RU2443435C2 - Tissues adhesives - Google Patents

Abstract

FIELD: medicine.

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

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

26 cl, 2 dwg, 8 ex

Description

The invention relates to a flexible sheet suitable for use as tissue adhesive and sealing material and intended for local therapeutic use on internal and external surfaces of the body. The invention also relates to a method for manufacturing such a sheet and to methods of using such a sheet. In particular, the invention relates to a self-adhesive, biocompatible and hydratable polymer sheet that can be used for therapeutic purposes, for example for wound healing, joining, sealing and hardening of weakened tissue, and for the delivery of therapeutic agents, to a method for manufacturing such a sheet and to methods for it application. In addition, the invention relates to implantable medical devices coated with a material similar to the material of said sheet.

The use of materials that adhere to biological tissues for a number of surgical and other therapeutic purposes is of considerable interest, since they, for example, represent an alternative to the use of mechanical bonds, such as stitches, braces, etc. Compositions of materials already proposed for this purpose include viscous solutions or gels, which are either formulated or prepared immediately prior to application by mixing the ingredients. Such compositions are then applied to the surface of the tissue using a special application device, such as a syringe.

Compositions of the above type have several disadvantages. If the composition has a low viscosity, then it can spread in different directions from the place of application, and, therefore, there are difficulties with its application to a precisely specified area of the fabric. On the other hand, if the composition has a high viscosity, then difficulties arise when applying it. In any case, since the composition is made in a hydrated form, its duration may be limited and premature curing may occur. Thus, you have to either fully use the entire prepared composition, or discard its unused portion. In addition, it is obvious that the preparation of compositions immediately before use by mixing the ingredients is time-consuming and time-consuming, and this may require the use of additional equipment. In addition to these disadvantages, the adhesion strength between the surfaces of the fabric, which can be provided by such a composition, may be less than expected.

Compositions made from materials for fabric adhesives are also applied to suitable substrates intended to be applied to the surface of the fabric. The widespread use of therapeutic materials in the form of a sheet, adhesive pad or film for local injection into internal or external organs of the body is widely known in medicine. However, a possible disadvantage of the previously proposed products, in addition to insufficient cohesive strength, is the insufficient degree of adhesion to the underlying tissue, especially with long-term use. Although at first the degree of adhesion may be satisfactory, subsequently the sheet may lag behind the fabric, often after several minutes or seconds, for example, as a result of hydration of the sheet after application. In addition, the flexibility of the product may not be sufficient to ensure that the product fits snugly on the surface on which it is applied, which can also adversely affect adhesion.

Due to the inadequate adhesion strength of these products, it may be necessary to provide additional reinforcement, for example, by mechanical connection using seams, staples and similar devices. Alternatively, the formation of chemical bonds between the adhesive composition and the underlying fabric and, therefore, the connection of the tissue surfaces with each other can be initiated by energy exposure (for example, light or heat). Obviously, this approach creates additional problems. In many cases, mechanical bonding, such as the use of seams or staples, is exactly what needs to be replaced or eliminated. In many cases, the use of such a fastener is either completely ineffective (for example, in the lungs), or undesirable, since the introduction of various types of fasteners causes further weakening of the tissue. The use of external energy requires the supply of a source of such energy and its impact. Such sources of energy can be expensive, causing difficulties in maintenance, in particular, in a limited space of the operating room or similar room. In addition, the use of external energy to create a connection can take a lot of time and (in some cases) require considerable attention from the surgeon, who must determine the moment when the supplied energy is sufficient to create a strong connection, but there will be no damage to the underlying tissue.

The disadvantage of sheet products used for the above purposes is the lack of necessary flexibility, which in many cases may be necessary or desirable. In particular, flexibility is needed in products used in endoscopic surgery (surgery in the minimal intervention area), which is now becoming increasingly important, where it is often required that the product be bent or rolled to a compact size before being inserted into the cavity. Attempts to make such products more flexible, for example, by introducing plasticizers can lead to a decrease in the adhesive ability of the product.

In accordance with the present invention, improvements are proposed in relation to sheets of fabric adhesives or similar products, the general characteristics of which are described above, as well as similar products made of materials proposed for fabric adhesives, which allow to overcome or essentially correct the above disadvantages and / or other deficiencies in materials used in accordance with the prior art.

SUMMARY OF THE INVENTION

According to a first aspect of the present invention, there is provided a multilayer sheet of fabric adhesive comprising a structural layer or laminate, said structural layer or laminate comprising one or more synthetic polymers having film-forming properties, and a layer of contact material is attached to said structural layer or laminate with a tissue in which said material contains groups capable of reacting with the tissue.

The main advantages of the sheet proposed according to the present invention are that it effectively attaches to the tissues, which allows the use of the specified sheet in a number of medical tasks. It was found that the proposed sheet has improved flexibility and at the same time maintains high adhesion strength. In preferred embodiments, the sheet exhibits initially high adhesion strength with respect to the fabric on which it is applied (and thus, the sheet can be considered self-adhesive), and in addition, the adhesion strength of the sheet to the fabric remains strong for a long period of time. Without resorting to any theory, it can be assumed that the initial strength of the sheet to adhere to the fabric is explained by the formation of electronic bonds between them, which are then supplemented or replaced by covalent chemical bonds between the groups of the composition capable of reacting with the fabric and the fabric, in particular, between the amino groups and / or thiol groups located on the surface of the tissue and functional groups of the sheet capable of reacting with the tissue.

It is believed that the initial adhesion strength of the sheet to the surface of the fabric is due to Van der Waals forces and / or hydrogen bonds formed between the sheet and the surface of the fabric. Upon contact with the tissue, the surface of the sheet undergoes hydration, leading to a reaction between functional groups capable of reacting with the tissue and the surface of the underlying tissue. Similar reactions between functional groups capable of reacting with tissue and the underlying tissue lead to very strong adhesion of the sheet and the surface of the tissue. The sheet can also absorb physiological fluids (when applied to tissue surfaces that release fluid) and any added solutions used to hydrate the sheet after it is applied to the surface (such fluids can be solutions commonly used in surgery for washing), which improving conformity and adhesion between the sheet and the surface of the fabric, as a result of which the adhesive sealant acquires hemostatic and pneumostatic properties.

The use of such sheets reduces or eliminates the need for additional measures, including mechanical bonding with the fabric (for example, seams or braces), or the need to use external energy in the form of heat or light, causing the sheet to adhere to the underlying fabric. Another advantage of the sheet proposed according to the present invention is that it is applied to the fabric in the form of a preformed product, and is not prepared by mixing materials immediately before use.

In addition, since the sheet is essentially inactive before hydration and subsequent contact with the surface of the tissue, a premature reaction inside the sheet is unlikely, which increases its shelf life, which can be, for example, more than six months under appropriate conditions at room temperature.

The term "sheet" means a product whose thickness is significantly less than its other dimensions. Alternatively, such an article may be described by the term “film” or “patch”.

In preferred embodiments of the present invention, the structural layer or laminate is a laminate comprising two or more discrete layers connected to each other. In particularly preferred embodiments, the laminate comprises alternating layers of a polymer having film-forming properties and a material containing reactive functional groups. It has been found that in general, sheets comprising a structural laminate have improved adhesion to fabrics and / or improved elasticity and / or greater stability in maintaining structural integrity compared to sheets comprising one structural layer.

In this case, the sheet proposed according to the present invention, most preferably includes an even number of layers and, in particular, alternating layers of a film-forming polymer and a material containing reactive groups. Thus, it can be considered that the sheet contains a structural laminate including n layers of a film-forming polymer and n-1 layers of a reactive material located between them, as well as a layer intended for contact with the tissue and containing material capable of reacting with the tissue. The value of n can be 1 - in this case, the sheet includes only one structural layer and a layer in contact with the tissue. Alternatively, n may be 2 or 3 — in this case, the sheet total includes 4 or 6 layers. Currently, sheets with n = 2 are most preferred.

The material containing reactive functional groups may be the same or similar to the material in contact with the tissue and capable of reacting with the tissue.

Another aspect of the present invention relates to a device suitable for implantation in a human or animal body, wherein at least a portion of the outer surface of said device is coated, comprising one or more polymers having film-forming properties, and at least a portion of said coating is bonded with a layer of material comprising functional groups capable of reacting with tissue.

In accordance with this aspect of the present invention, a film-forming polymer coating provides means for attaching a material comprising functional groups capable of reacting with tissue to the device, and wherein said material provides means for attaching the device to a desired site within the body. Thus, this aspect of the present invention can be especially important with regard to implantable devices that are otherwise difficult to fix in the desired position within the body, for example, because these devices are made of a material that is chemically inert and incapable of reaction with surrounding tissue or with chemical binding groups.

In the following detailed description of the invention, examples of embodiments of the invention that are in the form of sheets are mainly considered. However, it should be understood that, where possible, similar comments can be applied to embodiments of the invention, including coatings applied to implantable devices.

Another aspect of the present invention relates to a method for attaching one surface of a fabric to another fabric, or to a method for sealing a surface of a fabric; however, this method includes applying to the surface of the tissue sheet proposed in accordance with the first aspect of the present invention.

The sheet of the present invention can also be used to deliver one or more therapeutically active substances to the site on which the sheet is applied. In such cases, said substance (s) can be incorporated into the sheet, for example, by mixing them with other ingredients that are used to make the sheet. Alternatively, said substance (s) may be covalently linked to the components of the sheet. However, in other embodiments, the sheet does not contain therapeutically active ingredients. Similarly, one or more therapeutically active substances can be incorporated into a material applied to the outer surface of an implantable device according to a second aspect of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Abbreviations

AAc - Acrylic Acid

AIBN - azo-iso-butyronitrile

DCC - Dicyclohexylcarbodiimide

DCM - Dichloromethane

DCU - Dicyclohexylurea

DMF - dimethylformamide (DMF)

DMSO - Dimethyl Sulfoxide (DMSO)

DPBS - saline with phosphate buffer according to Dulbecco

ENT - ear, throat, nose

LDC - hydroxypropyl cellulose

IPA- isopropanol

M _n is the number average molecular weight

M _w - weight average molecular weight

MeOH - methanol

NHS - N-hydroxysuccinimide

NVP - N-vinylpyrrolidone

PEG - Polyethylene Glycol

PLG - Poly (DL-lactide-co-glycolide)

poly (VP-AAc) - copolymer of vinylpyrrolidone and acrylic acid

Poly (VP-AAc (NHS)) - a copolymer of vinylpyrrolidone and NHS-ester of acrylic acid

Poly (VP-AAc-AAc (NHS)) - a ternary copolymer of vinylpyrrolidone, acrylic acid and NHS-ester of acrylic acid

The nature of the structural layer or laminate

The sheet according to the first aspect of the present invention includes a structural layer or laminate, which includes at least one film-forming polymer. The structural layer or laminate may consist entirely or essentially consist of a film-forming polymer. In other embodiments, the structural layer or laminate for the most part consists of a film-forming polymer. For example, the structural layer or laminate may include more than 80%, more than 90%, or more than 95% wt. film-forming polymer.

For the manufacture of the first layer, various film-forming polymers suitable for this purpose can be used, provided that they have suitable film-forming properties and are suitable for medical use, in particular are non-toxic, biocompatible and usually biodegradable.

Most often, the first layer includes only one film-forming polymer. Alternatively, the first layer may be formed from more than one film-forming polymer.

The film-forming polymer may be synthetic, or it may be a natural material, or a polymer derived from a natural material.

The most preferred group of synthetic polymers that may be suitable for the implementation of the present invention are biodegradable polyesters. Specific examples of such polymers include polylactic acid and polyglycolic acid, and copolymers and mixtures of these acids. Other examples include polycaprolactones and polyhydroxyalkanoates, for example polyhydroxybutyrate, polyhydroxyvalerate and polyhydroxyhexanoate.

Currently, the most preferred ester-based polymers used according to the present invention are poly (lactide-co-glycolide) copolymers (also called lactic and glycolic acid copolymers), which are usually biocompatible and biodegradable, and also soluble in many organic solvents.

Currently, among particularly preferred embodiments of a sheet comprising a structural laminate, particularly preferred are embodiments comprising alternating layers of biodegradable material based on a polyester and a material containing reactive functional groups. Thus, a special aspect of the present invention relates to a multilayer sheet of fabric adhesive comprising a structural laminate, said laminate comprising n layers of biodegradable polyester and n-1 layers of material containing reactive functional groups located between said layers of biodegradable polyester, and a layer of material intended for contact with the tissue and capable of reacting with the tissue; wherein the values of n are 1, 2 or 3, most preferably 2.

In such examples of implementation, the layer farthest from the layer in contact with the fabric is a complex polyester, which essentially does not adhere to the fabric. Thus, these sheets in general will only adhere to the target tissue (to which a layer is applied that is in contact with the tissue and contains functional groups capable of reacting with the tissue), but will not adhere to surrounding tissues (e.g., cell or intraperitoneal walls).

Other examples of possible synthetic polymers used include aminated polymers, for example aminated polyethylene glycols (including polyethylene glycols commercially available under the JEFFAMINE trademark) and polyallylamines.

Other film-forming polymers possibly used in accordance with the present invention include polysaccharides and, in particular, basic polysaccharides.

The nature of the layer in contact with the tissue

The sheet according to the first aspect of the present invention includes a tissue contact layer that includes material containing functional groups capable of reacting with the tissue. Such material preferably includes one or more polymers containing functional groups capable of reacting with the tissue.

The term “functional groups capable of reacting with tissue” means functional groups capable of reacting with other functional groups located on the surface of the tissue to form covalent bonds with the tissue. Typically, tissues are partially composed of proteins, which usually contain fragments of thiols and fragments of primary amines. Many functional groups, for example imidoester, n-nitrophenyl carbonate, NHS ester, epoxides, isocyanates, acrylates, vinyl sulfones, orthopyridyl disulfide, maleimides, aldehyde groups, iodoacetamide and other groups, can react with thiols and primary amides and, thus, form “functional groups capable of reacting with tissue”. As used herein, the term NHS or NHS ester includes not only N-hydroxysuccinimide itself, but also derivatives thereof containing a substituted succinimidyl ring. An example of such a derivative is N-hydroxysulfosuccinimidyl and its salts, in particular the sodium salt, which can increase the solubility of a material capable of reacting with tissue.

The functional groups capable of reacting with the tissue, possibly used in accordance with the present invention, are any functional groups capable of reacting (under the most commonly used conditions, which are used when the composition is applied to the tissue, i.e. in an aqueous environment and without significant amounts of heat or other energy supplied from outside) with functional groups located on the surface of the fabric. Functional groups located on the surface of the tissue include thiol groups and amino groups, and thus functional groups capable of reacting with the tissue include groups reactive with thiol and / or amino groups. Their examples include:

imido ether;

n-nitrophenyl carbonate;

NHS ester;

epoxide;

isocyanate;

acrylate;

vinyl sulfone;

orthopyridyl disulfide;

maleimide;

aldehyde group and

iodoacetamide.

The most preferred functional group capable of reacting with tissue is the NHS ester group.

In addition to functional groups capable of reacting with a fabric, the polymer (s) constituting the material of the second layer may contain functional groups that are not capable of reacting on their own with the fabric on which the sheet is applied, but which provide good adhesion strength of the sheet to this fabric. In accordance with the present description, such functional groups are called "non-reactive functional groups." Examples of non-reactive functional groups include a hydroxyl group, heterocyclic amines and amides (for example, in vinyl pyrrolidone residues) and, in particular, carboxy groups (for example, contained in acrylic acid residues).

It is especially preferred if the functional groups capable of reacting with the tissue are activated derivatives of non-reactive functional groups. In some embodiments, all non-reactive functional groups can be activated, as a result of which they form functional groups capable of reacting with the tissue. In other embodiments, only some non-reactive functional groups can be activated and form functional groups capable of reacting with tissue. In the latter case, the initial strength of the contact adhesion of the sheet to the fabric on which it is applied, and the strength of longer-term adhesion, formed due to the formation of covalent bonds as a result of the reaction of functional groups capable of reacting with the tissue, with the functional groups of the tissue, can be different and vary due to the proportion of non-reactive groups that are in activated form.

The NHS ester group is a particularly preferred functional group capable of reacting with tissue, and therefore, the preferred polymers capable of reacting with tissue are polymers enriched in NHS ester groups. Particularly preferred polymers capable of reacting with tissue are the poly (VP-AAAc (NHS) and poly (VP-AAA-AAc (NHS)) copolymers.

The adequacy of the initial adhesion strength of the sheet to the tissue in the case of a bi-adhesive polymer (s) can be quantified in vitro, for example, by using the adhesion test. This test is carried out by allowing the sheet to adhere to a suitable substrate (fixed in a fixed position), while the load of the tensile testing apparatus is physically attached to another section of the sheet so that the sheet is not under load before the test. The load sensor can move along an axis substantially perpendicular to the longitudinal axis along which the substrate is located. The test involves the movement of the load sensor in the direction opposite to the substrate, with a constant, predetermined speed until the sheet comes off the substrate. The output value of this test is a quantitative measure of the energy required for the test sheet to adhere, i.e. cumulative energy needed to break the interaction between the sheet and the substrate to which it is adhered. Suitable cumulative sticking energy of the sheet of the present invention should be at least 0.5 mJ.

In some embodiments of the present invention, a preferred tissue-reactive polymer is a poly (VP-AAA-AAA (NHS) triple copolymer. The carboxyl groups of the poly (VP-AAc) fragment can be converted to NHS ester groups by reaction with NHS in the presence of dicyclohexylcarbodiimide (see Example 9). If the acid content in poly (VP-AAc) is determined (in moles), then the proportion of acid groups converted to groups capable of reacting with the tissue can be controlled by adding the desired molar percentage of NHS.

Another possible polymer that is capable of reacting with tissue and containing hydroxyl groups is an activated form of hydroxypropyl cellulose succinate (LDC), for example, succinate-NHS hydroxypropyl cellulose. In this case, some hydroxyl groups of the polymer are activated by NHS via bridges formed by succinic acid (see Example 11).

The properties of the fabric adhesive sheet can be optimized by incorporating other polymers and additives.

Improving additives

Despite the fact that the sheet proposed according to the first aspect of the present invention has adequate flexibility, it is sometimes desirable to increase the flexibility, elasticity and / or strength of the sheet in the wet state by adding to the structural layer or laminate and / or layer in contact with the fabric, one or several plasticizers and elastomers. In particular, to increase flexibility, low molecular weight particles, for example glycerol and low molecular weight polyethylene glycol, can be incorporated into the composition. Examples of suitable elastomers that can be incorporated into the product include poly (caprolactones), poly (urethanes) and poly (silicones). Such materials can increase the flexibility and / or elasticity of the sheet when added in concentrations of up to 30% wt. by weight of the ingredients that make up the leaf.

However, the introduction of high concentrations of such materials may have a negative effect on the adhesive ability of the sheet. To overcome this drawback, additives can be functionalized and include groups capable of reacting with the tissue, which can contribute to the bonding strength.

Buffer Agents

Reactions between leaf functional groups capable of reacting with tissue and functional groups located on the surface of the tissue can proceed differently depending on pH. Thus, it may be preferable to introduce buffering agents before application or, more preferably, to include a buffering agent in the composition used to prepare the sheet, in particular in the sheet layer in contact with the tissue. The average adhesion performance of some of the sheets of the present invention superimposed on an explanted pig liver can be improved by applying a phosphate / carbonate buffer having a pH of 10.5 to the surface of the tissue.

Joining sheet components during manufacture

The materials of the structural layer or laminate and / or tissue contact layer may be bonded during manufacture. Such a compound can increase the physical strength of the sheet and can optimize the properties of the sheet, in particular the time required for biodegradation of the sheet after application.

The connection can be made in various ways, including casting the constituent layers from conventional solvents. Another method involves the manufacture of a composition, in this method a structural layer or laminate and / or tissue contact layer are prepared comprising at least two functional groups capable of reacting with functional groups present in the material to be joined. Thus, said component acts as a crosslinking agent. Preferably, the crosslinking agent contains at least two functional groups in the same form. Thus, the crosslinking agent is most preferably a homobifunctional or homopolifunctional crosslinking agent.

Physical form of the sheet

Usually, the total sheet thickness can be from 0.01 to 1 mm, usually from 0.01 to 0.5 mm, most usually from 0.015 to 0.2 mm or from 0.015 to 0.1 mm, for example from 0.015 to 0.05 mm.

In currently preferred embodiments, the thickness of the layer in contact with the fabric is greater than the thickness of the structural layer or laminate. For example, the thickness of the layer in contact with the fabric may be more than 50% of the total thickness of the sheet or more than 60%.

The sizes with which the sheet can be made, or the sizes to which the sheet can be cut, range from a few square millimeters to several tens of square centimeters.

Sheet making

The most convenient method of manufacturing the sheet proposed according to the present invention includes the stepwise formation of individual layers that make up the sheet.

First, a structural layer or (preferably) a structural laminate layer farthest from the fabric contacting layer, for example, by casting a solution of the material that forms the layer in a suitable solvent, or on a suitable plate or form, or on a suitable release paper, may be prepared. for example, silicone-coated release paper. The spilled solution is then dried or allowed to dry, possibly under conditions including elevated temperature and / or reduced pressure.

Subsequent layers of the structural laminate can then be poured onto a preformed first layer, followed by drying of each new layer to remove solvent and, if necessary, curing to obtain the desired number of cross-links. Most preferably, curing is carried out under the influence of high temperatures (usually over a period of up to one hour or more, at temperatures up to 60 ° C. or higher).

Finally, a layer intended for contact with the fabric may be spilled onto the structural layer or laminate. In this case, after casting, it is preferable to dry to remove the solvent and cure to obtain the desired amount of cross-linking. Preferably, the cure is carried out at least partially under the influence of high temperatures (usually over a period of ten minutes to one hour or more, at temperatures up to 60 ° C).

The casting of each layer of the sheet can be performed as a separate operation. Alternatively, in particular in the case of relatively thick layers (i.e., relatively thick compared to other sheet layers), the layer can be made by sequential casting of thinner sublayers.

The water content in the sheet proposed according to the present invention, after its manufacture, but before use is usually less than 10% wt. and more often is less than 5% wt.

During manufacture, an image or an alphanumeric mark may be applied to the surface of the individual layers of the sheet. This mark can be used to distinguish the surface intended for gluing to the fabric, from non-adhesive surfaces; alternatively, it may be used to indicate the brand of the product or the manufacturer. Chromophores that can be used as markers include methylene blue.

Typically, the implantable devices of the present invention can be manufactured by any conventional method of coating the device. For example, the coating layers can be applied to the device in a manner analogous to the method of applying materials by casting onto a structural layer or laminate and a layer in contact with the fabric described above. Alternatively, the coating may be applied by immersion of the device in liquid compositions or by spraying liquid compositions onto the device.

Therapeutic use of the leaf

The sheet according to the present invention is suitable for application on both external and internal surfaces of the body, i.e. it can be applied locally to the external surface of the body (for example, the skin) or to the internal surfaces, for example the surfaces of internal organs exposed during surgical procedures, including traditional surgery and minimal surgery.

The sheet proposed according to the present invention is particularly suitable for use in the following surgical operations:

Thoracic (thoracic) region / cardiovascular surgery

General surgery

Ear, throat and nose

Urological operations

Oral / maxillofacial operations

Orthopedic Operations

Neurological operations

Gastroenterological operations

Ophthalmic surgery

Gynecological operations / obstetrics

Possible use cases are described in more detail below.

Wound healing

The ability of the leaf to dissolve means that the leaf can be used to support tissues and heal wounds of internal organs and superficial wounds. As soon as the leaf begins to decompose, there is an influx of fibroblasts to it, which begin to precipitate the components of the intercellular matrix. Thus, the sheet can be used as a dressing for both the external and internal surfaces of the body. In addition, to accelerate the healing process, factors such as growth factor and cAMP (cyclic adenosine monophosphate), which are known to promote the proliferation of skin cells, can be added to the composition. The sheet can be made in such a way that it allows you to control the penetration of moisture and pathogens, and thus, such a sheet can be, in particular, used in the treatment of burns.

Skin fusion

The sheet can be applied locally to fuse the edges of the wound (as an alternative to a surgical suture). Advantages of this use may include a reduction in scar formation, and thus, the proposed composition and sheet can be used in cosmetic “small” (outpatient) operations (for example, performed in emergency rooms). The self-adhesive properties of the sheet can facilitate its very quick application.

Hernia repair

The proposed sheet can be used to provide hardening during hernia healing operations. Self-adhesive attachment allows you to overcome the potential disadvantages of surgical mesh products, traditionally used to strengthen the peritoneal wall, the use of which is associated with suturing or staples on an already weakened area. A sheet designed for such an application may not dissolve for a short or long period of time, depending on the time required to heal any existing tissue damage. The sheet can also be overlaid so that the fabric is able to withstand the overlay of brackets.

The invention can also be applied to create an adhesive coating on mesh products used for the healing of hernias.

Anastomosis

The proposed sheet is a means for quickly sealing and preventing holes in connected tubular systems, for example blood vessels, in vascular implants and bladder implants, as well as in the gastrointestinal tract. The ability of a leaf to promote tissue healing can be a particularly valuable device used in the healing of nerve tissue.

Sealing large areas of fabric

The good sealing and technological properties of the sheet in combination with self-adhesive properties and the ability to cover a large surface area mean that the proposed sheet can be used with particular success to seal the surfaces of resected tissue, in particular, areas prone to diffuse bleeding (for example, liver). The proposed sheet is also an ideal support matrix for healing tissue in such areas. It can also help limit the flow of cerebrospinal fluid after a neurological intervention.

Sealing air leaks

In addition to the adhesive properties described above, the high tensile strength and good intrinsic elasticity of the sheet (after hydration and reaction of functional groups capable of reacting with the fabric) make it particularly suitable for sealing openings through which air in the lungs flows, in particular after resection of the lungs. In this case, after sealing, the sheet is an ideal support matrix for healing tissue in such areas.

Hemostasis

The proposed sheet may be superimposed on a bleeding site in which it acts as a physical barrier. Leaf material capable of reacting with tissue can immobilize proteins and thus contribute to hemostasis.

The introduction of therapeutic agents

Medicines, disinfectants and other therapeutic agents (including biologically active substances, such as growth factors, and even cells and cellular components) may be added to the solution (s) used to prepare the components of the sheet, or they may be covalently linked to these components in the manufacture of the sheet before its use. As soon as the sheet is in place, after application to the desired area, the medication is slowly released either by diffusion or caused by the design of the sheet, for example, controlled by the density of cross-linking inside the sheet, on which the rate of its resorption over time and, therefore, the release of the drug . The release rate can be controlled by selecting the appropriate sheet design. Thus, the sheet may be a means for delivering a known amount of the drug either to the body as a whole, or to a precisely defined area. The medication can be directly associated with the component of the solution used to make the sheet, or it can simply be dispersed in the solution.

Postoperative adhesion prevention

The formation of postoperative adhesions, that is, undesirable connective tissue between adjacent tissues, is a serious problem that accounts for most of the postoperative complications. This problem is especially common during bowel operations, after which adhesions can cause, for example, bowel twisting, which in the future may lead to the need for repeated surgery. The use of the sheet material of the present invention during surgery can effectively prevent the formation of postoperative adhesions between the operated tissue and adjacent tissues.

Minimal Intervention Procedures

The use of minimal intervention techniques to take tissue samples for biopsy, insert devices, deliver therapeutic agents and perform surgical procedures is a rapidly developing branch of surgery, alternative to traditional "open" surgical interventions. Procedures using minimal intervention are usually less painful, lead to the formation of smaller scars, contribute to faster recovery and cause fewer postoperative complications in patients, and also reduce the cost of medical care. The procedures are carried out using specially designed instruments that are inserted through small arthroscopic incisions. The sheet can be inserted into the body using existing and specially designed surgical instruments for minimal intervention and the trocar system, and the sheet itself can be given the appropriate shape, or the dimensions and configuration of the sheet can be prepared later, including stops for stapling instruments. The flexibility of the sheet allows you to give it a shape that reduces the overall size, for example, by folding or folding, which contributes to the use of the sheet during operations minimal intervention and / or other procedures with limited access to the treated area. The high initial strength of gluing the sheet to the fabric on which it is applied can also be considered an advantage when carrying out such procedures.

Brief Description of the Drawings

Figure 1 schematically and not to scale shows an example implementation of a sheet of fabric glue, proposed according to the present invention.

Figure 2 shows the synthesis scheme of the copolymer (N-vinylpyrrolidone ₅₀ / acrylic acid ₂₅ / ester of N-hydroxysuccinimide and acrylic acid ₂₅ ).

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The following more detailed description of the present invention with reference to Examples is given for illustrative purposes. Examples 1 and 2 describe the manufacture of fabric adhesive sheets of the invention. Examples 3-5 show the operational and technical characteristics of such sheets. Examples 6 and 7 describe the synthesis of a material containing groups capable of reacting with a fabric, which was used to make materials of Examples 1 and 2. Example 8 describes the synthesis of alternative types of material capable of reacting with a fabric.

Example 1

Preparation of a multilayer sheet

A multilayer sheet of fabric adhesive according to the present invention is shown schematically in FIG. The sheet includes a structural laminate and a layer intended for contact with the fabric.

The structural laminate has the following structure:

a) a first layer 1 consisting of PLGA;

b) a second layer 2 consisting of poly (VP-AAc-AAc (NHS)); and

c) a third layer 3 consisting of PLGA.

Tissue contact layer 4 is connected to third layer 3 and includes poly (VP-AAA-AAA (NHS)).

The thickness of the first and third layers 1, 3 is approximately 4 μm each, the thickness of the second layer 2 is approximately 3 μm. The thickness of the layer 4 intended for contact with the tissue is approximately 22 microns; this layer consists of three sublayers 4a-c having approximately equal thickness.

The sheet is prepared as follows:

1.1. Solution preparation

Three solutions are prepared as follows:

solution A includes 10 g of PLG dissolved in 100 ml of dichloromethane.

Solution B comprises 7.5 g of poly (VP-AAA-AAA (NHS)) dissolved in 100 ml of a dichloromethane / MeOH 15/4 mixture.

Solution C includes 2.5 g of methylene blue dissolved in 50 ml of water.

1.2. Casting layer 1

Solution A is poured onto silicone-coated release paper using a device called “K bar”. The film is dried for 30 minutes at 20 ° C / atmospheric pressure. The film is not removed from release paper.

1.3. Casting layer 2

Solution B is poured onto Layer 1 using the “K bar" device. The film is dried for 30 minutes at 20 ° C / atmospheric pressure. The film is not removed from release paper.

1.4. Logo laying on

On the surface of Layer 2, trademark / visual ligotype is applied with solution C.

1.5. Casting layer 3

Solution A is poured into Layer 2 using the “K bar" device. The film is dried for 30 minutes at 20 ° C / atmospheric pressure. The film is not removed from release paper.

1.6. Casting layer 4 ac

Solution B is poured into Layer 3 using the “K bar" device. The film is dried for 30 minutes at 20 ° C / atmospheric pressure. The film is not removed from release paper.

Solution B is poured onto Layer 4a using a “K bar” device. The film is dried for 30 minutes at 20 ° C / atmospheric pressure. The film is not removed from release paper.

Solution B is poured into Layer 4b using the “K bar" device. The film is dried for 16 hours at 20 ° C / reduced pressure. The film is not removed from release paper.

1.7. Cutting

The product is cut to the desired size using specially designed cutters and removed from release paper.

1.8. Final drying

The product is dried for 24 hours at 20 ° C / reduced pressure.

Example 2

Alternative layered sheet preparation

The bilayer sheet of fabric adhesive according to the present invention includes a structural layer and a layer intended for contact with the fabric.

The structural layer is made in the form of a single first layer 1 made of PLGA.

Tissue contact layer 2 is connected to the first layer 1 and includes poly (VP-AAc-AAc (NHS)).

The thickness of the first layer 1 is approximately 15 μm. The thickness of the layer 2 intended for contact with the tissue is approximately 22 microns.

The sheet is prepared as follows:

2.1. Solution preparation

Three solutions are prepared as follows:

solution A includes 10 g of PLG dissolved in 100 ml of dichloromethane.

Solution B comprises 10 g of poly (VP-AAA-AAA (NHS)) dissolved in 100 ml of a dichloromethane / MeOH 15/4 mixture.

Solution C includes 2.5 g of methylene blue dissolved in 50 ml of water.

2.2. Casting layer 1

Solution A is poured onto silicone-coated release paper using a device called “K bar”. The film is dried for 30 minutes at 20 ° C / atmospheric pressure. The film is not removed from release paper.

2.3. Casting layer 2

Solution B is poured onto Layer 1 using the “K bar" device. The film is dried for 30 minutes at 20 ° C / atmospheric pressure. The film is not removed from release paper.

2.4. Logo laying on

On the surface of Layer 2, trademark / visual ligotype is applied with solution C.

2.5 Slicing

The product is cut to the desired size using specially designed cutters and removed from release paper.

2.6. Final drying

The product is dried for 24 hours at 20 ° C / reduced pressure.

Example 3

In Vitro Bonding Strength

In vitro, the bonding strength of the sheet of the present invention to the liver was quantified using a Zwick universal testing machine. The average adhesion work after 5 minutes of soaking in physiological saline with phosphate buffer according to Dulbecco (DPBS) is usually from 7 to 14 mJ.

Example 4

physical characteristics

The product is a transparent / matte film through which the logo is visible. The tensile strength determined using the universal Zwick installation for testing is usually from 2 to 9 MPa.

Example 5

In Vivo Bonding Strength

Sheets of the species shown in Example 1 were used to stop bleeding, the flow of fluid and air from wounds obtained by standard biopsy of lung and liver tissue. After application, the sheet adheres firmly to the surface of the tissue, which leads to immediate stabilization of the damaged area and satisfactory hemostasis and / or pneumostasis.

Healing was evaluated macroscopically and using histological examination of the tissue. 14 days after application, a good degree of healing and sealing of the areas of initial damage was found, as well as the formation of normal tissue around the remains of the sheet. These residues were encapsulated with a thin fibrous coating. The remaining material was subjected to continuous resorption by macrophages involving cellular infiltrate, and the process usually completed within 50 days.

Example 6

Synthesis of a Triple Copolymer (VP-AAc-AAc (NHS))

The reaction is shown schematically in FIG. 2.

2000 ml of oxygen-free DMSO was heated to 80 ° C. Then, 121.3 g (1.09 mol) of N-vinylpyrrolidone and 78.7 g (1.09 mol) of acrylic acid were added to DMSO, followed by 0.04 g (2.44 × 10 ^-4 mol) of azo-iso butyronitrile. The reaction mixture was kept at 80 ° C for 17-19 hours and then allowed to cool to room temperature. 125.6 g (1.09 mol) of NHS were dissolved in a solution of the obtained polymer, and then 112.6 g (0.545 mol) of dicyclohexylcarbodiimide dissolved in 225 ml of DMF was added. The reaction mixture was stirred at room temperature for 96 hours. A reaction byproduct, dicyclohexylurea, was filtered off under reduced pressure on a glass filter. The polymer was isolated by mixing with 2000 ml of isopropanol, followed by precipitation from 13000 ml of diethyl ether, after which the precipitate was filtered off. The polymer was washed three times in 2500 ml of diethyl ether and then dried at 40 ° C. under reduced pressure.

Further, to remove traces of contaminants, the polymer was purified in a Soxhlet extractor using isopropanol.

After extraction in a Soxhlet extractor, the polymer was further purified by preparing a 6% (w / v) polymer solution in a dichloromethane / MeOH mixture (15/4 v / v), and then precipitated from a 50-fold excess of diethyl ether, after which was washed with diethyl ether. The purified polymer was dried at 40 ° C. under reduced pressure.

The approximate molecular weight of the polymer was: M _n = 2000-5000, M _w = 10000-30000.

Example 7

Alternative Triple Copolymer Synthesis (VP-AAc-AAc (NHS))

400 ml of oxygen-free toluene was heated to 80 ° C. Then, 31.6 g (0.28 mol) of N-vinylpyrrolidone and 20.6 g (0.28 mol) of acrylic acid were added to toluene, followed by the immediate addition of 0.1 g (6.1 × 10 ^-4 mol) of azo iso-butyronitrile. The reaction mixture was kept at 80 ° C for 17-19 hours. The polymer was isolated by precipitation from 2000 ml of a 1/1 (v / v) hexane / diethyl ether mixture, and then filtered under reduced pressure. The polymer was washed three times with 300 ml of diethyl ether and then dried in vacuo at 40 ° C.

The acid content of the copolymer (VP-AAc) was determined by titration with a 1.0 M sodium hydroxide solution. Then 50 mol%. acid groups were converted to NHS ester groups by reaction with NHS in the presence of dicyclohexylcarbodiimide. Then 33.7 g of a polymer (VP-AAc) containing 0.77 mol of functional groups of acrylic acid and 44.54 g (0.38 mol) of NHS were dissolved in 1000 ml of DMF at 25 ° C. After that, 79.77 g (0.38 mol) of dicyclohexylcarbodiimide was dissolved in 137 ml of DMF and added to the polymer solution and the reaction mixture was stirred at 25 ° C for 96 hours. A reaction byproduct, dicyclohexylurea, was filtered off under reduced pressure on a glass filter. The polymer was isolated by adding 1250 ml of isopropanol, followed by precipitation from 5000 ml of diethyl ether, after which the precipitate was filtered off. The polymer was washed three times in 1000 ml of diethyl ether and then dried at 40 ° C. under reduced pressure.

Further, in order to remove trace amounts of contaminants, the polymer can be purified using a number of known methods, for example, Soxhlet extraction, dialysis or washing with a suitable solvent, for example isopropanol. In addition, drying at elevated temperature and reduced pressure also helps to remove traces of solvents and other volatile substances.

Further, to remove traces of contaminants, the polymer was purified in a Soxhlet extractor using isopropanol.

After extraction in a Soxhlet extractor, the polymer was further purified by preparing a 6% (w / v) polymer solution in a dichloromethane / MeOH mixture (15/4 v / v), and then precipitated from a 50-fold excess of diethyl ether, after which was washed with diethyl ether. The purified polymer was dried at 40 ° C. under reduced pressure.

Example 8

Synthesis of Succinate-NHS Hydroxypropyl Cellulose

10 g of hydroxypropyl cellulose (M _w approximately equal to 370000) was dissolved in 350 ml of anhydrous N-methylpyrrolidone at 80 ° C. Then, 1.4 g (0.014 mol) of succinic anhydride and 1.71 g (0.014 mol) of 4-dimethylaminopyridine were added to the mixture. The reaction mixture was left overnight at 80 ° C. The solution was cooled to room temperature and 400 ml of isopropanol was added. The polymer was precipitated from 3000 ml of diethyl ether, filtered off and washed successively with 300 ml of diethyl ether. Finally, the polymer was dried in vacuo at 40 ° C.

The polymer was then dissolved in DMF and reacted with NHS in the presence of dicyclohexylcarbodiimide to give a compound containing NHS ester groups capable of reacting with amino groups and thiol groups.

Claims (26)

1. A multilayer sheet of tissue adhesive comprising a structural layer or laminate, said structural layer or laminate comprising one or more synthetic polymers having film-forming properties, and a layer of material for contact with a fabric comprising a triple copolymer is attached to said structural layer or laminate poly (VR-AAc-AAc (NHS)). 2. The sheet according to claim 1, which includes a structural laminate comprising two or more discrete layers connected to each other. 3. The sheet according to claim 2, in which the laminate includes alternating layers of a polymer having film-forming properties, and a material containing reactive functional groups. 4. The sheet according to claim 3, which includes a structural laminate comprising two layers of film-forming polymer and a layer of reactive material located between them, as well as a layer intended for contact with tissue. 5. The sheet according to claim 4, in which the reactive material comprises a triple poly copolymer (VP-AAc-AAc (NHS)). 6. The sheet according to claim 1, in which one or more polymers having film-forming properties are polyesters. 7. The sheet according to claim 6, in which the polyesters are selected from the group consisting of polylactic acid, polyglycolic acid, polycaprolactones, polyhydroxyalkanoates and copolymers and mixtures of any of these substances. 8. The sheet according to claim 7, in which the polyesters are selected from the group consisting of polylactic acid, polyglycolic acid and copolymers and mixtures of these acids. 9. The sheet of claim 8, in which the polyester is a poly (lactide-co-glycolide). 10. The sheet according to claim 3, in which the reactive functional groups are selected from the group consisting of imidoesters, p-nitrophenyl carbonate, NHS esters, epoxides, isocyanates, acrylates, vinyl sulfone, orthopyridyl disulfide, maleimides, aldehyde groups and iodoacetamide . 11. The sheet of claim 10, in which the reactive functional groups are NHS-ester groups. 12. The sheet according to claim 1, the total thickness of which is from 0.01 to 1 mm 13. The sheet according to item 12, the total thickness of which is from 0.015 to 0.05 mm 14. The sheet according to claim 1, in which the layer intended for contact with the fabric is more than 50% of the total thickness of the sheet. 15. The sheet according to claim 1, which includes a structural laminate, and the specified laminate includes n layers of film-forming polymer and n-1 layers of material containing reactive functional groups that are located between these layers of film-forming polymer, and a layer of material intended for contact with a fabric comprising a triple copolymer of poly (VP-AAc-AAc (NHS)); the values of n are 1, 2 or 3. 16. The sheet of clause 15, in which the film-forming polymer is a biodegradable polymer. 17. The sheet according to claim 1, which includes a structural laminate, wherein said laminate includes n layers of biodegradable polyester and n-1 layers of material containing reactive functional groups that are sandwiched between said layers of biodegradable polyester and a layer of material intended for contact with tissue, including a triple copolymer of poly (BP-AAA-AAA (NHS)); the values of n are 1, 2 or 3. 18. The sheet according to 17, in which the polyester is selected from the group consisting of polylactic acid, polyglycolic acid, polycaprolactones, polyhydroxyalkanoates and copolymers and mixtures of any of these substances. 19. The sheet of claim 18, wherein the polyester is selected from the group consisting of polylactic acid, polyglycolic acid and copolymers and mixtures of these acids. 20. The sheet according to claim 19, in which the polyester is a poly (lactide-co-glycolide). 21. The sheet according to clause 15, in which the material containing reactive functional groups, is a triple copolymer of poly (VP-AAA-AAA (NHS)). 22. The sheet according to any one of paragraphs.15-21, in which the value of n is 2. 23. The sheet according to item 22, in which the material intended for contact with the fabric is more than 50% of the total thickness of the sheet. 24. The sheet according to item 23, in which the material intended for contact with the fabric is more than 60% of the total thickness of the sheet. 25. A method of manufacturing a sheet in accordance with any of the preceding paragraphs, said method comprising the step-by-step formation of a layer (s) of a structural layer or laminate, followed by the formation of a layer intended for contact with tissue. 26. A method of attaching one surface of a fabric to another fabric, or a method of sealing the surface of a fabric; however, this method includes applying to the surface of the fabric a sheet made in accordance with any one of claims 1 to 24.

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