RU158996U1 - WOUND COVER - Google Patents

Abstract

1. Wound cover for the treatment of lesions of the mucous membranes and skin in the form of a multilayer film containing hyaluronic acid or its esters, a chitosan-containing component, as well as physiologically active and auxiliary substances, characterized in that the layer adjacent to the wound is made of hyaluronic acid or its derivatives, and the outer layer is made of a complex of chitosan with at least one organic acid with a chain length of C-C, and physiologically active substances are contained in the coating in the form of micelles. 2. The wound cover according to claim 1, characterized in that as physiologically active substances it contains at least one substance from the group of antibiotics, antiseptics, anti-inflammatory drugs, analgesics, anesthetics, immunomodulators, vitamins, amino acids fungicides, vitamins, and amino acids .3. The wound cover according to claim 1, characterized in that the micelles are made of carboxylic acids with a C-Cily chain length of their triglycerides. Wound cover according to claim 1, characterized in that the micelles are made of phospholipids. A wound dressing according to claim 1, characterized in that it contains plasticizers, taste regulators, colorants, preservatives or water-retaining agents as auxiliary substances. A wound dressing according to claim 1, characterized in that it further comprises a substrate.

Description

The utility model relates to the field of medicine and pharmacology, namely to composite film materials based on biodegradable polymers exhibiting antitumor, wound healing, anti-inflammatory, and antimicrobial properties. In particular, the invention relates to prolonged-action multilayer wound dressings based on biodegradable polysaccharides having adhesion to skin integuments and mucous membranes, as well as containing physiologically active substances.

The skin and mucous membranes are a barrier that protects the body from external influences and the penetration of pathogenic microflora into the body. Therefore, a violation of the anatomical integrity and / or functional activity of the epithelium as a result of traumatic effects, chronic diseases, infectious and inflammatory processes leads to a weakening of the protective function of the epithelium in the affected area, contributes to its bacterial infection and destruction.

The physiological process of wound healing is aimed at restoring the epithelium, reconstructing the damaged extracellular matrix [Vowden K., Vowden P. Wound Management Formulary and Educational Resourse Book. 2008, P.1; Mallefet P., Dweck A.C. Biomedical Scientist. 2008, V. 7, P. 609-615], and with the development of skin cancer - also to suppress malignant tumor processes [LCA Skin Cancer Clinical Guidelines, July 2014].

Violation of the wound healing process can lead to an increase in the timing and quality of healing, up to the appearance of chronic non-healing wounds and the development of irreversible pathological processes. Therefore, the drugs used in the treatment of epithelial diseases should be complex, that is, aimed both at reducing inflammation, and at stimulating proliferation and accelerating epithelization. And with malignant neoplasms, complex treatment should be aimed both at suppressing pathological proliferation and cell growth, restoring the epithelium, as well as normalizing the skin after radiation and radiotherapy

For the treatment of diseases of the skin and mucous membranes, including malignant diseases, systemic drugs are usually used - tablets, injection solutions, as well as external drugs in the form of creams, gels, solutions. The external use of funds allows you to protect the affected areas from environmental influences, contributes to the rapid achievement of therapeutically effective doses of physiologically active substances in the affected area, avoiding the complications and side effects inherent in the systemic use of drugs.

Given the variety of epithelial diseases, external drugs are developed in the form of wound dressings, film coatings, gels, foams, etc.

To protect wounds, in particular, classic wound dressings made of textile materials, for example Sterilux ^® based on non-woven fabric, for example Medicomp ^{®, are used} . The limitation of their use is associated with high adhesion to the surface of the damaged area, causing injury to the wound when changing the dressing, the lack of biological activity that promotes wound healing [Rippon M., White R., Davies P. Wounds UK. 2007. V. 3. N4. P. 76-86; Skórkowska-Telichowska K., Czemplik M., Kulma Α., Szopa J. Journal of the American Academy of Dermatology, 2013. V. 68, N4, P. 117-126].

Non-adhesive atraumatic dressings are being developed, such as hydrocolloid and hydrogel dressings, calcium or sodium alginate dressings, and foam dressings.

Hydrocolloidal compositions (dressings) have an inner layer of a gelling material based on the sodium salt of carboxymethyl cellulose, gelatin or pectin, fixed on a semi-permeable polyurethane base [Fletcher J. etc. Wound. International Online Journal, 2011, V. 2, N4, R. 1-6]. The composition may contain antimicrobial agents, for example, silver [Flores A. Wounds Essentials 2007, V. 2, P. 182-185]. Dressings absorb exudate, maintain hydration of the wound, prevent the penetration of bacteria, promote angiogenesis, but are mainly effective for treating dry wounds covered with fibrin clot and necrotic tissue [Queen D. Wounds International Online Journal 2009, V. 1, N1].

The disadvantage of hydrocolloid compositions is the inability to use for the treatment of mucous membranes, infected and necrotic wounds [Skórkowska-Telichowska K., Czemplik Μ., Kulma Α., Szopa J. Journal of the American Academy of Dermatology 2013, V. 68, N4, P. 117-126]. In addition, it is possible to soften the tissues of the damaged area with inadequate bandages [Vowden K., Vowden P. Wound Management. Formulary and Educational ResourseBook 2008, P. 33-36].

Compositions based on calcium salts of alginic acid [Sayag J., Meaume S., Bohbot S.J. of Wound Care 1996, V. 7, N8, P. 357-362] are used to treat bleeding wounds and may contain silver or zinc, which ensures their antimicrobial properties [Clark Μ. Wounds International Online J. 2012, V. 3, N. 7]. The disadvantages of the compositions are the lack of thermoregulation, the inability to use for dry wounds and wounds affected by anaerobic infections, the limited use for deep wounds [Skórkowska-Telichowska K., Czemplik Μ., Kulma Α., Szopa J.J. of American Academy of Dermatology 2013, V. 68, N4, P. 117-126] due to increased stimulation of fibroblasts [Widgerow A.D., etc. Anesthetic Plastic Surgery 2000, V. 24, N3, P. 227-234].

More effective are multilayer composite dressings. In particular, a three-layer polyurethane-based dressing is known, in which the layer in contact with the wound surface is made of soft silicone, the central layer maintains moisture and thermoregulation of the wound, and the upper, polyurethane, protects the wound from infection [Dykes PJ, Heggie R., Hill SA Wounds International Online Journal 2001, V. 10, N2, P. 7-10]. The compositions cannot be used for wounds with a low level of exudate due to increased granulation, as well as for dry wounds with black necrotic tissue or crust [Young T. British J. of Nursing 1995, V. 4, N3, P. 169-170; Skórkowska-Telichowska K., Czemplik M, Kulma Α., Szopa J.J. of American Academy of Dermatology 2013, V. 68, N4, P. 117-126].

The currently used drugs for external use cannot fully provide the conditions for optimal wound healing; they do not take into account the duration of the use of the drugs due to the high duration of most diseases of the epithelium and the potential toxicity of the long-term use of the drugs.

In this regard, the development of new compositions for topical use in the treatment of skin lesions is relevant.

In particular, the use of hyaluronic acid and its derivatives, which are widely used in reconstructive surgery, implantology, as well as cosmetology [Leach J.V., Schmidt S.Ε., seemed promising. Encyclopedia of Biomaterials and Biomedical Engineering 2004, Marcel Dekker, New York, P. 779-789; Dechert T.A. et. all. Wound Repair and Regeneration 2006, V. 14, P. 252-258]. Thus, a dressing for the restoration of skin integuments and mucous membranes after surgical operations is known, containing hyaluronic acid ester in combination with collagen fibers, or polysaccharides, semisynthetic and synthetic polymers, etc. [US 5520916, 1991]. The composition of the dressing, as a rule, includes a physiologically active substance (FAV) and an antibiotic - vancomycin. The effectiveness of a skin contact layer containing a hyaluronic acid ester can be enhanced [US 5658,582, 1993] by introducing an additional layer that acts as a liquid absorption enhancer. The layers are combined using a chemical coagulating agent, an adhesive agent, or by mechanical crosslinking. The composition of the inner layer may additionally include FAA, antibiotic, antiseptic, antimycotic, polypeptide or protein.

The disadvantage of this dressing is the complexity of the manufacturing process, as well as differences in the absorbing and thermoregulating ability of the ingredients, which can have a negative impact on the healing process.

One of the promising components in compositions for treating epithelium is chitosan, the biological activity of which is based on the ability to hydrolyze in the presence of lysozyme, the formation of chitooligosaccharides with antimicrobial, immunomodulatory activity, promoting wound healing and tissue repair [Aiba S. International J. Of Biological Macromolecules 1992, V. 14, N4, P. 225-228; Nwe, N. et all, Materials 2009, V. 2, P. 374-398; Ravi Kumar Μ.Ν. V. et all, Chemical Reviews 2004, V. 104, N12, P. 6017-6084; Lim S.-H., Hudson S.M. J. of Macromolecules Science. Part C. 2003, V. 43, N2, P. 223-269; Sanford P.A. Chitosan: Commercial uses and potential applications. In: Skjak G. et all, Chitin and Chitosan sources, Chemistry, Biochemistry, Physical Properties and Applications, Elsevier: London, UK. 1989. R. 51-69].

Known wound dressings containing a mixture of chitosan and hyaluronic acid. Thus, US Pat. No. 7,524,514 proposes a composition for tissue regeneration in the form of a liquid mass obtained by mixing dry particles of hyaluronic acid and chitosan, followed by hydration. The composition consists of insoluble chitosan, a viscoelastic gel of hyaluronic acid, fibers of a polyelectrolyte complex and a physiologically active substance (cytostatics, growth factors, hormones, antibiotics, etc.). A similar composition (US 2009/270346) also contains a mixture of chitosan, an oxidized polysaccharide (starch, cellulose, chitin, dextran, glycogen or hyaluronic acid) and physiologically active substances. The composition is applied to the tissues of the nasal cavities and sinuses, middle or inner ear, knee and vertebral cartilage. After stabilization, a protective layer is formed.

The disadvantages of the compositions is the low efficiency, the inability to effectively use on the surface of tissues in contact with the liquid, and the inclusion of FAA in the composition is significantly limited.

Obtaining the proposed composition is a multi-stage process. This is due, in particular, to the fact that the preparation of mixed compositions based on polyanionic (hyaluronic acid) and polycationic (chitosan) polysaccharides is complicated by the formation of a polyelectrolyte complex. It was shown that to prevent the production of a polyelectrolyte complex based on chitosan and sodium hyaluronate, polysaccharides are separately dissolved in 50% formic acid, the solutions are mixed, formed into films, dried and the film is washed from formic acid [Kim S.J. et all, J. of Applied Polymer Sci. 2004, V. 91, N5, P. 2908-2913; Kim S.J. et all, Solid State Ionics 2003, V. 164, P. 199-204].

Along with monofilms, multilayer dressing compositions are known in which chitosan is contained in one of the layers as a complex. Thus, the use of complexes based on a mixture of gelatin, chitosan and formaldehyde for the treatment of wounds is known (CN 1097980, 1995); gelatin and formaldehyde with antibiotic additives (RU 2033149, 1995); cellulose and chitosan (JP 0376029, 1990); collagen and chitosan (WO 8504413, 1986), which are then applied to a dressing of a polymeric material.

The main disadvantage of these coatings (compositions) is the low wound healing activity due to their sticking to the wound.

A dressing is known (RU 2270646,2006), which contains a polymer film with a hydrogel layer deposited on its surface, obtained by mixing solutions of chitosan with polyhydric alcohols and polyvinylpyrrolidone. The hydrogel is applied to a water-insoluble film with linear through pores, dried to a moisture content of less than 30%. The dressing promotes accelerated regeneration of damaged tissues, is able to absorb up to 8 g / g of exudate, and prevents wound infection.

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

A known composition comprising a sponge containing an absorbent material, for example, chitosan and hyaluronic acid or its derivatives, as well as FAV, in particular, coagulation factor, surface active, antimicrobial, antibacterial, painkiller FAV, vitamins, proteins, minerals, growth factors, chemotherapeutic, wound healing substances, amino acids, cells, enzymes, contrast and other substances [WO 2006/005340]. The composition is used either independently as a hemostatic agent, or for the delivery of FAA to the body.

The disadvantage of the composition is the lack of prolonged release of FAW, which requires a fairly frequent change in wound coverage.

The closest in technical essence to the claimed technical solution is a two-layer dressing (RU 2270646, 2006), which contains a polymer film with linear through pores, and a hydrogel layer deposited on its surface, obtained by mixing solutions of chitosan with polyhydric alcohols and polyvinylpyrralidone, followed by administration it contains FAV (antiseptics, antibiotics, silver salts, etc.). After application to the film, the gel layer is dried to a moisture content of less than 30%. The dressing promotes the accelerated regeneration of damaged tissues and is able to absorb up to 8 g / g of exudate, and prevents infection of the wound.

The disadvantages of the proposed solution are the need for a long time for the formation of a solid hydrogel (more than two to three days), insufficient sorption capacity, the absence of a prolonging effect, the possibility of draining the hydrogel from the wound during watering (absorption of exudate) and inefficiency for the treatment of skin cancer.

The technical problem solved by the authors was to expand the range of wound coverings, with the aim of creating more effective dosage forms based on chitosan and hyaluronic acid (or their derivatives), as well as physiologically active and auxiliary substances, in particular, having antitumor and prolonged effects on the body.

The technical result was achieved by creating a multilayer film coating, one of the layers contains hyaluronic acid and / or its esters, and the other is made of a complex of chitosan with at least one organic acid with a chain length of C ₂ -C ₇ , and the surfactant is contained in the form of micelles.

As a rule, the coating is made of two layers, the outer of which contains a chitosan complex, however, it is possible to supplement the coating by adhesively bonding a substrate made of a polymer film, non-woven or carbon fabric.

As a physiologically active substance (PAW), a wound coating contains at least one substance from the group that includes antibiotics, antiseptics, analgesics, anesthetics, immunomodulators, anti-inflammatory drugs, amino acids, fungicides, vitamins and amino acids, and plasticizers as auxiliary substances emulsifiers, flavoring agents, colorants, preservatives or water-retaining agents.

Micelles containing physiologically active substances, as a rule, are made of carboxylic acids with a chain length of C ₈ -C ₂₆ and / or their triglycerides and / or phospholipids.

If the composition of the wound cover further includes an adhesive-bonded substrate made of a polymer film, non-woven or carbon cloth, then it is applied to the chitosan layer, after which the composition is dried to a moisture content of 10-20%.

The coating is prepared as follows. A solution of hyaluronic acid or its salt is obtained by dissolving it in an aqueous solution containing biologically active and auxiliary substances. A solution of the chitosan complex is prepared by treating chitosan with a solution of a monobasic or polybasic organic acid or a mixture of acids, after which an additional filtration of the solution is carried out to remove insoluble particles and the resulting colloidal microparticles. (The best results were achieved if chitosan was dissolved in an aqueous solution of organic acids containing in a quantity of 1 g of chitosan: succinic - 0.56 g, glutamine - 10

0.59 g, aspartic - 0.52 g, milk - 0.50 g, ascorbic - 0.78 g, fumar - 0.65 g, maleic - 0.51 g, salicylic - 0.69 g)

The formation of layers is carried out, as a rule, on a balanced smooth glass, metal or polymer substrate by watering or extrusion through a die. The thickness of each layer of film medicinal compositions varies between 20-100 microns.

The essence and advantages of this technical solution are illustrated by the following examples.

Example 1. Obtaining a film drug composition containing the antibiotic ciprofloxacin in phospholipid micelles

A solution of 3.5 g of sodium hyaluronate (MM = 1.6 MDa, CPN, Czech Republic) in 150 ml of water is applied to an alcohol-free glass substrate located on a horizontal surface through a 110 mm wide die with a gap of 1.8 mm. The film is dried at room temperature for 15 hours. The film thickness is 35 microns. Humidity 18.0%.

Ciprofloxacin solution. To 0.1 g of lecithin is dissolved with vigorous stirring in 100 ml of distilled water for 30 minutes. 2.5 g of ciprofloxacin hydrochloride is added to the resulting solution, the FAV is dissolved with stirring for 20 minutes. A stable emulsion is formed containing ciprofloxacin in phospholipid micelles. The value of R _h micelles in solution is 130-210 nm.

3.5 g of chitosan (MM = 240 kDa, Ennagram, France) and 2.08 g of glutamic acid are dissolved in 100 ml of water with vigorous stirring. The solution is mixed with 50 ml of ciprofloxacin hydrochloride solution. The resulting solution is applied to a layer containing hyaluronic acid through a die with a gap of 1.5 mm. The film is dried at room 11

temperature for 15 hours. The thickness of the two-layer film is 120 microns, the humidity is 16.3%. The duration of exposure to the coating was 15 hours.

Example 2. Obtaining a film drug composition containing the antibiotic ciprofloxacin in oleic acid micelles.

A solution of 3.5 g of hyaluronic acid (MM = 1.6 MDa) and 0.075 g of potassium hydroxide in 150 g of water is applied to an alcohol-free glass substrate located on a horizontal surface through a die 110 mm wide with a gap of 3.3 mm. The film is dried at room temperature for 15 hours. Film thickness 60 μm. Humidity 10.0%.

Ciprofloxacin solution. To 400 μl of oleic acid, 200 ml of distilled water are added dropwise with vigorous stirring. The mixture is placed in an ultrasonic bath and incubated for 30 minutes. A stable emulsion is formed. 2.25 g of ciprofloxacin hydrochloride is dissolved in 75 g of the emulsion, and a stable emulsion containing the surfactant in micelles is obtained. The value of R _h micelles in solution is 110-220 nm.

To a mixture of 3.5 g of chitosan (MM = 240 kDa, Ennagram, France) and 2.08 g of glutamic acid, 94 ml of water are added, stirred on a mechanical stirrer for 3 hours until the chitosan is completely dissolved. The solution is heated in a water bath to 35 ° C, 75 ml of ciprofloxacin solution are added, and mixed thoroughly. pH = 4.94.

The obtained chitosan solution containing FAA micelles is applied to the layer containing hyaluronic acid through a die with a gap of 1.0 mm. The film is dried at room temperature for 15 hours. The thickness of the two-layer film is 85 μm, the humidity is 16.8%.

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Example 3. Obtaining a film drug composition containing a non-steroidal anti-inflammatory drug aceclofenac in phosphatidylserine micelles

4.0 g of sodium hyaluronate (MM = 1.6 MDa, CPN, Czech Republic) is dissolved in 200 ml of water with stirring for 4 hours. The solution is applied to a glass-free alcohol-free substrate located on a horizontal surface, through a 110 mm wide die with a gap of 2.4 mm. The film is dried at room temperature for 15 hours, then the hyaluronate solution is re-applied through a die with a 2.4 mm gap, and dried at room temperature for 15 hours. Film thickness 60 μm.

Aceclofenac solution. 60 mg of aceclofenac is dissolved in 2 ml of ethanol. With vigorous stirring, 800 μl of the resulting solution are added dropwise to 200 ml of a 0.25% solution of phosphatidylserine in water, the emulsion is stirred for 1 hour. The value of R _h micelles in solution is 160-220 nm.

To 4.0 g of chitosan (MM = 240 kDa, Ennagram, France), 200 ml of aceclofenac solution was added, stirred for 1 hour, then 2.4 g of glutamic acid was added, and stirred for 3 hours until the chitosan was completely dissolved. The resulting solution is applied to a layer containing hyaluronic acid through a die with a gap of 1.0 mm. The film is dried at room temperature for 6 hours. The thickness of the two-layer film is 150 microns.

Example 4. Obtaining a film drug composition containing diclofenac in the micelles of PEG-modified oil.

3.4 g of sodium hyaluronate (MM = 1.6 MDa, CPN, Czech Republic) are dissolved in 200 ml of water with stirring for 4 hours. The resulting solution is applied to an alcohol-free glass substrate located on a horizontal surface, through a 110 mm wide die with a gap of 13

2.4 mm. The film is dried at room temperature for 15 hours, then a solution of hyaluronic acid is re-applied, through a die with a gap of 2.4 mm, dried at room temperature for 15 hours. Film thickness 60 μm.

Diclofenac solution. 48.6 mg of diclofenac was dissolved in a mixture of 0.4 ml of diethylene glycol monoethyl ether (Transcutol P, Gattefosse, France) and 0.80 ml of PEG-8 olive oil (ResPharma, Italy). With vigorous stirring, 0.6 ml of the resulting solution was slowly added dropwise to 200 ml of water. The value of R _h micelles in solution is 140-270 nm.

200 ml of diclofenac solution are added to 4.0 g of chitosan (MM = 240 kDa, Ermagram, France), intensively stirred on a mechanical stirrer for 1 hour, 2.4 g of glutamic acid are added and stirred for 3 hours until the chitosan is completely dissolved.

The resulting solution is applied to a layer containing hyaluronate through a die with a gap of 1.5 mm. The film is dried at room temperature for 6 hours. The thickness of the two-layer film is 110 microns.

Example 5. Obtaining a film drug composition containing a steroidal anti-inflammatory agent prednisolone in oleic acid micelles

0.25 g of lecithin with vigorous stirring is dissolved in 200 ml of water. 4.0 g of sodium hyaluronate (MM = 1.6 MDa, CPN, Czech Republic) was dissolved in the resulting lecithin solution. The solution is applied to a glass-free alcohol-free substrate located on a horizontal surface, through a 110 mm wide die with a gap of 2.4 mm. The film is dried at room temperature for 15 hours to a moisture content of 17.5%, then the same solution is re-applied through a die with a gap of 2.4 mm, dried at room temperature for 15 hours. The film thickness is 80 microns.

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Prednisone Solution 60 mg of prednisolone is dissolved in 2 ml of a 2% solution of oleic acid in ethanol.

0.7 ml of a solution of prednisolone in oleic acid with vigorous stirring is emulsified in 200 ml of water, 4.0 g of chitosan is added (MM = 240 kDa, Ennagram, France), stirred on a mechanical stirrer for 1 hour. 2.4 g of glutamic acid are added and stirred for 3 hours until the chitosan is completely dissolved. The resulting solution is applied through a die with a gap of 1.0 mm onto a layer containing hyaluronate. The film is dried at room temperature for 6 hours. The thickness of the two-layer film is 140 microns.

Example 6. Obtaining a film drug composition containing prednisolone sodium phosphate in phosphatidylcholine micelles

2.0 g of sodium hyaluronate (MM = 1.6 MDa, CPN, Czech Republic) is dissolved in 100 ml of water, stirred for 4 hours. The resulting solution is applied to a glass-free alcohol-free substrate located on a horizontal surface through a die with a width of 110 mm with a gap of 2.0 mm. The film is dried at room temperature for 15 hours to a moisture of 16.5%, then a solution containing the physiologically active substance and hyaluronic acid is re-applied through a die with a gap of 2.4 mm, dried at room temperature for 15 hours. Film thickness 70 μm.

A solution of prednisolone sodium phosphate. 25 mg of prednisolone sodium phosphate and 1 g of phosphatidylcholine are dissolved with vigorous stirring in a mixture of 0.4 ml of Transcutol (Transcutol P, Gattefosse, France) and 200 ml of water. The value of R _h micelles in solution is 140-270 nm.

To 4.0 g of chitosan (MM = 240 kDa, Ennagram, France) 200 ml of a solution of prednisolone sodium phosphate are added, mixed on a mechanical 15

stirrer for 1 hour, add 2.4 g of glutamic acid and mix for 3 hours until complete dissolution of chitosan. Get a solution with microwaves of the PWS in chitosan.

The resulting solution is applied to a layer containing hyaluronic acid through a die with a gap of 2.0 mm. The film is dried at room temperature for 6 hours. The thickness of the two-layer film is 150 microns, and the humidity is 17%.

Example 7. Obtaining a film medicinal composition containing prednisolone in the micelles of PEG-modified oil

3.40 g of sodium hyaluronate (MM = 1.6 MDa, CPN, Czech Republic) is dissolved in 200 ml of water with stirring for 4 hours. The solution is applied to a glass-free alcohol-free substrate located on a horizontal surface, through a 110 mm wide die with a gap of 2.4 mm. The film is dried at room temperature for 15 hours to a moisture content of 14%. Film thickness 40 microns.

Prednisone Solution 80 mg of prednisolone is dissolved in a mixture of 0.8 ml of diethylene glycol monoethyl ether (Transcutol P, Gattefosse, France), 1.6 ml of PEG-8 avocado oil (ResPharma, Italy) and 1.6 ml of alcohol. With vigorous stirring, 2 ml of the resulting solution was added dropwise to 400 ml of water. The value of R _h micelles in solution is 150-270 nm.

To 4.0 g of chitosan (MM = 240 to Yes, Ennagram, France), 200 ml of prednisolone solution was added, stirred on a mechanical stirrer for 1 hour, then 2.4 g of glutamic acid was added and stirred for 3 hours until the chitosan was completely dissolved.

The resulting solution containing SPVS micelles is applied to a layer containing hyaluronic acid through a die with a gap of 1.9 mm. The film is dried at room temperature for 6 hours. The thickness of the two-layer film is 110 μm, the humidity is 15%.

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Example 8. Obtaining a film medicinal composition containing prednisolone in the micelles of PEG-modified oil

0.68 g of polyvinylpyrrolidone (Kollidon 90F, BASF, Germany) and 2.72 g of sodium hyaluronate (M = 1.6 MDa, CPN, Czech Republic) are dissolved in 200 ml of a 0.05% solution of chlorhexidine bigluconate with stirring for 4 hours. The resulting solution is applied to a glass-free alcohol-free substrate located on a horizontal surface through a die 110 mm wide with a gap of 2.4 mm. The film is dried at room temperature for 15 hours to a moisture content of 17%, then a solution containing micelles with FAW and hyaluronic acid is re-applied through a die with a gap of 2.4 mm, dried at room temperature for 15 hours. Film thickness 65 microns.

Dexamethasone Solution 80 mg of dexamethasone are dissolved in a mixture of 0.8 ml of diethylene glycol monoethyl ether (Transcutol P, Gattefosse, France), 1.6 ml of PEG-8 avocado oil (ResPharma, Italy) and 1.8 ml of alcohol. With vigorous stirring, 2 ml of the resulting solution was slowly added dropwise to 400 ml of water. The value of R _h micelles in solution is 180-240 nm.

200 ml of dexamethasone solution are added to 4.0 g of chitosan (MM = 240 kDa, Ennagram, France), stirred on a mechanical stirrer for 1 hour, after which 2.4 g of glutamic acid are added and stirred for 3 hours until the chitosan is completely dissolved, get a solution with microns FAV.

A chitosan solution with FAA is applied to a layer containing chlohexidine bigluconate and hyaluronate through a die with a gap of 1.3 mm. The film is dried at room temperature for 6 hours. The thickness of the two-layer film is 110 microns.

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Example 9. A sustained release film drug composition containing NSAIDs of ibuprofen in phospholipid micelles

0.5 g of sodium hyaluronate (MM = 1.9 MDa, Ennagram, France) is dissolved in 50 ml of a 0.1% emulsion of soya lecithin in water with stirring for 6 hours.

A hyaluronate solution is applied to a glass-free alcohol-free glass substrate located on a horizontal surface through a 110 mm wide die with a gap of 0.95 mm. The film is dried at room temperature for 10 hours to a moisture content of 10%. The film thickness is 30 microns.

Ibuprofen solution. To 500 mg of caprylic acid triglyceride (Mygliol Caprylic) add 50 mg of ibuprofen and 50 mg of soya lecithin (C ₁₆ -C ₂₀ ), stirred at 50 ° C for 4 hours until the FAV is completely dissolved. To the mixture with vigorous stirring on a mechanical stirrer, 50 g of water is added in portions. The value of R _h micelles in solution is 110-200 nm.

To 3.0 g of chitosan (MM = 240 kDa, Ennagram, France) and 0.6 g of glycerin (a water-retaining substance) are added to 150 ml of ibuprofen solution, stirred for 1 hour on a mechanical stirrer to swell chitosan, a solution of 1.53 g of maleic acid in 50 ml of water, stirred on a mechanical stirrer for 3 hours until the dissolution of chitosan. The solution is filtered in a press filter under pressure to remove a small amount of insoluble chitosan particles.

A solution of chitosan containing surfactant micelles is applied to the surface of a film based on hyaluronic acid through a die with a gap of 1.5 mm. The film is dried at room temperature and atmospheric pressure for 10 hours. Get a film with a thickness of 65 μm.

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Example 10. A prolonged-release film drug composition containing salicylic acid and the antibiotic azithromycin in oleic acid micelles

50 ml of water, 1 ml of a 20% solution of chlorhexidine bigluconate are added to 1.0 g of sodium hyaluronate (MM = 1.9 MDa, Ennagram, France), stirred at room temperature for 6 hours until the polysaccharide is completely dissolved.

A solution of hyaluronic acid is applied to a glass-free fat-free glass substrate located on a horizontal surface through a 110 mm wide die with a gap of 1.3 mm. The film is dried at room temperature for 10 hours to a moisture content of 12%. The film thickness is 35 microns.

Azithromycin solution. 750 mg of azithromycin dihydrate is added to 5 g of oleic acid and stirred at room temperature for 4 hours until the antibiotic is completely dissolved. 0.5 g of the resulting solution is added with vigorous stirring to 250 g of water. The value of R _h micelles in solution is 130-190 nm.

To 3.0 g of chitosan (MM = 240 kDa, Ennagram, France) and 0.6 g of glycerol are added to 200 ml of azithromycin solution, stirred vigorously on a mechanical stirrer for 1 hour to swell chitosan. 2.07 g of salicylic acid are added to the mixture, stirred on a mechanical stirrer for 3 hours until the chitosan is dissolved. The solution is filtered in a press filter under pressure to remove insoluble chitosan particles.

A solution of chitosan is applied to the surface of a film based on hyaluronic acid through a die with a gap of 1.0 mm. The film is dried at room temperature and atmospheric pressure for 10 hours. Get a film with a thickness of 85 μm.

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Example 11. A prolonged-release film drug composition containing the antibiotic clindamycin and an amino acid in oleic acid micelles

1.0 g of sodium hyaluronate (MM = 1.6 MDa, CPN, Czech Republic) and 0.05 g of leucine hydrochloride are dissolved in 50 ml of water, stirred for 4 hours. The resulting solution is applied to a glass-free alcohol-free substrate located on a horizontal surface through a die 110 mm wide with a gap of 2.4 mm. The film is dried at room temperature for 15 hours to a moisture content of 16%, re-applied the same solution through a die with a gap of 2.4 mm, dried at room temperature for 15 hours. Get a film with a thickness of 55 μm.

Clindamycin phosphate solution. 50 mg of clindamycin phosphate is dissolved in 1 ml of a 2% solution of oleic acid in ethanol. With vigorous stirring, drop 0.5 ml of the resulting solution to 250 ml of water.

To 4.0 g of chitosan (MM = 240 kDa, Ennagram, France), 200 ml of clindamycin phosphate solution was added, stirred on a mechanical stirrer for 1 hour, then 2.4 g of glutamic acid was added and stirred for 3 hours until the chitosan was completely dissolved and obtaining a stable emulsion.

The resulting solution is applied to a layer containing hyaluronate through a die with a gap of 1.0 mm. The film is dried at room temperature for 6 hours. The thickness of the two-layer film is 125 microns, the humidity is 9.7%.

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Example 12. A sustained-release film drug composition containing metronidazole and chlorhexidine in linolenic acid micelles

1.1 g of sodium hyaluronate (MM = 2.6 MDa, Ennagram, France) and 1 ml of a 20% solution of chlorhexidine bigluconate are dissolved in 50 ml of water with stirring for 5 hours. The solution is degassed under vacuum.

A hyaluronate solution containing chlorhexidine is applied to an alcohol-free glass substrate located on a horizontal surface through a 110 mm wide die with a gap of 1.2 mm, and dried at room temperature for 10 hours. Humidity 12.2%. The film thickness is 20 microns.

A solution of metronidazole and chlorhexidine. 0.2 g of linolenic acid and 0.07 g of Transcutol are introduced into 195 ml of water with vigorous stirring. In the emulsion obtained, 200 mg of metronidazole, 5 ml of a 20% solution of chlorhexidine bigluconate are dissolved to obtain a stable emulsion.

3.0 g of chitosan (MM = 192 kDa, Ennagram, France) is mixed with 200 ml of a solution of metronidazole and chlorhexidine, stirred for 1 hour to swell chitosan, 1.7 g of 90% lactic acid are added, and stirred for 3 hours complete dissolution of chitosan. The solution is filtered under pressure to remove microgel particles.

A solution of chitosan is applied to the surface of a film based on hyaluronic acid through a die with a gap of 0.65 mm. The film is dried at room temperature and atmospheric pressure for 10 hours. Get a film with a thickness of 45 μm and a moisture content of 8.9%.

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Example 13. A prolonged-release film drug composition containing metronidazole in sorbitol ester micelles

1.1 g of sodium hyaluronate is added to 50 g of water (MM = 2.6 MDa, Ennagram, France), stirred at room temperature for 6 hours until the polysaccharide is completely dissolved.

A hyaluronate solution is applied to a metal-free fat-free metal substrate located on a horizontal surface through a 110 mm wide die with a gap of 2.1 mm. The film is dried at room temperature for 10 hours to a moisture content of 15.3%. The film thickness is 55 microns.

Metronidazole Solution 80 mg of metronidazole, 0.8 g of sorbitol monolaurate and 200 ml of water are intensively stirred on a magnetic stirrer for 2 hours. The value of R _h micelles in solution is 140-210 nm. The solution is degassed under vacuum.

To 3.0 g of chitosan (MM = 192 kDa, Ennagram, France) was added to 200 ml of metronidazole solution, stirred for 1 hour on a mechanical stirrer to swell chitosan, 1.7 g of 90% lactic acid was added, and stirred until the chitosan was dissolved. The solution is filtered under pressure to remove insoluble chitosan particles in a press filter.

A solution of chitosan is applied to the surface of a film based on hyaluronic acid through a die with a gap of 0.65 mm. The film is dried at room temperature and atmospheric pressure for 10 hours. Get a film with a thickness of 85 μm.

Example 14. A prolonged-release film drug composition containing metronidazole in phosphatidylcholine micelles

1.0 g of sodium hyaluronate (MM = 2.6 MDa, Ennagram, France), 0.2 g of glycerol are dissolved in 50 ml of metronidazole solution. The solution is degassed under vacuum.

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A hyaluronate solution is applied to a glass-free alcohol-free glass substrate located on a horizontal surface through a 110 mm wide die with a gap of 1.1 mm, and the film is dried at room temperature for 10 hours to a moisture content of 14.5%. The film thickness is 20 microns.

Metronidazole Solution 250 ml of water are added to 0.5 g of phosphatidylcholine (Lipoid S 100), stirred on a magnetic stirrer at 70 ° C for 30 minutes until an emulsion is obtained, the solution is cooled to room temperature, 0.2 g of metronidazole is added, and stirred on a magnetic stirrer until complete dissolution. The value of R _h micelles in solution is 130-250 nm.

3.0 g of chitosan (MM = 192 kDa, Ennagram, France) is suspended in 200 ml of metronidazole solution, stirred on a mechanical stirrer for 1 hour to swell chitosan. 1.7 g of 90% lactic acid are added to the mixture, stirred for 3 hours until the chitosan is dissolved. The solution is filtered under pressure to remove microgel particles.

A chitosan solution is applied to the surface of the hyaluronate-based film through a die with a gap of 0.65 mm. The film is dried at room temperature and atmospheric pressure for 10 hours. Get a film with a thickness of 45 μm, a moisture content of 14.3%.

Example 15. A sustained release film drug composition containing the antimicrobial agent tinidazole, emulsifier and micelle former caprylic acid

1.0 g of sodium hyaluronate (MM = 2.6 MDa, Ennagram, France) is dissolved in 50 ml of water. The solution is degassed under vacuum.

On an alcohol-free glass substrate located on a horizontal surface, through a 110 mm die with a gap of 23

A 1.5 mm solution of hyaluronate is applied. The film is dried at room temperature for 10 hours to a moisture content of 13.2%. Film thickness 40 microns.

Tinidazole solution. 85 mg of tinidazole FAV, 250 ml of water, 0.150 mg of diethylene glycol monoethyl ether (Transcutol P, Gattefosse, France) and 0.25 g of caprylic acid are mixed until a stable emulsion is obtained.

To 3.0 g of chitosan (MM = 192 kDa, Ennagram, France), add 200 ml of tinidazole solution, stirred on a mechanical stirrer for 1 hour to swell chitosan. 1.7 g of 90% lactic acid are added to the mixture, stirred for 3 hours until the chitosan is dissolved. The solution is filtered in a press filter under pressure to remove insoluble particles.

On the surface of the film based on hyaluronic acid, a chitosan solution containing a surfactant is applied through a die with a gap of 0.85 mm. The film is dried at room temperature and atmospheric pressure for 10 hours. Get a film with a thickness of 70 μm.

Example 16. A sustained-release film drug composition containing metronidazole and ursolic acid in lecithin micelles

196 g of water is added to 4 g of sodium hyaluronate (MM = 2.6 MDa, Ennagram, France), stirred with a mechanical stirrer for 5 hours until the sodium hyaluronate is completely dissolved. A 2% solution of sodium hyaluronate with a viscosity of 63600 cPs (Brookfield RVDV-II + viscometer, spindle No. 5, 2 rpm, 25 ° C) and pH = 7.0 are obtained.

40 g of hyaluronate solution is applied to a glass substrate with a restriction ring with an area of S = 201 cm ² located on a horizontal surface, and evenly distributed on the surface of the substrate. The film is dried at room temperature and 24

atmospheric pressure for 8 hours to a moisture content of 17.2%. Get a film with a thickness of 45 μm.

The solution of the mixture of FAV. To 100 ml of water, 20 mg of metronidazole and 110 mg of lecithin, 5 mg of brilliant blue dye, a solution of 25 mg of ursolic acid sodium salt in 20 ml of water, 2 ml of a 20% solution of chlorhexidine bigluconate are added, stirred vigorously for 1 hour. The value of R _h micelles in solution is 170-230 nm.

2.2 g of chitosan (MM = 192 kDa, Ennagram) are suspended for 1 hour with 100 ml of a solution of the FAV mixture, 4 ml of acetic acid are added, and stirred with a mechanical stirrer for 5 hours. The solution is filtered in a press filter under pressure to remove insoluble particles. A solution with a viscosity of 217 cPs (Happler viscometer, 20 ° C) is obtained.

On top of the dried layer of sodium hyaluronate on a glass substrate with a restrictive ring, 22 g of a solution of chitosan is applied and evenly distributed over the surface. The film is dried at room temperature and atmospheric pressure for 4 hours. Get a film with a thickness of 130 microns and a moisture content of 18.3%.

Example 17. A prolonged-release film drug composition containing ornidazole, tetracycline, prilocaine in linolenic acid micelles

2.0 g of sodium hyaluronate (MM = 2.6 MDa, France) is added 100 ml of distilled water, stirred with a mechanical stirrer for 5 hours until the sodium hyaluronate is completely dissolved. Get a 2% solution of sodium hyaluronate with a viscosity of 63600 cps (Brookfleld RVDV-II + viscometer, spindle No. 5, 2 rpm, 25 ° C) and pH = 7.0.

On a glass substrate with a restrictive ring with an area of S = 201 cm ² located on a horizontal surface, 25

apply 45 g of hyaluronate solution, evenly distributed on the surface of the substrate. The film is dried at room temperature and atmospheric pressure for 8 hours to a moisture content of 17.6%. Get a film with a thickness of 45 μm.

FAV solution. 0.25 g of ornidazole is dissolved in 1.7 g of linolenic acid, 200 ml of water, 0.4 g of tetracycline hydrochloride, 0.05 g of prilocaine hydrochloride are added with vigorous stirring, stirred vigorously for 1 hour, and a stable emulsion is obtained. The value of R _h micelles in solution is 190-270 nm.

To 2.2 g of chitosan (MM = 192 kDa, Ennagram, France) add 50 ml of a 4% aqueous solution of acetic acid, 20 ml of a solution of FAV, mix with a mechanical stirrer for 5 hours. Get a solution of chitosan, with a viscosity of 217 cPs (Happler's viscometer, 20 ° C) containing micronized FAV.

On top of the dried layer of sodium hyaluronate on a glass substrate with a restrictive ring, 20 g of a solution of chitosan is applied and evenly distributed over the surface. The film is dried at room temperature and atmospheric pressure for 4 hours. Get a film with a thickness of 85 μm.

Example 18. A prolonged-action film drug composition containing ornidazole, chlorhexidine and vitamin B6 in linolenic acid micelles

To 2.6 g of sodium hyaluronate (MM = 2.6 MDa, Ennagram, France) and 1 g of glycerol are added 195 ml of distilled water, stirred with a mechanical stirrer for 5 hours until the hyaluronate is completely dissolved. Obtain a 1.3% solution of sodium hyaluronate with a viscosity of 34550 cps (Happler viscometer, 20 ° C).

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65 g of hyaluronate solution is applied to a glass substrate with a restriction ring with an area of S = 201 cm ² located on a horizontal surface, and evenly distributed on the surface of the substrate. The film is dried at room temperature and atmospheric pressure for 8 hours to a moisture content of 16.5%. Get a film with a thickness of 45 μm.

Orgidazole solution. 12 mg of ornidazole is dissolved in a mixture of 80 mg of linolenic acid and 10 mg of Transcutol, 20 ml of water are added with vigorous stirring. The value of R _h micellar particles in solution is 140-255 nm.

To 2.2 g of chitosan (MM = 192 kDa, Ennagram, France) 90 ml of a 2% aqueous solution of acetic acid, 10 ml of a solution of ornidazole, 1 ml of a 5% solution of pyridoxine hydrochloride are added, stirred with a mechanical stirrer for 5 hours A 2% chitosan solution containing FAW micelles with a viscosity of 217 cPs (Happler viscometer, 20 ° C) is obtained.

On top of the dried layer of sodium hyaluronate on a glass substrate with a restrictive ring with an area of 201 cm ² put 25 g of a solution of chitosan with FAV and evenly distributed over the surface. The film is dried at room temperature and atmospheric pressure for 10 hours. Get a film with a thickness of 105 μm, a moisture content of 14.4%.

Example 19. A prolonged-release film drug composition containing metronidazole, benzalkonium chloride and amino acids in oleic acid micelles

95 ml of distilled water are added to 1.3 g of sodium hyaluronate (MM = 2.6 MDa, Ennagram, France), stirred with a mechanical stirrer for 5 hours until the hyaluronate is completely dissolved 27

sodium. Obtain a 1.3% solution of sodium hyaluronate with a viscosity of 11480 cps (Happler's viscometer, 20 ° C).

65 g of hyaluronate solution is applied to a polymer substrate with a restriction ring with an area of S = 201 cm ² located on a horizontal surface, and evenly distributed on the surface of the substrate. The film is dried at room temperature and atmospheric pressure for 8 hours to a moisture content of 17.7%. Get a film with a thickness of 45 μm.

FAV solution. 300 mg of metronidazole and 60 mg of Transcutol are dissolved in 400 mg of oleic acid, 100 ml of water containing 20 mg of benzalkonium chloride, 20 mg of glycine, 20 mg of arginine hydrochloride and 20 mg of lysine hydrochloride are added with vigorous stirring. A stable emulsion of FAW is obtained. The value of R _h particles in solution is 130-250 nm.

To 2.2 g of chitosan (MM = 192 kDa, Ennagram, France) was added 50 ml of a 5% aqueous solution of acetic acid, 50 ml of a surfactant solution and 1 mg of brilliant blue dye, stirred with a mechanical stirrer for 5 hours. A 2% solution of chitosan is obtained with FAW micelles, with a viscosity of 217 cPs (Geppler's viscometer, 20 ° C).

On top of the dried layer of sodium hyaluronate on a glass substrate with a restrictive ring, 20 g of a solution of chitosan is applied and evenly distributed over the surface. The film is dried at room temperature and atmospheric pressure for 10 hours. Get a film with a thickness of 110 μm, a moisture content of 14.0%.

Example 20. A prolonged-release film drug composition containing the antiseptic chlorhexidine bigluconate in phosphatidylcholine micelles

To 2 g of sodium hyaluronate (MM = 2.6 MDa, Ennagram, France) and 400 mg of phosphatidylcholine (LipoidE 80 S), 196 ml of distilled 28

water, stirred with a mechanical stirrer for 5 hours until complete dissolution of sodium hyaluronate. A 2% sodium hyaluronate solution with a viscosity of 53400 cps (Brookfield RVDV-II + viscometer, spindle No. 5, 2 rpm, 25 ° C) and pH = 7.0 are obtained.

On a glass substrate with a set limiting ring area of 143 cm ^2, disposed on a horizontal surface is applied to 20 g of hyaluronate solution containing lecithin, distributed uniformly over the substrate surface. The film is dried at room temperature and atmospheric pressure for 6 hours to a moisture content of 18.0%. Get a film with a thickness of 25 μm.

To 2.2 g of chitosan (MM = 240 kDa, Ennagram, France) 105 ml of a 2% aqueous solution of acetic acid, 0.25 g of phosphatidylcholine and 5 ml of a 20% solution of chlorhexidine bigluconate are added, stirred vigorously with a mechanical stirrer for 5 hours, filtered through two layers of a synthetic filter under nitrogen pressure. Get a 2% solution of chitosan containing micelle FAV.

On top of the dried layer of sodium hyaluronate on a glass substrate with a restrictive ring with an area of 143 cm, 24 g of a solution of chitosan containing PAV micelles is applied and uniformly distributed over the surface. The film is dried at room temperature and atmospheric pressure for 7 hours. Get a film with a thickness of 70 μm.

Example 21. A prolonged-release film drug composition containing gentamicin sulfate, dexpanthenol and anesthetics in phosphatidylcholine micelles

To 1 g of sodium hyaluronate (MM = 2.6 MDa, Ennagram, France) and 0.5 g of glycerol are added 100 ml of distilled water, stirred with a mechanical stirrer for 5 hours until the sodium hyaluronate is completely dissolved. Obtain a 1% solution of sodium hyaluronate with a viscosity of 29

53400 cps (Brookfield RVDV-II + viscometer, spindle No. 5, 2 rpm, 25 ° C) and pH = 7.0.

On a glass substrate with a restriction ring with an area of S = 143 cm ² located on a horizontal surface, 36 g of a solution of hyaluronate are applied, they are evenly distributed on the surface of the substrate. The film is dried at room temperature and atmospheric pressure for 6 hours to a moisture content of 17.7%. Get a film with a thickness of 35 μm.

FAV solution. 0.5 g of phosphatidylcholine, 0.5 g of dexpanthenol, 5 ml of a 4% solution of gentamicin sulfate, 1 g of lidocaine, 0.1 g of prilocaine are dissolved in 95 ml of water, stirred vigorously for 3 hours to obtain a solution containing FAV micelles.

To 2.2 g of chitosan (MM = 240 to Yes, Ennagram, France), 106 g of a 2% aqueous solution of acetic acid are added, stirred with a mechanical stirrer for 5 hours. The solution is filtered through two layers of a synthetic filter under nitrogen pressure. To 50 g of the resulting solution add 50 ml of a solution of FAV. The solution was stirred for 3 hours. Get 1% solution of chitosan containing micelles of FAV.

On top of the dried layer of sodium hyaluronate, on a glass substrate with a restrictive ring, 24 g of a solution of chitosan containing FAW micelles is applied uniformly distributed over the surface. The film is dried at room temperature and atmospheric pressure for 8 hours. Get a film with a thickness of 65 μm, a moisture content of 11%.

Example 22. A prolonged-release film drug composition containing amino acids, vitamin B6, metronidazole and chlorhexidine bigluconate in sorbitol ester micelles

FAV solution. 0.4 g of sorbitol monolaurate, 0.25 g of metronidazole, 1.5 ml of a 0.5% aqueous solution of arginine hydrochloride, 3.5 ml of 5% aqueous 30

a solution of pyridoxine hydrochloride, 1 ml of a 20% aqueous solution of chlorhexidine is dissolved in 190 ml of water with vigorous stirring. A stable emulsion of FAW is obtained.

To 4.0 g of chitosan (MM = 192 kDa, Ennagram, France) and 0.40 g of sorbitol monolaurate, 196 ml of 0.75% aqueous succinic acid solution are added, stirred using a magnetic stirrer for 5 hours, centrifuged for 5 min at 5500 rpm to remove air bubbles and sedimentation of insoluble chitosan particles. Get a solution with pH = 5 and a dynamic viscosity of 7500 MPa · s (Happler viscometer, 20 ° C). 30 g of the resulting solution is mixed with 20 ml of a FAV solution with vigorous stirring. The solution is applied to a clean, alcohol-degreased glass substrate by slip casting using a die (pre-degreased with medical alcohol) with a width of PO mm, a gap of 1.5 mm. Leave to complete drying of the layer. Get a film with a thickness of 55 μm.

To 1 g of sodium hyaluronate (MM = 2.6 MDa, Ennagram, France) and 0.40 g of sorbitol monolaurate, 100 ml of a 0.0006% solution of succinic acid in water are added, stirred with a mechanical stirrer for 5 hours until the hyaluronate is completely dissolved . A 1% sodium hyaluronate solution with a viscosity of 29,800 cps is obtained (Brookfield RVDV-II + viscometer, spindle No. 5, 2 rpm) and pH = 6.5.

A solution of sodium hyaluronate is applied by slip casting on top of a dried layer based on chitosan and FAV, using a die (previously defatted with medical alcohol) with a width of PO mm, a gap of 0.95 mm. Left until the film completely dried. The thickness of the two-layer film is 85 microns.

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Example 23. A prolonged-release film drug composition containing metronidazole, vitamin B6, lidocaine, amino acids in micelles of lecithin and linolenic acid

A mixture of 3.9 g of sodium hyaluronate with MM = 330 kDa (WIRUD) and 11.5 g of sodium hyaluronate with MM = 2.6 MDa (Ennagram) with 3.71 g of polyvinylpyrrolidone (Kollidon 90F), 90 mg of peppermint oil and 600 ml of water is stirred on a mechanical stirrer for 3 hours until the components are completely dissolved, and then degassed under vacuum.

A hyaluronate solution is applied to a polymer-coated metal-free polymer coated substrate on a horizontal surface through a 110 mm wide die with a gap of 2.5 mm. The film is dried at room temperature for 10 hours to a moisture content of 15.8%. After the layer has dried, the same solution is re-applied using a die with a gap of 2.5 mm. The film is dried at room temperature for 10 hours to a moisture content of 11.8%. The film thickness is 100 microns.

FAV solution. To 200 mg of metronidazole, 20 mg of pyridoxine hydrochloride, 15 mg of lidocaine hydrochloride, 25 mg of alanine, 25 mg of glycine hydrochloride, 30 mg of proline, 20 mg of valine, 15 mg of arginine hydrochloride, 0.7 g of soya lecithin, 0.6 g of glycerol and 15 mg of peppermint oil is added 100 ml of water, stirred on a mechanical stirrer for 1 hour until a stable emulsion of FAW is obtained.

3.5 g of chitosan (MM = 192 kDa, Ennagram, France) are suspended in 100 ml of a FAV solution, a solution of 2.37 g of succinic acid in 30 g of water is added, and stirred on a mechanical stirrer for 3 hours until the chitosan is dissolved. The solution was filtered under vacuum to remove microgel particles.

On the surface of the film based on hyaluronate, a solution of chitosan containing micelles of surfactant is applied. The film is dried at room 32

temperature and atmospheric pressure for 10 hours. Get a film with a thickness of 145 microns. The moisture content of the film is 14.1%.

Example 24. A prolonged-release film drug composition containing metronidazole, clindamycin, lidocaine and amino acids in lecithin micelles

1 g of sodium hyaluronate (MM = 2.6 MDa, Ennagram, France) and 0.2 mg of glycerol are dissolved in 100 ml of water, stirring with a mechanical stirrer for 5 hours until the hyaluronate is completely dissolved. Get a 1% solution of sodium hyaluronate with a viscosity of 29,900 cps (Brookfield RVDV-II + viscometer, spindle No. 5, 2 rpm) and pH = 6.5.

A hyaluronate solution is applied to a glass-free alcohol-free glass substrate located on a horizontal surface through a 110 mm wide die with a gap of 1.95 mm. The film is dried at room temperature for 10 hours. After the layer has dried, the same solution is re-applied using a die with a gap of 1.95 mm. The film is dried at room temperature for 10 hours to a moisture content of 13.8%. The film thickness is 85 microns.

To a mixture of 3.52 g of chitosan (MM = 192 kDa, Ennagram, France), 2.37 g of succinic acid, 36 mg of pyridoxine hydrochloride, 125 mg of alanine, 310 mg of glycine hydrochloride, 155 mg of proline, 31 mg of valine, 185 mg of arginine hydrochloride, 54 mg of aspartame, 1.26 g of soya lecithin, 1.0 g of glycerin and 115 mg of peppermint oil add 130 ml of water, mix intensively on a mechanical stirrer for 3 hours until the chitosan is dissolved and a stable emulsion is obtained. The solution is filtered in a filter press under pressure to remove insoluble particles.

On the surface of the film based on hyaluronic acid, a solution of chitosan containing micelles of surfactant is applied. The film is dried at room 33

temperature and atmospheric pressure for 10 hours. Get a film with a thickness of 140 μm. Film moisture 14%.

Example 25. A prolonged-action film drug composition containing PBS prednisolone in lecithin and caprylic acid micelles applied to a non-woven fabric

300 ml of water are added to 4.5 g of sodium hyaluronate (MM = 1.6 MDa, CPN, Czech Republic) and stirred at room temperature for 12 hours until the polysaccharide is completely dissolved.

A hyaluronate solution is applied to a glass-free fat-free glass substrate located on a horizontal surface through a 110 mm wide die with a gap of 2.5 mm. The film is dried at room temperature for 10 hours to a moisture content of 20.0%. Film thickness 25 microns.

FAV solution. 62.5 mg of prednisone, 100 mg of soya lecithin, 500 mg of caprylic acid triglyceride (Mygliol caprylic) are intensively mixed with 50 ml of water to obtain a stable emulsion.

To 4.5 g of chitosan (MM = 240 kDa, Ennagram, France) and 2.34 g of aspartic acid are added to 250 ml of water, stirred on a mechanical stirrer for 3 hours until the chitosan is completely dissolved. 50 ml of a FAV solution are added to the solution, stirred for 40 minutes. The solution is filtered in a press filter under pressure.

A solution of chitosan with FAW micelles is applied to the surface of the hyaluronate-based film through a die with a gap of 2.1 mm, the layer is not dried, a non-woven fabric is applied on it (100% viscose, density 50 g / m ² ), pressed. The composition is dried at room temperature and atmospheric pressure for 10 hours to a moisture content of 14%.

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Example 26. A sustained release film drug composition applied to a nonwoven web containing an immunomodulator imiquimod, an amino acid in oleic acid micelles

A solution of 1.3% solution of sodium hyaluronate in water is applied to a glass-free fat-free glass substrate located on a horizontal surface through a 110 mm wide die with a gap of 2.5 mm. The film is dried at room temperature for 10 hours to a moisture content of 20.0%. The film thickness is 45 microns.

Imiquimod solution. To 2 g of oleic acid, 300 mg of imiquimod is added and stirred at room temperature for 24 hours until the FAV is completely dissolved. To 300 ml of water with vigorous stirring, 200 mg of a solution of imiquimod in oleic acid is added. The value of R _h particles in solution is 130-240 nm.

To 5.5 g of chitosan (MM = 240 kDa, Ennagram, France) and 2.9 g of aspartic acid are added to 200 ml of water, stirred vigorously until the chitosan is dissolved. The solution is filtered in a press filter under pressure to remove insoluble particles. 50 g of the resulting solution with vigorous stirring is mixed with 40 ml of imiquimod solution.

A solution of chitosan is applied to the surface of the hyaluronate-based film through a die with a gap of 2.1 mm, the layer is not dried, a pre-moistened non-woven fabric is applied (30% viscose, 70% polyester, density 50 g / m ² ), pressed and smoothed. The composition is dried at room temperature and atmospheric pressure for 10 hours.

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Example 27. A prolonged-action film drug composition containing PPS prednisone in lecithin and caprylic acid micelles applied to an activated carbon fabric

4.5 g of sodium hyaluronate (MM = 1.6 MDa, CPN, Czech Republic) are added to 300 ml of water with vigorous stirring, stirred at room temperature for 6 hours until the polysaccharide is completely dissolved. A hyaluronate solution is applied to a glass-free fat-free glass substrate located on a horizontal surface through a 110 mm wide die with a gap of 2.5 mm. The film is dried at room temperature for 10 hours to a moisture content of 18.0%. The film thickness is 45 microns.

Prednisone Solution 62.5 mg of prednisolone, 100 mg of lecithin, 500 mg of caprylic acid triglyceride (MygliolCaprylic) are intensively mixed for 60 minutes to obtain a stable emulsion. The value of R _h micelles in a solution of 180-290 nm

To 4.5 g of chitosan (MM = 240 kDa, Ennagram, France) and 2.34 g of aspartic acid are added to 250 ml of water, stirred on a mechanical stirrer for 3 hours until the chitosan is completely dissolved. 50 ml of prednisolone solution is added to the solution, 40 minutes are stirred vigorously. The solution is filtered in a press filter under pressure.

A solution of chitosan with FAW micelles is applied to the surface of the hyaluronate-based film through a die with a gap of 2.5 mm, the layer is not dried, an activated carbon fabric (ZorflexFM30K) is applied to it, pressed and smoothed. The composition is dried at room temperature and atmospheric pressure for 10 hours.

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Example 28. A film composition of prolonged action containing an immunomodulator imiquimod in oleic acid micelles deposited on an activated carbon fabric

A 1.5% hyaluronate solution (MM = 1.6 MDa, CPN, Czech Republic) is applied to an alcohol-free glass substrate located on a horizontal surface through a 110 mm wide die with a 1.4 mm gap. The film is dried at room temperature for 10 hours to a moisture content of 19.2%. Film thickness 25 microns.

Imiquimod solution. To 2 g of oleic acid, 300 mg of imiquimod is added and stirred at room temperature for 24 hours until the FAV is completely dissolved.

4.5 g of chitosan (MM = 240 kDa, Ennagram, France), 2.34 g of aspartic acid are added to 300 g of water, stirred on a mechanical stirrer for 3 hours until complete dissolution of chitosan, with vigorous stirring, 0.5 g of imiquimod solution is added in oleic acid. The solution is filtered under pressure to remove insoluble chitosan particles in a press filter.

A solution of chitosan with a surfactant is applied to the surface of the hyaluronate-based film through a die with a gap of 1.75 mm, then an activated carbon fabric (ZorflexFM10) is applied, pressed and leveled. The composition is dried at room temperature and atmospheric pressure for 10 hours.

Example 29. The study of the solubility of the chitosan complex in aqueous solutions of organic acids.

Studies of the solubility of the chitosan complex in aqueous solutions of organic acids were carried out in the range of polysaccharide concentrations from 0.02 to 5.0 wt%. A portion of chitosan is added to water, stirred for 2 hours, and organic acid is added in portions 37

or its solution, stirred for 1 hour to form a complex of chitosan with acids, and if chitosan is not completely dissolved, add the next portion of the acid. Determination of the solubility of the complex is carried out on the basis of a visual assessment of the transparency of the solution. The degree of deacetylation of chitosan is in the range of 80–95%, and the molecular weight in the range of 150–300 kD does not affect the quantitative characteristics of the solubility of the complex. The results are presented in Table 1.

Example 30. A study of the sustained release of a physiologically active substance from film pharmaceutical compositions

The prolonged release of physiologically active substances from film pharmaceutical compositions was studied using a USP Apparatus # 5 (Varian, USA) using a transdermal sandwich containing a skin-simulating synthetic membrane Strat-M (Merck-38

Millipore, Germany) and film composition samples of Examples 12, 14 and 15 containing metronidazole. The sandwich was placed at the bottom of a thermostatically controlled beaker (T = 37.0 ± 0.5 ° C), and the working medium was 0.05 M phosphate buffer with pH = 6.8. The release of metronidazole from the films was evaluated by UV spectroscopy at a wavelength of 320 nm using a VarianCary 50 spectrophotometer (Varian, USA).

As follows from Table 2, film medicinal compositions have a prolonged release of a physiologically active substance.

Example 31. A study of the swelling of film medicinal compositions in water

For the study used film medicinal compositions according to Examples 1-7, 10, 23, 24. The compositions show a high swelling in water.

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Example 32. The study of the permeability of moisture vapor through the film composition

For the study used the film drug composition according to Examples 10 and 13. The experiment was carried out at 20 ° C for 24 hours. The contact surface area of the film is 3 cm ² . The mass of the film at the beginning of the test is 43.0 ± 4.2 mg. About one experiment, the permeability of the film was determined by exposing the hyaluronate layer to air saturated with water vapor, and in the other, the chitosan layer. According to the results of the mass gain measurements, K _p , mg / cm ² was calculated, a coefficient characterizing the amount of water that penetrated through the surface unit of the film composition (Table 4) ..

40

The data confirm the high permeability of moisture vapor through the composition.

Example 33. A study of the effectiveness of prolonged-release film pharmaceutical compositions for the treatment of skin lesions caused by laser irradiation.

The effect of prolonged-release film drug compositions obtained according to Examples 14 and 24 on the healing process of laser burn wounds of the skin of the back of female rats was investigated.

The studies were carried out on female Wistar rats weighing 200 ÷ 250 g (laboratory animal nursery "Rappolovo" RAMS). Animals 41

kept on unlimited feed intake (standard diet for laboratory rats K-120, Inform-feed, Russia) and water.

Before the start of the study, animals were divided into 3 groups (2 experimental and 1 control) by randomization. Each group included 12 rats.

The animals underwent depilation of a portion of the skin of the back of the thoracic region with a size of about 4 cm ² , which was treated with a Lugol solution to increase the skin's absorption capacity for laser irradiation.

Round-shaped laser burns without violating the integrity of the skin with the formation of coagulation necrosis in the center of the wound were caused using a Lakhta-Milon semiconductor laser apparatus (Milon, Russia). The transmission of radiation to the object was carried out using an optical fiber connected to a defocusing nozzle. The radiation wavelength is 970 nm, the radiation power is 7 W, the continuous generation mode, the exposure time is 10 s. Power density 223 W / cm ² .

The studied film compositions were applied to the wound surface of the skin after wetting it with physiological saline, allowed to dry in air for 10 minutes, after which the animal was returned to the cell. In the control group, saline was applied to the wounds. The films were applied for 21 days, starting from the day the skin was damaged by the laser. New films were glued to the wounds only if they were absent during daily visual examination of animals.

Using a CCD-camera, back wounds were photographed on an IBM compatible personal computer and processed using the Video-Test Dynamics 4.0 software package (ISTA Ltd., Russia). The wound surface area was determined as the area of the secondary 42

a scab that forms at the site of the primary lesion and the swelling zone 24 hours or more after skin damage.

For histological examination, pieces of skin with a wound surface were taken during autopsy, fixed in 10% neutral formalin (pH = 7.2), and after dehydration, paraffin was filled. Sections of a thickness of 5 μm were prepared from paraffin blocks. Staining was performed with hematoxylin-eosin.

On the 7th day of the experiment, the water content in the tissues was determined by the method of titration according to K. Fisher.

The occurrence of complications of the wound process, the time of complete cleansing of the wound surface from crusts (time of epithelization) were recorded.

Statistical analysis of the results was performed using the StatSoftStatistica v6.0 software package and the MSExcel 2003 package.

The significance of the differences in the parameters was estimated using Student's t-test, Fisher's exact method (TMF). Values p <0.05 were considered significant.

The application of film medicinal compositions according to Examples 14 and 24 from an early date significantly accelerates the healing of laser burn wounds in female Wistar rats with the development of a formed scar covered with stratified squamous epithelium by day 21, moisturizes the wound surface and reduces its infection (Table 5-9 )

The average time of complete epithelization of the wound surface was significantly reduced by 13%. In the control group, by day 21, inflammatory infiltration of the connective tissue necrosis formed at the site remained.

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Example 34. The study of the effectiveness of medicinal compositions of prolonged action for the treatment of linear skin wounds

The experiments were performed on outbred male rats of the Sprague-Dawley line with a body weight of 190 + 210 g (Rappolovo kennel, Russian Academy of Sciences).

We studied the effectiveness of film compositions according to examples 17, 18, 20, 21. Each group included 10 animals.

Animals under chloroform anesthesia applied a linear wound 5 cm long in the longitudinal direction on their backs to their own fascia. The wound was moistened with saline. The edges of the wound brought together, put three sutures with threads at an equal distance from each other.

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The preparations were applied during suturing and daily on the surface of a moistened wound as the films resorbed for 7 days.

A separate group of animals did not receive treatment and served as a negative control (n = 10).

Within 7 days, the dynamics of the extinction of signs of the inflammatory process was evaluated. On day 8 after application of the wound, the suturing threads were removed, the animals were euthanized. Wound tensometry was performed. The mass of the load required to rupture the tissue testified to the maturity and strength of the formed scar.

Statistical processing was performed using the software packages StatSoftStatistica and Microsoft Excel. Differences between the samples were evaluated with Student's t-test. Values p <0.05 were considered significant.

Film wound coverage contributed to a decrease in the number of rats with wound discharge (Table 10-11).

The film compositions were well retained on the wound surface, forming a protective layer that promotes the regeneration and acceleration of epithelization and scarring.

The use of compositions contributed to a twofold increase in the strength of the scar, its maturation.

The studied film medicinal compositions have an anti-inflammatory effect and contribute to the formation of a mature connective tissue scar earlier than in the control group of animals.

Table 10. The effect of film medicinal compositions on the severity of inflammation.

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Example 35. A study of the effectiveness of film medicinal compositions for the treatment of gingivitis and periodontitis in patients

The study involved 45 patients aged 18 to 25 years, divided into 3 groups according to the diagnosis:

1 group (gingivitis). For the treatment, a sustained release film composition according to Example 23 was used.

2 group (periodontitis). For the treatment, a sustained release film composition according to Example 24 was used.

Group 3 (control) - the absence of clinically visible inflammation of the oral mucosa and periodontium.

Patients did not have chronic somatic diseases, a history of allergic reactions, or clinical signs of acute respiratory diseases during the experiment.

The course of treatment was 7 days. On days 1, 3, and 7, saliva, blood, and oral fluid of the gingival sulcus were taken, the hygiene index OHI-S (JC Green, JR Vermillion, 1969), and the papillo-marginal alveolar index РМА (Massler, Schour 1949, modified by Parma) were determined , 1960), periodontal index PI (Russel, 1956).

Biochemical identification of microorganisms was carried out using the test system ANAERotest and STREPTotest (Lachema, Czech Republic). The content of secretory immunoglobulin A (IglA), lactoferrin (LF), lysozyme (LZ), C - reactive protein (CRP), secretory phospholipase A2 (sPLA2), IgA, IgG, IgM immunoglobulins was determined in the oral fluid.

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Statistical data processing was carried out according to the standard software package Statistica 6.0. The critical level of reliability of the null statistical hypothesis is p≤0.05.

Shown (Table 12-14) the clinical effectiveness of the film compositions in 100% of cases of observation, the positive dynamics of clinical indices in the treatment process. The activity of the compositions was from medium to high (24–30 (S)), their use in the course of up to 7 days significantly reduced the total number of microorganisms in smears of the oral mucosa, but did not cause a violation of the natural microbiocenosis in the oral cavity.

The anti-inflammatory effect is confirmed by clinical, biochemical and microphysiological indicators, a decrease in the tension of local immunity. The maximum positive shift was observed after a three-day course of treatment.

Thus, it was shown that the prolonged-release film pharmaceutical compositions of Examples 23 and 24 have anti-inflammatory and antimicrobial effects and can be used in the complex treatment of dental patients with inflammatory diseases of the periodontium and oral mucosa.

Claims (6)

1. Wound cover for the treatment of lesions of the mucous membranes and skin in the form of a multilayer film containing hyaluronic acid or its esters, a chitosan-containing component, as well as physiologically active and auxiliary substances, characterized in that the layer adjacent to the wound is made of hyaluronic acid or its derivatives, and the outer layer is made of a complex of chitosan with at least one organic acid with a chain length of C ₂ -C ₇ , and physiologically active substances are contained in the coating in the form of micelles. 2. The wound cover according to claim 1, characterized in that as physiologically active substances it contains at least one substance from the group of antibiotics, antiseptics, anti-inflammatory drugs, analgesics, anesthetics, immunomodulators, vitamins, amino acids fungicides, vitamins, and amino acids. 3. The wound cover according to claim 1, characterized in that the micelles are made of carboxylic acids with a chain length of C ₈ -C ₂₆ or their triglycerides. 4. The wound cover according to claim 1, characterized in that the micelles are made of phospholipids. 5. A wound dressing according to claim 1, characterized in that it contains plasticizers, taste regulators, colorants, preservatives or moisture-retaining agents as auxiliary substances. 6. A wound dressing according to claim 1, characterized in that it further comprises a substrate.

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