Prolonged dosage forms of local activities that have an activating effect on the immune system

 

(57) Abstract:

The invention relates to the field of medicine and for the creation of a therapeutic agent. The tool is made in the form of a biocompatible polymer film of the hydrophilic and hydrophobic layers, the hydrophilic layer is included immunomodulators, Immunostimulants, antibiotics with immunotropic and immunomodulatory activity, drugs from plants and plant cytokines. The agent is effective in the treatment of infectious, inflammatory diseases of the mouth and periodontitis, as well as dermatitis, herpes, herpes, eczema, psoriasis, ulcers. 12 C.p. f-crystals, 2 tab.

The invention relates to medicine, namely to dentistry, and specifically relates to creating a prolonged dosage forms of local action for the treatment of infectious-inflammatory diseases of the oral cavity and periodontal.

Currently in the occurrence of inflammatory periodontal diseases (HICP) along with microbial considered and immune mechanisms (Levin and others Periodontics, 1999, 2, pp. 10-13; Smith and others, Periodontics, 1995, 1, pp. 27-29; Page, R. C., J. Periodontal, 1992, Vol. 63, 3, p.356-366; Socransky S. S. et al, J. Periodontal, 1992, Vol. 63, 3, p.322-331).

May the Sith from reactive processes in the body, which can both limit and facilitate destructive processes in periodontal tissues (Socransky S. S. et al, J. Periodontal, 1992, Vol. 63, 3, R. 322-331).

Local and systemic immunological mechanisms in such a situation is of particular importance: they have a confrontation on the influence of microflora on periodontal tissues and largely determine the course of the HICP. Therefore it is not always between the number of microorganisms and the activity of the inflammatory and destructive processes in periodontal tissues there is a direct link. The study of the immunological characteristics of patients with generalized periodontitis medium-heavy degree showed that all patients were identified changes as the overall status of local immunity (Piekarnia I. Ya. and other proceedings of the V Congress of the dental Association of Russia, Moscow, 1999, pp. 160-161).

The study of the local immunity of the oral cavity in patients with diabetes showed that it is changing, characterized by the decrease of the adsorption activity of epithelial cells (Zlobina O. A. and others, proceedings of the V Congress of the dental Association of Russia, Moscow, 1999, pp. 193-195).

For example, clinical and immunological studies of other disease with lesions of the mucous is E. humoral and cellular immune system (Rabinovich O. F. and other proceedings of the V Congress of the dental Association of Russia, Moscow, 1999, pp. 204-206; 206-208).

Thus, it can be assumed that the effectiveness of treatment of inflammatory and infectious diseases in the oral cavity and gums, in addition to General therapy largely depends on the use of funds that have a positive impact on the immune system, namely immunotropic funds, metabolic proofreaders, vitamins.

Described the use of drugs for local effects (for example, "Imudon, firm Solvay Pharma, France, prepared from a mixture of lysates of strains of the most common bacterial and fungal pathogens of pathological processes in the oral cavity, multivalent complex of the antibody) for the treatment of inflammatory and infectious diseases of the oral cavity in patients with signs of immune deficiency.

"Imudon successfully used in acute herpetic stomatitis in children (Elizarova C. M., Dramatico L. H., Fears S. Y. "Imudon in pediatric dentistry. Russian Medical journal 2000. 2) with chronic generalized periodontitis on the background of General somatic diseases (Novikova N. A., Kuzmin, Y. F., Shevchenko, S., A. Subbotin, N. "Medicine and technology". Spec. The issue is periodontal (Bezrukov, I. C. Periodontics. 2000. 3. - S. 46-47).

The closest in technical essence and the achieved result is a technical solution to a composition for drug delivery in the treatment of diseases of the oral cavity. The composition is made in the form of a film from the blend of hydrophobic and hydrophilic layers. The film includes antibiotics, antibacterial agents, surface-active substances, medicinal plant extracts and other [U.S. Pat. RF 2075.965]. They are intended for the treatment of inflammatory and infectious diseases of the mouth and periodontitis. Films of this type are available under the name "deplin and diplan-dent" (company "NORD-OST" the Russian Federation on THE 9391-001-292442200-98) and are widely used in dental practice. The technical task of the present invention is to expand the Arsenal of drugs prolonged action, used in the treatment of various diseases of the oral cavity, in particular for manufacturing a convenient dosage form local action providing an activating effect on the immune system. To expand the scope of and creation of new prolonged dosage forms of local action, in the composition of these films included:

a) substances that are able to provide to the government, providing an activating effect on the immune system include Exo-, endo -, and synthetic immunomodulators, immunostimulatory agents of animal and bacterial origin, vegetable cytokines.

It is known that certain antibiotics in addition to possess antibacterial and immune stimulating effect. Such antibiotics include, for example, gramicidin S, rifampicin, some macrolides and other

Thus, to prepare films in addition to drugs with typical immunotropic properties were used and antibiotics, with additional immunomoduliruushimi activity.

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

Films with hydrophilic side tightly fix the external hydrophobic layer thus has a protective function: prevents from falling components of oral fluid in the affected area, protect from mechanical impact, etc. in Addition to infectious and inflammatory diseases of the oral cavity (atty, gingivitis, periodontitis), who described the film will be widely used in the treatment of dermatitis, herpes, herpes, eczema, psoriasis, ulcers.

The proposed film is structurally consist of:

1) of the hydrophilic layer,

2) of the hydrophobic layer,

3) drugs

4) auxiliary components,

5) additionally, the film may contain a partially soluble polymers that are compatible with the main component of the hydrophilic layer.

1. As a core component to the hydrophilic layer are water-soluble natural or synthetic polymers and copolymers, derivatives thereof, in particular polysaccharides or their derivatives, such as tragakant, gelatin resin, denatured gelatin and collagen treated with succinic acid or phthalic anhydride, starch and its esters, cellulose ethers, as carboxymethylcellulose (sodium salt), hydroxyethyl cellulose, methylhydroxypropylcellulose, Arabian gum, agarose, agar-agar, xanthan gum, pectins, polymers, alginic acid and its salts (sodium and ammonium), propylene glycol is vinyl alcohol, the glycols, copolymers based on vinyl acetate, vinylpyrrolidone, vinyl ethers, maleic acid, polymers of acrylic and methacrylic acids, their salts and esters, water-soluble polymers of lactic and glycolic acid, water-soluble polyurethanes, polyesters organic dibasic acids, polysaccharides and their derivatives (acetates, alkyl-, hydroxypropyl-, carboxymethylcelluose, starch, amylose, and others), polyvinyl alcohol and its derivatives.

2. As a core component for hydrophobic layer (substrate) are insoluble or sparingly soluble in water polymers, such as ethylcellulose, propylethylene, acetylcellulose, carboxymethyl cellulose, collagen, polymers of esters of acrylic acid, derivatives of polyvinyl alcohol, polyurethanes, processed F-gas polyolefin, crosslinked derivatives algenio acid, textiles and nonwovens, moderately soluble modification of biodegradable polymers - polyglycolic acid, polylactic acid, polytetramethylene, polycaprolactone, poly (DL-decanolactone), polyacyladipate and their copolymers, some ion-exchange resins.

3. Drugs

A) Immunomodulators and IMM is the colony-stimulating factors, factor activation of macrophages, tumor necrosis factor, erythropoetin, mielopeptide;

b) exogenous immunomodulators of natural origin such as viruses, microorganisms, endotoxins, lipopolysaccharides, glucan;

C) synthetic high - and low-molecular substances, such as surfactants (adaptogens), derivatives of Piran, quinone, imidazole, fluorene, organophosphorus compounds, synthetic analogs of natural nucleotides nucleosides.

2) immune-boosting tools:

a) drugs of animal origin from

- thymus (thymus) animals

- the spleen of animals

- goitrous glands of mammals

b) preparations of bacterial origin

- a combination of drugs lysate of bacteria

bacterial ribosomes

drugs from the cell walls of bacteria

- high-molecular polysaccharide complexes from microorganisms.

3) Antibiotics with immunotropic and immunomodulatory activity:

- gramicidin

- rifampicin SV

- spiramycin (rovamycin)

- lincomycin

- seisin (modelid), Ceftriaxone (retrieval) and other III generation cephalosporins.

4) Drugs raati from extracts of various plants

- cotton, geranium, sumac, stem-roses and tucovica, Sophora japonica, turmeric, antaka.

5) Vegetable cytokines:

- TRANS-zeatin [6-(4-hydroxy-3-methyl)-TRANS-butene-2-yl]aminopurin

- kinetin-(6-furfurylaminopurine)

- 6-benzylaminopurine (N6-benzyladenine).

4. Accessories

a) a plasticizer content of plasticizers in hydrophilic and hydrophobic layers should be no more than 10% by weight of the main component of this layer,

b) the prolonging effect of the drug components are used in amounts of 0.005 to 0.05 mg/cm2in the finished film,

C) a pH - adjusting components are used in amounts of from 0.05 to 0.5 mg/cm2in the finished film,

g) a crosslinking agent for crosslinking the hydrophobic layer with hydrophilic is used in an amount up to 10% of the total weight of the film.

5. Partially-soluble polymers is mainly bionetwork polymers, such as polyglycolic acid, polylactic acid, polytetramethylene, polycaprolactone, poly(DL-decanolactone), polyalkylbenzene polymers and their copolymers, ion-exchange resins and shellac, cellulose derivatives, as ethylcellulose, cellulose acetate, Boticelli film ranges from 0-30% by weight of the basic component.

Thus, the proposed in this application film:

1. Taken in this dosage form local action to ensure the receipt of a carefully controlled amount of the drug in the affected area.

2. Prevent the spread of drugs and the supporting components of the film throughout the oral cavity, to prevent their uncontrolled effects on the mucosa and into the gastrointestinal tract,

3. Regulate pH at which maximize the activity and stability of this drug,

4. Have a prolonged effect that the concentration of the medication on the affected area was maximum,

5. Some of the films, in addition to immunomodulatory also possess antibacterial activity.

The thickness of the films is adjusted in the range of 0.02-0.06 mm; the ratio of the thickness of the hydrophilic layer to a hydrophobic ranges from 1:1 to 10:1.

Most films are sterilized by irradiation.

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

The following describes the gaining the measure, designed for casting a hydrophobic layer, and 5 g of plasticizer are dissolved in 500 cm isopropyl alcohol (mark O. S. h,) with stirring and heated in a water bath at 40-45oC. the resulting solution was cooled to 25oWith and filtered through a nylon cloth to sit 49-67 (GOST 1748-82),

b) casting the hydrophilic layer to 830 cm2deionized water with stirring is added 120 g of polymer, designed for casting hydrophilic layer, a 13.4 g of plasticizer. The dissolution is conducted at a temperature of 40-45oWith in 6 hours, if necessary, the mixing can be maintained for another 2 hours at 80-85oC. Cool the solution to 25oC, filtered through nylon cloth, impose additional 3.6 g of partially soluble polymer is stirred for further 4 hours at 40oWith, again filtered.

2. Casting films

a) applying a hydrophobic layer:

on a horizontal surface polished glass with anti-adhesive coating, size 30 x 40 cm, put 20 cm3the prepared solution for casting hydrophobic layer and evenly distribute the solution with a glass rod. The drying is performed in the chamber in a stream of inert gas at a temperature not exceeding 30oWith over OYA put 60-70 cm3solution to obtain a hydrophilic layer: the solution is evenly distributed over the surface and dried at a temperature not exceeding 25oWith the current of inert gas for approximately 48 hours. The end of drying is controlled by the water content in the finished film; it must be in the range of 5-7%, but not above 10%. The thickness of the films regulate within 0.02-0.06 mm,

C) the calculated amount of the drug and the auxiliary components are solutions of hydrophilic and/or hydrophobic layers before applying.

Example 1.

To 70 cm3solution for applying the hydrophilic layer is added 0.5 g of low molecular weight polyvinylpyrrolidone, 10 ml of 2% aqueous solution of gramicidin a (gramicidin), stirred at 25oWith up to complete dissolution. The resulting solution was poured onto the surface of pre-cooked, dried hydrophobic layer size 30 x 40 cm, evenly spread over the surface and dried for 48 hours at 25oWith up to a moisture content in the film to 5-7%. The finished two-layer film podumaut knife, gently pull it from the glass and cut the size of 50 x 100 mm

The thickness of the obtained films is 0.02-0.06 mm; the content of gramicidin With not less than 0.03 m Poulenc Korer, France). The content of rovamycine in the finished film thickness of 0.02-0.06 mm 0.01-0.03 mg/cm2.

Example 3.

Analogously to example 1 to prepare a film with tetrabrom (ceftriaxon, substance, ABOL honey, Russia). The content of Ceftriaxone in the finished film is 0.03-0.08 mg/cm2.

Example 4.

Analogously to example 1 preparing a film of Dibazol. The content of Dibazol in the finished film thickness of 0.02-0.06 mm is 0.03-0.08 mg/cm2.

Example 5.

The film methyluracil.

To 70 cm2solution for applying the hydrophilic layer is added 0.2 g of low molecular weight polyvinyl alcohol and the calculated amount of auxiliary components, stirred at 25oWith up to complete dissolution. Then enter 90 cm30,2% solution methyluracil, obtained by dissolving 0.2 g of methyluracil in 10 ml of a mixture of water - acetic acid (1:1), and again mix. The resulting solution was applied to the surface of pre-cooked, dried hydrophobic layer size 30 x 40 cm, evenly spread over the surface and dried in a stream of inert gas at 25-35oWith up to a moisture content of 5-7% in the finished film. Content methyluracil in GoToWebinar is 10:1. The content of the auxiliary component does not exceed 20% of the weight of the film. Analysis methyluracil in aqueous eluate from a film produced spectrophotometrically at a wavelength of 260 nm in a cell with a layer thickness of 10 mm, using as the reference solution water.

Example 6.

Analogously to example 5 to prepare a film with a synthetic immunomodulator Galavit -(sodium salt of 5-amino-1,2,3,4-tetrahydropyrazin-1,4-dione substance CJSC Medicor, Russia, registration card 97/91/3, health Ministry). The film thickness of 0.02-0.06 mm, the content of Galavit in the finished film of 0.03-0.08 mg/cm2. The film is stable under sterilization irradiation (typically 25 kGy).

Example 7.

Analogously to example 5 to prepare a film with aciclovir-9 [(y-hydroxyethoxy)-methyl] -guanine (substance Then. leaf d/in., 250 mg 1 in vials, Teva, Israel). The content of acyclovir in the film thickness of 0.02-0.06 mm is 0.03-0.08 mg/cm2.

Example 8.

Analogously to example 5 to prepare a film of splenin (protein-free extract of spleen of animals, the manufacturer Darnitsa). Content splenin in the film thickness of 0.02-0.06 mm is 0.03-0.08 mg/cm2.

Example 9.

Analogously to example 5 to prepare a film with Radostina (smesitel Vector-Pharm, Russia). The content of Radostina in the finished film thickness of 0.02-0.06 mm is 0.03-0.08 mg/cm2. The number of auxiliary components does not exceed 20% by weight of the finished film.

Example 10.

Analogously to example 5 to prepare a film with immunogenum (Binocs, Russia). Content imunofana in the finished film thickness of 0.02-0.06 mm 0.01-0.03 mg/cm2.

Example 11.

Analogously to example 5 to prepare a film with polyoxidonium (LLC Immupharma", Russia). The content of polyoxidonium in the finished film thickness of 0.02-0.06 mm 0.05-0.08 mg/cm2.

Example 12.

Analogously to example 5 to prepare a film with IFN (interferon-alpha-2, dry substance for injection, Vector-Pharm, Russia). Content reaferona in the finished film is not less than 0.01 mg/cm2.

Example 13.

Analogously to example 5 to prepare a film with reolacing (from lifl. powder from Biotec, Russia). The content of Roncoleukin in the finished film is not less than 0.01 mg/cm2.

Example 14.

Analogously to example 5 to prepare a film of the complex of rifampicin (substance, powder for injection 150 mg capsules Belmedpreparaty, Belarus) with a-cyclodextrin.

Content is ru 5 prepare a film of the hydrochloride of kinetin 6-(purullena)-purine (drug companies Sigma). The content of kinetin in the finished film is 0.01-0.03 mg/cm2.

Experiment 1

Study of therapeutic activity of film gramicidin a described in example 1 of this application

Antimicrobial action film with gramicidin a, prepared in accordance with the requirements described in example 1 of this application, was determined by the standard method of serial dilutions in liquid nutrient medium, followed by cultivation in aerobic (test strains Staphylococcus aureus P209, Bacillus cereus) and anaerobic conditions (Streptococcus sanguis, Peptostreptococcus pyogenes, Bacteroides melaninogenica). To create anaerobic conditions used oxygen-free gas mixture containing 80% nitrogen, 20% carbon dioxide and 20% hydrogen.

Studies were performed in accordance with the recommendations of the health Ministry Methods of microbiological analysis of the etiology of anaerobic bacteria" /Century And. Kocharova et al., M., 1996.

The results of the sensitivity studies of these strains of bacteria to the film with gramicidin s, compared with the standard 2% alcohol solution of gramicidin a, expressed as minimum inhibitory concentration presented in the table. It is established that a film of gramicidin With shows Wii - Peptostreptococcus, bacteroids, and streptococci S. sanguis. As is seen in table.1 data, the minimum inhibitory concentration data of the test strains to the film gramicidin a was not different, and in some cases was 1.5-2 times lower than the standard alcohol solution, i.e., exceeded last for antibacterial activity.

The data obtained indicate that the film gramicidin a in its activity against anaerobic bacteria significantly outperforms classical protivoavarijnye drugs - metronidazole and nitazol, including the composition of the polymer complexes - analogues of the invention (Patent N 1795646 RF/ Voronkov M. G., Lopyrev Century BC, Ushakov R. C., Tsarev Century. N. et al., 1990. Complex 2-acetylamino-5-nitrothiazole with polyvinylpyrrolidone possessing antimicrobial activity in relation to the etiology of anaerobic infections).

Experiment 2

Study the influence of the film with gramicidin a on respiratory metabolism of leukocytes in vitro (immunotropic effect on the level of granulocytes)

As a model to study the modulatory and anti-inflammatory activity film gramicidin a used luminol-dependent chemiluminescence Otavio cultivation of basic study in phosphate-buffered saline (0.5 to 500 μg/ml). Then the resulting solutions were added to the standard suspensions of peripheral blood leukocytes in the amount of 50 µl. Recorded peak values of spontaneous and zymosan-induced chemiluminescence. In addition, to calculate the integral indicator of activity of granulocytes index of phagocytosis.

The results were processed statistically using the computer program Microsoft Excel. To calculate the average value, the average error value, the coefficient student's t and the probability of differences R. the results of the study of granulocytes from 15 patients with cellulitis of the maxillofacial area showed that diplan induced a decrease in induced chemiluminescence about by 60.7%, and the index of phagocytosis by almost 50%. A different picture was observed when using the solutions goblinboy film gramicidin a in different concentrations.

The study of the immunomodulatory activity of the film with gramicidin

Found that the film with the gramicidin s - diplan caused a statistically significant increase in the stimulation index chemiluminescence of granulocytes to 7.5+0.1% compared with a pure solution of diplene (1,8+0,2, P<0,05). These data corresponded to the concentration of gramicidin a in complex with deploom 20 µg/ml, with other conanage explosion" in granulocytes of patients with phlegmon under influence of gramicidin S - deplin. So, for the concentration of gramicidin With 20 µg/ml duration was 2 times more than with 2% alcohol solution of gramicidin S, and was 21+1,2 min versus 10.5=1.5 min, respectively.

The data obtained allow to conclude that the immunomodulatory activity described earlier in gramicidin a and its complexes with polyvinylpyrrolidone and other polymers, medical devices, is stored in the composition described in this invention film gramicidin S.

Experiment 3

Study the influence of the film rovamycine on respiratory metabolism of leukocytes in vitro (immunotropic effect on the level of granulocytes)

Rapamycin at a dose of 100 μg/ml caused an increase in spontaneous chemiluminescence of 24%, and in doses of 1.10 or 50 μg/ml, at 50-57%. Induced chemiluminescence was reduced by 11% when adding the highest concentration of rovamycine, but increased by 13% with the introduction of antibiotic lowest concentration. As a result, the index of phagocytosis was decreased, respectively, 25% and 43%.

Thus, the results show that in a group of 12 people statistically significantly differed from the control of spontaneous chemiluminescence and the index of phagocytosis when adding rovamycine in registering sistersa complaining of bleeding gums when brushing teeth, pain when eating. If the inspection reveals a sharp hyperemia of the mucosa gingival, gingival papillae swollen, gipertrofirovannyy, bleeding upon probing, rich deposits of above - and subgingival plaque. Violations of periodontal connection unchecked, periodontal pockets are missing. Diagnosis: Chronic catarrhal gingivitis.

Treatment. Training in the rational rules of oral hygiene. Removed over - and subgingival dental plaque. On the gingival margin appliciruemah film with gramicidin S; the film is handed out to the patient with recommendations for its use in the home.

Through 2 days after the beginning of the film marked a significant reduction in redness and bleeding of the gingival margin, the disappearance of the swelling. Pain when eating significantly decreased, subjectively, the patient noted a positive trend. 6 days after the initial application: the mucous membrane of the gums pale pink color, bleeding and pain when eating and brushing your teeth are missing, signs of inflammation and swelling absent.

1. Remedy local action in the form of a biocompatible polymer plank is that the hydrophilic layer includes exogenous, endogenous or synthetic high - and low-molecular immunomodulators, Immunostimulants animal and bacterial origin, antibiotics with immunotropic and immunomodulatory activity, herbal drugs or herbal cytokines, as well as hydrophilic and hydrophobic layers contain auxiliary substances.

2. Means under item 1, characterized in that it contains endogenous Immunostimulants selected from the group of cytokines, interferons, interleukins, colony stimulating factor, factor activation of macrophages, tumor necrosis factor, erythropoietin, mielopid.

3. Means under item 1, characterized in that it contains exogenous immunomodulators of natural origin selected from the group of viruses, microorganisms, endotoxins, monopolistically, glucan.

4. Means under item 1, characterized in that it comprises a synthetic high - and low-molecular-weight substances selected from the group adaptogens, derivatives of Piran, quinone, imidazole, fluorene, organophosphorus compounds, synthetic analogs of natural nucleotides - nucleotides.

5. Means under item 1, characterized in that it contains immunomodulatory credit">

6. Means under item 1, characterized in that it contains endogenous Immunostimulants bacterial origin selected from the group lysate of bacteria, bacterial ribosome, the drug from the cell walls of bacteria, high molecular weight polysaccharide complex of microorganisms.

7. Means under item 1, characterized in that it contains an antibiotic with immunotropic and immunomodulatory activity selected from the group gramicidin S, rifampicin SV, spiramycin, lincomycin, ceftin, Ceftriaxone.

8. Means under item 1, characterized in that it contains a product of plant origin selected from the group Echinacea, licorice root, cotton, geranium, days for its sumakhs, rod-roses and tucovica, safora Japanese, turmeric, antaka.

9. Means under item 1, characterized in that it contains vegetable cytokines selected from the group of TRANS-zeatin [(6-(4-hydroxy-3-methyl)-TRANS-butene-2 Il] aminopurin; kinetin(6-furfuryl-aminopurin); 6-benzylaminopurine (N-benzylamino).

10. Means under item 1, characterized in that as auxiliary substances it contains a plasticizer, it may be included with both hydrophilic and hydrophobic layer in an amount of not more than 10% of Vista it contains substances that prolonging the action of drugs in the amount of 0.005 to 0.5 mg/cm2in the finished film.

12. Means under item 1, characterized in that as auxiliary substances it contains a pH regulating components in an amount of from 0.05 to 0.5 mg/cm2in the finished film.

13. Means under item 1, characterized in that as auxiliary substances 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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