RU2422133C1 - Hydrophylic gel, method of its obtaining (versions), wound covering and based on it bandage means - Google Patents

Abstract

FIELD: medicine, pharmaceutics. ^ SUBSTANCE: invention relates to field of medicine, namely to bandage means, used for treatment of burns, trophic ulcers and other skin lesions, as well as to methods of their obtaining. Described is gel, representing sparsely-cross-linked chitosan and polyanionic hydrocolloid polymer, which has 2-3 linkages of copolymers per chitosan molecule, and distributed in it auxiliary substances. As polyanionic hydrocolloid, used is suspension of sucralfate or polyalginic acid particles, containing 0.01-15 wt % of stabiliser. As stabiliser used is highly molecular polyalcohols, such as polyvinyl alcohol, polyethylene glycol, as well as polyvinylpyrrolidone or silver microparticles. Auxiliary substances are introduced into gel individually or together in concentrations from 0.01 to 30% of gel dry weight. Gel is obtained by mixing chitosan with polyanionic hydrocolloid, into which preliminarily introduced were stabiliser and auxiliary substances. Bandage material represents hydrogel layer, applied on biocompatible film from water-insoluble polymer with pores with diameter D=(0.01-5.0) mcm. Covering can be on wounds during long term from 2 to 20 days and produce medicinal effect during said period. ^ EFFECT: bandage means can be used in treatment of trophic ulcers and various wound types, including wounds polluted with microorganisms, trophic wounds and prolonged non-healing wounds, and also be applied as allogen skin substitute in operations aimed at recovery of skin in patients with extensive burns. ^ 16 cl, 11 ex

Description

The invention relates to medicine, specifically to dressings used to treat burns, trophic ulcers and other skin lesions, as well as to methods for their preparation.

Currently, the effectiveness of dressings in many cases is determined by biocompatibility with body tissues, sorbing properties, the ability to maintain moisture and gas exchange on the wound, prevent the development of infection, ease of use, the presence of various biologically active substances in their composition.

Among dressings, in particular, various medical dressings based on knitted and non-woven materials, for example Inadine (Jonson & Jonson, USA), consisting of a knitted viscose fabric impregnated with a solution of povidone iodine in polyethylene glycol, the disadvantage of which is small sorption (not more than 3 g), are known / g), low antimicrobial activity. Partially, these shortcomings were overcome in the Apolo-PAK gel dressing (Appolo Trading Company LLC TU 9392-002-42965160, 2002, Russia), which contains a carrier network and a gel based on acrylamide-acrylic acid copolymer with immobilized in it antiseptic iodovidone and anesthetic anilokain.

However, these dressings have a significant structural disadvantage, namely, that when opening the package, a significant part of the gel remains on the inner surface, and is not transferred to a burn wound with a carrier net. Another disadvantage is that the polymer monomers of the gel base are toxic, therefore, the presence of residual amounts of these monomers in the dressing due to technical defects or as a result of depolymerization of the dressing base in the body can lead to worsening of the course of the wound process. In addition, the sorption ability of the dressing is 2-3 g / g, which is clearly not enough for effective treatment of a burn wound.

The disadvantages inherent in Appolo-PAK dressings have been partially overcome in the Activetex HL gel-forming dressing, which has a textile, film or paper carrier with a complex of a biocompatible polymer and a drug, the antimicrobial chlorhexidine and local anesthetic, applied to it on at least one side - lidocaine. As a biocompatible material, a complex based on a polysaccharide and collagen or gelatin is used (RU 2101033, 1998). The complex characteristics of this dressing provides the possibility of treating certain types of burns. Its sorption capacity reaches 4.5 g / g. However, such sorption ability is in some cases insufficient. In addition, it is necessary to moisten them before applying and removing bandages, and there is also the possibility of film ingrowth into the wound.

A dressing containing a non-traumatic healing layer consisting of a textile carrier with drugs, a sorption layer of a perforated cotton cloth weighing 120-210 g / m ² , which is impregnated with an aqueous solution of a mixture of polyethylene glycols of 10-50 mg / has a higher sorption ability. cm ² and anesthetics 0.5-1.2 mg / cm ² , as well as a sorption layer located on top of the treatment layer made of a non-woven fabric that provides a sorption capacity of the dressing of at least 10 g / g (RU 2275179 , 2006). Antiseptics (chlorhexidine, furagin, iodoperon, povidone iodine, quinosole or dioxidine) or anesthetics (lidocaine, dicaine, anilocaine, trimecaine) can be used as medicines.

The dressing has a high degree of surface modeling, is convenient to use, and the combination of the sorption layer in combination with a medical perforated layer improves the sorption ability of the dressing to 10-20 g / g. The main disadvantage of this dressing is the use of textile and non-woven materials, which, after the termination of abundant exudation, can grow to the wound, as a result of which removal of the dressing when changing it can lead to injury to the regenerated tissues.

Known three-layer medical dressing with increased biocompatibility and improved permeability to water vapor, containing a base, a medicinal substance and a protective polymer coating (RU 2125859 1999). The first layer adjacent to the wound is made in the form of a film of a water-soluble polymer, for example: polyvinyl alcohol, methyl cellulose and / or its derivatives, polyethylene glycol, carboxymethyl cellulose, polyacrylic acid, polyacrylates. These polymers adhere well to the damaged surface due to moisture absorption, moisturize and swell, while maintaining elasticity. The second layer - the base is made of a biodegradable material - a glycolide-lactide copolymer, taken in a ratio of 70: 30-1: 99, respectively, or a mixture of this copolymer with 1-10 wt.% Polyether polyol and / or poly-N-vinylpyrrolidone. Such a biodegradable film has a high permeability with respect to water vapor: The biodegradation period, i.e. the time of complete resorption of the main layer is 1-7 weeks, depending on the specific composition of the claimed dressing. This ensures healing of the skin in case of injuries of various types and eliminates the need to remove the film with trauma to the skin. The third protective layer protects the wound surface from the penetration of pathogens from the outside and at the same time provides increased gas exchange. This layer is made in the form of a diffusion membrane of polysiloxane or its copolymers (silar, carbosil), or in the form of a microfiltration membrane of aliphatic polyamide, fluoroplastic, etc. with pore sizes of not more than 0.2 μm, providing impermeability to bacteria. The coating provides a sustained dosed release of the drug substance.

The dressing provides stimulation of the reparative regeneration of long-term non-healing wounds in the soft tissues, however, it does not have sufficient sorption and active therapeutic effect in the initial stage of treatment.

A dressing is known that solves the problem of increasing the therapeutic effectiveness of a dressing by ensuring a more complete penetration of the drug into the affected area and a more complete outflow of exudate from the affected area, which reduces the morbidity of dressings and their frequency (RU 2189210, 2002). The proposed multilayer medical dressing contains a successively hydrophobic atraumatic permeable layer, a treatment layer, a layer of a polymer film, and also an external protective breathable sorption layer located above the aforementioned, and the treatment layer and the layer of polymer film are made coaxially perforated. The atraumatic permeable layer can be made of a material obtained by weaving fibers (polyamide mesh) or by perforating a non-woven material, for example a polymer, which contributes to atraumatic dressing changing due to its hydrophobicity. The main purpose of this layer is to provide moisture absorption (the value of the latter is not less than 10 g - 17 g / g). The dressing adheres tightly to wounds located on body parts with different reliefs, provides good sorption, and has a beneficial effect on wound healing.

The disadvantages of the dressing is that it requires additional fixation, and its use does not exclude injury to the wound, since the contact layer is made of non-biodegradable material.

One of the promising materials for the manufacture of dressings is the hydrogel layer based on cellulose and carboxymethyl cellulose. The material is capable of absorbing aqueous saline in an amount of at least 15 times their own weight (according to the results of the free swell absorption test), with the formation of a swollen transparent gel (US 3731686, US 3589364, US 4634438, US 4634439; RF patent No. 2135212, 1999). The dressing material after such swelling retains a sufficiently fibrous nature to remove it from the wound as an integral dressing. Carboxymethyl cellulose filaments can be used to treat traumatic, surgical, or chronic wounds. However, the technology for producing such cellulose derivatives is technically complex, and the materials based on cellulose derivatives themselves are not biodegradable on the wound and require removal.

Superabsorbents used in personal care products, obtained on the basis of substances such as agar, pectin, natural resins, carboxyalkyl starch, carboxyalkyl cellulose, polyacrylates, polyacrylamides and hydrolyzed polyacrylonitrile, have a sorption capacity for water over 100 g / g. Thus, a supersorbent is known (RU 2152403, 2000), obtained on the basis of a water-swellable water-insoluble carboxyalkyl polysaccharide. The technology for its preparation includes the steps of preparing a homogeneous mixture consisting of a water-soluble polysaccharide and water, isolating the indicated polysaccharide from the mixture and heat treating the isolated carboxyalkyl polysaccharide at 200-250 ° C for 50-90 s, and the polysaccharide obtained by the specified method is also claimed. The polysaccharide has an initial absorption capacity under load of at least 17 g / g and retains at least about 50% of the initial absorption capacity under load after aging for 60 days at 24 ° C. and a relative humidity of at least 30%. A supersorbent based on it contains up to 20 wt.% Crosslinking agents, however, its use for medical purposes is not expected due to the low biocompatibility and toxicity of the material.

The most favorable form of coating for the course of the wound healing process is hydrophilic gels (hydrogels). However, when creating and using dressings with a hydrogel layer, there are still many problems that do not allow the full use of their consumer properties.

Ideal hydrogels should have a high degree of swelling when in contact with wound fluids, while not losing their integrity and not draining from the wound. They should have good adhesion to the wound, it is easy to repeat its contours. It is desirable that the hydrogels and their support layer in the composition of the dressing are transparent and allow you to monitor the condition of the wound without removing the dressing. From a safety point of view, it is desirable that the hydrogel be made from biodegradable natural and medical polymers that do not form toxic decomposition products in the body. From the point of view of industrial applicability, it is desirable that the hydrogel and dressing based on it could be obtained by simple technology without the use of organic solvents.

Irreversible hydrophilic gel and a dressing based on it are known (RU 2225185, 2004), which are used as a carrier of biologically active substances by introducing into the compositions for dressings, dermatologically compatible compositions, tampons for wounds, dressings for wounds, dressings for burns, dressings for delivery medicines, dry films, cosmetic masks and compresses. The gel is prepared by mixing a mixture of hydrophilic polyaldehyde obtained by grafting monomeric aldehydes onto poly (N-vinyl lactams), a polymer selected from the group consisting of polyamide, polyamine and polyalcohol, as well as biologically active additives (BAA). As a dietary supplement, it may contain nitroglycerin, scopolamine, pilocarpine, ergotamine tartrate, phenylpropanolamine and theophylline; antimicrobial agents such as tetracycline, neomycin, oxytetracycline, triclosan, sodium cefazolin, silver sulfadiazine, salicylates such as methyl salicylate and salicylic acid; nicotinates, such as methyl nicotinate; capsaicin, benzocaine, α-hydroxy acids, vitamins and biostatics. The gel can be combined in one product with a variety of substrates or substrates, including polymer films, for example, polyurethane, metal foil, fabrics and non-woven materials from natural and synthetic fibers, etc. For ease of use, the gel on the substrate is coated with an outer layer, which may be a film coated with silicone or polyethylene.

The gel has the property of resistance to cold flow, itself sticks to the skin and easily exfoliates. When used in the form of tampons or dressings for application to the wound cavity, it provides the dressings with such desirable properties as: biocompatibility; ability to match the wound cavity; lack of adhesion to the wound; ability to absorb exudate; the ability to remove one piece from a wound; the ability to maintain physical integrity after swelling in the exudate; ease of handling as it is not too sticky.

The disadvantage of the proposed hydrogel is the relatively low absorption capacity, which is mainly less than 10 g / g. Another dangerous point is that the acrolein used in its composition in monomeric form is toxic, and therefore, biodegradation products in a wound may be poorly compatible with the body.

The most promising for use in wound dressings are gels based on complexes of polyvinylpyrrolidone (PVP). Thus, a hydrogel is obtained by the interaction of polyvinylpyrrolidone with chitosan or its derivatives and can be used as a carrier of drugs for transdermal delivery and used as masks for the delivery of skin moisturizers. (US 5420197, 1995). It is a complex of neutralized chitosan and poly (N-vinyl lactam), which allows you to include various substrates and additives.

The gel is prepared by mixing aqueous solutions of poly (N-vinyl lactam) and neutralized chitosan at a weight ratio of 12/1 to 2/1 to form a mixture with a total polymer content of 5 to 20 wt.% And with the introduction of drugs during gel preparation. The resulting hydrogel is able to absorb exudate without loss of gel structure. The gel can be used in the filling cavity of wound healing material, wound dressings, drug delivery systems, cosmetic masks.

The advantage of this invention is the relative ease of obtaining a biocompatible wound healing material. The disadvantages of the hydrogel are the possibility of microbial contamination and inconvenience of use, because in a watered state, runoff is observed on the wound.

Closest to the claimed group of inventions is a dressing agent (RU 2270646, 2006), which contains a polymer film with a hydrogel layer deposited on its surface. The film is made of a biocompatible optically transparent polymer with through holes with a diameter of D = 0.01-3.0 μm and a density of N = (10 ³ -10 ⁹ ) 1 / cm ² , and a hydrogel obtained by mixing chitosan solutions with polyhydric alcohols and polyvinylpyrrolidone. The resulting hydrogel is applied to a water-insoluble film with linear through pores, dried to a moisture content of less than 30%. The dressing promotes the accelerated regeneration of damaged tissues and is able to absorb up to 8 g / g of exudate. The external film prevents the penetration of microorganisms into the wound, allowing you to visually monitor the processes taking place in the wound, and conveniently attaches to the wound surface.

The disadvantages of the proposed solution is the need for a long time for the formation of a solid hydrogel (more than two to three days), which impedes the industrial applicability of this method, insufficient sorption capacity, and the possibility of draining the hydrogel from the wound during watering (absorption of exudate).

The problem solved by the authors was the development of such a gel and a dressing based on it, which would have improved sorbing properties, maintain integrity after swelling in the exudate, have ease of manufacture and use, as well as the technology for their preparation.

The technical result is achieved by creating a gel, which is a rare cross-linked polymer of chitosan and polyanionic hydrocolloid, having 2-3 cross-linking of copolymers per chitosan molecule and excipients distributed therein.

As a polyanionic hydrocolloid, a suspension of particles of sucralfate or polyalginic acid containing 0.01-15 wt.% Stabilizer is used. The proportion of polyanionic colloid in the copolymer is from 0.1 to 10% by weight of the dry mixture.

The use of chitosan base in hydrogel also provides stimulation of reparative processes. A feature of the claimed chitosan hydrogels is the use of the antacid preparation Sucralfate as a structure-forming agent, which is currently widely used as an enveloping drug in the treatment of stomach ulcers. It was found that the introduction of a solution of sucralfate into concentrations of 0.1 to 10% in a neutralized chitosan solution leads to the rapid gelling of chitosan and the production of a stable gel. To prolong the process of structure formation to a technologically acceptable time (30-60 min), it is preferable to administer sucralfate as part of a solution of a viscous polymer with a viscosity above 800 MPa · s.

The use of sucralfate, along with the stabilization of the gel, also has biological significance, since Sucralfate has the ability to bind the epithelial growth factor (EGF) and fix it in the area of a peptic ulcer, thereby stimulating cell proliferation, development of the vasculature and tissue regeneration. In well-known sources, sucralfate was used as a composition in the form of ointments, creams (US 4,945,084; 5,196,405; 5,202,311; 5,478,814), in particular for stabilization of the main fibroblast growth factor (bFGF) and as an inducer of growth factors. Thus, it could be assumed that the introduction of sucralfate into the composition of the dressing would also help stabilize growth factors and, therefore, stimulate tissue regeneration.

High molecular weight polyalcohols, such as polyvinyl alcohol, polyethylene glycol, as well as polyvinylpyrrolidone or silver microparticles, are used as stabilizers.

As auxiliary substances, plasticizers and modifiers, such as glycerin and taurine, biologically active substances, in particular antioxidant enzymes of the body: superoxide dismutase, catalase, cytochrome C, glutathione; proteolytic enzymes, for example collagenase; anesthetics - dicain, anilocaine, trimecain, lidocaine, etc. antibiotics and antiseptics - gentamicin, chlorhexidine bigluconate, dioxidine, iodoperone, catamine, etc .; silver nanoparticles or colloidal particles. Excipients are introduced into the gel individually or together in concentrations from 0.01 to 30% of the dry weight of the gel.

The obtained hydrogel is a polymer matrix capable of passing up to the wound medicinal substances included in it with a hydrodynamic radius of up to 60, and in a swollen state up to 300 Ǻ. Such properties of the gel allow the use of numerous biologically active substances contained in the wound exudate (growth factors, cytokines, etc.), which themselves participate in the wound process and have regulatory activity. With conventional methods of treatment, exudate is removed and these substances do not participate in the wound process. If the hydrogels proposed in this invention are applied to the wounds, growth factors and cytokines are retained within the hydrogel, stabilize and subsequently can exert their effect, which favorably affects the course of reparative processes.

The main feature of the gel is its sparse structure - 2-3 cross-linking of copolymers per chitosan molecule. The use of more tightly crosslinked polymer networks makes it difficult for cells and enzymes that can biodegrade polymers to penetrate through them. Such polymers do not absorb tissue detritus well and cannot function as a temporary extracellular matrix and promote tissue regeneration. So, when a supersorbent is used on a wound based on a copolymer of acrylic and methacrylic acids tightly crosslinked by metal ions, a gel forms that fills the entire defect well. However, the growth of granulation tissue and epithelization, as well as further healing of the wound when using such a gel does not occur.

A hydrophilic gel is prepared in one of two ways.

According to the first embodiment, chitosan is mixed with a polyanionic hydrocolloid, into which a stabilizer and auxiliary substances are preliminarily introduced, and before mixing with chitosan, the hydrocolloid is alkalized to pH 5.5-6.5 by physicochemical activation by freezing, thawing, autoclaving, processing Microwave or ultrasound and / or polyanionic hydrocolloid is pre-added with 0.01-1 wt.% Polyelectrolyte, for example carboxymethyl cellulose, or alginic acid, and after mixing with chitosan with es stand for 30-60 minutes.

The proposed hydrogel formation mechanism consists in the formation of ionic bonds between the amino groups of chitosan and the carboxyl groups of the second ingredient. It should be borne in mind that the use of standard binding technology does not allow to achieve the solution of the task for the following reasons. First, the binding of polymers and the formation of a non-flowing gel capable of maintaining shape is a lengthy process and can take at least a month, because the interaction of the carboxyl group with the amino group of chitosan is sterically difficult. After the preparation of the hydrogel for a long time, the processes of structure formation take place in it, as evidenced by the constant increase in the shear modulus. This does not allow us to talk about the stability of the properties of the proposed material.

Secondly, a concentrated hydrogel layer deposited on a support material substrate is often capable of draining from it at an elevated ambient temperature and under load, the so-called cold fluidity. In addition, it is liquefied by watering and the action of wound enzymes (sorption of exudate on the wound) and is able to drain from it and the substrate, and the absorption capacity of such a hydrogel in water is only about 4 g / g.

In the proposed technology, the properties of the bound hydrogel are mainly determined by the intermolecular interaction of chitosan, and stabilizers such as polyvinylpyrrolidone (PVP) and polyalcohols act as a medium with a high viscosity (with a viscosity of more than 800 mPa · s), which inhibits the fast processes of crosslinking or aggregation of chitosan molecules. This allows you to get a uniform rarely cross-linked three-dimensional polymer matrix based on chitosan, biocompatible and with high absorption capacity. At the same time, the stabilizer carries out the binding (sorption) of the crosslinking agent, followed by its slow release for interaction with molecules of a positively charged polymer.

It is known that, depending on the pH of the solution, chitosan can either be in a dissolved state or precipitate. Between these two states there is a narrow pH range of 5.5-6.8, at which it can be in a gel state. However, achieving such a stable state is extremely difficult. The presence of a polymer that creates a highly viscous medium complicates the interaction of chitosan molecules and its release into the solid phase, but facilitates the transition to the gel phase. The simplest way to obtain a non-flowing stable chitosan gel is to alkalize the system in the presence of a high viscosity polymer by mixing polymer solutions. However, this action requires a very accurate calculation of the added alkali, which is difficult due to the fact that the properties of chitosan are determined by the degree of deacetylation and its molecular weight. Therefore, the estimated amount of alkali needed will vary from batch to batch of chitosan, and the excess alkali often affects only after some time, or when the conditions of gel flooding change - as a result, chitosan begins to precipitate. At the same time, the introduction of pure alkali into a solution containing chitosan, which is in critical condition at a pH close to precipitation, will inevitably cause the formation of a precipitate due to local high pH zones; therefore, it is proposed to introduce alkali into the system together with a highly viscous solution of another polymer.

As mentioned earlier, one of the disadvantages of obtaining hydrogels by the interaction of chitosan with free carboxyl groups. To accelerate the interaction between oppositely charged polymers, which allows the gelling of the system, it is advisable to process the solution of these polymers after mixing by freezing and thawing (cooling to -40 ° C), or by sonication or microwave, or by autoclaving, which improves the availability of charged groups macromolecules of polymers for interaction.

Another way to speed up the process of producing a bound hydrogel is to use small additives of ionic polymers capable of rapid complexation with chitosan, such as carboxymethyl cellulose, alginic acid, and the like. When aqueous solutions of chitosan and these polymers are mixed, the polymer complex almost immediately precipitates in the form of a dense precipitate. However, in a solution of a viscous polymer with a viscosity higher than 800 MPa · s, an addition to the chitosan solution of 0.01-1 wt.% Polyelectrolyte (carboxymethyl cellulose, or alginic acid or other biocompatible acidic polyelectrolyte) does not immediately coagulate, and a highly dispersed colloid suitable for application forms on a substrate or during mold casting for 30-60 minutes, during which the formation of an interpolymer polyelectrolyte complex with chitosan takes place, as a result of which the hydrogel is quickly gelled.

According to the second variant, after mixing chitosan with a polyanionic hydrocolloid, into which silver nitrate and auxiliary substances have been previously introduced, the product is exposed to light until silver monoclusters are formed.

The second variant of gel preparation was developed to establish the possibility of giving hydrogels the properties of weak superabsorbents and to significantly increase their sorption ability, provided that the binding speed of the ingredients is slow when metal ions are included in the process.

It is known that chitosan is capable of forming chelate bonds with most metal ions, which makes it widely applicable as a sorbent of radioactive isotopes. However, the rapid interaction of chitosan with metal ions does not allow obtaining hydrogels that are satisfactory in properties. So, the mixing of a solution of neutralized chitosan with a solution of silver nitrate leads to the formation of a black-brown solution, which is associated with the rapid reduction of silver and its precipitation in the form of a colloidal precipitate, which does not have high antimicrobial activity.

However, the authors found that if silver ions are first dispersed in a neutral polymer, then, after mixing with a solution of chitosan, the formation of a transparent, highly viscous gel is observed. With the introduction of silver nitrate in an amount of from 0.01 to 1 wt.% (Based on the dry matter content in the gel), a gelled gel containing silver in ionic form can be obtained. Upon subsequent exposure of the hydrogel for several hours, the gel turns yellow and slightly brown. Studying this process with a spectrophotometer made it possible to detect a plasma resonance peak at 400 nm, which indicates the transition of silver to a zero-valent form and the formation of silver nanoclusters up to 10 μm in size. With prolonged exposure, almost all silver goes into a zero-valent form, and the cluster size grows to 10-20 microns. The resulting hydrogel has a high sorption capacity (up to 40 g / g after four days of swelling), a slow rate of liquid sorption, high antimicrobial activity, is well compatible with body tissues, is able to maintain its integrity for a long time and not drain from the wound even with a high degree of swelling. Gels and dressings based on it have a high degree of surface modeling.

The proposed hydrogels can be used either independently or as part of wound applications in the form of a layer deposited on a substrate. As the substrate, the most favorable is a porous water-insoluble film of biocompatible materials.

The dressing based on the above gel is a hydrogel layer deposited on a biocompatible film of a water-insoluble polymer with pores with a diameter of D = (0.01-5.0) microns.

As the polymeric material for such a film, polytetrafluoroethylene, polyethylene terephthalate, alone or mixed with polypropylene, polysulfonamide, carboxymethyl cellulose, polyimide, copolymers of polyester and polyamide, silicone and other biocompatible porous polymeric materials can be taken. The film thickness is usually from 3 to 100 microns.

The dressing described above can be used both independently and in the composition of a multilayer dressing, including a hydrophobic atraumatic permeable layer, a treatment layer and a layer of a polymer film, replacing one or more layers included in its composition.

Dressings based on a combination of a polymer film and a hydrogel layer containing bioactive substances obtained according to the claimed invention can be used in the treatment of trophic ulcers and various types of wounds, including wounds contaminated with microorganisms, trophic and long-healing wounds, and can also used as a substitute for allogeneic skin when performing operations to restore the skin in patients with extensive burns. Coatings can be on wounds for a long period from 2 to 20 days and during this period they exert their therapeutic effect. The use of this kind of wound dressing allows you to implement the principle of "made the application of the coating and forgot."

The essence of the claimed invention is illustrated by the following examples.

Example 1 (analog). 200 ml of “Povidone” (10% solution of polyvinylpyrrolidone (PVP) with a molecular weight of about 3,000,000 Da) is made alkaline with a 10% sodium alkali solution to pH 9.0 ± 0.5. 20 ml of glycerol are added to the PVP solution with stirring. The resulting solution was autoclaved for 30 min at 1 atm and a temperature of + 121 ° C.

2 g of chitosan with a molecular weight ranging from 20,000 to 2,000,000 Da and a degree of deacetylation of more than 92% are filled with 100 ml of water and allowed to swell for 4 hours. Then, with stirring, 2 ml of acetic acid is added to the suspension. After thickening, the solution is left for a day. Then the solution is stirred, filtered from insoluble particles and neutralized with alkali to a pH of 6.1.

At room temperature, the PVP solution and chitosan solution are drained and vigorously stirred until a homogeneous solution for 10 minutes. Next, the gel is applied to a film with an area of 500 cm ² at the rate of 0.3 ml per 1 cm ² and dried to a moisture content of less than 50%. The resulting dressing has a pH in the range of 6.3 and is able to absorb 8 g / g of water per day.

In experiments on wounds, it was found that with abundant exudation, the hydrogel is heavily watered and can drain from the wound, which causes inconvenience in use.

Example 2. A solution of chitosan is prepared according to the method of example 1.

0.4 g of alginic acid is dissolved in 40 ml of water with alkalization with 0.1 N NaOH. 20 g (by dry weight) of polyvinyl alcohol with a molecular weight above 100,000 are dissolved by heating in 200 ml of deionized water. Then, 10 g of taurine and 40 ml of glycerol are introduced into the solution with stirring; after dissolution, 40 ml of alginic acid solution is introduced. The resulting solution is autoclaved for 30 minutes at a temperature of + 121 ° C.

At room temperature, the prepared solutions are drained and vigorously stirred until homogeneous for 10 minutes. During mixing, a finely dispersed colloid of the complex of chitosan and polyalginic acid is formed in the solution. After mixing, the gel is applied to the substrate and dried to a moisture content of less than 50%. The resulting dressing is capable of absorbing 8 g / g of water.

In experiments on wounds, it was found that with abundant exudation, the hydrogel does not drain from the wound during flooding.

Example 3. A solution of chitosan is prepared according to the method of example 1.

20 g of high molecular weight polyethylene oxide (with a molecular weight above 1,000,000 kDa) are dissolved in 200 ml of deionized water. 25 ml of glycerol are added to the resulting solution and mixed. Next, 40 ml of a polyalginic acid solution is introduced into the solution with stirring. At room temperature, the prepared solutions are drained and vigorously stirred until homogeneous for 10 minutes.

After mixing, the gel is applied to the film at the rate of 0.5 ml per 1 cm ² and dried to a moisture content of less than 50%. The resulting dressing is capable of absorbing 10 g / g of water.

Example 4. A solution of chitosan is prepared according to the method of example 1.

200 ml of “Povidone” is acidified with 0.1 N hydrochloric acid to a pH of 2.5 ± 0.5. 20 ml of glycerol are added to the PVP solution with stirring. 0.5 g of sucralfate (aluminum-sulfate sucrose complex) is added to the PVP solution with stirring. The solution was neutralized to pH 6.0. During neutralization, a finely dispersed Sucralfate colloid stabilized by PVP is formed.

At room temperature, the prepared solutions are drained and vigorously stirred until homogeneous for 10 minutes. After receiving the gel is applied to a substrate and dried to a moisture content of less than 50%. The resulting dressing is able to slowly (up to 4 days) sorb 20.4 g / g of water, without being exposed to cold flow.

Example 5. A solution of chitosan is prepared according to the method of example 1.

A PVP solution is prepared as in Example 4. 10 ml of a 0.02 N silver nitrate solution is added to the PVP solution with stirring.

At room temperature, the prepared solutions are drained and vigorously stirred until homogeneous for 10 minutes. After receiving the gel is applied to the substrate and kept in a lighted place for 6 hours. In this case, the gel is illuminated and silver goes into a zero-valent form, being released in the form of silver nanoclusters, up to 20 nm in size. The gel acquires a yellowish-brownish tint. The gel is dried to a moisture content of less than 50%. The resulting dressing is able to sorb up to 19.3 g / g of water for 4 days. On wounds, the material exhibits bactericidal activity.

Example 6. A solution of chitosan is prepared according to the method of example 1.

A PVP solution is prepared as in Example 4. Into a PVP solution, 10 ml of a solution containing 0.02 N silver nitrate and 0.04 N cerium nitrate are added with stirring.

At room temperature, the prepared solutions are drained and vigorously stirred until homogeneous for 10 minutes. After receiving the gel is applied to the substrate and kept in a lighted place for 6 hours. In this case, the gel is illuminated and silver goes into a zero-valent form, being released in the form of silver nanoclusters, up to 20 nm in size. The gel acquires a yellowish-brownish tint. The gel is dried to a moisture content of less than 50%. The resulting dressing is able to absorb up to 18.0 g / g of water for 4 days. On wounds, the material exhibits bactericidal activity.

Example 7. The bactericidal activity of the hydrogels obtained in examples 5 and 6 was investigated by introducing into the LB broth or into a liquid hydrolysis-milk medium a different amount of hydrogels, 20, 200, 2000 μg (by dry weight) / ml of medium. Hydrogels were added before inoculation or in the middle of the logarithmic growth phase of the test cultures. Cultivation was carried out in flat-bottomed polystyrene 96-cell tablets at a temperature of + 37 ° C. The optical density of the test cultures was measured on a vertical spectrophotometer for microplates "Bio-Rad" at a wavelength of 490 nm. The test cultures were opportunistic (S. enteritidis, S. flexneri, K. pneumoniae, S. aureus, C. albicans) and probiotic microorganisms: (E. coli M-17, L. casei Shirota, L. delbrueckii, L acidophilus). Seeding density varied in the range of 1-10 ⁷ CFU / ml (in order).

The comparative bactericidal activity of hydrogels was evaluated by the size of the zone of growth inhibition of microorganisms 48 hours after the application of drops of test solutions in a volume of 20 μl on the lawn of test cultures on solid nutrient media.

It was established that chitosan hydrogel itself, due to the presence of chitosan in the cationic biopolymer, inhibited the growth of microorganisms. The most sensitive to chitosan were representatives of the human intestinal microbiota - L. acidophilus and E. coli M-17, as well as S. flexneri and opportunistic S. enteritidis; the most resistant are K. pneumoniae and C. albicans. The degree of growth inhibition depended on the biological characteristics of microorganisms.

Figure 1 shows data on the growth efficiency of Staphylococcus aureus 209 in LB broth with the introduction of various amounts of chitosan (CS) and silver and cerium nanoparticles. It was shown that the inclusion of cluster silver in the composition of the hydrogel in concentrations of 0.1-0.05 mmol led to a complete suppression of the viability of the test cultures in all dilutions used after 18 hours of incubation. The growth inhibition zone of Staphylococcus aureus for the gel containing silver clusters obtained in Example 5 was 6 ± 1 mm, and for the gel containing silver clusters and cerium, 12 ± 2 mm.

The obtained result indicates the synergism of the joint bactericidal action of chitosan with the addition of cluster silver and cerium.

Example 8. A solution of chitosan is prepared according to the method of example 1.

10 g of Calydone (polyvinylpyrrolidone (PVP) manufactured by BASF under the brand name K-90) are dissolved in 180 ml of distilled water, acidified with 0.1 N hydrochloric acid to pH 2.5 ± 0.5. 20 ml of glycerol is added to the solution with stirring. 0.5 g of sucralfate (aluminum-sulfate sucrose complex) is added to the PVP solution with stirring. The solution was neutralized to pH 6.0. During neutralization, a finely dispersed Sucralfate colloid stabilized by PVP is formed.

After mixing the solutions of chitosan and calidone, 100 mg of the recombinant superoxide dismutase (SOD), identical to the human body antioxidant system enzyme, dissolved in 40 ml of deionized water, is introduced into the solution with stirring. The resulting gel is applied to the film at the rate of 0.3 ml per 1 cm ² and dried to a moisture content of less than 50%.

A piece of 2 × 2 cm is cut from the obtained dressing, placed in a glass with 20 ml of water and left for a day. After a day, the activity of SOD in water is determined and the yield is determined based on the activity of the introduced enzyme. In the first embodiment, the enzyme output per day is 17%.

The use of the SOD enzyme in wound dressings is especially effective in the early stages after an injury or burn. The use of superoxide dismutase in the early stages after an injury stops the generation of reactive oxygen species, prevents the development of lipid peroxidation and thereby preserves cell viability in the deeper layers of the skin.

Example 9. A gel is prepared according to the methodology of Example 8. After mixing the solutions of chitosan and calidone with stirring, 50 mg of the crab collagenase enzyme dissolved in 50 ml of deionized water and sterilized by filtration through a 0.2 μm membrane are introduced into the solution. The resulting gel is applied to the film at a rate of 0.4 ml per 1 cm ² and dried to a moisture content of less than 50%.

A piece of 2 × 2 cm is cut from the obtained dressing, placed in a glass with 20 ml of water and left for a day. After a day, the collagenolytic activity of the enzyme in water is determined and the yield is determined based on the activity of the introduced enzyme. The output of the enzyme per day was 24%.

Proteolytic enzymes in the dressings allow you to clean the wound from necrosis.

Example 10. Prepare a gel, as in example 8, with recombinant superoxide dismutase (SOD). After receiving the gel is applied to a substrate and dried to a moisture content of less than 50%.

Prepare the following gel, as in example 8, but without SOD.

With stirring, 150 mg of lidocaine dissolved in 15 ml of deionized water and 0.5 ml of a 20% solution of catamine are successively introduced into the gel. After receiving the gel is applied to the substrate over a layer of dried gel with SOD and dried to a moisture content of less than 50%. The resulting two-layer dressing can be used as a first aid.

Example 11. 2 g of N, O-carboxymethylchitosan with a degree of substitution close to 1 and a molecular weight close to 100 kDa are dissolved in 100 ml of deionized water. The solution is filtered.

200 ml of "Povidone" is acidified with 0.1 N hydrochloric acid to a pH of 2.5 + 0.5. 20 ml of glycerol are added to the PVP solution with stirring. 0.5 g of sucralfate (aluminum-sulfate sucrose complex) is added to the PVP solution with stirring. The solution was neutralized to pH 6.0.

At room temperature, the prepared solutions are drained and vigorously stirred until homogeneous for 10 minutes. After receiving the gel is applied to a substrate and dried to a moisture content of less than 50%. The resulting dressing is able to slowly (up to 4 days) absorb 40 g / g of water without being exposed to a cold stream.

Example 12. Treatment with dressings containing the inventive hydrogels.

Patient P., 53 years old. Diagnosis: Postthrombotic disease of the right lower limb. Trophic ulcers of the anterior surface of the middle third of the right lower leg. The patient complained of severe pain in the area of trophic ulcers. 5 years ago he suffered phlebothrombosis of the right thigh and lower leg. Trophic ulcers appeared 3 years ago after a minor injury to the lower leg. Sop .: GB II Art.

At the time of admission to the clinic, on the front surface of the right lower leg there were 2 trophic ulcers, with a total area of about 60 cm ² . Their bottom is formed by sluggish, the color of boiled meat, granulations, covered with fibrinous-purulent plaque. A wide area of dermatitis was observed around ulcers.

The treatment was started using compression therapy (bandage to the knee from elastic bandages of short elongation ROSIDAL K), dressings with collagenase obtained in Example 8, and a corticosteroid ointment for the dermatitis zone. Dressings were performed with a frequency of 1 to 2 days. After 6 days of treatment, the patient was no longer bothered by pain, a significant cleansing of trophic ulcers, a decrease in the area of dermatitis were noted.

At this stage, dressings with cluster silver, obtained according to Example 5, began to be used for dressings. The average frequency of coating changes is once every 3-4 days. Rapid epithelialization of the ulcer surface was noted.

During treatment, it was found that wound dressings based on chitosan gel have good adhesion. This allows them to be securely fixed on the wound surface. After application for ulcers, the volume of wound exudate significantly decreased. After 6-12 hours, the hydrocolloid layer of the wound cover in the projection of the ulcer significantly increased in volume, turning into a jelly-like mass 3-5 mm thick. Her color ranged from light to dark brown. From 2 days, starting from the edges of the ulcer, drying of the hydrocolloid was observed. It turned into a brown mass, under which active edge epithelization was detected.

After 2 months of treatment, the patient was matched with compression hosiery (golfs of compression class III). By this time, only a small crust was formed at the site of the former ulcer, formed by the dried dressing hydrocolloid. She left on her own after 2 weeks. At the control examination after 6 months, recurrence of a trophic ulcer was not found.

As the experiments showed, the claimed medical material creates the conditions for accelerating the processes of regeneration and epithelisapia; absorbs exudate, maintaining integrity after absorption; supports the supply of oxygen to the wound area; is a barrier to the penetration of microbes; promotes scarless wound healing due to the presence of chitosan and its biodegradation products in the wound; well models the surface of the wound; provides a prolonged exit to the wound of the included medicinal substances; atraumatic and non-toxic. Its use allows you to relieve pain and reduce treatment time.

Claims (16)

1. A hydrophilic wound gel based on a polymer complex of chitosan containing a solvent and excipients distributed therein, which is a rare-cross-linked polymer of chitosan and a polyanionic hydrocolloid, a hydrocolloid, which is sucralfate or polyalginic acid having 2-3 crosslinkings of copolymers per chitosan molecule . 2. The hydrophilic gel according to claim 1, characterized in that the proportion of polyannionic hydrocolloid, hydrocolloid, which is sucralfate or polyalginic acid, in the copolymer is from 0.1 to 5% by weight of the copolymer. 3. The hydrophilic gel according to claim 1, characterized in that as an auxiliary substance it contains 0.01-15 wt.% Stabilizer. 4. The hydrophilic gel according to claim 3, characterized in that it contains 0.01-0.1 wt.% Silver microparticles as stabilizers. 5. The hydrophilic gel according to claim 3, characterized in that it contains high molecular weight polyalcohols as stabilizers. 6. The hydrophilic gel according to claim 5, characterized in that it contains polyvinyl alcohol as high molecular weight polyalcohols. 7. The hydrophilic gel according to claim 5, characterized in that it contains polyethylene glycol as high molecular weight polyalcohols. 8. The hydrophilic gel according to claim 5, characterized in that it contains polyvinylpyrrolidone as a stabilizer. 9. The hydrophilic gel according to claim 1, characterized in that it contains plasticizers and modifiers, such as glycerin and / or taurine, in concentrations from 0.1 to 30% by dry weight as auxiliary substances. 10. The hydrophilic gel according to claim 1, characterized in that as auxiliary substances it contains biologically active substances selected from the group consisting of antioxidant enzymes of the body, proteolytic enzymes, anesthetics, antibiotics in concentrations from 0.01 to 30% by dry weight. , antiseptics, nanoparticles or colloidal particles of silver and / or cerium. 11. The method of producing a hydrophilic gel for wound dressing according to claim 1, comprising mixing chitosan with a polyanionic hydrocolloid, a hydrocolloid, which is sucralfate or polyalginic acid, into which a high molecular weight polyalcohol and auxiliary substances are preliminarily introduced, characterized in that before mixing with chitosan hydrocolloid when alkalized to pH 5.5-6.5 is subjected to physico-chemical activation by freezing-thawing, autoclaving, microwave processing or ultrasound. 12. The method of producing a hydrophilic gel according to claim 11, characterized in that to the polyanionic hydrocolloid, the hydrocolloid, which is sucralfate or polyalginic acid, preliminary added 0.01-1 wt.% Polyelectrolyte, for example carboxymethyl cellulose, or alginic acid, and after mixing with chitosan the mixture is incubated for 30-60 minutes 13. The method of producing a hydrophilic gel for wound dressing according to claim 1, comprising mixing chitosan with a polyanionic hydrocolloid, a hydrocolloid, which is sucralfate or polyalginic acid, into which silver nitrate and auxiliary substances are preliminarily introduced, after which the resulting product is exposed to light before the formation of silver monoclusters. 14. A hydrophilic gel-based wound dressing according to claim 1, comprising a chitosan complex, which is a rare crosslinked polymer of chitosan and a polyanionic hydrocolloid, a hydrocolloid, which is sucralfate or polyalginic acid, having 2-3 crosslinking copolymers per chitosan molecule according to claim 1, deposited on a substrate, which is a water-insoluble porous film made of a biocompatible material with pores with a diameter of 0.01-5.0 microns. 15. The wound cover of claim 14, wherein the biocompatible material is a polymer from the group consisting of polytetrafluoroethylene, polyethylene terephthalate, polypropylene, polysulfonamide, carboxymethyl cellulose, polyimide. 16. A multilayer wound dressing, including a hydrophobic atraumatic permeable layer, a treatment layer and a layer based on a hydrophilic gel containing a complex of chitosan, which is a rare crosslinked polymer of chitosan and polyanionic hydrocolloid, which is sucralfate or polyalginic acid having 2-3 crosslinked copolymers per chitosan molecule according to claim 1, deposited on a water-insoluble porous film made of a biocompatible material.

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