Agent of peptide structure possessing anti-inflammatory, antibacterial, wound-healing, regenerative, analgesic, burntreating action and based dosage forms

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmacology and medicine and concerns using a dipeptide of a general formula Tyr-Pro-X, where X - OH, NH2, OCH3, OC2H5, as an anti-inflammatory, antibacterial, wound-healing, regenerative, analgesic and burntreating agent for external application, as well as a dosage form for external application containing this dipeptide.

EFFECT: group of inventions provides preparing the effective agent for external applications with no side effects.

3 cl, 1 tbl, 22 ex

 

The invention relates to the field of biologically active compounds and can be used for wound healing drugs for the treatment of damaged skin, wounds, burns and skin diseases, method of its production.

The problem of treatment of wounds, burns and other skin damage, despite the large variety of proposed methods and drugs, remains relevant. In most cases, in the treatment of wounds preference is given to local drug treatment ((Gavrilyuk B.K. Nanocomposite regeneration system for the treatment of wounds/ B. K. Gavrilyuk, W. B. Gavrilyuk. - (Biophysics of complex systems) //Biophysics. - 2011. - T. 56, No. 6. - S-1141; Lloyd EU, Rodgers SU, Michener M, MS Williams. Outpatient burns: prevention and care. Am Fam Physician. 2012 Vol.85(1), P.25-32; Profyris C, Tziotzios C, Vale Do I. Cutaneous scarring: Pathophysiology, molecular mechanisms, and scar reduction therapeutics Part I. The molecular basis of scar formation. J Am Acad Dermatol. 2012, Vol.66(1), P.1-12; Elliot D, Sierakowski A. The surgical management of painful nerves of the upper limb: a unit perspective. J Hand Surg Eur Vol.2011 Vol.36(9), P.760-770). However, it should be noted that the effectiveness of the proposed treatment depends in this case not only on the correct choice of drug, but also the form in which it should be applied (Endorf FW, D. Ahrenholz Burn management. Curr Opin Crit Care. 2011 Vol.17(6), P.601-605). Widely used anti-inflammatory drugs, which are divided into steroid and non-steroid. Nonsteroidal protivo sporitelny means reduced exudation, inhibit proliferation of tissues, analgesic and reduce the temperature. Their disadvantage is the high toxicity. Steroid anti-inflammatory drugs are analogues of glucocorticoids. Power antiexudative action is superior to non-steroidal anti-inflammatory drugs several times, but do not possess analgesic and antipyretic action and with long-term use cause a disruption in hormonal levels in the body. Also used antimicrobials, however, they contribute allergization of an organism, the development of sustainable wound microflora and dysbacteriosis. The use of preparations of enzymes (proteases, trypsin, chemotrypsin, amino acids and others) are limited in their effectiveness only in the first phase of wound healing and the need for them to be combined with other wound healing drugs. A complex action on the wound have herbal medicines due to the content of complex flavonoid compounds and vitamins, but they do not have analgesic properties (Mendonca Machado N, Gragnani A, Masako Ferreira L. Bums, metabolism and nutritional requirements. Nutr Hosp.2011 Aug; 26(4):692-700; Lloyd EC, Rodgers SU, M Michener, MS Williams. Outpatient burns: prevention and care. Am Fam Physician. 2012 Vol.85(1), P.25-32). Known wound-healing and anti-inflammatory drugs in the form of creams and ointments containing active vases is in, fatty base (blend of lanolin and vaseline) and additives. However, lanolin base in these drugs interferes with the normal gas exchange, which reduces wound healing activity of the drug, especially when slow processes (Profyris With, Tziotzios With, Vale Do I. Cutaneous scarring: Pathophysiology, molecular mechanisms, and scar reduction therapeutics Part I. The molecular basis of scar formation. J Am Acad Dermatol. 2012, Vol.66(1), P.1-12.).

Effective forms of wound healing agents are gels. As the gel can be used polysaccharides: galactomannan, or glucomannan, or alginic acid or a salt of alginic acid, or agar-agar, or hyaluronic acid, or gelatin or pectin, or Aerosil, or zeolites, or collodion or 1,2 propylene glycol (Elliot D, Sierakowski A. The surgical management of painful nerves of the upper limb: a unit perspective. J Hand Surg Eur Vol.2011 Vol.36(9), P.760-770).

Known wound-drug "Liniment methyluracil (RF patent N 2007997, prior, from 08.07.92,, AK 9/06), containing as active substance β-form methyluracil, and as the base castor oil. The drug has increased wound healing activity due to the high bioavailability of the dosage form. However, in this drug active substance does not possess anti-infective and interferonogenna properties, which does not allow to treat infected wounds.

Ass is whose present invention is to provide means, devoid of the above disadvantages, the technical result achieved during the implementation of this task is to obtain an effective anti-inflammatory, wound healing and analgesic for external use.

This technical result is achieved by the fact that the active substance is used, the original substance of the peptide Tyr-Pro-X, where X IS HE, NH2The co3OS2H5in the following dosage forms: ointments, gels, liniments, aerosols, suppositories, skin patches, oral-getintegervalue tablets and drops.

In particular, the claimed use of the dipeptide of the General formula Tyr-Pro-X, where X IS HE, NH2The co3OS2H5as anti-inflammatory, antibacterial, wound healing, regenerative, analgesic and burns funds, as well as dosage form, containing as active substance dipeptide of the General formula Tyr-Pro-X, where X IS HE, NH2The co3OS2H5used as anti-inflammatory, antibacterial, wound healing, regenerative, analgesic and burns funds;

preferred, but not required versions of the dosage forms suggested by its performance as one of the following dosage forms: MAZ is, gel, liniment, spray, suppository, patch, orally-getintegervalue tablets, drops.

Peptide compounds according to the present application, their properties and the method of obtaining not described in literature.

The synthesis of compounds. Tyr-Pro-X was synthesized using tetrabutylammonium salts (TBA) and pivaloyl chloride (PivCL). For the synthesis of derivatives used D; L; DL amino acids. Evaporation of the solutions was carried out on a vacuum evaporator at 40°C. of the melting Temperature, defined on the table for melting Boetiys, are given without correction. Control of the synthesis and the identity of the compounds was checked by thin-layer chromatography on plates with silica gel firm Silufol (Czechoslovak) when spraying ninhydrin solution in the solvent system:

1 - hexane: acetone (3:2);

2 - acetate:acetone:50% acetic acid(2:1:1);

3 - benzene:ethanol (8:2);

4 - chloroform:methanol:ammonia (7:2.5:0.5);

5 - chloroform:methanol:ammonia(6:4:1);

6 - chloroform:methanol:acetic acid(42:7:1);

7 - acetone:benzene:acetic acid(2:1:1);

8 - chloroform:methanol:ammonia (8:1.75:0.25);

9 - chloroformmethanol (9:1);

10 - ethanol:ammonia (7:3).

11 - ISO-propanol:formic acid:water(20:1:5).

Further in the text in parentheses after the specified Rf solvent system.

All solvents were absoluteradio accordingly. The melting point was correctively. Column chromatography was performed using a media Silica gel L-40/100 m and Silasorb 600 [LC] company Chemapol (Czechoslovak).

Abbreviations: AC - acetate; BOC - tert-butyloxycarbonyl group; OBT - I-oxybenzoates; DMF is dimethylformamide; DCGK dicyclohexylcarbodiimide; PivCI - pivaloyl chloride; TBA is tetrabutylammonium; tea is triethylamine; OSu - N-oxysuccinimide ether; DCHK - N,N-dicyclohexylcarbodiimide; OMe methyl ether; DiBoc - tert-butyloxycarbonyl; TLC - thin layer chromatography.

Getting the dipeptide Tyr-Pro.

1. To Pro 150 mg (1.326 mmol) was added 2.83 ml (1.326 mol) 13% TBA, evaporated 1 times with ethanol, 1 times with ISO-propanol, 1 times with benzene, cooled to 0°C.

2. To a chilled solution of TBA Pro in 10 ml of abs. ethyl acetate while cooling was added in dry form DiBoc-Tyr-OSu 634.5 mg (1.326 mol), stirred 1 hour at room temperature on a magnetic stirrer, the reaction course was monitored by TLC in system (7).

Upon completion of the reaction the solvent was evaporated, added water, acidified NaHSO4(a five-fold excess) to pH 3, extracted 5 times with 50 ml ethyl acetate. The combined ethyl acetate fraction was washed with water, 10% solution of KHSO4, water, dried over MgSO4was evaporated, wizardly from ether-hexane (twice). The precipitated powder was dried in vacuum.

Yield 1.32 g (2.76 mmol).

Rf=0.382 (7).

The following examples illustrate the EF is aktivnosti application claimed a new peptide compounds as the active ingredient in anti-inflammatory, wound healing and analgesic drugs for external use, as well as options for obtaining such funds. It is implied that although in the detailed description and specific examples are disclosed preferred embodiments of the invention, they are shown here for illustration only, because from the description and the claims to a person skilled in the art will become apparent, various changes and improvements, not beyond being and scope of the invention.

Example 1. 100 suppositories: a solution of the substance of the peptide structure Tyr-Pro-X, where X IS HE, NH2The co3OS2H5with concentration C=1-50 mg/ml is injected 55,0 g of a melt of a mixture of PEG 1500 and PEG 400 with 5.0 g of the emulsifier, and then stirred for 10 minutes. To the mixture gradually add 275 g pre-molten hydrophobic bases (witepsol) with 15.0 g of stabilizer (nipagin) and stirred for 30 minutes. The obtained suspension is poured into pre-cooled suppozitornoj form and placed in the refrigerator at -4°C. the Drug is used as suppositories. 1 suppository contains 1-50 mg peptide Tyr-Pro-X, where X IS HE, NH2The co3OS2H5.

Example 2. 100 suppositories: a solution of the substance of the peptide structure Tyr-Pro-X, where X IS HE, NH2The co3OS2H5with koncentracias=1-50 mg/ml gradually add 275 g pre-molten difiles basis (Suppocire AP) with 15.0 g of stabilizer (nipagin) and stirred for 30 minutes. The obtained suspension is poured into pre-cooled suppozitornoj form and placed in the refrigerator at -4°C. the Drug is used as suppositories. 1 suppository contains 1-50 mg peptide Tyr-Pro-X, where X IS HE, NH2)Och3OS2H5.

Example 3. 100 g ointment: a solution of the substance of the peptide structure Tyr-Pro-X, where X IS HE, NH2The co3OS2H5with concentration C=1-50 mg/ml injected into 85,0 g of a melt of a mixture of PEG 1500 and PEG 400 with 5.0 g of stabilizer (nipazol), stirred for 30 minutes. The drug is used in the form of ointment, which contains 1-50 mg peptide Tyr-Pro-X, where X IS HE, NH2The co3OS2H5.

Example 4. 100 g ointment: a solution of the substance of the peptide structure Tyr-Pro-X, where X IS HE, NH2The co3OS2H5with concentration C=1-50 mg/ml is injected in 40.0 g of a melt of a mixture of PEG 1500 and PEG-40 with 5.0 g of the emulsifier, and then stirred for 10 minutes. To the mixture gradually add 45 grams of pre-melted hydrophobic bases (siloxane base) with 5.0 g of stabilizer (nipagin) and stirred for 30 minutes. The drug is used in the form of ointment, which contains 1-50 mg peptide Tyr-Pro-X, where X IS HE, NH2The co3OS2H5.

Example 5. 100 g of gel: a solution of the substance of the peptide structure Tyr-Pro-X, where X IS HE, NH2The co3OS2 H5with concentration C=1-50 mg/ml injected into 85,0 g of a melt of a mixture of PVP 12600 and PVP 8000 with 5.0 g of stabilizer (nipazol), stirred for 30 minutes. The drug is used in the form of a gel that contains 1-50 mg peptide Tyr-Pro-X, where X IS HE, NH2The co3OS2H5.

Example 6. 100 ml spray: a solution of the substance of the peptide structure Tyr-Pro-X, where X IS HE, NH2The co3OS2H5with concentration C=1-50 mg/ml is injected in a mixture containing 20 mg of propylene glycol, 20 mg PEG-1000 cetosteatil ether, 5 ml of purified water and 50 ml of ethanol rectified, stirred for 10 minutes and filled into polypropylene bottle with metering pump and nozzle. The drug is used in the form of spray, which contains 1-50 mg peptide Tyr-Pro-X, where X IS HE, NH2The co3OS2H5.

Example 7. 100 patches: 5 g of the substance of the peptide structure Tyr-Pro-X, where X IS HE, NH2The co3OS2H5injected into a mixture consisting of 9,72 g of poly(DL-lactide) and/or poly(DL-lactide-coglycolide) with a molecular weight of 50,000 and a ratio of 50:50 with 1.0 g of a stabilizer (sodium benzoate) in 60 ml of chloroform. The mixture was thoroughly stirred and poured a thin layer, and then dried with warm air to remove the organic solvent. The resulting film is combined with a woven base. The drug COI is lsout in the form of strips, contains 1-50 mg peptide Tyr-Pro-X, where X IS HE, NH2The co3OS2H5.

Example 8. 100 of oral desintegrating tablets: tablets were obtained by direct pressing on the tablet press mixture containing 1 g of the substance of the peptide structure Tyr-Pro-X, where X IS HE, NH2The co3OS2H5and 20 g of the combined filler "Ludiflash".

Example 9. 100 of oral desintegrating tablets: tablets produced by wet granulation tabletting a mixture containing 1 g of the substance of the peptide structure Tyr-Pro-X, where X IS HE, NH2The co3OS2H5and 20 g of the combined filler "Ludiflash".

Example 10. 100 of oral desintegrating tablets: tablets are produced using dry granulation tabletting a mixture containing 1 g of the substance of the peptide structure Tyr-Pro-X, where X IS HE, NH2The co3OS2H5and 20 g of the combined filler "Ludiflash".

Example 12. 1 ml solution for drops of solution of the substance peptide Tyr-Pro-X, where X IS HE, NH2The co3OS2H5with a concentration of C=0.01 to 10 mg injected into a mixture containing sodium phosphate 0.1 to 5.0 mg, sodium dihydrophosphate of 1.0-10.0 mg, sorbitol 1.0 to 25.0 mg, benzalkonium chloride 0.1 to 3.0 mg, lavender oil 1.0 to 30.0 mg, purified water to 1.0 ml of the Drug is used in the form of nasal drops, which contain the seeking of 0.01-10 mg peptide Tyr-Pro-X, where

H-HE, NH2The co3OS2H5.

Example 13. Study tools external use containing the original substance of the peptide structure Tyr-Pro-X, where X IS HE, NH2The co3OS2H5in formalin test pain to detect analgesic and anti-inflammatory activity.

Male outbred rats were placed in individual plastic boxes. Acute inflammatory reaction (edema) caused subplantar (under the plantar aponeurosis) the introduction of 50 μl of 5% formalin. Registered number of painful reactions (tapping his paw on the floor, gryzenia paws etc) in the first 5-10 minutes - I phase (impact on primary pain afferents) and 30-50 minute - II phase (pain resulting from inflammatory reaction) (Bannon et al., 1998). Criterion analgesic effect was considered significant decrease in the number of painful reactions in the experimental group relative to the control group.

The analyzed samples (sample 1 - ointment 5%, sample 2 - gel 10%) was applied to the paw simultaneously with the introduction of formalin males nonlinear albino rats weighing 200-300 g of the Control animals was applied external means without active substance. The results are shown in table 1.

Table 1
spacemy sample Phase IPhase II
Control (without active substance)6,2±1,29,8±4,1
Sample 1 (ointment 5%)5%3,5±1,8*4,9±2,7*
Sample 2 (gel 10%)10%1,1±0,4*0,9°±0,3*

* - significance compared with control at P<0,05.

From table 1 it is evident that the means of external application containing the original substance of the peptide structure Tyr-Pro-X, where X IS HE, NH2The co3OS2H5reduces pain sensitivity in the first phase of the formalin pain, characterizing the impact on primary afferents, and anti-inflammatory effect in the second phase, caused by the development of inflammation.

Thus, a means of external application containing the original substance of the peptide structure Tyr-Pro-X, where X IS HE, NH2The co3OS2H5has analgesic and anti-inflammatory effect in the formalin test of pain.

Example 14. Study tools external use containing the original substance of the peptide structure Tyr-Pro-X, g is e X - HE, NH2The co3OS2H5when modeling a thermal burn.

For modeling thermal burn used standard method (Kochetygova NI ABOUT how playing thermal burns. HP: Medicine, 1964, p.86) in rabbits of the chinchilla breed weight 2,8-3,2 kg Burns were applied to the lateral surface of the thigh. The plot side of the thigh of the animal was removed coat and applied to the skin ceramic crucible with a diameter of 1.5 cm, and heated in a muffle furnace to 600°C and for 5 sec. After that carried out the study in three groups of animals. In the first (control) group treatment was not performed. In the second (experimental) group treatment was performed by means of external application in the form of ointment without active substances manufactured according to the prototype. In the third (experimental) group treatment was performed by means of external application in the form of ointment with a concentration of active substance 5.0 wt.%. In the fourth (experienced) a group treated by the claimed means of external application with the concentration of active substance in the form of a gel 10.0 wt.%.

Animals were daily inspected, determined the condition and size of burn wounds. At 7, 14 and 28 days of burn wounds totally cut out together with a plot of healthy skin and subjected to histological examination.

In the control group in place of a thermal burn SRAS is after application formed the dry land of coagulation necrosis, clearly limited from the surrounding healthy tissue. After 1 day around this area formed the line of demarcation damaged epidermis size 3-4 mm Starting from the 2nd day on the surface of the burn wounds was formed fibrin film, which was totalsales and became darker in the first week. In the next 7 days on the periphery of the burn was observed hyperemia and formed inflammatory roller. The dimensions of the lesion were significantly decreased. To the 14th day from the start of the experiment, the tumor shrank by growing it with the periphery of the epidermis in the form of languages. By the 28th day of burn wound completely zarzuelas.

In the 2nd group of rabbits (use external use without active substance) the healing of burn wounds occurred in a shorter time than in the 1st group, but during the whole treatment period was significantly expressed in local inflammation. Form of burn wounds has changed due to the uneven integration of the epidermis. For 21 days the wound was completely epithelials from the edges, and by the 28th day fully healed.

In the 3rd group (external application of a therapeutic agent with a concentration of active substance 5.0 wt.%.) there were also good results. During the first seven days there was intense local inflammatory reaction, however, on the 14th day the inflammation was completely gone and Ojo the new wound epithelials by napoletane regenerating epithelium from the edges. Complete fusion of epithelial wound healing occurred on the 21st day of treatment, which is 7 days earlier than in the 2nd group (prototype), and two weeks earlier than in the control group. It was not observed the formation of scars.

In the 4th group (external application of a therapeutic agent with a concentration of active substance 10.0 wt.%.) were awarded the best results. During the first five days there was intense local inflammatory reaction, however, on the 10th day the inflammation was completely gone and the burn wound epithelials. Complete fusion of epithelial wound healing occurred on the 18th day of treatment, 10 days earlier than in the 2nd group (prototype) and control groups. It was not observed the formation of scars.

Thus, a means of external application containing the original substance of the peptide structure Tyr-Pro-X, where X is NH2The co3OS2H5shows high wound-healing, anti-inflammatory and anti-infective efficiency and shortens the treatment of infected wounds and burns.

Example 15. Study tools external use containing the original substance of the peptide structure Tyr-Pro-X, where X IS HE, NH2The co3OS2H5when modeling skin wounds.

The skin wound was modeled on the rabbits of the chinchilla breed weight is 2.8-3.2 kg For the modelirovaniya wounds in rabbits shaved area of soft tissue of the femoral part and the scalpel was made the cut depth of 1 cm and length 5 cm After that carried out the study in three groups of animals. In the first (control) group treatment was not performed. In the second (experimental) group treatment was performed by means of external application in the form of ointment without active substances manufactured according to the prototype. In the third (experimental) group treatment was performed by means of external application in the form of ointment with a concentration of active substance 5.0 wt.%.

The effectiveness of drugs in experimental and control groups were evaluated in terms of rejection of a scab, the wound cleansing from purulent-necrotic masses, the time of appearance of granulation tissue in the wound and the beginning of epithelialization on the dynamics of the regression of the inflammatory process, as well as on the dynamics of bacteriological contamination of the wound.

In the control group was formed, the ulcer with infiltration into the surrounding tissue. On the 6th day was the rejection of the scab and the regional granulation tissue, and to the 12-th day of treatment - the first signs of epithelialization. A complete reorganization of the wounds has come to the 21st day.

In the second group of rabbits was observed in the absence of purulent serous discharge wounds. Primary scab on the wound did not prevent formation of granulation. Rejection of the scab and the first signs of granulation were observed on the 6th day from the beginning of treatment. The emergence of epithelialization of wounds observed on the 12th day of treatment, and full sa is the situation of the wound occurred by 21-th day of treatment.

In the third group (means external use containing 5% solids) were awarded the best treatment results. 've never seen purulent or serous discharge from the wound, there was no inflammation, wound "dry", observed the formation and growth of granulation tissue (active in the periphery and islet in the center of the wound). Advanced development of granulation tissue promotes earlier epithelization and complete renovation of the wound, which occurred in this group, 9-th day from the beginning of treatment and complete cure wounds already in the 15-th day of treatment. It was not observed the formation of scars.

Thus, a means of external application containing the original substance of the peptide structure Tyr-Pro-X, where X IS HE, NH2The co3OS2H5has wound healing properties.

Example 16. Study tools external use containing the original substance of the peptide structure Tyr-Pro-X, where X IS HE, NH2The co3OS2H5in the test neurogenic pain syndrome caused by transection of the sciatic nerve as a model of neuropathic pain to detect analgesic and anti-inflammatory activity.

The experiments were conducted on males nonlinear albino rats weighing 200-250 g Neurogenic pain syndrome in male outbred rats were created by transection of the sciatic not the VA at the level of the popliteal fossa above his trifurcate on n.tibialis, n.peroneus and n.suralis and its subsequent legirovaniem to prevent regeneration. The development of pain syndrome was defined by the appearance of signs of autotomy on the operated foot. The intensity of autotomy was assessed on an 11-point scale: 1 point - damage 1 claw; 2, 3, 4 and 5 of the points - damage 2, 3, 4 and 5 claws; 6 points damage to the knuckle of one finger; 7, 8, 9, and 10 points damage phalanges respectively 2, 3, 4 and 5 fingers; 11 points of damage to the metatarsal bones. Dynamics of pain syndrome in rats experimental and control groups were followed for 25 days (Kryzhanovsky GN. and others 1991).

Animals of the control group on the day of transection of the sciatic nerve and the subsequent 10 days after surgery inflicted tool external application in the form of ointment without active substance, and the animals of the experimental group at the same time inflicted a means external application in the form of creams with the active substance at a dose of 10 mg/kg

In the control group of rats the development of autotomy after transection of the sciatic nerve appeared in 50% of animals on day 6 after surgery. The intensity of the pain reaction was 3.2±0.9 points. On day 9 the introduction of pain response was observed in 60% of animals corresponding to the intensity of 4.5±2.4 points. On the 18th day of painful reaction was developed in 70% and amounted to 6.5±3.1 points.

Application outdoor use the ez active substances not prevented the development of autotomy after transection of the sciatic nerve (40% of the animals on day 6 after surgery). The intensity of the pain reaction was 2.7±1.9 points. On day 9 the introduction of pain response was observed in 50% of animals corresponding to the intensity of 3.6±2.6 points. On the 18th day of painful reaction was developed in 60% and amounted to 5.2±2.4 points.

Application external application with the active substance prevented the development of pain. 6 and 9 day of painful reaction was not observed. On the 13th day of the experiment at day 5 after undo the connection appeared painful reaction in 10% of animals with medium intensity 1.0+1.0, and on the 18th day - 10% of the animals, the average intensity of the reaction was 2.0±1.0 points.

Thus, a means of external application containing the original substance of the peptide structure Tyr-Pro-X, where X IS HE, NH2The co3OS2H5that exhibits analgesic and anti-inflammatory effect in the test neurogenic pain syndrome caused by transection of the sciatic nerve.

Example 17. Study tools external use containing the original substance of the peptide structure Tyr-Pro-Tyr-Pro-X, where X IS HE, NH2The co3OS2H5, the patient E., 68 years. The patient was diagnosed purulent pimples on the face near the nose. On all affected areas were overlapped tool external application in the form of ointment. On the next day after a single application formed St. TLA crust, which was easily removed. On the face had no traces of wounds.

Example 18. Study tools external use containing the original substance of the peptide structure Tyr-Pro-X, where X IS HE, NH2The co3OS2H5, the patient A., 58 years, with a burn. The patient was diagnosed to burn I, II degrees two fingers (middle - area of 1.5 cm and an unnamed area of 1 cm) of the left hand in the area of the nail bed hot sunflower oil. Trauma household. Observed redness, swelling of skin, large clear vesicles with content. After application means external application in the form of a gel on the next day there was a significant decrease congestion, the almost complete absence of edema and content of bubbles. The tool used for 5 days. On the 5th day was observed delamination of a thin layer of the epidermis of the wound surface, which was formed young skin without scarring and inflammation. After 14 days there was complete restoration of the damaged surface.

Example 19. Study tools external use containing the original substance of the peptide structure Tyr-Pro-X, where X IS HE, NH2The co3OS2H5, So sick, 56 years, with a burn. The patient was diagnosed to burn I, II degrees back side of the left forearm at the wrist area - an area of 20 cm2hot steam. Trauma life of the Wai. Observed redness, swelling of skin, large small bubbles with the content. The tool was applied for 3 days. After application means external application in the form of ointments on the following day showed a significant reduction of hyperemia, the almost complete absence of edema and content of bubbles. On the 5th day was observed delamination of a thin layer of the epidermis of the wound surface, which was formed young skin without scarring and inflammation. After 14 days there was complete restoration of the damaged surface.

Example 20. Study tools external use containing the original substance of the peptide structure Tyr-Pro-X, where X IS HE, NH2The co3OS2H5have a sick child S., age 6. On the right hip of the child in the area of contact with the gum diagnosed hyperemic rough spot size of 1 cm2that has not been in for 7 days. After application means external application in the form of ointments on the following day the stain has disappeared, and appeared no more.

Example 21. Study tools external use containing the original substance of the peptide structure Tyr-Pro-X, where X IS HE, NH2The co3OS2H5. The patient Was 33 years. On the left side in the area of contact with the gum was damaged spot size of 1.5 cm2that is not proh who came for 10 days. After application means external application in the form of spray on the following day the stain has disappeared, and appeared no more.

Example 22. Study tools external use containing the original substance of the peptide structure Tyr-Pro-X, where X IS HE, NH2The co3OS2H5. Patient K., aged 45. On the left elbow of the patient was damaged spot area of 3 cm2that has not been in a long time. The patient repeatedly applied in medical institutions, but the results were not. After a single application of funds external application in the form of a patch two days after the stain has disappeared, and appeared no more.

1. The use of the dipeptide of the General formula Tyr-Pro-X, where X IS HE, NH2The co3OS2H5as anti-inflammatory, antibacterial, wound healing, regenerative, analgesic and burns funds for exterior use.

2. Dosage form for external use, containing as active substance dipeptide of the General formula Tyr-Pro-X, where X IS HE, NH2The co3OS2H5used as anti-inflammatory, antibacterial, wound healing, regenerative, analgesic and burns funds.

3. Form according to claim 2, in one of the following dosage forms: mA is ü, gel, liniment, spray, patch.



 

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2 ex

FIELD: medicine.

SUBSTANCE: formed sorbent comprises a nanodispersed mesoporous carbon material in the form of cylinders of the diameter of 8-13 mm, the length of 50-80 mm, the thickness of an external wall of 2.2-3.0 mm with one round inner passage or six triangular passages with the thickness of passage partition of 1.1-1.2 mm. The above sorbent contains at least 99.5 wt % of carbon, no more than 0.15 wt % of ash, no more than 0.30 wt % of sulphur; it has the total porosity not less than 0.4 cm3/g, the specific BET absorption surface of 200-300 m2/g and the crushing strength not less than 50 kg/cm2. The group of inventions also refers to a method for making the above sorbent involving mixing of nanodispersed carbon with 0.2-3% aqueous polyethylene oxide in ratio 1.0-1.2 respectively, extrusion of the mixture, drying of the extrudate, keeping at 200°C in an inert medium, thermal treatment in the hydrocarbon medium and activation with water steam at 700-950°C, and further pneumohydromechamnical treatment and drying. What is also declared is a method for prevention of suppurative septic complications in obstetric patients with a risk of an infection, involving the uterine cavity sanitation by placing the above sorbent therein in a capron container.

EFFECT: group of inventions enables reducing a risk of developing endometrium and reducing the number of antibiotics used in the obstetric patients.

3 cl, 2 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein R1 represents an alkoxy group or halogen; each U and V independently represents CH or N; "----" means a bond or is absent; W represents CH or N, or if "----" is absent, then W represents CH2 or NH, provided not all U, V and W represent N; A represents a bond or CH2; R2 represents H, or provided A means CH2, then it also can represent OH; each m and n are independently equal to 0 or 1; D represents CH2 or a bond; G represents a phenyl group that is single or double substituted in meta- and/or para-position(s) by substitutes specified in alkyl, C1-3alkoxy group and halogen, or G represents one of the groups G1 and G2: wherein each Z1, Z2 and Z3 represents CH; and X represents N or CH and Q represents O or S; it should be noted that provided each m and n are equal to 0, then A represents CH2; or a pharmaceutically acceptable salt of such compound. Besides, the invention refers to a pharmaceutical composition for treating a bacterial infection containing an active ingredient presented by a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert additive.

EFFECT: preparing the oxazolidine compounds applicable for preparing a drug for treating and preventing the bacterial infections.

14 cl, 8 dwg, 2 tbl, 33 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a pharmaceutical salt of 8-methyl-7-[5-methyl-6-(methylamino)-3-pyridinyl]-1-cyclopropyl-4-oxo-1,4-dihydro-3-quinoline carboxylic acid, characterised by that it is in form of a hydrochloride monohydrate and by solubility of at least 0.050 mg/ml water. The invention also relates to a pharmaceutical composition based on said pharmaceutical salt, use of said pharmaceutical salt and a method of treating or preventing bacterial infections based on use of said pharmaceutical salt.

EFFECT: obtaining a novel pharmaceutical salt of 8-methyl-7-[5-methyl-6-(methylamino)-3-pyridinyl]-1-cyclopropyl-4-oxo-1,4-dihydro-3-quinoline carboxylic acid, characterised by good solubility in water, which influences bioavailability of the active ingredient.

7 cl, 16 dwg, 2 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: feeding a medical solution is combined with an exposure to low-frequency ultrasound generated by a low-frequency ultrasonic cavitator that is AUZKh-100 PHOTEK apparatus. The medical solution is presented by a solution of metrogyl and dioxydine in ratio 5:1 or 1:1 respectively. The exposure involves feeding the solution at 0.2-0.5 ml/s. The cavitator is placed at 0.2-0.5 cm from a defect surface. First, the defect is exposed to an average-density ultrasonic flow of power 1.6-3 Wt/cm2 for 1-2 min. Then, the exposure is characterised by average-density ultrasonic power 3.1-8 Wt/cm2 for 4-10 min. The therapeutic course is 3-15 sessions every second day.

EFFECT: method provides the maximum mechanical debridement of the purulent-fibrinous impositions and the qualitative wound disinfection ensured by selecting the cavitation mode for specific drug preparations and deep penetration of the above drug preparations into the lesion.

3 cl, 1 ex

FIELD: veterinary medicine.

SUBSTANCE: composition comprises, by wt %: doxycycline hyclate - 5.0-15.0, bromhexine hydrochloride - 0.25-0.75, lactulose - 0.5-1.5, 2-pyrrolidone - the rest.

EFFECT: composition has a wide range of antibacterial activity when orally administered to animals, non-toxic and does not cause any complications and side effects during application.

7 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel 1-ω-aryloxyalkyl- and benzyl-substituted 2-iminobenzimidazolines and pharmacologically acceptable salts thereof of general formula 1 , where R = CH=CH2, R1 = 2-ClC6H4OCH2 (1b); R = CH=CH2, R1 = 4-ClC6H4OCH2 (1c); R = CH=CH2, R1 = 4-BrC6H4OCH2 (1d); R = CH=CH2, R1 = 2,4-Cl2C6H3OCH2 (1e); R = CH=CH2, R1 = 3,4-Cl2C6H3 (1f); R = CH=CH2, R1 = 4-FC6H4OCH2CH2 (1g); R = CH2N(C2H5)2, R1 = 4-C(CH3)3C6H4OCH2 (1h); R = CH2N(C2H5)2, R1 = 3,4-Cl2C6H3 (1i); R = R1 = 4-OCH3C6H4OCH2 (1j); R = 4-BrC6H4, R1 = 4-OCH3C6H4OCH2 (1k); R = 4-BrC6H4, R1 =2-OCH3C6H4OCH2 (1l); R = 4-NO2C6H4, R1 = 4-OCH3C6H4OCH2 (1m); R = 3,4-Cl2C6H3, R1 = 2-OCH3C6H4OCH2 (1n); R = 3,4-Cl2C6H3, R1 = 4-OCH3C6H4OCH2 (1o); R = C6H5OCH2, R1 = 4-OCH3C6H4OCH2 (1p); R = 2-CH3C6H4OCH2, R1 = 2-OCH3C6H4OCH2 (1q); R = 4-CH3C6H4OCH2, R1 = 2-OCH3C6H4OCH2 (1r); R = 4-C(CH3)3C6H4OCH2, R1 = 2-OCH3C6H4OCH2 (1s); R = 2-OCH3C6H4OCH2, R1 = 4-BrC6H4OCH2 (1t), having anti-protist and antibacterial activity.

EFFECT: obtaining novel compounds with useful biological activity.

1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to microbiology, biotechnology and pharmaceutics, and specifically to use of 1,3-benzodioxole derivatives of formula (1) as collective behaviour (quorum sensing) regulators in bacteria, particularly for regulating homoserine lactone-mediated quorum sensing in violacein-producing biotechnologically useful, putrefactive and pathogenic bacteria.

EFFECT: controlling biotechnological processes, preventing spoilage of agricultural products and controlling bacterial infections in plants, animals and humans.

2 dwg, 2 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to application of peptide, which has sequence originating from amino acid sequence of protein SNAP-25, for treatment of pain and/or inflammation.

EFFECT: obtaining novel composition.

9 cl, 1 dwg, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to field of organic chemistry, namely to novel compound of formula (I), where Y and Z, each independently, are selected from group, consisting of: a) phenyl, if necessary substituted with 1 or 2 R6; b) pyridine, imidazole, thiazole, furan, triazole, quinoline or imidazopyridine, if necessary substituted with 1 R6; and c) substituent, independently selected from group, consisting of hydrogen, C1-C6alkyl or pyperidine; R1, R2 and R3, each independently selected from group, consisting of hydrogen and halogen; A and B is each independently selected from hydrogen, OH and C1-C6alkyl; RA and RB are independently selected from group, consisting of hydrogen, C1-C6alkyl and C3-C8cycloalkyl; or RA and RB together with atom, to which they are attached, form 4-6-membered heterocycle, if necessary having additionally one heteroatom or functional heterogrpoup, selected from group, consisting of -O-, -NH, -N(C1-C6-alkyl)- and -NCO(C1-C6-alkyl)-, and 6-membered heterocycle can be additionally substituted with one or two C1-C6-alkyl groups; R4 and R5, each stands for hydrogen; and each R6 is selected from Br, Cl, F, I, C1-C6-alkyl, pyrrolidine, if necessary substituted with one C1-C6-alkyl, C1-C6alkoxy, halogen-C1-C6alkyl, hydroxyl-C1-C6alkylene, -(NRARB)C1-C6alkylene and (NRARB)carbonyl; or to its individual isomer, stereoisomer or enantiomer, or their mixture, if necessary pharmaceutically acceptable salt. Invention also relates to compound of formula (II), particular compounds of formula (I) and (II), pharmaceutical composition and industrial product based on compound of formula (I) and (II), method of treating said pathological conditions, method of obtaining formula (I) compound and to intermediate compound of formula 3.

EFFECT: novel compounds, useful as inhibitors of poly(ADP-ribose)polymerase, are obtained.

50 cl, 1 tbl, 159 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (1), having affinity to the µ-opioid receptor and the to the ORL1 receptor, a medicinal agent containing said compounds and use thereof to obtain a medicinal agent for treating pain and other diseases. In general formula (1), Y1, Y1', Y2, Y2', Y3, Y3', Y4 and Y4' denote -H; R1 and R2 independently denote -CH3; R3 denotes R0, where R0 denotes C1-8-alkyl; aryl, selected from phenyl which is unsubstituted or mono-substituted with -F, -Cl, -Br, -I, -CN or -OR0, where R0 denotes -C1-3-alkyl; unsubstituted heteroaryl, selected from a 5-member heteroaryl with one S atom as a heteroatom; R4 denotes R0, where R0 denotes aryl, selected from phenyl which is unsubstituted or mono-substituted with -F, -Cl, -Br, -I, -CN or -OR0, where R0 denotes -C1-3-alkyl; 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolyl, mono-substituted with -S(O)2-phenyl; unsubstituted -dihydroisoindolyl or unsubstituted -indolyl; or R4 denotes -OR0 or -SR0, where R0 denotes a cycloaliphatic group selected from -C5-6-cycloalkyl; aryl, selected from unsubstituted phenyl; C1-2-alkylaryl, where aryl denotes phenyl, which is unsubstituted or mono-substituted with -OR0, where R0 denotes -C1-3-alkyl; and R5 denotes -H or -CH3.

EFFECT: obtaining a medicinal agent for treating pain and other diseases.

7 cl, 3 tbl, 22 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medication for treatment or prevention of disease, which developed on the basis of structural and/or functional, and/or compositional changes of lipids in cell membranes, selected from cancer, vascular diseases, inflammatory diseases, metabolic diseases, obesity and excessive body weight, neurological or neurodegenerative disorders, which represents compound of formula COOR1-CHR2-(CH2)a-(CH=CH-CH2)b-(CH2)c-CH3 (I) or its pharmaceutically acceptable salts and derivatives, selected from esters, ethers, alkyl, acyl, phosphate, sulfate, ethyl, methyl or propyl; in which a and c can have independent values from 0 to 7; b can have independent values from 2 to 7, where R1 is selected from the following radicals: H, Na, K, CH3O, CH3-CH2O and OPO(O-CH2-CH3)2, and R2 is selected from the following radicals: OH, OCH3, O-CH3COOH, CH3, Cl, CH2OH, OPO(O-CH2-CH3)2, NOH, F, HCOO and N(OCH2CH3)2.Invention also relates to application of formula (I) compound and pharmaceutical composition, which contains it.

EFFECT: medications, based on claimed compound, are more efficient than medications of preceding level of technology.

22 cl, 7 dwg, 16 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented: using nalbuphine salt in the form of a hydrophilic emulsion suppository for treating moderate to severe pain syndrome, a pharmaceutical composition for the same application in the form of suppositories comprising nalbuphine hydrochloride as an active substance and a hydrophilic emulsion base in the following ratio, g/100 g of the composition: nalbuphine hydrochloride 0.0125-5.00, hydrophilic emulsion base up to 100 g, and a method for preparing the same.

EFFECT: effective and prolonged analgesic action with no laxative action has been shown.

7 cl, 3 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pyridoxine derivatives general formula I, where: when R2+R3=-C(CH3)2- or -CH(CH3)-; , when R1=H; R2=H; , when R1=H; R3=H; , .

EFFECT: pyridoxine derivatives, having high anti-inflammatory activity and low toxicity.

2 cl, 2 dwg, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to phenyl alkyl piperazines of formula (I) , in which: R1 represents independently on each other hydrogen atom, halogen atom, (C1-C5)alkyl group, (C1-C5)halogenalkyl group, (C1-C2)perfluoroalkyl group, (C1-C5)alkoxyl group or (C1-C2)perfluoroalkoxyl group; R2 stands for (C1-C5)alkyl group or (C1-C5)alkoxyl group, R3 represents (C1-C5)alkyl group; A represents =CH- and =N-; in form of base or additive salt with acid. Invention also relates to pharmaceutical composition for modulation of activity of TNF-alpha, which contains claimed compounds, and to method of their obtaining.

EFFECT: obtained are novel compounds which can be applied in medicine as medications for treating or preventing pain and/or diseases, associated with inflammatory of immune disorders.

24 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where A is a 6-member heteroaryl, having 1 nitrogen atom as a heteroatom, substituted with 2-3 substitutes such as indicated in the claim, R5 is a halogen atom, cyano or C1-C6alkyl, optionally substituted with a halogen atom; R6 is C1-C6 alkyl, optionally substituted with OH; C1-C3 alkenyl; a 5-member heteroaryl, having 2-4 heteroatoms, each independently selected from N, O or S, substituted with 0-2 substitutes such as indicated in the claim, R10 is a 5-member heteroaryl, having 2-3 heteroatoms, each selected from N, O or S, substituted with 0-2 substitutes, which are C1-C3 alkyl; R7, R8, R17 denote a hydrogen or halogen atom. The invention also relates to a pharmaceutical composition, having BK B2 receptor inhibiting activity, which contains compounds of formula (I), a method of inhibiting, a method of localising or detecting the BK B2 receptor in tissue, use of the compounds of compositions to produce a medicinal agent and methods for treatment.

EFFECT: compounds of formula (I) as BK B2 receptor inhibitors.

22 cl, 1 tbl, 54 ex

FIELD: medicine.

SUBSTANCE: present invention refers to biotechnology and medicine. What is presented is a method for preventing or treating an inflammatory disease, comprising the stages of producing an NR10 antibody having NR10-neutralising activity, and selecting an antibody inhibiting IL-31-dependent cell line growth, and administering the antibody to a patient with an inflammatory disease that is atopic dermatitis, chronic dermatitis, rheumatism or osteoarthritis.

EFFECT: present invention can find further application in the therapy of the inflammatory diseases.

10 cl, 13 dwg, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an implantable drug depot applicable for the release, prevention or treatment of a postoperative pain in a patient in need thereof; the implantable drug depot contains a therapeutically effective amount of clonidine or its pharmaceutically acceptable salt and polymer; the drug depot is implantable into percutaneously for the release, prevention or treatment of postoperative paints; the drug depot can release: 1) approximately 5% approximately to 45% of clonidine or its pharmaceutically acceptable salt to total clonidine or its pharmaceutically acceptable salt as a part of the depot for a first period making up to 48 hours; 2) approximately 55% approximately to 95% of clonidine or its pharmaceutically acceptable salt to total clonidine or its pharmaceutically acceptable salt as a part of the depot for the following period making at least 3 days.

EFFECT: implantable form enables the easy accurate implantation of the drug depot with minimum physical and psychological traumas of the patient.

15 cl, 2 tbl, 20 dwg, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmacology and medicine and concerns an immunostimulating composition, and methods for using it for enhancing the immune response, particularly for treating infections caused by bacterial and viral pathogens, to adjuvant compositions and methods for enhancing the antigen immunogenicity when used as an adjuvant of vaccines. The pharmaceutical composition of pattern-recognising receptor ligands contains muramyl peptide of structural formula N-acetylmuramyl-L-alanyl-D-isoglutamine and lipopolysaccharide or lipid A in the following proportions, wt %: muramyl peptide of structural formula N-acetylmuramyl-L-alanyl-D-isoglutamine 0.00001 to 0.01, lipopolysaccharide or lipid A 0.00001 to 0.01, a solvent - the rest.

EFFECT: group of inventions provides high immunostimulating activity and prolonged action of the composition.

7 cl, 5 ex, 1 tbl, 9 dwg

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