FI129856B - Pharmaceutical composition for the treatment of skin burn lesions - Google Patents

Abstract

The invention relates to medicine, particularly to the development and use of a new pharmaceutical agent intended to optimize the course of reparative regeneration processes in skin burns. Provided is the use of the peptide Thr-Gly-Glu-Asn-His-Arg-NH2 as a regulatory, protective, normalizing and anti-inflammatory agent for the treatment of skin burn lesions. Provided is a new composition of an anti-burn agent comprising the active component in the form of said regulatory peptide 0.1-100 mg/L, a hydrogel based on Carbopol ETD 2020 4.5 g/L, and distilled water in the rest. The composition is highly effective at low doses of the peptide Thr-Gly-Glu-Asn-His-Arg-NH2, is easy and simple to use.

Description

PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF SKIN BURN LESIONS

FIELD OF THE INVENTION The invention relates to medicine, and specifically to the development and use of a new pharmaceutical agent for the treatment of skin burn lesions. The use of a hydrogel comprising the regulatory peptide Thr-Gly-Glu-Asn-His-Arg-NH; is a promising technique for optimizing the course of reparative regeneration processes in skin burns.

BACKGROUND OF THE INVENTION The relevance of the drug development is determined that burns are one of the main causes of disability for adult and child population in developed countries, however, the problem of treating such victims remains largely unresolved (WHO Information Bulletin, 2018). According to the Federal State Statistics Service, in 2017, 278.2 thousand patients with a diagnosis of thermal and chemical burns were registered in the Russian Federation, with 68.7 thousand children among them (Oxcenoiir I' K. u np., 2017). The modern tactics of the treatment of burn lesions is a multidisciplinary and is carried out taking into account the peculiarities of the pathogenesis of burn disease and its complications (AnekceeB A.A. H np., 2002). In consequence of the progress of medical science, the pathogenetically substantiated methods of the antibacterial therapy and immunocorrection of the local wound treatment have been introduced (AnekceeB A.A., 1999). It seems promising to develop a new methods for treating superficial and deep burn lesions with the biotechnological products, including the cellular products, the biopolymer wound dressings with the living cells — N scaffolds (3uHoBbes E B. n np., 2017; Anekceep A.A. u np., 2012).

3 One of the promising pathways to improve the treatment of burn lesions involves the use of the growth stimulants and the regeneration factors, particularly the epidermal, fibroblastic, platelet- I derived growth factors: the platelet-derived growth factor (PDGFA + B), the insulin-like growth N factors (IGFI, II). However, now this approach has not yet led to the creation of a therapeutic N agent for the effective treatment of burn lesions.

O A new direction in the field of creating the effective and safe drugs of the regulatory, protective, normalizing, antitumor and anti-inflammatory effects is the creation of the pharmaceuticals based on the endogenous regulatory peptides that are highly effective and have low toxicity. An 1 example of such a regulatory peptide is a peptide of the general formula Thr-Gly-Glu-Asn-His- Arg, demonstrated the antitumor, protective and normalizing activity.

According to the Russian Federation patent No. 2213747, the regulatory activity of the peptide is shown when inducing the differentiation and inhibition of proliferation of the cancer cells (Russian Federation Patent No. 2213747, 10.10.2003). In the Russian Federation Patent No. 2557003, provided is the amide form of this regulatory peptide Thr-Gly-Glu-Asn-His-Arg-NH; as a neuroprotective and nootropic agent aimed at the prevention and the treatment of Alzheimer's disease and ischemic stroke (Russian Federation Patent No. 2557003, June 22, 2015). A patent is also known for the use of the regulatory hexapeptide Thr-Gly-Glu-Asn-His-Arg-NH> as an anxiolytic agent aimed for the prevention and treatment of anxiety disorders (Russian Federation Patent No. 2580311, March 14, 2016). The regulatory peptide Thr-Gly-Glu-Asn-His-Arg-NH2 proposed as a pharmaceutical composition for the treatment of burns, whose structure corresponds to the differentiation factor fragment 41 TGENHRA46, is present in the blood and central nervous system of mammals (Sewell et al., 2005). The regulatory peptide Thr-Gly-Glu-Asn-His-Arg-NH> is known to have a protective effect on the brain hippocampal cells, protecting them from the degradation caused by the toxic effect of the amyloid peptide (KoctaHan M.A. m np., 2006). Previously, during the study of the mechanism of the pharmacological effect of the regulatory peptide, it was shown that NMDA receptors are a functional target of the specific pharmacological effect of the regulatory peptide Thr-Gly-Glu-Asn-His-Arg-NH> (Zolotarev et al., 2016). The specific neuroprotective activity of the regulatory peptide is also associated with the stimulation of neurosteroidogenesis, the inhibition of 5-alpha reductase expression and the restoration of the steroid levels in pathology almost to the norm (Rzhevsky et al., 2005). The protective and nootropic effects of the regulatory peptide on the model of Alzheimer's disease are expressed in the almost complete - restoration of memory as a result of its chronic use (Bogachouk et al., 2016). A feature of the O effect of the regulatory peptide Thr-Gly-Glu-Asn-His-Arg-NFH2 is that it has a normalizing effect se on pathology, while it does not adversely affect on the control animals even at a dose hundreds = of times higher than the therapeutic one (JIunkua B.M. u np., 2016). E It was established that the regulatory peptide Thr-Gly-Glu-Asn-His-Arg fully retains the S differentiating activity of the full-length factor to induce the differentiation and inhibit the cell > proliferation, including HL-60 (Kocransitu M.A. u np., 2000). In addition, the regulatory peptide has the ability to interact with the lipids of the cell membranes, which affects the activity of the cytokines involved in the cell proliferation and differentiation along the granulocytic pathway (Ceicoea I'M. n np., 2009). It was shown that the regulatory peptide Thr-Gly-Glu-Asn-His-Arg 2 enhances the redox processes in the cells and increases the metabolic activity of the macrophages (Hannnenro E.J]. m np., 2005).

SUMMARY OF THE INVENTION The invention relates to medicine, particularly to the development and use of a new pharmaceutical composition intended to optimize the course of reparative regeneration processes in case of skin burns. Provided is the use of the peptide Thr-Gly-Glu-Asn-His-Arg-NH> as a regulatory, protective, normalizing and anti-inflammatory agent for the treatment of skin burn lesions. Provided is a new composition of an anti-burn agent comprising the active component in the form of said regulatory peptide (0.1-100 mg/L), a lightly crosslinked acrylic polymer, Carbopol ETD 2020 (4.5 g/L), and distilled water in the rest. The composition is highly effective at low doses of the regulatory peptide Thr-Gly-Glu-Asn-His-Arg-NH> and is simple to use: it may be used as a hydrogel. The proposed pharmaceutical composition may be used in clinical practice for the treatment of skin burn lesions.

TECHNICAL PROBLEM The use of the regulatory peptide, Thr-Gly-Glu-Asn-His-Arg-NH>, as the anti-burn drug is unknown. Thus, the technical problem of this invention is the discovery of the regulatory peptide, Thr-Gly-Glu-Asn-His-Arg-NH2, which has antitumor, neuroprotective, nootropic and anxiolytic activity, anti-burn activity, which will determine the possibility of its use at low concentrations as a drug, in the form of easy-to-use dosage form (as part of the hydrogel) without undesirable side effects with good tolerance.

S 3 SOLUTION TO PROBLEM

O I The above technical result is achieved by the fact that the well-known regulatory peptide of the a 0 general formula: Thr-Gly-Glu-Asn-His-Arg-NH; is used as the agent for the treatment of skin N burn lesions in the form of the solution in the hydrogel based on Carbopol ETD 2020 (Technical N Data Sheet, 2007).

N The medicinal composition of the anti-burn pharmaceutical composition comprising the active component dissolved in the hydrogel comprises the regulatory peptide Thr-Gly-Glu-Asn-His- 3

Arg-NH> as the active component, and Carbopol ETD 2020 as the lightly crosslinked acrylic polymer, and with the following ratio of components: The regulatory peptide Thr-Gly-Glu-Asn-His-Arg-NH2 is 0.1-100 mg/L. The lightly crosslinked acrylic polymer, Carbopol ETD 2020 is 4.5 g/L. The rest is distilled water. The dosage form is given the name Healinggel.

ADVANTAGEOUS EFFECTS OF THE INVENTION The use of the regulatory peptide Thr-Gly-Glu-Asn-His-Arg-NH for the treatment of burn lesions allows one to obtain a stable course of the reparative regeneration process even at low concentrations of the peptide in the hydrogel without any undesirable side effects. The severity of the anti-burn effect of this new drug, which occurs against the background of the traditional therapy for severe burn lesions, is realized in the form of the acceleration of the wound epithelization by Day 28 by 71.11% (p < 0.01) and the decrease in the incidence of the purulent complications by 62.5% (p < 0.05). A weekly use of the regulatory peptide, dissolved in the hydrogel at the concentration of 0.1 mg/L for the treatment of burn lesions caused by thermal burns of the skin of the III degree, made it possible to achieve a reduction of the initial wound area by 94.38% by Day 28. The treatment with this pharmaceutical agent resulted in the reduction in the wound area of 42% (to 0.90 cm?) compared to the group in which such treatment was not performed after the early necrectomy. An important advantage of this pharmaceutical composition for the treatment of skin burn lesions is that its use completely avoids the suppuration of the wounds that occurs in most animals after the early necrectomy of burn — lesions. A histological study of the biopsy wounds also found that the use of the regulatory

N N peptide leads to a significant improvement in the nature of burn wounds.

O

O - Thus, the data obtained indicate that the use of the regulatory peptide Thr-Gly-Glu-Asn-His-Arg-

O - NH; dissolved in the hydrogel based on Carbopol ETD 2020 can be the promising technique for a > optimizing the course of reparative regeneration processes in skin burns.

N N

LO a

N BRIEF DESCRIPTION OF THE DRAWINGS The invention is illustrated by the figures and the table: 4

Figure 1. Group No. 1 (HLDF-6, 100 mg/L), Day 14, the massive neutrophilic leukocytes infiltration of the granulation tissue, fibrin on its surface. Stained with hematoxylin, eosin, X50. Figure 2. The average number of the microvessels in the granulation tissue. 1 — 0.01%, 2 —

0.001%, 3 — 0.0001%, 4 — 0.00001%, 5 — the hydrogel without the peptide, 6 — necrectomy. Figure 3. Group No. 4 (HLDF-6 0.1 mg/L), Day 28, the fibrous connective tissue with the focal lymphocytes and macrophages infiltration. Stained with hematoxylin, eosin, X100. Figure 4. Group No. 6 (necrectomy without treatment), Day 28, the granulation tissue at the bottom of the defect. Stained with hematoxylin, eosin, X150. The results of a planimetric evaluation of the wound healing effect of the pharmaceutical agent comprising the solution of the regulatory peptide Thr-Gly-Glu-Asn-His-Arg-NH, (HLDF-6) in the hydrogel based on Carbopol ETD 2020 after necrectomy. Table 1 The wound area in time (day), cm? Comparison groups _ HLDF-6 100 mg/L — | 8,78+1,34 +, **| 3,78+1,49 * ** [1 80+0,82 * *¥/0,01+1,02 +, **

N O HLDF-6 10 mg/L |12,20+1,32 +, **|10,29+1,46 +, **|7,88+0,83 +, **|4,09+1,02 +, ** se HLDF-6 1 mg/L 11,08+1,30 +, **| 9 13+1,46 +, ** |2 93+0,83 + **[1,3941,03 *, ** S HLDF-6 0,1 mg/L — |11,68+1,31 +, **| 6,24+1,47 *, ** |0,94+0,81 *, **/0,90+1,00 +, ** E | 5 [Hydrogel without HLDF-6] — 9,02+1,31 4,63+1,47 1,42+0,84 1,13+1,01 2 |6| — Necrectomy — | 12,68+1,79 8.4942 45 3,00+0,14 1,54+0,18 > Note: * — significantly p < 0.05 compared to the hydrogel without HLDF-6; N ** — significantly p < 0.2 compared to the group in which early surgical necrectomy was N performed

The results of the planimetric evaluation of the wound healing effect of the pharmaceutical agent comprising the solution of the regulatory peptide Thr-Gly-Glu-Asn-His-Arg-NH, (HLDF-6) in the hydrogel based on Carbopol ETD 2020 after necrectomy.

DESCRIPTION OF THE EMBODIMENTS The invention is illustrated by the examples. EXAMPLE 1 Study of the effect of the solution of the regulatory peptide Thr-Gly-Glu-Asn-His-Arg-NH2 in the hydrogel based on Carbopol ETD 2020 on the effectiveness of local treatment of skin burns. The experiment involved 48 male Wistar-Kyoto rats weighing 230-250 g. All manipulations were performed under general inhalation anesthesia under the aseptic conditions. The burn was reproduced according to our own original technique (rationalization proposal of the S.M. Kirov Military Medical Academy No. 14287/1 of 01/19/2016). After preparation of the surgical field, the animal was fixed to the laboratory table. The burn area is 16 cm? (about 10% of the body area). On the depilated skin of the animal's back, an electrothermocouple sensor of an Electroline multimeter (China) was placed, which was used to determine the temperature of the skin and the metal heating plate. Exposure time is 10 s at a temperature on the skin surface of 95-97 °C. The pharmaceutical composition for the application to the wound surface was prepared by dissolving the regulatory peptide Thr-Gly-Glu-Asn-His-Arg-NH> in various dilutions in the hydrogel based on Carbopol ETD 2020 (0.45%). The hydrogel comprising the regulatory peptide Thr-Gly-Glu-Asn-His-Arg-NH, was applied daily to the wound surface for 7 days. 60 minutes after the burn all animals underwent necrectomy to their own fascia, the wound were fixed to the O underlying tissues with interrupted sutures.

O <Q The animals were divided into 6 groups of 8 animals each, taking into account the concentration O of the peptide Thr-Gly-Glu-Asn-His-Arg-NH; in the gel. The concentration was: 100 mg/L, 10

I T mg/L, 1 mg/L, 0.1 mg/L and 0 mg/L in groups No. 1, No. 2, No. 3, No. 4, No. 5, respectively. In & the active control group No. 6, only early surgical necrectomy was performed, without further O treatment.

N

N Evaluation of the treatment efficacy was performed daily, the examination of the wounds was carried out, the nature of the discharge was noted as well as the assessment of complications and 6 deaths. The burn area was determined by the planimetric method of L.N. Popova and the healing index was calculated according to the following formula: Healing Index = (S-Sn)*100/S*T where S is the burn area in the previous measurement, mm?; Sn is the burn area for the given measurement, mm”, T is the interval between measurements, day. It was found that early surgical necrectomy in the area of the deep skin burns, followed by the application of the hydrogel with the regulatory peptide Thr-Gly-Glu-Asn-His-Arg-NH, (HLDF- 6), was accompanied by the significant reduction in the wound area, while the value of the measurements was determined by the concentration of the regulatory peptide in the hydrogel (Table). In particular, on Day 28 in group No. 6 only necrectomy was performed on the wound area of 90.38% (up to 1.54 cm”), while the suppuration of the wounds was observed in 5 out of 8 animals. At the same time in group No. 5, in which the wound after necrectomy was treated with the hydrogel only, the treatment reduced the wound area by 27% (up to 1.13 cm?) compared to group No. 6 and the suppuration of the wounds was observed in 2 out of 8 animals. The best results were obtained in group No. 4 in which the wound after necrectomy was treated with the hydrogel comprising 0.1 mg/L of the regulatory peptide Thr-Gly-Glu-Asn-His-Arg-NH>. The treatment with the pharmaceutical agent comprising the regulatory peptide led to the decrease in the wound area of 42% (to 0.90 cm?) compared to group No. 6, and the suppuration of the wounds was completely avoided in animals. The similar results were obtained in group No. 1 in which the wound after necrectomy was treated with the hydrogel comprising 100 mg/L of the regulatory peptide Thr-Gly-Glu-Asn-His-Arg-NH,. The treatment with the pharmaceutical agent comprising the regulatory peptide at this concentration led to the decrease in the wound area by 41% (up to 0.91 cm?) compared to group No. 6 and the suppuration of the wounds was observed _ in 1 out of 8 animals.

N N EXAMPLE 2 = S Study of the effect of the regulatory peptide Thr-Gly-Glu-Asn-His-Arg-NH> solution in the I hydrogel based on Carbopol ETD 2020 in a histological study of the wound biopsies.

a & The biopsy samples for the histological study were selected on Day 14 and Day 28, they were O fixed in the 10% formalin solution followed by passing through the ascending alcohols (30-96%) ES and filling them with paraffin. The histological sections were stained with hematoxillin and eosin and studied by the light microscopy.

7

The histological study of the wound biopsies revealed that on Day 14 of the observation, the morphological picture in the burn area had a number of features, taking into account the choice of the treatment method. The postoperative wound in the different groups of animals was of the different area, covered with masses of fibrin densely infiltrated with the neutrophilic leukocytes (Fig. 1). The bottom of the wound defect is represented by the granulation tissue extending up to the muscle fascia. The macrophages and neutrophils are located diffusely, the surface layers are most densely infiltrated. In the areas adjacent to the fascia, the small foci of the lymphocyte infiltration are noted. In group No. 4 (HLDF-6 0.1 mg/L), the mixed cell infiltration slightly spread to the surrounding tissues, while in groups No. 1 (HLDF-6 100 mg/L), No. 2 (HLDF-6 10 mg/L) and No. 3 (HLDF-6 1 mg/L) rather large foci of the subepidermal leukocyte infiltration were detected. In group No. 5 (hydrogel without HLDF-6) the neutrophilic leukocytes are located not only in the dermis but also in the epidermis itself, forming a few microabscesses. In addition, in the granulation tissue, numerous proliferating full-blooded capillary type vessels are determined. The number of the microvessels in the granulation tissue in the groups differed significantly (Fig. 2). On Day 28, the bottom of the defect was represented by the fibrous connective tissue with a large number of the large fibroblasts (Fig. 3). The focal lymphocytes and macrophages infiltration remains in the connective tissue. Groups No. 1 (HLDF-6 100 mg/L) and No. 4 (HLDF-6 0.1 mg/L) demonstrate an insignificant number of the neutrophilic leukocytes, while in groups No. 2 (HLDF-6 10 mg/L) and 3 (HLDF-6 1 mg/L) their amount is moderate. In group No. 5, the number of the neutrophilic leukocytes is also moderate, but in a number of observations, the small intradermal abscesses were revealed. In group No. 5 (hydrogel without HLDF-6), the lympho-histiocytic infiltration is more pronounced, the foci are somewhat larger N and merge with each other. In addition, in group No. 5, the leukocyte infiltrates spread to the N epidermis along the edges of the defect. The connective tissue vessels are represented by the S capillaries and small venules. The endothelial cells of these vessels are large, proliferating, with > rounded hyperchromic nuclei and scanty eosinophilic cytoplasm.

T N At the same time, in biopsies taken from animals of group No. 6 that had underwent early N surgical necrectomy without the local treatment, in contrast to other groups, the layer of the N granulation tissue with large focal infiltration, mainly neutrophilic leukocytes, was located at the N bottom of the defect (Fig. 4). The foci were localized directly under the fibrinous exudate, on the surface of the defect. In some areas, the formation of the fibrous connective tissue with 8 numerous rather large fibroblasts is noted. The vessels in the tissue at the bottom of the defect are full-blooded, represented by multiple capillaries and a few small venules, with proliferating endothelium. The epidermis is along the edges of the defect with pronounced acanthosis, hyperkeratosis and small-focal leukocyte infiltration.

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3.1, Kosanes T.UH., Mypames A.H., borauyk A.Il. Pa3paGoTka HOBOro Heiiporiporektopa Ha ocHoBe mnentupa HLDF-6. «MHpopMaunoHHBIE TeXHOJIOTHH B MeNHIIHHE, ÖHOJNOrHN, apMakKonorun H 9KOoJIorum»: Martepuansl MexnyHaponHoii koHpepenuuu IT + M&Ec 2016 (T ypayd, 02-12 urons 2016 r). 2016. C. 89-99.

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Claims (4)

1. A pharmaceutical composition for use in the treatment of skin burn lesions, the pharmaceutical composition comprising an active component, a carrier, and distilled water, wherein the active component is the regulatory peptide, Thr-Gly-Glu-Asn-His-Arg-NH,, and the carrier is hydrogel.

2. The pharmaceutical composition for use according to claim 1, wherein the hydrogel is a hydrogel based on Carbopol ETD 2020.

3. The pharmaceutical composition for use according to claim 1 or 2, having the following ratio of components: the regulatory peptide Thr-Gly-Glu-Asn-His-Arg-NH> — from 0.1 to 100 mg/L, the hydrogel based on Carbopol ETD 2020 - 4.5 g/L, the rest - distilled water.

4. The regulatory peptide, Thr-Gly-Glu-Asn-His-Arg-NHo, for use in the treatment of skin burn lesions.

N

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