Composition based emulsion performancesin compounds for biomedical purposes

 

(57) Abstract:

The invention relates to medicine and serves for producing structures on the basis of perfluorocarbon emulsions used as artificial blood substitutes, contrast media and environments to preserve bodies. The invention consists in obtaining blood compositions on the basis of perfluorocarbon emulsions with a reduced number of adverse reactions and temporary stay performancesin compounds in the body. To obtain blood compositions are a mixture of 2,3,4 performancesin compounds (PFOS): performanceline, performativity, performancecriteria, performability in different ratios, emulsifiable the proxanol is chosen (or phospholipids) and then adding to the resulting emulsion PFOS electrolyte solution to obtain the concentration of the perfluorocarbon in the emulsion is from 1 to 20% , proxanol is chosen from 0.4 to 4.8%. The invention provides for obtaining blood compositions with improved medico-biological and physical-chemical characteristics and provides the expansion of applications of perfluorocarbon blood substitutes. 4 C.p. f-crystals, 1 table.

In the formulations based on perfluorocarbon emulsions are used, as a rule, two types of performancesin compounds. One of them is selected from the group (C8-C10containing, for example, perpendicular (PFD) or perforative (PFOB), the second group (C11-C12containing, for example, performapply (PVTPA), performancecriteria (PFMRP) or performability (PFTB). These perfluorocarbons dissolve about 40 vol.% oxygen (pO2= 760 mm RT. Art.) and 150 - 190 vol.% carbon dioxide (pCO2= 760 mm RT. Art.), whereupon they started to be used as the main component of casinosites when creating artificial blood. However, PFOS is not soluble in water and other liquids, so you can use them only in the form of emulsions with a certain amount of perfluorocarbon particles covered with a layer of emulsifier (proxanol is chosen), and the smaller the particle size of the emulsion, the better, because emulsions are administered intravenously and in large amounts can cause embolism (blockage) of the vessels. Compounds and their emulsions, connection of the second type, on the contrary, give emulsions of high stability, allowing you to store them without freezing, but they for several years not eliminated from the body.

Known composition of the emulsions containing, for example, perpendicular (PFD) and performapply (PVTPA), emulsifying agents, for example a copolymer of polyoxyethylene-propylene (pluronic F-68, domestic analogue-proxanol is chosen), the phospholipids of egg yolk or soybean phospholipids and water (patent USSR N-797546, publ. in bull. "Discoveries, inventions...", 1981, N2). In accordance with this composition, the concentration of the perfluorocarbon is 24% in a physiologically acceptable aqueous medium.

The disadvantages of this invention should be considered that the composition of the emulsion has a fairly coarse size particles and cannot be stored in unfrozen form.

In another emulsion prepared for medical purposes on the basis of the PFD and PPTP - Fluosol-DA 20%, from the same company, the average size is considerably less than the previous emulsion and was amount of 0.118 μm, proportion of particles with a size of from 0.2 to 0.5 μm was 7.8 per cent. In the composition as an emulsifier was used proxanol is chosen and phospholipids of egg yolk.

However, the average DIMETHYLPROPANE and sterilization is the integration of the particles of the emulsion. In addition, used as part of perfluorocarbons quickly escalated (T. Mitsuno et al., "Intake and retension of perfluorochemical substance of Fluosol-DA in human res", Proceedings of the 5. Int. Sympos. On Oxygen Carring Colloidal Blood Substituts, Meinz, March, 1981, P. 220). The composition of the emulsion is stored only in frozen form, because after 8-12 hours of storage at room temperature is the integration of the particles of the emulsion and therefore it becomes impossible its clinical application.

Known composition of perfluorocarbon emulsions for medical purposes (patent RF N-2070033, publ. in 1996, N 34), close to the claimed composition, which includes perpendicular or perforat-milbrae and performancecriteria in the ratio of 2/1 and concentration from 20 to 40% with an average particle size of from 0.06 to 0.11 μm.

The disadvantage of this composition is the maximum average particle size of the emulsion, average of 0.11 μm. In addition, the emulsions of this composition are present in coarse particles with a diameter from 0.2 to 0.4 μm in the amount of 0.4% (table 1), which may increase the number of reactive (side) reactions.

However, the main disadvantage of this composition is prolonged actually perfluorocarbons in organs and tissues of the second emulsion for biomedical purposes (RF patent N 2122404, publ. 1998, N 33), which includes perpendicular, performancecriteria, perforative, performability, emulsifiable 4% proxanol is chosen 268 to an average particle size of the emulsion 0.03-0.05 microns.

The disadvantage of this composition is prolonged perfluorocarbons in organs and tissues of the body, constituting 18-24 months. Another important factor related to the disadvantages of this structure are adverse reactions that are lower than the previous composition (patent RF N 2070033, publ. in 1996, N 34) by 10%, but still remain rather high - 20% (table 1).

The objective of the invention is to provide a composition based on the perfluorocarbon emulsion for biomedical purposes with a reduced number of adverse reactions and temporary stay performancesin compounds in the body.

The problem is solved in that in the claimed composition on the basis of perfluorocarbon emulsions for biomedical purposes, including the production of emulsions of PFOS by mixing different performancesin connections proxanol is chosen - emulsifying agent (or phospholipids), followed by homogenization of the mixture, according to the invention, performs), or PFD/performability (PFTB), or performancebased (PFOB)/PTBA, or PFOB/PFMSP in a ratio of from 1/1 to 10/10, respectively; or a mixture of three PFOS: PFOB/PFD/PFMSP or PFOB/PFD/PFTB in the ratio from 1/1/1 to 10/10/10, respectively; or from a mixture of four PFOS: PFOB/PFD/PFMP/PFTB in the ratio from 1/1/1/1 to 10/10/10/10 respectively, further comprises a physiologically acceptable electrolyte solution with the following concentrations of ingredients in the emulsion: sodium chloride solution to 6.0-9.0 g/l; potassium chloride - 0,39-0,41 g/l): magnesium chloride (calculated on the dry matter) - 0,19-0,21 g/l; sodium bicarbonate is 0.65 and 0.68 g/l; sodium phosphate one-deputizing (in terms of dry substance) is from 0.2 to 0.23 g/l; glucose-2.0-2.2 g/l; proxanol is chosen from 0.4% to 4.8%; perfluorocarbons from 1% to 20%.

The ratio of perfluorocarbons selected based on experimental studies. Thus, to increase the stability of perforamance during storage of the emulsion must always be perfluorocarbons, giving a stable emulsion, but it is difficult flushed out of the body is PFMSP or PFTB. To increase the concentration of PFOS in the emulsion to poorly flushed PFMRP and DFTBA added well displayed PFD or PFOB, but, respectively, giving an unstable emulsion is estom perfluorocarbons and respectively with different properties. The proposed structure on the basis of perfluorocarbon emulsions allows you to create a perfluorocarbon emulsion with a low degree of reactogenicity (2 times reduced side effects compared with the method of the equivalent), as in the diluted emulsion significantly reduced the number of coarse particles that can cause negative side reactions, by reducing the total number of all particles of the emulsion with 1,51018to 0,751018(table 1). All this contributes to the safe use of perfluorocarbon blood substitutes in medicine and the expansion of application fields (ultrasonic, radiographic and magnetic resonance tomography). Another important factor in improving the quality of the emulsion in the proposed structure is to increase the speed of removing the actual perfluorocarbons from organs and tissues in comparison with the method of the analogue. So, PFOS found in organs and tissues of about 18-24 months after the introduction of the emulsion-analogue. In the proposed composition of PFOS leave the body twice as fast through 9-12 months (table 1), which is very important in medical practice and has undoubtedly the advantage over other formulations peers.

Thus, the proposed SOS is thainee compared with structure-analog and composition of the Japanese drug Fluosol-DA 20%.

Getting the 10% (5% vol.) emulsion

Example 1. Perfluorocarbon mixture PFD/PFMSP in the ratio of 2/1 in the amount of 200 ml, containing 266 g PFD specific density 1,938 and 133 g PFMSP specific density 1,920, was passed through the homogenizer with 10-12% solution proxanol is chosen in the amount of 800 ml of the resulting mixture of PFOS and proxanol is chosen is diluted with 3000 ml of concentrated electrolyte solution, supporting the osmotic pressure. The average particle size of the emulsion was of 0.045 μm.

The final formulation of perfluorocarbon emulsion had the following composition: PFD/PFMRP (ratio 2/1) - 10% (5%), the proxanol is chosen - 2-2,4%, sodium chloride solution to 6.0-9.0 g/l; potassium chloride - 0,39-0,41 g/l; magnesium chloride (calculated on the dry matter) - 0,19-0,21 g/l; sodium bicarbonate is 0.65 and 0.68 g/l; sodium phosphate one-deputizing (in terms of dry substance) is from 0.2 to 0.23 g/l; glucose - 2.0-2.2 g/L. the resulting emulsion can be used as blood money intravenous and for domestic use, as well as the environment by ultrasound and magnetic resonance studies and external use.

Example 2. Composition-based emulsion was prepared as described in example 1. The ratio of PFOB/PFD/PTBA avsl 0,042 mm.

The final formulation of perfluorocarbon emulsion had the following composition: PFOB/PFD/PTBA ratio (10/2/1) - 10% (5%), the proxanol is chosen - 2-2,4%, sodium chloride solution to 6.0-9.0 g/l; potassium chloride - 3,39-0,41 g/l; magnesium chloride (calculated on the dry matter) -0,19-0,21 g/l: sodium bicarbonate is 0.65 and 0.68 g/l; sodium phosphate one-deputizing (in terms of dry substance) is from 0.2 to 0.23 g/l; glucose-2.0-2.2 g/L. the resulting emulsion can be used as a blood and contrast media intravenously and domestic use.

Example 3. Composition-based emulsion was prepared as described in example 1. The ratio of PFOB/PFD/PFMP/PTBA was 10/1/1, hanging PFOB/PFD/PFMP/PTBA respectively 182/182/18/18, the Average particle size of the emulsion was 0,050 mm.

The final formulation of perfluorocarbon emulsion had the following composition: PFOB/PFD/PFMP/PTBA (ratio 10/10/1/1) - 10% (5%), the proxanol is chosen - 2-2,4%, sodium chloride solution to 6.0-9.0 g/l; potassium chloride - 0,39-0,41 g/l; magnesium chloride (calculated on the dry matter) - 0,19-0,21 g/l; sodium bicarbonate is 0.65 and 0.68 g/l; sodium phosphate one-deputizing (in terms of dry substance) is from 0.2 to 0.23 g/l; glucose - 2.0-2.2 g/L. the resulting emulsion can be used as cruesome composition of 1% (0,5%) emulsion

Example 4. Composition-based emulsion was prepared as described in example 1. The ratio of the PFD/PFMRP was 2/1 with 200 ml sample PFD/PFMRP was 266/133 g, respectively. Density PFD - 1,938. Density PFMSP - 1,920. The average particle size of the emulsion was 0,031 mm.

The resulting emulsion is diluted 39000 ml of concentrated electrolyte solution, supporting the osmotic pressure.

The final formulation of perfluorocarbon emulsion had the following composition: PFD/PFMRP (ratio 2/1)-1% (0,5%), the proxanol is chosen of 0.4 - 0.6%, sodium chloride solution to 6.0-9.0 g/l; potassium chloride - 0,39-0,41 g/l; magnesium chloride (calculated on the dry matter) - 0,19-0,21 g/; sodium bicarbonate is 0.65 and 0.68 g/l; sodium phosphate one-deputizing (in terms of dry substance) is from 0.2 to 0.23 g/l; glucose - 2,0-2 2 g/L. the resulting emulsion can be used as cruezaweek and contrast media intravenously and at internal and external use.

Receive 20% (10%) emulsion

Example 5. Composition-based emulsion was prepared as described in example 1. The ratio of the PFD/PFMRP was 2/1 with 200 ml sample PFD/PFMRP was 266/133 g, respectively. tx2">

The resulting emulsion is diluted with 1000 ml of concentrated electrolyte solution, supporting the osmotic pressure.

The final formulation of perfluorocarbon emulsion had the following composition: PFD/PFMRP (ratio 2/1) - 20% (10%), the proxanol is chosen - 4-4,8%, sodium chloride solution to 6.0-9.0 g/l potassium chloride - 0,39-0,41 g/l; magnesium chloride (calculated on the dry matter) - 0,19-0,21 g/l; sodium bicarbonate is 0.65 and 0.68 g/l; sodium phosphate one-deputizing (in terms of dry substance) is from 0.2 to 0.23 g/l; glucose - 2.0-2.2 g/L. the resulting emulsion can be used as a blood and contrast media intravenously, for internal and external use.

1. Composition-based emulsions performancesin compounds (PFOS) for biomedical purposes, including various performancesee connection and proxanol is chosen or phospholipids, wherein the perfluorocarbon emulsion consisting of a mixture of two PFOS: performanceline (PFD)/performancecriteria (PFMRP, or PFD/performability (PFTB), or performancebased (PFOB)/PTBA, or PFOB/PFMSP in a ratio of from 1/1 to 10/10, respectively, or a mixture of three PFOS: PFOB/PFD/PFMSP or PFOB/PFD/PFTB in a ratio of 1/1 is respectively, further comprises a physiologically acceptable electrolyte solution with the following concentrations of ingredients in the emulsion : sodium chloride solution of 6.9 - 9.0 g/l, potassium chloride 0,39 - 0,41 g/l, magnesium chloride (calculated on the dry matter) 0,19 - 0,21 g/l of sodium bicarbonate to 0.65 and 0.68 g/l, sodium phosphate one-deputizing (in terms of dry substance) of 0.2 to 0.23 g/l, glucose 2.0 - 2.2 g/l, proxanol is chosen from 0.4 to 4.8%, perfluorocarbons from 1 to 20%.

2. The composition of the emulsion under item 1, characterized in that the emulsion is intended for intravenous and intraarterial administration and before use, diluted from 1.5 to 10 times any compatible with the emulsion solution or composition.

3. The composition of the emulsion on the PP.1 and 2, characterized in that the emulsion is intended for oral, intracavitary and external use.

4. The composition of the emulsion on the PP.1 to 3, characterized in that before applying the emulsion saturate any gas or mixture of gases.

5. The composition of the emulsion on the PP.1 to 4, characterized in that the emulsion is intended for use as contrast media for ultrasonic, radiographic and magnetic resonance studies.

 

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FIELD: medicine, surgical stomatology.

SUBSTANCE: in case of patient's average-severe or severe state before surgical interference or at satisfactory state - after surgical interference one should intravenously once introduce perfluorane at the dosage of 1-3 ml/kg body weight followed by daily treatment of the wound with perfluorane, washing and introducing perfluorane-impregnated gauze tampons till the end of exudation phase. The method enables to widen the number of preparations to treat odontogenic phlegmons of oral area, simplify therapeutic technique due to excluding the work with patient's blood, accelerate the process of purification and regeneration of soft tissues in the region of inflammation and shorten therapy terms.

EFFECT: higher efficiency of therapy.

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