsions of the present invention, as a rule, two types of organo perfluorine compounds are used simultaneously. One of them is selected from the group C 8 -C 10 , including, for example, perfluorodecalin (PFD) or perfluorooctyl bromide (PFOB), the second from the group C and -C | 2 containing, for example, perfluorotripropylamine (PFTPA), perfluoromethylcyclohexyl-piperidine (PFMCP) or perfluorotributylamine (PFTA). Compounds of the first type are rapidly eliminated from the body (within a month), but do not provide sufficient stability of the emulsions, while compounds of the second type, on the contrary, give the emulsion high stability, allowing them to be stored without freezing, but for a long time (from 8 months to 2- x years) are not excreted.

 Multicomponent mixtures of two PFOS can also be used, for example, PFD / PFTA, PFD / PFMTSP, PFOB / PFTA,

PFOB / PFMTSP or of three PFOS, for example PFOB / PFD / PFMTSP, PFOB / PFD / PFTA or of four PFOS, for example PFOB PFD / PFMTSP / PFTA.

 Special stabilizing additives are introduced to reduce the average particle diameter of the emulsion, increase dispersion and stability during long-term storage.

 As a stabilizing additive, non-toxic non-ionic high molecular weight surfactants (NSAS), in particular poloxamers (proxanols, pluronics, collifors, emuxols) are preferably used. Their amount in PFOS emulsions is, if possible, minimal and is determined only by the need for satisfactory emulsification and homogenization of PFOS. Minimizing the amount of surfactants is also associated with the fact that they affect the toxicity and reactogenicity of the PFOS emulsion.

Poloxamers are a copolymer of polyethylene oxide and polypropylene oxide of the general formula HO (C 2 H 4 O), „(СЗН 6 О) p2 Н 4 О)“, 'Н, where (m + m') varies from several units to several dozens; the molecular weight is from 1000 to 20,000, the proportion of polyoxyethylene blocks can be from 10 to 80% by weight.

 In a preferred embodiment of the present invention, a poloxamer is used under the trade name Proxanol 268, “Emuxol 268”, brand “A”, Kolliphor PI 88 (Collifor PI 88), Pluronic F68 (Pluronic F68), Synperonic F68 (Sinperonic F68), Lutrol F68 (Lutrol F68 )

C 10 - C 22 fatty acids and / or their salts or triglycerides and phospholipids of egg yolk or soy can also be used as stabilizing additives.

 In a preferred method of the present invention, a 10-30 mass% aqueous solution of a stabilizing additive is used, most preferably a 10-20 mass% aqueous solution.

The aqueous salt solution used in the method of the present invention is an aqueous solution of salts selected from NaCl, and optionally KCl, MgCl 2 , NaHCO 3 , NaH 2 PO 4 , Na 2 HP0 4 . The water-salt solution may contain glucose.

The amount of components of the water-salt solution used for mixing with the PFOS preemulsion is calculated so that to provide the following salt content in the finished PFOS emulsion: 82, 1-123.2 mM NaCl, 4.2-6.3 mM KCl, 1.6-2.4 mM MgCl 2 6.6-9.9 mM NaHC0 3 , 1, 3-2 mM NaH 2 P0 4 and 8.9-13.3 mM D-glucose or 4.8-7.2 g / l sodium chloride; 0.31-0.47 g / l potassium chloride; 0, 15-0.23 g / l magnesium chloride (in terms of dry matter); 0.55-0.83 g / l sodium bicarbonate; 0.16-0.24 g / l sodium phosphate monosubstituted (in terms of dry matter); 1, 6-2.4 g / l glucose.

 Below the claimed invention is illustrated by examples, which are in no way intended to limit the scope of the claimed invention.

 EXAMPLES

 Example 1. Obtaining a nanoemulsion containing 10 vol.% PFOS.

Before the homogenization process, the tightness of the circulation circuit is checked by filling it with a 13.3% aqueous solution of Poloxamer Emuxol 268 grade “A” in an amount 2-4 times the working volume of the pipelines and the working chamber of the homogenizer, with the homogenizer turned on at a pressure of 10-45.5 MPa followed by its discharge. Capacity 3 is filled with 2.52 l of a 13.3% aqueous solution of poloxamer Emuxol 268 grade "A". A mixture of PFOS, including 0.56 L of PFD and 0.28 L of PFMTSP, is gradually (dropwise) added to 2.52 L of a 13.3% aqueous solution of Poloxamer Emuxol 268 grade “A”. The pressure in the homogenizer is maintained in the range from 43.1 to 45.1 MPa and when the working chamber is cooled to 20-26 ° C. The pipelines of the circulation circuit are thermostated to create a temperature in the range of 7-15 ° C. Carry out 13 cycles of homogenization. Obtain 3.36 l of PFOS preemulsion containing 25% PFOS with an average particle size of 50-80 nm. 3.36 L of the resulting pre-emulsion is added to 5.04 L of a water-salt solution containing 1.7 times more dissolved salts (95.5 mm NaCl, 5.0 mm KCl, 2.2 mm MgCl 2 , 8, 1 mm NaHCO 3 , 1, 5 mM NaH 2 PO 4 , and 10.7 mM glucose) in relation to the concentration of salts in the nanoemulsion, in a ratio of 1: 1, 5, respectively. Get 8.4 l of PFOS nanoemulsion containing 10% PFOS with an average particle size of 50-80 nm.

PFOS nanoemulsion is poured into a sterile consumer container and stabilized at 4 ° C for 24 hours, after which it frozen at a temperature of - 15 ° C.

 In accordance with the procedure described in Example 1, an experimental series of PFOS 4e nanoemulsion with an average particle size of 64 nm is obtained.

 Example 2. Obtaining a nanoemulsion containing 10 vol.% PFOS.

Before filling the circulation circuit with a solution of a stabilizing additive, the tightness of the circulation circuit is checked by filling it with a 10% aqueous solution of Emuxol 268 poloxamer grade “A” in an amount 2-4 times the working volume of the pipelines and the working chamber of the homogenizer, with the homogenizer turned on at a pressure of 10-45 5 MPa followed by its discharge. The circulation loop is filled with 3.36 L of a 10% aqueous solution of Emoxol 268 Poloxamer brand “A”, after which a mixture of PFOS consisting of 0.56 L of PFD and 0.28 L of PFMTSP is gradually (jet) added to it. The pressure in the homogenizer is maintained in the range from 43.1 to 45, 1 MPa and when the working chamber is cooled to 20-26 ° C. The pipelines of the circulation circuit are thermostated to create a temperature in the range of 7-15 ° C. Carry out 10 cycles of homogenization. Obtain 3.36 l of PFOS preemulsion containing 25 vol.% PFOS with an average particle size of 50-80 nm. 3.36 L of the resulting pre-emulsion is added to 5.04 L of a water-salt solution containing 1.7 times more dissolved salts (93.7 mm NaCl, 5.1 mm KCl, 1.9 mm MgCl 2 , 7.5 mm NaHCO 3 , 1, 7 mM NaH 2 PO 4 , and 1 1.2 mM glucose) in relation to the salt concentration in the nanoemulsion, in a ratio of 1: 1.5, respectively. Get 8.4 l of PFOS nanoemulsion containing 10% PFOS with an average particle size of 50-80 nm. PFOS nanoemulsion is poured into a sterile consumer container and stabilized at a temperature of 4 ° C for 24 hours, after which it is frozen at a temperature of -15 ° C.

 In accordance with the procedure described in Example 2, an experimental series of PFOS Ze nanoemulsion with an average particle size of 53 nm is obtained.

 Example 3. Obtaining a nanoemulsion containing 10 vol.% PFOS.

Before filling the circulation circuit with a solution of a stabilizing additive, check the tightness of the circulation circuit by filling it with a 10% aqueous solution of the Lutrol F68 poloxamer (Lutrol F68) in an amount 2-4 times the working volume of the pipelines and the working chamber of the homogenizer, with the homogenizer turned on at a pressure of 10-45.5 MPa, followed by its discharge. The circulation circuit is filled with 3.36 l of a 10% aqueous solution of Emoxol 268 poloxamer grade “A”, after which a mixture of PFOS consisting of 0.56 l of PFD and 0.28 l of PFMTSP is gradually (dropwise) added to it. The pressure in the homogenizer is maintained in the range from 10 to 81 MPa and when the working chamber is cooled to 19-28 ° C. The pipelines of the circulation circuit are thermostated to create a temperature in the range of 10-20 ° C. Carry out 10 cycles of homogenization. Obtain 4.2 l of PFOS preemulsion containing 20 vol.% PFOS with an average particle size of 50-80 nm. 4.2 l of the resulting pre-emulsion is added to 4.2 l of a water-salt solution containing 2 times more dissolved salts (100.7 mm NaCl, 5.7 mm KCl, 2, 1 mm MgCl 2 , 7.9 mm NaHCO 3 , 1, 6 mM NaH 2 PO 4 , and 1, 0 mM glucose) in relation to the salt concentration in the nanoemulsion, i.e. in a ratio of 1: 1, respectively. Get 8.4 l of PFOS nanoemulsion containing 10% PFOS with an average particle size of 50-80 nm. PFOS nanoemulsion is poured into a consumer container and stabilized at a temperature of 4 ° C for 24 hours, after which it is frozen at a temperature of -16 ° C.

 In accordance with the procedure described in Example 3, an experimental series of PFOS nanoemulsion is obtained: a series of Zc with an average particle size of 53 nm.

 The methods of the method for producing PFOS nanoemulsion of Examples 1, 2 and 3 are a standard production technology supplemented by the stage of keeping the nanoemulsion before freezing in Example 1 or supplemented by the stage of pre-filling the circulation circuit with an aqueous solution of a stabilizing additive in Example 2 or supplemented by the stage of keeping the nanoemulsion before freezing, so and the stage of pre-filling the circulation circuit with an aqueous solution of a stabilizing additive in Example 3.

Example 4 (control). Obtaining a nanoemulsion containing 10 vol. % PFOS. Before the homogenization process, the tightness of the circulation circuit is checked by filling it with a 13.3% aqueous solution of Poloxamer Emuxol 268 grade “A” in an amount 2-4 times the working volume of the pipelines and the working chamber of the homogenizer, with the homogenizer turned on at a pressure of 10-45.5 MPa followed by its discharge. A mixture of PFOS, including 0.56 L of PFD and 0.28 L of PFMTSP, is gradually (jet) added to 2.52 L of a 13.3% aqueous solution of Poloxamer Emuxol 268 grade “A”. The pressure in the homogenizer is maintained in the range from 10 to 81 MPa and when the working chamber is cooled to 19-28 ° C. The pipelines of the circulation circuit are thermostated to create a temperature in the range of 10-20 ° C. Carry out 13 cycles of homogenization. Obtain 4.2 l of PFOS preemulsion containing 20 vol.% PFOS with an average particle size of 50-80 nm. 4.2 L of the resulting pre-emulsion is added to 4.2 L of a water-salt solution containing 2 times more dissolved salts (102.3 mm NaCl, 5.6 mm KCl, 2.0 mm MgCl 2 , 8.3 mm NaHCO 3 , 1, 8 mM NaH 2 PO 4 , and 1 1.2 mM glucose) with respect to the salt concentration in the nanoemulsion, i.e. in a ratio of 1: 1, respectively, 8.4 L of PFOS nanoemulsion containing 10 vol.% PFOS with an average particle size of 50-80 nm is obtained. PFOS nanoemulsion is frozen at a temperature of -17 ° C.

 According to the method described in Example 4, a control series of PFOS 1k nanoemulsion with an average particle size of 58 nm is obtained.

 The methodology for producing the PFOS nanoemulsion of Example 4 is a standard production technology (control).

 Example 5. Evaluation of the effect of aging PFOS nanoemulsion or pre-filling the circulation circuit with a solution of a stabilizing additive on the stability of the product.

 The stability of the PFOS nanoemulsion is determined by the change in the size of the part during storage. A normal average particle size is considered to be a size in the range from 30 to 150 nm.

 Nanoemulsion obtained in Examples 1 (series 4E), 2 (series Ze) and 4

(series 1k), thaw and determine the average particle size when stored at 4 ° C and -18 ° C. The average particle size of the emulsions and the particle diameter distribution are measured using an electron microscope.

 The data obtained are presented in Tables 1 and 2.

 Table 1

Storage stability of PFOS nanoemulsion at temperature

Figure imgf000019_0001

table 2

The stability of the PFOS nanoemulsion when stored at a temperature of -18 ° C

Figure imgf000019_0002

The presented measurements of the average particle size of the PFOS emulsion show that keeping PFOS nanoemulsion before freezing at 4 ° C for 24 hours or pre-filling the circulation circuit with a solution of a stabilizing additive before mixing the components significantly increases the shelf life of the product compared to the control:

 - the shelf life of the PFOS nanoemulsion according to Example 1 at a temperature of 4 ° C is 6 weeks, which is 3 weeks longer than the shelf life of the control series according to Example 4 (Table 1);

- the shelf life of the PFOS nanoemulsion according to Example 2 at a temperature of 4 ° C is 4 weeks, which is 1 week longer than the shelf life of the control series according to Example 4 (Table 1); - the shelf life of the PFOS nanoemulsion according to Example 1 at a temperature of -18 ° C is 48 months, which is 24 months longer than the shelf life of the control series according to Example 4 (Table 2);

 - the shelf life of the PFOS nanoemulsion according to Example 2 at a temperature of -18 ° C is 30 months, which is 6 months longer than the shelf life of the control series according to Example 4 (Table 2).

 Example 6. Evaluation of the effect of pre-filling the circulation circuit with a solution of a stabilizing additive and keeping PFOS nanoemulsion on the product stability.

 The stability of the PFOS nanoemulsion is determined by the change in the size of the part during storage. A normal average particle size is considered to be a size in the range from 30 to 150 nm.

 The nanoemulsion obtained in Examples 3 (series 3C) and 4 (series 1k) is thawed and the average particle size is determined during storage at a temperature of 4 ° C and at a temperature of -18 ° C.

 The average particle size of the emulsions and the particle diameter distribution are measured using an electron microscope.

 The data obtained are presented in Tables 3 and 4.

 Table 3

The stability of the PFOS nanoemulsion when stored at 4 ° C

Figure imgf000020_0001

Table 4

The stability of the PFOS nanoemulsion when stored at a temperature of -18 ° C

Series The average particle size of the emulsion PFOS (nm), interval 6 months

 0 6 12 18 24 30 36 42 48 54 60

1k 58 79 105 129 150 - - - - - -

Sc 53 53 53 54 54 53 55 54 '55 56 57 Analysis of the measurement data of the average particle size of PFOS nanoemulsion shows that filling the circulation circuit with a solution of a stabilizing additive and keeping PFOS nanoemulsion before freezing at 4 ° C for 24 hours significantly increases the shelf life of the product compared to the control:

 - the shelf life at a temperature of 4 ° C of the nanoemulsion according to Example 3 is 8 weeks, which is 5 weeks more than the control (Table 3);

 - the shelf life of the nanoemulsion according to Example 3 at a temperature of -18 ° C is 60 months, which is 36 months more than the control (Table 4).

 Moreover, the stability of PFOS nanoemulsion when using both filling the circulation circuit with a solution of a stabilizing additive and keeping PFOS nanoemulsion before freezing at 4 ° C for 24 hours significantly increases the shelf life of the product not only in comparison with the control product, but also in comparison with the product obtained using only filling the circulating circuit with a solution of a stabilizing additive or a nanoemulsion aging step.

 The above experimental data clearly prove that the use in the method of producing PFOS nanoemulsions of an additional stage of pre-filling the circulation circuit with an aqueous solution of a stabilizing additive and / or keeping PFOS nanoemulsion at a temperature of 2-10 ° C for more than 18 hours can significantly increase the stability of the emulsion and the term her storage.

 Example 7. Evaluation of the effect of pre-filling the circulation circuit with a solution of a stabilizing additive on the distribution of particle diameters.

 The average particle size of the emulsions and the particle diameter distribution are obtained by direct measurement of the particles of the nanoemulsion using electron microscopy. To prepare the sample, the method of negative contrast of the monolayer of particles of a nanoemulsion deposited on a collodion film was applied, uranyl nitrate. The image was obtained at an accelerating voltage of 80 kV in a JEM 100V electron microscope (JEOL, Japan).

The data obtained are presented in Table 5. Table 5

Figure imgf000022_0001

The presented data clearly indicate that the use of the stage of preliminary filling the circulation circuit with a solution of a stabilizing additive to obtain a nanoemulsion with an average particle size in the range of 30-80 nm requires three less homogenization cycles, which significantly reduces the time of the production process. Also, the PFOS nanoemulsion of series 4e, obtained without the preliminary stage of filling the circulation circuit with a solution of a stabilizing additive, has the required average particle size of 64 nm, but unlike the PFOS nanoemulsion, the Ze series contains particles larger than 200 nm, which increases the number of reactogenic reactions when it is used.

Claims

CLAIM
 1. A method of obtaining a sterile nanoemulsion of perfluororganic compounds (PFOS), including:
 - adding a mixture of PFOS to an aqueous solution of a stabilizing additive; - homogenization of a mixture of PFOS with an aqueous solution of a stabilizing additive to obtain a pre-emulsion of PFOS;
 -mixing the PFOS preemulsion with an aqueous saline solution to obtain a PFOS nanoemulsion;
 - keeping the PFOS nanoemulsion at a temperature of from 2 to 10 ° C for at least 18 hours.
 2. The method according to claim 1, further comprising pre-filling the circulation circuit with an aqueous solution of a stabilizing additive.
 3. A method of obtaining a sterile nanoemulsion of perfluororganic compounds (PFOS), including:
 pre-filling the circulation circuit with an aqueous solution of a stabilizing additive;
 - adding a mixture of PFOS to an aqueous solution of a stabilizing additive;
- homogenization of a mixture of PFOS with an aqueous solution of a stabilizing additive to obtain a pre-emulsion of PFOS;
 -mixing the PFOS preemulsion with a water-salt solution to obtain a PFOS nanoemulsion.
 4. The method according to PP. 1-3, in which the circulation circuit includes a container for receiving a mixture of PFOS with an aqueous solution of a stabilizing additive, a homogenizer and pipelines connecting the tank and the homogenizer.
 5. The method according to PP. 1-3, which is carried out under aseptic conditions.
6. The method according to PP. 1-3, in which, before starting the process, they check the tightness of the circulation circuit by washing it with a sterile aqueous solution of a stabilizing additive in a volume 2-4 times the working volume of the pipelines and the working chamber of the homogenizer at a pressure in the working chamber of the homogenizer 10-45, 5 MPa, followed by draining the aqueous solution.
7. The method according to PP. 1-3, in which the homogenization of the pre-emulsion PFOS is carried out at a pressure in the working chamber of the homogenizer in the range from 10 to 60.8 MPa, preferably in the range from 43, 1 to 45, 1 MPa.
 8. The method according to PP. 1-3, in which the temperature of the working chamber of the homogenizer is carried out to ensure the process temperature in the range from 19 to 30 ° C, preferably from 20 to 26 ° C.
 9. The method according to PP. 1-3, in which the temperature control of the pipelines of the circulation circuit is carried out to ensure the process temperature of the pipelines in the range from 5 to 20 ° C, preferably from 7 to 15 ° C.
 10. The method according to PP. 1-3, in which the circulation circuit contains one or more additional homogenizers connected in parallel to the main homogenizer of the circulation circuit.
 1 1. The method according to PP. 1-3, in which the homogenizer contains more than one working chamber, where the cameras are connected in parallel.
 12. The method according to PP. 1-3, in which the PFOS nanoemulsion is poured into a consumer container before aging.
 13. The method according to PP. 1-3, in which the consumer packaging with PFOS nanoemulsion is gently shaken until the contents are uniform.
 14. The method according to p. 12, in which the consumer packaging is a glass bottle, bottles, ampoules, syringe tubes, polymer containers, metal cylinders, tubes.
 15. The method according to p. 14, in which the size of the consumer packaging for the PFOS nanoemulsion intended for freezing does not exceed 500 ml.
 16. The method according to PP. 1-3, in which the PFOS nanoemulsion is maintained at a temperature of from 2 to 10 ° C for at least 18 hours, preferably at a temperature of 3-6 ° C for 18-30 hours, preferably at a temperature of 4 ° C for 24 hours.
 17. The method according to PP. 1-3, in which the obtained PFOS nanoemulsion is frozen.
18. The method according to p. 17, in which the PFOS nanoemulsion is frozen at temperature from -4 to -18 ° С.
 19. The method according to PP. 1-3, in which the aqueous solution of a stabilizing additive is 10-30 mass. % aqueous solution, preferably 10 to 20 mass. % water solution.
20. The method according to PP. 1-3, in which poloxamers are used as stabilizing additives, such as copolymers of polyoxyethylene and polyoxypropylene, C 10 -C 22 fatty acids and / or their salts or triglycerides or phospholipids of egg yolk or soy.
 21. The method according to claim 20, in which poloxamers with the trade names Proxanol 268, Emuxol are used as a stabilizing additive
268 brands A, Kolliphor PI 88 (Collifor PI 88), Pluronic F68 (Pluronic F68), Synperonic F68 (Sinperonic F68), Lutrol F68 (Lutrol F68).
22. The method according to PP. 1-3, in which as a mixture of PFOS use a mixture of at least one rapidly derived PFOS selected from C 8 -Su PFOS, and at least one slowly removed PFOS selected from C, -C 12 PFOS.
 23. The method according to item 22, in which the rapidly derived PFOS selected from perfluorodecalin (PFD) or perfluorooctyl bromide (PFOB) or mixtures thereof, and the slowly derived PFOS selected from perfluorotripropylamine (PFTPA), perfluoromethylcyclohexylpiperidine (PFMCPPtifliftin or Pperfluoro) mixtures.
 24. The method according to PP. 1-3, in which a mixture of PFOS for the preparation of a pre-emulsion is prepared by mixing one or more liquid PFOS.
25. The method according to PP. 1-3, in which the water-salt solution includes NaCl and water and, optionally, KCl, MgCl 2 , NaHCO 3 , NaH 2 PO 4 , Na 2 HPO.
 26. The method according A.25, in which the water-salt solution further comprises glucose.
27. The method according to PP. 1-3, in which the PFOS nanoemulsion contains 4.8-7.2 g / l sodium chloride; 0.31-0.47 g / l potassium chloride; 0, 15-0.23 g / l magnesium chloride (in terms of dry matter); 0.55-0.83 g / l sodium bicarbonate; 0, 16-0.24 g / l sodium phosphate monosubstituted (in terms of dry matter); 1, 6-2.4 g / l glucose.
28. The method according to PP. 1-3, in which the pH of the PFOS nanoemulsion is from 5 to 8.0.
 29. The method according to p, in which to adjust the pH change the quantitative content of sodium bicarbonate and sodium phosphate monosubstituted.
 30. The method according to PP. 1-3, in which the PFOS nanoemulsion has an average particle size of not more than 150 nm, preferably from 30 to 100 nm, most preferably from 30 to 80 nm.
PCT/RU2015/000318 2014-03-27 2015-05-21 Method for preparing a sterile nano emulsion of perfluoro-organic compounds WO2015147705A2 (en)

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