Method for preparing filling material for plastic surgery and instrumental cosmetology, filling material and method for introducing filling material into problem area

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely a method for preparing a filling material for plastic surgery and instrumental cosmetology. A method for preparing the filling material for plastic surgery and instrumental cosmetology consisting in the fact that sodium hyaluronate is prepared of cock's combs; a fraction of molecular weight 1000-2000 kDa is recovered; then sodium cations are substituted by cetylpyridinium cations; prepared hyaluronate ammonium salt is dissolved in an aprotonic solvent to produce internal esters; modified sodium hyaluronate is recovered by adding aqueous sodium chloride; sodium hyaluronate is deposited in acetone, dried and sterilised; thereafter the modified material is processed in a physiologically compatible aqueous solution to complete swelling and mechanically ground. The filling material for plastic surgery and instrumental cosmetology. The method for introducing the filling material for plastic surgery and instrumental cosmetology into problem area.

EFFECT: method enables preparing the biocompatible filling material with the pre-set physical-chemical properties.

3 cl, 3 tbl, 12 ex

 

The invention relates to medicine and can be used in plastic surgery and instrumental cosmetology for aesthetic correction of small defects of the skin, mainly on the face and neck, and hip problem areas.

Hyaluronic acid (ha) is a natural linear polysaccharide with unique biological and physico-chemical properties. Hyaluronic acid is present in various connective tissues of animals, such as skin and cartilage. Particularly rich in hyaluronic acid, the umbilical cord, synovial fluid, vitreous body and skin. In the skin and the cartilage of the role of hyaluronic acid is the binding of water and the maintenance of tone and elasticity of the fabric. In interstitial fluids viscous solution of hyaluronic acid serves as an emollient component, creating a cell protective environment.

In the composition of living organisms hyaluronic acid is mainly in the form of hyaluronates. Allocate and use it, usually in the form of sodium salt of hyaluronic acid is sodium hyaluronate.

Hereinafter, the term "Hyaluronic acid" is understood as the polyanion without specifying the corresponding cation and degree of dissociation (mark polyanion use the terms "hyaluronate" and "hyaluronan").

Hyaluronic acid has good what isometimes and does not cause the reaction to a foreign body or allergic reactions after implantation. These properties allow to use it in different areas of medicine such as surgery, dermatology, ophthalmology as well as in cosmetics and cosmetic surgery. The scope of products based on hyaluronic acid can significantly expand, changing its physical-chemical properties and increased resistance to depolymerization at the same time, retaining the compatibility with the tissues of mammals.

New biomaterials based on hyaluronic acid can be obtained by a variety of reactions according to the functional groups of the polymer. Chemically modified hyaluronic acid in the body is degraded at a slower rate, and cross-linked molecules, depending on the type of chemical modification and the degree of cross-stitching form a dense hydrogels that supports the specified volume and shape, or insoluble plastic materials. At the same time they retain the biocompatibility of natural jojoba.

There are different types of modification. For example, the method of crosslinking hyaluronic acid with the use of hydrophobic bonding or ionic bonding, which is run by her nucleophilic reagent [description of the invention to the US patent No. 4937270 from 18.09.1987, NCL. 514/777, publ. 26.06.1990].

There is a method of crosslinking hyaluronic acid by means of hydrophobin the th binding by the esterification of [description of the invention to the US patent No. 4851521 from 02.07.1986, NCL. 536/55 .1, publ. 25.02.1989].

There is a method of crosslinking hyaluronic acid by ionic binding of multivalent ions [description of the invention to the patent EP No. 0507604 A2 from 05.04.1991, IPC AC 31/40, AK 31/715, publ. 07.10.1992].

The disadvantages of these methods is that they contact force is weak compared to the strength of covalent binding, they are affected by external changes, such as pH, ionic strength, temperature and the like. In addition, when they are used as biomedical materials, the ability to remain in the living body is short, and it is difficult to adjust properly the ability to remain in the body to provide the physiological effects of hyaluronic acid on the body.

In addition, the known types of suture hyaluronic acid covalent binding through diphenylsulfone [description of the invention to the US patent No. 4582865 from 06.12.1984, NCL. 524/29, publ. 15.04.1986] and the stitching via epoxide [description of the invention to the US patent No. 4886787 from 13.02.1986, NCL. 514/57, publ. 12.12.1989]. The disadvantages of these methods is that crosslinking agents or crosslinking compounds used in these crosslinks in excess are toxic. In addition, the three-dimensional mesh structure is created by stapling at the same time, when diphenylsulfone, epoxide or the like enter the tsya in hyaluronic acid and educated structured gel based on hyaluronic acid is translated into an insoluble state in the solvent, such as water and the like. Unreacted low molecular weight compounds included therefore in the mesh structure, it is difficult to separate and remove.

On the other hand, it is known crosslinking of hyaluronic acid by cross-linking reaction fototerapia upon irradiation with ultraviolet rays [the Description of the patent WO No. 9718244 (A1) from 15.11.1995, IPC AC 47/36, publ. 22.05.1997] (JP-A-6-73102). This type of linkage has the advantage that photoreactivation derivative of hyaluronic acid that is injected photoreactivation cross-linking group, is soluble in water up to fotoallergiyami stitching and three-dimensional mesh structure is not formed at this time, so that unreacted low molecular weight compounds can be easily removed; photoreactive itself is so pure reaction that gives photoallergen derived crosslinked hyaluronic acid without unreacted low molecular weight compounds, and the resulting crosslinked structure is formed by covalent binding, so that the control ability to remain in the body vodootvedenija derived crosslinked hyaluronic acid can be easily carried out by adjusting the degree the stitching.

The above-mentioned photoallergen derived crosslinked hyaluronic acid is for p is imeneniya as biomedical materials, for example, anti-adhesive materials, which are investigated in plenkoobrazovatel form [Matsuda T., Moghaddam M.J., H. Miwa, K. Sakurai, Ilda F. Photoinduced prevention of tissue adhesion//ASAIO Journal. - 1992. - V.38(3). - P.M154-M157], but they are difficult to use to prevent adhesions in the thin parts of the tissues or organs. There is therefore a need for suitable for injection gel photoallergen crosslinked hyaluronic acid, which can be injected in such a delicate place. However, the hydrogel photoallergen crosslinked hyaluronic acid and the means of obtaining it are purely theoretical study and therefore their practical obtain unknown.

Also known a method of obtaining a biomaterial to prevent postoperative adhesions on the basis of sodium hyaluronate, which could potentially be used as a fill material for plastic surgery and instrumental cosmetology [description of the invention to the patent of Russian Federation №2177332 from 27.12.2001, IPC A61L 31/06, OR 41/00, publ. 27.12.2001]. The method comprises the substitution of the cations, sodium cations, Quaternary ammonium salts, dissolving ammonium salt hyaluronate in an aprotic solvent (in particular, dimethyl sulfoxide (DMSO)), obtaining internal ethers, the selection of modified sodium hyaluronate by adding an aqueous solution of sodium chloride, precipitation of sodium hyaluronate in AC the tone. Obtained by this way, the biomaterial is a benzyl ester of hyaluronic acid, which is from 75 to 100% of the carboxyl groups of hyaluronic acid tarifitsirovana benzyl radical. Up to 25% of carboxylic groups can be tarifitsirovana alkyl radical With10-C20-aliphatic alcohol, provided that at least 80% of the carboxyl groups tarifitsirovana. The biomaterial is made in the form of a membrane, a mesh, a woven or non-woven cloth or gel. Another variant of the biomaterial contains at least one derivative of hyaluronic acid, representing autoparacrine associated derivative of hyaluronic acid in which from 0.5 to 20% of carboxylic groups of hyaluronic acid cross-linked to a hydroxyl group of the same or different molecules of hyaluronic acid.

It should be noted that the use of mixed fractions of hyaluronic acid for obtaining the known method of inner esters can lead to the formation of a nonuniform mesh of relationships that may be unstable due to the effect of syneresis.

As starting compounds for carrying out synthesis using the hyaluronate in the form of water-soluble salts of Quaternary ammonium. The need for allocation of these salts in dry form by drying or freezing leads to degr the recommendations of the polymer chain from getting mixed in MM fractions, limit the volume and complicates the technology of production.

The task of the first invention group, and the technical result achieved is to create another method of obtaining fill material for plastic surgery and instrumental cosmetology on the basis of sodium hyaluronate is biocompatible with the tissues of mammals, which has predetermined physical and chemical properties: viscosity, plasticity, increased resistance to depolymerization and the predicted time of biodegradation.

To solve the problem and achieve the stated technical result in the method of obtaining fill material for plastic surgery and instrumental cosmetology, harakteryzuyetsya the fact that sodium hyaluronate is obtained from cocks ' combs, allocate it a fraction with a molecular weight of 1,000 to 2,000 kDa, then replace the sodium cations are cations of cetylpyridinium obtained ammonium salt hyaluronate is dissolved in an aprotic solvent, receive internal ethers, allocate modified sodium hyaluronate by adding an aqueous solution of sodium chloride, the precipitated sodium hyaluronate in acetone, dried and sterilized, after which the modified material is treated with a physiologically compatible aqueous solution until complete swelling and mechanical is Malchut to size particles of 50-100 microns.

Known injected implants on a ceramic base to fill wrinkles, skin depressions and scars containing microparticles biocompatible ceramic compounds in suspension in liquid media, where these microparticles are biodegradable and have a size of from 10 to 80 μm, the ceramic compound contains at least one component selected from the group consisting of tricalcium phosphate (VDR) and two-phase products (HRV), which include hydroxyapatite (NAR) and VDR variable in the relationship, with the specified component is wtsr, and the above-mentioned carrier liquid contains at least one compound based on hyaluronic acid and at least one biodegradable thixotropic connection with pseudoplastic-type properties [description of the invention to the patent of Russian Federation №2315627 from 27.01.2004, IPC A61L 27/12, A61L 27/50, A61L 27/58, A61L 27/46, A61F 2/00, publ. 27.01.2008].

The implant in accordance with the present invention has the form of microparticles, if necessary, the shape of the beads in suspension in the liquid medium carrying the said microparticles. These particles should have a diameter exceeding 10 μm, in order to avoid rapid or instant phagocytosis by macrophages. They should have a diameter less than 45 microns, so that they can be injected using a very fine needle (usually ranging in size from 25 to 30 G). Suppose the equipment, according to the invention, the carrier liquid is chosen so that it had its own viscosity sufficient for injection through a needle ranging in size from 25 to 30 G and to maintain the homogeneity of the mineral phase, which is a ceramic compound in suspension in the liquid phase, which is the carrier liquid.

Yet there is no information that allows to produce a comprehensive assessment wtsr in the process of filling wrinkles (intradermal injection). It is known that after 3 months showed a significant decrease in cell density of the connective capsule, as well as its thickness, which reflects the decrease in the intensity of the inflammatory response upon decomposition of the implant (approximately 50% in three months, which proves the complete disappearance of the product for the period from 8 to 16 months, depending on known models of decomposition). In the specification for the use of the particle "Biosorb®" is not specified the possibility of implantation of particles in soft tissue. The consequences of the constant presence of excess calcium in the soft tissues have not been investigated and may result in the appearance of calcification and dystrophic calcification. This type of calcification may occur as a response to any soft tissue injuries, including those associated with implantation of a medical device.

Known biocompatible polymeric material, consisting of hyaluronic acid is you, fixed the polymer carrier and water, at the same time as the fixed polymer carrier used net polyamines gel, the equilibrium swollen in the aqueous medium, or copolymers of unsaturated polyamines and uncharged water-soluble Ethylenediamine monomers obtained by the copolymerization in aqueous medium in the presence of crosslinking agents. [Description of the invention to the patent of Russian Federation №2162343 from 01.09.1999, IPC7A61L 15/00, A61L 27/00, A61K 31/728, publ. 27.01.2001]. This material can be used for the manufacture of a variety of implants in ophthalmology (e.g., intraocular and intracorneal lenses, contact lenses, devices for antiglaucomatous surgery, oculoplastics implants) and surgery (for example, implants, biopolymer bandages in plastic and reconstructive surgery).

Known material resistant to the action of proteolytic enzymes, is aboratories that provides permanent implants. The technology of the receipt of the biocompatible polymer material does not imply the grinding and injection method injection. The resistance of biomaterial in the tissues does not allow further correction region (for example, in the case of medical errors in the introduction), and in some cases may cause the appearance of granuloma, cyst what's knots and chronic inflammatory response with repeated injections.

Known Vodootvodny gel crosslinked hyaluronic acid, which can be used as a fill material for plastic surgery and instrumental cosmetology, with the storage modulus (G') of from 50 to 1500 PA, a loss modulus (G") of from 10 to 300 PA and a tan Delta (G"/G') of from 0.1 to 0.8 in dynamic viscoelasticity with the density of the polymer network (frequency cross-linking or grid nodes) from 0.01 to 0.5% per 1 mol of constituent disaccharide glycosides level of hyaluronic acid which is a hydrogel obtained by irradiation with ultraviolet rays photoreactivation a derivative of hyaluronic acid, which photoreactivation cross-linking group chemically linked to a functional group of hyaluronic acid and is derived from cinnamic acid, containing a spacer selected from a range that includes groups derived from amerosport, amino acids or peptide, these adjacent photoreactivation crosslinking group specified photoreactivation derived hyaluronic acid demonizovana by irradiation with ultraviolet rays with the formation of CYCLOBUTANE ring, with the formation of a mesh structure, and the gel is a hydrogel in such condition that it can be extracted for injection from the container during extrusion [description of the of the invention to the patent of Russian Federation №2197501 from 14.11.1996, IPC7SW 37/08, A61L 15/50, A61L 27/20, A61K 47/36, A61K 47/48, publ. 27.01.2003].

Irradiation of hyaluronic acid by ultraviolet radiation, on the one hand, leads to the formation of cross-links, on the other hand, to the breaking of its polymer chain, which can lead to the formation of a nonuniform mesh of relationships that may be unsustainable (to show the effect of syneresis). Also ultrafialove irradiation of the gel cross-linked hyaluronic acid leads to the formation of free radicals, contributing to its further destruction, and after the introduction of the drug intradermally and surrounding tissues. Ultraviolet light breaks the structure of the hydrogel, which is beginning to have improved adhesive properties, which contributes to more successful colonization on the micro-organisms.

The task of the second invention group, and the technical result achieved is to create another fill material for plastic surgery and instrumental cosmetology based on hyaluronic acid, a biocompatible with the tissues of mammals, which has predetermined physical and chemical properties: viscosity, plasticity, increased resistance to depolymerization and the predicted time of biodegradation.

To solve the problem and achieve the stated technical result fill m the material predetermined for plastic surgery and instrumental cosmetology based on hyaluronic acid produced by the method according to the first invention group.

There is a method of introducing a filling material for plastic surgery and instrumental cosmetology based on crosslinked hyaluronic acid (sodium hyaluronate) in the problem area, lies in its injecting by squeezing from a tube or syringe, etc. [Cm. description of the invention to the patent of Russian Federation №2197501].

Given the large variation in size of the molecules of hyaluronic acid, is not enough to have the filling material and the sample delivery means in the problem area. Need guaranteed sterility of the material and defined under the size of the molecules, the parameters of the needle to its introduction to the problem area.

The task of the third invention, and the technical result achieved is to create a way of introduction to the problem area of fill material for plastic surgery and instrumental cosmetology based on hyaluronic acid, a biocompatible with the tissues of mammals, which has predetermined physical and chemical properties: viscosity, plasticity, increased resistance to depolymerization and the predicted time of biodegradation.

To solve the problem and achieve the claimed technical effect in the way of introducing the filling material for plastic surgery and instrumental cosmetology in roblimo zone of fill material was obtained by the method according to the first invention group, sterilized and injected injection, the diameter of the needle within 25-27 G.

The third invention is illustrated in the drawing, where:

- figure 1 shows a General view of the device for implementing the method of introduction into the problem area of fill material for plastic surgery and instrumental cosmetology on the basis of sodium hyaluronate, with special shaft, disassembled (as delivered to the consumer, and the needle is conventionally not shown);

- figure 2 - view of the device prepared for injection in the problem area.

The method of obtaining fill material for plastic surgery and instrumental cosmetology, characterized in that sodium hyaluronate produced from primary raw materials, which is used, as a rule, rooster combs, allocate it a fraction with a molecular weight of 1,000 to 2,000 kDa, then replace the sodium cations are cations of cetylpyridinium obtained ammonium salt hyaluronate is dissolved in an aprotic solvent, such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), diethylacetamide (DEAM), sulfolane or other, get internal ethers and produce a modified sodium hyaluronate by adding a physiologically compatible aqueous solution of sodium chloride, the precipitated sodium hyaluronate in acetone, dried and sterility is, then the modified material is treated with a physiologically compatible aqueous solution until complete swelling and mechanically ground to a particle size of 50-100 μm.

This way we obtain the original fill material for plastic surgery and instrumental cosmetology based on hyaluronic acid, which is Packed for 1.0-1.5 ml, for example, the device comprising a sealed housing 1 with a cover in the form of the piston 2 and the tip-cone type 3 "Luer" with a screw cap Luer Lok (Luer Lock) for connection with the head 4 needle, the diameter of which ranges from 25 to 27 G (or from 0.41 mm to 0.51 mm). Further, the device and its contents are sterilized. In the initial state of the device, the tip 3 is closed by a removable stopper 5 and the rod 6 to reduce the dimensions to make seasoned normalized dose filling material 7 to the housing 1 for the subsequent Assembly with the piston 2 and is sealed. Thus, it becomes possible to carry out the method of injecting the filling material for plastic surgery and instrumental cosmetology based on hyaluronic acid in the problem area. Analyze the materiality of signs inventions. The method of obtaining fill material for plastic surgery and instrumental cosmetology on the basis of sodium hyaluronate includes p the torching of sodium hyaluronate, from raw materials, which is used, as a rule, rooster combs. Integral fractions of hyaluronic acid obtained by extraction from natural materials have a molecular weight varying in a wide range depending on the method of isolation and purification, is from about 30 to 3000 kDa. During the same extraction procedures can be obtained fairly broad molecular weight mixed fractions. The use of such fractions of hyaluronic acid to obtain a cross-linked products leads to the formation of a nonuniform mesh of relationships that can become unstable when changing external conditions (to show the effect of syneresis). To avoid syneresis of the products modifications to carry out the separation and purification of mixtures of molecular fractions by known methods, for example by ultrafiltration (see, for example, US No. 5925626 - Hyaluronic acid fractions having pharmaceutical activity, and pharmaceutical compositions containing the same, the fraction of hyaluronic acid with molecular weight of 50-100 500-730 kDa obtained by ultrafiltration integral fraction through a membrane with a pore size of 30 kDa: larger molecules remain on the filter, are smaller and are selected; or, see, for example, US No. 5559104 - fractions of hyaluronic acid with a molecular mass of 750-1250 kDa, obtained by the same method) or tangency is through filtering. Filtering systems tangential filtration is tangential flow through the ceramic or polypropylene membrane with a defined pore size.

In particular, you can use Proskurnya polysulfone membrane with a pore diameter of 1000 and 2000 kDa, allowing removal of hyaluronic acid from the contained impurities and to obtain a fraction of hyaluronic acid with a molecular weight of from 1000 to 2000 kDa.

Used in the invention, the fraction of hyaluronic acid with a molecular weight of from 1000 to 2000 kDa relates to high molecular weight fractions and the introduction of soft tissue exhibits anti-inflammatory properties, and also contributes to the inhibition of the aggregation and adhesion of platelets. While low and medium molecular fraction with a molecular mass of from 30 to 500 kDa can be Pro-inflammatory action (endocrinopathy factors of inflammation). The choice of these boundaries fractions of hyaluronic acid taken for carrying out modifications, due to the need for compensation of technological losses of molecular weight due to degradation of the polymer in the process of obtaining fill material to ensure the absence in the final product impurities of hyaluronic acid with a molecular weight of less than 500 kDa, which eliminates the possibility of any negative reactions. High is warnie fractions of hyaluronic acid with a weight of 2000 kDa and above have a higher viscosity consequently, a lower reactivity due to the large diffusion limitations.

The method of obtaining fill material on the basis of sodium hyaluronate includes obtaining a cross-linked derivatives of hyaluronic acid, characterized by a high biocompatibility. The materials are fully biodegradable materials with variable time degradation and do not require removal from the site of application. Being prepared in the form of gels, cross-linked derivatives provide plastic materials with a much higher viscosity than the unmodified polymer, making them suitable for different uses in plastic surgery and instrumental cosmetology.

As indicated above, the present invention is characterized materials, including derivatives of hyaluronic acid, especially derivatives with internal cross-links (internal esters"). The term "cross-linked" refers to a cross-connection between the carboxyl and hydroxyl groups of molecules, hyaluronate, and the term "internal ether" denotes, in particular, incomplete internal esters of hyaluronic acid formed cross-links between carboxyl and hydroxyl groups of the molecules of hyaluronate.

In the process of getting inside the x esters of hyaluronic acid necessary to activate the carboxyl groups of the molecules of hyaluronic acid. Unstable intermediate products obtained in the reaction activation spontaneously separated or after the addition of catalysts and/or as a result of increasing temperature, forming an internal hard-essential connection with the hydroxyl of the same or different molecules of hyaluronic acid. In accordance with the desired level of internal esterification activate either all or aliquot part of the carboxyl functional groups.

In particular, obtaining a complex inner esters of hyaluronic acid is carried out in dimethyl sulfoxide using iodide 1-methyl-2-chloropyridine (reagent Mukami). The reagent Mukami acts as an activator of the carboxyl groups of hyaluronate, forming with the latter intermediate, which in the presence of a tertiary amine formed with a hydroxyl group of another disaccharide glycosides link ester link:

Education internal ester linkages can occur in a fairly wide temperature range, for example between 0°C and 150°C, preferably at room temperature or slightly higher, for example between 20°C and 75°C. the Increase in temperature favors the formation of internal ester linkages, as the effect of radiation of a suitable wavelength, such as ultraviolet radiation. At the same time, p is the rise in temperature contributes to the degradation of the polymer chain. Lowering the temperature below 30°C leads to gel the reaction mixture. To reduce the degradation of hyaluronic acid and maintain the reaction mixture in the liquid state is preferable to conduct the reaction in the temperature range from 30 to 50°C.

Usually, to obtain intramolecular esters of hyaluronic acid as a starting compound used salts of Quaternary ammonium compounds having aliphatic part of the number of carbon atoms from 1 to 6, in particular hyaluronate tetrabutylammonium.

Hyaluronate tetrabutylammonium readily soluble in dimethyl sulfoxide, and water. It is produced by the methods of ion-exchange chromatography with subsequent drying out or freezing, which limits the volume and complicates the technology of production.

Instead of hyaluronate tetrabutylammonium as a starting compound can be used not water soluble hyaluronate N-cetylpyridinium. Hyaluronate N-cetylpyridinium widely used in the processes of purification and fractionation of hyaluronic acid, for example [description of the invention to the US patent No. 5925626 from 20.07.1999, NCL. 514/54, publ. 06.06.1995], as well as for the formation of cationic complexes in reactions acetylation of hyaluronic acid, for example [description of the invention to the US patent No. 6673919 from 06.01.2004, NCL. 536/124, publ. 28.05.2002]. Usually hyaluronate N-cetylpyridinium p is obtain by mixing equimolar solutions of sodium hyaluronate and chloride N-cetylpyridinium at a temperature hiscountry solution of sodium hyaluronate is usually 0.01 to 1%, preferably of 0.5%. Sediment hyaluronate N-cetylpyridinium separated by centrifugation or by filtration, washed with distilled water and dried in air, under vacuum or freeze.

Alternative drying technology hyaluronate N-cetylpyridinium is the distribution of sediments on the smooth surface in the form of a thin film, followed by drying at 50°C and subsequent grinding. This method allows you to obtain the dry product in the form of a film, which then dissolves faster in aprotic solvents, which allows to reduce thermal degradation of the chain of hyaluronic acid.

Crosslinked hyaluronic acid can precipitate, pouring in miscible with water, an organic solvent, for example acetone, methyl ethyl ketone, dimethylformamide, dimethylsulfoxide, methanol, ethanol, 2-propanol, acetonitrile, tetrahydrofuran, N-the organic and the like, preferably an alcohol, for example ethanol. The precipitate can be collected and dried, for example under reduced pressure.

Dry crosslinked hyaluronic acid can be crushed by any method well known in this field, for example by abrasion, grinding, tearing, etc. but it is preferable to grind the grinding at cryogenic mill. On the other hand, not crosslinked hyaluronic acid can be planted during cooling (cryopre IPFIREWALL) with the formation of small particles, which then can be dried, or not crosslinked hyaluronic acid can pulverize cryogenic mill and the resulting particles are then dried.

The dried modified product process bringing to full swelling by hydrating using a physiologically compatible aqueous solution and mechanically ground to a particle size of from 50-100 microns using grids. Crushed the modified product is placed in the delivery device in the problem area, and then subjected to sterilization.

The result is the original fill material for plastic surgery and instrumental cosmetology based on hyaluronic acid, which is Packed by 1.0 to 1.5 ml per special device for delivery to the problem area. This is enough for one full session of aesthetic correction and/or replacement small facial defects, i.e. to implement the method of introducing the filling material for plastic surgery and instrumental cosmetology in the problem area. The delivery device includes a sealed housing 1 with a cover in the form of the piston 2 and the tip of the cone 3 for connection with the head 4 needle, the diameter of which is in the range of 25-27 G (0,41-0.51 mm). When using a needle with a smaller diameter will require considerable effort on Vidal the content of the housing 1 with the corresponding consequences, such as reducing the accuracy of the coordination of the hands of the doctor and others, and the use of needles with a larger diameter will increase the trauma and pain of the procedure.

The implementation of the invention consider the following typical examples.

Example 1. Getting a working fractions of hyaluronic acid for further modification.

Hyaluronic acid is obtained by extraction from cocks ' combs. Purified integral fraction divide the speed by the method of tangential filtration followed by concentration and deposition substrate ethanol for conversion into dry matter. For fractionation using Proskurnya polysulfonamide membrane modules with a pore diameter of 0.1 and 0.2 μm of production "Bladisat". The result is hyaluronic acid for subsequent modification (see below for Examples 2-5) within the boundaries of molecular weight of 1000 kDa to 2000 kDa.

Example 2. Getting hyaluronate of cetylpyridinium.

to 5.00 g (12.4 mmol of monomer) of sodium hyaluronate dissolved in 1 l of distilled water under stirring on a magnetic stirrer for 4 hours. to 5.00 g (14 mmol) dnovotny salt of pyridinium chloride dissolved in 1 l of distilled water, heated to 30°C. the resulting solution heated to 60°C. and a solution of sodium hyaluronate are added to a solution of chloride of cetylpyridinium under stirring. Obtained the spengiu cooled to room temperature, the precipitate is filtered off, washed several times with distilled water, spread a thin layer on a glass surface and dried at 40°C for 4 hours. Get 7,56 g of dry hyaluronate of cetylpyridinium (output 94,5%).

The following examples describe obtaining cross-linked products of hyaluronic acid with different percentage of cross-connections, used for the production of concrete fill material. The percentage of cross-connections in the affected product, at least on its viscosity and resistance to depolymerization. For example, for problem areas-neck, thin, superficial wrinkles and areas with thin skin, you can use the filling material based on hyaluronic acid with 5% cross-links; for the correction of wrinkles and lip shape - from 15% cross-links; for the correction of wrinkles and folds, as well as hip replacement with 25% of cross-connections.

Example 3. Receiving a modified hyaluronic acid with 5% cross-ties for the lling material.

Description (properties) of the product: 5% carboxyl groups used for internal esterification; 95% of the carboxyl groups form salts with sodium.

6,445 g (10.0 mmol of monomer), hyaluronate N-cetylpyridinium dissolved in 250 ml of DMSO at 50°C, add of 0.07 ml (0.5 mmol) of t is ethylamino and the resulting mixture is stirred for 30 minutes.

A solution of 0.13 g (0.5 mmol) of iodide 2-chloro-1-methylpyridine in 50 ml of DMSO is slowly added dropwise over a period of time equal to 20 minutes, and the mixture was incubated for 15 hours at 30°C.

Then add a solution formed from 100 ml of water and 2.5 g of sodium chloride, and the resulting mixture was then slowly poured to 1250 ml of acetone, while maintaining constant stirring. Formed precipitate, which is then filtered and washed three times with 500 milliliters of an aqueous solution of acetone in the ratio of 5:1, then 500 ml of acetone and finally dried for 24 hours at 30°C. the Dried product suspension in 350 ml of 0.9% sodium chloride solution and then precipitated in 1750 ml of acetone. The precipitate is separated, washed with 500 milliliters of an aqueous solution of acetone in the ratio of 5:1, then 500 ml of acetone and finally dried for 24 hours at 30°C. are obtained as a result of 3.45 g of product (yield 86%).

Quantitative determination of the ester groups is carried out by the method of saponification, as described, for example, in "Quantitative organic analysis via functional groups", 4th edition (John Wiley and Sons), str-172.

An accurately weighed sample of 0.5 g of polymer is placed in a container of 200 ml, add 30 ml of 0.25 M (mol/l) alcohol solution of sodium hydroxide (NaOH). Capacity, sealed and heated at 100°C during the day. In parallel, heat 30 ml of 0.25 M alcohol solution of sodium hydroxide (NaOH). After ending the FL heat the solution is quantitatively transferred into a chemical beaker by adding 400 ml svezhekipyachenoy distilled water. The solution is titrated potentiometrically 0,25M solution of hydrochloric acid. On titration curves determine the equivalence point and the amount of hydrochloric acid followed by titration. The difference between the volumes of hydrochloric acid followed by titration of the control experiment, a solution of hyaluronic acid and solution of modified hyaluronic acid to determine the amount of acid, followed by saponification of the ether linkages. The data processing and calculation of the content of ester bonds oeffin terms of carboxyl group is conducted according to the following formulas:

yeff=neff/nCC=(VCC-Veff)PCHCl/nCC,

where VCCand Veffvolume of hydrochloric acid followed by titration of hyaluronic acid and a sample of the ether, respectively, ml;

CHClthe concentration of hydrochloric acid, CHCl=0.25 mol/l (mmol/ml);

hCC=1,25 - number of millimoles of hyaluronic acid taken for titration.

Example 4. Receiving a modified hyaluronic acid with 15% cross-ties for the lling material.

Description (properties) of the product: 15% of the carboxyl groups is used for internal esterification; 85% of the carboxyl groups form salts with sodium.

Receiving a modified hyaluronic acid with 15% of cross-connections and determination of ester groupprovides analogously to Example 3, choose 6,445 g (10.0 mmol of monomer), hyaluronate N-cetyl-pyridinium, of 0.21 ml (0.15 mmol) of triethylamine and 0.39 g (0.15 mmol) of iodide 2-chloro-1-methylpyridine.

Example 5. Receiving a modified hyaluronic acid with 25% of the cross-ties for the lling material.

Description (properties) of product: 25% of carboxylic groups used for internal esterification; 75% of carboxylic groups form salts with sodium.

Receiving a modified hyaluronic acid with 25% of cross-connections and the determination of the ester groups is carried out analogously to Example 3, choose 6,445 g (10.0 mmol of monomer), hyaluronate N-cetylpyridinium, of 0.35 ml (0.25 mmol) of triethylamine and 0.65 g (0.25 mmol) of iodide 2-chloro-1-methylpyridine.

Example 6. Obtain fill material from dehydrated (dehydrated) crosslinked hyaluronic acid.

Dry powder crosslinked hyaluronic acid suspended in phosphate buffer to obtain a suspension with a concentration of 10 mg/ml in the form of a thick mass or paste. Phosphate buffer has a pH of 7.4 and its osmotic concentration corresponds to 0.9% solution of sodium chloride, the composition of the solution: disubstituted phosphate sodium (Na2HPO4) - 0,610 g (or Na2HPO4·2H2O - 0,765 g), one-deputizing sodium phosphate (NaH2PO4·2H2O) - 0,088 g, sodium chloride and 17 g, distilled water - up to 2 L. the Osmolarity of the suspension is avodat to 300-340 mOsm (milliosmoles) by adding sodium chloride. The suspension is mechanically ground serial transmission through the grid with cell size (ERP) ≈0,5×0,5 mm and ≈0,1×0,1 mm the resulting product with a particle size of 50-100 μm is placed in the delivery device in the problem area. Why measure a given volume of the dispenser and is moved inward of the housing 1 from its open part 8. Further, with the simultaneous discharge of the air bubble in the housing 1 is inserted into the piston 2. The housing 1 is equipped with a stem 6, which is applied with the possibility of further Assembly or directly inserted (screwed) into the corresponding threaded socket 9 of the piston 2 with its threaded section 10. Then filled with product case 1, equipped with a stem 6, is subjected to sterilization, in particular autoclave at 120°C and a pressure of about 138 kPa for 25 min, and sealed, for example, in blister.

The resulting preparation, pre-packaged, as experience has shown, the optimal dose of 1.0 and/or 1.5 g in devices delivered in the problem area, ready for use for its intended purpose.

Example 7. Description dynamic viscosity of the hydrated gels of hyaluronic acid.

The rheological behavior of the gels obtained in examples 3-6, was estimated using a rotational viscometer "Polymer RPE-1M" perceiving elements "cone-plane" Q3-03. Conditions of erenia include temperature, equal to 37°C, the surface geometry, which is a flat plate, and the cone angle at the vertex of 0.3°, the gap between the surfaces 200 μm, gradient shear 501 c-1.

Measured in these conditions, the values of the dynamic viscosity of the gels was 470±30 MPa·s for the sample with 5% cross-links, 650±50 MPa·s for the sample with 15% of cross-connections and 740±50 MPa·s for the sample with 25% of cross-connections.

Example 8. The characteristic strength of the extrusion (extrusion) of hydrated gels of hyaluronic acid.

The force required for extrusion of the gel can be characterized by loading the gel volume of 2.25 ml in the case of the claimed device with an internal diameter 8,65 mm, equipped with a needle 27-th size (27 G, the inner diameter of 0.21 mm, the cross-sectional area 0,0346 mm2). The force required for extrusion of the gel through the said needle with a speed of 0.15 ml/min, was measured by placing the syringe in a syringe pump connected to the measurement system of forces.

At a temperature of approximately 25°C and the speed of extrusion of 0.15 ml/min extrusion force was 3.6 N (Newtons) for a 1.0% solution of unmodified hyaluronic acid; 2,9 N for the sample with 5% cross-links (obtained according to Examples 3 and 6); and 6.6 H for the sample with 15% cross-links (obtained according to Examples 4 and 6) and 9.7 N for the sample with 25% cross-links (obtained by P is emeram 5 and 6). These indicators are appropriate for conducting the expert manipulation of the device for delivery of fill material in the problem area.

Example 9. The characteristic resistance of the filling material to enzymatic hydrolysis.

The durability of the product when introduced into the organism is determined by its sensitivity to enzymatic hydrolysis, although there are other factors influencing the time of its location in the body (or the time resorption). The stability of the crosslinked hyaluronic acid in the enzymatic hydrolysis is measured by test in vitro, combining the gel with a known amount of enzyme hyaluronidase and registering the change in viscosity of the gel as a function of time or determining the concentration of the released low molecular weight hyaluronic acid (disaccharide glycosides of links).

To the gel, placed in a container, add a solution of testicular hyaluronidase (enzyme from bull testes). The hyaluronidase solution is prepared by dissolving the contents of 1 ampoule of medicine "Lydasum" (64 USD) in 5 ml of 0.15 M NaCl solution. To five servings of gel volume of 5 ml was added 0.25 ml hyaluronidase (0,64 $ /ml in the final solution) and stirred. The mixture is placed in a sterile box and incubated at 30°C for 1-14 days. To stop the hydrolysis mixture is boiled on a water bath at those who tell 10 min in 1, 2, 3, 7 and 14 days. After cooling to a temperature measured dynamic viscosity of the samples using a rotational viscometer "Polymer RPE-1M by the method described in Example 7. These information materials obtained in Examples 3-6 are presented in Table 1.

To determine the concentration of the released low molecular weight hyaluronic acid (disaccharide glycosides of links) in the solution during degradation spend photocolorimetric determination of glucosamine method Elson Morgana in each period of time (1, 2, 3, 7 and 14 days). Information for materials obtained in Examples 3-6 are presented in Table 2.

Thus, the composition of this example can be considered stable in the conditions of the test. Experienced in this field specialist will understand that the compositions are stable in such conditions, you can expect good stability in vivo.

Example 10. The study of fill material for plastic surgery and instrumental cosmetology toxicity and biocompatibility.

It is known that any effects on the body are reflected in changes in the blood system. Morphofunctional characteristics that maintain the integrity of red blood cells may change when exposed to a number of external and internal factors. Normal erythrocytes are able to a certain limit against octoate osmotic action, mechanical, chemical and thermal influences. It is characterized by the notion of resistance. Irrespective of the nature of the first pathogenic link external factors is membranopovrezhdayuschih effect. The membrane of erythrocytes reflects the biochemical structure of membranes of various tissues. Therefore, the study of osmotic resistance of erythrocytes - quantitative determination of the degree of hemolysis of erythrocytes in sauverny hypotonic solutions of sodium chloride, in the presence of an investigational drug can give information about the presence or absence membranopovrezhdayuschih components.

Reagents

The main solution (by its osmotic concentration corresponds to 10% sodium chloride solution) has a pH of 7.4, the composition of the solution: disubstituted phosphate sodium (Na2HPO4) - 27,31 g (or Na2HPO4·2H2O - 34,23, g), one-deputizing sodium phosphate (NaH2PO4·2H2O) - a 4.86 g, sodium chloride - 180 g, distilled water - up to 2 l of this stock solution was diluted in 10 times and get the solution appropriate for their osmotic concentration of 1% solution of sodium chloride. From this solution prepare working solutions of sodium chloride of the following concentrations, %: 0,85; 0,75; 0,70; 0,65; 0,60; 0,55; 0,50; 0,45; 0,40; 0,35; 0,30; 0,20 and 0.10.

The process of determining

In two sterile tubes with pre-made 2 to what Plame heparin take 1.5 ml of blood, mix and use for research, second left on the clock in thermostat. In a series of centrifuge tubes (14) pour 5 ml of working solutions of sodium chloride concentration from 1 to 0.10%. In each centrifuge tube add 0.02 ml of mixed heparinised blood and leave at room temperature for 30 minutes and Centrifuged the mixture of blood with solutions of sodium chloride at 2000 rpm for 5 minutes of each tube decant the supernatant and measured fotoelektrokalorimetry at a wavelength of 500-560 nm (green filter) in a cell with a layer thickness of 10 mm against the blank sample.

Idle test - supernatant in a test tube containing 1% sodium chloride solution.

Calculation

For 100% hemolysis take hemolysis in vitro, containing 0.1% sodium chloride solution. Calculate the percentage of hemolysis in each tube, comparing the magnitude of the extinction of the supernatant liquid with extinction, taken as 100%, according to the formula:

The percentage of hemolysis=Ex×100/E1,

where E1- the extinction of the supernatant liquid in the test tube with 0.1% solution of sodium chloride;

Ex- the extinction of the investigated samples;

100 - percentage of hemolysis in vitro with 0.1% solution of sodium chloride.

The next day repeat the study with blood, incubated 24 h at 37°C.

Experimental results DL the filling material, obtained in Examples 5 and 6, are summarized in Table 3, from which it follows that the values of osmotic resistance of erythrocytes on average, exceed the value of reference blood sample. It speaks to the lack in the filling material membranopovrezhdayuschih components, and thus of its biocompatibility and absence of a pronounced toxicity.

Example 11. Clinical efficacy.

Clinical efficacy of fill material was estimated on the basis of the Institute of plastic surgery and cosmetology (Moscow). Indications for use of the drug were photoaging, dry, Mature, dehydrated skin, correction of facial wrinkles, atrophic scars, contour deformations. Injections of the drug were carried out in 12 patients aged from 33 to 67 years. The drug was injected linear technology at a depth of 3-4 mm vnutriaortalina at an angle of 20-25 degrees to the skin surface, the cut needle (27 G) is directed downwards, in the areas of depression perpendicular to the wrinkles. After the introduction was carried out intense pressure at the injection site for a uniform distribution of the drug and a light massage with vessel restorative and anti-inflammatory cream. After the procedure, if necessary, use ice to reduce swelling and pain.

After the introduction of the drug within 15 days noted improvement tour is ora, color, alignment, elevation of the surface of the skin. Good result and a pronounced clinical effect was observed in nine (75%) patients, satisfactory in three (25%) patients. One (8%) of patients with a satisfactory result was observed allergic reaction that is not critical when carrying out such procedures.

The study confirmed the efficacy, safety, tolerability of fill material and the possibility of its use for contouring method biorevitalisation with the aim of aesthetic correction of the surface topography of the skin (wrinkles, folds, atrophic scars, contour deformations).

Example 12 - synthesis.

To obtain fill material for plastic surgery and instrumental cosmetology take the combs of roosters, from which is extracted hyaluronic acid in the form of its sodium salt. After cleaning allocate the fraction with molecular weight of 1000-2000 kDa and dissolved in water. Add an aqueous solution of chloride of cetylpyridinium to replace the cations, sodium cations of cetylpyridinium. The obtained water-insoluble ammonium salt hyaluronate is isolated and dried.

The selected salt is dissolved in dimethyl sulfoxide. After adding the appropriate reagents (see example 3) receive internal ethers. The addition of the same solution of sodium chloride cations of cetylpyridinium replace the sodium cations. Modified sodium hyaluronate precipitated in acetone and dried. The dried modified hyaluronate treated with physiologically compatible aqueous solution of phosphate buffer until complete swelling and mechanically ground to a particle size of 50-100 μm by sequentially passing through the grid with the appropriate mesh size.

The resulting product based on hyaluronic acid is a filling material for plastic surgery and instrumental cosmetology. For it is injected into the problem area using a special device with a needle, the diameter of which is within 25-27 G. This material is subjected to sterilization after it is put in the device for delivery.

Delivery of fill material in the problem area is a doctor-cosmetologist trained to work with polymer gels and procedures biorevitalisation.

The use of inventions have been created yet another way to obtain fill material for plastic surgery and instrumental cosmetology on the basis of sodium hyaluronate filling material biocompatible with the tissues of mammals, which has predetermined physical and chemical properties: viscosity, plasticity, increased resistance to depolymerization and predicted the time of biodegradation, and, accordingly, the method of its introduction in the problem area.

Table 1
The values of the dynamic viscosity of the samples during enzymatic hydrolysis
Time of enzymatic hydrolysis, the dayDynamic viscosity, MPa·s
the degree of crosslinking of 5%the degree of crosslinking 15%the degree of crosslinking 25%
0470±30650±50750±50
1140±10670±50760±60
2110±10690±40780±70
3120±10700±60800±70
7120±10400±30800±70
1420±1320±25 790±70

Table 2
The content of low molecular weight hyaluronic acid after enzymatic hydrolysis for samples with different degree of crosslinking, a certain method Elson-Morgan
Time of enzymatic hydrolysis, the dayThe content of low molecular weight hyaluronic acid, calculated on the mass of the sample, %
the degree of crosslinking of 5%the degree of crosslinking 15%the degree of crosslinking 25%
00,000,000,00
10,72±0,060,83±0,070,12±0,01
21,16±0,090,80±0,060,2±0,01
31,24±0,080,88±0,070,27±0,02
72,5±0,21,63±0,110,34 is 0,02
142,7±0,21,65±0,130,41±0,03

Table 3
Osmotic resistance of erythrocytes
The concentration of NaCl, %Hemolysis of erythrocytes, %
Sample 1Sample 2Sample 3Reference values
experiencecontrolexperiencecontrolexperiencecontrol
0,850000000
0,75000000 0
0,650000000
0,550000000
0,504535060-6
0,452427232744435-45
0,4085877584888750-100
0,35949293 93959590-100
0,25969893989510098-100
0,10100100100100100100100

1. The method of obtaining fill material for plastic surgery and instrumental cosmetology, characterized in that sodium hyaluronate is obtained from cocks ' combs, allocate it a fraction with a molecular weight of 1,000 to 2,000 kDa, then replace the sodium cations are cations of cetylpyridinium obtained ammonium salt hyaluronate is dissolved in an aprotic solvent, receive internal ethers, allocate modified sodium hyaluronate by adding an aqueous solution of sodium chloride, the precipitated sodium hyaluronate in acetone, dried and sterilized, after which the modified material is treated with a physiologically compatible aqueous solution until complete swelling and mechanically ground to a particle size of 50-100 μm.

2. apostasy material for plastic surgery and instrumental cosmetology based on hyaluronic acid, characterized in that it is obtained by the method according to claim 1.

3. The method of introducing the filling material for plastic surgery and instrumental cosmetology in the problem area, characterized in that the filling material obtained by the method according to claim 1, sterilized and injected injection, the diameter of the needle within 25-27 G.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention refers to medicine and aims at prevention of complications following the intestinal operations, at prevention of intestinal anastomotic leak, ischemic disorders in enteroenteroanastomosis in periotonitis, acute intestinal obstruction. There are involved the intra- and immediate postoperative introductions of hydroxyethyl starch (HES) 130/0.4 and balanced polyionic crystalloid solutions in ratio 1:3. The volume is gradually reduced to achieve the volume 3 times less than the initial one by the 7th day.

EFFECT: method enables reducing a probability of postoperative intestinal anastomotic leak.

1 ex

FIELD: medicine.

SUBSTANCE: there are presented hyaluronidase protein of molecular weight approximately 44±1 kDa containing an amino acid sequence at least by 90% identical to an amino acid sequence containing SEQ ID NO: I, SEQ ID NO: 2 and SEQ ID NO: 4 presented in the description, as well as DNA coding it. What is described is a pharmaceutical medical composition for increasing tissue penetration and decreasing connective tissue viscosity containing an effective amount of recovered said hyaluronidase and a pharmaceutically acceptable excipient, a carrier, a solvent and an additive agent. The following methods are presented: 1) prevented or minimised cicatrisation involving the local introduction of said pharmaceutical composition; 2) reduced wrinkle formation by decreasing connective tissue viscosity involving the local introduction of said pharmaceutical composition; 3) relieved discomfort and pain caused by rheumatic arthritis, systemic sclerosis, peritendinitis or tendovaginitis involving the introduction of said pharmaceutical composition into a patient; 4) improved agent penetration into tissue involving the introduction of the agent together with the pharmaceutical composition into an individual.

EFFECT: invention provides extending the range of pharmaceutical preparations.

14 cl, 23 tbl, 15 dwg, 12 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to surgery, and can be used for treatment of patients with purulent cholangitis. External regulated decompression of bile ducts by means of nasobiliary probe, gallbladder is ablated and drainage in choledoch is installed in patient. After that recanalisation of umbilical vein is performed, umbilical catheter is installed into its lumen. In post-operative period bile ducts are daily washed with drug mixture with antibiotic via nasobiliary probe for 6-8 days. Simultaneously intraportal introduction of antibiotic in dose 1.0 g, dissolved in 250 ml of 0.9% sodium chloride solution is performed via catheter in umbilical vein at rate 20 drops per 1 minute. Antibiotic is selected in accordance with bile microflora sensitivity.

EFFECT: method ensures efficient treatment of said pathology due to simultaneous impact on bile microflora with antibiotic solution both from the side of bile ducts and regionally, from liver side.

1 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to surgery, and can be used in treatment of patients with abdominal sepsis of peritoneal origin, complicated by coagulopathy. For this purpose performed is laparotomy with intraoperational introduction of double-lumen nasogastric probe into small intestine lumen below Treitz ligament) for active aspiration of intestinal contents. After that, sodium hypochlorite solution is introduced into abdominal cavity once and wound edges are sutured tightly to drainages. Immediately after that, intravenous infusion and intestinal dialysis with application of sodium hypochlorite are performed. 0.04% solution of sodium hypochlorite is used for sanitisation of abdominal cavity through drainage tubes and for intravenous infusions, 0.06% solution being used for intestinal dialysis. In post-operative period sanitisation of abdominal cavity, intestinal dialysis and intravenous infusions with sodium hypochlorite are performed one time per day during 1-3 days in dose 15 ml/kg.

EFFECT: method ensures efficient treatment of said pathology, and makes it possible to reduce manifestations of inflammatory reaction, as well as to prevent further development of coagulopathy due to considerable reduction of level of platelet aggregation as a result of activation of all links of coagulation link of hemostasis with sodium hypochlorite with specific sequence of actions.

1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to surgery, and can be used for prevention of purulent-septic complications in laparoscopic operations. For this purpose before beginning surgery ceftriaxon is introduced intravenously to create systemic antibacterial effect. After that, performed is targeted processing of patient's abdominal cavity with drug mixture, delivered to inflammation nidus through one or several trocars, used simultaneously to provide access to operation field. Used is drug mixture, which includes ceftriaxon and miramistin solution in weight ratio 1:8. Drug mixture is dispersed to fine-dispersive state and delivered within 16 minutes into abdominal cavity, to inflammation nidus, under excessive pressure by means of carbon dioxide or any other inert gas, simultaneously used to create pneumoperitineum.

EFFECT: method ensures increased efficiency of preventing purulent-septic complications after laparoscopic operations due to prevention of microbial contamination of those parts of abdominal cavity, which are not involved into inflammatory process, producing local antibacterial effect with increase of concentration of wide-spectrum antibiotic in inflammation nidus.

1 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: wound defect is reduced in layers that involves forming fragments of hernioprosthesis composite coated with a polymer composite to be implanted in any layer of the wound subcutaneously or intraperitoneally. The hernioprosthesis represents a mesh of warp structure of synthetic polymer untwisted pneumatically coupled non thermally fixed complex filaments. The polymer composite consists of a substance of poviargol and medical polyvinylpyrrolidone. Molecular weight of medical polyvinylpyrrolidone makes 13000-90000D at the relation, wt %; 45-55 : 45-55.

EFFECT: method enables studying tissue responses at simulating the environment of replacing hernioplasty with the use of the presented hernioprosthesis showing evident anti-inflammatory, anti-adhesion and reparative action.

9 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to surgery, and can be applied for sealing interintestinal anastomosis. For this purpose before immersion into abdominal cavity and suturing middle wound, application of 30-40 g of dry lyophilised cryoprecipitate is performed on serous cover of small intestine on entire circumference of interintestinal anastomosis. After that, either 2-3 ml of 5% calcium chloride solution or 4-5 ml of sterile thrombin 15 U NIH/ml, dissolved in 5% solution of aminocaproic acid, are added drop by drop into said cryoprecipitate. 60 seconds after formation of gel-like fibrin film re-application of the first or the second two-component composition is carried out.

EFFECT: method ensures increase of strength and biological impermeability of intestinal sutures at the background of extensive peritonitis due to efficient fixation of fibrin, which does not produce damaging impact on tissues, is capable of quick formation of fibrin film, is homologous and safe, penetrates zone of suture, filling holes from needle punctures, making it possible to close anastomosis on circumference evenly.

4 dwg, 4 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, specifically cardiology and cardiosurgery, and may be used for treating diffuse myocardial damage. That is ensured by cell sampling of mononuclear fraction of bone marrow in number of 10 mln cells. The 5 mln cells are introduced by aortic puncture between a coronary artery mouth and a short-term clamping point in an ascending section to a junction to a common carotid artery. The rest 5 mln cells are introduced by two injections. The first 2.5 mln cells are introduced in an apex of the left ventricular myocardium, while the second 2.5 mln cells are introduced into a side wall of the left ventricular myocardium.

EFFECT: method provides functional recovery of the damaged myocardium ensured by the enlarged area of the microvasculature in an ischemic segment of muscular tissue due to formation of local permanent loci of angiogenesis ensured by maximum cell accumulation for the first hour after transplantation and minimum escape from the myocardium for the first 20 hours after the combined introduction.

3 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely experimental medicine, surgery and aims at treating purulent wound in experiment. A method involves a pre-toilet, application of a dressing containing an iron nanoparticle suspension in the concentration of 0.1 mg/ml and a copper nanoparticle suspension in the concentration of 0.001 mg/ml in 0.9% normal saline prepared by plasma flow of temperature 5000-6000 K. Copper nanoparticle dispersion makes 30 nm, while iron nanoparticle dispersion is 70 nm.

EFFECT: along with simplified and cheaper treatment of purulent wounds, eliminated toxic action of the nanoparticles the method reduces time of elimination of contaminating agent substantially, provides wound sterility, faster wound regeneration and complete repair.

2 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, particularly to abdominal surgery, and may be applied for preoperative preparation of the patients suffering extensive peritonitis. That is ensured by abdominal paracentesis by the introduction of a catheter through a trocar into an abdominal cavity that is followed by aspiration of the pathological content. Immediately after aspiration of the pathological content, hyperosmolar 10% NaCl is introduced in the abdominal cavity in the amount twice exceeding that of the discharged pathological content. Thereafter, the catheter is clamped for 5-10 minutes, then opened, and the content is evacuated; antiseptic solutions are introduced in the abdominal cavity in the amount twice exceeding that of the hyperosmolar solution. Then the catheter is clamped for 5-10 minutes and opened, the content is evacuated; the abdominal cavity is irrigated with the antibacterial solution.

EFFECT: method provides reducing body intoxification, bacteremia and thereby enhancing the preoperative preparation for compensation of cardiovascular and pulmonary pathologies in somatically severe patients that enables reduced length of the operation and risk of postoperative complications.

5 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to surgery and may be used for making external osteosynthesis implants. An osteosynthesis system comprises a piece part on an external surface of which there is a layer of a polymer film in the electret state with the layer of the polymer film made of a fusible element. The group of inventions refers to a method for making the osteosynthesis system involving preparation the layer of the polymer film on an external surface of the piece part by coating the surface of the piece system with a fine fusible polymer powder, fusion thereof on the surface of the piece part and electrostatic charging of the prepared film.

EFFECT: group of invention provides making a uniform coating of the electret layer on the surface of the piece part of the osteosynthesis system firmly attached to the surface of the piece part that enables faster fusion of bone fragments due to electric stimulation and prevented implant corrosion.

10 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-substituted monomers and polymers, methods of producing such monomers and polymers and methods for their use for different medical purposes, e.g., in medical devices. Disclosed is a polymer which contains a repeating unit of formula (I), where X1 and X2 are independently selected from Br and I; y1 and y2 are equal to zero or an integer from 1 to 4, A1 is selected from a group consisting of , , , and , R3 is selected from C1-C30 alkyl, and C1-C30 heteroalkyl, C5-C30 aryl, C6-C30 alkylaryl and C2-C30 heteroaryl; R4 is selected from H, C1-C30 alkyl and C1-C30 heteroalkyl; R1 is (A) or (B); Z is O or S; R5 and R6 are selected from -CH=CH-, -CHJ1-CHJ2- and -(CH2)a-; a equals zero or an integer from 1 to 8; J1 and J2 are independently selected from H, Br and I; Q is a group which contains 20 or more carbon atoms; Rx is selected from optionally substituted branched or straight C7-C30 alkyl and optionally substituted C6-C30 aryl; and Ry is selected from hydrogen, optionally substituted branched or straight C1-C30 alkyl and optionally substituted C6-C30 aryl. Also disclosed are versions of said polymer, methods of producing said polymers and a medical device containing the disclosed polymers. The medical device is preferably a stent.

EFFECT: disclosed polymer has improved physical and chemical properties and is suitable for use in implantable medical devices.

31 cl, 1 dwg, 2 tbl, 3 ex

Tissues adhesives // 2443435

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine. What is described is a multilayer tissue adhesive sheet which contains a structure layer or a laminated plastic attached to a layer supposed to contact with tissue. The structure layer or the laminated plastic contains one or more synthetic polymers showing film-forming properties, while the tissue contact layer contains tercopolymer poly(VP-AAc-AAc(NHS)). The synthetic polymers showing film-forming properties are preferentially biodegradable polyesters, while the tissue reactive groups are most preferentially NHS-polyester groups.

EFFECT: sheet shows better flexibility and herewith keeps high adhesive strength.

26 cl, 2 dwg, 8 ex

FIELD: medicine.

SUBSTANCE: compositions, methods and sets applied to sealing of injured tissues are described herein; the compositions are produced by combining of the first transversally cross-linked component with the second transversally cross-linked component to the effect of formation of the porous matrix with spans, and combining of the porous matrix with the hydrocarbon gel forming component applied to filling-in at least some of the spans.

EFFECT: compositions have minimal turgescing properties.

15 cl, 15 tbl, 14 dwg, 26 ex

Implants with fk506 // 2332959

FIELD: medicine.

SUBSTANCE: invention refers to implants, in particular, to intracavernous or intravascular implants, and is preferable for treatment or preventive maintenance of coronary or peripheric narrowings or occlusions of vessels, in particular, narrowings, or stenosis or restenosis respectively, preferably for prevention of restenosis which, in chemically covalent or incovalent to the bound or physically fixed form, contain FK506, to the method of their obtaining and application.

EFFECT: reduction of inflammation centres.

52 cl, 7 dwg, 10 tbl, 9 ex

FIELD: medicine, plastic and reconstructive surgery.

SUBSTANCE: the present innovation deals with the ways for obtaining spongiform material out of biological tissues applied for treating contour skin deformations in plastic surgery or filling in volumetric defects of organs and soft tissues in reconstructive surgery. It is important to obtain spongiform material of wide functional properties and clinical efficiency. The method deals with mechanical purification of allogeneic connective-tissue neoplasms against the residues of adjacent tissues and foreign contaminations followed by washing in running water, treatment with 3%-hydrogen peroxide solution, rinsing in 0.9%-sodium chloride solution, homogenization till obtaining the homogeneous viscous mass to form the body of the required geometrical shape and size to subject it for frosting-defrosting cycles at the quantity of 2-7, moreover, frosting should be fulfilled steadily at the rate of about 0.1-1°C/min up to -40...-45°C to be kept at the temperature mentioned for 24 h followed by complete defrosting of biomaterial at +4°C, and in the course of the last cycle after frosting up to the desired temperature it is necessary to subject biomaterial for vacuum freeze drying to achieve the constant weight, then it should be hermetically sealed and sterilized with gamma-irradiation at the dosage of 2.5 MRad.

EFFECT: higher efficiency.

FIELD: medicine, thoracic surgery.

SUBSTANCE: the present innovation deals with treating the main bronchus stump during pneumonectomy and repeated operations on postoperational bronchial fistulas. One should apply an elastic hollow conductor under the bronchus, moreover, it is necessary to introduce one branch of pre-cooled clamp for soft tissues made of the fusion with a shape-memory effect. Then this conductor should be withdrawn out of operation wound, moreover, another branch should be applied onto opposite side of the bronchus. Then one should cover bronchial stump, tracheal bifurcation and adjacent tissues with granules out of porous titanium nickelide at particles size being ,1-1,0 mm at the quantity of 0.03-0.06 g/sq. cm. The innovation enables to decrease the number of postoperational complications, shorten the terms for healing bronchial stump and duration of operation due to proper applying the clamp for soft tissues.

EFFECT: higher reliability of sealing bronchial stump.

8 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: method involves placing cell-free dermal matrix into antibiotic solution before transplantation. The cell-free dermal matrix is poured with acetone cooled to -20°C in 1:10 proportion the day before transplantation. Desiccation and degreasing being done, the matrix is placed into antibiotic or antiseptic solution or their combination.

EFFECT: enhanced effectiveness in suppressing pathogenic microflora.

The invention relates to medicine, namely to surgery

FIELD: medicine, pharmaceutics.

SUBSTANCE: declared group of inventions refers to an intra-articular fluid (synovial fluid) simulator formulation, and to a method for preparing an additive to said formulation. The intra-articular fluid simulator formulation contains 15% aqueous medium molecular polyvinyl pyrrolidone, (0.5-1.5)-10-3 wt % of an additive with the antimicrobial properties and 0.05-2.5% of hyaluronic acid sodium salt in deionised water at the weight relation: of polyvinyl pyrrolidone: hyaluronic acid sodium salt as 1:(0.2-0.3). The additive is prepared of silver modified silicone nanoparticles at nanoparticle size 10-40 nm and silver amount in the additive 0.8-1.1 wt %. The method for preparing the additive to intra-articular fluid simulator formulation consists in preparing silicone nanoparticles by pyrolytic laser processing of monosilane (SiH4), modifying their surfaces by nanoparticle processing in 2-5% silver nitrate in deionised water and centrifuging the solution, multiply washing the deposition and centrifuging at each washing stage.

EFFECT: group of inventions provides preparing the biologically compatible intra-articular fluid simulator formulation showing the effective rheology, antimicrobial activity, and promoting repair action on cartilaginous tissues.

6 cl, 1 tbl, 1 dwg, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biochemistry. What is presented is a conjugate of hyaluronic acid and novocaine of a structure as defined in the patent claim containing 20-50% residues of novocaine.

EFFECT: conjugate is water-soluble; it possess the amphoteric properties and contains no side O-acylisourea.

3 tbl, 3 ex

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