The polymers of alkylarylsulfonates with antioxidant properties

 

(57) Abstract:

The invention relates to the field of medicine and for the application of polymer alkylarylsulfonates for effective inhibition of oxidant in chemical or biological system, as well as medications, including these polymeric compounds. Preferably, the drug includes a physiologically acceptable carrier, which may be selected from the group consisting of a physiological buffer solutions, isotonic saline, normal saline, ointments based on petroleum butter and paste from the cold. 3 C. and 30 C.p. f-crystals, 5 Il., 3 table.

The present invention relates to the use of polymer alkylarylsulfonates as antioxidants to suppress some oxidative chemical reactions that cause tissue damage and disease in mammals and plants.

Oxygen gives life aerobic plants and animals that need it for energy metabolism. It can also serve as a lethal factor for the same organisms when it moves from a stable state, as expressed in the presence of two atoms of oxygen (O2), lub one electron; b) hydrogen peroxide (H2O2), when reversed two electrons, or) is a lethal hydroxyl radical (.OH, when restored three electrons. In biological systems O2-and H2O2are byproducts of the metabolism of the host enzymes (oxygenase), which use oxygen as cofactor. H2O2also formed from the O2-when the enzymatic action of the peroxide-dismutase. However,.OH usually formed only in the case when O2-and H2O2interact with ions of transition metals, such as iron and copper, with dangerous cyclic auxiliare-reduction reactions:

O2-+Fe3- Fe2++O2< / BR>
H2O2+Fe2+- Fe3++.OH+-OH

The above reaction is called the Fenton reaction, caused by the peroxide. The Fenton reaction can also initiate other reducing agents such as salts of ascorbic acid in the presence of iron ion (+3) and H2O2.

Because O2-and H2O2are toxic to biological systems,.OH (and its alternative gipotetichiskoe unsaturated membrane lipids, damage to cellular proteins and mutagenic strand breaks of DNA. To prevent damage caused partially restored to normal conditions by the formula O2the cells produce a complex system of antioxidant enzymes (peroxide dismutase, catalase, glutathione peroxidase) and molecule antioxidants (glutathione, alpha-tocopherol, beta-carotene). However, when the formation of partially reduced forms O2exceeds the capacity of cellular antioxidants to protect against them, causes damage to the cells by oxidant. Now suppose that a growing number of diseases in mammals is associated with the formation of excessive amounts of partially reduced forms O2these diseases include reperfusion syndromes, myocardial infarction and sudden seizures, respiratory distress syndrome, adult, oxygen toxicity of the lung, the lung damage caused by asbestos, Parkinson's disease, heat and sun burn skin and damage to the gastrointestinal tract nonsteroidal anti-inflammatory drugs (see table IV, page 60, Haliwell B. and Gutteridge JMC. Methods in Enzymology, (1990) 186:1-85). In addition, studies show that cells of the respiratory tract in pain that the enzyme derived leukocytes, representing myeloperoxidase present in large numbers in the bronchial secretions of patients with cystic fibrosis, is subjected to the action of hydrogen peroxide, turn neutrophile leukocytes in HOCl/OCl, the main oxidant-derived leukocytes. See, for example, Cantin and other "Protection by Antibiotics Against Myeloperoxidase Dependent Cytotoxicity to Lung Epithelial Cells in Vitro", Journal of Clinical Investigation (January 1993) 91:38-45; Ramsey and others, "Efficacy of Aerosolized Tobramycin in Patients with Cystic Fibrosis", The New England Journal of Medicine (June 1993) 328:1740-1746; Vasconcellos and others, "Reduction in Viscosity of Cystic Fibrosis will excrete sputum in by Gelsolin", Science (February 1994) 263:969-971. The treatment of these diseases is on the road to prevent enzymatic formation of partially reduced forms O2or route of administration of exogenous antioxidants that restore the balance of oxidant-antioxidant in biological and chemical systems.

Antioxidants are compounds that can be easily oxidized with the formation of stable chemical forms. They can protect chemical and biological systems, undergoing oxidation faster than vital molecules of chemical and biological substances. Not all oxidizable compounds can function as antioxidant. For us what actionresponse against oxidant than a molecule of a chemical or biological substance, which he must defend. It is theoretically possible to synthesize many compounds with anti-oxidant. However, the factor limiting the use of these antioxidants for treatment of biological systems, is the toxicity inherent to the antioxidants. Thus, great advantages is the discovery of the fact that substances from the class of non-toxic ingredients commonly used in pharmaceutical preparations in medicine, are also potential antioxidants. Such compounds are not only able to react with the partially restored by the formula O2but they can be used to treat diseases caused by oxidants, while they themselves are not toxic to biological systems.

The polymers of alkylarylsulfonates known and used in industry as surface-active detergents and wetting agents (U.S. patent 2454541 included in the present description by reference). The polymers of alkylarylsulfonates described in this patent can be used according to the present invention.

The structural formula of the representative of this KL1,3,3-TETRAMETHYLBUTYL)phenol, formaldehyde and oxirane.

Tyloxapol use in pharmacological drugs for people over 30 years (Tainter, M. L. and other New England Journal of Medicine (1995), 253:764-767). Tyloxapol is relatively non-toxic and does not cause hemolysis of red blood cells at concentrations 1000 times the concentration of other detergents, which are hemolytic (Glassman HN. Science (1950) 111:688-689).

The present invention is to provide a method of inhibiting oxidative chemical reactions caused by partially reduced forms O2.

Another objective of the present invention is to provide a composition for the inhibition of oxidants.

Another object of the present invention is to provide drugs for the inhibition of oxidants in animals that is used for the treatment of cystic fibrosis patients, in order to protect patients from damage to the respiratory system OHCl/OCl, which for convenience hereinafter referred to as HOCl.

This object is achieved by the use of polymer alkylarylsulfonates General formula

< / BR>
where

R is ethylene;

R' is tert-octyl;

X is greater than 1, and Y is 8 - 18; the animals and plants.

As the polymer alkylarylsulfonates preferably used a polymer-based alkylacrylate, formaldehyde and oxirane, it is most preferable to use a polymer based on 4-(1,1,3,3-TETRAMETHYLBUTYL)phenol, formaldehyde and oxirane.

The task is also achieved by a composition for the inhibition of oxidant containing an effective amount of polymeric alkylarylsulfonates, the General formula of which is shown in Fig. 1.

The composition is preferably used for the inhibition of oxidant in chemical reactions, in particular for the inhibition of oxidants in animals and in plants.

According to preferred variants of the composition contains an effective amount of a polymer-based alkylacrylate, formaldehyde and oxirane and in a more preferred embodiment, it contains an effective amount of a polymer based on 4-(1,1,3,3-TETRAMETHYLBUTYL)phenol, formaldehyde and oxirane.

The composition may contain a physiologically acceptable carrier, which is selected from the group including physiological buffer solutions such as isotonic saline and normal saline.

occhialino is 6.4 - 7,5.

The composition can be used in combination with polimernym alcohol, such as cetyl alcohol.

The task is also achieved drug for the inhibition of oxidants in animals containing the active substance and conventional additives, in which the active substance use polymer alkylarylsulfonates, the General formula of which is shown in Fig. 1.

As the polymer alkylarylsulfonates in medicine it is preferable to use a polymer-based alkylacrylate, formaldehyde and oxirane, and more preferably a polymer based on 4-(1,1,3,3-TETRAMETHYLBUTYL)phenol, formaldehyde and oxirane.

The drug preferably has a pH in the range from 6.4 to 8.4.

According to preferred variants of execution of the present invention the drug is directly injected in small doses into the respiratory tract as an aerosol. In this embodiment, the drug is preferably contains a physiologically acceptable carrier, which may be selected from the group consisting of physiologically buffered solutions such as isotonic saline solution and HN, include isotonic saline, normal saline, sodium bicarbonate and mixtures thereof. The carrier may be selected from polimernogo alcohol, preferably of cetyl alcohol, glycerol and mixtures thereof.

According to other preferred variants of execution of the invention the drug is applied locally on the skin. In this embodiment, the drug is made in the form of ointments on the basis of petroleum butter or paste from the cold by the US Pharmacopoeia.

The drug is preferably administered together with a physiologically acceptable solution, which is used as a physiological buffer solutions.

In a preferred variant, the drug is used to treat nosological forms of cystic fibrosis in a mammal resulting from excessive amounts of HOCl.

The advantage of this invention is that therapeutic agent is obtained from a class of compounds with low toxicity potential with respect to biological systems.

From the following description, which includes several figures and examples, the specialist in this field will become more clear goals and mainly the drawings.

In Fig. 1 shows the structural formula of the class of compounds known as polymer alkylarylsulfonates.

In Fig. 2 is a diagram of the inhibitory effect of tyloxapol to the educational process .OH by the Fenton reaction, measured by the hydroxylation of salicylate.

In Fig. 3 is a diagram of the inhibitory effect of tyloxapol to the educational process.OH by the Fenton reaction, measured by the oxidation of sugar-2-deoxyribose.

In Fig. 4 shows the weight ratio of wet light/dry lung in rats exposed to 100% oxygen and treated with normal saline, tyloxapol and a mixture of tyloxapol with etilovym alcohol.

In Fig. 5 shows the accumulation plemennoi fluid in rats exposed to 100% oxygen and treated with normal saline, tyloxapol and a mixture of tyloxapol and cetyl alcohol.

The polymers of alkylarylsulfonates in General can be synthesized by the condensation of alkylarenes with formaldehyde, as described Bock and Rainey in U.S. patent 2454541 (1948, Rohm and Haas). Some specific polymers alkylarylsulfonates can easily synthesize the previously described methods, the purity can be purchased from the company Rohm and Haas Co., Philadelphia, PA.

For the treatment of respiratory diseases in mammals associated with excess of partially reduced forms O2the polymer alkylarylsulfonates dissolved in sterile 0.9% of NaCl solution to obtain the injection solution and set about pH to 7.0 by adding NaOH or HCl. To improve the efficiency of the mixture for protection against oxidants can be added polimerny alkyl - or allsport, for example, cetyl alcohol (hexadecanol) in an amount of 1 to 1.5 times the weight of tyloxapol. This mixture is then injected into the lung by direct filing in small doses in the respiratory tract. The mixture can also be introduced in the form of an aerosol spray using applicable in the clinic sprayer, working under pressure and providing inhaled particles with an average diameter of less than 5 microns. For example, prepare a 0.125% solution of tyloxapol in sterile 0,9% NaCl solution in distilled twice in a glass container with deionized water to obtain isotonic with respect to respiratory secretions. the pH is set to about 7,0 to prevent bronchospasm because of the excessive acidity or alkalinity. This mixture is sterilized by vakuumfiltre h is STU 5 ml with rubber stoppers fixed corrugated aluminum, removable closures. To provide additional sterilization of the product ampoules for standard doses aged in an autoclave at 125oC for 12 - 14 minutes To the above mixture to stabilize the droplet size with the introduction of the aerosol can add glycerin 5% concentration. For the introduction of effective dose are inhalation 3 ml of a sterile solution of tyloxapol in the form of an aerosol spray every 4 to 6 h using applied in the clinic, working under pressure sprayer (Acorn or deVilbiss). You can also spray the mixture into the respiratory system mechanical fan. Beta-sympathetic bronchodilatory-agonist (e.g., 1,25 - 2,5 mg albuterol) can be mixed with a solution of tyloxapol or spraying to prevent temporary bronchospasm, which may occur from use of the solution of tyloxapol.

For treatment of skin caused by oxidant damage, such as sunburn, prepare 0.5 to 5% mixture (weight/weight) of alkylarylsulfonate, such as tyloxapol, and industrial based ointment petroleum butter, for example, Aquaphor (Beiersdorf, Inc., Norwalk, CT), white petroleum butter or paste according to the Pharmacopoeia Increased understanding of the present invention provides the following examples, in more detail, illustrating some of the specific details of the invention.

In the example I shows the high activity of the polymer alkylarylsulfonates as inhibitors.OH in chemical systems. In example II shows therapeutic benefit of using polymer alkylarylsulfonates to prevent damage to the lungs of mammals when exposed to 100% oxygen. In study III demonstrated the high activity of the polymer alkylarylsulfonates as HOCl scavengers in chemical mixtures.

Example I

Inhibition of oxidant formed by the reaction of Fenton

In the first chemical system used for testing antioxidative activity of polymer alkylarylsulfonates, as a target molecule of the oxidizing agents used salicylate. Hydroxyl radical reacts with salicylic acid (2-oksibenzoynoy acid) with the formation of two deoxybenzoin acids, in particular 2,3 - and 2,5-deoxybenzoin acid. These gidroksilirovanii products are proof of education.OH (R. A. Floyd and others, Journal of Biochemical and Biophysical Methods (1984) 10:221-235; R. A. Floyd and others, Journal of Free Radicals in Biology and Medicine (1986) 2:13-18). Determination of 2,3 - and 2,5-dioxobenzo what the op. For education and discovery .OH use suspension 10 μm FeCl3, 1.0 mm H2O2, 1.0 mm ascorbate, and 10.0 μm salicylic acid. Add 0.1 ml of normal saline or tyloxapol (final concentration from 0.0 to 10 mg/ml). The reaction mixture is maintained at 45oC for 30 min and centrifuged for 10 min at 1200g. Insufficient liquid is centrifuged (Beckman Microfuge E) through the tubular filter (0.22 micron) (PGC Scientific 352 N - 118) at 15000g. 100 μl of the sample of the eluate served in the column GHUR C18 RP (h,7 mm, Beckman N 235329). Gidroksilirovanii products musk determine quantitatively using an electrochemical detector (Coulochem (ESA model 5100A), and the reduction potential of the detector is set to -0,40 B (DC). The oxidation potential of the safety cell (used as a screen) set to +0,40 B (DC). The measurements are performed twice. In Fig. 2 shows that the addition of tyloxapol to the reaction mixture inhibits the formation of.OH, and this process depends on the concentration.

The second chemical system used to study the antioxidant activity of polymer alkylarylsulfonates, as molecules of microducts. When heated with thiobarbituric acid (TBA) at low pH, these products form a chromophore pink color, which can be detected by absorption at a wavelength of 532 nm (B. Halliwell and J. M. C. Gutteridge. Methods in Enzymology (1990) 186:1-85). Chemical system used for the formation of oxidants, is a reaction mixture containing 10,0 µm FeCl3, 1.0 mm ascorbate, 1.0 mm H2O2and 1.0 mm deoxyribose in a balanced salt solution Hank. This system is suitable for measuring site-specific education.OH on biological molecules, as described by Halliwell and Gutteridge in the link above. Add 0.1 ml of normal saline or tyloxapol (final concentration of 0.0-10.0 mg/ml).

The reaction mixture is maintained at 45oC for 30 min and centrifuged at 1200g for 10 min To 1.0 ml of the supernatant liquid add one ml of the two acids, namely to 1.0% (W/V) TBA and 2.8% (W/V) trichloroacetic acid, heated for 10 min at 100oC, cooled on ice three times and determine the chromophore by its absorbance at a wavelength of 532 nm. In Fig. 3 shows that the addition of 10 mg/ml of tyloxapol to the reaction mixture leads to inhibition of the oxidation of deoxyribose that shows the absorbance okislitelnyh of alkylarylsulfonates use asbestos as a source of iron for the formation of oxidant and 2-deoxyribose as a target molecule for oxidants. The formation of oxidants in the use of asbestos has been described previously (A. J. Ghio and other American Journal of discrimination (Lung Cellular and Molecular discrimination 7) (1992) 263:L511-L518). The reaction mixture of a total volume of 2.0 ml of phosphate-saline buffer solution (FSB) contains the following reagents: 1.0mm deoxyribose, 1.0 mm H2O2, 1.0 mm ascorbate and 1.0 mg/ml crocidolite asbestos. The mixture was incubated at 37oC for 1 hour under stirring, and then centrifuged for 10 min at 1200g. Education oxidant set by determining the reactive TBQ-food deoxyribose, as described in detail above. Measurements carried out three times. The table shows that the addition of tyloxapol inhibited depending on the concentration of the formation of oxidants with the use of asbestos, as evidenced by the absorption of the product of the oxidation reaction at a wavelength of 532 nm.

Example II

Protection of the lungs of mammalian under the action of 100% oxygen

In order to determine whether polymer alkylarylsulfonate to protect intact biological systems from the harmful effects of oxidants, study their effect using well-known models of toxicity of oxygen towards the lungs (J. F. receive a dose of 0.5 ml normal saline, tyloxapol (6.0 mg) or tyloxapol (6.0 mg) and cetyl alcohol (hexadecanol, 11.0 mg). These rats (in each treated group (10 rats) and then exposed to either air or 100% oxygen in the cells of plexiglass with a speed of 10 l/min, the Percentage of oxygen regulate polarographic electrode and continuously support this value above 98%. The temperature is 20 - 22oC. survival Time is determined by monitoring the condition of the animals every 4 hours. Separate groups of rats received the same treatment in each group of 10 animals), exposed to 100% oxygen for 61 hours and then kill 100 mg/kg of pentobarbital entered administered intraperitoneally. Volume plemennoi fluid is measured by pumping the fluid from the chest cavity through a small incision in the diaphragm. For the left lung counting weight ratio - liquid filled light/dry lung after drying fabric within 96 h at 60oC. Data on survival rates are shown below in table II. Rats that received tyloxapol vnutritrahealno, survived in much greater numbers compared to the control animals that received saline (placebo). Protective effect of tyloxapol usilit light/dry lung were significantly lower in rats who received tyloxapol or a mixture of tyloxapol with etilovym alcohol (Fig. 4), which shows that tyloxapol or a combination of tyloxapol and cetyl alcohol protects against the formation of swelling under the action of an oxidant. In rats that received tyloxapol or tyloxapol in combination with etilovym alcohol, also there is less accumulation plemennoi fluid than in control animals that received saline (Fig. 5). These results demonstrate the ability of the polymer alkylarylsulfonates, such as tyloxapol, to protect tissue from oxidizing agents. A study of the surviving rats (table II) also shows that the protective action of the medicinal product is amplified in a mixture with alcohols, for example etilovym alcohol.

Example III

Remove HOCl

The activity of tyloxapol deleting OCl-1experience, studying its ability to prevent induced oxidant OCl-1the conversion of diethanolamine to the appropriate chloramine ("Determination of HOCl Production by Micloperoxidase", Robert A. Greenwald, editor, Handbook of Methods for Oxygen Radical Research, CRC Press, Boca Raton, Florida (1987), page 300). The reaction mixture contains 0.9 ml of 10.0 mm diethanolamine in 0.1 M buffer sodium acetate, pH 4.5. To this mixture is added either 100 ál of 0.1 M NaCl and measure absorb the measured absorbance at a wavelength of 280 nm. The difference in A280before and after addition of NaOCl is used as a measure of the concentration of stable chloramine. Experiments repeated three times. The results are shown below in table III.

Thus, tyloxapol is a potent inhibitor of oxidative activity of HOCl and shall be suitable to prevent HOCl caused oxidative damage to the Airways in the case of diseases such as cystic fibrosis. The use of tyloxapol by tracheal his introduction patients with cystic fibrosis leads to inhibition of HOCl formed in these patients and, therefore, protects them from oxidative damage. The result should be even better if mixed with tyloxapol a certain amount of cetyl alcohol, it is preferable to add the cetyl alcohol in an amount of 1 to 1.5 times the weight of tyloxapol. Sample preparation for the introduction of patients should be the same as described above, the most preferred inhalation 3 ml of a 0.125% aqueous solution of tyloxapol in the form of an aerosol spray every 4 to 6 hours

1. The use of polymer alkylarylsulfonates General formula

< / BR>
where R is ethylene;

R' is tert-octyl;

x is greater than 1, and y is 8 - 18,

for invisionize animals and plants.

3. Use one of the PP.1 and 2, where the polymer alkylarylsulfonates use polymer-based alkylacrylate, formaldehyde and oxirane.

4. Use one of the PP.1 to 3, where the polymer alkylarylsulfonates use polymer based on 4-(1,1,3,3-TETRAMETHYLBUTYL)phenol, formaldehyde and oxirane.

5. Composition for inhibiting oxidizing agents, characterized in that it contains an effective amount of polymeric alkylarylsulfonates under item 1.

6. The composition according to p. 5 for the inhibition of oxidant in chemical reactions.

7. The composition according to PP. 5 and 6 for the inhibition of oxidants in animals and in plants.

8. Composition according to any one of paragraphs.5 to 7, characterized in that it contains an effective amount of a polymer-based alkylacrylate, formaldehyde and oxirane.

9. The composition according to p. 8, characterized in that it contains an effective amount of a polymer based on 4-(1,1,3,3-TETRAMETHYLBUTYL)phenol, formaldehyde and oxirane.

10. Composition according to one of paragraphs.5 to 9, characterized in that it contains a physiologically acceptable medium.

11. The composition according to p. 10, characterized in that but who the target and normal saline.

12. The composition according to p. 10, characterized in that it is made in the form of ointment (based on petroleum butter) or in paste form.

13. Composition according to one of paragraphs.5 to 10, characterized in that it has a pH in the range of 6.4 - 7.5.

14. Composition according to one of paragraphs.5 to 13, characterized in that it is used in conjunction with polimernym alcohol, such as cetyl alcohol.

15. Drug for inhibition of oxidants in animals containing the active substance and conventional additives, characterized in that the active substance use polymer alkylarylsulfonates under item 1.

16. Drug under item 15, characterized in that the polymer alkylarylsulfonates use polymer-based alkylacrylate, formaldehyde and oxirane.

17. Drug under item 15, characterized in that the polymer alkylarylsulfonates use polymer based on 4-(1,1,3,3-TETRAMETHYLBUTYL)phenol, formaldehyde and oxirane.

18. The drug in one of the paragraphs.15 to 17, characterized in that it comprises a physiologically acceptable carrier.

19. Drug under item 18, characterized in that the nose is creative and normal saline.

20. Drug under item 19, wherein the physiological buffer solutions are selected from the group including isotonic saline solution, normal saline, sodium bicarbonate and mixtures thereof.

21. Drug under item 18, characterized in that the medium is selected from polimernogo alcohol.

22. Drug under item 21, wherein polimerny alcohol is chosen from cetyl alcohol, glycerol and mixtures thereof.

23. Drug under item 18, characterized in that it is made in the form of ointments on the basis of petroleum butter or paste.

24. The drug in one of the paragraphs.15 to 23, characterized in that the medicinal product has a pH in the range from 6.4 to 8.4.

25. The drug in one of the paragraphs.15 to 24, characterized in that it is injected directly into the respiratory tract.

26. The drug in one of the paragraphs.15 to 24, characterized in that it is used in aerosol form.

27. The drug in one of the paragraphs.15 to 24, characterized in that it is applied on the skin.

28. The drug in one of the paragraphs.15 to 24, characterized in that it is administered in conjunction with physiologically priemlemim solution using physiological buffer solutions.

30. Drug for p. 29, characterized in that the physiologically acceptable buffer solutions using physiological buffer solutions selected from the group comprising isotonic saline solution, normal saline, sodium bicarbonate or mixtures thereof.

31. The drug in one of the paragraphs.15 to 28, characterized in that it is used in combination with polimernym alcohol.

32. Drug under item 31, wherein polimerny alcohol is chosen from cetyl alcohol, glycerin, or a mixture thereof.

33. The drug in one of the paragraphs.15 - 32, characterized in that it is used for the treatment of nosological forms of cystic fibrosis in a mammal resulting from excessive amounts of HOCl.

 

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