RU2185806C1 - Prolonged medicinal forms of local action which produce antibacterial and immunoactivating capacity - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: the preparation is designed as a biocompatible polymeric film consisted of hydrophilic and hydrophobic layers. Hydrophilic layer includes immunomodulating, immunostimulating preparations, antibiotics, antimicrobial, antiphlogistic preparations and those to improve blood microcirculation, antioxidants. The suggested preparation of local action produces an activating impact upon immune system and, simultaneously, is of antiphlogistic, antibacterial, antioxidant action and improves blood microcirculation in gingival vessels to be highly efficient in treating parodontium diseases. EFFECT: higher efficiency of therapy. 14 cl, 2 tbl

Description

 The invention relates to medicine, in particular to dentistry, and describes the preparation of new topical drugs with antibacterial and immunoactivating ability.

 Currently, in the occurrence of inflammatory periodontal diseases (CDW), along with microbial mechanisms, immune mechanisms are also considered (Levin et al. Periodontology, 1999, 2 pp. 10-13, Orekhova et al. Periodontology, 1995, 1, pp. 27-29, Page RC, J. Periodontal, 1992. Vol. 63 3 p. 356-366. Socransky SS et al, J. Periodontal, 1992 Vol. 63. 3 p. 322-331).

 A study of the immunological parameters of patients with moderate to severe periodontitis showed that all patients showed changes in both general status and local immunity (I. Piekalnite et al., Proceedings of the Fifth Congress of the Russian Dental Association, Moscow, 1999, p. . 160-161).

 A study of local oral immunity in patients with diabetes mellitus showed that there is a change in it, characterized by a decrease in the adsorption activity of epithelial cells (Zlobina O.A. et al., Proceedings of the V Congress of the Russian Dental Association, Moscow 1999, pp. 193-195).

 On the example of a clinical and immunological study of another disease with lesions of the oral mucosa - lichen planus, it was also found that patients have a change in the humoral and cellular parts of the immune system (Rabinovich, O.F. et al., Proceedings of the V Congress of the Russian Dental Association, Moscow, 1999, pp. 204-206; 206-208).

 It is known that the development and outcome of odontogenic infection is determined by the state of the immunological reactivity of the body (T.G. Robustova, 1985, Oleinik et al. 1990-91, etc.). Therefore, the effectiveness of the treatment of infectious diseases in the oral cavity and gums, apparently, in addition to antibiotic therapy, also largely depends on the use of agents that have an activating effect on the human immune system - immunomodulators, metabolic correctors, vitamins, etc. (BC Starodubtsev et al. 1986 and others).

 If we also take into account that many antibacterial drugs currently used for general and local treatment of inflammatory diseases in the oral cavity, have an immunosuppressive effect on the body (which can adversely affect the course of the wound process) (M.M. Soloviev, 1985, A. Szentivayi 1987; D, Greenwood, 1989, etc.), the fact of the need for complex therapy - antibacterial and immunostimulating, is obvious.

 It was established that the reactivation of latent herpetic infection in patients with recurrent aphthous and herpetic stomatitis, lichen planus and with Melkerssson-Rosenthal syndrome occurs as a result of the development of an immunodeficiency state (Terekhova et al. Materials of the 2nd Congress of Dentists of the Caucasus. 1988. - P. 162 -164. Abstracts of the 1st Congress of Dentists of Estonia. 1988. - S. 210).

 It is believed that in such diseases, bacterial colonization at the first stage contributes to periodontal tissue diseases, followed by the development of inflammatory and dystrophic processes in them (Sjcransky SS et al., J. Periodontal, 1992. Vol. 63. 3. p. 322-331) .

 However, it was found that between the number of microflora and the activity of inflammatory and destructive processes in periodontal tissues, a direct relationship is not always observed. Local and general immunological mechanisms in this situation are of particular importance - they have anti-inflammatory effects of microflora on periodontal tissues and largely determine the course of CDW.

 In connection with such ideas, attempts were made to treat various periodontal diseases with drugs that have an activating effect on the body's immune system.

 This describes the use of the immunostimulating drug Imudon (a mixture of lysates of strains of the most common bacterial and fungal pathogens in the oral cavity, resorption tablets, Solvey-Pharma, France) for the treatment of acute herpetic stomatitis in children (Elizarova and other Russian Medical Journal 2000 . 2). Chronic generalized periodontitis on the background of general somatic diseases (Novikova N.A. et al. Medicine and technology. Special. Issue, Dentistry 1999, 1. - P. 35-37). However, the treatment was not always effective.

 An analysis of the results of the use of "Imudon" in patients with typical and atypical forms of inflammatory periodontal diseases showed that the drug has a surface effect due to the active restoration of local immunity factors and is more effective for minor violations of the local immune status (Bezrukova I.V., Periodontology. 2000 3. - S. 46-47).

 Improvement of the main clinical indicators (reduction of bleeding, tooth mobility, edema and hyperemia) in the group of patients with profound destructive changes in periodontal disease and in BPP (rapidly progressive periodontitis) occurred much later.

 All this indicates that in the presence of a highly active microbial factor in the oral cavity, treatment of periodontal diseases should be limited only to drugs that do not activate the immune system.

 An integrated approach to the treatment of inflammatory periodontal lesions is advisable: the use of drugs that eliminate the negative effects of the microflora of the oral cavity and at the same time normalize the status of the protective mechanisms of status (Bezrukova IV, Periodontology. 2000. 3. - P. 46-47).

 In particular, given the polymorphism of periodontal diseases when creating new drugs with complex effects, immunostimulating drugs, in addition to antibacterial drugs, must be combined with other drugs.

 For example, it is known that in the treatment of periodontitis anti-inflammatory and antioxidant drugs that improve blood microcirculation are effective (Belousov A.V., Chukhadzhyan G.A., Belousova M.A., Pat. RF 2.153.319; Zelenskaya A.V., Garage N.N. Proceedings of the V Congress of the Dental Association of Russia. 1999. - P. 127; Zakirova, ibid., - P. 125) and others.

 The closest in technical essence and the achieved result is a composition for the treatment of diseases of the gums and oral mucosa. It is made in the form of a film of combined hydrophilic and hydrophobic layers. The film includes antibiotics, antibacterial drugs, surfactants, extracts of medicinal plants (RF patent 2075965). Films are intended for the treatment of inflammatory and infectious diseases of the gums and oral mucosa. Films of this type are produced under the name "Diplen" and "Diplen-Denta" / company NORD-OST of the Russian Federation according to TU9391-001-292442200-98 / and are widely used in dental practice.

 The technical task of the present invention is to expand the arsenal of drugs, the creation of prolonged dosage forms of local combined action, containing a combination of substances that have an activating effect on the immune system with other drugs like antibiotics, antibacterial and anti-inflammatory drugs, drugs that improve blood microcirculation, antioxidants.

 The tool is intended for local action and is used to deliver strictly metered quantities of drugs to the affected area. It is made in the form of a film consisting of a joint hydrophobic and hydrophilic layers. Sources of drugs are included in the hydrophilic, adhesive film layer. The film additionally contains a number of auxiliary components, which are included in both the hydrophilic and hydrophobic layers of the film. Each of these components plays a role.

The proposed films are structurally composed of:
1) from the hydrophilic layer;
2) from a hydrophobic layer;
3) drugs;
4) auxiliary components;
5) in addition, the film may contain partially soluble natural and synthetic polymers compatible with the main component of the hydrophilic layer.

 1. The main component for the hydrophilic layer are water-soluble natural or synthetic polymers and copolymers, their derivatives, in particular polysaccharides or their derivatives, such as tragacanth, gelatin resin, denatured gelatin and collagen treated with succinic acid or phthalic anhydride, starch and its esters cellulose ethers like carboxymethyl cellulose (sodium salt), hydroxyethyl cellulose, methyl hydroxypropyl cellulose, gum arabic, agarose, agar-agar, xanthan gum, pectins, alginic polymers hydrochloric acid and its salts (sodium and ammonium), propylene glycol adipate, chitin, chitosan and their derivatives; synthetic polymers and copolymers such as polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycols, copolymers based on vinyl acetate, vinyl pyrrolidone, vinyl esters, maleic acid, polymers of acrylic and methacrylic acids, their salts and ethers, water-soluble polymers of lactic and glycolic polymers, organic water, water with polysaccharides and their derivatives (acetates, alkyl - hydroxypropyl - carboxymethyl cellulose, starch, amylose, etc.), polyvinyl alcohol and its derivatives.

 2. The main component for the hydrophobic layer (substrate) is water-insoluble or sparingly soluble polymers such as ethyl cellulose, propyl cellulose, cellulose acetate, carboxymethyl cellulose, collagen, polymers of polyvinyl alcohol, polyvinyl alcohol-treated polyurethanes, polyurethanes treated with F-gas polyolefins , crosslinked derivatives of alginic acid, nonwoven materials, sparingly soluble modifications of biodegradable polymers of polyglycolic acid, polylactic acid, polytetramethyl glycolide, poly rolaktona, poly (DL -dekanolaktona) polialkilenadipinaty and their copolymers, some ion exchange resins.

3. Medicines:
1. Substances that have an activating effect on the immune system.

Immunomodulators:
a) endogenous cytokines, interferons, interleukins, colony stimulating factors, macrophage activation factor, tumor necrosis factor, erythropoietins, myelopeptides.

 b) exogenous immunomodulators of natural origin, such as viruses, microorganisms, their endotoxins, lipopolysaccharides, glucans.

c) synthetic high and low molecular weight substances, such as surfactants (adaptogens), derivatives of pyran, imidazole, fluorene, organophosphorus compounds, synthetic analogues of natural nucleotides, nucleosides
2) Immunostimulating agents:
a) preparations of animal origin from
- thymus gland (thymus) of animals
- animal spleen
- mammalian goiter
b) preparations of bacterial origin
- combined preparations of bacterial lysate
- bacterial ribosomes
- preparations from the cell walls of bacteria
- high molecular weight polysaccharide complex of microorganisms
c) herbal preparations from
Plant cytokinins
- trans-zeatin [6- (4-hydroxy-3-methyl) -trans-buten-2-yl] aminopurine
- kinetin (6-furfurilaminopurin)
- 6-benzylaminopurine (N ⁶ -benzyladenine).

 2. Used as antibiotics: antibiotics formed by bacteria, in particular peptide antibiotics such as gramicidin, thyrocidin, bacitracin, tizotricin, polymyxins, as well as antibiotics formed by actinomycetes, fungi, lichens, higher plants and animals, including cephalosporins of all generations, aminoglycosides, tetracyclines, macrolides, aminoglycoside, lincosamide, etc.

Particular attention was paid to antibiotics that have both immunotropic and immunomodulating activity, such as:
- gramicidin C
- rifampicin SV
- spiramycin (rovamycin) and other macrolides
- lincomycin and other lincosamides
- cefizin (modevit), ceftrixonin and other third generation cephalosporins
3) Antimicrobial agents - benzalkonium chloride, benzethonium chloride, etilbenzetoniyhlorid, cetylpyridinium chloride, cetrimide, chlorhexidine salts, polyvinylpyrrolidone-iodine, imidazolidinyl urea, metronidazole, diazolidinyl urea, hydrogen peroxide and its crystalline complexes (with urea, polyvinylpyrrolidone, cyclodextrin), Ag-sulfazin, Ag-proteins , dioxidine, phenol and its derivatives.

 4) Anti-inflammatory drugs: benzidamine, diclofenac sodium, indomethacin, ketoprofen, ketorolac, metamizole sodium, piroxicam, etc.

 5) A tool that improves microcirculation.

It is known that in the development of periodontal diseases, tissue hypoxia plays an important role. An electron-histochemical study of tissues showed a significant decrease in the activity of respiratory enzymes and ATPase activity in endothelial cells and vascular pericytes compared to the norm. This indicates functional disturbances in the capillary wall that precede morphological changes. Significant fluctuations in PO ₂ in the gums are observed (Ivanov BC Periodontal disease - M., Medicine 1989).

 An increase in vascular tone, and subsequently prolonged persistent vasoconstriction, leads to a decrease in the number of functioning capillaries in the gums and an increase in the time of diffusion of oxygen from the vessels into the tissue. Violation of transcapillary exchange ultimately leads to tissue hypoxia.

 Structural and functional changes in periodontal microvessels and blood flow disorders in them are especially pronounced in patients with severe periodontitis.

To improve microcirculation in the gums, the following was introduced into the film composition as a second complement:
- vinpocetine
- xanthinonicotinate
- pentoxifylline
- tanakan
B. Antioxidants:
- dibunol
- echinochrome is a natural analogue of naphthoquinone
- probukol
- tocopherol acetate
- sodium selenite
4. Auxiliary components
a) plasticizers - the content of plasticizers in both the hydrophilic and hydrophobic layers should not exceed 10% of the weight of the main polymer component of this layer;
b) components prolonging the effect of drugs are used in an amount of from 0.005 to 0.05 mg / cm in the finished film;
c) pH-regulating components are used in an amount of from 0.05 to 0.5 mg / cm in the finished film;
g) crosslinking agents are used to crosslink the hydrophobic layer with the hydrophilic layer in an amount up to 10% of the total weight of the polymers.

 5. Partially soluble polymers are mainly bio-soluble polymers such as polyglycolic acid, polylactic acid, polytetramethylene glycolide, polycaprolactone, poly (DL-decanolactone), polyalkylene oxide polymers and their copolymers, ion-exchange resins, as well as shellac, cellulose derivatives, such as ethyl cellulose, cellulose acetate, butyl cellulose, partially water soluble polymers and vinyl acetate copolymers.

 Their content in the finished film ranges from 0-30% by weight of the main component. In most cases, they were introduced into the hydrophilic layer.

Thus, the films proposed in this application:
1. They have a combined effect due to the presence in the composition of one film of a combination of drugs that have an activating effect on the immune system with:
a) antibiotics;
b) antibacterial drugs;
c) anti-inflammatory drugs;
g) drugs that improve blood microcirculation;
e) antioxidant drugs.

2. Made in such a local dosage form to ensure the receipt of a strictly controlled amount of drugs in the affected area
3. Prevent the spread of drugs and auxiliary components in the film throughout the oral cavity, to prevent uncontrolled exposure to the mucosa and into the gastrointestinal tract.

 The thickness of the films is adjustable within 0.02-0.06 mm; the ratio of the thickness of the hydrophilic layer to the hydrophobic is from 1: 1 to 10: 1.

 Films were obtained in two stages: first one of the layers was cast on a horizontal surface (preferably hydrophobic), then a second layer was cast on a dried surface.

The following describes the receipt of films:
1. Preparation of stock solutions:
a) for casting a hydrophobic layer
40 g of a polymer intended for casting a hydrophobic layer, and 5 g of a plasticizer are dissolved in 500 cm of isopropyl alcohol (s.h. brand) with stirring and heating in a water bath at 40-45 ^o C. The resulting solution is cooled to 25 ^o C and filtered through a nylon cloth for screens 49-67 (GOST 1748-82);
b) for casting a hydrophilic layer to 830 cm ^{2 of} deionized water, with stirring, 120 g of a polymer intended for casting a hydrophilic layer, 13.4 g of plasticizer are added. Dissolution is carried out at a temperature of 40-45 ^o C for 6 hours; if necessary, stirring can be carried out for another 2 hours at 80-85 ^° C. Cool the solution to 25 ^{° C.} , filter through a nylon cloth, additionally add 3.6 g of partially soluble polymer, mix for 4 hours at 40 ^{° C.} , filter again.

2. Film casting:
a) applying a hydrophobic layer:
30 cm of the prepared solution for casting the hydrophobic layer is applied to the horizontal surface of polished glass with a release coating of size 30 x 40 cm and the solution is evenly distributed with a glass rod. Drying is carried out in a chamber in an inert gas stream at a temperature not exceeding 30 ^o C for 5 hours;
b) casting a hydrophilic layer
60-70 cm of solution is applied to the dried surface of the hydrophobic layer described above to obtain a hydrophilic layer: the solution is evenly distributed on the surface and dried at a temperature not exceeding 25 ^o C in an inert gas stream for about 48 hours. The end of drying is controlled by the water content in the finished film ; it should be in the range of 5-7%, but not higher than 10%. The thickness of the films is regulated within the range of 0.02-0.06 mm;
c) the calculated amounts of the drug and auxiliary components are added to the solutions of the hydrophilic and / or hydrophobic layers before application.

Examples
Example 1
0.5 g of low molecular weight polyvinylpyrrolidone is added to 60 cm ^{3 of the} solution for applying the hydrophilic layer, stirred, and after complete dissolution of the mixture, 0.3 doxycycline dissolved in 10 cm ^{3 of} water and 0.1 g of monoethanolamine are added. Stir until completely dissolved. 0.03 g of thymalin (a complex of polypeptides isolated from thymus of calves, substance - Belmedpreparaty) dissolved in 6 cm ^{3 of} water is added to the solution. The resulting solution is applied to the surface of a pre-prepared, dried hydrophobic layer 30 x 40 cm in size, evenly distributed over the surface and dried for 48 hours at 25 ^° C. The doxycycline content in the finished film is at least 0.03 mg / cm ² and thymalin 0.001 mg / cm ² .

Example 2
Analogously to example 1, a film is prepared from the complex of Rifampicin with β-cyclodskstrin (Substance, powder for injection 150 mg amp. - Belmedpreparaty, Belarus) and lycopide (N-acetylglucosaminyl-N-acetyl-muramyl-L-alanyl-D-isoglutamine. The drug CJSC Peptek, Russia).

The content of Rifampicin in the finished film is not less than 0.03 mg / cm ² and Likopida not less than 0.007 mg / cm ² .

Example 3
Analogously to example 1, a film is prepared from Rovamycin (spiramycin, Robn PoulecK-orer, France) and ribomunyl (bacterial ribosomes titrated up to 70% RNA and proteoglycons of the membrane part of Klebsiella pneumonue, preparation by Pierre Fabre Medicament, France). The content of Rovamycin in the finished film is not less than 0.03 mg / cm ² , and ribomunyl 0.01 mg / cm ² .

Example 4
Analogously to example 1, a film of Gramycidin C and splenin is prepared (protein-free bovine spleen extract, manufactured by Darnitsa). The content of Gramycidin C in the finished film is not less than 0.01 mg / cm ² and splenin 0.007 mg / cm ² (in terms of dry matter).

Example 5
Analogously to example 1, a film is prepared from clindamycin and Solco-Uravak (inactivated microorganisms of the selection strains of Solko Basel? Switzerland). The clindamycin content in the finished film is at least 0.05 mg / cm ² and solcourvac 0.006 mg / cm ² (in terms of dry matter).

 Example 6

Analogously to example 1, a film is prepared from lincomycin and Galavit (synthetic immunomodulator sodium salt 5-amino-1,2,3,4-tetri, hydrophtholazine-1,4-dione, ZAO Medicor, Moscow). The content of lincomycin and galavit in the finished film is not less than 0.05 mg / cm ² ,
Example 7
Analogously to example 1, a film is prepared from metronidazole and sodium nucleinate. The content of metronidazole in the finished film is not less than 0.01 mg / cm ² , sodium nucleinate 0.008 mg / cm ² .

Example 8
Analogously to example 1, a film is prepared from metronidazole and Ridostin (a mixture of sodium salts of double-stranded and single-stranded RNA; Vector Farm, Russia.) The content of metronidazole and Ridostin in the finished film is at least 0.01 mg / cm ² .

Example 9
Analogously to example 1, a film is prepared with Cycloferon (Polysan Russia) and sodium diclofenac. The content of cycloferon in the finished film with a thickness of 0.02-0.06 mm is 0.01-0.03 mg / cm ² , diclofenac sodium 0.03-0.05 mg / cm ² .

Example 10
Analogously to example 1, a film is prepared with Vinpocetine (Cavinton, Gideon Richter, Hungary) and lycopid (CJSC Peptek, RF).

The content of Vinpocetine and lycopide in the finished film with a thickness of 0.02-0.06 mm is 0.01-0.03 mg / cm ² .

Example 11
Analogously to example 1, a film is prepared with cyclophane (Polysan, RF "Polysan") and sodium selenite. The content of cyclophane in the finished film with a thickness of 0.02-0.06 mm is 0.01-0.03 mg / cm ² , sodium selenite 0.03-0.05 mg / cm ² .

Example 12
Analogously to example 1, a film with lincomycin is prepared. The content of lincomycinan in the finished film is 0.03-0.05 mg / cm ² half-dan is not less than 0.01 mg / cm. Half-Dan (complex of polyadenyl and polyuridyl acids, lyophilized powder, Lanspharm, Russia.)
Example 13
Analogously to example 1, a film is prepared with benzalkonium chloride and Reaferon (interferonatalf-2B, dry matter for injection, Vectorpharm, Russia). The content of Reaferon in the finished film with a thickness of 0.02-0.06 mm is not less than 0.01 mg / cm, benzalkonium chloride 0.03 mg / cm.

Experiment 1
Study of the effect of a film with lincomycin and galavit described in Example 6 of this application on in vitro respiratory metabolism of leukocytes (immunotropic effect at the level of granulocytes)
When conducting luminol-dependent chemiluminescence of leukocytes, it was found that all components of the film significantly activated spontaneous CL granulocytes, however, lincomycin compared with diplen reduced oxygen radical emission by 72.7%, and galavit increased by 160%.

 A similar picture was observed with respect to galavite in assessing the production of active oxygen radicals during phagocytosis (induced CD). Galavit sharply increased induced CL by 184.7% (P <0.05), that is, it had a pronounced stimulating effect. The diplenic film base, on the contrary, reduced the induced granulocyte reaction by 71.7%, which can be interpreted as depletion of cell reserves against the background of a sharp activation of the spontaneous reaction. Lincomycin did not have such an effect.

 Lincomycin is not only an antibacterial, but also a modulating component. Its incorporation into the film may reduce the emission of radicals induced by diplen. In addition, lincomycin, apparently, also contributes to the conservation of cellular activity resources by reducing the stimulating effect of galavit on the production of radicals during phagocytosis.

 On the other hand, the galavite itself is characterized by a stimulating effect without pronounced depletion of cellular resources.

The data obtained make it possible to characterize the combined dosage form of the film with lincomycin and galavit (Diplen GL) as a kind of complex modulator of leukocyte activity, since the pronounced stimulating effect of galavit and the effect of depletion of cell resources by diplen are leveled by the modulating effect of lincomycin. The optimal concentration of drugs in the film is 5 μg per 1 cm ² .

The effect of the components of the Diplen-GL adhesive film on the oxygen metabolism of neutrophils after incubation in vitro at 4 and 25 ^o C is shown in Tables 1, 2.

 Patient N., born in 1962, complained of bad breath, tooth mobility, itching in the gums, and soreness when brushing teeth. Objectively: the mucous membrane of the gingival margin is pasty, hyperemic, edematous, gingival papillae are cyanotic, bleed during instrumental examination. There is 1-2 degree tooth mobility, the depth of periodontal pockets in the area of the upper and lower jaw chewing teeth is 4-5 mm, there is purulent discharge in the area of individual teeth. Hygienic condition unsatisfactory, significant deposits of plaque and stone.

 Diagnosis: chronic generalized periodontitis of moderate severity.

 Treatment. Removal of dental deposits and curettage of periodontal pockets was performed under infiltration anesthesia. Training in brushing and oral care was provided. A film containing both lincomycin and Galavit (see Example 6 of this application) ("Diplen-GL") was applied to the gingival margin in 4 quadrants.

 The film is also issued by the patient for independent use twice a day after morning and evening brushing.

 On the 3rd day after the beginning of the application of the film, a significant improvement in the clinical condition was noted: suppuration from periodontal pockets stopped, pain and bleeding during meals and brushing decreased significantly. The severity of inflammatory phenomena in the cheap region is much lower than that in the initial treatment.

 When examined on the 10th day after the start of the treatment course: the mucous membrane of the gums is pink in color, adheres closely to the surface of the teeth; halitosis and bleeding during brushing and eating are not noted. The patient noted a decrease in tooth mobility and sore gums, as well as the disappearance of itching in the gums. Objective examination data allow us to state the relief of exacerbation of the inflammatory process in the periodontium and stabilization of the patient's condition. Turnout after 6 months in the absence of signs of exacerbation of the disease is recommended.

As an example, consider an extract from the medical history of patient I., born in 1947. He turned to the periodontics department with complaints of significant pain in the gums during eating and brushing, difficulty chewing food, bad breath, involuntary bleeding of the gums caused by mechanical irritants. On examination of the oral cavity - severe hyperemia and cyanosis of the gums. Swollen gum papillae. When probing with a button probe, the depth of periodontal pockets is 6 mm or more, purulent exudate and blood are released. An X-ray examination determines the destruction of the bone tissue of the interdental septa at 2/3 of the root length. Pathological mobility 3 degrees from 14 to 24 and 4 degrees - from 44 to 33 teeth. Microbiological examination showed a high degree of contamination (10 ⁸ -10 ⁹ CFU). Periodontopathogenic bacteria of 4 species (P. gingivalis, P. melaninogenica, S. intermedius, A. naeslundii), sensitive to roxithromycin, spiramycin, levomycetin, gramicidin C and rifampicin, were isolated. The chemiluminescence curve of granulocytes was hyperergic: a high-amplitude background reaction was observed, which sharply increased under the influence of Diplen, but assumed a normal form if it was combined with gramicidin C or lincomycin.

The patient was diagnosed with chronic generalized severe periodontitis in the acute stage. An anti-inflammatory treatment was carried out: application of a biopolymer film with gramicidin C on the gingival margin from the vestibular and oral sides. The dentist applied the film at the first and all subsequent visits. In addition, the biopolymer film with gramicidin C was used by patients at home for the night for another 7 days. During this period, the patient received 150 mg of roxithromycin 2 times a day before meals. On day 7, dental plaque removal and curettage were performed. After the treatment, the pain during eating and brushing, bleeding gums disappeared. Depth of periodontal pockets decreased within 4-5 mm. Indicators of microbial contamination of exudate decreased to 10 ⁵ CFU, bacteria of periodontopathogenic species disappeared. The patient underwent a patchwork operation in the periodontics department. The clinical effect was noted with repeated calls of the patient after 6 and 12 months. During microbiological control, only S. intermedius was isolated.

 Thus, after treatment using biopolymer adhesive membranes with antibacterial components, the clinical picture is normalized - IG, PMA are significantly reduced, bleeding and suppuration disappear, the degree of contamination of the periodontal pocket and the detection rate of aggressive periodontal pathogenic bacteria are reduced.

Claims (15)

 1. A topical therapeutic agent in the form of a biocompatible polymer film made of hydrophilic and hydrophobic layers and comprising drugs, characterized in that the hydrophilic layer includes exogenous, endogenous or synthetic high and low molecular weight immunomodulators, immunostimulants of animal, bacterial and plant origin, antibiotics with immunotropic and immunomodulating activity, antimicrobial, anti-inflammatory, antioxidant, micro irkulyatsiyu blood as well as hydrophilic and hydrophobic layers comprise auxiliaries.  2. The tool according to p. 1, characterized in that it contains endogenous immunostimulants selected from the group: cytokines, interferons, interleukins, colony stimulating factor, macrophage activation factor, tumor necrosis factor, erythropoietin, myelopeptides.  3. The tool according to p. 1, characterized in that it contains exogenous immunomodulators of natural origin, selected from the group: viruses, microorganisms, their endotoxins, monopolysaccharides, glucans.  4. The tool according to p. 1, characterized in that it contains synthetic high and low molecular weight substances selected from the group: adaptogens, derivatives of pyran, quinone, imidazole, fluorene, organophosphorus compounds, synthetic analogues of natural nucleotides - nucleotides.  5. The tool according to p. 1, characterized in that it contains an immunomodulating agent of animal origin, selected from the group of preparations of the thymus gland, spleen, goiter.  6. The tool according to p. 1, characterized in that it contains endogenous immunostimulants of bacterial origin, selected from the group: bacterial lysate, bacterial ribosomes, a preparation of bacterial cell walls, a high molecular weight polysaccharide complex of microorganisms.  7. The tool according to p. 1, characterized in that it contains plant cytokines selected from the group: trans-zeatin [6- (4-hydroxy-3-methyl) -trans-buten-2 yl] aminopurine; kinetin (6-furfuryl-aminopurin); 6-benzylaminopurine (N-benzylamine).  8. The tool according to p. 1, characterized in that it contains an antibiotic having immunotropic and immunomodulating activity, selected from the group of gramicidin C, rifampicin SV, spiramycin, lincomycin, cefizin, ceftriaxone.  9. The tool according to p. 1, characterized in that it contains antimicrobial agents selected from the group: benzalkonium chloride, benzethonium chloride, stilbetonium chloride, cetilliridinium chloride, cetrimide, chlorhexidine salts, polyvinylpyrrolidonide, imidazolidinylidene urea dihydroimide, urea dihydromene, urea dihydromene, urea dihydromene, urea.  10. The tool according to p. 1, characterized in that it contains anti-inflammatory drugs selected from the group: benzidamine, diclofenac sodium, indomethacin, ketoprofen, ketorolac, metamizole sodium, piroxicam.  11. The tool according to p. 1, characterized in that it contains a tool that improves blood microcirculation, selected from the group: vinpocetine, xanthynolnicotinate, pentoxifylline, tanakan, as well as antioxidants selected from the group: dibunol, echinochrome, probucol, tocopherol sodium selinite acetate .  12. The tool according to claim 1, characterized in that it contains a plasticizer as an auxiliary substance, while it can be included in both the hydrophilic and hydrophobic layers in an amount of not more than 10% by weight of the main component. 13. The tool according to p. 1, characterized in that as an auxiliary substance it contains substances that prolong the action of drugs in an amount of from 0.005 to 0.5 mg / cm ² in the finished film. 14. The tool according to p. 1, characterized in that as an auxiliary substance it contains pH regulatory components in an amount of from 0.05 to 0.5 mg / cm ² in the finished film.  15. The tool according to p. 1, characterized in that as an auxiliary substance it contains a crosslinking agent for crosslinking the hydrophilic and hydrophobic layers in an amount up to 10% of the total weight of the film.

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