Pharmacological composition of prolonged action

 

(57) Abstract:

The invention relates to medicine, and is intended for the treatment of inflammatory diseases of different etiologies. The invention consists in that the composition contains Jorgensen as active substances, dimexide as agent for enhancing the penetration of the active substance, and a stabilizing agent based on an aqueous solution of polyvinyl alcohol at a certain ratio of components, and a stabilizing agent contains an aqueous solution of polyvinyl alcohol in a mixture with an aqueous solution of food starch and glycerin, which allows to obtain a film-forming solution and then film with active and potentiate agents or gelling an aqueous solution of polyvinyl alcohol, which are embedded in a matrix of active and potentiate substance is gradually released when the intended use. The invention provides a composition for use primarily in the treatment of ENT diseases, dentistry and venerodermatology, a significant reduction of terms of treatment of diseases such as purulent outer and otitis media, periodontitis, aphthous stomatitis, disgidroticescoy eczema, ulcers. 4 C.p. f-crystals, 1 optical long-acting drugs, intended for treatment of various inflammatory diseases, mainly in otolaryngology, dentistry and dermatology.

Known therapeutic agent for suppressing pain, inflammation or spasm, namely inhibiting solution (RU, C. 97112158/14, publ. 20.06.99, a 61 K 38/08, C-l Omeros medical systems, Ink., US), comprising a set of solutions inhibiting agents acting through different molecular mechanisms of influence on specific target cells, which mediate the sources of pain, inflammation or spasm. Known means has a high efficiency due to the determination of the inhibiting agents, however, the need for continuous irrigation of the tissues complicates the procedure for its application requires a high consumption of medical products.

Known therapeutic agent in the form of a medicinal substance, translated into an amorphous state by joint thermo - or mechano-chemical treatment of water-soluble medicinal substance together with an agent which induces the transition to the amorphous state, which is chosen amino acid or its salt, urea, fumaric acid or its salt, microheli, maltose, maleic acid, mannitol and others, and Agincourt, the polyvinyl acetate, gelatin, soluble starch, pullulan, dextran and other (RU, C. 98103876/14, etc. 11.03.98, a 61 K 9/00, C-l Nissan chemical industries, Ltd., JP). Known therapeutic agent in the form of a pharmaceutical composition containing a solid dispersion moderately water-soluble medicinal substances, has a high therapeutic effect provided the optimal selection of the concentrations of the components, since the stabilization of the amorphous state is sensitive to the type and amount of stabilizing agent.

Known therapeutic agent for transdermal application, which represents the active substance is a steroid hormone, dispersed in a medium containing reinforcing penetration agent, and recorded in permeable polymer layer formed by the stabilizing agent, namely, the film-forming medical glue, for a given ratio of components (active substance: film former medical adhesive: volatile solvent).

Permeable layer protects in the manufacture of removable protective layer and use a remedy in the form of applications, in which the active substance is distributed evenly or splashes (EN, Pat. 2044541, PCT/EP 89/01200. so then on 11.10.89 DE, C-l Schering AG, DE, A 61 TO vozdeistviem, however, the active substance is a hormone(s) - withspecific for a number of diseases.

The most significant disadvantage of the known tools should be considered as a weakening of local immunity in the application of steroid hormones on the skin and mucous membranes, which in turn can lead to the activation of bacterial and fungal microflora.

In addition, the impact depends on the quality of the polymer layer and its ability to keep active substance in the presence of a stabilizing agent.

Known therapeutic agent, namely pharmaceutical composition for transdermal applications, including water-soluble active substance in an effective amount, enhance the penetration of the agent and a stabilizing agent at a given ratio of components is selected as the closest analogue of the proposed drug.

The task of the invention consists in the expansion of the means of transdermal prolonged action and increasing the effectiveness of therapeutic agents for use in otolaryngology, dentistry and dermatology.

The problem is solved by the fact that pharmacological composition comprising the active substance in affecting, in accordance with the invention contains as active ingredients: chlorhexidine, as well as enhancing the penetration of the agent - dimexide, in the following ratio, wt.%:

Chlorhexidine - 0,02-0,05

Dimexide - 7,0-27,0

The stabilizing agent - Rest

In addition, the composition additionally contains lidocaine in the amount of 0.5-2.0 wt.%.

In addition, the composition contains additionally solcoseryl in an amount of 0.1-2.0 wt.%.

In addition, the composition contains as a stabilizing agent, film-forming mixture of aqueous solutions of polyvinyl alcohol and starch food with glycerin, in the following ratio, wt.%:

Polyvinyl alcohol - 5,0-15,0

Starch food - 5,0-15,0

Glycerin - 10,0-30,0

Water - the Rest

In addition, the composition contains as a stabilizing agent, a gelling an aqueous solution of polyvinyl alcohol in the amount of 5.0 to 15.0 wt.%.

The invention consists in that in the presence of a stabilizing agent, based on PVA, allowing you to keep the skin and mucous active therapeutic substance, and substances that enhance transepithelial penetration of the active component, humiliate effective amount of the main active substance, that allows you to control and accelerate the healing process, minimizing the risk of side effects.

Components included in the composition, are used as drugs or are members of various dosage forms.

Chlorhexidine (SYN. Gibian HCG) is a drug from the group of halogenated, has antibacterial activity against many gram-positive and gram-negative bacteria, antifungal activity against fungi of the genus Candida, dermatophytes and Trichophyton /drugs foreign companies in Russia. The Handbook. Edited by Nikolaev Acting, 1993/. Antiseptic, anesthetic properties of chlorhexidine ensured its widespread use in surgical practice for washing wounds and body cavities after surgery, urology, gynecology, ophthalmology and very widely in otolaryngology and dentistry, while depending on the destination used ointments, gels, solutions of the active substance.

The Dimexidum (dimethylsulfoxide - DMSO) is an antiseptic agent that has anti-inflammatory and antimicrobic action, and also has local anesthetic properties when pain syndromes of different what with dissolved substances it penetrates through the skin and mucous membranes without damage to the latter, acting as a factor that is increasing the penetration of drugs across epithelial barriers.

The combination of properties of chlorhexidine (CHG) and Dimexidum due to the interaction of protonated forms of chlorhexidine with bipolar ions Dimexidum with the formation of ionic bonds in the complex. Prolongation of action of the active complex is achieved by introducing into the composition of polyvinyl alcohol (PVA). This polymer has the structure of the hydroxyl groups that can form hydrogen bonds with hydrogen atoms and nitrogen in the molecule chlorhexidine included in the complex. In addition, PVA and HCG in their structures contain methylene and hexamethylene group, which can also interact. All this leads to the immobilization of the complex HG with Dimexidum in spatial polymeric matrix.

Immobilization of the complex spatial polymeric matrix gives the opportunity to introduce small quantities of therapeutic components with specific properties, such as lidocaine - anaesthetic, and with antipruritic effect used in the treatment of atopic dermatitis, eczemas of various etiologies, aphthous stomatitis. Prolonged action of t is the spine of the subacute period of itching and pain of the skin on the background of the effect of HCG and Dimexidum.

Introduction to composition solkoserila in small quantities can be used in diseases associated with tissue damage (erosions, ulcers, and other). Solcoseryl improves trophism and regeneration of tissues, and its presence in the immobilized complex in combination with HCG and DMSO has antiseptic, antimicrobial properties, helps to prolong the effect and increase its effectiveness by combining the properties of all components while reducing the number of separate components of the composition.

The stabilizing agent on the basis of polyvinyl alcohol (PVA) is chosen, depending on the application, in a form resistant to mechanical stress and plastic polymer film or gel, which contain a matrix for immobilization of the active substance with an agent, reinforcing its action, and at the same time exhibit good adhesion to epithelial tissue - of skin or mucous membrane, allowing a gradual, prolonged transepithelial the release and permeation of the active therapeutic agent. The number of ingredients needed to obtain a specific form of the matrix, is chosen according to the required VR.11.87, publ. 15.12.91, BI N 46, 1991/.

The formation of a film stabilizing agent and its properties due to the structure and the properties of its components. PVA and starch are polymers, structuring the film, glycerin makes it more elastic. Polymer-starch, with good water absorption and swelling, as well as acceptable organoleptic properties, are included in amylose in the form of unbranched molecules helical structure with six monosaccharide units in each turn, attaches the appropriate size of the molecules in the internal channel of the spiral, and amylopectin, a branched fraction of starch with grandevalley structure, in which the separate parts of polyglycoside chains spirality like amylase. When forming the film of starch and PVA to form a polymer matrix of a mesh structure, in the micropores which are included medicinal substance.

The optimal concentrations of the component stabilizing agent, as determined in an independent study, are as follows, wt.%: PVA - 5,0-15,0, food starch - 5,0-15,0, glycerin 10,0-30,0, water - the rest.

If the content of PVA in stabilizing agent below 5.0 wt.%, the film is not formed, the composition ostvarimo in the water film, the output of the medicinal component of which is difficult.

When the starch content of less than 5.0 wt.% the resulting films are loose and scattered, and when the content of more than 15.0 wt.% decreases the rate of release of drug substances from the polymer matrix, decreases the efficiency of the component, enhancing the penetration of therapeutic component of the composition.

When the content of the glycerol is less than 10 wt.% the film is brittle, brittle, crumbly, which makes it unfit for use, and when its content is higher than 30 wt.% the resulting films are inhomogeneous structure, sticky and wet to the touch, which prevents their use.

In the presence of aqueous solution of PVA with a content of 5.0 to 15.0 wt.% the stabilizing agent is a gel-like consistency.

The technical result of the invention, a laboratory (in vitro, in vivo and preclinical studies of the inventive pharmaceutical composition, is that the components together, we could enhance therapeutic effect, and the choice of form and quantitative composition of the stabilizing agent can provide the use of the claimed composition on different sites and in cavities of the PR is compared with the known (recommended) quantities for target use.

The claimed composition was prepared as follows.

Scheme 1. A composition with a stabilizing agent in the form of a film.

The original solution of the foaming agent was prepared by obtaining an aqueous solution of polyvinyl alcohol (PVA) of a given concentration, which was heated on a magnetic stirrer until the 40oC.

Then in the heated solution was poured an aqueous starch solution of a given concentration and a specified number of glycerine, pre-mixed with the required amount of Dimexidum. The resulting mixture was heated to a temperature of 40-50oWith constant stirring for 15-20 min until a homogeneous mass in which using volumetric pipettes added the estimated number chlorhexidine (CG).

The resulting composition was poured into a form, which was placed in a thermostat for drying at a temperature of 40oWith during the day, after which the film was separated from the form for future use.

Scheme 2. A composition with a stabilizing agent in the form of a gel.

Prepared aqueous solution of Dimexidum desired concentration, was added to a solution of the PVA sample, stirred on a magnetic stirrer to obtain a gel-like mass, C for 15-20 min, then the gel is considered suitable for use.

Study of antimicrobial activity of the composition in the form of a carrier film and the gel was carried out by the method of disks to the test-culture - laboratory strains Golden stafilokok S. aureus 209. To confirm prolonged and enhanced action compositions investigated the impact of films and gel containing an aqueous solution of HG with DMSO, in comparison with films and gel-based PVA containing only HCG.

1. Standard discs, made of paper or film-based PVA, which includes HCG and/or HCG with DMSO, were placed in Petri dishes containing a layer of agar 5 mm and kept at a temperature of 37oSince, during the exposure time was the diffusion of the drug from the disk medium and a concomitant decrease in the concentration of the active substance. With an interval of 24 h, the discs were transferred into cups cooked the test culture, incubated for 20-24 h at 37 oC, then it was measuring the diameter of zones of inhibition of microbial growth, which was estimated change in antimicrobial activity depending on the time of use of the drug.

The results of studies of antimicrobial activity in the spine of an aqueous solution of HG appears in 1 day from the beginning of the experiment, and a sharp decrease in activity followed by 2-3 days;

b) introduction to the composition of DMSO increases antimicrobial activity, and the diameter of zone of inhibition increases on average by 3 +/ - 0.5 mm, almost without changing the character of the curve:

C) Antimicrobial properties of CHG in the composition with DMSO persist for 3-4 days, indicating the prolonged action of the composition;

g) compared with the solution using films contributes to a better diffusion of the drug, extending the period of its half-life.

Using the compositions obtained according to schemes 1, 2, conducted a study of its therapeutic effect on inflammatory diseases of the ear (acute and chronic purulent external otitis), inflammatory diseases of the oral cavity (periodontitis), microbial and fungal infections of the skin and mucous membrane.

Examples of specific performance.

1. The inventive pharmaceutical composition used in ENT practice in the treatment of acute and chronic external purulent otitis.

Testing conducted on three patients with an outer diffuse otitis media and one patient with mesotympanum and outer suppurative otitis media.

1.1. Patient A., aged 29, complaints of itching and boazii pathological detachable external ear canal. Objectively: the skin of the ear both ears, hyperemic, maseribane, swollen. The lumen of the external ear canal abruptly narrowed, filled with a Muco-purulent discharge. Sharp pain when pressing on the tragus of the ear and the walls of the external ear canal. Diagnosis: bilateral outer diffuse otitis media.

Before seeking care were treated independently of traditional folk and medication: antibiotics and antihistamines inside, turunda with boric alcohol and leaves of geranium, fucorcinum, sotradecol, lubrication of external ear canal antifungal ointment clotrimazole 2-3 times a day. Ongoing self-treatment for more than one week proved ineffective.

After seeking medical attention, with the consent of the patient to the external auditory meatus she was introduced turunda with gel, containing, by weight. %: HCG 0,03, DMSO 15, PVS 10, water the rest. After 30-40 minutes the itching stopped. In the next 2 days appointed antihistamine drug diasorin 1 tablet 2 times a day inside, toilet ear (dry method or boric alcohol), followed by the introduction of the pads with the composition for 30-40 min 1 per day and, subject to politologicheskijj antibiotics were not carried out. As a result of treatment were pain in the ear. After 5 days objective picture in the ear completely returned to normal, the swelling and redness of the skin, stopped gnetaceae. Subsequent observations within two months of the recurrence of the disease have been identified.

1.2. Patient N. , 40 years old, with a diagnosis of unilateral external recurrent diffuse otitis media (fifth aggravation). Before applying for medical assistance patient was treated independently (see example 1.1) by known means. Positive results occurred after 10-14 days. During the last exacerbation effect from the use of drugs during the week has not come, which was interpreted by the patient as the emergence of resistance to drugs used in self-treatment, after which the patient asked the doctor.

As in example 1.1, the patient was assigned turunda with composition-based gel, in which the content of components was, wt.%: HCG 0,02, DMSO 10, PVA 5, water the rest, with the same treatment regimen that in example 1.1. Subjectively, the patient was noted positive dynamics of the process: the subsidence of the itching in the ear, a sharp decrease of the discharge from it, improve hearing. The object is hyperemia of the skin. Side effects and allergic reactions are not identified. During the two months of monitoring disease recurrence was not observed.

1.3. Patient S., 44 years old, with a diagnosis of unilateral external recurrent otitis media, in order to ensure they received the pads with gel, in which the content of components was, wt.%: HG 0,05, DMSO 20, PVA 10, water the rest, the treatment was carried out according to the scheme of example 1.1. Subjectively: the observed fast dynamics improvement ear during treatment. Objective: purulent discharge from the ear stopped after two days, the 7th day the swelling and redness of the skin of the outer ear canal. Reducing the duration of treatment is associated with increased antimicrobial activity of the composition containing DMSO, which is not only enhancing the antimicrobial action of the agent, but also analgesic.

1.4. Patient X. , 62 years, from the age of three suffered bilateral chronic suppurative otitis media with frequent exacerbations and associated external otitis due to the constant irritation of the walls of the external ear canal Muco-purulent discharge. According to the testimony of the right ear removed a large polyp and granulation, and then discharge from the ear acquired slimy character, decreased, then the ode. According to the patient, previously it was treated by instillation of and introduction to the ears of Turunc with boric and levomitsetinovym alcohols, sulfacetamide, sotradecol, dioksidin. The effect (decrease puffiness of the skin, pain and itching in the ear) usually requires medical treatment for 3-6 weeks. In recent exacerbation of the disease the patient was noted hearing loss and mild pain in the right ear, stringy mucous-purulent discharge from it. Objective: the lumen of the external ear canal is narrowed, skin redness, maseribane, poor Muco-purulent discharge. The saved portion of the eardrum moderately hyperemic, perforation pus is not received; seeded discharge from the ear abundant growth of Staphylococcus aureus. Treated as in example 1.1, and discharge in the ear of the composition for 10 minutes after the dry toilet ear for the prevention of recurrent otitis media, and KUFA, on a background of reception of diazoline inside. After 7 days of outpatient treatment of ear discharge decreased, became scarce, acquired slimy character, and to the 11-th day after the start of treatment the patient objectively healthy. In the control seeding from ear Staphylococcus aureus not detected.

Monitoring statistics of patients with pus is Noah ear (after shower) and introduce it on Toronto even once a day for 30-40 min in all patients after 2-3 days abates pain in the ear, decreases the amount of discharge, it disappears unpleasant smell. The condition of all patients improved after an average of 7-10 days, with 90% of patients cease discharge from the patient's ear, disappears hyperemia and swelling of the skin of external ear canal, the eardrum becomes normal color. The lack of effect of the composition is caused, generally, by reducing the reactivity of the organism in connection with therapeutic diseases. There are no side effects and allergic reactions to the song, and also fungal infections, sometimes developing in a patient ear as a result of treatment with antibiotics, which is associated with the fungicidal activity of HCG.

2. Conducted a study of the composition to determine the possibility of its application in dentistry for the treatment of generalized periodontitis, in which the inflammatory process is caused by such organisms as Streptococcus, Staphylococcus, leptothrix and fungi of the genus Candida, etc.

Evaluation of the effectiveness of the composition was carried out in the experiment as follows. From the gingival pocket with a paper of pins swabs were taken and placed in a liquid nutrient medium (broth). Swabs were incubated at temperaturethe-salt, blood agars) in order to subsequently obtain pure culture (Streptococcus and others).

Method of disks in mesopatamia agar using pure cultures isolated from periodontal pockets, determined the influence of composition on the microorganisms, as measured by zone of inhibition of growth (at a temperature of 37o(C) during the observation time (1-5 days). The analysis showed that the inhibition of growth of microorganisms in the composition as a whole and its components in isolation is almost identical to the results shown in the table, and appeared to be particularly effective film with the active substance, consistently high effect of which was observed within 1-5 days, while the solutions provided equivalent antimicrobial activity only during the first day.

Conducted clinical research on the effectiveness of the composition against diseases of the oral cavity.

2.1. Patient B., aged 40 years, has complained of bleeding gums for a long time, when brushing your teeth and taking solid food. When the examination is marked hyperemia and swelling of the gingival margin, abundant above - and subgingival dental plaque, gingival pockets 5-7 mm with serous discharge, krovotechenii exacerbation, moderate severity.

By the standard method defined clinical indices, which amounted to: hygiene index Fedorov-Volodkina 4 points, PMA - 20,8%.

When x-ray examination revealed osteoporosis interdental septa and resorption of the alveolar bone from 1/3 to 2/3 length of roots for the upper and lower jaws.

After professional oral hygiene (removal of supra - and subgingival dental plaque in periodontal pockets was introduced film based on PVA, as the active substance-containing, wt.%: HCG 0,03, DMSO 25, the composition of the film was as follows, wt.%: an aqueous solution of PVA 10, an aqueous solution of starch 10,0, glycerin 10,0, water the rest.

Procedures were performed 2 times per week. Dissolving films continued for 30 minutes After 5 sessions of treatment indicated the disappearance of bleeding gums when brushing your teeth and eating, reducing redness and swelling of the gingival ticking.

2.2. Patient A. , 35 years old, came with complaints of pain in the mouth, impairing food intake. Inspection of the oral mucosa detected small atty. Diagnosis: recurrent aphthous stomatitis. The treatment with the use of a composition in the form of GE is directly on the mucous membrane of the mouth, covering atty, and repeated applications after eating and mouth. Subjectively: the effect of remitting pain came after about 15 min after the beginning of the procedure, atty quickly regressed. Objective: the overall improvement noted on the fourth day since the beginning of the application of the composition.

3. Conducted research on the possibility of using the compositions for treatment of diseases of the skin and mucous - purulent-inflammatory processes and fungal (Candida) lesions.

3.1 the Group of patients out of 3 people diagnosed with Lichen simpiex chronicus was conducted for each treatment using the compositions in the form of a gel based on PVA, in which the content of components was, wt.%: HCG 0,03, DMSO 25, PVA 10. The bandage with the gel applied on the affected skin for a period of 48 hours, then removed the blindfold. Subjective: each patient noted significant improvement in their condition, the disappearance of the attacks of itching, reduction of lichenization.

3.2 the Group of patients with disgestrotical eczema (4 people) for the treatment of superimposed bands with the gel containing the active substance, and after 48 h the bandages were removed. Subjective: in patients as a result of application of the composition was filmed itching, decreased the vesiculation, there was no prisoedinjajtesj eczema, as in example 3.2, but with the purpose of strengthening antipruritic and anti-inflammatory effect in the composition was introduced solcoseryl in the amount of 1 wt.%. After 48 h, the patient noted a decrease itching, objectively decreased vesiculation. After application of the composition in 1 week noted that the patient is healthy, joining a secondary infection was not observed.

3.4. Patient Century, 50 years, suffered from long-term nezajimavy ulcers in the leg region. The patient is assigned to treatment, as in example 2, and the composition was introduced lidocaine in the amount of 1 wt.% in order to enhance tissue regeneration. After 48 h after dressing noted cleansing ulcers from microflora and its epithelialization, and after two days marked decrease in the size of leg ulcers and persistent tendency to heal eroded surface.

The use of the composition makes it possible in the future to abandon the system of hormonal therapy in the treatment of certain skin diseases, which contributes to the immune status of the patient and in turn allows to avoid activation and fungal microflora.

Known application of antimicrobial drug prolonged action based solution HMPC And 61 To 6/02, 31/155/.

Known concomitant topical application of chlorhexidine and Dimexidum for the treatment of rubromycosis smooth skin disease caused by the fungus Trichophytum rubros /Pat. EN 1805960, C-l Sverdlovsk research Institute of STI, publ. 30.03.93/ aimed at decreasing time conversion rate of fungi in the centers of the lesions and reduce side effects, for which the foci of lesions grease 1% chlorhexidine solution 50% solution of Dimexidum scheme 2 times a day for 3 weeks. We can predict that in contrast to the known means of the inventive composition is prolonged action allows you to not only significantly reduce the effective amount of the active substance, but also to improve convenience of treatment, reduce the time of healing.

In addition, the use of active substances in the form of irrigation generally requires higher concentrations to achieve therapeutic effect, while the introduction of these substances into a polymer gel or a film having the properties of good fixation on the skin and mucous membrane, can significantly reduce current concentration, and ensure a long lasting effect on the lesion. This arrangement allows that in relation to the disease site, what contributes to the effectiveness of treatment due to the synergistic effect of the composition, due to the properties of its components, and minimize adverse effects from the use of drugs.

The claimed composition expands the Arsenal of drugs, broad-spectrum, has a therapeutic effect in diseases of the ear, throat, nose, mouth, mucous membrane and skin with minimal side effects due to gradual income of small amounts of active substance in the body, significantly reduces the time of treatment of primary patients and facilitates the course of chronic diseases.

1. Pharmacological composition of prolonged action, comprising at least one active substance in an effective amount, enhance the penetration of the agent and a stabilizing agent at a given ratio of components, characterized in that it contains as active substance chlorhexidine, and as a reinforcing penetration agent - dimexide, in the following ratio, wt. %:

Chlorhexidine - 0,02-0,05

Dimexide - 7,0-27,0

The stabilizing agent - Rest

2. The composition according to p. 1, characterized in that it complements niteline contains solcoseryl in an amount of 0.1-2.0 wt. %.

4. The composition according to p. 1, characterized in that it contains as a stabilizing agent, film-forming mixture of aqueous solutions of polyvinyl alcohol and starch food with glycerin, in the following ratio, wt. %:

Polyvinyl alcohol - 5,0-15,0

Starch food - 5,0-15,0

Glycerin - 10,0-30,0

Water - the Rest

5. The composition according to p. 1, characterized in that it contains as a stabilizing agent, a gelling an aqueous solution of polyvinyl alcohol in the amount of 5.0 to 15.0%.

 

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