RU2578969C1 - Agent for treating damage to external body tissues (versions) and method of producing same - Google Patents

Abstract

FIELD: medicine; pharmacology.

SUBSTANCE: described is agent for treating damages body tissues and to method for preparing it. Device is made in form of multilayer film, in which one of layers contains complex of chitosan with at least one carboxylic acid with chain length C₂-C₇, and layer adjoining wound, contains hyaluronic acid or derivatives thereof, wherein physiologically active substances contained in form of micelles and are initially in layer containing complex of chitosan in traumatic injuries or in both layers. Agent is obtained by introduction of micelles containing physiologically active or auxiliary substances in solution selected polysaccharide, successive formation of each separate layer of solutions polysaccharide containing micelles and drying layer till moisture content is 10-35% then film filmed from substrate.

EFFECT: agent possesses prolonged action.

14 cl, 11 tbl, 36 ex

Description

The invention relates to the field of medicine and pharmacology, in particular to composite film materials for the treatment of wounds and other injuries of the external tissues of the body based on biodegradable polymers exhibiting antitumor, wound healing, anti-inflammatory and antimicrobial properties, and a method for their preparation. In particular, the invention relates to sustained release film compositions 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 carcinogens and pathogenic microflora into the body. Violation of the anatomical integrity and / or functional activity of the epithelium as a result of exposure to carcinogens and the development of skin cancer, traumatic lesions, chronic diseases, infectious and inflammatory processes, etc. leads to a weakening of the protective function of the epithelium in the affected area, contributes to the development of diseases and its destruction.

The physiological process of wound healing is aimed at restoring the epithelium, reconstructing the damaged extracellular matrix [Vowden K., Vowden R. 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 restriction 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 A., 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, P.1-6]. The composition may contain antimicrobial agents, for example silver [Flores A. Wounds Essentials 2007, V.2, P.182-185]. Dressings absorb exudate, keep the wound moisturized, 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 M., Kulma A., 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 Resourse Book 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 provides their antimicrobial properties [Clark M. Wounds International Online J. 2012, V.3, N7 ]. 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 M., Kulma A., 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 A., 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 C.E. 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 5658582, 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 M.N.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. P.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 impedes the industrial applicability of the production method, the possibility of hydrogel swelling from the wound during watering (exudate absorption).

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]. At least on one of the surfaces of the sponge, as a rule, an additional protective layer (plate) is formed. The composition is used either independently as a hemostatic agent, or for the delivery of FAA to the body.

A method of manufacturing a composition involves mixing chitosan and hyaluronic acid or its derivatives with a solvent, followed by drying the resulting mixture at elevated temperature or by impregnating a chitosan-containing sponge with a solution of hyaluronic acid or its derivatives and subsequent drying. The introduction of FAV is carried out by soaking the sponge with their solution.

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

A common disadvantage of the above compositions is the lack of effectiveness in the treatment of skin cancer and the consequences of exposure to skin chemo and x-ray therapy.

The following types of malignant skin tumors are usually referred to as skin cancer: basal cell carcinoma, melanoma. Skin cancer is one of the most common tumors, the incidence of which has been increasing in recent years. The standardized incidence rates for skin cancer are 26 among men and 21 among women per 100 thousand of the population [http://www.lood.ru/skin-and-smooth/skincancer.html].

In skin cancer, radiation, surgical, cryogenic, laser and drug treatments are used, as well as their combinations. The choice of treatment method depends on the location, growth form, stage and histological structure of the tumor, as well as on the condition of the surrounding skin. The most commonly used surgical intervention is excision of the tumor, cryodestruction (removal under the influence of low temperature) or electrocoagulation (removal under the influence of current) of the tumor. The tumor is excised at a distance of 1-2 cm from the visible edge. Cryogenic exposure is carried out using liquid nitrogen. The tissue necrosis caused by cooling leads to the destruction of the neoplasm with subsequent healing without gross scars. The method can be applied for shallow skin infiltration.

Laser beam treatment is also quite effective. For tumor necrosis, as a rule, one session is enough. The healing of the site of necrosis occurs with the formation of a thin elastic scar. Radiation therapy is mainly used for tumors of small size and in cases where it is impossible to remove the tumor by surgical excision due to its location [RU 2189261, 2002]. The disadvantages of the method are radiation damage to healthy tissues (perichondritis, radiation ulcers), as well as the long (more than 1 month) duration of treatment [http://www.euroonco.ru/khirurgiya-kozhi/rak-kozhi].

Medication is usually used only as a component of combination treatment., Which, in addition, includes surgery and pre- or postoperative radiation therapy. As medicines were used 0.5% colchamin ointment, 25% ointment with podophylline, Gordeev’s liquid N 2, Karchauli liquid. In particular, for the treatment of basal cell carcinoma, 30% and 50% prospidinovaya ointment are used, and for the treatment of skin cancer stage I and II - 0.5%. colchamin ointment, which in addition to colchamine, contains antiseptic agents thymol and ethyl alcohol; as well as an antibiotic - synthomycin. (Mashkovsky M.D. Medicines, M., "Medicine", 1993).

The disadvantage of these compositions is the lack of selectivity and high toxicity. So, colchamin ointment has a skin-resorptive effect, which is manifested by leukopenia and other side effects, with the use of prospidin ointment hyperemia, swelling, fibrinous deposits of surrounding healthy tissue are possible.

The closest effect to be achieved for the treatment of skin cancer is Glycifon ointment, containing 5-50% diglycidyl methylphosphonic acid ester and auxiliary substances - lanolin, petrolatum, emulsion waxes [RU 2146927, 1998] The ointment is applied to the affected area and is effective for blastomatous cells . It is characterized by antimicrobial activity and harmlessness to surrounding normal tissues, as well as the absence of side skin-resorptive action.

The disadvantages of the ointment are the limited use (only blastomatous cells), as well as insufficient effectiveness when exposed to cancer cells and other skin lesions.

Closest to the technical nature of the claimed invention in relation to the effect on damage to the skin is a composition in the form of a foam or film for the delivery of FAWs into the systemic circulation through the surface of the epithelium of the mucous membranes [US 2004/0151774]. The composition may contain, in particular, chitosan and its derivatives, hyaluronic or polyacrylic acids, polyols and other compounds, solubilizers, preservatives, fillers, plasticizers or antioxidants, as well as FAA anti-osteoporotic, non-steroidal anti-inflammatory substances, calcium and potassium channel antagonists, anesthetics against , antiviral, antimicrobial compounds, and other substances. The composition can be made in the form of foam, or a single-layer film with different thickness and size.

A method of manufacturing this composition in the form of films consists in dissolving the polymer in an aqueous or non-aqueous solvent, for example, methanol, ethanol, glycerin, or in purified water, mixing the resulting solution with a solution of FAV in purified water, spraying the resulting mixture onto a glass plate, followed by drying at room temperature, or by freeze drying. The composition can be used both independently, for example, placed behind the cheek, in the nasal passage or vagina, applied to the scrotum tissue, or as a coating for a plate, cannula, tampon, pad, strip, ball, tablet, ring or granule for local delivery physiologically active substance. The therapeutically effective dose of FAA delivered to the systemic circulation is from 0.01 to 2000 mg.

The disadvantage of the composition and the method of its preparation is the absence of a prolonged action, which is especially important for the treatment of long-term wounds, wounds in patients with reduced immunity, the inability to use the oral epithelium for treatment without additional surface protection of the composition with a film of a hydrophobic water-insoluble polymer, in particular polyethylene terephthalate, polyethylene, nylon, low efficiency in the treatment of skin lesions, as well as low efficiency in the treatment of skin cancer and the result the effect on the skin of chemotherapy and radiotherapy.

The technical problem solved by the authors was to expand the range of compositions that normalize the injured state of the external tissues of the body in order to create more effective agents, in particular, those that are promising for the treatment of skin cancer and have a prolonged effect.

This problem was solved using one of the following options.

According to the first option, the wound cover is the most effective for the treatment of skin cancer and the negative effects of radiation and chemotherapy on the skin based on chitosan and hyaluronic acid (or their derivatives), as well as containing surfactants and excipients, made in the form of a multilayer film, in which one of of layers contains a complex of chitosan with at least one organic acid with a chain length of C ₂ -C ₇ , and the layer adjacent to the wound contains hyaluronic acid or its derivatives, and as a surfactant, it contains cytostatics that find dressed as micelles

As cytostatics, the coating contains bleomycin, fluorouracin, metronidazole or other drugs with a similar effect

According to the second option, more effective for the treatment of traumatic skin lesions, the technical result was achieved in that the wound cover for the treatment of lesions of the mucous membranes and skin, containing chitosan and hyaluronic acid or their derivatives, as well as surfactants and auxiliary substances, is made in the form of a multilayer film, wherein one of the layers contains a complex of chitosan with at least one organic acid with a c ₂ -C ₇ chain length and the layer adjacent to the wound, soderzhitgialuronovuyu acid or its derivatives, and PAC will win in the form of micelles and are placed in the layer containing a complex of chitosan.

A wound coating as a surfactant contains at least one substance from the groups that include cytostatics, antibiotics, antiseptics, analgesics, anesthetics, vitamins, fungicides, immunomodulators, anti-inflammatory drugs, amino acids, and dextran, alginic acid or sodium alginate as auxiliary substances , plasticizers, emulsifiers, taste regulators, colorants, preservatives, water-retaining agents.

Physiologically active substances in both variants are contained in a coating in the form of micelles made of carboxylic acids with a chain length of C ₈ -C ₂₆ and / or their triglycerides and / or phospholipids.

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 film coating with an adhesive-bonded substrate made of a polymer film, non-woven or carbon fabric.

A feature of the inventive coating according to the second embodiment is that the network structure formed when creating a complex of chitosan with organic acids with a chain length of C ₂ -C ₇ holds micelles with surfactants, controlling the rate of their migration into the wound from the chitosan layer, into the layer containing hyaluronic acid or its salts, at the same time "pumping" from it exudate coming from the wound. At the same time, hyaluronic acid provides optimal adhesion of the coating to the wound and optimal separation of exudate. For the first option, the prolonged effect is less important compared to the therapeutic effect, therefore, the surfactants are distributed across all layers.

The technical result with respect to the method of obtaining the coating was achieved by introducing micelles with physiologically active or auxiliary substances into the solution of the selected polysaccharide, sequentially forming each individual layer from polysaccharide solutions containing micelles and drying the layer to a moisture content of 10-35%, after which the films were removed from the substrate.

Micelles with physiologically active substances included and excipients can be introduced into the solvent until the polysaccharides are dissolved or into the resulting polysaccharide solution.

When the moisture content of the samples is 10–35%, the films are elastic and can be easily removed from the substrate. At a lower moisture content of the films, 5–8%, they lose elasticity, crumble when trying to remove them from the substrate, and when applied to such films molding solutions containing another polysaccharide, the first layer is defective. At higher humidity, the strength of the layer is significantly reduced.

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 10-35%.

A solution of hyaluronic acid or its salt was prepared by dissolving it in an aqueous solution containing physiologically active and auxiliary substances.

A solution of the chitosan complex was 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 was 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 an organic acid containing in a quantity of 1 g chitosan: succinic - 0.56 g, glutamic - 0.59 g, aspartic - 0.52 g, milk - 0.50 g, ascorbic - 0.78 g, fumaric - 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.

In the latter case, polysaccharide solutions with a viscosity of 1000-100000 cP are prepared. At a lower viscosity of the molding solution (less than ~ 1000 cP), it spontaneously flows out through the die or spreads over the surface of the substrate during drying; at high viscosity values (more than ~ 1,000,000 cP), the solutions cannot be processed, because do not have fluidity.

The thickness of each layer of film medicinal compositions varies, as a rule, within 20-100 microns and is determined by the required thickness of both the multilayer film as a whole and the individual constituent layers based on chitosan and based on hyaluronic acid.

Studies of the compositions were carried out as follows.

The hydrodynamic radius of particles in the solution (R _h ) was determined by dynamic light scattering at a wavelength of 632.8 nm at a temperature of 20 ° C using a PhotoCor setup. Before measuring the emulsion was diluted with water 20-50 times to obtain solutions with a micelle former (emulsifier) of 0.05 wt.%.

The water content in the films was determined by the Karl Fischer method on a Mettler Tolledo V30 automatic titrator using HYDRANAL®-Solvent and HYDRANAL®-Titrant 5 reagents. The measurements were carried out in accordance with protocol V20 (preliminary extraction), according to which the moisture content in the methanol extract was determined from films and in methanol (blank experiment). The calculations were performed under the assumption of 100% extraction of water from the films.

Studies of transdermal diffusion of physiologically active substances were carried out on a Varian USP Apparatus # 2 dissolution apparatus using a membrane and film sandwich located at the bottom of a thermostatically controlled beaker in accordance with the USP Apparatus # 5 specification. As a working medium (artificial saliva), a phosphate buffer of pH = 6.8 in an amount of 300 ml was used. The buffer temperature was 37 ± 0.5 ° C. Mixing was carried out at a speed of 50 rpm

A sandwich for transdermal diffusion was prepared as follows. On a glossy surface of a Strat-M membrane (Merck-Millipore) Ø47 mm, 3–4 drops of a phosphate buffer solution were applied to ensure adhesion of polymer compositions (films). The polymer composition was applied to a drop of a buffer solution with a hyauronate-based layer providing adhesion, and smoothed to the edges of the membrane by extruding the solution, after which it was dried for 1 hour. The film-coated membrane was tightly fixed between the substrate and the lid of the Quix Sep 5000 µl Ø44 mm dialysis cell. The sandwich was placed on the bottom of the glass with a buffer solution, and at certain intervals, samples were taken to determine the amount of surfactant transferred to the buffer solution. Metronidazole was determined by UV spectroscopy at a wavelength of 320 nm using a Varian Cary 50 spectrophotometer and a cuvette with an optical path length of 10 mm. Determination of prednisolone sodium phosphate was carried out by HPLC on an Alliance instrument (Waters) according to the procedure described in USP 31 ed.

The dynamic viscosity of polysaccharide solutions was determined on an eBrookfield RVDV-II rotational viscometer using disk spindles No. 1–7 at a rotation speed of 0.01 to 200 rpm and the speed of the falling pre-calibrated ball on a Geppler viscometer.

The study of the swelling of film medicinal compositions at 98% humidity was carried out as follows. To ensure a humid atmosphere, a saturated solution of copper sulfate was placed in a desiccator and kept at room temperature for 3 hours. Accurate weights of film-based drug compositions were hooked up in a desiccator, removed at certain intervals, weighed, and placed back into the desiccator. The weight gain of the film composition was calculated, in%, relative to the initial mass.

The study of the permeability of moisture vapor through film compositions was carried out according to a modified method of Bhuvaneshwari S. et all [International J. of Engineering Research and Application. 2011 V 1, N 2, R. 292-299]. To maintain a relative humidity of 90 ± 5%, a saturated sodium chloride solution was poured onto a Petri dish, the cup was placed on the bottom of the desiccator. 0.73 g of anhydrous calcium chloride was placed in glass vials (Schuette Biotec) with a diameter of 27 mm and a height of 50 mm. The film (the contact surface area is 3.1 cm ² ) was fixed on the necks of the bottles using screw caps with a hole and a silicone sealing ring. To assess the transmission of water vapor by each of the layers of a two-layer film, the film was fixed by the specified layer in the direction of water vapor. Next, the vials were placed in a desiccator with a saturated solution of sodium chloride. The permeability of moisture vapor through the film was evaluated by the increase in mass of the vial and quantitatively expressed as the amount of water penetrating through the unit area (K _p , mg / mm ² ).

The essence and advantages of the present invention are illustrated by the following examples.

Example 1 (option 1). Film drug composition containing cytostatic-bleomycin in phospholipid micelles

Bleomycin solution. 20 mg of bleomycin sulfate is dissolved in 50 ml of a 0.03% emulsion of soya lecithin in water with stirring for 0.5 hours. The value of R _h micelles in solution is 110-150 nm.

A solution of preservatives. 20 mg of nipagin and 10 mg of nipazole were dissolved in 2 ml of propylene glycol, the solution was mixed with 0.03% emulsion of soya lecithin in water.

To 3.0 g of chitosan (MM = 240 kDa, Ennagram, France) and 0.6 g of glycerol (a water-retaining substance) are added to 125 ml of a 0.03% emulsion of soya lecithin in water, stirred for 1 hour to swell chitosan, 5 ml are added preservative solution, a solution of a mixture of 0.9 g of succinic acid and 0.9 g of glutamic acid in 50 ml of water, stirred on a mechanical stirrer for 7 hours until the components are dissolved, 20 ml of bleomycin solution are added, stirred for 1 hour. The solution is filtered into a press filter under pressure.

A chitosan solution is applied to a glass-free fat-free glass substrate located on a horizontal surface through a die 110 mm wide with a gap of 1.4 mm. The film is dried at room temperature for 10 hours to a moisture content of 15%. The film thickness is 45 microns.

0.6 g of sodium hyaluronate (MM = 1.9 MDa, Ennagram, France) and 0.1 g of dextran (MM = 110 kD, Pharmacia Fine Chemicals AB Uppsala, Sweden) and 0.15 g of sodium alginate (ISP, Germany) are dissolved in 50 ml of a 0.03% emulsion of soya lecithin in water with stirring for 5 hours, add 5 ml of a solution of preservatives, 10 ml of a solution of bleomycin, mix for another 2 hours

A hyaluronic acid solution containing surfactant micelles is applied to the surface of a chitosan-based film through a die with a gap of 2.0 mm. The film was dried at room temperature for 3 hours. A film with a moisture content of 35% was obtained. A film of polytetrafluoroethylene (Ecoflon, Russia) is applied to the film. The composition is sealed in a combination bag to prevent drying.

Example 2 (option 1). Film drug composition containing cytostatic fluorouracil in phospholipid micelles

Fluorouracil solution. 85 mg of fluorouracil, 20 mg of nipagin and 10 mg of nipazole are dissolved in 5 ml of glycerol, the solution is mixed with 20 ml of a 0.05% emulsion of soya lecithin in water, stirred for 1 hour. The value of R _h , micelles in solution is 130-190 nm.

To 4.0 g of chitosan (MM = 240 kDa, Ennagram, France), 0.1 g of arginine hydrochloride, 0.2 g of lysine hydrochloride, 190 ml of a 0.8% solution of succinic acid in a 0.05% emulsion of soya lecithin in water are added , stirred on a mechanical stirrer for 5 hours to dissolve chitosan, add 10 ml of fluorouracil solution, mix for 2 hours. The solution is filtered in a press filter under pressure to remove insoluble chitosan particles.

A chitosan solution is applied to a glass-free fat-free glass substrate located on a horizontal surface through a die 110 mm wide with a gap of 1.2 mm. The film is dried at room temperature for 10 hours to a moisture content of 15%. Film thickness 40 microns.

0.6 g of sodium hyaluronate (MM = 1.9 MDa, Ennagram, France), 0.2 g of dextran (MM = 110 kDa, PharmaciaFineChemicals AB Uppsala, Sweden) and 0.05 g of sodium alginate (ISP, Germany) are dissolved in 45 ml of a 0.05% emulsion of soya lecithin in water with stirring for 2 hours, 10 ml of a fluorouracil solution are added, and stirred for another 2 hours.

A hyaluronic acid solution containing surfactant micelles is applied to the surface of a chitosan-based film through a die with a gap of 2.0 mm. The film is dried at room temperature and atmospheric pressure for 3 hours. A film is obtained with a moisture content of 32%. A film of polytetrafluoroethylene (Ecoflon, Russia) is applied to the film. The composition is sealed in a combination bag to prevent drying.

Example 3 (option 1). Film drug composition containing metronidazole in phosphatidylcholine micelles

Metronidazole Solution 1 g of metronidazole and dissolved in 25 ml of a 0.05% phosphatidylcholine emulsion in water, stirred for 1 hour. The value of R _h micelles in the solution is 140-205 nm.

A solution of preservatives. 20 mg of nipagin and 10 mg of nipazole were dissolved in 2 ml of propylene glycol, the solution was mixed with 20 ml of a 0.05% phosphatidylcholine emulsion in water.

To 4.0 g of chitosan (MM = 240 kDa, Ennagram, France) 190 ml of a 0.8% solution of succinic acid in a 0.05% emulsion of phosphatidylcholine in water are added, stirred for 6 hours until the chitosan is dissolved, 10 ml of a metronidazole solution are added, mixed on a mechanical stirrer for 2 hours. The solution is filtered in a press filter under pressure.

A chitosan solution is applied to a glass-free fat-free glass substrate located on a horizontal surface through a die 110 mm wide with a gap of 1.2 mm. The film is dried at room temperature for 8 hours to a moisture content of 15%. The film thickness is 45 microns.

0.6 g of sodium hyaluronate (MM = 1.9 MDa, Ennagram, France), 0.01 g of lysine hydrochloride 0.2 g of dextran (MM = 110 kDa, PharmaciaFineChemicals AB Uppsala, Sweden) and 0.15 g of sodium alginate (ISP, Germany) dissolve in 50 ml of a 0.05% phosphatidylcholine emulsion with stirring for 4 hours, add 10 ml of metronidazole solution, 1 ml of glycerol, 10 ml of preservative solution, mix for another 2 hours

A hyaluronic acid solution containing surfactant micelles is applied to the surface of a chitosan-based film through a die with a gap of 2.2 mm. The film is dried at room temperature and atmospheric pressure for 3 hours. A film with a moisture content of 28% is obtained. A film of polytetrafluoroethylene (Ecoflon, Russia) is applied to the film. The composition is sealed in a combination bag to prevent drying.

Example 4 (option 2). Obtaining a film drug composition containing the antibiotic ciprofloxacin in lecithin 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 μm. Humidity 18%.

Ciprofloxacin solution. 0.1 g of soya 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 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 temperature for 15 hours. The thickness of the two-layer film is 120 μm, the humidity is 16%. The exposure duration of the coating was 15 hours

Example 5 (option 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. The film thickness is 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 for 5 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.

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 17%.

Example 6 (option 2). 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 an alcohol-free glass substrate located on a horizontal surface through a 110 mm wide die with a gap 1.4 mm. The film is dried at room temperature for 15 hours, the hyaluronate solution is re-applied through a die with a gap of 1.4 mm, and dried at room temperature for 15 hours. The film thickness is 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 the 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 h, after which 2.4 g of glutamic acid was added, and stirred for 7 h 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 120 μm, the humidity is 18%.

Example 7 (option 2). Obtaining a film drug composition containing diclofenac in micelles of PEG-modified oil.

3.4 g of sodium hyaluronate (MM = 1.6 MDa, CPN, Czech Republic) is 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 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, and dried at room temperature for 15 hours. The film thickness is 60 μm.

Diclofenac solution. 48.6 mg of diclofenac is 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 (Res Pharma, 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.

To 4.0 g of chitosan (MM = 240 kDa, Ennagram, France), 200 ml of diclofenac solution was added, stirred vigorously for 1 h, 2.4 g of glutamic acid were added and stirred for 3 h until the chitosan was 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 μm, the humidity is 20%.

Example 8 (option 2). 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 18%, then the same solution is re-applied through a die with a gap of 2.4 mm, dried at room temperature for 15 hours. Film thickness 80 μm.

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 h. 2.4 g of glutamic acid are added. acid, and stirred for 7 hours until complete dissolution of chitosan. 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 9 (option 2). 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 and stirred for 4 hours. The resulting solution is applied to an alcohol-defatted glass substrate located on a horizontal surface through a die with a width of 110 mm s a gap of 2.0 mm. The film is dried at room temperature for 15 hours to a moisture content of 17%, 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. The film thickness is 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 sodium prednisolone phosphate solution was added, stirred for 1 h, 2.4 g of glutamic acid were added and stirred for 3 h until the chitosan was completely dissolved. 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 μm, the humidity is 17%.

Example 10 (option 2). Obtaining a film medicinal composition containing prednisone 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 an alcohol-free glass substrate located on a horizontal surface through a 110 mm die with a gap of 2 , 4 mm. The film is dried at room temperature for 15 hours to a moisture content of 12%. 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 (Res Pharma, 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 kDa, Ennagram, France), 200 ml of prednisolone solution was added, stirred for 1 h, then 2.4 g of glutamic acid was added and stirred for 5 h 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%.

Example 11 (option 2). Obtaining a film medicinal composition containing prednisone in the micelles of PEG-modified oil

0.68 g of polyvinylpyrrolidone (Kollidon90F, 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% chlorhexidine bigluconate solution with stirring for 4 hours. The resulting solution is applied to fat-free alcohol glass substrate located on a horizontal surface through a die with a width of 110 mm 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 surfactant 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 μm, humidity 19%.

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 for 1 hour, then 2.4 g of glutamic acid are added and stirred for 7 hours until the chitosan is completely dissolved, a solution with micelles is obtained FAV.

A chitosan solution with FAA is applied to a layer containing chlorhexidine bigluconate or aluronate 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 μm, the humidity is 22%.

Example 12 (option 2). Film drug composition containing salicylic acid and azithromycin antibiotic 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 are 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.

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 vigorously for 5 hours until the chitosan is dissolved. The solution is filtered in a press filter under pressure.

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 for 10 hours. The film thickness is 85 μm.

Example 13 (option 2). Film drug composition containing clindamycin antibiotic and 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 with a width of 110 mm with a gap of 1.4 mm. The film is dried at room temperature for 15 hours to a moisture content of 16%, the same solution is re-applied through a die with a gap of 1.4 mm, dried at room temperature for 15 hours. A film of 55 μm thickness is obtained.

Clindamycin phosphate solution. 50 mg of clindamycin phosphate is dissolved in 1 ml of a 2% solution of oleic acid in ethanol. With intensive mixed 0.5 ml of the resulting solution and 250 ml of water.

To 4.0 g of chitosan (MM = 240 kDa, Ennagram, France), 200 ml of clindamycin phosphate solution was added, stirred for 1 h, then 2.4 g of glutamic acid was added and stirred for 7 h until the chitosan was completely dissolved and a stable emulsion was obtained .

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 μm, the humidity is 10%.

Example 14 (option 2). 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%. 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 on a mechanical stirrer for 1 hour to swell chitosan, 1.7 g of 90% lactic acid are added, mixed for 3 hours to complete dissolution of chitosan. The solution is filtered 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 for 10 hours. A film is obtained with a thickness of 45 μm and a moisture content of 9%.

Example 15 (option 2). Film drug composition containing metronidazole in sorbitol ester micelles

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

A solution of metronidazole 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 the 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 on a mechanical stirrer for 1 hour to swell chitosan, 1.7 g of 90% lactic acid were added, and stirred until chitosan was dissolved. The solution is filtered in a press filter under pressure.

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. A film of a thickness of 85 μm is obtained.

Example 16 (option 2). Film drug composition containing antimicrobial 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.

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 1.5 mm. The film is dried at room temperature for 10 hours to a moisture content of 15%. 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 an emulsion is obtained.

To 3.0 g of chitosan (MM = 192 kDa, Ennagram, France), 200 ml of tinidazole solution was added, stirred for 1 h 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.

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. A film with a thickness of 70 μm is obtained.

Example 17 (option 2) .. 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. Get a 2% solution of sodium hyaluronate with a viscosity of 63600 cP (Brookfield RVDV-II + viscometer, spindle No. 5, 2 rpm, 25 ° C) and pH = 7.0.

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 atmospheric pressure for 8 hours to a moisture content of 17%. Get a film with a thickness of 45 μm.

The solution of the mixture of FAV. To 100 ml of water, add 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, stir vigorously for 1 hour. R _h value of micelles in solution is 170-230 nm.

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

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 for 8 hours. Film thicknesses 130 μm, humidity 18%.

Example 18 (option 2). 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 cP (Brookfield RVDV-II + viscometer, spindle No. 5, 2 rpm, 25 ° C) and pH = 7.0.

45 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 for 8 hours to a moisture content of 19%. 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 h, 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 surfactant solution, mix with a mechanical stirrer for 5 hours. A chitosan solution with a viscosity of 217 cP is obtained (Happler viscometer , 20 ° C) containing FAA micelles.

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. A film with a thickness of 85 μm is obtained.

Example 19 (option 2). 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 for 5 hours until the hyaluronate is completely dissolved. Obtain a 1.3% solution of sodium hyaluronate with a viscosity of 34550 cP (Happler's viscometer, 20 ° C).

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 for 8 hours to a moisture content of 17%. 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 for 5 hours. 2% chitosan solution containing FAA micelles with a viscosity of 217 cP (Happler viscometer, 20 ° C).

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. A film is obtained with a thickness of 105 μm, a moisture content of 14%.

Example 20 (option 2). Film medicinal 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 sodium hyaluronate is completely dissolved. Obtain a 1.3% solution of sodium hyaluronate with a viscosity of 11480 cP (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 for 8 hours to a moisture content of 18%. 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 a brilliant blue dye, stirred for 5 hours. A 2% solution of chitosan was obtained. FAV micelles with a viscosity of 217 cP (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. A film is obtained with a thickness of 110 μm and a moisture content of 14%.

Example 21 (option 2). Long-acting 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 80S), 196 ml of distilled water are added, stirred with a mechanical stirrer for 5 hours until the sodium hyaluronate is completely dissolved. A 2% sodium hyaluronate solution with a viscosity of 53400 cP is obtained (Brookfield RVDV-II + viscometer, spindle No. 5, 2 rpm, 25 ° C) and pH = 7.0.

On a glass substrate with a restrictive ring of 143 cm ² installed on a horizontal surface, 20 g of a hyaluronate solution is applied, uniformly distributed over the surface of the substrate. The film is dried at room temperature for 6 hours to a moisture content of 18%. 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 for 5 hours , filtered through two layers of a synthetic filter under nitrogen pressure. Get a 2% solution of chitosan containing micelle FAV.

On a layer of hyaluronate on a glass substrate with a restrictive ring with an area of 143 cm ² apply 24 g of a solution of chitosan containing micelle FAV. The film was dried at room temperature for 7 hours. A film with a thickness of 70 μm was obtained.

Example 22 (option 2). Film medicinal 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. A 1% sodium hyaluronate solution with a viscosity of 53400 cP (Brookfield RVDV-II + viscometer, spindle No. 5, 2 rpm, 25 ° C) and pH = 7.0 are obtained.

36 g of hyaluronate solution is applied to a glass substrate with a restriction ring with an area of S = 143 cm ² located on a horizontal surface. The film is dried at room temperature for 6 hours to a moisture content of 18%. The film thickness is 35 microns.

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 kDa, Ennagram, France) was added 106 ml of a 2% solution of acetic acid, stirred for 5 hours. The solution was filtered through two layers of a synthetic filter under nitrogen pressure. To 50 g of the solution, 50 ml of the FAV solution are added, stirred for 5 hours. A 1% chitosan solution containing FAV micelles is obtained.

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, distributed over the surface. The film is dried at room temperature for 12 hours. Thickness 65 μm, humidity 11%.

Example 23 (option 2). 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 a 5% aqueous solution of pyridoxine hydrochloride, 1 ml of a 20% aqueous solution of chlorhexidine are 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 0.4 g of sorbitol monolaurate, 196 ml of 0.75% aqueous succinic acid solution are added, stirred with a magnetic stirrer for 5 hours, centrifuged for 5 min at 5500 rpm for e-dissolved particles of chitosan. pH = 5 and 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-free glass substrate by slip casting using a die with a width of 110 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 0.4 g of sorbitol monolaurate, 100 ml of a 0.0006% solution of succinic acid in water are added, stirred for 5 hours until the hyaluronate is completely dissolved. Get a 1% solution of sodium hyaluronate with a viscosity of 29,800 SP (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 (110 mm pre-fat-free with medical alcohol), a gap of 0.95 mm, the film is dried for 10 hours. The thickness of the two-layer film is 85 μm, the humidity is 18% .

Example 24 (option 2). Film drug composition containing metronidazole, vitamin B6, lidocaine, amino acids in lecithin and linolenic acid micelles

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 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 16%, 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 18%. Film thickness 130 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 for 1 h, an 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 the mixture is stirred for 7 hours until the chitosan is dissolved. The solution is filtered under pressure.

On the surface of the film based on hyaluronate, a solution of chitosan containing micelles of surfactant is applied. A die with a width of 110 mm with a gap of 1.5 mm The film is dried at room temperature for 10 hours. Thickness 145 μm, film 14%.

Example 25 (option 2). 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 for 5 hours until the hyaluronate is completely dissolved. Get 1% sodium hyaluronate solution with a viscosity of 29900 cP (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 1.35 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 1.0 mm. The film is dried at room temperature for 10 hours to a moisture content of 14%. Thickness is 85 microns.

To a mixture of 3.52 g of chitosan (MM = 192 kDa, Ennagram, France), 2.2 g of succinic acid, 36 mg of pyridoxine hydrochloride, 125 mg of alanine, 310 mg of glycine hydrochloride, 120 mg of proline, 30 mg of valine, 180 mg of arginine hydrochloride, 55 mg of aspartame, 1.25 g of soya lecithin, 1.0 g of glycerin and 115 mg of peppermint oil add 130 ml of water, mix vigorously for 5 hours until the chitosan is dissolved and a stable emulsion is obtained. The solution is filtered in a filter press under pressure.

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 temperature and atmospheric pressure for 10 hours. A film is obtained with a thickness of 140 μm and a moisture content of 14%.

Example 26 (option 2). Film medicinal 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 2.0 mm. The film is dried at room temperature for 10 hours to a moisture content of 20%. The film thickness is 55 microns.

FAV solution. 62.5 mg of prednisolone, 100 mg of soya lecithin, 500 mg of caprylic acid triglyceride (Mygliolcaprylic) 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 6 hours until complete dissolution of chitosan, 50 ml of an FAA solution are added, and stirred for 40 minutes. The solution is filtered 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%.

Example 27 (option 2). Film medicinal composition deposited on a non-woven fabric containing an immunomodulator imiquimod and 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%. The film thickness is 45 microns.

Imiquimod solution. 300 mg of imiquimod are added to 2 g of oleic acid 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 non-woven fabric soaked in water is applied (30% viscose, 70% polyester, density 50 g / m ² ), pressed and smoothed. The composition is dried at room temperature for 10 hours to a moisture content of 17%, placed in a sealed bag of composite material.

Example 28 (option 2). Film drug composition containing Prednisolone SPVS in icaprilic acid lecithin micelles applied to activated carbon tissue

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%. 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 for 6 hours until complete dissolution of chitosan, 50 ml of prednisolone solution are added, and stirred vigorously for 40 minutes. The solution is filtered 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 (Zorflex FM30K) is applied to it, pressed and smoothed. The composition is dried at room temperature and atmospheric pressure for 10 hours, placed in a sealed bag of composite material.

Example 29 (option 2). A film composition 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%. Film thickness 25 microns.

Imiquimod solution. 300 mg of imiquimod are added to 2 g of oleic acid 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 the chitosan is completely dissolved, 0.5 g of imiquimod solution is added with vigorous stirring. in oleic acid. The solution is filtered in a press filter under pressure.

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 (Zorflex FM10) is applied, pressed and flattened. The composition is dried at room temperature and atmospheric pressure for 10 hours to a moisture content of 19%, placed in a sealed bag of composite material.

Example 30. The study of the solubility of the chitosan complex in aqueous solutions of organic acids.

The study of the solubility of the chitosan complex in aqueous solutions of organic acids was 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, organic acid or its solution is added in portions, mixed for 1 hour to form a complex of chitosan with acids, and if chitosan is not completely dissolved, the next portion of acid is added. 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 chitosan deacetylation in the range of 80–95%, and the molecular weight in the range of 150–300 kDa affect the quantitative characteristics of the solubility of the complex. The results are presented in Table 1.

Example 31 (option 1). An experimental study of the antitumor activity of sustained-release film drug compositions in vivo. ”

The effectiveness of prolonged-release film drug compositions obtained according to Examples 1, 2 and 3 on the course of induced skin cancer was studied.

The experiments used white outbred SHR female mice aged 3 months and weighing 20-22 g. Animals were kept under standard conditions (20 ± 2 ° C, lighting mode 12 hours light: 12 hours dark) and received drinking water and laboratory food for rodents adlibitum.

Model: Two-stage skin carcinogenesis caused by the carcinogenesis initiator dimethylbenzanthracene (DMBA), which leads to a mutation of the oncogen R _as , and the tumor promoter phorbol ester (TFA) for the selective growth of epidermal cells with the mutation R _as .

The animals performed hair depilation on the back in the area of the shoulder blades with a size of 1 × 1 cm, after 48 hours they were randomized into 5 groups. The number of animals with tumors in each group was 20.

DMBA (100 nmol / 100 μl of acetone) was applied twice a week to the depilated back skin area for 2 weeks, then TFA (17 nmol / 100 μl of acetone) was applied twice a week for the next 17 weeks. In control 1, acetone is applied twice a week for 20 weeks, in control 2 - DMBA / TFA and saline.

The compositions were used after the development of tumors in 70% of rodents, which were used in the experiment.

Before applying the compositions, a portion of the film was cut out with an area that allowed to close the studied portion of the back. Film fixation: medical hypoallergenic zinc oxide adhesive plaster on a tissue basis (SFM Hospital Products GmbH, Germany). The patch was glued over the compositions and around the body of the mouse. The composition was kept on the mouse for 2 days, then replaced with a similar one. To prevent drying, 0.3 ml of water was wetted on the composition for 2 days.

In the control, saline solution was similarly applied.

The course of treatment was carried out from 82 to 103 days of the experiment, the duration was 22 days, of which the duration of treatment was 14 days / 7 applications.

Efficiency assessment parameters: weekly examination, weighing, revealing the tumor, the time of the appearance of the tumor, photographing the back of mice (Canon Power Shot A540, macro mode), fixing the location and size of the tumors.

Time recording and cause of death of the animal, histological examination of tumors.

The experiment lasted 5 months, after which the mice were euthanized. Pathomorphological examination of organs and skin.

Statistical processing: MS Excel 2007, Statistica v.8.0. For average values, the Student criterion was used; for the analysis of frequency values, the Fisher method. Differences were considered significant at p <0.05.

Daily Observation Results:

In control animals (control 1), the application of a solvent of carcinogenesis inducers, acetone, did not lead to visible changes in the skin, animals with tumors were not detected.

In experimental animals and control 2: baldness, thickening, formation of horn masses and erosion, ulceration of individual sites, neoplasms in the form of small tubercles or nodular thickenings of the skin, in some cases, papillary neoplasms on the leg. Some of the formations increased in size, spreading deep into the skin. Some formations underwent spontaneous reverse development. Until the end of the experiment, new tumors arose.

Thus, for 22 days, treatment with skin cancer compositions in animals leads to a decrease in the number of tumors and a decrease in their area.

Example 32 (option 2). The study of the sustained release of physiologically active substances from film pharmaceutical compositions

The prolonged release of the physiologically active substance from film medicinal compositions was studied on a USP Apparatus # 5 (Varian, USA) using a transdermal sandwich containing a skin-simulating synthetic membrane Strat-M (Merck-Millipore, Germany) and samples of film compositions according to Examples 14, 15 and 20 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 estimated by UV spectroscopy at a wavelength of 320 nm using a Varian Saga 50 spectrophotometer (Varian, USA).

As follows from the analysis of the data of Table 4, film medicinal compositions have a prolonged release of a physiologically active substance.

Example 33. A study of the swelling of film medicinal compositions in water and the permeability of moisture vapor through film compositions

a) the study of swelling

For the study used film medicinal compositions according to Examples 4-10, 12, 24, 25. The compositions show a high swelling in water.

a) a study of the permeability of moisture vapor

For the study, we used the film drug composition according to Examples 12 and 15. The experiment was carried out at 20 ° C for 24 hours. The contact surface area of the film was 3 cm ² . The mass of the film at the beginning of the tests 43.0 ± 4.2 mg.

In 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. K _p , mg / cm ² , a coefficient characterizing the amount of water that penetrated through the surface unit of the film composition was calculated (Table 6).

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

Example 34. A study of the effectiveness of prolonged-release film pharmaceutical compositions for treating skin lesions caused by laser irradiation.

The effect of the compositions of Examples 15 and 25 on the healing process of laser burn wounds of the skin of the back of female rats was investigated.

Wistar female rats weighing 200–250 g were used (Rappolovo Laboratory Animal Nursery, RAMS). The animals were kept on unlimited feed intake (diet for rats K-120, Inform-feed, Russia) and adlibidum water.

Animals are divided into 3 groups by randomization. Each group included 12 rats.

Were performed depilation of the skin area of the back of the thoracic region, the size of the plot of about 4 cm ^{2 the} plot was treated with a solution of Lugol.

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 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 power is 7 W, the continuous generation mode, the exposure time is 10 s. Power density 223 W / cm ² .

The film compositions were applied to the wound surface of the skin after it was wetted with saline, then the animal was returned to the cell. The treatment was carried out for 21 days, starting from the day of damage. Film change was carried out daily. In the control group, saline was applied to the wounds.

CCD-video camera took photographs of back wounds on an IBM compatible personal computer, the data was processed by the software package Video-Test Dynamics 4.0 (ISTA Ltd., Russia).

The area of the wound surface was determined as the area of the secondary scab formed at the site of primary damage and the edema zone.

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

For histological analysis, skin pieces were taken, fixed in 10% neutral formalin, dehydrated, embedded in paraffin, and 5 μm thick sections were prepared. Staining was performed with hematoxylin-eosin.

On the 7th day, the water content in the tissues was determined by titration according to K. Fischer.

Statistical analysis of the results was carried out using the Stat Soft Statistica v6.0 software package and MS Excel 2003 package.

The significance of the differences was evaluated by Student's not-criterion, Fisher's method (TMF). p <0.05 were considered significant.

Treatment with the compositions of Examples 15 and 25 from an early date significantly accelerates the healing of laser burn wounds in female rats with the development of a shaped scar covered with stratified squamous epithelium by 21 days, moisturizes the wound surface and reduces its infection (Tables 7-9).

The time of complete epithelization of the wound surface was significantly reduced by 18-35%. In the control group, by day 21, inflammatory infiltration of the connective tissue necrosis formed at the site remained.

Example 35. A study of the effectiveness of drug 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 nursery). 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 were brought together, three sutures were applied with threads at an equal distance from each other.

Preparations (compositions according to examples 18, 19, 21, 22) were applied during suturing to the surface of the wound and changed daily for 7 days.

The control group of animals did not receive treatment (n = 10).

Within 7 days of treatment, the dynamics of the extinction of signs of the inflammatory process was evaluated. On day 8 after inducing wounds, the suturing threads were removed, the animals were euthanized. Wound tensometry was performed, measuring the mass of the load required to rupture the tissue, which testified to the strength of the formed scar.

Statistical processing was performed using the Stat Soft Statistica and Microsoft Excel programs. Differences between the samples were evaluated by t-student test. p <0.05 was considered significant differences.

The treatment of wounds with compositions helped to reduce 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 compositions have an anti-inflammatory effect and contribute to the formation of a mature connective tissue scar earlier in comparison with the control group of animals.

Example 36. The study of the effectiveness of film medicinal compositions for the treatment of gingivitis and periodontitis 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 24 was used.

2 group (periodontitis). For the treatment, a sustained release film composition according to Example 25 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 the 1st, 3rd, 7th day, saliva, blood, and oral fluid of the gingival sulcus were taken, the OHI-S hygiene index (JC Green, JR Vermillion, 1969), and the papillo-marginal alveolar index РМА (Massler, Schour 1949, c modifications of Parma, 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.

Statistical data processing was carried out according to the standard software package Statistica 6.0. The critical confidence level 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 medium to high (24 h ÷ 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 24 and 25 have anti-inflammatory and antimicrobial effects and can be used in the complex treatment of dental patients with inflammatory diseases of the periodontal and oral mucosa.

Claims (14)

1. A tool for treating damage to the external tissues of the body, containing a physiologically active substance and excipients, characterized in that it is made in the form of a multilayer film in which there is a layer containing hyaluronic acid or its derivatives, a layer containing a component of chitosan, and as the latter layer contains a complex of chitosan with at least one carboxylic acid with a chain length of C ₂ -C ₇ , hyaluronic acid or its derivatives are contained in a layer adjacent to the wound, and a layer containing chi tozan, in the outer layer, and as physiologically active substances it contains cytostatics in the form of micelles. 2. The tool according to p. 1, characterized in that as a cytostatic agent it contains bleomycin. 3. The tool according to p. 1, characterized in that as a cytostatic agent it contains fluorouracil. 4. The tool according to p. 1, characterized in that as a cytostatic agent it contains metronidazole. 5. The tool according to claim 1, characterized in that at least one substance from the group consisting of cytostatics, antibiotics, antiseptics, anti-inflammatory drugs, analgesics, anesthetics, immunomodulators, vitamins, amino acids fungicides, vitamins and amino acids. 6. The tool according to p. 1, characterized in that the micelles contain carboxylic acids with a chain length of C ₈ -C ₂₆ or their triglycerides. 7. The tool according to p. 1, characterized in that the micelles contain phospholipids. 8. The tool according to p. 1, characterized in that as auxiliary substances it contains plasticizers, taste regulators, dyes, preservatives or water-retaining agents. 9. The tool according to p. 1, characterized in that it further comprises a substrate. 10. The tool according to p. 9, characterized in that it contains a substrate made of a polymer film. 11. The tool according to p. 9, characterized in that it contains a substrate made of non-woven fabric. 12. The tool according to p. 9, characterized in that it contains a substrate made of carbon fabric. 13. The method of obtaining funds according to claim 1, which includes obtaining solutions of hyaluronic acid or its derivatives and a chitosan-containing component containing physiologically active and auxiliary substances, applying them to a plate and drying at room temperature, characterized in that the solution of the chitosan-containing component is prepared by dissolving chitosan in a solution of carboxylic acids of chain length C ₂ -C _7, physiologically active substance in the solution is administered in the form of micelles, the layers are alternately deposited on the plate, after you ushiv first layer to a moisture content of 10-20%. 14. The method of obtaining funds according to p. 13, characterized in that chitosan is dissolved in a solution of carboxylic acids, containing in the amount per 1 g of chitosan the following acids: succinic - 0.56 g, glutamic - 0.59 g, aspartic - 0.52 g, milk - 0.50 g, ascorbic - 0.78 g; fumaric - 0.65 g, maleic - 0.51 g, salicylic - 0.69 g.