Absorbable polyethylene diglycolate copolymers to reduce microbial adhesion to medical devices and implants

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, more specifically to absorbable polyether esters that have been found to reduce bacterial adhesion to materials such as medical devices and implants. Amorphous copolymers are used to produce a coating for medical devices and implants to reduce bacterial adhesion.

EFFECT: invention refers to new amorphous copolymers containing polyethylene diglycolate (PEDG) copolymerised with lactide-rich monomers.

15 cl, 4 dwg, 7 tbl, 13 ex

 

The SCOPE of the INVENTION

The present invention relates to absorbable polyether esters, which have been detected, reduce the adhesion of bacteria to the materials used in medical devices and implants. In particular, the invention relates to novel amorphous copolymers comprising polyethyleneglycole (PEDG), copolymerizable monomers with a high content of lactides, capable of forming an antimicrobial adhesive barriers.

It is reported that non-ionic surface-active substances (surfactants), such as Poloxamer 407 or Triton x100, can reduce the attachment of bacteria to medical implants. Wares and others (Veyries, et al.) in the article "Control of adhesion of Staphylococcus aureus to polymethylmethacrylate and increased susceptibility to antibiotics using Poloxamer 407" (Gets Control of Adhesion to Polymethylmethacrylate and Enhancement of Susceptibility to Antibiotics by Poloxamer 407) in the journal Antimicrobial agents and chemotherapy" (Antimicrobial Agents and Chemotherapy), I. 44, No. 4, April 2000, pages 1093-1096 report protivorededivne the effect of Poloxamer 407 on polymetylmetacrylate orthopedic cements and further possible impact on antibiotic activity. In addition, in the application WO 2004030715 described compositions to inhibit the attachment of microorganisms to surfaces of biomaterials, including polyesters, such as poloxamer, in relation to contact lenses is m However, the surfactants of these types are limited to a certain molecular weight, since they are practically not absorbed by the human body and can not pass through the liver or kidneys. In addition, such substances can be easily removed from the surface proteins of the blood.

A well-known surface modification by implantation of polyethylene glycol (PEG), however, the PEG is not absorbed by the human body. Ko and others (Ko et al.) in the article "Suppression of adhesion of Pseudomonas aeruginosa associated with the presence of lectins with carbohydrates, blocking receptors in vitro and in vivo (In Vitro and in Vivo Inhibition of Lectin Mediated Adhesion of Pseudomonas aeruginosa by Receptor Blocking Carbohydrates), the Institute of hygiene in Cologne, Germany, "Infection" (Infection) (Munich, Germany) (1987), 15(4), 237-40, reported that the adhesion of P. aeruginosa in vitro and in vivo promoted the receptor N-acetylneuraminic acid (NANA). They concluded that blocking receptors of bacterial lectins with specific carbohydrates may have clinical importance for preventing the attachment of bacteria to the cell bodies. However, this source does not mention preventing the attachment of bacteria using copolymers on the basis of diglycolate.

Angelic and others (Andjelic et al) in the article "Polyoxyethyl The Polyoxaesters) in the journal of Polymer International(2007), 56(9), 1063-1077 describe the use of absorbable polyoxyethyl and semi-crystalline copolymer d is I a variety of medical purposes including a lubricating coating and prevent adhesion. However, the inventors do not mention the use of copolymers based diglycolate to prevent bacterial adhesion.

The application of the U.S. 2006051398, Angelic and others (Andjelic et al) in the article "Hydrophilic absorbable copolyester provides a stable emission drugs" (Hydrophilic Absorbable Copolyester Exhibiting Zero-Order Drug Release), journal of Pharmaceutical research" (Pharmaceutical Research) (2006), 23(4), 821-834, report that fully amorphous copolymers of diglycolate polyethylene and glycolide can be used for various medical purposes. However, these sources do not mention preventing the attachment of bacteria using copolymers on the basis of diglycolate with a high content of lactides.

In the application of the U.S. 2008243101 describes the use of copolymers of diglycolate polyethylene and caprolactone as fillers in plastic surgery.

In applications U.S. 2008103284 and 2008103285 describe the use of a semi-crystalline copolymers of diglycolate of polyethoxyethanol and glycolide for various medical purposes, including as fibers, microspheres and non-woven structures, obtained by the blowing of the melt. However, these sources do not mention preventing the attachment of bacteria using copolymers on the basis of diglycolate with a high content of lactides.

Summarizing, with the polymers of diglycolate polyethylene with lactide not described in publicly available neither in the patent literature, and no proposals of their possible use as antibacterial coatings is not known.

Surprisingly, it was discovered that a new class of absorbable polymers soluble or dispersible in organic solvents, can be successfully used for coating medical devices and implants in order to reduce the attachment of bacteria and, in addition, may be useful as a system of issuing drugs.

GENERAL DESCRIPTION of the INVENTION

The present invention describes compositions containing amorphous copolyester containing the reaction product of polycondensation polyester and monomer with a high content of lactides, where the polycondensation polyester contains a reaction product diglycolic acid and/or its derivative and ethylene glycol; where copolyester contains from about 30 to 70% by weight of the polycondensation polyester, based on the total mass of sobolifera, and has an average molecular weight of from about 5000 to about 30000 g/mol, and is soluble in an organic solvent, most preferably in a non-toxic organic solvent. These compounds show the ability to limit the attachment of bacteria when used as coatings for medical devices.

BRIEF DESCRIPTION of FIGURES

In Fig. 1 shows the anti-adhesive properties of the compositions according to the present invention in comparison with a control sample, as well as the control sample with other polymer coatings according to the results of a 20-minute incubation tests.

In Fig. 2 shows the decrease in the attachment of bacteria using the compositions of the present invention in comparison with a control sample from the results of 24-hour incubation tests.

In Fig. 3 shows the antimicrobial zone of the results of inhibition for the compounds of the present invention in comparison with other materials for intervals of 24, 48 and 72 hours.

In Fig. 4 shows that the compositions according to the present invention can be used to produce coatings on implants in more than 20% by mass.

DETAILED description of the INVENTION

It was found that described here sobolifera can counteract the adhesion of microbes and to serve as coatings or films on medical devices, and may also contain material from which made itself a medical device. Sobolifera of the present invention are fully amorphous, which makes them soluble in various organic solvents, which, in turn, facilitates the application of the compositions according to the present invention in the form of coatings or films.

In one of the embodiments of the invention copolyester contains the reaction product of polycondensation polymer composition with a high content is of lactides, where polycondensation polyester contains a reaction product diglycolic acid and/or its derivative and ethylene glycol.

In another embodiment of the invention the polycondensation polyester contains a reaction product diglycolic acid and/or its derivative, up to 25 molar percent aliphatic docility, based on the total moles of acid, and ethylene glycol. In particular, the aliphatic dukeleto may be one aliphatic alpha-omega dicarboxylic acids, including, without limitation, 3,6-dioxaoctyl acid, 3,6,9-trioxadecyl acid and combinations thereof.

Polycondensation polyester can be synthesized by conventional methods using conventional processes. For example, when the condensation polymerization digitalia acid and ethylene glycol can be polymerized in the presence of a catalyst at elevated temperature and reduced pressure. Can be used in a variety of catalysts, it was found that the beneficial effect of providing organometallics connection. The catalyst for the polycondensation stage of the synthesis is preferably a material based on tin, for example octoate tin. The most preferred catalyst is an oxide dibutylamine present in the mixture diglycolic acid with a monomer of ethylene glycol in eno is but an effective molar ratio of monomer to catalyst, for example in the range from about to about 5000/1 100000/1. For example, it was found that the ratio 10000/1 is quite acceptable. The reaction is usually carried out in a temperature range from about 100°to about 220°C., preferably from about 140°to about 200°C. in an inert atmosphere until complete esterification diglycolic acid. Temperature 180°C has also been found that the preferred reaction temperature when using a reactor with a vertical stirrer. It should be noted that the optimal reaction temperature may depend on the reactor and catalyst level, however, it can be installed by a specialist normal skill level by conducting experiments. For the first stage of the polycondensation reaction (inert gas at atmospheric pressure) should polymerization under reduced pressure until the desired molecular weight and viscosity.

The weighted average molecular weight of the polycondensation polymer can be in the range of from about 2000 to about 10000 g/mol, preferably from about 4000 to about 7000 g/mol, and most preferably about 5000 g/mol. This corresponds to the range of its viscosity from about 0.20 to about 0.40 in DL/g

If the molecular weight of the polycondensation polymer is below about 2000 g/mol, the molecular weight of the end is palifera too small to obtain the desired mechanical characteristics required for many applications of medical devices. We found that in the General case, to achieve the required characteristics is not required molecular weight above about 10,000 g/mol. You can, however, be assumed that this value is not an absolute limit. You can, for example, to increase the molecular weight of the polycondensation polymer and to reduce the number lactides component used to prepare the final sobolifera.

The number of polycondensation of the polyester used for the preparation of sobolifera is about 30-70% by weight of the total weight of sobolifera.

In the present description, the term "with high content of lactides" refers to compositions containing monomers in the amount of more than 50% by weight, preferably from about 80 to about 100% by weight and most preferably 100% of lactides (l, d, dl, meso) by weight. Other components of the composition with a high content of lactides may include, without limitation, glycolide, p-dioxanone, trimethylantimony, tetramethylgermane, Epsilon-caprolactone, Delta valerolactone, beta-butyrolactone, Epsilon-decalactone, 2,5-dikeomaton, pivalate, alpha,alpha-diethylpropion, ethylene carbonate resulting, ethylenoxide, 3-methyl-1,4-dioxane-2,5-dione, 3,3-diethyl-1,4-dioxa the-2,5-dione, gamma-butyrolactone, 1,4-dioxan-2-it, 1,5-dioxan-2-it, 1,4-dioxane-2-it, 6,8-dioxabicyclo-7-he and combinations of two or more of these substances. Preferred Laktionova monomer is lactide (l, d, dl, meso).

In another embodiment, the invention copolyester may include the reaction product of polycondensation of polyester with two or more lactones. For example, copolyester may include the reaction product of polycondensation of the polyester, of at least 50 molar percent of the lactide, based on the total number of moles of lactone, and the second lactoovo monomer.

Sobolifera of the present invention can be easily synthesized by the reaction of homopolymer or copolymer dihydroxyindole(alkylenediamines), a composition with a high content of lactides by conventional methods using conventional processes. For example, polycondensation polyester is used as the α,ω-dihydroxy macroinitiator in the subsequent polymerization break the cycle". ROP) with lactide or lactoovo mixture. Lactonase monomers copolymerized with the formation of the polycondensation of the polyester in the presence of normal ORGANOMETALLIC catalyst at elevated temperature. The catalyst for polymerization with the opening cycle may already be present in the form of residual catalyst in polik is ndensation polyester, or at the second stage of the synthesis may be an additional catalyst. A suitable catalyst is introduced during the polymerization with the opening cycle, can be organometallics catalyst. The catalyst for polymerization with the opening of the loop is preferably a substance on the basis of tin, for example octoate tin, which appears quite effective amount of a mixture of monomers, preferably in a molar ratio of the number lactoovo monomer to catalyst in the range of from about 20000/1 to infinity (i.e., no additional catalyst is not used). Thus, it is possible to use a compound of tin (IV), for example oxide dibutylamine, in terms of number of docility, for example diglycolic acid, the amount of catalyst is about 10000/1 for the preparation of polycondensation of the polyester, and then, during the polymerization with the opening cycle, to enter the compound with tin (II), for example octoate tin, in a molar ratio of lactone to the amount of catalyst is about 240000/1. Alternatively, Capoliveri of the present invention can be synthesized without additional catalyst during the polymerization with the opening of the loop.

Stage polymerization opening cycle can be carried out in the same reactor, which used what was isovolta for the synthesis of polycondensation polyester, immediately after the completion of phase polycondensation, if this reactor can provide sufficient heat transfer and adequate mixing. Lactitol or lactoovo mixture can be introduced in solid form, in suspension or in the form of a melt. Alternatively, the polymerization opening cycle can be performed in one of the subsequent days in a separate reactor or in the reactor, which was used to obtain a polycondensation polyester. In this case, the polycondensation polyester is unloaded from the reactor and stored in the atmosphere, reducing the absorption of water and hydrolysis. With the introduction of lactides monomer can be entered in the solid state. The reactor should be closed and the pressure is lowered. To dry the reactor, it usually creates a vacuum for an extended period of time, for example overnight. After that, the reactor is injected nitrogen, to increase the pressure up to a level slightly above atmospheric, and repeat the cleaning cycle three times. The temperature of the reaction mass is brought to 130°C. after Reaching this temperature, turn the mixer. After that, the temperature was raised to 150°C and complete the mixing process. Phase mixing is essential to obtain spoliation of the present invention, because of insufficient mixing leads to the formation of homopolymer sequences that satimage to crystallize in more than the optimal level. To ensure that the reagents are completely mixed, you can use spectroscopic sensors direct action (for example, the sensors near infrared range). If you add additional catalyst, it is usually added after the content fully mixed. The temperature is quickly brought to a final reaction temperature, and most preferred is a temperature of 190°C, and this temperature is usually maintained for 4-5 hours. The exact reaction conditions depend on the catalyst and the final reaction temperature may vary from about 180 to 220°C. and preferably is from about 190°to about 200°C. the reaction Time may vary from about 90 minutes to several hours, depending on the catalyst and its level, and usually the reaction is carried out until the desired conversion of monomers to polymer.

An alternative reaction scheme used to prepare spoliation of the present invention, provided for the introduction into the reactor lactide or lactoovo mixture in the form of melt jet. Thus, first enter the polycondensation polyester, usually in the form of a stream of the melt, after which the reactor create a vacuum. The reactor is heated to 150°C. Then the reactor is injected molten LACT is d (or a mixture with a high content of lactides) at a temperature of about 135°C. Although the temperature of the mixture loaded when this drops slightly, it quickly again brought to 150°C, and then start mixing. After this point, perform the process described above.

Under the above described conditions sobolifera polycondensation polyester and lactide usually have an average molecular weight of from about 5,000 g/mol (also known as "Dalton") to about 30000 g/mol, preferably from about 10,000 g/mol to about 20,000 g/mol, and most preferably from about 12,000 g/mol to about 16000 g/mol. These molecular weight sufficient to provide an effective private viscosity, typically in the range of from about 0.20 to about 0.5 deciliter per gram (DL/g), preferably from about 0.30 to about of 0.40 DL/g, when measured in solution hexafluoroisopropanol (HFIP, eng. HFIP) with a concentration of 0.1 g/DL at 25°C.

Sobolifera of the present invention is completely amorphous, soluble in various organic solvents (easily soluble in acetone) and can be applied directly on the medical device in the form of a coating, or may contain material from which made such a device, such as an absorbable suture, fastener to tissue or bandage for wound healing. Used here, the term "readily soluble" means that the compositions of the present is Adamu invention is easily dissolved in organic solvents without the need of increasing the temperature or adjust the pH of the solvent.

For example, ultra-thin film coating material of the present invention can be applied to the mesh, foil or seams. Such coatings reduce the attachment of bacteria to the surface.

Suitable solvents for coating compositions of the present invention on the basis may include, without limitation, ethyl acetate, acetone, toluene, hexane, benzene, diethylether, chloroform, methylene chloride, tetrahydrofuran, acetonitrile, ethyllactate, N-methylpyrrolidone and benzyl alcohol, and mixtures thereof. However, it is preferable to use non-toxic organic solvents. Used herein, the term "non-toxic" includes any non-chlorinated and/or non-carcinogenic organic solvents having permitted exposure limit (Engl. PEL) of 100 mg/m3(based on 8-hour time-weighted average concentration (eng. TWA) according to the norms of labor protection Management US". OSHA [see, for example, the law of 29 CFR 1910.1000, table Z-1]). Among the non-toxic solvents include, without limitation, methanol, ethanol, 2-propanol, ethyl acetate, butyl acetate, 2-ethoxyethylacetate, acetone, methyl ethyl ketone (eng. MEK), toluene and xylene, the most preferred are ethanol, 2-propanol, ethyl acetate, acetone and methyl ethyl ketone (eng. MEK).

Alternatively, such products as medical devices, can bytesperline the formation of the described sobolifera various conventional methods of injection and extrusion and used directly in the human body. For example, Capoliveri can be molded in the form of a film and then sterilized by ethylene oxide, gamma or electron beam (dose of 15 to 40 kGy). Alternatively, Capoliveri can be components of medical devices, i.e., copolyester may be a single layer multi-layer mesh to repair the hernia, or may be suspended in the polymer solution and deposited on at least part of the medical device.

In one of the embodiments, the invention is a composition containing absorbed soporific polycondensation polyester and lactide, in particular absorbed copolyester containing the reaction product of poly(ethylene-co-ataxiatelangiectasia) (eng. PEDG-21) and lactide, where copolyester contains about 30-70% by weight of poly(ethylene-co-ataxiatelangiectasia), based on the total mass of sobolifera. Polycondensation polyester contains a reaction product diglycolic acid and/or its derivative with ethylene glycol and diethylene glycol, in which diethylene glycol is the dominant component in Volovoi mixture.

Poly(ethylene-co-ataxiatelangiectasia) (eng. PEDG-21) is completely amorphous polycondensation product diglycolic acid, ethylene glycol and diethylene glycol. If these two diol is used in an excessive amount, then the resulting product palikonda the compensation contains a finite group with a hydroxyl endings and can serve as a macroinitiator for the subsequent second stage polymerization break the cycle with Laktionova monomer, for example, the lactide. The number of polycondensation of the polyester used for the preparation of sobolifera of the present invention, is in the range from about 30% to 70% by weight of the total weight of sobolifera. Suitable lactide monomers that can be used in the polycondensation reaction with the polyester include, without limitation, lactides (l, d, dl, meso), and combinations thereof. Preferred lacheny monomer is l(-)lactide.

In another embodiment, the invention copolyester can contain the reaction product of polycondensation polyester and lactides composition containing the active agents. The use of active agent in the compositions of the present invention depends on the desired effect that you want to get. For example, it may be desirable to obtain an implant containing copolyester of the present invention, having at least one biologically active ingredient which can be release at the location of the implant after implantation. Substances, the most suitable as active agents may be natural or synthetic and include, without limitation, such as the following: antibiotics, antimicrobial agents, antibacterial agents, antiseptics, chemotherapeutic agents, cytotoxic agents, inhibitors of metastasis, antidiabetic the mini-agents antimycotics, gynecological agents, urological agents, antiallergic agents, sex hormones, inhibitors of sex hormones, hemostatic means, hormones, peptide-hormones, antidepressants, vitamins, such as vitamin C, antihistamines, deproteinisation DNA, plasmid DNA, cationic complexes of DNA, RNA, cellular components, vaccines, cells naturally present in the body, or genetically modified cells. The active agent may be present in an encapsulated or absorbed in the form. When using such active agents, the patient's condition can be improved according to their effect or therapeutic effect that can be achieved (for example the best wound healing or preventing or reducing inflammation).

When using the active agents as antibiotics, it is preferable to use such agents as gentamicin or antibiotic brand ZEVTERA™ (ceftobiprole medocaril) (produced by the company Basilea Pharmaceutica Ltd., Basel, Switzerland). Most preferred is the use of highly effective antimicrobial agents operating in a wide range against various bacteria and fungi (even in the presence of a liquid bodily tissues), such as octenidine, octenidindihydrochloride (available as active in the of radiant in sanitizer Octenisept® company Schülke & Mayr, Norderstedt, Germany), polyhexamethyleneguanidine (eng. PHMB) (available as the active ingredient in the drug Lavasept® company Braun, Switzerland), triclosan, copper (Cu), silver (Ag), nanosilver, gold (Au), selenium (Se), gallium (Ga), taurolidine, N-chlorotaurine, antiseptics, alcohol-based, such as a liquid mouthwash Listerine(R), LAE, MAPD, available as an active ingredient in the drug SCHERCODINETMM, OAPD, available as an active ingredient in the drug SCHERCODINETMO, and SAPD, available as an active ingredient in the drug SCHERCODINETMS, and most preferably, octenidindihydrochloride (hereinafter referred to as octenidine) and PHMB.

In addition, depending on the solubility of the active agent to dissolve the copolymer of the present invention and an active agent can be applied to the solvent system, as shown in example 11. In this example, when the floor grids by immersion for the dissolution of the active agent octenidine used a mixture of acetone and water. Of course, you can also use other suitable mixture of solvents, for example prepared from mixtures of ethyl acetate and methanol, or other solvents, which dissolve the appropriate active agents.

In addition, the compositions according to the present invention it is possible to enter and agents to give contrast. So contractor is the missing agent may be biocompatible dye, creating a visual contrast as described in the application EP1392198B1 or gas agent or gas-forming substance to create contrast in an ultrasound or a magnetic resonance imaging study (MRI), such as metal complexes such as GdDTPA, or super-paramagnetic nanoparticles (ResovistTMor EndoremTMas described in the application EP 1324783 B1. As described in the application EP1251794B1, you can enter a substance visible on the x-ray image, selected from the following groups: pure Zirconia, stabilized Zirconia, zirconium nitride, zirconium carbide, tantalum, tantalum pentoxide, barium sulfate, silver, silver iodide, gold, platinum, palladium, iridium, copper, iron oxides, not too magnetic implant steel, non-magnetic implant steel, titanium, alkali iodide, iodinated aromatic compounds, iodinated aliphatic compounds, iodinated oligomers, iodinated polymers, alloys of the aforementioned substances, which can be components of alloys.

The compositions of the present invention can be applied in the form of a coating on a medical device or implant, and in some cases can almost completely to serve as a material for a medical device or implant. Examples suitable for this purpose, medical devices and implants include, without limitation, W is s, tubes, implants, vascular stents, dental implants, fabric (woven, non-woven, decorated), mesh, beads, wool covers, films, foams, dressings for wounds and pockets.

If the medical device is not composed almost entirely of the material of the present invention, such a device, pregnacare for coating may contain at least one substance selected from the group consisting of polyhydroxybutyrate, polylactide, polyglycols, polyhydroxybutyrates, polyhydroxyvalerate, polycaprolactones, polydioxanone, synthetic and natural oligo - and polyaminoacid, polyphosphazenes, polyanhydrides, polyarteritis, polyphosphates, polyphosphonates, polyalcohol, polysaccharides, polyethers, polyamides, aliphatic polyesters, aromatic polyesters, natural polyaminoacid, synthetic polyaminoacid, genetically manufactured polyaminoacid, collagen, rh, collagen, silk, pseudopolynomial, polycyanoacrylates, polyethylene glycols, polyvinyl alcohols, derivatizing cellulose, fats, waxes, fatty acids, fatty acid complex esters, polyphosphate esters, copolymers polymerized substances from them, resorbable glass fibre materials, metals, alloys and combinations thereof. If the medical device is made in the form set is atogo implant, the preferred materials include at least one substance selected from the group consisting of polyalkenes, polypropylene, polyethylene, partially halogenated polyolefins, fully halogenated polyolefins, fluorinated polyolefins, polytetrafluoroethylene, fluoride of polyvinylidene, polyisoprene, polystyrene, polysilicones, polycarbonates, polyarylether ketones, polymethacrylate complex acid esters, polyacrylate acid complex esters, polyimides, copolymers polymerized substances and their mixtures.

For application materials according to the present invention in medical devices and implants, you can apply the usual methods, which include, without limitation, coating by dipping, spraying, ink-jet (jet solvent) application, causing swelling, spraying of powder materials with sintering, injection molding and plasma or laser deposition.

Preferably, in the coating compositions according to the present invention, the resulting coating was approximately 1000 million shares (0.1% by weight) to about 200,000 million shares (20% by mass, and most preferably from about 8000 million shares (of 0.8% by weight) to about 20,000 million shares (2.0% of the weight) of the implant.

EXAMPLE 1. Synthesis of poly(etilenglikolya) (PEDG) with hydroxyl end

If the used reactor with double hashing with overlapping blades type HELICONE (reactor brand Atlantic 10CV). After loading into the reactor 10,0 kg diglycolic acid, 13,9 kg of ethylene glycol (eng. EG) and 1.86 g of the catalyst in the form of oxide dibutyltin the pressure was reduced to values below 133,3 PA (1 Torr), and the reactor was left for the night with vacuum pressure. The next day, the vacuum was eliminated by using dry nitrogen (which can be replaced by argon, and started heating the mixture. When the reactor temperature reached 150°C, the speed of the stirrer was set at 30 rpm Soon appeared first distillate containing water is a by - product of esterification. The reaction continued at a temperature of 165°C for another couple of hours before until approximately all of the water was distilled and/or distillate appeared the first signs of ethylene glycol. After completion of the first nitrogen-argon stage the pressure was gradually reduced speed to full vacuum, the temperature load was maintained at 165°C. throughout the remaining period of the reaction was maintained pressure of about 3.9 to 6.7 PA (30-50 Torr). The viscosity of the melt and the solution was regularly checked to ensure that the desired molecular weight of the polymer. The polymer with a hydroxyl endings were released portions at different periods of the reaction under vacuum. The longer the duration of the reaction, the higher molecular weight material. The reaction product was Paul the awn amorphous colorless viscous liquid. Private viscosity (IV) produced formalising of diglycolate polyethylene (PEDG) was in the range of from about 0.30 to about of 0.40 DL/g, which corresponds to the weighted average molecular weight of from about 5000 to 10000 g/mol.

EXAMPLE 2. The copolymerization of poly(etilenglikolya) with hydroxyl end with L(-)-lactide (eng. PLLA) - copolymer composition (PEDG/PLLA in the ratio of 40/60% by weight)

Part of the poly(etilenglikolya) obtained in example 1 (36,0 g), IV=of 0.37 DL/g was placed in a 250-ml flask with a round bottom, kiln dried. In the glove box with a nitrogen atmosphere was introduced L(-)-lactide (54,0 g) and the catalyst in the form of octoate tin is 0.019 ml). On the neck 250-ml flask installed a mechanical stirrer, a nitrogen adapter and bearing stirrer. In the vessel created a vacuum with less pressure of 66.7 PA (500 mtorr) at room temperature and left overnight. The reaction with the polymer were carried out with the step change of temperature. The next day, the vacuum was removed, subjecting the flask to the effects of nitrogen, and placed it in an oil bath. The bath temperature was set at 190°C in the absence of mixing. When the temperature reached about 110°C, the mechanical stirrer was set at a speed of 4 rpm When the melt was in the form of a homogeneous and transparent at a temperature of about 170°C, the stirring speed was reduced to 2 Rev/min. the Reaction then continued the at 190°C for about 5 hours. After 5 hours the reaction was stopped and left the product to cool overnight in a nitrogen atmosphere.

With the bulb removed all the glass, leaving only a mechanical stirrer, a polymeric material and a flask with a round bottom. The flask was then wrapped with aluminum foil and separated from her polymer product by cooling with liquid nitrogen. The remaining glass shards removed from the polymer product by salifoski/stripper. Pieces of polymer was collected and placed on the tray with Teflon coating. The tray was placed in a vacuum oven and left under vacuum pressure for the night. The next day, the temperature in a vacuum oven set at 110°C and were removed from the polymer volatile components within 16 hours. Conversion of the polymer amounted to 98.5%.

At room temperature, the copolymer is a light yellow fully amorphous solid with a softening point set by Fisher-Jones, 98°C. the Average molecular weight Mw is 25900 g/mol, and IV of 0.65 DL/g

EXAMPLE 3. The copolymerization of poly(etilenglikolya) with hydroxyl end with L(-)-lactide (eng. PLLA) - copolymer composition (PEDG/PLLA in the ratio of 50/50% by weight)

Part of the poly(etilenglikolya) obtained in example 1 (50.0 g), IV=of 0.37 DL/g was placed in a 250-ml flask with a round bottom, kiln dried. In the glove box with a nitrogen atmosphere was introduced (-)-lactide (50.0 g) and the catalyst in the form of octoate tin (0,018 ml). The polymerization procedure was identical to the procedure described in example 2.

The final conversion of the polymer amounted, according to the calculation of 97.4%. At room temperature, the copolymer is a light yellow fully amorphous solid with a softening point set by Fisher-Jones, 83°C. the Average molecular weight Mw is 24000 g/mol, and IV of 0.53 DL/g

EXAMPLE 4. The copolymerization of poly(etilenglikolya) with hydroxyl end with L(-)-lactide (eng. PLLA) - copolymer composition (PEDG/PLLA in the ratio of 60/40% by weight).

Part of the poly(etilenglikolya) obtained in example 1 (60,0), with IV=of 0.37 DL/g was placed in a 250-ml flask with a round bottom, kiln dried. In the glove box with a nitrogen atmosphere was introduced L(-)-lactide (40,0 g) and the catalyst in the form of octoate tin (0,014 ml). The polymerization procedure was identical to the procedure described in example 2.

The final conversion of the polymer amounted, according to the calculation, 98,0%. At room temperature, the copolymer is a light yellow fully amorphous solid with a softening point set by Fisher-Jones, 81°C. the Average molecular weight Mw 18,500 g/mol, and IV of 0.45 DL/g

EXAMPLE 5A. The copolymerization of poly(etilenglikolya) with hydroxyl end with L(-)-lactide (eng. PLLA) - copolymer composition (PED/PLLA in the ratio of 60/40% by weight).

Part of the poly(etilenglikolya) obtained in example 1 (60,0), with IV=0,41 DL/g was placed in a 250-ml flask with a round bottom, kiln dried. In the glove box with a nitrogen atmosphere was introduced L(-)-lactide (40,0 g) and the catalyst in the form of octoate tin (0,014 ml). The polymerization procedure was the same as the procedure described in example 2.

The final conversion of the polymer amounted, according to the calculation, 99,0%. At room temperature, the copolymer is a light yellow fully amorphous solid. Average molecular weight Mw is 16800 g/mol, and IV of 0.50 DL/g, the Amount of residual L(-)-lactides monomer in the dried product amounted to 0.6% by mass.

EXAMPLE 5B. The copolymerization of poly(etilenglikolya) with hydroxyl end with L(-)-lactide (eng. PLLA) - copolymer composition (PEDG/PLLA in the ratio of 60/40% by weight).

Part of the poly(etilenglikolya) obtained in example 1 (60,0), with IV=0,31 DL/g was placed in a 250-ml flask with a round bottom, kiln dried. In the glove box with a nitrogen atmosphere was introduced L(-)-lactide (40,0 g) and the catalyst in the form of octoate tin (0,014 ml). The polymerization procedure was the same as the procedure described in example 2.

The final conversion of the polymer amounted, according to the calculation of 97.3%. At room temperature, the copolymer is a light yellow fully amorphous solid substances is O. Average molecular weight Mw is 11200 g/mol, and IV of 0.37 DL/g, the Amount of residual L(-)-lactides monomer in the dried product amounted to 0.4% by mass.

EXAMPLE 6. Dissolution in various organic solvents

It was found that the described copolymers PEDG/PLLA is easily dissolved in acetone and, in some embodiments of the invention, dissolve, but with difficulty, in ethyl acetate, ethyllactate, N-methylpyrrolidone and benzyl alcohol (for complete dissolution at room temperature sometimes require 18-24 hours). Copolymers PEDG/PLLA practically not dissolved in benzyl benzoate. It was also found that when the number of PLLA component relative to the number of PEDG solubility also increases. In addition, in those cases where the organic solvent was observed microdisperse copolymer PEDG/PLLA, as described in example 4 below (sic), was still quite acceptable solution for coating.

EXAMPLE 7. The study of the physical characteristics of the copolymers PEDG/PLLA

To study the physical characteristics of the copolymers described in examples 2-4, with the media company Tetrahedron for hot pressing (press MTP-14 TetrahedronTM for molding under pressure) were made several samples of the film thickness of 0.13 mm (0.005 inch). The results of the various physical ispy is any are shown in table 1.

Table 1
Some physical properties of the films PEDG/PLLA
Polymer filmsMW/IVWAXD Krist. (%)Tg/Tm (°C)Peak load, N (lb-force)Load at break, kg (lb-force)Elongation at break (%)The young's modulus, MPa (ksi)The spreading angle (Δ°)Abs. ADJ. t1/2hours
Example 226k
/0,65
028,5/-19,7 N (4,42 pound-force)2,00 kg (4,42 pound-force)5,61,82 MPa (120 ksi)6322
Example 324k
/0,54
019,5/-6,0 N (1,36 pound-force)0,47 kg (1.05 lb-force)709to 0.74 MPa (49 ksi)65 14
Example 419k
/0,45
015,0/-1,1 N (0.24 lb-force)of 0.08 kg (0.18 lb-force)14760.07 MPa (4,7 ksi)709
Notes:
1. The angle spread is a measure of the rate of absorption of water droplets of the polymer. Higher values correspond to more rapid diffusion of water into the polymer mass.
2. Data hydrolytic profile obtained using an automated hydrolysis apparatus at 75°C in deionized water, pH = 7,3 from 0.05 N NaOH.

As shown in table 1, the films made from polymers with a higher content of PEDG have a lower glass transition temperature Tg, the lower the tensile strength and modulus, but a much higher elongation. In addition, the increase in the number of PEDG surface and increases the overall hydrophilicity of the films in the measurement of contact angle and hydrolysis tests, respectively.

EXAMPLE 8. The study of the attachment of the bacteria in laboratory conditions (in vitro)

The procedure of coating:

of 0.13 mm (5 mil) polypropylene mesh material PROLENE is (produced by Ethicon, Inc.) were cut into strips with dimensions of 10 cm × 3 cm and are threaded through the bath for the coating containing 1,5% (by mass) of each of the compounds for the formation of the coating, at a rate of approximately 3 mm/s, air-dried, cut into pieces of desired size and sterilized with ethylene oxide.

Samples marked 71-1 and 71-2, with the copolymer described in example 4 showed microdispersion in ethyl acetate. The sample marked 71-3, covered with the copolymer described in example 2 formed a clear solution in ethyl acetate.

Test the attachment of bacteria in a short period of 20 minutes

This test was carried out for 20 minutes as follows: during the first 10 minutes pre-incubation of samples in plasma and in the next 10 minutes - attachment of bacteria in sodium phosphate buffer (eng. PBS), which clearly shows the early attachment of bacteria. Because triclosan is a time delay (the so-called "annihilation" or "time-to-kill"), it is useful to use it with some other agent that reduces the attachment of bacteria to the expiration of the "time of destruction. Loosely attached bacteria were removed from the samples by 3 times washing with a solution of Tween/Lecitin. The remaining attached bacteria were removed by ultrasonic treatment the TCI. The number of bacteria was determined by counting on agar plate.

The test results for the attachment of bacteria are shown in table 2 and Fig. 1. Surprisingly, in the samples of the present invention, covered PEDG/PLLA, observed a reduction in the attachment of bacteria to a greater extent than when using such a powerful inhibitors as triclosan or triclosan in combination with agents Triton X-100 and Lutron F68.

In addition, the antimicrobial activity of agents increases, as shown in the tests with the transfer of blood agar.

Table 2
The decrease in the adhesion of S. Aureus in the presence of proteins (FCS) of 0.13 mm (5 mil) polypropylene film Prolene® coated and uncoated
No. sampleProcessing%the content of the additiveAverage
Qty received SOME
STD. the disturbances of%Qty received SOMESTD. deviation
3400-45-G3Raw
mesh
01,55 E+051,77 E+040,271300311
3400-58-1TRICLOSAN1,55,08 E+042,28 E+040,08920,0400
TRICLOSAN+
TX100
1,5
1,5
3,22 E+045,35 E+030,05640,0094
3400-58-4TRICLOSAN+
Lutrol F68
1,5
1,5
4,13 E+041,24 E+040,07250,0217
3400-71-1PEDG/PLLA
60/40 (example 4)
1,52,50 E+043,61 E+030,04390,0063
3400-71-2TRICLOSAN +
PEDG/PLLA
60:40
(example 4)
1,5
1,5
2,22 E+041,73 E+030,03890,0030

The inoculum: 2,85 E+06 colony forming units (CFU). CFU)/ml

The total number of CFU - 5,70 E+07

EXAMPLE 9. Test n the attachment of S. Aureus over a long period (24 hours) to glycolide/ε-caprolactone films with a polymer coating and without it in the presence of proteins (FCS)

The plastic mass of the copolymer glycolide and ε-caprolactone (in molar %ratio of 75/25) was extruded in a film thickness of 50 μm. Such film thickness in the range of 10-100 μm show good results as an adhesion barrier to prevent the adhesion of bacteria in the intestines and can also be attached to the surgical mesh that is used as the adhesive barrier. In addition, glycolide/ε-caprolactone film thickness of about 100 μm is used as a reinforcing element in the device for repair of a hernia Ultrapro Hernia System™.

On glycolide/ε-caprolactone film was dip coated from a 1% (by weight) solution of the composition of example 5A and example 5B in acetone at incubation period of 2 minutes and the speed of drawing is about 3 mm/s

The samples were dried for 15 minutes, kept under vacuum, cut out of them disks with a diameter of 2 cm and sterilized using ethylene oxide, then dry Packed in aluminum blister packaging used for surgical sutures.

In the analysis under a light microscope (no heterogeneity was not observed.

The samples were inoculated in 2 ml of medium of S. aureus in the number of 1E6/ml, containing trypticase soy broth (eng. TSB), saline and 20% deactivated thermal impacts is of sterile fetal calf serum (eng. FCS) in the vibrator for 24 hours at 37°C. Loosely attached bacteria were removed from the samples by 3 times washing with a solution of Tween/Lecitin. The remaining attached bacteria were removed by ultrasonic treatment. The number of bacteria was determined by counting on agar plate. Table 3 shows the reduction of adhesion-SOME 64% and 79% for films coated with, respectively, the compositions of examples 5A and 5B, in comparison with grids uncoated (control grid). These results are presented graphically in Fig. 2.

Table 3
The decrease in the adhesion of bacteria S. Aureus to films with a thickness of 50 μm from glycolide and ε-caprolactone and films of glycolide and ε-caprolactone with the coating compositions of examples 5A and 5B in the presence of plasma proteins
SampleThe solution to coverThe average number of CFU on film% reduction of adhesion-SOME
Glycolide-ε-caprolactone film (control)Without coating395000%
Film with 1% of the coating from example 5A1% PEDG/PLLA 60/40
(mol. weight 16800) in acetone
1433364%
Film with 1% of the coating from example 5B1% PEDG/PLLA 60/40
(mol. weight 11200)
in acetone
816679%

EXAMPLE 10. The test zone of inhibition

Sterilized samples from example 8 were subjected to the test zone of inhibition using agar with sheep blood. Every 24 hours the samples were transferred to a new plate. All grids coated with triclosan showed stable results within 3 days.

The results of the test on the zone of inhibition are shown in table 4 and shown in Fig. 3. As shown in Fig. 3, all mesh with a coating of polymer or surfactant with triclosan showed an increase in zone of inhibition in blood agar compared with grids, covered only by triclosan. When this mesh, coated with the composition of example 2 of the present description, showed the largest zone of inhibition within 2 days. The sample covered only by the polymer of the present invention without triclosan showed weak bacteriostatic action at the 24-hour test, and the resulting zone of inhibition was 1.8 mm

table 4
Zone of inhibition in mm
DesignationProcessing24 hours48 h72 h
3400-58-1a 1.5% Triton X-100
1,5% Triclosan
6,17,5the 5.7
3400-58-41,5% Lutrol F68
1,5% Triclosan
the 5.76,36,5
3400-71-11.5% of PEDG/PLLA 60:40
(example 4)
1,800
3400-71-21.5% of PEDG/PLLA 60:40
(example 4)
1,5% Triclosan
6,94,23,4
3400-71-31.5% of PEDG/PLLA 40:60
(example 2)
1,5% Triclosan
8,87,65,5
3400-45-631,5% Triclosana 3.93,12,9

EXAMPLE 11. 7-day study, and then the bacteria E. Coli in vivo in rats

Control sample - grid with layers of film (AB119).

Easy surgical polypropylene mesh with a thickness of 0.09 mm (3.5 mils), with a grid structure Ultrapro®, was made using a heat treatment between glycolide/ε-caprolactone film thickness of 20 μm using 8-μm film of poly(p-dioxanone) (eng. PDS) as the molten adhesive. It was vyshtampovanny disks with a diameter of 1.5 cm, and these implants were Packed and sterilized with ethylene oxide.

The samples - grid with layers of film with a coating of 1600 million shares of octenidine dispersed in the composition PEDG/PLLA.

On the grid with layers of film (AB119) was coated by dipping in a solution of 0.1% of the hydrochloride of octenidine and 0.9% of a copolymer PEDG/PLLA in the ratio of 60/40 (example 5B, AB112) (by weight) in water with acetone in the ratio of 10%/90% (by weight), after which the samples were dried in air and in vacuum. This floor were full mesh and film. It was found that the number of octenidine applied to the implant was 1600 million shares.

Circular implants with a diameter of 1.5 cm (the test and control implants were implanted under the skin of young rats Sprague-Dawley male (weighing 300-400 g), after which it was produced by infection of Escherichia coli (strain ATCC 25922) 1E5 CFU. After 7 days was measured quantity bacter the th on the implant and surrounding tissues.

Table 5 shows the results of measurements on the grid and in the surrounding tissues. Floor grid structure from PEDG/PLLA in the ratio of 60/40, octenidine resulted in a significant decrease in the number of bacteria by more than 5 log (99.999% availability).

Table 5
The average number of CFU in log units on the grid and in biopsy tissue samples
E. Coli on the net
Average
number of log units on the grid
SDE. Coli in tissue
Average
number of log units per gram
SD
The control grid
(AB119)
7,050,367,410,44
Mesh octenidine and composition from example 5B
(AB112)
0,660,662,082,44
P<0,0000P<0,0003

EXAMPLE 12. 7-day study of infection from bacteria S. Aureus in vivo in rats

The same test that is described in PR is least 11, was conducted using bacteria Staphylococcus aureus (CBE 71) when the amount of inoculum 1E7 bacteria on the implant.

The sample grid (AB74, table 6) with a coating of a copolymer PEDG/PLLA (example 5B) showed a decrease in the number of bacteria in a week after implantation, approximately 80% compared with the control sample (polypropylene mesh).

The sample grid with a coating of a copolymer according to example 5B, octenidine (AB112, table 2) showed that one week after implantation of the mesh remained sterile. Neither on the net nor in the surrounding tissues, there was no live bacteria.

Table 6
The average number of CFU of bacteria S. aureus samples on the grid after 7 days after implantation in rats
SampleThe average number of CFU on the half-gridReduction, %
AB119
(control grid)
1,0 E+060
AB74
(mesh composition from example 5B)
the 1.6 E+0580
AB112
(the grid with the composition of example 5B and octenidine)
0,0, E+00Sterile sample

In order another example, without comparison, we conducted a two-week study in vivo in rats to determine the effectiveness of the coating octenidine in the amount of 1,700 million shares, deposited on the mesh with a layer glycolide-caprolactone copolymer. At the end of this study found only 10-100 bacteria on the implant. Requires additional comparative two-week test in vivo in rats to determine the effectiveness of combinations of compounds of the present invention with octenidine and set a positive effect of the presence of the compositions of the present invention.

EXAMPLE 13. Solubility in non-toxic solvents

This example illustrates the solubility of the compositions according to the present invention in acetone. In the order notes, it was found that the combination of octenidine with the compositions of the present invention are soluble in mixtures of acetone with water (90/10) (where acetone is used to hold the solution polymers of the present invention, and the water - to hold in solution octenidine).

The compositions of examples 5A and 5B were plotted on a composite material consisting of polypropylene mesh enclosed between glycolide-caprolactone film thickness of 20 μm. The results are shown in table 7 and shown in Fig. 4), show that the compositions according to the n of the present invention, dissolved in acetone, can be plotted on a grid of approximately 200000 million shares (20% by mass or more after drying.

Table 7
The quantity of coating material from PEDG/PLLA implants
The solution to cover,
% (by weight)
Qty in million shares implant
Example 5A1%24303
Example 5B1%21125
Example 5A2,50%47049
Example 5B2,50%49033
Example 5A5%112920
Example 5B5%98585
Example 5A10%201364
Example 5B10%205224

Although this invention has been presented and described is in the form of a detailed description of the variants of its implementation, specialists in this field will be clear that it can be made various changes in form and details of its implementation without departing from its essence and without departing from its scope.

1. Implantable medical device comprising a coating composition containing amorphous copolyester containing the reaction product of polycondensation of the polyester, and composition with a high content of lactides, containing more than 50 percent by weight of (l, d, dl, meso) lactide monomers, where the polycondensation polyester contains a reaction product diglycolic acid or its derivative and ethylene glycol; where copolyester contains from about 30 to 70% by weight of the polycondensation polyester, based on the total mass of sobolifera, and has an average molecular weight of from about 5000 to about 30000 g/mol, and is soluble in an organic solvent.

2. Medical device under item 1, in which copolyester contains from about 40 to 60% by weight of the polycondensation polyester, based on the total mass of sobolifera.

3. Medical device under item 1, in which copolyester contains about 50% by weight of the polycondensation polyester, based on the total mass of sobolifera.

4. Medical device under item 1, in which the average molecular weight of the polycondensation polymer is from about 2000 to 10000 g/mol.

5. Copper is Ty the device under item 1, optionally containing an active agent.

6. Medical device under item 5, in which the active agent is selected from the group consisting of natural ingredients, synthetic ingredients, antibiotics, chemotherapeutic agents, cytotoxic agents, inhibitors of metastasis, anti-diabetic agents, antimycotics, antimicrobial agents, antibacterial agents, vitamins, gynecological agents, urological agents, antiallergic agents, sex hormones, inhibitors of sex hormones, hemostatic agents, hormones, peptide hormones, vitamins, antidepressants, antihistamines, deproteinizing DNA, plasmid DNA, cationic complexes of DNA, RNA, cellular components, vaccines, cells, naturally present in the body, genetically modified cells, and mixtures thereof.

7. The medical device according to p. 6, in which the active agent is an antimicrobial agent selected from the group consisting of octenidine, polyhexamethyleneguanidine (RNPS), triclosan, copper, silver, nano-silver, gold, selenium, gallium, taurolidine, N-chlorotaurine, alcohol, LAE, MAPD, OAPD, and mixtures thereof.

8. The medical device according to p. 7, in which the antimicrobial agent is applied triclosan.

9. The medical device according to p. 7, in which the antimicrobial agent use aetsa of actinidin.

10. The medical device according to p. 7, in which the antimicrobial agent is applied RNPS.

11. Medical device under item 1, in which the remaining components of the composition with a high content of lactides contain at least one component selected from the group consisting of glycolide, R-dioxanone, trimethylaniline, tetramethylgermane, Epsilon-caprolactone, Delta-valerolactone, beta butyrolactone, Epsilon-decalactone, 2,5-dichotomiflorum, Pavlyuchenkov, alpha,alpha-diethylpropion, efilecabinet, ethylenoxide, 3-methyl-1,4-dioxane-2,5-dione, 3,3-diethyl-1,4-dioxane-2,5-dione, gamma-butyrolactone, 1,4-dioxan-2-it, 1,5-dioxan-2-it, 1,4-dioxane-2-it, 6,8-dioxabicyclo-7-she and their combinations.

12. Medical device under item 1, in which the medical device is selected from the group consisting of sutures, tubes, implants, vascular stents, dental implants, fabrics, grids, microspheres, coat, films, foams, nonwoven materials, woven materials, dressings, pockets, decorated fabrics, and combinations thereof.

13. Medical device under item 1, in which the organic solvent is non-toxic solvent.

14. Medical device under item 13, in which a non-toxic solvent selected from the group consisting of ethanol, 2-propanol, ethyl acetate, who Cetona, methyl ethyl ketone (MEK), and mixtures thereof.

15. Antimicrobial adhesion barrier comprising a coating composition containing amorphous copolyester containing the reaction product of polycondensation of the polyester, and composition with a high content of lactides, containing more than 50 percent by weight of (l, d, dl, meso) lactide monomers, where the polycondensation polyester contains a reaction product diglycolic acid or its derivative and ethylene glycol; where copolyester contains from about 30 to 70% by weight of the polycondensation polyester, based on the total mass of sobolifera, and has an average molecular weight of from about 5000 to about 30000 g/mol, and is soluble in an organic solvent.



 

Same patents:

FIELD: medicine.

SUBSTANCE: what is described is a biointegrated composite containing the following ingredients, wt %: collagen 5%-10%, polyazolidine ammonia modified by halogen hydrate ions 0.5%-4%, water dispersion of sub-micron flavonoid aggregates 0.5%-1%, water - the rest. What is described is a method for the coating formation, which consists in applying the biologically active composite by immersion or deposition followed by lyophilisation. The drying process is single-staged at a temperature of 3-5°C and pressure of 5×10-1 Pa. What is also described is a method for administering the biodegradable composite into a bone cavity by separating a mucoperiosteal flap of the operated portion of the alveolar process by special taps, burs and drills forming a bone bed to be filled with a targeted osteointegration substance, mounting an implant, placing back the flap and closing the wound.

EFFECT: composite has biocompatibility and haemocompatibility, optimal physical-chemical properties, as well as rapid resorbability in vivo with generating no toxic products and negative reactions when in use.

3 cl, 9 dwg, 2 tbl, 4 ex

FIELD: food industry.

SUBSTANCE: what is described is a polymeric composition formulation of poly(hydroxy butyrate-co-hydroxyvalerate) (PHB-co-PHV) with additionally administered poly(D,L-lactide) in a solid ratio of 3:1 and dissolved in chloroform to the concentration of 6-9%; the composition is thereafter mixed for 2 hours and heated to 35°C. What is described is a membrane prepared by electrostatic formation (electrospinning) which involves including biologically active substances of fibronolytic preparations or direct action anticoagulants in the structure of fibres.

EFFECT: membranes possess biocompatible properties, a biodegradation life no more than 60 days, and enable preventing the adhesion formation effectively in experiment.

2 cl, 2 tbl

FIELD: medicine.

SUBSTANCE: antimicrobial composition for coating a medical device includes a material, which forms a polymer film, and an antimicrobial preparation from the traditional Chinese medicine, selected from a group: extract of Houttuynia cordata, sodium houttuyfonat and sodium new houttuyfonat or their mixtures. The medical device, covered with an antimicrobial composition, is made in the form of an implanted device.

EFFECT: invention provides the antimicrobial effectiveness with respect to microorganisms - causative agents of surgical infections.

19 cl, 2 dwg, 7 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine. An implanted medical device for delivery of a number of medications to a place of intervention in accordance with the first version contains in fact a cylindrical intraluminal framework, a primer layer, the first and second coatings and, at least, one therapeutic preparation. The cylindrical intraluminal framework is expandable from the first diameter for delivery into a vessel to the second diameter for the vessel expansion. The intraluminal framework has a luminal surface and an abluminal surface. The distance between the luminal surface and the abluminal surface specifies a thickness of the intraluminal framework wall. The intraluminal framework also contains a multitude of holes, extending from the luminal to abluminal surface. The primer layer includes a multitude of layers and covers the luminal surface, the abluminal surface and surfaces of the multitude of holes. The first coating contains a material, which has the first electric charge, and is fixed to the primer layer. The second coating contains a material, which has the second electric charge and is fixed to the first coating only in the multitude of holes. The second electric charge is opposite to the first electric charge. The therapeutic preparation is placed in, at least, one of the multitude of holes. The second coating is made in the form of an intermediate layer between the first coating and, at least, one therapeutic preparation. The implanted medical device in accordance with the second version contains a cylindrical intraluminal framework, a layer of first coating, a layer of second coating and, at least, one therapeutic preparation. The cylindrical intraluminal framework is expandable from the first diameter for delivery into a vessel to the second diameter for the vessel expansion and has a luminal surface and an abluminal surface. The distance between the luminal surface and the abluminal surface specifies a thickness of the intraluminal framework wall. The intraluminal framework also contains a multitude of holes, extending from the luminal to abluminal surface. The first coating contains a material with the first electric charge, fixed on at least, a part of the abluminal surface, the luminal surface and surfaces of the multitude of holes. The layer of the second coating contains a material with the second electric charge, fixed on, at least, a part of the layer of the first coating. The second electric charge is opposite to the first electric charge. The therapeutic preparation is placed in, at least, one of the multitude of holes. The layer of the second coating is made in the form of an intermediate binding layer between the layer of the first coating and, at least, one therapeutic preparation, resulting in obtaining a layered configuration, in which the layer of the second coating is located between the layer of the first coating and, at least, one therapeutic agent, applied in, at least, one of the multitude of holes. The method of the coating application on the intraluminal framework, containing the multitude of holes, made in it, has the following stages: application of the layer of the first coating, containing the material, which has the first electric charge on, at least, a part of the surface of the intraluminal framework and the surface of the multitude of holes; application of the layer of the second coating, containing the material, which has the second electric charge, on, at least, a part of the first coating, with the second electric charge being opposite to the first electric charge; and application of, at least, one therapeutic preparation into, at least, one of the multitude of holes to form the layered configuration, in which the layer of the second coating is located between the layer of the first coating and, at least, one therapeutic agent, applied in, at least, one of the multitude of holes.

EFFECT: inventions ensure prevention of thrombosis and separation of the coating from the underlying surface of a stent.

13 cl, 11 dwg, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is a bioresorbable hydrogel polymer composition for cardiovascular surgery in the form of a film prepared by a reaction of natural polymers, biologically active substances, a solvent and a softening agent wherein the polymers are presented by cross-linked bioresorbable polymers - gelatin, chitosan or a mixture of chitosan and gelatin, chitosan and polyhydroxybutyrate; the biologically active substance or mixtures thereof are presented by the antioxidant L-carnosine, the anticoagulant heparin, the antiaggregant dipyridamole, acetylsalicylic acid, the non-steroid anti-inflammatory preparation acetylsalicylic acid, the antimicrobial preparations - ciprofloxacin, metronidazole; mechanical strength of the film is not less than 1.2 MPa, the relative elongation is no more than 160%, and the elasticity modulus is 0.4-5 MPa.

EFFECT: there are used hydrogel polymer compositions with the control bioresorption period, prolonged length of biologically active substance release, having biocompatible and thrombus-resistant properties and improved mechanical characteristics - higher softness and elasticity.

7 cl, 12 dwg, 2 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention refers to medical products, and to a method for making medical products. A carrier material is treated by electrolytic oxidation for pulse current feed at frequency of 50 to 10000 Hz onto the carrier material in an acidic bath or an alkaline bath to form a film having micropores and/or microroughnesses of the density of 5×104/mm2 or more on the surface of the carrier material, and then the carrier material is treated by iodine impregnation for impregnating the film with iodine or iodine compounds. The iodine compound preferentially represents iodine polyvinyl pyrrolidone, iodine β-cyclodextrine or silver iodide. The carrier material represents a material of Ti or a Ti alloy, stainless steel or a Co-Cr alloy. The film may be formed by using any of the chemical treatment, thermal treatment and mechanical treatment, or a combination of these treatments instead of electrolytic oxidation.

EFFECT: saving costs for preparing medical products with high microbial activity and long-time antimicrobial activity, and biological compatibility.

16 cl, 5 tbl, 3 dwg, 4 ex

FIELD: medicine.

SUBSTANCE: invention relates to chemical and pharmaceutical industry and represents implanted medical device, which contains: intra-lumen implanted construction; first coating, containing combination of rapamycin and probucol in therapeutic doses, enclosed in first polymer material, first coating being connected to the surface of intra-lumen implanted construction; and second coating, containing second polymer coating, containing second polymer material, connected to first coating, for regulation of rate of rapamycin and probucol eluting, second polymer material containing fluoropolymer.

EFFECT: invention provides treatment and prevention of disease and minimisation of organism response to introduction of medical device, stimulates healing and endoepithelisation, as well as provides control over rates of drug eluting from implanted medical devices and prevents restenosis.

49 cl, 7 ex, 97 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to textile treatment for cardiovascular surgery. A method involves textile treatment with a composition containing gelatin and intermolecular cross-linking of gelatin by an aqueous solution of glutaric dialdehyde, an antibiotic and 0.9% sodium chloride in certain proportions.

EFFECT: method enables make textiles hermetic and antimicrobial, reduced postoperative chemotherapeutic load on the patient.

5 cl, 11 tbl, 11 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine. Described is membrane envelope of implanted dosing system, which is suitable for hypodermic application. Membrane envelope contains first half and second half, and both halves contain continuous locking edge and are made with possibility of connection to each other by means of lockable connection. Locking edges of halves contain, at least, one hollow and/or, at least, one projection, made as continuous or discontinuous, and membrane envelope is made with possibility of locking in such a way, that, at least, one projection and/or, at least, one hollow of second half became opposite to, at least, one hollow and/or, at least one projection of first half by means of locking connection.

EFFECT: membrane envelope is suitable for hypodermic application aimed at separation of active agent in constant quantity during increased time interval.

10 cl, 2 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: present invention refers to medicine, more specifically to a biodegradable stents consisting of an internal biodegradable metal frame and an external polymer coating. The biodegradable coating consists of biodegradable polymers and can additionally contain at least one pharmacologically active substance, such as an anti-inflammatory, cytostatic, cytotoxic, antiproliferative agent, an anti-microtubule agent, an antiangiogenic, anti-restenosis (for restenosis), antifungicidal, anti-cancer, anti-migration, hypocoagulation and/or anti-thrombosis agent. The stent has a function of vessel lumen maintenance only during a period of time before repaired tissue is able to perform this function again.

EFFECT: making the biodegradable stent.

12 cl, 24 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is a method for measuring antimicrobial-coated tubular polyurethane products, including multiple-lumen polyurethane catheters consisting in the three-staged chlorhexidine and/or its salts modification. Chlorhexidine and/or its salts are impregnated on the product surface by processing the products in aqueous-alcohol solutions of chlorhexidine and/or its salts, removing excessive chlorhexidine and/or its salts from the product surface, applying a solution of polyurethane in tetrahydrofurane containing chlorhexidine and/or its salts, and evaporating tetrahydrofurane.

EFFECT: preparing the polyurethane products, eg catheters possessing the prolonged antimicrobial activity being in full accord with the multifunctionality of the multiple-lumen catheters.

9 cl, 1 tbl

FIELD: medicine.

SUBSTANCE: antimicrobial composition for coating a medical device includes a material, which forms a polymer film, and an antimicrobial preparation from the traditional Chinese medicine, selected from a group: extract of Houttuynia cordata, sodium houttuyfonat and sodium new houttuyfonat or their mixtures. The medical device, covered with an antimicrobial composition, is made in the form of an implanted device.

EFFECT: invention provides the antimicrobial effectiveness with respect to microorganisms - causative agents of surgical infections.

19 cl, 2 dwg, 7 tbl, 4 ex

Polymer material // 2497549

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is a device comprising a body frame having one or more surfaces, wherein at least one of the surfaces comprises a pH-sensitive layer containing a linear polymer, wherein the solubility of the above linear polymer grows from the first water solubility to the second water solubility at a starting pH value. What is also described is a method for building-up of the device and a method for prevention or relief of an infection.

EFFECT: device is resistant to infections and enables modulating the efficacy of the pH-sensitive layer; herewith a degree of solubility or erosion of the pH-sensitive layer can be decreased depending on the patient's state.

30 cl, 20 dwg, 8 ex

FIELD: medicine.

SUBSTANCE: invention refers to a new combination of a balloon catheter and a composition of an active substance attached to a surface of a balloon membrane. The invention also refers to a method of coating for making the balloon catheter and using it for treating and preventing vascular diseases.

EFFECT: balloon catheter causes no vessel tension with its membrane adjoining a vascular wall only in nonuniformity places, and the drug is delivered in these places only.

26 cl, 9 ex

FIELD: medicine.

SUBSTANCE: group of inventions relates to field of medicine. Tube for percutaneous endoscopic gastrostomy contains on surface region or inside this region chemical composition possessing antiseptic or antimicrobial action, releasing metal ions or colloidal metal. Chemical compound is contained in form of nanoparticles. Described is tube for enteral feeding containing coating with parylene or polyparylene. Into said coating introduced is and/or on it applied is chemical compound which possesses antiseptic or antimicrobial action, releasing ions of metal or colloidal metal.

EFFECT: acceleration of release of metal ions/colloidal metal due to which risk of infection, caused by introduction of food tube is reduced.

14 cl, 4 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine. There are described new special cylinders applicable for using in valvuloplasty of stenotic aortic valves, potentially applicable for valvuloplasty of the other cardiac valves. Their entire external surface, or its portion is coated with a medical substance which is released in valve tissue during a short-time contact with the cylinder in the process of dilatation. The medical substance counteracts with the process of restenosis which is almost always observed over a certain period of time. A cylinder shape can be classical cylindrical or hourglass-shaped that promotes target drug delivery to valve tissues. Local drug delivery substantially reduces a probability of restenosis.

EFFECT: favourable effect of the procedure on the patient is kept for a long time, while the procedure is transformed from temporarily relieving into a finishing therapeutic procedure.

12 cl, 11 dwg

FIELD: medicine.

SUBSTANCE: group of inventions refers to medical equipment, namely to a coating of balloon catheters. A balloon catheter with a citrate ester and at least one of cytostatic, cytotoxic, antiproliferative, antiangiogenic, antirestenotic, antineoplastic, antimigratory or athrombogenic active substance. The group of inventions also refers applying the citrate ester and at least one of the specified active substances for the coating of the balloon catheter.

EFFECT: group of inventions provides reducing time of penetration of the biologically active substances in the vascular walls, and also preventing restenosis.

8 cl, 5 dwg, 3 tbl, 32 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine. High antimicrobial activity and desired smoothness providing high thromboresistance are ensured by modifying a product surface, e.g. a polyurethane polyurethane with chlorhexidine and/or its salts with the modification procedure ensured by applying 0.5-4% polyurethane of molecular weight 10000 to 40000 units. in tetrahydrofurane containing chlorhexidine and/or its salts in the amount 0.25-5% (wt) in relation to polyurethane weight that is followed by tetrahydrofurane evaporation.

EFFECT: what is described is a polyurethane catheter with antimicrobial coating, the method for preparing the antimicrobial coating on polyurethane products and the method for producing the polyurethane catheters with the antimicrobial coating.

3 cl, 1 tbl

FIELD: medicine.

SUBSTANCE: offered is medical device adapted for local application or introduction in hollow tubes and containing therapeutic dose of N-{5-[4-(4-methylpiperazinomethyl) benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidinamine or its salt, crystal form with possible release thereof, its application for prevention or reduction of dysfunction caused by approach to vessels and related method of treatment (prevention). Particularly offered is method of restenosis treatment or prevention inpatients suffering from diabetes. It is detected that local introduction of M-{5-[4-(4-methylpiperazinomethyl) benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidinamine or its pharmaceutically acceptable salt or crystal form under declared method provides unexpectedly high stability of compound within 45 days compared to its activity value when introduced as free form.

EFFECT: provides high stability of compound.

5 cl, 7 ex

FIELD: medicine.

SUBSTANCE: method and device can be used for selective treatment of ill parts of tissue or organs of human bodies. Surface of medicinal devices being in contact with mentioned parts of body under pressure of medicinal devices are covered with lypophile, mainly water-insoluble medicinal aids being capable of connecting with any components of tissue, which medicinal preparations effect onto tissue immediately after contact and they effect for very short period of time without making dangerous effect onto adjacent healthy tissue. Device has balloon which surface is connected with lypophile, water-insoluble medicinal preparations being capable of binding with tissue. After contact with tissue is made, medicinal preparations are capable of instant release of biological active matters. Balloon is provided with preformed longitudinal folds. Biological active matter covers parts of balloon hidden by folds.

EFFECT: higher efficiency of treatment.

20 cl, 11 ex

FIELD: medicine.

SUBSTANCE: there are described new reinforced biodegradable frames for soft tissue regeneration; there are also described methods for living tissue support, extension and regeneration, wherein the reinforced biodegradable frame is applied for relieving the symptoms requiring high durability and stability apart from patient's soft tissue regeneration. What is described is using the frames together with cells or tissue explants for soft tissue regeneration in treating medical prolapsed, e.g. rectal or pelvic prolapse, or hernia.

EFFECT: frames are adequately durable to be applicable for implantation accompanying the medical conditions requiring the structural support of the injured tissues.

14 cl, 19 dwg, 2 tbl, 8 ex

Up!