RU2418574C2 - Solvating system and hermetic for medical application - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: claimed is application of: (a) solvating system which contains surface active substance, able to separate, remove or destruct in any other way, at least, part of biofilm, attached or adhered to a part of middle or internal ear, to the surface in nasal cavity or in sinus cavity, or to mouth or gullet tissue, and (b) polymer film-forming medical hermetic, able to form protective layer above the place, on which such biofilm was destroyed, and which possesses adhesion to natural tissues in the processed place and is resistant to separation or other destruction until natural decomposition or resorption of hermetic takes place, for manufacturing therapeutic system for treatment of infectious diseases of ear or throat, corresponding method of treatment and composition of said hermetic and anti-microbial preparation, which includes gallium-containing compound for application in the method. Demonstrated is 5.2-fold logarithmic reduction of the level of microbial contamination in vitro by cultures Staphylococcus aureus, Pseudomonas aeruginosa.

EFFECT: invention suggests efficiency of treatment by the claimed method of chronic otitis media with evaporation (COME), recurrent acute otitis media (RAOM), cholesteatoma, chronic rhinosinusitis.

71 cl, 4 dwg, 2 ex, 1 tbl

Description

FIELD OF THE INVENTION

[0001] The present invention relates to the treatment of infectious diseases of the ear, nose or throat, including chronic otitis externa (COME), recurrent acute otitis media (RAOM), cholesteatoma, chronic rhinosinusitis (CRS), pediatric chronic sinusitis, tonsillitis, adenoiditis, night apnea syndrome and chronic acute pharyngitis.

BACKGROUND

[0002] COME and RAOM are inflammatory diseases of the middle ear. Biofilm formation may be an important factor in the pathogenesis of COME, see Post J.C. "Direct evidence of bacterial biofilms in otitis media", Laryngoscope 111 (12): 2083-94 (2001), Ehrlich et al. "Mucosal Biofilm Formation on Middle-Ear Mucosa in the Chinchilla Model of Otitis Media", JAMA 287 (13 ): 1710-15 (2002) and Fergie N. et al. "Is otitis media with effusion a biofilm infection?", Clin Otolaryngol Allied Sci. 29 (1): 38-46 (2004). Biofilms are formed when bacteria interact with the surface to form polymer films (sometimes called exopolysaccharide or extracellular polysaccharide polymers) that cover the surface and further bacterial proliferation of the living colony. Bacteria that have settled in biofilms are much more difficult to remove or destroy than bacteria in a plactic (suspended) state, and they are extremely resistant to many antibiotics and biocides. The extracellular polysaccharide (EPS) matrix and toxins produced by a number of different bacteria have been shown to cause inflammation in the host. As it turned out, chronic inflammation associated with COME and RAOM is the reaction of the host to the formation of a bacterial biofilm.

[0003] Typically, patients suffering from COME and RAOM in the initial stage are treated with oral antibiotics and then, if necessary, are treated more aggressively with a tympanostomy tube. Sometimes in the event of a serious infection or a high content of sputum in the middle ear, the middle ear can be washed (for example, with saline). Although tympanostomy tubes are effective in most patients, approximately 20% of the patients whose tympanostomy tubes were originally placed in the ear required additional surgery (adenoidectomy, a second set of tympanostomy tubes and, usually, adenoidectomy and the introduction of a tympanostomy tube) to treat prolonged COME or continuous RAOM.

[0004] Cholesteatoma is another ear disease that is of concern. Although it was generally initially thought to be a cyst consisting of dermal cells, it turned out that bacterial biofilms are also involved in this disease, see Chole et al. "Evidence for Biofilm Formation in Cholesteatomas", Arch Otolaryngol Head Neck Surg. 128, pp. 1129-33 (Oct. 2002). Bacterial biofilms are apparently formed in the cholesteatoma, which provoke inflammation and cause the formation of a benign tumor, consisting mainly of bacteria in its center and dermal cells. A tumor can destroy both the chain of auditory ossicles (auditory bones) and the mastoid process, damaging the hearing. Surgery and excision is the most common way to remove cholesteatoma. Up to 25% of these procedures fail due to relapse of cholesteatoma and, therefore, require additional surgery or other treatment.

[0005] CRS is an inflammation of the paranasal sinuses and is associated with a previous or subsequent runny nose, nasal passages or facial pressure, pain or swelling of the face, lasting for at least about two weeks. CRS affects approximately 10% or more of the US population. Most patients with CRS in the first stage are treated with therapeutic methods, but each year hundreds of thousands of patients undergo functional endoscopic surgery of the paranasal sinuses (FESS) in the case of an untreatable CRS. CRS patients are often characterized by a reduced quality of life, and they may require millions of dollars in annual health care and work time losses. CRS is a Th1 and Th2 inflammatory response to a number of mechanisms, including, but not limited to, bacterial toxins, extracellular polysaccharide matrices secreted by bacteria and contained in the bacterial biofilm, fungi, developed allergic reactions to bacteria and fungi (IgE), and autoimmune violations. Bacteria associated with CRS and inflammation caused by them are selected from the group of Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumonia, Haemophilus influenzae and Moraxella catarrhalis. Biofilms containing one or more of these bacterial species and possibly also containing fungi can be an important factor in the pathogenesis of CRS, see, for example, Ramadan et al. "Chronic rhinosinusitis and biofilms", Otolaryngol Head Neck Surg. 132: 414-417 (2005) and Ferguson et al. "Demonstration of Biofilm in Human Bacterial Chronic Rhinosinusitis", Am J Rhinol, 5:19, pp. 452-57 (2005). Extracellular polysaccharide (EPS) matrix, toxins produced by a colony of bacteria, and fungi that a bacterial biofilm may contain, all of them can provoke an inflammatory reaction of the host.

[0006] Adenoids (nasopharyngeal tonsils) and tonsils (palatine tonsils) are susceptible to certain diseases of the ear, nose and throat, including COME, RAOM, pediatric chronic sinusitis, tonsillitis, adenoiditis, pediatric obstructive sleep apnea syndrome (OSA), OSA in adults and chronic acute pharyngitis. Lingual tonsils can also become infected and cause various problems. The treatment of these various diseases in the initial stages is usually carried out using oral methods of drug treatment or, in the case of OSA, by applying positive pressure in the airways (CPAP). The unsuccessful outcome of these treatments is often accompanied by surgical removal of the tonsils, adenoids or tonsils and adenoids, because they contain bacteria or make it difficult to anatomy. Complications associated with surgical removal procedures include postoperative bleeding, dehydration, weight loss, peritonsillar abscess, torticollis (neck stiffness), resumption of tissue growth, reoperation due to incomplete tissue removal, continuous COME or RAOM, continuous OSA and, in some cases, fatal outcome. Postoperative treatment has traditionally been limited to a specific diet, flushing and the use of oral antibiotics to prevent postoperative pain and infections.

[0007] The etiology and chronic nature of at least COME, RAOM, cholesteatomas, and CRS appear to be associated with the presence of bacterial biofilms, as well as difficulties in removing them after surgery.

SUMMARY OF THE INVENTION

[0008] Patients, both adults and children, as well as their parents, negatively relapse infection and the possible need for repeated or additional surgery. Although at the initial stage, in order to solve this problem, the introduction of increased doses of antibiotics is possible, as shown, antibiotics are ineffective against chronic infections in which the bacterial biofilm is involved, and their administration can also contribute to the development of drug resistance of the studied and other types of bacteria. It would be highly desirable to use alternative treatments that would reduce or eliminate the number of required antibiotics, which as yet prevent the relapse of the condition being treated. If a bacterial biofilm on the surface of the tissue is involved in the condition being treated, it would be preferable to remove or destroy this biofilm with greater efficiency than in the case of salt irrigation, so that antibiotics or the body's own natural protective mechanisms can more effectively attack the remaining bacteria. It would also be preferable to at least temporarily insulate or otherwise protect the surface being treated in this way in order to counteract bacterial adhesion and the re-formation of biofilms. It would also be preferable to do this in such a way as to meet the requirements of biocompatibility in contact with human tissue and to apply small dosages of the introduced substances with a minimum period of use. In our pending application, No. 11 / 739,508, filed April 24, 2007, the entire disclosure of which is incorporated herein by reference, describes a solvation system containing a compound that forms complexes with metal ions and a surfactant, and its use for the destruction of bacterial biofilms in the medium or internal ear.

[0009] In one aspect of the present invention, the use of:

(a) a surfactant capable of separating, removing or otherwise destroying at least a portion of a biofilm that is attached or adhered to at least a portion of the middle or inner ear, to a surface in the nasal cavity or in the cavity of the nasal sinuses or in the oral tissue or pharynx, and

(b) a polymer film-forming medical sealant that can create a protective layer over the place where such a biofilm has been destroyed to produce a drug system for treating infectious diseases of the ear, nose or throat.

[0010] In another aspect, the present invention provides a method for treating infectious diseases of an ear, nose or throat, comprising:

a) applying a solvating system containing a surfactant to a treatment area that has a bacterial biofilm attached to or adhered to at least a portion of the middle or inner ear, to a surface in the nasal cavity or in the cavity of the nasal sinuses or in the mouth tissue, or pharynx

b) separating, removing or otherwise destroying at least a portion of the biofilm, and

c) applying to the treatment site a protective layer of a polymer film-forming medical sealant.

[0011] Another aspect of the present invention is a composition that prevents re-bacterial colonization and the re-formation of biofilms on the tissue from which the biofilm has been previously removed, said composition comprising a polymer film-forming medical sealant and an antimicrobial agent comprising a gallium-containing compound.

[0012] The described use, method and composition can be used to treat the middle or inner ear or appropriate postoperative care and for rhinological treatment, treatment of the oral cavity or pharyngitis or appropriate postoperative care. The described method and composition can also be used to treat disorders or chronic conditions, including chronic otitis media with effusion, recurrent acute otitis media, cholesteatoma, chronic rhinosinusitis, pediatric chronic sinusitis, tonsillitis, adenoiditis, night apnea syndrome, chronic acute pharyngitis and other infectious diseases of the ear, sinuses, mouth or throat.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Fig. 1 is a cross-sectional diagram of a middle ear treated by the method described.

[0014] Fig. 2 is an enlarged view of a portion of Fig. 1.

[0015] Figure 3 is a schematic illustration of a sinus cavity that is treated using the described method.

[0016] FIG. 4 is a perspective view of a surgical biofilm removal tool that can be used in the described method.

[0017] The same standard symbols in the various drawings indicate the same elements. Elements in the drawings are made without regard to scale.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] The following detailed description contains some embodiments of the invention and is not intended to be limiting. In this document, all weights, quantities and ratios are expressed by weight, unless specifically indicated otherwise. The terms shown below have the following meanings.

[0019] The term "antimicrobial agent" refers to a substance having the ability to cause a decrease of more than 90% (namely, at least a decrease of 1 logarithmic order) of a population of one or more species of Staphycoccus aureus, Pseudomonas aeruginosa, Streptococcus pneumonia, Haemophilus influenzae influenzae or Moraxella catarrhalis or any other bacteria involved in the etiology of COME, RAOM, cholesteatoma or chronic rhinosinusitis, established using the procedure for determining the number of bacteria by seeding on the tablets described in the examples below.

[0020] The terms “adhered” and “adhered” when used in relation to a bacterial biofilm and a surface means that the biofilm is formed and at least partially covers or covers the surface and is somewhat resistant to removal from the surface. Since the nature of this relationship is complex and little studied, using this term does not imply a specific mechanism of attachment or adhesion.

[0021] The term "adhesion" refers to the adhesion of a material to tissues or tissue to a tissue with which it has been in close contact for a long time, or tissue that connects opposing tissues or prosthetic materials through a generally open space.

[0022] The term "bacterial biofilm" means a community of bacteria attached to the surface, with microorganisms in the community enclosed in an EPS matrix formed by bacteria.

[0023] The term "biocompatible" when applied to a substance means that the substance does not pose a significant hazard or does not have undesirable effects on the patient's body.

[0024] The term "biodegradable" when applied to a substance means that the substance will decompose or erode in vivo to form smaller chemical products. Such a degradation process may be of an enzymatic, chemical, or physical nature.

[0025] The term "bioabsorbable" when applied to a substance means that the substance is capable of being absorbed by the patient’s body.

[0026] The terms "separation", "removal" and "destruction" when applied to a bacterial biofilm that has attached or adhered to a surface, means that at least the larger amount of biofilm originally present on the surface is no longer attached or adhered to the surface . With this application, they do not imply a specific mechanism for separation, removal or destruction.

[0027] The term "hemostatic agent" means a device or material that stops bleeding.

[0028] The term "nasal cavity or sinus cavity" refers to various tissues, usually limiting the air ducts and cavities in the nose and sinus, including, but not limited to, nostrils, nasal concha, anterior, ethmoid, sphenoid, and maxillary sinuses, sinus opening and nasopharynx, and objects or products (such as prostheses, dressings or stents) that can be placed in the nasal cavity or sinus cavity.

[0029] The term "polymer sealant" means that the sealant is obtained from a synthetic cross-linked or non-cross-linked polymer, or the sealant is a natural material, such as a protein that has been cross-linked (for example, synthetic crosslinked protein).

[0030] The term "residence time" when applied to a polymer sealant at a treatment site refers to the period of time that the sealant remains in place in vivo with prolonged observation.

[0031] The term "complexing compound" means a chemical reagent that will bind to another substance, in particular a metal ion, to prevent or prevent the release of a substance from a solution. The term “complexing compound with a metal ion” means a complexing compound that will bind to one or more metal ions, such as alkali metals, alkaline earth metals, iron, and the like. in order to prevent or prevent the release of a metal ion from the solution. In order of increasing atomic weight, alkali metals are arranged as follows: lithium, sodium, potassium, rubidium, cesium and France, and alkaline earth metals are arranged as follows: beryllium, magnesium, calcium, strontium, barium and radium.

[0032] The term "solvating" means the formation of a solution or dispersion containing a solvent or other carrier in which the solute is dissolved or suspended.

[0033] As shown in FIG. 1, the described method can be implemented in the ear 10 by inserting a cannula 12 through the external auditory canal 14 and the auditory tube 16 (which, for example, may have been inserted through a myringotomy) or other accessible opening in the tympanic membrane 18 , and from there into the middle ear 20. The cannula 12 can also be inserted in other ways without a myringotomy, for example, through a needle or other guidance device directed through the ear, Eustachian tubes, nose or mouth, and controlled blindly or by using controlled methods such as mic endoscopy, directional endoscopy with a virtual image or directional surgery with an image using a flexible, rail device with a tip. As shown in FIG. 1, the distal end 22 of the cannula 12 is located above the isthmus 24 of the Eustachian tube 26. The cannula 12 can be positioned and optionally modified in shape or size so as to treat other parts of the middle ear 20 (which, for the purposes of this description, as believed to include at least the eardrum, the lining of the middle ear, internal structures such as the auditory ossicle chain, and border structures such as the mastoid process) or to treat parts of the inner ear (which for the purpose of this description, as the floor at least include semicircular canals 28 and cochlea 30). For example, if treatment of the inner ear is necessary, an additional opening may be made for insertion (for example, in the membrane near the cochlear or oval window).

[0034] Figure 2 is an enlarged view of a portion of Figure 1. Application of a solvating system to a bacterial biofilm near the neck of the Eustachian tube by distributing a solvating system through passages 34 located in the side wall 36 to a bacterial biofilm, such as a biofilm 38 located on the upper part 40 of the Eustachian tube 26 is shown. It is obvious to a person skilled in the art that the solvating the system can be applied to the desired site of treatment using methods or devices other than cannula 12. Typical methods indicated include trepanation and typical indicated devices roystva include syringes (e.g., glass syringes and bulb syringes) and other devices that can provide access to the middle or inner ear through the tympanic membrane, the Eustachian tubes or nose.

[0035] As shown in FIG. 3, the described method can be implemented in the nasal cavity or sinus cavity 100 of the patient, including the maxillary sinus sinuses 110a, 110b and the anterior sinuses 112a, 112b, which can be accessed through the nostrils 114a, 114b. It should be noted that the external features of the patient, including the nostrils 114a, 114b, are shown in dashed lines. If a patient suffers, for example, from chronic rhinosinusitis, one or more treatment sites, such as treatment site 116, associated with the surface of the maxillary sinus 110a, can be surgically treated to essentially remove part or all of the biofilm at the treatment site and prevent or inhibit bacterial re-colonization. Treatment site 116 includes the ciliary epithelium of the maxillary sinus 110a and the corresponding layer of bacteria inhabiting the corresponding biofilm (not shown in FIG. 3). The treatment site is not necessarily natural tissue and may instead be an artificial structure (not shown in FIG. 3), for example, sinus dressing or stent, at least partially coated with a layer of bacterial biofilm. The described solvation system can be applied to treatment site 116 by using an introducer 120 with an articulated nozzle 122 containing an irrigation channel (invisible in FIG. 3), through which the solvation system can move to the distal end of the introducer and from there to the treatment site. The solvating system and biofilm residues can be removed from the treatment site through an aspiration channel (invisible in FIG. 3). The described polymer film-forming medial sealant can be similarly applied to the treatment site using the same or different irrigation channel in introducer 120. It will be apparent to one skilled in the art that the solvation system, sealant or solvation system and sealant can be applied to the treatment site using other methods or device. Typical other methods include trepanation, and typical other devices include syringes (e.g., glass syringes and balloon syringes).

[0036] Figure 4 shows a typical biofilm surgical instrument 200 that can be used in the described method. The tool 200 includes a handle 202, an introducer 222, a nozzle 224 (mentioned but not shown) and channels for flushing and aspiration (not shown in FIG. 4). Tool 200 may also include a first power drive assembly 226 (mentioned but not shown) and a second power drive assembly 228 (mentioned but not shown). The control knob 230 in the first node of the actuator 226 can be controlled by the user and bend the introducer 222, and the control knob 232 in the second node of the actuator 228 can be controlled by the user and move or rotate the nozzle 224 relative to the introducer 222. The handle 202 generally serves as a container for accommodating various other parts of the tool 200 and holds the introducer 222. The handle 202 may have a convenient form for gripping the shape of the gun, limiting the grip 234 and nose 236. Size and the shape of the grip portion 234 is made so that the user can hold the tool in his hand, while the nose 236 is adapted to communicate with the introducer 222. The trigger 238 and the associated sensor and valve (not shown in FIG. 4) can be used to control the movement described the solvation system through the irrigation pipe 240 and from there to the distal end of the introducer 222 through the nozzle 224 and to the desired treatment site. Starting device 238 can be provided with the possibility of multidirectional movement and connected to one or more additional sensors and valves (not shown in Fig. 4) to control the removal of the solvation system, the remainder of the biofilm and other residues of organic substances from the treatment site through the nozzle 224 and from there to the suction pipe 242. The starting device 238 can also be used to control the movement of the described sealant through a separate cavity into the irrigation pipe 240 and from there to the distal end of the introduction and 222 through the nozzle 224 and to the desired treatment site.

[0037] The described method can also be implemented by applying a solvating system and sealant to the tonsils, adenoids or adjacent tissue. This can be done if the tonsils and adenoids are intact. The described method can also be implemented after surgery to remove tonsils or adenoids, or tonsils and adenoids, or instead of surgery, for example, by applying a solvating system and sealant to the pharynx, for example, to the tonsil sinus.

[0038] The solvation system can be guided through a catheter, cannula, syringe, introducer, or other suitable tube and attached to a preferred treatment site for the purpose of separating, removing, or otherwise destroying at least a portion of the bacterial biofilm that has attached or adhered to the treatment site. It is desirable to apply the solvation system at least in an amount and with a thickness sufficient to cover a preferred portion of the biofilm. Treatment may include chemical dilution or mechanical disruption. For example, the solvation system can be applied with appropriate care in the form of a spray under pressure in order to remove bacterial biofilms, bacteria and other foreign bodies at the treatment site. Application of a solvation system or other liquids (e.g., saline) to suitable treatment sites can be accomplished using large pressure, jet plume, movement, or other methods designed to perform hydrosurgical treatment of the wound at the treatment site. Not wanting to be bound by theory, the solvation system can dissolve the biofilm and transfer it into a solution or suspension so that the biofilm thus destroyed can be easily washed off or otherwise removed from the treatment site by aspiration, rinsing the cavity or other removal methods. For example, according to the procedure performed in the middle ear, this process can be carried out by means of myringotomy or through the Eustachian tube or nose. Any bacteria remaining at the treatment site can then be more easily attacked by an antimicrobial agent or the body's defenses. A bacterial attack can, for example, be facilitated by incorporating an antimicrobial agent into a solvation system or into a polymer film-forming medical sealant, or by separately applying an antimicrobial agent during or after surgery (for example, topically, orally or systemically). It may be preferable to inject a sufficient amount of the solvating system into the treatment area in order to displace pus or other substance that may be present there, allowing the excess substance to flow out of the treatment area until the color of the excess material no longer changes. The solvation system can be left in place until it can leak or otherwise stand out or dissolve, or the solvation system can be left for a suitable time (for example, several minutes, several hours or more), and then rinsed using saline or other suitable liquid. Preferably, if the solvation system is applied directly to the treatment site, since direct application can contribute to more rapid destruction of the biofilm. For example, for procedures performed in the middle or inner ear, it is preferable if the solvation solution is applied directly to the region of the middle or inner ear, and not just applied to the external auditory canal and allowed to move through the eardrum. The application of the solvation system and the removal of biofilms and bacteria shifted from their place or destroyed can also be repeated if it is necessary to ensure complete removal of harmful microorganisms.

[0039] In order to prevent re-bacterial colonization and re-formation of the biofilm, the described polymer film-forming medical sealant is also applied to the treated area. Application can, for example, be carried out using a cannula 12, as shown in FIG. 1 and FIG. 2, an introducer 120 or 222, as shown in FIG. 3 and FIG. 4, or a catheter, syringe or other suitable tube for dispersion film-forming medical sealant in the treated place. When applied, the sealant used can completely fill the treated area, but it is advisable not to do so, since it is preferable to apply it in the form of a film or other uniform coating that leaves at least a partial air hole in the treated area. For example, when coating a treated area, in the absence of filling the middle ear with a sealant, the auditory ossicle chain can remain free and move with the movement of the eardrum due to the pressure of sound waves, while the function of the middle and inner ear can be preserved during treatment. If necessary, the sealant can be applied to part or the entire chain of the auditory ossicles or to part or the entire eardrum to provide a degree of stabilization during healing. As an additional example, when applying only the coating, without filling the treated treatment site in the nose with a sealant, respiratory functions can be maintained during treatment. Preferably, the sealant adheres to natural tissues in the treated area and is resistant to separation or other degradation until the natural decomposition or resorption of the sealant occurs (for example, after a residence time of one or more days, weeks or months). During this time, the possibility of re-colonization or reinfection can be significantly reduced or prevented, while effective cure is achieved, and the formation of new ciliary (ciliated) epithelial cells. A sealant can provide various advantages from a therapeutic point of view, including, but not limited to, the ability to repel adherent bacteria (resistance to bacterial adhesion), anti-infective properties, local immune modulation, tissue protection, reduction or elimination of pain or bleeding, reduction of inflammation, optimizing the environment for resuming growth of ciliated epithelial cells, reducing adhesion to critical anatomical organs, or the like. These benefits can arise from a variety of mechanisms, including a) inhibiting bacterial colonization, b) inhibiting the interaction of bacteria with tissue, c) reducing the incidence of tissue or abscess, d) reducing or preventing the recurrence of a disease (for example, especially reducing chronic inflammation associated with bacterial toxin and EPS), e) covering and protecting the tissue during treatment, for example, by keeping the wound moist, which promotes platelet aggregation, or by closing a dry wound without roughness formation, f) hemostasis, g) optimizing the environment for the formation of ciliated cells of the mucous membrane, h) accelerating the growth or resumption of growth of cilia of the epithelium, i) preventing adhesion of the prosthesis or tympanous mucous grafts to native tissue, and j) delivery of the therapeutic agent (s) ) to the place of treatment. It is preferable that the sealant was attached to part of the mucous membrane, covered other parts of the mucous membrane, while leaving the cilia of the epithelium free in those parts to which it was not attached, allowing the cilia to make a natural rhythmic movement (namely, pulsation of the cilia), introduced antimicrobial agents or additional necessary therapeutic drugs, and prevented bacteria from sticking to the treatment site.

[0040] In the described method, various solvation systems can be used. As indicated above, the solvation system includes a surfactant. Preferably, the surfactant is water soluble and non-toxic. Typical surfactants include anionic surfactants, nonionic surfactants, cationic surfactants, and zwitterionic surfactants. Typical anionic surfactants include, but are not limited to, C6-C24 alkylbenzenesulfonates; C6-C24 olefinsulfonates; C6-C24 paraffinsulfonates; cumene sulfonate; xylene sulfonate; C6-C24 alkylnaphthalene sulfonates; sulfonates or disulfonates; C6-C24 alkyl or dialkyl diphenyl ethers; C4-C24 mono- or dialkyl sulfosuccinates; sulfonated or sulfated fatty acids; sulfates of C6-C24 alcohols (for example, sulfates of C6-C12 alcohols); C6-C24 sulfates of ethers having from 1 to about 20 ethylene oxide groups; C4-C24 alkyl, aryl or alkiparyl esters of phosphoric acid or their alkoxylated analogues having from 1 to about 40 ethylene, propylene or butylene oxide groups; and mixtures thereof. For example, the anionic surfactant may be sodium chenodeoxycholate, N-lauryl sarcosine sodium, lithium dodepyl sulfate, 1-octanesulfonic acid sodium, sodium cholate hydrate, sodium deoxycholate, sodium dodecyl sulfate (also known as sodium lauryl sulfate) or g.

[0041] Typical cationic surfactants include, but are not limited to, quaternary amino compounds of the formula

where each R, R ', R "and R'" represent a C1-C24 alkyl, aryl or aralkyl group which may contain one or more P, O, S or N heteroatoms, and X represents F, Cl, Br, I or alkyl sulfate. For example, the cationic surfactant may be hexadecylpyridinium chloride monohydrate or hexadecyltrimethylammonium bromide.

[0042] Typical non-ionic surfactants include, but are not limited to, C6-C24 alcohol ethoxylates (eg, C6-C14 alcohol ethoxylates) having from 1 to about 20 ethylene oxide groups (eg, from about 9 to about 20 ethylene oxide groups ); C6-C24 alkyl phenol ethoxylates (e.g., C8-C10 alkyl phenol ethoxylates) having from 1 to about 100 ethylene oxide groups (for example, from about 12 to about 20 ethylene oxide groups); C6-C24 alkylpolyglycosides (for example, C6-C20 alkylpolyglycosides) having from 1 to about 20 glycosidic groups (for example, from about 9 to about 20 glycoside groups); C6-C24 fatty acid ester ethoxylates, propoxylates or glycerides; C4-C24 mono- or dialkanolamides; and mixtures thereof. For example, the non-ionic surfactant may be polyoxyethylene glycol dodecyl ether, N-decanoyl-N-methylglucamine, digitonin, n-dodecyl-B-D-maltoside, octyl-B-O-glucopyranoside, octylphenylethylene-phenylenethenyl-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene-ethylene) polyethylenethenethylated polyethylenethenethylenated compounds is present.

[0043] Typical zwitterionic surfactants include, but are not limited to, aminoalkyl sulfonate compounds of the formula

where each R, R ', R "and R'" represent a C1-C24 alkyl, aryl or aralkyl group which may contain one or more P, O, S or N heteroatoms; amine oxide compounds having the formula

where each R, R 'and R "represents a C1-C24 alkyl, aryl or aralkyl group which may contain one or more P, O, S or N heteroatoms; and betaine compounds having the formula

where each R, R 'and R "represents a C1-C24 alkyl, aryl or aralkyl group that may contain one or more P, O, S or N heteroatoms, and n is about 1-10. For example, a zwitterionic surface The active substance may be 3 - [(3-cholamidopropyl) dimethylammonio] -2-hydroxy-1-propanesulfonate, 3 - [(3-cholamidopropyl) dimethylammonio] -1-propanesulfonate (sometimes called CHAPS), an internal salt of 3- ( decyldimethylammonio) propanesulfonate (ammoniocaprylylsulfobetaine), or N-dodecyl-N, N-dimethyl-3-ammonio-1-propanesulfonate.

[0044] Preferred surfactants include alkyl sulfates, alkyl sulfonates, aryl sulfonates, and zwitterionic surfactants. Preferred surfactants can be obtained as pure compounds, or in some examples, they can be obtained by using products such as Castile liquid soap. Surfactants may, for example, be present in a concentration of at least about 0.002 M, at least about 0.005 M, or at least about 0.01 M, for example, from about 0.002 to about 1 M, from about 0.005 to about 0.7 M or from about 0.01 to about 0.5 M. Expressed in weight percent relative to the solvating system, surfactants can, for example, be more than 0.2 wt.%, From about 0.3% to about 30%, from about 0.5% to about 25%, or from about 1% to about 20%. Increased amounts of surfactant can contribute to faster destruction of biofilms.

[0045] The solvation system may comprise a compound that is complexed with metal ions. Preferably, the complexing compound is a weak acid whose activity is sufficient to bind one or more metal ions in an exopolysaccharide or extracellular polysaccharide matrix, but which is not so strong as to harm the tissue being treated. Metal ions of interest (due to their likely participation in the bacterial biofilms under consideration) include sodium, calcium, and iron. Preferably, the compound forming the complex with metal ions is water soluble, non-toxic and, when used in the ear, does not tend to enhance long-term hearing loss. Typical acids include, but are not limited to, carboxylic acids, dibasic acids or tribasic acids such as formic acid, acetic acid, chloroacetic acid, dichloroacetic acid, oxalic acid, oxamic acid, glycolic acid, lactic acid, pyruvic acid, aspartic acid, fumaric acid, maleic acid, succinic acid, iminodiacetic acid, glutaric acid, 2-ketoglutaric acid, glutamic acid, adipic acid, citric acid, glucuronova acid, mupinovaya acid nitriltrehuksusnaya acid, salicylic acid, ketopimelinovaya acid, benzoic acid, mandelic acid, chloromandelic acid, phenylacetic acid, phthalic acid and boric acid; mineral acids such as hydrochloric acid, phosphoric acid and phosphonic acid; and mixtures thereof. Citric acid is the preferred acid. The compound forming a complex with metal ions may, for example, be present in a concentration of at least about 0.01 M, at least about 0.05 M, or at least about 0.1 M, for example, from about 0.01 to about 0.5 M, from about 0.05 to about 0.4 M, or from about 0.1 to about 0.3 M. An increase in the amount of the compound forming a complex with metal ions can contribute to faster destruction of the biofilm.

[0046] The solvation system may include various other ingredients, including water and other solvents (eg, alcohols), buffers, antimicrobials, and various excipients. Preferably, the solvation system comprises water and one or more buffering agents. Preferably, if the buffer substance maintains the solvation system at a pH suitable for contact with human tissue, and preferably at a pH greater than 5. For example, in the solvation system, a pH close to neutral can be set, for example, a pH greater than 5 and less than 8.5. Buffer substances can, for example, be up to about 25% relative to the weight of the solvation system. Typical buffering agents include, but are not limited to, potassium chloride, glycine, potassium hydrophthalate, sodium acetate, sodium barbitone, and sodium citrate. If the compound forming a complex with metal ions is a weak acid, it is desirable that the buffer substance is a salt of this acid.

[0047] Solvation systems containing one or more antimicrobial agents are also preferred. EPS matrix allows biofilm to adhere to the underlying surface and also protects embedded microorganisms; thus, the bacteria in the biofilm are approximately 100-1000 times more resistant to antibiotics than planktonic bacteria. After the biofilm breaks up into unbound polymers or fragments and solvates or is otherwise destroyed by the solvation system, the antimicrobial agent can attack the remaining bacteria much more effectively. Typical antimicrobial agents include active oxygen compounds, such as hydrogen peroxide, isolated or equilibrium-derived or isolated peracids, such as chloroperbenzoic acid, peracetic acid, perheptanoic acid, peroctanoic acid, perdecanoic acid, permuric acid, perlimono acid, perglycolic acid, permolactic acid perbenzoic acid and peracid monoesters derived from dibasic acids or dibasic esters such as adipic, succinic, glutaric or malonic acid; aminoglycosides; Amphenicol ampicillins; ansamycins; beta-lactams, such as carbacephemes, carbapenems, cephalosporins, cefamycins, monobactams, oxacephemes, penicillins and any derivatives thereof; carboxylic acid esters such as p-hydroxyalkyl benzoates and alkyl cinnamates; chitosan salts; lipids in a cubic phase; gallium-containing antimicrobial agents such as gallium acetylacetonate, gallium bromide, gallium chloride, gallium fluoride, gallium iodide, gallium maltolate, gallium nitrate, gallium nitride, gallium percolate, gallium phosphide and gallium sulfate; iodine-containing compounds and other active halogen compounds such as iodine, interhalides, polyhalides, metal hypochlorites, hypochlorous acid, metal hypobromites, hypobromic acid, chloro and bromohydantoins, chlorine dioxide and sodium chlorite; lincosamides; macrolides; nitrofurans; organic peroxides, including benzoyl peroxide and alkylbenzoyl peroxides; ozone; phenolic derivatives, including o-phenylphenol, o-benzyl-p-chlorophenol, tert-amylphenol and C1-C6 alkylhydroxybenzoates; quaternary ammonium compounds such as alkyldimethylbenzyl ammonium chloride and dialkyldimethyl ammonium chloride; quinolines; singlet oxygen generators; sulfonamides; sulfones; sulfonic acids such as dodecylbenzenesulfonic acid; tetracycline antibiotics such as tetracycline, chlortetracycline, oxytetracycline, demecocycline, doxycycline, lymecycline, meclocycline, metacycline, metocycline, minocycline and the like; vancomycin; their derivatives and mixtures. Many of these substances are classes that include useful specific substances, the specific use of which is well known to specialists in this field. For example, typical penicillins include, but are not limited to, amdinotsillin, amdinotsillin pivoxil, amoxicillin ampicillin, apaltsillin, aspoksitsillin, aksidotsillin, azlocillin, akampitsillin, bacampicillin, benzilpenitsillinovuyu acid, benzylpenicillin sodium, carbenicillin, karindatsillin, klometotsillin, cloxacillin, cyclacillin, dicloxacillin, epitsillin , phenbenicillin, phloxacillin, getacillin, lenampicillin, metampicillin, sodium methicillin, meslocillin, sodium nafcillin, oxacillin, penamecillin, penetamate hydriodide, penicillin illin G benetamine, penicillin G benzathine, penicillin G benzhydrylarnine, penicillin G calcium, penicillin G potassium, penicillin G. procaine, penicillin N, penicillin O, penicillin phenylcillinphenylphenylphenylphenylphenylphenylpine phenylcinephenylphenylphenylphenylphenylphenylphenylpine phenylcinephenylphenylphenylpine phenylbenzylphenylpinephenylbenzene phenylcinephenylphenylbenz , piperacillin, pivampicillin propicillin, quinacillin, sulbenicillin, sultamycillin, thalampicillin, temocillin, ticarcillin and mixtures thereof or other substances (e.g. penicillins mixed with clavulanic acid, such as a mixture of amoxicillin and clavulanic acid lots available as AUGMENTIN ™ from GlaxoSmithKline).

[0048] An antimicrobial agent, such as the agents described above, can be used in a separate treatment step (if necessary, in a suitable carrier) after applying the solvation system and before using the polymer film-forming medical sealant. An antimicrobial agent can also be used as part of a sealant. Whether it is used as part of a solvation system, in a separate stage, or as part of a sealant, it is preferable that the antimicrobial agent provides a decrease of more than 99% (namely, at least a decrease of 2 logarithmic orders), more than 99.9% ( namely, at least a decrease of 3 logarithmic orders), more than 99.99% numerical decrease (namely, at least a decrease of 4 logarithmic orders) or more than 99.999% (namely, at least a decrease 5 logarithmic orders) of a population of one or more bacteria S. aureus, P. aeruginosa, S. pneumonia, H. influenzae and M. Catarrhalis, which was evaluated by the procedure of determining the number of bacteria on the plates seeding as described hereinafter in the Examples.

[0049] The solvation system may contain additional therapeutic agents. Typical therapeutic agents include any substance suitable for otological, rhinological or pharyngitic use, including analgesics, anticholinergics, antifungal drugs, antihistamines, blood products, steroid or non-steroidal anti-inflammatory drugs, antiparasitic drugs, antiviral drugs, biostatic compositions, chemotherapies anti-blastoma drugs, cytokines, decongestants, immunosuppressants, mucolytic drugs atoms, nucleic acids, peptides, proteins, steroids, vasoconstrictors, vitamins, mixtures thereof and other therapeutic substances that are obvious to experts in this field. Some of these additional therapeutic agents are described in more detail below in connection with a polymer film-forming medical sealant. Other excipients that can be included in the solvation system include dyes, pigments, or other coloring agents (e.g., FD & C Red No. 3, FD & C Red No. 20, FD & C Yellow No. 6, FD & C Blue No.2, D&C Green No. 5, D&C Orange No. 4, D&C Red No. 8, caramel, titanium dioxide, fruit or vegetable colorants such as beetroot powder or beta-carotene, turmeric, red pepper and other materials known to specialists in this field); indicators; flavors or sweeteners, including, but not limited to, aniseed oil, cherry, cinnamon oil, citrus oil (e.g. lime oil, lemon or orange oil), cocoa, eucalyptus, herbal flavorings (e.g. clove oil, nutmeg oil sage or cassia oil), lactose, maltose, menthol, peppermint oil, saccharin, sodium cyclamate, spearmint oil, sorbitol, sucrose, vanillin, wintergreen oil, xylitol and mixtures thereof; antioxidants; defoamers; and rheological modifiers, including thickeners and thixotropic substances.

[0050] Preferably, the solvation system has a sufficiently low viscosity to easily adhere to the treatment site, for example, by applying a mechanical spray or other spray, rinsing a cavity, spraying, applying a drug, capillary flowing or seeping. Preferably, the solvating system can also be easily removed from the treatment site by subsequent rinsing, washing, draining or absorption. The solvation system should not be used in liquid form, but it can, for example, be used in the form of a powder, gel, foam, tampon, film strip, or other suitable form. The solvation system can be applied to treatment sites in the middle or inner ear, to related structures such as the Eustachian tubes, to the nasal cavity or nasal cavity, or to the tissues of the mouth or pharynx. The solvating system is particularly suitable for treating ciliated tissues. Preferably, the solvation system is biocompatible with sensitive tissues and structures of the middle or inner ear, and preferably does not contain ingredients that could harm such tissues or structures or excessively impair hearing for a long time.

[0051] In the described method, various polymer film-forming medical sealants can be used. Preferably, the sealant is a biodegradable or bioabsorbable material with an in vivo residence time of from one day to several (e.g., 2, 3 or 4) days, weeks or months. The sealant may be crosslinked, crosslinked prior to application to the treatment site, or become crosslinked after application. According to one embodiment of the invention, the sealant may be a viscoelastic material. According to another embodiment of the invention, the sealant may harden after use. The sealant may be a synthetic polymer (e.g., polyethylene glycol or PEG), a natural polymer (e.g., a polysaccharide, lipid or polypeptide), or a synthetically modified natural polymer (e.g., a polypeptide that has reacted with PEG). Other typical synthetic polymers include polyacetals, polyacrylic acids, polyalkylene oxalates, polyalkylene succinates, polyamides, polyamic acids, polyaspartic acid, polyanhydrides, polycaprolactones, polycarbonates, polycyanoacrylates, polydiaxonones, polyesters, polyethylene polyesters (polyethylene, polyethylene) other poly (glycolides), polyhydroxybutyrates, polyhydroxyvalerates, polyketals, poly (lactic acid) and other polylactides, including poly (lactide-co-glycolides), poly (i block acids), polyorthoesters, polyphosphazines, polyphosphoesters, polypropylene oxide (PPO), degradable polyurethanes, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP) and copolymers, terpolymers, their compositions and mixtures.

[0052] Typical polysaccharides include agar; cellulose and its derivatives, such as oxidized cellulose, hydroxyethyl cellulose, carboxymethyl cellulose (CMC), carboxymethylamylose (SMA), carboxyethyl cellulose and hydroxypropyl methyl cellulose (HPMC); chitin; chitosan and its derivatives, such as carboxymethylchitosan and trimethylchitosan; dextran and its derivatives, such as carboxymethyldextran; glycogen; glycosaminoglycans such as hyaluronan (for example, hyaluronic acid and its derivatives, including esters and polymers), heparin, heparin sulfate, dermatinsulfate and chondroitin-6-sulfate; resins such as alginate, gellan gum and xanthan gum; pectin; starch and its derivatives.

[0053] Typical lipids include glycerol-based lipid compounds, such as glycerol monooleate and liquid crystalline lipids, which can be introduced in liquid form and which, upon contact with moisture, enter a cubic phase and form a waxy cubic or crystalline material.

[0054] Typical polypeptides include albumin, collagen, gelatin, silk and their derivatives. For example, crosslinked hydrogels can be prepared from many polypeptides by reacting with a suitable crosslinking agent such as an aldehyde (e.g. glutaraldehyde or formaldehyde), carbodiimide, chitin, CMC, diisocyanate or glycol such as PEG.

[0055] The polymer film-forming medical sealant may include antimicrobials, additional therapeutic agents, and other excipients, like the substances mentioned above with respect to the solvation system. Sealants containing therapeutic substances that exhibit both anti-infective and anti-inflammatory properties (e.g. tetracyclines) are a preferred embodiment of the invention. Sealants containing additional therapeutic agents, such as antifungal drugs, antihistamines, steroidal or non-steroidal anti-inflammatory drugs, antiparasitic drugs, antiviral drugs, chemotherapeutic / anti-blastoma drugs, decongestants or mucolytic drugs, are another preferred embodiment of the invention. Sealants containing antimicrobial agents and additional therapeutic agents are another preferred embodiment of the invention. Typical antifungal drugs include, but are not limited to, allylamines, imidazoles, polyenes, thiocarbamates, triazoles, derivatives and mixtures thereof. Typical antihistamines include, but are not limited to, azelastine, diphenhydramine, loratidine, derivatives and mixtures thereof. Typical steroidal anti-inflammatory drugs include, but are not limited to, 21-acetoxypregnenolone, alklomethasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetanzone cortexone, deflocortone, cortexone, cortexone, cortexone, cortexone, cortexone, cortexone, cortexone, cortexone, cortexone, cortexone, cortexone , diflorazone, diflucortolone, difluprednat, enoxolone, fluazacort, flucloronide, flumethasone flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocorgolone, fluorometholone, fluperolone acetone t, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, chalcinonide, halobetazole propionate, halomethasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate, maziprednisolone, meprednisolone, meprednisolone, meprednisolone, meprednisolone, meprednisolone, meprednisolone, meprednisolone, meprednisolone -diethylaminoacetate, prednisone sodium phosphate, prednisone, predinal, predilidene, romexzolone, thixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, their derivatives water and mixtures. Preferred steroidal anti-inflammatory drugs include beclomethasone, budesonide, fluticasone proprionate and mometasone furoate. Typical non-steroidal anti-inflammatory drugs include, but are not limited to, COX inhibitors (COX-1 or COX non-specific inhibitors) and selective COX-2 inhibitors. Typical COX inhibitors include, but are not limited to, salicylic acid derivatives such as aspirin, sodium salicylate, choline magnesium trisalicylate, salicylate, diflunisal, sulfasalazine and olsalazine; para-aminophenol derivatives, as acetaminophen; indole and indenoacetic acids such as indomethacin and sulindac; heteroaryl acetic acids such as tolmetin, dicofenac and ketorolac; arylpropionic acids such as ibuprofen, naproxen, flurbiprofen, ketoprofen, phenoprofen and oxaprozin; Anthranilic acids (phenamates) such as mefenamic acid and meloxicam; enolic acids such as oxicams (piroxicam, meloxicam); alkanones such as nabumeton; their derivatives and mixtures. Typical COX-2 inhibitors include, but are not limited to, diaryl-substituted furanones, such as rofecoxib; diaryl-substituted pyrazoles, such as celecoxib; indoleacetic acids such as etodolac and sulfonanilides such as nimesulide; their derivatives and mixtures. Typical antiparasitic drugs include, but are not limited to, atovaquone clindamycin, dapzone, idoquinol, metronidazole, pentamidine, primaquine, pyrimethamine, sulfadiazine, trimethoprim / sufamethoxazole, trimethrexate, their derivatives and mixtures. Typical antiviral drugs include, but are not limited to, acyclovir, famciclovir, valaciclovir, edoxudine, ganciclovir, foscamet, cidovir (available as VISTIDE ™ from Gilead Sciences, Inc.), vitrazert, formivirsen, HPMPA (9- (3-hydroxy- 2-phosphonomethoxypropyl) adenine), PMEA (9- (2-phosphonomethoxyethyl) adenine), HPMPG (9- (3-hydroxy-2- (phosphonomethoxy) propyl) guanine), PMEG (9- [2- (phosphonomethoxy) ethyl] guanine), HPMRS (1- (2-phosphonomethoxy-3-3hydroxypropyl) cytosine), ribavirin, EICAR (5-ethyl-1-beta-D-ribofuranosylimidazole-4-carbonxamine), pyrazofurin (3- [beta-D- ribofuranose l] -4-hydroxypyrazole-5-carbochamine), 3-deazaguanine, GR-92938X (1-beta-D-ribofuranosylpyrazole-3,4-dicarbokhamide), LY253963 (1,3,4-thiadiazol-2-yl-cyanamide ), RD3-0028 (1,4-dihydro-2,3-benzoditin), CL387626 (4,4'-bis [4,6-di] [3-aminophenyl-N, N-bis (2-carbamoylethyl) - sulfonylimino] -13,5-triazin-2-yl-amino-biphenyl-2-, 2'-disulfonic acid, disodium salt), BABIM (bis [5-amidino-2-benzimidazolyl] methane), NIH351, derivatives thereof and mixtures. Typical chemotherapeutic / anti-blastoma drugs include, but are not limited to, antitumor drugs (e.g., cancer chemotherapeutic drugs, biological response modifiers, vascularization inhibitors, hormone receptor blocks and cryotherapeutic drugs or other substances that destroy or inhibit neoplasia or oncogenesis), such as alkylating agents or other substances that directly destroy cancer cells by attacking their DNA (e.g. cyclophosphamide and isophosphamide) with nitrosis chevins or other substances that destroy cancer cells by inhibitory changes necessary for cellular DNA repair (e.g. carmustine (BCNU) and lomustine (CCNU)), antimetabolites and other substances that block the growth of cancer cells, interfering with certain cell functions, usually synthesis DNA (e.g. 6 mercaptopurine and 5-fluorouracil (5FU)), antitumor antibiotics, and other compounds that act by binding to or penetrating DNA and preventing RNA synthesis (e.g., doxorubicin, daunorubicin, epirubicin, darubicin, mitomycin-C and bleomycin), plant (vinca) alkaloids and other antitumor preparations obtained from plants (for example, vincristine and vinblastine), steroid hormones, hormone inhibitors, hormone receptor antagonists and other substances that affect the growth of hormone receptors cancers (e.g. tamoxifen, herceptin, aromatase inhibitors such as aminoglitetamide and formestane, triazole inhibitors such as letrozole and anastrazole, and steroid inhibitors such as exemestane), antiangiogenic proteins, ma lazy molecules, gene treatments, or other substances that inhibit blood vessel development or vascularization of tumors (e.g. meth-1, meth-2 and thalidomide), bevacizumab (available as AVASTIN ^™ from Genentech), chalamin, endostatin, angiostatin, ANGIOZYME ™ from Ribozyme Pharmaceuticals, neovastat (available as AE-941 ^TM from AetePHK Zentaris), CC-5013 (available as REVIMID ™ from Celgene Corp.), copper-522 (available as VITAXIN ™ from Medlmmune, Inc.) 2-methoxyestradiol or 2ME2 (both available from the company PANZEM ^TM Entremed, Inc.), karboksiamidotriazol (CAI), etc. combretastatin A4 drug (CA4P), SU6668, SU1 1248, BMS-275291, COL-3, EMD 121974, IMC-1C1 1, IM862, TNP-470, celecoxib (available as CELEBREX ™ from Pfizer Inc.), refecoxib, interferon alpha, interleukin-12 (IL-12), or any compounds identified in Science Vol.289, Pages 1197-1201 (August 17, 2000), which is incorporated herein by reference, biological reaction modifiers (e.g., interferon, bacillus Calmetta-Guerin (BCG), monoclonal antibodies, interleukin 2, granulocyte colony stimulating factor (GCSF), etc.), PGDF recept antagonists orov, herceptin, asparaginase, busulfan, carboplatin, cisplatin, carmustine, chlorambucil, cytarabine, dacarbazine, etoposide, flucarbazine, fluorouracil, nemcitabine, hydroxyurea, ifosfemanotometophotomeptomethometophotomethometophotomethometophotomethometophotomethometophotomethometophotomethanotometophotomethometophotomethanotometopan threosulfan, vinblastine, vincristine, mitoazitron, oxaliplatin, procarbazine streptocid, taxol or paclitaxel, taxotere, analogues / congeners, their derivatives and mixtures. Typical decongestants include, but are not limited to, epinephrine, oxymetazoline, phenylephrine, pseudoephedrine, tetrahydrozolidine, xylometazoline, derivatives and mixtures thereof. Typical mucolytic drugs include, but are not limited to, acetylcysteine, dornase alpha, guaifenesin, derivatives and mixtures thereof.

[0056] In cases where it is desirable to remove water from the tissue, for example to remove fluid from polyps or edematous tissue, a hyperosmolar preparation may be used in the sealant. Typical hyperosmolar preparations include, but are not limited to, furosemide, sodium chloride gel, and other salt preparations that draw water from tissue or substances that directly or indirectly alter the osmotic content of the mucous layer. If a sustained release or delayed release of the therapeutic agent is desired, a sustained release modifier may also be included in the sealant. The therapeutic substance can also be encapsulated, for example, in polymer microspheres, with the aim of further delaying or slowing down the release of the therapeutic substance.

[0057] It is desirable that the sealant has a sufficiently low viscosity and is able to easily penetrate to the place to be treated, for example, by applying a mechanical spray or other spray, rinsing a cavity, spraying, applying a drug, capillary flowing or seeping. The sealant does not have to be used in liquid form, it can be used, for example, in the form of a powder, gel, foam, tampon, film strip or in another suitable form. The sealant may also be a flowing liquid that crosslinkes, polymerizes or otherwise changes its consistency to form a sealant. The sealant can be applied to the treatment site in the middle or inner ear, to related structures such as the Eustachian tubes, to the nasal cavity or cavity of the nasal sinuses, or to the tissue of the mouth or pharynx. The sealant is particularly suitable for the treatment of ciliary epithelial tissue. The sealant used may be bioabsorbable or biodegradable after a required period of time after treatment has occurred. It is desirable that the sealant has at least one characteristic that helps to keep the sealant at the treatment site. This characteristic can be selected from various properties, including, but not limited to, thickness, size, shape, density, viscosity, hardness, bioadhesiveness, mucoadhesiveness, method of application or administration, etc. The sealant can prevent re-bacterial colonization or the formation or re-formation of bacterial biofilms by coating the treated area (for example, the mucous membrane from which the bacterial biofilm was removed using a solvation system) with an alternative film structure whose surface is not readily permeable to bacteria associated with infectious diseases of the ear, nose or throat. Preferably, the sealant is biocompatible with sensitive tissues and structures of the middle or inner ear, and preferably does not contain ingredients that could potentially harm such tissues or structures or significantly impair hearing for a long time.

[0058] It is desirable that the solvating system and sealant can be used as part of a multi-stage treatment regimen, which results in the destruction of the bacterial biofilm and creates obstacles to its re-formation. For example, a number of steps can be carried out, which can be broadly classified as cleaning / destruction, destruction, protection / coating, aeration and cure. The stage of cleaning / destruction can be carried out by introducing a solvating system, as described above. The destruction step can be carried out by applying a suitable antimicrobial agent to the treatment site. As described above, this can be done by incorporating the antimicrobial agent into the solvation system, into the sealant, or into the solvation system and sealant. As indicated above, the antimicrobial agent can also be used as a separate step between the use of the solvation system and the use of sealant. The antimicrobial agent can also be applied or administered after surgery. Stage protection / coating can be performed by coating the protective layer of sealant at least part of the specified fabric, processed as described above. The aeration step can be carried out by maintaining or forming a suitable opening or openings (for example, a narrow long cut in the eardrum or openings in closed or partially closed nasal passages, sinuses or at the mouth of the sinuses) and keeping the openings or openings open for a period of time, sufficient to aerate the treatment site. The nature of the hole (s) and, in the treatment of the ear, the presence or absence of an inserted tympanostomy tube may affect the time period. For example, if an incision was made in the eardrum and the tube was not placed in this opening, the incision can remain open for several days and heal, thereby naturally closing the space inside the ear. The stage of treatment can be carried out by returning the cleaned, protected and closed surface of the tissue to a normal state, for example, by means of one or more healing mechanisms, such as modulation of the inflammatory response, phagocytosis, remodulation of the mucous membrane, the formation of new ciliary (ciliated) epithelial cells, or full or partial restoration of normal hearing, balance, or breathing. It is preferable if in some cases the described method can be carried out without surgical intervention, for example, in the treatment of the nose by applying and removing the solvation system and by applying the sealant using conventional aspiration / suction methods or by simply washing the affected nasal passages without infusing the solvation system or sealant into more difficult to reach sinuses outside their mouth.

[0059] The invention is also illustrated by the following non-limiting examples.

Example 1

[0060] Bacterial isolates of S. aureus and P. aeruginosa bacteria were recovered from the sinuses of patients with sinus diseases. Patients with cystic fibrosis or latent immunosuppressive disease (HIV infection, insulin-dependent diabetes mellitus, or renal disease) and patients taking antibiotics or oral prednisone in the previous month were excluded from the studies. All patients had unresponsive sinusitis, i.e. persistent symptoms, resistant to medical therapy, despite the fact that patients underwent functional endoscopic sinus surgery (FESS) to treat refractory chronic rhinosinusitis (CRS) with or without nasal polyposis. The manifestation of CRS was diagnosed in accordance with the 2003 American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) guidelines set forth by Benninger et al. "Adult chronic rhinosinusitis: Definitions, diagnosis, epidemiology and patnophysiology", Otolaryngol Head Neck Surg 129 (3 suppl): S1-S32 (2003). Selected patients were unresponsive to medical therapy for more than 12 months prior to sampling, and the FESS failure was considered unrelated to technical factors such as obstructive synechia, frontal sinus obstruction, or the remaining hooked process. Samples were taken sequentially, up to 10 samples of each of S. aureus and P. aeruginosa were obtained according to the direct endoscopy guide and using the procedure described by Nadel et al. "Endoscopically guided cultures in chronic sinusitis", Am f Rhinol 12: 233-241 (1998). Briefly, the process can be represented as follows: a local anesthetic was introduced, the nose wing was laid back, and an endoscope was used to visualize the middle course of the nose and the sinus cavity. A thin, flexible calcium alginate swab was inserted (STARSWAB II ™ Collection and Transport System, Starplex Scientific, Etobicoke, Ontario) and directed to the site of greatest suppuration. If suppuration was not observed, a smear was taken from the surface of the maxillary sinus within 15 seconds. They acted carefully to avoid contact with the side wall of the nose or the vestibule of the nose. Samples were placed on a plate and incubated using standard procedures. Bacteria were identified using the VITEK 2 ™ system (Biomerieux, Durham, North Carolina). Crystalline violet dye was used to confirm the presence of the biofilm according to the method described by Stepanovic et al. "A modified microtiter-plate test for quantification of staphylococcal biofilm formation", J Microbiol Methods 40: 175-179 (2000). For incubation and cultivation, pre-frozen strains were inoculated with 0.5% sheep blood on tryptic soy agar (TSA). After 24 hours, one to four colonies per strain were cultured on TSA. The cultures were incubated at 37 ° C for 24 hours to bring their condition to trypticase soy broth (TSB) -TSA and to ensure that there was no contamination. Then colonies grown on TSA solid medium were amplified in 5 ml of TSB medium by 0.5% glucose according to the method described by Gotz "Staphylococcus and biofilms", Mol Microbiol 43: 1367-1378 (2002), and incubated at 37 ° C for at least in 24 hours.

[0061] A droplet reactor (DFR) was used to determine the effectiveness of various test solutions applied to S. aureus and P. aeruginosa biofilms on slides coated with hydroxyapatite (HA) to remove these bacterial biofilms with and without hydrodynamic force. Slides in the DFR were tilted at an angle of 10 ° relative to the horizontal, thereby simulating the environment with a slight shift. DFR was placed in an incubator at 37 ° C under aerobic conditions. About 20 minutes before bacterial inoculation, a sterile medium (10% TSB for S. aureus; 1% TSB for P. aeruginosa) was dripped onto the slides in DFR and allowed to accumulate on the glasses to form the desired layer. Subsequently, slides were inoculated with 1 ml of S. aureus or P. aeruginosa culture. DFR was tilted so that the slides were placed horizontally for 4 hours, which allowed bacteria to attach to the substrate. Then the DFR was set so that the slides were again placed at a 10 ° angle, while the sterile medium dripped onto the glass at a speed of 10 ml per hour. After 3 days, biofilm removal experiments were performed. Used two methods of processing biofilms formed by each type of bacteria. The first use included static treatment in DFR, with a solvation system (called CAZS) dripping onto biofilms. The CAZS solvating agent contained non-ionized water, 25 g / L (corresponding to 0.13 M), citric acid, 5.35 g / L (corresponding to 0.02 M), caprylylsulfobetaine zwitterionic surfactant (CH ₃ (CH ₂ ) ₉ N ⁺ (CH ₃ ) ₂ CH ₂ CH ₂ CH ₂ SO ₃ ^- , CAS 15163-36-7) and a sufficient amount of sodium citrate (approximately 240 g / l) to buffer the system to a pH of 5.4. The second method of application included the application of saline or the application of CAZS outside DFR by rinsing with a jet under pressure in order to apply hydrodynamic force to the biofilm. A preliminary series of experiments were carried out for all treatment methods to ensure that the deviations between the glass slides were within the maximum permissible levels. In addition, various plates of both types of bacteria were prepared to determine deviations within the same series of experiments and within different series of experiments. A control slide was made for each series of DFR experiments. Three series of experiments were evaluated for each method of processing each type of bacteria.

[0062] In the static treatment, the flow in the DFR was stopped, the DFR was set in the horizontal direction, and the cover was removed. A 25 ml portion of CAZS was placed on one glass slide. Control slides were not treated with CAZS. After 10 minutes, the slides were washed with brine (25 ml). Then, the DFR was disconnected from the inlet tube, and each slide was removed from under the laminar cabinet and placed in a sterile 50 mm tube. After another wash with saline (2 ml), the surface of the slide was repeatedly scraped out and scrapings and saline were collected in the tube. The tube was shaken for 10 seconds, sonicated for 2 minutes and again shaken for 10 seconds to disperse the bacteria in suspension. Then the suspensions were diluted sequentially and 100 μl aliquots were placed in three TSA-containing plates and incubated at 37 ° C for 24 hours. Colony forming units (CFUs) were counted manually and the number of CFUs per square centimeter was calculated. The counts on the tablets were logarithmized (log 10) and expressed as the average value (± SD) obtained from the tablet counts of two series of DFR experiments for each of the three glass slides.

[0063] In hydrodynamic processing, the slides were removed from the DFR and placed in a glove box. Slides were placed in a holder and sprayed for about 20 seconds with about 150 ml of saline or CAZS using a pressure washer. Spraying was carried out by a smooth movement from side to side, so from top to bottom so that all areas were sprayed twice, once on each axis. Then the slides were placed in a sterile 50 ml tube, washed, scraped, dispersed, incubated and evaluated as described above.

[0064] The average (± SD) decrease (in percent) was calculated relative to the control values of the number of bacteria S. aureus and P. aeruginosa (namely, the number of CFUs on each plate) after each treatment method and the results were evaluated using two-sample t criteria (MINITAB ™ version 14, Minitab, State College, PA). It was believed that a value of f less than 0.05 represents a significant difference from the control value. The results are shown below in table 1, the results are expressed as the average number (± SD) of colony forming units per centimeter (log) obtained by evaluating three tablets twice.

Table 1
Determining the number of bacteria on tablets depending on the processing method Processing method Staphylococcus aureus Pseudomonas aeruginosa No (Control Samples) 8.7 ± 0.4 9.2 ± 0.2 Static Application CAZS 6.2 ± 0.3 6.3 ± 1.3 Hydrodynamic saline application 6.4 ± 0.2 6.9 ± 0.1 Hydrodynamic application of CAZS 4.8 ± 0.3 4.0 ± 0.5

[0065] The results in table 1 show that significant removal of bacterial biofilms has been achieved. Before treatment, abundant biofilms were formed in DFR cultures of both S. aureus and P. aeruginosa, and the amount of CFU for control samples ranged from 7.8 to 9.5 log / cm ² . Static administration of CAZS resulted in a 2.5-fold logarithmic decrease (5.11 × 10 ⁸ -1.65 × 10 ⁶ ; P = 0.001) of the amount of S. aureus CFUs and a 2.9-fold logarithmic decrease (1.69 × 10 ⁹ -1.91 × 10 ⁶ ; P = 0.002 ) amounts of P. aeruginosa CFUs. Mechanical failure using hydrodynamic saline alone separately reduced the amount of S. aureus CFUs by 2.3 logarithmic units (5.11 × 10 ⁸ -2.38 × 10 ⁶ ; P - 0.001) and the number of P. aeruginosa CFUs by 2.4 logarithmic units (1.69 × 10 ⁹ -7.31 × 10 ⁶ ; P = 0.001). However, mechanical failure using hydrodynamic treatment by CAZS reduced the amount of S. aureus CFU by 3.9 log units (5.1.1 × 10 ⁸ -6.37 × 10 ⁴ ; P = 0.001) and the number of P. aeruginosa CFU by 5.2 log units (1.69 × 10 ⁹ -1.04 × 10 ⁴ ; P = 0.001).

[0066] Confocal scanning laser microscopy (CSLM) was used to study three slides (for each treatment method and type of bacteria) on which the number of bacteria was not determined in order to obtain an image of the biofilm architecture in the control and processed samples. To perform CSLM, slides were stained using a BACLIGHT ™ Live / Dead kit (Molecular Probes, Invitrogen, Carlsbad, CA) containing two nucleic acid dyes (SYTO 9, which determines living cells by the presence of fluorescence in the green region of the visible spectrum, and propidium iodide, which allows you to determine dead cells by the presence of fluorescence in the red visible spectrum). After staining, the slides were examined using CSLM at 630-fold magnification using a LEICA ™ SP2 acoustic-optical beam splitter with a 2-photon MAI TAI ™ attachment (Leica Microsystems, Bannockburn, Illinois) for fluorescence excitation and detection in the green and red visible spectra . Each section of the glass slide was divided into 10 equal-sized segments. The microscope field of view was randomly selected from each segment, and images were obtained at 1 μm intervals from the top of the biofilm to the substrate, thereby creating a set of images for each location. CSLM analysis revealed that a thick biofilm covered the control slides. Hydrodynamic saline treatment and static treatment with CAZS markedly reduced the amount of biofilm coating and reduced the structure of the remaining biofilm. Hydrodynamic treatment by CAZS led to an even greater decrease in both the biofilm coating and the degree of ordering of the biofilm community. In general, the results obtained were consistent with the estimates for determining the number of bacteria on the tablets with respect to the reduction in the amount of biofilm achieved with each treatment method.

[0067] Of the three treatment methods studied, force irrigation by means of CAZS and pressure washing was the most effective in destroying the bacterial biofilm. Pressure irrigation using saline significantly reduced the amount of biofilm. However, the presence of a surfactant and citric acid in the irrigation solution significantly increased the decrease in the amount of CFU in both S. aureus and P. aeruginosa biofilms. There were large, statistically significant decreases, while the number of bacteria on the tablets on average logically decreased 3.9 and 5.2 times (decrease from 10,000 to 100,000 times) for S. aureus and P. aeruginosa biofilms, respectively. A decrease in this value in vitro indicates that an appropriate in vivo method of treating the middle or inner ear, nasal cavity or cavity of the nasal sinuses or tissues of the mouth and nasopharynx should effectively destroy the bacterial biofilms found in these places. The low level of persistent bacterial infection remaining after the above treatment can be reduced by protective mechanisms in the host organism, either topically or orally administered antimicrobial agent, as well as by applying a sealant as described above.

Example 2

[0068] Experimental studies using cultures of S. aureus and P. aeruginosa grown on solid TSA medium (namely, cultures obtained without the use of HA-coated glass slides and DFR, and with a lower likelihood of formation of persistent biofilms) indicate that a solvating system containing a surfactant but not a compound forming a complex with metal ions may be less effective as a biofilm disruptor than a solvating system that also contains a compound forming complex with metal ions. However, both solvation systems can more effectively destroy biofilms than saline.

Example 3

[0069] The CAZS solvation system used in Example 1 was modified by replacing some water with gallium nitrate so that the modified system contained 25% gallium nitrate. A control solution containing 25% gallium nitrate in non-ionized water was also prepared. When evaluated using the static processing method described in Example 1, the introduction of gallium nitrate resulted in a 3.4-fold logarithmic decrease (average of 4 series of experiment) of the amount of S. aureus CFUs and a 4.1-fold logarithmic decrease (average of 3 series of experiment) of the amount P. aeruginosa CFUs relative to the control solution. Statistical administration of a solution containing CAZS and gallium nitrate resulted in a 5.2-fold logarithmic decrease (average of 2 series of experiment) of S. aureus CFUs and a 5.5-fold logarithmic decrease (average of 2 series of experiment) of P. aeruginosa CFUs .

[0070] Although specific embodiments of the invention have been illustrated and discussed herein to describe preferred options, it will be apparent to those skilled in the art that a wide variety of alternative or equivalent implementations of the invention designed to achieve the same ends can be replaced with the specific ones shown and described variants of the invention, without departing from the essence of the present invention. Such an application is intended to cover any adaptations and variations of the preferred embodiments of the invention that are contemplated in this application. Therefore, it is obvious that this invention is limited only by the claims and their equivalents.

Claims (71)

1. Application: (a) a solvating system containing a surfactant capable of separating, removing or otherwise destroying at least a portion of a biofilm that is attached or adhered to at least a portion of the middle or inner ear to a surface in the nasal cavity or in the cavity of the nasal sinuses, or to the tissue of the mouth or pharynx, and
(b) a polymer film-forming medical sealant capable of forming a protective layer over the place where such a biofilm has been destroyed, and which has adhesion to natural tissues in the treated area and is resistant to separation or other destruction until natural decomposition or resorption occurs sealant for the manufacture of a medicinal system for the treatment of infectious diseases of the ear, nose or throat. 2. The use of (a) and (b) according to claim 1, characterized in that the surfactant contains an anionic surfactant, a nonionic surfactant, a cationic surfactant, a zwitterionic surfactant, or their mixture. 3. The use of (a) and (b) according to claim 1, characterized in that the surfactant includes alkyl sulfate, alkyl sulfonate or arylsulfonate. 4. The use of (a) and (b) according to claim 1, characterized in that the surfactant is at least about 0.2% relative to the mass of the solvating system. 5. The use of (a) and (b) according to claim 1, characterized in that the surfactant is from about 0.3% to about 30% relative to the weight of the solvating system. 6. The use of (a) and (b) according to claim 1, characterized in that the surfactant is from about 0.5% to about 25% relative to the weight of the solvating system. 7. The use of (a) and (b) according to claim 1, characterized in that the solvating system also contains a compound that forms a complex with metal ions. 8. The use of (a) and (b) according to claim 7, characterized in that the compound forming a complex with metal ions includes a compound forming a complex with sodium, calcium or iron. 9. The use of (a) and (b) according to claim 7, characterized in that the compound forming a complex with metal ions includes citric acid. 10. The use of (a) and (b) according to claim 7, characterized in that the compound forming a complex with metal ions is present in a concentration of from about 0.01 to about 0.5 M. 11. The use of (a) and (b) according to claim 1, characterized in that the solvating system also contains water and has a pH from about 5 to about 8.5. 12. The use of (a) and (b) according to claim 1, characterized in that the solvating system also contains a buffer. 13. The use of (a) and (b) according to claim 1, characterized in that the solvating system also includes an antimicrobial agent. 14. The use of (a) and (b) according to claim 1, characterized in that the sealant is viscoelastic. 15. The use of (a) and (b) according to claim 1, characterized in that the sealant hardens after use. 16. The use of (a) and (b) according to claim 1, characterized in that the sealant contains a polysaccharide. 17. The use of (a) and (b) according to claim 16, characterized in that the sealant contains cellulose, chitin, chitosan, dextran, glycogen, glycosaminoglycan, gum, pectin, starch or their derivatives. 18. The use of (a) and (b) according to claim 1, characterized in that the sealant contains hyaluronan. 19. The use of (a) and (b) according to claim 1, characterized in that the sealant contains carboxymethyl cellulose. 20. The use of (a) and (b) according to claim 1, characterized in that the sealant contains a lipid or polypeptide. 21. The use of (a) and (b) according to claim 1, characterized in that the solvating system or sealant also contains an antimicrobial agent. 22. The use of (a) and (b) according to item 21, wherein the antimicrobial agent includes gallium acetoacetonate; gallium bromide, gallium chloride, gallium fluoride, gallium iodide, gallium maltolate, gallium nitrate, gallium nitride, gallium percolate, gallium phosphite, gallium sulfate, or a mixture thereof. 23. The use of (a) and (b) according to claim 1, also including the use of an antimicrobial agent after the use of the solvating system and before using the sealant. 24. The use of (a) and (b) according to claim 1, characterized in that the solvation system and sealant provide a more than 1 logarithmic decrease in the in vitro population of one or more types of bacteria selected from the group Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumonia, Haemophilus influenzae, or Moraxella catarrhalis. 25. The use of (a) and (b) according to claim 1, characterized in that the solvating system and sealant provide a more than 2 logarithmic order reduction in the in vitro population of one or more types of bacteria selected from the group of Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumonia, Haemophilus influenzae, or Moraxella catarrhalis. 26. The use of (a) and (b) according to claim 1, characterized in that the solvation system and sealant provide a decrease of the in vitro population of one or more types of bacteria selected from the group Staphylococcus aureus, Pseudomonas aemginosa by more than 3 logarithmic orders, Streptococcus pneumonia, Haemophilus influenzae, or Moraxella catarrhalis. 27. The use of (a) and (b) according to claim 1, characterized in that the sealant further comprises an antifungal drug, an autohistamine, a steroidal or non-steroidal anti-inflammatory drug, an antiparasitic drug, an antiviral drug, a chemotherapeutic / anti-blast drug, a decongestant, or a mucolytic drug . 28. A method of treating infectious diseases of an ear, nose or throat, comprising: a) applying a solvating system containing a surfactant to a treatment site that has a bacterial biofilm that is attached or adhered to at least a portion of the middle or inner ear , to the surface in the nasal cavity or in the cavity of the nasal sinuses, or to the tissue of the mouth or pharynx, b) separating, removing or otherwise destroying at least part of the biofilm, and subsequent c) applying a protective layer to the treatment site medical sealant polymeric film former, which has a natural adhesion to the tissues in the treated site and is resistant to separation failure or another as long until a natural decomposition or resorption sealant. 29. The method according to p, characterized in that the treated place is in the middle ear. 30. The method according to p, characterized in that the treated place is in the nasal cavity or cavity of the nasal sinuses. 31. The method according to p. 28, comprising the use of a solvation system by spraying, washing, spraying, applying a drug, capillary leakage or seepage, and also including removing the solvation system from the treatment site by washing, washing, draining or absorbing. 32. The method according to p. 28, including the use of sealant by spraying, washing, spraying, applying, capillary flowing or seepage. 33. The method according to p. 28, including the use of a solvating system and sealant directly in the middle or inner ear. 34. The method according to p. 33, comprising the use of a sealant in the form of a film or a uniform coating. 35. The method according to clause 34, including the use of sealant without filling the treatment site. 36. The method according to p, characterized in that the surfactant contains an anionic surfactant, a nonionic surfactant, a cationic surfactant, a zwitterionic surfactant, or a mixture thereof. 37. The method according to p, characterized in that the surfactant includes alkyl sulfate, alkyl sulfonate or aryl sulfonate. 38. The method according to p, characterized in that the surfactant is at least about 0.2% relative to the mass of the solvating system. 39. The method according to p, characterized in that the surfactant is from about 0.3% to about 30% relative to the mass of the solvating system. 40. The method according to p, characterized in that the surfactant is from about 0.5% to about 25% relative to the mass of the solvating system. 41. The method according to p. 28, characterized in that the solvating system also contains a compound that forms a complex with metal ions. 42. The method according to paragraph 41, wherein the compound forming a complex with metal ions includes a compound forming a complex with sodium, calcium or iron. 43. The method according to paragraph 41, wherein the compound, forming a complex with metal ions, includes citric acid. 44. The method according to paragraph 41, wherein the compound forming a complex with metal ions is present in a concentration of from about 0.01 to about 0.5 M. 45. The method according to p, characterized in that the solvating system also contains water and has a pH from about 5 to about 8.5. 46. The method according to p, characterized in that the solvating system also contains a buffer. 47. The method according to p, characterized in that the solvating system also includes an antimicrobial agent. 48. The method according to p, characterized in that the sealant is viscoelastic. 49. The method according to p, characterized in that the sealant hardens after application. 50. The method according to p, characterized in that the sealant contains a polysaccharide. 51. The method according to p. 50, characterized in that the sealant contains cellulose, chitin, chitosan, dextran, glycogen, glycosaminoglycan, gum, pectin, starch or their derivatives. 52. The method according to p, characterized in that the sealant contains hyaluronan. 53. The method according to p, characterized in that the sealant contains carboxymethyl cellulose. 54. The method according to p, characterized in that the sealant contains a lipid or polypeptide. 55. The method according to p, characterized in that the solvating system or sealant also contain an antimicrobial agent. 56. The method according to claim 55, wherein the antimicrobial agent comprises gallium acetoacetonate, gallium bromide, gallium chloride, gallium fluoride, gallium iodide, gallium maltolate, gallium nitrate, gallium nitride, gallium percolate, gallium phosphite, gallium sulfate or a mixture thereof . 57. The method according to p. 28, also comprising the use of an antimicrobial agent after the use of the solvating system and before using the sealant. 58. The method according to p. 28, characterized in that the solvating system and sealant provide a more than 1 logarithmic decrease in the population of in vitro one or more types of bacteria selected from the group of Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumonia, Haemophilus influenzae or Moraxella catarrhalis. 59. The method according to p. 28, characterized in that the solvating system and sealant provide a more than 2 logarithmic order reduction in the in vitro population of one or more types of bacteria selected from the group of Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumonia, Haemophilus influenzae or Moraxella catarrhalis. 60. The method according to p. 28, characterized in that the solvating system and sealant provide a more than 3 logarithmic order reduction in the in vitro population of one or more types of bacteria selected from the group of Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumonia, Haemophilus influenzae or Moraxella catarrhalis. 61. The method according to p, characterized in that the sealant further includes an antifungal drug, antihistamine, steroid or non-steroidal anti-inflammatory drug, antiparasitic drug, antiviral drug, chemotherapeutic / anti-blast drug, decongestant drug or mucolytic drug. 62. A composition that prevents the re-bacterial colonization and re-formation of biofilms on the tissue from which the biofilm was removed for use in the treatment of diseases of the ear, throat, nose by the method according to claims 28, 55, 56, a composition containing (a) a polymer film-forming medical a sealant that is capable of forming a protective coating on such a fabric, adhesion to natural tissues in the treated area and is resistant to separation or other destruction until the natural decomposition or resorption of the sealant And (b) an antimicrobial agent comprising gallium-containing compound. 63. The composition according to p, characterized in that the sealant contains a synthetic polymer, a natural polymer or a synthetically modified natural polymer. 64. The composition according to p, characterized in that the sealant contains polyethylene glycol. 65. The composition according to p, characterized in that the sealant contains a polysaccharide, lipid or polypeptide. 66. The composition according to p, characterized in that the sealant contains carboxymethyl cellulose. 67. The composition according to item 62, wherein the sealant contains chitin. 68. The composition according to p, characterized in that the sealant contains hyaluronan. 69. The composition according to item 62, wherein the sealant contains collagen. 70. The composition according to p, characterized in that the sealant contains a polypeptide that has reacted with an aldehyde. 71. The composition according to p. 62, characterized in that the gallium-containing compound contains gallium acetoadetonate, gallium bromide, gallium chloride, gallium fluoride, gallium iodide, gallium maltolate, gallium nitrate, gallium nitride, gallium percolate, gallium phosphite, gallium sulfate or a mixture thereof .

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